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ImportanceAcute promyelocytic leukemia (APL) is an acute illness that presents with cytopenia, infections, and disseminated intravascular coagulation. Achieving remission has been shown to make a major difference in patient outcomes; however, early death rates in the first month have been as high as 30% due to acute presentation, comorbidities, the rarity of APL, and clinician inexperience.ObjectiveTo develop treatment strategies that would decrease estimated 1-month mortality from 30% to below 15%.Design, Setting, and ParticipantsIn this nonrandomized clinical trial, a treatment algorithm that focused on supportive care was used to prevent early death in patients with APL treated at academic and community health centers between August 2017 and July 2021. Because of the rarity of the disease, expert support was available 24/7 from 7 designated APL experts at 6 participating academic lead centers, and included an additional 293 community centers. When a patient presented with APL, an expert was contacted and a consensus treatment plan was developed using the algorithm and expert suggestions. There were no exclusion criteria and all patients with a confirmed diagnosis of APL regardless of age or comorbid conditions were enrolled. Expert support was provided throughout induction. Initial data analysis was conducted May 2023.Main Outcomes and MeasuresOne-month mortality; additional objectives were to compare outcomes in academic and community centers and assess 1-year and overall survival.ResultsA total of 201 patients were enrolled from 43 centers; 62 at lead centers and 139 from 37 community centers. The median age was 53 years (range, 18-91 years), with 72 patients (35.8%) who were aged 60 years or older; 105 patients (52.2%) were male. Fifty-two patients (26.4%) were diagnosed with high-risk APL. The 1-month mortality rate was 6 deaths of 201 patients (3.0%; 95% CI, 1.1%-6.4%) after adjusting for 1 interim analysis. In a secondary analysis using the Kaplan-Meier method, the 1-month overall survival (OS) rate was 97.0% (95% CI, 93.5%-98.6%) and the 1-year OS rate was 94.5% (95% CI, 90.3%-96.9%).Conclusions and RelevanceIn this nonrandomized clinical trial, use of an algorithm combined with expert support resulted in a dramatic decrease in early death in academic and community centers. Population-wide survival improved in this highly curable disease, which suggests that implementing an accessible support system with APL experts for comanagement is the most logical next step.Trial RegistrationClinicalTrials.gov Identifier: NCT03253848

Abstract Purpose: Selinexor is a first-in-class, central nervous system (CNS)–penetrant, oral inhibitor of exportin 1 (XPO1), the main nuclear exporter of many key tumor suppressors. We report a phase I trial of selinexor in children and adolescents with recurrent CNS and solid tumors (NCT02323880). Patients and Methods: A rolling six design was used to evaluate the maximum tolerated dose (MTD) and first dose pharmacokinetics of selinexor administered once (35–45 mg/m2) or twice (20–35 mg/m2) weekly during a 28-day cycle (part A). Ten additional patients with high-grade glioma (HGG) were treated at the MTD administered once weekly (part B). Results: In part A, 49 patients were enrolled. Continuous twice weekly dosing was limited by extended hematologic toxicity. The MTD on a twice weekly schedule for 3 weeks on/1 week off (twice weekly 3/1) was 20 mg/m2/dose. Dose-limiting toxicities (DLTs) on this schedule included fatigue, acute reversible neurologic changes, neutropenia, thrombocytopenia, and aspartate aminotransferase/alanine aminotransferase increase. On a continuous once weekly schedule, the MTD was 35 mg/m2/dose; DLTs included seizure and thrombocytopenia. In part B (HGG expansion), there were no additional DLTs observed. Non-DLTs included lymphopenia, leukopenia, neutropenia, thrombocytopenia, anorexia, fatigue, hypophosphatemia, nausea, and vomiting. There were no objective responses. The median number of cycles received was 1 (range, 1–9); eight of 59 patients (13.5%) received 5 to 9 cycles, five of whom had HGG. Conclusions: Selinexor-related toxicities were primarily hematologic and neurologic, requiring dose or dose-frequency reduction. The MTD and recommended initial phase II dose of selinexor in children and adolescents with recurrent solid and CNS tumors is 35 mg/m2/dose once weekly.

BACKGROUND: Catheter ablation of ventricular arrhythmias, one of the most rapidly growing procedures in cardiac electrophysiology, is associated with magnetic resonance imaging–detected brain lesions in more than half of cases. Although a retrograde aortic approach is conventional, modern tools enable entry through a transseptal approach that may avoid embolization of debris from the arterial system. We sought to test the hypothesis that a transseptal puncture would mitigate brain injury compared with a retrograde aortic approach. METHODS: The TRAVERSE trial (Transseptal Versus Retrograde Aortic Ventricular Entry to Reduce Systemic Emboli) was a multicenter randomized controlled comparative effectiveness trial. Patients with left ventricular arrhythmias undergoing catheter ablation procedures were randomly assigned to a transseptal puncture approach compared (1:1) with a retrograde aortic approach. The primary outcome was the presence of an acute brain lesion detected by magnetic resonance imaging. Secondary outcomes included clinically manifest complications, procedural efficacy, and 6-month neurocognitive assessments. RESULTS: Among the 62 patients randomly assigned to a retrograde aortic approach with postoperative brain magnetic resonance imaging, 28 (45%) exhibited an acute brain lesion compared with 19 of the 69 (28%) of those randomized to a transseptal puncture ( P =0.036). No differences in clinically manifest complications or procedural efficacy were observed. More patients in the retrograde aortic arm were categorized as having a high likelihood of cognitive impairment at 6 months (33% compared with 19% of those in the transseptal arm), but substantial loss to follow-up was present. CONCLUSIONS: Among patients undergoing left ventricular catheter ablation procedures, a transseptal approach reduced the risk of acute brain lesions by nearly half compared with a retrograde aortic approach without sacrificing safety or efficacy. Given a likely embolic pathogenesis, the brain magnetic resonance imaging findings may reflect a propensity to other organ damage; these findings may extend to other procedures requiring left ventricular entry. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03946072.

BACKGROUND: Patients with arrhythmogenic mitral valve prolapse syndrome are at increased risk for life-threatening ventricular arrhythmias, but studies have been limited by small sample sizes. We sought to assemble an international arrhythmogenic mitral valve prolapse syndrome registry to delineate the clinical, imaging, and treatment characteristics of patients with arrhythmogenic mitral valve prolapse syndrome who survived sudden cardiac arrest (SCA) or had sustained ventricular tachycardia (VT) or ventricular fibrillation. METHODS: In this descriptive registry, we characterized patients with arrhythmogenic mitral valve prolapse syndrome who survived SCA, sustained VT, or ventricular fibrillation. Deidentified data were abstracted locally and combined centrally. RESULTS: We included 148 patients who had SCA or VT/ventricular fibrillation. Patients had a mean age of 43.7±15.4 years; 68% were women, 73% had bileaflet prolapse, 65% had mitral annular disjunction, 67% had nonsustained VT, and 59% had inferolateral T-wave inversions. Syncope (n=54, 48%) and anterolateral T-wave inversion (n=26, 22%) were relatively common. Catheter ablation was performed in 50 (35%) patients for premature ventricular complexes and in 18 (17.7%) patients for VT. Sites of origin for arrhythmias were commonly in the papillary muscles, fascicles, mitral annulus, and inferior/inferolateral left ventricle. CONCLUSIONS: In this international descriptive registry of patients with arrhythmogenic mitral valve prolapse syndrome and SCA, patients were young, women, and had bileaflet mitral valve prolapse, mitral annular disjunction, inferolateral T-wave inversions, and nonsustained VT. A history of syncope and anterolateral T-wave inversions was relatively common in patients who survived SCA or sustained VT/ventricular fibrillation.

AbstractPresence of focal to bilateral tonic–clonic seizures (FBTCS) in focal epilepsy is associated with increased morbidity and mortality. Risk factors for FBTCS are poorly understood, and little is known regarding FBTCS recurrence after treatment initiation. This study aimed to investigate factors related to FBTCS in newly diagnosed focal epilepsy and their recurrence after starting antiseizure medications (ASMs) in the Human Epilepsy Project (HEP) cohort. HEP was an international, prospective cohort study that enrolled people with newly diagnosed focal epilepsy within 4 months of treatment initiation and followed them for up to 6 years. Baseline characteristics, treatment choices, and seizure outcomes were collected. Descriptive and inferential statistical analysis was conducted to assess the differences between study participants who had FBTCS and those who never experienced FBTCS. A total of 443 participants were included in this analysis; 77% (n = 342) had FBTCS at some point prior to or within the study period. In participants with FBTCS, regardless of initial seizure type, diagnosis was mostly made after FBTCS (335/342, 98%). After treatment initiation, FBTCS did not recur in 57% (n = 194/342) of cases. A higher number of total pretreatment seizures (median = 16 vs. 11, p = .048, Mann–Whitney U‐test), predominantly focal aware seizures (FAS) or focal impaired awareness seizures (FIAS; median = 15 vs. 10, p = .049, Mann Whitney U‐test), was associated with no recurrence in FBTCS after treatment initiation. Of 108 participants without FBTCS prior to treatment, only seven (6%) developed FBTCS after treatment initiation. There was no significant difference in choice of initial ASM class (levetiracetam vs. sodium channel blockers) between participants who experienced FBTCS and those who did not. This study highlights the significance of FBTCS among individuals with newly diagnosed focal epilepsy. The majority of participants who experienced FBTCS were diagnosed with epilepsy after experiencing their first FBTCS despite preceding FAS/FIAS. The more frequent FAS/FIAS in participants whose FBTCS resolved may be a characteristic of their epilepsy.

Background/Objectives: Performing endoscopic retrograde cholangiopancreatography (ERCP) in surgically altered gastrointestinal anatomy remains challenging, frequently necessitating the use of forward-viewing endoscopes. Given the challenge in endoscope selection based on the type of altered anatomy, the aim of this study was to examine ERCP success rates by specific endoscopes for different anatomy types. Methods: This single-center retrospective study examined ERCPs performed in patients with surgically altered gastrointestinal anatomy during an 18-year period. Enteroscopy success, cannulation success, and intervention success rates were compared between the different anatomy and endoscope types. Results: This study included a total of 334 adult patients (665 total ERCPs) with altered anatomy. The pediatric colonoscope was most frequently utilized (32.2%), and the majority of procedures were performed for biliary indications. Enteroscopy success was 82.2% in Roux-en-Y gastric bypass (RYGB), 97% in Billroth II, 91.5% in Whipple, and 93.2% in Roux-en-Y hepaticojejunostomy (RYHJ). Cannulation success was 90.5% in RYGB, 90.5% in Billroth II, 83.6% in Whipple, and 90.6% in RYHJ. Intervention success was 88.2% in Billroth II, 65.1% in RYGB, 81.6% in Whipple, and 87.5% in RYHJ. In patients with RYGB and RYHJ, SBE was utilized most frequently, with rotational enteroscopy having the highest success rates. The overall adverse event rate was 5.1%, with the majority of these being mild in severity. Conclusions: This large retrospective study found ERCP with forward-viewing endoscopes to be safe and effective for a variety of surgically altered anatomy types. Despite recent advances seen with endoscopic ultrasound-guided drainage procedures, this study advocates for ERCP as the initial approach for pancreaticobiliary access in surgically altered anatomy.

ABSTRACTIntroductionLung transplantation has been evolving since its inception in 1963. Over recent years, literature has suggested a shift in the perioperative strategy of mechanical support toward extracorporeal membrane oxygenation (ECMO) as the preferred modality of extracorporeal life support (ECLS) in lung transplantation. The Survey of ECLS Application in Lung transplantation (SEAL) was designed to elucidate the current practice patterns of perioperative ECLS within the United States.MethodsIn this cross‐sectional study, a physician from 62 adult lung transplantation centers across the United States of America (USA) was surveyed on their institutional practices regarding the perioperative management of lung transplantation patients, with a focus on mechanical support.ResultsThe survey completion rate was 74% (46/62 eligible institutions). Most transplant centers utilize venoarterial (VA) ECMO (78%, 36/46) and/or venovenous (VV) ECMO (93%, 29/43) as a bridge to lung transplantation. When ECLS is used intraoperatively, 61% of (28/46) responding programs use VA ECMO as their preferred support. All programs use transesophageal echocardiography (TEE) intraoperatively, 85% (33/39) cannulate for ECMO centrally, and 74% (29/39) use a combination of inhaled and intravenous anesthesia while using ECMO intraoperatively. Most programs do not use antifibrinolytic during VA ECMO (62%, 28/45). Anticoagulation management and VA ECMO flows throughout the procedure showed considerable variation.ConclusionData from SEAL illustrates that though there are some practice commonalities within the United States, there is also quite a bit of variability in practice. Multiple dominant practices within the USA are consistent with a recently published International Society of Heart and Lung Transplantation consensus.

AbstractIntroductionClinicopathological correlations differ by sex in Lewy body dementia (LBD). However, previous studies have focused on pathological staging systems that place less emphasis on regional pathologies.MethodsWe included 357 people (131 female, 226 male) with a high likelihood of LBD based on pathology from the Brain Bank for Neurodegenerative (Jacksonville, FL). Sex differences for regional Lewy body, senile plaque, and neurofibrillary tangle counts and their associations with clinical LBD diagnosis were assessed.ResultsFemales were less likely to have a clinical LBD diagnosis; they had more Lewy bodies, neurofibrillary tangles, and senile plaques in various regions than males (all p’s < 0.05). A higher likelihood of clinical LBD diagnosis was associated with more middle frontal, cingulate, and entorhinal Lewy body pathology, and more so for males than for females (all p’s < 0.045).DiscussionSex differences for clinicopathological correlations in LBD also occur at the regional pathology level. Females have a higher frequency of clinical misdiagnosis than males.Highlights Females have a higher risk of clinical underdiagnosis for Lewy body dementia (LBD) than males. Regional pathology counts differ by sex for people with a high likelihood of LBD. Regional pathology association with clinical LBD diagnosis differs by sex. Regional Lewy body counts have a stronger association with LBD phenotype for males.

Background To provide recommendations on risk mitigation, diagnosis and treatment of infectious complications associated with the practice of regional anesthesia, acute and chronic pain management. Methods Following board approval, in 2020 the American Society of Regional Anesthesia and Pain Medicine (ASRA Pain Medicine) commissioned evidence-based guidelines for best practices for infection control. More than 80 research questions were developed and literature searches undertaken by assigned working groups comprising four to five members. Modified US Preventive Services Task Force criteria were used to determine levels of evidence and certainty. Using a modified Delphi method, >50% agreement was needed to accept a recommendation for author review, and >75% agreement for a recommendation to be accepted. The ASRA Pain Medicine Board of Directors reviewed and approved the final guidelines. Results After documenting the incidence and infectious complications associated with regional anesthesia and interventional pain procedures including implanted devices, we made recommendations regarding the role of the anesthesiologist and pain physician in infection control, preoperative patient risk factors and management, sterile technique, equipment use and maintenance, healthcare setting (office, hospital, operating room), surgical technique, postoperative risk reduction, and infection symptoms, diagnosis, and treatment. Consensus recommendations were based on risks associated with different settings and procedures, and keeping in mind each patient’s unique characteristics. Conclusions The recommendations are intended to be multidisciplinary guidelines for clinical care and clinical decision-making in the regional anesthesia and chronic interventional pain practice. The issues addressed are constantly evolving, therefore, consistent updating will be required.