Chronic subdural haematoma (CSDH) is one of the most common neurological disorders, and is especially prevalent among elderly individuals. Surgical evacuation is the mainstay of management for symptomatic patients or haematomas exerting significant mass effect. Although burr hole craniostomy is the most widely practised technique worldwide, approximately 10-20% of surgically treated patients experience postoperative recurrence necessitating reoperation. Given the increasing incidence of CSDH in a growing elderly population, a need exists for refined techniques that combine a minimally invasive approach with clinical efficacy and cost-effectiveness. In addition, nonsurgical treatment modalities, such as steroids, are attracting considerable interest, as they have the potential to reduce postoperative recurrence or even replace the need for surgery in selected patients. This Review provides an overview of the contemporary management of CSDH and presents considerations regarding future approaches that could further optimize patient care and outcomes.

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Mitogen-activated protein (MAP) kinases phosphorylate the estrogen receptor and activate transcription from estrogen receptor-regulated genes. Here we examine potential interactions between the MAP kinase cascade and androgen receptor-mediated gene regulation. Specifically, we have studied the biological effects of mitogen-activated protein kinase kinase kinase 1 (MEKK1) expression in prostate cancer cells. Our findings demonstrate that expression of constitutively active MEKK1 induces apoptosis in androgen receptor-positive but not in androgen receptor-negative prostate cancer cells. Reconstitution of the androgen receptor signaling pathway in androgen receptor-negative prostate cancer cells restores MEKK1-induced apoptosis. MEKK1 also stimulates the transcriptional activity of the androgen receptor in the presence or absence of ligand, whereas a dominant negative mutant of MEKK1 impairs activation of the androgen receptor by androgen. These studies demonstrate an unanticipated link between MEKK1 and hormone receptor signaling and have implications for the molecular basis of hormone-independent prostate cancer growth.

One outstanding challenge for machine learning in diagnostic biomedical imaging is algorithm interpretability. A key application is the identification of subtle epileptogenic focal cortical dysplasias (FCDs) from structural MRI. FCDs are difficult to visualize on structural MRI but are often amenable to surgical resection. We aimed to develop an open-source, interpretable, surface-based machine-learning algorithm to automatically identify FCDs on heterogeneous structural MRI data from epilepsy surgery centres worldwide. The Multi-centre Epilepsy Lesion Detection (MELD) Project collated and harmonized a retrospective MRI cohort of 1015 participants, 618 patients with focal FCD-related epilepsy and 397 controls, from 22 epilepsy centres worldwide. We created a neural network for FCD detection based on 33 surface-based features. The network was trained and cross-validated on 50% of the total cohort and tested on the remaining 50% as well as on 2 independent test sites. Multidimensional feature analysis and integrated gradient saliencies were used to interrogate network performance. Our pipeline outputs individual patient reports, which identify the location of predicted lesions, alongside their imaging features and relative saliency to the classifier. On a restricted ‘gold-standard’ subcohort of seizure-free patients with FCD type IIB who had T1 and fluid-attenuated inversion recovery MRI data, the MELD FCD surface-based algorithm had a sensitivity of 85%. Across the entire withheld test cohort the sensitivity was 59% and specificity was 54%. After including a border zone around lesions, to account for uncertainty around the borders of manually delineated lesion masks, the sensitivity was 67%. This multicentre, multinational study with open access protocols and code has developed a robust and interpretable machine-learning algorithm for automated detection of focal cortical dysplasias, giving physicians greater confidence in the identification of subtle MRI lesions in individuals with epilepsy.

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Despite improved outcomes with current MM treatments, most patients (pts) will develop refractory disease, highlighting the need for novel treatments. GPRC5D is an orphan receptor whose transcript is highly expressed in primary MM cells but has generally limited expression elsewhere, making it an attractive therapeutic target. Talquetamab (JNJ-64407564) is a first-in-class bispecific antibody that binds to GPRC5D and CD3 to induce T cell-mediated killing of GPRC5D-expressing MM cells through the recruitment and activation of T cells. In preclinical models, talquetamab induced cell killing of primary MM cells and inhibited tumor formation and growth in MM mouse models. We present initial results from an ongoing phase 1 dose escalation study of talquetamab (NCT03399799). Eligible pts have measurable MM and progressed on or could not tolerate established therapies. Primary objectives are to characterize the safety of talquetamab and to identify a recommended phase 2 dose (RP2D). Escalating doses of intravenous (IV) or subcutaneous (SC) talquetamab ± step-up doses were assessed. Secondary objectives include characterizing the pharmacokinetics, pharmacodynamics, and preliminary efficacy. Adverse events (AEs) were graded per CTCAE, cytokine release syndrome (CRS) per Lee 2014. Response was assessed by the investigator according to IMWG criteria. As of 20 Jul 2020, 137 pts had received talquetamab; 102 by IV (0.5 - 180 µg/kg) and 35 by SC (5 - 800 µg/kg) dosing. Median age was 64 years (33 - 80; 31% were ≥70) and 22% had ISS stage III disease at study entry. Median number of prior therapies was 6 (2 - 20) over a median of 6.5 years (0.9 - 27) since diagnosis, 85% were refractory to last line of therapy, 79% triple-class refractory, 73% penta-drug exposed, and 31% penta-drug refractory. 13 (10%) pts had received selinexor and 21 (15%) had prior BCMA-directed therapy. Most frequently reported all grade AEs were anemia (50%), CRS (47%), neutropenia (45%), and lymphopenia (40%). Most common grade 3 - 4 AEs were lymphopenia (37%), anemia (27%), and neutropenia (25%). CRS was mostly grade 1 - 2 except for 5 pts with grade 3 CRS (˂8% of pts with CRS) that occurred with IV dosing; only grade 1 - 2 CRS was seen with SC dosing. CRS was generally confined to the first cycle with median time to onset of 1 day (1 - 3) for IV and 2 days (1 - 5) for SC dosing. Treatment-related neurotoxicity was reported in 7 (5%) pts (all resolved/resolving; median duration of 2 days [1 - 9]): 4 had grade 1 - 2 events and 3 had grade 3 events of delirium (n=1), decreased level of consciousness (n=1), or confusion (n=1). Six of 7 pts had neurotoxicity that occurred in the context of CRS, including all 3 grade 3 events. Infections were reported in 37% of pts (8% grade 3 - 4). Infusion related reactions (IV; 15%) and injection site reactions (SC; 14%) were grade 1 - 2 and generally occurred in cycle 1. Two dose-limiting toxicities were observed: clinically asymptomatic grade 4 increased lipase in the setting of a pancreatic plasmacytoma (7.5 µg/kg IV) and grade 3 maculopapular rash (135 µg/kg SC). The maximum tolerated dose (MTD) has not been defined. The half-life of talquetamab supports weekly IV dosing. Exposure increased in an approximately dose-proportional manner following the first IV dose (1.5 - 60 µg/kg). SC dosing resulted in lower Cmax with trough levels comparable to IV dosing at a similar dose. IV and SC dosing of talquetamab led to comparable increases in T cell activation and cytokines (e.g., IL-10, IL-2Rα, IL-6). Cytokine production was modulated with step-up dosing while T cell activation was maintained. Overall response rate (ORR) for IV doses of 20 - 180 µg/kg was 78% (14/18; 2 pending confirmation); 6/6 responded at the 60 µg/kg IV dose. ORR for SC doses of 135 - 405 µg/kg was 67% (8/12); 3/4 responded at the 405 µg/kg SC dose. Responses were noted starting at 1.0 µg/kg, were rapid at a median of 1 month (0.2 - 3), and durable with median not reached in 36/46 (4 pts with response 15+ months; longest at 23+ months). Data at higher doses are immature, and results will be updated at the meeting. GPRC5D is a novel target for MM and in the first clinical report of this first-in-class agent, encouraging clinical activity with manageable safety was observed with talquetamab in heavily pretreated pts with RRMM. A MTD has not been defined and dose escalation continues, with the study nearing a RP2D. The encouraging clinical activity supports monotherapy development and combination approaches. Disclosures Chari: Novartis: Honoraria; Array BioPharma: Honoraria; The Binding Site: Honoraria; Bristol Myers Squibb: Consultancy; Adaptive Biotechnology: Honoraria; Pharmacyclics: Research Funding; Karyopharm: Consultancy; Sanofi Genzyme: Consultancy; Seattle Genetics: Consultancy, Research Funding; Oncopeptides: Consultancy; Takeda: Consultancy, Research Funding; Antengene: Consultancy; Glaxo Smith Kline: Consultancy; Secura Bio: Consultancy; Amgen: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding. Berdeja:Takeda: Consultancy, Research Funding; Servier: Consultancy; Teva: Research Funding; Prothena: Consultancy; Poseida: Research Funding; Lilly: Research Funding; Novartis: Research Funding; Acetylon: Research Funding; BMS: Consultancy, Research Funding; CURIS: Research Funding; Karyopharm: Consultancy; Bluebird: Research Funding; EMD Sorono: Research Funding; Bioclinica: Consultancy; Kesios: Research Funding; Amgen: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Genentech, Inc.: Research Funding; Kite Pharma: Consultancy; CRISPR Therapeutics: Consultancy, Research Funding; Abbvie: Research Funding; Constellation: Research Funding; Cellularity: Research Funding; Vivolux: Research Funding; Legend: Consultancy; Glenmark: Research Funding; Celgene: Consultancy, Research Funding. Oriol:Janssen: Consultancy; Amgen: Consultancy, Speakers Bureau; Sanofi: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. van de Donk:BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; TAKEDA: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; ROCHE: Membership on an entity's Board of Directors or advisory committees; AMGEN: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Rodriguez:Oncopeptides: Consultancy; Sanofi: Consultancy; Abbvie: Consultancy; Kite: Consultancy; GSK: Consultancy; Janssen: Consultancy, Honoraria; Celgene-BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria; Medscape: Membership on an entity's Board of Directors or advisory committees. Askari:Hospital Universitario Fundacion Jimenez Diaz: Consultancy, Current Employment. Mateos:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy; Pharmamar: Consultancy; Adaptive: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; EDOMundipharma: Consultancy; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Minnema:Janssen Cilag: Honoraria; Celgene Corporation: Honoraria, Research Funding; Gilead: Honoraria; Amgen: Honoraria; Servier: Honoraria. Verona:Johnson & Johnson: Current Employment, Current equity holder in publicly-traded company. Girgis:Johnson & Johnson: Current Employment, Current equity holder in publicly-traded company. Prior:Johnson & Johnson: Current Employment, Current equity holder in publicly-traded company. Hilder:Johnson & Johnson: Current Employment, Current equity holder in publicly-traded company. Russell:Johnson & Johnson: Current Employment, Current equity holder in publicly-traded company. Goldberg:Johnson & Johnson: Current Employment, Current equity holder in publicly-traded company. Krishnan:Takeda: Speakers Bureau; Sanofi: Consultancy; Sutro: Membership on an entity's Board of Directors or advisory committees; Z Predicta: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy; Regeneron: Consultancy; Amgen: Speakers Bureau; BMS/Celgene: Consultancy, Other: Stock BMS, Speakers Bureau.

Summary Objective Drug‐resistant epilepsy (DRE) during the first few months of life is challenging and necessitates aggressive treatment, including surgery. Because the most common causes of DRE in infancy are related to extensive developmental anomalies, surgery often entails extensive tissue resections or disconnection. The literature on “ultra‐early” epilepsy surgery is sparse, with limited data concerning efficacy controlling the seizures, and safety. The current study's goal is to review the safety and efficacy of ultra‐early epilepsy surgery performed before the age of 3 months. Methods To achieve a large sample size and external validity, a multinational, multicenter retrospective study was performed, focusing on epilepsy surgery for infants younger than 3 months of age. Collected data included epilepsy characteristics, surgical details, epilepsy outcome, and complications. Results Sixty‐four patients underwent 69 surgeries before the age of 3 months. The most common pathologies were cortical dysplasia (28), hemimegalencephaly (17), and tubers (5). The most common procedures were hemispheric surgeries (48 procedures). Two cases were intentionally staged, and one was unexpectedly aborted. Nearly all patients received blood products. There were no perioperative deaths and no major unexpected permanent morbidities. Twenty‐five percent of patients undergoing hemispheric surgeries developed hydrocephalus. Excellent epilepsy outcome (International League Against Epilepsy [ILAE] grade I) was achieved in 66% of cases over a median follow‐up of 41 months (19–104 interquartile range [IQR]). The number of antiseizure medications was significantly reduced (median 2 drugs, 1–3 IQR, p < .0001). Outcome was not significantly associated with the type of surgery (hemispheric or more limited resections). Significance Epilepsy surgery during the first few months of life is associated with excellent seizure control, and when performed by highly experienced teams, is not associated with more permanent morbidity than surgery in older infants. Thus surgical treatment should not be postponed to treat DRE in very young infants based on their age.