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CLIN-NEURO-COGNITIVE NC-02. ASSESSING NEURO-COGNITIVE STATUS IN NEWLY PRESENTING PATIENTS WITH SUPRATENTORIAL INTRACRANIAL TUMOURS. Jennifer L. Scotland1, Ian R. Whittle1, and Ian J. Deary2; University of Edinburgh, Edinburgh, United Kingdom; Centre for Cognitive Ageing and Cognitive Epidemiology, Dept. of Psychology, University of Edinburgh, Edinburgh, United Kingdom INTRODUCTION: Neurocognitive endpoints are increasingly included in clinical trials in neuro-oncological settings (Meyers & Brown, 2006). There is a need to identify short, repeatable measures of cognition that are sensitive to impairment in this group. Previous authors have proposed such batteries. METHODS: Newly presenting patients with a radiological diagnosis of any intracranial tumour (n 1⁄4 118) were assessed, prior to any surgical intervention, on a number of standardised cognitive and other measures as part of a larger study (Scotland et al., 2012). Their performance was compared with that of patients admitted for elective spinal surgery (n 1⁄4 85) and a healthy control group (n 1⁄4 80). RESULTS: Analysis of covariance compared the performance of the three groups. Age, sex, and National Adult Reading Test score (used to assess premorbid function) were the covariates. Patients with intracranial tumours performed significantly worse on the majority of the tests. The intracranial tumour cohort had significantly lower scores than did the spinal surgery and healthy control groups on the following measures: immediate and delayed memory (Rey Auditory Verbal Learning Test, RAVLT; p , 0.001); Trail Making Test Part B (p , 0.001); digit-symbol coding (p , 0.001); and verbal fluency (Controlled Oral Word Association Test, COWAT; p 1⁄4 0.002 and p , 0.001, respectively). There was a moderate-to-large effect size in the participant group for all tests. DISCUSSION/CONCLUSIONS: The RAVLT, Trail Making Test Part B, and COWAT are sensitive measures of cognitive impairment in patients with brain tumours and support Meyers & Brown’s (2006) proposal for the inclusion of these tests in clinical trials that have neurocognitive endpoints. The verbal fluency test, in particular, has a number of potential advantages for use in neuro-oncological settings, given that it can be completed by patients with focal motor deficits and is available in alternate forms to reduce practice effects. NC-03. A STANDARD NEUROLINGUISTIC APPROACH TO

Ferumoxtran-10 (Combidex), a dextran-coated iron oxide nanoparticle, provides enhancement of intracranial tumours by magnetic resonance (MR) for more than 24 h and can be imaged histologically by iron staining. Our goal was to compare ferumoxtran imaging and histochemistry vs. gadolinium enhancement in malignant brain tumours on preoperative and postoperative MR.Seven patients with primary and metastatic malignant tumours underwent MR imaging with gadolinium and ferumoxtran both pre- and postoperatively. Normalized signal intensities on the ferumoxtran-enhanced scans were determined in representative regions of interest. Resected tissue from six ferumoxtran patients and from three patients who did not receive ferumoxtran was assessed for localization of iron in tumour and reactive brain.All malignant tumours (all of which enhanced by gadolinium MR) showed ferumoxtran accumulation with T1 and T2 signal changes, even using a 0.15 T intraoperative MR unit in one patient. Iron staining was predominantly in reactive cells (reactive astrocytes and macrophages) and not tumour cells. In five of the seven patients, including two patients who showed additional lesions, areas enhancing with ferumoxtran but not with gadolinium were observed. Comparison of the pre- and postoperative MR revealed residual ferumoxtran-enhancing areas in four of seven cases.In malignant tumours, ferumoxtran may show areas of enhancement, even with a 0.15 T intraoperative MR, that do not enhance with gadolinium. Ferumoxtran-enhancing lesions have persistent increased T1 signal intensity for 2-5 days, which may provide advantages over gadolinium for postoperative imaging. Histochemistry for iron shows uptake of ferumoxtran in reactive cells (astrocytes and macrophages) rather than tumour cells.

Central nervous system (CNS) drainage may occur via connections to the vasculature, but in animal models up to 50% occurs via perivascular, perineural and primitive lymphatic drainage to cervical lymph nodes. We evaluated efflux of particles from the brain to cervical lymph nodes in normal rats, using Combidex iron oxide-based magnetic resonance imaging (MRI) agent. After intracerebral, intraventricular, intracarotid or intravenous injection of Combidex in normal Long Evans rats, particle localization was assessed by MRI and histochemistry for iron and the dextran coat (n = 27). Intraventricular or intracerebral injection, but not intracarotid administration of Combidex (100 micro g), resulted in MRI signal changes in the deep cervical lymph nodes around the carotid artery, and, less strongly, in the superficial cervical nodes. Within 2 h of Combidex administration, iron was histologically localized in cervical lymph nodes, with patched staining of capsule and peripheral sinus consistent with delivery via multiple afferent lymphatic vessels. Lymph node staining in groups receiving CNS Combidex was significantly different from controls (P0.0001) and was significantly localized in the deep vs. superficial cervical lymph nodes (P = 0.0003). The trafficking of the superparamagnetic iron particles from the CNS in the rat could be visualized by MRI and histology. Combidex provides a powerful tool to rapidly assess drainage of virus-sized particles from the CNS.

Modulation of thiol levels may alter both the efficacy and toxicity of chemotherapeutic agents. We investigated cytoenhancement, using L-buthionine-[S,R]-sulfoximine (BSO) to reduce cellular glutathione levels prior to intracarotid alkylator administration. We also evaluated chemoprotection against chemotherapy-induced systemic toxicity when the thiol agents N-acetylcysteine (NAC) and sodium thiosulfate were administered into the descending aorta to limit brain delivery. BSO treatment reduced rat brain and intracerebral tumor glutathione levels by 50-65%, equivalent to the reduction in liver and s.c. tumor. BSO treatment significantly enhanced the toxicity of chemotherapy with carboplatin, melphalan, and etoposide phosphate against granulocytes, total white cells, and platelets. Intracarotid administration of NAC resulted in high delivery to the brain, whereas infusion via the descending aorta minimized brain delivery. When NAC, with or without sodium thiosulfate, was administered via aortic infusion prior to chemotherapy, the magnitude of the bone marrow toxicity nadir was minimized, even with BSO-enhanced myelosuppression. Thus, BSO depleted brain and brain tumor glutathione but thereby increased chemotherapy-induced myelosuppression. Surprisingly, although NAC was found to readily cross the blood-brain barrier when given into the carotid artery, aortic infusion of NAC resulted in minimal exposure to the central nervous system (CNS) vasculature because of rapid clearance. As a result, aortic infusion of NAC to perfuse bone marrow and minimize myelosuppression and toxicity to visceral organs could be performed without interfering with the CNS cytotoxicity of intracarotid alkylators, even after BSO depletion of CNS glutathione.

Carboplatin is effective in the treatment of malignant brain tumors. However, when administered in conjunction with osmotic opening of the blood-brain barrier (BBB), carboplatin is ototoxic. The purpose of this study was to determine whether delayed administration of sodium thiosulfate (STS), given after BBB closure, provided protection against carboplatin ototoxicity. Patients underwent monthly treatment with intra-arterial carboplatin (200 mg/m2/day x 2) in conjunction with osmotic opening of the BBB, for up to 1 year. Audiological assessment was conducted at baseline and within 24 h before each monthly treatment. STS was administered i.v. as one (20 g/m2) or two (20 g/m2 and 16 g/m2) 15-min doses, depending on baseline hearing status. The initial group received the first STS dose 2 h (or 2 and 6 h) after carboplatin (STS2) and a subsequent group received STS 4 h (or 4 and 8 h) after carboplatin (STS4). Audiological data were compared with a historical comparison group (HCG) treated with carboplatin without STS. Spearman correlation coefficients comparing STS 2 (n = 24), STS4 (n = 17), and HCG (n = 19) indicated significantly lower rates of ototoxicity with increased delay in STS (P = 0.0006). On the basis of the analysis of hearing levels, there were significant differences among the two STS groups and HCG at 8000 Hz (P = 0.0010) and at 4000 Hz (P = 0.0075). The log-rank test for time to ototoxicity indicated a significant difference between STS4 and HCG (P = 0.0018). Delayed STS was effective in protecting against carboplatin-induced hearing loss. STS delayed to 4 h after carboplatin significantly decreased time to development of ototoxicity and rate of ototoxicity when compared with HCG.

Modulation of glutathione has been proposed as a mechanism to alter the efficacy and toxicity of chemotherapeutic agents. We investigated in vitro cytoenhancement of chemotherapy toxicity by reducing cellular glutathione levels with L-buthionine-[S,R]-sulfoximine (BSO), and chemoprotection with small molecular weight sulfur-containing agents that mimic or replace glutathione. Cytotoxicity, caspase-2 enzymatic activity, and in situ DNA staining for apoptosis were assessed in cultured human small cell lung carcinoma cells and fibroblasts. BSO treatment reduced the half-maximal cytotoxic dose of the alkylating chemotherapeutics melphalan, carboplatin, and cisplatin, and increased the total magnitude of cell death. Melphalan was more sensitive than carboplatin or cisplatin to BSO. The chemoprotective agents sodium thiosulfate, N-acetylcysteine, and glutathione ethyl ester reduced the cytotoxicity of all three alkylating chemotherapeutics regardless of BSO treatment, but D-methionine was effective only against the platinum agents. N-Acetylcysteine was the most effective protectant tested. Chemoprotection against melphalan toxicity was maximally effective only if administered concurrent with chemotherapy, whereas chemoprotection for the platinum agents remained effective if delayed 4 h after chemotherapy. BSO enhancement and N-acetylcysteine chemoprotection for melphalan toxicity occurred at least partially through an apoptotic mechanism. Modulation of glutathione levels will be valuable in the clinical setting if chemotherapy and chemoprotectant can be physically and/or temporally separated. Cytoenhancement and chemoprotection may be particularly useful in the central nervous system where the blood-brain barrier of the cerebral vasculature creates two compartments, for cytoenhancement in brain tumors and systemic chemoprotection.

Platinum-based chemotherapeutic agents, such as carboplatin and cisplatin, are effective against many human tumors, but their use may be limited by a high incidence of ototoxicity. Delayed administration of the chemoprotective agent sodium thiosulfate (STS) reduces the ototoxicity of carboplatin in a guinea-pig model, when given up to 8 h after the chemotherapy, and also reduces hearing loss in patients given carboplatin with osmotic blood-brain barrier opening for treatment of brain tumors. We tested whether STS, given at times that achieved otoprotection, could impact the chemotherapeutic efficacy of carboplatin. The impact of STS was evaluated by measuring the onset of growth of LX-1 human small cell lung carcinoma s.c. xenografts in the nude rat. When STS was administered as two boluses, 2 and 6 h after treatment with carboplatin and etoposide, there was a decrease in the time to tumor progression. In contrast, when STS administration was delayed until 8 h after carboplatin/etoposide, there was no reduction in the antitumor cytotoxicity of the chemotherapy. STS infusion did not significantly affect ultrafilterable platinum pharmacokinetics in the guinea pig. To explore the potential wider applicability of STS, in a pilot study we tested its efficacy against cisplatin ototoxicity. Delayed administration of STS, 2 h after cisplatin, was protective against cisplatin-induced ototoxicity in the guinea pig model, as determined by electrophysiological measures. On the basis of these data, we suggest that delayed administration of STS may provide a mechanism to reduce the ototoxicity caused by administration of carboplatin or cisplatin for both central nervous system and systemic cancer chemotherapy.

The aim of this study was to determine the safety and efficacy of intraarterial chemotherapy with osmotic opening of the blood-brain barrier (BBB) for the treatment of malignant brain tumors when administered across multiple centers.Patients with primary central nervous system lymphoma (PCNSL), primitive neuroectodermal tumor (PNET), germ cell tumor, cancer metastasis to the brain, or low or high grade glioma were eligible. Prior to entry, magnetic resonance imaging or computed tomography brain scan, medical history, neurologic status, and Karnofsky performance status were reviewed at the coordinating center. Standardized anesthesia and intraarterial catheterization guidelines were followed by a multidisciplinary team at each center. Between March 1994 and November 1997, 5 universities treated 221 adult patients with intraarterial chemotherapy with or without osmotic opening of the BBB (2464 procedures).Of evaluable patients with PCNSL, 40 of 53 (75%) achieved complete response (CR). All evaluable patients with PNET (n = 17), metastatic disease (n = 12), or germ cell tumor (n = 4) achieved stable disease (SD) or better. Of 57 evaluable patients with glioblastoma multiforme, 45 (79%) achieved SD or better. Asymptomatic subintimal tear occurred in 11 of 221 patients (5%), pulmonary embolism in 6 of 221 (2.7%), and renal toxicity in 4 of 221 (1.8%). One patient with extensive glioma expired within 48 hours after treatment.Using standard guidelines and protocols, intraarterial chemotherapy with or without osmotic opening of the BBB is feasible across multiple centers with a low incidence of catheter-related complications. In patients with chemotherapy-sensitive tumors, such as PCNSL, PNET, germ cell tumor, and cancer metastasis to the central nervous system, enhanced delivery results in a high degree of tumor response, with an efficacy profile that is reproducible across multiple centers.

Patients with non-acquired immunodeficiency syndrome-related primary central nervous system lymphomas have the potential to achieve durable complete responses without radiotherapy, with treatment using enhanced chemotherapy delivery with blood-brain barrier disruption (BBBD). Reported 5-year survival rates with combined chemotherapy and radiotherapy were generally only 9 to 22% and were associated, in one study, with an overall 32% incidence of overt dementia and ataxia, which are dramatically increased among patients more than 60 years of age.At the Oregon Health Sciences University, 111 consecutive patients with non-acquired immunodeficiency syndrome-related central nervous system lymphomas were prospectively treated with methotrexate-based, BBBD-enhanced chemotherapy and underwent formal neuropsychological evaluations. Of those, 74 patients had no systemic lymphoma and had received no prior irradiation; those 74 patients are described in this report.The estimated 5-year survival rate for this group was 42%, and the median survival time was 40.7 months. Overall, 48 patients (65%) exhibited complete responses and 36 patients continued to exhibit complete responses after 1 year of BBBD-enhanced chemotherapy. Of those 36 patients, none demonstrated evidence of cognitive loss in neuropsychological tests and/or clinical examinations.BBBD-enhanced chemotherapy delivery, without subsequent radiotherapy, resulted in favorable survival and cognitive outcomes for patients with primary central nervous system lymphomas who had not previously undergone irradiation. A cooperative multicenter study of intravenous chemotherapy without radiotherapy versus BBBD-enhanced chemotherapy would address the feasibility and necessity of performing a Phase III study for these rare central nervous system malignancies.

BACKGROUND AND PURPOSE: Osmotic disruption of the blood-brain barrier (BBB) provides a method for transvascular delivery of therapeutic agents to the brain. The apparent global delivery of viral-sized iron oxide particles to the rat brain after BBB opening as seen on MR images was compared with the cellular and subcellular location and distribution of the particles. METHODS: Two dextran-coated superparamagnetic monocrystalline iron oxide nanoparticle contrast agents, MION and Feridex, were administered intraarterially in rats at 10 mg Fe/kg immediately after osmotic opening of the BBB with hyperosmolar mannitol. After 2 to 24 hours, iron distribution in the brain was evaluated first with MR imaging then by histochemical analysis and electron microscopy to assess perivascular and intracellular distribution. RESULTS: After BBB opening, MR images showed enhancement throughout the disrupted hemisphere for both Feridex and MION. Feridex histochemical staining was found in capillaries of the disrupted hemisphere. Electron microscopy showed that the Feridex particles passed the capillary endothelial cells but did not cross beyond the basement membrane. In contrast, after MION delivery, iron histochemistry was detected within cell bodies in the disrupted hemisphere, and the electron-dense MION core was detected intracellularly and extracellularly in the neuropil. CONCLUSION: MR images showing homogeneous delivery to the brain at the macroscopic level did not indicate delivery at the microscopic level. These data support the presence of a physiological barrier at the basal lamina, analogous to the podocyte in the kidney, distal to the anatomic (tight junction) BBB, which may limit the distribution of some proteins and viral particles after transvascular delivery to the brain.

Sodium thiosulfate (STS) provides protection against carboplatin-induced ototoxicity in an animal model. The purpose of this study was to determine the STS dose required for otoprotection, in patients with malignant brain tumors treated with carboplatin in conjunction with osmotic blood-brain barrier disruption. Twenty-nine patients received STS intravenously 2 hr after carboplatin. Doses were escalated from 4 g/m2 to 8, 12, 16 and 20 g/m2 on consecutive months. Audiologic assessment was performed at baseline and monthly. The audiograms were compared with those of 19 similarly treated historical control patients who did not receive STS. The incidence of ototoxicity in the historical control group of patients was 79% (15/19). This group had an average loss of 20.8 +/- 5.9 dB (n = 19) at 8 kHz after one treatment with carboplatin, whereas the STS treatment group lost only 3.7 +/- 2 dB (n = 15) after one treatment. This difference was statistically significant as assessed by Student's t test (P.05). Furthermore, patients in the STS treatment group with excellent base-line hearing showed little change in hearing thresholds at 8 kHz after the second treatment (8.0 +/- 8.3 dB) (n = 5) compared with the historical control patients with excellent base-line hearing, (40.5 +/- 8.6 dB) (n = 11). Our data support that doses of 16 or 20 g/m2 of STS decrease carboplatin-induced hearing loss without central nervous system entry. Clinical demonstration of an otoprotective effect with a two-compartment system to prevent drug-induced hearing loss, while preserving central nervous system cytotoxicity, has not been reported previously.

To assess how to maximize drug delivery to intracerebral tumors and surrounding brain, this study examined the effects of route and method of administration and tumor size on the distribution of three agents in a nude rat intracerebral tumor xenograft model. Aminoisobutyric acid (M(r) 103), methotrexate (M(r) 454), and dextran 70 (M(r) 70,000) were administered i.v. or intra-arterially (i.a.) with or without osmotic blood-brain barrier disruption (BBBD) at 8, 12, or 16 days after tumor cell inoculation (n = 72). A 2.2- to 2.5-fold increase in delivery to tumor and surrounding brain was observed when i.a. was compared with i.v., and a 2.5- to 7.6-fold increase was observed when BBBD was compared with the saline control. The combined effect of i.a. administration and BBBD was to increase delivery 6.3-16.7-fold. The greatest benefit of BBBD was seen in animals with 8-day tumors, whereas BBBD had less benefit in improving delivery to intracerebral tumor and brain around tumor as the tumors grew larger. Regional delivery decreased as the molecular weight of the agent increased. Based on these results, we suggest that i.a. administration of antitumor agents may be adequate to obtain initial responses in large, very permeable, intracerebral tumors. However, in smaller, less permeable tumors or after an initial response to treatment, there may be a significant therapeutic advantage to i.a. agent administration and BBBD.

Radiographic tumor response and survival were evaluated in the pediatric and young adult population with germ cell tumor, primary CNS lymphoma, or primitive neuroectodermal tumor receiving intra-arterial carboplatin- or methotrexate-based chemotherapy with osmotic blood-brain barrier disruption (BBBD).Thirty-four patients with histologically confirmed germ cell tumor (n = 9), primary CNS lymphoma (n = 9), or primitive neuroectodermal tumor (n = 16) were treated at the Oregon Health Sciences University from August 1981 through April 1995. Ages ranged from 1 to 30 years (mean, 18 years). Prior treatments included cranial radiation (n = 10) and chemotherapy (n = 18). All patients underwent extensive baseline neuropsychological evaluation and follow-up evaluation upon completion of the protocol, except for two patients who declined follow-up assessment.Six hundred and forty-five BBBD procedures were performed with no mortality. Significant complications included one episode of tonsillar herniation with no neurologic sequelae, 4% incidence of seizures, and 3% incidence of sepsis or granulocytopenic fever. Ototoxicity was seen in 61% of patients who received carboplatin chemotherapy. Eighty-two percent of the patients had an objective response to treatment, including 62% with complete response and 20% with partial response. For most patients, cognitive functioning was maintained or improved at follow-up; this pattern was statistically significant. Three of the test scores for the seven patients who did not receive radiation therapy showed a cognitive decline of at least one standard deviation. Among the nine patients who received radiation therapy before or after BBBD chemotherapy, 11 test scores showed a decline in cognitive function at one standard deviation or more.Durable responses were seen in patients with germ cell tumor and primary CNS lymphoma when treated with BBBD. Primitive neuroectodermal tumor requires post-chemotherapy radiotherapy for a durable response to be attained. Ototoxicity was a major form of toxicity in the patients who received carboplatin, but with the recent introduction of sodium thiosulfate, this problem has been markedly alleviated. Favorable cognitive outcomes appeared more likely for patients treated solely with BBBD chemotherapy and not with radiotherapy. Trends in the results for this sample are similar to those of previous research showing that radiotherapy is associated with cognitive decline. Current alternatives to enhanced drug delivery after BBBD include bone marrow transplantation; however, the increment in drug delivery is less, the number of courses is limited, and the morbidity and mortality are greater for bone marrow transplant than for BBBD. The current results suggest that in future trials, irradiation may not be needed in lymphoma and may not be necessary in some CNS germ cell tumors and that more focal radiotherapy should be further assessed in localized primitive neuroectodermal tumors.

Radiographic tumor response and survival were evaluated in patients receiving methotrexate-based chemotherapy with osmotic blood-brain barrier disruption with or without antecedent cranial radiation.Fifty-eight non-AIDS patients (38 males, 20 females) with histologically confirmed primary central nervous system lymphoma, primarily large cell or immunoblastic, were treated at the Oregon Health Sciences University from January 1982 through March 1992. Group 1 patients (n=19) received cranial radiation prior to referral; Group 2 (n=39) received initial blood-brain barrier disruption chemotherapy. Ages ranged from 5 to 71 years (median, 57); Karnofsky performance status was 40% to 100% on inclusion (median, 80) and all underwent extensive baseline neuropsychological evaluation.There was no significant difference in patient characteristics between the two groups. In 15 evaluable Group I patients, 14 demonstrated objective response and 7 of 14 (50%) achieved complete response. In Group 2, 34 of 35 evaluable patients demonstrated objective response, including 29 of 34 with complete response. Estimated median survival times for Group 1 and Group 2 patients were 16 and 41 months, respectively. Currently, 19 Group 2 patients and 2 Group 1 patients are alive. Extensive neuropsychological follow-up (up to 7 years from baseline) was completed in 23 patients, which demonstrated preservation or improved cognitive function in those receiving initial chemotherapy and blood-brain barrier disruption, most notably in patients older than 60 years.A plateau in survival curves suggests that a portion of primary central nervous system lymphoma patients may be cured with chemotherapy and blood-brain barrier disruption without the neurologic sequelae associated with cranial radiation.

The volume of distribution in tissue (Vt) that can be achieved by direct interstitial infusion of therapeutic agents into brain is limited. The maintenance of a pressure gradient during interstitial infusion to establish fluid convection has been shown to increase the Vt of small, medium, and large molecules. We have used monocrystalline iron oxide nanocompounds, superparamagnetic particles of sizes the same order of magnitude as virions, to investigate the effect of dose, the volume of infusate, and the time of infusion on the distribution of large molecules in rodent brain. Our initial study in rats (n = 6) replicated the results of a previously described report of convection-enhanced delivery in cats. At a constant rate and concentration, the Vt increased in a linear fashion, proportional to the increases in time, volume, and dose. When using a constant rate and a constant concentration, however, it is unclear which variable or variables (dose, volume, infusion time) have the greatest influence on this effect. Therefore, we assessed each variable independently (n = 12). When the iron dose was increased from 5.3 to 26.5 micrograms, there was a three- to fivefold increase in the Vt, depending on the volume and time of infusion (2 Microliters/20 min, 24 microliters/20 min, or 24 microliters/120 min) (P0.001). When the volume of infusate was increased from 2 to 24 microliters, at an infusion time of 20 minutes and a dose of either 5.3 or 26.5 micrograms, there was a 43 or 52% decline in the Vt, respectively (P = 0.018). When the time for the infusion of 24 microliters was increased from 20 to 120 minutes, there was a 79% increase in the Vt at a dose of 26.5 micrograms but no change in the Vt at a dose of 5.3 micrograms. The effect associated with infusion time was not significant (P = 0.113). Magnetic resonance imaging was performed to document the distribution of monocrystalline iron oxide nanocompounds in vivo, and histochemical staining for iron was used to document the distribution of monocrystalline iron oxide nanocompounds in tissue sections. The Vt for both methods was calculated by computer image analysis, and the correlation between magnetic resonance and histological volumes was determined (r2 = 0.93). On the basis of this model, we suggest that dose, rather than convection, might be the most important variable in maximizing the Vt and improved distribution might be achieved by administering an increased concentration of agent.

PURPOSE: To determine if tumor-specific monoclonal antibodies conjugated to superparamagnetic monocrystalline iron oxide nanoparticles can be used to yield specific diagnoses with the use of MR imaging. METHODS: Monoclonal antibodies conjugated to monocrystalline iron oxide nanoparticles were given to nude rats with intracranial tumors either by intravenous injection, intraarterial injection with osmotic blood-brain barrier disruption, or direct intratumoral inoculation. Either L6, a tumor-specific antibody, or P-1.17, a control isotype-matched antibody, was used. Coronal T1-weighted, T2-weighted, and spoiled gradient-recalled acquisition in the steady state images were obtained before, 30 minutes after, 6 hours after, and 24 hours after injection. RESULTS: Intravenous injection of greater than 2 mg of the tumor-specific antibody showed a specific pattern of enhancement of the tumors with the largest concentration of antibody in the area with the greatest density of tumor cells. The control antibody showed nonspecific changes. After intraarterial injection with barrier disruption to increase delivery globally or direct inoculation to increase delivery focally, no specific enhancement pattern was seen. CONCLUSION: Monoclonal antibodies conjugated with monocrystalline iron oxide particles may provide a method to obtain specific diagnoses with the use of MR imaging.

When carboplatin (cis-diammine-1,1-cyclobutane-dicarboxylato-platinum) delivery to brain tumors is optimized with osmotic blood-brain barrier disruption (BBBD), high frequency hearing loss can result. Treatment with sodium thiosulfate (STS) blocked carboplatin cytotoxicity against the LX-1 human small cell lung carcinoma cell line in vitro. STS decreased carboplatin-induced ototoxicity in a guinea pig model, as determined by electrophysiological measurements and analysis of inner ear outer hair cell numbers. Protection was found when STS was administered up to 8 h subsequent to carboplatin but not 24 h after carboplatin. In a rat model of osmotic BBBD, STS was neurotoxic when given immediately after BBBD but not when given 60 min after BBBD, when the barrier is reestablished. Thus, delayed administration of STS may provide a mechanism to reduce the cochlear toxicity caused by BBBD-enhanced carboplatin delivery to the brain.

The sequence of chemotherapy administered prior to cranial irradiation rather than the more traditional order of radiation followed by chemotherapy is currently being evaluated. This rodent study was designed to assess the sequencing of radiation therapy and chemotherapy administered with osmotic blood-brain barrier disruption (BBBD). Drug delivery and acute toxicity were evaluated. Two clinically relevant chemotherapy regimens were given with BBBD: intraarterial methotrexate (MTX, 1 g/m2), or a combination of intraarterial carboplatin (200 mg/m2) and i.v. etoposide (200 mg/m2). In a randomized protocol, the standard rodent model of 2000 cGy as a single fraction using parallel opposed portals was administered 30 days prior to, concurrent with (24 h prior), or 30 days after these two chemotherapeutic regimens. A total of 72 animals was evaluated in this study. The administration of external beam radiation therapy either prior to or concurrent with the administration of a high molecular weight marker 14C-labeled dextran 70 (Mr 70,000), or a low molecular weight marker 3H-labeled MTX (Mr 456) resulted in a statistically significant (P0.01) decrease in drug delivery when compared to animals not receiving cranial irradiation. Seizures were observed in 26% of the animals that received radiation prior to the administration of intraarterial MTX after BBBD. It did not matter whether the radiotherapy was administered 30 days prior to or concurrent with MTX. Seizures were not seen in any other group. The mortality in animals receiving radiotherapy 30 days prior to chemotherapy was significantly (P = 0.03) higher than the mortality in control animals receiving chemotherapy after osmotic BBBD, but no radiation. Drug delivery was significantly decreased when the animals received prior radiotherapy; the administration of radiation prior to MTX with BBBD resulted in an increased incidence of seizures, and there was a significant increase in mortality when cranial irradiation was given 30 days prior to chemotherapy administered with BBBD. With regard to delivery and toxicity, chemotherapy with BBBD administered prior to radiotherapy may have advantages over the other sequences utilizing chemotherapy and cranial irradiation.

PURPOSE: To establish changes on MR of the brain in a feline model of Sandhoff disease in order to develop standards by which this model may be used in future noninvasive studies. METHODS: Five affected felines and six age-matched, littermate controls were evaluated. T1- and T2-weighted images were obtained once or twice for each of four affected and five control animals at 4 1/2 to 12 weeks of age, for a total of 15 MR examinations. Images were evaluated qualitatively for the pattern of myelination and the size of the ventricular system. After the animals were killed, pathologic specimens of the brain were examined with light and electron microscopy, and pathologic changes were correlated with MR. RESULTS: Compared with control animals, affected animals showed MR evidence of delayed myelination, manifested by white matter signal hypointensity on T1-weighted images and signal hyperintensity on T2-weighted images. This finding was corroborated by histopathologic findings of decreased myelin in the subcortical and internal capsule regions. White matter abnormalities were not detected ultrastructurally in the animals examined. CONCLUSION: Although GM2 gangliosidosis is primarily a neuronal disease, MR imaging can show changes in myelination of white matter tracts that may be secondary to the neuronal damage. This provides a noninvasive method of in vivo monitoring as therapeutic strategies are developed in this animal model.

PURPOSE: To determine whether osmotic blood-brain barrier disruption is associated with MR abnormalities or cognitive deterioration and, if so, whether the MR findings correlate with cognitive test results. METHODS: Fifteen brain tumor patients who had a complete tumor response (nine central nervous system lymphoma, three germ cell and two astrocytoma, and one primitive neuroectodermal tumor) treated with blood-brain barrier disruption procedures (318 total procedures) with intraarterial chemotherapy were included. MR images were evaluated for the development of white matter hyperintensity, vascular lesions, or atrophy. Cognitive testing was performed to assess deterioration caused by this therapy. RESULTS: In two patients white matter hyperintensity developed, in two small vascular lesions developed, and in one mild atrophy developed. One infarct was asymptomatic and the second one resulted in mild dysesthesia in one upper extremity. No patient showed diminished cognitive function on the posttherapy evaluation. CONCLUSION: In patients undergoing blood-brain barrier disruption with intraarterial chemotherapy, new abnormalities on MR imaging may develop. These patients maintain the same level of cognitive and neurologic function and MR findings do not correlate with the results of cognitive testing.

The feasibility of utilizing the differential permeability of the blood-tumour barrier to low- vs. high-molecular-weight compounds is demonstrated in a brain tumour model. Nude rats (n = 27) with or without intracerebral tumours received intravenous [3H]methotrexate (M(r) 454), followed 60 min later by antimethotrexate antibody (M(r) 150,000) or nonspecific mouse antibody. Antimethotrexate antibody resulted in 93% binding of serum methotrexate. In contrast, the percentage of antibody-bound methotrexate in brain and intracerebral tumour was only slightly greater than preantibody protein binding. Methotrexate delivery to tumour was significantly greater than to brain adjacent to tumour and normal brain. The percentage delivery of [3H]methotrexate to all areas of brain was similar between animals receiving antimethotrexate antibody and nonspecific antibody. These findings support the theory that a drug rescue method may be developed that may permit the safe administration of increased dosages of chemotherapeutic drugs for the treatment of intracerebral tumours.

These studies highlight several factors that affect monoclonal antibody (Mab) localization to a tumor in the brain, including tumor permeability, nonspecific and specific binding, plasma half-life, radiolabeled antibody stability and the blood-brain barrier.A pancarcinoma Mab [L6 IgG, F(ab')2 and Fab] and an irrelevant isotype-matched antibody [P1.17 IgG and F(ab')2] were given with and without osmotic blood-brain barrier disruption in a LX-1 human small-cell lung carcinoma intracerebral xenograft model.Intracerebral tumor size and permeability to antibody increased with the selection of 10, 14 or 17 days postinoculation when antibody was administered. Barrier disruption increased the delivery, particularly at earlier time points, which was dependent on antibody-specific and nonspecific binding and tumor permeability. Dehalogenation and/or antibody binding stability also appeared to affect the percent delivery.These studies demonstrate important variables that should be considered when clinical trials are designed or Mab delivery and localization in intracerebral tumor models are evaluated.

Twelve adults (11 male, 1 female), diagnosed as having supratentorial gliomas, were treated with osmotic blood-brain barrier disruption and chemotherapy (intra-arterial methotrexate, 2500 mg/infusion; intravenous Cytoxan, 15 mg/kg/infusion; and oral procarbazine, 100 mg daily x 14 days) prior to radiotherapy. To assess higher cortical function, all patients underwent neuropsychological testing. Volumetric analysis of pretreatment and serial enhanced computerized tomographic scans were recorded. Four of ten patients with enhancing tumor showed radiographic tumor response, defined as 50% reduction of enhancing tumor volume. These four patients received no steroids at the time of maximum tumor response. Osmotic blood-brain barrier disruption and chemotherapy administered prior to radiotherapy can result in significant objective tumor responses with maintenance of cognitive function. It also offers a new and unique means to assess chemosensitivity, which may lead to improved treatment protocols.

This study was designed to test whether the Oregon THINK FIRST-Head and Spinal Cord Injury Prevention Program, developed for the high school audience and previously shown to have a beneficial effect, would have the same effect on students in middle school. During the spring of 1989, four schools (two high schools and two middle schools) participated. Two weeks before and after the presentation of the THINK FIRST program, 830 student questionnaires were distributed in classrooms. Questionnaire items were designed to measure knowledge, attitude, behavior, and demographic features. There was a significant difference between high school and middle school students on pretest knowledge (P = 0.0001). The average knowledge increase among all students was 0.81 correct responses (95% confidence interval: +/- 0.22) among 15 questions. The increment in knowledge did not differ significantly (P = 0.37) between high school and middle school students. One-way analysis of variance revealed no significant differences in pretest knowledge or knowledge increase associated with membership in Students Against Drunk Driving or acquaintance with someone having sustained a head or spinal cord injury. After the program, students were more likely to believe that there were actions they could take to keep from getting injured (P less than 0.0001). However, there was no change in self-reported seat belt use and most students reported that they "never" wore a bike helmet. The findings suggest that the THINK FIRST program is appropriate and beneficial for viewing by middle school-aged students.

PURPOSE: To describe the MR findings of primary CNS lymphoma. METHODS: MR scans of 20 patients with histologically proved primary CNS lymphoma were reviewed. We evaluated the size, multiplicity, signal intensities, and enhancement characteristics of the lesions. We divided the lesions into an enhancing area referred to as Zone 1 and abnormal signal surrounding this, referred to as Zone 2. RESULTS: Primary CNS lymphoma presented as solitary enhancing lesions in 40% of the patients and multiple lesions in 40%. Thirty-three separate lesions were visible: 58% abutted the ventricular system, 76% showed a homogenous enhancement pattern, and 79% showed marked enhancement. In 64% of the lesions, Zone 1 and Zone 2 showed different signal intensities on T1-weighted images. CONCLUSIONS: Primary CNS lymphoma usually presents as solitary or multiple dense homogenous enhancing lesions that abut an ependymal surface. These lesions can be divided into an enhancing area and an area of surrounding abnormal signal. These two areas often have different signal intensities on unenhanced T2-weighted images. These findings are sufficiently suggestive of the diagnosis of primary CNS lymphoma that a needle biopsy be performed based on these findings and appropriate therapy can then be instituted.

The blood-brain barrier (BBB) continues to interest neuroscientists, and is studied widely in a number of animal models and disease states. The breakdown of the BBB as a consequence of disease or injury is also studied extensively in animals and humans. However, the idea of transiently opening the BBB in a controlled fashion for the purpose of achieving increased drug permeability across the barrier is a relatively new concept. To adapt these techniques to the clinical setting has been considered desirable for improved treatment of central nervous system (CNS) disease, and recent progress has made this possible.

2013 Background: The rationale of vascular targeted agents (i.e., inhibitors of vascular endothelial growth factors [VEGF] or endothelial intergrins) in the therapy of central nervous system (CNS) malignancies is based upon the concept that normalization of tumor vasculature, with a decrease in tumor interstitial pressure, will improve access of cytoreductive drugs. However, previous studies in our laboratory have raised the serious concern that these agents rapidly normalize the blood-brain barrier (BBB) and therefore may result in restoration of the low permeability characteristics of the BBB. Methods: To evaluate this, we studied the effects of bevacizumab, an anti-VEGF agent on tumor vasculature by MRI, using gadolinium-enhanced T1 weighted sequences to assess permeability and the blood pool agent ferumoxytol to assess blood volume. Patient imaging studies were done on IRB approved protocols. Results: Utilizing two rat brain tumor models, we documented that bevacizumab rapidly decreases tumor enhancement, a pattern equivalent to administration of high dose steroid therapy. Correlative studies in rats and humans exploiting T2 weighted imaging, demonstrated resolution of tumor enhancement with occasional concomitant increase in tumor volume. In a parallel evaluation, pseudo-progression was seen in 9 of 14 glioblastoma patients treated with combined chemo-radiation. These inflammatory responses to treatment, when examined by dynamic MRI, were associated with a transient increase in tumor permeability and decreased cerebral blood volume. This increase could be blocked or reduced by decreasing vascular permeability with bevacizumab. Conclusions: These animal and human studies provide evidence that anti-vascular agents have a steroid-like effect; and in the CNS, may result in reduced delivery of cytoreductive agents to the tumor, thereby compromising standard chemo-radiotherapy. [Table: see text]

A series of cases are presented to illustrate various facets of the clinical management of pineal tumors. Emphasis is placed on markers of normal and neoplastic pineal function, and in particular melatonin. Although variable before therapy, after therapy four of five patients had little evidence of melatonin production, suggesting that pinealectomy had been complete.

The sublabial trans-sphenoidal approach for the ablation of pituitary tumors can cause denervation or pulp death of some of the anterior teeth. The problem results from the bone removal necessary for placement of the nasal retractor. When bone is removed close to the apices of the anterior teeth, root injury may occur. This complication may be avoided through preoperative evaluation of skeletal and dental morphology. This evaluation reveals the amount of bone between the tooth roots and the nasal floor and hence the ultimate access for the nasal retractor.

Current experience with 12 patients studied prospectively suggests a new approach in the diagnosis and treatment of primary central nervous system (CNS) lymphoma, integrating the techniques of needle brain biopsy, immunohistochemical staining for monoclonal antibody and chemotherapeutic drug delivery in association with blood-brain barrier modification. Computed tomography (CT)-guided needle biopsy of deep parenchymal lesions contributed to the diagnosis in six patients. Immunohistochemical staining methods detected monoclonal immunoglobulins in those patients so tested. Following diagnosis, the patients have been treated with multi-agent chemotherapy in conjunction with osmotic blood-brain barrier modification (five without antecedent cranial irradiation) with an initial complete response rate by CT scan in nine patients, a median follow-up of 19 months from diagnosis, and a 1-year survival of 75%. This experience emphasizes the value of CT-guided stereotaxic or CT-guided needle biopsy, which limits the need for therapy without a diagnosis or the need for a major craniotomy in what are commonly deep, paraventricular lesions. Immunoperoxidase cytochemical stains can detect monoclonal immunoglobulin characteristic of CNS B-cell malignant lymphomas and provide an important diagnostic aid when only modest quantities of tissue or cells are obtained. Finally, chemotherapy administered in conjunction with osmotic blood-brain barrier modification results in a clinical response rate and survival that are at least as effective as radiotherapy as a primary therapeutic modality.

The effect of reversible blood-brain barrier modification on the delivery of Adriamycin to the brain was studied in a rodent and canine model. Pharmacokinetic and physiological studies were done in these animals after a wide range of doses of Adriamycin (0.1 to 1.0 mg/kg) were administered into the carotid artery following osmotic barrier modification with mannitol. In the absence of barrier modification, no immunoreactive Adriamycin was detected in the cerebrum; whereas, following barrier modification, up to 4.5 micrograms of drug and/or metabolites per g of brain were found. Optimum tissue levels of Adriamycin and metabolites were achieved following barrier modification when the drug was administered by either bolus or slow continuous (15-min) infusion. Immunoreactive drug was identified in brain for up to 6 hr after administration. Significant functional neurotoxicity occurred at all dose levels, even at 0.1 mg/kg, a level at which Adriamycin concentration in the brain was below the level of detectability. Neuropathological examination revealed the presence of necrosis and hemorrhagic infarcts. Thus, these pharmacological and toxicity studies suggest that Adriamycin (or its metabolites) may produce significant clinical neurotoxicity when even small amounts penetrate the blood-brain barrier.

Metrizamide (Amipaque) is a new water-soluble contrast agent for use in the intrathecal space. Extensive animal and clinical studies have demonstrated its low toxicity. The advantages to the use of metrizamide include the fact that it is miscible with cerebrospinal fluid and can fill narrow spaces, is sufficiently radiopaque to outline delicate structures within the central nervous system, is completely resorbed from the subarachnoid space, and, to date, has not been implicated in the formation of adhesive arachnoiditis. Application of metrizamide to the evaluation of neurologically diseased patients has included myelography, intracranial cisternography, and ventriculography, as well as various techniques in conjunction with computerized tomography. These various uses of metrizamide are discussed together with some indications and advantages. Metrizamide has now replaced Pantopaque and gas as the most commonly used intrathecal contrast agent at the University of Texas Health Science Center at Dallas.

cis-Platinum, bleomycin, 5-fluorouracil, and cyclophosphamide were administered to rodent and canine models of osmotic blood-brain barrier modification to evaluate the relationship between tissue drug concentration in brain and the physiological and neuropathological effects of the drug. The toxicity studies were carried out in the canine, and the pharmacological studies were carried out in the rodent. Even without the osmotic procedure, intracarotid cis-platinum, in contrast to the other drugs, produced modification of the blood-brain barrier with resultant severe neurotoxicity. Osmotic blood-brain barrier modification was used to increase delivery of bleomycin and 5-fluorouracil to the ipsilateral brain region, but the increased delivery was associated with evident neurotoxicity. Cyclophosphamide administration in association with osmotic blood-brain barrier opening did not cause significant neural toxicity. These studies indicate that some chemotherapeutic agents given in association with osmotic blood-brain barrier opening can result in neurotoxicity. The corollary of the known limited neurotoxicity when these chemotherapeutic agents are used in a conventional manner appears to be due to the presence of the blood-brain barrier.

The ribonucleases (RNases) present in a number of human tissues, including heart, brain, lung, and kidney, were purified, partially characterized, and compared in their properties to the previously described RNases from human liver, spleen, pancreas, and serum. The enzymes appeared to fall into two major classes: liver-spleen type RNase and plasma-type RNase. These two types of enzymes were present in varying proportions in all tissues examined. The extent to which the tissues studied possibly contribute to serum RNase levels is discussed.

The responsiveness of lymphocytes obtained from patients with brain tumors to in vitro stimulation with mitogenic lectins was examined. The previously reported finding of decreased responsiveness was confirmed. To investigate the factors responsible for the hyporesponsiveness, mitogen (phytohemagglutinin and pokeweed mitogen) induced lymphocyte activation was evaluated using lymphocytes from 22 patients with brain tumors and 22 normal individuals. Lymphocytes from 13 patients with brain tumors, showed depressed responsiveness when cultured in autologous serum; in eight this was marked and in five moderate. Normal, rather than autologous, serum corrected lymphocyte function from only one of the markedly hyporesponsive patients, suggesting the existence of an intrinsic lymphocyte abnormality in some patients with brain tumors. However, serum from the hyporesponsive patients depressed mitogen-induced activation of lymphocytes from both tumor patients and normals. The presence of suppressive serum factors could not be related to the nature of the tumor (benign versus malignant, site, cell type or degree of anaplasia). The present studies showed that significant depression of in vitro lymphocyte responsiveness occurred with exposure to two anti-convulsant agents (phenytoin and phenobarbital) and dexamethasone. Thus, impaired lymphocyte function in patients with brain tumors may have a complex explanation with drug (corticosteroids, anticonvulsants) induced suppression playing a significant role.

Abundant proliferation of cells having the histologic and tinctorial features of microglia, were seen in the brain of 34-year old man who suffered cardiac arrest 10 days before death and whose bone marrow was nearly totally depleted of white-blood-cell precursors. It is suggested, that in adult human brains there are native microglial precursors which can take on a phagocytic function. Therefore, brain macrophages do not have to originate from circulating monocytes, as suggested by some animal studies.

Extracranial-intracranial arterial bypass procedures provide important augmentation of collateral circulation to cortical areas rendered potentially ischemic by therapeutic occlusion of major branches of the circle of Willis. Although the case studies reported to date in general reflect positively on this use of the bypass procedure, this report of a patient who failed to tolerate acute middle cerebral artery occlusion despite the presence of a patent superficial temporal-middle cerebral artery branch anastomosis points up several of the practical and theoretical limitations of this therapeutic approach. Certain modifications of the timing of the bypass procedure, the selection of donor and recipient arteries, and the mechanics of intracranial arterial occlusion may allow a wider application of extracranial-intracranial arterial bypass in this therapeutic setting.

Our current pineal region tumor series (n = 34) now spans 11 years and currently includes 15 patients with malignant pineal region tumors, only 3 of whom had pure germinomas. Complete gross microsurgical excision of well-encapsulated tumors was possible in 9 of 13 patients (69%) who underwent definitive surgical exploration. Subtotal excision only was possible in 2 of the other patients. In the remaining 2 patients who had pineal germinomas, a less aggressive subtotal excision was done because of the known radiosensitivity of this tumor. Four of the operative patients had a tumor of mixed histology with benign and malignant components, emphasizing the need for adequate tissue sampling (Table 20.2). Eleven of the 13 surgical patients received postoperative craniospinal radiation; a 6-month-old girl who had a gross total excision of a pineoblastoma was too young to be irradiated. Ten of the patients continue to do well up to 12 years postoperatively. In view of the fact that only 3 of the 15 patients had pure germinomas, these results appear to be better than those reported with shunting and radiotherapy. Only one of our surgical patients developed postoperative metastases, an embryonal cell tumor that spread to the spinal canal. In the 34 patients in this series with lesions of the pineal region, surgical exploration was associated with only one death (a patient with metastatic adenocarcinoma). As is common with the occipital transtentorial approach, a postoperative hemanopsia is common but usually transient. The wide exposure of this approach, however, may be responsible for the greater proportion of complete gross excisions of malignant pineal tumors using other approaches (24). We have also shown the importance of tumor markers and that germinomas are very sensitive to chemotherapy. Thus, microsurgery for pineal tumors provides a viable potential for complete gross tumor extirpation even with malignant lesions, and/or adequate tissue for diagnosis which is necessary in appropriate therapeutic planning for radiotherapy and/or chemotherapy. The traditional therapeutic approach of empiric radiotherapy without a tissue diagnosis for pineal lesions may no longer be acceptable.

Inadequate drug delivery to the brain, caused by an intact or partially intact blood-brain barrier (BBB), probably accounts for poor therapeutic responsiveness to cytoreductive drugs by malignant metastatic and primary brain tumors. Drug delivery can be enhanced in normal brains and brains with tumors by administering drugs into the carotid or vertebral circulation after osmotic opening of the BBB. The osmotic procedure in humans involves infusion into the carotid or vertebral arteries of a 25% mannitol solution for 30 s. The procedure is reversible, can be accomplished without long-term neurological deficits, and can be monitored in dogs and humans by means of enhanced computerized tomography. Osmotic BBB disruption, when combined with multiple drug administration, has proved effective in treating brain tumors in a small number of clinical cases.

Right brain regions of anesthetized rats were loaded with [3,5,7-3H]methotrexate ([3H]MTX) or with [14C]sucrose by infusing the tracers into the right carotid artery, after the blood-brain barrier had been opened by right carotid infusion of a hypertonic arabinose solution. During the 6 hr following the procedure, the [3H]MTX concentration in 7 right-sided brain regions, when normalized to the plasma concentration integral during tracer infusion, fell, with an average half-time of 4.8 hr as compared to less than 20 min for the initial rate of loss [14C]sucrose. Right-left brain concentration differences 3 hr after treatment were statistically significant (p less than 0.05) for [3H]MTX but not for [14C]sucrose. The results indicate that intracerebral [3H]MTX is lost more slowly than is intracerebral [14C]sucrose, possibly because [3H]MTX enters brain cells, whereas [14C]sucrose remains largely extracellular.

Human spleen RNase was purified using an immunoabsorbant produced with anti-human liver RNase serum. The purification was more rapid than the procedure used to purify the liver RNase, yet the final specific activity was similar. Problems encountered previously using immunoabsorbants to purify enzymes were to a large degree avoided by injecting only microgram amounts of human liver RNase directly into the popliteal lymph nodes of rabbits, thereby producing a low avidity antibody. The low avidity antibody permitted elution from the immunoabsorbant with only dilute citrate buffer and without significant denaturation. An examination of crude spleen homogenates did not reveal any other RNase to be present except that which bound to the antibody. The enzyme was found to be antigenically unrelated to the human plasma RNase. A comparison of the physical properties of the human spleen enzyme with those of the human liver enzyme did not reveal any significant differences.

We have developed a brain tumor model in the nude rat utilizing NCI-N417D human small cell carcinoma of the lung grown both intracerebrally and s.c. The median latency period from the time of intracerebral tumor inoculation to the onset of neurological symptoms is 13 days with an intracerebral tumor take rate of 91% (29 of 32). The median survival is 13 days, and all animals were dead by Day 26. The tumor is discrete, well circumscribed, with occasional leptomeningeal spread and with minimal evidence of surrounding cerebral edema. Intracerebrally, this tumor is usually impermeable to Evan's blue:albumin (Mr 68,500) but not fluorescein (Mr 376). Although variable, the intracerebral tumor is less permeable to methotrexate than is the same tumor grown s.c. in the same animal (P less than 0.005). The intraarterial and i.v. routes of methotrexate administration in the presence and absence of blood-brain barrier opening were evaluated. Drug delivery to the intracerebral tumor and ipsilateral brain was significantly (P less than 0.025) greater when the methotrexate was given intraarterially and was significantly (P less than 0.0025) increased after osmotic blood-brain barrier opening. After barrier opening, methotrexate concentration was enhanced 3- to 4-fold in tumor and 10- to 20-fold in brain around tumor. Thus, the nude rat provides a model to investigate the biology and therapeutic responsiveness of human small cell carcinoma of the lung grown intracerebrally where it develops a blood-tumor barrier similar to that seen in humans. This model further provides the unique opportunity to investigate the role of osmotic blood-brain barrier opening in the treatment of a tumor which is sensitive to chemotherapeutic agents and for which tumor-specific monoclonal antibodies are available.

A patient with a six-year history of seizures and a shorter history of a progressive hemiparesis, had a glioma. A partial frontal lobectomy was performed. The cerebrospinal fluid, 38 days post-operatively, prior to irradiation, had an increase in gamma globulins. Following cranial irradiation the CSF gamma globulin level returned to normal and the hemiparesis disappeared. The significance of these CSF changes is discussed.