Citations

Abstract The combination of enfortumab vedotin and pembrolizumab (EVP) has recently revolutionized care for patients with previously untreated locally advanced and metastatic urothelial carcinoma. However, predictive biomarkers of response, the optimal duration of EVP for patients who respond well to therapy, and the role of circulating tumor DNA to monitor treatment response have not yet been fully elucidated. In this molecular tumor board, we summarize 6 patients from 4 different academic institutions with unresectable or oligometastatic urothelial carcinoma who achieved long-term remission on surveillance after a short duration of EVP treatment that resulted in complete response on follow-up imaging followed by consolidative radical cystectomy. We discuss potential predictive biomarkers for patients with exceptional response to EVP. These findings highlight the need to determine an optimal duration of EVP to maximize efficacy while minimizing adverse events. We aim to further define and explore the value of local therapy with consolidative cystectomy in the setting of unresectable, locally advanced, oligometastatic disease, or those with metastatic disease who achieve complete response of disease outside of the bladder. Identifying this subset of patients who may be candidates for this type of multidisciplinary management may result in durable treatment-free remission.

BACKGROUND: Patients with functioning pituitary adenomas (FPA) require a multidisciplinary team-based approach to select best medical, surgical, and radiation treatments, including stereotactic radiosurgery (SRS). OBJECTIVE: The aim of this study was to provide evidence-based recommendations on the use of SRS for adult patients with FPA. METHODS: PubMed and Embase were searched from data base inception to June 8, 2021. Full-text articles were then screened using published exclusion/inclusion criteria. Evidence tables were developing based on data extraction from the full-text reviews, and evidence-based recommendations were finalized. RESULTS: Of the total 1842 abstracts pertinent to this topic, 343 full articles met eligibility. Of these, 21 met entry criteria and were included in the evidence tables. The provided Class III evidence supported 2 Level III recommendations: 1. SRS, hypofractionated SRS, fractionated (>5 fractions) radiotherapy, and conventional radiation therapy provide excellent radiographic control with variable hormonal reduction and endocrine remission rates. For SRS and fractionated radiotherapy hormonal reduction may continue for up to 10 years after treatment. 2. Clinicians may continue to administer endocrine suppressive medical treatment before SRS as this may not affect radiographic control. CONCLUSION: This systematic review provides evidence-based recommendations to guide providers caring for adult patients with FPA when making decisions pertinent to radiosurgery. The CNS Guidelines Committee will continue to pursue timely updates to further improve the care of patients with this diagnosis.

Abstract Background and Aims Type 1 short QT syndrome (SQT1) is a genetic channelopathy caused by gain-of-function variants in KCNH2, resulting in shortened cardiac repolarization and QT intervals, which predispose patients to ventricular arrhythmias and sudden cardiac death. This study aimed to investigate the therapeutic efficacy of KCNH2-specific suppression-and-replacement (KCNH2-SupRep) gene therapy in a transgenic rabbit model of SQT1. Methods KCNH2-SupRep was developed by combining a KCNH2-shRNA with its corresponding shRNA-immune KCNH2-cDNA into an AAV9 vector, delivered directly into the aortic root (1 × 1010 vg/kg). Therapeutic efficacy was evaluated in vivo by electrocardiogram, ex vivo by optical mapping, and at cellular levels by patch-clamp, calcium imaging, and qPCR in ventricular cardiomyocytes (VCMs). Results In vivo, KCNH2-SupRep normalized the heart rate-corrected QT interval (QTc) in SQT1 rabbits, without affecting repolarization heterogeneity. Ex vivo, KCNH2-SupRep corrected the action potential duration (APD90) and resolved the increased apicobasal APD90 heterogeneity observed in untreated (UT)-SQT1 hearts, supporting an antiarrhythmic effect, which was further validated by reduced re-entry formation in silico. At cellular levels, KCNH2-SupRep prolonged APD90 in VCMs from SupRep-SQT1 rabbits closer to wildtype levels compared with UT- and sham-SQT1. Additionally, KCNH2-SupRep restored the cellular surrogate of the electro-mechanical window and normalized IKr in nearly 50% of VCMs, in line with a 50%–60% suppression of the mutant KCNH2 transcript. Conclusions This proof-of-concept study is the first to demonstrate the efficacy of gene therapy for SQT1 in a medium-sized animal model. KCNH2-SupRep gene therapy successfully corrected the pathologic phenotype in vivo, ex vivo, and at cellular levels in transgenic SQT1 rabbits.

BACKGROUND AND OBJECTIVES: Single-session stereotactic radiosurgery (SRS) has limited role for large arteriovenous malformations (AVM). Volume-staged SRS (VS-SRS) is used to optimize outcomes, but studies reporting results are limited. METHODS: This multicenter retrospective cohort of 378 patients from 21 centers reports results of VS-SRS for the entire AVM nidus. We report favorable outcome, obliteration, hemorrhage, and permanent symptomatic adverse radiation effect rates. RESULTS: The median age was 31 years (IQR: 19-44) at the first volume stage, with patients treated in 2–4 stages. The median total nidus volume was 21 cm 3 (IQR: 13.9-30.1 cm 3 ), and a median prescription dose of 17 Gy (IQR: 16-18 Gy) was used. The median radiographic and clinical follow-up were 48 and 55 months, respectively. Seventy-seven patients (20.4%) had a favorable outcome, with the 3-year and 5-year rates being 3.9% and 18%, respectively. 127 patients (33.6%) achieved obliteration, with the 3-year and 5-year rates being 6.8% and 26%, respectively. Obliteration rates of AVMs <15 cm 3 were 81% and 31%, respectively. The latency period hemorrhage incidence rate was 3.02 cases per 100 patient-years; 52 patients (13.8%) had a bleed. Seventy-two patients (19%) had symptomatic adverse radiation effect; in 38 patients (10.1%), these were permanent. Total nidus volume, prescription dose at first stage, diffuse nidus, and prior hemorrhage were all independent affecting outcome rates. CONCLUSION: VS-SRS can be used to treat large AVMs as a standalone treatment. Obliteration rates and favorable outcomes are lower than that with smaller AVMs, and repeat treatment is often required. Optimizing treatment plans, by increasing prescription doses, reducing treatment volume at each stage, and increasing the number of stages, may lead to better outcomes.

ABSTRACT Rationale Longer duration of epilepsy before surgery is a predictor of poor outcome. While referral delays of surgical candidates are well documented, factors causing delay during the presurgical evaluation remain unclear and may vary depending on institutional characteristics. By benchmarking the duration of presurgical evaluation across multiple centers and identifying patient and evaluation characteristics contributing to duration, we can ascertain best practices and address modifiable contributors to reduce delays. Methods We queried the Pediatric Epilepsy Research Consortium Surgery Database, a prospective, observational multicenter study enrolling children 0–18 years at 27 US pediatric epilepsy centers, for all patients undergoing initial presurgical evaluation for drug‐resistant epilepsy (DRE). We included patients with completed evaluations and data on duration from initiation of presurgical evaluation to final surgical decision. We compared patient characteristics and evaluation components between those with long duration evaluations (> 75% quartile) and those with short evaluations (< 25% quartile). Akaike information criteria selection identified variables associated with longer duration. From these, we developed a logistic prediction model for evaluation duration, using a random 80/20 training/testing split of the entire cohort. The model was tested among institutions with ≥ 10 patients in the cohort to assess its accuracy in predicting long durations. Linear models for each site assessed each variable's impact on duration. Variables with < 10% of the patient population at each site were excluded. Beta values were compared to identify intra‐ and inter‐institution variability and to delineate institutions with the shortest added duration for each variable. Results Of 2318 patients undergoing surgical evaluation, 1655 (71%) from 23 sites had complete data. Median evaluation duration was 8 weeks (interquartile range 3–22); 453 (27%) were short‐duration evaluations and 414 (25%) were long‐duration evaluations. Multiple patient and evaluation characteristics were associated with duration (Table 1). Table 6 provides the average duration each variable contributes to evaluation by site, highlighting the shortest durations compared with other groups. Conclusions Duration of presurgical evaluation for DRE can be accurately modeled using multiple patient characteristics and testing strategies commonly employed in epilepsy surgery evaluations. This predictive model can not only estimate evaluation duration but also identify opportunities to improve systemic efficiency. Institution‐level modeling identifies specific program strengths, providing an opportunity to learn from successful processes. Subsequent research will focus on institutional process mapping to better understand systemic practices that lead to improved efficiencies, then sharing these processes across the consortium to shorten evaluation durations.

Objective Literature is limited regarding the relationship between cochlear magnetic resonance imaging fluid-attenuated inversion recovery (FLAIR) signal and hearing preservation after resection of vestibular schwannoma (VS). We hypothesize that increased preoperative FLAIR signal is associated with decreased odds of hearing preservation. Study Design Retrospective cohort study. Setting Single academic tertiary/quaternary care center. Patients Subjects with histologically confirmed intracanalicular VS (without extension into the cerebellopontine angle). Intervention Microsurgical resection via middle fossa approach. Main Outcome Measures A review of demographic, clinical, radiographic, and audiometric outcomes were performed. Hearing preservation was defined as American Academy of Otolaryngology–Head and Neck Surgery (AAO-HNS) class A or B hearing. Binary logistic regression analysis was performed with SPSS version 29. Results Twenty-seven subjects met inclusion criteria with median age at time of surgery of 47 (interquartile range [IQR]: 38–54) years; 92.60% were White; 66.67% had AAO-HNS class A, and 33.33% had class B hearing. Postoperatively, at median (IQR) of 11.50 (2.10–38.50) months, 44.40% had class A or B hearing. On logistic regression analysis, a ratio of cochlea-to-brainstem FLAIR signal greater than 0.6 was associated with decreased odds of hearing preservation at 11.50 months—odds ratio, 0.13; 95% confidence interval, 0.02–0.84. Age, sex, surgery duration, tumor volume and linear dimension, fundal cap of cerebrospinal fluid, and extent of resection were not associated with hearing preservation. Conclusion Increased cochlear FLAIR signal on preoperative imaging is associated with decreased likelihood of hearing preservation after resection of intracanalicular, sporadic VS via middle fossa approach.

Increases in aortic wave reflection and aortic pulsatile load are known contributors to hypertension, cardiovascular risk, and pulsatile stress to end organs. To our knowledge, this is the first study to demonstrate that evening binge alcohol consumption increases heart rate, aortic pulsatile load, and aortic augmentation index the following morning when compared with fluid control. These findings highlight the deleterious overnight cardiovascular effects of binge alcohol consumption in young adults.

ABSTRACT Background Preparation of the right ventricular outflow tract (RVOT) using covered stent placement is a common preparatory step for transcatheter pulmonary valve replacement (TPVR) to reduce the risk of disruption associated with dilating calcified RVOT conduits. Aim We present a novel method employing a self‐expanding covered aortic endoprosthesis and discuss its advantages as an alternative strategy. Methods Patients with congenital heart disease undergoing RVOT conduit preparation with the GORE TAG Thoracic Branch Endoprosthesis Extender (W.L. Gore & Associates, Newark, DE) followed by TPVR, were prospectively enrolled in a dedicated database. To date, 14 patients have been included. Data on demographics, diagnoses, procedural details, hemodynamic parameters, and outcomes were analyzed. Results Fourteen patients (median age: 35 years [range: 18–79]; 57% female) successfully underwent endograft placement immediately before TPVR. Treated conduits included pulmonary homografts ( n = 8), surgical bioprostheses ( n = 2), Hancock conduit ( n = 1), Contegra conduit ( n = 1), native RVOT ( n = 1), and Melody valve within a surgical bioprosthesis ( n = 1). Most patients presented with mixed stenosis and regurgitation ( n = 9), with the remaining having stenosis ( n = 4) or regurgitation ( n = 1). Valves implanted post‐preparation included the Sapien S3 valve (Edwards Lifesciences, Irvine, CA) ( n = 10) and the Melody valve (Medtronic, Minneapolis, MN) ( n = 5). Significant reductions in RVOT systolic gradient were observed (median 34 mmHg pre‐procedure to 3 mmHg post‐procedure), along with marked conduit expansion (median diameter 13 mm pre‐procedure to 25.5 mm post‐procedure). No complications were reported. Conclusions This study highlights the feasibility of a self‐expanding aortic endoprosthesis for RVOT preparation before TPVR. Further comparative study is warranted. Procedural success was achieved in all cases.

Objective: To determine the impact of modifiable surgical factors on ossiculoplasty outcomes after controlling for ear environment risk. Study Design: Multi-institutional retrospective review. Setting: Six tertiary care centers from 2011 to 2019. Patients Adults and children. Interventions: Ossiculoplasty, including synthetic ossicular replacement prosthesis, autograft interposition, bone cement repair, and mobilization. Main Outcome Measure: Correlation between modifiable surgical factors and pure-tone average air-bone gap (ABG) at most recent audiogram after controlling for preoperative risk using the statistically validated Ear Environment Risk (EER) score. Results: A total of 1,679 cases were included with a median follow-up time of 20 months (IQR, 5–51). After controlling for EER score, malleus engagement of prosthesis yielded favorable ABG versus direct contact to tympanic membrane without malleus engagement (beta = −2.4 dB [−3.8, −1.1], p < 0.001). For total ossicular replacement prostheses (TORP), use of a footplate prosthesis yielded favorable ABG as compared with no footplate prosthesis (−3.6 dB [−6.1, −1.1], p = 0.005). For synthetic prostheses, polyethylene prostheses had a less favorable ABG compared with full titanium or titanium with hydroxyapatite prostheses ( p < 0.05). In cases where the malleus was not engaged in reconstruction, amputation of the malleus head yielded worse ABG (+3.9 dB [1.2, 6.7], p = 0.005). There was no significant difference ( p > 0.05) in ABG for single-stage versus multistaged approach, use of a cartilage cap over the prosthesis versus no cartilage, use of bone cement to secure a PORP to the stapes versus no cement, mastoid cavity obliteration versus no obliteration, and incudostapedial joint reconstruction with joint prosthesis/bone cement versus synthetic PORP. Conclusions: With statistical correction for ear environment risk, several modifiable surgical factors are noted to impact ossiculoplasty hearing outcomes. Level of Evidence: 4.