Faculty Bibliography

Circulating tumor DNA (ctDNA) measurements can be used to estimate tumor burden, but avoiding false-positive results is challenging. Herein, digital next-generation sequencing (NGS) is evaluated as a ctDNA detection method. Plasma KRAS and GNAS hotspot mutation levels were measured in 140 subjects, including 67 with pancreatic ductal adenocarcinoma and 73 healthy and disease controls. To limit chemical modifications of DNA that yield false-positive mutation calls, plasma DNA was enzymatically pretreated, after which DNA was aliquoted for digital detection of mutations (up to 384 aliquots/sample) by PCR and NGS. A digital NGS score of two SDs above the mean in controls was considered positive. Thirty-seven percent of patients with pancreatic cancer, including 31% of patients with stages I/II disease, had positive KRAS codon 12 ctDNA scores; only one patient had a positive GNAS mutation score. Two disease control patients had positive ctDNA scores. Low-normal-range digital NGS scores at mutation hotspots were found at similar levels in healthy and disease controls, usually at sites of cytosine deamination, and were likely the result of chemical modification of plasma DNA and NGS error rather than true mutations. Digital NGS detects mutated ctDNA in patients with pancreatic cancer with similar yield to other methods. Detection of low-level, true-positive ctDNA is limited by frequent low-level detection of false-positive mutation calls in plasma DNA from controls.

BACKGROUND & AIMS/OBJECTIVE:Levels of carcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (CA19-9), and cancer antigen 125 (CA-125) in blood are used as markers to determine the response of patients with cancer to therapy, but are not used to identify patients with pancreatic cancer. METHODS:We obtained blood samples from 504 patients undergoing pancreatic surveillance from 2002 through 2018 who did not develop pancreatic cancer and measured levels of the tumor markers CA19-9, CEA, CA-125, and thrombospondin-2. Single-nucleotide polymorphisms (SNPs) in FUT3, FUT2, ABO, and GAL3ST2 that have been associated with levels of tumor markers were used to establish SNP-defined ranges for each tumor marker. We also tested the association between additional SNPs (in FUT6, MUC16, B3GNT3, FAM3B, and THBS2) with levels of tumor markers. To calculate the diagnostic specificity of each SNP-defined range, we assigned the patients under surveillance into training and validation sets. After determining the SNP-defined ranges, we determined the sensitivity of SNP-adjusted tests for the tumor markers, measuring levels in blood samples from 245 patients who underwent resection for pancreatic ductal adenocarcinoma (PDAC) from 2010 through 2017. RESULTS:A level of CA19-9 that identified patients with PDAC with 99% specificity had 52.7% sensitivity. When we set the cut-off levels of CA19-9 based on each SNP, the test for CA19-9 identified patients with PDAC with 60.8% sensitivity and 98.8% specificity. Among patients with FUT3 alleles that encode a functional protein, levels of CA19-9 greater than the SNP-determined cut-off values identified 66.4% of patients with PDAC, with 99.3% specificity. In the validation set, levels of CEA varied among patients with vs without SNP in FUT2, by blood group, and among smokers vs nonsmokers; levels of CA-125 varied among patients with vs without the SNP in GAL3ST2. The use of the SNPs to define the ranges of CEA and CA-125 did not significantly increase the diagnostic accuracy of the assays for these proteins. Combining data on levels of CA19-9 and CEA, CA19-9 and CA-125, or CA19-9 and thrombospondin-2 increased the sensitivity of detection of PDAC, but slightly reduced specificity. CONCLUSIONS:Including information on SNPs associated with levels of CA19-9, CEA, and CA-125 can improve the diagnostic accuracy of assays for these tumor markers in the identification of patients with PDAC. Clinicaltrials.gov no: NCT02000089.

BACKGROUND:Screening high-risk individuals (HRI) can detect potentially curable pancreatic ductal adenocarcinoma (PDAC) and its precursors. We describe the outcomes of high-risk individuals (HRI) after pancreatic resection of screen-detected neoplasms. METHODS:Asymptomatic HRI enrolled in the prospective Cancer of the Pancreas Screening (CAPS) studies from 1998 to 2014 based on family history or germline mutations undergoing surveillance for at least 6 months were included. Pathologic diagnoses, hospital length of stay, incidence of diabetes mellitus, operative morbidity, need for repeat operation, and disease-specific mortality were determined. RESULTS:Among 354 HRI, 48 (13.6%) had 57 operations (distal pancreatectomy (31), Whipple (20), and total pancreatectomy (6)) for suspected pancreatic neoplasms presenting as a solid mass (22), cystic lesion(s) (25), or duct stricture (1). The median length of stay was 7 days (IQR 5-11). Nine of the 42 HRI underwent completion pancreatectomy for a new lesion after a median of 3.8 years (IQR 2.5-7.6). Postoperative complications developed in 17 HRI (35%); there were no perioperative deaths. New-onset diabetes mellitus after partial resection developed in 20% of HRI. Fourteen PDACs were diagnosed, 11 were screen-detected, 10 were resectable, and 9 had an R0 resection. Metachronous PDAC developed in remnant pancreata of 2 HRI. PDAC-related mortality was 4/10 (40%), with 90% 1-year survival and 60% 5-year survival, respectively. CONCLUSIONS:Screening HRI can detect PDAC with a high resectability rate. Surgical treatment is associated with a relatively short length of stay and low readmission rate, acceptable morbidity, zero 90-day mortality, and significant long-term survival. CLINICAL TRIAL REGISTRATION NUMBER/BACKGROUND:NCT2000089.

BACKGROUND:The objective of this study was to validate and update the Amsterdam prediction model including tumor grade, lymph node ratio, margin status and adjuvant therapy, for prediction of overall survival (OS) after pancreatoduodenectomy for pancreatic cancer. METHODS:We included consecutive patients who underwent pancreatoduodenectomy for pancreatic cancer between 2000 and 2017 at 11 tertiary centers in 8 countries (USA, UK, Germany, Italy, Sweden, the Netherlands, Korea, Australia). Model performance for prediction of OS was evaluated by calibration statistics and Uno's C-statistic for discrimination. Validation followed the TRIPOD statement. RESULTS:Overall, 3081 patients (53% male, median age 66 years) were included with a median OS of 24 months, of whom 38% had N2 disease and 77% received adjuvant chemotherapy. Predictions of 3-year OS were fairly similar to observed OS with a calibration slope of 0.72. Statistical updating of the model resulted in an increase of the C-statistic from 0.63 to 0.65 (95% CI 0.64-0.65), ranging from 0.62 to 0.67 across different countries. The area under the curve for the prediction of 3-year OS was 0.71 after updating. Median OS was 36, 25 and 15 months for the low, intermediate and high risk group, respectively (P < 0.001). CONCLUSIONS:This large international study validated and updated the Amsterdam model for survival prediction after pancreatoduodenectomy for pancreatic cancer. The model incorporates readily available variables with a fairly accurate model performance and robustness across different countries, while novel markers may be added in the future. The risk groups and web-based calculator www.pancreascalculator.com may facilitate use in daily practice and future trials.

BACKGROUND:Solid pseudopapillary tumors (SPTs) are rare, benign tumors of the pancreas that present as heterogeneous masses. We sought to evaluate the short- and long-term outcomes of surgical resected SPTs. Patients managed via initial surveillance were compared to those who underwent upfront resection. METHODS:A prospectively maintained institutional database was used to identify patients who underwent surgical resection for a SPT between 1988 and 2018. Data on clinicopathological features and outcomes were collected and analyzed. RESULTS:Seventy-eight patients underwent surgical resection for SPT during the study period. The mean age was 34.0 ± 14.6 years and a majority were female (N = 67, 85.9%) and white (N = 46, 58.9%). Thirty patients (37.9%) were diagnosed incidentally. Imaging-based presumed diagnosis was SPT in 49 patients (62.8%). A majority were located in the body or tail of the pancreas (N = 47, 60.3%), and 48 patients (61.5%) underwent a distal pancreatectomy. The median tumor size was 4.0 cm (IQR, 3.0-6.0), nodal disease was present in three patients (3.9%), and R0 resection was performed in all patients. No difference was observed in clinicopathological features and outcomes between patients who were initially managed via surveillance and those who underwent upfront resection. None of the patients under surveillance had nodal disease or metastasis at the time of resection; however, one of them developed recurrence of disease 95.1 months after resection. At a median follow-up of 36.1 months (IQR, 8.1-62.1), 77 (%) patients were alive and one patient (1.3%) had a recurrence of disease at 95.1 months after resection and subsequently died due to disease. CONCLUSIONS:SPTs are rare pancreatic tumors that are diagnosed most frequently in young females. While a majority are benign and have an indolent course, malignant behavior has been observed. Surgical resection can result in exceptional outcomes.

INTRODUCTION:Improvement in imaging has resulted in frequent diagnosis of benign and premalignant pancreatic tumors. Pancreatic nerve sheath (PNS) tumors are one of the rarest pancreatic tumors. Literature on PNS is limited and their biology is poorly understood. Here, we report the largest series of PNS tumors to date and review the literature to evaluate the current data available on PNS tumors. METHODS:An institutional database was used to identify patients who underwent resection for PNS tumors. Clinicopathological characteristics and outcomes of these patients were reported. Furthermore, a review of literature was performed. RESULTS:From January 1994 through December 2016, seven patients underwent resection for PNS tumors. The median age was 57.7 years (IQR, 44.9-61.9) and the sex was approximately equally distributed (male = 4; 57.1%). Three (42.9%) patients were diagnosed incidentally and six (85.7%) were misdiagnosed as having other pancreatic tumors. The median tumor size was 2.1 (IQR 1.8-3.0) cm and six (85.7%) had no nodal disease. At a median follow-up of 15.5 (IQR 13.7-49.3) months, six patients were alive without evidence of disease and one patient was lost to follow-up. The literature review identified 49 studies reporting 54 patients with PNS tumors. Forty-six were misdiagnosed as having other pancreatic tumors. The median tumor size was 3.6 (range 1-20) cm, nodal disease was present in six patients (22.2%), and no patient had distant metastatic disease. At the time of last follow-up, all patients were free of disease. CONCLUSION:This is the largest single institution series on PNS tumors reported to date. These tumors are rare and are often misdiagnosed, given their radiological characteristics. PNS tumors have a benign course of disease and surgical resection results in favorable long-term outcomes.

We report a sensitive PCR-based assay called Repetitive Element AneupLoidy Sequencing System (RealSeqS) that can detect aneuploidy in samples containing as little as 3 pg of DNA. Using a single primer pair, we amplified ∼350,000 amplicons distributed throughout the genome. Aneuploidy was detected in 49% of liquid biopsies from a total of 883 nonmetastatic, clinically detected cancers of the colorectum, esophagus, liver, lung, ovary, pancreas, breast, or stomach. Combining aneuploidy with somatic mutation detection and eight standard protein biomarkers yielded a median sensitivity of 80% in these eight cancer types, while only 1% of 812 healthy controls scored positive.

BACKGROUND:Patients with high body mass index are associated with a higher risk of complications after open pancreatectomy. We aimed to investigate the perioperative outcome for patients with high body mass index after robotic pancreatectomy. METHODS:This is a retrospective, propensity-score matched cohort analysis. From our prospectively maintained database, we identified consecutive patients with body mass index >25 who underwent robotic pancreatectomy between January 2016 and December 2018. Propensity score matching with open pancreatectomy was applied in 1:2 fashion based on age, gender, American Society of Anesthesiologists classification, surgery type, histology, neoadjuvant therapy, and body mass index during the same study period. RESULTS:A total of 127 patients were included. The mean age for all patients was 61.7 ± 12.8 years and 65 (51.2%) were male. Median body mass index was 29.9 (interquartile range, 27.0-31.8) for both groups. Propensity score matching provided equally distributed general demographic and clinicopathological factors. Robotic pancreatectomy was associated with decreased blood loss (100 mL vs 300 mL, P < .001) and shorter hospital stay (7 vs 9 days, P = .019). CONCLUSION:Robotic pancreatectomy is associated with decreased blood loss and shorter length of hospital stay in overweight patients. Robotic approach may help alleviate morbidity in overweight patients undergoing pancreatectomy.

OBJECTIVE:The aim of this study was to investigate the key molecular alterations in small primary pancreatic neuroendocrine tumors (PanNETs) associated with the development of liver metastases. BACKGROUND:Well-differentiated PanNETs with small size are typically indolent; however, a limited subset metastasize to the liver. METHODS:A total of 87 small primary PanNETs (<3 cm), including 32 metastatic cases and 55 nonmetastatic cases after a 5-year follow-up, were immunolabeled for DAXX/ATRX and analyzed for alternative lengthening of telomeres (ALT) by Fluorescence In Situ Hybridization. A subset of these cases, 24 that metastasized and 24 that did not metastasize, were assessed by targeted next-generation sequencing and whole-genome copy number variation. RESULTS:In the entire cohort, high Ki-67 (OR 1.369; 95% CI 1.121-1.673; P = 0.002), N-stage (OR 4.568; 95% CI 1.458-14.312; P = 0.009), and ALT-positivity (OR 3.486; 95% CI 1.093-11.115; P = 0.035) were independently associated with liver metastases. In the subset assessed by next-generation sequencing and copy number variation analysis, 3 molecular subtypes with differing risks of liver metastases were identified. Group 1 (n = 15; 73% metastasized) was characterized by recurrent chromosomal gains, CN-LOH, DAXX mutations, and ALT-positivity. Group 2 (n = 19; 42% metastasized, including 5 G1 tumors) was characterized by limited copy number alterations and mutations. Group 3 (n = 14; 35% metastasized) were defined by chromosome 11 loss. CONCLUSIONS:We identified genomic patterns of small PanNETs associated with a different risk for liver metastases. Molecular alterations, such as DAXX mutations, chromosomal gains, and ALT, are associated with an increased risk of metastasis in small PanNETs. Therefore, targeted sequencing and/or ALT analysis may help in the clinical decisions for these small PanNETs.