Citations

Background and Aims: Cholangiocarcinoma (CCA) is a rare but aggressive malignancy with poorly understood genetic susceptibility. To date, genome-wide association studies (GWAS) investigating germline variants associated with CCA risk remain limited. We aimed to identify genetic risk loci for CCA and its clinical subtypes through comprehensive GWAS and post-GWAS analyses. Approach and Results: We conducted a GWAS of 2366 CCA cases and 11,750 controls of European ancestry. Genome-wide significant loci ( p <5×10 −8 ) were identified and further examined through fine-mapping, functional annotation, and HLA imputation. Subgroup analyses were conducted by CCA subtypes and primary sclerosing cholangitis (PSC) status. Cross-trait linkage disequilibrium score regression and Mendelian randomization were employed to investigate the shared genetic architecture and potential causal relationships with a diverse range of traits. We identified 1 new genome-wide significant variant, rs535777 (OR=1.44), near HLA-DRB1/DQA1 associated with CCA, and 2 variants associated with extrahepatic CCA: rs116224263 (OR=0.17) in LINC02506 at 4p15.1 and rs6914950 (OR=1.63) near HLA-DRB1/DQB1 . Stratified analyses revealed rs2395184 (OR=3.51) near HLA-DRA/DRB5 associated with PSC-related CCA, and rs142674434 (OR=2.98) in THSD7A at 7p21.3 associated with non-PSC-related CCA. HLA imputation uncovered new amino acid residues associated with disease risk. Cross-trait analyses identified shared genetic signals between CCA and anthropometric, lipidemic, lifestyle, and medical traits. Mendelian randomization supported putative causal associations for 12 traits with CCA or its subtypes. Conclusions: Our large-scale GWAS highlights new genetic variants and HLA-linked mechanisms underlying CCA susceptibility. Integrating multi-step post-GWAS approaches enhances understanding of CCA pathogenesis and may facilitate the development of risk biomarkers for early detection and precision prevention strategies.

Objective: Auditory nerve monitoring through electrically evoked compound action potentials (eCAP) can be used to assess cochlear neural integrity during vestibular schwannoma (VS) resection. Herein, we report on 5 cochlear implant (CI) patients who underwent VS resection with present eCAP responses both intraoperatively and postoperatively. Patients either did not perceive any sound through their CI or rapidly adapted to electrical stimulation, suggesting that the presence of eCAP does not guarantee auditory nerve function in patients with VS resection. Patients: Five patients who underwent simultaneous VS translabyrinthine resection and cochlear implantation. Interventions: Simultaneous cochlear implantation and translabyrinthine microsurgical VS resection. Main outcome measure: Electrically evoked compound action potential. Results: All patients had eCAP responses present during their VS resection and for at least 50 days post-surgery. Three of the 5 patients did not perceive any sound with their cochlear implant. This shows that the presence of an eCAP alone does not guarantee a functional auditory nerve or auditory perception. The other 2 patients could hear non-speech sounds, but these sounds quickly became inaudible, indicating that their auditory nerve lacked the ability to integrate the electrical stimulus over time. Conclusions: The presence of an eCAP response does not guarantee auditory sensation through a CI. Although eCAP measurements provide insight into the function of the distal end of the nerve, it does not ascertain integrity or function of the larger auditory nerve pathway. Therefore, eCAPs should not be used in isolation to monitor auditory nerve function during VS resection.

Abstract Acute, traumatic meniscus tears are common and should be repaired whenever possible. However, the biological age of the patient, along with the specific tear morphology, may significantly influence the selection of the repair technique, expected clinical outcomes and the postoperative rehabilitation protocol. Risk factors for failure of meniscus repair, such as ligament laxity, need to be addressed to improve the healing potential of the meniscus. Biologic augmentation strategies, including bone marrow stimulation, platelet‐rich plasma, fibrin clot, mesenchymal stem cells or meniscal wrapping, can be used to enhance healing and reduce failure of meniscus repair rates. However, the clinical evidence remains limited and of low quality. As such, the routine use of biologic augmentation in meniscus repair warrants critical evaluation. In patients with post‐meniscectomy syndrome, meniscus allograft transplantation (MAT) may be a viable option to reduce pain and joint degeneration and improve knee function. Meniscus implants provide alternatives to traditional MAT; however, their long‐term efficacy, chondroprotective effects and integration within the knee joint require further research. Meniscus reconstruction using tendon autografts has been described as an alternative treatment option in patients with meniscus loss. Emerging methods, such as gene therapy and repurposed drugs, demonstrate in vitro potential for advancing meniscal repair, although their clinical applications are still in their infancy. Future research is necessary to optimize meniscal repair techniques, enhance clinical efficacy, and ultimately, improve outcomes in patients. Level of Evidence Level V.

Abstract INTRODUCTION Associations of short‐term use of menopausal hormone therapy (mHT) with Alzheimer's disease (AD) and structural magnetic resonance imaging (MRI) biomarkers were investigated 10 years after an mHT trial. METHODS Recently menopausal women with good cardiovascular health were randomized to oral conjugated equine estrogens (oCEE) or transdermal 17β‐estradiol (tE2) and micronized progesterone, or placebo for 4 years. Amyloid beta (Aβ) on positron emission tomography, hippocampal atrophy, and dorsolateral prefrontal cortex thickness on MRI were assessed 10 years after completion of the mHT trial ( n = 266). RESULTS Aβ and structural MRI biomarkers were not different in the oCEE and tE2 groups compared to placebo. Apolipoprotein E ε4 status did not modify the findings. DISCUSSION There was no evidence of adverse effects or benefits associated with 4 years of use of oral or transdermal mHT on Aβ and structural MRI biomarkers in relatively healthy women, 10 years after mHT. Findings support the long‐term safety of short‐term use of mHT on brain health. CLINICAL TRIALS REGISTRATION NCT00154180 Kronos Early Estrogen Prevention Study (KEEPS) Highlights There were no menopausal hormone therapy–related adverse effects or benefits on amyloid beta and magnetic resonance imaging biomarkers in the long term. Apolipoprotein E ε4 carrier status did not modify these findings. Findings align with neutral cognitive and cerebrovascular outcomes in this cohort.

ABSTRACT Background Li Fraumeni syndrome (LFS) is a hereditary multi‐cancer syndrome caused by alterations in TP53 (MIM# 151623). Next generation sequencing (NGS) allows for the detection of TP53 variants at lower variant allele frequencies (VAFs). A TP53 variant with a VAF < 50% may represent mosaic LFS, aberrant clonal expansion (ACE), or possible circulating tumor DNA. Differentiation among these conditions is important for optimal patient management. Methods Genetic testing was performed using a custom gene panel, with an average read depth of 350× (range 166–553×). DNA extracted from four different tissues (blood, saliva, cultured skin fibroblasts, and colon) was sequenced. Results Here, we describe an adult female patient with a history of an adrenocortical neoplasm and osteosarcoma, diagnosed at 2 and 16 years of age, respectively. Testing of peripheral blood identified a pathogenic TP53 variant, c.733G>A, p.(Gly245Ser) (NM_000546.6); however, subsequent in vitro fertilization with preimplantation genetic testing for monogenic disorders (PGT‐M) did not identify this TP53 variant in any of nine embryos tested. Testing for possible mosaicism in the proband was performed on four different specimens, revealing variable VAFs of the TP53 variant (saliva: 44%; blood: 31%; cultured skin fibroblasts: 18%; and colon tissue: 9%). These results suggest a post‐zygotic event, consistent with mosaic LFS rather than ACE. Conclusion This case highlights the complexity of interpreting mosaic variants in the TP53 gene, and we propose a testing algorithm to aid in the delineation of this phenomenon when relaying cancer and reproductive risk information in the context of mosaicism.

Objective: To evaluate hearing outcomes after treatment with stereotactic radiosurgery (SRS) for sporadic vestibular schwannoma (VS) among patients with baseline 100% word recognition scores (WRS). Study design: Historical cohort. Setting: Tertiary academic medical center. Patients: Patients with 100% WRS on audiometric testing at initial treatment with SRS. Interventions: Gamma Knife SRS. Main outcome measures: Rate of maintaining serviceable hearing (SH), defined as American Academy of Otolaryngology-Head and Neck Surgery hearing class A or B. Results: In total, 125 patients had 100% WRS at SRS for sporadic VS. Median age at SRS was 56 years (IQR: 51 to 62) and median pure tone average (PTA) at SRS was 20 dB HL (IQR: 13 to 31). Sixty-eight patients progressed to non-SH at a median of 3.4 years after SRS (IQR: 1.0 to 8.6); the median duration of follow-up for the 57 patients who maintained SH was 5.1 years (IQR: 2.8 to 9.6). Rates of maintaining SH (95% CI, number still at risk) at 1, 3, 5, 7, and 10 years after SRS were 88% (82 to 94, 101), 75% (68 to 84, 81), 61% (53 to 71, 55), 58% (49 to 68, 43), and 44% (35 to 56, 26), respectively. Each 10-dB HL increase in PTA at SRS was associated with a 52% increased risk of progression to non-SH (hazard ratio: 1.52, 95% CI: 1.24-1.87, P <0.001). Conclusions: Despite having 100% pretreatment WRS, most patients with sporadic VS treated with SRS experienced clinically significant hearing decline over time. Even among this cohort of patients with excellent baseline hearing, at 10 years after treatment, only 44% of patients maintained SH.

Abstract Background New insights into community-acquired pleural infection microbiology may enable development of more rapid and accessible diagnostics that can streamline treatment. This study systematically compared molecular approaches for pathogen detection in pleural fluid from patients with such infections. Considering the need for rapid results with minimum hands-on time and test complexity, off-label use of the cassette-based, random-access BIOFIRE Joint Infection Panel (BF-JIP, bioMérieux) with and without supplementary in-house polymerase chain reaction (PCR) assays was evaluated. Methods Pleural fluids from 162 subjects from the Mayo Clinic (Rochester, Minnesota) and Haukeland University Hospital (Bergen, Norway), where molecular tests are routinely used for analyzing pleural fluid, were studied. The performance of the BF-JIP was compared to 16S rRNA gene PCR followed by Sanger and/or next-generation sequencing (16S rRNA gene PCR/sequencing), an in-house PCR panel specifically designed for pleural space infections, and culture. Results The BF-JIP supplemented with 3 in-house PCR assays targeting Fusobacterium nucleatum group, Streptococcus intermedius/constellatus, and Aggregatibacter aphrophilus detected 96.8% of pleural infections, providing complete microbial profiles in 70.1%. In comparison, the detection rate of 16S rRNA gene PCR/sequencing was 92.2%, providing complete microbial profiles in 87.0%. Culture detected bacteria in only 31.9% of pleural fluids, providing complete microbial profiles in 15.3%. Conclusions These results underscore the importance of molecular approaches in diagnosing pleural space infections and demonstrate the feasibility of panel-based PCR-based diagnostics for these sometimes-complex infections. The BF-JIP, designed for testing synovial fluid, could be modified to provide a useful diagnostic for testing pleural fluid.

Background A recent randomized prospective controlled trial demonstrated that atorvastatin for up to 2 years was safe but did not significantly alter rebleeding in cerebral cavernous malformations. However, any consequences of discontinuing atorvastatin remain unknown. We hypothesized that symptomatic hemorrhage (SH) recurs more frequently in cerebral cavernous malformations after discontinuation of atorvastatin than placebo. Methods We conducted a 12‐month posttreatment follow‐up of patients enrolled in the Atorvastatin Therapy in Cavernous Angiomas with Symptomatic Hemorrhage Exploratory Proof of Concept (AT CASH EPOC) trial (41 randomized to atorvastatin, 39 to placebo) to identify potential recurrent SH after trial drug discontinuation. Every SH was adjudicated by review of imaging and corresponding symptoms. Patients were excluded from follow‐up for <90% compliance with study drug, for its discontinuation <3 months after trial enrollment, for statin reinitiation <3 months after discontinuation, or for lack of follow‐up. Cases were censored during follow‐up upon cerebral cavernous malformation resection/radiation or later statin reinitiation. Results Follow‐up included 33 patients who had been randomized to placebo and 32 who had taken atorvastatin. Four SH events occurred at 3, 49, 84, and 225 days after atorvastatin discontinuation, and 1 SH at 395 days after discontinuing placebo. There was significantly lower symptomatic hemorrhage‐free survival in the atorvastatin‐discontinuation group (log‐rank χ 2 =4.136, P =0.042). The hazard ratio was 0.162 (95% CI, 0.027–0.977) for placebo versus atorvastatin discontinuation. Conclusions Discontinuation of atorvastatin was associated with a higher risk of recurrent SH compared with placebo discontinuation. Additional studies are warranted to confirm this hypothesis‐generating observation, examine potential mechanisms, and how best to mitigate this risk. REGISTRATION URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02603328.

Background: Embolic stroke of undetermined source (ESUS) comprises infarct mechanisms presumed to be embolic and non-lacunar. One explanation for the lack of superiority of anticoagulation over aspirin is the inclusion of subcortical infarcts with white matter disease (WMD), reflecting small vessel pathology. We hypothesized that WMD is associated with recurrent ischemic stroke (RIS) in ESUS and this risk is not lessened by anticoagulation. Methods: We conducted a secondary analysis of the multicenter Cardiac Abnormalities in Stroke Prevention and Recurrence (CASPR) registry, including ESUS patients from 27 U.S. centers (2015–2024). WMD severity was graded using the Fazekas scale from MRI and dichotomized as mild (0–1) vs. moderate-to-severe (2–3). The primary outcome was RIS. Secondary outcomes were major bleeding and all-cause mortality. Inverse probability of treatment weighting (IPTW) adjusted for baseline differences. Cox proportional hazards models assessed associations between WMD and outcomes. Subgroup analyses explored effect modification by age, risk factors, and treatment type. Results: Among 1,890 ESUS patients with MRI data, 684 (36.2%) had Fazekas 2–3. These patients were older with more vascular risk factors, but IPTW achieved covariate balance. In the weighted cohort, RIS occurred more frequently in Fazekas 2–3 vs. 0–1 (7.1% vs. 4.6%/year; HR 1.56, 95% CI 1.10–2.22, p = 0.01). Major bleeding and mortality were similar (bleeding: 1.7% vs. 1.8%/yr, HR 0.96, p = 0.92; death: 7.0% vs. 6.7%/yr, HR 1.04, p = 0.81). Subgroup analyses showed no interaction between WMD and age, vascular risk factors, or treatment type (antiplatelet vs. anticoagulation), suggesting consistent RIS risk in those with higher WMD. Discussion: Moderate-to-severe WMD identifies ESUS patients at higher risk of ischemic stroke recurrence, with no mitigation by anticoagulation. These findings suggest that WMD may indicate non-embolic mechanisms and support the use of imaging-based risk stratification in ESUS.