Immune response to enzyme replacement therapies in lysosomal storage diseases and the role of immune tolerance induction.

The US Food and Drug Administration (FDA) and National Organization for Rare Disease (NORD) convened a public workshop titled "Immune Responses to Enzyme Replacement Therapies: Role of Immune Tolerance Induction" to discuss the impact of anti-drug antibodies (ADAs) on efficacy and safety of enzyme replacement therapies (ERTs) intended to treat patients with lysosomal storage diseases (LSDs). Participants in the workshop included FDA staff, clinicians, scientists, patients, industry, and advocacy group representatives. The risks and benefits of implementing prophylactic immune tolerance induction (ITI) to reduce the potential clinical impact of antibody development were considered. Complications due to immune responses to ERT are being recognized with increasing experience and lengths of exposure to ERTs to treat several LSDs. Strategies to mitigate immune responses and to optimize therapies are needed. Discussions during the workshop resulted in the identification of knowledge gaps and future areas of research, as well as the following proposals from the participants: (1) systematic collection of longitudinal data on immunogenicity to better understand the impact of ADAs on long-term clinical outcomes; (2) development of disease-specific biomarkers and outcome measures to assess the effect of ADAs and ITI on efficacy and safety; (3) development of consistent approaches to ADA assays to allow comparisons of immunogenicity data across different products and disease groups, and to expedite reporting of results; (4) establishment of a system to widely share data on antibody titers following treatment with ERTs; (5) identification of components of the protein that are immunogenic so that triggers and components of the immune responses can be targeted in ITI; and (6) consideration of early ITI in patients who are at risk of developing clinically relevant ADA that have been demonstrated to worsen treatment outcomes.

RECURRENT SEPSIS IN A PATIENT WITH BILIARY HAMARTOMAS.

Biliary hamartomas or von Meyenburg complexes (VMCs) are hepatic tumour-like lesions related to congenital malformation of the ductal plate, and are part of the ciliopathy spectrum of disorders. The exact pathogenesis of VMCs is unclear and it remains controversial whether they have the potential for malignant transformation. Patients are often asymptomatic and VMCs are usually encountered as an incidental finding on imaging. We report a case of recurrent sepsis with an unidentified focus. It was later confirmed that biliary hamartomas were acting as a sanctuary for the persistent pathogenic agent. The authors hope to draw attention to the existence of this unusual focus of recurrent sepsis. LEARNING POINTS: Hepatobiliary sepsis is an unusual clinical presentation of biliary hamartomas.Clinicians should be aware of the infectious complications of these diffuse structural biliary ductal abnormalities.Early recognition of this atypical life-threatening clinical presentation is important for the prognosis.

Vitamina D associada à resistência insulínica / Vitamin D associated with insulin resistance

A vitamina D, obtida por forma endógena ou exógena, possui funções importantes no metabolismo da glicose. Sua deficiência está relacionada à resistência insulínica uma vez que essa vitamina atua diretamente nas células ß ­ pancreáticas, facilitando a secreção de insulina. Nesta revisão, realizou-se um levantamento bibliográfico, mediante consulta nos bancos de dados PubMed, SciELO e BVS, objetivando comprovar a relação existente entre a deficiência de vitamina D e a resistência à insulina.

Tumores renais: avaliação de fatores prognósticos de 98 casos em hospital de referência de Porto Alegre, Brasil / Renal tumors: evaluation of prognostic factors in 98 cases from a reference hospital in Porto Alegre, Brazil

Introduction: Renal cell carcinoma (RCC) is an aggressive disease worldwide. Objective: Study traditional prognostic factors associated with pathological reports and the novel markers survivin and B7-H1 by immunohistochemistry. Methods: In a reference hospital of Porto Alegre, Brazil, we conducted a cross-sectional study of RCC in patients who underwent radical nephrectomy between 2006 and 2009. We selected those who were diagnosed with the most common histologic subtypes: clear cell and papillary RCC. We retrospectively reviewed pathological data to determine traditional prognostic factors, like size, presence of coagulative necrosis, Fuhrman grade and tumor-node metastasis (TNM) system. Besides, we performed an immunohistochemistry (IHC) study with survivin and B7-H1. Results: Our sample had 98 cases, 90% of the cases were composed by clear cell histologic subtype, 73% were tumors classified as T1 and T2 in the TNM system, most were Fuhrman nuclear grade 2 or 3, and 70% were positive for necrosis. In relation to the new prognostic markers, we found 50 cases positive to survivin and 38 to B7-H1. In this investigation of traditional prognostic markers and new markers we observed that only necrosis was associated with positive results of biomarkers. < 0.001). Conclusion: This finding confirms previous studies that necrosis is an important factor to consider in the prognosis of RCC...

Introdução: O carcinoma de células renais (CCR) é uma doença de comportamento agressivo em todo o mundo. Objetivo: Estudar os fatores prognósticos tradicionais identificados no exame anatomopatológico e sua correlação com a expressão imunoistoquímica dos novos marcadores survivina e B7-H1. Materiais e métodos: Em um hospital de referência de Porto Alegre, foi realizado um estudo transversal de CCR, com pacientes que realizaram nefrectomia total, no período de 2006 a 2009. Foram selecionados aqueles com os tipos histológicos mais comuns: células claras e papilares. Fatores prognósticos tradicionais foram obtidos por meio da revisão de dados patológicos relevantes dos casos, como tamanho, necrose, tipo histológico, grau nuclear e sistema tumor-linfonodo-metástase (TNM). Também se realizou estudo imunoistoquímico (IMQ) da amostra, com o uso dos marcadores survivina e B7-H1. Resultados: Obtivemos 98 casos, com 90% deles do tipo células claras, 73% classificados como T1 e T2, a maioria com grau nuclear de Fuhrman 2 e 3 e cerca de 70% da amostra positivos para necrose. Já no estudo IMQ foi encontrada positividade em 38 casos para o B7-H1 e em 50 para survivina. Ao considerarmos a associação entre os fatores prognósticos tradicionais e a expressão dos marcadores, encontramos associação somente entre o grupo positivo para os marcadores e necrose (p < 0,001). Conclusão: Tal achado vai ao encontro dos dados da literatura que vêm realçando a importância da necrose no prognóstico dos CCR...

Perfil imuno-histoquímico de carcinomas mamários invasores em homens / Immunohistochemical profile of invasive male breast carcinomas

O câncer de mama em homens é uma doença incomum. A cada 150 casos de câncer de mama é esperada a ocorrência de apenas um no sexo masculino. Devido à baixa incidência desta neoplasia, grande parte do seu conhecimento é oriunda do carcinoma de mama no sexo feminino, cujos parâmetros diagnósticos, prognósticos e terapêuticos são bem estabelecidos na literatura. Entretanto, a distribuição dos fenótipos moleculares dos carcinomas da mama masculina é pouco conhecida. Pela análise de dados clínicos eimuno-histoquímicos estudamos os diferentes perfis de uma amostra de 20 casos de tumores invasores de mama em homens. Utilizamos um painel de cinco anticorpos composto por receptor de estrogênio, citoqueratinas 5/6, citoqueratinas 8/18, HER-1 e HER-2. Dos 20 casos examinados, 19 eram carcinomas do tipo ductal não-especial (95%) e um do tipo lobular (5%). A maioria dos casos foi composta pormastectomias (65%), sendo a média de tamanho das neoplasias de 2,8 cm e o grau histológico mais freqüente o II (60%). Do total, 86,6% dos casos apresentaram metástases linfonodais. O número médio de linfonodos comprometidos foi de 5,2 nas amostras com axila positiva. Foram determinados 14 tumores (70%) correspondentes ao fenótipo RE+/luminal, dois (10%) do tipo indeterminado, um único tumor (5%) do fenótipo Basal, e três de mama (15%) correspondendo ao fenótipo HER2-positivo. A imunofenotipagemdos carcinomas de mama no sexo masculino permite traçar paralelos com os tumores de mama feminina, possibilitando a elucidação de fatores intrínsecos à doença em cada um dos sexos.

Male breast cancer (MBC) is a rare disease. One out of 150 cases of breast cancer is expected to occur in the male gender. Due to the low incidence of this neoplasia, most information about it derives from female breast carcinoma, whose diagnostic, prognostic and therapeutical parameters are well established in the medical literature. However, the distribution of molecular phenotypes of male breast carcinomas is little known. We analyzed the clinical and immunohistochemical data of a sample comprising 20 cases of invasivemale breast tumor. We used a panel of five antibodies that encompasses estrogen receptor, cytokeratins 5/6,cytokeratins 8/18, HER1 and HER2. Among these 20 cases, 19 were non-special ductal carcinomas (95%) and one was a lobular carcinoma (5%). Most cases were mastectomies (65%) and the average size of the neoplasias was 2.8 cm. The most frequent histological grade was II (60%). Axillary lymph node metastases were presented by 86.6% of the total cases. The average number of affected lymph nodes was 5.2 in the samples with positive nodes. Fourteen tumors corresponded to ER+/luminal phenotype (70%), two were classified as undetermined (10%), one (5%) belonged to the basal phenotype and three breast tumors (15%) corresponded to HER2-positive phenotype. The immunohistochemical results of the male breast carcinomasallow us to make comparisons with female breast tumors, what may elucidate the intrinsic factors of thedisease in each gender.