[Combined treatment of rectal cancer with moderate risk of tumor progression]. / Rezul'taty primeneniya kombinirovannogo metoda lecheniya bol'nykh rakom pryamoi kishki so srednim riskom progressirovaniya opukholevogo protsessa.

OBJECTIVE: To increase the effectiveness of combined treatment in patients with rectal cancer and moderate risk of progression based on the concept of polyradiomodification (PRM). MATERIAL AND METHODS: The study included 337 patients with rectal cancer and moderate risk of tumor progression. A short course of radiotherapy (cRT) (5x5 Gy) combined with several radiomodifiers (cRT+PRM) was performed in 147 (43.6%) patients. Other 190 (56.4%) patients underwent cRT. The following radio modifiers were used: three-time application of local microwave hyperthermia (Yacht-3 or Yacht-4 devices), two-time intrarectal delivery of a biopolymer composition with Metronidazole before the 3rd and 5th irradiation sessions and two-week oral administration of Capecitabine (Xeloda) at a daily dose of 2.0 g/m2. Surgery was performed in 4-6 weeks after radiotherapy. RESULTS: CRT+PRM program increased 5-year relapse-free survival up to 81.3% compared to 60.3% after cRT alone (p=0.0003) due to significant reduction of the incidence of cancer recurrence from 8.4% to 0.7% (p=0.0013). More effective local growth control expanded the indications for sphincter-sparing surgery. These procedures were performed in 89.1% and 70.5% of patients, respectively (p=0.00001). In the cRT+PRM group, sphincter-sparing surgery reduced incidence of cancer recurrence from 13.7% to 0.8% (p=0.0110), distant metastases - from 23.9% to 13.7% (p=0.00349). CONCLUSION: Radiomodification in neoadjuvant radiotherapy is justified in patients with moderate risk of tumor progression, improves long-term results and increases the incidence of sphincter-sparing surgery.

Cases of Q fever detected in residents of the novosibirsk region hospitalized with suspection of infections transmitted by ticks.

Coxiella burnetii is the causative agent of Q fever (coxiellosis), which, in addition to acute manifestations, often occurs in a latent form, is prone to chronic course and, in the absence of antibiotic therapy, has a high risk of disability or death. As a result of the presence of a wide range of clinical manifestations specific to other infectious diseases, the use of laboratory test methods (LTM) is required to make a diagnosis. The presence of Q fever anthropurgic foci in the Novosibirsk region was described in the 90s of the last century, but due attention to its laboratory diagnostics is not paid in this region. The aim of the study was to identify genetic and serological markers of the causative agent, C. burnetii, in patients of the Novosibirsk region who were admitted for treatment with fever with suspected tick-borne infections (TBIs). DNA marker of the causative agent of Q fever was detected in blood samples by real time PCR in 9 out of 325 patients. In three patients, the presence of C. burnetii DNA was confirmed by sequencing of the IS1111 and htpB gene fragments. In ELISA tests, antibodies against the causative agent of coxiellosis were detected in the blood sera of 4 patients with positive results of PCR analysis. Contact with tick was registered in 7 out of 9 patients who had C. burnetii DNA and lacked markers of other TBIs. Six people were infected in the Novosibirsk region, two suffered from tick's bite in Altai, and one case was from the Republic of Kyrgyzstan. Thus, a complex approach using both PCR analysis and ELISA provided the identification of markers of the Q fever causative agent in patients admitted with suspected TBIs, thereby differentiating it from other infections. Contact with ticks in most cases suggests that infection with C. burnetii had a transmissible pathway.

Short-course preoperative radiotherapy combined with chemotherapy, delayed surgery and local hyperthermia for rectal cancer: a phase II study.

PURPOSE: The aim of this study was to investigate the feasibility of short-course radiotherapy with oral capecitabine, hyperthermia and delayed surgery for neoadjuvant treatment of rectal cancer. METHODS: Patients with clinically staged T2-3N0-2M0 primary rectal cancer were included. All patients received short-course 25 Gy in 5 Gy fractions radiotherapy with capecitabine, local hyperthermia and metronidazole. Capecitabine 1000 mg/m2 twice a day was given on days 1-14. Local hyperthermia, 41-45 °C for 60 min, was performed on days 3-5. Metronidazole 10 g/m2 was administered per rectum on days 3 and 5. The time interval to surgery was not less than four weeks after neoadjuvant treatment. The primary end-point was pathological complete response (pCR). Secondary end-points included neoadjuvant treatment toxicity, tumour regression, surgical and oncological outcomes. RESULTS: A total of 81 patients were included in the analysis. Ten (12.3%) patients had grade 3 toxicity and one (1.2%) patient had grade 4 toxicity. Sphincter-sparing surgery was performed for 78 (96.3%) patients. There was no postoperative mortality. Postoperative complications occurred in 11 (13.8%) patients. Sixteen (20%) patients had a pCR. The median follow-up was 40.9 months. There were no local recurrences. Nine (11.1%) patients developed distant metastases. Three-year overall survival was 97% and the three-year disease-free survival was 85%. CONCLUSIONS: Short-course radiotherapy with chemotherapy, radiosensitizers and delayed surgery is a feasible treatment for rectal cancer and may lead to tumour regression rate comparable with long-course chemoradiation.

Prophylaxis and treatment of radiation oral cavity mucositis by hydrogel preparations in patients with oropharyngeal cancer.

Development of radiation mucositis in patients with oropharingeal cancer who are treated by radiation therapy leads to constrains breaks, decreases of the quality of life and makes the radiation dose in target insufficient. All above mentioned increases recurrence risk. Since 2010 there was developed and introduced the method of prophylaxis and treatment of radiation injuries of oral cavity in patients with oropharingeal cancer which gives an ability to improve radiation treatment outcomes and the quality of life of patients.

[Primary multiple malignant lung tumors. References and a clinical observation].

The problem of primary multiple tumors is relevant to current clinical oncology because of increasing of number of patients with multiple malignant tumors and unsolved issues of treatment. Primary multiple malignant lung tumors is a common oncological situation requires an individualized, differentiated approach to treatment. The results of treatment are associated with the prevalence of the process, stages of tumor development, spare capacity of patients. There is presented clinical example of a patient with metachronous primary multiple malignant tumors of one lung.

[Detection of potential sites of recombination in the Tick-borne encephalitis virus by the methods of comparative genomics].

The results of the bioinformatic search for the potential sites of the recombination in the genome-wide structures of the tick-borne encephalitis virus (TBEV) through a series of software techniques were presented in this work. The genomes of the 55 TBEV strains were assayed, 21 of them showed the presence of the recombination sites. Recombinant strains belonged to the Far Eastern (19 strains) and European (2 strains) genotypes. 22 sites of the recombination attributed were identified to five types based on position, strain, and regional characteristics. The parental strains were identified based on the genotypic and geographical parameters, which do not contradict the possibility of the formation of the recombinants. Nearly two-thirds of the sites are located in the regions of NS4a and NS4b genes, which are the "hot spots" of the recombination, most of them being concentrated in the gene NS4. It was shown that the recombination processes did not occur at the level of the genotypes (European genotype) or certain groups within the genotype (Far East) and were typical of the peripheral populations.

[Conformal radiotherapy in nasopharyngeal cancer patients].

The paper is aimed at the determination of the efficiency of various technologies of conformal radiotherapy for patients with nasopharyngeal carcinoma. The study included 56 patients with squamous cell carcinoma of the nasopharynx treated with conformal radiotherapy. 3D-CRT was performed for 28 patients, IMRT--22 patients, RapidArc--6 patients. Dosimetric parameters were determined for planned volumes and organs at risk. TD on high-risk areas was 70Gy, intermediate-risk zones 60-66Gy and low-risk areas 50-56 Gy. There were determined session duration of exposure and the number of monitor units to evaluate the efficiency of treatment. Average (Dmean), maximum (Dmax) and the minimum (Dmin) dose for RapidArc, IMRT and 3D-CRT on PTV amounted to 70.2 Gy, 69.1 Gy and 70.7 Gy; 76.2 Gy, 76.1 Gy and 77Gr; 48.8, 54.4 and 46,6Gr respectively. Compared with IMRT and 3R-CRT RapidArc reduce Dmean in the brainstem and optic nerves by 14.1% and 23%; 12.2% and 25% respectively. The average number of MU (monitor unit) with RapidArc, IMRT and 3D-CRT was 357, 1386 and 870. The average session time of irradiation was: with RapidArc, IMRT and 3D-CRT--300, 900 and 480 seconds. Compared with IMRT and 3D-CRT average treatment time and the number of monitor units in RapidArc were reduced by 74%, 42% and 67%, 47%. Thus RapidArc and IMRT technologies allow getting a better dose distribution in the irradiated volume, compared with 3 D-CRT on homogeneity and conformity. RapidArc technique reduces the pressure on the critical organs, diminishes exposure to the session and a number of MU.

[The role of stereotactic radiotherapy in treatment of patients with metastatic lesion of lungs].

Since February 2012, in order to increase the effectiveness of treatment and quality of life of patients with disseminated disease, there was developed and implemented a method of stereotactic radiotherapy for metastatic lesion of lungs by tumors of different histological types. 20 patients were treated by stereotactic radiotherapy ROD 7 Gy in five sessions during 5 days. There were evaluated results of treatment and prospects of this method.

[Results of complex treatment of patients with squamous cell carcinoma of the anal canal using advanced radiotherapy technologies].

During recent decades radiotherapy is the basis, on which it is built a medical complex that is the first-line treatment of patients with squamous cell carcinoma of the anal canal. An increase of overall and disease-free survival and quality of life of patients with squamous cell carcinoma of the anal canal at the present stage of development of a comprehensive medical treatment is largely due to the improvement of technical equipment of radiotherapy departments of oncology clinics. The use of modem linear electron accelerators and systems of computer dosimetric planning to create a 3D program of isodose distribution, diagnostic devices (computed tomography and magnetic resonance imaging) as well as a number of other conditions permit accurate summarizing of proposed dose, reducing of absorbed dose to critical structures, diminishing unplanned interruptions in chemoradiotherapy course by means of modern technologies of conformal radiotherapy (3D CRT, IMRT, VMAT). The paper presents the preliminary results of a comprehensive medical treatment of 14 patients with squamous cell carcinoma of the anal canal.

[Complex treatment of breast cancer patients with brain metastases].

Brain metastases in breast cancer develop for 24-32 months after the detection of the primary tumor. The study included patients with brain metastases who were divided into three groups: the first group--with early chemoradiotherapy (CRT) without induction chemotherapy (IC) by capecitabine; the second group--with delayed CRT with 4 or 8 courses of IC by capecitabine; the third group (a historical control) who received only whole brain radiation therapy. The median time to progression of intracranial metastases was 15.3, 12 and 5 months, respectively. The median time to the intracranial progression significantly less in the third group (5 months) compared with the first (15.3 months) (p = 0.0007) and the second (12 months) (p = 0.027) groups. The overall survival rate was 22.1, 15.1 and 6.8 months in three groups, respectively.

[The role of stereotactic radiotherapy in the treatment of patients with liver metastases].

Application of modern linear electron accelerators, equipped with precise navigation systems, maximum conformal dose delivery as well as imaging of irradiated focus significantly increased possibilities of escalating of doses of ionizing radiation in a selected volume with the necessary protection of the surrounding critical structures. These technological solutions and modern ideas about possibilities of remote beam radiation therapy resulted in a significant increase of the role of radiation therapy and, in particular, stereotactic radiotherapy in the treatment of patients with liver metastases. This technique allows creating locally in metastatic tumor site a high dose of ionizing radiation causing by that the destruction of the tumor. This promising direction in treatment of liver metastases significantly expanded possibilities of complex treatment and enabled us to provide specific assistance to those patients who have been rejected from other methods of treatment.

[Radiation pneumonitis in the treatment of early-stage breast cancer].

Despite of improvement of radiotherapy techniques and increasing usage of conformal radiation therapy which provides decrease of dose for normal tissues and organs, cases of radiation-induced injuries are still registrated. The aim of this study is to determine frequency and severity of lung toxicity in 513 breast cancer patients with Tis-2N0-2M0 disease after breast conserving surgery and chemotherapy depending from radiation therapy technique and irradiation volume. It is quite clear that in breast cancer patients frequency of lung toxicity after breast conserving surgery and RT increases from 20-24% when irradiating only breast to 37-41% when irradiating breast and regional lymph nodes. In our analysis the frequency of lung toxicity was quite similar for 2D conventional therapy (27,4%) and for 3D conformal therapy (28,7%). The risk of developing radiation pneumonitis increases dramatically with extension of V20 for ipsilateral lung more than 30%, mean lung dose more than 18 Gy, in patients with initial small volume of the lung (less than 110 cm3).

[Possibilities of stereotactic radiotherapy in the palliative treatment of patients with pancreatic cancer].

Morbidity and mortality from pancreatic cancer is steadily increasing. Resectable cases are not more than 20%. Conventional schemes of chemoradiation and radiation therapy are durable over the time, have toxicity and low treatment outcomes. Many foreign authors consider as promising the technique of stereotactic radiotherapy, which is often used in pancreatic cancer and permit achieving high local control. At our institution there has been developed and introduced into clinical practice a method of stereotactic radiotherapy for the palliative treatment of patients with pancreatic cancer, which improved not only the duration but also the quality of life of patients.

Phase II study of concomitant chemoradiotherapy with local hyperthermia and metronidazole for locally advanced fixed rectal cancer.

AIM: Locally advanced fixed T4 rectal cancer has a poor prognosis and no standard treatment strategy. The aim of this study was to investigate the safety and efficacy of neoadjuvant chemoradiotherapy using hypofractionated radiotherapy combined with local hyperthermia, capecitabine, oxaliplatin and metronidazole. METHOD: Radiotherapy was given to a total dose of 40 Gy in 10 fractions. Capecitabine 650 mg/m(2) twice a day was given on days 1-22 and intravenous oxaliplatin 50 mg/m(2) was administered on days 3, 10 and 17. Local hyperthermia, 41-45°C for 60 min, was performed on days 8, 10, 15 and 17. Metronidazole 10 g/m(2) was administered per rectum on days 8 and 15. Surgery was carried out within 6-8 weeks after neoadjuvant treatment. The primary end-point was R0 resection rate. Secondary end-points included 2-year disease-free survival, 2-year overall survival, local recurrence rate, grade III-IV tumour regression (Dworak) and treatment toxicity. RESULTS: From July 2006 to February 2011, 64 previously untreated patients were enrolled. R0 resection was carried out in 59 (92.2%). Five (7.8%) remained inoperable. Seven (10.9%) patients had grade IV and 30 (46.9%) had grade III regression. The main grade III toxic events included diarrhoea (15.6%, n = 10), vomiting (3.1%, n = 2), proctitis (3.1%, n = 2) and skin reaction (1.6%, n = 1). Only one (1.6%) patient had grade IV diarrhoea and vomiting. The median follow-up was 24.9 months. Two-year overall survival was 91% and 2-year disease-free survival was 83%. CONCLUSION: Hyperthermia combined with chemotherapy to produce radiosensitization for locally advanced fixed primary rectal cancer is followed by a high R0 resection rate, with toxicity comparable with standard regimens.

[Genotypes 4 and 5 of the tick-borne encephalitis virus: features of the genome structure and possible scenario for its formation].

On the basis of the comparison of complete genome structures of 32 strains and gene E fragments (160 ndt) of 643 strains and RNA isolates of tick-borne encephalitis (TBE) virus, we confirmed our previously expressed assumption (Zlobin V.I. et al, 2001) of existence, along with the three major genotypes, of genotypes 4 (strain 178-79) and 5 (strain 886-84). "Mosaic" structure of the polyprotein in the two strains was established. It manifests itself in particular in the sequences of 14 positions (C-3, E-206, NS1-54, NS-285, NS2A-100, NS2A-127, NS2A-174, NS2A-175, NS2A-225, NS3-376, NS4B-28, NS4B-96, NS5-18, NS5-671) containing the amino acids strictly conserved for each of the three major genotypes and is consistent with a uniform pattern of distribution of nucleotide substitutions that are specific for genotypes 1, 2 and 3. Possible scenario of the origin of TBE genotypes 4 and 5 was suggested.

[Cryoradiation therapy of the patients presenting with locally advanced auricular skin cancer].

The objective of the present work was to improve the efficacy of treatment of locally advanced auricular skin cancer with the use of the newly proposed combined method including cryogenic and radiotherapy. The choice of the optimal temporal and thermal parameters of combined cryoradiotherapy was based on the results of previous experimental and theoretical investigations. Each radiation treatment session was immediately preceded by local cooling of the tumour down to 0°C - minus 5°C with a nitrogen vapour. Radiotherapy was performed with the use of either photon or electron radiation at a single local dose of 2 Gy-2.25 Gy (the total cumulative dose 64 Gy-68 Gy). As many as 14 patients presenting with locally advanced auricular skin cancer received combined cryogenic and radiotherapy; 10 of them had basal cell carcinoma and 4 squamous cell carcinoma. In all these cases, the treatment resulted in the complete regression of the tumours. Further observation during a follow-up period from 2 to 14 years in duration demonstrated that only two patients developed tumour relapses. These secondary neoplasms were successfully treated by cryodestruction (n=1) and surgical ablation (n=1). The proposed cryoradiotherapy made it possible to preserve the anatomical relief of the auricle and the auditory passage with good aesthetic and functional outcomes.

[Advances in radiotherapy of malignant tumours].

The authors discuss changes in the equipment and technologies of radiotherapy during the past 10-15 years. These changes ensured the improvement of diagnostics and treatment of neoplasms by two other main methods, surgical and medicamental. Modifications in the combined application of radiotherapy and surgery and of radio- and pharmacotherapy are discussed.

[Detection of recombinations in tick-borne encephalitis virus by using computer analysis of viral genomes].

Computer programs were used to search for tick-borne encephalitis (TBE) virus recombinants among the isolates whose complete nucleotide sequences are deposited in the GenBank database. The application of RDP, Chimaera, Maximum chi2, and TOPAL programs has revealed recombinant sites in a number of sequences, which indicates that TBE virus has recombinations and that the programs are suitable for their detection.

[Effectiveness of neoadjuvant chemoradiotherapy of locally advanced rectal cancer in conjunction with local hyperthermia and metronidazole].

Our study included 36 patients with hard fixed rectal tumors (T3, T4) who had received combined treatment at the Center's Clinics. On irrigoscopic evidence, lesions were more than 10 cm long. Radiotherapy was conducted thrice a week, STD of 4 Gy--TTD of 40 Gy; capecitabine, per os, 650 mg/m2 twice a day, days 1-22; oxaliplatin, 50 mg/m2, intravenously, days 3, 10 and 17; metronidazole in polymer composition, intrarectally, 10 mg/m2, twice, days 12 and 17 of radiotherapy; local hyperthermia (the <> installation), 460 mHz, 41-45 deg. C, 60 min, days 8, 12, 15 and 17. Diarrhea (stage III) was reported in 3 (8.3%); no toxicity (grade IV). Radical surgery was carried out in 35 (97.2%); sphincter-saving operation--20 (55.5%). Therapy-related pathomorphism (grade III-IV) was detected in 15 (42.8%). Combined neoadjuvant chemoradiotherapy plus polyradiomodification featured low toxicity and good tolerability and immediate effect.

Grain size dependent high-pressure elastic properties of ultrafine micro/nanocrystalline grossular.

We have performed sound velocity and unit cell volume measurements of three synthetic, ultrafine micro/nanocrystalline grossular samples up to 50 GPa using Brillouin spectroscopy and synchrotron X-ray diffraction. The samples are characterized by average grain sizes of 90 nm, 93 nm and 179 nm (hereinafter referred to as samples Gr90, Gr93, and Gr179, respectively). The experimentally determined sound velocities and elastic properties of Gr179 sample are comparable with previous measurements, but slightly higher than those of Gr90 and Gr93 under ambient conditions. However, the differences diminish with increasing pressure, and the velocity crossover eventually takes place at approximately 20-30 GPa. The X-ray diffraction peaks of the ultrafine micro/nanocrystalline grossular samples significantly broaden between 15-40 GPa, especially for Gr179. The velocity or elasticity crossover observed at pressures over 30 GPa might be explained by different grain size reduction and/or inhomogeneous strain within the individual grains for the three grossular samples, which is supported by both the pressure-induced peak broadening observed in the X-ray diffraction experiments and transmission electron microscopy observations. The elastic behavior of ultrafine micro/nanocrystalline silicates, in this case, grossular, is both grain size and pressure dependent.