Faculty Bibliography

BACKGROUND:Early-onset pancreatic cancer (EOPC), defined as age ≤ 45 years at diagnosis, accounts for 3% of all pancreatic cancer cases. Although differences in tumor biology have been suggested, available data are sparse and specific treatment recommendations are lacking. This study explores the clinicopathological features and oncologic outcomes of resected EOPC. PATIENTS AND METHODS/METHODS:Patients with EOPC undergoing resection between 2002 and 2018 were identified from the Heidelberg University Hospital and Johns Hopkins University registries. Median overall survival (OS) and recurrence-free survival (RFS) were analyzed, and prognostic factors were identified. RESULTS:The final cohort included 164 patients, most of whom had pancreatic ductal adenocarcinoma (PDAC, n = 136; 82.9%) or IPMN-associated pancreatic cancer (n = 17; 10.4%). Twenty (12.1%) patients presented with stage 1 disease, 42 (25.6%) with stage 2, 75 (45.7%) with stage 3, and 22 (13.4%) with oligometastatic stage 4 disease. Most patients underwent upfront resection (n = 113, 68.9%), whereas 51 (31.1%) individuals received preoperative treatment. Median OS and RFS were 26.0 and 12.4 months, respectively. Stage-specific median survival was 70.6, 41.8, 23.8, and 16.9 months for stage 1, 2, 3, and 4 tumors, respectively. Factors independently associated with shorter OS and RFS were R1 resections and AJCC stages 3 and 4. Notably, AJCC 3-N2 and AJCC 3-T4 tumors had a median OS of 20 months versus 29.5 months, respectively. CONCLUSION/CONCLUSIONS:Despite frequently presenting with advanced disease, oncologic outcomes in EOPC patients are satisfactory even in locally advanced cancers, justifying aggressive surgical approaches. Further research is needed to tailor current guidelines to this rare population.

BACKGROUND:The role of postoperative chemotherapy in patients with resected pancreatic cancer who receive neoadjuvant treatment is unknown. Clinicians use changes in CA19-9 and histopathologic scores to assess treatment response. We sought to investigate if CA19-9 normalization in response to NAT can help guide the need for postoperative treatment. METHODS:Patients with elevated baseline CA19-9 (CA19-9 > 37U/mL) who received NAT followed by surgery between 2011 and 2019 were retrospectively reviewed. Treatment response was determined by CA19-9 normalization following NAT and histopathologic scoring. The role of postoperative chemotherapy was analyzed in light of CA19-9 normalization and histopathologic response. RESULTS:We identified and included 345 patients. Following NAT, CA19-9 normalization was observed in 125 patients (36.2%). CA19-9 normalization was associated with a favorable histopathologic response (41.6% vs 23.2%, p < 0.001) and a lower ypT (p < 0.001) and ypN stage (p = 0.003). Receipt of adjuvant chemotherapy was associated with improved overall survival in patients in whom CA19-9 did not normalize following NAT (26.8 vs 16.4 months, p = 0.008). In patients who received 5FU-based NAT and in whom CA19-9 did not normalize, receipt of 5FU-based adjuvant chemotherapy was associated with improved OS (p = 0.014). CONCLUSION/CONCLUSIONS:CA19-9 normalization in response to NAT was associated with favorable outcomes and can serve as a biomarker for treatment response. In patients where CA19-9 did not normalize, receipt of postoperative chemotherapy was associated with improved OS. These patients also benefited from additional 5FU-based postoperative chemotherapy following 5FU-based NAT.

BACKGROUND:The ideal surveillance strategy after partial pancreatectomy for non-invasive IPMN remains undefined and existing guidelines provide conflicting recommendations. The present study was developed in anticipation of the joint meeting of the International Association of Pancreatology (IAP) and the Japan Pancreas Society (JPS) held in Kyoto in July 2022. METHODS:An international team of experts developed the four clinical questions (CQ) to operationalize issues pertaining to surveillance of patients in this context. A systematic review was designed following the PRISMA guidelines and registered in PROSPERO. The search strategy was executed in PubMed/Medline (Ovid), Embase, the Cochrane Library and Web of Science databases. Four investigators individually extracted data from the selected studies and drafted recommendations for each CQ. These were subsequently discussed and agreed upon that the IAP/JPS meeting. RESULTS:From a total of 1098 studies identified through the initial search, 41 studies were included in the review and informed the recommendations. No studies providing level one data were identified in this systematic review, all studies included were cohort or case-control studies. CONCLUSIONS:There is a lack of level 1 data addressing the issue of surveillance of patients following partial pancreatectomy for non-invasive IPMN. The definition of remnant pancreatic lesion in this setting is largely heterogeneous across all studies evaluated. Herein we propose an inclusive definition of remnant pancreatic lesions to guide future prospective efforts for reporting the natural history and long-term outcomes of these patients.

BACKGROUND:Intraductal papillary mucinous neoplasms (IPMNs), a type of cystic pancreatic cancer (PC) precursors, are increasingly identified on cross-sectional imaging and present a significant diagnostic challenge. While surgical resection of IPMN-related advanced neoplasia, i.e., IPMN-related high-grade dysplasia or PC, is an essential early PC detection strategy, resection is not recommended for IPMN-low-grade dysplasia (LGD) due to minimal risk of carcinogenesis, and significant procedural risks. Based on their promising results in prior validation studies targeting early detection of classical PC, DNA hypermethylation-based markers may serve as a biomarker for malignant risk stratification of IPMNs. This study investigates our DNA methylation-based PC biomarker panel (ADAMTS1, BNC1, and CACNA1G genes) in differentiating IPMN-advanced neoplasia from IPMN-LGDs. METHODS:Our previously described genome-wide pharmaco-epigenetic method identified multiple genes as potential targets for PC detection. The combination was further optimized and validated for early detection of classical PC in previous case-control studies. These promising genes were evaluated among micro-dissected IPMN tissue (IPMN-LGD: 35, IPMN-advanced neoplasia: 35) through Methylation-Specific PCR. The discriminant capacity of individual and combination of genes were delineated through Receiver Operating Characteristics curve analysis. RESULTS:As compared to IPMN-LGDs, IPMN-advanced neoplasia had higher hypermethylation frequency of candidate genes: ADAMTS1 (60% vs. 14%), BNC1 (66% vs. 3%), and CACGNA1G (25% vs. 0%). We observed Area Under Curve (AUC) values of 0.73 for ADAMTS1, 0.81 for BNC1, and 0.63 for CACNA1G genes. The combination of the BNC1/ CACNA1G genes resulted in an AUC of 0.84, sensitivity of 71%, and specificity of 97%. Combining the methylation status of the BNC1/CACNA1G genes, blood-based CA19-9, and IPMN lesion size enhanced the AUC to 0.92. CONCLUSION/CONCLUSIONS:DNA-methylation based biomarkers have shown a high diagnostic specificity and moderate sensitivity for differentiating IPMN-advanced neoplasia from LGDs. Addition of specific methylation targets can improve the accuracy of the methylation biomarker panel and enable the development of noninvasive IPMN stratification biomarkers.

BACKGROUND:Neoadjuvant therapy (NAT) is increasingly applied in pancreatic ductal adenocarcinoma (PDAC); however, accurate prediction of therapeutic response to NAT remains a pressing clinical challenge. Cancer-cell-derived sialylated immunoglobulin G (SIA-IgG) was previously identified as a prognostic biomarker in PDAC. This study aims to explore whether SIA-IgG expression in treatment-naïve fine needle aspirate (FNA) biopsy specimens could predict the pathological response (PR) to NAT for PDAC. METHODS:Endoscopic ultrasonography-guided FNA biopsy specimens prior to NAT were prospectively obtained from 72 patients with PDAC at the Johns Hopkins Hospital. SIA-IgG expression of PDAC specimens was assessed by immunohistochemistry. Associations between SIA-IgG expression and PR, as well as patient prognosis, were analyzed. A second cohort enrolling surgically resected primary tumor specimens from 79 patients with PDAC was used to validate the prognostic value of SIA-IgG expression. RESULTS:SIA-IgG was expressed in 58.3% of treatment-naïve FNA biopsies. Positive SIA-IgG expression at diagnosis was associated with unfavorable PR and can serve as an independent predictor of PR. The sensitivity and specificity of SIA-IgG expression in FNA specimens in predicting an unfavorable PR were 63.9% and 80.6%, respectively. Both positive SIA-IgG expression in treatment-naïve FNA specimens and high SIA-IgG expression in surgically resected primary tumor specimens were significantly associated with shorter survival. CONCLUSIONS:Assessment of SIA-IgG on FNA specimens prior to NAT may help predict PR for PDAC. Additionally, SIA-IgG expression in treatment-naïve FNA specimens and surgically resected primary tumor specimens were predictive of the prognosis for PDAC.

OBJECTIVE:To develop a predictive model of oncologic outcomes for patients with pancreatic ductal adenocarcinoma (PDAC) undergoing resection after neoadjuvant or induction chemotherapy use. BACKGROUND:Early recurrence following surgical resection for PDAC is common. The use of neoadjuvant chemotherapy prior to resection may increase the likelihood of long-term systemic disease control. Accurately characterizing an individual's likely oncologic outcome in the perioperative setting remains challenging. METHODS:Data from patients with PDAC who received chemotherapy prior to pancreatectomy at a single high-volume institution between 2007-2018 were captured in a prospectively collected database. Core clinicopathologic data were reviewed for accuracy and survival data were abstracted from the electronic medical record and national databases. Cox-proportional regressions were used to model outcomes and develop an interactive prognostic tool for clinical decision-making. RESULTS:A total of 581 patients were included with a median OS and RFS of 29.5 (26.5-32.5) and 16.6 (15.8-17.5) months, respectively. Multivariable analysis demonstrates OS and RFS were associated with type of chemotherapeutic used and the number of chemotherapy cycles received preoperatively. Additional factors contributing to survival models included: tumor grade, histopathologic response to therapy, nodal status, and administration of adjuvant chemotherapy. The models were validated using an iterative bootstrap method and with randomized cohort splitting. The models were well calibrated with concordance indices of 0.68 and 0.65 for the final OS and RFS models, respectively. CONCLUSION/CONCLUSIONS:We developed an intuitive and dynamic decision-making tool that can be useful in estimating OS, RFS and location-specific disease recurrence rates. This prognostic tool may add value to patient care in discussing the benefits associated with surgical resection for PDAC.

BACKGROUND AND AIMS/OBJECTIVE:Next-generation sequencing (NGS) of pancreatic cyst fluid is a useful adjunct in the assessment of patients with pancreatic cyst. However, previous studies have been retrospective or single institutional experiences. The aim of this study was to prospectively evaluate NGS on a multi-institutional cohort of patients with pancreatic cyst in real time. METHODS:The performance of a 22-gene NGS panel (PancreaSeq) was first retrospectively confirmed and then within a 2-year timeframe, PancreaSeq testing was prospectively used to evaluate endoscopic ultrasound-guided fine-needle aspiration pancreatic cyst fluid from 31 institutions. PancreaSeq results were correlated with endoscopic ultrasound findings, ancillary studies, current pancreatic cyst guidelines, follow-up, and expanded testing (Oncomine) of postoperative specimens. RESULTS:Among 1933 PCs prospectively tested, 1887 (98%) specimens from 1832 patients were satisfactory for PancreaSeq testing. Follow-up was available for 1216 (66%) patients (median, 23 months). Based on 251 (21%) patients with surgical pathology, mitogen-activated protein kinase/GNAS mutations had 90% sensitivity and 100% specificity for a mucinous cyst (positive predictive value [PPV], 100%; negative predictive value [NPV], 77%). On exclusion of low-level variants, the combination of mitogen-activated protein kinase/GNAS and TP53/SMAD4/CTNNB1/mammalian target of rapamycin alterations had 88% sensitivity and 98% specificity for advanced neoplasia (PPV, 97%; NPV, 93%). Inclusion of cytopathologic evaluation to PancreaSeq testing improved the sensitivity to 93% and maintained a high specificity of 95% (PPV, 92%; NPV, 95%). In comparison, other modalities and current pancreatic cyst guidelines, such as the American Gastroenterology Association and International Association of Pancreatology/Fukuoka guidelines, show inferior diagnostic performance. The sensitivities and specificities of VHL and MEN1/loss of heterozygosity alterations were 71% and 100% for serous cystadenomas (PPV, 100%; NPV, 98%), and 68% and 98% for pancreatic neuroendocrine tumors (PPV, 85%; NPV, 95%), respectively. On follow-up, serous cystadenomas with TP53/TERT mutations exhibited interval growth, whereas pancreatic neuroendocrine tumors with loss of heterozygosity of ≥3 genes tended to have distant metastasis. None of the 965 patients who did not undergo surgery developed malignancy. Postoperative Oncomine testing identified mucinous cysts with BRAF fusions and ERBB2 amplification, and advanced neoplasia with CDKN2A alterations. CONCLUSIONS:PancreaSeq was not only sensitive and specific for various pancreatic cyst types and advanced neoplasia arising from mucinous cysts, but also reveals the diversity of genomic alterations seen in pancreatic cysts and their clinical significance.

BACKGROUND:Although we previously proposed a nomogram to predict malignancy in intraductal papillary mucinous neoplasms (IPMN) and validated it in an external cohort, its application is challenging without data on tumor markers. Moreover, existing nomograms have not been compared. This study aimed to develop a nomogram based on radiologic findings and to compare its performance with previously proposed American and Korean/Japanese nomograms. METHODS:We recruited 3708 patients who underwent surgical resection at 31 tertiary institutions in eight countries, and patients with main pancreatic duct >10 mm were excluded. To construct the nomogram, 2606 patients were randomly allocated 1:1 into training and internal validation sets, and area under the receiver operating characteristics curve (AUC) was calculated using 10-fold cross validation by exhaustive search. This nomogram was then validated and compared to the American and Korean/Japanese nomograms using 1102 patients. RESULTS:Among the 2606 patients, 90 had main-duct type, 900 had branch-duct type, and 1616 had mixed-type IPMN. Pathologic results revealed 1628 low-grade dysplasia, 476 high-grade dysplasia, and 502 invasive carcinoma. Location, cyst size, duct dilatation, and mural nodule were selected to construct the nomogram. AUC of this nomogram was higher than the American nomogram (0.691 vs 0.664, P = .014) and comparable with the Korean/Japanese nomogram (0.659 vs 0.653, P = .255). CONCLUSIONS:A novel nomogram based on radiologic findings of IPMN is competitive for predicting risk of malignancy. This nomogram would be clinically helpful in circumstances where tumor markers are not available. The nomogram is freely available at http://statgen.snu.ac.kr/software/nomogramIPMN.

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.