Citations

PURPOSE On the basis of the results of the ZUMA-3 trial, brexucabtagene autoleucel (brexu-cel), a CD19-directed chimeric antigen receptor T-cell therapy, gained US Food and Drug Administration approval in October 2021 for adults with relapsed/refractory (R/R) B-cell ALL (B-ALL). We report outcomes of patients treated with brexu-cel as a standard therapy. METHODS We developed a collaboration across 31 US centers to study adults with B-ALL who received brexu-cel outside the context of a clinical trial. Data were collected retrospectively from October 2021 to October 2023. Toxicities were graded per American Society for Transplantation and Cellular Therapy guidelines for cytokine release syndrome (CRS) and immune effector cell–associated neurotoxicity syndrome (ICANS). RESULTS At the time of data lock, 204 patients had undergone apheresis and 189 were infused. Median follow-up time was 11.4 months. Forty-two percent of patients received brexu-cel in morphologic remission and would have been ineligible for participation in ZUMA-3. After brexu-cel, 151 achieved complete remission (CR), of which 79% were measurable residual disease (MRD) negative remissions. Median progression-free survival (PFS) was 9.5 months and median overall survival was not reached. Grade 3-4 CRS or ICANS occurred in 11% and 31%, respectively. In multivariable analysis, patients receiving consolidative hematopoietic cell transplantation (HCT; hazard ratio, 0.34 [95% CI, 0.14 to 0.85]) after brexu-cel had superior PFS compared with those who did not receive any consolidation or maintenance therapy. CONCLUSION Similar to ZUMA-3, high rates of MRD-negative CR were observed after brexu-cel treatment for R/R B-ALL. The use of HCT as consolidation after brexu-cel resulted in improved PFS.

Abstract BACKGROUND High-grade glioma (HGG) is the most common and aggressive form of primary brain cancer with poor prognosis. Standard of care surgery employs Magnetic Resonance Imaging (MRI) to identify the contrast enhancing (CE) core for resection, leaving behind an unresected non-enhancing (NE) invasive rim of tumor which borders healthy brain tissue and invariably contributes to recurrence. Recent multi-omic analyses identified predominant neuronal and immune signatures within NE tumor; understanding these signatures could provide key insights to combatting recurrence and improving patient outcomes. To this end, we utilized a novel graph database method to integrate multi-omic data from a unique dataset of multi-regional spatially-localized biopsies from the CE core and invasive NE rim from a large cohort of patients with HGG. MATERIAL AND METHODS 159 IDH-wildtype tumor biopsy samples from the NE and CE regions of 74 glioma patients were profiled by bulk RNA sequencing. Differentially expressed genes (DEG) (n=1159) across NE and CE samples were selected using EdgeR. Samples were hierarchically clustered (method = median) for each DEG and represented as nodes in a Neo4j graph network. Edges were generated between nodes sharing ≥ 1 sample. Modularity optimization was used to identify communities of densely connected nodes. Genes occurring exclusively within NE communities were localized by cell type using external single-cell RNA sequencing datasets and selected as candidate source nodes for NE network random walks. RBFOX1 was selected as a source (walk length = 5; 10,000 walks/source node). Random walks traversing samples with significantly elevated RBFOX1 expression (one-tailed test) were kept for analysis. Genes occurring at significantly high frequency (one-tailed test) within random walks were ranked by correlation with RBFOX1 expression in NE samples and analyzed by gene set enrichment analysis (GSEA) for biological processes using clusterProfiler. RESULTS RBFOX1, a neurodevelopmental regulator, was upregulated (logFC = 1.85) in NE samples and uniquely occurred in NE communities. We show RBFOX1 is differential expressed in the aggressive Neuronal glioma subtype and enriched in neuroepithelial/astrocyte subpopulations across single cell HGG datasets. NE network random walks identified 201 DEGs associated with RBFOX1. GSEA revealed upregulation of neurodevelopmental signatures and downregulation of proliferative pathways amongst RBFOX1’s network. CONCLUSION RBFOX1’s genetic network within NE tumor represents neurodevelopmental processes potentially underlying glioma invasiveness within the NE region. As such, understanding the mechanistic role of key genes within the RBFOX1 network may provide insight into novel strategies for targeting these invasive cells within an aggressive subtype of glioma in the NE rim.

Background/Objectives: Hypertrophic cardiomyopathy (HCM) is a common heart disorder characterized by the thickening of the heart muscle, particularly in the left ventricle, which increases the risk of cardiac complications. This study aims to analyze the expression of apoptosis-regulating genes (CASP8, CASP9, CASP3, BAX, and BCL2) in blood samples from HCM patients, to better understand their potential as biomarkers for disease progression. Methods: Quantitative real-time PCR (qPCR) was used to evaluate gene expression in blood samples from 93 HCM patients. The correlation between apoptosis-regulating genes was conducted and clinical parameters were integrated for feature importance and clustering analysis. Results: Most patients exhibited significant downregulation of CASP8, CASP9, and CASP3. In contrast, BAX expression was elevated in 71 out of 93 patients, while BCL2 was increased in 55 out of 93 patients. Correlation analysis revealed weak negative correlations between the BAX/BCL2 ratio and CASP gene expression. Conclusions: These findings suggest that reduced expression of apoptotic genes may indicate a protective cellular mechanism, which could serve as a biomarker for disease progression. Further studies are needed to investigate the potential for therapeutic modulation of these pathways to improve patient outcomes.

ABSTRACT Introduction: ASPS is a rare, soft tissue tumor which represents 0.2-1 % of soft tissue sarcomas. A characteristic nonreciprocal translocation is found in nearly all cases. The resulting ASPSCR1-TFE3 fusion gene is postulated to be involved in the pathogenesis of this tumor. Case report: 29 years-old female presented with abdominal pain for few months. MRI and CT revealed a large necrotic abdominopelvic mass, which is extra-uterine, extra-ovarian, and peritoneal nodules. Exploratory laparotomy revealed a large mass arising from the distal part of the descending colon involving the mesentery and the surrounding peritoneum. She underwent left colectomy with primary anastomosis, and resection of the involved adjacent peritoneal and mesenteric surface nodules. Histopathology revealed ASPS involving the outer serosal layer of the large bowel wall negative margins. It also involved the resected mesenteric fat, greater omentum, and peritoneum. No further treatment was received as the patient traveled to home country. Discussion: The treatment of early-stage ASPS involves radical surgical excision of the primary tumor. Traditionally, patients with advanced ASPS have limited therapeutic options because of the resistance of the tumor to conventional cytotoxic chemotherapy, however, it is a targetable sarcoma. The response rate of metastatic ASPS to targeted therapy is clinically meaningful, and comparable to that of first-line chemotherapy. Most patients who received targeted therapy achieved disease control. Patients who had refractory or progressive disease to one targeted agent demonstrated a response to other agents. More randomized trials are warranted to expand treatment options and compare them to standard care regimens. Conclusion: In conclusion, while radical surgical excision remains crucial for early-stage ASPS, the landscape for advanced cases is evolving with targeted therapies showing promising results. However, further randomized trials are necessary to broaden the treatment options available and to evaluate these new therapies against existing standard care regimens. This ongoing research is vital to improving outcomes for patients with ASPS and tailoring more effective treatment strategies. Highlights

AbstractObjectiveThe 2q24.2‐24.3 chromosome region encodes sodium channel genes important in severe childhood epilepsy, notably SCN1A linked to Dravet syndrome (DS). However, the roles of other genes, either within the SCN cluster or in the segments proximal to it, have not been clearly delineated. The combination of ketogenic diet and fenfluramine is known to provide substantial benefits to patients with DS, but there is a paucity of literature regarding its role in other developmental and epileptic encephalopathies (DEE). This report aims to further explore clinical findings and treatment outcomes in a patient with a complex epilepsy phenotype.MethodsOur patient's extensive diagnostic evaluation revealed 14 deleted genes within the 2q24.2‐24.3 chromosome region.ResultsThe patient initially presented with clusters of focal motor seizures with apnea and cyanosis requiring intubation as well as prolonged hospitalizations for status epilepticus. He has baseline hypotonia, dysphagia, and developmental delay. He had a >50% reduction in his seizures following a combination of ketogenic diet and fenfluramine. His seizures are now responsive to rescue midazolam, and he no longer has status epilepticus.InterpretationOur patient's remarkable clinical improvement suggests that this dual therapy may be beneficial in patients with DEE exhibiting pathogenic variations in this region of chromosome 2, beyond just DS.