4 resultados para Fetge-Biòpsia, Fetge-Transplantació,
Resumo:
RESUMO: Os carcinomas localizados no nariz so muito frequentes em todas as sries conhecidas. So de diagnstico clnico fcil e a sua confirmao por bipsia muito segura. As teraputicas mais indicadas so a cirurgia e a radioterapia, genericamente eficazes. Verifica-se, no entanto, que os pacientes continuam a solicitar tratamento em estdios muito avanados, mesmo conhecendo o diagnstico e tendo acesso aos servios sem custos. Esta situao poder explicar-se face ao curso relativamente lento de muitos destes tumores e idade geralmente avanada dos doentes que, de acordo com alguns inquritos, receiam mais a terapetica do que a doena. Para obteno de informao til para conduo deste problema, foram ainda analisados outros parmetros. A maioria dos pacientes continua a solicitar tratamento quando as leses envolvem duas subunidades nasais. Esta circunstncia permite planear o tratamento cirrgico com relativa facilidade, isto , com exrese e reconstruo cujo resultado esttico final bastante aceitvel. Os tumores de grandes dimenses, envolvendo vrias subunidades, sendo frequentes, raramente implicam rinectomia total. Pelo contrrio, so mais frequentes os tumores que envolvem metade do nariz e as estruturas vizinhas tais como o maxilar, a rbita e o lbio superior, atingindo mesmo a base do crnio. O controlo da doena nestes estdios muito difcil. No raramente, quando se cr que a doena est controlada, a cirurgia reconstrutiva bem como outras formas de reabilitao conjugadas, deixam ainda muita insatisfao. A nossa actividade tem-se desenvolvido seguindo os critrios adoptados nos melhores centros, isto , as tcnicas clssicas, complementadas com refinamentos recentes. Porm reflectindo sobre os resultados obtidos no tratamento de tumores do nariz, surge-nos um conjunto de questes para as quais ainda no encontrmos respostas cabais. Actuando de acordo com os princpios que definem o estado da arte, no obtivemos ainda resultados que satisfaam tanto os doentes quanto os cirurgies. Incessantemente procuramos novos dados tcnicos e cientficos que nos permitam sair deste ciclo vicioso em que o doente retarda a procura de assistncia, receoso de que a teraputica o deixe desfigurado. Tendo sempre em vista a obteno dos melhores resultados com o mnimo de tempos cirrgicos, valorizamos alguns detalhes praticados nos retalhos com padro vascular bem definido. Dado que as sequelas na zona dadora de tecidos so uma incontornvel preocupao, procuramos refinar a sua aplicao no sentido de as atenuarmos. A fronte, excelente zona dadora para reconstruco nasal major, era sede de sequelas actualmente inaceitveis. Estudado o comportamento dos tecidos na fronte, depois de levantado o retalho e efectuado o seu encerramento com uso da tcnica de expanso intra-operatria, determinmos a presena do Factor de Crescimento Vascular Endotelial no prprio retalho e na zona dadora, tendo em vista que a sua presena poder explicar o comportamento dos tecidos que foram submetidos a esta tcnica. Procurou-se estudar a qualidade da reconstruo em 45 pacientes submetidos a cirurgia de exrese e reconstruo nasal major, assim como a qualidade de vida, relacionada com a doena e a teraputica. Embora se possa admitir a existncia de dados sugestivos de estratgias mais adequadas, no foi possvel relacionar a qualidade da reconstruo com qualidade de vida dos pacientes. Poder eventualmente concluir-se que a observao permanente da reconstruo, com qualidade esttica e funcional, ser o melhor mtodo de alterar a ideia clssica, ainda muito divulgada, mas j ultrapassada, de que a cirurgia reconstrutiva do nariz no mais que transformar um defeito horroroso num defeito ridculo.---------------ABSTRACT: Malignant tumours found in the nose are very frequent in all known series. Clinical diagnosis is simple and confirmation of biopsy diagnosis is accessible and safe. The most advisable therapies are surgery and radiotherapy. Despite everything patients continue to wait until the tumour is in an advanced stage before asking for therapy, although they know the diagnosis and have free access to specialised services. This situation could probably be explained by the slow development rate of the tumours which is associated with the age of the patient. Upon inquiry, it was found that a significant number of patients are more afraid of therapy than of the disease itself. Other parameters have been analysed in order to obtain useful information about the management of this problem. The majority of patients seek adequate treatment when the lesions involve two nasal subunits. This allows the programming of surgical therapy with relative ease as they may be removed and reconstructed with interesting final aesthetical results. Large tumours involving several subunits are frequent, but they rarely call for total rhinectomy. On the contrary, tumours more frequently involve half of the nose and their neighbouring structures: for example, maxillary, orbital and upper lip, even reaching as far as the base of the skull. The control of the disease is very difficult in these stages.In cases in which it is believed that the disease is under control, reconstructive surgery in conjunction with other forms of rehabilitation still result in a lot of dissatisfaction. In our activity we try to follow the criteria adopted by the best centres following classic techniques, complemented with recent refinements. Reflecting on the treatment of tumours of the nose has led us to a series of questions to which we havent yet found the answers. In accordance with the defined principles of the state of the art it still doesnt satisfy either the patients or the surgeons. We are looking for new technical and scientific data which allows us to leave this vicious cycle, in that the deferred patient avoids looking for assistance, based on the fear that therapy could leave them disfigured. We attach importance to some practiced details on the well-defined vascular pattern of the flaps, with the principle aim of obtaining a good result, from the minimum number of operations. It is known that sequels in donor sites are a concern, so applied refinements are used in order to reduce the defect. The forehead has been considered an excellent donor site for major nasal reconstruction but the area of sequel is nowadays unacceptable. We tried to study the behaviour of the tissues of the forehead after taking the flap and closing the wound, using the intraoperative expansion technique. We determined the presence of Vascular Endothelial Growth Factor in the flaps and in the donor site, in which its presence could explain the behaviour of the tissues of the forehead that are submitted to this technique. The quality of the reconstruction was studied in 45 patients who were submitted to surgical exeresisand major nasal reconstruction, as was the relationship between the disease and the therapy regarding quality of life. It was not possible to directely relate the quality of the reconstruction to the quality of patients life, although some suggestive data of more adequate manegement may be interesting. One might eventually conclude that, permanent exposure of the reconstruction with aesthetic and funcional quality would be the best method in order to modify the classic idea which is still known although overridden today, that nasal reconstruction could transform a horrible defect into a ridiculous one.-------RSUM: Les carcinomes situs sur le nez sont trs frquents dans toutes les sries connues. Ils sont de diagnostic facile et la confirmation de ce dernier par une biopsie, est accessible et trs fiable. La chirurgie et la radiothrapie sont les thrapeutiques les mieux indiques. Toutefois les patients continuent de solliciter un traitement, seulement dans des tats trs avancs bien quils aient eu connaissance du diagnostic et ayant accs aux services. Cette situation pourra probablement sexpliquer par lvolution relativement indolente de beaucoup de tumeurs, associe lge des malades; bien que selon quelques enqutes ralises un nombre lev de malades craint davantage la thrapeutique que la maladie. Dautres paramtres sont analyss en vue dobtenir des informations utiles pour laccompagnement de ce problme. La majorit de nos patients sollicite le traitement adquat quand les lsions entourent deux sous-units nasales, ce qui permet de planifier le traitement chirurgique avec une certaine facilit, cest dire lexrse et la reconstruction ayant un rsultat final esthtique gnralement trs acceptable. Les tumeurs de grandes dimensions entourant diffrentes sous-units sont frquentes mais elles impliquent rarement une amputation nasal total. Au contraire, les tumeurs les plus frquentes sont celles qui entourent la moiti du nez et les structures voisines comme le maxillaire, lorbite et la lvre suprieure, parfois, elles peuvent mme atteindre la base du crne. Le contrle de la maladie dans ces tats est trs difficile et quand nous pensons que la maladie est contrle, la chirurgie reconstructrice associe dautres formes de rhabilitation provoquent encore une grande insatisfaction. Nous exerons notre activit en essayant de suivre les critres adopts dans les meilleurs centres. Nous appliquons les techniques classiques compltes de retouches pour obtenir un meilleur resultat. Le fait de traiter les tumeurs nasales nous fait rflchir et poser un ensemble de questions auxquelles nous navons pas pu trouver de rponses. En actuant en accord avec les principes qui dfinissent ltat de lart, nous navons pas obtenu de rsultats qui satisfassent les malades et les chirurgiens. Nous recherchons de nouvelles donnes techniques et scientifiques qui nous permettent de sortir de ce cercle vicieux dans lequel le patient retarde la recherche daide craignant que la thrapeutique le dfigure. Nous valorisons certains dtails pratiqus sur les lambeaux de patron vasculaire bien dfini et ayant comme principaux objectifs lobtention dun bon rsultat en moins de temps de chirurgie. Nous savons que les squelles de la zone donneuse de tissus sont proccupantes, ainsi, que les retouches qui ont t appliqus dans lobjectif de les attnuer. Le front, excellente zone donneuse pour la reconstruction nasale majeure, tait une source de squelle actuellement inacceptable. Nous avons tudi le comportement des tissus du front aprs avoir relev le lambeau et effectu la fermeture avec la technique de lexpansion intraoperative. Nous avons dtermin la prsence du Facteur de Croissance Vasculaire Endothliale dans le propre lambeau et dans la zone donneuse, celle-ci pourra expliquer le comportement des tissus du front qui ont t soumis cette technique. On a essay detudier la qualit de la reconstruction sur 45 patients soumis la chirurgie dexrse et la reconstruction nasal majeure, ainsi comme la qualit de vie en relation avec la maladie et la thrapie. Quoique lon puisse conclure par lexistence des donnes subjectives des stratgies plus justes, il est impossible de faire un rapport sur la qualit de la reconstruction avec la qualit de vie des patients. Eventuellement lon purrait conclure que lobservation permanente de la reconstruction avec qualit esthtique et fonctionnelle, se serait la meilleure mthod de changer lide classique, mais depasse, de que la rhinopoise nest pas que transformer un affreux dfaut par un dfaut ridicule.
Resumo:
Resumo: Os resultados das nossas investigaes, apresentadas ao longo desta dissertao,contriburam para a otimizao do diagnstico invasivo e no invasivo da osteodistrofia renal e permitiram evidenciar a relevncia, para a expresso clnica e histolgica da ODR, de algumas articularidades especficas da populao hemodialisada, nomeadamente: a utilizao de membranas de hemodilise mais biocompatveis e com elevada permeabilidade, o recurso a tcnicas de hemodiafiltrao com otimizao da capacidade convectiva, as limitaes dos marcadores bioqumicos de remodelao ssea ou a insuficincia / deficincia em vitamina D nativa (bem como os resultados da suplementao com esta vitamina). Testmos, pela primeira vez em doentes hemodialisados, novos marcadores da formao e reabsoro ssea, que validmos mediante a comparao com os resultados da histomorfometria ssea. No seu conjunto, e de forma integrada, as nossas investigaes permitiram-nos: - Evidenciar a diminuio da expresso do recetor da PTH/PTHrP na cartilagem de crescimento, num modelo animal de IRC, o que explica, pelo menos em parte, o atraso de crescimento observado nesta patologia, bem como a diminuio da resposta ao da PTH; - Demonstrar as vantagens da determinao da isoforma ssea da fosfatase alcalina, em relao fosfatase alcalina total, no diagnstico diferencial entre baixa e elevada remodelao ssea; - Utilizar, pela primeira vez em hemodialisados, a piridinolina e a desoxipiridinolina no diagnstico da reabsoro ssea. Este foi o primeiro marcador srico especfico da atividade osteoclstica, utilizado com sucesso em doentes anricos em hemodilise. Evidencimos uma excelente correlao destes dois marcadores bioqumicos com a superfcie osteoclstica e com o nmero de osteoclastos/mm2;- Demonstrar as acentuadas limitaes de outros marcadores da formao e reabsoro ssea (nomeadamente a osteocalcina, o propeptido carboxiterminal do procolagnio tipo I-PICP, e o Telopeptido do colagnio tipo I ICTP) com base nas correlaes entre os doseamentos sricos ou plasmticos destes marcadores e a bipsia ssea com avaliao histomorfomtrica; -Evidenciar as limitaes induzidas pela sobrecarga alumnica na interpretao dos nveis sricos dos marcadores no invasivos da remodelao ssea;-Testar a eficcia e segurana da utilizao de microdoses de desferroxamina na teraputica da intoxicao alumnica, em doentes com acentuada exposio a este metal;-Demonstrar que os doentes hemodialisados cronicamente com dialisadores de poliacrilonitrilo (membranas de alta permeabilidade),apresentavam menor ativao osteoblstica e osteoclstica, que os doentes dialisados com membranas de cuprofano(baixa permeabilidade), sendo os nveis de iPTH semelhantes em ambos os grupos estudados. Estes resultados apontam para uma menor ativao da remodelao ssea quando se utilizam membranas de hemodilise mais biocompatveis e/ou de maior permeabilidade, o que se poder relacionar com a ultrafiltrao de mediadores da ativao celular ou com a menor ativao dos mecanismos estimuladores da remodelao ssea, por parte destas membranas. Entre os mediadores da remodelao ssea que demonstrmos serem relevantes e estarem aumentados no soro de hemodialisados com membranas de baixo fluxo, contam-se a beta-2-microglobulina (2-M) e algumas citoquinas, com ao estimuladora das linhagens celulares envolvidas na remodelao ssea. Demonstrmos igualmente uma correlao positiva dos nveis sricos de 2-M com os nveis sricos da osteocalcina, da isoenzima ssea da fosfatase alcalina (marcadores da formao ssea) e com os nveis sricos da piridinolina (marcador da reabsoro ssea). Os nveis sricos de 2-M correlacionaram-se ainda, de forma negativa, com o volume osteoide (matriz ssea no calcificada). Nestes doentes hemodialisados, demonstrmos a presena de nveis sricos aumentados da interleucina-1, do antagonista do recetor da interleucina-1, da interleucina-6 e do recetor solvel da interleucina-6. Salientamos as relaes inversas que observmos, por um lado entre os nveis de antagonista do recetor da interleucina-1 e a superfcie osteoblstica, e por outro lado entre o rcio do recetor da interleucina-6 / interleucina-6 (IL6-r/IL6) e a superfcie osteoclstica. De acordo com estes nossos resultados originais, entendemos que a interferncia nos nveis circulantes e na ativao local destes mediadores poder justificar, em grande parte, o aumento da prevalncia de doena ssea adinmica, descrita por ns e por outros grupos. Evidencimos uma elevadssima prevalncia de doena adinmica (>50% dos doentes), numa populao de hemodialisados sem exposio prvia ao alumnio, tratados de acordo com os K/DOQI guidelines e que ao longo de um ano mantiveram nveis sricos de clcio e de fsforo controlados. Consequentemente, os doentes tratados de forma otimizada apresentaram uma prevalncia surpreendentemente elevada de doena adinmica. Os nossos resultados (classificados com o grau de evidncia mxima pelos peritos KDIGO) contriburam para dar suporte grande diferena nos guidelines K/DOQI (2003) e KDIGO (2009) no que respeita aos valores alvo da PTH. Estamos conscientes que de que o facto de termos uma percentagem to elevada de doena ssea adinmica nas nossas populaes de hemodialisados, bem como a demonstrao de que alguns doentes com valores de PTH intacta (2 gerao) de cerca de 600 pg/ml tinham doena ssea adinmica, condicionaram os novos objetivos KDIGO para a PTH. Os nossos resultados suportam, em nossa opinio, a adequao e vantagem da utilizao dos critrios da KDIGO em vez dos KDOQI. Tendo em conta que os primeiros definem objetivos para a PTH entre 2 e 9 vezes o limite superior do normal e no se comprometem com valores alvo absolutos e rgidos (definidos previamente nos KDOQI entre 150 e 300 pg/mL), esta nova abordagem parece-nos mais correta.Na nossa investigao clnica, caracterizmos ainda a populao hemodialisada portuguesa no que respeita aos nveis sricos de calcidiol, identificando a populao com suficincia, insuficincia ou deficincia em vitamina D3. Documentmos uma acentuada prevalncia de insuficincia e mesmo de deficincia nesta vitamina, numa vasta populao de hemodialisados, a qual, muito provavelmente, reflete de forma fidedigna, o que se pode observar na restante populao de doentes portugueses IRC em estdio 5d (em dilise). Descrevemos, pela primeira vez em doentes hemodialisados, uma associao entre deficincia em calcidiol e a presena de fatores de risco cardiovascular (que tm sido identificados nos doentes urmicos). A nossa investigao conduziu-nos a resultados originais, ao identificar os nveis baixos de 25(OH)vitamina D3 como um provvel fator de risco cardiovascular em hemodialisados, visto que a deficincia nesta vitamina se associou, de forma muito significativa, ao aumento da prevalncia de calcificaes vasculares, a inflamao, a presso de pulso mais elevada, a hipertrofia ventricular esquerda, a insuficincia cardaca e a nveis sricos aumentados de BNP-Brain natriuretic peptide. Finalmente, numa avaliao prospetiva, de interveno teraputica, corrigimos a insuficincia ou deficincia em 25(OH)vitamina D3 e demonstrmos que essa correo se associou a uma reduo dos fatores de risco cardiovascular. Esta ltima interveno foi totalmente inovadora, visto ser a primeira avaliao prospetiva da evoluo dos fatores de risco cardiovasculares, em funo da suplementao com vitamina D nativa, em doentes hemodialisados. Em resumo, pensamos que os resultados das nossas investigaes, acima sumarizadas e apresentadas ao longo dos diversos captulos desta dissertao,contribuiram para uma nova perspetiva da osteodistrofia renal e para recolocar o foco da ateno dos nefrologistas no tecido sseo e no eixo paratormona vitamina D remodelao ssea. Este eixo surje claramente envolvido em mltiplos processos fisiopatolgicos, que suportam a elevada morbilidade e mortalidade (nomeadamente de causa cardiovascular) observada nos doentes urmicos.---------ABSTRACT: The results of our research, presented throughout this thesis, contributed towards the optimisation of the invasive and non-invasive diagnosis of renal osteodystrophy. They have also highlighted the importance, to the clinical and histological expression of the ODR, of some specific characteristics of the haemodialysis population, including: the use of biocompatible high permeability haemodialysis membranes, the use of haemodiafiltration techniques with convection enhancement, as well as the limitations of biochemical markers of bone turnover or native vitamin D insufficiency/deficiency (along with the supplementation results of this vitamin). New bone formation and resorption markers, which were validated by comparison with the results of bone histomorphometry, have been tested for the first time on haemodialysis patients.As a whole, and in an integrated approach, our research enabled us to: - Show the decrease of the PTH/PTHrP receptor expression in cartilage growth, used on an IRC animal model, which explains, to some extent, not only the delayed growth observed in this pathology, but also the slow response to PTH. - Point out the advantages of the determination of bone isoform of alkaline phosphatase, in relation to the total alkaline phosphatase, in the differential diagnosis between low and high-bone turnover.- Use pyridinoline and deoxypyridinoline in the diagnosis of bone resorption for the first time on haemodialysis patients. This was the first specific serum market of the osteoclastic activity, which was successfully used on anuric patients undergoing haemodialysis treatment. We also observed an excellent correlation of these biochemical markers with the osteoclastic surface and the number of osteoclasts/mm2. - Demonstrate the sharp limitations of other markers of bone formation and resorption (namely osteocalcin, carboxyterminal propeptide of type I-PICP procollagen and telopeptide of type I-ICTP collagen) based on correlations between these markers serum or plasma assays and bone biopsy with histomorphometric assessment.-Show the limitations induced by aluminium overload in the interpretation of serum levels of bone remodelling non-invasive markers.-Test the efficacy and the safety of the use of deferoxamine microdoses for treatment of aluminium overload among patients with high levels of serum aluminium. - Demonstrate that patients with chronic haemodialysis dialysers of polyacrylonitrile (high permeability membranes) show a lower osteoblastic and osteoclastic activation than those undergoing dialysis with cuprofan membranes (low permeability), being the iPTH levels similar in both groups of patients. These findings point towards a lower activation of bone remodelling when using more biocompatible dialysis membranes and/or of higher permeability, which may relate to the ultrafiltration of cell activation mediators or to the lower activation of the stimulating mechanisms of bone remodelling, regarding the membranes. Beta-2-microglobulin (2-M) and some cytokines that play a role/participate in bone remodelling are among the bone remodelling mediators, which we demonstrated to be relevant and to be increased in the serum of haemodialysis with low flow membranes. We also proved that there is a positive correlation of serum 2-M levels not only with serum osteocalcin levels, of the bone isoenzyme of alkaline phosphatase (bone forming markers), but also with levels of serum pyridinoline (bone resorption marker).Serum 2-M levels correlate negatively with the volume of osteoid (uncalcified bone matrix). We also demonstrated the presence of elevated serum levels of interleukin-1,interleukin-1 receptor antagonist, interleukin-6 and soluble interleukin-6 receptor in haemodialysis patients. We stress the inverse relationship which we observed on one hand between the interleukin-1 receptor antagonist levels and the osteoblastic surface and on the other between the ratio of interleukin-6 receptor / interleukin-6 (IL6-r/IL6) and the osteoblastic surface. According to these unique findings, we believe that the interference in the circulating levels and in the local activation of these mediators may partly explain the rising prevalence of adynamic bone disease. A high prevalence of adynamic disease has also been observed in a haemodialysis population (>50% of patients) with no previous exposure to aluminium. The patients were treated according to K/DOQI guidelines and maintained controlled serum calcium and phosphorus levels over one year. As a result, the patients who received optimised treatment showed a surprisingly high prevalence of adynamic disease. Our results, which were ranked with the highest degree of evidence by KDIGO experts, contributed to the great difference regarding the target values of PTH in the K/DOQI (2003) and KDIGO (2009) guidelines. We are aware that the finding of such a high percentage of adynamic bone disease in our haemodialysis population, as well as the evidence that some patients with intact PTH values (2nd generation) of 600 pg/ml suffered from adynamic bone disease, have hindered, the new KDIGO objectives to PTH.In our opinion, our results support the suitability and the advantage of using KDIGO criteria instead of KDOQI. This seems to be the right approach when taking into consideration that KDIGO sets objectives to PTH between 2 and 9 times the normal upper limit and does not compromise with the rigid and absolute target values (between 150 and 300 pg/mL) previously defined by KDOQI. In our clinical research, the Portuguese haemodialysis population was characterised in terms of serum clacidiol levels and identified as having vitamin D3 sufficiency, insufficiency or deficiency. It was also recorded the prevalence of severe vitamin D3 insufficiency and even deficiency in a large haemodialysis population, which most likely provides a reliable picture of the rest of the population in IRC Portuguese patients with 5d stage (undergoing dialysis). We described for the first time in aemosialysis patients an association between calcidiol deficiency and the presence of ardiovascular risk factors, (which have been identified on uraemic patients).Our research led us to unique findings by having identified the low levels of 25(OH) vitamin D3 as a likely cardiovascular risk factor in patients undergoing haemodialysis treatment, given that deficiency in this vitamin has been significantly associated not only with a rise in the prevalence of vascular calcifications, but also inflammation, left ventricular hypertrophy, high pulse pressure and high serum BNPBrain natriuretic peptide levels. Finally, based on a prospective assessment of therapeutic intervention, 25(OH)vitamin D3 insufficiency or deficiency was corrected and we were able to demonstrate that this same correction was associated with a reduction in cardiovascular risk factors. This was a forward-looking intervention regarding the supplementation of native vitamin D in haemodialysis patients, since it was the first prospective assessment of the evolution of cardiovascular risk factors. In short, the results of our research, summarised above and presented throughout the various chapters of this thesis, contributed towards a new perspective of the renal osteodystrophy and also to draw the nephrologists attention to the bone tissue and to the axis PTH vitamin D bone remodelling. This axis appears clearly involved in multiple physiopathological processes, which support the high morbidity and mortality rate, (particularly of cardiovascular causes), observed in uraemic patients.
Resumo:
RESUMO: Contexto: As anomalias congnitas, com particular destaque para as neuploidias , afectam aproximadamente 2% dos recm-nascidos, constituindo causas frequentes de morbilidade e mortalidade. Actualmente, a avaliao do grau de risco para as aneuploidias mais prevalentes (T21, T13, T18) efectuada atravs do Rastreio Combinado do 1 Trimestre, devendo as grvidas com risco acrescido ser sujeitas a exames invasivos (ex.bipsia das vilosidades corinicas,amniocentese). Quanto mais qualidade existir num rastreio, menos falsos positivos existiro e menor o nmero de exames diagnsticos invasivos desnecessrios. As doenas autoimunes so doenas inflamatrias crnicas em cuja fisiopatologia se encontram distrbios da imunidade humoral e celular, dependentes de factores genticos, hormonais,psicolgicos e ambientais. Atingem mais o sexo feminino e durante a idade frtil,podendo influenciar o outcome da gravidez e a sade neonatal causando significativa morbilidade e mortalidade. O lpus eritematoso sistmico para alm de potencialmente afectado pelas alteraes imunoendcrinas fisiolgicas da gravidez, associa-se frequentemente a problemas de fertilidade. Recentemente, foi sugerido que as anormalidades ocorridas durante a invaso precoce do sinciciotrofoblasto, resultando em deficiente diferenciao, deficiente maturao e diminuio na produo de hCG, podero ser o mecanismo fisiopatolgico primrio para as perdas fetais no primeiro trimestre, nos doentes com SLE. A ocorrncia de nveis elevados de hCG total e -hCG livre no rastreio para despiste de sndrome de Down do segundo e do primeiro trimestre foi assinalada em grvidas portadoras de lpus, mas a escassez de estudos comprovativos e a pequena dimenso das amostras estudadas constituiu uma limitao significativa na fidedignidade dos resultados obtidos. Objectivos: O estudo teve como objectivos i. estabelecer valores normativos Portugueses e de distribuio para as MoMs dos parmetros sricos do primeiro trimestre, por semana de gestao:(PAPP-A e -hCG livre), ii. avaliar a influncia que as doenas autoimunes tm sobre as MoMs individuais dos parmetros bioqumicos PAPP-A e/ou -hCG livre, utilizados no rastreio pr-natal combinado do 1 trimestre, e iii. saber se as doenas autoimunes podem condicionar um aumento da taxa de resultados falsos positivos, com consequente aumento do nmero de amniocenteses. Metodologia: Estudo longitudinal prospectivo, consistindo num rastreio pr-natal combinado de 1 trimestre para pesquisa de aneuploidias, em duas amostras provenientes do Reino Unido (n= 45,854) e de Portugal (n=3122). Foram avaliados parmetros socio-demogrficos, ecogrficos, laboratoriais, e calculados os indicadores de desempenho do rastreio combinado. A execuo analtica dos testes bioqumicos sricos (PAPP-A e -hCG livre) foi realizada no autoanalisador Brahms Kryptor e no autoanalizador 6000 Delfia Xpress. Compararam-se os grupos autoimune e no autoimune das amostras. Resultados: Relativamente s caractersticas populacionais, o grupo auto imune tinha valores significativamente superiores nas variveis idade materna e idade gestacional. Comparando os grupos com e sem doena autoimune, constatou-se a existncia de uma elevao das MoMs da -hCG livre nas grvidas com doena autoimune, nomeadamente nos casos de lpus eritematoso sistmico. Concluses: os resultado obtidos reforam a indicao do rastreio combinado do 1 trimestre certificado pela FMF nas grvidas com doenas autoimunes, nomeadamente para as doentes com LES; no entanto, devem ser calculados e introduzidos factores de correco no algoritmo de risco, de modo a evitar a subida no nmero de resultados falso-positivos, e consequentemente a sobre- utilizao de mtodos invasivos.------------ ABSTRACT: Context: Congenital anomalies, with particular reference to aneuploidias, affect approximately 2% of newborns, and are frequent causes of morbidity and mortality. Currently, the risk evaluation for the most prevalent aneuploidias (T21, T13, T18) is carried out through the combined first trimester screening, and pregnant women with increased risk are subjected to invasive tests (e.g. villus biopsy done, amniocentesis). The more quality exists in a screening, less false positives exists and fewer unnecessary invasive diagnostic exams. Autoimmune diseases are chronic inflammatory diseases in whose pathophysiology are immune humoral and cellular disorders, dependent on genetic factors, hormonal, psychological and environmental factors. The disease is more prevalent among females, during the child-bearing age, and may influence the outcome of pregnancy and neonatal health causing significant morbidity and mortality. Lupus Erythematosus in addition to potentially affected by immunoendocrine physiological changes of pregnancy, is often associated with fertility problems. Recently, it has been suggested that the abnormalities that occurred during the early invasion of the syncytiotrophoblast, resulting in insufficient differentiation, deficient maturation and decrease in production of hCG may be the primary pathophysiological mechanism for fetal losses in the first quarter, in patients with SLE. The occurrence of elevated levels of total hCG and free -hCG in screening for Downs syndrome of the second and first trimester was reported in pregnant women with lupus, but the paucity of supporting studies and the small size of the samples studied constituted a significant limitation on the trustworthiness of the results obtained. Objectives: this study aims to i. establish normative values for the serum parameters MoMs (PAPP-A and free -hCG) and its distribution, in the first trimester, by week of pregnancy; ii. assess the influence that the autoimmune diseases have on the MoMs of individual biochemical PAPP-A and/or -hCG, used in antenatal screening combined for the first trimester, and iii. whether the autoimmune diseases may make an increased rate of false positives, with consequent increase in the number of amniocenteses.Methodology: Prospective longitudinal study, consisting of a combined first trimester antenatal screening for aneuploidies lookup in two samples from the United Kingdom (n=45.854) and Portugal (n= 3.122). Socio-demographic, echographic and laboratory parameters were evaluated, and combined screening performance indicators were calculated. The analytical run of serum biochemical tests (PAPP-A and -hCG) was held at the Brahms Kryptor and in Delfia Xpress 6000. Comparisons between autoimmune group and non-autoimmune group were made. Results: Relating to population characteristics, the autoimmune group had significantly diferente values in the variables maternal age and gestational age. Comparing the groups with and without autoimmune disease, it was noted that there is an elevation of the MoMs of free -hCG levels in pregnant women with autoimmune disease, particularly in cases of systemic lupus erythematosus. Conclusions: The results obtained reinforce the indication of FMF certified combined screening in pregnant women with autoimmune diseases, notably to the patients with SLE; However, correction factors should be calculated and entered in the risk algorithm, in order to avoid the rise in the number of false positive results, and consequently the over-use of invasive methods.
Resumo:
RESUMO:RESUMO: Nos ltimos anos a ultrassonografia emergiu como um instrumento importante no diagnstico da patologia torcica. O progresso tecnolgico possibilitou a conceo de novos equipamentos como a ecoendoscopia brnquica radial e linear. Verificou-se, igualmente, o aparecimento de indicaes para a realizao de ecografia transtorcica. Uma das principais doenas impulsionadoras da tcnica ultrassonogrfica no trax foi o cancro do pulmo, primeira causa de morte oncolgica a nvel mundial. A aplicabilidade e conhecimento do papel dos ultrassons no mbito do diagnstico e estadiamento do cancro do pulmo no se encontram esgotados, persistindo focos de controvrsia e dvida cientfica que se pretendem esclarecer. A presente tese foi organizada em cinco captulos: o primeiro abordou de forma geral e introdutria o estado da arte referente ultrassonografia torcica, cancro do pulmo e a sua conjugao; o segundo destacou os principais objetivos; o terceiro sumarizou a metodologia utilizada; o quarto englobou os cinco estudos publicados, descritos subsequentemente, e o quinto incluiu uma discusso concisa, as principais concluses e perspetivas futuras. O primeiro estudo avaliou a rentabilidade diagnstica, segurana e curva de aprendizagem num coorte de 179 doentes submetidos a ecoendoscopia brnquica linear. De acordo com as indicaes para este procedimento os doentes foram subdivididos em trs grupos: (1) diagnstico, (2) diagnstico e estadiamento e (3) estadiamento. Para o primeiro, segundo e terceiro grupos a sensibilidade da ecoendoscopia foi 86.1%, 86.7% e 95% respetivamente e a preciso tcnica foi 87.5%, 93.1% e 97.7% respetivamente. O treino originou um aumento progressivo do nmero de locais puncionados por doente, com menor durao e sem complicaes, comprovando a eficcia e segurana do mtodo quando realizado na populao Portuguesa por broncologistas com experincia. O segundo estudo foi conduzido para averiguar a eficcia e custo da ecoendoscopia brnquica linear realizada atravs da via area e/ou esfago no diagnstico de leses sugestivas de neoplasia do pulmo, aps ineficcia das tcnicas convencionais. Nos doentes includos prospetivamente alcanou-se um diagnstico definitivo em 106 casos (87.6%). A sensibilidade global para o diagnstico de cancro do pulmo foi 89.8%, a especificidade foi 100%, o valor preditivo positivo foi 100%, o valor preditivo negativo foi 20% e a preciso foi 90.1%. Esta estratgia ultrassonogrfica abrangente evitou intervenes cirrgicas diagnsticas em doentes anteriormente submetidos a broncoscopia flexvel ou puno aspirativa transtorcica guiada por tomografia computorizada, proporcionando uma reduo significativa dos custos. No terceiro estudo investigou-se a viabilidade e papel da conjugao da ecoendoscopia brnquica linear com tcnicas moleculares na avaliao de antignios tumorais e padres de metastizao ganglionar em doentes com cancro do pulmo de no-pequenas clulas (CPNPC). Os marcadores citoqueratina 19 (CK-19), antignio carcinoembrionrio (CEA), molcula de adeso celular epitelial (EPCAM), sialyl-Lewis X e CD44 foram determinados nos aspirados ganglionares de 33 doentes com neoplasia e 17 controlos 10 Ultrassonografia atravs de citometria de fluxo (CF) e reao em cadeia da polimerase em tempo real (RTPCR). Os doentes com CPNPC possuam um compartimento celular epitelial significativamente aumentado e com marcao superior de CK-19 comparativamente ao grupo de controlo. O compartimento imune foi tambm analisado nestas amostras e revelou-se alterado no CPNPC com aumento da populao de moncitos e diminuio das subpopulaes linfocitrias. Os transcriptos de CK-19, CEA e EPCAM estavam elevados nos doentes com cancro do pulmo, identificando-se uma correlao positiva entre estes marcadores e o tamanho da leso primria. Concluiu-se que a identificao de CK-19, CEA e EPCAM nas amostras obtidas por ecoendoscopia e avaliadas por CF e RTPCR foi vivel, podendo auxiliar na deteo de metstases ganglionares no CPNPC. O quarto estudo envolveu a combinao da ecoendoscopia brnquica radial com uma criosonda para o diagnstico de leses pulmonares slidas perifricas. Foi determinada a viabilidade, rentabilidade diagnstica, tamanho das amostras e segurana do mtodo. Leses inferiores a 40mm foram localizadas por ultrassonografia sendo os doentes randomizados para a realizao de bipsias transbrnquicas com pina seguidas por criosonda ou vice-versa. Nos 39 casos includos a leso foi visualizada pela minisonda em 31 doentes (79.5%), com 80.6% de prevalncia de cancro do pulmo na amostra. A rentabilidade diagnstica da pina de bipsia foi 61.3% e da criosonda foi 74.2%. O tamanho do tecido adquirido pelas criobipsias foi significativamente maior do que o alcanado por pina (11.17mm2 vs. 4.69mm2, p<0.001). Ocorreu um nico caso de hemorragia moderada, controlada atravs de medidas conservadoras. As bipsias transbrnquicas com criosonda sob orientao de ecoendoscopia radial foram seguras e eficazes na obteno de amostras histolgicas. O quinto estudo determinou o valor diagnstico da ecografia transtorcica na identificao de malignidade em doentes com derrame pleural de natureza indeterminada. Foram examinados de forma prospetiva 154 doentes. Os resultados clnicos e radiolgicos de cada caso foram ocultados ao executante do exame que gerou imagens estticas e vdeos ultrassonogrficos relevantes. Estes foram posteriormente visualizados, sendo as suas caractersticas classificadas por revisores independentes e comparadas com o diagnstico definitivo. Em 66 casos o diagnstico foi de derrame pleural maligno (68.2% com cancro do pulmo) e em 67 de derrame benigno. A ecografia torcica obteve 80.3% de sensibilidade, 83.6% de especificidade, 81.2% de valor preditivo negativo e 82.8% de valor preditivo positivo na deteo de malignidade. A nodularidade pleural ou diafragmtica, espessamento pleural superior a 10mm e sinal de swirling foram significativamente diferentes (p<0.001) sendo sugestivos de derrame maligno. A existncia de nodularidade pleural e ausncia de broncograma areo ecogrfico aumentaram a probabilidade de malignidade (OR 29.0 e OR 10.4, respetivamente). A ecografia transtorcica permitiu diferenciar derrame pleural maligno do benigno. A existncia de ndulos pleurais constituiu o fator discriminador mais relevante. Em concluso, os resultados desta tese possibilitam uma melhor compreenso do papel da ecoendoscopia brnquica (linear e radial) e ecografia transtorcica no diagnstico e estadiamento do cancro do pulmo, com implicaes e aplicabilidade na prtica clnica.------------- ABSTRACT: In recent years ultrasonography has emerged as an important instrument in the diagnosis of thoracic diseases. Technological progress has enabled the design of new equipment such as radial and linear endobronchial ultrasound. In addition, indications for transthoracic echography were established. One of the main diseases responsible for the progression of chest sonography was lung cancer, the leading cause of cancer mortality worldwide. The applicability and knowledge of the role of ultrasonography in diagnosing and staging lung cancer is not depleted, persisting foci of controversy and scientific doubt that we intend to elucidate. The present thesis was organized into five chapters: the first included a general introduction regarding chest ultrasound, lung cancer and their combination; the second emphasized the main objectives; the third summarized the methodology used; the fourth encompassed the five published studies, subsequently described, and the fifth included a concise discussion, the main findings and future perspectives. The first study evaluated the diagnostic yield, safety and learning curve in a cohort of 179 patients submitted to linear endobronchial ultrasound. According to procedure indications, the patients were divided into three groups: (1) diagnosis, (2) diagnosis and staging, and (3) staging. For the first, second and third groups, endobronchial ultrasound sensitivity was 86.1%, 86.7% and 95% respectively and accuracy was 87.5%, 93.1% and 97.7% respectively. Practise led to an increase number of punctured sites per patient, in a shorter period of time and without complications, proving the safety and efficacy of the method when performed in the Portuguese population by expert echoscopists. The second study was conducted to determine the efficacy and cost of linear endobronchial ultrasound performed through the airway and/or oesophagus for diagnosis of lesions suggestive of lung cancer, after failure of conventional techniques. Of the patients prospectively enrolled a definitive diagnosis was reached in 106 cases (87.6%). The overall sensitivity for the diagnosis of lung cancer was 89.8%, specificity was 100%, positive predictive value was 100%, negative predictive value was 20% and accuracy was 90.1%. In conclusion, this global ultrasonographic strategy avoided diagnostic surgical procedures in patients that had undergone flexible bronchoscopy or computed tomography-guided transthoracic needle aspiration, providing a significant cost reduction. In the third study, the feasibility and role of linear endobronchial ultrasound combined with molecular techniques in the evaluation of tumour antigens and patterns of lymph node metastasis in patients with non-small cell lung cancer (NSCLC) was investigated. Cytokeratin 19 (CK-19), carcinoembryonic antigen (CEA), epithelial cell adhesion molecule (EPCAM), sialyl Lewis-X and CD44 were determined in lymph node aspirates of 33 lung cancer patients and 17 controls, using flow cytometry (FC) and reverse transcription polymerase chain reaction (RT-PCR). In patients with NSCLC the epithelial cell compartment was significantly increased nd showed brighter CK-19 staining, compared to the control group. In NSCLC patients the immune compartment revealed an increased monocyte population and decreased lymphocyte subsets. The transcripts of CK- 19, CEA and EPCAM were higher in lung cancer patients and a positive correlation between these markers and the size of the primary lesion was also found. We concluded that the identification of CK-19, CEA and EPCAM in endobronchial ultrasound samples, using RT-PCR and FC was feasible and might aid in the detection of NSCLC lymph node metastases. The fourth study involved the combination of the radial endobronchial ultrasound with the cryoprobe for diagnosing solid peripheral lung lesions. We determined the feasibility, diagnostic yield, sample size and safety of the method. Lesions less than 40mm were located by ultrasound and forceps or cryobiopsies were performed in a randomized order. Of the 39 cases included, the lesion could be visualized by the miniprobe in 31 patients (79.5%), and lung cancer prevalence was 80.6%. The diagnostic yield of the biopsy forceps was 61.3% and for the cryobiopsy was 74.2 %. Cryobiopsies were significantly larger than forceps biopsies (11.17mm2 vs. 4.69mm2, p<0.001). There was only one case of moderate bleeding that was controlled by conservative measures. Transbronchial cryobiopsies under radial endobronchial ultrasound guidance were safe and effective in obtaining histological samples. The fifth study determined the diagnostic value of transthoracic sonography in predicting malignancy in patients with an undiagnosed pleural effusion. One hundred and fifty four patients were prospectively scanned. Relevant ultrasound images and videos were generated by an operator blinded to clinical and radiological results. These were subsequently visualized, its characteristics classified by independent reviewers and compared to the final diagnosis. A malignant pleural effusion was diagnosed in 66 cases (68.2 % with lung cancer) and a benign effusion in 67 cases. Thoracic ultrasound had a sensitivity of 80.3 %, specificity of 83.6%, negative predictive value of 81.2 % and positive predictive value of 82.8% to detect malignancy. The presence of pleural or diaphragmatic nodularity, pleural thickening greater than 10mm and swirling signal were significantly different (p<0.001 ), being suggestive of malignant effusion. The existence of pleural nodularity and absence of lung air bronchogram were more likely to indicate malignancy (OR 29.0 and OR 10.4, respectively). Transthoracic ultrasonography permits the distinction between malignant and benign pleural effusions. Pleural nodules were the most relevant feature. In conclusion, the results of this thesis provide a better understanding of the role of endobronchial ultrasound (linear and radial) and transthoracic sonography in lung cancer diagnosis and staging, with direct implications and applicability in clinical practice.
