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INTRODUCTION: Older patients are at higher risk of chemotherapy-induced toxicity, raising interest in less toxic anti-HER2 regimens for older persons with HER2-positive (HER2+) metastatic breast cancer (MBC). PATIENTS AND METHODS: This phase II study randomized (1:1) patients with HER2+ MBC, aged 70+ or frail 60+, to first line chemotherapy with metronomic oral cyclophosphamide (M) + Trastuzumab (T) and Pertuzumab (P) or TP alone. T-DM1 was offered in case of progression. RESULTS: In total, 39 and 41 patients were randomized to TP and TPM arm respectively. Median follow-up is 54.0 months. 24-month PFS was 18.7% (95% CI 8.2-32.4) and 28.7% (95% CI 15.8-43.0), respectively. A total of 49 (61.3%) patients died of whom 37 (75.5%) from disease progression; number of deaths per arm was 27 (69.2%) for TP and 22 (53.7%) for TPM. There was no significant difference in OS between the two arms (median OS TP vs TPM: 32.1 vs 37.5 months, p 0.25). Among the 40 patients who have started T-DM1 after disease progression on TP/TPM, PFS rate at 6 months after start of T-DM1 was 43.6% (95% CI: 27.7-58.5) and grade 3 or higher AE occurred in 18 pts (45%). CONCLUSIONS: Metronomic chemotherapy-based dual blockade (TPM), followed by T-DM1 after progression, provides an active and relatively well tolerated treatment option in an older/frail HER2+ MBC population, with a median survival of over 3 years. Nevertheless, the majority of this older/frail population died from breast cancer, highlighting the need for well tolerated and efficacious treatments in these patients. ispartof: BREAST vol:64 pages:100-111 ispartof: location:Netherlands status: published

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

© 2021 American Society of Human Genetics, EDEM3 encodes a protein that converts Man8GlcNAc2 isomer B to Man7-5GlcNAc2. It is involved in the endoplasmic reticulum-associated degradation pathway, responsible for the recognition of misfolded proteins that will be targeted and translocated to the cytosol and degraded by the proteasome. In this study, through a combination of exome sequencing and gene matching, we have identified seven independent families with 11 individuals with bi-allelic protein-truncating variants and one individual with a compound heterozygous missense variant in EDEM3. The affected individuals present with an inherited congenital disorder of glycosylation (CDG) consisting of neurodevelopmental delay and variable facial dysmorphisms. Experiments in human fibroblast cell lines, human plasma, and mouse plasma and brain tissue demonstrated decreased trimming of Man8GlcNAc2 isomer B to Man7GlcNAc2, consistent with loss of EDEM3 enzymatic activity. In human cells, Man5GlcNAc2 to Man4GlcNAc2 conversion is also diminished with an increase of Glc1Man5GlcNAc2. Furthermore, analysis of the unfolded protein response showed a reduced increase in EIF2AK3 (PERK) expression upon stimulation with tunicamycin as compared to controls, suggesting an impaired unfolded protein response. The aberrant plasma N-glycan profile provides a quick, clinically available test for validating variants of uncertain significance that may be identified by molecular genetic testing. We propose to call this deficiency EDEM3-CDG., This work was supported by the EU FP7 large-scale integrating project Genetic and Epigenetic Networks in Cognitive Dysfunction (241995) (to H.v.B.); National Institutes of Health (NIH) grants 5R01GM115730-03 (to M.H.), U54 NS115198 (to A.C.E. and M.H.), and T32GM008638 (to A.C.E.); and the Transatlantic Network of Excellence grant (10CVD03) from the Fondation Leducq and NIH NHGRI U01HG006398 (to D.J.R.). Family 4 was enrolled in the CAUSES Study; investigators include Shelin Adam, Christele Du Souich, Alison Elliott, Anna Lehman, Jill Mwenifumbo, Tanya Nelson, Clara Van Karnebeek, and Jan Friedman; it is funded by Mining for Miracles, British Columbia Children’s Hospital Foundation (grant number F15-01355) and Genome British Columbia (grant number F16-02276). D.L.P. is recipient of a CAPES Fellowship (99999.013311/2013-01). X.B. is supported by an AHA career development award (19CDA34630032).

The current study assessed breast cancer patients' somatic symptoms during the first six months post diagnosis and examined the moderating role of coping flexibility (i.e., trauma-focused and forward-focused coping strategies) on the association between reported somatic symptoms three months after breast cancer diagnosis and somatic symptoms six months after diagnosis.An international sample of 702 women diagnosed with breast cancer from four countries (Finland, Israel, Italy, Portugal) completed self-reported questionnaires at three time points: at the time of diagnosis (M0), three months post diagnosis (M3), and six months post diagnosis (M6). The questionnaires included the coping flexibility scale and questions about demographics, medical data, and somatic symptoms.The highest level of somatic symptoms was reported after three months post diagnosis (M3), as compared to M0 and M6. Both trauma-focused and forward-focused coping strategies moderated the relationship between somatic symptoms at M3 and somatic symptoms at M6.The findings highlight the importance of assessing somatic symptoms soon after breast cancer diagnosis and throughout the early phase of treatment. Coping flexibility can buffer the stability of the somatic symptoms during this initial phase.

Greater inflammatory signaling has been shown to promote breast cancer disease progression and poorer clinical outcomes. Lower social support and social well-being have been related to greater inflammatory signaling and poorer clinical outcomes in women with non-metastatic breast cancer, and this appears to be independent of depression. However, little is known about these associations in women with metastatic disease. s100A8/A9 and interleukin 1 beta (IL-1β) proteins are widely studied in breast cancer and are considered as biomarkers of cancer progression or as having a causal role in carcinogenesis and cancer progression and metastasis via inflammatory signaling. The aim of this study was to examine the associations between less social/family well-being (SWB) and S100A8/A9 and IL-1β levels in women diagnosed with metastatic breast cancer. Sixty women (Mean age 58.95 ​± ​1.49) with a diagnosis of metastatic breast cancer participated in the study. The Functional Assessment of Cancer Therapy (FACT) social and family well-being (SWB) subscale and the Hospital Anxiety Depression Scale (HADS) were administered to patients undergoing a first- or second-line endocrine or oral chemotherapy treatment and who were not experiencing brain metastasis or visceral crisis. Salivary s100A8/A9 and IL-1β levels were assessed at 5PM on two consecutive days and averaged. Multiple regression tested the independent contribution of SWB on s100 A8/A9 and IL-1b while controlling for depression. Lower levels of SWB were associated with greater S100A8/A9 (ß ​= ​-0.345, p ​= ​0.007) and IL-1β (ß ​= ​-0.286, p ​= ​0.027) levels and these associations remained significant after controlling for depression. This work provides new evidence for the role of decreased SWB and greater s100A8/A9 and IL-1b levels in patients diagnosed with metastatic breast cancer. Psychosocial interventions that promote social support and positive social interactions through interpersonal skills may help metastatic breast cancer patients to improve their SWB. This may have salutary effects on cancer-promoting processes, which could provide psychological and physical health benefits.

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.

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.

IntroductionPseudohypoparathyroidism is a genetically heterogeneous condition characterized by hypocalcemia and hyperphosphatemia resulting from end-organ resistance to parathyroid hormone (PTH). It is classified into several distinct entities (type Ia, Ib, Ic, type II), according to the molecular causes and clinical features of the patients.Case reportWe report a symptomatic case of a pediatric patient with hypocalcaemia, hyperphosphatemia, hypomagnesaemia and an elevated serum PTH level that presented with tetany. The molecular genetic test revealed a GNAS gene methylation defect of the A/B promoter, which confirms the diagnosis of a sporadic form of pseudohypoparathyroidism type Ib.

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.

Margaret Hutka1,*, Berta Sousa2, Felipe Ades3, Joost van de Vorst4, Pierluigi Bonomo5, Leticia De Mattos-Arruda6 1 Department of Medicine, The Royal Marsden NHS Foundation Trust, London, UK 2 Breast Unit, Champalimaud Cancer Center, Lisbon, Portugal 3 Breast Unit, Institut Jules Bordet, Universite Libre de Bruxelles, Belgium 4 Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands 5 Radiation Oncology, Azienda Ospedaliero Universitaria Careggi, Florence, Italy 6 Vall d’Hebron Institute of Oncology, Vall d’Hebron University Hospital, Barcelona, Spain

We performed homozygosity mapping in two recently reported pedigrees from Portugal and Mexico with an autosomal-recessive autoinflammatory syndrome characterized by joint contractures, muscle atrophy, microcytic anemia, and panniculitis-induced lipodystrophy (JMP). This revealed only one homozygous region spanning 2.4 Mb (5818 SNPs) on chromosome 6p21 shared by all three affected individuals from both families. We directly sequenced genes involved in immune response located in this critical region, excluding the HLA complex genes. We found a homozygous missense mutation c.224C>T (p.Thr75Met) in the proteasome subunit, beta-type, 8 (PSMB8) gene in affected patients from both pedigrees. The mutation segregated in an autosomal-recessive fashion and was not detected in 275 unrelated ethnically matched healthy subjects. PSMB8 encodes a catalytic subunit of the 20S immunoproteasomes called β5i. Immunoproteasome-mediated proteolysis generates immunogenic epitopes presented by major histocompatibility complex (MHC) class I molecules. Threonine at position 75 is highly conserved and its substitution with methionine disrupts the tertiary structure of PSMB8. As compared to normal lymphoblasts, those from an affected patient showed significantly reduced chymotrypsin-like proteolytic activity mediated by immunoproteasomes. We conclude that mutations in PSMB8 cause JMP syndrome, most probably by affecting MHC class I antigen processing.

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

Aim: MC (continuous administration of low doses of conventional chemotherapeutics) is characterized by an excellent therapeutic index. In fact, we recently demonstrated that 24% of patients with ABC receiving daily dalteparin and oral cyclophosphamide, twice-weekly methotrexate, and daily prednisone (dalCMP) achieved clinical benefit with minimal toxicity. While there are no predictive markers of response to MC, circulating miRNAs have a high potential to serve as easy accessible biomarkers. Hence we sought to generate a predictive plasma miRNA signature of response to dalCMP. Methods: We analyzed pre-treatment plasma samples from top-responders versus patients with dalCMP refractory ABC (n = 6 each) using the nCounter® miRNA expression assay (NanoString Technologies). Candidate miRNAs were validated by qRT-PCR. Results: Of 800 human miRNAs of miRBase v18.0, we identified 210 miRNAs expressed in all patient samples. Of these, the average expression of 24 miRNAs displayed a > 2-fold change in either direction in responders to dalCMP (mean ± SD time to tumor progression 65.6 ± 13.9 weeks) versus non-responders (3.2 ± 1.0 weeks). Student t-testing followed by Benjamini–Hochberg correction revealed 6 miRNAs significantly upregulated in non-responders: miR-451a, miR-122-5p, miR-142-3p, miR-548ai, miR-150-5p, and miR-342-3p. Using qRT-PCR, we confirmed the differential expression pattern of miR-451a, miR-122-5p, miR-142-3p, and miR-548ai. In contrast to our findings, miR-451a overexpression has been found by others to exert in vitro chemosensitizing properties, whereas miR-122-5p, miR-142-3p and miR-548ai have not been associated with chemosensitivity modulation to date. Conclusions: We describe the first candidate miRNA signature predicting response to MC (i.e. dalCMP), currently being validated in the original and extension dalCMP study populations (n = 92). This signature may become a helpful tool to select patients with ABC suitable for dalCMP, and to possibly predict response to other MC regimens as well as to MC used for other tumor types. Disclosure: All authors have declared no conflicts of interest.