Search

Exercise changes the tumor microenvironment by remodeling blood vessels and increasing infiltration by cytotoxic immune cells. The mechanisms driving these changes remain unclear. Herein, we demonstrate that exercise normalizes tumor vasculature and upregulates endothelial expression of VCAM1 in YUMMER 1.7 and B16F10 murine models of melanoma but differentially regulates tumor growth, hypoxia, and the immune response. We found that exercise suppressed tumor growth and increased CD8+ T-cell infiltration in YUMMER but not in B16F10 tumors. Single-cell RNA sequencing and flow cytometry revealed exercise modulated the number and phenotype of tumor-infiltrating CD8+ T cells and myeloid cells. Specifically, exercise caused a phenotypic shift in the tumor-associated macrophage population and increased the expression of MHC class II transcripts. We further demonstrated that ERK5 S496A knock-in mice, which are phosphorylation deficient at the S496 residue, mimicked the exercise effect when unexercised, yet when exercised, these mice displayed a reversal in the effect of exercise on tumor growth and macrophage polarization compared with wild-type mice. Taken together, our results reveal tumor-specific differences in the immune response to exercise and show that ERK5 signaling via the S496 residue plays a crucial role in exercise-induced tumor microenvironment changes. See related Spotlight by Betof Warner, p. 1158.

Background: Cardio‐oncology and emergency medicine are closely collaborative, as many cardiac events in cancer patients require evaluation and treatment in the emergency department (ED). Immune checkpoint inhibitors (ICIs) have become a common treatment for patients with head and neck cancer (HNC). However, the immune‐related adverse events (irAEs) from ICIs can be clinically significant. Methods: We reviewed and analyzed cardiovascular diagnoses among HNC patients who received ICI during the period April 1, 2016–December 31, 2020 in a large tertiary cancer center. Demographics, clinical and cancer‐related data were abstracted, and billing databases were queried for cardiovascular disease (CVD)‐related diagnosis using International Classification of Disease‐version10 (ICD‐10) codes. We recorded receipt of care at the ED as one of the outcome variables. Results: A total of 610 HNC patients with a median follow‐up time of 12.3 months (median, interquartile range = 5–30 months) comprised our study cohort. Overall, 25.7% of patients had pre‐existing CVD prior to ICI treatment. Of the remaining 453 patients without pre‐existing CVD, 31.5% (n = 143) had at least one CVD‐related diagnosis after ICI initiation. Tachyarrhythmias (91 new events) was the most frequent CVD‐related diagnosis after ICI. The time to diagnosis of myocarditis from initiation of ICI occurred the earliest (median 2.5 months, 1.5–6.8 months), followed by myocardial infarction (3.7, 0.5–9), cardiomyopathy (4.5, 1.6–7.3), and tachyarrhythmias (4.9, 1.2–11.4). Patients with myocarditis and tachyarrhythmias mainly presented to the ED for care. Conclusion: The use of ICI in HNC is still expanding and the spectrum of delayed manifestation of ICI‐induced cardiovascular toxicities is yet to be fully defined in HNC survivors. [ABSTRACT FROM AUTHOR]

In recent years, a dramatic breakthrough in cancer therapy emerged as a result of the introduction of immune-checkpoint inhibitor therapy (ICI). As new ICI agents and novel combinations of these agents came into use, the relative proportions of immune-related adverse effects (irAEs) seen in the emergency department (ED) have shifted. Here we describe emergent vs non-urgent presentation of cardiovascular events in cancer patients who received ICI in a comprehensive cancer center. A retrospective cohort study of patients 18 years and older who received ICI at our comprehensive cancer center between April 1st, 2016, and March 31st, 2020. Demographics, clinical and cancer-related data were collected from the institution's data warehouse. The billing database was queried for all cardiovascular-related diagnoses before and after ICI initiation from the patient's initial presentation up to 01/01/2022. Descriptive statistics and competing risk analyses were used to analyze the data. A total of 9,412 patients were included, with a median age of 64 years (interquartile range= 55-72 years), who were mostly white (80.4%). Lung, kidney/urinary bladder, and melanoma were the top three cancer diagnoses. Almost one-quarter of the patients had cardiovascular disease documented before ICI initiation. Of the remaining 7131 patients, 1877 (26.3%) patients had a new diagnosis of cardiovascular diseases documented after ICI therapy, with tachyarrhythmias (19.0%), diseases of the pericardium (5.6%), and heart failure (4.6%) being among the topmost frequent cardiovascular-related diagnosis after ICI. For most cardiovascular events, the risk was significantly higher in patients who were treated with combination ICI therapy, with hazard ratios ranging from 1.26 to 1.65. New diagnoses of myocarditis, heart failure, and tachyarrhythmias were more frequently documented during an ED presentation. The clinical use of ICI is still expanding, and early versus delayed manifestation of ICI-induced toxicities is yet to be defined in cancer patients. Understanding the timing and the acuity level of the presentation of cardiovascular events associated with ICI therapy will allow the provision of better care for this population. [ABSTRACT FROM AUTHOR]

Aim: This study leveraged standard-of-care CT scans of patients receiving unilateral radiotherapy (RT) for early tonsillar cancer to detect volumetric changes in the carotid arteries, and determine whether there is a dose-response relationship., Methods: Disease-free cancer survivors (>3 months since therapy and age > 18 years) treated with intensity modulated RT for early (T1-2, N0-2b) tonsillar cancer with pre- and post-therapy contrast-enhanced CT scans available were included. Patients treated with definitive surgery, bilateral RT, or additional RT before the post-RT CT scan were excluded. Isodose lines from treatment plans were projected onto both scans, facilitating the delineation of carotid artery subvolumes in 5 Gy increments (i.e. received 50-55 Gy, 55-60 Gy, etc.). The percent-change in sub-volumes across each dose range was examined., Results: Among 46 patients, 72 % received RT alone, 24 % induction chemotherapy followed by RT, and 4 % concurrent chemoradiation. The median interval from RT completion to the latest, post-RT CT scan was 43 months (IQR 32-57). A decrease in the volume of the irradiated carotid artery was observed in 78 % of patients, while there was a statistically significant difference in mean %-change (±SD) between the total irradiated and spared carotid volumes (-7.0 ± 9.0 vs. + 3.5 ± 7.2, respectively, p < 0.0001). Chemotherapy use, in addition to RT, was associated with a significant mean %-decrease in carotid artery volume compared to RT alone. No significant dose-response trend was observed in the carotid artery volume change within 5 Gy ranges., Conclusions: Our data show that standard-of-care oncologic surveillance CT scans can effectively detect reductions in carotid volume following RT for oropharyngeal cancer. Changes were equivalent between studied dose ranges, denoting no further dose-response effect beyond 50 Gy., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: EK is supported in part by NIH/NCI 1R01 HL157273 and CPRIT RP200381 both of which are not related to the current work. AD is supported in part by NIH and the Cancer Prevention Research Institute, has received consulting fees from Bayer, honorarium from Kaplan for Projects in Knowledge and travel support as speaker by the American College of Cardiology. EM has received consulting fees from RYVU and honoraria from UPTODATE as topic reviewer. CDF receives related grant, salary, and infrastructure support from MD Anderson Cancer Center via: the Charles and Daneen Stiefel Center for Head and Neck Cancer Oropharyngeal Cancer Research Program; the Program in Image-guided Cancer Therapy; and the NIH/NCI Cancer Center Support Grant (CCSG) Image-Driven Biology and Therapy (IDBT) Program (P30CA016672). Dr. Fuller has received unrelated grants/honoraria from Elekta AB, has received travel support from Philips Medical Systems, and has served in an advisory capacity for Siemens Healthineers., (© 2025 The Authors. Published by Elsevier B.V. on behalf of European Society for Radiotherapy and Oncology.)

Aims: Radiation therapy (RT) is an integral component of cancer therapy but associated with adverse events. Our goal was to establish risk prediction models for major adverse cardiovascular and cerebrovascular events (MACCE) after chest RT., Methods and Results: A retrospective study of lung/breast cancer patients who had chest RT with planning CT at Mayo Clinic between 01/2010 and 01/2014. Predictive models were developed based on weighted independent predictors using a derivation (406 lung and 711 breast cancer) and validation cohort (179 lung and 234 breast cancer). Patient characteristics, pre-RT CT for coronary artery calcification (CAC), and post-RT MACCE data were reviewed. Post-RT MACCE occurred in 6.1 and 5.6% in the derivation and validation cohort over a mean follow-up of 42 ± 13 months. Post-therapy model (C2AD2) included CAC (two points), MACCE history (two points), age ≥74 (three points), DM (two points), and mean heart radiation dose ≥ 850 mGy (two points), and pre-therapy model (C2AD) included post-therapy model parameters minus mean heart radiation dose. Both models stratified patients into three risk groups: low (0-2), intermediate (3-5), and high (≥6). Post-RT MACCE across these groups were 2.7, 8.9, and 19.8% in the derivation, and 3.9, 6.6, and 16.4% in the validation cohort for post-therapy model (C2AD2) and 2.8, 9.2, and 20.4% in the derivation and 3.7, 9.2, and 13.2% in the validation cohort for pre-therapy model. Both models showed statistically significant graded survival outcome., Conclusion: Post-therapy (C2AD2) and pre-therapy (C2AD) models are simple, easy to use and effective tools to stratify breast and lung cancer patients undergoing chest radiation for post-RT MACCE., Competing Interests: Conflict of interest: none declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Purpose: Radiation induced carotid artery disease (RICAD) is a major cause of morbidity and mortality among survivors of oropharyngeal cancer. This study leveraged standard-of-care CT scans to detect volumetric changes in the carotid arteries of patients receiving unilateral radiotherapy (RT) for early tonsillar cancer, and to determine dose-response relationship between RT and carotid volume changes, which could serve as an early imaging marker of RICAD., Methods and Materials: Disease-free cancer survivors (>3 months since therapy and age >18 years) treated with intensity modulated RT for early (T1-2, N0-2b) tonsillar cancer with pre- and post-therapy contrast-enhanced CT scans available were included. Patients treated with definitive surgery, bilateral RT, or additional RT before the post-RT CT scan were excluded. Pre- and post-treatment CTs were registered to the planning CT and dose grid. Isodose lines from treatment plans were projected onto both scans, facilitating the delineation of carotid artery subvolumes in 5 Gy increments (i.e. received 50-55 Gy, 55-60 Gy, etc.). The percent-change in sub-volumes across each dose range was statistically examined using the Wilcoxon rank-sum test., Results: Among 46 patients analyzed, 72% received RT alone, 24% induction chemotherapy followed by RT, and 4% concurrent chemoradiation. The median interval from RT completion to the latest, post-RT CT scan was 43 months (IQR 32-57). A decrease in the volume of the irradiated carotid artery was observed in 78% of patients, while there was a statistically significant difference in mean %-change (±SD) between the total irradiated and spared carotid volumes (7.0±9.0 vs. +3.5±7.2, respectively, p<.0001). However, no significant dose-response trend was observed in the carotid artery volume change withing 5 Gy ranges (mean %-changes (±SD) for the 50-55, 55-60, 60-65, and 65-70+ Gy ranges [irradiated minus spared]: -13.1±14.7, -9.8±14.9, -6.9±16.2, -11.7±11.1, respectively). Notably, two patients (4%) had a cerebrovascular accident (CVA), both occurring in patients with a greater decrease in carotid artery volume in the irradiated vs the spared side., Conclusions: Our data show that standard-of-care oncologic surveillance CT scans can effectively detect reductions in carotid volume following RT for oropharyngeal cancer. Changes were equivalent between studied dose ranges, denoting no further dose-response effect beyond 50 Gy. The clinical utility of carotid volume changes for risk stratification and CVA prediction warrants further evaluation.

The histone H3 lysine 4 (H3K4) methyltransferase KMT2D (also called MLL4) is one of the most frequently mutated epigenetic modifiers in medulloblastoma (MB) and other types of cancer. Notably, heterozygous loss of KMT2D is prevalent in MB and other cancer types. However, what role heterozygous KMT2D loss plays in tumorigenesis has not been well characterized. Here, we show that heterozygous Kmt2d loss highly promotes MB driven by heterozygous loss of the MB suppressor gene Ptch in mice. Heterozygous Kmt2d loss upregulated tumor-promoting programs, including oxidative phosphorylation and G-protein-coupled receptor signaling, in Ptch-mutant-driven MB genesis. Mechanistically, both downregulation of the transcription-repressive tumor suppressor gene NCOR2 by heterozygous Kmt2d loss and upregulation of the oncogene MycN by heterozygous Ptch loss increased the expression of tumor-promoting genes. Moreover, heterozygous Kmt2d loss extensively diminished enhancer signals (e.g., H3K27ac) and H3K4me3 signature, including those for tumor suppressor genes (e.g., Ncor2). Combinatory pharmacological inhibition of oxidative phosphorylation and the H3K4 demethylase LSD1 drastically reduced tumorigenicity of MB cells bearing heterozygous Kmt2d loss. These findings reveal the mechanistic basis underlying the MB-promoting effect of heterozygous KMT2D loss, provide a rationale for a therapeutic strategy for treatment of KMT2D-deficient MB, and have mechanistic implications for the molecular pathogenesis of other types of cancer bearing heterozygous KMT2D loss.