Local convection enhanced delivery of IL4-Pseudomonas exotoxin (NBI-3001) for treatment of patients with recurrent malignant glioma.

PURPOSE: This was an open-label, dose-escalation trial of intratumoral administration of IL-4 Pseudomonas Exotoxin (NBI-3001) in patients with recurrent malignant glioma. PATIENTS AND METHODS: A total of 31 patients with histologically verified supratentorial grade 3 and 4 astrocytoma were studied. Of these, twenty-five patients were diagnosed with glioblastoma multiforme (GBM) while six were diagnosed with anaplastic astrocytoma (AA). Patients were over 18 years of age and had Karnofsky performance scores > or = 60. Patients were assigned to one of four dose groups in a dose-escalation fashion: 6 microg/ml x 40 ml, 9 microg/ml x 40 ml, 15 microg/ml x 40 ml, or 9 microg/ml x 100 ml of NBI-3001 administered intratumorally via stereotactically placed catheters. Patients were followed with serial MRI scans and clinical assessments every four weeks for the first 16 weeks and then every eight weeks until week 26. RESULTS: No drug-related systemic toxicity, as evident by lack of hematological or serum chemical changes, was apparent in any patients; treatment-related adverse effects were limited to the central nervous system. No deaths were attributable to treatment. Drug-related Grade 3 or 4 toxicity was seen in 39% of patients in all dose groups and 22% of patients at the maximum tolerated dose of 6 microg/ml x 40 ml. The overall median survival was 8.2 months with a median survival of 5.8 months for the GBM patients. Six-month survival was 52% and 48%, respectively. Gadolinium-enhanced magnetic resonance imaging of the brain showed areas of decreased signal intensity within the tumor consistent with tumor necrosis following treatment in many patients. CONCLUSIONS: NBI-3001 appears to have an acceptable safety and toxicity profile when administered intratumorally in patients with recurrent malignant glioma.

Tumor resection in a shared-resource magnetic resonance operating room: experience at the University of Cincinnati.

INTRODUCTION: At the University of Cincinnati, we have developed a shared-resource magnetic resonance operating suite that facilitates performance of both neurosurgical and diagnostic procedures in a single unit. METHODS: The shared-resource magnetic resonance operating suite utilizes a Hitachi AIRIS II, 0.3-T, vertical field, open MRI unit located in the MROR. This magnet can be used for both diagnostic and interventional procedures. The addition of a rotating-operating table permits neurosurgical procedures to be performed outside of the 5-G line using standard neurosurgical equipment and operating microscopes. RESULTS: We review our results with the shared-resource magnetic resonance operating room including the tabulated results from 30 transsphenoidal procedures and 63 glioma procedures. In addition, 2832 diagnostic procedures have been performed in the first 4 years of use. CONCLUSION: The shared-resource intraoperative MRI facility produces high-quality intraoperative imaging studies, equal to those of high-resolution magnets, and is valuable in enabling the surgeon to achieve the planned degree of resection of glioma and pituitary tumors. The ability to perform diagnostic procedures in a shared unit has been a cost-effective solution for our institution.

Glioma resection in a shared-resource magnetic resonance operating room after optimal image-guided frameless stereotactic resection.

OBJECTIVE: We describe a shared-resource intraoperative magnetic resonance imaging (MRI) design that allocates time for both surgical procedures and routine diagnostic imaging. We investigated the safety and efficacy of this design as applied to the detection of residual glioma immediately after an optimal image-guided frameless stereotactic resection (IGFSR). METHODS: Based on the twin operating rooms (ORs) concept, we installed a commercially available Hitachi AIRIS II, 0.3-tesla, vertical field, open MRI unit in its own specially designed OR (designated the magnetic resonance OR) immediately adjacent to a conventional neurosurgical OR. Between May 1998 and October 1999, this facility was used for both routine diagnostic imaging (969 diagnostic scans) and surgical procedures (50 craniotomies for tumor resection, 27 transsphenoidal explorations, and 5 biopsies). Our study group, from which prospective data were collected, consisted of 40 of these patients who had glioma (World Health Organization Grades II-IV). These 40 patients first underwent optimal IGFSRs in the adjacent conventional OR, where resection continued until the surgeon believed that all of the accessible tumor had been removed. Patients were then transferred to the magnetic resonance OR to check the completeness of the resection. If accessible residual tumor was observed, then a biopsy and an additional resection were performed. To validate intraoperative MRI findings, early postoperative MRI using a 1.5-tesla magnet was performed. RESULTS: Intraoperative images that were suitable for interpretation were obtained for all 40 patients after optimal IGFSRs. In 19 patients (47%), intraoperative MRI studies confirmed that adequate resection had been achieved after IGFSR alone. Intraoperative MRI studies showed accessible residual tumors in the remaining 21 patients (53%), all of whom underwent additional resections. Early postoperative MRI studies were obtained in 39 patients, confirming that the desired final extent of resection had been achieved in all of these patients. One patient developed a superficial wound infection, and no hazardous equipment or instrumentation problems occurred. CONCLUSION: Use of an intraoperative MRI facility that permits both diagnostic imaging and surgical procedures is safe and may represent a more cost-effective approach than dedicated intraoperative units for some hospital centers. Although we clearly demonstrate an improvement in volumetric glioma resection as compared with IGFSR alone, further study is required to determine the impact of this approach on patient survival.

Distant wounded glioma syndrome: report of two cases.

OBJECTIVE AND IMPORTANCE: We describe two cases of distant wounded glioma syndrome complicating surgical resection of multifocal glioblastoma multiforme. This clinical entity was previously described as a local phenomenon resulting in postoperative hemorrhaging within the cavity of partially resected tumors. These cases are unique, in that the postoperative hemorrhaging occurred within distant tumor nodules after gross total resection of the primary lesion. CLINICAL PRESENTATION AND INTERVENTION: Two middle-aged men without known risk factors for postoperative hemorrhaging presented with multifocal glioblastoma multiforme. Each underwent surgical resection of the deficit-producing lesion and developed hemorrhage at distant tumor sites that were not directly manipulated during the surgical procedures. The distant hemorrhage caused new neurological deficits, with severe morbidity. CONCLUSION: We postulate that distant wounded glioma syndrome is a distinct clinical entity that causes remote postoperative hemorrhaging and that tumor-induced coagulopathy triggered by surgery seems to create a hypocoagulable state that is most concentrated within brain tissue. Because of their rich vascularity, these distant tumor nodules are more susceptible to hemorrhage, resulting from coagulation changes after tumor resection, than are other sites. They also exhibit increased blood flow after resection of a large mass, because of autoregulatory dysfunction induced by peritumoral edema, increasing the likelihood of hemorrhage at these sites.

Intraoperative magnetic resonance imaging to determine the extent of resection of pituitary macroadenomas during transsphenoidal microsurgery.

OBJECTIVE: Well-established surgical goals for pituitary macroadenomas include gross total resection for noninvasive tumors and debulking with optic chiasm decompression for invasive tumors. In this report, we examine the safety, reliability, and outcome of intraoperative magnetic resonance imaging (iMRI) used to assess the extent of resection, and thus the achievement of preoperative surgical goals, during transsphenoidal microneurosurgery. METHODS: Our magnetic resonance operating room contains a Hitachi AIRIS II 0.3-T, vertical-field open magnet (Hitachi Medical Systems America, Inc., Twinsburg, OH). A motorized scanner tabletop moves the patient between the imaging and operative positions. For transsphenoidal surgery, the patient is positioned directly on the scanner tabletop so that the surgical field is located between 1.2 and 1.6 m from the magnet isocenter. At this location, the magnetic field strength is low (<20 G), thus permitting the use of many conventional surgical instruments. Thirty consecutive patients with pituitary macroadenomas underwent tumor resection in our magnetic resonance operating room by use of a standard transsphenoidal approach. After initial resection, the patient was advanced into the scanner for imaging. If residual tumor was demonstrated and deemed surgically accessible, the patient underwent immediate re-exploration. RESULTS: iMRI was performed successfully in all 30 patients. In one patient, iMRI was used to clarify the significance of hemorrhage from the sellar region and resulted in immediate conversion of the procedure to a craniotomy. In the remaining 29 patients, initial iMRI demonstrated that the endpoint for extent of resection had been achieved in only 10 patients (34%) after an initial resection attempt, whereas 19 patients (66%) still had unacceptable residual tumor. All 19 of these latter patients underwent re-exploration. Ultimately, re-exploration resulted in the achievement of the planned endpoint for extent of resection in all of the 29 completed transsphenoidal explorations. Operative time was extended in all cases by at least 20 minutes. CONCLUSION: iMRI can be used to safely, reliably, and objectively assess the extent of resection of pituitary macroadenomas during the transsphenoidal approach. The surgeon is frequently surprised by the extent of residual tumor after an initial resection attempt and finds the intraoperative images useful for guiding further resection.

Permanent iodine-125 interstitial implants for the treatment of recurrent glioblastoma multiforme.

OBJECTIVE: Brachytherapy with temporary implants may prolong survival in patients with recurrent glioblastoma multiforme (GBM), but it is associated with relatively high costs and morbidity. This study reports the time to progression and survival after permanent implantation of iodine-125 seeds for recurrent GBM and examines factors predictive of outcome. METHODS: Forty patients with recurrent GBM were treated with maximal resection plus permanent placement of iodine-125 seeds into the tumor bed. A total dose of 120 to 160 Gy was administered, and patients were followed up with magnetic resonance imaging scans every 2 to 3 months. RESULTS: Actuarial survival from the time of implantation was 47 weeks, with 7 of 40 patients still alive at a median of 59 weeks after implantation. Survival was significantly better for patients younger than 60 years, and a trend for longer survival was demonstrated with gross total resection and tumors with a low MIB-1 (a nuclear antigen present in all cell cycles of proliferating cells) staining index. Median time to progression was 25 weeks and, on multivariate analysis, was favorably influenced by gross total resection and patient age younger than 60 years. After implantation, 27 of 30 patients with failure had a local component to the failure. No patient developed symptoms attributable to radiation necrosis or injury. CONCLUSION: Permanent iodine-125 implants for recurrent GBM result in survival comparable with that described in previous reports on temporary implants, but with less morbidity. Results are most favorable for patients who are younger than 60 years, and who undergo gross total resection. Despite this aggressive treatment, most patients die as a consequence of locally recurrent disease.

A syngeneic mouse glioma model for study of glioblastoma therapy.

Animal models of human tumors serve a vital role in the development and testing of new anticancer therapies. Since the immune system is likely to play an essential role in tumor eradication, there is a particular need for modeling human disease in immunocompetent hosts. Few models of glioma have been developed in immunocompetent mice that are commercially available and none of these tumors have histological and antigenic characteristics of human gliomas. We have used a cell line, 4C8, derived from a spontaneous glioma-like tumor that arose in a transgenic mouse to develop a new glioma model. The intracranial injection of 4C8 cells into immunocompetent syngeneic B6D2F1 mice resulted in tumors that were densely cellular, developed a pseudopallisading pattern of necrosis, and expressed GFAP; all important features of human malignant gliomas. The average neurological endpoint was 51 days after intracranial injection. The 4C8 cells also grew rapidly in the flank, retaining histologic features seen in intracranial tumors. Flank tumors reached an average volume of 100 mm3, a volume ideal for therapy testing, by 34 days postinjection. These results suggest that the 4C8 mouse glioma model is an excellent system in which to test new antiglioma therapies for use in humans.

Functional outcome of inpatient rehabilitation in persons with brain tumors.

OBJECTIVE: To document functional outcome in persons with brain tumors undergoing inpatient rehabilitation and to compare outcomes with a group of traumatically brain injured patients. DESIGN: Retrospective, descriptive, and case-matched. SETTING: A free-standing inpatient brain injury rehabilitation unit. PARTICIPANTS: Forty consecutive patients with a variety of tumor types (40% were either glioblastoma multiforme or meningioma) and a mean age of 53.1 (SD 15.4) years. Sixty percent were men, 25% had recurrent tumors, and 15% had metastatic disease. Also, 40 patients with traumatic brain injury (TBI) matched for age, gender, and admission functional status. MAIN OUTCOME MEASURES: Change in Functional Independence Measure (FIM) scores, length of rehabilitation stay (LOS), and discharge disposition. RESULTS: The mean LOS for the tumor group was 17.8 (SD 9.9) days, mean FIM gain was 25.4 (SD 20.1) points, and 82.5% were discharged home. No demographic or tumor characteristic was statistically significant in predicting functional outcome at discharge, but greater gains were seen for persons with the diagnosis of meningioma, those with left-sided cerebral lesions, and those not receiving radiation therapy. TBI patients made statistically significant greater gains in total FIM change (34.6 vs 25.4), self-care (12.3 vs 8.5), and social cognition (5.2 vs 3.6). However, FIM efficiency and LOS were not statistically different between the TBI and tumor groups (1.9 vs 1.5 FIM points/day and 22.1 vs 17.8 days, respectively). CONCLUSIONS: Daily functional gains made by persons with brain tumor undergoing rehabilitation were similar to those made by a group of persons with TBI matched by age, gender, and admission functional status. Further research should use larger samples and address the impact of psychosocial and team factors on LOS and discharge disposition.

Central auditory processing in a patient with bilateral temporal lobe tumors: case report.

The purpose of this article is to report the audiologic and central auditory processing abilities of a 34-year-old male with a right temporal lobe tumor and a history of bilateral tumors of the temporal lobes. The patient was evaluated presurgical re-exploration and again at 2.5 months and 4 months postoperatively. Test results demonstrated little change in peripheral hearing abilities; however, marked fluctuations were recorded on several tests administered postoperatively. Overall, this patient demonstrated a wide range of performance on tests of central auditory function, notably scores that decreased postoperatively and returned to better than baseline on the SCAN-A and repeated abnormal scores on the Pitch Pattern Sequence Test and the Symbol Digit Modality Test. Auditory Fusion Test-Revised results were initially normal, were markedly abnormal immediately postoperative, and returned to normal during the second postoperative visit. Our purpose in conducting this case study was to demonstrate, with central auditory processing test findings as well as magnetic resonance images, functional disorders of communication in a pre- and postoperative patient with a temporal lobe tumor.

Radiation therapy and hydroxyurea followed by the combination of 6-thioguanine and BCNU for the treatment of primary malignant brain tumors.

PURPOSE: This study was designed to evaluate a combined modality treatment for malignant gliomas using radiation therapy with a radiosensitizer and an adjuvant chemotherapy regimen designed to modify resistance to BNCU. METHODS AND MATERIALS: Patients were eligible if they were 15 years of age or older, and had newly diagnosed glioblastoma multiforme (GBM), or anaplastic glioma (AG). Treatment consisted of external beam radiotherapy given to a dose of 60 Gy using a single daily fraction Monday to Friday. Concurrent hydroxyurea at a dose of 300 mg/m2 every 6 h every other day was given during radiation. Following radiotherapy, patients were then treated with BCNU and 6-Thioguanine (6TG). The 6-TG was given by mouth every 6 h for 12 doses prior to BCNU. Patients were initially treated with 60 mg/m2/dose of 6TG, with escalation to a maximum dose of 100 mg/m2/dose. The primary study end points were time to tumor progression and survival. RESULTS: A total of 245 eligible patients were enrolled from 1/18/88 to 12/26/91. The histologic subtypes included 135 GBM, and 110 with AG (103 with anaplastic astrocytoma, 7 with high-grade mixed oligoastrocytoma). For the GBM group, the median time to tumor progression (TTP) and median survival were 33 (95% CI 26, 39) and 56 (95% CI 49, 69) weeks, respectively. For the AG group the median TTP was 282 weeks (95% lower confidence bound = 155 weeks). Median survival for this group has not been reached (95% lower confidence bound = 284 weeks) with a median follow-up for surviving patients of 298 weeks. A proportional hazards model was used to look at potential prognostic factors for survival, including initial Karnofsky Performance Scale (KPS), age, and extent of surgery, as well as dose of 6TG. Higher KPS, and lower age, predicted for longer survival (p < 0.01, < 0.001) in GBM patients; lower age was significant (p = 0.05) for AG cases. A higher (greater than 95 mg/m2) or lower dose of 6TG was not statistically significant in this model. CONCLUSIONS: This therapy was no more effective in patients with GBM than other reported series. In patients with malignant gliomas other than GBM, prolonged progression-free and overall survival is noted, without a median survival reached at the time of this report. In this subset of AG patients, survival is comparable to recent studies using halogenated prymidines during radiation and Procarbazine, CCNU, and Vincristine (PCV) as adjuvant chemotherapy.

A simple, reproducible technique for establishing leptomeningeal tumors in nude rats.

The incidence of leptomeningeal carcinomatosis is on the rise and current treatment modalities have limited efficacy. The development of new treatment strategies has been hampered by the lack of an appropriate animal model that accurately parallels the clinical condition. We have developed a new surgical technique for the establishment of leptomeningeal tumors in rats. Our technique is simple, reproducible and associated with low morbidity and mortality. Tumor implantation resulted in a defined neurological endpoint and a reproducible time course of disease progression using both human medulloblastoma and breast carcinoma cell lines. This animal model provides an appropriate system for testing conventional and new biologic therapies in both early and late stages of leptomeningeal disease.

Determination of lung as the primary site of cerebral metastatic adenocarcinomas using monoclonal antibody to thyroid transcription factor-1.

Determining the primary site of a cerebral metastatic adenocarcinoma is complicated by the histologic similarity of most adenocarcinomas. Thyroid Transcription Factor-1 (TTF-1) is a highly specific marker of peripheral airway cell neoplasms. Formalin fixed tissue from 30 patients with brain metastasis whose primary sources were clinically and histologically known with certainty were analyzed for immunoreactivity to TTF-1. There were 18 cases of metastatic lung adenocarcinoma. Other metastases were from breast (6), colon (1), prostate (1), kidney (1), paranasal sinus (1), melanoma (1), and intestinal carcinoid (1). No patients with carcinoma of the thyroid were found. Positivity was regarded as intense nuclear reactivity. Twelve (67%) metastatic lung adenocarcinomas stained for TTF-1. None of the cerebral metastases from other body sites showed positivity. In addition, normal brain tissue and astrocytic tumors did not stain for TTF-1. These data show that TTF-1 is a highly specific and reasonably sensitive marker for peripheral airway cell metastasis to the brain.

Corpus callosal changes associated with hydrocephalus: a report of two cases.

OBJECTIVE AND IMPORTANCE: Focal or diffuse corpus callosal changes can occur in patients with active hydrocephalus who undergo shunting procedures. The neural compression caused by active hydrocephalus and the conditions that follow ventricular shunting may contribute to the development of these changes. CLINICAL PRESENTATION: Two patients who underwent successful shunting for hydrocephalus subsequently developed thickening and diffuse signal changes in the corpus callosum, which were revealed by magnetic resonance imaging. The abnormal signal intensity extended laterally and linearly along the callosal fiber tracts and was not associated with mass effect. These changes persisted despite clinical improvement after the shunts were implanted. INTERVENTION: Detailed neuropsychological testing showed no evidence of residual cognitive impairment or any interruption of the interhemispheric transfer of information. It has been proposed that the impingement of the corpus callosum by the rigid falx may contribute to symptomatic hydrocephalus. Impingement may cause partial hemispheric disconnection, resulting from callosal axonal dysfunction. Our patients showed radiographic evidence of dramatic changes within the corpus callosum after ventricular shunting, consistent with a transcallosal demyelinating process. Patients demonstrated neither clinical nor neuropsychological evidence of callosal disconnection, even though the callosal changes persisted. In these two patients, it is reasonable to assume that the relative sparing of the splenium accounts for the lack of neuropsychological deficits. CONCLUSION: Based on our findings, conservative management, rather than a stereotactic biopsy or other forms of intervention, seems reasonable when these characteristic changes of the callosum are noted by magnetic resonance imaging after a shunt for hydrocephalus has been implanted in the patient.

A novel multiply-mutated HSV-1 strain for the treatment of human brain tumors.

A promising approach for the therapeutic treatment of brain tumors utilizes replication-competent, neuroattenuated herpes simplex virus-1 (HSV-1) mutants. This approach requires mutation of HSV-1 to eliminate killing of normal, nondividing cells of the brain (e.g., neurons). We have generated a HSV-1 double-mutant, designated 3616UB, by interrupting the uracil DNA glycosylase (UNG) gene in a previously studied ICP34.5 mutant, R3616. The HSV-1-encoded UNG gene is required for efficient HSV-1 replication in nondividing cells, but is dispensable for replication in rapidly dividing cells. The specific function of the HSV-1 ICP34.5 gene is not completely clear, but it is thought to be necessary for viral replication in cells of the nervous system, because, when mutated, the resultant viral strains are fully neuroattenuated. Strain 3616UB did not replicate in primary neuronal cultures in vitro or in mouse brain, but efficiently killed six of six human tumor cell lines within 6 days in vitro and successfully infected and replicated within brain tumor xenografts. The potential safety of 3616UB for human use is enhanced by an unexpected hypersensitivity to the antiherpetic drug ganciclovir. These data suggest that 3616UB may be effective for the treatment of human brain tumors. Intratumoral injection of 3616UB into human medulloblastoma or angiosarcoma xenografts established in severe combined immunodeficient (SCID) mice produced significant growth arrest and some tumor regressions. Strain 3616UB was as effective as R3616 in this therapy study and did not cause any obvious distress in the treated animals. Together, the data show that 3616UB is a very safe alternative to other HSV-1 mutants because the presence of two mutations reduces the possibility of recombinational events in situ that could lead to the generation of virulent viral progeny during 3616UB therapy.

Stereotactic radiosurgery for the treatment of brain metastases. Results of a single institution series.

BACKGROUND: Stereotactic radiosurgery is being used with increasing frequency for the treatment of brain metastases. Optimal patient selection and treatment factors continue to be defined. This study provides outcome data from a single institutional experience with radiosurgery and identifies parameters that may be useful for the proper selection and treatment of patients. METHODS: Eighty-four patients underwent stereotactic radiosurgery for brain metastases between September 1989 and November 1995. Seventy-nine patients (93%) were treated at recurrence after previous whole brain radiotherapy. Patients had between 1 and 6 lesions treated with a median minimum tumor dose of 1600 centigrays (cGy). Thirty-eight patients (45%) had active extracranial disease at the time of radiosurgery. RESULTS: Median survival for the entire group was 43 weeks from the date of radiosurgery and 71 weeks from the original diagnosis of brain metastases. Patients with 1 or 2 metastases had significantly improved survival compared with patients with > or = 3 metastases (P = 0.02), and patients without active extracranial tumor survived longer than those with extracranial disease (P = 0.03). Median time to failure for 145 evaluable lesions was 35 weeks. Local control was significantly improved for radiosurgery doses of > 1800 cGy, and for melanoma histology. CONCLUSIONS: These results are comparable to reports of patients treated with resection and significantly superior to results observed after whole brain radiotherapy. The authors conclude that stereotactic radiosurgery is an effective, low risk treatment for extending the survival of patients with recurrent brain metastasis. Although survival is best for patients with < or = two lesions and no active extracranial disease, selected patients with > two lesions or active extracranial tumor may benefit as well.

Primary T-cell lymphoma of the brain in acquired immunodeficiency syndrome: case report.

In patients with acquired immunodeficiency syndrome (AIDS), primary central nervous system lymphoma (PCNSL) is now the most common noninfectious intracranial mass lesion and the fourth leading cause of death. Most cases of PCNSL are B-cell in origin and are only rarely of T-cell origin. We report the first complete clinical description of T-cell PCNSL in a patient with AIDS. This patient underwent stereotactic biopsy of a cerebellar lesion that demonstrated T-cell lymphoma by immunohistochemical staining. The patient died from opportunistic infection after partial radiation therapy. Complete autopsy revealed no evidence of residual T-cell lymphoma. The authors compare T-cell PCNSL in patients with and without AIDS, and discuss differences between T-cell and B-cell PCNSL. In conclusion, T-cell PCNSL can occur in patients with AIDS. The tumor is often located infratentorially and appears to be radiosensitive. However, the patient's survival is short because death is usually caused by opportunistic infection rather than mass effect from lymphoma.

Intravenous carboplatin for recurrent gliomas. A dose-escalating phase II trial.

In a Phase II trial, 63 evaluable patients with recurrent glioma received i.v. infusions of carboplatin every 3 weeks beginning at a dose of 400 mg/m2. The dose was increased by 50 mg/m2 at each subsequent infusion until the maximum tolerated dose reached, as defined by a platelet count < 25,000/mm3 or an absolute neutrophil count (ANC) < 500/mm3. Treatment was then resumed at the previous dose level and continued until tumor progression occurred. There were 43 men and 20 women studied (mean age, 41 years; range, 6 months to 70.6 years). The combined response and stabilization rate was 29% for 31 patients with glioblastoma and 71.9% for 32 patients with other tumors; median time to tumor progression was 8.2 and 20.3 weeks and median survival was 25.9 and 58.3 weeks, respectively. Twenty patients had level 4 platelet toxicity and nine had level 4 ANC toxicity. Most tumors progressed before the maximum tolerated dose was reached. These results were not better than those from a previous trial of carboplatin at an initial dose of 350 mg/m2, which was escalated by 25 mg/ m2 after every two infusions. Therefore, an optimal dosing schedule was not achieved in this trial.

Role of genomic instability in meningioma progression.

Microsatellite length instability, probably resulting from defective DNA mismatch repair mechanisms, has been described in a variety of cancers. Such genetic instability may play a significant role in tumor formation and progression. To investigate the role of microsatellite alterations in meningioma tumorigenesis and progression, we examined 33 microsatellite markers on nine chromosomes for abnormalities in 18 benign, 15 atypical, and 11 malignant meningiomas. In each tumor, at least 15 markers were investigated. Microsatellite instability was not detected in any of the cases examined. However, loss of heterozygosity for markers from various chromosomes was seen frequently among atypical and malignant meningiomas. Although some of these chromosomal losses might represent random events, our data also indicate a role for specific loci on chromosome arms 14q, 1p, 10q, and possibly 9p in the development of malignancy in meningiomas. Our results argue against a significant role for a generalized microsatellite instability phenotype in meningiomas, but they suggest that genomic instability resulting in frequent allelic deletions may contribute to meningioma progression.

Protein and messenger RNA expression of connexin43 in astrocytomas: implications in brain tumor gene therapy.

The expression of connexin43, the primary gap-junction constituent of glial cells, was evaluated at the messenger RNA and protein levels in different grades of astrocytoma to investigate the relevance of gap junctions in herpes simplex virus-thymidine kinase (HSV-tk)-mediated gene therapy of brain tumors. Transduction of the retroviral-mediated HSV-tk gene into tumor cells with subsequent administration of ganciclovir has recently been used as an experimental therapeutic strategy for treatment of brain tumors. One aspect of this approach is the bystander effect, which augments the efficacy of this therapeutic approach. Glioblastoma cells with minimum levels of connexin43 protein were transfected with a connexin43 complementary DNA. These cells manifested a marked increase in the in vitro bystander effect, supporting the contention that the in vitro bystander effect is a consequence of metabolic cooperation between cells mediated by gap junctions. To assess relative levels of gap-junction protein expression in the relevant tumor type, we examined primary astrocytomas, primary astrocytoma cell cultures, and glioblastoma cell lines. Although most astrocytoma tumor samples expressed connexin43, they differed in the level of expression, with the greatest variation exhibited in high-grade astrocytomas. Primary glioblastoma cell cultures and established glioblastoma cell lines also displayed some variability in connexin43 levels. In aggregate, our results anticipate that glioblastomas will have a varied bystander effect during HSV-tk gene therapy depending on the level of connexin43 expression.

A method to reduce systematic spatial shift associated with magnetic resonance imaging.

To reduce the chemical shifts during magnetic resonance (MR) imaging, the authors replaced the petroleum gel in the Brown-Roberts-Well (BRW) MR localizer with chromium chloride. Computed tomography and MR scans were obtained of a phantom skull containing objects with known spatial coordinates. A 2-to 3-mm systematic spatial shift in the frequency-encoded direction was observed with petroleum gel, but not with CrCl3. Results were verified by reconstructing the three-dimensional spatial location of each object using X-Knife computer software. The authors conclude that spatial localization is more accurate with a CrCl3-filled than a petroleum-filled BRW-MR localizer.