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Resumen Introduccion y objetivos TPM1 es uno de los principales genes en la miocardiopatia hipertrofica (MCH). La informacion clinica sobre portadores es relativamente escasa, lo cual limita la interpretacion de los estudios geneticos. Nuestro objetivo es establecer la correlacion genotipo-fenotipo de la variante p.Arg21Leu de TPM1 en una serie de familias. Metodos Se evaluo el TPM1 mediante secuenciacion de nueva generacion en 10.561 probandos con cardiopatias hereditarias. Se genotipifico a los familiares mediante Sanger. Se analizaron la cosegregacion, las caracteristicas clinicas y los eventos cardiovasculares. Se estimo la distribuicion geografica de las familias en Portugal y Espana. Resultados Se identifico la variente p.Arg21Leu de TPM1 en 25/4.099 (0,61%) casos con MCH y estaba ausente en 6.462 controles con otras cardiopatias familiares (p Conclusiones P.Arg21Leu es una variante patogenica de TPM1 asociada con MCH de penetrancia tardia/incompleta y pronostico generalmente favorable

OBJECTIVE The main objective of this prospective multicenter study was to examine whether illness representations of control, affect, and coping behaviors mediate the effects of self-efficacy to cope with cancer on psychological symptoms and overall quality of life, in breast cancer patients. METHOD Data from 413 women (Mean age = 54.87; SD = 8.01), coming from four countries (i.e., Finland, Israel, Italy, Portugal), who received medical therapy for their early breast cancer, were analyzed. Coping self-efficacy was assessed at baseline. Potential mediators were assessed three months later, and outcomes after six months. RESULTS Coping self-efficacy was related to all mediators and outcomes. Illness representations of treatment control, positive and negative affect, and certain coping behaviors (mostly, anxiety preoccupation) mediated the effects of coping self-efficacy. Coping self-efficacy was related to each outcome through a different combination of mediators. CONCLUSIONS Coping self-efficacy is a major self-regulation factor which is linked to well-being through multiple cognitive, emotional, and behavioral pathways. Enhancement of coping self-efficacy should be a central intervention goal for patients with breast cancer, towards promotion of their well-being.

Objective To describe the antenatal and pathological features of an immature umbilical cord teratoma associated with exomphalos, and to review the literature on this subject. Case presentation An abdominal wall defect, suspected to be an exomphalos, was identified during routine ultrasound examination performed at 13 weeks of gestation. The pregnancy was terminated. Fetopathological examination revealed an immature umbilical cord teratoma associated with exomphalos. Chromosomal microarray analysis was normal. Conclusions Umbilical cord teratomas, albeit very rare, should be emphasized as a possible differential diagnosis when abdominal wall defects are detected. Since cord teratomas may lead to adverse fetal or neonatal outcomes, close follow-up of the fetus is recommended.

Spondyloepiphyseal dysplasia type Stanescu (SED-S) is a very rare type II collagenopathy. We describe an 8-year-old boy who presented with short trunk, C2-C3 vertebral fusion, hand, foot, leg and thigh pain, stiffness and limited joint mobility, and waddling gait. Radiographs showed platyspondyly with anterior wedging and endplate irregularities, broad femoral necks, and large epiphyses and epiphyseal equivalents. Differential diagnosis included progressive pseudorheumatoid dysplasia and SED-S. A skeletal dysplasia custom-designed NGS panel was performed and the heterozygous pathogenic variant c.620G>A; p.(Gly207Glu) in COL2A1 was detected, establishing the diagnosis of SED-S. Vertebral fusions, observed in our patient, have not been previously described in this dysplasia. This variant has not been previously associated with SED-S, but was reported in two other families with spondyloepiphyseal dysplasia. Thus, this case expands the clinical and mutational spectrum of SED-S and demonstrates that SED-S significantly overlaps with other skeletal dysplasias.

Pathogenic variants in the NGLY1 gene are associated with a Congenital Disorder of Deglycosylation (CDDG) characterized by delays in reaching developmental milestones, complex hyperkinetic movement disorder, transient elevation of transaminases, and alacrima or hypolacrima. To date, only few cases of NGLY1 deficiency have been identified and reported in the literature. This report highlights a first child of non‐consanguineous parents with no relevant family history who presented with hypotonia and poor weight gain since birth. At 2 months, the child developed paroxysmal cervical dystonia, posteriorly resolving spontaneously by age of 3. Subsequently, delays in reaching developmental milestones, ataxia, dyskinesia, visual impairment due to cone rod retinal dystrophy, low triglycerides, and persistently elevated liver transaminases were observed. Extensive etiological investigation was performed, including array‐CGH and metabolic evaluation with no abnormalities to note. Trio whole exome analysis identified a homozygous pathogenic variant of the NGLY1 gene, c.1891del (p.Gln631Serfs*7), consistent with CDDG. Both parents were confirmed to be heterozygous carriers. The authors discuss in this case, the clinical presentation, the diagnostic challenges, and review other relevant NGLY1 deficiency cases previously reported in the literature. This case, along with the previous reported in the literature, indicates that pathogenic variants in NGLY1 cause a recognizable phenotype and should be considered in patients with a typical presentation. It also suggests that decreased sweating is not present universally in these patients.

Objective: To describe the ultrasonographic, pathologic and molecular findings in a fetus with TAR syndrome, and to illustrate the contribution of chromosomal microarray analysis (CMA) to the etiological investigation of fetal upper limb reduction defects. Case report: A 35-year-old woman was referred for Genetic Counseling after pregnancy termination for severe upper limb bilateral phocomelia detected in the second trimester. Fetal autopsy showed severe shortening of the arms and forearms. The fetal skeletal survey confirmed the absence of the radii, ulnae and humeri. CMA revealed an interstitial deletion in 1q21 including the RBM8A gene. Subsequent Sanger sequencing of this gene identified a hypomorphic mutant allele, c.-21G > A, confirming the diagnosis of TAR syndrome. Conclusion: The differential diagnosis of upper limb defects is broad. Identification of their cause is essential for adequate genetic counseling including prognosis and recurrence risk estimation. CMA should be considered in fetuses with upper limb reduction defects, especially when the thumbs are present. Keywords: 1q21.1 microdeletion, Limb reduction defects, Phocomelia, RBM8A, Thrombocytopenia-absent radius (TAR) syndrome

Hyper-IgE syndromes and chronic mucocutaneous candidiasis constitute rare primary immunodeficiency syndromes with an overlapping clinical phenotype. In recent years, a growing number of underlying genetic defects have been identified. To characterize the underlying genetic defects in a large international cohort of 275 patients, of whom 211 had been clinically diagnosed with hyper-IgE syndrome and 64 with chronic mucocutaneous candidiasis, targeted panel sequencing was performed, relying on Agilent HaloPlex and Illumina MiSeq technologies. The targeted panel sequencing approach allowed us to identify 87 (32 novel and 55 previously described) mutations in 78 patients, which generated a diagnostic success rate of 28.4%. Specifically, mutations in DOCK8 (26 patients), STAT3 (21), STAT1 (15), CARD9 (6), AIRE (3), IL17RA (2), SPINK5 (3), ZNF341 (2), CARMIL2/RLTPR (1), IL12RB1 (1), and WAS (1) have been detected. The most common clinical findings in this cohort were elevated IgE (81.5%), eczema (71.7%), and eosinophilia (62.9%). Regarding infections, 54.7% of patients had a history of radiologically proven pneumonia, and 28.3% have had other serious infections. History of fungal infection was noted in 53% of cases and skin abscesses in 52.9%. Skeletal or dental abnormalities were observed in 46.2% of patients with a characteristic face being the most commonly reported feature (23.1%), followed by retained primary teeth in 18.9% of patients. Targeted panel sequencing provides a cost-effective first-line genetic screening method which allows for the identification of mutations also in patients with atypical clinical presentations and should be routinely implemented in referral centers., Projekt DEAL; German Ministry of Education and Research (BMBF) [01E01303, 01ZX1306F, 01ZX1306A]; E-rare program of the European Commission EURO-CMC [01GM1502]; German Center for Infection Research DZIF [8000805-3, TTU-IICH_07.801]; German Research Foundation (DFG) [390939984, 39087428], Open Access funding enabled and organized by Projekt DEAL. Financial support for this research came from the German Ministry of Education and Research (BMBF, grant no. 01E01303; sys-INFLAME grant nos. 01ZX1306F and 01ZX1306A), from the E-rare program of the European Commission EURO-CMC (01GM1502), and from the German Center for Infection Research DZIF (8000805-3 and TTU-IICH_07.801). This study was supported by the German Research Foundation (DFG) under Germany's Excellence Strategy CIBSS (EXC-2189) (Project ID 390939984) and RESIST (EXC 2155) (Project ID 39087428).

Congenital cranial dysinnervation disorders (CCDDs) are a heterogeneous group of neurodevelopmental phenotypes caused by a primary disturbance of innervation due to deficient, absent, or misguided cranial nerves. Although some CCDDs genes are known, several clinical phenotypes and their aetiologies remain to be elucidated. We describe a 12-year-old boy with hypotonia, developmental delay, sensorineural hearing loss, and keratoconjunctivitis due to lack of corneal reflex. He had a long expressionless face, severe oromotor dysfunction, bilateral agenesis/severe hypoplasia of the VIII nerve with marked atresia of the internal auditory canals and cochlear labyrinth malformation. Trio-exome sequencing identified a homozygous loss of function variant in the NEUROG1 gene (NM_006161.2: c.202G > T, p.Glu68*). NEUROG1 is considered a causal candidate for CCDDs based on (i) the previous report of a patient with a homozygous gene deletion and developmental delay, deafness due to absent bilateral VIII nerves, and severe oromotor dysfunction; (ii) a second patient with a homozygous NEUROG1 missense variant and corneal opacity, absent corneal reflex and intellectual disability; and (iii) the knockout mouse model phenotype which highly resembles the disorder observed in humans. Our findings support the growing compelling evidence that loss of NEUROG1 leads to a very distinctive disorder of cranial nerves development. info:eu-repo/semantics/publishedVersion

Background: Axillary staging in patients with complete response after neoadjuvant chemotherapy (NAC) is still controversial. Our objective was to test tattoo alone and subsequentially tattoo plus clip as markers in the targeted axillary dissection of ycN0 patients. Methods: Prospective cohort of cT1-T3, cN1 (proven histologically), M0 patients scheduled to receive NAC. Exclusion criteria were lobular histology, prior axillary surgery, and clinical N2/3. In cohort 1 this positive node (Neotarget node) was tattooed at diagnosis. If ycN0, a targeted axillary dissection was performed. After an interim analysis with negative results we changed the protocol in order to do a double marking procedure (Cohort 2): the positive node was clipped at diagnosis and after NAC a tattoo was done before surgery. Results: Thirteen patients in Cohort 1 and 18 patients in Cohort 2. Failure to identify the Neotarget node with multiple nodes retrieved in 9/13 (69%) of Cohort 1 patients. Also in 5/13 (38%) of Cohort 1 patients and 3/18 (17%) of Cohort 2 there was a failure to clearly identify tattooed nodes. In Cohort 2, clip identification by surgical specimen radiography allowed the identification of the tagged node in 17/18 (94,4%) of cases. The concordance between the clipped node and sentinel nodes was 16/18 (89%). Conclusions: The introduction of double marking by clipping the metastatic node and verifying their removal by surgical specimen radiography, using carbon ink as a tracer, allowed the identification of the metastatic node in 94% of cases, with a simple, reproducible, and easy-to-implement targeted axillary dissection procedure.

Purpose Pseudoxanthoma elasticum (PXE) is a recessive disorder involving skin, eyes and arteries, mainly caused by ABCC6 pathogenic variants. However, almost one fifth of patients remain genetically unsolved despite extensive genetic screening of ABCC6, as illustrated in a large French PXE series of 220 cases. We searched for new PXE gene(s) to solve the ABCC6-negative patients. Methods First, family-based exome sequencing was performed, in one ABCC6-negative PXE patient with additional neurological features, and her relatives. CYP2U1, involved in hereditary spastic paraplegia type 56 (SPG56), was selected based on this complex phenotype, and the presence of two candidate variants. Second, CYP2U1 sequencing was performed in a retrospective series of 46 additional ABCC6-negative PXE probands. Third, six additional SPG56 patients were evaluated for PXE skin and eye phenotype. Additionally, plasma pyrophosphate dosage and functional analyses were performed in some of these patients. Results 6.4% of ABCC6-negative PXE patients (n=3) harbored biallelic pathogenic variants in CYP2U1. PXE skin lesions with histological confirmation, eye lesions including maculopathy or angioid streaks, and various neurological symptoms were present. CYP2U1 missense variants were confirmed to impair protein function. Plasma pyrophosphate levels were normal. Two SPG56 patients (33%) presented some phenotypic overlap with PXE. Conclusion CYP2U1 pathogenic variants are found in unsolved PXE patients with neurological findings, including spastic paraplegia, expanding the SPG56 phenotype and highlighting its overlap with PXE. The pathophysiology of ABCC6 and CYP2U1 should be explored to explain their respective role and potential interaction in ectopic mineralization.

PurposePathogenic variants in INPP5E cause Joubert syndrome, a systemic disorder that can manifest with retinal degeneration among other clinical features. We aimed to evaluate the role of INPP5E variants in non-syndromic inherited retinal degenerations (IRDs) of varying severity.MethodsTargeted or genome sequencing were performed in 12 unrelated non-syndromic IRD families from multiple research hospitals. Detailed clinical examination was conducted in all probands. The impact of new likely pathogenic variants was modeled on a tertiary INPP5E protein structure and all the new and published variants were analyzed for their deleteriousness and phenotypic correlation.ResultsFourteen INPP5E rare alleles were detected, 12 of which were novel. Retinal degeneration in all 12 probands was clinically distinguishable on the basis of onset and severity into Leber congenital amaurosis (n=4) and a milder, later-onset rod-cone dystrophy (n=8). Two probands showed mild ciliopathy features that resolved in childhood. Analysis of the combined impact of both alleles in syndromic and non-syndromic INPP5E patients did not reveal clear genotype-phenotype correlation, suggesting involvement of genetic modifiers.ConclusionsThe study expands the phenotypic spectrum of disorders due to pathogenic variants in INPP5E and describes a new disease association with previously underdiagnosed forms of early-onset non-syndromic IRD.

Breast cancer is the most frequent event in Li-Fraumeni syndrome associated with germline TP53 variants. Some studies have shown that breast cancers in women with Li-Fraumeni syndrome are commonly HER2-positive, suggesting that HER2 amplification or over-expression in a young woman may be a useful criterion to test for germline variants in the TP53 gene. We assessed the prevalence of germline TP53 variants by Sanger sequencing or next-generation sequencing in 149 women with HER2-positive breast cancer diagnosed until age 40. The pattern of HER2 amplification was evaluated with dual-probe FISH in a subset of breast carcinomas from patients with germline TP53 variants as compared with those of noncarriers. Among 149 women tested, three presented a deleterious TP53 germline variant (2%), with one patient diagnosed at age 31 and the other two with bilateral breast cancer at ages 29/33 and 28/32, respectively. Three of the 36 patients (8.3%) with the first breast cancer diagnosed at age 31 or younger presented a pathogenic TP53 variant. Additionally, all TP53 deleterious variant carriers had a first degree relative diagnosed with different early-onset cancers (frequently not belonging to the Li-Fraumeni syndrome tumor spectrum) diagnosed at age 45 or younger. Higher levels of HER2 amplification were found in breast carcinomas of TP53 pathogenic variant carriers than in those of noncarriers. Deleterious germline TP53 variants account for a small proportion of early-onset HER2-positive breast cancers, but these seem to have higher HER2 amplification ratios. All TP53 pathogenic variant carriers found in this study had the first breast carcinoma diagnosed at age 31 or younger and a first-degree relative with early-onset cancer. Further studies are needed to clarify if HER2 status in early-onset breast cancer patients, in combination with other personal and/or familial cancer history, is useful to update the TP53 testing criteria.

Introduction and objectives TPM1 is one of the main hypertrophic cardiomyopathy (HCM) genes. Clinical information on carriers is relatively scarce, limiting the interpretation of genetic findings in individual patients. Our aim was to establish genotype-phenotype correlations of the TPM1 p.Arg21Leu variant in a serie of pedigrees. Methods TPM1 was evaluated by next-generation sequencing in 10 561 unrelated probands with inherited heart diseases. Familial genetic screening was performed by the Sanger method. We analyzed TPM1 p.Arg21Leu pedigrees for cosegregation, clinical characteristics, and outcomes. We also estimated the geographical distribution of the carrier families in Portugal and Spain. Results The TPM1 p.Arg21Leu variant was identified in 25/4099 (0.61%) HCM-cases, and was absent in 6462 control individuals with other inherited cardiac phenotypes (P .0001). In total, 83 carriers (31 probands) were identified. The combined LOD score for familial cosegregation was 3.95. The cumulative probability of diagnosis in carriers was 50% at the age of 50 years for males, and was 25% in female carriers. At the age of 70 years, 17% of males and 46% of female carriers were unaffected. Mean maximal left ventricular wall thickness was 21.4 ± 7.65 mm. Calculated HCM sudden death risk was low in 34 carriers (77.5%), intermediated in 8 (18%), and high in only 2 (4.5%). Survival free of cardiovascular death or heart transplant was 87.5% at 50 years. Six percent of carriers were homozygous and 18% had an additional variant. Family origin was concentrated in Galicia, Extremadura, and northern Portugal, suggesting a founder effect. Conclusions TPM1 p.Arg21Leu is a pathogenic HCM variant associated with late-onset/incomplete penetrance and a generally favorable prognosis.

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/publishedVersion

Patients with estrogen receptor-positive (ER +) early breast cancer (EBC) are at a continuous risk for distant relapse despite 5 years of standard endocrine therapy, even after 10–15 years after primary diagnosis. Hence, large randomized clinical trials were conducted to evaluate the role of extended endocrine treatment (ET) with the primary goal to prevent or at least delay distant relapse. Two very large trials of extended tamoxifen (TAM), the ATLAS and the aTTom trial, proved the efficacy of prolonged TAM particularly important after 10 years due to the carry-over effect of the five initial years. Additionally, the extended use of AIs after 5 years of tamoxifen, also proved to be efficacious in preventing late distant relapses. For letrozole (LET) it was shown in the MA.17 trial that it also improves overall survival (OS) in node-positive BC patients. There are many options and still unanswered questions related to extended ET, which are discussed in this review. The most important issue in deciding prolonged duration of ET is undoubtfully how to identify ER+ patients who benefit most from this approach. With this purpose, not only classical pathological factors have been studied, but also molecular profiles of individual tumors, which might help us in the near future to better tailor ET. Not only efficacy, but also toxicity of such prolonged treatment is essential for optimal use, particularly maintained compliance in a routine clinical practice. These issues are discussed in this review.

INTRODUCTION: Epileptic encephalopathies of childhood are characterized by early seizure-onset and adverse neurological outcomes. The development of new genetic techniques has allowed an exponential identification of the genes that are involved. Over the last years, we have observed a revolution in the diagnostic paradigm. However, there are no international guidelines regarding the diagnosis of genetic epileptic encephalopathies. We aim to discuss the current knowledge about the genetic architecture of epileptic encephalopathies of childhood. MATERIAL AND METHODS: review of the literature about infantile epileptic encephalopathies and the genetic tests currently available. A systematic approach and a diagnostic algorithm to use in clinical practice were proposed. RESULTS: Initially the patient's phenotype should be determined based on the seizure type, electroencephalogram pattern and neuroimaging. Patients with unclear etiology after brain magnetic resonance imaging should undergo an appropriate metabolic investigation to promptly exclude treatable conditions. Further studies should also include other genetic causes, mainly if associated with particular phenotypic features. Chromosomal microarray analysis should be firstly considered, particularly if dysmorphic or polymalformative abnormalities are present. If this is negative and/or there are no physical features, the next step should be next-generation sequencing multigene panels or whole-exome sequencing. Single gene study should only be considered when the patient's phenotype is highly suggestive of a specific syndrome. CONCLUSION: The revolution of the genetic knowledge about epileptic encephalopathies of childhood has led to a complex diagnostic approach. This new paradigm poses significant implications in genetic counselling, treatment and prognosis. Introdução: As encefalopatias epilépticas da infância constituem um grupo de patologias de início precoce e prognóstico neurológico reservado. O desenvolvimento das novas técnicas de estudo genético foi responsável pela identificação de novos genes implicados. Nos últimos anos, assistimos a uma revolução no seu paradigma diagnóstico. Contudo, actualmente não existem recomendações internacionais consensuais sobre a abordagem à investigação das encefalopatias epilépticas genéticas. Pretendemos discutir o conhecimento actual sobre a arquitectura genética das encefalopatias epilépticas infantis. Material e Métodos: Realizou-se uma revisão da literatura das encefalopatias epilépticas infantis genéticas e estudos utilizados no seu diagnóstico. Propomos uma abordagem sistematizada através de um algoritmo diagnóstico a utilizar na prática clínica. Resultados: Inicialmente deve-se determinar o fenótipo do doente com base no tipo de crises, padrão electroencefalográfico e neuroimagem. Nos doentes sem etiologia após resultados de ressonância magnética cranioencefálica, deve-se realizar estudo metabólico apropriado para o diagnóstico prioritário de doenças metabólicas tratáveis. A investigação de outras causas genéticas deve ser considerada, sobretudo perante características fenotípicas sugestivas. Primeiro deve-se realizar a análise de microarray cromossómico, principalmente se existirem alterações dismórficas ou polimalformativas. Se esta for negativa e/ou não existirem elementos físicos distintivos, o próximo passo deve ser realizar os painéis multigénicos ou sequenciação de exoma. Os estudos dirigidos do gene devem ser reservados para quando o fenótipo é indicativo de uma síndrome específica. Conclusão: A marcha diagnóstica das encefalopatias epilépticas tornou-se complexa com a expansão de conhecimentos genéticos. Este novo paradigma apresenta implicações terapêuticas, prognósticas e de aconselhamento familiar. info:eu-repo/semantics/publishedVersion

Background Cancer and its treatment represent major stressors requiring that patients make multiple adaptations. Despite evidence that poor adaptation to stressors is associated with more distress and negative affect (NA), neuroimmune dysregulation and poorer health outcomes, current understanding is very limited of how NA covaries with central nervous system changes to account for these associations. Methods NA was correlated with brain metabolic activity using 18 F-fluorodeoxyglucose positron emission tomography/computed tomography (18 F-FDG PET/CT) in several regions of interest in 61 women with metastatic breast cancer. Patients underwent 18 F-FDG PET/CT and completed an assessment of NA using the Brief Symptom Inventory. Results Regression analyses revealed that NA was significantly negatively correlated with the standardized uptake value ratio of the insula, thalamus, hypothalamus, ventromedial prefrontal cortex, and lateral prefrontal cortex. Voxel-wise correlation analyses within these 5 regions of interest demonstrated high left-right symmetry and the highest NA correlations with the anterior insula, thalamus (medial and ventral portion), lateral prefrontal cortex (right Brodmann area 9 [BA9], left BA45, and right and left BA10 and BA8), and ventromedial prefrontal cortex (bilateral BA11). Conclusions The regions of interest most strongly negatively associated with NA represent key areas for successful adaptation to stressors and may be particularly relevant in patients with metastatic breast cancer who are dealing with multiple challenges of cancer and its treatment.

Introduction: Thyroid hormones have an important role in the regulation of lipid metabolism. Higher levels of TSH could be associated with impaired lipid profile and cardiovascular disease, even with normal levels of free thyroxine (FT4). The aim of this study was to investigate the association between TSH levels and lipid profile in patients with primary hypothyroidism. Materials and methods: Retrospective evaluation of patients with primary hypothyroidism treated with levothyroxine (LT4), with normal levels of FT4. Patients with known dyslipidemia were excluded. Thyroid function, total cholesterol (TC), triglycerides (Tg), HDL-cholesterol (HDL) and LDL-cholesterol (LDL) were studied. Patients were divided according to their TSH levels: 0.05) and lower mean LDL levels (96.3mg/dL vs 106.7mg/dL, p>0.05). TSH values positively correlated with higher TC levels (r=0.319, p

The COVID-19 pandemic has important consequences for the mental health of populations. Patients with cancer, already at risk for poor mental health outcomes, are not expected to be spared from these consequences, prompting the need for health services to improve responsiveness. This article presents the research protocol for an implementation study designed to describe the uptake of a well-studied and recognized system for the treatment of depression and anxiety (Stepped-care) during the specific context of a Pandemic in an oncological site. The system set-up will be assisted by a digital platform (MoodUP), where patients undergoing cancer treatment will be screened for anxiety and depressive symptoms, triaged by severity level and algorithm-matched to recommended interventions. Patients undergoing cancer treatment at a cancer clinic in Portugal will be invited to subscribe to the MoodUP platform where they will complete a self-reported questionnaire (Hospital Anxiety and Depression Scale) to screen their anxiety and depressive symptoms. Data will be instantly collected, and an algorithm will activate severity-matched intervention suggestions, through a case manager that will coordinate care. The specific objectives of this study will be to describe the implementation and acceptability of the care system by patients and staff, the barriers to and facilitators of implementation, the proportion of patients accessing the system and their pathways through the various stepped-care interventions, and patient perceptions regarding the feasibility and appropriateness of the eHealth platform. Moreover, exploratory analyses will be conducted to describe patterns of anxiety and depression symptoms variation across all patients, as well as within sociodemographically, clinically and contextually characterized subgroups, to characterize their care needs and access, as well as to explore for whom the MoodUP care system may be more appropriate. This study is expected to improve processes for collaborative mental healthcare in oncology and accelerate the digitalization of services, towards the improvement of mental healthcare access, and management of high-risk patients, during the COVID-19 pandemic.

Displaying resilience following a diagnosis of breast cancer is crucial for successful adaptation to illness, well-being, and health outcomes. Several theoretical and computational models have been proposed toward understanding the complex process of illness adaptation, involving a large variety of patient sociodemographic, lifestyle, medical, and psychological characteristics. To date, conventional multivariate statistical methods have been used extensively to model resilience. In the present work we describe a computational pipeline designed to identify the most prominent predictors of mental health outcomes following breast cancer diagnosis. A machine learning framework was developed and tested on the baseline data (recorded immediately post diagnosis) from an ongoing prospective, multinational study. This fully annotated dataset includes socio-demographic, lifestyle, medical and self-reported psychological characteristics of women recently diagnosed with breast cancer (N = 609). Nine different feature selection and cross-validated classification schemes were compared on their performance in classifying patients into low vs high depression symptom severity. Best-performing approaches involved a meta-estimator combined with a Support Vector Machines (SVMs) classification algorithm, exhibiting balanced accuracy of 0.825, and a fair balance between sensitivity (90%) and specificity (74%). These models consistently identified a set of psychological traits (optimism, perceived ability to cope with trauma, resilience as trait, ability to comprehend the illness), and subjective perceptions of personal functionality (physical, social, cognitive) as key factors accounting for concurrent depression symptoms. A comprehensive supervised learning pipeline is proposed for the identification of predictors of depression symptoms which could severely impede adaptation to illness.

Macrodactyly in the context of tuberous sclerosis complex (TSC) is a known but rare manifestation. We report the case of a boy diagnosed with TSC at 2 years and 4 months of age, presenting with bilateral macrodactyly of the first three fingers of both hands, with underlying radiographic changes, in whom molecular analysis identified a frameshift mutation on the TSC1 gene (encoding hamartin), leading to a premature stop codon. We reviewed the literature for reported cases of TSC patients with the same manifestation. In four of 14 patients, including ours, macrodactyly caused some type of joint limitation or flexion deformity, thus contradicting the established idea that this is a finding without clinical significance. Our patient is, to our knowledge, the first reported to have clear bilateral involvement. We briefly discuss the underlying mechanism for this phenomenon, which has yet to be fully elucidated, although somatic mosaicism for loss of heterozygosity at TSC loci is a plausible explanation. © 2016 Wiley Periodicals, Inc.

A epidermólise bolhosa juncional é uma genodermatose caracterizada por fragilidade cutânea e formação de erosões e bolhas a nível da junção dermo-epidérmica, após trauma minor. Reportamos o caso clínico de um recém-nascido, sexo masculino, caucasiano, com erupção cutânea caracterizada por bolhas tensas e erosões nas mãos, abdómen e couro cabeludo. Realizou-se uma biopsia cutânea para imunoflurescência directa com painel de anticorpos, que foi compatível com o diagnóstico de epidermólise bolhosa juncional não-Herlitz. No estudo genético identificou-se 2 mutações no gene COL17A1. Destaca-se nos antecedentes familiares, um irmão com dermatose bolhosa, falecido na terceira semana de vida por intercorrência infeciosa, sem ter sido possível efectuar o diagnóstico definitivo que possibilitasse o diagnóstico pré-natal. Salientamos a importância da referenciação rápida destes doentes a centros especializados, de forma a possibilitar o diagnóstico precoce desta patologia, uma orientação clínica adequada e um correto aconselhamento genético, incluindo o diagnóstico pré-natal em futuras gravidezes.

Three overlapping conditions, namely Rothmund-Thomson (RTS), Baller-Gerold (BGS) and RAPADILINO syndromes, have been attributed to RECQL4 mutations. Differential diagnoses depend on the clinical presentation, but the numbers of known genes remain low, leading to the widespread prescription of RECQL4 sequencing. The aim of our study was therefore to determine the best clinical indicators for the presence of RECQL4 mutations in a series of 39 patients referred for RECQL4 molecular analysis and belonging to the RTS (27 cases) and BGS (12 cases) spectrum. One or two deleterious RECQL4 mutations were found in 10/27 patients referred for RTS diagnosis. Clinical and molecular reevaluation led to a different diagnosis in 7/17 negative cases, including Clericuzio-type poikiloderma with neutropenia, hereditary sclerosing poikiloderma, and craniosynostosis/anal anomalies/porokeratosis. No RECQL4 mutations were found in the BGS group without poikiloderma, confirming that RECQL4 sequencing was not indicated in this phenotype. One chromosomal abnormality and one TWIST mutation was found in this cohort. This study highlights the search for differential diagnoses before the prescription of RECQL4 sequencing in this clinically heterogeneous group. The combination of clinically defined subgroups and next-generation sequencing will hopefully bring to light new molecular bases of syndromes with poikiloderma, as well as BGS without poikiloderma.

Autosomal recessive congenital ichthyosis (ARCI) is a clinically and genetically heterogeneous group of cornification disorders characterized by generalized scaling of the skin. Mutations in the TGM1 gene occur in many patients with lamellar ichthyosis and also in patients with less severe forms of ARCI. We analyze the TGM1 gene locus in Italian and Portuguese patients with different clinical presentations of ARCI. We found that allelic heterogeneity at TGM1 is higher in Italy than in Portugal. Moreover, we evidenced founder effects for Portuguese TGM1 disease-associated alleles.

Objective To show the importance of measuring cholesterol precursor levels in amniotic fluid in all pregnancies with ultrasound features (such as holoprosencephaly) suggestive of Smith–Lemli–Opitz syndrome (SLOS), after exclusion of chromosomal anomalies. Case report A 28-year-old woman, gravida 1 para 0, performed chorionic villus sampling for fetal karyotyping at 13 weeks of gestation due to positive combined first trimester screening in a fetus with increased nuchal translucency and suspected holoprosencephaly. The result was normal – 46,XX. The diagnosis of alobar holoprosencephaly was confirmed at 15 weeks of gestation, and cardiac and limb defects were also identified. Thus, a syndromic cause was considered, specifically a chromosomal microdeletion syndrome or a monogenic entity such as SLOS. The latter was confirmed by measuring 7-dehydrocholesterol (7DHC) and 8-dehydrocholesterol (8DHC) in amniotic fluid. Molecular analysis of DHCR7 gene identified a homozygous mutation in intron 8, c.964-1G>C, providing molecular confirmation for this diagnosis. Conclusion The differential diagnosis of holoprosencephaly is broad. Identification of the cause of holoprosencephaly aids in establishing the prognosis and is essential to ascertain the mode of inheritance for adequate genetic counseling.

Neoadjuvant therapy (NT) has become a valuable research tool for the incorporation of alternative cytotoxic agents, as well as new biological therapies, into anthracycline and taxane chemotherapy-based regimens. Her-2-positive disease is predictive of higher pathological complete response (pCR) to neoadjuvant chemotherapy and trastuzumab. Benefits were also seen for the combination of trastuzumab with lapatinib or pertuzumab, suggesting that dual blockage of the HER-2 will probably emerge as the new standard. Triple-negative phenotype is also predictive of high pCR to NT, but the prognosis of patients whose tumours do not achieve a pCR after neoadjuvant chemotherapy with anthracyclines and taxanes is dismal. Currently, it is recommended to use the same chemotherapy regimens as in non-triple-negative disease. The suggested benefit of neoadjuvant platinum, mainly in BRCA1-related cancers, needs to be confirmed in large randomized trials. Bevacizumab combined with neoadjuvant chemotherapy yields increased pCR compared with non-bevacizumab treatment, in large randomized data recently published. One study suggested higher benefit in triple-negative tumours. Long-term follow-up of these trials is needed to understand the role of bevacizumab treatment in BC and its important to find predictive biomarkers of response to this drug.

Background and objectives: Bevacizumab, used in combination with chemotherapy has demonstrated efficacy in randomized trials in MBC. Hypertension, congestive heart failure and cardiomyopathy have been reported in trials of bevacizumab in breast cancer. The aim of this systematic review and meta analysis is to determine the overall risk of grade 3-4 hypertension (HTN), left ventricular dysfunction (LVD) and venous (VT) and arterial thromboembolic events (ATE) related to Bevacizumab in patients with MBC. Methods: We selected randomized phase III trials which compared chemotherapy with or without bevacizumab in MBC as first or second line therapy. Data extraction was carried out from results published in the literature or from conference proceedings of the selected studies. For the analysis, we used a fixed-effects and random effects models to calculate the pooled event-based relative risk ratios (RR) with 95% confidence interval (CI). The Cochran's Q statistic and I2 statistics were first calculated to assess the heterogeneity among the proportions of the included trials. We collected all grade 3-4 events reported in these trials in relation to cardiovascular events: HTN, LVD, congestive heart failure, cardiomyopathy, VT and ATE. Results: Five trials were included in the meta-analysis: E2100, AVADO, RIBBON-1, RIBBON-2 and Miller et al study (capecitabine alone or plus bevacizumab in previously treated MBC). In total 2126 patients received chemotherapy in combination with bevacizumab and 1444 chemotherapy alone. When there was tendency for heterogeneity, random-effects models were used. Thromboembolic events were pooled together as VT and ATE as information was not clear in some of the reported studies. CHF and cardiomyopathy were considered for LVD events in the Miller study as LVD was not reported. Patients treated with bevacizumab-containing regimens had a RR for HTN of 10.32 (95% CI, 4.23- 24.79; p Conclusion: HTN is a recognized side effect of bevacizumab therapy. The risk of LVD is also significantly higher with bevacizumab therapy (RR 2.58) as shown in this pooled analysis, but the risk of thrombotic events is not increased. Figure available in online version. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P6-12-01.

Context: Genetic lipodystrophies are rare disorders characterized by partial or complete loss of adipose tissue and predisposition to insulin resistance and its complications such as diabetes mellitus, hypertriglyceridemia, hepatic steatosis, acanthosis nigricans, and polycystic ovarian syndrome. Objective: The objective of the study was to report a novel autosomal recessive lipodystrophy syndrome. Results: We report the detailed phenotype of two males and one female patient, 26–34 yr old, belonging to two pedigrees with an autosomal recessive syndrome presenting with childhood-onset lipodystrophy, muscle atrophy, severe joint contractures, erythematous skin lesions, and microcytic anemia. Other variable clinical features include hypergammaglobulinemia, hepatosplenomegaly, generalized seizures, and basal ganglia calcification. None of the patients had diabetes mellitus or acanthosis nigricans. Two had mild hypertriglyceridemia and all had low levels of high-density lipoprotein cholesterol. Skin biopsy of an erythematous nodular skin lesion from one of the patients revealed evidence of panniculitis. The lipodystrophy initially affected the upper body but later became generalized involving abdomen and lower extremities as well. Conclusions: We conclude that these patients represent a novel autoinflammatory syndrome resulting in joint contractures, muscle atrophy, microcytic anemia, and panniculitis-induced lipodystrophy. The molecular genetic basis of this disorder remains to be elucidated.

Mutations in the gene that encodes Fibroblast Growth Factor Receptor 3 (FGFR3) are associated with Achondroplasia (MIM 100800), Hypochondroplasia (MIM 146000), Muenke Syndrome (MIM 602849), Thanatophoric Dysplasia (MIM 187600, MIM 187601) and Lacrimo-Auriculo-Dento-Digital Syndrome (MIM 149730).Here we report a clinical and molecular study in a large cohort of 125 Portuguese patients with these skeletal disorders. The identification of the P250R mutation allowed the confirmation of the Muenke Syndrome in 9 out of the 52 cases referred. Two known mutations were found in the Thanatophoric Dysplasia referred cases. No mutations were identified in the LADD syndrome patient. In Achondroplasia and Hypochondroplasia, genetic heterogeneity was present amongst the 70 clinically diagnosed patients with 5 different mutations identified. As in other studies, complex phenotypic heterogeneity amongst patients carrying the same gene defect was observed. In several cases, the new amino acids encoded, as a consequence of mutations, were related to the severity of patients' phenotype. The presence of 10 misdiagnosed cases emphasizes the importance of performing mutation analysis of the hotspot regions responsible for both dysplasias (Ach and Hch). For patients with an unquestionable clinical diagnosis, lacking the most common mutations, a complete screening of FGFR3 is necessary.

Resumo: Introdução: Os tumores epiteliais tímicos (TET), a maioria timomas, são neoplasias desenvolvidas a partir das células epiteliais do timo e constituem cerca de 30% das massas do mediastino anterior em adultos. Os timomas são constituídos por células sem características citológicas de malignidade, sendo o comportamento maligno determinado pela invasão da cápsula e estru-turas adjacentes. Estes tumores apresentam um amplo espectro de características clínicas e morfológicas, e as pequenas séries de doentes conhecidas tornam difícil o estabelecimento de um tratamento standard.Material e métodos: Efectuouse um estudo retrospectivo dos doentes admitidos com diagnóstico de ti moma no Instituto Português de Oncologia - Centro do Porto (IPO-Porto), de 1983 a 2004. Foram anali-sadas as suas características clínicas, classificação histológica segundo a OMS, o estadiamento de Masaoka, e a sua relação com as modalidades de tratamento. Procedeu-se à revisão dos registos clínicos destes doentes e revisão do material histológico para a classificação segundo critérios da OMS de 1999.Resultados: No IPO-Porto, entre 1983 e 2004, fo-ram tratados 28 doentes com TET. Destes, 21 eram timomas invasivos, sendo estes o objecto deste estudo. Dos dados demográficos salienta-se que eram 11 homens, 10 mulheres, com uma idade mediana de 55 anos (24-79 anos). A classificação histológica da OMS foi a seguinte: 2 doentes (9,5%) Tipo A, 6 (28,6%) tipo AB, 4 (19%) tipo B1, 2 (9,5%) tipo B2, 7 (33,4%) tipo B3. O estadiamento segundo Masaoka foi 9 doentes (42,8%) com estádio II, 6 (28,6%) com estádio III e 6 (28,6%) com estádio IVa. A maioria dos doentes apresentava sintomas locais à apresen-tação, com apenas 1 doente com diagnóstico de aplasia eritrocitária e 5 com Mastenia gravis (MG).Os 6 doentes submetidos apenas a ressecção cirúrgica completa não tiveram evidência de recorrência da doença (2 tipo A-II, 2 tipo AB-II, 1 tipo B1-II, 1 tipo B2-IVa), com follow-up variando entre 8 e 144 meses. 10 doentes com ressecção completa receberam tratamento adjuvante, 6 radioterapia (4 doentes B3-II, 2 doentes B3-III), 2 quimioterapia (AB-IVa) e 2 radioterapia e quimioterapia (B1-IVa, B2-III). Apenas os 2 doentes que efectuaram quimioterapia adjuvante reci-divaram, aos 168 e 46 meses, e morreram aos 168 e 49 meses. Os restantes doentes que efectuaram tratamento adjuvante encontram-se sem evidência de doença. Dos 5 doentes com ressecção incompleta seguido de tratamento complementar (2 doentes AB-III, 2 B1-IVa, 1 B3-III), 3 morreram aos 11 meses (B3-III), aos 12 meses (B1-IVa) e aos 241 meses (AB-III), este últi-mo por MG.Conclusões: Apesar de se tratar de uma pequena série, os factores preditivos de mau prognóstico foram a ressecção incompleta, estádio avançado e o subtipo histológico B3. à necessário investigar o papel do tratamento adjuvante e neoadjuvante no grupo de doentes com doença avançada e subtipo histológico B3.Rev Port Pneumol 2007; XIII (4): 553-585 Abstract: Introduction: Epithelial thymic tumours (ETT), which comprise the majority of thymomas, are neoplasias developed from the epithelial cells of the thymus and constitute around 30% of anterior mediastinal masses in adults. Thymomas consist of cells with no cytological characteristics of malignity; malignant behaviour is determined by invasion of the capsule and adjacent structures. These tumours present a broad spectrum of clinical and morphological characteristics and the small series of known patients makes establishing a standard treatment difficult.Material and methods: A retrospective study was made into thymoma diagnosed patients admitted to the Portuguese Oncology Institute in Porto (IPO-Porto) from 1983 to 2004. Clinical characteristics were analysed and a histological classification made in accordance with World Health Organization criteria, Masaoka staging, and their relation to treatment methods. A review of the clinical records of these patients was then made, as well as a review of histological material for classification in line with 1999 WHO criteria.Results: Twenty-eight ETT patients were treated at the IPO-Porto between 1983 and 2004. Of these, 21 had invasive thymomas and these are the subject of this study. Eleven subjects were male and 10 female, with a median age of 55 years (24-79 years). The WHO histological classification was as follows: 2 patients (9.5%) type A, 6 (28.6%) type AB, 4 (19%) type B1, 2 (9.5%) type B2, 7 (33.4%) type B3. Masaoka staging was 9 patients (42.8%) with stage II, 6 (28.6%) with stage III and 6 (28.6%) with stage IVa. The majority of patients had local symptoms, with only one subject diagnosed with erythrocyte aplasia and five with Myasthenia Gravis (MG).The 6 patients who were given complete surgical resection only showed no evidence of disease recurrence (2 type A-II, 2 type AB-II, 1 type B1-II, 1 type B2-IVa), with follow-up from 8-144 months. Ten patients with complete resection received adjuvant treatment; 6 radiotherapy (4 B3-II patients, 2 B3-III patients), 2 chemotherapy (AB-IVa) and 2 chemo and radiotherapy (B1-IVa, B2-III). Only the 2 patients who under-went adjuvant chemotherapy relapsed, at 168 and 46 months, dying at 168 and 49 months, respectively. The remaining patients who were given adjuvant treatment did not present signs of disease. Of the 5 subjects having incomplete resection followed by complementary treatment (2 AB-III patients, 2 B1-IVa patients, 1 B3-III patient), 3 died, at 11 months (B3-III), 12 months (B1-IVa) and 241 months (AB-III), the latter with MG.Conclusions: Predictive factors of bad prognosis here were incomplete resection, advanced staging and B3 histological subtype, the smallness of this series not-withstanding. It is necessary to investigate the role of adjuvant and neoadjuvant treatment in a group of subjects with advanced disease of the B3 histological subtype.Rev Port Pneumol 2007; XIII (4): 553-585 Palavras-chave: Tumores epiteliais tímicos, timomas, Miastenia gravis, quimioterapia, radioterapia, Key-words: Epithelial thymic tumours, thymomas, Myasthenia gravis, chemotherapy, radiotherapy

Introduction: Epithelial thymic tumours (ETT), which comprise the majority of thymomas, are neoplasias developed from the epithelial cells of the thymus and constitute around 30% of anterior mediastinal masses in adults. Thymomas consist of cells with no cytological characteristics of malignity; malignant behaviour is determined by invasion of the capsule and adjacent structures. These tumours present a broad spectrum of clinical and morphological characteristics and the small series of known patients makes establishing a standard treatment difficult. Material and methods: A retrospective study was made into thymoma diagnosed patients admitted to the Portuguese Oncology Institute in Porto (IPOPorto) from 1983 to 2004. Clinical characteristics were analysed and a histological classification made in accordance with World Health Organization criteria, Masaoka staging, and their relation to treatment methods. A review of the clinical records of these patients was then made, as well as a review of histological material for classification in line with 1999 WHO criteria. Results: Twenty-eight ETT patients were treated at the IPO-Porto between 1983 and 2004. Of these, 21 had invasive thymomas and these are the subject of this study. Eleven subjects were male and 10 female, with a median age of 55 years (24-79 years). The WHO histological classification was as follows: 2 patients (9.5%) type A, 6 (28.6%) type AB, 4 (19%) type B1, 2 (9.5%) type B2, 7 (33.4%) type B3. Masaoka staging was 9 patients (42.8%) with stage II, 6 (28.6%) with stage III and 6 (28.6%) with stage IVa. The majority of patients had local symptoms, with only one subject diagnosed with erythrocyte aplasia and five with Myasthenia Gravis (MG).The 6 patients who were given complete surgical resection only showed no evidence of disease recurrence (2 type A-II, 2 type AB-II, 1 type B1-II, 1 type B2- IVa), with follow-up from 8-144 months. Ten patients with complete resection received adjuvant treatment; 6 radiotherapy (4 B3-II patients, 2 B3-III patients), 2 chemotherapy (AB-IVa) and 2 chemo and radiotherapy (B1-IVa, B2-III). Only the 2 patients who underwent adjuvant chemotherapy relapsed, at 168 and 46 months, dying at 168 and 49 months, respectively. The remaining patients who were given adjuvant treatment did not present signs of disease. Of the 5 subjects having incomplete resection followed by complementary treatment (2 AB-III patients, 2 B1-IVa patients, 1 B3-III patient), 3 died, at 11 months (B3-III), 12 months (B1-IVa) and 241 months (AB-III), the latter with MG. Conclusions: Predictive factors of bad prognosis here were incomplete resection, advanced staging and B3 histological subtype, the smallness of this series notwithstanding. It is necessary to investigate the role of adjuvant and neoadjuvant treatment in a group of subjects with advanced disease of the B3 histological subtype. Resumo: Introdução: Os tumores epiteliais tímicos (TET), a maioria timomas, são neoplasias desenvolvidas a partir das células epiteliais do timo e constituem cerca de 30% das massas do mediastino anterior em adultos. Os timomas são constituídos por células sem características citológicas de malignidade, sendo o comportamento maligno determinado pela invasão da cápsula e estruturas adjacentes. Estes tumores apresentam um amplo espectro de características clínicas e morfológicas, e as pequenas séries de doentes conhecidas tornam difícil o estabelecimento de um tratamento standard. Material e métodos: Efectuou-se um estudo retrospectivo dos doentes admitidos com diagnóstico de timoma no Instituto Português de Oncologia - Centro do Porto (IPO-Porto), de 1983 a 2004. Foram analisadas as suas características clínicas, classificação histológica segundo a OMS, o estadiamento de Masaoka, e a sua relação com as modalidades de tratamento. Procedeuse à revisão dos registos clínicos destes doentes e revisão do material histológico para a classificação segundo critérios da OMS de 1999. Resultados: No IPO-Porto, entre 1983 e 2004, foram tratados 28 doentes com TET. Destes, 21 eram timomas invasivos, sendo estes o objecto deste estudo. Dos dados demográficos salienta-se que eram 11 homens, 10 mulheres, com uma idade mediana de 55 anos (24-79 anos). A classificação histológica da OMS foi a seguinte: 2 doentes (9,5%) Tipo A, 6 (28,6%) tipo AB, 4 (19%) tipo B1, 2 (9,5%) tipo B2, 7 (33,4%) tipo B3. O estadiamento segundo Masaoka foi 9 doentes (42,8%) com estádio II, 6 (28,6%) com estádio III e 6 (28,6%) com estádio IVa. A maioria dos doentes apresentava sintomas locais à apresentação, com apenas 1 doente com diagnóstico de aplasia eritrocitária e 5 com Mastenia gravis (MG).Os 6 doentes submetidos apenas a ressecção cirúrgica completa não tiveram evidência de recorrência da doença (2 tipo A-II, 2 tipo AB-II, 1 tipo B1-II, 1 tipo B2-IVa), com follow-up variando entre 8 e 144 meses. 10 doentes com ressecção completa receberam tratamento adjuvante, 6 radioterapia (4 doentes B3-II, 2 doentes B3-III), 2 quimioterapia (AB-IVa) e 2 radioterapia e quimioterapia (B1-IVa, B2-III). Apenas os 2 doentes que efectuaram quimioterapia adjuvante recidivaram, aos 168 e 46 meses, e morreram aos 168 e 49 meses. Os restantes doentes que efectuaram tratamento adjuvante encontram-se sem evidência de doença. Dos 5 doentes com ressecção incompleta seguido de tratamento complementar (2 doentes AB-III, 2 B1- IVa, 1 B3-III), 3 morreram aos 11 meses (B3-III), aos 12 meses (B1-IVa) e aos 241 meses (AB-III), este último por MG. Conclusões: Apesar de se tratar de uma pequena série, os factores preditivos de mau prognóstico foram a ressecção incompleta, estádio avançado e o subtipo histológico B3. à necessário investigar o papel do tratamento adjuvante e neoadjuvante no grupo de doentes com doença avançada e subtipo histológico B3. Key-words: Epithelial thymic tumours, thymomas, Myasthenia gravis, chemotherapy, radiotherapy, Palavras-chave: Tumores epiteliais tímicos, timomas, Miastenia gravis, quimioterapia, radioterapia

Deletions of the long arm of chromosome 6 were first described in 1973 by Mikkelsen et al. and they constitute rare genetic anomalies that usually occur de novo [1]. There are less than a hundred cases described worldwide and the phenotypes vary according to the size and location of the deleted region, although some common characteristics are frequently found, such as developmental delay, hypotonia, facial dysmorphisms, micrognathia, microcephaly, ear anomalies, inguinal and/or umbilical hernias and cardiac malformations [2–4]. Hopkin and its colleagues proposed the existence of three phenotypic groups, according to the deleted region. The first group would include the proximal deletions (6q11–q16), frequently associated to hernias, upslanting palpebral fissures and thin lips; the second one would include the medial deletions (6q15–q25), associated to an intrauterine growth retardation, respiratory distress, hypertelorism and upper limb malformations; finally, the third group would concern the terminal deletions (6q25–qter), associated to retinal abnormalities, cleft palate and genital hypoplasia [2]. A search of the published literature allowed the gathering of more specific and diagnostic features related to the first group (6q11–q16). We point out the presence of epicanthus, large nasal tip, anteverted nares, wide

The treatment of early breast cancer (EBC) is becoming increasingly complex, but also more effective as a better understanding of cancer biology is achieved with evolving research. Longer follow-up of prospective trials is crucial to evaluate the impact of current standard treatments in long-term outcome and safety. In this review we will summarise the current evidence for optimal treatment of EBC.

Breast cancer (BC) under age 40 is a complex disease to manage due to the additionally fertility-related factors to be taken in consideration. More than 90 % of young patients with BC are symptomatic. Women

The Aristaless-related homeobox (ARX) gene is implicated in intellectual disability with the most frequent pathogenic mutations leading to expansions of the first two polyalanine tracts. Here, we describe analysis of the ARX gene outlining the approaches in the Australian and Portuguese setting, using an integrated clinical and molecular strategy. We report variants in the ARX gene detected in 19 patients belonging to 17 families. Seven pathogenic variants, being expansion mutations in both polyalanine tract 1 and tract 2, were identifyed, including a novel mutation in polyalanine tract 1 that expands the first tract to 20 alanines. This precise number of alanines is sufficient to cause pathogenicity when expanded in polyalanine tract 2. Five cases presented a probably non-pathogenic variant, including the novel HGVS: c.441_455del, classified as unlikely disease causing, consistent with reports that suggest that in frame deletions in polyalanine stretches of ARX rarely cause intellectual disability. In addition, we identified five cases with a variant of unclear pathogenic significance. Owing to the inconsistent ARX variants description, publications were reviewed and ARX variant classifications were standardized and detailed unambiguously according to recommendations of the Human Genome Variation Society. In the absence of a pathognomonic clinical feature, we propose that molecular analysis of the ARX gene should be included in routine diagnostic practice in individuals with either nonsyndromic or syndromic intellectual disability. A definitive diagnosis of ARX-related disorders is crucial for an adequate clinical follow-up and accurate genetic counseling of at-risk family members. Unit for Multidisciplinary Research in Biomedicine, UMIB, ICBAS-UP, Porto, Portugal was funded by FEDER funds of the Operational Program for Competitiveness Factors – COMPETE through FCT – Foundation for Science and Technology under the project: Fcomp-01-0124-FEDER-015896. The Neurogenetics research program in the Department of Paediatrics, University of Adelaide, Australia was funded by the Australian National Health and Medical Research Council (Grant No. 1063025). C. S. is supported Australian Research Council (Future Fellowship FT120100086)

Male breast cancer is a rare disease for which treatment has been based on the evidence available from female breast cancer. The new genomic tools can better characterize the biology of breast cancer. It is hoping that these will help to clarify possible differences of breast cancer behaviour in male patients, which will have a major impact on treatment strategies and on the conduct of clinical trials in this setting. In this review we will summarize available information on epidemiology, risk factors for breast cancer in men, the new insights of the biology of this disease, current recommendations for treatment and insights for future research.

Costello syndrome is characterized by severe failure-to-thrive, short stature, cardiac abnormalities (heart defects, tachyarrhythmia, and hypertrophic cardiomyopathy (HCM)), distinctive facial features, a predisposition to papillomata and malignant tumors, postnatal cerebellar overgrowth resulting in Chiari 1 malformation, and cognitive disabilities. De novo germline mutations in the proto-oncogene HRAS cause Costello syndrome. Most mutations affect the glycine residues in position 12 or 13, and more than 80% of patients share p.G12S. To test the hypothesis that subtle genotype-phenotype differences exist, we report the first cohort comparison between 12 Costello syndrome individuals with p.G13C and individuals with p.G12S. The individuals with p.G13C had many typical findings including polyhydramnios, failure-to-thrive, HCM, macrocephaly with posterior fossa crowding, and developmental delay. Subjectively, their facial features were less coarse. Statistically significant differences included the absence of multifocal atrial tachycardia (P-value = 0.033), ulnar deviation of the wrist (P < 0.001) and papillomata (P = 0.003), and fewer neurosurgical procedures (P = 0.024). Fewer individuals with p.G13C had short stature (height below -2 SD) without use of growth hormone (P < 0.001). The noteworthy absence of malignant tumors did not reach statistical significance. Novel ectodermal findings were noted in individuals with p.G13C, including loose anagen hair resulting in easily pluckable hair with a matted appearance, different from the tight curls typical for most Costello syndrome individuals. Unusually long eye lashes requiring trimming are a novel finding we termed dolichocilia. These distinctive ectodermal findings suggest a cell type specific effect of this particular mutation. Additional patients are needed to validate these findings.

We performed a phase II trial to test whether a cyclooxygenase (COX-2) inhibitor, celecoxib, added to standard first-line combination chemotherapy (CT) and as maintenance therapy would improve outcomes in extensive-stage (ES) small-cell lung cancer (SCLC). This was a multicenter trial in CT-naive patients with ES-SCLC. They received standard cisplatin and etoposide (EP) up to 6 cycles and celecoxib 400 mg PO bid continuously until disease progression. Primary end points were response rate (RR), time to progression (TTP), and toxicity. Secondary were overall survival (OS) and quality of life. Of 74 expected patients, only 24 were enrolled and the study stopped earlier because of the published safety concerns about celecoxib. The patients, all male, were between 38 and 74 years. A total of 130 cycles of CT were administered. Toxicity associated with celecoxib was minimal. The RR was 56.5%. Median TTP and OS were 8.6 and 11.3 months, respectively. These data suggest that celecoxib may safely be combined with EP for treatment of ES-SCLC. This combination showed a promising activity and, despite the safety concerns regarding celecoxib, it would be interesting to further evaluate this regimen.

Worldwide, approximately 1.3 billion individuals are current smokers, and smoking is the second major cause of death. Currently, lung cancer is the most common type of cancer in Europe, and the third in the U.S. Until now, cytotoxic chemotherapy has had a limited impact on survival in metastatic non-small cell lung cancer (NSCLC). The central role of epidermal growth factor (EGF) and its receptor (EGFR) in lung carcinogenesis is well recognized. Genetic polymorphisms are variants in individual genomes that may be responsible for different functional molecular roles and contribute to variability in drug pharmacokinetic and pharmacodynamic processes. Herein, we review the literature on EGF and EGFR functions and activities, particularly the current role of their functional polymorphisms as related to NSCLC.