Faculty Bibliography

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.

The grading system for pancreatic neuroendocrine tumors (PanNETs) adopted in 2010 by the World Health Organization (WHO) mandates the use of both mitotic rate and Ki67/MIB-1 index in defining the proliferative rate and assigning the grade. In cases when these measures are not concordant for grade, it is recommended to assign the higher grade, but specific data justifying this approach do not exist. Thus, we counted mitotic figures and immunolabeled, using the Ki67 antibody, 297 WHO mitotic grade 1 and 2 PanNETs surgically resected at a single institution. We quantified the Ki67 proliferative index by marking at least 500 cells in "hot spots" and by using digital image analysis software to count each marked positive/negative cell and then compared the results with histologic features and overall survival. Of 264 WHO mitotic grade 1 PanNETs, 33% were WHO grade 2 by Ki67 proliferative index. Compared with concordant grade 1 tumors, grade-discordant tumors were more likely to have metastases to lymph node (56% vs. 34%) (P<0.01) and to distant sites (46% vs. 12%) (P<0.01). Discordant mitotic grade 1 PanNETs also showed statistically significantly more infiltrative growth patterns, perineural invasion, and small vessel invasion. Overall survival was significantly different (P<0.01), with discordant mitotic grade 1 tumors showing a median survival of 12 years compared with 16.7 years for concordant grade 1 tumors. Conversely, mitotic grade 1/Ki67 grade 2 PanNETs showed few significant differences from tumors that were mitotic grade 2 and either Ki67 grade 1 or 2. Our data demonstrate that mitotic rate and Ki67-based grades of PanNETs are often discordant, and when the Ki67 grade is greater than the mitotic grade, clinical outcomes and histopathologic features are significantly worse than concordant grade 1 tumors. Patients with discordant mitotic grade 1/Ki67 grade 2 tumors have shorter overall survival and larger tumors with more metastases and more aggressive histologic features. These data strongly suggest that Ki67 labeling be performed on all PanNETs in addition to mitotic rate determination to define more accurately tumor grade and prognosis.

BACKGROUND:Parenchymal-sparing pancreatic surgery is ideal for lesions such as small pancreatic neuroendocrine tumors (PanNET). However, precise localization of these small tumors at surgery can be difficult. The placement of fiducials under endoscopic ultrasound (EUS) guidance (EUS-F) has been used to direct stereotactic radiation therapy for pancreatic adenocarcinoma. This report describes two cases in which placement of fiducials was used to guide surgical resection. This study aimed to assess the feasibility, safety, and efficacy of using EUS-F for intraoperative localization of small PanNETs. METHODS:A retrospective study analyzed two consecutive patients with small PanNETs who underwent EUS-F followed by enucleation in a tertiary-care referral hospital. The following features were examined: technical success and complication rates of EUS-F, visibility of the fiducial at the time of surgery, and fiducial migration. RESULTS:In the study, EUS-F was performed for two female patients with a 7-mm and a 9-mm PanNET respectively in the uncinate process and neck of the pancreas. In both patients, EUS-F was feasible with two Visicoil fiducials (Core Oncology, Santa Barbara, CA, USA) placed either within or adjacent to the tumors using a 22-gauge Cook Echotip needle. At surgery, the fiducials were clearly visible on intraoperative ultrasound, and both the tumor and the fiducials were successfully enucleated in both cases. No complications were associated with EUS-F, and no evidence of pancreatitis was shown either clinically or on surgical pathology. This investigation had the limitations of a small single-center study. CONCLUSIONS:For patients undergoing enucleation, EUS-F is technically feasible and safe and aids intraoperative localization of small PanNETs.

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.

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.

Acinar cell cystadenoma (ACA) of the pancreas was initially described as a non-neoplastic cyst of the pancreas and, at that time, referred to as "acinar cystic transformation." In subsequent studies, these lesions were given the designation of "-oma," despite the relative lack of evidence supporting a neoplastic process. To characterize these lesions further, we examined the clinical, pathologic, and immunohistochemical features of 8 ACAs. The majority of patients were female (7 of 8, 88%) and ranged in age from 18 to 57 years (mean, 43 y). Grossly, the cysts involved the head (n=5), body (n=1), or the entire pancreas (n=2). ACAs were either multilocular (n=4) or unilocular (n=4) and ranged in size from 1.8 to 15 cm (mean, 6.8 cm). Histologically, multilocular ACAs were lined by patches of acinar and ductal epithelium. Immunolabeling, including double-labeling for cytokeratin 19 and chymotrypsin, highlighted the patchy pattern of the ductal and acinar cells lining the cysts. In some areas, the cysts with patches of acinar and ductal differentiation formed larger locules with incomplete septa as they appeared to fuse with other cysts. In contrast, the unilocular cases were lined by 1 to 2 cell layers of acinar cells with little intervening ductal epithelium. Nuclear atypia, mitotic figures, necrosis, infiltrative growth, and associated invasive carcinoma were absent in all cases. In addition, we assessed the clonal versus polyclonal nature of ACAs, occurring in women, using X-chromosome inactivation analysis of the human androgen receptor (AR) gene. Five of 7 cases were informative and demonstrated a random X-chromosome inactivation pattern. Clinical follow-up information was available for all patients, and follow-up ranged from 10 months to 7.8 years (mean, 3.6 y), with no evidence of recurrence or malignant transformation. We hypothesize that early lesions are marked by acinar dilatation that expands into and incorporates smaller ductules and later larger ducts. As the cysts increase in size, they fuse forming larger cysts. Later lesions demonstrate a unilocular cyst lined by predominantly acinar epithelium with scattered ductal cells. The term cystadenoma, with its neoplastic connotation, does not seem to accurately reflect the histologic, immunohistochemical, or molecular features of these lesions. We suggest readopting the term "acinar cystic transformation" until the non-neoplastic versus neoplastic origin of these lesions can be resolved.

BACKGROUND: The purpose of this study was to evaluate preoperative treatment with full-dose gemcitabine, oxaliplatin, and radiation therapy (RT) in patients with localized pancreatic cancer. METHODS: Eligibility included confirmation of adenocarcinoma, resectable or borderline resectable disease, a performance status /=3 adverse events during preoperative therapy included neutropenia (32%), thrombocytopenia (25%), and biliary obstruction/cholangitis (14%). Forty-three patients underwent resection (63%), and complete (R0) resection was achieved in 36 of those 43 patients (84%). The median overall survival was 18.2 months (95% confidence interval, 13-26.9 months) for all patients, 27.1 months (95% confidence interval, 21.2-47.1 months) for those who underwent resection, and 10.9 months (95% confidence interval, 6.1-12.6 months) for those who did not undergo resection. A decrease in CA 19-9 level after neoadjuvant therapy was associated with R0 resection (P = .02), which resulted in a median survival of 34.6 months (95% confidence interval, 20.3-47.1 months). Fourteen patients (21%) are alive and disease free at a median follow-up of 31.4 months (range, 24-47.6 months). CONCLUSIONS: Preoperative therapy with full-dose gemcitabine, oxaliplatin, and RT was feasible and resulted in a high percentage of R0 resections. The current results are particularly encouraging, because the majority of patients had borderline resectable disease.

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.