Gastro hep advances最新文献

英文中文

The Clinical Significance of Extrapancreatic Incidental Findings Detected During Pancreas Surveillance 胰腺监测中胰腺外偶然发现的临床意义

Gastro hep advances

Pub Date : 2025-09-27 DOI: 10.1016/j.gastha.2025.100818

Helena Saba , Elizabeth Abou Diwan , Hassan Sinan , Dimitri Melki , Mohamad Dbouk , Amanda Blackford , Linda Chu , Eun Ji Shin , Marcia Irene Canto , Michael Goggins

Background and Aims

Cancer screening tests have the potential to detect cancers and precancerous conditions, but one concern is the potential that screen-detected incidental findings lead to unnecessary, potentially harmful interventions. The aim of this study is to determine, the yield of extrapancreatic incidental findings that required management, including cancers, precancerous lesions, and other findings of diagnostic concern in patients undergoing pancreatic surveillance for their familial or genetic pancreatic cancer risk.

Methods

We reviewed the pancreatic surveillance records of 925 patients enrolled in the Cancer of Pancreas Screening studies at The Johns Hopkins Hospital from 1998 to 2023 who had undergone at least one pancreatic surveillance test. Significant extra-pancreatic incidental findings that required diagnostic evaluation and/or treatment were tabulated, including the resulting diagnostic tests, therapeutic interventions, and complications.

Results

The mean age/standard deviation at enrollment, of patients in the cohort was 58.0/10.4 years; 59.7% female), 220 (23.8%) had undergone baseline surveillance, 705 (76.2%) had undergone surveillance for a median of 4 years. Seventy-five extrapancreatic incidental findings were detected in 68 patients (7.3%), including 10 cancers, 80% of which were stage I and 8 (0.86%) precancerous lesions. Thirteen patients underwent surgical (n = 13), endoscopic (n = 9), or chemotherapy (n = 4). Twenty-five patients (2.7%) were recommended to undergo surveillance, (20 for nondysplastic Barrett’s esophagus). Three patients (0.33%) were considered overtreated in retrospect (2 cholecystectomies, 1 partial nephrectomy, all laparoscopic). One patient had a postoperative complication treated successfully.

Conclusion

Extrapancreatic incidental findings are commonly detected in patients undergoing pancreatic surveillance, but few signify serious pathology. Almost all interventions for incidental findings were for cancerous and precancerous lesions, with few instances of unnecessary interventions.

癌症筛查试验有可能发现癌症和癌前病变，但令人担忧的是，筛查检测到的偶然发现可能导致不必要的、潜在有害的干预。本研究的目的是确定需要治疗的胰腺外偶然发现的发生率，包括癌症、癌前病变和其他对家族性或遗传性胰腺癌风险进行胰腺监测的诊断性发现。方法：我们回顾了1998年至2023年在约翰霍普金斯医院参加胰腺癌筛查研究的925例患者的胰腺监测记录，这些患者至少接受过一次胰腺监测试验。需要诊断评估和/或治疗的重要胰腺外偶然发现被制成表格，包括由此产生的诊断测试、治疗干预和并发症。结果入组时患者的平均年龄/标准差为58.0/10.4岁；59.7%为女性)，220例（23.8%）接受了基线监测，705例（76.2%）接受了中位4年的监测。68例（7.3%）患者中发现75例胰腺外偶然发现，包括10例癌症，其中80%为I期，8例（0.86%）为癌前病变。13例患者接受了手术（n = 13）、内镜（n = 9）或化疗（n = 4）。25例（2.7%）患者被推荐接受监测（20例为非发育不良的Barrett食管）。3例（0.33%）患者被认为是过度治疗（2例胆囊切除术，1例肾部分切除术，均为腹腔镜）。1例患者术后并发症得到成功治疗。结论胰腺外意外发现在胰腺监测患者中很常见，但很少有严重的病理表现。几乎所有偶然发现的干预都是针对癌症和癌前病变，很少有不必要的干预。

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引用次数: 0

Cysteine Restriction Induces Ferroptosis Depending on the S-adenosylmethionine and Polyamine Biosynthetic Pathways in Hepatic Cancer Cells 半胱氨酸限制诱导肝癌细胞s -腺苷甲硫氨酸和多胺生物合成途径的铁下垂

Gastro hep advances

Pub Date : 2025-09-24 DOI: 10.1016/j.gastha.2025.100817

Keisuke Tada , Kazuki Mitsuyama , Hironari Nishizawa , Hiroki Shima , Akihiko Muto , Motoshi Wada , Daisuke Saigusa , Kazuhiko Igarashi

Background and Aims

Liver diseases such as hepatocellular carcinoma are known to be affected by nutrition and metabolic activities, but the mechanisms behind them remain unclear. We aimed to reveal the relationship between the concentration of sulfur-containing amino acids and hepatocellular response, and further investigated the mechanism focusing on methionine adenosyltransferase, which plays the central role in methionine metabolism by synthesizing S-adenosylmethionine (SAM).

Methods

Mouse hepatoma Hepa1 cells were cultured in media with reduced amounts of cysteine, methionine, or both. Cell death was monitored using propidium iodide and annexin V staining followed by flow cytometry. Metabolites were measured by mass spectrometry. Inhibitors of ferroptosis (Fer-1), necroptosis (GSK872), SAM synthesis (cycloleucine), or polyamine synthesis (sardomozide and difluoromethylornithine) were used.

Results

Cysteine restriction induced marked cell death, whereas simultaneous restriction of cysteine and methionine fully suppressed the cell death. Cysteine restriction-induced cell death was suppressed with Fer-1 and GSK872, suggesting the involvement of ferroptosis in this process. Cysteine restriction decreased reduced glutathione, which was rescued by simultaneous restriction of cysteine and methionine. Cysteine restriction-induced cell death was also suppressed by knockdown of MAT2A or its inhibitor cycloleucine. Furthermore, inhibitors of several enzymes in the polyamine biosynthetic pathway also suppressed the cell death. In contrast, primary culture of mouse hepatocytes did not show cell death upon cysteine restriction.

Conclusion

These results suggest that cysteine-glutathione and SAM-polyamine metabolic pathways are critical modulators of ferroptosis of hepatic cancer cells. Since normal liver cells were more resistant to ferroptosis than cancer cells, cysteine restriction may be exploited in treating hepatic cancer by inducing ferroptosis specifically in cancer cells without affecting normal cells in the liver.

背景和目的肝细胞癌等肝脏疾病已知受营养和代谢活动的影响，但其背后的机制尚不清楚。我们旨在揭示含硫氨基酸浓度与肝细胞反应之间的关系，并进一步研究其机制，重点关注蛋氨酸腺苷转移酶，该酶通过合成s -腺苷蛋氨酸（SAM）在蛋氨酸代谢中起核心作用。方法小鼠肝癌Hepa1细胞在半胱氨酸、蛋氨酸或两种培养基中培养。采用碘化丙啶和膜联蛋白V染色，流式细胞术监测细胞死亡情况。用质谱法测定代谢物。使用铁下垂（fe -1）、坏死性下垂（GSK872）、SAM合成（环油氨酸）或多胺合成（sardomozide和二氟甲基鸟氨酸）抑制剂。结果限制半胱氨酸可诱导细胞明显死亡，同时限制半胱氨酸和蛋氨酸可完全抑制细胞死亡。fe -1和GSK872抑制了半胱氨酸限制诱导的细胞死亡，提示铁下垂参与了这一过程。半胱氨酸限制减少还原性谷胱甘肽，通过同时限制半胱氨酸和蛋氨酸来挽救还原性谷胱甘肽。半胱氨酸限制诱导的细胞死亡也可以通过敲低MAT2A或其抑制剂环亮氨酸来抑制。此外，多胺生物合成途径中几种酶的抑制剂也抑制了细胞死亡。相比之下，原代培养的小鼠肝细胞在半胱氨酸限制下没有出现细胞死亡。结论半胱氨酸-谷胱甘肽和sam -多胺代谢途径是肝癌细胞铁下垂的重要调节因子。由于正常肝细胞比癌细胞对铁下垂的抵抗力更强，半胱氨酸限制可以通过在癌细胞中特异性诱导铁下垂而不影响肝脏中的正常细胞来治疗肝癌。

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引用次数: 0

Novel Digital Symptom Scores for Use in Gastroduodenal Disorder Testing Align With Rome IV Criteria 用于胃十二指肠疾病检测的新型数字症状评分符合罗马IV标准

Gastro hep advances

Pub Date : 2025-09-24 DOI: 10.1016/j.gastha.2025.100815

Armen A. Gharibans , I-Hsuan Huang , Gabriel Schamberg , Nicky Dachs , Jan Tack , Greg O’Grady

引用次数: 0

Differences in Clinical Presentation and Treatment Response of Patients With Eosinophilic Esophagitis Complicated by Esophageal Food Impaction 嗜酸性粒细胞性食管炎合并食管食物嵌塞的临床表现及治疗效果差异

Gastro hep advances

Pub Date : 2025-09-23 DOI: 10.1016/j.gastha.2025.100816

Walker D. Redd , Trevor S. Barlowe , Sean S. LaFata , Timothy S. Gee , Hannah L. Thel , Brenderia A. Cameron , Angela Z. Xue , Akshatha Kiran , Adolfo A. Ocampo , Justin McCallen , Christopher J. Lee , Stephanie A. Borinsky , Rayan N. Kaakati , Cary C. Cotton , Swathi Eluri , Craig C. Reed , Evan S. Dellon

引用次数: 0

Submit to Pearls From the Pros 提交给专业人士的珍珠

Gastro hep advances

Pub Date : 2025-09-22 DOI: 10.1016/j.gastha.2025.100813

David A. Katzka, Vinod K. Rustgi, Shanthi Srinivasan

引用次数: 0

Cholate Clearance: Improving the Assessment of Liver Health Compared to Current Liver Tests 与目前的肝脏检查相比，胆酸清除：改善肝脏健康评估

Gastro hep advances

Pub Date : 2025-09-18 DOI: 10.1016/j.gastha.2025.100814

James R. Burton Jr., Edward Mena, Bhaktasharan Patel

引用次数: 0

Changes on Nailfold Video Capillaroscopy Associate With High-Resolution Esophageal Manometry Findings in Patients With Scleroderma 硬皮病患者甲襞视频毛细血管镜变化与高分辨率食管压力测量结果相关

Gastro hep advances

Pub Date : 2025-09-18 DOI: 10.1016/j.gastha.2025.100811

Tian Li , Sehreen Mumtaz , Florentina Berianu , Kenneth R. Devault , Dawn L. Francis , Andree H. Koop

引用次数: 0

Outcome-Specific Cardiovascular and Hypertensive Risk Profiles in Metabolic Dysfunction-Associated Steatotic Liver Disease: Insights From a Competing Risk Cohort Analysis 代谢功能障碍相关脂肪变性肝病的结果特异性心血管和高血压风险概况：来自竞争风险队列分析的见解

Gastro hep advances

Pub Date : 2025-09-16 DOI: 10.1016/j.gastha.2025.100806

Masashi Hirooka , Teruki Miyake , Ryo Yano , Yoshiko Nakamura , Yuki Okazaki , Toyoki Shimamoto , Atsushi Yukimoto , Yasunori Yamamoto , Takao Watanabe , Osamu Yoshida , Kana Hirooka , Yoshio Tokumoto , Masanori Abe , Takeru Iwata , Yoichi Hiasa

Background and Aims

Metabolic dysfunction–associated steatotic liver disease (MASLD) is a cardiovascular risk factor affecting one in four adults globally. However, it remains unclear whether MASLD uniformly elevates risk across cardiometabolic outcomes. We investigated the outcome-specific associations of MASLD, incident cardiovascular disease (CVD), and hypertension (HTN) in a large Asian cohort.

Methods

We analyzed 24,384 adults (median age 51.4 years; 51.2% women) enrolled in a retrospective Japanese health-screening program (2007–2022). MASLD was diagnosed based on the criteria of ultrasonography-confirmed hepatic steatosis and metabolic dysfunction. Primary outcomes were major adverse cardiovascular events and new-onset arterial HTN. We applied time-dependent Cox regression, multistate modeling, and Fine-Gray competing risk analysis over 127,419 person-years (median follow-up: 5.2 years).

Results

Baseline MASLD prevalence was 23.8%. MASLD significantly increased the risk of CVD (adjusted hazard ratio: 1.83; 95% confidence interval: 1.63–2.07; P < .001), with a dose-dependent effect and stronger associations in younger adults. In contrast, MASLD was not associated with incident arterial HTN (hazard ratio: 1.02; 95% confidence interval: 0.95–1.09; P = .634). Competing risk analysis confirmed this divergence (interaction P < .001). MASLD accounted for 17.0% of all CVD events (population-attributable risk). Multistate models showed that MASLD preferentially progressed to CVD rather than HTN.

Conclusion

MASLD substantially increased cardiovascular risk but showed minimal association with HTN. These findings challenge the assumption of a uniform cardiometabolic risk in MASLD and underscore the need for outcome-specific risk stratification and targeted CVD prevention in patients with MASLD.

背景和目的代谢功能障碍相关脂肪变性肝病（MASLD）是影响全球四分之一成年人的心血管危险因素。然而，目前尚不清楚MASLD是否会统一地提高心脏代谢结果的风险。我们在一个大型亚洲队列中研究了MASLD、心血管疾病（CVD）和高血压（HTN）的结果特异性关联。方法：我们分析了2007-2022年日本回顾性健康筛查项目的24384名成年人（中位年龄51.4岁，51.2%为女性）。MASLD的诊断是基于超声确诊的肝脂肪变性和代谢功能障碍的标准。主要结局是主要不良心血管事件和新发动脉HTN。我们对127,419人年（中位随访时间：5.2年）进行了时间相关的Cox回归、多状态建模和Fine-Gray竞争风险分析。结果基线MASLD患病率为23.8%。MASLD显著增加CVD的风险（校正风险比：1.83；95%可信区间：1.63-2.07;P < .001），具有剂量依赖效应，且在年轻人中相关性更强。相反，MASLD与动脉HTN无关（风险比：1.02；95%可信区间：0.95-1.09;P = 0.634）。竞争风险分析证实了这种差异（相互作用P <； .001）。MASLD占所有CVD事件（人群归因风险）的17.0%。多状态模型显示MASLD优先发展为CVD而非HTN。结论masld显著增加心血管风险，但与HTN的相关性很小。这些发现挑战了MASLD中统一的心脏代谢风险的假设，并强调了对MASLD患者进行结果特异性风险分层和靶向CVD预防的必要性。

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引用次数: 0

Once-Daily Oral Ozanimod for Japanese Patients With Ulcerative Colitis: Results From the Phase 2/3 J-True North Study 日本溃疡性结肠炎患者每日一次口服Ozanimod：来自J-True North 2/3期研究的结果

Gastro hep advances

Pub Date : 2025-09-16 DOI: 10.1016/j.gastha.2025.100812

Hiroshi Nakase , Toshimitsu Fujii , Tadakazu Hisamatsu , Yasuo Suzuki , Mamoru Watanabe , Sakuma Takahashi , Makoto Ooi , Ken Takeuchi , Tsuguhiro Kimura , Ken Furuya , Nobuo Aoyama , Kenkei Hasatani , Noriyuki Horiki , Kazunari Kanke , Satoki Tokito , Souken Sai , Yoko Uchikawa , Shoichiro Goto , Go Fujimoto , Changliang Zhang , Toshifumi Hibi

Background and Aims

Ozanimod is a once-daily, oral, selective sphingosine 1-phosphate receptor 1 and 5 modulator. The objective of the randomized, phase 2/3 J-True North study (NCT03915769) was to assess the efficacy and safety of ozanimod in Japanese patients with moderately to severely active ulcerative colitis.

Methods

In the 12-week induction period (IP), patients were randomized 1:1:1 to receive placebo, ozanimod 0.46 mg, or ozanimod 0.92 mg. Patients who completed the IP with a clinical response at week (w) 12 were eligible to enter a 40-week maintenance period where they received the same treatment as they did in the IP. The primary endpoint was clinical response (complete Mayo score) at w12; clinical and mucosal secondary endpoints were assessed at w12 and w52.

Results

Of 198 patients randomized, 176 completed the IP. Of these patients, 97 entered and 77 completed the maintenance period. A significantly higher proportion of patients receiving ozanimod achieved clinical response at w12 versus placebo (ozanimod 0.46 mg: 52.9%, P = .0158; ozanimod 0.92 mg: 61.5%, P = .0006; vs placebo: 32.3%). Similar results were observed in the secondary endpoints where patients receiving ozanimod achieved higher rates of clinical remission, endoscopic improvement, and mucosal healing at w12 than those receiving placebo. Efficacy was maintained at w52 for all endpoints. Both doses of ozanimod were well tolerated, with no unexpected safety signals.

Conclusion

This large-scale clinical trial demonstrated the efficacy and safety of once-daily oral ozanimod in Japanese patients with moderately to severely active ulcerative colitis. This is the first time that the efficacy and safety of ozanimod were verified in a large number of patients in Asia.

背景和AimsOzanimod是一种每日一次，口服，选择性鞘氨醇1-磷酸受体1和5调节剂。这项随机2/3期J-True North研究（NCT03915769）的目的是评估ozanimod对日本中度至重度活动性溃疡性结肠炎患者的疗效和安全性。方法在12周诱导期（IP）中，将患者按1:1:1随机分为安慰剂组、ozanimod 0.46 mg组和ozanimod 0.92 mg组。在第12周完成IP并有临床反应的患者有资格进入为期40周的维持期，在此期间他们接受与IP相同的治疗。主要终点是w12时的临床反应（完全梅奥评分）；临床和粘膜次要终点在w12和w52时进行评估。结果198例患者中，176例完成了IP治疗。其中97例进入维持期，77例完成维持期。与安慰剂相比，接受ozanimod治疗的患者在w12时获得临床缓解的比例明显更高（ozanimod 0.46 mg: 52.9%, P = 0.0158; ozanimod 0.92 mg: 61.5%, P = 0.0006；相比安慰剂：32.3%）。在次要终点观察到类似的结果，接受ozanimod的患者在w12时获得更高的临床缓解率、内窥镜改善率和粘膜愈合率。所有终点的疗效维持在w52。两种剂量的ozanimod耐受性良好，没有意外的安全信号。结论：这项大规模临床试验证实了每日一次口服ozanimod治疗日本中重度活动性溃疡性结肠炎患者的有效性和安全性。这是ozanimod在亚洲首次在大量患者中得到有效性和安全性的验证。

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引用次数: 0

Whole Exome Sequencing in Children With Autoimmune Hepatitis Identified Mutations in Genes Involved in the mTORC1 Signaling Pathway 自身免疫性肝炎患儿的全外显子组测序鉴定了mTORC1信号通路相关基因的突变

Gastro hep advances

Pub Date : 2025-09-16 DOI: 10.1016/j.gastha.2025.100808

Léa-Philippine Gaigne , Caroline Besnard , Orianne Debeaupuis , Artem Degtiar , Duong Ho Nhat , Marie-Claude Stolzenberg , Fatou Camara , Olivier Pellé , Adrien Schvartz , Mélodie Perin , Marion ALMES , Amaria Darmellah-Remil , Emmanuel Gonzales , Antoine Gardin , Dalila Habes , Sylvie Destombe , Eleonora De Martin , Jean-Charles Duclos-Vallée , Peter D. Arkwright , Frédéric Rieux-Laucat , Aude Magerus

Background and Aims

Autoimmune hepatitis (AIH), a severe immune-mediated liver disease resulting from defective immune tolerance, was thought to be caused by monogenic predisposition with possible external triggers. The development of AIH in monogenic primary immune deficiencies prompted us to search for causative genetic defects in AIH.

Methods

Twenty-two children with AIH were included for whole exome sequencing analysis. Data were analyzed with an in-house software, combined with in silico tools and confirmed by Sanger sequencing. Mechanistic target of rapamycin (mTOR) pathway activation was assessed by phosphoS6-RP expression by fluorescence activated cells sorting.

Results

In six children with type 1 or type 2 AIH, seven rare missense candidate variants with damaging predictive scores were identified in five genes involved in the regulation of the mTOR complex 1 (mTORC1) signaling pathway (RRAGC, LAMTOR3, MTOR, TSC2, and PRKAG1). Excess of phosphorylated-S6 ribosomal protein expression both ex vivo by monocytes and in vitro by activated T cells demonstrated an abnormal activation of mTORC1 in five out of six tested patients. Persistent mTORC1 activation in starved activated T cells could be abolished by mTOR inhibitor.

Conclusion

These data showed that pediatric patients with AIH-1 or AIH-2, especially when burdened with poly-autoimmunity, may carry mutations in key partners of the mTORC1 signaling pathway. Moreover, even without identified genetic defect, we observed a deregulation of the mTOR pathway in five out of six tested patients. These results shed new light on the pathogenesis of AIH. Moreover, they suggested that the patients could benefit from specific targeted agents such as mTOR inhibitors.

背景和目的自身免疫性肝炎（AIH）是一种由免疫耐受缺陷引起的严重免疫介导的肝脏疾病，被认为是由单基因易感性和可能的外部触发因素引起的。AIH在单基因原发性免疫缺陷中的发展促使我们寻找AIH的致病遗传缺陷。方法对22例AIH患儿进行全外显子组测序分析。数据分析与内部软件，结合在硅工具和桑格测序确认。荧光活化细胞分选法检测磷酸hos6 - rp表达对雷帕霉素（mTOR）通路激活的机制靶点。结果在6例1型或2型AIH患儿中，在参与mTOR复合物1 （mTORC1）信号通路调控的5个基因（RRAGC、LAMTOR3、mTOR、TSC2和PRKAG1）中发现了7个具有破坏性预测评分的罕见错义候选变异体。体外单核细胞和体外活化的T细胞磷酸化- s6核糖体蛋白表达过量表明，6名测试患者中有5名mTORC1异常活化。mTOR抑制剂可以消除饥饿激活T细胞中mTORC1的持续激活。这些数据表明，患有AIH-1或AIH-2的儿科患者，特别是患有多重自身免疫的儿童，可能携带mTORC1信号通路的关键伙伴突变。此外，即使没有确定的遗传缺陷，我们也观察到6名测试患者中有5名mTOR通路的解除管制。这些结果对AIH的发病机制有了新的认识。此外，他们认为患者可能受益于特定的靶向药物，如mTOR抑制剂。

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