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.

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.

BACKGROUND:Reducing readmission is a key quality improvement target for policymakers. The purpose of the present study was to define incidence and identify factors associated with readmission after a hepatic resection. METHODS:Thirty-day readmission after discharge and factors associated with a higher risk of readmission were examined among patients undergoing a hepatic resection at Johns Hopkins Hospital between 2008 and 2012. RESULTS:Among the 338 patients, the median age was 57.9 years and 173 (51.2%) were men. Indications for surgery included colorectal cancer liver metastasis (38.2%), primary hepatic tumours (25.7%) and benign disease (3.3%). Surgical resection consisted of less than a hemi-hepatectomy in the majority of patients (n = 224, 66.3%). The median index hospitalization length-of-stay (LOS) was 5 days; 68.7% patients experienced at least one inpatient complication. Overall 30-day readmission was 14.2% (n = 48). The majority of readmitted patients (n = 46, 95.8%) had a complication prior to readmission. The median LOS for readmission was 4 [interquartile range (IQR) 2-6] days. On multivariable analysis, the strongest independent predictor of readmission was the presence of a major complication [odds ratio (OR) 5.30, 95% confidence interval (CI) 2.38-11.78, P < 0.001]. CONCLUSIONS:Readmission after a hepatic resection occurs in approximately one out of every seven patients. Patients who experience a post-operative complication are greater than five times more likely to be readmitted. Prospective studies are needed to evaluate methods to reduce unplanned readmissions.

BACKGROUND:Accurate assessment of complications is critical in analysing surgical outcomes. The post-operative morbidity index (PMI), derived from the Modified Accordion Severity Grading System and American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP), is a quantitative measure of post-operative morbidity. This study utilizes PMI to establish the complication burden for a distal pancreatectomy (DP). METHODS:From 2005-2011, nine centres contributed ACS-NSQIP complication data for 655 DPs. Each complication was assigned an Accordion severity weight ranging from 0.11 for grade 1 to 1.00 for grade 6 (death). The PMI is the sum of complication severity weights divided by the total number of patients. RESULTS:ACS-NSQIP complications occurred in 177 patients (27.0%). The non risk-adjusted PMI for DP is 0.087. Bleeding/Transfusion and Organ Space Infection were the most common complications. Frequency and burden differed across Accordion grades. While grade 4-6 complications represented only 15.4% of complication occurrences, they accounted for 30.4% of the burden. Subgroup analysis demonstrates that the PMI did not vary based on laparoscopic versus open approach or the performance of a splenectomy. DISCUSSION/CONCLUSIONS:This study uses two validated systems to quantitatively establish the morbidity of a DP. The PMI allows estimation of both the frequency and severity of complications and thus provides a more comprehensive assessment of risk.

BACKGROUND:Incidental pancreatic cysts are common, a small number of which are premalignant or malignant. Multidisciplinary care has been shown to alter management and improve outcomes in many types of cancers, but its role has not been examined in patients with pancreatic cysts. We assessed the effect of a multidisciplinary pancreatic cyst clinic (MPCC) on the diagnosis and management of patients with pancreatic cysts. METHODS:The referring institution and MPCC diagnosis and management plan were recorded. Patient were placed into one of five categories-no, low, intermediate, or high risk of malignancy within the cyst, and malignant cyst-on the basis of their diagnosis. Patients were assigned one of four management options: surveillance, surgical resection, further evaluation, or discharge with no further follow-up required. The MPCC was deemed to have altered patient care if the patient was assigned a different risk or management category after the MPCC review. RESULTS:Referring institution records were available for 262 patients (198 women; mean age 62.7 years), with data on risk category available in 138 patients and management category in 225. The most common diagnosis was branch duct intraductal papillary mucinous neoplasm. MPCC review altered the risk category in 11 (8.0%) of 138 patients. The management category was altered in 68 (30.2%) of 225 patients. Management was increased in 52 patients, including 22 patients who were recommended surgical resection. Management was decreased in 16 patients, including 10 who had their recommendation changed from surgery to surveillance. CONCLUSIONS:MPCC is helpful and alters the management over 30% of patients.

INTRODUCTION/BACKGROUND:No consensus exists for post-hepatectomy venous thromboembolic (VTE) prophylaxis. Factors impacting VTE prophylaxis patterns among hepato-pancreato-biliary (HPB) surgeons were defined. METHOD/METHODS:Surgeons were invited to complete a web-based survey on VTE prophylaxis. The impact of physician and clinical factors was analysed. RESULTS:Two hundred responses were received. Most respondents were male (91%) and practiced at academic centres (88%) in the United States (80%). Surgical training varied: HPB (24%), transplantation (24%), surgical oncology (34%), HPB/transplantation (13%), or no specialty (5%). Respondents estimated VTE risk was higher after major (6%) versus minor (3%) resections. Although 98% use VTE prophylaxis, there was considerable variability: sequential compression devices (SCD) (91%), unfractionated heparin Q12h (31%) and Q8h (32%), and low-molecular weight heparin (39%). While 88% noted VTE prophylaxis was not impacted by operative indication, 16% stated major resections reduced their VTE prophylaxis. Factors associated with the decreased use of pharmacologic prophylaxis included: elevated international normalized ratio (INR) (74%), thrombocytopaenia (63%), liver insufficiency (58%), large EBL (46%) and complications (8%). Forty-seven per cent of respondents wait until ≥post-operative day 1 (POD1) and 35% hold pharmacologic VTE prophylaxis until no signs of coagulopathy. A minority (14%) discharge patients on pharmacologic prophylaxis. While 81% have institutional VTE guidelines, 79% believe hepatectomy-specific guidelines would be helpful. CONCLUSION/CONCLUSIONS:There is considerable variation regarding VTE prophylaxis among liver surgeons. While most HPB surgeons employ VTE prophylaxis, the methods, timing and purported contraindications differ significantly.

BACKGROUND:The impact of postoperative complications on the administration of adjuvant therapy following pancreaticoduodenectomy (PD) for adenocarcinoma is still unclear. METHODS:A retrospective review of all patients undergoing PD at our institution between 1995 and 2011 was performed. Clinicopathological data, including Clavien-Dindo complication grade, time to adjuvant therapy (TTA), and survival, were analyzed. RESULTS:A total of 1,144 patients underwent PD for adenocarcinoma between 1995 and 2011. The overall complication rate was 49.1 % and clinically severe complications (≥IIIb) occurred in 4.2 %. Overall, 621 patients (54.3 %) were known to have received adjuvant therapy. The median TTA was 60 days. Although the presence of a complication was associated with a delay in TTA (p = 0.002), the grade of complication was not (p = 0.112). On multivariate analysis, only age > 68 years (p < 0.001) and length of stay >9 days (p = 0.002) correlated with no adjuvant therapy. Patients with postoperative complications were more likely to receive single adjuvant chemotherapy or radiation therapy (31.4 %) than were patients without complications (17.1 %; p < 0.001). Patients without a complication had a longer median survival compared with patients who experienced complications (19.5 vs. 16.1 months; p = 0.001). Patients without complications who received adjuvant therapy had longer median survival than patients with complications who received no adjuvant therapy (22.5 vs. 10.7 months; p < 0.001). Multivariate analysis demonstrated that complications [hazard ratio (HR) 1.16; p = 0.023] and adjuvant therapy (HR 0.67; p < 0.001) were related to survival. CONCLUSION/CONCLUSIONS:Complications and no adjuvant therapy are common following PD for adenocarcinoma. Postoperative complications delay TTA and reduce the likelihood of multimodality adjuvant therapy. Identifying patients at increased risk for complications and those unlikely to receive adjuvant therapy warrants further investigation as they may benefit from a neoadjuvant approach.

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.