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We described trends and disparities in utilization of systemic chemotherapy in metastatic hepato-pancreato-biliary (HPB) cancers.We queried the National Cancer Database for metastatic HPB cancers [hepatocellular carcinoma (HCC), biliary tract cancers (BTC), pancreatic adenocarcinoma (PDAC)]. We used multivariable analysis to examine the factors associated with utilization of systemic chemotherapy. We utilized marginal structural logistic models to estimate the effect of health insurance, facility type, or facility volume on utilization of systemic chemotherapy.We identified 162,283 patients with metastatic HPB cancers: 23,923 (14.7%) had HCC, 26,766 (16.5%) had BTC, and 111,594 (68.8%) had PDAC. A total of 37.2% patients with HCC, 55.6% with BTC, and 56.4% with PDAC received chemotherapy. Age ≥70 years and Charlson-Deyo score ≥2 were associated with lower likelihood of receiving chemotherapy across all cancers. Patients with private health insurance had higher receipt of chemotherapy. Receiving treatment at academic facilities had no effect on the receipt of chemotherapy. Treatment of patients with HCC or PDAC at high-volume facilities resulted in higher receipt of chemotherapy.A significant proportion of patients with metastatic HPB cancers do not receive systemic chemotherapy. Several disparities in administration of chemotherapy for metastatic HPB cancers exist.

To examine the average treatment effect of hepato-pancreato-biliary (HPB) cancer volume on survival outcomes of patients with non-resected pancreatic adenocarcinoma (PDAC).We queried the National Cancer Database (2004-2018) for patients with HPB malignancies (PDAC, pancreatic neuroendocrine neoplasms, hepatocellular carcinoma, biliary tract cancers). We determined the 25th, 50th, and 75th percentiles based on the total annual HPB volume. We then identified patients with non-resected PDAC. We utilized inverse probability (IP)-weighted Cox regression to estimate the effect of facility volume on overall survival (OS).We identified 710,988 patients with HPB malignancies. The 25th, 50th, and 75th percentiles of total annual HPB volume were 32, 71, and 177 cases/year, respectively. We included a total of 196,150 patients with non-resected PDAC. Patients treated at ≥25th, ≥50th, and ≥75th percentile facilities had improved median OS compared to those treated at facilities below these thresholds (5.8 vs. 4.2months, 6.5 vs. 4.5months, 7.5 vs. 4.8months, respectively; p 0.001 for all). Treatment at facilities ≥25th, ≥50th, and ≥75th percentile resulted in lower hazards of death than treatment at lower-percentile facilities (HR: 0.87, 95% CI: 0.84-0.90; HR: 0.87, 95% CI: 0.83-0.91; HR: 0.85, 95% CI: 0.79-0.91, respectively).Our data suggest that consolidation of care of patients with PDAC to high-volume centers may be beneficial even in the nonoperative setting.

Metabolites of tryptophan degradation are known to alter mood. Their effects have only been superficially examined in the context of pancreatic cancer. Herein, we study the role of indoleamine 2,3-dioxygenase 1 (IDO1), an enzyme important in the conversion of tryptophan to kynurenine, in a murine model of pancreatic cancer–associated depression. Behavioral tests (open field, forced swim, tail suspension, and elevated plus maze) and biochemical assays (LC-MS metabolomics) were used to characterize a depressive-phenotype in tumor-bearing mice (relative to non–tumor-bearing mice). In addition, we determine whether pharmacologic blockade of IDO1 affects mood in tumor-bearing mice. Immunocompetent mice bearing orthotopic pancreatic tumors exhibit depressive-like behavior relative to non–tumor-bearing mice. Pancreatic tumors strongly express IDO1. Consequently, serum kynurenine levels in tumor-bearing mice are elevated relative to non–tumor-bearing mice. Tumor-bearing mice treated with epacadostat, an IDO1 inhibitor, exhibited improved mood relative to mice receiving vehicle. There was a 95% reduction in serum kynurenine levels in mice receiving epacadostat relative to mice treated with vehicle. As confirmatory evidence of on-target activity, tumors of mice treated with epacadostat exhibited a compensatory increase in IDO1 protein levels. Escitalopram, an approved antidepressant, was ineffective at improving mood in tumor-bearing mice as measured by behavioral assays and did not affect kynurenine levels. Neither epacadostat, nor escitalopram, affected overall survival relative to vehicle. Mice with pancreatic cancer exhibit depressive-like behavior. Epacadostat was effective as an antidepressant for pancreatic cancer–associated depression in mice. These data offer a rationale to consider IDO1 inhibition as a therapeutic strategy to mitigate depressive symptoms in patients with pancreatic cancer.

Supplementary Figure from IDO1 Is a Therapeutic Target for Pancreatic Cancer–Associated Depression

Nutrient-deprived conditions in the tumor microenvironment (TME) restrain cancer cell viability due to increased free radicals and reduced energy production. In pancreatic cancer cells a cytosolic metabolic enzyme, wild-type isocitrate dehydrogenase 1 (wtIDH1), enables adaptation to these conditions. Under nutrient starvation, wtIDH1 oxidizes isocitrate to generate α-ketoglutarate (αKG) for anaplerosis and NADPH to support antioxidant defense. In this study, we show that allosteric inhibitors of mutant IDH1 (mIDH1) are potent wtIDH1 inhibitors under conditions present in the TME. We demonstrate that low magnesium levels facilitate allosteric inhibition of wtIDH1, which is lethal to cancer cells when nutrients are limited. Furthermore, the Food & Drug Administration (FDA)-approved mIDH1 inhibitor ivosidenib (AG-120) dramatically inhibited tumor growth in preclinical models of pancreatic cancer, highlighting this approach as a potential therapeutic strategy against wild-type IDH1 cancers.

Consensus guidelines recommend for perioperative chemotherapy and surgery for patients with clinical stage (cT) T2 or greater gastric adenocarcinoma. We compared adherence to guidelines in these patients stratified by race.Non-Hispanic White and Black patients with resected ≥cT2 gastric adenocarcinoma were identified within the National Cancer Database (2008-2017). We compared administration of preoperative chemotherapy by race, adjusting for clinicodemographic variables. We performed marginal standardization of logistic regression to calculate adjusted probabilities of administration of preoperative chemotherapy in patients under the age of 80 years with insurance.A total of 13,850 patients were identified (White = 12,161; Black = 1,689). Black race was associated with lower likelihood of receiving preoperative chemotherapy than White race (odds ratio = 0.46, 95% confidence interval: 0.39-0.54). Other factors associated with lower likelihood of preoperative chemotherapy included age ≥70 years, female sex, treatment at community facilities, non-private or no health insurance, and cT4 disease. Factors associated with higher likelihood of preoperative chemotherapy included treatment at high-volume facilities, longer distance to facility, higher education and income levels, cT3 disease, and cN+ disease. In patients80 years with insurance, marginal standardization models demonstrated that Black race was associated with a lower adjusted probability of receiving preoperative chemotherapy regardless of age, insurance payor, facility type/volume, distance to facility, cT stage, cN stage, sex, and education/income levels.Black race was associated with underutilization of preoperative chemotherapy for cT2 or greater gastric cancer, in discordance to published guidelines. The etiology of these disparities is multifactorial, and correcting the root causes represents a critical area for improvement.

Irreversible electroporation (IRE) is used as a locoregional treatment modality for patients with locally advanced pancreatic cancer (LAPC), but is non-curative and is associated with postoperative morbidity and mortality. We performed a systematic review and meta-analysis comparing survival outcomes of multimodal therapy with or without IRE.Separate searches were performed for multimodal therapy + IRE and multimodal therapy alone given the lack of comparative literature using PubMed, SCOPUS, and Cochrane Library in 3/2021. We determined overall survival (OS) and progression-free survival (PFS) from diagnosis and time of IRE. Treatment-related morbidity and mortality was determined.Of 585 published articles, 48 met inclusion criteria for IRE (n = 27) and without IRE (n = 21) with data for 1420 (IRE) and 1348 (without IRE) patients. The 6/12/24 months OS with IRE was 99%/84%/28%. The 6/12/24 months OS without IRE was 99%/80%/12%. At 12 months from IRE, OS was 55% and PFS was 12%. The mean major complication and 90-day mortality rates for IRE were 17.95% and 2.65%.Multimodal therapy alone is associated with similar OS to multimodal therapy + IRE in patients with LAPC. Most patients progress and nearly half die within 1 year of the IRE procedure. Given the lack of quality prospective data, IRE should remain experimental and be used with caution in LAPC.

Background Weight changes during neoadjuvant chemotherapy (NAC) for pancreatic cancer (PDAC) are not well studied. We hypothesized that weight loss may predict poor outcomes. Methods Weight change from NAC initiation to pancreatectomy was grouped: gain (≥5%), stable, and loss (≥5%). Pathologic, postoperative, and survival outcomes were compared. Results 95 patients were included: 31.6% lost weight, 58.9% maintained weight, and 9.5% gained weight. There were no differences in chemotherapeutic regimens. Median recurrence-free survival (RFS) and overall survival (OS) were similar between patients with stable weight and those who lost weight (RFS: 9.6vs14.0months; OS: 25.8vs26.7months). Among those who gained weight, RFS (29.5months) and OS (38.4months) were greater relative to the other weight categories. On multivariable regression, weight gain was associated with improved RFS compared to loss (HR = 0.16). Conclusion Most patients maintain or lose weight during NAC, and weight loss does not predict poor outcomes. Weight gain may predict improved RFS.

Most patients with pancreatic adenocarcinoma (PDAC) do not undergo surgical resection. The role of radiotherapy (RT) in non-operatively managed localized pancreatic adenocarcinoma is unclear.The National Cancer Database (2010-2016) was queried for patients with clinical stage II-III PDAC treated with multiagent systemic chemotherapy (CT) +/- RT but not surgery. Factors associated with the receipt of RT and overall survival were compared after adjusting for patient demographics and clinical characteristics.A total of 14,921 patients were included, of whom 9279 received CT and 5382 received CT + RT. Patients treated with CT + RT were more likely to be younger (65vs66yrs), treated at non-academic facilities (48.8%vs46.7%), have private insurance (40.3%vs36.5%), and have clinical T4 tumors (53.6%vs48.7%). Most patients who were treated with RT received external beam radiotherapy (89.3%), and the median dose was 5,000 cGy. Median time to start of RT was 129 days. CT + RT was associated with longer overall survival (15.9vs11.8mos,p 0.001), and remained associated with survival on multivariable analysis (HR 0.74, 95%CI 0.70-0.78). On a 4-month conditional survival analysis, combined CT + RT remained associated with improved survival compared to CT alone (16.0vs13.1mos,p 0.001).In patients with non-operatively managed localized pancreatic adenocarcinoma, combined radiotherapy and multiagent systemic chemotherapy is associated with improved overall survival compared to chemotherapy alone.

Background The Centers for Medicare and Medicaid Services proposed reimbursement cuts for operations in 2021. Literature examining reimbursement for common operations is scarce. Methods Reimbursement rates were abstracted (2011–2021). Trends in reimbursement rates were analyzed using linear regression. Results From 2011 to 2021, the national inflation rate was 16.3%. Unadjusted reimbursement rates for open and laparoscopic inguinal hernia repairs increased by 6.5% and 7.2%, respectively. There was an increase in unadjusted reimbursement for open appendectomies of 5.1% and 6.1% for laparoscopic. Unadjusted reimbursement for open cholecystectomies increased by 4.4%, but decreased by 6.8% for laparoscopic. When adjusted to 2021 values, reimbursement for all six operations decreased. Laparoscopic and open cholecystectomies experienced the largest decreases (19.8%, 10.2%). Conclusion Since 2011, there have been decreases in adjusted reimbursement for three common operations, independent of operative approach. Awareness of trends in reimbursement rates should be a priority to ensure sustainable general surgical care.

Background Guidelines recommend resection of non-functional neuroendocrine tumors of the pancreas (NF-pNETs) that are ≥2 cm in size. We compared utilization of surgery based on race. Methods We identified non-Hispanic White and Black patients with localized NF-pNETs ≥2 cm and Charlson-Deyo score 0–1 in the NCDB (2004–2016). We compared utilization of surgery by race, adjusting for clinicodemographic variables. Overall survival was compared based on management. Results A total of 3459 patients were included (White = 3005; Black = 454). Black patients were younger (58vs63 years) and more often treated at academic facilities (65.3%vs60.3%). Overall, Black and White patients underwent surgery at similar rates (77.3%vs79.6%). When stratified by primary site, Black patients with body/tail tumors were less likely to undergo surgery (78.5%vs84.7%). On multivariable analysis, Black race was associated with a lower likelihood of surgery overall (OR 0.74,p = 0.034) and in patients with body/tail tumors (OR 0.56,p = 0.001). Non-operative management was associated with a higher risk of death (HR 3.19,p Conclusion In a national cohort of patients with NF-pNETs meeting criteria for resection, Black race is associated with lower frequency of surgery. Operative intervention is associated with prolonged survival. Persistent racial disparities in management of a surgically curable disease should be targeted for improvement.

Background Although guidelines recommend open adrenalectomy for most resectable adrenal malignancies, minimally invasive adrenalectomies are performed. Robotic adrenalectomies have become more popular recently, but there is a paucity of literature comparing laparoscopic and robotic resections. Methods Patients who underwent a planned minimally invasive adrenalectomy for adrenal malignancies (adrenocortical carcinoma, malignant pheochromocytoma, other carcinoma) were identified in the National Cancer Database. The primary outcome was the conversion rate from minimally invasive to open. Other post-operative outcomes and survival were compared. Results 416 patients (76.5%) underwent a laparoscopic adrenalectomy and 128 (23.5%) underwent a robotic operation. Demographics and clinical characteristics were similar. Approximately 19% of tumors resected by a minimally invasive approach were > 10 cm. The intra-operative conversion rate was decreased among robotic adrenalectomies relative to laparoscopic on univariate (7.8% vs. 18.3%, p = 0.005) and multivariable (odds ratio 0.39, p = 0.01) analyses. Using marginal standardization, there was a stepwise increase in the conversion rate as tumor size increased ( 10 cm) for laparoscopic (7.5%, 18.0%, 33.2%) and robotic (3.1%, 8.3%, 17.3%) adrenalectomies. Operations which required conversion had a greater margin positivity rate, greater length of stay, and an association with poor overall survival. Conclusion In contrast to most clinical guidelines, minimally invasive adrenalectomies are being performed on large malignant tumors. A laparoscopic approach was associated with a greater conversion rate and subsequent poor outcomes. If a surgeon is not planning an open adrenalectomy, but adrenal malignancy is a possibility, robotic adrenalectomy may be the preferred approach for resectable adrenal tumors.

Elderly patients with adenocarcinoma of the pancreatic head can achieve reasonable survival with multimodal therapy. An analysis specific to cancers of the pancreatic tail has not been published.We identified patients ≥65 years with localized adenocarcinoma of the pancreatic tail in the National Cancer Database (2011-2017). Patients were grouped by age (65-79 and ≥80 years) and categorized by treatment regimen. Postoperative outcomes and survival were analyzed using propensity score matching and multivariable logistical regression.2168 patients were included: 73.9% were 65-79 years and 26.1% were ≥80 years. 34.1% of octogenarians did not receive any treatment, relative to 15.9% of younger patients (p 0.001). Thirty-day mortality rates were similar in operatively managed patients; however, the 90-day mortality rate among octogenarians was greater (3.0% vs. 7.8%, p 0.001; odds ratio [OR] = 1.85, 95% confidence interval [CI] = 1.07-3.19). Age ≥ 80 was not associated with survival on multivariable hazards regression (hazard ratio [HR] = 1.08, 95% CI = 0.95-1.24). After propensity matching, the addition of chemotherapy was not associated with improved survival relative to distal pancreatectomy alone among octogenarians (HR = 1.09, 95% CI = 0.72-1.65).Management of adenocarcinoma of the pancreatic tail varies based on patient age. Resection appears to play a key role in management, but there is substantial upfront risk. Shared decision making should be employed to balance the chance for long-term survival with the risk of early mortality.

There is evidence that neoadjuvant therapy is associated with improved survival compared with upfront pancreatectomy for pancreatic adenocarcinoma. Treatment at high-volume pancreatic surgery centers is associated with improved short-term postoperative outcomes compared with low-volume centers. We compared overall survival of patients with early-stage pancreatic adenocarcinoma who received neoadjuvant therapy before resection stratified by facility volume.Patients with clinical T0 to T2 pancreatic adenocarcinoma who received neoadjuvant therapy before pancreatoduodenectomy were identified in the National Cancer Database (2010-2016). High-volume pancreatic surgery centers performed ≥36 pancreatectomies/year. Patients were matched 1:1 by propensity score. Pathologic outcomes, postoperative outcomes, and overall survival were compared.Before matching, 1,449 patients were treated at low-volume centers and 250 at high-volume pancreatic surgery centers. After matching, there were 177 patients per group. High-volume pancreatic surgery centers were more commonly academic/research facilities (99.4% vs 54.0%; P.001), and patients traveled greater distances (65 vs 13 miles; P.001). Time from diagnosis to neoadjuvant therapy and surgery was similar. Treatment at high-volume pancreatic surgery centers was associated with shorter duration of stay (7 vs 8 days; P = .003) and lower 90-day mortality rate after pancreatoduodenectomy (0.0% vs 5.0%; P = .01). Patients treated at high-volume pancreatic surgery centers had improved overall survival (36.3 vs 29.4 months; P = .03; hazard ratio 0.73). On subset analysis of academic/research facilities, high-volume pancreatic surgery centers remained associated with shorter duration of stay, lower 90-day mortality, and greater overall survival.The majority of patients treated with neoadjuvant therapy for early-stage pancreatic adenocarcinoma received care at low-volume centers. Treatment at high-volume pancreatic surgery centers was associated with improved overall survival and short-term postoperative outcomes.

For patients with pancreatic cancer, survival rates lag behind other common cancers. This is in part due to the relative resistance to conventional chemotherapeutics and novel immune- or targeted-therapies. Ongoing research efforts are needed to identify and validate effective therapies. It is the unfortunate reality that a significant proportion of pre-clinical success does not translate into improved patient outcomes, likely due to a multitude of factors. In the current research landscape, flank xenograft models are commonly utilized to study pancreatic cancer, as this technique is fast, fairly non-invasive, and reliable. However, this model is not anatomically or physiologically accurate, does not impact other intra-abdominal organs, and experiments are often ended based on tumor size rather than systemic illness. Orthotopic injections of cancer cells directly into the pancreas for study of localized disease or into the spleen for study of hepatic metastases can be performed via a quick, reliable, minimally invasive surgical procedure with minimal morbidity and mortality. Existing methodologic reports are often sparse. Thus, there are significant knowledge and technical gaps for researchers attempting these techniques for the first time. In the current report, details of orthotopic pancreatic injections and splenic injections for metastatic disease are provided. Details of commonly encountered operative issues and mistakes are presented with suggestions to improve performance are described. A summary of expected outcomes is also provided herein.

Surgical volume-outcome relationships have been described for a variety of procedures. There is scant literature on total institutional volume and outcomes in patients who are nonoperatively managed. We examined the average treatment effect of total hepatopancreatobiliary malignancy case volume on survival outcomes of patients with nonresected hepatobiliary malignancies.We identified patients with hepatopancreatobiliary malignancies [pancreatic adenocarcinoma, pancreatic neuroendocrine neoplasms, hepatocellular carcinoma, biliary tract cancers] within the National Cancer Database (2004-2018). We determined percentile thresholds based on the total annual hepatopancreatobiliary malignancy case volume. We then identified nonoperatively managed patients with hepatocellular carcinoma or biliary tract cancers. We used inverse probability-weighted Cox regression to estimate the effect of facility volume on overall survival.We identified 710,988 patients with hepatopancreatobiliary malignancies. Total annual hepatopancreatobiliary malignancy case volume of 32, 71, and 177 cases/year corresponded to the 25th, 50th, and 75th percentiles. A total of 96,420 with hepatocellular carcinoma and 52,627 patients with biliary tract cancers were managed nonoperatively. In patients with hepatocellular carcinoma or biliary tract cancer, treatment at ≥25th, ≥50th, and ≥75th percentile facilities was associated with improved median, 1-, 2-, and 3-year overall survival compared with treatment at lower-percentile facilities. On inverse probability-weighted Cox analysis, treatment at higher-percentile facilities resulted in a lower hazard of death. Consistent findings were observed in patients with early or intermediate/advanced hepatocellular carcinoma or metastatic biliary tract cancers.Patients with nonoperatively managed hepatocellular carcinoma or biliary tract cancer who receive treatment at higher-volume facilities have improved survival outcomes. These data suggest regionalization of care for patients with hepatocellular carcinoma or biliary tract cancer to high-volume centers may improve survival.

To compare rates of venous thromboembolism (VTE) and postpancreatectomy hemorrhage (PPH) in patients with pancreatic or periampullary malignancy preimplementation and postimplementation of routine extended VTE prophylaxis.Guidelines recommend up to 28 days of VTE prophylaxis following major abdominal cancer operations. There is a paucity of data examining rates of VTE and PPH in patients who receive extended VTE prophylaxis following pancreatectomy.Single-institution analysis of patients who underwent pancreatectomy for malignancy (2004-2021). VTE and PPH rates within 90 days of discharge were compared based on receipt of extended VTE prophylaxis with enoxaparin.A total of 478 patients were included. Twenty-two (4.6%) patients developed a postoperative VTE, 12 (2.5%) of which occurred postdischarge. Twenty-five (5.2%) patients experienced PPH, 13 (2.7%) of which occurred postdischarge. There was no associated difference in the development of postdischarge VTE between patients who received extended VTE prophylaxis and those who did not (2.3% vs 2.8%, P=0.99). There was no associated difference in the rate of postdischarge PPH between patients who received extended VTE prophylaxis and those who did not (3.4% vs 1.9%, P=0.43). In the subset of patients on antiplatelet agents, the addition of enoxaparin did not appear to be associated with higher VTE (3.9 vs. 0%, P=0.31) or PPH (3.0 vs. 4.5%, P=0.64) rates.Extended VTE prophylaxis following pancreatectomy for malignancy was not associated with differences in postdischarge VTE and PPH rates. These data suggest extended VTE prophylaxis is safe but may not be necessary for all patients following pancreatectomy.

Introduction: Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer mortality in the United States. The poor prognosis is in part due to development of chemotherapy resistance, despite improvements in multiagent regimens. Our previous work demonstrated that oxidative stress plays an important role in drug resistance. Wild-type isocitrate dehydrogenase 1 (IDH1) is an important enzyme that generates cytosolic NADPH to maintain redox homeostasis and protect cancer cells from oxidative damage. Additionally, we demonstrated that ivosidenib (AG-120), an FDA-approved mutant IDH1 inhibitor, is actually a potent inhibitor of wild-type IDH1, under low magnesium and nutrient levels that are present in the tumor microenvironment. Methods: We evaluated IDH1 expression in PDAC using The Cancer Genome Atlas (TCGA). Cell viability was assessed by Trypan blue and PicoGreen in drug combination assays. Cellular reactive oxygen species (ROS) levels were determined by the DCFDA method. To further assess the therapeutic potential of AG-120 in combination with chemotherapy, tumor volume analyses were performed using patient-derived xenografts (PDX) in athymic nude mice, and survival studies were performed in C57BL/6J mice transplanted with orthotopic murine pancreatic cancer. Results: Analysis of TCGA data indicated that IDH1 is overexpressed in pancreatic cancer tumors. Treatment of MiaPaca2 and Panc1 cancer cells with 5- fluorouracil (5-FU) induced expression of wild-type IDH1 in vitro. Short-term cell viability data demonstrated that targeting IDH1 with AG-120 when combined with DNA-damaging agents (5-FU, oxaliplatin) had a synergistic effect with a positive synergy score and Bliss score greater than 1. Additionally, we assessed long-term cell survival using colony formation assays, which yielded a dramatic reduction in cell survival for both Panc1 and MiaPaCa-2 cells when 5-FU was combined with AG-120, as compared to single-agent controls. Inhibiting IDH1 impairs the ability of pancreatic cancer cells to scavenge ROS levels, enhances chemotherapy-induced apoptosis in pancreatic cancer cells via ROS-mediated damage in vitro. Both PDX tumor volume studies and overall survival analyses revealed that the combination of these AG-120 and chemotherapy synergistically enhanced anti-tumor activity and doubled the survival benefits as compared to single-agent alone. Conclusion: IDH1 plays a critical role in tumorigenesis and chemoresistance in pancreatic cancer. Our data demonstrate that IDH1 inhibition with AG-120 may enhance chemotherapy efficacy and represents an important area for future investigation in the form of clinical trials. Citation Format: Mehrdad Zarei, Omid Hajihassani, Jonathan J. Hue, Hallie J. Graor, Arian Hajihassani, Alexander W. Loftus, Luke D. Rothermel, Jordan M. Winter. Targeting wild-type IDH1 enhances chemosensitivity in pancreatic cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3701.

Background: Advanced and metastatic melanoma carries significant mortality despite recent advances. Metabolic plasticity is a hallmark of cancer and an important resistance mechanism in the face of anti-neoplastic therapies. We sought to understand the effect of chemotherapy, Temozolomide (TMZ), on OXPHOS and TCA cycle metabolism in melanoma cell lines. By understanding these metabolic adaptations to chemotherapy, we hope to identify novel combination therapies. Methods: A375 and SK-MEL-28 cell lines were used for all experiments. Cell viability assays were performed with 1500 cells per well, treated with TMZ and oligomycin or phenformin, and viability was assessed using PicoGreen dsDNA assay. Western blot was used with primary antibodies against TOM20 and Β-actin. LCMS metabolites were assessed by QTRAP triple quadrupole mass spectrometry coupled to a Prominence UFLC HPLC system. This assessed approximately 299 metabolites. Seahorse XFp miniextracellular analyzer was used to obtain OCR with and without TMZ exposure, and after sequential injections of oligomycin, FCCP, and rotenone with antimycin A. Mitochondrial assays included TMRE staining (membrane potential) and Mitotracker Green (mitochondrial mass). Results: Metabolic profiles of melanoma cell lines change with exposure to chemotherapy. After melanoma cells are exposed to IC30 dose of TMZ, LCMS metabolomics revealed statistically significant increase in TCA cycle metabolites such as succinate, succinyl CoA, malate, oxaloacetate, isocitrate, alpha-ketoglutarate, and fumarate. Melanoma increases OXPHOS in the presence of chemotherapy. Mitochondrial mass, measured by Mitotracker, increased in response to TMZ exposure. We also found increased mitochondrial membrane potential and increased TOM20 expression after cells were treated with TMZ. Seahorse XF Cell Mito Stress Assay demonstrated increased oxygen consumption rate after exposure to TMZ. We then combined TMZ and two mitochondrial inhibitors, phenformin (complex I) and oligomycin (complex V). Combination of phenformin and TMZ was synergistic in cell viability assays as determined by Bliss equation. Oligomycin sensitized both cell lines to TMZ. Discussion: We have shown that melanoma cells rely on mitochondrial function when exposed to TMZ by increasing levels of TCA cycle intermediates, increasing mitochondrial tropism, and increased expression of mitochondrial enzymes. This demonstrates a metabolic resistance mechanism in response to chemotherapy to promote melanoma cell survival. Finally, we exploit this adaptation by pharmacologic inhibition of mitochondrial electron transport chain (ETC) with phenformin and oligomycin A. This treatment was synergistic with conventional chemotherapy. Our findings point out that the ETC compartment of mitochondria could be a novel and readily available combination treatment strategy for patients with advanced and refractory melanoma. Citation Format: Alexander W. Loftus, Mehrdad Zarei, Omid Hajihassani, Johnathan J. Hue, Hallie J. Graor, Ali Vaziri-Gohar, Jordan M. Winter, Luke D. Rothermel. Chemotherapy alters mitochondrial metabolism in melanoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4839.

BACKGROUND AND OBJECTIVES This study investigated the impact of treating facility type on guideline-concordant sentinel lymph node biopsy (SLNB) management in T1a* (defined as a Breslow depth

Pancreatic ductal adenocarcinoma (PDAC) has the worst survival of common cancers, partly because there are no reliable early detection tests. Unintentional weight loss (≥ 5% decrease from baseline) has been linked to PDAC, but the frequency and severity of weight loss using objective measures, and its relationship to prognosis, have not been well characterized. We identified 390 patients with PDAC (all stages) and two or more prediagnosis weights in the electronic medical record. Percentage weight loss in the 365 and 180 days preceding diagnosis was calculated. Results were compared with raw weights of age- and sex-matched non-cancer controls (n = 780). Odds ratios for PDAC were calculated using conditional logistic regression. Cox proportional hazards models were used for survival. Within 1 year of diagnosis, more PDAC patients lost ≥ 5% weight relative to controls (74.9% vs. 11.2%; p

Robotic esophagectomies are increasingly common and are reported to have superior outcomes compared with an open approach; however, it is unclear if all institutions can achieve such outcomes. We hypothesize that early adopters of robotic technique would have improved short-term outcomes.The National Cancer Database (2010-2016) was used to identify robotic esophagectomies. Early adopters were defined as programs which performed robotic esophagectomies in 2010-2011, late adopters in 2012-2013. Outcomes of esophagectomies performed between 2014 and 2016 were compared and included length of stay, number of lymph nodes evaluated, readmission, conversion rate, and 90-day mortality. Multivariable regressions, accounting for robotic esophagectomy volume, were used to control for confounding factors.There were 37 early adopters and 35 late adopters. Between 2014 and 2016, 683 robotic esophagectomies were performed: 446 (65.3%) by early adopters and 237 (34.7%) by late adopters. Early adopters were more likely to be academic programs (96.2 versus 72.8%, P 0.01). Other clinical and demographic variables were similar. Late adopters were found to have decreased a number of lymph nodes evaluated (coefficient -2.407, P = 0.004) compared with early adopters. There were no significant differences in length of stay, readmissions, rate of positive margins, conversion from robotic to open, or 90-day mortality.When accounting for robotic esophagectomy volume, late adoption of robotic esophagectomy was associated with a reduced lymph node harvest, but other postoperative outcomes were similar. These data suggest that programs can safely start new robotic esophagectomy programs, but must ensure an adequate case load.

Resection of locoregional pancreatic neuroendocrine neoplasms (PanNENs) is typically recommended, but there is a paucity of data on the management of elderly patients.The National Cancer Database (2004-2016) was queried for patients 80 years or older with localized PanNENs. Patients were grouped as nonoperative or operative management. Postoperative outcomes and survival were compared.In total, 591 patients were included: 202 underwent resection, and 389 did not. Increasing age and pancreatic head tumors were associated with lower likelihood of resection. The overall 90-day mortality rate was 6.4%, which was higher for pancreatoduodenectomy than distal pancreatectomy (13.6% vs 5.1%, respectively). Operatively managed patients had longer median survival (80.8 vs 45.0 months, P0.001), and this association was independent of tumor location. On multivariable Cox regression, resection remained associated with longer survival (hazard ratio, 0.69; 95% confidence interval, 0.50-0.95). Among operatively managed patients, age and tumor location were not associated with survival; however, greater comorbidity and high-risk tumor-specific features were associated with worse survival.Resection of nonfunctional PanNENs in elderly patients is associated with improved survival compared with nonoperative management. Resection could be considered in appropriate operative candidates, regardless of tumor location, but the perioperative mortality rate must be considered.

Background Alternative treatment strategies in melanoma beyond immunotherapy and mutation-targeted therapy are urgently needed. Wild-type isocitrate dehydrogenase 1 (wtIDH1) has recently been implicated as a metabolic dependency in cancer. The enzyme protects cancer cells under metabolic stress, including nutrient limited conditions in the tumor microenvironment. Specifically, IDH1 generates NADPH to maintain redox homeostasis and produces α-ketoglutarate to support mitochondrial function through anaplerosis. Herein, the role of wtIDH1 in melanoma is further explored. Methods The expression of wtIDH1 was determined by qRT-PCR, and Western blot in melanoma cell lines and the effect of wtIDH1 on metabolic reprogramming in melanoma was interrogated by LC-MS. The impact of wtIDH1 inhibition alone and in combination with chemotherapy was determined in cell culture and mouse melanoma models. Results Melanoma patients express higher levels of the wtIDH1 enzyme compared to normal skin tissue, and elevated wtIDH1 expression portends poor patient survival. Knockdown of IDH1 by RNA interference inhibited cell proliferation and migration under low nutrient levels. Suppression of IDH1 expression in melanoma also decreased NADPH and glutathione levels, resulting in increased reactive oxygen species. An FDA-approved inhibitor of mutant IDH1, ivosidenib (AG-120), exhibited potent anti-wtIDH1 properties under low magnesium and nutrient levels, reflective of the tumor microenvironment in natura. Thus, similar findings were replicated in murine models of melanoma. In light of the impact of wtIDH1 inhibition on oxidative stress, enzyme blockade was synergistic with conventional anti-melanoma chemotherapy in pre-clinical models. Conclusions These results demonstrate the clinical potential of wtIDH1 inhibition as a novel and readily available combination treatment strategy for patients with advanced and refractory melanoma. Graphical Abstract Schematic shows increased wild-type IDH1 expression and activity as an adaptive response to metabolic stress induced by chemotherapy.

SummaryPancreatic cancer (Pancreatic Ductal Adenocarcinoma; PDAC) is highly resistant to chemotherapy. Effective alternative therapies have yet to emerge, leaving chemotherapy as the best available systematic treatment. The discovery of safe and available adjuncts that improve chemotherapeutic efficacy would potentially improve survival outcomes. We show that a hyperglycemic state enhances the efficacy of conventional single- and multi-agent chemotherapies against PDAC. Molecular analyses of tumors exposed to relatively high glucose levels revealed that a key metabolic pathway, glutathione biosynthesis, is diminished and underlies chemo-sensitization by enhancing oxidative injury to cancer cells. Inhibition of this pathway under normal conditions phenocopied a hyperglycemic state by enhancing chemotherapeutic efficacy in mouse PDAC, while rescuing the pathway under high glucose abrogated the anti-tumor effects observed with chemotherapy.

To determine the frequency of depression or anxiety preceding a diagnosis of pancreatic cancer (PC). Further, to examine the association of PC-associated depression or anxiety with treatment compliance and survival.856 patients with PC from a single institution were identified using International Classification of Diseases (ICD) codes. For each case, two non-cancer age- and sex-matched controls were included. Dates of depression or anxiety diagnosis identified using ICD codes were compared to the date of PC diagnosis. The medical record was queried to further explore psychiatric symptoms. Multivariable analyses were performed to examine if prediagnosis depression or anxiety was associated with receipt of treatment or survival.A greater proportion of patients with PC experienced depression or anxiety in the year preceding diagnosis than the overall frequency in controls (4.6% vs. 2.6%, p = 0.005) based on ICD codes. Patients with PC exhibited signs of prodromal depression or anxiety based on ICD codes, clinical documentation of psychiatric symptoms, or initiation of new psychiatric medications more often than controls (20.7% vs. 6.7%, p 0.001). Prediagnosis depression or anxiety was associated with a reduced likelihood of receiving chemotherapy (OR = 0.58, p = 0.04). There was an associated decrease in overall survival among patients with metastatic disease who experienced depression or anxiety before PC diagnosis (HR = 1.32, p = 0.04).The frequency of depression or anxiety among patients with PC was higher than the general population. Prediagnosis psychiatric symptoms were associated with reduced chemotherapy utilization and worse overall survival. Thus, timely identification and treatment of these symptoms may improve outcomes.

Pancreatic ductal adenocarcinoma (PDAC) has historically poor outcomes. Difficult decisions must be made by patients and providers, especially in the elderly for whom treatment morbidities may not be tolerable. Herein, we report treatment-dependent outcomes of octogenarians with localized PDAC. The National Cancer Database identified patients ≥60 years with localized PDAC of the pancreatic head (2011–2016). Patients were grouped by age (60–79 and ≥80 years) and categorized by treatment regimen: no treatment, chemotherapy, pancreaticoduodenectomy, pancreaticoduodenectomy with perioperative chemotherapy, or pancreaticoduodenectomy with adjuvant chemotherapy. Postoperative outcomes and survival were analyzed. A total of 35,409 patients were included, 8745 (24.7%) of which were ≥80 years. Over 52% of octogenarians did not receive any treatment, compared to 19.1% of younger patients (p

BACKGROUND Adrenocortical carcinoma (ACC) is often a contraindication to minimally invasive adrenalectomy (MIA). We used an administrative data set to analyze postoperative outcomes. We hypothesized that small tumors would have better short- and long-term outcomes, independent of the operative approach. METHODS The National Cancer Database (2010-2016) identified patients with ACC who underwent adrenalectomy. Tumors were grouped: 10 cm (n = 443). The primary and secondary outcomes were margin positivity and overall survival, respectively. RESULTS Nine hundred and ninety-nine patients were analyzed: 37% MIA and 63% open adrenalectomy (OA). As the size increased, the rate of attempted MIA decreased. Larger tumors were associated with conversion to open. Although tumors with local invasion and those which required conversion to open were associated with an increased likelihood of a positive margin, tumor size was not. Although "complete" MIA (vs. OA) and tumor size were not associated with differences in survival, conversion (HR = 1.83, p = .02), positive margins (HR = 1.54, p = .01), and local invasion (HR = 1.84, p

Introduction Surgical researchers seek to publish their findings in esteemed surgical journals to advance science and their careers. A detailed investigation of study and manuscript attributes in a specific research area, like pancreatic neoplasia, may yield informative insights for researchers looking to maximize research impact. Objectives We analyzed publications related to pancreatic surgery primarily focused on pancreatic and periampullary tumors in order to identify elements associated with acceptance into high impact journals and a high likelihood of future citations. Methods A comprehensive review of nine surgical journals was performed between 2010-19. Journals were grouped based on impact factor into high (>3), medium (1-3) and low ( Results A total of 1,044 out of 21,536 (4.8%) articles published in the index journals were related to pancreatic tumors. The most common focus of study was perioperative outcomes and complications (46.7%). There was significantly more number of authors, participating institutions, countries, and randomized clinical trials in higher impact journals as well as high-cited articles (p 0.05). Conclusion Pancreatic neoplasia continues to be extensively studied in surgical literature. Specific elements of study methodology and design were identified as potentially key attributes to acceptance in high impact journals and citation success.

Early detection is a valued strategy to decrease cancer mortality rates; however, new strategies are needed. Unintentional weight loss (UWL) is experienced by patients across the cancer spectrum, but often goes unnoticed. Patient-centered weight tracking may be a useful early detection marker. Fifty patients were enrolled in a prospective patient-centered weight tracking trial. Patients received a scale and monetary compensation to participate. A reminder to measure and record weight was texted to participants for 26 consecutive weeks. Most patients were black (86.0%) and female (68.0%). The median age was 47 years (range: 22-84 years). Many participants had Medicaid (42.0%) and the median household income by home zip code was $31,046. After 26 weeks, 90% of patients had recorded at least one weight. Among all patients, 73.7% of all possible weights were recorded and the median response rate per patient was 92.3% (24 of 26 weights). There was no difference in the response rates during the first and second halves of the study (77.7% vs. 69.7%, P = 0.53). The range of weight change over the study period was 16.1% loss to 25.0% gain, with 56% of patients maintaining stable weight. Seven patients (14.0%) lost more than 5% weight and 11 patients (22.0%) gained over 5%. Of the seven patients with weight loss, two (4.0% of the cohort) were determined to have UWL. Patient-centered weight tracking is feasible and inexpensive, and has potential as an early detector of UWL. Further studies are needed to apply this strategy to detect underlying malignancies.

We examined the association between Medicaid expansion (ME) and the diagnosis, treatment, and survival of patients with hepatocellular carcinoma (HCC).We identified patients with HCC65yrs with Medicaid or without insurance within the National Cancer Database before (2010-2013) or after (2015-2017) ME with early (cT1) or intermediate/advanced (cT2-T4 or M1) disease.We identified 4848 patients with HCC before and 4526 after ME. Prior to ME, there was no association between future ME status and diagnosis of early HCC (34.5% vs. 32.9%). There was no association between future ME status and treating early HCC with ablation, resection, or transplantation. Patients with early HCC in future ME states were less likely to die (HR = 0.81, 95% CI: 0.67-0.98). After ME, patients in ME states were more likely to be diagnosed with early HCC (39.2% vs. 32.1%). Patients with early disease in ME states were more likely to undergo resection (OR=1.78, 95% CI: 1.16-2.75) or transplantation (OR=3.20, 95% CI: 1.40-7.33). There was a further associated decrease in the hazard of death (HR=0.68, 95% CI: 0.54-0.86).ME was associated with early diagnosis of HCC. For early HCC, ME was associated with increased utilization of resection and transplantation and improvement in survival.

We describe factors associated with trial enrollment for patients with hepato-pancreato-biliary (HPB) malignancies. We analyzed the association and effect of trial enrollment on overall survival (OS).The National Cancer Database (2004-2017) was queried for common HPB malignancies (pancreatic adenocarcinoma [PDAC]neuroendocrine tumors, hepatocellular carcinoma [HCC], biliary tract cancers [BTC]). Multivariable logistic regression was used to identify factors associated with trial enrollment. OS was analyzed by multivariable Cox regression. Inverse-probability-weighted Cox regression was utilized to determine the effect of trial enrollment on OS.A total of 1573 (0.3%) of 511,639 patients were enrolled in trials; pancreatic malignancy: 1214 (0.4%); HCC: 217 (0.14%); BTC: 106 (0.15%). HCC and BTC were associated with lower likelihood of enrollment compared with pancreatic malignancy. Black and Hispanic patients were less likely to be enrolled compared to White patients. Treatment at academic facilities and metastatic disease were associated with higher likelihood of enrollment. Enrollment was associated with higher OS for PDAC, metastatic HCC, and metastatic BTC. Trial enrollment exhibited an OS advantage for PDAC and metastatic HCC.Nationally, fewer than 1% of patients with HPB malignancies were enrolled in clinical trials. There are racial, sociodemographic, and facility-based disparities in trial enrollment.

Objective measures of post-pancreatectomy weight change for pancreatic ductal adenocarcinoma (PDAC) have not been extensively studied for long-term outcomes. We used weight measurements in our institutional medical record to analyze trends in post-pancreatectomy weight and determine the association with disease status.Pancreatectomies for PDAC (n = 315) and benign indications (n = 111) were identified. Preoperative baseline, minimum postoperative (Min #1), and subsequent postoperative maximum (Max) weights were abstracted. Multivariable Cox hazards regression was conducted to analyze the association between weight change and survival.Median weight loss postoperatively in each group was 20 lbs. PDAC patients gained 10 lbs after Min #1 compared to 15 lbs in the benign cohort (p 0.001). Few patients returned to their preoperative weight (29.8% PDAC vs. 40.5% benign, p = 0.04). Patients with early PDAC recurrence ( 13 months) lost more weight (18.0% vs. 13.3% vs. 10.9%, p 0.001) and gained less weight (2.1% vs. 12.0% vs. 7.9%, p 0.001) compared with those with late cancer recurrence (≥ 13 months) or no evidence of active disease, respectively. PDAC patients lost 11.2 lbs in the year preceding recurrence diagnosis. Weight loss was not associated with survival; however, weight gain was associated with improved survival.Resections for PDAC are complicated by a similar degree of weight loss as patients with benign disease, and there is no association with survival. However, failure to gain weight is especially ominous. Weight loss after weight recovery foreshadows disease recurrence. These data suggest that rigorous weight tracking is an untapped surveillance strategy in patients with PDAC.

Not all patients with pancreatic adenocarcinoma (PDAC) tolerate multiagent neoadjuvant chemotherapy (NAC). We utilized institutional data and the National Cancer Database (NCDB) to investigate if time from diagnosis to NAC initiation is associated with survival.Patients who received NAC and underwent pancreatectomy at our institution (2010-2021) or within the NCDB (2010-2016) were identified. Time from diagnosis to NAC was grouped:21, 21-35, and35 d. Recurrence-free (RFS) and overall survival (OS) was compared.At our institution, 122 patients received NAC before pancreatectomy (21 d: n = 36; 21-35 d: n = 61;35 d: n = 25). Demographics, performance status, and anatomic resectability were similar. There was no difference in RFS (13.3 versus 12.4 versus 11.9 mo) or OS (26.7 versus 25.8 versus 26.1 mo) based on NAC timing. Patients who received FOLFIRINOX had an improvement in RFS (14.4 versus 12.2 versus 6.8 mo, P = 0.05) and OS (39.2 versus 21.4 versus 17.3 mo, P = 0.01) compared to gemcitabine with nab-paclitaxel or other regimens. Within the NCDB, 6713 patients were included (21 d: n = 2087; 21-35 d: n = 2656;35 d: n = 1970). There was no difference in OS (21.6 versus 20.9 versus 22.2 mo). Multiagent NAC was associated with improved OS compared to single-agent (22.6 versus 18.8 mo, P 0.001).Delay in NAC initiation for PDAC is not associated with survival. Patient optimization could be considered with the goal of improving tolerance of multiagent chemotherapy.

Although guidelines recommend open adrenalectomy for most resectable adrenal malignancies, minimally invasive adrenalectomies are performed. Robotic adrenalectomies have become more popular recently, but there is a paucity of literature comparing laparoscopic and robotic resections.Patients who underwent a planned minimally invasive adrenalectomy for adrenal malignancies (adrenocortical carcinoma, malignant pheochromocytoma, other carcinoma) were identified in the National Cancer Database. The primary outcome was the conversion rate from minimally invasive to open. Other post-operative outcomes and survival were compared.416 patients (76.5%) underwent a laparoscopic adrenalectomy and 128 (23.5%) underwent a robotic operation. Demographics and clinical characteristics were similar. Approximately 19% of tumors resected by a minimally invasive approach were 10 cm. The intra-operative conversion rate was decreased among robotic adrenalectomies relative to laparoscopic on univariate (7.8% vs. 18.3%, p = 0.005) and multivariable (odds ratio 0.39, p = 0.01) analyses. Using marginal standardization, there was a stepwise increase in the conversion rate as tumor size increased ( 5, 5-10, 10 cm) for laparoscopic (7.5%, 18.0%, 33.2%) and robotic (3.1%, 8.3%, 17.3%) adrenalectomies. Operations which required conversion had a greater margin positivity rate, greater length of stay, and an association with poor overall survival.In contrast to most clinical guidelines, minimally invasive adrenalectomies are being performed on large malignant tumors. A laparoscopic approach was associated with a greater conversion rate and subsequent poor outcomes. If a surgeon is not planning an open adrenalectomy, but adrenal malignancy is a possibility, robotic adrenalectomy may be the preferred approach for resectable adrenal tumors.

Background While adjuvant chemotherapy benefits patients with pancreatic ductal adenocarcinoma (PDAC), the importance of the time to initiation of adjuvant therapy remains unclear. Aim This study seeks to better understand whether the timing of postoperative chemotherapy initiation affects long‐term outcomes in PDAC. Methods and Results A systematic literature search was performed in Medline, Embase, and Cochrane Library in March 2020. Studies focused on the association between the timing of adjuvant therapy on long‐term outcomes in resected PDAC patients were included. The impact of early and delayed therapy as defined by the respective studies was evaluated using forest plot analysis. Overall survival (OS) and disease‐free survival (DFS) served as primary endpoints. Out of 3099 published articles, 10 retrospective studies met inclusion criteria. Combined, these studies included clinical data of 13 344 patients. The cut off used to define “early” and “delayed” treatment groups varied in the included studies ranging from 3 to 12 weeks. Due to this heterogeneity, a sub‐group analysis of three time cut offs was performed: 3 to 5 weeks, 6 to 8 weeks, and 9 to 12 weeks. There was a significant decrease in OS and DFS when adjuvant therapy was delayed by 3 to 5 weeks after surgery (OS, pooled hazard ratio [HR] = 1.86, 95% confidence interval [CI] = 1.25‐2.78; DFS, pooled HR = 1.62, 95% CI = 1.12‐2.34). However, due to small sample size and limited studies in this subgroup analysis, the results may be indeterminate. There was no significant decrease in OS with delayed initiation of adjuvant therapy by 6 to 8 weeks and 9 to 12 weeks. Similarly, delay in adjuvant therapy beyond 3‐5 weeks. Conclusions There was no conclusive evidence suggesting improved survival in patients starting treatment at various time cut offs. Studies investigating the extreme ends of the time‐to‐treatment spectrum may prove more informative.

Our research group recently surveyed the clinical trial landscape in pancreatic adenocarcinoma and identified 430 active trials. These represent an opportunity to expand treatment options for patients with pancreatic adenocarcinoma. Our primary objective was to detail clinical trial participation among patients with pancreatic adenocarcinoma. Our secondary objective was to evaluate survival.We queried the National Cancer Database (2004-2016) for patients with pancreatic adenocarcinoma. Patients were stratified by trial participation: clinical trial or non-trial. Multivariable logistic regression was used to identify variables associated with trial participation. The Kaplan-Meier method and multivariable Cox hazards regression were used to analyze survival.In total, 261,483 patients were included: 1,110 (0.4%) were enrolled in a clinical trial. A total of 57 Black patients participated in a clinical trial (0.19% of Black patients). This was lower compared to White patients (n = 955, 0.49% of White patients, P.001). After adjusting for demographic and clinical factors, Black patients were less likely to be enrolled in a clinical trial (odds ratio = 0.387, P.001). Patients treated at nonacademic medical centers were less likely to be in a clinical trial. Trial participation was associated with an increased median survival relative to non-trial patients (stage IV: 9.0 vs 3.8 months, P.001), and this association remained on multivariable regression (hazard ratio = 0.779, P.001).Fewer than 1% of patients with pancreatic adenocarcinoma participated in a clinical trial. There are racial and sociodemographic disparities in clinical trial enrollment. An association was observed between clinical trial participants and prolonged survival.