Citations

Abstract Sex differences in cancer outcome, including that of glioblastoma (GBM), are shaped by biological, hormonal, and immunological factors and impact disease progression, treatment responses, survival, and tumor microenvironment (TME) interactions. Platelets regulate the immune responses and tumor progression in many cancers, but it is not clear how they contribute to these sex-based differences by affecting the dynamics of the TME. Here, we show that GBM patients exhibit heightened platelet reactivity driven by PAR4 signaling. In murine GBM models, both pharmacological inhibition of PAR4 using BMS986120 and genetic deletion of PAR4 significantly prolong survival in females but not males. This survival advantage is estrogen dependent: it is preserved in chromosomal male-hormonal female mice within the four-core genotype model and is rescued in ovariectomized mice treated with estrogen. The survival benefit is TME specific and is mediated by platelet-driven enhancement of CD8⁺ T cell infiltration into the tumor. Inhibition of platelet PAR4 signaling increases calcium signaling through an estrogen-dependent interaction between PAR4 and estrogen receptor β (ERβ)—a receptor interaction not previously described. PAR4-activated platelets within the TME suppress CD8⁺ T cell function, and depletion of CD8⁺ T cells abolishes both the tumor-induced platelet reactivity and the survival benefit conferred by PAR4 inhibition. These findings establish platelet-mediated PAR4 signaling as a critical driver of tumor progression and identify sex-specific immune responses as key to therapeutic efficacy.

Abstract Anterior shoulder instability is a common cause of shoulder pain and dysfunction in young patients and may be associated with concomitant bony and soft tissue pathology. Humeral avulsion of the glenohumeral ligament (HAGL) and rotator cuff tears are often seen in the setting of traumatic anterior shoulder instability events, especially in patients over 40 years of age, and portend poor postoperative outcomes if not addressed appropriately. While arthroscopic repair of rotator cuff tears is standard of care, both arthroscopic and open approaches for HAGL repair have been described and are associated with good clinical outcomes. Open HAGL repair affords the ability to address additional pathologies, including subscapularis tears and biceps tendon tears/SLAP tears with open subpectoral tenodesis, with direct visualization of the tear, while affording protection of the neurovascular structures. In this Technical Note, the authors describe their preferred technique for combined arthroscopic rotator cuff tear and open HAGL repair. Technique Video video See video under supplementary data.

Abstract Brexucabtagene autoleucel (brexu-cel) is a chimeric antigen receptor T-cell therapy approved for relapsed/refractory mantle cell lymphoma (R/R MCL). Here, we report real-world effectiveness and safety outcomes of brexu-cel in a prospective study of patients with R/R MCL, including subgroups based on prior treatment with Bruton's tyrosine kinase inhibitor, bendamustine, or autologous hematopoietic cell transplant (auto-HCT) and number of prior therapy lines, using Center for International Blood and Marrow Transplant Research registry data. A total of 476 patients with R/R MCL who received brexu-cel between July 2020 and December 2022 were included in the analysis. With a median follow-up of 13.5 months, the overall response rate was 91% and complete response rate was 82%. One-year overall survival and progression-free survival rates were 76% and 63%, respectively. One-year cumulative incidence of nonrelapse mortality was 8%. Prior auto-HCT was associated with better duration of response within 6 months after infusion (hazard ratio [HR], 0.49; 95% confidence interval [CI], 0.28-0.85) but greater risk of immune effector cell–associated neurotoxicity syndrome (odds ratio [OR], 1.66; 95% CI, 1.06-2.60). Prior bendamustine was associated with increased risk of prolonged thrombocytopenia (OR, 1.90; 95% CI, 1.13-3.21). In patients with 1 to 2 prior therapy lines, relapse or progression was less frequent compared with those with ≥3 prior lines (HR, 0.64; 95% CI, 0.42-1.00). Collectively, our results suggest that real-world outcomes with brexu-cel were consistent with those of the ZUMA-2 trial, regardless of prior therapy type or number of prior therapy lines.

Abstract Background and Aims Truncating variants in the TTN gene (TTNtv) are the most common genetic cause of dilated cardiomyopathy (DCM) but also occur as incidental findings in the general population. This study investigated factors associated with the clinical manifestation of TTNtv. Methods An international multicentre retrospective observational study was performed in families with TTNtv-related DCM. Shared frailty models were used to estimate associations of variant characteristics with lifetime risk of DCM, and logistic regression to estimate odds ratios (ORs) for individual-level clinical risk factor profiles (cardiac conditions, cardiovascular comorbidities, lifestyle) and DCM. Results A total of 3158 subjects in 1043 families with TTNtv-related DCM were studied. TTNtv-positive subjects were 21-fold more likely to develop DCM [OR, 21.21; 95% confidence interval (CI), 14.80–30.39]. Disease onset was earlier in males, but was similar for TTNtv of different types and locations. The presence of clinical risk factors was associated with earlier DCM onset (OR, 3.41; 95% CI, 2.06–5.64), with a prior history of atrial fibrillation having a two-fold increased odds of DCM (OR, 2.05; 95% CI, 1.27–3.32). The prevalence of clinical risk factors increased with age; however, the strength of the DCM association was greatest for young-onset (<30 years) disease (OR, 4.75; 95% CI, 2.35–9.60). Administration of beta-adrenergic receptor or renin-angiotensin system-blocking drugs prior to overt DCM was associated with 87% reduced odds of DCM (OR, .13; 95% CI, .08–.23). Conclusions Disease onset in TTNtv-associated familial DCM is dependent on individual patient context and is potentially modifiable by risk factor management and prophylactic therapeutic intervention.

Abstract Epcoritamab and glofitamab are CD20-directed bispecific antibodies (BsAbs) approved in the United States for relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL). Limited data exist for patients treated outside of trials. Patients with R/R DLBCL receiving commercial epcoritamab or glofitamab between 1 January 2023 and 15 October 2024 were collected from 21 United States institutions. Among 245 patients, 156 received epcoritamab and 89 received glofitamab, 113 were refractory to front-line therapy, 40 had MYC and BCL2 and/or BCL6 rearrangements, 147 received prior chimeric antigen receptor T-cell therapy, and 174 patients would have been ineligible for registrational trials. The overall response rate (ORR) for epcoritamab and glofitamab was 51% (23% complete response, [CR]) and 53% (30% CR), respectively. Median progression-free survival (PFS) was 2.6 months (95% confidence interval [CI], 2.0-3.8 months), and median overall survival (OS) was 7.8 months (95% CI, 6.2-11.0 months). The 6-month PFS was 36% (95% CI, 30-44) and the 6-month OS was 60% (95% CI, 54-67). Both trial ineligibility and undetectable CD20 pre-BsAbs portended shorter PFS and OS. Of 17 individuals with paired biopsies, 15 (88.2%) lost CD20 expression after BsAbs with a median time to progression of 3.7 months. This analysis including patients with R/R DLBCL shows the ORR to CD3/CD20 BsAbs was comparable to pivotal trials, although PFS and OS were lower. Baseline undetectable levels of CD20 were associated with poor outcomes. These results demonstrate the activity of BsAbs in R/R DLBCL, and underscore the importance of target antigen expression.

ABSTRACTObjectivesThyroglossal duct cyst (TGDC) associated carcinoma is rare, accounting for less than 2% of TGDC cases. The majority of cases are classified as papillary thyroid carcinoma (PTC). Standard treatment for TGDC‐PTC involves a Sistrunk procedure and prophylactic total thyroidectomy (TT). However, the necessity of these extensive surgical interventions remains debated. This report aims to explore whether individualized surgical approaches may reduce morbidity while maintaining favorable oncological outcomes.MethodsRetrospective case series of three patients with TGDC‐PTC.ResultsThe age range at presentation for our patients with TGDC‐PTC was 26 to 50. Case 1 involved a 38‐year‐old patient with a cystic mass near the hyoid bone and submental lymphadenopathy who underwent cyst excision with level Ia lymph node clearance. Case 2 is of a 50‐year‐old patient with a history of TGDC‐PTC who presented with a recurrent neck mass 9 years after the initial surgery and underwent a revision Sistrunk procedure. Case 3 presents a 26‐year‐old patient with a large TGDC and a benign thyroid nodule who underwent a Sistrunk procedure. All three patients had PTC confirmed by final pathology. All had no evidence of recurrent disease at follow‐up evaluations ranging from 1 to 12 years.ConclusionThis case series demonstrates the feasibility and safety of individualized surgical management for TGDC‐PTC. Risk stratification allowed for tailored interventions and avoided overly aggressive approaches. Further studies are needed to establish definitive guidelines for managing TGDC‐PTC, particularly in low‐risk patients.Level of Evidence4.

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Adult Cancer Pain provide recommendations for the comprehensive management of pain in patients with cancer. This article will focus on methods for screening for pain, safe and appropriate prescription of opioid and miscellaneous analgesics, and the optimization of nonpharmacologic interventions including integrative and interventional strategies for treatment of cancer-related pain. Additionally, the NCCN Guidelines discuss methods for the safe reduction of opioids when appropriate, as well as techniques for encouraging the judicious use of opioids. The complete version of the NCCN Guidelines for Adult Cancer Pain addresses additional issues that are not covered here, including management of pain during a pain crisis, management of procedure-related pain and anxiety, pain management for cancer survivors, and the use of nonopioid and adjuvant analgesics for cancer-related pain.

A systematic review was conducted of studies published up to 30 August 2024. Studies comparing conventional visual field (VF) indices, ability to detect central visual field defects (CVFDs), structure–function (S-F) concordance, and test characteristics across the HVF 24-2C SITA-Faster, 24-2 SITA-Standard/Faster, and 10-2 SITA-Standard/Fast tests were included. Eight studies with 1239 subjects (49.1% male; mean age, 54.8–66.9 years) were analyzed. The 24-2C produced similar global VF indices compared to the 10-2 and 24-2 (Standard/Faster) (ICC = 0.95 and 0.80, p < 0.001), detected more VF defects and CVFD clusters, and demonstrated greater S-F concordance than the 24-2 (Standard/Faster). Although the 10-2 (Standard/Fast) detected significantly more CVFDs and had a greater S-F concordance, the agreement between the 24-2C and 10-2 grids was substantial (ĸ = 0.488 to 0.708). The 24-2C was also faster compared to the 24-2 Standard and 10-2 (Standard/Fast), with comparable false positives, higher false negatives, and fewer fixation losses than the 24-2 Standard. In conclusion, the HVF 24-2C is quicker and identifies more CVFDs than the 24-2 grid, demonstrates high agreement with the 10-2 grid, and aids in CVFD screening.

AbstractDespite advances in acute myeloid leukemia (AML) treatment, significant unmet medical needs remain. Surrogate end points for overall survival can accelerate the approval of novel therapies. Measurable residual disease (MRD) is a promising surrogate end point candidate, providing a sensitive and quantitative assessment of disease burden. Numerous studies have demonstrated that negative MRD status—across diverse methodologies, assessment timepoints and thresholds, patient subgroups, and clinical settings—independently predicts improved survival. Although MRD can inform therapeutic decisions at the patient level, its formal integration as a primary surrogate end point in regulatory frameworks for clinical trials requires rigorous validation. MRD Partnership and Alliance in AML Clinical Treatment (MPAACT) is a research consortium among industry and academic leaders. MPAACT actively engages with regulatory agencies, health technology assessment bodies, technology vendors, and patient groups to establish a pathway for validating MRD as a surrogate end point in AML clinical trials. For the current article, the authors reviewed the status of MRD assessment, its use in recent clinical trials, current MRD assessment methodologies, standardization, regulatory guidance, statistical approaches, and patient access considerations necessary for MRD to become a surrogate clinical trial end point. The extensive collaboration between MPAACT, global industry, and academic partners—including data sharing and resource integration—underscores the collective commitment to advancing AML therapies. Establishing MRD as a surrogate end point could accelerate the development and approval of innovative treatments, ultimately improving patient outcomes.