La thymectomie est un geste chirurgical fréquemment nécessaire lors des interventions cardiaques en période néonatale. Il est connu que la résection du thymus entraîne une lymphopénie ne semblant pas avoir de conséquences cliniques graves. La lymphopénie constatée serait plus importante chez les patients ayant eu une chirurgie cardiaque de type Fontan. Toutefois, on ignore si la lymphopénie est uniquement secondaire à la thymectomie ou si elle est liée à ce type particulier de chirurgie cardiaque. La présente recherche porte sur 19 patients opérés selon l'approche Fontan; ils ont été comparés à 6 patients "contrôle" ayant eu une thymectomie au cours d'une chirurgie cardiaque d'un autre type. Les résultats indiquent que les patients de type Fontan accusent une diminution du nombre de cellules naïves CD4+ et CD8+ et plus particulièrement une baisse de leurs émigrants thymiques (CD45RA+CD31+/CD4+). On note en contrepartie une expansion du répertoire mémoire (CD45RO+). Ces altérations lymphocytaires sont comparables aux contrôles. Il semble donc que les anomalies lymphocytaires relevées soient reliées principalement à la thymectomie et non pas au type de chirurgie. Les infections plus importantes chez les Fontan, quant à elles, pourraient s'expliquer par une évolution post-opératoire défavorable. / The thymectomy is a surgical procedure often done during cardiac surgery. It is well known that the resection of the thymus can cause alterations of lymphocyte subpopulations without major clinical consequences. This lymphopenia could be more pronounced in patients who undergone a cardiac surgery named "Fontan". Nevertheless, it is not known if these alterations are due to the thymectomy or this specific type of cardiac surgery. We recruited 19 patients with Fontan surgery and compared them to 6 patients who had a cardiac surgery of another type. Our results show decreased CD4+ and CD8+ naive T cells populations and more specifically, low numbers of thymic emigrants (CD45RA+CD31+/CD4+). Expansion of memory repertoire (CD45RO+) is also noted. These findings are also found in the control group. Thus, perturbations of T cells populations seem to be related to the thymectomy rather than the type of cardiac surgery. Infections were more severe in the Fontan group but they can be explained by an unfavourable post-operative evolution in this group of patients.

Die vorliegende Arbeit dient der Entwicklung und Evaluierung eines neuen operativen Zugangsweges zur Durchführung einer kompletten Thymektomie (Thx). Die erste klinische Umsetzung erfolgte 1994. Der thorakoskopische Zugang für die Thx wurde an der Chirurgischen Klinik der Charité nach den Prinzipien der "Good clinical practice" zur Einführung eines neuen operativen Verfahrens entwickelt. Eine retrospektive Kohortenstudie bestimmte den internen Standard der erreichbaren Ergebnisse einer Thx in konventioneller Operationstechnik bei MG. Die Daten des eigenen Krankengutes an der Charité waren mit den Literaturangaben übereinstimmend und somit repräsentativ für die Zielstellung eines neuen Operationsverfahrens. Die komplexe Evaluation des neuen operativen Zuganges der thorakoskopischen Thx (tThx) umfaßte neben dem Nachweis der Durchführbarkeit der tThx eine experimentelle anatomische Demonstration der adäquaten Radikalität. Es konnte gezeigt werden, daß eine unilaterale linksseitige thorakoskopische Operationstechnik mit 3 Trokaren im Vergleich zu einer rechtsseitigen 3-Trokar-Technik besser eine komplette Thx realisieren kann. Es folgte die Ausarbeitung einer detaillierten operativen Technik der tThx für den klinischen Einsatz, die den individuell verschiedenen anatomischen Gegebenheiten Rechnung trägt und beschrieben wird. Nach ermutigenden ersten klinischen Ergebnissen wurden dann die Resultate der prospektiven klinischen Untersuchung des Verfahrens an 60 konsekutiven Patienten erstmals nach den Empfehlungen für klinische Forschung der Task Force of the Medical Scientific Advisory Board of the Myasthenia Gravis Foundation of America standardisiert dargestellt. Die Hypothese der geringeren Beeinträchtigung und schnelleren Erholung der Atemfunktion nach tThx wurde in einem prospektiven Vergleich der tThx mit der am meisten akzeptierten und weitesten verbreiteten Operationstechnik der Thx untersucht und bewiesen. Schließlich wurden die Ergebnisse der funktionellen Besserung der MG nach tThx, Thx durch mediane Sternotomie oder Thx durch anterolaterale Thorakotomie in einer Matched-pair-Studie verglichen. Obwohl technisch anspruchsvoll, ließen sich vergleichsweise adäquate Resultate bei objektiven und subjektiven patientenbezogenen Vorteilen für die tThx nachweisen. Ein Studiendesign mit höherem Evidenzgrad erscheint unizentrisch aus ethischen und epidemiologischen Gründen sowie bezogen auf die Pathogenese der MG gegenwärtig für diese Fragestellung schwer erreichbar. In der Zusammenfassung kann die tThx das in der Einleitung beschriebene Dilemma der Suche nach dem optimalen operativen Verfahren zur Thx lösen, indem eine minimale Invasivität, die nicht weiter reduziert werden kann, durch einen optimalen Zugang über 3 Trokare erreicht wird. Dies führt zur Möglichkeit einer radikalen Thx durch die weite Exposition des vorderen Mediastinums. Die tThx sollte bevorzugt werden, da sie adäquate Raten der Verbesserung der MG mit einer minimal-invasiven Operationstechnik erreicht. Die umfassende Untersuchung dieser Technik sollte fortgesetzt werden. / The aim of the present work was to develop and evaluate a novel operation technique to perform a complete thymectomy (Thx). This new approach was first used in a clinical setting in 1994. The thoracoscopic approach for Thx was developed at the Humboldt University Medical School (Charité), Clinic of Surgery, Campus Mitte according to the principles of "good clinical practice" for the introduction of a new operation technique. The success of conventional Thx for MG was determined by a retrospective cohort study as an internal standard. The results of our own clinical series at the Charité corresponded with the data of large published series worldwide and, were thus representative for the aim of developing a new operation technique. Apart from the approval of feasibility, the complex evaluation of the new surgical approach comprised an experimental anatomical study to demonstrate adequate radicality. It could be shown that a unilateral left-sided thoracoscopic operation technique with only 3 trocars can better accomplish a complete Thx as compared to a right-sided 3-trocar-technique. The next step was the development of the detailed and standardized operation technique for the clinical application of thoracoscopic Thx (tThx) which considers the individually different anatomical circumstances and is described. After encouraging first results, the findings of the prospective clinical investigation of the procedure in the first 60 patients were presented, standardized according to the suggestions for clinical research of the Task Force of the Medical Scientific Advisory Board of the Myasthenia Gravis Foundation of America. The hypothesis of smaller impairment and faster recovery of pulmonary function after tThx was investigated and could be proved in a prospective comparison of tThx versus the most accepted and most common approach for Thx.Consequently, the results of functional improvement of MG after tThx, median sternotomy for Thx, and anterolateral thoracotomy for Thx were compared in a matched-pair study. Though technically demanding, tThx showed adequate results combined with objective and subjective patient-related advantages. For ethical and epidemiological reasons and due to the pathogenesis of MG a single-center study design with higher level of evidence seems difficult to achieve. In conclusion, tThx may solve the dilemma of the search for an optimal operation technique for Thx because minimal invasion is obtained by an optimal approach with only 3 trocars. This creates the possibility of radical Thx by wide exposure of the anterior mediastinum. The technique of tThx should be prefered because an adequate rate of improvement of MG is achieved by a minimally-invasive operation technique. The comprehensive investigation of this technique should be continued.

Thymome gehören zu den häufigsten Tumoren des Mediastinums. Die Thymektomie (Thx) gilt als Therapie der Wahl. Die adjuvante Radiotherapie (RTx) ist bei invasiven Thymomen ab Stadium II nach Masaoka je nach Histologie indiziert. Die adjuvante Chemotherapie (CTx) bei invasiven Thymomen und Thymuskarzinomen muss weiter evaluiert werden. Methodik: Retrospektiv wurden die Daten von 40 Patienten, die von 1/1983 bis 12/1998 wegen Thymustumor einer Thx unterzogen wurden, ausgewertet. Es erfolgte die (Re)Klassifikation nach Masaoka, Müller-Hermelink und WHO zur Evaluation ihrer prognostischen Relevanz. Eine systematische Analyse der Therapiestudien im Zeitraum 1970-1999 sollte die Rolle adjuvanter Therapie evaluieren und klinische Prognosefaktoren ermitteln. Ergebnisse: Die Daten von 40 Patienten (30 Frauen und 10 Männer, das mediane Alter 52 Jahre) wurden analysiert. In 19 Fällen lag eine thymom-assoziierte Myasthenia gravis vor. 35 Pat. Wurden R0 reseziert. Die Histologie zeigte: 32 Thymome, 4 Karzinome, 2 Karzinoide und 2 Zysten. Subgruppenanalyse zeigte folgende nicht-invasive Thymome: WHO A=8 (21,1%), WHO AB=11 (28,9%) und invasive Thymome: WHO B1=1 (2,6%) und B2=12 (31,6%), WHO C=6 (15,8%). Bei invasiven Thymomen und Thymuskarzinomen erfolgte in 8 Fällen eine adjuvante RTx und nur in 3 Fällen eine CTx. Bei einem Follow-up von 1-168 Monaten betrug das kumulat. Überleben nach 5 Jahren 83% und nach 10 Jahren 74%. In univariater Analyse beeinflussen die Müller-Hermelink- und Masaoka-Klassifikation sowie der Resktionsstatus das Gesamtüberleben positiv. Die multivariate Analyse nach Cox ergab keine statistisch Signifikanz. Die systematische Literaturanalyse schloss 191 Arbeiten ein. In 33 Arbeiten wird die Rolle der poteniellen Prädiktivfaktoren untersucht. Wir fanden 71 Artikel zur adjuvanten Therapie: 51 zur CTx und 20 zur RTx. Die adjuvante CTx (z.B. PAC-Schema) zeigt objektive Ansprechrate und bessert das Gesamtüberleben. Die RTx verringert das Rezidivrisiko evident und bessert das Gesamtüberleben. Schlussfolgerung: Die Thx ist die primäre Therapie. Eine adjuvante RTx soll bei allen invasiven Thymomen der WHO-Klasse B und C ab Stadium II nach Masaoka durchgeführt werden. Eine adjuvante Cisplatin-basierten CTx (z.B. PAC-Schema) ist ab dem Masaoka-Stadium III, bei Thymuskarzinomen und Rezidiven indiziert. / Thymoma belong to the most frequent tumors of the mediastinum. The thymectomy (Thx) is considered as therapy of choice. The adjuvante radiotherapy (RTx) is indicated in invasive thymoma starting from stage II Masaoka depending upon histology. The adjuvante chemotherapy (TX) in invasive thymoma and thymus carcinoma must be further evaluated. Patients and Methods: 40 patients the data were retrospectively analysed, who were submitted from 1/1983 to 12/1998 because of thymus tumors. It took place (Re)classifikation according to Masaoka, Mueller-Link and WHO for the evaluation of its prognostic relevance. A systematic analysis of the literature in the period 1970-1999 should evaluate the role of adjuvante therapy procedures and determine clinical prognosis factors. Results: The data of 40 patients (30 women and 10 men, median age 52 years) were analyzed. In 19 cases thymoma-associated Myasthenia gravis was showed. The histology showed: 32 thymoma, 4 carcinoma, 2 endocrine thymic tumors and 2 cysts: Subgroup analysis showed following non-invasive thymomas: WHO A=8 (21,1%), WHO AB=11 (28,9%) and invasive thymomas: WHO B1=1 (2,6%) and B2=12 (31,6%), WHO C=6 (15,8%). With invasive thymoma and thymus carcinoma. Adjuvante RTx took place in 8 patients with invasive tumors and 3 cases unterwent CTx. With a Follow UP of 1-168 months amounted to overall survive after 5 years 83% and after 10 years 74%. Univariate analysis showed that the Mueller-Hermelink and Masaoka classification as well as the resection extent influence the total surviving positively. The multivariate analysis after Cox did not result in statistically significance. The systematic literature analysis included 191 work. In 33 work the role of the predictive factors is examined. We found 71 articles to the adjuvante therapy: 51 to the TX and 20 to the RTx. The adjuvante CTx (e.g. PAC pattern) shows objective response rate and improves the total surviving. The RTx reduces the recurrence risk evidently and improves overall survival. Conclusion: The Thx is the primary therapy. A adjuvante RTx is to be executed with all invasive thymoma of the WHO class B and C starting from stage II-Masaoka. A adjuvante Cisplatin based TX (e.g. PAC pattern) is indicated starting from the Masaoka stage III, in thymic carcinomas and even in recurrence tumors.

La thymectomie est un geste chirurgical fréquemment nécessaire lors des interventions cardiaques en période néonatale. Il est connu que la résection du thymus entraîne une lymphopénie ne semblant pas avoir de conséquences cliniques graves. La lymphopénie constatée serait plus importante chez les patients ayant eu une chirurgie cardiaque de type Fontan. Toutefois, on ignore si la lymphopénie est uniquement secondaire à la thymectomie ou si elle est liée à ce type particulier de chirurgie cardiaque. La présente recherche porte sur 19 patients opérés selon l'approche Fontan; ils ont été comparés à 6 patients "contrôle" ayant eu une thymectomie au cours d'une chirurgie cardiaque d'un autre type. Les résultats indiquent que les patients de type Fontan accusent une diminution du nombre de cellules naïves CD4+ et CD8+ et plus particulièrement une baisse de leurs émigrants thymiques (CD45RA+CD31+/CD4+). On note en contrepartie une expansion du répertoire mémoire (CD45RO+). Ces altérations lymphocytaires sont comparables aux contrôles. Il semble donc que les anomalies lymphocytaires relevées soient reliées principalement à la thymectomie et non pas au type de chirurgie. Les infections plus importantes chez les Fontan, quant à elles, pourraient s'expliquer par une évolution post-opératoire défavorable. / The thymectomy is a surgical procedure often done during cardiac surgery. It is well known that the resection of the thymus can cause alterations of lymphocyte subpopulations without major clinical consequences. This lymphopenia could be more pronounced in patients who undergone a cardiac surgery named "Fontan". Nevertheless, it is not known if these alterations are due to the thymectomy or this specific type of cardiac surgery. We recruited 19 patients with Fontan surgery and compared them to 6 patients who had a cardiac surgery of another type. Our results show decreased CD4+ and CD8+ naive T cells populations and more specifically, low numbers of thymic emigrants (CD45RA+CD31+/CD4+). Expansion of memory repertoire (CD45RO+) is also noted. These findings are also found in the control group. Thus, perturbations of T cells populations seem to be related to the thymectomy rather than the type of cardiac surgery. Infections were more severe in the Fontan group but they can be explained by an unfavourable post-operative evolution in this group of patients.

Le développement d’un lymphome gastrique du MALT (LGM) émane d’un processus inflammatoire chronique initié par Helicobacter pylori.A partir du matériel issu d’un modèle animal de LGM, préalablement développé au laboratoire, basé sur des infections chez des souris thymectomisées à la naissance, la réponse inflammatoire gastrique favorable à l’émergence de LGM a été étudiée. Une dérégulation de cytokines et chimiokines au stade LGM a été identifiée permettant de recruter, faire proliférer et faire émerger des infiltrats lymphoïdes. La susceptibilité des souris thymectomisées à développer des lymphomes n’est pas liée à un déficit en lymphocytes T régulateurs. Cinq microARNs ont été retrouvés dérégulés au stade lymphome agissant probablement en synergie pour favoriser la prolifération lymphocytaire en particulier via un mécanisme anti-apoptotique. Enfin, nous décrivons un modèle original de LGM basé sur l’utilisation de souris C57BL6 exprimant la chimiokine APRIL humaine au niveau des lymphocytes T infectées par des espèces du genre Helicobacter. Ce modèle est prometteur pour une meilleure compréhension de la lymphomagénèse gastrique. / The development of gastric MALT lymphoma (GML) originates from a chronic inflammatory process initiated by Helicobacter pylori.The gastric inflammatory response was investigated in a mouse model of GML previously described by the laboratory using BALB/c mice thymectomized at day 3 post-birth and infected by H. pylori. A deregulation of numerous cytokines and chemokines at GML stage was identified which explained the recruitment, proliferation and emergence of lymphoid infiltrates. The susceptibility of thymectomized mice to develop lymphoma was not linked to a deficiency in regulatory T cells. A deregulation of 5 microRNAs was observed at lymphoma stage. These microRNAs may be involved in cell survival and lymphocyte proliferation and act in synergy to promote the development of GML. Finally, we described an original model of GML based on infection by Helicobacter species of transgenic C57BL6 mice expressing the human form of the cytokine APRIL in T cells. This model is promising for a better understanding of gastric lymphomagenesis.

INTRODUÇÃO: A Miastenia gravis (MG) é uma desordem imunológica com antígenos alvos conhecidos, com produção de anticorpos contra o receptor nicotínico de acetilcolina, AAChR e Musk, na junção neuromuscular, dificultando a transmissão do impulso nervoso e provocando fadiga e fraqueza flutuantes na musculatura ocular, facial, dos membros e respiratória. A terapêutica sintomática com inibidores de acetilcolinesterase e a etiopatogênica como a timectomia, corticosteróides, agentes citostásticos e imunoglobulinas são utilizadas e indicadas em acordo com a incapacidade e gravidade clínicas. A qualidade de vida (QV) é uma ferramenta utilizada para quantificar a eficácia e a resposta às terapêuticas adotadas, avaliar a efetividade e custos econômicos de novas estratégias terapêuticas, contribuir para planejar e aplicar os recursos para a saúde na comunidade. OBJETIVO: Avaliar a influência da terapêutica na QV e evolução clínica dos pacientes com MG. CASUÍSTICA: Foram avaliados 51 pacientes com MG, 38 submetidos a tratamento conservador e 13 timectomizados. MÉTODOS: Os instrumentos genéricos quantitativos de QV como WHOQOL, qualidade de vida relacionada à saúde (QVRS) SF-36, e depressão (BDI) foram utilizados. ESTATÍSTICA: Empregou-se análise univariada com os testes de Wilcoxon, U-Mann-Whitney, Fisher e razão de chance para avaliar a evolução clínica, a QV e QVRS e depressão; análise multivariada para a caracterização dos dois grupos de terapêutica considerando a interação de múltiplos fatores. RESULTADOS: O grupo submetido à terapêutica conservadora foi constituído por 16 pacientes do sexo masculino e 22 do feminino, com média de idade de 33,71±2,76 anos; o grupo timectomizado foi constituído por 6 homens e 7 mulheres, média de idade de 32,23±4,16 anos. Os pacientes do grupo conservador apresentaram melhora clínica estatisticamente significante (p <0,05) dos aspectos clínicos, da QV, da QVRS e depressão. Os timectomizados apresentaram melhora estatisticamente significante dos aspectos físicos e psicológicos da QV e QVRS e depressão, e melhora clínica evidente e não significante (p = 0,06). A análise multivariável mostrou r=0,65 para comparação das áreas; Wilks? Lambda para analisar as distâncias, X2 = 22,67; gl = 7; p = 0,05; as medidas centrais mostraram média = -0,42 dp = 1,0 para o grupo conservador; e média = 1,22, dp = 1,0 para o grupo timectomizado. CONCLUSÕES: Nesta amostra e no período avaliado constatamos que: 1) Os pacientes submetidos ao tratamento conservador apresentaram diferenças significantes com melhora clínica acentuada, de QV, de QVRS e depressão; 2) os timectomizados apresentaram melhora clínica, da QV e QVRS em seus aspectos físicos e psicológicos, e efetiva e significante melhora dos índices de depressão; 3) a análise multivariada revelou que a timectomia produziu efeito benéfico e significativo na recuperação da saúde e bem estar nos pacientes. / INTRODUCTION: Myasthenia gravis (MG) is an immune mediated disease with production of antibodies against post-synaptic acetylcholine receptor of neuromuscular junctions (AAChR,Musk) and orders in nervous impulse transmission. The disease´s clinical characteristics include fatigability and fluctuating weakness of voluntary muscles. Acetylcholinesterase inhibitors, thymectomy, corticosteroids, cytostatic agents and immunoglobulin are widely used and are indicated according to the patient´s disability and severity. Clinical manifestations, Quality of life (Qol), health-related (HRQol) analysis are used to evaluate response to therapy. Nowadays, Qol index is an important tool to evaluate the medical outcome, treatment efficacy, cost effectiveness and net benefit of new therapeutic strategies to determine whether their cost can be justified in the planning and application of health policies. OBJECTIVE: To evaluate the influence of conservative treatment and thymectomy on Qol and clinical response of myasthenic patients. SUBJECTS: Fifty-one myasthenic patients were chosen; 38 were submitted to conservative therapy and 13 to thymectomy. METHODS: Quantitative Qol tools such as WHOQOL, SF-36 and BDI were employed to evaluate Qol, HRQol and depression. STATISTICS: Univariate analysis by means of the Wilcoxon, U-Mann Whitney and Fisher tests, Chi-Square, odd ratio were used to follow the patient?s clinical status, evolution of Qol, HRQol and depression. Discriminant analysis was used to analyze the interation of multiple factors in the characterization of conservative and thymectomized groups. RESULTS: The conservative group of patients was constituted of 16 males and 22 females average age 33.71±2.76 years; the thymectomized group was composed of 6 males, 7 females, average age 32.23±4.16 years. Patients submitted to conservative therapy improved significantly in clinical progress, Qol, HRQol and depression. The follow-up of thymectomized patients showed a strong trend for clinical progress and significant improvement in physical and psychological Qol domains as well as in depression index. Discriminant analysis showed r = 0.65, p <0.05; Wilk?s Lambda X2 = 22.67, gl = 7; mean = -0.42, SD = 1.0 for conservative group; and mean = 1.22, SD = 1.0 for timectomized group. CONCLUSIONS: A prospective evaluation of a myasthenic patients sample revealed: 1) conservative treatment was found to have a strong and significant impact on clinical progress, Qol, HRQol and depression; 2) Thymectomy partly influenced Qol, specially physical and psychological aspects. There was also improvement in depression and clinical progress; 3) the evaluation of multiple parameters pointed to a strong and positive influence of thymectomy in the recovery of the patients.

Σκοπός: Η θυμεκτομή αποτελεί κοινώς αποδεκτή θεραπεία της μυασθένειας με τις διάφορες προσπελάσεις να αναφέρονται ως ανάλογης αξίας για την επίτευξη ύφεσης της νόσου. Έχοντας πλέον την μόνιμη σταθερή ύφεση ως καθαρή και μετρήσιμη νευρολογική έκβαση των μυασθενικών ασθενών μετά θυμεκτομή και γνωρίζοντας ότι η ύφεση της νόσου αποτελεί χρόνο-εξαρτώμενο γεγονός, πραγματοποιήσαμε μια αναδρομική μελέτη των ασθενών με μυασθένεια που αντιμετωπίστηκαν χειρουργικά με σκοπό τον πιο αξιόπιστο καθορισμό του ρόλου των μεγίστων θυμικών εκτομών και την ταυτοποίηση προγνωστικών παραγόντων για ύφεση της νόσου μετά θυμεκτομή. Υλικό και μέθοδος. Η μελέτη περιλαμβάνει 78 ασθενείς που υποβλήθηκαν σε τροποποιημένη μέγιστη θυμεκτομή από το 1990 έως το 2007. Οι ενδείξεις θυμεκτομής περιελάμβαναν: οφθαλμική μυασθένεια ανθιστάμενη στη φαρμακευτική αγωγή, γενικευμένη μυασθένεια και μυασθένεια με θύμωμα. Τα στοιχεία που συλλέχθηκαν αφορούσαν τη βαρύτητα της νόσου (τροποποιημένη Osserman ταξινόμηση), την προεγχειρητική φαρμακευτική αγωγή, την ηλικία έναρξης της νόσου (≤ 40/ > 40 έτη), το χρονικό διάστημα που μεσολάβησε από τη διάγνωση στη θυμεκτομή (≤ 12/ > 12 μήνες), το φύλο, την ιστολογία του θύμου αδένα, τη θνητότητα και τις επιπλοκές. Στους ασθενείς με θύμωμα περαιτέρω στοιχεία που ελήφθησαν υπόψη αφορούσαν τον ιστολογικό τύπο του θυμώματος κατά την Παγκόσμια Οργάνωση Υγείας και το στάδιο του όγκου κατά Masaoka. Η εκτίμηση της νευρολογικής έκβασης στο τέλος του μετεγχειρητικού follow up έγινε βάση της νέας ταξινόμησης του Αμερικανικού Ιδρύματος για τη Βαρεία Μυασθένεια με την πλήρη σταθερή ύφεση να λαμβάνεται υπόψη για τον καθορισμό της επάρκειας της διενεργηθείσας εκτομής και για τη σύγκριση των αποτελεσμάτων μας με αυτά προηγουμένων μελετών. Η στατιστική ανάλυση των αποτελεσμάτων έγινε με το SPSS 17 και αφορούσε δύο ομάδες ασθενών ανάλογα με την παρουσία ή μη θυμώματος. Η μέθοδος Kaplan-Meier χρησιμοποιήθηκε για την εκτίμηση της επίπτωσης των υπό εκτίμηση προγνωστικών παραγόντων στην επίτευξη της πλήρους ύφεσης ενώ η Cox Regression ανάλυση αποτέλεσε το μοντέλο για την ανάλυση της ταυτόχρονης επίδρασης των υπό μελέτη παραμέτρων στην επίτευξη πλήρους σταθερής ύφεσης. Τιμές του p < 0.05 θεωρήθηκαν στατιστικά σημαντικές. Αποτελέσματα: 51 ασθενείς είχαν μυασθένεια χωρίς θύμωμα και 27 ασθενείς παρανεοπλασματική μυασθένεια. Δεν υπήρχαν στατιστικά σημαντικές διαφορές στα προεγχειρητικά κλινικά χαρακτηριστικά των ασθενών πλην της αναμενομένης εμφάνισης της νόσου σε απώτερη ηλικία στους ασθενείς με θύμωμα. Η θνητότητα ήταν μηδενική ενώ η χειρουργική νοσηρότητα, ανάλογη προηγουμένων μελετών θυμεκτομής με διαφορετικού τύπου προσπέλασεις, ανήλθε στο 7,7% και ήταν ως επί το πλείστον ήσσονος σημασίας. Το ποσοστό μετεγχειρητικής μυασθενικής κρίσης ήταν μόλις 3,8%. Οι ασθενείς με μυασθένεια και θύμωμα βίωσαν όψιμη νευρολογική έκβαση ανάλογη αυτής των ασθενών χωρίς θύμωμα (πιθανότητα ύφεσης 74,5% vs 85,7%, p= 0.632). Η μη χρήση στεροειδών στην προεγχειρητική φαρμακευτική αγωγή, ως έμμεσος δείκτης της βαρύτητας της νόσου, σχετίστηκε με στατιστικά καλύτερη πιθανότητα για πλήρη ύφεση των συμπτωμάτων τόσο στους ασθενείς με θύμωμα (95% CI 2.687-339.182, p= 0.006) όσο και σε αυτούς χωρίς θύμωμα (CI 95% 1.607-19.183, P= 0.007) στην πολυπαραγοντική ανάλυση. Αξιόλογη διαφορά, αν και στατιστικά μη σημαντική, για τη έκβαση της νόσου είχε η πρώιμη σε σχέση με την απώτερη χειρουργική αντιμετώπιση των ασθενών. Στη σύγκριση των 27 ασθενών με μυασθένεια και θύμωμα με 12 επιπλέον ασθενείς που υποβλήθηκαν στην ίδια επέμβαση για θύμωμα άνευ μυασθένειας η παρουσία των συμπτωμάτων μυϊκής αδυναμίας συνδυάστηκε με στατιστικά σημαντική βελτίωση της επιβίωσης των ασθενών (100% vs 38,8% στη 10ετία, p< 0.001). Στους ασθενείς με μυασθένεια χωρίς θύμωμα και απώτερης ηλικιακά έναρξης της νόσου το ποσοστό σημαντικής βελτίωσης των μυασθενικών συμπτωμάτων, εξαιρουμένης της πλήρους ύφεσης, ήταν 70%. Στους ασθενείς με μυασθένεια και θύμωμα η ιστολογική ταυτοποίηση των θυμωμάτων κατά την Παγκόσμια Οργάνωση Υγείας προέκυψε στατιστικά σημαντική τόσο στην μονοπαραγοντική όσο και στην πολυπαραγοντική ανάλυση με τα θυμώματα τύπου Β2, Α και Β3 να επιτυγχάνουν από πολύ καλή έως άριστη πιθανότητα πλήρους ύφεσης και τα θυμώματα τύπου ΑΒ, Β1 και C να έχουν απογοητευτική έκβαση όσον αφορά την ίαση. Συμπεράσματα: Η παρούσα μελέτη δείχνει ότι η τροποποιημένη μεγίστη θυμεκτομή είναι ασφαλής και σχετίζεται με υψηλή πιθανότητα για ίαση των μυασθενικών ασθενών με και χωρίς θύμωμα. Οι ασθενείς πρέπει να αντιμετωπίζονται χειρουργικά πρώιμα μετά τη διάγνωση με κυριότερο προγνωστικό παράγοντα για το απώτερο νευρολογικό αποτέλεσμα την προεγχειρητική βαρύτητα της νόσου. Η ασφαλής και πιο αξιόπιστη εκτίμηση της τελευταίας απαιτεί πιο αντικειμενικά κριτήρια όπως αυτά που θεσπίστηκαν από το Αμερικανικό Ίδρυμα για τη Βαρεία Μυασθένεια. Η ενσωμάτωση σε αυτά τα κριτήρια μοριακών παραμέτρων που φαίνεται να επηρεάζουν την πρόγνωση της νόσου, ενδεχόμενα να βελτιώσουν την αξιοπιστία της κλινικής σταδιοποίησης του MGFA και να αναδείξουν υποομάδες ασθενών με διαφορετική νευρολογική πρόγνωση μετά από θυμεκτομή. Επίσης η πρώιμη διάγνωση των θυμωμάτων εξαιτίας των συνυπαρχόντων μυασθενικών συμπτωμάτων μπορεί να οδηγήσει σε καλύτερη επιβίωση τους συγκεκριμένους ασθενείς. Τέλος η νευρολογική έκβαση των ασθενών με θυμωματώδη μυασθένεια σχετίζεται με τον ιστολογικό τύπο των θυμωμάτων, αλλά όχι αναγκαία και με την κακοήθη συμπεριφορά τους. / Objective: Thymectomy represents a widely accepted treatment for myasthenia gravis with different surgical approaches reported as comparably efficient in achieving disease’s remission. With the complete stable remission being currently accepted as a clear measurable outcome of patients with myasthenia undergoing surgical treatment and the knowledge that disease’s remission should be evaluated as a time dependent event we proceeded to a retrospective analysis of our experience on the surgical management of myasthenic patients. The objective was to access the effect of maximal resection on the neurological outcome and identify predictors of disease remission. Materials and methods: The study group consisted of 78 patients who underwent modified maximal thymectomy for myasthenia from 1990 to 2007. Indications for thymectomy included: ocular myasthenia refractory to medical treatment, generalized myasthenia and thymomatous myasthenia. The data collected included preoperative disease’s severity (modified Osserman classification), preoperative medical treatment, age at onset of the disease (≤ 40/ > 40 years), time elapsed between diagnosis and thymectomy (≤ 12/ > 12 months), gender, thymus gland histology, mortality and morbidity. In thymoma patients further analysis was carried out according the World Health Organization histological classification and the Masaoka stage of the tumors. The evaluation of the neurological outcome at the end of follow up was performed according the Myasthenia Gravis Foundation of America classification. Both the effectiveness of the resection performed and the comparison of our results with those of previous studies were done using the complete stable remission as the end point of the study. The statistical analysis of the results was carried out using the SPSS 17. Kaplan-Meier life table analysis was performed and the log rank test was used to evaluate the effect of the variables examined on the distribution of disease’s remission over time. The Cox proportional hazard model was also applied to verify the concurrent effect of the evaluated factors on the achievement of complete stable remission. P values < 0.05 were considered statistically significant. Results: 51 patients suffered of non thymomatous myasthenia while 27 patients had myasthenia with thymoma. The two groups were comparable in refer to the clinical features of the patients apart the more advanced age at the time of the diagnosis for thymoma patients. There was no perioperative mortality, while the surgical morbidity was comparable to the one reported in other series of patients with different surgical approaches and was 7.7%. The rate of postoperative myasthenic crisis was only 3.8%. Thymoma and non thymoma patients experienced comparable complete stable remission prediction (74.5% vs 85.7% at 15 years, p= 0.632). The absence of steroids in the preoperative medical regimen was statistically associated with the achievement of complete stable remission in both thymoma (95% CI 2.687-339.182, p= 0.006) and non thymoma patients (CI 95% 1.607-19.183, P= 0.007) in multivariate analysis. There was an important difference, although not statistically significant, for the neurological outcome between early and late surgical treatment. When the 27 patients with myasthenia and thymoma were compared with other 12 patients similarly operated for thymoma without symptoms and signs of muscular weakness we found that the presence of myasthenia was statistically associated with improved survival (100% vs 38.8% at 10 years, p< 0.001). Non thymoma patients presenting with late onset myasthenia, experienced high improvement (complete stable remission excluded) rate reaching up to 70% at the end of follow up. Among patients with thymomatous myasthenia gravis the World Health Organization histological classification was statistically associated with the late neurological outcome. Thymoma types A, B3 and B2 reached a high to excellent prediction of disease’s remission while types AB, B2 and C had a disappointing neurological outcome. Conclusons: The present study demonstrated that the modified maximal thymectomy is a safe procedure, associated with an excellent neurological outcome in both thymomatous and non thymomatous myasthenia. The patients should be operated early after the diagnosis is made with the disease’s severity being the prime determinant of the possibility to achieve complete remission of myasthenic symptoms. The evaluation of disease’s severity requires objective criteria like the ones proposed by the Myasthenia Gravis Foundation of America. The inclusion in these criteria of molecular markers related to myasthenia’s prognosis and its neurological outcome after thymectomy may further enhance its validity and may allow the identification of subgroups of patients with different disease prognosis after thymectomy. The presence of muscular weakness may lead to early diagnosis and surgical treatment of thymomas with improved survival. Finally the neurologic outcome in thymoma patients after thymectomy may be statistically associated with the World Health Organization classification subtypes but not necessarily with the aggressiveness of these tumors.

Myasthenia Gravis (MG) is an autoimmune disease affecting neuromuscular transmission, in which the thymus is considered pathogenic organ. Earlier ideas suggesting that MG is only the receptors disease have been proven wrong. There are immunopathological changes in both target structures [specific receptors for acetylcholine (AChR] muscle-specific tyrosine kinase (MuSK) and low-density lipoprotein 4 (Lrp4)], the thymus, as well as in peripheral lymphoid organs. Initial findings of the humoral immunity defect with the decisive role of the pathologic autoantibodies, were corrected with findings of the immune dysregulation at the level of T lymphocytes. According to today's knowledge, the development and maintenance of MG involves almost all cell types of immune function in the autoimmune inflammation: helper CD4+ T lymphocytes, cytotoxic CD8+ T lymphocytes, regulatory CD4+CD25+ T lymphocytes, Th17 lymphocytes, B lymphocytes and plasma cells. Thymus plays a dominant immunopathogenetic role in younger patients with MG, while extrathymic mechanisms are applied in older patients. As a result of that, the thymectomy (TE) is generally accepted as part of treatment for MG. However, there is still no data verified by a prospective controlled study, which would demonstrate a useful result of this treatment...

INTRODUÇÃO: A Miastenia gravis (MG) é uma desordem imunológica com antígenos alvos conhecidos, com produção de anticorpos contra o receptor nicotínico de acetilcolina, AAChR e Musk, na junção neuromuscular, dificultando a transmissão do impulso nervoso e provocando fadiga e fraqueza flutuantes na musculatura ocular, facial, dos membros e respiratória. A terapêutica sintomática com inibidores de acetilcolinesterase e a etiopatogênica como a timectomia, corticosteróides, agentes citostásticos e imunoglobulinas são utilizadas e indicadas em acordo com a incapacidade e gravidade clínicas. A qualidade de vida (QV) é uma ferramenta utilizada para quantificar a eficácia e a resposta às terapêuticas adotadas, avaliar a efetividade e custos econômicos de novas estratégias terapêuticas, contribuir para planejar e aplicar os recursos para a saúde na comunidade. OBJETIVO: Avaliar a influência da terapêutica na QV e evolução clínica dos pacientes com MG. CASUÍSTICA: Foram avaliados 51 pacientes com MG, 38 submetidos a tratamento conservador e 13 timectomizados. MÉTODOS: Os instrumentos genéricos quantitativos de QV como WHOQOL, qualidade de vida relacionada à saúde (QVRS) SF-36, e depressão (BDI) foram utilizados. ESTATÍSTICA: Empregou-se análise univariada com os testes de Wilcoxon, U-Mann-Whitney, Fisher e razão de chance para avaliar a evolução clínica, a QV e QVRS e depressão; análise multivariada para a caracterização dos dois grupos de terapêutica considerando a interação de múltiplos fatores. RESULTADOS: O grupo submetido à terapêutica conservadora foi constituído por 16 pacientes do sexo masculino e 22 do feminino, com média de idade de 33,71±2,76 anos; o grupo timectomizado foi constituído por 6 homens e 7 mulheres, média de idade de 32,23±4,16 anos. Os pacientes do grupo conservador apresentaram melhora clínica estatisticamente significante (p <0,05) dos aspectos clínicos, da QV, da QVRS e depressão. Os timectomizados apresentaram melhora estatisticamente significante dos aspectos físicos e psicológicos da QV e QVRS e depressão, e melhora clínica evidente e não significante (p = 0,06). A análise multivariável mostrou r=0,65 para comparação das áreas; Wilks? Lambda para analisar as distâncias, X2 = 22,67; gl = 7; p = 0,05; as medidas centrais mostraram média = -0,42 dp = 1,0 para o grupo conservador; e média = 1,22, dp = 1,0 para o grupo timectomizado. CONCLUSÕES: Nesta amostra e no período avaliado constatamos que: 1) Os pacientes submetidos ao tratamento conservador apresentaram diferenças significantes com melhora clínica acentuada, de QV, de QVRS e depressão; 2) os timectomizados apresentaram melhora clínica, da QV e QVRS em seus aspectos físicos e psicológicos, e efetiva e significante melhora dos índices de depressão; 3) a análise multivariada revelou que a timectomia produziu efeito benéfico e significativo na recuperação da saúde e bem estar nos pacientes. / INTRODUCTION: Myasthenia gravis (MG) is an immune mediated disease with production of antibodies against post-synaptic acetylcholine receptor of neuromuscular junctions (AAChR,Musk) and orders in nervous impulse transmission. The disease´s clinical characteristics include fatigability and fluctuating weakness of voluntary muscles. Acetylcholinesterase inhibitors, thymectomy, corticosteroids, cytostatic agents and immunoglobulin are widely used and are indicated according to the patient´s disability and severity. Clinical manifestations, Quality of life (Qol), health-related (HRQol) analysis are used to evaluate response to therapy. Nowadays, Qol index is an important tool to evaluate the medical outcome, treatment efficacy, cost effectiveness and net benefit of new therapeutic strategies to determine whether their cost can be justified in the planning and application of health policies. OBJECTIVE: To evaluate the influence of conservative treatment and thymectomy on Qol and clinical response of myasthenic patients. SUBJECTS: Fifty-one myasthenic patients were chosen; 38 were submitted to conservative therapy and 13 to thymectomy. METHODS: Quantitative Qol tools such as WHOQOL, SF-36 and BDI were employed to evaluate Qol, HRQol and depression. STATISTICS: Univariate analysis by means of the Wilcoxon, U-Mann Whitney and Fisher tests, Chi-Square, odd ratio were used to follow the patient?s clinical status, evolution of Qol, HRQol and depression. Discriminant analysis was used to analyze the interation of multiple factors in the characterization of conservative and thymectomized groups. RESULTS: The conservative group of patients was constituted of 16 males and 22 females average age 33.71±2.76 years; the thymectomized group was composed of 6 males, 7 females, average age 32.23±4.16 years. Patients submitted to conservative therapy improved significantly in clinical progress, Qol, HRQol and depression. The follow-up of thymectomized patients showed a strong trend for clinical progress and significant improvement in physical and psychological Qol domains as well as in depression index. Discriminant analysis showed r = 0.65, p <0.05; Wilk?s Lambda X2 = 22.67, gl = 7; mean = -0.42, SD = 1.0 for conservative group; and mean = 1.22, SD = 1.0 for timectomized group. CONCLUSIONS: A prospective evaluation of a myasthenic patients sample revealed: 1) conservative treatment was found to have a strong and significant impact on clinical progress, Qol, HRQol and depression; 2) Thymectomy partly influenced Qol, specially physical and psychological aspects. There was also improvement in depression and clinical progress; 3) the evaluation of multiple parameters pointed to a strong and positive influence of thymectomy in the recovery of the patients.

Myasthenia Gravis (MG) is an autoimmune disease affecting neuromuscular transmission, in which the thymus is considered pathogenic organ. Earlier ideas suggesting that MG is only the receptors disease have been proven wrong. There are immunopathological changes in both target structures [specific receptors for acetylcholine (AChR] muscle-specific tyrosine kinase (MuSK) and low-density lipoprotein 4 (Lrp4)], the thymus, as well as in peripheral lymphoid organs. Initial findings of the humoral immunity defect with the decisive role of the pathologic autoantibodies, were corrected with findings of the immune dysregulation at the level of T lymphocytes. According to today's knowledge, the development and maintenance of MG involves almost all cell types of immune function in the autoimmune inflammation: helper CD4+ T lymphocytes, cytotoxic CD8+ T lymphocytes, regulatory CD4+CD25+ T lymphocytes, Th17 lymphocytes, B lymphocytes and plasma cells. Thymus plays a dominant immunopathogenetic role in younger patients with MG, while extrathymic mechanisms are applied in older patients. As a result of that, the thymectomy (TE) is generally accepted as part of treatment for MG. However, there is still no data verified by a prospective controlled study, which would demonstrate a useful result of this treatment...