Revisiting a series of epithelial salivary gland tumors in children and adolescents in southern Portugal

Trabalho Final do Curso de Mestrado Integrado em Medicina, Faculdade de Medicina, Universidade de Lisboa, 2014Introduction: Salivary gland tumors in pediatric population are extremely rare. Most papers are case reports or small series of cases. Objective: To analyze the clinical, epidemiological and histopathological features and outcomes of epithelial salivary gland tumors occurring in the pediatric population. Methods: During a 50-year period, a total of 54 epithelial salivary gland tumors were diagnosed in patients less than 19 years at Instituto Português de Oncologia de Lisboa Francisco Gentil. Demographic, clinical and follow-up data were obtained from medical records and histopathological features were reviewed. Results: The mean of age of the patients was 13.4 years. One case was congenital and the male to female ratio was 1:1.1. Thirty-seven tumors (68.5%) were benign and 17 (31.5%) malignant. Pleomorphic adenoma was the most common tumor type (61.1%), followed by mucoepidermoid carcinoma (22.2%). The parotid gland was affected in most cases (77.8%), followed by minor glands involvement (14.8%). All tumors in submandibular gland were benign. The recurrence rate was 21.6% for benign tumors and the 5-year survival rate was 82.4% for malignant tumors. Conclusions: Epithelial salivary gland tumors in southern Portugal pediatric patients are rare, specialy malignant tumors. Parotid gland is the most common involved site and pleomorphic adenoma and mucoepidermoid carcinoma are the most common benign and malignant tumor, respectively. There is a slight female predominance.Introdução: Os tumores das glândulas salivares são extremamente raros na população pediátrica. A maioria dos artigos científicos publicados são casos clínicos ou pequenas séries de casos. Objetivo: Análise das características clínicas, epidemiológicas e histopatológicas e dos resultados terapêuticos dos casos de tumores epiteliais das glândulas salivares na população pediátrica. Métodos: Durante um período de 50 anos, 54 tumores epiteliais das glândulas salivares foram diagnosticados no Instituto Português de Oncologia de Lisboa Francisco Gentil em doentes com idade inferior a 19 anos. Os dados demográficos, clínicos e de follow-up foram obtidos a partir dos processos clínicos e as características histopatológicas foram revistas. Resultados: A média de idade dos doentes foi de 13,4 anos. O ratio masculino/feminino foi de 1:1,1 e um dos casos era congénito. Trinta e sete tumores (68.5%) eram benignos e 17 (31.5%) malignos. O adenoma pleomórfico foi o tipo histológico mais frequente (61.1%), seguido do carcinoma mucoepidermóide (22,2%). A glândula parótida foi o local afetado na maioria dos casos (77,8%), seguida pelo envolvimento das glândulas salivares minor (14.8%). Todos os tumores da glândula submandibular eram benignos. A taxa de recorrência foi de 21.6% para os tumores benignos e a taxa de sobrevida aos 5 anos foi de 82.4% para os tumores malignos.Conclusões: Os tumores epiteliais das glândulas salivares são raros na população pediátrica do sul de Portugal. A glândula parótida é o local afetado na maioria dos casos; o adenoma pleomórfico e o carcinoma mucoepidermóide são os tumores benigno e maligno mais comuns, respetivamente. Verifica-se uma pequena predominância feminina

Fifteen years of clinical trials in Huntington’s disease: a very low clinical drug development success rate

© 2017 – IOS Press and the authors. All rights reservedBackground: Drug development in Huntington's disease (HD) is particularly challenging, and only two compounds are approved by the FDA. It is therefore essential to appraise drug development programs in order to understand the reasons for their failure during the early stages of development. Objectives: To describe the landscape of HD therapeutic development and critically explore the causes of compound attrition in the different stages of drug development, from phase 1 to phase 4. Methods: All HD clinical trials registered in the WHO International Clinical Trials Search Portal, from inception to May 2017, were analyzed. Two independent authors selected and extracted data. Success rate in a trial phase was calculated as the number of compounds that progressed to the next trial phase divided by the number of compounds in that phase. The overall success rate was calculated as the ratio between the number of compounds that receive regulatory approval and the total number of compounds. Results: Ninety-nine trials assessing 41 compounds and eleven non-pharmacological interventions (devices and cell therapies) were identified. Twenty-four (24.2%) were phase 1 trials, 46 (46.5%) phase 2, 20 (20.2%) phase 3, and two (2.0%) phase 4. Sixty trials (60.6%) received industry sponsorship. The most frequently studied compounds were creatine, latrepirdine and pridopidine. The mean number of participants enrolled was 92.0 and the length of treatment was 262.9 days, and both increased from phase 1 to phase 3 trials. The success rate was 25.0% from phase 1 to phase 2, 19.4% from phase 2 to phase 3, and 14.3% from phase 3 to approval. The overall success rate was 3.5%. Conclusions: Although HD is a rare condition, 99 HD trials were identified in a comprehensive clinical trial registry. We found a low success rate at earlier phases of drug-development and a very low trial success rate at later phases. There is a significant gap between drug discovery and development success rates that warrants careful appraisal and improvement.info:eu-repo/semantics/publishedVersio

Reporting and methodological quality of clinical trials on exercise therapy for Parkinson's disease

© 2019 Elsevier Ltd. All rights reserved.Background: Exercise therapy is becoming extremely relevant as a new efficacious intervention in multiple medical fields. Although several clinical trials have reported benefits of exercise therapy for Parkinson's disease (PD), recommendations and prescriptions for its use in clinical practice remain limited. Objectives: To evaluate the methodological quality and publication rate of clinical trials on exercise therapy for PD. Methods: We analyzed all clinical trials assessing exercise therapy for PD registered in the WHO International Clinical Trials Registry Platform and the ClinicalTrials.gov registries, from 2000 to 2017. We evaluated the methodological quality of trials using the Cochrane Risk of Bias criteria. Results: A total of 236 clinical trials were identified. Only 70 (29.7%) trials reported their findings, and 61 (25.8%) had results published in scientific journals. Most trials had an unclear risk of bias concerning incomplete and selective outcome reporting and lacked data on the randomization process, allocation concealment, blinding of participants and personnel, and outcomes assessors. Aerobic capacity was the most frequent type of exercise intervention. Conclusions: Although a large number of trials on exercise are registered in international portals, the quality of reporting remains suboptimal and only a quarter of trials have their results published in scientific journals. These two factors, in addition to the heterogeneity of the interventions tested and the unsatisfactory reported methodological quality of most trials, compromise the interpretation of study results. Therefore, higher quality clinical trials reports are needed to establish exercise as part of the PD armamentarium.UID/BIM/50005/2019, project funded by Fundação para a Ciência e a Tecnologia (FCT)/ Ministério da Ciência, Tecnologia e Ensino Superior (MCTES) through Fundos do Orçamento de Estado.info:eu-repo/semantics/publishedVersio

Precocious puberty and anal stenosis in an African patient with Rothmund–Thomson syndrome

© 2022 Wiley Periodicals LLC.Rothmund-Thomson syndrome (RTS) is a rare autosomal recessive disorder characterized by a rash that progresses to poikiloderma. Other common features include sparse hair, eyelashes and eyebrows, short stature, variable skeletal abnormalities, dental defects, cataracts, hypogonadism, and an increased risk for cancer, especially osteosarcoma and skin cancer. RTS is caused by biallelic pathogenic variants in ANAPC1 (Type 1 RTS) or RECQL4 (Type 2 RTS). We present an African girl with Type 2 RTS caused by a nonsense variant and an intronic variant in RECQL4. The patient presented precocious puberty, which has not been previously reported in RTS and that was treated with a GnRH analog, and anal stenosis, which has only been reported once. This case highlights the need to consider deep intronic variants in patients with RTS when pathogenic variants in the coding regions and exon/intron boundaries are not identified and expands the phenotypic spectrum of this disorder.info:eu-repo/semantics/publishedVersio

Study of rare familial monogenic dyslipidemias in Portugal

Dyslipidaemia is a disorder of lipid metabolism, characterized by either an increase or decrease in lipid particles, usually associated with triglycerides (TGs), LDL cholesterol (LDL-C) or HDL cholesterol (HDL-C). Most hyperlipidemia and HDL deficiency confer an increased cardiovascular risk while hypolipidemia, such as abeta or hypobetalipoproteinemia, may present different manifestations ranging from poor weight progression to neurological manifestations. From 2009, the Cardiovascular Investigation Group has been studying rare dyslipidaemias since there were no studies about these disorders in our country. In the context of this study, several index cases and family members with clinical diagnosis of different rare monogenic dyslipidemias or other pathologies in which dyslipidemia is the clinical factor that triggers the need for a genetic diagnosis, have been referred to our lab. The aim of this study is to review all cases with rare dyslipidaemia, either already studied or ongoing in our laboratory.Work supported by centregrant (toBioISI, Centre Reference: UID/MULTI/04046/2013), from FCT/MCTES/PIDDAC, PortugalN/

High prevalence of variants in skeletal dysplasia associated genes in individuals with short stature and minor skeletal anomalies

[EN]Objective: Next generation sequencing (NGS) has expanded the diagnostic paradigm turning the focus to the growth plate. The aim of the study was to determine the prevalence of variants in genes implicated in skeletal dysplasias in probands with short stature and mild skeletal anomalies. Design: Clinical and radiological data were collected from 108 probands with short stature and mild skeletal anomalies. Methods: A customized skeletal dysplasia NGS panel was performed. Variants were classified using ACMG recommendations and Sherloc. Anthropometric measurements and skeletal anomalies were subsequently compared in those with or without an identified genetic defect. Results: Heterozygous variants were identified in 21/108 probands (19.4%). Variants were most frequently identified in ACAN (n = 10) and IHH (n = 7) whilst one variant was detected in COL2A1, CREBBP, EXT1, and PTPN11. Statistically significant differences (P < 0.05) were observed for sitting height/height (SH/H) ratio, SH/H ratio standard deviation score (SDS), and the SH/H ratio SDS >1 in those with an identified variant compared to those without. Conclusions: A molecular defect was elucidated in a fifth of patients. Thus, the prevalence of mild forms of skeletal dysplasias is relatively high in individuals with short stature and mild skeletal anomalies, with variants in ACAN and IHH accounting for 81% of the cases. An elevated SH/H ratio appears to be associated with a greater probability in detecting a variant, but no other clinical or radiological feature has been found determinant to finding a genetic cause. Currently, we cannot perform extensive molecular studies in all short stature individuals so detailed clinical and radiological phenotyping may orientate which are the candidate patients to obtain worthwhile results. In addition, detailed phenotyping of probands and family members will often aid variant classification

Genetics of personalized medicine: cancer and rare diseases

The 21st annual meeting of the Portuguese Society of Human Genetics (SPGH), organized by Luísa Romão, Ana Sousa and Rosário Pinto Leite, was held in Caparica, Portugal, from the 16th to the 18th of November 2017. Having entered an era in which personalized medicine is emerging as a paradigm for disease diagnosis, treatment and prevention, the program of this meeting intended to include lectures by leading national and international scientists presenting exceptional findings on the genetics of personalized medicine. Various topics were discussed, including cancer genetics, transcriptome dynamics and novel therapeutics for cancers and rare disorders that are designed to specifically target molecular alterations in individual patients. Several panel discussions were held to emphasize (ethical) issues associated with personalized medicine, including genetic cancer counseling.info:eu-repo/semantics/publishedVersio

Koolen-de Vries syndrome – National Case Series with clinical and molecular characterization

Introduction: Koolen-de Vries Syndrome (KdVS) is a rare genetic condition, caused by a 17q21.31 microdeletion, or a pathogenic variant in KANSL1 gene. The clinical picture includes developmental delay (DD)/intellectual disability (ID) with expressive language particularly impaired, dysmorphisms, neonatal hypotonia, and friendly behaviour. Aim: To characterize at the molecular and clinical levels all patients in Portugal diagnosed with KdVS.N/

Unraveling the genetic background of individuals with a clinical familial hypercholesterolemia phenotype

Familial hypercholesterolemia (FH) is a common genetic disorder of lipid metabolism caused by pathogenic/likely pathogenic variants in LDLR, APOB, and PCSK9 genes. Variants in FH-phenocopy genes (LDLRAP1, APOE, LIPA, ABCG5, and ABCG8), polygenic hypercholesterolemia, and hyperlipoprotein (a) [Lp(a)] can also mimic a clinical FH phenotype. We aim to present a new diagnostic tool to unravel the genetic background of clinical FH phenotype. Biochemical and genetic study was performed in 1,005 individuals with clinical diagnosis of FH, referred to the Portuguese FH Study. A next-generation sequencing panel, covering eight genes and eight SNPs to determine LDL-C polygenic risk score and LPA genetic score, was validated, and used in this study. FH was genetically confirmed in 417 index cases: 408 heterozygotes and 9 homozygotes. Cascade screening increased the identification to 1,000 FH individuals, including 11 homozygotes. FH-negative individuals (phenotype positive and genotype negative) have Lp(a) >50 mg/dl (30%), high polygenic risk score (16%), other monogenic lipid metabolism disorders (1%), and heterozygous pathogenic variants in FH-phenocopy genes (2%). Heterozygous variants of uncertain significance were identified in primary genes (12%) and phenocopy genes (7%). Overall, 42% of our cohort was genetically confirmed with FH. In the remaining individuals, other causes for high LDL-C were identified in 68%. Hyper-Lp(a) or polygenic hypercholesterolemia may be the cause of the clinical FH phenotype in almost half of FH-negative individuals. A small part has pathogenic variants in ABCG5/ABCG8 in heterozygosity that can cause hypercholesterolemia and should be further investigated. This extended next-generation sequencing panel identifies individuals with FH and FH-phenocopies, allowing to personalize each person’s treatment according to the affected pathway