Tumour-selective activity of RAS-GTP inhibition in pancreatic cancer.

Broad-spectrum RAS inhibition has the potential to benefit roughly a quarter of human patients with cancer whose tumours are driven by RAS mutations1,2. 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 variants3. More than 90% of cases of human pancreatic ductal adenocarcinoma (PDAC) are driven by activating mutations in KRAS4. Here we assessed the therapeutic potential of RMC-7977 in a comprehensive range of PDAC models. We observed broad and pronounced anti-tumour activity across models following direct RAS inhibition at exposures that were well-tolerated in vivo. Pharmacological analyses revealed divergent responses to RMC-7977 in tumour versus normal tissues. Treated tumours exhibited waves of apoptosis along with sustained proliferative arrest, whereas normal tissues underwent only transient decreases in proliferation, with no evidence of apoptosis. In the autochthonous KPC mouse model, RMC-7977 treatment resulted in a profound extension of survival followed by on-treatment relapse. Analysis of relapsed tumours identified Myc copy number gain as a prevalent candidate resistance mechanism, which could be overcome by combinatorial TEAD inhibition in vitro. Together, these data establish a strong preclinical rationale for the use of broad-spectrum RAS-GTP inhibition in the setting of PDAC and identify a promising candidate combination therapeutic regimen to overcome monotherapy resistance.

Protein biomarkers and alternatively methylated cell-free DNA detect early stage pancreatic cancer.

OBJECTIVE: Pancreatic ductal adenocarcinoma (PDAC) is commonly diagnosed at an advanced stage. Liquid biopsy approaches may facilitate detection of early stage PDAC when curative treatments can be employed. DESIGN: To assess circulating marker discrimination in training, testing and validation patient cohorts (total n=426 patients), plasma markers were measured among PDAC cases and patients with chronic pancreatitis, colorectal cancer (CRC), and healthy controls. Using CA19-9 as an anchor marker, measurements were made of two protein markers (TIMP1, LRG1) and cell-free DNA (cfDNA) pancreas-specific methylation at 9 loci encompassing 61 CpG sites. RESULTS: Comparative methylome analysis identified nine loci that were differentially methylated in exocrine pancreas DNA. In the training set (n=124 patients), cfDNA methylation markers distinguished PDAC from healthy and CRC controls. In the testing set of 86 early stage PDAC and 86 matched healthy controls, CA19-9 had an area under the receiver operating characteristic curve (AUC) of 0.88 (95% CI 0.83 to 0.94), which was increased by adding TIMP1 (AUC 0.92; 95% CI 0.88 to 0.96; p=0.06), LRG1 (AUC 0.92; 95% CI 0.88 to 0.96; p=0.02) or exocrine pancreas-specific cfDNA methylation markers at nine loci (AUC 0.92; 95% CI 0.88 to 0.96; p=0.02). In the validation set of 40 early stage PDAC and 40 matched healthy controls, a combined panel including CA19-9, TIMP1 and a 9-loci cfDNA methylation panel had greater discrimination (AUC 0.86, 95% CI 0.77 to 0.95) than CA19-9 alone (AUC 0.82; 95% CI 0.72 to 0.92). CONCLUSION: A combined panel of circulating markers including proteins and methylated cfDNA increased discrimination compared with CA19-9 alone for early stage PDAC.

Inadequacy of the eighth edition of the American Joint Committee on Cancer pancreatic cancer staging system for invasive carcinoma associated with premalignant lesions in the pancreas: an analysis using the National Cancer Database.

BACKGROUND: Invasive carcinomas arising from premalignant lesions are currently staged by the same criteria as conventional pancreatic ductal adenocarcinoma. METHODS: Clinicopathologic information and survival data were extracted through a thorough search of histology codes from National Cancer Database (2006-2016). A total of 723 patients with invasive intraductal papillary mucinous neoplasm and mucinous cystic neoplasm were analyzed. RESULTS: The median age was 67 years, and 351 patients (48.5%) were male. There were 212 (29.3%), 232 (32.1%), 272 (37.6%), and 7 (1.0%) patients with T1, T2, T3, and T4 classification. Extrapancreatic extension (EPE) was present in 284 (39.3%). Age (HR = 1.504, 95% CI 1.196-1.891), R1 or R2 resection (HR = 1.585, 95% CI 1.175-2.140), and EPE (HR = 1.598, 95% CI 1.209-2.113) were independent prognostic factors for overall survival. Size criteria did not significantly affect survival. The median survival was 115.9 months for patients without EPE, compared to 34.2 months for those with EPE. EPE discriminated survival better than tumor size. DISCUSSION: The T classification of the eighth edition AJCC staging system is not adequate for invasive carcinomas associated with premalignant lesions of the pancreas. They merit a separate, dedicated staging system that uses appropriate prognostic factors.

Tumor-selective effects of active RAS inhibition in pancreatic ductal adenocarcinoma.

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.

Reconsidering the absence of extrapancreatic extension in T staging for pancreatic adenocarcinoma in the AJCC (8th ed) Staging Manual using the National Cancer Database.

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.

A blood-based metabolomic signature predictive of risk for pancreatic cancer.

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.

Innovation in the Surgical Management of Pancreatic Cystic Neoplasms: Same Operations, Narrower Indications, and an Individualized Approach to Decision-Making.

Historically, the management of pancreatic cystic neoplasms (PCN) has been operative. Early intervention for premalignant lesions, including intraductal papillary mucinous neoplasms (IPMN) and mucinous cystic neoplasms (MCN), offers an opportunity to prevent pancreatic cancer-with potential decrement to patients' short-term and long-term health. The operations performed have remained fundamentally the same, with most patients undergoing pancreatoduodenectomy or distal pancreatectomy using oncologic principles. The role of parenchymal-sparing resection and total pancreatectomy remains controversial. We review innovations in the surgical management of PCN, focusing on the evolution of evidence-based guidelines, short-term and long-term outcomes, and individualized risk-benefit assessment.

Associations Between Patient Characteristics and Whipple Procedure Outcomes Before and After Implementation of an Enhanced Recovery After Surgery Protocol.

PURPOSE: The Enhanced Recovery After Surgery (ERAS) protocol is a multimodal perioperative care bundle aimed to improve pancreatic surgery outcomes. This work evaluates whether a Whipple ERAS protocol can be safely implemented at a quaternary care center. We also aimed to assess if race and socioeconomic factors are associated with disparities in outcomes in patients undergoing a Whipple ERAS protocol. METHODS: A retrospective review identified demographic and clinical data for 458 patients undergoing pancreaticoduodenectomies (PDs) at a single institution from October 2017 to May 2022. Patients were split into two cohorts: pre-ERAS (treated before implementation) and ERAS (treated after). Outcomes included length of stay (LOS), 30-day readmission and mortality rates, and major complications. RESULTS: There were 213 pre-ERAS PD patients, and 245 were managed with an ERAS protocol. More ERAS patients had a BMI > 30 (15.5% vs. 8.0%; p = 0.01) and received neoadjuvant chemotherapy (15.5% vs. 4.2%; p < 0.001). ERAS patients had a higher rate of major complications (57.6% vs. 37.6%; p < 0.001). Medicaid patients did not have more complications or longer LOS compared to non-Medicaid patients. On univariate analysis, race/ethnicity or gender was not significantly associated with a higher rate of major complications or prolonged LOS. CONCLUSION: A Whipple ERAS protocol did not significantly change LOS, readmissions, or 30-day mortality. Rate of overall complications did not significantly change after implementation, but rate of major complications increased. These outcomes were not significantly impacted by race/ethnicity, gender, tumor staging, or insurance status.

Contemporary practice and perception of autologous blood salvage in hepato-pancreatico-biliary operations: an international survey.

BACKGROUND: This study aimed to assess contemporary knowledge, attitudes and behaviors around transfusion of intraoperative salvaged blood (sRBCt) during hepato-pancreatico-biliary (HPB) operations. Findings are meant to inform the design of future studies that address provider concerns to change behaviors and improve patient outcomes. METHODS: A survey was designed and assessed for relevance, readability and content, and distributed to an international audience of surgeons performing HPB operations. RESULTS: The 237 respondents were predominantly distributed across North America (37.55%), Europe (27.43%) and Asia (19.83%). Roughly one-half (52.74%) of respondents had used sRBCt in HPB surgery before. Transplantation surgeons were more likely than HPB surgeons to have previously used sRBCt [odds ratio = 5.18 (95% CI 1.89-14.20)]. More respondents believed sRBCt was safe for non-cancer versus cancer operations (68.57% vs. 24.17%, p < 0.0001). Less than half (45.71%) of respondents believed that sRBCt was safe in clean-contaminated fields. Most did not utilize preoperative strategies to avoid donor transfusion. CONCLUSION: Practices related to sRBCt in HPB operations vary widely and there is no consensus on its use. Concerns seem primarily related to cancer-specific and infectious outcomes. While further studies are pursued, surgeons may increase their utilization of preoperative strategies to boost hemoglobin levels for at risk patients.

A Transcriptome-Based Precision Oncology Platform for Patient-Therapy Alignment in a Diverse Set of Treatment-Resistant Malignancies.

Predicting in vivo response to antineoplastics remains an elusive challenge. We performed a first-of-kind evaluation of two transcriptome-based precision cancer medicine methodologies to predict tumor sensitivity to a comprehensive repertoire of clinically relevant oncology drugs, whose mechanism of action we experimentally assessed in cognate cell lines. We enrolled patients with histologically distinct, poor-prognosis malignancies who had progressed on multiple therapies, and developed low-passage, patient-derived xenograft models that were used to validate 35 patient-specific drug predictions. Both OncoTarget, which identifies high-affinity inhibitors of individual master regulator (MR) proteins, and OncoTreat, which identifies drugs that invert the transcriptional activity of hyperconnected MR modules, produced highly significant 30-day disease control rates (68% and 91%, respectively). Moreover, of 18 OncoTreat-predicted drugs, 15 induced the predicted MR-module activity inversion in vivo. Predicted drugs significantly outperformed antineoplastic drugs selected as unpredicted controls, suggesting these methods may substantively complement existing precision cancer medicine approaches, as also illustrated by a case study. SIGNIFICANCE: Complementary precision cancer medicine paradigms are needed to broaden the clinical benefit realized through genetic profiling and immunotherapy. In this first-in-class application, we introduce two transcriptome-based tumor-agnostic systems biology tools to predict drug response in vivo. OncoTarget and OncoTreat are scalable for the design of basket and umbrella clinical trials. This article is highlighted in the In This Issue feature, p. 1275.

High rate of stone-related complications after stapling the cystic duct during laparoscopic cholecystectomy-an underrecognized risk.

BACKGROUND: Laparoscopic staplers (LS) have been suggested as a safe alternative to metal clips in laparoscopic cholecystectomy when the cystic duct is too inflamed or wide for complete clip occlusion. We aimed to evaluate the perioperative outcomes of patients whose cystic ducts were controlled by LS and evaluate the risk factors for complications. METHODS: Patients who underwent laparoscopic cholecystectomy with LS used to control the cystic duct from 2005 to 2019 were retrospectively identified from an institutional database. Patients were excluded for open cholecystectomy, partial cholecystectomy, or cancer. Potential risk factors for complications were assessed using logistic regression analysis. RESULTS: Among 262 patients, 191 (72.9%) were stapled for size and 71 (27.1%) for inflammation. In total, 33 (16.3%) patients had Clavien-Dindo grade ≥ 3 complications, with no significant difference when surgeons chose to staple for duct size versus inflammation (p = 0.416). Seven patients had bile duct injury. A large proportion had Clavien-Dindo grade ≥ 3 postoperative complications specifically related to bile duct stones [n = 29 (11.07%)]. Intraoperative cholangiogram was protective against postoperative complications [odds ratio (OR) = 0.18 (p = 0.022)]. CONCLUSION: Whether these high complication rates reflect a technical issue with stapling, more challenging anatomy, or worse disease, findings question whether the use of LS during laparoscopic cholecystectomy is truly a safe alternative to the already accepted methods of cystic duct ligation and transection. Based on these findings, an intraoperative cholangiogram should be performed when considering a linear stapler during laparoscopic cholecystectomy to: (1) ensure the biliary tree is free of stones; (2) prevent inadvertent transection of the infundibulum rather than the cystic duct; and, (3) allow opportunity for safe alternative strategies when an IOC is not able to confirm anatomy. Otherwise, surgeons employing LS devices should be aware that patients are at higher risk for complications.

The role of local treatment including pancreatectomy for pancreatic ductal adenocarcinoma patients with isolated synchronous liver metastasis: Propensity score-matched analyses.

BACKGROUND: In an era of more effective chemotherapy for pancreatic ductal adenocarcinoma (PDAC), the paradigm of local treatment is changing. However, the efficacy of local treatment in patients with isolated liver metastasis remains unclear. Therefore, we aimed to evaluate the effectiveness of pancreatectomy ± local treatment for metastasis (cytoreductive surgery) in PDAC patients with isolated synchronous liver metastasis. METHODS: In total, 239 patients with isolated liver metastasis were extracted from Seoul National University Hospital (SNUH). For comparison, another 12 637 patients were extracted from the National Cancer Database (NCDB). Propensity score matching was performed to minimize confounding in both cohorts. Survival analyses stratified by the treatment delivered were performed using Kaplan-Meier estimates and log-rank tests. RESULTS: In the SNUH cohort, the median (interquartile range) survival was 20.5 (13.0-42.0) months for patients who underwent cytoreductive surgery plus chemotherapy versus 12.0 (10.0-18.0) months for those who received chemotherapy alone (P < .001). With the NCDB cohort, the median (interquartile range) survival was 15.6 (8.9-31.2) months for patients who underwent cytoreductive surgery plus chemotherapy versus 7.4 (3.4-13.2) months for those who received chemotherapy alone (P < .001). CONCLUSION: Patients with isolated synchronous liver metastasis should be considered for cytoreductive surgery in addition to effective chemotherapy.

HALO CleanSpace PAPR evaluation: Communication, respiratory protection, and usability.

OBJECTIVE: To evaluate a relatively new half-face-piece powered air-purifying respirator (PAPR) device called the HALO (CleanSpace). We assessed its communication performance, its degree of respiratory protection, and its usability and comfort level. DESIGN AND SETTING: This simulation study was conducted at the simulation center of the Royal Melbourne Hospital. PARTICIPANTS: In total, 8 voluntary healthcare workers participated in the study: 4 women and 4 men comprising 3 nursing staff and 5 medical staff. METHODS: We performed the modified rhyme test, outlined by the National Institute for Occupational Safety and Health (NIOSH), for the communication assessment. We conducted quantitative fit test and simulated workplace protection factor studies to assess the degree of respiratory protection for participants at rest, during, and immediately after performing chest compression. We also invited the participants to complete a usability and comfort survey. RESULTS: The HALO PAPR met the NIOSH minimum standard for speech intelligibility, which was significantly improved with the addition of wireless communication headsets. The HALO provided consistent and adequate level of respiratory protection at rest, during and after chest compression regardless of the device power mode. It was rated favorably for its usability and comfort. However, participants criticized doffing difficulty and perceived communication interference. CONCLUSIONS: The HALO device can be considered as an alternative to a filtering face-piece respirator. Thorough doffing training and mitigation planning to improve the device communication performance are recommended. Further research is required to examine its clinical outcomes and barriers that may potentially affect patient or healthcare worker safety.

Development, validation, and comparison of a nomogram based on radiologic findings for predicting malignancy in intraductal papillary mucinous neoplasms of the pancreas: An international multicenter study.

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.

Long-term follow-up experience with adjuvant therapy after irreversible electroporation of locally advanced pancreatic cancer.

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: 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.

Methionine oxidation activates pyruvate kinase M2 to promote pancreatic cancer metastasis.

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.

Can Surgical Resection of Metastatic Lesions Be Beneficial to Pancreatic Ductal Adenocarcinoma Patients with Isolated Lung Metastasis?

In the era of effective chemotherapy on pancreatic ductal adenocarcinoma (PDAC) with distant metastasis, data on the effects of metastatectomy are lacking. So, we investigated the effect of metastatectomy on survival after metastasis in PDAC patients with isolated lung metastasis. This retrospective study analyzed 1342 patients who were histologically diagnosed with PDAC with distant metastasis from January 2007 to December 2018, of which 83 patients had isolated pulmonary metastasis. Additionally, 4263 patients were extracted from the National Cancer Database (NCDB) and analyzed. Log-rank test and Kaplan−Meier survival analysis were used to analyze survival after metastasis. The five-year survival rate was significantly higher in patients who underwent pulmonary metastatectomy than in those who received only chemotherapy or supportive treatment (60.6% vs. 6.2% vs. 0.0%, p < 0.001). A similar trend was observed in the NCDB (two-year survival rate, 27.4% vs. 15.8% vs. 4.7%, p < 0.001). In the multivariate analysis, lung lesion multiplicity (hazard ratio (HR) = 2.004, p = 0.017), metastatectomy (HR = 0.278, p = 0.036), chemotherapy (HR = 0.434, p = 0.024), and chemotherapy cycles (HR = 0.300, p < 0.001) had significant effects on survival. Metastatectomy with primary pancreatic lesions is recommended with effective chemotherapy in PDAC patients with isolated lung metastasis.

Neoadjuvant chemoradiation alters the immune microenvironment in pancreatic ductal adenocarcinoma.

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 (Th, 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.

Socioeconomic Predictors of Access to Care for Patients with Operatively Managed Pancreatic Cancer in New York State.

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.