Metabolic Regulation of the Epigenome Drives Lethal Infantile Ependymoma.

Posterior fossa A (PFA) ependymomas are lethal malignancies of the hindbrain in infants and toddlers. Lacking highly recurrent somatic mutations, PFA ependymomas are proposed to be epigenetically driven tumors for which model systems are lacking. Here we demonstrate that PFA ependymomas are maintained under hypoxia, associated with restricted availability of specific metabolites to diminish histone methylation, and increase histone demethylation and acetylation at histone 3 lysine 27 (H3K27). PFA ependymomas initiate from a cell lineage in the first trimester of human development that resides in restricted oxygen. Unlike other ependymomas, transient exposure of PFA cells to ambient oxygen induces irreversible cellular toxicity. PFA tumors exhibit a low basal level of H3K27me3, and, paradoxically, inhibition of H3K27 methylation specifically disrupts PFA tumor growth. Targeting metabolism and/or the epigenome presents a unique opportunity for rational therapy for infants with PFA ependymoma.

Benchmarking multi-ancestry prostate cancer polygenic risk scores in a real-world cohort.

Prostate cancer is a heritable disease with ancestry-biased incidence and mortality. Polygenic risk scores (PRSs) offer promising advancements in predicting disease risk, including prostate cancer. While their accuracy continues to improve, research aimed at enhancing their effectiveness within African and Asian populations remains key for equitable use. Recent algorithmic developments for PRS derivation have resulted in improved pan-ancestral risk prediction for several diseases. In this study, we benchmark the predictive power of six widely used PRS derivation algorithms, including four of which adjust for ancestry, against prostate cancer cases and controls from the UK Biobank and All of Us cohorts. We find modest improvement in discriminatory ability when compared with a simple method that prioritizes variants, clumping, and published polygenic risk scores. Our findings underscore the importance of improving upon risk prediction algorithms and the sampling of diverse cohorts.

Systematic evidence review and meta-analysis of outcomes associated with cancer genetic counseling.

PURPOSE: Genetic counseling (GC) is standard of care in genetic cancer risk assessment (GCRA). A rigorous assessment of the data reported from published studies is crucial to ensure the evidence-based implementation of GC. METHODS: We conducted a systematic review and meta-analysis of 17 patient-reported and health-services-related outcomes associated with pre- and post-test GC in GCRA in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology. RESULTS: Twenty-five of 5393 screened articles met inclusion criteria. No articles reporting post-test GC outcomes met inclusion criteria. For patient-reported outcomes, pre-test GC significantly decreased worry, increased knowledge, and decreased perceived risk but did not significantly affect patient anxiety, depression, decisional conflict, satisfaction, or intent to pursue genetic testing. For health-services outcomes, pre-test GC increased correct genetic test ordering, reduced inappropriate services, increased spousal support for genetic testing, and expedited care delivery but did not consistently improve cancer prevention behaviors nor lead to accurate risk assessment. The GRADE certainty in the evidence was very low or low. No included studies elucidated GC effect on mortality, cascade testing, cost-effectiveness, care coordination, shared decision making, or patient time burden. CONCLUSION: The true impact of GC on relevant outcomes is not known low quality or absent evidence. Although a meta-analysis found that pre-test GC had beneficial effects on knowledge, worry, and risk perception, the certainty of this evidence was low according to GRADE methodology. Further studies are needed to support the evidence-based application of GC in GCRA.

Identifying factors and causal chains associated with optimal implementation of Lynch syndrome tumor screening: An application of coincidence analysis.

PURPOSE: This study compared Lynch syndrome universal tumor screening (UTS) across multiple health systems (some of which had 2 or more distinct UTS programs) to understand multilevel factors that may affect the successful implementation of complex programs. METHODS: Data from 66 stakeholder interviews were used to conduct multivalue coincidence analysis and identify key factors that consistently make a difference in whether UTS programs were implemented and optimized at the system level. RESULTS: The selected coincidence analysis model revealed combinations of conditions that distinguish 4 optimized UTS programs, 10 nonoptimized programs, and 4 systems with no program. Fully optimized UTS programs had both a maintenance champion and a positive inner setting. Two independent paths were unique to nonoptimized programs: (1) positive attitudes and a mixed inner setting or (2) limited planning and engaging among stakeholders. Negative views about UTS evidence or lack of knowledge about UTS led to a lack of planning and engaging, which subsequently prevented program implementation. CONCLUSION: The model improved our understanding of program implementation in health care systems and informed the creation of a toolkit to guide UTS implementation, optimization, and changes. Our findings and toolkit may serve as a use case to increase the successful implementation of other complex precision health programs.

Direct oral anticoagulants over warfarin at discharge associated with improved survival and patency in infra-geniculate bypasses with prosthetic conduits.

OBJECTIVE: There is no consensus on the optimal anticoagulant regimen following lower extremity bypass. Historically, warfarin has been utilized for prosthetic or compromised vein bypasses. Direct-acting oral anticoagulants (DOACs) are increasingly replacing warfarin in this context, but their efficacy in bypass preservation has not been well-studied. Recent studies have shown that DOACs may improve outcomes following bypasses; however, it is unclear if this is dependent upon type of bypass conduit. The goal of this study was to evaluate whether a difference exists between vein and prosthetic infra-geniculate bypasses outcomes based on the anticoagulant utilized on discharge, warfarin or DOAC. METHODS: The Vascular Quality Initiative infra-inguinal bypass database was queried for all patients who underwent an infra-geniculate bypass and were anticoagulation-naive at baseline but were discharged on either warfarin or DOACs. A survival analysis was performed for patients up to 1 year to determine whether the choice of discharge anticoagulation was associated with differences between those with vein vs prosthetic conduits in overall survival, primary patency, risk of amputation, or risk of major adverse limb events (MALE). A multivariable Cox proportional hazards analysis was performed to control for differences in baseline demographic factors between the groups. RESULTS: During the study period (2003-2020), 57,887 patients underwent infra-geniculate bypass. Of these, 3230 (5.5%) were anticoagulated on discharge. There was a similar distribution of anticoagulation between vein (n = 1659; 51.4%) and prosthetic conduits (n = 1571; 48.6%). Thirty-two percent were discharged on DOACs, and 68.0% were discharged on warfarin. For prosthetic conduits, being discharged on a DOAC was associated with improved outcomes on univariate and multivariable analyses revealing lower risk of overall mortality (hazard ratio [HR], 0.61; 95% confidence interval [CI], 0.41-0.93; P = .021), loss of primary patency (HR, 0.70; 95% CI, 0.55-0.89; P = .003), risk of amputation (HR, 0.71; 95% CI, 0.54-0.93; P = .013), and risk of MALE (HR, 0.80; 95% CI, 0.64-1.00; P = .048). Patients with a vein bypass had improved univariate outcomes for survival and primary patency; however, with multivariable analysis, there were no significant differences in outcomes between DOAC and warfarin. CONCLUSIONS: Anticoagulation-naive patients who underwent an infra-geniculate prosthetic bypass had higher rates of overall survival, bypass patency, amputation-free survival, and freedom from MALE when discharged on a DOAC compared with warfarin. Those with vein bypasses had similar outcomes regardless of the choice of anticoagulation.

Integration and usability of a digital cancer risk stratification tool to optimize identification of patients at risk for hereditary cancers: A pilot study.

BACKGROUND: Patients with a personal or family history of cancer may have elevated risk of developing future cancers, which often remains unrecognized due to lapses in screening. This pilot study assessed the usability and clinical outcomes of a cancer risk stratification tool in a gynecologic oncology clinic. METHODS: New gynecologic oncology patients were prompted to complete a commercially developed personal and family history-based risk stratification tool to assess eligibility for genetic testing using National Comprehensive Cancer Network criteria and estimated lifetime breast cancer risk using the Tyrer-Cuzick model. After use of the risk stratification tool, usability was assessed via completion rate and the System Usability Scale, and health literacy was assessed using the BRIEF Health Literacy Screening Tool. RESULTS: 130 patients were prompted to complete the risk stratification tool; 93 (72%) completed the tool. Race and ethnicity and insurance type were not associated with tool completion. The median System Usability Scale score was 83 out of 100 (interquartile range, 60-95). Health literacy positively correlated with perceived usability. Public insurance and race or ethnicity other than non-Hispanic White was associated with lower perceived usability. Sixty (65%) patients met eligibility criteria for genetic testing, and 21 (38% of 56 eligible patients) were candidates for enhanced breast cancer screening based on an estimated lifetime breast cancer risk of ≥20%. CONCLUSIONS: A majority of patients completed the digital cancer risk stratification tool. Older age, lower health literacy, public insurance, and race or ethnicity other than non-Hispanic White were associated with lower perceived tool usability.

Timely targeted testing for hereditary cancer syndromes - Importance of clinician-facilitated cascade testing in the first year post-diagnosis.

OBJECTIVE: Cascade testing for hereditary cancer syndromes allows relatives to estimate cancer risk and pursue prevention and early detection strategies. The current paradigm relies on patient coordinated care, resulting in only one-third of relatives successfully completing testing. Studies suggest that team-based approaches, where clinicians facilitate testing, can increase uptake. As institutions consider implementing such programs, understanding patient characteristics associated with interest is crucial for resource allocation. We aim to assess interest in clinician-facilitated testing and evaluate barriers. METHODS: Patients with cancer-associated pathogenic variants seen at a gynecologic oncology clinic were offered clinician-facilitated cascade testing. Patient interest and demographic variables were recorded and patients that declined were interviewed regarding the decision. RESULTS: From 11/2023-4/2024, 139 patients were offered clinician-facilitated cascade testing. Median patient age was 43 years (IQR 17), 97 (69.8 %) self-identified as White and 101 (72.7 %) as non-Hispanic. Fifty-six (40.3 %) patients harbored a BRCA1 pathogenic variant, 37 (26.6 %) BRCA2, and 46 (33.1 %) other cancer-associated genes. Fifty-seven (41.0 %) patients expressed interest in the intervention. Interested patients were more likely to have been diagnosed in the prior year vs. patients who were not interested on univariate (OR 4.6, 95 % CI 2.0-10.2, P = 0.0002) and multivariable analyses (adjusted OR 3.8, 95 % CI 1.622-9.009, P = 0.0022). CONCLUSIONS: Our study demonstrates that patients are almost five time more likely to be interested in cascade genetic testing within the first year of diagnosis of a pathogenic variant. Given the utility of such programs and their resource requirements, targeting this population could maximize effectiveness and uptake of cascade services.

Personalized survivorship care: Routine breast cancer risk assessment in the gynecologic oncology clinic.

INTRODUCTION: Gynecologic and breast cancers share several risk factors. Breast cancer risk assessment tools can identify those at elevated risk and allow for enhanced breast surveillance and chemoprevention, however such tools are underutilized. We aim to evaluate the use of routine breast cancer risk assessment in a gynecologic oncology clinic. METHODS: A patient-facing web-based tool was used to collect personal and family history and run four validated breast cancer risk assessment models (Tyrer-Cuzick (TC), Gail, BRCAPRO, and Claus) in a gynecologic oncology clinic. We evaluated completion of the tools and identification of patients at elevated risk for breast cancer using the four validated models. RESULTS: A total of 99 patients were included in this analysis. The BRCAPRO model had the highest completion rate (84.8%), followed by the TC model (74.7%), Gail model (74.7%), and the Claus model (52.1%). The TC model identified 21.6% of patients completing the model as having ≥20% lifetime risk of breast cancer, compared to 6.8% by the Gail model, and 0% for both the BRCAPRO and Claus models. The Gail model identified 52.5% of patients as having ≥1.67% 5-year risk of breast cancer. Among patients identified as high-risk for breast cancer and eligible for screening, 9/9 (100%) were referred to a high-risk breast clinic. CONCLUSION: Among patients that completed the TC breast cancer risk assessment in a gynecologic oncology clinic, approximately 1 in 5 were identified to be at significantly elevated lifetime risk for breast cancer. The gynecologic oncologist's office might offer a convenient and feasible setting to incorporate this risk assessment into routine patient care, as gynecologic oncologists often have long-term patient relationships and participate in survivorship care.

Cost-effectiveness of BRCA1 testing at time of obstetrical prenatal carrier screening for cancer prevention.

BACKGROUND: Improved technologies paired with an increase in access to genetic testing have led to the availability of expanded carrier screening evaluating hundreds of disorders. Currently, most autosomal dominant mutations, such as BRCA1, are not included in expanded carrier assays. Screening pregnant or preconception reproductive-aged women for BRCA1 may present a unique opportunity to perform population-based screening for patients at a time when precancer screening, chemoprevention, and/or risk-reducing surgery may be beneficial. OBJECTIVE: This study aimed to inform clinical decision-making as to whether the universal incorporation of BRCA1 testing at the time of obstetrical prenatal carrier screening is cost-effective. STUDY DESIGN: A decision analysis and Markov model was created. The initial decision point in the model was BRCA1 testing at the time of expanded carrier screening. Model probabilities, cost, and utility values were derived from published literature. For BRCA1-positive patients, the model simulated breast cancer screening and risk-reducing surgical interventions. A cycle length of 1 year and a time horizon of 47 years were used to simulate the lifespan of patients. The setting was obstetrical clinics in the United States, and the participants were a theoretical cohort of 1,429,074 pregnant patients who annually underwent expanded carrier screening. RESULTS: Among our cohort, BRCA1 testing resulted in the identification of an additional 3716 BRCA1-positive patients, the prevention of 1394 breast and ovarian cancer cases, and 1084 fewer deaths. BRCA1 testing was a cost-effective strategy compared with no BRCA1 testing with an incremental cost-effectiveness ratio of $86,001 per quality-adjusted life years. In a 1-way sensitivity analysis, we varied the prevalence of BRCA1 in the population from 0.00% to 20.00% and found that BRCA1 testing continued to be the cost-effective strategy until the prevalence rate was reduced to 0.16%. Multiple additional sensitivity analyses did not substantially affect the cost-effectiveness. CONCLUSION: The addition of BRCA1 testing to obstetrical prenatal carrier screening is a cost-effective management strategy to identify at-risk women at a time when cancer screening and preventive strategies can be effective. Despite the burden of additional genetic counseling, prenatal care represents a unique opportunity to implement population-based genetic testing.

Use of direct-acting oral anticoagulants associated with improved survival and bypass graft patency compared with warfarin after infrageniculate bypass.

OBJECTIVE: No consensus has yet been reached regarding the optimal antiplatelet and anticoagulant regimen for patients after lower extremity bypass. Usually, patients who have undergone below-the-knee bypass will begin oral anticoagulation therapy. Historically, the bypass has been with prosthetic conduits and the anticoagulation therapy has been warfarin. However, the use of direct-acting oral anticoagulants (DOACs) has been increasing owing to their relative ease of dosing. The goal of the present study was to evaluate whether a difference exists in the postoperative outcomes for patients who have undergone infrageniculate bypass stratified by the use of on DOACs vs warfarin. METHODS: The Vascular Quality Initiative infrainguinal bypass database was queried for all patients who had undergone infrageniculate bypass, been anticoagulation naive at baseline, and been discharged with anticoagulation therapy. A survival analysis was performed for patients for ≤2 years postoperatively to determine whether discharge with warfarin vs DOACs was associated with differences in overall mortality, loss of primary patency, risk of amputation, and risk of major adverse limb events (MALE). A multivariable Cox proportional hazards analysis was performed to control for differences in the baseline demographic factors between the two groups. RESULTS: During the study period (2007-2020) 57,887 patients had undergone infrageniculate bypass. Of these patients, 2786 had been anticoagulation naive and discharged with either warfarin (n = 1889) or DOACs (n = 897). Discharge with a DOAC was associated with a lower risk of overall mortality (hazard ratio [HR], 0.62; 95% confidence interval [CI], 0.47-0.83; P = .001), loss of primary patency (HR, 0.74; 95% CI, 0.62-0.87; P < .001), risk of amputation (HR, 0.70; 95% CI, 0.57-0.86; P = .001), and risk of MALE (HR, 0.83; 95% CI, 0.71-0.97; P = .017). CONCLUSIONS: Anticoagulation-naive patients who had undergone infrageniculate bypass had had higher rates of overall survival, bypass patency, amputation-free survival, and freedom from MALE when discharged with a DOAC than with warfarin.

Partner and localizer of BRCA2 (PALB2) pathogenic variants and ovarian cancer: A systematic review and meta-analysis.

OBJECTIVE: Approximately 20% of ovarian cancers are due to an underlying germline pathogenic variant. While pathogenic variants in several genes have been well-established in the development of hereditary ovarian cancer (e.g. BRCA1/2, RAD51C, RAD51D, BRIP1, mismatch repair genes), the role of partner and localizer of BRCA2 (PALB2) remains uncertain. We sought to utilize meta-analysis to evaluate the association between PALB2 germline pathogenic variants and ovarian cancer. METHODS: We conducted a systematic review and meta-analysis. We searched key electronic databases to identify studies evaluating multigene panel testing in people with ovarian cancer. Eligible trials were subjected to meta-analysis. RESULTS: Fifty-five studies met inclusion criteria, including 48,194 people with ovarian cancer and information available on germline PALB2 pathogenic variant status. Among people with ovarian cancer and available PALB2 sequencing data, 0.4% [95% CI 0.3-0.4] harbored a germline pathogenic variant in the PALB2 gene. The pooled odds ratio (OR) for carrying a PALB2 pathogenic variant among the ovarian cancer population of 20,474 individuals who underwent germline testing was 2.48 [95% CI 1.57-3.90] relative to 123,883 controls. CONCLUSIONS: Our meta-analysis demonstrates that the pooled OR for harboring a PALB2 germline pathogenic variant among people with ovarian cancer compared to the general population is 2.48 [95% CI 1.57-3.90]. Prospective studies evaluating the role of germline PALB2 pathogenic variants in the development of ovarian cancer are warranted.

Web-based tool for cancer family history collection: A prospective randomized controlled trial.

OBJECTIVES: Approximately 1% of individuals have a hereditary cancer predisposition syndrome, however, the majority are not aware. Collecting a cancer family history (CFH) can triage patients to receive genetic testing. To rigorously assess different methods of CFH collection, we compared a web-based tool (WBT) to usual care (clinician collects CFH) in a randomized controlled trial. METHODS: New gynecologic oncology patients (seen 9/2019-9/2021) were randomized to one of three arms in a 2:2:1 allocation ratio: 1) usual care clinician CFH collection, 2) WBT completed at home, or 3) WBT completed in office. The WBT generated a cancer-focused pedigree and scores on eight validated cancer risk models. The primary outcome was collection of an adequate CFH (based on established guidelines) with usual care versus the WBT. RESULTS: We enrolled 250 participants (usual care - 110; WBT home - 105; WBT office - 35 [closed early due to COVID-19]). Within WBT arms, 109 (78%) participants completed the tool, with higher completion for office versus home (33 [94%] vs. 76 [72%], P = 0.008). Among participants completing the WBT, 63 (58%) had an adequate CFH versus 5 (5%) for usual care (P < 0.001). Participants completing the WBT were significantly more likely to complete genetic counseling (34 [31%] vs. 15 [14%], P = 0.002) and genetic testing (20 [18%] vs. 9 [8%], P = 0.029). Participant and provider WBT experience was favorable. CONCLUSIONS: WBTs for CFH collection are a promising application of health information technology, resulting in more comprehensive CFH and a significantly greater percentage of participants completing genetic counseling and testing.

Percutaneous Transhepatic Cholangioscopy Interventions-Updates.

Percutaneous transhepatic cholangioscopy (PTCS) was initially described around the same time that peroral cholangioscopy (POSC) was developed. The cited utility attributed to PTCS is the ability to be utilized in the subset of patients with surgical proximal bowel anatomy, often precluding the use of traditional POSC. However, since first described, PTCS use has been limited due to a lack of physician awareness and a lack of procedure-specific equipment and supplies. With recent developments of PTSC-specific equipment, there has been an expansion in the possible interventions able to be performed during PTCS, resulting in a rapid increase in clinical use. This short review will serve as a comprehensive update of the previous and more recent novel interventions now able to be performed during PTCS.

"Go ahead and screen" - advice to healthcare systems for routine lynch syndrome screening from interviews with newly diagnosed colorectal cancer patients.

BACKGROUND: Lynch syndrome (LS) is the most common cause of inherited colorectal cancer (CRC). Universal tumor screening (UTS) of newly diagnosed CRC cases is recommended to aid in diagnosis of LS and reduce cancer-related morbidity and mortality. However, not all health systems have adopted UTS processes and implementation may be inconsistent due to system and patient-level complexities. METHODS: To identify barriers, facilitators, and suggestions for improvements of the UTS process from the patient perspective, we conducted in-depth, semi-structured interviews with patients recently diagnosed with CRC, but not screened for or aware of LS. Patients were recruited from eight regionally diverse US health systems. Interviews were conducted by telephone, 60-minutes, audio-recorded, and transcribed. An inductive, constant comparative analysis approach was employed.  RESULTS: We completed 75 interviews across the eight systems. Most participants were white (79%), about half (52%) were men, and the mean age was 60 years. Most self-reported either no (60%) or minimal (40%) prior awareness of LS. Overall, 96% of patients stated UTS should be a routine standard of care for CRC tumors, consistently citing four primary motivations for wanting to know their LS status and engage in the process for LS identification: "knowledge is power"; "family knowledge"; "prevention and detection"; and "treatment and surveillance." Common concerns pertaining to the process of screening for and identifying LS included: creating anticipatory worry for patients, the potential cost and the accuracy of the genetic test, and possibly having one's health insurance coverage impacted by the LS diagnosis. Patients suggested health systems communicate LS results in-person or by phone from a trained expert in LS; offer proactive verbal and written education about LS, the screening steps, and any follow-up surveillance recommendations; and support patients in communicating their LS screening to any of their blood relatives. CONCLUSION: Our qualitative findings demonstrate patients with CRC have a strong desire for healthcare systems to regularly implement and offer UTS. Patients offer key insights for health systems to guide future implementation and optimization of UTS and other LS screening programs and maximize diagnosis of individuals with LS and improve cancer-related surveillance and outcomes. TRIAL REGISTRATION: Not available: not a clinical trial.

Orange-red luminescence of samarium-doped bismuth-germanium-borate glass for light-emitting devices.

Samarium (Sm3+ )-doped glass has sparked a rising interest in demonstrating a noticeable emission in the range of 400-700, which is advantageous in solid-state lasers in the visible region, colour displays, undersea communication, and optical memory devices. This study reports the fabrication of Sm3+ -doped bismuth-germanium-borate glasses were established using a standard melt-quenching technique and inspection by absorption, steady-state luminescence, and transient studies. The typical peaks of Sm3+ ions were detected in the visible range under 403 nm excitation. A strong emission band was detected at 599 nm that resembles the 4 G5/2 →6 H7/2 transition of Sm3+ ions for BGBiNYSm0.5 glass. Furthermore, a reddish-orange (coral) luminescence at 646 nm that resembles the 4 G5/2 →6 H9/2 transition was also perceived. The stimulated emission cross-section of 4 G5/2 level for BGBiNYSm0.5 glass was 0.39 × 10-22  cm2 . Lifetime of the 4 G5/2 level was enhanced for the BGBiNYSm0.5 glass and decreased with an increase in active ion concentrations. The lifetime quenching of ions at the metastable state was because of energy transfer among Sm3+ ions by cross-relaxation channels. Commission Internationale de l'Éclairage (CIE) coordinates were evaluated from the emission spectra. Moreover, all the findings recommend these glass as light-emitting materials in the coral region at 599 nm for solid-state lighting applications.

De Novo Design and Development of a Nutrient-Rich Perfusate for Ex Vivo Lung Perfusion with Cell Culture Models.

Ex vivo lung perfusion (EVLP) has increased donor lung utilization through assessment of "marginal" lungs prior to transplantation. To develop it as a donor lung reconditioning platform, prolonged EVLP is necessary, and new perfusates are required to provide sufficient nutritional support. Human pulmonary microvascular endothelial cells and epithelial cells were used to test different formulas for basic cellular function. A selected formula was further tested on an EVLP cell culture model, and cell confluence, apoptosis, and GSH and HSP70 levels were measured. When a cell culture medium (DMEM) was mixed with a current EVLP perfusate-Steen solution, DMEM enhanced cell confluence and migration and reduced apoptosis in a dose-dependent manner. A new EVLP perfusate was designed and tested based on DMEM. The final formula contains 5 g/L Dextran-40 and 7% albumin and is named as D05D7A solution. It inhibited cold static storage and warm reperfusion-induced cell apoptosis, improved cell confluence, and enhanced GSH and HSP70 levels in human lung cells compared to Steen solution. DMEM-based nutrient-rich EVLP perfusate could be a promising formula to prolong EVLP and support donor lung repair, reconditioning and further improve donor lung quality and quantity for transplantation with better clinical outcome.

[AUDITORY OUTCOMES OF COCHLEAR IMPLANTATION IN MENIERE'S DISEASE].

BACKGROUND: Cochlear implants are valuable in the auditory rehabilitation of patients with severe to profound hearing loss. However, there is limited data on the outcomes of cochlear implantation in patients with Meniere's disease (MD). OBJECTIVES: In this study, we aim to evaluate the auditory outcomes of cochlear implantation in patients with MD. METHODS: A retrospective case series of patients with MD and severe to profound sensorineural hearing loss (SNHL), who underwent cochlear implantation at a tertiary academic center between 2006-2017. Patient's clinical characteristics and audiometric data were reviewed. RESULTS: The study included 20 ears in 19 patients with MD who underwent cochlear implantation with available pre- and postoperative audiometric data. There were 10 males and 9 females with a mean age of 63 years and a mean follow-up duration of 70.8 months. Pre- and post-implant CNC word recognition scores were 18.31% and 66.89%, respectively (p<0.001). Pre- and post-implant AzBio and/or HINT sentence recognition scores were 12.25% and 68.28% in quiet, respectively (p<0.001), and 18.25% and 63.43% in noise, respectively (p<0.001). CONCLUSIONS: Cochlear implantation resulted in an improvement of word and sentence recognition scores in MD patients. These results support the role of cochlear implants in the auditory rehabilitation of MD. DISCUSSION: Dr. Samy received research support from Cochlear Corporation.

What happens in the long term: Uptake of cancer surveillance and prevention strategies among at-risk relatives with pathogenic variants detected via cascade testing.

BACKGROUND: Cascade genetic testing for hereditary cancer syndromes offers affected relatives the opportunity to pursue cancer screening and risk-reducing surgery and thus reduces morbidity and mortality. The purpose of this study was to measure the long-term utilization of targeted cancer prevention and quality of life among at-risk relatives offered clinician-facilitated cascade genetic testing. METHODS: In a pilot study, at-risk relatives of patients with a hereditary cancer syndrome were contacted directly by the clinical team and offered telephone genetic counseling and genetic testing via an at-home, mailed saliva kit. Two-year follow-up results evaluating the use of targeted cancer prevention strategies and the quality of life for enrolled relatives were reported. Quality-of-life was measured with validated surveys, and scores were compared to the time of initial contact by the Wilcoxon signed-rank test. RESULTS: Ninety-five at-risk relatives were enrolled in the initial pilot study, and 72 (76%) participated in the 2-year follow-up; 57 of these (79%) had completed genetic testing. Twenty-five of those 57 relatives (44%) were found to harbor an inherited pathogenic variant. Guideline-based cancer surveillance was recommended to 18 relatives; 13 (72%) completed at least one recommended screening, and six (33%) completed all recommended screenings. Risk-reducing surgery was recommended to 10 relatives; four (40%) completed a total of eight procedures. Quality-of-life surveys demonstrated low levels of anxiety, depression, distress, and uncertainty. CONCLUSIONS: The 2-year follow-up of the original pilot study revealed that clinician-facilitated cascade testing resulted in genetically targeted cancer screening and prevention with preserved quality of life. These results, to be confirmed by larger randomized controlled trials, suggest that medical systems should consider supporting clinician-facilitated cascade testing programs.

Tellurophene-Tagging of Teniposide Facilitates Monitoring by Mass Cytometry.

Target engagement and the biodistribution of exogenously administered small molecules is rarely homogenous. Methods to determine the biodistribution at the cellular level are limited by the ability to detect the small molecule and simultaneously identify the cell types or tissue structures with which it is associated. The highly multiplexed nature of mass cytometry could facilitate these studies provided a heavy isotope label was available in the molecule of interest. Here we show it is possible to append a tellurophene to a known chemotherapeutic, teniposide, to follow this molecule in vivo. A semi-synthetic approach offers an efficient route to the teniposide analogue which is found to have similar characteristics when compared with the parent teniposide in vitro. Using mass cytometry we find the teniposide analogue has significant nonspecific binding to cells. In vivo the tellurium bearing teniposide produces the expected DNA damage in a PANC-1 xenograft model. The distribution of Te in the tissue is near the limits of detection and further work will be required to characterize the localization of this analogue with respect to cell type distributions.

Outcomes of great vessel debranching to facilitate thoracic endovascular aortic repair.

OBJECTIVE: With the expanding application of endovascular technology, the need to deploy into zone 0 has been encountered on occasion. In the present study, we evaluated the outcomes of great vessel debranching (GVD) as a method of extending the proximal landing zone to facilitate thoracic endovascular aortic repair (TEVAR). METHODS: We performed a single-center retrospective review of all patients who had undergone GVD followed by TEVAR between May 2013 and December 2020. The primary outcome was primary patency of all targeted vessels, with all-cause perioperative mortality as a secondary outcome. Kaplan-Meier analysis was used to account for censoring of mortality and primary patency. The extent of hybrid aortic repairs was characterized into type I (GVD plus TEVAR without ascending aorta or aortic arch reconstruction, type II (GVD plus TEVAR with ascending aorta reconstruction), and type III (GVD plus TEVAR with ascending aorta and aortic arch reconstruction with an elephant trunk (soft [surgical] or frozen [endovascular]]). RESULTS: A total of 42 patients (23 men [54.8%]; mean age, 62.2 ± 11.2 years) had undergone GVD, with 122 vessels revascularized (42 innominate, 42 left common carotid, and 38 left subclavian arteries). The indication for TEVAR was aneurysmal degeneration from aortic dissection in 32 patients (76.2%), a thoracic aneurysm in 9 patients (21.4%), and a perforated aortic ulcer in 1 patient (2.4%). The median duration between GVD and TEVAR was 82 days. The mean follow-up period was 25.7 ± 23.5 months. Type I repair was performed in 4, type II in 16, and type III in 22 patients. The perioperative mortality, stroke, and paraplegia rates were 9.5%, 7.1%, and 2.4%, respectively. Neither the extent of repair (P = .80) nor a history of aortic repair (P = .90) was associated with early mortality. Of the 38 patients who had survived the perioperative period, 6 had died >30 days postoperatively. At 36 months, the survival estimate was 68.6% (95% confidence interval, 45.7%-83.4%). The overall primary patency of the innominate artery, left common carotid artery, and left subclavian artery was 100%, 89.5%, and 94.1%, respectively. The primary-assisted patency rate was 100% for all the vessels. CONCLUSIONS: We found GVD to be a safe and effective method of extending the proximal landing zone into zone 0 with outstanding primary patency rates. Further studies are required to confirm the safety and longer term durability for these patients.