Non-small cell lung cancer (NSCLC) is the deadliest form of lung cancer and has a poor prognosis due to its high rate of metastasis. Notably, metastasis is one of the leading causes of death among cancer patients. Despite the clinical importance, the cellular and molecular mechanisms that govern the initiation, establishment and progression of metastasis remain unclear. Moreover, knowledge gained on metastatic process was largely based on cultured or in vitro manipulated cells that were reintroduced into immune-compromised recipient mice. In the present study, a spontaneous metastasis mouse model for NSCLC was generated with a heritable fluorescent tag (DsRed) driven by CAG (combination of cytomegalovirus early enhancing element and chicken beta actin) promoter in alveolar type II cells (SpC-rtTA/TetO-Cre/LSL-DsRed). This approach is essential, keeping in mind the reprogramming nature of Myc oncogene (Rapp et al, 2009). Such genetic lineage tracing approach not only allowed us to monitor molecular and cellular changes during development of primary tumor but also led us to identify the different stages of secondary tumor development in distant organs. Upon combined expression of oncogenic C Raf-BXB and c-Myc (MYC-BXB-DsRed) in lung alveolar type II epithelial cells, macroscopic lung tumors arose comprising of both cuboidal and columnal cellular features. C Raf-BXB induced tumors (CRAF-DsRed) exhibit cuboidal morphology and is non-metastatic whereas Myc-BXB induced lung tumors (Myc-BXB-DsRed) present cuboidal-columnar cellular features and is able to undergo metastasis mainly in liver. Surprisingly, cystic lesions which were negative for SpC (Surfactant protein C) and CCSP (Clara cell secretory protein), strongly expressed DsRed proteins indicating its origin from lung alveolar type II cells. Moreover, early lung progenitor markers such as GATA4 (GATA-binding protein 4) and TTF1 (Thyroid Transcription Factor 1) were still expressed in these early cystic lesions suggesting metastasis as a faulty recapitulation of ontogeny (Rapp et al, 2008). Interestingly, mixed cystic lesions and metastatic tumors contained DsRed and SpC positive cells. These results demonstrate secondary tumor progression from cystic, mixed cystic to malignant transformation. Our results shed tremendous light on reprogramming of metastasizing cells during secondary tumor development. Moreover, such fluorescent tagged metastatic mice model can also be used to track the migration ability of metastatic cancer cell to different organs and its potential to differentiate into other cell types such as blood vessel or stromal cell within the primary tumor. / Das nichtkleinzellige Lungenkarzinom (‚non-small cell lung cancer‘, NSCLC) ist die tödlichste Form des Lungenkrebses mit schlechter Prognose aufgrund hoher Metastasierungsneigung. Metastasierung ist eine der häufigsten Todesursachen bei Krebspatienten. Trotz ihrer klinischen Bedeutung sind die zellulären und molekularen Mechanismen der Entstehung, Etablierung und Progression von Metastasen weiterhin unklar. Darüberhinaus basiert das bisherige Wissen über den Metastasierungsprozess überwiegend auf Zellen, die entweder in vitro kultiviert oder manipuliert und danach in immundefiziente Mäuse rückübertragen wurden.In der vorliegenden Studie wurde ein Mausmodell mit erblichem Fluoreszenzmarker (DsRed) zur spontanen Metastasierung bei NSCLC entwickelt, der durch den CAG-Promotor (‚combination of cytomegalovirus early enhancing element and chicken beta actin‘) in alveolären Typ II-Zellen (SpC-rtTA/TetO-Cre/LSL-DsRed) exprimiert wird. Aufgrund des Reprogrammierungscharakters des Myc-Onkogens war dieser Ansatz essentiell (Rapp et al, 2009). Die Markierung der Zellpopulation auf genetischem Weg erlaubte uns zum einen, die molekularen und zellulären Veränderungen während der Bildung des Primärtumors zu verfolgen, zum anderen konnte so die Entwicklung von Sekundärtumoren unterschiedlicher Stadien in entfernten Organen identifiziert werden. Bei kombinierter Expression von onkogenem C Raf-BXB und c-Myc (MYC-BXB-DsRed) in Lungenalveolar-Epithelzellen vom Typ II entstanden makroskopische Tumore in der Lunge, die auf zellulärer Ebene sowohl kuboidalen als auch kolumnaren Charakter aufwiesen und Metastasen, vorwiegend in der Leber, ausbildeten. Durch C Raf-BXB (CRAF-DsRed) induzierte Tumore erschienen morphologisch als kuboidal ohne Metastasierungsneigung. Überraschenderweise exprimierten zystische Läsionen in der Leber, obwohl negativ für SpC (‚surfactant protein C‘) und CCSP (‚Clara cell secretory protein‘), als Kennzeichen für deren Ursprung aus Lungenalveolarzellen Typ II stark das DsRed-Protein. Darüberhinaus sind in den frühen zystischen Läsionen Marker für frühe Lungenvorläuferzellen wie GATA4 (‚GATA-binding protein 4‘) und TTF1 (‚thyroid transcription factor 1‘) weiterhin exprimiert, was auf den Metastasierungsprozess als gestörte Rekapitulation der Ontogenese hindeutet (Rapp et al, 2008). Metastatische Tumore und Mischformen zu zystischen Läsionen enthielten DsRed- und SpC-positive Zellpopulationen. Diese Ergebnisse weisen in Sekundärtumoren den Übergang von zystischer Läsion zur Mischform mit zystischem Anteil und zur malignen Transformation nach.Unsere Resultate werfen ein neues Licht auf Reprogrammierungsprozesse metastasierender Zellen bei der Bildung von Sekundärtumoren. Das vorgestellte fluoreszenzmarkierte und metastasenbildende Mausmodell kann zum einen zur Untersuchung der Migrationsfähigkeit metastasierender Krebszellen in unterschiedliche Organe verwendet werden. Darüberhinaus ermöglicht dieses Mausmodell die Untersuchung des Differenzierungspotenzials markierter Zellen in andere Zelltypen wie Blutgefäße oder Stromazellen im Primärtumor.

In der Nachsorge des Medulloblastoms wird standardmäßig auf die Bildgebung mittels Magnetresonanztomographie zurück gegriffen. Da die Erkrankung vor allem entlang der Liquorwege in Form einer kranialen oder spinalen Meningeose metastasiert, wurde anhand Daten der Therapieoptimierungsstudie "HIT 2000" verglichen, welche Lokalisation am häufigsten betroffen ist. Es zeigte sich, dass zu einem hohen Prozentanteil vor allem eine kombinierte Meningeose im Rezidiv oder Progress auftritt, gefolgt von einer kranialen Metastasierung. Dennoch gibt es eine Gruppe an Patienten, die eine isolierte spinale Meningeose entwickeln. / In the follow-up of patients with medulloblastoma, the MRI has been established as standard procedure. The tumor most often spreads via the cerebrospinal fluid as cranial oder spinal meningeoses. We compared the frequency of progress or relapse in children undergoing treatment according to the "HIT 2000" protocol. There could be shown, that the most common localization of meningeosis is both cranial and spinal, followed by isolated cranial meningeosis. Nevertheless there is a group of patients, developing an isolated spinal meningeosis.

Hintergrund und Zielsetzung: Eine zunehmende Anzahl von Studien belegt, dass Patienten mit pulmonaler Metastasierung extrathorakaler Tumore von einer chirurgischen Sanierung profitieren. Dabei werden bevorzugt nicht anatomische, Gewebe sparende Resektionen der suspekten Herde durchgeführt. Ziel dieser Arbeit war es, die Eigenschaften der laserchirurgischen Technik bei atypischen Keilresektionen zu analysieren sowie Langzeitergebnisse und Vor- oder Nachteile bezüglich Überleben und Morbidität gegenüber konventionellen Techniken zu untersuchen. Methoden Im Zeitraum von Juni 2006 bis Dezember 2010 wurden an der Universitätsklinik Würzburg mit Hilfe eines Martin® Nd:YAG MY40 1.3 Lasers 115 atypische Keilresektionen bei 82 Patienten mit pulmonalen Metastasen durchgeführt. Insgesamt wurden 507 suspekte Rundherde entfernt, im Durchschnitt 4 Herde pro Patient. Retrospektiv wurden die Morbidität und die Komplikationsraten in diesem Kollektiv untersucht sowie die Überlebenszeitanalyse anhand der Kaplan-Meier-Methode durchgeführt. Der Beobachtungszeitraum betrug 3 bis 7 Jahre. Ergebnisse Eine komplette Resektion (Resektionsgrad R0) wurde in 86,7% der Fälle pathologisch bestätigt, bei 9,9% der Patienten zeigte sich ein maligner Lymphknotenbefall. Die 1-, 3- und 5-Jahres Überlebensraten im Gesamtkollektiv betrugen 78,9%, 62,7% und 46,3%, wobei das Überleben nach kompletter Resektion deutlich besser war als nach R1- oder R2- Resektion (54,3% vs 16,7% nach 5 Jahren). Prognostisch günstig zeigte sich das Vorhandensein einer singulären Metastase im Vergleich zu einem multiplen Befall. Es gab keinen Überlebensvorteil bei Patienten mit 2-3 oder 4-10 Metastasen (31% vs 37% nach 5 Jahren). Die Komplikationsrate war mit 14,6% ähnlich wie bei konventionellen Techniken ohne schwerwiegende Vorfälle. Postoperativ schätzten nachsorgende Fachärzte die Lebensqualität und Lungenfunktion der Patienten zum Großteil als gut bis sehr gut ein. Zusammenfassung Die Laserchirurgie zeigt sich als schonende und komplikationsarme, dabei präzise und effektive Technik bei der Entfernung von Lungenmetastasen. Das 5–Jahres–Überleben in Würzburg war im Vergleich zu historischen Kollektiven von Patienten nach atypischer Keilresektion in konventioneller Staplertechnik signifikant höher. Vor allem Patienten mit multiplem oder rezidivierendem Befall profitieren von der Lasertechnik. / Objective: Recent studies confirm, that patients suffering from extrathoracic tumors with metastasis to the lung benefit from a surgical therapy, preferably in the form of non-anatomical pulmonary wedge resections. The aim of this study was to analyse the benefits and disadvantages of the increasingly popular lasersurgical technique and to examine, if any impact on survival can be noted in comparison to conventional techniques like resection with a surgical stapler. Patients and methods: Between June 2006 and Dezember 2010, 82 patients underwent a total of 115 pulmonary metastasectomies at the University clinic of Würzburg. All resections were performed using a Martin® Nd:YAG MY40 1.3 laser. A total of 507 nodules has been removed, with an average of 4 nodules per patient. In a retrospective analysis the morbdity and complication rates have been investigated, as well as the overall survival in comparison to historical collectives. The follow-up period ranged between 3 to 7 years. Results: Complete resections have been achieved in 86,7%, the pathological examination comfirmed lymph node involvement in 9,9%. The 1-, 3- and 5-years Kaplan-Meier survival rates (Kaplan-Meier) were 78,9%, 62,7% and 46,3% respectivly. The 5-year survival after R0-resection was significantly higher than after incomplete resections (54,3% vs 16,7%). The presence of singular metastasis was found to be an independent prognostic factor. No difference in survival has been noted comparing patients with 2-3 malign lesions to patients with 4-10 lesions (31% vs 37% after 5 years). Considering the total complication rate of 14,6% laser surgery seems comparable to stapler resection in that regard. No major complications have occured. The postoperative quality of living and lung function were considered „good“ or „very good“ in the majority of cases. Conclusion: Laser surgery seems to be a tissue sparing, accurate and effective resection technique for pulmonary metastasis with less morbidity. The 5-year survival in Würzburg was significantly higher when compared to other collectives consisting of patients resected with the stapler. Especially patients with multiple lesions or recurrent disease benefit from laser surgery.

Würzburg, Univ., Diss., 2008. / Zsfassung in dt. Sprache.

Regensburg, Univ., Diss., 2005.

Techn. Universiẗat, Diss., 2005--München.

Made available in DSpace on 2014-06-11T19:32:14Z (GMT). No. of bitstreams: 0 Previous issue date: 2009-02-01Bitstream added on 2014-06-13T19:02:40Z : No. of bitstreams: 1 paiva_ghrg_dr_botib.pdf: 1701322 bytes, checksum: d1fa5b5c562a2a6ce8ad0d14ab948d4a (MD5) / Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) / O câncer de próstata (CaP) é a neoplasia mais comumente diagnosticada entre homens no ocidente. Embora tratamentos efetivos para a doença localizada estejam disponíveis atualmente, não há terapia curativa para tumores metastáticos. Além disso, os marcadores diagnósticos utilizados na clínica não conseguem discriminar totalmente a evolução diferencial da doença. Desta forma, o conhecimento das diferenças biológicas entre tumores primários confinados ao órgão e metástases é essencial para o desenvolvimento de novos marcadores e identificação de alvos terapêuticos. Neste estudo a análise baseada na metodologia de HR-CGH cromossômico foi realizada para identificar alterações de ganhos e perdas genômicas em três grupos de amostras: o grupo I, que compreende amostras pareadas de tumor primário e respectivas metástases (11 casos); o grupo II, constituído de pacientes que apresentaram seguimento clínico favorável por mais de 10 anos (5 casos); e o grupo III, constituído por diferentes biópsias do mesmo paciente (5 pacientes com 2 biópsias cada). As amostras foram microdissecadas (amostras a fresco: a partir de lâminas de referência; em blocos de parafina: a laser) e após a obtenção de DNA foram amplificadas (amostras de arquivo: PCR-SCOMP) ou marcadas por nick-translation para a realização de HR-CGH. Os resultados de HR-CGH foram comparados com os dados obtidos da análise de CGH-array num subgrupo de amostras e revelaram concordâncias significativas. Os resultados obtidos na presente investigação revelaram perdas dos cromossomos 1p, 2, 3q, 4p, 5q, 7, 8, 9q, 10q, 11q, 12q, 14q, 15q, 16q, 17q, 18q, 19, 20q e 22q em 80% dos casos avaliados. Além disso, perdas em 17q11.2-25, por exemplo, foram detectadas exclusivamente nos tumores do grupo I e nas suas metástases, e não nos tumores do grupo II, sugerindo que esta alteração deve ser importante... / Prostate cancer (PCa) is the most commonly diagnosed non-cutaneous malignancy and the second leading cause of cancer mortality in men from Occident. Although effective treatments for the localized disease are available, there is no efficient therapy for metastatic tumors. Additionally, clinical diagnostic markers are not able to completely discriminate the differential evolution of the disease. The knowledge of biological differences between localized primary tumors and metastasis can establish new molecular markers and therapeutic targets. In this study, an analysis based on HR-CGH methodology was performed to identify imbalances genomic in three groups of samples: group I, paired samples of primary tumors and its metastasis (11 cases); group II, patients that exhibited favorable follow-up over 10 years (5 cases); and group III, different biopsies from the same patient (5 patients with 2 biopsies each). The tumor samples were submitted to microdissection procedures (fresh samples: from reference slides; paraffin embedded samples: laser), DNA extracted and amplified (archive sample: PCR-SCOMP) or labeled by nick-translation to HR-CGH. The HRCGH results were compared with data obtained from CGH-array analysis of a subgroup of samples and revealed significant concordances. In the present investigation, there were observed losses on chromosomes 1p, 2, 3q, 4p, 5q, 7, 8, 9q, 10q, 11q, 12q, 14q, 15q, 16q, 17q, 18q, 19, 20q and 22q in 80% of the cases. Losses in 17q11.2-25, for instance, were detected exclusively in tumor from group I and its metastasis, but were not found in tumors from group II, suggesting that this alteration must be important in the progression of the disease. Five genes were selected after the comparison between the HR-CGH and CGH-array data. The tumor suppressor genes ARID1A, MTSS1, NME1 and S100A4 and TOP2A (oncogenes) were evaluated by quantitative real time... (Complete abstract click electronic access below)

Orientador : Profª. Drª. Giseli Klassen / Coorientador : Profª. Edneia A. S. R. Cavalieri / Tese (doutorado) - Universidade Federal do Paraná, Setor de Ciências Biológicas, Programa de Pós-Graduação em Ciencias Biológicas (Microbiologia, Parasitologia e Patologia Básica). Defesa: Curitiba, 26/08/2016 / Inclui referências : f. 71-86 / Área de concentração: Patologia / Linha de pesquisa: Epigenética e câncer / Resumo: As metástases são a causa das mortes por câncer em 90% dos casos. No processo de metástases a destruição ou degradação da matriz extracelular é muito importante para o deslocamento das células tumorais malignas. Este processo é mediado por diversas enzimas, destacando-se a gelatinase B ou MMP-9. A epigenética estuda mecanismos de regulação da expressão gênica utilizando a metilação do DNA (em citosinas adjacentes a guaninas) e modificações pós-traducionais de histonas como principais mediadores. As ilhas de CpGs ao longo do promotor podem ser hipermetiladas e assim promover o silenciamento gênico e vice-versa. A partir deste conhecimento vem sendo utilizados diversos análogos de citosina a fim de inibir o processo de metilação de DNA. Nesse sentido esta em avançado estudo clínico o uso do 5-aza-2'- deoxicitosina (5-azadC) ou decitabine em alguns tipos de leucemias e doenças mielodisplásicas e provável inicio de utilização em tumores sólidos. Neste estudo o objetivo foi avaliar a expressão do gene MMP9 em linhagens de câncer de mama e com esses dados estudar o efeito da metilação do DNA e modificações de histonas no promotor e corpo do gene com e sem tratamento com decitabine. Para isso clonamos e sequenciamos uma região contendo CpGs da região promotora do gene MMP9 e também e ilhas de CpG no corpo do gene utilizando linhagens tumorais, PMC42, HeLa, MCF7 e MDA-MB-436. As linhagens MCF7 e MDA-MB-436 expressam baixos níveis de MMP9. Apos o tratamento destas 5- azadC foi observado aumento da expressão do gene e proteína MMP-9. O sequenciamento de CpGs na região promotora revelou que a metilação do DNA regula a expressão deste gene nas linhagens tumorais. Além disso a análise em amostras tumorais de pacientes que expressam MMP-9 também possuem estes CpGs desmetilados. A região intragênica contém 4 ilhas de CpG que foram clonadas em 2 fragmentos e denominadas CGI1 e CGI2. A CGI1 é altamente metiladas com ou sem tratamento com decitabine nas linhagens tumorais. Por outro lado a CGI2 apresentou alguns CpGs nas posições 12 a 30 que estavam metilados nas linhagens tumorais sem tratamento com decitabine, e que são desmetiladas após o tratamento. Novamente os resultados de contrapartida com amostras de tumores primários, estes mesmos CpGs encontraram-se desmetilados nos tumores mais agressivos e com presença de MMP-9 na imunohistoquímica. Afim de se avaliar o provável envolvimento de modificações de histonas foi realizada a imunoprecipitação de cromatina para as marcas de cromatina para abertura H3K4me3 e fechamento H3K27me3. Utilizando a linhagem MCF7 observou-se que após o tratamento com decitabine houve o enriquecimento da marca de abertura na região promotora onde se ligam os fatores de transcrição AP1 e NFkB. Além disso os CpGs 12-30 da CGI2 também apresentaram aumento da marca de abertura. Em conjunto esses resultados mostram um provável novo mecanismo de regulação da expressão gênica através de CpGs localizados em íntron no gene MMP9. Esses resultados são importantes no contexto do entendimento de mecanismos de expressão de MMP-9 em câncer de mama e também para o estudo de possível efeito de ativação de metástases com o uso do medicamento decitabine. / Abstract: Metastases are the cause of cancer deaths in 90% of cases. In the process of metastasis destruction or degradation of extracellular matrix it is important for the displacement of malignant tumor cells. This process is mediated by several enzymes, especially B-gelatinase or MMP-9. Epigenetic studies of regulatory mechanisms of gene expression using DNA methylation (adjacent cytosine to guanine) and post-translational modifications of histones as major mediators. The CpG islands along the promoter may be hypermethylated and thus promote gene silencing and vice versa. From this knowledge different cytosine analogues are used to inhibit the DNA methylation process. Accordingly this in advanced clinical study using 5-aza-2'-deoxicitosine (5-azadC) or decitabine in some types of leukemias and myelodysplastic diseases and probable beginning of use in solid tumors. In this study our goal was to evaluate the expression of MMP9 gene in breast cancer cell lines and study the effect of DNA methylation and histone modifications in the promoter gene and intragenic region with and without treatment with decitabine. To this we have cloned and sequenced a region containing CpGs of the MMP9 promoter region and CpG islands in the gene's body using tumor cell lines, PMC42, HeLa, MCF7 and MDA-MB-436. The lines MCF7 and MDA-MB-436 expressed low levels of MMP9. After treatment with 5-azadC was observed an increase in the gene expression and MMP-9 protein. The sequencing CpGs in the promoter region revealed that the DNA methylation regulates the expression of this gene in tumor cell lines. Further analysis of tumor samples from patients expressing MMP-9 also have these demethylated CpGs. The MMP9 intragenic region contains 4 CpG islands that were cloned in two fragments and called CGI1 and CGI2. The CGI1 was highly methylated with or without treatment with decitabine in tumor cell lines. On the other hand CGI2 have showed some CpGs in positions 12 to 30 that were methylated in tumor cell lines without treatment with decitabine, and are demethylated following treatment. Again counterpart results with primary tumor samples, the same CpG were demethylated in more aggressive tumors of MMP-9 positive in immunohistochemistry. In order to evaluate the probable involvement of histone modifications was performed chromatin immunoprecipitation to chromatin marks for H3K4me3 H3K27me3 opening and closing respectivelly. Using the MCF7 it was observed that after treatment with decitabine was enriching the opening tag in the promoter region which bind transcription factors NFkB and AP1. Additionally the CpG 12-30 of CGI2 also increased too. Together these results showed a possible new mechanism for regulation of gene expression through CpGs located in intron in MMP9 gene. These results are important in the context of understanding of MMP-9 expression mechanisms in breast cancer and also for the study of possible metastases activation with the use of decitabine drug.

Made available in DSpace on 2014-06-11T19:22:13Z (GMT). No. of bitstreams: 0 Previous issue date: 2010-08-26Bitstream added on 2014-06-13T19:27:12Z : No. of bitstreams: 1 batista_rp_me_botfm.pdf: 1066551 bytes, checksum: de54675f1bba1a1eee717c9815d050aa (MD5) / A alta incidência mundial do câncer o coloca como um grande problema de saúde pública, tanto em países desenvolvidos como em desenvolvimento. Suas particularidades, no que tange a malignidade, geram grandes problemas sociais e psicológicos nos indivíduos acometidos. O câncer é responsável por mais de 6 milhões de óbitos por ano, chegando a 12% de todas as causas no mundo. Grande número de pacientes já apresenta metástases à distância e em linfonodos adjacentes ao tumor no diagnóstico inicial. Assim como as metástases hepáticas, a disseminação linfonodal das neoplasias malignas entra como um dos principais fatores de prognóstico e recidiva das neoplasias. A ressecção cirúrgica linfonodal é considerada a principal modalidade terapêutica curativa, porém, em algumas situações, reveste-se de fatores limitantes, tais como número e localização dos linfonodos comprometidos e principalmente a aderência a órgãos e estruturas adjacentes. Ao considerar tais dificuldades e características da terapêutica das metástases linfonodais, novas opções de tratamento necessitam ser desenvolvidas. Para que estas novas opções terapêuticas tenham aplicabilidade é de se esperar que tenham uma boa taxa de eficácia, um baixo custo, pouca freqüência de efeitos colaterais e que sejam de fácil execução. Neste sentido, seguindo a linha de pesquisa do Laboratório de Cirurgia Experimental da Faculdade de Medicina de Botucatu- FMB/UNESP surgiu a ideia de avaliação dos efeitos do ácido acetilsalicílico em linfonodos normais em animais de experimentação para posterior embasamento e uso em linfonodos acometidos por tumor. No presente trabalho foram utilizadas as soluções bicarbonatadas de ácido acetilsalicílico a 10% e 20% injetadas em linfonodos mesentéricos de coelhos sadios, sendo seus efeitos avaliados em 24 horas e também em 7 dias. Nos grupos avaliados... / The high incidence of cancer worldwide poses as a great public health problem both in developed and developing countries. Its peculiarities with respect to malignancy generate great social and psychological problems for affected individuals. Cancer is responsible for more than six million deaths per year reaching 12% of all causes in the world. A large number of patients already have distant metastases in lymph nodes adjacent to the tumor at initial diagnosis. As well as liver metastases, the lymph node spread of malignant neoplasm comes in as one of the major factors of prognostic and recurrence of neoplasm. The lymph node resection surgery is considered the main type of treatment for cure but in some situations it presents limiting factors such as number and location of lymph nodes involved and especially the adherence to adjacent organs and structures. Considering such difficulties and therapeutic characteristics of lymph node metastases, new treatment options need to be developed. In order to have applicability it’s expected that these new treatment options have effectiveness, low cost, low frequency of side effects and they should be easily executed. Following the line of research at the Laboratory of Experimental Surgery of Botucatu School of Medicine FMB / UNESP, it came up the idea of evaluating the effects of aspirin in normal lymph nodes in experimental animals on a trial basis for later use in lymph nodes affected by tumor. The present work used bicarbonate acetylsalicylic acid solution at 10% and 20% injected into lymph nodes of healthy rabbits and had its effects evaluated at 24 hours and at 7 days. In the groups evaluated at 24 hours it was observed extensive necrosis and hemorrhage, a significant increase in apoptosis throughout the lymph node with medullary sinuses enlargement and an increase in germinal centers. In the groups evaluated at 7 days of solution... (Complete abstract click electronic access below)

Orientador: Rogério Saad Hossne / Banca: Fábio Vieira Teixeira / Banca: Juan Carlos Llanos / Resumo: A alta incidência mundial do câncer o coloca como um grande problema de saúde pública, tanto em países desenvolvidos como em desenvolvimento. Suas particularidades, no que tange a malignidade, geram grandes problemas sociais e psicológicos nos indivíduos acometidos. O câncer é responsável por mais de 6 milhões de óbitos por ano, chegando a 12% de todas as causas no mundo. Grande número de pacientes já apresenta metástases à distância e em linfonodos adjacentes ao tumor no diagnóstico inicial. Assim como as metástases hepáticas, a disseminação linfonodal das neoplasias malignas entra como um dos principais fatores de prognóstico e recidiva das neoplasias. A ressecção cirúrgica linfonodal é considerada a principal modalidade terapêutica curativa, porém, em algumas situações, reveste-se de fatores limitantes, tais como número e localização dos linfonodos comprometidos e principalmente a aderência a órgãos e estruturas adjacentes. Ao considerar tais dificuldades e características da terapêutica das metástases linfonodais, novas opções de tratamento necessitam ser desenvolvidas. Para que estas novas opções terapêuticas tenham aplicabilidade é de se esperar que tenham uma boa taxa de eficácia, um baixo custo, pouca freqüência de efeitos colaterais e que sejam de fácil execução. Neste sentido, seguindo a linha de pesquisa do Laboratório de Cirurgia Experimental da Faculdade de Medicina de Botucatu- FMB/UNESP surgiu a ideia de avaliação dos efeitos do ácido acetilsalicílico em linfonodos normais em animais de experimentação para posterior embasamento e uso em linfonodos acometidos por tumor. No presente trabalho foram utilizadas as soluções bicarbonatadas de ácido acetilsalicílico a 10% e 20% injetadas em linfonodos mesentéricos de coelhos sadios, sendo seus efeitos avaliados em 24 horas e também em 7 dias. Nos grupos avaliados... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: The high incidence of cancer worldwide poses as a great public health problem both in developed and developing countries. Its peculiarities with respect to malignancy generate great social and psychological problems for affected individuals. Cancer is responsible for more than six million deaths per year reaching 12% of all causes in the world. A large number of patients already have distant metastases in lymph nodes adjacent to the tumor at initial diagnosis. As well as liver metastases, the lymph node spread of malignant neoplasm comes in as one of the major factors of prognostic and recurrence of neoplasm. The lymph node resection surgery is considered the main type of treatment for cure but in some situations it presents limiting factors such as number and location of lymph nodes involved and especially the adherence to adjacent organs and structures. Considering such difficulties and therapeutic characteristics of lymph node metastases, new treatment options need to be developed. In order to have applicability it's expected that these new treatment options have effectiveness, low cost, low frequency of side effects and they should be easily executed. Following the line of research at the Laboratory of Experimental Surgery of Botucatu School of Medicine FMB / UNESP, it came up the idea of evaluating the effects of aspirin in normal lymph nodes in experimental animals on a trial basis for later use in lymph nodes affected by tumor. The present work used bicarbonate acetylsalicylic acid solution at 10% and 20% injected into lymph nodes of healthy rabbits and had its effects evaluated at 24 hours and at 7 days. In the groups evaluated at 24 hours it was observed extensive necrosis and hemorrhage, a significant increase in apoptosis throughout the lymph node with medullary sinuses enlargement and an increase in germinal centers. In the groups evaluated at 7 days of solution... (Complete abstract click electronic access below) / Mestre