Citations

Abstract Objective This study was undertaken to evaluate the safety and effectiveness of responsive thalamic stimulation as adjunctive therapy for drug‐resistant idiopathic generalized epilepsy (IGE) with generalized tonic–clonic seizures (GTCSs). Methods NAUTILUS is a prospective, multicenter, single‐blind, randomized sham‐controlled pivotal trial. Patients were ≥12 years of age with drug‐resistant IGE and ≥2 GTCSs over a 3‐month baseline. Bilateral depth leads were targeted to the centromedian thalamus. One month later, patients were randomized to Active (responsive stimulation, n = 44) or Sham (no stimulation, n = 43). The effectiveness evaluation period (EEP) began 3 months postimplant through 1 year. After a second GTCS in the EEP, patients transitioned to open‐label active stimulation. The primary safety endpoint was the serious adverse device‐related event (SADE) rate at 84 days postimplant. The primary effectiveness endpoint was time‐to‐second‐GTCS during the EEP. Additional endpoints included median percent change in days with any generalized seizure, GTCS frequency, and responder rate (RR). Results Eighty‐seven patients were implanted across 23 US centers. The SADE rate was significantly below the performance goal (6.9%, p < .0001), with no adverse effects on cognition, mood, or sleep. The prespecified primary effectiveness endpoint was not significant. However, a post hoc mixed‐effects model considering all EEP days demonstrated greater GTCS reduction in the originally randomized Active group (61%) compared to patients originally randomized to Sham (49%, p = .030). Eighteen‐month outcomes included 76.8% median GTCS reduction, 62.5% RR, 40% GTCS‐free at that timepoint, and 77.8% median reduction in days with any generalized seizure. More than 90% of patients and 86% of physicians reported improvement on Global Impression of Change scales. Significance NAUTILUS is the first randomized controlled neuromodulation trial in IGE. Responsive thalamic stimulation provided a clinically meaningful and durable reduction in seizures with an acceptable safety profile, offering a much‐needed option for drug‐resistant IGE.

Abstract Introduction Ph-like B-ALL is a poor-risk B-ALL subtype defined by gene expression signatures that resemble the BCR::ABL1-associated transcriptional program in the absence of the BCR-ABL1 oncoprotein. Recent studies have demonstrated that up to 80% of Ph-like B-ALLs have recurrent gene fusions involving cytokine receptors or tyrosine kinases that can be identified via cytogenetics, fluorescence in situ hybridization (FISH) or RNA sequencing. However, the inability to rapidly and accurately identify these alterations in the clinical setting is a major impediment to developing therapeutic strategies that may have efficacy in this B-ALL subtype. Here we used 88 patient (pt) samples to validate a rapid, streamlined clinical WGS assay (ChromoSeq) for B-ALL and assessed the diagnostic yield for Ph-like-associated SVs in 136 pts enrolled in the Alliance A041501 clinical trial. Methods ChromoSeq is a clinical WGS assay for hematologic malignancies that uses rapid laboratory workflows and focused analysis methods to identify clinically relevant SVs, copy number alterations and gene-level mutations. We updated the ChromoSeq pipeline for use in B-ALL pts and validated it using 88 retrospective B-ALL samples (80 adult/young adult and 8 pediatric from Washington University School of Medicine and St. Louis Children's Hospital), 54 of which were analyzed via RNAseq for gene fusions and a 6-gene Ph-like B-ALL signature (CA6, SPATS2L, MUC4, JCHAIN, BMPR1B, ADGRF1, NRXN3 and CRLF2). The “ChromoSeqV2” assay was then used to analyze 136 pretreatment blood or bone marrow samples from the Alliance A041501 (trial NCT03150693). These results were compared to data from RNAseq obtained for research purposes (N=35), clinical cytogenetics (N=69) and Ph-like classification via low-density microarray (LDA) card analysis (all pts). Results ChromoSeqV2 was validated in a CLIA-licensed setting using cohort of 88 retrospective B-ALL samples, 45 of which had ICC and WHO class-defining SVs based on G-banded karyotyping, FISH or RNAseq. ChromoSeqV2 detected 100% of the non-Ph-like SVs (37/37), including BCR::ABL1 (N=20), KMT2Ar (N=9), ETV6::RUNX1 (N=3), TCF3::PBX1 (N=1), and rearrangements involving MYC (N=2) or MEF2D (N=2). Fifteen patients met criteria for Ph-like B-ALL via cytogenetics or RNAseq either due to rearrangements of CRLF2 (N=5), JAK2 (N=2) or ABL2 (N=1) or high expression of a 6-gene Ph-like signature (N=7). ChromoSeqV2 detected a Ph-like SV in 93% of these cases (14/15) with 100% specificity in samples negative by RNAseq (N=23). ChromoSeqV2 was then used to profile 136 samples from the Alliance A041501 trial, where it identified ICC and WHO class-defining SVs in 87 pts (64%; 95% CI: 55-72%), including Ph-like SVs (56/136, 41%), KMT2A rearrangements (N=5), TCF3::PBX1 (N=3) and SVs involving MYC (N=3), MEF2D (N=2), DUX4 (N=2), and ZNF384 (N=1). Ph-like SVs were dominated by CRLF2 rearrangements (N=45) and included SVs involving EPOR (N=4), JAK2 (N=3), ABL1/ABL2 (N=2) and PDGFRB (N=1). IGH was the most common CRLF2 partner (N=32), followed by P2RY8::CRLF2 (N=7) and other genes (N=5). Multiple CRLF2 SVs were detected in 4 pts, and 33% (15/45) of pts with a CRLF2 rearrangement had a co-occurring CRLF2 gene mutation. The yield of ChromoSeqV2 for SVs in pts with the Ph-like expression signature via LDA card analysis was 66% (54/82; 95% CI 55%-76%) compared to 24% (11/45; 95% CI 13%-40%) by cytogenetics when these studies were successful and 70% (12/17; 95% CI 44%-90%) vs RNAseq in pts with available data. The sensitivity of ChromoSeqV2 for Ph-like SVs identified by either cytogenetics, FISH or RNAseq was 100% (21/21; 95% CI 84%-100%) and the positive predictive value of Ph-like SVs for the Ph-like expression signature by the LDA card assay was 96% (54/56; 95% CI 88%-99%). Conclusions Genomic assessment of 136 B-ALL pts from the Alliance A041501 trial using the ChromoSeqV2 rapid clinical WGS assay was 100% sensitive for Ph-like SVs identified by other molecular methods and had a 96% PPV for the Ph-like expression signature via LDA card analysis. The diagnostic yield of SV pts with the Ph-like signature was 66% using ChromoSeqV2, which was similar to RNAseq and superior to cytogenetics. These results demonstrate that ChromoSeqV2 is an effective approach for identifying potentially targetable rearrangements in B-ALL pts suspected of having the Ph-like phenotype. Support: U10CA180821, U10CA180882; . Servier; Pfizer.

Abstract Active learning strategies enhance medical education by fostering self‐directed learning, communication, and problem‐solving skills. The paper puzzle, a game‐based learning approach, provides an engaging way to reinforce anatomical knowledge and promote collaboration. This study assessed its impact on student performance and perceptions in clinical anatomy, comparing it to PowerPoint‐based imaging reviews and evaluating the role of Near Peer Teachers (NPTs). A prospective, longitudinal, quasi‐experimental study with a mixed‐methods approach was conducted on first‐year medical students enrolled in the Human Anatomy course. Surveys using a Likert scale assessed student and NPT perceptions, while focus groups and interviews provided qualitative insights. Thematic analysis identified key themes related to engagement, knowledge reinforcement, and effectiveness. A total of 907 medical students and 30 NPTs completed a survey, while 75 students and 10 NPTs participated in the qualitative phase. Students perceived the paper puzzle as an engaging and interactive review tool that reduced stress, increased involvement, and enhanced knowledge retrieval through collaboration and a structured gameplay loop. They also valued the emotional impact on learning. NPTs reported benefits for student motivation and teamwork but noted that time constraints limited content coverage. The activity's effectiveness was highly dependent on the NPT's facilitation, emphasizing the need for structured implementation. Findings suggested that game‐based learning strategies like the paper puzzle can improve motivation, teamwork, and content retrieving in anatomy education when carefully designed and effectively executed by NPTs.

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Pediatric Acute Lymphoblastic Leukemia (ALL) were developed as a result of meetings convened by a multidisciplinary panel of pediatric ALL experts, with the goal of providing recommendations on standard treatment approaches based on current evidence. The NCCN Guidelines for pediatric ALL focus on risk assessment and stratification of risk-adapted therapy; treatment strategies for BCR::ABL1 (Philadelphia chromosome [Ph])-negative and BCR::ABL1-positive B-cell lineage, T-cell lineage, and infant ALL; and supportive care considerations. This selection from the NCCN Guidelines for pediatric ALL focuses on the diagnosis of and management of pediatric T-ALL.

Abstract Background Massively parallel sequencing (MPS) of nucleic acids has been a transformative technology for basic and applied genomic science, increasing efficiencies and decreasing costs to enable studies of unprecedented scope and impact. In clinical settings, these technological and scientific advances have led to the development of tests that are increasingly fast, comprehensive, and more frequently employed. Practitioners of genomic medicine have applied these tools across clinical settings, including diagnosis of inherited disorders and cancers and infectious disease detection and surveillance. In recent years, the commercial marketplace for MPS sequencers and reagents has been dominated by a few companies. The growing demand for sequencing has led to the recent emergence of several new sequencing platforms with techniques that may provide alternatives or improvements to existing workflows or allow the adoption of sequencing workflows in new settings. Clinical genomics laboratories will evaluate these platforms from a unique perspective, focusing on how technological advancements can improve patient care. Content This review describes short-read sequencing platforms provided by Illumina, Element Biosciences, MGI, PacBio, Singular Genomics, Thermo Fisher Scientific, and Ultima Genomics. This review discusses their innovative approaches, principles, workflows, and applications. Summary This review aims to inform laboratory geneticists, clinicians, and researchers about emerging short-read technologies and their applications in clinical genomics. By highlighting their principles and potential contributions, we aim to assist laboratories in selecting suitable solutions for their sequencing needs considering key factors such as applications, throughput, and integration with existing laboratory workflows.

SummaryObjectiveEvaluate the seizure‐reduction response and safety of mesial temporal lobe (MTL) brain‐responsive stimulation in adults with medically intractable partial‐onset seizures of mesial temporal lobe origin.MethodsSubjects with mesial temporal lobe epilepsy (MTLE) were identified from prospective clinical trials of a brain‐responsive neurostimulator (RNS System, NeuroPace). The seizure reduction over years 2–6 postimplantation was calculated by assessing the seizure frequency compared to a preimplantation baseline. Safety was assessed based on reported adverse events.ResultsThere were 111 subjects with MTLE; 72% of subjects had bilateral MTL onsets and 28% had unilateral onsets. Subjects had one to four leads placed; only two leads could be connected to the device. Seventy‐six subjects had depth leads only, 29 had both depth and strip leads, and 6 had only strip leads. The mean follow‐up was 6.1 ± (standard deviation) 2.2 years. The median percent seizure reduction was 70% (last observation carried forward). Twenty‐nine percent of subjects experienced at least one seizure‐free period of 6 months or longer, and 15% experienced at least one seizure‐free period of 1 year or longer. There was no difference in seizure reduction in subjects with and without mesial temporal sclerosis (MTS), bilateral MTL onsets, prior resection, prior intracranial monitoring, and prior vagus nerve stimulation. In addition, seizure reduction was not dependent on the location of depth leads relative to the hippocampus. The most frequent serious device‐related adverse event was soft tissue implant‐site infection (overall rate, including events categorized as device‐related, uncertain, or not device‐related: 0.03 per implant year, which is not greater than with other neurostimulation devices).SignificanceBrain‐responsive stimulation represents a safe and effective treatment option for patients with medically intractable epilepsy, including patients with unilateral or bilateral MTLE who are not candidates for temporal lobectomy or who have failed a prior MTL resection.

SummaryObjectiveEvaluate the seizure‐reduction response and safety of brain‐responsive stimulation in adults with medically intractable partial‐onset seizures of neocortical origin.MethodsPatients with partial seizures of neocortical origin were identified from prospective clinical trials of a brain‐responsive neurostimulator (RNS System, NeuroPace). The seizure reduction over years 2–6 postimplantation was calculated by assessing the seizure frequency compared to a preimplantation baseline. Safety was assessed based on reported adverse events. Additional analyses considered safety and seizure reduction according to lobe and functional area (e.g., eloquent cortex) of seizure onset.ResultsThere were 126 patients with seizures of neocortical onset. The average follow‐up was 6.1 implant years. The median percent seizure reduction was 70% in patients with frontal and parietal seizure onsets, 58% in those with temporal neocortical onsets, and 51% in those with multilobar onsets (last observation carried forward [LOCF] analysis). Twenty‐six percent of patients experienced at least one seizure‐free period of 6 months or longer and 14% experienced at least one seizure‐free period of 1 year or longer. Patients with lesions on magnetic resonance imaging (MRI; 77% reduction, LOCF) and those with normal MRI findings (45% reduction, LOCF) benefitted, although the treatment response was more robust in patients with an MRI lesion (p = 0.02, generalized estimating equation [GEE]). There were no differences in the seizure reduction in patients with and without prior epilepsy surgery or vagus nerve stimulation. Stimulation parameters used for treatment did not cause acute or chronic neurologic deficits, even in eloquent cortical areas. The rates of infection (0.017 per patient implant year) and perioperative hemorrhage (0.8%) were not greater than with other neurostimulation devices.SignificanceBrain‐responsive stimulation represents a safe and effective treatment option for patients with medically intractable epilepsy, including adults with seizures of neocortical onset, and those with onsets from eloquent cortex.

Purpose Light chain (AL) amyloidosis is caused by the accumulation of misfolded proteins, which induces the dysfunction of vital organs. NEOD001 is a monoclonal antibody targeting these misfolded proteins. We report interim data from a phase I/II dose-escalation/expansion study of NEOD001 in patients with AL amyloidosis and persistent organ dysfunction (NCT01707264). Patients and Methods Patients who had completed at least one previous anti–plasma cell-directed therapy, had partial hematologic response or better, and had persistent organ dysfunction received NEOD001 intravenously every 28 days. Dose levels of 0.5, 1, 2, 4, 8, 16, and 24 mg/kg were evaluated (3 + 3 study design). Primary objectives were to determine the maximum tolerated dose and the recommended dose for future studies and to evaluate safety/tolerability. Secondary and exploratory objectives included pharmacokinetics, immunogenicity, and organ responses on the basis of published consensus criteria. Results Twenty-seven patients were enrolled in seven cohorts (dose-escalation component). No drug-related serious adverse events (AEs), discontinuations because of drug-related AEs, dose-limiting toxicities, or antidrug antibodies were reported. The most frequent AEs were fatigue, upper respiratory tract infection, cough, and dyspnea. Recommended dosing was 24 mg/kg. Pharmacokinetics support intravenous dosing every 28 days. Of 14 cardiac-evaluable patients, eight (57%) met the criteria for cardiac response and six (43%) had stable disease. Of 15 renal-evaluable patients, nine (60%) met the criteria for renal response and six (40%) had stable disease. Conclusion Monthly infusions of NEOD001 were safe and well tolerated. Recommended future dosing was 24 mg/kg. Organ response rates compared favorably with those reported previously for chemotherapy. A phase II expansion is ongoing. A global phase III study (NCT02312206) has been initiated. Antibody therapy targeting misfolded proteins is a potential new therapy for the management of AL amyloidosis.