1. 从“小炎症”到“大癌症”：慢性炎症与癌症的底层关联
1.1 慢性炎症的“持久战”：什么是慢性炎症？
想象一下，我们的身体里住着一群尽职尽责的“保安”（免疫细胞），它们每天都在巡逻，一旦发现有“坏人”（细菌、病毒等病原体）入侵，或者身体某个地方“着火了”（组织损伤），这群保安就会立刻冲上去，展开一场轰轰烈烈的“自卫反击战”。这就是我们常说的“急性炎症”。急性炎症的特点是来得快、去得也快，红、肿、热、痛这些症状就像警报声，提醒我们身体出了问题，然后保安们迅速平息“战火”，清理战场，身体很快就能恢复正常。
然而，有些时候，“战火”却迟迟无法平息，或者反反复复地烧个不停，这就演变成了“慢性炎症” 12。慢性炎症就像一场旷日持久的“持久战”，它不再像急性炎症那样声势浩大，而是以一种低调、隐蔽的方式持续进行。身体里的“保安”们虽然还在工作，但它们已经筋疲力尽，无法彻底清除“敌人”或修复损伤，反而可能因为长时间的“战斗”而误伤“友军” 3。
那么，究竟是什么原因让身体陷入这种无休止的“持久战”呢？常见的“肇事者”包括：
- 持续性感染： 比如某些病毒（像乙肝、丙肝病毒）或细菌（像幽门螺杆菌）在体内长期安家落户，免疫系统拿它们没办法，只能持续不断地攻击 45。
- 代谢异常： 肥胖就是其中一个重要原因。脂肪细胞过多会引发低水平的慢性炎症，就像身体里总有一小撮火苗在燃烧 6。
- 自身免疫疾病： 免疫系统“敌我不分”，把自己的细胞和组织当成敌人来攻击，比如类风湿关节炎、炎症性肠病等。
- 环境毒素和不良生活习惯： 吸烟、酗酒、空气污染、不良饮食、长期精神压力等，都会给身体带来持续性的刺激和损伤，从而引发慢性炎症 47。
慢性炎症之所以危险，是因为它就像一个“温水煮青蛙”的过程，症状可能不明显，甚至根本没有症状，但它却在暗中对我们的身体造成日积月累的伤害，为很多重大疾病埋下祸根，其中就包括癌症 4。
1.2 炎症-癌症的“危险循环”：慢性炎症如何成为癌症的温床？
慢性炎症与癌症之间，存在着一个你来我往、相互促进的“危险循环” 8。我们可以把这个过程想象成一个恶性工厂的建立和运作：
- “战场”的持续损伤与修复： 在慢性炎症的“战场”上，身体组织会不断地受到损伤，然后又不断地尝试修复。这个过程中，细胞需要加速分裂和生长来填补“空缺” 9。然而，细胞分裂的次数越多，出错的几率就越大，就像复印机不停地复印，时间久了总会出现错别字一样。这些“错别字”就是基因突变，它们是癌症发生的原始驱动力。
- “助燃剂”的煽风点火： 慢性炎症会释放出大量的“助燃剂”，我们称之为“炎症因子”和“生长因子”。这些物质就像给细胞生长加了速，也为癌细胞的生长提供了肥沃的土壤 9。它们不仅能直接刺激癌细胞的增殖，还能帮助癌细胞逃避免疫系统的追捕，甚至诱导新的血管生成，为肿瘤提供营养，让它们更加肆无忌惮地野蛮生长。
- 免疫系统的“疲惫与背叛”： 长期处于慢性炎症状态，身体的“保安队”（免疫系统）可能会变得疲惫不堪，无法有效识别和清除那些发生突变的“叛变”细胞，反而有时会成为癌细胞的“帮凶”，提供有利的生长环境 810。
- “毒素”的累积与DNA损伤： 慢性炎症还会产生大量的“氧化应激”产物，这些产物就像细胞内的“毒素”，可以直接攻击我们细胞的遗传物质——DNA，造成DNA损伤 9。DNA损伤如果不能及时修复，就可能导致基因突变，进一步增加癌变的风险。
简而言之，慢性炎症就像一个恶毒的“催化剂”和“孵化器”，它通过反复的组织损伤和修复、持续的炎症因子刺激、免疫系统的功能失调以及氧化应激带来的DNA损伤，一步步地为癌细胞的诞生、发展和扩散铺平道路，最终让“小炎症”酿成“大癌症” 89。
2. 慢性病毒性肝炎：肝脏反复“受伤”后的癌变陷阱
在所有与癌症相关的慢性炎症中，肝脏的慢性病毒性肝炎是一个非常典型且危害巨大的例子。肝脏，这个我们身体里最大的化工厂，每天都在默默地工作，代谢、解毒、生产各种重要物质。然而，一旦被乙肝病毒（HBV）或丙肝病毒（HCV）盯上，它就可能陷入一场无休止的“战争”，最终走向肝癌的深渊。
2.1 肝炎病毒的“潜伏战”：乙肝/丙肝如何引发慢性炎症？
想象一下，肝脏就像一个繁忙的“城市”，里面住着无数的“居民”（肝细胞）。而乙肝病毒（HBV）和丙肝病毒（HCV）就是两种非常狡猾的“入侵者”。它们不会像急性炎症那样直接摧毁城市，而是悄悄地潜入肝细胞内部，利用肝细胞的资源大量复制自己。这种感染一旦发生，往往就会变成一场漫长的“潜伏战” 11。
乙肝病毒（HBV）： 这种病毒感染后，大部分成年人可以通过自身的免疫力清除病毒。但对于一部分人，特别是围产期感染的婴儿，他们的免疫系统不够强大，无法彻底清除病毒，HBV就会在肝细胞里长期安家落户，形成慢性感染 12。虽然HBV自身并不直接杀死肝细胞，但它会引发身体免疫系统对被感染肝细胞的持续攻击。我们的免疫细胞会试图消灭藏匿病毒的肝细胞，就像“警察”追捕“坏蛋”一样。在这个过程中，无辜的肝细胞也会被卷入“战火”，造成肝脏组织反复损伤 12。更令人担忧的是，HBV还会悄悄地将自己的一部分遗传物质整合到肝细胞的DNA中，这就像在肝细胞的“设计图纸”上做了手脚，为未来的癌变埋下了伏笔 13。
丙肝病毒（HCV）： 与乙肝病毒类似，HCV也是一种非常擅长“躲猫猫”的病毒。一旦感染，大约75%到85%的人会发展成慢性丙型肝炎 11。HCV通过多种手段逃避免疫系统的侦察和清除，使得身体难以对其产生有效的免疫反应 14。HCV感染同样会导致免疫系统对肝细胞的持续攻击，引起肝脏反复的炎症和损伤 14。与HBV不同的是，HCV是一种RNA病毒，通常不会将自身基因整合到宿主细胞的DNA中，但它会通过病毒蛋白与细胞内的各种信号通路相互作用，直接或间接地促进细胞癌变 15。
无论是乙肝病毒还是丙肝病毒，它们在肝细胞内的持续存在，都会导致肝脏长期处于一种低水平的慢性炎症状态。肝细胞不断地被免疫系统攻击、受损、然后再生修复。这种周而复始的“损伤-修复”循环，正是肝脏走向癌变的第一步，也是最关键的一步。
2.2 从肝炎到肝癌的“三步曲”：纤维化→肝硬化→肝癌
肝炎病毒的“潜伏战”带来的持续炎症，就像在肝脏这片“土地”上不断制造着伤口。面对这些伤口，肝脏会启动自身的修复机制，但如果损伤持续不断，修复过程就会逐渐“跑偏”，最终形成一个从“受伤”到“变硬”，再到“癌变”的“三步曲” 16：
- 第一步：肝纤维化——“伤疤”初现。
当肝脏长期发炎、肝细胞反复受损死亡时，身体会启动修复程序，试图弥补这些损失。在这个过程中，一种平时“沉睡”在肝脏里的特殊细胞——肝星状细胞（Hepatic Stellate Cells, HSCs）会被“唤醒” 1718。你可以把它想象成肝脏里的“建筑工人”。正常情况下，它们安安静静地待着，肝脏有小损伤时，它们会出来帮忙修复。但当慢性炎症长期存在，这些“建筑工人”就会变得异常活跃和勤奋，开始大量生产一种叫做胶原蛋白的物质，也就是我们常说的“疤痕组织” 18。这些胶原蛋白会在肝细胞之间过度堆积，就像在原本柔软的肝脏里不断织入坚韧的“钢筋水泥”，导致肝脏组织变得僵硬，这就是肝纤维化 18。一开始的纤维化可能只是零星的“伤疤”，对肝功能影响不大，但它预示着肝脏健康正在恶化 19。而且，这些被激活的肝星状细胞还会释放一些信号分子，反过来促进肝癌的发生发展 202122。 - 第二步：肝硬化——“城市”彻底变硬，功能受损。
如果肝纤维化得不到控制，持续进展，肝脏内的“钢筋水泥”越积越多，最终会把整个肝脏变成一个又硬又凹凸不平的“石头疙瘩”，这就是肝硬化 16。肝硬化意味着肝脏的正常结构被严重破坏，无数肝细胞组成的“小叶”结构变得混乱不堪，肝脏的血流也会受到阻碍。这就像一个原本功能完善的城市，现在道路堵塞，工厂停工，居民生活一片混乱。肝脏的排毒、合成、代谢等功能都会大打折扣，出现各种严重的并发症，比如腹水、消化道出血、肝性脑病等 16。更糟糕的是，肝硬化是肝癌最主要的危险因素之一。统计数据显示，超过90%的肝癌都发生在肝硬化的基础上 2324。这时的肝脏，已经为癌细胞的出现准备好了“温床”。 - 第三步：肝癌——“叛变”的细胞失控生长。
在肝硬化的“废墟”之上，那些反复受损又反复增殖修复的肝细胞，在长期炎症、氧化应激、病毒基因整合（如乙肝病毒）以及免疫功能失调等多重打击下，基因出错的几率大大增加 2526。其中一些细胞可能会发生关键性的基因突变，获得失控生长的能力，彻底“叛变”成为癌细胞。它们不再遵守身体的指令，而是疯狂地分裂繁殖，形成恶性肿瘤，这就是肝细胞癌（HCC） 1626。
从慢性肝炎到肝癌，是一个漫长而隐蔽的过程。乙肝病毒和丙肝病毒的持续感染是肝癌发生的主要原因 25。肝脏长期处于慢性炎症状态，细胞损伤修复过程中的基因突变累积，加上肝星状细胞的异常激活和胶原蛋白的过度沉积，一步步将肝脏推向了纤维化、硬化，最终诱发了癌变。除了病毒因素，脂肪肝、酒精滥用等也会加剧肝纤维化和肝硬化的进程，进一步增加肝癌风险 2728。
2.3 阻断癌变的关键：抗病毒治疗与定期筛查的重要性
面对慢性肝炎这个通往肝癌的“危险路径”，我们并非束手无策。科学家们已经找到了“阻断”这条路径的关键方法：积极的抗病毒治疗和定期的肝癌筛查。
1. 抗病毒治疗：釜底抽薪，抑制病毒复制
对于乙肝和丙肝这两种病毒引起的慢性肝炎，最直接有效的办法就是用药物来抑制病毒的复制，减轻肝脏的炎症反应。这就像是从源头上“釜底抽薪”，减少肝脏反复损伤的机会。
对付乙肝病毒（HBV）： 目前主要使用的是核苷（酸）类似物（比如恩替卡韦、替诺福韦等）和干扰素 。核苷（酸）类似物的作用机制是干扰病毒的复制过程，就像给病毒的“生产线”设置了障碍，让它们无法继续制造新的病毒颗粒 。这类药物通常需要长期甚至终身服用，虽然不能彻底清除病毒，但能有效抑制病毒活性，降低肝炎发作的频率和强度，从而显著减少肝硬化和肝癌的发生风险 29303132。干扰素则是一种能调节免疫系统的药物，它能增强身体对抗病毒的能力，部分患者通过干扰素治疗可以实现病毒的长期抑制甚至清除，但副作用相对较多，使用需要更加谨慎 3334。
对付丙肝病毒（HCV）： 幸运的是，丙肝的治疗已经取得了突破性的进展。现在有一种叫做直接抗病毒药物（DAAs）的“神药”，它能够直接针对HCV复制过程中的关键环节进行打击。这些药物的治疗效果非常好，治愈率可以达到95%以上，很多患者在短时间内就能彻底清除体内的HCV病毒，从而大大降低肝硬化和肝癌的风险 34353637。
无论哪种抗病毒治疗，其核心目的都是通过抑制病毒复制，减少肝细胞的损伤和炎症，从而阻断或延缓肝纤维化、肝硬化向肝癌发展的进程 37。对于已经发展到肝硬化的患者，即使病毒被清除或抑制，仍需要警惕肝癌的风险，因为肝脏已经受到了不可逆的损伤 38。
2. 定期筛查：早发现、早治疗，抓住“救命稻草”
即使进行了抗病毒治疗，慢性肝炎患者，特别是已经有肝硬化的患者，仍有发生肝癌的风险。因此，定期的肝癌筛查就显得尤为重要，它能帮助我们在肝癌早期，也就是更容易治疗的阶段发现问题，就像在“星星之火”刚刚燃起时就把它扑灭。
常用的筛查方法主要有两种：
- 甲胎蛋白（AFP）检测： 甲胎蛋白是肝癌细胞分泌的一种蛋白质。通过抽血检测血液中AFP的含量，可以作为肝癌的一个“生物标记物” 。虽然AFP的升高不一定都是肝癌引起（比如慢性肝炎活动期也可能升高），但结合其他检查，它能提供重要的预警信息。
- 腹部超声检查： 这是一种无创、经济且常用的影像学检查。它能清晰地显示肝脏的形态、大小、内部结构，发现肝脏是否有占位性病变（也就是肿瘤） 。
很多专业机构都建议，对于慢性肝炎伴肝硬化的患者，或者其他高风险人群，应该每隔6个月进行一次腹部超声和AFP检测 39404142。研究表明，将超声和AFP检测结合起来，能显著提高早期肝癌的检出率 3942。
此外，随着科技的进步，一些更先进的检测手段也在发展中，比如通过检测血液中的循环肿瘤DNA（ctDNA）来发现早期肝癌，这有望在未来提供更精准的早期诊断 4344。
总而言之，对于慢性病毒性肝炎患者，积极遵从医嘱进行抗病毒治疗，最大程度地抑制病毒、减轻肝脏炎症；同时，不间断地进行定期的肝癌筛查，就像给肝脏装上“预警系统”，一旦出现异常就能及时发现并处理，这样才能最大限度地降低肝癌的发生风险，保护我们的生命健康。
3. 幽门螺杆菌胃炎：胃黏膜“持久战”后的癌变隐患
除了肝脏，我们的胃部也常常是慢性炎症的“受害者”，而这背后最常见的“元凶”就是一种叫做幽门螺杆菌（Helicobacter pylori，简称Hp）的细菌。这种细菌在全球范围内感染率极高，大约一半的人口都可能携带这种细菌 45。它可以在胃酸强腐蚀性的环境中安然无恙地生存，并且一旦在胃黏膜定居下来，就可能引发一场旷日持久的慢性炎症，最终为胃癌埋下隐患。
3.1 幽门螺杆菌的“入侵术”：细菌如何在胃里引发慢性炎症？
想象一下，我们的胃就像一个自带强大“腐蚀液”（胃酸）的“堡垒”，胃壁上覆盖着一层厚厚的“城墙”（胃黏膜），这层城墙能抵御胃酸的侵蚀，保护胃部免受损伤。然而，幽门螺杆菌这种狡猾的“入侵者”却拥有一套独特的“入侵术”，能成功突破这道防线，并在胃里安营扎寨，引发持续的“战火”：
- “伪装与钻营”：适应胃酸环境。 幽门螺杆菌最厉害的一点是它能分泌一种叫做尿素酶的物质。这种酶可以把胃里的尿素分解成氨。氨是碱性的，能中和胃酸，在细菌周围形成一个“保护罩”，让它不被胃酸杀死 4647。有了这个“保护罩”，Hp就能在胃里找到合适的落脚点，并在胃黏膜表面“钻营”进去，牢牢地附着在胃壁上。
- “毒性武器”：破坏胃黏膜屏障。 幽门螺杆菌并非“善类”，它还携带着多种“毒性武器”，也被称为毒力因子，来破坏我们的胃黏膜防线，并引发强烈的炎症反应 48。其中最臭名昭著的两个就是：
- CagA蛋白（细胞毒素相关基因A蛋白）： 这就像Hp抛出的一个“炸弹”。当Hp通过一个特殊的“注射器”系统（IV型分泌系统）把CagA蛋白注入到胃黏膜细胞里时，CagA就会在细胞内部大搞破坏，干扰细胞正常的信号传导，改变细胞的形态，甚至让细胞更容易发生癌变 4849。
- VacA蛋白（空泡细胞毒素A）： 这个“毒素”会导致胃黏膜细胞内部形成空泡，破坏细胞的结构和功能，削弱胃黏膜的屏障作用，让胃壁变得更加脆弱 4849。VacA还能抑制免疫细胞的活性，帮助Hp逃脱清除 50。
这些毒力因子还会直接或间接地破坏细胞间的紧密连接（tight junctions），紧密连接就像细胞之间相互连接的“水泥”，确保胃黏膜细胞排列紧密，形成一道难以逾越的屏障。一旦这些“水泥”被破坏，屏障出现“裂缝”，胃酸、消化酶和其他有害物质就能渗透进去，进一步损伤胃黏膜 51。
- “点燃战火”：激活免疫细胞。 幽门螺杆菌及其分泌的毒素还会像“警报器”一样，持续不断地激活胃黏膜下的各种免疫细胞。
因此，幽门螺杆菌的“入侵术”不仅包括了巧妙地适应胃部环境，还通过其独特的毒力因子直接破坏胃黏膜屏障，并持续不断地激活免疫系统，引发慢性炎症。这种慢性炎症就像在胃里埋下了一颗“定时炸弹”，让胃黏膜长期处于“战火连天”的状态，为后续的癌变埋下了伏笔 5960。
3.2 胃癌的“前奏曲”：从胃炎到肠化生、异型增生的演变
幽门螺杆菌（Hp）引起的慢性胃炎，如果长期得不到有效干预，就可能启动一个被称为“Correa's cascade”的胃癌演变过程。这个过程就像一首漫长而危险的“前奏曲”，胃黏膜在反复的炎症刺激下，会经历一系列逐步加重的病理变化，最终可能发展成胃癌 61。我们可以将其概括为：慢性胃炎 → 胃黏膜萎缩 → 肠上皮化生 → 异型增生 → 胃癌。
慢性胃炎：炎症的起点，黏膜的挣扎
正如前面所说，Hp在胃里安营扎寨后，会持续刺激胃黏膜，引发免疫反应，导致慢性胃炎。胃黏膜长期处于“战火”之中，虽然细胞会努力修复，但这种反复的损伤和修复，使得黏膜细胞始终处于一种不稳定的状态。炎症因子不断释放，细胞增殖加速，为后续的病变埋下伏笔。胃黏膜萎缩：腺体“凋零”，功能减退
慢性炎症持续多年后，胃黏膜的腺体细胞会逐渐减少甚至消失，胃壁变得越来越薄，这就是胃黏膜萎缩。萎缩的胃黏膜分泌胃酸和消化酶的能力会大大下降，胃的消化功能开始受到影响。这时候，胃黏膜的“城墙”变得更加脆弱，更容易受到外界刺激的伤害。肠上皮化生：胃细胞“变脸”成肠细胞
在胃黏膜萎缩的基础上，一些胃黏膜细胞为了适应长期炎症和胃内环境的改变，会发生一种奇怪的“变脸”现象——它们不再长成胃细胞的样子，反而变成了肠道细胞的模样，甚至开始分泌肠道细胞特有的黏液，这种现象叫做肠上皮化生（Intestinal Metaplasia，简称IM）62。这就像胃里的“原住民”为了生存，放弃了自己的身份，变成了“外来户”。肠上皮化生被认为是胃癌的癌前病变之一，有研究表明，肠上皮化生与结肠息肉的风险增加有关 62。有研究表明，幽门螺杆菌感染与异常的DNA甲基化有关，而DNA甲基化可能在胃黏膜萎缩和肠上皮化生等癌前病变中发挥关键作用 6364。肠上皮化生细胞的DNA异常甲基化，使得它们更可能转化为癌细胞 65。异型增生（不典型增生）：细胞“变异”，癌症边缘
如果肠上皮化生继续发展，细胞的形态和结构会发生进一步的异常变化，变得“不像好细胞”，甚至出现核增大、核分裂活跃等情况，这被称为异型增生（或称不典型增生）。异型增生根据其严重程度分为轻、中、重度。重度异型增生距离真正的胃癌只有一步之遥，被认为是高度的癌前病变，有很高的癌变风险。在这个阶段，细胞已经开始出现失控生长的趋势，基因突变也在不断累积。胃癌：癌细胞的彻底“叛变”
最终，在持续的炎症刺激、基因突变累积、细胞凋亡失衡以及免疫系统功能异常等多重因素的综合作用下，部分异型增生细胞会彻底突破束缚，获得无限增殖和侵袭的能力，最终形成胃癌 66。
癌变背后的“分子推手”：
在这个漫长的演变过程中，有一些关键的“分子推手”在暗中作祟：
- NF-κB通路的激活： 幽门螺杆菌感染会显著激活细胞内的NF-κB信号通路 6667。NF-κB就像细胞内的一个“总开关”，它被激活后，会促使细胞产生大量的炎症因子、细胞生长因子和抗凋亡蛋白 6869。这不仅加剧了炎症反应，还为受损细胞的异常增殖提供了有利条件，并抑制了癌变细胞的自我清除，从而促进癌前病变向癌症发展 66。
- DNA甲基化异常： 幽门螺杆菌的慢性感染还会导致胃黏膜细胞的DNA甲基化发生异常 647071。DNA甲基化是一种表观遗传学修饰，它不会改变DNA序列本身，但会影响基因的表达。当一些本应抑制肿瘤生长的基因（抑癌基因）的启动子区域发生异常甲基化时，这些基因就会被“沉默”，无法发挥正常功能，从而为癌细胞的生长提供了便利 636467。这种异常甲基化在慢性胃炎、肠上皮化生和异型增生阶段就已经出现，并且随着病变进展而加重 65。
- 氧化应激和DNA损伤： 幽门螺杆菌感染引起的炎症反应会产生大量的活性氧自由基，导致胃黏膜细胞持续处于氧化应激状态 66。活性氧会直接攻击DNA，造成DNA损伤和突变。如果这些损伤不能及时修复，就会导致基因组不稳定，增加癌变的风险 6672。有研究发现，在Hp感染的胃黏膜中，脂质过氧化产生的二羰基亲电试剂（如异左旋葡糖醛酸）会与DNA形成加合物，导致DNA损伤和体细胞突变，从而促进癌症发生 6672。
因此，幽门螺杆菌不仅仅是一个引发胃部不适的细菌，它更像是一个“慢性煽动者”，通过引发持续的炎症、改变细胞的正常生长调控，一步步地将胃黏膜推向胃癌的深渊。理解这一过程，对于我们早期预防和干预胃癌至关重要。
3.3 逆转风险的机会：根除Hp与胃黏膜监测的价值
面对幽门螺杆菌（Hp）在胃里布下的“癌变前奏曲”，我们并非无计可施。幸运的是，通过根除Hp感染和对胃黏膜进行定期监测，我们可以有效地“逆转”或“叫停”这场危险的演变，大大降低胃癌的发生风险。
1. 根除Hp：拆除“定时炸弹”，让炎症平息
既然幽门螺杆菌是胃癌发生的重要“元凶”，那么最直接有效的策略就是将其从胃中彻底清除。这就像拆除了胃里的“定时炸弹”，让持续已久的慢性炎症得以平息。
- 清除Hp的重要性： 大量研究证实，根除Hp感染能够显著降低胃炎的严重程度，逆转胃黏膜萎缩，甚至可能逆转部分肠上皮化生，从而有效降低胃癌的发生风险 737475。世界卫生组织（WHO）下属的国际癌症研究机构（IARC）早在1994年就将Hp列为I类致癌物，强调了其与胃癌的明确关联，并提示根除Hp可能预防胃癌的发生 76。
- 根除治疗方案： 目前常用的Hp根除治疗方案被称为三联疗法或四联疗法 777879。这些方案通常包括：
由于抗生素耐药性的不断增加，传统的三联疗法效果正在下降，而含有铋剂的四联疗法或不含铋剂的伴随疗法（concomitant therapy）正成为更推荐的一线治疗方案，尤其是在克拉霉素耐药率较高的地区 77787981。一般疗程为10-14天。治疗结束后，需要进行复查以确认Hp是否被成功清除。
成功根除Hp后，胃黏膜的炎症反应会明显减轻，胃黏膜萎缩和肠上皮化生的进展也会减缓甚至部分逆转，从而为胃黏膜的自我修复创造了条件，大大降低了胃癌的风险 74。
2. 胃黏膜监测：盯紧“癌前病变”，早期干预是关键
虽然根除Hp能有效降低胃癌风险，但对于已经存在胃黏膜萎缩、肠上皮化生或异型增生等癌前病变的患者，胃癌的风险依然存在。因此，定期的胃镜检查和活检监测变得至关重要，它能帮助我们在癌变发生前或早期发现问题，及时进行干预 7382。
- 胃镜筛查的价值：
- 直观观察： 胃镜可以直接观察胃黏膜的颜色、形态和质地，发现肉眼可见的异常病变，如溃疡、息肉、黏膜隆起或凹陷等。
- 活检病理： 通过胃镜取活组织进行病理检查（活检），是诊断胃黏膜萎缩、肠上皮化生、异型增生和胃癌的金标准 7382。病理医生会在显微镜下评估细胞的形态变化，判断病变的严重程度。建议采用规范的胃镜活检方案，比如“更新的悉尼系统”（Updated Sydney System），从胃的不同部位（如胃窦、胃体小弯、胃体大弯、胃角）取样，以全面评估胃黏膜状况 7382。
- 高危人群筛查： 对于有胃癌家族史、来自胃癌高发地区的第一代移民、以及存在严重胃黏膜萎缩、肠上皮化生或异型增生的人群，定期胃镜筛查尤其重要 738384。
- 监测频率：
- 内镜技术的发展： 随着内镜技术（如色素内镜、放大内镜、窄带成像NBI等）的进步，医生能更清楚地观察胃黏膜的微细结构和血管纹理，提高癌前病变和早期胃癌的检出率 7382。
总而言之，通过及时有效的Hp根除治疗，我们可以阻止或逆转胃黏膜的癌变进程，让胃部炎症平息；同时，对于已经存在癌前病变的患者，定期的胃镜监测则像一双“火眼金睛”，帮助我们及时发现潜在的风险，将胃癌扼杀在萌芽状态。两者的结合，为我们提供了逆转胃癌风险的重要机会。
4. 慢性胰腺炎：胰腺“反复发炎”后的癌变警报
胰腺，这个藏在我们胃后面深处的狭长腺体，虽然体积不大，但作用却非常关键。它不仅能分泌胰岛素等激素来调节血糖，还是身体里重要的“消化酶工厂”，生产各种消化酶来帮助我们分解食物。然而，一旦胰腺反复发炎，陷入慢性胰腺炎的泥潭，它就可能从一个默默奉献的器官，变成一个随时可能拉响“癌变警报”的危险之地。
4.1 胰腺的“自我攻击”：哪些因素引发慢性胰腺炎？
慢性胰腺炎的发生，常常是胰腺遭受反复“攻击”的结果。这些攻击让胰腺的细胞反复受损，然后又尝试修复，但最终却陷入了一种持续的炎症状态，并逐渐被纤维化的组织所取代，导致功能逐渐丧失 8687。那么，到底是谁在“攻击”我们的胰腺呢？常见的“肇事者”包括：
酒精：胰腺的“头号杀手”
长期大量饮酒是导致慢性胰腺炎最主要的原因之一 8889。酒精及其代谢产物对胰腺来说，就像“毒药”一样。它会直接损伤胰腺细胞（特别是腺泡细胞），让它们变得脆弱，更容易“自爆” 9091。更糟糕的是，酒精还会改变胰腺分泌物的性质，让消化酶在胰腺内部过早地被激活，而不是等到进入肠道才工作。这就像胰腺自己生产的“武器”在工厂里就炸开了，造成胰腺的“自我消化”和炎症 92。虽然酒精不直接导致慢性胰腺炎，但它使胰腺易受其他因素损害 89。胆道疾病（特别是胆结石）：堵塞的“下水道”
胆结石是急性胰腺炎最常见的原因，而反复的急性胰腺炎是发展成慢性胰腺炎的重要风险因素 93。我们的胰管和胆总管在汇合后常常共用一个出口进入小肠。如果胆结石卡在了这个共同出口，就像堵住了“下水道”，胰液无法顺利排出，导致胰管内压力升高，胰酶在胰腺内部“逆流而上”，过早激活，从而引发炎症和损伤 9294。遗传因素：隐藏的“先天缺陷”
有些人天生就带有某些基因缺陷，使得他们的胰腺更容易发炎。比如，与胰蛋白酶原（PRSS1）和胰酶抑制剂（SPINK1）基因相关的突变，会增加胰蛋白酶在胰腺内异常激活的风险，从而导致遗传性慢性胰腺炎 95。这就像胰腺的“出厂设置”就有问题，使得它对损伤的抵抗力更弱。代谢异常与肥胖：身体内部的“火药桶”
肥胖本身就是一种慢性炎症状态，它会增加急性胰腺炎的风险，并且可能加重胰腺炎的严重程度 96。高血脂，特别是高甘油三酯血症，也是一个重要的风险因素，过高的甘油三酯可能直接损伤胰腺细胞。糖尿病患者，特别是患有胰腺源性糖尿病（3c型糖尿病）的患者，也更容易发展为慢性胰腺炎 97。自身免疫性疾病：免疫系统的“误伤”
在少数情况下，免疫系统会错误地攻击自身的胰腺组织，导致自身免疫性胰腺炎。这就像身体的“保安”把自己的器官当成了敌人，从而引发持续的炎症反应。吸烟：火上浇油的“帮凶”
吸烟会增加慢性胰腺炎的发生风险和疾病进展，它可能通过多种机制直接或间接地损伤胰腺 88。
这些诱因最终都会导致一个共同的结果：胰腺腺泡细胞损伤和胰酶异常激活。胰腺腺泡细胞是分泌消化酶的“工厂”，当它们受损时，细胞内部的消化酶可能会提前被激活。这些被激活的消化酶就像“脱缰的野马”，在胰腺内部对胰腺组织进行“自我消化”，引起剧烈的炎症反应 86919899。这种持续的“自我攻击”和炎症，正是慢性胰腺炎的核心机制，也是它走向癌变的第一步。
4.2 炎症-纤维化的“恶性循环”：如何一步步靠近胰腺癌？
慢性胰腺炎的持续发展，不仅仅是让胰腺反复发炎那么简单。它会引发一个“炎症-纤维化”的恶性循环，一步步将胰腺推向胰腺癌的深渊。这个过程就像在胰腺这个“柔软的工厂”里，不断地堆积“水泥和钢筋”，最终导致工厂结构扭曲，功能失调，并为癌细胞的滋生创造条件 100。
胰腺纤维化：从“受伤”到“硬化”
当胰腺长期处于炎症状态，胰腺细胞（特别是腺泡细胞）反复受损时，身体会启动修复机制。在这个过程中，一种平时处于“休眠”状态的细胞——胰腺星状细胞（Pancreatic Stellate Cells, PSCs），会被炎症信号和损伤刺激“唤醒” 101102。
你可以把这些胰腺星状细胞想象成胰腺里的“维修工”。正常情况下，它们默默无闻，但一旦胰腺受损，它们就会变得异常活跃。它们会大量增殖，并从“休眠态”转变为“活化态”，变得像肌成纤维细胞一样，开始疯狂地生产和分泌大量的细胞外基质（ECM），其中最主要的就是胶原蛋白 100102103104。这些胶原蛋白在胰腺组织中过度沉积，就像在原本柔软的胰腺里不断填充“钢筋水泥”，导致胰腺组织变得坚硬，这就是胰腺纤维化 100105106。
胰腺星状细胞的活化，是胰腺纤维化的关键驱动力。酒精、氧化应激、炎症因子（如TGF-β1）等都会刺激PSC活化 101103107。活化后的PSC还会分泌更多的炎症因子和生长因子，形成一个自我强化的“恶性循环”，使得纤维化不断加重 101108。炎症微环境的“助推器”：为癌细胞铺路
胰腺纤维化不仅改变了胰腺的结构，还创造了一个充满炎症因子的独特微环境。这个微环境，简直就是癌细胞生长的“温床”，它通过多种方式助推胰腺癌的发生和发展 109：- 持续的炎症因子刺激： 慢性胰腺炎会导致胰腺局部长期存在高浓度的炎症因子，比如白细胞介素-1β (IL-1β)、白细胞介素-6 (IL-6)和肿瘤坏死因子 (TNF)等 110111。这些因子就像癌细胞的“营养液”和“生长激素”，能直接刺激胰腺导管上皮细胞的异常增殖，促进它们发生癌变 110111。例如，IL-1β可以促进胰腺癌细胞的炎症重编程和致病性 110。研究还发现，抑制IL-33的表达可以预防慢性胰腺炎及其癌症后果 112。
- 免疫细胞的“帮凶”： 在炎症微环境中，除了胰腺星状细胞，还有大量的免疫细胞，如巨噬细胞、中性粒细胞等。这些细胞在慢性炎症中可能“变节”，不再是身体的“守护者”，反而成为癌细胞的“帮凶” 113114。例如，肿瘤相关的巨噬细胞（TAMs）可以促进胰腺癌的发生和发展，其中一些巨噬细胞还会表达IL-1β，形成肿瘤细胞与巨噬细胞之间的炎症循环，进一步加剧炎症并促进癌细胞的恶性转化 110114。
- 缺氧环境： 纤维化的胰腺组织往往血供不足，形成局部缺氧环境。这种缺氧会进一步促进炎症反应和胰腺星状细胞的活化，并诱导缺氧诱导因子（HIF）的表达，HIF又可以促进某些生长因子的产生，加速癌细胞的增殖和侵袭 103。
- 基因突变累积： 在长期炎症和氧化应激的影响下，胰腺细胞的DNA更容易受损，可能导致基因突变不断累积。这些突变可能发生在关键的抑癌基因或原癌基因上，最终驱动胰腺导管上皮细胞发生恶性转化，形成胰腺导管腺癌（PDAC）。
胰腺癌的“前兆”：从炎症到癌变
慢性胰腺炎与胰腺癌的关联非常密切，它被认为是胰腺癌的一个重要风险因素，尤其是长期慢性胰腺炎的患者，其胰腺癌的风险会显著增加 87115116。研究发现，慢性胰腺炎患者体内产生的胶原蛋白，其组成和复杂性与胰腺癌患者体内的相似，这表明两者在纤维化机制上存在共同点 117。在慢性胰腺炎中，胰腺导管上皮细胞在炎症微环境的持续刺激下，会经历一系列异常增殖和分化的过程，最终可能发展为胰腺导管腺癌。纤维化是慢性胰腺炎和胰腺癌的病理特征之一，在两者向胰腺癌的转化过程中扮演着关键角色 106。
因此，慢性胰腺炎引发的炎症-纤维化恶性循环，不仅破坏了胰腺的正常结构和功能，更重要的是，它为胰腺细胞的恶性转化搭建了一个理想的“舞台”，并提供了癌细胞生长所需的各种“养料”和“助推力”，使得胰腺癌的发生风险大大增加。
4.3 降低癌变可能：控制诱因与胰腺癌早期识别
既然慢性胰腺炎是胰腺癌的一条“危险通道”，那么，我们能做的就是尽力“堵住”这条通道，或者至少“减慢”它的通行速度。这主要通过两个方面实现：控制和消除诱发慢性胰腺炎的因素，以及对高风险人群进行胰腺癌的早期识别和监测。
1. 控制诱因：从源头“止损”，保护胰腺
预防慢性胰腺炎的发生和进展，是降低胰腺癌风险的第一道防线。这需要我们从日常生活的方方面面入手，减少胰腺的“负荷”和“伤害”：
- 避免酒精：胰腺健康的“金科玉律”
长期过量饮酒是导致慢性胰腺炎的“罪魁祸首”，特别是对酒精性胰腺炎患者来说，戒酒是至关重要的治疗和预防手段 118。这就像给胰腺一个彻底的“休息”，让它不再遭受酒精的毒害。 - 控制胆道疾病：清除“交通堵塞”
胆结石是急性胰腺炎的重要诱因 119。及时治疗胆结石对于预防急性胰腺炎的发生和复发至关重要，从而可能降低发展为慢性胰腺炎的风险。 - 管理高甘油三酯血症：警惕血液中的“脂肪炸弹”
严重的甘油三酯升高（通常指血液甘油三酯水平超过500 mg/dL，甚至1000 mg/dL）是引起急性胰腺炎的常见原因，反复发作也会增加慢性胰腺炎的风险 120121。医生会建议通过饮食控制（低脂饮食）、运动以及药物治疗（如贝特类药物、Omega-3脂肪酸等）来降低甘油三酯水平，以预防胰腺炎的发生 122。对于有遗传性高甘油三酯血症的患者，基因检测可能有助于识别风险，并采取更积极的干预措施 121。 - 戒烟：摆脱胰腺的“隐形杀手”
吸烟不仅与胰腺癌直接相关 123，同时也是慢性胰腺炎常见的环境风险因素之一 118。因此，戒烟对于保护胰腺健康，降低胰腺癌风险具有重要意义。 - 健康饮食与生活方式：基础防护
保持健康的体重，均衡饮食，适度运动，避免暴饮暴食，这些都是减轻胰腺负担，预防各类慢性疾病，包括慢性胰腺炎的基础。
2. 胰腺癌的早期识别：拉响“警报”，抓住治疗窗
胰腺癌是一种非常凶险的癌症，早期症状不明显，发现时往往已是晚期，治疗效果不佳 124125。因此，对于慢性胰腺炎患者这种高风险人群，尤其需要高度警惕胰腺癌的发生，并采取积极的监测策略。
影像学检查：洞察胰腺内部的“秘密”
- CT或MRI扫描： 这些先进的影像学技术是发现胰腺异常的关键工具。通过定期进行增强CT或MRI检查，医生可以观察胰腺的形态、大小、内部结构，发现是否存在可疑的肿块、导管扩张或萎缩等胰腺癌的早期征象 126127。对于慢性胰腺炎患者，由于胰腺纤维化和炎症可能与早期胰腺癌表现相似，鉴别诊断具有挑战性，需要经验丰富的影像科医生仔细判读 127128。
- 内镜超声（EUS）： EUS是一种更精确的检查手段，医生会将带有超声探头的内窥镜伸入消化道，直接从胃或十二指肠壁对胰腺进行超声检查。它可以发现微小的病变，并可以在超声引导下进行细针穿刺活检（EUS-FNA），获取组织样本进行病理分析，这是确诊胰腺癌最可靠的方法之一 125。
血清肿瘤标志物 CA19-9：辅助判断的“晴雨表”
糖链抗原CA19-9是一种常用的血液肿瘤标志物。在胰腺癌患者中，CA19-9水平通常会升高，因此可以作为辅助诊断和监测的指标 129。然而，CA19-9的特异性不高，在慢性胰腺炎、胆道梗阻等良性疾病中也可能升高 129130。因此，CA19-9不能单独用于胰腺癌的诊断，但结合影像学检查和其他临床信息，它可以提高诊断的准确性，并用于监测胰腺癌的治疗效果和复发 130。有研究显示，CA19-9在胰腺癌诊断前两年就开始呈现指数级增长，提示其在早期检测中具有潜力，特别是与一些新的生物标志物（如TIMP1和LRG1）结合时，可以提高早期诊断率 129。高风险人群的个体化干预：
对于某些特定高风险的慢性胰腺炎患者，比如有遗传性胰腺炎家族史的个体 131，或者胰腺导管内乳头状黏液性肿瘤（IPMNs）等胰腺癌前病变的患者，可能需要更密切的监测频率和更积极的干预策略。医生会根据患者的具体情况（如年龄、病史、基因突变情况、影像学表现等）来制定个性化的监测方案，例如缩短影像学检查的间隔时间，甚至考虑预防性手术切除某些高风险病变。此外，新的研究方向包括粪便微生物组分析，这可能为胰腺癌的早期检测提供新的非侵入性方法 132。
通过积极控制诱发因素，我们可以减少胰腺的损伤和炎症，延缓慢性胰腺炎的进展；同时，结合影像学和肿瘤标志物等手段进行早期识别和监测，就像在胰腺内部安装了“预警系统”，一旦有癌变的苗头，就能及时发现并采取措施，争取宝贵的治疗时间。
5. 从“炎”到“癌”的阻断指南：普通人能做什么？
读到这里，你可能已经对慢性炎症与癌症之间的“隐秘联系”有了更深的理解，甚至感到一丝担忧：我的身体里会不会也有一个正在“温水煮青蛙”的慢性炎症？别担心，了解风险是为了更好地预防。作为普通民众，我们不是医生，无法进行专业的诊断和治疗，但我们可以学会识别身体发出的“危险信号”，并采取积极的生活方式干预，必要时寻求医疗帮助，从而最大限度地阻断“炎”到“癌”的危险路径。
5.1 识别“危险信号”：哪些慢性炎症需要特别警惕？
虽然身体的任何部位都可能发生慢性炎症，但有几种类型的慢性炎症，由于其与癌症的明确关联以及潜在的恶变风险，需要我们特别警惕。这些“危险信号”通常表现为：持续时间长、反复发作频率高以及伴随特定器官的功能异常。
持续不愈的感染性炎症：
- 持续时间： 任何感染性炎症，如果治疗后长时间（通常超过3个月）不消退，或者反复发作，就可能演变为慢性炎症。
- 典型案例：
- 慢性病毒性肝炎（乙肝、丙肝）： 如前文所述，这是肝癌的明确高危因素。如果被告知携带乙肝或丙肝病毒，即使没有明显症状，也必须定期检查，并遵医嘱进行抗病毒治疗。
- 幽门螺杆菌感染引起的慢性胃炎： 长期Hp感染导致的慢性胃炎，特别是伴有萎缩性胃炎、肠上皮化生和异型增生，是胃癌的明确“前奏”。如果出现长期胃部不适、消化不良，应及时就医检查Hp，并考虑根除治疗。
- 慢性胆囊炎、胆管炎： 长期慢性炎症可能增加胆囊癌和胆管癌的风险 133。如果反复出现右上腹疼痛、消化不良等症状，应及时检查胆道系统。
- 某些持续性HPV感染： 高危型人乳头瘤病毒（HPV）的持续感染是宫颈癌的主要原因，也与一些头颈部肿瘤有关。定期妇科检查和HPV疫苗接种是关键。
- 其他： 某些长期未愈合的慢性伤口、感染性溃疡等，也可能在长期炎症刺激下发生恶变。
自身免疫性疾病相关的炎症：
- 持续时间： 这类疾病通常是终身性的，炎症是持续存在的。
- 典型案例：
- 炎症性肠病（克罗恩病、溃疡性结肠炎）： 肠道的慢性炎症会显著增加结直肠癌的风险 134。患者需要定期进行肠镜检查以监测癌前病变。
- 类风湿性关节炎、系统性红斑狼疮等： 这些自身免疫病导致的全身性慢性炎症，虽然直接导致癌症的几率不如前面几种高，但可能增加某些淋巴瘤、白血病以及特定实体瘤的风险。
与代谢异常相关的慢性炎症：
器官特异性慢性炎症：
总结一下： 如果你发现自己身体的某个部位有长期不适，特别是上述提到的情况，比如持续超过3个月的胃痛、反复发作的腹泻、右上腹不适、或者被诊断出有慢性病毒感染、自身免疫病等，都应该提高警惕。这并不意味着一定会发展成癌症，但它们是身体发出的“警报”，提示你需要积极寻求医生的专业诊断和评估，必要时进行干预和监测，以便在“炎”到“癌”的关键路口，及时踩下“刹车”。
5.2 主动干预：生活方式与医疗手段的双重防护
明白了慢性炎症与癌症的关联，识别出危险信号后，接下来更重要的是采取行动。面对这场“炎”到“癌”的持久战，普通人并非只能被动接受，而是可以通过调整生活方式和积极配合医疗干预，形成一套“双重防护”，最大限度地降低风险，保护自身健康。
1. 生活方式干预：从日常做起，构建身体的“防火墙”
健康的生活方式是抵御慢性炎症和癌症最基础、也最重要的“防火墙”。这就像给我们的身体提供优质的“燃料”和良好的“维护”，让免疫系统保持最佳状态，减少炎症的发生。
戒烟：斩断“万恶之源”
吸烟是已知最明确的致癌因素之一，也是导致全身性慢性炎症的重要原因。香烟中的有害物质会直接损伤细胞DNA，并引发全身性的炎症反应，几乎与所有癌症都有关联。吸烟者患癌症和心血管疾病的风险比不吸烟者高出数倍 140141142。因此，无论何时，戒烟都是对健康最明智的投资。即便是有长期吸烟史的老年人，戒烟也能显著降低全因死亡率和癌症死亡率 140。限酒：保护肝胰胃的“清醒剂”
长期过量饮酒是多种慢性炎症的诱因，尤其是酒精性肝病、慢性胰腺炎和胃炎的元凶。酒精会直接毒害肝细胞和胰腺细胞，并刺激胃黏膜，加剧炎症反应，从而增加肝癌、胰腺癌和胃癌的风险。适度饮酒的界限因人而异，但对于有慢性炎症基础或高风险人群，最好能做到滴酒不沾。均衡饮食：身体的“抗炎特工队”
我们吃什么，很大程度上决定了身体是处于“促炎”还是“抗炎”状态。- 多吃抗炎食物： 蔬菜、水果、全谷物、坚果、豆类、香料和草药等植物性食物富含抗氧化剂和膳食纤维，具有显著的抗炎作用 143144。例如，地中海饮食和DASH饮食（得舒饮食）等以植物为基础的膳食模式，已被证实能降低氧化应激和炎症生物标志物水平，有助于预防慢性疾病 144。这些食物能帮助身体清理“垃圾”，修复损伤，并维持肠道菌群健康，从而降低慢性炎症水平。
- 少吃促炎食物： 红肉、加工肉类、精制碳水化合物、饱和脂肪和反式脂肪等食物会促进炎症反应 143。它们不仅会增加肥胖、糖尿病等代谢性疾病的风险，也直接或间接地增加多种癌症的风险 145。高糖饮食也会加剧炎症，并为癌细胞提供“养料”。
- 地中海饮食模式： 这种饮食模式被广泛推荐，它强调新鲜果蔬、鱼类、橄榄油、全谷物和适量坚果，限制红肉和加工食品，有助于减少全身性炎症，降低心血管疾病和癌症的风险。
控制体重：摆脱“肥胖炎症”的困扰
肥胖本身就是一种慢性炎症状态，过多的脂肪细胞会持续分泌炎症因子，导致全身性的低度炎症 146。这种“肥胖炎症”会增加多种癌症的风险，包括乳腺癌、结直肠癌、子宫内膜癌、肝癌、胰腺癌等。通过健康饮食和规律运动，将体重维持在健康范围内，是预防多种慢性疾病和癌症的关键。规律运动：免疫系统的“活力源泉”
适度的规律运动不仅能帮助控制体重，还能直接调节免疫系统功能，减轻全身炎症反应，改善代谢健康。运动能促进血液循环，帮助身体排出毒素，并提高细胞的抗氧化能力。
2. 医疗干预：精准打击，早期预警
除了生活方式的调整，积极配合医疗干预，特别是针对感染性炎症的根除治疗和针对癌前病变的定期监测，是阻断“炎”到“癌”路径的重要手段。
感染性炎症的根除治疗：消灭“罪魁祸首”
- 幽门螺杆菌（Hp）根除： 对于确诊的Hp感染，特别是伴有慢性胃炎、胃黏膜萎缩、肠上皮化生或异型增生的患者，应遵医嘱进行规范的根除治疗。成功清除Hp能够显著降低胃癌风险。
- 慢性病毒性肝炎（乙肝、丙肝）的抗病毒治疗： 乙肝和丙肝患者应在医生指导下，积极进行抗病毒治疗，抑制病毒复制，减轻肝脏炎症，从而降低肝硬化和肝癌的风险。丙肝目前已有高效治愈方案，应争取彻底清除病毒。
自身免疫性炎症的免疫调节：稳定“身体内战”
对于炎症性肠病、类风湿性关节炎等自身免疫性疾病，需要在风湿免疫科或消化科医生的指导下，使用免疫抑制剂或生物制剂等药物来控制炎症反应，维持疾病稳定。虽然这些药物本身可能有副作用，但有效控制炎症可以降低长期并发症，包括某些癌症的风险。定期体检与筛查：捕捉“癌变前兆”
没有任何症状不代表没有风险。定期体检和针对性的筛查是早期发现癌前病变和早期癌症，从而提高治愈率的关键 147148。- 胃镜和肠镜： 对于有胃癌或结直肠癌家族史、或者存在胃黏膜萎缩、肠上皮化生、溃疡性结肠炎等癌前病变的人群，应遵医嘱定期进行胃镜和肠镜检查。
- 肝癌筛查： 乙肝、丙肝病毒感染者，特别是伴有肝硬化的患者，应每半年进行一次甲胎蛋白（AFP）检测和腹部超声检查。
- 宫颈癌筛查： 女性应定期进行TCT和HPV检测。
- 肺癌筛查： 对于长期吸烟者或有职业暴露史等高危人群，低剂量螺旋CT（LDCT）可以有效筛查早期肺癌 149。
- 其他高风险人群的个体化筛查： 医生会根据个体的年龄、家族史、既往病史和生活习惯等，建议进行相应的筛查。例如，某些甲状腺髓样癌患者通过常规健康体检早期诊断，预后和生存率更好 150。定期健康检查在连接患者与推荐的预防服务方面非常重要 148151152153。
通过将健康的生活方式融入日常，并与医疗专业人员紧密合作，对慢性炎症进行积极的预防和管理，我们就能有效地“拆除”身体里的“癌变定时炸弹”，为自己争取一个更健康、更长久的未来。
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参考文献
1Inflammation mechanism and research progress of COPD.PubMed
Jiao Xu, Qingyue Zeng, Shuangqing Li, et al.
Front Immunol. 2024 Aug 9;15:1404615. doi: 10.3389/fimmu.2024.1404615. eCollection 2024.
Chronic obstructive pulmonary disease (COPD) is a common respiratory disease characterized by irreversible progressive airflow limitation, often manifested by persistent cough, sputum production and other respiratory symptoms that pose a serious threat to human health and affect the quality of life of patients. The disease is associated with chronic inflammation, which is associated with the onset and progression of COPD, but anti-inflammatory therapy is not first-line treatment. Inflammation has multiple manifestations and phenotypes, and this heterogeneity reveals different patterns of inflammation, making treatment difficult. This paper aims to explore the direction of more effective anti-inflammatory treatment by analyzing the nature of inflammation and the molecular mechanism of disease occurrence and development in COPD patients, and to provide new ideas for the treatment of COPD patients.
2Endometritis - Diagnosis,Treatment and its impact on fertility - A Scoping Review.PubMed
Neeta Singh, Ankita Sethi
JBRA Assist Reprod. 2022 Aug 4;26(3):538-546. doi: 10.5935/1518-0557.20220015.
Endometritis is defined as an infection or inflammation of the endometrium. Endometritis is of two types: acute and chronic. Acute endometritis is the symptomatic acute inflammation of the endometrium, which upon examination with a microscope shows micro-abscess and neutrophil invasion in the superficial endometrium. One of its most common manifestations is postpartum endometritis. Chronic endometritis is a silent disease usually diagnosed on the workup of secondary amenorrhoea and infertility. An important cause of chronic endometritis is tuberculosis, especially in developing nations. Chronic and acute endometritis have been associated with poor reproductive outcomes. Worse outcomes have been reported for individuals with chronic endometritis. This is a scoping review of endometritis and its impact on fertility.
3Neutrophils and NETs in modulating acute and chronic inflammation.PubMed
Fernanda V S Castanheira, Paul Kubes
Blood. 2019 May 16;133(20):2178-2185. doi: 10.1182/blood-2018-11-844530. Epub 2019 Mar 21.
Neutrophils are an absolutely essential part of the innate immune system, playing an essential role in the control of infectious diseases but more recently are also being viewed as important players in tissue repair. Neutrophils are able to counteract an infection through phagocytosis and/or the release of neutrophil extracellular traps (NETs). By contrast, neutrophils help repair damaged tissues, limiting NET production but still phagocytosing debris. However, when inflammation is recurrent, or the inciting agent persists, neutrophils through a frustrated inability to resolve the problem can release NETs to exacerbate tissue damage during inappropriate inflammation. In this review, we discuss the mechanisms of NET formation, as well as the apparent paradoxical role of neutrophils and NETs in host defense, chronic inflammation, and tissue disrepair.
4Chronic inflammation in the etiology of disease across the life span.PubMed
David Furman, Judith Campisi, Eric Verdin, et al.
Nat Med. 2019 Dec;25(12):1822-1832. doi: 10.1038/s41591-019-0675-0. Epub 2019 Dec 5.
Although intermittent increases in inflammation are critical for survival during physical injury and infection, recent research has revealed that certain social, environmental and lifestyle factors can promote systemic chronic inflammation (SCI) that can, in turn, lead to several diseases that collectively represent the leading causes of disability and mortality worldwide, such as cardiovascular disease, cancer, diabetes mellitus, chronic kidney disease, non-alcoholic fatty liver disease and autoimmune and neurodegenerative disorders. In the present Perspective we describe the multi-level mechanisms underlying SCI and several risk factors that promote this health-damaging phenotype, including infections, physical inactivity, poor diet, environmental and industrial toxicants and psychological stress. Furthermore, we suggest potential strategies for advancing the early diagnosis, prevention and treatment of SCI.
5Helicobacter pylori-induced gastric inflammation and gastric cancer.PubMed
Fei Wang, Wenbo Meng, Bingyuan Wang, et al.
Cancer Lett. 2014 Apr 10;345(2):196-202. doi: 10.1016/j.canlet.2013.08.016. Epub 2013 Aug 24.
Helicobacter pylori (H. pylori) infect over half of the world's population. The prevalence of H. pylori infection and the predominant genotype of H. pylori virulence factors vary considerably across different geographical regions. H. pylori could uniquely persist for decades in the harsh stomach environment, where it damages the gastric mucosa and changes the pattern of gastric hormone release, thereby affects gastric physiology. By utilizing various virulence factors, H. pylori targets different cellular proteins to modulate the host inflammatory response and initiate multiple "hits" on the gastric mucosa, resulting in chronic gastritis and peptic ulceration. Among the long-term consequences of H. pylori infection is gastric malignancies, particularly gastric cancer (GC) and gastric mucosa-associated lymphoid tissue (MALT) lymphoma. As such, H. pylori has been recognized as a class I carcinogen by the International Agency for Research on Cancer. Despite a close causal link between H. pylori infection and the development of gastric malignancies, the precise mechanisms involved in this process are still obscure. Studies over the past two decades have revealed that H. pylori exert oncogenic effects on gastric mucosa through a complex interaction between bacterial factors, host factors, and environmental factors. Numerous signaling pathways can be activated by H. pylori. In this review, we aim to elaborate on the recent developments in the pathophysiological mechanisms of H. pylori-induced gastric inflammation and gastric cancer.
6Obesity and Cancer Mechanisms: Tumor Microenvironment and Inflammation.PubMed
Neil M Iyengar, Ayca Gucalp, Andrew J Dannenberg, et al.
J Clin Oncol. 2016 Dec 10;34(35):4270-4276. doi: 10.1200/JCO.2016.67.4283. Epub 2016 Nov 7.
Purpose There is growing evidence that inflammation is a central and reversible mechanism through which obesity promotes cancer risk and progression. Methods We review recent findings regarding obesity-associated alterations in the microenvironment and the local and systemic mechanisms through which these changes support tumor growth. Results Locally, hyperadiposity is associated with altered adipose tissue function, adipocyte death, and chronic low-grade inflammation. Most individuals who are obese harbor inflamed adipose tissue, which resembles chronically injured tissue, with immune cell infiltration and remodeling. Within this distinctly altered local environment, several pathophysiologic changes are found that may promote breast and other cancers. Consistently, adipose tissue inflammation is associated with a worse prognosis in patients with breast and tongue cancers. Systemically, the metabolic syndrome, including dyslipidemia and insulin resistance, occurs in the setting of adipose inflammation and operates in concert with local mechanisms to sustain the inflamed microenvironment and promote tumor growth. Importantly, adipose inflammation and its protumor consequences can be found in some individuals who are not considered to be obese or overweight by body mass index. Conclusion The tumor-promoting effects of obesity occur at the local level via adipose inflammation and associated alterations in the microenvironment, as well as systemically via circulating metabolic and inflammatory mediators associated with adipose inflammation. Accurately characterizing the obese state and identifying patients at increased risk for cancer development and progression will likely require more precise assessments than body mass index alone. Biomarkers of adipose tissue inflammation would help to identify high-risk populations. Moreover, adipose inflammation is a reversible process and represents a novel therapeutic target that warrants further study to break the obesity-cancer link.
7Stress and inflammation - The need to address the gap in the transition between acute and chronic stress effects.PubMed
Nicolas Rohleder
Psychoneuroendocrinology. 2019 Jul;105:164-171. doi: 10.1016/j.psyneuen.2019.02.021. Epub 2019 Feb 20.
Stress responses help us navigate our environment and respond appropriately to threats. Stress systems communicate threats to the entire organism, and as such, also stimulate inflammatory mechanisms. This modulation might serve protective functions in the short term, but sustained low-grade inflammation has severe long-term health consequences. While we have reached a reasonable level of understanding of acute, as well as chronic stress effects on inflammatory mechanisms, there is a significant gap in our understanding of the transitional phase between acute and chronic stress. The purpose of this review is to first summarize current knowledge of our understanding of acute stress effects on inflammation, as well as of chronic stress effects on inflammation, and to then analyze the state of knowledge about the transitional phase between acute and chronic stress. Research discussed here shows that we are beginning to understand the early phase of repeated acute stress, but lack information on longer term exposure to repeated acute stress experiences. More research is needed to bridge this important gap und our conceptualization and understanding of the stress and health relationship.
8Inflammation: the incubator of the tumor microenvironment.PubMed
Dominic Denk, Florian R Greten
Trends Cancer. 2022 Nov;8(11):901-914. doi: 10.1016/j.trecan.2022.07.002. Epub 2022 Jul 28.
An inflammatory microenvironment, either conferred by an underlying chronic overt or smoldering inflammatory condition constitutes a prerequisite and fuel to essentially all cancers. The complex reciprocal interplay of different cell types in the tumor microenvironment (TME) determines patient outcome. Apart from the actual tumor cells, local and recruited nonmalignant cells as well as the intestinal microbiome actively shape polarization and plasticity of cells in the TME, thereby augmenting protumorigenic and prometastatic inflammatory processes. Here, we address the universality of inflammation in carcinogenesis, review distinct forms of tumor related inflammation and highlight critical processes in the TME actively sustaining a nurturing incubator for cancer progression and therapy resistance.
9Oxidative stress, inflammation, and cancer: how are they linked?PubMed
Simone Reuter, Subash C Gupta, Madan M Chaturvedi, et al.
Free Radic Biol Med. 2010 Dec 1;49(11):1603-16. doi: 10.1016/j.freeradbiomed.2010.09.006. Epub 2010 Sep 16.
Extensive research during the past 2 decades has revealed the mechanism by which continued oxidative stress can lead to chronic inflammation, which in turn could mediate most chronic diseases including cancer, diabetes, and cardiovascular, neurological, and pulmonary diseases. Oxidative stress can activate a variety of transcription factors including NF-κB, AP-1, p53, HIF-1α, PPAR-γ, β-catenin/Wnt, and Nrf2. Activation of these transcription factors can lead to the expression of over 500 different genes, including those for growth factors, inflammatory cytokines, chemokines, cell cycle regulatory molecules, and anti-inflammatory molecules. How oxidative stress activates inflammatory pathways leading to transformation of a normal cell to tumor cell, tumor cell survival, proliferation, chemoresistance, radioresistance, invasion, angiogenesis, and stem cell survival is the focus of this review. Overall, observations to date suggest that oxidative stress, chronic inflammation, and cancer are closely linked.
10Targeting cancer-promoting inflammation - have anti-inflammatory therapies come of age?PubMed
Jiajie Hou, Michael Karin, Beicheng Sun
Nat Rev Clin Oncol. 2021 May;18(5):261-279. doi: 10.1038/s41571-020-00459-9. Epub 2021 Jan 19.
The immune system has crucial roles in cancer development and treatment. Whereas adaptive immunity can prevent or constrain cancer through immunosurveillance, innate immunity and inflammation often promote tumorigenesis and malignant progression of nascent cancer. The past decade has witnessed the translation of knowledge derived from preclinical studies of antitumour immunity into clinically effective, approved immunotherapies for cancer. By contrast, the successful implementation of treatments that target cancer-associated inflammation is still awaited. Anti-inflammatory agents have the potential to not only prevent or delay cancer onset but also to improve the efficacy of conventional therapeutics and next-generation immunotherapies. Herein, we review the current clinical advances and experimental findings supporting the utility of an anti-inflammatory approach to the treatment of solid malignancies. Gaining a better mechanistic understanding of the mode of action of anti-inflammatory agents and designing more effective treatment combinations would advance the clinical application of this therapeutic approach.
11Hepatitis C.PubMed
M J Alter, E E Mast, L A Moyer, et al.
Infect Dis Clin North Am. 1998 Mar;12(1):13-26. doi: 10.1016/s0891-5520(05)70405-0.
Hepatitis C virus (HCV) has emerged as a major cause of chronic liver disease worldwide. The widespread endemicity of HCV infection is the result of a combination of factors, including those related to the genetic diversity of the virus and the host response and those related to the specific settings and behaviors that have facilitated transmission. Most people who contract HCV infection become persistently infected, and the mechanism by which persistent infection is established seems to be related to the lack of development of an effective neutralizing immune response. The magnitude of the spread of HCV infection primarily is related to specific risk factors for transmission. The most important human behavior related to the transmission of HCV has been injection drug use, which in many developed countries has been the leading source of HCV infection during the past 20 to 30 years. The recognition of the clinical importance of HCV infection has resulted in a substantial amount of attention and resources rapidly directed toward developing new and improved therapies. The perception, however, of the public health importance of HCV infection is still limited. Despite the knowledge that injection drug use is the major source of HCV infection in the United States, this message has not been included in prevention and treatment programs, and the resources needed to support strong public health programs have yet to be identified.
12Immune response and treatment targets of chronic hepatitis B virus infection: innate and adaptive immunity.PubMed
Peiyu Zheng, Yongqing Dou, Qinying Wang
Front Cell Infect Microbiol. 2023 Jun 22;13:1206720. doi: 10.3389/fcimb.2023.1206720. eCollection 2023.
Chronic hepatitis B virus (HBV) infection is a major global public health risk that threatens human life and health, although the number of vaccinated people has increased. The clinical outcome of HBV infection depends on the complex interplay between viral replication and the host immune response. Innate immunity plays an important role in the early stages of the disease but retains no long-term immune memory. However, HBV evades detection by the host innate immune system through stealth. Therefore, adaptive immunity involving T and B cells is crucial for controlling and clearing HBV infections that lead to liver inflammation and damage. The persistence of HBV leads to immune tolerance owing to immune cell dysfunction, T cell exhaustion, and an increase in suppressor cells and cytokines. Although significant progress has been made in HBV treatment in recent years, the balance between immune tolerance, immune activation, inflammation, and fibrosis in chronic hepatitis B remains unknown, making a functional cure difficult to achieve. Therefore, this review focuses on the important cells involved in the innate and adaptive immunity of chronic hepatitis B that target the host immune system and identifies treatment strategies.
13Chronic viral hepatitis and its association with liver cancer.PubMed
Thomas Tu, Sandra Bühler, Ralf Bartenschlager
Biol Chem. 2017 Jul 26;398(8):817-837. doi: 10.1515/hsz-2017-0118.
Chronic infection with hepatitis viruses represents the major causative factor for end-stage liver diseases, including liver cirrhosis and primary liver cancer (hepatocellular carcinoma, HCC). In this review, we highlight the current understanding of the molecular mechanisms that drive the hepatocarcinogenesis associated with chronic hepatitis virus infections. While chronic inflammation (associated with a persistent, but impaired anti-viral immune response) plays a major role in HCC initiation and progression, hepatitis viruses can also directly drive liver cancer. The mechanisms by which hepatitis viruses induce HCC include: hepatitis B virus DNA integration into the host cell genome; metabolic reprogramming by virus infection; induction of the cellular stress response pathway by viral gene products; and interference with tumour suppressors. Finally, we summarise the limitations of hepatitis virus-associated HCC model systems and the development of new techniques to circumvent these shortcomings.
14Immunopathogenesis of Liver Injury During Hepatitis C Virus Infection.PubMed
Mohammad Irshad, Priyanka Gupta, Khushboo Irshad
Viral Immunol. 2019 Apr;32(3):112-120. doi: 10.1089/vim.2018.0124. Epub 2019 Feb 28.
The present report describes current concepts about the mechanism of liver cell injury caused by host immune response against hepatitis C virus (HCV) infection in human beings. This report is based on the observations from experimental studies and follow-up actions on human liver diseases. The results from different investigations suggest that liver injury depends on the presentation of viral antigen and the level of host immune response raised against HCV-related peptides. Both innate and adaptive immunity are triggered to counter the viral onset. During development of host immunity, the cell-mediated immune response involving CD4 Th1 cells and CD8 cytotoxic T-lymphocyte (CTL) cells were found to play a major role in causing liver damage. The hepatic Innate lymphoid cells (ILCs) subsets are involved in the immune regulation of different liver diseases: viral hepatitis, mechanical liver injury, and fibrosis. Humoral immunity and natural killer (NK) cell action also contributed in liver cell injury by antibody-dependent cellular cytotoxicity (ADCC). In fact, immunopathogenesis of HCV infection is a complex phenomenon where regulation of immune response at several steps decides the possibility of viral elimination or persistence. Regulation of immune response was noted starting from viral-host interaction to immune reaction cascade engaged in cell damage. The activation or suppression of interferon-stimulated genes, NK cell action, CTL inducement by regulatory T cells (Treg), B cell proliferation, and so on was demonstrated during HCV infection. Involvement of HLA in antigen presentation, as well as types of viral genotypes, also influenced host immune response against HCV peptides. The combined effect of all these effector mechanisms ultimately decides the progression of viral onset to acute or chronic infection. In conclusion, immunopathogenesis of liver injury after HCV infection may be ascribed mainly to host immune response. Second, it is cell-mediated immunity that plays a predominant role in liver cell damage.
15Virus-specific mechanisms of carcinogenesis in hepatitis C virus associated liver cancer.PubMed
D R McGivern, S M Lemon
Oncogene. 2011 Apr 28;30(17):1969-83. doi: 10.1038/onc.2010.594. Epub 2011 Jan 24.
The development of hepatocellular carcinoma (HCC) in persons who are persistently infected with hepatitis C virus (HCV) is a growing problem worldwide. Current antiviral therapies are not effective in many patients with chronic hepatitis C, and a greater understanding of the factors leading to progression of HCC will be necessary to design novel approaches to prevention of HCV-associated HCC. The lack of a small animal model of chronic HCV infection has hampered understanding of these factors. As HCV is an RNA virus with little potential for integration of its genetic material into the host genome, the mechanisms underlying HCV promotion of cancer are likely to differ from other models of viral carcinogenesis. In patients persistently infected with HCV, chronic inflammation resulting from immune responses against infected hepatocytes is associated with progressive fibrosis and cirrhosis. Cirrhosis is an important risk factor for HCC independent of HCV infection, and a majority of HCV-associated HCC arises in the setting of cirrhosis. However, a significant minority arises in the absence of cirrhosis, indicating that cirrhosis is not a prerequisite for cancer. Other lines of evidence suggest that direct, virus-specific mechanisms may be involved. Transgenic mice expressing HCV proteins develop cancer in the absence of inflammation or immune recognition of the transgene. In vitro studies have revealed multiple interactions of HCV-encoded proteins with cell cycle regulators and tumor suppressor proteins, raising the possibility that HCV can disrupt control of cellular proliferation, or impair the cell's response to DNA damage. A combination of virus-specific, host genetic, environmental and immune-related factors are likely to determine the progression to HCC in patients who are chronically infected with HCV. Here, we summarize current knowledge of the virus-specific mechanisms that may contribute to HCV-associated HCC.
16Hepatitis B Virus-Associated Hepatocellular Carcinoma.PubMed
Giacomo Emanuele Maria Rizzo, Giuseppe Cabibbo, Antonio Craxì
Viruses. 2022 May 7;14(5):986. doi: 10.3390/v14050986.
Hepatitis B virus (HBV) is DNA-based virus, member of the Hepadnaviridae family, which can cause liver disease and increased risk of hepatocellular carcinoma (HCC) in infected individuals, replicating within the hepatocytes and interacting with several cellular proteins. Chronic hepatitis B can progressively lead to liver cirrhosis, which is an independent risk factor for HCC. Complications as liver decompensation or HCC impact the survival of HBV patients and concurrent HDV infection worsens the disease. The available data provide evidence that HBV infection is associated with the risk of developing HCC with or without an underlying liver cirrhosis, due to various direct and indirect mechanisms promoting hepatocarcinogenesis. The molecular profile of HBV-HCC is extensively and continuously under study, and it is the result of altered molecular pathways, which modify the microenvironment and lead to DNA damage. HBV produces the protein HBx, which has a central role in the oncogenetic process. Furthermore, the molecular profile of HBV-HCC was recently discerned from that of HDV-HCC, despite the obligatory dependence of HDV on HBV. Proper management of the underlying HBV-related liver disease is fundamental, including HCC surveillance, viral suppression, and application of adequate predictive models. When HBV-HCC occurs, liver function and HCC characteristics guide the physician among treatment strategies but always considering the viral etiology in the treatment choice.
17Hepatic stellate cells as key target in liver fibrosis.PubMed
Takaaki Higashi, Scott L Friedman, Yujin Hoshida
Adv Drug Deliv Rev. 2017 Nov 1;121:27-42. doi: 10.1016/j.addr.2017.05.007. Epub 2017 May 12.
Progressive liver fibrosis, induced by chronic viral and metabolic disorders, leads to more than one million deaths annually via development of cirrhosis, although no antifibrotic therapy has been approved to date. Transdifferentiation (or "activation") of hepatic stellate cells is the major cellular source of matrix protein-secreting myofibroblasts, the major driver of liver fibrogenesis. Paracrine signals from injured epithelial cells, fibrotic tissue microenvironment, immune and systemic metabolic dysregulation, enteric dysbiosis, and hepatitis viral products can directly or indirectly induce stellate cell activation. Dysregulated intracellular signaling, epigenetic changes, and cellular stress response represent candidate targets to deactivate stellate cells by inducing reversion to inactivated state, cellular senescence, apoptosis, and/or clearance by immune cells. Cell type- and target-specific pharmacological intervention to therapeutically induce the deactivation will enable more effective and less toxic precision antifibrotic therapies.
18Mechanisms of liver fibrosis and its role in liver cancer.PubMed
Debanjan Dhar, Jacopo Baglieri, Tatiana Kisseleva, et al.
Exp Biol Med (Maywood). 2020 Jan;245(2):96-108. doi: 10.1177/1535370219898141. Epub 2020 Jan 10.
UNLABELLED: Hepatic fibrogenesis is a pathophysiological outcome of chronic liver injury hallmarked by excessive accumulation of extracellular matrix proteins. Fibrosis is a dynamic process that involves cross-talk between parenchymal cells (hepatocytes), hepatic stellate cells, sinusoidal endothelial cells and both resident and infiltrating immune cells. In this review, we focus on key cell-types that contribute to liver fibrosis, cytokines, and chemokines influencing this process and what it takes for fibrosis to regress. We discuss how mitochondria and metabolic changes in hepatic stellate cells modulate the fibrogenic process. We also briefly review how the presence of fibrosis affects development of hepatocellular carcinoma. IMPACT STATEMENT: Advanced liver fibrosis results in cirrhosis, portal hypertension, and liver failure and often requires liver transplantation. Advanced liver fibrosis and cirrhosis are also major risk factors for hepatocellular carcinoma (HCC). Hepatic stellate cells (HSCs) play a pivotal role in the pathogenesis of liver fibrosis. In this review, we summarize the basic mechanisms that influence liver fibrosis development and how oxidative stress, mitochondrial dysfunction, and metabolic remodeling modulate HSC activation and indicate areas of potential therapeutic intervention.
19Intestinal flora plays a role in the progression of hepatitis-cirrhosis-liver cancer.PubMed
Shuyu Liu, Xilan Yang
Front Cell Infect Microbiol. 2023 Mar 9;13:1140126. doi: 10.3389/fcimb.2023.1140126. eCollection 2023.
The liver is a vital metabolism and detoxification organ of human body, which is involved in the biotransformation and metabolism of the organism. Hepatitis - cirrhosis - liver cancer are significant and common part of liver diseases. The pathogenesis of liver diseases is generally as followed: inflammation and other pathogenic factors cause persistent damage to the liver, leading to the activation of hepatic stellate cells (HSCs) and excessive deposition of extracellular matrix. Patients with chronic hepatitis have a high risk of developing into liver fibrosis, cirrhosis, and even life-threatening liver cancer, which poses a great threat to public health.As the first organ to come into contact with blood from the gut, the liver is profoundly affected by the intestinal flora and its metabolites, with leaky gut and flora imbalance being the triggers of the liver's pathological response. So far, no one has reviewed the role of intestinal flora in this process from the perspective of the progression of hepatitis-cirrhosis-liver cancer and this article reviews the evidence supporting the effect of intestinal flora in the progression of liver disease.
20Hepatic stellate cells promote hepatocellular carcinoma development by regulating histone lactylation: Novel insights from single-cell RNA sequencing and spatial transcriptomics analyses.PubMed
Yifan Yu, Yongnan Li, Long Zhou, et al.
Cancer Lett. 2024 Nov 1;604:217243. doi: 10.1016/j.canlet.2024.217243. Epub 2024 Sep 10.
This study evaluated the cellular heterogeneity and molecular mechanisms of hepatocellular carcinoma (HCC). Single cell RNA sequencing (scRNA-seq), transcriptomic data, histone lactylation-related genes were collected from public databases. Cell-cell interaction, trajectory, pathway, and spatial transcriptome analyses were executed. Differential expression and survival analyses were conducted. Western blot, Real-time reverse transcription PCR (qRT-PCR), and Cell Counting Kit 8 (CCK8) assay were used to detect the expression of αSMA, AKR1B10 and its target genes, and verify the roles of AKR1B10 in HCC cells. Hepatic stellate cell (HSC) subgroups strongly interacted with tumor cell subgroups, and their spatial distribution was heterogeneous. Two candidate prognostic genes (AKR1B10 and RMRP) were obtained. LONP1, NPIPB3, and ZSWIM6 were determined as AKR1B10 targets. Besides, the expression levels of AKR1B10 and αSMA were significantly increased in LX-2 + HepG2 and LX-2 + HuH7 groups compared to those in LX-2 group, respectively. sh-AKR1B10 significantly inhibited the HCC cell proliferation and change the expression of AKR1B10 target genes, Bcl-2, Bax, Pan Kla, and H3K18la at protein levels. Our findings unveil the pivotal role of HSCs in HCC pathogenesis through regulating histone lactylation.
21Friend or foe? The elusive role of hepatic stellate cells in liver cancer.PubMed
Bruno Cogliati, Chittampalli N Yashaswini, Shuang Wang, et al.
Nat Rev Gastroenterol Hepatol. 2023 Oct;20(10):647-661. doi: 10.1038/s41575-023-00821-z. Epub 2023 Aug 7.
Liver fibrosis is a substantial risk factor for the development and progression of liver cancer, which includes hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA). Studies utilizing cell fate mapping and single-cell transcriptomics techniques have identified quiescent perisinusoidal hepatic stellate cells (HSCs) as the primary source of activated collagen-producing HSCs and liver cancer-associated fibroblasts (CAFs) in HCC and liver metastasis, complemented in iCCA by contributions from portal fibroblasts. At the same time, integrative computational analysis of single-cell, single-nucleus and spatial RNA sequencing data have revealed marked heterogeneity among HSCs and CAFs, with distinct subpopulations displaying unique gene expression signatures and functions. Some of these subpopulations have divergent roles in promoting or inhibiting liver fibrogenesis and carcinogenesis. In this Review, we discuss the dual roles of HSC subpopulations in liver fibrogenesis and their contribution to liver cancer promotion, progression and metastasis. We review the transcriptomic and functional similarities between HSC and CAF subpopulations, highlighting the pathways that either promote or prevent fibrosis and cancer, and the immunological landscape from which these pathways emerge. Insights from ongoing studies will yield novel strategies for developing biomarkers, assessing prognosis and generating new therapies for both HCC and iCCA prevention and treatment.
22Opposing roles of hepatic stellate cell subpopulations in hepatocarcinogenesis.PubMed
Aveline Filliol, Yoshinobu Saito, Ajay Nair, et al.
Nature. 2022 Oct;610(7931):356-365. doi: 10.1038/s41586-022-05289-6. Epub 2022 Oct 5.
Hepatocellular carcinoma (HCC), the fourth leading cause of cancer mortality worldwide, develops almost exclusively in patients with chronic liver disease and advanced fibrosis. Here we interrogated functions of hepatic stellate cells (HSCs), the main source of liver fibroblasts, during hepatocarcinogenesis. Genetic depletion, activation or inhibition of HSCs in mouse models of HCC revealed their overall tumour-promoting role. HSCs were enriched in the preneoplastic environment, where they closely interacted with hepatocytes and modulated hepatocarcinogenesis by regulating hepatocyte proliferation and death. Analyses of mouse and human HSC subpopulations by single-cell RNA sequencing together with genetic ablation of subpopulation-enriched mediators revealed dual functions of HSCs in hepatocarcinogenesis. Hepatocyte growth factor, enriched in quiescent and cytokine-producing HSCs, protected against hepatocyte death and HCC development. By contrast, type I collagen, enriched in activated myofibroblastic HSCs, promoted proliferation and tumour development through increased stiffness and TAZ activation in pretumoural hepatocytes and through activation of discoidin domain receptor 1 in established tumours. An increased HSC imbalance between cytokine-producing HSCs and myofibroblastic HSCs during liver disease progression was associated with increased HCC risk in patients. In summary, the dynamic shift in HSC subpopulations and their mediators during chronic liver disease is associated with a switch from HCC protection to HCC promotion.
23Semaphorin 3C (Sema3C) reshapes stromal microenvironment to promote hepatocellular carcinoma progression.PubMed
Hao Peng, Meng Yang, Kun Feng, et al.
Signal Transduct Target Ther. 2024 Jul 3;9(1):169. doi: 10.1038/s41392-024-01887-0.
More than 90% of hepatocellular carcinoma (HCC) cases develop in the presence of fibrosis or cirrhosis, making the tumor microenvironment (TME) of HCC distinctive due to the intricate interplay between cancer-associated fibroblasts (CAFs) and cancer stem cells (CSCs), which collectively regulate HCC progression. However, the mechanisms through which CSCs orchestrate the dynamics of the tumor stroma during HCC development remain elusive. Our study unveils a significant upregulation of Sema3C in fibrotic liver, HCC tissues, peripheral blood of HCC patients, as well as sorafenib-resistant tissues and cells, with its overexpression correlating with the acquisition of stemness properties in HCC. We further identify NRP1 and ITGB1 as pivotal functional receptors of Sema3C, activating downstream AKT/Gli1/c-Myc signaling pathways to bolster HCC self-renewal and tumor initiation. Additionally, HCC cells-derived Sema3C facilitated extracellular matrix (ECM) contraction and collagen deposition in vivo, while also promoting the proliferation and activation of hepatic stellate cells (HSCs). Mechanistically, Sema3C interacted with NRP1 and ITGB1 in HSCs, activating downstream NF-kB signaling, thereby stimulating the release of IL-6 and upregulating HMGCR expression, consequently enhancing cholesterol synthesis in HSCs. Furthermore, CAF-secreted TGF-β1 activates AP1 signaling to augment Sema3C expression in HCC cells, establishing a positive feedback loop that accelerates HCC progression. Notably, blockade of Sema3C effectively inhibits tumor growth and sensitizes HCC cells to sorafenib in vivo. In sum, our findings spotlight Sema3C as a novel biomarker facilitating the crosstalk between CSCs and stroma during hepatocarcinogenesis, thereby offering a promising avenue for enhancing treatment efficacy and overcoming drug resistance in HCC.
24Mechanisms of hepatocellular carcinoma progression.PubMed
Olorunseun O Ogunwobi, Trisheena Harricharran, Jeannette Huaman, et al.
World J Gastroenterol. 2019 May 21;25(19):2279-2293. doi: 10.3748/wjg.v25.i19.2279.
Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver. It is the second leading cause of cancer-related deaths worldwide, with a very poor prognosis. In the United States, there has been only minimal improvement in the prognosis for HCC patients over the past 15 years. Details of the molecular mechanisms and other mechanisms of HCC progression remain unclear. Consequently, there is an urgent need for better understanding of these mechanisms. HCC is often diagnosed at advanced stages, and most patients will therefore need systemic therapy, with sorafenib being the most common at the present time. However, sorafenib therapy only minimally enhances patient survival. This review provides a summary of some of the known mechanisms that either cause HCC or contribute to its progression. Included in this review are the roles of viral hepatitis, non-viral hepatitis, chronic alcohol intake, genetic predisposition and congenital abnormalities, toxic exposures, and autoimmune diseases of the liver. Well-established molecular mechanisms of HCC progression such as epithelial-mesenchymal transition, tumor-stromal interactions and the tumor microenvironment, cancer stem cells, and senescence bypass are also discussed. Additionally, we discuss the roles of circulating tumor cells, immunomodulation, and neural regulation as potential new mechanisms of HCC progression. A better understanding of these mechanisms could have implications for the development of novel and more effective therapeutic and prognostic strategies, which are critically needed.
25Molecular mechanisms of viral hepatitis induced hepatocellular carcinoma.PubMed
Simmone D'souza, Keith Ck Lau, Carla S Coffin, et al.
World J Gastroenterol. 2020 Oct 14;26(38):5759-5783. doi: 10.3748/wjg.v26.i38.5759.
Chronic infection with viral hepatitis affects half a billion individuals worldwide and can lead to cirrhosis, cancer, and liver failure. Liver cancer is the third leading cause of cancer-associated mortality, of which hepatocellular carcinoma (HCC) represents 90% of all primary liver cancers. Solid tumors like HCC are complex and have heterogeneous tumor genomic profiles contributing to complexity in diagnosis and management. Chronic infection with hepatitis B virus (HBV), hepatitis delta virus (HDV), and hepatitis C virus (HCV) are the greatest etiological risk factors for HCC. Due to the significant role of chronic viral infection in HCC development, it is important to investigate direct (viral associated) and indirect (immune-associated) mechanisms involved in the pathogenesis of HCC. Common mechanisms used by HBV, HCV, and HDV that drive hepatocarcinogenesis include persistent liver inflammation with an impaired antiviral immune response, immune and viral protein-mediated oxidative stress, and deregulation of cellular signaling pathways by viral proteins. DNA integration to promote genome instability is a feature of HBV infection, and metabolic reprogramming leading to steatosis is driven by HCV infection. The current review aims to provide a brief overview of HBV, HCV and HDV molecular biology, and highlight specific viral-associated oncogenic mechanisms and common molecular pathways deregulated in HCC, and current as well as emerging treatments for HCC.
26Advances in molecular classification and precision oncology in hepatocellular carcinoma.PubMed
Sandra Rebouissou, Jean-Charles Nault
J Hepatol. 2020 Feb;72(2):215-229. doi: 10.1016/j.jhep.2019.08.017.
Hepatocellular carcinoma (HCC) arises from hepatocytes through the sequential accumulation of multiple genomic and epigenomic alterations resulting from Darwinian selection. Genes from various signalling pathways such as telomere maintenance, Wnt/β-catenin, P53/cell cycle regulation, oxidative stress, epigenetic modifiers, AKT/mTOR and MAP kinase are frequently mutated in HCC. Several subclasses of HCC have been identified based on transcriptomic dysregulation and genetic alterations that are closely related to risk factors, pathological features and prognosis. Undoubtedly, integration of data obtained from both preclinical models and human studies can help to accelerate the identification of robust predictive biomarkers of response to targeted biotherapy and immunotherapy. The aim of this review is to describe the main advances in HCC in terms of molecular biology and to discuss how this knowledge could be used in clinical practice in the future.
27Mechanisms of hepatocellular carcinoma and cirrhosis development in concurrent steatotic liver disease and chronic hepatitis B.PubMed
Saisai Zhang, Lung-Yi Mak, Man-Fung Yuen, et al.
Clin Mol Hepatol. 2025 Feb;31(Suppl):S182-S195. doi: 10.3350/cmh.2024.0837. Epub 2024 Nov 21.
Chronic hepatitis B (CHB) poses a major global public health challenge and is a leading cause of cirrhosis and liver cancer. Hepatic steatosis is common in individuals with CHB compared to the non-CHB population and is particularly prevalent in hepatitis B virus (HBV)-endemic regions, affecting about one-third of CHB patients. The interaction between hepatic steatosis and CHB-related disease progression is complex and still under debate. Evidence demonstrates that co-existing steatosis may worsen liver fibrosis while paradoxically increasing the likelihood of achieving better HBV control. In particular, despite the association of steatotic liver disease (SLD) with lower HBV viral loads and higher rates of HBsAg seroclearance, the coexistence of CHB and SLD can potentially accelerate liver disease progression. Factors such as fat deposition, lipotoxicity, oxidative stress, and chronic inflammation in SLD may foster a pro-fibrotic and pro-carcinogenic environment, accelerating the disease progression. Additionally, loss of global DNA methylation, changes in the immune microenvironment, and genetic susceptibility further contribute to the development of CHB-related cirrhosis and hepatocellular carcinoma (HCC). This review examines the mechanisms driving liver disease progression and the heightened risk of cirrhosis and HCC in patients with concurrent CHB and steatotic liver disease, underscoring the importance of prioritizing antiviral therapy for CHB in addition to addressing SLD.
28ALDH2 deficiency promotes alcohol-associated liver cancer by activating oncogenic pathways via oxidized DNA-enriched extracellular vesicles.PubMed
Wonhyo Seo, Yanhang Gao, Yong He, et al.
J Hepatol. 2019 Nov;71(5):1000-1011. doi: 10.1016/j.jhep.2019.06.018. Epub 2019 Jul 4.
BACKGROUND & AIMS: Excessive alcohol consumption is one of the major causes of hepatocellular carcinoma (HCC). Approximately 30-40% of the Asian population are deficient for aldehyde dehydrogenase 2 (ALDH2), a key enzyme that detoxifies the ethanol metabolite acetaldehyde. However, how ALDH2 deficiency affects alcohol-related HCC remains unclear. METHODS: ALDH2 polymorphisms were studied in 646 patients with viral hepatitis B (HBV) infection, who did or did not drink alcohol. A new model of HCC induced by chronic carbon tetrachloride (CCl) and alcohol administration was developed and studied in 3 lines of Aldh2-deficient mice: including Aldh2 global knockout (KO) mice, Aldh2*1/*2 knock-in mutant mice, and liver-specific Aldh2 KO mice. RESULTS: We demonstrated that ALDH2 deficiency was not associated with liver disease progression but was associated with an increased risk of HCC development in cirrhotic patients with HBV who consumed excessive alcohol. The mechanisms underlying HCC development associated with cirrhosis and alcohol consumption were studied in Aldh2-deficient mice. We found that all 3 lines of Aldh2-deficient mice were more susceptible to CCl plus alcohol-associated liver fibrosis and HCC development. Furthermore, our results from in vivo and in vitro mechanistic studies revealed that after CCl plus ethanol exposure, Aldh2-deficient hepatocytes produced a large amount of harmful oxidized mitochondrial DNA via extracellular vesicles, which were then transferred into neighboring HCC cells and together with acetaldehyde activated multiple oncogenic pathways (JNK, STAT3, BCL-2, and TAZ), thereby promoting HCC. CONCLUSIONS: ALDH2 deficiency is associated with an increased risk of alcohol-related HCC development from fibrosis in patients and in mice. Mechanistic studies reveal a novel mechanism that Aldh2-deficient hepatocytes promote alcohol-associated HCC by transferring harmful oxidized mitochondrial DNA-enriched extracellular vesicles into HCC and subsequently activating multiple oncogenic pathways in HCC. LAY SUMMARY: Alcoholics with an ALDH2 polymorphism have an increased risk of digestive tract cancer development, however, the link between ALDH2 deficiency and hepatocellular carcinoma (HCC) development has not been well established. In this study, we show that ALDH2 deficiency exacerbates alcohol-associated HCC development both in patients and mouse models. Mechanistic studies revealed that after chronic alcohol exposure, Aldh2-deficient hepatocytes produce a large amount of harmful oxidized mitochondrial DNA via extracellular vesicles, which can be delivered into neighboring HCC cells and subsequently activate multiple oncogenic pathways, promoting HCC.
29The progress of molecules and strategies for the treatment of HBV infection.PubMed
Youlu Pan, Heye Xia, Yanwen He, et al.
Front Cell Infect Microbiol. 2023 Mar 15;13:1128807. doi: 10.3389/fcimb.2023.1128807. eCollection 2023.
Hepatitis B virus infections have always been associated with high levels of mortality. In 2019, hepatitis B virus (HBV)-related diseases resulted in approximately 555,000 deaths globally. In view of its high lethality, the treatment of HBV infections has always presented a huge challenge. The World Health Organization (WHO) came up with ambitious targets for the elimination of hepatitis B as a major public health threat by 2030. To accomplish this goal, one of the WHO's strategies is to develop curative treatments for HBV infections. Current treatments in a clinical setting included 1 year of pegylated interferon alpha (PEG-IFNα) and long-term nucleoside analogues (NAs). Although both treatments have demonstrated outstanding antiviral effects, it has been difficult to develop a cure for HBV. The reason for this is that covalently closed circular DNA (cccDNA), integrated HBV DNA, the high viral burden, and the impaired host immune responses all hinder the development of a cure for HBV. To overcome these problems, there are clinical trials on a number of antiviral molecules being carried out, all -showing promising results so far. In this review, we summarize the functions and mechanisms of action of various synthetic molecules, natural products, traditional Chinese herbal medicines, as clustered regularly interspaced short palindromic repeats and their associated proteins (CRISPR/Cas)-based systems, zinc finger nucleases (ZFNs), and transcription activator-like effector nucleases (TALENs), all of which could destroy the stability of the HBV life cycle. In addition, we discuss the functions of immune modulators, which can enhance or activate the host immune system, as well some representative natural products with anti-HBV effects.
30Scientific and medical evidence informing expansion of hepatitis B treatment guidelines.PubMed
Patrick T Kennedy, Lena Allweiss, Antonio Bertoletti, et al.
Lancet Gastroenterol Hepatol. 2025 Oct;10(10):941-951. doi: 10.1016/S2468-1253(25)00053-6. Epub 2025 Jul 23.
Chronic hepatitis B treatment relies on nucleoside or nucleotide analogue drugs that suppress hepatitis B virus (HBV) replication, normalise liver enzymes, and slow disease progression with excellent safety profiles. Treatment is not curative, and patients remain at risk of cirrhosis and hepatocellular carcinoma. Treatment guidelines have generally restricted antiviral therapy to individuals with high HBV DNA and elevated ALT or hepatic fibrosis, often requiring longitudinal testing that can be scarcely available in resource-limited settings. Consequently, fewer than 3% of people living with HBV infection are receiving antiviral therapy. Guidelines from China and WHO recently broadened access criteria to antiviral therapy, but there are people who fall outside these guidelines who could still benefit from treatment initiation. The pathological processes induced by HBV infection are still active in these patients. We present the benefits and risks of expanding treatment eligibility. We believe that the benefits of reduced hepatic damage and carcinogenic stimuli greatly outweigh the risks.
31Past, present, and future of long-term treatment for hepatitis B virus.PubMed
Teresa Broquetas, José A Carrión
World J Gastroenterol. 2023 Jul 7;29(25):3964-3983. doi: 10.3748/wjg.v29.i25.3964.
The estimated world prevalence of hepatitis B virus (HBV) infection is 316 million. HBV infection was identified in 1963 and nowadays is a major cause of cirrhosis and hepatocellular carcinoma (HCC) despite universal vaccination programs, and effective antiviral therapy. Long-term administration of nucleos(t)ide analogues (NA) has been the treatment of choice for chronic hepatitis B during the last decades. The NA has shown a good safety profile and high efficacy in controlling viral replication, improving histology, and decreasing the HCC incidence, decompensation, and mortality. However, the low probability of HBV surface antigen seroclearance made necessary an indefinite treatment. The knowledge, in recent years, about the different phases of the viral cycle, and the new insights into the role of the immune system have yielded an increase in new therapeutic approaches. Consequently, several clinical trials evaluating combinations of new drugs with different mechanisms of action are ongoing with promising results. This integrative literature review aims to assess the knowledge and major advances from the past of hepatitis B, the present of NA treatment and withdrawal, and the future perspectives with combined molecules to achieve a functional cure.
32Patient and public health perspectives to inform expansion of hepatitis B treatment guidelines.PubMed
Chari Cohen, Thomas Tu, Philippa C Matthews, et al.
Lancet Gastroenterol Hepatol. 2025 Oct;10(10):952-962. doi: 10.1016/S2468-1253(25)00052-4. Epub 2025 Jul 23.
Chronic hepatitis B is associated with considerable morbidity and mortality worldwide. People living with hepatitis B face physical, emotional, social, and professional impacts, reducing their quality of life. Treatment with nucleoside or nucleotide analogues reduces the risk of liver cirrhosis and liver cancer and improves quality of life. However, few people globally are offered and can access affordable and long-term antiviral treatment. Moreover, little progress has been made towards meeting WHO hepatitis B elimination targets. The global landscape has been shifting towards expanding treatment criteria, but discussion surrounding patient and community perspectives has been inadequate. We should view treatment eligibility for hepatitis B virus infection from a public health and patient-centred approach. Here, we discuss the potential benefits and risks of expansion, implementation considerations, public health questions, and data needs surrounding the expansion of treatment eligibility. We conclude that there is a strong public health and community rationale for expanding treatment eligibility for people living with chronic hepatitis B.
33Treatment of hepatitis B: Is there still a role for interferon?PubMed
Mauro Viganò, Glenda Grossi, Alessandro Loglio, et al.
Liver Int. 2018 Feb;38 Suppl 1:79-83. doi: 10.1111/liv.13635.
The treatment of chronic hepatitis B (CHB) patients is based on monotherapy with pegylated-interferon (Peg-IFN) or with one of the three most potent nucleot(s)ide analogues (NUCs) with the best resistance profiles, i.e. entecavir (ETV), tenofovir disoproxil fumarate (TDF) and tenofovir alafenamide (TAF). Long-term NUCs treatment can achieve virological suppression in almost all patients. However, this requires lifelong therapy, is costly and the rate of hepatitis B surface antigen (HBsAg) seroclearance is low. A one-year course of Peg-IFN has the advantage of providing immune-mediated control of the hepatitis B virus (HBV) infection, the possibility of achieving a sustained off-treatment response in nearly 30% of the patients and ultimately, HBsAg loss in approximately 30%-50% of the latter patients during long-term off treatment follow-up. However, the major limitations to the extensive use of this treatment are the need for parenteral therapy and clinical and laboratory monitoring, the side-effects profile and contraindications in certain patients and the limited effectiveness in a large proportion of patients. Nevertheless, the cost-effectiveness of Peg-IFN can be significantly increased by careful patient selection based upon baseline alanine aminotransferase (ALT), HBV DNA levels, viral genotype, host genetic variants and especially by applying early on-treatment stopping rules based upon HBsAg kinetics. Recently, because of the different mechanisms of action of Peg-IFN and NUCs, the strategy of "adding-on" or "switching to" Peg-IFN in patients being treated with NUCs to accelerate the decline in HBsAg and enhance HBsAg seroclearance rates, has provided interesting results.
34Hepatitis B and C.PubMed
Wikrom Karnsakul, Kathleen B Schwarz
Pediatr Clin North Am. 2017 Jun;64(3):641-658. doi: 10.1016/j.pcl.2017.01.007.
Chronic viral hepatitis is a global health threat and financial burden. Hepatitis B and C viruses (HBV and HCV) are the most common causes of chronic viral hepatitis in the United States. Most cases are asymptomatic before adulthood. Research has resulted in effective therapy for HCV and the promise of effective therapies for HBV. For HCV, therapy is pegylated interferon and ribavirin. Clinical trials with effective direct-acting antiviral agents are underway in pediatrics. For HBV, approved agents are alpha-interferon, lamivudine, adefovir, tenofovir, and entecavir. However, treatment seldom results in functional cure and more effective therapies are urgently needed.
35Hepatitis C: Diagnosis and Management.PubMed
David L Maness, Elly Riley, Grant Studebaker
Am Fam Physician. 2021 Dec 1;104(6):626-635.
Screening recommendations and treatment guidelines for hepatitis C virus (HCV) infection have been updated. People at the greatest risk of HCV infection are those between 18 and 39 years of age and those who use injection drugs. Universal screening with an anti-HCV antibody test with follow-up reflex HCV RNA polymerase chain reaction testing for positive results to confirm active disease is recommended at least once for all adults 18 years and older and during each pregnancy. Any person with ongoing risk factors should be screened periodically as long as the at-risk behavior persists. One-time screening is recommended for patients younger than 18 years with risk factors. For treatment-naive adults without cirrhosis or with compensated cirrhosis, a simplified treatment regimen consisting of eight weeks of glecaprevir/pibrentasvir or 12 weeks of sofosbuvir/velpatasvir results in greater than 95% cure rates. Undetectable HCV RNA 12 weeks after completing therapy is considered a virologic cure (i.e., sustained virologic response). A sustained virologic response is associated with lower all-cause mortality and improves hepatic and extrahepatic manifestations, cognitive function, physical health, work productivity, and quality of life. In patients with compensated cirrhosis, posttreatment surveillance for hepatocellular carcinoma and esophageal varices should include abdominal ultrasonography (with or without alpha fetoprotein) every six months and upper endoscopy every two to three years. In the absence of cirrhosis, no liver-related follow-up is recommended.
36Symbiotic chemo- and immuno-therapy for hepatitis B and C viruses.PubMed
Babita Agrawal, Rakesh Kumar
World J Gastroenterol. 2016 Jul 7;22(25):5623-6. doi: 10.3748/wjg.v22.i25.5623.
Hepatitis B and C viruses (HBV and HCV), both cause serious chronic infections leading to fatal liver diseases. The prototype therapy for both HBV and HCV was based on IFN-α with or without ribavirin. The advent of direct-acting antivirals (DAA) for both HBV and HCV has remarkably improved the standard of treatment for both infections. While HCV can be eliminated following combination DAA therapy, HBV persists even after treatment, requiring life-long therapy with DAAs. Treatment with DAAs is also associated with high cost, the development of resistance and side effects. There is ample published evidence that both HBV and HCV can be eliminated from infected host cells through non-cytolytic immune mechanisms. We need to identify the mechanisms behind this successful elimination of replicating viruses and develop them into novel immunotherapeutic regimens. Moreover, a synergy of, chemo- and immuno-therapeutic strategies will be necessary to eradicate HBV or HCV from a host.
37Review of the Effects of Antiviral Therapy on Hepatitis B/C-Related Mortality and the Regression of Fibrosis.PubMed
Stephen Sinclair, Sean Shearen, Youssef Ghobrial, et al.
Viruses. 2024 Sep 27;16(10):1531. doi: 10.3390/v16101531.
Hepatitis B and Hepatitis C are viral causes of Hepatitis that lead to significant worldwide mortality and morbidity through the sequelae of fibrosis and hepatocellular carcinoma. In this review, we have summarized recent studies that have examined the effects of antiviral therapy on the regression of fibrosis and the reduction in mortalities associated with the viruses. Antiviral therapy significantly decreases mortality and induces the regression of fibrosis.
38HCC surveillance after SVR in patients with F3/F4 fibrosis.PubMed
George N Ioannou
J Hepatol. 2021 Feb;74(2):458-465. doi: 10.1016/j.jhep.2020.10.016. Epub 2020 Dec 7.
HCV eradication by antiviral treatment reduces but does not eliminate HCC risk. Patients with established cirrhosis require HCC surveillance "indefinitely" after sustained virologic response (SVR) because they appear to have a high risk of HCC even many years after SVR. Patients without established or known cirrhosis may still require surveillance after SVR if they have a sufficiently high HCC risk. In all patients who achieve SVR, the key question is how we can reliably estimate HCC risk, and the change in HCC risk over time, to determine whether the patient might benefit from HCC surveillance. HCC risk is one of the most important factors that should inform decisions of whether and how to screen for HCC. Promising strategies for estimating HCC risk include simplified scoring systems (such as fibrosis-4), liver elastography and multivariable HCC risk calculators. Such tools may enable risk stratification and individualised, risk-based surveillance strategies ("precision HCC screening") in the future.
39Surveillance Imaging and Alpha Fetoprotein for Early Detection of Hepatocellular Carcinoma in Patients With Cirrhosis: A Meta-analysis.PubMed
Kristina Tzartzeva, Joseph Obi, Nicole E Rich, et al.
Gastroenterology. 2018 May;154(6):1706-1718.e1. doi: 10.1053/j.gastro.2018.01.064. Epub 2018 Feb 6.
BACKGROUND & AIMS: Society guidelines differ in their recommendations for surveillance to detect early-stage hepatocellular carcinoma (HCC) in patients with cirrhosis. We compared the performance of surveillance imaging, with or without alpha fetoprotein (AFP), for early detection of HCC in patients with cirrhosis. METHODS: Two reviewers searched MEDLINE and SCOPUS from January 1990 through August 2016 to identify published sensitivity and specificity of surveillance strategies for overall and early detection of HCC. Pooled estimates were calculated and compared using the DerSimonian and Laird method for a random effects model. The study was conducted in accordance with Preferred Reporting Items for Systematic Review and Meta-analysis guidelines. RESULTS: Thirty-two studies (comprising 13,367 patients) characterized sensitivity of imaging with or without AFP measurement for detection of HCC in patients with cirrhosis. Ultrasound detected any stage HCC with 84% sensitivity (95% confidence interval [CI] 76%-92%), but early-stage HCC with only 47% sensitivity (95% CI 33%-61%). In studies comparing ultrasound with vs without AFP measurement, ultrasound detected any stage HCC with a lower level of sensitivity than ultrasound plus AFP measurement (relative risk [RR] 0.88; 95% CI 0.83-0.93) and early-stage HCC with a lower level of sensitivity than ultrasound plus AFP measurement (RR 0.81; 95% CI 0.71-0.93). However, ultrasound alone detected HCC with a higher level of specificity than ultrasound plus AFP measurement (RR 1.08; 95% CI 1.05-1.09). Ultrasound with vs without AFP detected early-stage HCC with 63% sensitivity (95% CI 48%-75%) and 45% sensitivity (95% CI 30%-62%), respectively (P = .002). Only 4 studies evaluated computed tomography or magnetic resonance image-based surveillance, which detected HCC with 84% sensitivity (95% CI 70%-92%). CONCLUSIONS: We found ultrasound alone has a low sensitivity to detect early stage HCC in patients with cirrhosis. Addition of AFP to ultrasound significantly increases sensitivity of early HCC detection in clinical practice.
40Circulating biomarkers in the diagnosis and management of hepatocellular carcinoma.PubMed
Philip Johnson, Qing Zhou, Doan Y Dao, et al.
Nat Rev Gastroenterol Hepatol. 2022 Oct;19(10):670-681. doi: 10.1038/s41575-022-00620-y. Epub 2022 Jun 8.
Hepatocellular carcinoma (HCC) is one of the most prevalent and lethal causes of cancer-related death worldwide. The treatment of HCC remains challenging and is largely predicated on early diagnosis. Surveillance of high-risk groups using abdominal ultrasonography, with or without serum analysis of α-fetoprotein (AFP), can permit detection of early, potentially curable tumours, but is limited by its insensitivity. Reviewed here are two current approaches that aim to address this limitation. The first is to use old re-emerged empirically derived biomarkers such as AFP, now applied within statistical models. The second is to use circulating nucleic acid biomarkers, which include cell-free DNA (for example, circulating tumour DNA, cell-free mitochondrial DNA and cell-free viral DNA) and cell-free RNA, applying modern molecular biology-based technologies and machine learning techniques closely allied to the underlying biology of cancer. Taken together, these approaches are likely to be complementary. Both hold considerable promise for achieving earlier diagnosis as well as offering additional functionalities including improved monitoring of therapy and prediction of response thereto.
41Is Screening for Hepatocellular Carcinoma Effective?PubMed
Rachel M Lee, Maria C Russell
Adv Surg. 2023 Sep;57(1):73-86. doi: 10.1016/j.yasu.2023.03.003. Epub 2023 Apr 28.
Hepatocellular carcinoma occurs primarily in patients with cirrhosis and is an important cause of cancer death. Screening for hepatocellular carcinoma every 6 months with ultrasound with or without alpha fetoprotein measurement is recommended by multiple professional societies. There are no randomized controlled trials in patients with cirrhosis documenting the effectiveness of screening in improving survival, however, making screening controversial. There are multiple retrospective and cohort studies, as well as pooled analyses that do show an association of screening with earlier stage at diagnosis, increased receipt of curative intent treatment, and improved overall survival. Though these studies are limited by lead and length time biases, they make compelling arguments in favor of screening. Additional research into barriers to receiving screening, barriers to receiving treatment, and the optimal screening modalities given the shift of cirrhosis etiology in the United States are needed to further improve patient outcomes.
43Simultaneous analysis of mutations and methylations in circulating cell-free DNA for hepatocellular carcinoma detection.PubMed
Pei Wang, Qianqian Song, Jie Ren, et al.
Sci Transl Med. 2022 Nov 23;14(672):eabp8704. doi: 10.1126/scitranslmed.abp8704.
Cell-free DNA (cfDNA)-based liquid biopsy is a promising approach for the early detection of cancer. A major hurdle is the limited yield of cfDNA from one blood draw, limiting the use of most samples to one test of either mutation or methylation. Here, we develop a technology, Mutation Capsule Plus (MCP), which enables multiplex profiling of one cfDNA sample, including simultaneous detection of genetic and epigenetic alterations and genome-wide discovery of methylation markers. With this technology, we performed de novo screening of methylation markers on cfDNA samples from 30 hepatocellular carcinoma (HCC) cases and 30 non-HCC controls. The methylation markers enriched in HCC cfDNA were further profiled in parallel with a panel of mutations on a training cohort of 60 HCC and 60 non-HCC cases, resulting in an HCC detection model. We validated the model in an independent retrospective cohort with 58 HCC and 198 non-HCC cases and got 90% sensitivity with 94% specificity. Furthermore, we applied the model to a prospective cohort of 311 asymptomatic hepatitis B virus carriers with normal liver ultrasonography and serum AFP concentration. The model detected four of the five HCC cases in the cohort, showing 80% sensitivity and 94% specificity. These findings demonstrate that the MCP technology has potential for the discovery and validation of multiomics biomarkers for the noninvasive detection of cancer. This study also provides a comprehensive database of genetic and epigenetic alterations in the cfDNA of a large cohort of HCC cases and high-risk non-HCC individuals.
45Trichilia catigua against Helicobacter pylori: An in vitro, molecular and in silico approach.PubMed
Mariane Roberta Ritter, Marcelo Tempesta de Oliveira, Juliana Santa Ardisson, et al.
Fitoterapia. 2024 Sep;177:106101. doi: 10.1016/j.fitote.2024.106101. Epub 2024 Jun 28.
Helicobacter pylori is a bacterium that is present in the stomach of about 50% of the global population and is associated with several gastric disorders, including cancer. Natural products with antimicrobial activity have been tested against H. pylori, among them Trichilia catigua (catuaba), which is widely distributed in Brazil. This study aimed to evaluate extracts of T. catigua bark against H. pylori via determination of the minimum inhibitory and bactericidal concentrations (MIC and MBC); evaluation of virulence factors by real-time PCR, synergism with standard antimicrobials and morphology by scanning electron microscopy and simulations of the mechanism of action by molecular docking. The ethyl acetate fraction provided the best results, with an MIC of 250 μg/mL and a 42.34% reduction in urease activity, along with reduced expression of the CagA and VacA genes, which encode for the main virulence factors. This fraction presented synergistic activity with clarithromycin, reducing the MIC of the drug by four-fold. Docking simulations suggested that the extracts inhibit fatty acid synthesis by the FAS-II system, causing damage to the cell membrane. Therefore, T. catigua extracts have potential as an adjuvant to treatment and are promising for the development of new anti-H. pylori drugs.
46infection: a dynamic process from diagnosis to treatment.PubMed
Qifang Sun, Chengzhi Yuan, Sainan Zhou, et al.
Front Cell Infect Microbiol. 2023 Oct 19;13:1257817. doi: 10.3389/fcimb.2023.1257817. eCollection 2023.
, a gram-negative microaerophilic pathogen, causes several upper gastrointestinal diseases, such as chronic gastritis, peptic ulcer disease, and gastric cancer. For the diseases listed above, has different pathogenic mechanisms, including colonization and virulence factor expression. It is essential to make accurate diagnoses and provide patients with effective treatment to achieve positive clinical outcomes. Detection of can be accomplished invasively and noninvasively, with both having advantages and limitations. To enhance therapeutic outcomes, novel therapeutic regimens, as well as adjunctive therapies with probiotics and traditional Chinese medicine, have been attempted along with traditional empiric treatments, such as triple and bismuth quadruple therapies. An infection, however, is difficult to eradicate during treatment owing to bacterial resistance, and there is no commonly available preventive vaccine. The purpose of this review is to provide an overview of our understanding of infections and to highlight current treatment and diagnostic options.
47Gastric Parietal Cell Physiology and Helicobacter pylori-Induced Disease.PubMed
Xuebiao Yao, Adam J Smolka
Gastroenterology. 2019 Jun;156(8):2158-2173. doi: 10.1053/j.gastro.2019.02.036. Epub 2019 Mar 1.
Acidification of the gastric lumen poses a barrier to transit of potentially pathogenic bacteria and enables activation of pepsin to complement nutrient proteolysis initiated by salivary proteases. Histamine-induced activation of the PKA signaling pathway in gastric corpus parietal cells causes insertion of proton pumps into their apical plasma membranes. Parietal cell secretion and homeostasis are regulated by signaling pathways that control cytoskeletal changes required for apical membrane remodeling and organelle and proton pump activities. Helicobacter pylori colonization of human gastric mucosa affects gastric epithelial cell plasticity and homeostasis, promoting epithelial progression to neoplasia. By intervening in proton pump expression, H pylori regulates the abundance and diversity of microbiota that populate the intestinal lumen. We review stimulation-secretion coupling and renewal mechanisms in parietal cells and the mechanisms by which H pylori toxins and effectors alter cell secretory pathways (constitutive and regulated) and organelles to establish and maintain their inter- and intracellular niches. Studies of bacterial toxins and their effector proteins have provided insights into parietal cell physiology and the mechanisms by which pathogens gain control of cell activities, increasing our understanding of gastrointestinal physiology, microbial infectious disease, and immunology.
48Gastric Epithelial Barrier Disruption, Inflammation and Oncogenic Signal Transduction by Helicobacter pylori.PubMed
Michael Naumann, Lorena Ferino, Irshad Sharafutdinov, et al.
Curr Top Microbiol Immunol. 2023;444:207-238. doi: 10.1007/978-3-031-47331-9_8.
Helicobacter pylori exemplifies one of the most favourable bacterial pathogens worldwide. The bacterium colonizes the gastric mucosa in about half of the human population and constitutes a major risk factor for triggering gastric diseases such as stomach cancer. H. pylori infection represents a prime example of chronic inflammation and cancer-inducing bacterial pathogens. The microbe utilizes a remarkable set of virulence factors and strategies to control cellular checkpoints of inflammation and oncogenic signal transduction. This chapter emphasizes on the pathogenicity determinants of H. pylori such as the cytotoxin-associated genes pathogenicity island (cagPAI)-encoded type-IV secretion system (T4SS), effector protein CagA, lipopolysaccharide (LPS) metabolite ADP-glycero-β-D-manno-heptose (ADP-heptose), cytotoxin VacA, serine protease HtrA, and urease, and how they manipulate various key host cell signaling networks in the gastric epithelium. In particular, we highlight the H. pylori-induced disruption of cell-to-cell junctions, pro-inflammatory activities, as well as proliferative, pro-apoptotic and anti-apoptotic responses. Here we review these hijacked signal transduction events and their impact on gastric disease development.
49Pathogenesis of Helicobacter pylori infection.PubMed
Johannes G Kusters, Arnoud H M van Vliet, Ernst J Kuipers
Clin Microbiol Rev. 2006 Jul;19(3):449-90. doi: 10.1128/CMR.00054-05.
Helicobacter pylori is the first formally recognized bacterial carcinogen and is one of the most successful human pathogens, as over half of the world's population is colonized with this gram-negative bacterium. Unless treated, colonization usually persists lifelong. H. pylori infection represents a key factor in the etiology of various gastrointestinal diseases, ranging from chronic active gastritis without clinical symptoms to peptic ulceration, gastric adenocarcinoma, and gastric mucosa-associated lymphoid tissue lymphoma. Disease outcome is the result of the complex interplay between the host and the bacterium. Host immune gene polymorphisms and gastric acid secretion largely determine the bacterium's ability to colonize a specific gastric niche. Bacterial virulence factors such as the cytotoxin-associated gene pathogenicity island-encoded protein CagA and the vacuolating cytotoxin VacA aid in this colonization of the gastric mucosa and subsequently seem to modulate the host's immune system. This review focuses on the microbiological, clinical, immunological, and biochemical aspects of the pathogenesis of H. pylori.
50Novel multiphoton intravital imaging enables real-time study of Helicobacter pylori interaction with neutrophils and macrophages in the mouse stomach.PubMed
Hellen Ishikawa-Ankerhold, Benjamin Busch, Almke Bader, et al.
PLoS Pathog. 2024 Sep 30;20(9):e1012580. doi: 10.1371/journal.ppat.1012580. eCollection 2024 Sep.
Helicobacter pylori (H. pylori) is a bacterial pathogen that exclusively colonizes the human gastric mucosa and can cause persistent infection. In this process, H. pylori employs various strategies to avoid recognition by the human immune system. These range from passive defense strategies (e.g., altered LPS or flagellin structures) that prevent recognition by pattern recognition receptors (PRRs) to more active approaches, such as inhibition of IL-2 secretion and proliferation of T cells via VacA. Despite the growing evidence that H. pylori actively manipulates the human immune system for its own benefit, the direct interaction of H. pylori with immune cells in situ is poorly studied. Here, we present a novel intravital imaging model of the murine stomach gastric mucosa and show for the first time the in situ recruitment of neutrophils during infection and a direct H. pylori-macrophage interaction. For this purpose, we applied multiphoton intravital microscopy adapted with live drift correction software (VivoFollow) on LysM-eGFP and CX3CR1-eGFP reporter mice strains in which specific subsets of leukocytes are fluorescently labeled. Multiphoton microscopy is proving to be an excellent tool for characterizing interactions between immune cells and pathogens in vivo.
51Tight junction disruption: Helicobacter pylori and dysregulation of the gastric mucosal barrier.PubMed
Tyler J Caron, Kathleen E Scott, James G Fox, et al.
World J Gastroenterol. 2015 Oct 28;21(40):11411-27. doi: 10.3748/wjg.v21.i40.11411.
Long-term chronic infection with Helicobacter pylori (H. pylori) is a risk factor for gastric cancer development. In the multi-step process that leads to gastric cancer, tight junction dysfunction is thought to occur and serve as a risk factor by permitting the permeation of luminal contents across an otherwise tight mucosa. Mechanisms that regulate tight junction function and structure in the normal stomach, or dysfunction in the infected stomach, however, are largely unknown. Although conventional tight junction components are expressed in gastric epithelial cells, claudins regulate paracellular permeability and are likely the target of inflammation or H. pylori itself. There are 27 different claudin molecules, each with unique properties that render the mucosa an intact barrier that is permselective in a way that is consistent with cell physiology. Understanding the architecture of tight junctions in the normal stomach and then changes that occur during infection is important but challenging, because most of the reports that catalog claudin expression in gastric cancer pathogenesis are contradictory. Furthermore, the role of H. pylori virulence factors, such as cytotoxin-associated gene A and vacoulating cytotoxin, in regulating tight junction dysfunction during infection is inconsistent in different gastric cell lines and in vivo, likely because non-gastric epithelial cell cultures were initially used to unravel the details of their effects on the stomach. Hampering further study, as well, is the relative lack of cultured cell models that have tight junction claudins that are consistent with native tissues. This summary will review the current state of knowledge about gastric tight junctions, normally and in H. pylori infection, and make predictions about the consequences of claudin reorganization during H. pylori infection.
52Helicobacter pylori disrupts gastric mucosal homeostasis by stimulating macrophages to secrete CCL3.PubMed
Yan-Fei Wei, Xue Li, Meng-Ran Zhao, et al.
Cell Commun Signal. 2024 May 10;22(1):263. doi: 10.1186/s12964-024-01627-5.
BACKGROUND: Helicobacter pylori (H. pylori) is the predominant etiological agent of gastritis and disrupts the integrity of the gastric mucosal barrier through various pathogenic mechanisms. After H. pylori invades the gastric mucosa, it interacts with immune cells in the lamina propria. Macrophages are central players in the inflammatory response, and H. pylori stimulates them to secrete a variety of inflammatory factors, leading to the chronic damage of the gastric mucosa. Therefore, the study aims to explore the mechanism of gastric mucosal injury caused by inflammatory factors secreted by macrophages, which may provide a new mechanism for the development of H. pylori-related gastritis. METHODS: The expression and secretion of CCL3 from H. pylori infected macrophages were detected by RT-qPCR, Western blot and ELISA. The effect of H. pylori-infected macrophage culture medium and CCL3 on gastric epithelial cells tight junctions were analyzed by Western blot, immunofluorescence and transepithelial electrical resistance. EdU and apoptotic flow cytometry assays were used to detect cell proliferation and apoptosis levels. Dual-luciferase reporter assays and chromatin immunoprecipitation assays were used to study CCL3 transcription factors. Finally, gastric mucosal tissue inflammation and CCL3 expression were analyzed by hematoxylin and eosin staining and immunohistochemistry. RESULTS: After H. pylori infection, CCL3 expressed and secreted from macrophages were increased. H. pylori-infected macrophage culture medium and CCL3 disrupted gastric epithelial cells tight junctions, while CCL3 neutralizing antibody and receptor inhibitor of CCL3 improved the disruption of tight junctions between cells. In addition, H. pylori-infected macrophage culture medium and CCL3 recombinant proteins stimulated P38 phosphorylation, and P38 phosphorylation inhibitor improved the disruption of tight junctions between cells. Besides, it was identified that STAT1 was a transcription factor of CCL3 and H. pylori stimulated macrophage to secret CCL3 through the JAK1-STAT1 pathway. Finally, after mice were injected with murine CCL3 recombinant protein, the gastric mucosal injury and inflammation were aggravated, and the phosphorylation level of P38 was increased. CONCLUSIONS: In summary, our findings demonstrate that H. pylori infection stimulates macrophages to secrete CCL3 via the JAK1-STAT1 pathway. Subsequently, CCL3 damages gastric epithelial tight junctions through the phosphorylation of P38. This may be a novel mechanism of gastric mucosal injury in H. pylori-associated gastritis.
53Immune responses to Helicobacter pylori infection.PubMed
Mati Moyat, Dominique Velin
World J Gastroenterol. 2014 May 21;20(19):5583-93. doi: 10.3748/wjg.v20.i19.5583.
Helicobacter pylori (H. pylori) infection is one of the most common infections in human beings worldwide. H. pylori express lipopolysaccharides and flagellin that do not activate efficiently Toll-like receptors and express dedicated effectors, such as γ-glutamyl transpeptidase, vacuolating cytotoxin (vacA), arginase, that actively induce tolerogenic signals. In this perspective, H. pylori can be considered as a commensal bacteria belonging to the stomach microbiota. However, when present in the stomach, H. pylori reduce the overall diversity of the gastric microbiota and promote gastric inflammation by inducing Nod1-dependent pro-inflammatory program and by activating neutrophils through the production of a neutrophil activating protein. The maintenance of a chronic inflammation in the gastric mucosa and the direct action of virulence factors (vacA and cytotoxin-associated gene A) confer pro-carcinogenic activities to H. pylori. Hence, H. pylori cannot be considered as symbiotic bacteria but rather as part of the pathobiont. The development of a H. pylori vaccine will bring health benefits for individuals infected with antibiotic resistant H. pylori strains and population of underdeveloped countries.
54Current research on the interaction between Helicobacter pylori and macrophages.PubMed
Yan-Fei Wei, Si-An Xie, Shu-Tian Zhang
Mol Biol Rep. 2024 Apr 10;51(1):497. doi: 10.1007/s11033-024-09395-8.
Helicobacter pylori (H. pylori) is a gram-negative bacteria with a worldwide infection rate of 50%, known to induce gastritis, ulcers and gastric cancer. The interplay between H. pylori and immune cells within the gastric mucosa is pivotal in the pathogenesis of H. pylori-related disease. Following H. pylori infection, there is an observed increase in gastric mucosal macrophages, which are associated with the progression of gastritis. H. pylori elicits macrophage polarization, releases cytokines, reactive oxygen species (ROS) and nitric oxide (NO) to promote inflammatory response and eliminate H. pylori. Meanwhile, H. pylori has developed mechanisms to evade the host immune response in order to maintain the persistent infection, including interference with macrophage phagocytosis and antigen presentation, as well as induction of macrophage apoptosis. Consequently, the interaction between H. pylori and macrophages can significantly impact the progression, pathogenesis, and resolution of H. pylori infection. Moreover, macrophages are emerging as potential therapeutic targets for H. pylori-associated gastritis. Therefore, elucidating the involvement of macrophages in H. pylori infection may provide novel insights into the pathogenesis, progression, and management of H. pylori-related disease.
55Helicobacter pylori infection promotes M1 macrophage polarization and gastric inflammation by activation of NLRP3 inflammasome via TNF/TNFR1 axis.PubMed
Xiao Fei, Sihai Chen, Leyan Li, et al.
Cell Commun Signal. 2025 Jan 6;23(1):6. doi: 10.1186/s12964-024-02017-7.
BACKGROUND: Macrophages play a crucial role in chronic gastritis induced by the pathogenic Helicobacter pylori (H. pylori) infection. NLRP3 inflammasome has emerged as an important component of inflammatory processes. However, the molecular mechanism by which H. pylori infection drives NLRP3 inflammasome and macrophages activation remains unclear. METHODS: Human gastritis tissues were collected for clinical significance of NLRP3. Infection with H. pylori was performed using in vitro and in vivo models. Bone marrow-derived macrophages (BMDMs) from wild-type (WT), Nlrp3-knockout (KO) and Tnfr1-KO mice were infected with H. pylori. Western blotting, qRT-PCR, immunofluorescence, immunohistochemistry and ELISA were utilized for functional and mechanistic studies. RESULTS: Single-cell RNA sequencing (ScRNA-seq) analysis of human gastric tissues, followed by validation, indicated that NLRP3 was primarily expressed in myeloid cells and was significantly increased in H. pylori-positive gastritis compared to H. pylori-negative gastritis. Infection with PMSS1 and NCTC11637 H. pylori strains induced NLRP3 inflammasome activation in vitro (THP1 cells) and in the insulin-gastrin (INS-GAS) transgenic mouse model. Deletion of NLRP3 in BMDMs showed marked inhibition of H. pylori-induced M1 macrophage polarization. Furthermore, NLRP3 inflammasome activation upon TNFα, or H. pylori stimulation, was partially blocked by TNFα/TNFR1 signaling inhibitors. Deletion of TNFR1 in BMDMs significantly impaired NLRP3 inflammasome activation and M1 macrophages induced by H. pylori. CONCLUSION: This study revealed that the activation of NLRP3 inflammasome, regulated by the TNF/TNFR1 signaling axis, is a key regulator of H. pylori-induced M1 macrophage activation and gastritis.
56Review article: Immunological determinants that may affect the Helicobacter pylori cancer risk.PubMed
T G Blanchard, S J Czinn
Aliment Pharmacol Ther. 1998 Feb;12 Suppl 1:83-90. doi: 10.1111/j.1365-2036.1998.00010.x.
A large body of literature supports a role for Helicobacter pylori as an environmental factor which contributes to the development of gastric cancer through an intermediate stage of atrophic gastritis. The mechanism(s) by which H. pylori-associated chronic inflammation progresses to more serious diseases such as peptic ulcer and gastric cancer in certain individuals is not clear. Variations in the phenotype or genotype of the infecting H. pylori strain can play a role in the severity of disease. However, individuals infected with the 'more virulent' strains of H. pylori often never develop serious disease. Our experiments in inbred strains of mice provide evidence that host genetics also play a significant role in H. pylori-related gastritis. We have demonstrated that gastritis is dominated by a TH1 adaptive immune response, the degree of which directly correlates with the severity of disease. Treatment of mice with IL-12 or anti-IFN-gamma antibodies can increase or decrease, respectively the severity of gastritis in infected mice and adoptive transfer of TH1 cell lines significantly exacerbates disease. Thus, the tendency of an individual to respond to infection with specific immune mechanisms can dramatically affect the severity of disease and possibly put an individual at increased risk of progressing to disorders such as gastric cancer.
57-associated Chronic Atrophic Gastritis and Progression of Gastric Carcinogenesis.PubMed
Na Rae Lim, Woo Chul Chung
Korean J Gastroenterol. 2023 Oct 25;82(4):171-179. doi: 10.4166/kjg.2023.097.
Chronic inflammation due to a () infection is a representative cause of gastric cancer that can promote gastric carcinogenesis by abnormally activating immune cells and increasing the inflammatory cytokines levels. infections directly cause DNA double-strand breaks in gastric epithelial cells and genetic damage by increasing the enzymatic activity of cytidine deaminase. Eventually, gastric cancer is induced through dysplasia. Hypermethylation of tumor suppressor genes is an important cause of gastric cancer because of a infection. In addition, the changes in gastric microbiota and the mucosal inflammatory changes associated with a co-infection with the Epstein-Barr virus are associated with gastric cancer development. DNA damage induced by and the subsequent responses of gastric stem cells have implications for gastric carcinogenesis. Although the pathogenesis of H. pylori has been established, many uncertainties remain, requiring more study.
58MicroRNA Modulation of Host Immune Response and Inflammation Triggered by .PubMed
Maria Oana Săsăran, Lorena Elena Meliț, Ecaterina Daniela Dobru
Int J Mol Sci. 2021 Jan 30;22(3):1406. doi: 10.3390/ijms22031406.
remains the most-researched etiological factor for gastric inflammation and malignancies. Its evolution towards gastric complications is dependent upon host immune response. Toll-like receptors (TLRs) recognize surface and molecular patterns of the bacterium, especially the lipopolysaccharide (LPS), and act upon pathways, which will finally lead to activation of the nuclear factor-kappa B (NF-kB), a transcription factor that stimulates release of inflammatory cytokines. MicroRNAs (MiRNAs) finely modulate TLR signaling, but their expression is also modulated by activation of NF-kB-dependent pathways. This review aims to focus upon several of the most researched miRNAs on this subject, with known implications in host immune responses caused by , including let-7 family, miRNA-155, miRNA-146, miRNA-125, miRNA-21, and miRNA-221. TLR-LPS interactions and their afferent pathways are regulated by these miRNAs, which can be considered as a bridge, which connects gastric inflammation to pre-neoplastic and malignant lesions. Therefore, they could serve as potential non-invasive biomarkers, capable of discriminating infection, as well as its associated complications. Given that data on this matter is limited in children, as well as for as significant number of miRNAs, future research has yet to clarify the exact involvement of these entities in the progression of -associated gastric conditions.
59Induction and Regulation of the Innate Immune Response in Helicobacter pylori Infection.PubMed
Alain P Gobert, Keith T Wilson
Cell Mol Gastroenterol Hepatol. 2022;13(5):1347-1363. doi: 10.1016/j.jcmgh.2022.01.022. Epub 2022 Feb 3.
Gastric cancer (GC) is the fifth most common cancer and the fourth most common cause of cancer-related death worldwide. The intestinal type of GC progresses from acute to chronic gastritis, multifocal atrophic gastritis, intestinal metaplasia, dysplasia, and carcinoma. Infection of the stomach by Helicobacter pylori, a Gram-negative bacterium that infects approximately 50% of the world's population, is the causal determinant that initiates the gastric inflammation and then disease progression. In this context, the induction of the innate immune response of gastric epithelial cells and myeloid cells by H. pylori effectors plays a critical role in the outcome of the infection. However, only 1% to 3% of infected patients develop gastric adenocarcinoma, emphasizing that other mechanisms regulate the localized non-specific response, including the gastric microbiota and genetic factors. This review summarizes studies describing the factors that induce and regulate the mucosal innate immune response during H. pylori infection.
60Single-cell RNA sequencing dissects the immunosuppressive signatures in Helicobacter pylori-infected human gastric ecosystem.PubMed
Wei Hu, Ze Min Chen, Ying Wang, et al.
Nat Commun. 2025 Apr 25;16(1):3903. doi: 10.1038/s41467-025-59339-4.
Helicobacter pylori (H. pylori) manipulates the host immune system to establish a persistent colonization, posing a serious threat to human health, but the mechanisms remain poorly understood. Here we integrate single-cell RNA sequencing and TCR profiling for analyzing 187,192 cells from 11 H. pylori-negative and 12 H. pylori-positive individuals to describe the human gastric ecosystem reprogrammed by H. pylori infection, as manifested by impaired antigen presentation and phagocytosis function. We further delineate a monocyte-to-C1QC macrophage differentiation trajectory driven by H. pylori infection, while T cell responses exhibit broad functional impairment and hyporesponsiveness with restricted clonal expansion capacity. We also identify an HLA-DRs- and CTLA4-expressing T cell population residing in H. pylori-inhabited stomach that potentially contribute to immune evasion. Together, our findings provide single-cell resolution information into the immunosuppressive microenvironment shaped by H. pylori infection, offering critical insights for developing novel therapeutic approaches to eliminate this globally prevalent pathogen.
61Berberine for gastric cancer prevention and treatment: Multi-step actions on the Correa's cascade underlie its therapeutic effects.PubMed
Qingsong Liu, Jianyuan Tang, Shuanglan Chen, et al.
Pharmacol Res. 2022 Oct;184:106440. doi: 10.1016/j.phrs.2022.106440. Epub 2022 Sep 13.
Gastric carcinoma (GC) is a complex multifactorial disease occurring as sequential events commonly referred to as the Correa's cascade, a stepwise progression from non-active or chronic active gastritis, to gastric precancerous lesions, and finally, adenocarcinoma. Therefore, the identification of novel agents with multi-step actions on the Correa's cascade and those functioning as multiple phenotypic regulators are the future direction for drug discovery. Recently, berberine (BBR) has gained traction owing to its pharmacological properties, including anti-inflammatory, anti-cancer, anti-ulcer, antibacterial, and immunopotentiation activities. In this article, we investigated and summarized the multi-step actions of BBR on Correa's cascade and its underlying regulatory mechanism in gastric carcinogenesis for the first time, along with a discussion on the strength of BBR to prevent and treat GC. BBR was found to suppress H. pylori infection, control mucosal inflammation, and promote ulcer healing. In the gastric precancerous lesion phase, BBR could reverse mucosal atrophy and prevent lesions in intestinal metaplasia and dysplasia by regulating inflammatory cytokines, promoting cell apoptosis, regulating macrophage polarization, and regulating autophagy. Additionally, the therapeutic action of BBR on GC was partly realized through the inhibition of cell proliferation, migration, and angiogenesis; induction of apoptosis and autophagy, and enhancement of chemotherapeutic drug sensitivity. BBR exerted multi-step actions on the Correa's cascade, thereby halting and even reversing gastric carcinogenesis in some cases. Thus, BBR could be used to prevent and treat GC. In conclusion, the therapeutic strategy underlying BBR's multi-step action in the trilogy of Correa's cascade may include "prevention of gastric mucosal inflammation (Phase 1); reversal of gastric precancerous lesions (Phase 2), and rescue of GC (Phase 3)". The NF-κB, PI3K/Akt, and MAPK signaling pathways may be the key signaling transduction pathways underlying the treatment of gastric carcinogenesis using BBR. The advantage of BBR over conventional drugs is its multifaceted and long-term effects. This review is expected to provide preclinical evidence for using BBR to prevent gastric carcinogenesis and treat gastric cancer.
62Is there any association between colonic polyps and gastric intestinal metaplasia?PubMed
Gülhan Kanat Ünler, Gülsüm Teke Özgür, Hüseyin Savaş Göktürk, et al.
Turk J Gastroenterol. 2016 May;27(3):221-6. doi: 10.5152/tjg.2016.15212.
BACKGROUND/AIMS: Chronic gastritis progression is a multistep process of atrophy, intestinal metaplasia (IM), and dysplasia, which may lead to invasive carcinoma. In this study, we identified an association of colonic polyps with gastric IM in patients undergoing colonoscopy. MATERIALS AND METHODS: This retrospective case-control, cross-sectional study was conducted in a tertiary-care institution in Turkey. Pathology and endoscopy reports were reviewed. The study group comprised 400 patients with colonic adenomatous polyps, and the control group comprised 360 patients without colonic adenomatous polyps on colonoscopy. RESULTS: The risk of gastric IM was 1.42-fold higher in the study group (p<0.05). The risk of IM in patients aged ≥50 years with colonic polyps was 3.35-fold higher than in those aged <50 years (p<0.05). The risk of Helicobacter pylori infection in the study group was 1.07-folder higher than that in the control group (p<0.05). H. pylori infection prevalence was higher only in patients with high-grade colonic polyp dysplasia (p<0.05). There were no statistically significant differences in the proportion of incomplete IM between the groups (p<0.05). CONCLUSION: This study observed increased rates of gastric IM with colonic polyps. An increased risk of gastric IM was associated with higher grades of polyp dysplasia.
63Helicobacter pylori and microRNAs: Relation with innate immunity and progression of preneoplastic conditions.PubMed
Diogo Libânio, Mário Dinis-Ribeiro, Pedro Pimentel-Nunes
World J Clin Oncol. 2015 Oct 10;6(5):111-32. doi: 10.5306/wjco.v6.i5.111.
The accepted paradigm for intestinal-type gastric cancer pathogenesis is a multistep progression from chronic gastritis induced by Helicobacter pylori (H. pylori) to gastric atrophy, intestinal metaplasia, dysplasia and ultimately gastric cancer. The genetic and molecular mechanisms underlying disease progression are still not completely understood as only a fraction of colonized individuals ever develop neoplasia suggesting that bacterial, host and environmental factors are involved. MicroRNAs are noncoding RNAs that may influence H. pylori-related pathology through the regulation of the transcription and expression of various genes, playing an important role in inflammation, cell proliferation, apoptosis and differentiation. Indeed, H. pylori have been shown to modify microRNA expression in the gastric mucosa and microRNAs are involved in the immune host response to the bacteria and in the regulation of the inflammatory response. MicroRNAs have a key role in the regulation of inflammatory pathways and H. pylori may influence inflammation-mediated gastric carcinogenesis possibly through DNA methylation and epigenetic silencing of tumor suppressor microRNAs. Furthermore, microRNAs influenced by H. pylori also have been found to be involved in cell cycle regulation, apoptosis and epithelial-mesenchymal transition. Altogether, microRNAs seem to have an important role in the progression from gastritis to preneoplastic conditions and neoplastic lesions and since each microRNA can control the expression of hundreds to thousands of genes, knowledge of microRNAs target genes and their functions are of paramount importance. In this article we present a comprehensive review about the role of microRNAs in H. pylori gastric carcinogenesis, identifying the microRNAs downregulated and upregulated in the infection and clarifying their biological role in the link between immune host response, inflammation, DNA methylation and gastric carcinogenesis.
64DNA methylation in gastric cancer, related to Helicobacter pylori and Epstein-Barr virus.PubMed
Keisuke Matsusaka, Sayaka Funata, Masashi Fukayama, et al.
World J Gastroenterol. 2014 Apr 14;20(14):3916-26. doi: 10.3748/wjg.v20.i14.3916.
Gastric cancer is a leading cause of cancer death worldwide, and significant effort has been focused on clarifying the pathology of gastric cancer. In particular, the development of genome-wide analysis tools has enabled the detection of genetic and epigenetic alterations in gastric cancer; for example, aberrant DNA methylation in gene promoter regions is thought to play a crucial role in gastric carcinogenesis. The etiological viewpoint is also essential for the study of gastric cancers, and two distinct pathogens, Helicobacter pylori (H. pylori) and Epstein-Barr virus (EBV), are known to participate in gastric carcinogenesis. Chronic inflammation of the gastric epithelium due to H. pylori infection induces aberrant polyclonal methylation that may lead to an increased risk of gastric cancer. In addition, EBV infection is known to cause extensive methylation, and EBV-positive gastric cancers display a high methylation epigenotype, in which aberrant methylation extends to not only Polycomb repressive complex (PRC)-target genes in embryonic stem cells but also non-PRC-target genes. Here, we review aberrant DNA methylation in gastric cancer and the association between methylation and infection with H. pylori and EBV.
65Precancerous nature of intestinal metaplasia with increased chance of conversion and accelerated DNA methylation.PubMed
Chihiro Takeuchi, Satoshi Yamashita, Yu-Yu Liu, et al.
Gut. 2024 Jan 5;73(2):255-267. doi: 10.1136/gutjnl-2023-329492.
OBJECTIVE: The presence of intestinal metaplasia (IM) is a risk factor for gastric cancer. However, it is still controversial whether IM itself is precancerous or paracancerous. Here, we aimed to explore the precancerous nature of IM by analysing epigenetic alterations. DESIGN: Genome-wide DNA methylation analysis was conducted by EPIC BeadArray using IM crypts isolated by Alcian blue staining. Chromatin immunoprecipitation sequencing for H3K27ac and single-cell assay for transposase-accessible chromatin by sequencing were conducted using IM mucosa. was induced using Tet-on gene expression system in normal cells. RESULTS: IM crypts had a methylation profile unique from non-IM crypts, showing extensive DNA hypermethylation in promoter CpG islands, including those of tumour-suppressor genes. Also, the IM-specific methylation profile, namely epigenetic footprint, was present in a fraction of gastric cancers with a higher frequency than expected, and suggested to be associated with good overall survival. IM organoids had remarkably high expression, and induction in normal cells led to accelerated induction of aberrant DNA methylation, namely epigenetic instability, by increasing DNA methyltransferase activity. IM mucosa showed dynamic enhancer reprogramming, including the regions involved in higher expression. had open chromatin in IM cells but not in gastric cells, and IM cells had frequent closed chromatin of tumour-suppressor genes, indicating their methylation-silencing. expression in IM-derived organoids was upregulated by interleukin-17A, a cytokine secreted by extracellular bacterial infection. CONCLUSIONS: IM cells were considered to have a precancerous nature potentially with an increased chance of converting into cancer cells, and an accelerated DNA methylation induction due to abnormal expression.
66Helicobacter pylori and gastric cancer: mechanisms and new perspectives.PubMed
Yantao Duan, Yonghu Xu, Yi Dou, et al.
J Hematol Oncol. 2025 Jan 23;18(1):10. doi: 10.1186/s13045-024-01654-2.
Gastric cancer remains a significant global health challenge, with Helicobacter pylori (H. pylori) recognized as a major etiological agent, affecting an estimated 50% of the world's population. There has been a rapidly expanding knowledge of the molecular and pathogenetic mechanisms of H. pylori over the decades. This review summarizes the latest research advances to elucidate the molecular mechanisms underlying the H. pylori infection in gastric carcinogenesis. Our investigation of the molecular mechanisms reveals a complex network involving STAT3, NF-κB, Hippo, and Wnt/β-catenin pathways, which are dysregulated in gastric cancer caused by H. pylori. Furthermore, we highlight the role of H. pylori in inducing oxidative stress, DNA damage, chronic inflammation, and cell apoptosis-key cellular events that pave the way for carcinogenesis. Emerging evidence also suggests the effect of H. pylori on the tumor microenvironment and its possible implications for cancer immunotherapy. This review synthesizes the current knowledge and identifies gaps that warrant further investigation. Despite the progress in our previous knowledge of the development in H. pylori-induced gastric cancer, a comprehensive investigation of H. pylori's role in gastric cancer is crucial for the advancement of prevention and treatment strategies. By elucidating these mechanisms, we aim to provide a more in-depth insights for the study and prevention of H. pylori-related gastric cancer.
67regulates stomach diseases by activating cell pathways and DNA methylation of host cells.PubMed
Yue Xi, Xiao-Li Zhang, Qing-Xin Luo, et al.
Front Cell Dev Biol. 2023 May 4;11:1187638. doi: 10.3389/fcell.2023.1187638. eCollection 2023.
One of the most prevalent malignant tumors of the digestive tract is gastric cancer (GC). Age, high salt intake, () infection, and a diet deficient in fruits and vegetables are risk factors for the illness. A significant risk factor for gastric cancer is infection with . Infecting gastric epithelial cells with virulence agents secreted by can cause methylation of tumor genes or carcinogenic signaling pathways to be activated. Regulate downstream genes' aberrant expression, albeit the precise mechanism by which this happens is unclear. Oncogene, oncosuppressor, and other gene modifications, as well as a number of different gene change types, are all directly associated to the carcinogenesis of gastric cancer. In this review, we describe comprehensive and its virulence factors, as well as the activation of the NF-κB, MAPK, JAK/STAT signaling pathways, and DNA methylation following infection with host cells via virulence factors, resulting in abnormal gene expression. As a result, host-related proteins are regulated, and gastric cancer progression is influenced. This review provides insight into the infection, summarizes a series of relevant papers, discusses the complex signaling pathways underlying molecular mechanisms, and proposes new approach to immunotherapy of this important disease.
68H. pylori-induced NF-κB-PIEZO1-YAP1-CTGF axis drives gastric cancer progression and cancer-associated fibroblast-mediated tumour microenvironment remodelling.PubMed
Bonan Chen, Xiaoli Liu, Peiyao Yu, et al.
Clin Transl Med. 2023 Nov;13(11):e1481. doi: 10.1002/ctm2.1481.
BACKGROUND: Gastric cancer (GC) is one of the most common tumours in East Asia countries and is associated with Helicobacter pylori infection. H. pylori utilizes virulence factors, CagA and VacA, to up-regulate pro-inflammatory cytokines and activate NF-κB signaling. Meanwhile, the PIEZO1 upregulation and cancer-associated fibroblast (CAF) enrichment were found in GC progression. However, the mechanisms of PIEZO1 upregulation and its involvement in GC progression have not been fully elucidated. METHODS: The CAF enrichment and clinical significance were investigated in animal models and primary samples. The expression of NF-κB and PIEZO1 in GC was confirmed by immunohistochemistry staining, and expression correlation was analysed in multiple GC datasets. GSEA and Western blot analysis revealed the YAP1-CTGF axis regulation by PIEZO1. The stimulatory effects of CTGF on CAFs were validated by the co-culture system and animal studies. Patient-derived organoid and peritoneal dissemination models were employed to confirm the role of the PIEZO1-YAP1-CTGF cascade in GC. RESULTS: Both CAF signature and PIEZO1 were positively correlated with H. pylori infection. PIEZO1, a mechanosensor, was confirmed as a direct downstream of NF-κB to promote the transformation from intestinal metaplasia to GC. Mechanistic studies revealed that PIEZO1 transduced the oncogenic signal from NF-κB into YAP1 signaling, a well-documented oncogenic pathway in GC progression. PIEZO1 expression was positively correlated with the YAP1 signature (CTGF, CYR61, and c-Myc, etc.) in primary samples. The secreted CTGF by cancer cells stimulated the CAF infiltration to form a stiffened collagen-enrichment microenvironment, thus activating PIEZO1 to form a positive feedback loop. Both PIEZO1 depletion by shRNA and CTGF inhibition by Procyanidin C1 enhanced the efficacy of 5-FU in suppressing the GC cell peritoneal metastasis. CONCLUSION: This study elucidates a novel driving PIEZO1-YAP1-CTGF force, which opens a novel therapeutic avenue to block the transformation from precancerous lesions to GC. H. pylori-NF-κB activates the PIEZO1-YAP1-CTGF axis to remodel the GC microenvironment by promoting CAF infiltration. Targeting PIEZO1-YAP1-CTGF plus chemotherapy might serve as a potential therapeutic option to block GC progression and peritoneal metastasis.
69Helicobacter pylori-induced RASAL2 Through Activation of Nuclear Factor-κB Promotes Gastric Tumorigenesis via β-catenin Signaling Axis.PubMed
Longlong Cao, Shoumin Zhu, Heng Lu, et al.
Gastroenterology. 2022 May;162(6):1716-1731.e17. doi: 10.1053/j.gastro.2022.01.046. Epub 2022 Feb 5.
BACKGROUND & AIMS: Helicobacter pylori infection is the predominant risk factor for gastric cancer. RAS protein activator like 2 (RASAL2) is considered a double-edged sword in carcinogenesis. Herein, we investigated the role of RASAL2 in response to H pylori infection and gastric tumorigenesis. METHODS: Bioinformatics analyses of local and public databases were applied to analyze RASAL2 expression, signaling pathways, and clinical significance. In vitro cell culture, spheroids, patient-derived organoids, and in vivo mouse models were used. Molecular assays included chromatin immunoprecipitation, co-immunoprecipitation, Western blotting, quantitative polymerase chain reaction, and immunocyto/histochemistry. RESULTS: H pylori infection induced RASAL2 expression via a nuclear factor-κB (NF-κB)-dependent mechanism whereby NF-κB was directly bound to the RASAL2 promoter activating its transcription. By gene silencing and ectopic overexpression, we found that RASAL2 upregulated β-catenin transcriptional activity. RASAL2 inhibited protein phosphatase 2A activity through direct binding with subsequent activation of the AKT/β-catenin signaling axis. Functionally, RASAL2 silencing decreased nuclear β-catenin levels and impaired tumor spheroids and organoids formation. Furthermore, the depletion of RASAL2 impaired tumor growth in gastric tumor xenograft mouse models. Clinicopathological analysis indicated that abnormal overexpression of RASAL2 correlated with poor prognosis and chemoresistance in human gastric tumors. CONCLUSIONS: These studies uncovered a novel signaling axis of NF-κB/RASAL2/β-catenin, providing a novel link between infection, inflammation and gastric tumorigenesis.
70Gastric Cancer in the Era of Epigenetics.PubMed
Grigorios Christodoulidis, Konstantinos-Eleftherios Koumarelas, Marina-Nektaria Kouliou, et al.
Int J Mol Sci. 2024 Mar 16;25(6):3381. doi: 10.3390/ijms25063381.
Gastric cancer (GC) remains a significant contributor to cancer-related mortality. Novel high-throughput techniques have enlightened the epigenetic mechanisms governing gene-expression regulation. Epigenetic characteristics contribute to molecular taxonomy and give rise to cancer-specific epigenetic patterns. (Hp) infection has an impact on aberrant DNA methylation either through its pathogenic CagA protein or by inducing chronic inflammation. The hypomethylation of specific repetitive elements generates an epigenetic field effect early in tumorigenesis. Epstein-Barr virus (EBV) infection triggers DNA methylation by dysregulating DNA methyltransferases (DNMT) enzyme activity, while persistent Hp-EBV co-infection leads to aggressive tumor behavior. Distinct histone modifications are also responsible for oncogene upregulation and tumor-suppressor gene silencing in gastric carcinomas. While histone methylation and acetylation processes have been extensively studied, other less prevalent alterations contribute to the development and migration of gastric cancer via a complex network of interactions. Enzymes, such as Nicotinamide N-methyltransferase (NNMT), which is involved in tumor's metabolic reprogramming, interact with methyltransferases and modify gene expression. Non-coding RNA molecules, including long non-coding RNAs, circular RNAs, and miRNAs serve as epigenetic regulators contributing to GC development, metastasis, poor outcomes and therapy resistance. Serum RNA molecules hold the potential to serve as non-invasive biomarkers for diagnostic, prognostic or therapeutic applications. Gastric fluids represent a valuable source to identify potential biomarkers with diagnostic use in terms of liquid biopsy. Ongoing clinical trials are currently evaluating the efficacy of next-generation epigenetic drugs, displaying promising outcomes. Various approaches including multiple miRNA inhibitors or targeted nanoparticles carrying epigenetic drugs are being designed to enhance existing treatment efficacy and overcome treatment resistance.
71Posttranslational modifications in Helicobacter pylori-associated gastric pathogenesis: Bridging inflammation and carcinogenesis.PubMed
Wei Li, Tong Liu, Tianhua Wu, et al.
Biochim Biophys Acta Rev Cancer. 2025 Nov;1880(6):189492. doi: 10.1016/j.bbcan.2025.189492. Epub 2025 Nov 7.
Helicobacter pylori (H. pylori), a Group I carcinogen that affects approximately half of the global population, is the primary aetiological agent of chronic gastritis, peptic ulcers, gastric adenocarcinoma, and gastric mucosa-associated lymphoid tissue lymphoma. Its pathogenesis involves intricate interactions among bacterial virulence factors, host genetics, and environmental factors. We detail the critical role of diverse protein posttranslational modifications (PTMs) in mediating H. pylori-induced gastric mucosal damage and carcinogenesis. We describe how H. pylori exploits and dysregulates a broad spectrum of host and bacterial PTMs (encompassing acetylation, ubiquitination, S-nitrosylation, disulfide bond formation, citrullination, methylation, glycosylation, phosphorylation, SUMOylation, and ADP-ribosylation) to establish infection, evade immune responses, drive chronic inflammation, and promote malignant transformation. Collectively, these findings reveal a complex, multilayered PTM network that is central to H. pylori pathogenesis. Understanding these mechanisms provides crucial insights for the development of novel diagnostic biomarkers; methylation profiles; anti-citrullinate keratin 1 (Cit-K1) antibodies, maps of PTM dynamics; targeted therapeutic strategies, including PTM enzyme inhibitors, antivirulence agents such as H. pylori disulfide bond-forming protein A inhibitors, epigenetic modulators, glycoconjugate vaccines/adhesion blockers, and optimized drug delivery systems such as N-acetylcysteine liposomes. Furthermore, this knowledge supports improved risk stratification for managing persistent cancer risk even after eradication.
72Dicarbonyl Electrophiles Mediate Inflammation-Induced Gastrointestinal Carcinogenesis.PubMed
Alain P Gobert, Olivier Boutaud, Mohammad Asim, et al.
Gastroenterology. 2021 Mar;160(4):1256-1268.e9. doi: 10.1053/j.gastro.2020.11.006. Epub 2020 Nov 13.
BACKGROUND & AIMS: Inflammation in the gastrointestinal tract may lead to the development of cancer. Dicarbonyl electrophiles, such as isolevuglandins (isoLGs), are generated from lipid peroxidation during the inflammatory response and form covalent adducts with amine-containing macromolecules. Thus, we sought to determine the role of dicarbonyl electrophiles in inflammation-associated carcinogenesis. METHODS: The formation of isoLG adducts was analyzed in the gastric tissues of patients infected with Helicobacter pylori from gastritis to precancerous intestinal metaplasia, in human gastric organoids, and in patients with colitis and colitis-associated carcinoma (CAC). The effect on cancer development of a potent scavenger of dicarbonyl electrophiles, 5-ethyl-2-hydroxybenzylamine (EtHOBA), was determined in transgenic FVB/N insulin-gastrin (INS-GAS) mice and Mongolian gerbils as models of H pylori-induced carcinogenesis and in C57BL/6 mice treated with azoxymethane-dextran sulfate sodium as a model of CAC. The effect of EtHOBA on mutations in gastric epithelial cells of H pylori-infected INS-GAS mice was assessed by whole-exome sequencing. RESULTS: We show increased isoLG adducts in gastric epithelial cell nuclei in patients with gastritis and intestinal metaplasia and in human gastric organoids infected with H pylori. EtHOBA inhibited gastric carcinoma in infected INS-GAS mice and gerbils and attenuated isoLG adducts, DNA damage, and somatic mutation frequency. Additionally, isoLG adducts were elevated in tissues from patients with colitis, colitis-associated dysplasia, and CAC as well as in dysplastic tumors of C57BL/6 mice treated with azoxymethane-dextran sulfate sodium. In this model, EtHOBA significantly reduced adduct formation, tumorigenesis, and dysplasia severity. CONCLUSIONS: Dicarbonyl electrophiles represent a link between inflammation and somatic genomic alterations and are thus key targets for cancer chemoprevention.
73AGA Clinical Practice Update on Screening and Surveillance in Individuals at Increased Risk for Gastric Cancer in the United States: Expert Review.PubMed
Shailja C Shah, Andrew Y Wang, Michael B Wallace, et al.
Gastroenterology. 2025 Feb;168(2):405-416.e1. doi: 10.1053/j.gastro.2024.11.001. Epub 2024 Dec 23.
DESCRIPTION: Gastric cancer (GC) is a leading cause of preventable cancer and mortality in certain US populations. The most impactful way to reduce GC mortality is via primary prevention, namely Helicobacter pylori eradication, and secondary prevention, namely endoscopic screening and surveillance of precancerous conditions, such as gastric intestinal metaplasia (GIM). An emerging body of evidence supports the possible impact of these strategies on GC incidence and mortality in identifiable high-risk populations in the United States. Accordingly, the primary objective of this American Gastroenterological Association (AGA) Clinical Practice Update (CPU) Expert Review is to provide best practice advice for primary and secondary prevention of GC in the context of current clinical practice and evidence in the United States. METHODS: This CPU Expert Review was commissioned and approved by the AGA Institute CPU Committee and the AGA Governing Board to provide timely guidance on a topic of high clinical importance to the AGA membership, and underwent internal peer review by the CPU Committee and external peer review through standard procedures of Gastroenterology. These best practice advice statements were drawn from a review of the published literature and expert opinion. Because systematic reviews were not performed, these best practice advice statements do not carry formal ratings regarding the quality of evidence or strength of the presented considerations. Best Practice Advice Statements BEST PRACTICE ADVICE 1: There are identifiable high-risk groups in the United States who should be considered for GC screening. These include first-generation immigrants from high-incidence GC regions and possibly other non-White racial and ethnic groups, those with a family history of GC in a first-degree relative, and individuals with certain hereditary gastrointestinal polyposis or hereditary cancer syndromes. BEST PRACTICE ADVICE 2: Endoscopy is the best test for screening or surveillance in individuals at increased risk for GC. Endoscopy enables direct visualization to endoscopically stage the mucosa and identify areas concerning for neoplasia, as well as enables biopsies for further histologic examination and mucosal staging. Both endoscopic and histologic staging are key for risk stratification and determining whether ongoing surveillance is indicated and at what interval. BEST PRACTICE ADVICE 3: High-quality upper endoscopy for the detection of premalignant and malignant gastric lesions should include the use of a high-definition white-light endoscopy system with image enhancement, gastric mucosal cleansing, and insufflation to achieve optimal mucosal visualization, in addition to adequate visual inspection time, photodocumentation, and use of a systematic biopsy protocol for mucosal staging when appropriate. BEST PRACTICE ADVICE 4: H pylori eradication is essential and serves as an adjunct to endoscopic screening and surveillance for primary and secondary prevention of GC. Opportunistic screening for H pylori infection should be considered in individuals deemed to be at increased risk for GC (refer to Best Practice Advice 1). Screening for H pylori infection in adult household members of individuals who test positive for H pylori (so-called "familial-based testing") should also be considered. BEST PRACTICE ADVICE 5: In individuals with suspected gastric atrophy with or without intestinal metaplasia, gastric biopsies should be obtained according to a systematic protocol (eg, updated Sydney System) to enable histologic confirmation and staging. A minimum of 5 total biopsies should be obtained, with samples from the antrum/incisura and corpus placed in separately labeled jars (eg, jar 1, "antrum/incisura" and jar 2, "corpus"). Any suspicious areas should be described and biopsied separately. BEST PRACTICE ADVICE 6: GIM and dysplasia are endoscopically detectable. However, these findings often go undiagnosed when endoscopists are unfamiliar with the characteristic visual features; accordingly, there is an unmet need for improved training, especially in the United States. Artificial intelligence tools appear promising for the detection of early gastric neoplasia in the adequately visualized stomach, but data are too preliminary to recommend routine use. BEST PRACTICE ADVICE 7: Endoscopists should work with their local pathologists to achieve consensus for consistent documentation of histologic risk-stratification parameters when atrophic gastritis with or without metaplasia is diagnosed. At a minimum, the presence or absence of H pylori infection, severity of atrophy and/or metaplasia, and histologic subtyping of GIM, if applicable, should be documented to inform clinical decision making. BEST PRACTICE ADVICE 8: If the index screening endoscopy performed in an individual at increased risk for GC (refer to Best Practice Advice 1) does not identify atrophy, GIM, or neoplasia, then the decision to continue screening should be based on that individual's risk factors and preferences. If the individual has a family history of GC or multiple risk factors for GC, then ongoing screening should be considered. The optimal screening intervals in such scenarios are not well defined. BEST PRACTICE ADVICE 9: Endoscopists should ensure that all individuals with confirmed gastric atrophy with or without GIM undergo risk stratification. Individuals with severe atrophic gastritis and/or multifocal or incomplete GIM are likely to benefit from endoscopic surveillance, particularly if they have other risk factors for GC (eg, family history). Endoscopic surveillance should be considered every 3 years; however, intervals are not well defined and shorter intervals may be advisable in those with multiple risk factors, such as severe GIM that is anatomically extensive. BEST PRACTICE ADVICE 10: Indefinite and low-grade dysplasia can be difficult to reproducibly identify by endoscopy and accurately diagnose on histopathology. Accordingly, all dysplasia should be confirmed by an experienced gastrointestinal pathologist, and clinicians should refer patients with visible or nonvisible dysplasia to an endoscopist or center with expertise in the diagnosis and management of gastric neoplasia. Individuals with indefinite or low-grade dysplasia who are infected with H pylori should be treated and have eradication confirmed, followed by repeat endoscopy and biopsies by an experienced endoscopist, as visual and histologic discernment may improve once inflammation subsides. BEST PRACTICE ADVICE 11: Individuals with suspected high-grade dysplasia or early GC should undergo endoscopic submucosal dissection with the goal of en bloc, R0 resection to enable accurate pathologic staging with curative intent. Eradication of active H pylori infection is essential, but should not delay endoscopic intervention. Endoscopic submucosal dissection should be performed at a center with endoscopic and pathologic expertise. BEST PRACTICE ADVICE 12: Individuals with a history of successfully resected gastric dysplasia or cancer require ongoing endoscopic surveillance. Suggested surveillance intervals exist, but additional data are required to refine surveillance recommendations, particularly in the United States. BEST PRACTICE ADVICE 13: Type I gastric carcinoids in individuals with atrophic gastritis are typically indolent, especially if <1 cm. Endoscopists may consider resecting gastric carcinoids <1 cm and should endoscopically resect lesions measuring 1-2 cm. Individuals with type I gastric carcinoids >2 cm should undergo cross-sectional imaging and be referred for surgical resection, given the risk of metastasis. Individuals with type I gastric carcinoids should undergo surveillance, but the intervals are not well defined. BEST PRACTICE ADVICE 14: In general, only individuals who are fit for endoscopic or potentially surgical treatment should be screened for GC and continued surveillance of premalignant gastric conditions. If a person is no longer fit for endoscopic or surgical treatment, then screening and surveillance should be stopped. BEST PRACTICE ADVICE 15: To achieve health equity, a personalized approach should be taken to assess an individual's risk for GC to determine whether screening and surveillance should be pursued. In conjunction, modifiable risk factors for GC should be distinctly addressed, as most of these risk factors disproportionately impact people at high risk for GC and represent health care disparities.
74Eradication of and Gastric Cancer: A Controversial Relationship.PubMed
Mariagrazia Piscione, Mariangela Mazzone, Maria Carmela Di Marcantonio, et al.
Front Microbiol. 2021 Feb 4;12:630852. doi: 10.3389/fmicb.2021.630852. eCollection 2021.
Worldwide, gastric cancer (GC) represents the fifth cancer for incidence, and the third as cause of death in developed countries. Indeed, it resulted in more than 780,000 deaths in 2018. appears to be responsible for the majority of these cancers. On the basis of recent studies, and either alone or combined with additional etiological factors, is considered a "type I carcinogen." Over recent decades, new insights have been obtained into the strategies that have been adopted by to survive the acidic conditions of the gastric environment, and to result in persistent infection, and dysregulation of host functions. The multistep processes involved in the development of GC are initiated by transition of the mucosa into chronic non-atrophic gastritis, which is primarily triggered by infection with . This gastritis then progresses into atrophic gastritis and intestinal metaplasia, and then to dysplasia, and following Correa's cascade, to adenocarcinoma. The use of antibiotics for eradication of can reduce the incidence of precancerous lesions only in the early stages of gastric carcinogenesis. Here, we first survey the etiology and risk factors of GC, and then we analyze the mechanisms underlying tumorigenesis induced by , focusing attention on virulence factor CagA, inflammation, oxidative stress, and ErbB2 receptor tyrosine kinase. Moreover, we investigate the relationships between eradication therapy and other diseases, considering not only cardia (upper stomach) cancers and Barrett's esophagus, but also asthma and allergies, through discussion of the "hygiene hypothesis. " This hypothesis suggests that improved hygiene and antibiotic use in early life reduces microbial exposure, such that the immune response does not become primed, and individuals are not protected against atopic disorders, asthma, and autoimmune diseases. Finally, we overview recent advances to uncover the complex interplay between and the gut microbiota during gastric carcinogenesis, as characterized by reduced bacterial diversity and increased microbial dysbiosis. Indeed, it is of particular importance to identify the bacterial taxa of the stomach that might predict the outcome of gastric disease through the stages of Correa's cascade, to improve prevention and therapy of gastric carcinoma.
75Screening and eradication of for gastric cancer prevention: the Taipei global consensus.PubMed
Jyh-Ming Liou, Peter Malfertheiner, Yi-Chia Lee, et al.
Gut. 2020 Dec;69(12):2093-2112. doi: 10.1136/gutjnl-2020-322368. Epub 2020 Oct 1.
OBJECTIVE: A global consensus meeting was held to review current evidence and knowledge gaps and propose collaborative studies on population-wide screening and eradication of for prevention of gastric cancer (GC). METHODS: 28 experts from 11 countries reviewed the evidence and modified the statements using the Delphi method, with consensus level predefined as ≥80% of agreement on each statement. The Grading of Recommendation Assessment, Development and Evaluation (GRADE) approach was followed. RESULTS: Consensus was reached in 26 statements. At an individual level, eradication of reduces the risk of GC in asymptomatic subjects and is recommended unless there are competing considerations. In cohorts of vulnerable subjects (eg, first-degree relatives of patients with GC), a screen-and-treat strategy is also beneficial. eradication in patients with early GC after curative endoscopic resection reduces the risk of metachronous cancer and calls for a re-examination on the hypothesis of 'the point of no return'. At the general population level, the strategy of screen-and-treat for infection is most cost-effective in young adults in regions with a high incidence of GC and is recommended preferably before the development of atrophic gastritis and intestinal metaplasia. However, such a strategy may still be effective in people aged over 50, and may be integrated or included into national healthcare priorities, such as colorectal cancer screening programmes, to optimise the resources. Reliable locally effective regimens based on the principles of antibiotic stewardship are recommended. Subjects at higher risk of GC, such as those with advanced gastric atrophy or intestinal metaplasia, should receive surveillance endoscopy after eradication of . CONCLUSION: Evidence supports the proposal that eradication therapy should be offered to all individuals infected with . Vulnerable subjects should be tested, and treated if the test is positive. Mass screening and eradication of should be considered in populations at higher risk of GC.
76Gastric CancerPubMed
Masahiro Asaka, Antonia R. Sepulveda, Toshiro Sugiyama, et al.
Nearly 20 years have elapsed since the discovery of (168). Due to the progress of research during this period, a causal link between and gastric mucosal lesions seems almost certain. Experimental ingestion of demonstrated that it caused gastritis in humans, with the inflammation being cured by eradication of the organism (103, 109). Furthermore, infection is one of the major causes of recurrent peptic ulcer disease (124, 164). Accordingly, patients with peptic ulcer disease are advised to undergo eradication therapy. Gastric cancer is one of the most common malignancies in the world, although the incidence and mortality rate have been decreasing in recent decades. The association between and gastric cancer has attracted great interest worldwide because the International Agency for Research on Cancer (IARC), a subordinate organization of the World Health Organization (WHO), identified as a "group 1 (definite carcinogen)" in 1994 (1). That is, the IARC concluded that was certainly linked to carcinogenesis on the basis of the results of epidemiologic studies. The association between and gastric cancer may be explained by two possible mechanisms: one is based on a carcinogenesis-promoting effect of itself and the other is based on the establishment of a carcinogenic environment due to long-term infection with . In the second case, although may have no carcinogenesis-promoting effect itself, infection causes inflammation of the gastric mucosa and chronic infection causes mucosal atrophy, resulting in intestinal metaplasia. These latter changes are considered precursors of gastric cancer. Research concerning the association between gastric cancer and has achieved enormous progress over time, leading to the recognition of this relationship by the WHO. One of the greatest concerns is to ascertain whether ultimately -induced gastritis may lead to gastric cancer. The onset of gastric cancer can be explained as being caused not only by infection, but also by a combination of various factors such as food and the environment. However, the possibility that the occurrence of gastric cancer, like the recurrence of peptic ulcer disease, can be prevented by eradication of has also been suggested. Further progress in epidemiologic research is needed to resolve this issue.
77Treatment of Helicobacter pylori in Special Patient Populations.PubMed
Cynthia T Nguyen, Kyle A Davis, Sarah A Nisly, et al.
Pharmacotherapy. 2019 Oct;39(10):1012-1022. doi: 10.1002/phar.2318. Epub 2019 Sep 2.
Helicobacter pylori infection can lead to gastritis, gastric and duodenal ulcers, and gastric cancer. Consequently, complete eradication is the goal of therapy. First-line therapy for H. pylori infection includes clarithromycin triple therapy (clarithromycin, proton pump inhibitor [PPI], and amoxicillin or metronidazole), bismuth quadruple therapy (bismuth salt, PPI, tetracycline, and metronidazole or amoxicillin), or concomitant therapy (clarithromycin, PPI, amoxicillin, and metronidazole). However, many patients have relative contraindications to the antibiotics included in these regimens, making therapy selection difficult. Furthermore, failure of initial therapy makes selection of second-line therapy challenging due to concerns for potential resistance to agents included in the initial regimen. This review discusses H. pylori microbiology, including antibiotic resistance, and summarizes the existing evidence for first- and second-line treatment regimens that may be considered for special populations such as patients with penicillin allergies, patients with or at risk for QTc-interval prolongation, and patients who are pregnant, breastfeeding, or elderly.
78Treatment of Helicobacter pylori infection: A clinical practice update.PubMed
Rocco Maurizio Zagari, Stefano Rabitti, Leonardo Henry Eusebi, et al.
Eur J Clin Invest. 2018 Jan;48(1). doi: 10.1111/eci.12857. Epub 2017 Dec 4.
BACKGROUND: Helicobacter pylori infection is still frequent in the community and all infected subjects should be offered an eradication therapy. Nowadays physicians have to face the challenge of antibiotic resistance in treating Helicobacter pylori-infected individuals. AIM: This review provides an overview of current international guidelines and reports recent evidence from systematic reviews and clinical trials on the treatment of Helicobacter pylori infection and should help physicians to better treat their patients. RESULTS: General rules to optimize the management of Helicobacter pylori infection include: (i) considering previous patient's exposure to antibiotics; (ii) using high dose of proton-pump inhibitors; and (iii) avoiding repeating the same regimen, if it has already failure. Bismuth quadruple therapy and concomitant therapy are the best first-line empirical treatments in areas with high clarithromycin resistance and in individuals with previous use of macrolides; otherwise, the 14-day clarithromycin-containing triple therapy is a valid regimen. The sequential therapy is no longer a suggested treatment by international guidelines. CONCLUSIONS: Current international guidelines are consistent in defining treatment strategies for Helicobacter pylori infection. The use of national registries to monitor the efficacy and tolerability of different regimens in the real world of clinical practice is now needed.
79Treatment of Helicobacter pylori infection: a clinical practice update.PubMed
Rocco M Zagari, Leonardo Frazzoni, Giovanni Marasco, et al.
Minerva Med. 2021 Apr;112(2):281-287. doi: 10.23736/S0026-4806.20.06810-X. Epub 2020 Jul 22.
Helicobacter pylori infection still represents a major health issue, especially in developing countries, with an estimate of 4 billion of infected subjects in 2015. The increase of antibiotic resistance has undermined the efficacy of standard triple therapy leading to more complex regimens. This review summarizes recommendations of international guidelines and reports the most recent evidence from meta-analyses and clinical trials on the treatment of Helicobacter pylori infection. The choice of H. pylori eradication regimen should be based on the local prevalence of clarithromycin resistance and the previous use of macrolides. Quadruple therapies (bismuth quadruple and concomitant) are the recommended regimens for the first-line treatment; a 14-day clarithromycin-containing triple therapy is suggested in areas with low prevalence of clarithromycin resistance and in patients without previous use of macrolides. Data on the efficacy of sequential therapy against clarithromycin resistant H. pylori strains are contradictory, and its use in the treatment of H. pylori infection is generally discouraged. Second-line treatments include levofloxacin-containing triple therapy and bismuth quadruple therapy. Probiotic supplementation should be used with the aim to reduce antibiotic-related adverse events. Recent evidence would support current guideline recommendations for the treatment of Helicobacter pylori infection.
80Role of Bismuth in the Eradication of Helicobacter pylori.PubMed
Huseyin Alkim, Ali Riza Koksal, Salih Boga, et al.
Am J Ther. 2017 Nov/Dec;24(6):e751-e757. doi: 10.1097/MJT.0000000000000389.
Bismuth salts exert their activity within the upper gastrointestinal tract through action of luminal bismuth. Bismuth exerts direct bactericidal effect on Helicobacter pylori by different ways: forms complexes in the bacterial wall and periplasmic space, inhibits different enzymes, ATP synthesis, and adherence of the bacteria to the gastric mucosa. Bismuth also helps ulcer healing by acting as a barrier to the aggressive factors and increasing mucosal protective factors such as prostaglandin, epidermal growth factor, and bicarbonate secretion. To date, no resistance to bismuth has been reported. Also synergism between bismuth salts and antibiotics was present. It was shown that metronidazole and clarithromycin resistant H. pylori strains become susceptible if they are administered together with bismuth. Bismuth-containing quadruple therapy was recommended both by the Second Asia-Pacific Consensus Guidelines and by the Maastricht IV/Florence Consensus Report as an alternative first choice regimen to standard triple therapy, in areas with low clarithromycin resistance, and it is recommended as the first-line therapeutic option in areas with a high prevalence of clarithromycin resistance. Greater than 90% eradication success can be obtained by bismuth-containing quadruple therapy. Choosing bismuth as an indispensable part of first-line therapy is logical as both metronidazole and clarithromycin resistances can be overcome by adding bismuth to the regimen.
81Therapeutic advances and future directions in eradication.PubMed
Vidya Suresh, Amritavarshini Sreekumar, Anil Kumar, et al.
Front Microbiol. 2025 Dec 3;16:1652943. doi: 10.3389/fmicb.2025.1652943. eCollection 2025.
is a globally prevalent pathogen associated with a spectrum of gastrointestinal diseases, including chronic gastritis, peptic ulcer disease, and gastric malignancies. Although clarithromycin-based triple therapy continues to be effective in certain geographic areas, increasing global resistance highlights the need for treatment approaches tailored to local antibiotic susceptibility patterns. Recent clinical trials have shifted toward optimized quadruple regimens, particularly bismuth- and vonoprazan-based therapies, and resistance-guided treatment. Novel agents such as Rifasutenizol (TNP-2198) are entering phase 3 evaluation and show activity against multidrug-resistant strains. Adjunctive and alternative strategies including probiotics, phytochemicals, phage-derived enzymes, and nanoparticle-based delivery demonstrate synergistic effects in improving eradication and reducing antibiotic-associated adverse events. Multi-strain probiotic formulations and plant-derived compounds such as curcumin, catechins, and quercetin consistently suppress virulence pathways and gastric inflammation in clinical and preclinical studies. This review provides an overview of current evidence from clinical trials and emerging therapeutic innovations, emphasizing balanced integration of conventional and next-generation approaches for sustainable global management.
82British Society of Gastroenterology guidelines on the diagnosis and management of patients at risk of gastric adenocarcinoma.PubMed
Matthew Banks, David Graham, Marnix Jansen, et al.
Gut. 2019 Sep;68(9):1545-1575. doi: 10.1136/gutjnl-2018-318126. Epub 2019 Jul 5.
Gastric adenocarcinoma carries a poor prognosis, in part due to the late stage of diagnosis. Risk factors include infection, family history of gastric cancer-in particular, hereditary diffuse gastric cancer and pernicious anaemia. The stages in the progression to cancer include chronic gastritis, gastric atrophy (GA), gastric intestinal metaplasia (GIM) and dysplasia. The key to early detection of cancer and improved survival is to non-invasively identify those at risk before endoscopy. However, although biomarkers may help in the detection of patients with chronic atrophic gastritis, there is insufficient evidence to support their use for population screening. High-quality endoscopy with full mucosal visualisation is an important part of improving early detection. Image-enhanced endoscopy combined with biopsy sampling for histopathology is the best approach to detect and accurately risk-stratify GA and GIM. Biopsies following the Sydney protocol from the antrum, incisura, lesser and greater curvature allow both diagnostic confirmation and risk stratification for progression to cancer. Ideally biopsies should be directed to areas of GA or GIM visualised by high-quality endoscopy. There is insufficient evidence to support screening in a low-risk population (undergoing routine diagnostic oesophagogastroduodenoscopy) such as the UK, but endoscopic surveillance every 3 years should be offered to patients with extensive GA or GIM. Endoscopic mucosal resection or endoscopic submucosal dissection of visible gastric dysplasia and early cancer has been shown to be efficacious with a high success rate and low rate of recurrence, providing that specific quality criteria are met.
83Screening and surveillance for gastric cancer in the United States: Is it needed?PubMed
Gwang Ha Kim, Peter S Liang, Sung Jo Bang, et al.
Gastrointest Endosc. 2016 Jul;84(1):18-28. doi: 10.1016/j.gie.2016.02.028. Epub 2016 Mar 3.
BACKGROUND AND AIMS: Although the incidence of gastric cancer in the United States is relatively low, the incidence of gastric cancer is higher than for esophageal cancer, for which clear guidelines for screening and surveillance exist. With the increasing availability of endoscopic therapy, such as endoscopic submucosal dissection, for treating advanced dysplasia and early gastric cancer, establishing guidelines for screening and surveillance of patients who are at high risk of developing gastric cancer has the potential to diagnose and treat gastric cancer at an earlier stage and improve mortality from gastric cancer. The aims of this article were to review the data regarding the risk factors for developing gastric cancer, methods for gastric cancer screening, and results of national screening programs. METHODS: A review of the existing literature related to the aims was performed. RESULTS: Risk factors for gastric cancer that were identified include race/ethnicity (East Asian, Russian, or South American), first-degree relative diagnosed with gastric cancer, positive Helicobacter pylori status, and presence of atrophic gastritis or intestinal metaplasia. Endoscopy has the highest rate of detecting gastric cancer compared with other gastric cancer screening methods. The national screening program in Japan has demonstrated a mortality reduction from gastric cancer based on cohort data. CONCLUSIONS: Gastric cancer screening with endoscopy should be considered in individuals who are immigrants from regions associated with a high risk of gastric cancer (East Asia, Russia, or South America) or who have a family history of gastric cancer. Those with findings of atrophic gastritis or intestinal metaplasia on screening endoscopy should undergo surveillance endoscopy every 1 to 2 years. Large prospective multicenter studies are needed to further identify additional risk factors for developing gastric cancer and to assess whether gastric cancer screening programs for high-risk populations in the United States would result in improved mortality.
84Cost Effectiveness of Gastric Cancer Screening According to Race and Ethnicity.PubMed
Monica Saumoy, Yecheskel Schneider, Nicole Shen, et al.
Gastroenterology. 2018 Sep;155(3):648-660. doi: 10.1053/j.gastro.2018.05.026. Epub 2018 May 17.
BACKGROUND & AIMS: There are marked racial and ethnic differences in non-cardia gastric cancer prevalence within the United States. Although gastric cancer screening is recommended in some regions of high prevalence, screening is not routinely performed in the United States. Our objective was to determine whether selected non-cardia gastric cancer screening for high-risk races and ethnicities within the United States is cost effective. METHODS: We developed a decision analytic Markov model with the base case of a 50-year-old person of non-Hispanic white, non-Hispanic black, Hispanic, or Asian race or ethnicity. The cost effectiveness of a no-screening strategy (current standard) for non-cardia gastric cancer was compared with that of 2 endoscopic screening modalities initiated at the time of screening colonoscopy for colorectal cancer: upper esophagogastroduodenoscopy with biopsy examinations and continued surveillance only if intestinal metaplasia or more severe pathology is identified or esophagogastroduodenoscopy with biopsy examinations continued every 2 years even in the absence of identified pathology. We used prevalence rates, transition probabilities, costs, and quality-adjusted life years (QALYs) from publications and public data sources. Outcome measures were reported in incremental cost-effectiveness ratios, with a willingness-to-pay threshold of $100,000/QALY. RESULTS: Compared with biennial and no screening, screening esophagogastroduodenoscopy with continued surveillance only when indicated was cost effective for non-Hispanic blacks ($80,278/QALY), Hispanics ($76,070/QALY), and Asians ($71,451/QALY), but not for non-Hispanic whites ($122,428/QALY). The model was sensitive to intestinal metaplasia prevalence, transition rates from intestinal metaplasia to dysplasia to local and regional cancer, cost of endoscopy, and cost of resection (endoscopic or surgical). CONCLUSIONS: Based on a decision analytic Markov model, endoscopic non-cardia gastric cancer screening for high-risk races and ethnicities could be cost effective in the United States.
85Cost-effectiveness of upper endoscopy for gastric cancer screening and surveillance in Western populations.PubMed
N E A Kapteijn, D T Mülder, I Lansdorp-Vogelaar
Best Pract Res Clin Gastroenterol. 2025 Mar;75:101982. doi: 10.1016/j.bpg.2025.101982. Epub 2025 Feb 1.
BACKGROUND: Gastric cancer (GC) is the fourth leading cause of cancer-related deaths worldwide, with highest incidence rates in Asia. Endoscopic screening may facilitate early detection and reduces mortality, but its cost-effectiveness in Western populations, where GC is less prevalent, remains unclear. This review aimed to evaluate the cost-effectiveness of endoscopic screening and surveillance for GC in Western countries, considering regional epidemiologic and economic differences. METHODS: A systematic search of literature was conducted using PubMed and Embase databases, focusing on studies evaluating the cost-effectiveness of endoscopy in asymptomatic individuals or high-risk subgroups in Western populations. Studies reporting incremental cost-effectiveness ratios (ICERs) compared to no screening/surveillance were included. RESULTS: In total fourteen studies were evaluated. Six studies reported on endoscopic screening in the general population, three on screening in high-risk individuals, and seven on endoscopic surveillance, with varying intervals ranging from one-time procedures to procedures every ten years. Endoscopic screening was generally not cost-effective in Western populations. However, screening for high-risk subgroups, or combined with colonoscopy, following a positive fecal immunochemical test, improved cost-effectiveness. Endoscopic surveillance was consistently cost-effective, particularly for individuals with gastric intestinal metaplasia (GIM), showing the best cost-effectiveness at a three-to five-year interval, with ICERs ranging from €18,336 per Quality-Adjusted Life Year (QALY) in Europe to $87,000 per QALY in the USA. For higher-risk lesions, like dysplasia or incomplete GIM, shorter surveillance intervals may be beneficial. CONCLUSION: While routine endoscopic screening may not be cost-effective in Western populations, surveillance for GIM every three to five years is economically sustainable. Higher-risk individuals with dysplasia or incomplete GIM may benefit from more frequent surveillance.
86Chronic pancreatitis.PubMed
Jorg Kleeff, David C Whitcomb, Tooru Shimosegawa, et al.
Nat Rev Dis Primers. 2017 Sep 7;3:17060. doi: 10.1038/nrdp.2017.60.
Chronic pancreatitis is defined as a pathological fibro-inflammatory syndrome of the pancreas in individuals with genetic, environmental and/or other risk factors who develop persistent pathological responses to parenchymal injury or stress. Potential causes can include toxic factors (such as alcohol or smoking), metabolic abnormalities, idiopathic mechanisms, genetics, autoimmune responses and obstructive mechanisms. The pathophysiology of chronic pancreatitis is fairly complex and includes acinar cell injury, acinar stress responses, duct dysfunction, persistent or altered inflammation, and/or neuro-immune crosstalk, but these mechanisms are not completely understood. Chronic pancreatitis is characterized by ongoing inflammation of the pancreas that results in progressive loss of the endocrine and exocrine compartment owing to atrophy and/or replacement with fibrotic tissue. Functional consequences include recurrent or constant abdominal pain, diabetes mellitus (endocrine insufficiency) and maldigestion (exocrine insufficiency). Diagnosing early-stage chronic pancreatitis is challenging as changes are subtle, ill-defined and overlap those of other disorders. Later stages are characterized by variable fibrosis and calcification of the pancreatic parenchyma; dilatation, distortion and stricturing of the pancreatic ducts; pseudocysts; intrapancreatic bile duct stricturing; narrowing of the duodenum; and superior mesenteric, portal and/or splenic vein thrombosis. Treatment options comprise medical, radiological, endoscopic and surgical interventions, but evidence-based approaches are limited. This Primer highlights the major progress that has been made in understanding the pathophysiology, presentation, prevalence and management of chronic pancreatitis and its complications.
87Management of chronic pancreatitis.PubMed
O Joe Hines, Stephen J Pandol
BMJ. 2024 Feb 26;384:e070920. doi: 10.1136/bmj-2023-070920.
Chronic pancreatitis results from repeated episodes of pancreatic inflammation and associated fibrosis leading to the loss of functional exocrine and endocrine pancreatic function. The disease is manifested by abdominal pain, deterioration in quality of life, food maldigestion and malabsorption, diabetes, and an increased risk for pancreatic adenocarcinoma. This review summarizes the latest evidence on the diagnosis and management of chronic pancreatitis and its manifestations. In particular, this review discusses advances in understanding of the role of genetic disorders in the mechanisms of the disease and surgical options for patients refractory to medical therapy. Furthermore, clinical trials are under way to develop medical therapeutics.
88Chronic pancreatitis.PubMed
Shounak Majumder, Suresh T Chari
Lancet. 2016 May 7;387(10031):1957-66. doi: 10.1016/S0140-6736(16)00097-0. Epub 2016 Mar 2.
Chronic pancreatitis describes a wide spectrum of fibro-inflammatory disorders of the exocrine pancreas that includes calcifying, obstructive, and steroid-responsive forms. Use of the term chronic pancreatitis without qualification generally refers to calcifying chronic pancreatitis. Epidemiology is poorly defined, but incidence worldwide seems to be on the rise. Smoking, drinking alcohol, and genetic predisposition are the major risk factors for chronic calcifying pancreatitis. In this Seminar, we discuss the clinical features, diagnosis, and management of chronic calcifying pancreatitis, focusing on pain management, the role of endoscopic and surgical intervention, and the use of pancreatic enzyme-replacement therapy. Management of patients is often challenging and necessitates a multidisciplinary approach.
89Alcoholic Pancreatitis(Archived)PubMed
Anton Klochkov, Pujitha Kudaravalli, Yizhe Lim, et al.
Alcohol use syndrome is one of the most common causes of both acute and chronic pancreatitis. Acute pancreatitis (AP) is a necro-inflammatory disease resulting from exocrine cell destruction by infiltrating inflammatory cells. The diagnostic criteria are typically when a patient presents with characteristic symptoms, elevated lipase levels, and distinct imaging findings. Treatment is mostly supportive as there is no specific pharmacotherapy for this disease. Acute pancreatitis will either resolve with the pancreas fully regenerating, lead to transient organ failure, or progress to cause systemic inflammation and multi-organ failure. In these severe cases, treatment may require antibiotics and more invasive therapies. Chronic pancreatitis (CP) is believed to result from recurrent attacks of acute pancreatitis, leading to the development of pancreatic insufficiency, steatorrhea, diabetes, pancreatic calcification, and fibrosis. While alcohol and its by-products alone do not directly cause this disease, they can predispose the pancreas to damage from otherwise benign agents. As a result, one of the main strategies to prevent recurrent attacks involve providing alcohol (and smoking) cessation counseling and strategies to patients.
90Alcohol and melatonin.PubMed
Natalia Kurhaluk
Chronobiol Int. 2021 Jun;38(6):785-800. doi: 10.1080/07420528.2021.1899198. Epub 2021 Mar 24.
Investigation of the pathogenesis of alcoholism in humans using different methodological approaches has facilitated detection of important biological factors of consequent metabolic diseases, endocrine disorders, and other medical conditions, such as alcoholic cardiomyopathy, alcoholic hypertension, heart and vascular lesions, alcoholic liver disease, alcoholic pancreatitis, etc. Alcohol abuse leads to damage to the nervous system, which can result in neurological and mental disorders, including alcoholic polyneuropathy, psychosis, and alcohol dementia. The complexity and versatility of the harmful effects of regular alcohol consumption on the human body can be considered in the perspective of a chronobiological approach, because alcohol is chronotoxic to biological processes. As a rhythm regulator, melatonin exerts a wide range of different effects: circadian rhythm regulation, thermoregulation, sleep induction, antioxidant, immunomodulatory, and anti-stress ones. This review presents from a chronobiological perspective the impact of melatonin on alcohol intoxication in terms of mental disorders, sleep and inflammation, hepatic injury, and mitochondrial function. It discusses the main clinical effects of melatonin on alcohol injury and the main targets as a therapy for alcohol disorders. Chronobiological effects of ethanol are related to melatonin suppression that has been associated with, among others, cancer risk. Exogenous melatonin seems to be a promising hepato- and immune-protector due to its antioxidant and anti-inflammatory properties, which in combination with other medicines makes it useful to prevent alcoholic organ damage. The reason for the scientific interest in melatonin as a treatment for alcoholism is obvious; the number of cases of this pathology that gives rise to metabolic syndrome, and its subsequent transformation into steatohepatitis, liver fibrosis, and cirrhosis, is increasing worldwide. Melatonin not only exerts antioxidant effects but it exerts various other effects contributing to the management of liver conditions. This review discusses the interaction between normal and pathological processes caused by alcohol consumption and the relationship between alcohol and melatonin in these conditions.
91Molecular mechanisms of pancreatitis: current opinion.PubMed
Alain Vonlaufen, Jeremy S Wilson, Minoti V Apte
J Gastroenterol Hepatol. 2008 Sep;23(9):1339-48. doi: 10.1111/j.1440-1746.2008.05520.x.
Pancreatitis (necroinflammation of the pancreas) has both acute and chronic manifestations. Gallstones are the major cause of acute pancreatitis, whereas alcohol is associated with acute as well as chronic forms of the disease. Cases of true idiopathic pancreatitis are steadily diminishing as more genetic causes of the disease are discovered. The pathogenesis of acute pancreatitis has been extensively investigated over the past four decades; the general current consensus is that the injury is initiated within pancreatic acinar cells subsequent to premature intracellular activation of digestive enzymes. Repeated attacks of acute pancreatitis have the potential to evolve into chronic disease characterized by fibrosis and loss of pancreatic function. Our knowledge of the process of scarring has advanced considerably with the isolation and study of pancreatic stellate cells, now established as the key cells in pancreatic fibrogenesis. The present review summarizes recent developments in the field particularly with respect to the progress made in unraveling the molecular mechanisms of acute and chronic pancreatic injury secondary to gallstones, alcohol and genetic factors. It is anticipated that continued research in the area will lead to the identification and characterization of molecular pathways that may be therapeutically targeted to prevent/inhibit the initiation and progression of the disease.
92Acute pancreatitis: etiology and common pathogenesis.PubMed
Guo-Jun Wang, Chun-Fang Gao, Dong Wei, et al.
World J Gastroenterol. 2009 Mar 28;15(12):1427-30. doi: 10.3748/wjg.15.1427.
Acute pancreatitis is an inflammatory disease of the pancreas. The etiology and pathogenesis of acute pancreatitis have been intensively investigated for centuries worldwide. Many causes of acute pancreatitis have been discovered, but the pathogenetic theories are controversial. The most common cause of acute pancreatitis is gallstone impacting the distal common bile-pancreatic duct. The majority of investigators accept that the main factors for acute billiary pancreatitis are pancreatic hyperstimulation and bile-pancreatic duct obstruction which increase pancreatic duct pressure and active trypsin reflux. Acute pancreatitis occurs when intracellular protective mechanisms to prevent trypsinogen activation or reduce trypsin activity are overwhelmed. However, little is known about the other acute pancreatitis. We hypothesize that acute biliary pancreatitis and other causes of acute pancreatitis possess a common pathogenesis. Pancreatic hyperstimulation and pancreatic duct obstruction increase pancreatic duct pressure, active trypsin reflux, and subsequent unregulated activation of trypsin within pancreatic acinar cells. Enzyme activation within the pancreas leads to auto-digestion of the gland and local inflammation. Once the hypothesis is confirmed, traditional therapeutic strategies against acute pancreatitis may be improved. Decompression of pancreatic duct pressure should be advocated in the treatment of acute pancreatitits which may greatly improve its outcome.
93Pancreatitis and Pancreatic Cancer.PubMed
Anne Walling, Robert Freelove
Prim Care. 2017 Dec;44(4):609-620. doi: 10.1016/j.pop.2017.07.004. Epub 2017 Oct 5.
Most cases of acute pancreatitis are related to gallstones. More than 80% resolve within a few days. The diagnosis is based on upper abdominal pain, elevated lipase and/or amylase, and transabdominal ultrasound findings. Management requires early aggressive hydration, pain control, nutritional support, and monitoring for progression. Patients who develop hypovolemia, systemic inflammatory response, pancreatic necrosis, and organ failure have high mortality, risk of recurrence, and progression to chronic pancreatitis (CP). Genetic predisposition and repeated injury may be necessary for CP. Management requires control of pain and exocrine and endocrine symptoms, plus reduction of risk factors, especially alcohol intake.
94Gallstones.PubMed
Frank Lammert, Kurinchi Gurusamy, Cynthia W Ko, et al.
Nat Rev Dis Primers. 2016 Apr 28;2:16024. doi: 10.1038/nrdp.2016.24.
Gallstones grow inside the gallbladder or biliary tract. These stones can be asymptomatic or symptomatic; only gallstones with symptoms or complications are defined as gallstone disease. Based on their composition, gallstones are classified into cholesterol gallstones, which represent the predominant entity, and bilirubin ('pigment') stones. Black pigment stones can be caused by chronic haemolysis; brown pigment stones typically develop in obstructed and infected bile ducts. For treatment, localization of the gallstones in the biliary tract is more relevant than composition. Overall, up to 20% of adults develop gallstones and >20% of those develop symptoms or complications. Risk factors for gallstones are female sex, age, pregnancy, physical inactivity, obesity and overnutrition. Factors involved in metabolic syndrome increase the risk of developing gallstones and form the basis of primary prevention by lifestyle changes. Common mutations in the hepatic cholesterol transporter ABCG8 confer most of the genetic risk of developing gallstones, which accounts for ∼25% of the total risk. Diagnosis is mainly based on clinical symptoms, abdominal ultrasonography and liver biochemistry tests. Symptoms often precede the onset of the three common and potentially life-threatening complications of gallstones (acute cholecystitis, acute cholangitis and biliary pancreatitis). Although our knowledge on the genetics and pathophysiology of gallstones has expanded recently, current treatment algorithms remain predominantly invasive and are based on surgery. Hence, our future efforts should focus on novel preventive strategies to overcome the onset of gallstones in at-risk patients in particular, but also in the population in general.
95Hereditary chronic pancreatitis.PubMed
Niels Teich, Joachim Mössner
Best Pract Res Clin Gastroenterol. 2008;22(1):115-30. doi: 10.1016/j.bpg.2007.10.019.
Hereditary chronic pancreatitis (HCP) is a very rare form of early-onset chronic pancreatitis. Apart from young age at diagnosis and a slower progression, the clinical course, morphological features and laboratory findings of HCP do not differ from those of patients with alcoholic chronic pancreatitis. Diagnostic criteria and treatment of HCP also resemble those of chronic pancreatitis of other causes. The clinical presentation is highly variable and includes chronic abdominal pain, impairment of endocrine and exocrine pancreatic function, nausea and vomiting, maldigestion, diabetes, pseudocysts, bile-duct and duodenal obstruction, and rarely pancreatic cancer. Fortunately, the disease is mild in most patients. Mutations in the PRSS1 gene, encoding cationic trypsinogen, play a causative role in chronic pancreatitis. It has been shown that the PRSS1 mutations increase autocatalytic conversion of trypsinogen to active trypsin, and thus probably cause premature, intrapancreatic trypsinogen activation, disturbing the intrapancreatic balance of proteases and their inhibitors. Other genes--such as the anionic trypsinogen (PRSS2), the serine protease inhibitor Kazal type 1 (SPINK1), and the cystic fibrosis transmembrane conductance regulator (CFTR)--have also been found to be associated with chronic pancreatitis (idiopathic and hereditary). Genetic testing should only be performed in carefully selected patients by direct DNA sequencing, and antenatal diagnosis should not be encouraged. Treatment focuses on enzyme and nutritional supplementation, pain management, pancreatic diabetes, and local organ complications such as pseudocysts and bile-duct or duodenal obstruction. The disease course and prognosis of patients with HCP is unpredictable. The risk of pancreatic cancer is elevated. Therefore, HCP patients should strongly avoid environmental risk factors for pancreatic cancer.
96Obesity and pancreatitis.PubMed
Biswajit Khatua, Bara El-Kurdi, Vijay P Singh
Curr Opin Gastroenterol. 2017 Sep;33(5):374-382. doi: 10.1097/MOG.0000000000000386.
PURPOSE OF REVIEW: The obesity pandemic poses a unique set of problems for acute pancreatitis - both by increasing acute pancreatitis incidence, and worsening acute pancreatitis severity. This review explores these associations, underlying mechanisms, and potential therapies. RECENT FINDINGS: We review how the obesity associated increase in gallstones, surgical, and endoscopic interventions for obesity management, diabetes, and related medications such as incretin-based therapies and hypertriglyceridemia may increase the incidence of acute pancreatitis. The mechanism of how obesity may increase acute pancreatitis severity are discussed with a focus on cytokines, adipokines, damage-associated molecular patterns and unsaturated fatty acid-mediated lipotoxicity. The role of obesity in exacerbating pancreatic necrosis is discussed; focusing on obesity-associated pancreatic steatosis. We also discuss how peripancreatic fat necrosis worsens organ failure independent of pancreatic necrosis. Last, we discuss emerging therapies including choice of intravenous fluids and the use of lipase inhibitors which have shown promise during severe acute pancreatitis. SUMMARY: We discuss how obesity may contribute to increasing acute pancreatitis incidence, the role of lipolytic unsaturated fatty acid release in worsening acute pancreatitis, and potential approaches, including appropriate fluid management and lipase inhibition in improving acute pancreatitis outcomes.
97Type 3c (pancreatogenic) diabetes mellitus secondary to chronic pancreatitis and pancreatic cancer.PubMed
Phil A Hart, Melena D Bellin, Dana K Andersen, et al.
Lancet Gastroenterol Hepatol. 2016 Nov;1(3):226-237. doi: 10.1016/S2468-1253(16)30106-6. Epub 2016 Oct 12.
Diabetes mellitus is a group of diseases defined by persistent hyperglycaemia. Type 2 diabetes, the most prevalent form, is characterised initially by impaired insulin sensitivity and subsequently by an inadequate compensatory insulin response. Diabetes can also develop as a direct consequence of other diseases, including diseases of the exocrine pancreas. Historically, diabetes due to diseases of the exocrine pancreas was described as pancreatogenic or pancreatogenous diabetes mellitus, but recent literature refers to it as type 3c diabetes. It is important to note that type 3c diabetes is not a single entity; it occurs because of a variety of exocrine pancreatic diseases with varying mechanisms of hyperglycaemia. The most commonly identified causes of type 3c diabetes are chronic pancreatitis, pancreatic ductal adenocarcinoma, haemochromatosis, cystic fibrosis, and previous pancreatic surgery. In this Review, we discuss the epidemiology, pathogenesis, and clinical relevance of type 3c diabetes secondary to chronic pancreatitis and pancreatic ductal adenocarcinoma, and highlight several important knowledge gaps.
98Loss of acinar cell VMP1 triggers spontaneous pancreatitis in mice.PubMed
Shaogui Wang, Xiaojuan Chao, Xiaoxiao Jiang, et al.
Autophagy. 2022 Jul;18(7):1572-1582. doi: 10.1080/15548627.2021.1990672. Epub 2021 Oct 28.
The pathogenesis of pancreatitis has been linked to disruption of organelle homeostasis including macroautophagy/autophagy dysfunction and endoplasmic reticulum (ER) stress. However, the direct impact of aberrant organelle function on pancreatitis initiation and progression is largely unknown. Recently an ER membrane protein, VMP1 (vacuole membrane protein 1), has been reported to play a crucial role in autophagosome formation. Notably, we found that VMP1 is downregulated in both human chronic pancreatitis (CP) and experimental mouse acute pancreatitis (AP). Pancreatic acinar cell-specific deletion promotes inflammation, acinar-to-ductal metaplasia, and fibrosis in mice, sharing histological similarities with human CP. Mechanistically, loss of pancreatic VMP1 leads to defective autophagic degradation and ER stress as well as activation of the NFE2L2/Nrf2 pathway. Genetic ablation of NFE2L2 attenuated pancreatitis in VMP1-deficient mice. Our data highlight the importance of VMP1 in modulating an integrated organelle stress response and its functional role in maintaining pancreas homeostasis in the context of CP. AMY: amylase; ADM: acinar-to-ductal metaplasia; AP: acute pancreatitis; CASP3: caspase 3; CP: chronic pancreatitis; DDIT3/CHOP: DNA damage inducible transcript 3; DKO, double knockout; ER: endoplasmic reticulum; GCLC: glutamate-cysteine ligase catalytic subunit; GCLM: glutamate-cysteine ligase modifier subunit; HSPA5/BIP: heat shock protein family A (Hsp70) member 5; KO: knockout; KRT19/CK19: keratin 19; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MPO: myeloperoxidase; NFE2L2/NRF2: nuclear factor, erythroid 2 like 2; ND: normal donor; NQO1: NAD(P)H quinone dehydrogenase 1; PCNA: proliferating cell nuclear antigen; RIPA: radio-immunoprecipitation; SQSTM1/p62: sequestosome 1; SOX9: SRY-box transcription factor 9; TAP: trypsinogen activation peptide; TFEB: transcription factor EB; TUNEL: terminal deoxynucleotidyl transferase dUTP nick end labeling; UB: ubiquitin; VMP1: vacuole membrane protein 1; XBP1: X-box binding protein 1; YAP1, Yes1 associated transcriptional regulator; ZG: zymogen granule.
99EMC6 regulates acinar apoptosis via APAF1 in acute and chronic pancreatitis.PubMed
Jie-Hui Tan, Rong-Chang Cao, Lei Zhou, et al.
Cell Death Dis. 2020 Nov 11;11(11):966. doi: 10.1038/s41419-020-03177-3.
Treatment of acute pancreatitis (AP) and chronic pancreatitis (CP) remains problematic due to a lack of knowledge about disease-specific regulatory targets and mechanisms. The purpose of this study was to screen proteins related to endoplasmic reticulum (ER) stress and apoptosis pathways that may play a role in pancreatitis. Human pancreatic tissues including AP, CP, and healthy volunteers were collected during surgery. Humanized PRSS1 (protease serine 1) transgenic (PRSS1) mice were constructed and treated with caerulein to mimic the development of human AP and CP. Potential regulatory proteins in pancreatitis were identified by proteomic screen using pancreatic tissues of PRSS1 AP mice. Adenoviral shRNA-mediated knockdown of identified proteins, followed by functional assays was performed to validate their roles. Functional analyses included transmission electron microscopy for ultrastructural analysis; qRT-PCR, western blotting, co-immunoprecipitation, immunohistochemistry, and immunofluorescence for assessment of gene or protein expression, and TUNEL assays for assessment of acinar cell apoptosis. Humanized PRSS1 mice could mimic the development of human pancreatic inflammatory diseases. EMC6 and APAF1 were identified as potential regulatory molecules in AP and CP models by proteomic analysis. Both EMC6 and APAF1 regulated apoptosis and inflammatory injury in pancreatic inflammatory diseases. Moreover, APAF1 was regulated by EMC6, induced apoptosis to injure acinar cells and promoted inflammation. In the progression of pancreatitis, EMC6 was activated and then upregulated APAF1 to induce acinar cell apoptosis and inflammatory injury. These findings suggest that EMC6 may be a new therapeutic target for the treatment of pancreatic inflammatory diseases.
100Pancreatic Stellate Cells and the Targeted Therapeutic Strategies in Chronic Pancreatitis.PubMed
Man Chang, Wenjuan Chen, Ruting Xia, et al.
Molecules. 2023 Jul 22;28(14):5586. doi: 10.3390/molecules28145586.
Chronic pancreatitis (CP) is a disease characterized by inflammatory recurrence that accompanies the development of pancreatic fibrosis. As the mystery of CP pathogenesis is gradually revealed, accumulating evidence suggests that the activation of pancreatic stellate cells (PSCs) and the appearance of a myofibroblast-like phenotype are the key gatekeepers in the development of CP. Targeting PSCs to prevent their activation and conversion to a myofibroblast-like phenotype, as well as increasing antioxidant capacity to counteract ongoing oxidative stress, are effective strategies for preventing or treating CP. Therefore, we reviewed the crosstalk between CP and pancreatic fibrosis, summarized the activation mechanisms of PSCs, and investigated potential CP therapeutic strategies targeting PSCs, including, but not limited to, anti-fibrosis therapy, antioxidant therapy, and gene therapy. Meanwhile, the above therapeutic strategies are selected in order to update the available phytopharmaceuticals as novel complementary or alternative approaches for the prevention and treatment of CP to clarify their potential mechanisms of action and their relevant molecular targets, aiming to provide the most comprehensive therapeutic treatment direction for CP and to bring new hope to CP patients.
101Mechanisms of pancreatic fibrosis and applications to the treatment of chronic pancreatitis.PubMed
Kyoko Shimizu
J Gastroenterol. 2008;43(11):823-32. doi: 10.1007/s00535-008-2249-7. Epub 2008 Nov 18.
Pancreatic stellate cells (PSCs) play a crucial role in pancreatic fibrogenesis in chronic pancreatitis and in the desmoplastic reaction of pancreatic cancer. When PSCs are stimulated by oxidative stress, ethanol and its metabolite acetaldehyde, and cytokines, the phenotype of quiescent fat-storing cells converts to myofibroblastlike activated PSCs, which then produce extracellular matrix, adhesion molecules, and various chemokines in response to cytokines and growth factors. Recent data suggest that PSCs have a phagocytic function. Plateletderived growth factor is a potent stimulator of PSC proliferation. Transforming growth factor beta, activin A, and connective tissue growth factor also play a role in PSC-mediated pancreatic fibrogenesis through autocrine and paracrine loops. Following pancreatic damage, pathophysiological processes that occur in the pancreas, including pancreas tissue pressure, hyperglycemia, intracellular reactive oxygen species production, activation of protease-activated receptor 2, induction of cyclooxygenase 2, and bacterial infection play a role in sustaining pancreatic fibrosis through increased PSC proliferation and collagen production by PSCs. Targeting PSCs might be an effective therapeutic approach in chronic pancreatitis. Various substances including vitamin A, vitamin E, polyphenols, peroxisome proliferator-activated receptor gamma ligands, and inhibitors of the renin-angiotensin system show great promise of being useful in the treatment of chronic pancreatitis.
102Roles of pancreatic stellate cells in pancreatic inflammation and fibrosis.PubMed
Atsushi Masamune, Takashi Watanabe, Kazuhiro Kikuta, et al.
Clin Gastroenterol Hepatol. 2009 Nov;7(11 Suppl):S48-54. doi: 10.1016/j.cgh.2009.07.038.
Over a decade, there is accumulating evidence that activated pancreatic stellate cells (PSCs) play a pivotal role in the development of pancreatic fibrosis. In response to pancreatic injury or inflammation, quiescent PSCs are transformed (activated) to myofibroblast-like cells, which express alpha-smooth muscle actin. Activated PSCs proliferate, migrate, produce extracellular matrix components, such as type I collagen, and express cytokines and chemokines. Recent studies have suggested novel roles of PSCs in local immune functions and angiogenesis in the pancreas. If the pancreatic inflammation and injury are sustained or repeated, PSC activation is perpetuated, leading to the development of pancreatic fibrosis. In this context, pancreatic fibrosis can be defined as pathologic changes of extracellular matrix composition in both quantity and quality, resulting from perpetuated activation of PSCs. Because PSCs are very similar to hepatic stellate cells, PSC research should develop in directions more relevant to the pathophysiology of the pancreas, for example, issues related to trypsin, non-oxidative alcohol metabolites, and pancreatic cancer. Indeed, in addition to their roles in chronic pancreatitis, it has been increasingly recognized that PSCs contribute to the progression of pancreatic cancer. Very recently, contribution of bone marrow-derived cells to PSCs was reported. Further elucidation of the roles of PSCs in pancreatic fibrosis should promote development of rational approaches for the treatment of chronic pancreatitis and pancreatic cancer.
103Pancreatic Acinar Cells-Derived Sphingosine-1-Phosphate Contributes to Fibrosis of Chronic Pancreatitis via Inducing Autophagy and Activation of Pancreatic Stellate Cells.PubMed
Decai Wang, Shengbo Han, Guozheng Lv, et al.
Gastroenterology. 2023 Dec;165(6):1488-1504.e20. doi: 10.1053/j.gastro.2023.08.029. Epub 2023 Aug 25.
BACKGROUND & AIMS: Studies have demonstrated that activated pancreatic stellate cells (PSCs) play a crucial role in pancreatic fibrogenesis in chronic pancreatitis (CP); however, the precise mechanism for PSCs activation has not been fully elucidated. We analyzed the role of injured pancreatic acinar cells (iPACs) in the activation of PSCs of CP. METHODS: Sphingosine kinase 1 (SPHK1)/sphingosine-1-phosphate (S1P) signaling was evaluated in experimental CP induced by cerulein injection or pancreatic duct ligation, as well as in PACs injured by cholecystokinin. The activation of PSCs and pancreatic fibrosis in CP samples was evaluated by immunohistochemical and immunofluorescence analyses. In vitro coculture assay of iPACs and PSCs was created to evaluate the effect of the SPHK1/S1P pathway and S1P receptor 2 (SIPR2) on autophagy and activation of PSCs. The pathogenesis of CP was assessed in SPHK1 mice or PACs-specific SPHK1-knockdown mice with recombinant adeno-associated virus serotypes 9-SPHK1-knockdown, as well as in mice treated with inhibitor of SPHK1 and S1P receptor 2 (S1PR2). RESULTS: SPHK1/S1P was remarkably increased in iPACs and acinar cells in pancreatic tissues of CP mice. Meanwhile, the pathogenesis, fibrosis, and PSCs activation of CP was significantly prevented in SPHK1 mice and recombinant adeno-associated virus serotypes 9-SPHK1-knockdown mice. Meanwhile, iPACs obviously activated PSCs, which was prevented by SPHK1 knockdown in iPACs. Moreover, iPACs-derived S1P specifically combined to S1PR2 of PSCs, by which modulated 5' adenosine monophosphate-activated protein kinase/mechanistic target of rapamycin pathway and consequently induced autophagy and activation of PSCs. Furthermore, hypoxia-inducible factor 1-α and -2α promoted SPHK1 transcription of PACs under hypoxia conditions, which is a distinct characteristic of the CP microenvironment. Coincidently, inhibition of SPHK1 and S1PR2 activity with inhibitor PF-543 and JTE-013 obviously impeded pancreatic fibrogenesis of CP mice. CONCLUSIONS: The activated SPHK1/S1P pathway in iPACs induces autophagy and activation of PSCs by regulating the S1PR2/5' adenosine monophosphate-activated protein kinase/mammalian target of rapamycin pathway, which promotes fibrogenesis of CP. The hypoxia microenvironment might contribute to the cross talk between PACs and PSCs in pathogenesis of CP.
104Targeting pancreatic stellate cells in chronic pancreatitis: Focus on therapeutic drugs and natural compounds.PubMed
Yang Wu, Chun Zhang, Mei Guo, et al.
Front Pharmacol. 2022 Oct 19;13:1042651. doi: 10.3389/fphar.2022.1042651. eCollection 2022.
Chronic pancreatitis (CP) is a precancerous illness linked to pancreatic ductal adenocarcinoma (PDAC), although the evolutionary mechanism is uncertain. CP is distinguished by severe fibrosis caused by the activation of pancreatic stellate cells (PSCs). The current clinical therapeutic protocol for CP lacks specific therapeutic medicines for the prevention and suppression of inflammation and fibrosis aggravating in CP. More research on specifically targeting PSCs would help facilitate the development of novel therapies for pancreatic fibrosis. Notably, using natural compounds from medicinal plants as new antifibrotic agents has become a focus of recent research and is widely employed as an alternative and complementary approach. Our goal was to shed light on the role of PSCs in the development of CP and provide a focused update on the new potential therapeutic strategies against PSCs in CP models. Future studies can refer to these possible strategies for drug design, bioavailability, pharmacokinetics, and other issues to obtain better clinical outcomes for treating CP.
105Corynoline protects chronic pancreatitis via binding to PSMA2 and alleviating pancreatic fibrosis.PubMed
Pengyuan Wang, Bangwei Huang, Yu Liu, et al.
J Gastroenterol. 2024 Nov;59(11):1037-1051. doi: 10.1007/s00535-024-02145-4. Epub 2024 Aug 15.
BACKGROUND: Pancreatic fibrosis is the main pathological feature of chronic pancreatitis. There is a lack of medications that effectively alleviate or reverse pancreatic fibrosis and thus cure chronic pancreatitis. METHODS: We screened drugs that could alleviate pancreatic fibrosis from 80 traditional Chinese medicine monomers and verified their efficacy and mechanisms. RESULTS: We preliminarily identified corynoline as an antifibrotic candidate by drug screening among 80 compounds. In vitro, corynoline dose-dependently reduces collagen I synthesis in pancreatic stellate cells induced by TGF-β1 and inhibits its activation. Furthermore, we found that corynoline could alleviate the morphological disruption, such as acinar cell atrophy, collagen deposition etc., as well as reduced pancreatic weight in mice with chronic pancreatitis. We further validated the antifibrotic effect of corynoline in mRNA and protein levels. We also found that corynoline could inhibit NF-κB signaling pathway in vitro and in vivo. Next, we identified PSMA2 as the binding protein of corynoline by Lip-SMap and validated it using DARTS. Moreover, the siRNA of PSMA2 disrupts the anti-fibrotic effect of corynoline. CONCLUSION: In conclusion, corynoline is a promising agent for the treatment of pancreatic fibrosis and chronic pancreatitis.
106Targeting Fibrosis: The Bridge That Connects Pancreatitis and Pancreatic Cancer.PubMed
Can Huang, Juan Iovanna, Patricia Santofimia-Castaño
Int J Mol Sci. 2021 May 7;22(9):4970. doi: 10.3390/ijms22094970.
Pancreatic fibrosis is caused by the excessive deposits of extracellular matrix (ECM) and collagen fibers during repeated necrosis to repair damaged pancreatic tissue. Pancreatic fibrosis is frequently present in chronic pancreatitis (CP) and pancreatic cancer (PC). Clinically, pancreatic fibrosis is a pathological feature of pancreatitis and pancreatic cancer. However, many new studies have found that pancreatic fibrosis is involved in the transformation from pancreatitis to pancreatic cancer. Thus, the role of fibrosis in the crosstalk between pancreatitis and pancreatic cancer is critical and still elusive; therefore, it deserves more attention. Here, we review the development of pancreatic fibrosis in inflammation and cancer, and we discuss the therapeutic strategies for alleviating pancreatic fibrosis. We further propose that cellular stress response might be a key driver that links fibrosis to cancer initiation and progression. Therefore, targeting stress proteins, such as nuclear protein 1 (NUPR1), could be an interesting strategy for pancreatic fibrosis and PC treatment.
107Piezo1-mediated stellate cell activation causes pressure-induced pancreatic fibrosis in mice.PubMed
Sandip M Swain, Joelle M-J Romac, Steven R Vigna, et al.
JCI Insight. 2022 Apr 22;7(8):e158288. doi: 10.1172/jci.insight.158288.
Pancreatic fibrosis is a complication of chronic pancreatitis and is a prominent feature of pancreatic cancer. Pancreatic fibrosis is commonly observed in patients with prolonged pancreatic duct obstruction, which elevates intrapancreatic pressure. We show here that increased pancreatic duct pressure causes fibrosis and describes the mechanism by which pressure increases deposition of extracellular matrix proteins and fibrosis. We found that pancreatic stellate cells (PSCs), the source of the extracellular matrix proteins in fibrosis, express the mechanically activated ion channel Piezo1. By increasing intracellular calcium, mechanical stress or the Piezo1 agonist Yoda1-activated PSCs manifest by loss of perinuclear fat droplets and increased TGF-β1, fibronectin, and type I collagen expression. These effects were blocked by the Piezo1 inhibitor GsMTx4 and absent in PSCs from mice with conditional genetic deletion of Piezo1 in stellate cells, as was pancreatic duct ligation-induced fibrosis. Although TRPV4 has been proposed to have direct mechanosensing properties, we discovered that PSCs from Trpv4-KO mice were protected against Yoda1-triggered activation. Moreover, mice devoid of TRPV4 were protected from pancreatic duct ligation-induced fibrosis. Thus, high pressure within the pancreas stimulates Piezo1 channel opening, and subsequent activation of TRPV4 leads to stellate cell activation and pressure-induced chronic pancreatitis and fibrosis.
108Molecular Mechanism of Pancreatic Stellate Cells Activation in Chronic Pancreatitis and Pancreatic Cancer.PubMed
Guihua Jin, Weilong Hong, Yangyang Guo, et al.
J Cancer. 2020 Jan 14;11(6):1505-1515. doi: 10.7150/jca.38616. eCollection 2020.
Activated pancreatic stellate cells (PSCs) are the main effector cells in the process of fibrosis, a major pathological feature in pancreatic diseases that including chronic pancreatitis and pancreatic cancer. During tumorigenesis, quiescent PSCs change into an active myofibroblast-like phenotype which could create a favorable tumor microenvironment and facilitate cancer progression by increasing proliferation, invasiveness and inducing treatment resistance of pancreatic cancer cells. Many cellular signals are revealed contributing to the activation of PSCs, such as transforming growth factor-β, platelet derived growth factor, mitogen-activated protein kinase (MAPK), Smads, nuclear factor-κB (NF-κB) pathways and so on. Therefore, investigating the role of these factors and signaling pathways in PSCs activation will promote the development of PSCs-specific therapeutic strategies that may provide novel options for pancreatic cancer therapy. In this review, we systematically summarize the current knowledge about PSCs activation-associated stimulating factors and signaling pathways and hope to provide new strategies for the treatment of pancreatic diseases.
109Inflammation and pancreatic cancer: An updated review.PubMed
Kamleshsingh Shadhu, Chunhua Xi
Saudi J Gastroenterol. 2019 Jan-Feb;25(1):3-13. doi: 10.4103/sjg.SJG_390_18.
Pancreatic cancer is a devastating disease with poor prognosis in the modern era. Inflammatory processes have emerged as key mediators of pancreatic cancer development and progression. Recently, studies have been carried out to investigate the underlying mechanisms that contribute to tumorigenesis induced by inflammation. In this review, the role of inflammation in the initiation and progression of pancreatic cancer is discussed.
110IL-1β macrophages fuel pathogenic inflammation in pancreatic cancer.PubMed
Nicoletta Caronni, Federica La Terza, Francesco M Vittoria, et al.
Nature. 2023 Nov;623(7986):415-422. doi: 10.1038/s41586-023-06685-2. Epub 2023 Nov 1.
Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease with high resistance to therapies. Inflammatory and immunomodulatory signals co-exist in the pancreatic tumour microenvironment, leading to dysregulated repair and cytotoxic responses. Tumour-associated macrophages (TAMs) have key roles in PDAC, but their diversity has prevented therapeutic exploitation. Here we combined single-cell and spatial genomics with functional experiments to unravel macrophage functions in pancreatic cancer. We uncovered an inflammatory loop between tumour cells and interleukin-1β (IL-1β)-expressing TAMs, a subset of macrophages elicited by a local synergy between prostaglandin E (PGE) and tumour necrosis factor (TNF). Physical proximity with IL-1β TAMs was associated with inflammatory reprogramming and acquisition of pathogenic properties by a subset of PDAC cells. This occurrence was an early event in pancreatic tumorigenesis and led to persistent transcriptional changes associated with disease progression and poor outcomes for patients. Blocking PGE or IL-1β activity elicited TAM reprogramming and antagonized tumour cell-intrinsic and -extrinsic inflammation, leading to PDAC control in vivo. Targeting the PGE-IL-1β axis may enable preventive or therapeutic strategies for reprogramming of immune dynamics in pancreatic cancer.
111Interleukin-6 in inflammatory and malignant diseases of the pancreas.PubMed
Marina Lesina, Sonja Maria Wörmann, Patrick Neuhöfer, et al.
Semin Immunol. 2014 Feb;26(1):80-7. doi: 10.1016/j.smim.2014.01.002. Epub 2014 Feb 23.
Interleukin-6 is an important pro-inflammatory cytokine strongly linked to the most burdened exocrine pancreatic diseases including acute pancreatitis, chronic pancreatitis and pancreatic cancer. However, its role in all these diseases is versatile and not completely defined. Several studies provided accumulating evidence that IL-6 is mainly involved in the JAK/STAT pathway activation promoting acute and chronic pancreatitis disease aggravation as well as pancreatic cancer initiation and progression. This review will focus on recent studies illustrating the role of IL-6 in acute and chronic pancreatitis and pancreatic oncogenesis. Further, a short overview of indicated disease pathologies will be given and the impact of IL-6 in JAK/STAT pathway, persistent STAT3 activation and cancer immunotherapy will be discussed.
112Statin prevents cancer development in chronic inflammation by blocking interleukin 33 expression.PubMed
Jong Ho Park, Mahsa Mortaja, Heehwa G Son, et al.
Nat Commun. 2024 May 30;15(1):4099. doi: 10.1038/s41467-024-48441-8.
Chronic inflammation is a major cause of cancer worldwide. Interleukin 33 (IL-33) is a critical initiator of cancer-prone chronic inflammation; however, its induction mechanism by environmental causes of chronic inflammation is unknown. Herein, we demonstrate that Toll-like receptor (TLR)3/4-TBK1-IRF3 pathway activation links environmental insults to IL-33 induction in the skin and pancreas inflammation. An FDA-approved drug library screen identifies pitavastatin to effectively suppress IL-33 expression by blocking TBK1 membrane recruitment/activation through the mevalonate pathway inhibition. Accordingly, pitavastatin prevents chronic pancreatitis and its cancer sequela in an IL-33-dependent manner. The IRF3-IL-33 axis is highly active in chronic pancreatitis and its associated pancreatic cancer in humans. Interestingly, pitavastatin use correlates with a significantly reduced risk of chronic pancreatitis and pancreatic cancer in patients. Our findings demonstrate that blocking the TBK1-IRF3-IL-33 signaling axis suppresses cancer-prone chronic inflammation. Statins present a safe and effective prophylactic strategy to prevent chronic inflammation and its cancer sequela.
113Single-cell RNA-seq analysis reveals BHLHE40-driven pro-tumour neutrophils with hyperactivated glycolysis in pancreatic tumour microenvironment.PubMed
Liwen Wang, Yihao Liu, Yuting Dai, et al.
Gut. 2023 May;72(5):958-971. doi: 10.1136/gutjnl-2021-326070. Epub 2022 Jun 10.
OBJECTIVE: Innate immunity plays important roles in pancreatic ductal adenocarcinoma (PDAC), as non-T-cell-enriched tumour. Neutrophils are major players in innate immune system. Here, we aimed to explore the heterogeneity and pro-tumour mechanisms of neutrophils in PDAC. DESIGN: We analysed single-cell transcriptomes of peripheral blood polymorphonuclear leucocytes (PMNs) and tumour-infiltrating immune cells from five patients with PDAC, and performed immunofluorescence/immunohistochemistry staining, multi-omics analysis and experiments to validate the discoveries of bioinformatics analysis. RESULTS: Exploration of the heterogeneity of tumour-associated neutrophils (TANs) revealed a terminally differentiated pro-tumour subpopulation (TAN-1) associated with poor prognosis, an inflammatory subpopulation (TAN-2), a population of transitional stage that have just migrated to tumour microenvironment (TAN-3) and a subpopulation preferentially expressing interferon-stimulated genes (TAN-4). Glycolysis signature was upregulated along neutrophil transition trajectory, and TAN-1 was featured with hyperactivated glycolytic activity. The glycolytic switch of TANs was validated by integrative multi-omics approach of transcriptomics, proteomics and metabolomics analysis. Activation of glycolytic activity by LDHA overexpression induced immunosuppression and pro-tumour functions in neutrophil-like differentiated HL-60 (dHL-60) cells. Mechanistic studies revealed BHLHE40, downstream to hypoxia and endoplasmic reticulum stress, was a key regulator in polarisation of neutrophils towards TAN-1 phenotype, and direct transcriptional regulation of BHLHE40 on TAN-1 marker genes was demonstrated by chromatin immunoprecipitation assay. Pro-tumour and immunosuppression functions were observed in dHL-60 cells overexpressing BHLHE40. Importantly, immunohistochemistry analysis of PDAC tissues revealed the unfavourable prognostic value of BHLHE40 neutrophils. CONCLUSION: The dynamic properties of TANs revealed by this study will be helpful in advancing PDAC therapy targeting innate immunity.
114TREM2 Depletion in Pancreatic Cancer Elicits Pathogenic Inflammation and Accelerates Tumor Progression via Enriching IL-1β Macrophages.PubMed
Daowei Yang, Xinlei Sun, Hua Wang, et al.
Gastroenterology. 2025 Jun;168(6):1153-1169. doi: 10.1053/j.gastro.2025.01.244. Epub 2025 Feb 14.
BACKGROUND & AIMS: Pancreatic ductal adenocarcinoma (PDAC) has a complex tumor microenvironment enriched with tumor-associated macrophages. Triggering receptor expressed on myeloid cells 2 (TREM2) is highly expressed by a subset of macrophages in PDAC. However, the functional role of TREM2 in PDAC progression remains elusive. METHODS: We generated a novel transgenic mouse model (KPPC;Trem2) that enables the genetic depletion of TREM2 in the context of spontaneous PDAC development. Single-cell RNA-sequencing analysis was used to identify changes in the tumor immune microenvironment on TREM2 depletion. We evaluated the impacts of TREM2 depletion on the tumor immune microenvironment to elucidate the functions of TREM2 in macrophages and PDAC development. RESULTS: Unexpectedly, genetic depletion of TREM2 significantly accelerated spontaneous PDAC progression and shortened the survival of KPPC;Trem2 mice. Single-cell analysis revealed that TREM2 depletion enhanced proinflammatory macrophages and exacerbated pathogenic inflammation in PDAC. Specifically, TREM2 functions as a key braking mechanism for the NLRP3/nuclear factor-κB/interleukin (IL)-1β inflammasome pathway, opposing to microbial lipopolysaccharide as the key activator of this pathway. TREM2 deficiency orchestrated with microbial lipopolysaccharide to trigger IL-1β upregulation and pathogenic inflammation, thereby fueling PDAC development. Notably, IL-1β inhibition or microbiome ablation not only reversed the accelerated PDAC progression caused by TREM2 depletion, but also further inhibited PDAC progression in the TREM2-depleted context. CONCLUSIONS: TREM2 depletion accelerates tumor progression by enhancing proinflammatory macrophages and IL-1β-mediated pathogenic inflammation in PDAC. The accelerated tumor progression by TREM2 depletion can be reversed by blocking IL-1β-associated pathogenic inflammation.
115Complications of Chronic Pancreatitis.PubMed
Mitchell L Ramsey, Darwin L Conwell, Phil A Hart
Dig Dis Sci. 2017 Jul;62(7):1745-1750. doi: 10.1007/s10620-017-4518-x. Epub 2017 Mar 9.
Chronic pancreatitis is a disease that leads to irreversible changes in the pancreatic morphology and function. The loss of function can lead to diabetes mellitus and exocrine pancreatic insufficiency. The inflammation and fibrosis can also lead to other complications including a chronic abdominal pain syndrome, metabolic bone disease, and pancretic cancer. This article reviews our current understanding of the mechanisms and management of these complications of chronic pancreatitis.
116A New Insight into Chronic Pancreatitis.PubMed
Tooru Shimosegawa
Tohoku J Exp Med. 2019 Aug;248(4):225-238. doi: 10.1620/tjem.248.225.
Chronic pancreatitis (CP) is a pancreatic disease with poor prognosis characterized clinically by abdominal pain, morphologically by pancreatic stones/calcification, duct dilatation and atrophy, and functionally by pancreatic exocrine and endocrine insufficiency. CP is also known as a risk factor for the development of pancreatic cancer. CP has long been understood based on a fixed disease concept deduced from the clinical and morphological features of the end-stage disease. However, identification of causal genes for hereditary pancreatitis and success in the isolation and culture of pancreatic stellate cells have advanced the understanding of the underlying pathological mechanisms, the early-stage pathophysiology, and the mechanisms behind pancreatic fibrosis. These advances have led to moves aimed at improving patient prognosis through prevention of disease progression by early diagnosis and early therapeutic intervention. The strategy for preventing disease progression has included a proposal for diagnostic criteria for early CP and introduction of a new definition of CP in consideration of the pathological mechanisms. Our group has been committed deeply to these studies and has provided a large amount of information to the world.
117Proteomic 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.
118Chronic Pancreatitis: Managing a Difficult Disease.PubMed
Phil A Hart, Darwin L Conwell
Am J Gastroenterol. 2020 Jan;115(1):49-55. doi: 10.14309/ajg.0000000000000421.
Chronic pancreatitis is characterized by progressive, irreversible morphologic and functional changes that are most commonly attributed to environmental insults, particularly when there is a genetic or anatomic predisposition. Heavy alcohol use and cigarette smoking are the most common environmental risk factors, but both may be absent. Antecedent episodes of acute pancreatitis occur in about half of patients. Abdominal pain is the most common symptom and requires a tailored approach depending on the anatomic changes in the pancreas. Other clinical manifestations include diabetes mellitus, exocrine pancreatic insufficiency, metabolic bone disease, pancreatic cancer, and anatomic complications. Current disease management is centered on risk factor reduction and screening for and treating disease complications. There are no current therapies to delay or retard disease progression, but there are ongoing efforts to more fully understand the natural history of chronic pancreatitis and underlying mechanisms of disease. These studies are expected to provide insights that will transform our approach to disease management and provide increased hope to patients.
119Pancreatitis in Pregnancy-Comprehensive Review.PubMed
Agnieszka Mądro
Int J Environ Res Public Health. 2022 Dec 3;19(23):16179. doi: 10.3390/ijerph192316179.
Acute and chronic pancreatitis, until recently observed incidentally in pregnancy, has occurred much more frequently in the last 2-3 decades. Particularly severe complications for the mother and fetus may be a consequence of acute pancreatitis. Therefore, it is important to know more about the diagnostic and therapeutic possibilities of pancreatic diseases in the course of pregnancy. Epidemiology, causes, clinical characteristics, differential diagnosis, and complex management are presented in this review. Particular emphasis is on the prevention of acute pancreatitis (AP) through the proper diagnosis and treatment of cholelithiasis and hypertriglyceridemia, both before and during pregnancy. The most up-to-date reports and management strategies are presented. This publication contributes to a wide group of scientists and practitioners better understanding the discussed issues, and indicates the directions of research for the future.
120Secondary HypertriglyceridemiaPubMed
Irwin Benuck, Don P. Wilson, Catherine McNeal
Hypertriglyceridemia (HTG) is often secondary to obesity-related insulin resistance (1,2), which is caused by excessive intake of fats and carbohydrates without compensatory utilization of these calories, but other common and rare causes should be considered (3,4,5). Genetic influences, gestational conditions, and nutrition in infancy and childhood contribute to HTG associated with formation of an atherogenic dyslipidemia profile consisting of high TG, low high-density lipoprotein-cholesterol (HDL-C), increased LDL particle number, smaller LDL size and density, and elevated apolipoprotein B. Very high TG levels generally result from defective disposal by lipoprotein lipase and can cause pancreatitis. Defining and treating the underlying cause are necessary to restore the lipids and lipoproteins to normal. Renal, hepatic, endocrine, immune, and pharmacological causes are in the differential diagnosis. Rare diseases such as lipodystrophy and glycogen storage disease are particularly challenging and require specific management strategies. Prevention of acute pancreatitis by lowering TG is a priority when TG is very high (> 1000 mg/dl), and lifestyle modification is the basis of management for all cases with high and moderately high levels. Since TG metabolism is associated with generation of an atherogenic dyslipidemia profile, predictors of coronary artery disease (CAD) such as LDL-C and non-HDL-C become targets when they exceed cut points. For complete coverage of all related areas of Endocrinology, please visit our on-line FREE web-text, WWW.ENDOTEXT.ORG.
121Genetic Testing for Hypertriglyceridemia in Academic Lipid Clinics: Implications for Precision Medicine-Brief Report.PubMed
Matthew R Deshotels, Trevor D Hadley, Mendel Roth, et al.
Arterioscler Thromb Vasc Biol. 2022 Dec;42(12):1461-1467. doi: 10.1161/ATVBAHA.122.318445. Epub 2022 Nov 3.
BACKGROUND: Severe hypertriglyceridemia is often caused by variants in genes of triglyceride metabolism. These variants include rare, heterozygous pathogenic variants (PVs), or multiple common, small-effect single nucleotide polymorphisms that can be quantified using a polygenic risk score (PRS). The role of genetic testing to examine PVs and PRS in predicting risk for pancreatitis and severity of hypertriglyceridemia is unknown. METHODS: We examined the relationship of PVs and PRSs associated with hypertriglyceridemia with the highest recorded plasma triglyceride level and risk for acute pancreatitis in 363 patients from 3 academic lipid clinics who underwent genetic testing (GBinsight's Dyslipidemia Comprehensive Panel). Categories of hypertriglyceridemia included: normal triglyceride (<200 mg/dL), moderate (200-499 mg/dL), severe (500-999 mg/dL), or very severe (≥1000 mg/dL). RESULTS: PVs and high PRSs were identified in 37 (10%) and 59 (16%) individuals, respectively. Patients with both had increased risk for very severe hypertriglyceridemia compared with those with neither genetic risk factor. Risk for acute pancreatitis was also increased in individuals with both genetic risk factors (odds ratio, 5.1 [=0.02] after controlling for age, race, sex, body mass index, and highest triglyceride level), but not in individuals with PV or high PRS alone. CONCLUSIONS: The presence of both PV and high PRS significantly increased risk for very severe hypertriglyceridemia and acute pancreatitis, whereas PV or PRS alone only modestly increased risk. Genetic testing may help identify patients with hypertriglyceridemia who have the greatest risk for developing pancreatitis and may derive the greatest benefit from novel triglyceride-lowering therapies.
122Triglyceride Lowering DrugsPubMed
Kenneth R. Feingold
The two major goals of the treatment of hypertriglyceridemia are the prevention of cardiovascular disease and pancreatitis. Here we discuss the drugs used for the treatment of hypertriglyceridemia: (niacin, fibrates, omega-3-fatty acids, and apo CIII inhibitors. Niacin decreases total cholesterol, TGs (20-50% decrease), LDL-C, and Lp(a). Additionally, niacin decreases small dense LDL resulting in a shift to large, buoyant LDL particles. Moreover, niacin increases HDL-C. Skin flushing, insulin resistance, and other side effects have limited the use of niacin. The enthusiasm for niacin has greatly decreased with the failure of AIM-HIGH and HPS-2 Thrive to decrease cardiovascular events when niacin was added to statin therapy. The omega-3-fatty acids eicosapentaenoic acid (C20:5n-3) (EPA) and docosahexaenoic acid (C22:6n-3) (DHA) lower TGs by 10-50% but do not affect total cholesterol, HDL-C, or Lp(a). LDL-C may increase with EPA + DHA when the TG levels are markedly elevated (>500mg/dL). EPA alone does not increase LDL-C. Omega-3-fatty acids have few side effects, drug interactions, or contraindications. Numerous studies of low dose omega-3-fatty acids on cardiovascular outcomes have failed to demonstrate a benefit. However, in the JELIS, REDUCE-IT, and RESPECT-EPA trials high doses of EPA alone reduced cardiovascular events while in the STRENGTH and OMEMI trials high doses of EPA+DHA did not reduce cardiovascular events. Fibrates reduce TG levels by 25-50% and increase HDL-C by 5-20%. The effect on LDL-C is variable. If the TG levels are very high (>500mg/dL), fibrate therapy may result in an increase in LDL-C, whereas if TGs are not markedly elevated fibrates decrease LDL-C by 10-30%. Fibrates also reduce apolipoprotein B, LDL particle number, and non-HDL-C and there may be a shift from small dense LDL towards large LDL particles. Fibrates do not have any major effects on Lp(a). Monotherapy with fibrates appears to reduce cardiovascular events particularly in patients with high TG and low HDL-C levels. In contrast, in the ACCORD LIPID and PROMINENT trials the addition of fibrates to statin therapy did not reduce cardiovascular disease, which has reduced the enthusiasm for using fibrates to reduce cardiovascular disease. In patients with diabetes fibrates appear to slow the progression of microvascular disease (retinopathy, nephropathy, and amputations, ulcers, and gangrene. Antisense oligonucleotides, volanesorsen and olezarsen, inhibit the production of apolipoprotein C-III and decrease TG levels in patients with severe hypertriglyceridemia including patients with the familial chylomicronemia syndrome (FCS). Studies also suggest that apo CIII inhibitors reduce episodes of pancreatitis in patients with severe hypertriglyceridemia. Patients with FCS have also reported that apo C-III inhibitors improved symptoms and reduced interference of FCS with work/school responsibilities. Of concern has been decreases in platelet levels with 47% of patients treated with volanesorsen developing platelet counts below100 x 109/L, a side effect that is not observed with olezarsen. Thus, a number of drugs are available for the treatment of hypertriglyceridemia and may be employed when lifestyle changes are not sufficient. For complete coverage of all related areas of Endocrinology, please visit our on-line FREE web-text, WWW.ENDOTEXT.ORG.
123Epidemiology 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.
124Pancreatic Cancer: A Review of Risk Factors, Diagnosis, and Treatment.PubMed
ZhiYu Zhao, Wei Liu
Technol Cancer Res Treat. 2020 Jan-Dec;19:1533033820962117. doi: 10.1177/1533033820962117.
This review aims to summarize the latest knowledge on factors, diagnosis, and treatment of pancreatic cancer, and aims to promote further research on this under-studied malignant tumor. At present, we urgently need to identify high-risk patients with precancerous diseases through screening approaches, so that medical professionals and the general public may better understand prevention strategies or early detection measures. Pancreatic cancer is a highly invasive malignant tumor with a fatal risk, mainly seen in men and older adults (60-85 years old). Pancreatic cancer is now increasingly observed in young patients. Because the disease has no early symptoms and can quickly invade surrounding tissues and organs, it is one of the deadliest cancers. With a view to identify the important factors for the development of pancreatic cancer, previous studies have found that smoking, alcohol, and chronic pancreatitis are considered high-risk factors. Recent studies have shown that abnormal metabolism of human microorganisms, blood type, and glucose and lipid levels are also important factors in the development of pancreatic cancer. Identifying early diagnosis options is an important way to improve detection and survival rates of pancreatic cancer. None of the many tumor markers associated with pancreatic cancer are highly specific, which also indicates further research is required to improve the early detection rate. Future directions in terms of treatment evaluating the relationship between the microbiology-free system and immunotherapy will bring a major breakthrough and is expected to bring exciting clinical applications in improving the life-cycle of pancreatic cancer patients.
125Advances in pancreatic cancer early diagnosis, prevention, and treatment: The past, the present, and the future.PubMed
Alessandro Mannucci, Ajay Goel
CA Cancer J Clin. 2025 Sep 19. doi: 10.3322/caac.70035.
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with a dismal prognosis, largely because of late-stage diagnosis and therapeutic resistance. PDAC incidence has been rising, with modifiable and non-modifiable risk factors contributing to disease development. Chronic pancreatitis, diabetes mellitus, smoking, obesity, and familial predisposition have been implicated in PDAC pathogenesis. Early clinical manifestations are vague and insidious; therefore, PDAC is often diagnosed at an advanced stage, limiting curative treatment options. Efforts to improve early detection have focused on serum biomarkers (e.g., carbohydrate antigen 19-9), imaging modalities, and liquid biopsies. Endoscopic ultrasound and magnetic resonance imaging have demonstrated potential in identifying early-stage disease in certain high-risk populations. Surgical resection remains the only potentially curative option, but only 15%-20% of patients have resectable disease at diagnosis. Neoadjuvant chemotherapy has emerged as a promising strategy to improve resectability and survival outcomes. For patients with locally advanced or metastatic PDAC, combination chemotherapy regimens such as FOLFIRINOX (folinic acid, 5-fluorouracil, irinotecan, and oxaliplatin), NALIRIFOX (5-fluorouracil, oxaliplatin, liposomal irinotecan, and leucovorin), and combined gemcitabine/nanoparticle albumen-bound paclitaxel offer survival benefits, although toxicity remains a concern, especially for platinum-based therapies. Several breakthroughs in molecular profiling have led to the development of targeted therapies, including sotorasib and olaparib. Immunotherapy has shown limited success in PDAC due to its immunosuppressive tumor microenvironment. However, novel combination approaches are under investigation, including quadruplet therapy, immune checkpoint inhibitors with oncolytic viruses, stromal-targeting agents, and personalized neoantigen vaccines. Key priorities for future research include identifying reliable biomarkers for early detection, refining patient selection for targeted therapies, and developing innovative strategies to overcome treatment resistance.
126Pancreatic Cancer and Its Mimics.PubMed
Frank H Miller, Camila Lopes Vendrami, Nancy A Hammond, et al.
Radiographics. 2023 Nov;43(11):e230054. doi: 10.1148/rg.230054.
Pancreatic ductal adenocarcinoma (PDAC) is the most common primary pancreatic malignancy, ranking fourth in cancer-related mortality in the United States. Typically, PDAC appears on images as a hypovascular mass with upstream pancreatic duct dilatation and abrupt duct cutoff, distal pancreatic atrophy, and vascular encasement, with metastatic involvement including lymphadenopathy. However, atypical manifestations that may limit detection of the underlying PDAC may also occur. Atypical PDAC features include findings related to associated conditions such as acute or chronic pancreatitis, a mass that is isointense to the parenchyma, multiplicity, diffuse tumor infiltration, associated calcifications, and cystic components. Several neoplastic and inflammatory conditions can mimic PDAC, such as paraduodenal "groove" pancreatitis, autoimmune pancreatitis, focal acute and chronic pancreatitis, neuroendocrine tumors, solid pseudopapillary neoplasms, metastases, and lymphoma. Differentiation of these conditions from PDAC can be challenging due to overlapping CT and MRI features; however, certain findings can help in differentiation. Diffusion-weighted MRI can be helpful but also can be nonspecific. Accurate diagnosis is pivotal for guiding therapeutic planning and potential outcomes in PDAC and avoiding biopsy or surgical treatment of some of these mimics. Biopsy may still be required for diagnosis in some cases. The authors describe the typical and atypical imaging findings of PDAC and features that may help to differentiate PDAC from its mimics. RSNA, 2023 Quiz questions for this article are available through the Online Learning Center. See the invited commentary by Zins in this issue.
127Pancreatitis and PDAC: association and differentiation.PubMed
Sherif B Elsherif, Mayur Virarkar, Sanaz Javadi, et al.
Abdom Radiol (NY). 2020 May;45(5):1324-1337. doi: 10.1007/s00261-019-02292-w.
The discrimination of mass-forming chronic pancreatitis (MFCP) from pancreatic ductal adenocarcinoma (PDAC) is a central diagnostic dilemma. It is important to differentiate these entities since they have markedly different prognoses and management. Importantly, the appearance of these two entities significantly overlaps on a variety of imaging modalities. However, there are imaging features that may be suggestive of one entity more than the other. MFCP and PDAC may show different enhancement patterns on perfusion computed tomography (CT) and/or dynamic contrast-enhanced MRI (DCE-MRI). The duct-penetrating sign on magnetic resonance cholangiopancreatography (MRCP) is more often associated with MFCP, whereas abrupt cutoff with upstream dilatation of the main pancreatic duct and the double-duct sign (obstruction/cutoff of both the common bile duct and pancreatic duct) are more often associated with PDAC. Nevertheless, tissue sampling is the most reliable method to differentiate between these entities and is currently generally necessary for management.
128Non-Neoplastic Masses of the Pancreas.PubMed
Barbara A Centeno, Sarah C Thomas
Monogr Clin Cytol. 2020;26:42-52. doi: 10.1159/000455734. Epub 2020 Sep 28.
Benign non-neoplastic solid lesions of the pancreas are comprised of several separate entities, with their diagnostic identification best performed in correlation with the radiographic and clinical features. These include all of the pancreatitides, intrapancreatic spleen, and a few other rare entities. Preoperative imaging may suggest the correct diagnosis, but occasionally the preoperative imaging findings may be misleading because they overlap with those of pancreatic neoplasms. Masses associated with typical pancreatitides are rarely sampled due to their distinct clinical picture and relative frequency; however, the uncommon variants of pancreatitis may also present as mass lesions mimicking malignancy. Herein, we will discuss the cytopathologic findings of several solid pancreatic lesions, including acute pancreatitis, chronic pancreatitis, autoimmune pancreatitis, paraduodenal or groove pancreatitis, and other mass lesions, such as intrapancreatic accessory spleen and abscess. The key cytological features, ancillary studies, and differential diagnoses will also be discussed.
129Lead-Time Trajectory of CA19-9 as an Anchor Marker for Pancreatic Cancer Early Detection.PubMed
Johannes F Fahrmann, C Max Schmidt, Xiangying Mao, et al.
Gastroenterology. 2021 Mar;160(4):1373-1383.e6. doi: 10.1053/j.gastro.2020.11.052. Epub 2020 Dec 14.
BACKGROUND & AIMS: There is substantial interest in liquid biopsy approaches for cancer early detection among subjects at risk, using multi-marker panels. CA19-9 is an established circulating biomarker for pancreatic cancer; however, its relevance for pancreatic cancer early detection or for monitoring subjects at risk has not been established. METHODS: CA19-9 levels were assessed in blinded sera from 175 subjects collected up to 5 years before diagnosis of pancreatic cancer and from 875 matched controls from the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial. For comparison of performance, CA19-9 was assayed in blinded independent sets of samples collected at diagnosis from 129 subjects with resectable pancreatic cancer and 275 controls (100 healthy subjects; 50 with chronic pancreatitis; and 125 with noncancerous pancreatic cysts). The complementary value of 2 additional protein markers, TIMP1 and LRG1, was determined. RESULTS: In the PLCO cohort, levels of CA19-9 increased exponentially starting at 2 years before diagnosis with sensitivities reaching 60% at 99% specificity within 0 to 6 months before diagnosis for all cases and 50% at 99% specificity for cases diagnosed with early-stage disease. Performance was comparable for distinguishing newly diagnosed cases with resectable pancreatic cancer from healthy controls (64% sensitivity at 99% specificity). Comparison of resectable pancreatic cancer cases to subjects with chronic pancreatitis yielded 46% sensitivity at 99% specificity and for subjects with noncancerous cysts, 30% sensitivity at 99% specificity. For prediagnostic cases below cutoff value for CA19-9, the combination with LRG1 and TIMP1 yielded an increment of 13.2% in sensitivity at 99% specificity (P = .031) in identifying cases diagnosed within 1 year of blood collection. CONCLUSION: CA19-9 can serve as an anchor marker for pancreatic cancer early detection applications.
130Carbohydrate antigen 19-9 for differential diagnosis of pancreatic carcinoma and chronic pancreatitis.PubMed
Si-Biao Su, Shan-Yu Qin, Wen Chen, et al.
World J Gastroenterol. 2015 Apr 14;21(14):4323-33. doi: 10.3748/wjg.v21.i14.4323.
AIM: To evaluate the utility of carbohydrate antigen 19-9 (CA19-9) for differential diagnosis of pancreatic carcinoma and chronic pancreatitis. METHODS: We searched the literature for studies reporting the sensitivity, specificity, and other accuracy measures of serum CA19-9 levels for differentiating pancreatic carcinoma and chronic pancreatitis. Pooled analysis was performed using random-effects models, and receiver operating characteristic (ROC) curves were generated. Study quality was assessed using Standards for Reporting Diagnostic Accuracy and Quality Assessment for Studies of Diagnostic Accuracy tools. RESULTS: A total of 34 studies involving 3125 patients with pancreatic carcinoma and 2061 patients with chronic pancreatitis were included. Pooled analysis of the ability of CA19-9 level to differentiate pancreatic carcinoma and chronic pancreatitis showed the following effect estimates: sensitivity, 0.81 (95%CI: 0.80-0.83); specificity, 0.81 (95%CI: 0.79-0.82); positive likelihood ratio, 4.08 (95%CI: 3.39-4.91); negative likelihood ratio, 0.24 (95%CI: 0.21-0.28); and diagnostic odds ratio, 19.31 (95%CI: 14.40-25.90). The area under the ROC curve was 0.88. No significant publication bias was detected. CONCLUSION: Elevated CA19-9 by itself is insufficient for differentiating pancreatic carcinoma and chronic pancreatitis, however, it increases suspicion of pancreatic carcinoma and may complement other clinical findings to improve diagnostic accuracy.
131[Hereditary pancreatitis].PubMed
Ming Tan, Ove B Schaffalitzky de Muckadell, Maiken Thyregod Jørgensen
Ugeskr Laeger. 2020 Feb 10;182(7).
Hereditary pancreatitis (HP) is an autosomal dominant disease with 80% penetrance. HP is characterised by the debut of recurrent acute pancreatitis episodes during childhood with gradual progression to chronic pancreatitis. Patients with phenotypic HP have a significantly increased lifetime risk of developing pancreatic ductal adenocarcinoma (PDAC). Patients with HP represent a rare but important group of high-risk individuals in need of early diagnosis and screening for potential PDAC. The aim of this review is to provide an overview of the epidemiology, genetics and clinical aspects of HP.
132A faecal microbiota signature with high specificity for pancreatic cancer.PubMed
Ece Kartal, Thomas S B Schmidt, Esther Molina-Montes, et al.
Gut. 2022 Jul;71(7):1359-1372. doi: 10.1136/gutjnl-2021-324755. Epub 2022 Mar 8.
BACKGROUND: Recent evidence suggests a role for the microbiome in pancreatic ductal adenocarcinoma (PDAC) aetiology and progression. OBJECTIVE: To explore the faecal and salivary microbiota as potential diagnostic biomarkers. METHODS: We applied shotgun metagenomic and 16S rRNA amplicon sequencing to samples from a Spanish case-control study (n=136), including 57 cases, 50 controls, and 29 patients with chronic pancreatitis in the discovery phase, and from a German case-control study (n=76), in the validation phase. RESULTS: Faecal metagenomic classifiers performed much better than saliva-based classifiers and identified patients with PDAC with an accuracy of up to 0.84 area under the receiver operating characteristic curve (AUROC) based on a set of 27 microbial species, with consistent accuracy across early and late disease stages. Performance further improved to up to 0.94 AUROC when we combined our microbiome-based predictions with serum levels of carbohydrate antigen (CA) 19-9, the only current non-invasive, Food and Drug Administration approved, low specificity PDAC diagnostic biomarker. Furthermore, a microbiota-based classification model confined to PDAC-enriched species was highly disease-specific when validated against 25 publicly available metagenomic study populations for various health conditions (n=5792). Both microbiome-based models had a high prediction accuracy on a German validation population (n=76). Several faecal PDAC marker species were detectable in pancreatic tumour and non-tumour tissue using 16S rRNA sequencing and fluorescence in situ hybridisation. CONCLUSION: Taken together, our results indicate that non-invasive, robust and specific faecal microbiota-based screening for the early detection of PDAC is feasible.
133Clinical treatment of cholangiocarcinoma: an updated comprehensive review.PubMed
Alessandra Elvevi, Alice Laffusa, Miki Scaravaglio, et al.
Ann Hepatol. 2022 Sep-Oct;27(5):100737. doi: 10.1016/j.aohep.2022.100737. Epub 2022 Jul 7.
Cholangiocarcinoma (CCA) is a heterogeneous group of neoplasms of the bile ducts and represents the second most common hepatic cancer after hepatocellular carcinoma; it is sub-classified as intrahepatic cholangiocarcinoma (iCCA) and extrahepatic cholangiocarcinoma (eCCA), the latter comprising both perihilar cholangiocarcinoma (pCCA or Klatskin tumor), and distal cholangiocarcinoma (dCCA). The global incidence of CCA has increased worldwide in recent decades. Chronic inflammation of biliary epithelium and bile stasis represent the main risk factors shared by all CCA sub-types. When feasible, liver resection is the treatment of choice for CCA, followed by systemic chemotherapy with capecitabine. Liver transplants represent a treatment option in patients with very early iCCA, in referral centers only. CCA diagnosis is often performed at an advanced stage when CCA is unresectable. In this setting, systemic chemotherapy with gemcitabine and cisplatin represents the first treatment option, but the prognosis remains poor. In order to ameliorate patients' survival, new drugs have been studied in the last few years. Target therapies are directed against different molecules, which are altered in CCA cells. These therapies have been studied as second-line therapy, alone or in combination with chemotherapy. In the same setting, the immune checkpoints inhibitors targeting programmed death 1 (PD-1), programmed death-ligand 1 (PD-L1), cytotoxic T-lymphocyte antigen-4 (CTLA-4), have been proposed, as well as cancer vaccines and adoptive cell therapy (ACT). These experimental treatments showed promising results and have been proposed as second- or third-line treatment, alone or in combination with chemotherapy or target therapies.
134Colorectal Cancer in Inflammatory Bowel Disease: Mechanisms and Management.PubMed
Shailja C Shah, Steven H Itzkowitz
Gastroenterology. 2022 Mar;162(3):715-730.e3. doi: 10.1053/j.gastro.2021.10.035. Epub 2021 Oct 29.
Patients with inflammatory bowel disease (IBD) are at increased risk of developing colorectal cancer (CRC), despite decreases in CRC incidence in recent years. Chronic inflammation is the driver of neoplastic progression, resulting in dysplastic precursor lesions that may arise in multiple areas of the colon through a process of field cancerization. Colitis-associated CRC shares many molecular similarities with sporadic CRC, and preclinical investigations have demonstrated a potential role for the microbiome in concert with the host immune system in the development of colitis-associated colorectal cancer (CAC). Some unique molecular differences occur in CAC, but their role in the pathogenesis and behavior of inflammation-associated cancers remains to be elucidated. Nonconventional types of dysplasia have been increasingly recognized, but their natural history is not well defined, and they have not been incorporated into surveillance algorithms. The concept of cumulative inflammatory burden highlights the importance of considering histologic inflammation over time as an important risk factor for CAC. Dysplasia is arguably the most important risk factor for developing CAC, and advances have been made in the endoscopic detection and removal of precancerous lesions, thereby deferring or avoiding surgical resection. Some of the agents used to treat IBD are chemopreventive. It is hoped that by gaining better control of the underlying inflammation with newer medications and better endoscopic detection and management, a more sophisticated appreciation of clinicopathologic risk factors, and growing awareness of the genetic, immunologic, and environmental causes of colitis- associated neoplasia, that colitis-associated colorectal neoplasia will become even more predictable and manageable in the coming years.
135Obesity, diabetes, and cancer: epidemiology, pathophysiology, and potential interventions.PubMed
Leonardo de Andrade Mesquita, Laura Fink Wayerbacher, Gilberto Schwartsmann, et al.
Arch Endocrinol Metab. 2023 Jun 19;67(6):e000647. doi: 10.20945/2359-3997000000647.
The proportion of deaths attributable to cancer is rising, and malignant neoplasms have become the leading cause of death in high-income countries. Obesity and diabetes are now recognized as risk factors for several types of malignancies, especially endometrial, colorectal, and postmenopausal breast cancers. Mechanisms implicated include disturbances in lipid-derived hormone secretion, sex steroids biosynthesis, hyperinsulinemia, and chronic inflammation. Intentional weight loss is associated with a mitigation of risk for obesity-related cancers, a phenomenon observed specially with bariatric surgery. The impact of pharmacological interventions for obesity and diabetes is not uniform: while metformin seems to protect against cancer, other agents such as lorcaserin may increase the risk of malignancies. However, these interpretations must be carefully considered, since most data stem from bias-prone observational studies, and high-quality randomized controlled trials with appropriate sample size and duration are needed to achieve definite conclusions. In this review, we outline epidemiological and pathophysiological aspects of the relationship between obesity, diabetes, and malignancies. We also highlight pieces of evidence regarding treatment effects on cancer incidence in these populations.
136Physical activity, sedentary behaviour, diet, and cancer: an update and emerging new evidence.PubMed
Jacqueline Kerr, Cheryl Anderson, Scott M Lippman
Lancet Oncol. 2017 Aug;18(8):e457-e471. doi: 10.1016/S1470-2045(17)30411-4. Epub 2017 Jul 26.
The lifestyle factors of physical activity, sedentary behaviour, and diet are increasingly being studied for their associations with cancer. Physical activity is inversely associated with and sedentary behaviour is positively (and independently) associated with an increased risk of more than ten types of cancer, including colorectal cancer (and advanced adenomas), endometrial cancers, and breast cancer. The most consistent dietary risk factor for premalignant and invasive breast cancer is alcohol, whether consumed during early or late adult life, even at low levels. Epidemiological studies show that the inclusion of wholegrain, fibre, fruits, and vegetables within diets are associated with reduced cancer risk, with diet during early life (age <8 years) having the strongest apparent association with cancer incidence. However, randomised controlled trials of diet-related factors have not yet shown any conclusive associations between diet and cancer incidence. Obesity is a key contributory factor associated with cancer risk and mortality, including in dose-response associations in endometrial and post-menopausal breast cancer, and in degree and duration of fatty liver disease-related hepatocellular carcinoma. Obesity produces an inflammatory state, characterised by macrophages clustered around enlarged hypertrophied, dead, and dying adipocytes, forming crown-like structures. Increased concentrations of aromatase and interleukin 6 in inflamed breast tissue and an increased number of macrophages, compared with healthy tissue, are also observed in women with normal body mass index, suggesting a metabolic obesity state. Emerging randomised controlled trials of physical activity and dietary factors and mechanistic studies of immunity, inflammation, extracellular matrix mechanics, epigenetic or transcriptional regulation, protein translation, circadian disruption, and interactions of the multibiome with lifestyle factors will be crucial to advance this field.
137Eosinophils in chronic obstructive pulmonary disease.PubMed
Marco Vanetti, Dina Visca, Francesco Ardesi, et al.
Ther Adv Respir Dis. 2025 Jan-Dec;19:17534666251335800. doi: 10.1177/17534666251335800. Epub 2025 May 28.
Chronic Obstructive Pulmonary Disease (COPD) is a heterogeneous lung condition characterised by chronic respiratory symptoms, fixed airway obstruction and persistent inflammation that leads to a progressive airflow limitation. Although COPD has traditionally been linked to neutrophilic inflammation, recent studies have identified a subset of patients - approximately 20%-40% - with elevated eosinophil levels in blood and sputum. Emerging evidence suggests that eosinophilic inflammation has a pivotal role in a subset of COPD patients and may influence disease progression, exacerbation frequency and therapeutic responses. This narrative review provides a comprehensive analysis of the role of eosinophils in COPD with particular attention to their role as biomarkers in blood and sputum. We evaluate the prevalence of eosinophilic inflammation in COPD exanimating different thresholds used in blood and in sputum to define it. In addition, we focus on eosinophilic COPD phenotype as a treatable trait, emphasising recent evidence that supports the effectiveness of biological target therapy.
138Chronic obstructive pulmonary disease's eosinophilic phenotype: Clinical characteristics, biomarkers and biotherapy.PubMed
Mauro Maniscalco, Claudio Candia, Pasquale Ambrosino, et al.
Eur J Intern Med. 2025 Jan;131:27-35. doi: 10.1016/j.ejim.2024.10.015. Epub 2024 Oct 22.
COPD is a chronic, heterogeneous inflammatory disorder of the airways with persistent and poorly reversible airflow limitation, causing symptoms such as cough, shortness of breath, and sputum production. Despite optimal treatment, some patients remain symptomatic due to the disease's heterogeneity, manifesting in various phenotypes. One notable phenotype involves eosinophilic inflammation, with a variable prevalence. Identifying eosinophilic phenotypes is crucial for tailored therapeutic strategies, as they respond favorably to corticosteroids and potentially biologics. Recent advances in both clinical trials and spontaneous research have helped understand the biological and clinical characteristics of this phenotype, although no universal consensus has been reached yet on the definition of the cut-off values of the eosinophil peripheral blood count. Moreover, there is evidence of novel emerging biomarkers which might go beyond the sole eosinophil count, while significant advancements in terms of pharmacological treatment have been made, with dupilumab being the first biological drug being licensed for COPD patients with elevated circulating eosinophils in the stable phase. In light of the above, although several papers have been written on the relationship between eosinophils and COPD, in the present work we endeavored to summarize and discuss the pivotal literature findings regarding the eosinophilic COPD in order to help define the biological and clinical features of this peculiar phenotype, with particular attention to the use of established and emerging biomarkers, as well as current and future therapeutic perspectives.
139Chronic inflammation in benign prostatic hyperplasia: Pathophysiology and treatment options.PubMed
So Inamura, Naoki Terada
Int J Urol. 2024 Sep;31(9):968-974. doi: 10.1111/iju.15518. Epub 2024 Jun 27.
Benign prostatic hyperplasia, a prevalent condition in aging men, is characterized by the proliferation of prostatic epithelial and stromal cells, which leads to bladder outlet obstruction and the exacerbation of lower urinary tract symptoms. There is increasing evidence that chronic prostatic inflammation contributes to the pathogenesis and progression of benign prostatic hyperplasia. This review explores the complex relationship between chronic inflammation and benign prostatic hyperplasia, focusing on the underlying mechanisms, clinical implications, and current therapeutic approaches. The pathophysiology of benign prostatic hyperplasia is multifaceted, involving factors such as hormonal changes, hypoxia, urine reflux into prostatic ducts and stroma, autoimmune responses, and infection-induced inflammation. Inflammatory cytokines, particularly interleukin-17 and interleukin-8, may play key roles in tissue remodeling and smooth muscle contraction within the prostate, thereby influencing benign prostatic hyperplasia progression. Current therapies for benign prostatic hyperplasia include α1-blockers, phosphodiesterase 5 inhibitors, 5α-reductase inhibitors, and plant-based treatments (e.g., pollen extract). These therapies aim to alleviate symptoms by reducing prostatic inflammation, improving blood flow, and inhibiting hormonal pathways involved in prostatic enlargement. However, patients with chronic prostatic inflammation often experience more severe lower urinary tract symptoms and may be resistant to conventional treatments. This resistance has prompted the exploration of alternative therapies targeting inflammation. Chronic prostatic inflammation plays a central role in the pathogenesis and severity of benign prostatic hyperplasia. An understanding of its mechanisms will enable the development of more effective treatments to improve the quality of life among patients with benign prostatic hyperplasia.
140Smoking cessation and mortality risk reduction in older adults with long-term smoking history.PubMed
Shimin Chen, Shanshan Yang, Shengshu Wang, et al.
BMC Public Health. 2024 Oct 14;24(1):2821. doi: 10.1186/s12889-024-20270-w.
BACKGROUND: The association between smoking cessation and decreased mortality existed among former smokers has been well documented. However, evidence is limited for smokers with long-term exposure. This study aims to quantify the association between smoking cessation and mortality by years since quitting in older adults with long-term smoking history. METHODS: Data from Beijing Healthy Aging Cohort Study (BHACS), conducted among communities aged over 55 years old at recruitment, were collected via questionnaire between July 2009 and September 2015 and followed up for all-cause and cancer mortality until March 2021. Self-reported smoking status and years since quitting were collected at baseline. Cox proportional hazards models were used to examine the association between smoking cessation and all-cause and cancer mortality. RESULTS: A total of 11 235 participants (43.9% male) were included, with a mean age of 70.35 (SD 7.71) years. Former smokers comprised 31.7% of the cohort, with a median smoking duration of 43 (IQR: 34-50) years. During 71 573 person-years of follow-up, there were 1 617 deaths (14.4% of the total cohort), of which 872 (17.7%) occurred among male participants. Compared with never smokers, HR (95%CI) for participants who current smoked was 2.898 (2.092-4.013); quit smoking less than 10 years (medians [quartiles] 4 [1, 7] years) before recruitment was 2.738(1.972-3.802); 10 to 20 years (16 [13, 20] years), 1.807(1.286-2.540); and 20 years or more (30 [25, 37] years), 1.293(0.981-1.705). The risk of all-cause and cancer mortality decreased gradually over years since quitting. Quitting less than 10 years, 10 to 20 years and 20 years or more, former smokers avoided an estimated 8.4%, 57.5% and 84.6% of excess all-cause mortality associated with current smoking, respectively. The association between smoking cessation and decreased mortality was observed among former smokers regardless of smoking history. CONCLUSIONS: In this study, current smoking was associated with nearly triple the mortality risk compared to never smoking. Smoking cessation, even after a long-term smoking history, was associated with significant decreases in the relative excess mortality linked to continuing smoking. The association were more pronounced in men.
141How to facilitate smoking cessation.PubMed
Furio Colivicchi, Stefania Angela Di Fusco, Vered Gil Ad, et al.
Prog Cardiovasc Dis. 2025 Sep-Oct;92:32-42. doi: 10.1016/j.pcad.2025.07.007. Epub 2025 Jul 16.
Despite a decline in global smoking prevalence over recent decades, cigarette smoking remains one of the main modifiable risk factors for cardiovascular disease. The cardiovascular benefits of smoking cessation are well established; however, quitting smoking remains a major challenge. In this review, we aim to highlight useful tools to support smokers in their cessation journey. These include brief counseling, cognitive and behavioral interventions, and pharmacological therapies (e.g. nicotine replacement therapy, bupropion, varenicline). We also discuss evidence regarding eHealth-based interventions and the potential impact of e-cigarettes on smoking cessation. Finally, we focus on the role of public health interventions in promoting smoking cessation.
142Risk Factors and Prevention of Cancer and CVDs: A Chicken and Egg Situation.PubMed
Maurizio Giuseppe Abrignani, Fabiana Lucà, Vincenzo Abrignani, et al.
J Clin Med. 2025 Apr 29;14(9):3083. doi: 10.3390/jcm14093083.
Cardiovascular diseases and cancer are the two primary causes of mortality worldwide. Although traditionally regarded as distinct pathologies, they share numerous pathophysiological mechanisms and risk factors, including chronic inflammation, insulin resistance, obesity, and metabolic dysregulation. Notably, several cancers have been identified as closely linked to cardiovascular diseases, including lung, breast, prostate, and colorectal cancers, as well as hematological malignancies, such as leukemia and lymphoma. Additionally, renal and pancreatic cancers exhibit a significant association with cardiovascular complications, partly due to shared risk factors and the cardiotoxic effects of cancer therapies. Addressing the overlapping risk factors through lifestyle modifications-such as regular physical activity, a balanced diet, and cessation of smoking and alcohol-has proven effective in reducing both CV and oncological morbidity and mortality. Furthermore, even in patients with established cancer, structured interventions targeting physical activity, nutritional optimization, and smoking cessation have been associated with improved outcomes. Beyond lifestyle modifications, pharmacological strategies play a crucial role in the prevention of both diseases. Several cardiovascular medications, including statins, aspirin, beta-blockers, and metformin, exhibit pleiotropic effects that extend beyond their primary indications, demonstrating potential anti-neoplastic properties in preclinical and observational studies. Recently, novel therapeutic agents have garnered attention for their possible cardioprotective and metabolic benefits. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and sodium-glucose cotransporter-2 inhibitors (SGLT2is), initially developed for managing type 2 diabetes, have shown CV and renal protective effects, alongside emerging evidence of their role in modulating cancer-related metabolic pathways. Inclisiran, a small interfering RNA targeting PCSK9, effectively lowers LDL cholesterol and may contribute to reducing CV risk, with potential implications for tumor biology. Additionally, sacubitril/valsartan, an angiotensin receptor-neprilysin inhibitor, has revolutionized heart failure management by improving hemodynamic parameters and exerting anti-inflammatory effects that may have broader implications for chronic disease prevention. Given the intricate interplay between CVD and cancer, further research is essential to clarify the exact mechanisms linking these conditions and assessing the potential of CV therapies in cancer prevention. This review aims to examine shared risk factors, consider the role of pharmacological and lifestyle interventions, and emphasize crucial epidemiological and mechanistic insights into the intersection of CV and oncological health.
143Overview of anti-inflammatory diets and their promising effects on non-communicable diseases.PubMed
Xiaoping Yu, Haomou Pu, Margaret Voss
Br J Nutr. 2024 Oct 14;132(7):898-918. doi: 10.1017/S0007114524001405. Epub 2024 Oct 16.
An anti-inflammatory diet is characterised by incorporating foods with potential anti-inflammatory properties, including fruits, vegetables, whole grains, nuts, legumes, spices, herbs and plant-based protein. Concurrently, pro-inflammatory red and processed meat, refined carbohydrates and saturated fats are limited. This article explores the effects of an anti-inflammatory diet on non-communicable diseases (NCD), concentrating on the underlying mechanisms that connect systemic chronic inflammation, dietary choices and disease outcomes. Chronic inflammation is a pivotal contributor to the initiation and progression of NCD. This review provides an overview of the intricate pathways through which chronic inflammation influences the pathogenesis of conditions including obesity, type II diabetes mellitus, CVD, autoinflammatory diseases, cancer and cognitive disorders. Through a comprehensive synthesis of existing research, we aim to identify some bioactive compounds present in foods deemed anti-inflammatory, explore their capacity to modulate inflammatory pathways and, consequently, to prevent or manage NCD. The findings demonstrated herein contribute to an understanding of the interplay between nutrition, inflammation and chronic diseases, paving a way for future dietary recommendations and research regarding preventive or therapeutic strategies.
144Dietary patterns and biomarkers of oxidative stress and inflammation: A systematic review of observational and intervention studies.PubMed
Krasimira Aleksandrova, Liselot Koelman, Caue Egea Rodrigues
Redox Biol. 2021 Jun;42:101869. doi: 10.1016/j.redox.2021.101869. Epub 2021 Jan 22.
INTRODUCTION: Oxidative stress and inflammation are known to play a critical role in ageing and chronic disease development and could therefore represent important targets for developing dietary strategies for disease prevention. We aimed to systematically review the results from observational studies and intervention trials published in the last 5 years on the associations between dietary patterns and biomarkers of oxidative stress and inflammation. METHODS: A systematic search of the PubMed, MEDLINE and Web of Science (January 2015 to October 2020) was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Methodological quality of selected studies was evaluated based on the NUTRIGRADE and BIOCROSS assessment tools. RESULTS: In total, 29 studies among which 16 observational studies and 13 intervention studies were found eligible for review. Overall, results indicated an inverse association between plant-based diets - the Mediterranean and Dietary Approaches to Stop Hypertension (DASH) diet - and oxidative stress and proinflammatory biomarkers. In observational studies, inverse associations were further revealed for the vegetarian diet, the USDA Healthy Eating Index (HEI) - based diet and the paleolithic diet, whereas a positive association was seen for western and fast food diets. Quality assessment suggested that majority of dietary intervention studies (n = 12) were of low to moderate quality. CONCLUSIONS: This study provides evidence that the plant-based dietary patterns are associated with lowered levels of oxidative stress and inflammation and may provide valid means for chronic disease prevention. Future large-scale intervention trials using validated biomarkers are warranted to confirm these findings.
145Introduction to Nutrition and Cancer.PubMed
Hanadi Talal Ahmedah, Haneen Adel Basheer, Inas Almazari, et al.
Cancer Treat Res. 2024;191:1-32. doi: 10.1007/978-3-031-55622-7_1.
By the beginning of the year 2021, the estimated number of new cancer cases worldwide was about 19.3 million and there were 10.0 million cancer-related deaths. Cancer is one of the deadliest diseases worldwide that can be attributed to genetic and environmental factors, including nutrition. The good nutrition concept focuses on the dietary requirements to sustain life. There is a substantial amount of evidence suggesting that a healthy diet can modulate cancer risk, particularly the risk of colorectal and breast cancers. Many studies have evaluated the correlation between our diet and the risk of cancer development, prevention, and treatment. The effect of diet on cancer development is likely to happen through intertwining mechanisms including inflammation and immune responses. For instance, a greater intake of red and processed meat along with low consumption of fruits and vegetables has been associated with increased levels of inflammatory biomarkers that are implicated in cancer development. On the other hand, the consumption of phytosterols, vitamins, and minerals, which exert antioxidant and anti-inflammatory roles have been linked to lower cancer risk, or even its occurrence prevention. In this book, we aim to summarize the current knowledge on the role of nutrition in cancer to provide the best scientific advice in this regard.
146Obesity and cardiovascular health.PubMed
Aimee Welsh, Muhammad Hammad, Ileana L Piña, et al.
Eur J Prev Cardiol. 2024 Jun 3;31(8):1026-1035. doi: 10.1093/eurjpc/zwae025.
Obesity has risen to epidemic levels worldwide over the past few decades and has become a huge global health burden owing to its direct contribution to the development of some of the most prevalent chronic diseases including diabetes, hypertension, hyperlipidaemia, and other cardiovascular diseases. Obesity is a disease of positive energy balance resulting from complex interactions between abnormal neurohumoral responses and an individual's socioeconomic, environmental, behavioural, and genetic factors leading to a state of chronic inflammation. Understanding the complex nature of the disease is crucial in determining the best approach to combat its rising numbers. Despite recent advancements in pharmacological therapy for the treatment of obesity, reversing weight gain and maintaining weight loss is challenging due to the relapsing nature of the disease. Prevention, therefore, remains the key which needs to start in utero and continued throughout life. This review summarizes the role obesity plays in the pathophysiology of various cardiovascular diseases both by directly affecting endothelial and myocyte function and indirectly by enhancing major cardiovascular risk factors like diabetes, hypertension, and hyperlipidaemia. We highlight the importance of a holistic approach needed to prevent and treat this debilitating disease. Particularly, we analyse the effects of plant-based diet, regular exercise, and non-exercise activity thermogenesis on obesity and overall cardiorespiratory fitness. Moreover, we discuss the significance of individualizing obesity management with a multimodal approach including lifestyle modifications, pharmacotherapy, and bariatric surgery to tackle this chronic disease.
147Principles of cancer screening: lessons from history and study design issues.PubMed
Jennifer M Croswell, David F Ransohoff, Barnett S Kramer
Semin Oncol. 2010 Jun;37(3):202-15. doi: 10.1053/j.seminoncol.2010.05.006.
Early detection of cancer has held great promise and intuitive appeal in the medical community for well over a century. Its history developed in tandem with that of the periodic health examination, in which any deviations--subtle or glaring--from a clearly demarcated "normal" were to be rooted out, given the underlying hypothesis that diseases develop along progressive linear paths of increasing abnormalities. This model of disease development drove the logical deduction that early detection, by "breaking the chain" of cancer development, must be of benefit to affected individuals. In the latter half of the 20th century, researchers and guidelines organizations began to explicitly challenge the core assumptions underpinning many clinical practices. A move away from intuitive thinking began with the development of evidence-based medicine. One key method developed to explicitly quantify the overall risk-benefit profile of a given procedure was the analytic framework. The shift away from pure deductive reasoning and reliance on personal observation was driven, in part, by a rising awareness of critical biases in cancer screening that can mislead clinicians, including healthy volunteer bias, length-biased sampling, lead-time bias, and overdiagnosis. A new focus on the net balance of both benefits and harms when determining the overall worth of an intervention also arose: it was recognized that the potential downsides of early detection were frequently overlooked or discounted because screening is performed on basically healthy persons and initially involves relatively noninvasive methods. Although still inconsistently applied to early detection programs, policies, and belief systems in the United States, an evidence-based approach is essential to counteract the misleading--even potentially harmful--allure of intuition and individual observation.
148Effect of periodic health exam on provider management of preventive services.PubMed
Phuong T Hoang, Dominic Hodgkin, John P Thomas, et al.
J Eval Clin Pract. 2019 Oct;25(5):827-833. doi: 10.1111/jep.13083. Epub 2018 Nov 29.
RATIONALE AND OBJECTIVE: To evaluate the relationship between receipt of annual physicals and the receipt of provider recommendation for preventive services, during a period when Medicare did not cover annual physicals (before 2011). METHODS: Electronic medical records of patients aged 65 years and older from a US health care system were extracted for the 2001 to 2007 period. A fixed-effects logistic model was used to assess the relationship between receipt of periodic health examination (PHE) and receipt of provider recommendation for mammogram screening for 6466 female Medicare beneficiaries. Logistic regression models were used to assess the relationship between receipt of PHE and receipt of provider recommendation for colonoscopy screening and pneumococcal vaccination for 10 318 Medicare beneficiaries. Nine primary care providers from the network were also interviewed, selected by random sampling stratified by care model. RESULTS: Electronic medical record analyses suggest that patients with a PHE were more likely to obtain provider recommendations for mammogram screening (OR = 2.17, P < 0.0001), colonoscopy screening (OR = 1.54, P < 0.0001), and pneumococcal vaccination (OR = 1.10, P < 0.0001). Providers suggested that prevention care quality improves with the PHE because certain screening measures (eg, skin cancer screening, breast exam) would be neglected without it, and healthy patients could miss recommended preventive services entirely. Without the PHE, some providers reported having tried to incorporate discussions of preventive services by scheduling more frequent follow-up chronic care visits than they would have otherwise, and some routinely charged Medicare for a more complex follow-up visit than they would have charged without the preventive service discussions. CONCLUSION: Periodic health examination is important in connecting patients to recommended preventive services. Provider interviews suggested that, indirectly, Medicare ended up paying for the PHE via greater frequency of follow-up visits or higher visit charges from providers integrating the services with other visits.
149Results of low-dose computed tomography as a regular health examination among Chinese hospital employees.PubMed
Yang Zhang, Sanghoon Jheon, Huimin Li, et al.
J Thorac Cardiovasc Surg. 2020 Sep;160(3):824-831.e4. doi: 10.1016/j.jtcvs.2019.10.145. Epub 2019 Nov 14.
OBJECTIVE: Lung cancer is traditionally more prevalent in the elderly patients, men, and smokers. However, as low-dose computed tomography (LDCT) is increasingly popular, we hypothesized the disease spectrum might change. METHODS: LDCT was performed as a part of regular health examinations in 8392 of 15,686 employees from 6 hospitals in different regions of China in 2012 to 2018. Clinicopathologic characteristics, including age, sex, smoking status, radiologic features, tumor histology, and pathologic stage, were retrospectively analyzed. RESULTS: LDCT incidentally detected lung cancer (pathologically confirmed) in a total of 179 (2.1%) hospital employees. The lung cancer detection rate was significantly greater in female than male (2.5% vs 1.3%, P = .001) patients. There was also a greater detection rate among nonsmokers than smokers, although statistical significance was not reached (2.2% vs 1.4%, P = .092). The lung cancer detection rate was 1.0% in the "age ≤40 years" group, 2.6% in the "40 < age ≤55 years" group, and 2.9% in the "age >55 years" group (P < .001). Among the hospital employees with lung cancer, 171 (95.5%) presented as ground-glass opacity, 177 (98.9%) were lung adenocarcinoma, 170 (95.0%) were early stage 0/IA, and 177 (98.9%) received curative surgical resection as the initial treatment. After a median follow-up of 38 months, no disease recurrence or death was observed among these patients. CONCLUSIONS: LDCT detected lung cancer in a significant proportion of young, female, and nonsmoking employees. The vast majority of these lung cancers were early stage, with extremely good prognosis.
150Medullary Thyroid Carcinoma Detected by Routine Health Screening Had Better Clinical Outcome and Survival.PubMed
Ji Hyun Yoo, Da Eun Leem, Bo Ram Kim, et al.
Endocrinol Metab (Seoul). 2025 Jun;40(3):414-420. doi: 10.3803/EnM.2024.2214. Epub 2025 Mar 5.
BACKGRUOUND: The benefits of early detection in medullary thyroid carcinoma (MTC) are not well established. This study investigates the impact of early detection of MTC on clinical outcomes. METHODS: This retrospective study evaluated 144 patients diagnosed with MTC at Samsung Medical Center between 1995 and 2019, classified as asymptomatic (mostly detected through routine health check-ups, including ultrasonography, calcitonin, or carcinoembryonic antigen levels) and symptomatic. Initial treatment response, final clinical outcomes, and cancer-specific survival were compared. RESULTS: MTC was diagnosed in 104 (72.2%) asymptomatic and 40 (27.8%) symptomatic patients. The symptomatic group showed a significantly larger primary tumor size, more frequent lateral neck lymph node metastasis, more advanced tumor, node, metastasis (TNM) staging, and higher pre- and postoperative serum calcitonin levels. For initial treatment response, the proportion of excellent responders was significantly higher in the asymptomatic group (71.2% vs. 40.0%), while that of patients with biochemical incomplete response (37.5% vs. 26.9%) and structural incomplete response (22.5% vs. 1.9%) was significantly higher in the symptomatic group (all P<0.001). For the final clinical outcomes, the rate of patients with no evidence of disease was higher in the asymptomatic group (67.3% vs. 30.0%), while the rate of patients with structurally identifiable disease was higher in the symptomatic group (45.0% vs. 7.7%) (P<0.001 for both). The symptomatic group had significantly poorer cancer-specific survival than the asymptomatic group (log-rank P=0.023). CONCLUSION: Compared with late diagnosis through symptomatic presentation, early diagnosis in asymptomatic patients results in significantly better initial treatment response, final clinical outcomes, and cancer-specific survival in patients with MTC.
151Ikigai and use of preventive healthcare services in Germany.PubMed
André Hajek, Angelina R Sutin, Antonio Terracciano, et al.
Prev Med. 2024 Dec;189:108159. doi: 10.1016/j.ypmed.2024.108159. Epub 2024 Oct 29.
OBJECTIVE: This study examined the association between ikigai (a Japanese concept akin to purpose in life or a rationale for existence) and use of preventive healthcare services. METHODS: Data were gathered in August and September of 2023 from a quota-based sample of 5000 individuals living in Germany (18 to 74 years). This sampling ensured representation across gender, age groups, and federal states to reflect the adult population of Germany. The recently validated German version of the Ikigai-9 scale (Ikigai-9-G) was used to assess ikigai. Outcomes were regular cancer screenings, flu vaccination, and routine health check-ups. Multiple logistic regressions were used. RESULTS: Ikigai was associated with higher odds of regular use of preventive healthcare services (regular flu vaccinations: OR = 1.01, 95 % CI: 1.002 to 1.02; regular cancer screenings: OR = 1.01, 95 % CI: 1.004 to 1.02; routine health check-ups: OR = 1.02, 95 % CI: 1.01 to 1.03), adjusting for sociodemographic, lifestyle, and health-related factors. The association between ikigai and preventive healthcare was not moderated by gender, age, or education. CONCLUSION: Higher ikigai is associated with preventive health measures, independent of key covariates. These findings are consistent with the literature on ikigai and better health-related outcomes and subjective well-being. Ikigai may help point to new ways to counter the low use of preventive services in Germany.
152Facilitators and Barriers to Cancer Screening Participation Across Southeastic Asia: A Scoping Review.PubMed
Isabelle Higgins, Paige Kleinig, Duy Toan Le, et al.
Psychooncology. 2025 Apr;34(4):e70139. doi: 10.1002/pon.70139.
OBJECTIVE: As the prevalence of cancer cases in Southeast Asia (SEA) increases, understanding facilitators and barriers to participation in and uptake of cancer screening is important. However, to date, no review has been undertaken on this topic. This review aimed to address this knowledge gap. METHODS: The search was conducted across academic databases and grey literature sources. Two reviewers independently screened the results, followed by data extraction. Social cognitive therapy was used as part of narrative synthesis of the data. RESULTS: Of the 735 studies, 26 were included. Barriers and facilitators were grouped into headings of personal, environmental, societal, and behavioural domains. The commonly reported barriers to participation in cancer screening included poor knowledge, emotional factors, belief of low personal susceptibility, lack of time, misperceptions, cost, inconvenience, social influence, and lack of skills required. The facilitators were education, greater self-perceived risk, reassurance, past medical history, reduced cost and improved access to healthcare, social supports, religious beliefs, and routine health check-ups. CONCLUSIONS: A multitude of barriers, and some facilitators, to participation in cancer screening were reported in the literature. This complexity highlights the importance of a multifaceted and nuanced strategy in promoting cancer screening in SEA countries.
153Effect of National Oral Health Screening Program on the Risk of Head and Neck Cancer: A Korean National Population-Based Study.PubMed
Chan Woo Wee, Hyo-Jung Lee, Jae-Ryun Lee, et al.
Cancer Res Treat. 2022 Jul;54(3):709-718. doi: 10.4143/crt.2021.834. Epub 2021 Oct 22.
PURPOSE: Poor oral health is associated with head and neck cancer (HNC). We evaluated whether a national oral health screening program (OHSP) could reduce the risk of HNC. MATERIALS AND METHODS: Data from 408,247 healthy individuals aged ≥ 40 years from the National Health Insurance System-National Health Screening program during 2003 and 2004 in Korea were analyzed. The risk of HNC was compared between subjects who underwent OHSP (HEALS-Dental+, n=165,292) and routine health check-ups only (HEALS-Dental‒, n=242,955). The impact of individual oral health-related factors on HNC risk was evaluated in HEALS-Dental+. RESULTS: A total of 1,650 HNC cases were diagnosed. The 10-year HNC-free rate was 99.684% with a median follow-up of 11 years. The risk of all HNC (hazard ratio [HR], 1.16; 95% confidence interval [CI], 1.03 to 1.29; p=0.011) and oropharyngeal cancer (HR, 1.48; 95% CI, 1.13 to 1.94; p=0.005) was significantly higher in HEALS-Dental‒ than in HEALS-Dental+. In HEALS-Dental+, oral cavity cancer was marginally reduced (p=0.085), and missing teeth was a significant factor for HNC (HR, 1.24; 95% CI, 1.02 to 1.50; p=0.032). Toothbrushing was a significant factor in univariate analysis (p=0.028), but not in multivariate analysis (p=0.877). CONCLUSION: The National OHSP significantly reduced the long-term HNC risk, particularly the incidence of oropharyngeal cancer. Routine OHSP should be considered at the population level.