Integration of radiation oncology teaching in medical studies by German medical faculties due to the new licensing regulations : An overview and recommendations of the consortium academic radiation oncology of the German Society for Radiation Oncology (DEGRO).

The new Medical Licensing Regulations 2025 (Ärztliche Approbationsordnung, ÄApprO) will soon be passed by the Federal Council (Bundesrat) and will be implemented step by step by the individual faculties in the coming months. The further development of medical studies essentially involves an orientation from fact-based to competence-based learning and focuses on practical, longitudinal and interdisciplinary training. Radiation oncology and radiation therapy are important components of therapeutic oncology and are of great importance for public health, both clinically and epidemiologically, and therefore should be given appropriate attention in medical education. This report is based on a recent survey on the current state of radiation therapy teaching at university hospitals in Germany as well as the contents of the National Competence Based Learning Objectives Catalogue for Medicine 2.0 (Nationaler Kompetenzbasierter Lernzielkatalog Medizin 2.0, NKLM) and the closely related Subject Catalogue (Gegenstandskatalog, GK) of the Institute for Medical and Pharmaceutical Examination Questions (Institut für Medizinische und Pharmazeutische Prüfungsfragen, IMPP). The current recommendations of the German Society for Radiation Oncology (Deutsche Gesellschaft für Radioonkologie, DEGRO) regarding topics, scope and rationale for the establishment of radiation oncology teaching at the respective faculties are also included.

Individual response of humans to ionising radiation: governing factors and importance for radiological protection.

Tissue reactions and stochastic effects after exposure to ionising radiation are variable between individuals but the factors and mechanisms governing individual responses are not well understood. Individual responses can be measured at different levels of biological organization and using different endpoints following varying doses of radiation, including: cancers, non-cancer diseases and mortality in the whole organism; normal tissue reactions after exposures; and, cellular endpoints such as chromosomal damage and molecular alterations. There is no doubt that many factors influence the responses of people to radiation to different degrees. In addition to the obvious general factors of radiation quality, dose, dose rate and the tissue (sub)volume irradiated, recognized and potential determining factors include age, sex, life style (e.g., smoking, diet, possibly body mass index), environmental factors, genetics and epigenetics, stochastic distribution of cellular events, and systemic comorbidities such as diabetes or viral infections. Genetic factors are commonly thought to be a substantial contributor to individual response to radiation. Apart from a small number of rare monogenic diseases such as ataxia telangiectasia, the inheritance of an abnormally responsive phenotype among a population of healthy individuals does not follow a classical Mendelian inheritance pattern. Rather it is considered to be a multi-factorial, complex trait.

Identification of the most significant electrode positions in electromyographic evaluation of swallowing-related movements in humans.

Surface electromyography (sEMG) is a well-established procedure for recording swallowing-related muscle activities. Because the use of a large number of sEMG channels is time consuming and technically sophisticated, the aim of this study was to identify the most significant electrode positions associated with oropharyngeal swallowing activities. Healthy subjects (N = 16) were tested with a total of 42 channels placed in M. masseter, M. orbicularis oris, submental and paralaryngeal regions. Each test subject swallowed 10 ml of water five times. After having identified 16 optimal electrode positions, that is, positions with the strongest signals quantified by the highest integral values, differences to 26 other ones were determined by a Mann-Whitney U test. Kruskal-Wallis H test was utilized for the analysis of differences between single subjects, subject subgroups, and single electrode positions. Factors associated with sEMG signals were examined in a linear regression. Sixteen electrode positions were chosen by a simple ranking of integral values. These positions delivered significantly higher signals than the other 26 positions. Differences between single electrode positions and between test subjects were also significant. Sixteen most significant positions were identified which represent swallowing-related muscle potentials in healthy subjects.

Development of curative therapies for Ewing sarcomas by interdisciplinary cooperative groups in Europe.

Curative therapies for Ewing sarcoma have been developed within cooperative groups. Consecutive clinical trials have systematically assessed the impact and timing of local therapy and the activity of cytotoxic drugs and their combinations. They have led to an increase of long-term disease-free survival to around 70% in patients with localized disease. Translational research in ES remains an area in which interdisciplinary and international cooperation is essential for future progress. This article reviews current state-of-the art therapy, with a focus on trials performed in Europe, and summarizes novel strategies to further advance both the cure rates and quality of survival.

Update on relapses in unilateral nephroblastoma registered in 3 consecutive SIOP/GPOH studies - a report from the GPOH-nephroblastoma study group.

INTRODUCTION: Treatment and stratification of progressive/relapsed unilateral nephroblastoma (PD) has significantly evolved over the last 20 years. Early PD (≤ 6 months), initial high risk histology, local stage III, multiple site PD and stage IV have been implemented as high risk classification factors and novel drugs have been introduced. PATIENTS AND METHODS: We analysed all 251 patients having had a unilateral nephroblastoma (Stage I-IV) and progressive disease who had been treated according to SIOP9/GPO (n = 77), SIOP93-1/GPOH (n = 93) and SIOP2001/GPOH (n = 81) initially. RESULTS: 3y-overall survival (OS) increased from 43% to 61% and 59% respectively (both p<0.01). 3y-OS for localized stage I-III rose from 43% to 65% and 68% respectively while only little improvement can be seen for initial stage IV patients with 43%, 53% and 44% respectively. Multivariate analysis confirmed high risk histology, local stage III, shorter time to PD, combined relapse as independent risk factors. 26 patients had received high-dose chemotherapy showing 64% 3y-OS compared to 54% for all non-transplanted (p=0.11). CONCLUSION: Structuring the treatment of progressive nephroblastoma as well as introducing new drugs have improved the outcome significantly. However improvement is depending on the specific risk profile. Very high risk tumours are often resistant to conventional treatment, hence an international uniform treatment concept is needed to achieve conclusive results in this small group.

Dose-escalated CHOEP for the treatment of young patients with aggressive non-Hodgkin's lymphoma: II. Results of the randomized high-CHOEP trial of the German High-Grade Non-Hodgkin's Lymphoma Study Group (DSHNHL).

BACKGROUND: The addition of etoposide to combination chemotherapy with cyclophosphamide, doxorubicin, vincristine and prednisone [etoposide to combination chemotherapy with cyclophosphamide, vincristine and prednisone (CHOEP)] improved outcome of young patients with good-prognosis aggressive lymphoma. To improve results further, the maximal dose-escalated version of CHOEP-21 tolerable without stem-cell support (high CHOEP: cyclophosphamide 1400 mg/m2, doxorubicin 65 mg/m2, vincristine 2 mg, etoposide 175 mg/m2 x3, prednisone 100 mg x5) was compared with CHOEP-21. PATIENTS AND METHODS: Intention-to-treat analysis of 389 young (18-60 years) patients with good-prognosis (age-adjusted International Prognostic Index = 0, 1) aggressive lymphoma randomized to CHOEP-21 (n = 194) or high CHOEP (n = 195). RESULTS: There was no difference in 3-year event-free (64% versus 67%; P = 0.734) or overall survival (83% versus 87%; P = 0.849). Neither low-risk nor low-intermediate risk patients benefited from high CHOEP. High CHOEP was more toxic than CHOEP-21 (grades 3 and 4 leukocytopenia 100% versus 87.2%, P < 0.001; thrombocytopenia 80.8% versus 9.6%, P < 0.001; infections 35% versus 11%, P < 0.001; therapy-associated deaths 3.1% versus 0%, P = 0.03). CONCLUSION: Dose-escalated CHOEP-21 does not provide clinical benefit for young patients with good-prognosis aggressive lymphomas. Since differences between chemotherapy regimens are compressed by the addition of rituximab, the results of this trial have bearing on strategies aiming to improve outcome of good-prognosis aggressive lymphomas in the rituximab era.

Ewing's tumors with primary lung metastases: survival analysis of 114 (European Intergroup) Cooperative Ewing's Sarcoma Studies patients.

PURPOSE: To analyze event-free survival (EFS) and prognostic factors in patients who present with Ewing's tumors (ET) of bone and synchronous pulmonary and/or pleural metastases (ppm). PATIENTS AND METHODS: Of 1,270 patients (pts) registered at the continental office of the German/European Intergroup Cooperative Ewing's Sarcoma Studies (CESS81, CESS86, EICESS92), 114 were diagnosed ET with ppm. Patients underwent neoadjuvant therapy and local treatment of the primary tumor. Whole-lung irradiation 15 to 18 Gy was applied to 75 ppm-pts. EFS and 95% confidence intervals (CIs) were estimated according to the Kaplan-Meier method, and prognostic factors were analyzed by log-rank tests and Cox and logistic regression procedures. RESULTS: On November 1, 1997, at a median time under study of 5.9 years, the 5-year EFS was 0.36 (95% CI, 0.26 to 0.46) and the 10-year EFS was 0.30 (95% CI, 0.19 to 0.41). Thirty-seven of 59 (63%) first relapses involved lung and/or pleura, and the lungs were the only site of relapse in 26 of 59 (44%) ppm-pts. Risk factors identified in univariate and multivariate tests were poor response of the primary tumor toward chemotherapy, metastatic lesions in both lungs, and treatment without additional lung irradiation. CONCLUSION: Chemotherapy response of the primary tumor is a prognostic factor in patients with ET with ppm. Strategies of treatment intensification warrant further evaluation.

Impact of preoperative bimodality induction including twice-daily radiation on tumor regression and survival in stage III non-small-cell lung cancer.

PURPOSE: The objective of this prospective study was to assess the feasibility, toxicity, and efficacy of an intensive trimodality approach in stage III non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Fifty-four patients with NSCLC and biopsy-proven N2 nodes (IIIA; n = 25) or N3 nodes or T4 lesions (IIIB; n = 29) were administered two initial cycles of ifosfamide, carboplatin, and etoposide; subsequent radiotherapy (45 Gy, twice-daily 1.5 Gy) with concurrent carboplatin and vindesine; and surgery if the patient's disease was resectable or conventional radiotherapy (16 Gy, 2 Gy/d) if the patient's disease was not resectable or incompletely resectable. RESULTS: Thirty-seven patients (69%) responded to preoperative induction. Forty of 54 patients (74%) had disease that was resectable, with 34 (63%) complete resections (R0). A substantial pathologic response (tumor regression [TR] > 90%) was achieved in 27 of 54 patients (50%) and is revealed as an independent predictor for long-term survival after surgery. Five treatment-related deaths (9%) occurred. With a median follow-up period of 44 months, calculated survival rates at 3 years were 35% for patients with stage IIIA disease, 26% for patients with stage IIIB disease, and 56% for patients with R0 disease and TR > 90%. CONCLUSION: This trimodality approach is feasible and results in encouraging 3-year survival rates in prognostically unfavorable patients with stage III NSCLC. Patients experiencing a 90% degree of pathologic TR were most likely to achieve long-term survival.

Primary gastrointestinal non-Hodgkin's lymphoma: I. Anatomic and histologic distribution, clinical features, and survival data of 371 patients registered in the German Multicenter Study GIT NHL 01/92.

PURPOSE: The study was initiated to obtain epidemiologic data and information on anatomic and histologic distribution, clinical features, and treatment results in patients with primary gastrointestinal non-Hodgkin's lymphomas (PGI NHL). PATIENTS AND METHODS: Between October 1992 and November 1996, 371 PGI NHL patients were eligible to evaluate clinical features. Radiotherapy and chemotherapy were stratified according to histologic grading, stage, and whether surgery had been carried out or not. RESULTS: A total of 74.8% patients had gastric NHL (PGL). Within the intestine, the small bowel and the ileocecal region were involved in 8.6% and 7.0% of the cases, respectively. Multiple GI involvement (MGI) was 6.5%. Approximately 90% of the GI NHL were in stages IE/IIE. Aggressive NHL accounted for the majority, with a distinguishable pattern in several sites. Forty percent of PGL were of low-grade mucosa-associated lymphatic tissue type. One third of large-cell lymphomas had low-grade components. Most intestinal NHL were germinal-center lymphomas. The site of origin was prognostic. In gastric and ileocecal lymphoma, event-free (EFS) and overall survival (OS) were significantly higher as compared with the small intestine or MGI (median time of observation, 51 months). In PGL, localized disease was prognostic for EFS and OS. Histologic grade influenced only EFS significantly. Numbers in intestinal lymphomas were too small for subanalyses. CONCLUSION: PGI NHL are heterogeneous diseases. The number of localized PGL allowed for detailed analyses. Larger studies are needed for stages III and IV and for intestinal NHL. A uniform reporting system for PGI NHL, in terms of definitions and histologic and staging classifications, is needed to facilitate comparison of treatment results.

Primary gastrointestinal non-Hodgkin's lymphoma: II. Combined surgical and conservative or conservative management only in localized gastric lymphoma--results of the prospective German Multicenter Study GIT NHL 01/92.

PURPOSE: The aim of the study was to obtain data on anatomic and histologic distribution, clinical features, and treatment results of patients with primary gastrointestinal non-Hodgkin's lymphomas, particularly combined surgical and conservative treatment (CSCT) versus conservative treatment (CT) alone for primary gastric lymphoma (PGL) in localized stages. PATIENTS AND METHODS: Whether the treatment included surgery was left to the discretion of each participating center. Radiotherapy (Rx) and chemotherapy were stratified according to histologic grading, stage, and the inclusion or omission of surgery as follows: patients with low-grade PGL were treated with extended-field (EF) Rx (30 Gy). In case of residual tumor after surgery or in case of CT only (in stage IIE after six cycles of cyclophosphamide, vincristine, and prednisone), an additional boost of 10 Gy was given. All patients with high-grade PGL were treated with four (stage IE) or six (stage IIE) cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone followed by EF Rx (stage IE) or involved-field (IF) Rx (stage IIE). Rx dosage corresponded to low-grade NHL. RESULTS: Between October 1992 and November 1996, 106 patients had CT only. The survival rate (SR) after 5 years was 84.4% and was influenced neither by patients' characteristics nor by stage or histologic grade. Seventy-nine patients had CSCT. Their SR was 82.0%. Complete resection of the tumor (R0) was prognostic for the overall survival (P =.0165) as compared with incomplete resection. CONCLUSION: Although the study was not randomized, a stomach-conserving approach may be favored.

Dose-dependent induction of transforming growth factor beta (TGF-beta) in the lung tissue of fibrosis-prone mice after thoracic irradiation.

PURPOSE: The lung is the major dose-limiting organ for radiotherapy of cancer in the thoracic region. The pathogenesis of radiation-induced lung injury at the molecular level is still unclear. Immediate cellular damage after irradiation is supposed to result in cytokine-mediated multicellular interactions with induction and progression of fibrotic tissue reactions. The purpose of this investigation was to evaluate the acute and long-term effects of radiation on the gene expression of transforming growth factor beta (TGF-beta) in a model of lung injury using fibrosis-sensitive C57BL/6 mice. METHODS AND MATERIALS: The thoraces of C57BL/6 mice were irradiated with 6 and 12 Gy, respectively. Treated and sham-irradiated control mice were sacrificed at times corresponding to the latent period (1, 3, 6, 12, 24, 48, 72 hours and 1 week postirradiation), the pneumonic phase (2, 4, 8, and 16 weeks postirradiation), and the beginning of the fibrotic phase (24 weeks postirradiation). The lung tissue from three different mice per dosage and time point was analyzed by a combination of polymerase chain reaction (PCR), immunohistochemistry, and light microscopy. The mRNA expression of TGF-beta was quantified by competitive reverse transcriptase/polymerase chain reaction (RT-PCR); the cellular origin of the TGF-beta protein was identified by immunohistochemical staining (alkaline phosphatase-anti-alkaline phosphatase [APAAP]). The cytokine expression on mRNA and protein level was correlated with the histopathological alterations. RESULTS: Following thoracic irradiation with a single dose of 12 Gy, radiation-induced TGF-beta release in lung tissue was appreciable already within the first hours (1, 3, and 6 hours postirradiation) and reached a significant increase after 12 hours; subsequently (48 hours, 72 hours, and 1 week postirradiation) the TGF-beta expression declined to basal levels. At the beginning of the pneumonic phase, irradiation-mediated stimulation of TGF-beta release reached maximal values at 2 and 4 weeks. The elevated levels of TGF-beta mRNA during the latent phase have been found to correlate with immunohistochemical staining of alveolar macrophages. The most striking increase in TGF-beta immunoreactivity was seen during the acute phase of pneumonitis. Throughout this observation period, type II pneumocytes and fibroblasts (apart from inflammatory cells) served as important sources of TGF-beta expression. Increased TGF-beta expression was detected prominently in regions of histopathologic radiation injury. After exposure to a single radiation dose of 6 Gy, the lung tissue revealed only a minor radiation-mediated TGF-beta mRNA response. The modest upregulation ranged from 6 hours to 48 hours after irradiation. Corresponding to the only minor histopathologic changes after thoracic irradiation with 6 Gy, measurement of TGF-beta mRNA levels during the later time points revealed no significant alterations in comparison to untreated control mice. CONCLUSIONS: This study demonstrates an acute and long-lasting increase in the expression of TGF-beta in lung tissue following thoracic irradiation with 12 Gy. The predominant localization of TGF-beta in areas of inflammatory cell infiltrates and fibrosis suggests involvement of this cytokine in the pathogenesis of radiation-induced pulmonal fibrosis. Further studies should be performed to explore the role of other cytokines in the development of radiation injury. An improved understanding of the underlying mechanisms of pulmonary fibrosis may eventually lead to modulatory intervention at the molecular level to modify the fibrotic process.

Radiation therapy in Ewing's sarcoma: an update of the CESS 86 trial.

PURPOSE: We present an update analysis of the multiinstitutional Ewing's sarcoma study CESS 86. METHODS AND MATERIALS: From January 1986 through June 1991, 177 patients with localized Ewing's sarcoma of bone, aged 25 years or less, were recruited. Chemotherapy consisted of four 9-week courses of vincristine, actinomycin D, cyclophosphamide, and adriamycin (VACA) in low-risk (extremity tumors < 100 cm3), or vincristine, actinomycin D, ifosfamide, and adriamycin (VAIA) in high-risk tumors (central tumors and extremity tumors > or = 100 cm3). Local therapy was an individual decision in each patient and was either radical surgery (amputation, wide resection) or resection plus postoperative irradiation with 45 Gy or definitive radiotherapy with 60 Gy (45 Gy plus boost). Irradiated patients were randomized concerning the type of fractionation in either conventional fractionation (once daily 1.8-2.0 Gy, break of chemotherapy) or hyperfractionated split-course irradiation simultaneously with the VACA/VAIA chemotherapy (twice daily 1.6 Gy, break of 12 days after 22.4 Gy and 44.8 Gy, total dose and treatment time as for conventional fractionation). For quality assurance in radiotherapy, a central treatment planning program was part of the protocol. RESULTS: Forty-four patients (25%) received definitive radiotherapy; 39 (22%) had surgery, and 93 (53%) had resection plus postoperative irradiation. The overall 5-year survival was 69%. Thirty-one percent of the patients relapsed, 30% after radiotherapy, 26% after radical surgery, and 34% after combined local treatment. The better local control after radical surgery (100%) and resection plus radiotherapy (95%) as compared to definitive radiotherapy (86%) was not associated with an improvement in relapse-free or overall survival because of a higher frequency of distant metastases after surgery (26% vs. 29% vs. 16%). In irradiated patients, hyperfractionated split-course irradiation and conventional fractionation yielded the same results (5-year overall survival of definitively irradiated patients 63% after conventional fractionation and 65% after hyperfractionation; relapse-free survival 53% vs. 58%; local control 76% vs. 86%, not significant). The six local failures after radiotherapy did not correlate with tumor size or response to chemotherapy. Radiation treatment quality (target volume, technique, dosage) was evaluated retrospectively and was scored as unacceptable in only 1 out of 44 patients (2%) with definitive radiotherapy. Grade 3-4 complications developed in 4 out of 44 (9%) patients after definitive radiotherapy. CONCLUSIONS: Under the given selection criteria for local therapy, radiation therapy yielded relapse-free and overall survival figures comparable to radical surgery. Hyperfractionated split-course irradiation simultaneously with multidrug chemotherapy did not significantly improve local control or survival.

Second malignancies after treatment for Ewing's sarcoma: a report of the CESS-studies.

PURPOSE: During recent years, more intensified systemic and local treatment regimens have increased the 5-year survival figures in localized Ewing's sarcoma to more than 60%. There is, however, concern about the risk of second malignancies (SM) in long-term survivors. We have analyzed the second malignancies in patients treated in the German Ewing's Sarcoma Studies CESS 81 and CESS 86. MATERIALS AND METHODS: From January 1981 through June 1991, 674 patients were registered in the two sequential multicentric Ewing's sarcoma trials CESS 81 (recruitment period 1981-1985) and CESS 86 (1986-1991). The systemic treatment in both studies consisted of a four-drug-regimen (VACA = vincristine, actinomycin D, cyclophosphamide, and adriamycin; or VAIA = vincristine, actinomycin D, ifosfamide, and adriamycin) and a total number of four courses, each lasting nine weeks, was recommended by the protocol. Local therapy in curative patients was either complete surgery (n = 162), surgery plus postoperative radiotherapy with 36-46Gy (n = 274), or definitive radiotherapy with 46-60Gy (n = 212). The median follow-up at the time of this analysis was 5.1 years, the maximum follow-up 16.5 years. RESULTS: The overall survival of all patients including metastatic patients was 55% after 5 years, 48% after 10 years, and 37% after 15 years. Eight out of 674 patients (1.2%) developed a SM. Five of these were acute myelogenic leukemias (n = 4) or MDS (n = 1), and three were sarcomas. The interval between diagnosis of Ewing's sarcoma and the diagnosis of the SM was 17-78 months for the four AMLs, 96 months for the MDS and 82-136 months for the three sarcomas. The cumulative risk of an SM was 0.7% after 5 years, 2.9% after 10 years, and 4.7% after 15 years. Out of five patients with AML/MDS, three died of rapid AML-progression, and two are living with disease. Local therapy (surgery vs. surgery plus postoperative irradiation vs. definitive radiotherapy) had no impact on the frequency of AML/MDS, but local therapy did influence the risk of secondary sarcomas. All three patients with secondary sarcomas had received radiotherapy; however, all three sarcomas were salvaged by subsequent treatment and are in clinical remission with a follow-up of 1 month, 4.3 years, and 7.5 years after the diagnosis of the secondary sarcoma. Thus far, SM contributed to less than 1 % (3/328) of all deaths in the CESS-studies. CONCLUSIONS: The risk of leukemia after treatment for Ewing's sarcoma is probably in the range of 2%. The risk of solid tumors also seems to be low within the first 10 years after treatment and remains in the range of 5 % after 15 years. In the CESS-studies, less than 1% of all deaths within the first 10 years after diagnosis were caused by SM. Effective salvage therapy for secondary sarcomas is feasible.

Radiotherapy in Ewing's sarcoma and PNET of the chest wall: results of the trials CESS 81, CESS 86 and EICESS 92.

PURPOSE: Treatment results and the pattern of relapse were evaluated in the multimodal treatment of Ewing's sarcomas of the chest wall. METHODS AND MATERIALS: In a retrospective analysis, 114 patients with non-metastatic Ewing's sarcoma of the chest wall were evaluated. They were treated in the CESS 81, CESS 86, or EICESS 92 studies between January 1981 and December 1993. The treatment consisted of polychemotherapy (VACA, VAIA, or EVAIA) and local therapy, either surgery alone (14 patients), radiotherapy alone (28 patients) or a combination of both (71 patients). The median follow-up was 46.6 months (range 5-170). A relapse analysis for all patients with local or combined relapses was performed. RESULTS: Overall survival was 60% after 5 years, event-free survival was 50%. Thirty-seven patients had a systemic relapse (32.4%), 11 patients had a local relapse alone (9.6%), and 3 patients had a combined local and systemic relapse (2.6%). The risk to relapse locally after 5 years was 0% after surgery alone, 19% after radiation alone, and 19% after postoperative irradiation. None of the 8 patients with preoperative irradiation have failed locally so far. With the introduction of central radiotherapy planning in CESS 86, local control of irradiated patients improved. Ten of 14 patients with local failure could be evaluated in the relapse analysis: 3 patients had an in-field relapse, 4 patients had a marginal relapse, 2 patients had a relapse outside the radiation fields, and 1 patient failed with pleural dissemination. Six treatment deviations were observed. CONCLUSION: Local control was best after surgery alone in a positively selected group of patients. Local control after radiation or combined radiation and surgery was good. With diligent performance of radiotherapy, it will be possible to further improve the results in the radiotherapy group.

Advantages of short-lived positron-emitting radioisotopes for intracoronary radiation therapy with liquid-filled balloons to prevent restenosis.

UNLABELLED: Balloon catheters filled with liquid radioisotopes provide excellent dose homogeneity for intracoronary radiation therapy but are associated with risk for rupture or leakage. We hypothesized that the safety of liquid-filled balloons may be improved once positron emitters with half-lives below 2 h are used instead of the high-energy beta-emitters 166Ho, 186Re, or 188Re, all of which have a longer half-life of at least 17 h. METHODS: To support this concept, the suitability of 18F (half-life, 109.8 min), 68Ga (half-life, 67.6 min), 11C (half-life, 20.4 min), 13N (half-life, 9.97 min), and 15O (half-life, 2.04 min) for intracoronary radiation therapy was evaluated. Potential tissue penetration of positron radiation was assessed in a series of phantom experiments using Gafchromic film. Antiproliferative efficacy of positrons emitted by 68Ga was investigated in vitro using cultured bovine aortic smooth muscle cells (BASMCs), and was compared with gamma-radiation emitted by 137Cs. To characterize the remaining risk, we estimated radiotoxicity after accidental intravascular balloon rupture on the basis of tabulated isotope-specific doses (ICRP 53) and compared these values with 188Re. RESULTS: Half-dose depth of tissue penetration measured in phantom experiments was 0.29 mm for 18F, 0.42 mm for 11C, 0.54 mm for 13N, 0.79 mm for 15O, and 0.9 mm for 68Ga. Irradiation of cultured BASMCs with positron radiation (68Ga) induced dose-dependent inhibition of proliferation with complete proliferative arrest at doses exceeding 6 Gy. ED(50) and ED(80) were 2.5 +/- 0.4 Gy (mean +/- SD) and 4.4 +/- 0.8 Gy, respectively. Antiproliferative efficacy was equal to that of the 662-keV gamma-radiation emitted by 137Cs (ED(50), 3.8 +/- 0.2 Gy; ED(80), 8.0 +/- 0.3 Gy). Estimates made for patient whole-body and organ doses were generally below 50 mSv/1.85 GBq for all investigated positron emitters. The same dose estimates for 188Re were 6-20 fold higher. CONCLUSION: Among the studied radioisotopes, 68Ga is the most attractive source for liquid-filled balloons because of its convenient half-life, sufficient positron energy (2.92 MeV), documented antiproliferative efficacy, and uncomplicated availability from a radioisotope generator. The safety profile for 68Ga is significantly better than that of 188Re, which suggests this radioisotope should be evaluated further in preclinical studies.

Postoperative radiotherapy in localized non-small cell lung cancer.

Surgery alone can cure 40-85% of patients with localized non-small cell lung cancer, depending on tumor stage and metastatic lymph-node involvement. As local failure rates occur in up to 50% of the cases, postoperative radiotherapy as an adjuvant treatment option has been evaluated in several trials. This review briefly summarizes the published data mainly from randomized trials. While most of the studies showed a decrease in local recurrence rate, especially in stage-III/N2 tumors after postoperative radiotherapy, no impact could be shown on overall survival. In early stages a detrimental effect of postoperative radiotherapy has been postulated, but those findings have to be interpreted with caution as radiation techniques used were suboptimal and probably not today's state of the art. A carefully designed randomized trial using modern radiotherapy techniques is warranted to define the impact of irradiation on completely resected NSCLC.

Regulation of the release of tumour necrosis factor (TNF)alpha and soluble TNF receptor by gamma irradiation and interferon gamma in Ewing's sarcoma/peripheral primitive neuroectodermal tumour cells.

This study analyses the production of tumour necrosis factor (TNF)alpha and soluble TNF receptor (sTNF-R) before and after exposure to gamma irradiation and interferon gamma (IFN gamma) in 12 cell lines derived from Ewing's sarcoma (ES)/peripheral primitive neuroectodermal tumours (pPNET). Supernatants from ES/pPNET cell cultures were tested in a TNF alpha-specific amplified enzyme-linked immunosorbent assay (ELISA), a bioassay, and sTNF-Rp55 and sTNF-Rp75 ELISA. The tumour cell lines released minimal amounts of TNF alpha, prominent amounts of sTNF-Rp55 (7/12 cell lines) and no sTNF-Rp75. Exposure to gamma irradiation (5 Gy) either induced (3/12) cell lines) or up-regulated (3/12 cell lines) TNF alpha release without changing sTNF-Rp55 and sTNF-Rp75 levels. Priming of cultures with recombinant human IFN gamma (rhIFN gamma) markedly enhanced TNF alpha secretion in the radiation-responsive cell lines and had no influence on sTNF-Rp55 and sTNF-Rp75 levels. rhIFN gamma affected the magnitude rather than the sensitivity of the radiation response. The TNF alpha secreted was bioactive, as shown by its cytotoxic effect of WEHI-164 cells, and neutralization of its activity by anti-TNF alpha monoclonal antibody. Herbimycin A (a tyrosine-specific protein kinase inhibitor) but not calphostin C (a protein kinase C inhibitor), H89 (a protein kinase A inhibitor), AA-COCF3 (a specific inhibitor of phospholipase A2) and MK-886 (a specific inhibitor of 5-lipoxygenase) abrogated gamma-irradiation-stimulated TNF alpha release. The antioxidants N-acetylcysteine, nordihydroguaiaretic acid and mepacrine dose-dependently inhibited gamma-irradiation-mediated TNF alpha production. Collectively our findings indicate that IFN gamma priming potentiates the secretion of bioactive TNF alpha by ES/pPNET cells in response to gamma irradiation without affecting sTNF-R release. The data suggest a requirement for protein tyrosine kinase activity and a role for reactive oxygen species in the gamma-irradiation-mediated intracellular signalling pathway leading to TNF alpha production.

The impact of intraoperative brachytherapy on surgery of Ewing's sarcoma.

Surgery of Ewing's sarcoma sometimes results in an inadequate surgical margin. The influence of intraoperative brachytherapy on local control of the tumor, operation time, blood loss, and surgical complications was evaluated, comparing the results of 20 patients who received brachytherapy to a series of 42 patients receiving surgery without brachytherapy. The dose of intraoperative brachytherapy ranged between 9 Gy and 21 Gy. The average operation time was longer in 20 cases with brachytherapy (7.9 h) than in 42 cases without brachytherapy (4.3 h) (P < 0.0001). The average blood loss in the groups with (3531 ml) and without brachytherapy (3515 ml) was comparable (P = 0.3840). The surgical complication rate in patients receiving brachytherapy was also similar to that of untreated patients (30% versus 31%, P = 0.7690). Local relapse developed in 1 of 20 patients who received brachytherapy and 1 of 42 patients without brachytherapy. On the basis of this analysis, it can be concluded that this procedure is safe and does not increase of the acute complication rate. The latest results of local controls are awaited.

Surgical complications after preoperative irradiation of Ewing's sarcoma.

The influence of preoperative irradiation on surgical complications in 42 patients with Ewing's sarcoma was analysed. After preoperative irradiation and chemotherapy, 35 of 40 patients showed a good histological response and 25 of 40 patients had no viable tumour cells in the resected specimen. Local relapse alone did not develop, local relapse and metastasis developed in 2 patients and metastasis alone in 15 patients. Surgical complications appeared in 12 of 42 patients: 9 of 19 central tumours (19 pelvic lesions), 1 of 13 proximal and 2 of 10 distal tumours. Surgical complications after preoperative irradiation are distributed as follows: delayed wound healing 8, hematoma 2, thrombosis 2, skin infection 1, and abscess 1. On the other hand, complications appeared in 2 of 28 patients without preoperative irradiation: none in 9 patients having central tumours including 2 pelvic lesions, 1 in 12 patients with proximal tumours, and 1 in 7 patients with distal tumours. The multivariate regression test showed that the tumour site (central) is an influencing factor in the appearance of surgical complications. In central tumours, the surgical complication rate increases after preoperative irradiation; however, it is affected by the increase of the ratio of patients with pelvic tumours.