Increased compliance with tumor treating fields therapy is prognostic for improved survival in the treatment of glioblastoma: a subgroup analysis of the EF-14 phase III trial.

BACKGROUND: Tumor treating fields (TTFields) is a non-invasive, antimitotic therapy. In the EF-14 phase 3 trial in newly diagnosed glioblastoma, TTFields plus temozolomide (TTFields/TMZ) improved progression free (PFS) and overall survival (OS) versus TMZ alone. Previous data indicate a ≥ 75% daily compliance improves outcomes. We analyzed compliance data from TTFields/TMZ patients in the EF-14 study to correlate TTFields compliance with PFS and OS and identify potential lower boundary for compliance with improved clinical outcomes. METHODS: Compliance was assessed by usage data from the NovoTTF-100A device and calculated as percentage per month of TTFields delivery. TTFields/TMZ patients were segregated into subgroups by percent monthly compliance. A Cox proportional hazard model controlled for sex, extent of resection, MGMT methylation status, age, region, and performance status was used to investigate the effect of compliance on PFS and OS. RESULTS: A threshold value of 50% compliance with TTFields/TMZ improved PFS (HR 0.70, 95% CI 0.47-1.05) and OS (HR 0.67, 95% CI 0.45-0.99) versus TMZ alone with improved outcome as compliance increased. At compliance > 90%, median survival was 24.9 months (28.7 months from diagnosis) and 5-year survival rate was 29.3%. Compliance was independent of gender, extent of resection, MGMT methylation status, age, region and performance status (HR 0.78; p = 0.031; OS at compliance ≥ 75% vs. < 75%). CONCLUSION: A compliance threshold of 50% with TTFields/TMZ correlated with significantly improved OS and PFS versus TMZ alone. Patients with compliance > 90% showed extended median and 5-year survival rates. Increased compliance with TTFields therapy is independently prognostic for improved survival in glioblastoma.

Treatment of clinically nonfunctioning pituitary adenomas with dopamine agonists.

OBJECTIVE: Clinically nonfunctioning pituitary adenoma (NFPA) remains the only pituitary tumor subtype for which no effective medical therapy is available or recommended. We evaluated dopamine agonist (DA) therapy for preventing growth of postsurgical pituitary tumor remnants. DESIGN: The study design included historical cohort analysis of clinical results at two pituitary referral centers with different standard practices for postoperative NFPA management: DA therapy or conservative follow-up. METHODS: Seventy-nine patients followed for 8.8±6.5 years were treated with DA, initiated upon residual tumor detection on postoperative MRI (preventive treatment (PT) group, n=55), or when tumor growth was subsequently detected during follow-up (remedial treatment (RT) group, n=24). The control group (n=60) received no medication. Tumoral dopamine and estrogen receptor expression assessed by quantitative RT-PCR and immunostaining were correlated with response to treatment. RESULTS: Tumor mass decreased, remained stable, or enlarged, respectively, in 38, 49, and 13% of patients in the PT group, and in 0, 53, and 47% of control subjects; shrinkage or stabilization was achieved in 58% of enlarging tumors in the RT group, P < 0.0001.Fifteen-year progression-free survival rate was 0.805, 0.24, and 0.04, respectively, for PT, RT, and control groups (P<0.001). About 42% of patients in the control group required additional surgery or radiotherapy, compared with 38 and 13% subjects in the RT and PT groups, respectively (P=0.002). Outcome measures were not related to NFPA D2R abundance. CONCLUSIONS: Dopamine agonist therapy in patients with NFPA is associated with decreased prevalence of residual tumor enlargement after transsphenoidal surgical resection.

Transarterial treatment with Onyx of intracranial dural arteriovenous fistula with cortical drainage in 17 patients.

BACKGROUND AND PURPOSE: Intracranial DAVFs with cortical venous drainage have a high tendency to bleed. Complete closure of these lesions is essential to prevent clinically deleterious events. We describe our experience using Onyx in an arterial approach for treatment of DAVFs in 17 patients. MATERIALS AND METHODS: Between 2006 and 2010, we used Onyx for performing transarterial embolization in 17 patients with intracranial DAVFs and cortical venous drainage. Clinical assessment was performed before and after every treatment at discharge and at follow-up. Fourteen patients underwent follow-up MR imaging and MRA, 8 of them also underwent follow-up diagnostic angiography. RESULTS: Fifteen patients (88%) underwent 1 procedure. Complete obliteration by embolization with Onyx was achieved in 16 patients (94% acute obliteration). The mean amount of Onyx injected was 2.3 mL (range, 0.4-4.8 mL). The sole technical complication was an embolus to a branch of the MCA, which was resolved by intra-arterial tPA injection. A clinical complication of transient trochlear nerve palsy in the same patient due to mass effect of Onyx resolved spontaneously within 3 months. CONCLUSIONS: Intra-arterial embolization of cranial DAVFs with cortical venous drainage by using Onyx results in a high rate of complete obliteration (94%) with low morbidity (6%). Follow-up DSA in 8 patients revealed no evidence of reopening.

Brain arteriovenous malformation treatment using a combination of Onyx and a new detachable tip microcatheter, SONIC: short-term results.

BACKGROUND AND PURPOSE: Endovascular embolization with Onyx is one of the tools used in the treatment of intracerebral AVMs. The recent introduction of a new microcatheter with detachable tip has led us to adopt a new treatment approach by using endovascular embolization with Onyx as the main treatment for brain AVM with curative intent. The purpose of the present study is to evaluate our initial results by using this new treatment strategy with special emphasis on the safety and feasibility of the technique. MATERIALS AND METHODS: Forty-three consecutive patients were treated by embolization for brain AVM over a 14-month period, mostly by using Onyx and a microcatheter with detachable tip. Twenty-six of these patients (60%) harbored Spetzler-Martin AVMs of grades 4-5. RESULTS: Endovascular treatments were completed in 29 out of 43 patients; the median number of procedures per patient was 2 (range, 1-4). Complete obliteration by using embolization exclusively was achieved in 16 patients, resulting in a 55% cure rate in patients who concluded treatments (16/29) and 37% in the cohort (16/43). The amount of Onyx injected by using microcatheters with detachable tips was significantly larger than that injected with the nondetachable microcatheters (mean volume, 2.5 +/- 2.2 versus 1.7 +/- 1.3 mL, respectively, P < .05, t test). Seven clinical complications were observed in a total of 76 embolization sessions (9.2%). CONCLUSIONS: Endovascular embolization of brain AVM by using Onyx and SONIC results in a relatively high complete obliteration. The use of the microcatheter with detachable tip adds several advantages, mainly in that higher volumes of Onyx can be safely injected.

Convection-enhanced drug delivery of interleukin-4 Pseudomonas exotoxin (PRX321): increased distribution and magnetic resonance monitoring.

Convection-enhanced drug delivery (CED) enables achieving a drug concentration within brain tissue and brain tumors that is orders of magnitude higher than by systemic administration. Previous phase I/II clinical trials using intratumoral convection of interleukin-4 Pseudomonas exotoxin (PRX321) have demonstrated an acceptable safety and toxicity profile with promising signs of therapeutic activity. The present study was designed to assess the distribution efficiency and toxicity of this PRX321 using magnetic resonance imaging (MRI) and to test whether reformulation with increased viscosity could enhance drug distribution. Convection of low- [0.02% human serum albumin (HSA)] and high-viscosity (3% HSA) infusates mixed with gadolinium-diethylenetriamine pentaacetic acid and PRX321 were compared with low- and high-viscosity infusates without the drug, in normal rat brains. MRI was used for assessment of drug distribution and detection of early and late toxicity. Representative brain samples were subjected to histological examination. Distribution volumes calculated from the magnetic resonance images showed that the average distribution of 0.02% HSA was larger than that of 0.02% HSA with PRX321 by a factor of 1.98 (p < 0.02). CED of 3.0% HSA, with or without PRX321, tripled the volume of distribution compared with 0.02% HSA with PRX321 (p < 0.015). No drug-related toxicity was detected. These results suggest that the impeded convection of the PRX321 infusate used in previous clinical trials can be reversed by increasing infusate viscosity and lead to tripling of the volume of distribution. This effect was not associated with any detectable toxicity. A similar capability to reverse impeded convection was also demonstrated in a CED model using acetic acid. These results will be implemented in an upcoming phase IIb PRX321 CED trial with a high-viscosity infusate.

The value of ventriculo-peritoneal shunting in patients with glioblastoma multiforme and ventriculomegaly.

BACKGROUND: Patients with an advanced-stage glioblastoma multiforme (GBM) often show general motor, gait, and cognitive deterioration. Some have radiological evidence of ventriculomegaly, but the relevance of this to their symptoms may be unclear. Distinction between tumour patients who have dilated fluid spaces as a consequence of tissue loss from surgery or treatment, and those who have a symptomatic hydrocephalic process, one who may gain benefit from insertion of a ventriculo-peritoneal shunt, is an important clinical challenge. METHODS: From a series of 530 GBM patients treated by a single surgeon (ZR), we retrospectively reviewed 16 patients with advanced-stage GBM who had presented with non-obstructive ventriculomegaly and clinical deterioration not explained by progressive disease. Each had been treated by insertion of a ventriculo- peritoneal shunt (VPS). Assessments included clinical features, Karnofsky Performance Scale, motor and cognitive findings, complications and survival. FINDINGS: Ten patients benefited from insertion of the shunt, with moderate to significant cognitive improvement. Of seven patients who presented with motor symptoms, such as gait instability, general weakness, and slowness, four patients showed significant motor improvement in addition to major cognitive improvement. Early infectious complication occurred in five patients; a late shunt infection in one; one patient had symptoms related to overdrainage; and in another a mechanical shunt malfunction occurred. Three patients died from shunt-related complications. CONCLUSIONS: Insertion of a ventriculo-peritoneal shunt can improve cognitive and motor function in a small subset of patients with advanced-stage glioblastoma multiforme and ventriculomegaly. Infection is a major risk in this patient population.

Tuberculum and diaphragma sella meningioma--surgical technique and visual outcome in a series of 20 cases operated over a 2.5-year period.

BACKGROUND: A retrospective analysis of 20 cases of tuberculum sella meningioma with emphasis on the surgical technique and visual outcome. METHODS: Between 2003 and 2006 twenty patients with tuberculum and diaphragma sella meningioma were treated at the Tel Aviv medical center. There were 17 females and 3 males. The age range was 28-83. Most patients presented with visual deterioration. Surgery was performed using the subfrontal approach. The visual function before and after surgery was evaluated as the main outcome parameter of the surgical treatment of these tumours. FINDINGS: In 16 patients complete tumour resection was achieved and in 4 subtotal removal was performed. Visual acuity improved in 32% of the eyes and deterioration was observed in two eyes (5%). Visual field improved in 28% of the eyes and deteriorated in 14%. There was no complete vision loss as a result of surgery. There was no mortality in our series. CONCLUSIONS: Tuberculum and diaphragma sella meningioma can be safely resected using the subfrontal approach with preservation and even improvement of visual function after surgery. Early surgery with better pre-operation visual function and smaller tumour size were associated with a better outcome.

Peri-operative brainstem infarct in a patient with antiphospholipid antibody (APLA) syndrome.

Antiphospholipid antibody (APLA) syndrome is a major risk factor for arterial and venous thrombosis. Surgical risks in patients known to suffer from APLA syndrome are usually related to haemorrhage or to thrombo-embolic events, such as deep venous thrombosis and pulmonary emboli. The rare published reports of patients with APLA syndrome undergoing neurosurgical procedures relate to haemostatic complication, with none alerting to the peri-operative risk of stroke in these patients. We present a case of a peri-operative stroke in a patient undergoing resection of a foramen magnum meningioma. We discuss the association of peri-operative stroke and APLA syndrome and emphasize the high risk it imposes for neurosurgical procedures in these patients. In addition, we suggest an anticoagulation treatment algorithm for APLA syndrome patients undergoing craniotomies.

Gliadel wafer in initial surgery for malignant glioma: long-term follow-up of a multicenter controlled trial.

OBJECTIVE: Adjuvant systemic chemotherapy increases survival of primary malignant glioma patients beyond 12-18 months. The only interstitial chemotherapy treatment approved for malignant glioma is Gliadel wafer containing carmustine (BCNU) placed in the resection cavity at surgery. Analysis of a large trial by Westphal and colleagues (n = 240) showed a 29% risk reduction (P = 0.03) in the BCNU wafer-treated group over the course of the 30-month trial. Long-term follow-up of these patients was undertaken to determine the survival benefit at 2 and 3 years. METHODS: Survival proportions for the placebo and treatment groups over the 56-month study were estimated by the Kaplan-Meier method. Multiple-regression analyses using the Cox proportional hazards model included prognostic factors of age, KPS, and tumor type. A secondary analysis was conducted for 207 GBM patients. RESULTS: Of the 59 patients available for long-term follow-up, 11 were alive at 56 months: 9 had received BCNU wafers and 2 had received placebo wafers. Median survival of patients treated with BCNU wafers was 13.8 months vs 11.6 months in placebo-treated patients (P = 0.017) with a hazard ratio of 0.73 (P = 0.018), representing a 27% significant risk reduction. This survival advantage was maintained at 1, 2, and 3 years and was statistically significant (P = 0.01) at 3 years. Two of 207 GBM patients remained alive at the end of the follow-up period, both in the BCNU wafer-treated group. CONCLUSION: Malignant glioma patients treated with BCNU wafers at the time of initial surgery in combination with radiation therapy demonstrated a survival advantage at 2 and 3 years follow-up compared with placebo.

Haemorrhagic complications and the incidence of asymptomatic bleeding associated with stereotactic brain biopsies.

OBJECT: Stereotactic brain biopsy is a routinely used technique for the diagnosis of brain lesions. Due to its minimally invasive nature, the potential risks associated with this procedure are sometimes underestimated. We have retrospectively analyzed the incidence of symptomatic and asymptomatic haemorrhagic complications associated with stereotactic biopsies. Various variables that may contribute to such complications have been retrospectively analyzed. METHODS: Medical and radiological records of 355 consecutive patients who underwent a diagnostic stereotactic brain biopsy were reviewed. The incidence of haemorrhage was derived from a routine post-operative CT scan done within 90-120 minutes of the biopsy. Demographic, radiographic, pathological, and clinical data were also extracted and evaluated for their possible association with haemorrhagic complications. RESULTS: Twenty-five patients (7%) experienced haemorrhagic complications associated with stereotactic biopsy, about half of whom (3.4%) were asymptomatic with no impact on the clinical course. Thirteen (3.6%) complications were symptomatic and two patients (0.6%) died. Lesions located in the brainstem were found to have a significantly higher rate of complications compared to other locations. No other variables, such as location, edema, number of biopsy specimens, or pre-existing neurological deficit showed a statistically significant impact on the incidence or severity of haemorrhage. Seven of the symptomatic complications occurred immediately post biopsy, but in six patients they developed within several hours and even days. The overall diagnostic yield of the biopsies was 93.8%, but was somewhat lower in patients experiencing a haemorrhagic complication. CONCLUSIONS: Stereotactic brain biopsy was associated with a low incidence of symptomatic haemorrhagic complications, morbidity and mortality, and a high diagnostic yield. About half of the haemorrhagic complications were asymptomatic. Lesions located in the brainstem had a higher rate of complications. No other clinical, radiographic, or pathological variables were found as predictors of increased risk for haemorrhage.

Management of pituitary apoplexy: clinical experience with 40 patients.

BACKGROUND: Pituitary apoplexy is a rare major clinical event with neurological, neuro-ophthalmological, cardiovascular and hormonal consequences, resulting from an acute infarction of pituitary adenoma. We report our experience with a series of 40 patients presenting with pituitary apoplexy. PATIENTS: Forty patients (27 males, 13 females; mean age, 51.2 yr) were admitted to our medical center between years 1985-2002 with acute presentation of pituitary apoplexy. Visual field defects occurred in 61% and ocular paresis in 40% of subjects. Sixty-three percent of adenomas were nonfunctional, and prolactinomas comprised 31%. RESULTS: Thirty-four patients underwent transsphenoidal pituitary decompression. Visual fields and ophthalmoplegia improved in 81% and 71%, respectively. During follow-up (4.5+/-5.4 yr), 79% of patients developed hypogonadotrophic hypogonadism, central hypothyroidism appeared in 54% and hypocortisolism--in 40% of patients. Permanent diabetes insipidus was diagnosed in 8%. Serial sellar MRI showed disappearance of pituitary tumor in 63% of operated subjects. Six patients (3 with PRL-secreting and 3 nonfunctional adenomas) were treated medically (corticosteroids, dopamine agonists), two patients (out of three) with visual deficits improved, and tumor shrinkage was noted in four. CONCLUSIONS: We present a large series of patients with pituitary apoplexy. Most subjects were operated, but six were treated conservatively. Almost all patients improved clinically, including those who were not operated, but hormonal deficiencies are very common.

Intraoperative imaging--MRI.

Neuronavigation has become a standard technique in many neurosurgical procedures where its use allow better positioning of the craniotomy flap, precise targeting of lesions, and better anatomical orientation. However, the imaging used in such procedures is acquired preoperatively and thus, cannot project the dynamic changes that occur during surgery and result in many cases in significant brain shift and decreased accuracy. Recent technological developments have yielded a variety of MRI machines that can be used intraoperatively and provide the surgeon with updated images, integrated navigation capabilities, full compensation for brain shifts, and the ability to assess the extent of resection of the lesion. The concepts behind such technologies vary from one manufacture to another resulting in systems that vary in complexity, ease of use, spatial demands, and cost. In this chapter we review our experience with two intraoperative MRI systems used in a variety of neurosurgical procedures: the GE Signa SP System and the Odin PoleStar System.

Comparative genomic hybridization analysis of radiation-associated and sporadic meningiomas.

Ionizing irradiation to the skull is a known risk factor for meningioma development. To gain insight into the molecular mechanisms that underlie radiation-associated meningioma (RAM), we characterized the somatic genetic alterations in 16 RAMs by using comparative genomic hybridization and compared the pattern of alterations with 17 nonradiation-associated meningiomas (non-RAM). Most tumors (29/33;87.9%) displayed at least one DNA copy number alteration, and 11 out of 33 (33%) exhibited four or more changes. The mean number of DNA copy number changes was similar in RAMs (2.4+/-1.9) and in non-RAMs (2.5+/-1.9). The most common DNA losses were noted in chromosome 22 (56.2% in RAM, and 47% in non-RAM) and chromosome 1 (37.5% in RAM and 35.3% in non-RAM), with no significant differences between the two groups. Noteworthy, gain in DNA copy number of chromosomes 8 and 12 was detected in two RAM tumors only. In conclusion, no significant differences were noted between RAMs and non-RAMs regarding the number of genetic changes and the extent and frequency of chromosomes 1 and 22 losses. These preliminary data suggest that the tumorogenic pathways of meningioma formation are similar, regardless of previous skull irradiation.

Comparative analysis of the NF2, TP53, PTEN, KRAS, NRAS and HRAS genes in sporadic and radiation-induced human meningiomas.

Irradiation to the head is associated with a significantly increased incidence of meningiomas. Radiation-induced meningiomas morphologically resemble their sporadically arising counterparts; however, they frequently exhibit a more malignant phenotype. Several genes have been shown to carry mutations in meningiomas, with the NF2 gene being most frequently affected. To examine whether the NF2 gene also plays a role in the development of radiation-induced meningiomas, we compiled a series of meningiomas from 25 patients with a history of previous cranial radiation. This series was compared with 21 atypical WHO grade II meningiomas and 15 anaplastic WHO grade III meningiomas, all from patients without a history of prior irradiation. NF2 mutations occurred significantly more often in sporadic atypical and anaplastic than in radiation-induced meningiomas (p < 0.02). In addition, all meningiomas were examined for mutations in the PTEN, TP53, HRAS, KRAS and NRAS genes. Two mutations in the TP53 gene in a sporadic and a radiation-induced tumor were detected. PTEN mutations were observed in 1 anaplastic and 1 radiation-induced meningioma. No structural alterations were seen in the RAS genes. Our data suggest that, while there is a certain overlap in the mutational spectrum, NF2 mutations may not play such a prominent role in the pathogenesis of radiation-induced compared to sporadic meningiomas.

Monitoring response to convection-enhanced taxol delivery in brain tumor patients using diffusion-weighted magnetic resonance imaging.

Convection-enhanced drug delivery (CEDD) is a novel approach to enhance the delivery of drugs directly into brain tumors. We have used diffusion-weighted MRI (DWMRI) to monitor the effects of intratumoral CEDD in three brain tumor patients treated with Taxol. Clear changes in the images and the water diffusion parameters were observed shortly after the initiation of treatment. Initially, a bright area corresponding to decreased diffusion appeared, followed by the appearance of a dark area of increased diffusion within the bright area. The time to appearance of the dark area varied among the patients, suggesting different response rates. In this work, we have demonstrated the feasibility of using DWMRI as a noninvasive tool to achieve unique early tissue characterization not attainable by other conventional imaging methods.

Monitored anesthesia care using remifentanil and propofol for awake craniotomy.

Adequate analgesia and sedation with adequate respiratory and hemodynamic control are needed during brain surgery in awake patients. In this study, a protocol using clonidine premedication, intraoperative propofol, remifentanil, and labetalol was evaluated prospectively in 25 patients (aged 50 +/- 16). In all but one patient, no significant problems regarding cooperation, brain swelling, or loss of control were noticed, and it was not necessary to prematurely discontinue any of the procedures. One patient, who was uncooperative and hypertensive, became apneic with increasing sedation, and needed a laryngeal mask airway inserted. Patients were hemodynamically stable; elevated systolic blood pressure (>or= 150 mm Hg) was measured infrequently, and there were no events of significant hypotension, tachycardia, or bradycardia. Events of hypoxemia (SAO2

Transsphenoidal surgery for acromegaly: endocrinological follow-up of 98 patients.

OBJECTIVE: Transsphenoidal surgery is the preferred treatment modality for growth hormone (GH)-secreting pituitary adenomas. In many series, the reported postoperative remission is based mainly on achievement of GH levels less than 2 ng/ml. Strict criteria for insulin-like growth factor I normalization and even lower GH levels (<1 ng/ml) are now suggested to define cure of acromegaly, but the evidence does not yet support such low GH levels in epidemiological follow-up. We analyzed our postoperative results in a large cohort of patients with acromegaly. METHODS: Ninety-eight patients harboring GH-secreting adenomas (46 microadenomas and 52 macroadenomas) underwent transsphenoidal surgery between 1990 and 1999. Ninety-one patients were operated for the first time, and 12 patients underwent reoperations because of previous surgical failure (7 had undergone surgery elsewhere previously). Biochemical remission was defined as a repeated fasting or glucose-suppressed GH level of 2 ng/ml or less, and a normal insulin-like growth factor I level. RESULTS: Remission was achieved in 74% of all patients after one operation, including 84% of patients with microadenomas and 64% of patients with macroadenomas. Seventy-three percent of patients with macroadenomas 11 to 20 mm in size achieved remission, as compared with a 20% remission rate for patients with adenomas larger than 20 mm. Patients with preoperative random GH levels lower than 50 ng/ml had a better outcome (85% remission), whereas GH greater than 50 ng/ml was associated with remission in 30% of the patients. Only one of the patients (8%) with postoperative active disease who underwent a second operation achieved remission. Recurrence was rare (one patient), and all failed surgical attempts could be detected during the immediate postoperative evaluation. CONCLUSION: On the basis of strict postoperative GH and insulin-like growth factor I criteria to define remission, our series demonstrates the efficacy of transsphenoidal surgery for acromegalic patients with microadenomas and noninvasive macroadenomas. However, patients with large adenomas (>20 mm) and preoperative GH greater than 50 ng/ml have a poor prognosis and require adjunctive medical or radiation therapy to control GH hypersecretion.

Intraarterial delivery of genetic vectors for the treatment of malignant brain tumors.

BACKGROUND: The transfer of therapeutic genes into malignant brain tumors has been the subject of intense preclinical and clinical research in recent years. Most approaches have used direct intratumoral placement of a variety of vectors and genes, such as retroviruses or adenoviruses carrying drug-susceptibility genes, modified replication-competent herpes virus, and several vectors carrying tumor suppressor genes such as the p53 gene. However, clinical results have so far been disappointing, mainly due to the limited ability to effectively distribute the genetic material into the target cell population. Accordingly, alternative delivery approaches into the central nervous system, e.g., intravascular, are under investigation. Genetic vectors administered intravascularly are unlikely to penetrate the blood-brain barrier and transfer a gene into brain or tumor parenchyma. However, intravascular delivery of vectors may target endothelial cells lining the blood vessels of the brain. Since endothelial cells participate in a variety of physiological and pathological processes in the brain, their modulation by gene transfer may be used for a variety of therapeutic purposes. Angiogenically stimulated endothelial cells within tumors replicate rapidly and hence may become targets for retroviral-mediated gene transfer. OBJECTIVE: To assess the anti-tumor effect of transferring a drug-susceptibility gene into endothelial cells of the tumor vasculature. METHODS: As a model for this approach we delivered concentrated retroviral vectors carrying a drug-susceptibility gene via the internal carotid artery of rats with malignant brain tumors. The safety and efficacy of this approach, without and with subsequent treatment with a pro-drug (ganciclovir), was evaluated. RESULTS: No acute or long-term toxicity was observed after intraarterial infusion of the vector. Treatment with ganciclovir resulted in variable hemorrhagic necrosis of tumors, indicating preferential transduction of the angiogenically stimulated tumor vasculature. This was accompanied by severe toxicity caused by subarachnoid hemorrhage and intracerebral hemorrhage in vascular territories shared by the tumor and adjacent brain. CONCLUSION: The data indicate that endothelial cells can be targeted by intraarterial delivery of retroviral vectors and can be used for devising new gene therapy strategies for the treatment of brain tumors.

Novel, compact, intraoperative magnetic resonance imaging-guided system for conventional neurosurgical operating rooms.

OBJECTIVE: Preliminary clinical experience with a novel, compact, intraoperative magnetic resonance imaging (MRI)-guided system that can be used in an ordinary operating room is presented. DESCRIPTION OF INSTRUMENTATION: The system features an MRI scanner integrated with an optical and MRI tracking system. Scanning and navigation, which are operated by the surgeon, are controlled by an in-room computer workstation with a liquid crystal display screen. The scanner includes a 0.12-T permanent magnet with a 25-cm vertical gap, accommodating the patient's head. The field of view is 11 x 16 cm, encompassing the surgical area of interest. The magnet is mounted on a transportable gantry that can be positioned under the surgical table when not in use for scanning, thus rendering the surgical environment unmodified and allowing the use of standard instruments. The features of the integrated navigation system allow flap planning and intraoperative tracking based on updated images acquired during surgery. OPERATIVE TECHNIQUE: Twenty patients with brain tumors were surgically treated using craniotomy or trans-sphenoidal approaches. One patient underwent conscious craniotomy with cortical mapping, and two underwent electrocorticography. EXPERIENCE AND RESULTS: Planning was accurate. Resection control images were obtained for all patients during surgery, with precise localization of residual tumor tissue. There were no surgical complications related to the use of the system. CONCLUSION: This intraoperative MRI system can function in a normal operating room modified only to eliminate radiofrequency interference. The operative environment is normal, and standard instruments can be used. The scanning and navigation capabilities of the system eliminate the inaccuracies that may result from brain shift. This novel type of intraoperative MRI system represents another step toward the introduction of the modality as a standard method in neurosurgery.