Citations

Abstract Objective The Genomic Medicine Working Group of the National Advisory Council for Human Genome Research virtually hosted its 13th genomic medicine meeting titled “Developing a Clinical Genomic Informatics Research Agenda”. The meeting’s goal was to articulate a research strategy to develop Genomics-based Clinical Informatics Tools and Resources (GCIT) to improve the detection, treatment, and reporting of genetic disorders in clinical settings. Materials and Methods Experts from government agencies, the private sector, and academia in genomic medicine and clinical informatics were invited to address the meeting's goals. Invitees were also asked to complete a survey to assess important considerations needed to develop a genomic-based clinical informatics research strategy. Results Outcomes from the meeting included identifying short-term research needs, such as designing and implementing standards-based interfaces between laboratory information systems and electronic health records, as well as long-term projects, such as identifying and addressing barriers related to the establishment and implementation of genomic data exchange systems that, in turn, the research community could help address. Discussion Discussions centered on identifying gaps and barriers that impede the use of GCIT in genomic medicine. Emergent themes from the meeting included developing an implementation science framework, defining a value proposition for all stakeholders, fostering engagement with patients and partners to develop applications under patient control, promoting the use of relevant clinical workflows in research, and lowering related barriers to regulatory processes. Another key theme was recognizing pervasive biases in data and information systems, algorithms, access, value, and knowledge repositories and identifying ways to resolve them.

AbstractOuter hair cell (OHC) metabolism is blocked by cisplatin. Concurrent changes in the renal handling of magnesium occur because of the damage cisplatin causes to the renal proximal tubule cells within the thick ascending loop of Henle. Although there is no evidence of cisplatin within the OHCs, there are significant levels of intracellular calcium, the antagonist to magnesium at the cell membrane. The OHC motile response is dependent on intracellular calcium. When the calcium current is suppressed by an antagonist, the extracellular OHC microphonic potential decreases. Magnesium deficiency is known to produce hyperexcitabililty within the central nervous system, including fatal audiogenic seizures. In addition, increases in the amplitude of the auditory brainstem response wave V occur with aminoglycoside therapy and magnesium deficiency. This paper illustrates the amplitude growth of distortion product otoacoustic emissions in two patients treated with cisplatin and explores the possible underlying reasons why this may be related to magnesium metabolism. Abbreviations: DPOAEs = distortion product otoacoustic emissions, OAEs = otoacoustic emissions, OHC = outer hair cell, TEOAEs = transient otoacoustic emissions

INTRODUCTION: Cerebral cavernous malformations (CCM) are the second commonest incidental finding on brain MRI and may cause symptomatic intracranial hemorrhage (ICH). However, the risk and predictors of ICH from CCM remain uncertain. HYPOTHESIS: Presentation with ICH or non-hemorrhagic focal neurological deficit (FND) attributable to CCM, brainstem CCM location, female sex, increasing age and multiple CCM predict ICH occurrence during follow-up without CCM treatment. METHODS: Three hospital-based cohorts and two cohorts from a population-based study provided individual patient data on clinical course from CCM diagnosis until either first CCM treatment or last available follow-up. We used survival analysis of each cohort to estimate the 5-year risk of symptomatic ICH or new FND, multivariable Cox regression to identify baseline predictors of outcome, and random-effects models to pool estimates in meta-analysis. RESULTS: Among 988 adults who experienced 62 ICHs during 3,232 person-years of follow-up, clinical presentation with ICH or FND (hazard ratio [HR] 7.4, 95% confidence interval [CI] 2.9-19.2) and brainstem CCM location (HR 5.7, 95% CI 3.2-10.3) were associated with a higher risk of a first ICH within five years of CCM diagnosis, but age, sex and CCM multiplicity were not. The 5-year estimated risk of ICH during untreated follow-up was 2.4% (95% CI 1.0-3.8) for 566 adults without ICH/FND from CCM outside the brainstem, 5.5% (95% CI 0-12.9) for 51 adults without ICH/FND from brainstem CCM, 10.6% (95% CI 5.1-16.1) for 198 adults with ICH/FND from CCM outside the brainstem, and 25.7% (95% CI 18.3-33.1) for 173 adults with ICH/FND from brainstem CCM. In secondary analyses of first ICH or FND, event rates increased but predictors remained unchanged. CONCLUSION: Mode of clinical presentation and CCM location are independently associated with ICH or FND within five years of CCM diagnosis, which can inform decisions about CCM treatment.

Background: Left ventricular assist device (LVAD) implantation is a new therapy for advanced heart failure (HF). The number of HF patients eligible for LVAD and the cardiology providers’ comfort level with referral for LVAD remains unclear. Objective: To assess provider perception of LVAD candidacy and LVAD referral patterns in consecutive HF patients. Methods: Providers completed a survey for each HF patient seen between March 1, 2013 and April 26, 2013. The survey listed standard LVAD candidacy criteria and asked 1) if a patient was an LVAD candidate (yes, no, unsure); 2) reasons patients were not LVAD candidates (check list, table); and 3) whether the patient had been referred for LVAD evaluation (yes, no, unsure). Results: Patients (n=522) were seen in a tertiary HF outpatient clinic (n=357; 68%), a tertiary HF inpatient service (n=36; 7%), a tertiary general cardiology service (n=45; 9%) or a community based outpatient cardiac clinic (n=84; 16%) Median age of patients was 73 years and 65% were male. Provider assessment of LVAD candidacy was “no” in 443 (85%), “yes” in 35 (7%) and “unsure” in 43 (8%) with ineligibility for LVAD attributed to multiple concerns (Table). Ninety percent of patients considered “too old” for LVAD were over 78 years of age. Provider designation of LVAD candidacy as yes or unsure varied across practice setting: tertiary HF outpatient clinic, 12%; tertiary HF inpatient service, 42%; tertiary general cardiology service, 22%; and community based outpatient cardiac clinic, 13%. In patients with a provider designation of LVAD candidacy as yes or unsure (n=78), only 21 (27%) patients had been referred for LVAD evaluation. Conclusion: When provided with LVAD candidacy criteria, providers indicated 15% of HF patients were (7%) or were possibly (8%) LVAD candidates but indicated that few patients had undergone a formal LVAD evaluation. These data suggest that measures to improve evaluation of HF patients for LVAD are needed.

Leadership education in medicine is evolving to better meet the challenges of health care complexity, interprofessional practice, and threats from viruses and budget cuts alike. In this commentary, the authors build upon the findings of a scoping review by Matsas and colleagues, published in the same issue, and ask us to imagine what a learning ecosystem around leadership might look like. They subsequently engage in their own synthesis of leadership development literature and propose 6 key principles for medical educators and health care leaders to consider when designing leadership development within their educational ecosystems: (1) apply a conceptual framework; (2) scaffold development-oriented approaches; (3) accommodate individual levels of adult development; (4) integrate diversity of perspective; (5) interweave theory, practice, and reflection; and (6) recognize the broad range of leadership conceptualization.

AbstractIntroductionMultiple positron emission tomography (PET) tracers are available for amyloid imaging, posing a significant challenge to consensus interpretation and quantitative analysis. We accordingly developed and validated a deep learning model as a harmonization strategy.MethodA Residual Inception Encoder‐Decoder Neural Network was developed to harmonize images between amyloid PET image pairs made with Pittsburgh Compound‐B and florbetapir tracers. The model was trained using a dataset with 92 subjects with 10‐fold cross validation and its generalizability was further examined using an independent external dataset of 46 subjects.ResultsSignificantly stronger between‐tracer correlations (P < .001) were observed after harmonization for both global amyloid burden indices and voxel‐wise measurements in the training cohort and the external testing cohort.DiscussionWe proposed and validated a novel encoder‐decoder based deep model to harmonize amyloid PET imaging data from different tracers. Further investigation is ongoing to improve the model and apply to additional tracers.

Abstract Differences by sex in lung cancer incidence and mortality have been reported which cannot be fully explained by sex differences in smoking behavior, implying existence of genetic and molecular basis for sex disparity in lung cancer development. However, the information about sex dimorphism in lung cancer risk is quite limited despite the great success in lung cancer association studies. By adopting a stringent two-stage analysis strategy, we performed a genome-wide gene–sex interaction analysis using genotypes from a lung cancer cohort including ~ 47 000 individuals with European ancestry. Three low-frequency variants (minor allele frequency &lt; 0.05), rs17662871 [odds ratio (OR) = 0.71, P = 4.29×10−8); rs79942605 (OR = 2.17, P = 2.81×10−8) and rs208908 (OR = 0.70, P = 4.54×10−8) were identified with different risk effect of lung cancer between men and women. Further expression quantitative trait loci and functional annotation analysis suggested rs208908 affects lung cancer risk through differential regulation of Coxsackie virus and adenovirus receptor gene expression in lung tissues between men and women. Our study is one of the first studies to provide novel insights about the genetic and molecular basis for sex disparity in lung cancer development.

427 Background: Derazantinib, a potent anti- FGFR1-3 oral kinase inhibitor, has shown clinically meaningful anti-tumor activity (21%), durable responses (median, 6.4 months), and progression-free survival (median, 8.0 months) in patients (pts) with FGFR2 fusion (FGFR2F)-positive intrahepatic cholangiocarcinoma (iCCA), and with a manageable toxicity profile. Herein, we report an interim analysis of the clinical efficacy data of derazantinib for pts with iCCA harboring FGFR2 mutations or amplifications (FGFR2M/A), a potential therapeutic option currently not addressed by FGFR inhibitors. Methods: Study FIDES-01 enrolls in a dedicated cohort pts with FGFR2M/A+ advanced iCCA who received previous chemotherapy. Pts receive 300 mg derazantinib daily until disease progression, death or intolerance. The primary endpoint is the proportion of pts alive and free of disease progression at 3 months (PFS3; RECIST 1.1, central imaging review) using a Simon’s two-stage sample-size minimizing statistical design. The interim analysis population comprises 23 pts dosed (intention to treat) who had at least one post-baseline tumor assessment (or clinical progression, or died) by June 3, 2021, using investigator assessments based on RECIST 1.1. Results: To date, 28 pts have been enrolled and dosed. FGFR2M/A observed in these pts included missense point mutations (78%), other short variants (11%) and amplifications (11%). Transition from stage 1 to stage 2 of the study was achieved earlier than planned after 8 (67%) of 12 pts were assessed as PFS3 based on central imaging review. In 23 pts included in this interim analysis for efficacy, the best overall response (investigator assessment) was confirmed partial response in two (8.7%) and stable disease in additional 15 pts (65.2%), resulting in a disease control rate of 73.9% (95% CI, 51.6–89.8). Using Kaplan-Meier analyses, the median PFS was 7.3 months (95%CI, 3.5–16.7) and the probability of being progression-free at 3 months and at 6 months were 76.3% (95%CI, 51.9–89.4) and 50.3% (95%CI, 21.7–73.4), respectively. Clinically meaningful anti-tumor efficacy was observed across all types of genetic aberrations. The safety profile of derazantinib in FGFR2M/A+ iCCA pts was consistent with that previously reported for FGFR2F+ iCCA pts. Conclusions: This interim data in study FIDES-01 suggest that derazantinib treatment provides clinical benefit to pts with advanced iCCA harboring FGFR2M/A who progressed after at least one line of standard chemotherapy. To our knowledge, this is the first report of clinically meaningful anti-tumor efficacy in a prospectively planned cohort of iCCA pts harboring FGFR2M/A. The study is ongoing to accrue 43 patients, assessing derazantinib as a therapeutic option for FGFR2M/A+ iCCA pts after disease progression on first-line treatment. Clinical trial information: NCT03230318.