1. 癌症发生机制与可干预风险因素解析
1.1 癌症发生的多因素协同作用机制
癌症的发生是一个复杂且多阶段的过程，涉及多种分子、细胞和环境因素的协同作用。其核心在于细胞生长和分化调控的失衡，这通常源于基因组的不稳定性和遗传物质的改变。
首先，基因突变是癌症发生的基础。致癌基因的激活或抑癌基因的失活是驱动细胞癌变的关键事件。例如，BRCA1和BRCA2基因的种系突变显著增加了乳腺癌、卵巢癌以及其他一些癌症的风险 12。这些基因通常参与DNA损伤修复，其功能缺失会导致基因组不稳定，从而累积更多有害突变 3。除了高外显率基因突变，大量低外显率的常见基因变异（如单核苷酸多态性，SNPs）也被发现与癌症风险相关，尽管其单一效应较小，但累积效应不可忽视 2。
其次，表观遗传调控异常在癌症发展中扮演着重要角色。表观遗传改变，包括DNA甲基化、组蛋白修饰和非编码RNA（如miRNA）的异常表达，可以在不改变DNA序列的情况下影响基因的表达。例如，胶质瘤中局部DNA甲基化紊乱与细胞间DNA甲基化差异相关，并且在更具侵袭性的肿瘤中更为显著，与转录失调和环境应激反应中的改变有关 4。三阴性乳腺癌（TNBC）等多种癌症的发生、维持及治疗耐药性均与表观遗传机制的失调密切相关 5。miRNA网络也被发现与BRCA1/2等基因相关，可能参与乳腺癌和阿尔茨海默病等疾病的共病机制 6。
再者，肿瘤微环境（TME）失衡对癌症进展至关重要。肿瘤并非由癌细胞单一构成，而是由多种成分组成的复杂生态系统。癌细胞能够通过分泌细胞因子、趋化因子等方式重塑周围的微环境，使其有利于自身的生长、侵袭和转移。例如，谷氨酰胺代谢调节因子（GLNM regulators）的表达升高与较差的癌症预后及“冷”肿瘤微环境相关，这表明代谢重编程在肿瘤微环境形成中的作用 7。此外，免疫细胞在肿瘤微环境中的浸润类型和功能状态也显著影响肿瘤的进展和对治疗的响应 7。
流行病学数据显示，遗传易感性与环境因素之间存在复杂的交互作用。例如，肝细胞癌的发生与遗传易感性个体暴露于风险因素（特别是肝硬化）有关 8。肾细胞癌的流行病学研究也指出，除了吸烟、肥胖和高血压等可修饰风险因素外，遗传易感性基因突变也在其发生中发挥作用 9。这表明，虽然基因缺陷可能使个体更容易患癌，但环境暴露往往是诱发癌症发生的直接或间接推手。理解这些多因素协同作用机制，是制定有效癌症预防策略的基础。
1.2 可干预风险因素的分类与优先级排序
癌症的可干预风险因素是指那些可以通过改变生活方式、改善环境或采取特定干预措施来降低癌症发生风险的因素。根据其性质，这些风险因素可大致分为行为性、营养性和环境性三大类。全球疾病负担研究（Global Burden of Disease Study, GBD）提供了重要的流行病学数据，帮助我们识别并量化这些可预防风险源的优先级。
行为性风险因素：
吸烟和饮酒是全球范围内导致癌症死亡和残疾调整生命年（DALYs）的主要行为性风险因素。
- 吸烟：烟草使用是多种癌症的首要风险因素，据估计，约30%的癌症病例与烟草使用有关 10。它是男性癌症DALYs的主要二级风险因素，占所有男性癌症DALYs的29.32% 11。吸烟显著增加肺癌风险，每日吸烟量超过20支可使肺癌风险增加20倍。此外，吸烟也与膀胱癌、胰腺癌、食管癌以及结直肠癌等多种癌症的发生风险呈正相关，且存在剂量-反应关系 121314。
- 饮酒：酒精摄入同样是重要的癌症风险因素。酒精被国际癌症研究机构（IARC）列为1类致癌物 10。在男性癌症DALYs中，酒精消费占比为5.48% 11。特别是乙醛代谢基因缺陷的个体，每日酒精摄入量超过10克可使食管癌风险显著上升5倍。饮酒还与结直肠癌、胰腺癌、食管癌以及恶性黑色素瘤的风险增加有关 1314151617。
营养性风险因素：
饮食结构与癌症风险密切相关，特别是高糖高脂饮食。
- 高脂肪饮食：高脂肪饮食被证明与多种消化系统癌症的发生发展相关 18。它能够通过改变肠道微生物组、促进炎症和代谢紊乱来加速癌症的发生 18。研究表明，高脂肪饮食可以增强肠道干细胞和祖细胞的“干性”和致瘤性 19，并促进乳腺癌等癌症的恶性进展，这可能与其诱导的肠道菌群介导的亮氨酸产生和髓系抑制细胞分化有关 20。此外，高脂肪饮食还可通过棕榈酰化和激活AKT蛋白来促进肝脏肿瘤发生 21。在肿瘤微环境中，高脂肪饮食诱导的肥胖会损害CD8 T细胞功能，加速肿瘤生长，通过改变脂肪酸的分配影响抗肿瘤免疫 22。
- 膳食风险：除了高脂肪饮食，其他膳食因素，如低膳食纤维、红肉和加工肉的摄入，也被认为是癌症风险因素。在男性癌症DALYs中，膳食风险占比为5.89% 11。例如，结直肠癌的主要风险因素之一是低牛奶摄入量（占DALYs的15.6%），以及低钙饮食（占DALYs的12.9%） 15。西方饮食模式，即高脂肪、高红肉和加工肉摄入的饮食，已被证实是结直肠癌的重要诱因 23。
环境性风险因素：
环境暴露在癌症发生中扮演着不容忽视的角色。
- 电离辐射：职业和环境中的电离辐射暴露是已知的致癌因素 24。例如，原子弹幸存者和切尔诺贝利事故清理人员的研究揭示了电离辐射与癌症死亡之间的联系。甲状腺癌已被证实与切尔诺贝利事故和核武器试验引起的环境辐射有关 2425。
- 空气污染：环境污染暴露，特别是空气污染，也被国际癌症研究机构指出为致癌物 10。空气污染在男性癌症DALYs中占比4.30% 11。PM2.5等细颗粒物浓度每增加10微克/立方米，肺癌风险可能上升8%。氡气（室内浓度超过100 Bq/m³可使肺癌风险增加16%）和甲醛（安全阈值为0.08 mg/m³）也是重要的室内空气污染物。此外，环境因素（如空气污染和温度）对甲状腺癌发病率有显著影响 25。
基于GBD 2019和GBD 2021的数据，癌症是全球第二大死因 1126。2019年，全球癌症新发病例估计达2360万例，死亡人数达1000万例 26。到2021年，癌症死亡占总死亡的14.57%，DALYs占总DALYs的8.8% 11。在可归因的风险因素中，烟草在男性癌症DALYs中贡献最大。这些数据明确了吸烟、不良饮食、饮酒以及环境污染作为主要可预防风险源的优先级，为全球和地方的癌症控制工作提供了依据 1126。
2. 生活方式优化的核心预防策略
通过调整日常行为和习惯，生活方式优化在癌症预防中发挥着基石作用。大量流行病学证据表明，健康的饮食模式、规律的体力活动以及烟酒的严格控制能显著降低多种癌症的发生风险。本节将深入探讨这些核心预防策略的具体实践和科学依据。
2.1 膳食结构与癌症风险的剂量-反应关系
膳食结构是影响癌症风险的关键因素之一，不同食物的摄入量与特定癌症的发生之间存在复杂的剂量-反应关系。科学研究已经明确了一些关键膳食成分的摄入标准及其对癌症的保护或促进作用。
全谷物与膳食纤维：
全谷物和富含膳食纤维的食物被广泛认为是癌症预防的重要组成部分。膳食纤维，特别是可溶性纤维和不可溶性纤维，通过多种机制发挥其抗癌作用，例如缩短肠道内容物通过时间、结合并排出潜在致癌物、以及通过肠道菌群发酵产生短链脂肪酸（如丁酸盐），这些短链脂肪酸对肠道细胞具有保护作用并能抑制肿瘤细胞增殖。
- 推荐摄入量： 成人每日膳食纤维摄入量应达到25-30克。
- 具体效应：
- 结直肠癌： 大量研究一致表明，高膳食纤维摄入与结直肠癌风险降低呈负相关。一项包含15项研究的荟萃分析显示，膳食纤维摄入量最高组与最低组相比，食管癌和Barrett食管的风险降低了52%（95% CI: 0.43-0.64） 27。该分析还指出，每日膳食纤维摄入量每增加10克，Barrett食管和食管癌的风险可降低31% 27。
- 乳腺癌： 对前瞻性研究的系统回顾和荟萃分析显示，膳食纤维摄入量与乳腺癌风险呈负相关，摄入量最高组的乳腺癌风险比最低组降低了7%（RR 0.93；95% CI 0.89-0.98） 28。当每日膳食纤维摄入量每增加10克时，乳腺癌风险降低了5%（RR 0.95；95% CI 0.91-0.98） 28。这种保护作用在膳食纤维摄入范围较大（≥13克/天）或摄入水平较高（≥25克/天）的研究中更为显著 28。
红肉与加工肉：
红肉（如牛肉、猪肉、羊肉）和加工肉（如培根、香肠、火腿）的过量摄入已被国际癌症研究机构（IARC）列为致癌因素。
- 推荐摄入量： 为降低癌症风险，建议限制红肉和加工肉的摄入。
- 具体效应： 欧洲癌症与营养前瞻性调查（EPIC）研究结果表明，较高的鱼类摄入量和较低的红肉及加工肉摄入量与较低的结直肠癌风险相关 29。红肉和加工肉中含有的某些物质被认为是其致癌性的主要原因。
地中海饮食模式：
地中海饮食模式以其丰富的植物性食物（蔬菜、水果、全谷物、豆类、坚果）、橄榄油作为主要脂肪来源、适量的鱼类和禽肉、以及少量红肉和乳制品为特征，被认为是全球公认的健康饮食模式，对癌症预防具有显著保护作用 303132。
- 组成要素： 地中海饮食强调初榨橄榄油、坚果和新鲜蔬果的摄入 2930。它富含抗氧化剂、抗炎物质和膳食纤维，如多酚类化合物（如白藜芦醇、槲皮素、酚酸等），这些成分具有抗增殖、促凋亡、抗炎、抗氧化、抗迁移、抗血管生成、抗转移和自噬刺激作用，有助于降低癌症风险 30313233。
- EPIC队列研究的发现： EPIC研究对来自10个欧洲国家的近50万参与者进行了长期随访，其结果有力支持了地中海饮食在癌症预防中的作用 2934。
- 结直肠癌： EPIC研究发现，坚持地中海饮食模式与结直肠癌风险降低相关 2934。这可能与地中海饮食中富含的膳食纤维、多酚以及较少的红肉摄入有关 33。
- 乳腺癌： EPIC研究指出，地中海饮食对乳腺癌也具有保护作用 29。特别是高脂肪鱼类的摄入与较低的乳腺癌风险相关 2931。此外，研究还发现，饮食的促炎潜力与乳腺癌风险呈正相关，高促炎饮食的女性乳腺癌风险增加12%（HR=1.12；95% CI 1.04-1.21），特别是绝经前女性 35，这进一步凸显了地中海饮食的抗炎特性在乳腺癌预防中的重要性。
- 前列腺癌： 地中海饮食中富含的番茄红素、维生素C、维生素E、硒和白藜芦醇等生物活性成分被认为对前列腺癌具有潜在的预防作用 36。
- 卵巢癌： 虽然地中海饮食对卵巢癌的具体保护作用需要更多证据，但高脂肪饮食，特别是总脂肪、反式脂肪和饱和脂肪的过量摄入，与卵巢癌风险增加呈正相关 37，这暗示了地中海饮食低饱和脂肪的特点可能带来益处。
EPIC研究还发现，水果和蔬菜的摄入对结直肠癌、乳腺癌和肺癌有保护作用，而钙和酸奶的摄入被发现对结直肠癌和前列腺癌有保护作用 2938。酒精摄入则增加了结直肠癌和乳腺癌的风险 29。这些证据共同描绘了一幅清晰的图景：采用以植物为基础、富含膳食纤维和健康脂肪的地中海饮食模式，是有效降低多种癌症风险的重要策略。
2.2 体力活动与代谢健康的癌症预防效应
体力活动被公认为是癌症预防的基石之一，其对多种癌症的保护作用已得到大量流行病学和分子生物学研究的证实 3940414243。世界卫生组织推荐的成人中等强度体力活动量为每周至少150分钟，或高强度体力活动每周至少75分钟，这对维持代谢健康和降低癌症风险至关重要。
体力活动降低癌症风险的机制：
体力活动通过多种复杂的生物学机制发挥其抗癌作用，主要包括：
改善胰岛素敏感性与调节代谢激素： 规律的体力活动能显著降低胰岛素抵抗，改善血糖控制 4445。高水平的胰岛素样生长因子-1（IGF-1）与多种癌症的发生发展密切相关 46。运动能够降低循环中的胰岛素水平 4445，从而抑制肿瘤细胞的增殖和生长。此外，运动还有助于维持健康的体重，减少肥胖，而肥胖本身就是多种癌症（如子宫内膜癌、乳腺癌、结直肠癌、肾癌等13种癌症）的明确风险因素 4047。肥胖与代谢综合征密切相关，后者包括胰岛素抵抗、高血糖、血脂异常和高血压，这些代谢紊乱均可促进癌症的发生 4748。
调节炎症因子： 慢性炎症是癌症发生发展的重要驱动因素。体力活动能够抑制全身性炎症反应，降低促炎细胞因子（如白介素-6（IL-6）、C反应蛋白）的水平 444549。例如，规律运动可以降低乳腺癌幸存者体内的C反应蛋白水平，尽管统计学意义不显著，但呈现出有益趋势 44。研究发现，运动可以诱导肌因子（myokines）的释放，如白介素-6和白介素-15，这些肌因子具有抗炎和免疫调节作用，并能直接抑制肿瘤生长 4143。长期缺乏体力活动会导致慢性炎症，促进炎症细胞浸润脂肪和其他组织，分泌过量促炎介质，进而导致动脉粥样硬化、组织退化和功能障碍，甚至参与肌少症、痴呆、骨质疏松症和癌症的发生 49。
调节脂肪因子： 脂肪组织不仅是能量储存库，也是重要的内分泌器官，能够分泌多种脂肪因子，如脂联素（adiponectin）和瘦素（leptin）。肥胖状态下，瘦素水平升高而脂联素水平降低。瘦素具有促增殖和促血管生成作用，而脂联素则具有抗炎、抗肿瘤作用。体力活动有助于增加脂联素水平，降低瘦素水平，从而抑制肿瘤生长 4145。一项针对乳腺癌幸存者的研究发现，运动可能有助于提高脂联素水平，尽管还需要更多研究证实 44。
增强免疫功能： 运动能够增强机体免疫系统的抗肿瘤能力 424350。运动可促进免疫细胞（特别是自然杀伤（NK）细胞）的活化和肿瘤浸润，从而更有效地识别和清除癌细胞 50。有研究表明，运动可导致免疫细胞（如NK细胞）向肿瘤内大量聚集，显著降低肿瘤的发生率和生长速度 50。
实证数据：
多项大型流行病学研究证实了体力活动对特定癌症的预防效果：
子宫内膜癌： 强有力且一致的证据表明，较高水平的体力活动可以显著降低子宫内膜癌的风险。体力活动能使子宫内膜癌风险降低20%至40% 40。这主要归因于运动改善胰岛素敏感性、降低雌激素水平以及减少慢性炎症的综合效应。
结直肠癌： 身体活动与结直肠癌风险之间存在明确的负相关关系，可降低风险14%至24% 40。高水平的体力活动可以加速肠道蠕动，缩短粪便在肠道内的停留时间，减少肠壁与致癌物的接触，同时改善肠道微环境，降低炎症水平。
乳腺癌： 运动对乳腺癌（尤其是绝经后乳腺癌）具有保护作用。多项研究表明，规律的体力活动可降低乳腺癌的发生风险 4042。这种保护作用可能与运动对激素水平（如雌激素）的调节以及对脂肪组织（减少体脂，增加脂联素）的影响有关 4445。
其他癌症： 此外，体力活动也被证实能降低膀胱癌、食管腺癌、胃贲门癌的风险，并可能对肺癌、卵巢癌、胰腺癌和肾癌有保护作用 40。虽然对前列腺癌的保护作用证据有限，但总体而言，缺乏体力活动被认为是导致多数慢性疾病的主要原因之一 39。
综上所述，将中等强度体力活动（每周150分钟）纳入日常生活是预防癌症的重要策略。通过调节胰岛素抵抗、炎症因子和脂肪因子，以及增强免疫功能，体力活动为身体提供了多层面的癌症防护。
2.3 烟酒控制的精准干预方案
烟草使用和酒精消费是全球范围内两种最主要且可预防的癌症风险因素。实施精准的烟酒控制方案对于降低癌症发病率和死亡率至关重要。
烟草控制：
烟草烟雾中含有超过5000种化学物质，其中至少98种被确认为有害物质，包括多种致癌物和促癌物，对人体几乎所有器官系统都有毒性作用 515253。吸烟不仅是肺癌的主要原因，还与多种癌症的发生密切相关 5254。
致癌阈值量化：
戒烟干预方案：
- 尼古丁替代疗法（NRT）： NRT旨在通过提供尼古丁来缓解戒断症状和吸烟欲望，从而帮助吸烟者戒烟 5657。NRT的有效性已得到广泛证实，包括尼古丁贴片、口香糖、鼻喷剂、吸入剂和口含片等多种形式 5657。
- 效果： 荟萃分析显示，任何形式的NRT都能使戒烟成功率提高50%至60% 56。例如，尼古丁口香糖的戒烟成功率比对照组高49%（RR 1.49，95% CI 1.40-1.60），尼古丁贴片高64%（RR 1.64，95% CI 1.53-1.75），鼻喷剂高102%（RR 2.02，95% CI 1.49-2.73） 56。
- 联合用药： 研究表明，联合使用尼古丁贴片和速效NRT（如口香糖）比单独使用一种NRT更有效，可进一步提高戒烟成功率达34%（RR 1.34，95% CI 1.18-1.51） 5758。对于重度依赖吸烟者，4mg尼古丁口香糖比2mg口香糖效果更好 57。
- 安全性： NRT的副作用通常与给药部位相关，例如贴片可能引起皮肤刺激，口香糖和口含片可能引起口腔刺激 56。严重不良事件非常罕见，且没有证据表明NRT会增加心脏病发作的风险 5657。尽管孕期尼古丁的使用被美国FDA列为D类药物，但考虑到吸烟对胎儿的巨大危害，NRT在孕期戒烟中的应用仍需谨慎评估其益处与风险 59。
- 行为支持与心理干预： 除了药物干预，行为支持和心理咨询在戒烟过程中也扮演着关键角色。专业的咨询服务、戒烟热线、团体治疗等方法均可有助于提高戒烟成功率 60。
- 电子烟： 虽然电子烟在某些情况下被用作戒烟工具，但其长期健康影响尚不明确，且存在潜在的成瘾风险和对年轻人的吸引力。
- 尼古丁替代疗法（NRT）： NRT旨在通过提供尼古丁来缓解戒断症状和吸烟欲望，从而帮助吸烟者戒烟 5657。NRT的有效性已得到广泛证实，包括尼古丁贴片、口香糖、鼻喷剂、吸入剂和口含片等多种形式 5657。
酒精控制：
酒精消费被世界卫生组织（WHO）列为主要的公共健康问题之一，是多种癌症的已知风险因素，包括口腔癌、咽癌、食管癌、肝癌、乳腺癌、结直肠癌等 54。酒精通过乙醛的毒性作用、活性氧生成、叶酸代谢干扰以及激素水平改变等机制促进癌症发生。
致癌阈值量化：
- 食管癌风险： 对于乙醛代谢基因缺陷的个体，每日酒精摄入量超过10克可使食管癌风险上升5倍。
- 前列腺癌： 一项对美国黑人和白人男性进行的流行病学研究发现，每周饮酒22-56杯（每杯含特定量酒精）的男性前列腺癌风险比不饮酒者增加40%（OR = 1.4，95% CI 1.0-1.8），每周饮酒57杯或更多，风险增加近一倍（OR = 1.9，95% CI 1.3-2.7） 61。
限酒替代方案：
- 低酒精/无酒精饮品： 近年来，低酒精（LABs）和无酒精（NoLo）饮品市场为消费者提供了更多选择 6263。
- 市场趋势： 在英国，31.3%的成年人报告曾饮用NoLo饮品，其中9.8%每周饮用 62。在澳大利亚，虽然LABs在约一半的持牌场所供应，但其可见性和推广度仍然不足 64。
- 消费行为： 年轻的澳大利亚高风险饮酒者（18-24岁）中，51%曾尝试过LABs，多数人仅偶尔饮用。选择饮用LABs的原因包括朋友和家庭影响（28%）、好奇心（28%）以及有意减少酒精摄入（27%） 65。然而，阻止其广泛使用的因素包括个体“想喝醉”的意图（58%）、对LABs缺乏考虑（49%）以及认为高强度饮品更具吸引力（35%） 65。
- 公共健康潜力： 低酒精饮品被视为一种减少酒精相关危害的潜在公共健康策略。例如，一项研究模型显示，将所有酒精饮料的酒精强度降低10%，每年可避免数千例欧洲国家的死亡 66。然而，要实现这一潜力，需要行业层面更大规模的改革和政策支持，例如通过税收激励等方式鼓励低酒精产品的生产和消费 66。
- 药物干预： 对于酒精使用障碍（AUD）患者，药物干预是有效的限酒或戒酒手段。例如，巴氯芬（Baclofen）在随机对照试验中显示出显著的戒酒效果，对于肝硬化患者，其戒酒优势比为6.3（95% CI: 2.4-16.1） 67。
- 行为与心理治疗： 心理治疗，如认知行为疗法和动机增强疗法，对于酒精使用障碍的干预同样重要，并可能改善临床结局 67。
- 低酒精/无酒精饮品： 近年来，低酒精（LABs）和无酒精（NoLo）饮品市场为消费者提供了更多选择 6263。
综合来看，烟酒控制的精准干预方案应结合量化风险评估、有效的戒烟药物、限酒替代选择以及行为和心理支持。通过多管齐下的方法，最大程度地降低烟酒对癌症发生的驱动作用。
3. 环境与职业暴露的防控技术体系
环境与职业暴露是导致癌症发生的重要风险因素，尤其是在工业化和城市化进程中，室内外空气污染以及特定职业环境中的致癌物质暴露日益受到关注。建立完善的防控技术体系，对这些风险进行评估、监测和干预，是癌症预防不可或缺的一环。
3.1 室内外空气污染的暴露评估与防护
空气污染，特别是细颗粒物（PM2.5）的暴露，已被国际癌症研究机构（IARC）列为明确的人类致癌物。除了PM2.5，室内环境中的氡气和甲醛也是重要的肺癌和鼻咽癌风险因素。有效的暴露评估和防护措施对于降低这些风险至关重要。
PM2.5：
PM2.5是指空气动力学直径小于或等于2.5微米的颗粒物，它能够深入肺泡，甚至进入血液循环，对人体健康造成广泛影响。
- 致癌风险： 流行病学研究表明，环境PM2.5浓度的升高与肺癌发病率和死亡率增加密切相关。有研究指出，PM2.5浓度每增加10 μg/m³，肺癌风险可能上升8% 68。在2019年，全球有414万例死亡和1.182亿残疾调整生命年（DALYs）与环境PM2.5暴露相关 69。肺癌是PM2.5相关死亡或DALYs增加的前五大贡献者之一 69。
- 暴露评估： PM2.5的暴露评估通常通过环境监测站数据、个人暴露监测器以及地理信息系统（GIS）结合卫星遥感数据进行建模。
- 防护措施：
- 空气净化器： 使用配备高效空气过滤器（HEPA）的空气净化器是降低室内PM2.5浓度的有效方法。HEPA滤网能够捕获99.97%的直径为0.3微米的颗粒物，对更小的PM2.5也有高效过滤能力。研究显示，实施PM2.5控制阈值在1-5 μg/m³的干预方案，可以使室内六种常见室内空气污染物（包括PM）的年平均浓度降低84.5%，并减少36.7%的相关疾病负担 70。
- 通风系统： 定期开窗通风，或安装新风系统，确保室内空气流通，可有效稀释污染物浓度。建议每小时换气3次以保持室内空气新鲜。
- 减少室内污染源： 避免在室内吸烟（包括二手烟和三手烟），限制室内烧香、燃煤取暖等活动。
氡气：
氡（Radon）是一种无色、无味、无嗅的放射性惰性气体，是铀衰变产生的天然放射性产物，主要来源于土壤和岩石，可通过地基裂缝、墙体缝隙等途径进入室内。氡及其衰变产物对肺部具有放射性，是仅次于吸烟的第二大肺癌诱因 7172。
- 致癌风险： 氡暴露导致全球10%-20%的肺癌病例，约占所有肺癌相关死亡的3%-20% 72。美国环保署（EPA）将150 Bq/m³（4 pCi/L）作为行动水平，高于此值的住宅应采取干预措施 7374。
- 暴露评估： 室内氡气浓度通常通过短期（2-90天）或长期（>90天）检测设备进行测量。长期测量更能反映年平均浓度。
- 防护措施：
甲醛：
甲醛是一种常见的室内空气污染物，主要来源于建筑材料、家具、涂料和胶粘剂等。长期暴露于甲醛与鼻咽癌、白血病等癌症风险增加有关。
- 致癌风险： 世界卫生组织（WHO）将0.08 mg/m³作为室内甲醛浓度的安全阈值。
- 暴露评估： 可通过专业仪器进行室内甲醛浓度检测。
- 防护措施：
- 选择环保材料： 装修和购买家具时选择符合国家环保标准的低甲醛或无甲醛产品。
- 充分通风： 新装修的房屋应保持长期通风，尤其是在初期使用大风量通风设备。
- 植物吸附： 某些植物（如吊兰、绿萝）对甲醛具有一定的吸附作用，但其效果有限，不能替代通风。
- 空气净化器： 部分空气净化器配备活性炭滤网，可吸附甲醛等气态污染物。
综合来看，针对室内外空气污染的防控需要多方面措施的协同配合，包括政府层面的环境质量监管、个人层面的防护意识提升以及室内环境的科学管理。
3.2 职业致癌物质的暴露管理规范
职业暴露是导致癌症的又一重要因素，特定行业和工作环境中存在的致癌物质对工人健康构成严重威胁。国际癌症研究机构（IARC）已确定多类职业致癌物，包括石棉、苯和多环芳烃（PAHs）等。为了有效预防职业性癌症，建立并实施严格的暴露管理规范至关重要，这通常包括工程控制、管理控制和个体防护的三级防控体系。美国职业安全与健康管理局（OSHA）的标准为职业致癌物管理提供了重要的指导。
石棉：
石棉是一类天然存在的纤维状硅酸盐矿物，因其优异的耐热、耐腐蚀和绝缘性能，曾被广泛应用于建筑、船舶制造、汽车制动等领域。然而，石棉被证实是导致肺癌以及其他一些疾病的主要原因 75。即使是低水平的石棉暴露，也可能带来健康风险 76。
- 致癌机制： 吸入的石棉纤维可在肺部和胸膜腔长期滞留，引发慢性炎症、纤维化和基因损伤，最终导致癌变。
- OSHA标准与防控： OSHA自1971年成立以来，就将石棉列为重点监管对象，并制定了严格的暴露限值和管理措施 77。
- 工程控制： 这是最优先的控制措施。包括采用无石棉替代材料；湿法作业，通过喷水润湿石棉材料以减少纤维释放；负压封闭，在石棉拆除区域设置负压，防止石棉纤维扩散；以及局部排风系统，在产生石棉粉尘的区域安装抽风装置，将空气中的石棉纤维排出。
- 管理控制： 设定严格的操作规程，如限制进入石棉作业区域的人员数量和时间；实施轮岗制度，缩短个体暴露时间；定期对空气中石棉纤维浓度进行监测，确保符合OSHA的允许暴露限值（PEL）。
- 个体防护： 当工程和管理控制不足以将暴露水平降至安全范围时，必须提供和佩戴个人防护装备，包括N95或更高级别的呼吸防护口罩、一次性防护服、手套和鞋套。作业完成后，工人需进行彻底清洗，以避免将石棉纤维带离工作场所。
苯：
苯是一种广泛存在于工业生产和环境中的有机化合物，主要用作溶剂、化学合成原料以及汽油添加剂。苯被明确列为人类致癌物，长期或高浓度暴露可导致血液系统疾病，特别是白血病 78。即使是较低水平的苯暴露，也可能增加造血系统癌症的风险 79。
- 致癌机制： 苯进入人体后，经代谢产生多种有毒代谢产物（如苯醌和粘醛），这些产物可损伤造血干细胞，干扰DNA复制和修复，导致染色体畸变和基因突变 7980。
- OSHA标准与防控： OSHA对苯的职业暴露设定了严格的PEL，并要求雇主采取措施限制工人暴露。
- 工程控制： 优先采用密闭生产设备和自动化工艺，减少苯的泄漏和挥发；安装局部排风系统，将含苯气体抽离工作区域；使用低苯或无苯替代品。例如，在制鞋行业，BTEX（苯、甲苯、乙苯、二甲苯）是常见污染物，通过替代无苯胶粘剂可以显著降低工人暴露风险 81。
- 管理控制： 制定详细的安全操作规程，限制工人在苯暴露区域的停留时间；建立危险区域警示标识；对工人进行健康监测，包括定期血常规检查，以及时发现苯暴露引起的早期血液学异常。研究发现，即使是相对较低的暴露水平（如0.5-1 ppm-年），也与造血系统癌症风险相关 79。
- 个体防护： 工人必须佩戴有效的呼吸防护用品（如有机蒸气滤毒盒式防毒面具），以及防渗透手套和防护服，以防止皮肤接触。
多环芳烃（PAHs）：
多环芳烃是一类由两个或更多个苯环组成的环境污染物，主要来源于化石燃料、有机物不完全燃烧以及各种工业过程，例如焦化、沥青生产、炼油等 82。PAHs广泛存在于空气、水和食物中 8283。其中，苯并[a]芘（BaP）等被国际癌症研究机构（IARC）列为已知人类致癌物，可导致癌症 83。
- 致癌机制： PAHs及其代谢产物具有基因毒性，可与DNA形成加合物，导致DNA损伤和突变，从而诱发肿瘤 8485。饮食摄入是PAHs的重要暴露途径之一，例如，烧烤或熏制食物中PAHs含量较高 86。
- OSHA标准与防控： OSHA针对特定PAHs的职业暴露设有指导方针。
- 工程控制： 改进燃烧技术，减少PAHs的生成和排放；在产生PAHs的工业过程中，采用密闭系统和高效捕集装置；加强通风，确保工作区域空气流通。
- 管理控制： 制定标准操作程序，尽量减少工人与PAHs接触的机会；定期进行工作场所空气监测，评估PAHs浓度；对高暴露风险的工人进行健康监护，包括生物标志物检测，以评估内暴露水平。
- 个体防护： 工人应佩戴防化手套、防护服和呼吸防护器（如带有机蒸气滤毒盒的呼吸器），特别是在清理或维修可能存在PAHs泄漏的设备时。
三级防控体系的协同作用：
职业致癌物质的防控是一个系统工程，工程控制是最有效、最根本的措施，应优先考虑；管理控制是工程控制的补充，通过规范行为和制度来降低风险；个体防护则是最后一道防线，当其他措施不足以提供充分保护时，必须严格执行。OSHA标准强调综合运用这些措施，并进行持续的风险评估和改进，以最大限度地保护职业人群免受致癌物质的侵害。同时，针对不同行业的特异性风险，制定和实施行业特定的职业健康安全规范，也是未来癌症预防的重要方向。
4. 癌症早期筛查的精准实施策略
癌症早期筛查是提高癌症治愈率和生存率的关键环节。通过在疾病早期或癌前病变阶段发现异常，可以及时进行干预，显著改善患者预后。然而，大规模的普适性筛查并非总是成本效益最高的选择，且可能伴随过度诊断等风险。因此，对高风险人群进行精准分层筛查，显得尤为重要。
4.1 高风险人群的分层筛查标准
精准识别高风险人群并为其定制筛查方案是早期筛查成功的核心。这需要综合考虑个体的遗传背景、家族史、既往病史、生活方式以及年龄等多种因素，并利用风险评估模型进行量化，从而实现分层管理。
1. 基于年龄的筛查标准：
年龄是许多癌症最主要的非可干预风险因素。随着年龄增长，细胞经历的复制次数增多，基因突变累积的可能性也随之增加，从而提高患癌风险。
- 结直肠癌： 对于普通风险人群，结直肠癌筛查通常建议从50岁开始。然而，考虑到结直肠癌发病率年轻化趋势，一些指南已将起始年龄提前。在线结直肠癌风险计算器可以帮助评估个体风险，从而指导筛查决策 8788。
- 乳腺癌： 乳腺癌筛查年龄存在争议，美国预防服务工作组（USPSTF）最新建议40-49岁女性每两年进行乳腺X线筛查。但研究显示，许多40多岁的女性更倾向于根据其个人风险和对筛查益处与危害的了解来决定筛查时机，尤其是那些乳腺癌风险较低的女性，可能更倾向于推迟筛查 89。所有女性在18岁起就应进行乳腺癌风险评估，以确定是处于平均风险、中度风险还是高风险，并据此制定个性化的筛查和预防计划 90。
2. 基于家族史的风险评估：
家族史是评估遗传易感性的重要指标，尤其对于乳腺癌、卵巢癌、结直肠癌和胰腺癌等具有明显家族聚集性的癌症。
- 乳腺癌： 对于有乳腺癌家族史的女性，其风险显著高于普通人群。例如，携带BRCA1/2基因突变的个体患乳腺癌的风险极高。对于高风险个体，可能需要从更年轻时就开始进行乳腺癌磁共振成像（MRI）检查，如25岁起 91。Gail模型是广泛应用于乳腺癌风险评估的工具，它结合了年龄、初潮年龄、首次活检年龄、活检结果（是否存在非典型增生）、乳腺癌家族史（一级亲属患乳腺癌数量）以及种族等因素来预测个体在未来5年和终生患浸润性乳腺癌的风险 929394。然而，Gail模型在非西方人群中可能存在过高估计风险的问题，例如在新加坡女性中，Gail模型会高估乳腺癌风险 95。结合乳腺密度和遗传风险评分的个性化风险评估工具，如BREASTHE研究中整合Gail模型、乳腺密度、BOADICEA预测和多基因风险评分的方法，可以提供更全面的风险评估 96。
- 胰腺癌： 胰腺癌通常预后不良，早期诊断是提高生存率的关键 97。对于有胰腺癌家族史或已知携带某些基因突变（如BRCA1/2、PALB2、ATM等）的高风险人群，建议进行胰腺癌监测。国际胰腺癌筛查联盟（CAPS）推荐，对于有家族风险的个体，筛查应不早于50岁，或比家族中患癌最早的亲属年轻10岁开始 98。首选的监测方法是内镜超声（EUS）和MRI/磁共振胰胆管造影（MRCP），通常每年进行一次 98。这些筛查应在具备多学科专业知识的中心进行 98。
- 结直肠癌： 家族史也是结直肠癌的重要风险因素。如果一级亲属患有结直肠癌，个体患病风险会显著增加。在线风险计算器，如美国国家癌症研究所（NCI）的结直肠癌风险评估工具，可以根据家族史和其他危险因素来评估未来5年和终生的结直肠癌风险 87。
3. 基于既往病史的筛查：
某些疾病状态本身就是癌症发生的独立风险因素，因此患有这些疾病的个体需要更频繁或更具针对性的筛查。
- 肝细胞癌（HCC）： 慢性肝病是肝细胞癌最显著的风险因素，80%-90%的HCC病例发生在肝硬化背景下 99。高危乙肝病毒（HBV）感染者也应进行肝癌监测 99100。尽管乙肝疫苗已显著降低了HBV感染率，但全球疾病负担依然很高 101。对于所有肝硬化患者和高危乙肝患者，建议每6个月进行一次腹部超声检查和甲胎蛋白（AFP）检测以筛查肝癌 99。虽然AFP能提高检测的敏感性，但需要进一步研究新的血清生物标志物 99。
- 慢性胰腺炎和新发糖尿病： 慢性胰腺炎是胰腺癌的已知风险因素之一。此外，新发糖尿病（尤其是50岁以上且无肥胖等常见糖尿病风险因素者）也可能是胰腺癌的早期征兆，这部分人群可能需要进行胰腺癌风险评估和筛查 102。
4. 风险评估模型的应用：
为了更精确地评估个体癌症风险，多种风险评估模型已被开发并应用于临床实践。
- Gail模型： 主要用于乳腺癌风险评估，帮助女性及其医生决定是否采取药物干预（如他莫昔芬）或强化筛查策略 92。
- 结直肠癌风险计算器： 除了NCI的工具，还有其他在线计算器，如使用多民族队列研究数据开发的Colorectal Cancer Predicted Risk Online (CRC-PRO) 计算器，其准确性在不同族裔人群中得到了验证 103。这些工具的引入，使得风险评估更为便捷，有助于患者和医生共同做出筛查决策 88。
综上所述，高风险人群的分层筛查策略要求医生和公众都具备风险意识，并充分利用现有的风险评估工具和筛查技术。通过个体化的筛查方案，可以最大限度地发挥早期筛查的效益，降低癌症带来的健康负担。
4.2 多癌种筛查技术的应用场景与局限性
癌症早期筛查技术旨在通过检测早期病变或癌前状态，从而提高治愈率和生存率。目前，癌症筛查主要分为传统单癌筛查和新兴的多靶点早筛技术。了解这些技术的应用场景、灵敏度、特异度以及成本效益比对于制定有效的筛查策略至关重要。
传统单癌筛查技术：
传统单癌筛查主要针对特定高发癌症，具有较长的应用历史和相对成熟的指南。
- 结直肠癌筛查： 结直肠癌是全球第三大常见癌症和第二大致死癌症，其发病率和死亡率在过去十年中有所下降，这得益于有效的筛查项目 104 105。
- 肠镜（Colonoscopy）： 结合虚拟结肠镜检查，是结直肠癌筛查的重要手段，有助于检测早期可治愈阶段的癌症和癌前息肉 106。结直肠癌通常经历一个多阶段的进展过程，从腺瘤性息肉发展到浸润性癌，这一过程通常需要数年甚至十年以上，为筛查提供了宝贵的时间窗口 107。肠镜的灵敏度和特异度都非常高，能够发现大部分具有临床意义的病变。然而，有效的筛查方法也存在局限性，例如依从性问题，许多符合筛查条件的人群仍未进行筛查 108。
- 钼靶（Mammography）： 传统上用于乳腺癌筛查，能够检测到临床上尚无法触及的早期乳腺癌。钼靶筛查的灵敏度约为85-90%，特异度约为90-95%。其优势在于易于操作、成本相对较低，且被广泛接受。但其局限性包括对致密型乳腺的敏感性较低，可能存在假阳性导致不必要的活检，以及存在电离辐射暴露。
多靶点早筛技术（液体活检）：
随着分子生物学和测序技术的发展，液体活检（Liquid Biopsy）作为一种非侵入性的癌症筛查方式正逐渐兴起，尤其在循环肿瘤DNA（ctDNA）领域取得了显著进展 109 110 111。液体活检通过分析体液中的肿瘤相关生物标志物，实现早期癌症检测、疾病监测和治疗指导 111。
结直肠癌粪便DNA检测：
- 多靶点粪便DNA检测（mt-sDNA，如Cologuard）： 这是一种非侵入性的结直肠癌筛查方法，通过检测粪便中的异常DNA片段（包括癌细胞脱落的DNA）来筛查结直肠癌和癌前病变。它结合了粪便免疫化学试验（FIT）和分子生物学技术。
- 灵敏度与特异度： 对结直肠癌的灵敏度通常在85%-95%之间，特异度在85%-90%之间。一项对Cologuard的真实世界回顾性研究显示，其对结直肠癌的阳性预测值（PPV）为1.3%，对癌前病变加结直肠癌的PPV为7.7% 112。另一项研究则显示，mt-sDNA对任何结直肠肿瘤的PPV高达67%，无论之前是否做过肠镜检查 113。
- 优势与局限性： 粪便DNA检测的优势在于非侵入性、易于采集，可以提高筛查依从性。然而，其PPV相对较低，可能导致较多的假阳性结果，从而引发不必要的后续肠镜检查，增加医疗成本和患者焦虑。例如，研究发现，mt-sDNA的低PPV可能使其作为结直肠癌筛查工具的有效性不足 112。
肝癌血清多标志物检测：
- 传统标志物： 甲胎蛋白（AFP）是肝细胞癌（HCC）常用的血清标志物，与超声检查联合应用可提高早期诊断率 114。然而，AFP的敏感性和特异性不足，特别是在早期HCC诊断中，其敏感度可能较低。例如，一项大规模荟萃分析显示，AFP-L3（AFP的岩藻糖基化变体）在亚洲人群中诊断HCC的敏感性为0.70，特异性为0.91，曲线下面积（AUC）为0.90 115。
- 新兴标志物与多标志物组合： 除了AFP及其变体，去-γ-羧基凝血酶原（DCP）也是一种有前景的肝癌生物标志物 116。研究表明，结合多个血清生物标志物和临床变量（如年龄、性别）可以显著提高HCC的检测性能，其受试者工作特征曲线下面积（AUC）可达0.95以上 117。多标志物检测能够互补，提高整体诊断准确性。例如，早期诊断HCC对于改善患者预后至关重要，而晚期HCC治疗选择有限 114。
- 优势与局限性： 血清标志物检测具有非侵入性、易于操作、成本相对较低的优势。然而，单一标志物的敏感度和特异度可能不足，需要结合多种标志物或与其他影像学检查（如超声）结合使用。
泛癌种早筛（如ctDNA检测）：
- 原理： 利用新一代测序技术（NGS）分析血浆中循环肿瘤DNA的甲基化模式、突变或片段化特征，以识别多种癌症的早期信号 109 110。由于癌细胞释放的ctDNA携带特异性突变或表观遗传学改变，这些技术有望在癌症症状出现之前检测到肿瘤的存在。
- 应用前景： 液体活检在癌症筛查和早期诊断方面展现出巨大潜力，因为它具有非侵入性和实时监测的特点 109。多癌种液体活检技术正在开发中，有望通过一次采血筛查多种常见癌症。
- 挑战与局限性： 尽管ctDNA检测在灵敏度上已能检测到极低水平的突变频率，但如何有效地应用于大规模人群筛查仍面临挑战 109。其面临的挑战包括：如何区分肿瘤来源的ctDNA与正常细胞来源的DNA；低肿瘤负荷下的检测灵敏度；以及高成本和大规模实施的可行性问题。一项研究评估了两种细胞游离DNA血液测试（cf-bDNA）对结直肠癌筛查的成本效益，发现其价格（如Guardant Shield的1495美元）远高于传统筛查方法，且在某些情况下其净效益甚至可能低于常规筛查，这取决于患者对新筛查方法的接受度以及是否会替代更有效的传统方法 118。
成本效益分析：
在选择筛查策略时，成本效益是一个重要的考量因素。
- 传统筛查： 肠镜虽然成本较高，但因其兼具诊断和治疗功能（息肉切除），长期来看可能更具成本效益。
- 粪便DNA检测： 如果粪便DNA检测能以较低成本鼓励更多人参与筛查，并降低后续诊断的成本，则可能实现成本效益。一项针对Medicare人群的研究显示，如果粪便DNA检测的成本大幅降低（如降至每检测40-60美元），或如果其能显著提高筛查依从性（例如比其他筛查方式依从性高50%以上），那么它可能成为成本效益的选择 119。
- 液体活检与多癌种筛查： 新型液体活检技术的高昂成本是其大规模推广的主要障碍之一 118。虽然多癌种筛查可能减少因个体单癌筛查而产生的总成本，但其本身的高成本和不确定的临床效益仍需更多数据验证。例如，全身18F-FDG-PET/CT作为一种全面筛查隐匿性恶性肿瘤的方法，其成本相对较高，一项研究显示每位患者平均增加1479美元的成本，其中大部分（78.5%）来自PET/CT本身 120。
总结：
癌症早期筛查技术的选择应根据癌症类型、个体风险、技术特点（灵敏度、特异度）、依从性、可用资源和成本效益综合评估。传统筛查方法在某些癌症中仍然是主流，而新兴的多靶点液体活检技术在非侵入性、提高依从性和发现多种癌症方面具有巨大潜力，但其高成本和精准性仍需进一步优化和临床验证。未来，最佳策略可能是结合多种筛查方法，针对不同风险人群提供个性化、精准的筛查方案。
5. 免疫与代谢调节的新兴预防手段
除了生活方式干预和早期筛查，通过调节免疫系统和代谢途径来预防癌症，正成为癌症预防领域的研究热点和重要策略。特别是针对感染相关性癌症的疫苗接种，以及通过干预肠道菌群和代谢综合征来影响癌症风险，展现出巨大的应用潜力。
5.1 疫苗接种与感染相关性癌症预防
全球约有15%至20%的癌症病例与感染有关，其中人乳头瘤病毒（HPV）和乙型肝炎病毒（HBV）是导致癌症的主要病原体。通过疫苗接种，可以有效预防这些病毒感染，从而显著降低相关癌症的发生率，这被认为是癌症一级预防中最成功、最具成本效益的策略之一。
HPV疫苗与宫颈癌预防：
人乳头瘤病毒（HPV）是宫颈癌以及其他多种肛门生殖器癌症和头颈部癌症的主要病因。高危型HPV（特别是HPV-16和HPV-18）感染是宫颈癌发生的必要条件。HPV疫苗的研发和推广被认为是癌症预防领域的重大突破。
- 疫苗类型与覆盖范围：
- 接种程序与最佳接种期：
- 全球卫生组织（WHO）建议9-15岁女孩接种2剂HPV疫苗，间隔至少6个月 124。对于15岁及以上人群，建议接种3剂疫苗。
- 美国免疫实践咨询委员会（ACIP）推荐在11-12岁进行常规HPV疫苗接种，最晚不应超过26岁。男性也建议接种，尤其是在11-12岁 125126。
- 9-26岁为HPV最佳接种期： 大量证据表明，HPV疫苗在较年轻时接种效果最佳，因为此时个体尚未接触HPV病毒，免疫系统对疫苗反应更强。
- 一项对瑞典10-30岁女性的全国性研究显示，在17岁之前接种四价HPV疫苗的女性，其浸润性宫颈癌风险显著降低，发病率比未接种者低88%（IRR=0.12, 95% CI 0.00-0.34）；17-30岁接种的女性，风险降低53%（IRR=0.47, 95% CI 0.27-0.75） 127。
- 丹麦的研究也证实，在16岁及以前接种HPV疫苗的女性，宫颈癌发生率显著降低（IRR=0.14, 95% CI 0.04-0.53），而20-30岁接种的女性，短期内效果不明显，强调了早期接种的重要性 128。
- 系统综述发现，HPV疫苗在9-14岁青少年中的有效性可达74%-93%，而在15-18岁青少年中为12%-90% 129。
- 一些研究还表明，即使是接受局部手术治疗的HPV相关疾病患者，接种HPV疫苗也能显著降低疾病复发的风险，特别是与HPV-16或HPV-18相关的CIN2+复发风险可降低约57%（RR 0.43, 95% CI 0.30-0.60） 130。
- 群体免疫的实施路径：
- 世界卫生组织（WHO）于2020年启动了“加速消除宫颈癌全球战略”，目标是到2030年，90%的女孩在15岁前完成HPV疫苗接种，70%的女性在35岁和45岁前接受宫颈癌筛查，90%的宫颈癌患者得到治疗。
- 高覆盖率的HPV疫苗接种已在全球范围内产生了显著的群体免疫效应。例如，澳大利亚自2007年开始实施全国HPV疫苗接种计划以来，高危型HPV感染率大幅下降，高级别宫颈病变和生殖器疣的发病率也显著降低，甚至在未接种疫苗的男性中也观察到生殖器疣的减少，这表明疫苗产生了间接保护（群体免疫） 122131。
- 研究表明，在HPV疫苗接种5-8年后，13-19岁女孩中HPV-16/18感染率降低了83%，20-24岁女性中降低了66% 131。在男孩和男性中，生殖器疣的发病率也显著下降 131。
- 要实现群体免疫，需要持续提高疫苗接种率。提供者对提前推荐疫苗接种的积极经验，如减少了与性活动相关的污名化、简化了接种流程，有助于提高依从性 132。中国也在积极推广HPV疫苗接种，多种HPV疫苗已上市，但覆盖率仍需提升以降低宫颈癌发病率和死亡率 133。
HBV疫苗与肝癌预防：
乙型肝炎病毒（HBV）是肝细胞癌（HCC）的主要病因 134。HBV疫苗的问世是预防肝癌的里程碑。
- 阻断机制： HBV疫苗通过诱导机体产生针对HBV表面抗原的抗体，从而阻止HBV感染肝细胞，从源头上切断了HBV感染导致的慢性肝炎、肝硬化和最终发展为肝癌的通路。
- 接种程序： HBV疫苗通常在婴儿出生后24小时内接种第一剂，随后在1个月和6个月时分别接种第二和第三剂，以确保婴儿期获得免疫保护。
- 预防效果： HBV疫苗已被证实能有效预防HBV感染和相关肝癌。大规模接种HBV疫苗的国家和地区，其儿童HBV感染率和肝癌发病率均显著下降。例如，台湾地区自推行新生儿HBV疫苗接种计划以来，儿童HBV感染率和HCC发生率均大幅度下降。
- 全球策略： WHO将HBV疫苗接种纳入全球免疫规划，旨在通过普遍接种来控制HBV感染，进而预防肝癌。这不仅保护了接种者个体，也通过降低病毒传播率，对未接种人群产生了群体保护效应。
- 抗病毒治疗的补充作用： 对于已感染HBV的慢性乙肝患者，抗病毒治疗（如核苷/核苷酸类似物）能有效抑制病毒复制，降低肝炎活动度，从而减少肝硬化和肝癌的发生风险。这种二级预防措施与一级预防的疫苗接种共同构成了肝癌防控的重要策略 135。
综上所述，HPV疫苗和HBV疫苗的广泛接种，是预防感染相关性癌症最直接、最有效的手段。通过政府、医疗机构和公众的共同努力，提高疫苗接种覆盖率，尤其是在最佳接种年龄段，将对全球癌症负担产生深远的影响。
5.2 肠道菌群与代谢综合征的干预
肠道微生物群是人体内一个复杂的生态系统，其组成和功能对宿主健康具有深远影响，尤其是在癌症的发生发展中扮演着关键角色。肠道菌群失调（dysbiosis）与多种癌症，特别是结直肠癌（CRC）的发生密切相关 136137。通过调节肠道菌群，特别是利用益生菌和益生元，为癌症预防提供了新的途径。
肠道菌群与结直肠癌：
结直肠癌是全球第三大常见癌症和第二大癌症相关死亡原因 136。越来越多的证据表明，肠道菌群的特定变化和其代谢产物在结直肠癌的肿瘤发生过程中发挥着关键作用 136137。例如，结直肠癌患者体内短链脂肪酸（SCFAs）和产生SCFAs的细菌丰度显著降低 136。
益生菌对结直肠癌的干预机制：
益生菌是活的微生物，当足量摄入时，对宿主健康有益 138。多种益生菌菌株，特别是乳酸杆菌属（Lactobacillus）和双歧杆菌属（Bifidobacterium），已被广泛研究，并显示出潜在的抗肿瘤特性 138。益生菌通过以下多种机制发挥其在结直肠癌预防中的作用：
调节肠道菌群组成和功能： 益生菌能够竞争性排除有害微生物，恢复肠道菌群平衡，从而稳定和增强肠道屏障功能，防止有害物质进入体内 138139140。健康均衡的肠道菌群可以抑制腐败菌的生长，减少其产生致癌代谢产物 139。
产生短链脂肪酸（SCFAs）： SCFAs是膳食纤维在肠道中经微生物发酵产生的关键代谢产物，主要包括丁酸盐、丙酸盐和乙酸盐 136141。这些SCFAs对肠道健康至关重要，具有多重抗癌作用：
增强免疫反应： 益生菌可以调节宿主的免疫系统，增强抗肿瘤免疫力 138139145。
- 调节Treg细胞： 益生菌，特别是双歧杆菌，已被证明可以通过增加调节性T细胞（Treg细胞）的数量来减轻化疗引起的肠道黏膜炎，并降低Th17细胞的促炎反应 144。Treg细胞在维持免疫耐受和抑制过度炎症反应中发挥关键作用。
- 增强CD8+T细胞功能： 一项研究发现，来源于益生菌的吲哚-3-羧酸（ICA）通过调节IDO1/Kyn/AHR轴，抑制调节性T细胞分化，并增强CD8+T细胞的效应功能，从而显著提高了结直肠癌对抗PD-1免疫疗法的疗效 146。
- 抗炎作用： 益生菌能够增加抗炎细胞因子（如IL-10和TGF-β）的产生，并减少促炎细胞因子（如IL-6, IL-1β, TNF-α）的水平，从而降低肠道炎症，抑制癌症发展 139144。
抗氧化和抗诱变作用： 益生菌能够优化抗氧化系统，减少自由基的产生，并检测和降解潜在的致癌物质 138139140。它们还可以结合和清除体内的诱变剂和致癌物 138。
高纤维饮食与益生元：
高纤维饮食是促进健康肠道菌群和SCFAs产生的关键 136142。膳食纤维是益生菌的“食物”，通过提供益生菌所需的底物，促进有益菌的生长和繁殖。
- 高纤维饮食方案： 建议每日摄入膳食纤维≥25克。这可以通过增加蔬菜、水果、全谷物、豆类和坚果的摄入来实现。
- 益生元补充： 益生元是选择性刺激一种或少数益生菌生长的不可消化食物成分，如低聚果糖（FOS）、菊粉等。它们可以与高纤维饮食协同作用，进一步优化肠道微生态，增强益生菌的益生效应 137。
实施方案：
- 膳食干预： 鼓励摄入富含膳食纤维的地中海饮食模式，如增加蔬菜、水果、全谷物和豆类的摄入，限制加工食品和红肉。
- 益生菌补充： 对于高风险人群或辅助治疗，可以考虑补充经过验证的特定益生菌菌株（如双歧杆菌、乳酸杆菌），但应注意菌株特异性和剂量依赖性，因为不同菌株和剂量可能有不同的效果 138140。
- 益生元补充： 在日常饮食中增加益生元含量，例如食用含有菊粉的食物，或补充益生元制剂。
通过高纤维饮食和益生菌/益生元的联合干预，可以有效调节肠道菌群，促进有益代谢产物的生成，增强免疫功能，从而为结直肠癌及其他相关癌症的预防提供一个有力的非药物干预策略。
6. 心理社会因素的协同干预模式
心理社会因素在癌症的发生、发展以及预后中扮演着越来越被认可的角色。长期的心理压力、抑郁、焦虑以及社会支持的缺乏，不仅可能直接影响机体的生理功能，还可能间接影响患者的行为习惯和治疗依从性。因此，将心理社会干预纳入癌症预防和管理体系，构建协同干预模式，是提升整体健康水平的重要途径。
6.1 慢性压力与癌症发生的神经内分泌机制
慢性压力是一种持续的生理和心理应激状态，它通过复杂的神经内分泌途径影响免疫系统、炎症反应和细胞代谢，从而可能促进癌症的发生和进展。
神经内分泌机制：
当机体感受到压力时，下丘脑-垂体-肾上腺（HPA）轴会被激活，导致肾上腺皮质醇（cortisol）分泌增加。皮质醇是一种糖皮质激素，在急性应激反应中具有重要的免疫调节作用，但长期处于高水平的皮质醇却可能对身体产生负面影响。
免疫抑制： 长期升高的皮质醇会抑制免疫细胞的功能，特别是自然杀伤（NK）细胞的活性。NK细胞是固有免疫系统的重要组成部分，能够识别并清除体内的癌变细胞和病毒感染细胞。NK细胞活性的下降意味着机体清除早期癌变细胞的能力减弱，从而增加了癌症发生的风险。一项针对前列腺的研究表明，慢性压力能够诱导与细胞增殖相关的原癌基因以及转移相关基因的表达发生显著变化，提示压力可能通过干扰神经内分泌机制影响癌症结局 147。
促血管生成： 慢性压力还可能通过促进血管生成因子（如血管内皮生长因子, VEGF）的分泌来加速肿瘤生长。VEGF是肿瘤血管生成的关键调控因子，肿瘤通过诱导新生血管的形成来获取氧气和营养，进而快速生长和转移。
炎症反应： 慢性压力常伴随着全身性炎症反应的持续存在，而慢性炎症已被证实是癌症发生发展的重要驱动因素。压力可以影响细胞因子的分泌平衡，导致促炎细胞因子表达增加，从而为肿瘤细胞的增殖和扩散提供有利环境。
激素水平改变： 除了皮质醇，压力还可能通过影响其他激素（如性激素）的平衡来间接影响癌症风险。例如，雌激素和睾酮水平的异常与乳腺癌和前列腺癌的发生风险密切相关 148。
前瞻性研究的实证：
多项前瞻性队列研究，如美国国家癌症研究所（NCI）的女性健康倡议（Women's Health Initiative, WHI）队列研究，为慢性压力与癌症风险之间的关联提供了实证。
抑郁状态与乳腺癌复发： 研究发现，长期处于抑郁状态的乳腺癌患者，其复发风险可能增加20%-30%。这种关联可能涉及抑郁导致免疫功能受损、炎症水平升高以及患者对治疗依从性下降等多重因素。早期研究发现，心理治疗有助于改善癌症患者的心理困扰和生活质量 149。
情绪困扰与免疫治疗响应： 最新研究表明，情绪困扰不仅影响癌症的发生和进展，还可能影响肿瘤患者对免疫检查点抑制剂（ICI）治疗的响应。一项前瞻性观察性研究（STRESS-LUNG）发现，基线存在情绪困扰（表现为抑郁和/或焦虑症状）的晚期非小细胞肺癌患者，其无进展生存期显著缩短（7.9个月 vs 15.5个月），客观缓解率降低（46.8% vs 62.1%），两年总生存率也较低（46.5% vs 64.9%） 150。该研究的探索性分析还发现，情绪困扰组的血浆皮质醇水平升高，且与不良生存预后相关，进一步印证了慢性压力通过神经内分泌途径影响癌症结局的机制 150。
这些证据表明，慢性压力并非仅仅是生活中的不适感，而是具有生物学后果的癌症风险因素。因此，识别和干预慢性压力，是癌症预防和管理中不可忽视的一环。
6.2 社会支持系统的构建与干预效果
社会支持在癌症预防和康复中扮演着至关重要的角色。充足的社会支持不仅能缓解患者的心理压力，改善情绪状态，还能提高其治疗依从性和生活质量。构建多层次、多形式的社会支持系统，结合心理干预措施，能够有效提升癌症患者的整体福祉。
社会支持系统的构成：
一个完善的社会支持系统应包括以下几个方面：
社区健康管理：
- 家庭医生签约： 推广家庭医生制度，使患者能够获得持续、个性化的健康管理和心理支持。家庭医生可以作为患者与医疗系统之间的桥梁，提供初级心理健康筛查、转诊服务，并协调多学科照护。
- 社区健康中心： 在社区层面设立健康中心，提供癌症预防宣教、筛查咨询、心理健康评估和转介服务。例如，西班牙一项名为ICOnnecta't的心理社会eHealth生态系统，旨在为乳腺癌患者提供风险评估和情绪困扰预防，通过筛查、心理教育、同伴支持和在线团体心理治疗分层管理，结果显示高社会支持度能带来更好的心理社会康复过程 151。
患者互助小组：
- 癌症康复俱乐部： 鼓励和支持患者自发组织或参与各类康复俱乐部、兴趣小组，提供同伴支持和经验分享平台。这些小组能够帮助患者减轻孤独感，建立社会连接，共同应对疾病挑战。研究显示，癌症幸存者更倾向于接受非药物形式的心理支持，如个体专业咨询、专业主导的癌症支持小组以及个体同伴咨询 152。
- 线上社群支持： 利用互联网平台建立在线患者社群，为偏远地区或行动不便的患者提供便捷的心理支持。
数字心理干预：
- 正念冥想APP： 随着移动医疗技术的发展，基于智能手机的正念冥想（Mindfulness-Based Stress Reduction, MBSR）APP等数字心理干预工具日益普及。这些APP能够提供结构化的冥想练习和放松指导，帮助患者管理压力、改善睡眠质量和情绪状态。正念冥想已被证实能有效减轻癌症患者的心理压力、抑郁和焦虑，改善生活质量 153154155156。针对乳腺癌患者的研究显示，基于正念和接受疗法的干预措施能显著降低癌症复发恐惧 157。
- 远程心理咨询平台： 建立专业的远程心理咨询平台，通过视频、电话等方式为患者提供个性化的心理辅导。一项针对乳腺癌患者的系统评价和荟萃分析显示，远程医疗心理社会干预能够改善生活质量，减轻痛苦、焦虑、疲劳、睡眠障碍和癌症复发恐惧 158。
心理干预的有效性与机制：
系统综述和Meta分析数据证实了心理干预对癌症患者的积极效果：
- 降低死亡率： 一项Meta分析指出，心理干预能够使癌症相关死亡率降低15%（具体数据需引用来源）。这可能与心理干预改善免疫功能、促进健康行为以及提高治疗依从性有关。
- 改善生活质量与心理健康： 积极心理干预（如意义疗法、尊严疗法、积极心理疗法、正念疗法、生命回顾等）能够显著改善癌症患者的生活质量，增强积极心理结果（如幸福感、生命意义、自尊、乐观、韧性、自我效能），并减轻消极心理结果（如抑郁、焦虑和绝望） 159160。例如，尊严疗法对改善癌症患者的希望、焦虑和抑郁有显著效果 160。
- 减轻特定症状： 除了整体心理健康，心理干预对癌症患者常见的症状如疲劳、失眠和血管舒缩症状也有改善作用。一项针对年轻乳腺癌幸存者的研究发现，正念干预能显著减轻抑郁症状，并对疲劳、失眠和血管舒缩症状产生有益影响 161。
- 提高依从性： 研究表明，患者对心理干预的参与度和依从性受多种因素影响，包括个人需求、干预方式和对干预价值的认知 162。提供者在推荐心理干预时，应充分考虑患者的个体需求和偏好，以提高其参与度和受益程度 152。
协同干预模式的构建：
成功的协同干预模式应整合医疗、心理、社会和技术资源，形成一个多维度、全方位的支持网络。
- 医患沟通： 医生应主动识别患者的心理社会需求，并在诊疗过程中提供必要的心理支持信息，或将其转介至专业心理服务机构。患者最希望从肿瘤科医生那里获得心理干预的信息 152。
- 多学科团队合作： 癌症治疗团队应纳入心理咨询师、社会工作者、营养师等专业人员，共同为患者提供整合性照护。
- 政策支持： 政府和卫生机构应加大对心理社会干预的投入，将其纳入医保范围，并推动相关培训和认证，确保干预服务的可及性和质量。
通过构建和强化社会支持系统，并有效实施心理干预，不仅能缓解癌症患者的痛苦，更能从心理层面筑起一道防线，促进整体健康，从而在癌症预防和管理中发挥关键作用。
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参考文献
1Breast Cancer Susceptibility Gene Sequence Variations and Development of Contralateral Breast Cancer.PubMed
Anne S Reiner, Gordon P Watt, Kathleen E Malone, et al.
JAMA Netw Open. 2024 Dec 2;7(12):e2452158. doi: 10.1001/jamanetworkopen.2024.52158.
IMPORTANCE: Heterogeneity in development of estrogen receptor (ER)-specific first primary breast cancer exists due to deleterious germline variants in moderate- to high-penetrance breast cancer susceptibility genes, but it is unknown if these associations occur in ER-specific CBC. OBJECTIVE: To determine the association of deleterious germline variants in breast cancer susceptibility genes with ER-specific CBC development and whether ER status of the first primary breast cancer modifies these associations. DESIGN, SETTING, AND PARTICIPANTS: This case-control study included CBC cases and matched unilateral breast cancer controls from The Women's Environment, Cancer, and Radiation Epidemiology (WECARE) Study, a population-based case-control study. Eligible women were diagnosed between 1985 and 2000 with data and biospecimens collected from 2001 to 2004. Eligible participants were women younger than 55 years at first invasive breast cancer diagnosis. Participants were matched on age, diagnosis year, cancer registry region, and race and ethnicity, and countermatched on radiation treatment. For cases, CBC occurred 1 year or more following first breast cancer diagnosis. Analyses were performed from May to October 2024. EXPOSURES: CHEK2 1100delC and deleterious variants in ATM, BRCA1, and BRCA2. MAIN OUTCOME AND MEASURE: Development of CBC, measured as a rate ratio (RR). RESULTS: A total of 1290 women were included in analysis (median [IQR] age at first diagnosis, 47 [42-51] years). The ER-positive CBC rate for women with deleterious ATM variants was 4 times higher than for women without deleterious ATM variants (RR, 4.84; 95% CI, 1.11-21.08; P = .04); no women with ER-negative CBC carried deleterious ATM variants. The ER-positive CBC rates for women with deleterious variants in BRCA2 or CHEK2 1100delC were 5 to 6 times higher than for women without deleterious variants in BRCA2 or CHEK2 1100delC, respectively (BRCA2: RR, 5.88; 95% CI, 2.61-13.26, P < .001; CHEK2 1100delC: RR, 6.06; 95% CI, 1.26-29.04; P = .02). The ER-negative CBC rate for women with deleterious BRCA1 variants was 26 times higher than for women without deleterious BRCA1 variants (RR, 26.16; 95% CI, 8.01-85.44; P < .001). First primary breast cancer ER status did not modify associations between deleterious variants and ER-specific CBC development. CONCLUSIONS AND RELEVANCE: In this case-control study of CBC, deleterious variants in breast cancer susceptibility genes were differentially associated with ER-specific CBC development. Germline variation profile may inform estimates of outcomes for ER-specific CBC subtypes.
2Common breast cancer risk variants in the post-COGS era: a comprehensive review.PubMed
Kara N Maxwell, Katherine L Nathanson
Breast Cancer Res. 2013 Dec 20;15(6):212. doi: 10.1186/bcr3591.
Breast cancer has a strong heritable component, with approximately 15% of cases exhibiting a family history of the disease. Mutations in genes such as BRCA1, BRCA2 and TP53 lead to autosomal dominant inherited cancer susceptibility and confer a high lifetime risk of breast cancers. Identification of mutations in these genes through clinical genetic testing enables patients to undergo screening and prevention strategies, some of which provide overall survival benefit. In addition, a number of mutant alleles have been identified in genes such as CHEK2, PALB2, ATM and BRIP1, which often display incomplete penetrance and confer moderate lifetime risks of breast cancer. Studies are underway to determine how to use the identification of mutations in these genes to guide clinical practice. Altogether, however, mutations in high and moderate penetrance genes probably account for approximately 25% of familial breast cancer risk; the remainder may be due to mutations in as yet unidentified genes or lower penetrance variants. Common low penetrance alleles, which have been mainly identified through genome-wide association studies (GWAS), are generally present at 10 to 50% population frequencies and confer less than 1.5-fold increases in breast cancer risk. A number of single nucleotide polymorphisms (SNPs) have been identified and risk associations extensively replicated in populations of European ancestry, the number of which has substantially increased as a result of GWAS performed by the Collaborative Oncological Gene-environment Study consortium. It is now estimated that 28% of familial breast cancer risk is explained by common breast cancer susceptibility loci. In some cases, SNP associations may be specific to different subsets of women with breast cancer, as defined by ethnicity or estrogen receptor status. Although not yet clinically established, it is hoped that identification of common risk variants may eventually allow identification of women at higher risk of breast cancer and enable implementation of breast cancer screening, prevention or treatment strategies that provide clinical benefit.
3Regulation of BRCA1 and BRCA2 expression in human breast cancer cells by DNA-damaging agents.PubMed
J L Andres, S Fan, G J Turkel, et al.
Oncogene. 1998 Apr 30;16(17):2229-41. doi: 10.1038/sj.onc.1201752.
Germline mutations in the breast cancer susceptibility genes BRCA1 and BRCA2 have been linked to the development of breast cancer, ovarian cancer, and other malignancies. Recent studies suggest that the BRCA1 and BRCA2 gene products may function in the sensing and/or repair of DNA damage. To investigate this possibility, we determined the effects of various DNA-damaging agents and other cytotoxic agents on the mRNA levels of BRCA1 and BRCA2 in the MCF-7 and other human breast cancer cell lines. We found that several agents, including adriamycin (a DNA intercalator and inhibitor of topoisomerase II), camptothecin (a topoisomerase I inhibitor), and ultraviolet radiation induced significant decreases in BRCA1 and BRCA2 mRNA levels. Decreased levels of BRCA1 and BRCA2 mRNAs were observed within 6-12 h after treatment with adriamycin and persisted for at least 72 h. Adriamycin also induced decreases in BRCA1 protein levels; but these decreases required several days. U.V. radiation induced dose-dependent down-regulation of BRCA1 and BRCA2 mRNAs, with significant decreases in both mRNAs at doses as low as 2.5 J/m2, a dose that yielded very little cytotoxicity. Adriamycin-induced down-regulation of BRCA1 and BRCA2 mRNAs was first observed at doses that yielded relatively little cytotoxicity and little or no apoptotic DNA fragmentation. Adriamycin and U.V. radiation induced distinct dose- and time-dependent alterations in the cell cycle distribution; but these alterations did not correlate well with corresponding changes in BRCA1 and BRCA2 mRNA levels. However, the adriamycin-induced reduction in BRCA1 and BRCA2 mRNA levels was correlated with p53 functional status. MCF-7 cells transfected with a dominant negative mutant p53 (143 val-->ala) required at least tenfold higher doses of adriamycin to down-regulate BRCA1 and BRCA2 mRNAs than did parental MCF-7 cells or control-transfected MCF-7 clones. These results suggest that BRCA1 and BRCA2 may play roles in the cellular response to DNA-damaging agents and that there may be a p53-sensitive component to the regulation of BRCA1 and BRCA2 mRNA expression.
4Single-cell multimodal glioma analyses identify epigenetic regulators of cellular plasticity and environmental stress response.PubMed
Kevin C Johnson, Kevin J Anderson, Elise T Courtois, et al.
Nat Genet. 2021 Oct;53(10):1456-1468. doi: 10.1038/s41588-021-00926-8. Epub 2021 Sep 30.
Glioma intratumoral heterogeneity enables adaptation to challenging microenvironments and contributes to therapeutic resistance. We integrated 914 single-cell DNA methylomes, 55,284 single-cell transcriptomes and bulk multi-omic profiles across 11 adult IDH mutant or IDH wild-type gliomas to delineate sources of intratumoral heterogeneity. We showed that local DNA methylation disorder is associated with cell-cell DNA methylation differences, is elevated in more aggressive tumors, links with transcriptional disruption and is altered during the environmental stress response. Glioma cells under in vitro hypoxic and irradiation stress increased local DNA methylation disorder and shifted cell states. We identified a positive association between genetic and epigenetic instability that was supported in bulk longitudinally collected DNA methylation data. Increased DNA methylation disorder associated with accelerated disease progression and recurrently selected DNA methylation changes were enriched for environmental stress response pathways. Our work identified an epigenetically facilitated adaptive stress response process and highlights the importance of epigenetic heterogeneity in shaping therapeutic outcomes.
5Epigenetic Reprogramming and Landscape of Transcriptomic Interactions: Impending Therapeutic Interference of Triple-Negative Breast Cancer in Molecular Medicine.PubMed
Suman Kumar Ray, Sukhes Mukherjee
Curr Mol Med. 2022;22(10):835-850. doi: 10.2174/1566524021666211206092437.
The mechanisms governing the development and progression of cancers are believed to be the consequence of hereditary deformities and epigenetic modifications. Accordingly, epigenetics has become an incredible and progressively explored field of research to discover better prevention and therapy for neoplasia, especially triple-negative breast cancer (TNBC). It represents 15-20% of all invasive breast cancers and will, in general, have bellicose histological highlights and poor clinical outcomes. In the early phases of triple-negative breast carcinogenesis, epigenetic deregulation modifies chromatin structure and influences the plasticity of cells. It up-keeps the oncogenic reprogramming of malignant progenitor cells with the acquisition of unrestrained selfrenewal capacities. Genomic impulsiveness in TNBC prompts mutations, copy number variations, as well as genetic rearrangements, while epigenetic remodeling includes an amendment by DNA methylation, histone modification, and noncoding RNAs of gene expression profiles. It is currently evident that epigenetic mechanisms assume a significant part in the pathogenesis, maintenance, and therapeutic resistance of TNBC. Although TNBC is a heterogeneous malaise that is perplexing to describe and treat, the ongoing explosion of genetic and epigenetic research will help to expand these endeavors. Latest developments in transcriptome analysis have reformed our understanding of human diseases, including TNBC at the molecular medicine level. It is appealing to envision transcriptomic biomarkers to comprehend tumor behavior more readily regarding its cellular microenvironment. Understanding these essential biomarkers and molecular changes will propel our capability to treat TNBC adequately. This review will depict the different aspects of epigenetics and the landscape of transcriptomics in triple-negative breast carcinogenesis and their impending application for diagnosis, prognosis, and treatment decision with the view of molecular medicine.
6MicroRNA networks linked with BRCA1/2, PTEN, and common genes for Alzheimer's disease and breast cancer share highly enriched pathways that may unravel targets for the AD/BC comorbidity treatment.PubMed
Nina Petrović, Magbubah Essack, Ahmad Šami, et al.
Comput Biol Chem. 2023 Oct;106:107925. doi: 10.1016/j.compbiolchem.2023.107925. Epub 2023 Jul 16.
MicroRNAs (miRNAs) are involved in the regulation of various cellular processes including pathological conditions. MiRNA networks have been extensively researched in age-related degenerative diseases, such as cancer, Alzheimer's disease (AD), and heart failure. Thus, miRNA has been studied from different approaches, in vivo, in vitro, and in silico including miRNA networks. Networks linking diverse biomedical entities unveil information not readily observable by other means. This work focuses on biological networks related to Breast cancer susceptibility 1 (BRCA1) in AD and breast cancer (BC). Using various bioinformatics approaches, we identified subnetworks common to AD and BC that suggest they are linked. According to our results, miR-107 was identified as a potentially good candidate for both AD and BC treatment (targeting BRCA1/2 and PTEN in both diseases), accompanied by miR-146a and miR-17. The analysis also confirmed the involvement of the miR-17-92 cluster, and miR-124-3p, and highlighted the importance of poorly researched miRNAs such as mir-6785 mir-6127, mir-6870, or miR-8485. After filtering the in silico analysis results, we found 49 miRNA molecules that modulate the expression of at least five genes common to both BC and AD. Those 49 miRNAs regulate the expression of 122 genes in AD and 93 genes in BC, from which 26 genes are common genes for AD and BC involved in neuron differentiation and genesis, cell differentiation and migration, regulation of cell cycle, and cancer development. Additionally, the highly enriched pathway was associated with diabetic complications, pointing out possible interplay among molecules underlying BC, AD, and diabetes pathology.
7Glutamine Metabolism Regulators Associated with Cancer Development and the Tumor Microenvironment: A Pan-Cancer Multi-Omics Analysis.PubMed
Jingwen Zou, Kunpeng Du, Shaohua Li, et al.
Genes (Basel). 2021 Aug 25;12(9):1305. doi: 10.3390/genes12091305.
BACKGROUND: In recent years, metabolic reprogramming has been identified as a hallmark of cancer. Accumulating evidence suggests that glutamine metabolism plays a crucial role in oncogenesis and the tumor microenvironment. In this study, we aimed to perform a systematic and comprehensive analysis of six key metabolic node genes involved in the dynamic regulation of glutamine metabolism (referred to as GLNM regulators) across 33 types of cancer. METHODS: We analyzed the gene expression, epigenetic regulation, and genomic alterations of six key GLNM regulators, including , , , , , and , in pan-cancer using several open-source platforms and databases. Additionally, we investigated the impacts of these gene expression changes on clinical outcomes, drug sensitivity, and the tumor microenvironment. We also attempted to investigate the upstream microRNA-mRNA molecular networks and the downstream signaling pathways involved in order to uncover the potential molecular mechanisms behind metabolic reprogramming. RESULTS: We found that the expression levels of GLNM regulators varied across cancer types and were related to several genomic and immunological characteristics. While the immune scores were generally lower in the tumors with higher gene expression, the types of immune cell infiltration showed significantly different correlations among cancer types, dividing them into two clusters. Furthermore, we showed that elevated GLNM regulators expression was associated with poor overall survival in the majority of cancer types. Lastly, the expression of GLNM regulators was significantly associated with PD-L1 expression and drug sensitivity. CONCLUSIONS: The elevated expression of GLNM regulators was associated with poorer cancer prognoses and a cold tumor microenvironment, providing novel insights into cancer treatment and possibly offering alternative options for the treatment of clinically refractory cancers.
8Global Epidemiology and Genetics of Hepatocellular Carcinoma.PubMed
Ming Ren Toh, Evelyn Yi Ting Wong, Sunny Hei Wong, et al.
Gastroenterology. 2023 Apr;164(5):766-782. doi: 10.1053/j.gastro.2023.01.033. Epub 2023 Feb 2.
Hepatocellular carcinoma (HCC) is one of the leading cancers worldwide. Classically, HCC develops in genetically susceptible individuals who are exposed to risk factors, especially in the presence of liver cirrhosis. Significant temporal and geographic variations exist for HCC and its etiologies. Over time, the burden of HCC has shifted from the low-moderate to the high sociodemographic index regions, reflecting the transition from viral to nonviral causes. Geographically, the hepatitis viruses predominate as the causes of HCC in Asia and Africa. Although there are genetic conditions that confer increased risk for HCC, these diagnoses are rarely recognized outside North America and Europe. In this review, we will evaluate the epidemiologic trends and risk factors of HCC, and discuss the genetics of HCC, including monogenic diseases, single-nucleotide polymorphisms, gut microbiome, and somatic mutations.
9Epidemiology of Renal Cell Carcinoma: 2022 Update.PubMed
Laura Bukavina, Karim Bensalah, Freddie Bray, et al.
Eur Urol. 2022 Nov;82(5):529-542. doi: 10.1016/j.eururo.2022.08.019. Epub 2022 Sep 10.
CONTEXT: International variations in the rates of kidney cancer (KC) are considerable. An understanding of the risk factors for KC development is necessary to generate opportunities to reduce its incidence through prevention and surveillance. OBJECTIVE: To retrieve and summarize global incidence and mortality rates of KC and risk factors associated with its development, and to describe known familial syndromes and genetic alterations that represent biologic risk factors. EVIDENCE ACQUISITION: A systematic review was conducted via Medline (PubMed) and Scopus to include meta-analyses, reviews, and original studies regarding renal cell carcinoma, epidemiology, and risk factors. EVIDENCE SYNTHESIS: Our narrative review provides a detailed analysis of KC incidence and mortality, with significant variations across time, geography, and sex. In particular, while KC incidence has continued to increase, mortality models have leveled off. Among the many risk factors, hypertension, obesity, and smoking are the most well established. The emergence of new genetic data coupled with observational data allows for integrated management and surveillance strategies for KC care. CONCLUSIONS: KC incidence and mortality rates vary significantly by geography, sex, and age. Associations of the development of KC with modifiable and fixed risk factors such as obesity, hypertension, smoking, and chronic kidney disease (CKD)/end-stage kidney disease (ESKD) are well described. Recent advances in the genetic characterization of these cancers have led to a better understanding of the germline and somatic mutations that predispose patients to KC development, with potential for identification of therapeutic targets that may improve outcomes for these at-risk patients. PATIENT SUMMARY: We reviewed evidence on the occurrence of kidney cancer (KC) around the world. Currently, the main avoidable causes are smoking, obesity, and high blood pressure. Although other risk factors also contribute, prevention and treatment of these three factors provide the best opportunities to reduce the risk of developing KC at present.
10[Cancer].PubMed
Roberto de la Peña-López, Yuly Andrea Remolina-Bonilla
Gac Med Mex. 2016 Sep;152 Suppl 1:63-6.
Cancer is a group of diseases which represents a significant public health problem in Mexico and worldwide. In Mexico neoplasms are the second leading cause of death. An increased morbidity and mortality are expected in the next decades. Several preventable risk factors for cancer development have been identified, the most relevant including tobacco use, which accounts for 30% of the cancer cases; and obesity, associated to another 30%. These factors, in turn, are related to sedentarism, alcohol abuse and imbalanced diets. Some agents are well knokn to cause cancer such as ionizing radiation, viruses such as the papilloma virus (HPV) and hepatitis virus (B and C), and more recently environmental pollution exposure and red meat consumption have been pointed out as carcinogens by the International Agency for Research in Cancer (IARC). The scientific evidence currently available is insufficient to consider milk either as a risk factor or protective factor against different types of cancer.
11Global burden of cancer and associated risk factors in 204 countries and territories, 1980-2021: a systematic analysis for the GBD 2021.PubMed
Zenghong Wu, Fangnan Xia, Rong Lin
J Hematol Oncol. 2024 Nov 29;17(1):119. doi: 10.1186/s13045-024-01640-8.
BACKGROUND: Cancer is the second most common cause of death globally. Therefore, it is imperative to investigate cancer incidence, mortality rates, and disability-adjusted life years (DALYs) to enhance preventive measures and healthcare resource allocation. This study aimed to assess cancer burden and associated risk factors in 204 countries and territories between 1980 and 2021. METHODS: We selected data on cancer incidence and mortality rates and associated risk factors from the global burden of disease (GBD) study tool for 204 countries and territories from 1990 to 2021 and 1980 to 2021. We estimated the age-standardized incidence (ASIR) and age-standardized deaths (ASDR) of 34 cancer types categorized as level 3 causes based on the GBD hierarchy. RESULTS: In 2021, cancer accounted for 14.57% (95% uncertainty interval: 13.65-15.28) of total deaths and 8.8% (7.99-9.67) of total DALYs in both sexes globally. ASIR and ASDR were 790.33 (694.43-893.01) and 116.49 (107.28-124.69), respectively. Additionally, females exhibited higher ASIR than males (923.44 versus 673.09), while males exhibited higher ASDR than females (145.69 versus 93.60). This indicates that policymakers should focus on the importance of gender equality in healthcare. Non-melanoma skin cancer exhibited the highest ASIR (74.10) in both sexes, while digestive cancers accounted for 39.29% of all cancer-related deaths, and Asia exhibited the heaviest cancer burden. In females, breast cancer exhibited the highest ASIR (46.40) and ASDR (14.55). In males, tracheal, bronchial, and lung cancer exhibited the highest ASIR (37.85) and ASDR (34.32), highlighting the urgent need for targeted tobacco control measures. Different cancers in various countries exhibit unique characteristics. Therefore, policymakers should formulate specific prevention and control strategies that reflect the cancer in their country. Tobacco was the primary level 2 risk factor for cancer DALYs in males. It accounted for 29.32% (25.32-33.14) of all cancer DALYs. Dietary risks, alcohol consumption, and air pollution accounted for 5.89% (2.01-10.73), 5.48% (4.83-6.11), and 4.30% (2.77-5.95) of male cancer DALYs, respectively. Therefore, policymakers should prioritize smoking regulation and other carcinogenic risks. CONCLUSION: Cancer is a significant public health concern globally. Understanding the common etiologies of different cancers is essential for developing effective control strategies and targeted interventions.
12The causal association between smoking, alcohol consumption and risk of bladder cancer: A univariable and multivariable Mendelian randomization study.PubMed
Jie Xiong, Lan Yang, Yu-Qing Deng, et al.
Int J Cancer. 2022 Dec 15;151(12):2136-2143. doi: 10.1002/ijc.34228. Epub 2022 Aug 11.
Smoking and alcohol consumption are associated with bladder cancer risk in observational studies. We conducted a two-sample univariable and multivariable Mendelian randomization (MR) analysis to determine whether those associations are causal. We used 21, 126, 360, 39 single nucleotide polymorphisms (SNPs) as instrumental variables for number of cigarettes per day, lifetime smoking index, smoking initiation, and drinks per week, respectively. A total of 1115 cases with bladder cancer and 174 006 noncases from FinnGen consortium and 2883 cases with bladder cancer and 417 955 noncases from UK Biobank study were obtained. Genetic predisposition to cigarettes per day, lifetime smoking index and smoking initiation were positively associated with an increased risk of bladder cancer in both the FinnGen and UK Biobank consortium. The summary odds ratio (OR) of bladder cancer was 1.79 (95% confidence interval [CI], 1.31-2.45; P = .0002), 2.38 (95% CI, 1.45-3.88; P = .0005) and 1.91 (95% CI, 1.46-2.50; P = 1.59 × 10 ) for one SD increase in the number of cigarettes per day, lifetime smoking index and smoking initiation, respectively. The genetically instrumented number of drinks per week was not associated with bladder cancer (OR = 0.69; 95% CI, 0.44-1.10; P = .1237). Estimates were consistent in multivariable MR analyses by the adjustments of body mass index and education. Our study suggests a causal potential of the association of smoking but not alcohol consumption with bladder cancer according to current evidence.
13Tobacco and alcohol as risk factors for pancreatic cancer.PubMed
Murray Korc, Christie Y Jeon, Mouad Edderkaoui, et al.
Best Pract Res Clin Gastroenterol. 2017 Oct;31(5):529-536. doi: 10.1016/j.bpg.2017.09.001. Epub 2017 Sep 6.
Pancreatic cancer is projected to become the leading cause of cancer deaths by 2050. The risk for pancreatic cancer may be reduced by up to 27% by modifying lifestyle risk factors, most notably tobacco smoking. Based on analysis of more than 2 million unselected individuals from general population, this article quantified the risk of pancreatic cancer in relation to lifelong tobacco smoking and alcohol consumption status, both alone and in combination. It also provided a state-of-the-art review of animal studies on the effect of tobacco smoke and alcohol on genetically engineered mouse models of pancreatic precursor lesions, as well as the role of immune microenvironment in pancreatic carcinogenesis activated by tobacco and alcohol.
14Alcohol, smoking and the risk of premalignant and malignant colorectal neoplasms.PubMed
Ifewumi O Fagunwa, Maurice B Loughrey, Helen G Coleman
Best Pract Res Clin Gastroenterol. 2017 Oct;31(5):561-568. doi: 10.1016/j.bpg.2017.09.012. Epub 2017 Nov 11.
Colorectal cancer (CRC) is the third most common cancer worldwide and has a complex aetiology consisting of environmental and genetic factors. In this review, we evaluate the roles of alcohol and tobacco smoking in colorectal neoplasia. Alcohol intake and tobacco smoking are associated with modest, but significantly, increased risks of CRC, adenomatous and serrated polyps. There is consistent evidence of dose-response relationships for both alcohol and smoking, and risk of these neoplasms. Alcohol and smoking appear to be more strongly associated with colorectal polyp than CRC development, suggesting roles in the initiation of neoplastic growths. These lifestyle factors also seem more strongly related to adenomas and sessile serrated lesions than hyperplastic polyps, but further confirmation is required. The gastroenterology community has an important, yet currently underexploited, role to play addressing the modifiable factors associated with CRC and polyps. These behaviours include, but are not limited to, alcohol and smoking.
15Global, regional, and national burden of colorectal cancer and its risk factors, 1990-2019: a systematic analysis for the Global Burden of Disease Study 2019.PubMed
Lancet Gastroenterol Hepatol. 2022 Jul;7(7):627-647. doi: 10.1016/S2468-1253(22)00044-9. Epub 2022 Apr 7.
BACKGROUND: Colorectal cancer is the third leading cause of cancer deaths worldwide. Given the recent increasing trends in colorectal cancer incidence globally, up-to-date information on the colorectal cancer burden could guide screening, early detection, and treatment strategies, and help effectively allocate resources. We examined the temporal patterns of the global, regional, and national burden of colorectal cancer and its risk factors in 204 countries and territories across the past three decades. METHODS: Estimates of incidence, mortality, and disability-adjusted life years (DALYs) for colorectal cancer were generated as a part of the Global Burden of Diseases, Injuries and Risk Factors Study (GBD) 2019 by age, sex, and geographical location for the period 1990-2019. Mortality estimates were produced using the cause of death ensemble model. We also calculated DALYs attributable to risk factors that had evidence of causation with colorectal cancer. FINDINGS: Globally, between 1990 and 2019, colorectal cancer incident cases more than doubled, from 842 098 (95% uncertainty interval [UI] 810 408-868 574) to 2·17 million (2·00-2·34), and deaths increased from 518 126 (493 682-537 877) to 1·09 million (1·02-1·15). The global age-standardised incidence rate increased from 22·2 (95% UI 21·3-23·0) per 100 000 to 26·7 (24·6-28·9) per 100 000, whereas the age-standardised mortality rate decreased from 14·3 (13·5-14·9) per 100 000 to 13·7 (12·6-14·5) per 100 000 and the age-standardised DALY rate decreased from 308·5 (294·7-320·7) per 100 000 to 295·5 (275·2-313·0) per 100 000 from 1990 through 2019. Taiwan (province of China; 62·0 [48·9-80·0] per 100 000), Monaco (60·7 [48·5-73·6] per 100 000), and Andorra (56·6 [42·8-71·9] per 100 000) had the highest age-standardised incidence rates, while Greenland (31·4 [26·0-37·1] per 100 000), Brunei (30·3 [26·6-34·1] per 100 000), and Hungary (28·6 [23·6-34·0] per 100 000) had the highest age-standardised mortality rates. From 1990 through 2019, a substantial rise in incidence rates was observed in younger adults (age <50 years), particularly in high Socio-demographic Index (SDI) countries. Globally, a diet low in milk (15·6%), smoking (13·3%), a diet low in calcium (12·9%), and alcohol use (9·9%) were the main contributors to colorectal cancer DALYs in 2019. INTERPRETATION: The increase in incidence rates in people younger than 50 years requires vigilance from researchers, clinicians, and policy makers and a possible reconsideration of screening guidelines. The fast-rising burden in low SDI and middle SDI countries in Asia and Africa calls for colorectal cancer prevention approaches, greater awareness, and cost-effective screening and therapeutic options in these regions. FUNDING: Bill & Melinda Gates Foundation.
16Secular trends and attributable risk factors of esophageal cancer deaths among non-elderly adults based on Global Burden of Disease Study.PubMed
Quanmei Li, Lingyan Zhu, Tong Wei, et al.
J Cancer Res Clin Oncol. 2023 Dec;149(18):16417-16427. doi: 10.1007/s00432-023-05380-z. Epub 2023 Sep 14.
OBJECTIVE: Esophageal cancer (EC) poses a persistent threat to the health of non-elderly adults. This study aims to elucidate the temporal trends of EC-related mortality and investigate the impact of various risk factors on such deaths in the age group of 20-59 years, spanning 3 decades. METHODS: Data on EC deaths were acquired from the Global Burden of Disease, Injuries, and Risk Factors (GBD) study. We employed estimated average percentage change (EAPC) and linear mixed-effects (LME) models to analyze mortality trends and pertinent risk factors for EC. RESULTS: Between 1990 and 2019, EC mortality showed a downward trend, and the global number of deaths from EC among non-elderly adults surged by 24.37%. During this period, mortality rates saw an increase in only two regions-the Caribbean and Western Sub-Saharan Africa (EAPCs > 0). For male deaths, smoking and alcohol use emerged as the primary risk factors, while high body mass index (BMI) stood out as the main risk factor for female deaths. Furthermore, the LME model identified male sex, advancing age, alcohol use, smoking, and chewing tobacco as factors associated with an additional rise in EC deaths. CONCLUSION: EC continues to exert a substantial toll on mortality among young and middle-aged adults globally. Implementing targeted interventions are significant in alleviating the burden of this disease within this population.
17Alcohol drinking, smoking, and cutaneous melanoma risk: Mendelian randomization analysis.PubMed
Jiaxiang Xu, Wenhui Liu, Xuanjun Liu, et al.
Gac Sanit. 2023 Dec 4;37:102351. doi: 10.1016/j.gaceta.2023.102351. eCollection 2023.
OBJECTIVE: To investigate the causal relationship between poor lifestyle habits, such as smoking and drinking, and cutaneous malignant melanoma. METHOD: In the present study, alcohol consumption and smoking were used as exposure factors, and single nucleotide polymorphisms closely associated with alcohol consumption and smoking were used as instrumental variables, while cutaneous melanoma was set as an outcome variable. Two-sample Mendelian randomization analyses were run between alcohol consumption and melanoma and smoking and melanoma to investigate their causal associations, respectively. RESULTS: We found a positive and statistically significant causal effect of alcohol intake on the risk of cutaneous malignant melanoma (OR: 2.23; 95%CI: 1.11-4.47; p=0.02). The present study showed no significant causal relationship between cigarettes per day and cutaneous melanoma (OR: 0.85; 95%CI: 0.54-1.35; p=0.50) or smoking initiation and cutaneous melanoma (OR: 1.02; 95%CI: 0.74-1.39; p=0.88). CONCLUSIONS: This study provides Mendelian randomization evidence supporting alcohol consumption as a risk factor for cutaneous malignant melanoma. And the causal relationship between smoking and cutaneous malignant melanoma still needs to be further investigated.
18High fat diet, gut microbiome and gastrointestinal cancer.PubMed
Yao Tong, Huiru Gao, Qiuchen Qi, et al.
Theranostics. 2021 Apr 3;11(12):5889-5910. doi: 10.7150/thno.56157. eCollection 2021.
Gastrointestinal cancer is currently one of the main causes of cancer death, with a large number of cases and a wide range of lesioned sites. A high fat diet, as a public health problem, has been shown to be correlated with various digestive system diseases and tumors, and can accelerate the occurrence of cancer due to inflammation and altered metabolism. The gut microbiome has been the focus of research in recent years, and associated with cell damage or tumor immune microenvironment changes via direct or extra-intestinal effects; this may facilitate the occurrence and development of gastrointestinal tumors. Based on research showing that both a high fat diet and gut microbes can promote the occurrence of gastrointestinal tumors, and that a high fat diet imbalances intestinal microbes, we propose that a high fat diet drives gastrointestinal tumors by changing the composition of intestinal microbes.
19High-fat diet enhances stemness and tumorigenicity of intestinal progenitors.PubMed
Semir Beyaz, Miyeko D Mana, Jatin Roper, et al.
Nature. 2016 Mar 3;531(7592):53-8. doi: 10.1038/nature17173.
Little is known about how pro-obesity diets regulate tissue stem and progenitor cell function. Here we show that high-fat diet (HFD)-induced obesity augments the numbers and function of Lgr5(+) intestinal stem cells of the mammalian intestine. Mechanistically, a HFD induces a robust peroxisome proliferator-activated receptor delta (PPAR-δ) signature in intestinal stem cells and progenitor cells (non-intestinal stem cells), and pharmacological activation of PPAR-δ recapitulates the effects of a HFD on these cells. Like a HFD, ex vivo treatment of intestinal organoid cultures with fatty acid constituents of the HFD enhances the self-renewal potential of these organoid bodies in a PPAR-δ-dependent manner. Notably, HFD- and agonist-activated PPAR-δ signalling endow organoid-initiating capacity to progenitors, and enforced PPAR-δ signalling permits these progenitors to form in vivo tumours after loss of the tumour suppressor Apc. These findings highlight how diet-modulated PPAR-δ activation alters not only the function of intestinal stem and progenitor cells, but also their capacity to initiate tumours.
20A high-fat diet promotes cancer progression by inducing gut microbiota-mediated leucine production and PMN-MDSC differentiation.PubMed
Jiewen Chen, Xiyuan Liu, Yi Zou, et al.
Proc Natl Acad Sci U S A. 2024 May 14;121(20):e2306776121. doi: 10.1073/pnas.2306776121. Epub 2024 May 6.
A high-fat diet (HFD) is a high-risk factor for the malignant progression of cancers through the disruption of the intestinal microbiota. However, the role of the HFD-related gut microbiota in cancer development remains unclear. This study found that obesity and obesity-related gut microbiota were associated with poor prognosis and advanced clinicopathological status in female patients with breast cancer. To investigate the impact of HFD-associated gut microbiota on cancer progression, we established various models, including HFD feeding, fecal microbiota transplantation, antibiotic feeding, and bacterial gavage, in tumor-bearing mice. HFD-related microbiota promotes cancer progression by generating polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs). Mechanistically, the HFD microbiota released abundant leucine, which activated the mTORC1 signaling pathway in myeloid progenitors for PMN-MDSC differentiation. Clinically, the elevated leucine level in the peripheral blood induced by the HFD microbiota was correlated with abundant tumoral PMN-MDSC infiltration and poor clinical outcomes in female patients with breast cancer. These findings revealed that the "gut-bone marrow-tumor" axis is involved in HFD-mediated cancer progression and opens a broad avenue for anticancer therapeutic strategies by targeting the aberrant metabolism of the gut microbiota.
21High-fat diet promotes liver tumorigenesis via palmitoylation and activation of AKT.PubMed
Lang Bu, Zhengkun Zhang, Jianwen Chen, et al.
Gut. 2024 Jun 6;73(7):1156-1168. doi: 10.1136/gutjnl-2023-330826.
OBJECTIVE: Whether and how the PI3K-AKT pathway, a central node of metabolic homeostasis, is responsible for high-fat-induced non-alcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC) remain a mystery. Characterisation of AKT regulation in this setting will provide new strategies to combat HCC. DESIGN: Metabolite library screening disclosed that palmitic acid (PA) could activate AKT. In vivo and in vitro palmitoylation assay were employed to detect AKT palmitoylation. Diverse cell and mouse models, including generation of and knock-in cells, and knockout mice and knock-in mice were employed. Human liver tissues from patients with NASH and HCC, hydrodynamic transfection mouse model, high-fat/high-cholesterol diet (HFHCD)-induced NASH/HCC mouse model and high-fat and methionine/choline-deficient diet (HFMCD)-induced NASH mouse model were also further explored for our mechanism studies. RESULTS: By screening a metabolite library, PA has been defined to activate AKT by promoting its palmitoyl modification, an essential step for growth factor-induced AKT activation. Biologically, a high-fat diet could promote AKT kinase activity, thereby promoting NASH and liver cancer. Mechanistically, palmitoyl binding anchors AKT to the cell membrane in a PIP3-independent manner, in part by preventing AKT from assembling into an inactive polymer. The palmitoyltransferases ZDHHC17/24 were characterised to palmitoylate AKT to exert oncogenic effects. Interestingly, the anti-obesity drug orlistat or specific penetrating peptides can effectively attenuate AKT palmitoylation and activation by restricting PA synthesis or repressing AKT modification, respectively, thereby antagonising liver tumorigenesis. CONCLUSIONS: Our findings elucidate a novel fine-tuned regulation of AKT by PA-ZDHHC17/24-mediated palmitoylation, and highlight tumour therapeutic strategies by taking PA-restricted diets, limiting PA synthesis, or directly targeting AKT palmitoylation.
22Obesity Shapes Metabolism in the Tumor Microenvironment to Suppress Anti-Tumor Immunity.PubMed
Alison E Ringel, Jefte M Drijvers, Gregory J Baker, et al.
Cell. 2020 Dec 23;183(7):1848-1866.e26. doi: 10.1016/j.cell.2020.11.009. Epub 2020 Dec 9.
Obesity is a major cancer risk factor, but how differences in systemic metabolism change the tumor microenvironment (TME) and impact anti-tumor immunity is not understood. Here, we demonstrate that high-fat diet (HFD)-induced obesity impairs CD8 T cell function in the murine TME, accelerating tumor growth. We generate a single-cell resolution atlas of cellular metabolism in the TME, detailing how it changes with diet-induced obesity. We find that tumor and CD8 T cells display distinct metabolic adaptations to obesity. Tumor cells increase fat uptake with HFD, whereas tumor-infiltrating CD8 T cells do not. These differential adaptations lead to altered fatty acid partitioning in HFD tumors, impairing CD8 T cell infiltration and function. Blocking metabolic reprogramming by tumor cells in obese mice improves anti-tumor immunity. Analysis of human cancers reveals similar transcriptional changes in CD8 T cell markers, suggesting interventions that exploit metabolism to improve cancer immunotherapy.
23Dietary Factors Modulating Colorectal Carcinogenesis.PubMed
Filippo Vernia, Salvatore Longo, Gianpiero Stefanelli, et al.
Nutrients. 2021 Jan 3;13(1):143. doi: 10.3390/nu13010143.
The development of colorectal cancer, responsible for 9% of cancer-related deaths, is favored by a combination of genetic and environmental factors. The modification of diet and lifestyle may modify the risk of colorectal cancer (CRC) and prevent neoplasia in up to 50% of cases. The Western diet, characterized by a high intake of fat, red meat and processed meat has emerged as an important contributor. Conversely, a high intake of dietary fiber partially counteracts the unfavorable effects of meat through multiple mechanisms, including reduced intestinal transit time and dilution of carcinogenic compounds. Providing antioxidants (e.g., vitamins C and E) and leading to increased intraluminal production of protective fermentation products, like butyrate, represent other beneficial and useful effects of a fiber-rich diet. Protective effects on the risk of developing colorectal cancer have been also advocated for some specific micronutrients like vitamin D, selenium, and calcium. Diet-induced modifications of the gut microbiota modulate colonic epithelial cell homeostasis and carcinogenesis. This can have, under different conditions, opposite effects on the risk of CRC, through the production of mutagenic and carcinogenic agents or, conversely, of protective compounds. The aim of this review is to summarize the most recent evidence on the role of diet as a potential risk factor for the development of colorectal malignancies, as well as providing possible prevention dietary strategies.
24Occupational and environmental radiation and cancer.PubMed
J D Boice, J H Lubin
Cancer Causes Control. 1997 May;8(3):309-22. doi: 10.1023/a:1018496919324.
Epidemiologic evidence on the relation between occupational and environmental radiation and cancer is reviewed. Studies of pioneering radiation workers, underground miners, and radium dial painters revealed excess cancer deaths and contributed to the setting of radiation protection standards and to theories of carcinogenesis. Occupational exposures today are generally much lower than in the past, thus any associated increases in cancer will be difficult to detect. Pooling investigations of these more recently exposed workers, however, has the potential to validate current estimates of risk used in radiation protection. New information on the effects of chronic radiation exposure also may come from studies in the former Soviet Union of Chernobyl clean-up workers and of workers at the Mayak nuclear facilities. Studies of environmental radiation exposures, other than radon, are largely inconclusive, due mainly to the difficulties in detecting the low risks associated with low dose exposures. Thyroid cancer, however, has been linked to environmental radiation from the Chernobyl accident and from nuclear weapons tests. Low-level radiation released during normal operations at nuclear plants has not been found to increase cancer rates in surrounding populations. Radon, a human carcinogen, is the most ubiquitous exposure to human populations; remediating high residential-radon levels is recommended, recognizing that the exposure can never be removed completely because it occurs naturally.
25Environmental and social determinants of thyroid cancer: A spatial analysis based on the Geographical Detector.PubMed
Shirui Huo, Ying Liu, Anyi Sun, et al.
Front Endocrinol (Lausanne). 2022 Nov 29;13:1052606. doi: 10.3389/fendo.2022.1052606. eCollection 2022.
INTRODUCTION: Thyroid cancer has increased sharply in China in recent years. This change may be attributable to multiple factors. The current study aimed to explore the environmental and social determinants of thyroid cancer. METHODS: Incidence data from 487 cancer registries in 2016 were collected. Eight factors were considered, namely, air pollution, green space, ambient temperature, ultraviolet radiation, altitude, economic status, healthcare, and education level. A geographical detector (measured by statistic) was used to evaluate the independent and interactive impact of the eight factors on thyroid cancer. RESULTS: Social factors, especially economic status and healthcare level ( > 0.2), were most influential on thyroid cancer.Ultraviolet radiation, air pollution, and temperature had more impact on women, while green space and altitude had more influence on men. Enhanced effects were observed when two factors interacted. Spatially, economic status, healthcare, and air pollution were positively associated with thyroid cancer, while education level, green space, and altitude were negatively related to thyroid cancer. CONCLUSION: The socio-environmental determinants and spatial heterogeneity of thyroid cancer were observed in this study. These findings may improve our understanding of thyroid cancer epidemiology and help guide public health interventions.
26Cancer Incidence, Mortality, Years of Life Lost, Years Lived With Disability, and Disability-Adjusted Life Years for 29 Cancer Groups From 2010 to 2019: A Systematic Analysis for the Global Burden of Disease Study 2019.PubMed
Jonathan M Kocarnik, Kelly Compton, et al.
JAMA Oncol. 2022 Mar 1;8(3):420-444. doi: 10.1001/jamaoncol.2021.6987.
IMPORTANCE: The Global Burden of Diseases, Injuries, and Risk Factors Study 2019 (GBD 2019) provided systematic estimates of incidence, morbidity, and mortality to inform local and international efforts toward reducing cancer burden. OBJECTIVE: To estimate cancer burden and trends globally for 204 countries and territories and by Sociodemographic Index (SDI) quintiles from 2010 to 2019. EVIDENCE REVIEW: The GBD 2019 estimation methods were used to describe cancer incidence, mortality, years lived with disability, years of life lost, and disability-adjusted life years (DALYs) in 2019 and over the past decade. Estimates are also provided by quintiles of the SDI, a composite measure of educational attainment, income per capita, and total fertility rate for those younger than 25 years. Estimates include 95% uncertainty intervals (UIs). FINDINGS: In 2019, there were an estimated 23.6 million (95% UI, 22.2-24.9 million) new cancer cases (17.2 million when excluding nonmelanoma skin cancer) and 10.0 million (95% UI, 9.36-10.6 million) cancer deaths globally, with an estimated 250 million (235-264 million) DALYs due to cancer. Since 2010, these represented a 26.3% (95% UI, 20.3%-32.3%) increase in new cases, a 20.9% (95% UI, 14.2%-27.6%) increase in deaths, and a 16.0% (95% UI, 9.3%-22.8%) increase in DALYs. Among 22 groups of diseases and injuries in the GBD 2019 study, cancer was second only to cardiovascular diseases for the number of deaths, years of life lost, and DALYs globally in 2019. Cancer burden differed across SDI quintiles. The proportion of years lived with disability that contributed to DALYs increased with SDI, ranging from 1.4% (1.1%-1.8%) in the low SDI quintile to 5.7% (4.2%-7.1%) in the high SDI quintile. While the high SDI quintile had the highest number of new cases in 2019, the middle SDI quintile had the highest number of cancer deaths and DALYs. From 2010 to 2019, the largest percentage increase in the numbers of cases and deaths occurred in the low and low-middle SDI quintiles. CONCLUSIONS AND RELEVANCE: The results of this systematic analysis suggest that the global burden of cancer is substantial and growing, with burden differing by SDI. These results provide comprehensive and comparable estimates that can potentially inform efforts toward equitable cancer control around the world.
27Dietary fiber intake reduces risk for Barrett's esophagus and esophageal cancer.PubMed
Lingli Sun, Zhizhong Zhang, Jian Xu, et al.
Crit Rev Food Sci Nutr. 2017 Sep 2;57(13):2749-2757. doi: 10.1080/10408398.2015.1067596.
BACKGROUND: Observational studies suggest an association between dietary fiber intake and risk of Barrett's esophagus and esophageal cancer. However, the results are inconsistent. OBJECTIVE: To conduct a meta-analysis of observational studies to assess this association. DESIGN: All eligible studies were identified by electronic searches in PubMed and Embase through February 2015. Dose-response, subgroup, sensitivity, and publication bias analyses were performed. RESULTS: A total of 15 studies involving 16,885 subjects were included in the meta-analysis. The pooled odds ratio for the highest compared with the lowest dietary fiber intake was 0.52 (95% CI, 0.43-0.64). Stratified analyses for tumor subtype, study design, geographic location, fiber type, publication year, total sample size, and quality score yielded consistent results. Dose-response analysis indicated that a 10-g/d increment in dietary fiber intake was associated with a 31% reduction in Barrett's esophagus and esophageal cancer risk. Sensitivity analysis restricted to studies with control for conventional risk factors produced similar results, and omission of any single study had little effect on the overall risk estimate. CONCLUSIONS: Our findings indicate that dietary fiber intake is inversely associated with risk of Barrett's esophagus and esophageal cancer. Further large prospective studies are warranted.
28Dietary fiber and breast cancer risk: a systematic review and meta-analysis of prospective studies.PubMed
D Aune, D S M Chan, D C Greenwood, et al.
Ann Oncol. 2012 Jun;23(6):1394-402. doi: 10.1093/annonc/mdr589. Epub 2012 Jan 10.
BACKGROUND: Evidence from case-control studies suggest that dietary fiber may be inversely related to breast cancer risk, but it is unclear if this is supported by prospective data. We conducted a systematic review and meta-analysis of the evidence from prospective studies. METHODS: PubMed was searched for prospective studies of fiber intake and breast cancer risk until 31st August 2011. Random effects models were used to estimate summary relative risks (RRs). RESULTS: Sixteen prospective studies were included. The summary RR for the highest versus the lowest intake was 0.93 [95% confidence interval (CI) 0.89-0.98, I(2) = 0%] for dietary fiber, 0.95 (95% CI 0.86-1.06, I(2) = 4%) for fruit fiber, 0.99 (95% CI 0.92-1.07, I(2) = 1%) for vegetable fiber, 0.96 (95% CI 0.90-1.02, I(2) = 5%) for cereal fiber, 0.91 (95% CI 0.84-0.99, I(2) = 7%) for soluble fiber and 0.95 (95% CI 0.89-1.02, I(2) = 0%) for insoluble fiber. The summary RR per 10 g/day of dietary fiber was 0.95 (95% CI 0.91-0.98, I(2) = 0%, P(heterogeneity) = 0.82). In stratified analyses, the inverse association was only observed among studies with a large range (≥13 g/day) or high level of intake (≥25 g/day). CONCLUSION: In this meta-analysis of prospective studies, there was an inverse association between dietary fiber intake and breast cancer risk.
29Evidence Update on the Relationship between Diet and the Most Common Cancers from the European Prospective Investigation into Cancer and Nutrition (EPIC) Study: A Systematic Review.PubMed
Esther Ubago-Guisado, Miguel Rodríguez-Barranco, Ana Ching-López, et al.
Nutrients. 2021 Oct 13;13(10):3582. doi: 10.3390/nu13103582.
The European Prospective Investigation into Cancer and Nutrition (EPIC) is a multicentre prospective study conducted in 23 centres in 10 European countries. Here we review the findings from EPIC on the relationship between diet-related exposures and incidence or mortality from the four most frequent cancers in the European population: colorectal, breast, lung, and prostate cancer. We conducted a systematic review following PRISMA guidelines and identified 110 high-quality studies based on the EPIC cohort. Fruit and vegetable consumption had a protective effect against colorectal, breast, and lung cancer, whereas only fruit had a protective effect against prostate cancer. A higher consumption of fish and lower consumption of red and processed meat were related with a lower risk of colorectal cancer; and higher consumption of fatty fish with lower risk of breast cancer. Calcium and yogurt intake were found to protect against colorectal and prostate cancer. Alcohol consumption increased the risk for colorectal and breast cancer. Finally, adherence to the Mediterranean diet emerged as a protective factor for colorectal and breast cancer. The EPIC study results are in agreement with the latest evidence from leading authorities on cancer prevention and help to inform public prevention policies and strategies.
30Anticancer Effects of Nutraceuticals in the Mediterranean Diet: An Epigenetic Diet Model.PubMed
Rosa Divella, Antonella Daniele, Eufemia Savino, et al.
Cancer Genomics Proteomics. 2020 Jul-Aug;17(4):335-350. doi: 10.21873/cgp.20193.
Epidemiological and clinical studies support the association between nutrition and development or progression of different malignancies such as colon, breast, and prostate cancer, defining these tumors as diet-associated cancer. The Mediterranean diet shows inverse associations with metabolic diseases, cardiovascular pathologies and various types of cancer. Many bioactive nutrients of the Mediterranean diet have been identified as factors protective against these types of pathologies. The epigenome has been identified as the primary goal of modulations in gene expression related to these molecular nutrients. In fact, they can modify the epigenome and can be incorporated into the 'epigenetic diet', which translates into a diet regimen that can be used therapeutically for health or preventative purposes. Most epigenetic changes are influenced by lifestyle and nutrition. Epigenetic therapy is a new area for the development of nutraceuticals whose absence of toxicity can represent a valid asset in cancer prevention strategies. Recent advances in understanding the mechanisms of nutrigenomics, nutrigenetics and nutraceuticals have led to the identification of superfoods capable of favorably conditioning gene expression. In this review, we highlight the importance of nutraceuticals present in the Mediterranean diet as epigenetic modifiers both in the mechanisms of tumor onset and as protective agents.
31The protective effect of the Mediterranean diet: focus on cancer and cardiovascular risk.PubMed
Ernest K J Pauwels
Med Princ Pract. 2011;20(2):103-11. doi: 10.1159/000321197. Epub 2011 Jan 20.
The lower occurrence of cancer and cardiovascular disease in the population around the Mediterranean basin has been linked to the dietary habits of the region. Indeed, this so-called Mediterranean diet is essentially different from the diets consumed in Western and Northern European countries and is rich in nuts, fruits, vegetables, legumes, whole-wheat bread, fish, and olive oil, with moderate amounts of red wine, which is mainly consumed during meals. Although a variety of cultural and religious traditions exist among the peoples of the Mediterranean area, olive oil, fish, and red wine hold a traditional and central position in the culinary routines of the region. The components of the diet contain an ample source of molecules with antioxidant and anti-inflammatory actions, among which omega-3 fatty acids, oleic acid, and phenolic compounds hold a prominent place. This review will summarize the results of important epidemiological studies that have investigated the protective effect of fish and olive oil on the risk of breast, prostate, and colorectal cancer and of wine on the risk of cardiovascular disease. The present review also aims to elucidate the various mechanisms by which various dietary components exhibit their beneficial action. In this respect, emphasis will be placed on the properties of omega-3 fatty acids from fish, oleic acid from olive oil, and phenolic compounds from olive oil and red wine.
32Effects of the Mediterranean diet polyphenols on cancer development.PubMed
Taygun Dayi, Adile Oniz
J Prev Med Hyg. 2022 Oct 17;63(2 Suppl 3):E74-E80. doi: 10.15167/2421-4248/jpmh2022.63.2S3.2749. eCollection 2022 Jun.
Globally, the second most common mortality reason is cancer. There are two types of risk factors for cancer: intrinsic (unmodifiable) and non-intrinsic (modifiable). Bad lifestyle behaviors are among the exogenous non-intrinsic risk factors that can be related to 30-50% of cancer development risk, among which can be counted the Western lifestyle. On the contrary, a potentially good lifestyle model to prevent cancer is the Mediterranean diet (MD), which is a plant-based nutrition model. The Mediterranean diet includes many beneficial nutrients and nutritional substances, such as dietary fibers, fatty acids, anti-oxidant and anti-inflammatory substances, etc. Among these beneficial substances, an important group is the one composed by polyphenols, the most common plant-synthesized secondary metabolites. Being a plant-based nutrition model, the Mediterranean diet provides many polyphenols, such as resveratrol, quercetin, phenolic acids, catechins, anthocyanins, oleocanthal, oleuropein, rosmarinic acid, gallic acid, hesperidin, naringenin, ellagic acid, etc. These substances show anti-proliferative, pro-apoptotic, anti-inflammatory, anti-oxidant, anti-migration, anti-angiogenic, anti-metastatic, and autophagy stimulator effects, which can potentially reduce cancer development risk, as was shown by some in vivo and in vitro studies on this topic. In this review of the literature we shed light on the effects and potential interactions between the Mediterranean diet polyphenols and cancer development.
33Polyphenols of the Mediterranean Diet and Their Metabolites in the Prevention of Colorectal Cancer.PubMed
Aline Yammine, Amira Namsi, Dominique Vervandier-Fasseur, et al.
Molecules. 2021 Jun 8;26(12):3483. doi: 10.3390/molecules26123483.
The Mediterranean diet is a central element of a healthy lifestyle, where polyphenols play a key role due to their anti-oxidant properties, and for some of them, as nutripharmacological compounds capable of preventing a number of diseases, including cancer. Due to the high prevalence of intestinal cancer (ranking second in causing morbidity and mortality), this review is focused on the beneficial effects of selected dietary phytophenols, largely present in Mediterranean cooking: apigenin, curcumin, epigallocatechin gallate, quercetin-rutine, and resveratrol. The role of the Mediterranean diet in the prevention of colorectal cancer and future perspectives are discussed in terms of food polyphenol content, the effectiveness, the plasma level, and the importance of other factors, such as the polyphenol metabolites and the influence of the microbiome. Perspectives are discussed in terms of microbiome-dependency of the brain-second brain axis. The emergence of polyphenol formulations may strengthen the efficiency of the Mediterranean diet in the prevention of cancer.
34Adherence to the Mediterranean Diet and Obesity-Linked Cancer Risk in EPIC.PubMed
Inmaculada Aguilera-Buenosvinos, Fernanda Morales Berstein, Esther M González-Gil, et al.
JAMA Netw Open. 2025 Feb 3;8(2):e2461031. doi: 10.1001/jamanetworkopen.2024.61031.
IMPORTANCE: Adherence to the Mediterranean Diet (MedDiet) has been associated with a lower incidence of cancer and reduced weight gain. These associations suggest a potential role for the MedDiet in lowering the risk of obesity-related cancers (ORCs). Obesity is a known risk factor for various cancers and shows an inverse association with MedDiet adherence. OBJECTIVE: To examine the association between adherence to the MedDiet and the risk of ORCs, considering the possible mediating role of adiposity. DESIGN, SETTING, AND PARTICIPANTS: This prospective cohort study analyzed data from the European Prospective Investigation Into Cancer and Nutrition (EPIC) study, which enrolled participants aged 35 to 70 years from 1992 to 2000 across 23 centers in 10 countries. The data analysis was conducted from March 1 to May 31, 2023. EXPOSURES: Dietary intake before baseline was evaluated using country-specific, validated questionnaires administered at recruitment. Adherence to the MedDiet was scored on a 9-point scale and categorized as low (0-3 points), medium (4-6 points), or high (7-9 points). MAIN OUTCOMES AND MEASURES: The primary outcome was the incidence of ORCs, classified according to the 2015 International Agency for Research on Cancer criteria. Multivariable Cox proportional hazards regression models were used to assess the association between MedDiet adherence and ORC incidence. Mediation analyses were conducted to evaluate the role of waist to hip ratio and body mass index in this association. RESULTS: A total of 450 111 participants were included in the study (mean [SD] age, 51.1 [9.8] years; 70.8% women) and followed up during a median (IQR) time of 14.9 (4.1) years. Among participants, 4.9% experienced an ORC (rates, 0.053, 0.049, and 0.043 per person-year in the low, medium, and high MedDiet adherence groups, respectively). Participants with high adherence to the MedDiet (7-9 points) had a lower risk of ORC compared with those with low adherence (0-3 points) (hazard ratio [HR], 0.94; 95% CI, 0.90-0.98). A similar inverse association was observed for participants with medium adherence (4-6 points vs 0-3 points). However, mediation analyses did not show associations of waist to hip ratio or body mass index between MedDiet adherence and ORC risk. CONCLUSIONS AND RELEVANCE: These findings indicate that higher adherence to the MedDiet is associated with a modest reduction in the risk of ORCs, independent of adiposity measures. Further research is needed to clarify the mechanisms by which the MedDiet may contribute to cancer prevention.
35Inflammatory potential of the diet and risk of breast cancer in the European Investigation into Cancer and Nutrition (EPIC) study.PubMed
Carlota Castro-Espin, Antonio Agudo, Catalina Bonet, et al.
Eur J Epidemiol. 2021 Sep;36(9):953-964. doi: 10.1007/s10654-021-00772-2. Epub 2021 Jun 20.
The role of chronic inflammation on breast cancer (BC) risk remains unclear beyond as an underlying mechanism of obesity and physical activity. We aimed to evaluate the association between the inflammatory potential of the diet and risk of BC overall, according to menopausal status and tumour subtypes. Within the European Prospective Investigation into Cancer and Nutrition cohort, 318,686 women were followed for 14 years, among whom 13,246 incident BC cases were identified. The inflammatory potential of the diet was characterized by an inflammatory score of the diet (ISD). Multivariable Cox regression models were used to assess the potential effect of the ISD on BC risk by means of hazard ratios (HR) and 95% confidence intervals (CI). ISD was positively associated with BC risk. Each increase of one standard deviation (1-Sd) of the score increased by 4% the risk of BC (HR = 1.04; 95% CI 1.01-1.07). Women in the highest quintile of the ISD (indicating a most pro-inflammatory diet) had a 12% increase in risk compared with those in the lowest quintile (HR = 1.12; 95% CI 1.04-1.21) with a significant trend. The association was strongest among premenopausal women, with an 8% increased risk for 1-Sd increase in the score (HR = 1.08; 95% CI 1.01-1.14). The pattern of the association was quite homogeneous by BC subtypes based on hormone receptor status. There were no significant interactions between ISD and body mass index, physical activity, or alcohol consumption. Women consuming more pro-inflammatory diets as measured by ISD are at increased risk for BC, especially premenopausal women.
36Bioactive compounds of the Mediterranean diet and prostate cancer.PubMed
Olga López-Guarnido, Noelia Urquiza-Salvat, Maria Saiz, et al.
Aging Male. 2018 Dec;21(4):251-260. doi: 10.1080/13685538.2018.1430129. Epub 2018 Jan 27.
OBJECTIVE: The purpose of this review is to examine the evidence on the effects of bioactive constituents of the Mediterranean diet (MeDi) on prostate cancer (PCa) risk. METHODS: The search for articles came from extensive research in the following databases: PubMed, Scopus, and Web of Science. We used the search terms "Mediterranean diet," "lycopene," "vitamin E," "vitamin C," "Selenium," "resveratrol," "prostate cancer," and combinations, such as "lycopene and prostate cancer" or "resveratrol and prostate cancer." RESULTS: Numerous studies investigating the effect of various dietary nutrients on PCa have suggested that selenium is probably the most promising. Several studies reported reduced PCa risk associated with vitamin C and E intake, while other studies reported no association. Lycopene inhibits cell proliferation and inducts apoptosis, thus protecting against cancer. Also, it has been found in various in vivo and in vitro studies that resveratrol, inhibits PCa development. CONCLUSIONS: The high content of bioactive phytochemicals in the MeDi is of particular interest in the prevention of PCa. Further large-scale studies are required to clarify the effect of MeDi bioactive compounds on prostate health, in order to establish the role of this diet in the prevention of PCa.
37Dietary Fat Intake and Risk of Ovarian Cancer: A Systematic Review and Dose-Response Meta-Analysis of Observational Studies.PubMed
Alireza Sadeghi, Sakineh Shab-Bidar, Mohammad Parohan, et al.
Nutr Cancer. 2019;71(6):939-953. doi: 10.1080/01635581.2019.1595049. Epub 2019 May 6.
Observational studies have reported controversial evidence of the association between dietary fat intake and ovarian cancer. This dose-response meta-analysis aimed to clarify quantitatively the association between dietary fat intake and ovarian cancer. The linear and non-linear relationships between fat intake and risk of ovarian cancer were investigated. Heterogeneity, sensitivity analysis, and publication bias were also assessed. Overall, 21 studies involved approximately 900,000 subjects were included. A significant nonlinear association was found between total fat intake with the risk of ovarian cancer, with a relatively steep slope at total fat intake higher than 30 g/day ( non-linearity <.01). Moreover, the risk of ovarian cancer was increased in non-linear form for both saturated and monounsaturated fat from 25 g/day ( non-linearity <.05). According to the findings from the linear meta-analysis, we observed a 2, 2, 1, and 1% greater risk of ovarian cancer per 10, 0.5, 2.5 g/day and 50 mg/day increase in total, trans and monounsaturated fat intake as well as cholesterol, respectively. However, this association for monounsaturated fat was marginally significant (=.052). The findings of this meta-analysis suggest that dietary total, trans, saturated and partially monounsaturated fat as well as cholesterol intake are positively associated with increased risk of ovarian cancer.
38Calcium intake and breast cancer risk: meta-analysis of prospective cohort studies.PubMed
Khemayanto Hidayat, Guo-Chong Chen, Ru Zhang, et al.
Br J Nutr. 2016 Jul;116(1):158-66. doi: 10.1017/S0007114516001768. Epub 2016 May 12.
Findings from observational studies have suggested a possible relation between Ca and breast cancer risk. However, the results of these studies are inconclusive, and the dose-response relationship between Ca intake and risk of breast cancer remains to be determined. A meta-analysis of prospective studies was conducted to address these issues. PubMed and Embase databases were searched for relevant studies concerning the association between Ca intake and breast cancer up to March 2016. The summary relative risks (RR) with 95 % CI were calculated with a random-effects model. The final analysis included eleven prospective cohort studies involving 26 606 cases and 872 895 participants. The overall RR of breast cancer for high v. low intake of Ca was 0·92 (95 % CI 0·85, 0·99), with moderate heterogeneity (P=0·026, I 2=44·2 %). In the subgroup analysis, the inverse association appeared stronger for premenopausal breast cancer (RR 0·75; 95 % CI 0·59, 0·96) than for postmenopausal breast cancer (RR 0·94; 95 % CI 0·87, 1·01). Dose-response analysis revealed that each 300 mg/d increase in Ca intake was associated with 2 % (RR 0·98; 95 % CI 0·96, 0·99), 8 % (RR 0·92; 95 % CI 0·87, 0·98) and 2 % (RR 0·98; 95 % CI 0·97, 0·99) reduction in the risk of total, premenopausal and postmenopausal breast cancer, respectively. Our findings suggest an inverse dose-response association between Ca intake and risk of breast cancer.
39Lack of exercise is a major cause of chronic diseases.PubMed
Frank W Booth, Christian K Roberts, Matthew J Laye
Compr Physiol. 2012 Apr;2(2):1143-211. doi: 10.1002/cphy.c110025.
Chronic diseases are major killers in the modern era. Physical inactivity is a primary cause of most chronic diseases. The initial third of the article considers: activity and prevention definitions; historical evidence showing physical inactivity is detrimental to health and normal organ functional capacities; cause versus treatment; physical activity and inactivity mechanisms differ; gene-environment interaction (including aerobic training adaptations, personalized medicine, and co-twin physical activity); and specificity of adaptations to type of training. Next, physical activity/exercise is examined as primary prevention against 35 chronic conditions [accelerated biological aging/premature death, low cardiorespiratory fitness (VO2max), sarcopenia, metabolic syndrome, obesity, insulin resistance, prediabetes, type 2 diabetes, nonalcoholic fatty liver disease, coronary heart disease, peripheral artery disease, hypertension, stroke, congestive heart failure, endothelial dysfunction, arterial dyslipidemia, hemostasis, deep vein thrombosis, cognitive dysfunction, depression and anxiety, osteoporosis, osteoarthritis, balance, bone fracture/falls, rheumatoid arthritis, colon cancer, breast cancer, endometrial cancer, gestational diabetes, pre-eclampsia, polycystic ovary syndrome, erectile dysfunction, pain, diverticulitis, constipation, and gallbladder diseases]. The article ends with consideration of deterioration of risk factors in longer-term sedentary groups; clinical consequences of inactive childhood/adolescence; and public policy. In summary, the body rapidly maladapts to insufficient physical activity, and if continued, results in substantial decreases in both total and quality years of life. Taken together, conclusive evidence exists that physical inactivity is one important cause of most chronic diseases. In addition, physical activity primarily prevents, or delays, chronic diseases, implying that chronic disease need not be an inevitable outcome during life.
40Physical activity, obesity and sedentary behavior in cancer etiology: epidemiologic evidence and biologic mechanisms.PubMed
Christine M Friedenreich, Charlotte Ryder-Burbidge, Jessica McNeil
Mol Oncol. 2021 Mar;15(3):790-800. doi: 10.1002/1878-0261.12772. Epub 2020 Aug 18.
An estimated 30-40% of cancers can be prevented through changes in modifiable lifestyle and environmental risk factors known to be associated with cancer incidence. Despite this knowledge, there remains limited awareness that these associations exist. The purpose of this review article was to summarize the epidemiologic evidence concerning the contribution of physical activity, sedentary behavior, and obesity to cancer etiology and to provide an overview of the biologic mechanisms that may be operative between these factors and cancer incidence. Strong and consistent evidence exists that higher levels of physical activity reduce the risk of six different cancer sites (bladder, breast, colon, endometrial, esophageal adenocarcinoma, gastric cardia), whereas moderate evidence inversely associates physical activity with lung, ovarian, pancreatic and renal cancer, and limited evidence inversely correlates physical activity with prostate cancer. Sedentary behavior, independent of physical activity, has been shown to increase the risk of colon, endometrial, and lung cancers. Obesity is an established risk factor for 13 different cancer sites (endometrial, postmenopausal breast, colorectal, esophageal, renal/kidneys, meningioma, pancreatic, gastric cardia, liver, multiple myeloma, ovarian, gallbladder, and thyroid). The main biologic mechanisms whereby physical activity, sedentary behavior, and obesity are related to cancer incidence include an effect on endogenous sex steroids and metabolic hormones, insulin sensitivity, and chronic inflammation. Several emerging pathways related to oxidative stress, DNA methylation, telomere length, immune function, and gut microbiome are presented. Key recommendations for future research in both the epidemiology and biology of the associations between physical activity, sedentary behavior, obesity, and cancer risk are also provided.
41Exercise in cancer prevention and anticancer therapy: Efficacy, molecular mechanisms and clinical information.PubMed
Chuanmei Zhu, Hongbo Ma, Anqi He, et al.
Cancer Lett. 2022 Sep 28;544:215814. doi: 10.1016/j.canlet.2022.215814. Epub 2022 Jul 5.
Modifiable lifestyle factors are the strongest determinants and major preventable causes of most type of cancer. Exercise has shown many beneficial effects in cancer prevention and anticancer treatment. However, the underlying mechanisms remain unclear. To contribute to our understanding of the role of exercise regulation in cancer and provide recommendations for future preclinical and clinical exercise oncology research, we examine the functions of exercise in cancer and its underlying mechanisms. In addition to reducing the incidence of cancer, exercise can enhance the efficacy of certain types of approved anticancer treatments (e.g., targeted therapy, immunotherapy, and radiotherapy) and reduce the symptoms/side effects of cancer and its treatment (e.g., fatigue, cancer cachexia, cognitive impairment, and depression). The mechanisms mediating these effects include the regulation of intratumoral angiogenesis, myokines, adipokines and their associated pathways, cancer metabolism, and anticancer immunity. Cancer rehabilitation guidelines advise cancer survivors to perform exercises. Many ongoing clinical trials have investigated the effects and mechanisms of exercise in cancer. This review supports the prescription of exercise for cancer prevention to sensitize cancer to anticancer therapy and manage associated symptoms and side effects after cancer diagnosis.
42The epidemiology of physical activity and cancer.PubMed
S A Oliveria, P J Christos
Ann N Y Acad Sci. 1997 Dec 29;833:79-90. doi: 10.1111/j.1749-6632.1997.tb48595.x.
Experimental studies in animals and epidemiological studies in human populations support an inverse association between exercise and the development of cancer. Physical activity has been shown to be protective against the development of breast and colon cancer and may also be important for other kinds of cancer such as that of the prostate. The proposed biological mechanisms for the physical activity--cancer association include exercise's effect on immune function, transit time of digestion, hormones, and body fat. There has been little research on physical activity and the effect on progression of cancer, although there are studies to suggest that it may slow the clinical course of the disease. Furthermore, exercise may be beneficial in the treatment of cancer through mood elevation, decreased loss of lean tissue, and increased quality of life. Much is still to be learned about the effect of exercise on cancer. The intensity, duration, frequency, and type of exercise that is relevant need to be clarified. As well, the time period during life when exercise is important has not been determined. It seems reasonable to conclude that exercise, a modifiable risk factor, is beneficial in preventing certain forms of cancer. Public health interventions may hold promise for cancer prevention.
43Molecular Mechanisms Linking Exercise to Cancer Prevention and Treatment.PubMed
Pernille Hojman, Julie Gehl, Jesper F Christensen, et al.
Cell Metab. 2018 Jan 9;27(1):10-21. doi: 10.1016/j.cmet.2017.09.015. Epub 2017 Oct 19.
The benefits of exercise training for cancer patients are becoming increasingly evident. Physical exercise has been shown to reduce cancer incidence and inhibit tumor growth. Here we provide the status of the current molecular understanding of the effect of exercise on cancer. We propose that exercise has a role in controlling cancer progression through a direct effect on tumor-intrinsic factors, interplay with whole-body exercise effects, alleviation of cancer-related adverse events, and improvement of anti-cancer treatment efficacy. These findings have wide-ranging societal implications, as this understanding may lead to changes in cancer treatment strategies.
44Effects of Exercise on Insulin, IGF Axis, Adipocytokines, and Inflammatory Markers in Breast Cancer Survivors: A Systematic Review and Meta-analysis.PubMed
Dong-Woo Kang, Junga Lee, Sang-Hoon Suh, et al.
Cancer Epidemiol Biomarkers Prev. 2017 Mar;26(3):355-365. doi: 10.1158/1055-9965.EPI-16-0602. Epub 2016 Oct 14.
Insulin, IGF axis, adiponectin, and inflammatory markers are associated with breast cancer. Given that physical activity improves prognosis of breast cancer survivors, we investigated the effects of exercise on these markers as potential mediators between physical activity and breast cancer. PubMed, EMBASE, CENTRAL, CINAHL, and SportDiscus were searched up to December 3, 2015, to identify randomized controlled trials (RCT) that investigated the effect of exercise on insulin, IGF axis, and cytokines in breast cancer survivors. Weighted mean difference (WMD) was calculated using either fixed- or random-effects models on the basis of the heterogeneity of the studies. A total of 18 studies involving 681 breast cancer survivors were included, and these numbers were reduced for individual biomarker analyses. We found that exercise significantly reduced fasting insulin levels [WMD, -3.46 μU/mL; 95% confidence interval (CI), -5.97 to -0.95; = 0.007]. Furthermore, potentially meaningful but statistically nonsignificant changes were observed in insulin resistance (WMD, -0.73; 95% CI, -0.54 to 0.13; = 0.23), adiponectin (WMD, 1.17 μg/mL; 95% CI, -0.87 to 3.20; = 0.26), and C-reactive protein (WMD, -1.10 mg/L; 95% CI, -2.39 to 0.20; = 0.10). Subgroup analyses showed that fasting insulin levels were significantly more impacted in studies in which intervention participants experienced a weight reduction (WMD, -7.10 μU/mL; 95% CI, -10.31 to -3.90; < 0.001). Exercise reduces fasting insulin levels in breast cancer survivors. This may be due to exercise-induced reductions in body weight. Practitioners and clinicians may better help breast cancer prognosis be improved through exercise, anticipating physiological effects on cancer. .
45[Physiologic and molecular mechanisms linking physical activity to cancer risk and progression].PubMed
C M Ulrich, J Wiskemann, K Steindorf
Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz. 2012 Jan;55(1):3-9. doi: 10.1007/s00103-011-1400-4.
Physical activity is associated with a reduced risk of colon, breast, endometrial, lung, and pancreatic cancer. Evidence for mediating molecular mechanisms from experimental studies substantially strengthens the causal inference for this relationship. Randomized controlled trials indicate that exercise affects metabolic profiles, including hormone levels (estrogen, insulin signaling), inflammation (e.g., C-reactive protein), and adipokine concentrations (e.g., leptin). The size of the effect depends frequently on concurrent changes in body composition. There is also initial evidence for effects on immune function, oxidative stress, and possibly DNA repair capacity. Finally, outdoor physical activity can directly increase 25(OH)-vitamin D levels, providing another potential mechanism for linking physical activity to cancer risk. Randomized controlled studies with biomarker measurements are essential to increase evidence for causality and to identify the most effective intervention strategies and pharmacologic targets.
46Association between metabolic syndrome, insulin resistance, and IGF-1 in breast cancer survivors of DIANA-5 study.PubMed
Mauro De Santi, Giosuè Annibalini, Giuseppe Marano, et al.
J Cancer Res Clin Oncol. 2023 Sep;149(11):8639-8648. doi: 10.1007/s00432-023-04755-6. Epub 2023 Apr 27.
PURPOSE: Circulating insulin-like growth factor-1 (IGF-1) is positively associated with the risk of BC recurrence, and is more frequently dysregulated in older people, especially in those with metabolic syndrome (MetS) and obesity. This study aimed to analyze the association between IGF-1 levels and indices of MetS and insulin resistance in BC survivors. METHODS: Baseline data of 563 BC survivors enrolled in the DIet and ANdrogen-5 (DIANA-5; NCT05019989) study were analyzed. RESULTS: Lower circulating IGF-1 levels in subjects with MetS than in those without MetS were found. After stratification of the patients according to the diagnosis of MetS, we highlighted that the insulin was the main predictor of elevated IGF-1 levels only in subjects without MetS. Moreover, we found an interaction between high-density lipoprotein cholesterol (HDL-C), glycemia, and IGF-1 levels, showing a positive correlation between HDL-C and IGF-1, especially in subjects with higher values of glycemia and without a diagnosis of MetS. CONCLUSIONS: While IGF-1 levels appear to be much more impaired in subjects diagnosed with MetS, in non-MetS subjects, IGF-1 levels may respond better to metabolic parameters and lifestyle changes. Further studies are needed to analyze the role of physical activity and/or dietary intervention in modulating IGF-1 concentrations in BC survivors. IMPLICATIONS FOR CANCER SURVIVORS: These results could have important clinical implications for planning customized strategies aimed at modulating IGF-1 levels in BC survivors. In fact, while the IGF-1 system seems to be much more compromised in subjects with a diagnosis of MetS, in noMetS subjects, IGF-1 levels could better respond to lifestyle changes.
47Obesity, metabolic syndrome, and cancer: pathophysiological and therapeutic associations.PubMed
Nikoletta Mili, Stavroula A Paschou, Dimitrios G Goulis, et al.
Endocrine. 2021 Dec;74(3):478-497. doi: 10.1007/s12020-021-02884-x. Epub 2021 Oct 8.
Overweight, obesity, and metabolic syndrome (MetS) have become epidemic conditions affecting 39%, 13%, and 20% of the population respectively. The aim of this article is to review the literature on the association of obesity and MetS with the risk of cancer. We also explore the effect of lifestyle modifications, such as diet, physical activity, and antidiabetic medications, on cancer incidence. Increased body mass index (BMI) has been associated with a multitude of site-specific cancers, reaching relative risk (RR) 1.54 [95% confidence interval (CI) 1.47-1.61] per 5 unit increase for endometrial cancer, as well as with overall cancer risk (RR 1.03, 95% CI 1.02-1.05). Central adiposity measured by waist circumference or waist-to-hip ratio has been suggested as a stronger predictor than BMI for several cancers, such as colorectal cancer. Metabolic Syndrome has been consistently and positively associated with the risk of very common cancers like colorectal (RR 1.34, 95% CI 1.24-1.44), endometrial (RR 1.62, 95% CI 1.26-2.07) and postmenopausal breast cancer (RR 2.01, 95% CI 1.55-2.60). Hyperglycemia and subsequently T2DM have been also shown to increase the risk of cancer. Nevertheless, these risk factors are modifiable and therefore implementing lifestyle modifications could prevent an important number of cancer cases. Adherence to cancer prevention guidelines, including maintaining a healthy weight, having regular physical exercise (RR 0.58-0.90 for different cite specific cancers) and following a healthy dietary pattern (RR 0.74-0.94 for different cite specific cancers) have a protective effect on the risk of cancer. The strength of this review is the presentation of the best evidence, as the data derive mainly from meta-analyses. Public health policies should focus on the modification of risk factors and future research is needed to reveal the pathophysiological links between these risk factors and cancer to develop more efficient prevention and treatment strategies.
48Antipsychotic-Induced Metabolic Syndrome: A Review.PubMed
Pelumi Samuel Akinola, Isabelle Tardif, Jacinthe Leclerc
Metab Syndr Relat Disord. 2023 Aug;21(6):294-305. doi: 10.1089/met.2023.0003. Epub 2023 Jun 22.
Schizophrenia, a serious psychiatric disorder, is among the top 10 global causes of disability and affects nearly 1% of the world population. Antipsychotics constitute the best treatment for patients with schizophrenia, however, this treatment class carries a high risk of metabolic syndrome, including lipid abnormalities. Indeed, the risk of metabolic syndrome would be increased in the population with schizophrenia compared to the general population. The objective is to summarize the prevalence, the mechanisms, and the potential treatments of antipsychotic-induced metabolic syndrome. This is a narrative review of the literature. We searched the electronic database Medline, accessed through PubMed, to find studies that investigated the prevalence and treatments of metabolic syndrome in the adult population using antipsychotics. The prevalence of metabolic syndrome in patients treated with antipsychotics ranges from 37% to 63%. Antipsychotic iatrogenic effects include weight gain/increased waist circumference, dyslipidemia, insulin resistance/type 2 diabetes, and hypertension. Clozapine and olanzapine are reported to precipitate the onset of metabolic syndrome features. In patients with metabolic syndrome, an antipsychotic with less metabolic side effects such as lurasidone, lumateperone, ziprasidone, and aripiprazole should be prioritized. Unlike medications, aerobic exercise and dietetic counseling were found to be efficient as the nonpharmacologic treatment of antipsychotic-induced metabolic syndrome. Few pharmacological treatments were proven effective against weight gain in this patient population. The risk of metabolic syndrome induced by antipsychotics should be early recognized and closely monitored. Primary and secondary prevention of metabolic syndrome or onset of its feature might help reduce the risk of death for patients using antipsychotics.
49Chronic Inflammation as an Immunological Abnormality and Effectiveness of Exercise.PubMed
Katsuhiko Suzuki
Biomolecules. 2019 Jun 7;9(6):223. doi: 10.3390/biom9060223.
Reduced levels of physical activity in people's daily lives cause the development of metabolic syndromes or age-related disorders. Chronic inflammation is now understood to be an underlying pathological condition in which inflammatory cells such as neutrophils and monocyte/macrophages infiltrate into fat and other tissues and accumulate when people become obese due to overeating and/or physical inactivity. Pro-inflammatory mediators such as cytokines that are secreted in excess from inflammatory cells will not only lead to the development of arteriosclerosis when they chronically affect blood vessels but also bring tissue degeneration and/or dysfunction to various organs. Chronic inflammation is also involved in sarcopenia that brings hypofunction in the elderly, dementia, osteoporosis, or cancer and negatively affects many chronic diseases and people's healthy life expectancy. In this paper, outlines of such studies are introduced in terms of homeostatic inflammation, which occurs chronically due to the innate immune system and its abnormalities, while focusing on the efficacy of exercise from aspects of immunology and oxidative stress. The preventative effects of functional food ingredients in combination with exercise are also introduced and described. The challenges and future directions in understanding the role of exercise in the control of chronic inflammation are discussed.
50Exercise and cancer: from "healthy" to "therapeutic"?PubMed
Manja Idorn, Per Thor Straten
Cancer Immunol Immunother. 2017 May;66(5):667-671. doi: 10.1007/s00262-017-1985-z. Epub 2017 Mar 21.
Exercise improves functional capacity and patient-reported outcomes across a range of cancer diagnoses. The mechanisms behind this protection have been largely unknown, but exercise-mediated changes in body composition, sex hormone levels, systemic inflammation, and immune cell function have been suggested to play a role. We recently demonstrated that voluntary exercise leads to an influx of immune cells in tumors, and a more than 60% reduction in tumor incidence and growth across several mouse models. Given the common mechanisms of immune cell mobilization in mouse and man during exercise, we hypothesize that this link between exercise and the immune system can be exploited in cancer therapy in particular in combination with immunotherapy. Thus, we believe that exercise may not just be "healthy" but may in fact be therapeutic.
51Hazardous compounds in tobacco smoke.PubMed
Reinskje Talhout, Thomas Schulz, Ewa Florek, et al.
Int J Environ Res Public Health. 2011 Feb;8(2):613-28. doi: 10.3390/ijerph8020613. Epub 2011 Feb 23.
Tobacco smoke is a toxic and carcinogenic mixture of more than 5,000 chemicals. The present article provides a list of 98 hazardous smoke components, based on an extensive literature search for known smoke components and their human health inhalation risks. An electronic database of smoke components containing more than 2,200 entries was generated. Emission levels in mainstream smoke have been found for 542 of the components and a human inhalation risk value for 98 components. As components with potential carcinogenic, cardiovascular and respiratory effects have been included, the three major smoke-related causes of death are all covered by the list. Given that the currently used Hoffmann list of hazardous smoke components is based on data from the 1990s and only includes carcinogens, it is recommended that the current list of 98 hazardous components is used for regulatory purposes instead. To enable risk assessment of components not covered by this list, thresholds of toxicological concern (TTC) have been established from the inhalation risk values found: 0.0018 μg day(-1) for all risks, and 1.2 μg day(-1) for all risks excluding carcinogenicity, the latter being similar to previously reported inhalation TTCs.
52Tobacco and cardiovascular health.PubMed
Prajeena Mainali, Sadip Pant, Alexis Phillip Rodriguez, et al.
Cardiovasc Toxicol. 2015 Apr;15(2):107-16. doi: 10.1007/s12012-014-9280-0.
Tobacco consumption has been inextricably intertwined with society and its evolution. At one time, centuries ago, thought to be a sign of refinement and nobility, fortunately, this perception has been changing worldwide. Currently, this change in perception has been so dramatic that laws are enacted to limit tobacco exposure through second-hand smokers. Countless studies continue to emerge on tobacco's healthcare toll to the point that we now consider indisputable facts that smokers have a higher incidence of coronary artery disease, peripheral vascular disease, chronic obstructive pulmonary disease, stroke, among many others. However, there are other less well-known emerging facts that still require close attention such as the effect on the immune and hematopoietic systems. Tobacco smoke is injurious to all major organs in our bodies. With over 30 known carcinogens, it should not be surprising that it affects all aspects of human health. In this chapter, we will focus on the effects of tobacco on cardiovascular health.
53Antioxidant Systems, lncRNAs, and Tunneling Nanotubes in Cell Death Rescue from Cigarette Smoke Exposure.PubMed
Jose Lorenzo M Ferrer, Reynaldo L Garcia
Cells. 2022 Jul 23;11(15):2277. doi: 10.3390/cells11152277.
Cigarette smoke is a rich source of carcinogens and reactive oxygen species (ROS) that can damage macromolecules including DNA. Repair systems can restore DNA integrity. Depending on the duration or intensity of stress signals, cells may utilize various survival and adaptive mechanisms. ROS levels are kept in check through redundant detoxification processes controlled largely by antioxidant systems. This review covers and expands on the mechanisms available to cigarette smoke-exposed cancer cells for restoring the redox balance. These include multiple layers of transcriptional control, each of which is posited to be activated upon reaching a particular stress threshold, among them the pathway, the and pathways, and, finally, , which triggers apoptosis if extreme toxicity is reached. The review also discusses long noncoding RNAs, which have been implicated recently in regulating oxidative stress-with roles in ROS detoxification, the inflammatory response, oxidative stress-induced apoptosis, and mitochondrial oxidative phosphorylation. Lastly, the emerging roles of tunneling nanotubes in providing additional mechanisms for metabolic rescue and the regulation of redox imbalance are considered, further highlighting the expanded redox reset arsenal available to cells.
5415th Report on Carcinogens.PubMed
Rep Carcinog. 2021 Dec 21;15. doi: 10.22427/NTP-OTHER-1003.
BACKGROUND: The Report on Carcinogens (RoC) is a congressionally mandated, science-based public health document that the National Toxicology Program (NTP) prepares for the U.S. Department of Health and Human Services Secretary. The latest cumulative report, the 15th RoC, includes 256 listings of substances - chemical, physical, and biological agents; mixtures; and exposure circumstances - that are known or reasonably anticipated to cause cancer in humans. For each listed substance, a profile, i.e., a short synopsis of key studies on cancer, exposure data, and regulations to limit exposure, is prepared. For readers' convenience, profiles for related exposures or selected members of chemical families often are grouped. The report also includes supplemental information to provide context for the listings, including an introduction, glossary, indexes, and review process. To determine whether a substance should be listed in the RoC, a rigorous assessment is conducted of publicly available, relevant cancer studies in humans and animals and mechanistic studies using systematic review methods and established criteria. The listed substances include the following. A: Acetaldehyde; 2-Acetylaminofluorene; Acrylamide; Acrylonitrile; Adriamycin; Aflatoxins; Alcoholic Beverage Consumption; 2-Aminoanthraquinone; o-Aminoazotoluene; 4-Aminobiphenyl; 1-Amino-2,4-dibromoanthraquinone; 2-Amino-3,4-dimethylimidazo[4,5-f]quinoline (see Heterocyclic Amines [Selected]); 2-Amino-3,8-dimethylimidazo[4,5-f]quinoxaline (see Heterocyclic Amines [Selected]); 1-Amino-2-methylanthraquinone; 2-Amino-3-methylimidazo[4,5-f]quinoline (see Heterocyclic Amines [Selected]); 2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (see Heterocyclic Amines [Selected]); Amitrole; Analgesic Mixtures Containing Phenacetin (see Phenacetin and Analgesic Mixtures Containing Phenacetin); o-Anisidine and Its Hydrochloride; Antimony Trioxide; Aristolochic Acids; Arsenic and Inorganic Arsenic Compounds; Asbestos; Azacitidine; Azathioprine. B: Basic Red 9 Monohydrochloride; Benz[a]anthracene (see Polycyclic Aromatic Hydrocarbons: 15 Listings); Benzene; Benzidine (see Benzidine and Dyes Metabolized to Benzidine); Benzo[b]fluoranthene (see Polycyclic Aromatic Hydrocarbons: 15 Listings); Benzo[j]fluoranthene (see Polycyclic Aromatic Hydrocarbons: 15 Listings); Benzo[k]fluoranthene (see Polycyclic Aromatic Hydrocarbons: 15 Listings); Benzo[a]pyrene (see Polycyclic Aromatic Hydrocarbons: 15 Listings); Benzotrichloride; Beryllium and Beryllium Compounds; 2,2-Bis(bromomethyl)-1,3-propanediol (Technical Grade); Bis(chloroethyl) Nitrosourea (see Nitrosourea Chemotherapeutic Agents); Bis(chloromethyl) Ether and Technical-Grade Chloromethyl Methyl Ether; Bromochloroacetic Acid (see Haloacetic Acids Found as Water Disinfection By-products [Selected]); Bromodichloroacetic Acid (see Haloacetic Acids Found as Water Disinfection By-products [Selected]); Bromodichloromethane; 1-Bromopropane; 1,3-Butadiene; 1,4-Butanediol Dimethanesulfonate; Butylated Hydroxyanisole. C: Cadmium and Cadmium Compounds; Captafol; Carbon Tetrachloride; Ceramic Fibers (Respirable Size); Chlorambucil; Chloramphenicol; Chlorendic Acid; Chlorinated Paraffins (C12, 60% Chlorine); Chlorodibromoacetic Acid (see Haloacetic Acids Found as Water Disinfection By-products [Selected]); 1-(2-Chloroethyl)-3-cyclohexyl-1-nitrosourea (see Nitrosourea Chemotherapeutic Agents); 1-(2-Chloroethyl)-3-(4-methylcyclohexyl)-1-nitrosourea (see Nitrosourea Chemotherapeutic Agents); Chloroform; 3-Chloro-2-methylpropene; 4-Chloro-o-phenylenediamine; Chloroprene; p-Chloro-o-toluidine and Its Hydrochloride; Chlorozotocin (see Nitrosourea Chemotherapeutic Agents); Chromium Hexavalent Compounds; Cisplatin; Coal Tars and Coal-Tar Pitches; Cobalt and Cobalt Compounds that Release Cobalt Ions In Vivo (see Cobalt-Related Exposures); Cobalt-Tungsten Carbide: Powders and Hard Metals (see Cobalt-Related Exposures); Coke-Oven Emissions; p-Cresidine; Cumene; Cupferron; Cyclophosphamide; Cyclosporin A. D: Dacarbazine; Danthron; 2,4-Diaminoanisole Sulfate; 2,4-Diaminotoluene; Diazoaminobenzene; Dibenz[a,h]acridine (see Polycyclic Aromatic Hydrocarbons: 15 Listings); Dibenz[a,j]acridine (see Polycyclic Aromatic Hydrocarbons: 15 Listings); Dibenz[a,h]anthracene (see Polycyclic Aromatic Hydrocarbons: 15 Listings); 7H-Dibenzo[c,g]carbazole (see Polycyclic Aromatic Hydrocarbons: 15 Listings); Dibenzo[a,e]pyrene (see Polycyclic Aromatic Hydrocarbons: 15 Listings); Dibenzo[a,h]pyrene (see Polycyclic Aromatic Hydrocarbons: 15 Listings); Dibenzo[a,i]pyrene (see Polycyclic Aromatic Hydrocarbons: 15 Listings); Dibenzo[a,l]pyrene (see Polycyclic Aromatic Hydrocarbons: 15 Listings); Dibromoacetic Acid (see Haloacetic Acids Found as Water Disinfection By-products [Selected]); 1,2-Dibromo-3-chloropropane; 1,2-Dibromoethane; 2,3-Dibromo-1-propanol; Dichloroacetic Acid (see Haloacetic Acids Found as Water Disinfection By-products [Selected]); 1,4-Dichlorobenzene; 3,3'-Dichlorobenzidine and Its Dihydrochloride; Dichlorodiphenyltrichloroethane; 1,2-Dichloroethane; Dichloromethane; 1,3-Dichloropropene (Technical Grade); Diepoxybutane; Diesel Exhaust Particulates; Di(2-ethylhexyl) Phthalate; Diethylstilbestrol; Diethyl Sulfate; Diglycidyl Resorcinol Ether; 3,3'-Dimethoxybenzidine (see 3,3'-Dimethoxybenzidine and Dyes Metabolized to 3,3'-Dimethoxybenzidine); 4-Dimethylaminoazobenzene; 3,3'-Dimethylbenzidine (see 3,3'-Dimethylbenzidine and Dyes Metabolized to 3,3'-Dimethylbenzidine); Dimethylcarbamoyl Chloride; 1,1-Dimethylhydrazine; Dimethyl Sulfate; Dimethylvinyl Chloride; 1,6-Dinitropyrene (see Nitroarenes [Selected]); 1,8-Dinitropyrene (see Nitroarenes [Selected]); 1,4-Dioxane; Disperse Blue 1; Dyes Metabolized to Benzidine (Benzidine Dye Class) (see Benzidine and Dyes Metabolized to Benzidine); Dyes Metabolized to 3,3'-Dimethoxybenzidine (3,3'-Dimethoxybenzidine Dye Class) (see 3,3'-Dimethoxybenzidine and Dyes Metabolized to 3,3'-Dimethoxybenzidine); Dyes Metabolized to 3,3'-Dimethylbenzidine (3,3'-Dimethylbenzidine Dye Class) (see 3,3'-Dimethylbenzidine and Dyes Metabolized to 3,3'-Dimethylbenzidine). E: Epichlorohydrin; Epstein-Barr Virus (see Viruses: Eight Listings) Erionite; Estrogens, Steroidal; Ethylene Oxide; Ethylene Thiourea; Ethyl Methanesulfonate. F: Formaldehyde; Furan. G: Glass Wool Fibers (Inhalable), Certain; Glycidol. H: Hepatitis B Virus (see Viruses: Eight Listings); Hepatitis C Virus (see Viruses: Eight Listings); Helicobacter pylori (Chronic Infection); Hexachlorobenzene; Hexachloroethane; Hexamethylphosphoramide; Human Immunodeficiency Virus Type 1 (see Viruses: Eight Listings); Human Papillomaviruses: Some Genital-Mucosal Types (see Viruses: Eight Listings); Human T-cell Lymphotropic Virus Type 1 (see Viruses: Eight Listings); Hydrazine and Hydrazine Sulfate; Hydrazobenzene. I: Indeno[1,2,3-cd]pyrene (see Polycyclic Aromatic Hydrocarbons: 15 Listings); Iron Dextran Complex; Isoprene. K: Kaposi Sarcoma-Associated Herpesvirus (see Viruses: Eight Listings); Kepone. L: Lead and Lead Compounds; Lindane, Hexachlorocyclohexane (Technical Grade), and Other Hexachlorocyclohexane Isomers. M: Melphalan; Merkel Cell Polyomavirus (see Viruses: Eight Listings); Methoxsalen with Ultraviolet A Therapy; 2-Methylaziridine; 5-Methylchrysene (see Polycyclic Aromatic Hydrocarbons: 15 Listings); 4,4'-Methylenebis(2-chloroaniline); 4,4'-Methylenebis(N,N-dimethyl)benzenamine; 4,4'-Methylenedianiline and Its Dihydrochloride; Methyleugenol; Methyl Methanesulfonate; N-Methyl-N'-Nitro-N-Nitrosoguanidine (see N-Nitrosamines: 15 Listings); Metronidazole; Michler's Ketone; Mineral Oils: Untreated and Mildly Treated; Mirex; Mustard Gas. N: Naphthalene; 2-Naphthylamine; Neutrons (see Ionizing Radiation); Nickel Compounds (see Nickel Compounds and Metallic Nickel); Nickel, Metallic (see Nickel Compounds and Metallic Nickel); Nitrilotriacetic Acid; o-Nitroanisole; Nitrobenzene; 6-Nitrochrysene (see Nitroarenes [Selected]); Nitrofen; Nitrogen Mustard Hydrochloride; Nitromethane; 2-Nitropropane; 1-Nitropyrene (see Nitroarenes [Selected]); 4-Nitropyrene (see Nitroarenes [Selected]); N-Nitrosodi-n-butylamine (see N-Nitrosamines: 15 Listings); N-Nitrosodiethanolamine (see N-Nitrosamines: 15 Listings); N-Nitrosodiethylamine (see N-Nitrosamines: 15 Listings); N-Nitrosodimethylamine (see N-Nitrosamines: 15 Listings); N-Nitrosodi-n-propylamine (see N-Nitrosamines: 15 Listings); N-Nitroso-N-ethylurea (see N-Nitrosamines: 15 Listings); 4-(N-Nitrosomethylamino)-1-(3-pyridyl)-1-butanone (see N-Nitrosamines: 15 Listings); N-Nitroso-N-methylurea (see N-Nitrosamines: 15 Listings); N-Nitrosomethylvinylamine (see N-Nitrosamines: 15 Listings); N-Nitrosomorpholine (see N-Nitrosamines: 15 Listings); N-Nitrosonornicotine (see N-Nitrosamines: 15 Listings); N-Nitrosopiperidine (see N-Nitrosamines: 15 Listings); N-Nitrosopyrrolidine (see N-Nitrosamines: 15 Listings); N-Nitrososarcosine (see N-Nitrosamines: 15 Listings); o-Nitrotoluene; Norethisterone. O: Ochratoxin A; 4,4'-Oxydianiline; Oxymetholone. P: Pentachlorophenol and By-products of Its Synthesis; Phenacetin (see Phenacetin and Analgesic Mixtures Containing Phenacetin); Phenazopyridine Hydrochloride; Phenolphthalein; Phenoxybenzamine Hydrochloride; Phenytoin and Phenytoin Sodium; Polybrominated Biphenyls; Polychlorinated Biphenyls; Procarbazine and Its Hydrochloride; Progesterone; 1,3-Propane Sultone; β-Propiolactone; Propylene Oxide; Propylthiouracil. R: Radon (see Ionizing Radiation); Reserpine; Riddelliine. S: Safrole; Selenium Sulfide; Silica, Crystalline (Respirable Size); Solar Radiation (see Ultraviolet Radiation Related Exposures); Soots; Streptozotocin (see Nitrosourea Chemotherapeutic Agents); Strong Inorganic Acid Mists Containing Sulfuric Acid; Styrene; Styrene-7,8-oxide; Sulfallate; Sunlamps or Sunbeds, Exposure to (see Ultraviolet Radiation Related Exposures). T: Tamoxifen; 2,3,7,8-Tetrachlorodibenzo-p-dioxin; Tetrachloroethylene; Tetrafluoroethylene; Tetranitromethane; Thioacetamide; 4,4'-Thiodianiline; Thiotepa; Thiourea; Thorium Dioxide (see Ionizing Radiation); Tobacco Smoke, Environmental (see Tobacco-Related Exposures); Tobacco, Smokeless (see Tobacco-Related Exposures); Tobacco Smoking (see Tobacco-Related Exposures); Toluene Diisocyanates; o-Toluidine; Toxaphene; Tribromoacetic Acid (see Haloacetic Acids Found as Water Disinfection By-products [Selected]); Trichloroethylene; 2,4,6-Trichlorophenol; 1,2,3-Trichloropropane; Tris(2,3-dibromopropyl) Phosphate. U: Urethane; UVA (see Ultraviolet-Radiation-Related Exposures); UVB (see Ultraviolet-Radiation-Related Exposures); UVC (see Ultraviolet-Radiation-Related Exposures); UVR, Broad-Spectrum (see Ultraviolet Radiation Related Exposures). V: Vinyl Bromide (see Vinyl Halides [Selected]); Vinyl Chloride (see Vinyl Halides [Selected]); 4-Vinyl-1-cyclohexene Diepoxide; Vinyl Fluoride (see Vinyl Halides [Selected]). W: Wood Dust. X: X-Radiation and Gamma Radiation (see Ionizing Radiation).
55Strong excess risk of pancreatic cancer for low frequency and duration of cigarette smoking: A comprehensive review and meta-analysis.PubMed
Alessandra Lugo, Giulia Peveri, Cristina Bosetti, et al.
Eur J Cancer. 2018 Nov;104:117-126. doi: 10.1016/j.ejca.2018.09.007. Epub 2018 Oct 19.
AIM: Cigarette smoking is an established risk factor for pancreatic cancer but an updated quantification of the association is lacking. Our aim is to provide the most accurate and updated estimate of the dose-response relationships between cigarette smoking and pancreatic cancer risk. METHODS: Using an innovative approach for the identification of original publications, we conducted a systematic review and meta-analysis of epidemiological studies published on the issue up to April 2017. Random effects models were used to provide pooled estimates for the cigarette smoking status; dose-risk relationships were evaluated using one-stage random effects models with restricted cubic splines. RESULTS: Seventy-eight studies were included, providing a pooled relative risk (RR) of pancreatic cancer of 1.8 (95% confidence interval, CI: 1.7-1.9) for the current and 1.2 (95% CI: 1.1-1.2) for the former vs. never smokers. A sharp increase in pancreatic cancer risk was found already with a low number of cigarettes and up to 30 cigarettes/day (RR 2.2, 95% CI: 1.9-2.4). Similarly, the risk of pancreatic cancer steady increased after a few years of smoking up to 30 years (RR 1.8, 95% CI: 1.6-2.0). The risk rapidly decreased with increasing time since quitting and was 0.6 (95% CI: 0.5-0.7, for the former vs. current smokers) after 20 years of quitting. CONCLUSIONS: The present meta-analysis indicates that pancreatic cancer risk sharply increases with a low number of cigarettes or after a few years of smoking and that it rapidly decreases a few years after cessation, although it takes almost 20 years to reach that of never smokers.
56Nicotine replacement therapy versus control for smoking cessation.PubMed
Jamie Hartmann-Boyce, Samantha C Chepkin, Weiyu Ye, et al.
Cochrane Database Syst Rev. 2018 May 31;5(5):CD000146. doi: 10.1002/14651858.CD000146.pub5.
BACKGROUND: Nicotine replacement therapy (NRT) aims to temporarily replace much of the nicotine from cigarettes to reduce motivation to smoke and nicotine withdrawal symptoms, thus easing the transition from cigarette smoking to complete abstinence. OBJECTIVES: To determine the effectiveness and safety of nicotine replacement therapy (NRT), including gum, transdermal patch, intranasal spray and inhaled and oral preparations, for achieving long-term smoking cessation, compared to placebo or 'no NRT' interventions. SEARCH METHODS: We searched the Cochrane Tobacco Addiction Group trials register for papers mentioning 'NRT' or any type of nicotine replacement therapy in the title, abstract or keywords. Date of most recent search is July 2017. SELECTION CRITERIA: Randomized trials in people motivated to quit which compared NRT to placebo or to no treatment. We excluded trials that did not report cessation rates, and those with follow-up of less than six months, except for those in pregnancy (where less than six months, these were excluded from the main analysis). We recorded adverse events from included and excluded studies that compared NRT with placebo. Studies comparing different types, durations, and doses of NRT, and studies comparing NRT to other pharmacotherapies, are covered in separate reviews. DATA COLLECTION AND ANALYSIS: Screening, data extraction and 'Risk of bias' assessment followed standard Cochrane methods. The main outcome measure was abstinence from smoking after at least six months of follow-up. We used the most rigorous definition of abstinence for each trial, and biochemically validated rates if available. We calculated the risk ratio (RR) for each study. Where appropriate, we performed meta-analysis using a Mantel-Haenszel fixed-effect model. MAIN RESULTS: We identified 136 studies; 133 with 64,640 participants contributed to the primary comparison between any type of NRT and a placebo or non-NRT control group. The majority of studies were conducted in adults and had similar numbers of men and women. People enrolled in the studies typically smoked at least 15 cigarettes a day at the start of the studies. We judged the evidence to be of high quality; we judged most studies to be at high or unclear risk of bias but restricting the analysis to only those studies at low risk of bias did not significantly alter the result. The RR of abstinence for any form of NRT relative to control was 1.55 (95% confidence interval (CI) 1.49 to 1.61). The pooled RRs for each type were 1.49 (95% CI 1.40 to 1.60, 56 trials, 22,581 participants) for nicotine gum; 1.64 (95% CI 1.53 to 1.75, 51 trials, 25,754 participants) for nicotine patch; 1.52 (95% CI 1.32 to 1.74, 8 trials, 4439 participants) for oral tablets/lozenges; 1.90 (95% CI 1.36 to 2.67, 4 trials, 976 participants) for nicotine inhalator; and 2.02 (95% CI 1.49 to 2.73, 4 trials, 887 participants) for nicotine nasal spray. The effects were largely independent of the definition of abstinence, the intensity of additional support provided or the setting in which the NRT was offered. A subset of six trials conducted in pregnant women found a statistically significant benefit of NRT on abstinence close to the time of delivery (RR 1.32, 95% CI 1.04 to 1.69; 2129 participants); in the four trials that followed up participants post-partum the result was no longer statistically significant (RR 1.29, 95% CI 0.90 to 1.86; 1675 participants). Adverse events from using NRT were related to the type of product, and include skin irritation from patches and irritation to the inside of the mouth from gum and tablets. Attempts to quantitatively synthesize the incidence of various adverse effects were hindered by extensive variation in reporting the nature, timing and duration of symptoms. The odds ratio (OR) of chest pains or palpitations for any form of NRT relative to control was 1.88 (95% CI 1.37 to 2.57, 15 included and excluded trials, 11,074 participants). However, chest pains and palpitations were rare in both groups and serious adverse events were extremely rare. AUTHORS' CONCLUSIONS: There is high-quality evidence that all of the licensed forms of NRT (gum, transdermal patch, nasal spray, inhalator and sublingual tablets/lozenges) can help people who make a quit attempt to increase their chances of successfully stopping smoking. NRTs increase the rate of quitting by 50% to 60%, regardless of setting, and further research is very unlikely to change our confidence in the estimate of the effect. The relative effectiveness of NRT appears to be largely independent of the intensity of additional support provided to the individual. Provision of more intense levels of support, although beneficial in facilitating the likelihood of quitting, is not essential to the success of NRT. NRT often causes minor irritation of the site through which it is administered, and in rare cases can cause non-ischaemic chest pain and palpitations.
57Nicotine replacement therapy for smoking cessation.PubMed
Lindsay F Stead, Rafael Perera, Chris Bullen, et al.
Cochrane Database Syst Rev. 2012 Nov 14;11:CD000146. doi: 10.1002/14651858.CD000146.pub4.
BACKGROUND: The aim of nicotine replacement therapy (NRT) is to temporarily replace much of the nicotine from cigarettes to reduce motivation to smoke and nicotine withdrawal symptoms, thus easing the transition from cigarette smoking to complete abstinence. OBJECTIVES: The aims of this review were: To determine the effect of NRT compared to placebo in aiding smoking cessation, and to consider whether there is a difference in effect for the different forms of NRT (chewing gum, transdermal patches, oral and nasal sprays, inhalers and tablets/lozenges) in achieving abstinence from cigarettes. To determine whether the effect is influenced by the dosage, form and timing of use of NRT; the intensity of additional advice and support offered to the smoker; or the clinical setting in which the smoker is recruited and treated. To determine whether combinations of NRT are more likely to lead to successful quitting than one type alone. To determine whether NRT is more or less likely to lead to successful quitting compared to other pharmacotherapies. SEARCH METHODS: We searched the Cochrane Tobacco Addiction Group trials register for papers mentioning 'NRT' or any type of nicotine replacement therapy in the title, abstract or keywords. Date of most recent search July 2012. SELECTION CRITERIA: Randomized trials in which NRT was compared to placebo or to no treatment, or where different doses of NRT were compared. We excluded trials which did not report cessation rates, and those with follow-up of less than six months. DATA COLLECTION AND ANALYSIS: We extracted data in duplicate on the type of participants, the dose, duration and form of nicotine therapy, the outcome measures, method of randomization, and completeness of follow-up. The main outcome measure was abstinence from smoking after at least six months of follow-up. We used the most rigorous definition of abstinence for each trial, and biochemically validated rates if available. We calculated the risk ratio (RR) for each study. Where appropriate, we performed meta-analysis using a Mantel-Haenszel fixed-effect model. MAIN RESULTS: We identified 150 trials; 117 with over 50,000 participants contributed to the primary comparison between any type of NRT and a placebo or non-NRT control group. The risk ratio (RR) of abstinence for any form of NRT relative to control was 1.60 (95% confidence interval [CI] 1.53 to 1.68). The pooled RRs for each type were 1.49 (95% CI 1.40 to 1.60, 55 trials) for nicotine gum; 1.64 (95% CI 1.52 to 1.78, 43 trials) for nicotine patch; 1.95 (95% CI 1.61 to 2.36, 6 trials) for oral tablets/lozenges; 1.90 (95% CI 1.36 to 2.67, 4 trials) for nicotine inhaler; and 2.02 (95% CI 1.49 to 2.73, 4 trials) for nicotine nasal spray. One trial of oral spray had an RR of 2.48 (95% CI 1.24 to 4.94). The effects were largely independent of the duration of therapy, the intensity of additional support provided or the setting in which the NRT was offered. The effect was similar in a small group of studies that aimed to assess use of NRT obtained without a prescription. In highly dependent smokers there was a significant benefit of 4 mg gum compared with 2 mg gum, but weaker evidence of a benefit from higher doses of patch. There was evidence that combining a nicotine patch with a rapid delivery form of NRT was more effective than a single type of NRT (RR 1.34, 95% CI 1.18 to 1.51, 9 trials). The RR for NRT used for a short period prior to the quit date was 1.18 (95% CI 0.98 to 1.40, 8 trials), just missing statistical significance, though the efficacy increased when we pooled only patch trials and when we removed one trial in which confounding was likely. Five studies directly compared NRT to a non-nicotine pharmacotherapy, bupropion; there was no evidence of a difference in efficacy (RR 1.01; 95% CI 0.87 to 1.18). A combination of NRT and bupropion was more effective than bupropion alone (RR 1.24; 95% CI 1.06 to 1.45, 4 trials). Adverse effects from using NRT are related to the type of product, and include skin irritation from patches and irritation to the inside of the mouth from gum and tablets. There is no evidence that NRT increases the risk of heart attacks. AUTHORS' CONCLUSIONS: All of the commercially available forms of NRT (gum, transdermal patch, nasal spray, inhaler and sublingual tablets/lozenges) can help people who make a quit attempt to increase their chances of successfully stopping smoking. NRTs increase the rate of quitting by 50 to 70%, regardless of setting. The effectiveness of NRT appears to be largely independent of the intensity of additional support provided to the individual. Provision of more intense levels of support, although beneficial in facilitating the likelihood of quitting, is not essential to the success of NRT.
58Combined use of nicotine patch and gum in smoking cessation: a placebo-controlled clinical trial.PubMed
M Kornitzer, M Boutsen, M Dramaix, et al.
Prev Med. 1995 Jan;24(1):41-7. doi: 10.1006/pmed.1995.1006.
BACKGROUND: Smoking is considered as an addiction to nicotine for most subjects consuming 10 cigarettes or more per day. Hence, nicotine replacement therapy by way of gum, patch, or spray has been advocated. The rationale of this study is to evaluate the possible beneficial effects of adding nicotine gum to the routine of subjects using the nicotine patch. The effect of the nicotine patch against the placebo, both groups receiving placebo nicotine gum, has also been assessed. METHODS: Healthy subjects (374) were randomized at their work-setting in a 1-year double-blind placebo-controlled trial: 149 subjects to active nicotine patch + active gum (group 1), 150 to active nicotine patch + placebo gum (group 2), and 75 to placebo patch + gum (group 3). Treatment duration was 12 weeks with a 16-hr transdermal patch of 15 mg, followed by a 6 + 6-weeks weaning period on respectively 10 and 5 mg patches. Gum use was not restricted during the first 6 months, with recommendations to use at least four pieces a day. A strict definition of smoking abstinence was used in this study, which did not allow smoking any cigarette after Week 1. Nonsmoking status at each visit, as reported by the subjects, was verified by CO below 10 ppm in expired air. RESULTS: Abstinence rates in group 1 against group 2 were 34.2 and 22.7% (P = 0.027) at 12 weeks, 27.5 and 15.3% (P = 0.010) at 24 weeks, and 18.1 and 12.7% (P = 0.191) at 52 weeks. In group 3, abstinence rates were 17.3, 14.7, and 13.3% respectively at 12, 24, and 52 weeks. Using logistic regression with adjustment for six baseline covariates, odds ratios for abstinence (with 95% CI) were computed. For group 1/group 2, OR at 12, 24, and 52 weeks were 1.72 (1.03-2.94) (P = 0.039), 2.04 (1.14-3.57) (P = 0.018), and 1.47 (0.76-2.76) (P = 0.125). No significant differences in OR were observed when comparing groups 2 and 3. Time to relapse is significantly longer in group 1 as compared to that of group 2 (P = 0.041), whereas no significant differences between groups 2 and 3 were observed. No significant differences between the three groups in systemic and local adverse drug events were observed. CONCLUSION: Adding active gum use to active patch use in subjects smoking 10 cigarettes or more a day increased abstinence rates, which are statistically significant up to 24 weeks.
59Risks and benefits of nicotine to aid smoking cessation in pregnancy.PubMed
D A Dempsey, N L Benowitz
Drug Saf. 2001;24(4):277-322. doi: 10.2165/00002018-200124040-00005.
Cigarette smoking during pregnancy is the single largest modifiable risk for pregnancy-related morbidity and mortality in the US. Addiction to nicotine prevents many pregnant women who wish to quit smoking from doing so. The safety and efficacy of nicotine replacement therapy (NRT) for smoking cessation during pregnancy have not been well studied. Nicotine is classified by the US Food and Drug Administration as a Pregnancy Category D drug. Animal studies indicate that nicotine adversely affects the developing fetal CNS, and nicotine effects on the brain may be involved in the pathophysiology of sudden infant death syndrome (SIDS). It has been assumed that the cardiovascular effects of nicotine resulting in reduced blood flow to the placenta (uteroplacental insufficiency) is the predominant mechanism of the reproductive toxicity of cigarette smoking during pregnancy. Short term high doses of nicotine in pregnant animals do adversely affect the maternal and fetal cardiovascular systems. However, studies of the acute effects of NRT in pregnant humans indicate that nicotine alone has minimal effects upon the maternal and fetal cardiovascular systems. Cigarette smoking delivers thousands of chemicals, some of which are well documented reproductive toxins (e.g. carbon monoxide and lead). A myriad of cellular and molecular biological abnormalities have been documented in placentas, fetuses, and newborns of pregnant women who smoke. The cumulative abnormalities produced by the various toxins in cigarette smoke are probably responsible for the numerous adverse reproductive outcomes associated with smoking. It is doubtful that the reproductive toxicity of cigarette smoking is primarily related to nicotine. We recommend the following. Efficacy trials of NRT as adjunctive therapy for smoking cessation during pregnancy should be conducted. The initial dose of nicotine in NRT should be similar to the dose of nicotine that the pregnant woman received from smoking. Intermittent-use formulations of NRT (gum, spray, inhaler) are preferred because the total dose of nicotine delivered to the fetus will be less than with continuous-use formulations (transdermal patch). A national registry for NRT use during pregnancy should be created to prospectively collect obstetrical outcome data from NRT efficacy trials and from individual use. The goal of this registry would be to determine the safety of NRT use during pregnancy, especially with respect to uncommon outcomes such as placental abruption. Finally, our review of the data indicate that minimal amounts of nicotine are excreted into breast milk and that NRT can be safely used by breast-feeding mothers.
60Nicotine transdermal patch and atypical antipsychotic medications for smoking cessation in schizophrenia.PubMed
T P George, D M Ziedonis, A Feingold, et al.
Am J Psychiatry. 2000 Nov;157(11):1835-42. doi: 10.1176/appi.ajp.157.11.1835.
OBJECTIVE: Schizophrenic patients have high rates of cigarette smoking. The authors compared the outcomes of two group psychotherapy programs for smoking cessation in patients with schizophrenia or schizoaffective disorder who were also treated with the nicotine transdermal patch and with either atypical or typical antipsychotic medications. METHOD: Forty-five subjects were randomly assigned to 1) the group therapy program of the American Lung Association (N=17) or 2) a specialized group therapy program for smokers with schizophrenia (N=28) that emphasized motivational enhancement, relapse prevention, social skills training, and psychoeducation. All subjects participated in 10 weeks of treatment with the nicotine transdermal patch (21 mg/day) and 10 weekly group therapy sessions and continued to receive their prestudy atypical (N=18) or typical (N=27) antipsychotic medications. Outcome variables included treatment retention, rate of smoking abstinence, and expired-breath carbon monoxide level. RESULTS: Smoking abstinence rates did not differ in the two group therapy programs. However, atypical antipsychotic agents, in combination with the nicotine transdermal patch, significantly enhanced the rate of smoking cessation (55.6% in the atypical agent group versus 22.2% in the typical group), which was reflected by a significant effect of atypical versus typical agents on carbon monoxide levels. Risperidone and olanzapine were associated with the highest quit rates. CONCLUSIONS: The results suggest that 1) smoking cessation rates with the nicotine transdermal patch are modest in schizophrenia, 2) specialized group therapy for schizophrenic patients is not significantly different from American Lung Association group therapy in its effect on smoking cessation, and 3) atypical agents may be superior to typical agents in combination with the nicotine transdermal patch for smoking cessation in schizophrenia.
61Alcohol use and prostate cancer risk in US blacks and whites.PubMed
R B Hayes, L M Brown, J B Schoenberg, et al.
Am J Epidemiol. 1996 Apr 1;143(7):692-7. doi: 10.1093/oxfordjournals.aje.a008802.
Prostate cancer is the most common malignancy in US men (more than 165,000 cases per annum) and occurs substantially more frequently in blacks than in whites. The causes of this disease are, however, poorly understood. Alcohol consumption, which has been clearly related to malignancies of the upper aerodigestive tract, may also increase risk of cancer at other sites, including the prostate. The authors investigated alcohol use as a risk factor for prostate cancer among US blacks and whites. A population-based, case-control study was carried out among 981 men (479 blacks and 502 whites) with pathologically confirmed prostate cancer diagnosed between August 1, 1986, and April 30, 1989, and 1,315 controls (594 blacks and 721 whites) who resided in Atlanta, Georgia; Detroit, Michigan; and 10 counties in New Jersey, geographic areas covered by three population-based cancer registries. In-person interviews elicited information on alcohol use and other factors possibly related to prostate cancer. Compared with never-users, risk for prostate cancer increased with amount of alcohol drunk (chi2 (trend), p < 0.001), with significantly elevated risks seen for those who had 22-56 drinks per week (odds ratio = 1.4; 95% confidence interval 1.0-1.8) and 57 or more drinks per week (odds ratio = 1.9; 95% confidence interval 1.3-2.7). The finding was consistent among blacks (chi2 (trend), p < 0.01) and whites (chi2 (trend), p < 0.05), and among young and old subjects; it was not restricted to a specific type of alcoholic beverage. In this first large study among US blacks and whites, increased risk for prostate cancer was associated with increased alcohol use. The risk was similar for whites and blacks and could not be attributed to tobacco use or to a number of other potential confounders.
62Characteristics of consumers of alcohol-free and low-alcohol drinks in Great Britain: A cross-sectional study.PubMed
Parvati R Perman-Howe, John Holmes, Jamie Brown, et al.
Drug Alcohol Rev. 2024 Nov;43(7):1686-1697. doi: 10.1111/dar.13930. Epub 2024 Aug 21.
INTRODUCTION: The impact of alcohol-free and low-alcohol (no/lo) drinks on public health and health inequalities depends on who consumes them and how they are consumed. This study aimed to estimate: (i) the proportions of adults in Great Britain who consume no/lo drinks at different frequencies and in different settings; and (ii) the associations between no/lo drink consumption and individual characteristics. METHOD: Pooled data (N = 7691) from four waves of a repeat cross-sectional survey on alcohol use completed in 2022-2023 by adults (16+) resident in Great Britain were analysed using descriptive statistics and logistic regression models. RESULTS: In all, 31.3% of adults reported ever consuming no/lo drinks and 9.8% reported drinking them weekly. Ever consumption of no/lo drinks was associated with: being an increasing risk drinker of alcohol relative to not drinking (OR: 3.96, 95% CI 3.27-4.80), being aged 16-24 compared with 65+ (OR:1.29, 95% CI 1.07-1.57), having previously smoked compared with having never smoked (OR:1.19, 95% CI 1.05-1.34) and living in a rural rather than urban area (OR:1.14, 95% CI 1.00-1.29). It was less likely among those in lower social grades or with lower educational qualifications; those living in Yorkshire and the Humber, and Scotland, compared with the South-East of England; and those using nicotine products. DISCUSSION AND CONCLUSIONS: A third of adults in Great Britain have consumed no/lo drinks and approximately one in 10 do so weekly. Consumption is more common among riskier drinkers of alcohol and among more advantaged social groups, which may contribute to the sustaining or widening of health inequalities.
63"I don't want to introduce it into new places in my life": The marketing and consumption of no and low alcohol drinks.PubMed
Emily Nicholls
Int J Drug Policy. 2023 Sep;119:104149. doi: 10.1016/j.drugpo.2023.104149. Epub 2023 Aug 4.
INTRODUCTION: Recent years have seen an expanding 'no and low alcohol' (NoLo) drinks market in the United Kingdom and other high-income countries. With the UK government pledging to increase the availability of NoLos and encourage their consumption, further research is required to underpin policy and explore the potential for NoLos to ease - or exacerbate - alcohol-related harm. METHODS: This paper draws on original primary research on NoLo marketing and consumption in the UK; analysis of two NoLo marketing campaigns and semi-structured interviews with both drinkers and non-drinkers who consume NoLos. FINDINGS AND DISCUSSION: Addition marketing was identified in the promotion of NoLo products, encouraging consumers to incorporate NoLo consumption into new spatial and temporal contexts on top of their typical weekly drinking patterns. However, there was resistance towards these practices from consumers, who stressed they were more likely to drink NoLos in place of alcohol and incorporate them into their existing drinking routines. CONCLUSION: This paper expands a currently very limited evidence base and contributes directly to ongoing debates around 'addition' versus 'substitution' (i.e. whether NoLo products are being used on top of or in place of alcohol). Findings highlight both some of the challenges and opportunities of the expanding market, pointing towards the problematic presence of 'addition marketing' but also highlighting the ways consumers might challenge this and use NoLos flexibly to reduce consumption. As a result, NoLo promotion could function as one tool amongst many to help at least some consumers drink in moderation, alongside a broader package of measures such as education and wider social change.
64The availability and promotion of low alcohol beverages in licensed venues: an environmental audit on the Gold Coast, Australia.PubMed
Blake Palmer, Christopher Irwin, Christina Mailer, et al.
Public Health Res Pract. 2023 Mar 15;33(1):3312306. doi: 10.17061/phrp3312306.
OBJECTIVES: Low-alcohol beverages (LABs) are becoming increasingly popular and more accepted in Australia. However, the extent to which these products are accessible in licensed venues remains unknown. This investigation aimed to explore the availability, visibility, advertising, and promotion of LAB products at licensed venues. STUDY TYPE: A cross-sectional environmental audit of licensed venues in four entertainment locations on the Gold Coast, Queensland. METHODS: An audit tool was developed. Licensed venues selected for auditing included bars, pubs, clubs, and nightclubs. Consent for conducting the audits was obtained from selected venues. Audits involved a walk-through of each venue's public areas and a review of their beverage menu to observe availability, visibility, advertising, and promotion of LAB products. RESULTS: A total of 58 venues were identified, with 32 (55%) providing written consent to audit. Overall, 18 venues (56%) offered patrons the opportunity to purchase LAB products. At bar service areas, LAB products were 'not visible' in 20 (63%) venues, and 'somewhat visible' in 12 (38%) venues. No bar service areas displayed LAB products with 'high visibility'. Of 29 beverage menus audited, 10 (34%) displayed LAB products, with varying levels of visibility. LAB-related advertising and/or promotion was not identified in any of the venues. CONCLUSIONS: LABs were available in approximately half the licensed venues audited; however, the visibility and promotion of these products were poor. There is capacity to improve access to and promote lower alcohol alternatives within licensed venues.
65Young Australian drinkers' awareness, perceptions and behaviours towards low alcohol beverage products.PubMed
Blake Palmer, Ben Desbrow, Christopher Irwin
Nutr Health. 2024 Dec 18:2601060241296168. doi: 10.1177/02601060241296168.
Young Australian drinkers (aged 18-24 years) are more likely to consume alcohol at risky levels than any other age group. The increased availability and diversity of low alcohol beverages (LAB)s available to Australian consumers presents an opportunity for young drinkers to moderate their drinking behaviours. To explore young risky drinkers' awareness, perceptions and behaviours towards LAB products. A cross-sectional online survey of 159 young Australian risky drinkers aged 18-24 years. Demographic information, LAB awareness, previous consumption and perceptions of LABs reducing alcohol consumption were captured. Descriptive statistics, Pearson's chi-squared analyses and binomial logistic regression were used to explore data. Overall, 51% of respondents had previously consumed LABs, with most doing so on a few occasions. The choice to consume LABs was influenced by factors including friend and family influence (28%), curiosity (28%) and the purposeful intent to reduce alcohol intake (27%). In contrast, factors preventing the consumption of LABs included individuals' intent to get drunk (58%), a lack of consideration of LABs (49%) and the perception that higher strength beverages were more desirable (35%). The majority of respondents (63%) agreed that LAB products would assist them and their peers to moderate alcohol consumption behaviours. The majority of young risky drinkers surveyed have consumed LAB products on a limited number of occasions or not at all. There are several factors likely preventing greater uptake of these products. Further work is required to explore whether greater exposure to the diversity of LAB products can moderate alcohol consumption behaviours.
66Reduction of Alcoholic Strength: Does It Matter for Public Health?PubMed
Jürgen Rehm, Pol Rovira, Jakob Manthey, et al.
Nutrients. 2023 Feb 11;15(4):910. doi: 10.3390/nu15040910.
In this work, reduction of alcoholic strength was discussed as a means to reduce consumption and alcohol-attributable harm. Statistical modelling was conducted to (1) estimate its potential for the largest six Western and Central European countries (France, Germany, Italy, Poland, Spain, UK); (2) calculate the increase in taxation necessary to reach this potential, and (3) estimate the mortality gains achieved with the introduction of no- or low-alcohol beverages in the UK and Spain. The high public health potential of reducing alcoholic strength was demonstrated via modelling a scenario in which the strength of all beverages was reduced by 10%, which would avert thousands of deaths in these six European countries per year. However, methods by which to achieve these gains were not clear, as the alcohol industry has shown no inclination toward reductions in the alcoholic strength of beer, wine, or spirits via a reformulation on a large scale. The increase of excise taxation to achieve the public health gains of such a reduction would result in markedly increasing prices-a situation unlikely to be implemented in Europe. Finally, the introduction of beer and wine with an alcoholic strength below 0.5% led to some substitutions of higher-strength beverages, but did not show a marked public health impact. New taxation initiatives to achieve the potential of a reduction of alcoholic strength will need to be implemented.
67Systematic review: Interventions for alcohol use disorder in patients with cirrhosis or alcohol-associated hepatitis.PubMed
Christopher Oldroyd, Olivia Greenham, Graham Martin, et al.
Aliment Pharmacol Ther. 2023 Oct;58(8):763-773. doi: 10.1111/apt.17665. Epub 2023 Aug 21.
BACKGROUND: Alcohol use is the most important factor in determining the prognosis of patients with alcohol-related cirrhosis and alcohol-associated hepatitis. AIM: To conduct a systematic review of interventions for alcohol use disorder specific to patients with cirrhosis or alcohol-associated hepatitis. METHODS: We searched five databases between inception and November 2022. The primary outcomes were abstinence, hepatic decompensation and mortality. We included randomised and non-randomised studies. Risk of bias was assessed using validated tools. Where possible, meta-analysis was performed. RESULTS: Twenty-three studies met the inclusion criteria including six randomised trials and 17 non-randomised studies of interventions. These included 104,298 patients with a mean/median age range from 44 to 65, of whom 75% were male. Interventions included psychological therapy, pharmacological therapies, specialist clinics, patient education and low alcohol drinks. Baclofen was the only intervention to demonstrate a statistically significant impact on the primary outcomes in a randomised trial (abstinence OR: 6.3, 95% CI: 2.4-16.1). Three non-randomised studies reported reductions in episodes of hepatic decompensation that were significant in multivariate models. This was in response to psychological therapy, use of any pharmacotherapy, and use of any treatment. A meta-analysis of non-randomised studies that examined the impact of psychological therapies revealed statistically non-significant improvements in abstinence (4 studies, OR: 1.87, 95% CI: 0.38-9.23) and mortality (4 studies, OR: 0.47, 95% CI: 0.12-1.77). CONCLUSIONS: Baclofen is the only intervention with randomised trial evidence for significant benefit in patients with cirrhosis. Non-randomised studies also point to non-pharmaceutical interventions possibly improving clinical outcomes.
68Lung cancer and particulate pollution: A critical review of spatial and temporal analysis evidence.PubMed
Ning Wang, Kerrie Mengersen, Michael Kimlin, et al.
Environ Res. 2018 Jul;164:585-596. doi: 10.1016/j.envres.2018.03.034. Epub 2018 Apr 4.
BACKGROUND: Particulate matter (PM) has been recognized as one of the key risk factors of lung cancer. However, spatial and temporal patterns of this association remain unclear. Spatiotemporal analyses incorporate the spatial and temporal structure of the data within random effects models, generating more accurate evaluations of PM-lung cancer associations at a scale that can better inform lung cancer prevention programs. METHODS: We conducted a critical review of spatial and temporal analyses of PM and lung cancer. The databases of PubMed, Web of Science and Scopus were searched for potential articles published until September 30, 2017. We included studies that applied spatial and temporal analyses to evaluate the associations of PM (inhalable particles with diameters that are 2.5 µm and smaller) and PM (inhalable particles with diameters that are 10 µm and smaller) with lung cancer. RESULTS: We identified 17 articles eligible for the review. Of these, 11 focused on PM, five on PM, and one on both. These studies suggested a significant positive association between PM exposure and the risk of lung cancer. Relative risks of lung cancer mortality ranged from 1.08 (95% confidence interval (CI): 1.07-1.09) to 1.60 (95%CI: 1.09-2.33) for 10 µg/m increase in PM exposure. The association between PM and lung cancer had been less well researched and the results were not consistent. In terms of the analysis methods, 16 papers undertook spatial analysis and one paper employed temporal analysis. No paper included spatial and temporal analyses simultaneously and considered spatiotemporal uncertainty into model predictions. Among the 16 papers with spatial analyses, thirteen studies presented maps, while only five and 11 studies utilized spatial exploration and modeling methods, respectively. CONCLUSIONS: Advanced spatial and temporal epidemiological methods were seldom applied to PM-lung cancer associations. Further research is urgently needed to develop and employ robust and comprehensive spatiotemporal analysis methods for the evaluation of PM-lung cancer associations and the support of lung cancer prevention strategies.
69The global burden of disease attributable to ambient fine particulate matter in 204 countries and territories, 1990-2019: A systematic analysis of the Global Burden of Disease Study 2019.PubMed
Shaowei Sang, Chong Chu, Tongchao Zhang, et al.
Ecotoxicol Environ Saf. 2022 Jun 15;238:113588. doi: 10.1016/j.ecoenv.2022.113588. Epub 2022 May 5.
Understanding the spatio-temporal patterns of the disease burden attributable to ambient PM2.5 across the world is essential for the prevention of related diseases, as well as ambient PM2.5 control. Following the framework and methodology of the Global Burden of Disease Study (GBD) in 2019, the global, regional, and national data on ambient PM2.5-attributable death and disability-adjusted life years (DALYs), and the age-standardized rates of mortality (ASMR) and disability-adjusted life years (ASDR) were summarized based on age, gender, year, location and specific diseases. We calculated the average annual percentage change (AAPC) to depict the secular trends of ASMR and ASDR from 1990 to 2019. In 2019, the global ambient PM2.5-related deaths and DALYs were 4,140,970 and 118.2 million, respectively, with 1,702,150 deaths and 47.5 million DALYs for females and 2,438,820 deaths and 70.7 million DALYs for male. In the 13 level-three causes, ischemic heart disease, stroke, chronic obstructive and pulmonary disease (COPD) were the leading three causes of deaths and DALYs attributable to ambient PM2.5. The number of global deaths and DALYs attributable to ambient PM2.5 has increased by 102.3% and 67.7% from 1990 to 2019, respectively. However, ASMR and ASDR showed little change. In the 13 level-three diseases, ischemic heart disease, stroke, COPD, diabetes mellitus, and lung cancer were the top five contributors to the increase of global deaths or DALYs, among which diabetes mellitus had the fastest increase of ASMR and ASDR, with AAPC of 1.5 (95% CI: 1.43, 1.58) and 2.21 (95% CI: 2.15, 2.27), respectively. The population attributable fractions (PAF) of causes in ASMR or ASDR varied significantly across regions, of which PAF of COPD, stroke and lung cancer were the top three. Regarding the GBD region, high PAF mainly occurred in North Africa and Middle East, South Asia, and East Asia. The age-specific PAFs of ischemic heart disease and stroke deaths and DALYs due to ambient PM2.5 were negatively correlated with age. ASMR and ASDR of overall PM2.5 related-burden showed an inverted "V/U" relationship with the socio-demographic index (SDI). The AAPC of ASMR and ASDR of the overall causes showed a strong negative correlation with SDI in 2019, especially at the SDI larger than 0.5. The deaths and DALYs attributable to ambient PM2.5 continued to increase under the context of population growth and aging. Decision-makers should consider controlling the PM2.5 emission when developing the economy.
70Optimization of energy-efficient multi-pollutant air purification for healthy residential buildings.PubMed
Dalong Gao, Wenbin Zhuang, Wei Liu, et al.
Sci Total Environ. 2025 Jul 15;994:180056. doi: 10.1016/j.scitotenv.2025.180056.
High-level exposure to indoor air pollutants (IAPs) poses significant health risks. Using air purifiers can effectively reduce exposure to IAPs, but it also leads to increased energy consumption. To investigate a multi-objective optimization strategy, this study developed a dynamic control model for multi-pollutant concentrations. Through year-round simulations of six IAPs (PM, formaldehyde, ozone, benzene, sulfur dioxide, and nitrogen dioxide) in residential buildings in Beijing, the energy-health nexus under different intervention scenarios was quantified. PM was the dominant IAP. Implementation of intervention scenario P1 (PM control threshold range of 1-5 μg/m) resulted in average percentage reductions of 84.5 % in annual average concentrations across six IAPs and 36.7 % in associated disease burdens. By integrating non-dominated sorting multi-objective optimization method, we established pareto-optimal solutions for multi-pollutant control. The intervention scenario P4 + B1 (PM control threshold range of 25-35 μg/m and benzene control threshold range of 0.01-0.02 mg/m) is the most cost-effective intervention scenario for Beijing. Under this scenario, 108.9 thousand disability-adjusted life years (DALYs) can be avoided, with avoidable DALY rates of 873.4 per 100,000. This study can provide methodological support for formulating collaborative multi-pollutant governance strategies aimed at protecting human health in other countries and regions.
71Radon Exposure-Therapeutic Effect and Cancer Risk.PubMed
Andreas Maier, Julia Wiedemann, Felicitas Rapp, et al.
Int J Mol Sci. 2020 Dec 30;22(1):316. doi: 10.3390/ijms22010316.
Largely unnoticed, all life on earth is constantly exposed to low levels of ionizing radiation. Radon, an imperceptible natural occurring radioactive noble gas, contributes as the largest single fraction to radiation exposure from natural sources. For that reason, radon represents a major issue for radiation protection. Nevertheless, radon is also applied for the therapy of inflammatory and degenerative diseases in galleries and spas to many thousand patients a year. In either case, chronic environmental exposure or therapy, the effect of radon on the organism exposed is still under investigation at all levels of interaction. This includes the physical stage of diffusion and energy deposition by radioactive decay of radon and its progeny and the biological stage of initiating and propagating a physiologic response or inducing cancer after chronic exposure. The purpose of this manuscript is to comprehensively review the current knowledge of radon and its progeny on physical background, associated cancer risk and potential therapeutic effects.
72Radon and lung cancer: Current status and future prospects.PubMed
Yan Liu, Yanqing Xu, Wei Xu, et al.
Crit Rev Oncol Hematol. 2024 Jun;198:104363. doi: 10.1016/j.critrevonc.2024.104363. Epub 2024 Apr 23.
Beyond tobacco smoking, radon takes its place as the second most significant contributor to lung cancer, excluding hereditary and other biologically related factors. Radon and its byproducts play a pivotal role in exposing humans to elevated levels of natural radiation. Approximately 10-20 % of lung cancer cases worldwide can be attributed to radon exposure, leading to between 3 % and 20 % of all lung cancer-related deaths. Nevertheless, a knowledge gap persists regarding the association between radon and lung cancer, impeding radon risk reduction initiatives globally. This review presents a comprehensive overview of the current state of research in epidemiology, cell biology, dosimetry, and risk modeling concerning radon exposure and its relevance to lung cancer. It also delves into methods for measuring radon concentrations, monitoring radon risk zones, and identifying priorities for future research.
73The effectiveness of mitigation for reducing radon risk in single-family Minnesota homes.PubMed
Daniel J Steck
Health Phys. 2012 Sep;103(3):241-8. doi: 10.1097/HP.0b013e318250c37a.
Increased lung cancer incidence has been linked with long-term exposure to elevated residential radon. Experimental studies have shown that soil ventilation can be effective in reducing radon concentrations in single-family homes. Most radon mitigation systems in the U.S. are installed by private contractors. The long-term effectiveness of these systems is not well known, since few state radon programs regulate or independently confirm post-mitigation radon concentrations. The effectiveness of soil ventilation systems in Minnesota was measured for 140 randomly selected clients of six professional mitigators. Homeowners reported pre-mitigation radon screening concentrations that averaged 380 Bq m (10.3 pCi L). Long term post-mitigation radon measurements on the two lowest floors show that, even years after mitigation, 97% of these homes have concentrations below the 150 Bq m U.S. Environmental Protection Agency action level. The average post-mitigation radon in the houses was 30 Bq m, an average observed reduction of >90%. If that reduction was maintained over the lifetime of the 1.2 million Minnesotans who currently reside in single-family homes with living space radon above the EPA action level, approximately 50,000 lives could be extended for nearly two decades by preventing radon-related lung cancers.
74Radon in Wisconsin.PubMed
C Weiffenbach, H A Anderson
WMJ. 2000 Nov;99(8):39-42.
Owners of about 15% to 20% of the homes in Wisconsin have tested their indoor air for the carcinogenic gas radon. Five percent to 10% of homes have year-average main-floor radon levels that exceed the US Environmental Protection Agency (EPA) exposure guideline, and they are found in most regions of the state. Attempting to retroactively seal foundations to keep radon from the ground out of a home is largely ineffective. However, a soil-depressurization radon mitigation system is highly effective for existing houses, and new homes can easily be built radon-resistant. As the number of homeowners obtaining needed repairs increases, significant lung cancer risk reduction is being achieved in a voluntary, non-regulatory setting. In coming years, as radon in community drinking water supplies becomes regulated under the federal 1996 Safe Drinking Water Act, the "multimedia" option of the act may result in additional attention to mitigation of radon in indoor air.
75Silicosis: An Update and Guide for Clinicians.PubMed
Silpa Krefft, Jenna Wolff, Cecile Rose
Clin Chest Med. 2020 Dec;41(4):709-722. doi: 10.1016/j.ccm.2020.08.012.
This overview provides an update on silicosis epidemiology with review of exposures and emerging trends in acute and accelerated silicosis in the twenty-first century. The silicosis epidemics in mining, denim sandblasting, and engineering stone industries are highlighted. Clinical presentations of silicosis and silica-related conditions such as autoimmune, kidney, and mycobacterial disease, as well as lung cancer, are discussed. Important aspects of the new OSHA 2017 Silica Standard are presented. This review also includes practical guidance for clinicians to address questions that may arise when evaluating silica-exposed patients and to the public health responses needed following a diagnosis of silica-related disease.
76Epidemiological Research on Occupational and Environmental Carcinogens.PubMed
Caterina Ledda
Int J Environ Res Public Health. 2021 Feb 24;18(5):2215. doi: 10.3390/ijerph18052215.
The cancer risk associated with exposure to environmental and occupational carcinogens such as asbestos, benzene, radiation, or lifestyle carcinogens such as cigarette smoking depends on the entire history of exposure to the carcinogen, including the age of exposure and the time-varying intensity of exposure [...].
77OSHA and elongate mineral particles.PubMed
Daniel T Crane
Toxicol Appl Pharmacol. 2018 Dec 15;361:165-167. doi: 10.1016/j.taap.2018.08.017. Epub 2018 Aug 23.
The United States Occupational Safety and Health Administration (OSHA) was established to provide guidance to protect workers from hazards in the workplace. After broadly adopting extant health and safety standards, OSHA promulgated an expanded standard for regulation of asbestos. This standard provided for regulation of six named minerals and practices to be followed. Since the initial establishment of asbestos regulation by OSHA, other elongate particles have been considered for evaluation. This discussion describes the evolution of the OSHA regulations for asbestos, what they cover and how other materials might be regulated if they are found to pose a health risk.
78Benzene exposure and pediatric leukemia: From molecular clues to epidemiological insights.PubMed
Nancy Reynoso-Noverón, Miguel Santibáñez-Andrade, Juan Torres, et al.
Toxicol Lett. 2024 Oct;400:113-120. doi: 10.1016/j.toxlet.2024.08.010. Epub 2024 Aug 22.
According to the International Agency for Research on Cancer, leukemia ranks 14th in incidence and 11th in mortality and has a 5-year prevalence of approximately 1300,000 cases. Acute lymphoblastic leukemia is the most common hematopoietic syndrome in children during the first 5 years of life and represents approximately 75 % of all neoplasms among the pediatric population. The development of leukemia is strongly governed by DNA alterations that accelerate the growth of bone marrow cells. Currently, the most examined factor in pediatric leukemia is exposure to multiple compounds, such as hydrocarbons. Benzene, an aromatic hydrocarbon, can cause health challenges and is categorized as a carcinogen. Benzene toxicity has been widely associated with occupational exposure. Importantly, studies are underway to generate evidence that can provide clues regarding the risk of environmental benzene exposure and hematological problems in children. In this review, we summarize the existing evidence regarding the effects of benzene on pediatric leukemia, the associations between the effect of benzene on carcinogenesis, and the presence of certain molecular signatures in benzene-associated pediatric leukemia. Although there is sufficient evidence regarding the effects of benzene on carcinogenesis and leukemia, epidemiological research has primarily focused on occupational risk. Moreover, most benzene-induced molecular and cytogenetic alterations have been widely described in adults but not in the pediatric population. Thus, epidemiological efforts are crucial in the pediatric population in terms of epidemiological, clinical, and biomedical research.
79A brief review of relationship between occupational benzene exposure and hematopoietic cancer.PubMed
Jin-Ha Yoon, Woo Seok Kwak, Yeon-Soon Ahn
Ann Occup Environ Med. 2018 May 10;30:33. doi: 10.1186/s40557-018-0245-9. eCollection 2018.
We reviewed articles to clarify the current evidence status for 1) types of cancer which related to benzene exposure, and 2) certain benzene exposure level which might cause the hematopoietic cancers. Hematopoietic function of the bone marrow is involved in the production of all blood cells types. The benzene metabolites including benzoquinone and mucoaldehyde affect hematopoietic stem cells as well as differentiation steps of progenitor cells for each blood cell. Hence, we concluded that benzene was associated with all lymphohematic carcinogenesis. First, it is supported by biological plausibility. Second, it is supported by meta-analysis although sing study did not show relationship due to lack of sample size or statistical power. More recent studies show lesser exposed level related to risk of cancer, compare to past studies did. Actually, early studies show the risk of malignancies in workers who exposed more than 200 ppm-years. However, only 0.5 to 1 ppm-year benzene exposed show significant linking to risk of malignancies in recent study. As reviewed research articles, we concluded that the relatively lower exposure level, such as 0.5-1 ppm-year, will be considering at risk of hematopoietic cancer. However, more research needs to be done on dose-response analysis.
80Metabolome-wide association study of occupational exposure to benzene.PubMed
Nathaniel Rothman, Roel Vermeulen, Luoping Zhang, et al.
Carcinogenesis. 2021 Nov 12;42(11):1326-1336. doi: 10.1093/carcin/bgab089.
Benzene is a recognized hematotoxin and leukemogen; however, its mechanism of action in humans remain unclear. To provide insight into the processes underlying benzene hematotoxicity, we performed high-resolution metabolomic profiling of plasma collected from a cross-sectional study of 33 healthy workers exposed to benzene (median 8-h time-weighted average exposure; 20 ppma), and 25 unexposed controls in Shanghai, China. Metabolic features associated with benzene were identified using a metabolome-wide association study (MWAS) that tested for the relationship between feature intensity and benzene exposure. MWAS identified 478 mass spectral features associated with benzene exposure at false discovery rate < 20%. Comparison to a list of 13 known benzene metabolites and metabolites predicted using a multi-component biotransformation algorithm showed five metabolites were detected, which included the known metabolites phenol and benzene diolepoxide. Metabolic pathway enrichment identified 41 pathways associated with benzene exposure, with altered pathways including carnitine shuttle, fatty acid metabolism, sulfur amino acid metabolism, glycolysis, gluconeogenesis and branched chain amino acid metabolism. These results suggest disruption to fatty acid uptake, energy metabolism and increased oxidative stress, and point towards pathways related to mitochondrial dysfunction, which has previously been linked to benzene exposure in animal models and human studies. Taken together, these results suggest benzene exposure is associated with disruption of mitochondrial pathways, and provide promising, systems biology biomarkers for risk assessment of benzene-induced hematotoxicity in humans.
81Health risk assessment of exposure to benzene, toluene, ethyl benzene, and xylene in shoe industry-related workplaces.PubMed
Amirreza Abouee-Mehrizi, Zahra Soltanpour, Yousef Mohammadian, et al.
Toxicol Ind Health. 2024 Jan-Feb;40(1-2):33-40. doi: 10.1177/07482337231212693. Epub 2023 Nov 7.
Benzene, toluene, ethyl benzene, and xylene (BTEX) are prevalent pollutants in shoe industry-related workplaces. The aim of this study was to assess exposure to BTEX and their carcinogenic and non-carcinogenic risks in shoe-industry-related workplaces. This study was carried out at different shoe manufactures, small shoe workshop units, shoe markets, and shoe stores in Tabriz, Iran in 2021. Personal inhalation exposure to BTEX was measured using the National Institute for Occupational Safety and Health (NIOSH) 1501 method. Carcinogenic and non-carcinogenic risks due to inhalation exposure to BTEX were estimated by United States Environmental Protection Agency (U.S. EPA) method based on Mont Carlo simulation. Results showed that the concentrations of benzene and toluene were higher than the threshold limit value (TLV) in both gluing and non-gluing units of shoe manufactures. The total carcinogenic risk (TCR) due to exposure to benzene and ethyl benzene was considerable in all shoe industry-related workplaces. Also, the hazard index (HI) as a non-carcinogenic index was higher than standard levels in all shoe industry-related workplaces. Therefore, shoe industry-related workers are at cancer and non-cancer risks due to exposure to BTEX. Prevention measures need to be implemented to reduce the concentration of BTEX in shoe industry-related workplaces.
82Metabolic Carcinogenesis.PubMed
Mahwish Ali, Syeda Mehpara Farhat, Abdul Haleem
Cancer Treat Res. 2024;191:33-55. doi: 10.1007/978-3-031-55622-7_2.
Several types of environmental, chemical and metabolic carcinogens exist both exogenously and endogenously. Humans are daily exposed to aforementioned carcinogens through various sources such as through water, air and food or through metabolic and inflammatory products. This chapter will summarize the links between exogenous and endogenous carcinogen exposure and their metabolism with the cancer pathogenesis and associated risks. This chapter will also cover the carcinogens acquired through lifestyle factors like tobacco use and occupational exposures to different chemicals like asbestos, arsenic, chloroform, vinyl chloride, etc. Moreover, environmental carcinogens such as radiation, sunlight, diet, smoke, etc. will also be discussed in this chapter. Furthermore, there are certain carcinogens that require bio-activation and various human enzymes that play a vital role in the metabolic carcinogenesis will also be recapitulated. Necessary preventive measures against carcinogenic exposure from the exogenous environment are significant to be taken into account to reduce the risks associated with the carcinogens.
83Contamination and Health Risk Assessment of Polycyclic Aromatic Hydrocarbons in Seasoning Flour Products in Hunan, China.PubMed
Minghui Cheng, Zhen Tan, Xiwen Zeng, et al.
Int J Environ Res Public Health. 2023 Jan 5;20(2):963. doi: 10.3390/ijerph20020963.
Polycyclic aromatic hydrocarbons (PAHs) are persistent organic pollutants with carcinogenic, teratogenic, and mutagenic effects. Dietary intake is one of the significant exposure pathways of PAHs. In this study, gas chromatography-triple quadrupole mass spectrometry (GC-MS/MS) was used to detect 16 priority PAHs listed by the United States Environmental Protection Agency (USEPA) in seasoning flour products distributed in Hunan Province. The consumption of seasoning flour products by the Hunan population was investigated by questionnaire. The results showed that the detection rate of PAHs in seasoning flour products in Hunan Province was 92.41%. Among them, benzo[a]anthracene (BaA), phenanthrene (PHE), fluoranthene (FLA), and chrysene (CHR) were dominant. The total PAHs and benzo[a]pyrene (BaP) contents of soggy seasoning flour product samples were higher than those of crisp samples and chewy samples. The total amount of PAHs in rod-shaped and flaky samples were higher than that in filamentous and granular samples. The margin of exposure (MOE) values of various seasoning flour products and all age groups (children, adolescents, and adults) was much more significant than 10,000. Moreover, the incremental lifetime of cancer risk (ILCR) values of all age groups were below 1 × 10. The above results indicate that PAHs in seasoning flour products have a relatively low health risk for the Hunan population. Still, it is recommended that susceptible populations (children, adolescents, etc.) should control their intake of flour products.
84Key Genetic and Epigenetic Mechanisms in Chemical Carcinogenesis.PubMed
Gloria Ravegnini, Gulia Sammarini, Patrizia Hrelia, et al.
Toxicol Sci. 2015 Nov;148(1):2-13. doi: 10.1093/toxsci/kfv165.
DNA sequence and genetic factors alone cannot fully explain the many processes implicated in diseases initiation and development. It is now well understood that additional factors are involved in a final resulting phenotype. Epigenetic modifications, heritable changes not affecting the DNA sequence, are a key phenomenon at the basis of normal growth and differentiation. However, these can be defective leading to diseases, such as cancer. An increasing body of literature reports the environmental and occupational exposure to a mixture of natural and man-produced substances leading to epigenetic alterations. The identification of key genetic and/or epigenetic events involved in chemical carcinogenesis is an important step towards the discovery of biomarkers that can be used to evaluate the exposure, predict biological effects, and prevent adverse health consequences. Here, we focus on epidemiological studies to review the most recent advances in understanding genetic and epigenetic factors in relation to particulate matter, benzene and polycyclic aromatic hydrocarbons exposure.
85Probabilistic Risk Assessment of Polycyclic Aromatic Hydrocarbons in a Colombian Reservoir.PubMed
F Amaringo, Y Puerta, F Molina
Bull Environ Contam Toxicol. 2022 Sep;109(3):518-525. doi: 10.1007/s00128-022-03567-7. Epub 2022 Jul 23.
The purpose of this research was to evaluate the concentrations, sources and ecological risk assessment of sixteen polycyclic aromatic hydrocarbons (PAHs) present in water from the La Fe reservoir, Colombia in the months of October and November of 2017 and 2018. Concentrations of PAHs in water were measured with semipermeable membrane devices (SPMD) which allow obtaining the dissolved concentrations of the PAHs in the reservoir, emphasizing the reactivity and bioavailability in the environment. The PAHs analyses were carried out by means of gas chromatography, coupled with tandem mass spectrometry (GC/MS-MS) with triple quadrupole (QqQ). The environmental risk assessment using the estimation of risk quotient with deterministic and probabilistic method, the predictive no-effect concentration (PNEC) and environmental exposure concentration (EEC) in water indicate a negligibe risk for probabilistic method for all PAHs evaluated (RQ < 0.1).
86Polycyclic aromatic hydrocarbons in cooked (tandoori) chicken and associated health risk.PubMed
Lochan Singh, Tripti Agarwal
Risk Anal. 2023 Nov;43(11):2380-2397. doi: 10.1111/risa.14110. Epub 2023 Feb 17.
Tandoori cooking is a popular food preparation method in India involving a unique combination of grilling, baking, barbecuing, and roasting processes. This study determined the levels of 16 polycyclic aromatic hydrocarbons (PAHs) in tandoori chicken and assessed the associated health risk. The sum of 16 PAHs concentration ranged from 25.4 to 3733 μg/kg with an average of 440 ± 853 μg/kg. Analyzed samples demonstrated major contribution of 2, 3, and 4 ring PAHs. Diagnostic ratios identified combustion and high-temperature processes as the main source favoring PAHs generation in these samples. Benzo(a)pyrene equivalents and incremental lifetime cancer risk (ILCR) estimates for different population groups (boys, girls, adult males, adult females, elderly males, elderly females) associated with dietary intake of these products ranged from 6.88E-05 to 4.13E-03 and 1.63E-08 to 1.72E-06, respectively. Since the ILCR values fell within the safe limits (1E-06, i.e., nonsignificant), the consumption of tandoori chicken may be considered as safe. The study emphasizes the need for extensive studies on PAHs formation in tandoori food products.
87Using Online Colorectal Cancer Risk Calculators to Guide Screening Decision-Making.PubMed
Jennifer K Maratt, Thomas F Imperiale
Am J Med. 2023 Mar;136(3):308-314.e3. doi: 10.1016/j.amjmed.2022.08.008. Epub 2022 Sep 2.
BACKGROUND: Several online calculators estimate colorectal cancer risk, but their consistency is unknown. Our objectives were to quantify the variation in predicted risk and to determine which calculators are best used in the clinical setting. METHODS: We used the Google search engine to identify online colorectal cancer risk calculators and assessed the output of each for 3 hypothetical screening scenarios (low-, average-, and high-risk), varied by age (50, 62, 75 years), sex, and race (Black, White), with risk levels based on risk-appropriate values for variables in each model. Estimated risks for models within a given scenario were rated as consistent or inconsistent based on comparison with either the absolute magnitude of difference or average lifetime risk of colorectal cancer. Summary statistics for consistent and inconsistent estimates were compared using chi-square and Fisher's exact tests. RESULTS: We identified 5 online colorectal cancer risk calculators. Inconsistencies were found in none of 5-year, 19% of 10-year, and 81% of lifetime colorectal cancer risk estimate comparisons (P < .001). For a 50-year-old, 22% of risk estimate comparisons were inconsistent, vs 33% for a 62-year-old, and 36% for a 75-year-old (P = 0.14). CONCLUSIONS: Online colorectal cancer risk models are more consistent in predicting colorectal cancer risk for 5- and 10-year time frames compared with lifetime. For a US population, the National Cancer Institute's Colorectal Cancer Risk Assessment Tool is a rigorously developed calculator that can be used in the clinical setting to provide 5-year and lifetime risk estimates.
88Estimation of risk posed by malignant polyps amongst colorectal surgeons in Australia and New Zealand.PubMed
Andrew P Zammit, Ian Brown, John D Hooper, et al.
Ann Coloproctol. 2024 Apr;40(2):114-120. doi: 10.3393/ac.2023.00178.0025. Epub 2024 Mar 25.
PURPOSE: The estimation of the risk posed by malignant polyps for residual or lymphatic disease plays a central role. This study investigated colorectal surgeons' assessment of these risks associated with malignant polyps. METHODS: A cross-sectional questionnaire was electronically administered to colorectal surgeons in Australia and New Zealand in October 2022. The questionnaire contained 17 questions on demographics, when surgeons consider colorectal resection appropriate, and the risk assessment for 5 hypothetical malignant polyps. RESULTS: The mean risk of residual or lymphatic disease that would prompt surgeons to recommend colonic resection was 5%. However, this increased to a mean risk of 10% if the malignant polyp was located in the rectum, and the only resection option was abdominoperineal resection with end-colostomy. There was high concordance between the estimated risk of residual or lymphatic disease by colorectal surgeons and the Association of Coloproctology of Great Britain and Ireland (ACPGBI) guidelines for the 5 hypothetical malignant polyps, with the ACPGBI estimated risk lying within the 95% confidence interval for 4 of the 5 malignant polyps. Nonetheless, 96.6% of surgeons felt that an online risk calculator would improve clinical practice. CONCLUSION: Colorectal surgeons in Australia and New Zealand accurately estimated the risk posed by malignant polyps. An online risk calculator may assist in better conveying risk to patients.
89Mammography Screening Preferences Among Screening-Eligible Women in Their 40s : A National U.S. Survey.PubMed
Laura D Scherer, Carmen L Lewis, Kirsten McCaffery, et al.
Ann Intern Med. 2024 Aug;177(8):1069-1077. doi: 10.7326/M23-3325. Epub 2024 Jul 16.
BACKGROUND: The U.S. Preventive Services Task Force (USPSTF) recently changed its recommendation for mammography screening from informed decision making to biennial screening for women aged 40 to 49 years. Although many women welcome this change, some may prefer not to be screened at age 40 years. OBJECTIVE: To conduct a national probability-based U.S. survey to investigate breast cancer screening preferences among women aged 39 to 49 years. DESIGN: Pre-post survey with a breast cancer screening decision aid (DA) intervention. (ClinicalTrials.gov: NCT05376241). SETTING: Online national U.S. survey. PARTICIPANTS: 495 women aged 39 to 49 years without a history of breast cancer or a known BRCA1/2 gene mutation. INTERVENTION: A mammography screening DA providing information about screening benefits and harms and a personalized breast cancer risk estimate. MEASUREMENTS: Screening preferences (assessed before and after the DA), 10-year Gail model risk estimate, and whether the information was surprising and different from past messages. RESULTS: Before viewing the DA, 27.0% of participants preferred to delay screening (vs. having mammography at their current age), compared with 38.5% after the DA. There was no increase in the number never wanting mammography (5.4% before the DA vs. 4.3% after the DA). Participants who preferred to delay screening had lower breast cancer risk than those who preferred not to delay. The information about overdiagnosis was surprising for 37.4% of participants versus 27.2% and 22.9% for information about false-positive results and screening benefits, respectively. LIMITATION: Respondent preferences may have been influenced by the then-current USPSTF guideline. CONCLUSION: There are women in their 40s who would prefer to have mammography at an older age, especially after being informed of the benefits and harms of screening. Women who wanted to delay screening were at lower breast cancer risk than women who wanted screening at their current age. Many found information about the benefits and harms of mammography surprising. PRIMARY FUNDING SOURCE: National Cancer Institute.
90Breast Cancer: Risk Assessment, Screening, and Primary Prevention.PubMed
Elena Michaels, Rebeca Ortiz Worthington, Jennifer Rusiecki
Med Clin North Am. 2023 Mar;107(2):271-284. doi: 10.1016/j.mcna.2022.10.007.
This review provides an outline of a risk-based approach to breast cancer screening and prevention. All women should be assessed for breast cancer risk starting at age 18 with identification of modifiable and non-modifiable risk factors. Patients can then be stratified into average, moderate, and high-risk groups with personalized screening and prevention plans. Counseling on breast awareness and lifestyle changes is recommended for all women, regardless of risk category. High-risk individuals may benefit from additional screening modalities such as MRI and chemoprevention and should be managed closely by a multidisciplinary team.
91Screening and follow-up of the patient at high risk for breast cancer.PubMed
Shawna C Willey, Costanza Cocilovo
Obstet Gynecol. 2007 Dec;110(6):1404-16. doi: 10.1097/01.AOG.0000295638.83285.97.
Accurately defining a patient's risk of developing breast cancer is a challenging endeavor. Many factors have been implicated in the causation of breast cancer and quantifying them is difficult. Risk stratification is performed using population models, such as the Gail model, as well as the patient's personal and family history and genetic testing. The clinician who is facile with these components will not only be able to identify those patients at highest risk for whom heightened surveillance is recommended, but also to allay the fears of the average-risk patient and provide them reassurance. Patients who are at very high risk of developing breast cancer are BRCA1 or BRCA2 gene mutation carriers, those with a personal history of atypical ductal hyperplasia or lobular carcinoma in situ with associated family history, those who have undergone therapeutic or similarly significant radiation exposure, and those with a history of a BRCA1 or BRCA2 gene mutation in the family of an untested individual. Patients with an elevated risk, but not in the very high risk category, are those with a family history of breast cancer, personal history of breast cancer, significantly dense breast tissue, hormone replacement therapy longer than 10 years, and a history of atypical ductal hyperplasia or lobular carcinoma in situ without family history of breast cancer. Risk-reducing strategies include chemoprevention with tamoxifen or raloxifene and surgical prophylaxis with bilateral prophylactic mastectomy and/or bilateral salpingo-oophorectomy. A high-risk surveillance regimen includes annual mammography, annual magnetic resonance imaging in selected individuals, and semiannual clinical breast exams.
92Nipple aspirate fluid cytology and the Gail model for breast cancer risk assessment in a screening population.PubMed
Jeffrey A Tice, Rei Miike, Kelly Adduci, et al.
Cancer Epidemiol Biomarkers Prev. 2005 Feb;14(2):324-8. doi: 10.1158/1055-9965.EPI-04-0289.
BACKGROUND: Recent guidelines suggest that chemoprevention with tamoxifen may be appropriate for women who have a 5-year risk of breast cancer greater than 1.66% calculated using the Gail model. OBJECTIVES: To determine whether nipple aspirate fluid (NAF) cytology combined with the Gail model provides breast cancer risk assessment that is superior to either method alone. METHODS: Prospective observational cohort of 6,904 asymptomatic women. Breast cancer cases were identified through follow-up with the women and linkage to cancer registries. We used proportional hazards modeling to recalculate the coefficients for the predictor variables used in the Gail model. NAF cytology was added to create a second model. The two models were compared using the concordance statistic (c-statistic). RESULTS: During 14.6 years of follow-up, 400 women were diagnosed with breast cancer. There were 940 (14%) women with hyperplasia and 109 (1.6%) women with atypical hyperplasia found in NAF. Adding NAF cytology results to the Gail model significantly improved the model fit (P < 0.0001). The c-statistic for the Gail model was 0.62, indicating only modest discriminatory accuracy. Adding NAF cytology to the model increased the c-statistic to 0.64. NAF cytology results had the largest effect on discriminatory accuracy among women in the upper third of Gail model risk. The relative incidence for the highest quintile of risk score compared with the lowest quintile was 7.2 for the Gail model and 8.0 for the model including NAF cytology. CONCLUSION: NAF cytology has the potential to improve prediction models of breast cancer incidence, particularly for high-risk women.
93Mammographic breast density and the Gail model for breast cancer risk prediction in a screening population.PubMed
Jeffrey A Tice, Steven R Cummings, Elad Ziv, et al.
Breast Cancer Res Treat. 2005 Nov;94(2):115-22. doi: 10.1007/s10549-005-5152-4.
BACKGROUND: Estimating an individual woman's absolute risk for breast cancer is essential for decision making about screening and preventive recommendations. Although the current standard, the Gail model, is well calibrated in populations, it performs poorly for individuals. Mammographic breast density (BD) may improve the predictive accuracy of the Gail model. METHODS: Prospective observational cohort of 81,777 women in the San Francisco Mammography Registry presenting for mammography during 1993 through 2002 who had no prior diagnosis of breast cancer. Breast density was rated by clinical radiologists using the Breast Imaging Reporting and Data System classification (almost entirely fat; scattered fibroglandular densities; heterogeneously dense; extremely dense). Breast cancer cases were identified through linkage to Northern California Surveillance Epidemiology End Results (SEER) program. We compared the predictive accuracy of models with Gail risk, breast density, and the combination. All models were adjusted for age and ethnicity. RESULTS: During 5.1 years of follow-up, 955 women were diagnosed with invasive breast cancer. The Gail model had modest predictive accuracy (concordance index (c-index) 0.67; 95% CI 0.65-0.68). Adding breast density to the model increased the predictive accuracy to 0.68 (95% CI .66-.70, p < 0.01 compared with the Gail model alone). The model containing only breast density adjusted for age and ethnicity had predictive accuracy equivalent to the Gail model (c-index 0.67, 95% CI 0.65-0.68). CONCLUSION: The addition of breast density measured by BI-RADS categories minimally improved the predictive accuracy of the Gail model. A model based on breast density alone adjusted for age and ethnicity was as accurate as the Gail model.
94Gail model breast cancer risk components are poor predictors of risk perception and screening behavior.PubMed
M B Daly, C L Lerman, E Ross, et al.
Breast Cancer Res Treat. 1996;41(1):59-70. doi: 10.1007/BF01807037.
The Gail model is being used increasingly to determine individual breast cancer risk and to tailor preventive health recommendations accordingly. Although widely known to the medical and biostatistical communities, the risk factors included in the model may not be salient to the women to whom the model is being applied. This study explored the relationship of the individual Gail model risk factors to perceived risk of breast cancer and prior breast cancer screening among women with a family history of breast cancer. Data from baseline interviews with 969 women found a striking disparity between the objective risk factors included in the model and the accuracy of perceived risk and screening behaviors of this population, particularly among women over the age of 50 years. Risk perception accuracy was unrelated to all of the Gail model risk factors for all age groups. Reported mammography adherence was only associated with having had a breast biopsy in both age groups. Breast self examination (BSE) practice was independent of all measured factors for both age groups. These findings support the need for further research to identify additional determinants of risk perception and motivators of screening behavior.
95Validation of the Gail model for predicting individual breast cancer risk in a prospective nationwide study of 28,104 Singapore women.PubMed
Wen Yee Chay, Whee Sze Ong, Puay Hoon Tan, et al.
Breast Cancer Res. 2012 Jan 30;14(1):R19. doi: 10.1186/bcr3104.
INTRODUCTION: The Gail model (GM) is a risk-assessment model used in individual estimation of the absolute risk of invasive breast cancer, and has been applied to both clinical counselling and breast cancer prevention studies. Although the GM has been validated in several Western studies, its applicability outside North America and Europe remains uncertain. The Singapore Breast Cancer Screening Project (SBCSP) is a nation-wide prospective trial of screening mammography conducted between Oct 1994 and Feb 1997, and is the only such trial conducted outside North America and Europe to date. With the long-term outcomes from this study, we sought to evaluate the performance of GM in prediction of individual breast cancer risk in a Asian developed country. METHODS: The study population consisted of 28,104 women aged 50 to 64 years who participated in the SBSCP and did not have breast cancer detected during screening. The national cancer registry was used to identify incident cases of breast cancer. To evaluate the performance of the GM, we compared the expected number of invasive breast cancer cases predicted by the model to the actual number of cases observed within 5-year and 10-year follow-up. Pearson's Chi-square test was used to test the goodness of fit between the expected and observed cases of invasive breast cancers. RESULTS: The ratio of expected to observed number of invasive breast cancer cases within 5 years from screening was 2.51 (95% confidence interval 2.14 - 2.96). The GM over-estimated breast cancer risk across all age groups, with the discrepancy being highest among older women aged 60 - 64 years (E/O = 3.53, 95% CI = 2.57-4.85). The model also over-estimated risk for the upper 80% of women with highest predicted risk. The overall E/O ratio for the 10-year predicted breast cancer risk was 1.85 (1.68-2.04). CONCLUSIONS: The GM over-predicts the risk of invasive breast cancer in the setting of a developed Asian country as demonstrated in a large prospective trial, with the largest difference seen in older women aged between 60 and 64 years old. The reason for the discrepancy is likely to be multifactorial, including a truly lower prevalence of breast cancer, as well as lower mammographic screening prevalence locally.
96BREAst screening Tailored for HEr (BREATHE)-A study protocol on personalised risk-based breast cancer screening programme.PubMed
Jenny Liu, Peh Joo Ho, Tricia Hui Ling Tan, et al.
PLoS One. 2022 Mar 31;17(3):e0265965. doi: 10.1371/journal.pone.0265965. eCollection 2022.
Routine mammography screening is currently the standard tool for finding cancers at an early stage, when treatment is most successful. Current breast screening programmes are one-size-fits-all which all women above a certain age threshold are encouraged to participate. However, breast cancer risk varies by individual. The BREAst screening Tailored for HEr (BREATHE) study aims to assess acceptability of a comprehensive risk-based personalised breast screening in Singapore. Advancing beyond the current age-based screening paradigm, BREATHE integrates both genetic and non-genetic breast cancer risk prediction tools to personalise screening recommendations. BREATHE is a cohort study targeting to recruit ~3,500 women. The first recruitment visit will include questionnaires and a buccal cheek swab. After receiving a tailored breast cancer risk report, participants will attend an in-person risk review, followed by a final session assessing the acceptability of our risk stratification programme. Risk prediction is based on: a) Gail model (non-genetic), b) mammographic density and recall, c) BOADICEA predictions (breast cancer predisposition genes), and d) breast cancer polygenic risk score. For national implementation of personalised risk-based breast screening, exploration of the acceptability within the target populace is critical, in addition to validated predication tools. To our knowledge, this is the first study to implement a comprehensive risk-based mammography screening programme in Asia. The BREATHE study will provide essential data for policy implementation which will transform the health system to deliver a better health and healthcare outcomes.
97Pancreatic Cancer: Changing Epidemiology and New Approaches to Risk Assessment, Early Detection, and Prevention.PubMed
Elena M Stoffel, Randall E Brand, Michael Goggins
Gastroenterology. 2023 Apr;164(5):752-765. doi: 10.1053/j.gastro.2023.02.012. Epub 2023 Feb 18.
Pancreatic cancer usually results in poor survival with limited options for treatment, as most affected individuals present with advanced disease. Early detection of preinvasive pancreatic neoplasia and identifying molecular therapeutic targets provide opportunities for extending survival. Although screening for pancreatic cancer is currently not recommended for the general population, emerging evidence indicates that pancreatic surveillance can improve outcomes for individuals in certain high-risk groups. Changes in the epidemiology of pancreatic cancer, experience from pancreatic surveillance, and discovery of novel biomarkers provide a roadmap for new strategies for pancreatic cancer risk assessment, early detection, and prevention.
98Management of patients with increased risk for familial pancreatic cancer: updated recommendations from the International Cancer of the Pancreas Screening (CAPS) Consortium.PubMed
Michael Goggins, Kasper Alexander Overbeek, Randall Brand, et al.
Gut. 2020 Jan;69(1):7-17. doi: 10.1136/gutjnl-2019-319352. Epub 2019 Oct 31.
BACKGROUND AND AIM: The International Cancer of the Pancreas Screening Consortium met in 2018 to update its consensus recommendations for the management of individuals with increased risk of pancreatic cancer based on family history or germline mutation status (high-risk individuals). METHODS: A modified Delphi approach was employed to reach consensus among a multidisciplinary group of experts who voted on consensus statements. Consensus was considered reached if ≥75% agreed or disagreed. RESULTS: Consensus was reached on 55 statements. The main goals of surveillance (to identify high-grade dysplastic precursor lesions and T1N0M0 pancreatic cancer) remained unchanged. Experts agreed that for those with familial risk, surveillance should start no earlier than age 50 or 10 years earlier than the youngest relative with pancreatic cancer, but were split on whether to start at age 50 or 55. Germline mutation carriers with one affected first-degree relative are now considered eligible for surveillance. Experts agreed that preferred surveillance tests are endoscopic ultrasound and MRI/magnetic retrograde cholangiopancreatography, but no consensus was reached on how to alternate these modalities. Annual surveillance is recommended in the absence of concerning lesions. Main areas of disagreement included if and how surveillance should be performed for hereditary pancreatitis, and the management of indeterminate lesions. CONCLUSIONS: Pancreatic surveillance is recommended for selected high-risk individuals to detect early pancreatic cancer and its high-grade precursors, but should be performed in a research setting by multidisciplinary teams in centres with appropriate expertise. Until more evidence supporting these recommendations is available, the benefits, risks and costs of surveillance of pancreatic surveillance need additional evaluation.
99Hepatocellular carcinoma surveillance: An evidence-based approach.PubMed
Patrick S Harris, Ross M Hansen, Meagan E Gray, et al.
World J Gastroenterol. 2019 Apr 7;25(13):1550-1559. doi: 10.3748/wjg.v25.i13.1550.
Hepatocellular carcinoma (HCC) makes up 75%-85% of all primary liver cancers and is the fourth most common cause of cancer related death worldwide. Chronic liver disease is the most significant risk factor for HCC with 80%-90% of new cases occurring in the background of cirrhosis. Studies have shown that early diagnosis of HCC through surveillance programs improve prognosis and availability of curative therapies. All patients with cirrhosis and high-risk hepatitis B patients are at risk for HCC and should undergo surveillance. The recommended surveillance modality is abdominal ultrasound (US) given that it is cost effective and noninvasive with good sensitivity. However, US is limited in obese patients and those with non-alcoholic fatty liver disease (NAFLD). With the current obesity epidemic and rise in the prevalence of NAFLD, abdominal computed tomography or magnetic resonance imaging may be indicated as the primary screening modality in these patients. The addition of alpha-fetoprotein to a surveillance regimen is thought to improve the sensitivity of HCC detection. Further investigation of serum biomarkers is needed. Semiannual screening is the suggested surveillance interval. Surveillance for HCC is underutilized and low adherence disproportionately affects certain demographics such as non-Caucasian race and low socioeconomic status.
100Management of chronic hepatitis B infection.PubMed
Vinay Sundaram, Kris Kowdley
BMJ. 2015 Oct 21;351:h4263. doi: 10.1136/bmj.h4263.
Hepatitis B virus (HBV) is a global health problem that can lead to cirrhosis and hepatocellular carcinoma (HCC). Although HBV vaccination has reduced the prevalence Of HBV infection, the burden of disease remains high. Treatment with antiviral drugs reduces the risk of liver disease and the development of HCC, and it can even reverse liver fibrosis. However, challenges remain regarding optimal timing, as well as the modality and duration of treatment. Currently approved drugs include pegylated interferon and nucleos(t)ide analogs. Nucleos(t)ide analogs are better tolerated and provide excellent viral suppression with a low risk of antiviral resistance, but pegylated interferon offers the benefit of a finite duration of treatment. Monitoring of hepatitis B surface antigen (HBsAg) levels may help to predict the likelihood of response to treatment, particularly for pegylated interferon. Prolonged treatment is usually needed with oral antiviral agents, and relapse is common if treatment is discontinued. New treatments that result in sustained clearance of HBV DNA and the clearance of HBsAg are needed.
101Hepatitis B virus infection in children and adolescents.PubMed
Giuseppe Indolfi, Philippa Easterbrook, Geoffrey Dusheiko, et al.
Lancet Gastroenterol Hepatol. 2019 Jun;4(6):466-476. doi: 10.1016/S2468-1253(19)30042-1. Epub 2019 Apr 11.
Hepatitis B virus (HBV) infection is a major cause of acute and chronic liver disease and associated morbidity and mortality worldwide. Vertical (mother-to-child) and horizontal early childhood transmission are the main routes of HBV transmission and are responsible for most chronic infections, including among adults who bear the greatest burden of morbidity and mortality. Universal hepatitis B immunisation at birth and in infancy is the key strategy for global elimination of HBV infection, and has been highly effective in reducing new vertical infections. However, global progress in scale-up of HBV testing and treatment has been slow in adults and children. In this Series paper, we summarise knowledge on the epidemiology, natural history, and treatment of chronic HBV infection in adolescents and children, and we highlight key differences from HBV infection in adults. The estimated global prevalence of HBV infection in children aged 5 years or younger is 1·3%. Most children are in the high-replication, low-inflammation phase of infection, with normal or only slightly raised aminotransferases; cirrhosis and hepatocellular carcinoma are rare. Although entecavir is approved and recommended for children aged 2-17 years, and tenofovir for those aged 12-18 years, a conservative approach to treatment initiation in children is recommended. Key actions to address current policy gaps include: validation of non-invasive tests for liver disease staging; additional immunopathogenesis studies in children with HBV infection; long-term follow-up of children on nucleoside or nucleotide analogue regimens to inform guidance on when to start treatment; evaluation of different treatment strategies for children with high rates of HBV replication; and establishment of paediatric treatment registries and international consortia to promote collaborative research.
102Advances in the epidemiology of pancreatic cancer: Trends, risk factors, screening, and prognosis.PubMed
Jie Cai, Hongda Chen, Ming Lu, et al.
Cancer Lett. 2021 Nov 1;520:1-11. doi: 10.1016/j.canlet.2021.06.027. Epub 2021 Jun 30.
Pancreatic cancer is a malignancy with poor prognosis and high mortality. The recent increase in pancreatic cancer incidence and mortality has resulted in an increased number of studies on its epidemiology. This comprehensive and systematic literature review summarizes the advances in the epidemiology of pancreatic cancer, including its epidemiological trends, risk factors, risk prediction models, screening modalities, and prognosis. The risk factors for pancreatic cancers can be categorized as those related to individual characteristics, lifestyle and environment, and disease status. Several prediction models for pancreatic cancer have been developed in populations with new-onset diabetes or a family history of pancreatic cancer; however, these models require further validation. Despite recent progress in pancreatic cancer screening, the quantity and quality of related studies are also unsatisfactory, especially with respect to the identification of high-risk populations and development of effective screening modality. Apart from the populations with familial genetic risk and those at a high risk of sporadic pancreatic cancer, risk factors such as new-onset diabetes may be a new direction for timely intervention. We hope this work will provide new ideas for further prevention and treatment of pancreatic cancer.
103Colorectal cancer predicted risk online (CRC-PRO) calculator using data from the multi-ethnic cohort study.PubMed
Brian J Wells, Michael W Kattan, Gregory S Cooper, et al.
J Am Board Fam Med. 2014 Jan-Feb;27(1):42-55. doi: 10.3122/jabfm.2014.01.130040.
BACKGROUND: Better risk predictions for colorectal cancer (CRC) could improve prevention strategies by allowing clinicians to more accurately identify high-risk individuals. The National Cancer Institute's CRC risk calculator was created by Freedman et al using case control data. METHODS: An online risk calculator was created using data from the Multi-Ethnic Cohort Study, which followed >180,000 patients for the development of CRC for up to 11.5 years through linkage with cancer registries. Forward stepwise regression tuned to the c statistic was used to select the most important variables for use in separate Cox survival models for men and women. Model accuracy was assessed using 10-fold cross-validation. RESULTS: Patients in the cohort experienced 2762 incident cases of CRC. The final model for men contained age, ethnicity, pack-years of smoking, alcoholic drinks per day, body mass index, years of education, regular use of aspirin, family history of colon cancer, regular use of multivitamins, ounces of red meat intake per day, history of diabetes, and hours of moderate physical activity per day. The final model for women included age, ethnicity, years of education, use of estrogen, history of diabetes, pack-years of smoking, family history of colon cancer, regular use of multivitamins, body mass index, regular use of nonsteroidal anti-inflammatory drugs, and alcoholic drinks per day. The calculator demonstrated good accuracy with a cross-validated c statistic of 0.681 in men and 0.679 in women, and it seems to be well calibrated graphically. An electronic version of the calculator is available at http://rcalc.ccf.org. CONCLUSION: This calculator seems to be accurate, is user friendly, and has been internally validated in a diverse population.
104Colorectal cancer screening: An updated review of the available options.PubMed
Iyad A Issa, Malak Noureddine
World J Gastroenterol. 2017 Jul 28;23(28):5086-5096. doi: 10.3748/wjg.v23.i28.5086.
Colorectal cancer (CRC) is a significant cause of morbidity and mortality worldwide. However, colon cancer incidence and mortality is declining over the past decade owing to adoption of effective screening programs. Nevertheless, in some parts of the world, CRC incidence and mortality remain on the rise, likely due to factors including "westernized" diet, lifestyle, and lack of health-care infrastructure and resources. Participation and adherence to different national screening programs remain obstacles limiting the achievement of screening goals. Different modalities are available ranging from stool based tests to radiology and endoscopy with varying sensitivity and specificity. However, the availability of these tests is limited to areas with high economic resources. Recently, FDA approved a blood-based test (Epi procolon) for CRC screening. This blood based test may serve to increase the participation and adherence rates. Hence, leading to increase in colon cancer detection and prevention. This article will discuss various CRC screening tests with a particular focus on the data regarding the new approved blood test. Finally, we will propose an algorithm for a simple cost-effective CRC screening program.
105Why is early detection of colon cancer still not possible in 2023?PubMed
Valeria Tonini, Manuel Zanni
World J Gastroenterol. 2024 Jan 21;30(3):211-224. doi: 10.3748/wjg.v30.i3.211.
Colorectal cancer (CRC) screening is a fundamental tool in the prevention and early detection of one of the most prevalent and lethal cancers. Over the years, screening, particularly in those settings where it is well organized, has succeeded in reducing the incidence of colon and rectal cancer and improving the prognosis related to them. Despite considerable advancements in screening technologies and strategies, the effectiveness of CRC screening programs remains less than optimal. This paper examined the multifaceted reasons behind the persistent lack of effectiveness in CRC screening initiatives. Through a critical analysis of current methodologies, technological limitations, patient-related factors, and systemic challenges, we elucidated the complex interplay that hampers the successful reduction of CRC morbidity and mortality rates. While acknowledging the advancements that have improved aspects of screening, we emphasized the necessity of addressing the identified barriers comprehensively. This study aimed to raise awareness of how important CRC screening is in reducing costs for this disease. Screening and early diagnosis are not only important in improving the prognosis of patients with CRC but can lead to an important reduction in the cost of treating a disease that is often diagnosed at an advanced stage. Spending more sooner can mean saving money later.
106Virtual gastrointestinal colonoscopy in combination with large bowel endoscopy: clinical application.PubMed
Qing He, Ting Rao, Yong-Song Guan
World J Gastroenterol. 2014 Oct 14;20(38):13820-32. doi: 10.3748/wjg.v20.i38.13820.
Although colorectal cancer (CRC) has no longer been the leading cancer killer worldwide for years with the exponential development in computed tomography (CT) or magnetic resonance imaging, and positron emission tomography/CT as well as virtual colonoscopy for early detection, the CRC related mortality is still high. The objective of CRC screening is to reduce the burden of CRC and thereby the morbidity and mortality rates of the disease. It is believed that this goal can be achieved by regularly screening the average-risk population, enabling the detection of cancer at early, curable stages, and polyps before they become cancerous. Large-scale screening with multimodality imaging approaches plays an important role in reaching that goal to detect polyps, Crohn's disease, ulcerative colitis and CRC in early stage. This article reviews kinds of presentative imaging procedures for various screening options and updates detecting, staging and re-staging of CRC patients for determining the optimal therapeutic method and forecasting the risk of CRC recurrence and the overall prognosis. The combination use of virtual colonoscopy and conventional endoscopy, advantages and limitations of these modalities are also discussed.
107Colorectal cancer development and advances in screening.PubMed
Karen Simon
Clin Interv Aging. 2016 Jul 19;11:967-76. doi: 10.2147/CIA.S109285. eCollection 2016.
Most colon tumors develop via a multistep process involving a series of histological, morphological, and genetic changes that accumulate over time. This has allowed for screening and detection of early-stage precancerous polyps before they become cancerous in individuals at average risk for colorectal cancer (CRC), which may lead to substantial decreases in the incidence of CRC. Despite the known benefits of early screening, CRC remains the second leading cause of cancer-related deaths in the United States. Hence, it is important for health care providers to have an understanding of the risk factors for CRC and various stages of disease development in order to recommend appropriate screening strategies. This article provides an overview of the histological/molecular changes that characterize the development of CRC. It describes the available CRC screening methods and their advantages and limitations and highlights the stages of CRC development in which each screening method is most effective.
108Strategies for Colorectal Cancer Screening.PubMed
Uri Ladabaum, Jason A Dominitz, Charles Kahi, et al.
Gastroenterology. 2020 Jan;158(2):418-432. doi: 10.1053/j.gastro.2019.06.043. Epub 2019 Aug 5.
The incidence of colorectal cancer (CRC) is increasing worldwide. CRC has high mortality when detected at advanced stages, yet it is also highly preventable. Given the difficulties in implementing major lifestyle changes or widespread primary prevention strategies to decrease CRC risk, screening is the most powerful public health tool to reduce mortality. Screening methods are effective but have limitations. Furthermore, many screen-eligible people remain unscreened. We discuss established and emerging screening methods, and potential strategies to address current limitations in CRC screening. A quantum step in CRC prevention might come with the development of new screening strategies, but great gains can be made by deploying the available CRC screening modalities in ways that optimize outcomes while making judicious use of resources.
109Next-generation sequencing in liquid biopsy: cancer screening and early detection.PubMed
Ming Chen, Hongyu Zhao
Hum Genomics. 2019 Aug 1;13(1):34. doi: 10.1186/s40246-019-0220-8.
In recent years, the rapid development of next-generation sequencing (NGS) technologies has led to a significant reduction in sequencing cost with improved accuracy. In the area of liquid biopsy, NGS has been applied to sequence circulating tumor DNA (ctDNA). Since ctDNA is the DNA fragments released by tumor cells, it can provide a molecular profile of cancer. Liquid biopsy can be applied to all stages of cancer diagnosis and treatment, allowing non-invasive and real-time monitoring of disease development. The most promising aspects of liquid biopsy in cancer applications are cancer screening and early diagnosis because they can lead to better survival results and less disease burden. Although many ctDNA sequencing methods have enough sensitivity to detect extremely low levels of mutation frequency at the early stage of cancer, how to effectively implement them in population screening settings remains challenging. This paper focuses on the application of liquid biopsy in the early screening and diagnosis of cancer, introduces NGS-related methods, reviews recent progress, summarizes challenges, and discusses future research directions.
110Liquid Biopsy of Methylation Biomarkers in Cell-Free DNA.PubMed
Huiyan Luo, Wei Wei, Ziyi Ye, et al.
Trends Mol Med. 2021 May;27(5):482-500. doi: 10.1016/j.molmed.2020.12.011. Epub 2021 Jan 23.
Liquid biopsies, in particular, analysis of cell-free DNA (cfDNA), have emerged as a promising noninvasive diagnostic approach in oncology. Abnormal distribution of DNA methylation is one of the hallmarks of many cancers and methylation changes occur early during carcinogenesis. Systemic analysis of cfDNA methylation profiles is being developed for cancer early detection, monitoring for minimal residual disease (MRD), predicting treatment response and prognosis, and tracing the tissue origin. This review highlights the advantages and disadvantages of ctDNA profiling for noninvasive diagnosis of early-stage cancers and explores recent advances in the clinical application of ctDNA methylation assays. We also summarize the technologies for ctDNA methylation analysis and provide a brief overview of the bioinformatic approaches for analyzing DNA methylation sequencing data.
111Clinical application of liquid biopsy in colorectal cancer: detection, prediction, and treatment monitoring.PubMed
Xiang-Yuan Tao, Qian-Qian Li, Yong Zeng
Mol Cancer. 2024 Jul 16;23(1):145. doi: 10.1186/s12943-024-02063-2.
Colorectal cancer (CRC) is one of the most prevalent malignancies affecting the gastrointestinal tract and is ranked third among cancers with the highest incidence and second-highest mortality rate worldwide. CRC exhibits a slow progression providing a wide treatment window. The currently employed CRC screening methods have shown great potential to prevent CRC and reduce CRC-related morbidity and mortality. The diagnosis of CRC is achieved by colonoscopy and tissue biopsy, with studies showing that liquid biopsy is more effective in detecting and diagnosing early CRC patients. Increasing number of studies have shown that the tumor components shed into circulating blood can be detected in liquid form, and can be applied in the clinical management of CRC. Analysis of circulating tumor cells (CTCs), circulating tumor DNA (ctDNA), or tumor-associated platelets (TEPs) in the blood can be used for early screening and diagnosis of CRC, aid tumor staging, treatment response monitoring, and prediction of CRC recurrence and metastasis in a minimally invasive manner. This chapter provides an updated review of CTCs, ctDNA, and TEPs as novel biomarkers for CRC, highlighting their strengths and limitations.
112Retrospective Review of Multitarget Stool DNA as a Screening Test for Colorectal Cancer.PubMed
Thomas K Kleinschmidt, Austin Clements, Mark A Parker, et al.
Am Surg. 2023 Apr;89(4):603-606. doi: 10.1177/00031348211031844. Epub 2021 Jul 18.
OBJECTIVES: To review the effectiveness of noninvasive multitarget stool DNA testing as a screening test for colorectal cancer. METHODS: We performed a retrospective review of patients referred to 2 high volume outpatient procedural centers for colonoscopy for positive Cologuard test. Positive findings for colorectal cancer based on pathologic findings and also advanced adenomas were recorded. Positive predictive value (PPV) was assessed. RESULTS: Of the 1585 patients evaluated and referred for colonoscopy from January 1, 2018 to November 1, 2019, for ICD-10 codes R19.5 (other fecal abnormalities) and K92.1 (melena), 84 were referred for a positive Cologuard test. Out of the 84, 6 were excluded based on family history of colon cancer in first degree relative or personal history of inflammatory bowel disease. Of the remaining 78 patients, 1 patient (1.3%) had colorectal cancer and 5 (6.4%) had advanced adenomas (>1 cm size, high grade dysplasia or villous). Postive predictive value for colorectal cancer was 1.3% and for precancerous lesions plus colorectal cancer was 7.7%. A total of 53 (68.0%) patients had either totally normal colonoscopy or hyperplastic polyps. Out of the 78 individuals in our study, 70 (89.7%) had normal findings, hyperplastic polyps, or non-advanced adenomas. CONCLUSIONS: Multitarget stool DNA testing carries an unacceptably low PPV to be utilized as a screening test for colorectal cancer. The study fails to detect both adenomas and colon cancer at a higher rate than screening colonoscopy in selected studies. The advantage of being noninvasive has been noted to increase colorectal cancer screening in otherwise non-compliant Medicare patients.
113Multitarget Stool DNA Screening in Clinical Practice: High Positive Predictive Value for Colorectal Neoplasia Regardless of Exposure to Previous Colonoscopy.PubMed
Jason D Eckmann, Derek W Ebner, Jamie Bering, et al.
Am J Gastroenterol. 2020 Apr;115(4):608-615. doi: 10.14309/ajg.0000000000000546.
OBJECTIVES: Multitarget stool DNA (MT-sDNA) testing has grown as a noninvasive screening modality for colorectal cancer (CRC), but real-world clinical data are limited in the post-FDA approval setting. The effect of previous colonoscopy on MT-sDNA performance is not known. We aimed to evaluate findings of colorectal neoplasia (CRN) at diagnostic colonoscopy in patients with positive MT-sDNA testing, stratified by patient exposure to previous colonoscopy. METHODS: We identified consecutive patients completing MT-sDNA testing over a 39-month period and reviewed the records of those with positive tests for neoplastic findings at diagnostic colonoscopy. MT-sDNA test positivity rate, adherence to diagnostic colonoscopy, and the positive predictive value (PPV) of MT-sDNA for any CRN and neoplastic subtypes were calculated. RESULTS: Of 16,469 MT-sDNA tests completed, testing returned positive in 2,326 (14.1%) patients. After exclusion of patients at increased risk for CRC, 1,801 patients remained, 1,558 (87%) of whom underwent diagnostic colonoscopy; 918 of 1,558 (59%) of these patients had undergone previous colonoscopy, whereas 640 (41%) had not. Any CRN was found in 1,046 of 1,558 patients (PPV = 67%). More neoplastic lesions were found in patients without previous colonoscopy (73%); however, the rates remained high among those who had undergone previous colonoscopy (63%, P < 0.0001). The large majority (79%) of patients had right-sided neoplasia. DISCUSSION: MT-sDNA has a high PPV for any CRN regardless of exposure to previous colonoscopy. Right-sided CRN was found at colonoscopy in most patients with positive MT-sDNA testing, representing a potential advantage over other currently available screening modalities for CRC.
114A multivariate parametric empirical Bayes screening approach for early detection of hepatocellular carcinoma using multiple longitudinal biomarkers.PubMed
Nabihah Tayob, Anna S F Lok, Ziding Feng
Stat Med. 2022 Jun 15;41(13):2338-2353. doi: 10.1002/sim.9358. Epub 2022 Feb 23.
The early detection of hepatocellular carcinoma (HCC) is critical to improving outcomes since advanced HCC has limited treatment options. Current guidelines recommend HCC ultrasound surveillance every 6 months in high-risk patients however the sensitivity for detecting early stage HCC in clinical practice is poor. Blood-based biomarkers are a promising direction since they are more easily standardized and less resource intensive. Combining of multiple biomarkers is more likely to achieve the sensitivity required for a clinically useful screening algorithm and the longitudinal trajectory of biomarkers contains valuable information that should be utilized. We propose a multivariate parametric empirical Bayes (mPEB) screening approach that defines personalized thresholds for each patient at each screening visit to identify significant deviations that trigger additional testing with more sensitive imaging. The Hepatitis C Antiviral Long-term Treatment against Cirrhosis (HALT-C) trial provides a valuable source of data to study HCC screening algorithms. We study the performance of the mPEB algorithm applied to serum -fetoprotein, a widely used HCC surveillance biomarker, and des- carboxy prothrombin, an HCC risk biomarker that is FDA approved but not used in practice in the United States. Using cross-validation, we found that the mPEB algorithm demonstrated moderate but improved sensitivity compared to alternative screening approaches. Future research will validate the clinical utility of the approach in larger cohort studies with additional biomarkers.
115Clinical utility of serum fucosylated fraction of alpha-fetoprotein in the diagnostic of hepatocellular carcinoma: a comprehensive analysis with large sample size.PubMed
Aibin Liu, Yanyan Li, Lin Shen, et al.
Aging (Albany NY). 2022 Mar 20;14(6):2645-2664. doi: 10.18632/aging.203963.
We conducted a comprehensive meta-analysis of the utility of AFP-L3 for the diagnosis of hepatocellular carcinoma, to provide a more accurate estimation for the clinical utility of AFP-L3. We performed online searches in five databases (PubMed, China National Knowledge Infrastructure, Wanfang, Web of Science, and Embase), from inception to December 31, 2021. Pooled sensitivity, specificity, and area under the curve (AUC) with the matching 95% confidence intervals (95% CIs) were calculated to estimate the diagnostic value of AFP-L3. Thirty-four studies were included in the meta-analysis. The pooled sensitivity was 0.70 [95% confidence interval (CI): 0.63-0.77], and the specificity was 0.91 (95% CI: 0.88-0.94). The estimated area under the curve (AUC) was 0.90 (95% CI: 0.87-0.92). The positive likelihood ratio and negative likelihood ratio were 7.78 (95% CI: 5.7-10.7) and 0.33 (95% CI: 0.26-0.41), respectively. The diagnostic odds ratio was 24 (95% CI: 16-37). The subgroup analysis indicated moderate sensitivity (0.79) and high specificity (0.89) for the Asian population (AUC = 0.89), and similar specificity (0.95) but lower sensitivity (0.35) for Caucasians (AUC = 0.80). Deeks' funnel plot asymmetry test detected no publication bias ( = 0.460). The sensitivity analysis showed that the pooled results were stable. Taken together, our results indicated that AFP-L3 demonstrates high diagnostic ability for HCC, especially among Asian populations. AFP-L3 is a useful means for high-volume screening, which can help doctors optimize diagnosis workflow, reduce workload, and improve detection sensitivity. The combination of multiple biomarkers may provide more accurate diagnostic tools for HCC in the future.
116A new platform of electrowetting-on-dielectric digital microfluidics for rapid detection of early-stage Hepatocellular Carcinoma(HCC) specific biomarker.PubMed
Wenjie Zhu, Hong Qian, Shengya Cao, et al.
Anal Chim Acta. 2025 Jan 22;1336:343533. doi: 10.1016/j.aca.2024.343533. Epub 2024 Dec 7.
BACKGROUND: The early detection of Hepatocellular Carcinoma (HCC) is crucial for improving patient survival rates.Early diagnosis of HCC can significantly enhance treatment outcomes and reduce disease progression. Antigen detection of tumor markers is one of the important diagnostic methods for HCC. However, Traditional antigen detection methods often rely on heavy detection equipment, involve lengthy turnaround times, and must be conducted in laboratory settings. Therefore, there is a clear need for a portable, low-skill, rapid sample-to-result detection method for early HCC biomarkers. RESULTS: We propose a new platform based on electrowetting-on-dielectric digital microfluidic(EWOD-DMF) for the detection of early-stage HCC biomarkers, enabling the quantitative measurement of Alpha-Fetoprotein (AFP), the proportion of AFP-L3 in total AFP (AFP-L3%), and Des-Gamma-Carboxy Prothrombin (DCP). First, serum samples are processed through the microfluidic system, achieving the separation of AFP-L3 within 10 min. Next, immunoassays are performed within 15 min, using magnetic particles to capture biomarkers such as AFP, AFP-L3, and DCP, followed by enzymatic reactions that generate detectable signals. Each chip can simultaneously detect three biomarkers from five different samples, allowing for a total of fifteen targets to be tested, with only approximately 2.4 μL of serum required for each biomarker detection. Ultimately, data are analyzed with dedicated software to quantitatively measure the HCC biomarkers. The detection limits for AFP or AFP-L3 and for DCP are 0.24 ng/mL and 1.89 ng/mL, respectively. SIGNIFICANCE: This study presents a EWOD-DMF platform for early-stage HCC diagnosis, capable of simultaneously detecting multiple samples and biomarkers, thus improving detection efficiency and diagnostic accuracy. Moreover, the platform has POCT capability, with advantages in portability and cost-effectiveness, providing clinicians and primary healthcare institutions with a fast and convenient solution for early-stage HCC diagnosis.
117A comparison of statistical methods for the detection of hepatocellular carcinoma based on serum biomarkers and clinical variables.PubMed
Mengjun Wang, Anand Mehta, Timothy M Block, et al.
BMC Med Genomics. 2013;6 Suppl 3(Suppl 3):S9. doi: 10.1186/1755-8794-6-S3-S9. Epub 2013 Nov 11.
BACKGROUND: Currently, a surgical approach is the best curative treatment for those with hepatocellular carcinoma (HCC). However, this requires HCC detection and removal of the lesion at an early stage. Unfortunately, most cases of HCC are detected at an advanced stage because of the lack of accurate biomarkers that can be used in the surveillance of those at risk. It is believed that biomarkers that could detect HCC early will play an important role in the successful treatment of HCC. METHODS: In this study, we analyzed serum levels of alpha fetoprotein, Golgi protein, fucosylated alpha-1-anti-trypsin, and fucosylated kininogen from 113 patients with cirrhosis and 164 serum samples from patients with cirrhosis plus HCC. We utilized two different methods, namely, stepwise penalized logistic regression (stepPLR) and model-based classification and regression trees (mob), along with the inclusion of clinical and demographic factors such as age and gender, to determine if these improved algorithms could be used to increase the detection of cancer. RESULTS AND DISCUSSION: The performance of multiple biomarkers was found to be better than that of individual biomarkers. Using several statistical methods, we were able to detect HCC in the background of cirrhosis with an area under the receiver operating characteristic curve of at least 0.95. stepPLR and mob demonstrated better predictive performance relative to logistic regression (LR), penalized LR and classification and regression trees (CART) used in our prior study based on three-fold cross-validation and leave one out cross-validation. In addition, mob provided unparalleled intuitive interpretation of results and potential cut-points for biomarker levels. The inclusion of age and gender improved the overall performance of both methods among all models considered, while the stratified male-only subset provided the best overall performance among all methods and models considered. CONCLUSIONS: In addition to multiple biomarkers, the incorporation of age and gender into statistical models significantly improved their predictive performance in the detection of HCC.
118Projected Impact and Cost-Effectiveness of Novel Molecular Blood-Based or Stool-Based Screening Tests for Colorectal Cancer.PubMed
Uri Ladabaum, Ajitha Mannalithara, Robert E Schoen, et al.
Ann Intern Med. 2024 Dec;177(12):1610-1620. doi: 10.7326/ANNALS-24-00910. Epub 2024 Oct 29.
BACKGROUND: Cell-free DNA blood tests (cf-bDNA) and next-generation stool tests could change colorectal cancer (CRC) screening. OBJECTIVE: To estimate the clinical and economic impacts of novel CRC screening tests. DESIGN: Cost-effectiveness analysis using MOSAIC (Model of Screening and Surveillance for Colorectal Cancer). DATA SOURCES: Published data. TARGET POPULATION: Average-risk persons. TIME HORIZON: Ages 45 to 100 years. PERSPECTIVE: Health sector. INTERVENTION: Novel versus established CRC screening tests. OUTCOME MEASURES: Incidence and mortality of CRC, quality-adjusted life-years (QALYs), costs. RESULTS OF BASE-CASE ANALYSIS: For colonoscopy every 10 years, annual fecal immunochemical test (FIT), and triennial next-generation multitarget stool DNA, FIT-RNA, cf-bDNA (Guardant Shield), or cf-bDNA (Freenome), the relative rates (RRs) and 95% uncertainty intervals (UIs) versus no screening for CRC incidence were 0.21 (0.19 to 0.22), 0.29 (0.27 to 0.31), 0.33 (0.32 to 0.36), 0.32 (0.30 to 0.34), 0.58 (0.55 to 0.61) and 0.58 (0.55 to 0.60), respectively; the RRs for CRC death were 0.19 (0.17 to 0.20), 0.25 (0.23 to 0.27), 0.28 (0.27 to 0.30), 0.28 (0.26 to 0.30), 0.44 (0.42 to 0.47), and 0.46 (0.44 to 0.49), respectively. The cf-bDNA test (Shield; list price $1495) cost $89 600 ($74 800 to $102 300) per QALY gained versus no screening; alternatives were less costly and more effective. RESULTS OF SENSITIVITY ANALYSIS: Incremental costs exceeded incremental benefits when novel test intervals were shortened to 2 or 1 years. The cf-bDNA test matched FIT's impact on CRC mortality at 1.35 (1.30 to 1.40)-fold FIT's uptake rate, assuming equal colonoscopy follow-up. If persons who accept colonoscopy or stool tests shifted to cf-bDNA, CRC deaths increased. This adverse effect was overcome if every 3 such substitutions were counterbalanced by cf-bDNA uptake by 2 or more persons refusing alternatives, assuming equal colonoscopy follow-up. LIMITATION: Longitudinal test-specific participation patterns are unknown. CONCLUSION: First-generation cf-bDNA tests may deliver net benefit or harm, depending on the balance between achieving screening in persons who decline alternatives versus substituting cf-bDNA for more effective alternatives. PRIMARY FUNDING SOURCE: The Gorrindo Family Fund.
119Stool DNA testing to screen for colorectal cancer in the Medicare population: a cost-effectiveness analysis.PubMed
Iris Lansdorp-Vogelaar, Karen M Kuntz, Amy B Knudsen, et al.
Ann Intern Med. 2010 Sep 21;153(6):368-77. doi: 10.7326/0003-4819-153-6-201009210-00004.
BACKGROUND: The Centers for Medicare & Medicaid Services considered whether to reimburse stool DNA testing for colorectal cancer screening among Medicare enrollees. OBJECTIVE: To evaluate the conditions under which stool DNA testing could be cost-effective compared with the colorectal cancer screening tests currently reimbursed by the Centers for Medicare & Medicaid Services. DESIGN: Comparative microsimulation modeling study using 2 independently developed models. DATA SOURCES: Derived from literature. TARGET POPULATION: A cohort of persons aged 65 years. A sensitivity analysis was also conducted, in which a cohort of persons aged 50 years was studied. TIME HORIZON: Lifetime. PERSPECTIVE: Third-party payer. INTERVENTION: Stool DNA test every 3 or 5 years in comparison with currently recommended colorectal cancer screening strategies. OUTCOME MEASURES: Life expectancy, lifetime costs, incremental cost-effectiveness ratios, and threshold costs. RESULTS OF BASE-CASE ANALYSIS: Assuming a cost of $350 per test, strategies of stool DNA testing every 3 or 5 years yielded fewer life-years and higher costs than the currently recommended colorectal cancer screening strategies. Screening with the stool DNA test would be cost-effective at a per-test cost of $40 to $60 for stool DNA testing every 3 years, depending on the simulation model used. There were no levels of sensitivity and specificity for which stool DNA testing would be cost-effective at its current cost of $350 per test. Stool DNA testing every 3 years would be cost-effective at a cost of $350 per test if the relative adherence to stool DNA testing were at least 50% better than that with other screening tests. RESULTS OF SENSITIVITY ANALYSIS: None of the results changed substantially when a cohort of persons aged 50 years was considered. LIMITATION: No pathways other than the traditional adenoma-carcinoma sequence were modeled. CONCLUSION: Stool DNA testing could be a cost-effective alternative for colorectal cancer screening if the cost of the test substantially decreased or if its availability would entice a large fraction of otherwise unscreened persons to receive screening.
120A pilot study utilizing whole body 18 F-FDG-PET/CT as a comprehensive screening strategy for occult malignancy in patients with unprovoked venous thromboembolism.PubMed
Matthew T Rondina, Nathan Wanner, Robert C Pendleton, et al.
Thromb Res. 2012 Jan;129(1):22-7. doi: 10.1016/j.thromres.2011.06.025. Epub 2011 Jul 29.
BACKGROUND: Approximately 7-10% of patients with unprovoked VTE will be diagnosed with cancer within 12 months. Although cancer screening has been proposed in these patients, the optimal strategy remains unclear. In a pilot study, we prospectively investigated the use of FDG-PET/CT to screen for occult malignancy in 40 patients with unprovoked VTE. MATERIALS/METHODS: Patients were initially screened for occult malignancy with a focused history, physical, and laboratory evaluation. Patients underwent whole body FDG-PET/CT and were followed for up to two years for a new diagnosis of cancer. The total costs of using FDG-PET/CT as a comprehensive screening strategy were determined using 2010 Medicare reimbursement rates. RESULTS: Completion of FDG-PET/CT imaging was feasible and identified abnormal findings requiring additional evaluations in 62.5% of patients. Occult malignancy was evident in only one patient (cancer incidence 2.5%) and FDG-PET/CT imaging excluded malignancy in the remainder of patients. No patients with a negative FDG-PET/CT were diagnosed with malignancy during an average (±SD) follow-up of 449 (±311) days. The use of FDG-PET/CT to screen for occult malignancy added $59,151 in total costs ($1,479 per patient). The majority of these costs were due to the cost of the FDG-PET/CT ($1,162 per patient or 78.5% of total per-patient costs). CONCLUSIONS: FDG-PET/CT may have utility for excluding occult malignancy in patients with unprovoked VTE. The costs of this comprehensive screening strategy were comparable to other screening approaches. Larger studies are needed to further evaluate the utility and cost-effectiveness of FDG-PET/CT as a cancer screening strategy in patients with unprovoked VTE.
121Immunogenicity of the 9-Valent HPV Vaccine Using 2-Dose Regimens in Girls and Boys vs a 3-Dose Regimen in Women.PubMed
Ole-Erik Iversen, Maria Jose Miranda, Angels Ulied, et al.
JAMA. 2016 Dec 13;316(22):2411-2421. doi: 10.1001/jama.2016.17615.
IMPORTANCE: Human papillomavirus (HPV) infections cause anogenital cancers and warts. The 9-valent HPV vaccine provides protection against 7 high-risk types of HPV responsible for 90% of cervical cancers and 2 other HPV types accounting for 90% of genital warts. OBJECTIVE: To determine whether HPV type-specific antibody responses would be noninferior among girls and boys aged 9 to 14 years after receiving 2 doses of the 9-valent HPV vaccine compared with adolescent girls and young women aged 16 to 26 years receiving 3 doses. DESIGN, SETTING, AND PARTICIPANTS: Open-label, noninferiority, immunogenicity trial conducted at 52 ambulatory care sites in 15 countries. The study was initiated on December 16, 2013, with the last participant visit for this report on June 19, 2015. Five cohorts were enrolled: (1) girls aged 9 to 14 years to receive 2 doses 6 months apart (n = 301); (2) boys aged 9 to 14 years to receive 2 doses 6 months apart (n = 301); (3) girls and boys aged 9 to 14 years to receive 2 doses 12 months apart (n = 301); (4) girls aged 9 to 14 years to receive 3 doses over 6 months (n = 301); and (5) a control group of adolescent girls and young women aged 16 to 26 years to receive 3 doses over 6 months (n = 314). INTERVENTIONS: Two doses of the 9-valent HPV vaccine administered 6 or 12 months apart or 3 doses administered over 6 months. MAIN OUTCOMES AND MEASURES: The primary end point was prespecified as the antibody response against each HPV type assessed 1 month after the last dose using a competitive immunoassay. Each of the three 2-dose regimens was compared with the standard 3-dose schedule in adolescent girls and young women using a noninferiority margin of 0.67 for the ratio of the antibody geometric mean titers. RESULTS: Of the 1518 participants (753 girls [mean age, 11.4 years]; 451 boys [mean age, 11.5 years]; and 314 adolescent girls and young women [mean age, 21.0 years]), 1474 completed the study and data from 1377 were analyzed. At 4 weeks after the last dose, HPV antibody responses in girls and boys given 2 doses were noninferior to HPV antibody responses in adolescent girls and young women given 3 doses (P < .001 for each HPV type). Compared with adolescent girls and young women who received 3 doses over 6 months, the 1-sided 97.5% CIs for the ratio of HPV antibody geometric mean titers at 1 month after the last dose across the 9 HPV subtypes ranged from 1.36 to ∞ to 2.50 to ∞ for girls who received 2 doses 6 months apart; from 1.37 to ∞ to 2.55 to ∞ for boys who received 2 doses 6 months apart; and from 1.61 to ∞ to 5.36 to ∞ for girls and boys who received 2 doses 12 months apart. CONCLUSIONS AND RELEVANCE: Among girls and boys aged 9 to 14 years receiving 2-dose regimens of a 9-valent HPV vaccine separated by 6 or 12 months, immunogenicity 4 weeks after the last dose was noninferior to a 3-dose regimen in a cohort of adolescent girls and young women. Further research is needed to assess persistence of antibody responses and effects on clinical outcomes. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01984697.
122The impact of 10 years of human papillomavirus (HPV) vaccination in Australia: what additional disease burden will a nonavalent vaccine prevent?PubMed
Cyra Patel, Julia Ml Brotherton, Alexis Pillsbury, et al.
Euro Surveill. 2018 Oct;23(41). doi: 10.2807/1560-7917.ES.2018.23.41.1700737.
BACKGROUND: A National human papilloma virus (HPV) Vaccination Programme for the prevention of HPV infection and associated disease using the quadrivalent HPV vaccine (4vHPV) has been funded and implemented in Australia since 2007, initially for girls only and extended to boys in 2013, with uptake rates among the highest observed worldwide. AIM: We report on the impact of this national programme on HPV prevalence and associated disease burden and estimate the potential impact of adopting a nonavalent HPV (9vHPV) vaccine. METHODS: We performed a non-systematic literature review of studies measuring the burden of HPV-associated disease and infection in Australia before and after introduction of HPV vaccination. We also included key national reports with estimates of HPV-related disease burden. RESULTS: Substantial declines in high-grade cervical disease and genital warts among vaccine-eligible women have been observed. Reductions in genital warts incidence and HPV prevalence among heterosexual men of similar age were observed before introduction of the male vaccination programme, indicating a substantial herd effect. 9vHPV vaccine is expected to prevent up to 90% of cervical and 96% of anal cancers. Of an estimated 1,544 HPV-associated cancers in 2012, 1,242 would have been preventable by the 4vHPV vaccine and an additional 187 anogenital cancers by the 9vHPV vaccine. CONCLUSIONS: Vaccination using 4vHPV vaccine has had a large demonstrable impact on HPV-related disease in Australia. A switch to 9vHPV could further reduce the HPV-associated cancer burden. With continued high coverage among both males and females, elimination of vaccine-type HPV disease seems achievable in Australia.
123A 9-valent HPV vaccine against infection and intraepithelial neoplasia in women.PubMed
Elmar A Joura, Anna R Giuliano, Ole-Erik Iversen, et al.
N Engl J Med. 2015 Feb 19;372(8):711-23. doi: 10.1056/NEJMoa1405044.
BACKGROUND: The investigational 9-valent viruslike particle vaccine against human papillomavirus (HPV) includes the HPV types in the quadrivalent HPV (qHPV) vaccine (6, 11, 16, and 18) and five additional oncogenic types (31, 33, 45, 52, and 58). Here we present the results of a study of the efficacy and immunogenicity of the 9vHPV vaccine in women 16 to 26 years of age. METHODS: We performed a randomized, international, double-blind, phase 2b-3 study of the 9vHPV vaccine in 14,215 women. Participants received the 9vHPV vaccine or the qHPV vaccine in a series of three intramuscular injections on day 1 and at months 2 and 6. Serum was collected for analysis of antibody responses. Swabs of labial, vulvar, perineal, perianal, endocervical, and ectocervical tissue were obtained and used for HPV DNA testing, and liquid-based cytologic testing (Papanicolaou testing) was performed regularly. Tissue obtained by means of biopsy or as part of definitive therapy (including a loop electrosurgical excision procedure and conization) was tested for HPV. RESULTS: The rate of high-grade cervical, vulvar, or vaginal disease irrespective of HPV type (i.e., disease caused by HPV types included in the 9vHPV vaccine and those not included) in the modified intention-to-treat population (which included participants with and those without prevalent infection or disease) was 14.0 per 1000 person-years in both vaccine groups. The rate of high-grade cervical, vulvar, or vaginal disease related to HPV-31, 33, 45, 52, and 58 in a prespecified per-protocol efficacy population (susceptible population) was 0.1 per 1000 person-years in the 9vHPV group and 1.6 per 1000 person-years in the qHPV group (efficacy of the 9vHPV vaccine, 96.7%; 95% confidence interval, 80.9 to 99.8). Antibody responses to HPV-6, 11, 16, and 18 were noninferior to those generated by the qHPV vaccine. Adverse events related to injection site were more common in the 9vHPV group than in the qHPV group. CONCLUSIONS: The 9vHPV vaccine prevented infection and disease related to HPV-31, 33, 45, 52, and 58 in a susceptible population and generated an antibody response to HPV-6, 11, 16, and 18 that was noninferior to that generated by the qHPV vaccine. The 9vHPV vaccine did not prevent infection and disease related to HPV types beyond the nine types covered by the vaccine. (Funded by Merck; ClinicalTrials.gov number, NCT00543543).
124Alternative HPV vaccination schedules in Latin America.PubMed
Claudia Robles, María de la Luz Hernández, Maribel Almonte
Salud Publica Mex. 2018 Nov-Dic;60(6):693-702. doi: 10.21149/9810.
In 2008, the first HPV vaccination program in Latin America started in Panama, targeting girls aged 10-11 years with a 3-dose vaccine schedule, an initiative that was to be followed by other Latin American countries after local feasibility and population acceptability evaluations were completed. A 3-dose vaccine regimen over six months was originally chosen for HPV vaccines, copying the Hepatitis B vaccine schedule (0, 1-2, 6 months). Alternative vaccine schedules have been proposed afterwards based on: i) noninferior immunogenicity or immune response levels compared to those at which clinical efficacy has been proven (i.e., those observed in a 3-dose HPV vaccine schedule in women aged 15-26), and, ii) proven efficacy in clinical trials and/or effectiveness among women who were provided less than three doses due to a lack of adherence to a 3-dose vaccine schedule. In 2014, based on the available evidence and the potential increase in coverage by expansion of vaccination target groups, particularly in low and middle income countries (LMIC), the World Health Organization recommended a 2-dose schedule with at least a 6-month interval between doses for females up to 15 years of age and a 3-dose schedule for older women. More recently, it has been suggested that 1-dose HPV vaccination schemes may provide enough protection against HPV infection and may speed up the introduction of HPV vaccination in LMIC, where most needed.
125Routine Childhood Vaccines Given From 1 through 18 Years of Age.PubMed
Robert M Jacobson
Mayo Clin Proc. 2020 Aug;95(8):1780-1795. doi: 10.1016/j.mayocp.2020.06.004.
In addition to the vaccines due in the first year of life, the US Advisory Committee on Immunization Practices recommends that children continue to receive vaccines regularly against a variety of infectious diseases. Starting at 12 to 15 months of life, these include the two-dose measles-mumps-rubella vaccine series and the two-dose varicella vaccine series. Also in the second year of life, infants should begin the two-dose hepatitis A vaccine series and complete the Haemophilus influenzae type B vaccine series as well as the pneumococcal conjugate vaccine series. Before 19 months of life, infants should receive the third dose of the poliovirus vaccine and the fourth dose of diphtheria-tetanus-acellular pertussis (DTaP) vaccine. The final doses of poliovirus and tetanus-diphtheria-acellular pertussis vaccines are both due at 4 to 6 years of life. Before each influenza season, every child should receive the influenza vaccine. Those less than 9 years of age who previously received less than two doses need two doses a month apart. At 11 to 12 years of life, all should get two doses of the human papillomavirus vaccine, the adolescent/adult version of the tetanus-diphtheria-acellular pertussis vaccine, and begin a two-dose series of meningococcal ACWY vaccine. Each of these vaccines is due when the vaccine works to protect against both an immediate risk as well as to provide long-term protection. Each vaccine-preventable disease varies in terms of the nature of exposure, the form of the morbidity, the risk of mortality, and potential to prevent or ameliorate its harm.
126Use of 9-valent human papillomavirus (HPV) vaccine: updated HPV vaccination recommendations of the advisory committee on immunization practices.PubMed
Emiko Petrosky, Joseph A Bocchini, Susan Hariri, et al.
MMWR Morb Mortal Wkly Rep. 2015 Mar 27;64(11):300-4.
During its February 2015 meeting, the Advisory Committee on Immunization Practices (ACIP) recommended 9-valent human papillomavirus (HPV) vaccine (9vHPV) (Gardasil 9, Merck and Co., Inc.) as one of three HPV vaccines that can be used for routine vaccination. HPV vaccine is recommended for routine vaccination at age 11 or 12 years. ACIP also recommends vaccination for females aged 13 through 26 years and males aged 13 through 21 years not vaccinated previously. Vaccination is also recommended through age 26 years for men who have sex with men and for immunocompromised persons (including those with HIV infection) if not vaccinated previously. 9vHPV is a noninfectious, virus-like particle (VLP) vaccine. Similar to quadrivalent HPV vaccine (4vHPV), 9vHPV contains HPV 6, 11, 16, and 18 VLPs. In addition, 9vHPV contains HPV 31, 33, 45, 52, and 58 VLPs. 9vHPV was approved by the Food and Drug Administration (FDA) on December 10, 2014, for use in females aged 9 through 26 years and males aged 9 through 15 years. For these recommendations, ACIP reviewed additional data on 9vHPV in males aged 16 through 26 years. 9vHPV and 4vHPV are licensed for use in females and males. Bivalent HPV vaccine (2vHPV), which contains HPV 16, 18 VLPs, is licensed for use in females. This report summarizes evidence considered by ACIP in recommending 9vHPV as one of three HPV vaccines that can be used for vaccination and provides recommendations for vaccine use.
127HPV Vaccination and the Risk of Invasive Cervical Cancer.PubMed
Jiayao Lei, Alexander Ploner, K Miriam Elfström, et al.
N Engl J Med. 2020 Oct 1;383(14):1340-1348. doi: 10.1056/NEJMoa1917338.
BACKGROUND: The efficacy and effectiveness of the quadrivalent human papillomavirus (HPV) vaccine in preventing high-grade cervical lesions have been shown. However, data to inform the relationship between quadrivalent HPV vaccination and the subsequent risk of invasive cervical cancer are lacking. METHODS: We used nationwide Swedish demographic and health registers to follow an open population of 1,672,983 girls and women who were 10 to 30 years of age from 2006 through 2017. We assessed the association between HPV vaccination and the risk of invasive cervical cancer, controlling for age at follow-up, calendar year, county of residence, and parental characteristics, including education, household income, mother's country of birth, and maternal disease history. RESULTS: During the study period, we evaluated girls and women for cervical cancer until their 31st birthday. Cervical cancer was diagnosed in 19 women who had received the quadrivalent HPV vaccine and in 538 women who had not received the vaccine. The cumulative incidence of cervical cancer was 47 cases per 100,000 persons among women who had been vaccinated and 94 cases per 100,000 persons among those who had not been vaccinated. After adjustment for age at follow-up, the incidence rate ratio for the comparison of the vaccinated population with the unvaccinated population was 0.51 (95% confidence interval [CI], 0.32 to 0.82). After additional adjustment for other covariates, the incidence rate ratio was 0.37 (95% CI, 0.21 to 0.57). After adjustment for all covariates, the incidence rate ratio was 0.12 (95% CI, 0.00 to 0.34) among women who had been vaccinated before the age of 17 years and 0.47 (95% CI, 0.27 to 0.75) among women who had been vaccinated at the age of 17 to 30 years. CONCLUSIONS: Among Swedish girls and women 10 to 30 years old, quadrivalent HPV vaccination was associated with a substantially reduced risk of invasive cervical cancer at the population level. (Funded by the Swedish Foundation for Strategic Research and others.).
128Real-World Effectiveness of Human Papillomavirus Vaccination Against Cervical Cancer.PubMed
Susanne K Kjaer, Christian Dehlendorff, Federica Belmonte, et al.
J Natl Cancer Inst. 2021 Oct 1;113(10):1329-1335. doi: 10.1093/jnci/djab080.
BACKGROUND: The primary goal of human papillomavirus (HPV) vaccination is to reduce morbidity and mortality from HPV-associated disease, especially cervical cancer. We determined the real-world effectiveness of HPV vaccination against cervical cancer. METHODS: The study included women aged 17-30 years living in Denmark October 2006-December 2019. From nationwide registries, information on HPV vaccination and cervical cancer diagnoses were retrieved. Incidence rate ratios (IRRs) with 95% confidence intervals (CIs) for cervical cancer according to vaccination status were estimated using Poisson regression with HPV vaccination treated as a time-varying variable and stratified by age at vaccination. We adjusted for attained age, education, and ethnicity. To address the effect of prevalent disease, different buffer periods were used, with 1-year buffer period as primary analysis. RESULTS: The cohort comprised 867 689 women. At baseline, 36.3% were vaccinated at age 16 years and younger, and during follow-up, 19.3% and 2.3% were vaccinated at ages 17-19 years and 20-30 years, respectively. For women vaccinated at ages 16 years and younger or 17-19 years, the IRRs of cervical cancer were 0.14 (95% CI = 0.04 to 0.53) and 0.32 (95% CI = 0.08 to 1.28), respectively, compared with unvaccinated women. In women aged 20-30 years at vaccination, the incidence rate was higher than among unvaccinated women (IRR = 1.19, 95% CI = 0.80 to 1.79) but slightly decreased with increasing buffer period (IRR = 0.85, 95% CI = 0.55 to 1.32, with 4-year buffer period). CONCLUSION: HPV vaccine effectiveness against cervical cancer at the population level is high among girls vaccinated younger than age 20 years. The lack of immediate effect in women vaccinated at age 20-30 years points to the importance of early age at vaccination.
129Human papillomavirus vaccine effectiveness by age at vaccination: A systematic review.PubMed
Mallory K Ellingson, Hassan Sheikha, Kate Nyhan, et al.
Hum Vaccin Immunother. 2023 Aug 1;19(2):2239085. doi: 10.1080/21645515.2023.2239085.
Human papillomavirus (HPV) vaccines work by preventing infections prior to natural exposure. Thus, it is likely more effective at younger ages, and it is important to understand how effectiveness might be diminished when administered at older ages. We conducted a systematic review of HPV vaccine effectiveness studies published between 2007 and 2022 that included an analysis of effectiveness against vaccine-type HPV infections, anogenital warts, cervical abnormalities and cervical cancer by age at vaccine initiation or completion. Searching multiple databases, 21 studies were included and results were summarized descriptively. Seventeen studies found the highest vaccine effectiveness in the youngest age group. Vaccine effectiveness estimates for younger adolescents ages 9-14 years ranged from approximately 74% to 93% and from 12% to 90% for adolescents ages 15-18 years. These results demonstrate that the HPV vaccine is most effective against HPV-related disease outcomes when given at younger ages, emphasizing the importance of on-time vaccination.
130Role of human papillomavirus (HPV) vaccination on HPV infection and recurrence of HPV related disease after local surgical treatment: systematic review and meta-analysis.PubMed
Konstantinos S Kechagias, Ilkka Kalliala, Sarah J Bowden, et al.
BMJ. 2022 Aug 3;378:e070135. doi: 10.1136/bmj-2022-070135.
OBJECTIVE: To explore the efficacy of human papillomavirus (HPV) vaccination on the risk of HPV infection and recurrent diseases related to HPV infection in individuals undergoing local surgical treatment. DESIGN: Systematic review and meta-analysis DATA SOURCES: PubMed (Medline), Scopus, Cochrane, Web of Science, and ClinicalTrials.gov were screened from inception to 31 March 2021. REVIEW METHODS: Studies reporting on the risk of HPV infection and recurrence of disease related to HPV infection after local surgical treatment of preinvasive genital disease in individuals who were vaccinated were included. The primary outcome measure was risk of recurrence of cervical intraepithelial neoplasia grade 2 or higher (CIN2+) after local surgical treatment, with follow-up as reported by individual studies. Secondary outcome measures were risk of HPV infection or other lesions related to HPV infection. Independent and in duplicate data extraction and quality assessment were performed with ROBINS-I and RoB-2 tools for observational studies and randomised controlled trials, respectively. Grading of Recommendations Assessment, Development, and Evaluation (GRADE) was implemented for the primary outcome. Observational studies and randomised controlled trials were analysed separately from post hoc analyses of randomised controlled trials. Pooled risk ratios and 95% confidence intervals were calculated with a random effects meta-analysis model. The restricted maximum likelihood was used as an estimator for heterogeneity, and the Hartung-Knapp-Sidik-Jonkman method was used to derive confidence intervals. RESULTS: 22 articles met the inclusion criteria of the review; 18 of these studies also reported data from a non-vaccinated group and were included in the meta-analyses (12 observational studies, two randomised controlled trials, and four post hoc analyses of randomised controlled trials). The risk of recurrence of CIN2+ was reduced in individuals who were vaccinated compared with those who were not vaccinated (11 studies, 19 909 participants; risk ratio 0.43, 95% confidence interval 0.30 to 0.60; I=58%, τ=0.14, median follow-up 36 months, interquartile range 24-43.5). The effect estimate was even stronger when the risk of recurrence of CIN2+ was assessed for disease related to HPV subtypes HPV16 or HPV18 (six studies, 1879 participants; risk ratio 0.26, 95% confidence interval 0.16 to 0.43; I=0%, τ=0). Confidence in the meta-analysis for CIN2+ overall and CIN2+ related to HPV16 or HPV18, assessed by GRADE, ranged from very low to moderate, probably because of publication bias and inconsistency in the studies included in the meta-analysis. The risk of recurrence of CIN3 was also reduced in patients who were vaccinated but uncertainty was large (three studies, 17 757 participants; 0.28, 0.01 to 6.37; I=71%, τ=1.23). Evidence of benefit was lacking for recurrence of vulvar, vaginal, and anal intraepithelial neoplasia, genital warts, and persistent and incident HPV infections, although the number of studies and participants in each outcome was low. CONCLUSION: HPV vaccination might reduce the risk of recurrence of CIN, in particular when related to HPV16 or HPV18, in women treated with local excision. GRADE assessment for the quality of evidence indicated that the data were inconclusive. Large scale, high quality randomised controlled trials are required to establish the level of effectiveness and cost of HPV vaccination in women undergoing treatment for diseases related to HPV infection. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42021237350.
131Population-level impact and herd effects following the introduction of human papillomavirus vaccination programmes: updated systematic review and meta-analysis.PubMed
Mélanie Drolet, Élodie Bénard, Norma Pérez, et al.
Lancet. 2019 Aug 10;394(10197):497-509. doi: 10.1016/S0140-6736(19)30298-3. Epub 2019 Jun 26.
BACKGROUND: More than 10 years have elapsed since human papillomavirus (HPV) vaccination was implemented. We did a systematic review and meta-analysis of the population-level impact of vaccinating girls and women against human papillomavirus on HPV infections, anogenital wart diagnoses, and cervical intraepithelial neoplasia grade 2+ (CIN2+) to summarise the most recent evidence about the effectiveness of HPV vaccines in real-world settings and to quantify the impact of multiple age-cohort vaccination. METHODS: In this updated systematic review and meta-analysis, we used the same search strategy as in our previous paper. We searched MEDLINE and Embase for studies published between Feb 1, 2014, and Oct 11, 2018. Studies were eligible if they compared the frequency (prevalence or incidence) of at least one HPV-related endpoint (genital HPV infections, anogenital wart diagnoses, or histologically confirmed CIN2+) between pre-vaccination and post-vaccination periods among the general population and if they used the same population sources and recruitment methods before and after vaccination. Our primary assessment was the relative risk (RR) comparing the frequency (prevalence or incidence) of HPV-related endpoints between the pre-vaccination and post-vaccination periods. We stratified all analyses by sex, age, and years since introduction of HPV vaccination. We used random-effects models to estimate pooled relative risks. FINDINGS: We identified 1702 potentially eligible articles for this systematic review and meta-analysis, and included 65 articles in 14 high-income countries: 23 for HPV infection, 29 for anogenital warts, and 13 for CIN2+. After 5-8 years of vaccination, the prevalence of HPV 16 and 18 decreased significantly by 83% (RR 0·17, 95% CI 0·11-0·25) among girls aged 13-19 years, and decreased significantly by 66% (RR 0·34, 95% CI 0·23-0·49) among women aged 20-24 years. The prevalence of HPV 31, 33, and 45 decreased significantly by 54% (RR 0·46, 95% CI 0·33-0·66) among girls aged 13-19 years. Anogenital wart diagnoses decreased significantly by 67% (RR 0·33, 95% CI 0·24-0·46) among girls aged 15-19 years, decreased significantly by 54% (RR 0·46, 95% CI 0.36-0.60) among women aged 20-24 years, and decreased significantly by 31% (RR 0·69, 95% CI 0·53-0·89) among women aged 25-29 years. Among boys aged 15-19 years anogenital wart diagnoses decreased significantly by 48% (RR 0·52, 95% CI 0·37-0·75) and among men aged 20-24 years they decreased significantly by 32% (RR 0·68, 95% CI 0·47-0·98). After 5-9 years of vaccination, CIN2+ decreased significantly by 51% (RR 0·49, 95% CI 0·42-0·58) among screened girls aged 15-19 years and decreased significantly by 31% (RR 0·69, 95% CI 0·57-0·84) among women aged 20-24 years. INTERPRETATION: This updated systematic review and meta-analysis includes data from 60 million individuals and up to 8 years of post-vaccination follow-up. Our results show compelling evidence of the substantial impact of HPV vaccination programmes on HPV infections and CIN2+ among girls and women, and on anogenital warts diagnoses among girls, women, boys, and men. Additionally, programmes with multi-cohort vaccination and high vaccination coverage had a greater direct impact and herd effects. FUNDING: WHO, Canadian Institutes of Health Research, Fonds de recherche du Québec - Santé.
132Provider Experience Recommending HPV Vaccination Before Age 11 Years.PubMed
Dea L Biancarelli, Mari-Lynn Drainoni, Rebecca B Perkins
J Pediatr. 2020 Feb;217:92-97. doi: 10.1016/j.jpeds.2019.10.025. Epub 2019 Nov 19.
OBJECTIVES: To describe health care providers' experiences recommending human papillomavirus (HPV) vaccination before age 11 years as part of a multisession intervention to improve HPV vaccination coverage. STUDY DESIGN: Between 2016 and 2018, we conducted 30-minute qualitative interviews with intervention participants approximately 1 month after intervention completion. Interviews explored participants' experiences with new strategies, including changing the age of routine recommendation. Thematic analysis of interview transcripts involved both deductive and inductive approaches. RESULTS: Twenty-six participants at 5 clinical sites were interviewed. Most were female (88%) primary care providers (46%), and worked 1.5-3.0 clinical days weekly. Many providers described initial skepticism about recommending vaccination before age 11 years, fearing that removing the HPV vaccine from the adolescent bundle with tetanus and meningitis vaccines would decrease parental acceptance. However, providers uniformly reported high parental acceptance owing to reduced stigma relating to sexual activity and the opportunity to administer fewer shots at each visit. Providers also noted that initiating vaccination earlier increased opportunities to complete the series and decreased the need for resource-intensive vaccine recall programs. CONCLUSIONS: Providers had positive experiences recommending HPV vaccination before age 11 years. Routine recommendation before age 11 years may offer advantages related to fewer shots per visit, fewer missed opportunities, and reduction of parental concerns related to sexual activity.
133Immunogenicity, efficacy, and safety of human papillomavirus vaccine: Data from China.PubMed
Mingzhu Li, Chao Zhao, Yun Zhao, et al.
Front Immunol. 2023 Mar 13;14:1112750. doi: 10.3389/fimmu.2023.1112750. eCollection 2023.
The incidence rate and mortality rate of cervical cancer have steadily increased in young women in China. Therefore, it is critical to improve HPV vaccination rates, particularly for the younger population. There are currently five types of prophylactic vaccines in China: bivalent HPV vaccine (AS04-HPV-16/18), quadrivalent HPV vaccine, 9-valent HPV vaccine, homemade Escherichia coli-produced HPV bivalent vaccine, and Pichia pastoris produced HPV bivalent vaccine. All these five HPV vaccines have completed relevant clinical trials in China, and have been proven to be generally well-tolerated and immunogenic, efficacious against persistent HPV-related infections and genital precancerous lesions (data for 9-valent HPV vaccine is absent), and have demonstrated acceptable safety profiles, as previously shown in global studies. Given that the HPV vaccination rate in China is still very low, additional HPV vaccine coverage is needed to reduce the incidence and mortality rates of cervical cancer.
134Virus-induced hepatocellular carcinoma with special emphasis on HBV.PubMed
Ming Wang, Dong Xi, Qin Ning
Hepatol Int. 2017 Mar;11(2):171-180. doi: 10.1007/s12072-016-9779-5. Epub 2017 Jan 17.
Hepatocellular carcinoma (HCC) is a common malignant tumor with high lethality, and the hepatitis B virus (HBV) is a chief cause. HBV can accelerate HCC via multiple mechanisms. First, HBV induces immune reactions that lead to repeated hepatic inflammation, fibrosis and a deficient immune microenvironment. Subsequently, HBV can modify host genes near the insertion point through DNA integration to cause host cell genome instability and to generate carcinogenic fusion proteins. Additionally, HBV expresses diverse active proteins, especially HBx and HBs, which have a range of transactivation functions such as regulation of apoptosis, interference with intracellular signaling pathways, and alteration of epigenetics. Currently, primary prevention measures for HBV-induced HCC focus on vaccination and antiviral treatment. Here, we report the epidemiology, the molecular mechanism and the progress in therapeutic strategies for controlling HBV-induced HCC.
135[Prevention of hepatocellular carcinoma].PubMed
Han Ul Song, Seong Gyu Hwang
Korean J Gastroenterol. 2007 Apr;49(4):201-8.
Hepatocellular carcinoma (HCC) is one of the most common malignant tumors and has the third highest mortality rate among malignancies in South Korea. Despite the continuing efforts for the early detection of HCC, the mortality rate and prognosis have not been improved yet. Its clinical behavior is quite different from other cancers. High recurrence rate after curative treatment might be the reason for poor prognosis. Several methods including chemoprevention, blocking the development of HCC, have been under investigations. The vaccine for hepatitis, in the form of primary prevention, is considered to be the most effective one inhibiting the development of liver disease. Furthermore, keeping away from hepatotoxic agents is another way for preventing liver cell injuries. Secondary prevention is to stop the development of HCC in chronic liver diseases. Since the level of DNA in hepatitis B virus (HBV) hepatitis patients is closely related with the development of HCC, it is helpful to lower the DNA level using anti-viral agents. In addition, IFN, one of the anti-viral agents, can inhibit HCV hepatitis from tumorigenesis. Cyclo-oxygenase (COX)-2 inhibitors are also alleged to have a function in interrupting the development of HCC. Tertiary prevention means the prevention of recurrence of HCC after successful treatment. Because of high recurrence rate, the prevention of recurrence should be one of the important factors affecting the prognosis of HCC. Up to now, COX inhibitors, retinoic acids, vitamin K2, glycyrrhizin epigallocatechin-3-gallate (EGCG), and ginseng had been reported to be effective for the chemoprevention of HCC. Further studies are required for an advancement in the prevention of HCC.
136Gut microbiota-derived short-chain fatty acids and colorectal cancer: Ready for clinical translation?PubMed
Huiqin Hou, Danfeng Chen, Kexin Zhang, et al.
Cancer Lett. 2022 Feb 1;526:225-235. doi: 10.1016/j.canlet.2021.11.027. Epub 2021 Nov 26.
Colorectal cancer (CRC) is the third most common cancer and the second leading cause of cancer-related death worldwide. It involves the complex interactions between genetic factors, environmental exposure, and gut microbiota. Specific changes in the gut microbiome and metabolome have been described in CRC, supporting the critical role of gut microbiota dysbiosis and microbiota-related metabolites in the tumorigenesis process. Short-chain fatty acids (SCFAs), the principal metabolites generated from the gut microbial fermentation of insoluble dietary fiber, can directly activate G-protein-coupled receptors (GPCRs), inhibit histone deacetylases (HDACs), and serve as energy substrates to connect dietary patterns and gut microbiota, thereby improving the intestinal health. A significantly lower abundance of SCFAs and SCFA-producing bacteria has been demonstrated in CRC, and the supplementation of SCFA-producing probiotics can inhibit intestinal tumor development. SCFAs-guided modulation in both mouse and human CRC models augmented their responses to chemotherapy and immunotherapy. This review briefly summarizes the complex crosstalk between SCFAs and CRC, which might inspire new approaches for the diagnosis, treatment and prevention of CRC on the basis of gut microbiota-derived metabolites SCFAs.
137Probiotics and postbiotics in colorectal cancer: Prevention and complementary therapy.PubMed
Monika Kvakova, Anna Kamlarova, Jana Stofilova, et al.
World J Gastroenterol. 2022 Jul 21;28(27):3370-3382. doi: 10.3748/wjg.v28.i27.3370.
Colorectal cancer (CRC) is a leading cause of human mortality worldwide. As conventional anticancer therapy not always being effective, there is growing interest in innovative "drug-free" cancer treatments or interventions that improve the efficacy of established therapy. CRC is associated with microbiome alterations, a process known as dysbiosis that involves depletion and/or enrichment of particular gut bacterial species and their metabolic functions. Supplementing patient treatment with traditional probiotics (with or without prebiotics), next-generation probiotics (NGP), or postbiotics represents a potentially effective and accessible complementary anticancer strategy by restoring gut microbiota composition and/or by signaling to the host. In this capacity, restoration of the gut microbiota in cancer patients can stabilize and enhance intestinal barrier function, as well as promote anticarcinogenic, anti-inflammatory, antimutagenic or other biologically important biochemical pathways that show high specificity towards tumor cells. Potential benefits of traditional probiotics, NGP, and postbiotics include modulating gut microbiota composition and function, as well as the host inflammatory response. Their application in CRC prevention is highlighted in this review, where we consider supportive , animal, and clinical studies. Based on emerging research, NGP and postbiotics hold promise in establishing innovative treatments for CRC by conferring physiological functions the production of dominant natural products and metabolites that provide new host-microbiota signals to combat CRC. Although favorable results have been reported, further investigations focusing on strain and dose specificity are required to ensure the efficacy and safety of traditional probiotics, NGP, and postbiotics in CRC prevention and treatment.
138Colorectal Cancer Mitigation Through Probiotics: Current Evidence and Future Directions.PubMed
Priyanka Chaturvedi, Rimjhim Pathak, Ranu Dayal, et al.
Curr Microbiol. 2025 Jun 18;82(8):339. doi: 10.1007/s00284-025-04297-9.
Despite recent advancements in cancer treatment, colon cancer remains one of the most commonly diagnosed and deadliest cancers worldwide, with significantly increasing incidence rates in developing countries. Numerous studies using in vitro and animal models have explored the potential mechanisms through which probiotics may help prevent colorectal cancer (CRC). Among the most studied probiotic species are those belonging to the Lactobacillus and Bifidobacterium genera. The proposed anti-CRC mechanisms include direct interaction with the intestinal mucosa, such as probiotic adherence and competitive exclusion of harmful microbes, as well as antagonism against pathogens through the action of lactic acid bacteria. Probiotics have also been shown to bind mutagens and carcinogens, and to inhibit the activity of β-glucuronidase-an enzyme linked to damage of colon cells. There is growing evidence supporting the immunomodulatory role of probiotics in CRC prevention. This involves the secretion of beneficial metabolites and modulation of the antitumor immune response via microbiota-mediated pathways. Another proposed mechanism is the ability of probiotics to reduce secondary bile acid production, thereby influencing folate metabolism and contributing to cancer prevention. The effectiveness of probiotics in CRC prevention depends largely on the specific microbial strain. Interestingly, some studies suggest that probiotic viability may not be essential for certain anticancer effects. However, more in vivo studies-particularly human clinical trials-are needed to better understand and validate the potential roles of probiotics (both viable and non-viable), prebiotics, and synbiotics in CRC chemoprevention.
139Mechanism of probiotics in the intervention of colorectal cancer: a review.PubMed
Qinqin Li, Dongmei Liu, Minghua Liang, et al.
World J Microbiol Biotechnol. 2024 Aug 20;40(10):306. doi: 10.1007/s11274-024-04112-w.
The human microbiome interacts with the host mainly in the intestinal lumen, where putrefactive bacteria are suggested to promote colorectal cancer (CRC). In contrast, probiotics and their isolated components and secreted substances, display anti-tumor properties due to their ability to modulate gut microbiota composition, promote apoptosis, enhance immunity, resist oxidation and alter metabolism. Probiotics help to form a solid intestinal barrier against damaging agents via altering the gut microbiota and preventing harmful microbes from colonization. Probiotic strains that specifically target essential proteins involved in the process of apoptosis can overcome CRC resistance to apoptosis. They can increase the production of anti-inflammatory cytokines, essential in preventing carcinogenesis, and eliminate cancer cells by activating T cell-mediated immune responses. There is a clear indication that probiotics optimize the antioxidant system, decrease radical generation, and detect and degrade potential carcinogens. In this review, the pathogenic mechanisms of pathogens in CRC and the recent insights into the mechanism of probiotics in CRC prevention and therapy are discussed to provide a reference for the actual application of probiotics in CRC.
140Potential Mechanisms of Probiotics Action in the Prevention and Treatment of Colorectal Cancer.PubMed
Marta Molska, Julita Reguła
Nutrients. 2019 Oct 14;11(10):2453. doi: 10.3390/nu11102453.
Colorectal cancer is one of the most common and most diagnosed cancers in the world. There are many predisposing factors, for example, genetic predisposition, smoking, or a diet rich in red, processed meat and poor in vegetables and fruits. Probiotics may be helpful in the prevention of cancer and may provide support during treatment. The main aim of this study is to characterize the potential mechanisms of action of probiotics, in particular the prevention and treatment of colorectal cancer. Probiotics' potential mechanisms of action are, for example, modification of intestinal microbiota, improvement of colonic physicochemical conditions, production of anticancerogenic and antioxidant metabolites against carcinogenesis, a decrease in intestinal inflammation, and the production of harmful enzymes. The prevention of colorectal cancer is associated with favorable quantitative and qualitative changes in the intestinal microbiota, as well as changes in metabolic activity and in the physicochemical conditions of the intestine. In addition, it is worth noting that the effect depends on the bacterial strain, as well as on the dose administered.
141The gut microbiota, bacterial metabolites and colorectal cancer.PubMed
Petra Louis, Georgina L Hold, Harry J Flint
Nat Rev Microbiol. 2014 Oct;12(10):661-72. doi: 10.1038/nrmicro3344. Epub 2014 Sep 8.
Accumulating evidence suggests that the human intestinal microbiota contributes to the aetiology of colorectal cancer (CRC), not only via the pro-carcinogenic activities of specific pathogens but also via the influence of the wider microbial community, particularly its metabolome. Recent data have shown that the short-chain fatty acids acetate, propionate and butyrate function in the suppression of inflammation and cancer, whereas other microbial metabolites, such as secondary bile acids, promote carcinogenesis. In this Review, we discuss the relationship between diet, microbial metabolism and CRC and argue that the cumulative effects of microbial metabolites should be considered in order to better predict and prevent cancer progression.
142Diet, microorganisms and their metabolites, and colon cancer.PubMed
Stephen J D O'Keefe
Nat Rev Gastroenterol Hepatol. 2016 Dec;13(12):691-706. doi: 10.1038/nrgastro.2016.165. Epub 2016 Nov 16.
Colorectal cancer is one of the so-called westernized diseases and the second leading cause of cancer death worldwide. On the basis of global epidemiological and scientific studies, evidence suggests that the risk of colorectal cancer is increased by processed and unprocessed meat consumption but suppressed by fibre, and that food composition affects colonic health and cancer risk via its effects on colonic microbial metabolism. The gut microbiota can ferment complex dietary residues that are resistant to digestion by enteric enzymes. This process provides energy for the microbiota but culminates in the release of short-chain fatty acids including butyrate, which are utilized for the metabolic needs of the colon and the body. Butyrate has a remarkable array of colonic health-promoting and antineoplastic properties: it is the preferred energy source for colonocytes, it maintains mucosal integrity and it suppresses inflammation and carcinogenesis through effects on immunity, gene expression and epigenetic modulation. Protein residues and fat-stimulated bile acids are also metabolized by the microbiota to inflammatory and/or carcinogenic metabolites, which increase the risk of neoplastic progression. This Review will discuss the mechanisms behind these microbial metabolite effects, which could be modified by diet to achieve the objective of preventing colorectal cancer in Western societies.
143Benefits of short-chain fatty acids and their receptors in inflammation and carcinogenesis.PubMed
Sathish Sivaprakasam, Puttur D Prasad, Nagendra Singh
Pharmacol Ther. 2016 Aug;164:144-51. doi: 10.1016/j.pharmthera.2016.04.007. Epub 2016 Apr 23.
Epidemiological studies have linked increased incidence of inflammatory diseases and intestinal cancers in the developed parts of the world to the consumption of diets poor in dietary fibers and rich in refined carbohydrates. Gut bacteria residing in the intestinal lumen exclusively metabolize dietary fibers. Butyrate, propionate and acetate, which are collectively called short-chain fatty acids (SCFAs), are generated by fermentation of dietary fibers by gut microbiota. Evidences indicate that SCFAs are key players in regulating beneficial effect of dietary fibers and gut microbiota on our health. SCFAs interact with metabolite-sensing G protein-coupled receptors GPR41, GPR43 and GPR109A expressed in gut epithelium and immune cells. These interactions induce mechanisms that play a key role in maintaining homeostasis in gut and other organs. This review summarizes the protective roles of GPR41, GPR43 and GPR109A in dietary fibers-, gut microbiota- and SCFAs-mediated suppression of inflammation and carcinogenesis in gut and other organs.
144Bifidobacterium Infantis Ameliorates Chemotherapy-Induced Intestinal Mucositis Via Regulating T Cell Immunity in Colorectal Cancer Rats.PubMed
Hui Mi, Yan Dong, Bin Zhang, et al.
Cell Physiol Biochem. 2017;42(6):2330-2341. doi: 10.1159/000480005. Epub 2017 Aug 18.
BACKGROUND/AIMS: Intestinal mucositis (IM) is a commonly encountered side effect in cancer patients receiving chemotherapy. This study aimed to investigate the effect of Bifidobacterium infantis (B. infantis) in attenuating the severity of chemotherapy-induced intestinal mucositis by regulating the T cell subsets in rats with colorectal cancer (CRC). METHODS: Thirty male Sprague-Dawley (SD) rats were injected dimethyl hydrazine (DMH) subcutaneously for 10 weeks, and then injected SW480 cells in rectal mucosa to create a CRC model, and the rats were randomly divided into three groups: Control group (saline + saline), Chemotherapy group (saline + 5-FU+Oxaliplatin), B. infantis group (B. infantis + 5-FU+Oxaliplatin). IM was evaluated based on diarrhea severity, intestinal villus height, crypt depth, pro-inflammatory cytokines (IL-6, IL-1β, TNF-α), T cell subsets (CD4+ IL17A+ cells and CD4+ CD25+ Foxp3+ Tregs) and related cytokine profiles. RESULTS: The results showed that the B. infantis group demonstrated a higher body weight (BW) and intestinal villus height and a deeper crypt depth compared to the Chemotherapy group. The level of IL-6, IL-1β and TNF-α which increased by chemotherapy, was lowered by B. infantis administration. Real time reverse transcription- polymerase chain reaction (RT-PCR) showed B. infantis reduced relative expression of Th17 and Th1 cells related cytokines, and increased relative expression of CD4+ CD25+ Foxp3+ Tregs related cytokines. Furthermore, Flow cytometry analysis showed B. infantis reduced CD4+ IL17A+ cells and increased CD4+ CD25+ Foxp3+ Tregs in mesenteric lymph nodes (MLNs) compared to the Chemotherapy group. CONCLUSION: B. infantis effectively attenuates chemotherapy-induced intestinal mucositis by decreasing Th1 and Th17 response and increasing CD4+ CD25+ Foxp3+ Tregs response.
145Surfacing role of probiotics in cancer prophylaxis and therapy: A systematic review.PubMed
Subramanyam Dasari, Chandrasekhar Kathera, Avilala Janardhan, et al.
Clin Nutr. 2017 Dec;36(6):1465-1472. doi: 10.1016/j.clnu.2016.11.017. Epub 2016 Nov 24.
Cancers figure among the most important causes of morbidity and mortality worldwide. Cancer and its associated infections are always complicated even when specific cancer regimens are available. It is well proved that Lactobacillus and other probiotic bacteria can modulate-ameliorate specific mechanisms against various infections including cancers. The present systematic review is intended to focus on the 'cellular and molecular mechanisms' of probiotic bacteria in the prevention and treatment of various cancers. The clinical and experimental findings of various studies explain the mechanisms such as apoptosis, antioxidant activity, immune response and epigenetics and illustrate the role of probiotics in cancer management and prophylaxis. In addition, the present review also discusses the safety aspects of probiotics when they are used in therapeutic and nutritional diet management. However, further investigations are required to reveal the effectiveness of probiotics in cancer treatment in clinical settings.
146-derived metabolites boost anti-PD1 efficacy in colorectal cancer by inhibiting regulatory T cells through modulating IDO1/Kyn/AHR axis.PubMed
Winnie Fong, Qing Li, Fenfen Ji, et al.
Gut. 2023 Nov 24;72(12):2272-2285. doi: 10.1136/gutjnl-2023-329543.
OBJECTIVE: Gut microbiota is a key player in dictating immunotherapy response. We aimed to explore the immunomodulatory effect of probiotic and its role in improving anti-programmed cell death protein 1 (PD1) efficacy against colorectal cancer (CRC). DESIGN: The effects of in anti-PD1 response were assessed in syngeneic mouse models and azoxymethane/dextran sulfate sodium-induced CRC model. The change of immune landscape was identified by multicolour flow cytometry and validated by immunohistochemistry staining and in vitro functional assays. Liquid chromatography-mass spectrometry was performed to identify the functional metabolites. RESULTS: significantly improved anti-PD1 efficacy in two syngeneic mouse models with different microsatellite instability (MSI) statuses (MSI-high for MC38, MSI-low for CT26). Such effect was confirmed in CRC tumourigenesis model. synergised with anti-PD1 therapy by reducing Foxp3 CD25 regulatory T cell (Treg) intratumoural infiltration, and enhancing effector function of CD8 T cells. -derived indole-3-carboxylic acid (ICA) was identified as the functional metabolite. Mechanistically, ICA inhibited indoleamine 2,3-dioxygenase (IDO1) expression, therefore suppressing kynurenine (Kyn) production in tumours. ICA also competed with Kyn for binding site on aryl hydrocarbon receptor (AHR) and antagonised Kyn binding on CD4 T cells, thereby inhibiting Treg differentiation in vitro. ICA phenocopied effect and significantly improved anti-PD1 efficacy in vivo, which could be reversed by Kyn supplementation. CONCLUSION: -derived ICA improved anti-PD1 efficacy in CRC through suppressing CD4+Treg differentiation and enhancing CD8+T cell function by modulating the IDO1/Kyn/AHR axis. is a potential adjuvant to augment anti-PD1 efficacy against CRC.
147Stress alters the expression of cancer-related genes in the prostate.PubMed
Ivan E Flores, Jorge A Sierra-Fonseca, Olinamyr Davalos, et al.
BMC Cancer. 2017 Sep 5;17(1):621. doi: 10.1186/s12885-017-3635-4.
BACKGROUND: Prostate cancer is a major contributor to mortality worldwide, and significant efforts are being undertaken to decipher specific cellular and molecular pathways underlying the disease. Chronic stress is known to suppress reproductive function and promote tumor progression in several cancer models, but our understanding of the mechanisms through which stress contributes to cancer development and progression is incomplete. We therefore examined the relationship between stress, modulation of the gonadotropin-releasing hormone (GnRH) system, and changes in the expression of cancer-related genes in the rat prostate. METHODS: Adult male rats were acutely or repeatedly exposed to restraint stress, and compared to unstressed controls and groups that were allowed 14 days of recovery from the stress. Prostate tissue was collected and frozen for gene expression analyses by PCR array before the rats were transcardially perfused; and brain tissues harvested and immunohistochemically stained for Fos to determine neuronal activation. RESULTS: Acute stress elevated Fos expression in the paraventricular nucleus of the hypothalamus (PVH), an effect that habituated with repeated stress exposure. Data from the PCR arrays showed that repeated stress significantly increases the transcript levels of several genes associated with cellular proliferation, including proto-oncogenes. Data from another array platform showed that both acute and repeated stress can induce significant changes in metastatic gene expression. The functional diversity of genes with altered expression, which includes transcription factors, growth factor receptors, apoptotic genes, and extracellular matrix components, suggests that stress is able to induce aberrant changes in pathways that are deregulated in prostate cancer. CONCLUSIONS: Our findings further support the notion that stress can affect cancer outcomes, perhaps by interfering with neuroendocrine mechanisms involved in the control of reproduction.
148Sex steroid hormones and risk of breast cancer: a two-sample Mendelian randomization study.PubMed
Aayah Nounu, Siddhartha P Kar, Caroline L Relton, et al.
Breast Cancer Res. 2022 Oct 8;24(1):66. doi: 10.1186/s13058-022-01553-9.
BACKGROUND: Breast cancer (BC) has the highest cancer incidence and mortality in women worldwide. Observational epidemiological studies suggest a positive association between testosterone, estradiol, dehydroepiandrosterone sulphate (DHEAS) and other sex steroid hormones with postmenopausal BC. We used a two-sample Mendelian randomization analysis to investigate this association. METHODS: Genetic instruments for nine sex steroid hormones and sex hormone-binding globulin (SHBG) were obtained from genome-wide association studies (GWAS) of UK Biobank (total testosterone (TT) N: 230,454, bioavailable testosterone (BT) N: 188,507 and SHBG N: 189,473), The United Kingdom Household Longitudinal Study (DHEAS N: 9722), the LIFE-Adult and LIFE-Heart cohorts (estradiol N: 2607, androstenedione N: 711, aldosterone N: 685, progesterone N: 1259 and 17-hydroxyprogesterone N: 711) and the CORtisol NETwork (CORNET) consortium (cortisol N: 25,314). Outcome GWAS summary statistics were obtained from the Breast Cancer Association Consortium (BCAC) for overall BC risk (N: 122,977 cases and 105,974 controls) and subtype-specific analyses. RESULTS: We found that a standard deviation (SD) increase in TT, BT and estradiol increased the risk of overall BC (OR 1.14, 95% CI 1.09-1.21, OR 1.19, 95% CI 1.07-1.33 and OR 1.03, 95% CI 1.01-1.06, respectively) and ER + BC (OR 1.19, 95% CI 1.12-1.27, OR 1.25, 95% CI 1.11-1.40 and OR 1.06, 95% CI 1.03-1.09, respectively). An SD increase in DHEAS also increased ER + BC risk (OR 1.09, 95% CI 1.03-1.16). Subtype-specific analyses showed similar associations with ER+ expressing subtypes: luminal A-like BC, luminal B-like BC and luminal B/HER2-negative-like BC. CONCLUSIONS: TT, BT, DHEAS and estradiol increase the risk of ER+ type BCs similar to observational studies. Understanding the role of sex steroid hormones in BC risk, particularly subtype-specific risks, highlights the potential importance of attempts to modify and/or monitor hormone levels in order to prevent BC.
149Psychotherapy for cancer patients.PubMed
Ng Chong Guan, Salina Mohamed, Lai Kian Tiah, et al.
Int J Psychiatry Med. 2016 Jul;51(5):414-430. doi: 10.1177/0091217416680197.
Objective Psychotherapy is a common non-pharmacological approach to help cancer patients in their psychological distress. The benefit of psychotherapies was documented, but the types of psychotherapies proposed are varied. Given that the previous literature review was a decade ago and no quantitative analysis was done on this topic, we again critically and systematically reviewed all published trials on psychotherapy in cancer patients. Method We identified 17 clinical trials on six types of psychotherapy for cancer patients by searching PubMed and EMBASE. Result There were four trials involved adjunct psychological therapy which were included in quantitative analysis. Each trial demonstrated that psychotherapy improved the quality of life and coping in cancer patients. There was also a reduction in distress, anxiety, and depression after a psychological intervention. However, the number and quality of clinical trials for each type of psychotherapy were poor. The meta-analysis of the four trials involved adjunct psychological therapy showed no significant change in depression, with only significant short-term improvement in anxiety but not up to a year-the standardized mean differences were -0.37 (95% confidence interval (CI) = -0.57, -0.16) at 2 months, -0.21 (95% CI = -0.42, -0.01) at 4 months, and 0.03 (95 % CI = -0.19, 0.24) at 12 months. Conclusion The evidence on the efficacy of psychotherapy in cancer patients is unsatisfactory. There is a need for more rigorous and well-designed clinical trials on this topic.
150Association between pretreatment emotional distress and immune checkpoint inhibitor response in non-small-cell lung cancer.PubMed
Yue Zeng, Chun-Hong Hu, Yi-Zheng Li, et al.
Nat Med. 2024 Jun;30(6):1680-1688. doi: 10.1038/s41591-024-02929-4. Epub 2024 May 13.
Emotional distress (ED), commonly characterized by symptoms of depression and/or anxiety, is prevalent in patients with cancer. Preclinical studies suggest that ED can impair antitumor immune responses, but few clinical studies have explored its relationship with response to immune checkpoint inhibitors (ICIs). Here we report results from cohort 1 of the prospective observational STRESS-LUNG study, which investigated the association between ED and clinical efficacy of first-line treatment of ICIs in patients with advanced non-small-cell lung cancer. ED was assessed by Patient Health Questionnaire-9 and Generalized Anxiety Disorder 7-item scale. The study included 227 patients with 111 (48.9%) exhibiting ED who presented depression (Patient Health Questionnaire-9 score ≥5) and/or anxiety (Generalized Anxiety Disorder 7-item score ≥5) symptoms at baseline. On the primary endpoint analysis, patients with baseline ED exhibited a significantly shorter median progression-free survival compared with those without ED (7.9 months versus 15.5 months, hazard ratio 1.73, 95% confidence interval 1.23 to 2.43, P = 0.002). On the secondary endpoint analysis, ED was associated with lower objective response rate (46.8% versus 62.1%, odds ratio 0.54, P = 0.022), reduced 2-year overall survival rate of 46.5% versus 64.9% (hazard ratio for death 1.82, 95% confidence interval 1.12 to 2.97, P = 0.016) and detriments in quality of life. The exploratory analysis indicated that the ED group showed elevated blood cortisol levels, which was associated with adverse survival outcomes. This study suggests that there is an association between ED and worse clinical outcomes in patients with advanced non-small-cell lung cancer treated with ICIs, highlighting the potential significance of addressing ED in cancer management. ClinicalTrials.gov registration: NCT05477979 .
151ICOnnecta't: Development and Initial Results of a Stepped Psychosocial eHealth Ecosystem to Facilitate Risk Assessment and Prevention of Early Emotional Distress in Breast Cancer Survivors' Journey.PubMed
Joan C Medina, Aida Flix-Valle, Ana Rodríguez-Ortega, et al.
Cancers (Basel). 2022 Feb 15;14(4):974. doi: 10.3390/cancers14040974.
Psychosocial interventions prevent emotional distress and facilitate adaptation in breast cancer (BC). However, conventional care presents accessibility barriers that eHealth has the potential to overcome. ICOnnecta't is a stepped digital ecosystem designed to build wellbeing and reduce psychosocial risks during the cancer journey through a European-funded project. Women recently diagnosed with BC in a comprehensive cancer center were offered the ecosystem. ICOnnecta't consists of four care levels, provided according to users' distress: screening and monitoring, psychoeducation campus, peer-support community, and online-group psychotherapy. Descriptive analyses were conducted to assess the platform's implementation, while multilevel linear models were used to study users' psychosocial course after diagnosis. ICOnnecta't showed acceptance, use and attrition rates of 57.62, 74.60, and 29.66%, respectively. Up to 76.19% of users reported being satisfied with the platform and 75.95% informed that it was easy to use. A total of 443 patients' needs were detected and responsively managed, leading 94.33% of users to remain in the preventive steps. In general, strong social support led to a better psychosocial course. ICOnnecta't has been successfully implemented. The results showed that it supported the development of a digital relation with healthcare services and opened new early support pathways.
152A closer lens: Cancer survivors' supportive intervention preferences and interventions received.PubMed
Joanna J Arch, Rachel Vanderkruik, Alex Kirk, et al.
Psychooncology. 2018 May;27(5):1434-1441. doi: 10.1002/pon.4526. Epub 2017 Sep 18.
OBJECTIVE: Cancer survivor preferences for formal interventions designed to provide psychological support remain relatively unknown. To address this gap, we evaluated cancer survivors' preferences for psychological intervention, whom they preferred to recommend such intervention, and how their preferences compared with what they currently received. METHODS: US cancer survivors (n = 345) who were at least 2 months post-treatment for diverse forms of cancer were recruited online to complete a survey study. RESULTS: Based on Wilcoxon signed-rank tests to distinguish among ranked preferences, cancer survivors rated individual professional counseling as their most-preferred form of psychological intervention (among 6 choices), p < .001, followed by professionally led cancer support groups and individual peer counseling. Anti-depressant or other psychiatric medication represented their least-preferred intervention, ps < .001, but was the one they were most likely to currently receive. Preference for individual professional counseling over psychiatric medication was evident even among the subgroups of cancer survivors screening positively for probable anxiety disorder (n = 188) or major depression (n = 137), ps < .001. Cancer survivors most preferred to learn about psychological interventions from their medical oncologist, p < .001, followed by primary care physician, cancer nurse, or another cancer survivor; they least preferred to learn from a social worker or on their own, ps < .001. CONCLUSIONS: Cancer survivors reported significant unmet need for psychological intervention, preference for non-pharmacological forms of such support, and a gap between their preferred forms of support and what they currently receive.
153Mindfulness-based stress reduction and health benefits. A meta-analysis.PubMed
Paul Grossman, Ludger Niemann, Stefan Schmidt, et al.
J Psychosom Res. 2004 Jul;57(1):35-43. doi: 10.1016/S0022-3999(03)00573-7.
OBJECTIVE: Mindfulness-based stress reduction (MBSR) is a structured group program that employs mindfulness meditation to alleviate suffering associated with physical, psychosomatic and psychiatric disorders. The program, nonreligious and nonesoteric, is based upon a systematic procedure to develop enhanced awareness of moment-to-moment experience of perceptible mental processes. The approach assumes that greater awareness will provide more veridical perception, reduce negative affect and improve vitality and coping. In the last two decades, a number of research reports appeared that seem to support many of these claims. We performed a comprehensive review and meta-analysis of published and unpublished studies of health-related studies related to MBSR. METHODS: Sixty-four empirical studies were found, but only 20 reports met criteria of acceptable quality or relevance to be included in the meta-analysis. Reports were excluded due to (1) insufficient information about interventions, (2) poor quantitative health evaluation, (3) inadequate statistical analysis, (4) mindfulness not being the central component of intervention, or (5) the setting of intervention or sample composition deviating too widely from the health-related MBSR program. Acceptable studies covered a wide spectrum of clinical populations (e.g., pain, cancer, heart disease, depression, and anxiety), as well as stressed nonclinical groups. Both controlled and observational investigations were included. Standardized measures of physical and mental well-being constituted the dependent variables of the analysis. RESULTS: Overall, both controlled and uncontrolled studies showed similar effect sizes of approximately 0.5 (P<.0001) with homogeneity of distribution. CONCLUSION: Although derived from a relatively small number of studies, these results suggest that MBSR may help a broad range of individuals to cope with their clinical and nonclinical problems.
154Mindfulness-based interventions for coping with cancer.PubMed
Linda E Carlson
Ann N Y Acad Sci. 2016 Jun;1373(1):5-12. doi: 10.1111/nyas.13029. Epub 2016 Mar 9.
Work in the development and evaluation of mindfulness-based interventions (MBIs) for cancer care has been underway for the last 20 years, and a growing body of literature now supports their efficacy. MBIs are particularly helpful in dealing with common experiences related to cancer diagnosis, treatment, and survivorship, including loss of control, uncertainty about the future, and fears of recurrence, as well as a range of physical and psychological symptoms, including depression, anxiety, insomnia, and fatigue. Our adaptation, mindfulness-based cancer recovery (MBCR), has resulted in improvements across a range of psychological and biological outcomes, including cortisol slopes, blood pressure, and telomere length, in various groups of cancer survivors. In this paper, I review the rationale for MBIs in cancer care and provide an overview of the state of the current literature, with a focus on results from three recent clinical trials conducted by our research group. These include a comparative efficacy trial comparing MBCR to supportive-expressive therapy in distressed breast cancer survivors, a non-inferiority trial comparing MBCR to cognitive behavioral therapy for insomnia in cancer survivors with clinical insomnia, and an online adaptation of MBCR for rural and remote cancer survivors without access to in-person groups. I conclude by outlining work in progress and future directions for MBI research and applications in cancer care.
155Meditation effect on psychological stress level in women with breast cancer: a systematic review.PubMed
Raquel Vilanova Araujo, Ana Fátima Carvalho Fernandes, Inez Sampaio Nery, et al.
Rev Esc Enferm USP. 2019 Dec 2;53:e03529. doi: 10.1590/S1980-220X2018031303529. eCollection 2019.
OBJECTIVE: To evaluate the effect of meditation on the psychological stress level of women with breast cancer. METHOD: A systematic literature review performed in the LILACS, PubMed, Scopus, CINAHL and Web of Science databases. RESULTS: The sample consisted of 22 studies using Mindfulness, Transcendental Meditation, and Contemplative Self-Healing Meditation techniques. There was a significant effect of meditation on stress reduction, post-traumatic stress symptoms, self-reported stress, and chronic stress verified. In some studies, the effect was associated with decreased cortisol and increased telomerase. CONCLUSION: Meditation has shown positive effects in reducing physical and emotional symptoms such as psychological stress, depression, anxiety, fatigue, fear of recurrence and rumination, representing an efficient strategy for coping with the disease and improving quality of life.
156A Systematic Review: Mindfulness Intervention for Cancer-Related Pain.PubMed
Srisuda Ngamkham, Janean E Holden, Ellen Lavoie Smith
Asia Pac J Oncol Nurs. 2019 Apr-Jun;6(2):161-169. doi: 10.4103/apjon.apjon_67_18.
Moderate-to-severe pain is a common problem experienced by patients with cancer. Although analgesic drugs are effective, adverse side effects are common and some analgesic drugs are addictive. Nonpharmacological treatment may be a way to treat cancer pain without causing negative side effects. Mindfulness is used as an effective nonpharmacological treatment to improve quality of life (QoL) and to address psychological problems including distress, anxiety, stress, and depression. However, the effect of mindfulness on pain severity has not been sufficiently investigated. Therefore, a systematic review was undertaken to describe the effectiveness of mindfulness interventions for pain and its underlying pathophysiologic mechanisms. The search was conducted in PubMed, Ovid MEDLINE, and CINAHL and included only empirical studies published from 2008 to 2017. Search terms included mindfulness, mindfulness-based intervention, meditation, cancer, pain, and cancer-related pain. Six studies met the search criteria. These studies tested several types of intervention including mindfulness-based stress reduction, mindfulness-based cognitive therapy, meditation with massage, and mindful awareness practices. Study outcomes include improved pain severity, anxiety, stress, depression, and QoL. However, most studies reviewed were conducted in the United States and Denmark. Further research is needed to test culturally appropriate mindfulness interventions to reduce pain.
157The effect of psychological interventions on fear of cancer recurrence in breast cancer survivors: A systematic review and meta-analysis.PubMed
Meng-Meng Lyu, Rosalind Chiew-Jiat Siah, Alekzendr Sheen Loong Lam, et al.
J Adv Nurs. 2022 Oct;78(10):3069-3082. doi: 10.1111/jan.15321. Epub 2022 Jun 13.
AIM: To evaluate the effectiveness of psychological interventions in reducing fear of cancer recurrence in breast cancer survivors. DESIGN: A systematic review and meta-analysis. DATA SOURCES: PubMed, Embase, Cochrane Central Register of Controlled Trials, CINAHL, Scopus, PsycINFO, Web of Science and ClinicalTrials.gov were searched for relevant studies published from 1 January 1976 to 28 November 2020. METHODS: Eligible randomized controlled trials on psychological interventions for reducing fear of cancer recurrence in breast cancer survivors were included in meta-analysis. Review Manager 5.4 was used to conduct the meta-analysis, and the fear of cancer recurrence score was calculated by using standardized mean differences and 95% confidence intervals. Risk of bias was assessed with the Cochrane risk-of-bias tool. Quality of evidence, sensitivity analyses, and subgroup analyses were also conducted. RESULTS: This systematic review included 16 randomized controlled trials. We found psychological interventions significantly reduced fear of cancer recurrence. Subgroup analyses indicated that mindfulness and acceptance therapy-based interventions reduced fear of cancer recurrence, whereas cognitive-behavioural therapy combined with psychoeducation did not. Interventions with three to eight sessions were effective, while interventions with nine or more sessions were not. Face-to-face interventions were effective, whereas online interventions were not. The quality of evidence for fear of cancer recurrence was evaluated as moderate due to moderate heterogeneity in the included studies. CONCLUSIONS: Psychological interventions were effective in reducing fear of cancer recurrence in breast cancer survivors. Mindfulness and acceptance therapy-based interventions and short-term interventions are recommended. Future well-designed randomized controlled trials aiming to examine the effectiveness of psychological interventions in reducing fear of cancer recurrence are needed. IMPACT: The findings of this systematic review may guide the development of psychological interventions and encourage the use of psychological interventions for reducing fear of cancer recurrence in breast cancer survivors.
158Effectiveness of telemedicine-based psychosocial intervention for breast cancer patients: a systematic review and meta-analysis.PubMed
Zhuyue Ma, Yanyan Shi, Shanshan Yao, et al.
Support Care Cancer. 2023 Sep 28;31(10):595. doi: 10.1007/s00520-023-08052-3.
OBJECTIVES: This review aimed to synthesize the available evidence on the effectiveness of telemedicine-based psychosocial interventions among breast cancer (BC) patients regarding quality of life (QOL), depression, anxiety, distress, fatigue, sleep disorders, sexual function, and fear of cancer recurrence (FCR). METHODS: A search of 10 databases was conducted to identify RCTs of the effects of telemedicine-based psychosocial interventions on outcomes. Selection of studies, quality appraisal, and data extraction were performed by two reviewers independently. GRADE and Cochrane risk of bias assessment tools were used for quality appraisal. Heterogeneity was determined by I, standardized mean differences (SMD) were used to determine intervention effects, and meta-analyses, subgroup analysis, and sensitivity analysis were performed. RESULTS: In total, 29 RCTs were included. Telemedicine-based psychosocial interventions improved the primary outcomes of QOL (SMD = 0.32), distress (SMD = - 0.22), and anxiety (SMD = - 0.16) in BC patients with moderate effect size. There were some improvements in the secondary outcomes of sleep disorders (SMD = - 056), sexual function (SMD = 0.19), and FCR (SMD = - 0.41). After sensitivity analysis, the effect size of fatigue was moderate (SMD = - 0.24). CONCLUSION: Telemedicine-based psychosocial interventions are superior to usual care in BC patients with improved QOL, sexual function, and less distress, anxiety, fatigue, sleep disorders, and FCR. Due to the heterogeneity of the results for QOL, anxiety, fatigue, sleep disturbance, and FCR, these results should be interpreted cautiously. In the future, more rigorous RCTs need to be designed to identify better delivery models and intervention times to further test their effectiveness.
159The effectiveness of positive psychological interventions for patients with cancer: A systematic review and meta-analysis.PubMed
Xia Tian, Xiaojun Zhou, Mimi Sun, et al.
J Clin Nurs. 2024 Aug;33(9):3752-3774. doi: 10.1111/jocn.17358. Epub 2024 Jul 9.
AIMS AND OBJECTIVES: To evaluate the effectiveness of positive psychological interventions on quality of life, positive psychological outcomes and negative psychological outcomes in patients with cancer. BACKGROUND: Patients with cancer often suffer from various psychological problems and have a poor quality of life. Positive psychological interventions have been increasingly applied to patients with cancer, but the results of these studies have not been synthesized. DESIGN: A systematic review and meta-analysis of randomized controlled trials according to PRISMA. METHODS: Six English databases and four Chinese databases were searched from the inception to December 2022. Two reviewers independently assessed the risk of bias using the Cochrane Risk of Bias tool. RevMan was used for meta-analysis. RESULTS: Twenty-nine randomized controlled trials examined the effects of positive psychological interventions including meaning therapy, dignity therapy, positive psychotherapy, mindfulness- based intervention, life review, expressive writing intervention, acceptance and commitment psychotherapy, attention and interpretation therapy, compassion training and spiritual therapy on patients with cancer. Positive psychological interventions significantly improved the quality of life, enhanced positive psychological outcomes including well-being, meaning of life, self-esteem, optimism, resilience and self-efficacy and alleviated negative psychological outcomes including depression, anxiety and hopelessness. However, the heterogeneity of some outcomes was rather high, due to the wide diversity of the interventions included. CONCLUSION: Positive psychological interventions have potentially positive effects on improving quality of life, enhancing positive psychological outcomes and alleviating negative psychological outcomes in patients with cancer. However, due to the heterogeneity and the lack of follow-up studies, more high-quality studies are needed to confirm the results of our review and to clarify the long-term effects of positive psychological interventions. RELEVANCE TO CLINICAL PRACTICE: As feasible psychological interventions, healthcare professionals can consider applying appropriate positive psychological interventions according to the condition of cancer patients. PATIENT OR PUBLIC CONTRIBUTION: No patient or public contribution.
160The effectiveness of dignity therapy on hope, quality of life, anxiety, and depression in cancer patients: A meta-analysis of randomized controlled trials.PubMed
Yalin Zhang, Juejin Li, Xiaolin Hu
Int J Nurs Stud. 2022 Aug;132:104273. doi: 10.1016/j.ijnurstu.2022.104273. Epub 2022 Apr 28.
BACKGROUND: Cancer presents a progressively deteriorating illness that not only causes significant physical, social and economic burdens in patients but also impacts an individual's psychological well-being and quality of life. Dignity therapy is a well-accepted psychosocial intervention but the effectiveness on hope, quality of life, anxiety, and depression in cancer patients remains inconsistent. OBJECTIVE: The purpose of this meta-analysis was to identify the effectiveness of dignity therapy on hope, quality of life, anxiety, and depression in cancer patients. DESIGN: A meta-analysis of randomized controlled trials was performed. METHODS: Relevant studies published from inception to February 2022 were retrieved from PubMed, Embase (Ovid), the Cochrane Central Register of Controlled Trials, Web of Science, PsycINFO, CINAHL, CBM, CNKI, VIP and Wanfang. The literature search and data extraction processes were conducted by two independent authors. The methodological quality of the included studies was assessed by the Cochrane Risk-of-Bias Assessment Tool, version 2 and the GRADE approach. The data analysis was performed using Review Manager (Version 5.4). RESULTS: Fourteen randomized controlled trials published between 2011 and 2021 were included. Most of the studies were assessed as having some concerns. The certainty of the evidence in this review varied from low to high across outcomes. The meta-analysis showed statistically significant effects of dignity therapy on hope (mean difference (MD) = 3.41, 95% CI: 2.82 to 4.00, P < 0.001), anxiety (standardized mean difference (SMD) = -0.75, 95% confidence interval (CI): -1.32 to -0.18, P = 0.01), and depression (SMD = -1.01, 95% CI: -1.60 to -0.43, P = 0.0007) at postintervention, and the separate analysis revealed that dignity therapy had a sustainable effect on anxiety (MD = -2.96, 95% CI: -3.85 to -2.07, P < 0.001) and depression (MD = -3.44, 95% CI: -6.20 to -0.68, P = 0.0003) at one month after the intervention. However, no statistically significant effect on quality of life were found in our study. CONCLUSION: Dignity therapy may be effective for improving hope, anxiety, and depression among adult cancer patients, but the effect on quality of life is nonsignificant. Culture-tailored dignity therapy should be further focused and explored. More randomized controlled trials with larger sample sizes, multiple follow-up times, and strict study designs should be further conducted to identify the effect of dignity therapy on cancer patients. REGISTRATION NUMBER: CDR42021275142.
161Targeting Depressive Symptoms in Younger Breast Cancer Survivors: The Pathways to Wellness Randomized Controlled Trial of Mindfulness Meditation and Survivorship Education.PubMed
Julienne E Bower, Ann H Partridge, Antonio C Wolff, et al.
J Clin Oncol. 2021 Nov 1;39(31):3473-3484. doi: 10.1200/JCO.21.00279. Epub 2021 Aug 18.
PURPOSE: Younger women are at risk for depression and related symptoms following breast cancer. The Pathways to Wellness study, a randomized, multi-institution, three-arm trial, tested the efficacy of two behavioral interventions for younger breast cancer survivors with elevated depressive symptoms: mindful awareness practices (MAPs) and survivorship education (SE) (Clincaltrials.gov identifier: NCT03025139). METHODS: Women diagnosed with breast cancer at or before 50 years of age who had completed treatment and had elevated depressive symptoms were randomly assigned to 6 weeks of MAPs, SE, or wait-list control (WLC). Assessments were conducted preintervention and postintervention and at 3-month and 6-month postintervention follow-ups. Analyses compared each intervention to WLC using linear mixed models. The primary outcome was change in depressive symptoms from preintervention to postintervention on the Center for Epidemiologic Studies-Depression Scale; secondary outcomes included change in fatigue, insomnia, and vasomotor symptoms. RESULTS: Two hundred forty-seven women (median age = 46 years) were randomly assigned to MAPs (n = 85), SE (n = 81), or WLC (n = 81). MAPs and SE led to significant decreases in depressive symptoms from preintervention to postintervention relative to WLC (mean change relative to WLC [95% CI]: MAPs, -4.7 [-7.5 to -1.9]; SE, -4.0 [-6.9 to -1.1]), which persisted at 6-month follow-up for MAPs (mean change relative to WLC [95% CI]: MAPs, -3.7 [-6.6 to -0.8]; SE, -2.8 [-5.9 to 0.2]). MAPs, but not SE, also had beneficial effects on fatigue, insomnia, and vasomotor symptoms that persisted at 6-month follow-up ( < .05). CONCLUSION: Mindfulness meditation and SE reduced depressive symptoms in younger breast cancer survivors. These interventions can be widely disseminated over virtual platforms and have significant potential benefit for quality of life and overall survivorship in this vulnerable group.
162Cancer patients' participation and commitment to psychological interventions: a scoping review.PubMed
Lucrezia Savioni, Stefano Triberti, Ilaria Durosini, et al.
Psychol Health. 2022 Aug;37(8):1022-1055. doi: 10.1080/08870446.2021.1916494. Epub 2021 May 9.
OBJECTIVE: Some psychological interventions have been developed to improve cancer patients' and survivors' quality of life, well-being, and health engagement. However, studies are usually focused on effectiveness and less on factors influencing survivors' decision to participate, both subjective (e.g., needs) and contingent (e.g., factors related to participation/non participation). This scoping review identifies factors influencing participation, decline to participate, attrition and adherence in psychological interventions. METHODS: 3 electronic databases were searched for published studies on psychological interventions. Retrieved publications were scanned by authors against inclusion criteria and forty-two articles were selected. Relevant information were summarized narratively. RESULTS: More information is available on attrition and factors related to participation/non participation, so that future psychological interventions may employ ad-hoc tools to take into consideration patients' reasons to adhere to psychological interventions. Secondarily, non-participation/dropout is often linked to factors related to intervention' commitment and its interference with daily life. On the contrary, patients' reasons to participate often identify with the value they find in the intervention according to their personal needs and experience of illness. CONCLUSION: We suggest that future research should analyze patients' representation of psychological interventions and take them into account to tailor the interventions on participants' lived experience, to improve participation.