Blueberry Muffin Syndrome and Hyperleukocytosis in a Newborn: A Diagnostic Challenge.

Blueberry muffin syndrome (BMS) in neonates, characterized by widespread nodular lesions, presents diagnostic challenges due to its diverse etiologies. Hyperleukocytosis, with leukocyte counts exceeding 100,000/µL, is a rare phenomenon associated with severe complications in neonates. Congenital leukemia (CL), a rare diagnosis within the first month of life, is linked to high mortality. This case report presents a unique case of BMS with hyperleukocytosis as the initial presentation of CL. A full-term male newborn, born after an uncomplicated pregnancy, except for Kell isoimmunization, with an Apgar score of 9/10, and an irrelevant family history, showed widespread purple nodules consistent with BMS at birth. Laboratory workup revealed mild anemia, hyperleukocytosis with immature granulocytes on peripheral blood (PB) smear, positive direct antiglobulin test, and elevated alanine aminotransferase and lactate dehydrogenase, without hyperbilirubinemia. Empirical antibiotics and hyperhydration were started, and the neonate was transferred to a level 3 neonatal intensive care unit for further evaluation. A comprehensive etiological investigation was conducted, comprising infectious, immunological, metabolic, and neoplastic factors. A skin nodule biopsy revealed an infiltrate of blast cells, indicative of leukemia cutis, and a bone marrow aspirate confirmed acute myeloid leukemia (AML). The patient successfully completed the NOPHO-DBH-2012 chemotherapy protocol at five months and remains in complete remission at nine months. This case report contributes to the literature by highlighting the diagnostic approach and management strategies for CL presenting with BMS and hyperleukocytosis. This case aims to enhance awareness and understanding of BMS as an initial manifestation of CL. Additionally, the challenges of treating leukemia in neonates, coupled with the lack of specific guidelines for this age group, further underscore the complexities in managing such patients.

Severe Hemolytic Anemia: Atypical Presentation of Cobalamin Deficiency.

Two severe cases of hemolytic anemia are described in different pediatric age groups, both linked to severe cobalamin deficiency from distinct causes. The first case refers to an exclusively breastfed infant with vitamin deficit secondary to maternal impaired absorption. Apart from the neurological deficits present at diagnosis, he also presented with infantile epileptic spasms syndrome a few months after treatment while having normal cobalamin serum levels. The second case refers to an adolescent with long-term inadequate intake. The occurrence of severe hemolytic anemia in cobalamin deficiency is exceptionally rare.

microRNA sequencing for biomarker detection in the diagnosis, classification and prognosis of Diffuse Large B Cell Lymphoma.

Despite being considered a single disease, Diffuse Large B Cell Lymphoma (DLBCL) presents with variable backgrounds, which results in heterogeneous outcomes among patients, with 40% of them still having primary refractory disease or relapse. Thus, novel biomarkers are needed. In addition, multiple factors regarding its pathogenesis remain unclear. In this context, recent investigations point to the relevance of microRNAs (miRNAs) in cancer. However, regarding DLBCL, there is inconsistency in the data reported. Therefore, in this work, the main goals were to determine a miRNA set with utility as biomarkers for DLBCL diagnosis, classification, prognosis and treatment response, as well as to decipher the mechanism of action of deregulated miRNAs in the origin of the disease. We analyzed miRNA expression in a cohort of 78 DLBCL patients and 17 controls using small RNA sequencing and performed a miRNA-mRNA interaction network analysis. This way, we were able to define new miRNA expression signatures for diagnosis, classification, treatment response and prognosis, and we identified plausible mechanisms of action by which deregulated miRNAs could be involved in DLBCL pathogenesis. In summary, our study remarks that miRNAs could play an important role in DLBCL.

Portal cavernoma in type 1 neurofibromatosis: A fortuitous or causal association?

Neurofibromatosis type 1 (NF-1) is a multisystem genetic disorder affecting the NF1 tumor suppressor gene. Patients typically develop superficial (cutaneous) and internal (plexiform) neurofibromas. The latter may rarely involve the liver locating in the hilum and encasing the portal vessels, leading to portal hypertension. Vascular abnormalities (NF-I vasculopathy) are a well-recognized manifestation of NF-1. Although the pathogenesis is not well-known, NF-1 vasculopathy involves arteries of both peripheral and cerebral territories, with venous thrombosis being exceptionally reported. Portal venous thrombosis (PVT) is the leading cause of portal hypertension in childhood and has been associated with several risk factors. Nevertheless, predisposing conditions remain unknown in more than 50% of the cases. The treatment options are limited, and its management is nonconsensual in the pediatric age. We report the case of a 9-year-old boy with clinically and genetically confirmed NF-1, diagnosed with portal venous cavernoma after an episode of gastrointestinal bleeding. There were no identifiable risk factors for PVT and intrahepatic peri-hilar plexiform neurofibroma was excluded by MRI imaging. To the best of our knowledge, this is the first report of PVT in NF-1. We speculate that NF-1 vasculopathy may have been a pathogenic factor, or instead, it was a fortuitous association.

One-Step Nucleic Acid Amplification (OSNA) of Sentinel Lymph Node in Early-Stage Endometrial Cancer: Spanish Multicenter Study (ENDO-OSNA).

The objective of this study was to evaluate the efficacy of one-step nucleic acid amplification (OSNA) for the detection of sentinel lymph node (SLN) metastasis compared to standard pathological ultrastaging in patients with early-stage endometrial cancer (EC). A total of 526 SLNs from 191 patients with EC were included in the study, and 379 SLNs (147 patients) were evaluated by both methods, OSNA and standard pathological ultrastaging. The central 1 mm portion of each lymph node was subjected to semi-serial sectioning at 200 µm intervals and examined by hematoxylin-eosin and immunohistochemistry with CK19; the remaining tissue was analyzed by OSNA for CK19 mRNA. The OSNA assay detected metastases in 19.7% of patients (14.9% micrometastasis and 4.8% macrometastasis), whereas pathological ultrastaging detected metastasis in 8.8% of patients (3.4% micrometastasis and 5.4% macrometastasis). Using the established cut-off value for detecting SLN metastasis by OSNA in EC (250 copies/µL), the sensitivity of the OSNA assay was 92%, specificity was 82%, diagnostic accuracy was 83%, and the negative predictive value was 99%. Discordant results between both methods were recorded in 20 patients (13.6%). OSNA resulted in an upstaging in 12 patients (8.2%). OSNA could aid in the identification of patients requiring adjuvant treatment at the time of diagnosis.

Respuesta inmunológica a varias proteínas del H. pylori en pacientes guatemaltecos / Inmune response to various H. pylori proteins in Guatemalan patients

Se determinó la respuesta inmunológica a proteínas recombinantes de Helicobacter pylori en pacientes dis-pépticos (adultos y niños), pacientes con cáncer gástrico y sus familiares asintomáticos adultos viviendo con ellos. Se utilizó la prueba recomLine® Helicobacter IgG e IgA, y con base en el reconocimiento de los factores de virulencia VacA y CagA se determinó si la cepa de H. pylori era de tipo I o II. El análisis de los datos fue descriptivo y analítico y se estimaron los intervalos de confianza de 95%, con un nivel de error de 0.05 y Odds ratio. El 58.7% (121/206) de los pacientes presentó la bacteria en tinción histológica de biopsia, positividad que disminuyó con la edad y daño histológico. La frecuencia de la respuesta a los anticuerpos IgG fue mayor que IgA, en ambos casos ésta fue menor en los niños. Las proteínas del H. pylori más reconocidas tanto por IgA como IgG fueron VacA y CagA, y la respuesta a las otras proteínas investigadas fue mayor al aumentar el daño histológi-co. La cepa tipo I fue la que predominó en la población en estudio con 66% (136/206). Se deben continuar con los estudios de prevalencia de la cepa tipo I del H. pylori y del reconocimiento de sus antígenos en la población guatemalteca a fin de determinar su utilidad en el diagnóstico y pronóstico de la infección.

The immune response to recombinant Helicobacter pylori proteins was determined in dyspeptic patients (adults and children), patients with gastric cancer and their asymptomatic adults' relatives living with them. The recomLine® Helicobacter IgG and IgA test was used and based on the recognition of the virulence factors VacA and CagA, it was determined whether the H. pylori strain was type I or II. The data analysis was descriptive and analytic, and 95% confidence intervals were estimated, with an error level of 0.05, and Odds ratio. The patients that presented the bacterium in histological biopsy were 58.7% (121/206), positivity that decreased with age and histological damage. The frecuency of response to IgG antibodies was higher than IgA, in both cases it was lower in children. VacA and CagA were the H. pylori proteins most recognized by both IgA and IgG and it was observed that the number of recognized proteins was greater with increasing histological damage. The type I strain was the one that predominated in the study population 66% (136/206). Prevalence studies of the type I strain of H. pylori ant the recognition of its antigens in the Guatemalan population should continue in order to determine its usefulness in the diagnosis and prognosis of infection.

Drugs targeting the JAK/STAT pathway for the treatment of immune-mediated inflammatory skin diseases: protocol for a scoping review.

INTRODUCTION: The Janus kinase and Signal Transducer and Activator of Transcription protein (JAK/STAT) pathway is known to be involved in inflammatory and neoplastic skin diseases, like psoriasis, atopic dermatitis, alopecia areata, vitiligo and melanoma. Improved knowledge of the components of this pathway has allowed the development of drugs, which act by inhibiting the pathway, blocking specific components. This offers new therapeutic opportunities. Although evidence on the use of JAK/STAT blockades in dermatological diseases is growing, none have been approved for use in treating skin diseases. The aim of this study is to develop an a priori protocol to broadly review the available evidence on the use of drugs targeting the JAK/STAT pathway in the treatment of dermatological diseases. METHODS AND ANALYSIS: For the conduction of the scoping review protocol, we will employ an established scoping review methodology described in the Joanna Briggs Institute manual. This methodology outlines a five-stage approach: (1) identify the research question; (2) identify relevant studies; (3) select studies; (4) chart the data and (5) collate, summarise and report the results, with an optional consultation exercise. Finally, we will use the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews to present the results. ETHICS AND DISSEMINATION: Since this is a review of the literature, ethics approval is not indicated. We will disseminate the findings from this study in publications in peer-reviewed journals as well as presentations at relevant national and international conferences.

Precise definition of PTEN C-terminal epitopes and its implications in clinical oncology.

Anti-PTEN monoclonal antibodies (mAb) are arising as important tools for immunohistochemistry (IHC) and protein quantification routine analysis in clinical oncology. Although an effort has been made to document the reliability of tumor tissue section immunostaining by anti-PTEN mAb, and to standardize their IHC use in research and in the clinical practice, the precise topological and biochemical definition of the epitope recognized by each mAb has been conventionally overlooked. In this study, six commercial anti-PTEN mAb have been validated and characterized for sensitivity and specificity by IHC and FISH, using a set of prostate and urothelial bladder tumor specimens, and by immunoblot, using PTEN positive and PTEN negative human cell lines. Immunoblot precise epitope mapping, performed using recombinant PTEN variants and mutations, revealed that all mAb recognized linear epitopes of 6-11 amino acid length at the PTEN C-terminus. Tumor-associated or disease-associated mutations at the PTEN C-terminus did not affect subcellular localization or PIP3 phosphatase activity of PTEN in cells, although resulted in specific loss of reactivity for some mAb. Furthermore, specific mimicking-phosphorylation mutations at the PTEN C-terminal region also abolished binding of specific mAb. Our study adds new evidence on the relevance of a precise epitope mapping in the validation of anti-PTEN mAb for their use in the clinics. This will be substantial to provide a more accurate diagnosis in clinical oncology based on PTEN protein expression in tumors and biological fluids.

Scoping Review on Use of Drugs Targeting Interleukin 1 Pathway in DIRA and DITRA.

INTRODUCTION: Deficiencies in interleukin (IL)-1 receptor (IL-R) antagonist (DIRA) and IL-36R antagonist (DITRA) are rare genetic autoinflammatory diseases related to alterations in antagonists of the IL-1 pathway. IL-1 antagonists may represent therapeutic alternatives. Here, we aim to provide a scoping review of knowledge on use of IL-1-targeting drugs in DIRA and DITRA. METHODS: An a priori protocol was published, and the study was conducted using the methodology described in the Joanna Briggs Institute Reviewer's Manual and the recently published PRISMA Extension for Scoping Review statement. A three-step search using MEDLINE and EMBASE databases until March 2018 with additional hand searching was performed. Data charting was performed. The search, article selection, and data extraction were carried out by two researchers independently. RESULTS: Twenty-four studies on use of anti-IL-1 drugs were included [15 studies including patients with diagnosis of DIRA (n = 19) and 9 studies including patients with diagnosis of DITRA (n = 9)]. Most studies followed a multicenter observational design. Among all patients who received treatment with anti-IL-1 drugs, nine and four mutations in IL1RN and IL36RN were found, respectively. Patients with DIRA were treated with anakinra (n = 17), canakinumab (n = 2), or rinolacept (n = 6). All patients with DITRA were treated with anakinra, and only one case was also treated with canakinumab. Time-to-response frequencies were evaluated as immediate, short, and medium-long term for DIRA (17/17, 15/17, and 9/10, respectively) and DITRA (7/9, 3/9, and 2/9, respectively). Most DITRA patients in whom anti-IL-1 treatment failed experienced good response to anti-tumor necrosis factor alpha or anti-IL-12/23 drugs. The safety profiles of treatments were similar in both diseases. CONCLUSIONS: Evidence on use of anti-IL-1 drugs in DIRA and DITRA is scarce and based on observational studies. Larger studies with better methodological quality are needed to increase confidence in use of these drugs in patients with DIRA and DITRA.

Laboratory diagnosis of chronic kidney disease in adults: an overview of hospitals inserted in the Portuguese National Health System / Diagnóstico laboratorial de doença renal crônica em adultos: visão geral dos hospitais inseridos no Sistema Nacional de Saúde de Portugal

ABSTRACT Introduction: The laboratory diagnosis of chronic kidney disease (CKD) is a simple and cost-effective procedure that allows the detection of early stages of the disease, which is essential to avoid kidney damage and a life threateaning event. It consists of measuring serum creatinine concentration, urinary albumin concentration and calculating the estimated glomerular filtration rate (eGFR). In 2012, the guidelines for laboratory evaluation of the CKD were published by the Kidney Disease: Improving Global Outcomes (KDIGO). Objectives: This study aimed to evaluate whether the laboratories in hospitals of the Portuguese National Health System follow these guidelines and provide a correct diagnosis of CKD. Material and method: A questionnaire composed of 32 questions was sent to the Clinical Pathology Services of all hospitals inserted in the System. Results: All 49 labs responded that measure serum creatinine, 18 reported measurering eGFR. Ten reported measuring eGFR only if specifically ordered. Forty-four measure total protein and albumin in the urine, three only protein, one albumin alone, and one measure none of them. The type of samples, methods, reagents, equipment, expression units of results and reference intervals varied. Conclusion: There is great variability among laboratories in relation to the methodology of measuring serum creatinine, albumin and total protein in the urine. There are wide variations in the release of results. Most laboratories do not follow the guidelines recommended by the KDIGO 2012. This work indicates that there is a need to develop education and alignment processes in the laboratory diagnosis of CKD in the laboratories installed in hospitals inserted in the Portuguese National Health System.

RESUMO Introdução: O diagnóstico laboratorial de doença renal crônica (DRC) é simples e econômico e permite a detecção de estágios iniciais da doença, o que é essencial para evitar danos renais e risco de morte. Consiste em medir a concentração de creatinina sérica e albumina urinária e calcular a taxa de filtração glomerular (eTFG). Em 2012, as diretrizes para avaliação laboratorial da DRC foram divulgadas pela Kidney Disease: Improving Global Outcomes (KDIGO). Objetivos: Os objetivos deste estudo são avaliar se os laboratórios em hospitais do Sistema Nacional de Saúde Português seguem essas diretrizes e se fornecem diagnóstico correto de DRC. Material e método: Um questionário com 32 perguntas foi enviado aos serviços de patologia clínica de todos os hospitais inseridos no sistema. Resultados: Todos os 49 laboratórios responderam que medem creatinina e 18, eTFG. Dez disseram que medem a eTFG apenas se especificamente solicitado. Quarenta e quatro medem proteínas totais e albumina urinária; três, apenas proteínas; um, somente albumina; e um não mede nenhuma delas. Tipo de amostras, métodos, reagentes, equipamentos, unidades de expressão dos resultados e intervalos de referência variaram. Conclusão: Existe grande variabilidade entre laboratórios em relação às metodologias de medida da creatinina sérica, albumina e proteínas totais na urina. Há grandes variações quanto à liberação dos resultados. A maioria dos laboratórios não segue as diretrizes recomendadas pela KDIGO 2012. Este trabalho indica que existe necessidade de serem desenvolvidos processos de educação e harmonização no diagnóstico laboratorial de DRC nos laboratórios instalados em hospitais inseridos no Sistema Nacional de Saúde Português.

Epigenetic profiling to classify cancer of unknown primary: a multicentre, retrospective analysis.

BACKGROUND: Cancer of unknown primary ranks in the top ten cancer presentations and has an extremely poor prognosis. Identification of the primary tumour and development of a tailored site-specific therapy could improve the survival of these patients. We examined the feasability of using DNA methylation profiles to determine the occult original cancer in cases of cancer of unknown primary. METHODS: We established a classifier of cancer type based on the microarray DNA methylation signatures (EPICUP) in a training set of 2790 tumour samples of known origin representing 38 tumour types and including 85 metastases. To validate the classifier, we used an independent set of 7691 known tumour samples from the same tumour types that included 534 metastases. We applied the developed diagnostic test to predict the tumour type of 216 well-characterised cases of cancer of unknown primary. We validated the accuracy of the predictions from the EPICUP assay using autopsy examination, follow-up for subsequent clinical detection of the primary sites months after the initial presentation, light microscopy, and comprehensive immunohistochemistry profiling. FINDINGS: The tumour type classifier based on the DNA methylation profiles showed a 99·6% specificity (95% CI 99·5-99·7), 97·7% sensitivity (96·1-99·2), 88·6% positive predictive value (85·8-91·3), and 99·9% negative predictive value (99·9-100·0) in the validation set of 7691 tumours. DNA methylation profiling predicted a primary cancer of origin in 188 (87%) of 216 patients with cancer with unknown primary. Patients with EPICUP diagnoses who received a tumour type-specific therapy showed improved overall survival compared with that in patients who received empiric therapy (hazard ratio [HR] 3·24, p=0·0051 [95% CI 1·42-7·38]; log-rank p=0·0029). INTERPRETATION: We show that the development of a DNA methylation based assay can significantly improve diagnoses of cancer of unknown primary and guide more precise therapies associated with better outcomes. Epigenetic profiling could be a useful approach to unmask the original primary tumour site of cancer of unknown primary cases and a step towards the improvement of the clinical management of these patients. FUNDING: European Research Council (ERC), Cellex Foundation, the Institute of Health Carlos III (ISCIII), Cancer Australia, Victorian Cancer Agency, Samuel Waxman Cancer Research Foundation, the Health and Science Departments of the Generalitat de Catalunya, and Ferrer.

Luminal B breast cancer subtype displays a dicotomic epigenetic pattern.

Luminal B breast tumors have aggressive clinical and biological features, and constitute the most heterogeneous molecular subtype, both clinically and molecularly. Unfortunately, the immunohistochemistry correlate of the luminal B subtype remains still imprecise, and it has now become of paramount importance to define a classification scheme capable of segregating luminal tumors into clinically meaningful subgroups that may be used clinically to guide patient management. With the aim of unraveling the DNA methylation profiles of the luminal subtypes currently being most used in the clinical setting, we have quantified the DNA methylation level of 27,578 CpG sites in 17 luminal B (ER+, Ki67 ≥ 20 % or PgR < 20 % and HER2-), 8 luminal A (ER+ and Ki67 > 20 %) and 4 luminal B-HER2+ (ER+ and HER2+) breast cancer samples by using the Illumina Infinium methylation microarray approach. Unsupervised hierarchical clustering revealed that DNA methylation stratifies luminal B samples in two categories with differing epigenetic and clinical features. One subgroup of luminal B samples showed a methylator phenotype and clustered with the lumB-HER tumors, while the other showed less methylated events, clustered with the luminal A. A 3 CpG marker panel capable of discriminating methylator versus non-methylator luminal B samples was identified and further validated in an independent cohort of patients. Our results provide evidence that DNA methylation and, more specifically, a panel of 3 CpG markers, enables the stratification of luminal B samples in two categories with differing epigenetic and clinical features and support the utilization of this panel for therapeutic stratification of patients with luminal breast cancer.

Methylation of CpG sites in BCL2 major breakpoint region and the increase of BCL2/JH translocation with aging.

The BCL2 breakage mechanism has been shown to be highly dependent on DNA methylation at the major breakpoint region (MBR) CpG sites. We recently described an increased frequency of BCL2/ JH translocation with aging. It is known that methylation levels change with aging. The present study aimed to determine whether methylation alterations at CpG sites of BCL2 MBR were the cause of increased breakages with aging. We analyzed the methylation levels of three CpG sites on the region by pyrosequencing and studied if methylation levels and/or polymorphisms affecting CpG sites were associated with an increase of translocations. We observed that although the methylation levels of MBR CpG sites were higher in individuals with BCL2/JH translocation, in contrast to our expectations, these levels decreased with the age. Moreover, we show that polymorphisms at those CpG sites leading to absence of methylation seem to be a protective factor for the apparition of translocations.

Disomy as the genetic underlying mechanisms of loss of heterozigosity in SDHD-paragangliomas.

CONTEXT: Succinate dehydrogenase complex, subunit D (SDHD) mutations cause pheochromocytoma/paraganglioma syndrome. SDHD, located at chromosome 11q23, shows a parent-of-origin effect because the disease is observed almost exclusively when the mutation is transmitted from the father, although some cases of maternal transmission have been reported. Several hypotheses have been proposed for this peculiar inheritance pattern, but the underlying mechanisms have not yet been clearly elucidated. OBJECTIVE: The objective of the study was to explain the parent-of-origin effect in a family, mainly affected by paternally transmitted paragangliomas, and with a maternally transmitted renal tumor. PATIENTS: Peripheral blood DNA from 15 carriers and 7 tumor DNA samples from SDHD-p.Trp5* carriers were studied. METHODS: We conducted mutation genotyping and microsatellite marker analysis in germline and tumor DNA and methylation status analysis in tumor DNA by methylation-specific multiplex ligation-dependent probe amplification. RESULTS: Mutation genotyping and microsatellite marker analysis demonstrated loss of heterozygosity of the wild-type allele (maternal) in all studied tumors, except the renal tumor, which lost the mutated allele (maternal), and the prostate tumor, which had no loss of heterozygosity. The methylation-specific multiplex ligation-dependent probe amplification demonstrated that the methylation profile corresponded exclusively to the paternal chromosome without genomic loss, suggesting paternal uniparental disomy as the mechanism underlying the parent-of-origin effect in this SDHD family. CONCLUSIONS: The paternal uniparental disomy involves the loss of maternally imprinted cell cycle regulators and the overexpression of paternally imprinted growth activators, leading to tumorigenesis in this syndrome.

Kallmann syndrome in a female adolescent: a new mutation in the FGFR1 gene.

The Kallmann syndrome is characterised by the association of hypogonadotropic hypogonadism and hypo/anosmia. It represents a phenotypically and genotypically heterogeneous clinical entity, with six genes identified so far in the literature-KAL1, FGFR1, PROKR2, PROK2, CHD7 and FGF8. Mutations in the FGFR1 gene can be found in approximately 10% of the patients. The authors present the case of a female adolescent with hypogonadotropic hypogonadism and impaired olfactory acuity in the presence of hypoplasia of the nasal sulcus and agenesis of the olfactory bulbs. The molecular analysis of the fibroblast growth factor receptor 1 identified a heterozygous mutation c.1377_78insA (p.V460SfsX3) in exon 10 of FGFR1 gene. This mutation has not yet been reported in the literature. A theoretical review of clinical features and therapeutic approach of this syndrome is also presented.

DNA methylation epigenotypes in breast cancer molecular subtypes.

INTRODUCTION: Identification of gene expression based breast cancer subtypes is considered as a critical means of prognostication. Genetic mutations along with epigenetic alterations contribute to gene expression changes occurring in breast cancer. So far, these epigenetic contributions to sporadic breast cancer subtypes have not been well characterized, and there is only a limited understanding of the epigenetic mechanisms affected in those particular breast cancer subtypes. The present study was undertaken to dissect the breast cancer methylome and deliver specific epigenotypes associated with particular breast cancer subtypes. METHODS: Using a microarray approach we analyzed DNA methylation in regulatory regions of 806 cancer related genes in 28 breast cancer paired samples. We subsequently performed substantial technical and biological validation by Pyrosequencing, investigating the top qualifying 19 CpG regions in independent cohorts encompassing 47 basal-like, 44 ERBB2+ overexpressing, 48 luminal A and 48 luminal B paired breast cancer/adjacent tissues. Using all-subset selection method, we identified the most subtype predictive methylation profiles in multivariable logistic regression analysis. RESULTS: The approach efficiently recognized 15 individual CpG loci differentially methylated in breast cancer tumor subtypes. We further identify novel subtype specific epigenotypes which clearly demonstrate the differences in the methylation profiles of basal-like and human epidermal growth factor 2 (HER2)-overexpressing tumors. CONCLUSIONS: Our results provide evidence that well defined DNA methylation profiles enables breast cancer subtype prediction and support the utilization of this biomarker for prognostication and therapeutic stratification of patients with breast cancer.

Breast and ovarian cancer risk evaluation in families with a disease-causing mutation in BRCA1/2.

Germline mutations in BRCA1 and BRCA2 confer high risks of breast and ovarian cancer, and their identification allows genetic testing of at-risk relatives. However, estimates of these risks illustrate controversies, depending on the published series. The penetrance, the earlier onset of the disease and the effect of mutations on the risk of developing breast and ovarian cancer were evaluated in 344 females belonging to 34 families from the Basque Country in Spain, in which BRCA1 or BRCA2 mutations were transmitted. Kaplan-Meier survival curves were used to derive cumulative probability curves for breast and ovarian cancer by mutation status, birth cohort and mutation position, and significance of the differences was assessed using the log-rank test. The estimated probability for breast cancer by age 70 is about 64% in BRCA1 and 69% in BRCA2, whereas the probability of developing ovarian cancer is about 37% and 25% for BRCA1 and BRCA2, respectively. There is a marginally significant higher risk of developing ovarian cancer in BRCA1 families than in BRCA2 families. The effect of birth cohort on breast cancer cumulative incidence presents an increased risk for females born after 1966 and a decreased risk for those born before 1940. There is no association between mutation position and breast cancer; however, ovarian cancer is associated to BRCA1, presenting exon 11 as an ovarian cluster. These results are important for the breast and ovarian cancer diagnosis and prevention in at-risk families.

Risco de hospitalizações repetidas em idosos usuários de um centro de saúde escola / Risk of repeated hospitalizations in elderly users of an academic health center

O objetivo deste trabalho foi estratificar 305 idosos com 65 anos ou mais, atendidos em um Centro de Saúde Escola (Botucatu, São Paulo, Brasil), quanto à probabilidade de admissão hospitalar repetida. Os dados foram coletados por meio de um instrumento de avaliação do risco de admissão hospitalar repetida, constituído por oito indicadores de saúde: autopercepção da saúde, hospitalização, consultas médicas, diabetes, doença cardiovascular, sexo, apoio social e idade. Verificou-se que 56,4 por cento dos entrevistados apresentaram baixa probabilidade de admissão hospitalar repetida; 26,9 por cento, média; 10,5 por cento, média-alta; e 6,2 por cento, alta. Na associação dos indicadores de saúde com a probabilidade de admissão hospitalar repetida, observou-se que, para idosos classificados como sendo de riscos médio, médio-alto e alto, em relação àqueles com baixo, os riscos relativos foram significativos: saúde média ou ruim (2,31); hospitalização (2,38); mais de três consultas médicas (1,75); diabetes (2,10); doença cardiovascular (2,76); homens (1,68); e 75 anos ou mais (1,62). Constatou-se que o instrumento utilizado possibilitou a estratificação dos idosos quanto ao risco de serem hospitalizados repetidas vezes, o que pode contribuir para propostas de reorganização dos serviços de saúde.

The aim of this study was to stratify 305 elderly (> 65 years) treated at an academic health center (Botucatu, São Paulo, Brazil) according to risk of repeated hospitalization. Data collection used an instrument to evaluate risk of repeated hospital admissions, including eight health indicators: self-rated health, hospitalizations, doctor visits, diabetes, cardiovascular disease, gender, social support, and age. 56.4 percent of interviewees presented low probability of repeated hospitalization, as compared to 26.9 percent medium, 10.5 percent medium-high, and 6.2 percent high probability. Combining health indicators with the probability of repeated hospitalization, for elderly classified as medium, medium-high, and high risk compared to low, the relative risk was significant: medium or bad health (2.31); hospitalization (2.38); > 3 doctor visits (1.75); diabetes (2.10); cardiovascular disease (2.76); male gender (1.68); and > 75 years of age (1.62). The instrument was able to stratify elderly at risk of repeated hospitalization and is thus useful for reorganizing public health services.