Faculty Bibliography

OBJECTIVE:To develop a nomogram estimating the probability of recurrence free at 5 years after resection for localized grade 1 (G1)/ grade 2 (G2) pancreatic neuroendocrine tumors (PanNETs). BACKGROUND:Among patients undergoing resection of PanNETs, approximately 17% experience recurrence. It is not established which patients are at risk, with no consensus on optimal follow-up. METHOD/METHODS:A multi-institutional database of patients with G1/G2 PanNETs treated at 2 institutions was used to develop a nomogram estimating the rate of freedom from recurrence at 5 years after curative resection. A second cohort of patients from 3 additional institutions was used to validate the nomogram. Prognostic factors were assessed by univariate analysis using Cox regression model. The nomogram was internally validated using bootstrap resampling method and on the external cohort. Performance was assessed by concordance index (c-index) and a calibration curve. RESULTS:The nomogram was constructed using a cohort of 632 patients. Overall, 68% of PanNETs were G1, the median follow-up was 51 months, and we observed 74 recurrences. Variables included in the nomogram were the number of positive nodes, tumor diameter, Ki-67, and vascular/perineural invasion. The model bias-corrected c-index from the internal validation was 0.85, which was higher than European Neuroendocrine Tumors Society/American Joint Committee on Cancer 8th staging scheme (c-index 0.76, P = <0.001). On the external cohort of 328 patients, the nomogram c-index was 0.84 (95% confidence interval 0.79-0.88). CONCLUSION/CONCLUSIONS:Our externally validated nomogram predicts the probability of recurrence-free survival at 5 years after PanNETs curative resection, with improved accuracy over current staging systems. Estimating individual recurrence risk will guide the development of personalized surveillance programs after surgery.

OBJECTIVE:To evaluate the influence of consensus guidelines on the management of intraductal papillary mucinous neoplasms (IPMN) and the subsequent changes in pathologic outcomes. BACKGROUND:Over time, multiple guidelines have been developed to identify high-risk IPMN. We hypothesized that the development and implementation of guidelines should have increased the percentage of resected IPMN with high-risk disease. METHODS:Memorial Sloan-Kettering (MSK), Johns Hopkins (JH), and Massachusetts General Hospital (MGH) databases were queried for resected IPMN (2000-2015). Patients were categorized into main-duct (MD-IPMN) versus branch-duct (BD-IPMN). Guideline-specific radiographic/endoscopic features were recorded. High-risk disease was defined as high-grade dysplasia/carcinoma. Fisher's exact test was used to detect differences between institutions. Logistic regression evaluated differences between time-points [preguidelines (pre-GL, before 2006), Sendai (SCG, 2006-2012), Fukuoka (FCG, after 2012)]. RESULTS:The study included 1210 patients. The percentage of BD-IPMN with ≥1 high-risk radiographic feature differed between centers (MSK 69%, JH 60%, MGH 45%; P < 0.001). In MD-IPMN cohort, the presence of radiographic features such as solid component and main pancreatic duct diameter ≥10 mm also differed (solid component: MSK 38%, JH 30%, MGH 18%; P < 0.001; duct ≥10 mm: MSK 49%, JH 32%, MGH 44%; P < 0.001). The percentage of high-risk disease on pathology, however, was similar between institutions (BD-IPMN: P = 0.36, MD-IPMN: P = 0.48). During the study period, the percentage of BD-IPMN resected with ≥1 high-risk feature increased (52% pre-GL vs 67% FCG; P = 0.005), whereas the percentage of high-risk disease decreased (pre-GL vs FCG: 30% vs 20%). For MD-IPMN, there was not a clear trend towards guideline adherence, and the rate of high-risk disease was similar over the time (pre-GL vs FCG: 69% vs 67%; P = 0.63). CONCLUSION/CONCLUSIONS:Surgical management of IPMN based on radiographic criteria is variable between institutions, with similar percentages of high-risk disease. Over the 15-year study period, the rate of BD-IPMN resected with high-risk radiographic features increased; however, the rate of high-risk disease decreased. Better predictors are needed.

BACKGROUND OR PURPOSE:Pancreatic ductal adenocarcinoma (PDAC) is commonly diagnosed by endoscopic ultrasound-guided fine needle aspiration (EUS-FNA). However, the diagnostic adequacy of EUS-FNA is often limited by low cellularity leading to inconclusive results. We aimed to investigate the feasibility and added utility of targeted next-generation sequencing (NGS) on PDAC EUS-FNAs. METHODS:EUS-FNAs were prospectively performed on 59 patients with suspected PDAC (2014-2017) at a high-volume center. FNAs were analyzed for the presence of somatic mutations using NGS to supplement cytopathologic evaluations and were compared to surgical specimens and circulating tumor DNA (ctDNA). RESULTS:Fifty-nine patients with suspected PDAC were evaluated, and 52 were diagnosed with PDAC on EUS-FNA. Four of the remaining seven patients had inconclusive EUS-FNAs and were ultimately diagnosed with PDAC after surgical resection. Of these 56 cases of PDAC, 48 (85.7%) and 18 (32.1%) harbored a KRAS and/or TP53 mutation on FNA NGS, respectively. Particularly, in the four inconclusive FNA PDAC diagnoses (false negatives), half harbored KRAS mutations on FNA. No KRAS/TP53 mutation was found in remaining three non-PDAC cases. All EUS-FNA detected KRAS mutations were detected in 16 patients that underwent primary tumor NGS (100% concordance), while 75% KRAS concordance was found between FNA and ctDNA NGS. CONCLUSION:Targeted NGS can reliably detect KRAS mutations from EUS-FNA samples and exhibits high KRAS mutational concordance with primary tumor and ctDNA. This suggests targeted NGS of EUS-FNA samples may enable preoperative ctDNA prognostication using digital droplet PCR and supplement diagnoses in patients with inconclusive EUS-FNA.

PURPOSE/OBJECTIVE:The resection of retropancreatic nerve plexuses for pancreatic head cancer became standard of care during open pancreatoduodenectomy to minimize local recurrences. Since more surgical centers are progressing on the learning curve, robotically-assisted pancreatoduodenectomy is now increasingly performed with decreasing anatomic exclusion criteria. To achieve comparable and favorable oncologic outcomes, advanced surgical techniques should be transferred and implemented when performing robotic resections. METHODS:The nomenclature and anatomic principles of retropancreatic nerve plexuses and three different levels of dissections are utilized based on established definitions. RESULTS:The en bloc dissection in the "TRIANGLE" area (triangular-shaped retropancreatic space enclosed by the common hepatic artery, superior mesenteric artery, and superior mesenteric vein/portal vein) and the periadventitial dissection of arteries for non-tunica media-invading tumors were executed robotically. Both can be utilized to achieve a radical dorsal and medial margin. Video recordings are provided to illustrate varying TRIANGLE dissections. CONCLUSION/CONCLUSIONS:To accomplish oncologic non-inferiority, established principles from open pancreatic resections can be incorporated precisely and safely, overcoming the lack of haptic feedback while exploiting the technological advantages of the robotically-assisted platform.

Objective/UNASSIGNED:We describe a rare case of profound subcutaneous insulin resistance (SIR) presumed due to a paraneoplastic process caused by pancreatic adenocarcinoma that improved with intravenous insulin and tumor resection. Methods/UNASSIGNED:An 80-year-old man with previously well-controlled type 2 diabetes mellitus had worsening glycemic control (hemoglobin A1C increase of 6.5% to 8.6% over 4 months) following a recent diagnosis of pancreatic adenocarcinoma. His blood glucose was uncontrolled at 600 mg/dL despite rapid up-titration of a subcutaneous basal-bolus insulin regimen totaling 1000 units/d. Extensive evaluation of insulin resistance including insulin antibodies and anti-insulin receptor antibodies was negative. Due to clinical deterioration, the patient underwent pancreaticoduodenectomy before the completion of neoadjuvant chemotherapy. The patient received intravenous insulin before surgery, which resulted in rapid improvement in glycemic control. The patient's blood glucose normalized, and he was maintained on metformin monotherapy following pancreaticoduodenectomy. Results/UNASSIGNED:This patient had evidence of SIR in the setting of pancreatic adenocarcinoma. SIR was likely a paraneoplastic process as glycemic control improved after tumor resection. Interestingly, the patient did not have hyperinsulinemia but rather evidence of β-cell dysfunction, which highlights the possibility of exogenous insulin resistance. Conclusion/UNASSIGNED:Paraneoplastic processes due to pancreatic adenocarcinoma can cause SIR, marked by profound hyperglycemia and deteriorating functional status. It is, therefore important to recognize this rare syndrome and appropriately escalate to a higher level of care and consider proceeding with tumor resection.

BACKGROUND:Biliary anastomotic stricture (BAS) is an uncommon complication of pancreaticoduodenectomy (PD). As PDs are performed more frequently, BAS may become a more common pathologic entity requiring clinical engagement. The aim of this study was to report the incidence of BAS in the modern era of pancreatic surgery and identify risk factors associated with it. METHODS:Patients undergoing PD at the Johns Hopkins Hospital between 2007 and 2016 were identified using an institutional registry and clinicopathological features were analyzed to identify risk factors associated with BAS. RESULTS:Of 2125 patients identified, 103 (4.9%) developed BAS. Factors independently associated with BAS included laparoscopic approach (HR:2.83,95%CI:1.35-5.92, p = 0.006), postoperative pancreatic fistula (HR:2.45,95%CI:1.56-4.16,p < 0.001), postoperative bile leak (BL) (HR:5.26,95%CI:2.45-11.28,p < 0.001), and administration of adjuvant radiation therapy (HR:6.01,95%CI:3.19-11.34,p < 0.001). Malignant pathology was associated with lower rates of BAS (HR:0.52,95%CI:0.30-0.92, p = 0.025). BL was associated with higher rates of early-BAS (HR:16.49,95%CI:3.28-82.94, p = 0.001) while use of Vicryl suture for biliary enteric anastomosis was associated with lower rates of early-BAS (HR:0.20,95%CI:0.05-0.93, p = 0.041). CONCLUSION:Approximately 5% of patients undergoing PD experience BAS. Multiple factors are associated with the development and timing of BAS.

AJCC TNM stage and WHO grade (G) are two widely used staging systems to guide clinical management for pancreatic neuroendocrine neoplasms (panNENs), based on clinical staging and pathological grading information, respectively. We proposed to integrate TNM stage and G grade into one staging system (TNMG) and to evaluate its clinical application as a prognostic indicator for panNENs. Accordingly, 5254 patients diagnosed with panNENs were used to evaluate and to validate the applicability of TNMG to panNENs. The predictive accuracy of TNMG system was compared with that of each separate staging/grading system. We found that TNM stage and G grade were independent risk factors for survival in both the Surveillance, Epidemiology, and End Result (SEER) and multicenter series. The interaction effect between TNM stage and G grade was significant. Twelve subgroups combining the TNM stage and G grade were proposed in the TNMG stage, which were classified into five stages TNMG. According to the TNMG staging classification in the SEER series, the estimated median survival for stages I, II, III, IV, and V were 203, 174, 112, 61, and 8 months, respectively. The predictive accuracy of TNMG stage was higher than that of TNM stage and G grade used independently. The TNMG stage classification was more accurate in predicting panNEN patient's prognosis than either the TNM stage or G grade.