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Abstract Background Despite advances in our understanding of the molecular underpinnings of meningioma progression and innovations in systemic and local treatments, recurrent meningiomas remain a substantial therapeutic challenge. The objective of this systematic review and meta-analysis is to provide a historical baseline, contemporary analysis, and propose a “rate of probable interest” to inform future clinical trial design and development on behalf of the Response Assessment in Neuro-Oncology meningioma group. Methods PubMed, ClinicalTrials.gov, and ASCOpubs databases were screened for clinical trials evaluating the activity of systemic therapies for adults with recurrent meningiomas. The pooled progression-free survival at 6-months and 1-year (PFS-6 and PFS-1 year) values were calculated using the random effects technique with I2 indices. Results The pooled PFS-6 and PFS-1 year rates for recurrent WHO grade 1 meningiomas were 43.6% (95% CI: 22.7-67.0%, I2 = 80%) and 21.7% (95% CI: 6.2-53.9%, I2 = 76%), and for grades 2-3 meningiomas, the PFS-6 was 38.0% (95% CI: 28.3-48.8%, I2 = 68%). In the targeted therapy group, PFS-6 and PFS-1 year rates stood at 62.0% (I2 = 58%) and 49.0% (I2 = 63%) for grade 1, while for grades 2-3 tumors, the PFS-6 rates with targeted therapy and immunotherapy were 42.1% (I² = 60%) and 46.0% (I² = 0%), respectively. The benchmarks were set at 67% and 54% for PFS-6 and PFS-1 year for grade 1 tumors, and PFS-6 of 49% for grades 2-3 tumors. Conclusions Several studies have reported outcomes in patients with recurrent meningiomas testing a variety of agents with modest, but variable and progressively increasing activity. In this context, we recommend new benchmarks for future trials to define efficacy of future investigational therapies.

AbstractBackgroundEvidence for abnormal amyloid‐β (Aβ) plaque accumulation is necessary prior to initiating anti‐amyloid therapy in early symptomatic Alzheimer’s disease (AD). While the clinical trials for lecanemab and related drugs utilized positron emission tomography (PET) to demonstrate brain amyloidosis, current appropriate use recommendations for clinical practice consider PET or cerebrospinal fluid (CSF) biomarkers as satisfactory for this purpose. Here, we present four clinical cases where CSF biomarker results were discordant from amyloid PET, with the potential to result in erroneous treatment targeting.MethodPatients were seen at a tertiary care subspecialty clinic in consideration for lecanemab therapy. All patients had office examination, neuropsychological assessment, structural magnetic resonance imaging (MRI), amyloid PET (with either 11C‐Pittsburgh compound B or 18F‐florbetapir), CSF AD biomarkers (Roche Elecsys p‐tau181/Aβ42 and Fujirebio Lumipulse Aβ42/Aβ40 ratios), and apolipoprotein E (APOE) allele testing. Amyloid PET interpretations were made by consensus visual review from experienced readers.ResultAll four patients had clinical diagnoses of mild cognitive impairment or mild dementia (Table 1). Two patients had positive CSF p‐tau181/Aβ42 and Aβ42/40 ratios with negative amyloid PET (indicating sparse to no neuritic plaques). Case 1 displayed aphasia (characterized by anomia and deep dysgraphia) and imaging findings possibly compatible with semantic dementia. Case 2 displayed a gait abnormality and imaging signs of abnormal CSF dynamics. Two other patients had negative CSF p‐tau181/Aβ42 measures with positive amyloid PET (indicating moderate to frequent neuritic plaques). In those instances, the clinical syndrome and imaging studies were strongly supportive of AD and the CSF Aβ42/40 ratio was “likely positive” (Table 1). For one patient (Case 4), tau PET and Lumipulse plasma p‐tau217 concentration were both positive.ConclusionClinicians prescribing anti‐amyloid therapies should be aware of the possibility for CSF biomarkers to be discordant from amyloid PET status in select scenarios. These cases highlight the value of considering PET imaging in the presence of clinically atypical features, concern for mixed etiology, or strong clinical suspicion for AD despite negative CSF biomarkers. Larger series are needed to identify broader patterns contributing to biomarker discordance by assay, modality (PET versus CSF/plasma measures), and medical/neurologic comorbidities.

AbstractBackgroundScalable, efficient methods are needed to enroll diverse populations of older adults into AD observational studies and clinical trials. We evaluated preliminary feasibility of a novel, digital, culturally informed approach to recruit and screen participants for the Alzheimer’s Disease Neuroimaging Initiative (ADNI4).MethodsDigital advertising tailored towards Black/African American and Latinx older adults residing near six clinical ADNI sites directed potential participants to a recruitment website (Figure 1). They completed digital surveys of demographics, ADNI exclusion criteria, memory concerns and changes, self‐report cognitive impairment, and the Everyday Cognition Scale (ECog)‐12 item. Participants also completed Novoic Storyteller, a self‐administered speech‐based cognitive test. Digital assessment results were used to prioritize those from minoritized ethnocultural groups, with low educational attainment, and possible Mild Cognitive Impairment (MCI) for remote blood draw at local Quest phlebotomy centers to obtain AD plasma biomarkers. Completion rates and digital assessment performance were compared between minoritized and non‐minoritized groups.ResultsOf 989 participants recruited from digital advertising efforts who provided contact information, 230 (23%) signed consent, and 183 (19%) completed at least one remote assessment (Table 1). 45% were from minoritized ethnocultural groups, 4% had ≤12 years of education, and 53% had evidence of possible MCI from digital assessments. 34 (19%) were referred to the plasma biomarker study, of which 21% completed blood draw. Compared to non‐minoritized participants, minoritized participants were less likely to report a diagnosed cognitive impairment or a family history of AD, less likely to have ECog scores indicative of MCI, and less likely to have a study partner. Minoritized participants had lower ECog and Novoic Storyteller completion rates.ConclusionRecruitment and assessment of a diverse cohort of older adults, including those with possible cognitive impairment, is feasible using culturally informed digital advertising. Improving study engagement and achieving educational diversity are key challenges. This approach is now being scaled up to facilitate recruitment into in‐clinic ADNI4, with the goal of enrolling 500 new participants: >50% from minoritized groups, 40% with MCI, and 80% amyloid positive across diagnostic groups. This approach can be adapted to facilitate recruitment and longitudinal assessment in other AD studies and trials.

AbstractBackgroundGenome‐wide association studies (GWAS) in Alzheimer’s disease (AD) leveraging endophenotypes beyond case/control diagnosis, such as brain amyloid β pathology, have shown promise in identifying novel variants and understanding their potential functional impact. In this study, we leverage two brain amyloid β pathology measurement modalities, PET imaging and neuropathology, to address sample size limitations and to discover novel genetic drivers of disease.MethodWe conducted a meta‐analysis on an amyloid PET imaging GWAS (N = 7,036, 35% amyloid positive, 53.67% female, age = 71) and an autopsy GWAS of brain amyloidosis (N = 6,519, 63.08% amyloid positive, 51.34% female, age at death = 83), both adjusted for covariates including age, sex and principal components of genetic ancestry. All participants in both GWAS were unrelated individuals of European descent. We defined amyloid positivity as moderate or frequent neuritic plaques using the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) staging scores within each autopsy cohort. A Gaussian mixture model (GMM) was applied to each amyloid PET imaging cohort to identify the cohort and tracer‐specific cut‐offs that differentiate amyloid positive and negative populations.ResultThe genome‐wide significant results from the meta‐analysis identified three known AD loci (APOE, CR1, and BIN1) and a novel chromosome 17 locus (rs35635959, intergenic, MAF = 0.27, OR = 1.18, p = 1.47 × 10‐8). The MAGMA gene‐level analysis excluding the APOE region suggests significant associations between rs35635959 and COASY, PLEKHH3, and TUBG2 on chromosome 17, implying the potential roles of these genes on amyloidosis. Functional annotations of rs35635959 leveraging brain eQTL databases indicate its association with differential gene expression of COASY and TUBG2 in AD brains. ROSMAP bulk and single‐nucleus RNAseq analyses link TUBG2 downregulation to the higher amyloid burden and AD diagnosis while suggesting such observations are enriched in excitatory and inhibitory neurons, reaching FDR significance.ConclusionThis study is the most extensive European GWAS of brain amyloidosis, and our findings replicate known AD loci and identify a possible novel locus (index SNP rs35635959) on chromosome 17. Functional annotations of the novel variant indicate TUBG2, implicating in microtubule organization, warrants further assessment. Ongoing efforts aim to validate these novel effects using independent datasets.

Abstract Background Benign breast disease (BBD) increases breast cancer (BC) risk progressively for women diagnosed with nonproliferative change, proliferative disease without atypia (PDWA), and atypical hyperplasia (AH). Leveraging data from 18 704 women in the Mayo BBD Cohort (1967-2013), we evaluated temporal trends in BBD diagnoses and how they have influenced associated BC risk over 4 decades. Methods BC risk trends associated with BBD were evaluated using standardized incidence ratios (SIRs) and age–period–cohort modeling across 4 eras—premammogram (1967-1981), precore needle biopsy (CNB) (1982-1992), transition to CNB (1993-2001), and CNB era (2002-2013). Results With a median follow-up of 15.8 years, 9.9% of women were diagnosed with BC (invasive and/or DCIS). From the premammogram era to the CNB era, we observed a significant increase in BC risk, rising from an SIR of 1.61 to 1.99. The proportion of proliferative BBD diagnoses (PDWA or AH) increased markedly over time (28.1%-49.7%), as did the proportion of DCIS events (11%-28%; χ2 P < .001). Within specific BBD categories, the risk of invasive BC increased modestly. Conclusions Absolute risk of BC within BBD categories remained stable, but the relative risk of BC after BBD increased over time due to notable increases in higher risk BBD lesions, specifically PDWA and AH. These findings illustrate how evolving screening practices have changed the risk profile of BBD and should inform management strategies for patients with BBD in modern clinical settings.

Abstract The overall goal of the Alzheimer's Disease Neuroimaging Initiative (ADNI) is to optimize and validate biomarkers for clinical trials while sharing all data and biofluid samples with the global scientific community. ADNI has been instrumental in standardizing and validating amyloid beta (Aβ) and tau positron emission tomography (PET) imaging. ADNI data were used for the US Food and Drug Administration (FDA) approval of the Fujirebio and Roche Elecsys cerebrospinal fluid diagnostic tests. Additionally, ADNI provided data for the trials of the FDA‐approved treatments aducanumab, lecanemab, and donanemab. More than 6000 scientific papers have been published using ADNI data, reflecting ADNI's promotion of open science and data sharing. Despite its enormous success, ADNI has some limitations, particularly in generalizing its data and findings to the entire US/Canadian population. This introduction provides a historical overview of ADNI and highlights its significant accomplishments and future vision to pioneer “the clinical trial of the future” focusing on demographic inclusivity. Highlights The Alzheimer's Disease Neuroimaging Initiative (ADNI) introduced a novel model for public‐private partnerships and data sharing. It successfully validated amyloid and Tau PET imaging, as well as CSF and plasma biomarkers, for diagnosing Alzheimer's disease. ADNI generated and disseminated vital data for designing AD clinical trials.

Abstract Adult primary leptomeningeal gliomatosis (PLG) is a rare, rapidly progressive and fatal disease characterized by prominent leptomeningeal infiltration by a glial tumor without an identifiable parenchymal mass. The molecular profile of adult PLG has not been well‐characterized. We report the clinical, pathological, and molecular findings of six adult PLG patients (five males and one female), median age 58 years. All cases exhibited pathological leptomeningeal enhancement at presentation. Leptomeningeal biopsy was diagnostic in five (of six) cases, revealing infiltration by an astrocytic glioma with mitotic activity, lacking microvascular proliferation or necrosis. One case was diagnosed at autopsy. All tumors were IDH‐wildtype, with five harboring TERT promoter mutations. Additional mutations identified were PTEN in one case, TP53 in two cases, and NF1 in two cases. A chromosome profile with +7/−10 was found in four cases, whereas the remaining two showed either chromosome 7 or 7p gain only. Four cases showed chromosome 9p loss with CDKN2A/B homozygous deletion, one case showed hemizygous CDKN2A/B loss, and one case showed intact chromosome 9 and CDK4/GLI1 amplification. DNA methylation profiling was performed in four cases and revealed a match to glioblastoma (GBM) family and mesenchymal typical class with high confidence scores in two cases; the other two cases showed only suggestive combined scores for GBM family and mesenchymal atypical class. The molecular profile of all cases closely aligned with that of adult‐type GBM, IDH‐wildtype, CNS WHO grade 4. All patients succumbed to the disease. In five cases with extensive leptomeningeal disease at diagnosis, the course was rapid, with median survival of 24 days following palliative care. Only one case, with relatively localized disease at diagnosis, received chemoradiation therapy and survived 535 days, raising the possibility that early diagnosis and timely treatment could improve outcome. A detailed list of previously reported cases is provided in a supplementary table.

Objectives: To describe member adherence to a mail-based, health insurer-sponsored gap closure program for colorectal cancer (CRC) screening using multi-target stool DNA (mt-sDNA; Cologuard ® ) tests. Methods: Combined patient data from Exact Sciences Laboratories LLC and data from mass-mailed mt-sDNA orders placed by a large Medicare Advantage Insurance Plan were analyzed (03/01/2023-06/30/2023). Adherence and time to test return were the primary and secondary outcomes, respectively. Their association with patient characteristics was evaluated using multivariable regression. Results: Among the 3201 member-patients included (86.6% aged 65-75 years; 58.7% female), adherence rate was 49.4%, and mean time to test return was 25.5 days. After multivariable adjustment, the odds of test return were significantly higher among 65- to 75-year-olds (odds ratio [OR] = 1.59 relative to 45- to 64-year-olds), those living in small towns (OR = 1.43 relative to metropolitan-located individuals), and with digital outreach via both SMS and email (OR = 4.31 relative to no digital outreach). Time to test return was shorter in 65- to 75-year-olds than in 45- to 64-year-olds and was not associated with other patient characteristics. Conclusions: Mass-mailed mt-sDNA tests for CRC screening were associated with an overall adherence rate of about 50% in this Medicare Advantage population, with higher likelihood of test return among patients receiving digital outreach.