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The perturbations in bile acids (BAs) in alcohol‐associated hepatitis (AH) and its relationship to disease severity is not well defined. The aims of this study were to define (1) the effects of heavy alcohol consumption on BAs and related microbiome, (2) the additional changes with AH, and (3) the relationship of these changes to disease severity. In this multicenter study, plasma and fecal BAs and related microbiome were interrogated in healthy individuals, heavy drinking controls (HDCs) without overt liver disease, and AH. Compared to healthy controls, HDCs had increased glycine‐conjugated 7α and 27α primary BAs and increased secondary BA glycocholenic sulfate (multiple‐comparison adjusted P < 0.05 for all). Plasma‐conjugated cholic and chenodeoxycholic acid increased in AH along with the secondary BAs ursodeoxycholic and lithocholic acid (P < 0.001 for all), whereas deoxycholic acid decreased; however fecal concentrations of both deoxycholic acid and lithocholic acid were decreased. Glycocholenic acid further increased significantly from HDCs to AH. HDCs and AH had distinct plasma and fecal BA profiles (area under the curve, 0.99 and 0.93, respectively). Plasma taurochenodeoxycholic acid and tauroursodeoxycholic acid were directly related to disease severity, whereas fecal ursodeoxycholic acid was inversely related. The fecal abundance of multiple taxa involved in formation of secondary BAs, especially deoxycholic acid (Clostridium cluster XIVa) was decreased in AH. Multiple genera containing taxa expressing 3α, 3β, 7α, and 7β epimerases were decreased with concordant changes in fecal BAs that required these functions for formation. Conclusion: There are distinct changes in BA‐transforming microbiota and corresponding BAs in AH that are related to disease severity.

AbstractGilteritinib is approved for the treatment of relapsed/refractory (R/R) acute myeloid leukemia (AML) with an FLT3‐mutation (FLT3mut+). However, the gilteritinib phase 3 ADMIRAL study (Perl et al NEJM 2019) was conducted prior to widespread adoption of either midostaurin as a component of standard intensive induction and consolidation or posttransplant FLT3 inhibitor maintenance. We performed a retrospective analysis using data from 11 US centers and where we identified 113 patients who received gilteritinib alone or as combination therapy for the treatment of R/R FLT3mut+ AML. The composite complete remission (CR) rate (CRc, defined as CR + CRi + CR with incomplete platelet recovery [CRp]) was 48.7% (n = 55). The CRc rate after treatment with gilteritinib in patients who were treated with only prior 7+3 and midostaurin with or without consolidation was 58% with a median survival of 7.8 months. Survival was longest in patients who obtained a CR, particularly a cMRD (clinical minimal or measurable residual disease) negative response; this remained significant after censoring at the time of stem cell transplant. The mitogen‐activated protein kinase pathway activating mutations that are known for gilteritinib resistance (NRAS, KRAS, and PTPN11) had lower CRc (35% vs. 60.5%) and lower median overall survival than patients' whose leukemia did not express these mutations (4.9 months vs. 7.8 months) (HR 2.4; 95% CI 1. 5.4) p value <.01.

Abstract Background Combination irinotecan and cetuximab is approved for irinotecan-refractory metastatic colorectal cancer (mCRC). It is unknown if adding bevacizumab improves outcomes. Patients and Methods In this multicenter, randomized, double-blind, placebo-controlled phase II trial, patients with irinotecan-refractory RAS-wildtype mCRC and no prior anti-EGFR therapy were randomized to cetuximab 500 mg/m2, bevacizumab 5 mg/kg, and irinotecan 180 mg/m2 (or previously tolerated dose) (CBI) versus cetuximab, irinotecan, and placebo (CI) every 2 weeks until disease progression or intolerable toxicity. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), objective response rate (ORR), and adverse events (AEs). Results The study closed early after the accrual of 36 out of a planned 120 patients due to changes in funding. Nineteen patients were randomized to CBI and 17 to CI. Baseline characteristics were similar between arms. Median PFS was 9.7 versus 5.5 months for CBI and CI, respectively (1-sided log-rank P = .38; adjusted hazard ratio [HR] = 0.64; 95% confidence interval [CI], 0.25-1.66). Median OS was 19.7 versus 10.2 months for CBI and CI (1-sided log-rank P = .02; adjusted HR = 0.41; 95% CI, 0.15-1.09). ORR was 36.8% for CBI versus 11.8% for CI (P = .13). Grade 3 or higher AEs occurred in 47% of patients receiving CBI versus 35% for CI (P = .46). Conclusion In this prematurely discontinued trial, there was no significant difference in the primary endpoint of PFS between CBI and CI. There was a statistically significant improvement in OS in favor of CBI compared with CI. Further investigation of CBI for the treatment of irinotecan-refractory mCRC is warranted. Clinical Trial Registration: NCT02292758

AbstractBackgroundIn preparation for treatment trials in frontotemporal dementia (FTD), sensitive assessments to detect early clinical deficits and track longitudinal changes are needed. Remote digital data collection using smartphones may improve sensitivity to detect and follow abnormalities by allowing novel methods of data capture and more frequent assessments. Furthermore, remote evaluations can reduce patient and staff burden. Despite these benefits, little is known about the reliability and validity of self‐administered cognitive testing completed on smartphones.MethodWe investigated self‐administered smartphone cognitive tests from the ALLFTD Mobile App in a mixed sample of 45 participants, including 10 functionally intact older adults, 24 participants from families harboring pathogenic FTD mutations (asymptomatic n=14; mildly symptomatic n=10;), and 11 symptomatic FTD‐spectrum participants. A subset (n=15) was missing CDR®+NACC‐FTLD data but consensus diagnoses were available. Participants were asked to complete five tests that were repeated three times over eight days. Tests included versions of N‐back, Stroop, Flanker, and Go/No‐Go paradigms, and an adaptive spatial working memory test. Reliability was assessed using split‐half reliability (first testing session, 100 simulations) and intraclass correlations (ICC) across the three testing sessions. Linear models were fitted to evaluate the association of test performance with age and disease severity (CDR®+NACC‐FTLD Global and Box Scores), covarying for sex and education level. Models evaluating age associations excluded symptomatic participants.ResultParticipants completed 72.4% of available instruments. Split‐half reliability (range: 0.76 to 0.97) and ICCs (0.70 to 0.92) suggested adequate‐to‐excellent internal consistency and test‐retest reliability. Across the five tests, negative associations were observed with CDR®+NACC‐FTLD Box Scores (ßs = ‐0.24 to ‐0.77), and in clinically asymptomatic individuals, negative associations were observed with age (ßs = ‐0.43 to ‐0.88). Performance on all measures was worse in symptomatic participants compared to asymptomatic (p‐values<.05). Mildly symptomatic cases (CDR®+NACC‐FTLD=0.5) performed worse on Stroop, Flanker, and spatial working memory than asymptomatic participants (p‐values<.03). Flanker and Stroop tasks consistently showed the strongest reliability and validity findings.ConclusionSmartphone adaptations of common neuropsychological tests produced promising preliminary results. Strong associations with disease severity and age suggest these metrics may be valid for detecting clinically relevant cognitive changes, even in mildly symptomatic FTD.

AbstractBackgroundAt present, no research criteria exist for the diagnosis of prodromal behavioral variant frontotemporal dementia (bvFTD). Leveraging data from carriers of pathogenic genetic mutations as a proxy for frontotemporal lobar degeneration pathology, we sought to develop and test a proposed set of research criteria for prodromal bvFTD, termed “Mild Behavioral and/or Cognitive Impairment in bvFTD” (MBCI‐FTD).MethodParticipants included 68 carriers of a pathogenic mutation in microtubule‐associated protein tau (MAPT), or progranulin (GRN), or a repeat expansion in chromosome 9 open reading frame 72 (C9orf72), with mild behavioral and/or cognitive changes. Based on extensive clinical workup, the prodromal mutation carrier group was divided into a Development Group (N=22) and a Test Group (N=46). The Development Group was selected to be the subset of the prodromal mutation carriers for whom we had longitudinal evidence of conversion to a bvFTD phenotype, and were used to develop the criteria. The Test Group was the remainder of the prodromal mutation carriers (e.g., single visits only) and was used to validate the criteria. Familial non‐carriers were included as controls (N=165).ResultFrequencies of behavioral and neuropsychiatric features, neuropsychological deficits, and social cognitive dysfunction in prodromal mutation carriers and non‐carrier controls were assessed. Based on sensitivity and specificity analyses, seven core features were identified: apathy without moderate‐severe dysphoria, behavioral disinhibition, irritability/agitation, reduced empathy/sympathy, repetitive behaviors (simple and/or complex), joviality/gregariousness, and appetite changes/hyperorality. Supportive features include a neuropsychological profile of impaired executive function or naming with intact orientation and visuospatial skills, reduced insight for cognitive or behavioral changes, and poor social cognition. Three core features or two core features plus one supportive feature are required for the diagnosis of Possible MBCI‐FTD; Probable MBCI‐FTD requires imaging or biomarker evidence, or a pathogenic genetic mutation. The proposed MBCI‐FTD criteria correctly classified 95% of the Development Group of prodromal mutation carriers, and 41% of the Test Group, with a false positive rate of <10%.ConclusionWe present the first diagnostic criteria for prodromal bvFTD. Future research should prioritize establishing generalizability to non‐genetic cases, and testing the specificity of these criteria against psychiatric, neurologic and other neurodegenerative diseases.

BACKGROUND: Minimally invasive surgical techniques have reinvigorated the role of surgical options for spontaneous intracranial hematomas; however, they are limited by the lack of real-time feedback on the extent of hematoma evacuation. OBJECTIVE: To describe the development of a MRI-guided catheter-based aspiration system, the ClearPoint Pursuit Neuroaspiration Device (ClearPoint Neuro) and validation in phantom models. METHODS: In this preclinical experimental trial, 8 phantom brains with skull models were created to simulate an intracranial hematoma with 2 clot sizes, 30 cc (small clot) and 60 cc (large clot). After registration, the aspiration catheter (Pursuit device) was aligned to the desired planned trajectory. The aspiration of the clot was performed under real-time MRI scan in 3 orthogonal views. The primary end point was reduction of the clot volume to less than 15 cc or 70% of the original clot volume. RESULTS: Successful completion of clot evacuation was achieved in all models. The average postaspiration clot volume was 9.5 cc (8.7 cc for small clots and 10.2 cc for large clots). The average percentage reduction of clot volume was 76.3% (range 58.7%-85.2%). The average total procedure time (from frame registration to final postaspiration clot assessment) was 50 min. The average aspiration time was 6.9 min. CONCLUSION: This preclinical trial confirms the feasibility and efficacy of MRI-guided aspiration under real-time image guidance in simulation models for intracranial hematoma. Clinical use of the system in patients would further validate its efficacy and safety.