Citations

AbstractObjectiveSeizures are a common manifestation of paraneoplastic neurologic syndromes. The objective of this study was to describe the seizure characteristics and outcomes in patients with high‐risk paraneoplastic autoantibodies (>70% cancer association) and to determine factors associated with ongoing seizures.MethodsPatients from 2000 to 2020 with seizures and high‐risk paraneoplastic autoantibodies were retrospectively identified. Factors associated with ongoing seizures at last follow‐up were evaluated.ResultsSixty patients were identified (34 males, median age at presentation = 52 years). ANNA1‐IgG (Hu; n = 24, 39%), Ma2‐IgG (n = 14, 23%), and CRMP5‐IgG (CV2; n = 11, 18%) were the most common underlying antibodies. Seizures were the initial presenting symptom in 26 (43%), and malignancy was present in 38 (63%). Seizures persisted for >1 month in 83%, and 60% had ongoing seizures, with almost all patients (55/60, 92%) still being on antiseizure medications at last follow‐up a median of 25 months after seizure onset. Ongoing seizures at last follow‐up were associated with Ma2‐IgG or ANNA1‐IgG compared to other antibodies (p = .04), highest seizure frequency being at least daily (p = .0002), seizures on electroencephalogram (EEG; p = .03), and imaging evidence of limbic encephalitis (LE; p = .03). Death occurred in 48% throughout the course of follow‐up, with a higher mortality in patients with LE than in those without LE (p = .04). Of 31 surviving patients at last follow‐up, 55% continued to have intermittent seizures.SignificanceSeizures in the setting of high‐risk paraneoplastic antibodies are frequently resistant to treatment. Ongoing seizures are associated with ANNA1‐IgG and Ma2‐IgG, high seizure frequency, and EEG and imaging abnormalities. Although a subset of patients may respond to immunotherapy and achieve seizure freedom, poor outcomes are frequently encountered. Death was more common among patients with LE.

AbstractThe gender pay gap among physicians is a well documented and persistent problem and has a profound impact on earnings over a career lifetime. This paper describes examples of concrete initiatives three institutions took to identify and address gender pay gaps. Salary audits at two academic emergency departments highlight the importance of not only ensuring equity in salary among physicians of the same rank but also monitoring whether women are achieving equal representation at higher academic ranks and leadership, elements that typically contribute to compensation. These audits reveal how senior rank and formal leadership roles are significantly associated with salary disparities. A third school of medicine–wide initiative entailed conducting comprehensive salary audits followed by review and adjustment of faculty compensation to achieve pay equity. Graduating residents and fellows seeking first jobs out of training and faculty looking to be compensated equitably would benefit from understanding the elements that drive their compensation and advocating for frameworks that are understandable and transparent.

BACKGROUND: Functional gallbladder disorder is most commonly defined by biliary colic and low ejection fraction (EF) on cholescintigraphy. Biliary hyperkinesia is a controversial type of functional gallbladder disorder, and its definition and the role of cholecystectomy in treating functional gallbladder disorder remains unclear. STUDY DESIGN: We conducted a retrospective review of patients who underwent cholecystokinin-stimulated cholescintigraphy and cholecystectomy at 3 Mayo Clinic sites between 2007 and 2020. Eligible patients were 18 years or older, presented with symptoms of biliary disease, had an EF greater than 50%, underwent cholecystectomy, and had no evidence of acute cholecystitis or cholelithiasis on imaging. We used receiver operating characteristics curve analysis to identify the optimal cutoff value that predicted symptom resolution within 30 days of cholecystectomy. RESULTS: A total of 2,929 cholecystokinin-stimulated cholescintigraphy scans were performed during the study period; the average EF was 67.5% and the median EF was 77%. Analyzing those with EFs greater than or equal to 50% yielded 1,596 patients with 141 (8.8%) going on to have cholecystectomy. No significant differences were found in age, sex, BMI, final pathology between patients with and without pain resolution. Using a cutoff EF of 81% was significantly associated with pain resolution after cholecystectomy (78.2% for EF greater than or equal to 81% vs 60.0% for EF less than 81%, p = 0.03). Chronic cholecystitis was found in 61.7% of the patients on final pathology. CONCLUSIONS: We determined that an EF cutoff of 81% is a reasonable upper limit of normal gallbladder EF. Patients with biliary symptoms and an EF greater than 81% but no evidence of biliary disease on ultrasound or scintigraphy can be classified as having biliary hyperkinesia. Based on our findings, we recommend cholecystectomy for this patient population.

Abstract Amyloid light-chain (AL) amyloidosis is a rare, typically fatal disease characterized by the accumulation of misfolded immunoglobulin light chains (LCs). Birtamimab is an investigational humanized monoclonal antibody designed to neutralize toxic LC aggregates and deplete insoluble organ-deposited amyloid via macrophage-induced phagocytosis. VITAL was a phase 3 randomized, double-blind, placebo-controlled clinical trial assessing the efficacy and safety of birtamimab + standard of care (SOC) in 260 newly diagnosed, treatment-naive patients with AL amyloidosis. Patients received 24 mg/kg IV birtamimab + SOC or placebo + SOC every 28 days. The primary composite end point was the time to all-cause mortality (ACM) or centrally adjudicated cardiac hospitalization ≥91 days after the first study drug infusion. The trial was terminated early after an interim futility analysis; there was no significant difference in the primary composite end point (hazard ratio [HR], 0.826; 95% confidence interval [CI], 0.574-1.189; log-rank P = .303). A post hoc analysis of patients with Mayo stage IV AL amyloidosis, those at the highest risk of early mortality, showed significant improvement in the time to ACM with birtamimab at month 9 (HR, 0.413; 95% CI, 0.191-0.895; log-rank P = .021). At month 9, 74% of patients with Mayo stage IV AL amyloidosis treated with birtamimab and 49% of those given placebo survived. Overall, the rates of treatment-emergent adverse events (TEAEs) and serious TEAEs were generally similar between treatment arms. A confirmatory phase 3 randomized, double-blind, placebo-controlled clinical trial of birtamimab in patients with Mayo stage IV AL amyloidosis (AFFIRM-AL; NCT04973137) is currently enrolling. The VITAL trial was registered at www.clinicaltrials.gov as #NCT02312206.

The EGFR-RAS-ERK pathway is one of the most important signaling cascades in cell survival, growth, and proliferation. Aberrant activation of this pathway is a common mechanism in various cancers. Here, we report that CDK2 is a novel regulator of the ERK pathway via USP37 deubiquitinase (DUB). Mechanistically, CDK2 phosphorylates USP37, which is required for USP37 DUB activity. Further, USP37 deubiquitinates and stabilizes ERK1/2, thereby enhancing cancer cell proliferation. Thus, CDK2 is able to promote cell proliferation by activating USP37 and, in turn, stabilizing ERK1/2. Importantly, combined CDK1/2 and EGFR inhibitors have a synergetic anticancer effect through the downregulation of ERK1/2 stability and activity. Indeed, our patient-derived xenograft (PDX) results suggest that targeting both ERK1/2 stability and activity kills cancer cells more efficiently even at lower doses of these two inhibitors, which may reduce their associated side effects and indicate a potential new combination strategy for cancer therapy.

Atrial fibrillation is a diverse clinical entity, with persistent atrial fibrillation (PeAF) being particularly challenging to manage. Through this paper, we discuss notable developments in our understanding of ablative strategies for managing PeAF, with a special focus on posterior wall isolation (PWI).

Objectives: The purpose of this study was to evaluate visual gaze patterns and the ability to correctly identify cancer among participants of different experience levels when viewing benign and malignant vocal cord lesions. Methods: Thirty-one participants were divided into groups based on level of experience. These included novice (medical students, PGY1-2 otolaryngology residents), intermediate (PGY3-5 otolaryngology residents, gastroenterology fellow), advanced practice providers (physician assistants, nurse practitioners, and speech language pathologists), and experts (board-certified otolaryngologists). Each participant was shown 7 images of vocal cord pathology including glottic cancer, infectious laryngitis, and granuloma and asked to determine the likelihood of cancer on a scale of certain, probable, possible, and unlikely. Eye tracking data were collected and used to identify the area of interest (AOI) that each participant fixated on first, fixated on the longest, and had the greatest number of fixations. Results: No significant differences were seen among groups when comparing AOI with first fixation, AOI with longest fixation, or AOI with most fixations. Novices were significantly more likely to rate a low likelihood of cancer when viewing infectious laryngitis compared to more experienced groups ( P < .001). There was no difference in likelihood of cancer rating among groups for the remaining images. Conclusions: There was no significant difference in gaze targets among participants of different experience levels evaluating vocal cord pathology. Symmetric appearance of vocal cord lesions may explain differences seen in likelihood of cancer rating among groups. Future studies with larger sample sizes will better elucidate gaze targets that lead to accurate diagnosis of vocal cord pathology.

Objective In certain cases, clinicians may consider continued observation of a vestibular schwannoma after initial growth is detected. The aim of the current work was to determine if patients with growing sporadic vestibular schwannomas could be stratified by the likelihood of subsequent growth based on initial growth behavior. Study Design Slice-by-slice volumetric tumor measurements from 3,505 serial magnetic resonance imaging studies were analyzed from 952 consecutively treated patients. Setting Three tertiary-referral centers. Patients Adults with sporadic vestibular schwannoma. Interventions Wait-and-scan. Main Outcome Measures Composite end point of subsequent growth- or treatment-free survival rates, where growth is defined as an additional increase of at least 20% in tumor volume from the volume at the time of initial growth. Results Among 405 patients who elected continued observation despite documented growth, stratification, of volumetric growth rate into less than 25% (reference: n = 107), 25 to less than 50% (hazard ratio [HR], 1.39; p = 0.06; n = 96), 50 to less than 100% (HR, 1.71; p = 0.002; n = 112), and at least 100% (HR, 2.01; p < 0.001; n = 90) change per year predicted the likelihood of future growth or treatment. Subsequent growth- or treatment-free survival rates (95% confidence interval) at year 5 after detection of initial growth were 31% (21–44%) for those with less than 25% growth per year, 18% (10–32%) for those with 25 to less than 50%, 15% (9–26%) for those with 50 to less than 100%, and 6% (2–16%) for those with at least 100%. Neither patient age (p = 0.15) nor tumor volume at diagnosis (p = 0.95) significantly differed across stratification groups. Conclusions At the time of diagnosis, clinical features cannot consistently predict which tumors will ultimately display aggressive behavior. Stratification by volumetric growth rate at the time of initial growth results in a stepwise progression of increasing likelihood of subsequent growth. When considering continued observation after initial growth detection, almost 95% of patients who have tumors that double in volume between diagnosis and the first detection of growth demonstrate further tumor growth or undergo treatment if observed to 5 years.

Objectives The current study characterizes age and incidence of cochlear implantation among qualifying children with congenital bilateral profound hearing loss in the U.S. Study Design Deidentified cochlear implantation data were acquired from prospectively collected patient registries from two cochlear implant (CI) manufacturers (Cochlear Americas and Advanced Bionics). Children <36 months old were assumed to have congenital bilateral profound sensorineural hearing loss. Setting U.S. CI centers. Patients Children <36 months old who received CIs. Interventions Cochlear implantation. Main Outcome Measures Age at implantation and incidence. Results A total of 4,236 children <36 months old underwent cochlear implantation from 2015 to 2019. The median age at implantation was 16 months (interquartile range, 12–24 mo) and did not change significantly during the 5-year study period (p = 0.09). Patients residing closer to CI centers (p = 0.03) and treated at higher-volume centers (p = 0.008) underwent implantation at a younger age. Bilateral simultaneous implantation increased from 38% to 53% of CI surgeries in 2015 and 2019, respectively. Children who received bilateral simultaneous CIs were younger compared with those receiving unilateral or bilateral sequential CIs (median, 14 versus 18 mo; p < 0.001). The incidence of cochlear implantation increased from 7,648 per 100,000 person-years in 2015 to 9,344 in 2019 (p < 0.001). Conclusion Although the incidence of pediatric CI recipients and the frequency of bilateral simultaneous implantation increased over the study period, age at implantation did not change significantly and far exceeded current Food and Drug Administration (9 mo) and American Academy of Otolaryngology and Head and Neck Surgery position statement (6–12 mo) guidelines.