Fibrolamellar hepatocellular carcinoma (FL-HCC) is a malignant liver tumor which is thought to be a variant of conventional hepatocellular carcinoma (HCC). It accounts for a small proportion of HCC cases and occurs in a distinctly different group of patients which are young and usually not in the setting of chronic liver disease. The diagnosis of FL-HCC requires the integration of clinical information, imaging studies, and histology. In terms of the treatment options, the only potentially curative treatment option for patients who have resectable disease is surgery either liver resection (LR) or liver transplantation (LT). When performed in a context of aggressive therapy, long-term outcomes after surgery, particularly liver resection for FL-HCC, were favorable. The clinical outcome of patients with unresectable disease is suboptimal with median survival of less than 12 months. The aim of this review is to update the available evidence on diagnosis, treatment options, outcome predictors, and recent developments of patients with this rare disease and to provide a summarized overview of the available literature.

Introduction: Quality of life is a long-term goal in nursing care. Nursing care in improving the quality of life should focus not only on physical aspects, but especially on support to return to everyday life, managing daily activities, at least to the extent that the patient has been able to handle them before staying at hospital. Methodology: The aim of the work was to evaluate the quality of life of patients before and after staying in ICU with a focus on patients after acute surgery associated with intestinal resection. The research sample consisted of patients who underwent acute surgery associated with intestinal resection and ICU staying. Quality of life was assessed before hospitalization and 3 months after discharging from the ICU. We have chosen SOFA, APACHE scoring systems to obtain data. The quality of life before hospitalization was evaluated by SF-36 and ADL, IADL questionnaires for daily activities. In the ICU dismission, the patients completed HADS (anxiety, depression), MAF (fatigue) questionnaires, 6-minute walk and sit / stand test. After the third month of convalescence, patients completed questionnaires: SF-36, IADL, ADL, HADS, MAF and 6. minute walk and sit / stand test. Results: 38 patients were evaluated. We found a significant difference in the development of all observed...

Introdução: As grandes perdas de maxila condicionam grande defeito oral que afetam a qualidade de vida do paciente em diversos domínios. Porém, não há na literatura um questionário específico para esta condição. Proposição: Desenvolver e validar um instrumento de qualidade de vida para as grandes perdas de maxila sem envolvimento facial. Material e Método: Elaboração de um questionário piloto baseado nos achados de outros estudos e seleção de perguntas de instrumentos já existentes que trabalham com domínios semelhantes. Em seguida, clínicos avaliaram estas questões, que poderiam sugerir a inclusão e exclusão de questões. A seguir, pacientes pontuaram os itens gerados numa escala de 0 a 10 segundo a relevância e importância para redução de itens segundo o método de impacto. Por fim, dois pesquisadores agruparam os itens em domínios e se determinou a consistência interna pelo coeficiente alfa de Cronbach. Resultados e Discussão: O questionário preliminar contou inicialmente com 60 questões que, após a entrevista com pacientes, foi reduzido a 33. O alfa de Cronbach foi de 0,92 e os itens foram separados em oito domínios: relações sociais; fala e voz; alimentação; emocional; bem estar material; dor; estética; e halitose. Apenas uma questão, que não obteve índice de impacto suficiente, foi incluída devido aos achados de outros estudos e falta de outra pergunta similar. O instrumento gerado necessita de um processo de validação final. Conclusões: Obtenção de um questionário preliminar sobre qualidade de vida nas grandes perdas de maxila sem envolvimento facial com validade de conteúdo. / Introduction: Maxilla defects affect patients quality of life on several domains. There is not a specific instrument to this condition. Proposition: Develop and validate a disease-specific health related quality of life questionnaire for acquired maxilla defect. Materials and Methods: To elaborate a pilot questionnaire based on other studies results and select questions using instruments that deal with similar domains. Then, experts assessed these items and could suggest including or excluding questions. After that, patients scored the items according to relevance and importance in order to reduce the number of questions using the impact method. At last, two researchers grouped the questions into domains and the internal consistency was calculated using the Cronbachs alpha coefficient. Results and Discussion: The pilot questionnaire contained 60 questions and after we performed the impact method it was reduced to 33 items. The Cronbachs alpha coefficient was 0,92. The researchers compiled the items into eight domains: social relationships; speech and voice; feeding; emotional; material wellbeing; pain; aesthetics ;and halitosis. Only one question did not reach the minimum impact score was included in the questionnaire due to findings in others studies and lack of a similar items. The preliminary instrument presented here needs to undergo a complete validation process in to assess the psychometric properties and to decide on the final version. Conclusions: A preliminary version of the instrument with content validity was obtained.

Introdução: A memória prospectiva (MP) refere-se a um conjunto de habilidades cognitivas que permitem lembrar-se de uma intenção a desempenhar no futuro, no momento adequado. Essa função é pouco avaliada em baterias neuropsicológicas que avaliam pessoas com epilepsia. Objetivo: Estudamos o impacto da cirurgia para epilepsia sobre a MP, componente prospectivo, em pessoas submetidas a lobectomia temporal unilateral para controle de epilepsia refratária ao tratamento clínico. Métodos: Comparamos o desempenho de MP em pessoas com epilepsia associada à esclerose mesial temporal à esquerda (EMTE) ou direita (EMTD) com dois grupos controles. Um grupo foi composto por indivíduos sem epilepsia (controles normais), e o outro por pessoas com epilepsia secundária à EMT, submetidos a avaliação e reavaliação neuropsicológica, sem intervenção cirúrgica (grupo clínico para controle teste/reteste). Resultados: Avaliamos 42 indivíduos sem epilepsia, 20 do grupo clínico (controle teste/reteste) e 39 do grupo cirúrgico (pré e pósoperatório). Comparamos o desempenho entre grupos e também a variação de desempenho individual, pelo índice de mudança confiável. Os grupos não diferiram em idade, escolaridade e quociente de inteligência. Na avaliação inicial, observou-se rebaixamento no desempenho em MP nos grupos clínico e cirúrgico (p < 0,01) (efeito lesão), sem diferença entre os grupos EMTE ou EMTD (efeito lateralidade). Para o grupo cirúrgico, observamos acentuada (p < 0,01) redução de crises e leve, porém significativa, redução de carga de drogas antiepilépticas pós-operatória. Observamos estabilidade em reteste de MP, declínio de memória verbal para o grupo EMTE e estabilidade de memória verbal e visual para o grupo EMTD. Conclusão: Embora exista um sistema de evocação compartilhado entre a MP e a memória episódica, a ressecção de estruturas temporais mesiais acometidas patologicamente não provoca declínio adicional em MP, mesmo quando se observou declínio de memória verbal no grupo EMTE. O comportamento dissociado de declínio de memória verbal para o grupo EMTE e preservação de MP após cirurgia de epilepsia sugere diferentes papeis das estruturas temporais mesiais nestes sistemas de memória. O papel do acometimento de estruturas extratemporais e de estruturas temporais não mesiais na MP em pacientes com EMT deverá ser melhor elucidado em estudos futuros / Introduction: Prospective memory (PM) refers to a set of cognitive abilities that allow recall of a previous intention to perform in the future, in the appropriate setting. This function is not usually evaluated in neuropsychological batteries used to evaluate people with epilepsy. Objective: We evaluated the impact of epilepsy surgery on the prospective component of PM, in people undergoing unilateral temporal lobectomy to treat medically refractory epilepsy. Methods: We compared performance in PM in people with left or right mesial temporal sclerosis (MTS) in the pre and postoperative periods with that of two control groups. One group was composed of people without epilepsy (normal controls), and another group was composed of people with epilepsy associated with mesial temporal sclerosis that underwent neuropsychological testing and retesting without undergoing surgery (clinical test/retest control group). Results: We studied 42 people without epilepsy, 20 clinical controls (test/retest group), and 39 patients that underwent epilepsy surgery (pre and postoperative testing). We compared groups performances and changes in individual performances with the reliable change index. Groups did not differ in age, education, and intelligence quotient. We found decreased preoperative PM performance for the clinical and surgical groups (p < 0.01) (lesion effect), without a difference between right and left groups (laterality effect). Postoperatively, there was a significant (p < 0.01) decrease in number of seizures, a small, but significant reduction in antiepileptic drug load, stable prospective memory, verbal and visual memory for right mesial temporal sclerosis, and decreased verbal memory in the left mesial temporal sclerosis group. Conclusion: In spite of a shared evocation system for episodic and prospective memory, resection of pathologically involved mesial temporal structures does not impact on prospective memory performance, even in the setting verbal memory decline in the left MTS group.The finding of dissociated verbal memory decline and PM stability after epilepsy surgery suggests a different role of mesial temporal lobe structures in these memory systems. The role of extratemporal and nonmesial temporal lobe structures in prospective memory in MTS patients should be evaluated in future studies

Ziel: Den Einfluss der Radikalität der Resektion eines Glioblastoma multiforme in Kombination mit einer adjuvanten Chemotherapie auf das Survival heraus zu arbeiten. Methoden: Zwischen 1997 und 2000 wurden 55 Patienten, die an einem primären Glioblastoma multiforme erkrankten, einer Tumorresektion unterzogen. Von den 55 Patienten waren 36 männlich und 19 weiblich. Im Mittel erkrankten die Patienten mit 56 Jahren. Tumorresektion und Radiatio wurden bei allen Patienten durchgeführt. 20 Patienten wurden darüber hinaus noch mit einer adjuvanten Chemotherapie behandelt. Ergebnisse: Die Patienten, die mit einer Chemotherapie behandelt wurden, zeigten ein signifikant längeres Überleben (85 versus 44 weeks). Und die Patienten mit einem postoperativen Resttumor profitierten am meisten von der adjuvanten Chemotherapie (75 versus 39 weeks). Zusammenfassung: Patienten, die mit einer adjuvanten Chemotherapie behandelt wurden zeigten ein signifikant längeres Überleben als die Patienten ohne diese Therapie. / Objective: To evaluate the influence of resection of a glioblastoma multiforme in combination with adjuvant chemotherapy regarding survival. Methods: From 1997 to 2000, 55 patients with primary glioblastoma multiforme underwent a tumor resection. Of the 55 patients 36 were male, 19 female, with an average age of 56 years. Tumor resection and radiatio were performed in all patients. 20 patients were treated additionally with chemotherapy. Results: Patients treated with chemotherapy displayed a significant longer survival (85 versus 44 weeks). And the patients with a residual postoperative tumor mass did benefit from adjuvant chemotherapy (75 versus 39 weeks). Conclusion: Patients treated with adjuvant chemotherapy had a significant longer survival then those without this therapy.

Patienten mit metastasierten Keimzelltumoren, die einen Progress oder ein Rezidiv ihrer Erkrankung nach einer cisplatinhaltigen Vortherapie erleiden, haben eine schlechte Prognose. Unter Verwendung einer erneuten konventionellen Chemotherapie können maximal 15-30% dieser Patienten geheilt werden, so dass die Mehrzahl der Patienten an ihrer Erkrankung verstirbt. Aus diesem Grund ist die Optimierung der therapeutischen Möglichkeiten ein wesentliches Ziel. Unsere Daten zeigen, dass die Hochdosischemotherapie (HDCT) eine wesentliche therapeutische Verbesserung darstellt und mittels dieser Therapie mit einem ereignisfreien Überleben von 30-60% zu rechnen ist. Eine "matched-pair" Analyse konnte im Hinblick auf das ereignisefreie und das Gesamtüberleben einen Vorteil von mehr als 10% zu Gunsten der HDCT feststellen. Darüber hinaus hat die zunehmende Erfahrung und die Verwendung von peripheren Blutstammzellen und hämatopoetischen Wachstumsfaktoren, den Einsatz der HDCT deutlich sicherer gemacht. Aus den genannten Gründen sollte alle Patienten mit Rezidiv oder Progress eines Keimzelltumors der HDCT zugeführt werden. Die operative Entfernung von residuellen Tumormanifestationen (RTR) nach primärere Chemotherapie ist heute Standard bei Patienten mit metastasierten Keimzelltumoren. Zwar findet sich in der histologischen Aufarbeitung bei den meisten Patienten ausschließlich nekrotisches Gewebe, doch werden bei einem Teil der Patienten auch Anteile von reifem Teratom und vitalen differenzierten und undifferenzierten Karzinomen gefunden. Während die Resektion von Nekrose keinen therapeutischen Benefit für den Patienten darstellt, ist die komplette Entfernung von reifem Teratom oder Zellen eines Karzinoms für die Prognose entscheidend. In Bezug auf die HDCT konnten bisher keine vergleichbaren Daten erhoben werden. Zur Evaluierung des Stellenwertes der RTR nach HDCT analysierten wir unser eigenes Patientenkollektiv und fanden, dass vergleichbar zur Primärtherapie alle Patienten nach Salvage-HDCT, die eine partielle markernegative oder markerpositive Remission erreicht haben, einer RTR zugeführt werden sollten. Bis auf intrazerebrale Reste sollten alle residuellen Tumormanifestationen komplett reseziert werden. Neben der Optimierung der therapeutischen Möglichkeiten ist auch die Minimierung der chemotherapieassoziierten Toxizitäten ein wesentlicher Bestandteil meiner wissenschaftlichen Arbeit. Aus diesem Grund evaluierten wir die Wirksamkeit der Substanz Amifostin im Hinblick auf die Verringerung von Toxizitäten, die Wirkung auf die Mobilisierung von peripheren Blutstammzellen und den Einfluß auf die Rekonstitution des Immunstatus bei Patienten mit rezidivierten oder progredienten Keimzelltumoren, die mittels einer konventionellen Chemotherapie und anschließender HDCT behandelt wurden. Der Einsatz von Amifostin erbrachte in diesem Zusammenhang und in diesem Patientenkollektiv keinen therapeutischen oder prophylaktischen Nutzen, so dass dessen Verwendung bei Patienten mit Keimzelltumoren nicht generell empfohlen werden kann. / Overall, patients with relapsed or progressive germ cell tumors (GCT) after cisplatin-based chemotherapy have a low chance of cure. Using conventional-dose chemotherapy as salvage treatment only 15-30% of the patients will become long-term survivors. It is well known that the majority of these patients will ultimately die of their disease. Therefore, improvment of standard treatment is clearly desirable. Our data has been established high-dose chemotherapy (HDCT) as an effective salvage modality with an event-free survival of 30-60%. A matched-pair analysis showed an advantage for HDCT compared with conventional-dose chemotherapy with improvement in event-free and overall survival of more than 10%. Furthermore, due to increasing clinical experience in the management of side-effects, the use of peripheral blood progenitor cells, and the availability of hematopoietic growth factors, HDCT has become relatively safe. In GCT patients with relapsed or rogressive disease HDCT has been demonstrated as a feasible and safe treatment concept which will be curative for a substantial proportion of these patients. Therefore, HDCT should be administered in patients with first relapse and unfavorable prognostic factors and as second or subsequent salvage treatment. Surgical resection of residual tumors (RTR) after first-line chemotherapy is recommended in patients with metastatic GCT. Necrosis will be the only histological finding in the majority of these patients. However, in others mature teratoma, viable cancer consisting of residual GCT, non germ-cell tumors, undifferentiated cancer or a combination of these histologies may be found. Whereas the resection of necrosis offers no therapeutic benefit, resection of mature teratoma or viable cancer adds to long-term event-free and overall survival in these patients. However, limited data exist on the results of surgery and the respective histologies in patients after first or subsequent salvage treatment with HDCT. To assess the contribution of RTR in this setting, we retrospectively analyzed a cohort of patients who had been treated with HDCT for relapsed or refractory GCT. Our data show that RTR contributes to the overall treatment outcome and should be offered to all patients with a partial remission after HDCT. Complete resections of all residual tumors outside the CNS should be attempted. Furthermore, we assessed the efficacy of amifostine for protection from chemotherapy-induced toxicities, for peripheral blood progenitor cell mobilization and for immune-reconstitution in patients treated with conventional-dose paclitaxel, ifosfamide, cisplatin (TIP) and high-dose carboplatin, etoposide and thiotepa (CET) followed by PBPC rescue. In conclusion, amifostine additional to conventional-dose chemotherapy or HDCT showed no unequivocal advantage in protection from treatment-related toxicities and had no effect neither on PBPC mobilization nor on immune-reconstitution.

INTRODUÇÃO: O câncer colorretal (CCR) é doença de grande importância, com elevada incidência e mortalidade. Restrito às camadas mucosa e submucosa, é denominado CCR precoce, sendo passível de tratamento endoscópico curativo na ausência de fatores de risco para metástases linfonodais. Entretanto, as técnicas para tal não são universalmente disponíveis, e muitos destes pacientes são tratados por ressecções cirúrgicas. OBJETIVO: Buscar estudos com os resultados do tratamento cirúrgico e endoscópico do CCR precoce e compará-los por meio de metanálise. MÉTODOS: Foi efetuada busca nas bases MEDLINE, EMBASE, LILACS, CENTRAL COCHRANE e EBSCO por estudos comparativos que incluíram pacientes com CCR precoce, submetidos a tratamento endoscópico ou cirúrgico. Dados de mortalidade, recidiva a longo prazo, taxas de ressecção em bloco e ressecção curativa, tempo de procedimento, taxas de complicações e complicações graves foram extraídos. Viés foi individualmente avaliado pela escala de Newcastle-Ottawa. Foram efetuados cálculos do risco absoluto (RA), seu aumento (ARA) ou redução (RAA), e dos números necessários para causar dano (NNH) ou tratar (NNT), com intervalo de confiança (IC) de 95% para significância estatística. Para metanálise dos dados, foi utilizado o programa RevMan 5, com uso do teste de Mantel-Haenszel para calcular um IC de 95%, e expressão dos resultados em gráficos de forest e funnel plot. A consistência entre os estudos foi relatada por I2. RESULTADOS: Foram encontradas 12.905 entradas via PUBMED e 12.818 via outras bases. Após remoção de duplicatas e aplicação dos critérios de inclusão e exclusão, restaram quatro estudos de coorte retrospectiva. Não foi observada diferença para mortalidade (339 pacientes) ou recorrência a longo prazo (577 pacientes). Foi observada superioridade do tratamento cirúrgico em 11% (-0,11 [IC 95% -0,14; -0,09, P < 0,05]) para taxa de ressecção em bloco (1.085 pacientes), e em 11% (-0,11 [IC 95% -0,21; -0,02, P < 0,05]) para taxa de ressecção curativa (1.112 pacientes). O tratamento endoscópico demonstrou superioridade de 7% (-0,07 [IC 95% -0,10; -0,03]) para taxa de complicações (1.085 pacientes), de 8% (-0,08 [IC 95% -0,15; -0,01]) para complicações graves (827 pacientes), e de 130 minutos (-130,34 [IC 95% -190,5; -70,17, P < 0,05) para tempo de procedimento (827 pacientes). CONCLUSÃO: Conforme os dados disponíveis na literatura, o tratamento do CCR precoce apresenta melhores resultados pela técnica cirúrgica quanto às taxas de ressecção em bloco e curativa, e menos complicações e menor tempo de procedimento pela técnica endoscópica. Não há diferença quanto às taxas de mortalidade e recidiva a longo prazo / INTRODUCTION: Colorectal cancer (CRC) represents an important disease, with high incidence and mortality. When restricted to the mucosa and submucosa it is called early CRC, with curative endoscopic treatment in the absence of histopathological conditions associated with high risk of linfonodal metastasis. However, such treatment techniques are not widely available, and many of these patients undergo surgical resection. OBJECTIVES: To search for studies of endoscopic and surgical treatment modalities for early CRC, and compare these results through meta-analysis. METHODS: MEDLINE, EMBASE, LILACS, CENTRAL COCHRANE, and EBSCO databases were searched for comparative studies, which included early CRC patients subjected to surgical or endoscopic treatments. Data regarding mortality, recurrence, en bloc resection rate, curative resection rate, procedure time, complications rate, and severe complications rate were extracted. Study bias was evaluated using the Newcastle-Ottawa score. Absolute Risk (AR), AR reduction (ARR), AR increase (ARI), and the number necessary to treat (NNT) or to harm (NNH) were computed, using a 95% confidence interval (CI) as statistically significant. RevMan 5 software was used for meta-analysis, applying Mantel-Haenszel tests to achieve a 95% CI; results were represented by forest and funnel plots. Consistency among studies was reported via I2. RESULTS: 12,905 entries were found via PUBMED, and 12,818 via other databases. After removal of duplicates and observation of inclusion and exclusion criteria, 4 retrospective cohort studies were considered for analysis. No differences in mortality (339 patients) and long-term recurrence (577) were observed between the two groups. Surgical treatment had higher rates of en bloc resection (-0.11 [95% CI -0.14, -0.09, P < 0.05] - 1,085 patients) and curative resection (-0.11 [IC 95% CI -0.21, - 0.02, P < 0.05] - 1,112 patients) when compared to endoscopic treatment. Endoscopic treatment had lower total complication rate (0.07 [IC 95% -0.10; - 0.03] - 1,085 patients), lower severe complication rate (-0.08 [IC 95% -0.15; - 0.01] - 827 patients), and shorter procedure time than the surgical treatment (-130.34 min [IC 95% -190.5; -70.17, P < 0.05] - 827 patients). CONCLUSION: According to available data, surgical treatment of early CRC yields better results regarding en bloc resection and curative resection rates; endoscopic treatment of early CRC results in lower complication rate and shorter procedure time. There are no differences in mortality and long-term recurrence rates

Der nach Leberoperation und -transplantation auftretende Ischämie-/ Reperfusionsschaden (I/R) und die konsekutive Inflammation des Lebergewebes stellen ein bedeutendes klinisches Problem dar. In der vorliegenden Arbeit wurden Einflüsse der warmen und kalten Ischämie (100% N2 bei 37°C bzw. 4°C) sowie der Exposition inflammatorischer Zytokine und Endotoxin (IL-1beta, 10 U/ml; IFN-gamma, 100 U/ml; TNF-alpha, 500 U/ml; LPS, 5 µg/ml) auf die Expression der Hämoxygenase-1 (HO- 1) mRNA und seines Proteins, einem Vertreter der Hitze-Schock-Proteine mit potentiell antioxidativer Wirkung, in humanen Hepatozytenprimärkulturen untersucht. Warme und kalte Ischämie stimulierten die HO-1 mRNA Expression in humanen Hepatozyten nach 0,5 bis 1h. Das HO-1 Protein wurde über 0,5-6h maximal exprimiert. Der Zellschaden, gemessen an der AST und LDH Freisetzung unter ischämischen Bedingungen wurde insbesondere nach 24 h beobachtet. Nach Zytokinexposition wurde die höchste Expressionsrate der mRNA durch IFN-gamma hervorgerufen, gefolgt von TNF-alpha, LPS und IL-1beta. Jedes einzelne Zytokin stimulierte die HO-1 mRNA Expression nach 0,5 h, erreichte ein Maximum nach 3 h und fiel nach 6 h ab. Nach Stimulation mit einem Zytokinmix (CM; IFN-gamma, TNF-alpha, IL-1beta, LPS) trat ein Maximum der HO-1 mRNA Expression erst nach 6 h ein, wobei ein signifikanter Zellschaden nach 12 h beobachtet wurde. Die HO-1 mRNA und Proteinexpression war nach Exposition von 6 h des Sauerstoffperoxides (H2O2, 200- 1000 µM) erhöht. Die HO-1 mRNA und Proteinexpression war nach S- nitrosoacetylpenicillamin (0.5 mM) Exposition, einem NO Donator, für 3-12 h verstärkt. Nach Cobalt-protoporphyrin (CoPP, 1µM) Exposition, einem potenten HO-1 Induktor, wurde eine erhöhte mRNA- und Proteinexpression beobachtet. Dass CoPP die HO-1 mRNA- und Proteinneusynthese induziert, konnte durch die selektive Blockade mit Actinomycin D und Cycloheximide bewiesen werden. Die Neusynthese konnte ebenfalls unter warmer und kalter Ischämie gezeigt werden. Hemin (10 µM), ein weiterer Induktor der HO-1, induzierte die HO-1 mRNA nach 3 h und das Protein nach 6 h. Die HO-1 Enzymaktivität wurde mittels Bilirubinbildung und Messung des Fe2+ Gehalts der Zellen bestimmt. Bei der Bilirubinbildung wurde die höchste Aktivität nach warmer Ischämie gemessen, gefolgt von kalter Ischämie, CM und der Kontrollgruppe. Die intrazelluläre Fe2+ Messung ergab ebenfalls die höchste Enzymaktivität nach warmer Ischämie. Die Vorbehandlung humaner Hepatozyten mit CoPP (1-50 µM) für 8 h, schützte die Zellen teilweise vor einer warmen und kalten Ischämie. Zusammenfassend zeigt diese Arbeit, dass die pharmakologische Induktion der HO-1 somit bei großen allgemeinchirurgischen Eingriffen, wie der Leberteilresektion oder der Transplantation, einen protektiven Effekt entfalten könnte. / Hepatic injury induced by ischemia/ reperfusion (I/R) and inflammation following surgeries or transplantations creates important clinical problems. In this study, the effect of inflammatory conditions such as cytokine/ endotoxin exposure (IL-1beta, IFN-gamma, TNF-alpha, LPS), warm and cold ischemia on HO-1 mRNA and protein, a member of heat shock proteins, was investigated. It was observed that IFN-gamma caused the highest HO-1 mRNA expression, followed by TNF-alpha, LPS and IL- 1beta. Each stimuli increased HO-1 mRNA expression after 0.5 h, peaked at 3 h and decreased after 6 h. Highest HO-1 protein expression was observed after 0.5 to 1 h of stimulation with IFN-gamma, which was followed by LPS, TNF-alpha and IL-1beta. The peak of HO-1 expression using all four stimuli (CM) was after 6 h. CM caused a significant increase in LDH and AST after 12 h. Warm and cold ischemia stimulated HO-1 mRNA expression in human hepatocytes at 0.5-1 h. HO-1 protein expression had its maximum between 0.5-6 h. Cellular damage measured as the release of LDH and AST was significant after 24 h. Mimicking oxydative stress, hepatocytes were exposed to 200-1000 µM H2O2 for 6 h which also showed an increased HO-1 mRNA and protein expression. HO-1 mRNA and protein expression revealed an increase after SNAP exposure at 3-12 h. Results with CoPP (10 µM), a potent inducer of HO- 1, displayed an increase in HO-1 mRNA and protein expression. It was proved, that CoPP induced new synthesis of mRNA and protein by its blocking agents such as actinomycin D and cycloheximide, respectively. Hemin (10 µM), another inducer of HO-1, triggered HO-1 mRNA expression after 3 h and protein expression after 6 h. The HO-1 enzyme activity was measured by bilirubin production after exposure to CM, as well as warm and cold ischemia. The highest enzyme activity was found after warm ischemia, followed by cold ischemia, CM and then by the control group. Fe2+ content of the cells, used as another method to judge HO-1 activity, confirmed our findings. Pre-treatment of human hepatocytes with different concentrations of CoPP (1-50 µM) protect cells against warm or cold ischemia. Therefore, we conclude that pharmacological induction of HO-1 may have therapeutic potential under inflammatory conditions such as seen during liver resection or liver transplantation.

INTRODUÇÃO: O tratamento padrão do Carcinoma Epidermoide do Ânus (CEDA) é a quimiorradioterapia ou radioterapia exclusiva. Os pacientes em que a terapêutica conservadora falha são tratados com Ressecção Abdominoperineal do Reto (RAP) de resgate. OBJETIVOS: Avaliar a sobrevivência com a RAP de resgate no CEDA, identificando os descritores favoráveis para sobrevivência maior e as características do agrupamento de variáveis relacionadas a descritores independentes de risco para mortalidade. MÉTODOS: Foram levantados dados através de 111 prontuários de portadores de CEDA, tratados inicialmente com quimiorradioterapia combinada ou radioterapia exclusiva e submetidos à RAP no período de outubro de 1982 a janeiro de 2011. RESULTADOS: A média de idade foi de 58 anos, 93 (83,8%) pacientes eram do sexo feminino e 80 (72,1%) da raça branca. O estadio cT3-4 compôs 66,7% e cN0 39,6% da casuística. A RAP foi indicada por persistência da doença (PD) em 61 (55%) pacientes e por recidiva (RD) em 50 (45%) pacientes. A ressecção cirúrgica sem resíduos tumorais (R0) foi realizada em 86 (77,5%) pacientes. O tempo médio de permanência hospitalar pós-operatório foi de 14 dias. A morbidade cirúrgica foi de 64,9%, sendo 78,3% dela devida às complicações da região perineal. Recidiva após RAP ocorreu em 68 (61,2%) pacientes, sendo 40 (58,8%) no primeiro ano do pós-operatório, a maioria locorregional (78%; 53/68). A mediana do seguimento foi de 16 meses (1,2-60 meses). Na análise multivariada, cirurgia R0 (p<0,001), invasão perineural vascular e/ou linfática negativa (p<0,0001) e linfonodo negativo na peça cirúrgica (p=0,03) foram estatisticamente associados à maior sobrevivência. CONCLUSÕES: A taxa de sobrevivência global estimada em cinco anos foi de 24,5%, com mediana de sobrevivência de 32 meses. O subgrupo de pacientes submetidos a cirurgias R0 em cujas peças cirúrgicas não foram encontrados invasão perineural vascular e/ou linfática nem linfonodos comprometidos apresentou taxa de sobrevivência estimada em três e cinco anos de 74,4% e 55,0%, respectivamente, com mediana de sobrevivência de 87 meses. Não houve diferença significativa entre pacientes que evoluíram com PD ou RD. Identificou-se a cirurgia R1-2, invasão perineural vascular e/ou linfática e linfonodo positivo na peça cirúrgica como fatores preditivos independentes de mortalidade / INTRODUCTION: The standard treatment for epidermoid carcinoma of the anus (ECA) is the association of chemotherapy (QT) and radiotherapy or exclusive radiotherapy (RT). When conservative treatment fails, patients are submitted to abdominoperineal resection of the rectum (APR). OBJECTIVES: To assess survival with salvage APR in ECA, identifying the most favorable independent descriptors for longer survival and the characteristics of the group of independent variables for mortality risk. METHODS: Data were collected from the medical records of 111 patients with ECA, initially treated with QT/RT or exclusive RT and later submitted to APR, from October 1982 to January 2011. RESULTS: Their mean age was 58 years, 93 (83.8%) patients were female, and 80 (72.1%) were Caucasian. The cT3-4 stage represented 66.7% of the case series and cN0, 39.6%. The APR was indicated due to persistence of disease (PD) in 61 (55%) patients and recurrence of disease (RD) in 50 (45%) patients. Surgical resection without residual tumor (R0) was performed in 86 (77.5%) patients. The mean postoperative hospital length of stay was 14 days. Surgical morbidity was 64.9%, of which, 78.3% related to perineal infection. Recurrence after APR was observed in 68 (61.2%) patients, 40 (58,8%; 40/68) of whom in the first postoperative year, mostly locoregional (78%; 53/68). The median follow-up was 16 months (1.2 - 60 months). On multivariate analysis, R0 surgery (p<0.001), absence of perineural and/or lymphovascular invasion (p<0.0001) and negative lymph node status in the surgical specimen (p=0.03) were associated with increased survival. CONCLUSION: Estimated overall survival rate in 5 years was 24.5%, with median survival of 32 months. There was no significant difference in survival after APR in patients who had PD or RD after conservative treatment. The subgroup of patients who underwent R0 and whose surgical specimen showed absence perineural and/or lymphovascular invasion and negative lymph nodes had an estimated survival rate at 3 and 5 years of 74,4% and 55,0%, respectively, with a median survival of 87 months. The following were identified as independent predictors of mortality: R1-2 surgery; presence perineural and/or lymphovascular invasion; and positive lymph node in the surgical specimen

Les cassures double brin de l’ADN (CDB) sont des lésions qui peuvent conduire à des réarrangements génétiques. Deux voies sont impliquées dans la réparation de ces dommages: la recombinaison homologue (HR) et la ligature d’extrémités nonhomologues (NHEJ).Au laboratoire un substrat intrachromosomique permettant de mesurer l’efficacité et la fidélité du NHEJ à été mis en place (Guirouilh-Barbat 2004). Cette approche a permis de démontrer l’existence d’une voie alternative à KU qui utilise des microhomologies présentes de part et d’autre de la cassure - le NHEJ alternatif (Guirouilh-Barbat 2004, Guirouilh-Barbat et Rass 2007). Les travaux de ma thèse consistent à caractériser les principaux acteurs de cette voie. En absence de KU, cette voie alternative du NHEJ, s'initierait tout d’abord parla résection d'extrémités d’ADN non protégées. Nous avons montré que l’activité nucléasique de MRE11 est nécessaire à ce mécanisme. La surexpression de MRE11 conduit à une stimulation du NHEJ, contrairement à l’extinction de la protéine par siRNA, résultant en une baisse de son efficacité de deux fois. Nos résultats montrent également que les protéines RAD50 et CtIP agissent dans la même voie que MRE11. De plus, dans les cellules déficientes pour XRCC4, la MIRIN – un inhibiteur du complexe MRN - conduit à une chute de l'efficacité de la réparation, démontrant le rôle de MRE11 dans la voie alternative du NHEJ. Nous avons aussi montré que MRE11 peut agir de manière dépendante et indépendante de la kinase ATM (Rass et Grabarz, Nat Struct Mol Biol 2009). L'initiation de la résection de la cassure doit être ensuite poursuivie par une dégradation plus importante de l'ADN qui est assuré par les protéines Exo1 et Sgs1/Dna2 chez la levure. Chez les mammifères, des études in vitro suggèrent un modèle similaire à deux étapes. Nous avons choisi de nous intéresser au rôle de la protéine BLM, qui est l’un des homologues humains de la RecQ hélicase Sgs1, dans la résection. Nos expériences montrent que l’absence de BLM diminue l’efficacité du NHEJ. De plus, l’extinction de BLM conduit à une augmentation d’évènements infidèles lors de la réparation par NHEJ et l’apparition d’évènements de résection de grande taille (>200nt). Ceci suggère que BLM protège contre de longues résections lors de la mise en place du NHEJ alternatif. De manière cohérente, BLM est impliquée dans la protection contre la résection dépendante de CtIP lors des étapes précoces de la recombinaison homologue. En conclusion, nos résultats montrent un rôle prédominant de BLM dans la protection contre un excès de résection médiée par CtIP. BLM interagit avec 53BP1 aux sites de dommages de manière dépendante d’ATM afin de réguler le processus de résection, en contrecarrant l’action de BRCA1. Ceci souligne à nouveau le rôle essentiel de BLM dans la protection contre la résection et la favorisation de la conversion génique sans crossing-over, ce qui est primordial pour le maintien de la stabilité du génome. / DNA double strand breaks (DSBs) are highly cytotoxic lesions, which can lead to genetic rearrangements. Two pathways are responsible for repairing these lesions : homologous recombination (HR) and non homologous end joining (NHEJ). In our laboratory, an intrachromosomal substrate has been established in order to measure the efficiency and the fidelity of NHEJ in living cells (Guirouilh-Barbat 2004). This approach led us to identify a KU-independent alternative pathway, which uses microhomologies in the proximity of the junction to accomplish repair – the alternative NHEJ (Guirouilh-Barbat 2004, Guirouilh-Barbat et Rass 2007). The goal of my thesis consisted in identifying and characterising major actors of this pathway. In the absence of KU, alternative NHEJ would be initiated by ssDNA resection of damaged ends. We showed that the nuclease activity of MRE11 is necessary for this mechanism. MRE11 overexpression leads to a two fold stimulation of NHEJ efficiency, while the extinction of MRE11 by siRNA results in a two fold decrease. Our results demonstrate that the proteins RAD50 and CtIP act in the same pathway as MRE11. Moreover, in cells deficient for XRCC4, MIRIN – an inhibitor of the MRN complex – leads to a decrease in repair efficiency, implicating MRE11 in alternative NHEJ. We also showed that MRE11 can act in an ATM-dependent and independent manner (Rass et Grabarz Nat Struct Mol Biol 2009). The initiation of break resection needs to be pursued by a more extensive degradation of DNA, which is accomplished in yeast by the proteins Exo1 and Sgs1/Dna2. In human cells, in vitro studies have recently proposed a similar model of a two-step break resection. We chose to elucidate the role of one of the human homologs of Sgs1 – the RecQ helicase BLM – in the resection process. Our experiments show, that he absence of BLM decreases the efficiency of end joining by NHEJ, accompanied by an increase in error-prone events, especially long-range deletions (>200nt). This suggests that BLM protects against extensive resection during alternative NHEJ. Furthermore, BLM is implicated in the protection against CtIP-dependent resection at the initiation of HR. In conclusion, our results show a major role of BLM in protecting against an excess of resection, mediated by the MRN cofactor – CtIP. BLM interacts with 53BP1 at sites of damage, in an ATM-dependent manner, in order to regulate the resection process and counteract BRCA1 activity. This underlines the novel role of BLM in the protection against resection and favouring gene conversion events without crossing-over, which is substantial for maintaining genomic integrity.