Genome-wide Rules of Nucleosome Phasing in Drosophila.

Regular successions of positioned nucleosomes, or phased nucleosome arrays (PNAs), are predominantly known from transcriptional start sites (TSSs). It is unclear whether PNAs occur elsewhere in the genome. To generate a comprehensive inventory of PNAs for Drosophila, we applied spectral analysis to nucleosome maps and identified thousands of PNAs throughout the genome. About half of them are not near TSSs and are strongly enriched for an uncharacterized sequence motif. Through genome-wide reconstitution of physiological chromatin in Drosophila embryo extracts, we uncovered the molecular basis of PNA formation. We identified Phaser, an unstudied zinc finger protein that positions nucleosomes flanking the motif. It also revealed how the global activity of the chromatin remodelers CHRAC/ACF, together with local barrier elements, generates islands of regular phasing throughout the genome. Our work demonstrates the potential of chromatin assembly by embryo extracts as a powerful tool to reconstitute chromatin features on a global scale in vitro.

Active promoters give rise to false positive 'Phantom Peaks' in ChIP-seq experiments.

Chromatin immunoprecipitation (ChIP) is widely used to identify chromosomal binding sites. Chromatin proteins are cross-linked to their target sequences in living cells. The purified chromatin is sheared and the relevant protein is enriched by immunoprecipitation with specific antibodies. The co-purifying genomic DNA is then determined by massive parallel sequencing (ChIP-seq).We applied ChIP-seq to map the chromosomal binding sites for two ISWI-containing nucleosome remodeling factors, ACF and RSF, in Drosophila embryos. Employing several polyclonal and monoclonal antibodies directed against their signature subunits, ACF1 and RSF-1, robust profiles were obtained indicating that both remodelers co-occupied a large set of active promoters.Further validation included controls using chromatin of mutant embryos that do not express ACF1 or RSF-1. Surprisingly, the ChIP-seq profiles were unchanged, suggesting that they were not due to specific immunoprecipitation. Conservative analysis lists about 3000 chromosomal loci, mostly active promoters that are prone to non-specific enrichment in ChIP and appear as 'Phantom Peaks'. These peaks are not obtained with pre-immune serum and are not prominent in input chromatin.Mining the modENCODE ChIP-seq profiles identifies potential Phantom Peaks in many profiles of epigenetic regulators. These profiles and other ChIP-seq data featuring prominent Phantom Peaks must be validated with chromatin from cells in which the protein of interest has been depleted.

Different chromatin interfaces of the Drosophila dosage compensation complex revealed by high-shear ChIP-seq.

Transcriptional enhancement of X-linked genes to compensate for the sex chromosome monosomy in Drosophila males is brought about by a ribonucleoprotein assembly called Male-Specific-Lethal or Dosage Compensation Complex (MSL-DCC). This machinery is formed in male flies and specifically associates with active genes on the X chromosome. After assembly at dedicated high-affinity "entry" sites (HAS) on the X chromosome, the complex distributes to the nearby active chromatin. High-resolution, genome-wide mapping of the MSL-DCC subunits by chromatin immunoprecipitation (ChIP) on oligonucleotide tiling arrays suggests a rather homogenous spreading of the intact complex onto transcribed chromatin. Coupling ChIP to deep sequencing (ChIP-seq) promises to map the chromosomal interactions of the DCC with improved resolution. We present ChIP-seq binding profiles for all complex subunits, including the first description of the RNA helicase MLE binding pattern. Exploiting the preferential representation of direct chromatin contacts upon high-energy shearing, we report a surprising functional and topological separation of MSL protein contacts at three classes of chromosomal binding sites. Furthermore, precise determination of DNA fragment lengths by paired-end ChIP-seq allows decrypting of the local complex architecture. Primary contacts of MSL-2 and MLE define HAS for the DCC. In contrast, association of the DCC with actively transcribed gene bodies is mediated by MSL-3 binding to nucleosomes. We identify robust MSL-1/MOF binding at a fraction of active promoters genome-wide. Correlation analyses suggest that this association reflects a function outside dosage compensation. Our comprehensive analysis provides a new level of information on different interaction modes of a multiprotein complex at distinct regions within the genome.

Fractionated stereotactic radiotherapy in patients with benign or atypical intracranial meningioma: long-term experience and prognostic factors.

PURPOSE: To analyze our long-term experience and prognostic factors after fractionated stereotactic radiotherapy (FSRT) in patients with benign or atypical intracranial meningioma. METHODS AND MATERIALS: Between January 1985 and December 2001, 317 patients with a median age of 55.7 years were treated with FSRT for intracranial meningioma. The tumor distribution was World Health Organization (WHO) Grade 1 in 48.3%, WHO Grade 2 in 8.2%, and unknown in 43.5%. Of the 317 patients, 97 underwent RT as their primary treatment, 79 underwent postoperative RT (subtotal resection in 38 and biopsy only in 41), and 141 were treated for recurrent disease. The median target volume was 33.6 cm(3) (range, 1.0-412.6 cm(3)). The median total dose was 57.6 Gy at 1.8 Gy/fraction five times weekly. RESULTS: The median follow-up was 5.7 years (range, 1.2-14.3 years). The overall local tumor control rate was 93.1% (295 of 317). Of the 317 patients, 72 had a partial response on CT/MRI and 223 (70.4%) remained stable. At a median of 4.5 years after FSRT, 22 patients (6.9%) had local tumor progression on MRI. Local tumor failure was significantly greater in patients with WHO Grade 2 meningioma (p <0.002) than in patients with WHO Grade 1 or unknown histologic features. Patients treated for recurrent meningioma showed a trend toward decreased progression-free survival compared with patients treated with primary therapy, after biopsy, or after subtotal resection (p <0.06). Patients with a tumor volume >60 cm(3) had a recurrence rate of 15.5% vs. 4.3% for those with a tumor volume of < or =60 cm(3) (p <0.001). In 42.9% of the patients, preexisting neurologic deficits improved. Worsening of preexisting neurologic symptoms occurred in 8.2%. Eight patients developed new clinical symptoms, such as reduced vision, trigeminal neuralgia, and intermittent tinnitus located at the side of the irradiated meningioma after FSRT. CONCLUSION: These data have demonstrated that FSRT is an effective and safe treatment modality for local control of meningioma with a low risk of significant late toxicity. We identified the tumor volume, indication for FSRT, and histologic features of the meningioma as statistically significant prognostic factors.

Treatment outcome after linac-based radiosurgery in cerebral arteriovenous malformations: retrospective analysis of factors affecting obliteration.

PURPOSE: We investigated patient outcome and factors affecting obliteration rate after radiosurgery in cerebral arteriovenous malformations (AVM). MATERIAL AND METHODS: We have treated 110 patients with cerebral AVM with linac-based radiosurgery (RS). AVM classification according Spetzler-Martin was 17 patients grade I (15%), 39 grade II (36%), 41 grade III (37%), 12 grade IV (11%) and 1 grade V (1%). Median single dose was 18 Gy. Mean treatment volume was 4.7 cc (range, 0.1-24.0 cc). Fifty-two patients experienced hemorrhage prior to RS. Median follow-up was 2.5 years. RESULTS: Actuarial complete obliteration rate (CO) was 51% after 3 years and 67% after 4 years. CO rate was significantly higher in AVM <3 cm (64% vs. 43%, P<0.04) and in patients with grade I/II vs. III-V (71% vs. 33%, P<0.001). CO was significantly improved after doses >18 Gy (P<0.02) and in male gender (P<0.04). In multivariate analysis Spetzler-Martin grade remained significant. Intracranial hemorrhage after RS occurred in 9 patients 13.9 months median after RS. Neurological dysfunction improved/completely dissolved or remained stable in 95% of patients. No new onset of neurological dysfunction was seen. No significant adverse effects after RS were seen. CONCLUSIONS: The rate of obliteration after RS in AVM depends on applied single dose as well as size and Spetzler-Martin grade. RS is an alternative to neurosurgery, especially in patients with small or surgically inaccesible AVM.

External beam radiotherapy in the treatment of male breast carcinoma: patterns of failure in a single institute experience.

AIMS AND BACKGROUND: We analyzed our own results in the treatment of male breast cancer patients with respect to local control, overall survival and possible prognostic factors for local and distant control. METHODS: Thirty-one patients with 32 carcinomas of the male breast were treated with radiotherapy. Twenty-five patients received radiotherapy to the chest wall including or not regional lymphatics after initial mastectomy (n = 23) or after surgery for local recurrence (n = 2). Median total dose was 60 Gy to the chest wall and 46 Gy to regional lymphatics. Seven patients with metastatic disease were referred for palliative radiotherapy. RESULTS: Overall survival after postoperative radiotherapy was 40% after a median follow-up of 4.3 years. Actuarial 3-, 5- and 10-year survival was 82.6%, 56.5% and 43.5%, respectively. Five-year progression-free survival was 62.5%. Survival was significantly affected by the presence of lymph node metastases (P <0.001). Local recurrence was seen in one patient after 29 months. CONCLUSIONS: Postoperative radiotherapy is important in the management of male breast cancer to improve local control and progression-free survival, resulting in one local failure in our analysis. The presence of lymph node metastases significantly impairs survival.

Clinical results of retreatment of vertebral bone metastases by stereotactic conformal radiotherapy and intensity-modulated radiotherapy.

PURPOSE: Reirradiation of spinal tumors is limited by the tolerance of the spinal cord. We evaluated local control, pain relief, neurologic improvement, side effects, and survival rates after fractionated conformal radiotherapy (FCRT) and intensity-modulated RT (IMRT) of recurrent spinal metastases. METHODS AND MATERIALS: Eighteen patients with 19 radiologic manifestations were retreated for recurrent spinal metastases using FCRT (n = 5) or IMRT (n = 14). All patients had previously undergone conventional RT (median dose 38 Gy). The indication for reirradiation was tumor progression associated with pain (n = 16) or neurologic symptoms (n = 12). The median time to recurrence was 17.7 months. The median total dose for reirradiation was 39.6 Gy. RESULTS: The overall local control rate was 94.7% after a median follow-up of 12.3 months. Of 16 patients with pain, 13 experienced significant relief after reirradiation. Neurologic improvement was obtained in 5 of 12 patients. Tumor size remained unchanged in 84.2%. A partial response was seen in 2 of 19 patients. One patient had local tumor progression 9.5 months after reirradiation. Six patients received chemotherapy after reirradiation because of progressive distant metastases. Twelve patients died 10.5 months median after reirradiation. No clinically significant late toxicity was seen after FCRT or IMRT. CONCLUSION: These data demonstrate that FCRT and IMRT are effective and safe in recurrent spinal tumors and can be offered to patients to achieve local control, as well as pain relief.

Fractionated stereotactic conformal radiotherapy in the management of large chemodectomas of the skull base.

PURPOSE: To evaluate the role of fractionated stereotactic conformal radiotherapy (FSRT) as a noninvasive method in the management of large chemodectomas of the skull base. METHODS AND MATERIALS: Twenty-two patients with chemodectomas of the skull base were treated with FSRT at our institution. Ten patients received primary RT, and 12 patients were treated for recurrent or progressive disease after primary surgery (8 patients) or embolization (4 patients). The median total dose was 57.6 Gy, with a median of 1.8 Gy/fraction. The median target volume was 71.8 cm3 (range, 10.5-212.2 cm3). The most common symptoms at the initial diagnosis were pulsatile tinnitus (16 patients), hearing loss (14 patients), and balance disturbance (14 patients). Twelve patients had additional cranial nerve deficits. RESULTS: The median follow-up was 5.7 years (range, 19-177 months). The actuarial overall survival rate was 89.5% at 5 and 10 years. The actuarial local control rate was 90.4% at 5 and 10 years. Seven patients (32%) had a partial response and 13 (59%) had stable disease of the irradiated chemodectoma. Two symptomatic patients developed recurrence after 19 and 32 months. Neurologic dysfunction improved or completely resolved in 59% and stabilized in 32%; 9% of patients experienced impairment of preexisting neurologic dysfunction. No patient developed new neurologic deficits after FSRT. RT was interrupted in 1 patient because of a maxillary bone abscess. In all other patients, no acute or late adverse reactions greater than Common Toxicity Criteria Grade 2 were seen. CONCLUSION: Fractionated stereotactic conformal radiotherapy is an effective and well-tolerated noninvasive treatment for chemodectomas, with excellent tumor control rates and a low risk of morbidity. It is an option for patients at greater risk of microsurgical resection or with residual and recurrent tumors.

Stereotactic conformal radiotherapy in patients with growth hormone-secreting pituitary adenoma.

PURPOSE: To evaluate the reduction of hormonal overproduction and side effects as well as survival rates after fractionated stereotactic conformal radiotherapy (FSRT) and radiosurgery in patients with growth hormone (GH)-secreting pituitary adenoma. METHODS AND MATERIALS: Between January 1989 and May 2001, 25 consecutive patients were treated with FSRT (n = 20) or radiosurgery (n = 5) for GH-secreting pituitary adenoma. Nine patients were treated for recurrent disease after primary surgery. One patient had primary radiotherapy because of inoperability, and 15 patients received radiotherapy after subtotal resection due to increased GH level. Median total dose was 52.2 Gy for FSRT and 15 Gy for radiosurgery. RESULTS: Radiologic local tumor control was 100% after a median follow-up of 59.8 months (range, 20.3-168.2 months). Seventeen patients had stable disease on CT/MRI, and eight showed a reduction of tumor volume on MRI scans. Endocrinologic control was 92% (23 of 25 patients). Two patients had an endocrinologic recurrence 21 and 54 months after FSRT. A normalization of preexisting acromegalic symptoms was seen in 1 patient, 4.5 years after FSRT. GH level normalized in 21 of 25 patients after 26 months median. Five of these patients underwent concurrent Octreotid therapy because of increased insulin-like growth factor I levels. Improvement of visual acuity was seen in 1 patient. New onset of clinically evident hypopituitarism as an adverse reaction of stereotactic radiotherapy was only infrequently observed in this series. CONCLUSION: Stereotactic conformal radiotherapy is effective and safe in the treatment of GH-secreting pituitary adenoma to reduce hormonal overproduction and to improve local control. It is an alternative option to surgery especially for patients at high risk of surgical complications due to comorbidity.

Treatment of brain metastases from non-small-cell lung cancer (NSCLC): radiotherapy.

Brain metastases occur frequently in lung-cancer patients and are associated with a crucial decrease in prognosis and impairment of Life quality. With improved treatment and earlier diagnosis of primary tumour as well as earlier detection of lesions due to improved neuroradiological diagnosis the incidence is apparently increasing. Whole-brain radiation therapy (WBRT) prolongs median survival from 1 to 3-6 months. One-year survival rate after WBRT is approximately 10-20%. Neurological function could be improved with minimal morbidity. However, long-term survival is observed in patients with favourable prognostic factors like controlled primary tumour site, no extracranial disease, good performance status and age <60 years. In these patients individually optimised aggressive treatment strategies are clearly justified. Surgical resection or radiosurgery (RS) combined with adjuvant WBRT prolong survival to approximately 8-11 months. Surgical resection is preferred when rapid relief of increased intracranial pressure is required. The incidence of new brain metastases is low in patients with poor prognostic factors. Palliative RS could be used in these patients to rapidly improve neurological deficits. In locally advanced NSCLC radiosurgery may be used to effectively control brain disease without delay in treatment of the primary tumour site. The role of prophylactic ("elective") cranial irradiation in NSCLC patients as well as the role of combined radiochemotherapy for brain metastases has to be addressed in further clinical trials in the future.

Treatment of brain metastases in patients with non-small cell lung cancer (NSCLC) by stereotactic linac-based radiosurgery: prognostic factors.

A restrospective study of patients with brain metastases from non-small cell lung cancer (NSCLC) is performed to identify patients who benefit from radiosurgery and to determine prognostic factors for survival. Eighty-six consecutive patients with a total of 110 brain metastases from NSCLC were treated with linac-based radiosurgery. Six patients with eight brain metastases who received radiosurgery as a focal boost to whole brain radiotherapy where excluded. Median age at treatment was 60 years. Median dose was 20 Gy/80%-isodose. A chi(2)-test was used to identify potential prognostic factors for local control of brain metastases and survival of the patients. Median follow-up was 6 months (range 1 1/2-77 months) with 17/80 patients still alive. Median actuarial survival was significantly longer (P<0.004) in patients with metachronous onset of brain metastases in comparison to synchronous onset (8.3 vs. 3.3 months). Survival was significantly increased after radiosurgery in the absence of extracranial tumor progression (P<0.03). Eleven patients (14%) developed new brain metastases after radiosurgery after a latency of median 5 months. Actuarial local control rate was 96% after 3 months. Local control was significantly increased with a prescribed dose > or=18 Gy/80%-isodose (P<0.01). We conclude that especially patients with poor prognostic factors and a limited number of brain metastases may be palliatively treated with radiosurgery alone. This approach allows to effectively control CNS manifestation of the disease and can be integrated into chemotherapeutic protocols.

Intensity-modulated radiotherapy of the female breast.

Current methods for intensity-modulated radiotherapy (IMRT) in breast cancer use forward planning based on equivalent radiological path length to design intensity modulated tangential beams. Compared to conventional tangential techniques, dose reduction of organs at risk is limited using these techniques. We developed a method for intensity modulation of multiple beams for adjuvant radiotherapy of breast cancer by application of a virtual bolus defined on CT for inverse optimization. This method enables multibeam IMRT, which provides improved sparing of lung and heart tissue. In this paper, we present the general aspects of this approach and an evaluation of the optimum beam configuration for IMRT based on inverse treatment planning. We compared this method to conventional techniques. Different clinical examples illustrate the possible indications and feasibility of this new approach. This method is superior to conventional techniques because of the reduction of high-dose area of a substantial cardiac volume in those cases where the parasternal lymph nodes are part of the target volume.

Human glioblastoma and carcinoma xenograft tumors treated by combined radiation and imatinib (Gleevec).

BACKGROUND AND PURPOSE: Imatinib (Gleevec, Glivec) is an inhibitor of alpha- and beta-platelet-derived growth factor receptors and other tyrosine kinases, that are also associated with the function of growth factors. Imatinib has been approved for the treatment of chronic myelogenous leukemia and gastrointestinal stromal tumors and is under investigation for the therapy of several other malignant tumors. Since radiotherapy is an important treatment option in many tumors, combined effects of imatinib and radiation were analyzed here. MATERIAL AND METHODS: In vitro, U87 cells (human glioblastoma), A431 cells (human epidermoid carcinoma), and HUVECs (human umbilical venous endothelial cells) were treated with imatinib alone and in combination with radiation. Clonogenic survival and cell proliferation were determined with and without additional radiation (0-10 Gy). In vivo, U87 and A431 cells (5 x 10(6)) were subcutaneously injected into hind limbs of balb c nu/u mice. Drug and radiation treatments started on day 0 when tumor volumes were approximately 400-500 mm(3). Tumors were treated with 5 x 5 Gy (U87) or 6 x 5 Gy (A431) on consecutive days from day 0. Imatinib was administered orally via the mouse diet starting on day 0 until the end of observation. Tumor growth and microvessel density (CD31 IHC) were analyzed. RESULTS: In vitro, imatinib increased radiosensitivity of U87 and A431 tumor cells as well as HUVECs in both clonogenic and cell number/proliferation assays. The enhancement of radiosensitivity in HUVECs was comparable to that observed in the tumor cells. In vivo, the concurrent and continuous administration of imatinib increased tumor growth delay of fractionated radiotherapy in the carcinoma and the glioblastoma models at reduced microvessel densities. No apparent additional toxicity by the combination of radiation and imatinib versus monotherapies was observed in terms of weight, skin, or general behavior. CONCLUSION: Imatinib (Gleevec), a "molecular targeted" approved drug for human malignancies, can enhance the tumor growth reduction induced by fractionated radiotherapy in glioblastoma and carcinoma models. The data provides a rationale to further investigate the combination.

Intensity-modulated radiotherapy of sacral chordoma--a case report and a comparison with stereotactic conformal radiotherapy.

In a case of partially resected sacral chordoma, the planning target volume (PTV) received 60 Gy and the gross target volume (GTV) 72 Gy using inversely planned, intensity-modulated, radiation therapy (IMRT). IMRT was compared with 3D-conformal radiotherapy (CRT). With IMRT, it was found that dose distribution is more homogeneous within the PTV outside the GTV and allows simultaneous dose escalation within the GTV. The volume of bowel receiving a dose higher than 40 Gy was reduced from 400 cc with CRT to 220 cc with IMRT. If particle therapy is not available, IMRT seems to be a promising alternative in the treatment of sacral chordomas.

[Inversely planned intensity modulated radiotherapy for irradiation of a woman with breast cancer and funnel chest]. / Invers geplante intensitätsmodulierte Strahlenbehandlung bei einer Patientin mit rechtsseitigem Mammakarzinom und Trichterbrust.

BACKGROUND: A 44-year old woman with breast cancer was transferred to our institution for irradiation. Due to a pronounced funnel chest no satisfying dose distribution was obtained by conventional techniques. Thus an intensity-modulated radiotherapy (IMRT) based on inverse optimisation was carried out. IMRT was compared to conventional techniques regarding dose distribution and feasibility. PATIENT AND METHODS: Tumor site was in the right middle lower quadrant. Target volume included the right breast and the parasternal lymph nodes. Target dose was 50.4 Gy. Based on inverse optimisation irradiation was carried out in "step-and-shoot"-technique with twelve intensity modulated beams with six intensity steps. Additionally, treatment plans were calculated using conventional techniques (technique A with two tangential wedged 6-MV photon beams, technique B with additional oblique 15-MeV electron portal). We analysed conformality and homogeneity of target volume and dose distribution within normal tissue. RESULTS: Dose conformality was substantially improved by IMRT. Dose homogeneity was slightly decreased compared to technique A. Lung volume irradiated with a dose higher than 20 Gy was reduced from 56.8% with technique A and 40.1% with technique B, respectively to 22.1% with IMRT. Treatment was tolerated well by the patient without relevant side effects. Mean treatment time was 19.5 min. CONCLUSION: The inversely planned IMRT using multiple beam directions is suitable for breast irradiation following breast conserving surgery. In the present case of a woman with funnel chest lung dose was substantially reduced without reduction of target dose. In which was the complex treatment technique leads to a clinically detectable advantage is examined at present, in the context of a study.

Number and orientation of beams in inversely planned intensity-modulated radiotherapy of the female breast and the parasternal lymph nodes.

Intensity-modulated radiotherapy (IMRT) provides better sparing of normal tissue. We evaluated the optimum beam configuration for IMRT based on inverse treatment planning in adjuvant radiotherapy for breast cancer in a case of left-sided tumor. In addition to radiotherapy planning with the conventional technique of tangential wedged 6-MV photon beams and an oblique 15-MeV electron beam, we performed inversely planned IMRT with the step-and-shoot-technique. Dose calculation was carried out using the treatment planning system Virtuos with the inverse optimization module KonRad adapted to it. IMRT plans were generated for 2 to 16 beams. The results were compared with conventional techniques. For a maximum treatment time of 20 minutes, it is shown that IMRT with 12 modulated photon beams and 7 intensity steps is best suited for treatment in the presented case. Compared with a conventional technique with photons combined with electrons, dose conformality and homogeneity of the planning target volume was increased. The mean heart dose was reduced from 9.1 Gy to 6.1 Gy. The volume of heart irradiated with a dose higher than 30 Gy was reduced from 7.6% to 1.9%, and the volume of the left lung from 13.6% to 11.5% as well. Inverse optimization for IMRT with multiple beams is feasible in the adjuvant treatment of breast cancer. Because of the reduction of the high-dose area of a substantial cardiac volume, it is superior to conventional techniques in cases where the parasternal lymph nodes should be integrated into the target volume. Here, a clinical advantage might be detectable.

[Virtual bolus for inversion radiotherapy planning in intensity-modulated radiotherapy of breast carcinoma within the scope of adjuvant therapy]. / Virtueller Bolus zur inversen Bestrahlungsplanung bei intensitätsmodulierter Radiotherapie des Mammakarzinoms im Rahmen der adjuvanten Therapie.

BACKGROUND: Intensity modulated radiotherapy (IMRT) provides better sparing of normal tissue. We investigated the feasibility of inverse treatment planning for IMRT in adjuvant radiotherapy for breast cancer. MATERIAL AND METHODS: In addition to radiotherapy planning in conventional technique with tangential wedged 6-MV-photon beams we performed inversely planned IMRT (KonRad). In the CT scans for treatment planning we defined a 10-mm bolus of -60 HE density. The influence of this bolus on planning optimization was determined by optimization without and dose calculation with and without bolus. Dose calculation after dose optimization with bolus was performed using different bolus thickness to determine the influence of the bolus on dose calculation. The results were compared with dose distribution in conventional technique. RESULTS: Inverse optimization with a dose algorithm which considers tissue inhomogeneity results in unintended dose increase at the patient surface. With a virtual 10-mm bolus used for inverse optimization the dose increase was reduced. Thus, skin sparing was identical to conventional planning. The relative dose distribution was negligibly affected by the use of a 10-mm bolus. Difference in absolute dose was 3.4% compared to calculation without bolus. Therefore, the bolus must be removed before final dose calculation. CONCLUSION: The realization of inverse optimization for IMRT of the breast requires the use of a virtual bolus. Thereby, IMRT in accordance to the consensus recommendations of the EORTC, BCCG and EUSOMA is possible. Especially, the same target definition as in conventional technique may be used. IMRT techniques with a conventional beam arrangement of two tangential fields or multiple beam techniques can be realized.

Results of three-dimensional stereotactically-guided radiotherapy in recurrent medulloblastoma.

PURPOSE: To evaluate survival rates and side effects after stereotactically-guided radiotherapy (SRT) in patients with recurrent medulloblastoma of the brain. METHODS AND MATERIALS: Between 1992 and 2000, 20 patients with 29 radiological manifestations were treated with fractionated SRT (n = 21) or radiosurgery (n = 8). Median age was 16 years with 6 patients < or = 14 years. All patients had prior cranio-spinal radiotherapy plus boost to the posterior fossa with a total dose of 54 Gy. Time to recurrence was 33 months mean. Eighteen of the 29 lesions were located within the boost volume. Chemotherapy was given according to current international study protocols (HIT) in all patients. Mean total dose for re-irradiation was 24 Gy for fractionated stereotactically-guided radiotherapy, and 15 Gy for radiosurgery. Mean follow-up was 88.5 months. RESULTS: Overall local control was 89.7%. Thirteen recurrences showed partial or complete response in CT/MR-imaging, 13 showed stable disease. Local tumor progression was seen 5 months mean after radiotherapy in three cases. A multifocal intracranial progression was seen in 9 patients, 5 patients developed additional spinal metastases. Thirteen patients died with disseminated cranio-spinal progression, after 72.6 months median. No late toxicity > CTC II(o) especially no brain radionecrosis was seen after radiotherapy. CONCLUSION: SRT is effective and safe in the treatment of recurrent medulloblastoma to improve local control without evident side effects. The main problem remains the control of subclinical cranio-spinal dissemination.

The role of stereotactically guided conformal radiotherapy for local tumor control of esthesioneuroblastoma.

BACKGROUND: In a retrospective analysis we compared conventional radiotherapy and stereotactically guided conformal radiotherapy (SCRT) in patients with esthesioneuroblastoma. PATIENTS AND METHODS: Between 1991 and 1999 14 patients with esthesioneuroblastoma underwent radiotherapy at our institution. Median follow-up was 30 months (range 12-107 months). Treatment included adjuvant radiotherapy (9), adjuvant radiochemotherapy (3) or radiotherapy alone (2). Eight patients received SCRT with 3-D treatment planning. For comparison a standard three-field plan for these patients and dose-volume histogram analyses were performed. Median total dose was 64 Gy using SCRT and 56 Gy with standard technique. RESULTS: Local tumor control rate was 50% with conventional radiotherapy and 75% with SCRT. Overall survival was 33.3% and 62.5%, respectively. Target coverage could be improved statistically significant (p < 0.05) and dose to critical structures was reduced using SCRT. Greatest differences were seen regarding volume above the 30%-isodose as well as mean dose of brain stem (p < 0.05). A reduction of maximum dose was seen using SCRT as consequence of a more homogeneous treatment. CONCLUSIONS: SCRT improves target coverage and sparing of organs at risk. Our clinical data although with low patient numbers suggest that the technical advantage translates into a clinical advantage. The use of SCRT appears to facilitate higher dose prescriptions without risking major acute and late side effects. Thus the risk of complications in this area is minimized. Adjuvant radiotherapy is a save and effective treatment modality for local control of esthesioneuroblastoma.