Faculty Bibliography

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.

Patients with pancreatic ductal adenocarcinoma (PDAC) are frequently staged as unresectable locally advanced pancreatic cancer (LAPC) at the time of diagnosis. Recently, the administration of multi-agent induction chemotherapy has resulted in treatment response in up to 60% of these patients rendering their tumors technically resectable. Operative strategies have evolved to allow for successful oncologic resection of LAPC. These technically complex procedures involving vascular resections and reconstructions are now being performed with increasing safety at high-volume centers. However, even after induction therapy and successful resection, disease recurrence sometimes occurs early on, limiting the benefit of resecting the local tumor. Therefore, selection of surgical candidates should factor in each patient's tumor biology which could result in accurate treatment guidance to improve patient outcomes while avoiding overtreatment. Well-informed patient selection is critical to improve outcomes in LAPC. Multidisciplinary teams have to determine the appropriate care for LAPC patients at the time of reevaluation after administration of induction chemotherapy. At this point the concept of favorable vs. unfavorable tumor biology becomes highly relevant and having access to biomarkers that are predictive of tumor behavior are of paramount importance. Currently, CA19-9 remains the only clinically utilized biomarker for PDAC, however, its use is limited by factors discussed in this review. While CA19-9 holds value in patient assessment, additional biomarkers are required that could supplement and improve the current ability to classify tumor biology and predict behavior in individual patients. Recent investigations on the use of circulating tumor DNA (ctDNA) and circulating tumor cells (CTCs) using liquid biopsies, as well as patient-derived organoids to characterize tumor biology have shown promise in achieving precise tumor biology-based patient stratification. Serial assessment of these biomarkers throughout therapy could supplement or even replace the anatomic criteria for resectability in the future.

BACKGROUND:Pancreatic ductal adenocarcinoma (PDAC) has a high propensity for systemic dissemination. Ovarian metastases are rare and poorly described. METHODS:We identified PDAC cases with ovarian metastasis from a prospectively maintained registry. We reported on the association between outcomes and clinicopathologic factors. Recurrence-free (RFS) and overall survival (OS) were calculated using Kaplan-Meier analysis. RESULTS:Twelve patients with PDAC and synchronous or metachronous ovarian metastases were identified. Nine patients (75%) underwent pancreatectomy for localized PDAC and developed metachronous ovarian recurrence. The median OS for all patients was 25.4 (IQR:15.4-82.9) months. For the nine patients with metachronous ovarian metastasis, the median RFS and OS were 14.2 (IQR:7.2-58.3) and 44.6 (IQR:18.6-82.9) months, respectively. Nodal disease, poor grade, vascular invasion in the pancreatic primary, and bilateral ovarian disease tended to confer worse outcomes. CONCLUSION/CONCLUSIONS:Patients with resected PDAC and ovarian recurrence tend to have a comparable disease course to more common patterns of recurrence. Primaries with nodal disease, poorer grade, vascular invasion, and bilateral ovarian disease were indicative of more aggressive disease biology. The ideal management remains largely unknown, and future collaborative efforts should optimize therapeutic strategies.

BACKGROUND AND PURPOSE:There is limited high-level evidence to guide locally advanced pancreas cancer (LAPC) management. Recent work shows that surgeons' preferences in LAPC management vary broadly. We sought to examine whether surgeon volume was associated with attitudes regarding LAPC management. METHODS:An electronic survey was distributed by email to an international cohort of pancreas surgeons to evaluate practice patterns regarding LAPC management. Clinical vignette-based questions evaluated surgeons' attitudes regarding patient eligibility and the proclivity to offer exploration. Surgeons were classified into "low-" or "high-volume" categories according to thresholds of self-reported annual pancreatectomy volume. Surgeon's attitudes regarding LAPC management and inclination to consider exploration were compared across annual volume categories. RESULTS:A total of 153 eligible responses were received from 4 continents, for an estimated response rate of 10.6%. Median duration of practice was 12 years (IQR 6-20). Most respondents reported >25 cases/year (89, 58.2%), of which 34 (22.2%) reported >50. Compared to surgeons with <25 cases/year, surgeons with >25 cases/year practiced longer (median 15 vs. 7.5 years, P<0.001) and were more likely to "always" recommend neoadjuvant chemotherapy (83.2% vs. 56.3%, P=0.001). Surgeons performing >50 cases/year were more likely to offer arterial resection (70.6% vs. 43.7%, P=0.006). The willingness to offer (or defer) exploration did not differ across any categories of surgeons' annual case volume. CONCLUSIONS:In an international survey of pancreas surgeons, the proclivity to consider exploration for LAPC was not associated with multiple categories of surgeon volume. Better evidence is needed to define the optimal management approach to LAPC.

OBJECTIVE:The aim of this study was to characterize the patterns and treatment of disease recurrence in patients achieving a pathological complete response (pCR) following neoadjuvant chemoradiation for advanced pancreatic ductal adenocarcinoma (PDAC). SUMMARY OF BACKGROUND DATA/BACKGROUND:A pCR is an independent predictor for improved survival in PDAC. However, disease recurrence is still observed in these patients. METHODS:Patients with advanced PDAC who were treated with neoadjuvant therapy and had a pCR were identified between 2009 and 2017. Overall survival (OS) was determined from the initiation of neoadjuvant, disease-free survival (DFS) from the date of surgery, and post-recurrence survival (PRS) from the date of recurrence. Factors associated with recurrence were analyzed using a Cox-regression model. RESULTS:Of 331 patients with borderline resectable or locally advanced PDAC, 30 achieved a pCR following neoadjuvant treatment and pancreatectomy. The median DFS for pCR patients was 29 months and OS 76 months. Recurrence was observed in 14 patients. No clinicopathologic or treatment characteristics were associated with survival. The median PRS following recurrence was 25 months. Treatment following recurrence included chemotherapy, radiation or ablation, and surgical resection. Hepatectomy or completion pancreatectomy was accomplished in 2 patients that remain alive 13 and 62 months, respectively, following metastasectomy. CONCLUSIONS:A pCR following neoadjuvant therapy in patients with advanced PDAC is associated with remarkable survival, although recurrence occurs in about half of patients. Nevertheless, patients with pCR and recurrence respond well to treatment and survival remains encouraging. Advanced molecular characterization and longitudinal liquid biopsy may offer additional assistance with understanding tumor biologic behavior after achieving a pCR.

IMPORTANCE:The progression of intraductal papillary mucinous neoplasms (IPMNs) of the pancreas to malignant disease is still poorly understood. Observational and surgical series have failed to provide comprehensive information. OBJECTIVE:To identify dynamic variables associated with the development of malignant neoplasms by combining pathological features with data from preoperative repeated observations. DESIGN, SETTING, AND PARTICIPANTS:The Crossover Observational Multicentric Study included a retrospective cohort of patients with branch-duct IPMNs (BD IPMNs) enrolled in a surveillance program from January 1, 2000, to December 31, 2019. Patients were enrolled from 5 referral centers: the Pancreas Institute, Verona, Italy; Seoul National University Hospital, Seoul, South Korea; Singapore General Hospital, Singapore; Johns Hopkins School of Medicine, Baltimore, Maryland; and University of Texas MD Anderson Cancer Center, Houston. Patients underwent a minimum of 12 months of preoperative surveillance (median, 37 [interquartile range (IQR), 20-68] months). MAIN OUTCOMES AND MEASURES:Dynamic variables associated with malignant disease were explored to estimate the presence of high-grade dysplasia (HGD) and invasive cancer at final pathological examination. RESULTS:A total of 292 patients were included in the analysis (137 women [46.9%] and 155 men [53.1%]; median age, 64 [IQR, 56-71] years). During surveillance, 27 patients (9.2%) developed a worrisome feature after 5 years, and 46 of 276 (16.7%) developed high-risk stigmata (HRS). At final pathological evaluation, 107 patients (36.6%) had HGD or invasive cancer, and 16 (5.5%) had IPMNs with concomitant pancreatic ductal adenocarcinoma. Rates of HGD and invasive cancer at pathological evaluation significantly differed between those without worrisome features and those developing HRS from a previous worrisome feature (9 [27.3%] vs 13 [61.9%]; P < .001). Developing an additional worrisome feature during surveillance (odds ratio [OR], 3.24 [95% CI, 1.38-7.60]; P = .007) or an HRS from a baseline worrisome feature (OR, 2.87 [95% CI, 1.01-8.17]; P = .048) was associated with HGD at final pathological evaluation. Among HRS, development of jaundice on a low-risk cyst was independently associated with invasive cancer (OR, 16.04 [95% CI, 2.94-87.40]; P = .001). CONCLUSIONS AND RELEVANCE:These findings suggest that in BD IPMNs under surveillance, harboring a stable worrisome feature carries the lowest risk of malignant disease. Development of additional worrisome features or HRS is associated with the presence of HGD, whereas the occurrence of jaundice is associated with invasive cancer.

OBJECTIVE:To evaluate the impact of postoperative glycemic control on postoperative morbidity in patients undergoing a pancreaticoduodenectomy. METHODS:A retrospective study was performed on patients at The Johns Hopkins Hospital between April 2015 and April 2016. Data were collected on postoperative insulin regimens, blood glucose, rates of hyperglycemia and hypoglycemia, and postoperative complications and were evaluated. RESULTS:Out of 244 patients, 114 (46.7%) experienced at least 1 hyperglycemic (>180 mg/dL) episode and 16 (6.6%) experienced at least 1 hypoglycemic episode (<70 mg/dL) during the first postoperative 24 hours. Early postoperative hyperglycemia (>180 mg/dL) was associated with a significantly higher rate of surgical site infections (15.7% vs 7%; P = 0.031). Late postoperative hyperglycemia (>180 mg/dL) was associated with a significantly higher rate of fistulas (4.3% vs 14.6%; P = 0.021). CONCLUSIONS:Early hyperglycemia (>180 mg/dL) is associated with a higher risk of surgical site infections while late hyperglycemia is associated with a higher risk of fistulas. Intensive glucose control (<150 mg/dL) was not demonstrated to decrease the risk of postoperative complications. Similar to other critically ill populations, targeting a glucose goal of <180 mg/dL may be an appropriate target to reduce morbidity without increasing the risk of hypoglycemia.