[Stereotactic radiosurgery and fractionated stereotactic radiotherapy of acoustic neuromas]. / Stereotaktische Radiochirurgie und Radiotherapie bei Akustikusneurinomen.

Stereotactic radiosurgery (SRS) is a neurosurgical field that has become increasingly important in the treatment of acoustic neuromas. Radiosurgical treatment modalities include the Gamma knife, the linear accelerator (LINAC), and the CyberKnife. Gamma knife radiosurgery (GKRS) is still unsurpassed in terms of the spatial accuracy of radiation delivery and has been used for decades in acoustic neuromas (>18000 patients). In contrast to surgical resection, the goal of SRS is long-term prevention of tumour growth with preservation of neurological function. Radiation-induced neuropathies rarely occur. However, there are essential differences between SRS and fractionated stereotactic radiotherapy (FSR) in terms of both their radiobiological effects and their modes of application. SRS can be performed in an outpatient setting. Neuromas of up to 3 cm in diameter represent potential candidates for SRS or FSR. For larger tumours, cystic lesions and neuromas with brain stem compression, microsurgical resection in experienced neurosurgical centres is still the preferred option. SRS (and FSR) are possible options for patients with tumour progression after subtotal surgery or tumour recurrence, or for patients unable or unwilling to undergo surgery.

Staged gamma knife radiosurgery for large critically located benign meningiomas: evaluation of a series comprising 20 patients.

OBJECTIVES: This study investigated the efficacy of staged radiosurgical treatment for intracranial meningiomas exceeding 3 cm in diameter. METHODS: Between April 1992 and May 2008, staged gamma knife radiosurgery was performed in 20 patients with large benign meningiomas. 14 patients had undergone surgery at least once. The patients' ages ranged between 26 and 73 years (median 60.5). Tumour volumes measured between 13.6 and 79.8 cm(3) (median 33.3) and treatment volumes between 5.4 and 42.9 cm(3) (median 19.0). Of 41 treatments, the prescription dose at the tumour margin was 12 Gy for 33 treatments, 10 Gy for one treatment, 14 Gy for four treatments, 15 Gy for one treatment and 25 Gy for a further two treatments (median 12 Gy to a marginal isodose of 45%). Median follow-up was 7.5 years. RESULTS: Tumour control was achieved in 90% of our series (25% tumour regression, 65% stable size). Two patients (10%) experienced tumour progression outlying the planning target volumes treated by an additional radiosurgical procedure. Thereafter tumour volume decreased in one patient and remained stable in the second one. Clinically, nine patients (45%) improved within the time of follow-up and 11 (55%) remained unchanged. CONCLUSION: As a result of excellent tumour control at a low concomitant morbidity, staged radiosurgical treatment for meningiomas represents a safe treatment modality that can be recommended for meningiomas in critical locations either after incomplete surgery or as primary treatment for patients with significant comorbidity.

Combined endoscopic surgery and radiosurgery as treatment modality for olfactory neuroblastoma (esthesioneuroblastoma).

OBJECT: Treatment of esthesioneuroblastoma (olfactory neuroblastoma) has been considerably improved by microsurgical techniques. Nevertheless, these rare tumours of the frontal skull base are still associated with high rates of tumour recurrence and mortality, thus remaining a challenge even for experienced surgeons. A novel therapeutic approach that combines endoscopic sinus surgery and Gamma Knife radiosurgery is presented here. Taking into account the rarity of the disease the present study comprises a relatively large series of patients treated in a similar manner. METHODS: 14 patients (8 males, 6 females) aged 27-75 years (median 38) were treated between May 1993 and December 2003. This series comprises 12 newly diagnosed esthesioneuroblastomas. Two more patients had already previously undergone surgery (24/39 months earlier). Paranasal and nasal endoscopic sinus surgery was performed. Marginal irradiation doses ranging from 15-34 Gy were given to the residual tumours by means of radiosurgery (Gamma Knife) involving 1-7 isocentres within 3 months after surgery. Median follow-up is 58 months (range 13-128). RESULTS: There was no mortality. In all patients tumour control was achieved within the treated area. 4 patients underwent a second radiosurgical procedure 6-79 months (median 34 months) after initial radiosurgery. One patients had to undergo an additional craniotomy because of extensive neoplastic infiltration, 1 developed postoperative liquorrhea, 1 case was complicated by bilateral frontal sinusitis. All patients complained of nasal discharge and crusts. Karnovsky Index--preoperatively ranging from 80%-100%--remained stable in 12 patients, an improvement was observed in 2 cases. CONCLUSIONS: Based on the favourable results recorded so far, the combination of endoscopic sinus surgery and radiosurgery can be considered a promising treatment option for esthesioneuroblastoma that merits further consideration.

Stereotactic radiosurgery for hypothalamic hamartomas.

Hypothalamic hamartomas are nonneoplastic lesions often characterized by central precocious puberty and gelastic epilepsy. Due to the delicate location surgery is often unsuccessful and associated with considerable risks. In the presented series, Gamma Knife radiosurgery was applied. Four cases (aged between 5-13 years) who presented with medically intractable gelastic epilepsy and increasing secondary generalization, abnormal behaviour and precocious puberty (3 cases) are reported. Hypothalamic hamartomas sized 11-17 mm had been diagnosed by MR imaging. Radiosurgical treatment was performed in general anaesthesia with margin doses of 12-14 Gy to the 50-90% isodoses covering volumes of 600-2300 mm3. After follow-up periods of 12 to 68 months, a continuing decrease both in seizure frequency and intensity was noted (outcome according to Engel: II a (3 cases) and III a (1 case)). All patients are socially reintegrated. MR imaging did not reveal significant changes concerning the size of the lesions. Gamma Knife radiosurgery can be an effective and safe alternative treatment modality for HH capable of achieving good seizure control and improving behavioural disorders in selected cases.

Optimal timing of neutron irradiation for boron neutron capture therapy after intravenous infusion of sodium borocaptate in patients with glioblastoma.

PURPOSE: A cooperative study in Europe and Japan was conducted to determine the pharmacokinetics and boron uptake of sodium borocaptate (BSH: Na(2)B(12)H(11)SH), which has been introduced clinically as a boron carrier for boron neutron capture therapy in patients with glioblastoma. METHODS AND MATERIALS: Data from 56 patients with glioblastoma who received BSH intravenous infusion were retrospectively reviewed. The pharmacokinetics were evaluated in 50 patients, and boron uptake was investigated in 47 patients. Patients received BSH doses between 12 and 100 mg/kg of body weight. For the evaluation, the infused boron dose was scaled linearly to 100 mg/kg BSH. RESULTS: In BSH pharmacokinetics, the average value for total body clearance, distribution volume of steady state, and mean residence time was 3.6 +/- 1.5 L/h, 223.3 +/- 160.7 L, and 68.0 +/- 52.5 h, respectively. The average values of the boron concentration in tumor adjusted to 100 mg/kg BSH, the boron concentration in blood adjusted to 100 mg/kg BSH, and the tumor/blood boron concentration ratio were 37.1 +/- 35.8 ppm, 35.2 +/- 41.8 ppm, and 1.53 +/- 1.43, respectively. A good correlation was found between the logarithmic value of T(adj) and the interval from BSH infusion to tumor tissue sampling. About 12-19 h after infusion, the actual values for T(adj) and tumor/blood boron concentration ratio were 46.2 +/- 36.0 ppm and 1.70 +/- 1.06, respectively. The dose ratio between tumor and healthy tissue peaked in the same interval. CONCLUSION: For boron neutron capture therapy using BSH administered by intravenous infusion, this work confirms that neutron irradiation is optimal around 12-19 h after the infusion is started.

Olfactory neuroblastoma (esthesioneuroblastoma): report of six cases treated by a novel combination of endoscopic surgery and radiosurgery.

Microsurgical techniques have considerably improved the results of surgical treatment for esthesioneuroblastoma (olfactory neuroblastoma). Nevertheless, these rare tumours of the frontal skull base are still associated with high rates of tumour recurrence and mortality, thus remaining a challenge even for experienced surgeons. A novel therapeutic approach that combines endoscopic sinus surgery and radiosurgery (gamma knife) is presented here. Six patients (3 males, 3 females) aged between 27 and 75 years (median 38 years) were treated between August 1993 and July 1999. Following paranasal and nasal endoscopic sinus surgery, marginal irradiation doses ranging from 16 to 34 Gy were applied radiosurgically involving up to 7 isocentres. At present, the median follow-up period is 57 months (range: 9 - 79 months). Without mortality, tumour control was achieved in all patients. One patient, who had to undergo additional craniotomy because of extensive neoplastic infiltration, developed postoperative liquorrhea. In another case the clinical course was complicated by a bilateral frontal sinusitis. All patients complained of nasal discharge and crusts. However, a preoperative Karnovsky Index ranging from 80 to 100 % remained stable in four patients whereas an improvement was observed in two patients. Based on the favourable results observed so far, the combination of endoscopic sinus surgery and radiosurgery can be considered as promising new option for the treatment of esthesioneuroblastoma that merits further investigation.

Gamma knife radiosurgery for hypothalamic hamartomas in patients with medically intractable epilepsy and precocious puberty. Report of two cases.

Hamartoma of the hypothalamus represents a well-known but rare cause of central precocious puberty and gelastic epilepsy. Due to the delicate site in which the tumor is located, surgery is often unsuccessful and associated with considerable risks. In the two cases presented, gamma knife radiosurgery was applied as a safe and noninvasive alternative to obtain seizure control. Two patients, a 13-year-old boy and a 6-year-old girl, presented with medically intractable gelastic epilepsy and increasing episodes of secondary generalized seizures. Abnormal behavior and precocious puberty were also evident. Magnetic resonance (MR) imaging revealed hypothalamic hamartomas measuring 13 and 11 mm, respectively. After general anesthesia had been induced in the patients, radiosurgical treatment was performed with margin doses of 12 Gy to 90% and 60% of isodose areas, covering volumes of 700 and 500 mm3, respectively. After follow-up periods of 54 months in the boy and 36 months in the girl, progressive decrease in both seizure frequency and intensity was noted (Engel outcome scores IIa and IIIa, respectively). Both patients are currently able to attend public school. Follow-up MR imaging has not revealed significant changes in the sizes of the lesions. Gamma knife radiosurgery can be an effective and safe treatment modality for achieving good seizure control in patients with hypothalamic hamartomas.

Postoperative treatment of glioblastoma with BNCT at the petten irradiation facility (EORTC protocol 11,961).

The boron neutron capture therapy is based on the reaction occurring between the isotope 10B and thermal neutrons. A low energy neutron is captured by the nucleus and it disintegrates into two densely ionising particles, Li nucleus and He nucleus (alpha particle), with high biological effectiveness. On the basis of comprehensive preclinical investigations in the frame of the European Collaboration with Na2B12H11SH (BSH), as boron delivery agent, the first European phase I, clinical trial was designed at the only available epithermal beam in Europe, at the High Flux Reactor, Petten, in the Netherlands. The goal of this study is to establish the safe BNCT dose for cranial tumors under defined conditions. BNCT is applied as postoperative radiotherapy in 4 fractions, after removal of the tumor for a group of patients suffering from glioblastoma, who would have no benefit from conventional treatment, but have sufficient life expectancy to detect late radiation morbidity due to BNCT. The starting dose is set at 80% of the dose where neurological effects occurred in preclinical large animal experiments following a single fraction. The radiation dose will be escalated, by constant boron concentration in blood, in 4 steps for cohorts of ten patients, after an observation period of at least 6 months after the end of BNCT of the last patient of a cohort. The adverse events on healthy tissues due to BSH and due to the radiotherapy will be analysed in order to establish the maximal tolerated dose and dose limiting toxicity. Besides of the primary aim of this study the survival will be recorded. The first patient was treated in October 1997, and further four patients have been irradiated to-date. The protocol design proved to be well applicable, establishing the basis for scientific evaluation, for performance of safe patient treatment in a very complex situation and for opening the possibility to perform further clinical research work on BNCT.

Radiosurgery of vestibular schwannomas: a minimally invasive alternative to microsurgery.

From April 1992 till December 1998 stereotactic radiosurgery (Gamma Knife) was applied to 192 patients with vestibular schwannomas. 56 of them had radiosurgery as primary treatment modality and were followed-up for at least 4 years (48-80 months, median 62). Without fatal complications, control of tumour growth was achieved in all but three cases, useful hearing being preserved in more than one half of the patients (62%). The neurological state improved in 30 patients (54%). Irradiation-associated adverse effects (18%) comprised neurological signs (incomplete facial palsy, four cases (two recovered completely), and mild trigeminal neuropathy, three cases, respectively) and morphological changes (three patients) marked by an enlargement of pre-existing cystic components calling for additional surgical treatment: Microsurgical decompression was performed in two cases, the third patient underwent a shunting procedure because of hydrocephalus formation. Based on the present data, radiosurgery represents an effective treatment for vestibular schwannomas associated with an exceptionally low mortality rate and a good quality of life. With respect to the preservation of cranial nerve function, results are comparable to microsurgical resection. A short duration of hospitalization and a quick return to normal activities constitute further advantages and contribute to cost effectiveness in public health care.

Boron neutron capture therapy for glioblastoma: improvement of boron biodistribution by hyaluronidase.

Boron neutron capture therapy (BNCT) represents a highly promising therapeutic alternative for the treatment of the most common malignant brain tumor, glioblastoma multiforme. Both the efficacy and safety of BNCT are greatly dependent on the pattern of 10B biodistribution. The present study investigates the influence of systemic hyaluronidase applied in combination with Na2B12H11SH (BSH), a boron carrier used in current clinical trials. The application of hyaluronidase was associated with a statistically significant improvement in the tumor/blood boron concentration ratio which suggests that hyaluronidase is capable of enhancing the therapeutic potential of BSH.

Pharmacokinetics of Na2B12H11SH (BSH) in patients with malignant brain tumours as prerequisite for a phase I clinical trial of boron neutron capture.

The disposition of Na2B12H11SH (BSH) in patients with malignant glioma has been investigated, in preparation for a Phase I clinical trial of boron neutron capture therapy. BSH was found to possess a linear disposition over the dosage interval investigated (up to 75 mg/kg). A bi-phasic blood pharmacokinetics was observed. Tumour-to-blood ratios showed variations between patients between 0.08 and 5.1. The data allow the definition of amount of BSH and timing of infusion for a Phase I clinical trial protocol.

Gamma knife for glioma: selection factors and survival.

PURPOSE: To determine factors associated with survival differences in patients treated with radiosurgery for glioma. METHODS AND MATERIALS: We analyzed 189 patients treated with Gamma Knife radiosurgery for primary or recurrent glioma World Health Organization (WHO) Grades 1-4. CONCLUSION: The median minimum tumor dose was 16 Gy (8-30 Gy) and the median tumor volume was 5.9 cc (1.3-52 cc). Brachytherapy selection criteria were satisfied in 65% of patients. Median follow-up of all surviving patients was 65 weeks after radiosurgery. For primary glioblastoma patients, median survival from the date of pathologic diagnosis was 86 weeks if brachytherapy criteria were satisfied and 40 weeks if they were not (p = 0.01), indicating that selection factors strongly influence survival. Multivariate analysis showed that increased survival was associated with five variables: lower pathologic grade, younger age, increased Karnofsky performance status (KPS), smaller tumor volume, and unifocal tumor. Survival was not found to be significantly related to radiosurgical technical parameters (dose, number of isocenters, prescription isodose percent, inhomogeneity) or extent of preradiosurgery surgery. We developed a hazard ratio model that is independent of the technical details of radiosurgery and applied it to reported radiosurgery and brachytherapy series, demonstrating a significant correlation between survival and hazard ratio. CONCLUSIONS: Survival after radiosurgery for glioma is strongly related to five selection variables. Much of the variation in survival reported in previous series can be attributed to differences in distributions of these variables. These variables should be considered in selecting patients for radiosurgery and in the design of future studies.

Na2B12H11SH (BSH) in combination with systemic hyaluronidase: a promising concept for boron neutron capture therapy for glioblastoma.

OBJECTIVE: In an attempt to optimize the therapeutic potential of Na2B12H11SH (BSH) for boron neutron capture therapy for glioblastoma, the present study investigates the influence of systemically applied hyaluronidase (a glycolytic enzyme that enhances the activity of chemotherapeutic agents in different types of cancer) on the biodistribution of BSH in patients with glioblastoma. METHODS: Patients in two uniform groups (Groups A and B, each of which had 10 patients with histologically confirmed glioblastomas) received BSH at a dose used in earlier therapeutic trials (75 mg/kg of body weight, administered intravenously) 24 hours before surgical debulkment. Patients from Group B received additional hyaluronidase (200,000 IU, administered intravenously) immediately before BSH infusion. Boron concentrations were analyzed by inductively coupled plasma-atomic emission spectroscopy. RESULTS: The application of hyaluronidase was associated with a statistically significant improvement in the tumor (maximum)-to-blood concentration ratio of 1.83 (range, 0.68-3.67) compared with 1.31 (range, 0.8-1.78) with BSH alone. Moreover, with the use of hyaluronidase, there was a tendency for a higher maximal concentration in tumor (not statistically significant). Boron accumulation in glioblastoma tissue was highly selective in both groups, with tumor-to-healthy brain concentration ratios ranging from 6:1 to 20:1. CONCLUSION: These preliminary data suggest that hyaluronidase improves BSH biodistribution and, consequently, the therapeutic potential of this boron carrier. This finding might be of clinical value in the future.

Assay of anticancer drugs in tissue culture: comparison of a tetrazolium-based assay and a protein binding dye assay in short-term cultures derived from human malignant glioma.

Because of the methodological difficulties associated with the MTT assay in screening short-term cultures derived from human malignant glioma, a chemosensitivity assay based on the protein staining using sulforhodamine B (SRB) has been optimized for use with these cells. SRB at a fixed dye concentration achieved maximal staining density at 20 min for most cell lines and this intensity was not further increased by using dye concentrations above 0.2%. A delay in staining after fixation did not significantly decrease staining intensity, but delay in dye extraction after fixation and staining did. There was an excellent quantitative and qualitative linear relationship between cell number determined by either the SRB assay or by cell counting, but not with the MTT assay which consistently underestimated the number of cells in assay plates. The MTT assay appeared to be incapable of detecting less than about 150 cells/well, while these small numbers of cell were readily detectable by either cell counting or SRB staining. There was a close correlation between chemosensitivity values derived from the MTT and SRB assays for procarbazine, CCNU and vincristine when the endpoint is taken as either the ID25, ID50 or ID75. The results indicate that the SRB is capable of producing broadly similar results to the MTT assay, but is more sensitive in the detection of small numbers of cells with a linear relationship between cell number and SRB staining intensity over a wide range of cell numbers. It is capable of producing data from short-term cultures from malignant glioma and offers technical advantages over the MTT assay in that plates may safely be stored at certain points during the assay without the need for immediate processing. The SRB assay provides a useful alternative to the MTT assay for determining the sensitivity of short-term cultures of human glioma to cytotoxic drugs.

Boron neutron capture therapy: boron biodistribution and pharmacokinetics of Na2B12H11SH in patients with glioblastoma.

Data on biodistribution and pharmacokinetics of Na2B12H11SH are few and lack in standardization. This study comprises a uniform series of 10 patients with glioblastoma administered Na2B12H11SH i.v. 24 h before surgery at a dose level used in earlier therapeutical trials (75 mg/kg body weight). Boron concentrations in tumor, normal brain, peritumoral edematous brain, blood, and urine were determined by inductively coupled plasma-atomic emission spectroscopy 24 h after Na2B12H11SH administration; boron uptake in tumor (mean, 12.2 micrograms/g) was sufficiently selective compared to concentrations in normal and edematous brain (1.2 and 2.3 micrograms/g, respectively). Mean concentration ratio of tumor:blood was slightly above unity. Boron concentration in blood decreased according to an open two-compartment model, mean excretion in urine over 24 h was 81.9%. The only side effect was an inconstant facial flush. Among efforts aiming at an optimized treatment protocol a dose escalation study seems to be justified.

Subcellular boron-10 localization in glioblastoma for boron neutron capture therapy with Na2B12H11SH.

Because of the short range of the highly energetic particles helium-4 and lithium-7 that results from neutron-induced disintegration of boron-10, the efficacy of Boron Neutron Capture Therapy (BNCT) is heavily dependent on 10B-microlocation. Despite the crucial importance of boron-10, there is little specific information with regard to the agent currently used for inducing BNCT, namely Na2B12H11SH. In the present study, a subcellular 10B-location was investigated in tumor tissue obtained from seven patients with glioblastoma World Health Organization Grade IV. These patients received Na2B12H11SH at doses used in therapeutic trials (75 mg/kg body weight in five patients, and 150 mg/kg body weight in two patients, respectively). In three cases, boron-10 was identified in glioblastoma cells by laser microprobe mass analysis. In these tumors, boron-10 was found only in the nuclei of neoplastic cells but not in other cell compartments. These preliminary results suggest a predominant association of Na2B12H11SH with the nuclei of malignant glioma cells and thus support the value of Na2B12H11SH as a suitable boron carrier for BNCT.

Extracranial-intracranial arterial bypass after cerebral foreign body embolization: effective treatment of transient ischemic attacks.

A case of traumatic foreign body embolism into the right intracranial carotid artery with stenosis of the right middle cerebral artery in a 9-year-old boy is presented. Initial hemiparesis and a consecutive asymptomatic interval of 12 months were followed by a period of frequent transient ischemic attacks. After an extracranial-intracranial arterial bypass had been performed 18 months later, symptoms ceased without relapse. A thorough review of the literature demonstrates the rare incidence of this entity.

Surgery of tumours of the lateral ventricle.

Tumours of the lateral ventricle in most cases enlarge significantly before signs and symptoms are exhibited. In the years between 1980 and 1991 we encountered 55 patients of all age groups with tumours of the lateral ventricle. All were diagnosed either by CT or MRI, and in lesions with good enhancement on CT additional angiography was performed. All 55 tumours were operated upon using microsurgical techniques. The approach was chosen according to the location of the tumour, preferably transcortical. In selected cases large tumours were removed in a two-stage operation. Only in one frontal horn and Cella media tumour an interhemispheric transcallosal approach was used. Postoperative or surgically related mortality was experienced in 3 cases. Life expectancy and morbidity were dependent upon histology.

Prognosis after acute subdural or epidural haemorrhage.

In a series of 171 patients suffering acute subdural haemorrhage (SDH) (111 patients) or epidural haemorrhage (EDH) (60 patients) after closed head injury accumulated during the years 1978-1985 at the University Hospital of Graz, the mortality rate and the grade of clinical recovery were evaluated. The overall mortality in acute SDH was 57%, in acute EDH 25%, the percentages of good recoveries--full recovery and minimal neurologic deficit--25 and 58%, respectively. Outcome was found to be predominantly influenced by the preoperative state of consciousness, associated brain lesions, and, in comatose patients, the duration of the time interval between onset of coma and surgical decompression. When this interval exceeded two hours, mortality from SDH rose from 47 to 80% (good outcomes 32 and 4%, respectively). In acute EDH an interval under two hours lead to 17% mortality and 67% of good recoveries compared to 65% mortality and 13% of good recoveries after an interval of more than two hours. Age and concomitant injuries of other body regions proved to be of secondary importance.