Evaluation of a New Inverse, Globally Convex Treatment Planning System Algorithm for Gamma Knife Radiation Surgery Within a Prospective Trial: Advantages and Disadvantages in Practical Application.

Purpose: A new inverse planning software called IntuitivePlan (IP) based on a global convex optimization algorithm was adopted for the Gamma Knife radiation surgery. We investigated IP's suitability for daily clinical use and its applicability for different cerebral entities. Methods and Materials: For 230 target volumes, IP was tested in a prospective trial. The computed treatment plans were compared with conventional expert preplans, which included forward planning by the expert and local internal optimization. Based on the same dose constraints, we used the default settings for the inverse calculation of the treatment plans. Plan quality metrics such as the Paddick conformity index were compared for both planning techniques with additional subdivisions into the 3 selectable IP planning strategies and different entity groups. Results: IP calculated treatment plans of quality similar to that of preplans created by expert planners. Some plan quality metrics, especially those related to conformity and dose gradient, attained statistically significantly higher scores combined with high coverage for the inversely generated plans except for the selectivity optimizing strategy. Normal brain volume receiving 10 Gy or 12 Gy or higher (V 1 0 Gy or V 1 2 Gy ) did not show significant differences for the coverage optimizing strategies. The IP software demonstrated significantly shorter planning times versus manual planning as well as greater numbers of isocenters, often associated with longer treatment times. In terms of total time, these differences almost balanced out again. Conclusions: Our results suggest that IP is advantageous for complex tumors. We observed general clinical significance for conformity and superiority for the selectivity optimizing strategy. In addition, the high-quality calculation from IP enables novices in the profession to achieve pre-treatment plans of a quality similar to that of expert planners. IP allows for optimizing the sparing of surrounding tissue and conformity for benign tumors within a short time. Thus, IP forms a solid basis for further planning on the treatment day.

[Surgical treatment and radiation therapy of brain metastases]. / Chirurgische Behandlung und Strahlentherapie von Hirnmetastasen.

The aim of this work is to outline the principles of interdisciplinary treatment of brain metastases. Interdisciplinary treatment is determined by the clinical situation, anatomical conditions and tumor entity and has the goal of reducing toxicity. Magnetic resonance imaging, computed tomography (CT) and positron emission tomography-CT are used to diagnose brain metastases. Neurosurgery is used for accessible, symptomatic metastases. For localized metastases, including multiple metastases, that are surgically inaccessible, radiosurgery is used. If possible, partial brain irradiation is preferred to whole-brain irradiation. Protection of the hippocampus during whole-brain radiotherapy reduces therapy toxicity. In emergency situations, steroids provide effective support and a neurosurgical intervention may be life-saving. The options for systemic drug therapy are increasing.

LINAC stereotactic radiosurgery for trigeminal neuralgia -retrospective two-institutional examination of treatment outcomes.

BACKGROUND: In this pooled 2-center series LINAC radiosurgery (SRS) has been applied as a treatment option for a subset of refractory trigeminal neuralgia (TN) patients. This study approached to retrospectively assess the efficacy and safety of LINAC SRS and to provide a brief overview addressed to the technical development from frame-based towards frameless robotic SRS. METHODS: From 2001 to 2017 n = 55 patients (pts) were treated, n = 28 were female (51%), mean age: 66 years (range 36-93 years); TN etiology: 37 classic TN, 15 multiple sclerosis (MS)-related TN, 2 symptomatic TN, and 1 atypical TN. Previous treatment was present in n = 35 (63.6%) pts. (some multiple or combined) with n = 23 microsurgical vascular decompression and n = 17 percutaneous retrogasserian rhizotomy. A 6 MV LINAC (4-5 mm collimators) was applied in all pts. (n = 26 framebased - n = 29 frameless robotic). The dorsal root entry zone (DREZ) was targeted in n = 35 cases and the retrogasserian target in n = 20 pts. with a homogeneous dose for the entire study cohort (90 Gy). SRS outcome was measured using the Barrow Neurological Institute (BNI) score for pain and hypaesthesia and statistically evaluated by univariate and multivariate analyzes. RESULTS: Mean follow-up (FU) was 30 months (2 lost FU); the total rate of post SRS BNI pain I-IIIa (=painfree w or w/o medication) was 69% (88% for the classic TN pts), 29% (38.8% classic TN) were classified as BNI pain I-II (=painfree w/o medication). A BNI hypaesthesia II-III was present in 9.4% (n = 5) and BNI hypaesthesia IV in n = 2. Between groups analysis demonstrated no correlation of SRS responsiveness with age, gender, MS- or not MS-associated TN, previous surgery, framebased/frameless robotic SRS. DREZ targeting significantly better suppressed TN compared to RG targeting (p = 0.01). Additionally, a statistical trend for a better BNI pain outcome (p = 0.07) along with a significant increase in BNI hypaesthesia (p = 0.01) was found when using a larger partial trigeminal 70 Gy volume. CONCLUSION: Our retrospective analysis support LINAC SRS as an effective and safe treatment option in TN. Frameless robotic SRS of TN is safe when using a dedicated LINAC system. A target definition closer to the brainstem and tendencially a larger target volume were associated with a better outcome for pain.

The impact of MRI steady-state sequences as an additional assessment modality in vestibular schwannoma patients after LINAC stereotactic radiotherapy or radiosurgery.

PURPOSE: Data concerning the clinical usefulness of steady-state sequences (SSS) for vestibular schwannomas (VS) after linear accelerator (LINAC) stereotactic radiosurgery (SRS) or stereotactic radiotherapy (SRT) are scarce. The aim of the study was to investigate whether SSS provide an additional useful follow-up (FU) tool to the established thin-layered T1 sequences with contrast enhancement. METHODS: Pre- and post-treatment SSS were identified in 45 consecutive VS patients (2012-2016) with a standardized FU protocol including SSS at 2-3 months and 6 months/yearly in our prospective database and were retrospectively re-evaluated. The SSS were used throughout for the segmentation of the cochlea and partly of the trigeminal nerve in the treatment planning. Data analysis included signal conversion in SSS and possible correlation with neuro-otological outcome and volumetric assessment after a certain time interval. RESULTS: The series included 42 SRS and 3 SRT patients (31 female/14 male; mean age 59.3 years, range: 25-81 years). An SSS signal conversion was observed in 20 tumors (44.4%) within a mean time of 11 months (range: 7-15 months). Mean FU time was 26 months (median of 4 FU visits) and demonstrated tumor volume shrinkage in 29 cases (64.4%) correlating with FU time (p = 0.07). The incidence rate of combined shrinkage and signal conversion (48.3%) compared to those without signal conversion (51.7%) did not differ significantly (p = 0.49). In case of an early signal conversion at the first FU, a weak statistical significance (p = 0.05) for a higher shrinkage rate of VS with signal conversion was found. Side effects in cases with signal conversion (9/20, 45%) were more frequently than without signal conversion (6/25, 24%) without reaching statistical significance (p = 0.13). CONCLUSION: Our data confirmed the usefulness of SSS for anatomical segmentation of VS in LINAC-SRS/SRT treatment planning and add data supporting their potential as an adjunctive FU option in VS patients.

A multimodal concept for invasive diagnostics and surgery based on neuronavigated voxel-based morphometric MRI postprocessing data in previously nonlesional epilepsy.

OBJECTIVE Diagnosis and surgical treatment of refractory and apparent nonlesional focal epilepsy is challenging. Morphometric MRI voxel-based and other postprocessing methods can help to localize the epileptogenic zone and thereby support the planning of further invasive electroencephalography (EEG) diagnostics, and maybe resective epilepsy surgery. METHODS The authors developed an algorithm to implement regions of interest (ROI), based on postprocessed MRI data, into a neuronavigation tool. This was followed by stereotactic ROI-guided implantation of depth electrodes and ROI-navigated resective surgery. Data on diagnostic yield, histology, and seizure outcome were collected and evaluated. RESULTS Fourteen consecutive patients with apparently nonlesional epilepsy were included in this study. Reevaluation of the MR images with the help of MRI postprocessing analysis led to the identification of probable subtle lesions in 11 patients. Additional information obtained by SPECT imaging and MRI reevaluation suggested possible lesions in the remaining 3 patients. The ROI-guided invasive implantation of EEG yielded interictal and ictal activity in 13 patients who were consequently referred to resective surgery. Despite the apparently negative MRI findings, focal cortical dysplasia was found in 64% of the patients (n = 9). At the last available outcome, 8 patients (57%) were completely seizure free (International League Against Epilepsy Class 1). CONCLUSIONS The results demonstrate the feasibility and usefulness of a robust and straightforward algorithm for implementation of MRI postprocessing-based targets into the neuronavigation system. This approach allowed the stereotactic implantation of a low number of depth electrodes only, which confirmed the seizure-onset hypothesis in 90% of the cases without causing any complications. Furthermore, the neuronavigated ROI-guided lesionectomy helped to perform resective surgery in this rather challenging subgroup of patients with apparent nonlesional epilepsy.

Treatment of Cerebral Arteriovenous Malformations with Radiosurgery or Hypofractionated Stereotactic Radiotherapy in a Consecutive Pooled Linear Accelerator Series.

OBJECTIVE: To review outcomes after linear accelerator stereotactic radiosurgery (SRS) and hypofractionated stereotactic radiotherapy (hfSRT) of arteriovenous malformations (AVMs) from a consecutive and pooled series of 2 Novalis centers and to analyze the influence of AVM size, Spetzler-Martin (SM) grade, pretreatment, and hemorrhagic versus nonhemorrhagic presentation. A subgroup analysis of A Randomized Trial of Unruptured Brain Arteriovenous Malformations (ARUBA)-eligible patients also was performed. METHODS: Prospectively collected treatment and outcome data were supplemented by retrospectively collected follow-up data for 93.8% of all patients. A total of 129 patients with AVM had SRS or hfSRT between 2000 and 2014 with the same linear accelerator system in 2 centers. Data analysis included initial presentation, SM grade, occlusion rates assessed by magnetic resonance and/or digital subtraction angiography, neurologic and therapeutic complications, and pretreatments. Statistical analysis was performed for patient demographic data and for factors potentially influencing outcome. RESULTS: Initial presentation was hemorrhage in 43.8% or seizures/neurologic deficits in 46.2%. The series included 6 SM grade I (5%), 26 SM II (21.5%), 55 SM III (45.5%), 28 SM IV (23%), and 6 SM V cases (5%). Pre-embolization was used in 36 patients (29.8%), 8 patients had previous surgery (6.6%), and 6 patients were irradiated before elsewhere (5%); 5 patients (4.2%) received multimodal pretreatment. Mean follow-up was 43 months. The occlusion rate for the total series was 71.1%, for SM I/II cases 80.6%, and 67.4% for the SM ≥ subgroup. The occlusion rate was 75.0% for the small volume (<4 cc) and 55.6% for the large volume (>10 cc) subgroup. There was no statistical difference between the occlusion rate of patients with or without pretreatment if taken all modalities together (72.7% and 69.7%, respectively). There was only a trend of a belated occlusion of pre-embolized AVMs. The occlusion rate for hemorrhagic AVM was with 77.4% better than for nonhemorrhagic (66.2%) or ARUBA-eligible AVMs (64.8%) but without reaching statistical significance. Neurologic deterioration was seen in 13.2% of the patients. There were 2 re-bleedings within 17-18 months (1.7%), 1 of them without a new neurologic deficit and total occlusion after re-SRS. One patient with pre-existing epilepsy died a sudden unexpected death (mortality rate: 0.8%). CONCLUSIONS: Overall SRS and hfSRT are valuable therapy options, especially in symptomatic patients with AVM, with a low rate of morbidity and mortality and an acceptable overall complete occlusion rate of >70% and >80% for SM I/II AVMs.

Low-dose radiosurgery or hypofractionated stereotactic radiotherapy as treatment option in refractory epilepsy due to epileptogenic lesions in eloquent areas - Preliminary report of feasibility and safety.

PURPOSE: The eradication of epileptogenic lesions (e.g. focal cortical dysplasia) can be used for treatment of drug-resistant focal epilepsy, but in highly eloquent cortex areas it can also lead to a permanent neurological deficit. In such cases the neuromodulation effect of low-dose high-precision irradiation of circumscribed lesions may represent an alternative therapy. METHOD: A total of 10 patients with eloquent localized lesions causing pharmacoresistant focal epilepsy were prospectively identified. After informed consent, six patients agreed and were treated with risk adapted low-dose radiosurgery (SRS) or hypofractionated stereotactic radiotherapy (hfSRT). Comprehensive data concerning treatment modalities and outcome after short-term follow up (mean=16.3 months) were prospectively collected and evaluated. RESULTS: From the six patients, two patients were treated with hfSRT (marginal dose 36 Gy) and four with SRS (marginal dose 13 Gy). Clinical target volume (CTV) ranged from 0.70 ccm to 4.32 ccm. The short-term follow-up ranged from 6 to 27 months. There were no side effects or neurological deficits after treatment. At last available follow-up two patients were seizure-free, one of them being off antiepileptic drugs. The seizure frequency improved in one and remained unchanged in three patients. CONCLUSION: Treatment of eloquent localized epileptogenic lesions by SRS and hfSRT showed no adverse events and an acceptable seizure outcome in this small prospective patient series. The relatively short-term follow-up comprises one of the study's drawbacks and therefore a longer follow-up should be awaited in order to evaluate the neuromodulation effect of the treatment. These preliminary results may however justify the initiation of a larger prospective trial investigating whether focused low-dose stereotactic irradiation could be an option for lesions in eloquent brain areas.

Surgery for spinal cord ependymomas: outcome and prognostic factors.

BACKGROUND: Spinal cord tumors account for 5% to 10% of all primary central nervous system tumors. The most common intramedullary neoplasms are ependymomas, composing 50% to 60% of spinal neuroepithelial tumors in adults. OBJECTIVE: To evaluate the clinical and oncological outcomes of patients with spinal ependymoma primarily treated with microsurgery. METHODS: Patient charts and operative notes were analyzed to evaluate the clinical and oncological outcomes of 57 patients (33 men, 24 women) undergoing surgery for spinal ependymal tumors between 1987 and 2007. Mean follow-up was 67 months (range, 1-195 months; median, 56 months). Histopathological findings were 1 subependymoma World Health Organization (WHO) grade I, 16 myxopapillary ependymomas WHO grade I, 39 ependymomas WHO grade II, and 1 anaplastic ependymoma WHO grade III. Histopathological diagnoses were reviewed in 52 cases (91%) using the 2007 WHO classification. RESULTS: There were 47 complete resections (83%). Only 4 patients (7%) underwent (postoperative) radiotherapy. Forty-nine of 57 patients (86%) had stable or improved McCormick grades directly after surgery. A permanent decrease in the McCormick grade was seen in 4 (7%) patients. Multivariate logistic regression revealed only the preoperative neurological status of the patient as an independent predictor of functional outcome (P = .007). Recurrent tumors were diagnosed 12 to 72 months after surgery in 5 of 57 patients (9%) including 3 of 16 myxopapillary ependymomas (19%). In 4 of 5 patients, the primary tumor was incompletely resected. The progression-free survival rate was 89% and 84% for all patients at 5 and 10 years, respectively. An incomplete resection proved the only independent predictor of progression-free survival (P = .05). CONCLUSION: These results support early surgery aiming at complete resection as the primary treatment for presumed spinal ependymomas. The prognosis after surgery for some myxopapillary ependymomas seems worse than generally believed.

Surgical treatment of choroid plexus tumors.

PURPOSE: The purpose of this study is to evaluate the results of microsurgical treatment for choroid plexus tumors (CPT) in adult patients. METHODS: From 1990 to 2008, 14 patients >18 years were treated at our institution for CPT, including seven males and seven females with a mean age of 46 years. Mean follow-up was 40 months. We reviewed the respective patients' charts, operative, and follow-up notes. Telephone interviews were performed as necessary. Neurological status was determined using the Karnofsky performance index pre- and post-operatively and at last follow-up. RESULTS: This series includes 12 plexus papillomas (CPP) and two atypical plexus papillomas (APP). Ten tumors were located in the fourth ventricle, two tumors in the cerebellopontine angle, one growth each in the third and lateral ventricle. In 12 cases, a complete tumor resection was achieved. No recurrence was observed in these cases. Two recurrent CPP were diagnosed 11 and 25 years after the initial surgery. Brain stem infiltration prevented a complete tumor removal in one case. In the other, the degree of resection after the first operation could not be ascertained. None of the patients received adjuvant chemo- or radiotherapy. In four patients (29%), a permanent ventricular-peritoneal shunt was necessary. Three patients initially presented with a Karnofsky index of 60 or below. During follow-up, three patients (21%) never improved beyond a Karnofsky index of 60. CONCLUSIONS: Surgery aiming radical excision is the key to successful treatment of CPP and APP in adults. Postoperative outcomes may be less than satisfactory in some patients.

Molecular genetics of meningiomas: from basic research to potential clinical applications.

To review our current understanding of the molecular pathogenesis of meningiomas, to suggest topics for future investigations, and to present perspectives for clinical application. Significant progress has been made in recent years in delineating the molecular mechanisms involved in meningioma formation, growth, and malignant progression. However, many questions remain unanswered. Mutations in the NF2 gene probably account for the formation of more than half of all meningiomas. On the other hand, the molecular events underlying the initiation of meningiomas without NF2 mutations have yet to be identified. Investigating hereditary conditions associated with an increased meningioma incidence and the mechanisms underlying the development of radiation-induced meningiomas could potentially yield relevant insights. Meningioma growth is sustained by the dysregulated expression of steroid hormones, growth factors, their receptors, and activation of signal transduction cascades. The underlying genetic causes are unknown. Malignant progression of meningiomas probably involves the inactivation of tumor suppressor genes on chromosomes 1p, 9p, 10q, and 14q. However, with the possible exception of INK4A/INK4B, the actual targets of these chromosomal losses have remained largely elusive. Cell cycle dysregulation and telomerase activation have been recognized as important steps in meningioma progression. Telomere dynamics, cell cycle control, and the mechanisms responsible for deoxyribonucleic acid damage control are tightly interwoven. Investigating genes involved in the maintenance of genomic integrity might significantly deepen the understanding of meningioma progression. An area that has received relatively little attention thus far is the genetic background of meningioma spread and invasion. Possible clinical applications of the molecular data available may include a meningioma grading system based on genetic alterations, as well as therapeutic strategies for refractory meningiomas aimed at interfering with signal transduction pathways.