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Combination Immunotherapy With Nivolumab Plus Ipilimumab in Melanoma of Unknown Primary
The Oncology Grand Rounds series is designed to place original reports published in the Journal into clinical context. A case presentation is followed by a description of diagnostic and management challenges, a review of the relevant literature, and a summary of the authors’ suggested management approaches. The goal of this series is to help readers better understand how to apply the results of key studies, including those published in Journal of Clinical Oncology , to patients seen in their own clinical practice .
Phase II Trial of Nivolumab Plus Doxorubicin, Vinblastine, Dacarbazine as Frontline Therapy in Older Adults With Hodgkin Lymphoma
PURPOSE We conducted a phase I/II study evaluating nivolumab plus doxorubicin, vinblastine, dacarbazine (N-AVD) as frontline therapy for treatment-naïve older adults (OA) with classical Hodgkin lymphoma (cHL; ClinicalTrials.gov identifier: NCT03033914 ). METHODS Patients age ≥60 years with newly diagnosed, any stage, cHL were treated with six cycles of AVD at standard doses plus nivolumab 240 mg intravenously once every 2 weeks (on days 1 and 15) of each cycle. A geriatric assessment was performed before therapy initiation. The primary end point was progression-free survival (PFS). RESULTS Patient characteristics (N = 40) included median age of 66 years (range, 60-78 years) with 38% ≥70 years, 78% with stage III/IV disease, 68% with International Prognostic Score of ≥3, 82% dependent in ≥1 activities of daily living, 23% dependent in ≥1 instrumental activities of daily living, 50% with impaired timed up and go test, and 40% with polypharmacy. Among 37 response-evaluable patients, the median follow-up was 49 months and 3-year PFS and overall survival (OS) were 79% and 97%, respectively. Overall, 50% patients experienced grade 3/4 treatment-related adverse events (TRAEs), including febrile neutropenia in 8%. Four (10%) patients stopped therapy due to TRAEs. There was no correlation between baseline geriatric impairments and survival outcomes or toxicities. Positron emission tomography-2 was not predictive of PFS or OS. CONCLUSION N-AVD is a highly effective and well-tolerated frontline regimen in OA with cHL across a wide range of geriatric impairments.
Erratum: Busulfan Plus Fludarabine Compared With Busulfan Plus Cyclophosphamide for AML Undergoing HLA-Haploidentical Hematopoietic Cell Transplantation: A Multicenter Randomized Phase III Trial
Radiative impact of record-breaking wildfires from integrated ground-based data
Abstract The radiative effects of wildfires have been traditionally estimated by models using radiative transfer calculations. Assessment of model-predicted radiative effects commonly involves information on observation-based aerosol optical properties. However, lack or incompleteness of this information for dense plumes generated by intense wildfires reduces substantially the applicability of this assessment. Here we introduce a novel method that provides additional observational constraints for such assessments using widely available ground-based measurements of shortwave and spectrally resolved irradiances and aerosol optical depth (AOD) in the visible and near-infrared spectral ranges. We apply our method to quantify the radiative impact of the record-breaking wildfires that occurred in the Western US in September 2020. For our quantification we use integrated ground-based data collected at the Atmospheric Measurements Laboratory in Richland, Washington, USA with a location frequently downwind of wildfires in the Western US. We demonstrate that remarkably dense plumes generated by these wildfires strongly reduced the solar surface irradiance (up to 70% or 450 Wm-2 for total shortwave flux) and almost completely masked the sun from view due to extremely large AOD (above 10 at 500 nm wavelength). We also demonstrate that the plume-induced radiative impact is comparable in magnitude with those produced by a violent volcano eruption occurred in the Western US in 1980 and continental cumuli.
Treatment of Pleural Mesothelioma: ASCO Guideline Update
ASCO Guidelines provide recommendations with comprehensive review and analyses of the relevant literature for each recommendation, following the guideline development process as outlined in the ASCO Guidelines Methodology Manual . ASCO Guidelines follow the ASCO Conflict of Interest Policy for Clinical Practice Guidelines . Clinical Practice Guidelines and other guidance (“Guidance”) provided by ASCO is not a comprehensive or definitive guide to treatment options. It is intended for voluntary use by clinicians and should be used in conjunction with independent professional judgment. Guidance may not be applicable to all patients, interventions, diseases or stages of diseases. Guidance is based on review and analysis of relevant literature and is not intended as a statement of the standard of care. ASCO does not endorse third-party drugs, devices, services, or therapies and assumes no responsibility for any harm arising from or related to the use of this information. See complete disclaimer in Appendix 1 and 2 (online only) for more . PURPOSE To provide evidence-based recommendations to practicing physicians and others on the management of pleural mesothelioma (PM). METHODS ASCO convened an Expert Panel of medical oncology, thoracic surgery, radiation oncology, pathology, cancer genetics, and advocacy experts to conduct an updated literature search, which included systematic reviews, meta-analyses, randomized controlled trials, and prospective and retrospective comparative observational studies published from 2016 through 2024. Outcomes of interest included survival, disease-free or recurrence-free survival, and quality of life. Expert Panel members used available evidence and informal consensus to develop evidence-based guideline recommendations. RESULTS The literature search identified 110 additional relevant studies to inform the evidence base for this guideline. RECOMMENDATIONS Evidence-based recommendations were developed for surgical cytoreduction, immunotherapy, chemotherapy, pathology, and germline testing in patients with PM. Additional information is available at www.asco.org/thoracic-cancer-guidelines .
Exosomes derived from hypoxic mesenchymal stem cell ameliorate premature ovarian insufficiency by reducing mitochondrial oxidative stress
Reply to: Accurate Determinants of Outcome in ALL
Environmental constraints and diffusion shaped the global transition to food production
Randomized Controlled Trial of a Virtually Delivered Exercise and Stress Management Program to Improve Physical Performance of Hematopoietic Cell Transplant Survivors
PURPOSE Because of advances in hematopoietic cell transplant (HCT), meeting the long-term health needs of increasing numbers of HCT survivors remains challenging. This multicenter trial aimed to assess the short- and long-term effects of an exercise and mindfulness intervention delivered by telehealth. METHODS One hundred thirty-nine participants >6 months post-HCT were randomly assigned 1:1 to a 6-week personalized exercise and mindfulness training with three motivation sessions at 3-6 months via an online meeting platform or usual care. Physical and quality-of-life (QOL) assessments were conducted online for 12 months. The primary end point was the 6-minute walk test (6-MWT) at 3 months. RESULTS The median time post-HCT was 21 months (range, 7-67 months). Improvement in mean difference of 6-MWT was found in the intervention group compared with control (intention-to-treat) at 3 months (51.4 m [95% CI, 27.3 to 75.5]; P < .001; effect size [ES], 0.52) and was maintained at 12 months (59.3 m, P = .003; ES, 0.60). Sustained improvements in mean difference for sit-to-stand (STS) at 3 and 12 months were seen. There were no significant changes in hand grip strength or QOL outcomes between groups. A significant difference in serum soluble intercellular adhesion molecule-1 (sICAM-1) concentration was observed between the intervention and control groups in the exploratory study. No intervention adverse events were found. CONCLUSION The supervised multimodal telehealth intervention provided clinically meaningful and durable improvement of physical capacity in HCT survivors. This home-based program has the potential to provide an unmet need for HCT survivors. Similar programs may benefit survivors of other cancers, organ transplants, and chronic disorders.
Population genetic structure and historical demography of Saccostrea echinata in the Northern South China sea and Beibu Gulf
Influence of Nucleophosmin ( <i>NPM1</i> ) Genotypes on Outcome of Patients With AML: An AIEOP-BFM and COG-SWOG Intergroup Collaboration
PURPOSE Several genomic subsets of NPM1 mutations with varying sequences (type A, B, D, etc) have been identified. Despite molecular heterogeneity, NPM1 mutations cumulatively portend a more favorable outcome, but biology and prognostic implications of different genomic subsets have not been extensively studied. In this multicentric study, we investigated the impact of NPM1 genotypes on patient's outcomes and interrogated the underlying biology of the different subtypes. MATERIALS AND METHODS Of more than 4,000 patients enrolled in multiple pediatric cooperative (AIEOP, BFM, ELAM02, NOPHO, DCOG, and COG trials), or adult (SWOG) trials, 348 pediatric and 75 adult AML patients with known NPM1 genotype and available outcome were selected for this study. Diverse NPM1 variants were correlated with the probabilities of overall survival (OS) and event-free survival. Nuclear localization and translational efficiency of the NPM1 variants was studied. RESULTS Evaluation of clinical outcome on the basis of NPM1 genotypes showed that patients with type A, B, and other rare variants had similarly favorable outcomes, whereas those with type D had a significantly worse outcome (OS of 63% for type D v 86% for type non-D, P = .005). Multivariate analysis confirmed type D as an independent prognostic factor associated with inferior OS (hazard ratio, 3; P = .005). In vitro, we demonstrated that in type D versus type A synonymous variants, codon optimality plays major roles in determining gene expression levels, and translation efficiency, which resulted in a more expressed NPM1-D mRNA and protein, mediating peculiar mitochondrial gene expression. CONCLUSION The evaluation of specific NPM1 genotypes identified AML patients with type D mutations being significantly associated with inferior outcomes, suggesting a reclassification of D cases to higher-risk groups.
Utilization of indocyanine green for intraoperative sentinel lymph node mapping in canine mammary tumors
Pooled Long-Term Outcomes With Nivolumab Plus Ipilimumab or Nivolumab Alone in Patients With Advanced Melanoma
PURPOSE Nivolumab (NIVO) + ipilimumab (IPI) combination and NIVO monotherapy have demonstrated durable clinical benefit in patients with unresectable/metastatic melanoma. This analysis describes long-term overall survival (OS) with the combination or monotherapy pooled across all major company-sponsored trials, as well as clinical factors associated with survival, in patients with immune checkpoint inhibitor (ICI) treatment–naïve unresectable/metastatic melanoma. METHODS Data were pooled from six CheckMate studies in ICI treatment–naïve patients receiving NIVO + IPI (NIVO 1 mg/kg + IPI 3 mg/kg or NIVO 3 mg/kg + IPI 1 mg/kg) or NIVO monotherapy (3 mg/kg). OS was assessed for each treatment, as well as in select subgroups. Cox proportional multivariate analysis (MVA) and classification and regression tree (CART) analyses were performed within treatment arms. RESULTS Median follow-up for OS was 45.0 months for patients treated with NIVO + IPI (n = 839) and 35.8 months for patients treated with NIVO (n = 536). OS was longer with NIVO + IPI versus NIVO monotherapy (hazard ratio, 0.78 [95% CI, 0.67 to 0.91]), with 6-year OS rates of 52% versus 41%, respectively. Consistent benefit was observed in BRAF -mutant and BRAF -wild-type patients and those with normal and elevated lactate dehydrogenase (LDH). Numerical difference in OS was also observed across PD-L1 expression levels, although more pronounced with no/low PD-L1 expression. Clinical factors associated with decreased survival in both the MVA and CART analyses were LDH > upper limit of normal with either treatment, age ≥65 years with NIVO + IPI, and the presence of liver metastases with NIVO monotherapy. CONCLUSION In this large, pooled nonrandomized retrospective analysis, we observed that NIVO + IPI provides longer OS than NIVO in patients with ICI treatment–naïve advanced melanoma and identifies clinical factors that appear to be associated with survival for each treatment, which may assist with treatment decision making.
The effects of the generative adversarial network and personalized virtual reality platform in improving frailty among the elderly
Estimating Long-Term Survivorship Rates Among Patients With Resected Stage III/IV Melanoma: Analyses From CheckMate 238 and European Organization for Research and Treatment of Cancer 18071 Trials
PURPOSE Standard-of-care treatments for patients with resected stage III/IV melanoma include the immuno-oncology (IO) agents nivolumab (NIVO) and ipilimumab (IPI). This study used mixture cure models (MCMs) to estimate cure rates among patients treated with NIVO or IPI in the phase III CheckMate 238 (ClinicalTrials.gov identifier: NCT02388906 ) and European Organization for Research and Treatment of Cancer (EORTC) 18071 (ClinicalTrials.gov identifier: NCT00636168 ) trials, and to assess the impact of use of adjuvant immunotherapy on cure rates versus watchful waiting. METHODS MCMs were applied to patient-level recurrence-free survival data from CheckMate 238 and EORTC 18071. Cured patients were assumed to experience no disease recurrence and mortality risks similar to the general population. Uncured patients were at risk of disease recurrence and all-cause death. The survival trend of the cured patients was estimated using life expectancy data for a general population with the same baseline demographic characteristics. A regression model assessed the odds ratios (ORs) of cure across key subgroups on the basis of baseline characteristics of the study populations. RESULTS In CheckMate 238, estimated cure rates were 48.3% (95% CI, 41.8 to 54.9) with NIVO and 38.2% (95% CI, 32.7 to 44.1) with IPI. In EORTC 18071, estimated cure rates were 38.0% (95% CI, 32.1 to 44.2) with IPI and 29.2% (95% CI, 24.4 to 34.6) with placebo. In the indirect comparison of the two trials, the odds of cure were significantly higher with NIVO than with placebo (OR, 2.33 [95% CI, 1.49 to 3.65]). CONCLUSION Analyses involving two large phase III trials investigating adjuvant IO treatment for resected melanoma demonstrate higher cure rates for both NIVO and IPI than placebo, with NIVO providing the highest cure rate. Similar cure rates were estimated for patients treated with IPI in both trials, despite staging and dosing differences.
Maternal dietary DHA and EPA supplementation ameliorates adverse cardiac outcomes in THC-exposed rat offspring
Abstract Cannabis use in pregnancy is associated with low birthweight outcomes. Recent preclinical data suggests that maternal Δ9-tetrahydrocannabinol (THC) exposure leads to decreases in birthweight followed by early cardiac deficits in offspring. Currently, no studies have explored an intervention for these maternal THC-induced deficits. Omega-3 fatty acids have been shown to exhibit cardioprotective effects. In this present study, we demonstrated that maternal dietary supplementation of omega-3 fatty acids ameliorates both THC-induced fetal growth and postnatal cardiac deficits in offspring. Our data indicates this may be underpinned by alterations in cardiac and hepatic fatty acids and reduction in markers of cardiac collagen deposition. Interestingly, the cardioprotective effects of omega-3s may be further underscored by decreased signaling of the cardiac endocannabinoid system. With increasing rates of cannabis use in pregnancy and recent evidence of subsequent cardiometabolic aberrations in offspring, our data suggests a potential intervention for THC-induced fetal growth and cardiac disturbances in offspring.
Chimeric Antigen Receptor-T Cells in Colorectal Cancer: Pioneering New Avenues in Solid Tumor Immunotherapy
Colorectal cancer (CRC) remains a major global health burden, being one of the most prevalent cancers with high mortality rates. Despite advances in conventional treatment modalities, patients with metastatic CRC often face limited options and poor outcomes. Chimeric antigen receptor-T (CAR-T) cell therapy, initially successful in hematologic malignancies, presents a promising avenue for treating solid tumors, including CRC. This review explores the potential of CAR-T cell therapy in CRC by analyzing clinical trials and highlighting prominent CRC-specific targets. We discuss the challenges such as immunosuppressive microenvironment, tumor heterogeneity, and physical barriers that limit CAR-T efficacy. Emerging strategies, such as logic-gated and dual-targeting CAR-T cells, offer practical solutions to overcome these hurdles. Furthermore, we explore the combination of CAR-T cell therapy with immune checkpoint inhibitors to enhance T-cell persistence and tumor infiltration. As the field continues to evolve, CAR-T cell therapies hold significant potential for revolutionizing the treatment landscape of CRC.