A phase I radiation dose-escalation study to determine the maximal dose of radiotherapy in combination with weekly gemcitabine in patients with locally advanced pancreatic adenocarcinoma

<p>Abstract</p> <p>Background</p> <p>The primary objective of this study was to determine the maximum tolerated dose (MTD) of escalating doses of radiotherapy (RT) concomitantly with a fixed dose of gemcitabine (300 mg/m²/week) within the same overall treatment time.</p> <p>Methods</p> <p>Thirteen patients were included. Gemcitabine 300 mg/m²/week was administered prior to RT. The initial dose of RT was 45 Gy in 1.8 Gy fractions, escalated by adding 5 fractions of 1.8 Gy (one/week) to a dose of 54 Gy with a total duration kept at 5 weeks. All patients received a dynamic MRI to assess the pancreatic respiratory related movements. Toxicity was scored using the RTOG-EORTC toxicity criteria.</p> <p>Results</p> <p>Three of six patients experienced an acute dose limiting toxicity (DLT) at the 54 Gy dose level. For these patients a grade III gastro-intestinal toxicity (GI) was noted. Patients treated at the 45 Gy dose level tolerated therapy without DLT. The 54 Gy dose level was designated as the MTD and was deemed not suitable for further investigation.</p> <p>Between both dose levels, there was a significant difference in percentage weight loss (p = 0.006) and also in cumulative GI toxicity (p = 0.027). There was no grade 3 toxicity in the 45 Gy cohort versus 4 grade 3 toxicity events in the 54 Gy cohort. The mean dose to the duodenum was significantly higher in the 54 Gy cohort (38.45 Gy vs. 51.82 Gy; p = 0.001).</p> <p>Conclusion</p> <p>Accelerated dose escalation to a total dose of 54 Gy with 300 mg/m²/week gemcitabine was not feasible. GI toxicity was the DLT. Retrospectively, the dose escalation of 9 Gy by accelerated radiotherapy might have been to large. A dose of 45 Gy is recommended. Considering the good patient outcomes, there might be a role for the investigation of a fixed dose of gemcitabine and concurrent RT with small fractions (1.8 Gy/day) in borderline resectable or unresectable non-metastatic locally advanced pancreatic cancer.</p

Multi-institutional expert update on the use of laparoscopic bile duct exploration (LBDE) in the management of choledocholithiasis: lesson learned from 3950 procedures

Background: Recently there has been a growing interest in the laparoscopic management of common bile duct stones with gallbladder in situ (LBDE), which is favoring the expansion of this technique. Our study identified the standardization factors of LBDE and its implementation in the single-stage man agement of choledocholithiasis. Methods: A retrospective multi-institutional study among 17 centers with proven experience in LBDE was performed. A cross-sectional survey consisting of a semi-structured pretested questionnaire was distributed covering the main aspects on the use of LBDE in the management of choledocholithiasis. Results: A total of 3950 LBDEs were analyzed. The most frequent indication was jaundice (58.8%). LBDEs were performed after failed ERCP in 15.2%. The most common approach used was the transcystic (63.11%). The overall series failure rate of LBDE was 4% and the median rate for each center was 6% (IQR, 4.5-12.5). Median operative time ranged between 60-120 min (70.6%). Overall morbidity rate was 14.6%, with a postoperative bile leak and complications ≥3a rate of 4.5% and 2.5%, respectively. The operative time decreased with experience (P = .03) and length of hospital stay was longer in the presence of a biliary leak (P = .04). Current training of LBDE was defined as poor or very poor by 82.4%. Conclusion: Based on this multicenter survey, LBDE is a safe and effective ap proach when performed by experienced teams. The generalization of LBDE will be based on developing training programs

Higher Postoperative Mortality and Inferior Survival After Right-Sided Liver Resection for Perihilar Cholangiocarcinoma:Left-Sided Resection is Preferred When Possible

BACKGROUND: A right- or left-sided liver resection can be considered in about half of patients with perihilar cholangiocarcinoma (pCCA), depending on tumor location and vascular involvement. This study compared postoperative mortality and long-term survival of right- versus left-sided liver resections for pCCA.METHODS: Patients who underwent major liver resection for pCCA at 25 Western centers were stratified according to the type of hepatectomy-left, extended left, right, and extended right. The primary outcomes were 90-day mortality and overall survival (OS).RESULTS: Between 2000 and 2022, 1701 patients underwent major liver resection for pCCA. The 90-day mortality was 9% after left-sided and 18% after right-sided liver resection (p &lt; 0.001). The 90-day mortality rates were 8% (44/540) after left, 11% (29/276) after extended left, 17% (51/309) after right, and 19% (108/576) after extended right hepatectomy (p &lt; 0.001). Median OS was 30 months (95% confidence interval [CI] 27-34) after left and 23 months (95% CI 20-25) after right liver resection (p &lt; 0.001), and 33 months (95% CI 28-38), 27 months (95% CI 23-32), 25 months (95% CI 21-30), and 21 months (95% CI 18-24) after left, extended left, right, and extended right hepatectomy, respectively (p &lt; 0.001). A left-sided resection was an independent favorable prognostic factor for both 90-day mortality and OS compared with right-sided resection, with similar results after excluding 90-day fatalities.CONCLUSIONS: A left or extended left hepatectomy is associated with a lower 90-day mortality and superior OS compared with an (extended) right hepatectomy for pCCA. When both a left and right liver resection are feasible, a left-sided liver resection is preferred.</p

Higher Postoperative Mortality and Inferior Survival After Right-Sided Liver Resection for Perihilar Cholangiocarcinoma:Left-Sided Resection is Preferred When Possible

BACKGROUND: A right- or left-sided liver resection can be considered in about half of patients with perihilar cholangiocarcinoma (pCCA), depending on tumor location and vascular involvement. This study compared postoperative mortality and long-term survival of right- versus left-sided liver resections for pCCA.METHODS: Patients who underwent major liver resection for pCCA at 25 Western centers were stratified according to the type of hepatectomy-left, extended left, right, and extended right. The primary outcomes were 90-day mortality and overall survival (OS).RESULTS: Between 2000 and 2022, 1701 patients underwent major liver resection for pCCA. The 90-day mortality was 9% after left-sided and 18% after right-sided liver resection (p &lt; 0.001). The 90-day mortality rates were 8% (44/540) after left, 11% (29/276) after extended left, 17% (51/309) after right, and 19% (108/576) after extended right hepatectomy (p &lt; 0.001). Median OS was 30 months (95% confidence interval [CI] 27-34) after left and 23 months (95% CI 20-25) after right liver resection (p &lt; 0.001), and 33 months (95% CI 28-38), 27 months (95% CI 23-32), 25 months (95% CI 21-30), and 21 months (95% CI 18-24) after left, extended left, right, and extended right hepatectomy, respectively (p &lt; 0.001). A left-sided resection was an independent favorable prognostic factor for both 90-day mortality and OS compared with right-sided resection, with similar results after excluding 90-day fatalities.CONCLUSIONS: A left or extended left hepatectomy is associated with a lower 90-day mortality and superior OS compared with an (extended) right hepatectomy for pCCA. When both a left and right liver resection are feasible, a left-sided liver resection is preferred.</p

Association of Adipose tissue inflammation with histologic severity of nonalcoholic fatty liver disease

BACKGROUND & AIMS : The prevalence of nonalcoholic fatty liver disease (NAFLD) has increased with the obesity pandemic. We analyzed the transcriptional profiles of subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT), and phenotypes and functional characteristics of adipocyte tissue macrophages (ATMs), in obese patients undergoing bariatric surgery. METHODS : We collected anthropometric data; plasma samples; and SAT, VAT, and liver tissues from 113 obese patients undergoing bariatric surgery at academic hospitals in Europe (Antwerp and Leuven) and South Africa. Based on clinical and histologic features, patients were assigned to the following groups: obese, NAFLD, nonalcoholic steatohepatitis (NASH), or NASH with fibrosis. Microarray analyses were performed to identify genes expressed differentially among groups. We measured levels of cytokines and chemokines in plasma samples and levels of RNAs in adipose tissues by quantitative reverse-transcription polymerase chain reaction. ATMs were isolated from patients and 13 lean individuals undergoing cholecystectomy (controls), analyzed by flow cytometry, and cultured; immunophenotypes and levels of cytokines and chemokines in supernatants were determined. RESULTS : We observed increased expression of genes that regulate inflammation in adipose tissues from patients with NAFLD and NASH; expression of these genes increased as disease progressed from NAFLD to NASH. We found 111 genes associated with inflammation that were expressed differentially between VAT and SAT. Serum levels of interleukin 8, chemokine (C-C motif) ligand 3, and tumor necrosis factor-a correlated with liver inflammation and NAFLD activity score. We developed 2 models that could be used to determine patients’ liver histology based on gene expression in VAT and SAT. Flow cytometry showed increased proportions of CD11cþCD206þ and CCR2þ macrophages in VAT from patients with NASH, and supernatants of cultured macrophages had increased levels of cytokines and chemokines compared with controls. CONCLUSIONS : VAT and SAT from patients with NAFLD and NASH have an increased expression of genes that regulate inflammation, and ATM produce increased levels of inflammatory cytokines, compared with adipose tissues from controls. We identified an expression profile of 5 genes in SAT that accurately predict liver histology in these patients. Transcript profiling: accession numbers: GSE58979 and GSE59045.Schalk van der Merwe, Chantal Mathieu, Frederik Nevens, David Cassiman, and Sven Francque are recipients of the Flanders fund for scientific research (FWO klinisch mandaat), and Hannelie Korf is a recipient of the FWO postdoctoral mandate. Research at the Department of Endocrinology, Diabetology and Metabolism and the Department of Gastroenterology and Hepatology of the Antwerp University Hospital (Belgium) was supported by the European Union: FP6 (HEPADIP contract LSHM-CT-2005-018734) and FP7-HEALTH (RESOLVE no. 305707). Supported by a fellowship from the South African Gastroenterology Association and a scholarship from the European Association for the Study of the Liver (J.d.P.). This research also was supported by a research grant from the Gastro foundation of South Africa. The authors specifically acknowledge the support of Dr. Chris Kassianides. Also funded in part by a grant from the Deutsche Forschungsgemeinschaft DFG-SFB 1052/1: Obesity Mechanisms (projects A04) and by the Helmholtz Alliance Imaging and Curing Environmental Metabolic Disease through the Initiative and Networking Fund of the Helmholtz Association (M.G.).http://www.journals.elsevier.com/gastroenterology2016-09-30hb2016Internal Medicin

Macrophage scavenger receptor 1 mediates lipid-induced inflammation in non-alcoholic fatty liver disease

Background & Aims: Obesity-associated inflammation is a key player in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). However, the role of macrophage scavenger receptor 1 (MSR1, CD204) remains incompletely understood. Methods: A total of 170 NAFLD liver biopsies were processed for transcriptomic analysis and correlated with clinicopathological features. Msr1(-/-) and wild-type mice were subjected to a 16-week high-fat and high-cholesterol diet. Mice and ex vivo human liver slices were treated with a monoclonal antibody against MSR1. Genetic susceptibility was assessed using genome-wide association study data from 1,483 patients with NAFLD and 430,101 participants of the UK Biobank. Results: MSR1 expression was associated with the occurrence of hepatic lipid-laden foamy macrophages and correlated with the degree of steatosis and steatohepatitis in patients with NAFLD. Mice lacking Msr1 were protected against diet-induced metabolic disorder, showing fewer hepatic foamy macrophages, less hepatic inflammation, improved dyslipidaemia and glucose tolerance, and altered hepatic lipid metabolism. Upon induction by saturated fatty acids, MSR1 induced a pro-inflammatory response via the JNK signalling pathway. In vitro blockade of the receptor prevented the accumulation of lipids in primary macrophages which inhibited the switch towards a proinflammatory phenotype and the release of cytokines such as TNF-alpha Targeting MSR1 using monoclonal antibody therapy in an obesity-associated NAFLD mouse model and human liver slices resulted in the prevention of foamy macrophage formation and inflammation. Moreover, we identified that rs41505344, a polymorphism in the upstream transcriptional region of MSR1, was associated with altered serum triglycerides and aspartate aminotransferase levels in a cohort of over 400,000 patients. Conclusions: Taken together, our data suggest that MSR1 plays a critical role in lipid-induced inflammation and could thus be a potential therapeutic target for the treatment of NAFLD. Lay summary: Non-alcoholic fatty liver disease (NAFLD) is a chronic disease primarily caused by excessive consumption of fat and sugar combined with a lack of exercise or a sedentary lifestyle. Herein, we show that the macrophage scavenger receptor MSR1, an innate immune receptor, mediates lipid uptake and accumulation in Kupffer cells, resulting in liver inflammation and thereby promoting the progression of NAFLD in humans and mice. (C) 2021 The Authors. Published by Elsevier B.V. on behalf of European Association for the Study of the Liver.Peer reviewe

Higher Postoperative Mortality and Inferior Survival After Right-Sided Liver Resection for Perihilar Cholangiocarcinoma: Left-Sided Resection is Preferred When Possible

BACKGROUND: A right- or left-sided liver resection can be considered in about half of patients with perihilar cholangiocarcinoma (pCCA), depending on tumor location and vascular involvement. This study compared postoperative mortality and long-term survival of right- versus left-sided liver resections for pCCA. METHODS: Patients who underwent major liver resection for pCCA at 25 Western centers were stratified according to the type of hepatectomy-left, extended left, right, and extended right. The primary outcomes were 90-day mortality and overall survival (OS). RESULTS: Between 2000 and 2022, 1701 patients underwent major liver resection for pCCA. The 90-day mortality was 9% after left-sided and 18% after right-sided liver resection (p < 0.001). The 90-day mortality rates were 8% (44/540) after left, 11% (29/276) after extended left, 17% (51/309) after right, and 19% (108/576) after extended right hepatectomy (p < 0.001). Median OS was 30 months (95% confidence interval [CI] 27-34) after left and 23 months (95% CI 20-25) after right liver resection (p < 0.001), and 33 months (95% CI 28-38), 27 months (95% CI 23-32), 25 months (95% CI 21-30), and 21 months (95% CI 18-24) after left, extended left, right, and extended right hepatectomy, respectively (p < 0.001). A left-sided resection was an independent favorable prognostic factor for both 90-day mortality and OS compared with right-sided resection, with similar results after excluding 90-day fatalities. CONCLUSIONS: A left or extended left hepatectomy is associated with a lower 90-day mortality and superior OS compared with an (extended) right hepatectomy for pCCA. When both a left and right liver resection are feasible, a left-sided liver resection is preferred

Laparoscopic hepaticojejunostomy and gastroenterostomy for unresectable pancreatic head cancer

info:eu-repo/semantics/nonPublishe