Ventriculolumbar Perfusion Research Articles

Cerebrospinal fluid neurofilament light chain as a potential prognostic biomarker for leptomeningeal metastasis.

The present study aimed to evaluate whether the cerebrospinal fluid (CSF) neurofilament light chain (NfL) is a potential prognostic marker for patients with leptomeningeal metastasis (LM). NfL levels were measured in CSF using a single-molecule array assay. A total of 42 patients with LM who were treated with ventriculo-lumbar perfusion (VLP) chemotherapy and had available stored CSF samples from the lumbar subarachnoid space before VLP chemotherapy were included in the present study, in order to investigate the prognostic value of CSF NfL. The median CSF NfL level in patients with LM was 8.15 ng/ml; 30% of patients who had died at the time of analysis had CSF NfL levels higher than the calculated overall prognostic cut-off value (11 ng/ml). The median overall survival after initiation of VLP chemotherapy was significantly longer in patients with LM and low CSF NfL levels compared with in patients with LM and high CSF NfL levels (P<0.001). The statistical significance remained after adjusting for other known prognostic factors and in a subgroup analysis according to age. In conclusion, CSF NfL could be considered a putative prognostic marker in patients with LM treated with VLP chemotherapy.

CYFRA 21-1 levels in cerebrospinal fluid as a putative therapeutic monitoring biomarker for patients with leptomeningeal carcinomatosis: A pilot study.

To investigate the feasibility of cerebrospinal fluid (CSF) CYFRA 21-1 levels as a therapeutic monitoring biomarker in leptomeningeal carcinomatosis (LMC) patients undergoing ventriculo-lumbar perfusion (VLP) chemotherapy. The levels of CYFRA 21-1 in 42 CSF samples from 15 LMC patients were analyzed using an electrochemiluminescence immunoassay. Samples were collected at individual time points during VLP chemotherapy. Therapeutic outcomes were measured as improvements in the Karnofsky Performance Status (KPS) score and decreasing intracranial pressure (ICP) as the main endpoint of VLP chemotherapy. Changes in CSF CYFRA 21-1 levels, protein levels, and cytology results were also investigated. We subsequently evaluated whether these changes were correlated with KPS score and ICP. The CSF CYFRA 21-1 levels at individual time points were associated with KPS score and ICP. The KPS scores (p= 0.007) and ICP (p= 0.018) of patients with high CSF CYFRA 21-1 levels were significantly different from those of patients with low CSF CYFRA 21-1 levels. By contrast, CSF protein levels and cytological responses were not significantly associated with KPS scores and ICP. CSF CYFRA 21-1 may have utility as a therapeutic monitoring biomarker to design personalized therapeutic strategies in LMC patients undergoing VLP chemotherapy.

Efficacy of Slow Rate Ventriculolumbar Perfusion Chemotherapy for Leptomeningeal Carcinomatosis: Interim Result of a Phase II Study.

BackgroundTo evaluate the efficacy of modified ventriculolumbar perfusion (VLP) chemotherapy with methotrexate on leptomeningeal carcinomatosis in terms of symptomatic response and side effects.MethodsPrevious infusion rate of 20 mL/h was reduced to 15 mL/h for the purpose of decreasing constitutional side effects of VLP such as nausea/vomiting, insomnia and confusion. The primary outcome was the response rate of increased intracranial pressure (ICP), and the secondary outcome was the occurrence of side effects compared to previous 20 mL/h trial. This interim analysis to validate the reduced infusion rate is not to affect the original effect of VLP chemotherapy.ResultsAll forty-seven patients were enrolled including 22 patients with increased ICP. Thirteen patients out of these (59%) got normalized ICP after VLP chemotherapy. Moderate to severe (grade 2–3) confusion was observed in 3 patients (6%) and it was significantly reduced compared to those (23%) in the VLP 20 mL/h (p=0.017). Grade 2–3 nausea/vomiting was also reduced from 64% to 45% but failed to reach statistical significance (p=0.08). Median overall survival (OS) was 5.3 months (95% confidence interval, 3.55–7.05) and patients OS, who received maintenance VLP was significantly prolonged compared to patients who underwent induction VLP only (5.8 vs. 3.4 months, p=0.025).ConclusionVLP of reduced perfusion rate (15 mL/h) showed compatible control rate of increased ICP at this interim analysis. Decreased moderate to severe side effects and prolonged OS in patients received maintenance VLP encourage us to evaluate the effectiveness of this trial further.

Diagnostic and prognostic values of cerebrospinal fluid CYFRA 21-1 in patients with leptomeningeal carcinomatosis.

ObjectivesTo investigate the diagnostic and prognostic values of cerebrospinal fluid (CSF) CYFRA 21-1 in patients with leptomeningeal carcinomatosis (LMC).MethodsConcentration of CSF CYFRA 21-1 was detected using electro-chemiluminescent immunoassay. The difference in level of CYFRA 21-1 between 61 patients with LMC and 200 patients with other neurological disease was evaluated, and diagnostic performance of CSF CYFRA 21-1 was investigated. In LMC patients treated with ventriculo-lumbar perfusion (VLP) chemotherapy, prognostic performance of CSF CYFRA 21-1 was evaluated.ResultsThe CSF CYFRA 21-1 was significantly higher in LMC patients than that in patients with other neurological diseases (p<0.001). The sensitivity, specificity, accuracy, and positive and negative predictive values were 80.3%, 95.0%, 91.6%, 83.1%, and 94.1% for CSF CYFRA 21-1, and 65.6%, 100%, 92.0%, 100%, and 90.5% for CSF cytology, respectively. The use of high CSF CYFRA 21-1 and/or positive CSF cytology findings resulted in an increased sensitivity of 85.3%, without compromising specificity. LMC patients with high CSF CYFRA 21-1 were more frequently accompanied by positive CSF cytology results than those with low CSF CYFRA 21-1. The median overall survival was longer in LMC patients with low CSF CYFRA 21-1 than in those with high CSF CYFRA 21-1 (p=0.031). During VLP chemotherapy, the clinical responses were found to be correlated with the biological responses, including the level of CSF CYFRA 21-1 and intracranial pressure.ConclusionsCSF CYFRA 21-1 might be regarded as an additional diagnostic tool for LMC and a potential significant prognostic biomarker in LMC patients treated with VLP chemotherapy.

Surgical Treatment for Leptomeningeal Disease.

Advancements in cancer treatment have led to more cases of leptomeningeal disease, which requires a multimodal approach. Treatment modalities are reviewed from a neurosurgical standpoint, focusing on intrathecal chemotherapy and shunting devices. Potential complications and how to avoid them are discussed. The Ommaya reservoir and the chemoport are used for administering intrathecal chemotherapy. Use of ventriculo-lumbar perfusion can efficiently deliver chemotherapeutic agents and improve intracerebral pressure. Shunting systems, in conjunction with all of their variations, address the challenge of hydrocephalus in leptomeningeal carcinomatosis. Misplaced catheters, malfunction of the system, and shunt-related infections are known complications of treatment. From an oncological perspective, the surgical treatment for leptomeningeal disease is limited; however, neurosurgery can be used to aid in the administration of chemotherapy and address the issue of hydrocephalus. Minimizing surgical complications is important in this sensitive patient population.

Recent Advancements of Treatment for Leptomeningeal Carcinomatosis.

Treatment of Leptomeningeal carcinomatosis (LMC) from solid cancers has not advanced noticeably since the introduction of intra-cerebrospinal fluid (CSF) chemotherapy in the 1970's. The marginal survival benefit and difficulty of intrathecal chemotherapy injection has hindered its wide spread use. Even after the introduction of intraventricular chemotherapy with Ommaya reservoir, frequent development of CSF flow disturbance, manifested as increased intracranial pressure (ICP), made injected drug to be distributed unevenly and thus, the therapy became ineffective. Systemic chemotherapy for LMC has been limited as effective CSF concentration can hardly be achieved except high dose methotrexate (MTX) intravenous administration. However, the introduction of small molecular weight target inhibitors for primary cancer treatment has changed the old concept of 'blood-brain barrier' as the ultimate barrier to systemically administered drugs. Conventional oral administration achieves an effective concentration at the nanomolar level. Furthermore, many studies report that a combined treatment of target inhibitor and intra-CSF chemotherapy significantly prolongs patient survival. Ventriculolumbar perfusion (VLP) chemotherapy has sought to increase drug delivery to the subarachnoid CSF space even in patients with disturbed CSF flow. Recently authors performed phase 1 and 2 clinical trial of VLP chemotherapy with MTX, and 3/4th of patients with increased ICP got controlled ICP and the survival was prolonged. Further trials are required with newly available drugs for CSF chemotherapy. Additionally, new LMC biologic/pharmacodynamic markers for early diagnosis and monitoring of the treatment response are to be identified with the help of advanced molecular biology techniques.

Ventriculolumbar Perfusion Chemotherapy for the Treatment of Leptomeningeal Carcinomatosis

To define the maximum tolerated dose, toxicities, and pharmacokinetics of the ventriculolumbar perfusion (VLP) chemotherapy for leptomeningeal carcinomatosis, according to different modes of administration, perfusion rate, and daily methotrexate (MTX) dose. For bolus injection modes, a designated MTX dose was given every 12 hours, for 3 consecutive days, with artificial cerebrospinal fluid perfusion. The starting daily MTX dose was 40 mg for 40 mL/h perfusion, and 24 mg for 20 mL/h, respectively. Although in continuous infusion modes, MTX premixed in artificial cerebrospinal fluid was infused for 3 consecutive days. The dose-limiting toxicity (DLT) was defined to be equal to or more than grade 3 side effects, as per the Common Terminology Criteria for Adverse Events. The perfusion rate of 40 mL/h provoked perfusion-related symptoms, such as nausea/vomiting and insomnia, and revealed DLTs including encephalopathy in more than 1/3 of patients in both administration modes when the daily MTX dose of 40 mg was given. The schedule of 20 mL/h perfusion with the daily MTX dose of 24 mg showed milder perfusion-related side effects and provoked no DLT in both administration modes. The relationship between the peak MTX concentration and encephalopathy was not statistically significant. Of 19 patients with increased intracranial pressure, the intracranial pressure was normalized in 14 patients after VLP therapy. This study disclosed the VLP chemotherapy with a perfusion rate of 20 mL/h and the daily MTX dose of 24 mg could be adopted for future study.

Successful large-volume cerebrospinal fluid aspiration for an accidental overdose of intrathecal cytarabine

Intrathecal therapy with cytarabine is widely used in the treatment of acute lymphocytic leukemia. We report the first case of accidental intrathecal cytarabine overdose in an adult patient. Overdose of intrathecal chemotherapy has been reported to cause severe neurological damage including seizures, coma and death. Methotrexate levels can help guide intrathecal dosing of methotrexate, but no such test is commercially available for cytarabine. There are no standardized treatment recommendations for the management of this medical emergency. Intrathecal methotrexate overdose has been variously treated with cerebrospinal fluid drainage or exchange. Ventriculo-lumbar perfusion, steroids and leucovorin have also been used. It seems crucial to quickly remove as much drug as possible from the cerebrospinal fluid. Our patient was successfully treated with large-volume cerebrospinal fluid aspiration through an Ommaya reservoir. She did not suffer any significant immediate or late complications at 4 months of follow-up.

Successful Use of Intrathecal Carboxypeptidase G2 for Intrathecal Methotrexate Overdose: A Case Study and Review of the Literature

Clinical Practice Points Intrathecal (IT) methotrexate (MTX) overdose is a medical emergency. Available interventions include cerebrospinal fluid (CSF) drainage and ventriculolumbar perfusion, which are limited by timing and/or availability. Carboxypeptidase G2 hydrolyzes MTX into inactive metabolites and represents a promising agent for the treatment of IT MTX overdose. We set out to compile and review available animal data and human case reports using carboxypeptidase G2 by the IT route in the setting of IT MTX overdose. A review of the literature reveals promising results with IT carboxypeptidase G2, including a nearly 2-log reduction in CSF MTX levels and excellent neurologic outcomes in patients receiving 155 to 600 mg of IT MTX. Additionally, we have included a new report of a 66-year-old woman with primary CNS lymphoma who inadvertently received a 150-mg dose of IT MTX. Immediate treatment consisted of CSF drainage and intravenous dexamethasone and leucovorin. She subsequently received 2000 U of IT carboxypeptidase G2 11 hours after the overdose along with continued supportive care. CSF MTX levels promptly decreased and the patient was discharged with no residual neurologic deficits. IT carboxypeptidase G2 leads to rapid reduction of CSF MTX levels in patients with IT MTX overdose and is associated with excellent neurologic outcomes. Further studies are needed to clarify the role of this intervention in the context of existing drainage techniques.

Intrathecal chemotherapy for refractory disseminated medulloblastoma

To analyze the effect of intrathecal (IT) chemotherapy for disseminated medulloblastoma. Twenty-one patients received IT chemotherapy using the chemotherapeutic agents of methotrexate (MTX) and nitrosoureas (ACNU, MCNU) including nine patients for residual leptomeningeal lesions after initial surgery and radiation, and 12 for a recurrence with leptomeningeal dissemination. Of these 21 patients, 12 received a lumbar and/or ventricular bolus injection of the chemotherapeutic agents, one received the ventriculolumbar perfusion of the agents, and eight received both the perfusion and bolus injection. The doses ranged from 6-7 mg/m(2) of ACNU for perfusion and 3-3.5 mg/m(2) of ACNU, MCNU, or MTX for the bolus injection, and the cycles were administered from 3 to 12 times for perfusion and from 5 to 54 times for the bolus injection. The effects of chemotherapy were assessed by both radiological and cytological examinations, and the clinical symptoms were also assessed. Radiological and/or cytological responses were observed in 10 of 21 patients (47.6%), including seven cases demonstrating a complete remission. The 5-year overall survival rate and 5-year survival rate after dissemination were 61.5 and 46.4%, respectively. Five patients who received a lumbar bolus injection of nitrosoureas experienced paraplegia and double incontinence. One patient who received a ventricular injection of nitrosoureas experienced truncal ataxia. IT chemotherapy was found to be effective in some cases with refractory disseminated medulloblastoma and it seems to be an appropriate treatment choice for leptomeningeal recurrence. However, the frequent bolus injections of nitrosoureas should be avoided to prevent the side effects.

Ventriculo-Lumbar Perfusion in Acute Ischemic Stroke

Effective treatment for severe ischemic stroke continues to be largely an unmet medical need. Using a nonvascular (paravascular cerebrospinal fluid) pathway to provide oxygen and nutrients to ischemic tissues may be a means of treating this disease. The primary objective of this study was to evaluate the safety and technical feasibility of ventriculo-lumbar perfusion with the oxygenated fluorocarbon nutrient emulsion (OFNE) perfusion system in the treatment of patients with severe hemispheric cerebral ischemia. Four patients were enrolled in this pilot study. At admission, patients' National Institutes of Health Stroke Scale scores ranged from 16 to 24. The perfusion pathway was successfully established in all four patients. Maximum perfusion rates varied from 25 to 40 mL/minute; total volume perfused over the 24-hour period ranged from 30.6 to 45.8 L. ICP ranged from -3 to 16 mmHg during the perfusion. The 24-hour perfusion was successfully completed in all four patients with no serious adverse events during the perfusion. It is technically feasible and safe to establish a ventriculo-lumbar perfusion pathway using a specially designed lumbar drainage catheter and to control intracranial pressure while perfusing large volumes of OFNE.

Intrathecal methotrexate neurotoxicity: clinical correlates and antidotal treatment

The neurotoxicity of methotrexate (MTX) is more severe when administered intrathecally (IT) than by the oral and intravenous (IV) routes, and has been reported even with a single administration of therapeutic doses of 12 or 15 mg. Prompt recognition and treatment are essential to improve the outcome after massive IT-MTX overdose. Treatment options include CSF drainage or CSF exchange, ventriculolumbar perfusion, IT corticosteroids to reduce CSF inflammation and IV leucovorin to reduce systemic toxicity. Toxicity resulting from IT injection of leucovorin is controversial. CSF drainage and exchange are particularly effective if performed soon after the overdose. In this paper we describe a protocol of treatment for severe cases of IT-MTX overdose in excess of 100 mg. The mainstay of treatment is dilution and removal from CSF of excessive methotrexate alongside with specific antidotal therapy.

Supratentorial Cerebrospinal Fluid Production Rate in Healthy Adults: Quantification with Two-dimensional Cine Phase-Contrast MR Imaging with High Temporal and Spatial Resolution

A method for objectively determining supratentorial cerebrospinal fluid (CSF) production rate is described. The method employs cine phase-contrast magnetic resonance imaging with high temporal and spatial resolution at the level of the aqueduct of Sylvius. Automatic encircling of the aqueduct was accomplished by using a pulsatility-based segmentation approach. Results in 23 healthy adults (18 men, five women; age range, 21-39 years) yielded an average CSF production rate of 305 microL/min +/- 145 (standard deviation); this rate is in good agreement with literature-reported values obtained with invasive ventriculolumbar perfusion measurements. Average operator imprecision was 23.1% if automatic segmentation was not used. The proposed method is potentially an effective means for measuring supratentorial CSF production rate in humans.

Ventriculolumbar perfusion chemotherapy with methotrexate and cytosine arabinoside for meningeal carcinomatosis: A pilot study in 13 patients

Thirteen patients with meningeal carcinomatosis were treated by ventriculolumbar perfusion using methotrexate (MTX) and cytosine arabinoside (Ara-C). MTX (10-30 mg) and Ara-C (40 mg) were infused at 8- to 12-hour intervals on six or nine occasions via an Ommaya reservoir placed in the lateral ventricle. Nine of thirteen patients had evaluable response (69% response rate with a mean survival of 8.8 months among responders) and ventriculolumbar perfusion therapy was effective in improving cerebral, cranial nerve, and spinal root signs and symptoms, especially sensorimotor disturbance in the lower limbs. Three of the six bedridden patients became ambulatory without assistance and two of the four patients who were walking with assistance became ambulatory without assistance. Urinary incontinence also markedly improved, except in one nonresponder. Lumbar cerebrospinal fluid parameters (cytological findings and tumor markers) also improved in association with the clinical improvement. Our pilot results were encouraging, especially the improvement of sensorimotor function in the lower limbs. However, the toxicity was unacceptable when compared with that of standard intrathecal chemotherapy. Thus, this therapy needs to be investigated further to establish the most appropriate drug doses and perfusate volume to reduce toxicity as well as determine its true efficacy in the treatment of meningeal carcinomatosis.

Successful Treatment of Intrathecal Methotrexate Overdose by Using Ventriculolumbar Perfusion and Intrathecal Instillation of Carboxypeptidase G2

Prompt and appropriate management measures are critical in order to achieve a favorable outcome after a major overdose of intrathecally (IT) administered methotrexate (MTX). Published information available to guide clinicians in the immediate management of this medical emergency is scant. Herein we describe a 6-year-old boy with acute lymphoblastic leukemia who received an inadvertent overdose of 600 mg of IT administered MTX instead of the intended dose of 12 mg. Severe acute neurotoxicity developed rapidly. Lumbar puncture and drainage of 15 mL of cerebrospinal fluid 2 hours after administration resulted in removal of 32% of the administered drug. Ventriculolumbar perfusion with 240 mL of warmed isotonic saline through ventricular and lumbar catheters for 3 hours resulted in removal of a total of 90% of the drug within 8 1/2 hours after administration. IT administration of 2,000 U of carboxypeptidase G2 (CPDG2), an enzyme that inactivates MTX, resulted in a further 150-fold reduction in cerebrospinal fluid MTX concentration. The patient experienced complete recovery. To our knowledge, this is the first reported case of the use of IT instillation of CPDG2 for the treatment of an overdose of IT administered MTX in a human, and it is only the second reported favorable outcome after an IT overdose of more than 500 mg of MTX. Minor IT overdoses of MTX can be managed by immediate lumbar drainage alone. Major overdoses may also necessitate prompt ventriculolumbar perfusion, IT instillation of CPDG2, and further supportive measures for a successful outcome after this infrequent but potentially catastrophic event.

Neurotoxicity and pharmacokinetics of ventriculolumbar perfusion of methyl 6-[3-(2-chloroethyl)-3-nitrosoureido]-6-deoxy-alpha-D-gluco-pyranoside (MCNU) in dogs

Ventriculolumbar perfusion of methyl 6-[3-(2-chloroethyl)-3-nitrosoureido]-6-deoxy-alpha-D-glucopyranoside (MCNU), a water soluble nitrosourea with log P -0.71, may be efficacious in the treatment of subarachnoid dissemination of malignant glioma. We used 2 dogs to study the neurotoxicity and pharmacokinetics of MCNU. MCNU (1 mg), dissolved in 10 ml of artificial CSF, was administered via the right lateral ventricle during a period of 18 to 42 min and the CSF was drained by lumbar puncture. The perfusion was repeated once a week for 10 consecutive weeks. No neurological and systemic symptoms were noted after perfusion. Histological examination of the brain and spinal cord showed local denudation of the ependyma and local subependymal spongy degeneration and gliosis in the lateral ventricle into which MCNU was administered in one dog and local denudation of the ependyma in the other. When administration was over a period of 21 to 38 min, the MCNU concentration in the lumbar CSF peaked at 11.11 to 50.67 micrograms/ml, in 28 to 78 min. The area under the drug concentration-time curve (AUC) was 1152 micrograms x min/ml on average, significantly larger than that of ACNU. The elimination phase followed linear kinetics and the half-time was 41.1 min on average, significantly longer than that of ACNU. These findings suggest that ventriculolumbar perfusion of MCNU may be effective in the treatment of subarachnoid dissemination of malignant glioma notwithstanding some local histological changes.

Ventriculolumbar Perfusion of 3-[(4-Amino-2-methyl-5-pyrimidinyl)methyl]-1-(2-chloroethyl)-1-nitrosourea Hydrochloride

We report on the toxicity, intrathecal pharmacokinetics, and therapeutic effect of the ventriculolumbar perfusion of 3-[(4-amino-2-methyl-5-pyrimidinyl)methyl]-1-(2-chloroethyl)-1-nitros our ea hydrochloride (ACNU) against the subarachnoid dissemination of primary central nervous system tumors. Fifteen patients received ventriculolumbar perfusion of ACNU. One was treated with ventriculolumbar perfusion of ACNU alone, and the others underwent concomitant systemic chemotherapy; three of these patients received irradiation as well. ACNU was administered at an initial dose of 0.5 and was increased to 1.5 to 10.0 mg in six patients. Because of a lack of Level 2 or greater toxicity, the subsequent seven patients received 8.7 to 10.0 mg of ACNU dissolved in artificial cerebrospinal fluid (CSF) at a concentration of 0.1 mg/ml, from the start of the treatment. During ACNU administration, the lumbar CSF was drained at approximately the same rate as that of the infusion. Twelve patients received from 3 to 42 courses (average, 14 courses). The cumulative dose of ACNU ranged from 5 to 330.4 mg (average, 82.9 mg). One patient had a convulsion; two patients experienced transient headache, nausea, and vomiting; two others reported transient headache, nausea, vomiting, and fecal incontinence; and one experienced transient nausea, vomiting, and fecal incontinence. No side effects were noted in the other nine patients. When 9.0 to 9.5 mg of ACNU, dissolved in 90 to 95 ml of artificial CSF, was administered for 37 to 52 min, the maximum concentration of ACNU in the lumbar CSF was 9.86 to 12.79 micrograms/ml and the area under the drug concentration-time curve was 260.8 to 502.5 micrograms.min/ml.(ABSTRACT TRUNCATED AT 250 WORDS)

Distribution of intrathecally administered ACNU in mongrel dogs: Pharmacokinetics and quantitative autoradiographic study

The pharmacokinetics of 1-(4-amino-2-methyl-5-pyrimidinyl) methyl-3-(2-chloroethyl)-3-nitrosourea (ACNU) in the cerebrospinal fluid (CSF), were determined in dogs after ventriculolumbar perfusion (VLP, n = 6), and bolus injection into the ventricle (VB, n = 2), cisterna magna (MB, n = 5), and lumbar cistern (LB, n = 3), by high-performance liquid chromatography. The VLP method introduced effective amounts of ACNU into the lumbar cistern for cell kill in vitro. That is, the areas under the time concentration curve (AUC) of ACNU in the lumbar CSF for those receiving a 1.5 mg perfusion of ACNU were 481, 791, and 520 μg · min/ml and those receiving a 5 mg perfusion were 1,081, 2,048, and 1,215 μg · min/ml, respectively. These values were superior to 3-log cell kill condition of 9L gliosarcoma and 1.5-log cell kill of HU-126 human glioma cell line. Among the groups to which 5 mg of ACNU was administered, the VLP method attained significantly higher AUC values in the lumbar CSF than MB method. Quantitative autoradiography using an imaging plate system was performed in the VLP group (n = 2), VB group (n = 1), MB group (n = 2), and LB group (n = 2) using a 10 μCi/kg [ethylene- 14C] ACNU dose which is thought to be related to the alkylating activity of ACNU. The VLP method attained a stable and abundant distribution of ACNU in the neural axis from the ventricular cavity to the lumbar cistern, but the cerebral convexity surface was devoid of a significant level of ACNU. When the MB method was used, the pharmacokinetic data varied in the cisterna magna and lumbar region, and again no significant level of ACNU was detected in the ventricular cavity. With the LB method, although a rich distribution was detected in the spinal cord, the concentration decreased abruptly at the upper cervical level. The VB method was unsatisfactory for obtaining an effective amount of ACNU in the lumbar region. The research and testing to date indicate that the VLP method is the procedure of choice in the treatment of meningeal dissemination.

Intrathecal ACNU treatment of B16 melanoma leptomeningeal metastasis in a new athymic rat model.

To evaluate new cytotoxic drugs for intrathecal treatment we developed an experimental model of leptomeningeal metastasis by intracisternal injection of 10(4) B16-F10 melanoma cells in nude rats. One hour in vitro incubation with 20 micrograms/ml ACNU (area under the drug concentration-time curve = 1200 microgramsxmin/ml) induced a 4-log kill of B16 melanoma cells. A single or repeated non-toxic dose of 1 mg/kg was injected into the cisterna magna of rats inoculated with tumor (area under the drug concentration-time curve assuming an even cerebrospinal fluid distribution greater than 7000 microgramsxmin/ml). Median survival free of symptoms was 16 days (range 14-27) for controls (n = 9) and 18 days (range 17-23) for rats treated with ACNU on day 4 (n = 9). Animals treated both on day 2 and 8 (n = 8) developed symptoms on day 21 (range 13-35). Neurological symptoms and neuropathological examination in animals with increased survival indicated local suppression of tumor growth in the cisterna magna but increased spinal seeding and mass growth. From these results and the available pharmacokinetic data on ACNU it is concluded that bolus injection of ACNU--although locally effective--is not a sufficient treatment of widespread leptomeningeal metastasis. An increased therapeutic efficacy might be achieved by ventriculolumbar perfusion.

Evidence for a probenecid-sensitive transport system of acid monoamine metabolites from the spinal subarachnoid space

The location of probenecid-sensitive elimination mechanisms of monoamine metabolites from the cerebrospinal fluid of the cat was determined with ventriculo-cisternal or ventriculo-lumbar perfusion techniques. These techniques were described in detail. Levels of endogenous homovanillic acid and 5-hydroxyindoleacetic acid were assayed in the perfusate. Probenecid administration induced the most marked increase of the levels of the monoamine metabolites in the ventriculo-lumbar perfusates. It was concluded that probenecid blocked the transport of both metabolites from the spinal subarachnoid space.