Two urea transporters, UT-A1 and UT-A3, are expressed in the kidney terminal inner medullary collecting duct (IMCD) and are important for the production of concentrated urine. UT-A1, as the largest isoform of all UT-A urea transporters, has gained much attention and been extensively studied; however, the role and the regulation of UT-A3 are less explored. In this study, we investigated UT-A3 regulation by glycosylation modification. A site-directed mutagenesis verified a single glycosylation site in UT-A3 at Asn279. Loss of the glycosylation reduced forskolin-stimulated UT-A3 cell membrane expression and urea transport activity. UT-A3 has two glycosylation forms, 45 and 65 kDa. Using sugar-specific binding lectins, the UT-A3 glycosylation profile was examined. The 45-kDa form was pulled down by lectin concanavalin A (Con A) and Galant husnivalis lectin (GNL), indicating an immature glycan with a high amount of mannose (Man), whereas the 65-kDa form is a mature glycan composed of acetylglucosamine (GlcNAc) and poly-N-acetyllactosame (poly-LacNAc) that was pulled down by wheat germ agglutinin (WGA) and tomato lectin, respectively. Interestingly, the mature form of UT-A3 glycan contains significant amounts of sialic acid. We explored the enzymes responsible for directing UT-A3 sialylation. Sialyltransferase ST6GalI, but not ST3GalIV, catabolizes UT-A3 α2,6-sialylation. Activation of protein kinase C (PKC) by PDB treatment promoted UT-A3 glycan sialylation and membrane surface expression. The PKC inhibitor chelerythrine blocks ST6GalI-induced UT-A3 sialylation. Increased sialylation by ST6GalI increased UT-A3 protein stability and urea transport activity. Collectively, our study reveals a novel mechanism of UT-A3 regulation by ST6GalI-mediated sialylation modification that may play an important role in kidney urea reabsorption and the urinary concentrating mechanism.
by
Raul S. Gonzalez;
Pelin Bagci;
Olca Basturk;
Michelle Reid;
Serdar Balci;
Jessica H. Knight;
So Yeon Kong;
Bahar Memis;
Kee-Taek Jang;
Nobuyuki Ohike;
Takuma Tajiri;
Sudeshna Bandyopadhyay;
Alyssa Krasinskas;
Grace E. Kim;
Jeanette D. Cheng;
Nazmi Adsay
Distal common bile duct carcinoma is a poorly characterized entity for reasons such as variable terminology and difficulty in determining site of origin of intrapancreatic lesions. We compared clinicopathologic features of pancreatobiliary-type adenocarcinomas within the pancreas, but arising from the distal common bile duct, with those of pancreatic and ampullary origin. Upon careful review of 1017 pancreatoduodenectomy specimens with primary adenocarcinoma, 52 (5%) qualified as intrapancreatic distal common bile duct carcinoma. Five associated with an intraductal papillary neoplasm were excluded; the remaining 47 were compared to 109 pancreatic ductal adenocarcinomas and 133 ampullary carcinomas. Distal common bile duct carcinoma patients had a younger median age (58 years) than pancreatic ductal adenocarcinoma patients (65 years) and ampullary carcinoma patients (68 years). Distal common bile duct carcinoma was intermediate between pancreatic ductal adenocarcinoma and ampullary carcinoma with regard to tumor size and rates of node metastases and margin positivity. Median survival was better than for pancreatic ductal adenocarcinoma (P=0.0010) but worse than for ampullary carcinoma (P=0.0006). Distal common bile duct carcinoma often formed an even band around the common bile duct and commonly showed intraglandular neutrophil-rich debris and a small tubular pattern. Poor prognostic indicators included node metastasis (P=0.0010), lymphovascular invasion (P=0.0299), and margin positivity (P=0.0069). Categorizing the tumors based on size also had prognostic relevance (P=0.0096), unlike categorization based on anatomic structures invaded. Primary distal common bile duct carcinoma is seen in younger patients than pancreatic ductal adenocarcinoma or ampullary carcinoma. Its prognosis is significantly better than pancreatic ductal adenocarcinoma and worse than ampullary carcinoma, at least partly because of differences in clinical presentation. Use of size-based criteria for staging appears to improve its prognostic relevance. Invasive pancreatobiliary-type distal common bile duct carcinomas are uncommon in the West and have substantial clinicopathologic differences from carcinomas arising from the pancreas and ampulla.
by
Faiz Gani;
Stephen Buettner;
Gergios A. Margonis;
Cecelia G. Ethun;
George Poultsides;
Thuy Tran;
Kamran Idrees;
Chelsea A. Isom;
Ryan C. Fields;
Bradley Krasnick;
Sharon M. Weber;
Ahmed Salem;
Robert C.G. Martin;
Charles Scoggins;
Perry Shen;
Harveshp D. Mogal;
Carl Schmidt;
Eliza Beal;
Ioannis Hatzaras;
Rivfka Shenoy;
Shishir Maithel;
Timothy M. Pawlik
Background: Although radical re-resection for gallbladder cancer (GBC) has been advocated, the optimal extent of re-resection remains unknown. The current study aimed to assess the impact of common bile duct (CBD) resection on survival among patients undergoing surgery for GBC. Methods: Patients undergoing curative-intent surgery for GBC were identified using a multi-institutional cohort of patients. Multivariable Cox-proportional hazards regression was performed to identify risk factors for a poor overall survival (OS).
Results: Among the 449 patients identified, 26.9% underwent a concomitant CBD resection. The median number of lymph nodes harvested did not differ based on CBD resection (CBD, 4 [IQR: 2–9] vs. no CBD, 3 [IQR: 1–7], P = 0.108). While patients who underwent a CBD resection had a worse OS, after adjusting for potential confounders, CBD resection did not impact OS (HR = 1.40, 95%CI 0.87–2.27, P = 0.170). Rather, the presence of advanced disease (T3: HR = 3.11, 95%CI 1.22–7.96, P = 0.018; T4: HR = 7.24, 95%CI 1.70–30.85, P = 0.007) and the presence of disease at the surgical margin (HR = 2.58, 95%CI 1.26–5.31, P = 0.010) were predictive of a worse OS.
Conclusions: CBD resection did not yield a higher lymph node count and was not associated with an improved survival. Routine CBD excision in the re-resection of GBC is unwarranted and should only be performed selectively.
Background
Most studies have failed to identify any prognostic value of the current T-stage protocol for pancreatic ductal adenocarcinoma (PDAC) by the American Joint Committee on Cancer and the Union for International Cancer Control unless some grouping was performed.
Methods
To document the parameters included in this T-stage protocol, 223 consecutive pancreatoduodenectomy specimens with PDAC were processed by a uniform grossing protocol.
Results
Peripancreatic soft tissue (PST) involvement, the main pT3 parameter, was found to be inapplicable and irreproducible due to lack of a true capsule in the pancreas and variability in the amount and distribution of adipose tissue. Furthermore, 91 % of the cases showed carcinoma in the adipose tissue, presumably representing the PST, and thus were classified as pT3. An additional 4.5 % were qualified as pT3 due to extension into adjacent sites. The T-stage defined as such was not found to have any correlation with survival (p = 0.4). A revised T-stage protocol was devised that defined pT1 as 2 cm or smaller, pT2 as >2–4 cm, and pT3 as larger than 4 cm. This revised protocol was tested in 757 consecutive PDACs. The median and 3-year survival rates of this size-based protocol were 26, 18, 13 months, and 40 %, 26 %, 20 %, respectively (p < 0.0001). The association between higher T-stage and shorter survival persisted in N0 cases and in multivariate modeling. Analysis of the Surveillance, Epidemiology, and End Results database also confirmed the survival differences (p < 0.0001).
Conclusions
This study showed that resected PDACs are already spread to various surfaces of the pancreas, leaving only about 4 % of PDACs to truly qualify as pT1/T2, and that the current T-stage protocol does not have any prognostic correlation. In contrast, as shown previously in many studies, size is an important prognosticator, and a size-based T-stage protocol is more applicable and has prognostic value in PDAC.
by
B. Joseph Elmunzer;
Jose Serrano;
Amitabh Chak;
Steven A. Edmundowicz;
Georgios I. Papachristou;
James M. Scheiman;
Vikesh K. Singh;
Shyam Varadurajulu;
John J. Vargo;
Field Willingham;
Todd H. Baron;
Gregory A. Coté;
Joseph Romagnuolo;
April Wood-Williams;
Emily K. Depue;
Rebecca L. Spitzer;
Cathie Spino;
Lydia D. Foster;
Valerie Durkalski
BACKGROUND: The combination of prophylactic pancreatic stent placement (PSP) - a temporary plastic stent placed in the pancreatic duct - and rectal non-steroidal anti-inflammatory drugs (NSAIDs) is recommended for preventing post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP) in high-risk cases. Preliminary data, however, suggest that PSP may be unnecessary if rectal NSAIDs are administered. Given the costs and potential risks of PSP, we aim to determine whether rectal indomethacin obviates the need for pancreatic stent placement in patients undergoing high-risk ERCP.
METHODS/DESIGN: The SVI (Stent vs. Indomethacin) trial is a comparative effectiveness, multicenter, randomized, double-blind, non-inferiority study of rectal indomethacin alone versus the combination of rectal indomethacin and PSP for preventing PEP in high-risk cases. One thousand four hundred and thirty subjects undergoing high-risk ERCP, in whom PSP is planned solely for PEP prevention, will be randomized to indomethacin alone or combination therapy. Those who are aware of study group assignment, including the endoscopist, will not be involved in the post-procedure care of the patient for at least 48 hours. Subjects will be assessed for PEP and its severity by a panel of independent and blinded adjudicators. Indomethacin alone will be declared non-inferior to combination therapy if the two-sided 95 % upper confidence bound of the treatment difference is less than 5 % between the two groups. Biological specimens will be obtained from trial participants and centrally banked.
DISCUSSION: The SVI trial is designed to determine whether PSP remains necessary in the era of NSAIDs pharmacoprevention. The associated bio-repository will establish the groundwork for important scientific breakthrough.