Pub Date : 2024-03-26eCollection Date: 2024-01-01DOI: 10.21037/tgh-23-97
Daniela Kerguelen Murcia, Joy S Li, Uma R Phatak
Background and objective: Ketamine offers a promising solution to common postoperative issues in abdominal surgery, including pain, nausea, opioid use, and opioid-related side effects. The purpose of this literature review is to analyze the benefits and potential adverse effects associated with the intraoperative utilization of ketamine during abdominal surgeries.
Methods: A comprehensive search of PubMed and Ovid MEDLINE was conducted by two independent reviewers. Studies were included if they targeted adult patients and evaluated intra-operative use of ketamine for abdominal operations.
Key content and findings: We identified 13 studies of intraoperative use of ketamine in abdominal surgery. The results of these studies showed improved pain management as demonstrated by lower pain scores, decreased hyperalgesia, and a decreased need for additional analgesics. The results also demonstrated a decrease in opioid consumption during the critical 24-hour postoperative period. However, a few studies reported undesirable side effects such as hallucinations and delirium.
Conclusions: The intraoperative use of ketamine holds promise as a valuable adjunct to anesthesia during abdominal surgeries. Studies support its use in improving post-operative pain and decreasing opioid consumption. Due to risks of adverse effects, further studies in larger patient populations may help identify which patients will benefit the most. This review offers a succinct selection of the pertinent literature.
{"title":"Impact of intra-operative ketamine on postoperative outcomes in abdominal surgery: a narrative review.","authors":"Daniela Kerguelen Murcia, Joy S Li, Uma R Phatak","doi":"10.21037/tgh-23-97","DOIUrl":"10.21037/tgh-23-97","url":null,"abstract":"<p><strong>Background and objective: </strong>Ketamine offers a promising solution to common postoperative issues in abdominal surgery, including pain, nausea, opioid use, and opioid-related side effects. The purpose of this literature review is to analyze the benefits and potential adverse effects associated with the intraoperative utilization of ketamine during abdominal surgeries.</p><p><strong>Methods: </strong>A comprehensive search of PubMed and Ovid MEDLINE was conducted by two independent reviewers. Studies were included if they targeted adult patients and evaluated intra-operative use of ketamine for abdominal operations.</p><p><strong>Key content and findings: </strong>We identified 13 studies of intraoperative use of ketamine in abdominal surgery. The results of these studies showed improved pain management as demonstrated by lower pain scores, decreased hyperalgesia, and a decreased need for additional analgesics. The results also demonstrated a decrease in opioid consumption during the critical 24-hour postoperative period. However, a few studies reported undesirable side effects such as hallucinations and delirium.</p><p><strong>Conclusions: </strong>The intraoperative use of ketamine holds promise as a valuable adjunct to anesthesia during abdominal surgeries. Studies support its use in improving post-operative pain and decreasing opioid consumption. Due to risks of adverse effects, further studies in larger patient populations may help identify which patients will benefit the most. This review offers a succinct selection of the pertinent literature.</p>","PeriodicalId":94362,"journal":{"name":"Translational gastroenterology and hepatology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11074488/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140878326","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-03-22eCollection Date: 2024-01-01DOI: 10.21037/tgh-23-84
Jing Xu, Zhikai Chi
Background and objective: Esophageal carcinoma with switch/sucrose nonfermenting (SWI/SNF)-related, matrix-associated, actin-dependent regulator of chromatin, subfamily A, member 4 (SMARCA4) mutation is a rare variant of malignant esophageal epithelial neoplasm, which is characterized by the loss of SMARCA4/BRG1 protein on immunohistochemistry or alterations in the SMARCA4 gene on sequencing. Only a few case series and case reports of esophageal carcinoma with SMARCA4 mutations have been published in the English literature; the rarity of the disease poses significant diagnostic challenges for surgical pathologists and could potentially lead to delayed or suboptimal patient care. Herein, we reviewed the available literature on esophageal carcinoma with SMARCA4 mutations to discuss its epidemiology, clinical presentation, pathological and molecular features, diagnostic challenges, treatment, and prognosis.
Methods: The PubMed, Scopus, Ovid, and Google Scholar databases were extensively reviewed. The references included in the articles were cross-examined to identify any missing articles. We searched for all published literature on esophageal carcinoma with SMARCA4 mutations from inception of the databases to date.
Key content and findings: Esophageal carcinoma with SMARCA4 mutations is most common in middle-aged and older men. Barrett esophagus and gastroesophageal reflux disease (GERD) are the most associated risk factors. Dysphagia was the most common initial clinical presentation. Esophagogastroduodenoscopy (EGD) is the preferred diagnostic modality. Microscopically, the tumor cells exhibited epithelioid features mixed with variable components of rhabdoid and glandular differentiation. The tumor cells showed variable immunoreactivity for cytokeratin and sometimes weakly expressed neuroendocrine or B-lymphocyte markers (Pax5), which are potential diagnostic pitfalls. Melanoma marker tests showed negative results. The SMARCB1/INI1 protein remains intact, and a definitive diagnosis necessitates the presence of either SMARCA4/BRG1 protein loss or SMARCA4 gene mutations. Esophageal carcinoma with SMARCA4 mutations shows overly aggressive behavior and presents with advanced stages of disease; most patients succumb to the disease within 1 year of initial diagnosis.
Conclusions: Esophageal carcinoma with SMARCA4 mutation is an overly aggressive disease, and further research on the affected molecular pathway may help improve its prognosis.
背景和目的:食管癌伴有开关/蔗糖不发酵(SWI/SNF)相关、基质相关、肌动蛋白依赖的染色质调节因子A亚家族成员4(SMARCA4)突变是恶性食管上皮肿瘤的一种罕见变异,其特征是免疫组化显示SMARCA4/BRG1蛋白缺失或测序显示SMARCA4基因发生改变。英文文献中仅发表了几例SMARCA4基因突变食管癌的系列病例和病例报告;这种疾病的罕见性给外科病理学家的诊断带来了巨大挑战,并可能导致患者治疗的延误或不理想。在此,我们回顾了关于SMARCA4突变食管癌的现有文献,讨论了其流行病学、临床表现、病理和分子特征、诊断挑战、治疗和预后:广泛查阅了 PubMed、Scopus、Ovid 和 Google Scholar 数据库。方法:我们广泛查阅了 PubM、Scopus、Ovid 和 Google Scholar 数据库,并交叉检查了文章中的参考文献,以确定是否有遗漏的文章。我们检索了从数据库建立至今所有关于SMARCA4突变食管癌的已发表文献:SMARCA4突变的食管癌最常见于中老年男性。巴雷特食管和胃食管反流病(GERD)是最相关的风险因素。吞咽困难是最常见的初始临床表现。食管胃十二指肠镜检查(EGD)是首选的诊断方式。显微镜下,肿瘤细胞表现为上皮样特征,并混有横纹肌样和腺体分化的不同成分。肿瘤细胞对细胞角蛋白有不同的免疫反应,有时还弱表达神经内分泌或 B 淋巴细胞标记物(Pax5),这些都是潜在的诊断陷阱。黑色素瘤标记物检测结果为阴性。SMARCB1/INI1蛋白保持完整,要明确诊断,必须存在SMARCA4/BRG1蛋白缺失或SMARCA4基因突变。SMARCA4基因突变的食管癌表现出过度的侵袭性,并出现晚期病变;大多数患者在最初诊断后一年内死亡:结论:SMARCA4基因突变的食管癌是一种侵袭性很强的疾病,进一步研究受影响的分子通路可能有助于改善其预后。
{"title":"Esophageal carcinoma with <i>SMARCA4</i> mutation: a narrative review for this rare entity.","authors":"Jing Xu, Zhikai Chi","doi":"10.21037/tgh-23-84","DOIUrl":"10.21037/tgh-23-84","url":null,"abstract":"<p><strong>Background and objective: </strong>Esophageal carcinoma with switch/sucrose nonfermenting (SWI/SNF)-related, matrix-associated, actin-dependent regulator of chromatin, subfamily A, member 4 (<i>SMARCA4</i>) mutation is a rare variant of malignant esophageal epithelial neoplasm, which is characterized by the loss of SMARCA4/BRG1 protein on immunohistochemistry or alterations in the <i>SMARCA4</i> gene on sequencing. Only a few case series and case reports of esophageal carcinoma with <i>SMARCA4</i> mutations have been published in the English literature; the rarity of the disease poses significant diagnostic challenges for surgical pathologists and could potentially lead to delayed or suboptimal patient care. Herein, we reviewed the available literature on esophageal carcinoma with <i>SMARCA4</i> mutations to discuss its epidemiology, clinical presentation, pathological and molecular features, diagnostic challenges, treatment, and prognosis.</p><p><strong>Methods: </strong>The PubMed, Scopus, Ovid, and Google Scholar databases were extensively reviewed. The references included in the articles were cross-examined to identify any missing articles. We searched for all published literature on esophageal carcinoma with <i>SMARCA4</i> mutations from inception of the databases to date.</p><p><strong>Key content and findings: </strong>Esophageal carcinoma with <i>SMARCA4</i> mutations is most common in middle-aged and older men. Barrett esophagus and gastroesophageal reflux disease (GERD) are the most associated risk factors. Dysphagia was the most common initial clinical presentation. Esophagogastroduodenoscopy (EGD) is the preferred diagnostic modality. Microscopically, the tumor cells exhibited epithelioid features mixed with variable components of rhabdoid and glandular differentiation. The tumor cells showed variable immunoreactivity for cytokeratin and sometimes weakly expressed neuroendocrine or B-lymphocyte markers (Pax5), which are potential diagnostic pitfalls. Melanoma marker tests showed negative results. The SMARCB1/INI1 protein remains intact, and a definitive diagnosis necessitates the presence of either SMARCA4/BRG1 protein loss or <i>SMARCA4</i> gene mutations. Esophageal carcinoma with <i>SMARCA4</i> mutations shows overly aggressive behavior and presents with advanced stages of disease; most patients succumb to the disease within 1 year of initial diagnosis.</p><p><strong>Conclusions: </strong>Esophageal carcinoma with <i>SMARCA4</i> mutation is an overly aggressive disease, and further research on the affected molecular pathway may help improve its prognosis.</p>","PeriodicalId":94362,"journal":{"name":"Translational gastroenterology and hepatology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11074479/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140878324","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-03-22eCollection Date: 2024-01-01DOI: 10.21037/tgh-23-93
Xinwan Wu, Yuwei Chen, Meiru Jiang, Long Guo
Background: Serine/threonine kinase 1 (PIM1) plays a crucial role in cell growth, differentiation, and apoptosis. However, its role in the pathogenesis of concanavalin A (ConA)-induced acute hepatitis is not well understood. PIM1 kinase inhibitor can reduce the expression of PIM1. This study aims to investigate the effects of PIM1 kinase inhibitor and its protective mechanism in ConA-induced acute hepatitis.
Methods: C57/BL six mice were injected with ConA (20, 15, and 12 mg/kg) to induce acute hepatitis, and PIM1 kinase inhibitor SMI-4a (60 mg/kg) was administered orally 24 h before ConA injection. The survival rate of the mice was observed after ConA injection. The levels of serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were measured. Serum inflammatory factors were detected by enzyme-linked immunosorbent assay (ELISA). Hematoxylin-eosin (HE) staining was performed on liver tissue collected at different time points. The major cytokines expression in liver tissue was detected by quantitative real-time polymerase chain reaction (qRT-PCR). The number of macrophages, T-cell and neutrophils in liver tissue were detected by flow cytometry (FCM). PIM1 in liver tissue was detected by western blot (WB) and qRT-PCR. SMI-4a (80 µM) was pretreated for 24 h and ConA (400 µg/mL) was stimulated for 12 h in RAW264.7 cell model. Phosphorylated p65 (p-p65) and cleaved caspase-3 (c-caspase-3) in liver tissue and macrophages were detected by WB.
Results: Different concentrations of ConA caused different acute hepatitis mortality, 12 mg/kg concentration within 24 h of the mortality showed a gradient increase. The levels of AST and ALT increased significantly at 12 h after ConA injection. PIM1 expression was upregulated at 12 h. SMI-4a can suppress the PIM1 expression. SMI-4a suppressed cytokines production, AST, and ALT in ConA-treated serum. SMI-4a suppressed the major cytokines in liver tissue. Tests in liver tissue showed that SMI-4a reduced the number of T cells, neutrophils, and macrophages. SMI-4a inhibited the inflammatory response by downregulating the expression of p-p65. Meanwhile, apoptosis was decreased by decreasing the expression of c-caspase-3.
Conclusions: In conclusion, the protective effect of SMI-4a against acute hepatitis is by reducing the inflammatory response and apoptosis. These findings suggest that SMI-4a may have therapeutic potential in the treatment of autoimmune hepatitis.
{"title":"PIM1 inhibitor SMI-4a attenuated concanavalin A-induced acute hepatitis through suppressing inflammatory responses.","authors":"Xinwan Wu, Yuwei Chen, Meiru Jiang, Long Guo","doi":"10.21037/tgh-23-93","DOIUrl":"10.21037/tgh-23-93","url":null,"abstract":"<p><strong>Background: </strong>Serine/threonine kinase 1 (PIM1) plays a crucial role in cell growth, differentiation, and apoptosis. However, its role in the pathogenesis of concanavalin A (ConA)-induced acute hepatitis is not well understood. PIM1 kinase inhibitor can reduce the expression of PIM1. This study aims to investigate the effects of PIM1 kinase inhibitor and its protective mechanism in ConA-induced acute hepatitis.</p><p><strong>Methods: </strong>C57/BL six mice were injected with ConA (20, 15, and 12 mg/kg) to induce acute hepatitis, and PIM1 kinase inhibitor SMI-4a (60 mg/kg) was administered orally 24 h before ConA injection. The survival rate of the mice was observed after ConA injection. The levels of serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were measured. Serum inflammatory factors were detected by enzyme-linked immunosorbent assay (ELISA). Hematoxylin-eosin (HE) staining was performed on liver tissue collected at different time points. The major cytokines expression in liver tissue was detected by quantitative real-time polymerase chain reaction (qRT-PCR). The number of macrophages, T-cell and neutrophils in liver tissue were detected by flow cytometry (FCM). PIM1 in liver tissue was detected by western blot (WB) and qRT-PCR. SMI-4a (80 µM) was pretreated for 24 h and ConA (400 µg/mL) was stimulated for 12 h in RAW264.7 cell model. Phosphorylated p65 (p-p65) and cleaved caspase-3 (c-caspase-3) in liver tissue and macrophages were detected by WB.</p><p><strong>Results: </strong>Different concentrations of ConA caused different acute hepatitis mortality, 12 mg/kg concentration within 24 h of the mortality showed a gradient increase. The levels of AST and ALT increased significantly at 12 h after ConA injection. PIM1 expression was upregulated at 12 h. SMI-4a can suppress the PIM1 expression. SMI-4a suppressed cytokines production, AST, and ALT in ConA-treated serum. SMI-4a suppressed the major cytokines in liver tissue. Tests in liver tissue showed that SMI-4a reduced the number of T cells, neutrophils, and macrophages. SMI-4a inhibited the inflammatory response by downregulating the expression of p-p65. Meanwhile, apoptosis was decreased by decreasing the expression of c-caspase-3.</p><p><strong>Conclusions: </strong>In conclusion, the protective effect of SMI-4a against acute hepatitis is by reducing the inflammatory response and apoptosis. These findings suggest that SMI-4a may have therapeutic potential in the treatment of autoimmune hepatitis.</p>","PeriodicalId":94362,"journal":{"name":"Translational gastroenterology and hepatology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11074483/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140878359","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-03-21eCollection Date: 2024-01-01DOI: 10.21037/tgh-23-96
Bhavana Tetali, Suraj Suresh
Background and objective: As our understanding of the pathophysiology of irritable bowel syndrome (IBS) has advanced, so too has the therapeutic landscape, offering a myriad of approaches to alleviate symptoms and enhance the well-being of patients. This review paper is dedicated to a comprehensive exploration of the diverse therapeutic modalities available for managing IBS. By delving into the complexities of IBS therapeutics, our aim is to contribute to the enhancement of patient care and the overall quality of life for patients grappling with this complex condition.
Methods: This review utilized information from PubMed/MEDLINE using the key search term "irritable bowel syndrome" as well as the 2020 American College of Gastroenterology (ACG) and 2022 American Gastroenterological Association (AGA) society guidelines on IBS. The search was restricted to articles in the English language only and included peer-reviewed observational studies and randomized controlled trials (RCTs) in adult patients from April 22, 2020 to October 16, 2023.
Key content and findings: This review will start with an overview of the current guidelines for pharmacologic therapies for IBS as recommended by the ACG and the AGA, with an emphasis on clinical trials published after the most recent guidelines. It will then delve into the literature on dietary modifications, probiotics, fecal microbiota transplant, behavioral therapy, and complementary and alternative medicine approaches to IBS.
Conclusions: It is evident that the management of IBS has transcended a one-size-fits-all approach. As the field of IBS management continues to evolve, it is imperative for physicians to stay informed and receptive to the array of therapeutic options available, ultimately providing patients with the most effective and personalized care.
{"title":"Management of irritable bowel syndrome: a narrative review.","authors":"Bhavana Tetali, Suraj Suresh","doi":"10.21037/tgh-23-96","DOIUrl":"10.21037/tgh-23-96","url":null,"abstract":"<p><strong>Background and objective: </strong>As our understanding of the pathophysiology of irritable bowel syndrome (IBS) has advanced, so too has the therapeutic landscape, offering a myriad of approaches to alleviate symptoms and enhance the well-being of patients. This review paper is dedicated to a comprehensive exploration of the diverse therapeutic modalities available for managing IBS. By delving into the complexities of IBS therapeutics, our aim is to contribute to the enhancement of patient care and the overall quality of life for patients grappling with this complex condition.</p><p><strong>Methods: </strong>This review utilized information from PubMed/MEDLINE using the key search term \"irritable bowel syndrome\" as well as the 2020 American College of Gastroenterology (ACG) and 2022 American Gastroenterological Association (AGA) society guidelines on IBS. The search was restricted to articles in the English language only and included peer-reviewed observational studies and randomized controlled trials (RCTs) in adult patients from April 22, 2020 to October 16, 2023.</p><p><strong>Key content and findings: </strong>This review will start with an overview of the current guidelines for pharmacologic therapies for IBS as recommended by the ACG and the AGA, with an emphasis on clinical trials published after the most recent guidelines. It will then delve into the literature on dietary modifications, probiotics, fecal microbiota transplant, behavioral therapy, and complementary and alternative medicine approaches to IBS.</p><p><strong>Conclusions: </strong>It is evident that the management of IBS has transcended a one-size-fits-all approach. As the field of IBS management continues to evolve, it is imperative for physicians to stay informed and receptive to the array of therapeutic options available, ultimately providing patients with the most effective and personalized care.</p>","PeriodicalId":94362,"journal":{"name":"Translational gastroenterology and hepatology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11074491/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140878328","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Background and objective: As tumors invade major abdominal veins, surgical procedures are transformed from simple and basic to complicated and challenging. In this narrative review, we focus on what is currently known and not known regarding the technical aspects of major abdominal venous resection and its reconstruction, patency, and oncologic benefit in a cross-cutting perspective.
Methods: A systematic literature search was performed in PubMed and Semantic Scholar from inception up to October 18, 2023. We reviewed 106 papers by title, abstract, and full text regarding resection or reconstruction of the inferior vena cava, hepatic vein confluence, portal vein (PV), and middle hepatic vein (MHV) tributaries in living donor liver transplantation (LDLT) in a cross-cutting perspective.
Key content and findings: The oncologic benefit of aggressive hepatic vein resection with suitable reconstruction against adenocarcinoma remains unclear, and further studies are required to clarify this point. A superior mesenteric/PV resection is now a universal, indispensable, and effective procedure for pancreatic ductal adenocarcinoma. Although many case series using tailor-made autologous venous grafts have been reported, not only size mismatch but also additional surgical incisions and a longer operation time remain obstacles for venous reconstruction. The use of autologous alternative tissue remains only an alternative procedure because the patency rate of customized tubular conduit type to interpose or replace the resected vein is not known. Unlike arterial replacement, venous replacement using synthetic vascular grafts is still rarely reported and there are several inherent limitations except for reconstruction of tributaries of MHV in LDLT.
Conclusions: Various approaches to abdominal vein resection and replacement or reconstruction are technically feasible with satisfactory results. Synthetic vascular grafts may be appropriate but have a certain rate of complications.
{"title":"Resection and reconstruction of the largest abdominal vein system (the inferior vena cava, hepatic, and portal vein): a narrative review.","authors":"Junichi Kaneko, Yoshihiro Hayashi, Yusuke Kazami, Yujiro Nishioka, Akinori Miyata, Akihiko Ichida, Yoshikuni Kawaguchi, Nobuhisa Akamatsu, Kiyoshi Hasegawa","doi":"10.21037/tgh-23-90","DOIUrl":"10.21037/tgh-23-90","url":null,"abstract":"<p><strong>Background and objective: </strong>As tumors invade major abdominal veins, surgical procedures are transformed from simple and basic to complicated and challenging. In this narrative review, we focus on what is currently known and not known regarding the technical aspects of major abdominal venous resection and its reconstruction, patency, and oncologic benefit in a cross-cutting perspective.</p><p><strong>Methods: </strong>A systematic literature search was performed in PubMed and Semantic Scholar from inception up to October 18, 2023. We reviewed 106 papers by title, abstract, and full text regarding resection or reconstruction of the inferior vena cava, hepatic vein confluence, portal vein (PV), and middle hepatic vein (MHV) tributaries in living donor liver transplantation (LDLT) in a cross-cutting perspective.</p><p><strong>Key content and findings: </strong>The oncologic benefit of aggressive hepatic vein resection with suitable reconstruction against adenocarcinoma remains unclear, and further studies are required to clarify this point. A superior mesenteric/PV resection is now a universal, indispensable, and effective procedure for pancreatic ductal adenocarcinoma. Although many case series using tailor-made autologous venous grafts have been reported, not only size mismatch but also additional surgical incisions and a longer operation time remain obstacles for venous reconstruction. The use of autologous alternative tissue remains only an alternative procedure because the patency rate of customized tubular conduit type to interpose or replace the resected vein is not known. Unlike arterial replacement, venous replacement using synthetic vascular grafts is still rarely reported and there are several inherent limitations except for reconstruction of tributaries of MHV in LDLT.</p><p><strong>Conclusions: </strong>Various approaches to abdominal vein resection and replacement or reconstruction are technically feasible with satisfactory results. Synthetic vascular grafts may be appropriate but have a certain rate of complications.</p>","PeriodicalId":94362,"journal":{"name":"Translational gastroenterology and hepatology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11074493/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140878361","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-03-15eCollection Date: 2024-01-01DOI: 10.21037/tgh-23-69
Khaldoun Almhanna, Rimini Breakstone, Alexander Raufi, Roxanne Wood, Amy Webber, Sopha Dionson, Lindsay Cavanagh, Attila A Seyhan, Howard Safran, Wafik El-Deiry
Background: Immune checkpoint inhibitors alone, or in combination with chemotherapy failed to provide meaningful clinical activity for patients with microsatellite stable (MSS) colorectal cancer (CRC). ONC201 is a small molecule that inactivates AKT and ERK signaling and actives the TRAIL pathway. Preclinical studies indicated potential benefits of combining ONC201 with checkpoint inhibitors. This is a phase Ib/II trial of ONC201 plus nivolumab for patient with MSS CRC who progressed on standard treatment.
Methods: Enrolled patients received ONC201 plus nivolumab in a dose de-escalation fashion to determine the maximum tolerated dose (MTD). Additional patients were enrolled in the dose-expansion cohort. ONC201 at a dose of 625 mg was given orally at day -7 of cycle 1, followed by weekly dosing. Nivolumab was given every 2 weeks at 240 mg IV starting on day 1 of every cycle (cycle =28 days). The primary end point was dose-limiting toxicity (DLT) during the observation window (run-in dose day -7, cycle 1 to assessment pre-dosing cycle 2). The plan was to enroll 28 additional patients at the MTD so that a total of 34 patients would be treated at the MTD. Pharmacokinetics (PKs) and tumor biopsies were collected at several time points per study protocol.
Results: A total of 13 patients (8 patients in the dose escalation *6 evaluable*) were enrolled between December 4, 2019 and March 2021. All patients had received ≥2 previous lines of chemotherapy and had confirmed microsatellite stability or mismatch repair-proficient tumors. No DLTs were observed with 625 mg ONC201 in the first three patients. Three additional patients were enrolled at the same dose to confirm safety. Two patients progressed during the DLT period and had to be replaced. During the dose-expansion part, five patients were enrolled and none required dose reduction or modification. No objective tumor response was observed in the 13 treated patients. Disease progression was confirmed at the time of the first imaging evaluation at 8 weeks following cycle 2. Post discussion at the Data and Safety Monitoring Board (DSMB) on May 25, 2021, the principal investigator (PI) and Committee voted to close the study to new patient enrollment prior to reaching accrual of 34 patients, secondary to lack of efficacy.
Conclusions: In this study of patients with advanced MSS CRC, combination ONC201/nivolumab was well-tolerated; objective responses to ONC201/nivolumab were not observed.
{"title":"Nivolumab plus ONC201 plus in microsatellite stable (MSS) metastatic colorectal cancer (mCRC) patients: a Brown University Oncology Research Group phase Ib/II study (BrUOG379).","authors":"Khaldoun Almhanna, Rimini Breakstone, Alexander Raufi, Roxanne Wood, Amy Webber, Sopha Dionson, Lindsay Cavanagh, Attila A Seyhan, Howard Safran, Wafik El-Deiry","doi":"10.21037/tgh-23-69","DOIUrl":"10.21037/tgh-23-69","url":null,"abstract":"<p><strong>Background: </strong>Immune checkpoint inhibitors alone, or in combination with chemotherapy failed to provide meaningful clinical activity for patients with microsatellite stable (MSS) colorectal cancer (CRC). ONC201 is a small molecule that inactivates AKT and ERK signaling and actives the TRAIL pathway. Preclinical studies indicated potential benefits of combining ONC201 with checkpoint inhibitors. This is a phase Ib/II trial of ONC201 plus nivolumab for patient with MSS CRC who progressed on standard treatment.</p><p><strong>Methods: </strong>Enrolled patients received ONC201 plus nivolumab in a dose de-escalation fashion to determine the maximum tolerated dose (MTD). Additional patients were enrolled in the dose-expansion cohort. ONC201 at a dose of 625 mg was given orally at day -7 of cycle 1, followed by weekly dosing. Nivolumab was given every 2 weeks at 240 mg IV starting on day 1 of every cycle (cycle =28 days). The primary end point was dose-limiting toxicity (DLT) during the observation window (run-in dose day -7, cycle 1 to assessment pre-dosing cycle 2). The plan was to enroll 28 additional patients at the MTD so that a total of 34 patients would be treated at the MTD. Pharmacokinetics (PKs) and tumor biopsies were collected at several time points per study protocol.</p><p><strong>Results: </strong>A total of 13 patients (8 patients in the dose escalation *6 evaluable*) were enrolled between December 4, 2019 and March 2021. All patients had received ≥2 previous lines of chemotherapy and had confirmed microsatellite stability or mismatch repair-proficient tumors. No DLTs were observed with 625 mg ONC201 in the first three patients. Three additional patients were enrolled at the same dose to confirm safety. Two patients progressed during the DLT period and had to be replaced. During the dose-expansion part, five patients were enrolled and none required dose reduction or modification. No objective tumor response was observed in the 13 treated patients. Disease progression was confirmed at the time of the first imaging evaluation at 8 weeks following cycle 2. Post discussion at the Data and Safety Monitoring Board (DSMB) on May 25, 2021, the principal investigator (PI) and Committee voted to close the study to new patient enrollment prior to reaching accrual of 34 patients, secondary to lack of efficacy.</p><p><strong>Conclusions: </strong>In this study of patients with advanced MSS CRC, combination ONC201/nivolumab was well-tolerated; objective responses to ONC201/nivolumab were not observed.</p>","PeriodicalId":94362,"journal":{"name":"Translational gastroenterology and hepatology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11074474/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140878358","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-03-15eCollection Date: 2024-01-01DOI: 10.21037/tgh-23-104
Calvin Q Pan, James S Park
{"title":"Revamping hepatitis C global eradication efforts: towards simplified and enhanced screening, prevention, and treatment.","authors":"Calvin Q Pan, James S Park","doi":"10.21037/tgh-23-104","DOIUrl":"10.21037/tgh-23-104","url":null,"abstract":"","PeriodicalId":94362,"journal":{"name":"Translational gastroenterology and hepatology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11074485/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140878362","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-03-15eCollection Date: 2024-01-01DOI: 10.21037/tgh-23-62
Jasleen Singh, Brittney Ibrahim, Nicholas J Jackson, Haydar Khalil, Julia Valenzuela, Beshoy Yanny, Sammy Saab
Background: Non-invasive tests (NITs) can be used to estimate the severity of fibrosis in patients with nonalcoholic fatty liver disease (NAFLD) but their diagnostic accuracy is variable. Hispanic patients are at increased risk of NAFLD and diabetes. We evaluate the diagnostic performance of the fibrosis index based on 4 factors (FIB-4) in a population of Hispanic patients who underwent vibration-controlled transient elastography (VCTE).
Methods: A total of 1,524 patients underwent VCTE at University of California, Los Angeles from July 18, 2019 to June 7, 2022. Ultimately 110 patients were identified as Hispanic, with confirmed NAFLD. Sensitivity, specificity, positive predictive value and negative predictive value of FIB-4 threshold ≥1.3 were calculated. Logistic regression models were used to determine updated thresholds for patients with and without diabetes based on Youden's index.
Results: Of the 110 patients, the majority (65%) were female. Prevalence of diabetes was higher in the group with clinically significant fibrosis (76% vs. 36%, P<0.001). Using a FIB-4 threshold ≥1.3 to predict clinically significant fibrosis (F2-F4 on VCTE), area under the receiver operating characteristic (AUROC) was 0.74. By incorporating diabetes status, AUROC was 0.81 when employing a FIB-4 threshold of ≥1.0 in patients with diabetes and ≥1.5 in patients without diabetes.
Conclusions: Using a FIB-4 threshold of ≥1.0 in patients with diabetes and ≥1.5 in patients without diabetes improves the diagnostic performance of the test. The new FIB-4 including diabetes status will lead to improved screening in patients who are at risk of clinically significant fibrosis.
{"title":"Lower FIB-4 threshold in patients with diabetes improves diagnostic accuracy of the test in a Hispanic population.","authors":"Jasleen Singh, Brittney Ibrahim, Nicholas J Jackson, Haydar Khalil, Julia Valenzuela, Beshoy Yanny, Sammy Saab","doi":"10.21037/tgh-23-62","DOIUrl":"10.21037/tgh-23-62","url":null,"abstract":"<p><strong>Background: </strong>Non-invasive tests (NITs) can be used to estimate the severity of fibrosis in patients with nonalcoholic fatty liver disease (NAFLD) but their diagnostic accuracy is variable. Hispanic patients are at increased risk of NAFLD and diabetes. We evaluate the diagnostic performance of the fibrosis index based on 4 factors (FIB-4) in a population of Hispanic patients who underwent vibration-controlled transient elastography (VCTE).</p><p><strong>Methods: </strong>A total of 1,524 patients underwent VCTE at University of California, Los Angeles from July 18, 2019 to June 7, 2022. Ultimately 110 patients were identified as Hispanic, with confirmed NAFLD. Sensitivity, specificity, positive predictive value and negative predictive value of FIB-4 threshold ≥1.3 were calculated. Logistic regression models were used to determine updated thresholds for patients with and without diabetes based on Youden's index.</p><p><strong>Results: </strong>Of the 110 patients, the majority (65%) were female. Prevalence of diabetes was higher in the group with clinically significant fibrosis (76% <i>vs.</i> 36%, P<0.001). Using a FIB-4 threshold ≥1.3 to predict clinically significant fibrosis (F2-F4 on VCTE), area under the receiver operating characteristic (AUROC) was 0.74. By incorporating diabetes status, AUROC was 0.81 when employing a FIB-4 threshold of ≥1.0 in patients with diabetes and ≥1.5 in patients without diabetes.</p><p><strong>Conclusions: </strong>Using a FIB-4 threshold of ≥1.0 in patients with diabetes and ≥1.5 in patients without diabetes improves the diagnostic performance of the test. The new FIB-4 including diabetes status will lead to improved screening in patients who are at risk of clinically significant fibrosis.</p>","PeriodicalId":94362,"journal":{"name":"Translational gastroenterology and hepatology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11074489/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140878327","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-02-04eCollection Date: 2024-01-01DOI: 10.21037/tgh-23-21
Zhi-Hui Chen, Ying-Ying Tang, Si-Yuan Sheng, Chuan-Gang Lu, Kai-Wu Xu, Guan-Jun Chen, Yan-Feng Wang, Yong Gu, Xin-Ming Song, Hai Hong
Background: Crohn's disease (CD) is a chronic inflammatory bowel disease with significant morbidity, affecting millions worldwide. The intricacies of immune responses in CD, especially post-treatment, remain a vital area of exploration. While memory T (Tm)-cell subsets play a pivotal role in adaptive immunity, their specific function in patients with CD after treatment is not well-understood. This study aims to investigate the effect and function of Tm-cell subsets in these patients, addressing a crucial knowledge gap in the context of CD therapeutics.
Methods: A total of eight patients diagnosed with CD were selected based on predefined inclusion criteria. All patients were treated with either anti-inflammatory agents, immunosuppressive drugs, or a combination of both. For comparison, healthy donors were enrolled based on exclusion of autoimmune or inflammatory diseases. Peripheral blood mononuclear cells (PBMCs) and lymphocytes were isolated from blood and lymph node tissue respectively. The phenotype and cytokine production of T lymphocytes from both CD patients and healthy donors were analyzed using flow cytometry. Statistical comparisons of the outcomes between CD patients and healthy donors were made using Mann-Whitney test (two-tailed) and Student t-test.
Results: Post-treatment CD patients exhibited an altered T cell distribution with a notable increase in CD8+ T cells in PBMCs (P=0.0005), and altered frequencies of CD4+ and CD8+ T cells in mesenteric lymph nodes (MLNs). Tm cells showed decreased interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α) production, with significant alterations in the frequency of IFN-γ-producing CD8+ stem cell-like Tm (Tscm) cells in lesions of the MLNs from patients with CD (CD-M-Lys) compared to healthy MLNs from patients with CD (N-M-Lys) (P=0.0152). Differences in tissue-resident Tm (Trm)-cell subset frequencies were observed between the MLNs and small intestinal mucosa in CD patients.
Conclusions: The treatments with anti-inflammatory agents and/or immunosuppressive drugs have a significant effect on the frequency and function of Tm-cell subsets. Clinically, these findings suggest a potential therapeutic avenue in modulating Tm-cell responses, which might be particularly beneficial for conditions where immune response modulation is crucial. Further clinical studies are warranted to explore the full therapeutic implications of these findings.
背景:克罗恩病(Crohn's disease,CD)是一种慢性炎症性肠病,发病率很高,影响着全球数百万人。克罗恩病中错综复杂的免疫反应,尤其是治疗后的免疫反应,仍然是一个重要的探索领域。虽然记忆 T(Tm)细胞亚群在适应性免疫中起着举足轻重的作用,但它们在 CD 患者治疗后的具体功能尚不十分清楚。本研究旨在调查 Tm 细胞亚群在这些患者中的作用和功能,填补 CD 治疗方面的知识空白:方法:根据预先确定的纳入标准,共选择了八名确诊为 CD 的患者。所有患者均接受了抗炎药物、免疫抑制剂或两者的联合治疗。为了进行比较,在排除自身免疫或炎症疾病的基础上,还选取了健康供体。分别从血液和淋巴结组织中分离出外周血单核细胞(PBMC)和淋巴细胞。使用流式细胞术分析了 CD 患者和健康供体的 T 淋巴细胞的表型和细胞因子分泌情况。采用曼-惠特尼检验(双尾)和学生 t 检验对 CD 患者和健康供体的结果进行统计比较:结果:治疗后 CD 患者的 T 细胞分布发生了改变,PBMCs 中 CD8+ T 细胞明显增加(P=0.0005),肠系膜淋巴结(MLNs)中 CD4+ 和 CD8+ T 细胞的频率也发生了改变。Tm细胞显示干扰素-γ(IFN-γ)和肿瘤坏死因子-α(TNF-α)产生减少,与CD患者的健康MLNs(N-M-Lys)相比,CD患者的MLNs病变(CD-M-Lys)中产生IFN-γ的CD8+干细胞样Tm(Tscm)细胞的频率发生了显著变化(P=0.0152)。在CD患者的MLNs和小肠粘膜之间观察到了组织驻留Tm(Trm)细胞亚群频率的差异:结论:使用抗炎药物和/或免疫抑制剂治疗对 Tm 细胞亚群的频率和功能有显著影响。在临床上,这些研究结果表明,调节 Tm 细胞反应是一种潜在的治疗途径,对于免疫反应调节至关重要的疾病尤其有益。要全面探索这些发现的治疗意义,还需要进一步的临床研究。
{"title":"Crohn's disease treatment and memory T-cell subset changes: insights from a case series.","authors":"Zhi-Hui Chen, Ying-Ying Tang, Si-Yuan Sheng, Chuan-Gang Lu, Kai-Wu Xu, Guan-Jun Chen, Yan-Feng Wang, Yong Gu, Xin-Ming Song, Hai Hong","doi":"10.21037/tgh-23-21","DOIUrl":"10.21037/tgh-23-21","url":null,"abstract":"<p><strong>Background: </strong>Crohn's disease (CD) is a chronic inflammatory bowel disease with significant morbidity, affecting millions worldwide. The intricacies of immune responses in CD, especially post-treatment, remain a vital area of exploration. While memory T (Tm)-cell subsets play a pivotal role in adaptive immunity, their specific function in patients with CD after treatment is not well-understood. This study aims to investigate the effect and function of Tm-cell subsets in these patients, addressing a crucial knowledge gap in the context of CD therapeutics.</p><p><strong>Methods: </strong>A total of eight patients diagnosed with CD were selected based on predefined inclusion criteria. All patients were treated with either anti-inflammatory agents, immunosuppressive drugs, or a combination of both. For comparison, healthy donors were enrolled based on exclusion of autoimmune or inflammatory diseases. Peripheral blood mononuclear cells (PBMCs) and lymphocytes were isolated from blood and lymph node tissue respectively. The phenotype and cytokine production of T lymphocytes from both CD patients and healthy donors were analyzed using flow cytometry. Statistical comparisons of the outcomes between CD patients and healthy donors were made using Mann-Whitney test (two-tailed) and Student <i>t</i>-test.</p><p><strong>Results: </strong>Post-treatment CD patients exhibited an altered T cell distribution with a notable increase in CD8<sup>+</sup> T cells in PBMCs (P=0.0005), and altered frequencies of CD4<sup>+</sup> and CD8<sup>+</sup> T cells in mesenteric lymph nodes (MLNs). Tm cells showed decreased interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α) production, with significant alterations in the frequency of IFN-γ-producing CD8<sup>+</sup> stem cell-like Tm (Tscm) cells in lesions of the MLNs from patients with CD (CD-M-Lys) compared to healthy MLNs from patients with CD (N-M-Lys) (P=0.0152). Differences in tissue-resident Tm (Trm)-cell subset frequencies were observed between the MLNs and small intestinal mucosa in CD patients.</p><p><strong>Conclusions: </strong>The treatments with anti-inflammatory agents and/or immunosuppressive drugs have a significant effect on the frequency and function of Tm-cell subsets. Clinically, these findings suggest a potential therapeutic avenue in modulating Tm-cell responses, which might be particularly beneficial for conditions where immune response modulation is crucial. Further clinical studies are warranted to explore the full therapeutic implications of these findings.</p>","PeriodicalId":94362,"journal":{"name":"Translational gastroenterology and hepatology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11074482/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140878323","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"TMEM43 promotes the development of hepatocellular carcinoma by activating VDAC1 through USP7 deubiquitination","authors":"Nannan Zhang, Feiran Wang, Xiaobing Yang, Quhui Wang, Renan Chang, Lirong Zhu, M. Feitelson, Zhong Chen","doi":"10.21037/tgh-23-108","DOIUrl":"https://doi.org/10.21037/tgh-23-108","url":null,"abstract":"","PeriodicalId":94362,"journal":{"name":"Translational gastroenterology and hepatology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139637635","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}