Epidemiological profile and clinical characteristics of 491 Brazilian patients with neurofibromatosis type 1.

BACKGROUND: Neurofibromatosis type 1 (NF1) is a chronic and progressive autosomal dominant genetic and sporadic disease characterized by cutaneous and neurological abnormalities. Plexiform neurofibroma (PN), a significant cause of clinical complications in NF-1, is a benign tumor of the peripheral nerve sheath that involves multiple nerve fascicles. Although there is an important number of patients who are affected by NF1 in Brazil, there is little data on the behavior of the disease in the national literature as well as in other low- and middle-income countries. METHODS: We performed a retrospective analysis of 491 patients with NF1 followed at two reference centers in Brazil. RESULTS: Approximately 38% of patients had PNs, resulting in reduced life quality. The median patient age with PNs was 30 years (range: 6 to 83 years). Head and neck, and extremity were the main affected locations with 35.8 and 30.6%, respectively. PNs were classified as asymptomatic in 25.1% of patients, while 52.5% presented symptomatic and inoperable tumors. The most common manifestations related to PNs were disfigurement and orthopedic involvement. Twenty patients developed neoplasms and ten (50%) presented with malignant peripheral nerve sheath tumors (MPNST). The prevalence of MPNST in our study was 2.9%. CONCLUSIONS: Patients with NF1 experience clinically significant morbidity, especially when it is associated with PN. Though there are many patients affected by NF1 in Brazil and other low- and middle-income countries, there is little data available in the corresponding literature. Our results are comparable to the previous results reported from higher-income countries and international registries.

Allogeneic haematopoietic stem cell transplantation resets T- and B-cell compartments in sickle cell disease patients.

Objectives: Allogeneic haematopoietic stem cell transplantation (allo-HSCT) is the only currently available curative treatment for sickle cell disease (SCD). Here, we comprehensively evaluated the reconstitution of T- and B-cell compartments in 29 SCD patients treated with allo-HSCT and how it correlated with the development of acute graft-versus-host disease (aGvHD). Methods: T-cell neogenesis was assessed by quantification of signal-joint and ß-chain TCR excision circles. B-cell neogenesis was evaluated by quantification of signal-joint and coding-joint K-chain recombination excision circles. T- and B-cell peripheral subset numbers were assessed by flow cytometry. Results: Before allo-HSCT (baseline), T-cell neogenesis was normal in SCD patients compared with age-, gender- and ethnicity-matched healthy controls. Following allo-HSCT, T-cell neogenesis declined but was fully restored to healthy control levels at one year post-transplantation. Peripheral T-cell subset counts were fully restored only at 24 months post-transplantation. Occurrence of acute graft-versus-host disease (aGvHD) transiently affected T- and B-cell neogenesis and overall reconstitution of T- and B-cell peripheral subsets. B-cell neogenesis was significantly higher in SCD patients at baseline than in healthy controls, remaining high throughout the follow-up after allo-HSCT. Notably, after transplantation SCD patients showed increased frequencies of IL-10-producing B-regulatory cells and IgM+ memory B-cell subsets compared with baseline levels and with healthy controls. Conclusion: Our findings revealed that the T- and B-cell compartments were normally reconstituted in SCD patients after allo-HSCT. In addition, the increase of IL-10-producing B-regulatory cells may contribute to improve immune regulation and homeostasis after transplantation.

Long-Term Effects of Allogeneic Hematopoietic Stem Cell Transplantation on Systemic Inflammation in Sickle Cell Disease Patients.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only currently available curative treatment for sickle cell disease (SCD). However, the effects of HSCT on SCD pathophysiology are poorly elucidated. Here, we assessed red blood cell (RBC) adhesiveness, intensity of hemolysis, vascular tone markers and systemic inflammation, in SCD patients treated with allogeneic HSCT. Thirty-two SCD patients were evaluated before and on long-term follow-up after HSCT. Overall survival was 94% with no severe (grade III-IV) graft-vs-host disease and a 22% rejection rate (graft failure). Hematological parameters, reticulocyte counts, and levels of lactate dehydrogenase (LDH), endothelin-1 and VCAM-1 normalized in SCD patients post-HSCT. Expression of adhesion molecules on reticulocytes and RBC was lower in patients with sustained engraftment. Levels of IL-18, IL-15 and LDH were higher in patients that developed graft failure. Increased levels of plasma pro-inflammatory cytokines, mainly TNF-α, were found in SCD patients long-term after transplantation. SCD patients with sustained engraftment after allo-HSCT showed decreased reticulocyte counts and adhesiveness, diminished hemolysis, and lower levels of vascular tonus markers. Nevertheless, systemic inflammation persists for at least five years after transplantation, indicating that allo-HSCT does not equally affect all aspects of SCD pathophysiology.

Brazilian Nutritional Consensus in Hematopoietic Stem Cell Transplantation: children and adolescents.

The Brazilian Nutritional Consensus in Hematopoietic Stem Cell Transplantation: Children and Adolescents was developed by dietitians, physicians, and pediatric hematologists from 10 Brazilian reference centers in hematopoietic stem cell transplantation. The aim was to emphasize the importance of nutritional status and body composition during treatment, as well as the main characteristics related to patient´s nutritional assessment. This consensus is intended to improve and standardize nutrition therapy during hematopoietic stem cell transplantation. The consensus was approved by the Brazilian Society of Bone Marrow Transplantation.

Hematopoietic stem cell transplantation reverses white matter injury measured by diffusion-tensor imaging (DTI) in sickle cell disease patients.

Brain injury in sickle cell disease (SCD) comprises a wide spectrum of neurological damage. Neurocognitive deficits have been described even without established neurological lesions. DTI is a rapid, noninvasive, and non-contrast method that enables detection of normal-appearing white matter lesions not detected by conventional magnetic resonance imaging (MRI). The aim of the study was to evaluate if stem cell transplantation can revert white matter lesions in patients with SCD. Twenty-eight SCD patients were evaluated with MRI and DTI before and after allogeneic hematopoietic stem cell transplantation (HSCT), compared with 26 healthy controls (HC). DTI metrics included fractional anisotropy (FA), mean diffusivity (MD), radial (RD), and axial (AD) diffusivity maps, global efficiency, path length, and clustering coefficients. Compared to HC, SCD patients had a lower FA (p = 0.0086) before HSCT. After HSCT, FA increased and was not different from healthy controls (p = 0.1769). Mean MD, RD, and AD decreased after HSCT (p = 0.0049; p = 0.0029; p = 0.0408, respectively). We confirm previous data of white matter lesions in SCD and present evidence that HSCT promotes recovery of brain injury with potential improvement of brain structural connectivity.

Brazilian Nutritional Consensus in Hematopoietic Stem Cell Transplantation: children and adolescents / Consenso Brasileiro de Nutrição em Transplante de Células-Tronco Hematopoiéticas: crianças e adolescentes

ABSTRACT The Brazilian Nutritional Consensus in Hematopoietic Stem Cell Transplantation: Children and Adolescents was developed by dietitians, physicians, and pediatric hematologists from 10 Brazilian reference centers in hematopoietic stem cell transplantation. The aim was to emphasize the importance of nutritional status and body composition during treatment, as well as the main characteristics related to patient´s nutritional assessment. This consensus is intended to improve and standardize nutrition therapy during hematopoietic stem cell transplantation. The consensus was approved by the Brazilian Society of Bone Marrow Transplantation.

RESUMO O Consenso Brasileiro de Nutrição em Transplante de Células-Tronco Hematopoiéticas: crianças e adolescentes foi elaborado com a participação de nutricionistas, médicos nutrólogos e médicos hematologistas pediátricos de 10 centros brasileiros que são referência em transplante de células-tronco hematopoiéticas. O objetivo foi salientar a importância do estado nutricional e da composição corporal durante o tratamento, bem como as principais características relacionadas à avaliação nutricional do paciente. As intenções, ao se estabelecer o consenso, foram aprimorar e padronizar a terapia nutricional durante o transplante de células-tronco hematopoiéticas. O consenso foi aprovado pela Sociedade Brasileira de Transplante de Médula Óssea.

Treatment of Recurrent Urinary Tract Infection Symptoms with Urinary Antiseptics Containing Methenamine and Methylene Blue: Analysis of Etiology and Treatment Outcomes.

PURPOSE: Urinary antiseptics including methenamine and methylene blue are used in the symptomatic treatment of urinary tract infections (UTIs). PATIENTS AND METHODS: This was a prospective, double-blind, randomized, double-dummy safety and efficacy study of 2 urinary antiseptic combinations in the symptomatic treatment of recurrent cystitis: methenamine 120mg + methylene blue 20mg (Group A) versus acriflavine 15mg + methenamine 250mg + methylene blue 20mg + Atropa belladonna L. 15mg (Group B). All subjects underwent pretreatment urine culture and antibiotic sensitivity tests prior to 3-day oral treatment with study drug, followed by 3 days of antibiotic therapy (based on urine culture) + study drug treatment. Efficacy was evaluated using the Urinary Tract Infection Symptoms Assessment Questionnaire (UTISA). The primary endpoint was the percentage of patients presenting improvement in cystitis manifestations on the UTISA domain "Urination Regularity" at Visit 2. The primary safety variable was the incidence of treatment-related adverse events. RESULTS: A total of 144 subjects were randomized per group and 272 completed the study. Primary endpoint analysis demonstrates homogeneity between treatment groups, with 69.4% and 72.2% subjects, respectively, showing improvement in the score of the urinary regularity UTISA domain after 3 days of treatment (p= 0.87). At Visit 2, incidence of treatment-related adverse events was higher in Group B (Group A: n= 11, Group B: n= 31, p= 0.0057). CONCLUSION: Both treatments were effective in reducing UTI symptoms assessed by UTISA questionnaire after 3 days of treatment. The two regimens were comparable in incidence of adverse events, but the combination of methenamine + methylene blue resulted in fewer treatment-related adverse effects.

Allogeneic Hematopoietic Stem Cell Transplantation for Children and Adolescents with Acute Myeloid Leukemia in Brazil: A Multicentric Retrospective Study.

The survival rates of children with high-risk acute myeloid leukemia (AML) treated with hematopoietic stem cell transplant (HSCT) range from 60% to 70% in high-income countries. The corresponding rate for Brazilian children with AML who undergo HSCT is unknown. We conducted a retrospective analysis of 114 children with AML who underwent HSCT between 2008 and 2012 at institutions participating in the Brazilian Pediatric Bone Marrow Transplant Working Group. At transplant, 38% of the children were in first complete remission (CR1), 37% were in CR2, and 25% were in CR3+ or had persistent disease. The donors included 49 matched-related, 59 matched-unrelated, and six haploidentical donors. The most frequent source of cells was bone marrow (69%), followed by the umbilical cord (19%) and peripheral blood (12%). The 4-year overall survival was 47% (95% confidence interval [CI] 30%-57%), and the 4-year progression-free survival was 40% (95% CI 30%-49%). Relapse occurred in 49 patients, at a median of 122 days after HSCT. There were 65 deaths: 40 related to AML, 19 to infection, and six to graft versus host disease. In conclusion, our study suggests that HSCT outcomes for children with AML in CR1 or CR2 are acceptable and that this should be considered in the overall treatment planning for children with AML in Brazil. Therapeutic standardization through the adoption of multicentric protocols and appropriate supportive care treatment will have a significant impact on the results of HSCT for AML in Brazil and possibly in other countries with limited resources.

MicroRNA profile of pediatric pilocytic astrocytomas identifies two tumor-specific signatures when compared to non-neoplastic white matter.

PURPOSES: Pilocytic astrocytoma (PA) is a low-grade neoplasm frequently found in childhood. PA is characterized by slow growth and a relatively good prognosis. Genetic mechanisms such as activation of MAPK, BRAF gene deregulation and neurofibromatosis type 1 (NF1) syndrome have been associated with PA development. Epigenetic signature and miRNA expression profile are providing new insights about different types of tumor, including PAs. METHODS: In the present study we evaluated global miRNA expression in 16 microdissected pediatric PA specimens, three NF1-associated PAs and 11 cerebral white matter (WM) samples by the microarray method. An additional cohort of 20 PAs was used to validate by qRT-PCR the expression of six miRNAs differentially expressed in the microarray data. RESULTS: Unsupervised hierarchical clustering analysis distinguished one cluster with nine PAs, including all NF1 cases and a second group consisting of the WM samples and seven PAs. Among 88 differentially expressed miRNAs between PAs and WM samples, the most underexpressed ones regulate classical pathways of tumorigenesis, while the most overexpressed miRNAs are related to pathways such as focal adhesion, P53 signaling pathway and gliomagenesis. The PAs/NF1 presented a subset of underexpressed miRNAs, which was also associated with known deregulated pathways in cancer such as cell cycle and hippo pathway. CONCLUSIONS: In summary, our data demonstrate that PA harbors at least two distinct miRNA signatures, including a subgroup of patients with NF1/PA lesions.

Prolonged viremia in dengue virus infection in hematopoietic stem cell transplant recipients and patients with hematological malignancies.

Fever, skin rash, headache, and thrombocytopenia are considered hallmarks of dengue infection. However, these symptoms are frequently observed in infectious and non-infectious complications of hematopoietic stem cell transplant recipients and oncohematological patients. Thus, laboratory confirmation of dengue is relevant for prompt intervention and proper management of dengue in endemic and non-endemic regions. Because no prospective study of dengue has been conducted in these populations, the actual morbidity and mortality of dengue is unknown. In the present series, we describe five cases of dengue in patients living in endemic areas, emphasizing the prolonged course of the disease and the occurrence of prolonged viremia.

Neurofibromatosis: part 2--clinical management.

Part 1 of this guideline addressed the differential diagnosis of the neurofibromatoses (NF): neurofibromatosis type 1 (NF1), neurofibromatosis type 2 (NF2) and schwannomatosis (SCH). NF shares some features such as the genetic origin of the neural tumors and cutaneous manifestations, and affects nearly 80 thousand Brazilians. Increasing scientific knowledge on NF has allowed better clinical management and reduced rate of complications and morbidity, resulting in higher quality of life for NF patients. Most medical doctors are able to perform NF diagnosis, but the wide range of clinical manifestations and the inability to predict the onset or severity of new features, consequences, or complications make NF management a real clinical challenge, requiring the support of different specialists for proper treatment and genetic counseling, especially in NF2 and SCH. The present text suggests guidelines for the clinical management of NF, with emphasis on NF1.

Neurofibromatosis: part 2 – clinical management / Neurofibromatoses: parte 2 – manejo clínico

Part 1 of this guideline addressed the differential diagnosis of the neurofibromatoses (NF): neurofibromatosis type 1 (NF1), neurofibromatosis type 2 (NF2) and schwannomatosis (SCH). NF shares some features such as the genetic origin of the neural tumors and cutaneous manifestations, and affects nearly 80 thousand Brazilians. Increasing scientific knowledge on NF has allowed better clinical management and reduced rate of complications and morbidity, resulting in higher quality of life for NF patients. Most medical doctors are able to perform NF diagnosis, but the wide range of clinical manifestations and the inability to predict the onset or severity of new features, consequences, or complications make NF management a real clinical challenge, requiring the support of different specialists for proper treatment and genetic counseling, especially in NF2 and SCH. The present text suggests guidelines for the clinical management of NF, with emphasis on NF1.

A primeira parte desta diretriz abordou o diagnóstico diferencial das neurofibromatoses (NF): neurofibromatose do tipo 1 (NF1), neurofibromatose do tipo 2 (NF2) e schwannomatose (SCH). As NF compartilham algumas características, como a origem neural dos tumores e sinais cutâneos, e afetam cerca de 80 mil brasileiros. O aumento do conhecimento científico sobre as NF tem permitido melhor manejo clínico e redução da morbidade das complicações, resultando em melhor qualidade de vida para os pacientes com NF. A maioria dos médicos é capaz de realizar o diagnóstico das NF, mas a variedade de manifestações clínicas e a dificuldade de se prever o surgimento e a gravidade de complicações, torna o manejo da NF um desafio para o clínico e envolve diferentes especialistas para o tratamento adequado e aconselhamento genético, especialmente a NF2 e a SCH. O presente texto sugere algumas orientações para o acompanhamento dos portadores de NF, com ênfase na NF1.

Mucopolissacaridose tipo I - revisão dos aspectos clínicos e terapêuticos / Mucopolysaccaridosis type I - review of clinical and therapeutic aspects

As mucopolissacaridoses são doenças genéticas raras, classificadas como erros inatos do metabolismo, caracterizadas pela deficiência de enzimas lisossômicas específicas que afetam o catabolismo dos glicosaminoglicanos. O acúmulo progressivo dos glicosaminoglicanos leva ao comprometimento de diversos órgãos, particularmente o encéfalo. Por se tratar de uma doença rara e multissistêmica a participação de uma equipe multidisciplinar de profissionais especializados é sempre recomendada para um melhor diagnóstico e tratamento. A mucopolissacaridose tipo I é uma doença lisossômica crônica, progressiva e multissistêmica, causada pela deficiência ou ausência de atividade da enzima a-L-iduronidase (IDUA). Este artigo faz uma revisão dos principais aspectos clínicos e terapêuticos da mucopolissacaridose tipo I.

Neurofibromatoses: part 1 - diagnosis and differential diagnosis.

Neurofibromatoses (NF) are a group of genetic multiple tumor growing predisposition diseases: neurofibromatosis type 1 (NF1), neurofibromatosis type 2 (NF2) and schwannomatosis (SCH), which have in common the neural origin of tumors and cutaneous signs. They affect nearly 80 thousand of Brazilians. In recent years, the increased scientific knowledge on NF has allowed better clinical management and reduced complication morbidity, resulting in higher quality of life for NF patients. In most cases, neurology, psychiatry, dermatology, clinical geneticists, oncology and internal medicine specialists are able to make the differential diagnosis between NF and other diseases and to identify major NF complications. Nevertheless, due to its great variability in phenotype expression, progressive course, multiple organs involvement and unpredictable natural evolution, NF often requires the support of neurofibromatoses specialists for proper treatment and genetic counseling. This Part 1 offers step-by-step guidelines for NF differential diagnosis. Part 2 will present the NF clinical management.

Neurofibromatoses: part 1 diagnosis and differential diagnosis / Das neurofibromatoses: parte 1 diagnostico e diagnostico diferencial

Neurofibromatoses (NF) are a group of genetic multiple tumor growing predisposition diseases: neurofibromatosis type 1 (NF1), neurofibromatosis type 2 (NF2) and schwannomatosis (SCH), which have in common the neural origin of tumors and cutaneous signs. They affect nearly 80 thousand of Brazilians. In recent years, the increased scientific knowledge on NF has allowed better clinical management and reduced complication morbidity, resulting in higher quality of life for NF patients. In most cases, neurology, psychiatry, dermatology, clinical geneticists, oncology and internal medicine specialists are able to make the differential diagnosis between NF and other diseases and to identify major NF complications. Nevertheless, due to its great variability in phenotype expression, progressive course, multiple organs involvement and unpredictable natural evolution, NF often requires the support of neurofibromatoses specialists for proper treatment and genetic counseling. This Part 1 offers step-by-step guidelines for NF differential diagnosis. Part 2 will present the NF clinical management.

Neurofibromatoses (NF) constituem um grupo de doenças genéticas com predisposição ao crescimento de múltiplos tumores: tipo 1 (NF1), tipo 2 (NF2) e schwannomatose (SCH). Estas doenças têm em comum a origem neural dos tumores e os sinais cutâneos. Afetam cerca de 80 mil brasileiros. O maior conhecimento científico sobre as NF tem permitido melhor manejo clínico, redução da morbidade das complicações e melhor qualidade de vida. Na maioria dos casos, os especialistas em neurologia, dermatologia, genética clínica, oncologia e medicina interna estão capacitados a realizar o diagnóstico diferencial e identificar suas principais complicações. Devido à sua variabilidade fenotípica, curso progressivo, multiplicidade de órgãos acometidos e evolução imprevisível, as NF frequentemente necessitam de especialistas em NF para o acompanhamento. A Parte 1 deste texto oferece orientações para o diagnóstico de cada tipo de NF e discute os diagnósticos diferenciais com outras doenças. A Parte 2 oferecerá orientações em relação ao manejo clínico das NF.

Mucopolissacaridose III B: revisão dos aspectos clínicos com ênfase no diagnóstico precoce

Objetivo: Realizar uma revisão da literatura sobre mucopolissacaridose tipo III, enfatizando as manifestações clínicas e o diagnóstico precoce. Fontes de dados: Bases de dados MEDLINE e artigos selecionados pertinentes ao assunto, publicados até o momento, buscados de acordo com os seguintes termos: ?mucopolissacaridose?, ?Sanfilippo?, ?licosaminoglicanos?. Síntese dos dados: As mucopolissacaridoses (MPS) III (síndrome de Sanfilippo) são doenças genéticas, causadas por deficiências enzimáticas, com consequente acúmulo lisossomal de mucopolissacarideos nos tecidos, resultando em sinais e sintomas permanentes e progressivos. São subdivididas em quatro subtipos: III-A, III-B, III-C e III-D, de acordo com a deficiência enzimática específica. São caracterizadas por fenótipo clínico característico, combinado com doença neurodegenerativa precoce e grave, com proeminentes distúrbios de comportamento e convulsões. O diagnóstico oportuno e precoce é fundamental para não só melhorar o tratamento de suporte do paciente, como também para oferecer à família aconselhamento genético. Conclusões: Enfatizamos a necessidade de reconhecimento, pelo pediatra, do fenótipo MPS III típico.

Moyamoya syndrome associated with neurofibromatosis type I in a pediatric patient.

CONTEXT: Neurofibromatosis type 1 (NF-1) is the most prevalent autosomal dominant genetic disorder among humans. Moyamoya disease is a cerebral vasculopathy that is only rarely observed in association with NF-1, particularly in the pediatric age range. The present study reports an occurrence of this association in an infant. CASE REPORT: An eight-month-old female presented convulsive seizures with clonic movements. The patient suffered an ischemic stroke with hemiparesis. Magnetic resonance imaging revealed radiological findings compatible with moyamoya disease. The diagnosis of NF-1 was made at the age of 20 months. CONCLUSION: Despite the rarity of this association in childhood, children with focal neurological symptoms and a diagnosis of NF-1 deserve to be investigated for moyamoya syndrome.