What is the value of emission tomography studies in patients with a primary glioblastoma multiforme treated by 192Ir brachytherapy?

BACKGROUND: We studied the use of (201)Thallium SPECT and L-[1-(11)C]-tyrosine PET in patients with a primary glioblastoma multiforme treated with (192)Ir brachytherapy after surgery and external beam radiation therapy. We hypothesised that the patients most likely to benefit from further surgery after deterioration would be those with radiation necrosis and would be recognised by a negative emission tomography scan. METHODS: Twenty-one patients underwent (201)Thallium SPECT performed before brachytherapy, and this was repeated in 19 patients when recurrence was suspected. Nine patients also underwent a PET scan at the same time. Nine patients underwent a second operation. FINDINGS: SPECT and PET were highly concordant concerning the prediction of radionecrosis and/or tumour recurrence. Repeat surgery did not lead to a significant increase in survival. There was no significant association between the duration of survival and tumour-to-background ratio but the number studied was small. Both SPECT and PET showed highly active lesions, which were proved to be recurrent tumour by clinical and histological follow-up. CONCLUSION: Although PET and SPECT are both highly sensitive in detecting active tumour tissue, emission tomography was not clinically valuable in the investigation of patients with a primary glioblastoma treated with brachytherapy.

Surgical considerations in movement disorders: deep brain stimulation, ablation and transplantation.

Surgical therapy for movement disorders has been practiced since the early 20th century, mostly for Parkinson's disease. At its onset, large destructive procedures like open resection of cortex, parts of the basal ganglia or its fibre connections produced variable, ill-documented results. With the introduction of the stereotactic operating technique in the second half of the century, ablative surgery became more refined, and more selective interventions became possible to alleviate the suffering of those patients for whom no other treatment modalities were yet available. However, the introduction of levodopa-based pharmacological therapy pushed surgical therapy almost completely to the background. In the past two decades, there has been a resurgence of interest in surgery for movement disorders, due to both limitations of long-term pharmacological therapy and the advent of the treatment modality of deep brain stimulation. The subject has now grown into a large field of clinical and scientific interest. Parkinson's disease is the most widespread surgical indication, but in other movement disorders considerable improvement can be achieved by surgery as well, most notably in dystonia. A short review of the surgical therapy for these disorders is presented.

Unilateral pallidotomy versus bilateral subthalamic nucleus stimulation in Parkinson's disease: one year follow-up of a randomised observer-blind multi centre trial.

BACKGROUND: To investigate whether STN stimulation is more efficacious than unilateral pallidotomy in advanced Parkinson's disease (PD) one year after surgery. METHOD: Thirty-four patients with advanced PD were randomly assigned to unilateral pallidotomy or bilateral STN stimulation. Outcome measures were parkinsonian symptoms in off and on phases (UPDRS 3), dyskinesias, functional status, Parkinson's disease quality of life questionnaire, the effects on separate symptoms, timed tests, patient diaries, dopaminergic drugs changes, adverse effects, and global outcome scale. Patients were assessed before surgery, six months and one year after surgery. The primary outcome measure was the off phase UPDRS 3 at six months follow-up. FINDINGS: The off phase UPDRS 3 score improved from 46.5 to 32 points in the pallidotomy patients and from 51.5 to 24 in the STN stimulation patients (p = 0.002). On phase UPDRS 3 and off phase Schwab and England functional scale improved significantly in favour of the STN stimulation patients. Dopaminergic drugs reduction was larger in the STN group although the difference between the treatment groups was not significant. One patient in each group had a major adverse effect. CONCLUSIONS: Bilateral STN stimulation is more efficacious than unilateral pallidotomy in advanced PD up to one year after surgery.

Radiation-enhanced vascular endothelial growth factor (VEGF) secretion in glioblastoma multiforme cell lines--a clue to radioresistance?

OBJECTIVE: Postoperative radiotherapy is standard treatment for patients with a glioblastoma multiforme (GBM). However, a GBM is radioresistant and almost always recurs, even after a high dose of radiation. A GBM is characterized by its extensive neo-angiogenesis, which can be attributed to the high levels of vascular endothelial growth factor (VEGF). The scope of this study is to investigate the VEGF secretion by GBM cells with different radiosensitivity after irradiation. METHODS: Three human GBM cell lines (U251, U251-NG2 and U87) were irradiated with single doses of 0, 5, 10 and 20 Gy of gamma-rays from a (137)Cs source. VEGF levels in medium were measured by ELISA at 24, 48 and 72 h after radiation. Cell survival was measured by the XTT assay 7 days after irradiation. RESULTS: Following single dose radiation, the VEGF levels showed a dose dependent increase in U251, U251-NG2 and U87 glioma cells. Both base-line and radiation-enhanced VEGF levels were about 10-fold higher in U87 compared to U251 and U251-NG2 cells. In addition, in the XTT assay, the U87 was more radioresistant than both U251 and U251-NG2 cell lines (dose modifying factor (DMF) = 1.6 and 1.7 resp). CONCLUSION: Irradiation enhanced VEGF secretion in all three tested glioma cell lines (up to eight times basal levels). It is tempting to associate the radiation-enhanced VEGF secretion with an increased angiogenic potential of the tumor, which may be a factor in radioresistance.

[Headache and impaired consciousness due to the spontaneous intracranial hypotension syndrome]. / Hoofdpijn en verminderd bewustzijn veroorzaakt door het spontane liquorhypotensiesyndroom.

A 51-year-old man presented with a 6-week history of progressive headache, confusion and ataxic gate. The symptoms were not preceded by trauma or lumbar puncture. A CT-scan of the brain revealed bilateral subdural fluid accumulation and hyperdensities in the subarachnoid space. In view of the signs of a subarachnoid haemorrhage, angiography was performed but showed no indications of an aneurysm. An MRI-scan of the head revealed abnormalities in line with intracranial hypotension. CT-myelography of the whole spine revealed a cerebrospinal fluid leak at the level of the fifth and sixth thoracic vertebrae. The patient recovered completely after placement of an epidural blood patch at this level. Spontaneous intracranial hypotension shows clinical similarities with the symptoms following a lumbar puncture. In most cases it can be treated by conservative measures. However, invasive measures are sometimes necessary to close the defect in the meninges.

Quality of life after brachytherapy in patients with glioblastoma multiforme.

As quality of life (QoL) is perhaps the most important outcome for patients treated for glioblastoma multiforme (GBM), we measured QoL in GBM patients after brachytherapy. QoL was assessed by questionnaires for both patients and partners before brachytherapy and at various times during follow-up in 21 GBM patients by an extension of the Rotterdam Symptom Checklist (e-RSCL), consisting of four subscales. The Karnofsky Performance Scale (KPS) was also measured. Analysis of variance was done to evaluate the direct effect of brachytherapy (visit 1-2, short-term) and during follow up (visit 1-4, longer-term). Significant short-term effects were found for two subscales of the e-RSCL. Longer-term effects were found for all four subscales and for the KPS. A high correlation between partner and patient's QoL assessment was found. QoL in GBM patients after brachytherapy can therefore be carefully monitored with a subjective instrument such as the e-RSCL. Patients and partners experience QoL equally.

Unilateral pallidotomy versus bilateral subthalamic nucleus stimulation in PD: a randomized trial.

OBJECTIVE: To compare the efficacy of unilateral pallidotomy and bilateral subthalamic nucleus (STN) stimulation in patients with advanced Parkinson disease (PD) in a randomized, observer-blind, multicenter trial. METHODS: Thirty-four patients with advanced PD were randomly assigned to have unilateral pallidotomy or bilateral STN stimulation. The primary outcome was the change from baseline to 6 months in the motor part of the Unified PD Rating Scale (motor UPDRS) in the off phase. Secondary outcomes were parkinsonian symptoms in the on phase (motor UPDRS), dyskinesias (Clinical Dyskinesia Rating Scale and dyskinesias UPDRS), functional status (activities of daily living UPDRS and Schwab and England scale), PD Quality of Life questionnaire, changes in drug treatment, and adverse effects. RESULTS: The off phase motor UPDRS score improved from 46.5 to 37 points in the group of pallidotomy patients and from 51.5 to 26.5 in the STN stimulation patients (p = 0.002). Of the secondary outcome measures, on phase motor UPDRS and dyskinesias UPDRS improved significantly in favor of the STN stimulation patients. Reduction of antiparkinsonian drugs was greater after STN stimulation than after pallidotomy. One patient in each group had a major adverse effect. CONCLUSIONS: Bilateral STN stimulation is more effective than unilateral pallidotomy in reducing parkinsonian symptoms in patients with advanced PD.

[Neurosurgery or endovascular treatment for subarachnoid hemorrhage due to ruptured aneurysm? In case of doubt choose endovascular treatment]. / Operatie of endovasculaire behandeling bij subarachnoïdale bloeding door een gebarsten aneurysma? Bij twijfel kiezen voor endovasculaire behandeling.

In the 'International subarachnoid aneurysm trial' (ISAT), patients with ruptured intracranial aneurysms were randomised to endovascular detachable coil treatment or craniotomy with clipping of the aneurysm if either treatment was judged to be suitable. Of all patients assessed for eligibility, endovascular treatment was considered the best treatment for 29% and neurosurgical clipping was considered best for 38%, in 11% the treatment was unknown, which left 22% for whom there was no preference for one of the two treatments and who gave permission for randomisation. In patients allocated endovascular treatment, 24% was dependent or dead at 1 year versus 31% of patients allocated neurosurgical treatment. The relative-risk reduction in dependency or death at 1 year was 23%. The risk of re-bleeding after 1 year was 2 per 1276 patient years in patients allocated endovascular treatment and 0 per 1081 patient years in those allocated neurosurgical treatment. Based on these results it is estimated that in the Netherlands each year at least 500 patients with a ruptured intracranial aneurysm should be treated with endovascular coiling within 3 days of the haemorrhage. This treatment can best be limited to a few centres, since it will otherwise not be possible to gain sufficient experience. The same applies to neurosurgical treatment since the number of patients treated with neurosurgical clipping will decrease.

A comparison of neuropsychological effects of thalamotomy and thalamic stimulation.

OBJECTIVE: The neuropsychological effects of thalamotomy and thalamic stimulation in patients with severe drug-resistant tremor due to PD, essential tremor (ET), or MS were compared in a randomized trial. METHODS: Complete neuropsychological evaluations at baseline and 6 months after surgery were obtained in 62 patients who underwent thalamotomy (n = 32: 21 PD, 6 ET, 5 MS) or thalamic stimulation (n = 30: 19 PD, 7 ET, 4 MS). RESULTS: Six months after thalamotomy, a decline was seen in the scores of the Stroop Color-Word Test, with the exception of the interference score. In the thalamic stimulation group, no significant changes were found on any of the cognitive tests. Age, diagnosis, disease severity, and baseline cognitive status were not correlated to cognitive changes. A difference in score changes between right- and left-sided surgery was found in verbal fluency and Stroop Test scores after both thalamotomy and thalamic stimulation. CONCLUSIONS: Both thalamotomy and thalamic stimulation are associated with a minimal overall risk of cognitive deterioration. Verbal fluency decreased after both left-sided thalamotomy and thalamic stimulation.

Morbidity and mortality following pallidotomy in Parkinson's disease: a systematic review.

OBJECTIVE: To study the frequency of morbidity and mortality associated with pallidotomy. METHOD: The authors searched the MEDLINE electronic database for pallidotomy articles reported between January 1992 and December 2000. They selected studies by the following criteria: original clinical data, unequivocal description of morbidity and mortality, and unselected consecutive cases. The authors extracted the following data: number of patients, unilateral or bilateral procedures, age, localization technique, follow-up time, number of patients with adverse effects, number of patients with permanent adverse effects (>3 months), types of adverse effects, and mortality. RESULTS: For unilateral pallidotomy, 12 prospective studies included 334 patients. Of these patients, 30.2% (95% CI, 25.3 to 35.2) had adverse effects, and 13.8% (95% CI, 10.1 to 17.5) had permanent adverse effects. A symptomatic infarction or hemorrhage occurred in 3.9% (95% CI, 2.1 to 6.6). The mortality rate was 1.2% (95% CI, 0.3 to 3.0). In the series with microelectrode recording, the frequency of adverse effects was 14.4% (95% CI, 4.7 to 24.1) higher and the frequency of stroke was 4.9% (95% CI, 1.4 to 8.4) higher. The most frequent adverse effects were problems with speech (11.1%) and facial paresis (8.4%). For bilateral pallidotomy, five historical cohort studies including 20 patients were available for review. Fourteen patients had an adverse effect, and the most frequent adverse effects were impairments of speech and cognition. CONCLUSIONS: The risk of permanent adverse effects associated with unilateral pallidotomy was 13.8%. A symptomatic infarction or hemorrhage occurred in 3.9% of patients, and the associated mortality rate was 1.2%.

Proliferation- and apoptosis-related proteins in intracranial ependymomas: an immunohistochemical analysis.

UNLABELLED: As the value of grading of ependymomas is currently debated we studied the expression of proliferation- and apoptosis-related proteins in these tumors as these mechanisms both are suggested to be important in tumor growth. We characterized the immunohistochemical expression of p53, Mdm2, Bcl-2, and Bax in 51 intracranial ependymomas. We also assessed the apoptosis- and proliferation-index, measured by MIB-1, PCNA-immunohistochemistry, and analyzed the clinical parameters. Of all used antibodies, the correlation with survival and the correlation among ordered categories was assessed. None of the analyzed immunohistochemical variables were significantly correlated with tumor grade. On the other hand, PCNA, MIB-1, and p53 were significantly related to the survival of the patient. In multivariate analysis, p53 was the only independent predictive variable (p = 0.0132). CONCLUSION: The strongest predictors of survival in univariate analysis were the expression of PCNA, MIB-1 and p53. In multivariate analysis a p53 expression > 1% showed to be significantly related with a worse survival. The predicting value of p53 expression has to be confirmed by others before solid conclusions can be made. Apoptosis seems not to be an important mechanism in tumor growth in ependymomas. The expression of Mdm2, Bcl-2, and Bax were not related to survival.

Outcome of unilateral pallidotomy in advanced Parkinson's disease: cohort study of 32 patients.

OBJECTIVES: In a randomised trial to study the efficacy of unilateral pallidotomy in patients with advanced Parkinson's disease, patients having pallidotomy within 1 month after randomisation were compared with patients having pallidotomy 6 months after the primary outcome assessment. Of the 37 patients enrolled 32 had a unilateral pallidotomy. The follow up study of these patients is presented to report (1) clinical outcome; (2) adverse effects; (3) cognitive and behavioural effects; (4) relation between lesion location and outcome; and (5) preoperative patient characteristics predictive for good outcome. METHODS: Outcome measures were the motor section of the unified Parkinson's disease rating scale (UPDRS), levodopa induced dyskinesias, disability, quality of life, and a comprehensive neuropsychological assessment. Multivariate logistic regression was used to identify preoperative patient characteristics independently associated with good outcome. RESULTS: Off phase assessment showed a reduction in parkinsonism from 49 to 36.5 points on the UPDRS 6 months after surgery. Improvements were also demonstrated for activities of daily living and quality of life. In the on phase dyskinesias were reduced. All effects lasted up to 12 months after surgery. Three patients had major permanent adverse effects. Besides worsening of verbal fluency after left sided surgery, systematic cognitive deterioration was not detected. Patients taking less than 1000 levodopa equivalent units (LEU)/day were more likely to improve. CONCLUSIONS: The positive effects of unilateral pallidotomy are stable up to 1 year after surgery. Patients taking less than 1000 LEU per day were most likely to improve.

GOA, a novel gene encoding a ring finger B-box coiled-coil protein, is overexpressed in astrocytoma.

Serial analysis of gene expression (SAGE) was used to identify a gene named GOA (gene overexpressed in astrocytoma), which codes for a novel Ring finger B-box coiled-coil (RBCC) protein. Northern blot hybridization showed overexpression of GOA in 9 of 10 astrocytomas. Except for kidney, in which high expression was found, expression levels in normal tissues were low and comparable to normal brain. Immunohistochemistry demonstrated presence of GOA, with prominent nuclear staining, in astrocytoma tumor cells and astrocytes of fetal brain, but virtual absence in mature astrocytes. Overexpression was not due to amplification, since amplification of GOA was only found in one of 65 astrocytomas. GOA was localized to 17q24-25, a region that is frequently gained or amplified in a number of other tumor types. GOA contains two LXXLL motifs, which are thought to be important for nuclear receptor binding. Our data suggest an important role of GOA in the process of dedifferentiation that is associated with astrocytoma tumorigenesis and possibly with that of other tumor types as well.

Prognostic factors in glioblastoma multiforme. 10 years experience of a single institution.

BACKGROUND: To analyze prognostic factors in patients with a glioblastoma multiforme treated in an academic institute over the last 10 years. PATIENTS AND METHOD: From 1988 to 1998, 198 patients with pathologically confirmed glioblastoma multiforme were analyzed. Five radiation schedules were used mainly based on pretreatment selection criteria: 1. 60 Gy in 30 fractions followed by an interstitial iridium-192 (Ir-192) boost for selected patients with a good performance and a small circumscribed tumor, 2. 66 Gy in 33 fractions for good performance patients, 3. 40 Gy in eight fractions or 4. 28 Gy in four fractions for poor prognostic patients and 5. no irradiation. RESULTS: Median survival was 16 months, 7 months, 5.6 months, 6.6 months and 1.8 months for the groups treated with Ir-192, 66 Gy, 40 Gy, 28 Gy and the group without treatment, respectively. No significant improvement in survival was encountered over the last 10 years. At multivariate analysis patients treated with a hypofractionated scheme showed a similar survival probability and duration of palliative effect compared to the conventionally fractionated group. The poor prognostic groups receiving radiotherapy had a highly significant better survival compared to the no-treatment group. Patients treated with an Ir-192 boost had a better median survival compared to a historical group matched on selection criteria but without boost treatment (16 vs 9.7 months, n.s.). However, survival at 2 years was similar. Analysis on pretreatment characteristics at multivariate analysis revealed age, neurological performance, addition of radiotherapy, total resection, tumor size post surgery and deterioration before start of radiotherapy (borderline) as significant prognostic factors for survival. CONCLUSION: Despite technical developments in surgery and radiotherapy over the last 10 years, survival of patients with a glioblastoma multiforme has not improved in our institution. The analysis of prognostic factors corresponded well with data from the literature. A short hypofractionated scheme seems to be a more appropriate treatment for patients with intermediate or poor prognosis as compared to a conventional scheme. The benefit in median survival for patients treated with an interstitial boost is partly explained by patient selection. Since there were no long-term survivors with this boost treatment, its clinical value, if there is one, is still limited.

[Stereotaxic neurosurgery for treatment of Parkinson disease]. / Stereotactische neurochirurgie bij de behandeling van de ziekte van Parkinson.

Three target structures are available in stereotactic surgery for Parkinson's disease: the thalamus, the globus pallidus and the subthalamic nucleus. The subthalamic nucleus appears to be the most promising structure. However, the thalamus can be considered in the case of an incapacitating tremor presenting as a primary symptom. Surgery in the globus pallidus may be as effective as in the subthalamic nucleus, but in the latter it is often accompanied by a reduction in dopaminergic medication. The surgical technique of electrical stimulation causes fewer adverse effects than that of coagulation and can therefore be applied bilaterally, but does require more intense postoperative care. In the selection of patients for surgery, levodopa responsiveness plays an important role in predicting effectiveness, except in the case of tremor.

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.