Biochemical phenotyping of paroxysmal nocturnal hemoglobinuria reveals solute carriers and ß-oxidation deficiencies.

INTRODUCTION: Paroxysmal nocturnal hemoglobinuria (PNH) is a clonal disease of hematopoietic cells with a variable clinical spectrum characterized by intravascular hemolysis, high risk of thrombosis, and cytopenias. To understand the biochemical shifts underlying PNH, this study aimed to search for the dysfunctional pathways involved in PNH physiopathology by comparing the systemic metabolic profiles of affected patients to healthy controls and the metabolomic profiles before and after the administration of eculizumab in PNH patients undergoing treatment. METHODS: Plasma metabolic profiles, comprising 186 specific annotated metabolites, were quantified using targeted quantitative electrospray ionization tandem mass spectrometry in 23 PNH patients and 166 population-based controls. In addition, samples from 12 PNH patients on regular eculizumab maintenance therapy collected before and 24 hours after eculizumab infusion were also analyzed. RESULTS: In the PNH group, levels of the long-chain acylcarnitines metabolites were significantly higher as compared to the controls, while levels of histidine, taurine, glutamate, glutamine, aspartate and phosphatidylcholines were significantly lower in the PNH group. These differences suggest altered acylcarnitine balance, reduction in the amino acids participating in the glycogenesis pathway and impaired glutaminolysis. In 12 PNH patients who were receiving regular eculizumab therapy, the concentrations of acylcarnitine C6:1, the C14:1/C6 ratio (reflecting the impaired action of the medium-chain acyl-Co A dehydrogenase), and the C4/C6 ratio (reflecting the impaired action of short-chain acyl-Co A dehydrogenase) were significantly reduced immediately before eculizumab infusion, revealing impairments in the Acyl CoA metabolism, and reached levels similar to those in the healthy controls 24 hours after infusion. CONCLUSIONS: We demonstrated significant differences in the metabolomes of the PNH patients compared to healthy controls. Eculizumab infusion seemed to improve deficiencies in the acyl CoA metabolism and may have a role in the mitochondrial oxidative process of long and medium-chain fatty acids, reducing oxidative stress, and inflammation.

Treating Adult Acute Lymphoblastic Leukemia in Brazil-Increased Early Mortality Using a German Multicenter Acute Lymphoblastic Leukemia-based regimen.

BACKGROUND: Acute lymphoblastic leukemia (ALL) in adults is an invariably aggressive and rare disease. Its treatment is based on the use of multidrug regimens, which have been improved since the 1970s. Few published data are available on the results of adult ALL treatment in Latin America. MATERIALS AND METHODS: We retrospectively analyzed the data from 59 patients with ALL treated from 2009 to 2015 at Hospital of Clinics of University of São Paulo, using an adapted German Multicenter ALL (GMALL) protocol (07/2003). RESULTS: The median patient age was 35 years (range, 16-71 years), with 76% of new cases of B-cell lineage. Central nervous system involvement was present in 29%. Most patients were in the high-risk group, using the original GMALL criteria (68%). The early death rate was 17%, preventing early evaluation of the response in these patients. Despite a reasonable complete remission rate (76%), most patients eventually died of sepsis, especially during the induction phase and salvage regimens. The median overall survival was 17 months. CONCLUSION: Intensified chemotherapy protocols for adult ALL have succeeded in achieving better survival rates in adults, especially younger adults. The low overall survival found with GMALL in Brazil's public hospital denotes the importance of optimizing the adaptations of international protocols for treatment of ALL in nondeveloped countries and, in parallel, improving supportive care in public services.

Apresentação incomum de vasculite associada à infecção por vírus C da hepatite / Uncommon presentation of vasculitis associated to infection with hepatitis C vírus

A vasculite é uma síndrome pleomórfica composta por um grupo heterogêneo de processos inflamatórios que acometem principalmente a parede dos vasos sangüíneos. A infecção pelo vírus C da hepatite (VCH) pode associar-se a manifestações extra-hepáticas, incluindo doenças auto-imunes. Duas formas de vasculite podem associar-se ao VCH: a crioglobulinemia mista e a semelhante à poliarterite nodosa. O diagnóstico e o manuseio terapêutico nessas condições são desafios. Existem poucos dados a respeito da eficácia da terapia antiviral em pacientes com VCH crônica e doenças auto-imunes. Apresentamos um relato de caso de vasculite de pequenos vasos de apresentação incomum associado ao VCH.

Vasculitis is a pleomorfic inflammatory syndrome that involves mainly the wall of blood vessels. The hepatitis C virus infection may be associated to extra-hepatic manifestations, including autoimmune diseases. Two forms of vasculitis have been associated to hepatitis C virus, namely: mixed cryoglobulinemia and polyarteritis nodosa. The diagnosis and the therapeutic management of these conditions are clinical challenges. There are few data available in the literature about the antiviral treatment efficacy in patients with hepatitis C virus and autoimmune diseases. We describe an unusual patient displaying vasculitis of small vessels and with hepatitis C virus infection.