Anubhav Mittal

Fluid therapy in acute pancreatitis: anybody's guess.

Objective: The aim of this study was to systematically review and evaluate the quality of current evidence about fluid therapy (FT) in acute pancreatitis (AP). Background: Intravenous FT is thought to be important in the early management of patients with AP. Clinically relevant questions remain regarding the type of fluid, the rate of administration, and the goal of FT. Methods: A comprehensive literature search for human studies was performed using online databases (MEDLINE, EMBASE, PubMed, and the Cochrane Library). The quality of the entire body of evidence was then graded according to the Grading of Recommendations Assessment, Development and Evaluation Working Group guidelines in relation to 3 key areas: type of fluid, rate of fluid administration, and goal-directed FT. Results: The initial search yielded 410 studies, of which 15 met the inclusion criteria. Only 2 randomized studies compared types of fluids. Nine studies looked at aggressive versus nonaggressive resuscitation protocols, of which 4 concluded that an aggressive approach yielded better outcomes and 5 concluded that a nonaggressive approach was better. Two studies investigated goal-directed FT, using different goals; one demonstrating benefit and the other none. Analysis of the body of evidence as per the Grading of Recommendations Assessment, Development and Evaluation Working Group revealed that the majority of evidence was of low or very low quality. Conclusions: FT is considered a cornerstone of the early management of patients with AP and yet the evidence on which it is based remains paltry and of poor quality. This systematic review has demonstrated the equipoise necessary for the design of randomized controlled trials to answer pressing questions relating to the type of fluid, the rate of administration, and how FT should be guided.

Changes in the mesenteric lymph proteome induced by hemorrhagic shock.

Biologically active factors produced by the intestine and transported by the aqueous and protein fraction of mesenteric lymph are now thought to contribute significantly to the development of distant organ failure in hemorrhagic shock. Despite the likely relevance of the protein composition of mesenteric lymph conditioned by hemorrhagic shock, there is no detailed description of its proteome. The aim of this study was to provide the first comprehensive description of the proteome of hemorrhagic shock-conditioned mesenteric lymph. Mesenteric lymph was collected from 16 male Wistar rats randomized to group 1 (n = 8) sham control and group 2 (n = 8) with hemorrhagic shock. The lymph was subjected to proteomic analysis using iTRAQ and liquid chromatography-tandem mass spectrometry. Sixty of the 245 proteins had a significant increase in their relative abundance in the hemorrhagic shock group. A bioinformatics approach highlighted the importance of the key gene ontology pathways relating to response to injury and metabolic responses as changing most significantly in shock. Using an interactome, we identified several highly connected proteins: 14-3-3 Zeta, 14-3-3 epsilon, actin, aldolase A, calmodulin, cofilin 1, cystatin C, fatty acid-binding protein 4, profilin 1, prolyl 4-hydrolase, peptidylprolyl isomerase, and transgelin. This study provides the first detailed description of protein changes in hemorrhagic shock-conditioned mesenteric lymph, and using a bioinformatics approach, we identified several targets for possible further research.ABBREVIATIONS-HS-hemorrhagic shock; ML-mesenteric lymph; HS-ML-hemorrhagic shock-conditioned mesenteric lymph; MODS-multiple organ dysfunction syndrome; LC-liquid chromatography; MS-mass spectrometry

Loss of BAP1 Expression Occurs Frequently in Intrahepatic Cholangiocarcinoma.

AbstractBRCA1-associated protein 1 (BAP1) is a deubiquitinating enzyme that functions as a tumor suppressor gene. Double hit BAP1 inactivation has been reported in a range of tumor types, including intrahepatic cholangiocarcinoma (ICC), sometimes in association with germline mutation.We performed immunohistochemistry for BAP1 on a well-characterized cohort of 211 ICC patients undergoing surgical resection with curative intent at 3 institutions based in 3 different countries. The median age at diagnosis was 65 years (range, 36.5–86) and 108 (51%) were men. Negative staining for BAP1 (defined as completely absent nuclear staining in the presence of positive internal controls in nonneoplastic cells) occurred in 55 ICCs (26%). BAP1 loss predicted a strong trend toward improved median survival of 40.80 months (95% CI, 28.14–53.46) versus 24.87 months (95% CI, 18.73–31.01), P = 0.059). In a multivariate model including age, sex, BAP1 status, tumor stage, tumor grade, lymphovascular invasion, and tumor size, female sex was associated with improved survival (hazard ratio [HR] 0.54; 95% CI, 0.34–0.85), while advanced tumor stage and lymphovascular invasion (HR 1.89; 95% CI, 1.09–3.28) correlated with decreased survival. In a multivariate analysis, high grade tumors were associated with BAP1 loss (odds ratio [OR] 3.32; 95% CI, 1.29–8.55), while lymphatic invasion was inversely associated with BAP1 loss (OR 0.36; 95% CI, 0.13–0.99).In conclusion, we observed a trend toward improved prognosis in ICC associated with absent expression of BAP1 and an association of BAP1 loss with higher histological grade and absent lymphatic invasion. Female sex was associated with improved survival while advanced tumor stage and lymphatic invasion were associated with decreased survival.

Somatostatin Receptor SSTR-2a Expression Is a Stronger Predictor for Survival Than Ki-67 in Pancreatic Neuroendocrine Tumors.

AbstractSomatostatin receptors (SSTR) are commonly expressed by neuroendocrine tumors. Expression of SSTR-2a and SSTR-5 may impact symptomatic management; however, the impact on survival is unclear. The aim of this study is to correlate SSTR-2a and SSTR-5 expression in pancreatic neuroendocrine tumors (PNETs) with survival.This study is designed to determine the prognostic significance of somatostatin receptors SSTR-2a and SSTR-5 in PNETs.This retrospective cohort study included cases of resected PNETs between 1992 and 2014. Clinical data, histopathology, expression of SSTR and Ki-67 by immunohistochemistry, and long-term survival were analyzed.A total of 99 cases were included in this study. The mean age was 57.8 years (18–87 years) and median tumor size was 25 mm (range 8–160 mm). SSTR-2a and SSTR-5 expression was scored as negative (n = 19, 19.2%; n = 75, 75.8%, respectively) and positive (n = 80, 80.1%; n = 24, 24.2%). The median follow-up was 49 months. SSTR-2a expression was associated with improved overall survival, with cumulative survival rates at 1, 3, and 5 years being 97.5%, 91.5%, and 82.9%, respectively. Univariate analysis demonstrated better survival in SSTR-2a positive patients (log rank P = 0.04). SSTR-5 expression was not associated with survival outcomes (log rank P = 0.94). Multivariate analysis showed that positive SSTR-2a expression is a stronger prognostic indicator for overall survival [Hazard Ratio (HR): 0.2, 95% Confidence interval (CI): 0.1–0.8] compared to high Ki-67 (HR: 0.8, 95% CI: 0.1–5.7).Expression of SSTR-2a is an independent positive prognostic factor for survival in PNETs.

Early organ-specific mitochondrial dysfunction of jejunum and lung found in rats with experimental acute pancreatitis

INTRODUCTION Multiple organ dysfunction is the main cause of death in severe acute pancreatitis. Primary mitochondrial dysfunction plays a central role in the development and progression of organ failure in critical illness. The present study investigated mitochondrial function in seven tissues during early experimental acute pancreatitis. METHODS Twenty-eight male Wistar rats (463 ± 2 g; mean ± SEM) were studied. Group 1 (n= 8), saline control; Group 2 (n= 6), caerulein-induced mild acute pancreatitis; Group 3 (n= 7) sham surgical controls; and Group 4 (n= 7), taurocholate-induced severe acute pancreatitis. Animals were euthanased at 6 h from the induction of acute pancreatitis and mitochondrial function was assessed in the heart, lung, liver, kidney, pancreas, duodenum and jejunum by mitochondrial respirometry. RESULTS Significant early mitochondrial dysfunction was present in the pancreas, lung and jejunum in both models of acute pancreatitis, however, the Heart, liver, kidney and duodenal mitochondria were unaffected. CONCLUSIONS The present study provides the first description of early organ-selective mitochondrial dysfunction in the lung and jejunum during acute pancreatitis. Research is now needed to identify the underlying pathophysiology behind the organ selective mitochondrial dysfunction, and the potential benefits of early mitochondrial-specific therapies in acute pancreatitis.

Distal pancreatectomy, splenectomy, and celiac axis resection (DPS-CAR): common hepatic arterial stump pressure should determine the need for arterial reconstruction.

BACKGROUND Tumors arising in the neck and body of the pancreas often invade the common hepatic artery and celiac axis (CA), necessitating distal pancreatectomy, splenectomy, and celiac axis resection (DPS-CAR). In these patients, the need for revascularization of the common hepatic artery (CHA) can be avoided on the basis of the pressure change in the CHA after clamping of the CA. METHODS All patients presenting to North Shore Hospital Campus of University of Sydney with advanced pancreatic malignancy of the neck and body between 2007 and 2014 were included in the study. The pressure in the CHA was measured pre- and postclamping of the CA; a decrease of more than 25% in the mean arterial pressure necessitated vascular reconstruction of the CHA. RESULTS Seven patients underwent a DPS-CAR between 2007 and 2014. Arterial reconstruction was required in 2 patients based on a decrease of >25% mean arterial pressure in the CHA after clamping the CA. There was no in hospital or 90-day mortality, and no patients developed ischemic hepatitis. CONCLUSION A single-stage DPS-CAR with selective arterial reconstruction based on the CHA pressure change after clamping the CA is a safe approach.

Patient-derived xenograft models of colorectal cancer in pre-clinical research: a systematic review

AIMS We sought to objectively assess the internal and external validity of patient-derived xenograft (PDX) models as a platform in pre-clinical research into colorectal cancer (CRC). Metastatic disease is the most common cause of death from CRC, and despite significant research, the results of current combination chemotherapy and targeted therapies have been underwhelming for most of this patient group. One of the key factors limiting the success of translational CRC research is the biologically inaccurate models in which new therapies are developed. METHODS We used the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) checklist and SYRCLE (Systematic Review Centre for Laboratory animal Experimentation) guidelines to search Ovid MEDLINE and Embase databases up to July 2015 to identify studies involving PDX models of CRC where the model had been validated across multiple parameters. Data was extracted including host mouse strain, engraftment rate, site of engraftment, donor tumour source and development of metastases in the model. RESULTS Thirteen articles satisfied the inclusion criteria. There was significant heterogeneity amongst the included studies, but overall the median engraftment rate was high (70%) and PDX models faithfully recapitulated the characteristics of their patient tumours on the microscopic, genetic and functional levels. CONCLUSIONS PDX models of CRC have a reasonable internal validity and a high external validity. Developments in xenografting technology are broadening the applications of the PDX platform. However, the included studies could be improved by standardising reporting standards and closed following the ARRIVE (Animals in Research: Reporting In Vivo Experiments) guidelines.

Extended pancreatoduodenectomy as defined by the International Study Group for Pancreatic Surgery is associated with worse survival but not with increased morbidity

BACKGROUND Recently, the International Study Group for Pancreatic Surgery presented a consensus statement on the definition of an extended pancreatoduodenectomy (PD) for pancreatic ductal adenocarcinoma (PDAC). Because extended resections are associated with increased morbidity and mortality, prognostic factors for outcome are mandatory to optimize patient selection. The aim of this study was to apply the new definition of an extended PD and to assess prognostic factors for short-term complications and survival in patients with PDAC. METHODS A retrospective analysis was performed on a prospectively collected database running from 2004 to 2014. Inclusion criteria were all PD resections with histopathology-proven PDAC. Clinical data, operative results, and short- and long-term outcomes were analyzed. RESULTS We included 177 patients who underwent PD for PDAC in this study. Sixty-six patients (37%) underwent a standard PD and 111 (63%) underwent an extended PD. No differences were found in duration of postoperative stay (median, 13 days) or overall complication rate of 35% (n = 61). Severe complications occurred in 24 patients (13%). Male sex (odds ratio, 2.4; 95% CI, 0.9-6.6) was a prognostic factor for severe complications. There was no in-hospital or 90-day mortality in either group. Multivariate survival analysis showed that poor tumor differentiation (hazard ratio [HR], 2.0; 95% CI, 1.3-3.1), lymph node metastasis (HR, 2.3; 95% CI, 1.4-3.9), neural invasion (HR, 1.9; 95% CI, 1.2-3.1), were independent prognostic factors for worse survival. An extended resection was associated with worse survival, but was not an independent prognostic factor (HR, 1.5; 95% CI, 1.0-2.3). CONCLUSION Extended PD is associated with worse survival but not with increased morbidity.

Redox status of acute pancreatitis as measured by cyclic voltammetry: initial rodent studies to assess disease severity.

Objective:To determine whether serum antioxidant capacity as measured by the electrochemical technique cyclic voltammetry could be used to resolve differences in the severity of an inflammatory disease such as acute pancreatitis. Design:Experimental animal study. Setting:Animal laboratory, Department of Surgery, Faculty of Medical and Health Sciences, University of Auckland, New Zealand. Subjects:Male Wistar rats. Interventions:A total of 48 inbred male Wistar rats were studied in five experimental groups. Group 1 (baseline reference, immediate euthanasia, n = 14) had no surgical intervention. Group 2 (sham, n = 9) had identical surgical procedures to the pancreatitis groups except for the intraductal infusion. Groups 3–5 (n = 9, n = 10, and n = 6, respectively) had acute pancreatitis induced by the pancreatic intraductal infusion of 3%, 4%, or 5% sodium taurocholate, respectively. Groups 2–5 were killed after 12 hrs. Measurements and Main Results:Cyclic voltammetry involves scanning the voltage of a working electrode while recording the anodic current produced as the low molecular weight antioxidants in the solution are oxidized on the surface of the working electrode. The current produced is proportional to the combined concentration of the antioxidants. There was a significant positive correlation of the first cyclic voltammetric peak maximum with pancreatic histologic severity (Spearman’s r = .51, p = .007) and with a number of other markers of systemic severity, notably bicarbonate (r = −.57, p = .002), base excess (r = −.65, p < .001), urea (r = .68, p < .001), and calcium (r = −.60, p = .008). The first cyclic voltammetric peak maximum was superior at indicating the severity of the disease state compared with a standard method of total antioxidant capacity measurement. Conclusions:In experimental pancreatitis, the first cyclic voltammetric peak maximum showed significant correlations with histologic and systemic indices of severity. Further clinical studies are now needed to define the role of cyclic voltammetry in monitoring the progression of this and other severe illness in the critical care setting.

Systematic review of peri-operative prognostic biomarkers in pancreatic ductal adenocarcinoma

BACKGROUND Pancreatic ductal adenocarcinoma (PDAC) continues to be associated with a poor prognosis. This systematic review aimed to summarize the literature regarding potential prognostic biomarkers to facilitate validation studies and clinical application. METHODS A systematic review was performed (2004-2014) according to PRISMA guidelines. Studies were ranked using REMARK criteria and the following outcomes were examined: overall/disease free survival, nodal involvement, tumour characteristics, metastasis, recurrence and resectability. RESULTS 256 biomarkers were identified in 158 studies. 171 biomarkers were assessed with respect to overall survival: urokinase-type plasminogen activator receptor, atypical protein kinase C and HSP27 ranked the highest. 33 biomarkers were assessed for disease free survival: CD24 and S100A4 were the highest ranking. 17 biomarkers were identified for lymph node involvement: Smad4/Dpc4 and FOXC1 ranked highest. 13 biomarkers were examined for tumour grade: mesothelin and EGFR were the highest ranking biomarkers. 10 biomarkers were identified for metastasis: p16 and sCD40L were the highest ranking. 4 biomarkers were assessed resectability: sCD40L, s100a2, Ca 19-9, CEA. CONCLUSION This review has identified and ranked specific biomarkers that should be a primary focus of ongoing validation and clinical translational work in PDAC.