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Background: Portal vein arterialization (PVA) is a possible option when hepatic artery reconstruction is impossible during liver resection. The aim of this study was to review the literature on the clinical application of PVA in hepatopancreatobiliary (HPB) surgery. Methods: We performed a systematic review according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. We systematically searched the PubMed, Embase and Web of Science databases until December 2019. Experimental (animal) studies, review articles and letters were excluded. Results: Twenty studies involving 57 patients were included. Cholangiocarcinoma was the most common indication for surgery (40 patients [74%]). An end-to-side anastomosis between a celiac trunk branch and the portal vein was the main PVA technique (35 patients [59%]). Portal hypertension was the most common longterm complication (12 patients [21%] after a mean of 4.1 mo). The median followup period was 12 (range 1-87) months. The 1-, 3- and 5-year survival rates were 64%, 27% and 20%, respectively. Conclusion: Portal vein arterialization can be considered as a rescue option to improve the outcome in patients with acute liver de-arterialization when arterial reconstruction is not possible. To prevent portal hypertension and liver injuries due to thrombosis or overarterialization, vessel calibre adjustment and timely closure of the anastomosis should be considered. Further prospective experimental and clinical studies are needed to investigate the potential of this procedure in patients whose liver is suddenly de-arterialized during HPB procedures. Contexte: L'arterialisation de la veine porte (AVP) est une option envisageable lorsqu'il est impossible de reconstruire l'artere hepatique au moment d'une resection du foie. Le but de cette etude etait de faire le point sur la litterature concernant l'application clinique de l'AVP en cours de chirurgie hepatopancreatobiliaire (HPB). Methodes: Nous avons procede a une revue systematique selon les directives PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses). Nous avons interroge systematiquement les bases de donnees PubMed, Embase et Web of Science jusqu'a decembre 2019. Les etudes experimentales (chez l'animal), les articles de synthese et les lettres ont ete exclus. Resultats : Vingt etudes regroupant 57 patients ont ete incluses. Le cholangiocarcinome etait la plus frequente indication de la chirurgie (40 patients [74 %]). L'anastomose terminolaterale d'une branche du tronc caeliaque avec la veine porte a ete la principale technique dAVP (35 patients [59 %]). L'hypertension portale a ete la plus frequente complication (12 patients [21 %] apres une moyenne de 4,1 mois). Le suivi median a ete de 12 mois (eventail, 1-87 mois). Les taux de survie moyens a 1, 3 et 5 ans ont ete de 64 %, 27 % et 20 %, respectivement. Conclusion : L'arterialisation de la veine porte peut etre consideree comme une option de dernier ressort pour ameliorer l'etat des patients victimes d'une desarterialisation hepatique aigue lorsque la reconstruction arterielle est impossible. Pour prevenir l'hypertension portale et les lesions au foie dues a la thrombose ou a l'hyperarte rialisation, il faut veiller a ajuster le calibre vasculaire et fermer rapidement l'ana stomose. D'autres etudes experimentales et cliniques prospectives s'imposent afin d'analyser le potentiel de cette intervention chez les patients dont le foie se trouve subitement desarterialise durant une chirurgie HPB., Over the past decade, surgical developments, better patient selection and advances in perioperative management have increased the rate of liver resection for benign and malignant liver lesions. (1,2) Although liver [...]

Although subtypes of pancreatic ductal adenocarcinoma (PDAC) have been described, this malignancy is clinically still treated as a single disease. Here we present patient-derived models representing the full spectrum of previously identified quasimesenchymal (QM-PDA), classical and exocrine-like PDAC subtypes, and identify two markers--HNF1A and KRT81--that enable stratification of tumors into different subtypes by using immunohistochemistry. Individuals with tumors of these subtypes showed substantial differences in overall survival, and their tumors differed in drug sensitivity, with the exocrine-like subtype being resistant to tyrosine kinase inhibitors and paclitaxel. Cytochrome P450 3A5 (CYP3A5) metabolizes these compounds in tumors of the exocrine-like subtype, and pharmacological or short hairpin RNA (shRNA)-mediated CYP3A5 inhibition sensitizes tumor cells to these drugs. Whereas hepatocyte nuclear factor 4, alpha (HNF4A) controls basal expression of CYP3A5, drug-induced CYP3A5 upregulation is mediated by the nuclear receptor NR1I2. CYP3A5 also contributes to acquired drug resistance in QM-PDA and classical PDAC, and it is highly expressed in several additional malignancies. These findings designate CYP3A5 as a predictor of therapy response and as a tumor cell-autonomous detoxification mechanism that must be overcome to prevent drug resistance., PDAC is a very aggressive disease with poor prognosis (1). In both Europe and the USA, pancreatic cancer is the fourth leading cause of cancer deaths (2,3). Treatment with gemcitabine [...]

The composition of tumor-targeted T cell infiltrates is a major prognostic factor in colorectal cancer (CRC) outcome; however, the functional role of these populations in prolonging patient survival remains unclear. Here, we evaluated 190 patients with CRC for the presence of functionally active tumor-infiltrating lymphocytes (TILs), the tumor specificity of these TILs, and the correlation between patient TILs and long-term survival. Using intracytoplasmic cytokine staining in conjunction with HLA multimers loaded with tumor peptide and antigen-specific cytokine secretion assays, we determined that TNF-α expression delineates a population of tumor antigen-specific (TA-specific) cytotoxic T lymphocytes (CTLs) present within tumors from patients with CRC. Upregulation of TNF-α expression in TILs strongly correlated with an increase in the total amount of intratumoral TNF-α, which is indicative of tumor-specific CTL activity. Moreover, a retrospective multivariate analysis of 102 patients with CRC, which had multiple immune parameters evaluated, revealed that increased TNF-α concentration was an independent prognostic factor. Together, these results indicate that the prognostic impact of T cell infiltrates for CRC maybe largely based on subpopulations of active TA-specific T cells within the tumor, suggesting causal implication for these cells in patient survival. Additionally, these results support the use of intratumoral TNF-α, which is indicative of T cell function, as a prognostic parameter for CRC., Introduction Colorectal cancer (CRC) is the third most frequent malignancy worldwide. Each year there are approximately 1 million new cases of CRC and half a million deaths attributable to this [...]

A study was conducted to evaluate and compare the safety and efficacy of adjuvant chemotherapy treatment with fluorouracil plus folinic acid as against gemcitabine following pancreatic cancer resection. Results indicated that treatment with fluorouracil plus folinic acid was found to be more effective than gemcitabine in improving outcomes in the case of such patients.

Autoantibodies, a hallmark of both autoimmunity and cancer, represent an easily accessible surrogate for measuring adaptive immune responses to cancer. Sera can now be assayed for reactivity against thousands of proteins using microarrays, but there is no agreed-upon standard to analyze results. We developed a set of tailored quality control and normalization procedures based on ELISA validation to allow patient comparisons and determination of individual cutoffs for specificity and sensitivity. Sera from 60 patients with pancreatic cancer, 51 patients with ovarian cancer, and 53 age-matched healthy donors were used to assess the binding of IgG antibodies against a panel of >8000 human antigens using protein microarrays and fluorescence detection. The resulting data interpretation led to the definition and ranking of proteins with preferred recognition by the sera from cancer patients in comparison with healthy donors, both by frequency and strength of signal. We found that 202 proteins were preferentially immunogenic in ovarian cancer sera compared to 29 in pancreatic cancer, with few overlaps. Correlates of autoantibody signatures with known tumor expression of corresponding antigens, functional pathways, clinical stage, and outcome were examined. Serological analysis of arrays displaying the complete human proteome (seromics) represents a new era in cancer immunology, opening the way to defining the repertoire of the humoral immune response to cancer. serum antibody | biomarkers | protein microarrays | serology | autoantigen doi/ 10.1073/pnas.0914213107

Chronic inflammation, fibrosis, atrophy, malignant transformation, and thromboembolic events are hallmarks of chronic pancreatic disease. Extracellular nucleotides have been implicated as inflammatory mediators in many pathological situations. However, there are minimal data detailing expression of ectonucleotidases and type-2 purinergic receptors (P2R) in chronic pancreatitis and pancreatic cancer. We have therefore defined tissue distribution and localization of the CD39 family of ectonucleotidases and associated P2R in human disease. Transcripts of ectonucleotidases (CD39 and CD39L1) together with P2R (P2[X.sub.7], P2[Y.sub.2], and P2[Y.sub.6]) are significantly increased in both chronic pancreatitis and pancreatic cancer. CD39 and CD39L1 are preferentially associated with the vasculature and stromal elements in pathological tissues. P2[X.sub.7] mRNA upregulation was associated with chronic pancreatitis, and heightened protein expression was found to be localized to infiltrating cells. P2[Y.sub.2] was markedly upregulated in biopsies of pancreatic cancer tissues and expressed by fibroblasts adjacent to tumors. High-tissue mRNA levels of CD39 significantly correlated with better long-term survival after tumor resection in patients with pancreatic cancer. Heightened expression patterns and localization patterns of CD39, P2[X.sub.7], and P2[Y.sub.2] infer associations with chronic inflammation and neoplasia of the pancreas. Our data suggest distinct roles for CD39 and P2-purinergic signaling in both tissue remodeling and fibrogenesis with respect to human pancreatic diseases. type-2 purinergic receptors; chronic pancreatitis; pancreatic cancer; pancreas

In acute pancreatitis, local as well as systemic organ complications are mediated by the activation of various inflammatory cascades. The role of complement in this setting is unclear. The aim of the present study was to determine the level of complement activation in experimental pancreatitis, to evaluate the interaction of complement and leukocyte-endothelium activation, and to assess the effects of complement inhibition by soluble complement receptor 1 (sCR1) in this setting. Necrotizing pancreatitis was induced in Wistar rats by the combination of intravenous cerulein and retrograde infusion of glycodeoxycholic acid into the biliopancreatic duct; edematous pancreatitis was induced by intravenous cemlein only. In control animals, a sham operation (midline laparotomy) was performed. Complement activation, leukocyte sequestration, and pancreatic as well as pulmonary injury were assessed in the presence/ absence of sCR1. Increased levels of C3a were found in necrotizing but not in edematous pancreatitis. When complement activation in necrotizing pancreatitis was blocked by sCR1, levels of C3a and total hemolytic activity (CH50) were decreased. Leukocyte-endothelial interaction, as assessed by intravital microscopy, and pancreatic as well as pulmonary organ injury (wet-to-dry weight ratio, MPO activity, and histology) were ameliorated by sCR1. As a result of the present study, necrotizing but not edematous pancreatitis is characterized by significant and early complement activation. Based on the interaction of complement and leukocytes, complement inhibition by sCR1 may be a valuable option in the treatment of leukocyte-associated organ injury in severe pancreatitis. necrotizing pancreatitis; complement activation; soluble complement receptor 1; leukocyte endothelial interaction; lung injury

The extracellular matrix (ECM) facilitates pancreatic cancer cells survival, which is of central importance for pancreatic adenocarcinoma that is highly fibrotic. Here, we show that reactive oxygen species (ROS) mediate the prosurvival effect of ECM in human pancreatic cancer cells. Fibronectin and laminin stimulated ROS production and NADPH oxidase activation in pancreatic cancer cells. Both pharmacological and molecular approaches show that fibronectin stimulated ROS production through activation of NADPH oxidase and NADPH oxidase-independent pathways and that 5-1ipoxygenase (5-LO) mediates both these pathways. Analyses of the mechanisms of ROS production by ECM proteins and growth factors indicate that activation of NADPH oxidase (Nox4) is a common mechanism employed both by ECM proteins and growth factors to increase ROS in pancreatic cancer cells. We also found that Nox4 is present in human pancreatic adenocarcinoma tissues and that these tissues display membrane NADPH oxidase activity. ECM proteins and growth factors activate NADPH oxidase through different mechanisms; in contrast to ECM proteins, growth factors activate NADPH oxidase through 5-LO-independent mechanisms. Inhibition of 5-LO or NADPH oxidase with pharmacological inhibitors of these enzymes and with Nox4 or 5-LO antisense oligonucleotides markedly stimulated apoptosis in cancer cells cultured on fibronectin. Our results indicate that ROS generation via 5-LO and downstream NADPH oxidase mediates the prosurvival effect of ECM in pancreatic cancer cells. These mechanisms may play an important role in pancreatic cancer resistance to treatments and thus represent novel therapeutic targets. pancreas

In acute pancreatitis, ICAM-1 is upregulated in various organs and contributes to the development of organ injury. To investigate the effects of pancreatic proteases on ICAM-I expression and their role in the early process of eukocyte migration, human umbilical vein endothelial cells (HUVECs) were incubated with serum subjected to limited trypsin digestion and Wistar rats were injected with trypsin. Significant upregulation of membrane-bound ICAM-1 was seen on HUVECs incubated with trypsinated serum. Likewise, soluble ICAM-1 increased in the supernatant of HUVECs. Changes of membrane-bound ICAM-I and soluble 1CAM-1 were maximal with high concentrations of trypsin. HUVECs incubated with TNF-[alpha] (positive control) showed similar changes. In the pancreas and lungs of animals infused with trypsin, ICAM-1 and leukocyte sequestration were increased compared with controls. Reflecting the relevance of protease-induced ICAM-1 expression in leukocyte migration, leukocyte-endothelium interaction, as assessed by intravital microscopy, was markedly increased by trypsin. Inhibition of ICAM-1 ameliorated these changes significantly. In conclusion, trypsinated serum induces the upregulation of both membrane-bound ICAM-1 on endothelial cells and soluble ICAM-1. These changes contribute to the early steps of leukocyte migration in acute pancreatitis. The role of soluble ICAM-1 remains to be investigated. adhesion molecules; endothelial cells; proteases; systemic inflammatory response syndrome

Objective: To investigate the perioperative and oncologic long-term outcomes of patients with LAPC after surgical resection at a high-volume center for pancreatic surgery. Background: The role of surgery in LAPC with arterial involvement is controversial. Methods: We analyzed 385 consecutive patients undergoing PAR (n = 195) or PAD (n = 190) of the encased artery for LAPC between January 1, 2003 and April 30, 2019. Results: There were 183 total pancreatectomies, 113 partial pancreatoduodenectomies, 79 distal pancreatectomies, and 10 resections for tumor recurrences, including 121 multivisceral resections and 171 venous resections. Forty-three patients (11.4%) had resectable oligometastatic disease. All of the 190 patients undergoing PAD (100%) and 95 of the 195 patients undergoing PAR (48.7%) received neoadjuvant chemotherapy. The R0 (circumferential resection margin negative) resection rate was 28%. The median hospital stay was 15 days (range: 3-236). The median survival after surgery for LAPC was 20.1 months and the overall 5-year survival rate 12.5%. In-hospital mortality was 8.8% for the entire patient cohort (n = 385). With increasing case load and growing expertise, there was a significant reduction of in-hospital mortality to 4.8% (n = 186) after 2013 (P = 0.005). The learning curve of experienced pancreatic surgeons for PAR was 15 such procedures. Conclusion: Our data demonstrate that an arterial surgical approach is effective in LAPC with promising long-term survival. PAD after neoadjuvant treatment is safe. PAR is a technically demanding procedure and requires a high level of expertise. [ABSTRACT FROM AUTHOR]