Association of Target Therapy Gene Expression with Metastasizing of Clear-Cell Renal Cell Carcinoma.

We analyzed association of the levels of VEGFA, RAF1, and mTOR gene expression in the tissue of clear-cell renal cell carcinoma (ccRCC) with tumor metastasizing. Significant association with metastases was found only for VEGFA gene: OR=6.641, 95%CI=2.111-20.696. The risk of metastasis associated with reduced expression of VEGFA gene - 2.467, 95%CI=1.238-4.915. An association of VEGFA gene expression with the time to the metastasis appearance was revealed (p=0.0005). Reduced expression of the VEGFA gene is associated with reduction of the time to metastasis appearance; the median of this time is shifted from 46 to 2 months. Analysis of tumor samples with reduced expression of the VEGFA gene revealed association of increased expression of RAF1 (p=0.003) and mTOR genes (p=0.038) with metastasis.

Expression Profiles of Genes-Potential Therapy Targets-and Their Relationship to Survival in Renal Cell Carcinoma.

The main mechanisms of pathogenesis of clear cell renal cell carcinoma (CCRCC) are realized through the PI3K-AKT-mTOR and Ras-RAF-ERK signaling pathways. Targeted therapy is directed primarily at the genes and their encoded products that are components of these pathways. The levels of expression and coexpression of target genes were determined, and the difference in the functioning of the genes of one of the two major signaling pathways in tumors of CCRCC patients with different life duration (more and less than 3.5 years) and the relationship of the VEGFA gene expression level with the life duration was revealed.

[Alteration of VHL gene in patients with metastatic renal cell carcinoma].

Blocks of preparations from 22 patients with metastatic renal cell carcinoma on target therapy were studied. The patients were examined for mutations/methylation of VHL gene. The mutations were detected in 10 (45.5%) of 22 patients, VHL methylation was found in 1 (4.5%) patient. Overall survival was 36.4 and 66.7% in the groups of patients with and without gene VHL alteration, respectively. Progression-free survival was 47.6 and 57.1%, respectively (p = 0.619), relapse-free survival--63.6 and 45.5%, respectively (p = 0.682), progression was registered in 36.4 and 54.5%, respectively (p = 0.682). Gene VHL inactivation had no effect on prognosis of the disease and results of anti-angiogenic therapy.

[Localization of point mutations in the coding part of the VHL gene in clear cell renal cancer].

VHL gene is often inactivated in sporadic clear cell renal cancer (CCRC) due to somatic mutations, and it's germline mutations cause hereditary CCRC--von Hippel-Lindau syndrome. Localization of mutations in VHL, identification of new mutations and their influence on CCRC progression and sensitivity to targeted therapy are actual problems in modern oncogenetics. We have provided search and characterization of mutations in 248 primary CCRC using SSCP-analysis and sequencing. Somatic mutations were detected in 37.5% of samples, 72% of mutations were identified for the first time. New missense-mutations were analyzed by alignment programs and three-dimensional structure modeling. Mutation frequency was compared in different groups of patients in respect to stage, grade, and metastases. It was demonstrated that 39.1% samples with stage I harbor somatic mutations, however, no association with progression or metastases was found. We also have investigated localization of mutations in the VHL coding part and positions of missense-mutations and inframe deletions/insertions focusing on VHL critical sequences. VHL mutation analysis performed in this study improve the possibilities of laboratory diagnostics of familial and sporadic CCRC.

Role of radiation therapy in localized non-Hodgkin's lymphoma.

Relapse occurs in 50% of patients receiving radiation for clinical stage (C.S.) I and II nodal and extranodal non-Hodgkin's lymphoma (N.H.L.). Prior to the introduction of intensive chemotherapy those failing primary control with irradiation and most of those who relapsed died of their disease with a resultant overall mortality of 50%. An analysis of Princess Margaret Hospital results with radiation for C.S. I and II N.H.L. between January 1967 and December 1978 revealed that tumour bulk, age, stage and histology were of independent prognostic significance. It was possible to group patients using combinations of these attributes so that each group encompassed only patients with similar outcomes. Such prognostic groups were identified separately within the low grade and the intermediate plus high grade categories of the Working Formulation. Patients with a high probability of cure with radiation were so defined. Also those patients in whom chemotherapy would be optimal initial therapy were also defined. Such patients were in the intermediate plus high grade histology groups. Thirty percent of all patients with low grade histology lymphoma had an actuarial survival of 83%, and relapse-free rate of 63% at 10 years. By implication, approximately 20% of all patients with these histologies seen at the Princess Margaret Hospital for the same time period achieved prolonged relapse-free survival by localized therapy. This is at variance with the implications of staging from studies where laparotomy and multiple bone marrow biopsies have been used. Such aggressive staging procedures suggest truly localised disease in only 5-6% of patients with low grade lymphoma. A significant relationship between radiation dose and disease control was demonstrated only for patients with intermediate and high grade lymphoma of medium or large bulk. A minimum tumour dose of 30 Gy was required for optimal local control with radiation.

"Local" treatment of early breast cancer.

T1N0 and T2N0 breast cancer should be treated initially by local excision only. Subsequent review of the patient's clinical, investigative, and histologic presentation must then guide future treatment decisions. If further treatment is deemed necessary, then consideration should be given to wider excision, total mastectomy, or local irradiation, in that order. Subsequent development of axillary lymphadenopathy signals disseminated disease and requires systemic, not local, therapy initially.

Survival and complications of radiotherapy following involved and extended field therapy of Hodgkin's disease, stages I and II. A collaborative study.

A collaborative trial with random assignment to involved field or extended field radiotherapy for localized Hodgkin's disease was begun in 1967. Case accession was completed in 1973, with 224 eligible patients assigned to involved field and 243 to extended field. With a median follow-up time of 27 months no significant survival difference is found between involved and extended field regimens for the total patient group or for most subgroups defined by age, sex, histology, stage, class, and use of laparotomy for staging. A single exception is an improved survival in the involved field group for female patients. Survival free of distant extension shows a similar lack of treatment effect, but survival free of any extension, local or distant, shows a significant benefit from extended field treatment. Complications of radiotherapy are significantly increased following extended field treatment. Survival following local extension is similar to survival following periods free of any extension.

Hodgkin's disease in children. A retrospective analysis: 1958-73.

One hundred nine children with Hodgkin's disease consecutively treated at The Princess Margaret Hospital, Toronto, during 1958-1973 are reviewed. Crude 5-year survival rates, regardless of stage, were 1958-64--50%; 1965-68--73%; and 1969-73--95%. The corresponding 5-year relapse-free rates were 19%, 20%, and 57%. This progressive improvement in results was associated with the sequential introduction of lymphography and laparotomy with splenectomy, the change from involved field to extended field irradiation, and the introduction of multiple agent chemotherapy, at first for generalized relapse and recently as elective initial therapy, combined with extended field irradiation for children in advanced stages.

A retrospective analysis of the clinical results in relation to the Rappaport histological classification.

The Rappaport classification of the non-Hodgkin's lymphomata was applied to 460 cases at the Princess Margaret Hospital. Statistically significant differences in the numerical incidence between the nodular and diffuse patterns was found for the entire series and for the lymphocytic, "histiocytic" and mixed cell types individually. All of the undifferentiated types were diffuse. These differences were sustained for the degrees of differentiation within the lymphocytic group. The "histiocytic" group was not subclassified by differentiation. The cell types differed in the numerical distribution of the patterns. The lymphocytics were predominantly diffuse but their nodular forms constituted a higher proportion of the nodular pattern than did their diffuse types of the diffuse group. More of the well differentiated lymphocytics were nodular than were diffuse and they formed a higher proportion of the nodular group than they did of the diffuse. On the other hand, the poorly differentiated lymphocytics were predominantly diffuse and these were less well represented in the nodular group than in the diffuse tumours. The intermediate differentiated types were usually diffuse but slightly better represented in the nodular group. Most tumours of the "histiocytic" type were diffuse and these constituted a higher proportion of diffuse than the nodular tumours. The mixed cell lesions were predominantly nodular and comprised a much higher proportion of nodular lesions than diffuse. No real differences were identified amongst the histological types according to age or sex distributions. The crude survival to 4 years differed significantly for the histological types. For the entire series and for each cellular type, the nodular patterns were superior to the diffuse, although, in the lymphocytic well differentiated types, pattern made no real difference to survival.