Faculty Bibliography

BACKGROUND:Two types of pancreatic duct stents are used to improve postoperative outcomes of pancreatic anastomosis. The aim of this meta-analysis was to evaluate and compare the postoperative outcomes of patients with internal or external stenting during pancreaticoduodenectomy (PD). METHODS:We searched PubMed, EMBASE, the Cochrane Library and Web of Science databases until the end of December, 2014. Studies comparing outcomes of external vs. internal stent placement in PD were eligible for inclusion. Included literature was extracted and assessed by two independent reviewers. RESULTS:Seven articles were identified for inclusion: three randomized controlled trials (RCTs) and four observational clinical studies (OCS). The meta-analyses revealed that use of external stents had advantage on reducing the incidences of pancreatic fistula (PF) in total [odds ratio (OR) =0.69; 95% confidence interval (CI), 0.48-0.99; P=0.04], PF in soft pancreas (OR =0.30; 95% CI, 0.16-0.56; P=0.0002) and delayed gastric emptying (DGE) (OR =0.58; 95% CI, 0.38-0.89; P=0.01) compared with internal stents. There were no significant differences in other postoperative outcomes between two stenting methods, including postoperative morbidity (OR =0.93; 95% CI, 0.39-2.23; P=0.88), overall mortality (OR =0.70; 95% CI, 0.22-2.25; P=0.55), and intra-abdominal collections (OR =0.67; 95% CI, 0.26-1.71; P=0.40). CONCLUSIONS:Based upon this meta-analysis, the use of external pancreatic stents might have potential benefit in reducing the incidence of PF and DGE. Due to the limited number of original studies, more RCTs are needed to further support our result and clarify the issue.

BACKGROUND:Stereotactic body radiation therapy (SBRT) is a promising option for patients with pancreatic cancer (PCA); however, limited data support its efficacy. This study reviews our institutional experience of SBRT in the treatment of locally advanced (LAPC) and borderline resectable (BRPC) PCA. METHODS:Charts of all PCA patients receiving SBRT at our institution from 2010 to 2014 were reviewed. Most patients received pre-SBRT chemotherapy. Primary endpoints included overall survival (OS) and local progression-free survival (LPFS). Patients received a total dose of 25-33 Gy in five fractions. RESULTS:A total of 88 patients were included in the analysis, 74 with LAPC and 14 with BRPC. The median age at diagnosis was 67.2 years, and median follow-up from date of diagnosis for LAPC and BRPC patients was 14.5 and 10.3 months, respectively. Median OS from date of diagnosis was 18.4 months (LAPC, 18.4 mo; BRPC, 14.4 mo) and median PFS was 9.8 months (95 % CI 8.0-12.3). Acute toxicity was minimal with only three patients (3.4 %) experiencing acute grade ≥3 toxicity. Late grade ≥2 gastrointestinal toxicity was seen in five patients (5.7 %). Of the 19 patients (21.6 %) who underwent surgery, 79 % were LAPC patients and 84 % had margin-negative resections. CONCLUSIONS:Chemotherapy followed by SBRT in patients with LAPC and BRPC resulted in minimal acute and late toxicity. A large proportion of patients underwent surgical resection despite limited radiographic response to therapy. Further refinements in the integration of chemotherapy, SBRT, and surgery might offer additional advancements toward optimizing patient outcomes.

OBJECTIVES/OBJECTIVE:Lymphopenia is a common consequence of chemoradiation therapy yet is seldom addressed clinically. This study was conducted to determine if patients with locally advanced pancreatic cancer (LAPC) treated with definitive chemoradiation develop significant lymphopenia and if this affects clinical outcomes. METHODS:A retrospective analysis of patients with LAPC treated with chemoradiation at a single institution from 1997 to 2011 was performed. Total lymphocyte counts (TLCs) were recorded at baseline and then monthly during and after chemoradiation. The correlation between treatment-induced lymphopenia, established prognostic factors, and overall survival was analyzed using univariate Cox regression analysis. Important factors identified by univariate analysis were selected as covariates to construct a multivariate proportional hazards model for survival. RESULTS:A total of 101 patients met eligibility criteria. TLCs were normal in 86% before chemoradiation. The mean reduction in TLC per patient was 50.6% (SD, 40.6%) 2 months after starting chemoradiation (P<0.00001), and 46% had TLC<500 cells/mm. Patients with TLC<500 cells/mm 2 months after starting chemoradiation had inferior median survival (8.7 vs. 13.3 mo, P=0.03) and PFS (4.9 vs. 9.0 mo, P=0.15). Multivariate analysis revealed TLC<500 cells/mm to be an independent predictor of inferior survival (HR=2.879, P=0.001) along with baseline serum albumin (HR=3.584, P=0.0002), BUN (HR=1.060, P=0.02), platelet count (HR=1.004, P=0.005), and radiation planning target volume (HR=1.003, P=0.0006). CONCLUSIONS:Severe treatment-related lymphopenia occurs frequently after chemoradiation for LAPC and is an independent predictor of inferior survival.

PURPOSE/OBJECTIVE:The purpose of the study is to evaluate the CT appearance and pattern of metastatic disease of patients with surgically resected well-differentiated duodenal neuroendocrine tumors who underwent pre-operative dual-phase CT. METHODS:Clinical and pathologic records and CT images of 28 patients (average age 58.0 years) following Whipple procedure were retrospectively reviewed. The size, morphology (polypoid, intraluminal mass or wall thickening, intramural mass), location, CT attenuation in the arterial and venous phases, and the presence of lymph node or liver metastases were recorded. RESULTS:On CT, 19 patients (67.8%) had neuroendocrine tumors manifested as polypoid or intraluminal masses (38 lesions, multiple tumors in 3 patients), 4 patients (14.3%) had tumors manifested as wall thickening or intramural masses, and in 5 patients (17.9%), the primary tumor was not visualized. Lesions not seen at CT were less than 0.8 cm on pathologic diagnosis. The mean size of polypoid tumors on CT was 1.2 cm (range 0.3-3.8 cm); 24 tumors were 1.0 cm or smaller, and 14 tumors were larger than 1.0 cm. Most lesions were hypervascular in the arterial phase (19/23 patients) with an increase in tumor enhancement in the venous phase in 14 patients (60.9%), decrease in enhancement in 7 patients (30.4%), and no change in enhancement in 2 patients (8.7%). Thirteen patients (46.4%) had metastatic disease from carcinoid tumor, most commonly regional enhancing lymphadenopathy. CONCLUSION/CONCLUSIONS:Duodenal carcinoid tumors commonly appear as an enhancing mass in either the arterial or venous phases. If a primary tumor is not seen in the duodenum, adjacent enhancing lymphadenopathy can be a clue to the presence of a duodenal carcinoid tumor.

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.