Hepatobiliary complications of immune checkpoint inhibitors in cancer.

Immune checkpoint inhibitors (ICIs) have dramatically changed the landscape of cancer therapy. Over the last decade, both their primary focus in trials and clinical application have exponentially risen, with repeated demonstrations of their efficacy in improving survival in various cancer types. The adverse effects of these drugs on various organ systems were recognised in early phase studies. Given their relatively new emergence on the market, there has been increasing interest into short- and long-term effects and management of ICIs in real-world settings. ICI-related hepatobiliary toxicities are often challenging to diagnose and difficult to distinguish from other causes of deranged liver biochemical tests. The aim of this review is to provide an up-to-date and detailed exploration of the hepatobiliary complications of ICIs, including pathogenesis and approaches to diagnosis and management.

[Anastomotic leakage in hepato-pancreato-biliary surgery]. / Anastomoseninsuffizienzen in der hepatopankreatobiliären Chirurgie.

Severe complications following hepato-pancreato-biliary surgery are frequently due to leakage of anastomoses. Local intraoperative and systematic measures can reduce the incidence of leaks and leak-related sequelae. The early identification of leak-related sequelae, such as hemorrhage is pivotal to reduce the mortality risk. Therefore, perioperative risk stratification incorporating surgical and patient risk factors is crucial. The management of anastomotic leaks is complex and an interdisciplinary treatment is therefore recommended. The treatment depends on the institutional expertise, localization, characteristic features of the anastomosis and the onset of insufficiency. This article describes the different concepts of the diagnostics, prevention, consequences and management of anastomotic leakage in hepato-pancreato-biliary surgery in more detail.

Essential Elements in Synoptic Operative Reports for Hepato-Pancreato-Biliary Cancer Surgery: An HPB/CGSO Training Program Survey.

BACKGROUND: Synoptic operative reports (SORs) are checklists or templates that contain standardized elements of an operation. These elements are associated with standardized inclusion of critical elements of the operative report that translate into numerous potential benefits. Whereas SORs for melanoma, breast, and colorectal cancer surgery have already been widely implemented, similar templates for hepato-pancreato-biliary (HPB) cancer surgery are currently lacking. METHODS: An anonymous voluntary online survey was distributed to HPB attendings and fellows at HPB and complex general surgical oncology (CGSO) fellowship programs. RESULTS: The 54 participants in this study comprised 31 (57%) HPB surgery attendings, 15 (28%) HPB surgery fellows, and 8 (15%) CGSO fellows. Notably, only six (11%) participants reported consistent use of an HPB SOR. The most commonly reported barriers to SOR uptake were the "lack of a readily available template" (55%) and the "lack of consensus/guidelines" (49%). Despite these limiting factors, a majority of respondents indicated a strong willingness to use a standardized and readily available HPB SOR (mean, 4.13/5 ± 1.23). This interest did not differ between attendings and fellows (p = 0.52) or between the participants stratified by surgical experience (p = 0.58). Finally, the participants were provided a comprehensive list of possible elements to incorporate into a standardized pancreatic and hepatobiliary SOR. After the exclusion of elements with less than 75% agreement, the pancreatic SORs included 17 (57%) of 30 possible elements, and the hepatobiliary SORs included 19 (76%) of 25 possible elements. CONCLUSION: Broad consensus on several elements of the HPB SOR suggests that uptake should be accelerated in HPB surgery.

Gallstones in a Looking-Glass: A Case Report on the Successful Laparoscopic Management of Cholelithiasis in Situs Inversus Totalis.

Situs inversus is an uncommon congenital condition where the internal organs are arranged in a mirrored or reversed orientation within the body. In this unique anatomical variation, the placement of visceral organs is flipped, presenting a mirror-image configuration relative to their standard positions. While situs inversus itself does not predispose an individual to gallbladder disorders, the anatomical variation poses unique challenges for healthcare professionals in managing abdominal pathologies. This case report describes the successful management of a 52-year-old male patient with situs inversus totalis who presented with gallstone-induced obstructive jaundice and underwent endoscopic retrograde cholangiopancreatography (ERCP) with stenting, followed by a laparoscopic cholecystectomy. The surgical procedure required exceptional visual-motor skills and extensive reorientation to accurately identify and navigate the left upper quadrant anatomy, which is the mirror image of the typical surgical approach. The case highlights the importance of thorough preoperative planning, comprehensive anatomical knowledge, and a multidisciplinary team approach to ensure favorable outcomes for patients with this rare condition.

Endoscopic biliary drainage for distal bile duct obstruction due to pancreatic cancer.

Approximately 60% of pancreatic cancers occur in the pancreatic head and may present as obstructive jaundice due to bile duct invasion. Obstructive jaundice often leads to poor general conditions and acute cholangitis, interfering with surgery and chemotherapy and requiring biliary drainage. The first choice of treatment for biliary drainage is the endoscopic transpapillary approach. In unresectable tumors, self-expandable metal stents (SEMSs) are most commonly used and are classified into uncovered and covered SEMSs. Recently, antireflux metal stents and large- or small-diameter SEMSs have become commercially available, and their usefulness has been reported. Plastic stents are infrequently used in patients with resectable biliary obstruction; however, owing to the recent trend in preoperative chemotherapy, SEMSs are frequently used because of the long time to recurrent biliary obstruction. Endoscopic ultrasound-guided biliary drainage (EUS-BD) is often performed in patients who are not eligible for the transpapillary approach, and favorable outcomes have been reported. Different EUS-BD techniques and specialized stents have been developed and can be safely used in high-volume centers. The indications for EUS-BD are expected to further expand in the future.

Feasibility, safety and preliminary efficacy of preoperative stereotactic radiotherapy on the future pancreatic neck transection margin to reduce the risk of pancreatic fistula after high-risk pancreatoduodenectomy (FIBROPANC): protocol for a multicentre, single-arm trial.

INTRODUCTION: Postoperative pancreatic fistula (POPF) occurs in 25% of patients undergoing a high-risk pancreatoduodenectomy (PD) and is a driving cause of major morbidity, mortality, prolonged hospital stay and increased costs after PD. There is a need for perioperative methods to decrease these risks. In recent studies, preoperative chemoradiotherapy in patients with pancreatic ductal adenocarcinoma (PDAC) reduced the rate of POPF seemingly due to radiation-induced pancreatic fibrosis. However, patients with a high risk of POPF mostly have a non-pancreatic periampullary tumour and do not receive radiotherapy. Prospective studies using radiotherapy specifically to reduce the risk of POPF have not been performed. We aim to assess the safety, feasibility and preliminary efficacy of preoperative stereotactic radiotherapy on the future pancreatic neck transection margin to reduce the rate of POPF. METHODS AND ANALYSIS: In this multicentre, single-arm, phase II trial, we aim to assess the feasibility and safety of a single fraction of preoperative stereotactic radiotherapy (12 Gy) to a 4 cm area around the future pancreatic neck transection margin in patients at high risk of developing POPF after PD aimed to reduce the risk of grade B/C POPF. Adult patients scheduled for PD for malignant and premalignant periampullary tumours, excluding PDAC, with a pancreatic duct diameter ≤3 mm will be included in centres participating in the Dutch Pancreatic Cancer Group. The primary outcome is the safety and feasibility of single-dose preoperative stereotactic radiotherapy before PD. The most relevant secondary outcomes are grade B/C POPF and the difference in the extent of fibrosis between the radiated and non-radiated (uncinate margin) pancreas. Evaluation of endpoints will be performed after inclusion of 33 eligible patients. ETHICS AND DISSEMINATION: Ethical approval was obtained by the Amsterdam UMC's accredited Medical Research Ethics Committee (METC). All included patients are required to have provided written informed consent. The results of this trial will be used to determine the need for a randomised controlled phase III trial and submitted to a high-impact peer-reviewed medical journal regardless of the study outcome. TRIAL REGISTRATION NUMBER: NL72913 (Central Committee on Research involving Human Subjects Registry) and NCT05641233 (ClinicalTrials).

PET/MRI: pictorial review of hepatobiliary and pancreatic applications.

PET and MRI both play valuable roles in the management of hepatobiliary and pancreatic (HBP) malignancies. Simultaneous PET/MRI combines the excellent soft-tissue resolution and anatomic details from MRI with functional information from PET in a single comprehensive examination. MRI is the main imaging modality in evaluating HCC, playing important roles in screening, characterization, local extent, and evaluating tumor response, whereas 18F-fluorodeoxyglucose (FDG) PET can help evaluate for lymph node involvement and metastatic disease. In cholangiocarcinoma and pancreatic malignancies, both PET and MRI have excellent utility in initial staging as well as assessing treatment response. In all HBP malignancies, FDG-PET/MRI is a unique problem-solving tool in complex cases and diagnostic challenges, especially after locoregional therapy and when differentiating residual or recurrent viable disease from inflammatory and other benign processes. In this manuscript, we review the role of PET/MRI in the diagnosis, staging, assessing treatment response, and characterizing post-treatment processes. With the introduction of multiple new tracers, the value of PET/MRI has not yet been fully realized, and more studies are needed to demonstrate the utility and efficacy of PET/MRI in improving patient care in hepatobiliary and pancreatic oncology.

Biliary Anomalies in VACTERL Syndrome: A Case Report.

The VACTERL/VATER association is a rare congenital disorder characterized by the presence of at least three of its main components: vertebral defects, anal atresia, cardiovascular anomalies, tracheoesophageal fistulas, esophageal atresia, renal anomalies, and limb defects. The exact cause of the VACTERL association is not fully understood. Most cases occur randomly. However, some research suggests that genetics and environmental factors may play a role. In addition to the core components of the VACTERL association, affected individuals may also have anomalies beyond the typical features. Biliary anomalies, although not classically included in the definition, have been documented in individuals with VACTERL syndrome, adding more complexity to this condition. Patients with biliary anomalies may present with jaundice, abdominal pain, or poor growth. The presence of biliary anomalies in individuals with VACTERL syndrome can have an impact on their care and outcomes. Detecting and treating these anomalies usually involves a multidisciplinary team. Timely identification and proper management of these bile-related issues are essential to prevent complications such as cholangitis.

Psychotropic medication and hepatobiliary health: Ultrasound observations on patients with schizophrenia.

OBJECTIVE: This study sought to examine the association between antipsychotic drug use and hepatobiliary health based on serum markers and ultrasound observations on a sample of patients with schizophrenia compared to age and gender matched healthy controls. METHODS: The 120 patients with schizophrenia and 60 control subjects had their blood drawn to measure liver function tests and underwent hepatobiliary ultrasonography to determine hepatobiliary lesions. Liver function tests included total cholesterol (TC), triglycerides (TG), alanine aminotransferase (ALT), and aspartate aminotransferase (AST). Standardized cross-sectional images of the liver and kidneys were obtained from patients and controls, and analyses were stratified by length of taking psychotropic medication among those with schizophrenia. Liver echo attenuation coefficients, liver-kidney ratios, and liver fat content were determined. RESULTS: Psychotropic drug use was associated with greater liver burden and liver lesions in patients with schizophrenia compared to controls. The levels of TC, TG, ALT and AST in patients with schizophrenia were also all significantly higher among patients with schizophrenia. Long-term psychotropic medication was associated with increased levels of fatty liver in patients compared with controls. Levels of TC, TG, ALT and AST were all significantly higher in the long-term psychotropic medication use group than in the short-term group. Liver echo attenuation coefficient, liver-kidney ratio, and liver fat content were also higher in the long-term medication use group compared to the short-term group. CONCLUSION: Antipsychotic drug use, particularly long-term use, is associated with increased liver burden in patients with schizophrenia, impaired lipid metabolism, increased liver lesions and fat content.

Randomized, controlled, multi-center phase II study of postoperative enoxaparin treatment for venous thromboembolism prophylaxis in patients undergoing surgery for hepatobiliary-pancreatic malignancies.

Purpose: Postoperative venous thromboembolism (VTE) risk is pronounced after abdominal cancer surgery. Enoxaparin shows promise in preventing VTE in gastrointestinal, gynecological, and urological cancers, but its application after surgery for hepatobiliary-pancreatic malignancy has been under-evaluated due to bleeding concerns. We confirmed the safety of enoxaparin administration in patients undergoing curative hepatobiliary-pancreatic surgery for malignancies in a prospective, multi-center, phase I study. Methods: The study was conducted from April 2015 to May 2021 across eight specialized centers. Patients (n = 262) were randomized to enoxaparin prophylaxis given postoperatively for 8 days (n = 131) or control (n = 131). The primary endpoint was the efficacy in reducing VTE. Secondary endpoints examined safety. Results: The full analysis set included 259 patients (131 control, 129 enoxaparin). The per-protocol population included 233 patients (117 control, 116 enoxaparin). Most cases were hepatic malignancies (111 control, 111 enoxaparin). The median administration duration of enoxaparin was 7 days, with 92% receiving 4000 units/day. Despite a reduction in the relative risk (RR) of VTE due to postoperative enoxaparin administration, the results were not significant (control: four cases, 3.4% vs. treatment: two cases, 1.7%; RR 0.50, 95% CI 0.09-2.70; p = 0.6834). No significant difference was found in the incidence of bleeding events (control: five cases, 4.3% vs. treatment: five cases, 4.3%, RR 1.00, 95% CI 0.53-1.89; p = 1.0000). Conclusions: The perioperative administration of enoxaparin in hepatobiliary-pancreatic malignancies is feasible and safe. However, further case accumulation and investigation are necessary to assess its potential in reducing the occurrence of VTE.

Not just a BLiP: early experience with a novel multidisciplinary case conference for benign hepatopancreatobiliary disease at a tertiary Canadian healthcare center.

BACKGROUND: Benign Liver and Pancreas (BLiPs) rounds, implemented in 2022 at our Canadian tertiary care center, are a novel concept of a multidisciplinary case conference (MCC) for discussion of benign hepatopancreatobiliary (HPB) disease. BLiPs Rounds are a monthly virtual meeting of surgeons, gastroenterologists, and interventional radiologists experienced in biliary and pancreatic disease. METHODS: This case series was completed to review the patient cases discussed over the first year of BLiPs rounds, and to evaluate the effect of the multidisciplinary discussion on patient management plans. Meeting minutes were reviewed for BLiPs rounds between May 2022 and July 2023. Data were collected retrospectively on all discussed patients by review of the electronic medical record, and analyzed using frequencies and means with standard deviations. RESULTS: Between May 2022 and July 2023, 56 cases were discussed at 12 case conferences. 68% of cases concerned pancreatic pathology, 25% concerned biliary pathology, the remainder liver or duodenal pathology. 49 cases (88%) were presented to discuss therapeutic options, and 7 presented as diagnostic challenges. Cases were usually presented once, but 7 patients were discussed at multiple conferences due to complex issues or ongoing symptomatology. 40 patients (71%) had undergone previous endoscopic, percutaneous, or surgical interventions prior to discussion. Endoscopic intervention was recommended in 32% of cases, percutaneous interventional approach in 13%, a combined endoscopic and percutaneous approach in 9%, and surgery in 18%. Repeat imaging or observation was recommended in 29% of cases. Discussion at rounds led to a change or adjustment in the proposed management in 46 cases (82%). The plan recommended by the MCC was carried out in 71% of cases. CONCLUSION: BLiPs case conference provides a valuable venue to discuss cases, encourage interdisciplinary collaboration, and refine treatment approaches, leading to a change in proposed management plan in over three-quarters of cases presented.

Intracholecystic Papillary Neoplasm: A Case Report.

We present a case of a 30-year-old female with symptomatic gallstones and associated gallbladder polyps. An incidental finding of intracholecystic papillary neoplasm (ICPN) with high-grade dysplasia was found after pathological examination of the gallbladder after robotic cholecystectomy. This rare condition can be associated with malignant transformation. In this case report, we discuss this rare entity and share our experience and review of the literature.

Establishment and long-term expansion of adult hepatobiliary organoids co-cultured with liver endothelial cells.

The liver has a unique ability to regenerate in response to injury or disease with hepatocytes and biliary epithelial cells (BECs) driving the regenerative response. Liver progenitor cells (LPCs) also play role in regeneration with the ability to differentiate into either hepatocytes or BECs. However, during chronic liver disease, the regenerative capacity of the liver is impaired. The use of LPCs is a promising therapeutic strategy for patients with chronic liver diseases. LPCs can be expanded in vitro as self-renewing organoids, however, most approaches to LPC organoids do not include critical cells from the LPC niche in 3D organoid cultures. In this study, we highlight the role of liver endothelial cells (LiECs), as a part of LPC niche, in supporting the hepatobiliary organoids in long-term culture even in the absence of defined growth supplements, such as Wnt agonists. Furthermore, LiECs alter the gene expression profile of hepatobiliary organoids involved in inflammation, migration, extracellular matrix organization, and receptor signaling pathway through paracrine manner. Our findings expand the role of LiECs for regulating stemness of LPCs and elucidate a role for niche cells in a LPC organoid co-culture model with a reduction in growth supplements.

Decoding the microbiota metabolome in hepatobiliary and pancreatic cancers: Pathways to precision diagnostics and targeted therapeutics.

We delve into the critical role of the gut microbiota and its metabolites in the pathogenesis and progression of hepatobiliary and pancreatic (HBP) cancers, illuminating an urgent need for breakthroughs in diagnostic and therapeutic strategies. Given the high mortality rates associated with HBP cancers, which are attributed to aggressive recurrence, metastasis, and poor responses to chemotherapy, exploring microbiome research presents a promising frontier. This research highlights how microbial metabolites, including secondary bile acids, short-chain fatty acids, and lipopolysaccharides, crucially influence cancer cell behaviors such as proliferation, apoptosis, and immune evasion, significantly contributing to the oncogenesis and progression of HBP cancers. By integrating the latest findings, we discuss the association of microbial alterations with HBP cancers, key metabolites, and their implications, and how metabolomics and microbiomics can enhance diagnostic precision. Furthermore, the paper explores strategies for targeted therapies through microbiome metabolomics, including the direct therapeutic effects of microbiome metabolites and potential synergistic effects on conventional therapies. We also recognize that the field of microbial metabolites for the diagnosis and treatment of tumors still has a lot of problems to be solved. The aim of this study is to pioneer microbial metabolite research and provide a reference for HBP cancer diagnosis, treatment, and prognosis.

Comparison of fibroblast growth factor 19 concentrations between dogs with and without gallbladder mucoceles.

BACKGROUND: Fibroblast growth factor 19 (FGF19) is an enterohepatic hormone the synthesis of which is stimulated by bile acid activation of the nuclear farnesoid X receptor (FXR) in ileal enterocytes. Increased production of FGF19 downregulates hepatocyte bile acid synthesis and gluconeogenesis, while concurrently upregulating hepatocyte glycogenesis and gallbladder (GB) filling. The physiologic impact of this regulatory cycle is illustrated in cholecystectomized humans, in whom the disturbed meal-related flux of GB bile decreases serum FGF19 concentrations. OBJECTIVE: Determine if serum FGF19 concentrations are lower in dogs with clinical GB mucoceles (GBMs) than in control dogs. ANIMALS: Seven dogs with GBM diagnosed using abdominal ultrasonography, biochemical markers, and GB histopathology. Forty-two control dogs without gastrointestinal or hepatobiliary disorders also were evaluated. Health status of controls was assessed by physical examination and diagnostic hematologic and biochemical test results. METHODS: Prospective cross-sectional study to compare fasting plasma or serum FGF19 concentrations between groups. Concentrations of FGF19 were quantified by a commercially available FGF19 ELISA. RESULTS: Concentrations of FGF19 were significantly lower in dogs with clinical GBM (median, 14.0 pg/mL; range, 12.8-67.2) than in control dogs (median, 145.3 pg/mL; range, 36.5-285.1). CONCLUSIONS AND CLINICAL IMPORTANCE: In dogs, GBM is associated with significantly decreased serum FGF19 concentrations. We speculate that this finding reflects compromised GB contraction and decreased enterohepatic circulation of bile flow. Subnormal FGF19 concentrations may influence bile acid synthesis and hepatic metabolism.

Long-term gastrointestinal and hepatobiliary outcomes of COVID-19: a multi-nationwide cohort study from South Korea, Japan, and the UK.

Background/Aims: Considering emerging evidence on long COVID, comprehensive analyses of the post-acute complications of long COVID in the gastrointestinal and hepatobiliary systems are needed. We aimed to investigate the impact of COVID-19 on the long-term risk of gastrointestinal and hepatobiliary outcomes and other digestive abnormalities in various follow-up periods. Methods: We used three large-scale population-based cohorts: the Korean cohort (discovery cohort), the Japanese cohort (validation cohort-A), and the UK Biobank (validation cohort-B). 10,027,506 Korean, 12,218,680 Japanese, and 468,617 UK patients aged ≥20 years, including those with SARS-CoV-2 infection between 2020 and 2021 matched to non-infected control patients. Seventeen gastrointestinal and eight hepatobiliary outcomes as well as nine other digestive abnormalities following SARS-CoV-2 infection were identified and compared with contemporary controls. Results: The discovery cohort, consisting of 10,027,506 individuals (mean age 48.4 years; 49.9% female), revealed heightened risks of gastrointestinal diseases (HR: 1.15; 95% CI: 1.08-1.22), hepatobiliary diseases (1.30; 1.09-1.55), and other digestive abnormalities (1.05; 1.01-1.10) beyond the first 30 days after infection, following exposure-driven propensity score-matching. These results indicate a pronounced association as the severity of COVID-19 increases. The SARS-CoV-2 vaccination was found to lower the risk of gastrointestinal diseases but did not affect hepatobiliary diseases and other digestive disorders. The results derived from validation cohorts were consistent. Over time, the risk profile was most pronounced during the initial 3 months; however, it persisted for >6 months in validation cohorts, but not in the discovery cohort. Conclusions: The incidences of gastrointestinal disease, hepatobiliary disease, and other digestive abnormalities increased in patients with SARS-CoV-2 infection during the post-acute phase.

Indocyanine Green and Hepatobiliary Surgery: An Overview of the Current Literature.

Indocyanine green (ICG) is an inert polypeptide that almost totally binds to high molecular weight plasma proteins; it is cleared by the hepatocytes and directly excreted into the bile with a half-life of about 3-5 minutes. Specific systems are required to see fluorescent images. The use of this dye has been reported in different surgical specialties, and the applications in hepatobiliary surgery are widening. Being firstly used to evaluate the preoperative liver function, intra- and postoperative dynamic checking of hepatic activity has been reported and integrated within perioperative protocols allowing a tailored treatment allocation. Intravenous injection (IV) or injection into the gallbladder can ease difficult cholecystectomy. Biliary leakage detection could be enhanced by IV ICG injection. Although with some contrasting results, the use of ICG for both delineating the limits of the resection and tumor-enhanced visualization was demonstrated to improve short- and long-term outcomes. Although the lack of strong evidence still precludes the introduction of this tool in clinical practice, it harbors great potential in liver surgery.