Primary CNS lymphoma in immunocompetent patients from 1989 to 2001: a retrospective analysis of 164 cases uniformly diagnosed by stereotactic biopsy.

BACKGROUND: We present outcome data of a cohort of 164 immunocompetent PCNSL patients uniformly diagnosed at a single center for stereotactic neurosurgery, and evaluate the acceptance and impact of combination radiotherapy (RT) and chemotherapy (CHT) with high-dose methotrexate (HD-MTX) over time. METHOD: We assessed choice of treatment and patient survival in a series of 164 PCNSL cases diagnosed from 1989 to 2001, and performed a re-evaluation of histopathology and pre-operative clinical data. FINDINGS: From 1989 to 1993, RT was the predominant therapy, and additional CHT did not improve survival. After 1994, the use of combination CHT/RT increased continuously, consistently contained MTX, and was associated with longer survival than RT only: median survival was 14 months after CHT/RT (2-year survival 35.7%) and 10 months (2-year survival 26.2%) after RT only (not significant). Overall median survival remained poor, increasing from six (1989-1993) to nine months (1994-2001) (p = 0.008). Survival was variable, with a few patients surviving >4 years after diagnosis in the CHT/RT as well as in the RT only group. CONCLUSIONS: Despite considerable improvement of PCNSL therapy, the overall benefit of combined CHT/RT versus RT only was lower than that expected from previous phase II clinical trials. The striking variability of survival in either treatment group may suggest a yet undefined biological heterogeneity of PCNSL, which may also include a more aggressive PCNSL subtype in the group of patients with rapidly progressive disease and not eligible for standard therapy.

Low-grade gliomas -- current concepts.

Diffuse astrocytomas, oligodendrogliomas, and oligoastrocytomas (mixed gliomas) WHO grade II, pleomorphic xanthoastrocytomas (PXAs), pilocytic astrocytomas, and subependymal giant cell astrocytomas (SEGAs) are often referred to as low-grade gliomas. WHO grade II astrocytomas, oligodendrogliomas, and mixed gliomas are characterized by their infiltrative growth, frequent tumor recurrence and a more than 50 % risk for malignant progression. In contrast, pilocytic astrocytomas and SEGAs are circumscribed tumors amenable to a (radio)surgical cure. There are few universally accepted guidelines for the treatment of low-grade gliomas. In this review, three neurosurgeons, a neurologist, a neuropathologist, and a radiation oncologist discuss some of the difficult issues surrounding the diagnosis and treatment of low-grade gliomas from their individual points of view (i. e., classification and neuropathology, MR imaging, stereotactic biopsy, microsurgery, interstitial radiotherapy/brachytherapy, radiotherapy, wait and see strategy).

Interstitial stereotactic radiosurgery.

Stereotactic radiosurgery by means of interstitial application of either radionuclides or radiation devices has been used extensively in primary and secondary brain tumors. A few centers have gained sufficient expertise and clinical data to scientifically evaluate this treatment modality. Interstitial stereotactic radiosurgery is limited to circumscribed lesions with a diameter of 3.5 cm or less. The radiobiology of interstitial radiosurgery is quite well elaborated as to doses, dose rates and effects on vascular physiology. Efficacy in low grade gliomas is well documented by several European centers using 125-J sources. Different modes of implantation have been used and evaluated including single fraction treatment using a miniature linear accelerator (Photoelectron). In malignant gliomas interstitial radiosurgery has been investigated in a prospective, randomised, controlled trial and not shown to be effective. Steretactic interstitial radiosurgery is a powerful treatment option in circumscribed CNS tumors like some low grade gliomas and metastasis but does play no major role in the treatment of malignant glioma.

Radiobiological effects of photon radiosurgery on choroid plexus cells in vitro.

The standard surgical treatment of hydrocephalus by cerebrospinal fluid (CSF) shunt is accompanied by numerous complications. The search for alternative treatment methods includes resection, coagulation and irradiation of part of the plexus choroideus. The reduction of CSF secretion after choroid plexus (CP) irradiation has been investigated only on the experimental level. The new Photon Radiosurgery System (PRS) now also provides clinically the opportunity to induce selective radionecrosis on the CP with high efficiency and safety. In order to achieve a basic understanding of the reaction of CP cells after PRS irradiation, we investigated the cell death after different irradiation doses using TB dye-exclusion and MTT assay on sheep choroid plexus (SCP) cells. We observed a dose-dependent decrease in cell survival with increasing doses of irradiation (9, 18, 27 and 36 Gy). Lower irradiation doses (9, 18 Gy) induced an initial decrease of cell survival. Cells were able to recover from day 6 on and achieved a similar cell viability compared to non-irradiated cells on day 12. In contrast, higher doses (27 and 36 Gy) of irradiation induced a constant decrease of the cell survival over 12 days. These results clearly demonstrate that PRS irradiation is able to induce radionecrosis of CP cells which are responsible for the secretion of CSF. Interstitial photon radiosurgery can provide the opportunity to deliver the irradiation dose locally to CP with minimal exposure of surrounding tissue. Our basic data support further studies investigating this concept in animal models and clinically.

Reversible coma with raised intracranial pressure: an unusual clinical manifestation of CADASIL.

A 50-year-old woman presented with recurrent episodes of headache, nausea and disturbed consciousness that were fully reversible within a few days. Clinical and radiological findings suggested raised intracranial pressure, which on one occasion was confirmed by intracranial pressure monitoring. Magnetic resonance imaging performed in the asymptomatic interval disclosed a diffuse leukoencephalopathy. Brain biopsy surprisingly revealed the typical vascular changes of CADASIL and subtle endothelial alterations. The white matter showed edematous changes and reactive gliosis. Mutational analysis of the Notch3 gene revealed a previously unreported mutation. We suggest that a transient disturbance of the blood-brain barrier related to the underlying vascular pathology may have caused this unusual presentation of CADASIL.

The effects of continuous and single-dose radiation on choline uptake in organotypic tissue slice cultures of rabbit hippocampus.

The objective of the present study was to determine the time-dependent course of choline uptake in mature organotypic slice cultures of rabbit hippocampal formation and to assess the effects of continuous and single high-dose irradiation on choline uptake in cultivated slices in vitro. Transverse slices of hippocampus were dynamically incubated in a cerebrospinal fluid-like culture medium for 72 h. To study the changes in choline uptake longitudinally, the slice cultures were processed with 0.1 microM [3H]-choline, and tritium accumulation was counted. Two different gamma irradiation sources (125I seeds and a clinical 60Co source) were used as representative models of interstitial radiosurgery and other radiosurgical techniques. A total dose of approximately 6000 cGy was delivered to the brain slices in one session or in a continuous, relatively low-dose rate fashion, and their effects on high-affinity choline uptake were examined. In another set of experiments with 125I, 5 microM hemicholinium-3 was used in choline uptake procedures as a competitive high-affinity choline uptake inhibitor. The results can be summarized as follows: (1) in the control group of the hippocampal tissue culture, there was a significant increase in tritium accumulation values from 0 to 48 h and a decrease thereafter; (2) continuous 125I irradiation caused a highly significant depression of the accumulation of tritium compared to that observed in the control group throughout its application for 72 h; (3) there was no significant change in the accumulation of tritium in the slices after single high-dose rate irradiation with a 60Co source; and (4) 5 microM hemicholinium significantly depressed the accumulation of tritium in both the control and the 125I-irradiated groups, and there was no longer a difference between 125I-irradiated and control groups when both groups were treated with hemicholinium. These results demonstrate that the delivery of continuous but relatively low-dose rate gamma irradiation is more efficacious than single high-dose external irradiation on high-affinity choline uptake in hippocampal nervous tissue. The results also indicate that continuous irradiation specifically affected the high-affinity energy-dependent choline uptake mechanism, whereas nonspecific choline uptake did not seem to be disturbed.

Immediate and long term outcome after infrathalamic and thalamic lesioning for intractable Tourette's syndrome.

OBJECTIVE: The surgical treatment of intractable Tourette's syndrome is controversial. Experience with 17 consecutive patients treated between 1970 and 1998 is reviewed and the efficacy and safety of surgical treatment is assessed. METHODS: These patients were retrospectively reclassified into subtypes according to the protocol of the Tourette's Syndrome Study Group. One patient was excluded from the study. Ventriculography based stereotactic zona incerta (ZI) and ventrolateral/ lamella medialis thalamotomy (VL/LM) were performed on all patients. The preoperative, postoperative, and late tic severities were assessed by the tic severity rating scale. The median follow up of 11 patients (65%) was 7 years (range 3.5-17 years) and six patients were lost to long term follow up. RESULTS: Median age was 23 years (range 11-40) at the time of surgery. Median duration of illness was 14 years (range 3-33). The mean preoperative motor and vocal tic severities were estimated to be 4.44 (SD 0.63) and 3.81 (SD 0.66), respectively. Unilateral ZI lesioning and VL/LM lesioning selected by asymmetry of symptoms provide an effective control of tic severity (p motor and vocal<0.001). In attenuation of contralateral symptoms, a second surgical intervention in the relevant side could reduce tic severity sufficiently (p motor<0.01; p vocal<0.005). Transient complications occurred in 68% of patients. Only one permanent complication was registered in six patients followed up after unilateral surgery. Two out of five patients followed up after bilateral surgery had disabling side effects of surgery. CONCLUSIONS: ZI and VL/LM lesioning provide a significant long term reduction of tic severity in intractable Tourette's syndrome. Adequate selection of the side of first intervention might prevent the patient from increased risk of bilateral surgery.

Early effects of PRS-irradiation for 9L gliosarcoma: characterization of interphase cell death.

We characterized the interphase cell death of 9L gliosarcoma after high-dose-rate, low-energy photon irradiation using the Photon Radiosurgery System (PRS), a novel device for interstitial radiotherapy. Within 24 hours after irradiation with a dose of 18 Gray, 22.0% of cells underwent metabolic cell death, whereas dead cells in controls stayed less than 5.0% (p<0.005). In the majority of sensitive cells, loss of membrane integrity preceded the lethal morphological changes. The response was dose-dependent over the range of 9-18 Gray, but saturation was obtained over 18 Gray. On the other hand, a significant (p < 0.01) increase in the number of TUNEL-positive cells with apoptotic morphology was detected 6-24 hours after irradiation, but the fraction remained 1.9-2.1% of the population and was independent of the doses between 9 and 25 Gray. Apoptotic cells were rarely observed in the control cells (0.3-0.6%). Our data indicate that single high-dose irradiation induces both necrotic and apoptotic interphase cell death in 9L gliosarcoma, but rapid cell death mostly occurs through the non-apoptotic pathway.

The role of tumor resection in the treatment of glioblastoma multiforme in adults.

BACKGROUND: The therapeutic impact of tumor resection is poorly defined. Therefore the current study was conducted. METHODS: A retrospective, 2-institutional study was conducted (1991-1994) to compare the treatment results of stereotactic biopsy plus radiation therapy (99 patients; tumor dose: 60 gray [Gy]) with those of surgical resection plus radiation therapy (126 patients; tumor dose: 60 Gy). Only adult patients with supratentorial, lobar located, de novo glioblastoma were included. Survival time was analyzed with the Kaplan-Meier method. Prognostic factors were obtained from the multivariate Cox proportional hazards model. RESULTS: Patients were categorized in the Radiation Therapy Oncology Group (RTOG) Classes IV (46 patients), V (157 patients), and VI (22 patients). The resection group and the biopsy group did not differ in terms of age, pretreatment Karnofsky performance status KPS), gender, duration of symptoms, presenting symptoms, tumor location, tumor size, and the frequency of midline shift. Patients in the biopsy group more often were found to have left-sided tumors (P < 0.001). Transient perioperative morbidity and mortality rates were 1% and 1%, respectively, in the biopsy group and 5% and 1.6%, respectively, in the resection group (P > 0.05). The median survival time was 37 weeks for the resection group and 33 weeks for the biopsy group. The difference was not statistically significant (P = 0.09). The most favorable pretreatment prognostic factor was patient age < 60 years (P < 0.01). Tumor resection was highly effective in patients with midline shift (P < 0.01). In patients without midline shift radiation therapy alone was found to be as effective as tumor resection plus radiation therapy (P = 0.5). Patients with midline shift were more likely to have a worse KPS during the course of primary radiation therapy (P < 0.05). CONCLUSIONS: For RTOG Classes IV-VI patients with moderate mass effect of the tumor, radiation therapy alone is a rational treatment strategy. Tumor resection should be performed in patients with pretreatment midline shift whenever possible.

[Neuronavigation. Computer-assisted neurosurgery]. / Neuronavigation. Computerassistierte Neurochirurgie.

The use of stereotactic methods for the resection of subcortical lesions is heavily advocated in clinical neurosurgery introducing the term "neuronavigation". Though being an unequivocally elegant technique for the localisation and delineation of pathological lesions in the central nervous system neuronavigation has not been validated by any prospective randomized controlled trial. The method is prone to significant errors as to the intraoperative localisation based upon preoperative three-dimensional images. The maximum error can be up to 2.6 cm depending on the extent of the so-called brain shift. In comparison classical frame based stereotaxy has a mean error of +/- 1 mm and remains the gold standard for the exact three-dimensional localisation of a given lesion. The value of neuronavigation is evident for small deep seated vascular lesions. For metastatic tumors or skull base tumors the usefulness is rather marginal because alternative therapies are available with proven and equivalent efficacy and reduced morbidity on one hand, and because of the anatomy of the tumor which makes neuronavigation unnecessary. For the currently most common application of neuronavigation, i.e. surgery of gliomas, no significant improvements of therapeutic results can be expected from neuronavigation. The biology of gliomas limits any mechanical approaches.

Molecular genetic analysis as a tool for evaluating stereotactic biopsies of glioma specimens.

Over the last years, distinct genetic lesions have been associated with individual tumor entities. Stereotactic biopsy has become an essential diagnostic tool in surgical neuro-oncology. In order to evaluate the potential of molecular analyses in stereotactic biopsies, we examined a series of 156 human brain tumors from patients undergoing stereotactic biopsy for molecular alterations typically seen in astrocytic gliomas and compared those results with a control group of 268 astrocytic tumors obtained at open surgery. Stereotactic biopsies of astrocytomas with borderline histopathological features between the WHO grades II and III showed a higher rate of allelic losses on chromosome 10 than those of the WHO grade II from open surgery (p = 0.011). Stereotactic biopsies of astrocytomas with borderline histopathological features between the WHO grades III and IV showed a higher rate of allelic losses on chromosome 10 than those of the WHO grade III from open surgery (p = 0.013). This indicates that stereotactic biopsies with features intermediate between grades are likely to correspond to the higher malignancy grade. Our data demonstrate that molecular genetic approaches can be successfully applied to stereotactic glioma biopsies. The difference in the distribution of malignancy associated genetic alterations between a stereotactic and openly resected group of gliomas indicates that histopathology may underestimate the malignant potential in some stereotactic specimens. We propose to further evaluate the molecular analysis of stereotactic glioma biopsies as a useful adjunct to standard histopathological procedures.

Regional cerebral blood flow in peritumoral brain edema during dexamethasone treatment: a xenon-enhanced computed tomographic study.

OBJECTIVE: Regional cerebral flood flow (rCBF) in peritumoral brain edema is assumed to be decreased because of increased interstitial pressure. Impaired blood flow might lead to local hypoxia, altered metabolism, and disturbed ion homeostasis, thus causing neurological sequelae. Steroid treatment is thought to positively influence the sequelae of brain edema. We aimed to determine the rCBF in peritumoral edema in humans receiving dexamethasone treatment and the relationship of rCBF to global CBF. METHODS: We measured rCBF in 11 patients with untreated anaplastic gliomas or glioblastomas that were World Health Organization Grade III or IV restricted to one hemisphere with significant peritumoral edema who were receiving a standard dose of dexamethasone. rCBF was determined using stable xenon-enhanced computed tomography in a stereotactic frame. Edema was defined both by means of actual histology (stereotactic biopsies) and by imaging criteria. RESULTS: rCBF in peritumoral edema was decreased by 32% as compared with contralateral normal white matter. In each patient, this reduction was linearly related to blood flow in nonaffected white matter and cortex. The flow ratio in the different compartments was 1 (edema):1.5 (contralateral white matter):2.7 (contralateral cortex). Absolute perfusion values in contralateral cortex (means +/- standard deviations) (29.9+/-7.1 ml/100 g/min) and contralateral white matter (16.1+/-3.7 ml/100 g/min) were significantly decreased as well. CONCLUSION: Our study demonstrated that rCBF in peritumoral brain edema during steroid treatment is still decreased and is in a range in which it may cause neurological sequelae. Also, global CBF was decreased in all patients.

The risk of interstitial radiotherapy of low-grade gliomas.

BACKGROUND AND PURPOSE: The risk of side effects of low activity (i.e. <20 mCi) Iodine-125I (125I) interstitial radiotherapy was analyzed in patients with low-grade gliomas. MATERIALS AND METHODS: Permanent (247 patients) or temporary 125I-implants (268 patients) were used with a median reference dose of 60 Gy and 100 Gy, respectively, which was calculated to the outer rim of the tumour. The mean dose rate for temporary implants was low (median, 10 cGy/h). Risk factors were obtained from the multivariate proportional-hazards model. RESULTS: Radiogenic complications occurred in 39/515 patients (28 patients with transient symptoms and 11 patients with progressive symptoms). The most important risk factor was the volume of the intratumoural 200 Gy isodose. Available experimental data have associated a high dose zone in this range with the size of the treatment induced radionecrosis. Rapid tumour shrinkage (decrease of the tumour volume > or =50%) within the first 6 months with subsequent centripetal movement of non-pathologic tissue into the high dose zone and a reimplantation were additional risk factors. Radiation injury after rapid tumour shrinkage could be better avoided with temporary implants. A 200 Gy isodose volume <4.5 ml corresponded to an estimated risk of radiogenic complications <3%. There was a steep increase of the risk beyond this limit. Translation of the 200 Gy isodose volume in terms of the treatment volume and the reference dose allows rational treatment planning. The estimated risk of a temporary implant with an applied reference dose of 60 Gy and a treatment volume <23 ml was <3%. CONCLUSIONS: The intratumoural necrotizing effect of a low activity 125I implant limits its application to small treatment volumes. Radiation injury outside the treatment volume can be better avoided with temporary implants in the case of rapid tumour shrinkage.

[Stereotactic treatment of movement disorders]. / Stereotaktische Behandlung der Bewegungsstörungen.

Stereotactic surgery for movement disorders is currently undergoing a re-evaluation. A new understanding of the pathophysiology makes the surgical lesion a logical step for the aleviation of both hyperkinetic symptoms such as tremor and hypokinetic symptoms like bradykinesia. Advances in imaging and electrophysiological control render these procedures more accurate and safer. Indications are medically refractory, Parkinsonean tremor, essential tremor, cerebellar tremor, bradykinesia and L-Dopa induced dyskinesis. The standard procedure is ablative surgery, i.e. thalamotomy for tremors and pallidotomy for bradykinesia, dystonia and L-Dopa induced dyskinesias. Deep brain stimulation is a novel alternative for selected patients which is currently evaluated. Neural transplantation of autologus, fetal or genetically manipulated cell suspensions into the striatum for the time being is experimental.

Significant reduction of seizure incidence and increase of benzodiazepine receptor density after interstitial radiosurgery in low-grade gliomas.

Epilepsy is the leading symptom in low grade gliomas. In order to evaluate the effect of interstitial radiosurgery on seizure incidence the authors retrospectively analysed the outcome of 80 patients with temporal grade-II astrocytomas and a history of epilepsy. Patients were treated by 125-iodine temporary implants using 60 Gy as reference dose. The dose rate was 9.6 +/- 1.6 cGy/h. Median follow-up was 4.1 years. In 20 patients benzodiazepine receptor imaging was performed using single photon emission computed tomography and iomazenil. Treatment with carbamazepine alone led to a significant reduction in seizure incidence with 28% of patients being seizure-free (p < 0.05). Interstitial radiosurgery led to a further reduction of seizures rendering 40% of patients seizure-free after 3 months. After 6 months only 21% of patients still had seizures that were refractory to medical treatment (p < 0.01). SPECT imaging revealed that all tumours had a significant reduction of benzodiazepine receptors which also applied to the surrounding brain. After interstitial radiosurgery of tumours, receptor density increased in brain adjacent to the tumour (0.68 to 0.94 ratio ipsi to contralateral brain, p < 0.01) coincident with significant tumour shrinkage. Thus, in epileptogenic temporal low grade gliomas, interstitial radiosurgery not only reduced the tumour burden but also effectively treated the concomitant epilepsy, resulting in 79% of patients being seizure-free after combined treatment by radiosurgery and anticonvulsive medication. These results compare favourably to the outcome after resection in lesional epilepsy raising the issue of radiosurgery as a less invasive alternative to open epilepsy surgery.

Effect of LINAC radiosurgery on regional cerebral blood flow, glucose metabolism and sodium-potassium AtPase in skull base meningiomas and metastasis.

Stereotactic radiosurgery is an elegant alternative to microsurgery in both skull base meningiomas and solitary brain metastasis. Though efficacy for both entities has been established prognostic variables pertaining to individual tumour biology have not yet been identified. Therefore the authors measured regional glucose utilisation, thallium-uptake and blood flow in 20 patients (10 meningiomas, 10 metastasis) before and after LINAC radiosurgery. Measurements were performed using SPECT and stable xenon-CT. The mean tumour dose given was 16.3 and 19.5 Gy in meningiomas and metastasis respectively. Metastatic tumours were hypermetabolic in comparison to contralateral normal brain and responders to radiosurgery showed a lower tumour/brain ratio than non-responders (1.43 vs 0.91 respectively, p < 0.01). Meningiomas did not exhibit hypermetabolism and therapeutic outcome was not related to glucose utilisation. Thallium-uptake, however, was closely related to therapeutic response in meningiomas (1.37 vs 2.2 in responders vs non-responders, p < 0.01). This relationship could not be established in metastatic lesions. Blood flow was widely distributed in both meningiomas and metastasis (26-72.8 and 30.2-70.8 ml/100 g/min). rCBF did not correlate with therapeutic outcome. Using FDG-SPECT and thallium-201-SPECT the authors were able to distinguish between tumours likely to respond to stereotactic radiosurgery and those not prone to respond. Furthermore the methodology can be used to monitor therapeutic response in treated tumours before morphologic changes occur.

Supratentorial World Health Organization Grade 2 astrocytomas and oligoastrocytomas. A new pattern of prognostic factors.

BACKGROUND: Prognostic factors for adult patients with supratentorial World Health Organization (WHO) Grade 2 astrocytomas and poorly defined. METHODS: The prognostic importance of pretreatment patient- and tumor-related factors was analyzed retrospectively in 197 adult patients with supratentorial astrocytomas (n = 153) or oligoastrocytomas (n = 44) using the multivariate Cox proportional hazards model. Endpoints were death and date of malignant transformation. All patients were treated similarly between 1979 and 1992 with iodine-125 implants as the primary treatment. RESULTS: A new prognostic pattern was detected. Unfavorable prognostic factors with regard to survival were 1) a tumor volume > or = 20 mL; 2) a performance status < or = 80; and 3) age > or = 40 years for the female subpopulation. Midline shift (another important tumor-related factor after univariate analysis) was highly correlated with tumor volume and therefore not included in the multivariate model. Risk factors of malignant transformation were 1) a tumor volume > or = 20 mL; 2) an enhancement in the computed tomography scan; and 3) age > or = 40 years for the female subpopulation. Prognostic factors created subsets of patients with 5-year survival rates ranging from as low as 5% to as high as 79%. CONCLUSIONS: Any treatment decision or evaluation of treatment efficacy should take into account the strong influence of both patient- and tumor-related factors. Any further study design should consider the detected interaction between gender and age and the importance of tumor volume.