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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.

Guidelines addressing melanoma in-transit metastasis (ITM) recommend immune checkpoint inhibitors (ICI) as a first-line treatment option, despite the fact that there are no efficacy data available from prospective trials for exclusively ITM disease. The study aims to analyze the outcome of patients with ITM treated with ICI based on data from a large cohort of patients treated at international referral clinics.A multicenter retrospective cohort study of patients treated between January 2015 and December 2020 from Australia, Europe, and the USA, evaluating treatment with ICI for ITM with or without nodal involvement (AJCC8 N1c, N2c, and N3c) and without distant disease (M0). Treatment was with PD-1 inhibitor (nivolumab or pembrolizumab) and/or CTLA-4 inhibitor (ipilimumab). The response was evaluated according to the RECIST criteria modified for cutaneous lesions.A total of 287 patients from 21 institutions in eight countries were included. Immunotherapy was first-line treatment in 64 (22%) patients. PD-1 or CTLA-4 inhibitor monotherapy was given in 233 (81%) and 23 (8%) patients, respectively, while 31 (11%) received both in combination. The overall response rate was 56%, complete response (CR) rate was 36%, and progressive disease (PD) rate was 32%. Median PFS was ten months (95% CI 7.4-12.6 months) with a one-, two-, and five-year PFS rate of 48%, 33%, and 18%, respectively. Median MSS was not reached, and the one-, two-, and five-year MSS rates were 95%, 83%, and 71%, respectively.Systemic immunotherapy is an effective treatment for melanoma ITM. Future studies should evaluate the role of systemic immunotherapy in the context of multimodality therapy, including locoregional treatments such as surgery, intralesional therapy, and regional therapies.

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.

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.

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.

Purpose: Uveal melanoma is a rare melanoma variant with no effective therapies once metastases develop. Although durable cancer regression can be achieved in metastatic cutaneous melanoma with immunotherapies that augment naturally existing antitumor T-cell responses, the role of these treatments for metastatic uveal melanoma remains unclear. We sought to define the relative immunogenicity of these two melanoma variants and determine whether endogenous antitumor immune responses exist against uveal melanoma.Experimental Design: We surgically procured liver metastases from uveal melanoma (n = 16) and cutaneous melanoma (n = 35) patients and compared the attributes of their respective tumor cell populations and their infiltrating T cells (TIL) using clinical radiology, histopathology, immune assays, and whole-exomic sequencing.Results: Despite having common melanocytic lineage, uveal melanoma and cutaneous melanoma metastases differed in their melanin content, tumor differentiation antigen expression, and somatic mutational profile. Immunologic analysis of TIL cultures expanded from these divergent forms of melanoma revealed cutaneous melanoma TIL were predominantly composed of CD8+ T cells, whereas uveal melanoma TIL were CD4+ dominant. Reactivity against autologous tumor was significantly greater in cutaneous melanoma TIL compared with uveal melanoma TIL. However, we identified TIL from a subset of uveal melanoma patients which had robust antitumor reactivity comparable in magnitude with cutaneous melanoma TIL. Interestingly, the absence of melanin pigmentation in the parental tumor strongly correlated with the generation of highly reactive uveal melanoma TIL.Conclusions: The discovery of this immunogenic group of uveal melanoma metastases should prompt clinical efforts to determine whether patients who harbor these unique tumors can benefit from immunotherapies that exploit endogenous antitumor T-cell populations. Clin Cancer Res; 22(9); 2237–49. ©2015 AACR.

Supplementary Figure Legend. Weak and insufficient tumor responses after MDA specific CD8+ T cell clone infusion

Supplementary Figure 1. PET-CT scan images

Supplementary Figure 1. In situ MRI assessment of tumor melanin content. Supplementary Figure 2. UM and CM liver metastases demonstrate similar immunophenotype profile.

Purpose: Adoptive transfer of autologous tumor infiltrating lymphocytes (TIL) can mediate durable cancer regression in selected patients with metastatic melanoma. However, the tumor antigens associated with these favorable responses remain unclear. We hypothesized that a clinical strategy involving the iterative adoptive transfer of selected autologous antigen-specific T-cell clones could help systematically define immunologic targets associated with successful cancer therapy, without the interpretative ambiguity of transferring polyclonal populations. Here, we evaluated the clinical efficacy of CD8+ T-cell clones specific for the melanocyte differentiation antigens (MDA), gp100 and MART-1, respectively.Experimental Design: We conducted two consecutive phase II clinical trials involving the adoptive transfer of highly selected autologous antigen-specific CD8+ T-cell clones against gp100 and MART-1, respectively. Fifteen patients with HLA-A2+ treatment-refractory metastatic melanoma received highly avid MDA-specific CD8+ T-cell clones specific for either gp100 (n = 10) or MART-1 (n = 5) with or without intravenous interleukin-2 (IL2) after a lymphodepleting myeloablative preparative regimen.Results: Of the 15 treated patients, we observed immune-mediated targeting of skin melanocytes in 11 patients (73%) and clonal engraftment in eight patients (53%) after cell transfer. There were only transient minor tumor regressions observed, but no objective tumor responses based on Response Evaluation Criteria in Solid Tumor (RECIST) criteria.Conclusions: Despite successful clonal repopulation and evidence of in vivo antigen targeting, the poor therapeutic efficacy after the adoptive transfer of autologous MDA-specific T cells raises significant concerns regarding future immunotherapy efforts targeting this class of tumor antigens. Clin Cancer Res; 21(3); 534–43. ©2014 AACR.

Supplementary Methods: Detailed information regarding additional materials and methods.

The optimal T-cell attributes for adoptive cancer immunotherapy are unclear. Recent clinical trials of ex vivo–expanded tumor-infiltrating lymphocytes indicated that differentiated T effector cells can elicit durable antitumor responses in some patients with cancer, with their antitumor activity tightly correlated with their persistence in the host. Thus, there is great interest in the definition of intrinsic biomarkers that can predict the conversion of short-lived tumor antigen–specific T effector cells into long-lived T memory cells. Long-term persistence of ex vivo–expanded tumor-specific CD8+ T effector clones has been reported in refractory metastatic melanoma patients after adoptive T-cell transfer. By using highly homogeneous clone populations from these preparations, we performed a comparative transcriptional profiling to define preinfusion molecular attributes that can be ascribed to an effector-to-memory transition. Through this route, we discovered that preinfusion T-cell clones that expressed the IL7 receptor (IL7R) and c-myc were more likely to persist longer after adoptive transfer to patients. The predictive value of these two biomarkers was strengthened by using IL7R protein, IL7-induced pSTAT5, and c-myc mRNA expression to prospectively identify human tumor-specific T effector clones capable of engraftment into immunodeficient mice. Overall, our findings reveal IL7R and c-myc expression as intrinsic biomarkers that can predict the fate of CD8+ T effector cells after adoptive transfer. Cancer Res; 75(16); 3216–26. ©2015 AACR.

Supplementary Table and Figures Supplementary Table 1: Differentially expressed genes between persisting and non-persisting clones. Supplementary Figure 1: % IL-7R expressing cells in the infusion bag correlates with persistence of CD8+ effector clones. Supplementary Figure 2: Representative phenotypic profiling of IL7R+ and IL7R- subsets found within infused effector clones. Supplementary Figure 3: IL-7R expression correlates with c-myc mRNA expression in CD8+ effector clones. Supplementary Figure 4: IL-7R expression correlates with induced pSTAT5 expression in CD8+ effector clones.

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: Several drugs and treatment modalities are under investigation to improve current melanoma therapy options. This review profiles the trends in clinical trial investment in late-stage melanoma, and anticipates what changes are expected in melanoma treatment, with a focus on exploratory drug mechanisms. Methods: We reviewed nine international clinical trial databases for registered, interventional, and phase 3 cutaneous melanoma clinical trials since 2010. Results: 73 trials studied drug therapies in late-stage (stage III and IV) melanoma. Exploratory mechanisms were investigated in 32% (23/73) of the late-stage melanoma drug therapy trials. Most exploratory drug trials include immunotherapy drug mechanisms (15/23 trials). Two exploratory mechanisms showed promise: the anti-LAG3 antibody, relatlimab, and the hapten modified vaccine, MVax. Many (52%) trials of exploratory mechanisms are ongoing including the use of adoptive cell transfer immunotherapies, dendritic cell vaccine therapy, and histone deacetylase (HDAC) inhibitors, among others. Conclusions: Since most clinical trials focus on previously approved drug mechanisms, it is likely that paradigm-changing treatments will involve these therapies being used in new treatment contexts or combinations. Only 2 exploratory drug mechanisms studied since 2010 have achieved promising results in the phase 3 setting, though many other trials are ongoing at this time.

Longer time from diagnosis to definitive surgery (TTDS) is associated with increased melanoma-specific mortality. Although black patients present with later-stage melanoma and have worse survival than non-Hispanic white patients, the association between race and TTDS is unknown.To investigate racial differences in time to melanoma treatment.Retrospective review of the National Cancer Database (2004-2015). Multivariable logistic regression was used to evaluate the association of race with TTDS, controlling for sociodemographic/disease characteristics.Of the 233,982 patients with melanoma identified, 1221 (0.52%) were black. Black patients had longer TTDS for stage I to III melanoma (P .001) and time to immunotherapy (P = .01), but not for TTDS for stage IV melanoma or time to chemotherapy (P .05 for both). When sociodemographic characteristics were controlled for, black patients had over twice the odds of having a TTDS between 41 and 60 days, over 3 times the odds of having a TTDS between 61 and 90 days, and over 5 times the odds of having a TTDS over 90 days. Racial differences in TTDS persisted within each insurance type. Patients with Medicaid had the longest TTDS (mean, 60.4 days), and those with private insurance had the shortest TTDS (mean, 44.6 days; P .001 for both).Targeted approaches to improve TTDS for black patients are integral in reducing racial disparities in melanoma outcomes.

BACKGROUND: While resection is a recommended treatment for patients with stage 1 hepatocellular carcinoma (HCC), it remains controversial for multifocal disease. We sought to identify patients with multifocal HCC with survival after resection similar to patients with clinical stage 1 HCC. METHODS: The National Cancer Database was queried to identify patients that underwent resection for HCC. RESULTS: In this study, 2990 patients with a single tumor, and 1087 patients with multifocal disease confined to one lobe underwent resection. In the multifocal cohort, patients with clinical stage 3 (HR 1.54, CI 1.31–1.81, p < 0.0001) or 4 (HR 2.27, CI 1.57–3.29, p < 0.0001) disease, and those with moderately-differentiated (HR 1.32, CI 1.06–1.64, p = 0.012) or poorly differentiated/undifferentiated tumors (HR 1.53, CI 1.20–1.95, p = 0.0006) were associated with worse overall survival (OS). There was no difference in OS between patients with well-differentiated clinical stage 2 multifocal HCC and those with all grades of clinical stage 1 HCC (median of 84.8 (CI 66.3–107.2) vs 76.2 months (CI 71.2–81.3), respectively, p = 0.356). CONCLUSIONS: Patients with well-differentiated, clinical stage 2 multifocal HCC confined to one lobe experience similar OS following hepatic resection to patients with clinical stage 1 disease. These findings may impact the management of select patients with multifocal HCC.

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.

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.

Cardiac angiosarcoma is a rare malignancy with an aggressive course and poor prognosis. We present a 26‐year old man who came to our clinic with shortness of breath and was diagnosed with a right‐sided atrial mass. He underwent urgent resection of the mass. The pathology confirmed the mass to be cardiac angiosarcoma with positive microscopic margins (R1 resection). Since reresection was not feasible, the patient started treatment with concurrent paclitaxel (80 mg/m2 weekly) and proton beam therapy (61 Cobalt equivalent delivered over five weeks). After completing the concurrent chemotherapy and radiation therapy, he was treated with adjuvant chemotherapy using gemcitabine (900 mg/m2 on Days 1 and 8) and docetaxel (100 mg/m2 on Day 8) every three weeks. After three cycles, the patient developed severe dermatitis, and hence further chemotherapy was withheld. The patient is alive at 26 months since receiving his surgery and 18 months since the completion of treatment. Patients with cardiac angiosarcoma who undergo R1 resection have a median survival of six months. More radical approaches such as orthotopic heart‐lung transplant or prolonged durations of chemotherapy lead to minimal improvement in survival at the cost of increased morbidity. Here, we describe a novel approach to a rare disease that resulted in prolonged survival and led to a better quality of life without any long‐term morbidity to the patient., Cardiac angiosarcoma is a rare tumor of the heart associated with a poor prognosis. Patients who undergo R1 resection have a median survival of six months. Multiple efforts to improve the outcome have resulted in severe morbidity and mortality, without increasing survival. Here, we report a novel approach of concurrent chemotherapy and proton beam therapy followed by adjuvant chemotherapy that resulted in continued survival beyond two years without any recurrence or any toxicity to the heart.

OBJECTIVE: To assess the impact of a granular measure of socioeconomic deprivation on pancreatic surgical and cancer-related outcomes at a high-volume cancer center that employs a standardized clinic pathway. SUMMARY BACKGROUND DATA: Prior research has shown that low socioeconomic status leads to less treatment and worse outcomes for pancreatic adenocarcinoma. However, these studies employed inconsistent definitions and categorizations of socioeconomic status, aggregated individual socioeconomic data using large geographic areas, and lacked detailed clinicopathologic variables. METHODS: We conducted a retrospective cohort study of 1,552 pancreatic adenocarcinoma patients between 2008 and 2015. Patients were stratified using the Area Deprivation Index, a validated dataset that ranks census block groups based on socioeconomic deprivation (SED). Multivariable models were used in the curative surgery cohort to predict the impact of SED on 1) grade 3/4 Clavien-Dindo complications, 2) initiation of adjuvant therapy 3) completion of adjuvant therapy, and 4) overall survival RESULTS: Patients from high SED neighborhoods constituted 29.9% of the cohort. Median overall survival was 28 months. The rate of Clavien-Dindo grade 3/4 complications was 14.2% and completion of adjuvant therapy was 65.6%. There was no evidence that SED impacted surgical evaluation, receipt of curative-intent surgery, postoperative complications, receipt of adjuvant therapy or overall survival. CONCLUSIONS: While nearly one-quarter of curative-intent surgery patients were from high SED neighborhoods, this factor was not associated with measures of treatment quality or survival. These observations suggest that treatment at a high-volume cancer center employing a standardized clinical pathway may in part address socioeconomic disparities in pancreatic cancer.

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.

Background: Routine sentinel lymph node biopsy (SLNB) has been recommended against by Choosing Wisely© Foundation due to its low value in clinical node negative, hormone receptor positive breast cancer patients age≥70 years old. We used the National Cancer Database (NCDB) to examine the effect of SLNB omission and outcomes in this population. We hypothesized that SLNB would be beneficial in this population.Methods: The National Cancer Database was queried for women diagnosed with primary unilateral invasive clinical stage T1N0M0 hormone receptor positive, HER-2 negative breast cancer from 2012-2017. Patients age ≥ 70 years old with Charlson Score ≥1 who underwent partial mastectomy and received hormonal therapy were included in the study cohort. Patients received neoadjuvant therapy or underwent upfront axillary lymph node dissection (ALND) were excluded. A 1:3 propensity match with replacement was performed to compare SLNB omission vs. SLNB group controlling age, race, comorbidities, insurance and facility. Overall survival was analyzed using stratified multivariable Cox proportional hazard regression analysis.Results: Of 14,150 patients, 1,928 (13.6%) omitted SLNB and 12,222 (86.4%) underwent SLNB, including 1,545/12,222 (12.6%) who proceeded to ALND. Central portion tumor location (OR=1.77, P=0.001), clinical T1c (OR= 2.49, P Citation Format: Lifen Cao, Megan E Miller, Luke D Rothermel, Alberto J Montero, Christopher W Towe, Robert Shenk. Less is not necessarily more: A propensity matched national analysis on effect and outcome of sentinel lymph node biopsy omission [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr PD7-08.

Hepatocellular carcinoma (HCC) is a leading cause of cancer mortality. Operative management of early disease includes ablation, resection, and transplantation. We compared the operative management of early-stage HCC in patients stratified by race.We identified patients with cT1 HCC and Charlson-Deyo score 0-1 in the National Cancer Database (2004-2016). We compared operative/non-operative management by race, adjusting for clinicodemographic variables. We performed marginal standardization of logistic regression to ascertain adjusted probabilities of resection or transplantation in patients under 70 years of age with insurance.A total of 25,029 patients were included (White = 20,410; Black = 4619). After adjusting for clinico demographic variables, Black race was associated with a lower likelihood of undergoing operative intervention (OR 0.89,p = 0.009). Black patients were more likely to undergo resection (OR 1.23,p 0.001) and less likely to undergo transplantation (OR 0.60,p 0.001). Marginal standardization models demonstrated Black race was associated with increased probability of resection in patients50yrs, with private insurance/Medicare, and lower probability of transplantation regardless of age or insurance payor.Black race is associated with lower rates of hepatic transplantation and higher rates of hepatic resection for early HCC regardless of age or insurance payor. The etiology of these disparities is multifactorial and correcting the root causes represents a critical area for improvement.

Background: Immunotherapy (IT) has led to improved survival in several common cancers but success in pancreatic ductal adenocarcinoma (PDAC) has been limited. We analyzed if combination IT–chemotherapy (IT-CT) is associated with improved survival compared with chemotherapy alone (CT) in patients with metastatic PDAC. Methods: The National Cancer Database (2004–2016) was queried for patients who were diagnosed with metastatic PDAC. Patients were categorized by treatment group: CT only and IT-CT. Patients were excluded if they received radiation or a surgical procedure. The primary outcome was overall survival. Results: A total of 59,289 patients were identified, of whom 58,947 (99.4%) received CT and 342 (0.6%) received IT-CT. The IT-CT group was younger, had fewer comorbidities, and was more often treated at an academic center. The utilization of multiagent CT was similar between the groups. Median survival of patients treated with IT-CT was longer than CT alone (7.9 months vs. 6.3 months, p = 0.005). On multivariable analysis, receipt of IT-CT was associated with a survival advantage as compared with CT (hazard ratio = 0.86, 95% confidence intervals 0.76–0.97) when adjusting for demographics and type of CT regimen. Conclusion: In patients with metastatic PDAC, it appears that combination IT-CT may perhaps be associated with a survival advantage compared with CT alone.

INTRODUCTION: Indolamine 2,3-dioxygenase 1 (IDO1) is upregulated in tumors. It facilitates catabolism of tryptophan to kynurenine and downstream metabolites, which are associated with psychiatric symptoms. To this point, 20% of patients at our institution developed psychiatric symptoms months before pancreatic cancer (PC) diagnosis. This proportion was threefold greater relative to non-cancer controls (6.7%), supplying indirect evidence of a biochemical link. Herein, we investigate IDO1 as a target in pancreatic cancer-associated depression. METHODS: Human and murine PC cells were used in vitro. Protein levels were assessed using western blotting and cell survival by PicoGreen. For in vivo studies, murine PC cells were injected into the pancreatic tail. Control mice underwent an acellular injection. Mice were treated with epacadostat (an IDO1 inhibitor), escitalopram, or vehicle. To evaluate depressive-like behavior, mice were subjected to the forced swim and tail suspension tests. The open field test was used to monitor mobility. Tumors were analyzed using western blotting and serum metabolites were assessed using LC-MS. RESULTS: Murine and human PC cells had undetectable basal IDO1 protein levels; however, there was a strong induction with interferon-gamma. There was a further increase in IDO1 with added epacadostat. Escitalopram had no effect on IDO1 levels. Epacadostat and escitalopram did not impact PC cell viability. Physical mobility of PC mice was similar to controls over the study period. PC mice were more immobile relative to controls during the forced swim (percent immobile: 16.0% v 8.2%, p Citation Format: Jonathan J. Hue, Hallie J. Graor, Mehrdad Zarei, Ali Vaziri-Gohar, Erryk S. Katayama, Karen Ji, Omid Hajihassani, Alexander W. Loftus, Luke D. Rothermel, Jordan M. Winter. IDO1 is a potential target to combat pancreatic cancer-associated depression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2321.

Introduction: Pancreatic cancer (PC) is resistant to systemic therapies. This is at least in part due to the characteristically harsh tumor microenvironment which limits the delivery of systemic therapies and is not conducive to anti-tumor immune cell function. Unfortunately, development of novel therapeutics is arduous. Thus, identification of methods to augment the efficacy of existing therapeutics, such as immunotherapies, represents an attractive option. Herein, we attempt to sensitize PC to a colony stimulating factor 1 receptor (CSF1R) inhibitor by augmenting peripheral glucose levels. Methods Murine PC cells (KPC) and bone marrow derived macrophages were cultured in hypoglycemic (≤2.5mM) or hyperglycemic (25mM) conditions. Phenotypic (western blot, flow cytometry), metabolic (seahorse, LC-MS metabolomics), and cell survival (clonogenic assay) assays were performed. KPC cells were orthotopically injected into the pancreas of immunocompetent mice for survival studies. Mice were randomized to pexidartinib (a CSF1R inhibitor) or vehicle and received either normal water of 30% dextrose (D30). Results: In a co-culture experiment, tumor-supporting M2 macrophages increased KPC cell growth by 30%, whereas tumor-fighting M1 macrophages decreased KPC growth by 95%. M1 macrophages were poorly suited to survive in hypoglycemic conditions as compared to hyperglycemic conditions (relative survival: 38% vs 100%, p Conclusion: Higher glucose conditions promote M1 macrophage survival and function, while preventing the switch to an M2 phenotype. Also, higher peripheral glucose levels appear to sensitize PC to a CSF1R inhibitor. We plan to validate these findings using other immunotherapeutics (e.g., checkpoint inhibitors). Citation Format: Jonathan J. Hue, Mehrdad Zarei, Hallie J. Graor, Erryk S. Katayama, Omid Hajihassani, Alexander W. Loftus, Luke D. Rothermel, Ali Vaziri-Gohar, Jordan M. Winter. Glucose is important for macrophage metabolism and response to immunotherapy in a pancreatic cancer model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3133.

Background:Low health literacy is associated with increased resource use and poorer outcomes in medical and surgical patients with various diseases. This observational study was designed to determine (1) the prevalence of low health literacy among surgical patients with cancer at an NCI-designated Comprehensive Cancer Center (CCC), and (2) associations between health literacy and clinical outcomes.Methods:Patients receiving surgery (N=218) for gastrointestinal (60%) or genitourinary cancers (22%) or sarcomas (18%) were recruited during their postsurgical hospitalization. Patients self-reported health literacy using the Brief Health Literacy Screening Tool (BRIEF). Clinical data (length of stay [LoS], postacute care needs, and unplanned presentation for care within 30 days) were abstracted from the electronic medical records 90 days after surgery. Multivariate linear and logistic regressions were used to examine the relationship between health literacy and clinical outcomes, adjusting for potential confounding variables.Results:Of 218 participants, 31 (14%) showed low health literacy (BRIEF score ≤12). In regression analyses including 212 patients with complete data, low health literacy significantly predicted LoS (β = −1.82; 95% CI, −3.00 to −0.66;P=.002) and postacute care needs (odds ratio [OR], 0.25; 95% CI, 0.07–0.91). However, health literacy was not significantly associated with unplanned presentation for care in the 30 days after surgery (OR, 0.51; 95% CI, 0.20–1.29).Conclusions:This study demonstrates the prevalence of low health literacy in a surgical cancer population at a high-volume NCI-designated CCC and its association with important clinical outcomes, including hospital LoS and postacute care needs. Universal screening and patient navigation may be 2 approaches to mitigate the impact of low health literacy on postsurgical outcomes.

Background: Immunotherapy (IT) has led to improved survival in several common cancers but success in pancreatic ductal adenocarcinoma (PDAC) has been limited. We analyzed if combination IT-chemotherapy (IT-CT) is associated with improved survival compared to chemotherapy alone (CT) in patients with metastatic PDAC. Methods: The National Cancer Database (2004-2016) was queried for patients who were diagnosed with metastatic PDAC. Patients were categorized by treatment group: CT only and IT-CT. Patients were excluded if they received radiation or a surgical procedure. The primary outcome was overall survival.Results: A total of 59,289 patients were identified, of whom 58,947 (99.4%) received CT and 342 (0.6%) received IT-CT. The IT-CT group was younger, had fewer comorbidities, and was more often treated at an academic center. The utilization of multi-agent chemotherapy was similar between the groups. Median survival of patients treated with IT-CT was longer than CT alone (7.9 vs 6.3 months, p=0.005). On multivariable analysis, receipt of IT-CT was associated with a survival advantage as compared to CT (HR=0.86, 95% CI 0.76-0.97) when adjusting for demographics and type of chemotherapy regimen.Conclusions: In patients with metastatic PDAC, it appears that combination IT-CT may be associated with a survival advantage compared to CT alone.

Background Immune checkpoint inhibitors (ICI) and targeted therapies (TT) have improved the survival outcomes in patients with advanced melanoma. However, less is known about their impact on Asian patients with melanoma. In this study, we hypothesize that patients of Asian ancestry would have improved survival for advanced melanoma since the introduction of ICI and TT in 2011. Methods Asian patients with melanoma were identified in the National Cancer Database (NCDB) from 2004–2016. Patient, tumor, and treatment characteristics were compared for populations treated before and after 2011 using Chi-square analyses. Overall survival (OS) was analyzed using Kaplan-Meier estimates. Results 1,411 Asian patients with melanoma were identified. Overall, 21% were melanoma in situ, and 79% were invasive melanomas. 62% of patients did not have a documented histologic subtype. The most common reported histologies were superficial spreading (14%) and acral lentiginous (10%) melanomas. Primary locations included 41% lower extremity, 17% upper extremity, and 11% head and neck. The age at diagnosis has increased during the study period - 38% over 60 years old in 2004, to 54% in 2016 (P Conclusions Asian patients with melanoma are receiving diagnoses at older ages. Despite decreases in OS for all Asian patients with melanoma, advanced stage IV of the diseases have improved outcomes for the group treated in the era of ICI and TT. Further investigation is warranted to understand the treatment, patient, and tumor characteristics that predict response in this demographic of patients.

Highlights • The diagnosis of serous cystadenoma is challenging. • Surgery may be indicated for select serous cystadenoma. • Serous cystadenocarcinoma is a rare entity and histologically indistinguishable from its benign counterpart., Introduction Advanced imaging has led to an increase in the incidental diagnosis of pancreatic cysts. Serous cystadenomas (SCAs) account for nearly 30% of cases. These are typically considered benign lesions but up to 16% of cases are resected for aggressive behavior and symptoms. Presentation of case A 64 year old female presented with a large incidental cyst in the pancreatic body. Pre-operative imaging conferred a diagnosis of SCA. After 2 years the cyst grew resulting in abdominal pain. Enlargement was associated with splenic vein occlusion and varices of the short gastric vessels. This change in behavior was concerning for malignant transformation. The cyst was resected by distal pancreatectomy and splenectomy. The patient recovered with minimal morbidity. Final pathology revealed a 15.5 × 10.3 × 8.5 cm SCA with negative margins. Discussion In this case a patient presents with aggressive radiographic features and new symptoms suggesting malignant transformation of a previously diagnosed SCA on imaging. Although malignant variants can be diagnosed by findings of metastatic deposits at the time of surgery or as recurrence years later, histologic findings cannot discriminate benign from malignant potential. Preoperative imaging is challenging with erroneous characterization in nearly 60% of cases. Conclusion Based on the low risk of malignancy, selective surgical resection for SCA appears warranted. Accepted indications for surgery include development of symptoms or concern for correct diagnosis in a medically fit individual. Routine resection for cysts >4 cm has been suggested however, prospective studies are needed to determine benefit over risk rationale.

Non-functional neuroendocrine tumors of the pancreas (NF-pNETs) are uncommon. Consensus guidelines have conflicting recommendations. We performed a nationwide analysis of patterns in management and outcomes based on facility type and tumor size.The National Cancer Database (2004-2016) was queried for patients with localized NF-pNETs (1 cm, 1-2 cm,2 cm) stratified by facility type. Management decisions, operative outcomes, and survival were compared.A total of 7170 patients were included in the analysis (1 cm = 916; 1-2 cm = 2180;2 cm = 4074). Most patients were treated at academic facilities (62.8%). Over 67% of patients with tumors1 cm underwent resection, independent of facility type (p = 0.443). There was no association between facility type and operative vs non-operative management of patients with NF-pNETs 1-2 cm in size. Patients treated at academic facilities were more likely to undergo resection for tumors2 cm compared to other facility types. Resection was associated with improved survival among patients with tumors 1-2 cm (HR = 0.43,p 0.001) and2 cm (HR = 0.32,p 0.001), but not1 cm (HR = 0.64,p = 0.054), as compared to non-operative management.There is heterogeneity in management of NF-pNETs across facility types. Treatment at academic facilities appears to be associated with higher resection rates for tumors2 cm. There appears to be an independent association between operative management and improved survival for tumors ≥1 cm in size.

The use of minimally invasive approaches for pancreatoduodenectomy has increased in recent years, but the risk of postoperative VTE is undefined. We aimed to compare venous thromboembolism (VTE) rates after open and minimally invasive pancreatoduodenectomy using an administrative dataset. Patients who underwent pancreatoduodenectomy within the National Surgical Quality Improvement Program targeted pancreatectomy database (2016–2018) were identified. VTE was compared between patients who underwent open or minimally invasive pancreatoduodenectomy directly and after propensity score matching 1:1 for demographics, comorbidities, and peri-/intra-operative factors. A total of 12,227 patients underwent pancreatoduodenectomy during the study period (open: n = 11,217; minimally invasive: n = 1010). Before matching, the VTE rate was higher among patients who underwent minimally invasive pancreatoduodenectomy (5.2% vs. 3.8%, p = 0.033), and minimally invasive resection was independently associated with VTE (OR = 1.46, 95%CI = 1.09–2.06). After matching, there were 916 patients per group without differences in demographics or comorbidities. Patients who underwent minimally invasive pancreatoduodenectomy had longer median operative times (422 vs. 348 min). The VTE rate remained higher following minimally invasive pancreatoduodenectomy after matching (5.1% vs. 2.9%, p = 0.018), mainly driven by a higher DVT rate (3.9% vs. 1.7%, p = 0.005). Minimally invasive pancreatoduodenectomy is associated with a higher postoperative VTE rate compared to open pancreatoduodenectomy.

Purpose: Uveal melanoma is a rare melanoma variant with no effective therapies once metastases develop. Although durable cancer regression can be achieved in metastatic cutaneous melanoma with immunotherapies that augment naturally existing antitumor T-cell responses, the role of these treatments for metastatic uveal melanoma remains unclear. We sought to define the relative immunogenicity of these two melanoma variants and determine whether endogenous antitumor immune responses exist against uveal melanoma. Experimental Design: We surgically procured liver metastases from uveal melanoma (n = 16) and cutaneous melanoma (n = 35) patients and compared the attributes of their respective tumor cell populations and their infiltrating T cells (TIL) using clinical radiology, histopathology, immune assays, and whole-exomic sequencing. Results: Despite having common melanocytic lineage, uveal melanoma and cutaneous melanoma metastases differed in their melanin content, tumor differentiation antigen expression, and somatic mutational profile. Immunologic analysis of TIL cultures expanded from these divergent forms of melanoma revealed cutaneous melanoma TIL were predominantly composed of CD8+ T cells, whereas uveal melanoma TIL were CD4+ dominant. Reactivity against autologous tumor was significantly greater in cutaneous melanoma TIL compared with uveal melanoma TIL. However, we identified TIL from a subset of uveal melanoma patients which had robust antitumor reactivity comparable in magnitude with cutaneous melanoma TIL. Interestingly, the absence of melanin pigmentation in the parental tumor strongly correlated with the generation of highly reactive uveal melanoma TIL. Conclusions: The discovery of this immunogenic group of uveal melanoma metastases should prompt clinical efforts to determine whether patients who harbor these unique tumors can benefit from immunotherapies that exploit endogenous antitumor T-cell populations. Clin Cancer Res; 22(9); 2237–49. ©2015 AACR.