Fiocruz lança Estratégia para Terapias Avançadas no tratamento de câncer e doenças raras

Como parte da Estratégia e em parceria com o Ministério da Saúde (MS), a Fundação assinou um acordo de colaboração com a organização norte-americana sem fins lucrativos Caring Cross, que prevê a transferência de tecnologia, pelo Instituto de Tecnologia em Imunobiológicos (Bio-Manguinhos/Fiocruz), para a produção de células CAR-T e vetores lentivirais.

[Prevention and control of birth defects and rare diseases in the era of genomic medicine].

Birth defects and rare diseases have become major public health problems, and early prevention and control are the most effective interventions. In recent years, with the rapid development of genomic techniques such as high-throughput sequencing, the level of screening and diagnosis of genetic birth defects and rare diseases has been greatly improved. This article reviews the application of genomic technologies in the pre-pregnancy, preimplantation, prenatal and neonatal stages, as well as the trend of clinical transformation, highlighting the broad prospects of constructing an early and precise prevention and control system in the era of genomic medicine.

[Focus on the development of preimplantation genetic testing in the field of birth defects and rare diseases prevention and control].

Birth defects and rare diseases are serious challenges in China and even in the world, and most of them lack effective treatment. Preimplantation genetic testing (PGT) prevents the occurrence of this kind of disease at the source by carrying out genetic testing in the preimplantation stage and selecting normal embryos for transplantation. In this paper, the methods of PGT for birth defects and rare diseases and their latest progress are described.

HU é habilitado a oferecer Serviço Especializado em Doenças Raras

O Ministério da Saúde habilitou o Hospital Universitário (HU-UFJF/Ebserh) a ter um serviço de referência no atendimento a doenças raras. Os pacientes do Sistema Único de Saúde (SUS) poderão contar com diagnóstico clínico e molecular; aconselhamento genético; exames laboratoriais e de imagem; tratamentos específicos (quando disponíveis); reabilitação e orientações aos usuários, familiares e cuidadores quanto a doenças específicas. O Serviço Especializado em Doenças Raras pretende proporcionar atendimento multidisciplinar ao usuário, buscando a excelência na assistência global da pessoa com doença rara. Além disso, contribuirá na formação e no treinamento de profissionais da atenção primária no atendimento, reconhecimento e encaminhamento desses pacientes.

Epidemiologic Research of Rare Cancers: Trends, Resources, and Challenges.

BACKGROUND: The goals of this project were to assess the status of NCI's rare cancer-focused population science research managed by the Division of Cancer Control and Population Sciences (DCCPS), to develop a framework for evaluation of rare cancer research activities, and to review available resources to study rare cancers. METHODS: Cancer types with an overall age-adjusted incidence rate of less than 20 cases per 100,000 individuals were identified using NCI Surveillance, Epidemiology and End Results (SEER) Program data. SEER data were utilized to develop a framework based on statistical commonalities. A portfolio analysis of DCCPS-supported active grants and a review of three genomic databases were conducted. RESULTS: For the 45 rare cancer types included in the analysis, 123 active DCCPS-supported rare cancer-focused grants were identified, of which the highest percentage (18.7%) focused on ovarian cancer. The developed framework revealed five clusters of rare cancer types. The cluster with the highest number of grants (n = 43) and grants per cancer type (10.8) was the cluster that included cancer types of higher incidence, average to better survival, and high prevalence (in comparison with other rare cancers). Resource review revealed rare cancers are represented in available genomic resources, but to a lesser extent compared with more common cancers. CONCLUSIONS: This article provides an overview of the rare cancer-focused population sciences research landscape as well as information on gaps and opportunities. IMPACT: The findings of this article can be used to develop efficient and comprehensive strategies to accelerate rare cancer research.See related commentary by James V. Lacey Jr, p. 1300.

Pharmacological management of rare coagulation factor deficiencies besides hemophilia.

INTRODUCTION: Rare coagulation factor deficiencies are less-known disorders with variable effects on the patient's life. Management of such patients is a challenge due to the paucity of evidence-based data, more so when patients with these rare disorders encounter a more rare, related condition, like inhibitor development or thrombosis. AREA COVERED: A comprehensive literature search related to RCFDs and management was performed in PubMed in order to discuss therapeutic options and challenges, prophylaxis, management of minor and major surgeries, obstetric and gynecological complications, inhibitor development, and thrombosis. EXPERT OPINION: Although significant changes have occurred in the management of RCFDs in recent years, more evidence-based studies besides expert opinion are needed for optimal management.

[Characteristics of rare diseases in Zhejiang province, 2007-2017].

Objective: To understand the characteristics of 24 388 inpatients with rare diseases in Zhejiang province during 2007-2017 and provide evidence for rare disease prevention and control. Methods: Inpatient data of rare diseases and the number of hospitalization in each year were collected in 10 hospitals of class Ⅲ (A) in Zhejiang province from 2007 to 2017, and descriptive statistical analysis was used. Results: A total of 24 388 cases of rare diseases were found, accounting for 2.69‰ (24 388/9 054 201) of total hospitalized cases. The top 3 types of rare diseases were "diseases of blood and blood-forming organs and certain disorders involving immune mechanism" (32.81%, 8 001/24 388), "congenital malformations, deformations and chromosomal abnormalities" (24.87%, 6 065/24 388) and "diseases of the nervous system" (19.01%, 4 635/24 388). The number of rare disease cases increased year by year from 2007 to 2017 with an average annual growth of 19.69%, however, the proportion of rare disease cases in the annual number of hospitalized cases only showed upward trend during 2016-2017, the time distribution of different types of rare diseases had different characteristics. The male to female ratio of rare diseases cases was 1.35∶1(13 990/10 398), "diseases of the digestive system" (4.45∶1, 1 180/265), "consequences of injury, poisoning and other external causes" (3.51∶1, 281/80) and "diseases of the nervous system" (2.26∶1, 3 213/1 422) had the highest male to female ratio. The distributions of rare disease types and diseases of different types in different age groups varied. The top 10 rare diseases accounted for 53.55% (13 060/24 388) of the total cases, and the top 3 diseases were adult idiopathic neutropenia (14.41%, 3 515/24 388), corticobasal degeneration (7.60%, 1 854/24 388) and henock-schoenlein purpura (6.01%, 1 466/24 388). Conclusion: The analysis on the characteristics of 24 388 rare disease cases in Zhejiang during 2007-2017 provided reference evidence for the promotion of rare disease research, monitoring, building registration database, and development of the prevention and control strategy for rare diseases in China.

Diagnosis and detection of sarcoidosis: an official American Thoracic Society Clinical Practice Guideline

The diagnosis of sarcoidosis is not standardized but is based on three major criteria: a compatible clinical presentation, finding nonnecrotizing granulomatous inflammation in one or more tissue samples, and the exclusion of alternative causes of granulomatous disease. There are no universally accepted measures to determine if each diagnostic criterion has been satisfied; therefore, the diagnosis of sarcoidosis is never fully secure. Systematic reviews and, when appropriate, meta-analyses were performed to summarize the best available evidence. The evidence was appraised using the Grading of Recommendations, Assessment, Development, and Evaluation approach and then discussed by a multidisciplinary panel. Recommendations for or against various diagnostic tests were formulated and graded after the expert panel weighed desirable and undesirable consequences, certainty of estimates, feasibility, and acceptability. The clinical presentation, histopathology, and exclusion of alternative diagnoses were summarized. On the basis of the available evidence, the expert committee made 1 strong recommendation for baseline serum calcium testing, 13 conditional recommendations, and best practice statement. All evidence was very low quality.The panel used systematic reviews of the evidence to inform clinical recommendations in favor of or against various diagnostic tests in patients with suspected or known sarcoidosis. The evidence and recommendations should be revisited as new evidence becomes available.

Understanding the role of the cytoprotective transcription factor nuclear factor erythroid 2-related factor 2-lessons from evolution, the animal kingdom and rare progeroid syndromes.

The cytoprotective transcriptor factor nuclear factor erythroid 2- related factor 2 (NRF2) is part of a complex regulatory network that responds to environmental cues. To better understand its role in a cluster of inflammatory and pro-oxidative burden of lifestyle diseases that accumulate with age, lessons can be learned from evolution, the animal kingdom and progeroid syndromes. When levels of oxygen increased in the atmosphere, mammals required ways to protect themselves from the metabolic toxicity that arose from the production of reactive oxygen species. The evolutionary origin of the NRF2-Kelch-like ECH-associated protein 1 (KEAP1) signalling pathway from primitive origins has been a prerequisite for a successful life on earth, with checkpoints in antioxidant gene expression, inflammation, detoxification and protein homoeostasis. Examples from the animal kingdom suggest that superior antioxidant defense mechanisms with enhanced NRF2 expression have been developed during evolution to protect animals during extreme environmental conditions, such as deep sea diving, hibernation and habitual hypoxia. The NRF2-KEAP1 signalling pathway is repressed in progeroid (accelerated ageing) syndromes and a cluster of burden of lifestyle disorders that accumulate with age. Compelling links exist between tissue hypoxia, senescence and a repressed NRF2 system. Effects of interventions that activate NRF2, including nutrients, and more potent (semi)synthetic NRF2 agonists on clinical outcomes are of major interest. Given the broad-ranging actions of NRF2, we need to better understand the mechanisms of activation, biological function and regulation of NRF2 and its inhibitor, KEAP1, in different clinical conditions to ensure that modulation of this thiol-based system will not result in major adverse effects. Lessons from evolution, the animal kingdom and conditions of accelerated ageing clarify a major role of a controlled NRF2-KEAP1 system in healthy ageing and well-being.

Osteogénesis imperfecta de tipo III en niño ecuatoriano / Osteogenesis imperfecta type III in an Ecuadorian child

Introducción: la osteogénesis imperfecta es una rara enfermedad genética hereditaria caracterizada por su heterogeneidad causada por defectos del tejido conectivo con el rasgo de fragilidad ósea determinante de múltiples fracturas, incluso prenatales; deformidades de huesos largos y columna vertebral y otros síntomas extra-esqueléticos, como escleróticas de color azul, dentinogénesis imperfecta, trastorno de audición y afectación cardiovascular. Objetivo: Presentar un paciente con las características clínicas e imagenológicas de osteogénesis imperfecta de tipo III. Presentación del caso: Niño ecuatoriano de 4 años de edad de baja talla con antecedente de fracturas múltiples desde los 8 meses de nacido, con deformidad en columna vertebral demostrada por radiología por cifoescoliosis en forma de "S" y fracturas vertebrales, con deformidad progresiva en huesos largos; ha sufrido 16 fracturas, no deambula, sensorio presente, orientado en tiempo y espacio, desarrollo cognitivo normal para la edad. La fragilidad ósea del niño según el fenotipo clasifica al diagnóstico de tipo III de osteogénesis imperfecta, el cual es progresivo e invalidante por las deformidades óseas y múltiples fracturas demostradas en exámenes imagenológicos, sin modificaciones en el color de escleróticas, de herencia presumiblemente dominante. Conclusiones: La descripción clínica y radiológica de osteogénesis imperfecta, afección poco conocida, correspondiente al fenotipo III de la enfermedad, reportada en niño ecuatoriano de 4 años de edad, con talla baja que no deambula, expresión de la severidad de su afección genética, con severas alteraciones óseas por su fragilidad con fracturas múltiples en huesos largos y vértebras(AU)

Introduction: Osteogenesis imperfecta is a rare hereditary genetic disease characterized by its heterogeneity caused by connective tissue defects with the feature of bone fragility determining multiple fractures, even prenatal ones; also deformities of long bones and spine, and other extra-skeletal symptoms, such as blue sclerotic, dentinogenesis imperfecta, hearing disorder and cardiovascular affectations. Objective: To present a patient with clinical and radiological findings of osteogenesis imperfect type III. Case presentation: Ecuadorean male child of 4 years old, with a short height, history of multiple fractures from 8 months of age, with spinal deformity demonstrated by radiology due to "S" shaped kyphoscoliosis and vertebral fractures, with progressive deformity in long bones. The boy has suffered 16 fractures, he does not wander, and he is sensory present, oriented in time and space, with normal cognitive development for his age. The bone fragility of the child according to the phenotype classifies in the type III diagnosis of osteogenesis imperfecta, which is progressive and invalidating due to bone deformities and multiple fractures evidenced in imaging tests, without changes in the color of sclerotics and of presumably dominant inheritance. Conclusions: The clinical and radiological description of osteogenesis imperfecta, which is little-known pathology, corresponding to type III phenotype is reported in a 4-year-old boy who, due to his involvement, has a short height and does not wander as a consequence of the severity of bone affectations with fractures in long bones and vertebrae, mainly produced by the fragility of the bones due to his genetic disease(AU)

Recomendação nº 048, de 08 de novembro de 2019: recomenda aos Deputados Federais e Senadores da República, que rejeitem o veto do Presidente da República ao Projeto de Lei nº 6566/2013, tendo em vista que a garantia de recursos públicos para pesquisas sobre doenças raras ou negligenciadas é matéria de interesse público e de alta relevância social / Recommendation No. 048, of November 8, 2019: recommends that Federal Deputies and Senators of the Republic, reject the President of the Republic's veto of Bill 6566/2013, in view of the fact that the guarantee of public resources for research on diseases rare or neglected is a matter of public interest and of high social relevance

Recomenda aos Deputados Federais e Senadores da República, que rejeitem o veto do Presidente da República ao Projeto de Lei nº 6.566/2013, tendo em vista que a garantia de recursos públicos para pesquisas sobre doenças raras ou negligenciadas é matéria de interesse público e de alta relevância social.

Primary prevention as an essential factor ensuring sustainability of health systems: the example of congenital anomalies.

Protection of early development contributes to health of next generations. Congenital anomalies (and other adverse reproductive outcomes) are an important public health issue and early indicator of public health risks, as early development is influenced by many risk factors (e.g., nutrition, lifestyles, pollution, infections, medications, etc). Effective primary prevention requires an integrated "One Health" approach, linking knowledge and action. This requires surveillance of health events and potential health-damaging factors, science-based risk analysis, citizens' empowerment and education of health professionals. From the policy standpoint, joint budgeting mechanisms are needed to sustain with equity intersectoral actions (involving policy domains of health, social affairs, education, agriculture and environment). States should devote resources to strengthen registries and systematic data collection for surveillance of congenital anomalies, to better inform national prevention strategies. Investing in primary prevention based on scientific evidence is essential to support sustainable and resilient health systems and sustainable development of the society.

Effect of mobile phone text messaging for improving the uptake of influenza vaccination in patients with rare diseases.

OBJECTIVES: Influenza vaccine is recommended in some chronic medical conditions, including several rare diseases. The objectives of the study were to assess the effect of text message reminders on influenza vaccination uptake of patients with selected rare diseases and delayed vaccination, and to describe their characteristics. METHODS: Quasi-experimental pre-post intervention study performed along the 2016 influenza vaccination campaign in the Autonomous Community of Madrid. Unvaccinated patients diagnosed with a selected rare disease were targeted for intervention. SMS were sent to them at least one month after the beginning of the campaign, in four consecutive weeks. Those with no mobile phones available or no certainty of message reception, were assigned as controls. The association between the reception of the SMS and vaccination uptake was assessed using multiple poisson regression models. RESULTS: Of 69.040 patients with delayed vaccination, 87.2% received an SMS reminder in the asigned contact mobile telephone. Global influenza vaccine coverage reached 41.3%. The uptake of influenza vaccine was significantly higher among those receiving the reminder (9.3% vs. 7.1% in the control group, p < 0.001). Those who received a SMS reminder were 30% more likely to uptake seasonal influenza vaccine. By sex and age, the reception of the reminder was associated with a significantly higher probability of vaccination in men ≥65 years with at least a concurrent chronic condition (IRR: 1.58, CI95%: 1.25-2.00). Among women, this higher probability was detected in those between 14 and 64 years of age (IRR: 1.41, CI95%: 1.22-1.63), and ≥65 years without concurrent chronic conditions (IRR: 1.40, CI95%: 1.05-1.89). CONCLUSION: Although the intervention was modestly effective, it proved beneficial in some cases. It can be an additional strategy to improve vaccine uptake, since it is simple, feasible, affordable and easily scalable, particularly when immunization and target population data are available in population registries.

Severe fever and thrombocytopenia syndrome virus infection: Considerations for vaccine evaluation of a rare disease.

Infection caused by the severe fever and thrombocytopenia syndrome virus (SFTSV) causes a hemorrhagic illness with a mortality between 20% and 40%. Initially recognized in 2009 in China, cases have additionally been documented in Japan and Korea although retrospective studies have documented seroprevalence since 1996. Although case rates have increased due to increased awareness and more widely available diagnostics, SFTSV infection remains rare with the highest rates documented in Korea for Jeju Province (3.5 cases per 100,000 population) and the Inje-gun region (66.2 cases per 100,000). Because of the very low incidence of infection, a placebo-controlled study with 1:1 randomization to evaluate an SFTSV vaccine would require a sample size that is 25% greater than the region of study. We discuss alternatives to licensure. Vaccine effectiveness may be assessed through a registry, comparing rates of infection over time between vaccine recipients versus regional populations. Modeled data can be updated based on actual case rates and population changes over the years of follow-up. Using one model, statistically significant differences are seen after 10 years in Inje-gun and 15 years of follow-up in Jeju. This approach may be applicable to other uncommon infectious diseases for which a standard study design is difficult.

Differential methylation in rare ophthalmic disorders: a systematic review protocol.

BACKGROUND: Rare ophthalmic conditions often cause degenerative vision loss which leads to loss of independence, ability to work and ultimately quality life. Differential methylation is an epigenomic marker that is a feature of several diseases, including eye conditions. This review will aim to elucidate the extent to which differential methylation has been identified in rare ophthalmic conditions. METHODS: A systematic review will be conducted of articles found in the electronic databases MEDLINE, EMBASE, PubMed and Cochrane Library of Systematic Reviews. Grey literature databases GreyLit and OpenGrey will be searched for relevant unpublished sources. Reference lists of articles which meet eligibility criteria will also be screened for forward and reverse citations. Eligibility criteria will include quantitative articles published, before July 2018, written in English and featuring analysis of differential methylation in rare ophthalmic disorders. Studies will be screened firstly by title, abstract and keywords and then by full text for any remaining sources, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Data extraction of key characteristics will be completed using customised forms. Methodological rigour will be assessed using customised forms modelled on the Joanna Briggs Institute critical appraisal forms. DISCUSSION: This systematic review will enable us to identify if differential methylation can be used to characterise rare ophthalmic disease, which could have crucial implications for improving the accuracy and speed of diagnosis, identifying novel therapeutic targets to reduce or prevent vision loss and overall improving understanding of rare ophthalmic disease. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42018094231.

The international WAO/EAACI guideline for the management of hereditary angioedema-The 2017 revision and update.

Hereditary Angioedema (HAE) is a rare and disabling disease. Early diagnosis and appropriate therapy are essential. This update and revision of the global guideline for HAE provides up-to-date consensus recommendations for the management of HAE. In the development of this update and revision of the guideline, an international expert panel reviewed the existing evidence and developed 20 recommendations that were discussed, finalized and consented during the guideline consensus conference in June 2016 in Vienna. The final version of this update and revision of the guideline incorporates the contributions of a board of expert reviewers and the endorsing societies. The goal of this guideline update and revision is to provide clinicians and their patients with guidance that will assist them in making rational decisions in the management of HAE with deficient C1-inhibitor (type 1) and HAE with dysfunctional C1-inhibitor (type 2). The key clinical questions covered by these recommendations are: (1) How should HAE-1/2 be defined and classified?, (2) How should HAE-1/2 be diagnosed?, (3) Should HAE-1/2 patients receive prophylactic and/or on-demand treatment and what treatment options should be used?, (4) Should HAE-1/2 management be different for special HAE-1/2 patient groups such as pregnant/lactating women or children?, and (5) Should HAE-1/2 management incorporate self-administration of therapies and patient support measures?

Rare disease prevention and treatment: the need for a level playing field.

Pharmacogenetic tests are being used increasingly to prevent rare and potentially life-threatening adverse drug reactions. For many tests, however, cost-effectiveness is hard to demonstrate, and with the exception of a few cases, widespread implementation remains a distant prospect. Many orphan drugs for rare diseases are also not cost effective but are nonetheless normally reimbursed. In this article, we argue that the health technology assessment of pharmacogenetic tests aimed to prevent rare but severe adverse drug reactions should be on a level playing field with orphan drugs. This is supported by a number of arguments, concerning the severity, rarity and iatrogenic nature of adverse drug reactions, the distribution of benefits and costs and societal preference towards prevention over treatment.

Congenital Anomalies: Cluster Detection and Investigation.

This work summarizes the main aspects to be considered around birth defects (or congenital anomalies) clusters. Most birth defects (BD), considered individually, fall into the definition of rare diseases (RD), according to their low frequency. Likewise, many RD are congenital, because their manifestations are present at birth or can be even evident before the delivery. It has been estimated that overall 7.9 million children are born each year with serious BD of genetic or partially genetic origin, and additional hundreds of thousands more are born with serious BD of post-conception origin.A "birth defect cluster" can be defined as an unusual aggregation of cases (grouped in place and time) that is suspected to be greater than expected, even though the expected number may not be known. These clusters are incidents or occurrences that let us turn the challenge of identifying the causal agent(s) involved in the origin of such clusters, into an opportunity to exert primary prevention, and thus achieve the ultimate goal of enabling infants being born healthy. Therefore, any program or system involved in BD surveillance and research should devote part of its activities to detect and investigate clusters, to ensure that such opportunity for primary prevention will be conveniently leveraged. Regardless the type of cluster, there are several phases that must be undertaken sequentially for proper control and the maximum benefit for the population: cluster detection, evaluation and investigation, management, adoption of preventive measures, and communication of the results to the public or target population.