Faculty Bibliography

BACKGROUND:A computed tomography (CT) scan is often the only study needed prior to surgery for resectable solid pancreas masses. However, many patients are evaluated with multiple studies and interventions that may be unnecessary. METHODS:We conducted a retrospective review of patients who presented to the Johns Hopkins Multidisciplinary Pancreas Cancer Clinic with a clearly resectable solid pancreas mass, >1 cm in size over a 2-year period (6/2007-6/2009) and underwent resection. Pancreas specialists reviewed patient records and identified an index CT with a solid pancreas mass deemed to be resectable for curative intent. Data were collected on all studies and interventions between the index CT and the surgery. RESULTS:A total of 101 patients had an index CT. Following the index CT and before surgery, 78 patients had at least one CT, 19 had magnetic resonance imaging, 9 had a positron emission tomography scan, and 66 underwent pancreatic biopsy. Patients underwent a mean of three studies with a mean added cost of $3,371 per patient. Preoperative tests and interventions were associated with a longer time to definitive surgical intervention. CONCLUSION/CONCLUSIONS:Wide variation exists for evaluation of newly discovered resectable solid pancreas masses, which is associated with delays to surgical intervention and added costs.

PURPOSE/OBJECTIVE:Our goal was to identify circulating micro RNA (miRNA) levels that could distinguish patients with low-stage pancreatic cancer from healthy and disease controls. EXPERIMENTAL DESIGN/METHODS:We measured 735 miRNAs in pancreatic cancer case and control sera by QRTPCR using TaqMan MicroRNA Arrays. After array analysis, we selected 18 miRNA candidates for validation in an independent set of cases and control samples. RESULTS:Of the significantly elevated circulating miRNAs in patients with pancreatic cancer compared with controls, miR-1290 had the best diagnostic performance: receiver operating characteristic (ROC) analysis on miR-1290 serum level yielded curve areas (AUC) of 0.96 [95% confidence interval (CI), 0.91-1.00], 0.81 (0.71-0.91), and 0.80 (0.67-0.93), for subjects with pancreatic cancer (n = 41) relative to healthy controls (n = 19), subjects with chronic pancreatitis (n = 35), and pancreatic neuroendocrine tumors (n = 18), respectively. Serum miR-1290 levels were also significantly higher than healthy controls among patients with intraductal papillary mucinous neoplasm (IPMN; n = 20; AUC = 0.76, 0.61-0.91). Serum miR-1290 levels distinguished patients with low-stage pancreatic cancer from controls better than CA19-9 levels, and like CA19-9, higher miR-1290 levels predicted poorer outcome among patients undergoing pancreaticoduodenectomy. Greater numbers of miR-1290 transcripts were detected by FISH in primary pancreatic cancer and IPMN than normal pancreatic duct cells. miR-1290 influenced in vitro pancreatic cancer cell proliferation and invasive ability. Several other circulating miRNAs distinguished sera of patients with pancreatic cancer from those of healthy controls with AUCs >0.7, including miR-24, miR-134, miR-146a, miR-378, miR-484, miR-628-3p, and miR-1825. CONCLUSIONS:The detection of elevated circulating miR-1290 has the potential to improve the early detection of pancreatic cancer.

PURPOSE/OBJECTIVE:Long-term survival rates for patients with resected pancreatic ductal adenocarcinoma (PDAC) have stagnated at 20% for more than a decade, demonstrating the need to develop novel adjuvant therapies. Gemcitabine-erlotinib therapy has demonstrated a survival benefit for patients with metastatic PDAC. Here we report the first phase 2 study of erlotinib in combination with adjuvant chemoradiation and chemotherapy for resected PDAC. METHODS AND MATERIALS/METHODS:Forty-eight patients with resected PDAC received adjuvant erlotinib (100 mg daily) and capecitabine (800 mg/m(2) twice daily Monday-Friday) concurrently with intensity modulated radiation therapy (IMRT), 50.4 Gy over 28 fractions followed by 4 cycles of gemcitabine (1000 mg/m(2) on days 1, 8, and 15 every 28 days) and erlotinib (100 mg daily). The primary endpoint was recurrence-free survival (RFS). RESULTS:The median follow-up time was 18.2 months (interquartile range, 13.8-27.1). Lymph nodes were positive in 85% of patients, and margins were positive in 17%. The median RFS was 15.6 months (95% confidence interval [CI], 13.4-17.9), and the median overall survival (OS) was 24.4 months (95% CI, 18.9-29.7). Multivariate analysis with adjustment for known prognostic factors showed that tumor diameter >3 cm was predictive for inferior RFS (hazard ratio, 4.01; P=.001) and OS (HR, 4.98; P=.02), and the development of dermatitis was associated with improved RFS (HR, 0.27; P=.009). During CRT and post-CRT chemotherapy, the rates of grade 3/4 toxicity were 31%/2% and 35%/8%, respectively. CONCLUSION/CONCLUSIONS:Erlotinib can be safely administered with adjuvant IMRT-based CRT and chemotherapy. The efficacy of this regimen appears comparable to that of existing adjuvant regimens. Radiation Therapy Oncology Group 0848 will ultimately determine whether erlotinib produces a survival benefit in patients with resected pancreatic cancer.

BACKGROUND:Intraductal papillary mucinous neoplasms (IPMNs) are the most common cystic precursor lesions of invasive pancreatic cancer. The recent identification of activating GNAS mutations at codon 201 in IPMNs is a promising target for early detection and therapy. The purpose of this study was to explore clinicopathological correlates of GNAS mutational status in resected IPMNs. METHODS:Clinical and pathologic characteristics were retrieved on 54 patients in whom GNAS codon 201 mutational status was previously reported ("historical group", Wu et al. Sci Transl Med 3:92ra66, 2011). In addition, a separate cohort of 32 patients (validation group) was included. After microdissection and DNA extraction, GNAS status was determined in the validation group by pyrosequencing. RESULTS:GNAS activating mutations were found in 64% of the 32 IPMNs included in the validation group, compared with a previously reported prevalence of 57% in the historical group. Overall, 52 of 86 (61%) of IPMNs demonstrated GNAS mutations in the two studies combined. Analysis of both groups confirmed that demographic characteristics, tumor location, ductal system involvement, focality, size, grade of dysplasia, presence of an associated cancer, and overall survival were not correlated with GNAS mutational status. Stratified by histological subtype, 100% of intestinal type IPMNs demonstrated GNAS mutations compared to 51% of gastric IPMN, 71% of pancreatobiliary IPMNs, and 0% of oncocytic IPMNs. CONCLUSIONS:GNAS activating mutations can be reliably detected in IPMNs by pyrosequencing. In terms of clinicopathological parameters, only histological subtype was correlated with mutational frequency, with the intestinal phenotype always associated with GNAS mutations.

Pancreatic cancer is currently one of the deadliest of the solid malignancies. However, surgery to resect neoplasms of the pancreas is safer and less invasive than ever, novel drug combinations have been shown to improve survival, advances in radiation therapy have resulted in less toxicity, and enormous strides have been made in the understanding of the fundamental genetics of pancreatic cancer. These advances provide hope but they also increase the complexity of caring for patients. It is clear that multidisciplinary care that provides comprehensive and coordinated evaluation and treatment is the most effective way to manage patients with pancreatic cancer.

BACKGROUND:Studies reporting perioperative outcomes after pancreaticoduodenectomy (PD) have focused on morbidity and mortality. Understanding factors that impact hospital duration of stay may have cost-saving implications. We sought to examine variation in duration of stay after PD occurring at the patient, surgeon, and hospital levels. METHODS:Year-specific PD volumes for both surgeons and hospitals were determined from the 2003-2009 Nationwide Inpatient Sample and grouped into terciles. Patient age, gender, and comorbidities were examined. Median duration of stay was calculated and modified Poisson regression examined factors associated with duration of stay. RESULTS:Among 5,190 individuals undergoing PD, median age was 65 years and 49.3% were female. Median duration of stay was 13 days (range, 0-234). Older patients and those with comorbid illness were more likely to have duration of stay of ≥ 14 days (P < .001). Median annual surgeon volume was 8 (interquartile range [IQR], 2-19; range, 1-54). Annual hospital volume ranged from 1 to 129 (median, 18; IQR, 6-52). Both low surgeon and hospital PD volume were associated with longer durations of stay (P < .001). In multivariable modeling, age remained associated with duration of stay (relative risk [RR], 1.007 per year; P < .001); however, comorbidity did not. Patients operated on by high-volume surgeons (RR, 0.67) or at high-volume hospitals (RR, 0.75) had a reduced risk of a prolonged duration of stay of ≥ 14 days (both P < .001). CONCLUSION/CONCLUSIONS:PD patients treated by higher volume surgeons and at higher volume hospitals had a shorter duration of stay. Although some patient-level factors impact duration of stay after PD, nonclinical factors such as surgeon and hospital volume were also important contributors to duration of stay.

BACKGROUND:Little is known about current surveillance patterns after treatment of colorectal liver metastasis (CRLM) or whether the intensity of surveillance correlates with outcome. We sought to define current population-based patterns of surveillance and investigate whether intensity of surveillance impacted outcome. METHODS:We queried the Surveillance, Epidemiology, and End Results-linked Medicare database for patients with CRLM diagnosed between 1991 and 2005 who underwent liver resection and/or tumor ablation. Frequency of post-treatment abdominal computed tomography (CT), magnetic resonance imaging (MRI), or positron emission tomography (PET) was recorded for ≤ 5 years after treatment. The association between frequency of imaging with secondary interventions and long-term survival were analyzed. RESULTS:We identified 1,739 patients with CRLM treated with surgery; median age was 73 years, and the majority were male (52.6%). CRLM treatment consisted of liver resection (61%), ablation (32%), or both simultaneously (6%). CT (97%) was utilized more often for post-treatment surveillance compared with MRI (7%) and PET (18%). A temporal trend was noted with more frequent surveillance imaging obtained in post-treatment year 1 (2.4 scans/year) versus year 5 (0.6 scans/year; P = .01); 66% of living patients had no imaging after 2 years. Frequency of surveillance imaging correlated with procedure type (total number of scans/5 years: resection, 5.0; ablation, 4.6; resection and ablation, 6.2; P = .01). Other factors associated with a greater frequency of surveillance included younger age at diagnosis, geographic location in the South, and CRLM directed surgery in 2000 through 2005 (all P < .05). Overall survival did not differ by intensity of surveillance imaging (3-4 scans/yr, 43 months vs 2 scans/yr, 57 months vs 1 scan/yr, 54 months; P = .08). CONCLUSION/CONCLUSIONS:Marked heterogeneity exists in how often surveillance imaging is obtained after treatment of CRLM. Intensity of imaging does not affect time to second procedure or median survival duration. Surveillance guidelines for CRLM need to be refocused to provide the best value for healthcare resources.

OBJECTIVE:In 2012, Medicare began cutting reimbursement for hospitals with high readmission rates. We sought to define the incidence and risk factors associated with readmission after surgery. METHODS:A total of 230,864 patients discharged after general, upper gastrointestinal (GI), small and large intestine, hepatopancreatobiliary (HPB), vascular, and thoracic surgery were identified using the 2011 American College of Surgeons National Surgical Quality Improvement Program. Readmission rates and patient characteristics were analyzed. A predictive model for readmission was developed among patients with length of stay (LOS) 10 days or fewer and then validated using separate samples. RESULTS:Median patient age was 56 years; 43% were male, and median American Society of Anesthesiologists (ASA) class was 2 (general surgery: 2; upper GI: 3; small and large intestine: 2; HPB: 3; vascular: 3; thoracic: 3; P < 0.001). The median LOS was 1 day (general surgery: 0; upper GI: 2; small and large intestine: 5; HPB: 6; vascular: 2; thoracic: 4; P < 0.001). Overall 30-day readmission was 7.8% (general surgery: 5.0%; upper GI: 6.9%; small and large intestine: 12.6%; HPB: 15.8%; vascular: 11.9%; thoracic: 11.1%; P < 0.001). Factors strongly associated with readmission included ASA class, albumin less than 3.5, diabetes, inpatient complications, nonelective surgery, discharge to a facility, and the LOS (all P < 0.001). On multivariate analysis, ASA class and the LOS remained most strongly associated with readmission. A simple integer-based score using ASA class and the LOS predicted risk of readmission (area under the receiver operator curve 0.702). CONCLUSIONS:Readmission among patients with the LOS 10 days or fewer occurs at an incidence of at least 5% to 16% across surgical subspecialties. A scoring system on the basis of ASA class and the LOS may help stratify readmission risk to target interventions.