A phase II study of FOLFOX combined with nab-paclitaxel in the treatment of metastatic or advanced unresectable gastric, gastroesophageal junction adenocarcinoma: a Big Ten Cancer Research Consortium trial.

BACKGROUND: Doublet platinum or taxane-based therapies are the current standard backbone of treatment for advanced gastric/gastroesophageal junction (GEJ) adenocarcinoma. Previously used anthracycline-based triplet regimens are no longer used routinely due to toxicity and lack of superior efficacy. We hypothesized that the addition of nab-paclitaxel to FOLFOX (FOLFOX-A) would induce higher efficacy and better tolerability. PATIENTS AND METHODS: Eligible patients with chemotherapy-naïve advanced unresectable HER2-negative gastric or GEJ adenocarcinoma were enrolled in this phase II single-arm trial of FOLFOX (oxaliplatin 85 mg/m2, leucovorin 400 mg/m2, 5-FU 2400 mg/m2 over 46-48 hours) + nab-paclitaxel (150 mg/m2) every 14 days of a 28-day cycle. Evaluable disease according to RECIST v1.1 for solid tumors was required. The primary endpoint was the objective response rate. Simon's optimal 2-stage design was used to test 5% versus 20% response rate with 90% power and 10% one-sided type I error rate. RESULTS: The study enrolled 39 patients. Median age was 63 (range 20-80) years, 30 (77%) were male, 34 (94%) were White, and 21 (57%) had gastric tumors. The median number of cycles completed was 4.5 (range: 0-36), and 25 patients required dose reductions or discontinuation of at least one component due to toxicity. Of the 38 patients evaluable for response, 15 (42.9%) had complete/partial response (CR/PR) as the best response, and 13 (37.1%) had stable disease. progression-free survival (PFS) and OS data were available for 38 patients, with a median follow-up duration of 27 months (range: 18.2-51.9 months for censored patients). Median PFS was 6.6 months (95% CI: 5.6-12.9), with 31.0% (95% CI: 18.4%-52.4%) 12-month PFS rate. The median OS was 10.5 months (95% CI: 8.8-20.7), 12-month OS rate was 44.7% (95% CI: 31.4%-63.7%). Treatment-related grade 3-4 toxicities included peripheral sensory neuropathy and anemia (18.4% each), neutropenia (15.8%), and diarrhea and lymphopenia (7.9% each). CONCLUSIONS: FOLFOX-A has a significant response rate, expected toxicities, and should be considered for future investigation in combination with immunotherapy given the recent approvals.

Abiraterone, Olaparib, or Abiraterone + Olaparib in First-Line Metastatic Castration-Resistant Prostate Cancer with DNA Repair Defects (BRCAAway).

PURPOSE: Deleterious germline/somatic homologous recombination repair mutations (HRRm) are present in ∼25% of patients with metastatic castration-resistant prostate cancer (mCRPC). Preclinically, poly(ADP-ribose) polymerase (PARP) inhibition demonstrated synergism with androgen receptor pathway (ARP)-targeted therapy. This trial evaluated the efficacy of ARP inhibitor versus PARP inhibitor versus their combination as first-line therapy in patients with mCRPC with HRRms. PATIENTS AND METHODS: BRCAAway is a biomarker preselected, randomized, phase 2 trial. Patients with BRCA1/2 and/or ATM alterations were randomized 1:1:1 to Arm1: abiraterone (1,000 mg)/prednisone (5 mg BID) (Abi/pred), Arm2: olaparib (300 mg BID) (Ola), or Arm3: abiraterone/prednisone + olaparib (Abi/pred + Ola). Single-agent arms could cross over at progression. Exploratory Arm4 patients with other HRRms received olaparib alone. The primary endpoint was progression-free survival (PFS), and secondary endpoints were objective response, PSA response, and safety. RESULTS: Sixty-one of 165 eligible patients had BRCA1/2 or ATM mutations: median age: 67 (IQR, 62-73) years. Mutations: BRCA1 n = 3, BRCA2 n = 46, ATM n = 11, and multiple n = 1; 33 germline and 28 somatic mutations. Median PFS [95% confidence interval (CI)]: Abi/pred, 8.6 months (m; 2.9, 17), Ola, 14 m (8.4, 20), and Abi/pred + Ola, 39 m [22, not reached (NR)]. There were no G4/5 adverse events; 8/19 patients on Abi/pred treatment crossed over to Ola, and 8/21 vice versa. Median PFS (95% CI) from crossover: Ola-after-Abi/pred, 8.3 m (5.5, 15) and Abi/pred-after-Ola, 7.2 m (2.8, NR). Median PFS (95% CI) from randomization: Ola-after-Abi/pred, 16 m (7.8, 25) and Abi/pred-after-Ola, 16 m (11, NR). Seventeen of 165 patients with other HRRms received olaparib: median PFS (95% CI): 5.5 m (2, 11). CONCLUSIONS: In patients with mCRPC with BRCA1/2 or ATM HRRm, Abi/pred + Ola was well tolerated and demonstrated longer PFS versus either agent alone or sequentially.

A Phase II Trial of Bevacizumab in Patients with Recurrent/Progressive Solid Tumor Brain Metastases That Have Progressed Following Whole-Brain Radiation Therapy.

Patients with solid tumor brain metastases that progress after whole-brain radiation have limited options. This prospective trial investigated the efficacy, safety, and tolerability of bevacizumab as salvage therapy in this population. Eligible patients received bevacizumab 10 mg/kg intravenously every 2 weeks until progression. The primary endpoint was radiologic response using Response Assessment in Neuro-Oncology (RANO) criteria. The secondary endpoints were progression-free survival (PFS), overall survival (OS), duration of response, and safety. Quality of life (QOL) was studied using the Functional Assessment of Cancer Therapy-Brain (FACT-Br) scale. Twenty-seven patients were enrolled, with twenty-four having evaluable data for response. The majority of histologies (n = 21, 78%) were breast cancer. The remaining histologies were non-small-cell lung cancer (n = 4, 15%), neuroendocrine cancer (n = 1, 3%), and papillary fallopian serous adenocarcinoma (n = 1, 3%). Eighteen patients had radiologic response, with two patients demonstrating partial response (8.33%) and sixteen patients demonstrating stable disease (66.7%). The median duration of response was 203 days. PFS at 6 months was 46%, median PFS was 5.3 m, and median OS was 9.5 m. Treatment was well tolerated, with six patients experiencing grade 3 lymphopenia and hypertension. There was one grade 3 thromboembolism. QOL was not negatively impacted. Bevacizumab is a safe and feasible salvage treatment with durable response and favorable overall survival for patients with progressive brain metastases after whole-brain radiation.

Scalable Telehealth Cancer Care: integrated healthy lifestyle program to live well after cancer treatment.

Northwestern University's Center for Scalable Telehealth Cancer Care (STELLAR) is 1 of 4 Cancer Moonshot Telehealth Research Centers of Excellence programs funded by the National Cancer Institute to establish an evidence base for telehealth in cancer care. STELLAR is grounded in the Institute of Medicine's vision that quality cancer care includes not only disease treatment but also promotion of long-term health and quality of life (QOL). Cigarette smoking, insufficient physical activity, and overweight and obesity often co-occur and are associated with poorer treatment response, heightened recurrence risk, decreased longevity, diminished QOL, and increased treatment cost for many cancers. These risk behaviors are prevalent in cancer survivors, but their treatment is not routinely integrated into oncology care. STELLAR aims to foster patients' long-term health and QOL by designing, implementing, and sustaining a novel telehealth treatment program for multiple risk behaviors to be integrated into standard cancer care. Telehealth delivery is evidence-based for health behavior change treatment and is well suited to overcome access and workflow barriers that can otherwise impede treatment receipt. This paper describes STELLAR's 2-arm randomized parallel group pragmatic clinical trial comparing telehealth-delivered, coach-facilitated multiple risk behavior treatment vs self-guided usual care for the outcomes of reach, effectiveness, and cost among 3000 cancer survivors who have completed curative intent treatment. This paper also discusses several challenges encountered by the STELLAR investigative team and the adaptations developed to move the research forward.

A randomized Phase I pre-operative window trial of transdermal endoxifen in women planning mastectomy: Evaluation of dermal safety, intra-mammary drug distribution, and biologic effects.

Breast cancer prevention only requires local exposure of the breast to active drug. However, oral preventive agents entail systemic exposure, causing adverse effects that limit acceptance by high-risk women. Drug-delivery through the breast skin is an attractive option, but requires demonstration of dermal safety and drug distribution throughout the breast. We formulated the tamoxifen metabolite (E/Z)-endoxifen for transdermal delivery and tested it in a placebo-controlled, double-blinded Phase I trial with dose escalation from 10 to 20 mg daily. The primary endpoint was dermal toxicity. Thirty-two women planning mastectomy were randomized (2:1) to endoxifen-gel or placebo-gel applied to both breasts for 3-5 weeks. Both doses of endoxifen-gel incurred no dermal or systemic toxicity compared to placebo. All endoxifen-treated breasts contained the drug at each of five sampling locations; the median per-person tissue concentration in the treated participants was 0.6 ng/g (IQR 0.4-1.6), significantly higher (p < 0.001) than the median plasma concentration (0.2 ng/mL, IQR 0.2-0.2). The median ratio of the more potent (Z)-isomer to (E)-isomer at each breast location was 1.50 (IQR 0.96-2.54, p < 0.05). No discernible effects of breast size or adiposity on tissue concentrations were observed. At the endoxifen doses and duration used, and the tissue concentration achieved, we observed a non-significant overall reduction of tumor proliferation (Ki67 LI) and significant downregulation of gene signatures known to promote cancer invasion (FN1, SERPINH1, PLOD2, PDGFA, ITGAV) (p = 0.03). Transdermal endoxifen is an important potential breast cancer prevention agent but formulations with better dermal penetration are needed.

Circulating Tumor Cells Prediction in Hormone Receptor Positive HER2-Negative Advanced Breast Cancer: A Retrospective Analysis of the MONARCH 2 Trial.

BACKGROUND: The MONARCH 2 trial (NCT02107703) showed the efficacy of abemaciclib, a cyclin-dependent kinase 4 & 6 inhibitor (CDK4/6i), in combination with fulvestrant for hormone receptor-positive, HER2-negative metastatic breast cancer (MBC). The aim of this analysis was to explore the prediction of circulating tumor cells (CTCs) stratification using machine learning for hypothesis generation of biomarker-driven clinical trials. PATIENTS AND METHODS: Predicted CTCs were computed in the MONARCH 2 trial through a K nearest neighbor (KNN) classifier trained on a dataset comprising 2436 patients with MBC. Patients were categorized into predicted Stage IVaggressive (pStage IVaggressive, ≥5 predicted CTCs) or predicted Stage IVindolent (pStage IVindolent, <5 predicted CTCs). Prognosis was tested in terms of progression-free-survival (PFS) and overall survival (OS) through Cox regression. RESULTS: Patients classified as predicted pStage IVaggressive and predicted pStage Stage IVindolent were, respectively, 183 (28%) and 461 (72%). After multivariable Cox regression, predicted CTCs were confirmed as independently associated with prognosis in terms of OS, together with ECOG performance status, liver involvement, bone-only disease, and treatment arm. Patients in the pStage Stage IVindolent subgroup treated with abemaciclib experienced the best prognosis both in terms of PFS and OS. The treatment effect of abemaciclib on OS was then explored through subgroup analysis, showing a consistent benefit across all subgroups. CONCLUSION: This study is the first analysis of CTCs modeling for stage IV disease stratification. These results show the need to expand biomarker profiling in combination with CTCs stratification for improved biomarker-driven drug development.

Epidemiology and survival outcomes of HIV-associated cervical cancer in Nigeria.

INTRODUCTION: Invasive cervical cancer (ICC) is an HIV-associated cancer that is preventable and precancerous stages including early ICC stages could be detected through screening offering opportunities for treatment and cure. The high incidence in women living with HIV and late presentation often at advanced stages of ICC with limited treatment facilities often result in early mortality. We sought to compare the epidemiologic characteristics and survival differences in HIV status of ICC patients in Nigeria. METHODS: We conducted a cohort study at two federal academic hospital-based research sites in Jos University Teaching Hospital, and Lagos University Teaching Hospital Nigeria, between March 2018 and September 2022. We enrolled women with histologically confirmed ICC with known HIV status, and FIGO staging as part of the United States of America's National Institutes of Health/National Cancer Institute funded project titled 'Epigenomic Biomarkers of HIV-Associated Cancers in Nigeria'. The primary outcome was all-cause mortality with assessment of overall survival (OS) and time to death after ICC diagnosis. OS distribution was estimated using the method of Kaplan-Meier and compared between groups using the log-rank test. RESULTS: A total of 239 women with confirmed ICC were enrolled and included in this analysis, of whom 192 (80.3%) were HIV-negative (HIV-/ICC +), and 47 (19.7%) were HIV-positive (HIV +/ICC +). The HIV +/ICC + patients were younger with median age 46 (IQR: 40-51) years compared to 57 (IQR: 45-66) among HIV-/ICC + (P < 0.001). Squamous cell carcinoma was the commonest histopathologic variant in 80.4% of ICC diagnosis, moderately differentiated tumor grade in 68.1% in both groups. HIV +/ICC + diagnosis was at FIGO advanced stages in 64.9% compared to 47.9% in HIV-/ICC +. The HIV-/ICC + women had better OS compared to HIV +/ICC + participants (p = 0.018), with 12-month OS 84.1% (95%CI 75-90%) and 67.6% (95%CI 42-84%) respectively. CONCLUSION: ICC is diagnosed at a relatively young age in women living with HIV, with a significantly lower overall survival probability compared to women without HIV. The trend of presentation and diagnosis at advanced stages in women living with HIV could partly explain the differences in overall survival.

Financial hardship is associated with employment challenges and reduced quality of life in early Parkinson's disease.

Introduction: Motor and nonmotor Parkinson's disease (PD) symptoms can negatively influence employment, which may contribute to financial hardship. This article explores the association between financial hardship, employment challenges, and quality of life in people with early PD. Methods: We measured financial hardship with a validated summary item (5-point scale, lower score - less hardship) and the Comprehensive Score for Financial Toxicity (0-44, lower score worse toxicity) in a cohort of 60 employed individuals with early PD (<5 years). We used Spearman's Correlations and nonparametric tests to identify associations between financial hardship, demographic characteristics, PD-related factors, employment factors, and quality of life (Neuro-QOL computer adapted measures). Results: The sample was mostly white (93 %) and male (65 %). The plurality were highly-educated with graduate degrees (42 %). Of the 60 participants, 23 (38 %) reported a little bit and 14 (23 %) reported somewhat or more hardship. Comprehensive financial toxicity (22.0 ± 8.7) was correlated moderately (ρ = -0.56) with the single-item summary score. High financial hardship was associated with reduced confidence in job retention (ρ = -0.43, p = 0.001) and reduced perceived workplace success (ρ = -0.352, p = 0.006). Financial hardship was also associated with poorer quality of life in five Neuro-QOL domains: lower extremity function, satisfaction with social roles and activities, depression, anxiety, and stigma (p < 0.05). Conclusion: Financial hardship was common and was associated with employment challenges and poor quality of life. Further work should explore the effects of medical and psychosocial interventions to alleviate financial and employment challenges in individuals with early PD.

Presurgical Oral Tamoxifen vs Transdermal 4-Hydroxytamoxifen in Women With Ductal Carcinoma In Situ: A Randomized Clinical Trial.

Importance: Oral tamoxifen citrate benefits women with ductal carcinoma in situ (DCIS), but concern about toxic effects has limited acceptance. Previous pilot studies have suggested transdermal 4-hydroxytamoxifen gel has equivalent antiproliferative efficacy to oral tamoxifen, with low systemic exposure. Objective: To demonstrate that 4-hydroxytamoxifen gel applied to the breast skin is noninferior to oral tamoxifen in its antiproliferative effect in DCIS lesions. Design, Setting, and Participants: This randomized, double-blind, phase 2 preoperative window trial was performed at multicenter breast surgery referral practices from May 31, 2017, to January 27, 2021. Among 408 women with estrogen receptor-positive DCIS who were approached, 120 consented and 100 initiated study treatment. The most common reasons for nonparticipation were surgical delay, disinterest in research, and concerns about toxic effects. Data were analyzed from January 26, 2021, to October 5, 2022. Intervention: Random assignment to oral tamoxifen citrate, 20 mg/d, and gel placebo or 4-hydroxytamoxifen gel, 2 mg/d per breast, and oral placebo, for 4 to 10 weeks, followed by DCIS resection. Main Outcomes and Measures: The primary end point was absolute change in DCIS Ki-67 labeling index (Ki67-LI). Secondary end points included 12-gene DCIS Score, breast tissue tamoxifen metabolite concentrations, tamoxifen-responsive plasma protein levels, and patient-reported symptoms. Noninferiority of Ki67-LI reduction by 4-hydroxytamoxifen gel was tested using analysis of covariance; within- and between-arm comparisons were performed with paired t tests for mean values or the Wilcoxon rank sum test for medians. Results: Of 90 participants completing treatment (mean [SD] age, 55 [11] years; 8 [8.9%] Asian, 16 [17.8%] Black, 8 [8.9%] Latina, and 53 [58.9%] White), 15 lacked residual DCIS in the surgical sample, leaving 75 evaluable for the primary end point analysis (40 in the oral tamoxifen group and 35 in the 4-hydroxytamoxifen gel group). Posttreatment Ki67-LI was 3.3% higher (80% CI, 2.1%-4.6%) in the 4-hydroxytamoxifen gel group compared with the oral tamoxifen group, exceeding the noninferiority margin (2.6%). The DCIS Score decreased more with oral tamoxifen treatment (-16 [95% CI, -22 to -9.4]) than with 4-hydroxytamoxifen gel (-1.8 [95% CI, -5.8 to 2.3]). The median 4-hydroxytamoxifen concentrations deep in the breast were nonsignificantly higher in the oral tamoxifen group (5.7 [IQR, 4.0-7.9] vs 3.8 [IQR, 1.3-7.9] ng/g), whereas endoxifen was abundant in the oral tamoxifen group and minimal in the 4-hydroxytamoxifen gel group (median, 13.0 [IQR, 8.9-20.6] vs 0.3 [IQR, 0-0.3] ng/g; P < .001). Oral tamoxifen caused expected adverse changes in plasma protein levels and vasomotor symptoms, with minimal changes in the transdermal group. Conclusions and Relevance: In this randomized clinical trial, antiproliferative noninferiority of 4-hydroxytamoxifen gel to oral tamoxifen was not confirmed, potentially owing to endoxifen exposure differences. New transdermal approaches must deliver higher drug quantities and/or include the most potent metabolites. Trial Registration: ClinicalTrials.gov Identifier: NCT02993159.

Phase Ib trial of inhaled iloprost for the prevention of lung cancer with predictive and response biomarker assessment.

Introduction: Iloprost, a prostacyclin analog, has lung cancerpreventive activity in preclinical models and improved dysplasia in former smokers in a phase IIb trial. Oral iloprost is currently unavailable. We performed a phase Ib trial of inhaled iloprost in former smokers to assess tolerance and compliance. Methods: Participants self-administered nebulized iloprost (5ug) or placebo four (QID) or two (BID) times daily. As QID dose was well tolerated and due to expiration of the placebo, the BID dosing and placebo were eliminated early on in the trial. Bronchoscopy with biopsyat six standard sites was performed at treatment initiation and two months post-iloprost, with exploratory histological analysis. Bulk RNA sequencing, single cell RNA sequencing and an in vitro assay of epithelial progenitor cell iloprost response were performed on a subset of biopsies in an exploratory investigation of response mechanisms and predictive biomarkers. Results and discussion: Thirty-four of a planned 48 participants were recruited to the trial.Inhaled iloprost was well tolerated with no adverse events > grade 2. Compliance was 67% in the QID group. The trial was not powered to detect histologic response and none was found. Bulk RNA sequencing of biopsies pre/post iloprost suggest that iloprost is immunomodulatory and downregulates cell proliferation pathways. Single cell RNA sequencing showed an increase in CD8-positive T cells with upregulation of genes in interferon γ signaling. In vitro iloprost response by epithelial progenitor cells correlated with histologic response with kappa coefficient of 0.81 (95% CI 0.47, 1.0). Inhaled iloprost was well tolerated with suboptimal compliance. Molecular analysis suggested that iloprosthas immunomodulatory and antiproliferative effects.The progenitor cell iloprost response assay may be a promising avenue to develop predictive biomarkers. Clinical trial registration: https://clinicaltrials.gov/study/NCT02237183, identifier NCT02237183.

Epidemiology and Survival outcomes of HIV-associated cervical cancer in Nigeria.

Introduction: Invasive cervical cancer (ICC) is an HIV-associated cancer that is preventable and precancerous stages including early ICC stages could be detected through screening offering opportunities for treatment and cure. The high incidence in women living with HIV and late presentation often at advanced stages of ICC with limited treatment facilities often result in early mortality. We sought to compare the epidemiologic characteristics and survival differences in HIV status of ICC patients in Nigeria. Methods: We conducted a cohort study at two federal academic hospital-based research sites in Jos University Teaching Hospital, and Lagos University Teaching Hospital Nigeria, between March 2018 and September 2022. We enrolled women with histologically confirmed ICC with known HIV status, and FIGO staging as part of the United States of America's National Institutes of Health/National Cancer Institute funded project titled 'Epigenomic Biomarkers of HIV-Associated Cancers in Nigeria'. The primary outcome was all-cause mortality with assessment of overall survival (OS) and time to death after ICC diagnosis. OS distribution was estimated using the method of Kaplan-Meier and compared between groups using the log-rank test. Results: A total of 239 women with confirmed ICC were enrolled and included in this analysis, of whom 192 (80.3%) were HIV-negative (HIV-/ICC+), and 47 (19.7%) were HIV-positive (HIV+/ICC+). The HIV+/ICC) patients were younger with median age 46 (IQR: 40-51) years compared to 57 (IQR: 45-66) among HIV-/ICC+) (P<0.001. Squamous cell carcinoma was the commonest histopathologic variant in 80.4% of ICC diagnosis, moderately differentiated tumor grade in 68.1% in both groups. HIV+/ICC+ diagnosis was at FIGO advanced stages in 64.9% compared to 47.9% in HIV-/ICC+. The HIV-/ICC+ women had better OS compared to HIV+/ICC+ participants (p=0.018), with 12-month OS 84.1% (95%CI: 75% - 90%) and 67.6% (95%CI: 42%-84%) respectively. Conclusion: ICC is diagnosed at a relatively young age in women living with HIV, with a significantly lower overall survival probability compared to women without HIV. The trend of presentation and diagnosis at advanced stages in women living with HIV could partly explain the differences in overall survival.

Integrated Multi-Omic Analysis Reveals Immunosuppressive Phenotype Associated with Poor Outcomes in High-Grade Serous Ovarian Cancer.

High-grade serous ovarian cancer (HGSOC) is characterized by a complex genomic landscape, with both genetic and epigenetic diversity contributing to its pathogenesis, disease course, and response to treatment. To better understand the association between genomic features and response to treatment among 370 patients with newly diagnosed HGSOC, we utilized multi-omic data and semi-biased clustering of HGSOC specimens profiled by TCGA. A Cox regression model was deployed to select model input features based on the influence on disease recurrence. Among the features most significantly correlated with recurrence were the promotor-associated probes for the NFRKB and DPT genes and the TREML1 gene. Using 1467 transcriptomic and methylomic features as input to consensus clustering, we identified four distinct tumor clusters-three of which had noteworthy differences in treatment response and time to disease recurrence. Each cluster had unique divergence in differential analyses and distinctly enriched pathways therein. Differences in predicted stromal and immune cell-type composition were also observed, with an immune-suppressive phenotype specific to one cluster, which associated with short time to disease recurrence. Our model features were additionally used as a neural network input layer to validate the previously defined clusters with high prediction accuracy (91.3%). Overall, our approach highlights an integrated data utilization workflow from tumor-derived samples, which can be used to uncover novel drivers of clinical outcomes.

Racial and ethnic disparities in surgery for kidney cancer: a SEER analysis, 2007-2014.

BACKGROUND AND OBJECTIVES: Compared with White patients, Black and American Indian/Alaskan Native (AI/AN) patients experience higher rates of kidney cancer incidence, and Black, AI/AN, and Hispanic patients face later stages of disease at diagnosis, poorer survival rates, and greater risk of mortality. Despite the importance that appropriate treatment has in ensuring positive outcomes, little is known about the association between race and ethnicity and receipt of treatment for kidney cancer. Accordingly, the aim of this study was to explore differences in receipt of treatment and patterns of refusal of recommended treatment by race and ethnicity. DESIGN: 96,745 patients ages 45-84 with kidney cancer were identified in the Surveillance, Epidemiology, and End Results (SEER) program between 2007 and 2014. Logistic regression models were used to examine the association of race and ethnicity with treatment and with patient refusal of recommended treatment. Outcomes of interest were (1) receiving any surgical procedure, and (2) refusing recommended surgery. RESULTS: Relative to White patients, Black and AI/AN patients had lower odds of undergoing any surgical procedure (OR = 0.76; 95% CI: 0.72-0.81; p < 0.001, and OR = 0.92; 95% CI: 0.76-1.10; p = 0.36, respectively) after adjusting for gender, age, insurance status, stage at diagnosis, unemployment status, education status, and income as additive effects. Black and AI/AN patients also had higher odds of refusing recommended surgery (OR = 1.93; 95% CI: 1.56-2.39; p < 0.001, and OR = 1.99; 95% CI: 1.05-3.76; p = 0.035, respectively). Hispanic patients had slightly higher odds of undergoing any surgical procedure (OR = 1.10; 95% CI: 1.04-1.17; p = 0.001) and lower odds of refusal (OR = 0.67; 95% CI: 0.50-0.90; p = 0.007, respectively). CONCLUSIONS: Compared with White patients, Black patients were less likely to receive potentially life-saving surgery, and both Black and AI/AN patients were more likely to refuse recommended surgery.

Development of a Remote Version of the Graded Redefined Assessment of Strength, Sensation, and Prehension (GRASSP): Validity and Reliability.

BACKGROUND: The Graded Redefined Assessment of Strength, Sensation, and Prehension (GRASSP V1.0) was developed in 2010 as a 3-domain assessment for upper extremity function after tetraplegia (domains: Strength, Sensibility, and Prehension). A remote version (rGRASSP) was created in response to the growing needs of the field of Telemedicine. OBJECTIVE: The purpose of this study was to assess the psychometric properties of rGRASSP, establishing concurrent validity and inter-rater reliability. METHODS: Individuals with tetraplegia (n = 61) completed 2 visits: 1 in-person and 1 remote. The first visit was completed in-person to administer the GRASSP, and the second visit was conducted remotely to administer the rGRASSP. The rGRASSP was scored both by the administrator of the rGRASSP (Examiner 1), and a second assessor (Examiner 2) to establish inter-rater reliability. Agreement between the in-person and remote GRASSP evaluations was assessed using the intraclass correlation coefficient (ICC) and Bland-Altman agreement plots. RESULTS: The remote GRASSP demonstrated excellent concurrent validity with the GRASSP (left hand intraclass correlation coefficient (ICC) = .96, right ICC = .96). Concurrent validity for the domains was excellent for strength (left ICC = .96, right ICC = .95), prehension ability (left ICC = .94, right ICC = .95), and prehension performance (left ICC = .92, right ICC = .93), and moderate for sensibility (left ICC = .59, right ICC = .68). Inter-rater reliability for rGRASSP total score was high (ICC = .99), and remained high for all 4 domains. Bland-Altman plots and limits of agreements support these findings. CONCLUSIONS: The rGRASSP shows strong concurrent validity and inter-rater reliability, providing a psychometrically sound remote assessment for the upper extremity in individuals with tetraplegia.

Targeting ULK1 Decreases IFNγ-Mediated Resistance to Immune Checkpoint Inhibitors.

Immune checkpoint inhibitors (ICI) have transformed the treatment of melanoma. However, the majority of patients have primary or acquired resistance to ICIs, limiting durable responses and patient survival. IFNγ signaling and the expression of IFNγ-stimulated genes correlate with either response or resistance to ICIs, in a context-dependent manner. While IFNγ-inducible immunostimulatory genes are required for response to ICIs, chronic IFNγ signaling induces the expression of immunosuppressive genes, promoting resistance to these therapies. Here, we show that high levels of Unc-51 like kinase 1 (ULK1) correlate with poor survival in patients with melanoma and overexpression of ULK1 in melanoma cells enhances IFNγ-induced expression of immunosuppressive genes, with minimal effects on the expression of immunostimulatory genes. In contrast, genetic or pharmacologic inhibition of ULK1 reduces expression of IFNγ-induced immunosuppressive genes. ULK1 binds IRF1 in the nuclear compartment of melanoma cells, controlling its binding to the programmed death-ligand 1 promoter region. In addition, pharmacologic inhibition of ULK1 in combination with anti-programmed cell death protein 1 therapy further reduces melanoma tumor growth in vivo. Our data suggest that targeting ULK1 represses IFNγ-dependent immunosuppression. These findings support the combination of ULK1 drug-targeted inhibition with ICIs for the treatment of patients with melanoma to improve response rates and patient outcomes. IMPLICATIONS: This study identifies ULK1, activated downstream of IFNγ signaling, as a druggable target to overcome resistance mechanisms to ICI therapy in metastatic melanoma.

Resource and Reimbursement Barriers to Comprehensive Cancer Care Delivery: An Analysis of Association of Community Cancer Centers Survey Data.

PURPOSE: Comprehensive cancer care (CCC) delivery is recommended in guidelines and considered essential for high-quality cancer management. Barriers, such as insufficient reimbursement, prevent consistent access to and delivery of CCC. Association of Community Cancer Centers conducted a national survey to elucidate capacity and barriers to CCC delivery to inform policy and value-based payment reform. METHODS: Survey methodology included item generation with expert review, iterative piloting, and cognitive validity testing. In the final instrument, 27 supportive oncology services were assessed for availability, reasons not offered, and coverage/reimbursement. RESULTS: 204 of 704 member programs completed survey questions. Despite most services being reported as offered, a minority were funded through insurance reimbursement. The services least likely to obtain reimbursement were those that address practical and family/childcare needs (0.7%), caregiver support (1.5%), advanced care directives (1.7%), spiritual services (1.8%), and navigation (2.7%). These findings did not vary by region or practice type. CONCLUSION: There is a lack of sufficient reimbursement, staffing, and budget to provide CCC across the United States. Care models and reimbursement policies must include CCC services to optimize delivery of cancer care.

Telemedicine Use Among Physiatrists During the Early Phase of the COVID-19 Pandemic and Potential for Future Use.

Introduction: With the coronavirus disease 2019 (COVID-19) pandemic causing the need for social distancing, telemedicine saw a significant increase in use to provide routine medical care. As a field, physiatry had already been implementing telemedicine prior to the pandemic. In this study, we characterized the use of telemedicine among physiatrists during the early phase of the COVID-19 pandemic to understand the barriers and facilitators to implementing telemedicine use in the field of physiatry in the future. Methods: Online survey of a cross-sectional sample of physiatrists. Analysis was conducted using logistic regression. Results: One hundred seventy one (n = 171) participants completed the survey. Before the pandemic, only 17.5% of respondents used telemedicine. In the logistic regression, physicians who used a hospital-provided platform were more likely to use telemedicine in the future compared with those who used their own secure platform, conducted a phone visit, and used a non-secure platform or other platforms. The three most popular barriers identified were "inability to complete the physical examination," "patients lack of access to technology," and "patients lack of familiarity with the technology." Discussion: Focus on education on telemedicine functional examination strategies and technology strategies for patients and providers (including addressing the digital divide and hospital-provided secure platforms) are potential targets of implementation strategies for greater telemedicine uptake for physiatrists in the future.

Identification and Characterization of a Novel Indoleamine 2,3-Dioxygenase 1 Protein Degrader for Glioblastoma.

Indoleamine 2,3-dioxygenase 1 (IDO1) is a potent immunosuppressive enzyme that inhibits the antitumor immune response through both tryptophan metabolism and non-enzymatic functions. To date, most IDO1-targeted approaches have focused on inhibiting tryptophan metabolism. However, this class of drugs has failed to improve the overall survival of patients with cancer. Here, we developed and characterized proteolysis targeting chimeras (PROTACs) that degrade the IDO1 protein. IDO1-PROTACs were tested for their effects on IDO1 enzyme and non-enzyme activities. After screening a library of IDO1-PROTAC derivatives, a compound was identified that potently degraded the IDO1 protein through cereblon-mediated proteasomal degradation. The IDO1-PROTAC: (i) inhibited IDO1 enzyme activity and IDO1-mediated NF-κB phosphorylation in cultured human glioblastoma (GBM) cells, (ii) degraded the IDO1 protein within intracranial brain tumors in vivo, and (iii) mediated a survival benefit in mice with well-established brain tumors. This study identified and characterized a new IDO1 protein degrader with therapeutic potential for patients with glioblastoma.

Clinical and Biological Activity of Chemoimmunotherapy in Advanced Endometrial Adenocarcinoma: A Phase II Trial of the Big Ten Cancer Research Consortium.

Purpose: The objective of this study was to assess the efficacy and safety of pembrolizumab in combination with standard carboplatin/paclitaxel in patients with advanced endometrial cancer (EC). Patients and Methods: This single-arm, open-label, multi-center phase II study enrolled patients with RECIST measurable advanced EC. Patients could have received < 1 prior platinum-based regimen and < one non-platinum chemotherapy. The primary endpoint was objective response rate (ORR). Planned sample size of 46 subjects provided 80% power to detect 15% ORR improvement compared to historical control rate of 50%. Results: 46 patients were enrolled, and 43 were evaluable for ORR. Median age was 66 (range: 43-86). Thirty-four (73.9%) patients had recurrent and 12 (26.1%) primary metastatic EC. Patients received carboplatin AUC 6, paclitaxel 175mg/m2 and pembrolizumab 200mg IV every 3 weeks for up to 6 cycles. ORR was 74.4% (32/43), higher than historic controls (p = 0.001). Median PFS was 10.6 months (95% CI 8.3-13.9 months). The most common grade 1-2 treatment related adverse event (TRAEs) included anemia (56.5%), alopecia (47.8%), fatigue (47.8%) and neuropathy (13%), while the most common grade 3-4 TRAEs were lymphopenia, leukopenia, and anemia (19.6% each). High-dimensional spectral flow cytometry (CyTEK) identified enrichment in peripheral CD8+ and CD4+ T cell populations at baseline in responders. The CD8+ T cell compartment in responders exhibited greater expression levels of PD-1 and PD-L1 and higher abundance of effector memory CD8+ cells compared to non-responders. Conclusions: Addition of pembrolizumab to carboplatin and paclitaxel for advanced EC was tolerated and improved ORR compared to historical outcomes.