Synthetic phosphopeptides: From spike-in standards to affinity tools for protein-protein interaction studies.

Synthetic isotope labeled phosphopeptides are valuable tools for the quantification and validation of phosphoproteome data. Here, we report that the same set of phosphopeptides, which are used as spike-in standards, can be successfully applied for identification of stimulus specific protein-protein interactions mediated by the respective phosphorylation sites. As a proof-of-concept, binding of two γH2AX (pS139) phosphosite specific interaction partners, MDC1 and 53BP1, was confirmed and elevated binding affinity was revealed in response to ionizing radiation. Our strategy is generally applicable and enables multiplexed validation and functional analysis of phosphorylation sites offering great potential for the follow-up of phosphoproteome studies.

Carbon ion radiotherapy in Japan: an assessment of 20 years of clinical experience.

Charged particle therapy is generally regarded as cutting-edge technology in oncology. Many proton therapy centres are active in the USA, Europe, and Asia, but only a few centres use heavy ions, even though these ions are much more effective than x-rays owing to the special radiobiological properties of densely ionising radiation. The National Institute of Radiological Sciences (NIRS) Chiba, Japan, has been treating cancer with high-energy carbon ions since 1994. So far, more than 8000 patients have had this treatment at NIRS, and the centre thus has by far the greatest experience in carbon ion treatment worldwide. A panel of radiation oncologists, radiobiologists, and medical physicists from the USA and Europe recently completed peer review of the carbon ion therapy at NIRS. The review panel had access to the latest developments in treatment planning and beam delivery and to all updated clinical data produced at NIRS. A detailed comparison with the most advanced results obtained with x-rays or protons in Europe and the USA was then possible. In addition to those tumours for which carbon ions are known to produce excellent results, such as bone and soft-tissue sarcoma of the skull base, head and neck, and pelvis, promising data were obtained for other tumours, such as locally recurrent rectal cancer and pancreatic cancer. The most serious impediment to the worldwide spread of heavy ion therapy centres is the high initial capital cost. The 20 years of clinical experience at NIRS can help guide strategic decisions on the design and construction of new heavy ion therapy centres.

Single nucleotide polymorphisms and haplotypes in the gene for vascular endothelial growth factor and risk of prostate cancer.

Vascular endothelial growth factor (VEGF) plays a key role in the regulation of angiogenesis and has been related to cancer development and progression. To evaluate the role of VEGF single nucleotide polymorphisms (SNPs) and haplotypes in prostate cancer, we performed a case-control study including 702 prostate cancer patients and 702 male age-matched healthy control subjects. Seven VEGF candidate polymorphisms were determined by 5'-nuclease (TaqMan) assays. Furthermore, VEGF plasma levels and genotypes were analysed in a group of 64 healthy men. Haplotype analysis showed two separate blocks of high-linkage disequilibrium, formed by five polymorphisms upstream of the coding sequence (promoter and 5'-untranslated region) and two polymorphisms downstream of the coding sequence. None of the single polymorphisms or haplotypes was significantly associated with the presence of prostate cancer. In a multivariate regression analysis including age, VEGF genotypes and haplotypes as covariates and VEGF plasma level as dependent variable, none of the VEGF polymorphism or haplotypes was a significant predictor of VEGF plasma levels. The present data suggest that polymorphisms or haplotypes in the VEGF gene do not modify the risk of prostate cancer.

Reirradiation tolerance of the human brain.

PURPOSE: To give an overview of current available clinical data on reirradiation of glioma with respect to the tolerance dose of normal brain tissue. METHODS AND MATERIALS: Clinical brain reirradiation studies from January 1996 to December 2006 were considered on radiation-induced late adverse effects-i.e., brain tissue necrosis. The studies were analyzed by using the linear quadratic model to derive information on the cumulative biologic effective tolerance dose (BED(cumulative)) and equivalent doses in 2-Gy fractions (normalized total doses, NTD(cumulative)) for the healthy human brain. RESULTS: The NTD(cumulative) in conventional reirradiation series (NTD(cumulative) of 81.6-101.9 Gy) were generally lower than in fractionated stereotactic radiotherapy (FSRT) (NTD(cumulative) of 90-133.9 Gy.) or LINAC-based stereotactic radiosurgery series (NTD(cumulative) of 111.6-137.2 Gy). No correlation between the time interval between the initial and reirradiation course and the incidence of radionecrosis was noted. The analysis showed the prescribed NTD(cumulative) to increase with decreasing treatment volume, which is allowed by modern conformal radiation techniques. CONCLUSION: Radiation-induced normal brain tissue necrosis is found to occur at NTD(cumulative) >100 Gy. The applied reirradiation dose and NTD(cumulative) increases with a change in irradiation technique from conventional to radiosurgery re-treatment, without increasing the probability of normal brain necrosis. Taken together, modern conformal treatment options, because of their limited volume of normal brain tissue exposure, allow brain reirradiation for palliative treatment of recurrent high grade glioma with an acceptable probability of radionecrosis.

ENLIGHT: European network for Light ion hadron therapy.

The European Network for Light Ion Hadron Therapy (ENLIGHT) was established in 2002 following various European particle therapy network initiatives during the 1980s and 1990s (e.g. EORTC task group, EULIMA/PIMMS accelerator design). ENLIGHT started its work on major topics related to hadron therapy (HT), such as patient selection, clinical trials, technology, radiobiology, imaging and health economics. It was initiated through CERN and ESTRO and dealt with various disciplines such as (medical) physics and engineering, radiation biology and radiation oncology. ENLIGHT was funded until 2005 through the EC FP5 programme. A regular annual meeting structure was started in 2002 and continues until today bringing together the various disciplines and projects and institutions in the field of HT at different European places for regular exchange of information on best practices and research and development. Starting in 2006 ENLIGHT coordination was continued through CERN in collaboration with ESTRO and other partners involved in HT. Major projects within the EC FP7 programme (2008-2014) were launched for R&D and transnational access (ULICE, ENVISION) and education and training networks (Marie Curie ITNs: PARTNER, ENTERVISION). These projects were instrumental for the strengthening of the field of hadron therapy. With the start of 4 European carbon ion and proton centres and the upcoming numerous European proton therapy centres, the future scope of ENLIGHT will focus on strengthening current and developing European particle therapy research, multidisciplinary education and training and general R&D in technology and biology with annual meetings and a continuously strong CERN support. Collaboration with the European Particle Therapy Network (EPTN) and other similar networks will be pursued.

Union of light ion therapy centers in Europe (ULICE EC FP7) - Objectives and achievements of joint research activities.

Under the umbrella of the European Network for Light Ion Therapy (ENLIGHT), the project on Union of Light Ion Centers in Europe (ULICE), which was funded by the European Commission (EC/FP7), was carried out from 2009 to 2014. Besides the two pillars on Transnational Access (TNA) and Networking Activities (NA), six work packages formed the pillar on Joint Research Activities (JRA). The current manuscript focuses on the objectives and results achieved within these research work packages: "Clinical Research Infrastructure", "Biologically Based Expert System for Individualized Patient Allocation", "Ion Therapy for Intra-Fractional Moving Targets", "Adaptive Treatment Planning for Ion Radiotherapy", "Carbon Ion Gantry", "Common Database and Grid Infrastructures for Improving Access to Research Infrastructures". The objectives and main achievements are summarized. References to either publications or open access deliverables from the five year project work are given. Overall, carbon ion radiotherapy is still not as mature as photon or proton radiotherapy. Achieved results and open questions are reflected and discussed in the context of the current status of carbon ion therapy and particle and photon beam therapy. Most research topics covered in the ULICE JRA pillar are topical. Future research activities can build upon these ULICE results. Together with the continuous increase in the number of particle therapy centers in the last years ULICE results and proposals may contribute to the further growth of the overall particle therapy field as foreseen with ENLIGHT and new joint initiatives such as the European Particle Therapy Network (EPTN) within the overall radiotherapy community.

Interleukin-10 [ATA] promoter haplotype and prostate cancer risk: a population-based study.

Interleukin-10 (IL-10) is a multifunctional cytokine acting as inhibitor of inflammatory and immune responses as well as tumour induced angiogenesis. A common [ATA] haplotype formed by polymorphisms at positions -1082, -819 and -592in the promoter of the IL-10 gene is a strong determinant for IL-10 expression. The presence of this haplotype can be determined by analysis of the -592C>A polymorphism. To analyse the role of the IL-10 [ATA] haplotype in prostate cancer we performed a case-control study including 561 prostate cancer patients and 561 male, age-matched, control subjects without malignant disease. The IL-10 -592C>A polymorphism was determined by a 5'-nuclease assay (TaqMan). IL-10 -592 CC, CA and AA genotype frequencies were not significantly different between patients (53.6%, 40.0%, 6.4%) and controls (54.3%, 39.6%, 6.1%; p=0.96). IL-10 genotypes were furthermore not associated with tumour characteristics such as histological grade, T stage, PSA levels at diagnosis, or age at diagnosis. Therefore we conclude that the IL-10 -592C>A promoter polymorphism, tagging the IL-10 low-producer [ATA] haplotype, is not associated with risk for prostate cancer.

Monte Carlo study of microdosimetric diamond detectors.

Ion-beam therapy provides a high dose conformity and increased radiobiological effectiveness with respect to conventional radiation-therapy. Strict constraints on the maximum uncertainty on the biological weighted dose and consequently on the biological weighting factor require the determination of the radiation quality, defined as the types and energy spectra of the radiation at a specific point. However the experimental determination of radiation quality, in particular for an internal target, is not simple and the features of ion interactions and treatment delivery require dedicated and optimized detectors. Recently chemical vapor deposition (CVD) diamond detectors have been suggested as ion-beam therapy microdosimeters. Diamond detectors can be manufactured with small cross sections and thin shapes, ideal to cope with the high fluence rate. However the sensitive volume of solid state detectors significantly deviates from conventional microdosimeters, with a diameter that can be up to 1000 times the height. This difference requires a redefinition of the concept of sensitive thickness and a deep study of the secondary to primary radiation, of the wall effects and of the impact of the orientation of the detector with respect to the radiation field. The present work intends to study through Monte Carlo simulations the impact of the detector geometry on the determination of radiation quality quantities, in particular on the relative contribution of primary and secondary radiation. The dependence of microdosimetric quantities such as the unrestricted linear energy L and the lineal energy y are investigated for different detector cross sections, by varying the particle type (carbon ions and protons) and its energy.

Patterns of care in radiotherapy of breast cancer in Austria 1985: data acquisition and comparison with data of US-PCS 1983.

PURPOSE: In Austria, a Patterns of Care Study (PCS) has been conducted to evaluate the standards of practice for breast cancer patients. The year 1985 was selected in order to establish a base data set. MATERIALS AND METHODS: At all nine radiation therapy facilities active in patient treatment in 1985, ten patients charts were randomly selected and reviewed. Evaluation of the radiotherapeutic standards was the principal purpose, however, surgical and histopathological parameters were also considered. RESULTS: Results of the Austrian PCS (including 90 patients) were compared with the "1983 Patterns of Care Process Survey for Definitive Breast Irradiation" performed in 1983 in the U.S. (including 191 patients). Documentation of pathologic tumour size (83% vs. 73%), histologic tumour subtype (99% vs. 97%) and microscopic margin analysis (60% vs. 51%) showed comparable results. Technical equipment was obviously quite different in the two countries, cobalt therapy was used in 25% in the US-PCS compared to 71% in the Austrian PCS. A clear difference also was obtained concerning the use of wedges for tangential breast/thoracic wall fields (64% vs. 21%) and the frequency of portal films (93% vs. 26%). CONCLUSIONS: Comparing both PCS studies, we found overall many similarities. Differences could be obtained in the quality level of radiation treatment, as for example use of wedges for tangential fields and the number of portal films. In a next step, a further Austrian PCS is planned to compare the Austrian base data from 1985 with quality standards from 1993 and 2001.

Epidemiological aspects of hadron therapy: a prospective nationwide study of the Austrian project MedAustron and the Austrian Society of Radiooncology (OEGRO).

BACKGROUND: The planned MedAustron hadron therapy facility is designed to compare proton and carbon ion beam therapy under the same technical conditions. For the calculation of the number of potential patients for hadron therapy so far, only epidemiological estimations on cancer incidence are available without inclusion of the percentage of patients routinely referred to conventional radiotherapy. MATERIALS AND METHODS: Nationwide prospective survey to collect disease and treatment related data on patients receiving conventional radiotherapy at all 12 treatment facilities. Epidemiological cancer incidence (Statistic Austria 1999) were correlated with the number of patients receiving conventional radiotherapy. Based on published clinical and experimental results on proton and carbon ion therapy, a calculation of patient's subgroups suitable for hadron therapy was performed at five European University hospitals involved in the HICAT, CNAO, ETOILE and MEDAustron project. Using the mean values of the University specific percentages per tumour site, the number of potential patients was estimated. RESULTS: In Austria, a total of 3783 patients started radiotherapy during the study period of 3 months resulting in an approximated number of 15132 patients per year. The number of potential patients was estimated to 2044 per year, representing 5.6% of all newly diagnosed cancer patients and 13.5% of all irradiated cancer patients. CONCLUSION: There is a clear place for a hadron therapy facility in Austria, based on pattern of care in radiotherapy, cancer incidence and indications.

The med AUSTRON/OGRO patterns of care study on radiotherapy indications in Austria.

PURPOSE: In Austria a national survey was conducted by Med AUSTRON/Osterreichische Gesellschaft for Radio--Onkologie, Radiobiologie und Medizinische Radiophysik (OGRO) in order to estimate the indications, patient numbers and radiotherapy treatment planning procedures and performances at all Austrian radiotherapy institutes. Results were correlated with incidence rates (Austrian cancer registry) to determine patterns of radiotherapy practice in Austria. MATERIAL AND METHODS: At 12 radiotherapy departments of Austria data of all patients receiving irradiation within a 3 months (2002/2003) period were assessed. On the basis of a questionnaire number of treated patients, indications, and parameters of disease (stage, histology) and treatment modalities were evaluated. Results were analysed with regard to different tumour groups, according to academic and non academic hospitals, and correlated with epidemiological data on cancer incidence. RESULTS: In total, 3783 patients were registered within this period. According to the different tumour entities percentages of patients receiving radiotherapy within initial treatment varied from 3% to 90 % (e.g. brain tumours: 77%, breast cancer: 90%, prostate cancer: 35%). The most frequent indications to radiotherapy per radiotherapy department were breast cancer (range 22%-35%; mean 26%), urological tumours (range 6%-27%; mean 12%) and bone metastases (mean 10%, range 3%-17%). CONCLUSION: In Austria breast cancer, urological tumours and bone metastases are representing the most common indications to radiotherapy. Among the different departments variations in indications to radiotherapy were observed. Our study is the first evaluation of radiotherapeutic management in Austria.

Assessment of improved organ at risk sparing for meningioma: light ion beam therapy as boost versus sole treatment option.

PURPOSE: To compare photons, protons and carbon ions and their combinations for treatment of atypical and anaplastical skull base meningioma. MATERIAL AND METHODS: Two planning target volumes (PTVinitial/PTVboost) were delineated for 10 patients (prescribed doses 50 Gy(RBE) and 10 Gy(RBE)). Plans for intensity modulated photon (IMXT), proton (IMPT) and carbon ion therapy ((12)C) were generated assuming a non-gantry scenario for particles. The following combinations were compared: IMXT+IMXT/IMPT/(12)C; IMPT+IMPT/(12)C; and (12)C+(12)C. Plan quality was evaluated by target conformity and homogeneity (CI, HI), V95%, D2% and D50% and dose-volume-histogram (DVH) parameters for organs-at-risk (OAR). If dose escalation was possible, it was performed until OAR tolerance levels were reached. RESULTS: CI was worst for IMXT. HI<0.05±0.01 for (12)C was significantly better than for IMXT. For all treatment options dose escalation above 60 Gy(RBE) was possible for four patients, but impossible for six patients. Compared to IMXT+IMXT, ion beam therapy showed an improved sparing for most OARs, e.g. using protons and carbon ions D50% was reduced by more than 50% for the ipsilateral eye and the brainstem. CONCLUSION: Highly conformal IMPT and (12)C plans could be generated with a non-gantry scenario. Improved OAR sparing favors both sole (12)C and/or IMPT plans.

External beam radiotherapy of recurrent glioma: radiation tolerance of the human brain.

Malignant gliomas relapse in close proximity to the resection site, which is the postoperatively irradiated volume. Studies on re-irradiation of glioma were examined regarding radiation-induced late adverse effects (i.e., brain tissue necrosis), to obtain information on the tolerance dose and treatment volume of normal human brain tissue. The studies were analyzed using the linear-quadratic model to express the re-irradiation tolerance in cumulative equivalent total doses when applied in 2 Gy fractions (EQD2cumulative). Analysis shows that the EQD2cumulative increases from conventional re-irradiation series to fractionated stereotactic radiotherapy (FSRT) to LINAC-based stereotactic radiosurgery (SRS). The mean time interval between primary radiotherapy and the re-irradiation course was shortened from 30 months for conventional re-irradiation to 17 and 10 months for FSRT and SRS, respectively. Following conventional re-irradiation, radiation-induced normal brain tissue necrosis occurred beyond an EQD2cumulative around 100 Gy. With increasing conformality of therapy, the smaller the treatment volume is, the higher the radiation dose that can be tolerated. Despite the dose escalation, no increase in late normal tissue toxicity was reported. On basis of our analysis, the use of particle therapy in the treatment of recurrent gliomas, because of the optimized physical dose distribution in the tumour and surrounding healthy brain tissue, should be considered for future clinical trials.

The role of radiation therapy after incomplete resection of penile cancer.

PURPOSE: To retrospectively assess the outcome in patients treated with adjuvant radiotherapy for penile cancer. PATIENTS AND METHODS: Between 1987 and 2006, 24 patients (median age, 62.7 years; range, 35.5-90.4 years) with squamous cell carcinoma of the penis (T1, n = 10; T2, n = 11; T3, n = 3) received megavoltage external radiotherapy (n = 22) or (192)Ir high-dose-rate brachytherapy (n = 2) following total penectomy (n = 7), partial penectomy (n = 10), or local excision (n = 7); lymphadenectomy was performed in eight patients. In 14 patients, radiotherapy was delivered after incomplete tumor resection, and in 20 patients the planning target volume included the regional lymph nodes. Median total dose of external radiotherapy was 56 Gy/1.8-2 Gy (range, 50-60 Gy). Brachytherapy was given with a total dose of 45 Gy/3 Gy. RESULTS: During a median follow-up of 58.4 months, penile or perineal recurrence was found in four patients giving a 5-year local control rate of 74.8%. Regional failure occurred in two patients. 5-year metastases-free survival and progression-free survival rates were 86.7% and 64.5%, respectively. Four patients died due to tumor progression. The actuarial 5-year cause-specific and overall survival rates were 84.3 and 56.6%, respectively. CONCLUSION: Radiation therapy is a successful method of treatment for penile cancer in terms of local control and organ preservation after microscopically incomplete surgery. Radiotherapy of the regional lymph nodes might also be effective in preventing regional recurrence and can be considered in case of high-risk features and following excision of extensive lymph node involvement.

The Glu228Ala polymorphism in the ligand binding domain of death receptor 4 is associated with increased risk for prostate cancer metastases.

BACKGROUND: Death receptor 4, encoded by the TNFRSF10A gene, is an important mediator of apoptosis and its dysfunction may be related to cancer development and distant tumor spread. A single nucleotide polymorphism in TNFRSF10A (Glu228Ala, rs20576) within a conserved region of the extracellular cysteine-rich domain of death receptor 4 has been associated with an increased risk for a variety of tumor entities. Aim of the present study was to evaluate the role of the TNFRSF10A polymorphism in metastatic progression of prostate cancer after radiation therapy. METHODS: We carried out a prospective study including 702 prostate cancer patients from the Austrian PROCAGENE (Prostate Cancer Genetics) study. Development of metastases was examined in regular follow-up investigations. TNFRSF10A genotypes were determined by a 5'-nuclease assay (TaqMan). RESULTS: Within a median follow-up time of 10 months (range 0-60 months), 24 (3.4%) patients developed metastases. In a Cox regression model including age at diagnosis and risk group as potential confounders, carriage of an 228Ala allele was associated with a relative risk of 2.47 (95% CI 1.10-5.54; P=0.028) for metastases. TNFRSF10A genotypes were not associated with tumor stage, grade, risk group or age at diagnosis. CONCLUSION: We conclude that the TNFRSF10A Glu228Ala polymorphism may be a novel independent risk factor for prostate cancer metastases after radiation therapy.

Long-term follow-up of patients with pituitary macroadenomas after postoperative radiation therapy: analysis of tumor control and functional outcome.

PURPOSE: Evaluation of long-term tumor control, normalization of hormonal hypersecretion, including incidence and time course of pituitary dysfunction following postoperative radiotherapy of pituitary macroadenomas. PATIENTS AND METHODS: In a retrospective study, the data of 87 patients with pituitary macroadenomas (61 non-secreting adenomas, 26 secreting adenomas) treated between 1984 and 1994 were analyzed. All patients underwent surgery and received postoperative external-beam radiotherapy with a mean dose of 50.4 Gy (range 46-54 Gy). RESULTS: After a follow-up of 15 years the local tumor control rate achieved was 93.0% for non-secreting adenomas and 100% for secreting adenomas, respectively. Normalization of endocrine hypersecretion was noted in 24 of 26 patients (92%). Detailed endocrinological follow-up data were analyzed by an experienced endocrinologist in 77 patients. After a median follow-up of 10.54 years (mean 10.22; range 1.39-20.75 years), in 75 of 77 patients (97%) a hypopituitarism was observed (partial hypopituitarism, n = 28 [36%], panhypopituitarism, n = 47 [61%]), and 68 out of 77 patients (88%) showed evidence of radiotherapy-induced pituitary disorders. The somatotropic function was most commonly affected, followed by gonadal, thyroid and adrenal function. The gonadal axis showed to be the first to be disturbed. 67 patients (87%) required a hormone replacement therapy. CONCLUSION: Radiotherapy after pituitary surgery is highly effective in reducing hormonal hypersecretion and preventing recurrences of pituitary adenomas. However, pituitary insufficiencies are commonly observed after radiotherapy requiring a close follow-up to ensure timely diagnosis of pituitary dysfunction and an early inception of hormone replacement therapy.

Austrian breast cancer patterns-of-care studies PCS93 and PCS01 versus PCS85 to identify changes in national practice.

PURPOSE: To determine the patterns of evaluation and treatment in Austrian breast cancer patients treated with surgery and radiotherapy in 1993 (PCS93) and 2001 (PCS01), and to compare these with the results of PCS85. MATERIAL AND METHODS: According to the evaluation process of the Austrian PCS85, ten randomly selected patient charts from every Austrian radiotherapy center from 1993 (n=100) as well as 2001 (n=120) were reviewed. The work-up included surgical and (histo)pathologic information, systemic therapy and detailed information on radiation therapy. RESULTS: Availability of histopathologic core data improved distinctly between 1985 and 2001. In 1985, treatment planning included fluoroscopic simulation and/or computed tomography in 55% of the cases as compared to 100% in 2001. The technical equipment in Austria changed distinctly. In 2001, 84% of the breast/chest wall fields and all regional node fields (+/- electrons) were treated by photons. Radiotherapy of the supraclavicular (77% vs. 28%), internal mammary (62% vs. 7.5%) and axillary nodes (51% vs. 5%) diminished from 1985 to 2001. A tumor bed boost was given in 34% of the patients in 1985 compared to 73% in 2001. The use of wedges (21% vs. 97%) and the number of port films (26% vs. 90%) increased substantially. CONCLUSION: Comparing both recent Austrian Patterns-of-Care surveys to the results obtained in 1985, an obvious increase in the quality level of histopathologic reporting as well as radiation treatment planning and delivery was found.

Lymphatic fistulas: obliteration by low-dose radiotherapy.

BACKGROUND: Lymphatic drainage from the surgical wound is an uncommon but challenging complication of surgical intervention. Protracted lymphorrhea contributes to morbidity, favors infections and results in a prolonged hospital stay. Treatment options include surgical ligation and, more conservatively, leg elevation, continuous local pressure, subatmospheric pressure dressings, and low-dose radiotherapy. This study examines the efficacy of low-dose radiotherapy. PATIENTS AND METHODS: 17 patients (19 fistulas) with lymphorrhea following vena saphena harvesting (n = 7), femoropopliteal bypass (n = 3), varicose vein surgery (n = 2), hip arthroplasty (n = 3; five fistulas), shunt surgery (n = 1), and piercing (n = 1) were referred for external radiotherapy. Depending on the depth of the fistula, orthovoltage (n = 12), electrons (4-11 MeV; n = 2) or photons (8 MV; n = 3) were used. Fractions between 0.3 Gy and 2 Gy were applied; the individual total dose depended on the success of the radiotherapy, i. e., the obliteration of the lymph fistula, and varied from 1 to 12 Gy. RESULTS: In 13 out of 17 patients complete obliteration of the fistula was achieved. Interestingly, this was achieved in nine of the ten patients irradiated with total doses of