Identification of Plasma Metabolomic Biomarkers of Juvenile Idiopathic Arthritis.

Identification of disease and therapeutic biomarkers remains a significant challenge in the early diagnosis and effective treatment of juvenile idiopathic arthritis (JIA). In this study, plasma metabolomic profiling was conducted to identify disease-related metabolic biomarkers associated with JIA. Plasma samples from treatment-naïve JIA patients and non-JIA reference patients underwent global metabolomic profiling across discovery (60 JIA, 60 non-JIA) and replication (49 JIA, 38 non-JIA) cohorts. Univariate analysis identified significant metabolites (q-value ≤ 0.05), followed by enrichment analysis using ChemRICH and metabolic network mapping with MetaMapp and Cytoscape. Receiver operating characteristic (ROC) analysis determined the top discriminating biomarkers based on area under the curve (AUC) values. A total of over 800 metabolites were measured, consisting of 714 known and 155 unknown compounds. In the discovery cohort, 587 metabolites were significantly altered in JIA patients compared with the reference population (q < 0.05). In the replication cohort, 288 metabolites were significantly altered, with 78 overlapping metabolites demonstrating the same directional change in both cohorts. JIA was associated with a notable increase in plasma levels of sphingosine metabolites and fatty acid ethanolamides and decreased plasma levels of sarcosine, iminodiacetate, and the unknown metabolite X-12462. Chemical enrichment analysis identified cycloparaffins in the form of naproxen and its metabolites, unsaturated lysophospholipids, saturated phosphatidylcholines, sphingomyelins, ethanolamines, and saturated ceramides as the top discriminating biochemical clusters. ROC curve analysis identified 11 metabolites classified as highly discriminatory based on an AUC > 0.90, with the top discriminating metabolite being sphinganine-1-phosphate (AUC = 0.98). This study identifies specific metabolic changes in JIA, particularly within sphingosine metabolism, through both discovery and replication cohorts. Plasma metabolomic profiling shows promise in pinpointing JIA-specific biomarkers, differentiating them from those in healthy controls and Crohn's disease, which may improve diagnosis and treatment.

Multi-institutional analysis of outcomes in acute myeloid leukemia patients with central nervous system involvement.

We evaluated outcomes of AML patients with central nervous system (CNS) involvement at two academic institutions. Fifty-two adult patients were identified. Neurologic symptoms were reported in 69% of patients, with headache the most common (33%). 84% (n = 42) of patients cleared their cerebrospinal fluid (CSF), with a median number of one dose of intrathecal (IT) chemotherapy. Of these patients, 21% (n = 9) had a CSF relapse, with 67% (n = 6) of those experiencing CSF relapse also having concurrent bone marrow relapse. Of the 36 patients with baseline neurologic symptoms, 69% had improvement in symptoms post-IT therapy. The median overall survival was 9.3 months and 3.5 months for patients with CNS involvement diagnosed before/during induction and at relapse, respectively. In this study, IT therapy was rapidly effective in clearing CSF blasts and improving neurologic symptoms in most patients. Few patients experienced CSF relapse, which predominantly occurred in the setting of concomitant bone marrow relapse.

Morphologic, immunophenotypic, molecular genetic, and clinical characterization in patients with SRSF2-mutated acute myeloid leukemia.

OBJECTIVES: SRSF2 mutations are known to be associated with poor outcomes in myelodysplastic neoplasm, but studies on their prognostic impact on acute myeloid leukemia (AML) remain limited. In this retrospective study, we analyzed clinical and pathologic characteristics of patients with AML and correlated the outcomes with SRSF2 mutations. METHODS: We characterized the morphologic, immunophenotypic, molecular, and clinical findings in AML with mutated SRSF2 and compared them with SRSF2 wild-type (WT) myeloid neoplasms (MNs). RESULTS: Using next-generation sequencing, we identified 134 patients with MNs and SRSF2 mutations (85 with AML and 49 with MNs) in addition to 342 SRSF2-WT AMLs. Fifty-two (62%) patients with altered SRSF2 demonstrated a variable degree of morphologic dysplasia. The most frequent immunophenotypic aberrancies in SRSF2-mutant AML included diminished CD33 expression and overexpression of CD7, CD56, or CD123, similar to WT AML. More IDH1/2 (P = .015) and NPM1 (P = .002) mutations were seen in SRSF2-mutant AML than in SRSF2-mutant non-AML. Further, more IDH1/2, ASXL1, RUNX1, and STAG2 mutations were observed in SRSF2-mutant AML than in SRSF2-WT AML (P < .0001 to P = .001). Finally, patients with SRSF2-mutant AML showed a significantly worse overall survival (OS) than patients with SRSF2-WT AML (P < .0001), but this worse OS appeared to be rescued by allogeneic stem cell transplant (allo-SCT). CONCLUSIONS: Acute myeloid leukemia with altered SRSF2 shows a variable degree of morphologic dysplasia without uniform immunophenotypic aberrancies. SRSF2 mutations appear to be independent poor prognostic factors, but allo-SCT has improved the clinical outcomes in patients with SRSF2-mutant AML.

Incidence, Contributing Factors, and Implications for Clinical Management of Polycythemia in Transmasculine Patients on Testosterone.

Purpose: The goal of this study was to evaluate contributing factors and management strategies for polycythemia in transmasculine patients on testosterone therapy. Methods: A retrospective analysis of medical records was performed for transmasculine patients on testosterone for at least 12 months. Data collected from each patient included age, body mass index (BMI), nicotine dependence, pulmonary disease status, obstructive sleep apnea (OSA) status, oophorectomy status, and testosterone route of administration. For patients who developed polycythemia, polycythemia management strategy data were collected. Results: Five-hundred-eleven patients were evaluated and 113 (22%) experienced an episode of polycythemia. Within the polycythemia group, 77% of patients were younger than age 40, 56% had a BMI >30.0, 44% had current or former nicotine dependence, 12% had a pulmonary disease, 12% had OSA, and 47% had received an oophorectomy. The polycythemia group had a significantly higher average age, BMI, and dose of testosterone, and also had a higher proportion of patients with OSA and an oophorectomy. Conclusion: These results revealed that polycythemia is a common side effect for transmasculine patients on testosterone. Importantly, previous oophorectomy may be associated with polycythemia which appears to be a novel finding. This finding requires further research but provides the potential to be an important screening consideration for transmasculine patients after oophorectomy. Polycythemia will continue to be a major concern for patients on testosterone therapy, and this study provided important information for clinical practice and future research that will lead to improved outcomes.