Citations

ABSTRACT Genomic instability is a defining hallmark of breast cancer, yet the mechanisms by which tumors tolerate persistent DNA damage remain poorly understood. We performed a comprehensive, multi-cohort analysis of breast cancer datasets to define how DNA damage response (DDR) and replication stress tolerance (RST) networks are rewired in genomically unstable tumors. Using fraction of genome altered (FGA) as a chromosomal instability metric, we show that BRCA-mutant tumors exhibit elevated genomic instability coupled with increased expression of homologous recombination, Fanconi anemia, mismatch repair, base excision repair, and alternative end-joining pathways. Strikingly, heightened pathway activity correlates with increased genome alteration, supporting a model of damage tolerance rather than repair restoration. RST programs, including fork remodeling, protection, and single strand DNA gap suppression, further contribute to tumor fitness under replication stress. These adaptive states are enriched in aggressive subtypes, intensified with progression, and associate with pathway-specific mutational burden. Co-occurrence and mutual exclusivity mapping uncovered non-random subtype-relevant genetic interactions states among major drivers and DDR genes, nominating context-specific synthetic lethal opportunities. Our findings identify compensatory genome-maintenance programs as central drivers of tumor resilience and highlight pathway-specific vulnerabilities for targeted therapeutic intervention.

Abstract Glioblastoma (GBM) is the most common and lethal primary malignant brain tumor in adults, with median survival remaining approximately 12–15 months despite aggressive multimodal therapy. Therapeutic resistance and tumor recurrence are driven in part by limited drug penetration across the blood–brain barrier (BBB) and the persistence of brain cancer stem cells (BCSCs), highlighting the need for brain-penetrant therapeutic platforms capable of achieving sustained intratumoral delivery. Here, we developed a dendrimer-based nanotherapeutic by conjugating metformin to a fourth-generation hydroxyl-terminated polyamidoamine dendrimer (P4-MET) to enhance intracranial bioavailability and therapeutic efficacy in GBM. P4-MET exhibited favorable pharmacokinetic properties, including prolonged retention within the tumor microenvironment, and demonstrated enhanced cytotoxicity against GBM cell lines relative to free metformin (f-MET). Mechanistical studies with transcriptomic profiling by RNA sequencing revealed distinct treatment-associated molecular signatures, identifying BOLA2B as the most significantly differentially expressed gene between treatment groups. Specifically, BOLA2B expression was markedly elevated in f-MET–treated cells but not so following P4-MET treatment. Given the established association of BOLA2B with mTORC1 signaling and GPX4-mediated ferroptosis resistance, these findings suggest that P4-MET may, at least in part, enhance therapeutic efficacy by modulating ferroptosis-associated pathways. In orthotopic GBM models, combination treatment with P4-MET and radiotherapy (RT) significantly prolonged overall survival and increased tumor cell death compared with either monotherapy alone, consistent with a synergistic radiosensitizing effect. Importantly, P4-MET demonstrated minimal systemic toxicity, supporting its favorable therapeutic index and translational potential. Collectively, these findings establish P4-MET as a brain-penetrant nanomedicine platform that improves metformin delivery, modulates ferroptosis-related signaling networks, and potentiates radiotherapeutic response in GBM. This study highlights the potential of dendrimer-enabled metabolic nanotherapies to overcome therapeutic resistance in malignant brain tumors.

Background. Solid organ transplant recipients (SOTRs) are at heightened risk for cardiovascular implantable electronic device-related complications, particularly infection, because of chronic immunosuppression and comorbidities. Although leadless pacemakers (LPs) reduce infection risk by eliminating transvenous leads and generator pockets, adoption in SOTRs has remained limited, largely because earlier systems were restricted to single-chamber ventricular pacing and lacked physiologic atrioventricular synchrony. The helix-fixation Aveir LP platform enables atrial, ventricular, and dual-chamber leadless pacing, but clinical experience in transplant recipients remains limited. Methods. We conducted a retrospective, multisite analysis across an integrated health system, identifying all adult SOTRs who underwent Aveir LP implantation between January 2022 and October 2025. Clinical characteristics, transplant details, pacing indications, device configuration, procedural outcomes, and follow-up data were collected. Primary outcomes included procedural success, complications, and device-related infection. Secondary outcomes included pacing performance, need for system revision or upgrade, and early device durability. Results. Thirteen SOTRs (mean age 64 ± 15 y; 15% female) underwent Aveir LP implantation, including atrial (n = 4), ventricular (n = 5), and dual-chamber (n = 4) systems. Transplanted organs included heart (46%), lung (31%), kidney (38%), and liver (15%), with 31% having multiple organ transplants. Over half of patients were critically ill at implantation, and 46% were dialysis-dependent, representing a high-risk cohort. All procedures were acutely successful with no intraprocedural complications. During a median follow-up of 258 d (interquartile range, 216–641 d), no device-related infections occurred. Electrical performance remained stable, with 1 atrial device replacement at 2.5 y for elevated capture thresholds. Conclusions. In a high-risk population of SOTRs, atrial and atrioventricular synchronous leadless pacing using the Aveir platform was feasible, achieved high acute procedural success, and demonstrated favorable early safety signals, including absence of device-related infection over available follow-up. Larger studies with longer-term follow-up are needed to define durability and long-term outcomes.

Novel systemic anticancer therapies, including immune checkpoint inhibitors (ICIs), antibody-drug conjugates (ADCs), bispecific antibodies, and next-generation targeted agents, have improved survival, expanded into earlier disease settings, and created a growing population of long-term survivors. However, these therapies introduce toxicity profiles that differ substantially from those of traditional cytotoxic chemotherapy, including differences in organs affected, timing of onset, management strategies, and long-term sequelae. Tailored approaches to monitoring, diagnosis, and treatment are therefore required, along with stronger evidence to guide strategies that reduce morbidity and mortality while maintaining antitumor efficacy. Importantly, patients' lived experiences of toxicity often do not align with clinician-graded Common Terminology Criteria for Adverse Events classifications. Nonobservable symptoms, daily functioning, and quality of life must also be taken into account. Here, ocular and cutaneous adverse events are used as illustrative examples of how toxicities that may appear mild can become unacceptable when they impair function, quality of life, or treatment sustainability. Interdisciplinary collaboration between oncologists and organ specialists is essential for optimal recognition and management. At the same time, the evidence base for toxicity risk and management must continue to evolve through registries such as Side Effect Registry Immuno-Oncology and prospective comparative studies. Better tailored treatment strategies, particularly for immune-related adverse events, are needed to preserve both tumor response and organ function while reducing reliance on corticosteroids and broad immunosuppression. Although these therapies are highly effective, their risks must be better understood and managed to maximize patient benefit.

PURPOSE External beam radiation therapy (EBRT) has gained delayed acceptance as a recommended first-line treatment modality for patients with hepatocellular carcinoma (HCC), given limited evidence that it improves overall survival (OS). We analyzed individual patient data (IPD) from an international cohort to assess OS among patients with HCC treated with EBRT. METHODS We performed a systematic review of publications that assessed EBRT, met prespecified technical standards for HCC, and reported OS (search date December 15, 2022). Corresponding authors were invited to submit IPD for the study. We performed Kaplan-Meier survival analyses to determine OS and restricted mean survival time (RMST) stratified by Barcelona Clinic Liver Cancer (BCLC) stage and treatment status (ie, treatment-naïve and experienced). We performed random effects Cox proportional hazards modeling to assess clinical characteristics associated with OS. RESULTS Data were provided on 4,913 patients treated with EBRT with a median follow-up time of 5.0 years. The median OS was 6.8 years (95% CI, 5.7 to 8.7) for BCLC-0 and 4.6 years (95% CI, 4.1 to 5.1) for BCLC-A. Among treatment-naïve patients, the median OS was not reached (95% CI, 8.6 to not reached) for BCLC-0 and was 5.4 years (95% CI, 4.5 to 6.7) for BCLC-A. In multivariable models, more advanced BCLC stage, higher tumor burden, worse performance status, and Child-Pugh class B or C were associated with a higher risk of mortality. Ablative radiation dose and more recent year of treatment were associated with a reduced risk of death. CONCLUSION To our knowledge, this study represents the largest multinational cohort of patients with HCC treated with EBRT. OS outcomes with EBRT for very early- and early-stage HCC appear to be comparable with resection, thermal ablation, and other ablative locoregional therapies. These data support the inclusion of EBRT in the BCLC HCC clinical decision-making process.

ABSTRACT Novel β-lactam/β-lactamase inhibitors (βL/βLIs) are important therapies for carbapenem-resistant Pseudomonas aeruginosa (CRPA). However, the global extent of resistance to these agents and the impact of resistance on patient outcomes are unclear. We therefore evaluated patients with CRPA isolates at 35 hospitals (nine countries) from December 2018 to November 2019. Antimicrobial susceptibility testing was performed at a central laboratory by agar dilution for ceftolozane-tazobactam (C/T) and ceftazidime-avibactam (CZA) and by broth microdilution for imipenem-relebactam (I/R). Characteristics and outcomes, including desirability of outcome rankings (DOOR), were compared between patients infected with isolates not susceptible vs susceptible to each agent. Of 800 CRPA isolates, susceptibility to C/T, CZA, and I/R was 69%, 67%, and 33%, respectively. USA isolates ( n = 526) were more frequently susceptible to these agents than isolates from other countries ( n = 274; C/T: 83% vs 42%; CZA: 77% vs 47%; I/R: 37% vs 23%; P < 0.001 for each comparison) and isolates with carbapenemases ( n = 157) were less frequently susceptible than isolates without carbapenemases ( n = 643; C/T: 7% vs 84%; CZA: 24% vs 77%; I/R: 6% vs 39%; P < 0.001 for each comparison). Thirty-day mortality and DOOR were similar overall in patients infected with isolates not susceptible vs susceptible to each βL/βLI. However, the adjusted probability of a better DOOR outcome for a randomly selected patient with bacteremia due to a C/T-not susceptible vs -susceptible isolate was 38.2% (95% confidence interval, 25.6%–52.7%). Resistance to novel βL/βLIs, especially I/R, is common in CRPA, particularly outside the USA and in carbapenemase-producing isolates. Additional treatment options are needed for CRPA infections.