Faculty Bibliography

BACKGROUND:Solid pseudopapillary neoplasms (SPNs) of the pancreas are rare with low-grade malignancy and unclarified clinicopathological features. This study aimed to examine their characteristics and re-evaluate current treatments. METHODS:Databases from three sources were screened for patients with SPNs. We compared the perioperative variables, clinical data, overall survival (OS), and prognostic factors for recurrence among the three corresponding cohorts. RESULTS:We identified 286 patients diagnosed with SPNs between 1988 and 2020. Patients were mostly women (81%; median age: 38 years), and peak incidence was observed in women of 20-29 years of age. SPNs had a peak incidence in Asian men at 50-59 years of age (p = 0.002) and a delayed peak incidence in Asian women at 30-39 years of age (p < 0.001). Treatment strategies differed significantly across the institutions and included variations in the number of harvested lymph nodes and rates of vascular resection. Lymph node positivity was the only predictor of postoperative recurrence (odds ratio, 2.2; 95% confidence interval, 1.38-2.99; p = 0.007). Higher rates of lymphovascular invasion (p = 0.02), perineural invasion (p < 0.001), and R1 margin involvement (p < 0.001), as seen in one institution, did not result in poorer long-term survival in terms of the overall (p = 0.43), SPN-specific (p = 0.69), and recurrence-free survivals (p = 0.067). CONCLUSIONS:In contrast to previous findings that SPNs are prevalent in young women, a racial predilection for middle-aged Asian men and a delayed female peak incidence were noted. Parenchyma-preserving pancreatectomy may be an acceptable treatment. Non-radical surgery may be appropriate in patients with multiple comorbidities.

BACKGROUND:Nonfunctional pancreatic neuroendocrine tumors display a wide range of biological behavior, and nodal disease is associated with metastatic disease and poorer survival. The aim of this study was to develop a tool to predict nodal disease in patients with small (≤2 cm) nonfunctional pancreatic neuroendocrine tumors. METHODS:A multicenter retrospective study was performed on patients undergoing resection for small nonfunctional pancreatic neuroendocrine tumors. Patients with genetic syndromes, metastatic disease at diagnosis, neoadjuvant therapy, or positive resection margin were excluded. Factors associated with nodal disease were identified to develop a predictive model. Internal validation was performed using bootstrap with 1,000 resamples. RESULTS:Nodal disease was observed in 39 (11.1%) of the 353 patients included. Presence of nodal disease was significantly associated with lower 5-year disease-free survival (71.6% vs 96.2%, P < .001). Two predictors were strongly associated with nodal disease: G2 grade (odds ratio: 3.51, 95% confidence interval: 1.71-7.22, P = .001) and tumor size (per mm increase, odds ratio: 1.14, 95% confidence interval: 1.03-1.25, P = .009). Adequate discrimination was observed with an area under the curve of 0.71 (95% confidence interval: 0.63-0.80). Based on risk distribution, 3 risk groups of nodal disease were identified; low (<5%), intermediate (≥5% to <20%), and high (≥20%) risk. The observed mean risk of nodal disease was 3.7% in the low-risk patients, 9.6% in the intermediate-risk patients, and 30.4% in the high-risk patients (P < .001). The 10-year disease-free survival in the low, intermediate, and high-risk groups was 100%, 88.8%, and 50.1%, respectively. CONCLUSION/CONCLUSIONS:Our model using tumor grade and size can predict nodal disease in small nonfunctional pancreatic neuroendocrine tumors. Integration of this tool into clinical practice could help guide management of these patients.

OBJECTIVE:To investigate the role of intraoperative EBL on development of CR-POPF after pancreatoduodenectomy (PD). BACKGROUND:Minimizing EBL has been shown to decrease transfusions and provide better perioperative outcomes in PD. EBL is also felt to be influential on CR-POPF development. METHODS:This study consists of 5534 PDs from a 17-institution collaborative (2003-2018). EBL was progressively categorized (≤150 mL; 151-400 mL; 401-1,000 mL; >1,000 mL). Impact of additive EBL was assessed using 20 3-factor fistula risk score (FRS) scenarios reflective of endogenous CR-POPF risk. RESULTS:CR-POPF developed in 13.6% of patients (N = 753) and median EBL was 400 mL (interquartile range 250-600 mL). CR-POPF and Grade C POPF were associated with elevated EBL (median 350 vs 400 mL, P = 0.002; 372 vs 500 mL, P < 0.001, respectively). Progressive EBL cohorts displayed incremental CR-POPF rates (8.5%, 13.4%, 15.2%, 16.9%; P < 0.001). EBL >400 mL was associated with increased CR-POPF occurrence in 13/20 endogenous risk scenarios. Moreover, 8 of 10 scenarios predicated on a soft gland demonstrated increased CR-POPF incidence. Hypothetical projections demonstrate significant reductions in CR-POPF can be obtained with 1-, 2-, and 3-point decreases in FRS points attributed to EBL risk (12.2%, 17.4%, and 20.0%; P < 0.001). This is especially pronounced in high-risk (FRS7-10) patients, who demonstrate up to a 31% reduction (P < 0.001). Surgeons in the lowest-quartile of median EBL demonstrated CR-POPF rates less than half those in the upper-quartile (7.9% vs 18.8%; P < 0.001). CONCLUSION/CONCLUSIONS:EBL independently contributes significant biological risk to CR-POPF. Substantial reductions in CR-POPF occurrence are projected and obtainable by minimizing EBL. Decreased individual surgeon EBL is associated with improvements in CR-POPF.

BACKGROUND:Postoperative chemotherapy following pancreatic cancer resection is the standard of care. The utility of postoperative chemotherapy for patients who receive neoadjuvant therapy (NAT) is unclear. METHODS:Patients who underwent pancreatectomy after NAT with FOLFIRINOX or gemcitabine-based chemotherapy for non-metastatic pancreatic adenocarcinoma (2015-2019) were identified. Patients who received less than 2 months of neoadjuvant chemotherapy or died within 90 days from surgery were excluded. RESULTS:A total of 427 patients (resectable, 22.2%; borderline resectable, 37.9%; locally advanced, 39.8%) were identified with the majority (69.3%) receiving neoadjuvant FOLFIRINOX. Median duration of NAT was 4.1 months. Following resection, postoperative chemotherapy was associated with an improved median overall survival (OS) (28.7 vs. 20.4 months, P = 0.006). Risk-adjusted multivariable modeling showed negative nodal status (N0), favorable pathologic response (College of American Pathologists score 0 & 1), and receipt of postoperative chemotherapy to be independent predictors of improved OS. Regimen, duration, and number of cycles of NAT were not significant predictors. Thirty-four percent (60/176) of node-positive and 50.1% (126/251) of node-negative patients did not receive postoperative chemotherapy due to poor functional status, postoperative complications, and patient preference. Among patients with node-positive disease, postoperative chemotherapy was associated with improved median OS (27.2 vs. 10.5 months, P < 0.001). Among node-negative patients, postoperative chemotherapy was not associated with a survival benefit (median OS, 30.9 vs. 36.9 months; P = 0.406). CONCLUSION/CONCLUSIONS:Although there is no standard NAT regimen for patients with pancreatic cancer, postoperative chemotherapy following NAT and resection appears to be associated with improved OS for patients with node-positive disease.

OBJECTIVES/OBJECTIVE:To identify predictors, patterns, and timing of recurrence after resection of invasive carcinomas arising in association with an IPMN. BACKGROUND:Postoperative management of an invasive carcinoma arising in association with an intraductal papillary mucinous neoplasm (IPMN), a biologically distinct entity from PanIN-derived pancreatic ductal adenocarcinoma (PDAC), remains largely based on guidelines for PanIN-derived PDAC. To minimize treatment failure and inform disease-specific management, cancer recurrence must be better characterized. METHODS:Patients were identified from a prospectively maintained registry between 1996 and 2018. Predictors of recurrence were evaluated by employing Cox regression models to determine risk-adjusted hazard ratios (HR) with 95% confidence intervals (95%CI). The patterns and timing of recurrence were recognized and compared utilizing a log-rank test, respectively. RESULTS:Of the 213 patients included, 92 (43.2%) recurred with a median RFS of 23.7 months (16.7-30.7). The predominant pattern of recurrence included any systemic (65.2%). The median time to local recurrence was longer than systemic (21.6 versus 11.4 months, p = 0.05). Poor differentiation [HR: 3.01, 95%CI (1.06-8.61)] and nodal disease [N1, HR: 2.23, 95%CI (1.12-4.60); and N2, HR: 5.67 95%CI (2.93-10.99)] emerged as independent predictors of systemic recurrence. For local-specific recurrences, poor differentiation [HR: 3.73, 95%CI (1.04-13.45)] and an R1 margin [high-grade dysplasia or invasive carcinoma; HR: 2.66, 95%CI (1.14-6.21)] emerged as independent predictors. CONCLUSIONS:The predominant pattern of recurrence after resection of invasive carcinomas arising in association with IPMNs is systemic, and occurs earlier than local recurrence. Poor differentiation and nodal disease are associated with systemic recurrence while poor differentiation and an R1 margin are associated with local recurrence. Future studies should investigate the role of systemic (chemotherapy) versus local (radiation) therapies and surveillance strategies in a personalized manner.

Pancreatic ductal adenocarcinoma is the third-leading cause of all cancer-related deaths in the US. While 20% of patients have resectable disease at diagnosis, improved control of systemic disease using effective chemotherapeutic regimens allows for aggressive operations involving complex vascular resection and reconstruction. A pancreas protocol computed tomography (PPCT) is the gold standard imaging modality in determining local resectability (degree of tumor-vessel involvement), however, it is limited by the inter-operator variability. While post-processing-3D-rendering helps, it does not allow for real-time dynamic assessment of resectability. A recent development in post-process-rendering called cinematic rendering (CR) overcomes this by utilizing advanced light modeling to generate photorealistic 3D images with enhanced details. Cinematic rendering allows for nuanced visualization of areas of interest. Our preliminary experience, as one of the first centers to incorporate the routine use of CR, has proven very useful in surgical planning. For local determination of resectability, vascular mapping allows for accurate assessment of major arteries and the portovenous system. For the portovenous anatomy it assists in determining the optimal surgical approach (extent of resection, appropriate technique for reconstruction, and need for mesocaval shunting). For arterial anatomy, vessel encasement either represents dissectible involvement via periadventitial dissection or true vessel invasion that is unresectable. CR could potentially provide superior ability than traditional PPCT to discern between the two. Additionally, CR allows for better 3D visualization of arterial anatomic variants which, if not appreciated preoperatively, increases risk of intraoperative ischemia and postoperative complications. Lastly, CR could help avoid unnecessary surgery by enhanced identification of occult metastatic disease that is metastatic disease that is otherwise not appreciated on a standard PPCT.

Background/UNASSIGNED:Recent literature suggests wide variations exist in the international management of locally advanced pancreatic cancer. This study sought to evaluate how geography contributes to variations in management of locally advanced pancreatic cancer. Methods/UNASSIGNED:An electronic survey investigating preferences for the evaluation and management of locally advanced pancreatic cancer was distributed to an international cohort of pancreatic surgeons. Surgeons were classified according to geographic location of practice, and survey responses were compared across locations. Results/UNASSIGNED:A total of 153 eligible responses were received from 4 continents: North and South America (n = 94, 61.4%), Europe (n = 25, 16.3%), and Asia (n = 34, 22.2%). Preferences for the use and duration of neoadjuvant chemotherapy and radiotherapy varied widely. For example, participants in Asia commonly preferred 2 months of neoadjuvant chemotherapy (61.8%), whereas North and South American participants preferred 4 months (52.1%), and responses in Europe were mixed (P = .006). Participants in Asia were less likely to consider isolated liver or lung metastases contraindications to exploration and consequently had a greater propensity to consider exploration in a vignette of oligometastatic disease (56.7% vs North and South America: 25.6%, Europe: 43.5%; P = .007). Conclusion/UNASSIGNED:In an international survey of pancreatic surgeons, attitudes regarding locally advanced pancreatic cancer and metastatic disease management varied widely across geographic locations. Better evidence is needed to define optimal management of locally advanced pancreatic cancer.

RATIONALE/BACKGROUND:Patient-derived organoids (PDOs) are a promising technology to support precision medicine initiatives for patients with pancreatic ductal adenocarcinoma (PDAC). PDOs may improve clinical next-generation sequencing (NGS) and enable rapid ex vivo chemotherapeutic screening (pharmacotyping). METHODS:PDOs were derived from tissues obtained during surgical resection and endoscopic biopsies and studied with NGS and pharmacotyping. PDO-specific pharmacotype is assessed prospectively as a predictive biomarker of clinical therapeutic response by leveraging data from a randomized-controlled clinical trial. RESULTS:Clinical sequencing pipelines often fail to detect PDAC-associated somatic mutations in surgical specimens that demonstrate a good pathological response to previously administered chemotherapy. Sequencing the PDOs derived from these surgical specimens, after biomass expansion, improves the detection of somatic mutations and enables quantification of copy number variants. The detection of clinically relevant mutations and structural variants is improved following PDO biomass expansion. On clinical trial, PDOs were derived from biopsies of treatment naïve patients prior to treatment with FOLFIRINOX (FFX). Ex vivo PDO pharmacotyping with FFX components predicted clinical therapeutic response in these patients with borderline resectable or locally advanced PDAC treated in a neoadjuvant or induction paradigm. PDO pharmacotypes suggesting sensitivity to FFX components were associated with longitudinal declines of tumor marker, CA-19-9 and favorable RECIST imaging response. CONCLUSION/CONCLUSIONS:PDOs establishment from tissues obtained from patients previously receiving cytotoxic chemotherapies can be accomplished in a clinically-certified laboratory. Sequencing PDOs following biomass expansion improves clinical sequencing quality. High in-vitro sensitivity to standard-of-care chemotherapeutics predicts good clinical response to systemic chemotherapy in PDAC.

OBJECTIVE:Prospective evaluation of 2 clinical-molecular models in patients with unknown pathology who underwent endoscopic ultrasound with fine-needle aspiration (EUS-FNA) for a cystic lesion of the pancreas. SUMMARY OF BACKGROUND DATA/BACKGROUND:Preoperative prediction of histologic subtype (mucinous vs nonmucinous) and grade of dysplasia in patients with pancreatic cystic neoplasms is challenging. Our group has previously published 2 clinical-molecular nomograms for intraductal papillary mucinous neoplasms (IPMN) that incorporated both clinical/radiographic features and cyst fluid protein markers (sFASL, CA72-4, MMP9, IL-4). METHODS:This multiinstitutional study enrolled patients who underwent EUS-FNA for a cystic lesion of the pancreas. Treatment recommendations regarding resection were based on standard clinical, radiographic, and endoscopic features. Predicted probabilities of high-risk IPMN (high-grade dysplasia/invasive cancer) were calculated using the previously developed clinical-molecular nomograms. RESULTS:Cyst fluid was obtained from 100 patients who underwent diagnostic EUS-FNA. Within this group there were 35 patients who underwent resection, and 65 were monitored radiographically. Within the group that underwent resection, 26 had low-risk IPMN or benign non-IPMN lesions, and 9 had high-risk IPMN. Within the surveillance group, no patient progressed to resection or developed cancer after a median follow-up of 12 months (range: 0.5-38). Using the clinical/radiographic nomogram alone, 2 out of 9 patients with high-risk IPMN had a predicted probability >0.5. In the clinical-molecular models, 6 of 9 patients in model 1, and 6 of 9 in model 2, had scores >0.5. CONCLUSIONS:This prospective study of patients with unknown cyst pathology further demonstrates the importance of cyst fluid protein analysis in the preoperative identification of patients with high-risk IPMN. Longer follow-up is necessary to determine if this model will be useful in clinical practice.