Citations

AbstractThe active involvement of citizen scientists in setting research agendas, partnering with academic investigators to conduct research, analyzing and disseminating results, and implementing learnings from research can improve both processes and outcomes. Adopting a citizen science approach to the practice of precision medicine in clinical care and research will require healthcare providers, researchers, and institutions to address a number of technical, organizational, and citizen scientist collaboration issues. Some changes can be made with relative ease, while others will necessitate cultural shifts, redistribution of power, recommitment to shared goals, and improved communication. This perspective, based on a workshop held at the 2018 AMIA Annual Symposium, identifies current barriers and needed changes to facilitate broad adoption of a citizen science-based approach in healthcare.

Background and Aims Interleukin‐22 has beneficial effects on inflammation and impaired hepatic regeneration that characterize alcohol‐associated hepatitis (AH). F‐652 is a recombinant fusion protein of human interleukin‐22 and immunoglobulin G2 fragment crystallizable. This study aims to assess the safety and efficacy signals of F‐652 in patients with moderate and severe AH. Approach and Results A phase‐2 dose‐escalating study was carried out. F‐652 (10 μg/kg, 30 μg/kg, or 45 μg/kg) administered on days 1 and 7 was tested in 3 patients each with moderate (Model for End‐Stage Liver Disease [MELD] scores: 11‐20) and severe AH (MELD scores: 21‐28). Safety was defined by absence of serious adverse events and efficacy was assessed by Lille score, changes in MELD score, and serum bilirubin and aminotransferases at days 28 and 42. Three independent propensity‐matched comparator patient cohorts were used. Plasma extracellular vesicles and multiplex serum cytokines were measured to assess inflammation and hepatic regeneration. Eighteen patients (9 moderate and 9 severe AH) were enrolled, 66% were male, and the mean age was 48 years. The half‐life of F‐652 following the first dose was 61‐85 hours. There were no serious adverse events leading to discontinuation. The MELD score and serum aminotransferases decreased significantly at days 28 and 42 from baseline (P < 0.05). Day‐7 Lille score was 0.45 or less in 83% patients as compared with 6%, 12%, and 56% among the comparator cohorts. Extracellular vesicle counts decreased significantly at day 28 (P < 0.013). Cytokine inflammatory markers were down‐regulated, and regeneration markers were up‐regulated at days 28 and 42. Conclusions F‐652 is safe in doses up to 45 μg/kg and associated with a high rate of improvement as determined by Lille and MELD scores, reductions in markers of inflammation and increases in markers of hepatic regeneration. This study supports the need for randomized placebo‐controlled trials to test the efficacy of F‐652 in AH.

Objective: Takotsubo syndrome (TTS) is characterized by acute left ventricular dysfunction, which can contribute to intraventricular thrombus and embolism. Still, prevalence and clinical impact of thrombus formation and embolic events on outcome of TTS patients remain unclear. This study aimed to investigate clinical features and outcomes of patients with and without intraventricular thrombus or embolism. Additionally, factors associated with thrombus formation or embolism, as well as predictors for mortality, were identified. Approach and Results: TTS patients enrolled in the International Takotsubo Registry at 28 centers in Australia, Europe, and the United States were dichotomized according to the occurrence/absence of intraventricular thrombus or embolism. Patients with intraventricular thrombus or embolism were defined as the ThrombEmb group. Of 1676 TTS patients, 56 (3.3%) patients developed intraventricular thrombus and/or embolism following TTS diagnosis (median time interval, 2.0 days [range, 0–38 days]). Patients in the ThrombEmb group had a different clinical profile including lower left ventricular ejection fraction, higher prevalence of the apical type, elevated levels of troponin and inflammatory markers, and higher prevalence of vascular disease. In a Firth bias-reduced penalized-likelihood logistic regression model apical type, left ventricular ejection fraction ≤30%, previous vascular disease, and a white blood cell count on admission >10×10 3 cells/μL emerged as independent predictors for thrombus formation or embolism. Conclusions: Intraventricular thrombus or embolism occur in 3.3% of patients in the acute phase of TTS. A simple risk score including clinical parameters associated with intraventricular thrombus formation or embolism identifies patients at increased risk. Clinical Trial Registration: URL: http://www.clinicaltrials.gov . Unique identifier: NCT01947621.

Abstract Background: Novel therapies are required to improve the outcome of patients with AML. New agents are asked to demonstrate an overall survival (OS) benefit before qualifying for FDA approval. The long duration of clinical trials required in order to achieve this endpoint hampers quick evaluation of candidate therapies, including novel agents. Identification of reliable surrogate endpoints for OS in AML is needed. Here we compare the results of therapy for patients with untreated AML ages 16-60 years on the Eastern Cooperative Oncology Group 1900 trial (E1900) of induction chemotherapy followed by consolidation and autologous transplant in order to evaluate the validity of an event free survival (EFS) endpoint as a surrogate for OS. Methods:OS was measured from randomization for induction therapy to death from any cause (censored at last contact). EFS was measured from randomization to induction treatment failure, relapse after compete response (CR), or death in remission (censored at last contact). Hazard ratios (HR) were computed using Cox proportional hazards models. The association between EFS and OS was evaluated using the Kendall tau-a rank correlation for censored data. Results:There were657 patients enrolled of which 426 patients relapsed or had induction treatment failure before death or date of last contact. Median EFS and OS were 8.0 months (95% CI, 6.3 to 9.7 months) and 23.6 months (95% CI, 16.9 to 23.6 months), respectively. With a median follow-up of 80.1 months, there is a statistically significant correlation between EFS and OS (Kendall tau-a = 0.467, 95% confidence interval (CI) = (0.425, 0.510), p<0.001). This correlation was similarly significant at a median follow-up of 25.2 months (Kendall tau-a = 0.361, 95% CI (0.323, 0.400), p <0.001) when the E1900 trial was originally reported (Fernandez et al. NEJM 2009). Key findings reported based on the original OS endpoint are similar when analyzed with an EFS endpoint (Table 1). High-dose daunorubicin (90 mg/m2) (DNR 90) confers both an EFS and OS benefit in patients aged < 50 years and patients with intermediate cytogenetic risk, and does not confer an EFS or OS benefit in older patients and patients with unfavorable cytogenetic risk, on univariate analysis. Divergent results are only seen in the small subset of favorable cytogenetic risk patients, where DNR 90 conferred an OS benefit (p=0.027) without an EFS benefit (p=0.32). Both EFS and OS endpoints consistently reflect the impact of mutation status on survival. The presence of a FLT3-ITD or DNMT3A mutation has a negative impact on both EFS and OS while an IDH2 mutation has a favorable impact on EFS and OS. The presence of a NPM1 mutation confers a favorable impact on EFS and OS in patients who received DNR 90 and did not impact EFS or OS in patients receiving standard-dose daunorubicin (45 mg/m2) (DNR 45). The presence of an IDH1 mutation does not impact EFS or OS. Conclusions:The results of E1900 demonstrating superiority of DNR 90 in AML induction in patients up to age 60 are concordant when using an EFS or OS endpoint. This is true for the group as a whole as well as for subgroups for which targeted agents are in development (FLT3/IDH2 inhibitors). Further investigation of whether EFS is a reliable surrogate for OS is warranted in AML. If confirmed, its use as a primary endpoint could be adopted by regulatory agencies in order to allow more rapid completion of clinical trials in AML and bring new therapies to AML patients in a timely fashion. Table 1. Results of E1900 based on an EFS endpoint versus an OS endpoint. Subgroup N OS HR (DNR 90/DNR 45) & 95% CI Wald P EFS HR (DNR 90/DNR 45) & 95% CI Wald P DNR 45 DNR 90 Age < 50 yrs ³ 50 yrs 188 142 172 155 0.66 (0.50, 0.85) 0.81 (0.62, 1.06) 0.002 0.118 0.64 (0.50, 0.82) 0.86 (0.67, 1.10) 0.0004 0.23 Cytogenetic Favorable Intermediate Unfavorable 38 141 59 51 127 63 0.51 (0.28, 0.93) 0.68 (0.50, 0.92) 0.79 (0.54, 1.16) 0.027 0.012 0.225 0.76 (0.44, 1.31) 0.63 (0.47, 0.83) 0.72 (0.49, 1.05) 0.32 0.001 0.09 Subgroup N OS HR (MUT/WT) & 95% CI Wald P EFS HR (MUT/WT) & 95% CI Wald P FLT3-ITD WT MUT 456 147 1.62 (1.31, 2.01) <.0001 1.48 (1.21, 1.82) 0.0002 DNMT3A WT MUT 371 119 1.30 (1.03, 1.65) 0.03 1.23 (0.98, 1.54) 0.07 IDH1 WT MUT 465 36 0.88 (0.59, 1.33) 0.55 0.91 (0.62, 1.34) 0.64 IDH2 WT MUT 451 50 0.63 (0.43, 0.93) 0.02 0.68 (0.48, 0.97) 0.03 NPM1 DNR 45 DNR 90 245 257 0.84 (0.61, 1.16) 0.60 (0.41, 0.89) 0.30 0.01 0.90 (0.66, 1.22) 0.59 (0.41, 0.84) 0.49 0.004 Disclosures No relevant conflicts of interest to declare.

Abstract Glioblastoma (GBM) is the most aggressive of all the brain tumors with a median patient survival less than 15 months. Despite of surgical resection, radiotherapy, and chemotherapy, recurrence rate is almost 100%. A great percentage of GBM tumors (~60%) infiltrate and contact the ventricular-subventricular zone (V-SVZ). Interestingly, these tumors are the most aggressive, and invariably lead to higher distal recurrence rates, shorter time to tumor progression, and lower overall survival of the patient. The reason for this role of V-SVZ-proximity on the outcome of GBM patients is unknown. We suggest that a potential explanation is the interaction of GBM with the V-SVZ. This region is the largest neurogenic niche in the adult brain where neural stem cells (NSCs) give rise to newborn neuroblasts that migrate toward the olfactory bulb. In GBM there is a cell subpopulation called brain tumor stem cells (BTSCs) with NSCs-like characteristics, but with added potential for tumor initiation, recurrence and invasiveness. Tumor microenvironment plays an important role in migration and invasion process. In the present work, we used the total exosome isolation kit to purify Extracellular Vesicles (EVs) from human primary cultures of BTSCs. We determined that BTSCs-derived EVs contain specific information that is transfer to primary cultures of human Neural Progenitors Cells (NPCs) modulating their proliferation rate, cell viability, and migration. In addition, we identify that NPCs taken up BTSCs-derived EVs and significantly increase the expression levels of stemness-related genes such as Nestin, Nanog, and Sox2, suggesting that a phenotypic transdifferentiation is being carry out. These results support our hypothesis that GBM modulate the tumor microenvironment close to the V-SVZ by releasing EVs that target cellular components in this region and promote their phenotypic transformation, highlighting that NPCs biology changes in the context of tumor environment.

Abstract OBJECTIVE Our goal is to identify new pathways perturbed in and which may lead to GRS. METHODS We collected brain transcriptome levels from healthy controls (n=5), patients with GRS (n=9), glioma without seizures (non-GRS, n=8), and idiopathic temporal lobe epilepsy (iTLE, n=7) using Illumina-based poly-A capture high-throughput RNA sequencing approach. Differential gene expression analysis was conducted to ascertain expression differences between the four groups. We identified molecular pathways enriched for differentially expressed genes (DEG) using Ingenuity Pathway Analysis. DEGs were defined as those with log2 fold change ≥ 2 and q-value < 0.01 when compared to GRS. RESULTS Principal component analysis revealed that diagnostic grouping was the main determinant of the transcriptome variance. We identified 212 DEGs in the GRS vs. non-GRS analysis. Among these, 108 genes were up-regulated and 104 genes were down-regulated. Among the genes that were down‐regulated, there was significant enrichment for those involved in acute phase response signaling and immune cell trafficking (e.g. H19, BMP5, CXCL8). Compared to iTLE samples, there were 1015 DEGs in the GRS samples. Among these 877 genes were up-regulated and 138 genes were down-regulated. There was significant enrichment for genes involved in cell-to-cell signaling among those that were either uniquely up‐regulated (e.g. NRK, RGS10, SLC4A4, and SELPLG) or down‐regulated in the GRS samples (e.g. SLC9A3 –Na+/H+ exchanger; SLC5A5-sodium-glucose co-transporter family). Further, two of the most down-regulated genes in samples with GRS, SCLC17A6- vesicular glutamate transporter 2 and FOSB, have previously been shown to be involved in glutamatergic transmission. CONCLUSIONS Our findings suggest that inflammation-related processes and alterations in cell-to cell signaling may underlie the pathogenesis of GRS. Our results also provide support for perturbations in glutamatergic transmission in GRS. Our findings require replication in larger human cohorts and functional experiments to explore the function of the genes perturbed in GRS.

Background Left ventricular ( LV ) recovery in takotsubo syndrome ( TTS ) occurs over a wide‐ranging interval, varying from hours to weeks. We sought to investigate the clinical predictors and prognostic impact of recovery time for TTS patients. Methods and Results TTS patients from the International Takotsubo Registry were included in this study. Cut‐off for early LV recovery was determined to be 10 days after the acute event. Multivariable logistic regression was used to assess factors associated with the absence of early recovery. In‐hospital outcomes and 1‐year mortality were compared for patients with versus without early recovery. We analyzed 406 patients with comprehensive and serial imaging data regarding time to recovery. Of these, 191 (47.0%) had early LV recovery and 215 (53.0%) demonstrated late LV improvement. Patients without early recovery were more often male (12.6% versus 5.2%; P =0.011) and presented more frequently with typical TTS (76.3% versus 67.0%, P =0.040). Cardiac and inflammatory markers were higher in patients without early recovery than in those with early recovery. Patients without early recovery showed unfavorable 1‐year outcome compared with patients with early recovery ( P =0.003). On multiple logistic regression, male sex, LV ejection fraction <45%, and acute neurologic disorders were associated with the absence of early recovery. Conclusions TTS patients without early LV recovery have different clinical characteristics and less favorable 1‐year outcome compared with patients with early recovery. The factors associated with the absence of early recovery included male sex, reduced LV ejection fraction, and acute neurologic events. Clinical Trial Registration URL : http://www.clinicaltrials.gov . Unique identifier: NCT 01947621.

Purpose The primary aim was to examine the utility of the Western Aphasia Battery–Revised (WAB-R; Kertesz, 2007 ) for classifying variants of primary progressive aphasia (PPA). Traditional WAB-R metrics of Aphasia Quotient (AQ), subtest scores, WAB-R classification, and several novel metrics were examined. A secondary aim was to examine these same WAB-R metrics in individuals with primary progressive apraxia of speech (PPAOS). Method A retrospective analysis of WAB-R records from 169 participants enrolled in a study of neurodegenerative speech and language disorders was conducted. PPA/PPAOS classification was determined by consensus review of speech, language, and cognitive profiles. Scores on each of the WAB-R subtests were obtained to derive AQ, WAB-R aphasia profile, and 3 ratios reflecting relative performance on subtests. Results Mean AQ was significantly higher in the PPAOS group compared to all PPA variants except primary fluent aphasia. AQ above the normal cutoff was observed for 20% of participants with PPA. Significant main effects of group were noted for each of the subtests. Follow-up comparisons most frequently discriminated PPAOS, primary agrammatic aphasia (PAA), and logopenic progressive aphasia. Primary fluent aphasia and semantic dementia (SD) subtest scores were less distinctive, with the exception of Naming for SD, which was significantly lower than for PAA and PPAOS. When the WAB-R AQ detected aphasia, a classification of anomic aphasia was most frequently observed; this pattern held true for each of the PPA variants. The mean Information Content:Naming ratio was highest for SD, and the mean Comprehension:Fluency ratio was highest for PAA. Conclusions In the current study, AQ underestimated the presence of PPA and WAB-R classification did not distinguish among PPA classification determined by consensus. Performance on individual subtests and relative performance across subtests demonstrated inconsistent alignment with PPA classification. We conclude the WAB-R in isolation is inadequate to detect or characterize PPA. We instead suggest utilizing the WAB-R as 1 component of a comprehensive language and motor speech assessment when PPA is suspected.