Faculty Bibliography

BACKGROUND:The widespread use of diagnostic imaging has led to an increase in the incidence and diagnosis of benign liver tumors. The objective of this study was to define the overall use and temporal trends of operative procedures for benign liver tumors using a nationally representative cohort. METHODS:All patients who underwent liver surgery for benign liver tumors between 2000 and 2011 were identified from the Nationwide Inpatient Sample database. Trends in annual volume of liver procedures were analyzed using the average annual percent change (AAPC) assessed by joinpoint analysis. RESULTS:There were 2,489 open (94.5%) and 144 (5.5%) minimally invasive surgical (MIS) procedures. Partial hepatectomy accounted for 43.8% of all cases (n = 1,153). Surgery for patients with benign liver tumors increased from 156 in 2000 to 272 in 2011 (AAPC, 5.8%; 95% CI, 3.2-8.6%). There was decline in the relative use of open operative procedures from 98.1% in 2000 to 92.3% in 2011 (AAPC, -0.4%; 95% CI, -0.7 to -0.1%). In contrast, the proportion of MIS procedures increased from 1.9% in 2000 to 7.7% in 2011 (AAPC, 7.4%; 95% CI, 1.9-13.3%). The median duration of stay among all patients was 5 days (interquartile range, 4-7; 5 days [open] vs 3 days [MIS]; P < .001). Inpatient mortality was 0.6% (n = 15 [open] vs n = 0 [MIS]; P = .43) and did not change during the study period (P > .05). CONCLUSION/CONCLUSIONS:Overall volume of surgical management of benign liver tumors has increased substantially over the past decade. There has been a relative shift away from open procedures toward MIS procedures.

BACKGROUND:It is estimated that approximately 10% of pancreatic cancers have a familial component. Many inheritable genetic syndromes are associated with increased risk of pancreatic cancer, such as Peutz-Jeghers syndrome, hereditary breast-ovarian cancer and familial atypical multiple mole melanoma, but these conditions account for only a minority of familial pancreatic cancers. Previous studies have identified an increased prevalence of noninvasive precursor lesions, including pancreatic intraepithelial neoplasia, in the pancreata of patients with a strong family history of pancreatic cancer. A detailed investigation of the histopathology of invasive familial pancreatic cancer could provide insights into the mechanisms responsible for familial pancreatic cancer, as well as aid early detection and treatment strategies. METHODS:We have conducted a blinded review of the pathology of 519 familial and 651 sporadic pancreatic cancers within the National Familial Pancreas Tumor Registry. Patients with familial pancreatic cancer were defined as individuals from families in which at least a pair of first-degree relatives have been diagnosed with pancreatic cancer. RESULTS:Overall, there were no statistically significant differences in histologic subtypes between familial and sporadic pancreatic cancers (p > 0.05). In addition, among surgical resection specimens within the study cohort, no statistically significant differences in mean tumor size, location, perineural invasion, angiolymphatic invasion, lymph node metastasis and pathologic stage were identified (p > 0.05). CONCLUSIONS:Similar to sporadic pancreatic cancer, familial pancreatic cancer is morphologically and prognostically a heterogeneous disease.

OBJECTIVE:The significance of indeterminate pulmonary nodules (IPNs) in patients undergoing resection of pancreatic ductal adenocarcinoma (PDAC) is unknown. We sought to define the prevalence and impact of IPN in such patients. METHODS:We studied all patients who underwent surgical resection of PDAC between 1980 and 2013. IPN was defined as ≥1 well-defined lung nodule(s) less than 3 cm in diameter. Survival was assessed using univariate and multivariate Cox models. RESULTS:Of the 2306 resected patients, 374 (16.2 %) had a preoperative chest computed tomography (CT) scan. Of these patients, 183 (49 %) had ≥1 IPN. Demographic and clinicopathological characteristics were similar among patients with or without IPN (all P>0.05). Median survival was comparable among patients who did (15.6 months) or did not (18.0 months) have IPN (P=0.66). Of the 183 patients with IPN, 29 (16 %) progressed to clinically recognizable metastatic lung disease compared to 13 % without IPN (P=0.38). The presence of >1 IPN was associated with the development of lung metastasis (relative risk 1.58, 95 % CI 1.03-2.4; P=0.05). However, lung metastasis was not associated with survival (P=0.24). CONCLUSIONS:An IPN proved to be a lung metastasis in only one of six patients with PDAC undergoing surgical resection in this study. Survival was not impacted, even among patients who developed lung metastasis. Patients with PDAC who have IPN should not be precluded from surgical consideration.

PURPOSE/OBJECTIVE:The median survival following surgical resection of pancreatic ductal adenocarcinoma (PDAC) is currently <20 months. However, survival ≥10 years is achieved by a small subset of patients who are defined as very long-term survivors (VLTS). The goal of this study was to determine whether specific genetic alterations in resected PDACs determined very long-term survival. EXPERIMENTAL DESIGN/METHODS:We sequenced the exomes of eight PDACs from patients who survived ≥10 years. On the basis of the results of the exomic analysis, targeted sequencing of selected genes was performed in a series of 27 additional PDACs from VLTSs. RESULTS:KRAS mutations were identified in 33 of 35 cancers (94%) from VLTSs and represented the most prevalent alteration in our cohort. TP53, SMAD4, and CDKN2A mutations occurred in 69%, 26%, and 17%, respectively. Mutations in RNF43, which have been previously associated with intraductal papillary mucinous neoplasms, were identified in four of the 35 cancers (11%). Taken together, our data show no difference in somatic mutations in carcinomas from VLTSs compared with available data from PDACs unselected for survival. Comparison of clinicopathologic features between VLTSs and a matching control group demonstrated that younger age, earlier stage, well/moderate grade of differentiation, and negative resection margins were associated with VLTS. However, more advanced stage, poor grade, or nodal disease did not preclude long-term survival. CONCLUSIONS:Our results suggest that in most patients, somatic mutations in commonly mutated genes are unlikely to be the primary determinant of very long-term survival following surgical resection of PDAC.

BACKGROUND:This phase 2 multi-institutional study was designed to determine whether gemcitabine (GEM) with fractionated stereotactic body radiotherapy (SBRT) results in acceptable late grade 2 to 4 gastrointestinal toxicity when compared with a prior trial of GEM with single-fraction SBRT in patients with locally advanced pancreatic cancer (LAPC). METHODS:A total of 49 patients with LAPC received up to 3 doses of GEM (1000 mg/m(2)) followed by a 1-week break and SBRT (33.0 gray [Gy] in 5 fractions). After SBRT, patients continued to receive GEM until disease progression or toxicity. Toxicity was assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events [version 4.0] and the Radiation Therapy Oncology Group radiation morbidity scoring criteria. Patients completed the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (QLQ-C30) and pancreatic cancer-specific QLQ-PAN26 module before SBRT and at 4 weeks and 4 months after SBRT. RESULTS:The median follow-up was 13.9 months (range, 3.9-45.2 months). The median age of the patients was 67 years and 84% had tumors of the pancreatic head. Rates of acute and late (primary endpoint) grade ≥ 2 gastritis, fistula, enteritis, or ulcer toxicities were 2% and 11%, respectively. QLQ-C30 global quality of life scores remained stable from baseline to after SBRT (67 at baseline, median change of 0 at both follow-ups; P>.05 for both). Patients reported a significant improvement in pancreatic pain (P = .001) 4 weeks after SBRT on the QLQ-PAN26 questionnaire. The median plasma carbohydrate antigen 19-9 (CA 19-9) level was reduced after SBRT (median time after SBRT, 4.2 weeks; 220 U/mL vs 62 U/mL [P<.001]). The median overall survival was 13.9 months (95% confidence interval, 10.2 months-16.7 months). Freedom from local disease progression at 1 year was 78%. Four patients (8%) underwent margin-negative and lymph node-negative surgical resections. CONCLUSIONS:Fractionated SBRT with GEM results in minimal acute and late gastrointestinal toxicity. Future studies should incorporate SBRT with more aggressive multiagent chemotherapy.

BACKGROUND:Pancreatic ductal adenocarcinoma (PDA) is comprised of a prominent desmoplastic stromal compartment and only 10-40% of the tumour consists of PDA cells. However, how stromal components should be assessed and how the characteristics of the stromal compartment determine clinical outcomes in PDA patients remain unknown. METHOD/METHODS:A cohort of 66 consecutive patients who underwent pancreaticoduodenectomy and were primarily followed at Johns Hopkins Hospital between 1998 and 2004, and treated with adjuvant therapy, were included in a retrospective analysis. Resected PDA blocks with good tissue preservation were available for all patients. A new, computer-aided, quantitative method was developed to assess the density and activity of stroma in PDAs and the associations of these characteristics with clinical outcomes. RESULTS:High stromal density in resected PDA was found to be significantly associated with longer disease-free [adjusted hazard ratio (aHR) 0.39; P = 0.001] and overall (aHR 0.44; P = 0.004) survival after adjusting for the use of pancreatic cancer vaccine therapy, as well as gender and resection margin positivity. Stromal activity, representing activated pancreatic stellate cells in PDAs, was not significantly associated with the prognosis of resected PDAs. CONCLUSIONS:These results illustrate the complexity of the role of stroma in PDAs. Further exploration of the prognostic ability of the characteristics of stroma is warranted.

INTRODUCTION/BACKGROUND:Intraductal papillary mucinous neoplasms (IPMNs) of the pancreas are precursor lesions that progress to invasive cancer through progressively worsening dysplasia. Although smoking is an established risk factor for pancreatic adenocarcinoma, potential associations with IPMN grade of dysplasia remain unclear. METHODS:Pancreatic resections for IPMN from 1995 to 2013 were retrospectively reviewed. A total of 446 patients in which the smoking status was documented were identified. RESULTS:Smoking history was positive in 47% of patients. Of smokers, 50% had branch-duct, 14% had main-duct, and 36% had mixed-type IPMN. Patients with main-duct IPMN were more commonly smokers (65%), compared to smoking history in 46% with mixed and 44% with branch-duct IPMN (p = 0.03). High-grade dysplasia occurred in 25% of smokers and 21% of nonsmokers (p = 0.32), and invasive carcinoma in 25% of smokers and 25% nonsmokers (p = 0.95). On multivariate analysis, duct size was independently associated with high-grade dysplasia (OR = 3.17, 95% CI = 1.79-5.64, p < 0.001). Presence of mural nodules (OR = 3.34, 95% CI = 1.82-6.12, p < 0.001), duct size (OR = 3.87, 95% CI = 2.21-6.75, p < 0.001), and symptoms (OR = 7.10, 95% CI = 3.80-13.08, p < 0.001), but not smoking history (OR = 1.10, 95% CI = 0.64-1.88, p = 0.73), were independent predictors of invasive carcinoma. Median overall survival was 70 months for smokers and 88 months for nonsmokers (p = 0.68). CONCLUSION/CONCLUSIONS:Positive smoking history correlated with duct type classification but does not appear to be a risk factor for harboring high-grade dysplasia or invasive carcinoma in IPMNs.

PURPOSE/OBJECTIVE:We investigated the incremental diagnostic yield of S-MRCP in a population with high prevalence of small pancreatic cysts. METHODS:Standard MRCP protocol was performed with and without secretin using 1.5 T units in subjects undergoing pancreatic screening because of a strong family history of pancreatic cancer as part of the multicenter Cancer of the Pancreas Screening-3 trial (CAPS 3). All studies were reviewed prospectively by two independent readers who recorded the presence and number of pancreatic cysts, the presence of visualized ductal communication before and after secretin, and the degree of confidence in the diagnoses. RESULT/RESULTS:Of 202 individuals enrolled (mean age 56 years, 46% males), 93 (46%) had pancreatic cysts detected by MRCP, and 64 of the 93 had pre-and post-secretin MRCP images available for comparison. Data from the 128 readings show that 6 (6/128=4.7%) had ductal communication visualized only on the secretin studies compared to pre-secretin studies (odds ratio 1.28, p=0.04). In addition, there was a statistically significant increase in confidence in reporting ductal communication after secretin compared to before secretin (p<0.0005). CONCLUSION/CONCLUSIONS:At 1.5 T MRI, the use of secretin can improve the visualization of ductal communication of cystic pancreatic lesions.

BACKGROUND:Postoperative readmissions have been proposed by Medicare as a quality metric and can impact provider reimbursement. Because readmission after pancreatectomy is common, we sought to identify factors associated with readmission to establish a predictive risk scoring system. STUDY DESIGN/METHODS:A retrospective analysis of 2,360 pancreatectomies performed at 9 high-volume pancreatic centers between 2005 and 2011 was performed. Forty-five factors strongly associated with readmission were identified. To derive and validate a risk scoring system, the population was randomly divided into 2 cohorts in a 4:1 fashion. A multivariable logistic regression model was constructed and scores were assigned based on the relative odds ratio (OR) of each independent predictor. A composite Readmission after Pancreatectomy (RAP) score was generated and then stratified to create risk groups. RESULTS:Overall, 464 (19.7%) patients were readmitted within 90 days. Eight pre- and postoperative factors, including earlier MI (OR = 2.03), American Society of Anesthesiologists class ≥ 3 (OR = 1.34), dementia (OR = 6.22), hemorrhage (OR = 1.81), delayed gastric emptying (OR = 1.78), surgical site infection (OR = 3.31), sepsis (OR = 3.10), and short length of stay (OR = 1.51) were independently predictive of readmission. The 32-point RAP score generated from the derivation cohort was highly predictive of readmission in the validation cohort (area under the receiver operating curve = 0.72). The low-risk (0 to 3), intermediate-risk (4 to 7), and high-risk (>7) groups correlated with 11.7%, 17.5%, and 45.4% observed readmission rates, respectively (p < 0.001). CONCLUSIONS:The RAP score is a novel and clinically useful risk scoring system for readmission after pancreatectomy. Identification of patients with increased risk of readmission using the RAP score will allow efficient resource allocation aimed to attenuate readmission rates. It also has potential to serve as a new metric for comparative research and quality assessment.

BACKGROUND:Pancreatic adenosquamous carcinoma (PASC) accounts for only 1-4% of all exocrine pancreatic cancers and carries a particularly poor prognosis. This retrospective study was performed to determine whether inclusion of a platinum agent as part of adjuvant therapy is associated with improved survival in patients with resected PASC. METHODS:Records of all patients who underwent pancreatic resection at Johns Hopkins Hospital from 1986 to 2012 were reviewed to identify those with PASC. Multivariable Cox proportional hazards modeling was used to assess for significant associations between patient characteristics and survival. RESULTS:In total, 62 patients (1.1%) with resected PASC were identified among 5,627 cases. Median age was 68 [interquartile range (IQR), 57-77] and 44% were female. Multivariate analysis revealed that, among all patients (n=62), the following factors were independently predictive of poor survival: lack of adjuvant therapy [hazard ratio (HR) =3.6; 95% confidence interval (CI), 1.8-7.0; P<0.001], margin-positive resection (HR =3.5; 95% CI, 1.8-6.8; P<0.001), lymph node involvement (HR =3.5; 95% CI, 1.5-8.2; P=0.004), and age (HR =1.0; 95% CI, 1.0-1.1; P=0.035). There were no significant differences between patients who did and did not receive adjuvant therapy following resection (all P>0.05). A second multivariable model included only those patients who received adjuvant therapy (n=39). Lack of inclusion of a platinum agent in the adjuvant regimen (HR =2.4; 95% CI, 1.0-5.8; P=0.040) and larger tumor diameter (HR =1.3; 95% CI, 1.0-1.6; P=0.047) were independent predictors of inferior survival. CONCLUSIONS:Addition of a platinum agent to adjuvant regimens for resected PASC may improve survival among these high-risk patients, though collaborative prospective investigation is needed.