Treatment with therapeutic anticoagulation is not associated with immunotherapy response in advanced cancer patients.

BACKGROUND: Recent preclinical data suggest that there may be therapeutic synergy between immune checkpoint blockade and inhibition of the coagulation cascade. Here, we investigate whether patients who received immune checkpoint inhibitors (ICI) and were on concomitant anticoagulation (AC) experienced better treatment outcomes than individuals not on AC.Affiliation: Kindly confirm if corresponding authors affiliation is identified correctly.The corresponding author's affiliation is correct. METHODS: We studied a cohort of 728 advanced cancer patients who received 948 lines of ICI at NYU (2010-2020). Patients were classified based on whether they did (n = 120) or did not (n = 828) receive therapeutic AC at any point during their treatment with ICI. We investigated the relationship between AC status and multiple clinical endpoints including best overall response (BOR), objective response rate (ORR), disease control rate (DCR), progression free survival (PFS), overall survival (OS), and the incidence of bleeding complications.Affiliations: Journal instruction requires a country for affiliations; however, this is missing in affiliations 1 to 5. Please verify if the provided country is correct and amend if necessary.The country is correct for all affiliations (1 - 5). RESULTS: Treatment with AC was not associated with significantly different BOR (P = 0.80), ORR (P =0.60), DCR (P =0.77), PFS (P = 0.59), or OS (P =0.64). Patients who received AC were significantly more likely to suffer a major or clinically relevant minor bleed (P = 0.05). CONCLUSION: AC does not appear to impact the activity or efficacy of ICI in advanced cancer patients. On the basis of our findings, we caution that there is insufficient evidence to support prospectively evaluating the combination of AC and immunotherapy.

The ongoing racial disparities in melanoma: An analysis of the Surveillance, Epidemiology, and End Results database (1975-2016).

BACKGROUND: Although most patients with cutaneous melanoma are non-Hispanic whites (NHWs), minorities consistently suffer worse melanoma-specific survival (MSS). Much of the literature comes from analyses of registries from the 1990s and 2000s. OBJECTIVE: We sought to evaluate whether and to what degree racial disparity in MSS persists since 2010. METHODS: We analyzed 381,035 patients from the Surveillance, Epidemiology, and End Results registry. Race categories included Hispanic, NHW, non-Hispanic black (NHB), non-Hispanic Asian or Pacific Islander (NHAPI), and non-Hispanic American Indian/Alaska Native (NHAIAN). We evaluated the association between MSS and race in 3 time periods: before the year 2000, 2000 to 2009, and 2010 or later. NHW was the reference group for all analyses. RESULTS: Racial disparity worsened from before the year 2000 to 2010 or later for Hispanic (P < .001), NHB (P = .024), and NHAPI (P < .001) patients. Across all minority groups, patients with localized disease suffered increasing disparity (P = .010 for Hispanic, P < .001 for NHB, P = .023 for NHAPI, and P = .042 for NHAIAN patients). Among those with regional and distant disease, Hispanic patients were the only minority to experience worsening disparity (P = .001 and P = .019, respectively). LIMITATIONS: Lack of immunotherapy and targeted treatment information. CONCLUSIONS: Racial disparity in MSS is worsening. Improving postdiagnosis management for minorities with localized disease is imperative to mitigate disparity and improve survival.

Management of Melanoma during Pregnancy: A Case Series of 11 Women Treated at NYU Langone Health.

OBJECTIVES: Melanoma is one of the most common malignancies diagnosed during pregnancy. This study examined the impact of pregnancy on management decisions of melanoma patients treated at NYU Langone Health (NYULH). METHODS: We analyzed data for patients who were pregnant at initial or recurrent melanoma diagnosis at NYULH from 2012 to 2019 with prospective protocol-driven follow-up. RESULTS: Of the 900 female patients accrued during this period, 11 women in the childbearing range were pregnant at melanoma diagnosis. Six patients presented with early (stage 0 or I) disease and five with advanced (stage III or IV) melanoma. Women with early stage disease had normal deliveries and minimal changes to their treatment timeline and regimen. However, patients with more advanced stage disease opted for either termination of the pregnancy or early delivery and altered treatment timelines because of pregnancy. CONCLUSION: Both melanoma stage and gestational age at diagnosis contribute to the differences in the therapeutic management of melanoma in pregnant women. Given the complexity and variety of each case of melanoma during pregnancy, informed discussion between patients and physicians allows for individualized treatment plans that address each patient's unique situation.

HDAC5 enhances IRF3 activation and is targeted for degradation by protein C6 from orthopoxviruses including Monkeypox virus and Variola virus.

Histone deacetylases (HDACs) regulate gene expression and innate immunity. Previously, we showed that HDAC5 is degraded during Vaccinia virus (VACV) infection and is a restriction factor for VACV and herpes simplex virus type 1. Here, we report that HDAC5 promotes interferon regulatory factor 3 (IRF3) activation downstream of Toll-IL-1 receptor (TIR) domain-containing adaptor molecule-1 or Sendai virus-mediated stimulation without requiring HDAC activity. Loss of HDAC5-mediated IRF3 activation is restored by re-introduction of HDAC5 but not HDAC1 or HDAC4. The antiviral activity of HDAC5 is antagonized by VACV protein C6 and orthologs from the orthopoxviruses cowpox, rabbitpox, camelpox, monkeypox, and variola. Infection by many of these viruses induces proteasomal degradation of HDAC5, and expression of C6 alone can induce HDAC5 degradation. Mechanistically, C6 binds to the dimerization domain of HDAC5 and prevents homodimerization and heterodimerization with HDAC4. Overall, this study describes HDAC5 as a positive regulator of IRF3 activation and provides mechanistic insight into how the poxviral protein C6 binds to HDAC5 to antagonize its function.

Teaching Future Teachers: Development of a Students-as-Teachers Advanced Elective for Post-Clerkship Medical Students.

Although teaching is an essential part of Graduate Medical Education and the practice of medicine, it is not often formally taught in Undergraduate Medical Education. Vanderbilt University School of Medicine (VUSM) has addressed this gap by creating a year-long Students-as-Teachers elective for post-clerkship medical students. The elective utilizes diverse activities to emphasize core tenets of medical education theory while simultaneously providing authentic teaching opportunities. The success of the elective is primarily attributable to its structure and design, the collaborative and supportive medical education environment, and student initiative and engagement. This manuscript describes the implementation and outcomes of the Students-as-Teachers elective.

Clinical outcomes in cancer patients with COVID-19.

BACKGROUND: Early reports on cancer patients with coronavirus disease 2019 (COVID-19) corroborated speculation that cancer patients are at increased risk for becoming infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and developing severe COVID-19. However, cancer patients are a heterogeneous population and their corresponding risk may be different. AIM: To compare COVID-19 presentation in patients with active malignancy to those with a history of cancer to determine the impact of cancer status on COVID-19 outcomes in the two groups. METHODS AND RESULTS: Of the 6724 patients who were hospitalized at NYU Langone Health (3/16/20-7/31/20) and tested positive for SARS-CoV-2, 580 had either active cancer (n = 221) or a history of cancer (n = 359). We compared the baseline clinicodemographic characteristics and hospital courses of the two groups. We studied the relationship between cancer status and the rate of admission to the intensive care unit (ICU), use of invasive mechanical ventilation (IMV), and all-cause mortality. The two groups had similar laboratory results associated with COVID-19 infection, incidence of venous thromboembolism, and incidence of severe COVID-19. Active cancer status was not associated with the rate of ICU admission (p = .307) or use of IMV (p = .236), but was significantly associated with worse all-cause mortality in both univariate and multivariate analysis with odds ratios of 1.48 (95% confidence interval [CI]: 1.04-2.09; p = .028) and 1.71 (95% CI: 1.12-2.63; p = .014), respectively. CONCLUSION: Active cancer patients had worse survival outcomes compared to patients with a history of cancer despite similar COVID-19 disease characteristics in the two groups. Our data suggest that cancer care should continue with minimal interruptions during the pandemic to bring about response and remission as soon as possible.

Chronic Immune-Related Adverse Events Following Adjuvant Anti-PD-1 Therapy for High-risk Resected Melanoma.

Importance: Agents targeting programmed cell death 1 (PD-1)/PD ligand 1 (PD-L1) improve long-term survival across many advanced cancers and are now used as adjuvant therapy for resected stage III and IV melanomas. The incidence and spectrum of chronic immune-related adverse events (irAEs) have not been well defined. Objective: To determine the incidence, time course, spectrum, and associations of chronic irAEs arising from adjuvant anti-PD-1 therapy. Design, Setting, and Participants: This retrospective multicenter cohort study was conducted between 2015 and 2020 across 8 academic medical centers in the United States and Australia. Patients with stage III to IV melanomas treated with anti-PD-1 in the adjuvant setting were included. Main Outcomes and Measures: Incidence, types, and time course of chronic irAEs (defined as irAEs persisting at least 12 weeks after therapy cessation). Results: Among 387 patients, the median (range) age was 63 (17-88) years, and 235 (60.7%) were male. Of these patients, 267 (69.0%) had any acute irAE, defined as those arising during treatment with anti-PD-1, including 52 (19.5%) with grades 3 through 5 events; 1 patient each had fatal myocarditis and neurotoxicity. Chronic irAEs, defined as those that persisted beyond 12 weeks of anti-PD-1 discontinuation, developed in 167 (43.2%) patients, of which most (n = 161; 96.4%) were mild (grade 1 or 2) and most persisted until last available follow-up (n = 143; 85.6%). Endocrinopathies (73 of 88; 83.0%), arthritis (22 of 45; 48.9%), xerostomia (9 of 17; 52.9%), neurotoxicities (11 of 15; 73.3%), and ocular events (5 of 8; 62.5%) were particularly likely to become chronic. In contrast, irAEs affecting visceral organs (liver, colon, lungs, kidneys) had much lower rates of becoming chronic irAEs; for example, colitis became chronic in 6 of 44 (13.6%) cases, of which 4 of 6 (66.7%) resolved with prolonged follow-up. Age, gender, time of onset, and need for steroids were not associated with the likelihood of chronicity of irAEs. Conclusion and Relevance: In this multicenter cohort study, chronic irAEs associated with anti-PD-1 therapy appear to be more common than previously recognized and frequently persisted even with prolonged follow-up, although most were low grade. The risks of chronic irAEs should be integrated into treatment decision-making.

Baseline prognostic nutritional index and changes in pretreatment body mass index associate with immunotherapy response in patients with advanced cancer.

BACKGROUND: Recent research suggests that baseline body mass index (BMI) is associated with response to immunotherapy. In this study, we test the hypothesis that worsening nutritional status prior to the start of immunotherapy, rather than baseline BMI, negatively impacts immunotherapy response. METHODS: We studied 629 patients with advanced cancer who received immune checkpoint blockade at New York University. Patients had melanoma (n=268), lung cancer (n=128) or other primary malignancies (n=233). We tested the association between BMI changes prior to the start of treatment, baseline prognostic nutritional index (PNI), baseline BMI category and multiple clinical end points including best overall response (BOR), objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS) and overall survival (OS). RESULTS: Decreasing pretreatment BMI and low PNI were associated with worse BOR (p=0.04 and p=0.0004), ORR (p=0.01 and p=0.0005), DCR (p=0.01 and p<0.0001), PFS (p=0.02 and p=0.01) and OS (p<0.001 and p<0.001). Baseline BMI category was not significantly associated with any treatment outcomes. CONCLUSION: Standard of care measures of worsening nutritional status more accurately associate with immunotherapy outcomes than static measurements of BMI. Future studies should focus on determining whether optimizing pretreatment nutritional status, a modifiable variable, leads to improvement in immunotherapy response.