Faculty Bibliography

PURPOSE/OBJECTIVE:Numerous biomarkers for pancreatic cancer have been reported. We determined the extent to which such biomarkers are expressed throughout metastatic progression, including those that effectively predict biologic behavior. EXPERIMENTAL DESIGN/METHODS:Biomarker profiling was performed for 35 oncoproteins in matched primary and metastatic pancreatic cancer tissues from 36 rapid autopsy patients. Proteins of significance were validated by immunolabeling in an independent sample set, and functional studies were performed in vitro and in vivo. RESULTS:Most biomarkers were similarly expressed or lost in expression in most samples analyzed, and the matched primary and metastases from a specific patient were most similar to each other than to other patients. However, a subset of proteins showed extensive interpatient heterogeneity, one of which was p38 MAPK. Strong positive pp38 MAPK immunolabeling was significantly correlated with improved postresection survival by multivariate analysis (median overall survival 27.9 months, P = 0.041). In pancreatic cancer cells, inhibition of functional p38 by SB202190 increased cell proliferation in vitro in both low-serum and low-oxygen conditions. High functional p38 activity in vitro corresponded to lower levels of pJNK protein expression, and p38 inhibition resulted in increased pJNK and pMKK7 by Western blot analysis. Moreover, JNK inhibition by SP600125 or MKK7 siRNA knockdown antagonized the effects of p38 inhibition by SB202190. In vivo, SP600125 significantly decreased growth rates of xenografts with high p38 activity compared with those without p38 expression. CONCLUSIONS:Functional p38 MAPK activity contributes to overall survival through JNK signaling, thus providing a rationale for JNK inhibition in pancreatic cancer management.

BACKGROUND:Race-based disparities in operative morbidity and mortality have been demonstrated for various procedures, including pancreatoduodenectomy (PD). Race-based differences in hospital length-of-stay (LOS), especially related to provider volume at the surgeon and hospital level, remain poorly defined. METHODS:Using the 2003-2009 Nationwide Inpatient Sample, we determined year-specific PD volumes for surgeons and hospitals and grouped them into terciles. Patient race (white, black, or Hispanic), age, sex, and comorbidities were examined. Median length of stay was calculated, and multivariable logistic regression was used to examine factors associated with increased LOS. RESULTS:Among 4,319 eligible individuals, 3,502 (81.1%) were white, 423 (9.8%) were black, and 394 (9.1%) were Hispanic. Overall median LOS was 12 days (range, 0-234). Median annual surgeon volume was 8 (interquartile range [IQR], 2-19; range, 1-54). Annual hospital volume ranged from 1 to 129 (median, 19; IQR, 7-55). White patients were more likely to have been treated at medium- to high-volume hospitals (odds ratio [OR] 1.53, P < .001) and by medium- to high-volume surgeons (OR 1.62, P < .001) than black or Hispanic patients. After PD, white, black, and Hispanic patients demonstrated similar in-hospital mortality (5.1%, 5.7% and 7.2% respectively P = .250). After adjustment, black (OR 1.36, P = .010) and Hispanic (OR 1.68, P < .001) patients were more likely to have a greater LOS after PD. CONCLUSION/CONCLUSIONS:Black and Hispanic PD patients were less likely than white patients to be treated at higher-volume hospitals and by higher-volume surgeons. Proportional mortality and LOS after PD were greater among black and Hispanic patients.

INTRODUCTION/BACKGROUND:Primary pancreatic neuroendocrine tumors are a well-established disease entity, however, neuroendocrine metastases to the pancreas from other sites have been scarcely documented. Specifically, pancreatic metastases from a pulmonary carcinoid tumor have only previously been described in a single case report. PRESENTATION OF CASE/METHODS:We sought to outline our institutional experience of two patients with pulmonary neuroendocrine tumors that developed metastases to the pancreas, confirmed by gross pathology and immunohistochemistry. In both cases, the pancreatic metastases were surgically resected and their pulmonary origin were discovered post-operatively. DISCUSSION/CONCLUSIONS:Our findings should raise awareness to the possibility of metastatic disease when evaluating a pancreatic mass in a patient with a clinical history of pulmonary carcinoid tumor. Expert opinion on immunohistochemically differentiating a primary pancreatic neuroendocrine malignancy from a metastasis should be employed in these cases. CONCLUSION/CONCLUSIONS:Establishing this diagnosis pre-operatively could affect the decision to proceed with surgical resection, given the morbidity of pancreatectomy and the unknown long-term clinical outcome of patients with pulmonary carcinoid tumors metastatic to the pancreas.

BACKGROUND:The use of minimally invasive surgery (MIS) techniques for pancreatic and liver operations remains ill defined. We sought to compare inpatient outcomes among patients undergoing open versus MIS pancreas and liver operations using a nationally representative cohort. METHODS:We queried the Nationwide Inpatient Sample database for all major pancreatic and hepatic resections performed between 2000 and 2011. Appropriate International Classification of Diseases, 9th Revision (ICD-9) coding modifiers for laparoscopy and robotic assist were used to categorize procedures as MIS. Demographics, comorbidities, and inpatient outcomes were compared between the open and MIS groups. RESULTS:A total of 65,033 resections were identified (pancreas, n = 36,195 [55.7%]; liver, n = 28,035 [43.1%]; combined pancreas and liver, n = 803 [1.2%]). The overwhelming majority of operations were performed open (n = 62,192, 95.6%), whereas 4.4% (n = 2,841) were MIS. The overall use of MIS increased from 2.3% in 2000 to 7.5% in 2011. Compared with patients undergoing an open operation, MIS patients were older and had a greater incidence of multiple comorbid conditions. After operation, the incidence of complications for MIS (pancreas, 35.4%; liver, 29.5%) was lower than for open (pancreas, 41.6%; liver, 33%) procedures (all P < .05) resulting in a shorter median length of stay (8 vs 7 days; P = .001) as well as a lower in-hospital mortality (5.1% vs 2.8%; P = .001). CONCLUSION/CONCLUSIONS:During the last decade, the number of MIS pancreatic and hepatic operations has increased, with nearly 1 in 13 HPB cases now being performed via an MIS approach. Despite MIS patients tending to have more preoperative medical comorbidities, postoperative morbidity, mortality, and duration of stay compared favorably with open surgery.

Branch duct intraductal papillary mucinous neoplasms (BD-IPMN) are pre-malignant pancreatic cystic lesions which carry a small risk of malignant transformation within the cyst. Guidelines exist with respect to surveillance of the cysts using computed tomography, magnetic resonance imaging, and/or endoscopic ultrasound (EUS). There are reports that patients with IPMNs are at increased risk of developing pancreatic adenocarcinoma, which arises in an area separate to the IPMNs. We present two cases of pancreatic adenocarcinoma arising within the parenchyma, distinct from the IPMN-associated cyst, identified with EUS. This case report highlights that patients with BD-IPMN are at increased risk for pancreatic adenocarcinoma separate from the cyst and also the importance for endosonographers to carefully survey the rest of the pancreatic parenchyma separate from the cyst in order to identify small pancreatic adenocarcinomas.

Intraductal papillary mucinous neoplasms (IPMNs) have malignant potential and can progress from low- to high-grade dysplasia to invasive adenocarcinoma. The management of patients with IPMNs is dependent on their risk of malignant progression, with surgical resection recommended for patients with branch-duct IPMN (BD-IPMN) who develop high-risk features. There is increasing evidence that liver transplant (LT) patients are at increased risk of extrahepatic malignancy. However, there are few data regarding the risk of progression of BD-IPMNs in LT recipients. The aim of this study was to determine whether LT recipients with BD-IPMNs are at higher risk of developing high-risk features than patients with BD-IPMNs who did not receive a transplant. Consecutive patients who underwent an LT with BD-IPMNs were included. Patients with BD-IPMNs with no history of immunosuppression were used as controls. Progression of the BD-IPMNs was defined as development of a high-risk feature (jaundice, dilated main pancreatic duct, mural nodule, cytology suspicious or diagnostic for malignancy, cyst diameter ≥3 cm). Twenty-three LT patients with BD-IPMN were compared with 274 control patients. The median length of follow-up was 53.7 and 24.0 months in LT and control groups, respectively. Four (17.4%) LT patients and 45 (16.4%) controls developed high-risk features (P = 0.99). In multivariate analysis, progression of BD-IPMNs was associated with age at diagnosis but not with LT. There was no statistically significant difference in the risk of developing high-risk features between the LT and the control groups.

BACKGROUND:The impact of regionalization on morbidity, failure to rescue (FTR), length of stay (LOS), and readmission remains unclear. We sought to examine hospital-volume-related differences in outcomes following complex hepato-pancreatico-biliary (HPB) surgery and define potential benefits of regionalization across quality metrics. METHODS:Patients undergoing HPB surgery in the Surveillance, Epidemiology and End Results (SEER)-Medicare linked data from 1986 to 2002 were identified. Hospital volume was stratified into tertiles (low volume [LV] <4 cases/year; intermediate volume [IV] 4-10 cases/year; high volume [HV] ≥11 cases/year). The incidence of complications, FTR (mortality following a complication), and LOS was compared across hospital-volume strata. A counterfactual model examined hypothetical outcomes assuming all patients had been treated at HV centers. RESULTS:Ten thousand two hundred eight patients underwent pancreatic (46.1 %), hepatic (36.2 %), or biliary (17.8 %) procedures. Overall mean age ranged from 72.7 years at HV centers to 73.4 at LV centers (P < 0.001), and patients at HV centers (75.4 %) were more likely to have ≥3 comorbidities versus IV (70.0 %) or LV (64.7 %) centers (P < 0.001). The incidence of post-operative complications was lower at HV (39.1 %) compared with IV (41.9 %) or LV (44.8 %) centers. Major complications included hemorrhagic anemia (7.3 %), failure to thrive (5.1 %), and respiratory infection/failure (3.5 %); each was less common in HV hospitals (P < 0.05). FTR after major complication tended to be higher at LV (36.7 %) and IV (37.3 %) hospitals compared with HV hospitals (29.7 %) (P = 0.10). Mortality was higher at LV (10.5 %) and IV (8.1 %) hospitals versus HV centers (5.4 %) (P < 0.001). HV hospital patients had shorter median LOS (10 days) compared with IV (12 days) or LV (12 days) hospital patients (P < 0.001). Readmission varied across centers (HV 19.1 % vs. IV 19.2 % vs. 16.7 %; P = 0.02). In a counterfactual model with all patients treated at a HV center, 6.4 % fewer complications and a 26.0 % increase in post-complication rescue would be expected, along with a 32.0 % reduction in index mortality and an 8.1 % reduction in total patient-days. A minor increase in readmissions (7.1 %) would be anticipated with 13.3 % fewer deaths during readmission. CONCLUSION/CONCLUSIONS:Although patients treated at HV hospitals had more medical comorbidities, outcomes across a wide spectrum of quality metrics were better than at IV or LV hospital following complex HPB surgery. A 20-30 % reduction in morbidity and mortality and an 8 % reduction in hospital patient-days could be anticipated had all patients been treated at HV hospitals.