Citations

BackgroundCXCR4 mediates the retention and survival of acute myelogenous leukemia blasts in bone marrow and contributes to their resistance to chemotherapy. The authors evaluated a combination of the high‐affinity CXCR4 antagonist BL‐8040 with high‐dose cytarabine (HiDAC) chemotherapy in a phase 2a study of patients with relapsed and refractory AML.MethodsForty‐two patients received treatment with BL‐8040 monotherapy for 2 days followed by a combination of BL‐8040 with HiDAC for 5 days. Six escalating BL‐8040 dose levels were investigated (0.5, 0.75, 1.0, 1.25, 1.5, and 2.0 mg/kg), and 1.5 mg/kg was selected as the dose for the expansion phase (n = 23).ResultsBL‐8040 in combination with HiDAC was safe and well tolerated at all dose levels. Clinical response was observed with BL‐8040 doses ≥1.0 mg/kg. The composite response rate (complete remissions plus complete remissions with incomplete hematologic recovery of platelets or neutrophils) was 29% (12 of 42) in all patients and 39% (9 of 23) in the 1.5‐mg/kg phase. The median overall survival was 8.4 months for all patients, 10.8 months in the 1.5‐mg/kg phase, and 21.8 months for responding patients in the 1.5‐mg/kg cohort. Two days of BL‐8040 monotherapy triggered the mobilization of blasts into peripheral blood, with significantly higher mean fold‐changes in responders versus nonresponders. This was accompanied by a decrease in bone marrow blasts.ConclusionsThe current results demonstrate the efficacy of CXCR4 targeting with BL‐8040 and support continued clinical development in acute myelogenous leukemia.

Abstract Background/Introduction Truncating variants in TTN-encoded titin (TTNtvs) underlie ∼25% of familial dilated cardiomyopathy (DCM) cases. In addition, TTNtvs are over-represented in alcoholic, peripartum, and chemotherapy-induced CM suggesting that risk factors may play a substantive role in the penetrance and expressivity of TTN-mediated DCM. Purpose To determine the prevalence and clinical impact of risk factors for TTN-mediated DCM within a single center cohort of unrelated patients with pathogenic (P)/likely pathogenic (LP) TTNtvs. Methods In this retrospective study, an institutionally developed natural language processing algorithm was used to identify all TTNtv-positive patients evaluated clinically between 01/2012 and 12/2019. Each TTNtv was then mapped to the TTN reference sequence (NM_133378.4) and classified according to a strict interpretation of the 2015 American College of Medical Genetics and Genomics (ACMG) guidelines. After exclusion of individuals with complex congenital heart disease, ischemic heart disease, and those without ACMG P/LP TTNtvs, available medical records were reviewed for risk factors such as long-term heavy alcohol consumption (>80 grams/day), cardiotoxic chemotherapy exposure, morbid obesity (body mass index >40), biopsy/imaging-confirmed myocarditis, peripartum/tachycardia-mediated CM, and valvular heart disease. Results Overall, 33 ACMG P/LP TTNtv-positive patients were identified (40% female; mean age at presentation 45±16 years; mean LVEF at presentation 38%±17%). Of note, 17/33 (52%) presented with heart failure (HF) and 4/33 (12%) presented with sustained ventricular arrhythmias (VAs). The remaining 12 (36%) TTNtv-positive patients presented with incidentally detected asymptomatic left ventricular systolic dysfunction (n=9) or as a result of genetic cascade screening (n=3). In comparison to TTNtv-positive patients with non-HF presentations, those with HF had worse left ventricular function (mean LVEF: 26% ± 11% vs 51% ±12%; p<0.001) and were more likely to have ≥1 risk factor [11/17 (65%) vs 4/16 (25%); p=0.04]. Unexpectedly, the 7 TTNtv-positive patients that presented with (n=4) or subsequently developed (n=3) sustained VAs were younger at the time of presentation (34±13 years vs 48±15 years; p=0.04) and displayed a similar degree of left ventricular dysfunction to those without sustained VAs (mean LVEF: 42% ± 17% vs 36% ± 17%; p=ns). Interestingly, the only risk factor over-represented amongst those with sustained VAs was bileaflet mitral valve prolapse [3/7 (43%) vs 0/26 (0%); p=0.006]. Conclusion The majority of TTNtv-positive patients (14/23; 61%) with a history of HF and/or sustained VAs possessed ≥1 acquired risk factor providing further evidence that gene-environment interaction(s) exert a crucial role in the manifestation of TTN-mediated disease. Funding Acknowledgement Type of funding source: None

Abstract Background Heart transplant (HTx) patients can develop graft dysfunction (GD) without biopsy evidence of cell or antibody mediated rejection. Cardiac MRI (CMR) can detect inflammatory or infiltrative causes of cardiomyopathy however CMR findings in HTx recipients with GD have not been previously described. Purpose We sought to identify CMR characteristics of HTx patients with GD, and evaluate its additive value in its diagnosis and prognosis. Methods CMR has been performed routinely to evaluate GD at our institutions. There were 37 HTx recipients who presented with acute decline in left ventricular ejection fraction (LVEF) of <50% and >10% from baseline, with no biopsy evidence of rejection between 2007 and 2018. Coronary angiogram with IVUS was done to rule out allograft vasculopathy. Treatment of GD was per discretion of the treating clinician. Responders were defined as those with LVEF improvement >10% at 180 days or greater post-presentation. LV and RV indices, the presence and pattern of late gadolinium enhancement (LGE) were determined by CMR. Results There were 34% females and mean age at transplant was 49±13 years. Median time from HTx to GD was 1.2 years. Presenting symptoms were heart failure (n=25), cardiogenic shock (n=1) and 11 patients were asymptomatic. Mean LVEF at presentation was 37±12% and donor specific antibodies were detected in 38% patients. Most patients were treated with steroid bolus (n=29), and/or plasmapheresis (n=23). There were no major changes made in immunosuppression in 6 patients. Delayed enhancement MRI was performed with standard inversion-recovery (IR) gradient echo sequences, between 5 and 20 minutes after institutional-standard protocol administration of IV gadolinium contrast. Biventricular LGE was present in 18/37 (49%) patients with GD and was more prevalent in responders (57%, 13 of 23) than non-responders (35%, 5 of 14), although not statistically significant (p=0.21). There were two patterns of LGE noted: 1) Diffuse epicardial (10 patients out which 9 were responders) and 2) Patchy pattern with non-specific distribution (8 patients out of which 4 were responders). Myocardial edema by triple IR sequencing was seen in 6 patients, all having diffuse epicardial pattern of enhancement matching the delayed enhancement pattern. When comparing different treatment groups, among those treated for GD (n=31), 12 of 21 (57%) responders had LGE and 4 of 10 (40%) non-responders had LGE (p=0.37), a pattern similar to the broader population. Among those not treated for GD (n=6), 1 of 2 responders had LGE and 1 of 4 non-responders had LGE (p=0.5). Conclusion CMR identified inflammation as a potential cause of GD in approximately 50% of HTx patients. There are 2 distinct patterns of LGE observed in GD, diffuse epicardial (56%) and patchy (44%). Although the presence of LGE in itself is not associated with myocardial recovery, 90% of patients with a diffuse epicardial pattern have recovery of GD. Funding Acknowledgement Type of funding source: None

Introduction: Stem cell (SC) therapy is a potential method of repairing the heart after injury. However, SCs have been shown to have poor survival after transplantation, at least in part, due to a hostile pro-inflammatory ischemic myocardium. Thus, there is significant interest in the identification of strategies that can increase the retention/survival of SCs after transplantation. Here we seek to investigate whether the use of an immunomodulatory hydrogel, containing anti-inflammatory sinapic acid (SA), promotes the survival of SCs after transplantation. Methods: Myocardial infarction was induced in rats followed by the delayed delivery of A) mesenchymal stem cells (MSCs), B) MSCs in a hydrogel without SA or C) MSCs in a hydrogel containing SA (10μM). Delivery of MSCs (7.5 x 10 5 in 30μL) occurred 7 days after MI, representing the subacute stage and to minimize acute inflammation. Survival of MSCs, stably expressing firefly luciferase under the constitutive CMV promoter, was followed longitudinally using bioluminescence imaging. Results: Panels A-C provide representative images of the viability of MSCs in different groups, with the quantification shown in panel D. There were no differences in survival when MSCs were delivered alone (A) or in a hydrogel without SA (B). However, the survival of MSCs was significantly increased when they were transplanted in a hydrogel with the anti-inflammatory SA (C). Conclusions: Here we provide evidence of the potential for an immunomodulatory hydrogel to enhance the viability of MSCs after infarction, which may lead to improvement of cardiac function. Furthermore, use of this hydrogel in combination with stem cells could be a potential therapeutic strategy for ameliorating cardiac repair after significant damage.

This prospective case series compared the accuracy of ultrasound (US) to magnetic resonance imaging (MRI) in differentiating complete displaced (CD) thumb ulnar collateral ligament (UCL) tears from nondisplaced injuries in 10 patients with suspected traumatic thumb UCL injuries. Ultrasound identified 100% (2 of 2) of MRI‐documented CD tears, both of which were further confirmed during surgical repair. Ultrasound identified the absence of CD tears in the remaining 8 patients. Although MRI is the reference standard imaging modality for characterizing thumb UCL injuries, ultrasound should be considered an accurate, cost‐effective, and alternative imaging modality to differentiate surgical versus nonsurgical thumb UCL injuries.

ABSTRACT Background An unmet clinical need in Parkinson's disease (PD) is to identify biomarkers for diagnosis, preferably in peripherally accessible tissues such as skin. Immunohistochemical studies have detected pathological α‐synuclein (αSyn) in skin biopsies from PD patients albeit sensitivity needs to be improved. Objective Our study provides the ultrasensitive detection of pathological αSyn present in the skin of PD patients, and thus, pathological αSyn in skin could be a potential biomarker for PD. Methods The real‐time quaking‐induced conversion assay was used to detect pathological αSyn present in human skin tissues. Further, we optimized this ultra‐sensitive and specific assay for both frozen and formalin‐fixed paraffin‐embedded sections of skin tissues. We determined the seeding kinetics of the αSyn present in the skin from autopsied subjects consisting of frozen skin tissues from 25 PD and 25 controls and formalin‐fixed paraffin‐embedded skin sections from 12 PD and 12 controls. Results In a blinded study of skin tissues from autopsied subjects, we correctly identified 24/25 PD and 24/25 controls using frozen skin tissues (96% sensitivity and 96% specificity) compared to 9/12 PD and 10/12 controls using formalin‐fixed paraffin‐embedded skin sections (75% sensitivity and 83% specificity). Conclusions Our blinded study results clearly demonstrate the feasibility of using skin tissues for clinical diagnosis of PD by detecting pathological αSyn. Moreover, this peripheral biomarker discovery study may have broader translational value in detecting misfolded proteins in skin samples as a longitudinal progression marker. © 2020 International Parkinson and Movement Disorder Society

AbstractIdiopathic multicentric Castleman disease (iMCD) is a rare immunologic disorder characterized by systemic inflammation, multicentric lymphadenopathy, and organ dysfunction. Enlarged lymph nodes demonstrate a spectrum of characteristic but variable histopathologic features historically categorized into hyaline vascular (HV) (or hypervascular [HyperV] more recently), plasmacytic, or “mixed.” Though the etiology is unknown, a pro‐inflammatory cytokine storm, often involving interleukin‐6 (IL‐6), contributes to pathogenesis. Anti‐IL‐6 therapy with siltuximab is the only FDA‐ or EMA‐approved treatment based on efficacy and safety in multiple studies. Importantly, no patients considered to have HV histopathology achieved the primary endpoint in the Phase II study. NCCN currently recommends siltuximab first‐line for iMCD, except for patients considered to have HV histopathology. We investigated whether histopathologic subtype should guide siltuximab treatment decisions. Secondary analyses of clinical trial and real‐world data revealed similar clinical benefit across histopathologic subtypes. Notably, only 18 of 79 patients in the Phase II study were consistently classified into histopathologic subtype by three independent review panels, demonstrating limited reliability to guide treatment decisions. Real‐world data further demonstrate siltuximab's effectiveness in patients considered to have HV (or HyperV). Though histopathology is a critical component for diagnosis, there is insufficient evidence to guide treatment based solely on lymph node histopathologic subtype.

Introduction: A number of clinical and radiological predictors of either stone impaction or ureteral stone passage (SP) have been proposed. We aimed at identifying the key predictors of successful SP by using readily available CT-based tools/measurements. Methods: Patients presenting to the emergency department from February 2017 to February 2018 with an acute unilateral ureteral stone confirmed on non-contrast CT and managed conservatively were followed for SP. Patients with renal impairment, sepsis or requiring emergent intervention were excluded. Patients were followed at 1 month to confirm SP (stone collection/repeat imaging) or failure of passage. The CT variables analyzed included: Stone factors [location, size, volume, HU density (HUD)], impaction factors [ureteral HUD above and below the stone, maximal ureteral wall thickness (UWT) at the stone site, contralateral UWT, and ureteral diameter above and below the stone]. Binary logistic regression analysis was performed to identify predictors of SP. Results: Forty-nine patients met study inclusion criteria, of whom 32 (65.3%) passed the stone without further intervention. Patients with successful passage were more likely to have smaller, lower volume and less dense stones located in the distal ureter ( p < 0.01). Lower ureteral HUD below the stone, lower maximal UWT, and lower ureteral diameter above the stone were associated with successful passage ( p < 0.01). On multivariable logistic regression analysis, only maximal UWT at the stone site was a significant independent predictor of SP outcome ( p = 0.01). Youden's criterion identified 2.3 mm as the optimal UWT cut-off point, which will accurately predict SP with 82.4% sensitivity and 87.5% specificity. Conclusions: Maximal UWT at the stone site was the most significant predictor of successful passage in acute unilateral ureteral stones, with an optimal cut-off point of 2.3 mm. Further prospective studies are needed to accurately predict spontaneous SP.