Twenty Years of a Pre-Symptomatic Testing Protocol for Late-Onset Neurological Diseases in Portugal.

INTRODUCTION: The national protocol of genetic counselling and pre-symptomatic testing for late-onset neurological diseases began in Portugal in 1995. Initially, it was accessible only to adults at-risk for Machado-Joseph disease, but was later extended to other hereditary ataxias, to Huntington's disease and to familial amyloid polyneuropathy caused by Val30Met mutation at the transthyretin gene. The aim of this study was to describe the profile of the population seeking pre-symptomatic testing, while also reflecting on the experience of conducting the protocol of multidisciplinary sessions since 1996. MATERIAL AND METHODS: We conducted a retrospective study and collected data from clinical records of consultands who requested pre-symptomatic testing at our centre in Porto (Portugal) during the first twenty years of practice (1996 - 2015). RESULTS: A total of 1446 records were reviewed. The most common reason for testing was to reduce uncertainty (41.7%). The rate of withdrawals before results disclosure was lower (16%) than reported in other international experiences with pre-symptomatic testing, while 45% of the consultands dropped out the protocol after learning the test results (73.5% of them were non-carriers). As far as the mutation carriers were concerned, 29.6% adhered to the protocol a year after test disclosure. Consultands that had learned about presymptomatic testing through healthcare professionals tended to adhere more to pre-symptomatic testing consultations. DISCUSSION: The profile of Portuguese consultands at risk for late-onset neurological diseases is similar to those reported in other international programs. The largest group in this data set was the one comprising the subjects at risk for familial amyloid polyneuropathy caused by Val30Met mutation at the transthyretin gene, and it is likely that therapeutic options for this condition may have influenced this result. Adherence to pre-symptomatic testing may change in the future since effective therapies are available (or given the fact that people think effective treatments are imminent). CONCLUSION: This study reflects the first comprehensive description of a Portuguese experience with pre-symptomatic testing for late onset neurological diseases. The development of innovative approaches to improve the consultands' experience with pre-symptomatic testing and their engagement in genetic departments is still a challenge in Portuguese genetics healthcare departments. A better coordination among primary care and genetics healthcare services is needed.

Introdução: Em 1995 foi iniciado em Portugal um protocolo nacional para o aconselhamento genético e teste pré-sintomático de doenças neurológicas de início tardio. Inicialmente, foi disponibilizado para indivíduos adultos em risco para a doença de Machado-Joseph e posteriormente estendido a outras ataxias hereditárias, doença de Huntington e polineuropatia amiloidótica familiar ATTR Val30Met. O objetivo deste estudo é descrever o perfil dos consultandos envolvidos no teste pré-sintomático desde 1996, e refletir no protocolo de sessões multidisciplinares. Material e Métodos: Realizámos um estudo retrospetivo com recolha de dados dos processos clínicos dos utentes que solicitaram teste pré-sintomático ao longo dos primeiros 20 anos do Centro de Genética Preditiva e Preventiva (1996 - 2015), localizado no Porto, Portugal. Resultados: Analisámos um total de 1446 processos clínicos; a principal motivação para a realização do teste pré-sintomático foi o alívio da incerteza (41,7%). A taxa de abandono do protocolo antes da comunicação dos resultados do pré-sintomático (16% dos casos) foi mais baixa do que em outras experiências internacionais; 45% dos consultandos abandonaram o protocolo depois de saberem o resultado do teste pré-sintomático (73,5% dos quais eram não-portadores). 29,6% de consultandos portadores continuaram envolvidos no protocolo um ano após saberem o resultado do teste pré-sintomático. Os consultandos encaminhados para o protocolo através de outros profissionais de saúde revelaram maior adesão ao protocolo. Discussão: O perfil sociodemográfico dos consultandos no Centro de Genética Preditiva e Preventiva é similar ao reportado noutras experiências internacionais. Os consultandos em risco para polineuropatia amiloidótica familiar ATTR Val30Met representaram o maior grupo nos nossos dados, sendo provável que as opções terapêuticas disponíveis para esta doença tenham influenciado este resultado. A adesão ao teste pré-sintomático poderá alterar-se no futuro quando terapias eficazes estiverem disponíveis (ou as pessoas as percepcionem como estando iminentes). Conclusão: Este trabalho constitui a descrição mais completa até ao momento publicada acerca da realização de teste pré-sintomático em Portugal. O desenvolvimento de abordagens com vista à melhoria da experiência dos consultandos com os testes pré-sintomáticos e ao seu envolvimento nos serviços de genética é um desafio atual, assim como a melhor articulação dos mesmos com os cuidados de saúde primários.

Oophoropexy to the round ligament after recurrent adnexal torsion / Ooforopexia ao ligamento redondo em um caso de torção anexial recorrente

Abstract Recurrent adnexal torsion is a rare gynecological emergency. We report a case of recurrent ipsilateral adnexal torsion in a woman with polycystic ovaries, previously submitted to a laparoscopic plication of the utero-ovarian ligament. Due to the recurrence after the plication of the utero-ovarian ligament, the authors performed a laparoscopic oophoropexy to the round ligament, which is an underreported procedure. The patient was asymptomatic for 1 year, after which she had a new recurrence and needed a unilateral laparoscopic adnexectomy. Since then, she regained the quality of life without any gynecological symptoms. Oophoropexy to the round ligament may be considered when other techniques fail or, perhaps, as a first option in selected cases of adnexal torsion, as it may allow the prevention of recurrence without increasing morbidity while preserving the adnexa.

Resumo A torção anexial recorrente é uma emergência ginecológica rara. Os autores descrevem um caso de torsão anexial unilateral recorrente em uma paciente com síndrome de ovário policístico, previamente submetida a plicatura do ligamento utero-ovárico por laparoscopia. Nesta circunstância, os autores decidiram realizar uma ooforopexia laparoscópica ao ligamento redondo, uma técnica pouco descrita na literatura. A paciente manteve-se assintomática durante 1 ano, período após o qual teve nova recorrência, tendo-se decidido realizar uma anexectomia laparoscópica unilateral. Desde então, ela recuperou a qualidade de vida sem qualquer sintoma ginecológico. A ooforopexia ao ligamento redondo é uma técnica que deverá ser considerada quando outras falham e, em casos selecionados de torsão anexial recorrente, poderá ser considerada a primeira abordagem, para prevenir a recorrência e preservar o anexo.

Oophoropexy to the Round Ligament after Recurrent Adnexal Torsion.

Recurrent adnexal torsion is a rare gynecological emergency. We report a case of recurrent ipsilateral adnexal torsion in a woman with polycystic ovaries, previously submitted to a laparoscopic plication of the utero-ovarian ligament. Due to the recurrence after the plication of the utero-ovarian ligament, the authors performed a laparoscopic oophoropexy to the round ligament, which is an underreported procedure. The patient was asymptomatic for 1 year, after which she had a new recurrence and needed a unilateral laparoscopic adnexectomy. Since then, she regained the quality of life without any gynecological symptoms.Oophoropexy to the round ligament may be considered when other techniques fail or, perhaps, as a first option in selected cases of adnexal torsion, as it may allow the prevention of recurrence without increasing morbidity while preserving the adnexa.

A torção anexial recorrente é uma emergência ginecológica rara. Os autores descrevem um caso de torsão anexial unilateral recorrente em uma paciente com síndrome de ovário policístico, previamente submetida a plicatura do ligamento utero-ovárico por laparoscopia. Nesta circunstância, os autores decidiram realizar uma ooforopexia laparoscópica ao ligamento redondo, uma técnica pouco descrita na literatura. A paciente manteve-se assintomática durante 1 ano, período após o qual teve nova recorrência, tendo-se decidido realizar uma anexectomia laparoscópica unilateral. Desde então, ela recuperou a qualidade de vida sem qualquer sintoma ginecológico.A ooforopexia ao ligamento redondo é uma técnica que deverá ser considerada quando outras falham e, em casos selecionados de torsão anexial recorrente, poderá ser considerada a primeira abordagem, para prevenir a recorrência e preservar o anexo.

Relevance of serum biomarkers associated with melanoma during follow-up of anti-CTLA-4 immunotherapy.

Metastatic melanoma is a rapidly spreading cancer whose prognosis remains poor although important therapy advances in recent years. Ipilimumab, an anti-CTLA-4 immunotherapy used in advanced melanoma, is an effective immunotherapy alone or combined with other agents but with few predictive biomarkers of response. Here, we sought to analyze the potential of S100B, MIA, soluble MICA, anti-MICA antibodies and LDH as serum biomarkers of response and survival in a cohort of 77 advanced melanoma patients subjected to ipilimumab. Lower levels of S100B, and LDH at baseline and at weeks 3 and 6 correlated to a better response and survival. After multivariate analysis LDH maintained its independence at baseline and week 6, whereas S100B might be a useful tool for anti-CTLA-4 treatment monitoring after the first two doses of ipilimumab (W6). In addition, higher sMICA serum levels at baseline were associated with less frequency of irAEs.

Ipilimumab reshapes T cell memory subsets in melanoma patients with clinical response.

PURPOSE: Therapy targeting CTLA-4 immune checkpoint provides increased survival in patients with advanced melanoma. However, immunotherapy is frequently associated with delayed and heterogeneous clinical responses and it is important to identify prognostic immunological correlates of clinical endpoints. EXPERIMENTAL DESIGN: 77 patients with stage III/IV melanoma were treated with ipilimumab alone every 3 weeks, during 9 weeks. Blood samples were collected at the baseline and before each dose for in depth immune monitoring. RESULTS: The median follow-up was 28 mo with a median survival of 7 mo. Survival and clinical benefit were significantly improved when absolute lymphocyte count at the baseline was above 1 × 10(9)/L. Notably, ipilimumab had a global effect on memory T cells, with an early increase of central and effector subsets in patients with disease control. By contrast, percentages of stem cell memory T cells (TSCM) gradually decreased despite stable absolute counts and sustained proliferation, suggesting a process of differentiation. Higher proportions of eomes(+) and Ki-67(+) T cells were observed, with enhanced skin homing potential and induction of cytotoxic markers. CONCLUSION: These results suggest that CTLA-4 blockade is able to reshape the memory subset with the potential involvement of Eomes and memory subsets including TSCM.

Mature Cystic Teratoma of Ovary with Abnormally High Levels of Ca19-9: A Case Report.

Mature cystic teratomas, or dermoid tumors, are the most common benign ovarian neoplasms in young women. Malignant transformation is rare, and occurs in less than 2% of the cases. The heterogeneous histological composition of these tumors may be responsible for the occasional elevation of various tumor markers, such as Ca19-9 and Ca125. We describe one case of mature cystic teratoma in a 50-year old woman with the second highest level of Ca19-9 (8922.76 UI/mL) described in the literature. We concluded that abnormal levels of Ca19-9 are not necessarily associated with ovarian malignancy, and may lead to unnecessary medical intervention and patient anxiety. Therefore, the clinical features, imaging studies and antigen testing should be interpreted carefully, and should not limit the surgical approach.

Mature Cystic Teratoma of Ovary with Abnormally High Levels of Ca19-9: A Case Report / Teratoma maduro cístico do ovário com níveis aberrantes de Ca19-9: caso clínico

Abstract Mature cystic teratomas, or dermoid tumors, are the most common benign ovarian neoplasms in young women. Malignant transformation is rare, and occurs in less than 2% of the cases. The heterogeneous histological composition of these tumors may be responsible for the occasional elevation of various tumor markers, such as Ca19-9 and Ca125. We describe one case of mature cystic teratoma in a 50-year old woman with the second highest level of Ca19-9 (8922.76 UI/mL) described in the literature. We concluded that abnormal levels of Ca19-9 are not necessarily associated with ovarian malignancy, and may lead to unnecessary medical intervention and patient anxiety. Therefore, the clinical features, imaging studies and antigen testing should be interpreted carefully, and should not limit the surgical approach.

Resumo Os teratomas maduros císticos do ovário, ou tumores dermoides, são as neoplasias benignas mais frequentes em mulheres jovens. A sua transformação maligna é rara, e ocorre emmenos de 2% dos casos. A composição histológica heterogénea destes tumores pode ser responsável pela ocasional elevação de marcadores tumorais, como o Ca19-9 e o Ca125. Descrevemos umcaso de teratoma maduro cístico do ovário numa paciente de 50 anos com o segundo valor mais elevado de Ca19-9 (8922,76 UI/mL) descrito na literatura. Concluímos que níveis anormalmente elevados de Ca19-9 não estão necessariamente associados a tumores malignos, e podem conduzir a intervenções médicas desnecessárias e contribuir para o aumento da ansiedade da paciente. Portanto, as características clínicas, os estudos imagiológicos e os marcadores tumorais devem ser interpretados cuidadosamente, e não devem limitar o tipo de conduta cirúrgica.

CD158k is a reliable marker for diagnosis of Sézary syndrome and reveals an unprecedented heterogeneity of circulating malignant cells.

The diverse aspects of cutaneous T-cell lymphomas may impede the diagnosis of Sézary syndrome (SS) and mycosis fungoides (MF), in particular, at early stages of the disease. We defined the CD158k/KIR3DL2 molecule as a first positive cell surface marker for Sézary cells (SCs). Here, we designed an optimized flow cytometry gating strategy, allowing the definition of lymphocytes of different sizes and defects of cell surface markers. Quantification by cytomorphology, flow cytometry, or clonal evaluation, gave similar results at initial time points and during the evolution in a prospective study involving 64 consecutive cutaneous T-cell lymphoma or erythrodermic patients. We found that CD158k+ T cells and circulating CD4+ T cells from MF patients exhibited unexpected patterns of cell surface expression with a marked heterogeneity of circulating lymphocytes even at initial diagnosis. Taken together, our results show that a multistep gating of CD158k+ cells is reliable to assess tumor burden in case of SS and suggest that both circulating MF CD4+ T cells and CD158k+ T cells are not homogeneous distinct memory populations. Further phenotypic and functional characterizations of such subsets are needed to better understand the underlying molecular mechanisms leading to the development of these diseases.