Directional DBS leads show large deviations from their intended implantation orientation.

OBJECTIVE: Lead orientation is a new degree of freedom with directional deep brain stimulation (DBS) leads. We investigated how prevalent deviations from the intended implantation direction are in a large patient cohort. METHODS: The Directional Orientation Detection (DiODe) algorithm to determine lead orientation from postoperative CT scans was implemented into the open-source Lead-DBS toolbox. Lead orientation was analyzed in 100 consecutive patients (198 leads). Different anatomical targets and intraoperative setups were compared. RESULTS: Deviations of up to 90° from the intended implantation direction were observed. Deviations of more than 30° were seen in 42% of the leads and deviations of more than 60° in about 11% of the leads. Deviations were independent from the neuroanatomical target and the stereotactic frame but increased depending on which microdrive was used. DISCUSSION: Our results indicate that large deviations from the intended implantation direction are a common phenomenon in directional leads. Postoperative determination of lead orientation is thus mandatory for investigating directional DBS.

[Computer-controlled high-precision radiation]. / Computergesteuerte Hochpräzisionsbestrahlung.

The irradiation of tumors in the brain is challenging due to the proximity of radiation sensitive critical structures and the tumors to be treated. In addition, irradiation above a certain level can cause irreversible damage to nerve tissue. The irradiation of benign and malignant brain tumors requires precise techniques to preserve critical structures while simultaneously administering a high radiation dose for maximum effectiveness. Therefore, stereotaxy, as a subspecialty of neurosurgery, has developed various irradiation techniques, e. g., intracerebral application of interstitial brachytherapy (SBT; stereotactic brachytherapy) and stereotactic radiosurgery (SRS). Due to the development of computer-controlled radiation techniques (e. g., Cyberknife) over the last 20 years, SRS has gained increasing importance.

Stereotactic brachytherapy using iodine 125 seeds for the treatment of primary and recurrent anaplastic glioma WHO° III.

The current study analyzed the outcome after stereotactic brachytherapy (SBT) using iodine-125 seeds in anaplastic astrocytoma, oligoastrocytoma or oligodendroglioma not suitable for resection. Out of 223 patients harbouring a malignant glioma treated according to a prospective protocol, 172 patients were selected who received SBT to treat a WHO grade III de-novo/residual tumor (n = 99) or a tumor recurrence after multimodal treatment (n = 73). We assessed progression free survival (PFS), overall survival (OS), radiological and clinical outcome and determined prognostic factors using univariate and multivariate regression analyses. The median follow-up time was 38 months. Median OS and median PFS was 28.9 and 21.4 months in the de-novo group vs. 49.4 and 32.6 months in the recurrence group. Recurrent tumors had more frequently (p = 0.01) an oligodendroglial-component compared to de novo tumors. According to cohort-specific univariate analyses KPS at SBT had a significant (p = 0.008) impact on OS in the de-novo group. In the recurrence group, (Cox regression analysis) OS was significantly associated with histology subtype (oligoastro-/oligodendroglioma vs. astrocytoma, p = 0.043). Transient and permanent morbidity (~1 %) was low. For patients unable to undergo surgery due to eloquent tumour location or reduced general condition SBT is an effective treatment option, which does not foreclose additional therapeutic interventions.

Voxel-based dose calculation in radiocolloid therapy of cystic craniopharyngiomas.

Very high doses are administered in radiocolloid therapy of cystic craniopharyngiomas. However individual dose planning is not common yet mainly due to insufficient image resolution. Our aim was to investigate whether currently available high-resolution image data can be used for voxel-based dose calculation for short-ranged ß-emitters ((32)P,(90)Y,(186)Re) and to assess the achievable accuracy. We developed a convolution algorithm based on voxelized dose activity distributions and dose-spread kernels. Results for targets with 5-40 mm diameter were compared with high-resolution Monte Carlo calculations in spherical phantoms. Voxel size was 0.35 mm. Homogeneous volume and surface activity distributions were used. Dose-volume histograms of targets and shell structures were compared and γ index (dose tolerance 5%, distance to agreement 0.35 mm) was calculated for dose profiles along the principal axes. For volumetric activity distributions 89.3% ± 11.9% of all points passed the γ test (mean γ 0.53 ± 0.16). For surface distributions 33.6% ± 14.8% of all points passed the γ test (mean γ 2.01 ± 0.60). The shift of curves in dose-volume histograms was -1.7 Gy ± 7.6 Gy (-4.4 Gy ± 24.1 Gy for (186)Re) in volumetric distributions and 46.3% ± 32.8% in surface distributions. The results show that individual dose planning for radiocolloid therapy of cystic craniopharyngiomas based on high-resolution voxelized image data is feasible and yields highly accurate results for volumetric activity distributions and reasonable dose estimates for surface distributions.

Endocrine and visual function after fractionated stereotactic radiotherapy of perioptic tumors.

PURPOSE: To find out whether the use of stereotactic techniques for fractionated radiotherapy reduces toxicity to the endocrine and visual system in patients with benign perioptic tumors. PATIENTS AND METHODS: From 1993 to 2009, 29 patients were treated with fractionated stereotactic radiotherapy. The most frequent tumor types were grade I meningioma (n = 11) and pituitary adenoma (n = 10, 7 nonfunctioning, 3 growth hormone-producing). Patients were immobilized with the GTC frame (Radionics, USA) and the planning target volume (PTV; median 24.7, 4.6-58.6 ml) was irradiated with a total dose of 52.2 Gy (range, 45.0-55.8 Gy) in 1.8-Gy fractions using a linear accelerator (6 MeV photons) equipped with a micro-multileaf collimator. Maximum doses to the optic system and pituitary gland were 53.4 Gy (range, 11.5-57.6 Gy) and 53.6 Gy (range, 12.0-57.9 Gy). RESULTS: Median follow-up was 45 months (range, 10-105 months). Local control was achieved in all but 1 patient (actuarial rate 92% at 5 years and 10 years). In 9 of 29 patients (31%), partial remission was observed (actuarial response rate 40% at 5 years and 10 years). In 4 of 26 patients (15%) with at least partial pituitary function, new hormonal deficits developed (actuarial rate 21% at 5 years and 10 years). This rate was significantly higher in patients treated for a larger PTV (< /> 25 ml: 0% vs. 42% at 5 years and 10 years, p = 0.028). Visual function improved in 4 of 15 patients (27%) who had prior impairment. None of the patients developed treatment-related optic neuropathy, but 2 patients experienced new disease-related visual deficits. CONCLUSION: Fractionated stereotactic radiotherapy for benign tumors of the perioptic and sellar region results in satisfactory response and local control rates and does not affect the visual system. The assumption that patients can be spared hypophyseal insufficiency only holds for small tumors.

LINAC-radiosurgery for nonsecreting pituitary adenomas. Long-term results.

BACKGROUND AND PURPOSE: Stereotactic linear accelerator-based radiosurgery (LINAC-RS) is increasingly used for microsurgically inaccessible or recurrent pituitary adenomas. This single-center study evaluates the long-term follow-up after LINAC-RS of nonsecreting pituitary adenomas (NSA). PATIENTS AND METHODS: Between 1992 and August 2008, 65 patients with NSA were treated. Patient treatment and follow-up were conducted according to a prospective protocol. Indications for LINAC-RS were (1) tumor recurrence or (2) residual tumor. Three patients were treated primarily. For analysis of prognostic factors, patients were grouped according to epidemiological or treatment-associated characteristics. RESULTS: A total of 61 patients with a follow-up ≥ 12 months (median 83 months, range 15-186 months, longest follow-up of published radiosurgery series) were evaluated with regard to their clinical, radiological, and endocrinological course. The median tumor volume was 3.5 ml (± 4.3 ml, range 0.3-17.3 ml) treated with a median surface and maximum dose of 13.0 Gy and 29.7 Gy, respectively. Local tumor control was achieved in 98%. One patient died of unrelated cause after 36 months and 1 patient developed a radiation-induced seizure disorder. Visual complications did not occur. In 37 of 41 patients (90.2%), pituitary function remained stable. Maximum dose to the pituitary ≤ 16 Gy and female gender were positive prognostic factors for the preservation of pituitary function. CONCLUSION: LINAC-RS is a minimally invasive, safe, and effective treatment for recurrent NSA or microsurgically inaccessible residual tumor. LINAC-RS yielded a high rate of local long-term tumor control with a small number of radiation-induced side effects.

The influence of head frame distortions on stereotactic localization and targeting.

A strong attachment of a stereotactic head frame to the patient's skull may cause distortions of the head frame. The aim of this work was to identify possible distortions of the head frame, to measure the degree of distortion occurring in clinical practice and to investigate its influence on stereotactic localization and targeting. A model to describe and quantify the distortion of the Riechert-Mundinger (RM) head frame was developed. Distortions were classified as (a) bending and (b) changes from the circular ring shape. Ring shape changes were derived from stereotactic CT scans and frame bending was determined from intraoperative stereotactic x-ray images of patients with implanted 125I-seeds acting as landmarks. From the examined patient data frame bending was determined to be 0.74 mm+/-0.32 mm and 1.30 mm in maximum. If a CT-localizer with a top ring is used, frame bending has no influence on stereotactic CT-localization. In stereotactic x-ray localization, frame bending leads to an overestimation of the z-coordinate by 0.37 mm+/-0.16 mm on average and by 0.65 mm in maximum. The accuracy of patient positioning in radiosurgery is not affected by frame bending. But in stereotactic surgery with an RM aiming bow trajectory displacements are expected. These displacements were estimated to be 0.36 mm+/-0.16 mm (max. 0.74 mm) at the target point and 0.65 mm+/-0.30 mm (max. 1.31 mm) at the entry point level. Changes from the circularring shape are small and do not compromise the accuracy of stereotactic targeting and localization. The accuracy of CT-localization was found to be close to the resolution limit due to voxel size. Our findings for frame bending of the RM frame could be validated by statistical analysis and by comparison with an independent patient examination. The results depend on the stereotactic system and details of the localizers and instruments and also reflect our clinical practice. Therefore, a generalization is not possible. Preliminary experience with a new MR-compatible RM head frame made of ceramics shows no frame distortions as with the conventional frame made of an Al-Cu-Mg alloy.

Radiosurgery for cerebral arteriovenous malformations in hereditary hemorrhagic telangiectasia.

The authors evaluated the efficacy of radiosurgery (RS) for cerebral arteriovenous malformations in hereditary hemorrhagic telangiectasia (HHT AVMs). Two patients with seven HHT AVMs were treated by linear accelerator-RS. Complete obliteration was achieved 18 to 24 months post-treatment without side effects. Because HHT AVMs are small and multiple, RS is superior to microsurgery because it is noninvasive and all AVMs can be treated in one session regardless of their location.

MR-guided stereotactic neurosurgery--comparison of fiducial-based and anatomical landmark transformation approaches.

For application in magnetic resonance (MR) guided stereotactic neurosurgery, two methods for transformation of MR-image coordinates in stereotactic, frame-based coordinates exist: the direct stereotactic fiducial-based transformation method and the indirect anatomical landmark method. In contrast to direct stereotactic MR transformation, indirect transformation is based on anatomical landmark coregistration of stereotactic computerized tomography and non-stereotactic MR images. In a patient study, both transformation methods have been investigated with visual inspection and mutual information analysis. Comparison was done for our standard imaging protocol, including t2-weighted spin-echo as well as contrast enhanced t1-weighted gradient-echo imaging. For t2-weighted spin-echo imaging, both methods showed almost similar and satisfying performance with a small, but significant advantage for fiducial-based transformation. In contrast, for t1-weighted gradient-echo imaging with more geometric distortions due to field inhomogenities and gradient nonlinearity than t2-weighted spin-echo imaging, mainly caused by a reduced bandwidth per pixel, anatomical landmark transformation delivered markedly better results. Here, fiducial-based transformation yielded results which are intolerable for stereotactic neurosurgery. Mean Euclidian distances between both transformation methods were 0.96 mm for t2-weighted spin-echo and 1.67 mm for t1-weighted gradient-echo imaging. Maximum deviations were 1.72 mm and 3.06 mm, respectively.

Geometrical and dosimetrical characterization of the photon source using a micro-multileaf collimator for stereotactic radiosurgery.

A micro-multileaf collimator (microMLC) for stereotactic radiosurgery is used for determination of the spatial intensity distribution of the photon source of a linear accelerator. The method is based on grid field dose measurements using film dosimetry and is easy to perform. Since the microMLC does not allow 'direct' imaging of the photon source, special software has been developed to analyse grid field measurements. Besides the source-density function, grid field analysis yields the position of the focal spot in the room laser coordinate system of the linear accelerator and the position of the treatment head rotation axis and the inclination angle of the leaf bank. Thus the method can be used for base dosimetry and for quality assurance in radiosurgery using a microMLC.

On isocentre adjustment and quality control in linear accelerator based radiosurgery with circular collimators and room lasers.

We have developed a densitometric method for measuring the isocentric accuracy and the accuracy of marking the isocentre position for linear accelerator based radiosurgery with circular collimators and room lasers. Isocentric shots are used to determine the accuracy of marking the isocentre position with room lasers and star shots are used to determine the wobble of the gantry and table rotation movement, the effect of gantry sag, the stereotactic collimator alignment, and the minimal distance between gantry and table rotation axes. Since the method is based on densitometric measurements, beam spot stability is implicitly tested. The method developed is also suitable for quality assurance and has proved to be useful in optimizing isocentric accuracy. The method is simple to perform and only requires a film box and film scanner for instrumentation. Thus, the method has the potential to become widely available and may therefore be useful in standardizing the description of linear accelerator based radiosurgical systems.

Brachytherapy: Results of two different therapy strategies for patients with primary glioblastoma multiforme.

BACKGROUND: In the current study, the authors describe and compare two different strategies of brachytherapy for the treatment of patients with primary glioblastoma multiforme (GBM). METHODS: The study was comprised of 84 patients. Forty-five patients were implanted with permanent or temporary low activity iodine-125 ((125)I) seeds in Cologne and 21 patients were implanted with temporary iridium-192 ((192)Ir) wires in Amsterdam. Both groups received external beam radiation therapy (EBRT); the (125)I group received 10-30 grays (Gy) with the implant in situ and the (192)Ir group received 60 Gy before implantation. In Cologne, implantation was performed after a diagnostic stereotactic biopsy whereas in Amsterdam implantation took place after cytoreductive diagnostic surgery. In addition, 18 patients in Amsterdam served as a control group. This group received only EBRT after cytoreductive surgery. RESULTS: In both groups the mean age of the patients was between 50-55 years, with 80% of the patients age > 45 years. The mean implantation volume encompassed by the referenced isodose was 23 cm(3) for (125)I and 48 cm(3) for (192)Ir. Initial dose rates were 2. 5-2.9 centigrays (cGy)/hour for permanent (125)I, 4.6 cGy/hour for temporary (125)I, and 44-100 cGy/hour (mean, 61 cGy) for (192)Ir. A total dose of 50-60 Gy, 60-80 Gy, and 40 Gy, respectively, was administered at the outer margins of the tumor. The median survival was approximately 16 months for both the (125)I group and the (192)Ir group. This was 6 months longer than the median survival in the control group. Reoperations were performed in 4 patients in the (125)I group (9%) versus 7 patients in the (192)Ir group (33%). No complications or late reactions were reported in the (125)I group, whereas one case of hemorrhage and three cases of delayed stroke were observed in the (192)Ir group. CONCLUSIONS: The equal median survival times in these two brachytherapy groups with such different dose rate radiation schedules support the hypothesis that dose rate does not play a major role in the survival of patients with primary GBM.

Computer simulation of cytotoxic and vascular effects of radiosurgery in solid and necrotic brain metastases.

PURPOSE: Solid and necrotic brain tumors respond to radiosurgery, although necrotic lesions often contain a significant proportion of hypoxic cells which cannot become reoxygenated during the short overall treatment time of single dose application. In addition to the direct cytotoxic action, delayed vascular occlusion followed by ischemic tumor cell death could contribute to the effect of radiosurgery. MATERIALS AND METHODS: In order to determine the impact of the two possible effects on tumor response, a 3-dimensional computer simulation was developed and fitted to response data obtained from 90 patients who were treated by LINAC radiosurgery for 1-3 brain metastases with median marginal doses of 20 Gy. Complete response rates were as follows: small, solid lesions (diameter 0.4-1 cm), 52% (12/23); large solid lesions (1.1-5.2 cm), 28% (17/60); large necrotic lesions, 12% (6/50). The 3-dimensional computer model simulated the growth of small solid and large, solid or necrotic tumors situated in a vascularized stroma. Oxygen supply, tumor cell division (cell cycle time 5 days), neovascularization, tumor cell kill by single dose irradiation (linear-quadratic model, alpha/beta=10 Gy, oxygen enhancement ratio 3.0) and time-dependent vascular occlusion (alpha/beta=3 Gy) were modeled by Monte-Carlo simulation techniques. RESULTS: In the presence of neovascularization, solid tumors with a hypoxic fraction of 1-2% developed. Without neoangiogenesis, central necrosis occurred, and tumors had a hypoxic fraction of 20-25%. Assuming a pure cytotoxic effect of radiosurgery, neither the dose-response relationship for the solid lesions of different size nor that for the large lesions with solid or necrotic appearance could be reproduced for any given level of radiosensitivity. This was only possible by introducing a vascular effect that led to the occlusion of >/=99% of the vessels at the border of the target volume within 1 year after irradiation. In the presence of the vascular effect, the apparent radiosensitivity of the tumor cells was increased by 50-100%. Calculations of the dose-equivalent for the vascular effect show that it contributes 19-33% of the overall effect of single dose radiosurgery. CONCLUSION: This simulation study suggests that the therapeutic effect of single radiosurgery in malignant brain tumors cannot be understood without the consideration of vascular effects. The computer model might serve as a basis for exploring new treatment modalities that modify both cytotoxic and vascular effects of radiosurgery.

Ionizing radiation-induced apoptosis of proliferating stem cells in the dentate gyrus of the adult rat hippocampus.

The occurrence of radiation-induced apoptosis in normal brain was investigated using an animal model of radiosurgery. Adult male Fischer rats aged 3 to 4 months were subjected to single dose convergent beam irradiation (10 Gy). Apoptotic cell death was determined by in situ labeling of DNA nick ends (TUNEL) and light microscopic evaluation of cell morphology. Five hours after irradiation, a highly significant increase of apoptotic cells in the subgranular zone of the dentate gyrus was paralleled by a corresponding significant decrease of cells immunoreactive for the proliferation marker Ki-67. Morphology, location and distribution of cells affected by radiation-induced apoptosis in the dentate gyrus subgranular zone, together with NeuN-immunohistochemistry, support the contention that these cells belong to the immature progenitor population responsible for neurogenesis in the adult rat hippocampus.

Computerized optimization of multiple isocentres in stereotactic convergent beam irradiation.

A method for the fully computerized determination and optimization of positions of target points and collimator sizes in convergent beam irradiation is presented. In conventional interactive trial and error methods, which are very time consuming, the treatment parameters are chosen according to the operator's experience and improved successively. This time is reduced significantly by the use of a computerized procedure. After the definition of target volume and organs at risk in the CT or MR scans, an initial configuration is created automatically. In the next step the target point positions and collimator diameters are optimized by the program. The aim of the optimization is to find a configuration for which a prescribed dose at the target surface is approximated as close as possible. At the same time dose peaks inside the target volume are minimized and organs at risk and tissue surrounding the target are spared. To enhance the speed of the optimization a fast method for approximate dose calculation in convergent beam irradiation is used. A possible application of the method for calculating the leaf positions when irradiating with a micromultileaf collimator is briefly discussed. The success of the procedure has been demonstrated for several clinical cases with up to six target points.

Linear accelerator radiosurgery for recurrent malignant tumors of the skull base.

The efficacy of linear accelerator-based radiosurgery for patients who have preirradiated recurrent nasopharyngeal carcinomas and unresectable recurrent sarcomas invading the base of skull was assessed. Thirteen patients were treated: 8 patients had carcinomas arising from the nasopharynx (lymphoepithelioma, 4; squamous cell carcinoma, 2; adenoid-cystic, 2); 5 patients had sarcomas (rhabdomyosarcoma, 1; chordoma, 1; chondrosarcoma, 1; hemangiopericytoma, 2). All patients had had repeated tumor resections or irradiation, hindering any further conventional fractionated radiotherapy or surgery. Convergent-beam irradiation was performed with a modified linear accelerator (8-MeV photons). Because of irregular tumor configuration, multiple (up to seven) isocenters had to be used in 10 of 13 patients to match the target volume with the reference isodose (60%-80%). Each isocenter was irradiated with 6 to 10 arcs. The median planning target volume was 33 mL (4-128 mL) and the median dose was 15 Gy (9-24 Gy). Median survival time was 9 months in 8 patients who had recurrent nasopharyngeal carcinomas. Three patients who had complete or partial tumor remission survived 1.5 to 3.5 years. All of the sarcoma patients responded to radiosurgery. After a follow-up of 28 to 67 months, 4 of 5 patients are alive. This investigation demonstrates that radiosurgery is an effective tool in palliative treatment for patients who have recurrent, extensively pretreated nasopharyngeal cancer. Patients who have recurrent sarcomas of the base of skull may be treated for long-term palliation or even for cure.

Quantification of tumor reoxygenation during accelerated radiation therapy.

PURPOSE: To determine the effect of accelerated fractionated radiation therapy on the reoxygenation of chronic hypoxic tumor cells by means of a three-dimensional Monte Carlo simulation. MATERIALS AND METHODS: Tumor growth (cell cycle time [Tc] of 2 or 5 days), irradiation (alpha = 0.3 Gy-1, alpha/beta = 10 Gy), oxygen tension (oxygen enhancement ratio of 3.0), capillary network distortion, and shrinkage of a small (10(4)-cell) tumor were modeled on a workstation. Conventional (2 Gy delivered five times per week), accelerated (1.6 Gy delivered twice a day for 5 d/wk), and split-course (1.6 Gy delivered twice a day for 5 d/wk with a break in week 3) radiation therapies were simulated with total doses of 50-70 Gy. RESULTS: Tumors grew in cords with a central necrotic area surrounded by hypoxic cells (hypoxic fraction, 25%). If undisturbed tumor shrinkage occurred, complete reoxygenation took 2 1/2 weeks for accelerated, 3-5 weeks for split-course, or 4-6 weeks for conventional radiation therapy. If shrinkage was prevented, the hypoxic fraction rose to 90%-100% at 2-3 weeks. In the shrinking, reoxygenation tumors with a Tc of 2 days, accelerated radiation therapy increased tumor control by 40%-80% over the control with conventional radiation therapy. With split-course therapy, this advantage was lost at doses below 70 Gy. Shrinking tumors with a Tc of 5 days were all controlled with 50 Gy. CONCLUSION: Fast-growing tumors that reoxygenate by shrinking are especially sensitive to acceleration and treatment breaks.

Cystic craniopharyngioma: long-term results after intracavitary irradiation with stereotactically applied colloidal beta-emitting radioactive sources.

OBJECTIVE: Long-term follow-up data were analyzed to assess the value of intracavitary irradiation with stereotactically applied beta-emitting radioisotopes for the treatment of craniopharyngioma cysts. METHODS: Sixty-two of 70 consecutive patients with predominantly cystic craniopharyngiomas were selected for retrospective analysis. Beta-Emitting isotopes were injected intracystically using a computed tomography-guided and computer-assisted three-dimensional stereotactic treatment planning and application system (cumulative dose to the inner surface of the cyst wall, 200 Gy). RESULTS: The tumor response rate gained with yttrium-90-labeled silicate (66 of 78 cysts) or phosphorous-32-labeled chromic phosphate (8 of 78 cysts) was 79.5%. Four cysts treated with rhenium-186-labeled sulfate did not respond. Mean survival after intracavitary irradiation was 9.0 +/- 0.9 years (median follow-up, 11.9 yr). In patients with solitary cysts, the mean survival was 12.5 +/- 1.4 years (actuarial 5- and 10-yr survival rates, 80 and 64%, respectively). Six months postoperatively, visual deficits (38 of 62 patients) had improved in 23 patients and were stable in 15 patients. The side effects that occurred 6 to 12 months after treatment with yttrium-90 were complete blindness (three patients), worsening of visual field cuts (one patient), third nerve palsy (one patient), and diabetes insipidus and/or panhypopituitarism (three patients). CONCLUSIONS: Intracavitary irradiation using yttrium-90 or phosphorous-32 is highly effective in the treatment of cystic craniopharyngiomas. If applied as initial treatment in patients with solitary cysts, it is the only required therapy over a long period.