Safety of First-Line Nivolumab Plus Ipilimumab in Patients With Metastatic NSCLC: A Pooled Analysis of CheckMate 227, CheckMate 568, and CheckMate 817.

Introduction: We characterized the safety of first-line nivolumab plus ipilimumab (NIVO+IPI) in a large patient population with metastatic NSCLC and efficacy outcomes after NIVO+IPI discontinuation owing to treatment-related adverse events (TRAEs).

Methods: We pooled data from three first-line NIVO+IPI studies (NIVO, 3 mg/kg or 240 mg every 2 wk; IPI, 1 mg/kg every 6 wk) in metastatic NSCLC (CheckMate 227 part 1, CheckMate 817 cohort A, CheckMate 568 part 1). Safety end points included TRAEs and immune-mediated adverse events (IMAEs) in the pooled population and patients aged 75 years or older.

Tailored text message and web intervention for smoking cessation in U.S. socioeconomically-disadvantaged young adults: A randomized controlled trial.

The prevalence of cigarette smoking in young adults is higher among those with socioeconomic disadvantage than those without. Low treatment-seeking among young adult smokers is compounded by few efficacious smoking cessation interventions for this group, particularly socioeconomically-disadvantaged young adults (SDYA) who smoke cigarettes. The goal of this study was to test a tailored smoking-cessation intervention for SDYA.

Lurbinectedin Inhibits the EWS-WT1 Transcription Factor in Desmoplastic Small Round Cell Tumor.

Desmoplastic small round cell tumor (DSRCT) is a rare pediatric sarcoma with poor overall survival. This tumor is absolutely dependent on the continued expression and activity of its defining molecular lesion, the EWS-WT1 transcription factor. Unfortunately, the therapeutic targeting of transcription factors is challenging, and there is a critical need to identify compounds that inhibit EWS-WT1.

National Cancer Database trends in surgical resection of the breast primary for stage IV breast cancer.

Background: Survival benefit after resection of the breast primary for women with metastatic breast cancer reported in retrospective studies has not been uniformly confirmed by randomized controlled trials. To assess the need for dissemination of trial results by the ACS Cancer Research Program Dissemination and Implementation (ACS CRP D&I) committee, we analyzed trends and predictors of surgery and other therapies for stage IV breast cancer.

Methods: The National Cancer Database (NCDB) was queried to identify women diagnosed with clinical stage IV breast cancer of ductal, lobular, or metaplastic histology between 2004 and 2017.

Targeting CAR and Nrf2 improves cyclophosphamide bioactivation while reducing doxorubicin-induced cardiotoxicity in triple-negative breast cancer treatment.

Cyclophosphamide (CPA) and doxorubicin (DOX) are key components of chemotherapy for triple-negative breast cancer (TNBC), although suboptimal outcomes are commonly associated with drug resistance and/or intolerable side effects. Through an approach combining high-throughput screening and chemical modification, we developed CN06 as a dual activator of the constitutive androstane receptor (CAR) and nuclear factor erythroid 2-related factor 2 (Nrf2). CN06 enhances CAR-induced bioactivation of CPA (a prodrug) by provoking hepatic expression of CYP2B6, while repressing DOX-induced cytotoxicity in cardiomyocytes in vitro via stimulating Nrf2-antioxidant signaling.

Converting Tumoral PD-L1 into a 4-1BB Agonist for Safer and More Effective Cancer Immunotherapy.

Dose-limiting toxicities are thought to temper the efficacy of single-agent 4-1BB agonists. To overcome this hurdle, in this issue of Cancer Discovery, Muik and colleagues report preclinical and clinical studies describing a first-in-class bispecific fusion protein targeting 4-1BB and PD-L1. See related article by Muik et al.

Human constitutive androstane receptor represses liver cancer development and hepatoma cell proliferation by inhibiting erythropoietin signaling.

The constitutive androstane receptor (CAR) is a nuclear receptor that plays a crucial role in regulating xenobiotic metabolism and detoxification, energy homeostasis, and cell proliferation by modulating the transcription of numerous target genes. CAR activation has been established as the mode of action by which phenobarbital-like nongenotoxic carcinogens promote liver tumor formation in rodents. This paradigm, however, appears to be unrelated to the function of human CAR (hCAR) in hepatocellular carcinoma (HCC), which remains poorly understood.

Self-reported symptoms among cancer survivors in the Women's Health Initiative (WHI) Life and Longevity after Cancer (LILAC) cohort.

Purpose: Due to cancer survivors living longer and morbidity associated with cancer treatments, it is necessary to understand symptoms experienced by cancer survivors. This study will analyze the symptom burden among a large cohort of survivors across multiple cancer sites.

Methods: Data from the Women's Health Initiative (WHI) Life and Longevity After Cancer (LILAC) study were used to examine the symptom burden of older cancer survivors.

Impact of an Embedded Palliative Care Clinic on Healthcare Utilization for Patients With a New Thoracic Malignancy.

Introduction: Palliative care is beneficial for patients with advanced lung cancer, but the optimal model of palliative care delivery is unknown. We investigated healthcare utilization before and after embedding a palliative care physician within a thoracic medical oncology "onco-pall" clinic.

Methods: This is a retrospective cross-sectional cohort study comparing healthcare outcomes in two cohorts: "pre-cohort" 12 months prior to and "post-cohort" 12-months after the onco-pall clinic start date.

Phase I Trial Characterizing the Pharmacokinetic Profile of N-803, a Chimeric IL-15 Superagonist, in Healthy Volunteers.

The oncotherapeutic promise of IL-15, a potent immunostimulant, is limited by a short serum The fusion protein N-803 is a chimeric IL-15 superagonist that has a >20-fold longer in vivo versus IL-15. This phase 1 study characterized the pharmacokinetic (PK) profile and safety of N-803 after s.c.

Clinical Effectiveness and Safety of Anti-PD-(L)1 Therapy Among Older Adults With Advanced Non-Small Cell Lung Cancer.

Introduction: As a result of the approval of several immune checkpoint inhibitors (ICIs) for the treatment of non-small cell lung cancer (NSCLC), many older adults are being treated with ICIs. Older adults are underrepresented in most pharmaceutical clinical trials. Therapy outcomes in this population with ICIs is particularly important since, age related factors may have an influence on the immune system.

An international analysis evaluating frontline bendamustine with rituximab in extranodal marginal zone lymphoma.

Extranodal marginal zone lymphoma (EMZL) is a heterogeneous non-Hodgkin lymphoma. No consensus exists regarding the standard-of-care in patients with advanced-stage disease. Current recommendations are largely adapted from follicular lymphoma, for which bendamustine with rituximab (BR) is an established approach.

Distribution of copy number variations and rearrangement endpoints in human cancers with a review of literature.

Copy number variations (CNVs) which include deletions, duplications, inversions, translocations, and other forms of chromosomal re-arrangements are common to human cancers. In this report we investigated the pattern of these variations with the goal of understanding whether there exist specific cancer signatures. We used re-arrangement endpoint data deposited on the Catalogue of Somatic Mutations in Cancers (COSMIC) for our analysis.

Surgery-mediated tumor-promoting effects on the immune microenvironment.

Surgical resection continues to be the mainstay treatment for solid cancers even though chemotherapy and immunotherapy have significantly improved patient overall survival and progression-free survival. Numerous studies have shown that surgery induces the dissemination of circulating tumor cells (CTCs) and that the resultant inflammatory response promotes occult tumor growth and the metastatic process by forming a supportive tumor microenvironment (TME). Surgery-induced platelet activation is one of the initial responses to a wound and the formation of fibrin clots can provide the scaffold for recruited inflammatory cells.

Safety and antitumor activity of dostarlimab in patients with advanced or recurrent DNA mismatch repair deficient/microsatellite instability-high (dMMR/MSI-H) or proficient/stable (MMRp/MSS) endometrial cancer: interim results from GARNET-a phase I, single-arm study.

Background: Dostarlimab is a humanized monoclonal antibody that binds with high affinity to PD-1, resulting in inhibition of binding to PD-L1 and PD-L2. We report interim data from patients with endometrial cancer (EC) participating in a phase I trial of single-agent dostarlimab.

Methods: GARNET, an ongoing, single-arm, open-label, phase I trial of intravenous dostarlimab in advanced solid tumors, is being undertaken at 123 sites.

Treatment with soluble CD24 attenuates COVID-19-associated systemic immunopathology.

Background: Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19) through direct lysis of infected lung epithelial cells, which releases damage-associated molecular patterns and induces a pro-inflammatory cytokine milieu causing systemic inflammation. Anti-viral and anti-inflammatory agents have shown limited therapeutic efficacy. Soluble CD24 (CD24Fc) blunts the broad inflammatory response induced by damage-associated molecular patterns via binding to extracellular high mobility group box 1 and heat shock proteins, as well as regulating the downstream Siglec10-Src homology 2 domain-containing phosphatase 1 pathway.

Arginine Depletion in Human Cancers.

Arginine is encoded by six different codons. Base pair changes in any of these codons can have a broad spectrum of effects including substitutions to twelve different amino acids, eighteen synonymous changes, and two stop codons. Four amino acids (histidine, cysteine, glutamine, and tryptophan) account for over 75% of amino acid substitutions of arginine.

Dual PD-1 and CTLA-4 Checkpoint Blockade Using Balstilimab and Zalifrelimab Combination as Second-Line Treatment for Advanced Cervical Cancer: An Open-Label Phase II Study.

Purpose: Balstilimab (antiprogrammed death-1) and zalifrelimab (anticytotoxic T-lymphocyte-associated antigen-4) are two new checkpoint inhibitors emerging as promising investigational agents for the treatment of advanced cervical cancer. This phase II trial (ClinicalTrials.gov identifier: NCT03495882) evaluated the combination of balstilimab plus zalifrelimab in patients with recurrent and/or metastatic cervical cancer who relapsed after prior platinum-based therapy.

Integrating Self-Report and Psychophysiological Measures in Waterpipe Tobacco Message Testing: A Novel Application of Multi-Attribute Decision Modeling.

Background: Waterpipe (i.e., hookah) tobacco smoking (WTS) is one of the most prevalent types of smoking among young people, yet there is little public education communicating the risks of WTS to the population.

Acute cardiotoxicity after initiation of the novel tyrosine kinase inhibitor gilteritinib for acute myeloid leukemia.

Background: Gilteritinib is a novel FMS-like tyrosine kinase 3 inhibitor recently approved by the United States Food and Drug Administration in 2018 for relapsed or refractory acute myeloid leukemia. However, gilteritinib may be associated with underrecognized cardiotoxicities.

Case Presentation: This case describes a patient with a history significant for hyperlipidemia who was diagnosed with relapsed acute myeloid leukemia.

Immune checkpoint inhibitor-related thrombocytopenia: incidence, risk factors and effect on survival.

Introduction: Immune checkpoint inhibitors (ICI) are associated with unique immune-related adverse events (irAEs). Immune-related thrombocytopenia (irTCP) is an understudied and poorly understood toxicity; little data are available regarding either risk of irTCP or the effect of irTCP on clinical outcomes of patients treated with ICI.

Methods: We conducted a retrospective review of sequential cancer patients treated with ICI between 2011 and 2017 at our institution.

A Novel Role for RNF126 in the Promotion of G2 Arrest via Interaction With 14-3-3σ.

Purpose: Cell cycle checkpoints and DNA repair are important for cell survival after exogenous DNA damage. Both rapid blockage of G2 to M phase transition in the cell cycle and the maintenance of relatively slow G2 arrest are critical to protect cells from lethal ionizing radiation (IR). Checkpoint kinase 1 is pivotal in blocking the transition from G2 to M phases in response to IR.