Faculty Bibliography

Intraductal papillary mucinous neoplasms (IPMNs) are precursors to pancreatic cancer; however, little is known about genetic heterogeneity in these lesions. The objective of this study was to characterize genetic heterogeneity in IPMNs at the single-cell level. We isolated single cells from fresh tissue from ten IPMNs, followed by whole genome amplification and targeted next-generation sequencing of pancreatic driver genes. We then determined single-cell genotypes using a novel multi-sample mutation calling algorithm. Our analyses revealed that different mutations in the same driver gene frequently occur in the same IPMN. Two IPMNs had multiple mutations in the initiating driver gene KRAS that occurred in unique tumor clones, suggesting the possibility of polyclonal origin or an unidentified initiating event preceding this critical mutation. Multiple mutations in later-occurring driver genes were also common and were frequently localized to unique tumor clones, raising the possibility of convergent evolution of these genetic events in pancreatic tumorigenesis. Single-cell sequencing of IPMNs demonstrated genetic heterogeneity with respect to early and late occurring driver gene mutations, suggesting a more complex pattern of tumor evolution than previously appreciated in these lesions. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Pancreatic cancer is a lethal disease in a large part due to the systemic nature at the time of diagnosis. In those patients who undergo a potentially curative resection of pancreatic cancer, the overwhelming majority will have systemic relapse. Circulating tumor cells are an important mediator of the development of metastases. Circulating tumor cells have been identified in patients with clinically localized resectable pancreatic cancer and exist as several phenotypes. Mesenchymal and stem cell-like phenotypes of circulating tumor cells predict early recurrence and worse survival. This review focuses on the current understanding of circulating tumor cells in pancreatic cancer and how this information can be used in developing more effective therapy in the future.

INTRODUCTION:Approximately, 20% of patients with pancreatic ductal adenocarcinoma have resectable disease at diagnosis. Given improvements in locoregional and systemic therapies, some patients with borderline resectable pancreatic cancer (BRPC) can now undergo successful resection. The outcomes of patients with BRPC after neoadjuvant therapy remain unclear. METHODS:A prospectively maintained single-institution database was utilized to identify patients with BRPC who were managed at the Johns Hopkins Pancreas Multidisciplinary Clinic (PMDC) between 2013 and 2016. BRPC was defined as any tumor that presented with radiographic evidence of the involvement of the portal vein (PV) or superior mesenteric vein (SMV) that was deemed to be technically resectable (with or without the need for reconstruction), or the abutment (< 180° involvement) of the common hepatic artery (CHA) or superior mesenteric artery (SMA), in the absence of involvement of the celiac axis (CA). We collected data on treatment, the course of the disease, resection rate, and survival. RESULTS:Of the 866 patients evaluated at the PMDC during the study period, 151 (17.5%) were staged as BRPC. Ninety-six patients (63.6%) underwent resection. Neoadjuvant chemotherapy was administered to 142 patients (94.0%), while 78 patients (51.7%) received radiation therapy in the neoadjuvant setting. The median overall survival from the date of diagnosis, of resected BRPC patients, was 28.8 months compared to 14.5 months in those who did not (p < 0.001). Factors associated with increased chance of surgical resection included lower ECOG performance status (p = 0.011) and neck location of the tumor (p = 0.001). Forty-seven patients with BRPC (31.1%) demonstrated progression of disease; surgical resection was attempted and aborted in 12 patients (7.9%). Eight patients (5.3%) were unable to tolerate chemotherapy; six had disease progression and two did not want to pursue surgery. Lastly, four patients (3.3%) were conditionally unresectable due to medical comorbidities at the time of diagnosis due to comorbidities and failed to improve their status and subsequently had progression of the disease. CONCLUSION:After initial management, 31.1% of patients with BRPC have progression of disease, while 63.6% of all patients successfully undergo resection, which was associated with improved survival. Factors associated with increased likelihood of surgical resection include lower ECOG performance status and tumor location in the neck.

BACKGROUND:Intraductal papillary mucinous neoplasms (IPMNs) are precursor lesions to the development of pancreatic adenocarcinoma. We determined if non-O blood groups are more common in patients with IPMN and if blood group is a risk factor for progression to invasive pancreatic cancer among patients with IPMN. METHODS:The medical records were reviewed of all patients undergoing resection of an IPMN at Johns Hopkins Hospital from June 1997 to August 2016. Potential risk factors of high-grade dysplasia and associated adenocarcinoma were identified through a multivariate logistic regression model. RESULTS:Seven hundred and seventy-seven patients underwent surgical resection of an IPMN in which preoperative blood type was known. Sixty-two percent of IPMN patients had non-O blood groups (vs. 57% in two large US reference cohorts, P = 0.002). The association between non-O blood group was significant for patients with IPMN with low- or intermediate-grade dysplasia (P < 0.001), not for those with high-grade dysplasia (P = 0.68). Low- and intermediate-grade IPMNs were more likely to have non-type O blood compared to those with high-grade IPMN and/or associated invasive adenocarcinoma (P = 0.045). Blood type O was an independent predictor of having high-grade dysplasia without associated adenocarcinoma (P = 0.02), but not having associated invasive cancer (P = 0.72). The main risk factor for progression to invasive cancer after surgical resection was IPMN with high-grade dysplasia (P = 0.002). CONCLUSION:IPMN patients are more likely to have non-O blood groups than controls, but type O blood group carriers had higher odds of having high-grade dysplasia in their IPMN. These results indicate blood group status may have different effects on the risk and progression of IPMNs.

BACKGROUND:Readmission has received attention as a potential healthcare quality metric. No studies have investigated the relationship between readmission and survival in patients undergoing rectal cancer surgery. The aims of this study were to identify factors associated with 30-day readmission after rectal cancer surgery and to determine the impact of readmission on overall survival (OS). METHODS:Patients who underwent surgical treatment for rectal/rectosigmoid adenocarcinoma stages I-IV were identified using the National Cancer Database (2004-2014). Multivariable logistic regression was used to identify factors for readmission. 2:1 nearest neighbor caliper matching without replacement was used to ensure similarity of patients being compared. Survival analyses were performed using Kaplan-Meier method along with log-rank test and Cox proportional hazards model. RESULTS:Of 110,167 patients, 7045 (6.39%) were readmitted. Factors associated with readmission included higher Charlson comorbidity score, non-private or no insurance, procedure type, hospitals in the Northeast, South, and Midwest regions, and prolonged length of stay. Within the matched cohort (13,756 non-readmitted and 6878 readmitted), readmitted patients had worse 5- and 10-year OS regardless of cancer stage (p < 0.001) and procedure type. Five- and 10-year OS were 58.98% and 41.01% for readmitted patients, 64.96% and 43.50% for non-readmitted patients. Readmitted patients had shorter OS by 13.14 months and increased risk of mortality (HR 1.20, 95% CI 1.15-1.25, p < 0.001). CONCLUSIONS:Thirty-day readmission after rectal cancer surgery is associated with decreased OS. Efforts to reduce readmissions should be considered to advance cancer care and enhance the potential for improved patient survival.

Pancreatic cysts are common and often pose a management dilemma, because some cysts are precancerous, whereas others have little risk of developing into invasive cancers. We used supervised machine learning techniques to develop a comprehensive test, CompCyst, to guide the management of patients with pancreatic cysts. The test is based on selected clinical features, imaging characteristics, and cyst fluid genetic and biochemical markers. Using data from 436 patients with pancreatic cysts, we trained CompCyst to classify patients as those who required surgery, those who should be routinely monitored, and those who did not require further surveillance. We then tested CompCyst in an independent cohort of 426 patients, with histopathology used as the gold standard. We found that clinical management informed by the CompCyst test was more accurate than the management dictated by conventional clinical and imaging criteria alone. Application of the CompCyst test would have spared surgery in more than half of the patients who underwent unnecessary resection of their cysts. CompCyst therefore has the potential to reduce the patient morbidity and economic costs associated with current standard-of-care pancreatic cyst management practices.

OBJECTIVE:The aim of this study was to investigate the relationship between drain fluid amylase value on the first postoperative day (DFA1) and clinically relevant fistula (CR-POPF) after distal pancreatectomy (DP), and to identify the cut-off of DFA1 that optimizes CR-POPF prediction. BACKGROUND:DFA1 is a well-recognized predictor of CR-POPF after pancreatoduodenectomy, but its role in DP is largely unexplored. METHODS:DFA1 levels were correlated with CR-POPF in 2 independent multi-institutional sets of DP patients: developmental (n = 338; years 2012 to 2017) and validation cohort (n = 166; years 2006 to 2016). Cut-off choice was based on Youden index calculation, and its ability to predict CR-POPF occurrence was tested in a multivariable regression model adjusted for clinical, demographic, operative, and pathological variables. RESULTS:In the developmental set, median DFA1 was 1745 U/L and the CR-POPF rate was 21.9%. DFA1 correlated with CR-POPF with an area under the curve of 0.737 (P < 0.001). A DFA1 of 2000 U/L had the highest Youden index, with 74.3% sensitivity and 62.1% specificity. Patients in the validation cohort displayed different demographic and operative characteristics, lower values of DFA1 (784.5 U/L, P < 0.001), and reduced CR-POPF rate (10.2%, P < 0.001). However, a DFA1 of 2000 U/L had the highest Youden index in this cohort as well, with 64.7% sensitivity and 75.8% specificity. At multivariable analysis, DFA1 ≥2000 U/L was the only factor significantly associated with CR-POPF in both cohorts. CONCLUSION:A DFA1 of 2000 U/L optimizes CR-POPF prediction after DP. These results provide the substrate to define best practices and improve outcomes for patients receiving DP.

OBJECTIVE:To establish an international core set of patient-reported outcomes (PROs) selected by both patients and healthcare providers (HCPs) from the United States (US), Europe, and Asia. SUMMARY BACKGROUND DATA:PROs are increasingly recognized in pancreatic cancer studies. There is no consensus on which of the many available PROs are most important. METHODS:A multicenter Delphi study among patients with pancreatic cancer (curative- and palliative-setting) and HCPs in 6 pancreatic centers in the US (Baltimore, Boston), Europe (Amsterdam, Verona), and Asia (Mumbai, Seoul) was performed. In round 1, participants rated the importance of 56 PROs on a 1 to 9 Likert scale. PROs rated as very important (scores 7-9) by the majority (≥80%) of curative- and/or palliative-patients as well as HCPs were included in the core set. PROs not fulfilling these criteria were presented again in round 2, together with feedback on individual and group ratings. Remaining PROs were ranked based on the importance ratings. RESULTS:In total 731 patients and HCPs were invited, 501 completed round 1, and 420 completed both rounds. This included 204 patients in curative-setting, 74 patients in palliative-setting, and 142 HCPs. After 2 rounds, 8 PROs were included in the core set: general quality of life, general health, physical ability, ability to work/do usual activities, fear of recurrence, satisfaction with services/care organization, abdominal complaints, and relationship with partner/family. CONCLUSIONS:This international Delphi study among patients and HCPs established a core set of PROs in pancreatic cancer, which should facilitate the design of future pancreatic cancer trials and outcomes research.