Faculty Bibliography

BACKGROUND:The use of minimally invasive surgery (MIS) techniques for pancreatic and liver operations remains ill defined. We sought to compare inpatient outcomes among patients undergoing open versus MIS pancreas and liver operations using a nationally representative cohort. METHODS:We queried the Nationwide Inpatient Sample database for all major pancreatic and hepatic resections performed between 2000 and 2011. Appropriate International Classification of Diseases, 9th Revision (ICD-9) coding modifiers for laparoscopy and robotic assist were used to categorize procedures as MIS. Demographics, comorbidities, and inpatient outcomes were compared between the open and MIS groups. RESULTS:A total of 65,033 resections were identified (pancreas, n = 36,195 [55.7%]; liver, n = 28,035 [43.1%]; combined pancreas and liver, n = 803 [1.2%]). The overwhelming majority of operations were performed open (n = 62,192, 95.6%), whereas 4.4% (n = 2,841) were MIS. The overall use of MIS increased from 2.3% in 2000 to 7.5% in 2011. Compared with patients undergoing an open operation, MIS patients were older and had a greater incidence of multiple comorbid conditions. After operation, the incidence of complications for MIS (pancreas, 35.4%; liver, 29.5%) was lower than for open (pancreas, 41.6%; liver, 33%) procedures (all P < .05) resulting in a shorter median length of stay (8 vs 7 days; P = .001) as well as a lower in-hospital mortality (5.1% vs 2.8%; P = .001). CONCLUSION/CONCLUSIONS:During the last decade, the number of MIS pancreatic and hepatic operations has increased, with nearly 1 in 13 HPB cases now being performed via an MIS approach. Despite MIS patients tending to have more preoperative medical comorbidities, postoperative morbidity, mortality, and duration of stay compared favorably with open surgery.

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.

Branch duct intraductal papillary mucinous neoplasms (BD-IPMN) are pre-malignant pancreatic cystic lesions which carry a small risk of malignant transformation within the cyst. Guidelines exist with respect to surveillance of the cysts using computed tomography, magnetic resonance imaging, and/or endoscopic ultrasound (EUS). There are reports that patients with IPMNs are at increased risk of developing pancreatic adenocarcinoma, which arises in an area separate to the IPMNs. We present two cases of pancreatic adenocarcinoma arising within the parenchyma, distinct from the IPMN-associated cyst, identified with EUS. This case report highlights that patients with BD-IPMN are at increased risk for pancreatic adenocarcinoma separate from the cyst and also the importance for endosonographers to carefully survey the rest of the pancreatic parenchyma separate from the cyst in order to identify small pancreatic adenocarcinomas.

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.

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.

BACKGROUND:The incidence of venous thromboembolism (VTE) among patients undergoing hepatic surgery is poorly defined, leading to varied use of VTE prophylaxis among surgeons. We sought to define the incidence of VTE after liver surgery and identify risk factors associated with VTE. METHODS:Incidence of VTE and associated risk factors within 90 days of hepatic resection between 2006 and 2012 at a major academic center was analyzed. Risk factors for VTE were identified using univariate and multivariate analyses. RESULTS:A total of 599 patients were included in the study cohort; 30 (5.0 %) had a prior history of VTE. The indications for surgery were malignant (90.8 %) and benign lesions (9.2 %). The majority of patients underwent a minor hepatectomy (<3 Couinaud segments; n = 402, 67.1 %) while 195 (32.6 %) patients underwent a major hepatectomy (≥3 Couinaud segments). Three hundred seven (51.3 %) patients were started on VTE chemoprophylaxis preoperatively with 407 (67.8 %) patients receiving VTE chemoprophylaxis within 24 h of surgery. Twenty-eight (4.7 %) patients developed VTE; 20 (3.3 %) had deep venous thrombosis (DVT), 11 (1.8 %) had pulmonary embolism (PE), and three (0.5 %) developed both DVT and PE. Among the VTE patients, 23 (82.1 %) had received VTE chemoprophylaxis. On multivariate analyses, history of VTE (odds ratio [OR] 4.51, 95 % confidence interval [CI] 1.81-17.22, P = 0.03), prolonged operative time (OR 1.17 per additional hour, 95 % CI 1.04-1.32, P = 0.009), and increased length of stay (LOS) (OR 1.07, 95 % CI 1.02-1.12, P = 0.01) were independent risk factors for VTE. CONCLUSION/CONCLUSIONS:VTE within 90 days of hepatic resection is common, occurring in nearly one in 20 patients. Most VTE events occurred among patients who received current best practice prophylaxis for VTE. More aggressive strategies to identify and reduce the risk of VTE in patients at highest risk of VTE, including those with a history of VTE, extended operative time, and prolonged LOS, are warranted.

CpG island methylator phenotype (CIMP) has been found in multiple precancerous and cancerous lesions, including colorectal adenomas, colorectal cancers, and duodenal adenocarcinomas. There are no reports in the literature of a relationship between CIMP status and clinicopathologic features of sporadic duodenal adenomas. This study sought to elucidate the role of methylation in duodenal adenomas and correlate it with KRAS and BRAF mutations. CIMP+ (with more than 2 markers methylated) was seen in 33.3% of duodenal adenomas; 61% of these CIMP+ adenomas were CIMP-high (with more than 3 markers methylated). Furthermore, CIMP+ status significantly correlated with older age of patients, larger size and villous type of tumor, coexistent dysplasia and periampullary location. MLH1 methylation was seen in 11.1% of duodenal adenomas and was significantly associated with CIMP+ tumors, while p16 methylation was an infrequent event. KRAS mutations were frequent and seen in 26.3% of adenomas; however, no BRAF mutations were detected. Furthermore, CIMP-high status was associated with larger size and villous type of tumor and race (non-white). These results suggest that CIMP+ duodenal adenomas may have a higher risk for developing malignancy and may require more aggressive management and surveillance.

PURPOSE/OBJECTIVE:To determine how often loss of ataxia-telangiectasia-mutated (ATM) protein expression occurs in primary pancreatic ductal adenocarcinomas and to determine its prognostic significance. EXPERIMENTAL DESIGN/METHODS:The expression of ATM and TP53 was determined by immunohistochemistry in 397 surgically resected pancreatic ductal adenocarcinomas (Hopkins; Johns Hopkins Medical Institutions, Baltimore, MD), a second set of 159 cases (Emory; Emory University Hospital, Atlanta, GA), and 21 cancers after neoadjuvant chemoradiotherapy. Expression was correlated with the clinicopathologic parameters, including survival. RESULTS:Tumoral ATM loss was observed in one cancer known to have biallelic inactivation of ATM and 50 of the first 396 (12.8%) cases, significantly more often in patients with a family history of pancreatic cancer (12/49; 24.5%) than in those without (38/347; 11.0%; P = 0.019). In the Hopkins series, ATM loss was associated with a significantly decreased overall survival in patients whose cancers had normal TP53 expression (P = 0.019) and was a significant independent predictor of decreased overall survival (P = 0.014). Seventeen (10.7%) of 159 Emory cases had tumoral ATM loss and tumoral ATM loss/normal TP53 was associated with poorer overall survival (P = 0.1). Multivariate analysis of the combined Hopkins/Emory cases found that tumoral ATM loss/normal TP53 was an independent predictor of decreased overall survival [HR = 2.61; confidence interval (CI), 1.27-5.37; P = 0.009]. Of 21 cancers examined after neoadjuvant chemoradiotherapy, one had tumoral loss of ATM; it had no histologic evidence of tumor response. CONCLUSIONS:Tumoral loss of ATM protein was detected more often in patients with a family history of pancreatic cancer than in those without. Patients whose pancreatic cancers had loss of ATM but normal TP53 had worse overall survival after pancreatic resection.

INTRODUCTION/BACKGROUND:Obesity is an epidemic in the U.S.A., with approximately 7% of the population considered morbidly obese (BMI > 40 or >35 with significant comorbidities). DISCUSSION/CONCLUSIONS:Weight loss surgery is recognized as a durable solution to both obesity and obesity-associated morbidities. With an increasing number of pancreatic lesions being discovered on cross-sectional imaging, the pancreatic surgeon is increasingly likely to encounter patients with prior bariatric surgery who are in need of pancreaticoduodenectomy. As such, surgeons need to be familiar with the various bariatric operations, as well as the manner in which to handle prior bariatric reconstructions at the time of pancreatic surgery. Literature on this topic, however, is scarce with only a handful of small case series. CONCLUSION/CONCLUSIONS:We herein review the different operations performed for weight loss, as well as provide an overview of the available operative approaches for reconstruction after pancreaticoduodenectomy in postbariatric surgical patients.