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Hypofractionated Conformal Stereotactic Radiotherapy for Arteriovenous Malformations

OBJECTIVEArteriovenous malformations (AVMs) are congenital vascular lesions that are associated with high morbidity and mortality if left untreated. There are several options for treatment, including radiotherapy. Safe and effective single-fraction radiotherapy for patients with large AVMs has been considered difficult. METHODSBetween December 1986 and June 2001, 36 patients with cerebral AVMs were treated with hypofractionated conformal stereotactic radiotherapy at Umeå University Hospital. Twenty-nine patients have been followed angiographically to date and are reported in this study. RESULTSTwenty-four (83%) of 29 patients (mean AVM volume, 11.5 cm3) underwent complete obliteration of their AVMs. The rates of angiographically verified total obliteration at 2 years after treatment were 56% for AVMs 4 to 10 cm3 and 50% for AVMs larger than 10 cm3. The obliteration rate increased considerably with extended follow-up. Five years after treatment, the obliteration rates were 81% for AVMs 4 to 10 cm3 and 70% for AVMs larger than 10 cm3. CONCLUSIONHypofractionated conformal stereotactic radiotherapy may be an important alternative to single-fraction radiotherapy in patients with large AVMs or AVMs located in eloquent areas, because it allows the administration of a higher radiation dose than is possible to deliver in single-fraction radiosurgery. With our technique of hypofractionated conformal stereotactic radiotherapy, the rate of obliterating AVMs was comparable to that of single-dose radiosurgery, although the volumes of the irradiated AVMs in our study were larger than those reported previously.

Effects of radiotherapy and estramustine on the microvasculature in malignant glioma

Tumour angiogenesis is essential for progression of solid tumours and constitutes an interesting target for therapy. However, impaired tumour blood supply may also be an important obstacle for treatment by radiotherapy and chemotherapy. Estramustine has been shown to increase tumour blood flow and potentiate the effect of radiotherapy in experimental glioma. This study investigated the effects of fractionated radiotherapy and estramustine on angiogenesis in malignant glioma. The intracerebral BT4C rat glioma model was used and the animals were given whole brain radiotherapy 4 Gy × 5 days alone or in combination with estramustine 20 mg kg-1 i.p. daily. Tumour microvascular density (MVD) was assessed by manual and computerized morphometrical analysis. Expression of vascular endothelial growth factor (VEGF) was studied by in situ hybridization. Radiotherapy decreased MVD to 157 vessels per mm2 compared to 217 vessels per mm2 in controls. Estramustine counteracted this anti-angiogenic effect and potentiated the anti-tumoural effect of radiotherapy. In addition, vessel size increased after estramustine treatment. Five days after completion of radiotherapy the expression of VEGF was increased in the centre of the tumours. In conclusion, fractionated radiotherapy decreases microvascular density in experimental malignant glioma. This effect was abolished by estramustine. The anti-vascular effect of irradiation is important to recognize when combining radiotherapy with cytotoxic drugs.

INFLUENCE OF PREVIOUS TREATMENT ON OUTCOME AFTER GLYCEROL RHIZOTOMY FOR TRIGEMINAL NEURALGIA

The aim of the present study was to evaluate the influence of previous treatment on outcome and sensory disturbance after a retrogasserian glycerol injection for trigeminal neuralgia. Ninety-nine patients with trigeminal neuralgia underwent a retrogasserian glycerol rhizotomy. Fifty-three of those patients experienced recurrent pain after the previous treatment. At the 1 year follow-up, the outcome was excellent or good in 83% of patients with no previous treatment, compared with 60 and 75% in those patients with earlier glycerol injections or radiofrequency lesions, respectively. Quantitatively assessed, the sensory impairment was most pronounced in patients who had earlier radio-frequency lesions compared with patients not treated previously. The occurrence of dysesthesia was more frequent in patients who had been surgically treated earlier. A review of the literature showed that the concentration of the glycerol preparation used probably is of great importance in terms of pain relief and sensory sequelae.

Air-ventriculography provokes an anterior displacement of the third ventricle during functional stereotactic procedures.

SummaryThe width of the third ventricle, the length of the anterior commissure-posterior commissure line (AC-PC line), the spatial position of the midplane of the third ventricle, and the co-ordinates of the AC, the PC, and of 17 brain targets in the thalamus, hypothalamus and pallidum, were assessed on a pre-operative Stereotactic computed-tomography (CT) study and compared to measurements on intra-operative air-ventriculography, using a non-invasive relocatable Stereotactic frame.There were no significant differences in the length of the ACPC line, in the position of the midsagittal plane of the third ventricle, or in the vertical or lateral co-ordinates of the AC, the PC and the cerebral targets, between measurements on CT and on air-ventriculography. However, the width of the third ventricle was significantly larger, and the spatial positions of both AC and PC were significantly more anterior on air-ventriculography than on the CT study. This anterior dislocation of the commissures was presumably due to the insufflation of air into the ventricles of patients being in the supine position during surgery.

Interleukin-2 and histamine in combination inhibit tumour growth and angiogenesis in malignant glioma.

Biotherapy including interleukin-2 (IL-2) treatment seems to be more effective outside the central nervous system when compared to the effects obtained when the same tumour is located intracerebrally. Recently published studies suggest that reduced activity of NK cells in tumour tissue can be increased by histamine. The present study was designed to determine whether IL-2 and histamine, alone or in combination, can induce anti-tumour effects in an orthotopic rat glioma model. One group of rats was treated with histamine alone (4 mg kg–1s.c. as daily injections from day 6 after intracranial tumour implantation), another group with IL-2 alone as a continuous subcutaneous infusion and a third group with both histamine and IL-2. The animals were sacrificed at day 24 after tumour implantation. IL-2 and histamine in combination significantly reduced tumour growth. The microvessel density was significantly reduced, an effect mainly affecting the small vessels. No obvious alteration in the pattern of VEGF mRNA expression was evident and no significant changes in apoptosis were observed. Neither IL-2 nor histamine alone caused any detectable effects on tumour growth. Histamine caused an early and pronounced decline in tumour blood flow compared to normal brain. The results indicate that the novel combination of IL-2 and histamine can be of value in reducing intracerebral tumour growth and, thus, it might be of interest to re-evaluate the therapeutic potential of biotherapy in malignant glioma.

Uptake and retention of estramustine and the presence of estramustine binding protein in malignant brain tumours in humans

Estraumustine phosphate (EMP), a cytotoxic drug used in the treatment of prostatic carcinoma, has been shown to exert cytotoxic effects on glioma cells in vitro. The drug uptake is assumed to depend on a specific estramustine binding protein (EMBP). One of the main difficulties in achieving cytotoxic effect in malignant brain tumours is believed to be due to the poor penetration of cytotoxic drugs into tumour tissue. In patients with malignant supratentorial brain tumours we have analysed the uptake of EMP metabolites in tumour tissue after oral administration and demonstrated EMBP in the same tissue specimens. Sixteen patients were given 280 mg EMP orally 14 h prior to surgery. Specimens from brain tumour tissue, cystic fluid, and serum were collected during surgery. Using gas chromatography the metabolites of EMP, estramustine (EaM) and estromustine (EoM), were quantified, EMBP was demonstrated by immunohistochemistry. The mean concentrations of EaM and EoM, expressed in ng g-1, were 60.3 and 38.4 in tumour tissue and 3.5 and 56.3 in serum, respectively. An accumulation of EaM in tumour tissue was found with a mean concentration gradient of 16.1 versus serum, while the gradient for EoM was 0.76. EMBP was demonstrated with a high degree of staining in all but one tumour. The high concentrations of EaM and EoM found in malignant brain tumour tissue correspond to potentially cytotoxic levels. The present results as well as the earlier in vitro demonstrated cytotoxic effects on glioma cells strengthen the possibility of a therapeutic effect of EMP in the treatment of malignant brain tumours.

Thalamic Stereotaxis for Chronic Pain: Ablative Lesion or Stimulation?

Twenty-five patients underwent 33 stereotactic procedures on the thalamus for the treatment of persistent pain of benign or malignant origin. There were 19 ablative and 14 stimulation procedures. The thalamic targets were the centrum medianum (CM), the pulvinar, the nucleus ventralis posteromedialis and/or the nucleus ventralis posterolateralis. Ablative surgery was successful in 52.6% of the procedures, and chronic stimulation in 66%. Stimulation in the ventroposterior group of the thalamus was most effective for peripheral deafferentation pain while ablative stereotaxis on the CM may be more appropriate for patients with central pain or cancer pain. ¿¿

Relation between sensory disturbance and outcome after retrogasserian glycerol rhizotomy

SummaryThe relation between postoperative sensory deterioration and surgical outcome in 54 patients treated by retrogasserian glycerol rhizotomy for trigeminal neuralgia was studied. The facial sensibility was assessed one day and three months postoperatively. Thresholds for perception and pain were determined quantitatively using transcutaneous electrical stimulation and clinically by light touch and pinprick tests. At a follow-up one year after surgery there was no significant difference in pain relief between patients who did show and patients who did not show sensory deterioration at the one day or three months evaluations. Nevertheless, there was a tendency for higher recurrence rate in patients with mild or no sensory disturbance.

Microvascular decompression for trigeminal neuralgia: no relation between sensory disturbance and outcome.

Trigeminal nerve microvascular decompression (MVD) relieves the pain in a great majority of patients. However, there has been a debate regarding whether the pain-relieving effect is due to the decompression itself or a surgical trauma to the nerve. In 37 consecutive patients, the facial sensibility was quantitatively assessed and the function of other cranial nerves was investigated before and after MVD. The patients were followed for 1-5 years (mean 3.4 years) to assess the surgical outcome. Twelve patients (32%) experienced a mild postoperative sensory deficit assessed by clinical examination. When measured quantitatively with electrical stimulation, sensory thresholds for perception and pain were elevated more than 25% in 16 of the patients (43%). All together 19 patients (51%) did not have any sensory deficit as assessed by either of the two methods used. No severe postoperative cranial nerve dysfunctions were noted in this series. Three patients (8%) had a recurrence of pain at 7-9 months postoperatively. Two of those patients had a moderate elevation of measured sensory thresholds. All 19 patients with no cranial nerve deficits after MVD experienced an excellent pain relief. It seems that trauma to the trigeminal nerve is not a prerequisite for obtaining pain relief after MVD for trigeminal neuralgia.

Tumor Blood Flow and the Cytotoxic Effects of Estramustine and Its Constituents in a Rat Glioma Model

OBJECTIVE Estramustine (EaM) is a conjugate of nor-nitrogen mustard (NNM) and 17 beta-estradiol (E2) that has cytotoxic and radiosensitizing effects on experimental malignant glioma. Its mechanism of action is only partly understood. To further investigate the mechanism in vivo, the effects on tumor blood flow (TBF) and tumor growth were analyzed. METHODS TBF was measured by radioactive microspheres, and tumor growth was measured by weight. Apoptosis was evaluated by in situ end labeling and gel electrophoresis. The effects of the constituents NNM and E2 were also evaluated. RESULTS EaM increased TBF to 153.8 ml/100 g/min after 3 days and to 153.9 ml/100 g/min after 10 days of treatment, compared with 94.0 ml/100 g/min in untreated controls. Cerebral blood flow did not change after EaM treatment. NNM increased TBF but also showed a tendency to increase cerebral blood flow. E2 increased TBF, whereas cerebral blood flow was unchanged. EaM resulted in a rapid reduction in tumor weight from 230 mg in untreated animals to 146 mg after 3 days of treatment. EaM induced an early transient fragmentation of deoxyribonucleic acid in glioma but not in the normal brain. Neither NNM nor E2 affected tumor weight. CONCLUSION EaM increases TBF in the BT4C rat glioma model with a concomitant rapid antitumoral effect. The increase in TBF could partially be induced by an estrogen-like action of EaM, but the rapid cytotoxic effect of the drug is obviously attributed to the intact EaM compound. This cytotoxic effect might be attributable to the induction of programmed cell death.