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David W. Beck, Jeffrey J. Olson and Edward J. Urig

✓ The treatment of trigeminal neuralgia by percutaneous retrogasserian glycerol rhizotomy was assessed in a series of 58 patients with a follow-up period ranging from 2 to 40 months postoperatively. All patients were considered medical failures prior to the procedure. Idiopathic trigeminal neuralgia was the diagnosis in 54 patients, and four patients had trigeminal neuralgia associated with multiple sclerosis. Forty-two patients (72%) reported complete relief from the procedure and are taking no medications. Four patients (7%) are much improved and require only minimal drug therapy. Twelve patients (21%) were considered treatment failures. The recurrence rate after initial relief of symptoms was 11%. Ten patients (17%) noticed a mild decrease in facial sensation following the procedure, and one additional patient had a profound sensory loss including loss of corneal reflex. The authors conclude that, while percutaneous retrogasserian glycerol rhizotomy may be useful in the treatment of trigeminal neuralgia, more clinical series and documentation of recurrence rate and complications are needed before any firm conclusions can be reached as to the efficacy of this therapy.

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James B. Stubbs, Roger H. Frankel, Karl Schultz, Ian Crocker, Dirck Dillehay and Jeffrey J. Olson

Object. The objectives of this study were to evaluate the safety and performance of a new brachytherapy applicator in the treatment of resected brain tumors in a canine model.

Methods. The brachytherapy applicator is an inflatable balloon catheter that is implanted in the resection cavity remaining after a brain tumor has been debulked. After implantation the balloon is inflated with Iotrex, a sterile solution containing organically bound iodine-125. The low-energy photons emitted by the iodine-125 deposit a therapeutic radiation dose across short distances from the surface of the balloon. After delivery of a prescribed radiation dose to the targeted volume, the radioactive fluid is retrieved and the catheter removed.

Small resections of the right frontal lobe were performed in large dogs. Magnetic resonance (MR) images were obtained and used to assess tissue response and to measure the conformance between the resection cavity wall and the balloon surface. In four animals a dose ranging from 36 to 59 Gy was delivered. Neurological status and histological characteristics of the brain were assessed in all dogs.

Implantation and explantation as well as inflation and deflation of the device were easily accomplished and well tolerated. The device was easily visualized on MR images, which demonstrated the expected postsurgical changes. The resection cavity and the balloon were highly conformal (range 93–100%). Histological changes to the cavity margin were consistent with those associated with surgical trauma. Additionally, radiation-related changes were observed at the margins of the resection cavity in dogs in which the brain was irradiated.

Conclusions. This balloon catheter and 125I radiotherapy solution system can safely and reliably deliver radiation to the margins of brain cavities created by tumor resection. Results of this study showed that intracranial pressure changes due to balloon inflation and deflation were unremarkable and characteristic of the imaging properties and radiation safety profile of the device prior to its clinical evaluation. Clinically relevant brachytherapy (adequate target volume and total dose) was accomplished in all four animals subjected to treatment.

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Jeffrey J. Olson, David W. Beck, Janet Schlechte and Pao-Min Loh

✓ Speculation that meningiomas are subject to endocrine influence is supported by their higher incidence in women, reports of exacerbation of symptoms during pregnancy, and the discovery that these tumors harbor progesterone- and estrogen-binding proteins. To evaluate if these properties could be exploited therapeutically, specimens from three convexity meningiomas were used for estrogen- and progesterone-binding protein assays and establishment of tissue cultures. Each tumor (designated A, B, and C, respectively) was grown in experimental media containing 7.5 × 10−5 to 10−12 M 17β-estradiol, 2.5 × 10−4 to 10−12 M progesterone, 10−7 to 10−9 M tamoxifen (an estrogen antagonist), and 10−6 to 10−10 M RU486 (a progesterone antagonist). After incubation, cell growth was compared to control preparations by counting the meningioma cells present in each medium.

Tumors A, B, and C contained estrogen-binding proteins of 8.45, 13.6, and 26.9 fmol/mg cytosol protein and progesterone-binding proteins of 210, 130, and 126 fmol/mg cytosol protein, respectively. The media containing 17β-estradiol and progesterone caused 21% to 36% growth stimulation in Tumors A and B. In Tumor A, the addition of tamoxifen stimulated growth by 35%, while it caused only transient stimulation in Tumor B and had no effect on Tumor C. RU486, the progesterone antagonist, caused inhibition of cell growth in all three tumors, ranging from 18% to 36%.

These data suggest that selected meningiomas are subject to hormonal influence in vitro. The inhibition of meningioma growth in vitro by the antiprogesterone, RU486, has not been previously reported, and serves to encourage further development of alternative modes of therapy for recurrent and unresectable meningiomas.

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Jeffrey J. Olson, Robert Friedman, Kathryn Orr, Thomas Delaney and Edward H. Oldfield

✓ Pentobarbital reduces cerebral radiation toxicity; however, the mechanism of this phenomenon remains unknown. As an anesthetic and depressant of cerebral metabolism, pentobarbital induces its effects on the central nervous system by stimulating the binding of gamma-aminobutyric acid (GABA) to its receptor and by inhibiting postsynaptic excitatory amino acid activity. The purpose of this study is to investigate the role of these actions as well as other aspects of the radioprotective activity of pentobarbital.

Fischer 344 rats were separated into multiple groups and underwent two dose-response evaluations. In one set of experiments to examine the relationship of radioprotection to pentobarbital dose, a range of pentobarbital doses (0 to 75 mg/kg) were given intraperitoneally prior to a constant-level radiation dose (70 Gy). In a second series of experiments to determine the dose-response relationship of radiation protection to radiation dose, a range of radiation doses (10 to 90 Gy) were given with a single pentobarbital dose (60 mg/kg intraperitoneally). Further groups of animals were used to evaluate the importance of the timing of pentobarbital administration, the function of the (+) and (−) isomers of pentobarbital, and the role of an alternative GABA agonist (diazepam). In addition, the potential protective effects of alternative methods of anesthesia (ketamine) and induction of cerebral hypometabolism (hypothermia) were examined.

Enhancement of survival time from acute radiation injury due to high-dose single-fraction whole-brain irradiation was maximal with 60 mg/kg of pentobarbital, and occurred over the range of all doses examined between 30 to 90 Gy. Protection was seen only in animals that received the pentobarbital before irradiation. Administration of other compounds that enhance GABA binding (Saffan and diazepam) also significantly enhanced survival time. Ketamine and hypothermia were without protective effect.

Protection from acute radiation-induced mortality by pentobarbital in the rat model is a reproducible phenomenon and is associated with the GABA agonistic activity of the compound. This property of GABA agonists offers the potential for a novel approach to enhancement of the efficacy of radiation therapy in the treatment of brain tumors.

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Jeffrey J. Olson, David W. Beck, Janet A. Schlechte and Pao-Min Loh

✓ Meningiomas have been shown to have steroid-binding proteins. In vitro, estradiol, progesterone, and the antiestrogen tamoxifen stimulate tumor growth. However, incubation of tumor cells with an antiprogesterone agent results in tumor inhibition. In this investigation, a human meningioma was implanted subcutaneously in athymic nude mice. Two treatment groups were established, one receiving the antiprogesterone agent RU-38486 (10 mg/kg/day in suspension) and the other receiving only vehicle. After 3 months, the tumor growth index (defined as the tumor volume at 3 months divided by the initial tumor volume) was 0.25 ± 0.46 (mean ± standard deviation) in the group receiving antiprogesterone and was 1.54 ± 0.58 in the control group (p = 0.041). Further investigation of the effect of antiprogestational agents on the growth and hormone-binding proteins of other meningiomas will better define the mechanism of their effects.

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Jeffrey J. Olson, Robert Friedman, Kathryn Orr, Thomas Delaney and Edward H. Oldfield

✓ Radiation therapy is an important component of brain tumor treatment, but its efficacy is limited by its toxicity to the surrounding normal tissue. Pentobarbital acts as a cerebral radioprotectant, but the selectivity of its protection for the central nervous system has not been demonstrated. To determine if pentobarbital also protects tumor against ionizing radiation, five groups of Fischer 344 rats were observed after exposure to varying combinations of the presence or absence of implanted tumor, pentobarbital, and radiation treatment. The first three groups underwent cerebral implantations of a suspension of 9L gliosarcoma cells. Group 1 was left untreated and served as tumor-bearing controls. Group 2 received 30 Gy of whole-brain x-irradiation without anesthesia 8 days after tumor implantation. Group 3 received the same radiation treatment 15 minutes after pretreatment with 60 mg/kg of pentobarbital intraperitoneally. Groups 4 and 5 served as radiation controls, receiving 30 Gy of x-irradiation while awake and 30 Gy of x-irradiation after pentobarbital administration, respectively. Survival was calculated from the death of the last tumor-bearing rat.

The mean survival time in tumor-bearing control rats was 20.8 ± 2.6 days (± standard deviation). X-irradiation alone significantly enhanced the period of survival in rats implanted with the 9L tumor (29.7 ± 5.6 days, p < 0.003). Further significant prolongation of survival was seen with the addition of pentobarbital to the treatment regimen (39.9 ± 13.5 days, p < 0.01). Nontumor-bearing rats irradiated while awake (Group 4) survived 30.9 ± 2.3 days. All of their pentobarbital-anesthetized counterparts in Group 5 survived. If pentobarbital had offered radioprotection to the tumor, then Group 3 would have had a shorter survival period than Group 2. This implies that the enhancement of survival time after irradiation results from selective protection of normal brain in this model.

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Joseph M. Zabramski, Donald Whiting, Rabih O. Darouiche, Terry G. Horner, Jeffrey Olson, Claudia Robertson and Allan J. Hamilton

Object. Catheter-related infection of the cerebrospinal fluid (CSF) pathways is a potentially life-threatening complication of external ventricular drainage. A major source of infection is bacterial contamination along the external ventricular drain (EVD) catheter track. The authors examined the efficacy of EVD catheters impregnated with minocycline and rifampin in preventing these catheter-related infections.

Methods. The authors conducted a prospective, randomized clinical trial at six academic medical centers. All hospitalized patients 18 years or older who required placement of an EVD catheter were eligible for inclusion in the study. Patients were randomly assigned to undergo placement of an EVD with a catheter impregnated with minocycline and rifampin or a standard untreated catheter (control group). To assess primary outcome, CSF samples were collected using a sterile technique at the time of catheter insertion, at least every 72 hours while the catheter remained in place, and at the time of catheter removal. At the time of removal, CSF cultures were obtained from the tip and tunneled segments of each catheter by performing semiquantitative roll-plate and quantitative sonication techniques.

Of the 306 patients enrolled in the study, data from 288 were included in the final analysis. Eighteen patients were excluded from analysis: 14 because the ventricular catheter was in place less than 24 hours, and four because CSF cultures obtained at the time of catheter insertion were positive for infection. Of these 288 patients, 139 were assigned to the control group and 149 to the treatment group. The two groups were well matched with respect to all clinical characteristics, including patient sex and mean age, indication for catheter placement, and length of time the catheter remained in place. The antibiotic-impregnated catheters were one half as likely to become colonized as the control catheters (17.9 compared with 36.7%, respectively, p < 0.0012). Positive CSF cultures were seven times less frequent in patients with antibiotic-impregnated catheters compared with those in the control group (1.3 compared with 9.4%, respectively, p = 0.002).

Conclusions. The use of EVD catheters impregnated with minocycline and rifampin can significantly reduce the risk of catheter-related infections.

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Edward H. Oldfield, Robert Friedman, Timothy Kinsella, Ross Moquin, Jeffrey J. Olson, Kathryn Orr and Anne Marie DeLuca

✓ To determine if barbiturates would protect brain at high doses of radiation, survival rates in rats that received whole-brain x-irradiation during pentobarbital- or lidocaine-induced anesthesia were compared with those of control animals that received no medication and of animals anesthetized with ketamine. The animals were shielded so that respiratory and digestive tissues would not be damaged by the radiation. Survival rates in rats that received whole-brain irradiation as a single 7500-rad dose under pentobarbital- or lidocaine-induced anesthesia was increased from between from 0% and 20% to between 45% and 69% over the 40 days of observation compared with the other two groups (p < 0.007). Ketamine anesthesia provided no protection. There were no notable differential effects upon non-neural tissues, suggesting that pentobarbital afforded protection through modulation of ambient neural activity during radiation exposure.

Neural suppression during high-dose cranial irradiation protects brain from acute and early delayed radiation injury. Further development and application of this knowledge may reduce the incidence of radiation toxicity of the central nervous system (CNS) and may permit the safe use of otherwise “unsafe” doses of radiation in patients with CNS neoplasms.

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Ju He, Jeffrey J. Olson, A. Jonas Ekstrand, Andrei Serbanescu, Jing Yang, Margaret K. Offermann and C. David James

✓ Previously these authors and others demonstrated frequent homozygous deletions of the chromosome 9p—localized class I interferon (IFN) gene cluster in glioblastoma tumors and cell lines. To investigate the biological effects of class I IFN gene transfer and constitutive expression in glioblastoma cells devoid of this gene cluster, the authors have developed a stable IFN “transfectant” of the cell line U118. The expression of IFNα protein in the U118 transfectant clone is associated with decreased levels of DNA synthesis exhibited by cultures of transfected cells, reduced colony-forming ability in soft agar, and loss of tumorigenicity in athymic nude mice. To address the molecular consequences of constitutive IFNα synthesis, they examined the expression of four genes whose transcription has been shown to be responsive to IFN-mediated signal transduction and could be important to the observed antiproliferative and antitumor effects. Northern blot analysis revealed that changes in the levels of messenger (m)RNA for two of these genes, c-myc and mhc class I, are minor. However, mRNAs for oligoadenylate synthetase (OAS) as well as double-stranded RNA-activated protein kinase (PKR), which are not expressed in parental U118 cells, were constitutively express ed in IFNα transfectants. These results indicate a differential responsiveness among these four genes to constitutive IFNα expression, and suggest that the suppression of U118-transformed phenotypes by IFNα transfection may be mediated by the induction of specific IFN response genes thought to have a negative growth-regulatory function.

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Kurt E. Weaver, Andrew Poliakov, Edward J. Novotny, Jared D. Olson, Thomas J. Grabowski and Jeffrey G. Ojemann

OBJECTIVE

The acquisition and refinement of cognitive and behavioral skills during development is associated with the maturation of various brain oscillatory activities. Most developmental investigations have identified distinct patterns of low-frequency electrophysiological activity that are characteristic of various behavioral milestones. In this investigation, the authors focused on the cross-sectional developmental properties of high-frequency spectral power from the brain’s default mode network (DMN) during goal-directed behavior.

METHODS

The authors contrasted regionally specific, time-evolving high gamma power (HGP) in the lateral DMN cortex between 3 young children (age range 3–6 years) and 3 adults by use of electrocorticography (ECoG) recordings over the left perisylvian cortex during a picture-naming task.

RESULTS

Across all participants, a nearly identical and consistent response suppression of HGP, which is a functional signature of the DMN, was observed during task performance recordings acquired from ECoG electrodes placed over the lateral DMN cortex. This finding provides evidence of relatively early maturation of the DMN. Furthermore, only HGP relative to evoked alpha and beta band power showed this level of consistency across all participants.

CONCLUSIONS

Regionally specific, task-evoked suppression of the high-frequency components of the cortical power spectrum is established early in brain development, and this response may reflect the early maturation of specific cognitive and/or computational mechanisms.