Citations

Background: Hyperkinetic biliary dyskinesia, defined as a gallbladder ejection fraction (EF) ≥80% on cholecystokinin (CCK)-stimulated hepatobiliary iminodiacetic acid scans in the setting of biliary-type pain, has been increasingly recognized as a potential functional gallbladder disorder. The clinical significance of this entity and the role of cholecystectomy remain uncertain. Patients and Methods: We conducted a systematic review and meta-analysis of studies reporting outcomes in patients with CCK-hepatobiliary iminodiacetic acid EF ≥80% who underwent cholecystectomy due to non-acute biliary-type pain. Primary outcomes included mean EF, rates of symptom resolution and improvement following cholecystectomy, and prevalence of chronic cholecystitis on pathology. Secondary outcomes included normal histology rates and symptom reproduction with CCK stimulation. All statistical analyses were conducted in R (version 4.5.0) using a random-effects model to obtain pooled estimates. Results: A total of 14 retrospective studies, including 686 patients, were analyzed. The pooled mean gallbladder EF was 90.27% (95% CI: 88.73–91.80, I 2 = 86.6%). Symptom resolution occurred in 83.1% (95% CI: 76.7–89.4, I 2 = 76.8%), and symptom improvement in 91.6% (95% CI: 89.0–94.2, I 2 = 29.7%) of patients following cholecystectomy. Histopathologic analysis revealed chronic cholecystitis in 85.1% (95% CI: 76.9–93.4, I 2 = 90.6%) of surgical specimens, while normal gallbladder histology was rare, observed in only 9.9% (95% CI: 4.6–15.2, I 2 = 83.7%). The pooled risk ratio indicated a 6.70-fold higher likelihood of chronic cholecystitis compared with normal histology (95% CI: 3.69–12.17, I 2 = 65.2%, P = 0.0022). Functional reproduction of symptoms during CCK stimulation was frequent, with a pooled rate of 78.3% (95% CI: 70.4–86.3, I 2 = 35.6%). Egger regression test suggested potential publication bias for the normal histology outcome ( P = 0.0223), but not for symptom resolution ( P = 0.1589). Conclusions: This meta-analysis suggests that a high gallbladder EF in the setting of biliary-type pain could represent clinically relevant hyperkinetic biliary dyskinesia rather than normal physiology. Cholecystectomy appears to provide meaningful symptom relief in appropriately selected patients, and pathologic findings frequently indicate underlying chronic inflammation. Further studies are needed to establish clear diagnostic cutoffs and guide management.

Purpose Radioligand therapy (RLT) with [ 177 Lu] Lu-PSMA-617 has shown significant benefits in metastatic castration-resistant prostate cancer (mCRPC), including prolonged overall survival (OS) and progression-free survival (PFS), as well as improved quality of life. For patients previously treated with [ 177 Lu]Lu-PSMA-617 who subsequently experience disease progression, retreatment with [ 177 Lu] Lu-PSMA-617 has emerged as a potential approach, yet data on the outcomes of RLT retreatment remains limited. This study aimed to assess the efficacy and safety of retreatment RLT in mCRPC. Methods Clinical and imaging data of patients who underwent at least two cycles of [ 177 Lu] Lu-PSMA-617, followed by a second course of treatment with [ 177 Lu] Lu-PSMA-617 between March 2018 and December 2024, were retrospectively reviewed. Endpoints included biochemical response, imaging response, toxicity, PSA-PFS, rPFS, and OS. Radiologic and biochemical responses were evaluated using RECIST 1.1 criteria and PSA levels, respectively. Results A total of 589 patients underwent [ 177 Lu] Lu-PSMA-617 RLT, of whom 20 (3.4%, 20/589) received RLT retreatment. The median age was 71.3 years (range: 63.7–95.2), and the median follow-up was 73.3 months (95% CI, 35.7–77.2 months) after the initial treatment and 21.7 months (95% CI, 16.9–26.0 months) after retreatment. The initial treatment involved a median of 4.5 cycles (range: 2–6). Following the first course of RLT, 15 patients (75%, 15/20) had exhibited a >50% decline in PSA levels, including 9 who achieved a >90% decrease. Additionally, 12 patients (60%, 12/20) had demonstrated a complete or partial imaging response, while 3 (15%, 3/20) patients had stable disease, and 5 (25%, 5/20) patients had progressive radiologic disease. Patients received a median of 4 retreatment cycles (range, 1–6), and the median interval between initial RLT and retreatment RLT was 33.1 months (IQR, 16.2–48.9 months; range, 10.7–58.8 months). A PSA decline of ≥50% was observed in 9 out of 20 patients (45%, 9/20). An imaging response was observed in 10 patients (50%, 10/20), with 4 achieving a complete response and 6 achieving a partial response, whereas 10 patients (50%, 10/20) showed progression. The median PSA-PFS was 9.8 months (95% CI, 4.1–17.9 months), and the median rPFS was 8.2 months (95% CI, 3.3–17.9 months). Eight deaths occurred during follow-up. The estimated Kaplan Meier OS rates were 83.6% at 12 months (95% CI, 57.3%–94.4%) and 53.7% at 24 months (95% CI, 28.3%–73.7%). Grade 2 renal toxicity was observed in one patient (5%, 1/20). Three patients (15%, 3/20) developed Grade 2 anemia. Notably, no grade 3 or grade 4 adverse events were observed during either treatment period. Conclusion In our cohort, retreatment with [¹ 77 Lu]Lu-PSMA-617 RLT was associated with biochemical and imaging responses in some patients, with observed survival outcomes that support further investigation. However, given the retrospective single-arm design and small sample size, large prospective studies are needed to more rigorously evaluate the safety, efficacy, and optimal patient selection for retreatment RLT.

Objective To evaluate whether local field potential (LFP) spectral profiles can serve as a candidate “spectral fingerprint” for physiological confirmation of centromedian-parafascicular (CM–Pf) targeting during thalamic deep brain stimulation (DBS) for drug resistant epilepsy (DRE). Methods This is a retrospective study of 10 patients (20 leads) who underwent CM-DBS implantation for DRE at a single tertiary center. Postoperative CT and preoperative MRI were co-registered, normalized to the Montreal Neurological Institute (MNI) space, and reconstructed using Lead-DBS software to anatomically localize contacts. BrainSense™ Survey recordings were obtained at least 3 weeks post-implant during routine programming. LFP frequency content was analyzed, and prominent peaks were identified and classified into canonical frequency bands (theta, alpha, beta). These spectral profiles were then mapped to MRI-based anatomical localizations, and statistical tests were applied to assess associations between peak patterns, contact localizations and thalamic subregions. Results Contacts were distributed as follows: 50 in the CM, 16 in the Parafascicular (Pf), 15 in the Centrolateral, 8 in the Mediodorsal, and 7 in the Ventrolateral (VL) nuclei. Of the 10 representative spectral localizations confined to the CM/CM-Pf region, 8 (80%) displayed a distinct dual-peak spectral profile with peaks in the theta/low alpha (5.5–9 Hz) and high beta (20–30 Hz) bands (mean frequencies: 7.63 Hz and 21.02 Hz, Fisher’s exact test, p < 0.001). Single-peak profiles showed no significant association with specific nuclei ( p = 0.871). Contacts overlapping other thalamic nuclei more frequently exhibited narrow 10–15 Hz peaks ( p = 0.005) or triple-peak profiles ( p = 0.02), suggesting mixed structural contributions. Conclusion A dual- band candidate spectral pattern consisting of theta/low alpha and high beta peaks was associated with the CM-Pf region in this cohort. This finding provides early evidence supporting the feasibility of incorporating passive LFP recordings as a physiologic marker of target engagement. Future work to prospectively compare bipolar survey-based localization with monopolar recording strategies could enable development of a state-based, physiologically informed spectral atlas to refine CM-Pf targeting in thalamic neuromodulation for DRE.

Importance Transvaginal pelvic imaging is an integral and sensitive aspect of gynecologic care that individuals find both invasive and burdensome. At-home transvaginal imaging provides an opportunity to navigate these barriers to care. Objective To evaluate the use of at-home transvaginal ultrasonography for gynecologic assessment, as measured by diagnostic imaging quality and participant satisfaction, in a broad sampling of women aged 22 to 50 years. Design, Setting, and Participants Prospective, interventional, single group nonrandomized clinical trial with blinded review of collected images from premenopausal women aged 22 to 50 from Florida, Massachusetts, Maryland, Maine, Minnesota, New Hampshire, Texas, Utah, Virginia, Vermont, and Washington, DC. Images were gathered between July 2022 and July 2023, and data were analyzed from April to September 2025. Intervention At-home pelvic ultrasonography guided by verbal communication with a fully trained remote sonographer who had real-time access to study images. Cine clips were used to capture standard views of the uterus, ovaries, cervix, and posterior cul-de-sac. Main Outcomes and Measures Primary outcomes were image quality and participant net promoter score (NPS), reflecting participants' likelihood of recommending the procedure, with higher scores indicating greater likelihood. Secondary outcomes included minor pain or discomfort, sonographer reported experience and/or pain, and all other adverse events. Results A total of 265 participants (mean [SD] age, 32 [6.7] years; mean [SD] body mass index, 27.0 [5.6]) enrolled in the trial, and 263 ultrasonographic scans were completed. Image quality showed that 253 at-home ultrasonographic scans (96.2%) met diagnostic quality while 10 (3.8%) did not. NPS was significantly higher with use of the at-home ultrasonography (59) compared with in-clinic scans (24), with an adjusted difference of 33.7 (95% CI, 23.3-44.0; z = 6.35; P < .001). No adverse events were reported. Conclusions and Relevance This nonrandomized clinical trial of at-home pelvic ultrasonography in premenopausal women demonstrated that broad use of at-home gynecologic ultrasonography technology is feasible, safe, and preferred by participants and sonographers compared with in-clinic ultrasonography. At-home ultrasonographic imaging presented an innovative and clinically acceptable alternative to in-clinic care, providing opportunities for improved access to and decreased burden of gynecologic and reproductive care. Registration ClinicalTrials.gov NCT05443698

Abstract Embryonal tumors with multilayered rosettes (ETMR) are rare, highly aggressive tumors of infancy with extremely poor outcomes and no established standard of care therapy. ETMRs were recognized as a distinct molecular entity in 2016, however, the absence of prospective, biology-driven clinical trials has limited translation of these insights into standardized, risk-adapted treatment approaches for this vulnerable population. To address this gap, the Collaborative Network for Neuro-oncology Clinical Trials (CONNECT) developed CURE(Clinical trial advancing Understanding of Rare Embryonal Brain Tumors), an international, multi-institutional, molecularly guided umbrella trial. All patients enroll through the centralized CURE-Screening protocol, which provides rapid comprehensive molecular profiling with real-time central pathology, molecular, and radiographic review to confirm diagnosis, define molecular subtype, and determine eligibility and assignment to disease-specific treatment arms. CURE-ETMR represents the first disease-specific arm to open within this platform. Following centralized screening, children with newly diagnosed ETMR are assigned to clinically defined risk strata using integrated molecular, radiographic, and clinical criteria. Patients will be treated using a risk-adapted multimodal approach in which we prioritize maximal safe surgical resection with consideration of second-look surgery based on centralized imaging review; administer induction chemotherapy followed by consolidation with high-dose chemotherapy and autologous hematopoietic cell rescue or dose-intensified chemotherapy, selectively incorporate radiation sparing approach or early focal radiotherapy for patients with unresectable residual disease or brainstem involvement; deliver intrathecal chemotherapy for leptomeningeal prophylaxis; and include biologically informed maintenance therapy. In parallel, protocol-required longitudinal collection of tumor tissue, cerebrospinal fluid, blood, and advanced neuroimaging supports integrated molecular, liquid biopsy, and imaging biomarker analyses to identify predictors of treatment response, resistance, and relapse. Primary objectives include evaluation of feasibility, safety, progression-free survival, and overall survival compared with molecularly annotated historical cohorts. This centralized screening to assignment framework establishes a scalable model for prospective, biology-driven trials in rare embryonal brain tumors.

Abstract Histopathological assessment has served as the gold standard for diagnosing Alzheimer’s disease (AD). Emerging technological advancements, including the development of amyloid positron emission tomography (PET), have enabled early detection of amyloid pathology, one of the neuropathological hallmarks of AD. Genome-wide association study (GWAS) across cohorts of aging and AD, leveraging different measurements of amyloid burden, may facilitate the identification of novel genetic variants that drive the earliest neuropathological changes in AD. This study presents the largest GWAS of brain amyloidosis to date, leveraging amyloid β (Aβ) measured by in vivo amyloid PET and postmortem histopathology from 13,555 individuals of European ancestry. Amyloid positivity was defined as moderate or frequent neuritic plaques according to the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) staging scores for each postmortem cohort. A Gaussian mixture model (GMM) was applied to each amyloid PET cohort to identify the cohort and tracer-specific cut-offs that differentiate amyloid positive and negative populations. In silico and ex vivo analyses further characterized implicated loci, including interrogating the association between bulk and single-nucleus gene expression profiles and AD-related traits. Genetic covariance analysis assessed the extent amyloid PET and postmortem measures reflect the shared genetic architecture of brain amyloidosis. Our combined amyloidosis GWAS identified three established AD risk loci: BIN1 (rs6733839, OR = 1.20, 95% CI 1.14-1.26, P = 1.32 × 10−11), CR1 (rs4844610, OR = 1.24, 95% CI = 1.16-1.32, P = 4.21 × 10−10), APOE (rs429358, OR = 4.01, 95% CI = 3.66-4.38, P = 4.54 × 10−201), and a newly identified brain amyloidosis-associated variant on chromosome 17 (rs35635959, OR = 1.18, 95% CI = 1.12-1.25, P = 1.47 × 10−8). SuSiE fine-mapping identified a single credible set of 15 putative causal variants with rs35635959 as the lead variant. Subsequent eQTL and SuSiE-based colocalization analyses prioritized rs35635959 as a strong eQTL for TUBG2, encoding tubulin gamma 2, which is involved in microtubule organization and synaptic plasticity. Further cell-type-specific characterization of this gene in neurons from dorsolateral prefrontal cortex tissue indicated that decreased TUBG2 expression was associated with increased Aβ burden and AD case status (PFDR < 0.045). Furthermore, our study is the first to report a modest genetic covariance (covariance=0.17, P < 6.54 × 10−8) between the genetic architecture of amyloid burden captured by different modalities. While APOE showed a strong association with both amyloid endophenotypes, the observed genetic covariance was not substantially attenuated after excluding variants within the APOE region (covariance=0.16, P < 1.32 × 10−7). Our results highlight the benefits of leveraging compatible, harmonized AD endophenotypes to increase power to uncover new molecular insights into the etiology of AD neuropathology. Wang et al. present the largest GWAS of brain amyloidosis to date, analysing 13,555 individuals using amyloid PET and postmortem Aβ measures. They identify a novel amyloidosis-associated variant on chromosome 17, demonstrate genetic covariance between modalities, and highlight complex traits sharing genetic architecture with Aβ burden.