[STUDYING THE ACUTE TOXICITY OF DEXTRAN POLYALDEHYDE CONJUGATE WITH ISONICOTINIC ACID HYDRAZIDE.]

The acute toxicity of a new antubercular drug, dextran polyaldehyde conjugate with isonicotinic acid hydrazide (dextrazide), has been studied on animals, HepaRG cell line, and FRSN human skin fibroblasts. Average tolerable doses (LD(10), LD(16)), half-lethal doses (LD(50)), and lethal doses (LD(84)) of dextrazide have been determined for intraperitoneal introduction in mice and rats and intravenous injection in rabbits.

[Immediate and long-term results of simultaneous chemoradiotherapy in non-traditional modes of fractionation in the treatment of patients with oropharyngeal squamous cell carcinoma].

The analysis of the effectiveness of treatment was carried out in 257 patients with squamous cell carcinoma of the mucous membranes of the oral cavity and oropharynx. Two methods of irradiation were used in combination with concurrent polychemotherapy: standard radiotherapy (2 Gy 5 times a week) and radiotherapy in non-traditional modes of fractionation with uneven breaking of the daily dose into two fractions (1 Gy + 1.5 Gy or 1 Gy + 2 Gy with 4-hour intervals) to a focal dose of 60 Gy. Chemoradiotherapy with fractionated dose was more effective than standard chemoradiotherapy in frequency of objective tumor responses and regional metastases in the absence of increasing the number of early radiation reactions and late radiation damages. External beam radiotherapy in non-traditional modes of fractionation with simultaneous polychemotherapy exposure can significantly improve the results of the overall five-year survival compared with conventional fractionation technique--60.4 +/- 4.5%, 63.3 +/- 8.2% vs 27.6 +/- 10.2%, respectively.

[Radiation therapy for medullary thyroid carcinoma].

The paper analyzes the effectiveness of external beam radiation therapy of medullary thyroid cancer in 38 patients. The radiation therapy of the first phase combined therapy was performed in 9 (24 %) patients: after treatment, 5 patients had a partial response, 4--stabilization. The radiation therapy of the second phase combined therapy was performed in 27 (71%) patients: after treatment, 2 patients had a complete response (booster method), 5--partial response, 4--stabilization. External beam therapy has been performed in 2 (5 %) patients with palliative and symptomatic goals. Additionally has been estimated level of calcitonin in patients after combined treatment. The calcitonin level becomes normal without radiation therapy. Therefore, exposure for medullary thyroid carcinoma is questionable (exception for cases gain exposure to the rest of the tumor).

[Concurrent radiochemotherapy in the treatment of squamous cell oral and oropharyngeal cancer].

The aim of this study was to evaluate the end results of the radiochemotherapy of 237 patients with squamous cell carcinoma of oral mucosa (locally advanced, stage III-IV, - 134; 56.4%, and metastases to regional lymph nodes of the neck - 91; 38.4%) carried out at the Center's Clinic. Interstitial neutron (252 californium) plus polychemotherapy was given to 26 (11%) (group 1); neutron + distant radio + polychemotherapy - 34 (14 %) (group 2); distant fractionated radiotherapy + polychemotherapy - 177 (75%) (group 3). Complete response was reported in 190 (80.2%); partial - 44 (18.6%) and stabilization - 3 (1.3%). Overall response was 98.8%; 5-year survival - 64.5 +/- 3.3%, irrespective of tumor site, grade and method of treatment. Concomitant modality proved highly effective, free from toxic and functional or cosmetic harm.

[Early-onset radiation complications and tissue damage in the treatment of head and neck tumors].

The report discusses the results of an evaluation of the effectiveness of combined radiotherapy in 1,192 cases of head and neck tumors divided into 4 groups: distant radiotherapy in standard fractions of 1.8-2.3 Gy, 5 times a week, TTD of 60 Gy (group 1 - 486 40.8%); radiotherapy + local UHF hyperthermia + regional intraarterial chemotherapy + hyper glycemia + administrations of regional intraarterial chemotherapy + hyperglycemia + local UHF hyperthermia (group 2 - 244 20.5%); accelerated superfractition radiotherapy with variable STD of 1 and 1.5/2 Gy, TTD of 60 Gy, plus neoadjuvant polychemotherapy with cisplatin 100 mg/lm2 + 5-fluorouracil, continuous intravenous infusion of 3,000 mg for 72 h (group 3 - 204 17%1); combined photon-neutron therapy (group 4 - 258 21.6%): neutron beam therapy - 36 (3%); interstitial neutron brachytherapy with 252 Cf sources in combination with external beam gamma-therapy and chemotherapy. Overall radiation injury incidence was 1,087 (91.2%); oral mucositis grade I (WHO) - 110 (9.2%), grade II - 166(13.9%), grade III - 811 (68%), radiation dermatitis - 279 (23.4%), grade I/II - 196 (16.4%), grade III/IV - 83 (7%). Grade III/IV side effects developed in 26.7% after gamma therapy and in 72.2% - in the photon-neutron group (p < or = 0.0001). Skin damage was rare, as expected, in the photon-brachytherapy group (1.8%) (p < or = 0.0001). Hence, Cf252 neutron brachytherapy and radiotherapy with concomitant chemotherapy appeared to produce the most sparing effects.

[Neck skin-muscular flap use in cases of expanded operations on the occasion of malignant neoplasms of maxillo-facial region].

Comparative analysis of the results of different flaps, cut out on side surface of the neck for plastic cover of extensive defects of maxillo-facial region (MFR) formed after malignant tumors ablation, use was carried out. Reconstructive plastic operations were performed in 84 patients: displacement of neck skin-facial flap on the stem in 54 (64.1%) patients, use of neck skin-muscle flap (SMF) in 20 (23.8%) patients, use of improved method of skin-muscle transplant forming from only medial part of nodding muscle in 10 (12.1%) patients. Good cosmetic and functional results were received in 62 (73.8%) observations. Use of complex SMF after surgical interventions in cases of malignant tumors in MFR let reduce the number of postoperative complications and provide earlier rehabilitation of this heavy group of patients.

[Diagnosis and treatment policy in familial thyroid cancer].

Thirty-two cases of hereditary medullary thyroid carcinoma (HMTC) and 95 sporadic HMTC (SHMTC), 44 familial papillary TC (FPTC), and 172 sporadic cases were comparatively analyzed to improve the diagnosis and treatment of familial thyroid cancer. A hundred and one DNA samples from patients with MTC and their relatives were examined. BRAF and RET/PTC gene mutations were investigated in 6 patients with FPTC. The frequencies of familial TC, HNTC, and FPTC were 6 6, 26.5, and 4.3%, respectively. The mean age of patients with HMTC and SHMTC was 30.J±13.6 and 46.3±J3.1 years, respectively (p < 0.0001); tumor multicentricity was 87.5 and 36.8% (p < 0 0001) and bilaterality was 87.5 and 0%, respectively (p < 0.001). Inheritable RET mutations were detected in 16 families. Eight asymptomatic carriers of RET mutations were revealed; 3 of them underwent preventive thyroidectomy. There was the commonest (63.6%) codon 634 mutation in which the earliest manifestation and aggressive course of the disease were observed. The efficiency of screening for type 2 multiple endocrine neoplasia syndrome Increased by 1.8 times (from 31.2 to 51.2%). In the mother and daughter with FPTC, silent mutation was found in codon 891 of RET gene exon 15. Genetic examination of the relatives of patients with HMTC made it possible to diagnose the disease at its early stage and to perform preventive surgical treatment. The aggressiveness of HMTC makes it necessary to make total thyroidectomy. The absence of differences in the clinical course of familial and sporadic PTC predetermines uniform treatment policy.

[RET and GFRA1 germline polymorphisms in medullary thyroid cancer patients].

The role of RET and GFRA1 germline polymorphisms in predisposition to sporadic medullary thyroid cancer (MTC) and polymorphisms' modulation effect on clinical features of inherited and sporadic MTC were investigated. Blood samples from 67 MTC patients (22 hereditary and 45 sporadic), 3 asymptomatic mutant RET gene carriers and 178 ethnically matched healthy control individuals were tested. Screening of RET exons and portion of introns 1, 8, 10, 13, 14, 15, 16 and GFRA1 5'-UTR was performed by means of direct sequencing and PCR-RFLP. 8 polymorphic variants of RET gene (exons 11, 13, 14, 15 and introns 1, 8, 13, 14) and 4 GFRA1 polymorphisms in GFRA1 were detected. Linkage disequilibrium was found between RET variants G691S and S904S, L769L and IVS8, S836S and IVS13. In sporadic MTCs, allelic frequency of only one polymorphic RET variant, L769L, was significantly decreased versus control group. In hereditary MTCs, a significant over-representation of S836S and under-representation of S904S sequence variants were observed as compared to sporadic MTCs and controls. No co-segregation was found between individual polymorphisms and phenotype of sporadic MTC. In patients with inherited MTC whose genotype was presented with polymorphic L769L and wild-type S836S, disease onset occurred 20 years later than in individuals with polymorphic L769L and S836S or wild-type L769L (p = 0.01) suggestive of a possible protective role of L769L in MTC development and modulating effect of a combination of L769L with wild-type S836S on clinical outcome of inherited MTC.

[Familial well-differentiated thyroid carcinoma].

Medical Research Institute of Radiology, Russian Academy Forty-eight cases of familial disease (24 families) (4.3%) were identified among 1,118 patients with well-differentiated thyroid carcinoma who had been either examined or treated at the Clinic of Medical Research Institute of Radiology (1995-2004). In 86% of the study group, papillary thyroid carcinoma (PTC) was associated with tumor of the identical histological pattern while the remaining families revealed association with follicular or medullary thyroid cancer. Carcinoma inheritable from mother was the most frequent (75%). No differences in manifestation, histological pattern, stage or clinical course were established following a detailed evaluation of clinico-morphological data on 43 familial and 172 sporadic (control) cases in both groups. The analysis pointed to a significantly higher incidence of concomitant thyroid pathology in the familial thyroid cancer group. Molecular-genetic study of RET-protooncogene and gene BRAF in 6 blood samples from PTC-bearers established RET-mutation (mother and daughter) in codon 891 (exon 15) G2673A (TCG->TCA). No mutation in BRAF was found.

[Frequency of RET/PTC rearrangement and somatic BRAF mutation in papillary thyroid cancer].

Frequency of RET/PTC rearrangement and somatic BRAF mutation was investigated in patients with papillary thyroid cancer (PTC) vis-a-vis relevant demographic and clinico-pathological features. The study group included 76 patients with a female/male ratio of 4.8:1; mean age - 45.7 +/- 9.7 yrs. BRAF mutation was identified in 49 (65%) (V600E--47, KSRWS600--1 and E585K--1). RET rearrangement was detected in 9 (12%): RET/PTC1--5, RET/PTC3--2, unspecified RET/PTC--1 and delta RET/PTC--1. It was age at diagnosis alone that proved to be consistently associated with BRAF mutations (p = 0.017). Younger tumor patients were mostly prone to RET/PTC rearrangement (p = 0.08). No correlation between mutation and clinico-pathological features was established.

[Frequency of mutant lymphocytes in T-cell receptor locus as a possible predictor of thyroid cancer development in irradiated and unirradiated persons].

Was compared frequency of lymphocytes mutant at loci of T-cell receptor (TCR) from samples of peripheral blood taken from 186 healthy donors and 46 untreated thyroid cancer patients, including the persons exposed to ionizing radiation as a result of inhabitation in radioactive polluted region of Russian Federation. Was shown that the cell mutation rate within thyroid cancer group was significantly higher than the same parameter for the healthy person with similar age distribution (p < 0.01). It could be a result of such factors as genotoxic influence, different sensitivity or possible genome instability (including radiation-induced). It was found that 37% of patients have the increased frequency of somatic mutation cells, i.e. it exceeded 95% confidence interval for the screening group. The presented results cause to anticipate that TCR-test could be used as one of criteria for formation groups of high cancer risk development.

[Immediate and long-term results of plastic reconstruction of soft tissues of the head and neck in areas previously treated with surgery for tumor and radiation injury].

The efficiency was studied of vascularized tissue complexes in 346 cancer patients with extensive facial injuries to the head and neck who had undergone combined treatment. Free microsurgical autotransplantation was carried out in 7 (2%) patients, deltapectoral graft--151 (44%), sternocleidomastoid myocutaneous flap--39 (11%), pectoralis major flap--10 (3%), bi- and tri-lobed flap--55 (16%), temporal musculoperiosteal flap--25 (7%), cheek flap--24 (6.9%), thoraco-dorsal axillary flap--24 (6.9%), frontal flap--6 (1.7%), free-flap transfer--5 (1.5%). Although most vascularized tissue complexes were placed in previously irradiated areas, primary engraftment was reported in 249 (72%) patients, while peripheral or partial necrosis in distal part of flap- in 97 (28%). Good cosmetic and functional results were obtained in 298 (86%) patients who considered themselves cured.

[Assay of thyrocalcitonin in cervical lymph node using fine-needle washings for the diagnosis of disseminated medullary thyroid carcinoma]. / Opredelenie soderzhaniia tireokal'tsitonina v punktate limfaticheskikh uzlov shei dlia diagnostiki metastazov medulliarnogo raka shchitovidnoi zhelezy.

Fine-needle aspiration biopsy of cervical lymph nodes was carried out in 22 patients with suspected metastatic involvement with medullary thyroid carcinoma (MTS). It was followed by cytopathological examination of aspirates and assay of of thyrocalcitonin (TCT) in fine-needle washings. TCT determinations proved highly informative as well as significantly high in all seven cases of MTS involvement (26-8,484.87 pg/ml, mean 2,208 +/- 1,722 pg/ml).

Neutron brachytherapy in the treatment of melanoma.

PURPOSE: The use of Cf-252 for treatment of cutaneous malignant melanoma is presented. METHODS AND MATERIALS: From 1975 to 1992, plaque Cf-252 applicator neutron brachytherapy was performed in nine patients with skin malignant melanoma of head and neck or chest wall. Neutron brachytherapy alone was applied in six patients; two patients received neutron brachytherapy before and one after photon teletherapy. Tumor neutron brachytherapy doses ranged from 3.9-11.5 Gy. Four patients underwent surgical resection of the primary tumor and in six cases, regional lymph node dissection was done. RESULTS: The patients survival times ranged from 3 months to 12 years; 2-year survival was 50% and 30% of the patients lived 3 years. The mean survival time was 39 months. All but 1 patients died because of distant metastases. Local tumor control was achieved in all cases. CONCLUSION: The clinical study shows the relative sensitivity of melanoma to the neutron irradiation and offer new possibilities in Cf-252 brachytherapy.

Perioperative neutron brachytherapy with californium-252.

Between 1973 and 1988, 495 patients were treated with Cf-252 neutron brachytherapy. Cf-252 neutron therapy sources developed in the USSR has been used in the trial. A numerical reconstruction method for localization of Cf-252 cell coordinates by projections on orthogonal radiographs has been designed and used for treatment planning. Eight (1.6%) patients with recurrent and persistent head and neck tumors and ages from 32 to 48 years (mean age 43 years) were treated with Cf-252 perioperative neutron brachytherapy. There were three patients with oral cavity, one with oropharynx, three with parotid gland cancers, and one with a skin tumor. The dose rate ranged fro 3.2 cGy/h to 11.1 cG/h, the minimal peripheral dose ranged from 3 Gy to 8 Gy. Initial local control was achieved in all patients. Local recurrence developed in two cases. Three patients died in first year after therapy. Three patients died during the second year. Two patients are long term cures, one patient more than nine years and one eight years, that is 25% of the treated patients.

[Clinical assessment of various methods of radio-modification in radiotherapy of advanced oropharyngeal cancer]. / Klinicheskaia otsenka razlichnykh metodik radiomodifikatsii pri luchevoi terapii rasprostranennogo raka orofaringeal'noi oblasti.

The purpose of the study was to evaluate the effectiveness of RF-hyperthermia and regional intraarterial hyperglycemia as adjuvant radiotherapy vs conventional radiotherapy of advanced head and neck cancers. Altogether 115 patients with advanced T3-T-4 carcinoma of the tongue, oral cavity and oropharynx underwent external radiotherapy (Co-60). An RF capacitative heating device operating at 40.68 MHz was employed twice a week, a total of 4 sessions per patient. Intratumor temperature was 41.5-43 degrees C. Hyperglycemia was performed via the branches of the carotid artery, a total of 3 sessions per patient. There were 4 groups (1-31 patients on conventional radiotherapy; 2-24 patients on thermoradiotherapy; 3-30 patients on radiotherapy plus regional hyperglycemia; 4-30 patients underwent combined radio-modification). A complete response was 29% for conventional radiotherapy, 67% for thermoradiotherapy, 60% for radiotherapy plus hyperglycemia, and 77% for combined radio-modification. A 2-year local control was found to be 13% for radiotherapy, 37% for thermoradiotherapy, 17% for radiotherapy plus hyperglycemia, and 35% for combined radio-modification. Only hyperthermia was found to improve a 2-year local control of advanced oropharyngeal cancer.

[Immune homeostasis in patients with head and neck cancer]. / Immunnyi gomeostaz u bol'nykh rakom golovy i shei.

Immunologic parameters in head and neck cancer patients measured prior to treatment, in remission, at relapse and in cases of lymph node metastases developing 1-3 years following radiation treatment proved different. Evaluation of immune status, alongside with other diagnostic methods, can be used to confirm remission and diagnose relapse.

[The technology of preparation and experience in the clinical use of 252Cf sources]. / Tekhnologiia izgotovleniia i opyt klinicheskogo primeneniia istochnikov 252Cf.

The paper is concerned with analysis of technology, developed in our country for the manufacture and use of pin sources with linear and inhomogeneous (stepped) distribution of 252Cf and sources of flexible assemblies in interstitial radiotherapy of tumors. Clinical analysis contains 407 cases of therapy of head and neck tumors over the period of 1979-1987. In the authors' opinion, the most promising sources (with regard to the frequency of use) are pin sources with homogeneous radionuclide distribution and flexible assemblies.