Citations

ObjectiveThe degree to which various treatment modalities modify vestibular schwannoma (VS)–associated symptoms has received limited attention. The purpose of this study was to determine how different treatment modalities affect subjective symptoms in those presenting with VS.Study DesignProspective survey.SettingTertiary neurotology referral center.MethodsPatients with sporadic VS who received treatment at our institution were prospectively surveyed with a VS symptom questionnaire. Those who completed a baseline survey prior to treatment and at least 1 posttreatment survey were included. The prospective survey evaluated the severity of self‐reported symptoms (Likert scale, 1‐10), including tinnitus, dizziness or imbalance, headaches, and hearing loss.ResultsA total of 244 patients were included (mean age, 57 years). The mean duration of follow‐up was 2.1 years, and the median number of surveys completed was 2 (interquartile range, 1‐3). Seventy‐eight (32%) cases were managed with observation, 118 (48%) with microsurgery, and 48 (20%) with radiosurgery. Multivariable analyses revealed no statistically significant difference in the change in tinnitus (P =. 15), dizziness or imbalance (P = 0.66), or headaches (P =. 24) among treatment groups. Evaluation of clinically important differences demonstrated that microsurgery leads to significant bidirectional changes in headaches.ConclusionsLimited prospective data exist regarding the progression or resolution of subjective symptoms in those presenting with VS. This study suggests that tinnitus, dizziness or imbalance, and headaches are unlikely to be significantly modified by treatment modality and generally should not be used to direct treatment choice.

TPS258 Background: Engineered toxin bodies (ETBs) are comprised of a proprietarily engineered form of Shiga-like Toxin A subunit genetically fused to antibody-like binding domains. ETBs work through novel mechanisms of action & are capable of forcing internalization, self-routing through intracellular compartments to the cytosol & inducing potent cell-kill via the enzymatic & permanent inactivation of ribosomes. MT-5111 is a de-immunized ETB targeting HER2+ solid tumors. Its novel mechanism of action, via enzymatic ribosome inactivation, may not be subject to resistance mechanisms that exist for tyrosine kinase inhibitors, antibody-drug conjugates, or antibody modalities. MT-5111 binds an epitope on HER2, distinct from trastuzumab or pertuzumab, that may provide for combination potential with other HER2-targeting agents. MT-5111 is a 55 kilodalton protein & may have improved tumor penetration capability. The objective of this trial will be to determine the safety, tolerability, & maximum tolerated dose (MTD) of MT-5111 in patients (pts) with advanced HER2+ solid tumors. Methods: This Phase 1, first-in-human, open-label, dose escalation & expansion study will evaluate MT-5111 monotherapy in pts with HER2-positive solid tumors. The primary objective is to determine the MTD; secondary objectives include pharmacokinetics, tumor response & immunogenicity. Part 1 consists of MT-5111 dose escalation (0.5, 1.0, 2.0, 3.0, 4.5, 6.75, 10µg/kg/dose) based on a modified 3+3 design (n≤42 pts); Part 2 (dose expansion) will evaluate MT-5111 at the MTD in ≤98 pts. All pts will be administered MT-5111 over 30 min via IV infusion on Days 1, 8, & 15 of each 21-day cycle until disease progression, unacceptable toxicity, death, withdrawal of consent, or another reason for withdrawal. Part 1 will include pts with any HER2+ solid cancers. Part 2 will enroll 3 expansion cohorts: HER2+ breast (BC), HER2+ gastric or gastroesophageal junction adenocarcinomas (collectively referred as gastroesophageal adenocarcinomas [GEA]) & other HER2+ solid cancers. Immunohistochemistry (IHC) status must be 2+ or 3+, regardless of in situ hybridization (ISH) results; if no IHC is available for pts with BC or GEA, ISH criteria per the American Society of Clinical Oncology College of American Pathologists guidelines will be used. In metastatic cases, HER2 positivity must be demonstrated on metastatic lesions. Pts with HER2+ BC should have had ≥2 lines of HER2-directed therapy; pts with HER2+ GEA should have received or been intolerant to trastuzumab. Pts with evaluable disease may be included in Part 1; in Part 2, all pts must have ≥1 measurable lesion per Response Evaluation Criteria in Solid Tumors v1.1. Further details can be found on clinicaltrials.gov (NCT04029922). Enrollment, which began in September 2019, is ongoing. Clinical trial information: NCT04029922.

423 Background: Advanced PDAC remains a deadly disease with a 5-year survival rate of less than 10%. cfDNA - based next generation sequencing (NGS) may identify actionable alterations in patients with PDAC. In this study, we aim to determine the feasibility of utilizing serial cfDNA NGS testing and its potential relevance in predicting therapeutics outcomes. Methods: A total of 23 PDAC patients with PDAC cfDNA isolated from plasma collected at diagnosis and upon disease progression to first line SOC therapy and were analyzed on a 73-74 gene NGS panel (Guardant Health). Changes in molecular profiles from baseline to progression were analyzed for overall survival, progression free survival (PFS), and treatment response. PFS and OS were analyzed using the Kaplan-Meier method and the log-rank test was used to compare the survival of different groups of patients. All p-values were two-sided. Analyses were performed using R (version 3.5.1, R Foundation, Vienna, Austria). Results: In this retrospective study, the 1-year probability of survival was 71% (median 473 days) and the 1-year PFS was 14% (median 212 days). TP53 and KRAS were the most frequently mutated genes identified in baseline samples, with 78% prevalence for each. Patients with clearance of TP53 17% (3/18) patients and/or KRAS 33% (6/18) patients clones after first line therapy significantly increases PFS (p=0.0056 and p=0.037, with HR of 0.087 and 0.32, respectively). However, appearance of TP53 or KRAS alterations upon progression does not significantly affect overall survival or PFS. Conclusions: The preliminary results from this study suggest that cfDNA clearance of TP53 and/or KRAS alterations may predict for improved PFS in PDAC. Confirmation of these findings in larger studies is warranted.

AbstractIntroductionMachine learning models were used to discover novel disease trajectories for autosomal dominant Alzheimer's disease.MethodsLongitudinal structural magnetic resonance imaging, amyloid positron emission tomography (PET), and fluorodeoxyglucose PET were acquired in 131 mutation carriers and 74 non‐carriers from the Dominantly Inherited Alzheimer Network; the groups were matched for age, education, sex, and apolipoprotein ε4 (APOE ε4). A deep neural network was trained to predict disease progression for each modality. Relief algorithms identified the strongest predictors of mutation status.ResultsThe Relief algorithm identified the caudate, cingulate, and precuneus as the strongest predictors among all modalities. The model yielded accurate results for predicting future Pittsburgh compound B (R2 = 0.95), fluorodeoxyglucose (R2 = 0.93), and atrophy (R2 = 0.95) in mutation carriers compared to non‐carriers.DiscussionResults suggest a sigmoidal trajectory for amyloid, a biphasic response for metabolism, and a gradual decrease in volume, with disease progression primarily in subcortical, middle frontal, and posterior parietal regions.

Abstract BACKGROUND Low-grade intracranial dural arteriovenous fistulas (dAVF) have a benign natural history in the majority of cases. The benefit from treatment of these lesions is controversial. OBJECTIVE To compare the outcomes of observation versus intervention for low-grade dAVFs. METHODS We retrospectively reviewed dAVF patients from institutions participating in the CONsortium for Dural arteriovenous fistula Outcomes Research (CONDOR). Patients with low-grade (Borden type I) dAVFs were included and categorized into intervention or observation cohorts. The intervention and observation cohorts were matched in a 1:1 ratio using propensity scores. Primary outcome was modified Rankin Scale (mRS) at final follow-up. Secondary outcomes were excellent (mRS 0-1) and good (mRS 0-2) outcomes, symptomatic improvement, mortality, and obliteration at final follow-up. RESULTS The intervention and observation cohorts comprised 230 and 125 patients, respectively. We found no differences in primary or secondary outcomes between the 2 unmatched cohorts at last follow-up (mean duration 36 mo), except obliteration rate was higher in the intervention cohort (78.5% vs 24.1%, P < .001). The matched intervention and observation cohorts each comprised 78 patients. We also found no differences in primary or secondary outcomes between the matched cohorts except obliteration was also more likely in the matched intervention cohort ( P < .001). Procedural complication rates in the unmatched and matched intervention cohorts were 15.4% and 19.2%, respectively. CONCLUSION Intervention for low-grade intracranial dAVFs achieves superior obliteration rates compared to conservative management, but it fails to improve neurological or functional outcomes. Our findings do not support the routine treatment of low-grade dAVFs.

Abstract The primary aim of this randomized clinical trial is to investigate the effects of ultrasound-guided transversus abdominis plane (TAP) vs ultrasound-guided trigger point injections (TPIs) on numerical rating scale pain scores at month 3 follow-up in patients with a chronic abdominal wall pain. The primary outcome measure was the difference in mean numeric rating scale pain scores between the TAP and TPI groups at month 3 in an intent-to-treat (ITT) analysis. A total of 60 patients were randomized 1:1 to receive an ultrasound-guided TAP block (n = 30) or an ultrasound-guided TPI (n = 30). No significant group differences in baseline demographic or clinical characteristics were observed. The mean baseline pain score for the TAP and TPI groups was 5.5 and 4.7, respectively. In the ITT analysis at month 3, the between-group difference in pain scores was 1.7 (95% confidence interval, 0.3-3.0) favoring the TPI group. In a secondary per-protocol analysis, the between-group difference in pain scores was 1.8 (95% confidence interval, 0.4-3.2) favoring the TPI group. For the ITT and per-protocol analyses, the group differences in pain scores were consistent with a medium effect size. The main finding of this randomized clinical trial is that adults with chronic abdominal wall pain who received a TPI reported significantly lower pain scores at month 3 follow-up compared with patients who received a TAP block.

ObjectiveTo determine if there is an association between authors’ financial conflict of interest and published position on clinical use of hypoglossal nerve stimulation for obstructive sleep apnea.Study DesignRetrospective cross‐sectional analysis.SettingInternational roster of authors and articles analyzed.MethodsA Google Scholar search was performed for editorials and reviews citing the 2014 New England Journal of Medicine article on hypoglossal nerve stimulation for obstructive sleep apnea. Included articles were coded as favorable or neutral. Conflict of interest was recorded as declared by the authors in these articles and as independently searched in the Open Payments registry.ResultsSixteen articles from 45 independent authors were analyzed. Nine articles by authors were coded as favorable. Among authors of articles with favorable views, 16 (59%) had a financial conflict of interest with the manufacturer of the hypoglossal nerve stimulator device, as opposed to only 1 of 21 (5%) authors of neutral/unfavorable articles. When we included only authors to whom payments could be identified or excluded on Open Payments, 16 of 20 (80%; 95% CI, 62%‐98%) authors of favorable articles had a financial conflict, while 1 of 10 (10%; 95% CI, 0%‐29.6%) of neutral/unfavorable articles did (P =. 004).ConclusionOur study demonstrates an association between published position on hypoglossal nerve stimulator use and financial conflict with the device manufacturer. Several undeclared conflicts were also found, suggesting a role for independent search for conflicts during the review process.

Abstract Introduction: Even physicians who routinely work in complex, dynamic practices may be unprepared to optimally manage challenging critical events. High-fidelity simulation can realistically mimic critical clinically relevant events, however the reliability and validity of simulation-based assessment scores for practicing physicians has not been established.Methods: Standardised complex simulation scenarios were developed and administered to board-certified, practicing anesthesiologists who volunteered to participate in an assessment study during formative maintenance of certification activities. A subset of the study population agreed to participate as the primary responder in a second scenario for this study. The physicians were assessed independently by trained raters on both teamwork/behavioural and technical performance measures. Analysis using Generalisability and Decision studies were completed for the two scenarios with two raters.Results: The behavioural score was not more reliable than the technical score. With two raters > 20 scenarios would be required to achieve a reliability estimate of 0.7. Increasing the number of raters for a given scenario would have little effect on reliability.Conclusions: The performance of practicing physicians on simulated critical events may be highly context-specific. Realistic simulation-based assessment for practicing physicians is resource-intensive and may be best-suited for individualized formative feedback. More importantly, aggregate data from a population of participants may have an even higher impact if used to identify skill or knowledge gaps to be addressed by training programs and inform continuing education improvements across the profession.

Background Several studies have shown improved outcomes in closed compared with open medical and surgical intensive care units. However, very little is known about the ideal organizational structure in the modern cardiac intensive care unit (CICU). Methods and Results We retrospectively reviewed consecutive unique admissions (n=3996) to our tertiary care CICU from September 2013 to October 2017. The aim of our study was to assess for differences in clinical outcomes between an open compared with a closed CICU. We used multivariable logistic regression adjusting for demographics, comorbidities, and severity of illness. The primary outcome was in‐hospital mortality. We identified 2226 patients in the open unit and 1770 in the closed CICU. The unadjusted in‐hospital mortality in the open compared with closed unit was 9.6% and 8.9%, respectively ( P =0.42). After multivariable adjustment, admission to the closed unit was associated with a lower in‐hospital mortality (odds ratio [OR], 0.69; 95% CI: 0.53–0.90, P =0.007) and CICU mortality (OR, 0.70; 95% CI, 0.52–0.94, P =0.02). In subgroup analysis, admissions for cardiac arrest (OR, 0.42; 95% CI, 0.20–0.88, P =0.02) and respiratory insufficiency (OR, 0.43; 95% CI, 0.22–0.82, P =0.01) were also associated with a lower in‐hospital mortality in the closed unit. We did not find a difference in CICU length of stay or total hospital charges ( P >0.05). Conclusions We found an association between lower in‐hospital and CICU mortality after the transition to a closed CICU. These results may help guide the ongoing redesign in other tertiary care CICUs.