Use of Checkpoint Inhibitors in Gray Zone Lymphoma.

Checkpoint inhibitors, cancer immunotherapies, are the new forms of treatment for gray zone lymphoma, a rare subtype that combines the characteristics of both Hodgkin and non-Hodgkin disease forms. Programmed cell death protein 1/programmed cell death ligand 1 (PD-L1/PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) modulate the immune system function. Immunological checkpoints can be stimulatory or inhibitory, and tumors can use these checkpoints to protect against immune system attacks. This is a case report of a difficult diagnosis and describes the most current treatment using checkpoint inhibitors, through the review of the clinical record of a patient diagnosed with gray area lymphoma in August 2019, using a descriptive and cross-sectional analysis of the clinical history and disease evolution. The case showed that pembrolizumab therapy is an effective treatment option for patients with rare gray zone lymphoma refractory to different lines of treatment. Both the diagnosis and treatment of gray area lymphoma remain a challenge for the medical and multiprofessional teams, and collaboration between them ensured effective treatment for the patient.

Gene expression of HIF-1α and VEGF in response to hypoxia in sickle cell anaemia: Influence of hydroxycarbamide.

Hypoxia and hemoglobin S polymerization are two triggers responsible for initiating erythrocyte sickling and the consequent clinical sickle cell anemia (SCA) events. The objective of this study was to investigate the expression of hypoxia-responsive genes in SCA, testing for correlation with the clinical-laboratorial characteristics of the patient and hydroxyurea therapy. Our results showed, for the first time, a significantly increased expression of HIF-1α and VEGF genes in patients with SCA and an inverse dose-response relationship with hydroxyurea therapy. These results suggest that hypoxic stress may be involved in both the severity of SCA and its response to treatment.

Clinical difference between identical twins with sickle cell anemia / Diferenças clínicas entre gêmeas idênticas com anemia falciforme

ABSTRACT Sickle cell anemia (SCA) is a genetic disease that causes important clinical manifestations due to chronic hemolysis and vascular occlusion. The aim of this study was to report a rare case of monozygotic twins diagnosed with SCA, presenting a different clinical characteristic. An interview with the patients was carried out and the medical records were consulted. One patient has a history of malleolar ulcer in the left back, while the other does not. Both patients used hydroxyurea at the same dosage. This study shows that SCA presents, in addition to genetic factors, non-genetic factors involved in the severity of the disease and its clinical manifestations. Studies are needed that may contribute to the understanding of the clinical heterogeneity of SCA.

RESUMEN La anemia de células falciformes (ACF) es una enfermedadgenética que causa importantes manifestaciones clínicas debido a la anemia hemolítica crónica y a la oclusión vascular. El objetivo de este estudio fue reportar un caso raro de gemelas monocigóticas con diagnóstico de ACF, presentando una característica clínica diferente. Se realizó una entrevista con las pacientes, consultándose sus fichas médicas. Una paciente tiene historia de úlcera maleolar en la región izquierda, mientras la otra no. Ambas hacían tratamiento con hidroxiurea en la misma dosis. Este estudio demuestra que la ACF presenta, además de factores genéticos, factores no genéticos involucrados en la severidadde la enfermedad y sus manifestaciones clínicas. Son necesarios estudios que contribuyan para la comprensión de la heterogeneidad clínica de la ACF.

RESUMO A anemiafalciforme (AF) é uma doença genética que causa importantes manifestações clínicas devido à hemólise crônica e à oclusão vascular. O objetivo deste estudo foi relatar um caso raro de gêmeas univitelinas com diagnóstico de AF, apresentando uma característica clínica diferente. Uma entrevista com as pacientes foi realizada, e os prontuários foram consultados. Uma paciente tem história de úlcera maleolar na região esquerda, enquanto a outra não. Ambas as pacientes faziam tratamento com hidroxiureia na mesma dosagem. Este estudo mostra que a AF apresenta, além de fatores genéticos, fatores não genéticos envolvidos na gravidade da doença e suas manifestações clínicas, sendo necessários estudos quepossam contribuir para o entendimento da heterogeneidade clínica da AF.

Double-Blind Clinical Trial of Arginine Supplementation in the Treatment of Adult Patients with Sickle Cell Anaemia.

BACKGROUND: Sickle cell anaemia (SCA) is the most prevalent monogenic disease in Brazil. In SCA, haemoglobin S (HbS) is formed, which modifies red blood cell morphology. Intravascular haemolysis occurs, in which free Hb and free radicals degrade nitric oxide (NO) and release arginase, which reduces arginine levels. Because arginine is a substrate for NO formation, this decrease leads to reduced NO (vasodilator) synthesis. SCA treatment uses hydroxyurea (HU) to maintain high foetal haemoglobin (HbF) levels and reduces HbS to avoid haemolytic episodes. OBJECTIVE: To analyse the efficacy of L-arginine as an adjuvant in the treatment of SCA patients. SETTING: The State Blood Centre of Ceará, Brazil. METHODS: This was a randomized double-blind clinical study of adults with SCA with continuous use of HU at the State Blood Centre of Ceará. The clinical study enrolled 25 patients receiving HU + L-arginine (500 mg) and 25 patients receiving HU + placebo. The treatment was carried out over four months. Laboratory tests were performed to determine the levels of the following: (1) complete blood count; (2) nitrite + nitrate; (3) HbF; and (4) reticulocytes. The clinical experiments were performed by a haematologist. The main outcome measures were nitrite and pain. RESULTS: Statistical analysis showed that the levels of NO were increased in the study group, and there was also a reduction in pain frequency using a pain frequency scale by day, week, and month. The levels of nitrite plus nitrate in the group receiving placebo plus HU did not change among the times evaluated (38.27 ± 17.27 mg/L, 39.49 ± 12.84 mg/L, 34.45 ± 11.25 mg/L, p >0.05), but in the patients who received supplementation with L-arginine plus HU, a significant increase in nitrite plus nitrate levels was observed between M0 and M4 (36.55 ± 20.23 mg/L versus 48.64 ± 20.63 mg/L, p =0.001) and M2 and M4 (35.71 ± 15.11 mg/L versus 48.64 ± 20.63 mg/L, p <0.001). It is important to note that the increase in nitrite plus nitrate levels occurred only in the fourth month of follow-up of patients in the treatment group, showing that at least 4 months of supplementation with L-arginine is necessary to show an increase in these metabolites in the serum. CONCLUSION: The use of L-arginine as a coadjuvant in the treatment of sickle cell anaemia may function as a potential tool for pain relief, consequently improving the life of patients.

Analysis of BCL11A gene polymorphisms and hemolysis parameters in patients with sickle-cell disease / Análise dos polimorfismos do gene BCL11A e parâmetros de hemólise em pacientes com anemia falciforme

ABSTRACT Introduction: Patients with sickle-cell disease (SCD) present chronic hemolysis with increased serum biomarkers. Genetic polymorphisms of the BLC11A gene modulate fetal hemoglobin (HbF), thus reducing hemolysis Objective: To associate the polymorphisms of BCL11A gene with the hemolysis markers: reticulocyte, bilirubin, uric acid, lactate dehydrogenase (LDH), and methemoglobin (MetHb) in SCD patients. Methods: The study included 45 patients with SCD of both sexes using hydroxyurea (HU), treated at a Hospital in Fortaleza, Ceará, Brazil, along with 80 healthy individuals as the control group. MetHb, uric acid, and bilirubin measurements were carried out with the spectrophotometric method, and LDH with a kinetic method, a reticulocyte count by a manual method; and evaluation of BCL11A polymorphisms, in real time polymerase chain reaction (PCR). Data were analyzed using the statistical software GraphPad Prism. The level of significance was set at < 5%. Results: In region rs7557939 of the BCL11A gene genotype, A/G showed a significant increase of MetHb (p = 0.0297), and the A/A genotype showed high concentration of LDH (p = 0.0316) in the same region. The use of HU at doses ≥ 10 mg/kg/day showed a decrease of LDH (p = 0.02), and treatment for > 50 months was linked to the reticulocyte count (p = 0.0155). Conclusion: Polymorphisms in the rs7557939 region of the BCL11A gene appear to somehow interfere in the clinical setting of patients with SCD, suggesting relation with the concentration of MetHb and LDH. This study pioneered an investigation into the association of hemolysis biomarkers with BCL11A gene polymorphisms in SCD.

RESUMO Introdução: Pacientes com anemia falciforme (AF) apresentam hemólise crônica com biomarcadores séricos aumentados. Os polimorfismos genéticos do gene BLC11A modulam a hemoglobina fetal (HbF), reduzindo, assim, a hemólise. Objetivo: Associar os polimorfismos do gene BCL11A aos marcadores de hemólise: reticulócitos, bilirrubina, ácido úrico, lactato desidrogenase (LDH) e meta-hemoglobina (MetHb) em pacientes com AF. Métodos: O estudo incluiu 45 pacientes com AF que utilizavam hidroxiureia (HU), tratados em um hospital de Fortaleza, Ceará, Brasil, e 80 indivíduos saudáveis como grupo-controle. A dosagem de MetHb, ácido úrico e bilirrubina foi realizada por método espectrofotométrico; LDH, pelo método cinético; contagem de reticulócitos, pelo método manual; e avaliação de polimorfismos BCL11A, por reação em cadeia da polimerase (PCR) em tempo real. Os dados foram analisados usando o software estatístico GraphPad Prism. O nível de significância foi < 5%. Resultados: Na região rs7557939 do gene BCL11A, o genótipo A/G mostrou aumento significativo de MetHb (p = 0,0297), e o genótipo A/A esteve relacionado com a alta concentração de LDH (p = 0,0316). Pacientes em uso de HU em doses ≥ 10 mg/kg/dia apresentaram diminuição de LDH (p = 0,02), e o tratamento por mais de 50 meses foi relacionado com a contagem de reticulócitos (p = 0,0155). Conclusão: Polimorfismos na região rs7557939 do gene BCL11A parecem interferir de alguma forma nas manifestações clínicas de pacientes com AF, o que sugere uma relação com a concentração de MetHb e LDH. Este estudo foi pioneiro na investigação da associação de biomarcadores de hemólise com polimorfismos do gene BCL11A na AF.