Diss. (sammanfattning) Stockholm : Karol. inst. / Härtill 5 uppsatser.

Diss. Stockholm : Karol. inst.

Ph.D.

O objetivo deste trabalho foi comparar o prognóstico de sobrevida da graduação histológica após efeito da quimioterapia (graus I versus II de Huvos), visando também identificar fatores prognósticos no que diz respeito à sobrevida livre de recidiva local (SLRL), sobrevida livre de metástase (SLM) e sobrevida global (SG), em pacientes portadores de osteossarcoma primário não metastático ao diagnóstico. Vinte e quatro entre 45 pacientes admitidos no Instituto de Ortopedia e Traumatologia do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo IOT/HC/FMUSP, entre 2000 e 2004, foram eleitos para o estudo, segundo os critérios de inclusão e exclusão utilizados. As probabilidades de sobrevida acumuladas foram feitas pela técnica de Kaplan-Meier e os índices I e II de HUVOS comparados pelos testes de Log Rank. A análise multivariada foi feita pela técnica de regressão logística com modelo de risco proporcional de COX e a validade estatística estabelecida para valores de p<0,05. Os graus I e II de Huvos, quando comparados, não foram considerados de valor prognóstico em nenhuma das sobrevidas estudadas (SLRL, SLM e SG). Os fatores adversos que influenciaram o risco de recidiva local e a sobrevida global, na análise univariada foram: subtipo histológico diferente do osteoblástico (p=0,017) e o tamanho tumoral maior que 15 cm (p=0,048). Em relação à SLM o subtipo não osteoblástico (p=0,007) teve um pior prognóstico. O subtipo histológico manteve sua significância na análise multivariada em todas as sobrevidas estudadas / The purpose of this study was to compare the prognostic of survivor of histologic graduation post chemotherapy (Huvos´s grade I versus II), aiming to identify prognostic factors concerning to local recurrence free survival (LRFS), metastases free survival (MFS) and overall survival (OS) in patients with nonmetastatic primary osteosarcoma. This study included 24 patients registred in the Instituto de Ortopedia e Traumatologia do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo - Brazil, from 2000 to 2004. Survivor rates were calculed using Kaplan-Meier method. Huvos´s grade (I e II) were compared using the Log Rank test. Cox proportional hazards model was used for multifatorial analysis. Statistical significance was defined as a p value less than 0, 05. The Huvos´s grade I versus II was not significant factor for LRFS, MFS or OS. The adverse factors for LRFS and OS in univariate analysis were nonosteoblastic histologic subtypes (p=0,017) and large tumor (p=0,048). For MFS nonosteoblastic histologic subtypes (p=0,007) had worse prognostic. The histologic subtypes maintained their significance in multivariate testing on all studied survivor

O objetivo deste trabalho foi comparar o prognóstico de sobrevida da graduação histológica após efeito da quimioterapia (graus I versus II de Huvos), visando também identificar fatores prognósticos no que diz respeito à sobrevida livre de recidiva local (SLRL), sobrevida livre de metástase (SLM) e sobrevida global (SG), em pacientes portadores de osteossarcoma primário não metastático ao diagnóstico. Vinte e quatro entre 45 pacientes admitidos no Instituto de Ortopedia e Traumatologia do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo IOT/HC/FMUSP, entre 2000 e 2004, foram eleitos para o estudo, segundo os critérios de inclusão e exclusão utilizados. As probabilidades de sobrevida acumuladas foram feitas pela técnica de Kaplan-Meier e os índices I e II de HUVOS comparados pelos testes de Log Rank. A análise multivariada foi feita pela técnica de regressão logística com modelo de risco proporcional de COX e a validade estatística estabelecida para valores de p<0,05. Os graus I e II de Huvos, quando comparados, não foram considerados de valor prognóstico em nenhuma das sobrevidas estudadas (SLRL, SLM e SG). Os fatores adversos que influenciaram o risco de recidiva local e a sobrevida global, na análise univariada foram: subtipo histológico diferente do osteoblástico (p=0,017) e o tamanho tumoral maior que 15 cm (p=0,048). Em relação à SLM o subtipo não osteoblástico (p=0,007) teve um pior prognóstico. O subtipo histológico manteve sua significância na análise multivariada em todas as sobrevidas estudadas / The purpose of this study was to compare the prognostic of survivor of histologic graduation post chemotherapy (Huvos´s grade I versus II), aiming to identify prognostic factors concerning to local recurrence free survival (LRFS), metastases free survival (MFS) and overall survival (OS) in patients with nonmetastatic primary osteosarcoma. This study included 24 patients registred in the Instituto de Ortopedia e Traumatologia do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo - Brazil, from 2000 to 2004. Survivor rates were calculed using Kaplan-Meier method. Huvos´s grade (I e II) were compared using the Log Rank test. Cox proportional hazards model was used for multifatorial analysis. Statistical significance was defined as a p value less than 0, 05. The Huvos´s grade I versus II was not significant factor for LRFS, MFS or OS. The adverse factors for LRFS and OS in univariate analysis were nonosteoblastic histologic subtypes (p=0,017) and large tumor (p=0,048). For MFS nonosteoblastic histologic subtypes (p=0,007) had worse prognostic. The histologic subtypes maintained their significance in multivariate testing on all studied survivor

Diss. (sammanfattning) Stockholm : Karol. inst., 2002. / Härtill 4 uppsatser.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2010.

Breast cancer is the most commonly diagnosed cancer in women. Despite recent advances in screening and early detection, breast cancer continues to result in a high incidence of morbidity and mortality. In its late stage the majority of patients exhibit signs of destructive skeletal metastasis. This complication is promoted by the production of growth factors by tumor cells which can induce tumor cell proliferation via their interaction with their respective receptors to initiate the vicious cycle of bone resorption. Inhibition of growth factors signaling through their receptors can therefore serve as a useful therapeutic approach to block bone metastasis. / The biological characteristics of cancer cells along with the targeting properties of immune system offer a novel approach in the treatment of breast cancer. Directed against HER-2/nue oncogene, the recombinant humanized monoclonal antibody, Trastuzumab (Herceptin), has shown significant clinical benefits for the treatment of HER-2 positive metastatic breast cancer. / In the present study, the effects of Herceptin and its molecular mechanism of action in abrogating the development and progression of osteolytic bone metastasis is investigated in an experimental mouse model of skeletal metastasis using human breast cancer cells BT-474 which are known to express high levels of HER-2. Treatment of BT-474 cells with Herceptin caused a dose dependent decrease in cell proliferation. In in vivo studies BT-474 cells were injected by into the left ventricle of female BALB/c nu/nu mice. Intraperitoneal infusion of Herceptin from the day of tumor cell inoculation or at the time of radiologically detectable skeletal metastasis either slowed the development or prevented the progression of skeletal metastasis as compared to control groups of animals receiving non-specific IgG. Bone histological analysis of long bones showed the ability of Herceptin to reduce the ratio of tumor volume to bone volume as well as mitotic index when Herceptin treatment was initiated from the day of tumor cell inoculation. Immunohistochemical analysis of long bones showed a significantly lower level of activated (phosphorylated) MAPK in bones of Herceptin treated animals. These studies demonstrate the ability of Herceptin to inhibit the development and abrogate the progression of skeletal metastasis associated with breast cancer by blocking the HER-2 mediated signaling pathways.

No description available.

Prostate cancer remains one of the most commonly diagnosed cancers in men and is a leading cause of cancer death. While great success has been achieved at curing early stage prostate cancer, limited success has been obtained when treating late-stage hormone independent prostate cancer. This is due to the increased propensity for skeletal and non-skeletal metastases. Thus development of novel effective therapeutic modalities against late stage prostate cancer is of critical importance. / Towards these objectives, I have focused my attention on the role of prostate secretory protein (PSP-94) which is expressed in normal individuals and in patients with early stage prostate cancer. Using our well established in vivo models of prostate cancer, I have evaluated the ability of PSP-94 and its amino acids 31-45 required (PCK3145) to decrease tumor growth and skeletal metastases in vivo and evaluated the potential mechanism(s) associated with PCK3145 anti-cancer actions. / Prostatic cancer can also develop as a result of epigenetic activation of tumor promoting genes. To evaluate the role of methylation in prostate cancer, late stage prostate cancer cells were treated with the universal methylating agent S-adenosylmethionine (SAM) and an anti-sense oligonucleotide directed against MBD2 (AS). Scrambled oligonucleotide was included as a control (S). Both SAM and MBD2-AS resulted in inhibition in uPA, MMP-2 and VEGF production leading to decreased tumor cell invasive capacity. However, SAM and MBD2-AS were not able to either further repress partially methylated genes (GSTP1) or reactivate already methylated genes (AR). Furthermore, SAM and MBD2-AS treatment resulted in significant reduction in tumor growth in vivo . Immunohistochemical and RT-PCR analyses carried out on SAM and MBD2-AS tumors revealed decreased protein and mRNA expression of uPA and MMP-2 which was partially due to increased methylation of the respective promoters even after 10 weeks post in vitro treatment as analyzed by bisulfate sequencing. In addition decreased levels of angiogenesis and tumor survival markers were observed. / Collectively, these studies are aimed at the development of novel reliable approached to diagnose and treat advanced, hormone refractory prostate cancer to reduce tumor associated morbidity and mortality.