Global metabolomic profiling of tumor tissue and paired serum samples to identify biomarkers for response to neoadjuvant FOLFIRINOX treatment of human pancreatic cancer.

Neoadjuvant chemotherapy (NAT) is increasingly used for the treatment of non-metastatic pancreatic ductal adenocarcinoma (PDAC) and is established as a standard of care for borderline resectable and locally advanced PDAC. However, full exploitation of its clinical benefits is limited by the lack of biomarkers that assess treatment response. To address this unmet need, global metabolomic profiling was performed on tumor tissue and paired serum samples from patients with treatment-naïve (TN; n = 18) and neoadjuvant leucovorin calcium (folinic acid), fluorouracil, irinotecan hydrochloride and oxaliplatin (FOLFIRINOX)-treated (NAT; n = 17) PDAC using liquid chromatography mass spectrometry.

Pancreatic duct occlusion with polychloroprene-based glue for the management of postoperative pancreatic fistula after pancreatoduodenectomy-an outdated approach?

Background: Managing postoperative pancreatic fistula (POPF) presents a formidable challenge after pancreatoduodenectomy. Some centers consider pancreatic duct occlusion (PDO) in reoperations following pancreatoduodenectomy as a pancreas-preserving procedure, aiming to control a severe POPF. The aim of the current study was to evaluate the short- and long-term outcomes of employing PDO for the management of the pancreatic stump during relaparotomy for POPF subsequent to pancreatoduodenectomy.

Fatty acids abrogate the growth-suppressive effects induced by inhibition of cholesterol flux in pancreatic cancer cells.

Background: Despite therapeutic advances, the prognosis of pancreatic ductal adenocarcinoma (PDAC) remains extremely poor. Metabolic reprogramming is increasingly recognized as a key contributor to tumor progression and therapy resistance in PDAC. One of the main metabolic changes essential for tumor growth is altered cholesterol flux.

Pancreatic stellate cell-induced gemcitabine resistance in pancreatic cancer is associated with LDHA- and MCT4-mediated enhanced glycolysis.

Background: Profound resistance to chemotherapy remains a major challenge in achieving better clinical outcomes for patients with pancreatic ductal adenocarcinoma (PDAC). Recent studies indicate that gemcitabine (GEM) resistance is promoted both by pancreatic stellate cells (PSCs) and through increased glycolysis. However, it remains unknown whether PSCs affect GEM sensitivity via glycolytic regulation.

Neoadjuvant chemotherapy is associated with an altered metabolic profile and increased cancer stemness in patients with pancreatic ductal adenocarcinoma.

The modest clinical benefits of neoadjuvant chemotherapy (NAT) in pancreatic ductal adenocarcinoma (PDAC) are associated with a lack of robust data on treatment-induced changes in the tumor. To this end, comparative proteomic profiling of tumor tissue samples from treatment-naïve (TN, n = 20) and NAT-treated (n = 22) PDACs was performed. Differentially expressed proteins were identified and correlation with overall survival (OS) was performed.

Morphological Heterogeneity in Pancreatic Cancer Reflects Structural and Functional Divergence.

Inter- and intratumor heterogeneity is an important cause of treatment failure. In human pancreatic cancer (PC), heterogeneity has been investigated almost exclusively at the genomic and transcriptional level. Morphological heterogeneity, though prominent and potentially easily assessable in clinical practice, remains unexplored.

Stellate Cells Aid Growth-Permissive Metabolic Reprogramming and Promote Gemcitabine Chemoresistance in Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDAC), also known as pancreatic cancer (PC), is characterized by an overall poor prognosis and a five-year survival that is less than 10%. Characteristic features of the tumor are the presence of a prominent desmoplastic stromal response, an altered metabolism, and profound resistance to cancer drugs including gemcitabine, the backbone of PDAC chemotherapy. The pancreatic stellate cells (PSCs) constitute the major cellular component of PDAC stroma.

Differential Gemcitabine Sensitivity in Primary Human Pancreatic Cancer Cells and Paired Stellate Cells Is Driven by Heterogenous Drug Uptake and Processing.

Gemcitabine resistance in pancreatic ductal adenocarcinoma (PDAC) is attributed to cancer cell-intrinsic drug processing and the impact of the tumor microenvironment, especially pancreatic stellate cells (PSCs). This study uses human PDAC-derived paired primary cancer cells (PCCs) and PSCs from four different tumors, and the PDAC cell lines BxPC-3, Mia PaCa-2, and Panc-1, to assess the fate of gemcitabine by measuring its cellular uptake, cytotoxicity, and LC-MS/MS-based metabolite analysis. Expression analysis and siRNA-mediated knockdown of key regulators of gemcitabine (hENT1, CDA, DCK, NT5C1A) was performed.

Establishment and Characterization of Paired Primary Cultures of Human Pancreatic Cancer Cells and Stellate Cells Derived from the Same Tumor.

Pancreatic ductal adenocarcinoma (PDAC) is characterized by an extremely poor prognosis, and its treatment remains a challenge. As the existing in vitro experimental models offer only a limited resemblance to human PDAC, there is a strong need for additional research tools to better understand PDAC tumor biology, particularly the impact of the tumor stroma. Here, we report for the first time the establishment and characterization of human PDAC-derived paired primary monolayer cultures of (epithelial) cancer cells (PCCs) and mesenchymal stellate cells (PSCs) derived from the same tumor by the outgrowth method.

Secretion of fibronectin by human pancreatic stellate cells promotes chemoresistance to gemcitabine in pancreatic cancer cells.

Background: Gemcitabine remains a cornerstone in chemotherapy of pancreatic ductal adenocarcinoma (PDAC) despite suboptimal clinical effects that are partly due to the development of chemoresistance. Pancreatic stellate cells (PSCs) of the tumor stroma are known to interact with pancreatic cancer cells (PCCs) and influence the progression of PDAC through a complex network of signaling molecules that involve extracellular matrix (ECM) proteins. To understand tumor-stroma interactions regulating chemosensitivity, the role of PSC-secreted fibronectin (FN) in the development of gemcitabine resistance in PDAC was examined.

Pancreatoduodenectomy with venous resection for ductal adenocarcinoma rarely achieves complete (R0) resection.

Background: Pancreatoduodenectomy with venous resection is considered standard of care for patients with tumour involvement of the superior mesenteric/portal vein (SMV/PV) and deemed justified if an R0-resection can be achieved. The aim of this study was to provide a detailed pathology assessment of the site and extent of margin involvement in specimens resulting from pancreatoduodenectomy with venous resection.

Methods: Retrospective observational study including patients undergoing pancreatoduodenectomy with or without venous resection for pancreatic ductal adenocarcinoma between 2015 and 2017.

Clinical relevance of pancreatobiliary and intestinal subtypes of ampullary and duodenal adenocarcinoma: Pattern of recurrence, chemotherapy, and survival after pancreatoduodenectomy.

Background: The clinical relevance of the classification of ampullary adenocarcinoma (AC) into pancreatobiliary (PB) or intestinal (Int) subtypes has not been resolved.

Methods: Clinicopathological factors, survival, and localization and treatment of recurrence were investigated for patients with AC and duodenal adenocarcinoma (DC) treated by pancreatoduodenectomy from 2000 to 2015.

Results: A total of 109 AC (45 PB, 64 Int) and 71 DC (all Int) were identified.

Commonly Used Pancreatic Stellate Cell Cultures Differ Phenotypically and in Their Interactions with Pancreatic Cancer Cells.

Activated pancreatic stellate cells (PSCs) play a central role in the tumor stroma of pancreatic ductal adenocarcinoma (PDAC). Given the limited availability of patient-derived PSCs from PDAC, immortalized PSC cell lines of murine and human origin have been established; however, it is not elucidated whether differences in species, organ disease status, donor age, and immortalization alter the PSC phenotype and behavior compared to that of patient-derived primary PSC cultures. Therefore, a panel of commonly used PSC cultures was examined for important phenotypical and functional features: three primary cultures from human PDAC, one primary from normal human pancreas, and three immortalized (one from human, two from murine pancreas).

Risk for hemorrhage after pancreatoduodenectomy with venous resection.

Purpose: No consensus exists on the optimal anticoagulation therapy after pancreatoduodenectomy with venous resection (PDVR). The aim of the study was to analyze perioperative outcomes of patients receiving low- vs high-dose anticoagulation therapy and to identify risk factors for postpancreatectomy hemorrhage in patients undergoing PDVR.

Methods: Retrospective study of patients undergoing PDVR at a tertiary referral center between January 2006 and April 2017.

Pancreatic Cancer Chemoresistance to Gemcitabine.

Pancreatic ductal adenocarcinoma (PDAC), commonly referred to as pancreatic cancer, ranks among the leading causes of cancer-related deaths in the Western world due to disease presentation at an advanced stage, early metastasis and generally a very limited response to chemotherapy or radiotherapy. Gemcitabine remains a cornerstone of PDAC treatment in all stages of the disease despite suboptimal clinical effects primarily caused by molecular mechanisms limiting its cellular uptake and activation and overall efficacy, as well as the development of chemoresistance within weeks of treatment initiation. To circumvent gemcitabine resistance in PDAC, several novel therapeutic approaches, including chemical modifications of the gemcitabine molecule generating numerous new prodrugs, as well as new entrapment designs of gemcitabine in colloidal systems such as nanoparticles and liposomes, are currently being investigated.

Portal vein reconstruction using primary anastomosis or venous interposition allograft in pancreatic surgery.

Objective: Superior mesenteric vein/portal vein (SMV/PV) resection and reconstruction during pancreatic surgery are increasingly common. Several reconstruction techniques exist. The aim of this study was to evaluate characteristics of patients and clinical outcomes for SMV/PV reconstruction using interposed cold-stored cadaveric venous allograft (AG+) or primary end-to-end anastomosis (AG-) after segmental vein resections during pancreatic surgery.

Functional heterogeneity in tumor-derived human pancreatic stellate cells: Differential expression of HGF and implications for mitogenic signaling and migration in pancreatic cancer cells.

The pancreatic stellate cell (PSC) is the principal cell type of the desmoplastic stroma of pancreatic ductal adenocarcinoma (PDAC). PSCs interact with cancer cells and influence the progression of the disease through a complex network of signaling molecules including hepatocyte growth factor (HGF). Functional heterogeneity of PSCs within a tumor might conceivably influence tumor progression.

Trends in indications, complications and outcomes for venous resection during pancreatoduodenectomy.

Background: Pancreatoduodenectomy with superior mesenteric-portal vein resection has become a common procedure in pancreatic surgery. The aim of this study was to compare standard pancreatoduodenectomy with pancreatoduodenectomy plus venous resection at a high-volume centre, and to examine trends in management and outcome over a decade for the latter procedure.

Methods: This retrospective observational study included all patients undergoing pancreatoduodenectomy with or without venous resection at Oslo University Hospital between January 2006 and December 2015.

Smoking, alcohol and family history of cancer as risk factors for small intestinal neuroendocrine tumors: a systematic review and meta-analysis.

Objectives: Risk factors for small intestinal neuroendocrine tumors (SI-NETs) are not well understood. The aim of this systematic literature review was to identify risk factors for SI-NET and to further assess these by meta-analysis.

Material And Methods: PubMed and abstracts from the ENETS and NANETS were searched for studies published until May 2015.

Dissection of Pancreatic Resection Specimens.

Specimen grossing is a key step in the pathology examination of pancreatic resection specimens. Optimal display of pathologic changes and extensive tissue sampling are important determinants of the quality of pathology reporting. Divergence in macroscopic examination practice has led to considerable variation in the reporting of factors that are of clinical and prognostic significance.

Upregulation of INS-IGF2 read-through expression and identification of a novel INS-IGF2 splice variant in insulinomas.

Fusion transcripts arising from the combination of exons residing on neighboring genes on the same chromosome may give rise to chimeric or novel proteins. Such read-through transcripts have been detected in different cancers where they may be of pathogenetic interest. In this study, we describe for the first time the expression of a read-through transcript in insulinomas, a functioning neuroendocrine pancreatic neoplasm.