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Background: Desmoplasia in medulloblastoma is often diagnosed in adult patients and was repeatedly associated with improved results. Today, all medulloblastoma patients receive intensive multimodal treatment including surgery, radiotherapy and chemotherapy. This study was set up to investigate treatment outcome and prognostic factors after radiation therapy in patients with desmoplastic medulloblastomas., Methods: Twenty patients treated for desmoplastic medulloblastoma in the Department of Radiation Oncology at the University of Heidelberg between 1984 and 2007 were included. Data were collected retrospectively. Tumor resection was performed in all patients. All patients underwent postsurgical radiotherapy (RT). Two patients underwent whole brain radiotherapy (WBRT), and 18 patients received craniospinal irradiation (CSI). In all patients, an additional boost was delivered to the posterior fossa. The median dose to the whole brain and the craniospinal axis was 35.2 Gray (Gy), and 54.4 Gy to the posterior fossa. Fourteen patients received chemotherapy, including seven who were treated with combined radiochemotherapy and twelve who received adjuvant chemotherapy. Statistical analysis was performed using the log-rank test and the Kaplan-Meier method., Results: Median follow-up was 59 months. Overall (OS), local (LPFS) and distant progression-free survival (DPFS) was 80%, 71.2%, and 83.3% at 60 months. Patients who suffered from local or distant relapses had significantly worse outcome. Five patients died from recurrent medulloblastoma. Treatment-associated toxicity was acceptable., Conclusions: Multimodal approaches with surgical resection followed by chemoirradiation achieved high response rates with long OS in desmoplastic medulloblastoma patients. Staging parameters expected to predict for poor prognosis did not significantly influence outcome. However, success of any first line regimen had strong impact on disease control, and remission was achieved in no patient with relapsing disease. Multimodal concepts must be evaluated in further clinical trials.

Purpose: To analyze our experiences concerning radiation treatment in patients with osteosarcoma., Materials and Methods: Since 1981, 40 patients with osteosarcoma have undergone radiotherapy in Heidelberg; 3 of them were immediately lost to follow-up. Twenty patients with metastases were treated palliatively and 17 patients were treated with a curative intent., Results: Interestingly, 14 of the 17 patients treated with a curative intent were referred to our clinic during the last 8 years, whereas the number of patients referred for palliation decreased. The mean dose applied for palliation was 47 Gy (range, 26 Gy to > 70 GyE), for cure was 59 Gy (range, 45 Gy to > 70 GyE). Local control until death could be achieved in 15 of the 20 palliatively treated patients, with a mean survival of 7 months after radiation. Five patients experienced local failure with symptom recurrence, and 3 of them had received doses > 60 Gy. At last follow-up, 3 of the 17 curatively treated patients had experienced local recurrence. Median follow-up was 32 months (range, 3-144). Estimated 5-year overall survival and local control rates were 38% and 68%, respectively. Local disease-free survival was shorter in patients treated for recurrent, inoperable or incompletely resected tumors and doses below 60 Gy., Conclusions: With adequate doses, long-term local control is possible even in inoperable or incompletely resected tumors. Improvements of systemic therapy and modern radiation techniques have begun to bring the possibly curative role of radiation treatment back to the fore. However, in disseminated tumors, even doses beyond 60 Gy do not guarantee local control, suggesting an extremely low radiosensitivity of certain kinds of osteosarcoma.

Non-invasive treatment of hepatic metastases has become a focal point of interdisciplinary oncology especially since the advent of stereotactic radiation techniques. Worldwide several centers have shown that this treatment is a curative and well tolerated regimen with excellent rates of local control. Modern devices which combine radiation therapy with imaging techniques (image-guided radiotherapy) in particular allow precise dose application, especially for hypofractionated treatment concepts requiring daily repositioning.

Purpose: Stem-like tumor cells comprise a highly tumorigenic and therapy-resistant tumor subpopulation, which is believed to substantially influence tumor initiation and therapy resistance in glioma. Currently, therapeutic, drug-induced differentiation is considered as a promising approach to eradicate this tumor-driving cell population; retinoic acid is well known as a potent modulator of differentiation and proliferation in normal stem cells. In glioma, knowledge about the efficacy of retinoic acid-induced differentiation to target the stem-like tumor cell pool could have therapeutic implications., Experimental Design: Stem-like glioma cells (SLGC) were differentiated with all-trans retinoic acid-containing medium to study the effect of differentiation on angiogenesis, invasive growth, as well as radioresistance and chemoresistance of SLGCs. In vivo effects were studied using live microscopy in a cranial window model., Results: Our data suggest that in vitro differentiation of SLGCs induces therapy-sensitizing effects, impairs the secretion of angiogenic cytokines, and disrupts SLGCs motility. Further, ex vivo differentiation reduces tumorigenicity of SLGCs. Finally, we show that all-trans retinoic acid treatment alone can induce antitumor effects in vivo., Conclusions: Altogether, these results highlight the potential of differentiation treatment to target the stem-like cell population in glioblastoma., (Copyright (c) 2010 AACR.)

The Heidelberg Ion Therapy Center (HIT) offers treatment of particle therapy with variety of ion species for over 1300 patients yearly. In November 2009, patient treatment has begun. The aim of the center is to provide high-end radiotherapy, and to define the role of particle therapy through clinical trials., (Copyright 2010 Elsevier Ireland Ltd. All rights reserved.)

Background: We analyzed outcome after a carbon ion boost in combination with precision photon radiation therapy in patients with meningiomas., Patients and Methods: Ten patients with meningiomas were treated with carbon ion RT as part of a Phase I/II trial. Carbon ion RT was conducted in conjunction with fractionated stereotactic RT (FSRT) or intensity-modulated RT (IMRT). Eight patients were treated as primary RT, in 2 patients carbon ion RT was performed as re-irradiation. Carbon ion RT was applied with a median dose of 18 GyE, and photon RT was applied with a median dose of 50.4 Gy. Two patients with a history of former irradiation received 18GyE of carbon ion RT and a reduced dose of photon treatment., Results: The median follow-up time was 77 months. Five patients died during follow-up, of which four died of tumor progression. In the group treated in the primary situation, actuarial survival rates after RT were 75% and 63% at 5 and 7 years. After re-irradiation, both patients died at 10 and 67 months, respectively. Actuarial local control rates after primary RT were 86% and 72% at 5 and 7 years. Two patients developed tumor recurrence after re-irradiation, 6 and 67 months after treatment., Conclusion: In conclusion, carbon ion radiation shows promising results in patients with atypical or anaplastic meningiomas. Further evaluation in a larger, prospective study in comparison to proton RT or modern photon RT is needed to corroborate these results., (Copyright 2010 Elsevier Ireland Ltd. All rights reserved.)

Background: Osteosarcoma is the most common primary malignant bone tumor in children and adolescents. For effective treatment, local control of the tumor is absolutely critical, because the chances of long term survival are <10% and might effectively approach zero if a complete surgical resection of the tumor is not possible. Up to date there is no curative treatment protocol for patients with non-resectable osteosarcomas, who are excluded from current osteosarcoma trials, e.g. EURAMOS1. Local photon radiotherapy has previously been used in small series and in an uncontrolled, highly individualized fashion, which, however, documented that high dose radiotherapy can, in principle, be used to achieve local control. Generally the radiation dose that is necessary for a curative approach can hardly be achieved with conventional photon radiotherapy in patients with non-resectable tumors that are usually located near radiosensitive critical organs such as the brain, the spine or the pelvis. In these cases particle Radiotherapy (proton therapy (PT)/heavy ion therapy (HIT) may offer a promising new alternative. Moreover, compared with photons, heavy ion beams provide a higher physical selectivity because of their finite depth coverage in tissue. They achieve a higher relative biological effectiveness. Phase I/II dose escalation studies of HIT in adults with non-resectable bone and soft tissue sarcomas have already shown favorable results., Methods/design: This is a monocenter, single-arm study for patients > or = 6 years of age with non-resectable osteosarcoma. Desired target dose is 60-66 Cobalt Gray Equivalent (Gy E) with 45 Gy PT (proton therapy) and a carbon ion boost of 15-21 GyE. Weekly fractionation of 5-6 x 3 Gy E is used. PT/HIT will be administered exclusively at the Ion Radiotherapy Center in Heidelberg. Furthermore, FDG-PET imaging characteristics of non-resectable osteosarcoma before and after PT/HIT will be investigated prospectively. Systemic disease before and after PT/HIT is targeted by standard chemotherapy protocols and is not part of this trial., Discussion: The primary objectives of this trial are the determination of feasibility and toxicity of HIT. Secondary objectives are tumor response, disease free survival and overall survival. The aim is to improve outcome for patients with non-resectable osteosarcoma., Trial Registration: Registration number (ClinicalTrials.gov): NCT01005043.

Purpose: To evaluate the outcomes of patients with vestibular schwannoma (VS) treated with fractionated stereotactic radiotherapy (FSRT) vs. those treated with stereotactic radiosurgery (SRS)., Methods and Materials: This study is based on an analysis of 200 patients with 202 VSs treated with FSRT (n = 172) or SRS (n = 30). Patients with tumor progression and/or progression of clinical symptoms were selected for treatment. In 165 out of 202 VSs (82%), RT was performed as the primary treatment for VS, and for 37 VSs (18%), RT was conducted for tumor progression after neurosurgical intervention. For patients receiving FSRT, a median total dose of 57.6 Gy was prescribed, with a median fractionation of 5 x 1.8 Gy per week. For patients who underwent SRS, a median single dose of 13 Gy was prescribed to the 80% isodose., Results: FSRT and SRS were well tolerated. Median follow-up time was 75 months. Local control was not statistically different for both groups. The probability of maintaining the pretreatment hearing level after SRS with doses of < or =13 Gy was comparable to that of FSRT. The radiation dose for the SRS group (< or =13 Gy vs. >13 Gy) significantly influenced hearing preservation rates (p = 0.03). In the group of patients treated with SRS doses of < or =13 Gy, cranial nerve toxicity was comparable to that of the FSRT group., Conclusions: FSRT and SRS are both safe and effective alternatives for the treatment of VS. Local control rates are comparable in both groups. SRS with doses of < or =13 Gy is a safe alternative to FSRT. While FSRT can be applied safely for the treatment of VSs of all sizes, SRS should be reserved for smaller lesions.

Objectives: Patients with SSADH deficiency, a disorder of chronically elevated endogenous GABA and GHB, were studied for sleep symptoms and polysomnography. We hypothesized that patients would have excessive daytime somnolence and decreased REM sleep., Design: Polysomnography and MSLT were performed on patients enrolled for comprehensive clinical studies of SSADH deficiency., Setting: Sleep studies were obtained in the sleep laboratories at CNMC and NIH., Patients: Sleep recordings were obtained in 10 patients with confirmed SSADH deficiency., Interventions: Thirteen overnight polysomnograms were obtained in 10 patients (7 male, 3 female, ages 11-27 y). Eleven MSLT studies were completed in 8 patients., Measurements and Results: Polysomnograms showed prolongation of REM stage latency (mean 272 +/- 89 min) and decreased percent stage REM (mean 8.9%, range 0.3% to 13.8%). Decreased mean sleep latency was present in 6 of 11 MSLTs., Conclusions: SSADH deficiency is associated with prolonged latency to stage REM and decreased percent stage REM. This disorder represents a model of chronic GABA and GHB accumulation associated with suppression of REM sleep.

Purpose: Patients with anaplastic gliomas have a more favorable overall survival than patients with glioblastomas. In most analyses, WHO grade III and 1V tumors are not analyzed separately. The present analysis reports outcome after postoperative radiotherapy in patients with WHO grade III gliomas., Patients and Methods: Between January 1988 and January 2007, 127 patients with WHO grade III tumors were treated with radiotherapy; the histological classification was pure astrocytoma in 104 patients, oligoastrocytoma in 12 and pure oligodendroglioma in 11 patients. Median age was 48 years. After the primary diagnosis, a biopsy had been performed in 72 patients; subtotal and total resections were performed in 37 and 18 patients, respectively. In all patients radiotherapy was applied with a median dose of 60 Gy in conventional fractionation. The median follow-up time was 18 months., Results: Median overall survival was 17 months. Overall survival was significantly influenced by the extent of surgery. Median overall survival was 32 months after complete resection, 36 months after subtotal resection, and 12 months after biopsy. Median overall survival was 7 months for patients with anaplastic astrocytomas, 44 months for patients with mixed tumors, and 47 months for those with pure oligodendrogliomas. Age significantly influenced overall survival. Median progression-free survival was 9 months; the extent of neurosurgical resection significantly influenced progression-free survival., Conclusion: Patients with WHO grade III anaplastic astrocytomas, oligodendrogliomas and oligoastrocytomas show favorable overall survival after postoperative radiotherapy compared with glioblastoma patients and should therefore be analyzed separately. Radiochemotherapy might further improve outcome.

Introduction: To assess long-term outcome in 85 patients with brain stem gliomas treated with fractionated stereotactic radiation therapy (FSRT)., Patient and Methods: Thirty-nine patients were females, and 46 were males. Median age at primary diagnosis was 26 years. Thirty-one patients were younger than 18 years. Histopathological examination confirmed a low-grade glioma in 57 patients. Of the group of high-grade gliomas, six were anaplastic astrocytomas, and two were classified as glioblastoma. Radiation therapy was performed as FSRT. The median target volume was 101 ml. We applied a median dose of 54 Gy in conventional fractionation of 1.8 Gy. In seven of 85 patients (8%) FSRT was performed as re-irradiation., Results: The median follow-up time was 42 months. Median overall survival (OS) was 81 months. OS rates were 77% at 12 months, 70% at 24 months, and 63% at 36 months. Significant impact on OS could be shown for pilocytic histology, age, neurosurgical resection as well as for the presence of cyst on MR-imaging. Median progression-free survival (PFS) after FSRT was 52 months. PFS rates at 12 months were 70%, and 63% and 58% at 24 and 36 months, respectively. Histology, partial neurosurgical resection and the duration of symptoms could be identified as significant prognostic factors., Conclusion: Long-term outcome of FSRT in patients with brain stem gliomas is acceptable with low rates of side effects. Significant impact on outcome could be shown for histology, age, extent of neurosurgical resection as well as for cyst formation. No dose-response relationship could be observed.

Background: The current study was conducted to evaluate the outcome of carbon ion radiotherapy (RT) in children and young adults with skull base chordomas and chondrosarcomas., Methods: Between 1997 and 2007, 394 patients were treated with carbon ion RT at Gesellschaft für Schwerionenforschung in Darmstadt, Germany. Of these patients, 17 patients were aged

Purpose: To investigate the cytotoxic effect of high linear-energy transfer (LET) carbon irradiation on glioblastoma cells lines in combination with temozolomide (TMZ)., Methods and Materials: The cell lines U87-MG expressing wild-type p53 and LN229 expressing both mutant and wild-type p53 were irradiated with monoenergetic carbon ion beams (LET 172 keV/microm) or an extended Bragg peak (LET 103 keV/microm) after treatment with 10 microM or 20 microM TMZ. Cytotoxicity was measured by a clonogenic survival assay, and cell growth as well as cell cycle progression, were examined., Results: The p53 mutant was more sensitive to X-ray irradiation than the p53 wild type cell line, which was also expressed in a shorter G2 block. High LET carbon ions show an increased biological effectiveness in both cell lines, which is consistent with the predictive calculations by the Local Effect Model (LEM) introduced by Scholz et al. The cell line LN229 was more sensitive to TMZ treatment than the U87MG cell line expressing wild-type p53 only. The combination of TMZ and irradiation showed an additive effect in both cell lines., Conclusion: High LET carbon ion irradiation is significantly more effective for glioblastoma cell lines compared to photon irradiation. An additional treatment with TMZ may offer a great chance especially for several tumor types.

Radiation therapy is a main pillar in the multimodal treatment of gliomas. However, application of radiation has to be adapted to the distinct characteristics of the various glioma subtypes, with respect to dosing, time-point of irradiation, choice of treatment technique, and more recently, of radiation quality.Treatment of low-grade gliomas has been characterized by much controversy, which is still ongoing. For anaplastic gliomas, addition of chemotherapy to radiation alone is currently being discussed and is evaluated in prospective trials. For glioblastomas, a change in treatment paradigm has taken place with the alkylating agent temozolomide, which could increase survival significantly for the first time in many centuries. Moreover, the first steps toward pretreatment stratification have been established by defining the role of MGMT-promotor methylation for treatment response and outcome.Over the last few years, particle therapy with protons and carbon ions has become available. These new radiation qualities now offer promising treatment alternatives that will be evaluated within clinical studies in the near future and have the potential to further improve outcome in patients with gliomas.

Purpose: To evaluate outcome after fractionated stereotactic radiotherapy (FSRT) and concomitant daily temozolomide (TMZ) in patients with recurrent gliomas., Materials and Methods: Twenty-five patients with recurrent or progressive gliomas were treated with FSRT in combination with TMZ at the Department of Radiation Oncology, University of Heidelberg. Histologic classification at primary diagnosis included low-grade astrocytoma in 7 patients (28%), grade III gliomas in 10 patients (40%) and glioblastoma in 8 patients (32%). All patients had undergone at least one neurosurgical resection, which was complete in 5 patients (20%), subtotal in 13 patients (52%) and a biopsy only in 7 patients (28%). Nineteen patients (76%) had undergone neurosurgical resection for tumor recurrence. All patients had received radiation therapy with a median dose of 60 Gy. The median time interval between primary RT and re-irradiation was 36 months. Using FSRT, we applied a median total dose of 36 Gy in a median fractionation of 5 x 2 Gy/week. Chemotherapy with TMZ was applied in a median dose of 50 mg/m(2)., Results: Median overall survival was 59 months. Median survival from re-irradiation was 8 months. Actuarial survival rates at 6 and 12 months were 81% and 25%. Median PFS was 5 months; actuarial PFS rates at 6 and 12 months were 48% and 16%. Treatment could be completed in all patients as scheduled without interruptions >3 days. No severe treatment-related side effects could be observed., Conclusion: Re-irradiation and TMZ is safe and effective in a subgroup of patients with recurrent gliomas. Further evaluation of radiochemotherapy regimens for recurrent or progressive gliomas is warranted.

Outcome after radiochemotherapy (RCHT) with temozolomide (TMZ) versus radiotherapy (RT) for WHO grade III astrocytic tumors was evaluated. No significant difference in overall survival or progression-free survival between both groups was calculated. RCHT seems not to result in an improved outcome. Further randomized studies are needed to support these results.

Purpose: To assess the outcome of 57 patients with localized ependymomas treated with radiotherapy (RT)., Methods and Materials: Fifty-seven patients with localized ependymomas were treated with RT. Histology was myxopapillary ependymoma (n = 4), ependymoma (n = 23), and anaplastic ependymoma (n = 30). In 16 patients, irradiation of the craniospinal axis (CSI) was performed with a median dose of 20 Gy. Forty-one patients were treated with local RT, with a local dose of 45 Gy to the posterior fossa, including a boost to the tumor bed of 9 Gy. In 19 patients, the tumor bed was irradiated with a median dose of 54 Gy., Results: Overall survival after primary diagnosis was 83% and 71% at 3 and 5 years. Five-year overall survival was 80% in low-grade and 79% in high-grade tumors. Survival from RT was 79% at 3 and 64% at 5 years. We could not show a significant difference in overall survival between CSI and local RT only. Freedom of local failure was 67% at 5 years in patients treated with CSI and 60% at 5 years after local RT. A rate of 83% for distant failure-free survival could be observed in the CSI group as opposed to 93% in the group receiving local RT only., Conclusion: Local RT in patients with localized tumors is equieffective to CSI. The radiation oncologist must keep in mind that patients with localized ependymomas benefit from local doses > or =45 Gy.

Purpose: To evaluate toxicity and outcomes in patients with primary glioblastoma (GB) treated with postoperative radiochemotherapy (RCHT) with temozolomide (TMZ) comparing two dose regimens., Methods and Materials: A total of 160 patients with histologically confirmed GB were treated with postoperative RCHT with TMZ. Of the patients, 66 were female and 94 were male, with a median age of 60 years. After the primary diagnosis, a biopsy had been performed in 42 patients; a subtotal and total resection was conducted in 66 and 52 patients. Postoperative radiotherapy was applied with a median dose of 60 Gy with a median fractionation of 5 x 2Gy/week. Concomitant TMZ was prescribed at 50 mg/m(2) in 123 patients (Group A) and at 75 mg/m(2) in 37 patients (Group B). Patients were followed in 3-months intervals, with a median follow-up of 13 months., Results: Overall survival (OS) rates in Group A vs. Group B were 67% and 79% at 1 year and 43% vs. 49% at 2 years, respectively (p = 0.69). Progression-free survival was 49% vs. 54% at 1 year and 22% vs. 29% at 2 years (p = 0.31). Hematologic toxicity was not statistically significant over the 6-week RCHT period except for a significant decrease in platelets during Week 6 (p = 0.01) in Group B., Conclusions: Overall survival seems to be comparable in both groups, although longer follow-up and a larger group of patients are needed to corroborate these results. Lower dosing of TMZ also is associated with a more beneficial toxicity profile.

Purpose: To evaluate efficacy and toxicity in elderly patients with glioblastoma multiforme (GBM) treated with postoperative radiochemotherapy with temozolomide (TMZ)., Patients and Methods: Forty-three patients aged 65 years or older were treated with postoperative with radiochemotherapy using TMZ for primary GBM. Median age at primary diagnosis was 67 years; 14 patients were female, 29 were male. A complete surgical resection was performed in 12 patients, subtotal resection in 17 patients, and biopsy only in 14 patients. Radiotherapy was applied with a median dose of 60 Gy, in a median fractionation of 5x2 Gy/wk. Thirty-five patients received concomitant TMZ at 50 mg/m2, and in 8 patients 75 mg/m2 of TMZ was applied. Adjuvant cycles of TMZ were prescribed in 5 patients only., Results: Median overall survival was 11 months in all patients; the actuarial overall survival rate was 48% at 1 year and 8% at 2 years. Median overall survival was 18 months after complete resection, 16 months after subtotal resection, and 6 months after biopsy only. Median progression-free survival was 4 months; the actuarial progression-free survival rate was 41% at 6 months and 18% at 12 months. Radiochemotherapy was well tolerated in most patients and could be completed without interruption in 38 of 43 patients. Four patients developed hematologic side effects greater than Common Terminology Criteria Grade 2, which led to early discontinuation of TMZ in 1 patient., Conclusions: Radiochemotherapy is safe and effective in a subgroup of elderly patients with GBM and should be considered in patients without major comorbidities.

Background: The present study evaluates the outcome of 19 children with rhabdomyosarcoma of the head-and-neck region treated with Intensity Modulated Radiotherapy (IMRT) or Fractionated Stereotactic Radiotherapy (FSRT) between August 1995 and November 2005., Methods: We treated 19 children with head-and-neck rhabdomyosarcoma with FSRT (n = 14) or IMRT (n = 5) as a part of multimodal therapy. Median age at the time of radiation therapy was 5 years (range 2-15 years). All children received systemic chemotherapy according to the German Soft Tissue Sarcoma Study protocols. Median size of treatment volume for RT was 93,4 ml. We applied a median total dose of 45 Gy (range 32 Gy - 54 Gy) using a median fractionation of 5 x 1,8 Gy/week (range 1,6 Gy - 1,8 Gy). The median time interval between primary diagnosis and radiation therapy was 5 months (range 3-9 months)., Results: After RT, the 3- and 5-year survival rate was 94%. The 3- and 5-year actuarial local control rate after RT was 89%. The actuarial freedom of distant metastases rate at 3- and 5-years was 89% for all patients. Radiotherapy was well tolerated in all children and could be completed without interruptions > 4 days. No toxicities >CTC grade 2 were observed. The median follow-up time after RT was 17 months., Conclusion: IMRT and FSRT lead to excellent outcome in children with head-and-neck RMS with a low incidence of treatment-related side effects.

Re-irradiation for recurrent gliomas has been discussed controversially in the past. This was mainly due to only marginal palliation while being associated with a high risk for side effects using conventional radiotherapy. With modern high-precision radiotherapy re-irradiation has become a more wide-spread, effective and well-tolerated treatment option. Besides external beam radiotherapy, a number of invasive and/or intraoperative radiation techniques have been evaluated in patients with recurrent gliomas. The present article is a review on the available methods in radiation oncology and summarizes results with respect to outcome and side effects in comparison to clinical results after neurosurgical resection or different chemotherapeutic approaches.

Background: The majority of glioblastoma multiforme (GBM) cells express the epidermal growth factor receptor (EGFR). The present study evaluates the combination of temozolomide (TMZ), EGFR inhibition, and radiotherapy (RT) in GBM cell lines., Methods and Materials: Human GBM cell lines U87, LN229, LN18, NCH 82, and NCH 89 were treated with various combinations of TMZ, RT, and the monoclonal EGFR antibody cetuximab. Responsiveness of glioma cells to the combination treatment was measured by clonogenic survival., Results: Overall, double and triple combinations of RT, TMZ, and cetuximab lead to additive cytotoxic effects (independent toxicity). A notable exception was observed for U87 and LN 18 cell lines, where the combination of TMZ and cetuximab showed substantial antagonism. Interestingly, in these two cell lines, the combination of RT with cetuximab resulted in a substantial increase in cell killing over that expected for independent toxicity. The triple combination with RT, cetuximab, and TMZ was nearly able to overcome the antagonism for the TMZ/cetuximab combination in U87, however only marginally in LN18, GBM cell lines., Conclusion: It appears that EGFR expression is not correlated with cytotoxic effects exerted by cetuximab. Combination treatment with TMZ, cetuximab and radiation resulted in independent toxicity in three out of five cell lines evaluated, the antagonistic effect of the TMZ/cetuximab combination in two cell lines could indicate that TMZ preferentially kills cetuximab-resistant cells, suggesting for some cross-talk between toxicity mechanisms. Expression of EGFR was no surrogate marker for responsiveness to cetuximab, alone or in combination with RT and TMZ.

Background: The long-term outcome in patients with craniopharyngiomas treated with fractionated stereotactic radiotherapy (FSRT) was evaluated., Methods: A total of 40 patients with craniopharyngiomas were treated between May 1989 and July 2006 with FSRT. Most patients were treated for tumor progression after surgery. A median target dose of 52.2 grays (Gy) (range, 50.4-56 Gy) was applied in a median conventional fractionation of 5 x 1.8 Gy per week. Follow-up examinations included thorough clinical assessment as well as contrast-enhanced magnetic resonance imaging scans., Results: After a median follow-up of 98 months (range, 3-326 months), local control was 100% at both 5 years and 10 years. Overall survival rates at 5 years and 10 years were 97% and 89%, respectively. A complete response was observed in 4 patients and partial responses were noted in 25 patients. Eleven patients presented with stable disease during follow-up. Acute toxicity was mild in all patients. Long-term toxicity included enlargement of cysts requiring drainage 3 months after FSRT. No visual impairment, radionecrosis, or development of secondary malignancies were observed., Conclusions: The long-term outcome of FSRT for craniopharyngiomas is excellent with regard to local control as well as treatment-related side effects., ((c) 2007 American Cancer Society.)

Purpose: The aim of this study was to evaluate the effectiveness and toxicity of carbon ion radiotherapy in chordomas of the skull base., Methods and Materials: Between November 1998 and July 2005, a total of 96 patients with chordomas of the skull base have been treated with carbon ion radiation therapy (RT) using the raster scan technique at the Gesellschaft für Schwerionenforschung (GSI) in Darmstadt, Germany. All patients had gross residual tumors. Median total dose was 60 CGE (range, 60-70 CGE) delivered in 20 fractions within 3 weeks. Local control and overall survival rates were calculated using the Kaplan-Meier method. Toxicity was assessed according to the Common Terminology Criteria (CTCAE v.3.0) and the Radiation Therapy Oncology Group (RTOG) / European Organization for Research and Treatment of Cancer (EORTC) score., Results: Mean follow-up was 31 months (range, 3-91 months). Fifteen patients developed local recurrences after carbon ion RT. The actuarial local control rates were 80.6% and 70.0% at 3 and 5 years, respectively. Target doses in excess of 60 CGE and primary tumor status were associated with higher local control rates. Overall survival was 91.8% and 88.5% at 3 and 5 years, respectively. Late toxicity consisted of optic nerve neuropathy RTOG/EORTC Grade 3 in 4.1% of the patients and necrosis of a fat plomb in 1 patient. Minor temporal lobe injury (RTOG/EORTC Grade 1-2) occurred in 7 patients (7.2%)., Conclusions: Carbon ion RT offers an effective treatment option for skull-base chordomas with acceptable toxicity. Doses in excess of 75 CGE with 2 CGE per fraction are likely to increase local control probability.

Neisseria meningitidis, a causative agent of bacterial meningitis, has a relatively small repertoire of transcription factors, including NMB0573 (annotated AsnC), a member of the Lrp-AsnC family of regulators that are widely expressed in both Bacteria and Archaea. In the present study we show that NMB0573 binds to l-leucine and l-methionine and have solved the structure of the protein with and without bound amino acids. This has shown, for the first time that amino acid binding does not induce significant conformational changes in the structure of an AsnC/Lrp regulator although it does appear to stabilize the octameric assembly of the protein. Transcriptional profiling of wild-type and NMB0573 knock-out strains of N. meningitidis has shown that NMB0573 is associated with an adaptive response to nutrient poor conditions reflected in a reduction in major surface protein expression. On the basis of its structure and the transcriptional response, we propose that NMB0573 is a global regulator in Neisseria controlling responses to nutrient availability through indicators of general amino acid abundance: leucine and methionine.

Aim: The cost-effectiveness of Carbon ion radiotherapy (RT) for patients with skull base chordoma is analyzed., Materials and Methods: Primary treatment costs and costs for recurrent tumors are estimated. The costs for treatment of recurrent tumors were estimated using a sample of 10 patients presenting with recurrent chordoma at the base of skull at DKFZ. Using various scenarios for the local control rate and reimbursements of Carbon ion therapy the cost-effectiveness of ion therapy for these tumors is analyzed., Results: If local control rate for skull base chordoma achieved with carbon ion therapy exceeds 70.3%, the overall treatment costs for carbon RT are lower than for conventional RTI. The cost-effectiveness ratio for carbon RT is 2539 Euro per 1% increase in survival, or 7692 Euro per additional life year., Conclusion: Current results support the thesis that Carbon ion RT, although more expensive, is at least as cost-effective as advanced photon therapies for these patients. Ion RT, however, offers substantial benefits for the patients such as improved control rates and less severe side effects.

Purpose: To evaluate the clinical outcome of intensity-modulated radiotherapy (IMRT) in patients with mucosal melanoma (MM) of the nasal cavity and paranasal sinuses., Patients and Methods: Between January 1999 and September 2004, eight patients with histologically proven MM of the nasal cavity and paranasal sinuses were treated with IMRT. A median dose of 66 Gy was applied to the macroscopic tumor (gross tumor volume [GTV]; range, 60-68 Gy) as an integrated boost and a median dose of 59 Gy (range, 54-64 Gy) to the clinical target volume (CTV) with IMRT., Results: Treatment-related toxicity was very mild in most patients. Overall survival was 80% at 5 years. Calculated from treatment with IMRT as primary radiotherapy, survival was 100% at 1 year and 75% at 3 years. After IMRT, local progression-free survival was 71.4% at 1 year and 57.1% at 3 years, respectively. Distant progression-free survival after IMRT was 57.1% at 1 year and 28.6% at 3 years., Conclusion: Local dose escalation with IMRT yields good treatment results with respect to local and distant tumor control as well as survival, while treatment-related toxicity can be minimized.

Purpose: To evaluate the effectiveness and toxicity of carbon ion radiotherapy in chondrosarcomas of the skull base., Patients and Methods: Between November 1998 and September 2005, 54 patients with low-grade and intermediate-grade chondrosarcomas of the skull base have been treated with carbon ion radiation therapy (RT) using the raster scan technique at the Gesellschaft für Schwerionenforschung in Darmstadt, Germany. All patients had gross residual tumors after surgery. Median total dose was 60 CGE (weekly fractionation 7 x 3.0 CGE). All patients were followed prospectively in regular intervals after treatment. Local control and overall survival rates were calculated using the Kaplan-Meier method. Toxicity was assessed according to the Common Terminology Criteria (CTCAE v.3.0) and the Radiation Therapy Oncology Group (RTOG)/European Organization for Research and Treatment of Cancer (EORTC) score., Results: Median follow-up was 33 months (range, 3-84 months). Only 2 patients developed local recurrences. The actuarial local control rates were 96.2% and 89.8% at 3 and 4 years; overall survival was 98.2%at 5 years. Only 1 patient developed a mucositis CTCAE Grade 3; the remaining patients did not develop any acute toxicities >CTCAE Grade 2. Five patients developed minor late toxicities (RTOG/EORTC Grades 1-2), including bilateral cataract (n = 1), sensory hearing loss (n = 1), a reduction of growth hormone (n = 1), and asymptomatic radiation-induced white matter changes of the adjacent temporal lobe (n = 2). Grade 3 late toxicity occurred in 1 patient (1.9%) only., Conclusions: Carbon ion RT is an effective treatment for low- and intermediate-grade chondrosarcomas of the skull base offering high local control rates with low toxicity.

(23)Na MRI has the potential to noninvasively detect sodium (Na) content changes in vivo. The goal of this study was to implement (23)Na MRI in a clinical setting for neurooncological and muscular imaging. Due to the biexponential T(2) decay of the tissue Na signal with a short component, which ranges between 0.5-8 ms, the measurement of total Na content requires imaging techniques with echo times (TEs) below 0.5 ms. A 3D radial pulse sequence with a TE of 0.2 ms at a spatial resolution of 4 x 4 x 4 mm(3) was developed that allows the acquisition and presentation of Na images on the scanner. This sequence was evaluated in patients with low- and high-grade gliomas, and higher (23)Na MR signals corresponding to an increased Na content were found in the tumor regions. The contrast-to-noise ratio (CNR) between tumor and white matter increased from 0.8 +/- 0.2 to 1.3 +/- 0.3 with tumor grade. In patients with an identified muscular (23)Na channelopathy (Paramyotonia congenita (PC)), induced muscle weakness led to a signal increase of approximately 18% in the (23)Na MR images, which was attributed to intracellular Na(+) accumulation in this region.

Modern techniques in radiation oncology, such as fractionated stereotactic radiotherapy (FSRT), stereotactic radiosurgery (SRS) or intensity modulated radiotherapy (IMRT) allow the application of high local doses to defined treatment volumes, while normal structures in close vicinity can be spared; high local control rates can be achieved, while treatment-related toxicity can be minimized. Innovative Hi-Art tomotherapy systems offer an alternative, combining a 6 MV photon accelerator with a CT scanner. Ion beams, such as protons and carbon ions, have been shown to be beneficial for distinct tumor entities. Both offer a characteristic physical dose distribution with an inverse dose profile contributing to beneficial dose conformality. Carbon ions also offer the advantage of increased relative biological effectiveness. For certain tumor types, a significant increase in local control and survival rates could be obtained with carbon ions.

Background: To assess the role of Fractionated Stereotactic Radiotherapy (FSRT) in the management of ependymomas., Methods: From January 1992 to July 2003, FSRT was performed in 19 patients with histologically confirmed ependymomas. The median age was 15 years, 5 patients were younger than 4 years of age. Twelve patients received FSRT as primary postoperative radiotherapy after surgical resection. In 6 patients irradiation of the posterior fossa was performed with a local boost to the tumor bed, and in 4 patients the tumor bed only was irradiated. In 7 patients FSRT was performed as re-irradiation for tumor progression. This patient group was analyzed separately. A median dose of 54 Gy was prescribed in a median fractionation of 5 x 1.8 Gy per week for primary RT using 6 MeV photons with a linear accelerator. For FSRT as re-irradiation, a median dose of 36 Gy was applied. All recurrent tumors were localized within the former RT-field., Results: The 5- and 10-year overall survival rates were 77% and 64%, respectively. Patients treated with FSRT for primary irradiation showed an overall survival of 100% and 78% at 3 and 5 years after irradiation of the posterior fossa with a boost to the tumor bed, and a survival rate of 100% at 5 years with RT of the tumor bed only. After re-irradiation with FSRT, survival rates of 83% and 50% at 3-and 5 years, respectively, were obtained.Progression-free survival rates after primary RT as compared to re-irradiation were 64% and 60% at 5 years, respectively.FSRT was well tolerated by all patients and could be completed without interruptions due to side effects. No severe treatment related toxicity > CTC grade 2 for patients treated with FSRT could be observed., Conclusion: The present analysis shows that FSRT is well tolerated and highly effective in the management of ependymal tumors. The rate of recurrences, especially at the field border, is not increased as compared to conventional radiotherapy consisting of craniospinal irradiation and a local boost to the posterior fossa.

Introduction: The aim of the study was to evaluate the clinical outcome of intensity modulated radiotherapy (IMRT) in 46 patients with paranasal sinus tumors with special respect to treatment-related toxicity., Patients and Methods: We treated 46 patients with histologically proven tumors of the paranasal sinuses with IMRT. Histological classification included squamous cell carcinoma in 6, adenocarcinoma in 8, adenoidcystic carcinoma in 20 and melanoma in 8 patients, respectively. Six patients had been treated with RT during initial therapy after primary diagnosis, and IMRT was performed for the treatment of tumor progression as re-irradiation., Results: Overall survival rates were 96% at 1 year, 90% at 3 years. Calculated from the initiation of IMRT as primary radiotherapy, survival rates at 1 and 3 years were 95% and 80%. In six patients IMRT was performed as re-irradiation, and survival rate calculated from re-irradiation was 63% at 1 year. Local control rates were 85% at 1, 81% at 2 and 49% at 3 years after primary RT and 50% at 1 year after re-irradiation. Distant metastases-free survival in patients treated with IMRT as primary RT was 83% after 1 and 64% after 3 years. For patients treated as primary irradiation with IMRT, the distant control rate was 83% at 1 year and 0% at 2 years. No severe radiation-induced side-effects could be observed., Conclusion: IMRT for tumors of the paranasal sinuses is associated with very good tumor control rates. Treatment-related acute and long-term toxicity can be minimized as compared to historical results with conventional RT.

Background: The implementation of combined radiochemotherapy (RCHT) with temozolomide (TMZ) has lead to a significant increase in overall survival times in patients with Glioblastoma multiforme (GBM), however, outcome still remains unsatisfactory. The majority of GBMs show an overexpression and/or amplification of the epidermal growth factor receptor (EGFR). Therefore, addition of EGFR-inhibition with cetuximab to the current standard treatment approach with radiotherapy and TMZ seems promising., Methods/design: GERT is a one-armed single-center phase I/II trial. In a first step, dose-escalation of TMZ from 50 mg/m2 to 75 mg/m2 together with radiotherapy and cetuximab will be performed. Should safety be proven, the phase II trial will be initiated with the standard dose of 75 mg/m2 of TMZ. Cetuximab will be applied in the standard application dose of 400 mg/m2 in week 1, thereafter at a dose of 250 mg/m2 weekly. A total of 46 patients will be included into this phase I/II trial. Primary endpoints are feasibility and toxicity, secondary endpoints are overall and progression-free survival. An interim analysis will be performed after inclusion of 15 patients into the main study. Patients' enrollment will be performed over a period of 2 years. The observation time will end 2 years after inclusion of the last patient., Discussion: The goal of this study is to evaluate the safety and efficacy of combined RCHT-immunotherapy with TMZ and cetuximab as first-line treatment for patients with primary GBM.

Purpose: To evaluate the effectiveness and long-term outcome of stereotactic radiosurgery (SRS) for acoustic neuromas (AN)., Patients and Methods: Between 1990 and 2001, we treated 26 patients with 27 AN with SRS. Two patients suffered from neurofibromatosis type 2. Before SRS, a subtotal or total resection had been performed in 3 and in 5 patients, respectively. For SRS, a median single dose of 13 Gy/80% isodose was applied., Results: The overall actuarial 5-year and 10-year tumor control probability in all patients was 91%. Two patients developed tumor progression after SRS at 36 and 48 months. Nineteen patients (73%) were at risk of treatment-related facial nerve toxicity; of these, 1 patient developed a complete facial nerve palsy after SRS (5%). A total of 93% of the lesions treated were at risk of radiation-induced trigeminal neuralgia. Two patients (8%) developed mild dysesthesia of the trigeminal nerve after SRS. The hearing preservation rate in patients with useful hearing before SRS was 55% at 9 years., Conclusion: Stereotactic radiosurgery results in good local control rates of AN and the risk of cranial nerve toxicities is acceptable. As toxicity is lower with fractionated stereotactic radiotherapy, SRS should be reserved for smaller lesions.

Purpose: To evaluate the efficacy of fractionated stereotactic radiotherapy (FSRT) performed as reirradiation in 172 patients with recurrent low- and high-grade gliomas., Patients and Methods: Between 1990 and 2004, 172 patients with recurrent gliomas were treated with FSRT as reirradiation in a single institution. Seventy-one patients suffered from WHO grade 2 gliomas. WHO grade 3 gliomas were diagnosed in 42 patients, and 59 patients were diagnosed with glioblastoma multiforme (GBM). The median time between primary radiotherapy and reirradiation was 10 months for GBM, 32 months for WHO grade 3 tumors, and 48 months for grade 2 astrocytomas. FSRT was performed with a median dose of 36 Gy in a median fractionation of 5 x 2 Gy/wk., Results: Median overall survival after primary diagnosis was 21 months for patients with GBM, 50 months for patients with WHO grade 3 gliomas, and 111 months for patients with WHO grade 2 gliomas. Histologic grading was the strongest predictor for overall survival, together with the extent of neurosurgical resection and age at primary diagnosis. Median survival after reirradiation was 8 months for patients with GBM, 16 months for patients with grade 3 tumors, and 22 months for patients with low-grade gliomas. Only time to progression and histology were significant in influencing survival after reirradiation. Progression-free survival after FSRT was 5 months for GBM, 8 months for WHO grade 3 tumors, and 12 months for low-grade gliomas., Conclusion: FSRT is well tolerated and may be effective in patients with recurrent gliomas. Prospective studies are warranted for further evaluation.

Purpose: To assess the effect of reirradiation in recurrent WHO grade III astrocytomas., Patients and Methods: From January 1995 to July 2003, 40 patients with grade III gliomas were treated with fractionated stereotactic reirradiation at the time point of recurrence. Median size of planning target volume for reirradiation was 56.2 ml (range 25.1-296.2 ml). A median target total dose of 36 Gy (range 20-57.6 Gy) was applied using a median fractionation of 5 x 2 Gy/week with a 6-MeV linear accelerator., Results: Radiotherapy was well tolerated by all patients. No toxicities > CTC grade 2 developed. Median overall survival calculated from the time point of primary diagnosis was 48 months (range 7-180 months). The 5- and 10-year overall survival rates were 49.5% and 24.7%, respectively. From the time point of reirradiation, median survival was 16 months (range 1-98 months). Median progression-free survival from the time point of reirradiation was 8 months (range 1-72 months). No prognosticators for survival or progression-free survival after reirradiation could be identified., Conclusion: Fractionated stereotactic radiotherapy is well tolerated and effective in patients with recurrent grade III astrocytomas.

Background: Radiotherapy (RT) plays a major role in the management of hemangiopericytomas (HAP). The present analysis evaluates the role of precision RT in the management of HAP of the central nervous system (CNS) and represents one of the largest series of HAP treated with RT that can be found in the literature., Methods: Of 37 consecutive patients with histologically confirmed HAP who were treated at the institution between 1984 and 2004, the majority, 25 tumors, was localized within the skull base (n = 25) and 4 tumors were localized at the spine. In 25 patients, high-precision RT was delivered as fractionated stereotactic RT or intensity modulated RT. Median age at primary diagnosis was 40.5 years (range, 10-77 yrs). After primary diagnosis, surgical resection was performed in 23 patients. A median total dose of 54 Gy was delivered in a fractionation of 5 x 1.8-2 Gy per week. The median planning target volume was 58.2 mL (range, 10-412 mL). The median follow-up time was 34 months (range, 3-166 mos)., Results: Radiotherapy was well tolerated by all patients. Seventeen patients of this series remain alive. Overall survival rates at 5 and 10 years are 100% and 64%, respectively. Actuarial survival rates after RT were 85% and 69% at 3 and 5 years, respectively. Progression-free survival after RT 80% and 61% at 3 and 5 years, respectively., Conclusion: High-precision RT is an effective and safe treatment modality for patients with HAP of the CNS and the spine and achieves highly acceptable tumor control, while sparing normal tissue.

Background: This article describes the results of a study of stereotactic radiosurgery (SRS) in the treatment of patients with recurrent malignant glioma., Methods: Thirty-two patients with recurrent glioblastoma multiforme (GBM) were treated for 36 lesions with SRS from 1993 to 2001. Nineteen patients were male and 13 were female. The median age at primary diagnosis of the tumor was 56 years (range, 33-76 yrs). At the time of initial diagnosis a total neurosurgical resection was performed in 7, a subtotal resection in 21, and a biopsy in 4 patients. Histology evaluations revealed glioblastoma multiforme (WHO Grade IV) in all 32 patients. In all patients radiotherapy was performed as the first-line therapy, applied as fractionated external beam radiotherapy. The median interval between primary irradiation and reirradiation was 10 months. The median dose applied was 15 Gy (range, 10-20 Gy) prescribed to the 80% isodose line that encompassed the target volume. No concomitant chemotherapy was applied., Results: Treatment was well tolerated by all patients. No acute toxicities > CTC Grade II occurred. No severe long-term toxicities including radionecrosis were observed. The median follow-up time was 13 months (range, 1-89 mo). All patients died of tumor progression during follow-up. The median overall survival from primary diagnosis of the tumor was 22 months (range, 9-133 mo). The survival rate at 1 year was 90%, and 49% and 26% at 2 and 3 years, respectively. Median overall survival after SRS was 10 months. At 6 and 12 months after SRS, survival rates were 72% and 28%, respectively. Median progression-free survival after SRS was 7 months., Conclusions: SRS offers effective treatment as a salvage therapy for a subgroup of patients with smaller lesions of recurrent GBM., (Copyright 2005 American Cancer Society)

Purpose: To assess the long-term outcome and toxicity of fractionated stereotactic radiotherapy for acoustic neuromas in 106 patients treated in a single institution., Patients and Methods: Between October 1989 and January 2004, fractionated stereotactic radiotherapy (FSRT) was performed in 106 patients with acoustic neuroma (AN). The median total dose applied was 57.6 Gy in median single fractions of 1.8 Gy in five fractions per week. The median irradiated tumor volume was 3.9 mL (range, 2.7-30.7 mL). The median follow-up time was 48.5 months (range, 3-172 months)., Results: Fractionated stereotactic radiotherapy was well tolerated in all patients. Actuarial local tumor control rates at 3- and 5- years after FSRT were 94.3% and 93%, respectively. Actuarial useful hearing preservation was 94% at 5 years. The presence of neurofibromatosis (NF-2) significantly adversely influenced hearing preservation in patients that presented with useful hearing at the initiation of RT (p = 0.00062). Actuarial hearing preservation without the diagnosis of NF-2 was 98%. In cases with NF-2, the hearing preservation rate was 64%. Cranial nerve toxicity other than hearing impairment was rare. The rate of radiation induced toxicity to the trigeminal and facial nerve was 3.4% and 2.3%, respectively., Conclusion: Fractionated stereotactic radiotherapy is safe and efficacious for the treatment of AN, with mild toxicity with regard to hearing loss and cranial nerve function. FSRT might be considered as an equieffective treatment modality compared to neurosurgery and therefore represents an interesting alternative therapy for patients with AN.

Purpose: To assess the feasibility, efficacy and toxicity of fractionated stereotactic radiotherapy in the treatment of recurrent glioblastoma multiforme., Patients and Methods: From January 1995 to July 2003, 53 patients with histologically proven glioblastoma multiforme were treated at recurrence with fractionated stereotactic radiation therapy. A median dose of 36 Gy using a median fractionation of 5 x 2 Gy/week was applied., Results: Median overall survival was 21 months, and median overall survival from the time point of re-irradiation was 8 months. The median time interval between primary and secondary radiation therapy was 10 months. In this patient population, no variables predicting longer overall survival could be determined. However, neurosurgical resection at relapse was associated with increased survival after re-irradiation (p=0.04), but left progression-free survival unaltered. Treatment was well-tolerated and no severe toxicities developed., Conclusion: Stereotactically guided fractionated re-irradiation is a safe and effective treatment modality in selected cases of recurring glioblastoma multiforme. Since this is not a randomized study, further evaluation in larger patient collectives is warranted. Also, based on recent results of radiochemotherapy in the treatment of primary glioblastoma multiforme, concomitant chemotherapy at relapse might be considered in the future.

Purpose: To evaluate the effectiveness and toxicity of fractionated stereotactically guided radiotherapy (FSRT) in the management of optic glioma., Methods and Materials: Fifteen patients with optic pathway gliomas were treated with FSRT at our institution between 1990 and 2003. A median target dose of 52.2 Gy (range, 45.2-57.6 Gy) was applied using a median fractionation of 5 fractions of 1.8 Gy weekly using a linear accelerator., Results: The median follow-up time was 97 months (range, 8-151 months). Of the 15 patients, 1 died of tumor progression during the follow-up period. The progression-free survival rate at 3 and 5 years was 92% and 72%, respectively. The median overall survival after FSRT was 90 months (range, 8-151 months). The 5-year survival rate after FSRT was 90%. We did not observe secondary malignancies., Conclusion: Fractionated stereotactic radiotherapy was safe and well tolerated in all patients. The good tumor control and the potential of sparing normal brain tissue, especially the pituitary gland in lesions involving the optic chiasm, permit effective treatment of patients with optic nerve gliomas. Longer follow-up is needed to assess the incidence of late effects fully.

Purpose: To retrospectively analyze the outcomes and benefits from radiation therapy (RT) as a component of multimodal treatment for oligodendroglioma and oligoastrocytoma, assessing local control and survival rates and evaluating prognostic factors., Methods and Materials: We retrospectively reviewed 56 adult patients with supratentorial oligodendroglioma or oligoastrocytoma treated at our institution from January 1990 to December 2003 with fractionated stereotactic RT (FSRT)., Results: Fractionated stereotactic RT was well tolerated in all patients, without side effects. Median survival and progression-free survival calculated from the initiation of radiotherapy were 48 months (range, 2-133 months) and 38 months (range, 2-132 months), respectively. Progression-free survival rates after radiation were 89% at 1 year and 52% at 5 years. Of 26 recurrences, 92% developed in field. With regard to histology, overall survival rates in the World Health Organization (WHO) Grade II group were 89% and 74% at 5 and 10 years, respectively. In patients with WHO Grade III tumors, overall survival rates at 5 and 10 years were 69% and 46%, respectively. No prognosticators could be identified for median survival and progression-free survival after radiotherapy. Median overall survival calculated from primary diagnosis was 77.5 months (range, 3-214 months). The Cox regression multivariate analysis for age and neurologic symptoms showed a significance of p = 0.003 for age and p = 0.037 for the presence of neurologic symptoms on overall survival since primary diagnosis., Conclusions: Commonly, conventional conformal RT is applied in the treatment of brain tumors. In FSRT, the tumor volume can be irradiated with high doses, sparing volume of normal brain tissue. Our data are in accordance with survival times found in the literature. Ninety-two percent of all recurrences occurred within the defined target volume, confirming that reduction of the RT portals by the use of FSRT does not lead to an increased rate of recurrences at the field border or out of field. Fractionated stereotactic RT can therefore be implemented as an effective and safe modality in the therapy of primary oligodendroglioma and oligoastrocytoma.

Background and Purpose: The role of radiochemotherapy in the treatment of primary glioblastoma multiforme is still discussed controversially. To evaluate the feasibility and toxicity of irradiation and concomitant administration of 50 mg/m(2) temozolomide in patients with primary malignant glioma, this phase I/II study was conducted., Patients and Methods: 53 Patients with histologically confirmed WHO grade IV malignant glioma were enrolled into the study. All patients were treated with radiation therapy up to a total dose of 60 Gy using conventional fractionation of 5 x 2.0 Gy/week. Temozolomide was administered orally each therapy day at a dose of 50 mg/m(2)., Results: Prior to radiochemotherapy, complete resection (n = 14), subtotal resection (n = 22) or a biopsy (n = 17) of the tumor was performed. The median time interval between surgery and radiochemotherapy was 21 days. Treatment-related toxicity was very mild. Acute toxicity > grade 2 was observed in one patient who developed grade 4 hemotoxicity. Minor side effects of chemotherapy included nausea and vomiting. No severe late effects were observed. Median progression-free and overall survival were 8 and 19 months, respectively. The overall survival rate was 72% at 1 and 26% at 2 years. Age and extent of surgery significantly influenced survival., Conclusion: The combination of temozolomide plus radiation therapy is feasible and safe in terms of toxicity. Overall survival times were relatively long compared to survival times reported for radiotherapy alone. The application of 50 mg/m(2) of temozolomide can be performed throughout the whole time course without interruption due to side effects and might largely contribute to the prolonged overall survival. Further evaluation is warranted as to which dose of temozolomide is optimal with regard to tumor response and toxicity.

Purpose: To assess the effectiveness of re-irradiation in recurrent low-grade gliomas (LGG)., Patients and Methods: Sixty-three patients were treated with fractionated stereotactic re-irradiation in the case of recurrent gliomas. At primary diagnosis of the tumor, the histology was grade II astrocytoma, oligodendroglioma or oligoastrocytoma. Fifty-two (82.5%) recurrences were in-field, three (4.8%) were localized at the field border, and eight (12.7%) tumors were localized completely out-field of the former RT field, respectively. Using three to four irregular non-coplanar fields formed with a multi-leaf-collimator, we applied a median total dose of 36 Gy (range 15-62 Gy)with a weekly fractionation of 5 x 2 Gy/week depending on the size and the location of the lesion. No concomitant chemotherapy was applied., Results: Radiation was well tolerated by all patients. No severe side effects occurred. Median overall survival was 111 months (range 12-240 months). Extent of neurosurgical resection significantly influenced overall survival (P = 0.02). Median interval between the first radiation therapy and re-irradiation was 50 months (range 5-204 months). From the time point of re-irradiation, median survival was 23 months. Median progression-free survival from the time point of re-irradiation was 12 months (range 2-63 months). No prognosticators could be identified for survival from re-irradiation and progression free survival., Conclusion: Our retrospective data suggest that stereotactically guided fractionated re-irradiation in recurrent glioma represents an effective treatment option with good results and few complications. However, further investigation is warranted to consolidate these results and to combine radiation with chemotherapy in the case of recurrent LGG.

In the framework of the European Network for Research in Light Ion Hadron Therapy (ENLIGHT), the health economics group develops a methodology for assessing important investment and operating costs of this innovative treatment against its expected benefits. The main task is to estimate the cost per treated patient. The cost analysis is restricted to the therapeutic phase from the hospital point of view. An original methodology for cost assessment per treatment protocol is developed based on standard costs. Costs related to direct medical activity are based on the production process analysis, whereas indirect and non direct medical costs are allocated to each protocol using relevant cost-drivers. The resulting cost model will take into account the specificities of each therapeutic protocol as well as the particularities of each of the European projects.

Background and Purpose: The role of stereotactic radiosurgery (SRS) alone or in combination with whole brain radiotherapy (WBRT) in the treatment of cerebral metastases from breast carcinoma is discussed controversially. To elucidate the role of SRS in this context, a retrospective study evaluating the benefit of SRS and prognostic factors for survival was performed., Patients and Methods: From 1986 to 2003, 62 patients with cerebral metastases from breast cancer were treated for 103 lesions. Ten patients received SRS alone (group 1), 13 patients were treated with WBRT and SRS as a focal boost (group 2), and 39 patients received WBRT and salvage SRS (group 3) for recurrent metastases at a later time point., Results: Survival was increased in patients receiving SRS only compared to WBRT and SRS as a focal boost. Patients < 40 years of age had a favorable outcome (p > 0.04). However, no other prognostic factors could be identified. Overall tolerance of radiation was acceptable. Median local control intervals were 9 months for all patients, 6.5 months in group 1, 4 months in group 2, and 9 months in group 3, respectively. There were no significant intergroup differences., Conclusion: SRS alone is an effective treatment for patients with one to three brain metastases from breast cancer. A randomized trial should be performed to evaluate whether WBRT is a necessary component in the primary treatment of these patients. Salvage SRS is an effective therapy option after WBRT.

Efforts have been made to extend the application of intensity-modulated radiotherapy to a variety of organs. One of the unanswered questions is whether breathing-induced organ motion may lead to a relevant over- or underdosage, e.g., in treatment plans for the irradiation of lung cancer. Theoretical considerations have been made concerning the different kinds of IMRT but there is still a lack of experimental data. We examined 18 points in a fraction of a clinical treatment plan of a NSCLC delivered in static IMRT with a new phantom and nine ionization chambers. Measurements were performed at a speed of 12 and 16 breathing cycles per minute. The dose differences between static points and moving target points ranged between -2.4% and +5.5% (mean: +0.2%, median: -0.1%) when moving with 12 cycles min(-1) and between -3.6% and +5.0% (mean: -0.4%, median: -0.6%) when moving with 16 cycles min(-1). All differences of measurements with and without movements were below 5%, with one exception. In conclusion, our results underline that at least in static IMRT breathing effects (concerning target dose coverage) due to interplay effects between collimator leaf movement and target movement are of secondary importance and will not reduce the clinical value of IMRT in the step-and-shoot technique for irradiation of thoracic targets.

Adrenal chromaffin cells and sympathetic neurons are related, but phenotypically distinct derivatives of the neural crest. Molecular cues that determine the chromaffin cell phenotype have not yet been identified; in contrast to a widely held belief, glucocorticoid signaling is apparently not relevant (Development 126 (1999) 2935). Transforming growth factor-betas (TGF-betas) regulate various aspects of embryonic development and are expressed in the environment of sympathoadrenal (SA) progenitor cells. We have previously shown that neutralization of endogenous TGF-beta from E4 to E8 in the quail embryo significantly increases numbers of adrenal tyrosine hydroxylase-positive cells. Whether endogenous TGF-beta may also be involved in influencing phenotypic development of adrenal chromaffin cells and their SA progenitors has not been analyzed. We now demonstrate that neutralization of endogenous TGF-beta1, -beta2 and -beta3 with a pan-anti-TGF-beta antibody in quail embryos during distinct time windows does not alter phenotypic development of chromaffin cells. In situ hybridizations revealed unaltered expression of neurofilament (NF-160), synaptotagmin I and neurexin I in adrenal glands. Likewise, the NF-associated antigen 3A10, and polyphosphorylated NF epitopes (RT 97) were unaltered. Most importantly, the typical ultrastructure of adrenal chromaffin cells including their large chromaffin secretory granules, a hallmark of the neuroendocrine phenotype, which distinguishes them from sympathetic neurons, was not affected. We therefore conclude that neutralization of endogenous TGF-beta influences chromaffin cell proliferation, but does not interfere with the development of the typical chromaffin cell phenotype.

Chromaffin cells and sympathetic neurons are derivatives of the sympathoadrenal cell lineage of the neural crest. Although they are similar with respect to many cell biological aspects, chromaffin cells, in contrast to sympathetic neurons, continue to synthesize DNA and proliferate through their whole life span. Large numbers of neural and hormonal signals have been implicated in the regulation of chromaffin cell proliferation based on in vitro studies. We have previously shown that chromaffin cells synthesize and release transforming growth factor-beta (TGF-beta) and that exogenously applied TGF-beta suppresses chromaffin cell proliferation in vitro. We show now that TGF-beta is also a physiologically relevant factor in the control of cell division in developing chromaffin cells. We have neutralized endogenous TGF-beta in quail embryos using a monoclonal antibody recognizing all three TGF-beta isoforms, TGF-beta1, -beta2, and -beta3. Embryos deprived of TGF-beta show a prominent increase in numbers of tyrosine hydroxylase (TH)-immunoreactive adrenal chromaffin cells and TH-positive cells incorporating 5'-bromo-2'deoxyuridine. This is the first documentation of the physiological significance of a factor that has been suggested to play a role in the regulation of chromaffin cell mitosis based on in vitro experiments., (Copyright 2000 Wiley-Liss, Inc.)