O carcinoma verrucoso (CV), é considerado uma variante do carcinoma espinocelular (CEC) bem diferenciado, que se caracteriza por sua baixa agressividade e bom prognóstico e acomete principalmente a laringe e a boca. Um total de 1613 carcinomas espinocelulares primários de boca, cirurgicamente excisados entre 1980 e 2000, foram revisados dos arquivos dos Departamentos de Patologia e Cirurgia de Cabeça e Pescoço e Otorrinolaringologia do Hospital do Câncer A.C. Camargo. Dez CVs foram identificados e analisados quanto ao gênero, idade, raça, tabagismo, etilismo, localização do tumor primário, classificação pelo sistema TNM, tratamento, ocorrência de recidiva tumoral, metástases em linfonodos regionais, a distância e de segundo tumor primário. Analisaram-se também a expressão imuno-histoquímica e a hipermetilação da região promotora do gene da E-caderina, e os valores obtidos foram comparados com carcinomas espinocelulares bem diferenciados de boca sem (CEC-pN0) e com (CEC-pN+) comprometimento linfonodal. As probabilidades de sobrevidas, acumuladas nos períodos de cinco e dez anos para os grupos tumorais, foram calculadas pelo método de Kaplan-Meier. Os resultados demonstraram uma predileção dos CVs por pacientes do gênero masculino, tabagistas e etilistas, com idade superior a 67 anos, ocorrendo principalmente no lábio inferior. O tempo de história clínica foi maior que 16 meses e nenhum paciente com CV foi submetido à radioterapia e/ou quimioterapia pós-operatória. Microscopicamente as lesões eram bem características com intensa queratinização, padrão de invasão compressivo, pouca atipia e margens cirúrgicas livres. Uma maior expressão imunohistoquímica da E-caderina foi verificada nos carcinomas verrucosos quando comparados aos grupos de CEC-pN0 e CEC-pN+, sendo a diferença entre os grupos estatisticamente significativa (p= 0,016). O perfil de metilação do gene da E-caderina foi estatisticamente semelhante (p= 0,975) e superior a 50% nos três grupos de carcinomas de boca avaliados (CV, CEC-pN0 e CEC-pN+). A sobrevida global do grupo CV foi superior aos grupos de CECs bem diferenciados tanto em cinco quanto em dez anos (p= 0,012). Com base nestes resultados concluímos que o carcinoma verrucoso bucal apresenta um comportamento clínico e biológico relativo à expressão da E-caderina, mais favorável quando comparado carcinoma espinocelular bem diferenciado. A presença da hipermetilação do gene da E-caderina em neoplasias malignas com baixo potencial invasivo e metastático como o CV sugere que este evento epigenético ocorre precocemente nos mecanismos envolvidos na progressão tumoral. / Verrucous carcinoma (VC), is considered a variant of well differentiated squamous cell carcinoma, that is characterized by its low aggressiveness and good prognostic and arises most frequently in the larynx and oral cavity. A total of 1613 cases of surgically excised primary oral squamous cell carcinoma from the files of Otohinolaryngology, Head and Neck Surgery, and Pathology Departments of the A.C. Camargo Cancer Hospital, from 1980 to 2000, were retrospectively reviewed. Ten cases of CVs were identified and analyzed as for the gender, age, race, tobacco and alcohol abuse, localization, stage by the TNM-UICC, treatment, lymph nodes involvement, local and cervical recurrences, distant metastasis and second primary tumors. In addition, we investigated the immunohistochemical expression of the Ecadherin and the promoter region hypermethylation of the E-cadherin gene of VCs comparing with oral well differentiated squamous cell carcinoma without (SCC-pN0) and with (SCCpN+) lymph nodes involvement. The 5 and 10-year survival rates were calculated by Kaplan- Meyer method. The results demonstrated a predilection of VCs for patients of the masculine gender, with positive tobacco and alcohol history, with age older than 67 years and arise predominantly in the inferior lip. The clinical history was longer than 16 months and no patient with VC was submitted the radiotherapy and/or chemotherapy postoperative. The histopathologic analysis showed a heavily keratinized lesion with compressive invasion pattern, little atypia and free surgical margins. In comparison with SCC-pN0 and SCC-pN+, verrucous carcinoma showed a higher immunohistochemical expression of the E-cadherin score (p= 0,016). More than 50% of the tumors showed the hypermethylation of the Ecadherin gene and no statistically significant differences (p= 0,975) were found among VC, SCC-pN0 and SCC-pN+ groups. Verrucous carcinoma of the oral cavity had significantly better 5-year and 10-year overall survival rates than the well differentiated squamous cell carcinomas (p= 0,012). These results permit to conclude that the oral verrucous carcinoma presents more favorable clinical and biological behavior related to the immunohistochemical expression of the E-cadherin when compared with well differentiated squamous cell carcinoma. The presence of the hypermethylation of the E-cadherin gene in the malignant tumors with lower potential invasive and metastatic, such as VC, suggests that this epigenetic event happens early in the mechanisms involved in the tumoral progression.

O carcinoma verrucoso (CV), é considerado uma variante do carcinoma espinocelular (CEC) bem diferenciado, que se caracteriza por sua baixa agressividade e bom prognóstico e acomete principalmente a laringe e a boca. Um total de 1613 carcinomas espinocelulares primários de boca, cirurgicamente excisados entre 1980 e 2000, foram revisados dos arquivos dos Departamentos de Patologia e Cirurgia de Cabeça e Pescoço e Otorrinolaringologia do Hospital do Câncer A.C. Camargo. Dez CVs foram identificados e analisados quanto ao gênero, idade, raça, tabagismo, etilismo, localização do tumor primário, classificação pelo sistema TNM, tratamento, ocorrência de recidiva tumoral, metástases em linfonodos regionais, a distância e de segundo tumor primário. Analisaram-se também a expressão imuno-histoquímica e a hipermetilação da região promotora do gene da E-caderina, e os valores obtidos foram comparados com carcinomas espinocelulares bem diferenciados de boca sem (CEC-pN0) e com (CEC-pN+) comprometimento linfonodal. As probabilidades de sobrevidas, acumuladas nos períodos de cinco e dez anos para os grupos tumorais, foram calculadas pelo método de Kaplan-Meier. Os resultados demonstraram uma predileção dos CVs por pacientes do gênero masculino, tabagistas e etilistas, com idade superior a 67 anos, ocorrendo principalmente no lábio inferior. O tempo de história clínica foi maior que 16 meses e nenhum paciente com CV foi submetido à radioterapia e/ou quimioterapia pós-operatória. Microscopicamente as lesões eram bem características com intensa queratinização, padrão de invasão compressivo, pouca atipia e margens cirúrgicas livres. Uma maior expressão imunohistoquímica da E-caderina foi verificada nos carcinomas verrucosos quando comparados aos grupos de CEC-pN0 e CEC-pN+, sendo a diferença entre os grupos estatisticamente significativa (p= 0,016). O perfil de metilação do gene da E-caderina foi estatisticamente semelhante (p= 0,975) e superior a 50% nos três grupos de carcinomas de boca avaliados (CV, CEC-pN0 e CEC-pN+). A sobrevida global do grupo CV foi superior aos grupos de CECs bem diferenciados tanto em cinco quanto em dez anos (p= 0,012). Com base nestes resultados concluímos que o carcinoma verrucoso bucal apresenta um comportamento clínico e biológico relativo à expressão da E-caderina, mais favorável quando comparado carcinoma espinocelular bem diferenciado. A presença da hipermetilação do gene da E-caderina em neoplasias malignas com baixo potencial invasivo e metastático como o CV sugere que este evento epigenético ocorre precocemente nos mecanismos envolvidos na progressão tumoral. / Verrucous carcinoma (VC), is considered a variant of well differentiated squamous cell carcinoma, that is characterized by its low aggressiveness and good prognostic and arises most frequently in the larynx and oral cavity. A total of 1613 cases of surgically excised primary oral squamous cell carcinoma from the files of Otohinolaryngology, Head and Neck Surgery, and Pathology Departments of the A.C. Camargo Cancer Hospital, from 1980 to 2000, were retrospectively reviewed. Ten cases of CVs were identified and analyzed as for the gender, age, race, tobacco and alcohol abuse, localization, stage by the TNM-UICC, treatment, lymph nodes involvement, local and cervical recurrences, distant metastasis and second primary tumors. In addition, we investigated the immunohistochemical expression of the Ecadherin and the promoter region hypermethylation of the E-cadherin gene of VCs comparing with oral well differentiated squamous cell carcinoma without (SCC-pN0) and with (SCCpN+) lymph nodes involvement. The 5 and 10-year survival rates were calculated by Kaplan- Meyer method. The results demonstrated a predilection of VCs for patients of the masculine gender, with positive tobacco and alcohol history, with age older than 67 years and arise predominantly in the inferior lip. The clinical history was longer than 16 months and no patient with VC was submitted the radiotherapy and/or chemotherapy postoperative. The histopathologic analysis showed a heavily keratinized lesion with compressive invasion pattern, little atypia and free surgical margins. In comparison with SCC-pN0 and SCC-pN+, verrucous carcinoma showed a higher immunohistochemical expression of the E-cadherin score (p= 0,016). More than 50% of the tumors showed the hypermethylation of the Ecadherin gene and no statistically significant differences (p= 0,975) were found among VC, SCC-pN0 and SCC-pN+ groups. Verrucous carcinoma of the oral cavity had significantly better 5-year and 10-year overall survival rates than the well differentiated squamous cell carcinomas (p= 0,012). These results permit to conclude that the oral verrucous carcinoma presents more favorable clinical and biological behavior related to the immunohistochemical expression of the E-cadherin when compared with well differentiated squamous cell carcinoma. The presence of the hypermethylation of the E-cadherin gene in the malignant tumors with lower potential invasive and metastatic, such as VC, suggests that this epigenetic event happens early in the mechanisms involved in the tumoral progression.

Note:

Note:

Inaugural dissertation.--Universität Greifswald.

Orientador : Profª. Drª. Juliana Geremias Chichorro / Coorientadora : Profª. Drª. Alexandra Acco / Tese (doutorado) - Universidade Federal do Paraná, Setor de Ciências Biológicas, Programa de Pós-Graduação em Farmacologia. Defesa: Curitiba, 29/07/2016 / Inclui referências : f. 99-112 / Resumo: Existem diversos estudos que demonstram que o uso de vitaminas do complexo B pode ajudar no controle da dor neuropática em diversos modelos. Atualmente, apenas a droga carbamazepina, um anticonvulsivante, é aprovado pela agência americana Food and Drug Administration (FDA) para o tratamento da neuralgia trigeminal, mas a sua utilização está associada a inúmeros efeitos adversos. Este estudo fornece evidências de que o uso das vitaminas do complexo B tiamina (vitamina B1), piridoxina (vitamina B6) e cianocobalamina (vitamina B12), isoladamente ou em associação com a carbamazepina, atenua a hiperalgesia ao calor, ao frio e mecânica em um modelo de dor neuropática trigeminal em ratos. Nossos resultados mostram que o tratamento diário (durante 5 dias, com início no dia da cirurgia e término no dia 4 pós-cirúrgico) dos animais com as vitaminas B1, B6 e B12, isoladamente nas doses de 180, 180 e 18 mg/kg, respectivamente, por via subcutânea (s.c.), preveniu o desenvolvimento de hiperalgesia ao calor após constrição do nervo infraorbital (CION). Por outro lado, apenas a vitamina B12 (18 mg/kg, s.c., durante 5 dias) foi capaz de reduzir a hiperalgesia ao frio, e essa redução foi observada nos dias 6 e 9 após a constrição do nervo. Além disso, apenas o tratamento com a vitamina B6 (180 mg/kg, s.c., durante 5 dias, com início no dia 8 e término no dia 12 pós-cirúrgico) promoveu o aumento do limiar mecânico dos animais submetidos a CION, a partir do dia 10 após a cirurgia e manteve-se até o término do período de avaliação (dia 20 pós-cirúrgico). Adicionalmente, uma única administração intraperitonial (i.p.) de carbamazepina (30 mg/kg) foi capaz de reduzir a hiperalgesia ao calor e ao frio no 4º dia após a lesão do nervo, mas não foi capaz de modificar o limiar mecânico avaliado no 20º dia após o procedimento cirúrgico. A associação de baixas doses de cada vitamina, B1, B6 e B12 (18, 18 e 1,8 mg/kg, s.c., 5 administrações) com a carbamazepina (10 mg/kg, i.p., administração única) reduziu acentuadamente a hiperalgesia ao calor, enquanto a combinação da vitamina B12 com a carbamazepina (mesmas doses acima) promoveu a reversão da hiperalgesia ao frio, ambas avaliadas no dia 4 pós-cirúgico. Em conclusão, sugerimos que as vitaminas B1, B6 e B12 podem ser uma alternativa ou ser utilizadas como adjuvantes para controlar alguns aspectos da dor em pacientes que sofrem de neuralgia trigeminal. Mais estudos são necessários para elucidar os mecanismos subjacentes aos efeitos antihiperalgésicos dessas vitaminas. Palavras-chave: Neuralgia do trigêmeo, Constrição, Nervo infraorbital, Hiperalgesia térmica, Hiperalgesia mecânica, Ratos. / Abstract: A growing body of evidence obtained in various pain models, suggests that the use of B complex vitamins can help control neuropathic pain. Currently, only carbamazepine, an anticonvulsant drug, is approved by the Food and Drug Administration American Agency for the treatment of trigeminal neuralgia, but its use is associated with numerous adverse effects. This study provides evidence that B1, B6 and B12 vitamins, alone or in combination with carbamazepine, ameliorate heat, cold and mechanical hyperalgesia in a rat model of trigeminal neuropathic pain. Herein, we demonstrated that repeated subcutaneous (s.c.) treatment (for 5 days, starting on the day of surgery up to day 4 after surgery) of rats with B1, B6 or B12 vitamin (180, 180 or 18 mg/kg, respectively) prevented the development of heat hyperalgesia after constriction of the infraorbital nerve (CION). On the other hand, only B12 vitamin treatment (18 mg/kg, s.c., for 5 days) was able to reduce the cold hyperalgesia and such reduction was observed on days 6 and 9 after CION surgery. Moreover, only B6 vitamin treatment (180 mg/kg, s.c., for 5 days, starting on day 8 up to day 12 post-surgery) promoted an increase in the mechanical threshold of rats submitted to CION, starting on day 10 after surgery and persisting up to day 20 post-surgery. Additionally, a single intraperitoneal (i.p.) administration of carbamazepine (30 mg/kg) was able to reduce heat and cold hyperalgesia on day 4 after nerve injury, but was not able to modify the mechanical hyperalgesia assessed on day 20 post-surgery. The combination of lower doses of all three B vitamins (B1, B6 and B12, at 18, 18 e 1.8 mg/kg, s.c., 5 injections) with carbamazepine (at 10 mg/kg, i.p., single injection) caused a marked reduction of heat hyperalgesia, while the combination of B12 with carbamazepine (same doses above) promoted the reversion of cold hyperalgesia, both evaluated on day 4 post-surgery. In conclusion, we suggest that vitamins B1, B6 and B12 could be an alternative or be used as adjuvants to control some aspects of pain in patients suffering from trigeminal neuralgia. Further studies are necessary to elucidate the mechanisms underlying the antihyperalgesic effects of B complex vitamins. Key Words: Trigeminal neuralgia, Constriction, Infraorbital nerve, Thermal Hyperalgesia, Mechanical Hyperalgesia, Rats.

BARBOSA, André Luiz dos Reis. Modificação da resposta inflamatória sistêmica em ratos inoculados com carcinossarcoma 256 de Walker : papel da degranulação mastocitária. 2007. 135 f. Dissertação (Mestrado em Farmacologia) - Universidade Federal do Ceará. Faculdade de Medicina, Fortaleza, 2007. / Submitted by denise santos (denise.santos@ufc.br) on 2012-03-05T16:34:11Z No. of bitstreams: 1 2007_dis_alrbarbosa.pdf: 1315775 bytes, checksum: a521b830535e3317c03833bdd0c1667c (MD5) / Approved for entry into archive by Eliene Nascimento(elienegvn@hotmail.com) on 2012-03-07T11:38:06Z (GMT) No. of bitstreams: 1 2007_dis_alrbarbosa.pdf: 1315775 bytes, checksum: a521b830535e3317c03833bdd0c1667c (MD5) / Made available in DSpace on 2012-03-07T11:38:06Z (GMT). No. of bitstreams: 1 2007_dis_alrbarbosa.pdf: 1315775 bytes, checksum: a521b830535e3317c03833bdd0c1667c (MD5) Previous issue date: 2007 / Our objective was to evaluate the effect of the 256 Walker carcinossarcoma inoculation, as well as the time course of tumoral development, upon the acute inflammatory response in rats. Wistar rats, 180-220g, received intramuscular 106 tumor cells injections. At the end of 4, 7 or 10 days, wistar rats were separated into 4 groups, with 6 animals per group. The control group, were not inoculated with tumoral cells. Several parameters were evaluated: paw edema induced by carrageenan (Cg; 300μg/hind) or dextran (Dxt, 500μg/hind paw), myeloperoxidase activity (MPO), neutrophil migration to peritoneal cavity induced by carrageenan, cutaneous vascular permeability induced by bradykinin (2μg/site), serotonin (1μg/site), histamine (30μg/site), substance P (250ng/site), capsaicin (50μg/site) or 48/80 compound (1 μg/site) and mast cell degranulation induced by 48/80 compound. Paw edema was evaluated in the contra lateral hind paw of the tumor and measured at 0, 1, 2, 3 and 4h for Cg, and 0, 30’, 1, 2, 3 and 4h.for Dxt by plethysmometry. Neutrophil migration was induced by Cg injection in the contralateral hind paw or in the peritoneal cavity. After 4h, rats were sacrificed and the skin of the hind paw was harvested to measure neutrophil infiltration by MPO assay. Neutrophil migration induced by Cg was also evaluated in the peritoneal cavity, with the total e differential leucocytes counted. In order to measure cutaneous vascular permeability, immediately after intradermic stimulus injections (bradykinin, histamine, serotonin, substance P, capsaicin or 48/80 compound) Evans Blue dye was administrated (0,1mL/100g of per animal) by endovenous route. After 30 min rats were sacrificed and the skin was harvested to evaluate Evans Blue extravasations by spectrofotometry. Mast cells degranulation was evaluated in the in mesentery incubated with 48/80 compound and colored with toluidine blue. Our results shows that, in animals inoculated with the carcinossarcoma, there was a significant inhibition in the Cg and Dxt- induced paw edema, with maximal effect at the 7th and 10th days. There were no differences in MPO activity and neither in the peritoneal neutrophil infiltration induced by Cg in rats inoculated with the carcinossarcoma when compares to normal animals. After 4 and 7 days of the tumor inoculation, we observed a significant inhibition of the vascular permeability induced only by bradikinin, serotonin and 48/80 compound.. In the 10th day after the carcinossarcoma inoculation, there was a significant inhibition of the vascular permeability induced by all inflammatory stimulus tested, when we compared animals not inoculated. Mast cell degranulation was decreased in the 4th, 7th and 10th days after carcinossarcoma inoculation. These results suggested that the tumor microenvironment decreased the acute inflammatory response probably due to a inhibition of the mast cell degranulation. / No presente estudo avaliou-se os efeitos da inoculação do carcinosarcoma 256 de Walker, bem como o curso de seu desenvolvimento, sobre a reação inflamatória sistêmica. Ratos Wistar machos, pesando entre 180 a 220g, foram inoculados, por via intramuscular, com 106 células tumorais na coxa direita. Os experimentos foram realizados após o 4º, 7º e 10º dias (4D, 7D e 10D) da inoculação do carcinossarcoma 256 de Walker. O grupo controle não foi inoculado as células tumorais. Os ratos foram divididos em grupos experimentais com n = 6, nos quais foram avaliados os seguintes parâmetros: edema de pata por carragenina (Cg; 300μg/pata direita) ou dextrana (Dxt; 500μg/pata direita), atividade da enzima mieloperoxidase (MPO), migração de neutrófilos para cavidade peritoneal induzidas por carragenina (Cg; 300μg/pata direita), permeabilidade vascular cutânea induzidas por bradicinina (2μg/sítio), histamina (30μg/sítio), serotonina (1μg/sítio), substância P (250ng/sítio), capsaicina (50μg/sítio) ou composto 48/80 (1μg/sítio) e degranulação mastocitária induzida por composto 48/80. A intensidade do edema foi avaliada na pata contralateral ao tumor 1, 2, 3 e 4 hs (Cg) e 30’ ,1 2, 3, ,4 hs (Dxt) por pletismometria. A migração de neutrófilos foi induzida pela administração de Cg (300μg/pata) na pata contralateral ao tumor ou na cavidade peritoneal. Após 4 horas, os ratos foram sacrificados e as peles das patas foram retiradas para medir indiretamente a infiltração de neutrófilos, pela técnica da dosagem da atividade da MPO, e a migração de neutrófilos para cavidade peritoneal foi avaliada através da contagem total e diferencial de leucócitos. Em relação a permeabilidade vascular cutânea, imediatamente após as injeções intradérmicas dos estímulos (bradicinina, histamina, serotonina, substância P, capsaicina ou composto 48/80), foi administrado azul de Evans (0,1mL/100g do animal), na veia do plexo peniano. Após 30 min, os ratos foram sacrificados e a pele do dorso retirada, para avaliar o extravasamento do azul de Evans por espectrometria. A degranulação de mastócitos do mesentério foi avaliada após coloração com azul de toluidina, sendo contados os mastócitos degranulados num total de 100 células. Os animais com tumor apresentaram uma inibição significativa do edema de pata, com efeito máximo observado nos 7 º e 10 º dias, tanto com a Cg, quanto com Dxt, quando comparados com o controle sem tumor. Em nenhum dos dias estudados, foram observadas diferenças na atividade da MPO na pata e nem na avaliação da migração de neutrófilos para a cavidade péritoneal induzidas por Cg. Após 4 e 7 dias da inoculação do tumor, o animais apresentaram uma significativa diminuição na permeabilidade vascular cutânea induzida por bradicinina, serotonina, e composto 48/80. No entanto, o aumento da permeabilidade vascular induzida por histamina, substância P e capsaicina não foi alterada nesses dois dias. No 10 º dia, observou-se uma diminuição da permeabilidade vascular induzida por todos os estímulos quando comparado com o grupo sem tumor. A degranulação mastócitária foi inibida em animais com tumor nos 4º, 7º e 10º dias em comparação com o grupo controle. Tais dados sugerem que o microambiente do tumor de Walker diminui o curso da resposta inflamatória através da inibição da degranulação dos mastocitos.

Made available in DSpace on 2012-09-06T01:11:36Z (GMT). No. of bitstreams: 2 license.txt: 1748 bytes, checksum: 8a4605be74aa9ea9d79846c1fba20a33 (MD5) 627.pdf: 1386418 bytes, checksum: 2e705d3dabbd982d0b2918fad161a251 (MD5) Previous issue date: 2003 / O presente trabalho procura descrever o perfil epidemiológico e a sobrevida de 1 e 5 anos em uma coorte de pacientes com carcinoma hepatocelular acompanhados no Instituto Nacional do Câncer (INCA), localizado no município do Rio de Janeiro. Foi realizado um estudo retrospectivo de 115 pacientes, matriculados no INCA-RJ no período de 1990 à 2000. Utilizou-se o método de Kaplan Meier e de Regressão de Cox para a análise e construção das curvas de sobrevida. O perfil da coorte estudada foi de pacientes sintomáticos (94 por cento) em estágio avançado de doença (41,3 por cento estadiamento IV), com média de idade de 53,6 anos, sem variação entre os sexos. A razão M/F encontrada foi de 1,3:1.A sobrevida de 1 ano foi de 30,5 por cento, com mediana de 4,6 meses. Pela análise univariada, os pacientes com melhor sobrevida foram aqueles submetidos a algum tratamento, com menos de 55 anos, com 1-3 nódulos menores que 10 cm e com nível de alfafetoproteína menor ou igual a 500 ng/ml, os quais apresentaram sobrevida de 1 ano de 44,9 por cento, 36,7 por cento, 46,5 por cento e 44,3 por cento, respectivamente. Apenas 3,4 por cento dos pacientes sobreviveram além de 5 anos. Na análise multivariada, foram construídos dois modelos: no primeiro observou-se uma Hazard Ratio (HR) de 3,92 (IC 95 por cento 1,79-8,61) para os pacientes com nódulos múltiplos, controlando as variáveis idade, cirrose e tratamento. No segundo modelo, a HR para os pacientes com nível sérico de alfafetoproteína > 500 ng/ml, foi de 2,02 (IC 95 por cento 1,17-3,49), controlando o efeito do tratamento. A média de idade observada tende a se aproximar dos valores descritos em regiões com alta incidência para o carcinoma hepatocelular, contudo a razão M/F foi inferior ao registrado em áreas com baixa incidência. Os pacientes submetidos a alguma intervenção terapêutica apresentaram melhor sobrevida em relação aos não tratados. Pacientes com alfafetoproteína elevada ou com nódulos múltiplos apresentaram pior prognóstico

A research report submitted to the faculty of Health Sciences University of Witwatersrand, in partial fulfilment for the degree of Master of Medicine (M.Med) Radiation Oncology. Johannesburg 2014 / Background Larynx preservation is the standard recommended treatment approach for cancer of the larynx. We looked at results of patient treated with larynx preserving approach at our institution. Objectives The study objectives included describing the demographics of the population in the study and comparing characteristics and outcomes for patients in the different treatment groups. We also assessed waiting time for treatment, treatment completion rates and overall treatment time for all the patients in the study group. Outcomes of patients at last follow up and survival for different stages of disease were described. Materials and Methods A retrospective study of patients with cancer of the larynx treated at Charlotte Maxeke Academic Hospital department of radiation oncology between the year 2007 and 2009. All patients who received radiotherapy including palliative and radical cases were assessed. Outcomes were measured from end of treatment to 1 year and 2 years follow up for survival. Results We identified 106 eligible patients. The mean age was 58.6 years (standard deviation of 10.051).Two thirds (67%) of the patients presented with stage IVa disease, 14% had stage IVb, 13% had stage III, and very few patients had stage I and II disease 4% and 2% respectively. One third of patients were treated with radical chemotherapy plus radiotherapy and majority of them received only 1 cycle of chemotherapy. The other 26 % of patients treated with radical intent received radiotherapy alone. A significant number of our patients (42 %) were treated with palliative intent of which 13 % were patients who had disease progression while awaiting treatment. The majority of patients (53%) had an improvement in symptoms while (5.7%) had died and (17%) were lost to follow-up. Conclusion Waiting time prior to radiotherapy is a major problem in our institution as our overall mean waiting time was 98.5 days. Patients who had disease progression as defined by change in the treatment intent from radical to palliative treatment (13%) had a mean waiting time of 187.9 days which was almost double our overall mean waiting time and significantly worse than that recommended by standard of care. Although this waiting time was not statistically significant when compared with other patients treated with radical intent, it is a concern for the department to have such long waiting time prior to therapy and is probably a reflection of inadequate statistical power. Of the radical cases those treated with chemotherapy and radiotherapy very few (2.9%) completed 3 cycles of chemotherapy therefore we had low treatment completion rates. Some patients did not receive their 2nd or 3rd cycle of chemotherapy due to low creatinine clearance other patients reasons for not completing chemotherapy was not documentation in their medical records. Although concurrent chemotherapy plus radiotherapy is the standard of care for larynx preservation, most of our patients received suboptimal treatment to the recommended schedule and a significant number of our patients were treated with palliative intent. Chemotherapy was not administered in some patients because of low CD4 count value. Unfortunately this was not recorded systematically and HIV status was not an entry or exclusion factor so no comparisons could be made. The chemotherapy schedule was not given to many patients at the recommended schedule of 3 cycles so we were not able to compare this with the literature. Resources constraints with regards to diagnostic and radiological facilities resulted in us not having measurable tumour volume increase to evaluate disease progression during waiting time and to evaluate response to treatment at follow-up. We have identified that patients are receiving inadequate treatment at the Department of Radiation Oncology with waiting times in excess of that recommended in the literature. Several reasons have been tentatively identified. Additional research in a form of prospective study is required in our department to assess if we could improve the number of patients treated with radical intent by giving induction chemotherapy during the waiting time for patients with advanced stage III & IV disease who have a good performance status. Protocols in our department need to be reviewed for patients with early disease to be treated with shorter regimen and a higher dose fractionation schedule of 2.25Gy as this will also reduce our overall treatment time and waiting time for treatment while improving local control.

Hepatocellular carcinoma (HCC) is a leading cause of death in both Africa and Asia. It is multifactorial in aetiology and complex in its pathogenesis. Genes that might affect tumour progression, invasion, and metastasis are good candidates to investigate in attempting to understand the transformation process. The p53, RBI, BRCA1, BRCA2, WT1 and Ecadherin genes were analysed for allelic imbalance/loss of heterozygosity (LOH), polymorphisms, and mutations. Tumour and non-tumorous liver tissue from 25 southern African blacks were examined, using polymerase chain reaction restriction fragment length polymorphisms (PCR-RFLP) and PCR-single stranded conformational polymorphisms (SSCP), sequencing, and Southern blotting techniques. Allele frequencies for polymorphisms at the WEI, D13S137, D13S120, D13S127, D17S855, D16S301, and D16S260 loci were determined in 20 random African blacks using microsatellite analysis to determine allele frequencies, polymorphism information content (PIC) and diversity (H) values. To our knowledge this has not been done previously for these loci in this population. The chromosomal region l i p 13, containing the VV77 gene, and the gene itself has been reported to be deleted in 4.5% of HCCs. LOH was detected at the WT1 locus for 1/13 HCCs (8%) in this study. The RBI gene has been described to be mutated in 32.4% (China), 33.3% (Korea), 29% and 50% tJapan), and 27% (Australia), of advanced stage HCCs. In our study LOH at this locus was found in 3/19 HCCs (16%). Our finding of LOH at the BRCA2 locus in 2/20 HCCs (10%) supports the previously proposed notion that BRCA2 may function as a tumour suppressor gene in a hormone-related pathway in the liver, and that it may in some way be involved in HCC. No conclusive findings were made for any o f the other loci. Microsatellite instability was detected in 3/22 (14%) individuals. We propose that microsatellite/genomic instability may play a role in a subset of HCCs only. O f this population, 27 % had the specific p53 codon 249 AGG-AGT mutation in some tumour and non-tumorous liver. This was expected as the great majority of the individuals were from Mozambique, a country where heavy aflatoxin exposure is prevalent. All the loci examined in the allele frequency studies proved to be highly informative, showing high PIC and ED values, and should therefore be useful in population studies.