Diss. (sammanfattning) Linköping : Linköpings universitet, 2007. / Härtill 5 uppsatser.

Introdução: O ameloblastoma é uma neoplasia odontogênica invasiva localmente e de grande significado clínico. Este estudo avaliou o tratamento do ameloblastoma comparando dois métodos terapêuticos: curetagem e curetagem seguida de crioterapia. Método: análise retrospectiva de 53 pacientes portadores de ameloblastoma tratados no Serviço de Cirurgia e Traumatologia Buco-Maxilo-Facial do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo entre 1997 e 2006. Dados demográficos, clínicos, radiográficos e histopatológicos foram analisados. Análise estatística foi realizada para avaliar diferenças na ocorrência de recidiva entre os dois tipos de tratamento conservador e outras variáveis referentes ao tumor. Resultados: 25 pacientes eram homens e 28 mulheres, com idade média de 27,1 anos. A mandíbula foi afetada em 49 casos (92,5%). Radiograficamente, a imagem mais comum foi a multilocular (67,3%). O tamanho radiográfico médio das lesões foi de 62 mm (5 a 115 mm). Os padrões histopatológicos predominantes foram o folicular e o plexiforme com 17 casos (32,1%) cada, seguido pelo misto com 11 casos (20,8%). Ameloblastoma unicístico representou 11,3% da amostra com seis casos. O tratamento consistiu de curetagem seguida de crioterapia em 30 casos (56,6%), curetagem em 18 (33,9%), mandibulectomia segmentar em quatro (7,6%) e ressecção de partes moles em um (1,9%). Não houve diferença estatística no índice de recidiva entre as duas formas de tratamento conservador. Localização, tipo histopatológico, aspecto radiográfico e histórico de tratamento prévio do tumor não tiveram relação com índice de recidiva. Deiscência foi a complicação mais freqüente em ambos os tratamentos. Fratura patológica da mandíbula e formação de seqüestro ósseo foram complicações associadas predominantemente com a crioterapia, quando comparadas à curetagem. Conclusão: A taxa de recidiva do ameloblastoma tratado por curetagem (5,5%) e curetagem seguida de crioterapia (10%) foi baixa em comparação com a maioria dos estudos da literatura. Recidivas diagnosticadas e tratadas em tempo oportuno não representaram insucesso do tratamento. / Introduction: The ameloblastoma is a locally aggressive odontogenic neoplasm with important clinical implications. This study evaluated the effectiveness of ameloblastoma treatment comparing two therapeutic methods: curettage and curettage followed by cryotherapy. Method: Retrospective review of fifty three patients with ameloblastoma from the Service of Maxillofacial Surgery and Traumatology of the Clinics Hospital, Faculty of Medicine, São Paulo University, from 1997 to 2006. The demographics aspects, clinics, radiographics and histologic types of the lesions were analysed. Additionally, the results and the postoperative complications related to both treatment modalities were also evaluated. Statistical analysis to observe the difference in the local recurrence rate and clinical variations between the two techniques was performed. Results: Eighteen patients (33.9%) were treated with curettage, 30 (56.6%) with curettage following by cryotherapy, segmentar mandibulectomy in four (7.6%) and ressection of soft parts in one (1.9%). Of the 53 patients, twenty five were female and twenty eight were male, with a mean age of 27.1 years. The mandible was the most affected site (92.5%). Radiographically, the most common aspect was multilocular image (67.3%) with a medium size of 62 mm. Follicular and plexiform ameloblastoma were the most common histological type (32.1%, each), followed by mixed of two or more histological types (20.8%) and unicystic type (11.3%). No statistical difference was revealed concerning the local recurrence rates. In addition, the site of occurrence, histologic types, radiographics aspects or previous history of ameloblastoma treatment did not show any correlation with local recurrence. Dehiscence was the complication more frequent of the both treatments. Pathological jaw fractures and formation of bony kidnapping were the complications predominantly associated with curettage following by cryotherapy. Conclusion: The recurrence rate of the ameloblastomas treated by curettage (5.5%) and curettage following by cryotherapy (10%) was low in comparison with most of the studies of the literature. Recurrences diagnosed and treated in opportune time did not represent failure of the treatment.

O câncer gástrico precoce é definido como adenocarcinoma que não ultrapassa a camada submucosa, independentemente o acometimento linfonodal. O diagnóstico é feito através do exame de endoscopia digestiva alta e da avaliação histopatológica. Pode ser tratado através de mucosectomia endoscópica, sendo reconhecidos vários fatores que influenciam a chance de cura após a ressecção. Quando o adenocarcinoma gástrico precoce bem diferenciado está à restrito a mucosa, com margens de ressecção livres de neoplasia, sem ulceração histológica, invasão linfática ou venosa é alta a chance de cura após a ressecção endoscópica. A freqüência de recidiva local nestes casos varia de 2,8% a 5,7%. Por outro lado, a expressão de antígenos por células tumorais detectadas através da imunohistoquímica pode indicar o comportamento biológico dos tumores. O carcinoma gástrico precoce tipo diferenciado pode apresentar propriedades fenotípicas diferentes que se correlacionam com a expressão de mucinas. Através da expressão de mucinas é possível estratificar o adenocarcinoma diferenciado em tipo intestinal, gástrico, misto ou indeterminado. O objetivo deste estudo foi avaliar os fatores preditivos para a ressecção incompleta e recidiva local do câncer gástrico precoce tratado através de mucosectomia endoscópica e com acompanhamento superior a um ano. De junho de 1994 a dezembro de 2005, avaliaram-se 46 pacientes com câncer gástrico precoce submetidos a 47 mucosectomias endoscópicas. Através da análise de dados de prontuário, identificaram-se possíveis fatores preditivos para a ressecção endoscópica incompleta e para a recidiva local. Vinte e dois pacientes com critérios para alta probabilidade de cura foram avaliados prospectivamente em relação aos fatores para recidiva e submetidos a perfil imunohistoquímico das lesões ressecadas. Houve recuperação de peças ressecadas em 18 (81,8%) casos. Neste grupo, houve recidiva local em cinco (27,7%) casos. Assim, os pacientes foram avaliados pelos dados demográficos, endoscópicos e histopatológicos. As mucosectomias endoscópicas foram consideradas como ressecção completa ou incompleta. No grupo ressecção completa, os pacientes foram divididos nos subgrupos com ou sem recidiva. Os pacientes com critérios de alta probabilidade para cura foram divididos nos grupos com ou sem recidiva e comparados pelos dados demográficos, endoscópicos, e histopatológicos e imunohistoquímico. As peças ressecadas foram avaliadas quanto à expressão dos marcadores Muc-2, Muc-5a, CD-10, p-53 e Ki-67. O tempo médio de seguimento foi de 69,4 meses ± 36,5 meses. Sobrevida em cinco anos foi de 84,78%. Observaram-se sete (15,21%) óbitos. Houve ressecção completa em 36 casos (76,6%). Foram fatores preditivos de ressecção incompleta, as localizações em parede posterior de terço superior e inferior do estômago (p= 0,035), o tipo histológico indiferenciado (p=0,021), o tamanho da lesão maior que dois centímetros (p= 0,022) e o número de fragmentos maiores ou iguais a dois fragmentos (p= 0,013). Em análise estatística multivariada, o tipo histológico indiferenciado (OR= 0,8; IC (95%)= 0,036-0.897) e números de fragmentos (OR=7,34; IC (95%) = 1.266- 42.629) foram fatores preditivos independentes para ressecção incompleta. No grupo ressecção completa, observou-se que quanto maior o tamanho da lesão, maior o número de fragmentos ressecados (p=0,018). Houve recidiva local em 9 casos (25%). Como fator preditivo para recidiva local, destaca-se a técnica tipo cap com 5/7 casos (71,4%) (p=0,006). Na análise dos pacientes com critérios de alta probabilidade de cura, os dados demográficos (sexo, idade e raça), endoscópicos (tipo macroscópico, localização, número de fragmentos ressecados, técnica de ressecção empregada) e histopatológico (tamanho da lesão e nível de invasão) não mostraram diferença estatística significativa entre os grupos sem ou com recidiva. A análise imunohistoquímica revelou que o marcador Muc-5a esteve presente em 4/5 (80%) dos casos do grupo com recidiva (p=0,026) e quando se estratificaram os casos pela expressão de mucinas, observou-se que o tipo misto se apresentou em 4/5 (80%) casos no grupo com recidiva e o tipo intestinal em 10/13(76,9%) casos no grupo sem recidiva (p=0,004). O adenocarcinoma indiferenciado e números de fragmentos são fatores preditores para ressecção incompleta. O tamanho e a localização da lesão também foram fatores preditores de ressecção incompleta, porém, não de forma independente. A recidiva local teve como fator preditivo o tipo de técnica. O estudo imunohistoquímico se mostrou importante na presunção de recidiva local, nos casos em que os critérios para alta probabilidade de cura foram respeitados. O adenocarcinoma gástrico com expressão das mucinas para o fenótipo do tipo misto se mostrou como fator preditivo para recidiva local do câncer gástrico precoce. / Endoscopic mucosal resection (EMR) has recently become an accepted treatment for early gastric cancer. The histopathologic criteria that are used to define curative endoscopic resection include: intramucosal well-differentiated adenocarcinoma, lateral and deep margins free of tumor, no histologic ulceration, and lastly, no venous or lymphatic emboli. These criteria were defined by a large series of EMR from Japanese centers. Local neoplastic recurrence has been described in up to 6% of cases even when all of the above mentioned criteria are met. On the other hand, the antigen expression of neoplastic cells is related to the biologic behavior of several tumors. The aim of this study was evaluate the factors that predict incomplete resection and local recurrence of early gastric cancer treated by EMR followed up for at least one year in a Western tertiary referral center. It was also evaluated the role of different type of mucins, p53 and ki-67 expression as predictive factors of recurrence even when the standard histopathologic criteria for cure were met. The patients were evaluated retrospectively from June 1994 to December 2005. Forty six patients (23 female and 23 male; mean age 69 ± 14.1y) with early gastric cancer were submitted to EMR. Twenty-two patients with a diagnosis of early gastric cancer were considered cured by EMR were evaluated prospectively for local reccurrence. Local recurrences occurred in five (22.7%) of them. It was possible to perform immunohistochemistry panel in 18 (81.8%) resected specimens. Demographic data (gender, age and race), endoscopic (macroscopic classification, localization, number of resected fragments and technique employed) were retrospectively collected. Histopathologic data (size of tumor, depth of invasion and adenocarcinoma classification) were prospectively assessed by one senior pathologist blinded to the previous diagnosis. Resection was considered incomplete when the lateral or deep margins of the specimen proved positive for tumor. In the complete resection group, patients were followed up, and at the end of this study were divided into two groups: patients recurrence with and without local recurrence. The patients with histopathologic criteria for cure were divided into two groups: with local recurrence and without local recurrence. These were then compared by demographic, endoscopic, histologic and immunohistochemistry profiles. Expression of Muc-2, Muc-5a, CD-10, p-53 and ki-67 were analyzed. Mucin expression allowed a reclassification of the well- differentiated gastric cancer in intestinal, gastric, mixed or null phenotypes. The mean follow up was 69.4 months ± 36.5 months. Five-year survival was 84.78%. Seven (15.21%) patients died from other diseases not related to the gastric lesion. Complete resection was possible in 36 cases (76,6%). Predictive factors for incomplete resection were localization (p= 0,035), histologic type (p=0,021), size of the lesion (p= 0,022) and number of fragments resected (p= 0,013). In the multivariate statistical analysis, the undifferentiated histologic type (OR= 0,8; IC (95%)= 0,036-0.897) and piece-meal resection (OR=7,34; IC (95%) = 1.266-42.629) were independent risk factors for incomplete resection. On the other hand, in the complete resection group, it was noted that lesions >2cm were more frequently resected in piece-meal fashion (p=0,018). Local recurrence occured in 9 cases (group I) (25%). The cap technique was the only predictive factor for local recurrence (5/7 cases - 71,4%, p=0,006). In the group of patients with histopathologic criteria for cure, the demographic (gender, age and race), endoscopic (macroscopic classification, localization, total number of resected fragments, EMR technique) and histopathologic findings (size of the tumor and depth of invasionm1, m2,m3), p-53 and ki-67 expressions did not correlate with neoplastic recurrence. Muc-5a marker was expressed in 80%(4/5) of the cases in group I and in 15.4% (12/13) of the cases in group II (p=0,026). The mixed phenotype (Muc-2 and Muc- 5a positive) was found in 80%(4/5) of the cases of group I and the intestinal type (Muc-2 positive and Muc-5a negative) in 76.9% (10/13) of group II (p=0,004). In conclusion, the undifferentiated adenocarcinoma and piece-meal resection were independent risk factors for incomplete resection. The cap technique for EMR was related to local recurrence after complete resection. Larger lesions are usually resected in more than one fragment. The expression of Muc-5a and the mixed phenotype of well-differentiated adenocarcinoma were related to a higher probability of local recurrence after EMR of early gastric lesions considered cured by the endoscopic intervention.

INTRODUÇÃO: Aproximadamente 50% dos pacientes com tumor colorretal apresentam metástase hepática e a hepatectomia é o procedimento terapêutico de escolha. Discutem-se diversos fatores prognósticos, entre eles a margem cirúrgica é um fator sempre recorrente, pois não existe consenso da distância mínima necessária entre o nódulo metastático e a linha de secção hepática. Alguns autores identificaram que a margem cirúrgica maior que 1cm é um fator de melhor prognóstico com maior sobrevida e menor recidiva. Contudo, outros estudos demonstram resultados semelhantes entre pacientes com margens cirúrgicas maiores que 1cm, exíguas e até mesmo microscopicamente acometidas. Essas controvérsias conduzem à idéia de que outros fatores biológicos possam estar envolvidos na fisiopatologia de recorrência. Assim sendo, é de grande importância a avaliação da relação das margens cirúrgicas de ressecções hepáticas de metástases de câncer colorretal com a sobrevida e recidiva da doença. OBJETIVOS: Avaliar as margens cirúrgicas e o tipo de borda tumoral nas ressecções de metástases hepáticas de câncer colorretal e sua correlação com recidiva local e sobrevida. MÉTODOS: Estudo retrospectivo, baseado na revisão dos prontuários de 91 pacientes submetidos à ressecção de metástases hepáticas de neoplasia colorretal, durante o período compreendido entre janeiro de 2000 e dezembro de 2009. Revisão histopatológica prospectiva de todos os casos com aferição da menor margem cirúrgica e classificação das bordas tumorais como expansiva ou infiltrativa. RESULTADOS: Não houve diferença estatística nas taxas de recidiva e no tempo de sobrevivência global entre as margens livres e acometidas, assim como não houve diferença entre as margens subcentimétricas e maiores de 1cm. A sobrevida livre de doença dos pacientes com margens microscopicamente acometidas foi significativamente menor do que os pacientes com margens livres (p=0,002). A análise multivariada identificou o tipo de borda infiltrativa como fator de risco para recidiva (0,05). A sobrevida livre de doença foi significativamente menor nos pacientes com borda infiltrativa em comparação com os tumores com bordas expansivas (p=0,05). CONCLUSÕES: As ressecções de metástase hepática com margens livres de doença, independentemente da distância da margem, não influencia na recidiva tumoral (hepática ou extra-hepática) ou sobrevida do paciente. A borda tumoral do tipo infiltrativa foi fator de risco para recidiva / INTRODUCTION: Approximately 50% of patients with colorectal cancer have liver metastases and hepatectomy is the therapeutic procedure of choice. Surgical margin is an ever-recurring discussed prognostic factor, because there is no consensus of the minimum required distance between the metastatic nodule and the liver section line. Some authors reported surgical margin larger than 1 cm as a better prognosis factor ensuring longer survival rates and lower recurrence. However, other studies showed similar outcomes among patients with surgical margins larger than 1 cm, narrow margins and even microscopically affected ones. These controversies led the idea that other biological factors may be involved in the pathophysiology of recurrence. Therefore, it is valuable to assess the relationship between surgical margins of liver resection for colorectal cancer metastases with survival and recurrence. OBJECTIVES: To evaluate the surgical margins size and tumors growth pattern of colorectal liver metastases and its correlation with local recurrence and survival. METHODS: A retrospective study based on review of medical records of 91 patients undergoing resection of colorectal liver metastases during the period between January 2000 and December 2009. In addition, we undertook a detailed pathologic analysis of each pathological specimen with record of the closest surgical margins and tumors growth pattern classification as pushing or infiltrative. RESULTS: There was no statistical difference in recurrence rates and overall survival time between positive or negative margins, as well as no difference between the margins of 1cm width or more with subcentimeter margins. The disease-free survival of patients with microscopically positive margins was significantly lower than patients with negative margins (p = 0.002). Multivariate analysis identified infiltrative tumor growth pattern as a risk factor for recurrence (p=0.05). Disease-free survival was significantly lower in patients with infiltrative growth pattern compared to tumors with expansive margins (p = 0.05). CONCLUSIONS: Colorectal liver metastases resection with negative margins, regardless of width, has no influence on recurrence (hepatic or extrahepatic), neither on patient survival. The infiltrative tumor growth pattern type was a risk factor for recurrence

Introdução: O carcinoma epidermóide de cabeça e pescoço tem na cirurgia e na radioterapia, as principais modalidades terapêuticas iniciais. Nas recidivas loco-regionais, a cirurgia é a escolha padrão de tratamento. Objetivos: Identificação de fatores prognósticos clínicos, histopatológicos e biomoleculares e a avaliação da sobrevida após cirurgia de resgate. Casuística e Métodos: Estudo retrospectivo de pacientes submetidos a tratamento cirúrgico inicial, com revisão de variáveis histopatológicas e expressão imunohistoquímica de VEGF, ciclina d1 e EGF-R no tumor inicial e no resgate. Das recidivas, 10 eram de estádio clínico precoce (I e II) e 18, avançado (III e IV). O período de seguimento médio foi de 33,4 meses. Resultados: A comparação das variáveis histológicas e dos marcadores moleculares no tumor inicial e na recidiva não apresentou alterações estatisticamente significantes. A sobrevida global após cirurgia de resgate foi superior nas recidivas com diagnóstico após seis meses (p=0,02). Conclusões: Os achados sugerem que a expressão de VEGF superior a 75% é fator preditivo para controle da doença após a recidiva. A sobrevida entre o tempo decorrido do tratamento inicial e a recidiva foi estatisticamente significante / Introduction: The usual management of squamous cell carcinoma (SCC) head and neck is the surgery associated or not to post surgical radiotherapy. Salvage surgery is the first therapeutic option for recurrent tumors. Objective: The identification of prognostic factors and to assess survival interval after salvage surgery for SCC. Methods: Retrospective analysis of patients treated with surgery and review of histopathological variables and immunohistochemical expression of VEGF, EGF-R and Ciclina in the initial tumor and salvage surgery. Twenty eight patients were submitted salvage surgery with 10 were staged as early tumors (I and II) and 18 as advanced ones (III and IV). The average follow-up was 33.4 months. Results: The comparison of histopathologicals variables in the initial tumor and loco regional recurrence no statistically significant changes. Survival after salvage surgery was 70% in cases with recurrences diagnosed after six months of follow-up (p=0.02). Conclusions: The findings suggest that variables immunohistopathologicals in loco regional recurrence were of minor importance in prognosis. The time between the initial treatment and recurrence loco regional was independent variable of survival

INTRODUÇÃO: Recidivas locais e loco-regionais são as principais causas de falha do tratamento em pacientes portadores de carcinomas epidermóides de boca e orofaringe. A cirurgia de resgate é geralmente a melhor opção terapêutica para esses pacientes. Esse estudo tem por objetivo avaliar a importância prognóstica da expressão das proteínas EGFR, MMP-2, MMP-9 e VEGF em pacientes com recidiva local submetidos à cirurgia de resgate. CASUÍSTICA E MÉTODOS: Os prontuários de 111 pacientes portadores de recorrência local de carcinomas epidermóides de boca e orofaringe foram analisados de forma retrospectiva. A localização do tumor primário foi o lábio em 10 casos (9%), a cavidade oral em 68 (61%) e a orofaringe em 33 (30%). O tratamento prévio foi cirurgia em 33 casos (30%), radioterapia associada ou não à quimioterapia baseada em cisplatina em 46 (41%) e cirurgia com radioterapia adjuvante em 32 (29%). A expressão das proteínas EGFR, MMP-2, MMP-9 and VEGF foi avaliada com a técnica do Tissue Microarray. RESULTADOS: O intervalo livre de doença variou de 0,89 a 140,9 meses, com uma mediana de 6,87 meses. As recidivas foram diagnosticadas em intervalo de tempo inferior a 1 ano em 69 pacientes (62,2%) e após 1 ano em 42 (37,8%). Os pacientes com intervalo livre de doença inferior a 1 ano apresentaram pior resultado de sobrevida (p=0,01). O estádio clínico da recidiva (rEC) foi I ou II em 31 casos (27,9%) e III ou IV em 80 (72,1%). Pacientes com doença em estádio clínico mais avançado (rEC III ou IV) apresentaram piores taxas de sobrevida específica por câncer (p=0,04). Hiper-expressão do EGFR foi associada a pior resultado do tratamento. Os casos com EGFR positivo obtiveram sobrevida específica por câncer em 3 anos de 27,2%, enquanto pacientes com EGFR negativo alcançaram 64,3% de sobrevida em 3 anos (p=0,001). A expressão das proteínas MMP-2, MMP-9 e VEGF não se mostrou significativa para o prognóstico (p=0,83, p=0,15 e p=0,86, respectivamente). Na análise multivariada, apenas o intervalo livre de doença e a expressão do EGFR foram associadas à maior risco de morte. CONCLUSÕES: Recidivas locais de carcinomas epidermóides de boca e orofaringe são associadas a mau prognóstico. Intervalo livre de doença superior a 1 ano e ausência de expressão do EGFR foram os principais fatores associados a melhores resultados de sobrevida específica por câncer em pacientes submetidos à cirurgia de resgate. / INTRODUCTION: Local and regional relapses are the main sites of treatment failure in patients with oral and oropharyngeal squamous cell carcinoma. In these instances, salvage surgery is the most widely used treatment approach. The aim of this study is to analyze the prognostic effect of the expression of EGFR, MMP-2, MMP-9 and VEGF in patients with recurrent cancer sumitted to salvage surgery. METHODS: The charts of 111 patients with local recurrence of oral or oropharyngeal squamous cell carcinomas were retrospectively analyzed. The tumor sites were: the lip in 11 cases (9%), the oral cavity in 68 (61%) and the oropharynx in 33 (30%). The previous treatment was: Surgery in 33 patients (30%), radiotherapy with or without cisplatin based chemotherapy in 46 (41%) and surgery with adjuvant radiotherapy in 32 (29%). EGFR, MMP-2, MMP-9 and VEGF expressions were analyzed with tissue microarray immunohistochemical technique. RESULTS: The disease-free interval ranged from 0.89 to 140.9 months with a median of 6.87 months. The patients were categorized into two groups: Those with recurrence in less than 1 year (69 patients - 62.2%) and those with recurrence after 1 year (42 - 37.8%). The group with the shorter disease-free interval presented a worse prognosis (p=0.01). The clinical stage of recurrence (rCS) was I/II in 31 cases (27.9%) and III/IV in 80 cases (72.1%). Patients with more advanced diseases (rCS III/IV) had worse rates of cancer specific survival (CSS) than patients with rCS I/II (p=0.04). An over-expression of EGFR was associated with worse treatment results. Positive EGFR cases had a 3 year CSS of 27.2%, while EGFR negative patients had 64.3% (p=0.001). The MMP-2 and MMP-9 over-expression were also associated with a worse prognosis but without statistical significance (p=0.83 and p=0.15). VEGF expression did not show prognostic significance in this group of patients. In a multivariate analysis only the disease-free interval and over-expression of EGFR were associated with a higher risk of death. CONCLUSION: Local recurrence in oral and oropharyngeal squamous cell carcinomas usually indicates an unfavorable prognosis. A disease-free interval greater than 1 year and a negative EGFR expression are the main prognostic factors which indicate a better cancer specific survival rate in patients submitted to salvage surgery.

INTRODUÇÃO: Recidivas locais e loco-regionais são as principais causas de falha do tratamento em pacientes portadores de carcinomas epidermóides de boca e orofaringe. A cirurgia de resgate é geralmente a melhor opção terapêutica para esses pacientes. Esse estudo tem por objetivo avaliar a importância prognóstica da expressão das proteínas EGFR, MMP-2, MMP-9 e VEGF em pacientes com recidiva local submetidos à cirurgia de resgate. CASUÍSTICA E MÉTODOS: Os prontuários de 111 pacientes portadores de recorrência local de carcinomas epidermóides de boca e orofaringe foram analisados de forma retrospectiva. A localização do tumor primário foi o lábio em 10 casos (9%), a cavidade oral em 68 (61%) e a orofaringe em 33 (30%). O tratamento prévio foi cirurgia em 33 casos (30%), radioterapia associada ou não à quimioterapia baseada em cisplatina em 46 (41%) e cirurgia com radioterapia adjuvante em 32 (29%). A expressão das proteínas EGFR, MMP-2, MMP-9 and VEGF foi avaliada com a técnica do Tissue Microarray. RESULTADOS: O intervalo livre de doença variou de 0,89 a 140,9 meses, com uma mediana de 6,87 meses. As recidivas foram diagnosticadas em intervalo de tempo inferior a 1 ano em 69 pacientes (62,2%) e após 1 ano em 42 (37,8%). Os pacientes com intervalo livre de doença inferior a 1 ano apresentaram pior resultado de sobrevida (p=0,01). O estádio clínico da recidiva (rEC) foi I ou II em 31 casos (27,9%) e III ou IV em 80 (72,1%). Pacientes com doença em estádio clínico mais avançado (rEC III ou IV) apresentaram piores taxas de sobrevida específica por câncer (p=0,04). Hiper-expressão do EGFR foi associada a pior resultado do tratamento. Os casos com EGFR positivo obtiveram sobrevida específica por câncer em 3 anos de 27,2%, enquanto pacientes com EGFR negativo alcançaram 64,3% de sobrevida em 3 anos (p=0,001). A expressão das proteínas MMP-2, MMP-9 e VEGF não se mostrou significativa para o prognóstico (p=0,83, p=0,15 e p=0,86, respectivamente). Na análise multivariada, apenas o intervalo livre de doença e a expressão do EGFR foram associadas à maior risco de morte. CONCLUSÕES: Recidivas locais de carcinomas epidermóides de boca e orofaringe são associadas a mau prognóstico. Intervalo livre de doença superior a 1 ano e ausência de expressão do EGFR foram os principais fatores associados a melhores resultados de sobrevida específica por câncer em pacientes submetidos à cirurgia de resgate. / INTRODUCTION: Local and regional relapses are the main sites of treatment failure in patients with oral and oropharyngeal squamous cell carcinoma. In these instances, salvage surgery is the most widely used treatment approach. The aim of this study is to analyze the prognostic effect of the expression of EGFR, MMP-2, MMP-9 and VEGF in patients with recurrent cancer sumitted to salvage surgery. METHODS: The charts of 111 patients with local recurrence of oral or oropharyngeal squamous cell carcinomas were retrospectively analyzed. The tumor sites were: the lip in 11 cases (9%), the oral cavity in 68 (61%) and the oropharynx in 33 (30%). The previous treatment was: Surgery in 33 patients (30%), radiotherapy with or without cisplatin based chemotherapy in 46 (41%) and surgery with adjuvant radiotherapy in 32 (29%). EGFR, MMP-2, MMP-9 and VEGF expressions were analyzed with tissue microarray immunohistochemical technique. RESULTS: The disease-free interval ranged from 0.89 to 140.9 months with a median of 6.87 months. The patients were categorized into two groups: Those with recurrence in less than 1 year (69 patients - 62.2%) and those with recurrence after 1 year (42 - 37.8%). The group with the shorter disease-free interval presented a worse prognosis (p=0.01). The clinical stage of recurrence (rCS) was I/II in 31 cases (27.9%) and III/IV in 80 cases (72.1%). Patients with more advanced diseases (rCS III/IV) had worse rates of cancer specific survival (CSS) than patients with rCS I/II (p=0.04). An over-expression of EGFR was associated with worse treatment results. Positive EGFR cases had a 3 year CSS of 27.2%, while EGFR negative patients had 64.3% (p=0.001). The MMP-2 and MMP-9 over-expression were also associated with a worse prognosis but without statistical significance (p=0.83 and p=0.15). VEGF expression did not show prognostic significance in this group of patients. In a multivariate analysis only the disease-free interval and over-expression of EGFR were associated with a higher risk of death. CONCLUSION: Local recurrence in oral and oropharyngeal squamous cell carcinomas usually indicates an unfavorable prognosis. A disease-free interval greater than 1 year and a negative EGFR expression are the main prognostic factors which indicate a better cancer specific survival rate in patients submitted to salvage surgery.

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Shading Accent 3"/> <w:LsdException Locked="false" Priority="61" Name="Light List Accent 3"/> <w:LsdException Locked="false" Priority="62" Name="Light Grid Accent 3"/> <w:LsdException Locked="false" Priority="63" Name="Medium Shading 1 Accent 3"/> <w:LsdException Locked="false" Priority="64" Name="Medium Shading 2 Accent 3"/> <w:LsdException Locked="false" Priority="65" Name="Medium List 1 Accent 3"/> <w:LsdException Locked="false" Priority="66" Name="Medium List 2 Accent 3"/> <w:LsdException Locked="false" Priority="67" Name="Medium Grid 1 Accent 3"/> <w:LsdException Locked="false" Priority="68" Name="Medium Grid 2 Accent 3"/> <w:LsdException Locked="false" Priority="69" Name="Medium Grid 3 Accent 3"/> <w:LsdException Locked="false" Priority="70" Name="Dark List Accent 3"/> <w:LsdException Locked="false" Priority="71" Name="Colorful Shading Accent 3"/> <w:LsdException Locked="false" Priority="72" Name="Colorful List Accent 3"/> <w:LsdException Locked="false" Priority="73" Name="Colorful Grid Accent 3"/> <w:LsdException Locked="false" Priority="60" Name="Light Shading Accent 4"/> <w:LsdException Locked="false" Priority="61" Name="Light List Accent 4"/> <w:LsdException Locked="false" Priority="62" Name="Light Grid Accent 4"/> <w:LsdException Locked="false" Priority="63" Name="Medium Shading 1 Accent 4"/> <w:LsdException Locked="false" Priority="64" Name="Medium Shading 2 Accent 4"/> <w:LsdException Locked="false" Priority="65" Name="Medium List 1 Accent 4"/> <w:LsdException Locked="false" Priority="66" Name="Medium List 2 Accent 4"/ / <p>Free radicals are produced in our body under physiological conditions. Although in very low concentrations, they can show some toxic effects. While trying to bind electrons, in the chemical reaction of oxidation, they rapidly and unpredictably bind to adjacent molecules- proteins, lipids, carbohydrates and nucleic acids from which the structural elements of the cell are made, triggering the internal pathway of apoptosis. Antioxidants are substances that prevent or significantly reduce the oxidation of biomolecules. Oxidative stress is a condition that occurs when the production of free radicals exceeds the capacity of antioxidant enzymes to neutralize them. The antioxidant enzymes include: superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione reductase (GR), and glutathione-S-transferase (GST). Lipid Peroxidation (LP) is the process of oxidation of polyunsaturated fatty acids by free radicals. Malondialdehyde is a biochemical marker by which it is possible to measure the degree of oxidative damage of cell membranes. The oxidative modification of DNA leads to a change in DNA structure that results in genetic damage. The most commonly used marker of oxidative stress is urinary 8-hydroxy-2-deoxiguanosine (8-OHdG). The damage to proteins, lipids and DNA is an important basis for many diseases such as atherosclerosis, neurodegenerative diseases, diabetes, obesity, aging, retinopathy, chronic inflammatory disease and cancer. Starting from the hypothesis that these biomolecules are different at different stages of the disease, they could represent a prognostic marker of the progression of the disease. The aim of the study was to examine whether there were differences between the control group (healthy women), the patients with precancerous lesions on the cervix (HSIL), the patients with early stage cervical cancer (FIGO Ia-Ib) and the patient with locally advanced cervical cancer (IIa - IV) in the indicators of DNA damage (determining the value of 8-OHdG), indicators of oxidative stress (by determining the lipid peroxidation intensity (TBARS)), indicators of antioxidant defense (by determining the activity of antioxidative enzymes of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase GPx), glutathione reductase (GR), and glutathione-S-transferase (GST)). In addition, the aim of the study was to compare the values of 8- OHdG, lipid peroxidation products (TBARS) and the activity of antioxidant enzymes (SOD, CAT, GST, GPx, GR) within the group of patients with early stage cervical cancer divided into two subgroups- with low and high risk in relation to the relapse of the disease. The research was performed at the Clinic for operative oncology, Department of Gynecology at the Institute of Oncology of Vojvodina, Medical Faculty in Novi Sad, Department of Pharmacy and the Institute for Health Care of Novi Sad in the period from 2013 to 2017. Samples of blood and urine of the patients were collected, prepared adequately and stored at -80 &deg; until the analysis. The activity of the antioxidant enzymes as well as the lipid peroxidation were determined by spectrophotometric methods, and the concentration of 8-OHdG was determined by gas chromatography with mass detection. The approval of the Ethical Committee of the Institute for Oncology of Vojvodina was obtained before conducting the research. It has been shown that there are statistically significant differences between the control group (healthy women), patient with precancerous cervical lesions (HSIL), the patients with early stage cervical cancer (FIGO Ia-Ib) compared to a group of patients with locally advanced cervical cancer (IIa-IV) in indicators of damage to DNA (concentration of 8-OHdG), indicators of oxidative stress (lipid peroxidation (TBARS)), indicators of antioxidant defense (activities of antioxidant enzymes SOD, CAT and GST). There was no difference between the groups in activity of glutathione peroxidase enzyme (GPx) and glutathione reductase (GR). There were no differences in the concentration of 8-OHdG, lipid peroxidation products (TBARS) and the activity of antioxidant enzymes (SOD, CAT, GST, GPx and GR) within the group of patients with locally restricted cervical cancer divided into two subgroups with low and high risk in relation on relapses of the disease. CAT and GST activities were the best predictors of disease recurrence among defined groups. Based on the activities of these two oxidative enzymes, the separation of the group of patients who did not experience disease recurrence after a follow-up period from the other two groups in which recurrence of the disease occurred was possible. Based on the obtained results it is concluded that it is possible to use the studied biomarkers as diagnostic markers in patients with cervical cancer. These biomolecules can help in the patient&#39;s classification into certain groups according to the stage of the disease, and consequently the more efficient choice of appropriate treatment. In addition, CAT and GST enzyme activity have been shown to be predictors of disease recurrence in defined patient groups.</p>

Diss. (sammanfattning) Linköping : Linköpings universitet, 2005. / Härtill 4 uppsatser.

<p>UVOD: Glavni problem u lečenju karcinoma dojke je kako na osnovu kliničke klasifikacije i morfolo&scaron;kih osobina tumora predvideti njegovo dalje pona&scaron;anje. Vrlo često ni kombinacija standardnih prognostičkih faktora ne daje odgovor o potrebi davanja adjuvantne hemioterapije. U cilju sprovođenja adekvatne dalje terapije karcinoma dojke i otkrivanja agresivnih tipova tumora, a nakon hirur&scaron;kog lečenja, postoji stalna potreba za pronalaženjem novih pokazatelja pomoću kojih bi se identifikovale bolesnice koje imaju povećan rizik od razvoja relapsa bolesti. CILJEVI: Ciljevi su bili da se utvrdi prisustvo, lokalizacija i distribucija tumor infiltri&scaron;ućih limfocita, kako ukupnih, tako i CD4+ i CD8+ T limfocita u tumoru dojke, njihova povezanost sa standardnim prognostičkim parametrima, kao i njihov prognostički značaj tj. razlike u nivou infiltracije limfocita u tumoru u odnosu na pojavu relapsa bolesti i dužinu preživljavanja. METOD: Istraživanjem je obuhvaćeno 120 bolesnica sa invazivnim duktalnim karcinomom, sa tumorom lokalizovanim samo u dojci, bez zahvatanja kože i grudnog mi&scaron;ića, sa veličinom tumora do 5 cm, bez udaljenih visceralnih i ko&scaron;tanih metastaza, koje su operisane u Institutu za onkologiju Vojvodine. U istraživanje su uključene bolesnice bez metastaza u limfnim čvorovima pazu&scaron;ne jame i bolesnice sa metastazama u limfnim čvorovima pazu&scaron;ne jame. Istraživanjem nisu obuhvaćene bolesnice koje su primale neoadjuvantnu (preoperativnu) hemioterapiju, kao ni bolesnice sa multifokalnim i multicentričnim tumorima. REZULTATI: Gust limfocitni infiltrat uočen je u 14% tumora dojke, umeren limfocitni infiltrat uočen je u 38%, a oskudan u 43% tumora dojke. Limfocitni infiltrat nije uočen u 5% tumora. Gust infiltrat CD4+ limfocita uočen je u 8% tumora dojke, umeren u 44%, a oskudan u 43% tumora dojke. CD4+ limfociti nisu uočeni u 5% tumora. Gust infiltrat CD8+ limfocita uočen je u 1% tumora dojke, umeren u 23%, a oskudan u 66% tumora dojke. CD8+ limfociti nisu uočeni u 10% tumora. Utvrđena je pozitivna povezanost između nivoa TIL-a i CD4+ limfocita i veličine tumora, histolo&scaron;kog stepena diferentovanosti tumora, prisustva metastaza u limfnim čvorovima pazu&scaron;ne jame, HER-2 statusa, tripl negativnog tumora i relapsa bolesti. Utvrđena je negativna povezanost između nivoa TIL-a i CD4+ limfocita i estrogen i progesteron receptora, kao i godina starosti. Utvrđena je pozitivna povezanost između nivoa CD8+ limfocita i histolo&scaron;kog gradusa tumora, kao i HER-2 statusa. Utvrđena je negativna povezanost između nivoa CD8+ limfocita i estrogen i progesteron receptora, kao i godina starosti. ZAKLJUČAK:Rezultati ovog istraživanja pokazuju povezanost tumor infiltri&scaron;ućih limfocita i CD4+ limfocita sa brojnim negativnim prognostičkim faktorima, te kraćim vremenom slobodnog intervala bez bolesti, &scaron;to sve ukazuje na to da su tumor infiltri&scaron;ući limfociti kao i CD4+ limfociti lo&scaron; prognostički faktor kod bolesnica sa rakom dojke.</p> / <p>INTRODUCTION: The main problem in the treatment of breast cancer that based on clinical classification and morphological characteristics of the tumor to predict its future behavior. Very often, not a combination of standard prognostic factors does not answer the need of giving adjuvant chemotherapy. In order to implement adequate further treatment of breast cancer and detection aggressive types of tumor, after surgical treatment, there is a constant need to find new indicators by which we can identify patients who have an increased risk of relapse. OBJECTIVES: The objectives were to determine the presence, localization and distribution of tumor infiltrating lymphocytes, in total, as well as CD4+ and CD8+ T lymphocytes in breast cancer, their correlation with standard prognostic parameters, as well as their prognostic value i.e. differences in the level of infiltration of lymphocytes in a tumor in relation to the occurrence of disease relapse and survival. METHOD: The study included 120 patients with invasive ductal carcinoma, tumor localized only in the breast without involvement of the skin and pectoral muscle, the size of tumors up to 5 cm without distant visceral and bone metastases, which are operated at the Institute of Oncology. The study included patients without metastases in axillary lymph nodes and patients with metastases in axillary lymph nodes. The research not covered by patients receiving neoadjuvant chemotherapy, or patients with multifocal and multicentric tumors. RESULTS: The high amount of lymphocytic infiltrate was observed in the 14% a breast tumor, a moderate amount of lymphocytic infiltrate was observed in 38%, and the low in 43% breast tumors. Lymphocytic infiltrate was not observed in 5% of the tumor. High CD4+ lymphocyte infiltration was observed in 8% of breast, moderate in 44%, and the low in 43% of breast tumors. CD4+ lymphocytes were not observed in 5% tumors. High infiltration of CD8+ lymphocytes was observed in 1% of breast, moderate in 23%, and the low 66% breast tumors. CD8+ lymphocytes have not been observed in 10% tumors. There is a positive correlation between the level of TIL and CD4+ lymphocytes and tumor size, histological grade of tumor differentiation, presence of metastases in axillary lymph nodes, HER-2 status, triple negative tumors and relapses of disease. There was a negative correlation between the level of TIL and CD4+ cell counts and estrogen and progesterone receptors, as well as age. There is a positive correlation between the level of CD8+ cells and histological grade of the tumor, and HER-2 status. There was a negative correlation between the level of CD8+ lymphocytes and estrogen and progesterone receptors, as well as age. CONCLUSION: The results of this study demonstrate the association between tumor infiltrating lymphocytes and CD4+ lymphocytes with a number of negative prognostic factors, and shorter free interval without the disease, all of which indicates that the tumor infiltrating lymphocytes and CD4+ lymphocytes bad prognostic factor in patients with breast cancer.</p>