Citations

Abstract To elucidate the molecular basis of multiple system atrophy (MSA), a neurodegenerative disease, we conducted a genome-wide association study (GWAS) in a Japanese MSA case/control series followed by replication studies in Japanese, Korean, Chinese, European, and North American samples. In the GWAS stage, rs2303744 on chromosome 19 showed a suggestive association (P = 6.5 × 10− 7) that was replicated in additional Japanese samples (P = 2.9 × 10− 6, odds ratio (OR) = 1.58; 95% confidence interval (CI), 1.30–1.91), and then confirmed as highly significant in a meta-analysis of East Asian population data (P = 5.0 × 10− 15, OR = 1.49; 95% CI 1.35–1.65). The association of rs2303744 with MSA remained significant in combined European/North American samples (P = 0.017, OR = 1.12; 95% CI 1.02–1.23) despite allele frequencies being quite different between these populations. rs2303744 leads to an amino acid substitution in PLA2G4C that encodes the cPLA2γ lysophospholipase/transacylase. The cPLA2γ-Ile143 isoform encoded by the MSA risk allele has significantly decreased transacylase activity compared with the alternate cPLA2γ-Val143 isoform, and may perturb membrane phospholipids and promote oligodendroglial pathology.

Abstract Background: Outcomes of adults with relapsed/refractory T-cell acute lymphoblastic leukemia or lymphoma (T-ALL or T-LBL respectively) and acute myeloid leukemia (AML) have remained poor despite the availability of newer agents. CD38 is a 45 kDa transmembrane glycoprotein expressed by lymphoid and myeloid cells with several important functions including a role in immune escape from tumor cells [Chillemi A et al. Front Immunol 2017, Furano A et al. J Immunol 1990]. Several studies have demonstrated that CD38 is expressed in tumor cells of patients with T-ALL and AML and potentially targetable using CD38 blocking agents [Naik J et al. Haematologica 2019, Bride KL et al. Blood 2018, Tembhare et al. J Immunother Cancer 2020, Farber M et al. ASH 2018]. XmAb18968 is structurally distinct CD3-CD38 bi-specific T-cell engager with a full fragment crystallizable (Fc) domain modified to minimize Fcγ receptor binding and non-selective activation of T cells and other immune effector cells. XmAb18968 has optimized relative affinities for both CD3 and CD38 which results in reduced cytokine release without compromising target cell killing. We hypothesize targeting CD38 in relapsed/refractory- T-cell ALL/LBL and AML is safe and feasible using XmAb18968, a novel CD3-CD38 bispecific antibody. Study design and methods: This is an investigator-sponsored multi-institutional phase I study evaluating the safety and tolerability of XmAb18968. Patients aged 18 years or above with T-ALL, T-LBL or AML (including undifferentiated leukemia and bi phenotypic leukemia), in relapsed/refractory status (at least one line of prior therapy) including measurable residual disease relapse, CD38 expression ≥ 20%, and adequate organ function will be eligible. Major exclusion criteria are hematopoietic cell transplantation (HCT) within 6 months of enrollment, active acute GVHD, veno-occlusive disease, and acute promyelocytic leukemia. The study is planned to be conducted at 6 sites in United States. The primary endpoint is to determine the recommended phase 2 dose (RP2D) and toxicity profile of XmAb18968. The secondary endpoints include determination of response rates, duration of response, survival and pharmacokinetics. Exploratory endpoints include correlation of responses with genomic profile, assessment of serum cytokine response, identifying the changes in phenotypic expression of activated T-cells and leukemic cells, correlation of the phenotypic expression with changes in the transcriptome at the single-cell level, proteomics evaluation of cytokine secretion at the single-cell level and correlation of response with N-glycan profiling, quantitative site-occupancy and direct glycopeptide analysis. The study will follow 3+3 design for dose escalation and de-escalation in case of dose limiting toxicity (DLT). Dose escalation will proceed in two separate groups: Group A for subjects with T-ALL and T-LBL and Group B for subjects with AML. Patients will be entered sequentially to each dose level, starting with the first dose level. The DLT observation period for dose-escalation will be 28-days. RP2D will be defined as the highest dose level at which none of the first 3 treated subjects, or no more than 1 of the first 6 treated subjects experience a DLT. A minimum of 24 and a maximum of 60 patients will be needed for the dose escalation phase. Disclosures Guru Murthy: Curio Sciences: Honoraria; Techspert: Consultancy; Qessential: Honoraria; CancerExpertNow: Honoraria; DAVA Oncology: Honoraria; TG Therapeutics: Other: Advisory board meeting; Cardinal health: Honoraria; Guidepoint: Consultancy. Johnson: Miltenyi Biotec: Research Funding. Abedin: AltruBio: Research Funding; Amgen: Honoraria; Agios: Honoraria; Helsinn: Research Funding; Pfizer: Research Funding; Astellas Pharma Inc.: Research Funding; Actinium: Research Funding. Stock: Pfizer: Consultancy, Honoraria, Research Funding; amgen: Honoraria; agios: Honoraria; jazz: Honoraria; kura: Honoraria; kite: Honoraria; morphosys: Honoraria; servier: Honoraria; syndax: Consultancy, Honoraria; Pluristeem: Consultancy, Honoraria. Shah: Precision Biosciences: Consultancy; Kite, a Gilead Company: Consultancy, Honoraria, Other: Expenses, Research Funding; Pharmacyclics/Janssen: Honoraria, Other: Expenses; Acrotech/Spectrum: Honoraria; BeiGene: Consultancy, Honoraria; Amgen: Consultancy; Pfizer: Consultancy, Other: Expenses; Novartis: Consultancy, Other: Expenses; Bristol-Myers Squibb/Celgene: Consultancy, Other: Expenses; Adaptive Biotechnologies: Consultancy; Servier Genetics: Other; Jazz Pharmaceuticals: Research Funding; Incyte: Research Funding. Leonard: Amgen: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees. Pratz: Agios: Consultancy; BMS: Consultancy, Honoraria; Novartis: Consultancy; Astellas: Consultancy, Honoraria, Research Funding; Cellgene: Consultancy, Honoraria; Millenium: Research Funding; University of Pennsylvania: Current Employment; Abbvie: Consultancy, Honoraria, Research Funding. Luger: Syros: Honoraria; Agios: Honoraria; Daiichi Sankyo: Honoraria; Jazz Pharmaceuticals: Honoraria; Brystol Myers Squibb: Honoraria; Acceleron: Honoraria; Astellas: Honoraria; Pfizer: Honoraria; Onconova: Research Funding; Celgene: Research Funding; Biosight: Research Funding; Hoffman LaRoche: Research Funding; Kura: Research Funding. Badar: Pfizer Hematology-Oncology: Membership on an entity's Board of Directors or advisory committees. Atallah: Novartis: Consultancy, Honoraria, Research Funding; Amgen: Consultancy; Abbvie: Consultancy, Speakers Bureau; Takeda: Consultancy, Research Funding; BMS: Honoraria, Speakers Bureau; Pfizer: Consultancy, Research Funding.

Background Musculocontractural Ehlers−Danlos syndrome is caused by biallelic loss-of-function variants in CHST14 (mcEDS-CHST14) or DSE (mcEDS-DSE). Although 48 patients in 33 families with mcEDS-CHST14 have been reported, the spectrum of pathogenic variants, accurate prevalence of various manifestations and detailed natural history have not been systematically investigated. Methods We collected detailed and comprehensive clinical and molecular information regarding previously reported and newly identified patients with mcEDS-CHST14 through international collaborations. Results Sixty-six patients in 48 families (33 males/females; 0–59 years), including 18 newly reported patients, were evaluated. Japanese was the predominant ethnicity (27 families), associated with three recurrent variants. No apparent genotype–phenotype correlation was noted. Specific craniofacial (large fontanelle with delayed closure, downslanting palpebral fissures and hypertelorism), skeletal (characteristic finger morphologies, joint hypermobility, multiple congenital contractures, progressive talipes deformities and recurrent joint dislocation), cutaneous (hyperextensibility, fine/acrogeria-like/wrinkling palmar creases and bruisability) and ocular (refractive errors) features were observed in most patients (>90%). Large subcutaneous haematomas, constipation, cryptorchidism, hypotonia and motor developmental delay were also common (>80%). Median ages at the initial episode of dislocation or large subcutaneous haematoma were both 6 years. Nine patients died; their median age was 12 years. Several features, including joint and skin characteristics (hypermobility/extensibility and fragility), were significantly more frequent in patients with mcEDS-CHST14 than in eight reported patients with mcEDS-DSE. Conclusion This first international collaborative study of mcEDS-CHST14 demonstrated that the subtype represents a multisystem disorder with unique set of clinical phenotypes consisting of multiple malformations and progressive fragility-related manifestations; these require lifelong, multidisciplinary healthcare approaches.

Aims The outcomes of patients presenting with acute myocarditis and life‐threatening ventricular arrhythmias (LT‐VA) are unclear. The aim of this study was to assess the incidence and predictors of recurrent major arrhythmic events (MAEs) after hospital discharge in this patient population. Methods and results We retrospectively analysed 156 patients (median age 44 years; 77% male) discharged with a diagnosis of acute myocarditis and LT‐VA from 16 hospitals worldwide. Diagnosis of myocarditis was based on histology or the combination of increased markers of cardiac injury and cardiac magnetic resonance (CMR) Lake Louise criteria. MAEs were defined as the relapse, after discharge, of sudden cardiac death or successfully defibrillated ventricular fibrillation, or sustained ventricular tachycardia (sVT) requiring implantable cardioverter‐defibrillator therapy or synchronized external cardioversion. Median follow‐up was 23 months [first to third quartile (Q1–Q3) 7–60]. Fifty‐eight (37.2%) patients experienced MAEs after discharge, at a median of 8 months (Q1–Q3 2.5–24.0 months; 60.3% of MAEs within the first year). At multivariable Cox analysis, variables independently associated with MAEs were presentation with sVT [hazard ratio (HR) 2.90, 95% confidence interval (CI) 1.38–6.11]; late gadolinium enhancement involving ≥2 myocardial segments (HR 4.51, 95% CI 2.39–8.53), and absence of positive short‐tau inversion recovery (STIR) (HR 2.59, 95% CI 1.40–4.79) at first CMR. Conclusions Among patients discharged with a diagnosis of myocarditis and LT‐VA, 37.2% had recurrences of MAEs during follow‐up. Initial CMR pattern and sVT at presentation stratify the risk of arrhythmia recurrence.

Objective Intrahepatic cholangiocarcinoma (ICC)—a rare liver malignancy with limited therapeutic options—is characterised by aggressive progression, desmoplasia and vascular abnormalities. The aim of this study was to determine the role of placental growth factor (PlGF) in ICC progression. Design We evaluated the expression of PlGF in specimens from ICC patients and assessed the therapeutic effect of genetic or pharmacologic inhibition of PlGF in orthotopically grafted ICC mouse models. We evaluated the impact of PlGF stimulation or blockade in ICC cells and cancer-associated fibroblasts (CAFs) using in vitro 3-D coculture systems. Results PlGF levels were elevated in human ICC stromal cells and circulating blood plasma and were associated with disease progression. Single-cell RNA sequencing showed that the major impact of PlGF blockade in mice was enrichment of quiescent CAFs, characterised by high gene transcription levels related to the Akt pathway, glycolysis and hypoxia signalling. PlGF blockade suppressed Akt phosphorylation and myofibroblast activation in ICC-derived CAFs. PlGF blockade also reduced desmoplasia and tissue stiffness, which resulted in reopening of collapsed tumour vessels and improved blood perfusion, while reducing ICC cell invasion. Moreover, PlGF blockade enhanced the efficacy of standard chemotherapy in mice-bearing ICC. Conclusion PlGF blockade leads to a reduction in intratumorous hypoxia and metastatic dissemination, enhanced chemotherapy sensitivity and increased survival in mice-bearing aggressive ICC.

AbstractPurposeDevelop a framework to quantify the size, location and severity of femoral and acetabular‐sided cartilage and labral damage observed in patients undergoing hip arthroscopy, and generate a database of individual defect parameters to facilitate future research and treatment efforts.MethodsThe size, location, and severity of cartilage and labral damage were prospectively collected using a custom, standardized post‐operative template for 100 consecutive patients with femoroacetabular impingement syndrome. Chondrolabral junction damage, isolated intrasubstance labral damage, isolated acetabular cartilage damage and femoral cartilage damage were quantified and recorded using a combination of Beck and ICRS criteria. Radiographic measurements including alpha angle, head–neck offset, lateral centre edge angle and acetabular index were calculated and compared to the aforementioned chondral data using a multivariable logistic regression model and adjusted odd’s ratio. Reliability among measurements were assessed using the kappa statistic and intraclass coefficients were used to evaluate continuous variables.ResultsDamage to the acetabular cartilage originating at the chondrolabral junction was the most common finding in 97 hips (97%) and was usually accompanied by labral damage in 65 hips (65%). The width (p = 0.003) and clock‐face length (p = 0.016) of the damaged region both increased alpha angle on anteroposterior films. 10% of hips had femoral cartilage damage while only 2 (2%) of hips had isolated defects to either the acetabular cartilage or labrum. The adjusted odds of severe cartilage (p = 0.022) and labral damage (p = 0.046) increased with radiographic cam deformity but was not related to radiographic measures of acetabular coverage.ConclusionsDamage at the chondrolabral junction was very common in this hip arthroscopy cohort, while isolated defects to the acetabular cartilage or labrum were rare. These data demonstrate that the severity of cam morphology, quantified through radiographic measurements, is a primary predictor of location and severity of chondral and labral damage and focal chondral defects may represent a unique subset of patients that deserve further study.Level of evidenceIV.

AbstractIntroductionWe sought to assess the individual and combined contribution of limbic and neocortical α‐synuclein, tau, and amyloid β (Aβ) to duration of illness in dementia with Lewy bodies (DLB).MethodsQuantitative digital pathology of limbic and neocortical α‐synuclein, tau, and Aβ was assessed in 49 patients with clinically probable DLB. Regression modeling examined the unique and shared contribution of each pathology to the variance of illness duration.ResultsPatients with diffuse Lewy body disease had more severe pathology of each type and a shorter duration of illness than individuals with transitional Lewy body disease. The three pathologies accounted for 25% of the total variance of duration of illness, with 19% accounted for by α‐synuclein alone or in combination with tau and Aβ. When the diffuse Lewy body disease group was examined separately, α‐synuclein deposition significantly exceeded that of tau and Aβ. In this model, 20% of 24% total variance in the model for duration of illness was accounted for independently by α‐synuclein.DiscussionIn DLB, α‐synuclein is an important predictor of disease duration, both independently and synergistically with tau and Aβ.