Faculty Bibliography

Emerging evidence implicates microbiome involvement in the development of pancreatic cancer (PaCa). Here, we investigate whether increases in circulating microbial-related metabolites associate with PaCa risk by applying metabolomics profiling to 172 sera collected within 5 years prior to PaCa diagnosis and 863 matched non-subject sera from participants in the Prostate, Lung, Colorectal, and Ovarian (PLCO) cohort. We develop a three-marker microbial-related metabolite panel to assess 5-year risk of PaCa. The addition of five non-microbial metabolites further improves 5-year risk prediction of PaCa. The combined metabolite panel complements CA19-9, and individuals with a combined metabolite panel + CA19-9 score in the top 2.5th percentile have absolute 5-year risk estimates of >13%. The risk prediction model based on circulating microbial and non-microbial metabolites provides a potential tool to identify individuals at high risk of PaCa that would benefit from surveillance and/or from potential cancer interception strategies.

PURPOSE:Although the concept of extrapancreatic extension (EPEx) was removed in the eighth edition of the American Joint Committee on Cancer pancreatic cancer staging system, several studies have supported the prognostic significance of EPEx. This study aimed to investigate the significance of EPEx in pancreatic ductal adenocarcinoma (PDAC) using the National Cancer Database (NCDB). METHODS:Data of patients who underwent resection for PDAC between 2006 and 2016 were extracted and analyzed from the NCDB. Cases arising from premalignant lesions, those with metastases, and those treated with neoadjuvant therapy were excluded. RESULTS:Among 37,634 patients, the median overall survival was 23 months and the 5-year survival rate was 22.7%. The EPEx prevalence was the lowest for T1 stage (63.2%) and increased with each T-stage (T2:83.4%, T3:85.8%). The overall survival was better in EPEx-negative patients than in EPEx-positive patients (median 33.7 vs. 21.5 months; p<0.001). When the T-stages were stratified by EPEx, EPEx-positive patients showed worse survival in all T-stages than EPEx-negative patients. Survival was comparable between T1 EPEx-positive and T2 or T3 EPEx-negative patients (p=0.088 and p=0.178, respectively). Furthermore, T2 and T3 EPEx-negative patients had similar survival to each other (p=0.877), and distinctly superior survival compared to T2 and T3 EPEx-positive patients (p<0.001). CONCLUSIONS:EPEx was an important prognostic factor in the overall cohort and in differentiating between T stages. This study strongly suggests that staging systems should reinstate EPEx and apply it to all T-stages, especially in T1, where EPEx was absent in 36% of patients.

Broad-spectrum RAS inhibition holds the potential to benefit roughly a quarter of human cancer patients whose tumors are driven by RAS mutations. However, the impact of inhibiting RAS functions in normal tissues is not known. RMC-7977 is a highly selective inhibitor of the active (GTP-bound) forms of KRAS, HRAS, and NRAS, with affinity for both mutant and wild type (WT) variants. As >90% of human pancreatic ductal adenocarcinoma (PDAC) cases are driven by activating mutations in KRAS, we assessed the therapeutic potential of RMC-7977 in a comprehensive range of PDAC models, including human and murine cell lines, human patient-derived organoids, human PDAC explants, subcutaneous and orthotopic cell-line or patient derived xenografts, syngeneic allografts, and genetically engineered mouse models. We observed broad and pronounced anti-tumor activity across these models following direct RAS inhibition at doses and concentrations that were well-tolerated in vivo. Pharmacological analyses revealed divergent responses to RMC-7977 in tumor versus normal tissues. Treated tumors exhibited waves of apoptosis along with sustained proliferative arrest whereas normal tissues underwent only transient decreases in proliferation, with no evidence of apoptosis. Together, these data establish a strong preclinical rationale for the use of broad-spectrum RAS inhibition in the setting of PDAC.

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.

Patients with pancreatic ductal adenocarcinoma (PDAC) have a grim prognosis despite complete surgical resection and intense systemic therapies. While immunotherapies have been beneficial with many different types of solid tumors, they have almost uniformly failed in the treatment of PDAC. Understanding how therapies affect the tumor immune microenvironment (TIME) can provide insights for the development of strategies to treat PDAC. We used quantitative multiplexed immunofluorescence (qmIF) quantitative spatial analysis (qSA), and immunogenomic (IG) analysis to analyze formalin-fixed paraffin embedded (FFPE) primary tumor specimens from 44 patients with PDAC including 18 treated with neoadjuvant chemoradiation (CRT) and 26 patients receiving no treatment (NT) and compared them with tissues from 40 treatment-naïve melanoma patients. We find that relative to NT tumors, CD3⁺ T cell infiltration was increased in CRT treated tumors (p = .0006), including increases in CD3⁺CD8⁺ cytotoxic T cells (CTLs, p = .0079), CD3⁺CD4⁺FOXP3^- T helper cells (T_h, p = .0010), and CD3⁺CD4⁺FOXP3⁺ regulatory T cells (Tregs, p = .0089) with no difference in CD68⁺ macrophages. IG analysis from micro-dissected tissues indicated overexpression of genes involved in antigen presentation, T cell activation, and inflammation in CRT treated tumors. Among treated patients, a higher ratio of Tregs to total T cells was associated with shorter survival time (p = .0121). Despite comparable levels of infiltrating T cells in CRT PDACs to melanoma, PDACs displayed distinct spatial profiles with less T cell clustering as defined by nearest neighbor analysis (p < .001). These findings demonstrate that, while CRT can achieve high T cell densities in PDAC compared to melanoma, phenotype and spatial organization of T cells may limit benefit of T cell infiltration in this immunotherapy-resistant tumor.

Cancer mortality is primarily a consequence of its metastatic spread. Here, we report that methionine sulfoxide reductase A (MSRA), which can reduce oxidized methionine residues, acts as a suppressor of pancreatic ductal adenocarcinoma (PDA) metastasis. MSRA expression is decreased in the metastatic tumors of PDA patients, whereas MSRA loss in primary PDA cells promotes migration and invasion. Chemoproteomic profiling of pancreatic organoids revealed that MSRA loss results in the selective oxidation of a methionine residue (M239) in pyruvate kinase M2 (PKM2). Moreover, M239 oxidation sustains PKM2 in an active tetrameric state to promote respiration, migration, and metastasis, whereas pharmacological activation of PKM2 increases cell migration and metastasis in vivo. These results demonstrate that methionine residues can act as reversible redox switches governing distinct signaling outcomes and that the MSRA-PKM2 axis serves as a regulatory nexus between redox biology and cancer metabolism to control tumor metastasis.

BACKGROUND:Opioids are central to analgesia for pancreatic diseases. Individuals undergoing pancreatectomy have largely been excluded from studies of opioid use, because of malignancy or chronic use. Surgeons need to understand usage patterns, and practices that may incline patients toward persistent post-operative use. METHODS:A retrospective study using IBM Watson Health MarketScan database examined patterns of peri-pancreatectomy opioid use between 2009 and 2017. Patients were grouped by opioid use 12 months to 31 days prior to pancreatectomy and followed for persistent use (refills 90-180 days postoperatively). Morphine milligram equivalents (MME) were calculated. Multivariable models explored associations between clinical characteristics, perioperative use and persistent use. RESULTS:Opioids were used within the year prior to surgery by 35.6% of 8325 patients. The median MME for opioid naïve patients (400 mg) was a fraction of the 1800 mg prescribed to chronic opioid users for peri-operative analgesia. The rate of persistent opioid use was 15.1% among naïve, 27.2% among intermittent and 77.3% among chronic opioid users. Multivariable models demonstrated naïve and intermittent users who filled a prescription within 30 days prior to pancreatectomy, those who were prescribed total MME ≥1500 mg, and a ≥14 day supply were most at risk of persistent opioid use. Almost 23% of chronic users stopped using opioids post-operatively, suggesting surgery can provide relief. CONCLUSION:Preoperative and persistent opioid use after pancreatectomy is substantially greater than expected based on other operations. Providers may mitigate this by recognizing the issue, managing expectations, and altering the timing and quantities of opioids prescribed.

BACKGROUND:Irreversible electroporation (IRE) expands the surgical options for patients with unresectable pancreatic cancer. This study evaluated for differences in survival stratified by type of IRE and receipt of adjuvant chemotherapy. METHODS:Patients with locally advanced pancreatic cancer treated by IRE (2012-2020) were retrospectively included. Overall survival (OS) and recurrence-free survival (RFS) were compared by type of IRE (in situ for local tumor control or IRE of potentially positive margins with resection) and by receipt of adjuvant chemotherapy. RESULTS:Thirty-nine patients had IRE in situ, 61 had IRE for margin extension, and 19 received adjuvant chemotherapy. Most (97.00%) underwent induction chemotherapy. OS was 28.71 months (interquartile range [IQR] 19.17, 51.19) from diagnosis, with no difference by IRE type (hazard ratio [HR] 1.05 for margin extension [p = 0.85]) or adjuvant chemotherapy (HR 1.14 [p = 0.639]). RFS was 8.51 months (IQR 4.95, 20.17) with no difference by IRE type (HR 0.90 for margin extension [p = 0.694]) or adjuvant chemotherapy (HR 0.90 [p = 0.711]). CONCLUSION/CONCLUSIONS:These findings suggest that adjuvant therapy may have limited benefit for patients treated with induction chemotherapy followed by local control with IRE for unresectable pancreatic cancer. Further study of the duration and timing of systemic therapy is warranted to maximize benefit and limit toxicity.

PURPOSE:We evaluated how race and socioeconomic factors impact access to high-volume surgical centers, treatment initiation, and postoperative care for pancreatic cancer in a state with robust safety net insurance coverage and healthcare infrastructure. METHODS:The New York Statewide Planning and Research Cooperative System was analyzed. Patients with pancreatic cancer resected from 2007 to 2017 were identified by ICD and CPT codes. Primary outcomes included surgery at low-volume facilities (< 20 pancreatectomies/year), time to therapy initiation, and time to postoperative surveillance imaging (within 60-180 days after surgery). RESULTS:In total, 3312 patients underwent pancreatectomy across 124 facilities. Median age was 67 years (IQR 59, 75) and 55% of patients were male. Most (72.7%) had surgery at high-volume centers. On multivariable analysis, odds ratios for surgery at low-volume centers were increased for Black race (2.21 (95% CI 1.69-2.88)), Asian race (1.64 (95% CI 1.09-2.43)), Hispanic ethnicity (1.68 (95% CI 1.24-2.28)), Medicaid insurance (2.52 (95% CI 1.79-3.56)), no insurance (2.24 (95% CI 1.38-3.61)), lowest income quartile (3.31 (95% CI 2.14-5.32)), and rural zip code (2.49 (95% CI 1.69-3.65)). Patients treated at low-volume centers waited longer to initiate treatment (hazard ratio (HR) 0.91 (95% CI 0.81-1.01)). Black patients underwent the least surveillance imaging (50.4%; p < 0.0001), while Asian (HR 2.04, 95% CI 1.40-2.98)) and Hispanic patients (HR 1.36 (95% CI 1.00-1.84)) were more likely to have surveillance imaging. CONCLUSIONS:Race independently affected access to high-volume facilities and surveillance imaging. When considered in light of other accumulating evidence, future efforts might investigate the perceptions and logistical considerations noted by providers and patients alike to identify the etiology of these disparities and then institute corrective measures.

BACKGROUND:This study aimed to determine the rate, timing, and predictors of diabetes and exocrine pancreatic insufficiency after pancreatectomy in order to inform preoperative patient counseling and risk management strategies. METHODS:Using prescription claims as a surrogate for disease prevalence, IBM Watson Health MarketScan was queried for claims patterns pre- and post-pancreatectomy. Multivariable models explored associations between clinical characteristics and medication use within 2 years of surgery. RESULTS:In total, 18.96% of 2,848 pancreaticoduodenectomy (PD) patients and 18.95% of 1,858 distal pancreatectomy (DP) patients had preoperative diabetic medication prescription claims. Fewer (6.6% and 3.88%, respectively) had pancreatic enzyme replacement therapy (PERT) claims. Diabetic medication claims increased to 28.69% after PD and 38.59% after DP [adjusted relative risk (aRR) = 1.36 (95% CI 1.27, 1.46)]. Other associated factors included age > 45, medical comorbidity, and obesity. The incidence of new diabetic medication claims among medication naïve patients was 13.78% for PD and 24.7% for DP (p < 0.001) with a median 4.7 and 4.9 months post-operatively. The prevalence of PERT claims was 55.97% after PD and 17.06% after DP [aRR = 0.32 (0.29, 0.36)]. The incidence of postoperative PERT claims 53.98% (PD) and 14.84% (DP) (p < 0.0001). The median time to new PERT claim was 3.0 (PD) and 3.2 (DP) months, respectively. Claims for both diabetic medications and PERT rose sharply after surgery and plateaued within 6 months. CONCLUSIONS:This study defines prevalence, timing, and predictors for post-pancreatectomy insufficiency to inform preoperative counseling, risk modification strategies, and interventions related to quality of life.