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Monzón, Gonzales Janneth Silvana. "Tumores del intestino delgado: Perfil Clínico-Patológico, Enero 2003 a Marzo 2005, Hospital Edgardo Rebagliati Martins." Bachelor's thesis, Universidad Ricardo Palma, 2006. http://cybertesis.urp.edu.pe/handle/urp/199.
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El objetivo principal de este trabajo es definir las características clínicas de los tumores de intestino delgado según su tipo.
Se revisaron retrospectivamente los archivos de anatomía patológica y los archivos de historias clínicas del Hospital Edgardo Rebagliati Martins, eligiendo los casos con diagnóstico de tumores benignos y malignos del intestino delgado, correspondientes al período de enero de 2003 a marzo de 2005. De ellos se seleccionó un total de 107 casos que cumplían con los criterios de inclusión y se estudió su historial clínico para llenar la ficha de recolección de datos.
De la observación de los 107 casos seleccionados surge como categoría relevante el predominio del tumor de tipo histológico maligno, siendo el más frecuente el adenocarcinoma (68,9%), seguido del linfoma (21,60%). Entre los tumores benignos el más recurrente resulta ser el pólipo del duodeno (46,15%).
La edad promedio de aparición de la enfermedad fue a partir de la sexta década de vida y, en cuanto a las manifestaciones clínicas, el dolor abdominal fue el predominante en todos los tipos de tumor encontrados.
Con este trabajo demostramos que la disminución de peso corporal y el dolor abdominal son manifestaciones importantes para el diagnóstico. Frente a todo paciente de 60 años o más con disminución de peso, recurrente dolor abdominal y sin otra molestia aparente debe pensarse en tumor de intestino delgado.
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Swanson, Kristin Rae. "Mathematical modeling of the growth and control of tumors /." Thesis, Connect to this title online; UW restricted, 1999. http://hdl.handle.net/1773/6764.
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Cuny, Thomas. "New regulatory mechanisms in the growth of endocrine tumors : digestive neuroendocrine tumors, pitiutary adenomas." Thesis, Aix-Marseille, 2016. http://www.theses.fr/2016AIXM5061.
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Bien que rares, les tumeurs endocrines développées chez l'Homme demeurent problèmatiques. Une meilleure compréhension des mécanismes qui régulent leur croissance constitue un objectif essentiel pour identifier des cibles thérapeutiques nouvelles.Dans la première partie de cette thèse, nous avons étudié l'impact du microenvironnement tumoral (MeT), définit par l'ensemble des facteurs qui encerclent la niche tumorale primitive, sur la croissance des tumeurs endocrines digestives. In vitro, nous observons un effet prolifératif réciproque entre des fibroblastes, l'une des cellules pivots du MeT, et des lignées cellulaires humaines de tumeurs endocrines pancréatiques, tel qu'il est susceptible d'exister in situ. Dans une seconde partie, nous avons montré que le pegvisomant, un antagoniste du récepteur de l'hormone de croissance utilisé chez des patients atteint d'adénome hypophysaire somatotrope, n'a pas d'effet prolifératif in vitro sur les cellules somatotropes adénomateusesAlthough rare, endocrine tumors developed in Humans remain problematic, such as a better understanding of their regulatory mechanisms of growth represent a step forward to identify new therapeutical targets.In the first part of this thesis, we investigated the impact of the tumor microenvironment (TME), as defined by the factors surrounding the tumor primitive niche, on the growth of human digestive endocrine tumors. We, here, showed the occurrence of a reciprocal proliferation between human fibroblasts, a key cell within the TME, and human pancreatic neuroendocrine tumor cell lines, suggesting that human fibroblasts may constitue a new therapeutical target of interest in the TME of digestive endocrine tumors. In a second part, we showed that pegvisomant (PEG), a growth hormone receptor antagonist currently used in patients with GH-secreting pituitary adenoma, did not impact in vitro the proliferation rate of GH-secreting adenoma cells and therefore is suitable in patients with a persisting GH-secreting pituitary adenoma residue after surgery
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Tai, Kai-chun Dora, and 戴啟真. "Krukenberg tumours of colorectal origin: experience of a tertiary referral centre and review of theliterature." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2010. http://hub.hku.hk/bib/B4562043X.
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Nakayama, Tomitaka. "MDM2 gene amplification in bone and soft-tissue tumors : association with tumor progression in differentiated adiposetissue tumors." Kyoto University, 1997. http://hdl.handle.net/2433/202202.
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Cataldo, A. "ANTI-TUMOR ACTIVITY OF CPG-ODN IN OVARIAN XENOGRAFT TUMORS." Doctoral thesis, Università degli Studi di Milano, 2014. http://hdl.handle.net/2434/229558.
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Synthetic oligodeoxynucleotides expressing CpG motifs (CpG-ODN), Toll-like receptor 9 (TLR9) agonists, are able to induce innate/adaptive immune responses and can enhance the antitumor activity of DNA-damaging chemotherapy and radiation therapy in preclinical mouse models.
It was recently reported that peritumoral CpG-ODN treatment in preclinical models of ovarian cancer, activating TLR-9 expressing cells in tumor microenvironment, induces modulation of DNA repair genes and sensitizes cancer cells to DNA-damaging Cisplatin treatment.
In this thesis we investigated whether this treatment induces modulation of miRNAs in tumor cells and their relevance to chemotherapy response. Array analysis identified 20 differentially expressed miRNAs (16 down- and 4 up-regulated) in human IGROV-1 ovarian tumor cells from CpG-ODN-treated mice versus controls. Evaluation of the role of the 3 most differentially expressed miRNAs on sensitivity to Cisplatin of IGROV-1 cells revealed significant increased Cisplatin cytotoxicity upon ectopic expression of hsa-miR-302b (up-modulated in our array), but no increased effect upon reduced expression of hsa-miR-424 or hsa-miR-340 (down-modulated in our array). The impact of expression levels of all 20 differentially expressed miRNAs were associated with time to replase and overall survival probability in two data sets of ovarian cancer patients treated with platinum. It was found that hsa-miR-302b expression was significantly associated with time to relapse or overall survival in these patients. Use of bio-informatics tools identified 19 mRNAs potentially targeted by hsa-miR-302b, including HDAC4 gene, which has been reported to mediate Cisplatin sensitivity in ovarian cancer. Both HDAC4 mRNA and protein levels were significantly reduced in IGROV-1 cells overexpressing hsa-miR-302b. Altogether, these findings indicate that hsa-miR-302b acts as a ‘‘chemosensitizer’’ in human ovarian carcinoma cells and may represent a biomarker able to predict response to Cisplatin treatment. Moreover, the identification of miRNAs that improve sensitivity to chemotherapy provides the experimental underpinning for their possible future clinical use.
In the second part of this thesis we tested the efficacy of CpG-ODN in combination with other possible therapeutic agents in ovarian carcinoma ascites-bearing athymic mice, to mimic clinical treatment situations in advanced human ovarian disease.
Mice injected i.p. with IGROV-1 ovarian cancer cells were treated at different stages of ascites progression for 4 weeks with CpG-ODN alone or in combination with Bevacizumab, Polyinosinic:Polycytidylic acid (Poly(I):Poly(C)), Gefitinib, Cetuximab and Cisplatin.
In mice treated when ascitic fluid began to accumulate, CpG-ODN combined with Bevacizumab, Poly(I): Poly(C) or Gefitinib did not significantly increase Median Survival Times (MST), as compared with that using CpG-ODN alone, whereas MST in mice treated with CpG-ODN plus Cetuximab was significantly increased (>103 days for combination vs 62 days for CpG alone; P = 0.0008), with 4/8 mice alive at the end of the experiment. In mice showing evident and established ascites, evaluated with increase of abdominal volume and body weight (27.9 ± 0.8 g after vs 23 ± 1.1 g before tumor cell injection), treatment with Cisplatin in addition to CpG-ODN/Cetuximab led to significantly increased MST (105.5 days; P = 0.001), with all mice still alive at 85 days, over that using CpG ODN/Cetuximab (66 days), Cetuximab/Cisplatin (18.5 days), Cisplatin (23 days) or saline (16 days). At a very advanced stage of disease (body weight: 31.4 ± 0.9 g), when more than half of control mice had to be sacrificed 6 days after starting treatments, the triple-combination therapy still increased MST (45 days; P = 0.0089) vs controls.
These data indicated that CpG-ODN combination therapies that enhance the immune response in the tumor microenvironment and concomitantly target tumor cells are highly efficacious even in experimental advanced malignancies. Although differences in the distribution of TLR9 in mice and humans and the enrichment of this receptor on innate immune cells of athymic mice must be considered, our results indicate a promising strategy to treat ovarian cancer patients with bulky ascites.
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Marcu, Loredana Gabriela. "Deterministic modelling of kinetics and radiobiology of radiation-cisplatin interaction in the treatment of head and neck cancers." Title page, contents and abstract only, 2004. http://hdl.handle.net/2440/37961.
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One of the main objectives of combining radiation treatment and chemotherapy is to obtain a therapeutic gain by an improved tumour control with less or no enhancement of normal tissue toxicity. The optimal schedule for the combined treatment of cisplatin-radiation is still under investigation. Neither the optimal time interval, nor the most adequate sequence of administration of cisplatin and radiation are known. The results of the trials are also inconclusive. Some trials showed a supra-additive effect from the administration of cisplatin before radiotherapy, others, on contrary, from the injection of drug after radiotherapy. The present work encompasses the major challenges brought by the combined modality treatment: cisplatin-radiotherapy. The major goal of this work was to investigate the optimal treatment sequencing between cisplatin and radiotherapy and also the optimal schedule for head and neck carcinomas. Therefore, a computer-based tumour model with literature-given biological parameters has been developed which has allowed the simulation of treatment with radiation and chemotherapy. Radiotherapy has been simulated on the virtual tumour and the effects of radiotherapy on tumour regression and regrowth have been analyzed. Also, the mechanisms of cisplatin's action on tumour have been implemented, and the phenomena of drug resistance and tumour repopulation during chemotherapy studied. Finally, the combined modality treatment has been simulated, and the effect of drug-radiation interaction on tumour behaviour evaluated. The current investigation has shown that cisplatin administered immediately before radiation gives similar tumour control to the post-radiation sequencing of the drug. Furthermore, the killing effect of the combined modality treatment on tumour increases with the increase in cell recruitment. The individual cell kill produced by cisplatin and radiation leads to an additive-only tumour response when the treatments are given concurrently, and for a synergistic effect cisplatin must potentiate the effect of radiation. The final conclusion, by which cisplatin administered on a daily basis leads to a better tumour control than cisplatin administered weekly, is in accordance with the latest trial results on head and neck cancers. Therefore, treatment regimens that correlate better with the pharmacokinetics and the radiobiological properties of the therapeutic agents result in better outcomes.Thesis (Ph.D.)--School of Chemistry and Physics, 2004.
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Lu, Dan. "Tumor priming enhances particle delivery to and transport in solid tumors." Columbus, Ohio : Ohio State University, 2006. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1144936804.
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Martinez, Mata Guillermo. "Mixomas odontogenicos : analise clinicopatologica e imunohistoquimica de 67 casos." [s.n.], 2005. http://repositorio.unicamp.br/jspui/handle/REPOSIP/288397.
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Orientador: Oslei Paes de AlmeidaDissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Odontologia de Piracicaba
Made available in DSpace on 2018-08-05T09:05:53Z (GMT). No. of bitstreams: 1 MartinezMata_Guillermo_M.pdf: 1070617 bytes, checksum: 13db66187a1a59eeaa5b18ca3a02cb9d (MD5) Previous issue date: 2005
Resumo: O objetivo deste trabalho foi analisar as características clínicas, radiográficas, histopatológicas e perfil imunohistoquímico de 67 casos de mixomas odontogênicos (MOs), assim como relatar uma das casuísticas mais extensas da literatura mundial. Nesta pesquisa, o gênero feminino foi o mais afetado com 48 casos (71,64%) enquanto o gênero masculino foi em 19 (28,36%) (relação homem/mulher 1:2,5). A idade dos pacientes variou de 10 a 84 anos, média de 32,7. O sitio mais afetado foi a mandíbula em 27 casos (40.29%) Clinicamente, os MOs apresentaram-se como lesões assintomáticas em 29 (43,28%) casos, em 9 (13,43%) houve dor leve a moderada enquanto em outros 9 (13,43%) houve aumento de volume com evolução lenta. Radiograficamente dos 47 casos com dados disponíveis, 29 (43,28%) casos foram descritos como lesões radiolúcidas e 18 (26,86%) como mistas/multiloculares com aparência de favos de mel ou bolhas de sabão. Microscopicamente MOs apresentaram abundantes células fusiformes e estreladas homogêneas dispersas em um estroma mixóide e frouxo sem apresentar mitoses ou pleomorfismo celular. Em 6 casos (8,95%) evidenciaram presença de epitélio e 16 (23,88%) apresentaram calcificações do tipo distrófica. A reatividade de mastócitos foi positiva pela imunohistoquímica (clone AA1) em 27 casos (40,29%) e na coloração de azul de toluidina em 19 (28,35%). Treze dos 67 casos apresentaram epitélio imunoreativo para o coquetel de citoqueratinas AE1/AE3 e CK 14. Apenas 2 dos 13 casos foram positivos para CK 19 sugerindo uma possível origem odontogênica. As células fusiformes e estreladas foram reativas para vimentina em 67 casos, para a-actina músculo liso específica em 27 casos (40,29%) e para desmina em 6 (8,95%). Todos os casos foram negativos para a proteína S-100 e CK 8. O anticorpo CD-34 foi positivo em 20 (29,85%) casos, evidenciando múltiplas estruturas vasculares de diversos tamanhos. O marcador de proliferação celular Ki-67 foi positivo em apenas 2 casos apesar de sua alta taxa de recorrência. Baseado nestes achados, podemos sugerir que provavelmente os MOs sejam derivados de elementos mesenquimais, possivelmente de células fibroblásticas modificadas com características de miofibroblastos , e que outras nomenclaturas seriam mais adequadas para denominar esta lesão, tais como mixomas da região maxilar ou mixomas dos ossos gnáticos
Abstract: The aim of this study was to analyze the immunohistochemical profile and clinical, radiographical and histopathological characteristics of 67 cases of odontogenic myxoma (OM), as well as to report the greatest series related in the world literature. Females were more affected with 48 cases (71,64%) whereas males were in 19 (26.83%), male-female ratio 1:2.5. The patient¿s age ranged from 10 to 84 years (mean 32,7 years). The most frequent site affected was mandible with 27 cases (40,29%). Clinically, 29 cases (43,28%) of OM were asymptomatic, 9 cases (13,43%) presented pain and another 9 (13.43%) showed swelling. Radiographically, we disposed of clinical information in 47 cases, of which 29 (43,28%) cases were radioluced lesions and 18 (26,86%) were described as mixed/multilobular lesions of honey/comb or soap/bubble appearance. Microscopically, OM was constituted by a myxomatous background with spindle-shaped and stellate cells. Mitoses and pleomorphism were absent. Epithelium was present in 6 (8,95%) cases and 16 (23.88%) presented dystrophic calcifications. Immunohistochemical analyses revealed that 27 cases (40.29%) were positives for mast cell (clone AA1) and 19 (28,35%) positives for toluidine blue. Thirteen cases (19,47%) were positives for the antibody PAN CK AE1/AE3 and CK 14 respectively. Only 2 cases (2,98%) were positives for CK 19 suggering an possible odontogenic origin. The spindle-shaped and stellate cells showed positivity for vimentin in 67 cases, 27 cases (40,29%) for a-smooth muscle actin positives and 6 (8,95%) for desmin. All 67 cases were S-100 and CK 8 negatives. Twenty cases (29,85%) were immunopositives for CD-34, demonstring multiples blood vessels. Expression of the marker of cellular proliferation Ki-67 was low, being present only in two cases. Based on these findings, we can suggest that OM probably derives from mesenchymal elements, possibly modified fibroblasts with miofibroblastic diferentation, and that others nomenclatures as mixoma of the jaws could be suggest for this lesion
Mestrado
Patologia
Mestre em Estomatopatologia
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Furtado, LuÃs Edmundo Teixeira de Arruda. "IdentificaÃÃo de glicoproteÃnas em membrana de tumores primÃrios do sistema nervoso central utilizando lectinas vegetais acopladas a fluoresceÃna." Universidade Federal do CearÃ, 2010. http://www.teses.ufc.br/tde_busca/arquivo.php?codArquivo=4868.
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FundaÃÃo Cearense de Apoio ao Desenvolvimento Cientifico e TecnolÃgicoCoordenaÃÃo de AperfeiÃoamento de Pessoal de NÃvel Superior
Lectinas sÃo proteÃnas que pertencem a um grupo heterogÃneo de molÃculas com capacidade de ligaÃÃo especÃfica e reversÃvel a carboidratos. Desde sua descoberta, as lectinas se tornaram importantes ferramentas para a investigaÃÃo de fenÃmenos como a adesÃo, a migraÃÃo e a proliferaÃÃo celular, em condiÃÃes normais e patolÃgicas. Durante o processo de diferenciaÃÃo, cÃlulas tumorais apresentam vÃrios graus de modificaÃÃo na expressÃo de glicoproteÃnas de membrana. Neste aspecto, a investigaÃÃo da estrutura da membrana tumoral pode ser compreendida como um mÃtodo sensÃvel e especÃfico de diagnÃstico. Portanto, o reconhecimento de marcadores capazes de identificar e quantificar estas caracterÃsticas, pode ser usado como ferramenta de diagnÃstico. Neste trabalho propomos um modelo experimental para detectar marcadores de membrana de tumores primÃrios do Sistema Nervoso Central usando lectinas vegetais (Con A e Con Br) acopladas à cromÃforos. Amostras de tumores foram obtidas de pacientes que tinham diagnÃstico clÃnico e radiolÃgico de tumores do Sistema Nervoso Central, apÃs cirurgias realizadas no ServiÃo de Neurologia da Santa Casa de MisericÃrdia de Sobral. As amostras foram processadas e investigadas com tÃcnicas imunohistoquÃmicas, usando lectinas vegetais acopladas à fluoresceÃna, e microscopia de fluorescÃncia. Os resultados mostraram que meningiomas e gliomas apresentaram um padrÃo diferente de interaÃÃo com Con Br-FITC e Con A-FITC quando comparados ao controle (BSA/FITC). Estes dados sugerem que as lectinas vegetais estudadas podem ser ferramentas Ãteis na identificaÃÃo de marcadores de membrana em tumores primÃrios do Sistema Nervoso Central.
Lectins are proteins that belong to a heterogeneous group of molecules capable of binding specifically and reversibly to carbohydrates. Since its discovery, lectins have become important tools for investigating phenomena such as adhesion, migration and cell proliferation in normal and pathological conditions. In the process of differentiation, tumor cells display different degrees of modification in the expression of membrane glycoproteins. In this respect, the investigation of membrane structure tumor can be understood as a sensitive and specific method of diagnosis. Therefore, the recognition of markers capable of identifying and quantifying these characteristics can be used as diagnostic tool. In this paper we propose an experimental model to detect markers of the membrane of primary tumors of the central nervous system using plant lectins (Con A and Con Br) attached to the chromophores. Tumor samples were obtained from patients who had clinical and radiological diagnosis of tumors of the central nervous system after surgeries performed at the Department of Neurology, Santa Casa de Misericordia de Sobral. The samples were processed and investigated with immunohistochemical techniques, using plant lectins coupled to fluorescein, and fluorescence microscopy. The results showed that meningiomas and gliomas showed a different pattern for interaction with Con Br-FITC and Con A-FITC compared to control (BSA / FITC). These data suggest that the studied plant lectins can be useful tools in identifying membrane markers in primary tumors of the central nervous system.
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Bodily, Weston Reed. "Integrative Analysis to Evaluate Similarity Between BRCAness Tumors and BRCA Tumors." BYU ScholarsArchive, 2017. https://scholarsarchive.byu.edu/etd/6800.
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The term "BRCAness" is used to describe breast-cancer patients who lack a germline mutation in BRCA1 or BRCA2, yet who are believed to express characteristics similar to patients who do have a germline mutation in BRCA1 or BRCA2. Although it is hypothesized that BRCAness is related to deficiency in the homologous recombination repair (HRR) pathways, relatively little is understood about what drives BRCAness or what criteria should be used to assign patients to this category. We hypothesized that patients whose tumor carries a genomic or epigenomic aberration in BRCA1 or BRCA2 should be classified under the BRCAness category and that these tumors would exhibit downstream effects (additional mutations or gene-expression changes) similar to patients with germline BRCA1/2 mutations. To better understand BRCAness, we examined similarities and differences in gene-expression profiles and somatic-mutation "signatures" among 1054 breast-cancer patients from The Cancer Genome Atlas. First, we categorized patients into three categories: those who carried a germline BRCA1/2 mutation, those whose tumor carried a genomic aberration or DNA hypermethylation in BRCA1/2 (the BRCAness group), and those who fell into neither of the first two groups. Upon evaluating the gene-expression data in context of the PAM50 subtypes, we did not observe significant similarity between the germline BRCA1/2 and BRCAness groups, but we did observe enrichment within the basal subtype, especially for BRCAness tumors with hypermethylation of BRCA1/2. However, the gene-expression profiles were fairly heterogeneous; for example, BRCA1 patients differed significantly from BRCA2 patients. In agreement with prior findings, certain mutational signatures—especially "Signature 3"—were enriched for patients with germline BRCA1/2 mutations as well as for BRCAness patients. Furthermore, we observed significant similarity between germline BRCA1/2 patients and patients with germline mutations in PALB2, RAD51B, and RAD51C, genes that are key parts of the HRR pathway and that interact with BRCA1/2. Our findings suggest that the BRCAness category does have biological and clinical relevance but that the criteria for including patients in this category should be carefully defined, potentially including BRCA1/2 hypermethylation and homozygous deletions as well as germline mutations in PALB2, RAD51B, and RAD51C.
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Neto, Daniel Messias de Moraes. "Predição do risco individual de micrometástase do tumor carcinóide típico broncopulmonar em função de variáveis clínicas, anatomopatológicas e biomarcadores teciduais." Universidade de São Paulo, 2011. http://www.teses.usp.br/teses/disponiveis/5/5156/tde-06052011-115608/.
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Introdução: Os tumores carcinóides broncopulmonares típicos são proliferações malignas neuroendócrinas. Até bem pouco tempo eram consideradas como adenomas, isto é, tumores benignos. Porém com o avanço dos estudos anatomopatológicos, foi identificada a sua face maligna, pois apresenta as principais características das neoplasias malignas, quais sejam: metástase e invasão tecidual local. Além das metástases, estes tumores são capazes de produzir outra entidade ainda pouco estudada e conhecida que é a micrometástase. Estas correspondem a metástases menores que 2mm de diâmetro, que podem ou não se desenvolver, causando recidiva tumoral. Por sua vez as micrometástases são divididas em grupos de células tumorais, com diâmetro de 0,2 a 2mm e células tumorais isoladas, com diâmetro menor do que 0,2 mm. A literatura nos mostra que a incidência de micrometástase varia entre 10 a 90% dos pacientes em diversos tumores estudados. No caso dos carcinóides típicos temos pouca informação a respeito, sendo que a literatura nos mostra que a micrometástase em tumores carcinóides é considerada com fator de pior prognóstico. Porém não é o que observamos clinicamente, uma vez que temos o seguimento de inúmeros pacientes por mais de 10 anos, sem a recidiva tumoral em linfonodos mediastinais (seguimento clínicoradiológico). Objetivos: Verificar a presença de micrometástases em suas diversas formas, em pacientes portadores de carcinóide típico broncopulmonar, e verificar a possibilidade da predição do risco individual destas micrometástases em função de variáveis clínicas, anatomopatológicas e biomarcadores teciduais. Casuística e Métodos: Quarenta e nove pacientes portadores de carcinóide típico broncopulmonar com acompanhamento mínimo de 5 anos foram estudados. Todos foram submetidos a ressecção linfonodal por amostragem ou radical. As seguintes variáveis foram coletadas dos prontuários ou por entrevista: gênero, idade, localização do tumor em relação à carina (central ou periférico), diâmetro da lesão, comprometimento da margem cirúrgica, estadiamento TNM, ocorrência de metástases linfonodais, bem como quantidade de linfonodos acometidos por neoplasia em relação ao total dissecado, metástases à distância e tempo de sobrevivência. Os linfonodos foram analisados por coloração de hematoxilina-eosina e por imuno-histoquímica (Sinaptofisina e Cromogranina A) para pesquisa de micrometástase. Resultados: O grupo foi composto por 19 homens (38,8%) e 30 mulheres (61,2%). A idade média dos pacientes foi de 41,3 anos. Houve uma distribuição regular entre todos os lobos pulmonares acometidos. Em relação às vias aéreas, 78% dos tumores eram centrais e 22% eram periféricos. O diâmetro do maior eixo do tumor primário dos 49 pacientes variou de cinco a 80 milímetros, com mediana de 25 e intervalo interquartil 25 a 75% entre 16 e 35 milímetros. Em 54% dos casos foi realizada lobectomia pulmonar, 18% pneumonectomia, 12% bilobectomias e 16% procedimentos poupadores (segmentectomias, broncoplastias e nodulectomias). Em 12% dos casos houve comprometimento da margem cirúrgica. Em 42,8% dos casos houve imunomarcação por pelo menos um dos biomarcadores Sinaptofisina ou Cromogranina A para micrometástase. Em 18,4% dos casos foi diagnosticada macrometástase linfática, e em 1 caso ocorreu metástase hematogênica. Foram realizadas 4 baterias de testes avaliando os grupos sem e com metástases/micrometástases para se verificar a possibilidade de predição do risco individual de micrometástase. Conclusão: Foi possível encontrar micrometástases linfáticas utilizando imuno-histoquímica (Sinaptofisina e Cromogranina A). Não foi possível predizer o risco individual de micrometástases nos grupos estudados. Não houve diferença entre os grupos sem e com qualquer tipo de micrometástase. Não foi possível estabelecer correlação entre incidência de metástase e micrometástase nesta amostra populacional.Introduction: The typical lung carcinoids are neuroendocrine tumors. Until short time ago they were considered adenomas, that is, benign tumors. Although, due to the anatomopathologic advances, it was identified its malignant behavior, once it presents the main characteristics of the malignant tumors: matastasis and local invasion. Beyond the metastasis, this tumor is able to produce another entity not yet well studied, the micrometastasis. This corresponds to metastasis shorter than 2mm in diameter that can or not develop and cause tumoral recurrence. The micrometastasis are divided in two groups: clusters, with diameter between 0,2 and 2mm, and isolated tumor cells, with diameter less than 0,2mm. The medical literature shows that the incidence of micrometastasis of different tumors has a wide variation, between 10 to 90%. In the case of the typical lung carcinoids few information is presented, and the presence of the micrometastasis worsen prognosis. On the other hand this is not what we usually see clinically, once the follow up of numerous patients of our casuistic for more than 10 years did not show the recurrence of the desease in the mediastinal lymphnodes. Objectives: Verify the presence of micrometastasis in its various forms in patients comited by lung carcinoid tumors and verify the possibility to predict the individual risk of micrometastasis from clinical and anatomopathological variables and tissue biomarkers. Casuistic and Methods: Forty nine patients with lung carcinoid tumors with follow up of at least 5 years were studied. All of them were submitted to mediastinal lymphnode dissection during the surgical procedure. The data collected was: age, gender, tumor location (central or peripherical), diameter, compromised surgical edge, TNM stage, lymphatic metastasis, hematogenic metastasis and survive. The lymphnodes were analised by Hematoxilin-Eosin and immunohistochemistry (Synaptophysin and Chromogranin A) in order to search for micrometastasis. Results: There were 19 men (38,8%) and 30 women (61,2%) with a mean age of 41,3 years. There was a regular distribution in all pulmonary lobes. There were 78% of central and 22% periferic tumors. The diameter varied between 0,5 to 80mm, with median in 25. In 54% of the cases was performed pulmonary lobectomy, in 18% pneumonectomy, in 12% bilobectomy and in 16% other procedures (bronchoplasty, wedge resection, nodulectomy). In 42,8% there was immunostaining with Synatophysin or Chromogranin A to micrometastasis. In 18,4% was diagnosed macrometastasis and in 1 case there was haematogenic metastasis. It was done 4 batteries of statistical tests to verify the possibility of prediction of the individual risk of micrometastasis. Conclusion: It was possible to find lymphatic micrometastasis using immunostaining with Synaptophysin and Chromogranin A. It was not possible to predict the individual risk of micrometastasis in the studied groups. There was no difference between the groups with or without micrometastasis. It was not possible to estabilish a correlation between the incidence of macro and micrometastasis in this population.
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Leruste, Amaury. "Immune context of malignant rhabdoid tumors : description and identification of new therapeutic targets." Thesis, Université Paris-Saclay (ComUE), 2019. http://www.theses.fr/2019SACLS050.
Full textAbstract:
Les tumeurs rhabdoïdes (TR) constituent un rare cancer indifférencié du jeune enfant et du nourrisson, avec un âge médian au diagnostic de 20 mois. Ces tumeurs sont caractérisées par une inactivation biallélique du gène suppresseur de tumeur SMARCB1, un des membres du complexe SWI/SNF, acteur majeur du remodelage de la chromatine, sans autre altération génomique récurrente. Le pronostic des TR est péjoratif, le taux de survie globale atteignant 30% dans la plupart des séries, malgré des approches thérapeutiques conventionnelles particulièrement agressives. Les approches d’immunothérapies ont obtenu un succès certain dans certains cancers de l’adulte, et récentes analyses de l’infiltrat immun des cancers pédiatriques ne montrent pas un fort taux de tumeurs infiltrées à l’exception de rare types de cancers dont les TR intracrâniennes. Nous avons donc procédé à une analyse multimodale de l’infiltrat immun de cohortes de patients ainsi que d’un modèle de TR murines établi dans notre laboratoire. Nous avons identifié une forte proportion de tumeurs infiltrées dans certains sous-groupes de TR. Cet infiltrat était composé à la fois de cellules myéloïdes incluant des populations au phénotype immunosuppresseur, et lymphocytaires T notamment de phénotype résident mémoire caractérisées par une forte expansion clonale probablement spécifique d’un antigène tumoral. Nous avons identifié des cibles thérapeutiques communes aux tumeurs humaines et au modèle murin syngénique, et trouvé que cibler l’infiltrat lymphocytaire T ou myéloïde était susceptible d’induire une réponse tumorale complète avec induction d’une mémoire immunitaire, confirmant le caractère immunogénique des TR, et apportant de nouvelles stratégies thérapeutiques utiles en clinique. Enfin, nous avons identifié que les TR étaient le site d’une réexpression de rétrovirus endogènes, dépendante de celle de SMARCB1, avec activation des voies de l’interféron, apportant une base à une immunogénicité des TR issue du génome non codantRhabdoid tumors (RT) are highly undifferentiated cancers occurring in infancy and early childhood, with a median age at diagnosis about 20 months. These tumors are characterized by the biallelic inactivation of SMARCB1 tumor suppressor gene, core member of the SWI/SNF complex, one major chromatin remodeling actor, in an otherwise highly stable genome. The prognosis of RT is dismal with overall survival hardly reaching 30% in most series, despite particularly aggressive conventional treatment. Immunotherapy approaches has gained a striking success within some adult cancer types and recent analyses of immune cell content of pediatric cancers don’t reveal a high rate of infiltrated tumors, except in few tumor types such as intracranial rhabdoid tumors. Then, we conducted a comprehensive analysis of the immune context of both human RT cohorts and a mouse RT model, including at single cell level. We identified a high recurrence of infiltrated tumors, in a RT-subgroup related manner, composed of both myeloid cells including cells with immune suppressive phenotypes, and T cells with notably a tissue resident memory phenotype demonstrating a high clonal expansion highly suggestive of immunogenicity. We identified common targetable immune populations between human and mouse RTs, and found that targeting both T and myeloid infiltrating cells was able to induce complete anti-tumor response with induced memory, confirming the immunogenic properties of RTs, and identifying new therapeutic strategies of clinical relevance. We finally identified that RTs were the site of SMARCB1-dependent endogenous retroviruses reexpression, with subsequent activation of interferon signaling, likely triggering the immune response in the context of RT, and providing a basis of non-coding genome-driven immunogenicity for these tumors
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Krogh, Karin. "Isolamento e caracterização de genes diferencialmente expressos em insulinomas benigos humanos." Universidade de São Paulo, 2005. http://www.teses.usp.br/teses/disponiveis/46/46131/tde-16022007-122349/.
Full textAbstract:
Os insulinomas são os mais comuns neoplasmas endócrinos pancreáticos, constituindo cerca de 17% de todos os tumores neuroendócrinos do trato digestivo. São tumores raros, que tem, como principal manifestação clínica, a hipoglicemia, a qual é ocasionada por secreção exagerada de insulina pelo tumor. Devido ao fato de serem tumores raros, o conhecimento das mudanças genéticas associadas à iniciação e progressão desses tumores é muito limitado. Em função disto, o objetivo deste trabalho é a identificação de genes diferencialmente expressos em insulinomas benignos humanos, visando o melhor entendimento dos mecanismos moleculares do processo tumorigênico dos insulinomas e a descoberta de novos alvos moleculares para terapia. Utilizando-se a plataforma de \"bioarrays\" CodeLink foram identificados 354 genes mais expressos nos insulinomas benignos, sendo que 16% estavam envolvidos em proliferação. Dentre estes genes foram escolhidos 6 genes para validação por \"Real-Time PCR\", onde os genes SPARCL1, PRSS11 STAT4, ECRG4, ASCL1 confirmaram sua expressão diferencial nos tumores, porém a diferença do gene IGFALS não foi estatisticamente significativa. Através da técnica \"Representational Difference Analysis\", isolou-se o clone FLJ13072, como super-expresso nos insulinomas benignos quando comparado à ilhotas normais, sendo que a seqüência protéica putativa deste gene apresenta um domínio conservado de helicase, podendo estar envolvido em eventos de transcrição, tradução, reparo de DNA e remodelamento de cromatina. Uma das dificuldades encontradas no estudo dos insulinomas é a falta de linhagens celulares humanas. Por esta razão, iniciou-se o estabelecimento de culturas primárias e precoces de insulinomas humanos visando sua utilização como modelos celulares para futuros estudos funcionais dos genes identificados.Insulinomas are the most common pancreatic endocrine neoplasms, comprising around 17% of all neuroendocrine tumors of the digestive tract. These rare tumors have hypoglycemia as the main clinical manifestation, caused by over secretion of insulin by the tumor. Based on that, the objective of this work is the identification of differentially expressed genes in human benign insulinomas, aiming at the better understanding of the molecular mechanisms of their tumorigenic process and the discovery of new molecular targets for therapeutics. Using the CodeLink bioarrays platform (GE Healthcare) 354 genes upregulated in human benign insulinomas were identified, among which, 16% are involved in cell proliferation. From these genes, 6 were chosen for validation by Real Time PCR, where SPARCL1, PRSS11, STAT4, ECRG4 and ASCL1 were shown to be upregulated in all benign tumors, however the expression difference of IGFALS gene were not statistically significant. Using the RDA (Representational Difference Analysis) methodology, the unknown gene FLJ13072 was shown to be upregulated in benign isulinomas when compared to normal pancreatic islets. The putative protein product from this gene has an helicase domain, being possibly involved in processes like transcription, translation, DNA repair and chromatin remodeling. An important drawback for the study of insulinomas is the lack of human cell lines. Because of that, the establishment of early primary cultures of human insulinomas was initiated, aiming at its use as a cell model for future functional studies of the genes identified.
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Barazeghi, Elham. "Studies of epigenetic deregulation in parathyroid tumors and small intestinal neuroendocrine tumors." Doctoral thesis, Uppsala universitet, Endokrinkirurgi, 2017. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-330810.
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Deregulation of the epigenome is associated with the initiation and progression of various types of human cancers. Here we investigated the level of 5-hydroxymethylcytosine (5hmC), expression and function of TET1 and TET2, and DNA methylation in parathyroid tumors and small intestinal neuroendocrine tumors (SI-NETs). In Paper I, an undetectable/very low level of 5hmC in parathyroid carcinomas (PCs) compared to parathyroid adenomas with positive staining, suggested that 5hmC may represent a novel biomarker for parathyroid malignancy. Immunohistochemistry revealed that increased tumor weight in adenomas was associated with a more aberrant staining pattern of 5hmC and TET1. A growth regulatory role of TET1 was demonstrated in parathyroid tumor cells. Paper II revealed that the expression of TET2 was also deregulated in PCs, and promoter hypermethylation was detected in PCs when compared to normal parathyroid tissues. 5-aza-2′-deoxycytidine treatment of a primary PC cell culture induced TET2 expression and further supported involvement of promoter hypermethylation in TET2 gene repression. TET2 knockout demonstrated a role for TET2 in cell growth and migration, and as a candidate tumor suppressor gene. In Paper III, variable levels of 5hmC, and aberrant expression of TET1 and TET2 were observed in SI-NETs. We demonstrated a growth regulatory role for TET1, and cytoplasmic expression with absent nuclear localization for TET2 in SI-NETs. In vitro experiments supported the involvement of exportin-1 in TET2 mislocalization, and suggested that KPT-330/selinexor, an orally bioavailable selective inhibitor of exportin-1 and nuclear export, with anti-cancer effects, could be further investigated as a therapeutic option in patients with SI-NETs. In Paper IV, DNA methylation was compared between SI-NET primary tumors and metastases by reduced representation bisulfite sequencing. Three differentially methylated regions (DMR) on chromosome 18 were detected and chosen for further analyses. The PTPRM gene, at 18p11, displayed low expression in SI-NETs with high levels of methylation in the presumed CpG island shores, and in the DMR rather than the promoter region or exon 1/intron 1 boundary. PTPRM overexpression resulted in inhibition of cell growth, proliferation, and induction of apoptosis in SI-NET cells, suggesting a role for PTPRM as an epigenetically deregulated candidate tumor suppressor gene in SI-NETs.
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Abrahão, Patricia Gemma Strappa. "Estudo retrospectivo de 3091 casos de neoplasias epiteliais primarias de glandulas salivares maiores e menores intra-orais." [s.n.], 2009. http://repositorio.unicamp.br/jspui/handle/REPOSIP/288365.
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Orientador: Oslei Paes de AlmeidaTese (doutorado) - Universidade Estadual de Campinas, Faculdade de Odontologia de Piracicaba
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Resumo: O objetivo deste estudo foi analisar retrospectivamente as características histológicas e epidemiológicas de 3091 casos de neoplasias epiteliais primárias de glândulas salivares maiores e menores intra-orais do Brasil, México, Guatemala, Peru, Uruguai e EUA. . Foram incluidos neste estudo 1766 casos do Brasil, 544 casos dos EUA, 405 do Uruguai, 151 casos do Peru, 134 casos da Guatemala e 91 casos do México. 56,84% dos tumores eram benignos correspondendo a 1757 casos e 43,16% malignos, correspondendo a 1334 casos. O principal sítio para ocorrência de tumores benignos e malignos foi a glândula parótida (n=1291; 41.77%) seguido do palato (n=733; 23,71%) e glândula submandibular (n=241; 7.80%). Não foram observados tumores benignos na glândula sublingual ou intraósseos. O Adenoma pleomórfico (n=1324; 42,83%) foi o tumor benigno predominante das glândulas salivares maiores e menores intra-orais, e o carcinoma mucoepidermóide (n= 586; 18,96%) foi o maligno mais comum em todos os países analisados, com exceção do Peru onde o tumor maligno mais prevalente foi o Carcinoma adenóide cístico. No total houve maior prevalência para o gênero feminino (1,31:1), sendo que, nos tumores benignos e malignos a relação foi de (1,46:1) e (1,13:1) respectivamente. Os tumores benignos tiveram maior incidência na 5ª década e os malignos na 6ª década. O Tumor de Warthin teve prevalência na sétima década de vida e o adenoma canalicular na oitava década de vida. Os 15 tumores intra-ósseos envolveram principalmente a mandíbula, sendo que o carcinoma mucoepidermóide correspondeu a 86,67% dos casos. Em crianças e adolescentes os tumores epiteliais de glândulas salivares benignos foram os mais prevalentes em todos os países analisados, quase todos representados pelo Adenoma Pleomórfico. Nesta faixa etária, o Carcinoma Mucoepidermóide foi o tumor maligno mais prevalente. Os locais mais acometidos foram glândula parótida e palato e o gênero feminino o mais afetado
Abstract: The aim of this study was to analyse retrospectively the histological and epidemiological characteristics of 3091 cases of intraoral primary epithelial neoplasms of the minor and major salivary glands. It was included on this study, 1766 cases from Brazil, 544 from the U.S., 405 from Uruguay, 151 from Peru, 134 from Guatemala and 91 from Mexico. Benign tumors corresponded to 1757 cases (56.84%), and there were 1334 malignancies ( 43.16%). The main sites of benign and malignant tumours were the parotid gland (n=1291; 41.77%), followed by palate (n= 733, 23.71%) and submandibular gland (n=241, 7.80%). Benign tumours on sublingual gland and intraosseous were not observed. Pleomorphic Adenoma (n=1234, 42.83%) was the predominant benign tumour on major and minor salivary glands, and Mucoepidermoid Carcinoma (n=586, 18.96%) was the most common malignant tumour in all countries but Peru, where the most prevalent malignant tumour was the Adenoid Cystic Carcinoma. Considering all tumors there was a higher prevalence in females (1.31:1), with proportions of 1.46:1 and 1.13:1 for the benign and malignant tumors respectively. Benign tumours had greater incidence on the 5th decade of life and malignancies in the 6th decade. Warthin's tumor and canalicular adenoma had a peak of incidence in the 7th and 8th decades respectively. All 15 intraosseous tumors were malignant, involving mainly the mandible, and mucoepidermoid carcinoma corresponded to 86.67% of the cases. In children and adolescents predominated the benign tumors in all countries studied, and almost all were pleomorphic adenoma. On this age group mucoepidermoid carcinoma was the most prevalent malignant tumor
Doutorado
Patologia
Doutor em Estomatopatologia
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Rocha, Lilia Alves. "Estudo da expressão imunoistoquimica de KI-67, Mcm-2 e HOXB7 em neoplasias basaloides de cabeça e pescoço." [s.n.], 2010. http://repositorio.unicamp.br/jspui/handle/REPOSIP/288419.
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Orientador: Pablo Augustin VargasTese (doutorado) - Universidade Estadual de Campinas, Faculdade de Odontologia de Piracicaba
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Resumo: O presente trabalho avaliou a expressão dos marcadores de proliferação celular Ki-67, Mcm-2 e HOXB7 em neoplasias malignas epiteliais basalóides de cabeça e pescoço. Foram avaliadas 42 amostras tumorais da região de cabeça e pescoço, sendo 15 de carcinoma espinocelular pouco diferenciado (CEC-pd), 18 de carcinoma escamoso basalóide (CEB) e nove de carcinoma adenóide cístico tipo sólido (CAC-sólido). Os dados clinicopatológicos foram coletados de formulários de encaminhamento para biópsia. Todas as amostras foram submetidas à análise imunoistoquímica para os três marcadores. A idade média dos pacientes avaliados foi de 57 (±14,5) anos, e a maioria pertenceu ao gênero masculino (76%). A expressão de Ki-67 nas amostras de CAC-sólido foi menor quando comparada com os demais grupos tumorais (IM=18,74% ±8,3, p<0,05). A proteína Mcm-2 apresentou um maior IM no grupo CEB (IM=55,57% ±13,4, p<0,05), quando comparado com os grupos CEC-pd (IM=35,55% ±19,5) e CAC-sólido (IM=28,60%, ±10,1). Este mesmo padrão foi observado para a proteína HOXB7, que apresentou um maior IM no grupo de CEB (IM=31,28% ±11,6, p<0,05), quando comparado aos demais grupos (CEC-pd: IM=23,19% ±8,4 e CAC-sólido: IM=18,66% ±9,8). Como o CEB apresenta um comportamento clínico mais agressivo quando comparado ao CEC-pd e CAC-sólido, os altos IMs para Mcm-2 e HOXB7 em CEB sugerem uma relação direta entre a maior expressão dessas proteínas e a agressividade tumoral. Os IMs de Mcm-2 e HOXB7 foram crescentes para os grupos CAC-sólido, CEC-pd e CEB. Assim, sugerimos que as proteínas Mcm-2 e HOXB7 podem ser úteis no diagnóstico diferencial de CEB, CEC-pd e CAC-sólido. Estudos adicionais devem ser realizados para confirmar nossos achados e determinar o valor prognóstico de Mcm-2 e HOXB7 nestas neoplasias malignas de cabeça e pescoço.
Abstract: The aims of this study were to determine the expression of Mcm-2, Ki-67 and HOXB7 in malignant basaloid tumors located in the head and neck region, and to evaluate their usefulness for diagnosis or prediction of tumor behaviour. There were 18 basaloid squamous cell carcinoma (BSCC), 15 squamous cell carcinoma poorly differentiated (SCC-pd), and nine adenoid cystic carcinoma solid type (AdCC-st). Clinicopathological data were collected retrospectively and immunohistochemical analyses of Ki-67, Mcm-2 and HOXB7 were performed on all lesions (n=42). The nuclear stain was considered as positive or negative, and labelling index (LI) for each tumor was determined by counting the percentage of positive cells in six random fields. The mean age of patients was 57 years (±14,5), and the most was male (76%). Ki-67 expression was lower in AdCC-st (LI=18,74% ±8,3, p<0,05) than in BSCC (LI=42,22%) and SCC-pd (LI=43,54) groups. Mcm-2 LI was higher in BSCC (LI=55,57% ±13,4, p<0,05) than in SCC-pd (LI=35,55 ±19,5) and AdCC-st (LI=28,60% ±10,1). A similar result was observed in HOXB7 that showed a higher LI expression in BSCC group (LI=31,28% ±11,6, p<0,05) than in SCC-pd (IM=23,19% ±8,4) and AdCC-st (LI=18,66% ±9,8). It was not possible to establish a correlation between LI and outcome for any of the markers. The present study suggests that Mcm-2 and HOXB7 may be useful for differential diagnosis among BSCC, SCC-pd and AdCC-st. Further studies are needed to assess the value of Mcm-2 and HOXB7 as a predictor of recurrence and survival in malignant basaloid tumors of head and neck region.
Doutorado
Patologia
Doutor em Estomatopatologia
18
Zare, Fatemeh. "Tumors and Ly6Chigh Monocytes." Doctoral thesis, Universitat de Barcelona, 2015. http://hdl.handle.net/10803/291941.
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Cancer immunotherapy represents a treatment strategy which is being clinically tested to complement surgery, radiotherapy and chemotherapy – the current cornerstones of our fight against cancer. It has become clear now, that tumors not only escape immune recognition but also actively suppress antitumor immune responses. In order to improve cancer immunotherapy, effective manipulation of the immune system to break self-tolerance need to be designed and approaches that counteract immunosuppressive mechanisms need to be developed. The tumor microenvironment encompasses a wide variety of immune cells, which macrophages comprise the most dominant portion of them and thus are the major players in the connection between inflammation and cancer. These tumor-associated macrophages (TAMs) are derived from blood monocyte precursors and subsequently acquire distinct characteristics as a result of tumor micro-environmental cues. Monocytes are a heterogeneous population in the blood with an enormous plasticity whose fate and functions are dictated by the microenvironment. Therefore, the roles of specific Monocytes subsets in tumor progression and the molecular mechanisms for their impacts need to be elucidated. Ly6Chigh and Ly6Clow are two main different types of murine monocytes subsets that have been defined by distinct phenotypes and immunoregulatory functions. Recent data demonstrates that Ly6Chigh monocytes can recruit to inflammation loci while Ly6Clow monocytes are patrolling cells. We have developed a method to produce large number of Ly6Chigh monocytes in vitro. In our study we observed that, injection of these cells affects tumor progression in breast cancer and C26 colon carcinoma. Activation of Ly6Clow monocytes by pro- or anti-inflammatory cytokines, results in a genetic expression profile, corresponding to pro- or anti-inflammatory genes, respectively. Injection of pre- activated Ly6Clow monocytes toward pro- or anti-inflammatory polarization in C26 colon carcinoma showed that anti-inflammatory activated monocytes are more beneficial in delaying cancer cachexia. Increased knowledge of monocytes improves the chances to find therapies against a broad spectrum of diseases including cancer, where monocytes have opposing roles of either being beneficial or detrimental to the host.
Using C26 cancer model we were interested to study the impact of activation of Ly6Chigh monocytes toward pro or anti-inflammatory phenotype on the progression of cancer. We conducted the C26 cancer model injecting Ly6Chigh monocytes treated with IL-4 or INF-. before injection. Among the groups of treatment, Ly6Chigh monocytes activated with IL-4 were the most beneficial on cancer progression, since they had the highest survival rate and the least tumor volume rise among all groups. Since the whole cachectic muscles are inflamed and injured in C26-bearing mice and activated Ly6Chigh monocytes injected in this cancer model apart from recruiting to tumor site have played substantial role by affecting cachectic muscle repair.
In summary, we defined a new regulatory role of recruiting Ly6Chigh monocytes in cancer, which might be clinically relevant in developing novel immunotherapeutic strategies. Although, underlying mechanism by which Ly6Chigh monocytes influences the tumor progression have yet to be established and it requires further studies to characterize the phenotype of these cells after recruitment in cancer. So far, since the inflammatory genes involved in tumor progression were differently regulated in tumors infiltrated with Ly6Chigh monocytes, our hypothesis is that the recruitment of Ly6Chigh monocytes, alter the balance of pro-inflammatory/anti-inflammatory pool of macrophages in the cancer and this is the main reason why modulation impacts occur in this study. While pro-inflammatory macrophages will be able to induce wound hilling and revascularization, the anti-inflammatory macrophages will block the tumor growth through the production of fibrosis.
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Padera, Timothy P. (Timothy Patrick) 1975. "Lymphatic pathophysiology of tumors." Thesis, Massachusetts Institute of Technology, 2003. http://hdl.handle.net/1721.1/29591.
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Thesis (Ph. D.)--Harvard-MIT Division of Health Sciences and Technology, 2003.Includes bibliographical references (leaves 146-166).
Lymph node metastases have a negative impact on cancer survival, but the mechanisms for lymphatic metastasis are not well understood. The universal finding in solid tumors of an absence of functional lymphatic vessels seems paradoxical, as cancer cells do travel through lymphatics in order to disseminate. In order to address some of these issues, this thesis proposes two etiologies for the absence of functional lymphatic vessels in solid tumors. The first hypothesis addresses whether Vascular Endothelial Growth Factor-C (VEGF-C), a lymphangiogenic factor, was sufficient to induce lymphatic function in tumors. The overexpression of VEGF-C in tumors leads to an increase in lymph node metastasis as well as structures that positively stain for lymphatic markers, but does not induce functional lymphatics within the tumor. Thus VEGF-C is not sufficient to grow functional lymphatic vessels in tumors. The second hypothesis addresses whether mechanical forces generated by the proliferation of cancer cells in a confined space compress lymphatic vessels in tumors. The mechanical forces inside of the tumor were reduced by the selective killing of human cancer cells grown in mice by Diphtheria Toxin. Tumor cell death leads to an increase in the fraction of lymphatics with open lumen. In addition, lymphatic vessels with open lumen are surrounded by a lower cellular density than collapsed vessels. Thus, relieving solid stress allows lymphatic vessels to open. However, function was not restored in these vessels. This is presumably due to the inability of the lymphatic vessels to completely open along its entire length, leaving focal areas of lymphatic collapse. Compressive forces are common to all growing tumors, giving credence to the mechanical etiology of the absence of functional lymphatic vessels in tumors, regardless of tumor type or organ site.
(cont.) These findings lead to an interesting question: Does cancer treatment in humans relieve the mechanical compression allowing lymphatic and blood vessels to open? Furthermore, would the resumption of function of compressed blood and lymphatic vessels lead to a paradoxical increase in metastasis? These questions require further investigation.
by Timothy P. Padera.
Ph.D.
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Siesjö, Peter. "Immunotherapy of rat brain tumors with mutagen induced, cross-reactive tumor cell variants." Lund : Section of Tumor Immunology, Dept. of Cell and Molecular Biology, University of Lund, 1997. http://books.google.com/books?id=TXZrAAAAMAAJ.
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Tan, Ern Yu. "Loss of protein folding gene expression in human tumors." Thesis, University of Oxford, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.670106.
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De, Villiers Neil Heinrich. "Tumour metabolism and radioprotection of normal tissue in BALB/c and CBA mice." Thesis, Cape Technikon, 1992. http://hdl.handle.net/20.500.11838/1494.
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Thesis (Master Diploma (Medical Technology) -- Cape Technikon, Cape Town, 1992The steady state in a tumour rapidly changes with its growth and the subsequent deteriorating blood and nutrient supply. This adaptation in the steady state of the tumour is shown in the increased lactate dehydrogenase and acid phosphatase activity in the tumour during it's growth. These alterations in the tumour metabolism places an increased burden on the body to supply nutrient and to discard the waste products of the tumour. This is demonstrated at the macroscopic level by the decreasing body weight and food intake when the tumour burden increases, and also at the metabolic levels by the responses of certain glycolytic and Cori cycle enzymes. Furthermore three distinct stages were observed in the Corl cycle response to the influence of the tumour namely, a silent or preclinical stage, a hypermetabolic stage and a hypometabolic stage. Although the decreasing body weight cannot be directly linked to the process of gluconeogenesis, the onset of anorexia appeared to coincide with the end of the hypermetabolic stage and the beginning of the hypometabolic stage in gluconeogenesis. This clearly shows that the body's steady state is adversely affected by the presence of the tumour and that the conditions at the metabolic level seem to cause the anorexia. Furthermore, it is well known that the success of cancer therapies depends entirely on the effectiveness o{the modality to kill the tumour cell and on the ability . of the host to absorb the damage caused by the modality without being destroyed in the process itself. The second part of this study demonstrates the radioprotective effects of ATP at all levels. It is clear from this work that ATP had a bigger influence in protecting the normal tissue than it had on the tumour tissue. This was demonstrated by the response of acid phosphatase (AP) and glucose-6-phosphate dehydrogenase (G-6-PDH) in the tumour and testis. Furthermore, it would seem that ATP has a multifactorial interaction with the cell, two possible mechanisms of protection are indicated by these results. The fIrst of these interactions is through the receptors of the cell to stimulate enhanced glycolysis, for higher energy production and thus repair. The second possibility is the interaction of ATP with the receptor of the cell to inhibit the production of free radicals and thus damage, as demonstrated by the response of G-6-PDH and AP.
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Martínez, Marisol Martínez 1982. "Estudo comparativo das características clínico-patológicas e imunohistoquímicas de tumores odontogênicos malignos e benignos = Comparative study of clinico-pathologic features of malignant and benign odontogenic tumors." [s.n.], 2014. http://repositorio.unicamp.br/jspui/handle/REPOSIP/288357.
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Orientador: Oslei Paes de AlmeidaTese (doutorado) - Universidade Estadual de Campinas, Faculdade de Odontologia de Piracicaba
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Resumo: Os tumores odontogênicos (TO) são um grupo heterogêneo de lesões derivadas de tecidos dentários, que ocorrem nos ossos gnáticos e tecidos adjacentes. Os TO são raros, na grande maioria benignos, representando menos de 4% de todos os espécimes recebidos em laboratórios de patologia bucal. Os TO malignos frequentemente apresentam dificuldades para diagnóstico e correta classificação, com vários pontos ainda não bem esclarecidos. O objetivo desse trabalho foi comparar as características clínicas, histológicas e imunohistoquímicas do carcinoma ameloblástico (CA) e fibrosarcoma ameloblástico (FSA) e dos seus respectivos correspondentes benignos ou seja ameloblastoma (AM) e fibroma ameloblástico (FA). O carcinoma escamocelular intra-ósseo primário (CEIP) também foi comparado com carcinoma escamocelular de mucosa bucal (CEMB). Foi avaliada a expressão imunohistoquímica de citoqueratinas 5, 7, 8, 14, 19, marcadores de proliferação celular Ki-67, p53, p63 e moléculas de adesão celular CD138 (Syndecan), E-cadherin e ?-catenin. Os resultados mostraram que o CA expressaram mais altos níveis Ki-67, p53 e p63 do que AM por tanto, poderiam ser usados como marcadores para diferenciar essas duas lesões. A expressão de CKs 5 e 19 foram alteradas com relação ao padrão observado em AM, pelo que alterações genéticas de essas proteínas poderiam estar presentes nas células malignas. CK19 pode ser um bom marcador para tumores odontogênicos benignos como AM mas não em malignos pois a expressão nestes é variável. Nas moléculas de adesão celular particularmente CD138 não foi observada diminuição da expressão em AC comparada com AM. As características histológicas assim como o perfil imunohistoquímico do CEMB e CEIP foram similares, por tanto, sugere-se que as características clínicas e radiográficas sejam os principais parâmetros para ser considerados no diagnóstico. Nos casos de fibroma ameloblástico (FA) e fibrosarcoma ameloblástico (AFS) a expressão de CKs foi similar em intensidade e localização e Ki-67 em FSA foi mais alto comparado com FA enquanto que p53 foi negative e ambas lesões. A expressão das moléculas de adesão foi similar em ambas lesões sendo mais intensa com CD138. Finalmente, foram ilustradas as características clínicas e histopatológicas de um caso de fibroodontoma ameloblástico pigmentado e um caso de CEIP originado a partir da transformação maligna de um queratocisto
Abstract: Odontogenic tumors correspond to a heterogenous group of lesions derived from dental tissues, involving the jaws and adjacent tissues. OT are rare, the majority benign, representing less than 4% of all specimens of an oral pathology laboratory. OTs frequently present difficulties for the correct diagnosis and classification, with various points yet to be clarified. The objective of this study was to analyze the clinical, histological and the expression of immunohistochemical markers in malignant odontogenic tumors and the benign counterparts. We assessed CK5, 7, 8, 14, 19, Ki-67, p53, p63, CD138 (Syndecan), E-cadherin and ?-catenin expression by immunohistochemistry in 15 and 9 cases of ameloblastoma (AM) and ameloblastic carcinoma (AC) respectively. Dez cases of primary intraosseous squamous cell carcinoma (PIOSCC), 9 cases of squamous cell carcinoma of mouth (OSCC), 8 cases of ameloblastic fibroma and ameloblastic fibrosarcoma (AFS). Also, these were compared expression patterns between these groups. In summary, Ki-67, p53 and p63 expression were higher in AC than in AM and could be used as markers of malignant transformation of AM. CKs 5 and 19 expression in AC are altered in relation to the pattern found in AM, also CK19 is a good marker for benign odontogenic tumors as AM. Our results do not permit to confirm that expression of CD138, is decreased in AC in relation to AM. The histological features as well as the immunohistochemical profile of OSCC and PIOSCC were similar, therefore, suggests that the clinical and radiographic features are the main parameters to be considered for diagnosis. In both AF and AFS the CKs expression in odontogenic islands was similar in intensity and localization, except CK7 that in most cases of AF was focally positive, while in AFS most cases were negative. Ki-67 proliferative index was higher in AFS that in AF, and p53 was negativo in both lesions. Expression of adhesion molecules was similar in AF and AFS, being most intense for CD138
Doutorado
Patologia
Doutora em Estomatopatologia
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Safdar, Shahana. "Peptide-targeted nitric oxide delivery for the treatment of glioblatoma multiforme." Diss., Georgia Institute of Technology, 2012. http://hdl.handle.net/1853/45797.
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Glioblastoma multiforme (GBM) is the most common malignant central nervous system tumor. The ability of glioma cells to rapidly disperse and invade healthy brain tissue, coupled with their high resistance to chemotherapy and radiation have resulted in extremely poor prognoses among patients. In recent years, nitric oxide (NO) has been discovered to play a ubiquitous of role in human physiology and studies have shown that, at sufficient concentrations, NO is able to induce apoptosis as well as chemosensitization in tumor cells. This thesis discusses the synthesis and characterization of targeted NO donors for the treatment of GBM.
Two glioma targeting biomolecules, Chlorotoxin (CTX) and VTWTPQAWFQWVGGGSKKKKK (VTW) were reacted with NO gas to synthesize NO donors. These NO donors, CTX-NO and VTW-NO, released NO for over 3 days and were able to induce cytotoxicity in a dose dependent manner in glioma cells. The biggest advantage, a result of the targeted delivery of NO, was that the NO donors did not have toxic effects on astrocytes and endothelial cells. To characterize the chemosensitizing effects of CTX-NO, cells were incubated with CTX-NO prior to exposure to temozolomide (TMZ) or carmustine (BCNU). These drugs are the most popular chemotherapeutics used in the treatment of GBM, but have only shown modest improvements in patient survival. Viability studies showed that CTX-NO selectively elicited chemosensitivity in glioma cells, whereas the chemosensitivty of astrocytes and endothelial cells remained unaffected. Further investigation showed that CTX-NO pretreatment decreased O6-methylguanine DNA methyltransferase (MGMT) and p53 levels, suggesting that a decrease in DNA repair ability may be the mechanism by which chemosensitivity is induced.
Lastly, the effects of CTX-NO on glioma cell invasion and migration were studied using Boyden chamber and modified scratch assays. Non-toxic doses of CTX-NO decreased glioma cell invasion in a dose dependent manner. Studies quantifying matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9) surface expression demonstrated that while MMP-2 expression was decreased by both CTX and CTX-NO, MMP-9 expression was decreased only by CTX-NO. Furthermore quantifying MMP-2 and MMP-9 activity levels showed that NO and CTX work synergistically to decrease the activity of the enzymes. These studies demonstrate that the decrease in glioma invasion resulting from CTX-NO treatment was partially a consequence of decreased levels of surface and activated MMP-2 and MMP-9. The work presented in this thesis describes a novel approach to treating GBM that can be modified to develop treatments for various other tumors. Furthermore this is the first study to develop glioma-targeting NO donors.
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吳燕燕 and Yin-yin Go. "Quantitative structural studies of neoplasms of the parotid gland." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 1995. http://hub.hku.hk/bib/B31212281.
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Chan, Chiu-lung Richie, and 陳肖龍. "Mucosal melanoma of the head and neck." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2011. http://hub.hku.hk/bib/B46632876.
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Zhu, Quan. "Role of CDP in MMTV transcriptional regulation and tumorigenesis." Access restricted to users with UT Austin EID, 2001. http://wwwlib.umi.com/cr/utexas/fullcit?p3037038.
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Johansson, Soller Maria. "Cytogenetic studies of lung tumors." Lund : Dept. of Clinical Genetics, University of Lund, 1994. http://catalog.hathitrust.org/api/volumes/oclc/39068855.html.
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Yun, Michael Jino. "Radiosurgery for Malignant Brain Tumors." VCU Scholars Compass, 1994. http://scholarscompass.vcu.edu/etd/5088.
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Radiosurgery using the Linear Accelerator or the Gamma Knife has proven to be an effective treatment modality for malignant brain tumors. In comparison to other treatments, radiosurgery can be performed on an outpatient basis and is noninvasive (Table 5). Due to the functional properties of radiosurgical devices, they are ideal for patients who are unable to undergo surgical removal of their brain tumors. The sharp dose drop—off beyond the tumor margin allows for high dosage tumor irradiation while sparing normal brain tissue. Many procedures that involve radiosurgery use it as a ”boost” therapy in conjunction with surgical resection and whole brain irradiation. ”Boost" therapy enhances the standard treatment procedure for malignant brain tumors.
Unfortunately, radiosurgery is not always able to halt the progression of malignant brain tumors. Patients with metastatic brain tumors usually succumb to systemic disease. Patients who have gliomas generally die due to the inability of local tumor control. However, the use of radiosurgery can contribute to increasing a patient’s quality of life. Often, treatment is followed by a decrease in corticosteroid administration and an improvement in a patient's neurological status. The future directions of radiosurgery could include the development and implementation of a randomized studies to determine a dose-volume protocol for gliomas and the different forms of metastases. Also, an investigation should be undertaken to determine whether the use of high (50 Gy or more) radiosurgical doses as the only treatment for gliomas and cerebral metastases would prove to be a more effective use than ”boost” therapy.
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Vamvakidou, Alexandra P. T̈ozeren Aydin. "Phenotypic heterogeneity of breast tumors /." Philadelphia, Pa. : Drexel University, 2007. http://hdl.handle.net/1860/1777.
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Einarsdóttir, Hildur. "Imaging of soft tissue tumors /." Stockholm, 2003. http://diss.kib.ki.se/2003/91-7349-647-2/.
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Kjellman, Magnus. "Genetic characterization of adrenocortical tumors /." Stockholm, 1999. http://diss.kib.ki.se/1999/91-628-3358-8/.
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Jandial, Rahul. "Lineage mapping of brain tumors." Diss., Connect to a 24 p. preview or request complete full text in PDF format. Access restricted to UC campuses, 2008. http://wwwlib.umi.com/cr/ucsd/fullcit?p3306998.
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Thesis (Ph. D.)--University of California, San Diego, 2008.Title from first page of PDF file (viewed June 30, 2008). Available via ProQuest Digital Dissertations. Vita. Includes bibliographical references (p. 125-137).
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Nguyen, Thi Trang Huyen. "How are pancreatic tumors innervated?" Thesis, Aix-Marseille, 2017. http://www.theses.fr/2017AIXM0536.
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L’adénocarcinome canalaire du pancréas (PDAC) est un des cancers les plus agressifs avec un taux de survie à 5 ans de moins de 5 %. Une des raisons est l’absence de traitement thérapeutique efficace. Des efforts afin d’identifier de nouvelles cibles pour le traitement du PDAC sont donc nécessaires. Il a été démontré que la dénervation du pancréas régule la progression des PDAC dans des modèles murins. De plus, on a rapporté que les axones du système nerveux périphérique (SNP) innervent les tumeurs pancréatiques, mais l'identité précise des fibres infiltrant la tumeur est inconnue.Ici, nous avons caractérisé le remodelage des principales divisions du SNP, y compris les systèmes autonomes et sensoriels, dans des modèles murins qui récapitulent la maladie humaine. Nous avons aussi commencé à caractériser l'innervation des PDAC dans des échantillons humains. Nous avons observé une augmentation de la densité des fibres sympathiques positives pour la tyrosine hydroxylase (TH) dans les lésions pré-tumorales du pancréas, alors qu'une forte densité de fibres sensorielles positives pour le peptide lié au gène de la calcitonine (CGRP) a été observée dans les PDAC. Fait intéressant, alors que dans tissus normaux les axones sympathiques et sensoriels sont principalement associés aux vaisseaux sanguins, ils sont majoritairement isolés dans les lésions pré-tumorales et les PDAC. Ces données suggèrent que la plasticité axonale survient aux stades précoces du développement tumoral pour les fibres sympathiques et à un stade plus tardif pour les fibres sensorielles. Ce travail suggère de nouvelles cibles potentielles pour le traitement des PDACPancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers with 5-year survival rate of less than 5%. One reason to explain this poor outcome is that there has been no effective therapeutic treatment for PDAC patients. Thus, efforts to identify novel targets for PDAC treatment are required. Denervation of the pancreas has been shown to regulate PDAC progression in murine models. In addition, axons of the peripheral nervous system (PNS) have been reported to innervate pancreatic tumors, but the precise identity of the tumor-infiltrating fibers is unknown. Here we characterized the remodeling of the main divisions of the PNS, including autonomic and sensory systems, in mouse models, which recapitulate the human disease. We also started to characterize the innervation of human PDAC samples. We observed an increased density of tyrosine hydroxylase (TH)-positive sympathetic fibers in pre-tumoral lesions of the pancreas, while a high density of calcitonin gene-related peptide (CGRP)-positive sensory fibers was seen within PDAC. Interestingly, whereas in the normal tissues TH+ and CGRP+ axons were mostly associated to blood vessels, they were mainly isolated in lesions and PDAC. These data suggest that axonal plasticity occurs at the early stage of tumor development for sympathetic fibers and at the late stage for sensory fibers. This work suggests potential novel targets for the treatment of PDAC
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Taylor, Charles Dariush. "Structural characterisation and analysis of human cripto-1." Thesis, University of Oxford, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.670042.
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Monteiro, Vasconcelos Ines [Verfasser]. "Epigenetic quantification of tumor-infiltrating T-lymphocytes in epithelial ovarian tumors / Ines Monteiro Vasconcelos." Berlin : Medizinische Fakultät Charité - Universitätsmedizin Berlin, 2014. http://d-nb.info/1052529828/34.
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Wang, Dian. "Mutational Inactivation of The P53 Tumor Suppressor Gene in Chemically-Induced Rat Esophageal Tumors /." The Ohio State University, 1996. http://rave.ohiolink.edu/etdc/view?acc_num=osu1487933245536557.
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Jin, Ling. "Study of tumorigenesis by means of transgenic mouse models expressing RET/PTC3 rearrangement and E7 under control of bovine thyroglobulin promoter and CD1 mouse strain treated with acrylamide." Doctoral thesis, Universite Libre de Bruxelles, 2009. http://hdl.handle.net/2013/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/210285.
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Thyroid carcinomas are the most common endocrine tumors in humans. There are three major types of carcinomas of thyrocyte origin, including papillary, follicular, and anaplastic carcinomas. Papillary thyroid carcinoma (PTC) is the most common type of thyroid malignancy accounting 80% of thyroid cancer cases, and present several histologic variants, namely classical (45%), follicular (18%), solid, diffuse-sclerosing, cribriform, … .Specific genetic events represent early initiating and late triggering events. Several genetic lesions have been identified in various thyroid carcinomas and some of them are specifically associated to one type thyroid cancer. For instance, RET/PTC is the most common molecular event in the radiation-associated PTC in childhood. In the first part of the work, we studied two transgenic mouse models: the Tg-RET/PTC3 (Tg-RP3) mouse and the Tg-E7 mouse. Both strains express the human origin transgene (RET/PTC3 rearrangement or E7) exclusively in the thyroid under the control of the bovine thyroglobulin promoter.
Our study of these two models showed:
In both E7 and RET/PTC3 mouse models, the thyroids exhibited hyperplasia with own 'oncogene-dependent' follicular cell characteristics. Small follicular cells with hyperchromatic nuclei with an increased nucleus/cytoplasm ratio were numerous in the E7 mice, and large cells with convex apical border, a decreased nucleus/cytoplasm ratio, a pale nucleus and dispersed chromatin were found in the RET/PTC3 mice.
At 6, 10 months and later on, E7 mice developed huge heterogeneous, normal functional thyroid goiter, with no tumor formation.
As in previous studies on transgenic RET/PTC3 mouse models, the generally encountered features such as solid tumours were present. We also observed conventional variant of human PTC at late age (since 11 month-old) with quite low incidence (4%). In addition to solid and conventional variant PTCs, 28% of mice developed a peculiar big size thyroid tumor pattern with “proliferative papillary cystic changes with spindle cells and remodelling” and macrophage infiltration in the cysts at as early as 2 month of age; this kind of tumor histologically resembles the rare human young age 'diffused sclerosing' variant PTC (DSVP), but disappeared after 6 month. The other peculiar tumor exhibits morphological similarity with another rare human FAP-associated (Familial Adenomatous colonic polyposis) cribriform PTC, which showed a mixed architecture of several histological patterns (solid, follicular, cribriform). At 6 months, 26% of mice presented the cribriform tumor pattern.
From the analyse of the proliferation index in the two models, we conclude that RET/PTC3 fusion protein over stimulates MAPK and Akt/PKB-signalling pathways, through Ras-Raf-Mek-Erk, Ras-PI3-K/Akt/PKB, particularly in the large cells which were strongly positive for three proliferation markers. E7 bypasses these two pathways, by directly binding to Rb1 protein and releasing the E2F transcription factor which induces cell proliferation.
So RET/PTC3 and E7 mice present several morphologic features which mimic human PTC tumors; RET/PTC3 could therefore be used as a partial model for human PTCs.
Further investigation of gene expression will allow the characterization of the molecular phenotype of the observed variants.
In the second part of the work, we attempted to generate by xenobiotic administration an in vivo model of thyroid carcinoma. Chronic exposure of CD1 mice to acrylamide in the drinking water during 6 and 8 months at doses of 3mg/kg per day similar to those causing thyroid tumorigenesis after 2 years in rats, did not induce any thyroid tumors whatever the level of thyroid stimulation.
Doctorat en Sciences biomédicales et pharmaceutiques
info:eu-repo/semantics/nonPublished
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Cuellar, Baena Sandra Patricia. "Quantificação de sinais de MRS do cérebro in-vivo para classificação de tumores." [s.n.], 2008. http://repositorio.unicamp.br/jspui/handle/REPOSIP/277860.
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Orientador: Gabriela CastellanoDissertação (mestrado) - Universidade Estadual de Campinas, Instituto de Fisica Gleb Wataghin.
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Resumo: Este trabalho visou o estudo e validação de técnicas de pre-processamento e quantificação de dados provenientes da técnica de Espectroscopia por Ressonância Magnética (MRS, do inglês Magnetic Resonance Spectroscopy), obtidos do cérebro humano in vivo, para a extração de informação que fosse clinicamente relevante para o estudo e diagnostico de tumores cerebrais. Para isso, foi feito o estudo da técnica com base na literatura, incluindo a revisão dos aspectos físicos envolvidos, estudando os métodos computacionais utilizados para o pre-processamento e quantificação dos dados, e os aspectos bioquímicos dos metabólicos de interesse presentes no cérebro humano, passiveis de serem quantificados através da técnica. Especificamente, foi estudado um método de quantificação de dados de MRS, o método. AMARES (Advanced Method for Accurate, Robust and Efficient Spectral fitting of MRS data), aplicado na quantificação de dados de MRS adquiridos de sujeitos controles e pacientes portadores de tumores cerebrais, provenientes de uma base de dados do Laboratório de Neuroimagem (LNI - Hospital das Clinicas - UNICAMP). Isso foi feito utilizando o software de domínio público jMRUI (http://sermn02.uab.es/mrui/)[1], que possui o método AMARES já implementado. Estes resultados foram comparados com resultados provenientes de uma quantificação manual desses mesmos dados, realizada previamente como parte do projeto de doutorado da Dra. Andréia Vasconcellos (atual docente do Depto. de Radiologia da FCM/UNICAMP)[2]. Foi verificada a concordância entre os dois métodos de quantificação, e também a viabilidade de usar os resultados da quantificação com o método automático para alem de diferenciar entre os grupos de pacientes e controles, realizar a separação dos Pacientes com tumores em diferentes grupos. Obteve-se que os resultados obtidos com o método automático foram mais precisos e consistentes que os obtidos com o método manual, e permitiram uma melhor classificação dos tipos de tumores. Adicionalmente, foram incluídos neste trabalho os resultados do estudo de perfis metabólicos ex vivo em tumores cerebrais pediátricos através da técnica HR-MAS (do inglês High Resolution Magic Angle Spinning). Este estudo adicional foi realizado no Laboratório de Imagem Molecular da Faculdade de Medicina da Universidade de Valencia (Espanha) através do Programa Santander de Mobilidade Internacional e financiado através de uma bolsa do Banco Santander-Banespa.
Abstract: The aim of this work was to study and validate techniques for pre-processing and quantificating Magnetic Resonance Spectroscopy data, obtained in vivo from the human brain, in order to get information clinically useful for the study and diagnosis of brain tumors. Therefore, a literature-based study of the technique was made, including a review of the Physics concepts involved, the data acquisition process in the scanner and the computational methods used to pre-process and quantificate the spectral data, as well as the biochemical aspects of the metabolites of interest in the human brain that can be detected by this technique. Special attention was given to the AMARES (Advanced Method for Accurate, Robust and Efficient Spectral fitting of MRS data) method for MRS data quantification, which was studied and applied to the quantification of data from control subjects and patients with brain tumors. The data came from a database of the Neuroimaging Laboratory (LNI - Hospital das Clinicas - UNICAMP). The quantification with AMARES was made through the jMRUI software (http://sermn02.uab.es/mrui/) [1], a public domain software for processing and quantification of MRS data. These results were compared to the results obtained with a manual quantification of the same data, previously done as part of the PhD thesis work of Dr. Andreia Vasconcellos (lecturer from the Radiology Department of the School of Medicine, UNICAMP) [2]. The agreement between the results from both quantification methods was verified, as well as the feasibility of using the automatic quantification results to differentiate among tumor types, besides differentiating between patients and controls. Results obtained by the automatic method were more accurate and consistent than those obtained by the manual method allowing a better classification. Additionally, in this work were included the results of the study of ex vivo and in vivo metabolic profiling in pediatric brain tumors using the HR-MAS (High Resolution Magic Angle Spinning) technique. This study was carried out in the Molecular Imaging Laboratory, School of Medicine at the University of Val¿encia (Spain), within the Santander-Banespa Bank International Exchange Program.
Mestrado
Física
Mestre em Física
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Pedro, Renato Nardi. "Uso da nanopartícula de ouro ligada a moléculas de fator alfa de necrose tumoral como adjuvante da termoablação por radiofrequência de tumores renais = modelo animal experimental." [s.n.], 2010. http://repositorio.unicamp.br/jspui/handle/REPOSIP/310676.
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Orientadores: Marcelo Lopes de Lima, Nelson Rodrigues Netto JuniorTese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas
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Resumo: O tratamento definitivo das massas renais malignas é primordialmente cirúrgico, sendo a nefrectomia radical eleita por muitos anos a cirurgia padrão para o tratamento do câncer renal localizado. Entretanto, com o envelhecimento populacional, maiores são as preocupações em se manter a capacidade funcional dos órgãos e sistemas do corpo humano. Portanto, a necessidade de se preservar tecido renal sadio durante o tratamento do câncer renal localizado, com auxílio de cirurgias parciais poupadoras de néfrons, se tornou imperativa. O tratamento de lesões renais sólidas pequenas passou a ter diferentes formas de abordagem, que variam desde técnicas de termoablação percutânea ou laparoscópica, nefrectomia parcial laparoscópica e aberta à até tradicional nefrectomia radical aberta. O uso de modalidades de tratamento cirúrgico com mínimo grau de agressão passou a ganhar atenção, devido à rápida recuperação do paciente, ao menor risco de complicações cirúrgicas e aos bons resultados oncológicos. Ablação por radiofreqüência (ARF) tem se mostrado um meio eficiente no tratamento de tumores renais pequenos e exofiticos. Atualmente, sua indicação é restrita a lesões de até 4 cm. O presente estudo foi montado para avaliar o uso conjunto da nanopartícula de ouro e fator alfa de necrose tumoral (TNF alfa) à ARF no tratamento de um modelo experimental de tumor renal. Materiais e Métodos: Trinta e sete coelhos brancos da raça New Zealand tiveram implantados em seus rins, através de uma laparotomia, um fragmento de 1 mm3 de tumor VX-2. Após 14 dias do implante, quando seus rins haviam desenvolvido uma lesão tumoral sólida menor que 1 cm, os animais foram divididos em 3 grupos de 10 e 1 grupo de 7 integrantes (sham) de acordo com o tratamento selecionado para o tumor renal focal: 1) Nanopartícula com TNF alfa; 2) Ablação por radiofreqüência; 3) Nanopartícula com TNF alfa seguido de Ablação por radiofreqüência; 4) Grupo sham. Todos os animais foram submetidos a mesma cronologia de tratamento, composta por 2 laparotomias e eutanásia. Os grupos tratados com as nanopartículas de ouro com fator alfa de necrose tumoral isolada ou complementarmente, as receberam 4 horas antes do procedimento cirúrgico na dose de 200 µm/Kg. A análise de resultados foi realizada com medidas macroscópicas e microscópicas do volume da área de ablação ou tumoral, segundo a fórmula do volume de uma elipsóide. Avaliação estatística foi realizada com Teste T Student, sendo considerado significante p<0.05. Resultados: O grupo que recebeu a nanopartícula com fator alfa de necrose tumoral e depois foi submetido à ARF apresentou maior zona de morte celular completa quando comparado ao grupo tratado somente com ablação por radiofreqüência (0.30 ± 0.07 vs 0.23 ± 0.03 mL, P=.03). A zona de transição foi menor no grupo que recebeu a nanopartícula com fator alfa de necrose tumoral e ablação por radiofreqüência quando comparada ao grupo tratado somente com ablação por radiofreqüência (0.08 ± 0.02 vs 0.13 ± 0.05 mL, P =.01). Conclusão: O presente estudo demonstrou que o uso da nanopartícula de ouro com TNF alfa sensibiliza o insulto térmico sofrido por tumores sólidos decorrentes da ablação por radiofreqüência
Abstract: Radical nephrectomy has long been considered as gold standard treatment for localized renal tumors. However due to an increase in life expectation, organ sparing surgeries have emerged with the purpose of preserving as much healthy tissue as possible. Therefore, nephron sparing surgeries have become another valid option for localized renal tumors. There are different modalities of nephron sparing procedures, including open partial nephrectomy, laparoscopic nephrectomy and termoablative procedures. The later is associated with less morbidity and fast patient recovery. Radiofrequency ablation (RFA) is a well-known termoablative procedure and it has been most effective when the tumors are small, exophytic, and away from vital structures. The present study was designed to analyze the adjuvant use of gold nanoparticle with tumor necrosis factor alpha prior to radiofrequency ablation in a translational model of localized renal tumor. Material and Methods: A total of 37 New Zealand White rabbits had VX-2 tumors implanted into their kidneys; they were allowed to grow for 14 days, when a tumor mass of less than 1 cm could be detected. The animals were then split into 3 treatment groups of 10 rabbits each and a sham group of 7 rabbits as follows: (1) Tumor necrosis factor alpha plus nanoparticle, (2) Radiofrequency ablation, (3) Tumor necrosis factor alpha nanoparticle (200 µm/Kg) followed 4 hours later by radiofrequency ablation. All groups were subjected to the same milestones of the experiment which was comprised of 2 laparotomies and sacrification. Gross and microscopic measurements of the ablation size as well as histological analysis using hematoxylin and eosin staining were performed to determine the effect of TNF alpha nanoparticle on the ablation. Statistical analysis was performed with Student's T test, considering p < 0.05 as significant. Results: The RFA plus TNF alpha nanoparticle group had a larger zone of complete cell death than the RFA-only group (0.30 ± 0.07 vs 0.23 ± 0.03 mL, P=.03). The zone of partially ablated tissue was smaller in the RFA plus TNF alpha nanoparticle group than in the RFA-only group (0.08 ± 0.02 vs 0.13 ± 0.05 mL, P =.01). Conclusions: We have demonstrated the efficacy of TNF alpha nanoparticle in enhancing RFA in a translational kidney tumor model. The potential usage of TNF alpha nanoparticle to improve RFA of renal cell carcinoma merits further study
Doutorado
Fisiopatologia Cirúrgica
Doutor em Ciências
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Capdevila, i. Castillón Jaume. "Tipificació molecular de tumors neuroendocrins gastroenteropancreàtics. Desenvolupament de noves teràpies i búsqueda de nous biomarcadors." Doctoral thesis, Universitat Autònoma de Barcelona, 2016. http://hdl.handle.net/10803/399562.
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El coneixement de la biologia molecular responsable de la carcinogènesi de les neoplàsies neuroendocrines segueix essent limitada avui en dia. Aquest fet, ha limitat la identificació de biomarcadors pronòstics i predictius i el desenvolupament de teràpies dirigies en aquesta població de pacients. L’objectiu de la present tesi doctoral ha estat identificar les alteracions genòmiques i epigenòmiques de neoplàsies neuroendocrines digestives i valorar la possibilitat de crear models murins derivats de pacients com a pas previ al disseny d’estudis clínics en pacients segons les alteracions moleculars observades. El treball s’ha centrat en carcinomes neuroendocrins de primari colònic, un tipus tumoral poc freqüent, d’elevada agressivitat i orfe de tractament.
Inicialment, a través del grup nacional de tumors endocrins (GETNE) s’han identificat mostres tumorals parafinades de pacients amb carcinomes neuroendocrins de primari colònic, s’ha confirmat el diagnòstic anatomopatològic i s’han realitzat estudis genòmics i epigenòmics per a la correcta tipificació molecular de les alteracions presents en aquest tipus de tumor. Paral·lelament, s’ha aconseguit crear un model murí derivat de pacient amb carcinoma neuroendocrí portador de mutació en el gen BRAF per a poder realitzar experiments in vitro amb teràpies dirigides contra aquesta mutació. En resum, els resultats han permès identificar les mutacions més prevalents en carcinomes neuroendocrins de còlon, destacant l’elevat percentatge de mutacions V600E en el gen BRAF comparat amb l’adenocarcinoma de còlon. Així mateix, el perfil de metil·lació de l’ADN dels carcinoma neuroendocrins de còlon és significativament diferent a l’observat en adenocarcinomes de còlon, que juntament amb el perfil genòmic i l’inestabilitat cromosòmica observada en el neuroendocrí confirmen les diferències tant en l’origen de les dues neoplàsies, com en la biologia molecular i la probabilitat de resposta a teràpies dirigides confirmada en els models PDX.
Els resultats del present treball de tesi doctoral permetran continuar amb l’estudi de les característiques moleculars d’aquesta població de pacients, la búsqueda de nous biomarcadors i el disseny d’estudis dirigits per a una població de pacients actualment orfe de tractament efectiu.The knowledge of the molecular biology of the neuroendocrine tumors carcinogenesis is still limited today. This fact has limited predictive and prognostic biomarker identification and the development of therapies aimed at this population of patients. The aim of this work was to identify genomic and epigenomic changes of neuroendocrine tumors of gastrointestinal tract and assess the possibility of creating mouse models derived from patients as a prelude to the design of clinical studies in patients based on the molecular alterations observed. The work has focused on primary colonic neuroendocrine carcinomas, a rare, treatment orphan and highly aggressive tumor. Initially, through the national group of endocrine tumors (GETNE) paraffin-embedded tumor samples were identified of patients with neuroendocrine carcinoma of primary colonic. After centrally pathological confirmation genomic and epigenomic studies have been conducted to characterize the molecular alterations of this tumor type. Meanwhile, it has managed to create an animal model derived from patients with neuroendocrine carcinoma carrier of the gene mutation in BRAF to carry out experiments in vitro with targeted therapies against this mutation. In summary, the results have enabled us to identify the most prevalent mutations in neuroendocrine carcinomas of the colon, highlighting the high percentage of mutations V600E in the gene BRAF compared with the adenocarcinoma of the colon. Also, the DNA methylation profile of neuroendocrine carcinoma of the colon is significantly different from that observed in adenocarcinomas of the colon, which together with the genomic profile and chromosomal instability observed in neuroendocrine carcinomas confirm the differences in the origin of the two cancers, the molecular biology of both cancer types and the likelihood of response to targeted therapies confirmed in the PDX models. The results of this doctoral thesis will continue with the study of the molecular characteristics of this patient population, the search for new biomarkers and the design of clinical trials aimed for an orphan patient population currently lacking of effective treatment.
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de, Villiers Neil Heinrich. "Tumour metabolism and radioprotection of normal tissue in Balb/c and CBA mice." Thesis, Cape Technikon, 1992. http://hdl.handle.net/20.500.11838/2253.
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Thesis (MTech (Medical Technology))--Cape Technikon, 1992.The steady state in a tumour rapidly changes with its growth and the subsequent deteriorating blood and nutrient supply. This adaptation in the steady state of the tumour is shown in the increased lactate dehydrogenase and acid phosphatase activity in the tumour during it's growth. These alterations in the tumour metabolism places an increased burden on the body to supply nutrient and to discard the waste products of the tumour. This is demonstrated at the macroscopic level by the decreasing body weight and food intake when the tumour burden increases, and also at the metabolic levels by the responses of certain glycolytic and Cori cycle enzymes. Furthermore three distinct stages were observed in the Cori cycle response to the influence of the tumour namely, a silent or preclinical stage, a hypermetabolic stage and a hypometabolic stage. Although the decreasing body weight cannot be directly linked to the process of gluconeogenesis, the onset of anorexia appeared to coincide with the end of the hypermetabolic stage and the beginning of the hypometabolic stage in gluconeogenesis. This clearly shows that the body's steady state is adversely affected by the presence of the tumour and that the conditions at the metabolic level seem to cause the anorexia. Furthermore, it is well known that the success of cancer therapies depends entirely on the effectiveness of the modality to kill the tumour cell and on the ability' of the host to absorb the damage caused by the modality without being destroyed in the process itself. The second part of this study demonstrates the radioprotective effects of ATP at all levels. It is clear from this work that ATP had a bigger influence in protecting the normal tissue than it had on the tumour tissue. This was demonstrated by the response of acid phosphatase (AP) and glucose-ó-phosphate dehydrogenase (G-6-PDH) in the tumour and testis. Furthermore, it would seem that ATP has a multifactorial interaction with the cell, two possible mechanisms of protection are indicated by these results. The first of these interactions is through the receptors of the cell to stimulate enhanced glycolysis, for higher energy production and thus repair. The second possibility is the interaction of ATP with the receptor of the cell to inhibit the production of free radicals and thus damage, as demonstrated by the response of G-6-PDH and AP.
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Jimenez, Carolina Dias [UNESP]. "Relação entre os sinais clínicos neurológicos e os achados tomográficos de 20 cães com suspeita de neoplasia intracraniana." Universidade Estadual Paulista (UNESP), 2010. http://hdl.handle.net/11449/94577.
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O intuito deste estudo foi determinar se os sinais neurológicos apresentados por cães com suspeita de neoplasia intracraniana foram compatíveis com a localização anatômica do tumor determinada com a utilização da tomografia computadorizada. Foram estudados 20 cães submetidos a avaliação neurológica e exame tomográfico encefálico. Estes cães foram divididos em 3 grupos de acordo com a área anatômica envolvida. Grupo I (n=14) animais com lesão em telencéfalo, diencéfalo e síndrome cerebral. Grupo II (n=4) lesão em tronco encefálico e cerebelo com síndrome cerebelar e de tronco encefálico. Grupo III (n=2) cães com lesão em diencéfalo compatível com tumor hipofisário apresentando síndrome cerebral. Aproximadamente 65% dos cães apresentaram sinais neurológicos compatíveis com a localização da lesão tumoral, evidenciada na tomografia. Nos outros animais (35%) todos pertencentes do grupo I foram observados sinais clínicos não associados à lesão tumoral primária estando provavelmente associados aos efeitos secundários decorrentes da lesão, tais como edema peritumoral, hemorragia, hidrocefalia, aumento de pressão intracraniana, processos inflamatórios dentre outros
The purpose of this study was to determine if neurological signs shown by dogs with suspected intracranial neoplasm were consistent with the anatomical location of the tumor determined using computed tomography. We studied 20 dogs underwent neurological evaluation and brain CT scan. These dogs were divided into three groups according to the anatomic area involved. Group I (n = 14) animals with lesions in the telencephalon, diencephalon and brain syndrome. Group II (n = 4) lesion in brain stem and cerebellum with cerebellar syndrome and brainstem. Group III (n = 2) in dogs with injuries consistent with diencephalon pituitary tumor presenting brain syndrome. Approximately 65% of dogs had neurologic signs consistent with the location of the tumor, shown on CT. In other animals (35%) all belonging to group I showed no clinical signs associated with primary tumor and is probably associated with side effects resulting from injury, such as peritumoral edema, hemorrhage, hydrocephalus, increased intracranial pressure, inflammatory processes and others
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Barreta, Amilcar 1980. "Laparoscopia na abordagem inicial de tumores anexiais = Laparoscopy for diagnosis and treatment of adnexal tumors." [s.n.], 2012. http://repositorio.unicamp.br/jspui/handle/REPOSIP/312141.
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Orientadores: Sophie Françoise Mauricette Derchain, Joana Fróes Bragança BastosDissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas
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Resumo: Introdução: O câncer de ovário é o sétimo câncer mais comum em mulheres. A sensibilidade e especificidade dos exames laboratoriais e de imagem não são adequadas para o diagnóstico de câncer de ovário. Atualmente o padrão-ouro para o diagnóstico do câncer de ovário é o exame histopatológico em parafina. Por este motivo, aproximadamente 10% das mulheres terão que ser operadas devido a um tumor anexial durante sua vida. A laparoscopia é comumente usada na tentativa de reduzir a morbidade cirúrgica nestes casos. Objetivo: Avaliar as diferenças nas características clínicas, no diagnóstico histopatológico, na duração da cirurgia e na incidência de complicações cirúrgicas em mulheres submetidas à laparoscopia e à laparotomia para diagnóstico e tratamento de tumores anexiais, e avaliar os fatores associados à falha da laparoscopia (conversão à laparotomia). Sujeitos e métodos: Para este estudo prospectivo foram convidadas a participar 210 mulheres com tumor anexial, dentre as quais foram incluídas 133 mulheres com indicação cirúrgica. Oitenta e oito mulheres foram submetidas à laparotomia e 45 foram submetidas à laparoscopia. Catorze das 45 laparoscopias foram convertidas à laparotomia durante o procedimento cirúrgico. Foi avaliado se idade, índice de massa corpórea (IMC), número de cirurgias abdominais prévias, níveis do marcador tumoral CA-125, valores do Índice de Risco de Malignidade (IRM), maior diâmetro do tumor, diagnóstico histopatológico, duração da cirurgia e número de complicações cirúrgicas diferiram entre o grupo de mulheres submetidas à laparoscopia e o grupo submetido à laparotomia, e se estes fatores estiveram associados à conversão da laparoscopia em laparotomia. Foram também avaliados os motivos intraoperatórios para conversão da laparoscopia em laparotomia conforme relatado pelos cirurgiões nos registros cirúrgicos. Resultados: A prevalência de tumores malignos neste estudo foi de 30%. Os níveis do CA-125, os valores do IRM, o maior diâmetro do tumor e a duração da cirurgia foram maiores no grupo da laparotomia que no grupo da laparoscopia. A incidência de complicações foi similar quando comparados os grupos de laparotomia e laparoscopia e quando comparados os grupos de laparoscopias bem sucedidas com o grupo de laparoscopias convertidas à laparotomia. Quando foram analisadas mulheres com tumores anexiais benignos, a incidência de complicações foi menor no grupo da laparoscopia quando comparado ao grupo da laparotomia. Os fatores associados à falha da laparoscopia (conversão à laparotomia) foram o maior diâmetro do tumor e a presença de tumor maligno. Durante a laparoscopia, os principais motivos relatados nos registros cirúrgicos como causa de conversão em laparotomia foram: o diâmetro do tumor e a presença de aderências peritoneais. Conclusões: Este estudo sugere que o diâmetro do tumor, a presença de aderências peritoneais e a presença de um tumor maligno são as principais causas de conversão de uma laparoscopia em laparotomia. A conversão, entretanto, não aumenta a incidência de complicações cirúrgicas
Abstract: Introduction: Ovarian cancer is the seventh most common cancer in women. Imaging and laboratorial exams do not have adequate sensitivity and specificity to diagnose adnexal cancer. The gold-standard for adnexal cancer diagnose is the histopathological exam at paraffin section. For this reason about 10% of the women will have to be operated by an adnexal tumor during their lifetime. Laparoscopy is frequently used to reduce surgical morbidity at those cases. Objective: To assess the differences in clinical factors, histopathologic diagnose, operative time and complication rates between women undergoing laparoscopy or laparotomy to diagnose and treat an adnexal mass and to evaluate the factors that are associated with laparoscopy failure and conversion to laparotomy. Subjects and methods: In this prospective study, 210 women were invited to participate, of which 133 women with adnexal masses were included. Eighty-eight women underwent laparotomy and 45 women underwent laparoscopy. Fourteen of the 45 laparoscopies were further converted to laparotomy during the surgical procedure. We assessed whether age, body mass index (BMI), previous abdominal surgeries, CA-125 levels, Index of Risk of Malignancy (IRM), tumor diameter, histological diagnose, operative time and surgical complication rates differed from laparoscopy to laparotomy group and whether those factors were associated with conversion of laparoscopy to laparotomy. We also assessed surgical logs to evaluate the intraoperative reasons, as stated by the surgeons, to convert a previously indicated laparoscopy to laparotomy. Results: 30% of women at our study had malignant tumors. CA-125 levels, IRM values, tumor diameter and operative times were higher for the laparotomy group compared to the laparoscopy group. Complication rates were similar for the laparoscopy and laparotomy groups and also for successful laparoscopy and laparoscopy converted to laparotomy groups. Surgical complication rate in women with benign tumors was lower for the laparoscopy group compared to that for the laparotomy group. The clinical factors associated with laparoscopy failure (conversion to laparotomy) were the largest tumor diameter and malignancy. During laparoscopy, adhesions and the largest tumor diameter were the principal factors reported as causes of conversion. Conclusions: This study suggests that tumor diameter, peritoneal adhesions and the presence of a malignant tumor were the principal causes of laparoscopy conversion to laparotomy. However the conversion did not increase complication rates
Mestrado
Oncologia Ginecológica e Mamária
Mestre em Ciências da Saúde
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Fonseca, Felipe Paiva 1986. "Semaphorins and neuropilins in salivary gland tumors : Semaforinas e neuropilinas em tumores de glândulas salivares." [s.n.], 2015. http://repositorio.unicamp.br/jspui/handle/REPOSIP/288411.
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Orientador: Pablo Agustin VargasTese (doutorado) - Universidade Estadual de Campinas, Faculdade de Odontologia de Piracicaba
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Resumo: Tumores de glândulas salivares correspondem a aproximadamente 3% de todas as neoplasias de cabeça e pescoço e as neoplasias malignas derivadas destas estruturas anatômicas ainda representam um grande desafio para a oncologia de cabeça e pescoço devido a sua difícil abordagem cirúrgica e pobre resposta às outras abordagens terapêuticas. Um melhor entendimento do seu perfil molecular contribuiria significativamente para um melhor manejo terapêutico futuro e o estudo do potencial angiogênico dos tumores de glândulas salivares representa um interessante alvo de investigação. Tem sido demonstrado que as semaforinas induzem a apoptose de células tumorais, modulam a migração celular neoplásica e inibem a angiogênese em diferentes neoplasias humanas, competindo com o fator de crescimento endotelial vascular (VEGF) pela ligação aos seus principais receptores, as neuropilinas-1 e -2, desta forma inibindo os efeitos mitogênicos e pró-angiogênicos de VEGF. Assim, o objetivo deste estudo é investigar a expressão das semaforinas de classe 3 A e B (Sema3A e Sema3B), e dos seus receptores neuropilinas-1 e -2 (Np-1 e Np-2) em tumores de glândulas salivares, determinando seus significados clínicos. Duzentos e quarenta e oito tumores benignos e malignos de glândulas salivares selecionados de quatro instituições brasileiras foram organizados em blocos de parafina em microarranjo tecidual em matriz e submetidos a reações de imunoistoquímica contra CD34, Sema3A, Sema3B, Np-1 e Np-2. As imunoreações foram quantificadas utilizando algoritmos digitais e os resultados foram correlacionados com parâmetros clinicopatológicos e índices de sobrevida. Tumores malignos apresentaram uma maior densidade vascular, porém uma menor área vascular do que sua contraparte benigna. Em glândulas salivares normais a expressão de Np-1 e -2 esteve restrita às células ductais, enquanto que Sema3A e Sema3B estiveram principalmente no componente acinar. Tumores benignos e malignos revelaram uma expressão similar de todos os marcadores e a co-expressão de Np-1/Np-2 correlacionou-se significativamente com a ocorrência de parestesias e estágios mais avançados dos tumores. Apesar de não ser estatisticamente significativa, a sobre-expressão simultânea de ambos os receptores também indicou uma menor taxa de sobrevida. Desta forma, Sema3A, Sema3B, Np-1 e Np-2 devem estar envolvidas no desenvolvimento das glândulas salivares normais e na patogênese das neoplasias benignas e malignas derivadas destas estruturas; entretanto, a expressão destas proteínas não apresentou um potencial prognóstico estatisticamente significativo no presente estudo
Abstract: Salivary gland tumors correspond to approximately 3% of all head and neck neoplasms and the malignant neoplasias derived from these anatomic structures still represent a major pitfall in head and neck oncology because of their difficult surgical approach and poor response to other therapies. A better understanding of their molecular basis would significantly aid to an improved future management and the study of salivary gland tumors angiogenic potential represents an interesting target of investigation. It has been shown that semaphorins induce tumor cell apoptosis, modulate tumor cell migration and inhibit angiogenesis in different human neoplasms, competing with vascular endothelial growth factor (VEGF) for biding to their main receptors, the neuropilins-1 and -2, thereby inhibiting mitogenic and pro-angiogenic effects of VEGF. Hence, the objective of this study is to investigate the expression of class 3 Semaphorins A and B, and their receptors neuropilins-1 and -2 in salivary gland tumors, determining their clinical significance. Two hundred and forty eight benign and malignant salivary gland tumors selected from four Brazilian institutions were organized in tissue microarray paraffin blocks and submitted to immunohistochemical reactions against CD34, Sema3A, Sema3B, Np-1 and Np-2. The immunoreactions were quantified using digital algorithms and the results were correlated with clinicopathological parameters and survival rates. Malignant tumors presented an increased vascular density but a lower vascular area than their benign counterparts. In normal salivary glands Np-1 and Np-2 expression was restricted to ductal cells, whereas Sema3A and Sema3B were positive mainly in serous acinar compartment. Benign and malignant tumors revealed a similar expression of all markers and the co-expression of Np-1/Np-2 significantly correlated with the occurrence of paresthesia and higher stages of the tumors. In addition, although not statistically significant, simultaneous overexpression of both receptors also indicated an inferior survival rate. Hence, these results suggest that Sema3A, Sema3B, Np-1 and Np-2 may be involved in the development of normal salivary glands and in the pathogenesis of benign and malignant neoplasms derived from these structures; however, the expression of these proteins did not present a statistically significant prognostic potential in the current study
Doutorado
Patologia
Doutor em Estomatopatologia
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Machado, Lucas Faria Abrahão. "Pesquisa de biomarcadores como fator prognóstico nos tumores da família do sarcoma de Ewing." Universidade de São Paulo, 2017. http://www.teses.usp.br/teses/disponiveis/5/5140/tde-10112017-115117/.
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INTRODUÇÃO: Os tumores da família do sarcoma de Ewing (TFSE) compreendem um espectro de neoplasias de células neuroectodérmicas dos ossos e partes moles de comportamento biológico agressivo e prognóstico reservado, caracterizadas por translocações envolvendo um dos genes da família TET/FET e um dos genes da família ETS, mais comumente EWSR1 e FLI1. Com o avanço da medicina personalizada, cresce a demanda por biomarcadores em TFSE que tenham valor como fatores prognósticos e potencial para futuras terapias-alvo específicas. Este estudo propôs biomarcadores, incluindo proteínas relacionadas à supressão tumoral, proliferação celular, metabolismo energético, atividade imune, vias de reparo do DNA e células tronco. MÉTODOS: A expressão imuno-histoquímica dos biomarcadores MTAP, p16, STAG2, p53, USP22, PTEN, RKIP, Ciclina D1, MCTs (1, 2 e 4), CD147, CA IX, GLUT1, BRACHYURY, PD-L1, OCT4 e SALL4 foi analisada em uma série bem caracterizada de 113 TFSE através de amostras em tissue microarrays (TMA). Os perfis de expressão foram então associados aos parâmetros clínico-patológicos dos pacientes e à sobrevida global para uma análise do impacto no prognóstico. RESULTADOS: A hiperexpressão de p53 mostrou associação estatisticamente significativa com menor sobrevida global (p < 0,001), doença metastática no diagnóstico (p = 0,017) e idade acima de 20 anos (p = 0,04). A perda de expressão de MTAP (p = 0,039) e de Brachyury (p = 0,008) também se associaram significativamente com menor sobrevida global. Em relação às características clínicas dos pacientes, doença metastática no diagnóstico e etnia não-branca foram associados a um pior prognóstico. CONCLUSÕES: Os biomarcadores p53, MTAP e Brachyury foram identificados como fatores independentes relacionados ao prognóstico. A utilização destes biomarcadores como fator prognóstico nos TFSE pode auxiliar na estratificação de risco dos pacientes e até mesmo estimular o desenvolvimento de drogas-alvo específicasINTRODUCTION: The Ewing sarcoma family of tumors (ESFT) comprises a spectrum of neoplasms of neuroectodermal cells of the bones and soft tissues with an aggressive biological behavior and poor outcome, characterized by translocations involving one of the genes of the TET/FET family and one of the genes of the ETS family, most commonly EWSR1 and FLI1. With the progress of personalized medicine, there is a great demand for biomarkers in ESFT that could have prognostic values and the potential for future targeted therapies. This study proposed the evaluation of protein expression of different classes of biomarkers, including proteins related to tumor suppression, cell proliferation, energy metabolism, immune activity, DNA repair pathways and stem cells. METHODS: Immunohistochemical expression of the biomarkers MTAP, p16, STAG2, p53, USP22, PTEN, RKIP, Cyclin D1, MCTs (1, 2 and 4), CD147, CA IX, GLUT1, BRACHYURY, PD-L1, OCT4 and SALL4 was analyzed in a well-characterized series of 113 ESFT in a tissue microarray (TMA) platform. Expression profiles were then associated with patients\' clinical-pathological parameters and overall survival for analysis of the prognostic impact. RESULTS: p53 hyperexpression showed a statistically significant association with lower overall survival (p <0.001), metastatic disease at diagnosis (p = 0.017) and age over 20 years (p = 0.04). Loss of MTAP (p = 0.039) and Brachyury (p = 0.008) were also significantly associated with lower overall survival. Regarding the clinical characteristics of the patients, metastatic disease at diagnosis and non-white ethnicity were associated with a worse prognosis. CONCLUSIONS: The biomarkers p53, MTAP and Brachyury were identified as independent factors related to the prognosis. The use of these biomarkers as a prognostic factor in ESFT may aid in the risk stratification of patients and even stimulate the development of specific targeted drugs
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Soldatelli, Jéssica Silveira. "Efeitos da combinação de temozolomida e ditelureto de difenila em linhagens celulares de glioblastoma." reponame:Repositório Institucional da UCS, 2018. https://repositorio.ucs.br/11338/4064.
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Os gliomas representam mais de 70% dos tumores cerebrais primários. Os glioblastomas multiformes são gliomas malignos caracterizados por baixa incidência, mas altas taxas de mortalidade. Apesar da responsividade inicial ao tratamento padrão realizado com o quimioterápico alquilante temozolomida (TMZ), poucos foram os avanços para o prognóstico dos pacientes nos últimos 10 anos. Isso deve-se ao fato desses tumores serem raramente passíveis de ressecção cirúrgica e apresentarem alta taxa de recorrência. Além disso, a eficácia de seu tratamento encontra barreiras como efeitos colaterais indesejáveis e resistência quimioterápica. Nesse cenário, a descoberta de novas substâncias que possam atuar com efeito aditivo ou sinérgico e aumentem a sensibilização de células tumorais ao tratamento, torna-se uma estratégia terapêutica no campo da oncologia. O ditelureto de difenila (DTDF) é um composto orgânico contendo telúrio que apresenta interessantes efeitos biológicos in vitro, como antioxidante, quimioprotetivo, citotóxico e antitumoral. Sendo assim, o objetivo deste estudo foi avaliar os efeitos do DTDF e do quimioterápico TMZ, em regimes isolados e em associação. Para tal foram investigados seus efeitos citotóxicos, após exposição aguda e crônica, em culturas celulares de glioma não-resistente (M059J) e resistente à TMZ (GBM). No ensaio de viabilidade celular a TMZ apresentou citotoxicidade para as linhagens celulares testadas, com valor de IC50 maior na linhagem resistente do que quando comparado à linhagem não-resistente. Este dado foi confirmado pelo teste de duplicação cumulativa de população e, também, pela coloração com laranja de acridina, após o tratamento de 120 h, por observar-se um aumento na frequência de células positivas para a formação de organelas vesiculares ácidas em ambas as linhagens, sendo predominantemente em células GBM. Além disso, foi observado que o tratamento associando DTDF e a TMZ apresentou uma maior citotoxicidade quando comparado aos tratamentos isolados, após 120 h de tratamento. Portanto, o DTDF sensibilizou as células ao tratamento com TMZ. Essa sensibilização ocorreu em níveis aproximados para ambas as linhagens, sendo os efeitos do DTDF independentes do perfil de resistência à TMZ. Em conjunto, os dados desse trabalho sugerem o uso do DTDF em associação à TMZ como uma estratégia para reduzir as doses de TMZ empregadas na clínica e diminuir efeitos colaterais aos pacientes em tratamento de gliomaGliomas represent more than 70% of primary brain tumors. Malignant gliomas are characterized by low incidence, but high mortality rates. Despite the initial responsiveness to the standard treatment with the chemotherapeutic alkylating temozolomide (TMZ), few advances have been made in the prognosis of patients in the last 10 years. This is due to the fact that these tumors are rarely amenable to surgical resection and have a high rate of recurrence. Moreover, the effectiveness of this treatment encounters barriers such as undesirable side effects and chemotherapeutic resistance. In this scenario, the discovery of new substances that may act with additive or synergistic effect and increase the sensitization of tumor cells to the treatment becomes a therapeutic strategy in the field of oncology. Diphenyl ditelluride (DPDT) is a derivative of tellurium used in various reactions of organic synthesis and has interesting in vitro biological effects, as antioxidant, chemoprotective, cytotoxic and antitumor agent. Therefore this work aimed to evaluate the cytotoxic effects of this organotellurium compound and the chemotherapeutic, TMZ, in isolated and in association regimens, after acute and chronic exposure, of non-resistant (M059J) and TMZ- resistant (GBM) glioma cells. Through the cell viability assay, it was shown that TMZ is cytotoxic for both cell lines tested, showing a higher IC50 value in the resistant line when compared to the other line. This data was confirmed by the cumulative population doubling test. In addition, by the acridine orange staining, it was verified that autophagy might favor the chemoresistance, although not being the main resistance mechanism in the lines tested. It was observed that DPDT clearly has a dose-dependent cytotoxic effect on the M059J and GBM cell lines, in a lower concentration range than that used with TMZ. DPDT sensitized the cells to TMZ treatment as evidenced by the decline in cell viability. It is important to point out that this sensitization occurred in low and approximate IC50 values after both 24 h and 120 h of treatment, being the effects of the DPDT independent of the resistance profile to TMZ. Taken together, data from this work suggest the use of DPDT in association with TMZ as an interesting strategy to reduce the doses of TMZ used in the clinic and to reduce side effects to patients under treatment of glioma.
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Hartman, Caio Augusto 1977. "Ultrassonografia e CA-125 como preditores de malignidade em mulheres com tumores anexiais." [s.n.], 2012. http://repositorio.unicamp.br/jspui/handle/REPOSIP/312140.
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Orientadores: Sophie Françoise Mauricette Derchain, Cássia Raquel Teatin JuliatoDissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas
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Resumo: Introdução: O câncer de ovário é a mais letal das neoplasias ginecológicas e representa a quinta causa mais comum de morte por câncer em mulheres. A sobrevida é baixa e não ultrapassa 40% após 5 anos e está diretamente relacionada ao estádio da doença ao diagnóstico. Não há até hoje, nenhum método de rastreamento que se mostrou efetivo na redução da mortalidade por esta neoplasia. Entretanto, a ultrassonografia (US) e o CA-125 são muito utilizados na diferenciação das tumorações anexiais. Apesar de todos os estudos realizados com US, não existe um consenso sobre os critérios a serem utilizados na diferenciação pré-operatória destes tumores. Frente ao achado de um tumor anexial, o ginecologista deve avaliar o risco de malignidade do mesmo, para instituir um preparo pré-operatório mais adequado, prever a extensão do procedimento e suas possíveis complicações. Objetivo: avaliar os critérios ultrassonográficos de Timmerman et al. e os valores do CA-125 como indicadores de risco para malignidade em mulheres com tumores anexiais. Sujeitos e métodos: este é um estudo de corte transversal no qual foram incluídas 105 mulheres, com 112 tumores anexais. Estas foram submetidas a coleta de sangue periférico para dosagem de CA-125 e exame de ultrassonografia (US). O exame de US foi realizado utilizando descrição padronizada. Informações sobre mais de 40 variáveis morfológicas e de Doppler foram coletadas. A seguir, os tumores anexiais foram classificados segundo 5 critérios de benignidade: (B1) cisto unilocular, (B2) presença de componentes sólidos menores que 7mm, (B3) presença de sombra acústica, (B4) tumor multilocular com paredes lisas medindo menos que 100mm e (B5) ausência de fluxo ao Doppler (índice de cor 1). Os 5 critérios de malignidade foram: (M1) tumor sólido irregular, (M2) presença de ascite, (M3) presença de pelo menos 4 projeções papilíferas, (M4) tumor multilocular sólido irregular com maior medida ? 100mm e (M5) alto fluxo ao Doppler (índice de cor 4). O padrão-ouro foi considerado o resultado do exame anátomo patológico das peças cirúrgicas. Resultados: dos 112 tumores, 81 (72,3%) eram benignos e 31 (27,7%) malignos. Os critérios ultrassonográficos foram aplicáveis a 91 (81,2%) dos tumores e resultaram em sensibilidade de 90% e especificidade de 87%. Nos tumores não classificáveis segundo os critérios, utilizamos a avaliação subjetiva para classificá-los como benignos ou malignos e obtivemos sensibilidade de 66,7% e especificidade de 75%. O CA-125 apresentou sensibilidade de 69% e especifidade de 87,8%. Nos tumores ultrassograficamente classificados como benignos, tanto a idade como os valores do CA-125 não contribuíram adicionalmente para a detecção dos tumores histologicamente malignos. Já no grupo de tumores ultrassonograficamente classificados como malignos, a idade e os valores de CA-125 contribuíram significativamente para a detecção de tumores histologicamente malignos (p = 0.025). Conclusões: A maioria dos tumores pode ser corretamente classificada segundo os critérios ultrassonográficos, com sensibilidade e especificidade semelhantes a do estudo original de Timmerman. O CA-125 isoladamente apresentou menor desempenho que o US na discrimação de tumores anexiais. Quando associamos o CA-125 à idade e aos critérios ultrassonográficos em um modelo de regressão logística, obtivemos melhora no desempenho na discriminação dos tumores ultrassograficamente malignos
Abstract: Introduction: Ovarian cancer is the deadliest gynecologic neoplasm and it is the fifth leading cause of cancer-related deaths in women. The survival rate is low, not exceeding 40% after 5 years and is directly related to tumor stage at the time of diagnosis. To date there is still no screening method that is effective at reducing mortality from this neoplasm. However, ultrasonography and CA-125 are widely used in the differentiation of adnexal tumors. Despite all studies conducted with US, there is no consensus on the criteria to be used in the preoperative differentiation of these tumors. When an adnexal tumor is found, the gynecologist should assess the risk of tumor malignancy to institute a more appropriate preoperative preparation, predict the extension of the surgical procedure along with its potential complications. Objective: to evaluate ultrasound criteria of Timmerman et al. and CA-125 values as indicators of malignancy risk in women with adnexal tumors. Subjects and methods: a prospective study was conducted, including 105 women with 112 adnexal tumors. These women underwent peripheral blood collection for CA-125 measurement and ultrasound (US). US evaluation was performed by using standardized classification. Information on more than 40 morphologic and Doppler variables was obtained. Adnexal tumors were then classified according to 5 features of benign disorders: (B1) unilocular ovarian cyst, (B2) presence of solid components in which the largest solid component is < 7mm, (B3) presence of acoustic shadows, (B4) multilocular tumor with smooth walls measuring less than 100mm and (B5) no detectable Doppler flow (color score 1). The 5 features of malignancy were: (M1) irregular solid tumor, (M2) presence of ascites, (M3) presence of at least 4 papillary projections, (M4) irregular solid multilocular tumor with largest measurement ? 100mm and (M5) high color content on Doppler exam (color score 4). Histopathological analysis of surgical specimens was considered the gold standard. Results: among the 112 tumors, 81 (72.3%) were benign and 31 (27.7%) were malignant. Ultrasound criteria were applicable to 91 (81.2%) of the tumors and resulted in a sensitivity of 90% and specificity of 87%. In tumors not classifiable according to criteria, we used subjective assessment to classify these tumors as benign or malignant, obtaining a sensitivity of 66.7% and specificity of 75%. CA-125 had a sensitivity of 69% and specificity of 87.8%. In tumors sonographically classified as benign, both age and CA-125 values did not contribute any further to the detection of histologically malignant tumors. In contrast, in the group of tumors classified as malignant on ultrasound, the age and the CA-125 values contributed significantly to the detection of histologically malignant tumors (p = 0.025). Conclusions: The majority of tumors may be correctly classified according to ultrasound criteria, with sensitivity and specificity similar to those of the original study by Timmerman. Measurement of CA-125 levels alone showed a worse performance than US evaluation in discriminating adnexal tumors. CA-125 measurement associated with age and ultrasound criteria in a logistic regression model, resulted in a better performance in discriminating the sonographically malignant tumors
Mestrado
Oncologia Ginecológica e Mamária
Mestre em Ciências da Saúde
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Grochot, Rafael Maciel. "Expressão do PD-L1 em neoplasias cervicais e seu impacto em sobrevida associado à infiltração linfocitária peritumoral e à expressão de FOXP3." reponame:Repositório Institucional da UCS, 2018. https://repositorio.ucs.br/11338/3902.
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Louzao, Boado Ánxela. "Investigating the role of testis-mitochondiral genes in Drosophila lethal (3) malignant brain tumor." Doctoral thesis, Universitat de Barcelona, 2019. http://hdl.handle.net/10803/667514.
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Genetically tractable models such as Drosophila melanogaster may help to identify new approaches to halt malignant growth. During my doctoral thesis, I performed a screen to find mitochondrial genes required for the growth of lethal (3) malignant brain tumor. I discovered that several testis-mitochondrial genes, i.e. genes with a mitochondrial function and a maximum expression in testes, were required for the growth of l(3)mbt tumors, rescuing both viability and brain anatomy traits. Nevertheless, inhibition of testis-mitochondrial genes did not affect either wild-type or brat tumor development. One of these testis-mitochondrial genes, ttm2, was found to be expressed both in wild-type and l(3)mbt brains. In addition, when overexpressed in an otherwise wild-type background, Ttm2 produces hyperplasia specifically in the neuroepithelial cells of the medial outer proliferative center (OPC). Yet, ectopic expression of Ttm2 in either central brain or medulla neuroblasts does not affect neuroblast division or number, suggesting that the brain cell types are differentially sensitive to mitochondrial function alteration. The data presented in this thesis project provides novel information about the critical role of mitochondria controlling both cell fate and carcinogenesis.Durante los últimos años, el uso de Drosophila melanogaster como organismo modelo ha servido para identificar nuevos mecanismos moleculares implicados en el crecimiento tumoral. Durante mi tesis doctoral, descubrí que varios genes mitocondriales son necesarios para el crecimiento del tumor cerebral causado por la falta de función del gen lethal (3) malignant brain tumor (l(3)mbt). En concreto, varios genes mitocondriales testiculares, es decir, genes con función mitocondrial y máxima expresión en el testículo de machos adultos, son imprescindibles para el desarrollo de tumores l(3)mbt. Sin embargo, la función de estos genes mitocondriales testiculares es prescindible tanto para el desarrollo de cerebros “wild-type” como del tumor cerebral brat. Uno de estos genes mitocondriales testiculares, ttm2, se expresa tanto en cerebros normales como en cerebros tumorales l(3)mbt. Además, cuando ttm2 es sobreexpresado en el neuroepitelio del cerebro larvario, produce hiperplasia. Esta hiperplasia es específica de las células mediales del “outer proliferative center” (OPC), sin afectar ni al “inner proliferative center” (IPC) ni a los neuroblastos del cerebro. Estos resultados sugieren que los diferentes tipos celulares del cerebro de la larva de Drosophila tienen requerimientos metabólicos distintos y no reaccionan de igual manera a la alteración de la función mitocondrial. Los resultados presentados en esta tesis doctoral proporcionan nuevos datos que confirman el papel crítico de la mitocondria tanto en el proceso de carcinogénesis como en el mantenimiento de la identidad celular.