Citations

Abstract Zanubrutinib is a second-generation Bruton Tyrosine Kinase (BTK) inhibitor, FDA-approved for Mantle Cell Lymphoma (MCL), designed to be more selective and potentially better tolerated than first-generation agents like Ibrutinib. Progressive multifocal leukoencephalopathy (PML), a rare but severe complication, has not previously been reported with Zanubrutinib. We report a 74-year-old woman with a germline CHEK2 mutation and asymptomatic MCL (CD5+, cyclin D1+, Ki67 10–20%) diagnosed in 2016, managed with surveillance. In 2023, she was also diagnosed with localized breast cancer treated with lumpectomy and exemestane. Later that year, she developed new headaches. Brain MRI revealed diffuse bilateral pachymeningeal enhancement, suspicious for lymphomatous spread, without parenchymal involvement. By early 2024, follow-up imaging showed stable pachymeningeal enhancement with new scattered punctate right frontal subcortical lesions, coinciding with systemic MCL progression. Spinal imaging revealed epidural and bone marrow involvement; CSF was negative for malignancy. Zanubrutinib was initiated in March 2024. By August 2024, new bilateral frontal and parietal fuzzy hyperintense and faintly enhancing white matter lesions emerged, while prior punctate lesions regressed. Biopsy confirmed PML with JC virus DNA by in situ hybridization and absence of B-cell clonality. Zanubrutinib was discontinued. Follow-up imaging showed regression of lesions without new enhancement, consistent with immune reconstitution. The initial subcortical punctate lesions remained stable. In 2025, she was diagnosed with localized pancreatic adenocarcinoma, precluding cytotoxic therapy initially due to concern for PML reactivation. However, as of May 2025, neuroimaging remains stable, and patient was started on palliative gemcitabine/paclitaxel. This is the first reported case of PML associated with Zanubrutinib. It underscores the importance of vigilance for PML even in patients without overt immunosuppression, especially those with overlapping malignancies and treatment exposures in the correct clinical context.

Abstract BACKGROUND CNS germinoma is typically treated with combination of chemotherapy and radiotherapy, with steroids used temporarily for symptom management. METHODS We report a case of CNS germinoma initially treated with steroid monotherapy with reduction in radiographic enhancement. RESULTS A 25 year old male initially presented with polydipsia and polyurea that improved with desmopressin, consistent with central diabetes insipidus. Brain imaging was unremarkable and he was lost to follow up. 3 years later, he developed progressively worsening bitemporal scotomas, intermittent binocular horizontal diplopia, reduced visual acuity, headaches, weight gain, and sexual dysfunction. MRI brain revealed enhancement of the pituitary stalk, optic chiasm and optic nerves, floor of the third ventricle, lateral ventricles, periventricular white matter, and anterior corpus callosum and fornix with associated T2 hyperintensity within the optic chiasm and adjacent brain parenchyma. Biopsy was consistent with germinoma. He was started on a dexamethasone taper beginning at 4 mg every 6 hours and plateauing at 4 mg twice daily. 3 weeks after steroid initiation, the areas of enhancement surrounding the frontal horns of the lateral ventricles showed reduction in size. DISCUSSION Reduced tumoral enhancement with steroid monotherapy is a well-known phenomenon in CNS lymphoma and has been reported in gliomas, attributed to direct induction of apoptosis in CNS lymphoma and alterations in the blood brain barrier via suppression of vascular permeability factors in both. This case adds to the scant literature regarding change in enhancement patterns with steroid monotherapy in CNS germinomas, which is likely related to a reduction in tumoral diffuse lymphocyte infiltration with steroid administration. The reduction in enhancement seen in multiple CNS mass-like pathologies emphasizes the importance of a tissue diagnosis for germinomas, as this steroid response is transient and not indicative of true tumor regression. Definitive treatment of germinomas is combination chemotherapy and radiation.

Abstract BACKGROUND Glioblastoma (GBM) is highly aggressive with poor prognosis, especially in recurrent cases where treatments are limited. Intra-arterial (IA) Yttrium-90 (Y90) microsphere therapy, FDA-approved for hepatocellular carcinoma, offers the potential for targeted radiotherapy in recurrent GBM (rGBM). The FRONTIER trial evaluated the safety and feasibility of IA Y90-glass microsphere treatment for rGBM under an FDA Investigational Device Exemption. Materials and METHODS This prospective, single-arm, multi-center study included patients with rGBM in non-dominant, non-eloquent regions. The primary endpoint was 30-day incidence of treatment-related limiting toxicities (primarily ≥grade 3 non-hematologic, with exclusions). Secondary endpoints included adverse event (AE) rate, neurological changes, technical success (PET absorbed dose within ±20% of target), and efficacy. Treatment regions, defined via cerebral angiography-MRI fusion to cover the recurrent lesion, were targeted with 40±4Gy. Post-treatment evaluations included MRI, Y90-PET, and neurological assessments. RESULTS The procedure was well-tolerated by all twelve subjects and discharge occurred the following day with no decline in neurologic status. No limiting toxicities or device-related AEs were reported. Five patients experienced 8 procedure-related AEs (6 Grade 1, 2 Grade 3). Technical success was 100%, with post-treatment Y90-PET derived median absorbed dose of 41.5 Gy to the treatment region (median volume 80.3 cc). The median tumor absorbed dose was considerably higher at 124.2 Gy (median tumor volume 5.8 cc), indicating preferential tumor perfusion. At 2 months, 67% had stable disease, and 33% showed reduced T1-contrast enhancing volume within the treated area. Median progression-free survival was 3.1 (95% CI 0.92-NE) and overall survival (OS) was 9.3 months (95% CI 5.0-NE) from Y90 treatment. Exploratory analysis revealed a significant OS benefit for patients receiving a tumor absorbed dose above the median (11.9 vs 5.7 months, p=0.0073). CONCLUSION Results from this initial cohort suggest IA Y90-microsphere therapy is technically feasible and well-tolerated in rGBM. Further investigation is warranted.

The NCCN Guidelines for Prostate Cancer provide a framework on which to base decisions for patients with prostate cancer across the disease spectrum. The Guidelines sections included in this article focus on metastatic castration-sensitive prostate cancer (mCSPC), nonmetastatic castration-resistant prostate cancer (CRPC), and metastatic CRPC (mCRPC). For patients with mCSPC, disease characteristics, such as whether metastases arose synchronously or metachronously and the degree of metastatic burden, impact therapy decisions, including how much treatment intensification is appropriate and when prostate-directed and/or metastasis-directed therapy should be considered. In the mCRPC setting, androgen deprivation therapy is continued with the sequential or concurrent addition of certain androgen receptor pathway inhibitors, chemotherapies, immunotherapies, radiopharmaceuticals, and/or targeted therapies. The NCCN Prostate Cancer Panel emphasizes a shared decision-making approach in all disease settings based on patient preferences, prior treatment exposures, biomarkers, the extent and location of metastases, symptoms, and potential side effects.

Abstract INTRODUCTION The Consortium for Clarity in Alzheimer's disease related dementias (ADRD) Research Through Imaging (CLARiTI) is a study that aims to collect standardized imaging and plasma biomarkers on 2000 Clinical Core participants enrolled across all Alzheimer's Disease Research Centers (ADRC) sites. We sought to summarize the known heterogeneity across centers regarding scientific focus and initial enrollment plans for CLARiTI. METHODS We developed and distributed a survey capturing information on the 36 CLARiTI site's theme/expertise, recruitment plans, and the intersection of CLARiTI with other ADRC imaging efforts. RESULTS Anticipated CLARiTI enrollees spanned 11 different categories of suspected etiologies underlying impairment. A wide range of risk factors were endorsed across sites regarding the enrollment of unimpaired individuals. Variability also existed regarding site‐level strategies in enrollment into CLARiTI versus other imaging efforts. DISCUSSION We anticipate that the 2000 individuals that will enroll into CLARiTI will reflect the clinical heterogeneity already in place across the ADRC network. Highlights The ADRC Consortium for Clarity in ADRD Research Through Imaging (CLARiTI) will leverage and contribute to the existing Alzheimer's Disease Research Centers (ADRC) program by supporting standardized imaging and plasma collection across all centers. We summarize the variation in scientific focus and enrollment plans across ADRC sites participating in CLARiTI. The anticipated CLARiTI cohort will reflect the clinical heterogeneity that already exists across the ADRC network. CLARiTI will contribute to scientific goals related to the detection of multi‐etiological signatures relevant for Alzheimer's disease and related disorders (ADRDs).

ABSTRACT IPTA created the SMARTER Initiative to address persistent gaps in pediatric transplant education worldwide. Through webinars, podcasts, case discussions, and interactive resources, SMARTER provides trainees and allied professionals with accessible, peer‐reviewed content across all major organ systems. The program is designed for global reach, with downloadable modules, mobile compatibility, and recorded sessions to accommodate different regions and time zones. Since its launch, SMARTER has shown strong engagement, with fellows reporting that the platform helps them prepare for board exams, improve clinical decision‐making, and connect learning directly to patient care. Survey feedback highlights high satisfaction and identifies opportunities for further growth, such as expanded case‐based modules, procedural videos, and simulation exercises. By reducing disparities in transplant training and supporting collaboration, SMARTER is positioned to strengthen existing curricula and promote a better‐prepared, more globally connected transplant workforce.

Abstract Background and Aims Patients with catecholaminergic polymorphic ventricular tachycardia (CPVT) are at risk for potentially life-threatening arrhythmic events (AEs) even while treated with β-blockers. The aim was to develop a model for individualized prediction of AEs in patients with RYR2-mediated CPVT on β-blocker monotherapy. Methods The derivation and independent validation cohorts included 743 and 129 patients, respectively. AEs were defined as arrhythmic syncope, appropriate implantable cardioverter–defibrillator shock, sudden cardiac arrest (SCA), and sudden cardiac death. Near-fatal or fatal AEs (nf/fAEs) included all AEs except for arrhythmic syncope. Prediction models using Cox regression were developed and internally and externally validated. Results A total of 102 (13.7%) patients in the derivation cohort and 24 (18.6%) patients in the validation cohort experienced ≥1 AE over a median follow-up of 5.1 [interquartile range (IQR), 7.7] and 2.4 (IQR, 4.4) years, respectively. Predictors of AE were arrhythmic syncope or SCA prior to diagnosis and age at β-blocker initiation. In the derivation and validation cohorts, the optimism-corrected C-indices of the models for AE were 0.67 [95% confidence interval (CI) 0.62–0.72] and 0.59 (95% CI 0.48–0.71), respectively. For nf/fAEs, ventricular arrhythmia severity before β-blocker initiation was a fourth independent predictor, and C-indices of the models in the derivation and validation cohorts were 0.74 (95% CI 0.68–0.80) and 0.60 (95% CI 0.47–0.72), respectively. In the derivation cohort, calibration slopes were 1.00 (95% CI 0.59–1.41) for AE and 1.00 (95% CI 0.69–1.32) for nf/fAE. Conclusions These externally validated risk prediction models using clinical parameters accurately distinguished CPVT patients on β-blocker monotherapy at low and high risk for future AEs while treated with β-blockers. These models provide guidance for implementation of clinical management therapies to prevent AEs in patients with CPVT.

Importance Transthyretin amyloid cardiomyopathy (ATTR-CM), a progressive disease caused by misfolded transthyretin (TTR), occurs as wild-type (ATTRwt-CM) or variant (ATTRv-CM) forms. p.Val142Ile is the most common variant in the US, linked to rapid progression and increased mortality. Acoramidis achieves near-complete (≥90%) TTR stabilization and showed clinical benefit in the 30-month ATTRibute-CM trial and through month 42 in the ongoing open-label extension (OLE). Objective To evaluate the efficacy of acoramidis in ATTRwt-CM, ATTRv-CM, and variant subgroups (p.Val142Ile and non-p.Val142Ile). Design, Setting, and Participants This international, multicenter, phase 3, randomized placebo-controlled study took place from April 2019 to May 2023 with ongoing OLE (month 42). ATTRibute-CM enrolled 632 participants with ATTR-CM; 611 of 632 were included in the modified intention-to-treat (mITT) population. There were 380 participants who continued into the OLE. These data were analyzed from January 2025 to July 2025. Interventions Oral acoramidis, 712 mg, or placebo twice daily for 30 months, followed by 12 months of open-label treatment. Main Outcomes and Measures All-cause mortality (ACM), cardiovascular-related hospitalizations (CVH), serum TTR, 6-minute walk distance, Kansas City Cardiomyopathy Questionnaire Overall Summary score, and N-terminal pro B-type natriuretic peptide in participants with ATTRwt-CM and ATTRv-CM. Post-hoc analyses were conducted in variant subgroups, including p.Val142Ile. Results Overall, 552 participants with wild-type ATTR-CM (mean [SD] age, 78 [6.3] years; 92.0% male and 8.0% female) and 59 participants with variant ATTR-CM (mean [SD] age, 73 [7.7] years; 77.3% male and 22.7% female) were randomized (mITT population), including 35 with p.Val142Ile. Consistent efficacy was observed in wild-type and variant subgroups for ACM/CVH through month 30 and ACM through month 42. At month 30, acoramidis reduced the risk of ACM/first CVH vs placebo by 31% in ATTRwt-CM (hazard ratio [HR], 0.69; 95% CI, 0.52-0.90; P = .007) and by 59% in ATTRv-CM (HR, 0.41; 95% CI, 0.21-0.81; P = .01). ACM was reduced through month 42 with HRs of 0.70 (95% CI, 0.50-0.98; P = .04) and 0.41 (95% CI, 0.19-0.93; P = .03) in the ATTRwt-CM and ATTRv-CM groups, respectively. Consistent treatment benefit was observed in participants with ATTRwt-CM and ATTRv-CM for secondary end points. Within variant subgroups (p.Val142Ile vs non-p.Val142Ile), consistent treatment benefits were observed for ACM/CVH through month 30 and ACM through month 42. Conclusions and Relevance The beneficial effect of acoramidis was observed consistently in ATTRwt-CM and ATTRv-CM groups. These hypothesis-generating results indicate that further studies are warranted to better characterize the therapeutic benefit of acoramidis in variant subgroups. Trial Registration ClinicalTrials.gov Identifiers: NCT03860935 ; NCT04988386

BACKGROUND: Elevated blood pressure (BP) is a major contributor to coronary artery disease. We explored the impact of life-course BP on later-life normalized stress myocardial blood flow (sMBF N ) and myocardial perfusion reserve by cardiovascular magnetic resonance (CMR). METHODS: MyoFit46 prospectively recruited ≈500 National Survey of Health and Development 1946 birth cohort participants, aged ≈77 years, to undergo stress perfusion and late gadolinium enhancement CMR. Systolic (SBPs) and diastolic BPs were recorded at 36, 43, 53, 63, 69, and 77 years. For each participant, the annual rates of BP change (steepness of BP increase) and area under the BP trajectory curve (cumulative life-course BP burden) were derived using mixed-effects models. The associations between BP measures and CMR metrics were tested using generalized linear and additive models, adjusted for antihypertensive use, demographics, lifestyle choices, and comorbidities. Cross-sectional associations between CMR metrics and major adverse cardiovascular events (myocardial infarction, stroke, and heart failure) were also tested. Mediation analyses explored the mechanistic pathways linking life-course BPs, myocardial perfusion, and myocardial fibrosis. RESULTS: Among 459 included MyoFit46 participants, each 10 mm Hg higher SBP at 36 to 69 years was associated with 3% to 6% lower sMBF N by CMR at 77 years. At 43 to 63 years, as SBPs rose from 120 to 140 mm Hg, sMBF N was 18% to 24% lower. Having a sustained higher SBP by 10 mm Hg from 36 to 77 years was associated with 11% (95% CI, 8–14) lower sMBF N at 77 years. Each 1 mm Hg/y steeper SBP rise during age intervals 36 to 43, 43 to 53, 53 to 63, and 63 to 69 years was associated with 2% to 6% lower sMBF N at 77 years, associations not conditional on baseline or final BPs in each age interval. Associations may be clinically relevant as each 1% lower sMBF N was associated with 3% higher odds of major adverse cardiovascular events. sMBF N mediated ≈20% to ≈40% of the associations between life-course SBPs and late gadolinium enhancement at 77 years. Results were similar for diastolic BP, myocardial perfusion reserve, or sMBF (not normalized). CONCLUSIONS: Higher life-course BPs, steeper increases, and greater cumulative BP burden associate with lower myocardial perfusion by CMR at 77 years, which can be linked with higher odds of major adverse cardiovascular events and greater myocardial fibrosis burden. This underscores the importance of early life BP screening and guiding hyperetension treatment based on longitudinal BP trajectories (rather than relying solely on cross-sectional BPs). REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT05455125.