Genotype-phenotype correlations in CFEOM syndrome : studies in the portuguese population

Trabalho de projecto de mestrado em Medicina (Oftalmologia) apresentado à Faculdade de Medicina da Universidade de CoimbraIntrodução: Fibrose congénita dos músculos extra-oculares (FCMEO) constitui um grupo raro de patologias caracterizadas por oftalmoplegia congénita, não progressiva e restritiva dos músculos extra-oculares, com ou sem ptose palpebral. FCMEO está associada a desenvolvimento anormal da totalidade ou parte dos nervos óculo-motor (III) e troclear (IV) e da consequente inervação aberrante dos músculos extra-oculares e/ou músculo elevador palpebral. Objectivos: Realizar uma completa caracterização fenotípica de doze pacientes Portugueses, realizar um estudo genético para os “hotspot” das mutações da FCMEO no gene KIF21A por sequenciação directa (em nove pacientes de seis famílias independentes) e estabelecer potenciais correlações genótipo-fenótipo. Métodos: Avaliação clínica e análise mutacional do gene KIF21A em doze pacientes portugueses com FCMEO. Resultados: Fibrose congénita dos músculos extra-oculares foi demonstrada em todos os casos. Identificamos dez pacientes com FCMEO do tipo 1 e dois pacientes com provável FCMEO do tipo 3. Todos os pacientes têm ptose bilateral com posição anómala da cabeça compensatória com o queixo levantado, 92% têm ambliopia, 42% têm inervação aberrante, 42% têm patologias sistémicas associadas (tais como atraso mental em 25% e polidactilia em 8,3%). A maioria dos pacientes têm oftalmoplegia com os olhos fixos em infradução (sendo incapazes de elevar os olhos acima da linha média vertical), estrabismo horizontal com exotropia variável e movimentos oculares bruscos. Os resultados da análise mutacional estão pendentes.Introduction: Congenital fibrosis of the extraocular muscles (CFEOM) describes a group of rare congenital non-progressive, restrictive ophthalmoplegia of the extraocular muscles with or without ptosis. They are associated with abnormal development of all or part of the oculomotor (III) and the trochlear (IV) nerves and resultant aberrant innervations of extraocular muscles and/or levator. Objective: To perform a complete phenotypical characterization of twelve affected Portuguese individual, a genetic evaluation searching for the “hotspot” CFEOM mutations in KIF21A by direct sequencing (in nine patients of six independent families) and to establish a potential genotype-phenotype correlations. Methods: Clinical evaluation and mutation analyses of the KIF21A gene in twelve Portuguese patients with CFEOM. Results: Congenital fibrosis of the extraocular muscles was demonstrated in all cases. We identified ten patients with CFEOM type 1 and two patients with probable CFEOM type 3. All patients have bilateral ptosis with a compensatory chin up head posture, 92% have amblyopia, 42% neural misdirection, 42% have associated systemic features (such as intellectual development delay in 25% and polydactyly in 8,3%). Most patients have ophthalmoplegia with the eyes fixed in infraducted position (with the inability to elevate the eyes above the vertical midline), horizontal strabismus with variable exotropia and jerky eye movements. Mutational analysis results are pending. 3 Conclusions: We characterize, from a clinical and genetic standpoint, the first group of portuguese families with CFEOM. In-depth knowledge of this group of conditions is invaluable for appropriate treatment and counseling of these patients

Caso pedagógico arredonda estratégia de marketing de causas

Classificação: JEL: M14, M31O presente caso pedagógico foi desenvolvido no âmbito da Responsabilidade Social Empresarial (RSE), mais concretamente a partir da ferramenta Marketing de Causas (MC) e aplica-se à realidade da marca portuguesa Arredonda, criada pela Associação Link com um único propósito – angariar fundos para instituições de solidariedade social e causas sociais. O Arredonda é uma marca inovadora que prima pela diferença na forma de angariação de fundos e cujo conceito assenta no licenciamento do programa a diferentes marcas de serviços. Com base nas informações e nos dados, gentilmente concedidos pela Associação Link e pela Worten e Lidl – marcas a quem o programa já foi licenciado – e tendo em consideração a extensa recolha de informação, foi possível aprofundar o conhecimento sobre o Arredonda e identificar o que faz este programa ter o sucesso que se tem vindo a verificar, nomeadamente, através da recepção de dois galardões Ouro dos “Prémios à Eficácia da Comunicação”, evento organizado pela Associação Portuguesa de Anunciantes (APAN) e pelo Grupo Consultores (GC). O caso impõe ainda a ponderação sobre diferentes conceitos, conectados entre si – Responsabilidade Social Empresarial, Marketing Social e Marketing de Causas – sendo destacado este último através da reflexão sobre os principais benefícios, bem como desafios apresentados às empresas na abordagem ao tema. As questões de partida, bem como os exemplos apresentados e definição de conceitos solidificam os conhecimentos de uma realidade aplicável à gestão de empresas e, em última análise, permitem explorar os objetivos e oportunidades de negócio que vão ao encontro de iniciativas como o Arredonda.This case study was developed within Corporate Social Responsibility (CSR), specifically within the Cause Related Marketing (CRM) tool, and applies to the Portuguese brand Arredonda (broadly translated to “Round-up”), which was created by Associação Link with a sole purpose – to raise funds for social causes and non-for-profit organisations. Arredonda is an innovative brand known for the different manner of fundraising, and whose concept is based on the licensing of the Arredonda programme to different brands of large distribution. Based on the information and data kindly provided by Associação Link, Worten and Lidl – brands which have licensed the Arredonda programme –, and considering the wide information collected, it was possible to further understand the Arredonda concept, and identify the key factors for the recent success of this campaign. Furthermore, the campaign has been awarded two Golden awards named “Prémios à Eficácia da Comunicação” (Prizes to the Efficiency of Communication) by the Associação Portuguesa de Anunciantes (Portuguese Advertiser Association) and the Grupo Consultores (Consultores Group). The case study presented herein involves weighting different interrelated concepts – Corporate Social Responsibility (CSR), Social Marketing and Cause Related Marketing (CRM) –, the latter being highlighted through the analysis of the main benefits and challenges presented to companies addressing this matter. The issues analysed herein, together with the examples given and the concepts defined, solidify the knowledge of a reality that may be applied to business management, and ultimately allow us to explore the objectives and business opportunities which meet initiatives like Arredonda

The impact of anemia on treatment management and clinical outcomes of women hospitalized for uterine leiomyomas

Objectives: Uterine leiomyomas are the most common benign gynecological tumors. Symptomatic leiomyomas represent a major cause of hospitalization, particularly those associated with abnormal uterine bleeding (AUB) and anemia. The aim of this study was to identify predictors of anemia in women hospitalized due to uterine leiomyomas and evaluate its impact on treatment management and clinical outcomes.Material and methods: Population-based retrospective study of women hospitalized for uterine fibroids in publichospitals in mainland Portugal between 2010 and 2015. Data were extracted from the national database of the CentralAdministration of the Portuguese Health System. Comparative and multivariable logistic regression analysis was performed to assess outcomes.Results: A total of 36 295 patients were hospitalized due to uterine leiomyomas during this period. Of those, 11.5%presented with anemia. Age, obesity, intramural type of leiomyoma and AUB are independent predictors of anemia(p < 0.001, AUC 0.7056). Anemia was associated with a high risk of inpatient hospitalization (OR: 5.161, 95% CI: 4.376–6.085), urgent admission (OR: 1.953, 95% CI: 1.797–2.121), radical surgical approach (OR: 2.559, 95% CI: 2.298–2.849), laparoscopic hysterectomy (OR: 1.575, 95% CI: 1.393–1.780) and intra- and post-operative complications (OR: 5.285, 95% CI: 4.332–6.448). It was also associated with longer hospital stays (p < 0.001). These outcomes were more pronounced in acute anemic patients.Conclusions: Anemia has a significant impact on treatment approaches and clinical outcomes of women hospitalized for uterine leiomyomas. Age, obesity, intramural leiomyomas and AUB are some predictors of anemia that could represent a risk-stratification opportunity, allowing for its prompt identification and correction, therefore improving patient care

Impact of gestational weight gain on obstetric and neonatal outcomes in obese diabetic women

Both obesity and gestational diabetes mellitus are increasing in prevalence, being a major health problem in pregnancy with independent and additive impact on obstetrics outcomes. It is recognized that inadequate gestational weight gain is an independent risk factor for pregnancy-related morbidity. The aim of this study was to evaluate the effect of gestational weight gain on obstetric and neonatal outcomes in obese women with gestational diabetes

Marking Techniques for Targeted Axillary Dissection Among Patients With Node-Positive Breast Cancer Treated With Neoadjuvant Chemotherapy

Invasive breast cancer with axillary lymph node (LN) invasion is a continuing problem worldwide. The morbidity associated with axillary LN dissection along with the high rate of nodal downstaging after neoadjuvant chemotherapy (NACT) made the standard treatment shift towards less invasive surgery. Sentinel lymph node biopsy (SLNB) after NACT is associated with high false-negative rates (13%-14%). To overcome this problem, it was concluded that the positive nodes should first be indicated with image-detectable markers and then removed together with SLNB: targeted axillary dissection (TAD). This review aims to describe and evaluate the different marking techniques for TAD in patients with node-positive breast cancer treated with NACT, namely: clip placement and guidewire localization; clip placement and 125I-labelled radioactive seed localization; clip placement and skin mark; clip placement and intraoperative ultrasound; tattooing with a sterile black carbon suspension; magnetic seeds; radar and infrared light technology localization. Targeted axillary dissection techniques have shown false-negative rates below 9% and identification rates above 95%. The most studied technique is guidewire localization, as it is also the oldest one. However, according to data gathered from this review, some newer techniques have shown to be very promising due to their statistical results and management factors

Awareness of the Causes Leading to Surgical Ablation of Ovarian Function in Premenopausal Breast Cancer—A Single-Center Analysis

Background and Objectives: Ovarian surgical ablation (OSA) in estrogen receptor-positive (ER+) breast cancer is usually performed to halt ovarian function in premenopausal patients. Since alternative pharmacological therapy exists and few studies have investigated why surgery is still performed, we aimed to analyze the reasons for the use of OSA despite the remaining controversy. Materials and Methods: Premenopausal ER+ breast cancer patients treated at a tertiary center (2005–2011) were selected, and patients with germline mutations were excluded. Results: Seventy-nine patients met the inclusion criteria. Globally, the main reasons for OSA included: continued menstruation despite hormone therapy with or without ovarian medical ablation (OMA) (34.2%), patient informed choice (31.6%), disease progression (16.5%), gynecological disease requiring surgery (13.9%), and tamoxifen intolerance/contraindication (3.8%). In women aged ≥45 years, patient choice was significantly more frequently the reason for OSA (47.4% versus 17.1% (p = 0.004)). For those aged <45 years, salvation attempts were significantly more frequent as compared to older women (26.8% versus 5.3% (p = 0.01)). In 77.8% of women undergoing OSA with menstrual cycle maintenance, surgery was performed 1–5 years after diagnosis, while surgery was performed earlier (0–3 months after diagnosis) in patients undergoing OSA as an informed choice (56.0%), as a salvation attempt (53.8%), or due to gynecological disease (63.6%). The leading reason for OSA in women previously undergoing OMA was continued menstruation (60.0%). Conclusions: This study suggests a possible failure of pharmacological ovarian suppression and reinforces the need for shared decision-making with patients when discussing treatment strategies, although validation by further studies is warranted due to our limited sample size

Awareness of the Causes Leading to Surgical Ablation of Ovarian Function in Premenopausal Breast Cancer-A Single-Center Analysis

Background and Objectives: Ovarian surgical ablation (OSA) in estrogen receptor-positive (ER+) breast cancer is usually performed to halt ovarian function in premenopausal patients. Since alternative pharmacological therapy exists and few studies have investigated why surgery is still performed, we aimed to analyze the reasons for the use of OSA despite the remaining controversy. Materials and Methods: Premenopausal ER+ breast cancer patients treated at a tertiary center (2005-2011) were selected, and patients with germline mutations were excluded. Results: Seventy-nine patients met the inclusion criteria. Globally, the main reasons for OSA included: continued menstruation despite hormone therapy with or without ovarian medical ablation (OMA) (34.2%), patient informed choice (31.6%), disease progression (16.5%), gynecological disease requiring surgery (13.9%), and tamoxifen intolerance/contraindication (3.8%). In women aged ≥45 years, patient choice was significantly more frequently the reason for OSA (47.4% versus 17.1% (p = 0.004)). For those aged <45 years, salvation attempts were significantly more frequent as compared to older women (26.8% versus 5.3% (p = 0.01)). In 77.8% of women undergoing OSA with menstrual cycle maintenance, surgery was performed 1-5 years after diagnosis, while surgery was performed earlier (0-3 months after diagnosis) in patients undergoing OSA as an informed choice (56.0%), as a salvation attempt (53.8%), or due to gynecological disease (63.6%). The leading reason for OSA in women previously undergoing OMA was continued menstruation (60.0%). Conclusions: This study suggests a possible failure of pharmacological ovarian suppression and reinforces the need for shared decision-making with patients when discussing treatment strategies, although validation by further studies is warranted due to our limited sample size

A new application to one‑step nucleic acid amplification‑discarded sample in breast cancer: Preliminary results

The one-step nucleic acid amplification (OSNA) assay is a molecular method used for detecting breast cancer (BC) metastasis in sentinel lymph nodes (SLNs). However, this method has a major disadvantage, since it prevents tissue structure analysis, while only one molecular marker can be evaluated, namely cytokeratin 19 mRNA. The aim of the present study was to evaluate whether an OSNA-discarded sample could be suitable for the gene expression analysis of the SLN microenvironment. The remaining intermediate phase of the centrifuged SLN homogenate obtained from the OSNA assay of samples from two patients with BC was used for mRNA extraction. Subsequently, the expression of five genes, namely forkhead box, cluster of differentiation 4 and three control genes, was determined by reverse transcription-quanti-tative PCR analysis. The results demonstrated that high-quality RNA was extracted. Therefore, this RNA may be used for gene expression analyses to predict novel molecular biomarkers associated with immuno-inflammatory microenvironment. © 2021, Spandidos Publications. All rights reserved

One Step Nucleic Acid Amplification (OSNA) Lysate Samples Are Suitable to Establish a Transcriptional Metastatic Signature in Patients with Early Stage Hormone Receptors-Positive Breast Cancer

The One Step Nucleic Acid Amplification (OSNA) is being adopted worldwide for sentinel lymph nodes (SLNs) staging in breast cancer (BC). As major disadvantage, OSNA precludes prognostic information based on structural evaluation of SLNs. Our aim is to identify biomarkers related to tumor-microenvironment interplay exploring gene expression data from the OSNA remaining lysate. This study included 32 patients with early stage hormone receptors-positive BC. Remaining OSNA lysates were prepared for targeted RNA-sequencing analysis. Identification of differentially expressed genes (DEGs) was performed by DESeq2 in R and data analysis in STATA. The results show that, in metastatic SLNs, several genes were upregulated: KRT7, VTCN1, CD44, GATA3, ALOX15B, RORC, NECTIN2, LRG1, CD276, FOXM1 and IGF1R. Hierarchical clustering analysis revealed three different clusters. The identified DEGs codify proteins mainly involved in cancer aggressiveness and with impact in immune response. The overexpression of the immune suppressive genes VTCN1 and CD276 may explain that no direct evidence of activation of immune response in metastatic SLNs was found. We show that OSNA results may be improved incorporating microenvironment-related biomarkers that may be useful in the future for prognosis stratification and immunotherapy selection. As OSNA assay is being implemented for SLNs staging in other cancers, this approach could also have a wider utility