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The significant pharmacological activity of 2,3-benzodiazepine-4-ones led to an increased interest in this compound family. However, the literature of the closely related 2,3,4-benzothiadiazepine 2,2-dioxides is rather scarce. Earlier we elaborated a synthesis of 5-aryl congeners variously substituted at the aromatic ring. In the present study, a new synthetic route was investigated via highly versatile intermediates, to extend the reaction to a wider aromatic substitution pattern and to the preparation of 5-alkyl and 5-H derivatives. The essence of this approach is, starting from benzaldehyde acetals, acetophenone and benzophenone ketals, to synthesize ortho-formyl- and ortho-acyl-arylmethanesulfonyl chlorides, which are suitable precursors of the target compounds. The synthesis was implemented as follows: ortho-lithiation of the corresponding acetals and ketals and subsequent treatment with paraformaldehyde, or alternatively in two steps, with DMF or ethyl formate, followed by reduction with NaBH4, led to the corresponding hydroxymethyl derivatives. Reaction of these latter with methanesulfonyl chloride gave mesylates that were used to S-alkylate thiourea to afford S-alkylisothiouronium salts. The final steps of the synthesis were carried out in a telescoped reaction. Treatment of the S-alkylisothiouronium salts with N-chlorosuccinimide resulted in the corresponding arylmethanesulfonyl chlorides. Subsequent reaction with hydrazine hydrate followed by an acidic treatment gave 2,3,4-benzothiadiazepine 2,2-dioxides.

The development of a new three‐component chromatography‐free reaction of isocyanides, amines and elemental sulfur allowed us the straightforward synthesis of thioureas in water. Considering a large pool of organic and inorganic bases, we first optimized the preparation of aqueous polysulfide solution from elemental sulfur. Using polysulfide solution, we were able to omit the otherwise mandatory chromatography, and to isolate the crystalline products directly from the reaction mixture by a simple filtration, retaining the sulfur in the solution phase. A wide range of thioureas synthesized in this way confirmed the reasonable substrate and functional group tolerance of our protocol., An efficient organic solvent‐ and catalyst‐free multicomponent method in water is developed for the chromatography‐free synthesis of thioureas. The aqueous solution of elemental sulfur prepared with organic bases enables the avoidance of chromatography for the separation of sulfur from the product. A wide range of thioureas have been synthesized using this method, highlighting challenging biaryl derivatives.

We have developed the continuous-flow synthesis of thioureas in a multicomponent reaction starting from isocyanides, amidines, or amines and sulfur. The aqueous polysulfide solution enabled the application of sulfur under homogeneous and mild conditions. The crystallized products were isolated by simple filtration after the removal of the co-solvent, and the sulfur retained in the mother liquid. Presenting a wide range of thioureas synthesized by this procedure confirms the utility of the convenient continuous-flow application of sulfur.

The Cover Feature shows the application of aqueous polysulfide solutions in the chromatography‐free multicomponent synthesis of thioureas. We have used a large pool of bases to cleave the octasulfur ring generating water‐soluble, zwitterionic polsulfide chains. Using these aqueous solutions as sulfurating agents, we were able to omit the otherwise mandatory chromatography to separate the organic products from the excess of sulfur. The methodology has been validated in a wide range of synthesis scenarios highlighting challenging biaryl derivatives and the marketed drug, thiocarlide. More information can be found in the Full Paper by András Gy. Németh et al.[Image: see text]

Pesticide producers cannot ignore their possible obligations under the REACH regulation controlling registration, evaluation and authorization of chemicals, as only the active ingredients (and not the other composites) are exempted from REACH requirements, and more specifically only those quantities of these substances, which are used for plant protection purposes. Registration requirements show similarities with the pesticide authorization process, moreover, the required ecotoxicological tests for pesticide active substances are of the same extent as in the case of industrial substances manufactured/imported in quantities of at least 100 tons per year. A further common characteristic is the higher legal level and more centralized feature of the regulations, leading to the establishment of different authorization zones within the European Union. Although this is considered a favorable trend in case of chemical substances from the aspect of the free movement of goods, possible benefits of zonification regarding pesticides are rather questionable due to the significant differences in ecological characteristics among different areas of the European Union. Studies on genotoxic and endocrine disrupting effects are challenging the fundamentals of toxicology. Conflicting results burden the treatment of endocrine disrupters; laying down the foundations of a testing framework, and legal regulation is still ongoing. Their controversial situation is demonstrated by a few examples.

Background. The visualization of any morphological volume (i.e. CT, MRI) together with an additional second morphological volume (i.e. CT, MRI) or functional data set, which may come from SPECT or PET, is a new method for treatment planning, verification and follow-up of interstitial irradiation. Method. The authors present their experience on interstitial irradiation of brain tumours with stereotactically implanted I-125 seeds supported by image fusion. The image fusion was performed by the BrainLab-Target 1.13 software on Alfa 430 (Digital) workstation before, during, and after interstitial irradiation of brain tumours with Iodine125 seeds. Results and Interpretation. On the basis of 20 brachytherapeutic image fusion of stereotactic CT (slices with fiducials) with additional stereotactic CT, MRI, PET and SPECT images provides more accurate and precise target volume, more exact localization of catheters and isotope seeds (verification fusion), differentiation between the localization and amount of the necrotic and proliferating parts of the tumours and shows the volume changes in consequence of interstitial irradiation. The image fusion should help to improve the accuracy and minimize the perifocal morbidity of interstitial irradiation.

INTRODUCTION: Combined modality treatment with chemotherapy and radiotherapy in locally advanced head and neck cancers is an effective and often the only treatment with a chance of cure. An alternative is to use chemotherapeutic agents at low doses as radiosensitizers. In this study we examined the radiosensitizing effect of low dose Taxol in locally advanced head and neck cancer. Patients and methods: 26 patients with locally advanced squamous cell carcinoma of the oral cavity and the oropharynx were treated with external beam radiotherapy up to doses of 66-70 Gy and received concomitantly 2 mg/m(2) Taxol intravenously three times a week. Response rates according to WHO criteria, side effects according to the National Cancer Institute Common Toxicity Criteria, overall and progression-free survival were evaluated. RESULTS: All patients completed the therapy. Median radiation dose was 66 Gy, Taxol dose 40 mg/m(2) and treatment duration 54 days. 8 weeks after completion of therapy complete response was 30.8%, partial response 34.6%, stable disease 11.5% and progressive disease 23.1%. The median follow-up time was 25 months (9-36). At the cloes- out date 12 (46,1%) of the patients were alive, 9 without evidence of disease. The estimated median overall survival was 22 months (CI 14.2-34.6), the median progression-free survival 12 months (CI 5.2-18.8). We observed four grade 4, fourteen grade 3 and numerous grade 1-2 side effects. There was no treatment related death. DISCUSSION: Our regimen resulted in a worse response rate than the aggressive chemoradiation protocols treating the same disease. However, the two-year survival was comparable with the results of other studies. The advantages of our schedule are that it is well tolerated, easy to perform on an outpatient basis, resource effective and does not deteriorate the general condition of the patients, therefore successive therapy can be carried out immediately if necessary. We intend to evaluate the effectivity of this treatment in a study comparing radiotherapy with Taxol sensitization versus radiotherapy alone.

STUDY OBJECTIVE: Description and evaluation of radiotherapy of inoperable brain stem tumours. Possibilities of improving therapeutic results. MATERIALS AND METHODS: Between 1987 and 2000 43 patients (23 boys and 20 girls, mean age 8.5+/-4.4 years) with brain stem tumours were treated with 6 MV and 9 MV X-ray. The doses administered ranged from 30 to 66 Gy; mean 50.41+/-7.67 Gy. Treatment in each case was performed according to CT- and /or MR-based radiotherapy plan. Since 2000 3D conformal radiotherapy plans have been prepared by using image fusion. RESULTS: All patients were followed. The mean follow-up period was 19.4 months (range: 1 to 112 months). For survival statistics the 2 to 3-year overall and symptom-free survivals were taken into account, the former ones in the function of tumour localisations. The gender of children did not affect the survival (p0.74). No significant difference was found as to survival in the function of tumour localisation either (p0.87). CONCLUSION: According to the literature data the results expected were not achieved by hyperfractionation and by delivering an overall focal dose of 72 to 78 Gy. Results can be improved by precise patient fixation and the routine application of 3D conformal radiotherapy plans prepared by CT- and MR-based image fusion. These together can result the correctly reproducible patient fixation, the homogenous radiation delivery in the target volume and the reduction of injury in the surrounding tissues. Irradiation should be performed also in histologically not verified tumours since a 24.6 month transitory improvement could be achieved in 60.5% of our patients.

AIM: The importance of 3D conformal percutan and brachytherapy treatment planning based on CT and MRI examinations in treatment of oral cavity tumors. Introducing of the planning procedure and the selection aspects. METHOD: We present the treatment planning based on CT and MRI slices of an oral cavity tumor. The percutan or interstitial boost follow the percutan irradiation of the involved regions and lymph nodes, regarding to the target volume and the critical organs. RESULT: Our ADAC 3D planning system gives us the possibility to add the first line and the boost treatment plans, to determine and compare the dose distribution within the planned target volume and the radiation load of the critical organs. CONCLUSION: The comparative 3D radiation planning system allows higher local dose escalation required for the effective radiation treatment of oral cavity tumors with maximal protection of the surrounding healthy tissues.

AIM: To determine the effect of radiosensitization with Taxol and multimodality treatments on the survival of advanced oral and oropharyngeal cancer. Patients, methods: 56 patients with St. III-IV oral or oropharyngeal cancer were treated with external beam radiotherapy; 26 of them were sensitized by low-dose paxlitaxel and 30 were irradiated traditionally. The median follow up was 23 months (17-36). Endpoints of the study were: response to radiotherapy, progression-free and overall survival and the results of surgery and chemotherapy following radiation. RESULTS: 73.3% (41/56) of treatments resulted in CR or PR with median 10 months (0-33) progression-free and 14 months (4-33) overall survival. There was no significant difference between the radiosensitized and traditional radiotherapy group (p=0.6). The survival was significantly influenced by the stage of tumor and the response to primary radiotherapy. Seven (38.9%) of 16 patients treated also by either surgery or chemotherapy for recurrent or residual disease are free of cancer, 6 (35%) alive with tumor and 5 (26.1%) died with median survivals of 21, 20.5 and 18 months, respectively. Those treated only with radiotherapy with or without sensitization are free of cancer in 31.6%, alive with cancer 5.3%, died 63.2%. CONCLUSION: There were significant correlation between tumor stage, response to radiotherapy and combined modality treatment, and surival. The radiosensitizing effect of Taxol was not obvious so far, it may be apparent in the future by analyzing the long term survival data.

PURPOSE: To evaluate the effect of tumour bed boost on local tumour control (LTC) after breast conserving surgery in a prospective study. METHODS: Between 1995 and 1998, 207 women with early invasive breast cancer who underwent conservative operation were treated by 50 Gy irradiation to the whole breast and then randomly assigned to receive either no further radiotherapy (n=103) or a boost to the tumour bed (n=104) with either 16 Gy electron (n=52) or 12-14.25 Gy high dose rate brachytherapy (n=52). RESULTS: At a median follow-up of 4.25 years the crude rate of local recurrence was 6.7% with and 13.6% without boost. The respective rates of tumour bed relapse were 3.8% vs. 10.7%. The 4 year probability of LTC, relapse-free survival and breast cancer-specific survival was 94.2% vs. 85.1% (p=0.1176), 82.3% vs. 67.2% (p=0.0438) and 84.8% vs. 90.9% (p=0.1111), respectively, in favour of the boost group. Systemic treatments had no significant impact on LTC (88.9% with and 89.6% without systemic treatment, p=0.8858). CONCLUSION: Tumour bed boost decreased the incidence of local and tumor bed relapses with a reduction of 50% and 64%, respectively. Relapse-free survival was improved significantly with boost. However, the influence of boost treatment on breast cancer-specific survival should be tested in further studies. In spite of the higher incidence of late radiation side effects in the boost arm, boost dose is strongly recommended for patients at high risk for local recurrence. The final results of the EORTC trial and other ongoing studies will help to clarify the indication of boost dose according to prognostic subgroups.

AIM: To demonstrate the role, the execution and the importance of the computed tomography (CT) based three-dimensional brachytherapy and conformal percutan radiotherapy in the treatment of the advanced tumour of the base of tongue. METHODS: Between January 1993 and June 2000, 27 patients with stage III-IV squamous cell cancers of the base of tongue were treated after 60 Gy percutan irradiation with interstitial, high dose rate brachytherapy (23 patients) or conformal, multi-fields radiotherapy (4 patients) as a boost. The dose of the boost irradiation varied between 12 and 24 Gy. RESULTS: Boost irradiation was well tolerated by the patients. The local tumour control at the mean follow-up period (39 months) was 52%. Using this two treatment methods in case of percutan conformal irradiation 6%, in case of brachytherapy 1.5% of the mandible received the prescribed boost dose. The spinal cord received a maximum of 15%, and 8% of the boost dose, respectively, depending on the two treatment types. CONCLUSION: With the help of these two radiotherapeutic modalities locally higher cumulative dose and better tumour control can be achieved without the higher risk of radiation injury of the surrounding normal tissues and the two most critical organs (medulla, mandible).

PURPOSE: To demonstrate a conventional and a new therapeutic method of 3D treatment planning in maxilla tumors, the process of 3D treatment planning and its significance and to compare these two methods. METHOD: We performed 2D and 3D treatment plans. The ADAC planning system was used in the 3D treatment planning. CT and MRI scans were taken on the target volume and on each scan we demarcated the target volume and the critical organs. The irregular fields were obtained by 3D graphic reconstruction provided by the treatment planning programme. RESULTS: Compared to the conventional treatment planning more favourable dose distribution was obtained within the target volume and the radiation burden of the critical organs was kept under their tolerance doses. CONCLUSION: In conformal 3D treatment planning the shape and size of the irradiated volume are in good conformity with those of the target volume. In this way the radiation burden of the critical organs and adjacent intact tissues can be reduced.

The authors review the value of radiotherapy in the multidisciplinary treatment of early (stage 0-II) breast cancer and describe past achievements, current scientific evidences and possible future prospects of clinical research. Results of randomized studies proved that conservative surgery with radiotherapy is equally effective to mastectomy for the treatment of in situ and invasive breast cancer, both in terms of local control and overall survival. In the nineties, findings of prospective clinical trials indicate that the use of irradiation in high-risk patients provides both a significant improvement in loco-regional control and survival rate. The magnitude of survival benefit with appropriate patient selection and radiotherapy technique is similar to that seen with adjuvant systemic therapy. Radiotherapy of early breast cancer is based on level I scientific evidences in the vast majority of cases. Remaining controversial issues are subjects of several ongoing international and Hungarian prospective randomized studies.

Radiosensitivity of tumor cells is thought to be modulated by p53 and bcl2 proteins. High level of wild type p53 is required for radiation induced apoptosis. The aim of the present study is to investigate the significance of gene dosages of p53, bcl2 and c myc in radiation induced apoptosis. The base line and 30 Gy, 60 Gy gamma radiation induced values of p53 and bcl2 were estimated by Western blot in 60 biopsies of head and neck cancer. Our results suggest that the radiosensitivity of head and neck cancer depends on the ratio of p53 and bcl2 gene dosages. High level of p53 is counter-balanced by high bcl2 gene dosage resulting in radioresistance. Amplification of c myc can compensate for the low p53 level and suggests radiosensitivity of tumor cells. Our studies indicated that the prediction of radiosensitivity of tumor cells could be based on the simultaneous evaluation of p53, bcl2 and c myc levels.

The elaboration of a CT-based three-dimensional radiation therapy plan is described, which is applicable for any location and extension of intrathoracic paraaortic lymph node metastases. Calculations for high energy photon beams from a 15 MeV linear accelerator have been performed. The treatment plan enables a high radiation dose in the target volume and adequate sparing of the spinal cord.

WHILE isolating strains of Rhizobium lupini from the nodules of Lupinus luteus grown on the acid sandy soil of the Nyirseg area in north-eastern Hungary, I succeeded in isolating, on a Rhizobium medium, two red micro-organisms. These have been labelled Pr and E.3. They came from places several miles apart. The plants from which the Pr and E.3 strains derived were in a state of fluorescence and conspicuously larger than the surrounding lupins.

By using LR-115, CR-39 and termoluniescens detectors, long-term alpha- and gamma-activity measurements have been carried out to study the shape of radon distributions under different environmental conditions. The Rn profiles have been measured in vertical direction in soils, wells and underground caverns. A four-year seasonal variation of the mean Rn content in soil gas at shallow depth and a variation of the Rn concentration in the air of a Hungarian cave system during a three-year period is presented. It is found that the seasonal variation of the mean gamma dose rate measured by CaSO4:Dy TL-detectors in cave air and the seasonal Rn-pattern measured by nuclear track detectors in cave soil gas display a definite correlation. It is proved that the difference between the outdoor and indoor temperatures plays a predominant role in the formation of seasonal variations of Rn concentration. A new method is developed to measure the degree of equilibrium between Rn and its daughter products.