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.

This cohort study evaluates the reduction in risk of high-grade serous carcinoma among women undergoing opportunistic bilateral salpingectomy in Canada.

Abstract Introduction: Total knee arthroplasty (TKA) for knee osteoarthritis (OA) provides pain relief and functional improvement for many patients. The endocannabinoid system (ECS) regulates pain and inflammation through central and peripheral mechanisms and may be affected by acetaminophen. There is limited information on how surgery and perioperative care affect the ECS. Objective: We designed this study to examine the effect of surgery and acetaminophen on the ECS and determine whether perioperative endocannabinoids were associated with pain resolution after surgery. Methods: Forty adult patients with OA undergoing TKA were enrolled in a prospective observational cohort study and provided preoperative cerebrospinal fluid (CSF) and blood samples at 3 time points (before surgery, after intravenous acetaminophen, and 24 hours postoperative). Defense and Veterans Pain Rating Scale scores at rest and with activity were recorded in the preoperative holding area, in the operating room after intravenous acetaminophen before spinal anesthesia, and 24 to 48 hours postoperatively. Cerebrospinal fluid and plasma endocannabinoids were quantified using a validated liquid chromatography/mass spectrometry assay. We analyzed the data using linear regression models with sex, age, and body mass index as covariates. Results: Patients undergoing TKA have higher CSF and plasma concentrations of N-acylethanolamines anandamide and its congeners compared with control subjects. Patients with higher pain scores had lower CSF anandamide levels before and after surgery and higher levels of 2-arachidonoylglycerol before surgery but not after. Conclusion: Chronic pain, acetaminophen, and surgery are associated with endogenous endocannabinoid levels and may present an opportunity for developing targeted nonopioid perioperative analgesia after TKA.

Abstract In adult-type diffuse gliomas CDKN2A and/or CDKN2B (CDKN2A/B) deletions often co-occur with deletion of MTAP, suggesting that MTAP immunohistochemistry (IHC) may be a surrogate marker of CDKN2A/B status. However, the association between CDKN2A/B and MTAP deletion at the genomic level remains unknown. We assessed CDKN2A/B and MTAP deletions by chromosomal microarray in 333 adult-type diffuse gliomas and performed MTAP IHC on a subset (n = 63). CDKN2A/B and MTAP deletions were detected in 216 and 215 cases, respectively, and were concurrent in 99.5% (215/216). While most tumors with CDKN2A/B homozygous deletion (n = 148) showed concurrent MTAP homozygous deletion (108/148; 73.0%), a subset harbored MTAP heterozygous deletion (39/148; 26.4%). By analyzing the size of the chromosomal alterations, we demonstrate that initial large chromosomal 9p losses result in concurrent heterozygous deletion of CDKN2A/B and MTAP whereas smaller “second hit” deletions leading to homozygous CDKN2A/B deletion do not always encompass the MTAP locus. Discordant CDKN2A/B and MTAP tumors affect the association between MTAP IHC and copy number status of MTAP and CDKN2A/B. These findings suggest that adult-type diffuse gliomas, regardless of IDH status, follow a stereotypic pathway involving concurrent CDKN2A/B and MTAP heterozygous deletion but may diverge for CDKN2A/B and MTAP homozygous deletion.

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.

BACKGROUND: Myocardial flow reserve (MFR), measured by positron emission tomography (PET) myocardial perfusion imaging, provides valuable information on epicardial coronary disease, diffuse atherosclerosis, and microvascular function. Despite its routine use, the prognostic efficacy of 13 N-ammonia PET MFR remains unconfirmed in larger multicenter cohorts of patients with suspected or known coronary artery disease. METHODS: We considered patients from 5 sites in the REFINE PET (Registry of Flow and Perfusion Imaging for Artificial Intelligence with PET) registry who underwent 13 N-ammonia PET myocardial perfusion imaging for coronary artery disease. Clinical and imaging data were collected at the time of myocardial perfusion imaging. MFR was quantified as the ratio of stress to rest myocardial blood flow, using QPET software (Cedars-Sinai Medical Center, Los Angeles, CA). The primary outcome was all-cause mortality. Survival analyses were performed using Kaplan-Meier and Cox regression models adjusted for clinical and imaging covariates. RESULTS: In total, 6277 patients were included (median age of 65 years, 56% male). Median follow-up time was 3.8 years. There were 1895 patients with MFR ≤2 and 4382 with MFR >2. Patients with MFR ≤2 had significantly higher mortality than those with MFR >2 (n=701 [37.0%] versus n=537 [12.3%], respectively; P <0.001). Annualized all-cause mortality rates by MFR and summed stress score ranged from 1.7 to 15.8. In multivariable analysis, MFR ≤2 was independently associated with increased all-cause mortality in the overall population (hazard ratio, 2.70 [95% CI, 2.41–3.03]; P <0.001), even among patients with no perfusion defects (hazard ratio, 2.36 [95% CI, 1.93–2.89]; P <0.001). Mortality risk decreased across increasing MFR deciles, ranging from hazard ratio, 2.73 (95% CI, 2.39–3.11) to hazard ratio, 0.35 (95% CI, 0.25–0.49). CONCLUSIONS: In this large multicenter cohort, MFR derived from 13 N-ammonia PET myocardial perfusion imaging is a strong, independent predictor of all-cause mortality, even in patients with normal perfusion. An MFR of ≤2 identifies elevated risk, while higher values are associated with improved survival. These findings support the routine integration of MFR to enhance risk stratification in patients with suspected or known coronary artery disease.

Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease associated with exposure to repetitive head impacts (RHIs), characterized by tau tangles around small blood vessels at the depths of the sulci. Currently, CTE can be diagnosed only postmortem , but can present with an array of cognitive, behavioral, mood, and motor symptoms. However, traumatic brain injury is also associated with increased risk of Alzheimer’s disease (AD) and may lead to comorbid neuropathology. Characterization of the in vivo biomarkers of CTE is a necessary next step to facilitate accurate diagnoses. We examined the profile of cerebrospinal fluid (CSF) biomarkers of amyloid-β, total tau (tTau), and phospho-tau (pTau) in a cohort of former professional (PRO, n = 100) and college (COL, n = 40) football players at high risk of CTE compared to asymptomatic unexposed controls (UE, n = 43). CSF was collected under controlled conditions using collection, processing, and cryostorage kits provided by the DIAGNOSE CTE Research Project Biomarker Core, and concentrations of Aβ 40 , Aβ 42 , tTau, and pTau (pTau 181 , pTau 217 , pTau 231 ) were measured at the University of Gothenburg, Sweden, using immunoassays. Associations between CSF biomarker levels with football history, and diagnosis of traumatic encephalopathy syndrome (TES) were examined using linear regression, and corrected for age, education, APOE -ε4 allele status, race, and body mass index. Our analysis revealed that football exposure affected both CSF Aβ 40 ( p = 0.039) and Aβ 42 ( p = 0.038), particularly among those under 60 years of age in the PRO compared to the UE exposure group. Among former football players, estimates of RHI exposure were not generally associated with CSF Aβ, tTau, and pTau biomarker levels. CSF Aβ 40 ( p = 0.0041) and Aβ 42 ( p = 0.011) were lower in former football players with TES diagnosis compared to unexposed participants, although CSF Aβ, tTau, and pTau biomarker levels did not differ between former players with and without a TES diagnosis. Among former football players, reduced CSF Aβ 40 ( p = 0.011) and Aβ 42 (p = 6e-04) were observed in those with cognitive impairment compared to those with neurobehavioral dysregulation. The findings of significant associations of reduced CSF Aβ levels with RHI in elite football players are in line with recent postmortem studies; however, the lack of relationship with CSF tTau and pTau species observed to be altered in the setting of AD suggests that the pathological features of CTE reflected in fluid biomarkers are complex and require further study. The overlapping comorbid age-dependent features of neurodegeneration that occur in those at risk for CTE suggest that tau pathology in CTE is not reliably reflected by currently available fluid biomarkers and that the use of multiple biomarkers related to the compound characteristics of CTE may be required for early detection.

Abstract Purpose To evaluate alcohol intake trends and identify demographic, clinical, lifestyle and socioeconomic factors associated with alcohol consumption in late survivorship among breast cancer survivors. Methods Individuals diagnosed with stage 0–3 breast cancer enrolled in the Mayo Clinic Breast Disease registry between 2014 to 2022 reported their average weekly alcohol intake at baseline (time of diagnosis) and at approximately four years post-diagnosis. Alcohol intake was divided into four categories and cross-sectional associations with demographic, clinical, and lifestyle factors were examined using Monte Carlo-based Fisher exact tests and multivariable multinomial logistic regression. Changes in alcohol consumption from baseline to Year 4 were evaluated using Bowker’s test of symmetry and multinomial models. Results Among 719 participants, alcohol intake 4 years post diagnosis closely resembled baseline patterns, with 30.2% of patients reporting no alcohol use and 48.8% of patients consuming 1–4 drinks per week. Younger age and current smoking status were strongly associated with higher intake at Year 4. Exercise and better physical health were associated with higher alcohol intake in univariable models, however not in adjusted models. From time of diagnosis to Year 4, 15.6% of patients decreased their alcohol intake, 10.2% increased alcohol intake, and 74.3% reported no change. Higher levels of mild intensity exercise were associated with an elevation in alcohol intake over time. Conclusion Alcohol consumption remained stable in late survivorship, in contrast to the initial decline in alcohol use during early survivorship seen in this cohort. Younger age and smoking were key associations with higher alcohol intake.

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.