Citations

AbstractBackgroundRapidly progressive dementia (RPD) is variably defined across published cohorts. A standardized definition is needed to support multicenter studies required to inform the causes of RPD and optimize recognition and management of treatment‐responsive causes. An optimal definition will capture the broad spectrum of causes of RPD, adequately differentiate patients with rapid and typically progressive presentations of neurodegenerative disease, and be reliably implemented across healthcare settings and centers.MethodThe Clinical Dementia Rating® (CDR) is a validated dementia staging tool that is widely used in clinical trials and observational studies. We applied the CDR to diagnose RPD in patients who developed dementia (CDR ≥1) within 1 year or incapacitation (CDR ≥2) within 2 years of symptom onset. This definition was prospectively applied to patients with suspected RPD at Mayo Clinic in Florida (MCF: Jacksonville, FL; Jan 2020 – Oct 2023) and Washington University in St. Louis (WU: Saint Louis, MO; Jun 2016 – Dec 2019), and retrospectively applied to individuals within the National Alzheimer’s Coordinating Center (NACC) dataset. Criteria performance was compared across cohorts.ResultTwo‐hundred twenty‐six patients were referred with suspected RPD at MCF‐WU. Of these, 155/226 (68.6%) met our proposed RPD criteria, including patients with Alzheimer disease and related dementias (ADRD; 34/155, 21.9%), Creutzfeldt Jacob disease (CJD; 25/155, 16.1%), autoimmune encephalitis (52/155, 33.5%), vascular pathologies (14/155, 9.0%), toxic/metabolic disruptions (7/155, 4.5%) and primary psychiatric disorders (4/155, 2.6%). A small subset of NACC participants met our proposed RPD criteria (836/20,418; 0.04%), emphasizing the unique nature of RPD. Causes of RPD in NACC included ADRD (676/836, 80.1%), CJD (72/836, 8.6%), and vascular pathologies (24/836, 2.9%). Rates of progression (∆CDR sum‐of‐boxes/year) clearly distinguished patients with RPD from non‐RPD in both cohorts (MCF‐WU, 13.6±5.8 vs 4.7±5.9, p<0.001; NACC, 6.7±3.1 vs. 1.7±1.4, p<0.001).ConclusionOur CDR‐based definition of RPD distinguished patients with a broad spectrum of causes of RPD from those with typically progressive dementia across multiple cohorts. Broad application of this criteria would standardize diagnosis of RPD and support the design and implementation of multicenter studies RPD.

Abstract BMT CTN (Blood and Marrow Transplant Clinical Trials Network) 1506 (“MORPHO”) was a randomized study of gilteritinib compared with placebo as maintenance therapy after hematopoietic cell transplantation (HCT) for patients with FLT3-ITD–mutated acute myeloid leukemia (AML). A key secondary end point was to determine the impact on survival of before and/or after HCT measurable residual disease (MRD), as determined using a highly sensitive assay for FLT3-ITD mutations. Generally, gilteritinib maintenance therapy was associated with improved relapse-free survival (RFS) for participants with detectable peri-HCT MRD, whereas no benefit was evident for those lacking detectable MRD. We conducted a post hoc analysis of the data and found that the level of MRD detected with this approach correlated remarkably with RFS and relapse risk, and that MRD detectable at any level negatively affected RFS. In the placebo arm, 42.2% of participants with detectable FLT3-ITD MRD relapsed compared with 13.4% of those without detectable MRD. We found that 14.8% of participants had multiple FLT3-ITD clones detected as MRD and had worse survival irrespective of treatment arm. Finally, we examined the kinetics of FLT3-ITD clonal relapse or eradication and found that participants on the placebo arm with detectable MRD relapsed rapidly after HCT, often within a few weeks. MRD-positive participants on the gilteritinib arm relapsed either with FLT3 wild-type clones (assessed by capillary electrophoresis), after cessation of gilteritinib with persistent MRD, or on progression of multiclonal disease. These data demonstrate the potential of FLT3-ITD MRD to guide therapy with gilteritinib for this subtype of AML. This trial was registered at www.clinicaltrials.gov as #NCT02997202.

Importance Monoclonal antibodies (mAbs) targeting calcitonin gene-related peptide (CGRP) or its receptor (anti-CGRP mAbs) offer effective migraine-specific preventive treatment. However, concerns exist about their potential cardiovascular risks due to CGRP blockade. Objective To compare the incidence of cardiovascular disease (CVD) between Medicare beneficiaries with migraine who initiated anti-CGRP-mAbs vs onabotulinumtoxinA in the US. Design, Setting, and Participants This retrospective, sequential cohort study was conducted among a nationally representative population-based sample of Medicare claims from May 2018 through December 2020. Data analysis was performed from August to December 2023. This study included fee-for-service Medicare beneficiaries aged 18 years or older with migraine who initiated either anti-CGRP mAbs or onabotulinumtoxinA. Beneficiaries who had a history of myocardial infarction (MI), stroke, cluster headache, malignant cancer, or hospice service within a 1-year baseline period prior to treatment initiation were excluded. To minimize channeling bias from new drug introductions and time-related bias due to the COVID-19 pandemic, 5 cohorts were established, representing sequential 6-month calendar intervals based on the initial prescription or date of index anti-CGRP mAbs or onabotulinumtoxinA use. Exposure Anti-CGRP mAbs vs onabotulinumtoxinA. Main Outcomes and Measures The primary outcome was time to first MI or stroke. Secondary outcomes included hypertensive crisis, peripheral revascularization, and Raynaud phenomenon. The inverse probability of treatment-weighted Cox proportional hazards models were used to compare outcomes between the 2 treatment groups. Results Among 266 848 eligible patients with migraine, 5153 patients initiated anti-CGRP mAbs (mean [SD] age, 57.8 [14.0] years; 4308 female patients [83.6%]) and 4000 patients initiated onabotulinumtoxinA (mean [SD] age, 61.9 [13.7] years; 3353 female patients [83.8%]). Use of anti-CGRP mAbs was not associated with an increased risk of composite CVD events (adjusted hazard ratio [aHR], 0.88; 95% CI, 0.44-1.77), hypertensive crisis (aHR, 0.46; 95% CI, 0.14-1.55), peripheral revascularization (aHR, 1.50; 95% CI, 0.48-4.73), or Raynaud phenomenon (aHR, 0.75; 95% CI, 0.45-1.24) compared with onabotulinumtoxinA. Subgroup analyses by age group and presence of established non-MI or stroke CVD showed similar findings. Conclusions and Relevance In this cohort study, despite initial concerns regarding the cardiovascular effects of CGRP blockade, anti-CGRP mAbs were not associated with an increased risk of CVD compared with onabotulinumtoxinA among adult Medicare beneficiaries with migraine, who were predominantly older adults or individuals with disability. Future studies with longer follow-up periods and in other populations are needed to confirm these findings.

Abstract Pharmacogenomics (PGx) is focused on the relationship between an individual's genetic makeup and their response to medications, with the overarching aim of guiding prescribing decisions to improve drug efficacy and reduce adverse events. The PGx and genomic medicine communities have worked independently for over 2 decades, developing separate standards and terminology, making implementation of PGx across all areas of genomic medicine difficult. To address this issue, the Clinical Genome Resource (ClinGen) Pharmacogenomics Working Group (PGxWG) was established by the National Institutes of Health (NIH)-funded ClinGen to initially create frameworks for evaluating gene–drug response clinical validity and actionability aligned with the ClinGen frameworks for evaluating monogenic gene–disease relationships, and a framework for classifying germline PGx variants similar to the American College of Medical Genetics (ACMG) and Association of Molecular Pathology (AMP) system for interpretation of disease-causing variants. These frameworks will leverage decades of work from well-established PGx resources facilitating buy-in among PGx stakeholders. In this report, we describe the background and major activities of the ClinGen PGxWG, and how this initiative will facilitate the critical inclusion of PGx into the larger context of genomic medicine.

AbstractBackgroundPatients with the precipitous onset of cognitive symptoms (i.e., suspected rapid progressive dementia [RPD]) may continue to decline (true RPD) or may stabilize or improve (non‐RPD). Recognizing patients with RPD early in the disease course is important to support clinical care and enrollment in research.MethodPatients referred for the evaluation of suspected RPD were prospectively enrolled and followed for up to 2 years at Mayo Clinic in Florida (Jacksonville, FL; Jan‐2020 – Oct‐2023) and Washington University in St. Louis (Saint Louis, MO; Jun‐2016 – Dec‐2019). Clinical data were independently reviewed by two dementia specialists who established clinical diagnoses, referencing published criteria. Patients were diagnosed with RPD if they progressed to dementia (global Clinical Dementia Rating® [CDR] ≥1) within 1 year or incapacitation (CDR ≥2) within 2 years of symptom onset. Univariate statistics compared demographics, clinical details, and test results between patients with RPD and non‐RPD. Variables with p<0.1 were entered into a multivariate logistic regression model to identify factors associated with RPD.ResultOf 248 patients referred for suspected RPD, 187 (75.4%) met stated criteria for RPD. Patients with RPD were older (62.6±14.4 years vs 55.0±18.3 years; p<0.001), and more likely to be diagnosed with Alzheimer disease or related dementias (28.3% vs 9.8%; p = 0.003) or Creutzfeldt‐Jakob (19.1% vs 4.6%; p = 0.008). Non‐RPD cases were more often attributed to autoimmune/inflammatory disease (42.6% vs 29.4%, p = 0.061) or other causes (e.g., psychiatric, neoplasms, toxic/metabolic; 34.4% vs 16.6%, p = 0.006). After controlling for age, hallucinations (OR, 2.81; 95%CI: 1.21‐6.52), elevated CSF protein (OR, 2.43; 95%CI: 1.17‐5.03), and CSF white blood cell count <5 cells/mm3 (OR, 2.77; 95%CI: 1.32‐5.85) were independently associated with RPD. Cortical visual loss (15/183, 8.2%) and substantial brain atrophy on MRI (27/184, 14.7%) were specific to patients with RPD, representing additional distinguishing features.ConclusionHallucinations, cortical visual loss, substantial atrophy on MRI, elevated CSF protein, and normal CSF white blood cell count were independently associated with RPD. Early detection of these features in patients with suspected RPD may inform clinical care and enrollment in research studies of RPD.

INTRODUCTION: Metabolic dysfunction-associated steatotic liver disease (MASLD) is an important public health threat, potentially leading to chronic liver disease and liver cancer. Current guidelines recommend using the Fibrosis-4 score for initial identification of subjects at risk of future complications. We formulate a novel population screening strategy based on the Steatosis-Associated Fibrosis Estimator (SAFE) score, recently developed for MASLD risk stratification in primary care. METHODS: We interrogated the National Health and Nutrition Examination Survey data, 2017–20, in which a sample of subjects representative of US civilian population underwent vibration-controlled transient elastography (VCTE). The current guideline and a new, SAFE-based proposal were applied to these data to project the number of subjects to be diagnosed with liver fibrosis gauged by liver stiffness measurement (LSM), including significant (LSM ≥8 kPa) and advanced (LSM ≥12 kPa) fibrosis, as well as the number of VCTEs to be performed. RESULTS: In the survey data, 2,691 subjects, projecting to 75.8 million US adults, were found to have MASLD, of whom 11% had LSM 8–12 kPa and 6% LSM ≥12 kPa. When the current guideline was applied, 18.1 million VCTEs would be needed to diagnose 3.5 million subjects with LSM ≥8 kPa and 1.7 million subjects with LSM ≥12 kPa. In comparison, a new approach based on the SAFE score would detect 4.9 million with LSM ≥8 kPa and 2.5 million subjects with LSM ≥12 kPa (37% and 45% improvement over the current guideline, respectively), while requiring 5.0 million fewer VCTEs (28% reduction). DISCUSSION: The proposed population risk stratification approach using the SAFE score is simpler and substantially more effective, yielding more subjects with liver fibrosis while requiring less resources compared with the currently recommended algorithm.

Abstract Myelodysplastic syndromes/neoplasms (MDSs) are heterogeneous stem cell malignancies characterized by poor prognosis and no curative therapies outside of allogeneic hematopoietic stem cell transplantation. Despite some recent approvals by the US Food and Drug Administration, (eg, luspatercept, ivosidenib, decitabine/cedazuridine, and imetelstat), there has been little progress in the development of truly transformative therapies for the treatment of patients with MDS. Challenges to advancing drug development in MDS are multifold but may be grouped into specific categories, including criteria for risk stratification and eligibility, response definitions, time-to-event end points, transfusion end points, functional assessments, and biomarker development. Strategies to address these challenges and optimize future clinical trial design for patients with MDS are presented here.

Trends in diagnostic biopsy sample collection approaches for primary bone sarcomas have shifted in the past 2 decades. Although open/incisional biopsies used to be the predominant approach to obtain diagnostic material for Ewing sarcoma and osteosarcoma, image-guided core needle biopsies have increased in frequency and are safe for patients. These procedures are less invasive and reduce recovery times but have potential limitations. The quantity and quality of tissue obtained through these procedures vary between institutions. Acquired viable tissue volumes can be low, limiting the conduct of downstream expanded clinical workup, molecular analyses, and research. Patients with advanced Ewing sarcoma and osteosarcoma continue to have overall poor outcomes despite dose-intensive cytotoxic chemotherapy. The biology of treatment resistance is not currently well understood, partly due to limited availability of relevant tissue to study. There is a need for access to quality tumor specimens for molecular and other analyses to identify high-risk tumor subsets and drive discovery to improve patient outcomes. Given broad variability in bone tumor tissue procurement and processing across member institutions, the Children’s Oncology Group Bone Tumor Committee convened a multidisciplinary group of experts to outline the current and near-future tissue needs for optimal clinical care and access to research platforms. The goal of this working group was to provide high-level guidance on biopsy practices that safely meet these evolving needs. Harmonizing tissue collection practices is paramount to improving the care of children, adolescents, and young adults diagnosed with Ewing sarcoma and osteosarcoma.

Abstract INTRODUCTION Early‐onset Alzheimer's disease (EOAD) manifests prior to the age of 65, and affects 4%–8% of patients with Alzheimer's disease (AD). The current analyses sought to examine longitudinal cognitive trajectories of participants with early‐onset dementia. METHODS Data from 307 cognitively normal (CN) volunteer participants and those with amyloid‐positive EOAD or amyloid‐negative cognitive impairment (EOnonAD) were compared. Cognitive trajectories across a comprehensive cognitive battery spanning 42 months were examined using mixed‐effects modeling. RESULTS The EOAD group displayed worse cognition at baseline relative to EOnonAD and CN groups, and more aggressive declines in cognition over time. The largest effects were observed on measures of executive functioning domains, while memory declines were blunted in EOAD. DISCUSSION EOAD declined 2–4× faster than EOnonAD, and EOAD pathology is not restricted to memory networks. Early identification of deficits is critical to ensure that individuals with sporadic EOAD can be considered for treatment using disease‐modifying medications. Highlights Represents the most comprehensive longitudinal characterization of sporadic EOAD to date. The trajectory of cognitive declines was steep for EOAD participants and worse than for other groups. Executive functioning measures exhibited the greatest declines over time in EOAD.

Abstract INTRODUCTION Early‐onset Alzheimer's disease (EOAD) and late‐onset Alzheimer's disease (LOAD) share similar amyloid etiology, but evidence from smaller‐scale studies suggests that they manifest differently clinically. Current analyses sought to contrast the cognitive profiles of EOAD and LOAD. METHODS Z‐ score cognitive‐domain composites for 311 amyloid‐positive sporadic EOAD and 314 amyloid‐positive LOAD participants were calculated from baseline data from age‐appropriate control cohorts. Z‐ score composites were compared between AD groups for each domain. RESULTS After controlling for cognitive status, EOAD displayed worse visuospatial, executive functioning, and processing speed/attention skills relative to LOAD, and LOAD displayed worse language, episodic immediate memory, and episodic delayed memory. DISCUSSION Sporadic EOAD possesses distinct cognitive profiles relative to LOAD. Clinicians should be alert for non‐amnestic impairments in younger patients to ensure proper identification and intervention using disease‐modifying treatments. Highlights Both early‐onset Alzheimer's disease (EOAD) and late‐onset Alzheimer's disease (LOAD) participants displayed widespread cognitive impairments relative to their same‐aged peers. Cognitive impairments were more severe for EOAD than for LOAD participants in visuospatial and executive domains. Memory and language impairments were more severe for LOAD than for EOAD participants Results were comparable after removing clinical phenotypes of posterior cortical atrophy (PCA), primary progressive aphasia (lv‐PPA), and frontal‐variant AD.