1. 胰腺癌流行病学特征与预防紧迫性分析
1.1 全球及区域发病与死亡趋势
胰腺癌作为一种高度致死性的消化道恶性肿瘤，其全球发病率和死亡率在过去几十年中持续上升，对全球公共卫生构成了日益严峻的挑战 12。根据GLOBOCAN 2012年的估计，全球每年约有33.8万人罹患胰腺癌，导致超过33.1万人死亡，使其成为全球第七大癌症死因 3。到2018年，全球新发胰腺癌病例已达458,918例，死亡人数为432,242例 4。最新的数据显示，2022年全球约有510,922例新发病例和467,409例死亡，胰腺癌已成为全球第六大癌症相关死因 2。
从地理分布来看，胰腺癌的发病率和死亡率在发达国家和高人类发展指数（HDI）地区（如北美、欧洲）普遍较高 356。例如，2018年，高人类发展指数地区的年龄标准化发病率和死亡率分别达到7.7和4.9（每10万人）5。预计到2050年，全球胰腺癌的发病率将增至每10万人18.6例，年均增长1.1%，新发病例总数可能达到998,663例，这预示着胰腺癌将带来巨大的公共卫生负担 12。
胰腺癌发病率和死亡率的增长主要受多种因素驱动：
- 人口老龄化：胰腺癌的发病风险随年龄增长而显著增加，全球人口结构的老龄化是其负担加重的重要原因 16。
- 风险因素的流行：吸烟、肥胖、糖尿病等已确定的风险因素在全球范围内的普遍存在和蔓延，是推动胰腺癌发病率上升的关键驱动力 1345。例如，吸烟导致了2017年全球21.1%的胰腺癌死亡，高空腹血糖和高体重指数分别导致了8.9%和6.2%的死亡 6。针对高空腹血糖引起的胰腺癌死亡人数，在1990年至2019年间几乎增加了两倍，预计到2040年仍将持续增长 7。
- 早期发病胰腺癌（EOPC）的上升趋势：值得关注的是，尽管胰腺癌多发于老年人群，但在年龄小于50岁的年轻人群中，早期发病胰腺癌（EOPC）的发病率和死亡率也呈现上升趋势 58。1990年至2019年间，全球EOPC的年龄标准化发病率增加了46.9%，死亡率增加了44.6% 8。特别是在亚洲男性中，EOPC的发病率和死亡率增长最快 8。
胰腺癌的这些流行病学特征凸显了对其进行有效预防的紧迫性。由于其解剖位置特殊，胰腺癌通常在疾病晚期出现明显临床症状才被诊断，这使得早期诊断极其困难 149。因此，深入了解其风险因素并采取积极的预防策略，对于减轻日益增长的全球胰腺癌负担至关重要 134。
1.2 预防对改善预后的关键价值
胰腺癌的预后极差，其5年生存率长期徘徊在低位，是所有恶性肿瘤中最低的之一，在美国约为10% 10，全球范围内不足5% 11。在一些研究中，5年生存率甚至低至7% 12。这一严峻的现实主要源于胰腺癌高度侵袭性的生物学特性、早期症状的缺乏以及诊断时的晚期阶段 101314。大多数胰腺癌患者在确诊时已处于晚期或已发生转移，仅有10%-15%的患者有机会进行手术切除 13。手术切除是目前唯一可能治愈胰腺癌的手段 10，但即使接受了手术，患者的预后也往往不佳。例如，一项回顾性研究显示，在接受标准化、多模式治疗的胰腺癌患者中，手术切除组的中位总生存期为28.4个月，5年生存率为31.6%，而未手术治疗组的中位总生存期为13.0个月，5年生存率为15.0% 15。另一项针对高危人群筛查的研究表明，通过筛查发现的胰腺癌患者，其5年生存率可达50%，远高于对照组的9% 16。这些数据突出强调了早期诊断和干预对于改善预后的重要性。
鉴于胰腺癌早期诊断的挑战性，预防策略在改善患者预后方面具有不可替代的关键价值。预防措施可以分为两个主要层面：一级预防和二级预防。
一级预防旨在通过消除或减少风险因素来降低胰腺癌的发生率 17。这包括生活方式干预（如戒烟、健康饮食、适度运动）、控制代谢性疾病（如糖尿病和肥胖）以及避免接触已知致癌物。通过一级预防，可以在疾病发生之前就对其进行干预，从源头上减少癌症的发生。例如，吸烟是胰腺癌的重要风险因素 10，戒烟无疑能有效降低患癌风险。对人群进行广泛的一级预防教育和干预，可以显著降低整个社会的胰腺癌发病负担。
二级预防则侧重于对高危人群进行早期筛查，以便在癌前病变或早期癌症阶段发现病灶，从而实现及时干预和治疗 1318。由于胰腺癌的临床症状不典型，且常常在晚期才出现 13，因此，对于有遗传易感性或高风险因素的个体进行系统性筛查至关重要 1819。早期检测，特别是当肿瘤小于10毫米时，其5年生存率可显著提高，甚至达到80% 20。这表明，如果在非常早期阶段（如通过高危人群筛查）发现并切除肿瘤，患者的长期生存率将得到极大改善 16。常用的筛查手段包括磁共振成像/磁共振胰胆管造影（MRI/MRCP）和内镜超声（EUS）19。虽然目前尚无普遍适用于普通人群的有效筛查方法 18，但针对高危人群的精准筛查已被证明能够发现更小、更早期的病变，并显著提高生存率 16。
一级预防和二级预防并非相互独立，而是相辅相成、协同作用的。一级预防可以减少需要进行二级预防的人群数量，而二级预防则为高危个体提供了早期发现和治疗的机会。两者的结合是降低胰腺癌死亡率、改善患者整体预后的最有效路径。在胰腺癌这种致死率高、早期诊断困难的恶性肿瘤面前，预防的价值不言而喻，它为我们提供了扭转当前困境的关键策略 21。
2. 胰腺癌发病机制与核心风险因素解析
2.1 遗传易感性与分子机制
胰腺癌的发病机制复杂，遗传因素在其发生发展中扮演着重要角色。虽然大多数胰腺癌病例为散发性，但遗传易感性在其中发挥作用 2223，主要通过遗传性胰腺癌综合征和家族聚集性胰腺癌体现。对这些遗传基础的深入理解，有助于精准识别高危人群并指导预防策略。
2.1.1 遗传性胰腺癌综合征与基因突变
多种遗传性癌症综合征与胰腺癌风险增加相关，其中最受关注的是与DNA损伤修复相关的基因突变，尤其是BRCA1和BRCA2基因。
- BRCA1/2 基因突变：BRCA1和BRCA2是肿瘤抑制基因，其种系突变（germline mutation）主要与遗传性乳腺癌和卵巢癌相关，但也显著增加胰腺癌的风险 2425。研究表明，BRCA1突变会使胰腺癌风险增加2.36倍，而BRCA2突变则会使风险增加3.34倍 26。BRCA2突变携带者胰腺癌的绝对风险，到80岁时可达到约2.5% 26。在胰腺导管腺癌（PDAC）患者中，BRCA1/2的种系突变并不少见，它们影响了肿瘤的发生发展，并对PARP抑制剂（PARPi）的治疗敏感性有重要影响 242728。日本的一项研究发现，在1005名胰腺癌患者中，BRCA2、ATM和BRCA1的致病性变异与胰腺癌显著相关 29。
- CDKN2A 基因突变：CDKN2A基因编码p16蛋白，是一种重要的细胞周期抑制剂。其种系突变与家族性非典型多发性黑色素瘤和胰腺癌综合征（FAMMM）相关，显著提高胰腺癌发病风险 2325。研究表明，CDKN2A是胰腺癌中重要的基因改变之一 30。
- ATM 基因突变：ATM基因编码的蛋白参与DNA损伤应答通路。ATM基因的种系突变也与胰腺癌风险增加有关 2529。
- PALB2 基因突变：PALB2基因与BRCA2相互作用，在DNA双链断裂修复中发挥关键作用。PALB2的种系突变同样会增加胰腺癌的风险，且携带PALB2致病性变异的晚期胰腺癌患者对PARP抑制剂敏感 2528。
- 其他遗传综合征：其他与胰腺癌风险增加相关的综合征包括Peutz-Jeghers综合征（STK11基因突变）、遗传性胰腺炎（PRSS1基因突变）、林奇综合征（错配修复基因突变，如MLH1、MSH2等）和家族性腺瘤性息肉病（APC基因突变）等 232531。
这些基因突变通过多种分子机制促进胰腺癌发生，包括DNA修复缺陷导致基因组不稳定性增加、细胞周期调控失常、细胞增殖异常等。例如，BRCA1/2的缺陷导致同源重组修复（HRR）功能受损，使得细胞更容易积累DNA损伤，从而增加癌变风险 27。
2.1.2 家族聚集性风险与GWAS研究
除了已知的遗传综合征，家族性胰腺癌（FPC）病例中已知致病基因突变的比例有限，这表明尚有许多未知的遗传因素或复杂的遗传模式在其中发挥作用 31。家族性胰腺癌被定义为至少有两名一级亲属患有胰腺导管腺癌的家族 2331。这类家族成员患胰腺癌的风险显著高于普通人群。
全基因组关联研究（GWAS）通过扫描人类基因组，识别与特定疾病风险相关的常见遗传变异（如单核苷酸多态性，SNP）。GWAS研究已经发现了一些与胰腺癌风险相关的常见变异，例如：
- KLHL17 基因多态性：GWAS研究发现，KLHL17基因的某些多态性与胰腺癌风险相关，该基因可能参与炎症调控，进而影响胰腺癌的发生发展。
- 其他基因座：除了KLHL17，GWAS还陆续发现了其他与胰腺癌相关的基因座，这些变异通常效应量较小，但共同作用可能构成重要的风险因素。例如，有研究通过全基因组测序在家族性胰腺癌患者的一级亲属中识别出与癌症相关基因富集的稀有种系变异，包括PALD1、LRP1B、COL4A2等，这些基因可能参与细胞外基质、小分子转运、先天免疫系统和离子通道转运等功能，提示其在胰腺癌易感性中的潜在作用 32。
总而言之，胰腺癌的遗传易感性是一个多层次、多因素的复杂网络。从高穿透性致病基因突变到效应量较小的常见遗传变异，共同构成了个体罹患胰腺癌的遗传基础。识别和理解这些遗传机制，对于开发更精准的风险评估模型、制定个性化的筛查策略以及探索新的预防和治疗靶点具有深远意义。
2.2 环境与生活方式风险因素
环境暴露和生活方式因素是胰腺癌发生发展中可干预的重要风险因素。这些因素通过诱导慢性炎症、代谢紊乱和DNA损伤等多种机制，显著增加个体患胰腺癌的风险。
2.2.1 吸烟
吸烟是公认的、最重要的胰腺癌可预防风险因素之一 33。流行病学研究一致表明，吸烟是胰腺癌的独立风险因素 34。吸烟不仅增加胰腺癌的发病风险，还可能影响胰腺炎的进展，胰腺炎本身也是胰腺癌的风险因素 34。烟草与酒精均可作为胰腺癌的风险因素，并可共同作用 33。戒烟是降低胰腺癌风险最有效的策略之一 34。
2.2.2 肥胖
肥胖的全球流行与胰腺癌发病率的上升密切相关 35。多项研究证实，肥胖（通常通过身体质量指数，BMI衡量）是胰腺癌的独立风险因素。肥胖个体患胰腺癌的风险比正常体重者有所增加 35。肥胖与胰腺癌之间的关联机制复杂，可能涉及以下方面：
- 慢性炎症：肥胖患者常伴有全身性慢性低度炎症，脂肪组织会分泌多种促炎细胞因子（如IL-6、TNF-α），这些因子可促进胰腺细胞的异常增殖和分化，增加癌变风险 36。
- 胰岛素抵抗和高胰岛素血症：肥胖导致胰岛素抵抗，胰腺β细胞为代偿性分泌更多胰岛素，引起高胰岛素血症。高水平的胰岛素及其类似物（如胰岛素样生长因子-1，IGF-1）是细胞生长和分裂的强效刺激物，可能促进胰腺癌细胞的生长 35。
- 脂肪因子失衡：肥胖改变了脂肪因子的分泌模式，例如，瘦素水平升高而脂联素水平降低。瘦素具有促肿瘤作用，而脂联素具有抗肿瘤作用，这种失衡可能促进胰腺癌的发生发展 36。
- 中性粒细胞胞外诱捕网（NETs）：研究表明，肥胖可以显著促进小鼠胰腺导管上皮内瘤变（mPanIN）的进展，这与肥胖诱导的NETs形成有关。NETs通过TLR4依赖性途径诱导导管细胞的炎症反应，从而促进胰腺癌发生。二甲双胍能够显著逆转肥胖和NETs的促肿瘤作用 37。
2.2.3 2型糖尿病
2型糖尿病与胰腺癌之间存在复杂的双向关联。长期存在的2型糖尿病是胰腺癌的风险因素，而新发糖尿病，特别是老年人新发糖尿病，可能是胰腺癌的早期表现之一 38。
- 长期2型糖尿病作为风险因素：长期患有2型糖尿病的个体，其患胰腺癌的风险增加，这可能与高血糖、高胰岛素血症以及相关的慢性炎症反应有关 38。有研究识别出2型糖尿病和胰腺癌共享的基因特征和生物学机制，例如S100A6基因在胰腺癌中高表达，并与患者较差的总生存期相关，且参与了糖代谢相关通路，表明其可能作为胰腺癌和2型糖尿病的共同生物标志物和治疗靶点 39。
- 新发糖尿病作为胰腺癌表现：新发糖尿病，特别是老年人新发糖尿病，可能与胰腺癌的发生有关 38。这提示胰腺癌本身可能导致患者出现糖尿病症状。因此，新发糖尿病，尤其是无其他明显高危因素的老年患者，应警惕胰腺癌的可能性，这为胰腺癌的早期诊断提供了窗口 38。
2.2.4 饮食因素
饮食习惯对胰腺癌的发生发展具有重要影响，其中超加工食品、高糖饮食和低纤维摄入是尤其值得关注的风险因素。
- 超加工食品（UPF）：超加工食品的摄入与多种癌症风险增加相关，包括胰腺癌。一项系统综述和荟萃分析显示，高摄入超加工食品与胰腺癌风险增加相关（HR = 1.49, 95% CI 1.07-2.07） 40。超加工食品通常富含添加糖、不健康脂肪和盐，但膳食纤维和微量营养素含量低，其生产过程中可能产生有害化合物。这些成分和特点通过促进炎症、氧化应激、代谢紊乱和肠道菌群失调，可能共同促进胰腺癌的发生。
- 高糖饮食：高糖饮食，特别是添加糖的过量摄入，与肥胖和2型糖尿病密切相关，进而间接增加胰腺癌风险。高糖摄入导致血糖快速升高和胰岛素抵抗，与上述肥胖和糖尿病的机制类似，可能直接或间接促进胰腺细胞的癌变。
- 低纤维摄入：膳食纤维摄入不足是西方饮食模式的常见特点。膳食纤维有助于维持健康的肠道菌群，促进肠道蠕动，减少有害物质的吸收。低纤维饮食可能导致肠道菌群失调，增加肠道通透性，从而促进全身性炎症反应和代谢紊乱，这些都可能影响胰腺健康并增加胰腺癌风险。此外，肠道微生物群被发现与胰腺癌的发生发展、肿瘤微环境重塑以及对化疗的反应均有重要关联 414243。不健康的饮食模式（如低纤维）会改变肠道菌群组成，可能影响微生物衍生的代谢产物，进而影响胰腺癌的发生和治疗效果 42。例如，微生物衍生的色氨酸代谢产物吲哚-3-乙酸（3-IAA）与胰腺癌化疗效果相关，提示通过饮食干预调节微生物代谢产物可能改善治疗效果 42。
综上所述，吸烟、肥胖、2型糖尿病以及不健康的饮食习惯是胰腺癌重要的环境与生活方式风险因素。这些因素通过复杂的机制相互作用，共同促进胰腺癌的发生。因此，在个体和公共卫生层面，采取积极的生活方式干预措施对于降低胰腺癌的发病率至关重要。
2.3 疾病相关风险与潜在中介
除了遗传和生活方式因素，一些疾病状态也与胰腺癌的发生密切相关，它们通过持续的炎症、组织损伤或异常细胞重塑等机制，逐步诱导胰腺上皮内瘤变（PanIN）的进展，最终导致浸润性胰腺癌。
2.3.1 慢性胰腺炎
慢性胰腺炎是胰腺癌最明确的疾病相关风险因素之一。慢性胰腺炎患者发展为胰腺癌的标准化发病率比（SIR）为14-18，且吸烟会进一步增加这一风险 44。慢性胰腺炎向胰腺癌转化的机制复杂，主要涉及：
- 持续性炎症：慢性胰腺炎的特征是胰腺组织的反复炎症和纤维化。持续的炎症反应会导致炎症细胞浸润，形成一个促肿瘤微环境 44。
- 细胞损伤与再生：慢性炎症导致胰腺细胞反复损伤和再生。这种持续的细胞增殖过程增加了DNA复制错误的几率，从而累积基因突变 44。例如，癌基因KRas突变是胰腺癌中最常见的基因变异之一，而KRas突变被认为在胰腺癌的起始和进展中起关键作用 4546。
- 纤维化与肿瘤微环境：慢性胰腺炎会引发显著的胰腺纤维化（Pancreatic Fibrosis, PF），其特征是胰腺肌成纤维细胞（Pancreatic Myofibroblasts, PMFs）的激活和细胞外基质（ECM）的过度沉积 4748。这种纤维化的肿瘤微环境为癌细胞提供支持，并可能阻碍治疗药物的递送 47。研究显示，胰腺导管腺癌（PDAC）发展过程中，ECM的组成和复杂性会发生显著变化，并且在慢性胰腺炎与PDAC之间存在相似的基质变化 48。
- 胰腺上皮内瘤变（PanIN）进展：慢性胰腺炎诱导胰腺腺泡细胞向导管细胞的化生（acinar-to-ductal metaplasia, ADM），这是PanIN形成的关键起始步骤 454649。ADM被认为是胰腺癌的癌前病变 4650。在存在致癌性KRas突变或持续性表皮生长因子受体（EGF-R）信号传导的情况下，ADM细胞可进一步发展为PanIN，并最终进展为胰腺癌 45。多项研究发现，炎症通过不同通路，如NF-κB信号，调控PanIN的形成和进展 5152。
2.3.2 胃食管反流病（GERD）
虽然胃食管反流病（GERD）主要影响食管，但有研究提示其可能与胰腺癌存在间接关联。虽然这种关联的直接机制尚不完全清楚，但可能的解释包括：
- 慢性炎症：GERD导致的慢性炎症，尤其是 Barrett 食管等，可能与全身性炎症反应有关，或暗示个体存在更普遍的炎症易感性，从而间接影响胰腺。
- 共享风险因素：GERD与肥胖、吸烟等胰腺癌的共同风险因素重叠 5354。例如，肥胖是GERD的重要风险因素，而肥胖本身就是胰腺癌的独立风险因素。这表明GERD可能作为这些共同风险因素的中介，或与其协同作用，增加胰腺癌的风险。
- 药物使用：部分用于治疗GERD的药物，如质子泵抑制剂（PPIs），长期使用是否对胰腺健康产生影响，仍需进一步研究。
2.3.3 其他疾病与中介
- 胆结石：胆结石是与肥胖相关的消化系统疾病之一，可能通过多种机制对胰腺健康产生影响，从而间接增加胰腺癌的风险 53。
- 胰腺囊性病变：某些类型的胰腺囊性病变，尤其是导管内乳头状黏液性肿瘤（IPMNs），被认为是胰腺癌的重要癌前病变。IPMNs根据其细胞学特征和异型增生程度，从低级别异型增生进展到高级别异型增生，最终可能发展为浸润性胰腺癌 5556。对IPMNs进行多组学分析发现，高级别IPMNs与低级别病变相比，糖基化水平和肿瘤进展通路显著富集，并且一些与高级别IPMN相关的蛋白（如PLOD3、IRS2、LGALS9、Trop-2）也被鉴定出来，提示这些蛋白在病变进展中起关键作用 55。对这些病变的早期识别和监测，对于预防胰腺癌至关重要。
总之，慢性胰腺炎、特定胰腺囊性病变以及可能与胰腺癌共享风险因素的疾病（如GERD）通过复杂的生物学途径，包括持续炎症、DNA损伤累积和异常细胞重塑，驱动胰腺癌前病变（PanIN）的发生和发展。了解这些疾病相关风险和潜在中介，对于制定胰腺癌的综合预防和早期干预策略具有重要意义。
3. 基于生活方式的一级预防核心策略
胰腺癌的一级预防侧重于通过改变生活方式来降低发病风险。由于胰腺癌的诊断和治疗挑战，生活方式干预被认为是当前最有前景的预防途径之一。科学研究已经积累了大量证据，表明健康的饮食模式和生活习惯能够显著降低胰腺癌的发生率。
3.1 饮食干预的科学依据与实践指南
饮食作为日常生活中最核心且可控的因素之一，对胰腺癌的预防具有举足轻重的作用。多项研究表明，采纳健康的饮食模式可显著降低胰腺癌风险，某些特定营养素和食品成分也展现出明确的保护或致病效应。
3.1.1 健康饮食模式的保护作用
多项前瞻性队列研究和荟萃分析一致指出，坚持健康的饮食模式，如地中海饮食，能够有效降低胰腺癌的发病风险。参考文献[2]指出，低地中海饮食依从性与胰腺癌风险增加相关，表明坚持健康的饮食模式具有保护作用。这些饮食模式的共同特点是强调植物性食物（蔬菜、水果、全谷物、豆类和坚果）的摄入，限制红肉、加工肉类、高糖饮料和精制谷物。它们通过提供丰富的抗氧化剂、膳食纤维和抗炎成分，同时减少促炎和致癌物质的摄入，从而发挥预防作用。
3.1.2 关键保护性营养素与食品成分
- 膳食纤维：膳食纤维在胰腺癌预防中扮演着关键角色。一项对17,155,277名个体进行的伞形综述（umbrella review）发现，膳食纤维摄入与多种慢性疾病风险降低相关，其中就包括胰腺癌，具有“令人信服的证据”（Class I） 57。高膳食纤维摄入量与较低的胰腺癌风险呈显著负相关。膳食纤维通过调节肠道微生物组、降低炎症反应、改善胰岛素敏感性和促进饱腹感从而减少能量摄入，间接或直接地发挥保护作用 57。
- ω-3脂肪酸：ω-3脂肪酸（主要来源于深海鱼类、亚麻籽等）因其强大的抗炎特性而备受关注。研究表明，较高的ω-3脂肪酸摄入量与较低的胰腺癌发病率相关 58。ω-3脂肪酸能够调节细胞信号通路，抑制炎症介质的产生，从而可能对抗胰腺癌的发生发展。
- 叶酸：叶酸（维生素B9）是DNA合成和修复以及甲基化的关键辅酶。流行病学研究提示，较高的叶酸摄入量可能与较低的胰腺癌风险相关，尤其是在叶酸摄入不足的人群中 5960。叶酸可能通过维持DNA的完整性、防止基因突变以及调节表观遗传修饰来发挥保护作用 59。
- 水果和蔬菜：富含水果和蔬菜的饮食通常提供丰富的维生素、矿物质、膳食纤维和植物化学物质，这些成分具有抗氧化和抗炎特性。多项研究表明，高摄入水果和蔬菜与胰腺癌风险降低相关 61。
3.1.3 限制有害食品成分的实践建议
- 超加工食品（UPF）：超加工食品与胰腺癌风险的增加密切相关。一项系统综述和荟萃分析发现，超加工食品摄入量每增加10%，胰腺癌风险增加1.49倍（HR=1.49） 。这些食品通常富含添加糖、不健康脂肪、盐和食品添加剂，但缺乏膳食纤维和微量营养素。建议消费者应尽量减少对超加工食品的摄入，选择新鲜、未经加工的食材。
- 添加糖：高糖饮食，特别是添加糖的过量摄入，与肥胖和2型糖尿病密切相关，进而间接增加胰腺癌风险。每日额外摄入25克添加糖，胰腺癌风险增加22%。建议严格控制添加糖的摄入，限制含糖饮料、甜点和加工食品中的隐形糖分。
- 红肉和加工肉类：高摄入红肉和加工肉类（如香肠、培根）与胰腺癌风险增加有关 61。这些食品中可能含有N-亚硝基化合物和血红素铁，可能通过诱导DNA损伤和氧化应激促进胰腺癌的发生。
- 高脂饮食：虽然脂肪是人体必需的营养素，但高总脂肪摄入，特别是饱和脂肪和反式脂肪的摄入，与胰腺癌风险增加相关 586061。相反，坚果和多不饱和脂肪酸（PUFA）的较高摄入与胰腺癌发病率降低相关 58。因此，建议选择健康的脂肪来源，如植物油、坚果、种子和鱼类，并限制不健康脂肪的摄入。
- 促炎饮食：欧洲癌症与营养前瞻性调查（EPIC）研究发现，具有较高促炎潜力的饮食（通过饮食炎症评分ISD评估）与胰腺癌风险增加11%相关（HR 1.11，95% CI 1.02-1.22），提示慢性炎症在胰腺癌发生中的作用 62。因此，采纳抗炎饮食模式（如地中海饮食）可能有助于降低风险。
综上所述，健康的饮食干预应遵循“多植物、少加工、控糖控脂”的原则，强调增加膳食纤维、ω-3脂肪酸和叶酸的摄入，并严格限制超加工食品、添加糖、红肉和不健康脂肪的摄入，从而有效降低胰腺癌的发生风险。
3.2 运动与代谢调控的防癌机制
规律的体育锻炼，特别是好氧运动，已被证实能有效降低多种癌症的发病风险，包括胰腺癌 63。其防癌机制复杂多样，主要通过改善代谢健康、调节免疫系统以及直接影响肿瘤微环境等方面发挥作用。
3.2.1 运动对胰腺癌抗肿瘤免疫的增强作用
好氧运动能够通过多种途径增强机体的抗肿瘤免疫力，从而抑制胰腺癌的发生和发展：
- 激活IL-15/IL-15Rα轴：研究表明，好氧运动能够减少胰腺导管腺癌（PDA）的肿瘤生长，其机制在于运动能够调节全身和肿瘤内部的免疫环境。具体而言，运动促进了免疫细胞的动员，并增加了肿瘤浸润性IL-15Rα⁺CD8⁺T细胞的数量。这些IL-15Rα⁺CD8⁺T细胞被认为是发挥肿瘤保护作用的关键细胞。在临床样本中，也观察到运动能够增加肿瘤内CD8⁺T细胞的数量 63。白细胞介素-15（IL-15）是一种重要的细胞因子，在T细胞和自然杀伤（NK）细胞的增殖、存活和功能维持中发挥关键作用。运动激活IL-15/IL-15Rα轴，可以增强抗肿瘤免疫反应，为胰腺癌的治疗提供了新的思路 63。
- 改善免疫监视：规律运动有助于维持免疫系统的稳态，提高免疫细胞的活性和巡逻能力，从而更有效地识别和清除癌变细胞，减少癌症的发生。
- 降低慢性炎症：运动具有抗炎作用，可以降低全身性慢性低度炎症水平。慢性炎症是胰腺癌发生发展的重要驱动因素之一，通过抑制炎症，运动可以减少对胰腺细胞的损伤和癌变风险。
3.2.2 运动对代谢健康的调节作用
运动是改善代谢健康的有效手段，而代谢紊乱（如肥胖、胰岛素抵抗和2型糖尿病）是胰腺癌的重要风险因素。运动通过以下方式降低胰腺癌风险：
- 体重管理：运动有助于消耗能量，减少脂肪堆积，从而有效控制体重。肥胖是胰腺癌的独立风险因素，通过维持健康的体重，可以显著降低胰腺癌的发生风险。
- 改善胰岛素敏感性：规律运动可以增加机体对胰岛素的敏感性，降低胰岛素抵抗，从而减少高胰岛素血症的发生。高胰岛素血症被认为是促进胰腺细胞增殖和癌变的因素之一。
- 降低血糖水平：运动能促进肌肉对葡萄糖的摄取和利用，有助于稳定血糖水平，这对于预防和管理2型糖尿病及其相关的胰腺癌风险至关重要。
3.2.3 冷暴露与棕色脂肪激活的潜在防癌价值
除了传统的运动方式，近年来研究发现，通过冷暴露激活棕色脂肪组织（BAT）也可能为胰腺癌预防提供新的策略：
- 抑制肿瘤糖酵解：癌细胞通常表现出高糖酵解率（Warburg效应），这为其快速增殖提供了能量。研究显示，将荷瘤小鼠暴露于寒冷条件下，可以显著抑制包括胰腺癌在内的多种实体瘤的生长。其机制在于，冷诱导的BAT激活能够显著降低血糖水平，并阻碍癌细胞的糖酵解代谢。当BAT被切除或在冷暴露下喂食高糖饮食时，肿瘤生长会恢复；而Ucp1（BAT产热的关键介质）的基因缺失则会消除冷触发的抗癌效应 64。
- 改善代谢微环境：BAT的激活能够通过增加葡萄糖摄取和能量消耗，改善全身代谢状况，从而减少癌细胞可利用的营养物质，并可能改变肿瘤微环境，使其不利于肿瘤生长。
- 初步临床证据：一项初步的人体研究发现，温和的冷暴露可以在健康人和癌症患者体内激活大量的BAT，并观察到肿瘤组织中葡萄糖摄取减少 64。这提示冷暴露激活BAT可能是一种简单有效的癌症治疗和预防新策略，未来可能与现有抗癌疗法结合使用 64。
3.2.4 运动与DNA甲基化衰老的关联
值得注意的是，除了对免疫和代谢的直接影响，运动对细胞层面的健康也具有深远意义。有研究表明，增加体育锻炼可以显著减少与癌症相关通路中的随机表观遗传突变（SEMs），这是一种DNA甲基化衰老生物标志物。例如，在“饮食、体育活动和乳腺X线照相术”（DAMA）研究中，一项为期2年的饮食和体育活动干预试验显示，增加体育活动能够显著减缓DNAmGrimAge时钟，并降低癌症相关通路中的表观遗传突变负荷 65。这表明运动可能通过调节表观遗传机制，维持基因组稳定性，从而降低胰腺癌的发生风险。
综合来看，规律的体育锻炼，特别是好氧运动，通过增强抗肿瘤免疫、改善代谢健康和影响表观遗传调控等多重机制，为胰腺癌的一级预防提供了强有力的支持。而冷暴露激活棕色脂肪的发现，则进一步拓宽了代谢干预在胰腺癌预防中的潜力。
3.3 综合生活方式评分的协同效应
鉴于胰腺癌发病机制的复杂性和多因素性，单一的生活方式干预往往难以实现最佳的预防效果。越来越多的研究证据表明，将多个健康生活方式因素进行综合评估和干预，其协同效应远超单一因素的调整。这种综合生活方式评分（Composite Lifestyle Score, CLS）方法能够更好地量化个体对健康生活方式的依从性，并预测其胰腺癌的发生风险。
例如，在欧洲癌症与营养前瞻性调查（EPIC）研究中，研究人员构建了一个健康生活方式指数（HLI），综合考虑了吸烟、饮酒、膳食暴露、体力活动以及整体和中心性肥胖（通过BMI和腰臀比衡量）等因素。结果显示，HLI和HLI（基于腰臀比）每增加一个标准差，胰腺癌的风险比（HR）分别为0.84（95% CI: 0.79, 0.89）和0.77（95% CI: 0.72, 0.82）66。这意味着，对健康生活方式的更高依从性与胰腺癌风险呈负相关，并且这种关联超越了单纯避免吸烟的益处66。这项研究强调，公共卫生措施如果能针对健康生活方式的整体依从性，将对胰腺癌发病率产生重要影响66。
另一项来自新加坡华人健康研究的长期前瞻性队列研究也强有力地支持了综合生活方式干预的协同效应。该研究对63,257名45至74岁的华人进行了长达25年的随访，评估了身体质量指数、吸烟、健康饮食指数（AHEI-2010）、睡眠时长和体力活动等健康生活方式因素的综合评分与胰腺癌风险的关系。结果发现，代表更健康生活方式的综合评分越高，患胰腺癌的风险显著降低67。与评分在0-1分（代表不健康生活方式）的个体相比，评分达到2、3、4、5以及6-7分的个体，其胰腺癌发病率的多变量调整风险比（HRs）分别为0.60、0.48、0.45、0.41和0.38（p < 0.0001）67。这意味着，拥有最健康生活方式的个体，其胰腺癌风险可降低高达62%67。这种负相关性在男性和女性、饮酒者和非饮酒者中均表现一致，并且在没有糖尿病史的参与者中更为显著67。
这些研究结果共同强调了一个核心实践意义：多因素干预优于单因素调整。胰腺癌的预防不应仅仅关注某一个风险因素的改变（如戒烟），而应倡导一种全面的、整体性的健康生活方式。例如，地中海饮食模式，作为一种包含多种健康饮食成分的综合模式，其非依从性与乳腺癌发生存在协同效应，尤其与吸烟、缺乏体育活动和饮酒等其他风险因素共同作用时，这种协同效应更为显著68。因此，推广综合健康生活方式策略，包括保持健康体重、戒烟、遵循健康饮食模式、保证充足睡眠以及进行规律体育活动，能够更有效地降低胰腺癌的总体发病风险。公共卫生项目应着力于促进全面的生活方式改变，而非仅仅关注单一行为的修正，以期实现更显著的预防效果。
4. 高危人群的早期筛查与二级预防实践
由于胰腺癌在普通人群中发病率相对较低，且目前的筛查技术尚不足以实现大规模人群的普查，因此，对高危人群进行精准识别和定期筛查是胰腺癌二级预防的关键策略 969。这种针对性的筛查旨在早期发现癌前病变或可手术的早期胰腺癌，从而显著改善患者的预后 70。
4.1 高危人群的精准识别
精准识别高危人群是实施胰腺癌早期筛查的前提。目前，高危人群主要根据遗传因素、家族史以及某些特定疾病（如新发糖尿病）来界定 18。
4.1.1 遗传性综合征
多种遗传性癌症综合征与胰腺癌风险增加密切相关。对于携带特定种系基因突变的个体，其胰腺癌发病风险显著高于普通人群，因此被视为高危人群 7172。
- 佩茨-杰格斯综合征 (Peutz-Jeghers Syndrome, PJS)：由STK11基因种系突变引起，患者胰腺癌风险极高。PJS患者的胰腺癌筛查应从35岁开始 71。
- 遗传性胰腺炎 (Hereditary Pancreatitis, HP)：主要由PRSS1基因突变导致，终生胰腺癌风险达40%-50% 71。对于HP患者，建议从40岁开始进行胰腺癌筛查 71。
- CDKN2A 基因突变：CDKN2A（或p16）基因突变与家族性非典型多发性黑色素瘤和胰腺癌综合征相关。携带此突变的个体，其胰腺癌筛查应从40岁开始 71。
- 林奇综合征 (Lynch Syndrome)：由错配修复基因（如MLH1, MSH2, MSH6, PMS2）种系突变引起。伴有胰腺癌家族史的林奇综合征患者，其胰腺癌风险增加，建议进行筛查 71。
- BRCA1/BRCA2、PALB2 和 ATM 基因突变：这些基因主要参与DNA损伤修复。其种系突变不仅增加乳腺癌和卵巢癌风险，也显著增加胰腺癌风险 71。例如，BRCA2突变携带者到80岁时胰腺癌的绝对风险可达约2.5% 71。对携带这些基因突变且有一位或多位一级亲属患有胰腺癌的个体，建议进行筛查 71。
4.1.2 家族史
胰腺癌家族史是评估个体风险的重要指标。家族性胰腺癌（Familial Pancreatic Cancer, FPC）是指在没有任何已知遗传综合征的情况下，家族中有多个成员患有胰腺癌。
- 定义标准：国际癌症胰腺筛查联盟 (International Cancer of the Pancreas Screening, CAPS) 将高危人群定义为：至少有两名一级亲属（父母、兄弟姐妹或子女）患有胰腺癌的个体；或者有已知与胰腺癌相关的种系突变（如CDKN2A、BRCA1/2、PALB2、ATM、MLH1、MSH2、MSH6、PMS2、STK11或PRSS1）的个体 56。美国胃肠病学会 (AGA) 建议，对患有胰腺癌的患者的至少两名一级亲属有患癌史的个体，应考虑进行胰腺癌筛查 71。
- 筛查起始年龄：对于家族史相关的高危人群，筛查通常建议从50岁开始，或者比家族中最小发病年龄提前10年开始 5671。
4.1.3 新发糖尿病
2型糖尿病与胰腺癌之间存在复杂且双向的关联 73。长期存在的2型糖尿病是胰腺癌的风险因素，而新发糖尿病（特别是老年人新发）则可能是胰腺癌的早期临床表现之一 973。
- 风险评估：约1%的50岁以上新发糖尿病患者在3年内被诊断出胰腺癌 74。新发糖尿病患者在诊断后的3年内，其患胰腺癌的风险比一般人群高出8倍 9。这意味着，对于近期确诊糖尿病的老年患者，尤其是那些没有典型糖尿病风险因素（如肥胖）的患者，应高度警惕胰腺癌的可能 18。
- 风险预测模型：为了更有效地识别新发糖尿病患者中的高风险个体，研究人员开发了风险预测模型。例如，END-PAC（Enriching New-Onset Diabetes for Pancreatic Cancer）模型结合了体重变化、血糖变化和糖尿病发病年龄等因素，能够有效识别新发糖尿病患者中胰腺癌的高风险人群。该模型通过对独立人群队列的验证，显示出良好的预测性能，一个得分达到3分或以上的患者，其胰腺癌的患病率比普通新发糖尿病患者高4.4倍 74。这种模型可以帮助临床医生对新发糖尿病患者进行更精准的风险分层，指导是否需要进一步的胰腺癌筛查。
4.1.4 多组学模型提升风险分层效率
随着生物技术的发展，结合多组学数据（如基因组学、蛋白质组学、代谢组学、微生物组学）和机器学习算法，可以构建更精准的风险预测模型，进一步提升高危人群识别的效率 7576777879。
- NODM-PC 风险预测模型：例如，一项研究利用多种生物标志物（包括新的胰腺癌风险生物标志物，如CA19-9、miR-196a、HbA1c）和临床数据，开发了针对新发糖尿病患者的胰腺癌风险预测模型，其C-index高达0.823。这类模型通过整合多维度数据，可以更准确地识别那些患有糖尿病且胰腺癌风险高的个体，从而为他们提供个性化的筛查方案。
- 整合多模态数据：结合遗传变异、血液生物标志物、影像学特征以及临床病史，利用人工智能和机器学习技术，有望开发出能够更早、更准确地预测胰腺癌风险的工具。例如，循环肿瘤DNA (ctDNA) 和微生物组等新型生物标志物，正在被探索用于高危人群的早期检测和风险评估。
通过对上述遗传因素、家族史、新发糖尿病以及新兴的多组学风险预测模型的综合运用，可以实现胰腺癌高危人群的精准识别，为后续的早期筛查和干预提供坚实的基础。
4.2 筛查技术与生物标志物开发
针对胰腺癌高危人群的早期筛查，多种技术手段正在不断发展和完善，主要包括影像学检查和生物标志物检测。这些方法的结合应用旨在提高早期诊断的敏感性和特异性，从而为患者争取更早的干预时机。
4.2.1 影像学筛查手段
影像学技术是胰腺癌早期筛查的基石，主要包括磁共振胰胆管造影（Magnetic Resonance Cholangiopancreatography, MRCP）、内镜超声（Endoscopic Ultrasound, EUS）以及磁共振成像（Magnetic Resonance Imaging, MRI）等。这些技术在发现胰腺实性病变和囊性病变方面各具优势。
- MRI/MRCP：磁共振成像（MRI）和磁共振胰胆管造影（MRCP）是非侵入性检查，无辐射暴露，被认为是胰腺成像的最佳非侵入性技术之一 80。它们在评估胰腺导管系统、发现胰腺囊性病变和实性病变方面具有高分辨率。MRCP尤其适用于评估胰管的形态学改变，如狭窄、扩张或分支胰管的异常，这对于发现导管内乳头状黏液性肿瘤（IPMNs）等癌前病变至关重要。MRI则能提供更全面的胰腺实质信息，结合弥散加权成像（DWI）和动态对比增强MRI（DCE-MRI）等功能性成像技术，可以提高对胰腺肿瘤的检出能力和对肿瘤侵袭性的预测 81。尽管如此，MRI/MRCP对于直径小于1cm的早期胰腺癌或高级别PanIN的检出率仍有局限性。
- EUS（内镜超声）：内镜超声（EUS）是一种侵入性但敏感的检查方法，它通过内镜将超声探头置于胃肠道内，紧邻胰腺，从而获得高分辨率的胰腺图像。EUS在发现小至几毫米的胰腺病变方面表现出卓越的优势 82。EUS还可以进行细针穿刺活检（EUS-FNA），获取组织样本进行病理学诊断，从而确诊病变性质。由于其较高的敏感性，EUS常被推荐用于高危人群的胰腺癌筛查，尤其是在MRI/MRCP发现可疑病变后进一步明确诊断或在初始筛查中作为补充手段。然而，EUS的侵入性、操作依赖性以及并发症风险是其普及的限制因素。
- CT（计算机断层扫描）：CT是胰腺癌诊断和分期的常用手段，特别是在评估肿瘤的可切除性方面。然而，CT在早期胰腺癌的发现和对小于1cm病变的识别上敏感性可能不如EUS和MRI。一项荟萃分析指出，CT和MRI在诊断和血管侵犯方面的敏感性及特异性相似 83。因此，CT通常不作为高危人群的一线筛查工具，更多用于确诊后的分期和评估。
4.2.2 新型生物标志物开发
除了传统的CA19-9等血清标志物（其敏感性和特异性有限，尤其是在早期胰腺癌诊断中），研究人员正在积极探索多种新型生物标志物，以期实现胰腺癌的超早期检测。
- 唾液真菌群：唾液作为一种非侵入性样本，其微生物组构成可能反映全身健康状况。有研究探索了唾液微生物组在胰腺癌诊断中的潜力。例如，一项研究发现唾液中曲霉菌（Aspergillus）等真菌的特征性改变可能与胰腺癌相关，其诊断效能较高，曲线下面积（AUC）可达0.983。这表明唾液真菌群可能成为一种潜在的早期诊断标志物。
- 血清MMP9：基质金属蛋白酶9（MMP9）是一种参与细胞外基质降解的酶，在肿瘤的侵袭和转移中发挥关键作用。多项研究表明，MMP9在胰腺癌患者中表达升高，且其水平可能与疾病进展相关 84。早期研究发现，血清MMP9水平在胰腺癌患者中显著高于慢性胰腺炎患者和健康对照组，并可能与肿瘤分期和预后相关 858687。例如，MMP9与VNN1的组合可能作为区分胰腺癌相关糖尿病与2型糖尿病的生物标志物 88。虽然MMP9在检测晚期胰腺癌中具有一定适用性，但其在早期诊断中的相关性尚待进一步确认 84。此外，有研究发现血清来源的细胞外囊泡（EV）RNA中的MMP9水平在晚期胰腺癌患者中相对较高，这提示EV-RNA MMP9可能作为一种非侵入性标志物，尤其在评估疾病进展方面具有潜力 89。
- miRNA（微小RNA）：miRNA是一类小的非编码RNA分子，通过调控基因表达在肿瘤发生发展中发挥重要作用。在胰腺癌中，许多miRNA的表达水平发生改变，例如，miRNA-21、miRNA-155等在胰腺癌组织和血清中呈高表达，而miRNA-148a等则呈低表达。系统综述和荟萃分析显示，miRNA生物标志物在早期胰腺癌检测中表现出较高的诊断准确性，汇总敏感性为0.88，特异性为0.91，曲线下面积（AUC）为0.95 90。miRNA可以通过液体活检（如血清、唾液、尿液）进行检测，具有非侵入性优势，是极具潜力的早期诊断标志物。
- ctDNA（循环肿瘤DNA）：循环肿瘤DNA（ctDNA）是指由肿瘤细胞释放到血液中的游离DNA片段。ctDNA携带肿瘤特异性基因突变或表观遗传改变，是“液体活检”的重要组成部分。在胰腺癌中，ctDNA被认为在早期诊断、监测治疗反应、检测复发和追踪耐药性方面具有巨大潜力 919293。对于监测胰腺上皮内瘤变（PanIN）的进展，ctDNA可以检测到KRAS等早期驱动基因突变，从而可能在影像学可见肿瘤形成之前提供预警。研究发现，ctDNA生物标志物在早期胰腺癌检测中具有高特异性（0.94），但敏感性相对较低（0.65），汇总AUC为0.92 90。ctDNA的分析方法包括下一代测序（NGS）和液滴数字PCR（ddPCR），并已被用于识别治疗选择性耐药突变和评估治疗反应 94。
- 其他生物标志物：除了上述，长非编码RNA（lncRNA）也被发现与胰腺癌的发生和进展有关，具有作为诊断和预后生物标志物的潜力 95。此外，外泌体非编码RNA（exosomal ncRNA）也是新兴的研究热点，它们能够反映肿瘤的独特分子特征，在胰腺癌的诊断和治疗中展现出广阔前景 96。
这些新型生物标志物的开发和应用，有望克服现有筛查手段的局限性，特别是在早期检测和对癌前病变（如PanIN）进展的监测方面，为胰腺癌的二级预防提供更精准、更及时的工具。
4.3 筛查方案的优化与挑战
针对高危人群的胰腺癌筛查，尽管其在早期检测和改善预后方面具有显著价值，但在具体实施中仍面临诸多挑战。现有的筛查指南，如美国国家综合癌症网络（NCCN）和美国胃肠病学会（AGA）的建议，为高危人群的筛查提供了框架，但如何优化筛查方案、平衡筛查效益与潜在风险，是当前亟待解决的问题。
4.3.1 现有筛查指南与推荐
当前针对胰腺癌高危人群的筛查指南主要基于家族史和基因突变状态，并明确了筛查的起始年龄和间隔频率：
- 筛查起始年龄：
- 筛查间隔：
AGA指南强调，磁共振成像（MRI）和内镜超声（EUS）联合使用是高危人群胰腺癌筛查的首选模式 71。
4.3.2 筛查面临的挑战
尽管筛查指南已相对明确，但其在临床实践中仍面临多重挑战，主要包括过度诊断、假阳性以及由此带来的心理和经济负担：
过度诊断与假阳性：
- 胰腺癌筛查，尤其是在健康人群或低风险人群中，可能导致大量良性病变被发现，这些病变可能永远不会发展为临床意义上的胰腺癌。这些“过度诊断”可能导致不必要的侵入性检查（如EUS-FNA、手术），甚至带来并发症风险。
- 影像学检查（如MRI/EUS）的假阳性率较高，即发现可疑病变但最终证实为良性。这些假阳性结果会给患者带来巨大的心理压力和焦虑，担心患癌，并可能因此接受后续不必要的检查和治疗。
- 目前的遗传测试（GT）覆盖率仍然偏低，即使在高危人群中也存在差距。一项针对高危乳腺癌、卵巢癌、胰腺癌和前列腺癌患者的调查显示，只有17%的患者接受了遗传测试，尽管这一比例从2013年的9%增加到2019年的21% 98。这意味着大量高危人群可能未被识别，从而错失筛查机会。
心理负担：
- 接受胰腺癌筛查的个体，特别是那些家族中有多名成员患癌的个体，本身就背负着沉重的心理压力。筛查过程中任何可疑的结果，即使最终证实为良性，都可能导致长期的焦虑、抑郁和生活质量下降。患者可能需要反复的检查和随访，这种不确定性会持续影响其心理健康。
经济负担：
- 胰腺癌的筛查费用高昂，特别是需要定期进行的MRI/EUS检查以及后续可能的活检和手术。对于许多个体和医疗系统而言，这构成了显著的经济负担。同时，频繁的检查还可能带来时间成本和交通成本。
- 此外，筛查效率受到医疗资源限制的影响，胰腺癌筛查需要经验丰富的放射科医生和胃肠病学家，以及高端的影像设备，这些资源在许多地区是稀缺的。
4.3.3 个性化筛查策略的必要性
为了解决上述挑战，实现胰腺癌筛查的最大效益，个性化筛查策略变得尤为重要：
精准风险分层：
- 结合遗传学、家族史、临床特征（如新发糖尿病）、生物标志物（如ctDNA、miRNA）以及多组学数据，开发更精确的风险预测模型，将高危人群进一步细分为不同风险等级。例如，利用人工智能驱动的方法，结合遗传信息和临床数据，可以更准确地识别哪些个体真正需要高强度的筛查，哪些可以采用较宽松的随访方案 99。
- 考虑年龄依赖性：一些研究表明，遗传和生活方式干预在年轻个体（如60岁以下）中可能效果更显著。因此，筛查策略应根据个体的年龄和风险变化进行动态调整。
多学科团队决策：
- 由遗传咨询师、胃肠病学家、肿瘤学家、放射科医生和病理学家组成的多学科团队，共同评估高危个体的风险，并制定个体化的筛查方案 71。这种模式可以确保筛查决策的全面性和专业性，同时为患者提供充分的遗传咨询和心理支持，缓解其焦虑。
新型生物标志物的整合：
- 将唾液真菌群、血清MMP9、miRNA、ctDNA等新型无创或微创生物标志物整合到筛查流程中，可以作为影像学检查的补充，提高筛查的敏感性和特异性。例如，生物标志物异常可能提示需要更频繁或更深入的影像学检查。
- 在监测PanIN进展方面，ctDNA等液体活检技术具有巨大潜力，有望在影像学可见病变之前发现分子层面的异常，为早期干预提供更早的窗口。
风险-效益平衡的持续评估：
- 持续进行研究，评估不同筛查策略的成本效益、心理影响和患者依从性。通过真实的临床数据，不断优化筛查指南，确保筛查措施在有效性、安全性、经济可及性和患者接受度之间取得最佳平衡。
总之，胰腺癌高危人群的早期筛查是二级预防的关键，但其复杂性要求我们必须超越一刀切的模式，转向更加精细化、个性化的筛查策略。这不仅需要医学技术的进步，也需要多学科协作和对患者全方位的关注。
5. 药物与代谢干预的预防潜力与安全性
在胰腺癌的预防策略中，药物与代谢干预展现出独特的潜力。特别是针对与胰腺癌发病密切相关的代谢性疾病，如2型糖尿病，其治疗药物的安全性评估及其潜在的防癌或致癌风险，成为研究的重要焦点。
5.1 GLP-1受体激动剂的胰腺安全性评估
胰高血糖素样肽-1受体激动剂（GLP-1RA）是一类广泛应用于2型糖尿病治疗的药物，通过模拟GLP-1的作用，促进胰岛素分泌、抑制胰高血糖素分泌、延缓胃排空并增加饱腹感，从而有效控制血糖和减轻体重。然而，自其上市以来，GLP-1RA与胰腺炎及胰腺癌风险的潜在关联一直备受关注。
5.1.1 GLP-1RA与胰腺炎/胰腺癌风险的争议与现状
早期动物研究和一些观察性研究曾提示GLP-1RA可能增加胰腺炎和胰腺癌的风险，引发了广泛担忧。然而，随后进行的大量临床试验、真实世界数据分析和荟萃分析并未明确支持这一担忧，反而多数研究表明GLP-1RA的胰腺安全性良好。
- SUSTAIN/PIONEER 试验数据：司美格鲁肽（Semaglutide）是新一代的GLP-1RA，在SUSTAIN（皮下注射司美格鲁肽）和PIONEER（口服司美格鲁肽）等大型临床试验中对其心血管结局和安全性进行了广泛评估。这些研究以及后续的系统综述和荟萃分析均未发现司美格鲁肽与胰腺癌风险增加之间存在明确的因果关联 100101102。一项针对司美格鲁肽安全性的系统综述和荟萃分析（包括37项随机对照试验和19项真实世界研究）得出结论，司美格鲁肽的使用与任何类型癌症的风险增加无关，包括胰腺癌（与安慰剂组相比，OR=0.25，95%CI：0.03-2.24；与主动对照组相比，OR=0.40，95%CI：0.09-1.87），且证据等级高 101。
- 多项荟萃分析与真实世界数据：一项包含7项心血管结局试验（涉及56,004名参与者）的系统综述和荟萃分析显示，GLP-1RA治疗并未增加严重低血糖、胰腺炎或胰腺癌的风险 103。另一项针对GLP-1RA（包括艾塞那肽、利拉鲁肽、利西那肽、阿必鲁肽、度拉鲁肽或司美格鲁肽）的荟萃分析，涵盖了所有持续时间超过11周的随机临床试验，也未发现GLP-1RA与胰腺炎或胰腺癌的发生率存在显著差异 104。
- 长期随访研究：一项基于以色列大型健康服务机构的队列研究，对超过54万名2型糖尿病患者进行了长达9年的随访。结果显示，与基础胰岛素相比，GLP-1RA治疗并未增加胰腺癌的发生风险，即使在开始治疗5至7年后，风险比也未显著升高（HR=0.50，95%CI：0.15-1.71）105。另一项利用真实世界数据进行的“目标试验模拟”研究也发现，GLP-1RA与胰腺癌发病率的降低相关（与六种非GLP-1RA降糖药物相比，HRs范围为0.42-0.82），且在肥胖和吸烟患者中效果更明显 106。
5.1.2 潜在机制与监测要点
尽管目前主流证据表明GLP-1RA不会增加胰腺癌风险，但在临床实践中仍需保持警惕，并关注特定人群的监测。
- GLP-1RA的安全性评估：现有证据表明，GLP-1RA的胰腺安全性良好，并没有明确的证据表明其增加胰腺炎或胰腺癌的风险 107。GLP-1RA通过其独特的机制，有效改善血糖控制和减轻体重，这些益处在胰腺癌预防中可能发挥间接的保护作用，尤其是在控制糖尿病和肥胖这两个重要风险因素方面。
- 糖尿病视网膜病变（DRP）患者的监测：对于合并糖尿病视网膜病变（DRP）的患者，尤其是那些同时使用胰岛素治疗的患者，在接受司美格鲁肽治疗时需要密切监测 100。这是因为司美格鲁肽强效的降糖作用可能导致血糖水平快速变化，理论上可能加重既有的DRP。虽然这与胰腺癌风险无直接关联，但凸显了在特殊糖尿病并发症患者中，需综合评估药物的整体安全性。
- 新发糖尿病患者的考量：如前所述，新发糖尿病，特别是老年人新发糖尿病，可能是胰腺癌的早期表现。在这种情况下，无论是否使用GLP-1RA，都应警惕胰腺癌的可能性，并根据风险评估进行相应的筛查。此时，GLP-1RA的使用不应掩盖对潜在胰腺癌的警惕。
总而言之，GLP-1RA在2型糖尿病治疗中具有良好的心血管和代谢益处，目前的证据并未支持其增加胰腺癌风险。然而，由于胰腺癌的低发病率，以及药物长期使用的数据仍在积累中，对于GLP-1RA的胰腺安全性仍需持续关注，并强调对高危患者（如合并DRP）的个体化监测。
5.2 代谢与营养干预的新方向
除了传统的药物疗法，代谢调控和营养干预作为胰腺癌预防和辅助治疗的新方向，正受到越来越多的关注。这些新兴策略旨在通过调节机体代谢、增强免疫功能和改善营养状态，从而抑制肿瘤生长、降低转移风险或改善患者预后。
5.2.1 NPY1R拮抗剂抑制转移的潜在价值
神经肽Y（NPY）系统，除了在能量稳态中发挥作用，也被发现与多种癌症的肿瘤发生有关 108。近年来研究揭示，NPY及其受体（特别是NPY1R）在胰腺癌的转移过程中扮演着重要角色 108109。
- NPY/NPY1R信号通路上调：研究发现，在胰腺癌小鼠模型和人类胰腺癌患者中，NPY及其受体NPY1R的表达均上调 108。这表明NPY/NPY1R信号通路可能是胰腺癌进展的潜在驱动因素。
- 抑制转移作用：通过基因工程改造的自发性KPC小鼠模型（一种模拟人类胰腺癌的动物模型）发现，胰腺特异性或全身性敲除NPY1R显著减少了胰腺癌向肝脏的转移 108。进一步的体外实验显示，NPY1R拮抗剂BIBO3304能显著降低KPC细胞在细胞衍生基质上的迁移能力 108。在胰腺癌脾内转移模型中，药理学抑制NPY1R（使用BIBO3304）也显著减少了肝脏转移 108。
- 临床转化前景：这些结果表明NPY/NPY1R信号通路是胰腺癌中一个尚未被识别的抗转移靶点 108。NPY1R拮抗剂如BIBO3304，可能作为潜在的药物干预策略，用于抑制胰腺癌的转移，尤其对于已发生或高风险转移的患者，具有重要的临床转化前景。对Y受体（YRs）的拮抗剂，特别是Y2R/Y5R拮抗剂，以及NPY或PYY激动剂，被视为有前景的抗肿瘤治疗策略 109。
5.2.2 冷暴露激活棕色脂肪（BAT）的临床转化可能
如前所述，冷暴露激活棕色脂肪组织（BAT）已被证明能够通过降低血糖和抑制肿瘤糖酵解来抑制包括胰腺癌在内的多种实体瘤生长 64。
- 抗肿瘤机制：癌细胞通常依赖糖酵解获取能量，而BAT的激活能够显著降低血液中的葡萄糖水平，从而“饿死”癌细胞，阻碍其增殖和转移 64。
- 临床转化潜力：这项新发现为癌症治疗提供了一个全新的概念和范式，提示冷暴露或通过药物、设备激活BAT，无论是单独使用还是与其他抗癌疗法联合，都有可能成为有效治疗各种癌症的普遍方法 64。目前已有初步人体研究显示，温和冷暴露可激活健康人和癌症患者体内的BAT，并减轻肿瘤组织的葡萄糖摄取 64。未来，将冷暴露作为一种非侵入性、低成本的辅助疗法，用于胰腺癌的预防或治疗，具有巨大的临床转化潜力。
5.2.3 免疫营养在胰腺癌管理中的作用
胰腺癌患者常伴有恶病质、营养不良和免疫功能受损，这不仅影响治疗耐受性，也降低术后并发症的发生率和生存质量 110111。免疫营养（Immunonutrition, IN）作为一种特殊的营养支持，旨在通过补充具有免疫调节作用的营养素来改善患者的免疫和营养状态。
- 改善术前营养状态：免疫营养在胰腺癌患者术前预康复（prehabilitation）中发挥着关键作用 110111。胰腺癌患者常因外分泌功能不全和肿瘤本身导致营养失衡，易发生营养不良和肌肉减少症。术前免疫营养能够有效改善患者的营养状况，增强体能，使其更好地耐受后续的手术和化疗 110112。一项研究表明，术前使用免疫营养的胰腺癌患者，其术后并发症显著减少，住院时间缩短，并且营养风险指数（NRI）和白蛋白水平改善 113。
- 降低术后并发症：多项随机对照试验和荟萃分析证实，围手术期（特别是术前）免疫营养能显著降低胰腺癌患者术后感染并发症的发生率，并缩短住院时间 114115116。免疫营养通常包含精氨酸、ω-3脂肪酸和核苷酸等成分 114。例如，一项研究对接受胰十二指肠切除术（PD）的患者进行了对比，结果显示免疫营养组的术后并发症发生率低于标准肠内营养组和全肠外营养组，且感染并发症的严重程度更低，住院时间更短 116。
- ω-3脂肪酸的抗肿瘤潜力：ω-3脂肪酸（如EPA和DHA）是免疫营养的关键成分之一。它们不仅具有抗炎作用，还能直接抑制肿瘤生长和转移 117118119。在胰腺癌小鼠模型中，ω-3脂肪酸干预显著减少了肿瘤体积以及肺部和肝脏转移，并有改善生存率的趋势。这种抗肿瘤作用伴随着肿瘤膜脂肪酸谱的改变，并能诱导癌细胞凋亡，同时显著减少肿瘤纤维化，这与Sonic Hedgehog水平降低相关 117。尽管早期研究对ω-3脂肪酸在癌症恶病质中的作用存在争议 120121，但其在调节信号通路、改善膜结构和功能以及产生生物活性脂质介质方面的作用，使其在胰腺癌预防和辅助治疗中仍具有重要潜力 119。
- 生物电阻抗相角（PA）监测：相角（PA）作为生物电阻抗分析的指标，可以反映细胞膜的完整性和细胞健康状况。研究发现，围手术期免疫营养能够显著提高胰腺癌患者的相角值，改善术后恢复，并与术后并发症的发生率呈负相关。因此，PA可作为评估免疫营养有效性和预测术后并发症的有用工具 122。
综合来看，NPY1R拮抗剂和冷暴露激活BAT代表了代谢调控在胰腺癌治疗和预防中的前沿探索，而免疫营养，特别是包含ω-3脂肪酸的方案，在改善胰腺癌患者术前营养状态和降低术后并发症方面已取得明确成效。这些策略共同为胰腺癌的综合管理提供了新的思路和工具。
5.3 药物预防的争议与展望
胰腺癌的药物预防，即通过药物或营养补充剂来降低其发病风险，是一个充满希望但也伴随争议的领域。尽管许多化合物在体外或动物模型中表现出抗癌潜力，但其在人体内的预防效果和安全性仍需严格验证。
5.3.1 营养素预防证据的局限性
- 叶酸 (Folate)：
- 潜在益处：叶酸作为DNA合成、修复和甲基化过程中的关键辅因子，理论上可通过维持基因组稳定性和预防DNA损伤来发挥抗癌作用。一项荟萃分析确实指出，较高的膳食叶酸摄入量与食管癌、胃癌和胰腺癌的风险降低相关，其中胰腺癌的风险比（OR）为0.731（95% CI = 0.555-0.907）123。线性剂量反应分析表明，膳食叶酸摄入量每增加100 μg/天，胰腺癌风险可降低6% 123。
- 争议与局限性：然而，关于叶酸补充剂与胰腺癌风险的关联仍存在争议。一些研究未能发现补充叶酸的保护作用，甚至有研究提示高剂量的叶酸补充可能增加某些癌症的风险。这种差异可能与叶酸的剂量、来源（膳食 vs. 补充剂）、研究人群的基因背景以及叶酸状态基线水平等因素有关。因此，目前不推荐通过补充高剂量叶酸来预防胰腺癌，更应关注通过均衡饮食摄入足量的天然叶酸。
- 维生素D (Vitamin D)：
- 潜在益处：维生素D在胰腺岛细胞和导管细胞中表达1α-羟化酶，可生成生物活性形式的1,25-二羟基维生素D，提示其可能影响胰腺功能和胰腺癌病因学 124。一些生态学研究发现阳光暴露与胰腺癌死亡率降低有关，且血清25-羟基维生素D水平被认为是维生素D状态的最佳指标 124。
- 争议与局限性：尽管前瞻性流行病学研究提示较高的维生素D水平可能与胰腺癌风险降低相关，但一项巢式病例对照研究却显示，较高的维生素D水平可能使胰腺癌风险增加3倍 124。这些研究的局限性在于，一些研究未能测量胰腺癌患者的维生素D状态，而另一些研究则是在特定吸烟人群中进行的 124。因此，在得出维生素D在胰腺癌病因学中潜在作用的结论之前，需要更多的研究，特别是关于诊断前维生素D状态与胰腺癌风险的检查。目前，尚无足够证据支持将维生素D补充剂作为胰腺癌的预防策略。
- 其他营养素和天然化合物：
5.3.2 靶向AhR通路调节肿瘤微环境的潜在策略
芳香烃受体（Aryl Hydrocarbon Receptor, AhR）是一种配体激活的转录因子，在肿瘤免疫、炎症和代谢中发挥关键作用。研究表明，AhR在胰腺导管腺癌（PDAC）的肿瘤相关巨噬细胞（TAMs）中高度活跃，并通过抑制抗肿瘤免疫促进肿瘤生长 127。
- 色氨酸代谢产物与AhR激活：肿瘤微环境中的色氨酸（Tryptophan）代谢，特别是通过犬尿氨酸通路产生的代谢产物，能够激活AhR 127128129。乳酸杆菌对膳食色氨酸的代谢产物吲哚类物质，是TAMs中AhR活性的重要驱动因素 127。高水平的犬尿氨酸与PDAC患者预后不良相关 129。
- AhR抑制的预防潜力：
- 抑制IDH1：吲哚胺2,3-双加氧酶1（IDO1）是犬尿氨酸通路的关键酶，负责色氨酸向犬尿氨酸的转化。IDO1在PDAC组织和细胞中过表达，其表达水平与患者生存期呈负相关 128130。IDO1/TDO（色氨酸2,3-双加氧酶）双重抑制剂RY103能够显著阻断犬尿氨酸通路，靶向Kyn-AhR通路，从而抑制PDAC细胞的迁移和侵袭，并在PDAC小鼠模型中表现出临床前疗效，改善IDO1/TDO介导的免疫抑制 128。
- 药物重塑：帕金森病药物卡比多巴（Carbidopa）被发现是AhR的激动剂，它能够抑制PDAC细胞中IDO1的表达，并通过AhR途径直接或间接（通过干扰JAK/STAT通路）减弱肿瘤生长 130。另一项研究也发现，包括多巴胺在内的神经活性激素可诱导CYP1A1等药物代谢酶的表达，且多巴胺本身也具有AhR活性 131。最新的病例对照研究显示，包括卡比多巴在内的抗帕金森病药物与胰腺癌风险降低相关，提示其可能具有潜在的预防作用 132。
- 饮食干预：减少膳食色氨酸的摄入能够降低TAMs的AhR活性，并促进肿瘤内TNFαIFNγCD8 T细胞的积累，从而抑制肿瘤生长 127。这提示饮食干预可能通过调节肠道微生物代谢色氨酸来影响AhR通路，进而调节肿瘤微环境。
5.3.3 其他药物预防的争议与展望
- 二甲双胍 (Metformin) 与阿司匹林 (Aspirin)：
- 他汀类药物 (Statins)：
- GSTP1抑制剂：
- 潜在益处：KRAS突变在胰腺癌早期发生，但缺乏特异性抑制剂。谷胱甘肽-S转移酶p1（GSTP1）被发现是突变KRAS信号的自分泌刺激物，因此被认为是胰腺癌化学预防的替代靶点。O-Hexadecyl-γ-glutamyl-S-benzyl-cysteinyl-D-phenyl glycine-Ethylester (HGBPE) 是一种GSTP1抑制剂，在诱导的大鼠胰腺癌模型中，HGBPE显著降低了导管复合体和腺癌的发生率，表明其作为潜在化学预防剂的有效性 135。
- 展望：GSTP1抑制剂是靶向早期KRAS突变的新策略，具有重要的临床转化潜力，但仍处于临床前研究阶段。
综上所述，药物和营养干预在胰腺癌预防中具有广阔前景，但仍需在临床研究中克服挑战。未来的方向将集中于更深入地理解分子机制，开发靶向关键通路的精准药物，并结合多组学数据进行个性化的预防策略。对于备受关注的营养素如叶酸和维生素D，目前不建议盲目补充，而应以健康均衡的饮食为基础。
6. 多维度预防策略的协同与实施挑战
胰腺癌的发生是遗传、环境和生活方式等多种因素复杂交互作用的结果。因此，有效的预防策略需要多维度、协同性的干预。然而，将这些策略落地实施，并使其真正惠及高危人群和普通大众，仍面临诸多挑战。
6.1 遗传与环境因素的交互作用
胰腺癌的预防策略，特别是生活方式干预，并非一概而论，其效果可能受到个体遗传背景的影响，并表现出年龄依赖性。深入理解遗传与环境因素的交互作用，对于制定更精准、更有效的预防指南至关重要。
6.1.1 生活方式干预对高遗传易感性人群的强化保护效应
越来越多的证据表明，健康的生活方式能够对高遗传风险个体提供显著的保护作用，甚至在一定程度上抵消遗传因素带来的风险。
- UK Biobank 研究证据：一项基于UK Biobank大型前瞻性队列研究，纳入了340,631名参与者，旨在全面评估生活方式、遗传因素及其联合作用与胰腺癌风险的关系。研究通过构建多基因风险评分（PRS）来量化遗传风险，并构建健康生活方式评分（HLS）来评估生活方式的健康程度。结果发现：
这些结果强调了，无论个体的遗传易感性如何，采纳健康的生活方式都是预防胰腺癌的重要策略。对于那些已知携带高风险基因突变的个体，积极的生活方式干预甚至可能成为降低其绝对风险、改善预后的关键。
6.1.2 年龄依赖性对预防时机的指导意义
UK Biobank的研究还揭示了生活方式和遗传因素与胰腺癌关联的年龄依赖性，这对预防措施的启动时机提供了重要指导：
- 生活方式干预的早期效应更显著：研究发现，在≤60岁的参与者中，健康生活方式与胰腺癌风险降低的关联最为显著（HR = 0.35；95% CI，0.23-0.54）136。这表明在较年轻时采纳并坚持健康生活方式，能够获得更大的相对风险降低。
- 遗传风险在年轻时更突出：同样，高PRS与胰腺癌的关联在≤60岁的参与者中更为强烈（HR = 1.89；95% CI，1.30-2.73）136。这提示，遗传因素在胰腺癌的早期发病中可能扮演更重要的角色。
- 绝对风险降低在老年人中更明显：尽管生活方式的相对风险降低在年轻人中更显著，但在>70岁的参与者中，健康生活方式带来的绝对风险降低更为明显（ARR = 0.19%；95% CI，0.13%-0.26%）136。这反映了老年人群基础发病率更高，即使相对风险降低幅度较小，其对个体而言的绝对获益可能更大。
这些年龄依赖性的发现具有重要的实践意义：
- 强调早期干预：为了最大限度地发挥预防作用，应鼓励人们在年轻时就开始采纳并维持健康的生活方式。青少年和成年早期是培养健康习惯的关键时期，此时的干预可能对胰腺癌的长期风险产生深远影响。
- 个性化预防策略：基于年龄和遗传风险，可以制定更加个性化的预防方案。例如，对于年轻且具有高遗传风险的个体，应特别强调生活方式干预，并考虑更早启动筛查。而对于老年人，即使相对风险降低幅度不如年轻人，但鉴于其较高的基础发病率，健康生活方式的维持仍然能够带来显著的绝对健康益处。
- 基因-环境交互的分子基础：基因-环境交互作用不仅体现在流行病学层面，也深入到分子机制。例如，胰腺损伤（环境因素）与Kras致癌基因突变（遗传因素）的协同作用，可以在小鼠胰腺癌模型中显著加速早期瘤变病变的形成137。这种交互作用在48小时内就能产生独特的染色质状态，促使胰腺上皮细胞发生“腺泡向瘤变”的染色质转变，从而驱动癌前病变的发展137。早期激活的报警素细胞因子白介素33（IL-33）在组织损伤后迅速激活，与突变Kras协同作用，进一步促进早期瘤变的表观遗传重塑137。这为理解遗传和环境因素如何共同启动癌变过程提供了分子框架。
总而言之，胰腺癌的预防需要将遗传背景与生活方式因素相结合，并考虑年龄的维度。针对高遗传风险的个体，通过积极的生活方式干预可以获得强化保护。同时，鉴于生活方式干预在年轻时期能够实现更显著的相对风险降低，公共卫生和临床实践应着重于倡导和促进在生命早期就建立和维持健康的饮食、运动等生活习惯，从而在最大程度上降低胰腺癌的总体负担。
6.2 预防策略的落地障碍与优化路径
尽管胰腺癌的预防策略已日益完善，但其在实际应用中仍面临诸多落地障碍，尤其是在高危人群筛查覆盖率和患者依从性方面。这些障碍往往根植于复杂的社会文化因素，需要系统性的优化路径来解决。
6.2.1 筛查覆盖率低与患者依从性差的社会文化因素
筛查覆盖率低 (仅3%-5%高危人群参与)：
- 知晓度不足：公众对胰腺癌的高致死性、早期症状不明显以及高危人群需要筛查的认知普遍不足。许多高危个体可能根本不知道自己处于高风险中，也未被告知需要进行定期筛查。
- 医疗可及性限制：高质量的胰腺癌筛查，特别是EUS和MRI等影像学检查，需要专业的设备和经验丰富的医师团队。这使得筛查服务在地理上、经济上和时间上对许多患者而言难以负担或获取。特别是偏远地区或经济欠发达地区的居民，可能无法获得相应的筛查机会。
- 医疗系统支持不足：在许多国家和地区的医疗体系中，胰腺癌的高危人群筛查尚未被完全整合到常规医疗实践中，缺乏统一的筛查流程、转诊路径和报销政策。
- 医生认知差异：即使是医生，也可能对胰腺癌高危人群的界定标准、筛查指征和推荐方案存在认知差异，导致未能及时向患者推荐筛查。
患者依从性差 (如饮食运动干预脱落率高)：
- 生活方式改变的挑战：改变长期形成的生活习惯（如饮食结构、运动频率）对个体而言是极具挑战性的。这需要强大的自我约束力、家庭和社会支持，以及对健康益处的深刻理解和持续激励。
- 心理负担与焦虑：高危人群本身就承受着患癌的心理压力。筛查的假阳性结果、持续的监测要求以及生活方式干预带来的不适感，都可能加重其心理负担，导致依从性下降。例如，一项研究发现，尽管筛查对高危人群的生存具有益处，但依从性较差，年龄和筛查方式可能是影响依从性的因素 16138。
- 文化与经济障碍：某些文化背景下，饮食习惯根深蒂固，难以改变。同时，健康食品和运动设施的成本，对经济条件有限的个体也是一种负担。
- 缺乏个性化指导：标准化的饮食运动建议可能无法满足个体化的需求。缺乏专业的营养师、运动教练或健康管理师的持续指导和支持，使得患者难以坚持。
- 干预措施的复杂性与时效性：一些干预措施可能操作复杂，或需要长时间才能看到效果，这可能削弱患者的坚持动力。例如，一项关于胰腺癌患者支持性护理和营养指导的初步研究显示，尽管患者参与意愿高，但仍有24%的患者在研究结束前退出或死亡，部分原因可能与干预措施的强度和疾病进展有关 139。
6.2.2 优化路径：数字健康与社区教育的推广方案
为了克服上述障碍，需要创新性的策略，特别是利用数字健康技术和加强社区教育，以提高筛查覆盖率和患者依从性。
数字健康技术的应用：
- 可穿戴设备监测运动：智能手表、运动手环等可穿戴设备能够实时监测个体的运动量、心率、睡眠等生理数据。这些数据可以帮助高危人群了解自己的运动状况，设定个性化目标，并通过数据反馈形成积极的激励机制。与健康管理APP结合，可提供定制化的运动计划和健康指导，并通过社交互动增加坚持动力。
- 智能营养追踪与个性化饮食建议：利用AI驱动的应用程序，通过拍照识别食物、记录膳食摄入，为用户提供营养分析和个性化的饮食建议。例如，根据个体的遗传风险、代谢特征和饮食偏好，推荐符合胰腺癌预防原则的健康食谱，并监测超加工食品、高糖食品的摄入。
- 远程健康管理平台：建立综合性的远程健康管理平台，连接高危人群、医生、营养师和健康管理师。通过在线咨询、视频问诊、远程数据监测，实现对高危人群的持续性、个性化管理，及时解决其在生活方式干预和筛查过程中的疑问和困难。
- 智能筛查提醒与预约：通过手机APP、短信或电子邮件，定期提醒高危人群进行筛查，并提供便捷的在线预约服务，简化筛查流程，提高依从性。
- 基因检测与风险评估数字化：通过数字化平台整合基因检测结果和家族史信息，生成个体化的胰腺癌风险报告，并提供可操作的预防建议，帮助高危人群更直观地理解自身风险。
社区教育的推广方案：
- 健康饮食科普活动：在社区、学校、企业等场所定期举办健康饮食讲座、烹饪示范、营养咨询等活动，普及胰腺癌预防知识，推广健康饮食理念（如地中海饮食模式、膳食纤维的重要性）。强调超加工食品、高糖饮食的危害，并提供具体的替代方案。
- 健康生活方式宣传：利用多媒体平台（社交媒体、短视频、广播电视）制作和传播关于胰腺癌预防的科普内容，生动形象地展示健康生活方式（戒烟、限酒、适度运动）对降低癌症风险的重要性。
- 建立支持小组与同伴教育：在高危人群中建立胰腺癌预防支持小组，邀请成功改变生活方式或积极参与筛查的患者分享经验，提供情感支持和实用建议。通过同伴教育，利用榜样的力量促进生活方式的改变。
- 与基层医疗机构合作：加强基层医务人员对胰腺癌高危人群筛查指征和生活方式干预的培训，使其成为社区健康教育和推广的骨干力量。在常规体检中纳入胰腺癌风险评估问卷，并对高危个体进行初步的健康宣教和转诊。
- 政策倡导与环境支持：推动政府出台支持健康饮食和运动的政策，如实施糖税、改善食品标签、建设更多公共体育设施、推广无烟环境等，为公众采纳健康生活方式创造有利的外部环境。
通过数字健康技术的赋能和社区教育的普及，可以有效弥合胰腺癌预防策略与实际落地之间的鸿沟，提升高危人群的筛查覆盖率和患者依从性，从而真正发挥预防策略在降低胰腺癌负担中的关键作用。
6.3 未来研究方向与政策建议
胰腺癌的预防是一项长期而复杂的任务，需要持续的科学研究、政策支持和社会参与。未来的研究应聚焦于更深入地理解胰腺癌的发生机制，开发更精准的风险预测工具，并推动将研究成果转化为切实可行的公共卫生政策。
6.3.1 多组学整合在风险预测中的应用
为了克服传统单一生物标志物或风险因素在胰腺癌风险预测上的局限性，未来的研究应大力推动多组学整合（基因组、代谢组、微生物组）的应用。
- 基因组学与遗传风险评估：通过全基因组测序（WGS）、全外显子组测序（WES）和更全面的GWAS研究，识别新的与胰腺癌相关的常见和稀有遗传变异。结合多基因风险评分（PRS），将个体的遗传易感性更精确地量化。特别是对于携带高风险基因突变（如BRCA1/2、CDKN2A、PALB2等）的个体，结合其他组学数据进行更精细的风险分层。
- 代谢组学与早期生物标志物：代谢组学能够识别与疾病发生发展相关的内源性小分子代谢产物。通过分析血液、尿液、唾液或胰液中的代谢物谱，有望发现胰腺癌超早期诊断的生物标志物，甚至在影像学可见病变之前发出预警。例如，一些独特的代谢通路变化可能预示着胰腺癌前病变（如PanIN）的进展。
- 微生物组学与肠-胰轴：肠道菌群与胰腺健康之间存在“肠-胰轴”的复杂互动。微生物组学的研究将揭示特定肠道菌群组成或代谢产物与胰腺癌风险的关联。通过分析粪便、唾液或胰液中的微生物DNA/RNA，可以识别与胰腺癌风险增加或保护作用相关的微生物特征。未来研究可进一步探索如何通过饮食、益生菌/益生元等干预手段调节微生物组，从而降低胰腺癌风险。
- 多组学数据融合与AI：将基因组、代谢组和微生物组等多源异构数据进行深度融合，并结合人工智能（AI）和机器学习算法，构建高精度的胰腺癌风险预测模型。这些模型将能够整合遗传背景、环境暴露、生活方式和生理生化指标，实现对个体胰腺癌风险的精准评估和动态监测。例如，文献中提出的综合了生物标志物发现、基因筛选和人工智能驱动成像的多学科方法，有望通过改进风险分层来革新NOD-PC风险评估和增强早期检测 140。未来，AI技术在处理复杂多组学数据和识别隐蔽模式方面的优势，将进一步提升风险分层的效率和准确性。
6.3.2 呼吁建立全球胰腺癌预防协作网络
胰腺癌的预防工作面临地域差异大、数据分散等挑战。建立一个全球性的胰腺癌预防协作网络至关重要。
- 数据共享与标准化：协作网络应致力于推动全球范围内胰腺癌流行病学数据、临床数据和组学数据的共享与标准化。通过建立统一的数据平台和生物样本库，实现大样本、多中心、多民族人群的研究，从而提高研究结果的普适性和可靠性。
- 指南制定与推广：协作网络可以汇聚全球顶尖专家，共同制定基于最新证据的胰腺癌预防指南。这些指南不仅应涵盖生活方式干预和高危人群筛查，还应包括遗传咨询、心理支持等全方位内容，并根据不同国家和地区的实际情况进行本土化调整和推广。
- 新兴技术评估与转化：协作网络应设立专门机构，负责评估和推广胰腺癌预防领域的新兴技术和策略，例如新型生物标志物、AI辅助诊断工具以及药物和代谢干预的新进展。加速将实验室研究成果转化为临床实践和公共卫生政策。
6.3.3 推动指南更新与公共卫生政策
基于最新的研究证据，现有的胰腺癌预防指南和公共卫生政策需要进行持续的更新和调整，以更好地应对胰腺癌带来的挑战。
- 将超加工食品摄入纳入风险评估：鉴于越来越多的证据表明超加工食品（UPF）与胰腺癌风险之间存在显著关联（例如，UPF摄入量每增加10%，胰腺癌风险增加1.49倍）40，应强烈建议将超加工食品的摄入量纳入胰腺癌风险评估体系，并在预防指南中明确限制其摄入的建议。
- 公共卫生政策的改革：
- 糖税和脂肪税：借鉴烟草税的成功经验，考虑征收糖税和脂肪税，以提高不健康食品的价格，从而减少消费，鼓励生产商开发更健康的替代品。
- 食品标签改革：推行更清晰、更易理解的食品营养标签，特别是对超加工食品的识别和警示，帮助消费者做出更健康的食物选择。例如，在食品包装上明确标注高糖、高盐、高脂肪或超加工食品的警示标识。
- 健康饮食环境建设：政府应通过政策支持，增加健康食品的可及性和可负担性，例如，在社区推广农贸市场、支持健康餐饮业的发展、限制快餐店在学校和居民区的数量等。
- 加强健康教育与宣传：通过媒体、学校和社区等多种渠道，加强对公众关于胰腺癌风险因素、预防知识和健康生活方式的教育和宣传，提升公众的健康素养和自我管理能力。
- 支持肥胖和糖尿病管理：将肥胖和2型糖尿病的有效管理作为国家优先公共卫生议题，加大对相关疾病预防和治疗的投入，因为这两种疾病是胰腺癌的重要可干预风险因素。
通过多组学整合、全球协作以及政策干预，我们有望构建一个更全面、更精准、更有效的胰腺癌预防体系，从而显著降低胰腺癌的发病率和死亡率，改善全球公共健康。
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参考文献
1Pancreatic cancer: A review of epidemiology, trend, and risk factors.PubMed
Jian-Xiong Hu, Cheng-Fei Zhao, Wen-Biao Chen, et al.
World J Gastroenterol. 2021 Jul 21;27(27):4298-4321. doi: 10.3748/wjg.v27.i27.4298.
Despite rapid advances in modern medical technology and significant improvements in survival rates of many cancers, pancreatic cancer is still a highly lethal gastrointestinal cancer with a low 5-year survival rate and difficulty in early detection. At present, the incidence and mortality of pancreatic cancer are increasing year by year worldwide, no matter in the United States, Europe, Japan, or China. Globally, the incidence of pancreatic cancer is projected to increase to 18.6 per 100000 in 2050, with the average annual growth of 1.1%, meaning that pancreatic cancer will pose a significant public health burden. Due to the special anatomical location of the pancreas, the development of pancreatic cancer is usually diagnosed at a late stage with obvious clinical symptoms. Therefore, a comprehensive understanding of the risk factors for pancreatic cancer is of great clinical significance for effective prevention of pancreatic cancer. In this paper, the epidemiological characteristics, developmental trends, and risk factors of pancreatic cancer are reviewed and analyzed in detail.
2Trends in the Global Incidence of Pancreatic Cancer and a Brief Review of its Histologic and Molecular Subtypes.PubMed
Premila Devi Leiphrakpam, Sanjib Chowdhury, Michelle Zhang, et al.
J Gastrointest Cancer. 2025 Feb 24;56(1):71. doi: 10.1007/s12029-025-01183-2.
The global burden of pancreatic cancer has more than doubled in recent decades. It is now the sixth leading cause of cancer-related death worldwide, with an estimated 510,922 new cases and 467,409 deaths in 2022. The incidence of the disease continues to rise annually, with projections indicating a 95.4% increase in new cases by 2050, potentially reaching a total of 998,663 new cases globally. The overall five-year survival rate for pancreatic cancer is 10% worldwide, showing only a modest improvement compared to the past decade. The rising trends in the incidence rates are likely to continue as the global population ages and access to healthcare improves. The relatively low survival rate is primarily attributed to late-stage diagnoses and the lack of an effective screening method. Currently, population-based screening for asymptomatic individuals is not recommended, highlighting the importance of identifying and monitoring individuals at high risk for pancreatic cancer. Numerous studies have highlighted the differences in the molecular pathology of pancreatic cancer, underscoring the need for continued research to better understand these differences. The silent progression of the disease, poor prognosis, lack of screening options, and the necessity to improve our comprehension of its molecular characteristics emphasize the critical need for ongoing monitoring of disease trends at the population level. This review article analyses trends in the incidence of pancreatic cancer and its histological subtypes and provides an update on its molecular subtypes.
3Epidemiology of pancreatic cancer.PubMed
Milena Ilic, Irena Ilic
World J Gastroenterol. 2016 Nov 28;22(44):9694-9705. doi: 10.3748/wjg.v22.i44.9694.
Cancer of the pancreas remains one of the deadliest cancer types. Based on the GLOBOCAN 2012 estimates, pancreatic cancer causes more than 331000 deaths per year, ranking as the seventh leading cause of cancer death in both sexes together. Globally, about 338000 people had pancreatic cancer in 2012, making it the 11 most common cancer. The highest incidence and mortality rates of pancreatic cancer are found in developed countries. Trends for pancreatic cancer incidence and mortality varied considerably in the world. A known cause of pancreatic cancer is tobacco smoking. This risk factor is likely to explain some of the international variations and gender differences. The overall five-year survival rate is about 6% (ranges from 2% to 9%), but this vary very small between developed and developing countries. To date, the causes of pancreatic cancer are still insufficiently known, although certain risk factors have been identified, such as smoking, obesity, genetics, diabetes, diet, inactivity. There are no current screening recommendations for pancreatic cancer, so primary prevention is of utmost importance. A better understanding of the etiology and identifying the risk factors is essential for the primary prevention of this disease.
4Epidemiology of Pancreatic Cancer: Global Trends, Etiology and Risk Factors.PubMed
Prashanth Rawla, Tagore Sunkara, Vinaya Gaduputi
World J Oncol. 2019 Feb;10(1):10-27. doi: 10.14740/wjon1166. Epub 2019 Feb 26.
Pancreatic cancer is the seventh leading cause of cancer-related deaths worldwide. However, its toll is higher in more developed countries. Reasons for vast differences in mortality rates of pancreatic cancer are not completely clear yet, but it may be due to lack of appropriate diagnosis, treatment and cataloging of cancer cases. Because patients seldom exhibit symptoms until an advanced stage of the disease, pancreatic cancer remains one of the most lethal malignant neoplasms that caused 432,242 new deaths in 2018 (GLOBOCAN 2018 estimates). Globally, 458,918 new cases of pancreatic cancer have been reported in 2018, and 355,317 new cases are estimated to occur until 2040. Despite advancements in the detection and management of pancreatic cancer, the 5-year survival rate still stands at 9% only. To date, the causes of pancreatic carcinoma are still insufficiently known, although certain risk factors have been identified, such as tobacco smoking, diabetes mellitus, obesity, dietary factors, alcohol abuse, age, ethnicity, family history and genetic factors, , non-O blood group and chronic pancreatitis. In general population, screening of large groups is not considered useful to detect the disease at its early stage, although newer techniques and the screening of tightly targeted groups (especially of those with family history), are being evaluated. Primary prevention is considered of utmost importance. Up-to-date statistics on pancreatic cancer occurrence and outcome along with a better understanding of the etiology and identifying the causative risk factors are essential for the primary prevention of this disease.
5Worldwide Burden of, Risk Factors for, and Trends in Pancreatic Cancer.PubMed
Junjie Huang, Veeleah Lok, Chun Ho Ngai, et al.
Gastroenterology. 2021 Feb;160(3):744-754. doi: 10.1053/j.gastro.2020.10.007. Epub 2020 Oct 13.
BACKGROUND & AIMS: We evaluated global and regional burdens of, risk factors for, and epidemiologic trends in pancreatic cancer among groups of different sexes and ages. METHODS: We used data from the GLOBOCAN database to estimate pancreatic cancer incidence and mortality in 184 countries. We examined the association between lifestyle and metabolic risk factors, extracted from the World Health Organization Global Health Observatory database, and pancreatic cancer incidence and mortality by univariable and multivariable linear regression. We retrieved country-specific age-standardized rates (ASRs) of incidence and mortalities from cancer registries from 48 countries through 2017 for trend analysis by joinpoint regression analysis. RESULTS: The highest incidence and mortality of pancreatic cancer were in regions with very high (ASRs, 7.7 and 4.9) and high human development indexes (ASRs, 6.9 and 4.6) in 2018. Countries with higher incidence and mortality were more likely to have higher prevalence of smoking, alcohol drinking, physical inactivity, obesity, hypertension, and high cholesterol. From 2008 to 2017, 2007 to 2016, or 2003 to 2012, depending on the availability of the data, there were increases in incidence among men and women in 14 (average annual percent changes [AAPCs], 8.85 to 0.41) and 17 (AAPCs, 6.04 to 0.87) countries, respectively. For mortality, the increase was observed in 8 (AAPCs, 4.20 to 0.55) countries among men and 14 (AAPCs, 5.83 to 0.78) countries among women. Although the incidence increased in 18 countries (AAPCs, 7.83 to 0.91) among individuals 50 years or older, an increasing trend in pancreatic cancer was also identified among individuals younger than 50 years and 40 years in 8 (AAPCs, 8.75 to 2.82) and 4 (AAPCs, 11.07 to 8.31) countries, respectively. CONCLUSIONS: In an analysis of data from 48 countries, we found increasing incidence and mortality trends in pancreatic cancer, especially among women and populations 50 years or older, but also among younger individuals. More preventive efforts are recommended for these populations.
6The global, regional, and national burden of pancreatic cancer and its attributable risk factors in 195 countries and territories, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017.PubMed
Lancet Gastroenterol Hepatol. 2019 Dec;4(12):934-947. doi: 10.1016/S2468-1253(19)30347-4. Epub 2019 Oct 21.
BACKGROUND: Worldwide, both the incidence and death rates of pancreatic cancer are increasing. Evaluation of pancreatic cancer burden and its global, regional, and national patterns is crucial to policy making and better resource allocation for controlling pancreatic cancer risk factors, developing early detection methods, and providing faster and more effective treatments. METHODS: Vital registration, vital registration sample, and cancer registry data were used to generate mortality, incidence, and disability-adjusted life-years (DALYs) estimates. We used the comparative risk assessment framework to estimate the proportion of deaths attributable to risk factors for pancreatic cancer: smoking, high fasting plasma glucose, and high body-mass index. All of the estimates were reported as counts and age-standardised rates per 100 000 person-years. 95% uncertainty intervals (UIs) were reported for all estimates. FINDINGS: In 2017, there were 448 000 (95% UI 439 000-456 000) incident cases of pancreatic cancer globally, of which 232 000 (210 000-221 000; 51·9%) were in males. The age-standardised incidence rate was 5·0 (4·9-5·1) per 100 000 person-years in 1990 and increased to 5·7 (5·6-5·8) per 100 000 person-years in 2017. There was a 2·3 times increase in number of deaths for both sexes from 196 000 (193 000-200 000) in 1990 to 441 000 (433 000-449 000) in 2017. There was a 2·1 times increase in DALYs due to pancreatic cancer, increasing from 4·4 million (4·3-4·5) in 1990 to 9·1 million (8·9-9·3) in 2017. The age-standardised death rate of pancreatic cancer was highest in the high-income super-region across all years from 1990 to 2017. In 2017, the highest age-standardised death rates were observed in Greenland (17·4 [15·8-19·0] per 100 000 person-years) and Uruguay (12·1 [10·9-13·5] per 100 000 person-years). These countries also had the highest age-standardised death rates in 1990. Bangladesh (1·9 [1·5-2·3] per 100 000 person-years) had the lowest rate in 2017, and São Tomé and Príncipe (1·3 [1·1-1·5] per 100 000 person-years) had the lowest rate in 1990. The numbers of incident cases and deaths peaked at the ages of 65-69 years for males and at 75-79 years for females. Age-standardised pancreatic cancer deaths worldwide were primarily attributable to smoking (21·1% [18·8-23·7]), high fasting plasma glucose (8·9% [2·1-19·4]), and high body-mass index (6·2% [2·5-11·4]) in 2017. INTERPRETATION: Globally, the number of deaths, incident cases, and DALYs caused by pancreatic cancer has more than doubled from 1990 to 2017. The increase in incidence of pancreatic cancer is likely to continue as the population ages. Prevention strategies should focus on modifiable risk factors. Development of screening programmes for early detection and more effective treatment strategies for pancreatic cancer are needed. FUNDING: Bill & Melinda Gates Foundation.
7Pancreatic cancer mortality trends attributable to high fasting blood sugar over the period 1990-2019 and projections up to 2040.PubMed
Yongguang Wei, Zedong Qin, Xiwen Liao, et al.
Front Endocrinol (Lausanne). 2024 Jul 5;15:1302436. doi: 10.3389/fendo.2024.1302436. eCollection 2024.
BACKGROUND: Pancreatic cancer (PC) is a prevalent malignancy within the digestive system, with diabetes recognized as one of its well-established risk factors. METHODS: Data on PC mortality attributed to high fasting blood sugar were retrieved from the Global Burden of Disease (GBD) study 2019 online database. To assess the temporal trends of PC burden attributable to high fasting plasma glucose (HFPG), estimated annual percentage changes (EAPCs) for age-standardized death rates (ASDRs) between 1990 and 2019 were determined using a generalized linear model. Furthermore, a Bayesian age-period-cohort (BAPC) model using the integrated nested Laplacian approximation algorithm was employed to project the disease burden over the next 20 years. RESULTS: Globally, the crude death number of PC attributable to HFPG almost tripled (from 13,065.7 in 1990 to 48,358.5 in 2019) from 1990 to 2019, and the ASDR increased from 0.36/100,000 to 0.61/100,000 with an EAPC of 2.04 (95% CI 1.91-2.16). The population aged ≥70 years accounted for nearly 60% of total deaths in 2019 and experienced a more significant increase, with the death number increasing approximately fourfold and the ASDR increasing annually by 2.65%. In regions with different sociodemographic indexes (SDIs), the highest disease burden was observed in the high-SDI region, whereas more pronounced increasing trends in ASDR were observed in the low to middle-SDI, low-SDI, and middle-SDI regions. Additionally, a significantly negative association was found between EAPCs and ASDRs of PC attributable to HFPG from 1990 to 2019. Moreover, the BAPC model predicts that ASDR and age-standardized disability-adjusted life-years (DALYs) rate for PC attributed to HFPG was projected to increase obviously for men and women from 2019 to 2040. CONCLUSIONS: The burden of PC attributed to HFPG has increased globally over the past three decades, with the elderly population and high-SDI regions carrying a relatively greater disease burden, but more adverse trends observed in low-SDI areas. Furthermore, the burden is projected to continue increasing over the next 20 years. Hence, more tailored prevention methodologies should be established to mitigate this increasing trend.
8Global, regional, and national burdens of early onset pancreatic cancer in adolescents and adults aged 15-49 years from 1990 to 2019 based on the Global Burden of Disease Study 2019: a cross-sectional study.PubMed
Zheng Li, Xiaojie Zhang, Chongyuan Sun, et al.
Int J Surg. 2024 Apr 1;110(4):1929-1940. doi: 10.1097/JS9.0000000000001054.
BACKGROUND: Early-onset pancreatic cancer (EOPC) in younger populations (age ≤50 years) is likely to be a more aggressive phenotype characterized by poor differentiation. The emerging analysis of the global burden of EOPC is limited and outdated. AIM: To systematically investigate the burden and trend of EOPC based on global populations. METHODS: In this systematic analysis based on the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019, the authors present the number of cases, age-standardized rates (ASRs) per 100 000 population, and risk factors for 204 countries and territories. The average annual percentage changes (AAPCs) for the incidence, mortality, and disability-adjusted life-years (DALYs) of EOPC were calculated using joinpoint regression analysis. RESULTS: According to the GBD 2019 estimates, there were 36 852 new cases of EOPC and 32 004 related deaths. East Asia had the highest number of cases, with 11 401 incidences and 10 149 deaths. The ASRs were 0.94 per 100 000 individuals for incidence and 0.81 per 100 000 for mortality. From 1990 to 2019, the age-standardized incidence increased by 46.9%, mortality increased by 44.6%, and DALYs increased by 41.9% globally. In trend analysis, the global incidence (AAPC, 1.26), mortality (AAPC, 1.24), and DALYs (AAPC, 1.25) of EOPC showed an increasing pattern. The ASRs of incidence, mortality, and DALYs of EOPC in Africa, America, and Asia exhibited a continuous upward trend, while the trend in Europe was fluctuating. Asian males exhibited the fastest growth in incidence (AAPC, 2.15) and mortality (AAPC, 2.13), whereas males in the Americas experienced the slowest increase in new cases (AAPC, 0.72) and deaths (AAPC, 0.67). A certain proportion of EOPC DALYs were attributable to known risk factors: tobacco smoking (13.3%), high BMI, 5.6%, and high fasting plasma glucose 3.2%. Integrating the socio-demographic index (SDI), ASRs of incidence and mortality initially increased with rising SDI, reaching a peak in central Europe (1.5 per 100 000 <ASRs <2.0 per 100 000), and decreased with further increase in SDI in 2019. CONCLUSIONS: The findings offer valuable insights into the global distribution and magnitude of the EOPC burden. The burden is increasing at a rapid pace worldwide, particularly in Asia, and is notably high in central and eastern Europe. This highlights the need for additional preventive control efforts targeting high-risk populations.
9Early Detection of Pancreatic Cancer: Opportunities and Challenges.PubMed
Aatur D Singhi, Eugene J Koay, Suresh T Chari, et al.
Gastroenterology. 2019 May;156(7):2024-2040. doi: 10.1053/j.gastro.2019.01.259. Epub 2019 Feb 2.
Most patients with pancreatic ductal adenocarcinoma (PDAC) present with symptomatic, surgically unresectable disease. Although the goal of early detection of PDAC is laudable and likely to result in significant improvement in overall survival, the relatively low prevalence of PDAC renders general population screening infeasible. The challenges of early detection include identification of at-risk individuals in the general population who would benefit from longitudinal surveillance programs and appropriate biomarker and imaging-based modalities used for PDAC surveillance in such cohorts. In recent years, various subgroups at higher-than-average risk for PDAC have been identified, including those with familial risk due to germline mutations, a history of pancreatitis, patients with mucinous pancreatic cysts, and elderly patients with new-onset diabetes. The last 2 categories are discussed at length in terms of the opportunities and challenges they present for PDAC early detection. We also discuss current and emerging imaging modalities that are critical to identifying early, potentially curable PDAC in high-risk cohorts on surveillance.
10Pancreatic cancer.PubMed
Jonathan D Mizrahi, Rishi Surana, Juan W Valle, et al.
Lancet. 2020 Jun 27;395(10242):2008-2020. doi: 10.1016/S0140-6736(20)30974-0.
Pancreatic cancer is a highly fatal disease with a 5-year survival rate of approximately 10% in the USA, and it is becoming an increasingly common cause of cancer mortality. Risk factors for developing pancreatic cancer include family history, obesity, type 2 diabetes, and tobacco use. Patients typically present with advanced disease due to lack of or vague symptoms when the cancer is still localised. High quality computed tomography with intravenous contrast using a dual phase pancreatic protocol is typically the best method to detect a pancreatic tumour and to determine surgical resectability. Endoscopic ultrasound is an increasingly used complementary staging modality which also allows for diagnostic confirmation when combined with fine needle aspiration. Patients with pancreatic cancer are often divided into one of four categories based on extent of disease: resectable, borderline resectable, locally advanced, and metastatic; patient condition is also an important consideration. Surgical resection represents the only chance for cure, and advancements in adjuvant chemotherapy have improved long-term outcomes in these patients. Systemic chemotherapy combinations including FOLFIRINOX (5-fluorouracil, folinic acid [leucovorin], irinotecan, and oxaliplatin) and gemcitabine plus nab-paclitaxel remain the mainstay of treatment for patients with advanced disease. Data on the benefit of PARP inhibition as maintenance therapy in patients with germline BRCA1 or BRACA2 mutations might prove to be a harbinger of advancement in targeted therapy. Additional research efforts are focusing on modulating the pancreatic tumour microenvironment to enhance the efficacy of the immunotherapeutic strategies.
11Pancreatic Neoplasms and Autophagy.PubMed
Linzi A Barton, Jun Ren
Curr Drug Targets. 2018;19(9):1018-1023. doi: 10.2174/1389450117666160622220915.
Pancreatic cancer is predicted to be the second deadliest malignancy (a median survival of 4-6 months and a 5-year survival of less than 5%) in the USA by 2020. Although current medical detection technologies have dramatically improved the survival rate for patients with other gastrointestinal malignancies, the dismal clinical outcome remains somewhat unchanged for patients with pancreatic cancer. Preclinical evidence suggests that pancreatic cancer may be benefited from early administration of systemic therapy in addition to surgery. New biomarkers should help to identify those patients possibly candidates for various systemic therapy including chemotherapy. Classical anticancer drugs such as FOLFIRINOX (folinic acid, 5-fluorouracil, irinotecan, and oxaliplatin), and nabpaclitaxel plus gemcitabine only produced some modest improvements in survival. To this end, novel therapeutic avenues are sought for pancreatic cancer. This mini-review summarizes the state-of-the-art of pancreatic cancer treatment, and possible role of autophagy in therapeutics against pancreatic cancer.
12Chemoprevention and Treatment of Pancreatic Cancer: Update and Review of the Literature.PubMed
Julia Benzel, Volker Fendrich
Digestion. 2018;97(4):275-287. doi: 10.1159/000485741. Epub 2018 Mar 27.
BACKGROUND: Pancreatic ductal adenocarcinoma is one of the most lethal types of cancer with a 5-year survival rate of around 7%. Due to the relatively poor prognosis, the potential need of an effective chemoprevention is highly needed. SUMMARY: Different risk factors like smoking or hereditary tumour syndromes should be known for early detection of pancreatic intraepithelial neoplasia. Chemopreventive dietary agents include curcumin, capsaicin and flavonoid, whereas potential chemopreventive drugs compromise aspirin, metformin or statins. This review aims to give an overview on potential risk factors for the development of pancreatic cancer. Furthermore, we try to summarise known chemopreventive agents to support the fight against this lethal disease. Key Messages: On the one hand, there are natural agents that exhibit preventive properties and can lead to the prohibition of pancreatic cancer. On the other hand, there are drugs and agents that are currently used in other contexts and are thus already approved and studied in terms of their mechanisms of effects and the related secondary effects.
13Early screening and diagnosis strategies of pancreatic cancer: a comprehensive review.PubMed
Jinshou Yang, Ruiyuan Xu, Chengcheng Wang, et al.
Cancer Commun (Lond). 2021 Dec;41(12):1257-1274. doi: 10.1002/cac2.12204. Epub 2021 Jul 31.
Pancreatic cancer is a highly malignant digestive system tumor with a poor prognosis. Most pancreatic cancer patients are diagnosed at an advanced stage or even metastasis due to its highly aggressive characteristics and lack of typical early symptoms. Thus, an early diagnosis of pancreatic cancer is crucial for improving its prognosis. Currently, screening is often applied in high-risk individuals to achieve the early diagnosis of pancreatic cancer. Fully understanding the risk factors of pancreatic cancer and pathogenesis could help us identify the high-risk population and achieve early diagnosis and timely treatment of pancreatic cancer. Notably, accumulating studies have been undertaken to improve the detection rate of different imaging methods and the diagnostic accuracy of endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) which is the golden standard for pancreatic cancer diagnosis. In addition, there are currently no biomarkers with sufficient sensitivity and specificity for the diagnosis of pancreatic cancer to be applied in the clinic. As the only serum biomarker approved by the United States Food and Drug Administration, carbohydrate antigen 19-9 (CA19-9) is not recommended to be used in the early screening of pancreatic cancer because of its limited specificity. Recently, increasing numbers of studies focused on the discovering of novel serum biomarkers and exploring their combination with CA19-9 in the detection of pancreatic cancer. Besides, the application of liquid biopsy involving circulating tumor cells (CTCs), circulating tumor DNA (ctDNA), microRNAs (miRNAs), and exosomes in blood and biomarkers in urine, and saliva in pancreatic cancer diagnosis are drawing more and more attention. Furthermore, many innovative technologies such as artificial intelligence, computer-aided diagnosis system, metabolomics technology, ion mobility spectrometry (IMS) associated technologies, and novel nanomaterials have been tested for the early diagnosis of pancreatic cancer and have shown promising prospects. Hence, this review aims to summarize the recent progress in the development of early screening and diagnostic methods, including imaging, pathological examination, serological examination, liquid biopsy, as well as other potential diagnostic strategies for pancreatic cancer.
14Challenges in diagnosis of pancreatic cancer.PubMed
Lulu Zhang, Santosh Sanagapalli, Alina Stoita
World J Gastroenterol. 2018 May 21;24(19):2047-2060. doi: 10.3748/wjg.v24.i19.2047.
Pancreatic cancer is a growing source of cancer related death, yet has poor survival rates which have not improved in the last few decades. Its high mortality rate is attributed to pancreatic cancer biology, difficulty in early diagnosis and the lack of standardised international guidelines in assessing suspicious pancreatic masses. This review aims to provide an update in the current state of play in pancreatic cancer diagnosis and to evaluate the benefits and limitations of available diagnostic technology. The main modalities discussed are imaging with computed tomography, magnetic resonance imaging, endoscopic ultrasound and positron emission tomography and tissue acquisition with fine needle aspiration. We also review the improvements in the techniques used for tissue acquisition and the opportunity for personalised cancer medicine. Screening of high risk individuals, promising biomarkers and common mimickers of pancreatic cancer are also explored, as well as suggestions for future research directions to allow for earlier detection of pancreatic cancer. Timely and accurate diagnosis of pancreatic cancer can lead to improvements in the current poor outcome of this disease.
155-Year survival rate over 20 % in pancreatic ductal adenocarcinoma: A retrospective study from a Chinese high-volume center.PubMed
Xiang Li, Yiwen Chen, Guoliang Qiao, et al.
Cancer Lett. 2025 Jun 1;619:217658. doi: 10.1016/j.canlet.2025.217658. Epub 2025 Mar 19.
Standardized clinical management of pancreatic adenocarcinoma (PDAC) remains challenging and high-volume centers provide essential insights for establishing effective multimodal treatment approaches. This retrospective observational study evaluated the impact of standardized, multimodal clinical management on survival outcomes in patients with PDAC across all stages, based on NCCN guidelines resectability criteria, at a high-volume center. From 2019, 4143 patients were diagnosed with PDAC, with 3268 patients receiving further treatment, including surgical resection and/or systemic therapy. The median overall survival (OS) was 18.5 (95 %CI 17.5-19.4) months for the treated cohort and the 5-year survival rate reached 23.3 %. Patients who underwent surgical resection had significantly improved median OS compared to those who received non-surgical treatments (28.4 months vs. 13.0 months, P < 0.001), with corresponding 5-year survival rates of 31.6 % vs. 15.0 %. Moreover, the patients who received NAT followed by surgical resection had improved survival outcomes compared to those who underwent upfront surgical resection in both resectable (median OS: 37.5 months vs. 28.9 months, P < 0.01) and borderline resectable group (median OS: 31.8 months vs. 18.4 months, P < 0.001). This study demonstrated a 5-year survival rate exceeding 20 % for PDAC across all stages at our center. The application of evidence-based treatment strategies through the multidisciplinary team, accompanying with standardized and comprehensive therapeutic managements, high patient adherence, have been considered as critical determinants in enhancing therapeutic efficacy and improving long-term prognosis for patients with PDAC.
16Pancreatic Cancer Surveillance and Survival of High-Risk Individuals.PubMed
Amanda L Blackford, Marcia Irene Canto, Mohamad Dbouk, et al.
JAMA Oncol. 2024 Aug 1;10(8):1087-1096. doi: 10.1001/jamaoncol.2024.1930.
IMPORTANCE: Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease with increasing incidence. The majority of PDACs are incurable at presentation, but population-based screening is not recommended. Surveillance of high-risk individuals for PDAC may lead to early detection, but the survival benefit is unproven. OBJECTIVE: To compare the survival of patients with surveillance-detected PDAC with US national data. DESIGN, SETTING, AND PARTICIPANTS: This comparative cohort study was conducted in multiple US academic medical centers participating in the Cancer of the Pancreas Screening program, which screens high-risk individuals with a familial or genetic predisposition for PDAC. The comparison cohort comprised patients with PDAC matched for age, sex, and year of diagnosis from the Surveillance, Epidemiology, and End Results (SEER) program. The Cancer of the Pancreas Screening program originated in 1998, and data collection was done through 2021. The data analysis was performed from April 29, 2022, through April 10, 2023. EXPOSURES: Endoscopic ultrasonography or magnetic resonance imaging performed annually and standard-of-care surgical and/or oncologic treatment. MAIN OUTCOMES AND MEASURES: Stage of PDAC at diagnosis, overall survival (OS), and PDAC mortality were compared using descriptive statistics and conditional logistic regression, Cox proportional hazards regression, and competing risk regression models. Sensitivity analyses and adjustment for lead-time bias were also conducted. RESULTS: A total of 26 high-risk individuals (mean [SD] age at diagnosis, 65.8 [9.5] years; 15 female [57.7%]) with PDAC were compared with 1504 SEER control patients with PDAC (mean [SD] age at diagnosis, 66.8 [7.9] years; 771 female [51.3%]). The median primary tumor diameter of the 26 high-risk individuals was smaller than in the control patients (2.5 [range, 0.6-5.0] vs 3.6 [range, 0.2-8.0] cm, respectively; P < .001). The high-risk individuals were more likely to be diagnosed with a lower stage (stage I, 10 [38.5%]; stage II, 8 [30.8%]) than matched control patients (stage I, 155 [10.3%]; stage II, 377 [25.1%]; P < .001). The PDAC mortality rate at 5 years was lower for high-risk individuals than control patients (43% vs 86%; hazard ratio, 3.58; 95% CI, 2.01-6.39; P < .001), and high-risk individuals lived longer than matched control patients (median OS, 61.7 [range, 1.9-147.3] vs 8.0 [range, 1.0-131.0] months; 5-year OS rate, 50% [95% CI, 32%-80%] vs 9% [95% CI, 7%-11%]). CONCLUSIONS AND RELEVANCE: These findings suggest that surveillance of high-risk individuals may lead to detection of smaller, lower-stage PDACs and improved survival.
17Genomics in Primary and Secondary Prevention of Pancreatic Cancer.PubMed
Núria Malats, Esther Molina-Montes, Carlo La Vecchia
Public Health Genomics. 2017;20(2):92-99. doi: 10.1159/000477234. Epub 2017 Jul 8.
BACKGROUND: Pancreatic cancer (PC) is one of the deadliest cancers worldwide for which little clinical progress has been made in the last decades. Furthermore, increased trends of PC mortality rates have been reported in Westernised countries. PC is usually diagnosed in advanced stages, precluding patients of an effective treatment. Identifying high-risk populations and early detection markers is the first and crucial step to impact on these figures and change the PC horizon. AIMS/OBJECTIVES: To discuss the published body of evidence on host and tumor genomics promising markers for primary and/or secondary personalised PC prevention, as well as the future perspectives in the field. METHODS: A review of the literature was performed to identify germline and tumor DNA and RNA markers that showed potential usefulness in defining the high-risk population, diagnosing the disease early, and identifying new carcinogens associated with PC. RESULTS: Only high-penetrance inherited mutations are used, at present, to define the high-risk PC population. Although there are some promising genomics markers to be used as early detection tests, none has been validated adequately to be integrated into the clinics routine. CONCLUSIONS: Despite of important efforts made in the recent time, little progress has been made to better characterise high-risk PC populations and to identify genomics-based markers for its early diagnosis. PC rates continue to rise, and this disease is becoming a real public health problem in the Westernised world. International and multidisciplinary strategies to identify new markers and properly validate the promising ones are urgently needed to implement cost-efficient primary and secondary prevention interventions in PC.
18Early detection of pancreatic cancer.PubMed
Stephen P Pereira, Lucy Oldfield, Alexander Ney, et al.
Lancet Gastroenterol Hepatol. 2020 Jul;5(7):698-710. doi: 10.1016/S2468-1253(19)30416-9. Epub 2020 Mar 2.
Pancreatic ductal adenocarcinoma is most frequently detected at an advanced stage. Such late detection restricts treatment options and contributes to a dismal 5-year survival rate of 3-15%. Pancreatic ductal adenocarcinoma is relatively uncommon and screening of the asymptomatic adult population is not feasible or recommended with current modalities. However, screening of individuals in high-risk groups is recommended. Here, we review groups at high risk for pancreatic ductal adenocarcinoma, including individuals with inherited predisposition and patients with pancreatic cystic lesions. We discuss studies aimed at finding ways of identifying pancreatic ductal adenocarcinoma in high-risk groups, such as among individuals with new-onset diabetes mellitus and people attending primary and secondary care practices with symptoms that suggest this cancer. We review early detection biomarkers, explore the potential of using social media for detection, appraise prediction models developed using electronic health records and research data, and examine the application of artificial intelligence to medical imaging for the purposes of early detection.
19Familial pancreatic cancer.PubMed
Lorenzo Del Nero, Emanuele Dabizzi, Antonella De Ceglie, et al.
Clin Res Hepatol Gastroenterol. 2023 Mar;47(3):102079. doi: 10.1016/j.clinre.2023.102079. Epub 2023 Jan 18.
Pancreatic cancer (PC) carries a poor prognosis with an overall 5-year survival of less than 10%. Early diagnosis, though cumbersome, is essential to allow complete surgical resection. Therefore, primary and secondary prevention are critical to reduce the incidence and to potentially prevent mortality. Given a relatively low lifetime risk of developing PC, identification of high-risk individuals is crucial to allow identification of pre-malignant lesions and small, localized tumors. Although 85-90% of PC cases are sporadic, we could consider risk stratification for the 5-10% of patients with a family history and the 3-5% of cases due to inherited genetic syndromes. These high-risk populations should be considered for screening and surveillance of PC. MRI/MRCP and EUS are the preferred modalities, due to their high sensitivity in lesion detection. Surveillance should be personalized, considering genetics and family history, and assessment of risk factors that may increase cancer risk. Screening programs should be limited to tertiary referral center, with high-volumes and adequate facilities to manage these patients.
20Detecting Early Pancreatic Cancer: Current Problems and Future Prospects.PubMed
Hiroyuki Matsubayashi, Hirotoshi Ishiwatari, Keiko Sasaki, et al.
Gut Liver. 2020 Jan 15;14(1):30-36. doi: 10.5009/gnl18491.
The number of patients with pancreatic cancer (PC) is currently increasing in both Korea and Japan. The 5-year survival rate of patients with PC 13.0%; however, resection with minimal invasion (tumor size: ≤10 mm) increases the 5-year survival rate to 80%. For this reason, early detection is essential, but most patients with early-stage PC are asymptomatic. Early detection of PC has been reported to require screening of high-risk individuals (HRIs), such as those with a family history of PC, inherited cancer syndromes, intraductal papillary mucinous neoplasm, or chronic pancreatitis. Studies on screening of these HRIs have confirmed a significantly better prognosis among patients with PC who were screened than for patients with PC who were not screened. However, to date in Japan, most patients with early-stage PC diagnosed in routine clinics were not diagnosed during annual health checks or by surveillance; rather, PC was detected in these patients by incidental findings during examinations for other diseases. We need to increase the precision of the PC screening and diagnostic processes by introducing new technologies, and we need to pay greater attention to incidental clinical findings.
21Pancreatic Adenocarcinoma: Trends in Epidemiology, Risk Factors, and Outcomes.PubMed
Elham Afghani, Alison P Klein
Hematol Oncol Clin North Am. 2022 Oct;36(5):879-895. doi: 10.1016/j.hoc.2022.07.002. Epub 2022 Sep 23.
Pancreatic cancer is one of the most lethal cancers in the world; it is a silent disease in which symptoms do not present until advanced stages, thereby reducing the 5-year survival rate to 10%. The global burden of pancreatic cancer has doubled over the past 25 years despite advancements in medicine. This review aims to discuss the global trends and disparities in pancreatic cancer, as well as the up-to-date literature on the known risk factors. A better understanding of these risk factors will reduce mortality by providing opportunities to screen these patients as well as counseling on lifestyle modifications.
22Pancreatic cancer epidemiology: understanding the role of lifestyle and inherited risk factors.PubMed
Alison P Klein
Nat Rev Gastroenterol Hepatol. 2021 Jul;18(7):493-502. doi: 10.1038/s41575-021-00457-x. Epub 2021 May 17.
Pancreatic cancer is a leading cause of cancer death worldwide and its global burden has more than doubled over the past 25 years. The highest incidence regions for pancreatic cancer include North America, Europe and Australia, and although much of this increase is due to ageing worldwide populations, there are key modifiable risk factors for pancreatic cancer such as cigarette smoking, obesity, diabetes and alcohol intake. The prevalence of these risk factors is increasing in many global regions, resulting in increasing age-adjusted incidence rates for pancreatic cancer, but the relative contribution from these risk factors varies globally due to variation in the underlying prevalence and prevention strategies. Inherited genetic factors, although not directly modifiable, are an important component of pancreatic cancer risk, and include pathogenic variants in hereditary cancer genes, genes associated with hereditary pancreatitis, as well as common variants identified in genome-wide association studies. Identification of the genetic changes that underlie pancreatic cancer not only provides insight into the aetiology of this cancer but also provides an opportunity to guide early detection strategies. The goal of this Review is to provide an up-to-date overview of the established modifiable and inherited risk factors for pancreatic cancer.
23Familial pancreatic cancer.PubMed
Gloria M Petersen
Semin Oncol. 2016 Oct;43(5):548-553. doi: 10.1053/j.seminoncol.2016.09.002. Epub 2016 Sep 22.
Familial pancreatic cancer (FPC) includes those kindreds that contain at least two first-degree relatives with pancreatic ductal adenocarcinoma. At least 12 known hereditary syndromes or genes are associated with increased risk of developing pancreatic cancer, the foremost being BRCA2 and CDKN2A. Research into the identification of mutations in known cancer predisposition genes and through next-generation sequencing has revealed extensive heterogeneity. The development of genetic panel testing has enabled genetic risk assessment and predisposition testing to be routinely offered. Precision oncology has opened the possibility of "incidental" germline mutations that may have implications for family members. However, in both cases, evidence-based recommendations for managing patients and at-risk family members in light of genetic status remain emergent, with current practice based on expert opinion.
24BRCA-mutant pancreatic ductal adenocarcinoma.PubMed
Eleonora Lai, Pina Ziranu, Dario Spanu, et al.
Br J Cancer. 2021 Nov;125(10):1321-1332. doi: 10.1038/s41416-021-01469-9. Epub 2021 Jul 14.
Despite continued research, pancreatic ductal adenocarcinoma (PDAC) remains one of the main causes of cancer death. Interest is growing in the role of the tumour suppressors breast cancer 1 (BRCA1) and BRCA2-typically associated with breast and ovarian cancer-in the pathogenesis of PDAC. Indeed, both germline and sporadic mutations in BRCA1/2 have been found to play a role in the development of PDAC. However, data regarding BRCA1/2-mutant PDAC are lacking. In this review, we aim to outline the specific landscape of BRCA-mutant PDAC, focusing on heritability, clinical features, differences between BRCA1 and 2 mutations and between germline and sporadic alterations, as well as established therapeutic strategies and those that are still under evaluation.
25Geographical, ethnic, and genetic differences in pancreatic cancer predisposition.PubMed
Sherilyn Zi Hui Liew, Kwok Wing Ng, Nur Diana Binte Ishak, et al.
Chin Clin Oncol. 2023 Jun;12(3):27. doi: 10.21037/cco-23-8.
Pancreatic cancer remains a leading cause of cancer-related mortality worldwide. Treatment outcomes remain largely dismal despite significant medical advancements. This lends urgency to the need to understand its risk factors in order to guide early detection and improve outcomes. There are both modifiable and non-modifiable risk factors, the more established of such being that of age, smoking, obesity, diabetes mellitus (DM), alcohol and certain genetic predisposition syndromes with underlying germline mutations. Some genetic predisposition syndromes such as BRCA1/2, PALB2, ATM, and CDKN2A are well-established, arising from germline mutations that result in carcinogenesis through mechanisms such as cell injury, dysregulation of cell growth, dysfunctional DNA repair, and disruption of cell mobility and adhesion. There is also a significant proportion of familial pancreatic cancer (FPC) for which the underlying predisposing genetic mechanism is not yet understood. Nuances have emerged in the ethnic and geographical differences of pancreatic cancer predisposition, and these may be attributed to differences in lifestyle, standard of living, socioeconomic factors, and genetics. This review describes in detail the factors contributing to pancreatic cancer with focus on ethnic and geographical differences and hereditary genetic syndromes. Greater insight into the interplay of these factors can guide clinicians and healthcare authorities in addressing modifiable risk factors, implementing measures for early detection in high-risk individuals, initiating early treatment of pancreatic cancer, and directing future research towards existing knowledge deficits, in order to improve survival outcomes.
26Cancer Risks Associated With and Pathogenic Variants.PubMed
Shuai Li, Valentina Silvestri, Goska Leslie, et al.
J Clin Oncol. 2022 May 10;40(14):1529-1541. doi: 10.1200/JCO.21.02112. Epub 2022 Jan 25.
PURPOSE: To provide precise age-specific risk estimates of cancers other than female breast and ovarian cancers associated with pathogenic variants (PVs) in and for effective cancer risk management. METHODS: We used data from 3,184 and 2,157 families in the Consortium of Investigators of Modifiers of to estimate age-specific relative (RR) and absolute risks for 22 first primary cancer types adjusting for family ascertainment. RESULTS: PVs were associated with risks of male breast (RR = 4.30; 95% CI, 1.09 to 16.96), pancreatic (RR = 2.36; 95% CI, 1.51 to 3.68), and stomach (RR = 2.17; 95% CI, 1.25 to 3.77) cancers. Associations with colorectal and gallbladder cancers were also suggested. PVs were associated with risks of male breast (RR = 44.0; 95% CI, 21.3 to 90.9), stomach (RR = 3.69; 95% CI, 2.40 to 5.67), pancreatic (RR = 3.34; 95% CI, 2.21 to 5.06), and prostate (RR = 2.22; 95% CI, 1.63 to 3.03) cancers. The stomach cancer RR was higher for females than males (6.89 2.76; = .04). The absolute risks to age 80 years ranged from 0.4% for male breast cancer to approximately 2.5% for pancreatic cancer for carriers and from approximately 2.5% for pancreatic cancer to 27% for prostate cancer for carriers. CONCLUSION: In addition to female breast and ovarian cancers, and PVs are associated with increased risks of male breast, pancreatic, stomach, and prostate (only PVs) cancers, but not with the risks of other previously suggested cancers. The estimated age-specific risks will refine cancer risk management in men and women with PVs.
27TPX2 serves as a novel target for expanding the utility of PARPi in pancreatic cancer through conferring synthetic lethality.PubMed
Mingming Xiao, Rong Tang, Haoqi Pan, et al.
Gut. 2025 Feb 6;74(3):410-423. doi: 10.1136/gutjnl-2024-332782.
BACKGROUND: PARP inhibitors (PARPi) have been licensed for the maintenance therapy of patients with metastatic pancreatic cancer carrying pathogenic germline BRCA1/2 mutations. However, mutations in BRCA1/2 are notably rare in pancreatic cancer. OBJECTIVE: There is a significant unmet clinical need to broaden the utility of PARPi. DESIGN: RNA sequencing was performed to screen potential targets for PARPi sensitivity. The synthetic lethal effects were verified in patient-derived xenograft (PDX), xenograft and patient-derived organoid models. Mechanisms were explored via LC‒MS/MS, coimmunoprecipitation, laser microirradiation, immunofluorescence, the homologous recombination (HR) or non-homologous end joining (NHEJ) reporter system, in situ proximity ligation assay and live-cell time-lapse imaging analyses. RESULTS: Targeting protein for Xenopus kinesin-like protein 2 (TPX2) is an exploitable vulnerability. TPX2 was downregulated in PDX models sensitive to PARPi, and TPX2 inhibition conferred synthetic lethality to PARPi both and . Mechanistically, TPX2 functions in a cell cycle-dependent manner. In the S/G2 phase, ATM-mediated TPX2 S634 phosphorylation promotes BRCA1 recruitment to double-strand breaks (DSBs) for HR repair, whereas non-phosphorylated TPX2 interacts with 53BP1 to recruit it for NHEJ. The balance between phosphorylated and non-phosphorylated TPX2 determines the DSB repair pathway choice. During mitosis, TPX2 phosphorylation enhances Aurora A activity, promoting mitotic progression and chromosomal stability. Targeting TPX2 S634 phosphorylation with a cell-penetrating peptide causes genomic instability and mitotic catastrophe and enhances PARPi sensitivity. Additionally, the inhibition of TPX2 or S634 phosphorylation combined with gemcitabine further sensitised pancreatic cancer to PARPi. CONCLUSIONS: Our findings revealed the dual-functional significance of TPX2 in controlling DNA DSB repair pathway choice and mitotic progression, suggesting a potential therapeutic strategy involving PARPi for patients with pancreatic cancer.
28PARP Inhibitors in Pancreatic Cancer.PubMed
Timothy J Brown, Kim A Reiss
Cancer J. 2021;27(6):465-475. doi: 10.1097/PPO.0000000000000554.
Despite representing only 5% of all annual cancer diagnoses in the United States, pancreatic cancer is projected to become the second leading cause of cancer-related death within the next 10 years. Progress in the treatment of advanced pancreatic cancer has been slow. Systemic therapies rely on combination cytotoxic agents, with limited options at progression. Recently, poly(ADP-ribose) polymerase inhibitors have demonstrated clinical activity in patients with advanced pancreatic cancer and pathogenic variants in BRCA1, BRCA2, and PALB2. In this review, we discuss the development of poly(ADP-ribose) polymerase inhibitors in pancreatic cancer, relevant clinical trials, and future directions.
29Genetic characterization of pancreatic cancer patients and prediction of carrier status of germline pathogenic variants in cancer-predisposing genes.PubMed
Keijiro Mizukami, Yusuke Iwasaki, Eiryo Kawakami, et al.
EBioMedicine. 2020 Oct;60:103033. doi: 10.1016/j.ebiom.2020.103033. Epub 2020 Sep 24.
BACKGROUND: National Comprehensive Cancer Network (NCCN) recently recommended germline genetic testing for all pancreatic cancer patients. However, the genes targeted by genetic testing and the feasibility of selecting patients likely to carry pathogenic variants have not been sufficiently verified. The purpose of this study was to genetically characterize Japanese patients and examine whether the current guideline is applicable in this population. METHODS: Using targeted sequencing, we analyzed the coding regions of 27 cancer-predisposing genes in 1,005 pancreatic cancer patients and 23,705 controls in Japan. We compared the pathogenic variant frequency between cases and controls and documented the demographic and clinical characteristics of carrier patients. We then examined if it was possible to use machine learning to predict carrier status based on those characteristics. FINDINGS: We identified 205 pathogenic variants across the 27 genes. Pathogenic variants in BRCA2, ATM, and BRCA1 were significantly associated with pancreatic cancer. Characteristics associated with carrier status were inconsistent with previous investigations. Machine learning classifiers had a low performance in determining the carrier status of pancreatic cancer patients, while the same classifiers, when applied to breast cancer data as a positive control, had a higher performance that was comparable to that of the NCCN guideline. INTERPRETATION: Our findings support the clinical significance of multigene panel testing for pancreatic cancer and indicate that at least 3.4% of Japanese patients may respond to poly (ADP ribose) polymerase inhibitor treatments. The difficulty in predicting carrier status suggests that offering germline genetic testing for all pancreatic cancer patients is reasonable. FUNDING: AMED under Grant Number JP19kk0305010 and Australian National Health and Medical Research funding (ID177524).
30Whole genomes redefine the mutational landscape of pancreatic cancer.PubMed
Nicola Waddell, Marina Pajic, Ann-Marie Patch, et al.
Nature. 2015 Feb 26;518(7540):495-501. doi: 10.1038/nature14169.
Pancreatic cancer remains one of the most lethal of malignancies and a major health burden. We performed whole-genome sequencing and copy number variation (CNV) analysis of 100 pancreatic ductal adenocarcinomas (PDACs). Chromosomal rearrangements leading to gene disruption were prevalent, affecting genes known to be important in pancreatic cancer (TP53, SMAD4, CDKN2A, ARID1A and ROBO2) and new candidate drivers of pancreatic carcinogenesis (KDM6A and PREX2). Patterns of structural variation (variation in chromosomal structure) classified PDACs into 4 subtypes with potential clinical utility: the subtypes were termed stable, locally rearranged, scattered and unstable. A significant proportion harboured focal amplifications, many of which contained druggable oncogenes (ERBB2, MET, FGFR1, CDK6, PIK3R3 and PIK3CA), but at low individual patient prevalence. Genomic instability co-segregated with inactivation of DNA maintenance genes (BRCA1, BRCA2 or PALB2) and a mutational signature of DNA damage repair deficiency. Of 8 patients who received platinum therapy, 4 of 5 individuals with these measures of defective DNA maintenance responded.
31Familial pancreatic cancer: Concept, management and issues.PubMed
Hiroyuki Matsubayashi, Kyoichi Takaori, Chigusa Morizane, et al.
World J Gastroenterol. 2017 Feb 14;23(6):935-948. doi: 10.3748/wjg.v23.i6.935.
Familial pancreatic cancer (FPC) is broadly defined as two first-degree-relatives with pancreatic cancer (PC) and accounts for 4%-10% of PC. Several genetic syndromes, including Peutz-Jeghers syndrome, hereditary pancreatitis, hereditary breast-ovarian cancer syndrome (HBOC), Lynch syndrome, and familial adenomatous polyposis (FAP), also have increased risks of PC, but the narrowest definition of FPC excludes these known syndromes. When compared with other familial tumors, proven genetic alterations are limited to a small proportion (< 20%) and the familial aggregation is usually modest. However, an ethnic deviation (Ashkenazi Jewish > Caucasian) and a younger onset are common also in FPC. In European countries, "anticipation" is reported in FPC families, as with other hereditary syndromes; a trend toward younger age and worse prognosis is recognized in the late years. The resected pancreases of FPC kindred often show multiple pancreatic intraepithelial neoplasia (PanIN) foci, with various K- mutations, similar to colorectal polyposis seen in the FAP patients. As with HBOC patients, a patient who is a mutation carrier with unresectable pancreatic cancer (accounting for 0%-19% of FPC patients) demonstrated better outcome following platinum and Poly (ADP-ribose) polymerase inhibitor treatment. Western countries have established FPC registries since the 1990s and several surveillance projects for high-risk individuals are now ongoing to detect early PCs. Improvement in lifestyle habits, including non-smoking, is recommended for individuals at risk. In Japan, the FPC study group was initiated in 2013 and the Japanese FPC registry was established in 2014 by the Japan Pancreas Society.
32Whole genome sequencing identifies rare germline variants enriched in cancer related genes in first degree relatives of familial pancreatic cancer patients.PubMed
Ming Tan, Klaus Brusgaard, Anne-Marie Gerdes, et al.
Clin Genet. 2021 Nov;100(5):551-562. doi: 10.1111/cge.14038. Epub 2021 Aug 3.
First-degree relatives (FDRs) of familial pancreatic cancer (FPC) patients have increased risk of developing pancreatic ductal adenocarcinoma (PDAC). Investigating and understanding the genetic basis for PDAC susceptibility in FPC predisposed families may contribute toward future risk-assessment and management of high-risk individuals. Using a Danish cohort of 27 FPC families, we performed whole-genome sequencing of 61 FDRs of FPC patients focusing on rare genetic variants that may contribute to familial aggregation of PDAC. Statistical analysis was performed using the gnomAD database as external controls. Through analysis of heterozygous premature truncating variants (PTV), we identified cancer-related genes and cancer-driver genes harboring multiple germline mutations. Association analysis detected 20 significant genes with false discovery rate, q < 0.05 including: PALD1, LRP1B, COL4A2, CYLC2, ZFYVE9, BRD3, AHDC1, etc. Functional annotation showed that the significant genes were enriched by gene clusters encoding for extracellular matrix and associated proteins. PTV genes were over-represented by functions related to transport of small molecules, innate immune system, ion channel transport, and stimuli-sensing channels. In conclusion, FDRs of FPC patients carry rare germline variants related to cancer pathogenesis that may contribute to increased susceptibility to PDAC. The identified variants may potentially be useful for risk prediction of high-risk individuals in predisposed families.
33Tobacco 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.
34The epidemiology of pancreatitis and pancreatic cancer.PubMed
Dhiraj Yadav, Albert B Lowenfels
Gastroenterology. 2013 Jun;144(6):1252-61. doi: 10.1053/j.gastro.2013.01.068.
Acute pancreatitis is one of the most frequent gastrointestinal causes of hospital admission in the United States. Chronic pancreatitis, although lower in incidence, significantly reduces patients' quality of life. Pancreatic cancer is associated with a high mortality rate and is one of the top 5 causes of death from cancer. The burden of pancreatic disorders is expected to increase over time. The risk and etiology of pancreatitis differ with age and sex, and all pancreatic disorders affect the black population more than any other race. Gallstones are the most common cause of acute pancreatitis, and early cholecystectomy eliminates the risk of future attacks. Alcohol continues to be the single most important risk factor for chronic pancreatitis. Smoking is an independent risk factor for acute and chronic pancreatitis, and its effects could synergize with those of alcohol. Significant risk factors for pancreatic cancer include smoking and non-O blood groups. Alcohol abstinence and smoking cessation can alter the progression of pancreatitis and reduce recurrence; smoking cessation is the most effective strategy to reduce the risk of pancreatic cancer.
35Pancreatic cancer and obesity: epidemiology, mechanism, and preventive strategies.PubMed
Prashanth Rawla, Krishna Chaitanya Thandra, Tagore Sunkara
Clin J Gastroenterol. 2019 Aug;12(4):285-291. doi: 10.1007/s12328-019-00953-3. Epub 2019 Feb 20.
The prevalence of obesity has seen a global increase in the past decades, escalating to one of the major epidemiological challenges today. Global economic growth has caused changes in dietary and physical activity patterns fueling obesity across age, gender, and income groups. The implications are many, as obesity has been associated with numerous serious health conditions, ultimately affecting morbidity and mortality. There is a growing recognition of the risk a high body mass index confers on the development and outcome of several malignancies, including pancreatic cancer. Pancreatic cancer is a highly lethal disease with exceptionally poor outcome, with incidences rising worldwide. Due to vague symptoms and no screening recommendations, a vast majority of patients are diagnosed at late stages, with already advanced disease and no opportunity for surgical intervention. Obesity mediates risk for pancreatic cancer through insufficiently understood mechanisms, possibly including inflammation and hormonal misbalance. As excess abdominal adiposity is among the few modifiable risk factors for pancreatic cancer onset, enduring weight loss could manifest an effective preventive measure. Lifestyle modifications on a population level aimed to reduce obesity could also scale down the grim pancreatic cancer rates. In cases when these measures alone are insufficiently effective, bariatric surgery can be an advantageous alternative. Extremely obese patients exhibit many health benefits following bariatric surgery along with weight loss, consequently reducing the chances of pancreatic cancer, especially if additionally adopting healthy lifestyle habits.
36Obesity, pancreatitis, and pancreatic cancer.PubMed
Andrew A Gumbs
Obes Surg. 2008 Sep;18(9):1183-7. doi: 10.1007/s11695-008-9599-3. Epub 2008 Jun 19.
The only universally accepted risk factors for the development of pancreatic cancer are a positive family history or a history of smoking. Although the contribution of pancreatitis to pancreatic carcinogenesis has been debated for decades in the epidemiology literature, the actual mechanism is still unclear. With the rising epidemic of obesity, scientists have begun to focus on the contribution of chronic inflammatory state of morbidly obese patients in an effort to better understand the contribution of inflammation to the comorbidities of obesity. Notably, population studies are beginning to show that one of the most serious potential comorbidities of obesity is an increased lifetime risk of developing cancer. In this article, the current literature that exists supporting this Chronic Inflammatory Hypothesis as it pertains to obesity and pancreatic carcinogenesis is reviewed. To date, studies have focused on interleukin-6, a cytokine known to play a role in obesity, chronic pancreatitis and pancreatic cancer. The anti-inflammatory adipocytokine, adiponectin, has also shown promise as a key player in this mechanism and has recently been found to be more specific than standard tumor markers in differentiating pancreatic cancer from chronic pancreatitis. If the pathogenesis of pancreatic cancer is related to hormone levels associated with obesity, such as adipocytokines, and cytokines associated with chronic inflammation, this could potentially lead to the development of new pancreatic cancer tumor markers and ultimately new therapies and methods of prevention.
37Metformin inhibits neutrophil extracellular traps-promoted pancreatic carcinogenesis in obese mice.PubMed
Guangfu Wang, Hao Gao, Shangnan Dai, et al.
Cancer Lett. 2023 May 28;562:216155. doi: 10.1016/j.canlet.2023.216155. Epub 2023 Apr 6.
Obesity has been linked to a higher risk of pancreatic cancer. However, the mechanism by which obesity promote pancreatic carcinogenesis is still unclear. We investigated the effect of obesity on pancreatic carcinogenesis in Pdx1-Cre; LSL-Kras (KC) mice. Metformin was administrated to rescue the effects of obesity and NETs. The pro-tumorigenic effects of neutrophil extracellular traps (NETs) were further evaluated in vivo and vitro. We found that obesity significantly promoted the progression of murine pancreatic ductal intraepithelial neoplasia (mPanIN). The proliferation rate and epithelial-mesenchymal transition (EMT) of mPanIN ductal cells were increased in obese mice. More visceral adipocytes, PD-L1 neutrophil infiltration and NETs formation were found in the pancreas of obese mice and visceral adipocytes could recruit neutrophils and promote NETs formation. The latter could induce an inflammatory response in ductal cells via TLR4-dependent pathways both in vivo and vitro, as demonstrated by upregulation of IL-1β. Metformin and DNase I significantly reversed the pro-tumorigenic effects of obesity and NETs in vivo and in vitro. Our study provides causal evidence for the contribution of obesity in promoting pancreatic carcinogenesis in genetic model and reveals the mechanism by NETs to regulate mPanIN progression.
38Diabetes, Pancreatogenic Diabetes, and Pancreatic Cancer.PubMed
Dana K Andersen, Murray Korc, Gloria M Petersen, et al.
Diabetes. 2017 May;66(5):1103-1110. doi: 10.2337/db16-1477.
The relationships between diabetes and pancreatic ductal adenocarcinoma (PDAC) are complex. Longstanding type 2 diabetes (T2DM) is a risk factor for pancreatic cancer, but increasing epidemiological data point to PDAC as also a cause of diabetes due to unknown mechanisms. New-onset diabetes is of particular interest to the oncology community as the differentiation of new-onset diabetes caused by PDAC as distinct from T2DM may allow for earlier diagnosis of PDAC. To address these relationships and raise awareness of the relationships between PDAC and diabetes, a symposium entitled Diabetes, Pancreatogenic Diabetes, and Pancreatic Cancer was held at the American Diabetes Association's 76th Scientific Sessions in June 2016. This article summarizes the data presented at that symposium, describing the current understanding of the interrelationships between diabetes, diabetes management, and pancreatic cancer, and identifies areas where additional research is needed.
39Identification of the Shared Gene Signatures and Biological Mechanism in Type 2 Diabetes and Pancreatic Cancer.PubMed
Yifang Hu, Ni Zeng, Yaoqi Ge, et al.
Front Endocrinol (Lausanne). 2022 Mar 31;13:847760. doi: 10.3389/fendo.2022.847760. eCollection 2022.
BACKGROUND: The relationship between pancreatic cancer (PC) and type 2 diabetes mellitus (T2DM) has long been widely recognized, but the interaction mechanisms are still unknown. This study was aimed to investigate the shared gene signatures and molecular processes between PC and T2DM. METHODS: The Gene Expression Omnibus (GEO) database was used to retrieve the RNA sequence and patient information of PC and T2DM. Weighted gene co-expression network analysis (WGCNA) was performed to discover a co-expression network associated with PC and T2DM. Enrichment analysis of shared genes present in PC and T2DM was performed by ClueGO software. These results were validated in the other four cohorts based on differential gene analysis. The predictive significance of S100A6 in PC was evaluated using univariate and multivariate Cox analyses, as well as Kaplan-Meier plots. The biological process of S100A6 enrichment in PC was detected using Gene Set Enrichment Analysis (GSEA). The involvement of S100A6 in the tumor immune microenvironment (TIME) was assessed by CIBERSORT. assays were used to further confirm the function of S100A6 in PC. RESULTS: WGCNA recognized three major modules for T2DM and two major modules for PC. There were 44 shared genes identified for PC and T2DM, and Gene Ontology (GO) analysis showed that regulation of endodermal cell fate specification was primarily enriched. In addition, a key shared gene was derived in the validation tests. S100A6 was shown to be highly expressed in PC compared to non-tumor tissues. PC patients with high S100A6 expression had worse overall survival (OS) than those with low expression. GSEA revealed that S100A6 is involved in cancer-related pathways and glycometabolism-related pathways. There is a strong relationship between S100A6 and TIME. functional assays showed that S100A6 helped to induce the PC cells' proliferation and migration. We also proposed a diagram of common mechanisms of PC and T2DM. CONCLUSIONS: This study firstly revealed that the regulation of endodermal cell fate specification may be common pathogenesis of PC and T2DM and identified S100A6 as a possible biomarker and therapeutic target for PC and T2DM patients.
40Ultra-processed food consumption and cancer risk: A systematic review and meta-analysis.PubMed
Irja Minde Isaksen, Simon Nitter Dankel
Clin Nutr. 2023 Jun;42(6):919-928. doi: 10.1016/j.clnu.2023.03.018. Epub 2023 Mar 30.
BACKGROUND: Ultra-processed foods (UPF) have become a staple of the diet in many countries, concomitant with increases in non-communicable diseases including cancer. AIM: The aim of this systematic literature review was to evaluate associations between the consumption of UPF and cancer risk. METHODS: A systematic literature search for observational studies investigating the association between cancer risk and UPF consumption, determined by the NOVA classification system, was performed. Random-effects meta-analyses were conducted. Independent review and risk of bias assessment was performed independently by the authors using the National Institutes of Health's Study Quality Assessment Tools. RESULTS: Eleven reports were identified, including eight retrospective case-control studies and three prospective cohorts. The outcome was risk of total cancer and/or one or more of the following cancers: colorectal, breast, prostate, pancreatic, chronic lymphocytic leukemia and central nervous system tumors. Nine studies reported a significant positive association between UPF intake and all the assessed cancers except prostate, after adjustment for confounding factors including obesity and total energy intake. A 10% increment in the diet's proportion of UPF was associated with increased risk of overall cancer (HR = 1.13, 95% CI 1.07 to 1.18) and breast cancer (HR = 1.11, 95% CI 1.01 to 1.21). In addition, a high intake of UPF was associated with increased risk of colorectal cancer (OR = 1.30, 95% CI 1.11 to 1.51) and pancreatic cancer (HR = 1.49, 95% CI 1.07 to 2.07). More modest associations were found for chronic lymphocytic leukemia and central nervous system tumors. Common limitations of several of the studies included no prior assessment of diet before known diagnosis (the case-control studies), higher participation rates among cases, and likely misclassification of several foods as UPF or non-UPF. CONCLUSION: In conclusion, the available suggestive evidence shows a consistent significant association between intake of UPF and the risk of overall and several cancers, including colorectal-, breast- and pancreatic cancer. These data may inform updated dietary guidelines, policy makers and the public towards improving public health.
41The Pancreatic Cancer Microbiome Promotes Oncogenesis by Induction of Innate and Adaptive Immune Suppression.PubMed
Smruti Pushalkar, Mautin Hundeyin, Donnele Daley, et al.
Cancer Discov. 2018 Apr;8(4):403-416. doi: 10.1158/2159-8290.CD-17-1134. Epub 2018 Mar 22.
We found that the cancerous pancreas harbors a markedly more abundant microbiome compared with normal pancreas in both mice and humans, and select bacteria are differentially increased in the tumorous pancreas compared with gut. Ablation of the microbiome protects against preinvasive and invasive pancreatic ductal adenocarcinoma (PDA), whereas transfer of bacteria from PDA-bearing hosts, but not controls, reverses tumor protection. Bacterial ablation was associated with immunogenic reprogramming of the PDA tumor microenvironment, including a reduction in myeloid-derived suppressor cells and an increase in M1 macrophage differentiation, promoting TH1 differentiation of CD4 T cells and CD8 T-cell activation. Bacterial ablation also enabled efficacy for checkpoint-targeted immunotherapy by upregulating PD-1 expression. Mechanistically, the PDA microbiome generated a tolerogenic immune program by differentially activating select Toll-like receptors in monocytic cells. These data suggest that endogenous microbiota promote the crippling immune-suppression characteristic of PDA and that the microbiome has potential as a therapeutic target in the modulation of disease progression. We found that a distinct and abundant microbiome drives suppressive monocytic cellular differentiation in pancreatic cancer via selective Toll-like receptor ligation leading to T-cell anergy. Targeting the microbiome protects against oncogenesis, reverses intratumoral immune tolerance, and enables efficacy for checkpoint-based immunotherapy. These data have implications for understanding immune suppression in pancreatic cancer and its reversal in the clinic. .
42Microbiota-derived 3-IAA influences chemotherapy efficacy in pancreatic cancer.PubMed
Joseph Tintelnot, Yang Xu, Till R Lesker, et al.
Nature. 2023 Mar;615(7950):168-174. doi: 10.1038/s41586-023-05728-y. Epub 2023 Feb 22.
Pancreatic ductal adenocarcinoma (PDAC) is expected to be the second most deadly cancer by 2040, owing to the high incidence of metastatic disease and limited responses to treatment. Less than half of all patients respond to the primary treatment for PDAC, chemotherapy, and genetic alterations alone cannot explain this. Diet is an environmental factor that can influence the response to therapies, but its role in PDAC is unclear. Here, using shotgun metagenomic sequencing and metabolomic screening, we show that the microbiota-derived tryptophan metabolite indole-3-acetic acid (3-IAA) is enriched in patients who respond to treatment. Faecal microbiota transplantation, short-term dietary manipulation of tryptophan and oral 3-IAA administration increase the efficacy of chemotherapy in humanized gnotobiotic mouse models of PDAC. Using a combination of loss- and gain-of-function experiments, we show that the efficacy of 3-IAA and chemotherapy is licensed by neutrophil-derived myeloperoxidase. Myeloperoxidase oxidizes 3-IAA, which in combination with chemotherapy induces a downregulation of the reactive oxygen species (ROS)-degrading enzymes glutathione peroxidase 3 and glutathione peroxidase 7. All of this results in the accumulation of ROS and the downregulation of autophagy in cancer cells, which compromises their metabolic fitness and, ultimately, their proliferation. In humans, we observed a significant correlation between the levels of 3-IAA and the efficacy of therapy in two independent PDAC cohorts. In summary, we identify a microbiota-derived metabolite that has clinical implications in the treatment of PDAC, and provide a motivation for considering nutritional interventions during the treatment of patients with cancer.
43Roles of microbiota in pancreatic cancer development and treatment.PubMed
Mariana Santos Cruz, Joseph Tintelnot, Nicola Gagliani
Gut Microbes. 2024 Jan-Dec;16(1):2320280. doi: 10.1080/19490976.2024.2320280. Epub 2024 Feb 27.
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with poor prognosis. This is due to the fact that most cases are only diagnosed at an advanced and palliative disease stage, and there is a high incidence of therapy resistance. Despite ongoing efforts, to date, the mechanisms underlying PDAC oncogenesis and its poor responses to treatment are still largely unclear. As the study of the microbiome in cancer progresses, growing evidence suggests that bacteria or fungi might be key players both in PDAC oncogenesis as well as in its resistance to chemo- and immunotherapy, for instance through modulation of the tumor microenvironment and reshaping of the host immune response. Here, we review how the microbiota exerts these effects directly or indirectly via microbial-derived metabolites. Finally, we further discuss the potential of modulating the microbiota composition as a therapy in PDAC.
44Chronic inflammation and pancreatic cancer.PubMed
Colin J McKay, Paul Glen, Donald C McMillan
Best Pract Res Clin Gastroenterol. 2008;22(1):65-73. doi: 10.1016/j.bpg.2007.11.007.
There is a proven association between carcinoma of the pancreas and both the sporadic and hereditary forms of chronic pancreatitis. In chronic pancreatitis the standardised incidence ratio for development of pancreatic cancer is 14-18 and is further increased by cigarette smoking. Underlying mechanisms are unclear but current theories point to the progressive accumulation of genetic mutations as a consequence of repeated DNA damage and cell regeneration in an environment favouring proliferation and neovascularisation. In patients who develop pancreatic cancer, there is interest in the role of the inflammatory response in the development of cancer cachexia and in determining prognosis. Furthermore, markers of a systemic inflammatory response have prognostic significance in both advanced, inoperable pancreatic cancer and in patients undergoing resection. Further understanding of the details of the relationship between inflammation, carcinogenesis and cancer prognosis may lead to new therapeutic possibilities as part of multi-modality management of this difficult disease.
45Protein kinase D1 drives pancreatic acinar cell reprogramming and progression to intraepithelial neoplasia.PubMed
Geou-Yarh Liou, Heike Döppler, Ursula B Braun, et al.
Nat Commun. 2015 Feb 20;6:6200. doi: 10.1038/ncomms7200.
The transdifferentiation of pancreatic acinar cells to a ductal phenotype (acinar-to-ductal metaplasia, ADM) occurs after injury or inflammation of the pancreas and is a reversible process. However, in the presence of activating Kras mutations or persistent epidermal growth factor receptor (EGF-R) signalling, cells that underwent ADM can progress to pancreatic intraepithelial neoplasia (PanIN) and eventually pancreatic cancer. In transgenic animal models, ADM and PanINs are initiated by high-affinity ligands for EGF-R or activating Kras mutations, but the underlying signalling mechanisms are not well understood. Here, using a conditional knockout approach, we show that protein kinase D1 (PKD1) is sufficient to drive the reprogramming process to a ductal phenotype and progression to PanINs. Moreover, using 3D explant culture of primary pancreatic acinar cells, we show that PKD1 acts downstream of TGFα and Kras, to mediate formation of ductal structures through activation of the Notch pathway.
46Carcinogenesis of Pancreatic Ductal Adenocarcinoma.PubMed
Peter Storz, Howard C Crawford
Gastroenterology. 2020 Jun;158(8):2072-2081. doi: 10.1053/j.gastro.2020.02.059. Epub 2020 Mar 19.
Although the estimated time for development of pancreatic ductal adenocarcinoma (PDA) is more than 20 years, PDAs are usually detected at late, metastatic stages. PDAs develop from duct-like cells through a multistep carcinogenesis process, from low-grade dysplastic lesions to carcinoma in situ and eventually to metastatic disease. This process involves gradual acquisition of mutations in oncogenes and tumor suppressor genes, as well as changes in the pancreatic environment from a pro-inflammatory microenvironment that favors the development of early lesions, to a desmoplastic tumor microenvironment that is highly fibrotic and immune suppressive. This review discusses our current understanding of how PDA originates.
47Molecular mechanisms of pancreatic myofibroblast activation in chronic pancreatitis and pancreatic ductal adenocarcinoma.PubMed
Andrew Cannon, Christopher Michael Thompson, Rakesh Bhatia, et al.
J Gastroenterol. 2021 Aug;56(8):689-703. doi: 10.1007/s00535-021-01800-4. Epub 2021 Jul 19.
Pancreatic fibrosis (PF) is an essential component of the pathobiology of chronic pancreatitis (CP) and pancreatic ductal adenocarcinoma (PDAC). Activated pancreatic myofibroblasts (PMFs) are crucial for the deposition of the extracellular matrix, and fibrotic reaction in response to sustained signaling. Consequently, understanding of the molecular mechanisms of PMF activation is not only critical for understanding CP and PDAC biology but is also a fertile area of research for the development of novel therapeutic strategies for pancreatic pathologies. This review analyzes the key signaling events that drive PMF activation including, initiating signals from transforming growth factor-β1, platelet derived growth factor, as well as other microenvironmental cues, like hypoxia and extracellular matrix rigidity. Further, we discussed the intracellular signal events contributing to PMF activation, and crosstalk with different components of tumor microenvironment. Additionally, association of epidemiologically established risk factors for CP and PDAC, like alcohol intake, tobacco exposure, and metabolic factors with PMF activation, is discussed to comprehend the role of lifestyle factors on pancreatic pathologies. Overall, this analysis provides insight into the biology of PMF activation and highlights salient features of this process, which offer promising therapeutic targets.
48Proteomic analyses of ECM during pancreatic ductal adenocarcinoma progression reveal different contributions by tumor and stromal cells.PubMed
Chenxi Tian, Karl R Clauser, Daniel Öhlund, et al.
Proc Natl Acad Sci U S A. 2019 Sep 24;116(39):19609-19618. doi: 10.1073/pnas.1908626116. Epub 2019 Sep 4.
Pancreatic ductal adenocarcinoma (PDAC) has prominent extracellular matrix (ECM) that compromises treatments yet cannot be nonselectively disrupted without adverse consequences. ECM of PDAC, despite the recognition of its importance, has not been comprehensively studied in patients. In this study, we used quantitative mass spectrometry (MS)-based proteomics to characterize ECM proteins in normal pancreas and pancreatic intraepithelial neoplasia (PanIN)- and PDAC-bearing pancreas from both human patients and mouse genetic models, as well as chronic pancreatitis patient samples. We describe detailed changes in both abundance and complexity of matrisome proteins in the course of PDAC progression. We reveal an early up-regulated group of matrisome proteins in PanIN, which are further up-regulated in PDAC, and we uncover notable similarities in matrix changes between pancreatitis and PDAC. We further assigned cellular origins to matrisome proteins by performing MS on multiple lines of human-to-mouse xenograft tumors. We found that, although stromal cells produce over 90% of the ECM mass, elevated levels of ECM proteins derived from the tumor cells, but not those produced exclusively by stromal cells, tend to correlate with poor patient survival. Furthermore, distinct pathways were implicated in regulating expression of matrisome proteins in cancer cells and stromal cells. We suggest that, rather than global suppression of ECM production, more precise ECM manipulations, such as targeting tumor-promoting ECM proteins and their regulators in cancer cells, could be more effective therapeutically.
49Glycogen synthase kinase-3β ablation limits pancreatitis-induced acinar-to-ductal metaplasia.PubMed
Li Ding, Geou-Yarh Liou, Daniel M Schmitt, et al.
J Pathol. 2017 Sep;243(1):65-77. doi: 10.1002/path.4928. Epub 2017 Jul 27.
Acinar-to-ductal metaplasia (ADM) is a reversible epithelial transdifferentiation process that occurs in the pancreas in response to acute inflammation. ADM can rapidly progress towards pre-malignant pancreatic intraepithelial neoplasia (PanIN) lesions in the presence of mutant KRas and ultimately pancreatic adenocarcinoma (PDAC). In the present work, we elucidate the role and related mechanism of glycogen synthase kinase-3beta (GSK-3β) in ADM development using in vitro 3D cultures and genetically engineered mouse models. We show that GSK-3β promotes TGF-α-induced ADM in 3D cultured primary acinar cells, whereas deletion of GSK-3β attenuates caerulein-induced ADM formation and PanIN progression in Kras transgenic mice. Furthermore, we demonstrate that GSK-3β ablation influences ADM formation and PanIN progression by suppressing oncogenic KRas-driven cell proliferation. Mechanistically, we show that GSK-3β regulates proliferation by increasing the activation of S6 kinase. Taken together, these results indicate that GSK-3β participates in early pancreatitis-induced ADM and thus could be a target for the treatment of chronic pancreatitis and the prevention of PDAC progression. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
50Pancreatic intraepithelial neoplasia.PubMed
Kyoichi Takaori, Ralph H Hruban, Anirban Maitra, et al.
Pancreas. 2004 Apr;28(3):257-62. doi: 10.1097/00006676-200404000-00008.
Great efforts have been devoted to detecting preinvasive precursors to ductal carcinoma of the pancreas in the hope of improving the currently bleak prognosis of invasive pancreatic cancer. Intensive investigations of the pancreas have led to the recognition of intraductal papillary mucinous neoplasms (IPMNs) and the detection of preinvasive precursors to conventional ductal carcinoma. The pancreatic intraepithelial neoplasia (PanIN) nomenclature for precursor lesions of ductal carcinoma was developed at the "Pancreatic Cancer Think Tank" held in the United States in 1999. However, some reports of precursor lesions have suggested that these definitions do not encompass the full spectrum of precursors of ductal carcinoma, and these issues were the subject of the "Forum on Carcinoma In Situ of the Pancreas" held in Japan in 2002. After this forum, it became clear that the existing definitions of PanINs needed to be revised and expanded. Both participants of the Pancreatic Cancer Think Tank and the Forum gathered together at a meeting on precursor lesions of pancreatic cancer in 2003, and an international consensus on the diagnostic criteria for PanINs and IPMNs was created. We describe herein the current understanding of precursor lesions of pancreatic cancer.
51NEMO/NF-κB signaling functions as a double-edged sword in PanIN formation versus progression to pancreatic cancer.PubMed
Miltiadis Tsesmelis, Ulrike F G Büttner, Melanie Gerstenlauer, et al.
Mol Cancer. 2024 May 16;23(1):103. doi: 10.1186/s12943-024-01989-x.
BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is marked by a dismal survival rate, lacking effective therapeutics due to its aggressive growth, late-stage diagnosis, and chemotherapy resistance. Despite debates on NF-κB targeting for PDAC treatment, no successful approach has emerged. METHODS: To elucidate the role of NF-κB, we ablated NF-κB essential modulator (NEMO), critical for conventional NF-κB signaling, in the pancreata of mice that develop precancerous lesions (KC mouse model). Secretagogue-induced pancreatitis by cerulein injections was utilized to promote inflammation and accelerate PDAC development. RESULTS: NEMO deletion reduced fibrosis and inflammation in young KC mice, resulting in fewer pancreatic intraepithelial neoplasias (PanINs) at later stages. Paradoxically, however, NEMO deletion accelerated the progression of these fewer PanINs to PDAC and reduced median lifespan. Further, analysis of tissue microarrays from human PDAC sections highlighted the correlation between reduced NEMO expression in neoplastic cells and poorer prognosis, supporting our observation in mice. Mechanistically, NEMO deletion impeded oncogene-induced senescence (OIS), which is normally active in low-grade PanINs. This blockage resulted in fewer senescence-associated secretory phenotype (SASP) factors, reducing inflammation. However, blocked OIS fostered replication stress and DNA damage accumulation which accelerated PanIN progression to PDAC. Finally, treatment with the DNA damage-inducing reagent etoposide resulted in elevated cell death in NEMO-ablated PDAC cells compared to their NEMO-competent counterparts, indicative of a synthetic lethality paradigm. CONCLUSIONS: NEMO exhibited both oncogenic and tumor-suppressive properties during PDAC development. Caution is suggested in therapeutic interventions targeting NF-κB, which may be detrimental during PanIN progression but beneficial post-PDAC development.
52Targeting pancreatitis blocks tumor-initiating stem cells and pancreatic cancer progression.PubMed
Altaf Mohammed, Naveena B Janakiram, Venkateshwar Madka, et al.
Oncotarget. 2015 Jun 20;6(17):15524-39. doi: 10.18632/oncotarget.3499.
Recent development of genetically engineered mouse models (GEMs) for pancreatic cancer (PC) that recapitulates human disease progression has helped to identify new strategies to delay/inhibit PC development. We first found that expression of the pancreatic tumor-initiating/cancer stem cells (CSC) marker DclK1 occurs in early stage PC and in both early and late pancreatic intraepithelial neoplasia (PanIN) and that it increases as disease progresses in GEM and also in human PC. Genome-wide next generation sequencing of pancreatic ductal adenocarcinoma (PDAC) from GEM mice revealed significantly increased DclK1 along with inflammatory genes. Genetic ablation of cyclo-oxygenase-2 (COX-2) decreased DclK1 in GEM. Induction of inflammation/pancreatitis with cerulein in GEM mice increased DclK1, and the novel dual COX/5-lipoxygenase (5-LOX) inhibitor licofelone reduced it. Dietary licofelone significantly inhibited the incidence of PDAC and carcinoma in situ with significant inhibition of pancreatic CSCs. Licofelone suppressed pancreatic tumor COX-2 and 5-LOX activities and modulated miRNAs characteristic of CSC and inflammation in correlation with PDAC inhibition. These results offer a preclinical proof of concept to target the inflammation initiation to inhibit cancer stem cells early for improving the treatment of pancreatic cancers, with immediate clinical implications for repositioning dual COX/5-LOX inhibitors in human trials for high risk patients.
53Obesity-Related Digestive Diseases and Their Pathophysiology.PubMed
Su Youn Nam
Gut Liver. 2017 May 15;11(3):323-334. doi: 10.5009/gnl15557.
Obesity is a growing medical and public health problem worldwide. Many digestive diseases are related to obesity. In this article, the current state of our knowledge of obesity-related digestive diseases, their pathogenesis, and the medical and metabolic consequences of weight reduction are discussed. Obesity-related digestive diseases include gastroesophageal reflux disease, Barrett's esophagus, esophageal cancer, colon polyp and cancer, nonalcoholic fatty liver disease, hepatitis C-related disease, hepatocellular carcinoma, gallstone, cholangiocarcinoma, and pancreatic cancer. Although obesity-related esophageal diseases are associated with altered mechanical and humoral factors, other obesity-related digestive diseases seem to be associated with obesity-induced altered circulating levels of adipocytokines and insulin resistance. The relationship between functional gastrointestinal disease and obesity has been debated. This review provides a comprehensive evaluation of the obesity-related digestive diseases, including pathophysiology, obesity-related risk, and medical and metabolic effects of weight reduction in obese subjects.
54Focus on gastroesophageal reflux disease in patients with cystic fibrosis.PubMed
Annarita Bongiovanni, Sara Manti, Giuseppe Fabio Parisi, et al.
World J Gastroenterol. 2020 Nov 7;26(41):6322-6334. doi: 10.3748/wjg.v26.i41.6322.
Gastroesophageal reflux disease (GERD) is a common gastrointestinal disorder in cystic fibrosis (CF), and based on various studies, its prevalence is elevated since childhood. There are several pathogenetic mechanisms on the basis of association between CF and GERD. However, there are no specific guidelines for GERD in CF patients, so diagnosis is based on guidelines performed on patients not affected by CF. The aim of this review is to provide the pathophysiology, diagnostic and therapeutic options, complications, and future directions in the management of GERD patients with CF.
55Multi-omic profiling of intraductal papillary neoplasms of the pancreas reveals distinct patterns and potential markers of progression.PubMed
Yuefan Wang, Tung-Shing M Lih, Jae W Lee, et al.
Cancer Cell. 2025 Nov 10;43(11):2156-2170.e6. doi: 10.1016/j.ccell.2025.08.001. Epub 2025 Aug 28.
To enable early detection of pancreatic cancer from precancerous lesions, we analyze proteins and glycoproteins from 64 intraductal papillary mucinous neoplasms (IPMNs), 55 cyst fluid samples, 104 pancreatic ductal adenocarcinomas (PDACs), and various types of normal samples using mass spectrometry. High-grade IPMNs show enrichment of glycosylation level and tumor progression pathways compared to low-grade lesions. High-grade IPMN associated proteins, such as PLOD3, IRS2, LGALS9, and Trop-2, are identified and validated using immunolabeling and laser microdissection. Some high-grade associated proteins are also detected in pancreatic cyst fluids, which allows us to link proteins and glycoproteins expressed in neoplastic cells to clinically accessible biospecimens. Altered glycosylation level of extracellular matrix (ECM) proteins is observed in IPMNs compared to normal ducts. Additionally, we identify a subset of IPMNs with PDAC-like features, including elevated expression of ECM proteins. These findings offer insight into progression-associated proteins and emphasize the diagnostic and therapeutic potential of these proteins in pancreatic tumors.
56Management 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.
57The impact of dietary fiber consumption on human health: An umbrella review of evidence from 17,155,277 individuals.PubMed
Nicola Veronese, Vincenza Gianfredi, Marco Solmi, et al.
Clin Nutr. 2025 Aug;51:325-333. doi: 10.1016/j.clnu.2025.06.021. Epub 2025 Jul 7.
BACKGROUND: Dietary fiber plays a crucial role in disease prevention through multiple protective mechanisms. While previous reviews have examined its health effects, recent advances necessitate an updated synthesis of the evidence. OBJECTIVES: This umbrella review systematically evaluates meta-analyses of observational studies to assess the strength and credibility of associations, and the quality of evidence linking dietary fiber intake to diverse health outcomes, providing a comprehensive assessment of these associations. METHODS: We updated our previous umbrella review by searching major databases (October 21, 2017-December 1, 2024) for meta-analyses on dietary fiber and health outcomes. Methodological quality was assessed using AMSTAR-2 (A Measurement Tool to Assess Systematic Reviews), and evidence credibility was classified based on predefined criteria, accounting for heterogeneity (I), small-study effects, and excess significance bias. RESULTS: Thirty-three meta-analyses covering 38 health outcomes and 17,155,277 individuals were included. Of these, 29 (76 %) reported significant inverse associations (p < 0.05) between higher fiber intake and disease risk. Convincing evidence (Class I) was identified for cardiovascular disease (CVD) mortality, pancreatic cancer, and diverticular disease. Highly suggestive evidence (Class II) supported associations with all-cause mortality, CVD, coronary heart disease and ovarian cancer. Suggestive evidence (Class III) was observed for 16 outcomes, while six outcomes (16 %) exhibited weak evidence (Class IV). Quality assessment indicated that six meta-analyses were of high methodological quality, while others had some methodological limitations. CONCLUSIONS: Higher dietary fiber intake is associated with lower risk of multiple chronic diseases, particularly CVD mortality, pancreatic cancer, and diverticular disease. Despite these benefits, intake remains below recommended levels worldwide. Public health strategies should promote fiber-rich diets, and future research should further elucidate the role of specific fiber types in disease prevention. SYSTEMATIC REVIEW REGISTRATION: https://osf.io/37tyc/.
58Examining the dietary contributions of lipids to pancreatic cancer burden (1990-2021): incidence trends and future projections.PubMed
Kexin Jiang, Zhirong Zhao, Mu Yuan, et al.
Lipids Health Dis. 2025 Feb 21;24(1):62. doi: 10.1186/s12944-025-02468-y.
BACKGROUND: Pancreatic cancer (PC) ranks sixth globally among cancer deaths, imposing a significant burden on healthcare systems worldwide. Although diet is known to be a major risk factor, Although diet is a well-established risk factor for PC, the precise dietary components linked to the disease remain inconclusive, with studies showing varying results across different populations and regions. This study addresses this gap through a comprehensive analysis of PC incidence trends from 1990 to 2021, with a specific focus on associations with age, dietary patterns, and socio-demographic determinants. METHODS: The data utilized in this study were obtained from the 2021 Global Burden of Disease (GBD) results database, updated on May 16, 2024. Unlike traditional single-variable correlation analyses, a Bayesian generalized linear model was applied to assess the association between food intake and disease incidence during the period 1990-2021. To account for variations related to year and region, these variables were incorporated as covariates in the model, allowing for a more nuanced and comprehensive analysis of the background factors. Finally, the "BAPC" package was employed to project age-standardized incidence rates of PC through the year 2051. RESULTS: The global incidence of PC increased from 3.90 per 100,000 people (95% CI: 3.69, 4.08) in 1990 to 6.44 per 100,000 (95% CI: 5.86, 6.93) in 2021. The analysis revealed significant associations between PC incidence and the intake of nuts, omega-3 fatty acids, polyunsaturated fatty acids (PUFA), trans fats, dietary sodium, and calcium. In typical countries, higher intake of nuts and PUFA was associated with a reduced incidence of PC, while trans fats were positively correlated with increased incidence. The age-standardized Bayesian Age-Period-Cohort (BAPC) prediction indicates that the incidence rates of PC will show a downward trend after 2021. CONCLUSIONS: From 1990 to 2021, the global incidence of PC exhibited a rapid upward trend, suggesting an increasing global healthcare burden. The findings of this study suggest that dietary lipid intake is significantly associated with PC incidence at a global level. This finding underscores the importance of dietary fat composition, particularly in the context of pancreatic cancer prevention, suggesting that individuals should pay attention to the types and sources of fats in their diets to mitigate disease risk.
59Nutrients and the Pancreas: An Epigenetic Perspective.PubMed
Andee Weisbeck, Rick J Jansen
Nutrients. 2017 Mar 15;9(3):283. doi: 10.3390/nu9030283.
Pancreatic cancer is the fourth most common cause of cancer-related deaths with a dismal average five-year survival rate of six percent. Substitutional progress has been made in understanding how pancreatic cancer develops and progresses. Evidence is mounting which demonstrates that diet and nutrition are key factors in carcinogenesis. In particular, diets low in folate and high in fruits, vegetables, red/processed meat, and saturated fat have been identified as pancreatic cancer risk factors with a proposed mechanism involving epigenetic modifications or gene regulation. We review the current literature assessing the correlation between diet, epigenetics, and pancreatic cancer.
60Is dietary fat, vitamin D, or folate associated with pancreatic cancer?PubMed
G V Sanchez, S J Weinstein, R Z Stolzenberg-Solomon
Mol Carcinog. 2012 Jan;51(1):119-27. doi: 10.1002/mc.20833.
Although potentially modifiable risk factors for pancreatic cancer include smoking, obesity, and diabetes, less is known about the extent to which diet affects cancer risk. Recent studies have demonstrated some consistency for dietary fat being associated with elevated pancreatic cancer risk, particularly from animal sources. However, less is known about which fatty acids pose the greatest risk. Vitamin D, due to its endogenous production following UV-B exposure, is a unique risk factor in that researchers have created several methods to assess its exposure in humans. Studies that measured vitamin D exposure differently have shown inconsistent results. Dietary studies suggest protective associations, whereas studies of circulating 25-hydroxyvitamin D status show null or positive associations with low or very high concentrations, respectively. Several, but not all epidemiologic studies provide evidence of an inverse relationship between total and/or dietary folate and risk of pancreatic cancer. Protective associations for circulating folate are more often observed among populations with inadequate status. This article reviews the current epidemiological and experimental evidence investigating the relationship of dietary fat, vitamin D, and folate with pancreatic cancer. Additionally the mechanisms by which these risk factors may contribute to cancer, the methodological challenges involved with assessing risk, and other obstacles encountered when ascertaining the magnitude and direction of these three exposures are discussed.
61What Dietary Patterns and Nutrients are Associated with Pancreatic Cancer? Literature Review.PubMed
Mohammed O Ibrahim, Haya Abuhijleh, Reema Tayyem
Cancer Manag Res. 2023 Jan 6;15:17-30. doi: 10.2147/CMAR.S390228. eCollection 2023.
This narrative review summarizes the main findings of observational studies (case-control and cohort) as well as systematic reviews and meta-analyses on the role of nutrients and dietary patterns on pancreatic cancer (PC) risk and elucidates possible mechanisms for the association between nutrients or specific food components and the risk of PC. A literature search of MEDLINE (PubMed), Google Scholar, ScienceDirect, and Scopus was performed. An extensive search of related articles published in the English language from 1985 to 2022 was carried out. Our search included macro- and micronutrient intake as well as dietary patterns associated with PC. In conclusion, the consumption of a diet high in nutrients such as sugar, fats, and red and processed meats can increase the risk of PC. Conversely, a high dietary intake of fresh fruit and vegetables and their associated nutrients like fiber, antioxidants, and polyphenols may prevent PC. Dietary patterns loaded with red and processed meats were also linked to an increased risk of PC, whereas dietary patterns rich in plant-based foods like vegetables, fruits, whole grains, and legumes were associated with a reduced risk of PC. Dietary fiber, fat-soluble vitamins, water-soluble vitamins, and minerals might also play a protective role against PC.
62Inflammatory potential of diet and pancreatic cancer risk in the EPIC study.PubMed
Valerie Cayssials, Genevieve Buckland, Marta Crous-Bou, et al.
Eur J Nutr. 2022 Aug;61(5):2313-2320. doi: 10.1007/s00394-022-02809-y. Epub 2022 Jan 29.
PURPOSE: There is existing evidence on the potential role of chronic inflammation in the pathogenesis of pancreatic cancer (PC) and on how risk may be modulated by dietary factors. Pro-inflammatory diets are suggested to be associated with increased risk of PC but, so far, evidence remains not conclusive. We examined the association between the dietary inflammatory potential and PC risk within the European Prospective Investigation into Cancer and Nutrition (EPIC) study, which includes 450,112 participants. METHODS: After a 14-year follow-up, a total of 1239 incident PC cases were included in this study. The inflammatory potential of the diet was estimated using an Inflammatory Score of the Diet (ISD). Hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between the ISD and PC were estimated using multivariable Cox regression models, adjusted for known risk factors for PC. RESULTS: Participants with higher ISDs had a higher risk of developing PCs. In the fully adjusted multivariate model, the risk of PC increased by 11% (HR 1.11, 95% CI 1.02-1.22) for 1 point each standard deviation increase in the ISD score. Neither obesity nor any other known risk factor for PC showed statistically significant interactions. CONCLUSION: To the best of our knowledge, this is the first prospective study reporting a positive relationship between the inflammatory potential of diet and PC. Since early diagnosis and treatment of pancreatic cancer might be challenging, prevention remains the major hope for reducing the burden of this disease.
63Exercise-induced engagement of the IL-15/IL-15Rα axis promotes anti-tumor immunity in pancreatic cancer.PubMed
Emma Kurz, Carolina Alcantara Hirsch, Tanner Dalton, et al.
Cancer Cell. 2022 Jul 11;40(7):720-737.e5. doi: 10.1016/j.ccell.2022.05.006. Epub 2022 Jun 2.
Aerobic exercise is associated with decreased cancer incidence and cancer-associated mortality. However, little is known about the effects of exercise on pancreatic ductal adenocarcinoma (PDA), a disease for which current therapeutic options are limited. Herein, we show that aerobic exercise reduces PDA tumor growth, by modulating systemic and intra-tumoral immunity. Mechanistically, exercise promotes immune mobilization and accumulation of tumor-infiltrating IL15Rα CD8 T cells, which are responsible for the tumor-protective effects. In clinical samples, an exercise-dependent increase of intra-tumoral CD8 T cells is also observed. Underscoring the translational potential of the interleukin (IL)-15/IL-15Rα axis, IL-15 super-agonist (NIZ985) treatment attenuates tumor growth, prolongs survival, and enhances sensitivity to chemotherapy. Finally, exercise or NIZ985 both sensitize pancreatic tumors to αPD-1, with improved anti-tumor and survival benefits. Collectively, our findings highlight the therapeutic potential of an exercise-oncology axis and identify IL-15 activation as a promising treatment strategy for this deadly disease.
64Brown-fat-mediated tumour suppression by cold-altered global metabolism.PubMed
Takahiro Seki, Yunlong Yang, Xiaoting Sun, et al.
Nature. 2022 Aug;608(7922):421-428. doi: 10.1038/s41586-022-05030-3. Epub 2022 Aug 3.
Glucose uptake is essential for cancer glycolysis and is involved in non-shivering thermogenesis of adipose tissues. Most cancers use glycolysis to harness energy for their infinite growth, invasion and metastasis. Activation of thermogenic metabolism in brown adipose tissue (BAT) by cold and drugs instigates blood glucose uptake in adipocytes. However, the functional effects of the global metabolic changes associated with BAT activation on tumour growth are unclear. Here we show that exposure of tumour-bearing mice to cold conditions markedly inhibits the growth of various types of solid tumours, including clinically untreatable cancers such as pancreatic cancers. Mechanistically, cold-induced BAT activation substantially decreases blood glucose and impedes the glycolysis-based metabolism in cancer cells. The removal of BAT and feeding on a high-glucose diet under cold exposure restore tumour growth, and genetic deletion of Ucp1-the key mediator for BAT-thermogenesis-ablates the cold-triggered anticancer effect. In a pilot human study, mild cold exposure activates a substantial amount of BAT in both healthy humans and a patient with cancer with mitigated glucose uptake in the tumour tissue. These findings provide a previously undescribed concept and paradigm for cancer therapy that uses a simple and effective approach. We anticipate that cold exposure and activation of BAT through any other approach, such as drugs and devices either alone or in combination with other anticancer therapeutics, will provide a general approach for the effective treatment of various cancers.
65DNA methylation-based biomarkers of aging were slowed down in a two-year diet and physical activity intervention trial: the DAMA study.PubMed
Giovanni Fiorito, Saverio Caini, Domenico Palli, et al.
Aging Cell. 2021 Oct;20(10):e13439. doi: 10.1111/acel.13439. Epub 2021 Sep 18.
Several biomarkers of healthy aging have been proposed in recent years, including the epigenetic clocks, based on DNA methylation (DNAm) measures, which are getting increasingly accurate in predicting the individual biological age. The recently developed "next-generation clock" DNAmGrimAge outperforms "first-generation clocks" in predicting longevity and the onset of many age-related pathological conditions and diseases. Additionally, the total number of stochastic epigenetic mutations (SEMs), also known as the epigenetic mutation load (EML), has been proposed as a complementary DNAm-based biomarker of healthy aging. A fundamental biological property of epigenetic, and in particular DNAm modifications, is the potential reversibility of the effect, raising questions about the possible slowdown of epigenetic aging by modifying one's lifestyle. Here, we investigated whether improved dietary habits and increased physical activity have favorable effects on aging biomarkers in healthy postmenopausal women. The study sample consists of 219 women from the "Diet, Physical Activity, and Mammography" (DAMA) study: a 24-month randomized factorial intervention trial with DNAm measured twice, at baseline and the end of the trial. Women who participated in the dietary intervention had a significant slowing of the DNAmGrimAge clock, whereas increasing physical activity led to a significant reduction of SEMs in crucial cancer-related pathways. Our study provides strong evidence of a causal association between lifestyle modification and slowing down of DNAm aging biomarkers. This randomized trial elucidates the causal relationship between lifestyle and healthy aging-related epigenetic mechanisms.
66Healthy lifestyle and the risk of pancreatic cancer in the EPIC study.PubMed
Sabine Naudin, Vivian Viallon, Dana Hashim, et al.
Eur J Epidemiol. 2020 Oct;35(10):975-986. doi: 10.1007/s10654-019-00559-6. Epub 2019 Sep 28.
Pancreatic cancer (PC) is a highly fatal cancer with currently limited opportunities for early detection and effective treatment. Modifiable factors may offer pathways for primary prevention. In this study, the association between the Healthy Lifestyle Index (HLI) and PC risk was examined. Within the European Prospective Investigation into Cancer and Nutrition cohort, 1113 incident PC (57% women) were diagnosed from 400,577 participants followed-up for 15 years (median). HLI scores combined smoking, alcohol intake, dietary exposure, physical activity and, in turn, overall and central adiposity using BMI (HLI) and waist-to-hip ratio (WHR, HLI), respectively. High values of HLI indicate adherence to healthy behaviors. Cox proportional hazard models with age as primary time variable were used to estimate PC hazard ratios (HR) and 95% confidence intervals (CI). Sensitivity analyses were performed by excluding, in turn, each factor from the HLI score. Population attributable fractions (PAF) were estimated assuming participants' shift to healthier lifestyles. The HRs for a one-standard deviation increment of HLI and HLI were 0.84 (95% CI: 0.79, 0.89; p = 4.3e-09) and 0.77 (0.72, 0.82; p = 1.7e-15), respectively. Exclusions of smoking from HLI resulted in HRs of 0.88 (0.82, 0.94; p = 4.9e-04). The overall PAF estimate was 19% (95% CI: 11%, 26%), and 14% (6%, 21%) when smoking was removed from the score. Adherence to a healthy lifestyle was inversely associated with PC risk, beyond the beneficial role of smoking avoidance. Public health measures targeting compliance with healthy lifestyles may have an impact on PC incidence.
67Composite Score of Healthy Lifestyle Factors and the Risk of Pancreatic Cancer in a Prospective Cohort Study.PubMed
Hung N Luu, Pedram Paragomi, Renwei Wang, et al.
Cancer Prev Res (Phila). 2022 Jan;15(1):29-36. doi: 10.1158/1940-6207.CAPR-21-0205. Epub 2021 Oct 12.
While the associations between individual lifestyle factors and risk of pancreatic cancer were studied extensively, their combined impact has not been examined. We evaluated the association of a composite score of healthy lifestyle factors, including body mass index, cigarette smoking, the Alternative Healthy Eating Index-2010 (AHEI-2010), sleep duration, and physical activity with pancreatic cancer risk in the Singapore Chinese Health Study, an ongoing prospective cohort study of 63,257 Chinese aged 45 to 74 years at enrollment in 1993 to 1998 with up to 25 years of follow up. Cox proportional hazard regression method was used to estimate HR and its 95% confidence interval (CI) with adjustment for multiple potential confounders. We identified 316 incident pancreatic cancer cases among the cohort participants after a mean 17 years of follow up. Individuals with higher composite scores representing healthier lifestyle were at significantly lower risk of pancreatic cancer. The multivariate-adjusted HRs (95% CIs) of pancreatic cancer incidence for the composite scores 2, 3, 4, 5, 6 to 7 were 0.60 (0.50-0.91), 0.48 (0.32-0.71), 0.45 (0.31-0.67), 0.41 (0.27-0.62), and 0.38 (0.24-0.62), respectively, compared with the scores 0 to 1 ( < 0.0001). The inverse association was more apparent among participants without diabetes history and was robust in men and women as well as in alcohol drinkers and nondrinkers. In summary, the association for pancreatic cancer risk was stronger for the aggregated than individual healthy lifestyle factors. These findings suggest that a more comprehensive lifestyle modification strategy would be more effective for prevention of pancreatic cancer than the change of a single lifestyle factor. PREVENTION RELEVANCE: In this large prospective Asian study, we calculated a composite score of healthy lifestyle factors, including body mass index, cigarette smoking, the Alternative Healthy Eating Index-2010 (AHEI-2010), sleep duration, and physical activity and found this composite score was associated with a significant reduction in pancreatic cancer risk, by as much as 62%. This finding suggests that public health programs emphasizing comprehensive lifestyle modification strategy would be more effective for prevention of pancreatic cancer than the change of a single lifestyle factor.
68Non-adherence to Mediterranean diet and synergy with lifestyle habits in the occurrence of breast cancer: a case-control study in Italy.PubMed
G La Torre, I De Carlo, C Sestili, et al.
Eur Rev Med Pharmacol Sci. 2021 Jul;25(13):4535-4539. doi: 10.26355/eurrev_202107_26246.
OBJECTIVE: The aim of this study was to assess the synergistic effect of non-adherence to the Mediterranean Diet (MD) and lifestyle habits on the occurrence of breast cancer (BC). PATIENTS AND METHODS: A case-control study was carried out from September 2018 to February 2019 at the Teaching Hospital "Umberto I" in Rome. A Food Frequency Questionnaire was used for assessing the level of adherence to MD, the IPAQ Questionnaire to measure physical activity, and AUDIT-C to estimate alcohol consumption. The possible interaction between risk factors was tested using the synergism index. RESULTS: A total of 94 cases and 88 controls were enrolled (median age 55.8 for cases and 57.9 for controls). The MD Score over 6 was associated with low odds of having breast cancer (OR = 0.29; 95% CI: 0.12-0.69). There is a clear indication for the additivity and synergism between non-adherence to MD and many risk factors on the occurrence of BC: current smoker (S = 2.02; 95% CI 0.62-8.07), physical inactivity (S = 2.14; 95% CI 0.71 2-8.28) and alcohol consumption (S = 3.02; 95% CI 0.91-12.95). CONCLUSIONS: Primary prevention of BC can benefit from intervention targeting nutritional and lifestyle factors that act synergistically.
69Pancreatic 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.
70Pancreatic cancer screening.PubMed
Chris M Lindquist, Frank H Miller, Nancy A Hammond, et al.
Abdom Radiol (NY). 2018 Feb;43(2):264-272. doi: 10.1007/s00261-017-1308-z.
PURPOSE: This article reviews the current evidence surrounding pancreatic cancer screening. The current targets of screening include identification of early pancreatic cancer, as well as the two most important precursor lesions; intraductal papillary mucinous neoplasm and high grade pancreatic intraepithelial neoplasia. Given the relatively low incidence of pancreatic adenocarcinoma in the general population, patients with elevated risk based on family history or an underlying genetic syndrome are felt to be the most appropriate patients to undergo screening. METHODS: An extensive review of the literature was performed and the major findings of the available literature regarding pancreatic screening are reviewed in detail. RESULTS: Several prospective trials have evaluated pancreatic cancer screening in high-risk groups. The results of those trials are summarized in this article. Current consensus guidelines and recommendations from the International Cancer of the Pancreas Screening Consortium Summit are also discussed. CONCLUSIONS: The exact benefit of pancreatic cancer screening remains unclear at this time, but emerging evidence suggests that there is a window of opportunity to detect precursor lesions and early pancreatic adenocarcinomas in high-risk patient populations. Better understanding of the pathway of carcinogenesis will hopefully improve our ability to detect early, resectable pancreatic carcinomas, and provide a mortality benefit to patients at significantly elevated risk of pancreatic adenocarcinoma.
71AGA Clinical Practice Update on Pancreas Cancer Screening in High-Risk Individuals: Expert Review.PubMed
Harry R Aslanian, Jeffrey H Lee, Marcia Irene Canto
Gastroenterology. 2020 Jul;159(1):358-362. doi: 10.1053/j.gastro.2020.03.088. Epub 2020 May 19.
DESCRIPTION: The purpose of this American Gastroenterological Association Institute Clinical Practice Update is to describe the indications for screening for pancreas cancer in high-risk individuals. METHODS: The evidence reviewed in this work is based on reports of pancreas cancer screening studies in high-risk individuals and expert opinion. BEST PRACTICE ADVICE 1: Pancreas cancer screening should be considered in patients determined to be at high risk, including first-degree relatives of patients with pancreas cancer with at least 2 affected genetically related relatives. BEST PRACTICE ADVICE 2: Pancreas cancer screening should be considered in patients with genetic syndromes associated with an increased risk of pancreas cancer, including all patients with Peutz-Jeghers syndrome, hereditary pancreatitis, patients with CDKN2A gene mutation, and patients with 1 or more first-degree relatives with pancreas cancer with Lynch syndrome, and mutations in BRCA1, BRCA2, PALB2, and ATM genes. BEST PRACTICE ADVICE 3: Genetic testing and counseling should be considered for familial pancreas cancer relatives who are eligible for surveillance. A positive germline mutation is associated with an increased risk of neoplastic progression and may also lead to screening for other relevant associated cancers. BEST PRACTICE ADVICE 4: Participation in a registry or referral to a pancreas Center of Excellence should be pursued when possible for high-risk patients undergoing pancreas cancer screening. BEST PRACTICE ADVICE 5: Clinicians should not screen average-risk individuals for pancreas cancer. BEST PRACTICE ADVICE 6: Pancreas cancer screening in high-risk individuals should begin at age 50 years, or 10 years younger than the initial age of familial onset. Screening should be initiated at age 40 years in CKDN2A and PRSS1 mutation carriers with hereditary pancreatitis and at age 35 years in the setting of Peutz-Jeghers syndrome. BEST PRACTICE ADVICE 7: Magnetic resonance imaging and endoscopic ultrasonography (EUS) should be used in combination as the preferred screening modalities in individuals undergoing pancreas cancer screening. BEST PRACTICE ADVICE 8: The target detectable pancreatic neoplasms are resectable stage I pancreatic ductal adenocarcinoma and high-risk precursor neoplasms, such as intraductal papillary mucinous neoplasms with high-grade dysplasia and some enlarged pancreatic intraepithelial neoplasias. BEST PRACTICE ADVICE 9: Screening intervals of 12 months should be considered when there are no concerning pancreas lesions, with shortened intervals and/or the performance of EUS in 6-12 months directed towards lesions determined to be low risk (by a multidisciplinary team). EUS evaluation should be performed within 3-6 months for indeterminate lesions and within 3 months for high-risk lesions, if surgical resection is not planned. New-onset diabetes in a high-risk individual should lead to additional diagnostic studies or change in surveillance interval. BEST PRACTICE ADVICE 10: Decisions regarding therapy directed towards abnormal findings detected during screening should be made by a dedicated multidisciplinary team together with the high-risk individual and their family. BEST PRACTICE ADVICE 11: Surgical resection should be performed at high-volume centers. BEST PRACTICE ADVICE 12: Clinicians should consider discontinuing pancreas cancer screening in high-risk individuals when they are more likely to die of non-pancreas cancer-related causes due to comorbidity and/or are not candidates for pancreas resection. BEST PRACTICE ADVICE 13: The limitations and potential risks of pancreas cancer screening should be discussed with patients before initiating a screening program.
72Familial Pancreatic Cancer.PubMed
Julia Benzel, Volker Fendrich
Oncol Res Treat. 2018;41(10):611-618. doi: 10.1159/000493473. Epub 2018 Sep 28.
Familial pancreatic cancer accounts for 10% of all patients with pancreatic cancer. Because the 5-year survival rate of pancreatic cancer is only 7%, screening programs for high-risk individuals are essential and might be advantageous. Pancreatic ductal adenocarcinoma mostly shows symptoms at an advanced state and treatment is not efficient enough to cure most patients. People with hereditary tumor syndromes or their affected relatives can also be included in such screening programs. Besides the collection of data to investigate the background of the disease, these screening programs aim to diagnose and treat precursor lesions so that more dangerous, invasive lesions are prevented. These precursor lesions can be pancreatic intraepithelial neoplasia, intraductal papillary mucinous neoplasm, and mucinous cystic neoplasm. This review summarizes the latest knowledge of pancreatic screening programs, shows the procedure of pancreatic cancer screening, and gives an overview of current guidelines.
73Diabetes and pancreatic cancer: Exploring the two-way traffic.PubMed
Ayan Roy, Jayaprakash Sahoo, Sadishkumar Kamalanathan, et al.
World J Gastroenterol. 2021 Aug 14;27(30):4939-4962. doi: 10.3748/wjg.v27.i30.4939.
Pancreatic cancer (PC) is often associated with a poor prognosis. Long-standing diabetes mellitus is considered as an important risk factor for its development. This risk can be modified by the use of certain antidiabetic medications. On the other hand, new-onset diabetes can signal towards an underlying PC in the elderly population. Recently, several attempts have been made to develop an effective clinical tool for PC screening using a combination of history of new-onset diabetes and several other clinical and biochemical markers. On the contrary, diabetes affects the survival after treatment for PC. We describe this intimate and complex two-way relationship of diabetes and PC in this review by exploring the underlying pathogenesis.
74Model to Determine Risk of Pancreatic Cancer in Patients With New-Onset Diabetes.PubMed
Ayush Sharma, Harika Kandlakunta, Sajan Jiv Singh Nagpal, et al.
Gastroenterology. 2018 Sep;155(3):730-739.e3. doi: 10.1053/j.gastro.2018.05.023. Epub 2018 Jun 11.
BACKGROUND & AIMS: Of patients with new-onset diabetes (NOD; based on glycemic status) older than 50 years, approximately 1% are diagnosed with pancreatic cancer (PC) within 3 years. We aimed to develop and validate a model to determine risk of PC in patients with NOD. METHODS: We retrospectively collected data from 4 independent and nonoverlapping cohorts of patients (N = 1,561) with NOD (based on glycemic status; data collected at date of diagnosis and 12 months previously) in the Rochester Epidemiology Project from January 1, 2000 through December 31, 2015 to create our model. The model weighed scores for 3 factors identified in the discovery cohort to be most strongly associated with PC (64 patients with PC and 192 with type 2 diabetes): change in weight, change in blood glucose, and age at onset of diabetes. We called our model Enriching New-Onset Diabetes for Pancreatic Cancer (ENDPAC). We validated the locked-down model and cutoff score in an independent population-based cohort of 1,096 patients with diabetes; of these, 9 patients (82%) had PC within 3 years of meeting the criteria for NOD. RESULTS: In the discovery cohort, the END-PAC model identified patients who developed PC within 3 years of diabetes onset (area under receiver operating characteristic curve 0.87); a score of at least 3 identified patients who developed PC with 80% sensitivity and specificity. In the validation cohort, a score of at least 3 identified 7 of 9 patients with PC (78%) with 85% specificity; the prevalence of PC in patients with a score of at least 3 (3.6%) was 4.4-fold greater than in patients with NOD. A high END-PAC score in patients who did not have PC (false positives) was often due to such factors as recent steroid use or different malignancy. An ENDPAC score no higher than 0 (in 49% of patients) meant that patients had an extremely low risk for PC. An END-PAC score of at least 3 identified 75% of patients in the discovery cohort more than 6 months before a diagnosis of PC. CONCLUSIONS: Based on change in weight, change in blood glucose, and age at onset of diabetes, we developed and validated a model to determine risk of PC in patients with NOD based on glycemic status (END-PAC model). An independent prospective study is needed to further validate this model, which could contribute to early detection of PC.
75An Integrated Multi-Omics Analysis Identifying Immune Subtypes of Pancreatic Cancer.PubMed
Yongcheng Su, Fen Wang, Ziyu Lei, et al.
Int J Mol Sci. 2023 Dec 21;25(1):142. doi: 10.3390/ijms25010142.
Limited studies have explored novel pancreatic cancer (PC) subtypes or prognostic biomarkers based on the altered activity of relevant signaling pathway gene sets. Here, we employed non-negative matrix factorization (NMF) to identify three immune subtypes of PC based on C7 immunologic signature gene set activity in PC and normal samples. Cluster 1, the immune-inflamed subtype, showed a higher response rate to immune checkpoint blockade (ICB) and had the lowest tumor immune dysfunction and exclusion (TIDE) scores. Cluster 2, the immune-excluded subtype, exhibited strong associations with stromal activation, characterized by elevated expression levels of transforming growth factor (TGF)-β, cell adhesion, extracellular matrix remodeling, and epithelial-to-mesenchymal transition (EMT) related genes. Cluster 3, the immune-desert subtype, displayed limited immune activity. For prognostic prediction, we developed an immune-related prognostic risk model (IRPM) based on four immune-related prognostic genes in pancreatic cancer, RHOF, CEP250, TSC1, and KIF20B. The IRPM demonstrated excellent prognostic efficacy and successful validation in an external cohort. Notably, the key gene in the prognostic model, RHOF, exerted significant influence on the proliferation, migration, and invasion of pancreatic cancer cells through in vitro experiments. Furthermore, we conducted a comprehensive analysis of somatic mutational landscapes and immune landscapes in PC patients with different IRPM risk scores. Our findings accurately stratified patients based on their immune microenvironment and predicted immunotherapy responses, offering valuable insights for clinicians in developing more targeted clinical strategies.
76Prediction of survival and recurrence in patients with pancreatic cancer by integrating multi-omics data.PubMed
Bin Baek, Hyunju Lee
Sci Rep. 2020 Nov 3;10(1):18951. doi: 10.1038/s41598-020-76025-1.
Predicting the prognosis of pancreatic cancer is important because of the very low survival rates of patients with this particular cancer. Although several studies have used microRNA and gene expression profiles and clinical data, as well as images of tissues and cells, to predict cancer survival and recurrence, the accuracies of these approaches in the prediction of high-risk pancreatic adenocarcinoma (PAAD) still need to be improved. Accordingly, in this study, we proposed two biological features based on multi-omics datasets to predict survival and recurrence among patients with PAAD. First, the clonal expansion of cancer cells with somatic mutations was used to predict prognosis. Using whole-exome sequencing data from 134 patients with PAAD from The Cancer Genome Atlas (TCGA), we found five candidate genes that were mutated in the early stages of tumorigenesis with high cellular prevalence (CP). CDKN2A, TP53, TTN, KCNJ18, and KRAS had the highest CP values among the patients with PAAD, and survival and recurrence rates were significantly different between the patients harboring mutations in these candidate genes and those harboring mutations in other genes (p = 2.39E-03, p = 8.47E-04, respectively). Second, we generated an autoencoder to integrate the RNA sequencing, microRNA sequencing, and DNA methylation data from 134 patients with PAAD from TCGA. The autoencoder robustly reduced the dimensions of these multi-omics data, and the K-means clustering method was then used to cluster the patients into two subgroups. The subgroups of patients had significant differences in survival and recurrence (p = 1.41E-03, p = 4.43E-04, respectively). Finally, we developed a prediction model for prognosis using these two biological features and clinical data. When support vector machines, random forest, logistic regression, and L2 regularized logistic regression were used as prediction models, logistic regression analysis generally revealed the best performance for both disease-free survival (DFS) and overall survival (OS) (accuracy [ACC] = 0.762 and area under the curve [AUC] = 0.795 for DFS; ACC = 0.776 and AUC = 0.769 for OS). Thus, we could classify patients with a high probability of recurrence and at a high risk of poor outcomes. Our study provides insights into new personalized therapies on the basis of mutation status and multi-omics data.
77Development of a 12-biomarkers-based prognostic model for pancreatic cancer using multi-omics integrated analysis.PubMed
Yanhui Jia, Meiyan Shen, Yan Zhou, et al.
Acta Biochim Pol. 2020 Dec 1;67(4):501-508. doi: 10.18388/abp.2020_5225.
Pancreatic cancer is one of the most malignant tumors of the digestive system, with insidious, rapid onset and high mortality. The 5-year survival rate is only 10%. Therefore, in-depth exploration of the potential mechanism affecting the prognosis of pancreatic cancer, and search for biomarkers that can effectively predict the prognosis of pancreatic cancer are of practical clinical importance. The mRNA sequencing data, miRNA sequencing data, methylation data and SNP data of pancreatic cancer patients available in The Cancer Genome Atlas (TCGA) were used for analysis to identify biomarkers that significantly affect the prognosis for the patients. Finally, a prognostic prediction model was developed using principal component analysis (PCA) method. The genes that significantly affected the prognosis of pancreatic cancer were as follows: 5 DmiRNAs (hsa-mir-1179, hsa-mir-1224, hsa-mir-1251, hsa-mir-129-1 and hsa-mir-129-2), 6 DmRNAsandDMsandMethyCor database entries (MAPK8IP2, CPE, DPP6, MSI1, IL20RB and S100A2), and FMN2 gene from differential expressed mRNAs and differential single-nucleotide polymorphism (DmRNAsandDSNPs) database. Prognostic index (PI)=∑iwi xi - 0.717716. A patient was predicted as high/low risk if the PI was larger/smaller than 0.034045. Our study resulted in a comprehensive prognostic model for pancreatic cancer patients based on multi-omics analysis, which could offer better guidance for the clinical management of patients with early-stage pancreatic cancer.
78Anoikis-Related Gene Signature for Prognostication of Pancreatic Adenocarcinoma: A Multi-Omics Exploration and Verification Study.PubMed
Jin Zhang, Xuesong Li, Yi Lu, et al.
Cancers (Basel). 2023 Jun 11;15(12):3146. doi: 10.3390/cancers15123146.
Anoikis, a form of apoptosis that occurs due to detachment of cells from the extracellular matrix, has been linked to the development of cancer in several studies. However, its role in pancreatic cancer remains incompletely understood. In this study, we utilized univariate Cox regression and LASSO regression analyses to establish a prognostic model for pancreatic adenocarcinoma based on anoikis-related genes in the TCGA database. Additionally, we performed univariate and multifactorial Cox analyses of protein expression results for TCGA pancreatic adenocarcinoma. We further explored the difference in immune infiltration between the high-risk and low-risk groups and verified the expression of the screened genes using quantitative real-time PCR (qRT-PCR). Our findings indicate that numerous anoikis-related genes are linked to pancreatic adenocarcinoma prognosis. We identified seven prognostic genes (MET, DYNLL2, CDK1, TNFSF10, PIP5K1C, MSLN, GKN1) and validated that their related proteins, such as EGFR and MMP2, have a significant impact on the prognosis of pancreatic adenocarcinoma. Based on clustering analyses of the seven prognostic genes, patients could be classified into three distinct categories, for which somatic mutations varied significantly across the groups. High-risk and low-risk groups also exhibited significant differences in immune infiltration. All genes were found to be highly expressed in pancreatic cancer cell lines (ASPC-1, CFPAC-1) as compared to a normal pancreatic cell line (HPDE). Based on the seven anoikis-related genes, we formulated a robust prognostic model with high predictive accuracy. We also identified the significant impact of KRAS, P53, and CDKN2A mutations on the prognosis of this fatal disease. Therefore, our study highlights the crucial role of anoikis in the development of the pancreatic adenocarcinoma tumor microenvironment.
79Multi-omics integration and machine learning uncover molecular basal-like subtype of pancreatic cancer and implicate A2ML1 in promoting tumor epithelial-mesenchymal transition.PubMed
Jiachen Ge, Jianping Cai, Gaolei Zhang, et al.
J Transl Med. 2025 Jul 4;23(1):741. doi: 10.1186/s12967-025-06711-z.
BACKGROUND: Pancreatic cancer (PC) represents a highly heterogeneous malignancy with poor prognosis, where precise molecular subtyping facilitates comprehensive understanding of disease progression. METHODS: Transcriptomic, methylation, and mutational data from 168 PC samples were integrated. The molecular subtypes were established and validated across 13 independent cohorts utilizing ten distinct classification methods. Prognostic genes were identified to construct predictive models through various machine learning approaches. Following the identification of A2ML1 as a key gene, its expression profile was detected using RT-qPCR, western blotting, and immunohistochemistry. We subsequently conducted functional experiments to elucidate the mechanism of A2ML1 in promoting PC progression. RESULTS: Through multi-omics integration, we classified PC into two molecular subtypes with distinct prognostic outcomes. Pathway enrichment analysis revealed subtype-specific characteristics, subsequently validated in external cohorts. Using 23 prognostic genes, we developed and validated a prognostic signature through 101 machine learning algorithms and their combinations, with ridge regression demonstrating optimal performance. This signature demonstrated superior accuracy compared to multiple published signatures. The risk scores showed significant correlations with drug sensitivity, clinical characteristics, and patient outcomes. We further validated that A2ML1 expression was significantly elevated in PC tissues compared to normal counterparts. A2ML1 promoted PC progression through downregulation of LZTR1 expression and subsequent activation of the KRAS/MAPK pathway, ultimately driving epithelial-mesenchymal transition (EMT). CONCLUSION: In this study, we uncovered molecular basal-like subtype of PC and developed a prognostic signature using ridge regression. A2ML1 was identified as a crucial regulator of EMT in PC progression.
81Prognostication and response assessment in liver and pancreatic tumors: The new imaging.PubMed
Riccardo De Robertis, Paolo Tinazzi Martini, Emanuele Demozzi, et al.
World J Gastroenterol. 2015 Jun 14;21(22):6794-808. doi: 10.3748/wjg.v21.i22.6794.
Diffusion-weighted imaging (DWI), dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and perfusion computed tomography (CT) are technical improvements of morphologic imaging that can evaluate functional properties of hepato-bilio-pancreatic tumors during conventional MRI or CT examinations. Nevertheless, the term "functional imaging" is commonly used to describe molecular imaging techniques, as positron emission tomography (PET) CT/MRI, which still represent the most widely used methods for the evaluation of functional properties of solid neoplasms; unlike PET or single photon emission computed tomography, functional imaging techniques applied to conventional MRI/CT examinations do not require the administration of radiolabeled drugs or specific equipments. Moreover, DWI and DCE-MRI can be performed during the same session, thus providing a comprehensive "one-step" morphological and functional evaluation of hepato-bilio-pancreatic tumors. Literature data reveal that functional imaging techniques could be proposed for the evaluation of these tumors before treatment, given that they may improve staging and predict prognosis or clinical outcome. Microscopic changes within neoplastic tissues induced by treatments can be detected and quantified with functional imaging, therefore these techniques could be used also for post-treatment assessment, even at an early stage. The aim of this editorial is to describe possible applications of new functional imaging techniques apart from molecular imaging to hepatic and pancreatic tumors through a review of up-to-date literature data, with a particular emphasis on pathological correlations, prognostic stratification and post-treatment monitoring.
82Endosonography and endoscopic magnetic resonance imaging.PubMed
S Nakazawa, K Inui
Baillieres Best Pract Res Clin Gastroenterol. 1999 Apr;13(1):21-31. doi: 10.1053/bega.1999.0005.
Endosonography is an important modality for the diagnosis and staging of oesophageal, gastric, colorectal and pancreatobiliary malignancy. It is also recognized as a reliable method for the evaluation of submucosal tumours of the gastrointestinal tract, for differentiating benign lesions from giant gastric folds, and for the localization of pancreatic endocrine tumours. The latest development, that of endosonographic fine-needle aspiration, provides for the cytological diagnosis of gastrointestinal tumours. This new technique may also be used for endoscopic therapy. High-frequency probes can be used to make a more accurate diagnosis of superficial carcinoma of the gastrointestinal tract, for three-dimensional imaging of gastrointestinal tumours and for intraductal ultrasonography of the bile duct and pancreatic duct. Endoscopic magnetic resonance imaging provides information not obtainable with endosonography or other modalities. It has high potential in the diagnosis and staging of gastrointestinal and pancreatobiliary tumours.
83Imaging Tests for the Diagnosis and Staging of Pancreatic Adenocarcinoma: A Meta-Analysis.PubMed
Jonathan R Treadwell, Hanna M Zafar, Matthew D Mitchell, et al.
Pancreas. 2016 Jul;45(6):789-95. doi: 10.1097/MPA.0000000000000524.
Imaging tests are central to the diagnosis and staging of pancreatic adenocarcinoma. We performed a systematic review and meta-analysis of the pertinent evidence on 5 imaging tests (computed tomography (CT), magnetic resonance imaging, CT angiography, endoscopic ultrasound with fine-needle aspiration, and combined positron emission tomography with CT). Searches of several databases up to March 1, 2014, yielded 9776 articles, and 24 provided comparative effectiveness of 2 or more imaging tests. Multiple reviewers applied study inclusion criteria, extracted data from each study, rated the risk of bias, and graded the strength of evidence. Data included accuracy of diagnosis and resectability in primary untreated pancreatic adenocarcinoma, including tumor stage, nodal stage, metastases, and vascular involvement. Where possible, study results were combined using bivariate meta-analysis. Studies were at low or moderate risk of bias. Most comparisons between imaging tests were insufficient to permit conclusions, due to imprecision or inconsistency among study results. However, moderate-grade evidence revealed that CT and magnetic resonance imaging had similar sensitivities and specificities for both diagnosis and vascular involvement. Other conclusions were based on low-grade evidence. In general, more direct evidence is needed to inform decisions about imaging tests for pancreatic adenocarcinoma.
84MMP9 and pancreatic cancer.PubMed
Veronika Roskovicova, Jana Katuchova, Ivana Vecurkovska, et al.
Bratisl Lek Listy. 2024;125(11):724-727. doi: 10.4149/BLL_2024_110.
BACKGROUND: Pancreatic carcinoma is one of the most severe oncological diseases of the gastrointestinal tract. At the time of diagnosis, up to 28% of patients have metastatic liver damage, and only 5% of patients survive five years. Scientific research focuses on non-invasive markers that could help screen for the disease and identify patients more quickly. Potential biomarkers also include matrix metalloproteinases, which play a role in oncogenesis. MATERIAL AND METHODS: We prospectively followed 46 patients with pancreatic cancer and benign pancreatic diseases from September 2022 to March 2023. We determined the level of MMP9 in serum and tissue biopsied during surgeries. RESULT: As a result, MMP9 levels were elevated from the T2 stage. The correlation between disease stage and MMP9 level was not confirmed in lower stages, possibly due to the small group of patients. CONCLUSION: MMP9 seems suitable for detecting late stages of pancreatic cancer, possibly for secondary prevention. We could not confirm a correlation between MMP9 levels and the initial stages of the disease (Tab. 1, Fig. 3, Ref. 21). Text in PDF www.elis.sk Keywords: pancreatic cancer, MMP9, marker, non-invasive, screening.
85Proteomic analysis identifies MMP-9, DJ-1 and A1BG as overexpressed proteins in pancreatic juice from pancreatic ductal adenocarcinoma patients.PubMed
Mei Tian, Ya-Zhou Cui, Guan-Hua Song, et al.
BMC Cancer. 2008 Aug 16;8:241. doi: 10.1186/1471-2407-8-241.
BACKGROUND: There is an urgent need to discover more sensitive and specific biomarkers to improve early diagnosis and screen high-risk patients for pancreatic ductal adenocarcinoma (PDAC). Pancreatic juice is an ideal specimen for PDAC biomarkers discovery, because it is an exceptionally rich source of proteins released from pancreatic cancer cells. METHODS: To identify novel potential biomarkers for PDAC from pancreatic juice, we carried out difference gel electrophoresis (DIGE) and tandem mass spectrometry (MS/MS) to compare the pancreatic juice profiling from 9 PDAC patients and 9 cancer-free controls. Of the identified differently expressed proteins, three up-regulated proteins in pancreatic cancer juice, matrix metalloproteinase-9 (MMP-9), oncogene DJ1 (DJ-1) and alpha-1B-glycoprotein precursor (A1BG), were selected for validation by Western blot and immunohistochemistry. Serum MMP-9 levels were also detected by enzyme linked immunosorbent assay (ELISA). RESULTS: Fourteen proteins were up-regulated and ten proteins were down-regulated in cancerous pancreatic juice compared with cancer-free controls. Increased MMP-9, DJ-1 and A1BG expression in cancerous pancreatic juice were confirmed by Western blot. Immunohistochemical study showed MMP-9, DJ-1 and A1BG positively expressed in 82.4%, 72.5% and 86.3% of pancreatic cancer tissues, significantly higher than that in normal pancreas tissues. Up-regulation of DJ-1 was associated with better differentiation (p < 0.05). Serum MMP-9 levels were significantly higher in PDAC (255.14 ng/ml) than those in chronic pancreatitis (210.22 ng/ml, p = 0.009) and healthy control (203.77 ng/ml, p = 0.027). CONCLUSION: The present proteome analysis revealed MMP-9, DJ-1 and A1BG proteins as elevated in pancreatic juice from PDAC, which suggest their further utility in PDAC diagnosis and screening. This is the first time A1BG was identified as a potential biomarker in pancreatic cancer associated samples. The measurement of serum MMP-9 might be clinically useful for PDAC diagnosis.
86Expression and Prognostic Value of Small Mothers Against Decapentaplegic 7, Matrix Metalloproteinase 2, and Matrix Metalloproteinase 9 in Resectable Pancreatic Ductal Adenocarcinoma.PubMed
Li Zhou, Jun Lu, Zhi-Yong Liang, et al.
Pancreas. 2021 Sep 1;50(8):1195-1201. doi: 10.1097/MPA.0000000000001892.
OBJECTIVE: Thus far, expression, clinicopathologic, and prognostic implication of small mothers against decapentaplegic 7 (Smad7), matrix metalloproteinase 2 (MMP2), and matrix metalloproteinase 9 (MMP9) in pancreatic ductal adenocarcinoma (PDAC) were rarely investigated or controversial. METHODS: Expression of Smad7, MMP2, and MMP9 was detected using immunohistochemistry in tissue microarrays based on 322 patients with curatively resected PDAC. Their expression pattern, clinicopathologic, and prognostic relevance were further evaluated. RESULTS: Smad7 expression was found to be lower in tumor than in adjacent nontumor tissues, whereas tumoral MMP2 and MMP9 staining scores were much higher than in adjacent nontumor ones. Furthermore, Smad7 was negatively associated with serum carbohydrate antigen 19-9 level. Univariate survival analyses showed that patients with high Smad7 tumors had significantly better disease-specific survival (P = 0.0007), whereas MMP2 and MMP9 predicted poor disease-specific survival (P = 0.0211 and 0.0404). In multivariate Cox regression test, Smad7 was an independent prognostic indicator (P = 0.021). In addition, these 3 proteins were also prognostic in many subgroups. CONCLUSIONS: Smad7 and MMP2/9 significantly predict good or poor prognosis in resectable PDAC, respectively. Therefore, the genes might serve as a tool or targets for molecular therapy in PDAC.
87TNM staging for GIT cancers is correlated with the level of MMPs and TGF-β1.PubMed
Nahla E El-Ashmawy, Naglaa F Khedr, Mohamed G Mansour, et al.
Clin Exp Med. 2020 Nov;20(4):545-555. doi: 10.1007/s10238-020-00651-2. Epub 2020 Aug 8.
Gastrointestinal (GIT) cancers represent the third common cancers worldwide, characterized by rapid progression and higher mortality rate. Matrix metalloproteinases (MMPs) play an important role in cancer metastases. The present study was conducted to estimate and evaluate the role of MMP-7, -9, -10 and -12 and TGF β1 along with conventional biomarkers (CEA and CA19-9) in gastric (GC), pancreatic (PC) and colorectal cancer (CRC) staging system according to tumor size (T), included lymph node (N) and metastasis (M). Seventy-five patients were divided into GC group (n = 25), PC group (n = 25), CRC group (n = 25) and twenty-five healthy subjects (control group). Serum levels of MMP-7, -10 and -12 were assayed simultaneously using luminex multiplex technique. Also, MMP-9, TGF-β1, CA19-9 and CEA were determined by ELISA. MMP-7,-9,-10, -12, TGF-β1 and CEA levels were significantly (p < 0.001) higher in GIT cancer groups compared with control. CA19-9 was significantly (p < 0.001) higher in PC and CRC groups compared with control. MMP-9 was positively correlated with TNM staging in PC patients. MMP-12 was negatively correlated with T in PC and positively correlated with M in CRC group. CA 19-9 was positively correlated with M grade in CRC. Depending on the estimated cutoff values of area under receiver curve; CA19-9 and MMP-7 were excellent diagnostic markers in PC, CEA and MMP-7 were excellent in CRC, and MMP-7 and MMP-9 were excellent in GC. Our findings indicated the clinical utility of MMPs in diagnosis and TNM staging of GIT cancers along with CEA and CA19-9.
88Novel blood biomarkers of pancreatic cancer-associated diabetes mellitus identified by peripheral blood-based gene expression profiles.PubMed
Hai Huang, Xin Dong, Mu Xing Kang, et al.
Am J Gastroenterol. 2010 Jul;105(7):1661-9. doi: 10.1038/ajg.2010.32. Epub 2010 Jun 22.
OBJECTIVES: The prognosis of pancreatic cancer is still very poor, and the ability to detect pancreatic cancer in high-risk groups at an early stage is therefore essential for improving its long-term survival. The purpose of this study was to explore specific biomarkers that can differentiate pancreatic cancer-associated diabetes from type 2 diabetes, for the early detection of pancreatic cancer. METHODS: From January 2006 to July 2008, 102 peripheral blood samples were collected from 25 patients diagnosed with pancreatic cancer and diabetes, 27 patients with pancreatic cancer without diabetes, 25 patients with diabetes mellitus >5 years, and 25 healthy controls. Thirty-two samples were used in microarray experiments to find differentially expressed genes specific for pancreatic cancer-associated diabetes. The results were further validated by quantitative real-time PCR for 101 blood samples. Protein expression of selected genes in serum and tissues was also detected. RESULTS: Using microarray analysis, we found 58 genes to be unique in patients with pancreatic cancer-associated diabetes, including 23 upregulated genes and 35 downregulated genes. Eleven upregulated genes were further validated by RT-PCR, and two of these genes-vanin-1 (VNN1) and matrix metalloproteinase 9 (MMP9)-were selected for logistic regression analysis. The combination of VNN1 and MMP9 showed the best discrimination of pancreatic cancer-associated diabetes from type 2 diabetes. The protein expression of MMP9 and VNN1 was in accordance with the gene expression. CONCLUSIONS: Our results indicate that the combination of VNN1 and MMP9 may be used as a novel blood biomarker panel for the discrimination of pancreatic cancer-associated diabetes from type 2 diabetes.
89Identification of potential biomarkers for digestive system cancers from serum-derived extracellular vesicle RNA.PubMed
Xuan Zhang, Di Xia, Rui-Xian Wang, et al.
Clin Chim Acta. 2022 Jun 1;531:36-47. doi: 10.1016/j.cca.2022.03.009. Epub 2022 Mar 12.
BACKGROUND: Poor prognosis of digestive system cancers is mainly owing to lack of accurate and timely diagnosis. The exploration of novel tumor biomarkers from extracellular vesicle (EV) might be helpful to clinical diagnosis for digestive system cancers. METHODS: Several public databases were first used for a preliminary screening of candidate genes. The RNA levels of these candidate genes were then detected in cancer cell lines and the patients serum-derived EVs by PCR Array or digital PCR, respectively. RESULTS: We found that 4 EV-RNAs, ANLN, ITGA6, KRT18, and MMP9, had a lower level in gastrointestinal cancer patients than in benign gastrointestinal diseases patients and healthy controls, while 3 EV-RNAs, ANLN, ITGA6, and KRT18, had a lower level in pancreatic cancer patients than in benign pancreatic diseases patients or healthy individuals. And EV-RNA of MMP9 had a relatively higher level in advanced pancreatic cancer patients than in early-stage patients. Moreover, ROC analysis demonstrated that the determination of the above EV-RNAs could increase the ability of traditional tumor biomarkers to distinguish benign and malignant diseases. CONCLUSIONS: The serum-derived EV-RNAs of ANLN, ITGA6, KRT18, and MMP9 could be served as novel, non-invasive biomarkers for digestive system cancers.
90The role of novel biomarkers in the early diagnosis of pancreatic cancer: A systematic review and meta-analysis.PubMed
Zeyi Zheng, Ziyu Lu, Fei Yan, et al.
PLoS One. 2025 May 23;20(5):e0322720. doi: 10.1371/journal.pone.0322720. eCollection 2025.
BACKGROUND: Early detection of pancreatic cancer is essential for improving survival rates. However, noninvasive diagnostic methods are lacking. Novel biomarkers, detectable through liquid biopsy, such as circulating tumor DNA (ctDNA), microRNAs (miRNAs), protein markers, and metabolites, hold promise for early diagnosis. METHODS: A systematic search of PubMed, Embase, Web of Science, and the Cochrane Library was conducted for studies published from January 2014 to May 2024. Studies were included if they evaluated novel biomarkers for early pancreatic cancer detection, reported diagnostic performance metrics (sensitivity, specificity), and had a QUADAS-2 score of ≥3. Data on study characteristics, patient demographics, biomarker types, and diagnostic performance were extracted following PRISMA guidelines. A bivariate random-effects model was used to calculate pooled sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), and diagnostic odds ratio (DOR). The area under the summary receiver operating characteristic (SROC) curve assessed overall diagnostic accuracy. The primary outcome was the diagnostic accuracy (sensitivity and specificity) of novel biomarkers in detecting early-stage pancreatic cancer. RESULTS: A total of 43 studies involving 19,326 participants were included, with 2,749 patients having stage I or II pancreatic cancer. The pooled sensitivities and specificities were as follows:. miRNA Biomarkers: Sensitivity 0.88 (95% CI 0.79-0.93), Specificity 0.91 (95% CI 0.82-0.95), DOR 72.68 (95% CI 26.64-198.24), AUC 0.95. Protein Biomarkers: Sensitivity 0.79 (95% CI 0.70-0.86), Specificity 0.88 (95% CI 0.82-0.93), DOR 27.74 (95% CI 14.32-53.76), AUC 0.90. Metabolite Biomarkers: Sensitivity 0.84 (95% CI 0.73-0.92), Specificity 0.85 (95% CI 0.81-0.88), DOR 31.76 (95% CI 12.38-81.48), AUC 0.90. ctDNA Biomarkers: Sensitivity 0.65 (95% CI 0.48-0.81), Specificity 0.94 (95% CI 0.88-0.97), DOR 27.73 (95% CI 12.91-59.55), AUC 0.92. Subgroup analyses showed combining biomarkers with CA19-9 improved diagnostic accuracy. Sensitivity analyses confirmed the robustness of the findings. CONCLUSIONS: Novel biomarkers, particularly miRNAs and protein markers, demonstrate high diagnostic accuracy for early pancreatic cancer detection and have potential for clinical application in improving early diagnosis and patient outcomes. SYSTEMATIC REVIEW REGISTRATION: https://www.crd.york.ac.uk/prospero/, Identifier: PROSPERO (CRD42024553633).
91Liquid biopsies in pancreatic cancer.PubMed
Nabiollah Kamyabi, Vincent Bernard, Anirban Maitra
Expert Rev Anticancer Ther. 2019 Oct;19(10):869-878. doi: 10.1080/14737140.2019.1670063. Epub 2019 Sep 26.
: Pancreatic ductal adenocarcinoma (PDAC) is a disease of high lethality. Invasive tissue biopsies of primary or metastatic lesions remain the gold standard for diagnosis, but repeated sampling is infeasible. Noninvasive liquid biopsies offer new opportunities for early diagnosis for high-risk cohorts, and for the longitudinal analysis of tumor evolution and progression in patients on therapy. Liquid biopsies can capture tumor-associated components, such as circulating tumor DNA (ctDNA), extracellular vesicles (EVs), and circulating tumor cells (CTCs), each of which provides genomic and molecular information about the underlying PDAC that can potentially inform clinical decisions. : Here, we reviewed current knowledge and recent technological advances regarding liquid biopsy in PDAC and mention the pitfalls and benefits in each methodology. We also discuss clinical correlative studies for diagnosis and prognosis in PDAC. :In pancreatic cancer where tissue samples are limited and repeated tissue biopsies are mostly invasive and infeasible, liquid biopsies opened a new window for tumor diagnosis, molecular stratification, and treatment monitoring. While none of the isolation and analysis methods have gained widespread clinical acceptance, it is imperative that the advantages and limitations of each platform for isolation and analysis of tumor associated components are taken into consideration.
92Circulating Tumor Cells and Circulating Tumor DNA Provide New Insights into Pancreatic Cancer.PubMed
Yang Gao, Yayun Zhu, Zhou Yuan
Int J Med Sci. 2016 Nov 4;13(12):902-913. doi: 10.7150/ijms.16734. eCollection 2016.
Pancreatic cancer has a rather dismal prognosis mainly due to high malignance of tumor biology. Up to now, the relevant researches on pancreatic cancer lag behind seriously partly due to the obstacles for tissue biopsy, which handicaps the understanding of molecular and genetic features of pancreatic cancer. In the last two decades, liquid biopsy, including circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA), is promising to provide new insights into the biological and clinical characteristics of malignant tumors. Both CTCs and ctDNA provide an opportunity for studying tumor heterogeneity, drug resistance, and metastatic mechanism for pancreatic cancer. Furthermore, they can also play important roles in detecting early-stage tumors, providing prognostic information, monitoring tumor progression and guiding treatment regimens. In this review, we will introduce the latest findings on biological features and clinical applications of both CTCs and ctDNA in pancreatic cancer. In a word, CTCs and ctDNA are promising to promote precision medicine in pancreatic cancer.
93Liquid biopsies for management of pancreatic cancer.PubMed
Mohamadmahdi Samandari, María Gil Julia, Alistair Rice, et al.
Transl Res. 2018 Nov;201:98-127. doi: 10.1016/j.trsl.2018.07.008. Epub 2018 Jul 26.
Pancreatic cancer is one of the main causes of cancer-related deaths worldwide. It is asymptomatic at an early stage, and most diagnosis occurs when the disease is already at a late stage, by which time the tumor is nonresectable. In order to increase the overall survival of patients with pancreatic cancer, as well as to decrease the cancer burden, it is necessary to perform early diagnosis, prognosis stratifications and cancer monitoring using accurate, minimally invasive, and cost-effective methods. Liquid biopsies seek to detect tumor-associated biomarkers in a variety of extractable body fluids and can help to monitor treatment response and disease progression, and even predict patient outcome. In patients with pancreatic cancer, tumor-derived materials, primarily circulating tumor DNA, circulating tumor cells and exosomes, are being studied for inclusion in the management of the disease. This review focuses on describing the biology of these biomarkers, methods for their enrichment and detection, as well as their potential for clinical application. Moreover, we discuss the future direction of liquid biopsies and introduce how they can be exploited toward point of care personalized medicine for the management of pancreatic cancer.
94Using circulating cell-free DNA to monitor personalized cancer therapy.PubMed
Michael Oellerich, Ekkehard Schütz, Julia Beck, et al.
Crit Rev Clin Lab Sci. 2017 May;54(3):205-218. doi: 10.1080/10408363.2017.1299683. Epub 2017 Apr 10.
High-quality genomic analysis is critical for personalized pharmacotherapy in patients with cancer. Tumor-specific genomic alterations can be identified in cell-free DNA (cfDNA) from patient blood samples and can complement biopsies for real-time molecular monitoring of treatment, detection of recurrence, and tracking resistance. cfDNA can be especially useful when tumor tissue is unavailable or insufficient for testing. For blood-based genomic profiling, next-generation sequencing (NGS) and droplet digital PCR (ddPCR) have been successfully applied. The US Food and Drug Administration (FDA) recently approved the first such "liquid biopsy" test for EGFR mutations in patients with non-small cell lung cancer (NSCLC). Such non-invasive methods allow for the identification of specific resistance mutations selected by treatment, such as EGFR T790M, in patients with NSCLC treated with gefitinib. Chromosomal aberration pattern analysis by low coverage whole genome sequencing is a more universal approach based on genomic instability. Gains and losses of chromosomal regions have been detected in plasma tumor-specific cfDNA as copy number aberrations and can be used to compute a genomic copy number instability (CNI) score of cfDNA. A specific CNI index obtained by massive parallel sequencing discriminated those patients with prostate cancer from both healthy controls and men with benign prostatic disease. Furthermore, androgen receptor gene aberrations in cfDNA were associated with therapeutic resistance in metastatic castration resistant prostate cancer. Change in CNI score has been shown to serve as an early predictor of response to standard chemotherapy for various other cancer types (e.g. NSCLC, colorectal cancer, pancreatic ductal adenocarcinomas). CNI scores have also been shown to predict therapeutic responses to immunotherapy. Serial genomic profiling can detect resistance mutations up to 16 weeks before radiographic progression. There is a potential for cost savings when ineffective use of expensive new anticancer drugs is avoided or halted. Challenges for routine implementation of liquid biopsy tests include the necessity of specialized personnel, instrumentation, and software, as well as further development of quality management (e.g. external quality control). Validation of blood-based tumor genomic profiling in additional multicenter outcome studies is necessary; however, cfDNA monitoring can provide clinically important actionable information for precision oncology approaches.
95LncRNAs: Novel Biomarkers for Pancreatic Cancer.PubMed
Soudeh Ghafouri-Fard, Mohadeseh Fathi, Tianyue Zhai, et al.
Biomolecules. 2021 Nov 10;11(11):1665. doi: 10.3390/biom11111665.
Pancreatic cancer is one of the most deadly neoplasms and the seventh major cause of cancer-related deaths among both males and females. This cancer has a poor prognosis due to the lack of appropriate methods for early detection of cancer. Long non-coding RNAs (lncRNAs) have been recently found to influence the progression and initiation of pancreatic cancer. MACC1-AS1, LINC00976, LINC00462, LINC01559, HOXA-AS2, LINC00152, TP73-AS1, XIST, SNHG12, LUCAT1, and UCA1 are among the oncogenic lncRNAs in pancreatic cancer. On the other hand, LINC01111, LINC01963, DGCR5, MEG3, GAS5, and LINC00261 are among tumor suppressor lncRNAs in this tissue. In the current review, we summarize the roles of these two classes of lncRNAs in pancreatic cancer and discuss their potential as attractive diagnostic and prognostic biomarkers for pancreatic cancer. We also identified that the low expression of MEG3, LINC01963, and LINC00261 and the high expression of MACC1-AS1, LINC00462, LINC01559, and UCA1 were significantly correlated with worse survival in pancreatic cancer patients. Further research on these lncRNAs will provide new clues that could potentially improve the early diagnosis, prognostic prediction, and personalized treatments of patients with pancreatic cancer.
96Liquid biopsies and exosomal ncRNA: Transforming pancreatic cancer diagnostics and therapeutics.PubMed
Ashok Kumar Balaraman, Ehssan Moglad, Muhammad Afzal, et al.
Clin Chim Acta. 2025 Feb 1;567:120105. doi: 10.1016/j.cca.2024.120105. Epub 2024 Dec 18.
Pancreatic cancer is a highly fatal malignancy due to poor early detection rate and resistance to conventional therapies. This review examines the potential for liquid biopsy as a transformative technology to identify diagnostic and therapeutic targets in pancreatic cancer. Specifically, we explore emerging biomarkers such as exosomal non-coding RNAs (ncRNAs), circulating tumor DNA (ctDNA), and circulating tumor cells (CTCs). Tumor-derived exosomes contain nucleic acid and protein that reflect the unique molecular landscape of the malignancy and can serve as an alternative diagnostic approach vs traditional biomarkers like CA19-9. Herein we highlight exosomal miRNAs, lncRNAs, and other ncRNAs alongside ctDNA and CTC-based strategies, evaluating their combined ability to improve early detection, disease monitoring and treatment response. Furthermore, the therapeutic implications of ncRNAs such as lncRNA UCA1 and miR-3960 in chemoresistance and progression are also discussed via suppression of EZH2 and PTEN/AKT pathways. Emerging therapeutic strategies that target the immune response, epithelial-mesenchymal transition (EMT) and drug resistance are explored. This review demonstrates a paradigm shift in pancreatic cancer management toward personalized, less invasive and more effective approaches.
97Pancreatic Cancer Surveillance and Novel Strategies for Screening.PubMed
Beth Dudley, Randall E Brand
Gastrointest Endosc Clin N Am. 2022 Jan;32(1):13-25. doi: 10.1016/j.giec.2021.08.008.
Individuals with a genetic susceptibility to pancreatic ductal adenocarcinoma (PDAC) may benefit from surveillance to increase the likelihood of early detection. Currently, candidates for surveillance are identified based on genetic test results and family history of PDAC, and surveillance is accomplished through imaging of the pancreas (endoscopic ultrasound or MRI). Novel methods that incorporate personalized risk, biomarkers, and radiomics are being investigated in an attempt to improve identification of at-risk individuals and to increase detection of precursor and early-stage lesions.
98Genetic Testing Among Patients with High-Risk Breast, Ovarian, Pancreatic, and Prostate Cancers.PubMed
Nina M Clark, Emma A Roberts, Catherine Fedorenko, et al.
Ann Surg Oncol. 2023 Mar;30(3):1312-1326. doi: 10.1245/s10434-022-12755-y. Epub 2022 Nov 5.
BACKGROUND: The National Comprehensive Cancer Network recommends genetic testing in patients with potentially hereditary breast, ovarian, pancreatic, and prostate cancers (HBOPP). Knowledge of genetic mutations impacts decisions about screening and treatment. METHODS: A retrospective cohort study of 28,586 HBOPP patients diagnosed from 2013 to 2019 was conducted using a linked administrative-cancer database in the Seattle-Puget Sound SEER area. Guideline-concordant testing (GCT) was assessed annually according to guideline updates. Frequency of testing according to patient/cancer characteristics was evaluated using chi-squared tests, and factors associated with receipt of genetic testing were identified using multivariable logistic regression. RESULTS: Testing occurred in 17% of HBOPP patients, increasing from 9% in 2013 to 21% in 2019 (p < 0.001). Ovarian cancer had the highest testing (40%) and prostate cancer the lowest (4%). Age < 50, female sex, non-Hispanic White race, commercial insurance, urban location, family history of HBOPP, and triple negative breast cancer (TNBC) were associated with increased testing (all p < 0.05). GCT increased from 38% in 2013 to 44% in 2019, and was highest for early age at breast cancer diagnosis, TNBC, male breast cancer, and breast cancer with family history of HBOPP (all > 70% in 2019), and lowest for metastatic prostate cancer (6%). CONCLUSIONS: The frequency of genetic testing for HBOPP cancer has increased over time. Though GCT is high for breast cancer, there are gaps in concordance among patients with other cancers. Increasing provider and patient education, genetic counseling, and insurance coverage for testing among HBOPP patients may improve guideline adherence.
99Informatics strategies for early detection and risk mitigation in pancreatic cancer patients.PubMed
Di Jin, Najeeb Ullah Khan, Wei Gu, et al.
Neoplasia. 2025 Feb;60:101129. doi: 10.1016/j.neo.2025.101129. Epub 2025 Jan 21.
This review provides a comprehensive overview of the current landscape in pancreatic cancer (PC) screening, diagnosis, and early detection. This emphasizes the need for targeted screening in high-risk groups, particularly those with familial predispositions and genetic mutations, such as BRCA1, BRCA2, and PALB2. This review highlights the sporadic nature of most PC cases and significant risk factors, including smoking, alcohol consumption, obesity, and diabetes. Advanced imaging techniques, such as Endoscopic Ultrasound (EUS) and Contrast-Enhanced Harmonic Imaging (CEH-EUS), have been discussed for their superior sensitivity in early detection. This review also explores the potential of novel biomarkers, including those found in body fluids, such as serum, plasma, urine, and bile, as well as the emerging role of liquid biopsy technologies in analyzing circulating tumor DNA (ctDNA), circulating tumor cells (CTCs), and exosomes. AI-driven approaches, such as those employed in Project Felix and CancerSEEK, have been highlighted for their potential to enhance early detection through deep learning and biomarker discovery. This review underscores the importance of universal genetic testing and the integration of AI with traditional diagnostic methods to improve outcomes in high-risk individuals. Additionally, this review points to future directions in PC diagnostics, including next-generation imaging, molecular biomarkers, and personalized medicine, aiming to overcome current diagnostic challenges and improve survival rates. Ultimately, the review advocates the adoption of informatics and AI-driven strategies to enhance early detection, reduce morbidity, and save lives in the fight against pancreatic cancer.
100Safety of Semaglutide.PubMed
Mark M Smits, Daniël H Van Raalte
Front Endocrinol (Lausanne). 2021 Jul 7;12:645563. doi: 10.3389/fendo.2021.645563. eCollection 2021.
The glucagon-like peptide-1 receptor agonist (GLP-1RA) semaglutide is the most recently approved agent of this drug class, and the only GLP-1RA currently available as both subcutaneous and oral formulation. While GLP-1RAs effectively improve glycemic control and cause weight loss, potential safety concerns have arisen over the years. For semaglutide, such concerns have been addressed in the extensive phase 3 registration trials including cardiovascular outcome trials for both subcutaneous (SUSTAIN: Semaglutide Unabated Sustainability in Treatment of Type 2 Diabetes) and oral (PIONEER: Peptide InnOvatioN for the Early diabEtes tReatment) semaglutide and are being studied in further trials and registries, including real world data studies. In the current review we discuss the occurrence of adverse events associated with semaglutide focusing on hypoglycemia, gastrointestinal side effects, pancreatic safety (pancreatitis and pancreatic cancer), thyroid cancer, gallbladder events, cardiovascular aspects, acute kidney injury, diabetic retinopathy (DRP) complications and injection-site and allergic reactions and where available, we highlight potential underlying mechanisms. Furthermore, we discuss whether effects are specific for semaglutide or a class effect. We conclude that semaglutide induces mostly mild-to-moderate and transient gastrointestinal disturbances and increases the risk of biliary disease (cholelithiasis). No unexpected safety issues have arisen to date, and the established safety profile for semaglutide is similar to that of other GLP-1RAs where definitive conclusions for pancreatic and thyroid cancer cannot be drawn at this point due to low incidence of these conditions. Due to its potent glucose-lowering effect, patients at risk for deterioration of existing DRP should be carefully monitored if treated with semaglutide, particularly if also treated with insulin. Given the beneficial metabolic and cardiovascular actions of semaglutide, and the low risk for severe adverse events, semaglutide has an overall favorable risk/benefit profile for patient with type 2 diabetes.
101Semaglutide and cancer: A systematic review and meta-analysis.PubMed
Lakshmi Nagendra, Harish Bg, Meha Sharma, et al.
Diabetes Metab Syndr. 2023 Sep;17(9):102834. doi: 10.1016/j.dsx.2023.102834. Epub 2023 Jul 26.
BACKGROUND: French national health care insurance system database has suggested 1-3 years use of glucagon like peptide-1 receptor agonists (GLP1RA) (exenatide, liraglutide and dulaglutide) may be linked with increased occurrence of thyroid cancer. Similar data on semaglutide is not-available. Hence, we undertook this systematic review to look at the safety of semaglutide focussing on different cancers. METHODS: Databases were searched for randomized controlled trials (RCTs) and real-world studies involving patients receiving semaglutide in the intervention-arm. Primary outcome was to evaluate the occurrence of pancreatic and thyroid cancers. Secondary outcomes were to the evaluate occurrence of any other malignancies or severe adverse-events. RESULTS: Data from 37 RCTs and 19 real-world studies having 16,839 patients in placebo-control group, 16,550 patients in active-control group and 13,330 patients in real-world studies were analysed. Compared to placebo, occurrence of pancreatic cancer [OR 0.25 (95%CI: 0.03-2.24); P = 0.21], thyroid cancer [OR 2.04 (95%CI: 0.33-12.61); P = 0.44; I = 0%] and all neoplasms (benign, malignant and otherwise unspecified) [OR 0.95 (95%CI:0.62-1.45); P = 0.82; I = 0%] was similar in the semaglutide group. Compared to active controls, occurrence of pancreatic cancer [OR 0.40 (95%CI:0.09-1.87); P = 0.26; I = 0%], thyroid cancer [OR 1.19 (95%CI:0.15-9.66); P = 0.87; I = 0%] and all neoplasms (benign, malignant and otherwise unspecified) [OR 0.91 (95% CI: 0.44-1.89); P = 0.79; I = 0%] were similar in the semaglutide group. Real-world data analysis revealed single case each of pancreatic cancer and B-cell lymphoma. CONCLUSION: Semaglutide use in RCTs and real-world studies was not associated with an increased risk of any types of cancer, and this conclusion is supported by a high grade of evidence.
102Efficacy and Cardiovascular Safety of GLP-1 Receptor Analogues.PubMed
Anoop Mohamed Iqbal, Nasvin Imamudeen, Amjad Basheer, et al.
Curr Drug Saf. 2021;16(2):197-206. doi: 10.2174/1574886315999201208212356.
Glucagon-like peptide- 1 receptor analogs (GLP-1RAs) are incretin mimetics with potent glucose-dependent insulinotropic action that translates to glycemic control in people with type- -2 diabetes mellitus (T2DM). These agents potentially have the ability to stimulate proliferation or prevent apoptosis of pancreatic β-cells, induce weight-loss and provide vascular benefits in patients with T2DM. Newer GLP-1RA, semaglutide has shown a robust reduction in HbA1c up to 1.5 - 1.8%. However, individual differences exist between the different GLP-1RAs, in terms of efficacy, pharmacokinetics, tolerability, and vascular protection. The potential of vascular protection offered by newer anti-diabetic agents has generated a lot of excitement in the field of diabetes, and to a large extent, is now driving treatment decisions. So far, six cardiovascular outcome trials of GLP-1 RAs have been published, analyzing lixisenatide (ELIXA), liraglutide (LEADER), semaglutide (SUSTAIN-6), long-acting exenatide (EXSCEL), dulaglutide (REWIND), and oral semaglutide (PIONEER 6) with a follow-up duration of 2-4 years. LEADER, REWIND and SUSTAIN-6 trials have demonstrated a reduction in rates of major adverse cardiovascular events with active GLP-1 RA treatment, but ELIXA, PIONEER 6 and EXSCEL, have been neutral. In this review, we discuss the available evidence from randomized controlled trials (RCTs) analyzing the cardiovascular effects of various GLP-1 RAs with the aim of comparing individual drugs. We have also summarized the general aspects of GLP-1RAs that can be applied in clinical practice.
103Cardiovascular, mortality, and kidney outcomes with GLP-1 receptor agonists in patients with type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials.PubMed
Søren L Kristensen, Rasmus Rørth, Pardeep S Jhund, et al.
Lancet Diabetes Endocrinol. 2019 Oct;7(10):776-785. doi: 10.1016/S2213-8587(19)30249-9. Epub 2019 Aug 14.
BACKGROUND: Glucagon-like peptide-1 (GLP-1) receptor agonists differ in their structure and duration of action and have been studied in trials of varying sizes and with different patient populations, with inconsistent effects on cardiovascular outcomes reported. We aimed to synthesise the available evidence by doing a systematic review and meta-analysis of cardiovascular outcome trials of these drugs. METHODS: We searched MEDLINE (via PubMed) and the Cochrane Central Register of Controlled Trials for eligible placebo-controlled trials reporting major adverse cardiovascular events (MACE; ie, cardiovascular death, stroke, or myocardial infarction) up to June 15, 2019. We did a meta-analysis using a random-effects model to estimate overall hazard ratios (HRs) for MACE, its components, death from any cause, hospital admission for heart failure, kidney outcomes, and key safety outcomes (severe hypoglycaemia, pancreatitis, and pancreatic cancer). We also examined MACE in several subgroups based on patient characteristics (history of cardiovascular disease, BMI, age, baseline HbA1c, and baseline estimated glomerular filtration rate), trial duration, treatment dosing interval, and structural homology. FINDINGS: Of 27 publications screened, seven trials, with a combined total of 56 004 participants, were included: ELIXA (lixisenatide), LEADER (liraglutide), SUSTAIN-6 (semaglutide), EXSCEL (exenatide), Harmony Outcomes (albiglutide), REWIND (dulaglutide), and PIONEER 6 (oral semaglutide). Overall, GLP-1 receptor agonist treatment reduced MACE by 12% (HR 0·88, 95% CI 0·82-0·94; p<0·0001). There was no statistically significant heterogeneity across the subgroups examined. HRs were 0·88 (95% CI 0·81-0·96; p=0·003) for death from cardiovascular causes, 0·84 (0·76-0·93; p<0·0001) for fatal or non-fatal stroke, and 0·91 (0·84-1·00; p=0·043) for fatal or non-fatal myocardial infarction. GLP-1 receptor agonist treatment reduced all-cause mortality by 12% (0·88, 0·83-0·95; p=0·001), hospital admission for heart failure by 9% (0·91, 0·83-0·99; p=0·028), and a broad composite kidney outcome (development of new-onset macroalbuminuria, decline in estimated glomerular filtration rate [or increase in creatinine], progression to end-stage kidney disease, or death attributable to kidney causes) by 17% (0·83, 0·78-0·89; p<0·0001), mainly due to a reduction in urinary albumin excretion. There was no increase in risk of severe hypoglycaemia, pancreatitis, or pancreatic cancer. INTERPRETATION: Treatment with GLP-1 receptor agonists has beneficial effects on cardiovascular, mortality, and kidney outcomes in patients with type 2 diabetes. FUNDING: None.
104Safety issues with glucagon-like peptide-1 receptor agonists (pancreatitis, pancreatic cancer and cholelithiasis): Data from randomized controlled trials.PubMed
Matteo Monami, Besmir Nreu, Alessia Scatena, et al.
Diabetes Obes Metab. 2017 Sep;19(9):1233-1241. doi: 10.1111/dom.12926. Epub 2017 Jun 20.
AIM: Glucagon-like peptide 1 receptor agonists (GLP1-RA) have been associated with an increased risk of pancreatitis and pancreatic cancer. Prior meta-analyses of randomized controlled trials failed to show any significant increase of risk; however, those meta-analyses did not include the recently published cardiovascular outcome trials (CVOT) with GLP1-RA, which provide a substantial additional body of data. The aim of the present meta-analysis is to assess the effect of GLP1-RA on pancreatitis, pancreatic cancers and cholelithiasis. MATERIALS AND METHODS: A Medline search for GLP-1 receptor agonists (exenatide, liraglutide, lixisenatide, albiglutide, dulaglutide or semaglutide) was performed, collecting all randomized clinical trials with a duration >11 weeks, enrolling patients with type 2 diabetes and comparing a GLP-1 receptor agonist with placebo or any other non-GLP-1 receptor agonist drug. RESULTS: Of the 113 trials fulfilling inclusion criteria, 13 did not report information on pancreatitis, whereas 72 reported no events in all treatment groups. The incidence of pancreatitis and pancreatic cancer with GLP1-RA was not significantly different from that observed in comparator arms (MH-OR [95% CI] 0.93 [0.65-1.34], P = .71, and 0.94 [0.52-1.70], P = .84, respectively), whereas, a significantly increased risk of cholelithiasis (MH-OR [95% CI] 1.30 [1.01-1.68], P = .041) was detected. CONCLUSIONS: Presently available data confirm the safety of GLP-1 receptor agonists for pancreatitis. Conversely, therapy with those drugs is associated with an increased risk of cholelithiasis, which deserves further investigation.
105Glucagon-Like Peptide-1 Receptor Agonists and Pancreatic Cancer Risk in Patients With Type 2 Diabetes.PubMed
Rachel Dankner, Havi Murad, Nirit Agay, et al.
JAMA Netw Open. 2024 Jan 2;7(1):e2350408. doi: 10.1001/jamanetworkopen.2023.50408.
IMPORTANCE: Concerns have been raised that glucagon-like peptide-1 receptor agonists (GLP-1RA) may increase the risk of pancreatic cancer. OBJECTIVE: To investigate the association of GLP-1RA treatment with pancreatic cancer incidence over 9 years of follow-up. DESIGN, SETTING, AND PARTICIPANTS: In this population-based historical cohort study, adult patients (aged 21 to 89 years) with type 2 diabetes insured by Clalit Healthcare Services, the largest state-mandated health organization in Israel, were followed up from 2009, when GLP-1RA became available in Israel, until pancreatic cancer diagnosis, death, reaching age 90 years, or end of follow-up (December 2017). Data were analyzed from June 2022 to November 2023. EXPOSURES: Treatment with GLP-1RA was compared with basal insulin. MAIN OUTCOME AND MEASURES: Pancreatic cancer incidence was compared according to weighted cumulative exposures to GLP-1RA and to basal insulin in a Cox model implemented in discrete time, with time origin at 2 years after diabetes diagnosis, adjusting for confounding. In sensitivity analyses, propensity score-matched pair new-user design and prevalent new-user design were used for the comparison. Because of risk for reverse-causation bias, results in the fifth to seventh year after medication were emphasized. RESULTS: During a cumulative follow-up of 3 290 439 person-years of 543 595 adults with a mean (SD) age of 59.9 (12.8) years (277 502 women [51%]) with incident diabetes, 1665 patients received pancreatic cancer diagnoses. In total, 33 377 patients (6.1%) used GLP-1RA and 106 849 (19.7%) used basal insulin. The estimated hazard ratio (HR) for pancreatic cancer associated with incremental use of 1 defined daily dose per day of GLP-1RA compared with basal insulin in the fifth to seventh year previously (all other characteristics, including age, sex, ethnic background, sociodemographic status, baseline body mass index, smoking history, history of pancreatitis, other glucose-lowering medications treatment history, and length of diabetes, being equal) was 0.50 (95% CI, 0.15-1.71). The new-user and prevalent new-user designs showed HRs from the fifth year onwards following initiation of GLP-1RA vs basal insulin of 0.52 (95 % CI, 0.19-1.41) and 0.75 (95 % CI, 0.37-1.53), respectively. CONCLUSIONS AND RELEVANCE: In this historical cohort study of adults with type 2 diabetes, no support for an increased pancreatic cancer incidence over 7 years following start of GLP-1RA treatment was found. However, monitoring for pancreatic cancer risk beyond 7 years following initiation of therapy is still required. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02072902.
106Glucagon-like peptide-1 receptor agonists and pancreatic cancer risk: target trial emulation using real-world data.PubMed
Lindsey Wang, QuanQiu Wang, Li Li, et al.
J Natl Cancer Inst. 2025 Mar 1;117(3):476-485. doi: 10.1093/jnci/djae260.
BACKGROUND: Data on the effects of glucagon-like peptide-1 receptor agonists (GLP-1RAs) on pancreatic cancer incidence are limited and inconsistent. Here we evaluate the association of GLP-1RAs, alone and in combinations, with incident pancreatic cancer risk in a real-world population, stratified by obesity and smoking status. METHODS: This retrospective cohort included patients with type 2 diabetes mellitus who were prescribed GLP-1RAs or other nonglucagon-like peptide-1 receptor agonist antidiabetes medications between January 2013 and March 2019 and had no prior diagnosis of pancreatic cancer. The incident (first-time) diagnosis of pancreatic cancer during a 5-year follow-up was compared between propensity-score matched cohorts of patients prescribed GLP-1RAs vs other nonglucagon-like peptide-1 receptor agonist antidiabetes medications. Subgroup analyses were performed in patients stratified by the status of obesity and tobacco use disorder. We also compared GLP-1RA combination therapies with monotherapies. Time-to-first-event analysis was performed using Cox proportional hazards and Kaplan-Meier survival analysis, with the hazard ratio and 95% confidence interval calculated. RESULTS: The study population comprised 1 636 056 eligible patients including 167 091 prescribed GLP-1RAs and 1 468 965 prescribed other antidiabetes medications. GLP-1RAs were associated with a statistically significant decreased risk for pancreatic cancer incidence compared with each of 6 nonglucagon-like peptide-1 receptor agonist antidiabetes medications with hazard ratios ranging from 0.42 to 0.82. The reduction was greater in patients with obesity and tobacco use disorder than in those without. GLP-1RA combination therapies were associated with lower pancreatic cancer risk compared with monotherapies. CONCLUSIONS: GLP-1RAs were associated with reduced pancreatic cancer incidence in patients with type 2 diabetes mellitus. Further studies and trials are needed to explore mechanisms and confirm causal effects.
107Adverse Effects of GLP-1 Receptor Agonists.PubMed
Theodosios D Filippatos, Thalia V Panagiotopoulou, Moses S Elisaf
Rev Diabet Stud. 2014 Fall-Winter;11(3-4):202-30. doi: 10.1900/RDS.2014.11.202. Epub 2015 Feb 10.
Glucagon-like peptide-1 (GLP-1) receptor agonists are a class of injective anti-diabetic drugs that improve glycemic control and many other atherosclerosis-related parameters in patients with type 2 diabetes (T2D). However, the use of this relatively new class of drugs may be associated with certain adverse effects. Concerns have been expressed regarding the effects of these drugs on pancreatic and thyroid tissue, since animal studies and analyses of drug databases indicate an association of GLP-1 receptor agonists with pancreatitis, pancreatic cancer, and thyroid cancer. However, several meta-analyses failed to confirm a cause-effect relation between GLP-1 receptor agonists and the development of these adverse effects. One benefit of GLP-1 receptor agonists is that they do not cause hypoglycemia when combined with metformin or thiazolidinediones, but the dose of concomitant sulphonylurea or insulin may have to be decreased to reduce the risk of hypoglycemic episodes. On the other hand, several case reports have linked the use of these drugs, mainly exenatide, with the occurrence of acute kidney injury, primarily through hemodynamic derangement due to nausea, vomiting, and diarrhea. The most common symptoms associated with the use of GLP-1 receptor agonists are gastrointestinal symptoms, mainly nausea. Other common adverse effects include injection site reactions, headache, and nasopharyngitis, but these effects do not usually result in discontinuation of the drug. Current evidence shows that GLP-1 receptor agonists have no negative effects on the cardiovascular risk of patients with T2D. Thus, GLP-1 receptor agonists appear to have a favorable safety profile, but ongoing trials will further assess their cardiovascular effects. The aim of this review is to analyze critically the available data regarding adverse events of GLP-1 receptor agonists in different anatomic systems published in Pubmed and Scopus. Whenever possible, certain differences between GLP-1 receptor agonists are described. The review also provides the reader with structured data that compare the rates of the most common adverse effects for each of the various GLP-1 receptor agonists.
108Targeting the NPY/NPY1R signaling axis in mutant p53-dependent pancreatic cancer impairs metastasis.PubMed
Cecilia R Chambers, Supitchaya Watakul, Peter Schofield, et al.
Sci Adv. 2025 Mar 14;11(11):eadq4416. doi: 10.1126/sciadv.adq4416. Epub 2025 Mar 12.
Pancreatic cancer (PC) is a highly metastatic malignancy. More than 80% of patients with PC present with advanced-stage disease, preventing potentially curative surgery. The neuropeptide Y (NPY) system, best known for its role in controlling energy homeostasis, has also been shown to promote tumorigenesis in a range of cancer types, but its role in PC has yet to be explored. We show that expression of NPY and are up-regulated in mouse PC models and human patients with PC. Moreover, using the genetically engineered, autochthonous KPC mouse model of PC, we demonstrate that pancreas-specific and whole-body knockout of significantly decreases metastasis to the liver. We identify that treatment with the NPY1R antagonist BIBO3304 significantly reduces KPC migratory capacity on cell-derived matrices. Pharmacological NPY1R inhibition in an intrasplenic model of PC metastasis recapitulated the results of our genetic studies, with BIBO3304 significantly decreasing liver metastasis. Together, our results reveal that NPY/NPY1R signaling is a previously unidentified antimetastatic target in PC.
109Neuropeptide Y Peptide Family and Cancer: Antitumor Therapeutic Strategies.PubMed
Manuel Lisardo Sánchez, Francisco D Rodríguez, Rafael Coveñas
Int J Mol Sci. 2023 Jun 9;24(12):9962. doi: 10.3390/ijms24129962.
Currently available data on the involvement of neuropeptide Y (NPY), peptide YY (PYY), and pancreatic polypeptide (PP) and their receptors (YRs) in cancer are updated. The structure and dynamics of YRs and their intracellular signaling pathways are also studied. The roles played by these peptides in 22 different cancer types are reviewed (e.g., breast cancer, colorectal cancer, Ewing sarcoma, liver cancer, melanoma, neuroblastoma, pancreatic cancer, pheochromocytoma, and prostate cancer). YRs could be used as cancer diagnostic markers and therapeutic targets. A high Y1R expression has been correlated with lymph node metastasis, advanced stages, and perineural invasion; an increased Y5R expression with survival and tumor growth; and a high serum NPY level with relapse, metastasis, and poor survival. YRs mediate tumor cell proliferation, migration, invasion, metastasis, and angiogenesis; YR antagonists block the previous actions and promote the death of cancer cells. NPY favors tumor cell growth, migration, and metastasis and promotes angiogenesis in some tumors (e.g., breast cancer, colorectal cancer, neuroblastoma, pancreatic cancer), whereas in others it exerts an antitumor effect (e.g., cholangiocarcinoma, Ewing sarcoma, liver cancer). PYY or its fragments block tumor cell growth, migration, and invasion in breast, colorectal, esophageal, liver, pancreatic, and prostate cancer. Current data show the peptidergic system's high potential for cancer diagnosis, treatment, and support using Y2R/Y5R antagonists and NPY or PYY agonists as promising antitumor therapeutic strategies. Some important research lines to be developed in the future will also be suggested.
110Immunonutrition and prehabilitation in pancreatic cancer surgery: A new concept in the era of ERAS® and neoadjuvant treatment.PubMed
Raffaele De Luca, Luca Gianotti, Paolo Pedrazzoli, et al.
Eur J Surg Oncol. 2023 Mar;49(3):542-549. doi: 10.1016/j.ejso.2022.12.006. Epub 2022 Dec 22.
Pancreatic cancer (PC) is an aggressive disease, with a growing incidence, and a poor prognosis. Neoadjuvant treatments in PC are highly recommended in borderline resectable and recently in upfront resectable PC. PC is characterized by exocrine insufficiency and nutritional imbalance, leading to malnutrition/sarcopenia. The concept of malnutrition in PC is multifaceted, as the cancer-related alterations create an interplay with adverse effects of anticancer treatments. All these critical factors have a negative impact on the postoperative and oncological outcomes. A series of actions and programs can be implemented to improve resectable and borderline resectable PC in terms of postoperative complications, oncological outcomes and patients' quality of life. A timely nutritional evaluation and the implementation of appropriate evidence-based nutritional interventions in onco-surgical patients should be considered of importance to improve preoperative physical fitness. Unfortunately, nutritional care and its optimization are often neglected in real-world clinical practice. Currently available studies and ERAS® guidelines mostly support the use of pre- or perioperative medical nutrition, including immunonutrition, in order to decrease the rate of postoperative infections and length of hospital stay. Further data also suggest that medical nutrition should be considered proactively in PC patients, to possibly prevent severe malnutrition and its consequences on disease and treatment outcomes. This narrative review summarizes the most recent data related to the role of prehabilitation, ERAS® program, medical nutrition, and the timing of intervention on clinical outcomes of upfront resectable and borderline PC, and their potential implementation within the timeframe of neoadjuvant treatments.
111Prehabilitation and Immunonutrition in Pancreatic Cancer Therapy.PubMed
Madeline Roorbach, Whitney Bleakley, Maria C Russell
Surg Oncol Clin N Am. 2026 Jan;35(1):55-69. doi: 10.1016/j.soc.2025.03.004. Epub 2025 Jun 7.
Pancreatic cancer is an aggressive disease with demanding therapies. Patients often present physically and nutritionally debilitated and then are required to undergo rigorous chemotherapy and/or chemoradiation, as well as operative interventions. Ensuring that patients are physically, nutritionally, and psychosocially supported may promote tolerance of neoadjuvant treatments to ensure progression to and success of surgery.
112Effectiveness of dietary prehabilitation in patients with gastric, pancreatic, and colorectal cancers: a systematic review.PubMed
Dominika Grońska, Marcin Wojnarski, Andrzej Budzyński, et al.
Pol Arch Intern Med. 2025 Aug 26;135(7-8). doi: 10.20452/pamw.17015. Epub 2025 May 22.
INTRODUCTION: Gastric, pancreatic, and colorectal cancers pose a serious health challenge, characterized by high morbidity and mortality rates. Dietary prehabilitation, aimed at optimizing nutritional status before treatment, has proven to be a promising strategy for improving outcomes. OBJECTIVES: Our aim was to assess the effectiveness of dietary prehabilitation in improving clinical outcomes, including nutritional status, length of hospital stay, and quality of life in patients with gastric, pancreatic, and colorectal cancers. PATIENTS AND METHODS: We systematically reviewed randomized controlled trials and observational studies in accordance with the PRISMA guidelines. Electronic databases searched included Embase, CINAHL, Cochrane Central Register of Controlled Trials, Medline, and Google Scholar. RESULTS: Twelve studies focusing on pretreatment dietary interventions were identified. Dietary prehabilitation, particularly using oral nutritional supplements or immunonutrition, reduced postoperative complications and improved nutritional status, especially in malnourished patients. CONCLUSIONS: Dietary prehabilitation appears to benefit patients with gastric, pancreatic, and colorectal cancers, particularly in terms of postoperative outcomes and nutritional status.
113Efficacy of preoperative immunonutrition in locally advanced pancreatic cancer undergoing irreversible electroporation (IRE).PubMed
R C G Martin, S Agle, M Schlegel, et al.
Eur J Surg Oncol. 2017 Apr;43(4):772-779. doi: 10.1016/j.ejso.2017.01.002. Epub 2017 Jan 19.
BACKGROUND: Improved preoperative immunonutrition has been shown to decrease the length of stay (LOS) and complications among patients undergoing elective gastrointestinal cancer surgeries. The purpose of this study was to determine whether preoperative immunonutrition supplementation decreases postoperative LOS, infectious complications, and morbidity in patients undergoing irreversible electroporation (IRE) surgery for locally advanced pancreatic cancer (LAPC). METHODS: At a regional hepatopancreatobiliary referral center within an academic medical center 71 patients receiving IRE treatment of LAPC were included in the study. The participants were divided into those receiving preoperative immunonutrition (n = 44) and those receiving no supplemental preoperative immunonutrition (n = 27). Main outcomes and measures were LOS, postoperative complications, nutritional risk index (NRI), and albumin levels. RESULTS: Patients in both groups were similar for preoperative nutrition parameters and operative therapy. Patients in the immunonutrition group experienced a statistically significant decrease in postoperative complications (p = 0.05) and LOS (10.7 vs. 17.4, p = 0.01), and less of a decrease in nutritional risk index (-12.6 vs. -16.2, p = 0.03) and albumin levels (-1.1 vs. -1.5, p < 0.01). CONCLUSION: Preoperative immunonutrition was clinically significant in decreasing postoperative complications, LOS, and improving post-surgery NRI and albumin levels in patients receiving elective IRE treatment of non-resectable pancreatic cancer. These results indicate that preoperative immunonutrition is effective and feasible in this subset of cancer patients.
114The Role of Immunonutrition in Patients Undergoing Pancreaticoduodenectomy.PubMed
Beata Jabłońska, Sławomir Mrowiec
Nutrients. 2020 Aug 23;12(9):2547. doi: 10.3390/nu12092547.
Pancreaticoduodenectomy (PD) is one of the most difficult and complex surgical procedures in abdominal surgery. Malnutrition and immune dysfunction in patients with pancreatic cancer (PC) may lead to a higher risk of postoperative infectious complications. Although immunonutrition (IN) is recommended for enhanced recovery after surgery (ERAS) in patients undergoing PD for 5-7 days perioperatively, its role in patients undergoing pancreatectomy is still unclear and controversial. It is known that the proper surgical technique is very important in order to reduce a risk of postoperative complications, such as a pancreatic fistula, and to improve disease-free survival in patients following PD. However, it has been proven that IN decreases the risk of infectious complications, and shortens hospital stays in patients undergoing PD. This is a result of the impact on altered inflammatory responses in patients with cancer. Both enteral and parenteral, as well as preoperative and postoperative IN, using various nutrients, such as glutamine, arginine, omega-3 fatty acids and nucleotides, is administered. The most frequently used preoperative oral supplementation is recommended. The aim of this paper is to present the indications and benefits of IN in patients undergoing PD.
115Immunonutrition in Patients with Pancreatic Cancer Undergoing Surgical Intervention: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.PubMed
Fu-An Yang, Yang-Ching Chen, Cheng Tiong
Nutrients. 2020 Sep 12;12(9):2798. doi: 10.3390/nu12092798.
Immunonutrition is administered to improve the outcome of patients with pancreatic cancer undergoing surgery. However, its effect and mechanism of action remain unclear. Therefore, we conducted this systematic review and meta-analysis to assess its effects on postoperative outcome and the immune system. Randomized controlled trials (RCTs) were identified and data extracted by two reviewers independently from electronic databases from their inception to 31 October 2019. The result was expressed as the risk ratio (RR) for categorical variables and mean difference (MD) for continuous variables with 95% confidence intervals (CIs). Six RCTs published from 1999 and 2016, with a total of 368 patients, were included. The results revealed that immunonutrition significantly decreased the rate of infectious complications (RR = 0.47, 95% CI (0.23, 0.94), = 0.03) and the length of hospital stay (MD = -1.90, 95% CI (-3.78, -0.02), = 0.05) by modulating the immune system, especially in preoperative group in subgroup analysis. We therefore recommend that patients with pancreatic cancer undergoing surgery could take the advantage of immunonutrition, especially in the preoperative period.
116Complications of pancreatic surgery and the role of perioperative nutrition.PubMed
V Di Carlo, L Gianotti, G Balzano, et al.
Dig Surg. 1999;16(4):320-6. doi: 10.1159/000018742.
BACKGROUND: According to international guidelines, artificial nutrition may be indicated after pancreaticoduodenectomy (PD). This clinical study was designed to evaluate whether the route of administration and the composition of the postoperative nutritional support could affect outcome. METHODS: One hundred patients who underwent PD for cancer of the pancreatic head were prospectively studied. Patients were randomized to receive a standard enteral formula (SEN; n = 35) or immunonutrition with an enteral formula enriched with arginine, omega-3 fatty acids, and RNA (IEN group; n = 33), or total parenteral nutrition (TPN; n = 32). Postoperative feeding was started within 12 h after surgery. The three regimens were isoenergetic and isonitrogenous. Tolerance of enteral feeding, rate and severity of postoperative complications, and length of hospital stay (LOS) were evaluated. RESULTS: Full nutritional goal (25 kcal/kg) was achieved in 84% of enterally fed patients versus 96% in the parenteral group (p = NS). The rate of postoperative complications was lower in the IEN group (33%) than in the SEN (40%) and TPN groups (59%). The severity of infectious complications (sepsis score) was lower in the IEN (5.5) than the SEN (7.9) and TPN groups (10.4; p < 0.05). LOS was shorter in the IEN than in the SEN and TPN groups (16.3 vs. 17.8 vs. 19.3 days, respectively; p < 0.05). CONCLUSIONS: In patients undergoing PD the established nutritional goal can be obtained by enteral feeding. Immunonutrition seems to improve outcome.
117Novel inhibitory effect of Omega-3 fatty acids regulating pancreatic cancer progression.PubMed
María I Garay, Tamara Mazo, Victoria Ferrero, et al.
Carcinogenesis. 2025 Jan 20;46(1). doi: 10.1093/carcin/bgae081.
Pancreatic cancer is a devastating malignancy in great need of new and more effective treatment approaches. In recent years, studies have indicated that nutritional interventions, particularly nutraceuticals, may provide novel avenues to modulate cancer progression. Here, our study characterizes the impact of ω-3 polyunsaturated fatty acids, eicosapentaenoic acid, and docosahexaenoic acid, as a nutraceutical intervention in pancreatic cancer using a genetically engineered mouse model driven by KrasG12D and Trp53R172H. This model closely resembles human pancreatic carcinogenesis, offering a disease relevant platform for translational research. Our findings showed that ω-3 polyunsaturated fatty acids intervention (using a diet supplemented with 6% cod liver oil) significantly reduced tumor volume as well as lung and liver metastasis and a trend toward improved survival rate compared with control treated mice. This antitumoral effect was accompanied by distinct changes in tumor membrane fatty acid profile and eicosanoids release. Furthermore, the eicosapentaenoic acid and docosahexaenoic acid intervention also reduced malignant histological parameters and induced apoptosis without affecting cell proliferation. Of note is the significant reduction in tumor fibrosis that was associated with decreased levels of Sonic Hedgehog, a major ligand controlling this cellular compartment in pancreatic cancer. All together our results demonstrate the impact of eicosapentaenoic acid and docosahexaenoic acid as antitumor regulators in pancreatic cancer, suggesting potential for ω-3 polyunsaturated fatty acids as a possible antitumoral dietary intervention. This research opens new avenues for integrating nutraceutical strategies in pancreatic cancer management.
118Role of omega-3 polyunsaturated fatty acids in preventing gastrointestinal cancers: current status and future perspectives.PubMed
Ho-Jae Lee, Young-Min Han, Jeong Min An, et al.
Expert Rev Anticancer Ther. 2018 Dec;18(12):1189-1203. doi: 10.1080/14737140.2018.1524299. Epub 2018 Sep 24.
Although inflammation is defensive and healing process that maintains organ homeostasis, unresolved inflammation can lead to diseases. Polyunsaturated fatty acids (PUFAs), especially n-6 PUFAs abundant in Western diet, are precursors of pro-inflammatory mediators, whereas n-3 PUFAs possess anti-inflammatory properties. Therefore, interest in the cancer-preventive effect of n-3 PUFAs is increasing. Areas covered: We have observed significant reductions of gastrointestinal tumorigenesis in the Fat-1 transgenic mouse as evidenced that the decrease in Helicobacter pylori-infected gastric tumorigenesis, colon, biliary, and pancreatic cancer was seen in Fat-1 mice producing n-3 PUFAs. However, despite many studies showing benefits, evidence-based medicine regarding molecular pathology, epidemiology, and clinical achievement of cancer prevention of n-3 PUFAs are still limited. Expert commentary: Primary deficiency of eicosapentaenoic acids and docosahexaenoic acids in Western diets can explain the risk of cancer development and the importance of n-3/n-6 PUFA ratio in reducing cancer risk. Alteration of cell membrane composition during carcinogenesis is particularly important, due to increased rate of lipid/cholesterol synthesis in cancerous tissues. Here, we discuss that direct incorporation of n-3 PUFAs in the cell membrane corrects abnormal cellular proliferation and decreases inflammation-associated carcinogenesis. This is exemplified by cancer-preventive effects of n-3 PUFAs as fat sources for gastrointestinal cancers.
119The Complexity of Omega-3 Fatty Acid Modulation of Signaling Pathways Related to Pancreatic Cancer.PubMed
Carolina Torres, Andrew M Diaz, Daniel R Principe, et al.
Curr Med Chem. 2018;25(22):2608-2623. doi: 10.2174/0929867324666170616111225.
Cancer is a major public health problem worldwide and is the second leading cause of death in the United States. Although cancer death rate has dropped by 23% since 1991, there are certain types of cancer for which death rates are still increasing, such as pancreatic cancer. There is an urgent need to find new therapies that could help improve this dreadful outcome. In this regard, the role of nutrition in health and disease has attracted much attention. Several dietary components are involved in metabolic, physiologic and cell signaling affecting tumor growth and progression. Although lipids, and more specifically polyunsaturated fatty acids, have been traditionally studied due to their health effects in cardiovascular disease, it is now clear that they can impact an extensive array of cellular processes that influence a wide range of diseases such as type II diabetes, inflammatory disorders and cancer. These biological activities may be grouped as regulation of: (1) membrane structure and function, (2) intracellular signaling pathways, (3) transcription factor activity, (4) gene expression, and (5) production of bioactive lipid mediators. The aim of this review is to assimilate the current state of knowledge about these potential mechanism(s) of action and signaling pathways modulated by polyunsaturated fatty acids in pancreatic cancer.
120Omega-3 fatty acids for the treatment of cancer cachexia: issues in designing clinical trials of dietary supplements.PubMed
Lindsey Harle, Todd Brown, Daniel Laheru, et al.
J Altern Complement Med. 2005 Dec;11(6):1039-46. doi: 10.1089/acm.2005.11.1039.
Complementary and alternative medicine (CAM) is increasingly popular, despite the limited evidence of the efficacy and safety of some forms of CAM. Cancer patients often turn to CAM therapies for the relief of treatment- induced side-effects and comorbidities. Cancer-associated weight loss commonly results in decreased functional status, life expectancy, and quality of life. Despite the high morbidity and mortality associated with cancer cachexia, mainstream treatments do not sustain weight. Although nutritional supplements are commonly used, many of these have not been tested in clinical trials. The issues faced in dietary supplement research differ from those in pharmaceutical drug trials. These include problems with standardization, contamination, and compliance documentation. A double-blind, randomized, placebo-controlled trial is proposed to evaluate the efficacy and safety of fish oil supplementation for the treatment of cachexia in pancreatic cancer patients. The primary outcome measure will be lean body mass; secondary outcomes include functional status and quality of life. The methodology of the clinical trial is reviewed here and the unique problems faced by investigators in designing studies of dietary supplements are discussed.
121Fish oil supplementation in the treatment of cachexia in pancreatic cancer patients.PubMed
Todd T Brown, Danielle L Zelnik, Adrian S Dobs
Int J Gastrointest Cancer. 2003;34(2-3):143-50. doi: 10.1385/IJGC:34:2-3:143.
Patients with pancreatic cancer often experience a loss of weight and appetite, known as the anorexia-cachexia syndrome, which is associated with decreased quality of life and reduced survival. Research into the biological mechanisms of cachexia has demonstrated that an array of inflammatory mediators and tumor-derived factors cause appetite suppression, skeletal muscle proteolysis, and lipolysis,producing an overall hypercatabolic state that contributes to loss of fat and lean body mass. Omega-3 polyunsaturated fatty acids (n-3 PUFAs) have been shown to modulate levels of proinflammatory cytokines, hepatic acute phase proteins, eicosanoids, and tumor-derived factors in animal models of cancer and may reverse some aspects of the process of cachexia. Results of clinical trials of n-3 PUFAs in the form of fish oils have been mixed, but should encourage further investigation into dietary fish oil supplementation, including the most effective route of administration and the proper dosage to promote optimal weight maintenance and to limit side effects. Concerns about standardization and quality control should also be considered. With the current available evidence, a recommendation for the use of omega 3 polyunsaturated fatty acids in pancreatic cancer cachexia is premature.
122Phase Angle and Postoperative Complications in a Model of Immunonutrition in Patients with Pancreatic Cancer.PubMed
Magdalena Boćkowska, Przemysław Kostro, Zbigniew Krzysztof Kamocki
Nutrients. 2023 Oct 11;15(20):4328. doi: 10.3390/nu15204328.
BACKGROUND: The aim of this study was to determine the influence of our own model of immunonutrition on phase angle and postoperative complications. Our goal was to establish modern prehabilitation procedures for patients operated on for pancreatic cancer. METHODS: Patients with pancreatic cancer who qualified for surgical treatment were divided into two groups. Group I (20 patients; 12 with pancreatic head cancer, 8 with pancreatic tail/body cancer) was given immunonutrition (Impact Oral 3× a day, 237 mL, for 5 days before surgery, and after surgery for an average of 3.5 days). Group II (20 patients; 12 with pancreatic head cancer, 8 with pancreatic tail/body cancer) did not receive immunonutrition. Body weight, body mass index and phase angle were assessed on admission to the hospital, after preoperative immunonutrition, on the third and eighth postoperative days. C-reactive protein and Interleukin-1 α were measured on admission to the hospital, after preoperative immunonutrition, on the eighth postoperative day. Postsurgical complications were assessed via Clavien-Dindo classification. RESULTS: On admission to the hospital, the phase angle was 5.0° (4.70-5.85) in Group I and 5.1° (5.00-6.25) in Group II. After 5 days of using preoperative immunonutrition, it increased statistically significantly ( < 0.02) to 5.35°. In Group I, on the third day after surgery, it decreased statistically significantly ( < 0.001) to 4.65°, and then, increased to 4.85° on the eighth day. In Group II, statistically significant decreases in the phase angle were observed on the third (4.5°; < 0.002) and eighth (4.55°; < 0.008) days after surgery. A statistically significant increase in CRP (86.6 mg/dL; < 0.02) and IL-1α (18.5 pg/mL; < 0.03) levels was observed on the eighth day after surgery in this group. In Group I, a statistically significant negative correlation (R -0.501106; < 0.002) of the phase angle after 5 days of preoperative immunonutrition with postoperative complications was observed. CONCLUSIONS: This study used our own model of immunonutrition in patients undergoing surgery for pancreatic cancer. The applied model of perioperative IN improved the postoperative course of patients operated on due to pancreatic cancer. Fewer complications were observed in patients in the group receiving IN. Also, the PA value increased after the 5-day preoperative IN, and the use of perioperative IN improved the PA value on the eighth postoperative day compared to the group that did not receive IN. On this day, an increase in inflammatory parameters was also observed in the group that did not receive IN. In addition, PA correlated negatively with complications. The PA can be a useful tool to assess the effectiveness of the applied IN, and thus, to predict the occurrence of postoperative complications. Therefore, there is a further need for studies on larger groups of patients.
123Associations between dietary folate intake and risks of esophageal, gastric and pancreatic cancers: an overall and dose-response meta-analysis.PubMed
Wen Liu, Heng Zhou, Yaoqi Zhu, et al.
Oncotarget. 2017 Jun 28;8(49):86828-86842. doi: 10.18632/oncotarget.18775. eCollection 2017 Oct 17.
There are still some controversies on the association between dietary folate intake and the risk of upper gastrointestinal cancers including esophageal, gastric and pancreatic cancers. Hence, a comprehensive meta-analysis on all available literatures was performed to clarify the relationship between dietary folate intake and risks of upper gastrointestinal cancers. An electric search was performed up to December 12, 2016 within the PubMed, MEDLINE AND EMBASE databases. Ultimately, a total of 46 studies which evaluated the association between folate intake and risks of upper gastrointestinal cancers were included. According to the data from included studies, the pooled results showed significant association between folate intake and esophageal (OR = 0.545, 95%CI = 0.432-0.658), gastric (OR=0.762, 95%CI=0.648-0.876) and pancreatic (OR=0.731, 95%CI=0.555-0.907) cancers. Linearity dose-response analysis indicated that with 100μg/day increment in dietary folate intake, the risk of esophageal, gastric and pancreatic cancers would decrease by 9%, 1.5% and 6%, respectively. These findings indicated that higher level of dietary folate intake could help for preventing upper gastrointestinal cancers including esophageal, gastric and pancreatic cancers.
124Vitamin D and pancreatic cancer.PubMed
Rachael Z Stolzenberg-Solomon
Ann Epidemiol. 2009 Feb;19(2):89-95. doi: 10.1016/j.annepidem.2008.03.010. Epub 2008 May 27.
Sun exposure has been associated with lower death rates for pancreatic cancer in ecological studies. Skin exposure to solar ultraviolet B radiation induces cutaneous production of precursors to 25-hydroxy (OH) vitamin D (D) and is considered the primary contributor to vitamin D status in most populations. Pancreatic islet and duct cells express 25-(OH) D(3)-1alpha-hydroxylase that generates the biologically active 1,25-dihydroxy(OH)(2) D form. Thus, 25(OH)D concentrations could affect pancreatic function and possibly pancreatic cancer etiology. Serum 25-(OH)D is the major circulating vitamin D metabolite and is considered the best indicator of vitamin D status as determined by the sun and diet. Although recent prospective epidemiologic studies of higher predicted vitamin D status score and vitamin D intake and pancreatic cancer risk suggest protective associations, a nested case-control study showed a significant 3-fold increased risk for pancreatic cancer with higher vitamin D status. Limitations of these studies include the former do not measure vitamin D status on pancreatic cancer cases and the later was conducted in a male smoker population. More research is needed, particularly examination of pre-diagnostic vitamin D status and risk of pancreatic cancer, prior to conclusions for vitamin D's potential role in the etiology of this highly fatal cancer.
125Chemoprevention strategies for pancreatic cancer.PubMed
Silvia D Stan, Shivendra V Singh, Randall E Brand
Nat Rev Gastroenterol Hepatol. 2010 Jun;7(6):347-56. doi: 10.1038/nrgastro.2010.61. Epub 2010 May 4.
Pancreatic cancer has a poor prognosis and is often diagnosed at an advanced stage, which makes it difficult to treat. The low survival rate of patients with pancreatic cancer points towards an increased need for novel therapeutic and chemopreventive strategies and also early detection of this disease. Increased consumption of fruits and vegetables has been associated with a reduced risk of pancreatic cancer. Synthetic and natural, diet-derived bioactive compounds have been evaluated as pancreatic cancer chemopreventive agents and have demonstrated various degrees of efficacy in cellular and in vivo animal models. Some chemopreventive agents (for example, curcumin or resveratrol) have also been reported to sensitize pancreatic cancer cells to standard chemotherapeutic drugs (for example, gemcitabine or erlotinib), which suggests that chemopreventive agents could potentially be used as potentiators of standard chemotherapy. Few clinical trials of pancreatic cancer chemopreventive agents have been completed and some are in early phases. Further development of pancreatic cancer chemopreventive agents may prove to be tremendously valuable for individuals at high risk of developing pancreatic cancer and patients who present with premalignant lesions. This Review discusses the current state of the pancreatic cancer chemoprevention field and highlights the challenges ahead.
126Targeting Cancer Stem Cells for Chemoprevention of Pancreatic Cancer.PubMed
Dharmalingam Subramaniam, Gaurav Kaushik, Prasad Dandawate, et al.
Curr Med Chem. 2018;25(22):2585-2594. doi: 10.2174/0929867324666170127095832.
Pancreatic ductal adenocarcinoma is one of the deadliest cancers worldwide and the fourth leading cause of cancer-related deaths in United States. Regardless of the advances in molecular pathogenesis and consequential efforts to suppress the disease, this cancer remains a major health problem in United States. By 2030, the projection is that pancreatic cancer will be climb up to be the second leading cause of cancer-related deaths in the United States. Pancreatic cancer is a rapidly invasive and highly metastatic cancer, and does not respond to standard therapies. Emerging evidence supports that the presence of a unique population of cells called cancer stem cells (CSCs) as potential cancer inducing cells and efforts are underway to develop therapeutic strategies targeting these cells. CSCs are rare quiescent cells, and with the capacity to self-renew through asymmetric/symmetric cell division, as well as differentiate into various lineages of cells in the cancer. Studies have been shown that CSCs are highly resistant to standard therapy and also responsible for drug resistance, cancer recurrence and metastasis. To overcome this problem, we need novel preventive agents that target these CSCs. Natural compounds or phytochemicals have ability to target these CSCs and their signaling pathways. Therefore, in the present review article, we summarize our current understanding of pancreatic CSCs and their signaling pathways, and the phytochemicals that target these cells including curcumin, resveratrol, tea polyphenol EGCG (epigallocatechin- 3-gallate), crocetinic acid, sulforaphane, genistein, indole-3-carbinol, vitamin E δ- tocotrienol, Plumbagin, quercetin, triptolide, Licofelene and Quinomycin. These natural compounds or phytochemicals, which inhibit cancer stem cells may prove to be promising agents for the prevention and treatment of pancreatic cancers.
127Tryptophan-derived microbial metabolites activate the aryl hydrocarbon receptor in tumor-associated macrophages to suppress anti-tumor immunity.PubMed
Kebria Hezaveh, Rahul S Shinde, Andreas Klötgen, et al.
Immunity. 2022 Feb 8;55(2):324-340.e8. doi: 10.1016/j.immuni.2022.01.006.
The aryl hydrocarbon receptor (AhR) is a sensor of products of tryptophan metabolism and a potent modulator of immunity. Here, we examined the impact of AhR in tumor-associated macrophage (TAM) function in pancreatic ductal adenocarcinoma (PDAC). TAMs exhibited high AhR activity and Ahr-deficient macrophages developed an inflammatory phenotype. Deletion of Ahr in myeloid cells or pharmacologic inhibition of AhR reduced PDAC growth, improved efficacy of immune checkpoint blockade, and increased intra-tumoral frequencies of IFNγCD8 T cells. Macrophage tryptophan metabolism was not required for this effect. Rather, macrophage AhR activity was dependent on Lactobacillus metabolization of dietary tryptophan to indoles. Removal of dietary tryptophan reduced TAM AhR activity and promoted intra-tumoral accumulation of TNFαIFNγCD8 T cells; provision of dietary indoles blocked this effect. In patients with PDAC, high AHR expression associated with rapid disease progression and mortality, as well as with an immune-suppressive TAM phenotype, suggesting conservation of this regulatory axis in human disease.
128IDO1/TDO dual inhibitor RY103 targets Kyn-AhR pathway and exhibits preclinical efficacy on pancreatic cancer.PubMed
Heng Liang, Tianqi Li, Xin Fang, et al.
Cancer Lett. 2021 Dec 1;522:32-43. doi: 10.1016/j.canlet.2021.09.012. Epub 2021 Sep 11.
Indoleamine 2,3-dioxygenase 1 (IDO1) catalyzing the conversion of tryptophan (Trp) to kynurenine (Kyn) in kynurenine pathway (KP) is involved in the immunosuppression in pancreatic cancer (PC), but the value of IDO1 as an independent prognostic marker for PC is uncertain. Moreover, the correlation between tryptophan 2,3-dioxygenase (TDO), an isozyme of IDO1, and PC is largely unknown. Using TCGA database, the correlation between IDO1 and/or TDO expression and PC patients' survival was analyzed. The expressions of IDO1 and TDO in PC cells and PC mice were examined. The effects of IDO1, TDO or dual inhibition on IDO1 and TDO effector pathway (Aryl hydrocarbon receptor, AhR) and on migration and invasion of PC cells were investigated. The block effect of IDO1/TDO dual inhibitor RY103 on KP was evaluated. The preclinical efficacy of RY103 and its immunomodulatory effect on KPIC orthotopic PC mice and Pan02 tumor-bearing mice were explored. Results showed that IDO1/TDO co-expression is an independent prognostic marker for PC. RY103 can significantly block KP and target Kyn-AhR pathway to blunt the migration and invasion of PC cells, exhibit preclinical efficacy and ameliorate IDO1/TDO-mediated immunosuppression in PC mice.
129NO /RUNX3/kynurenine metabolic signaling enhances disease aggressiveness in pancreatic cancer.PubMed
Limin Wang, Wei Tang, Shouhui Yang, et al.
Int J Cancer. 2020 Jun 1;146(11):3160-3169. doi: 10.1002/ijc.32733. Epub 2019 Nov 19.
Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy and is refractory to available treatments. Delineating the regulatory mechanisms of metabolic reprogramming, a key event in pancreatic cancer progression, may identify candidate targets with potential therapeutic significance. We hypothesized that inflammatory signaling pathways regulate metabolic adaptations in pancreatic cancer. Metabolic profiling of tumors from PDAC patients with a high- (>median, n = 31) and low-NOS2 (inducible nitric oxide synthase; <median, n = 32) mRNA expression was performed. Differentially abundant metabolites were analyzed and linked with patient survival. The functional role of the prognostically significant metabolite and the mechanism of its regulation by NOS2/NO (nitric oxide)-mediated signaling pathway was elucidated. The level of kynurenine, a tryptophan metabolite, was associated with high NOS2 expression, and a higher level of kynurenine predicted poor survival in patients (n = 63, p = 0.01). Gene expression analysis in PDAC tumors (n = 63) showed a positive correlation between the expression of NOS2 and the tryptophan/kynurenine pathway genes, including indoleamine-2,3-dioxygenase 1 (IDO1) and several aryl hydrocarbon receptor (AHR)-target genes including NFE2L2 (NRF2), SERPINB2, IL1b, IL6 and IL8, which are implicated in pancreatic cancer. Consistently, treatment of pancreatic cancer cell lines with NO donor induced IDO1, kynurenine production and the expression of AHR-target genes. Furthermore, kynurenine treatment enhanced spheroid growth and invasive potential of pancreatic cancer cell lines. Mechanistically, NO -induced IDO1/Kynurenine/AHR signaling was mediated by RUNX3 transcription factor. Our findings identified a novel NO /RUNX3/Kynurenine metabolic axis, which enhances disease aggressiveness in pancreatic cancer and may have potential translational significance in improving disease outcome.
130Carbidopa, an activator of aryl hydrocarbon receptor, suppresses IDO1 expression in pancreatic cancer and decreases tumor growth.PubMed
Ksenija Korac, Devaraja Rajasekaran, Tyler Sniegowski, et al.
Biochem J. 2022 Sep 16;479(17):1807-1824. doi: 10.1042/BCJ20210851.
IDO1 is an immunomodulatory enzyme responsible for tryptophan catabolism. Its expression in immune cells, especially the DCs, has attracted attention because it leads to tryptophan depletion at the immunological synapse, thereby causing T-cell anergy and immune evasion by the tumor cells. Cancer cells also overexpress IDO1. Immunotherapy targeting IDO1 has been one of the focus areas in cancer biology, but lately studies have identified non-immune related functions of IDO1 leading to a paradigm shift with regard to IDO1 function in the context of tumor cells. In this study, we show that PDAC tissues and PDAC cells overexpress IDO1. The expression level is reciprocally related to overall patient survival. We further show that carbidopa, an FDA-approved drug for Parkinson's disease as well as an AhR agonist, inhibits IDO1 expression in PDAC cells. Using athymic nude mice, we demonstrate that carbidopa-mediated suppression of IDO1 expression attenuates tumor growth. Mechanistically, we show that AhR is responsible for carbidopa-mediated suppression of IDO1, directly as a transcription factor and indirectly by interfering with the JAK/STAT pathway. Overall, targeting IDO1 not only in immune cells but also in cancer cells could be a beneficial therapeutic strategy for PDAC and potentially for other cancers as well and that carbidopa could be repurposed to treat cancers that overexpress IDO1.
131Dopamine is an aryl hydrocarbon receptor agonist.PubMed
Hyejin Park, Un-Ho Jin, Keshav Karki, et al.
Biochem J. 2020 Oct 16;477(19):3899-3910. doi: 10.1042/BCJ20200440.
Tryptophan metabolites exhibit aryl hydrocarbon receptor (AhR) agonist activity and recent studies show that the phenylalanine metabolites serotonin and carbidopa, a drug used in treating Parkinson's disease, activated the AhR. In this study, we identified the neuroactive hormone dopamine as an inducer of drug-metabolizing enzymes CYP1A1, CYP1B1, and UGT1A1 in colon and glioblastoma cells and similar results were observed for carbidopa. In contrast, carbidopa but not dopamine exhibited AhR activity in BxPC3 pancreatic cancer cells whereas minimal activity was observed for both compounds in Panc1 pancreatic cancer cells. In contrast with a previous report, the induction responses and cytotoxicity of carbidopa was observed only at high concentrations (100 µM) in BxPC3 cells. Our results show that similar to serotonin and several tryptophan metabolites, dopamine is also an AhR-active compound.
132The protective role of anti-parkinsonian drugs in pancreatic cancer risk: A comprehensive case-control study in Taiwan.PubMed
Hsuan-Chia Yang, Wen-Chi Chou, Phung-Anh Nguyen, et al.
Cancer Sci. 2025 Mar;116(3):783-791. doi: 10.1111/cas.16422. Epub 2024 Dec 4.
Pancreatic cancer is among the deadliest cancers, with a grim prognosis despite advances in treatment. We conducted a population-based case-control study from Taiwan, linking Health and Welfare Data Science Center data to the Taiwan Cancer Registry, which offers a promising strategy for its treatment through drug repurposing. The study aims to identify the association of anti-parkinsonian drugs with pancreatic cancer risk across different age groups. The analysis encompassed 18,921 pancreatic cancer cases and 75,684 matched controls, employing conditional logistic regression to assess the impact of anti-parkinsonian drugs on the risk of pancreatic cancer. Key findings revealed a statistically significant association of the administration with specific anti-parkinsonian medications, including anticholinergic agents, tertiary amines, dopa derivatives, and dopamine receptor agonists, with a reduction in pancreatic cancer risk. These associations were represented as adjusted odds ratios (aORs), ranging from 0.620 (95% CI 0.470-0.810) to 0.764 (95% CI 0.655-0.891). Further, age-stratified analysis revealed variations in efficacy across different age groups. Anticholinergic agents and tertiary amines exhibited greater effectiveness in the 40-64-year age group (aOR, 0.653; 95% CI, 0.489-0.872), whereas dopa derivatives and dopamine receptor agonists were particularly efficacious in the cohort aged ≥65 years (aOR, 0.728; 95% CI, 0.624-0.850 and aOR, 0.665; 95% CI, 0.494-0.894, respectively). Notably, specific drugs such as trihexyphenidyl, levodopa/dopa decarboxylase inhibitor (DDCI), and pramipexole demonstrated a significant decrease in cancer risk, especially in the elderly population. These preliminary findings can contribute to the possible therapeutic role of anti-parkinsonian drugs in the treatment of pancreatic cancer.
133Repurposing of metformin and aspirin by targeting AMPK-mTOR and inflammation for pancreatic cancer prevention and treatment.PubMed
Wen Yue, Chung S Yang, Robert S DiPaola, et al.
Cancer Prev Res (Phila). 2014 Apr;7(4):388-97. doi: 10.1158/1940-6207.CAPR-13-0337. Epub 2014 Feb 11.
Pancreatic cancer, as the fourth leading cause of cancer-related deaths, carries a poor prognosis with a median survival of 6 months and a dismal 5-year survival rate of 3% to 5%. These statistics highlight an urgent need for novel chemopreventive and therapeutic strategies for this malignancy. Metformin and aspirin have been explored as two emerging cancer chemoprevention agents for different types of cancers, including pancreatic cancer. Here, we review the effects of both metformin and aspirin on pancreatic tumorigenesis and their potential actions in pancreatic cancer. Special attention is paid to their effects on the important signaling pathways of pancreatic cancer development as well as possible mechanisms for synergy between these two agents. For metformin, the most important mechanism may involve the inhibition of mTOR signaling via AMP-activated protein kinase (AMPK)-dependent and -independent pathways. For aspirin, the major mechanism is the anti-inflammatory action through the inhibition of COX-1/COX-2 and modulation of the NFκB or STAT3 pathway. In addition, aspirin may activate AMPK, and both agents may affect Notch, Wnt/β-catenin, and other signaling pathways. The combination of metformin and aspirin will provide additive and possibly synergistic effects for the prevention and treatment of pancreatic cancer.
134Anti-tumor effect of statin on pancreatic adenocarcinoma: From concept to precision medicine.PubMed
Chung-Tsui Huang, Yao-Jen Liang
World J Clin Cases. 2021 Jun 26;9(18):4500-4505. doi: 10.12998/wjcc.v9.i18.4500.
A statin is a cholesterol-lowering agent, which inhibits HMG-CoA (3-hydroxy-3-methylglutaryl-coenzyme A) reductase and subsequently reduces the cholesterol precursor, and was first used commercially in 1987. The concept of cholesterol restriction leading to cancer cell dysfunction was proposed in 1992. The interruption of different signaling pathways has been proved in preclinical experiments to elucidate the anti-tumor mechanism of statins in pancreatic adenocarcinoma. Observational studies have shown that the clinical use of statins is beneficial in patients with pancreatic adenocarcinoma, including a chemoprevention effect, post-surgical resection follow-up and therapeutic prognosis of advanced cancer stage. Arrest of the cancer cell cycle by the combined use of gemcitabine and statin was observed in a cell line study. The effect of microbiota on the tumor microenvironment of pancreatic adenocarcinoma is a new therapeutic approach as statins can modulate the gut microbiota. Hence, further randomized trials of statins in pancreatic adenocarcinoma treatment will be warranted with application of precision medicine from microbiota-derived, cell cycle-based and signaling pathway-targeted research.
135Chemoprevention of pancreatic cancer by inhibition of glutathione-S transferase P1.PubMed
Takahiro Kogawa, Yasushi Sato, Rai Shimoyama, et al.
Invest New Drugs. 2021 Dec;39(6):1484-1492. doi: 10.1007/s10637-021-01129-y. Epub 2021 May 24.
Pancreatic cancer is among the most refractory malignancies with poor prognosis. Thus, preventive approaches, in addition to the development of novel therapeutic strategies are essential for this type of cancer. KRAS mutations occur very early in the development of pancreatic cancers and could be targeted for its prevention, yet specific inhibitors for mutated KRAS are lacking. Accordingly, Glutathione-S Transferase p1 (GSTP1), which we recently found to be an autocrine stimulator of mutated KRAS signaling, is predicted to be an alternative target for chemoprevention of pancreatic cancer. In this study, chemopreventive effects of O-Hexadecyl-γ-glutamyl-S-benzyl-cysteinyl-D-phenyl glycine-Ethylester (HGBPE), which we previously synthesized to inhibit GSTP1 activity, was analyzed for its effect on the prevention of a rat pancreatic carcinogenesis model induced by 7,12-dimethyl-benzanthracene (DMBA). Rats administered with DMBA were grouped into five cohorts. In the treated group I, which was treated neither with HGBPE nor vehicle, sequential appearance of precancerous lesions, ductal complexes, and adenocarcinoma was confirmed as previously reported. We also confirmed in this group that mutations of KRAS and expression of GSTP1 simultaneously occurred in the ductal complex. To rats of groups II and IV, HGBPE was administered, and vehicle to those of group III and V. In groups of II and IV, the incidence of both ductal complex and adenocarcinoma were significantly lower than those in groups III and V. These data clearly suggest the efficacy of HGBP as a potential chemopreventive agent for pancreatic cancer.
136Association of genetic risk and lifestyle with pancreatic cancer and their age dependency: a large prospective cohort study in the UK Biobank.PubMed
Liangtang Zeng, Zhuo Wu, Jiabin Yang, et al.
BMC Med. 2023 Dec 8;21(1):489. doi: 10.1186/s12916-023-03202-0.
BACKGROUND: Pancreatic cancer (PC) is influenced by both genetic and lifestyle factors. However, further research is still needed to comprehensively clarify the relationships among lifestyle, genetic factors, their combined effect on PC, and how these associations might be age-dependent. METHODS: We included 340,631 participants from the UK Biobank. Three polygenic risk score (PRS) models for PC were applied, which were derived from the previous study and were categorized as low, intermediate, and high. Two healthy lifestyle scores (HLSs) were constructed using 9 lifestyle factors based on the World Cancer Research Fund/American Institute of Cancer Research (WCRF/AICR) lifestyle score and the American Cancer Society (ACS) guidelines and were categorized as unfavorable, intermediate, and favorable. Data were analyzed using Cox proportional hazards models. RESULTS: There were 1,129 cases of incident PC during a median follow-up of 13.05 years. Higher PRS was significantly associated with an increased risk of PC (hazard ratio [HR], 1.58; 95% confidence intervals [CI], 1.47-1.71). Adhering to a favorable lifestyle was associated with a lower risk (HR, 0.48; 95% CI, 0.41-0.56). Participants with an unfavorable lifestyle and a high PRS had the highest risk of PC (HR, 2.84; 95% CI, 2.22-3.62). Additionally, when stratified by age, a favorable lifestyle was most pronounced associated with a lower risk of PC among participants aged ≤ 60 years (HR, 0.35; 95% CI, 0.23-0.54). However, the absolute risk reduction was more pronounced among those aged > 70 years (ARR, 0.19%, 95% CI, 0.13%-0.26%). A high PRS was more strongly associated with PC among participants aged ≤ 60 years (HR, 1.89; 95% CI, 1.30-2.73). Furthermore, we observed a significant multiplicative interaction and several significant additive interactions. CONCLUSIONS: A healthy lifestyle was associated with a lower risk of PC, regardless of the participants' age, sex, or genetic risk. Importantly, our findings indicated the age-dependent association of lifestyle and genetic factors with PC, emphasizing the importance of early adoption for effective prevention and potentially providing invaluable guidance for setting the optimal age to start preventive measures.
137A gene-environment-induced epigenetic program initiates tumorigenesis.PubMed
Direna Alonso-Curbelo, Yu-Jui Ho, Cassandra Burdziak, et al.
Nature. 2021 Feb;590(7847):642-648. doi: 10.1038/s41586-020-03147-x. Epub 2021 Feb 3.
Tissue damage increases the risk of cancer through poorly understood mechanisms. In mouse models of pancreatic cancer, pancreatitis associated with tissue injury collaborates with activating mutations in the Kras oncogene to markedly accelerate the formation of early neoplastic lesions and, ultimately, adenocarcinoma. Here, by integrating genomics, single-cell chromatin assays and spatiotemporally controlled functional perturbations in autochthonous mouse models, we show that the combination of Kras mutation and tissue damage promotes a unique chromatin state in the pancreatic epithelium that distinguishes neoplastic transformation from normal regeneration and is selected for throughout malignant evolution. This cancer-associated epigenetic state emerges within 48 hours of pancreatic injury, and involves an 'acinar-to-neoplasia' chromatin switch that contributes to the early dysregulation of genes that define human pancreatic cancer. Among the factors that are most rapidly activated after tissue damage in the pre-malignant pancreatic epithelium is the alarmin cytokine interleukin 33, which recapitulates the effects of injury in cooperating with mutant Kras to unleash the epigenetic remodelling program of early neoplasia and neoplastic transformation. Collectively, our study demonstrates how gene-environment interactions can rapidly produce gene-regulatory programs that dictate early neoplastic commitment, and provides a molecular framework for understanding the interplay between genetic and environmental cues in the initiation of cancer.
138Suboptimal adherence to surveillance in high-risk individuals for pancreatic cancer at a tertiary care academic center: Lessons from real-world surveillance patterns.PubMed
Alice A Lee, Abigail Twoy, Audrey Sutton, et al.
Pancreatology. 2025 Jun;25(4):540-543. doi: 10.1016/j.pan.2025.05.002. Epub 2025 May 10.
BACKGROUND/OBJECTIVES: Screening for pancreatic ductal adenocarcinoma alters the course of disease among high-risk individuals (HRIs) and is recommended by multiple societies including the International Cancer of the Pancreas Screening Consortium, American Gastroenterological Association, and American Society of Gastrointestinal Endoscopy. However, there are limited analyses on the screening rates and barriers to adherence among HRIs. This study aims to describe real-world longitudinal screening adherence of a HRI surveillance cohort and identify potential barriers to adherence. METHODS: Patients followed by Stanford's Benign Pancreas Clinic were identified as HRIs if they met screening criteria per the latest abovementioned screening guidelines, and were included in our study if they underwent at least 1 screening exam. Data on HRIs were obtained retrospectively from our hospital's electronic health record system. Patient and screening characteristics were analyzed by adherence rates. RESULTS: 262 HRIs undergoing recommended screening were identified. The mean follow-up time per patient was 4.9 years and the mean successful annual screening rate within the entire cohort was 67%. HRIs in the lowest quartile of adherence were more likely to have more EUS rather than MRI surveillance exams compared to those who were completely adherent (p = 0.01). HRIs who were completely adherent were also an older cohort compared to those with non-complete adherence (p = 0.02) or in the lowest quartile of adherence (p = 0.01). CONCLUSIONS: It is difficult to achieve high adherence rates for annual pancreatic cancer screening of HRIs as recommended by the latest guidelines. Age and screening modality may be factors that contribute to adherence difficulty.
139Early Supportive and Nutritional Care For Adults With Pancreatic Cancer: A Pilot Study.PubMed
Yu Chen Lin, Kea Turner, Sahana Rajasekhara, et al.
J Pain Symptom Manage. 2025 Nov;70(5):490-502. doi: 10.1016/j.jpainsymman.2025.07.032. Epub 2025 Aug 13.
CONTEXT: Individuals diagnosed with advanced pancreatic cancer face a poor prognosis, heightening the importance of interventions aimed at improving quality of life. Quality of life for individuals with pancreatic cancer is highly influenced by symptom burden and nutritional status. Programs are needed that coordinate palliative and nutrition care for this population. OBJECTIVES: To address this gap, we conducted a single-arm feasibility trial of Support Through Remote Observation and Nutrition Guidance Plus Supportive Care (STRONG+), a 12-week team-based digital intervention to reduce malnutrition and improve quality of life for individuals with advanced pancreatic cancer. METHODS: Participants initiating palliative chemotherapy were referred for early and ongoing dietitian-led nutrition counseling and supportive care visits led by a palliative care specialist during the first three months of chemotherapy. Participants also logged food intake daily and completed patient-reported outcome assessments monthly, data that was shared with the dietitian and palliative care specialist through a web-based dashboard. Feasibility and acceptability outcomes were compared against prespecified benchmarks. Preliminary effectiveness was evaluated based on change in patient outcomes between baseline and last follow-up at 16 weeks using linear and ordered logistic regression models. Outcomes included malnutrition risk assessed using the Patient-Generated Subjective Global Assessment Short Form and health-related quality of life measured using the FACT-G. Qualitative data obtained through interviews with participants, their caregivers, and clinicians was analyzed for themes. RESULTS: Among the 83 eligible patients who were invited to participate in the study, 50 patients consented to participate. A total of 12 individuals withdrew or died prior to study conclusion. Participants who completed the study (N = 38) had a mean age of 65. Feasibility benchmarks were achieved for participant recruitment (60% vs. benchmark: 50%), attrition (24% vs. benchmark: 30%), study assessment completion (84% vs. benchmark: 70%), and adherence to nutritional counseling (68% vs. benchmark: 60%) and supportive care visits (61% vs. benchmark: 60%). Participants found the overall intervention to be highly acceptable (94% vs. benchmark: 70%). Caregivers also rated the intervention as highly satisfactory (87%). Compared to baseline, participants saw decreased malnutrition risk (P < .001) and improved general health-related quality of life (P = .009) at the end of the study (16 weeks). Participants cited benefits of the intervention including increased knowledge about self-managing nutrition and improved symptom management. Participants provided recommendations for intervention refinement, such as providing recipes and more hands-on nutrition instruction. CONCLUSION: Study findings suggest the intervention may be feasible and acceptable. Future research is needed to refine the intervention and test the intervention in a fully powered trial. Because the study focused on patients initiating palliative chemotherapy who may benefit from nutrition counseling, findings may be limited in generalizability to all individuals with pancreatic cancer.
140Current paradigm and futuristic vision on new-onset diabetes and pancreatic cancer research.PubMed
Russell Moreland, Abigail Arredondo, Anupam Dhasmana, et al.
Front Pharmacol. 2025 May 23;16:1543112. doi: 10.3389/fphar.2025.1543112. eCollection 2025.
New-onset diabetes (NOD) has emerged as a potential early indicator of pancreatic cancer (PC), necessitating a refined clinical approach for risk assessment and early detection. This study discusses critical gaps in understanding the NOD-PC relationship and proposes a multifaceted approach to enhance early detection and risk assessment. We present a comprehensive clinical workflow for evaluating NOD patients, incorporating biomarker discovery, genetic screening, and AI-driven imaging to improve PC risk stratification. While existing models consider metabolic factors, they often overlook germline genetic predispositions that may influence disease development. We propose integrating germline genetic testing to identify individuals carrying pathogenic variants in cancer-susceptibility genes (CSGs), enabling targeted surveillance and preventive interventions. To advance early detection, biomarker discovery studies must enroll diverse patient populations and utilize multi-omics approaches, including genomics, proteomics, and metabolomics. Standardized sample collection and AI-based predictive modeling can refine risk assessment, allowing for personalized screening strategies. To ensure reproducibility, a multicenter research approach is essential for validating biomarkers and integrating them with clinical data to develop robust predictive models. This multidisciplinary strategy, uniting endocrinologists, oncologists, geneticists, and data scientists, holds the potential to revolutionize NOD-PC risk assessment, enhance early detection, and pave the way for precision medicine-based interventions. The anticipated impact includes improved early detection, enhanced predictive accuracy, and the development of targeted interventions to mitigate PC risk.