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According to the analysis results of the longterm treatment experience of more than 800 patients with osteosarcomas the authors began to perform the new record of the osteosarcoma treatment, the basic aims of which are the increase of the number of patients with promunced medicinal pathomorphism at the expence of more intensive preoperative chemotherapy. After chemotherapy intensification the incidence of side effects increases. The data on the osteosarcoma pathogenesis with the sexual steroid hormones are obtained. It is emphasized that the immediate and remote results of the extremity osteosarcoma treatment can be achieved only in the highly specialized centers provided with current diagnosis methods, treatment monitoring and supporting therapy measures.

The content of urokinase- and tissue-type plasminogen activators and plasminogen activator inhibitor PAI-1 in the cytosol of primary and metastatic melanomas and benign skin pigment neoplasms was estimated by enzyme immunoassay. It was shown that local growth and invasion of melanomas are related to suppressed expression of tissue plasminogen activator. The content of urokinase plasminogen activator increases in patients with distant metastases and large thickness of the primary tumor.

Arachidonic acid metabolites are measured in primary osteogenic sarcomas, benign neoplasms, and tumor-like bone lesions. In typical osteogenic sarcomas, the contents of E and F2α prostaglandins are significantly higher than in benign bone tumors or tumor-like bone lesions. Neoadjuvant chemotherapy has different effects on the levels of prostaglandins E and F2α, thromboxane B2, and prostaglandin F1α in osteogenic sarcomas, its effectiveness depending on the mechanism of drug action and individual sensitivity of tumor cells to this drug. A negative correlation is established between the content of prostaglandins E in osteogenic sarcoma and the degree of therapeutic pathomorphosis of the tumor in patients treated with adriamycin during the preoperative period. A single transfusion of a suspension of nonactivated allogenic bone marrow cells markedly reduces the content of prostaglandins E in osteogenic sarcoma.

Expression of urokinase- and tissue-type plasminogen activators and their inhibitor PAI-1 in the cytosolic fraction of 20 osteosarcomas, 20 chondrosarcomas, 13 giant-cell bone tumors, 5 Ewing's sarcomas, and 7 osteochondral exostoses was studied by enzyme immunoassay. The content of urokinase-type plasminogen activator increased, while the concentration of tissue-type plasminogen activator decreased in bone tumors of various histological compositions compared to osteochondral exostoses. A positive correlation was found between PAI-1 content and the volume of osteo- and chondrosarcomas. Expression of urokinase-type plasminogen activator increased in patients with primary osteosarcomas characterized by early generalization of the pathological process.

The content of calmodulin in chondrosarcomas was notably lower in patients with early relapses or generalized tumor process in comparison with patients without postoperation relapses. The mean level of calmodulin in chondrosarcomas virtually did not depend on patient's sex and age and tumor location in bones. There was a tendency to an inverse correlation between calmodulin level in chondrosarcoma and the degree of tumor differentiation. The highest level of calmodulin was detected in the cytosolic fraction of chondrosarcomas containing no estrogen and androgen receptors.

Blood concentration of soluble Fas antigen is higher in patients with benign and malignant tumors in comparison with healthy subjects, which probably suggests its involvement into tumorigenesis.

Expression of the mutant protein-suppressor of tumor growth p53 and the receptor of epidermal growth factor of type II--HER-2/neu may serve as prognostic factors for patients with chondrosarcoma of malignancy grade II. Combined expression of these proteins in the tumor tissue correlates with shorter 5-year survival of recurrence-free patients. The data obtained may be used for prognosis of chondrosarcoma course and choice of adequate therapy.

The paper considers data of the long-term studies of androgen metabolism, baseline serum levels of reproductive steroid hormones and their receptors in the tumor, in the blood concentrations of sex steroid-binding globulin and pituitary hormones, the expression of epidermal growth factor, its receptors and ligands, soluble Fas-antigen, vascular endothelial growth factor, angiogenin, and the content of calmodulin, cAMP in the osteosarcoma in 300 patients aged 14 to 56 years, which were made at the N. N. Blokhin Russian Cancer Research Center, Russian Academy of Medical Sciences. Analyzing the findings identified some lines in the study of new pathogenetic treatments for osteosarcoma, aimed at regulating androgen metabolism, correcting the cyclooxygenase pathway of arachidonic acid, the expression of receptors of epidermal growth factor and its ligands, the processes of neoangiogenesis in the tumor. A role of the above parameters in the pathogenesis of osteosarcoma is discussed.

Phase-I clinical studies of teraphtal and a "teraphtal + ascorbic acid" catalytic system have been completed. The dose-limiting toxicity and maximum tolerable dose were not reached even at the end of maximal dose trials. No side-effects characteristic of antitumor cytostatic drugs were registered. The gravest side-effect ever recorded was a collapse which could not be linked to teraphtal dosage and was probably caused by hypersensitivity to the drug. The drug was recommended for phase II trials.

The Russian Cancer Research Center has experience in diagnosing and treating more than 800 patients with osteosarcoma who have been treated at the Clinic of General Oncology since 1952. Survival rates were no more than 10% before the 1970s when the only treatment was surgical. The use of adjuvant chemotherapy after radical surgery has increased survival up to 45-60%. In 1982 to 1986, a protocol involving intraarterial chemotherapy with adriamycin, 90 mg/m2, radiation therapy in a dose of 40 Gy, preserving surgery, and adjuvant chemotherapy was used to improve local and regional guidance. Survival was 55-60%. The high incidence of purulent complications prompted us to do away with radiation therapy. A protocol of neoadjuvant therapy that implies preoperative intraarterial monotherapy with cisplatin, 120-150 mg/m2, adriamycin, 90 mg/m2 or large-dose methotrexate (8-10 g/m2) was implemented in 1986 to 1998. The best results were achieved only in patients with complete tumor necrosis, among whom survival being over 70%. Preserving surgery following ineffective chemotherapy caused a high incidence of local relapses (30%). The second line of chemotherapy did not greatly improve prognosis when a histological response was slight. Complete tumor necrosis was noted only 10% of more than 150 patients so survival in the whole group was 40%. In 1998, a new protocol was initiated to improve immediate and late outcomes. Preoperatively, 3-4 sessions with adriamycin, 90 mg/m2 and cisplatin, 120 mg/m2, are performed. Postoperatively, 3 or 4 sessions of chemotherapy with the same drugs are made if there is a marked therapeutical pathomorphism. If a response is weak, 6 sessions with ethoposide, 100 mg/m2 and iphosphamide, 1.8 g/m2 during 1-5 days are given. This study has covered just 30 patients. The rate of a full histological responses has increased by 4 times. In every second patient, an amputable tumor could be made a resectable one. The proportion of candidates for preserving surgery has increased up to 90%. Intensified chemotherapy increased the incidence of severe adverse effects, primarily degrees 3-4 hematological toxicity reaching 40%. At the turn of centuries, osteosarcoma is a highly promising curable disease. The survivals of 65-70% and satisfactory functional results can be achieved only at highly specialized centers.

Expression of urokinase- and tissue-type plasminogen activators and their inhibitor PAI-1 in the cytosolic fraction of 20 osteosarcomas, 20 chondrosarcomas, 13 giant-cell bone tumors, 5 Ewing's sarcomas, and 7 osteochondral exostoses was studied by enzyme immunoassay. The content of urokinase-type plasminogen activator increased, while the concentration of tissue-type plasminogen activator decreased in bone tumors of various histological compositions compared to osteochondral exostoses. A positive correlation was found between PAI-1 content and the volume of osteo- and chondrosarcomas. Expression of urokinase-type plasminogen activator increased in patients with primary osteosarcomas characterized by early generalization of the pathological process.

The content of urokinase- and tissue-type plasminogen activators and plasminogen activator inhibitor PAI-1 in the cytosol of primary and metastatic melanomas and benign skin pigment neoplasms was estimated by enzyme immunoassay. It was shown that local growth and invasion of melanomas are related to suppressed expression of tissue plasminogen activator. The content of urokinase plasminogen activator increases in patients with distant metastases and large thickness of the primary tumor.

This paper presents results of comparative enzyme immunoassay of soluble serum Fas antigen (sFas) in 98 patients with benign and malignant bone tumors, 15 patients with mechanical bone traumas, and 60 normal individuals of compatible age. The prevalence and concentration of sFas were significantly greater in patients with bone tumors than in normal donors and patients with mechanical bone traumas. The association of sFas with the pathogenesis of primary bone tumors is discussed in the paper.

Serum contents of leptin and soluble Fas antigen were measured in 28 patients with osteosarcoma, 7 with neuroectodermal bone tumors, and 17 healthy subjects. The incidence and levels of soluble Fas antigen in patients with osteosarcoma and neuroectodermal bone tumors were higher than in healthy subjects and did not depend on sex and age in both healthy subjects and patients. Serum concentration of leptin in women was higher than in men (both in healthy controls and patients) and was lower in healthy subjects compared to patients with osteosarcoma and neuroectodermal bone tumors. A trend to a negative correlation between the concentrations of leptin and soluble Fas antigen in female patients with osteosarcoma and male patients with neuroectodermal bone tumors was revealed. The role of leptin and soluble Fas antigen in the pathogenesis of primary bone tumors is discussed.

The paper provides data of comparative assessment of activity of the key enzymes in metabolism of androgens in various morphological variants of sarcomas and benign bone tumors in 46 patients within the age range from 15 to 61, which were under treatment in the ORC named after N. N. Blokhin, RAMS, from 1996 to 1997. On the basis on publications and our own research results we can suggest that malignant human bone tumors of various histogenesis are subject to metabolic processes of testosterone (T), the principal androgen regulator in the bone tissue, as well as formation in bones of 5 alpha-dihydrotestosterone (DHT). One cannot exclude a possibility that metabolism of androgen in bone tissues is directed towards formation of other androgens (in addition to DHT), which may participate in the bone tissue regulation, for instance, 3 alpha- and 3 beta-diols; specific activity of the latter has recently been intensively scrutinized. One can expect that further research shall disclose the clinical significance of metabolism of androgens and of individual androgens in human bone formations.

The role of androgens in human normal and neoplastic bone tissues is still unclear. The paper presents data on metabolism of androgens in homogenates of malignant (osteosarcoma, chondrosarcoma, Ewing and giant cell) and benign primary tumors from 46 male and female patients aged 14-58 years. Using two substrates (testosterone and 5 alpha-dihydrotestosterone) for the first time are shown activities of main enzymes of androgen metabolism in all tumor types. 5 alpha-reductase activity was similar in all tumors, 3 alpha-hydroxysteroid dehydrogenase activity was the highest while that of 17 beta-hydroxysteroid dehydrogenase was the lowest. Unknown metabolite(s) of 5 alpha-dehydrotestosterone was discovered which may be hydroxy-metabolites of 5 alpha-androstane-3 beta, 17 beta-diol. A principal scheme of androgen metabolism in human neoplastic tissue is proposed.

Three hundred and ninety-three patients with IIB osteosarcoma were treated at the author's institution between 1955 and 1986. In the first stage of the study, 88 patients were treated with surgery only. The five-year disease-free survival rate was 7%. In the second stage of the study, the efficacy of preventive chemotherapy after radical surgery was studied in 55 patients. The five-year disease-free survival rate was 34.4%. In the third stage of the study, the efficacy of combination therapy consisting of preoperative treatment, limb-saving surgery, and preventive chemotherapy was studied in 66 patients. The five-year disease-free survival rate was 35.5%. The authors examined results in 21 patients with Grade IV responses to evaluate the relationship between prognosis and morphogenic changes after preoperative radiotherapy and chemotherapy. The five-year disease-free survival rate was 57.9%. In the fourth stage of the study (conducted in 1986), two regimens of preoperative chemotherapy were initiated. The first regimen consists of intraarterial platinum infusions to patients with lower extremity bone damage. The second regimen consists of high-dose methotrexate infusions. The preliminary conclusion is that primary tumor damage is significantly more marked after intraarterial cisplatin infusion.

Results of examination and treatment of 24 patients with primary neoplasms of the sternum including chondrosarcoma (18 cases), solitary plasmacytoma (5) and osteogenic sarcoma (1) were analysed. The diagnosis was based mainly on X-ray procedures and was further improved by computed tomography which allowed to precisely evaluate the extent of intrathoracic mass and its relation to adjacent mediastinal structures. Surgery was the main procedure used for the treatment of primary tumors of the sternum. Sixteen patients were operated on, and not a single case showed involvement of the mediastinum. Closure of defect was the major difficulty involved in the surgical treatment. Adequate resection of the sternum followed by autoplasty yielded good results.

Principles of evaluating prognosis in parosteal sarcoma were developed with respect to clinical and morphological pattern of disease and type of treatment. A mathematical model for making prognosis and a procedure for its multifactorial analysis were suggested.

The content of calmodulin in homogenates prepared from various morphological variants of primary osteogenic sarcoma varies fromn 408 to 14,255 ng/mg total protein and is lowered by neoadjunctive chemotherapy. The 5-year incidence of metastases is lower when the calmodulin content in the tumor is>6000 ng/mg protein. At calmodulin content

From 1976 to 1980, 377 randomized patients were entered in a multicentric study supported by the W.H.O. Melanoma Group. In this report, only 196 patients are considered for analysis: 31.6 % were excluded because of inadequate treatment or protocol violations. Three arms of treatment were compared: DTIC alone, DTIC plus bacillus Calmette-Guérin, and DTIC plus Corynebacterium parvum. No significant difference in terms of complete response plus partial response was detected among the three regimens. Twenty-five patients (12.7 %) responded with complete tumor regression, and 18 (9.3 %) with partial regression. Complete plus partial responses were thus achieved in 22 % of evaluable patients. Responders had a longer median survival than nonresponders. Overall median survival was 6 months. Brain metastases were detected in 17 % of the patients. Median time from the beginning of treatment to the diagnosis of CNS involvement was 4 months. There is no evidence that active aspecific immunotherapy added to DTIC increases the response rate in patients with disseminated disease. The toxic effects were acceptable, and no drug-related death was observed.

Results of a prospective randomized clinical trial conducted by the WHO Collaborating Centers for the Evaluation of Methods of Diagnosis and Treatment of Melanoma are reported. Five-hundred-fifty-three Stage I patients whose limbs were affected entered the study; 267 were submitted to wide excision and immediate node dissection and 286 had wide excision and node dissection at the time clinically positive nodes were detected. Survival curves of the two treatment groups could be superimposed. No subsets of patients benefitted from immediate node dissection. The authors conclude that delayed node dissection is as effective as the immediate dissection in Stage I melanoma of the extremities if the patient can be checked every three months. If the quarterly follow-up is not guaranteed, immediate node dissection is advisable, at least for melanomas thicker than 2 mm.

553 patients with stage I malignant melanoma of the limbs entered a prospective randomized clinical trial carried out by the W.H.O. Collaborating Centres for Evaluation of Methods of Diagnosis and Treatment of Melanoma from September 1967 to January 1974. 286 patients were submitted to wide excision of primary and node dissection at the time as appearance of regional lymph node metastases and 267 to wide excision and immediate node dissection. Survival was identical in the 2 groups. Different subsets of patients were evaluated to assess whether some groups of patients may benefit from immediate node dissection. As regards sex, females and a significantly higher survival rate than males (p < 0.05), but results were not improved by immediate node dissection. Maximum diameter and elevation of primary melanoma were significantly related to survival but also in these cases immediate node dissection did not achieve better results. 63 patients had an excisional biopsy of their melanoma within 4 weeks before final treatment. This procedure did not worsen survival and also in this case immediate node dissection did not improve survival. 273 cases were classified according to histologic type: survival of superficial spreading and nodular melanoma was not different at a statistically significant level after the 2 treatment modalities. 325 cases were considered classifiable according to Clark's levels, out of these 165 were submitted to immediate node dissection. Neither level III nor level IV cases showed higher survival rate after immediate node dissection. Maximum tumor thickness according to Breslow was evaluated in 338 cases: 188 were submitted to wide excision and immediate node dissection. In no clusters of thickness did the enlarged surgical procedure achieve better results. The authors conclude that there is good evidence that in stage I melanoma of the extremities delayed dissection is as effective as the immediate one in the control of the disease if the patient can be kept under strict clinical control. Immediate node dissection is advisable if the quarterly follow-up is not guaranteed, at least for melanomas thicker than 2 mm.

The effectiveness of cis-diammine-dichloroplatinum (cisplatinum, platidiam, DDP) alone or as a component of combined treatment was evaluated in 85 patients with osteogenic sarcoma. The said drugs were used as adjuvants following radical surgery (group I-18 cases), in combined treatment of solitary and single lung metastases (group 2-7 cases) and in 60 patients with advanced tumors (group 3). An analysis of long-term results showed response in 30.8% in group 3. In group 2, application of chemotherapy plus surgery was followed by remissions of 2-46+-month duration (mean-13.9 months). In group I, 78.7% are expected to survive metastasis-free more than 12 months. Toxicity was moderate, with nausea and vomiting (87.1%), myelosuppression (52.8%), nephrotoxicity (48.6%) and alopecia (75.7%) being the most common side-effects.

The results of treatment of 315 cases of osteogenic sarcoma are presented. Available methods of primary tumor therapy fail to prevent dissemination of neoplastic disease by blood circulation. However, following a prophylactic course of chemotherapy (adriamycin, vincristine, cyclophosphamide, sarcolysine), 3- and 5-year survival rates in 45 cases of limb amputation for osteosarcoma increased to 38.1% and 30.5%, respectively. No recurrences were observed in 39 patients with extensive segmental resection of bone who preoperatively received intra-arterial infusions and radiation therapy; the 3-year survival rates were a high as 43.9% and patients showed good performance. The method offers good advantages in the treatment of patients with osteogenic sarcoma.

The results of combination therapy of 510 patients with osteosarcoma were analysed. It was established that most advantage is offered by this therapy in cases of osteogenic sarcoma and Ewing's sarcoma supplemented with surgery whenever required. A 33.9 and 30.1% increases in 3- and 6-year survival, respectively, were registered in 50 cases of osteogenic sarcoma, following amputation and a course of polychemotherapy (adriamycin, vincristin, sarcolysin and cyclophosphamide). There were no relapses in 40 cases of extensive segmental resection of the site of bone lesion with preoperative intra-arterial infusion of adriamycin, radiation therapy and adjuvant polychemotherapy. This scheme resulted in 4-year survival in 55.7% and good performance. A 5-year survival rose to 40.8% in 45 cases of Ewing's sarcoma, following adjuvant therapy with sarcolysin or cyclophosphamide administered after a course of radiation therapy in the dose of 50-60 Gy.

Experience in the management of 142 patients with local osteogenic sarcoma who received intra-arterial adriamycin infusion followed by en bloc resection of an affected bone and irradiation (20–36 Gy) is presented here. Various modalities of adjuvant chemotherapy (not randomized) were also applied. With surgery alone, only 7.0% of patients survived free of disease 5 years from the primary treatment Adjuvant chemotherapy (adriamycin + vincristine + melphalan + cyclophosphamide) increased this rate to 35.5%; in patients with grade 4 tumor damage, the rate increased to 57.9%. In adjuvant monochemotherapy with adriamycin, 73.0% of patients survived free of metastases for 2 years. The third regimen of adjuvant chemotherapy (cisplatin + adriamycin + cyclophosphamide) gives 76.0% of patients 2 years disease-free survival.

Radical surgery was performed in 69 cases of primary and recurrent localized soft-tissue sarcomas (extended dissection of tumor--53, exarticulation or amputation--16) after a course of non-uniform irradiation, when other methods of specific treatment had failed. Areas of exposed tumors were irradiated with focal doses of 90-120 Gy, screened areas--with 40-60 Gy. Radiation was delivered through a latticed diaphragm from the same field. Postoperative complications due to intensive irradiation and radiation injury were comparable to those involved in standard radiation procedures. A 5-year survival rate was 50% (primary tumor--16 and relapse--77%).