Application of five prognostic survival scores to primary myelofibrosis in 62 Brazilian patients.

Primary myelofibrosis (PM) is a Philadelphia-negative clonal hematopoietic stem cell disorder characterized by intense reactive changes of bone marrow stroma with collagen fibrosis, osteosclerosis and angiogenesis. PM usually affects elderly people, and approximately half of the patients present JAK2V617F mutation. PM clinical course varies from 1 to 30 years, evolving from asymptomatic into progressive bone marrow failure, symptomatic splenomegaly or acute leukemia in 10-20 % of cases. PM risk stratification is based on parameters predicting survival, and several attempts have been made to identify clinical and laboratory features that could predict PM patient survival. This study applied five prognostic scores: Dupriez, Cervantes, Mayo, IPSS and DIPSS-Plus in 62 Brazilians patients from three centers, and compared their relevance and clinical usefulness considering the scores' parameters, fibrosis, JAK2V617F mutation, splenomegaly, hepatomegaly and treatment. According to the Cervantes, Dupriez and Mayo scores, most patients were stratified into low-risk group. However, when IPSS and DIPSS-Plus were applied, most patients were classified into an intermediate range, being low risk in only 11 and 13 % of patients, respectively. Overall survival at 4 years was 84 %. The Cervantes score was the only one that remained significantly associated with survival in a multivariate analysis. In conclusion, the Cervantes score remains important to the prognostication of PM.

Cytogenetic studies of Brazilian pediatric myelodysplastic syndrome cases: challenges and difficulties in a large and emerging country.

Myelodysplastic syndromes (MDS) and juvenile myelomonocytic leukemia (JMML) are rare hematopoietic stem cell diseases affecting children. Cytogenetics plays an important role in the diagnosis of these diseases. We report here the experience of the Cytogenetic Subcommittee of the Brazilian Cooperative Group on Pediatric Myelodysplastic Syndromes (BCG-MDS-PED). We analyzed 168 cytogenetic studies performed in 23 different cytogenetic centers; 84 of these studies were performed in patients with confirmed MDS (primary MDS, secondary MDS, JMML, and acute myeloid leukemia/MDS+Down syndrome). Clonal abnormalities were found in 36.9% of the MDS cases and cytogenetic studies were important for the detection of constitutional diseases and for differential diagnosis with other myeloid neoplasms. These data show the importance of the Cooperative Group for continuing education in order to avoid a late or wrong diagnosis.

Cytogenetic studies of Brazilian pediatric myelodysplastic syndrome cases: challenges and difficulties in a large and emerging country

Myelodysplastic syndromes (MDS) and juvenile myelomonocytic leukemia (JMML) are rare hematopoietic stem cell diseases affecting children. Cytogenetics plays an important role in the diagnosis of these diseases. We report here the experience of the Cytogenetic Subcommittee of the Brazilian Cooperative Group on Pediatric Myelodysplastic Syndromes (BCG-MDS-PED). We analyzed 168 cytogenetic studies performed in 23 different cytogenetic centers; 84 of these studies were performed in patients with confirmed MDS (primary MDS, secondary MDS, JMML, and acute myeloid leukemia/MDS+Down syndrome). Clonal abnormalities were found in 36.9% of the MDS cases and cytogenetic studies were important for the detection of constitutional diseases and for differential diagnosis with other myeloid neoplasms. These data show the importance of the Cooperative Group for continuing education in order to avoid a late or wrong diagnosis.

Invasive fungal diseases in haematopoietic cell transplant recipients and in patients with acute myeloid leukaemia or myelodysplasia in Brazil.

Invasive fungal disease (IFD) shows distinct regional incidence patterns and epidemiological features depending on the geographic region. We conducted a prospective survey in eight centres in Brazil from May 2007 to July 2009. All haematopoietic cell transplant (HCT) recipients and patients with acute myeloid leukaemia (AML) or myelodysplasia (MDS) were followed from admission until 1 year (HCT) or end of consolidation therapy (AML/MDS). The 12-month cumulative incidence (CI) of proven or probable IFD was calculated, and curves were compared using the Grey test. Among 237 AML/MDS patients and 700 HCT recipients (378 allogeneic, 322 autologous), the 1-year CI of IFD in AML/MDS, allogeneic HCT and autologous HCT was 18.7%, 11.3% and 1.9% (p <0.001), respectively. Fusariosis (23 episodes), aspergillosis (20 episodes) and candidiasis (11 episodes) were the most frequent IFD. The 1-year CI of aspergillosis and fusariosis in AML/MDS, allogeneic HCT and autologous HCT were 13.4%, 2.3% and 0% (p <0.001), and 5.2%, 3.8% and 0.6% (p 0.01), respectively. The 6-week probability of survival was 53%, and was lower in cases of fusariosis (41%). We observed a high burden of IFD and a high incidence and mortality for fusariosis in this first multicentre epidemiological study of IFD in haematological patients in Brazil.

Systemic vasculitis in myelodysplastic syndromes.

The development of immunological abnormalities in various neoplasms is a rather common phenomenon. The prevalence of life-threatening systemic vasculitis in malignancy, however, is much lower. Nonetheless we found an unexpected frequency of several autoimmune manifestations, including systemic vasculitis, in certain myelodysplastic syndromes. We illustrate this finding with the case of a 43-year-old man with signs of polyarteritis nodosa-like systemic vasculitis during progression of chronic myelomonocytic leukaemia. Subsequently, we review the literature on the combination of myelodysplastic syndromes and systemic vasculitis and discuss the prognostic consequences, considerations for treatment and possible pathophysiological mechanisms.

Does soy increase blood counts in myelodysplastic syndromes? / Será que a soja aumenta as contagens sanguíneas em síndrome mielodisplásica?

Myelodysplastic syndromes (MDS) are a group of clonal stem cell diseases characterized by ineffective hematopoiesis, bone marrow hyperproliferation, cytopenias in peripheral blood and risk of transformation into acute leukemia. We decided to investigate the effects of a soy concentrate on MDS patients based on the follow-up results of a 61 year-old Japanese female patient who was diagnosed with MDS and refractory cytopenia with multilineage dysplasia in 2003 (hemoglobin = 11g/dL; white blood cells count = 2,500/uL and platelets = 25,000/uL; marrow with mild dysplasia and normal karyotype; paroxysmal nocturnal hemoglobinuria was excluded). She started using soy as a dietary supplementation in May 2004 and presented a gradual increment in blood counts, achieving normalization approximately eight months afterwards. Among the soy components, the main compounds with anti-carcinogenic activity are the isoflavones (genistein and daidzein). Based on these lines of evidence, we proposed to administer daily a standard soy concentrate to 14 MDS out-patients for a minimum period of three months and maximum of 12 months, in an attempt to evaluate prospectively the possible increase in hemoglobin, neutrophils and platelet counts. A historical control group was used to compare results. The use of a soy concentrate in a standardized manner was associated with an increase in neutrophil and/or platelet counts in some cases, but spontaneous increments were also observed in historical controls. This preliminary study does not allow establishing a relation between soy supplementation and blood cell count increase.

As síndromes mielodisplásicas (SMD) são um grupo das doenças clonais de células-tronco caracterizado por hematopoese ineficaz, hiperproliferação de medula óssea, citopenias no sangue periférico e risco de transformação para leucemia aguda. Decidimos investigar os efeitos de um concentrado de soja em pacientes com SMD com base no fato de termos o seguimento de uma paciente japonesa, de 61 anos de idade, que foi diagnosticada em 2003 com SMD, citopenia refratária com displasia subtipo multilinhagens (hemoglobina = 11 g/dL; contagem de glóbulos brancos = 2.500/uL e plaquetas = 25.000/uL; medula com displasia leve e cariótipo normal; hemoglobinúria paroxística excluída), e que começou a usar a soja como suplemento alimentar em maio de 2004, apresentando gradual aumento da contagem das células sanguíneas, atingindo a normalização cerca de oito meses depois. Entre os componentes da soja, os principais compostos com propriedades anticarcinogênese são as isoflavonas (Ge nisteína e daidzeína). Com base nessas linhas de evidência, foi proposto oferecer diariamente um concentrado de soja padrão, por um período mínimo de três meses e máximo de doze meses, a 14 pacientes ambulatoriais, na tentativa de avaliar, prospectivamente, o possível aumento de hemoglobina, neutrófilos e plaquetas. Um grupo controle histórico foi utilizado para comparar os resultados. O uso de um concentrado de soja de forma padronizada foi associado ao aumento na contagem de neutrófilos e/ou de plaquetas em alguns casos, mas aumentos espontâneos também foram observados em controles históricos. Este estudo preliminar não permite estabelecer relação entre o uso de soja e o aumento na contagem sanguínea.

Increased chromosome damage in systemic sclerosis skin fibroblasts.

OBJECTIVE: To evaluate chromosome damage, by means of micronucleus frequency, in dermal fibroblasts from affected and non-affected skin from systemic sclerosis (SSc) patients and from controls. METHODS: Primary fibroblast cultures were obtained by biopsy from affected and non-affected skin from SSc patients. Control fibroblasts were derived from skin remnants from plastic surgery in healthy adults. The number of micronuclei-bearing cells per 1000 binucleated cells (MN+ cells/1000 BN) was determined in cultures with and without clastogenic stimulus (bleomycin 3 µg/mL). RESULTS: Primary cultures from 10 SSc patients (affected and non-affected skin) and nine controls were analysed by two blinded examiners. In the absence of bleomycin, the frequency of MN+ cells was higher in cultures from affected (14.01 ± 11.96 MN+ cells/1000 BN; p = 0.004) and non-affected (15.41 ± 13.58 MN cells/1000 BN; p = 0.005) skin from SSc patients as compared to fibroblasts from healthy controls (4.74 ± 3.30 MN cells/1000 BN). In bleomycin-treated cultures, the frequency of MN cells was higher in SSc affected (38.03 ± 26.14 MN cells/1000 BN; p = 0.041) and non-affected skin (38.47 ± 17.88 MN cells/1000 BN; p = 0.034) as compared to healthy control fibroblasts (20.54 ± 13.09 MN cells/1000 BN). There was no difference in the frequency of MN cells in cultures from affected and non-affected skin of SSc patients. CONCLUSIONS: This is the first demonstration that dermal fibroblasts from SSc patients present an increased frequency of spontaneous and clastogen-induced micronuclei. Increased clastogenesis seems to be a widespread phenomenon in SSc because fibroblasts from clinically affected and non-affected skin presented the equivalent increased micronuclei counts.

Comparison of I-FISH and G-banding for the detection of chromosomal abnormalities during the evolution of myelodysplastic syndrome

Myelodysplastic syndrome (MDS) patients with a normal karyotype constitute a heterogeneous group from a biological standpoint and their outcome is often unpredictable. Interphase fluorescence in situ hybridization (I-FISH) studies could increase the rate of detection of abnormalities, but previous reports in the literature have been contradictory. We performed I-FISH and conventional karyotyping (G-banding) on 50 MDS patients at diagnosis, after 6 and 12 months or at any time if a transformation to acute myeloid leukemia (AML) was detected. Applying a probe-panel targeting the centromere of chromosomes 7 and 8, 5q31, 5p15.2 and 7q31, we observed one case with 5q deletion not identified by G-banding. I-FISH at 6 and 12 months confirmed the karyotype results. Eight cases transformed to AML during follow-up, but no hidden clone was detected by I-FISH in any of them. The inclusion of I-FISH during follow-up of MDS resulted in a small improvement in abnormality detection when compared with conventional G-banding.

Comparison of I-FISH and G-banding for the detection of chromosomal abnormalities during the evolution of myelodysplastic syndrome.

Myelodysplastic syndrome (MDS) patients with a normal karyotype constitute a heterogeneous group from a biological standpoint and their outcome is often unpredictable. Interphase fluorescence in situ hybridization (I-FISH) studies could increase the rate of detection of abnormalities, but previous reports in the literature have been contradictory. We performed I-FISH and conventional karyotyping (G-banding) on 50 MDS patients at diagnosis, after 6 and 12 months or at any time if a transformation to acute myeloid leukemia (AML) was detected. Applying a probe-panel targeting the centromere of chromosomes 7 and 8, 5q31, 5p15.2 and 7q31, we observed one case with 5q deletion not identified by G-banding. I-FISH at 6 and 12 months confirmed the karyotype results. Eight cases transformed to AML during follow-up, but no hidden clone was detected by I-FISH in any of them. The inclusion of I-FISH during follow-up of MDS resulted in a small improvement in abnormality detection when compared with conventional G-banding.

Association of loss of heterozygosity with cytogenetic abnormalities in acute myeloid leukemia and myelodysplastic syndrome.

Deletions on chromosomes 5 and 7 are frequently seen in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). It is assumed that these deletions indicate loss of tumor suppressor genes on these chromosomes and until these tumor suppressor genes are identified, the functional consequences of these deletions and the molecular basis of these myeloid disorders cannot be completely understood. We evaluated loss of heterozygosity (LOH) in 44 patients (18 MDS and 26 AML, diagnosed according to WHO classification criteria) at diagnosis, using a four-microsatellite marker panel: an intragenic marker on the 7th intron of gene IRF-1 of the 5q31.1 region and three markers located inside the 7q31.1 region and correlated the LOH with karyotype abnormalities. The microsatellites chosen corresponded to chromosome regions frequently deleted in MDS/AML. The samples with Q (peak area) less than or equal to 0.50 were indicative of LOH. The percent of informative samples (i.e., heterozygous) for the intragenic microsatellite in gene IRF-1 and in loci D7S486, D7S515 and D7S522 were 66.6, 73.7, 75.5, and 48.8%, respectively. Cytogenetic abnormalities by G-banding were found in 36% (16/44) of the patients (2 of 18 MDS and 14 of 26 AML patients). We found a significantly positive association of the occurrence of LOH with abnormal karyotype (P < 0.05; chi-square test) and there were cases with LOH but the karyotype was normal (by G-banding). These data indicate that LOH in different microsatellite markers is possibly an event previous to chromosomal abnormalities in these myeloid neoplasias.