Faculty Bibliography

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.

BACKGROUND:Patients with pancreatic ductal adenocarcinoma (PDAC) and liver metastasis are treated with palliative chemotherapy, whereas similar patients with metastatic colorectal cancer are considered for aggressive surgery. METHODS:Using an institutional database, PDAC patients undergoing liver resection for isolated metastasis were identified. Their overall survival (OS), treatment factors, and clinicopathological variables associated with survival were also evaluated. RESULTS:Forty-seven patients underwent curative-intent surgery for metastatic PDAC to the liver between 2000 and 2019. Median OS was 21.9 months from diagnosis. Fourteen patients underwent unplanned resection of radiographically occult liver metastasis during pancreatectomy with median OS of 8.7 months. On the other hand, 29 patients received systemic chemotherapy followed by planned resection; this cohort had the most favorable prognosis following aggressive surgery with median OS being 38.1 months from diagnosis and 24.1 months from surgery. Preoperative chemotherapy (HR = 7.1; p = .002) and moderate to well differentiation of the primary tumor (HR = 3.7; p = .003) were associated with prolonged survival in multivariate analysis, whereas lymph node metastases, response to preoperative therapy, number of liver metastasis, and extent of liver surgery were not. CONCLUSIONS:In select patients with PDAC and isolated liver metastasis, curative-intent surgery can result in meaningful survival. This aggressive approach seems most beneficial in patients following induction chemotherapy.

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 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.

OBJECTIVES/OBJECTIVE:The aim of the study was to assess the association of circulating tumor cells (CTCs) with survival as a biomarker in pancreatic ductal adenocarcinoma (PDAC) within the context of a delay in initiation of adjuvant therapy. BACKGROUND:Outcomes in patients with PDAC remain poor and are driven by aggressive systemic disease. While systemic therapies improve survival in resected patients, factors such as a delay in initiation of adjuvant therapy are associated with worse outcomes. CTCs have previously been shown to be predictive of survival. METHODS:A retrospective study was performed on PDAC patients enrolled in the prospective CLUSTER trial (NCT02974764) on CTC-dynamics at the Johns Hopkins Hospital. CTCs were isolated based on size (ISET; Rarecells) and counted and characterized by subtype using immunofluorescence. The preoperative and postoperative blood samples were used to identify two CTC types: epithelial CTCs (eCTCs), expressing pan-cytokeratin, and transitional CTCs (trCTCs), expressing both pan-cytokeratin and vimentin. Patients who received adjuvant therapy were compared with those who did not. A delay in receipt of adjuvant therapy was defined as initiation of therapy ≥8 weeks after surgical resection. Clinicopathological features, CTCs characteristics, and outcomes were analyzed. RESULTS:Of 101 patients included in the study, 43 (42.5%) experienced a delay in initiation and 20 (19.8%) did not receive adjuvant therapy. On multivariable analysis, presence of transitional CTCs (trCTCs, P=0.002) and absence of adjuvant therapy (P=0.032) were associated with worse recurrence-free survival (RFS). Postoperative trCTC were associated with poorer RFS, both in patients with a delay in initiation (12.4 vs. 17.9 mo, P=0.004) or no administration of adjuvant chemotherapy (3.4 vs. NR, P=0.016). However, it was not associated with RFS in patients with timely initiation of adjuvant chemotherapy (P=0.293). CONCLUSION/CONCLUSIONS:Postoperative trCTCs positivity is associated with poorer RFS only in patients who either experience a delay in initiation or no receipt of adjuvant therapy. This study suggests that a delay in initiation of adjuvant therapy could potentially provide residual systemic disease (trCTCs) a window of opportunity to recover from the surgical insult. Future studies are required to validate these findings and explore the underlying mechanisms involved.

OBJECTIVE:The aim of the study was to assess the association between persistent CTCs and subsequent recurrence in patients who were clinically recurrence free approximately 12 months postoperatively. BACKGROUND:Circulating tumor cells have been proposed as biomarkers to predict survival in pancreatic cancer. Some patients demonstrate persistent CTCs postoperatively which could represent minimal residual disease. METHODS:Patients from previously published prospective CLUSTER trial without clinical evidence of recurrence 12 months postoperatively and CTC testing performed 9-15 months postoperatively were included. Presence of epithelial (eCTCs) and transitional CTCs (trCTCs) was evaluated as predictor of recurrence. Kaplan-Meier curve, log-rank test, and Cox model were used for survival analysis. RESULTS:Thirty-three of 129 eligible patients (CLUSTER trial) were included. The trCTC positive and negative patients were well-balanced in clinicopathological features. Patients with trCTCs had a recurrence rate per-person-month of 10.3% compared to 3.1% in trCTCs negative patients with a median time to recurrence of 3.9 versus 27.1 months, respectively. On multivariable analysis trCTCs positivity was associated with higher risk of late recurrence (HR:4.7,95%CI:1.2-18.3, P=0.024). Fourteen (42.4%) patients recurred during the second postoperative year. 1-year postoperative trCTCs positivity was associated with a higher rate of recurrence during the second year (OR:13.1,95%CI:1.6-1953.4,P=0.028, AUC=0.72). Integrating clinicopathological features with trCTCs increased the AUC to 0.80. A majority of trCTCs positive patients (N=5, 62.5%) had multi-site recurrence, followed by local-only (N=2, 25.0%) and liver-only (N=1, 12.5%) recurrence. This was in striking contrast to trCTCs negative patients, where a majority (N=6, 66.7%) had a local-only recurrence, followed by liver-only (N=2, 22.2%) and multi-site (N=1, 11.1%) recurrence. CONCLUSION/CONCLUSIONS:In patients deemed to be clinically disease free 12 months postoperatively, trCTCs positivity is associated with higher rates of subsequent recurrence with distinct patterns of recurrence. CTCs could be used a putative biomarker to guide patient prognostication and management in pancreatic cancer.

OBJECTIVE:To establish an evidence-based cut-off and predictors for early recurrence in patients with resected locally advanced pancreatic cancer (LAPC). SUMMARY BACKGROUND DATA/BACKGROUND:It is unclear how many and which patients develop early recurrence after LAPC resection. Surgery in these patients is probably of little benefit. METHODS:We analyzed all consecutive patients undergoing resection of LAPC after induction chemotherapy who were included in prospective databases in the Netherlands (2015-2019) and the Johns Hopkins Hospital (2016-2018). The optimal definition for "early recurrence" was determined by the post-recurrence survival (PRS). Patients were compared for overall survival (OS). Predictors for early recurrence were evaluated using logistic regression analysis. RESULTS:Overall, 168 patients were included. After a median follow-up of 28 months, recurrence was observed in 118 patients (70.2%). The optimal cut-off for RFS to differentiate between early (n=52) and late recurrence (n=66) was 6 months (P<0.001). OS was 8.4 months (95%CI 7.3-9.6) in the early recurrence group (n=52) versus 31.1 months (95%CI 25.7-36.4) in the late/no recurrence group (n=116) (P<0.001). A preoperative predictor for early recurrence was post-induction therapy CA19-9≥100 U/mL (OR4.15, 95%CI 1.75-9.84, P=0.001). Postoperative predictors were poor tumor differentiation (OR4.67, 95%CI 1.83-11.90, P=0.001) and no adjuvant chemotherapy (OR6.04, 95%CI 2.43-16.55, P<0.001). CONCLUSION/CONCLUSIONS:Early recurrence was observed in one third of patients after LAPC resection and was associated with poor survival. Patients with post-induction therapy CA19-9 ≥100 U/mL, poor tumor differentiation and no adjuvant therapy were especially at risk. This information is valuable for patient counseling before and after resection of LAPC.