Faculty Bibliography

BACKGROUND:To date, no consensus has been reached regarding which primary tumor subtypes are managed appropriately with hepatic metastectomy. Specifically, the role of hepatic resection for metastatic periampullary or pancreatic adenocarcinoma remains controversial. METHODS:Between 1995 and 2005, 1563 patients underwent surgical resection for periampullary carcinoma (n=608 patients) or pancreatic adenocarcinoma (head, n=905 patients; tail, n=50 patients). Data on demographics, operative details, primary tumor status, and-when indicated-extent of hepatic metastasis were collected. RESULTS:Of the 1563 patients who underwent resection of periampullary or pancreatic adenocarcinoma, 22 patients (1.4%) underwent simultaneous hepatic resection for synchronous liver metastasis. The primary tumor site was ampullary (n=1 patient ), duodenal (n=2 patients), distal bile duct (n=2 patients), or pancreas (head, n=10 patients; tail, n=7 patients). The majority of patients (86.4%) had a solitary hepatic metastasis, and the median size of the largest lesion was 0.6 cm. Hepatic metastectomy included wedge resection (n=20 patients), segmentectomy (n=1 patient), and hemihepatectomy (n=1 patient). After matching patients on primary tumor histology and location, the median survival of patients who underwent hepatic resection of synchronous metastasis was 5.9 months compared with 5.6 months for patients who underwent palliative bypass alone (P=.46) and 14.2 months for patients with no metastatic disease who underwent primary tumor resection only (P<.001). Pancreatic (median, 5.9 months) versus nonpancreatic (median, 9.9 months) primary tumor histology was not associated with a difference in survival in patients who underwent resection of synchronous liver metastasis (P=.43). CONCLUSIONS:Even in well selected patients with low-volume metastatic liver disease, simultaneous resection of periampullary or pancreatic carcinoma with synchronous liver metastases did not result in long-term survival in the overwhelming majority of patients.

The goal of this article is to describe the different types of benign pancreatic neoplasms, methods to distinguish between them, and treatment options. Pancreatic adenocarcinoma is associated with specific neoplastic lesions that are similar in radiographic appearance to some benign lesions. The correct differentiation of these malignant and premalignant lesions from their benign counterpart is paramount to their proper management.

The prognosis of patients with cholangiocarcinoma historically has been poor, even after surgical resection. Although data from some single-institution series indicate improvement over historical results, survival after surgical therapy for cholangiocarcinoma has not been investigated in a population-based study. We used the Surveillance, Epidemiology, and End Results database to identify patients who underwent surgery for cholangiocarcinoma from 1973 through 2002. Multivariate modeling of survival after surgery for intrahepatic cholangiocarcinoma showed an improvement in survival only within the last decade studied, resulting in a cumulative 34.4% improvement in survival from 1992 through 2002. In contrast, multivariate modeling of survival after surgery for extrahepatic cholangiocarcinoma revealed a 23.3% increase in adjusted survival per each decade studied, resulting in a cumulative 53.7% improvement from 1973 through 2002. We conclude that survival after surgery for extrahepatic cholangiocarcinoma has dramatically improved since 1973. Patients with intrahepatic cholangiocarcinoma, however, have achieved an improvement in survival largely confined to more recent years. We suggest that these trends are largely caused by developments in imaging technology, improvements in patient selection, and advances in surgical techniques.

BACKGROUND:The presence or absence of lymph node metastases is known to be an important prognostic factor for patients with pancreatic cancer. Few studies have investigated the ratio of the number of lymph nodes harboring metastatic cancer to the total number of lymph nodes examined (lymph node ratio [LNR]) with regard to outcome after pancreaticoduodenectomy for ductal cancer of the pancreas. METHODS:Between 1995 and 2005, a total of 905 patients underwent pancreaticoduodenectomy for pancreatic adenocarcinoma. Demographics, operative data, number of lymph nodes evaluated, number of lymph nodes with metastatic carcinoma, LNR, pathologic margin status, and long-term survival were analyzed. RESULTS:There were 187 (20.7%) of the 905 patients who had negative peripancreatic lymph nodes (N0), whereas 718 (79.3%) of the 905 patients had lymph node metastases (N1). The median number of lymph nodes evaluated in the N0 group was 15 versus 18 in the N1 group (P = .12). At median follow-up of 24 months, the median survival for all patients was 17.4 months, and the 5-year actuarial survival rate was 16.1%. Patients with lymph node metastases had a shorter median overall survival (16.5 months) compared with patients with negative lymph nodes (25.3 months; P = .001). Compared with the total number of lymph nodes examined or total number of lymph node metastases, LNR was the most compelling predictor of survival. As the LNR increased, median overall survival decreased (LNR = 0, 25.3 months; LNR > 0 to 0.2, 21.7 months; LNR > 0.2 to 0.4, 15.3 months; LNR > 0.4, 12.2 months; P = .001). After adjusting for other factors associated with survival, LNR remained an independent predictor of overall survival (P < .001). CONCLUSIONS:After pancreaticoduodenectomy for adenocarcinoma of the pancreas, LNR was one of the most powerful predictors of survival. LNR should be considered when stratifying patients in future clinical trials.

Pancreatic duct stenting remains an attractive strategy to reduce the incidence of pancreatic fistulas following pancreaticoduodenectomy (PD) with encouraging results in both retrospective and prospective studies. We performed a prospective randomized trial to test the hypothesis that internal pancreatic duct stenting reduces the development of pancreatic fistulas following PD. Two hundred thirty-eight patients were randomized to either receive a pancreatic stent (S) or no stent (NS), and stratified according to the texture of the pancreatic remnant (soft/normal versus hard). Four patients were excluded from the study; in three instances due to a pancreatic duct that was too small to cannulate and in the other instance because a total pancreatectomy was performed. Patients who randomized to the S group had a 6-cm-long segment of a plastic pediatric feeding tube used to stent the pancreaticojejunostomy anastomosis. In patients with a soft pancreas, 57 randomized to the S group and 56 randomized to the NS group. In patients with a hard pancreas, 58 randomized to the S group and 63 randomized to the NS group. The S and NS groups for the entire study population, as well as for the subgroup of high-risk patients with soft pancreata, were similar as regard to demographics, past medical history, preoperative symptoms, preoperative procedures, and intraoperative data. The pancreatic fistula rate for the entire study population was 9.4%. The fistula rates in the S and NS subgroups with hard pancreata were similar, at 1.7% and 4.8% (P = 0.4), respectively. The fistula rates in the S and NS subgroups with soft pancreata were also similar, at 21.1% and 10.7% (P = 0.1), respectively. A nonstatistically significant increase in the pancreatic fistula rate in the S group persisted after adjusting for the operating surgeon and technical details of the operation (e.g., anastomotic technique, anastomotic orientation, pancreatic duct size, and number of intra-abdominal drains placed). In patients with soft pancreata, 63% percent of the pancreatic fistulas in stented patients required adjustment to the clinical pathway (including two deaths), compared to 47% of the pancreatic fistulas in patients in the NS group (P = 0.3). Internal pancreatic duct stenting does not decrease the frequency or the severity of postoperative pancreatic fistulas.

Glutamine is an essential nutrient for gut functions, but the regulation of its uptake by intestinal mucosal cells is poorly understood. Given the pivotal role of epidermal growth factor (EGF) in regulating gut metabolism, growth, and differentiation, this in vitro study was designed to investigate the intracellular signaling pathways involved in the regulation of EGF-mediated intestinal glutamine transport in intestinal epithelia. Continuous incubation with EGF (>30 hours, 100 ng/ml) stimulated glutamine transport activity across intestinal epithelial Caco-2 cell apical membrane. Exposure to EGF for 48 hours resulted in an increase in transport activity (50%) and glutamine transport system B gene ATB(0) mRNA levels (ninefold). EGF stimulated glutamine transport activity by increasing the glutamine transporter maximal velocity (V(max)) without altering the transporter apparent affinity (K(m)). Furthermore, EGF stimulated both intracellular protein kinase C and mitogen-activated protein kinase MEK1/2 activities. The EGF-stimulated glutamine transport activity was attenuated individually by the specific protein kinase C inhibitor chelerythrine chloride and the mitogen-activated protein kinase MEK1 inhibitor PD 98059. These data suggest that EGF activates glutamine transport activity across intestinal epithelial membrane via a signaling mechanism that involves activation of protein kinase C and the mitogen-activated protein kinase MEK1/2 cascade. EGF activates glutamine transport via alterations in transporter mRNA levels and the number of functional copies of transporter units.

During chronic metabolic acidosis, renal glutamine utilization increases markedly. We studied the expression of the system N1 (SN1) amino acid transporter in the kidney during chronic ammonium chloride acidosis in rats. Acidosis caused a 10-fold increase in whole kidney SN1 mRNA level and a 100-fold increase in the cortex. Acidosis increased Na(+)-dependent glutamine uptake into basolateral and brush-border membrane vesicles (BLMV and BBMV, respectively) isolated from rat cortex (BLMV, 219 +/- 66 control vs. 651 +/- 180 pmol. mg(-1). min(-1) acidosis; BBMV, 1,112 +/- 189 control vs. 1,652 +/- 148 pmol. mg(-1). min(-1) acidosis, both P < 0.05). Na(+)-independent uptake was unchanged by acidosis in BLMV and BBMV. The acidosis-induced increase in Na(+)-dependent glutamine uptake was eliminated by histidine, confirming transport by system N. SN1 protein was detected only in BLMV and BBMV from acidotic rats. After recovery from acidosis, SN1 mRNA and protein and Na(+)-dependent glutamine uptake activity rapidly returned to control levels. These data provide evidence that regulation of expression of the SN1 amino acid transporter is part of the renal homeostatic response to acid-base imbalance.

L-Arginine uptake by the small intestine can play a pivotal role in regulating nitric oxide synthesis and immune functions in catabolic states. We previously showed that protein kinase C (PKC) activation stimulates intestinal brush-border membrane arginine transport. However, the signaling pathways implicated in this activation have not been studied. The purpose of this study was to investigate the intracellular signal transduction pathways involved in the protein kinase C stimulation of arginine transport across the apical membrane of intestinal epithelial Caco-2 cells. [3H]-L-arginine transport activity, Northern blot analysis of mRNA levels of the intestinal arginine transporter CAT1, and Western blot analysis of the mitogen-activated protein (MAP) kinases phospho-p44/42 activity and phospho-MEK1/2 were measured in cultured Caco-2 cells treated with phorbol ester (phorbol 12-myristate 13-acetate, TPA; 0 to 0.5 micromol/L), and the MEK1 inhibitor PD 98059 (0 to 50 micromol/L). Phorbol ester stimulated intestinal arginine transport activity. Arginine transporter gene CAT1 mRNA, phospho-p44/42, and phospho-MEK1/2 levels were stimulated in phorbol ester-treated cells, compared with the control group. Phorbol ester stimulation of arginine transport activity and transporter CAT1 mRNA levels was blocked by PD 98059. These data suggest that phorbol ester stimulates arginine transport in Caco-2 cells via signaling pathways that lead to increased transcription and/or stabilization of CAT1 mRNA. Protein kinase C and MAP kinases MEK1/2 and p44/42 are key intracellular regulators involved in this signal transduction cascade.