In vitro cell barrier models have been increasingly integrated into pharmaceutical and academic research pipelines to evaluate drug safety and drug delivery due to a shift towards New Approach Methodologies (NAMs) in research and regulatory safety assessment. Such models require reliable and interpretable functional readouts. Bioimpedance-based monitoring, particularly transepithelial/endothelial electrical resistance (TEER), is a widely adopted readout due to its non-invasive and real-time capabilities. However, substantial variability arises from differences in measurement settings, frequency selection, electrode configuration, impedance measuring techniques, and data analysis strategies. In numerous studies, TEER is approximated from single-frequency impedance magnitude measurements, which do not isolate the resistive component associated with tight junction-mediated paracellular transport but instead reflect the combined response of a coupled electrochemical system. This review clarifies impedance measuring techniques and systematically analyzes impedance-based measurement and analysis strategies for in vitro biological cell barrier integrity. We compare mono-frequency and broadband acquisition approaches, examine the influence of electrode-electrolyte interfaces, electrode geometry, and culture configuration, and evaluate equivalent circuit modeling and phase-resolved electrical impedance spectroscopy (EIS). Based on this comparison, we propose a three-level analytical hierarchy adapted to experimental objectives and instrumentation constraints. We conclude that phase-informed impedance analysis and harmonized reporting are essential to improve measurement reproducibility, inter-platform comparability, and integration of impedance-derived cell barrier assessment within NAMs-oriented research workflows.
Various acute phase proteins (APPs) are already used as diagnostic biomarkers or are considered promising candidates. The aim of this study was to measure the concentrations of haptoglobin and pig major acute phase protein (pig-MAP) in the serum, milk and saliva of healthy sows before and after parturition. The measurements from 19 sows were included in the evaluation. Samples were taken at seven time points including T0 (112th day of pregnancy), T1 (intrapartum/birth of the first piglet), T2 (12 h postpartum), T3 (24 h postpartum), T4 (48 h postpartum), T5 (72 h postpartum) and T6 (14 d postpartum), and general condition parameters, such as the rectal temperature, were recorded. The samples were analysed using ELISA kits. The correlation between the APPs in different body fluids was investigated. For serum and saliva concentrations, time points T1-T6 were compared to time point T0 to detect changes in APP concentration compared to prepartum levels. The pig-MAP levels in serum at time points T3-T5 were significantly increased compared to T0; the haptoglobin levels at time points T2-T5 were significantly increased compared to T0; and the rectal temperature was significantly increased at all later time points compared to T0. Comparison of T0-T5 to T6 (milk T1-T5 to T6) revealed that pig-MAP in serum, at time points T4 and T5, and haptoglobin levels, at T3-T5, were significantly different compared to T6. For both APPs in milk, the concentrations at all time points (T1-T5) were significantly elevated compared to T6. In saliva, there was a significant increase at T5 compared to T6 for haptoglobin. This descriptive pilot study provides insights into the magnitude, timing and significance of the increase in APP levels in sows during and after parturition and can be used as a basis for future studies on the early detection and diagnosis of diseases during this period.
In May 2025, the International Alliance for Biological Standardization (IABS) held a workshop on analytical and bioprocess platforms for biological product development and commercialization. This workshop explored the use of platform approaches and technologies in product development and registration. The topics discussed included the creation, verification, and maintenance of platform technologies, their lifecycle management, their application in regulatory submissions, and the transition from early clinical trials to commercial approval. The participants highlighted the importance of clearly defining the boundaries and applicability of platform approaches in pharmaceutical development. A consistent and open dialogue between industry stakeholders, regulatory reviewers, and health authorities is essential to ensure a shared understanding and alignment in defining the platform landscape.
Despite growing interest in the therapeutic potential of 3,4-methylenedioxymethamphetamine (MDMA), no targeted measure to systematically assess side effects of MDMA-assisted psychotherapy (MDMA-AP) exists. Our aim was to develop an MDMA-Assisted Psychotherapy Side Effects Tool (M-SET) to capture side effects over the course of MDMA-AP. Informed by a systematic review and a review of other relevant questionnaires, we drafted a list of potential side effects. Face and content validation were obtained via a modified two-round online Delphi process involving experts in MDMA-AP and the neuropsychopharmacology of MDMA. Twelve experts consented to participate over two rounds of Delphi panel deliberations (response rate: Round 1 = 83-92%, Round 2 = 75%). The Delphi panellists were asked to keep, discard, modify or suggest additional items. The final version of the M-SET consists of 165 items across four questionnaires that collect information at screening, baseline, the day of medication sessions and longer term follow-up. The use of a modified Delphi technique proved a successful method to generate content for the first structured tool designed to evaluate side effects specifically associated with MDMA-AP. The M-SET is recommended for use in both research and clinical settings. Its implementation has the potential to improve the safety of delivering MDMA-AP as well as support the development of a more systematic and robust evidence base on its safety and tolerability.
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Treatment for mucopolysaccharidosis II (MPS II; Hunter syndrome) via enzyme replacement therapy with intravenous idursulfase (Elaprase) has been available for over 15 years. This treatment has led to survival of more patients into adulthood and a concomitant rise in the need for transition of care from paediatric to adult care teams; however, implementation of transition pathways is not standardized. This cross-sectional, non-interventional, multi-country qualitative interview study recruited patients with MPS II (n = 13), caregivers of patients with MPS II (n = 23) and healthcare professionals (n = 24) across six countries (Canada, Colombia, Germany, Mexico, the UK and the USA) to investigate approaches to transition of care in MPS II. Data were collected via a sociodemographic questionnaire, a clinical characteristics form and semi-structured interviews. The interviews identified four overarching themes: transition of care approaches and their drivers, components of a successful transition programme, challenges or barriers to transitioning to adult care and suggested improvements to transition of care. Transition pathways showed high variability within and between countries. Participants reported essential items for successful transition, including continuity of care, a key contact person and empowering patients as early as possible in the process. Proposed improvements for transition included additional educational/support resources, psychological support and implementation of protocols to guide a standardized approach. Our study highlights the need for the establishment of common standards for the transition of care from paediatric to adult services for patients with MPS II. Based on the interview responses, we have proposed additional considerations for patients with neuronopathic MPS II. The findings may inform the development of effective transition practices for MPS II and other rare diseases, to optimize the transition of care experience for patients, caregivers and healthcare professionals.
In ARASENS, risk of death was significantly reduced by 32.5% with darolutamide in combination with androgen deprivation therapy (ADT) and docetaxel (hazard ratio [HR], 0.68; 95% confidence interval [CI], 0.57-0.80; p < 0.001) in patients with metastatic hormone-sensitive prostate cancer (mHSPC). We assessed efficacy and safety of darolutamide in European patients from ARASENS. Patients were randomized 1:1 to darolutamide 600 mg or placebo twice daily in combination with ADT and docetaxel. Primary endpoint was overall survival. Secondary endpoints included time to metastatic castration-resistant prostate cancer (mCRPC), time to pain progression, time to first symptomatic skeletal event (SSE), time to initiation of subsequent systemic antineoplastic therapy, and safety. In ARASENS, 472 (36%) patients were from Europe; 240 received darolutamide and 232 received placebo. Patient baseline characteristics were similar to those of the overall population. Darolutamide reduced the risk of death by 37% (HR, 0.63; 95% CI, 0.48-0.83), and delayed time to mCRPC, time to pain progression, time to first SSE, and time to initiation of subsequent systemic antineoplastic therapy compared with placebo. Incidences of serious treatment-emergent adverse events (TEAEs) were lower with darolutamide versus placebo (37.9% vs. 43.1%) compared with the overall population (44.8% vs. 42.3%). In European patients with mHSPC, darolutamide improved overall survival and secondary endpoints including time to mCRPC and time to pain progression. Darolutamide was well tolerated with similar incidence of TEAEs between treatment groups. Efficacy and safety findings in European patients were consistent with the overall ARASENS population.
In preliminary studies, dabrafenib plus trametinib showed clinically beneficial results in patients with radioactive iodine-refractory BRAFV600E-positive differentiated thyroid cancer. However, the combination has not been studied in a phase 3 trial yet. To address this, we studied the efficacy and safety of dabrafenib plus trametinib in patients with radioactive iodine-refractory BRAFV600E-positive differentiated thyroid cancer. In this phase 3, global, randomised, double-blind, placebo-controlled trial, previously treated patients aged ≥18 years with locally advanced or metastatic, radioactive iodine-refractory BRAFV600E-positive differentiated thyroid cancer and Eastern Cooperative Oncology Group performance status 0-2 were enrolled from 42 sites in 11 countries. Participants were randomly assigned (2:1) to receive either dabrafenib (150 mg orally; twice daily) plus trametinib (2 mg orally; once daily) or matching placebos. Randomisation was computer generated and was stratified by the number of previous vascular endothelial growth factor receptor-targeted therapies and previous lenvatinib treatment with block sizes of six per stratum combination. Patients, investigators, and funders were masked to treatment assignment. The primary endpoint was progression-free survival, defined as time from randomisation or start of the treatment to first progression or death, assessed by the blinded independent review committee per Response Evaluation Criteria in Solid Tumors version 1.1 in all randomly assigned patients. The secondary outcomes were overall survival, overall response rate, duration of response, and safety. This trial is registered with ClinicalTrials.gov, NCT04940052, and is ongoing. From Dec 10, 2021, to May 09, 2024, 153 patients with differentiated thyroid cancer were assigned to receive either dabrafenib plus trametinib (n=101) or placebo (n=52). 73 (48%) participants were male and 80 (52%) participants were female, mean age was 62·6 years (SD 10·2), 18 (12%) participants were White, 131 (86%) were Asian, three (2%) were Black or African American, and one (1%) was from multiple races. With a median follow-up of 17·4 months (IQR 10·5-25·2), progression-free survival was significantly longer in patients in the dabrafenib plus trametinib group compared with those in the placebo group (median 12·8 months [95% CI 10·2-21·2] vs 3·7 months [2·3-7·5]; stratified hazard ratio [HR] 0·38, 95% CI 0·25-0·57; p<0·0001). Dabrafenib plus trametinib treatment resulted in a significantly higher overall response rate (58 [57%] of 101) compared with placebo (two [4%] of 52; stratified difference 53% [95% CI 42-64, p<0·0001]). An interim analysis of overall survival did not achieve significance for dabrafenib plus trametinib over placebo (stratified HR 0·66, 95% CI 0·36-1·19; p=0·083]. The median duration of response was not reached. The most common grade 3 or worse adverse event was pneumonia, which occurred in eight (8%) of 101 patients in the dabrafenib plus trametinib group and one (2%) of 52 patients in the placebo group. Any-grade serious adverse events occurred in 43 (43%) patients in the dabrafenib plus trametinib group and 13 (25%) patients in the placebo group. One (1%) on-treatment death occurred in the dabrafenib plus trametinib group due to cerebrovascular accident, which was assessed by the investigator as related to the study drug. The most common adverse event in the dabrafenib plus trametinib group was pyrexia (n=48; 48%). Adverse events leading to discontinuation occurred in eight (8%) patients in the dabrafenib plus trametinib group and three (6%) patients in the placebo group. Grade 5 adverse events of pneumonia (n=2; 2%), bradycardia (n=1; 1%), cerebrovascular accident (n=1; 1%), septic shock (n=1; 1%), and squamous cell carcinoma (n=1; 1%) occurred in the dabrafenib plus trametinib group and events of pericardial effusion and multiple organ dysfunction syndrome occurred in one patient each (2%) the placebo group. Serous retinopathy adverse events were seen in seven (7%) patients in the dabrafenib plus trametinib group and none in the placebo group. In previously-treated patients with locally advanced or metastatic, radioactive iodine-refractory BRAFV600E-positive differentiated thyroid cancer, dabrafenib plus trametinib showed significant benefits for progression-free survival and overall response rate, with no new safety signals. These findings support the second-line use of dabrafenib plus trametinib in patients with radioactive iodine-refractory BRAFV600E-positive differentiated thyroid cancer. Novartis Pharmaceuticals.
The serine-threonine protein kinase B-RAF (BRAF) V600 mutation confers a poor prognosis in metastatic colorectal cancer (mCRC). Mosperafenib is a novel, paradox-breaking BRAF inhibitor (BRAFi). In this analysis of a phase I study (ISRCTN13713551), we evaluated circulating tumor DNA (ctDNA) as a prognostic and predictive biomarker for mosperafenib monotherapy in BRAF V600-mutant mCRC. We analyzed 49 biomarker-evaluable patients with mCRC (BRAF V600-mutant; 23 BRAFi-naive, and 26 BRAFi-experienced). Plasma samples were collected at baseline and longitudinally. ctDNA levels were quantified using tumor-naive and tumor-informed assays and correlated with RECIST 1.1 response and progression-free survival (PFS). Mutational profiles were assessed to identify resistance mechanisms. Low baseline ctDNA (≤10% tumor fraction) was prognostic for longer median PFS (mPFS; 284 vs. 59 days; HR = 0.32, P = 0.00051). Early ctDNA dynamics were highly predictive; a ≥75% ctDNA reduction at cycle 1 day 15 (C1D15; "molecular response") correlated with longer mPFS (281 vs. 43 days, P < 0.0001). This molecular response occurred in all BRAFi-naive patients versus 48% of BRAFi-experienced patients. Preexisting MAPK pathway resistance mutations were prevalent and prognostic for poor outcomes in the BRAFi-experienced cohort (HR = 3.5, P = 0.003), whereas BRAFi-naive patients acquired these at progression. ctDNA is a powerful biomarker for mosperafenib-treated BRAF V600-mutated mCRC. Low baseline ctDNA is highly prognostic, whereas an early, deep molecular response at C1D15 predicts durable benefit. This response is largely confined to BRAFi-naive patients, as preexisting MAPK pathway alterations in BRAFi-experienced patients correlate with lack of response. These findings support using early ctDNA dynamics as an efficacy endpoint in future trials. This study in BRAF V600-mutant mCRC treated with mosperafenib confirms ctDNA's translational utility. Low baseline ctDNA associated with longer PFS and an early deep molecular response predicted durable clinical benefit, supporting its use as an early efficacy endpoint. In addition, ctDNA monitoring enables identification of resistance mechanisms.
The global expansion of highly pathogenic avian influenza A (H5N1), particularly the clade 2.3.4.4b lineage, has renewed urgent concerns about its pandemic potential in the context of its ongoing panzootic expansion and increasing cross-species transmission. Despite decades of preparedness initiatives, critical technological and structural gaps persist, especially in low- and middle-income countries (LMICs), where both vaccine access and sustainable manufacturing capacity remain limited. In this perspective, we examine key lessons from past influenza pandemics and global preparedness strategies, including the Global Action Plan for Influenza Vaccines, highlighting persistent challenges related to sustainable manufacturing capacity and equitable vaccine access. Additionally, we examine the potential of messenger RNA (mRNA) vaccine platforms to address these limitations, given their rapid design, scalable manufacturing, and adaptability to emerging pathogens. Moreover, we examine the role of neuraminidase (NA) as a complementary antigen capable of broadening immune protection and reducing viral transmission. Finally, we describe recent advances in Latin America, focusing on Argentina's participation in the mRNA Technology Transfer Programme co-led by the World Health Organization (WHO) and the Medicines Patent Pool (MPP), as a model for strengthening regional manufacturing capacity and contributing to global pandemic preparedness. Together, these elements indicate that effective H5N1 pandemic preparedness will require the integration of improved antigen design, flexible mRNA platforms, and sustainable regional manufacturing systems aligned with global procurement strategies.
CD40 activation on dendritic cells (DCs) enhances tumor antigen cross-priming of tumor-specific cytotoxic T lymphocytes, strengthening anticancer immune responses. RO7300490 is a fibroblast activation protein (FAP)-targeted CD40 agonist antibody. In this phase I study, 80 patients with advanced and/or metastatic solid tumors received RO7300490 biweekly (dose range 16-1,100 mg). The primary objective was to evaluate safety and tolerability. Secondary/exploratory objectives included pharmacokinetics, antitumor activity and pharmacodynamics. Treatment-related adverse events (TRAEs) occurred in 53 patients (66.3%) and were mostly grade 1-2. Grade 3-4 TRAEs (3.8%) and TRAEs leading to discontinuation (2.5%) were uncommon. No grade 5 TRAEs were reported. RO7300490 showed target-mediated drug disposition, with sustained exposure at higher doses. No objective responses and limited clinical activity (disease control rate 42.5%) were observed despite rapid and persistent tumor uptake of radiolabeled RO7300490. Intratumoral pharmacodynamic activity was demonstrated by a significant increase in DC-LAMP+ DC density in paired tumor biopsies. An increase in B cell density was also observed, along with the formation of pretertiary lymphoid structures, co-organized in focal micro-neighborhoods with DCs. In summary, treatment with a tumor-targeted CD40 agonist antibody is feasible, clinically manageable and induces immunomodulation of the tumor microenvironment. ClinicalTrials.gov registration: NCT04857138 .
Little is known about how three-dimensional chromatin topology shapes mammalian craniofacial development. In mouse cranial neural crest cells, a Polycomb Repressive Complex 2 (PRC2)-dependent chromatin architecture is established before migration. This configuration maintains craniofacial gene promoters poised and connects them with distal Polycomb tethering elements, positioning promoters in spatial proximity to future long-range enhancers. Deletion of Ezh2 disrupts this early topology, causing inappropriate gene derepression in post-migratory craniofacial subpopulations where these genes are normally silenced, and failure of long-range enhancer recruitment where activation is required, thereby impairing proper gene expression. We further identify a distal Polycomb tethering element essential for Hoxa2 enhancer recruitment across topologically associating domains. Thus, Polycomb acts not only as a transcriptional repressor, but also as a chromatin-folding organizer that prepares developmental genes for later activation, by facilitating subsequent recruitment of distal active enhancers previously not in contact. Polycomb-mediated topology therefore orchestrates the transition from progenitor plasticity to precise spatiotemporal control of morphogenetic gene programs during neural crest development and face formation.
Fibroblast activation protein (FAP) is an attractive target for radiopharmaceutical therapy. Phase I of the LuMIERE study (ClinicalTrials.gov, NCT04939610) investigated the safety of [177Lu]Lu-FAP-2286 (177Lu-FAP-2286) in heavily pretreated patients with advanced solid tumors and identified the recommended phase II dosage (RP2D). LuMIERE is a prospective, open-label, non-randomized, phase I/II, multicenter study. Phase I followed a Bayesian optimal interval design evaluating four escalating activity levels of 177Lu-FAP-2286 (3.70, 5.55, 7.40, and 9.25 GBq). Patients were selected by positive [68Ga]Ga-FAP-2286 (68Ga-FAP-2286, also known as [68Ga]Ga-HKG301) PET/CT imaging on all target lesions (SUVmax ≥1.5× SUVmean of mediastinal blood pool). 177Lu-FAP-2286 was administered intravenously every 6 weeks for ≤6 cycles. The primary endpoint was dosage-limiting toxicities (DLTs) and treatment-emergent adverse events (TEAEs). Of 35 patients imaged with 68Ga-FAP-2286, 27 received 177Lu-FAP-2286 (3.70 GBq, n=3; 5.55 GBq, n=6; 7.40 GBq, n=7; 9.25 GBq, n=11). Two DLTs were observed: one patient who received 5.55 GBq of 177Lu-FAP-2286 experienced Grade 4 lymphopenia and one patient who received 9.25 GBq experienced Grade 3 hemoptysis; these were the only treatment-related Grade ≥3 TEAEs. All-cause Grade ≥3 TEAEs were reported for 11 patients (40.7%). The RP2D for 177Lu-FAP-2286 monotherapy was determined as 9.25 GBq. Preliminary RECIST efficacy findings demonstrated partial response in one patient and stable disease in 10 patients (maintained for at least two assessments in six patients). 177Lu-FAP-2286 was well tolerated in patients with advanced solid tumors. The safety and preliminary efficacy findings support its continued development in phase II.
Pleuroparenchymal fibroelastosis (PPFE) is a progressive interstitial lung disease (ILD) with defining histology of intra-alveolar fibrosis with septal elastosis (AFE), suggesting unique cellular disease processes. Here, we present a binational single-nucleus RNA sequencing atlas of PPFE, based on explanted lungs from 40 patients. Immunofluorescence microscopy, RNA in situ hybridization, micro-computed tomography (CT), and hierarchical phase-contrast (HiP) synchrotron CT provided spatial context. We identify PPFE-associated adventitial and elastofibrotic fibroblasts as key drivers of elastotic remodeling within an inflammatory microenvironment, maintained by immune cells forming tertiary lymphoid structures. Spatial mapping reveals an intriguing zonation of AFE, maintained by intercellular circuits between PPFE-associated cell types. Comparative analysis with idiopathic pulmonary fibrosis highlights CTHRC1+ fibrotic fibroblasts and aberrant basaloid cells as conserved profibrotic cellular machinery mediating collagen deposition across ILDs. This integrative atlas defines the cellular landscape of PPFE and dissects elastotic from fibrotic remodeling, providing a molecular rationale for niche-specific therapeutic strategies.
We evaluated cibisatamab, a carcinoembryonic antigen (CEA)-directed CD3 T cell-engaging bispecific antibody, in combination with FAP-4-1BBL, a fibroblast activation protein (FAP)-targeted 4-1BB ligand providing tumor-localized co-stimulation, in an open-label phase 1b dose-escalation study in patients with microsatellite-stable (MSS) metastatic colorectal cancer (mCRC) progressing after two or more prior therapies. Patients received cibisatamab with escalating doses of FAP-4-1BBL weekly or every 3 weeks after obinutuzumab pretreatment to mitigate anti-drug antibody formation. The primary endpoint was safety; secondary endpoints included antitumor activity, pharmacokinetics and biomarker analyses. Among 52 treated patients, the combination showed a manageable safety profile. Dose-limiting toxicities occurred in 2 out of 52 patients (3.8%). Cytokine release syndrome (CRS) occurred in 30 out of 52 patients (57.7%; grade ≥3: 2 out of 52, 3.8%) and was manageable; after a cycle 1 cibisatamab dose reduction to 60 mg, serious CRS occurred in 4 out of 27 patients (14.8%; grade ≥3: 0 out of 27). Gastrointestinal toxicities consistent with CEA-directed T cell engagement were observed. Colitis occurred in 7 out of 52 patients (13.5%), including immune-mediated enterocolitis and one fatal cytomegalovirus colitis. No maximum tolerated dose of FAP-4-1BBL was established. Confirmed partial responses were observed in 7 out of 52 patients (13.5%). Pharmacodynamic analyses demonstrated systemic immune activation, including increased IFNγ, soluble CD25, soluble 4-1BB (CD137) and activated, proliferating CD8+ T cells. Paired tumor biopsies showed increased intratumoral CD8+ and CD8+Ki67+ T cell infiltration. These findings demonstrate the feasibility of combining tumor antigen-directed T cell engagement with localized co-stimulation, with evidence of immune activation and preliminary antitumor activity supporting further clinical development. ClinicalTrials.gov identifier: NCT04826003 .
PURPOSE: The role of adjuvant fractionated radiotherapy (aFRT) after gross total resection (GTR) of WHO-2 meningiomas remains unclear. We aimed to estimate the effect of aFRT on recurrence risk and survival following GTR and subtotal resection (STR). METHODS: We analyzed 1452 patients with WHO-2 from our international, multicenter database (followed between 1989 and 2019). Outcomes were recurrence (10-year follow-up) and death (5-year follow-up). Risk estimates were obtained using competing risks and survival analysis. Average treatment effects were estimated by G-computation, adjusted for potential confounding by age, sex, Simpson grade, Ki-67 proliferation index, location, country group (universal healthcare or not), and year of treatment initiation. The robustness of findings was examined through sensitivity analyses. RESULTS: Overall, 276 of 1452 patients (19.0%) received aFRT. Among GTR patients, unadjusted analysis showed comparable recurrence proportions between irradiated and non-irradiated patients (25.5% vs. 22.8% within 5 years). Adjusted analyses provided no evidence that aFRT reduced the risk of recurrence (largest difference: −2.7%, 95% CI −5.6 to 0.2); although, the CIs include the possibility of small beneficial effects. In STR patients, aFRT was associated with reduced recurrence risk in both unadjusted and adjusted analyses. Unexpectedly, a higher mortality was observed among irradiated GTR patients, largely driven by older patients with low Ki-67 PI receiving aFRT. Sensitivity analyses showed similar results for patients with STR but discrepancy in estimates for those with GTR. CONCLUSION: Adjuvant FRT showed a consistent reduction in recurrence risk after STR while inconsistent recurrence risk estimates were observed for patients with GTR. The findings reflect efficacy of aFRT using real-world data without standardized guidelines.
Mosunetuzumab is approved as an intravenous (IV) formulation for relapsed/refractory (R/R) follicular lymphoma (FL) after ≥ 2 prior therapies. A subcutaneous (SC) formulation, aiming to improve patient safety and convenience, has been developed. We report the primary analysis of pharmacokinetics (PK), efficacy, and safety of mosunetuzumab SC (N = 94; median follow-up: 26.1 months) at the recommended Phase 2 dose (Cycle [C]1 Day [D]1: 5 mg; C1D8 and D15, and C2D1 onwards: 45 mg) in patients with R/R FL after ≥ 2 prior therapies, alongside data from a within-study comparator cohort of mosunetuzumab IV in a similar patient population (N = 90; median follow-up: 22.5 months). The co-primary PK endpoints (Ctrough and AUC) were met, demonstrating non-inferior exposure of mosunetuzumab SC versus IV (observed Ctrough[C3]: geometric mean ratio [GMR] 1.39 [90% confidence interval (CI): 1.20-1.61]; AUC0-84: GMR 1.06 [90% CI: 0.92-1.21]). Mosunetuzumab SC efficacy was consistent with IV: overall response rate, 76.6% (95% CI: 66.7-84.7); complete response rate, 61.7% (95% CI: 51.1-71.5); median duration of complete response, 34.6 months (95% CI: 20.7-not evaluable [NE]); and median progression-free survival, 23.7 months (95% CI: 14.6-NE). Mosunetuzumab SC demonstrated a favorable safety profile versus mosunetuzumab IV with a numerically lower rate (29.8% vs. 44.4%) and severity (grade ≥ 2: 9.6% vs. 18.9%) of cytokine release syndrome (CRS) events. Mosunetuzumab SC combines the benefits of short administration time, fixed-duration treatment, outpatient accessibility, and low CRS rate, offering clinically meaningful improvements in patient convenience and safety. Trial Registration: www.clinicaltrials.gov: NCT02500407.
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The Ki-67 proliferation index (Ki-67 PI) has been associated with meningioma recurrence, yet its clinical utility remains debated. Whether Ki-67 PI provides prognostic information across subgroups defined by both WHO grade and extent of resection remains to be investigated. We analyzed 5,050 patients with intracranial meningiomas from the international PERNS cohort (42 centers, diagnosed between 1989-2019) who underwent surgical resection without postoperative radiotherapy. Ki-67 PI prognostic accuracy was assessed up to 10 years postoperatively by using ROC analyses and estimating its association with the risk of recurrence. Results demonstrated that the prognostic value of Ki-67 PI differed by subgroups defined by WHO grade and Simpson grade. For patients with the same Simpson grade (1-3), the predictive accuracy of Ki-67 PI for 10-year recurrence risk was stronger in WHO-2 than in WHO-1. Within WHO-1 and WHO-2 meningiomas, the predictive accuracy of Ki-67 PI increased with higher Simpson grade (1-3). However, no predictive value was observed in Simpson grade 4 resections regardless of WHO grade. These findings highlight that Ki-67 PI should be interpreted in the context of both WHO grade and extent of resection, and, if done so, may offer potential value to refine individualized surveillance strategies in meningioma patients with gross total resection in the initial 10-year postoperative timeframe. Findings cannot be extrapolated beyond 10 years, which may be particularly relevant for WHO-1 tumors with low Ki-67 PI and Simpson grade 1 resection.
Sex-specific outcomes after breakthrough ischemic stroke on oral anticoagulation (OAC) are unexplored. We compared 90-day outcomes by sex and explored modifiers. ASPERA-R (Advancing Knowledge in Ischemic Stroke Patients on Oral Anticoagulants retrospective cohort; NCT06823466) was an international, multicenter, retrospective study enrolling adults (aged >18 years) with breakthrough ischemic stroke on OAC for atrial fibrillation. Primary outcome was 90-day return to baseline neurologic function (modified Rankin Scale [mRS] score 0-1 maintained if prestroke 0-1; or same/lower mRS score if prestroke ≥2). Secondary outcomes were 90-day mRS shift, recurrent ischemic stroke/transient ischemic attack, myocardial infarction, and all-cause and vascular death. Safety outcomes included 90-day moderate-to-severe bleeding, intracranial hemorrhage, 24-hour hemorrhagic transformation, and 24-hour symptomatic intracranial hemorrhage. We applied inverse probability weighting and regression models to compare outcomes. Prespecified subgroup analysis tested sex-specific interactions. We included 1649 patients (women, 52.2%; mean±SD age, 78.0±10.7 years). Women were older (80.2±9.6 versus 76.3±10.8 years; unweighted standardized mean difference=0.376), had higher baseline National Institutes of Health Stroke Scale score (13 [interquartile range, 9-19] versus 9 [interquartile range, 4-17]; unweighted standardized mean difference=0.227), and worse prestroke mRS score (unweighted standardized mean difference=0.237). After weighting, women were less likely to return to baseline neurologic function (35.2% versus 42.7%; adjusted risk ratio, 0.82 [95% CI, 0.71-0.96]; P=0.015), had worse mRS distribution (adjusted odds ratio, 1.17 [95% CI, 1.01-1.37]; P=0.043), and had higher recurrent ischemic stroke/transient ischemic attack (4.8% versus 2.8%; adjusted hazard ratio [HR], 1.70 [95% CI, 1.01-2.86]; P=0.045). Women showed a trend toward more moderate-to-severe bleeding (4.6% versus 2.8%; adjusted HR, 1.63 [95% CI, 0.96-2.72]; P=0.070). Subgroup analyses revealed significant sex interactions for OAC type, competing cause, endovascular treatment, and OAC restart. Women had worse 90-day outcomes than men after breakthrough ischemic stroke on OAC for atrial fibrillation, highlighting the need for sex-aware management.