Targeted nuclear factor-kappaB suppression enhances gemcitabine response in human pancreatic tumor cell line murine xenografts.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is an almost uniformly fatal malignancy characterized by resistance to chemotherapy. Currently, gemcitabine is the agent used most commonly but demonstrates only a partial response. The transcription factor nuclear factor-kappaB (NF-κB), known to be involved in the inflammatory response, is constitutively activated in PDAC and further activated by gemcitabine. Our aim was to examine the effects of targeted NF-κB suppression on gemcitabine resistance using an in vivo tumor growth model. METHODS: To suppress the NF-κB pathway, the mutant IκBα super-repressor protein was stably expressed in PaCa-2 human PDAC cells. Athymic mice were injected subcutaneously with IκBα-super-repressor (SR) or vector-expressing PaCa-2 cells and randomized to receive phosphate-buffered saline (PBS) or 100 mg/kg gemcitabine(gem) for 4 weeks. RESULTS: The mean increase in tumor volume was 47 mm(3) (89%) and 196 mm(3) (326%) in gem/SR and gem/vector groups, respectively (P = .03). The PBS-treated groups demonstrated greater tumor growth, ∼340 mm(3) (850%) increase, in both PBS/vector and PBS/SR groups. Intratumoral NF-κB activity was decreased in gem/SR compared with the gem/vector group (P = .04). Decreased Ki-67 positivity was noted in gem/SR (49%) versus gem/vector tumors (73%) (P = .04), with no difference in apoptosis (apoptag, P = .3) or angiogenesis (CD31+, P = .9). CONCLUSION: Stable IκBα-SR expression in vivo potentiated the antitumor effects of gemcitabine, resulting in decreased tumor growth in association with decreased cell proliferation. Molecular suppression of the NF-κB pathway decreases successfully gemcitabine resistance in a relatively chemoresistant PDAC line. Thus, NF-κB-targeted agents may complement gemcitabine-based therapies and decrease chemoresistance in patients with PDAC.

Survival after resection for invasive intraductal papillary mucinous neoplasm and for pancreatic adenocarcinoma: a multi-institutional comparison according to American Joint Committee on Cancer Stage.

BACKGROUND: Survival after resection for invasive intraductal papillary mucinous neoplasm (inv-IPMN) is superior to pancreatic ductal adenocarcinoma (PDAC). This difference may be explained by earlier presentation of inv-IPMN. We hypothesized that inv-IPMN has survival comparable with PDAC after resection when matched by stage. STUDY DESIGN: From 1999 to 2009, 113 patients underwent resection for inv-IPMN at 2 large academic institutions. These data were compared with 845 patients during the same period undergoing resection for PDAC. Demographics, pathology, and overall survival (OS) were compared according to current American Joint Committee on Cancer stage. RESULTS: Mean age with inv-IPMN and PDAC was 68 and 65 years, respectively. Follow-up was 33 and 24 months for inv-IPMN and PDAC, respectively. Median OS was 32 months for inv-IPMN and 17 months in PDAC (p < 0.001). Median OS in lymph node-negative inv-IPMN was 41 months and 24 months in PDAC (p = 0.003), with the greatest absolute difference in stage Ia patients with OS of 80 and 50 months in inv-IPMN and PDAC, respectively (p = 0.03). In node-positive patients, OS was 20 months in inv-IPMN and 15 months in PDAC (p = 0.06). Of inv-IPMN, 24% was colloid versus 75% of tubular subtype; 37(85%) of node-positive inv-IPMN were tubular subtype. Median OS was 23 and 127 months for tubular and colloid subtypes, respectively (p < 0.001). CONCLUSIONS: When matched by stage, inv-IPMN has superior survival after resection compared with PDAC. This disparity is greatest in node-negative and least in node-positive disease. These findings suggest the behaviors of inv-IPMN and PDAC, although different, converge with advancing American Joint Committee on Cancer stage because of a greater proportion of tubular subtype.

Side-branch intraductal papillary mucinous neoplasms of the pancreatic head/uncinate: resection or enucleation?

INTRODUCTION: Side-branch intraductal papillary mucinous neoplasms (IPMN) of the pancreatic head/uncinate are an increasingly common indication for pancreaticoduodenectomy (PD). However, enucleation (EN) may be an alternative to PD in selected patients to improve outcomes and preserve pancreatic parenchyma. AIM: To determine peri-operative outcomes in patients with side-branch IPMN of the pancreatic head/uncinate undergoing EN or PD compared with a cohort of patients with pancreatic adenocarcinoma (PA) undergoing PD. METHODS: Retrospective review of a prospectively collected, combined, academic institutional series from 2005 to 2008. Of 107 pancreatic head/uncinate IPMN, enucleation was performed in 7 (IPMN EN) and PD was performed in 100 (IPMN PD) with 17 of these radiographically amenable to EN (IPMN PD(en) ). During the same time period, 281 patients underwent PD for PA (Control PD). RESULTS: Operative time was shorter (p<0.05) and blood loss (p<0.05) was less in the IPMN EN group compared with all other groups. Peri-operative mortality and morbidity of all IPMN groups (IPMN EN, IPMN PD(en) ) were similar to the Control PD group. Overall pancreatic fistulae rate in the IPMN EN group was higher than in the IPMN PD(en) and Control PD groups; however, the rate of grade C pancreatic fistulae was the same in all groups. CONCLUSIONS: Pancreaticoduodenectomy for side-branch IPMNs can be performed safely. Compared with PD, enucleation for IPMN has less blood loss, shorter operative time and similar morbidity, mortality, hospital length of stay (LOS) and readmission rate. Enucleation should be considered more frequently as an option for patients with unifocal side-branch IPMN.

Natural language processing for the development of a clinical registry: a validation study in intraductal papillary mucinous neoplasms.

BACKGROUND: Medical natural language processing (NLP) systems have been developed to identify, extract and encode information within clinical narrative text. However, the role of NLP in clinical research and patient care remains limited. Pancreatic cysts are common. Some pancreatic cysts, such as intraductal papillary mucinous neoplasms (IPMNs), have malignant potential and require extended periods of surveillance. We seek to develop a novel NLP system that could be applied in our clinical network to develop a functional registry of IPMN patients. OBJECTIVES: This study aims to validate the accuracy of our novel NLP system in the identification of surgical patients with pathologically confirmed IPMN in comparison with our pre-existing manually created surgical database (standard reference). METHODS: The Regenstrief EXtraction Tool (REX) was used to extract pancreatic cyst patient data from medical text files from Indiana University Health. The system was assessed periodically by direct sampling and review of medical records. Results were compared with the standard reference. RESULTS: Natural language processing detected 5694 unique patients with pancreas cysts, in 215 of whom surgical pathology had confirmed IPMN. The NLP software identified all but seven patients present in the surgical database and identified an additional 37 IPMN patients not previously included in the surgical database. Using the standard reference, the sensitivity of the NLP program was 97.5% (95% confidence interval [CI] 94.8-98.9%) and its positive predictive value was 95.5% (95% CI 92.3-97.5%). CONCLUSIONS: Natural language processing is a reliable and accurate method for identifying selected patient cohorts and may facilitate the identification and follow-up of patients with IPMN.

Robotic distal pancreatectomy: cost effective?

BACKGROUND: Minimally invasive techniques and even robotics in pancreaticobiliary surgery are being used increasingly. Cost-effectiveness is a practical burden associated with the introduction of surgical innovation. This study compares the costs and the outcomes of open, laparoscopic, and robotic distal pancreatectomies. We hypothesized that robotic distal pancreatectomy is cost-effective. METHODS: Between August 2008 and August 2009, 77 distal pancreatectomies were performed at a single academic medical center. A retrospective analysis of prospectively collected data on demographics, short-term outcomes, and direct cost was performed. RESULTS: Thirty-two open distal pancreatectomies, 28 laparoscopic distal pancreatectomies, and 17 robotic distal pancreatectomies were performed. Age, American Society of Anesthesia preoperative risk score, and specimen length were similar. Indications for laparoscopic distal pancreatectomies and robotic distal pancreatectomies included more cystic neoplasms (49%) and fewer malignancies (29%) versus open distal pancreatectomies (16% and 47%). Spleen preservation occurred in 65% robotic distal pancreatectomies versus 12% and 29% in open distal pancreatectomies and laparoscopic distal pancreatectomies (P < .05). The operative time averaged 298 minutes in robotic distal pancreatectomies versus 245 and 222 minutes in open distal pancreatectomies and laparoscopic distal pancreatectomies (P < .05). Blood loss and morbidity were similar with no mortality. The length of stay was 4 days in robotic distal pancreatectomies versus 8 and 6 in open distal pancreatectomies and laparoscopic distal pancreatectomies (P < .05). The total cost was $10,588 in robotic distal pancreatectomies versus $16,059 and $12,986 in open distal pancreatectomies and laparoscopic distal pancreatectomies. CONCLUSION: These data suggest direct hospital costs are comparable among all groups. They suggest a shorter length of stay in robotic versus laparoscopic or open approaches. Finally, spleen and vessel preservation rates may improve with a robotic approach at the expense of increased operative time. In summary, robotic distal pancreatectomy is safe and cost effective in selected cases.