Citations

Abstract Purpose: DROSHA, DGCR8, and DICER1 regulate miRNA biogenesis and are commonly mutated in cancer. Although DGCR8 and DICER1 germline pathogenic variants (GPV) cause autosomal dominant tumor predisposition, no association between DROSHA GPVs and clinical phenotypes has been reported. Experimental Design: After obtaining informed consent, sequencing was performed on germline and tumor samples from all patients. The occurrence of germline DROSHA GPVs was investigated in large pediatric and adult cancer datasets. The population prevalence of DROSHA GPVs was investigated in the UK Biobank and Geisinger DiscovEHR cohorts. Results: We describe nine children from eight families with heterozygous DROSHA GPVs and a diagnosis of pineoblastoma (n = 8) or Wilms tumor (n = 1). A somatic second hit in DROSHA was detected in all eight tumors analyzed. All pineoblastoma tumors analyzed were classified as miRNA processing–altered 1 subtype. We estimate the population prevalence of germline DROSHA loss-of-function variants to be 1:3,875 to 1:4,843 but find no evidence for increased adult cancer risk. Conclusions: This is the first report of DROSHA-related tumor predisposition. As pineoblastoma and Wilms tumor are also associated with DICER1 GPVs, our results suggest that the tissues of origin for these tumors are uniquely tolerant of general miRNA loss. The miRNA processing–altered 1 pineoblastoma subtype is associated with older age of diagnosis and better outcomes than other subtypes, suggesting DROSHA GPV status may have important clinical and prognostic significance. We suggest that genetic testing for DROSHA GPVs be considered for patients with pineoblastoma, Wilms tumor, or other DICER1-/DGCR8-related conditions and propose surveillance recommendations through research studies for individuals with DROSHA GPVs.

The optimal patient panel size (PPS) in primary care and the factors determining it remain unclear. We conducted a meta-narrative review of the literature to evaluate factors influencing PPS and assess its association with patient outcomes. A comprehensive search of electronic databases was performed from inception through December 2023, focusing on original studies reporting factors used to determine PPS and related outcomes (eg, clinical outcomes, process measures, and resource utilization). A total of 48 studies were included, identifying 7 key factors influencing PPS. Smaller panels were associated with improved patient satisfaction, continuity of care, and health promotion, while clinical outcomes, utilization, and costs showed minimal impact by PPS. Panel size was primarily associated with patient age, sex, comorbidities, and practice type and structure. Community-based centers typically managed smaller panels, often staffed by female clinicians and serving socioeconomically disadvantaged populations with greater health needs than hospital-based practices. Female clinicians were also independently associated with managing smaller panels, higher quality care indicators, fewer emergency department visits, and improved patient satisfaction. Determining the ideal PPS is a multifaceted process influenced by practice setting, patient demographics, and clinician characteristics. While practice-related factors showed limited association with PPS, patient-reported outcomes were more closely linked to it. Primary care practices should tailor panel sizes to their patient populations, emphasizing a patient-centered approach and ensuring adequate infrastructure support to optimize care delivery.

ABSTRACT Alzheimer's disease (AD) is the leading cause of dementia in the elderly, marked by abnormal protein buildup (beta‐amyloid and tau) resulting in neuronal loss, especially in the medial temporal lobe and other limbic regions. The presence of transactive response DNA binding protein 43 (TDP‐43) immunoreactive inclusions in medial temporal lobe regions has also been associated with neuroimaging changes in limbic regions. It has been proposed that hypometabolism in limbic regions on [ 18 F] fluorodeoxyglucose positron emission tomography (FDG‐PET) in a patient with a slowly evolving amnestic syndrome may be a signature of the presence of TDP‐43. In this context, we observed an 86‐year‐old Caucasian female with dementia characterized by a slowly evolving amnestic syndrome, along with focal medial temporal atrophy evident on MRI and hypometabolism in limbic regions on FDG‐PET. The patient subsequently died and underwent an autopsy. We performed detailed neuroimaging and digital neuropathological analyses of the hippocampal subfields to better understand the relationship between clinico‐imaging findings and histopathology. In addition to TDP‐43, we identified three other pathological processes in the medial temporal lobe: sequestosome‐1/p62, argyrophilic grain disease (AGD), and primary age‐related tauopathy (PART). Hippocampal subfield volumes and rates of atrophy were no different from those of matched healthy controls, except for the atrophy rate in cornu ammonis 1 (CA1). Digital histopathology revealed the relative highest burden of pathology for p62, followed by TDP‐43, AGD, and PART in CA1. Multiple pathological processes appear to have contributed to the hippocampal atrophy and hypometabolism in our patient with a slowly progressive amnestic syndrome.

Background: Latinas with mammographic dense breasts are at increased risk of breast cancer. This randomized controlled trial tests the effectiveness of three breast density (BD) educational approaches on adherence to subsequent mammography screening among Latinas receiving care at a Federally Qualified Health Center (FQHC). Measure(s): Adherence was ascertained using electronic health record and survey responses. Kaplan–Meier estimates of the time to subsequent mammogram were used to obtain adherence rates at 1- and 2-years post baseline mammogram. Cox modeling assessed whether adherence differed by patient characteristics or group assignment. Results: This analysis was limited to Latinas enrolled between October 27, 2016, and December 21, 2018 ( n = 946; 66.1% <50 years of age, 53.5% with dense breasts). Adherence rates at 1 year was 24.8% increasing to 51.7% by year 2. Latinas randomized to the Promotora + brochure + letter arm (hazard ratio [HR]: 1.09 [95% confidence interval [95% CI] 0.87 to 1.36]) or brochure + letter (HR: 1.03 [95% CI 0.82 to 1.29]) arm were not more likely to be adherent to subsequent mammography compared to the letter only arm ( p = 0.76) . Adjusting for age and study group, having more prior mammograms, being “extremely likely” to get an annual mammogram, and having more confidence to get an annual mammogram at baseline were significant drivers of subsequent adherence. Conclusion: Informational interventions targeting BD education alone are unlikely to significantly improve adherence to subsequent mammography among Latinas receiving care in FQHCs.

ABSTRACTIntroduction/AimsHealthcare utilization and costs in myotonic dystrophy (DM) are not well understood. This study describes the burden of DM and its associated costs.MethodsWe performed a retrospective study using data from a large U.S. administrative claims database to identify commercially insured individuals with DM and compared healthcare utilization and cost with a matched cohort. Analyses were performed between the cohorts with ≥ 3 years of insured follow‐up.ResultsWe identified 1182 DM individuals with coverage at least 3 year prior and 3 years following an index DM diagnosis from January 1, 2009 to December 31, 2018. Compared to controls, DM individuals were 3.7 times more likely to be hospitalized (p < 0.0001), 2.4 times more likely to visit an emergency department (p < 0.0001), and had twice as many outpatient visits (p < 0.0001) in the first year post‐diagnosis, with similar utilization at 2‐ and 3‐years post‐diagnosis. Annual mean costs were 3.9 times higher for health plan paid costs (p < 0.0001) and 2.6 times higher for patient‐paid costs (p < 0.0001) for DM individuals than controls in the first year post‐diagnosis, with similar costs at 2‐ and 3‐years post‐diagnosis. Factors associated with higher costs included the need for durable medical equipment, including gait aids or respiratory support devices.DiscussionIndividuals with DM experience significantly higher healthcare utilization and associated healthcare costs than controls of similar age, sex, race, and census region. The findings show the high clinical and economic burden of DM, highlighting the importance of improving cost‐effective care delivery in this population.

Background and Objectives: Hearing loss is relatively common in older individuals, and individuals with frontotemporal lobar degeneration (FTLD) are no exception; this can exacerbate communication difficulties stemming from speech-language impairments. The co-occurrence of these symptoms can contribute to increased frustration and isolation for patients and their communication partners. The objective of this study was to evaluate the feasibility of self-administered hearing testing. Ultimately, this could be administered remotely, which would increase access to assessment and inform management for this population. Method: Seventeen patients with underlying FTLD, clinically presenting with progressive apraxia of speech with and without agrammatic aphasia, independently completed the Home Hearing Test supervised while in office. Results: Three patients self-reported hearing loss, but results for 100% recommended formal evaluation. Eleven patients demonstrated good test accuracy. Six patients had “poor” or not computable accuracy; among them, five had evidence of cognitive impairment and/or behavioral changes, and one had known severe hearing loss, although differences between those with good and poor test accuracy were not significant. Patients with poor test accuracy had more difficulty with limb praxis. Conclusions: Most participants independently completed the test, though some had reduced test accuracy that may have been associated with cognitive impairment and/or limb apraxia. This study supports the need for hearing screenings in all patients with progressive apraxia of speech and aphasia and highlights both the feasibility and caution required in implementing self-administered testing protocols. Further work should evaluate the feasibility of in-home hearing screenings in a broader range of FTLD phenotypes and directly compare sensitivity and specificity of hearing loss detection with in-clinic administration. Supplemental Material: https://doi.org/10.23641/asha.28306613

247 Background: Approximately 10% to 15% of men with metastatic castration-resistant prostate cancer (mCRPC) harbor germline mutations. Circulating tumor-derived DNA (ctDNA) as non-invasive approach to characterizing somatic alterations. In this study, we report longitudinal ctDNA assessments in mCRPC patients who have undergone germline testing. Methods: A total of 238 patients, who had undergone both germline testing and ctDNA assessment from Tulane Cancer Center were included in this study. Germline testing was conducted using a multi-gene cancer panel from Invitae, covering 50-86 genes, while somatic alterations in ctDNA were tested through Guardant 360, including 70-83 genes. Somatic alterations with <0.1%, synonymous, and variants of unknown significance were excluded from analyses. Statistical analyses were performed using Pearson Chi-Square Test or Fisher Exact Test. Results: From 2015-2024, 17.2% (41/238) had pathogenic or likely-pathogenic (P/LP) germline mutations. The most common pathogenic germline mutations were in BRCA2 (17.1%; 7/41), BRCA1 (9.8%; 4/41), and CHEK2 (9.8%; 4/41). In ctDNA, germline positive patients were more likely to have frameshift mutations (OR= 1.75, 95% C.I. [1.09, 2.81], p=0.02) and less likely to have copy number amplifications (OR= 0.58, 95% C.I. [0.36, 0.93], p= 0.03) compared to germline negative patients. Among mCRPC patients with germline HRR P/LP mutations, frameshift alterations were significantly more frequent (OR=5.03, 95% CI [2.03, 13.23], p-value=0.0008). mCRPC patients with germline P/LP mutations were more likely to have somatic mutations in BRCA2 (OR=2.85; 95% CI: [1.62, 4.93]; p=0.0002) and GATA3 (OR=3.37, 95% CI: [1.26, 8.51]; p=0.016) detected ctDNA and less likely to have EGFR alterations (mutations and/or amplifications) (OR=0.46; 95%CI: [0.25, 0.80]; p=0.0094). BRCA2 somatic mutations are also more likely to be detected in patients with germline P/LP mutations in HRR genes (OR=0.11, 95% CI [0.03, 0.33], p=0.00004). Conclusions: mCRPC patients with pathogenic germline mutations are more likely to have frameshift and less likely to have copy number amplifications compared to germline negative mCRPC patients. Frameshift mutations are more likely to be detected in patients with germline P/LP in HRR genes. Patients with germline P/LP mutations are more likely to have somatic mutations BRCA2 and GATA3 and less likely to have mutations and/or amplifications in EGFR.

245 Background: Circulating tumor DNA (ctDNA) can be used as a prognostic biomarker in mCRPC patients, with changes in ctDNA providing insight into patient survival. In this study, we evaluate the ctDNA landscape of patients with mCRPC prior to their death. Methods: A retrospective clinical data review, 2015-2024, was conducted at Tulane Cancer Center to identify mCRPC patients who underwent ctDNA testing prior to death. All ctDNA data were obtained through a multi-gene cancer panel via the Guardant 360 assay (70-83 genes). Lethal mCRPC was defined as patients who underwent ctDNA testing ≤3 months prior to death. A matched control group (CTRL) was defined as mCRPC patients with ctDNA collection ≥2 years prior to death or most recent follow-up. Statistical analyses were performed using Pearson Chi-Square Test or Fisher Exact Test whenever appropriate. Furthermore, survival analysis was conducted using the Kaplan-Meier method. Results: There were 70 patients in lethal mCRPC group and 157 patients in CTRL group. Compared to the CTRL group, in lethal mCRPC, somatic mutations and/or amplifications in BRAF(OR=2.1549, 95% C.I. [1.1136,4.1523], p=0.0298), CCND2 (OR=3.7925, 95% C.I.[1.1937,13.3380], p=0.03326), MYC (OR=2.6332, 95%C.I. [1.4158, 4.9120], p=0.0029), PDGFRA (OR=2.5235, 95% C.I. [1.1438, 5.5793], p=0.0291), and PIK3CA (OR=2.0328, 95% C.I. [1.1098, 3.7166], p=0.02846) were significantly more frequent. Additionally, lethal mCRPC patients were more likely to have missense (OR=4.3194, 95% C.I. [1.443456,19.3338], p=0.01687) and nonsense (OR=1.9364, 95% C.I. [1.06091,3.5250], p=0.04112) mutations at the end-of-life. Patients with a higher allelic fraction (≥0.6%) of TP53 alterations had a shorter median survival (p-value= 0.034). Conclusions: ctDNA mutations and/or amplifications in BRAF, CCND2, MYC, PDGFRA, and PIK3CA were more frequently detected in lethal mCRPC compared to matched CTRLs. Additionally, mCRPC patients with a lethal phenotype were more likely to have missense and nonsense mutations compared to the CTRL group. CtDNA assessment of copy number alterations was limited to amplifications only; additionally, with this assay, distinguishing between gene level and large scale chromosomal amplification is not assessable. Though this study is limited to a single-institution with retrospective analyses of clinical testing, understanding the somatic landscape of lethal mCRPC is critical for development of new biomarkers, strategies and ultimately druggable targets.