Citations

We present a subset analysis on the adolescent cohort of the S1826 randomized phase three trial, comparing nivolumab, doxorubicin, vinblastine, dacarbazine (N-AVD) to brentuximab vedotin-AVD (BV-AVD) in newly diagnosed advanced-stage (AS, stages III and IV) classic Hodgkin lymphoma (cHL). Among 994 patients enrolled, 24% (n = 240) were age 12-17 years. The 3-year progression-free survival (PFS) was significantly higher in the N-AVD group (93% [95% CI, 87 to 96]) compared with the BV-AVD group (82% [95% CI, 73 to 88]; hazard ratio, 0.37 [95% CI, 0.17 to 0.80]). One N-AVD and two BV-AVD patients received protocol-specified residual site radiotherapy (RT). Rates of febrile neutropenia and sepsis were low in both groups. Severe immune-related adverse events were infrequent, although thyroid dysfunction was seen in 7% with N-AVD. Sensory neuropathy (grade ≥2) was more frequent with BV-AVD (14% v 7%) by clinician report. Although premature discontinuation of therapy was reported in 12 N-AVD patients and four BV-AVD patients, no PFS events were noted in the N-AVD group. Patient-reported outcomes indicated less toxicity with N-AVD. N-AVD demonstrated high 3-year PFS in adolescents with AS cHL, with minimal RT use. S1826 exemplifies the benefits of harmonized clinical trial protocols, resulting in timely access to novel agents for adolescents.

Abstract Homozygous deletions in the gene encoding methylthioadenosine phosphorylase (MTAP) occur in ∼10% of patients with cancer, including up to 45% in some tumor types, and may be associated with poor prognosis. MTAP deficiency causes accumulation of its catabolic target methylthioadenosine (MTA) that outcompetes S-adenosyl methionine (SAM) for binding to protein arginine methyltransferase 5 (PRMT5), partially inhibiting PRMT5 activity as a posttranslational regulator of a variety of critical cellular functions. Prior anticancer treatments developed to target PRMT5 exhibited high rates of dose-limiting hematologic toxicities because of a lack of selectivity for tumor cells. More recently, several agents have been developed that exploit the vulnerability of MTAP-deleted cancer cells to further inhibition of the PRMT5 pathway, selectively inducing synthetic lethality in those cancer cells. MTA-cooperative PRMT5 inhibitors such as BMS-986504/MRTX1719 and AMG 193 target the PRMT5–MTA complex, whereas inhibitors of the SAM synthetase methionine adenosyl transferase 2A, such as IDE397, deprive PRMT5 of its methyl donor SAM. In this review article, we summarize the mechanisms of action, preclinical data, and clinical data available thus far for these novel classes of oncology precision medicine and discuss potential future directions relevant to MTAP deletion as a promising synthetic lethal vulnerability for cancer therapy.

BACKGROUND AND OBJECTIVES: Minimum clinically important differences (MCIDs) for patient-reported outcome metrics (PROMs) in patients with cervical spondylotic myelopathy (CSM) lack consensus on the most appropriate calculation method. This retrospective study aimed to identify the optimal MCIDs for commonly used PROMs in CSM. METHODS: The CSM database from the Quality Outcomes Database SpineCORe Study Group was analyzed. Baseline, 3-month, and 24-month PROM values for Neck Disability Index (NDI), 5-dimension Euro-quality of life (EQ-5D) in quality-adjusted life years, modified Japanese Orthopaedic Association (mJOA) score, and neck/arm pain numeric rating scale (NRS) were collected. MCIDs were calculated for each PROM using previously validated techniques. MCID values were compared using the area under the curve (AUC) with the North American Spine Society satisfaction scale as an anchor. RESULTS: A total of 1141 patients with CSM undergoing surgery were included in this analysis. Improvement of ≥30% from baseline was the optimal MCID for NDI and neck/arm NRS. At 24 months, the optimal percentage cutoff MCID for these instruments resulted in AUCs of 0.76, 0.72, and 0.67, similar to the 30% improvement method, with AUCs of 0.73, 0.71, and 0.67, respectively. Numeric cutoffs (0.065 at 3 months; 0.149 at 24 months) were the superior MCIDs for EQ-5D. For mJOA score, a severity-adjusted MCID outperformed other methods, yielding an AUC of 0.67 at 24 months. MCIDs were achieved in 63% of patients for NDI, 59% for neck pain NRS, 61% for arm pain NRS, 52% for EQ-5D, and 59% for mJOA score at 24 months. CONCLUSION: Using the Quality Outcomes Database SpineCORe data set, we defined optimal MCIDs for key PROMs in CSM. A ≥30% improvement from baseline was optimal in NDI and arm/neck NRS. An absolute numeric cutoff was superior for EQ-5D (0.149 at the 24-month follow-up). A severity-adjusted MCID performed best for mJOA score. These redefined benchmarks better capture the treatment impact and guide care decisions for patients with CSM.

Objectives: To identify factors associated with short-term mortality among patients receiving microaxial flow pump (mAFP) therapy for acute myocardial infarction-related cardiogenic shock (AMI-CS). Data Sources: We searched four databases (MEDLINE, Embase, CENTRAL, and Scopus) from January 1, 2004, to January 1, 2025. Study Selection: We selected English-language studies that included adults with AMI-CS receiving mAFP and evaluated factors associated with short-term mortality. We excluded patients receiving concurrent venoarterial extracorporeal membrane oxygenation, as well as studies that solely included patients presenting with out-of-hospital cardiac arrest. Data Extraction: Two authors performed citation screening and data extraction. For each factor evaluated in at least two studies, we performed meta-analyses of adjusted odds ratios (aORs) using a random-effects model. Risk of bias was evaluated using the Quality in Prognosis Studies tool, and the certainty of evidence was evaluated using Grading of Recommendations, Assessment, Development, and Evaluations methodology. Data Synthesis: Our primary analysis included 18 studies, encompassing 20,617 patients. Median short-term mortality across studies was 50.7% (interquartile range 38.4–55.3%). Factors associated with short-term mortality based on high-certainty evidence included: increased age (aOR, 1.04 per year [95% CI, 1.03–1.05 per year] or ≥ 65 yr (aOR, 2.42 yr [95% CI, 0.77–7.64 yr]), female sex (aOR, 1.26 [95% CI, 1.09–1.45]), higher body mass index (aOR, 1.05 per point [95% CI, 1.04–1.07 per point]), higher heart rate (aOR, 1.02 per beats/min [95% CI, 1.01–1.02 per beats/min]), higher serum creatinine (aOR, 1.35 per mg/dL [95% CI, 1.08–1.70 per mg/dL]), mechanical ventilation (aOR, 2.53 [95% CI, 1.82–3.53]), vasopressors (aOR, 1.52 [95% CI, 1.11–2.08] for any vasopressors and aOR, 1.37 [95% CI, 1.18–1.58] per each vasopressor), presentation with ST-elevation myocardial infarction (aOR, 1.59 [95% CI, 1.11–2.26]), cardiac arrest (aOR, 2.85 [95% CI, 2.22–3.64]), and hypoxic-ischemic brain injury (aOR, 5.36 [95% CI, 3.03–9.47]). Conclusions: We identified several prognostic factors associated with short-term mortality in AMI-CS patients receiving mAFP support. This work may help inform clinicians, patients, and families regarding utilization of mAFP in AMI-CS.

The treatment landscape for multiple myeloma (MM) is evolving rapidly and includes several new options. The management must be tailored to the individual. The NCCN Guidelines for MM provide a framework to base decisions regarding diagnosis, workup, treatment, and follow-up of both newly diagnosed and previously treated relapsed/refractory MM. This manuscript outlines the recommendations from NCCN Guidelines for MM specific to newly diagnosed MM (NDMM).

Abstract Ferritin, consisting of ferritin heavy chain (FTH1) and light chain (FTL) subunits, is an essential intracellular iron storage protein fundamental for cellular function. However, the source and the biological role of extracellular ferritin (ex-ferritin) are less understood. Recent studies have linked elevated serum ex-ferritin with adverse outcomes in individuals with acute respiratory distress syndrome (ARDS). In this study, we demonstrate that both FTH1 and FTL are significantly enriched in the serum, blood monocytes, and alveolar macrophages (AMs) of individuals with ARDS, a phenomenon we successfully replicate in a murine hyperoxia-induced acute lung injury (HALI) model. We show that FTH1 is consistently upregulated in macrophages during lung injury development, and mice with a targeted deletion of FTH1 in myeloid (LysMcre) or resident lung macrophage (Cd11ccre) populations exhibit attenuated HALI. This reduced injury is linked to macrophage resistance to ferroptotic cell death, ferritinophagy, altered airway inflammatory responses, and lower lung extracellular iron and higher levels of FTL-ex-ferritin. Transplantation of FTL-ex-ferritin-enriched bronchoalveolar lavage fluid to wild-type mice protected against HALI. The ratio of FTL-ex-ferritin to FTH1 in the serum of individuals with ARDS who died was higher than that of those that survived, suggesting that the balance between FTH1 and FTL may play a role in injury modulation. Our findings highlight macrophage ferritin as a key regulator of macrophage survival and the response of the lung to injury, presenting a potentially targetable pathway for ARDS treatment.

Abstract Background The number of cancer survivors aged older than 65 years is rising rapidly. Current evidence‐based exercise guidelines lack specific guidance for older cancer survivors as a result of insufficient evidence. An expert panel was convened to develop consensus‐based recommendations for exercise in older cancer survivors. Methods The development of recommendations was guided by the Grading of Recommendations Assessment, Development, and Evaluation Evidence‐to‐Decision framework for good practice statements. The panel drew from the available literature, a Delphi survey of exercise and health professionals, other exercise guidelines, clinical and research expertise, and interest‐holder input provided by a community advisory board of older cancer survivors and caregivers ( n = 11). Recommendations had to be deemed accessible (i.e., no added barriers) to older cancer survivors and feasible to implement. The panel voted on the strength of the recommendation for or against each statement, with consensus set at 85% agreement. Results Consensus was reached on 11 recommendations covering the following areas: medical evaluation/clearance for exercise, pre‐exercise assessment, exercise prescription, exercise tolerance and safety, exercise delivery, and behavioral support. The recommendations aimed to promote engagement in and uptake of appropriately prescribed exercise programming by older cancer survivors, while keeping barriers and risks as low as possible. Conclusions Older cancer survivors can benefit from appropriately prescribed exercise, which should be an essential component of their cancer care. Exercise and health professionals need to consider the unique needs of older cancer survivors to ensure that exercise is safe and effective for this population, while also reducing barriers to reach as many people as possible.

Abstract Background Bedaquiline, pretomanid, and linezolid with or without moxifloxacin (BPaL/M) are recommended oral 6-month treatment regimens for multidrug- or rifampin-resistant (MDR/RR) tuberculosis (TB). Since the US rollout of these regimens in 2019, the US Centers for Disease Control and Prevention (CDC) and partners have identified patients who failed or relapsed on these regimens. Methods Here, we report a case series of US patients with TB treated with BPaL/M-containing regimens, who experienced adverse outcomes during the period 2022‒2024, including drug resistance, relapse, and treatment failure. Results Clinical and public health outcomes were significant for US patients reported. There were 8 patients identified (n = 8). 5 (62.5%) were male, with a median age 57 years, 2 (25%) were previously treated for TB, and 8 (100%) presented with cavitary disease. This included a patient who died from infectious TB with acquired resistance after exposing over 100 healthcare workers, a waitress who was found to have highly infectious TB at the time of her relapse, and a son who contracted Mycobacterium tuberculosis (Mtb) with reduced activity to bedaquiline from his mother in a household transmission event. Conclusions These patients highlight consequences, both for the individual and public health, of relapse and treatment failure in real-life operational settings that may not be readily evident in well-controlled and well-resourced clinical trials. Despite the advent of shorter and better tolerated bedaquiline-based regimens, US clinicians continue to face challenges in managing drug-resistant TB. These data support the need for expert management of these patients beyond routine TB care, as well as the need for close monitoring and follow-up months after treatment completion.

Introduction Previous studies have demonstrated that C 11 choline positron emission tomography/computed tomography (Choline-PET/CT) can localize abnormal parathyroid glands in the reoperative setting. This study assesses a large volume of patients with primary hyperparathyroidism (1HPT) who underwent Choline-PET/CT to confirm its utility in the setting of negative or equivocal conventional imaging. Methods All patients who underwent Choline-PET/CT for evaluation of 1HPT from July 2017 to July 2024 at a single institution were reviewed. Inclusion criteria were patients who underwent parathyroidectomy and had lab testing to assess for cure (defined as >50% drop from baseline PTH and into normal range, or resolution of hypercalcemia at follow-up). Sensitivity, positive predictive value (PPV), false negative rate (FNR), and accuracy were compared to conventional imaging (neck ultrasound, parathyroid scan, and parathyroid four-dimensional CT (4D-CT)). Subgroup analysis was conducted comparing sensitivity of modalities among index operations and separately in reoperations. Results 84 patients were included for analysis. 61 failed to localize on at least one conventional modality, and 15 failed to localize on all conventional studies. 67 patients (80%) achieved cure, of which 53 were reoperations. Choline-PET/CT outperformed conventional modalities across sensitivity, PPV, FNR, and accuracy. Choline-PET/CT also outperformed conventional modalities when comparing sensitivity in both subgroups. Conclusion C 11 choline-PET/CT is a valuable imaging modality in the reoperative setting and demonstrates utility for index operations. It provides localization when other modalities fail and allows for a high surgical cure rate. Further investigation into its utility as a primary imaging modality is warranted.

Abstract Secondary central nervous system (CNS) large B-cell lymphoma (SCNSL) occurs in the de novo setting, as a CNS-isolated relapse, or synchronous (concomitant CNS and systemic) relapse. SCNSL is a devastating event without therapeutic consensus. Thus, we aimed to evaluate treatment outcomes in an international cohort. Progression-free survival (PFS), overall survival (OS), and cumulative incidence of relapse (CIR, estimated using competing-risk models) were reported. Prognostic factors were identified in a 6-month landmark multivariate analysis. Outcomes after thiotepa autologous stem cell transplant (ASCT) and chimeric antigen receptor (CAR) T-cell therapy (CAR-T) delivered at relapse were compared after propensity score matching (PSM). A total of 1139 patients were included in the analysis (de novo: 537; relapsed SCNSL: 602). Two-year PFS estimates were 40.4%, 43.9%, and 16.2% for de novo SCNSL, CNS-isolated relapse, and synchronous relapse, respectively. Patients with CNS-isolated relapse demonstrated low rates of systemic recurrence (24-month CIR, 6%). Thiotepa-ASCT correlated with longer survival in de novo SCNSL (PFS: hazard ratio [HR], 0.57; P = .005; and OS: HR, 0.62; P = .023) and CNS-isolated relapses (PFS: HR, 0.55; P = .002; and OS: HR, 0.39; P< .0001). ASCT (thiotepa or no thiotepa) also associated with improved survival in synchronous relapses (PFS: HR, 0.57; P = .023; and OS: HR, 0.48; P = .019). Higher survival with thiotepa-ASCT than CAR-T was observed after PSM (PFS: HR, 0.45; P = .005 and OS: HR, 0.41; P = .014). These data support thiotepa-ASCT in eligible patients, particularly de novo disease and CNS-isolated relapses. CNS-isolated relapse was infrequently associated with systemic recurrence, supporting treatment regimens adopted from primary CNS lymphoma.