Idiosyncratic drug‐induced liver injury (DILI) is a rare, often difficult‐to‐predict adverse reaction with complex pathomechanisms. However, it is now evident that certain forms of DILI are ...immune‐mediated and may involve the activation of drug‐specific T cells. Exosomes are cell‐derived vesicles that carry RNA, lipids, and protein cargo from their cell of origin to distant cells, and they may play a role in immune activation. Herein, primary human hepatocytes were treated with drugs associated with a high incidence of DILI (flucloxacillin, amoxicillin, isoniazid, and nitroso‐sulfamethoxazole) to characterize the proteins packaged within exosomes that are subsequently transported to dendritic cells for processing. Exosomes measured between 50 and 100 nm and expressed enriched CD63. Liquid chromatography–tandem mass spectrometry (LC/MS‐MS) identified 2,109 proteins, with 608 proteins being quantified across all exosome samples. Data are available through ProteomeXchange with identifier PXD010760. Analysis of gene ontologies revealed that exosomes mirrored whole human liver tissue in terms of the families of proteins present, regardless of drug treatment. However, exosomes from nitroso‐sulfamethoxazole‐treated hepatocytes selectively packaged a specific subset of proteins. LC/MS‐MS also revealed the presence of hepatocyte‐derived exosomal proteins covalently modified with amoxicillin, flucloxacillin, and nitroso‐sulfamethoxazole. Uptake of exosomes by monocyte‐derived dendritic cells occurred silently, mainly through phagocytosis, and was inhibited by latrunculin A. An amoxicillin‐modified 9‐mer peptide derived from the exosomal transcription factor protein SRY (sex determining region Y)‐box 30 activated naïve T cells from human leukocyte antigen A*02:01–positive human donors. Conclusion: This study shows that exosomes have the potential to transmit drug‐specific hepatocyte‐derived signals to the immune system and provide a pathway for the induction of drug hapten‐specific T‐cell responses.
For gastric cancer surgery is the mainstay treatment. Chemotherapy seems to improve the survival results. But chemotherapy is not a complication-free therapy and its role has been questioned by some ...trials.
To determine whether post-surgical chemotherapy should be used routinely in resectable gastric cancer.
We searched the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE, and Science Citation Index Expanded (July 2013).
Randomised controlled trials (RCT) comparing post-surgical chemotherapy versus surgery alone for resectable gastric cancer.
Two authors independently assessed trials for inclusion and independently extracted the data. We analysed the data with both the fixed-effect and the random-effects models using the RevMan analysis software. We calculated the hazard ratio (HR) with 95% confidence interval (CI) based on intention-to-treat or available case analysis.
The authors identified 34 studies (7824 patients) reporting overall survival (OS) and only 15 reporting disease free survival (DFS) as well. Post-surgical chemotherapy showed an improvement in OS (HR 0.85; 95% CI 0.80 to 0.90) and an improvement in DFS (HR 0.79; 95% CI 0.72 to 0.87), although all the trials had a high risk of bias.The planned analysis of quality of life, return to work, and number of hospital admissions was impossible to complete as the outcome data for the analysis were not available from any trials.
Post-surgical chemotherapy should be used routinely for resectable gastric cancer where possible. Further RCTs are needed to determine the role at each stage of disease.
Background
Preoperative diagnosis for suspected gallbladder cancers is challenging, with a risk of overtreating benign disease, for example, xanthogranulomatous cholecystitis, with radical ...cholecystectomies. We retrospectively evaluated the surgeon's intraoperative assessment alone, and with the addition of intraoperative frozen sections, for suspected gallbladder cancers from a tertiary hepatobiliary multidisciplinary team (MDT).
Methods
MDT patients with complex gallbladder disease were included. Collated data included demographics, MDT discussion, operative details, and patient outcomes.
Results
A total of 454 patients with complex gallbladder disease were reviewed, 48 (10.6%) were offered radical surgery for suspected cancer. Twenty‐five underwent frozen section that led to radical surgery in 6 (25%). All frozen sections were congruent with final histopathology but doubled the operating time (p < 0.0001). Both the surgeon's subjective and additional frozen section's objective assessment, allowed for de‐escalation of unnecessary radical surgery, comparing favourably to a 13.0% cancer diagnosis among radical surgery historically.
Conclusions
The MDT process was highly sensitive in identifying gallbladder cancers but lacked specificity. The surgeon's intraoperative assessment is paramount in suspected cancers, and deescalated unnecessary radical surgery. Intraoperative frozen section was a safe and viable adjunct at a cost of resources and operative time.
Background
Scoring systems were developed to stratify patients with colorectal liver metastases considered for liver resection into different risk groups. Such scores have never been evaluated in ...recurrent liver metastases. The aim of this study was to evaluate whether these scores are applicable to patients with recurrent colorectal liver metastases and treated with curative intent.
Methods
We retrospectively analyzed data from 375 consecutive patients who underwent liver surgery for colorectal liver metastases between June 2010 and August 2015. Seventy‐three patients developed liver‐limited recurrence treated with curative intent. The predictive value of 6 scores (Fong, Sofocleous, Nagashima, Nordlinger, Konopke, and the Basingstoke index) was assessed in this set of patients.
Results
Median follow‐up was 36.2 months. Overall survival and progression‐free survival were 33.6 and 5.6 months, respectively. When scores were applied for OS, none showed a significant stratification between patients, although Nagashima's score showed a significant difference in overall survival between patients from the low‐risk group and those from the intermediate‐ and high‐risk groups (40.8 vs 30.5 months, P = 0.039). For PFS, only Fong's score showed a statistically significant stratification (6.6 vs 4.7 months, P = 0.027).
Conclusion
Scoring systems are of limited‐value in stratifying patients operated on for recurrent colorectal liver metastases.
Background
Neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) and lymphocyte-to-monocyte ratio (LMR) have been identified as potential prognostic factors for overall survival ...(OS) in primary colorectal cancer, and there is a growing interest in their use in colorectal liver metastases (CLMs). However, optimal cut-off values for these ratios have not been defined by making comparison between series difficult. This study aimed to confirm the prognostic value of inflammatory scores in patients undergoing resection for CLM.
Methods
We retrospectively analysed data from 376 consecutive patients who underwent liver surgery for CLM between June 2010 and August 2015. We assessed the reproducibility of previously published ratios and determined new cut-off values using the Cut-off Finder web-based tool. Relations between cut-off values and OS were analysed with Kaplan–Meier log-rank survival analysis and multivariate Cox models.
Results
Three hundred and forty-three patients had full preoperative blood tests for calculation of NLR, PLR and LMR. The number of cut-off values which showed a significant discrimination for OS was 49/249 (19.7%) for NLR, 28/316 (8.9%) for PLR and 22/214 (10.3%) for LMR, all with a scattered nonlinear distribution.
Conclusions
This study showed that inflammatory scores expressed as ratios do not seem to be consistently reliable prognostic markers in patients with resectable CLM.
Summary
Aspartate transaminase, a liver specific enzyme released into serum following acute liver injury, is used in experimental organ preservation studies as a measure of liver IR injury. Whether ...post‐operative serum transaminases are a good indicator of IR injury and subsequent graft and patient survival in human liver transplantation remains controversial. A single centre prospectively collected liver transplant database was analysed for the period 1988–2012. All patients were followed up for 5 years or until graft failure. Transaminase levels on the 1st, 3rd and 7th post‐operative days were correlated with the patient demographics, operative outcomes, post‐operative complications and both graft and patient survival via a binary logistic regression analysis. Graft and patient survival at 3 months was 80.3% and 87.5%. AST levels on the 3rd (P = 0.005) and 7th (P = 0.001) post‐operative days correlated with early graft loss. Patients were grouped by their AST level (day 3): <107iU, 107–1213iU, 1213–2744iU and >2744iU. The incidence of graft loss at 3 months was 10%, 12%. 27% and 59% and 1‐year patient mortality was 12%, 14%, 27% and 62%. Day 3 AST levels correlate with patient and graft outcome postliver transplantation and would be a suitable surrogate endpoint for clinical trials in liver transplantation.
Peri-hilar cholangiocarcinoma (pCCA) is chemorefractory and limited genomic analyses have been undertaken in Western idiopathic disease. We undertook comprehensive genomic analyses of a U.K. ...idiopathic pCCA cohort to characterize its mutational profile and identify new targets. Whole exome and targeted DNA sequencing was performed on forty-two resected pCCA tumors and normal bile ducts, with Gene Set Enrichment Analysis (GSEA) using one-tailed testing to generate false discovery rates (FDR). 60% of patients harbored one cancer-associated mutation, with two mutations in 20%. High frequency somatic mutations in genes not typically associated with cholangiocarcinoma included mTOR, ABL1 and NOTCH1. We identified non-synonymous mutation (p.Glu38del) in MAP3K9 in ten tumors, associated with increased peri-vascular invasion (Fisher's exact, p < 0.018). Mutation-enriched pathways were primarily immunological, including innate Dectin-2 (FDR 0.001) and adaptive T-cell receptor pathways including PD-1 (FDR 0.007), CD4 phosphorylation (FDR 0.009) and ZAP70 translocation (FDR 0.009), with overlapping HLA genes. We observed cancer-associated mutations in over half of our patients. Many of these mutations are not typically associated with cholangiocarcinoma yet may increase eligibility for contemporary targeted trials. We also identified a targetable MAP3K9 mutation, in addition to oncogenic and immunological pathways hitherto not described in any cholangiocarcinoma subtype.
Liver-limited recurrence after resection of colorectal liver metastases is a frequent occurrence, and can in some cases be treated with curative intent. Although surgical re-resection remains ...standard of care, there is growing interest in the role of ablation in this setting. The aim of this study was to compare the outcomes after curative-intent ablation and resection in patients with recurrent colorectal liver metastases.
We retrospectively analysed data from 366 consecutive patients who underwent liver resection for colorectal liver metastases between June 2010 and August 2015. Sixty-four developed liver-limited recurrence which was treated with curative intent, thirty-three (51.6%) by ablation and 31 (48.4%) by repeat resection.
Patient groups were well matched, with surgically resected patients showing higher pre-operative carcinoembryonic antigen levels and larger metastases. There were fewer post-operative complications and shorter length of stay in the ablation group (p < 0.02). After a median follow-up of 36.2 months, median overall survival was the same for both the resected and ablated groups at 33.3 months. Median progression-free survival was longer for patients treated with surgery (10.2 months) compared to ablation (4.3 months) (p = 0.002).
Ablation or resection for liver-limited recurrence after surgery for colorectal liver metastases is associated with improved overall survival compared with systemic chemotherapy alone, and should always be considered for patients with resectable liver recurrence. Although ablation seemed to be associated with a shorter progression-free survival, post-procedure morbidity was significantly lower. The choice between ablation and resection should therefore be made on a personalised basis.
Graft failure and postoperative mortality are the most serious complications after liver transplantation. The aim of this study is to establish a prognostic scoring system to predict graft and ...patient survival based on serum transaminases levels that are routinely used during the postoperative period in human cadaveric liver transplants.
Postoperative graft failure and patient mortality after liver transplant were analyzed from a consecutive series of 1299 patients undergoing cadaveric liver transplantation. This was correlated with serum liver function tests and the rate of reduction in transaminase levels over the first postoperative week. A cut-off transaminase level correlating with graft and patient survival was calculated and incorporated into a scoring system.
Aspartate-aminotransferase (AST) on postoperative day one showed significant correlation with early graft failure for levels above 723U/dl and early postoperative mortality for levels above 750U/dl. AST reduction rate (day 1 to 3) greater than 1.8 correlated with reduced graft failure and greater than 2 with mortality. Alanine-aminotransferase (ALT) reduction in the first 48h post transplantation also correlated with outcomes.
A scoring system with these three variables allowed us to classify our patients into three groups of risk for early graft failure and mortality.
Ectopic or heterotopic pancreas is defined as the presence of pancreatic tissue in an anatomical place not related to the pancreas, being it most frequent locations the stomach and small bowel. Its ...finding in the gallbladder is exceptional. Since the first case was reported by Otschkin in 1916, about 30 cases have been described in literature. We report the case of a 43 years-old male patient who had an urgent laparoscopic cholecystectomy with the diagnosis of acute cholecystitis, which pathological study showed the existence of chronic cholecystitis with heterotopic pancreatic tissue in the gallbladder wall.
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