[Discordance of estrogen receptor status between primary and metastatic breast cancer--possible reasons and prognostic value].

The aim of the review was systematization of the data on discordance in expression of estrogen receptors between primary and metastatic breast cancer, different metastases and repeated analyses of the same tissue. The possible reasons for the phenomenon are discussed. The authors emphasize the need to analyze estrogen receptors in breast cancer metastases, regardless of the receptor status of the primary tumor, for predicting the course of the metastatic disease and providing an adequate treatment of the metastatic tumor in strict accordance with its receptor status during drug therapy. The works cited in the search engine Pub Med to May 2013 were analyzed.

[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.

[Estrogen receptors beta--new target in cellular lung cancer treatment].

Literature review upon various types of estrogen receptors expression (type alpha and beta) in the cells of cellular lung cancer, their participation in estrogen and antiestrogen effects implementation, influence of estrogens and antiestrogens on occurrence and progression of malignant lung tumors in animals and humans. Were analyzed reasons of data ambiguity on type beta estrogen receptors (ERbeta) expression frequency. The results of authors own research in quantitative assessment of ERbeta expression in tumor tissue of patients with cellular lung cancer (79 male and 22 female patients are presented in this article. An increase in expression rate and incidence of tumors with high ERbeta level has been shown in patients with lung adenocarcinoma regardless of smoking status or gender. A new strategy of antiestrogen use, especially tamoxifen, has been formulated for cellular lung cancer treatment. Authors believe in a positive effect of adjuvant treatment with tamoxifen in patients with ERbeta-positive cellular lung cancer used independently or during and after the chemotherapy, by analogy with breast cancer patients.

[Tamoxifen molecular targets different from estrogen receptors].

Experimental studies showing ever new biological effects of tamoxifen on tumor cells, both expressing and nonexpressing estrogen receptors, are providing a novel conception of the drug, likely well known at present. The review describes tamoxifen targets, whose blocking induces inhibition of tumor cell growth and angiogenesis, stimulation of the programmed cell death (apoptosis, autophagia and necrosis), inhibition of multiple drug resistance mechanism and inhibition of invasion and metastasizing. In all the events, the results of the tamoxifen interaction with the cells are prognostically favourable from the viewpoint of both the inhibition of the tumor growth and metastasizing and the susceptibility to the medicinal therapy, that is considered by some authors as an extremely important addition to the tamoxifen antiestrogenic effect. The strategy of long-term tamoxifen adjuvant therapy of breast cancer with positive status of the estrogen reseptors was developed by Craig V. Jordan as far back as in the seventies of the XXth century, however there are arguments allowing to consider it also useful for the treatment of other tumors. First of all it is the fact described lately in regard to expression of estrogen beta-reseptors in solid tumors of practically all known localization and histological types, that are also the targets of tamoxifen. Apart from estimation of estrogen receptors, it is believed by some authors that molecular and biological choice of patients is necessary with an account of expression of other cell targets of antiestrogen for complete realization of all the aspects of tamoxifen biological activity in long-term adjuvant therapy of malignant tumors of various localization.

[Treatment of advanced ovarian cancer: results of the Department of Clinical Pharmacology and Chemotherapy, N.N. Blokhin RORC from 1993-2010].

The aim of this study was to analyse the outcome of ovarian cancer depending on the type of surgical debulking, the strategy of treatment of recurrent cancer, and other clinical factors. We performed retrospective analysis of patients with stage IC-IV ovarian cancer treated at the Department of Clinical Pharmacology and Chemotherapy in 1993-2010. A total of 353 patients were included. The medians of progression-free and overall survival were 11.3 and 40.8 months respectively. The results of the treatment depended on the mode of surgical debulking, histological type and stage of the tumour, regimen of front-line chemotherapy. The main prognostic factor in recurrent ovarian cancer was the number of potentially effective anticancer agents used during the treatment.

[Docetaxel as a component in the combined therapy of locally advanced squamous cell carcinoma of the glottis and oral cavity].

Two modalities of chemoradiotherapy for locally advanced squamous cell cancer of oro-hypopharynx and oral cavity were compared in the treatment of 34 patients. Five-year survival after cisplatin, 5-FU, taxotere, and carboplatin plus irradiation with TTD of 68-72 Gy (group 1) was 59.5% versus 13.8% without taxotere (group 2). Relapse was in 9 cases (60%) (4 - group 1 and 5 - group 2). Post-therapeutic complication stage III-IV was 57.8% (group 1) and 48% (group 2).

[Docetaxel in the treatment of metastatic gastric cancer].

Since the late 1990s, docetaxel (Dtx), an antitubular drug, has been studied as a tool for the treatment of GC. Maximum effectiveness of docetaxel as monotherapy amounted to 24%, with a median survival of 7 months. Two-drug combinations were developed containing docetaxel with 5-fluorouracil (DF) and docetaxel with cisplatin (DC). They proved effective in 43 and 33% of the cases respectively and ensured a similar median survival of 9-10 months. Clinical studies of a three-component combination containing docetaxel, 5-fluorouracil and cisplatin (DCF) as first-line therapy of metastatic GC were carried out in the XXIst century and showed its efficacy in 50% of the cases with a median survival of 10-12 months. The DCF regimen may be considered as a new standard for the treatment of patients with metastatic GC and satisfactory health status (ECOG 0-1). The combination is being modified to improve its toxicity profile by substituting oxaliplatin for cisplatin and oral fluoropyrimidines for i.v. 5-fluorouracil.

[HERV-K-associated carcinogenesis: co-expression of viral and cellular proteins in the development of human germ-cell tumors].

To elucidate the role of some viral and cellular proteins in the occurrence and development of HERV-K-associated germ-cell tumors (GCT), reverse-transcription polymerase chain reaction using specific primers has been employed to study the transcription of the protein Rec HERV-K and the possible interaction of the protein Rec(cORF), that has transforming properties, and the cellular protein PLZF, that is a negative regulator of cell division, in human GCT tissues, in the testicular parenchyma adjacent to a tumor, and in the normal testicular tissues. It was shown that there was expression of Rec(cORF) of mRNA, rather than cellular PLZF in all malignant GCT tissues, this led to the conclusion that no interaction occured between the Rec HERV-K and PLZF proteins in the GCT cells. At the same time co-expression of Rec and PLZF protein was first revealed at the level of transcription in the testicular parenchyma adjacent to a tumor that exhibited carcinoma in situ cells. By taking into account that the protein Rec HERV-K has transforming activity and it is presumed to be Implicated in the development of GCT, the authors discuss a possible role in the Rec HERV-K/HTDV and cellular PLZF interaction in the pathogenesis of GST at the early stages of its genesis.

[Estrogen receptor expression in tumors different from breast cancer].

A review of the literature data on expression of estrogen receptor alpha and beta (ERalpha and ERbeta) in tumors different from breast cancer. The results regarding the ERalpha and ERbeta expression frequency in non-small cell and small cell lung cancer, colorectal cancer, esophageal, ovarian, prostate and brain tumors are presented. High frequency of estrogen receptor expression (in up to 50 and more per cent of cases) in various types of tumors, differences between ERalpha and ERbeta in expression frequency, prognostic significance and prediction of the neoplastic process aggressiveness as well as in biological implications of interaction with antiestrogens (antagonistic and/or agonistic effect) are shown. The data on comparative evaluation of ERalpha and ERbeta expression in lung, ovarian, prostate tumor cells and corresponding nonneoplastic tissues are reported. Authors consider necessary to include the ERalpha and ERbeta detection into the routine clinical practice not only in breast cancer but in other tumors as well. Prospects of the clinical application of antiestrogens, in particular tamoxifen, in adjuvant therapy of different tumors with positive ER status are discussed.

[The distribution of HLA genes in Russian patients with germ cell tumors].

The correlation between DRB1, DQA1, and DQB1 genes of HLA class II, and the development of germ cell tumors (GCTs), as well as serological response to HERV-K proteins were investigated. Genomic DNA prepared from 99 GST patients was subjected to HLA typing by polymerase chain reaction (PCR) using the set of sequence specific primers (PCR-SSP). This set of primers made it possible to detect 14 specificities of DRB 1 locus, 12 alleles and groups of alleles of DQB 1 locus, and 8 alleles of DQA1 locus. Alongside with the definition of the occurrence of HLA markers in the total group of patients, the frequency of the occurrence of HLA-DR-DQ alleles was calculated in: 1) patients with different morphological forms of GSTs (seminomas and non-seminomas); 2) GCT patients producing or non-producing antibodies to Gag and/or Env HERV-K proteins. The comparison group consisted of 300 Moscow blood donors. The study did not reveal statistically significant differences in the frequency of the occurrence of DRB1, DQA1, and DQB1 alleles between the total group of GCT patients, its subgroup, and the control group. Thus, the data obtained demonstrated the absence of a strict correlation between the distribution of HLA class II alleles and GCT occurrence in the Russian population, as well as the ability of GCT patients to develop an antibody to HERV-K proteins, though more numerous observations are required to confirm this conclusion.

[Antibodies to stuctural proteins of endogenous retrovirus of the HERV-K/HTDV family as markers of human germ cell tumors].

Human germ cell tumors (GCT) have been found to be closely associated with the expression of HERV-K/HTDV proviruses and most patients with GCT produce antibodies to the major HERV-K/HTDV Gag and Env proteins. The findings have shown a strong association of the level of HERV-K/HTDV antibodies with the clinical course of the disease and therapy success, which makes it possible to confirm the fact that viral protein antibodies may be used as an additional marker of GCT.

[Range of combined treatment of locally advanced skin cancer].

Due to combined use of surgery, chemo- and radiotherapy, 58.8% of patients with locally advanced squamous cell carcinoma survived for 5 years. More organ-saving operations could be performed as a result of administering cisplatin, bleomycin and 5-fluorouracil chemotherapy in conjunction with radiation and subsequent surgery. Greater extent of tumor excision and microsurgery involved lower incidence of relapse. Yet, the preliminary results of our combined treatment pointed to relatively high frequency of objective response matched by lower incidence of relapse which calls for further investigation.

[Germ cell tumors of the testis: current status and future progress]. / Germinogennye opukholi iaichka: sostoianie problemy i nauchnyi progress.

The treatment of testicular cancer has undergone considerable evolution since the introduction of cisplatin and widespread recognition of its curative potentials at any stages of disease. This article provides an overview on statistical and epidemiological information, the latest developments in testicular cancer biology. Also, the results of treating 360 patients with nonseminomatous and 97 patients with seminomatous germ cell tumors are presented. A combined chemotherapy with cisplatin, etoposide and bleomycin demonstrates the highest rate of activity in nonseminomatous germ cell tumor patients. Surgical resection of residual masses after chemotherapy continues to be an important component of combined modality therapy in nonseminomatous testicular tumors. The needs for regular clinical examination during a follow-up have been underlined.

[Infusion of high doses of platidiam in the treatment of patients with germ cell testicular tumors]. / Infuzii vysokikh doz platidiama pri lechenii bol'nykh s germinogennymi opukholiami iaichka.

Sixteen patients with metastases of germ cell tumours were given VAB-6 combination chemotherapy including vinblastine, actinomycin-D, cyclophosphamide, bleomycin and platidiam (cis-platin). To intensify treatment 150 mg/m2 platidiam was administered by 24--hour infusion. Complete remission was observed in eight (50%) patients after chemotherapy alone; additional three (18.8%) cases were rendered tumor--free by surgery. At 20-26 months posttreatment, two cases were in relapse, and ten patients were alive. Toxicity was moderate. Infusion of high-dose platidiam assures a high complete remission rate, particularly, in cases of advanced germ cell tumours.

[Results of chemotherapy in patients with disseminated testicular tumors]. / Rezul'taty khimioterapii bol'nykh s disseminirovannymi opukholiami iaichka.

Results of treatment of 44 patients with disseminated non-seminomatous testicular tumors versus advancement are discussed in the paper. In cases of minimal and moderate advancement (group 1), induction chemotherapy included three cycles of VAB-6 regimen (vinblastine, actinomycin D, bleomycetin, cyclophosphamide plus 120 mg/m2 platidiam) whereas cases of advanced tumor (group 2) received six such cycles; two of them used 150 mg/m2 platidiam dropwise in a 3% sodium chloride solution. Complete regression was observed in 22 of 24 (96.1%) patients of group 1 and in seven out of 20 (35%) cases of group 2; it was registered in 100, 81.8 and 38% of patients with minimal, moderately- and far-advanced disease, respectively. Patients were followed for 4-23 months (average 14.5 months). Eight cases relapsed. At the time of this writing, 38 out of 44 (86.3%) patients are alive, and 23 out of 29 (79.3%) continue in complete remission. Toxicity was moderate. Application of 3% NaCl prevented nephrotoxicity of high-dose (150 mg/m2) platidiam.

[The results of the use of bleomycin and its analogs in the VAB-6 protocol in treating testicular tumors]. / Rezul'taty primeneniia bleomitsina i ego analogov v kombinatsii VAB-6 pri lechenii opukholei iaichka.

Efficacy and toxicity of VAB-6 combinations with bleomycin, bleomycetin or peplomycin were studied in treatment of 77 patients with metastases of germ-cell tumors: testicle tumors in 71 patients and extragonadal tumors in 6 patients. After the chemotherapy complete regression was observed in 37 patients (48.7 per cent). In 44 patients (57.1 per cent) residual metastases after the chemotherapy were resected. The frequency of complete regression after using the VAB-6 combinations with bleomycin, bleomycetin and peplomycin amounted to 58.8, 61.5 and 47.1 per cent respectively. The treatment results depended on the disease extent. When the disease extent was minimal complete regression was observed in 87.5 per cent of the patients. The respective figures for the disease moderate and significant extents were 66.7 and 37.8 per cent. During the average observation period of 22.1 months (7-40 months) 39 patients survived and had no signs of the disease. The combinations markedly differed in their toxicity.

[Management and drug therapy of patients with disseminated testicular tumors]. / Opyt vedeniia i lekarstvennaia terapiia bol'nykh s disseminirovannymi testikuliarnymi opukholiami.

The experience gained in the treatment of 111 cases of testicular tumor is summarized in the paper. Methods of management of testicular cancer in the eighties differ significantly from those employed in the seventies. A set of drugs used is different. The share of cases of monochemotherapy has decreased markedly. PVB and VAB-6 schemes are highly effective inducing complete or partial remission in 80-90% of cases. Issues of treatment of patients with massive metastases in retroperitoneal lymph nodes and lungs remain unresolved. Timely diagnosis of dissemination will improve chemotherapy results.

[High-dose ifosfamide in the treatment of patients with soft tissue sarcoma]. / Primenenie vysokikh doz ifosfamida u bol'nykh sarkomami miagkikh tkanei.

The increasing doses of 2.4-3.5 g/m2 ifosfamide, i/v, dropwise, were administered for 40 min, on days 1-5 each week, for 3 weeks, in 4 courses. Simultaneously, MESNA was given in a dose two-thirds of that of ifosfamide. The maximum single tolerable dose of ifosfamide was 3.2 g/m2. The dose of 3.5 g/m2 proved neurotoxic causing encephalopathy. The other toxic effects were stage III-IV neutropenia (47%), nausea and vomiting (91%) and weakness (33%). No clinical evidence of renal failure was attributed to the high dosage of the drug in the course of assays of biochemical components of the blood, blood- and urine-beta-2-microglobulins, N-acetyl-D-hexoaminidase (NAG) level in urine, creatinine clearance and complex renoscintigraphy data. On days 3-5, ifosfamide treatment was followed by increase in NAG and beta-2-microglobulin levels in urine which pointed to the toxic effect exerted on the epithelium of renal tubules. The antitumor effect was apparent in 5 (29%) patients for 6 months, which testifies to the high effectiveness of ifosfamide treatment for soft-tissue sarcoma.