Citations

Background Neurofibromatosis type 1 (NF1) is a genetic disorder in which plexiform neurofibromas (PNs) develop in approximately 30% to 50% of affected individuals, often causing substantial morbidity. Treatment of NF1-associated PNs is challenging due to disease variability and tumor complexity. Observations In the Phase 2b ReNeu trial (NCT03962543), mirdametinib, a mitogen-activated protein kinase kinase 1/2 (MEK) inhibitor, demonstrated efficacy and a manageable safety profile in children and adults with symptomatic PNs, achieving confirmed objective responses in 52% of children and 41% of adults, with substantial reductions in target tumor PN volume and improvements in patient- and parent proxy-reported outcomes. However, dermatologic adverse events (AEs) are common with MEK inhibitors, including mirdametinib, and can impact adherence and quality of life. While the ReNeu protocol included supportive care considerations for skin reactions associated with mirdametinib, some investigators recognized a need for more detailed guidance. The ReNeu Scientific Steering Committee, in collaboration with oncology and oncodermatology experts, developed expert-driven recommendations for the proactive management of mirdametinib-related skin AEs. Conclusions These strategies emphasize early recognition, individualized care, and timely intervention to help reduce the severity of mirdametinib-related skin AEs, minimize dose modifications, and support treatment continuity and long-term treatment goals. Although these recommendations were specifically developed for mirdametinib based on ReNeu trial experience, they may also provide practical guidance for managing skin AEs associated with other MEK inhibitors in clinical practice.

Purpose To assess the reliability, predictability, and discriminative capacity of 3 anatomic measurements, tibial tubercle‐trochlear groove (TT‐TG), tibial tubercle‐posterior cruciate ligament, and patellar tendon‐lateral trochlear ridge (PT‐LTR), where PT‐LTR may offer a complementary approach to assessing recurrent patellofemoral instability (PFI) risk. Methods Patients diagnosed with PFI before primary patellofemoral stabilization surgery at a single institution between 2022 and 2024 were included. A control group without PFI was propensity matched 1:1 for age, sex, and laterality. Magnetic resonance images were evaluated to measure TT‐TG, tibial tubercle‐posterior cruciate ligament, and PT‐LTR. A priori power analysis determined the cohort size. Statistical analyses compared differences between the PFI and control groups with Student t‐tests, receiver operating characteristic analyses, and area under the curve with resultant sensitivity, specificity, and an optimal cutoff. Results Patients included 50 knees with PFI (28 women, 22 men; mean age 18 ± 5 years). The control group included 50 knees (27 women, 23 men; mean age 18 ± 4 years). Excellent inter‐ and intra‐rater reliability (intraclass correlation coefficient > 0.7) was shown for TT‐TG and PT‐LTR in the PFI and control groups. The distances for TT‐TG, tibial tubercle‐posterior cruciate ligament, and PT‐LTR were significant predictors ( P ≤ .025) of PFI. The average PT‐LTR distance difference for the PFI and control groups was 7.0 mm ( P < .001). PT‐LTR showed an area under the curve of 0.80 and, when ≥4.6 mm, was 66% sensitive and 92% specific for PFI. Conclusions The PT‐LTR distance is a reliable and discriminative metric for identifying PFI in both pediatric and adult populations. A PT‐LTR cutoff value of 4.6 mm showed diagnostic discrimination and substantially high specificity for recurrent PFI, indicating strong ability to identify patients with instability. Level of Evidence Level III, retrospective case control study.

Abstract Global incidence and mortality rates for endometrial and cervical cancers have been steadily rising, while these rates for ovarian cancer have decreased. Although these cancers represent unique diseases and challenges, overlapping biology and responses to targeted and immunotherapies create opportunities to advance research through shared knowledge and resources. In 2025, investigators funded by National Cancer Institute (NCI) Specialized Programs of Research Excellence (SPORE) and other NCI-supported grants convened a hybrid meeting to identify challenges and knowledge gaps in translational research, highlight advances, define shareable resources and technologies, and foster collaboration among the Gynecologic Cancer SPORE sites, patient advocates, and NCI staff. Special sessions were arranged for presentations by Patient Advocates, Early-stage Investigators, Investigators Transitioning to Gynecologic Cancer Research. Meeting-wide workshops on Sharing Resources and Reducing Time to Activation of Clinical Trials and networking events were included. Collectively, the presentations converged on three overarching themes: (i) interception and early disease biology, (ii) development of innovative targeted and immune-based therapies, (iii) critical role of shared resources and collaborative infrastructure in accelerating translational progress. The unifying theme across disease sites was molecular advances to improve early detection/prevention and to drive therapeutic advancements. Novel findings discussed included: candidate precursor cells and mechanisms of high grade serous ovarian cancer development; therapeutic vaccines and their delivery methods for cervical dysplasia; identification of immune-targetable ovarian cancer antigens; various novel molecularly targeted drugs and immune-based agents for endometrial and ovarian cancers; and approaches to bypass drug resistance. Workshops delineated actionable strategies to further advance gynecologic cancer translational research.

Abstract The apolipoprotein E ε4 ( APOE4 ) allele is the strongest genetic risk factor for late-onset Alzheimer’s disease (AD), yet the mechanistic underpinnings by which it alters human microglial function remain poorly understood. Here, we utilize CRISPR/Cas9-engineered isogenic human induced pluripotent stem cell-derived microglia-like cells (iMGs) expressing APOE3 or APOE4 to systematically interrogate genotype-dependent effects on microglial proteomes and their secreted extracellular vesicles (EVs) under basal and fibrillar amyloid-β (fAβ)-challenged conditions. Quantitative proteomics revealed that APOE4 iMGs exhibit downregulated RNA processing, impaired phagocytosis, and exacerbated pro-inflammatory signaling, particularly upon fAβ exposure. Functionally, APOE4 iMGs demonstrated increased NF-κB activation, enhanced neuronal apoptosis and tau pathology in 2D and 3D co-culture systems. Interestingly, APOE4 iMGs released greater amount of EVs enriched in proteasomal components over APOE3 iMG. Integrated proteomic analyses further highlighted APOE4 -specific selective packaging of EV cargo linked to neuron-glia communication, inflammatory signaling, and proteostasis dysregulation, suggesting a potent, non-cell-autonomous mechanism driving neuronal damage. Consistently, these APOE4 iMGEVs were preferentially internalized by neurons, leading to disrupted neuronal proteostasis, impaired neuronal firing, and increased tau phosphorylation, particularly under pathological stress. Notably, pharmacologic inhibition of NF-κB in APOE4 iMGs reduced EV cargo-loading of proteasomal molecules and mitigated iMGEV-driven neuronal dysfunction and tau pathology. These findings establish a mechanistic link between APOE4 , dysregulated microglial homeostasis, and microglial EV-mediated propagation of proteostatic dysfunction and neurodegeneration, advancing our understanding of how APOE4 contributes to AD pathogenesis.

Purpose To evaluate implantation rates, time to implantation, and predictors of implantation following matrix‐induced autologous chondrocyte implantation (MACI) biopsy for knee chondral defects. Methods Patients undergoing MACI biopsy or implantation for symptomatic knee chondral defects from 2017 to 2024 at a single institution were reviewed. At a minimum 1‐year follow‐up, the decision to proceed with implantation, recurrent symptoms, complications, and reoperations were assessed. Kaplan‐Meier analysis estimated time to implantation, and multivariable logistic regression identified predictors of MACI implantation. Results A total of 208 knees in 202 patients (mean age 28.0 ± 10.9 years, range 11‐59) underwent MACI biopsy for 243 chondral defects (patella [38%], femoral condyle [34%], and trochlea [26%]). At a mean follow‐up of 4.3 years (range 1.0‐8.3), 64 knees (31%) proceeded to second‐stage MACI implantation. Among 144 knees not implanted, 87 (60%) reported symptom improvement, and 26 (18%) had persistent symptoms. The remaining 22% did not undergo implantation due to another cartilage procedure, insurance denial, or pending scheduling. Patients who underwent biopsy at the home institution had a shorter time from biopsy to implantation compared with those biopsied at outside institutions (6.1 vs 13.1 months, P = .001). Median time to implantation was 9.4 months (95% confidence level: 7.2‐12.2) for home biopsies. Lower body mass index was associated with progression to implantation after adjusting for covariates (odds ratios 0.92, P = .019). Patients implanted within 4 months had larger chondral defects (4.0 vs 3.0 cm 2 , P = .045). At a mean 4.1‐year follow‐up, 6 patients (8%) experienced postoperative complications, including 3 (4%) who required revision chondroplasty. Conclusions MACI biopsy for knee chondral defects resulted in approximately one‐third of patients proceeding to MACI implantation, at a median of 9.4 months after biopsy. Lower body mass index was associated with higher likelihood of progression to implantation, larger chondral defects with earlier implantation, and among patients who did not proceed to implantation, approximately 60% reported symptom improvement following concomitant chondroplasty at the time of biopsy. Level of Evidence Level IV, retrospective case series.

Importance Recent case reports suggest that B antigen–containing blood products may be associated with anaphylactic transfusion reactions in recipients with preformed immunoglobulin E to galactose- α -1,3-galactose (alpha-gal). Objective To test the association of local alpha-gal syndrome (AGS) prevalence and allergic transfusion reaction (ATR) in patients with blood type O. Design, Setting, and Participants In this international, multicenter, retrospective cohort study at academic medical centers, sites were assigned to AGS high- or low-prevalence clusters based on the known geographic distribution of AGS. Data were collected on platelet or plasma transfusions and ATRs during 2020 to 2024. Consecutive patients receiving platelet or plasma transfusions were included. Exposures Patients with blood type O who received B or AB units and patients with blood type O who received O units (reference group) in AGS high- and low-prevalence clusters were compared. Main Outcomes and Measures Before data collection, the hypothesis was that if transfusion-related alpha-gal syndrome (TRAGS) is a true clinical entity, excess ATRs to group B or AB units would be detected in AGS high-prevalence regions exclusively. The main measure was the overall risk ratio (RR) for ATRs to B or AB plasma or platelets in AGS high- vs low-prevalence clusters. Results In total, 558 823 platelet and plasma transfusions at 40 sites in 5 countries were analyzed, of which ATRs occurred in 1744 transfusions (0.3%). In the US AGS high-prevalence cluster (9 sites), significantly more ATRs of any severity occurred among patients with blood type O who received B or AB units vs patients with blood type O who received O units (overall RR, 3.93; 95% CI, 2.96-5.21; P &amp;lt; .001). In contrast, in the primary analysis of the AGS low-prevalence cluster (15 sites), excess ATRs to B or AB units were not detected. In subgroup analyses among patients with blood type O receiving B units, the RR for moderate to severe ATRs was 9.14 (95% CI, 5.39-15.52; P &amp;lt; .001) in the AGS high-prevalence cluster vs 2.15 (95% CI, 1.34-3.47; P = .002) in the AGS low-prevalence cluster. Outside the US, a signal consistent with TRAGS was not detected. Conclusions and Relevance This cohort study provides provocative epidemiologic evidence that TRAGS may be a unique manifestation of AGS and a previously unrecognized risk associated with transfusion. In AGS high-prevalence regions, blood collectors and hospital transfusion services should consider approaches to preventing severe ATRs from B or AB plasma or platelet units.

Myeloproliferative neoplasm (MPN) patients are at risk of splanchnic vein thromboses (SVT). Prior studies have failed to demonstrate a benefit of hydroxyurea therapy in preventing recurrent thrombosis after SVT, but are limited by small sample sizes and inability to account for starting, stopping, or switching of cytoreductive therapies. To better assess the impact of cytoreductive therapy on thrombosis recurrence, we performed a retrospective cohort study of MPN-SVT patients from the international GASTRO-MPN Consortium, treating cytoreductive therapy as a time-dependent covariate. We identified 757 patients, of which 43% were treated with cytoreductive therapy. During a median follow-up of 7.4 years, 256 patients (34%) had thrombosis recurrence; 145 (19%) had SVT extension/recurrence/TIPS thrombosis, 138 (18%) an thrombosis recurrence outside the splanchnic bed (74% were venous). Additionally, 262 patients (35%) experienced clinically relevant bleeding and 170 (22%) died. After adjusting for age, sex, prior thrombosis, timing of MPN diagnosis relative to SVT, anticoagulation initiation within 30 days of SVT diagnosis, MPN type, JAK2 status, other cancers and cirrhosis, cytoreductive therapy was associated with a decreased risk of recurrent thrombosis (HR 0.67 95%CI 0.50-0.89, p=0.01). This was driven by a lower risk of SVT extension/recurrence (HR 0.62 95%CI 0.42-0.90, p=0.01) but not by extra-splanchnic thrombosis recurrence (HR 0.97 95%CI 0.72-1.30, p=0.82). In a subgroup of patients without erythrocytosis/thrombocytosis at initial SVT (n=275), cytoreductive therapy was associated with a HR 0.65 (95%CI 0.40-1.07, p=0.09) for recurrent thrombosis. These data support the use of cytoreductive therapy in MPN-SVT patients to prevent recurrent thrombosis, particularly SVT extension/recurrence.

PURPOSE EA1181 (ClinicalTrials.gov identifier: NCT04266249 ) is a single-arm trial evaluating neoadjuvant taxane, trastuzumab, and pertuzumab (THP) in patients with clinical stage II/IIIa human epidermal growth factor receptor 2 (HER2)–positive breast cancer. This report focuses on the secondary end points of pathologic complete response (pCR) rates and associated factors. The primary end point—3-year recurrence-free survival among patients achieving a pCR (ypT0/Tis, ypN0)—will be reported when data mature. METHODS Patients received four cycles of trastuzumab and pertuzumab (HP) with either once per week paclitaxel (12 weeks) or docetaxel (every 3 weeks for four cycles), followed by surgery. Clinicopathologic characteristics were assessed in all patients. The HER2DX pCR score was determined using diagnostic biopsy samples in a representative subset. Logistic regression models identified factors associated with pCR. RESULTS A total of 2,175 patients were enrolled (781 HER2+/estrogen receptor‑negative [ER–]; 1,394 HER2+/ER+). Of 2,141 patients who initiated THP, the overall pCR rate was 43.8%: 63.7% in HER2+/ER– and 32.4% in HER2+/ER+ tumors. Higher pCR rates were observed in tumors that were ER-negative or low ER expressing, progesterone receptor-negative or low expressing, HER2 immunohistochemistry (IHC) 3+, and in patients treated with once per week paclitaxel. T3 disease was associated with a lower pCR rate in HER2+/ER– tumors; otherwise, tumor (T) and nodal (N) stage did not significantly affect pCR. Among 569 patients assessed for HER2DX pCR scores, a high score was independently associated with higher pCR rates, after adjustment for clinicopathologic variables. CONCLUSION Neoadjuvant THP achieved pCR in nearly two-thirds of patients with HER2+/ER– and one third with HER2+/ER+ breast cancer. Low hormone receptor expression, HER2 IHC 3+ status, once per week paclitaxel use, and a high HER2DX pCR score were independent predictors of pCR. These findings should help optimize risk stratification and treatment personalization for patients with HER2-positive breast cancer.