Faculty Bibliography

BACKGROUND:The determination of the primary tumor origin in patients with neuroendocrine tumor liver metastases (NELM) can pose a considerable management challenge. Recent studies have shown that the alternative lengthening of telomeres (ALT) is prevalent in some human tumors, including pancreatic neuroendocrine tumors (PanNET), and can be useful in predicting tumor biology. In this study, we aimed to evaluate the use of ALT as a biomarker in patients with NELM, in particular to predict the site of origin of metastases. METHODS:Tissue microarrays (TMAs) were constructed using tumor tissue from NELM patients undergoing liver resection between 1998 and 2010. These included 43 PanNET and 47 gastrointestinal carcinoid tumors. The TMAs were tested for ALT using telomere-specific fluorescent in situ hybridization. The association between ALT positivity and clinicopathologic features and long-term outcomes was investigated. RESULTS:Alternative lengthening of telomeres was positive (ALT+) in 26 (29%) of the 90 tumors included in the TMAs. Pancreatic neuroendocrine tumors were ALT+ in 56% of patients, compared with only 4% ALT+ among gastrointestinal carcinoid tumors (p < 0.001). The specificity of ALT for detecting pancreatic origin was 96% and the positive predictive value was 92%, and sensitivity was 56% and the negative predictive value was 70%. Additionally, ALT was associated with the pattern of metastatic disease: ALT+ NELM were more likely to have oligometastases (p = 0.001) and less likely to be bilateral in distribution (p = 0.05) than were ALT tumors. In addition, ALT+ was associated with improved prognosis in the PanNET patient population. CONCLUSIONS:Alternative lengthening of telomeres was found to be a useful biomarker in patients with NELM. This marker can be helpful in guiding therapy by identifying the site of origin in patients in whom the primary site is unknown.

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.

PURPOSE/OBJECTIVE:Although previous studies have demonstrated the prognostic value of positron emission tomography (PET) parameters in other malignancies, the role of PET in pancreatic cancer has yet to be well established. We analyzed the prognostic utility of PET for patients with locally advanced pancreatic cancer (LAPC) undergoing fractionated stereotactic body radiation therapy (SBRT). MATERIALS AND METHODS/METHODS:Thirty-two patients with LAPC in a prospective clinical trial received up to 3 doses of gemcitabine, followed by 33 Gy in 5 fractions of 6.6 Gy, using SBRT. All patients received a baseline PET scan prior to SBRT (pre-SBRT PET). Metabolic tumor volume (MTV), total lesion glycolysis (TLG), and maximum and peak standardized uptake values (SUVmax and SUVpeak) on pre-SBRT PET scans were calculated using custom-designed software. Disease was measured at a threshold based on the liver SUV, using the equation Livermean + [2 × Liversd]. Median values of PET parameters were used as cutoffs when assessing their prognostic potential through Cox regression analyses. RESULTS:Of the 32 patients, the majority were male (n=19, 59%), 65 years or older (n=21, 66%), and had tumors located in the pancreatic head (n=27, 84%). Twenty-seven patients (84%) received induction gemcitabine prior to SBRT. Median overall survival for the entire cohort was 18.8 months (95% confidence interval [CI], 15.7-22.0). An MTV of 26.8 cm(3) or greater (hazard ratio [HR] 4.46, 95% CI 1.64-5.88, P<.003) and TLG of 70.9 or greater (HR 3.08, 95% CI 1.18-8.02, P<.021) on pre-SBRT PET scan were associated with inferior overall survival on univariate analysis. Both pre-SBRT MTV (HR 5.13, 95% CI 1.19-22.21, P=.029) and TLG (HR 3.34, 95% CI 1.07-10.48, P=.038) remained independently associated with overall survival in separate multivariate analyses. CONCLUSIONS:Pre-SBRT MTV and TLG are potential predictive factors for overall survival in patients with LAPC and may assist in tailoring therapy.

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.

High-dose-rate intraoperative radiation therapy (HDR-IORT) has historically provided effective local control (LC) for patients with unresectable and recurrent tumors. However, IORT is limited to only a few specialized institutions and it can be difficult to initiate an HDR-IORT program. Herein, we provide a brief overview on how to initiate and implement an HDR-IORT program for a selected group of patients with gastrointestinal and pelvic solid tumors using a multidisciplinary approach. Proper administration of HDR-IORT requires institutional support and a joint effort among physics staff, oncologists, surgeons, anesthesiologists, and nurses. In order to determine the true efficacy of IORT for various malignancies, collaboration among institutions with established IORT programs is needed.

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.

Pancreatic cancer is the deadliest of all solid malignancies. Early detection offers the best hope for a cure, but characteristics of this disease, such as the lack of early clinical symptoms, make the early detection difficult. Recent genetic mapping of the molecular evolution of pancreatic cancer suggests that a large window of opportunity exists for the early detection of pancreatic neoplasia, and developments in cancer genetics offer new, potentially highly specific approaches for screening of curable pancreatic neoplasia. We review the challenges of screening for early pancreatic neoplasia, as well as opportunities presented by incorporating molecular genetics into these efforts.

Pancreatic ductal adenocarcinoma (PDAC) is considered a "nonimmunogenic" neoplasm. Single-agent immunotherapies have failed to demonstrate significant clinical activity in PDAC and other "nonimmunogenic" tumors, in part due to a complex tumor microenvironment (TME) that provides a formidable barrier to immune infiltration and function. We designed a neoadjuvant and adjuvant clinical trial comparing an irradiated, granulocyte-macrophage colony-stimulating factor (GM-CSF)-secreting, allogeneic PDAC vaccine (GVAX) given as a single agent or in combination with low-dose cyclophosphamide to deplete regulatory T cells (Treg) as a means to study how the TME is altered by immunotherapy. Examination of resected PDACs revealed the formation of vaccine-induced intratumoral tertiary lymphoid aggregates in 33 of 39 patients 2 weeks after vaccine treatment. Immunohistochemical analysis showed these aggregates to be regulatory structures of adaptive immunity. Microarray analysis of microdissected aggregates identified gene-expression signatures in five signaling pathways involved in regulating immune-cell activation and trafficking that were associated with improved postvaccination responses. A suppressed Treg pathway and an enhanced Th17 pathway within these aggregates were associated with improved survival, enhanced postvaccination mesothelin-specific T-cell responses, and increased intratumoral Teff:Treg ratios. This study provides the first example of immune-based therapy converting a "nonimmunogenic" neoplasm into an "immunogenic" neoplasm by inducing infiltration of T cells and development of tertiary lymphoid structures in the TME. Post-GVAX T-cell infiltration and aggregate formation resulted in the upregulation of immunosuppressive regulatory mechanisms, including the PD-1-PD-L1 pathway, suggesting that patients with vaccine-primed PDAC may be better candidates than vaccine-naïve patients for immune checkpoint and other immunomodulatory therapies.

INTRODUCTION/BACKGROUND:Resident operative autonomy and case volume is associated with posttraining confidence and practice plans. Accreditation Council for Graduate Medical Education requirements for graduating general surgery residents are four liver and three pancreas cases. We sought to evaluate trends in resident experience and autonomy for complex hepatopancreatobiliary (HPB) surgery over time. METHODS:We queried the Accreditation Council for Graduate Medical Education General Surgery Case Log (2003-2012) for all cases performed by graduating chief residents (GCR) relating to liver, pancreas, and the biliary tract (HPB); simple cholecystectomy was excluded. Mean (±SD), median [10th-90th percentiles] and maximum case volumes were compared from 2003 to 2012 using R(2) for all trends. RESULTS:A total of 252,977 complex HPB cases (36% liver, 43% pancreas, 21% biliary) were performed by 10,288 GCR during the 10-year period examined (Mean = 24.6 per GCR). Of these, 57% were performed during the chief year, whereas 43% were performed as postgraduate year 1-4. Only 52% of liver cases were anatomic resections, whereas 71% of pancreas cases were major resections. Total number of cases increased from 22,516 (mean = 23.0) in 2003 to 27,191 (mean = 24.9) in 2012. During this same time period, the percentage of HPB cases that were performed during the chief year decreased by 7% (liver: 13%, pancreas 8%, biliary 4%). There was an increasing trend in the mean number of operations (mean ± SD) logged by GCR on the pancreas (9.1 ± 5.9 to 11.3 ± 4.3; R(2) = .85) and liver (8.0 ± 5.9 to 9.4 ± 3.4; R(2) = .91), whereas those for the biliary tract decreased (5.9 ± 2.5 to 3.8 ± 2.1; R(2) = .96). Although the median number of cases [10th:90th percentile] increased slightly for both pancreas (7.0 [4.0:15] to 8.0 [4:20]) and liver (7.0 [4:13] to 8.0 [5:14]), the maximum number of cases preformed by any given GCR remained stable for pancreas (51 to 53; R(2) = .18), but increased for liver (38 to 45; R(2) = .32). The median number of HPB cases that GCR performed as teaching assistants (TAs) remained at zero during this time period. The 90th percentile of cases performed as TA was less than two for both pancreas and liver. CONCLUSION/CONCLUSIONS:Roughly one-half of GCR have performed fewer than 10 cases in each of the liver, pancreas, or biliary categories at time of completion of residency. Although the mean number of complex liver and pancreatic operations performed by GCR increased slightly, the median number remained low, and the number of TA cases was virtually zero. Most GCR are unlikely to be prepared to perform complex HPB operations.