cefoxitin and Pancreatic-Neoplasms

Surgical site infection after pancreaticoduodenectomy is often caused by pathogens resistant to standard prophylactic antibiotics, suggesting that broad-spectrum antibiotics may be more effective prophylactic agents. This article describes the rationale and methodology underlying a multicenter randomized trial evaluating piperacillin-tazobactam compared with cefoxitin for surgical site infection prevention following pancreaticoduodenectomy. As the first US randomized surgical trial to utilize a clinical registry for data collection, this study serves as proof of concept for registry-based clinical trials.

Topics: Antibiotic Prophylaxis; Cefoxitin; Clinical Trials, Phase III as Topic; Humans; Pancreatic Neoplasms; Pancreaticoduodenectomy; Piperacillin, Tazobactam Drug Combination; Randomized Controlled Trials as Topic; Registries; Surgical Wound Infection

Topics: Amylases; Antigens, Neoplasm; Antigens, Tumor-Associated, Carbohydrate; Biogenic Polyamines; Biomarkers, Tumor; CA-19-9 Antigen; Carcinoembryonic Antigen; GPI-Linked Proteins; Humans; Isoenzymes; Membrane Glycoproteins; Mesothelin; Oligosaccharides; Pancreatic Elastase; Pancreatic Neoplasms; Sialyl Lewis X Antigen

Human pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive and lethal malignancies in the world and despite great efforts in research types of treatment remain limited. A frequently detected alteration in PDACs is a truncated O-linked N-acetylgalactosamine (GalNAc) glycosylation with expression of the Tn antigen. Changes in O-glycosylation affect posttranslationally modified O-GalNAc proteins resulting in profound cellular alterations. Tn antigen is a tumor associated glycan detected in 75-90 % of PDACs and up to 67 % in its precursor lesions. Since the role of Tn antigen expression in PDAC is insufficiently understood we analyzed the impact of COSMC mediated Tn antigen expression in two human PDAC cell lines on cellular oncogenic properties.. Forced expression of Tn antigen on O-glycosylated proteins in pancreatic cancer cells was induced by lentiviral-mediated knockdown of the COSMC chaperone, which prevented O-glycan elongation beyond the initial GalNAcα1- residue on O-linked glycoproteins. Altered O-GalNAc glycosylation was analyzed in human pancreatic cancer cell lines Panc-1 and L3.6pl using Western and Far-Western blot as well as immunocytochemical techniques. To assess the biological implications of COSMC function on oncogenic properties, cell viability assays, scratch assays combined with live cell imaging, migration and apoptosis assays were performed. Lectin based glycoprotein enrichment with subsequent mass spectrometric analysis identified new cancer O-GalNAc modified proteins. Expression of Tn antigen bearing Nucleolin in patient derived PDAC tumor specimens was evaluated and correlated with clinicopathological data.. Tn antigen expression was induced on various O-GalNAc glycoproteins in COSMC deficient cell lines compared to the control. Proliferation was reduced (p < 0.001) in COSMC knockdown cells, whereas migration was increased (p < 0.001) and apoptosis was decreased (p = 0.03), highlighting the importance of Tn antigen expression on metastatic and anti-apoptotic behavior of PDAC derived cells. Nucleolin was identified as O-GalNAc modified protein in COSMC deficient PDAC cell lines. Interestingly, immunohistochemical staining and co-localization studies of patient derived PDACs revealed poor survival for patients with strong co-localization of Tn antigen and Nucleolin (p = 0.037).. This study substantiates the influence of altered O-glycan (Tn/STn) expression on oncogenic properties in pancreatic cancer and identifies O-GalNAc modified Nucleolin as novel prognostic marker.

Topics: Adenocarcinoma; Antigens, Tumor-Associated, Carbohydrate; Carcinogenesis; Carcinoma, Pancreatic Ductal; Cell Line, Tumor; Cell Movement; Cell Proliferation; Cell Survival; Gene Expression Regulation, Neoplastic; Gene Knockdown Techniques; Glycosylation; Humans; Mass Spectrometry; Molecular Chaperones; N-Acetylgalactosaminyltransferases; Neoplasm Proteins; Nucleolin; Pancreatic Neoplasms; Phosphoproteins; Polysaccharides; RNA-Binding Proteins; RNA, Messenger

Topics: Aged; Anti-Bacterial Agents; Bacteremia; Bacterial Proteins; beta-Lactam Resistance; beta-Lactamases; Catheter-Related Infections; Cefoxitin; Cross Infection; Diarrhea; Drug Resistance, Multiple, Bacterial; Drug Therapy, Combination; Enterococcus faecalis; Glycopeptides; Humans; Klebsiella Infections; Klebsiella pneumoniae; Male; Pancreatic Neoplasms; Pneumonia, Bacterial; Postoperative Complications; Prostatitis; Substrate Specificity; Urinary Catheterization

The aim of this study was to evaluate the expression of blood group Tn and sialyl-Tn antigens in the pancreas to determine whether they could help to interpret histochemically needle biopsies obtained from the pancreas. Lectin and immunohistochemistry was carried out using the biotin-labeled Vicia villosa agglutinin isolectin B4 and the mouse monoclonal antibody MLS102 to detect the Tn and sialyl-Tn blood-group antigens in the pancreas. All the pancreatic ductal adenocarcinomas (11/11) were positively stained by V. villosa agglutinin and MLS102 monoclonal antibody. None of the normals or chronic pancreatitics bound MLS102 monoclonal antibody. The acini of all the normals and chronic pancreatitics were V. villosa agglutinin positive, which was absent in the normal ductal cells and present only sparingly in the chronic pancreatitis ductal tissues (10/16). Thus, both the Tn and the sialyl-Tn blood-group antigens are present in pancreatic ductal tissues that have undergone malignant transformation. MLS102 is superior to V. villosa agglutinin in distinguishing malignant from normal and nonmalignant pancreatic tissues in needle biopsies.

Topics: Adenocarcinoma; Antibodies, Monoclonal; Antigens, Tumor-Associated, Carbohydrate; Biomarkers, Tumor; Biopsy, Needle; Chronic Disease; Humans; Immunohistochemistry; Lectins; Pancreas; Pancreatic Neoplasms; Pancreatitis; Plant Lectins

Pancreatic cancer has a poor prognosis, and early diagnosis of carcinoma and discrimination between malignant and benign conditions are difficult. Many pancreatic cancer-associated antigens, such as CA 19-9, DU-PAN-2, YPan-1, and SPan-1, have been studied. However, expression of Tn, sialosyl-Tn, and T antigens in tissues of different types of pancreatic neoplasms has not been investigated systematically. Moreover, little is known about the distribution of different types of apomucins in the pancreas.. The expression of Tn, sialosyl-Tn, and T antigens and DF3 (mammary type apomucin) and intestinal MRP (intestinal type apomucin) was examined immunohistochemically in 47 pancreatic tumors: 36 invasive ductal carcinomas, 5 intraductal papillary tumors, and 6 adenomas.. In normal pancreatic tissues, neither Tn nor sialosyl-Tn antigen was expressed. In contrast, expression of both Tn and sialosyl-Tn antigens was observed in all the invasive ductal carcinomas and intraductal papillary tumors. None of the adenomas expressed both Tn and sialosyl-Tn. DF3 antigen was expressed in all invasive ductal carcinomas but not in intraductal papillary tumors, whereas intestinal MRP was expressed in all the intraductal papillary tumors but not in the invasive ductal carcinomas.. The results from this study suggest that the expression of the mucin core protein and mucin carbohydrate antigens is correlated with the biologic behavior of pancreatic tumors. In particular, the expression of mammary type mucin core protein and intestinal type mucin core protein showed a striking contrast between invasive ductal carcinomas with a poor prognosis and intraductal papillary tumors with a favorable prognosis.

Topics: Adenoma; Antigens, Neoplasm; Antigens, Tumor-Associated, Carbohydrate; Antigens, Viral, Tumor; Biomarkers, Tumor; Carcinoma, Intraductal, Noninfiltrating; Carcinoma, Papillary; Humans; Immunohistochemistry; Membrane Glycoproteins; Mucin-1; Mucin-2; Mucins; Neoplasm Proteins; Pancreas; Pancreatic Neoplasms

Carbohydrate antigens representing some of the initial steps in mucin O-linked glycosylation were examined in specimens of normal pancreas, chronic pancreatitis, and pancreatic adenocarcinoma. Tn antigen, recognized by Vicia villosa lectin, was expressed by all specimens of normal pancreas (acinar cells) and pancreatic cancers and all but one case of chronic pancreatitis. Sialosyl Tn antigen, recognized by monoclonal antibody TKH2, was expressed in a cancer-associated fashion, being completely absent in normal pancreas but expressed by 56% of chronic pancreatitis and 97% of pancreatic cancers. T antigen, recognized by monoclonal antibody AH9-16, was expressed in 68% of normal pancreas (acinar cells), 67% of chronic pancreatitis, and 48% of pancreatic cancer tissues. These results indicate that normal acinar cells of the pancreas are capable of expressing selected carbohydrate structures associated with the initial steps of mucin glycosylation. The marked expression of sialosyl Tn compared with T antigen in pancreatic cancers suggests that with malignant transformation there is selective usage of glycosyltransferase enzymes involved in mucin oligosaccharide synthesis.

Topics: Adenocarcinoma; Adenocarcinoma, Mucinous; Antibodies, Monoclonal; Antigens, Neoplasm; Antigens, Tumor-Associated, Carbohydrate; Biomarkers, Tumor; Chronic Disease; Disaccharides; Humans; Immunoenzyme Techniques; Pancreas; Pancreatic Neoplasms; Pancreatitis

Expression of blood-group antigens A, B, Le(a), sialyl-Le(a) (sLe(a)), Le(b), Le(x), Le(y), precursor type I, Tn and sialyl-Tn (sTn) was examined in non-neoplastic pancreas (n = 37) and pancreas cancer (n = 21) using mouse monoclonal antibodies (MAbs). Immunohistochemical assays were performed on sections of paraffin-embedded tissues using the avidin-biotin complex method. In normal pancreas, antibodies detecting Le(a), sLe(a) and Tn reacted with ductal epithelium, and antibodies detecting A and B reacted with acini and ducts, independently of secretor status. Le(x) was weakly expressed in ducts and acini, and sTn could not be detected in normal pancreas. Expression of Le(b), Le(y) and precursor type I was regulated by secretor status: Le(b) and Le(y) were expressed in ducts of secretor and Le(a-b-) individuals, but not in ducts of non-secretors; precursor type I was weakly expressed in acini and ducts of non-secretors and Le(a-b-) individuals, and was absent in acini and ducts of secretors. The following alterations in the expression of blood-group antigens were observed in pancreas cancer: (1) enhanced expression of Le(x), Tn and sTn; (2) enhanced expression of precursor type I independently of secretor status; (3) loss of regulation of Le(b) by the secretor gene; (4) decreased expression of Le(y). The weak expression of precursor type I. Tn and sTn in non-neoplastic pancreas, and their stronger expression in pancreas cancer, suggests that up-regulation of their expression is associated with malignant transformation of pancreatic duct cells.

Topics: ABO Blood-Group System; Antibodies, Monoclonal; Antigens, Neoplasm; Antigens, Tumor-Associated, Carbohydrate; Biomarkers, Tumor; Blood Group Antigens; Humans; Immunoenzyme Techniques; Lewis Blood Group Antigens; Pancreas; Pancreatic Neoplasms