Functional polymorphisms of DNA repair genes in Latin America reinforces the heterogeneity of Myelodysplastic Syndrome

Abstract Nucleotide excision repair pathway (NER) is an essential mechanism for single-strand breaks (SSB) repair while xeroderma pigmentosum family (XPA to XPG) is the most important system to NER. Myelodysplastic syndrome (MDS) is a heterogeneous hematological cancer characterized by cytopenias and risk of acute myeloid leukemia (AML) transformation. MDS pathogenesis has been associated with problems of DNA repair system. This report aimed to evaluate NER polymorphisms (XPA rs1800975, XPC rs2228000, XPD rs1799793 and XPF rs1800067) in 269 MDS patients of different populations in Latin America (173 Brazilian and 96 Argentinean). Genotypes were identified in DNA samples by RT-qPCR using TaqMan SNP Genotyping Assay. Regarding rs1799793 polymorphism of XPD for Brazilian population, the heterozygous genotype AG presented a high odds ratio (OR) to have a normal karyotype (p= 0.012, OR=3.000) and the mutant homozygous genotype AA was associated to a high OR of AML transformation (p= 0.034, OR=7.4). In Argentine population, the homozygous mutant AA genotype of rs1800975 polymorphism of XPA was associated with an increased odd to have hemoglobin levels below 8g/dL (p= 0.013, OR=10.000) while for the rs1799793 polymorphism of XPD, the heterozygous AG genotype decreased OR to be classified as good (p< 0.001, OR=9.05 × 10−10), and intermediate (p< 0.001, OR=3.08 × 10−10), according to Revised-International Prognostic Scoring System. Regarding the rs1800067 polymorphisms of XPF, the homozygous mutant AA genotype showed a decreased OR to be classified as good (p< 0.001, OR=4.03 × 10−13) and intermediate (p< 0.001, OR=2.54 × 10−13). Our report reinforces the heterogeneity of MDS and demonstrates the importance of ethnic differences and regional influences in pathogenesis and prognosis of MDS.

Clarithromycin-resistant H. pylori primary strains and virulence genotypes in the Northeastern region of Brazil

ABSTRACT The increase of H. pylori resistance to clarithromycin is a concern. This study evaluated the prevalence of H. pylori's primary resistance to clarithromycin and its association with virulence factors in adult dyspeptic patients and asymptomatic children. The gastric mucosa from patients (153 gastritis, 24 gastric cancer, 21 peptic ulcer) and gastric juice obtained by string test from 24 H. pylori and 23S rRNA positive asymptomatic children were included. The clarithromycin resistance was assessed by TaqMan RT-PCR 23S rRNA point mutations, A2142G and/or A2143G, and H. pylori virulence markers by PCR. Overall, the clarithromycin resistance was 14.4% (32/222), 14.2% in adults, and 12% in children, whereas origin, gender, and disease were not distinctive factors. The most prevalent point mutation was A2143G (62.5%). The point mutation was significantly less frequent in cagA-positive (11.4%) than in cagA-negative (23.6%) strains (p=0.03 OR = 0.4 95%CI = 0.19 - 0.91) as well as in cagE-positive (10.2%), cagE-negative (21.2%) (p=0.03 OR: 0.4 I.C:0.20-0.91). No difference was found in iceA or vacA alleles genotypes. Primary resistance to clarithromycin was lower than that reported in Southeast Brazil. The cagA and cagE positive H. pylori samples have few point mutations suggesting that individuals infected with virulent strains may be more susceptible to anti-H. pylori treatment.

Splicing factor SF3B1 mutations and ring sideroblasts in myelodysplastic syndromes: a Brazilian cohort screening study

ABSTRACT Background: Myelodysplastic syndromes (MDS) comprise a group of malignant clonal hematologic disorders characterized by ineffective hematopoiesis and propensity for progression to acute myeloid leukemia. Acquired mutations in the gene encoding RNA splicing factor 3B subunit 1 (SF3B1) are highly associated with the MDS subtypes presenting ring sideroblasts, and represent a specific nosological entity. The effects of these mutations on clinical outcomes are diverse and contrasting. Methods: A cohort of 91 Brazilian MDS patients, including patients with ring sideroblasts in the bone marrow, were screened for mutations in the SF3B1 hotspots (exons 12-15) by direct Sanger sequencing. Results: SF3B1 heterozygous mutations were identified in six patients (7%), all of them with ring sideroblasts, thus confirming the association between SF3B1 mutations and myelodysplastic syndrome subtypes bearing this morphologic feature (frequency of 6/13, p-value < 0.0001). Conclusion: This is the first screening of SF3B1 mutations in a cohort of Brazilian myelodysplastic syndrome patients. Our findings confirm that mutations in this splicing gene correlate with bone marrow ringed sideroblasts.

Síndrome mielodisplásica: quais pacientes devem receber decitabina? / Myelodisplastic syndrome: which patients should receive decitabine?

Síndrome mielodisplásica é uma doença clonal da célula-tronco hematopoética, caracterizada por uma hematopoiese ineficaz, displasias e citopenias no sangue periférico. O tratamento atualmente realizado tem como base a transfusão de concentrado de hemácias e plaquetas, sempre que necessário. A decitabina (5-aza-2´deoxycitidine) é um agente hipometilante desenvolvido em 1964 e tem demonstrado resposta em pacientes com SMD. Esta droga é um análogo do nucleosídeo citosina que, uma vez incorporado ao DNA, inibe a metilação do DNA. Como resultado, ocorre silenciamento gênico, incluindo genes supressores de tumorais que podem ser re-ativados e expressos. Esta droga tem sido usada para tratar pacientes com SMD dos subgrupos intermediário 1, intermediário 2 e alto risco do Sistema de Escores Prognósticos Internacional - IPSS, com 30%(1) de taxa de resposta global. O objetivo deste trabalho é rever as indicações e como usar decitabina em pacientes com SMD.

Pioderma gangrenoso bolhoso e síndrome mielodisplásica / Bullous pyoderma gangrenosum and myelodysplastic syndrome

O pioderma gangrenoso pode apresentar-se como manifestação paraneoplásica. Relata-se um caso de pioderma gangrenoso, da variante bolhosa, acompanhado de bicitopenia, em que foi evidenciado, por meio de mielograma, biópsia de medula óssea e cariótipo, padrão compatível com síndrome mielodisplásica, subtipo citopenia refratária com displasia de multilinhagens. Foi tratado com dapsona, obtendo cicatrização das lesões. O pioderma gangrenoso pode associar-se a doenças sistêmicas, devendo a síndrome mielodisplásica ser considerada nos casos acompanhados de citopenias. Portanto, o pioderma gangrenoso pode ser um marcador cutâneo de doença sistêmica de prognóstico reservado.

Pyoderma gangrenosum can present as a cutaneous manifestation of paraneoplastic syndromes. A case of bullous pyoderma gangrenosum associated with bicytopenia is described. During the complementary investigation, myelogram, bone marrow biopsy and karyotype were performed, and showed a pattern consistent with myelodysplastic syndrome. The patient was treated with dapsone with improvement. Pyoderma gangrenosum can be a manifestation of systemic diseases. The possibility of myelodysplastic syndrome should always be considered in patients with pyoderma gangrenosum associated with cytopenia. Pyoderma gangrenosum could indicate poorer prognosis in patients with systemic diseases.

Septic arthritis as the first sign of Candida tropicalis fungaemia in an acute lymphoid leukemia patient

Fungal infections caused by Candida species have increased in incidence during the past two decades in England, North America and Europe. Candidal arthritis is rare in patients who are not intravenous drug users or are who not using a prostheses. We report the case of a 24-year-old man with acute lymphoid leukemia, who developed Candida tropicalis arthritis during an aplastic period after chemotherapy. This is the eighth case described in the literature of C. tropicalis causing arthritis without intra-articular inoculation. We call attention to an unusual first sign of fungal infection: septic arthritis without intra-articular inoculation. However, this case differs from the other seven, since despite therapy a fast and lethal evolution was observed. We reviewed reported cases, incidence, risk factors, mortality and treatment of neutropenic patients with fungal infections.

Síndrome ATRA: experiência de 10 anos / ATRA Syndrome: 10 year experience

A leucemia promielocítica aguda (LPA) é um subtipo de leucemia mielóide aguda (LMA) responsável por 10 por cento de todas as LMAs. Geralmente, o tratamento da LPA consiste de quimioterapia e uso de ácido transretinóico (ATRA). O maior efeito colateral do ATRA é a "Síndrome ATRA", que ocorre com uma freqüência de quase 30 por cento. Estudamos a apresentação clínica e a incidência da Síndrome ATRA em pacientes com LPA admitidos no Hospital São Paulo (da Escola Paulista de Medicina-UNIFESP). Treze pacientes com LPA fizeram uso de ATRA. A síndrome foi diagnosticada em cinco pacientes (38 por cento) com idade média de 29 anos e que estavam,em média, no décimo dia do uso de ATRA. Os achados clínicos mais freqüentes foram insuficiência respiratória, infiltrado pulmonar à radiografia e febre. Este relato chama a atenção para a necessidade do diagnóstico precoce dessa síndrome, com a introdução de dexametasona ao primeiro sinal no intuito de êxito terapêutico.

Dor lombar durante infusão de estreptoquinase

We report the case of a 57-year-old male patient with severe low back pain during streptokinase infusion administered to treat typical chest pain and elevation of the ST segment in the inferior wall. We reviewed the literature, emphasizing the differential diagnosis, the pathophysiology, and management of the event

Linfoma não-Hodgkin de pequenas células não-clivadas, tipo Burkitt com apresentação clínica de hipercalcemia: relato de caso / Small noncleaved cells, Burkitt type, non-Hodgkin lymphoma with clinical presentation of hypercalcemia: case report

Neste artigo, os autores apresentam um caso de uma paciente de 60 anos que procurou um serviço de emergência com quadro de vômitos incoercíveis e que apresentava nos exames de urgência uma hipercalcemia de 19g/dL. Após estabilização do cálcio sérico com hidratação, corticóide e bifosfonatos, a elaboração diagnóstica revelou um linfoma de pequenas células não clivadas, tipo Burkitt, um linfoma não-Hodgkin que raramente tem sido associado a essa apresentação inicial. Os autores fazem, ainda, uma breve revisão da literatura sobre as neoplasias mais comumente associadas à hipercalcemia.

Poroceratose de Mibelli e transformação maligna: relato de caso e revisão de literatura / Porokeratosis of Mibelli and malignant change: case report and literature review

Poroceratose é dermatose de origem genética caracterizada por lesões circulares com atrofia central e bordas elevadas que correspondem, histopatologicamente, a uma coluna de células paraceratóticas, a lamela cornóide. Apresenta-se o caso de paciente de 69 anos, portador de lesões de pele com aspecto de poroceratose de Mibelli clássica desde a infância. Procurou atendimento médico para realizar ressecção cirúrgica de tumor de pele no dorso, lesão que iniciara como as outras e que vinha aumentando de tamanho há aproximadamente 3 anos. O exame histopatológico dessa lesão revelou carcinoma basoescamoso. O diagnóstico de poroceratose foi confirmado por biópsia de uma das lesões de pele. Ressalta-se o padrão de herança familiar dessa doença, sua associação com exposição à radiação ultravioleta e os principais aspectos concercentes à transformação maligna. Diante de propostas terapêuticas não efetivas, sugere-se o seguimento ambulatorial periódico dos pacientes com poroceratose de Mibelli para diagnóstico precose de possíveis lesões neoplásicas