High-dose intravenous methotrexate for patients with nonleukemic leptomeningeal cancer: is intrathecal chemotherapy necessary?

PURPOSE: Standard treatments for neoplastic meningitis are only modestly effective and are associated with significant morbidity. Isolated reports suggest that concurrent systemic and intrathecal (i.t.) therapy may be more effective than i.t. therapy alone. We present our experience, which includes CSF and serum pharmacokinetic data, on the use of high-dose (HD) intravenous (i.v.) methotrexate (MTX) as the sole treatment for neoplastic meningitis. PATIENTS AND METHODS: Sixteen patients with solid-tumor neoplastic meningitis received one to four courses (mean, 2.3 courses) of HD (8 g/m2 over 4 hours) i.v. MTX and leucovorin rescue. Serum and CSF MTX concentrations were measured daily. Toxicity, response, and survival were retrospectively compared with a reference group of 15 patients treated with standard i.t. MTX during the same time interval. RESULTS: Peak methotrexate concentrations ranged from 3.7 to 55 micromol/L (mean, 17.1 micromol/L) in CSF and 178 to 1,700 micromol/L (mean, 779 micromol/L) in serum. Cytotoxic CSF and serum MTX concentrations were maintained much longer than with i.t. dosing. Toxicity was minimal. Cytologic clearing was seen in 81% of patients compared with 60% of patients treated intrathecally (P = .3). Median survival in the HD i.v. MTX group was 13.8 months versus 2.3 months in the i.t. MTX group (P = .003). CONCLUSION: HD i.v. MTX is easily administered and well tolerated. This regimen achieves prolonged cytotoxic serum MTX concentrations and CSF concentrations at least comparable to those achieved with standard i.t. therapy. Cytologic clearing and survival may be superior in patients treated with HD i.v. MTX. Prospective studies and a reconsideration of the use of i.t. chemotherapy for patients with neoplastic meningitis are warranted.

Unexpected in vitro chemosensitivity of malignant gliomas to 4-hydroxyperoxycyclophosphamide (4-HC).

To individually tailor chemotherapy for patients with malignant gliomas according to tumor chemosensitivity, a rapid assay system which can be performed with a high success rate is needed. The fluorescent cytoprint assay (FCA) can assess multiple chemotherapeutic agents using small (approximately 500 cells) tumor aggregates very quickly (approximately 1 wk). Tissue samples from 51 patients with malignant gliomas obtained either at time of initial diagnosis (n = 34) or at recurrence were assayed using this method. The assay success rate approached 90% in those culture samples which were histologically verified as tumor. A meaningful number of agents could be tested both on samples obtained by stereotactic biopsy (median, 5) and on specimens from more extensive resections (median, 6). One hundred ninety-three FCAs were performed on a samples obtained from 36 patients. In only twenty six assays (14%) was an agent deemed sensitive (> 90% cell kill) to a chemotherapeutic agent. Sixty-two percent of sensitive FCAs were observed in tumors tested against the activated analog of cyclophosphamide, 4-hydroxyperoxycyclophosphamide (4-HC), where a sensitivity rate (# samples sensitive/total tested against agent) of 64% (95 % CI, 36.6-77.9%) was noted. This rate was significantly higher than with any other agent tested (p = 0.012, two sided McNemar's test) and was not affected by age, histology or disease status. We conclude that: (1) the FCA represents a feasible method for quickly assaying tumors for sensitivity to multiple chemotherapeutic agents; and (ii) malignant gliomas may be particularly sensitive to 4-HC.

A technique for accurate planning of stereotactic brain implants prior to head ring fixation.

PURPOSE: A two-step procedure is described for accurate planning of stereotactic brain implants prior to head-ring fixation. METHODS AND MATERIALS: Approximately 2 weeks prior to implant a CT scan without the head ring is performed for treatment-planning purposes. An entry point and a reference point, both marked with barium and later tattooed, facilitate planning and permit correlation of the images with a later CT scan. A plan is generated using a conventional treatment-planning system to determine the number and activity of I-125 seeds required and the position of each catheter. I-125 seed anisotropy is taken into account by means of a modification to the treatment planning program. On the day of the implant a second CT scan is performed with the head ring affixed to the skull and with the same points marked as in the previous scan. The planned catheter coordinates are then mapped into the coordinate system of the second CT scan by means of a manual translational correction and a computer-calculated rotational correction derived from the reference point coordinates in the two scans. RESULTS: The rotational correction algorithm was verified experimentally in a Rando phantom before it was used clinically. For analysis of the results with individual patients a third CT scan is performed 1 day following the implant and is used for calculating the final dosimetry. CONCLUSION: The technique that is described has two important advantages: 1) the number and activity of seeds required can be accurately determined in advance; and 2) sufficient time is allowed to derive the best possible plan.

Quantification and pharmacokinetics of blood-brain barrier disruption in humans.

Hyperosmolar blood-brain barrier disruption (HBBBD), produced by infusion of mannitol into the cerebral arteries, has been used in the treatment of brain tumors to increase drug delivery to tumor and adjacent brain. However, the efficacy of HBBBD in brain tumor therapy has been controversial. The goal of this study was to measure changes in vascular permeability after HBBBD in patients with malignant brain tumors. The permeability (K1) of tumor and normal brain blood vessels was measured using rubidium-82 and positron emission tomography before and repeatedly at 8- to 15-minute intervals after HBBBD. Eighteen studies were performed in 13 patients, eight with glioblastoma multiforme and five with anaplastic astrocytoma. The HBBBD increased K1 in all patients. Baseline K1 values were 2.1 +/- 1.4 and 34.1 +/- 22.1 microl/minute/ml (+/- standard deviation) for brain and tumor, respectively. The peak absolute increases in K1 following HBBBD were 20.8 +/- 11.7 and 19.7 +/- 10.7 microl/minute/ml for brain and tumor, corresponding to percentage increases of approximately 1000% in brain and approximately 60% in tumor. The halftimes for return of K1 to near baseline for brain and tumor were 8.1 +/- 3.8 and 4.2 +/- 1.2 minutes, respectively. Simulations of the effects of HBBBD made using a very simple model with intraarterial methotrexate, which is exemplary of drugs with low permeability, indicate that 1) total exposure of the brain and tumor to methotrexate, as measured by the methotrexate concentration-time integral (or area under the curve), would increase with decreasing infusion duration and would be enhanced by 130% to 200% and by 7% to 16%, respectively, compared to intraarterial infusion of methotrexate alone; and 2) exposure time at concentrations above 1 microM, the minimal concentration required for the effects of methotrexate, would not be enhanced in tumor and would be enhanced by only 10% in brain. Hyperosmolar blood-brain barrier disruption transiently increases delivery of water-soluble compounds to normal brain and brain tumors. Most of the enhancement of exposure results from trapping the drug within the blood-brain barrier, an effect of the very transient alteration of the blood-brain barrier by HBBBD. Delivery is most effective when a drug is administered within 5 to 10 minutes after disruption. However, the increased exposure and exposure time that occur with methotrexate, the permeability of which is among the lowest of the agents currently used clinically, are limited and the disproportionate increase in brain exposure, compared to tumor exposure, may alter the therapeutic index of many drugs.

Multidisciplinary approach to malignant gliomas.

Primary malignant brain tumors are among the most difficult human malignancies to manage. Other common tumors such as in the lung or breast generally can be cured if caught at an early stage. A 2 cm adenocarcinoma in the peripheral lung field without mediastinal or systemic metastasis can be cured. A small breast carcinoma which has not invaded into the regional lymph nodes can generally be removed with the expectation of permanent control. However, a 1 cm glioblastoma in the anterior right frontal lobe, even with gross total resection and maximum adjunctive radiation, will recur and cause death within a year or two. There is no realistic possibility of cure or even long-term survival. These patients pose unusual management problems. They require different medications such as anticonvulsants and steroids. There are neurocognitive problems and the quality of life is usually worse than for the other common malignancies. They require a multidisciplinary approach with health care providers skilled in a variety of disciplines. Malignant gliomas have two components. There is the main bulk of the tumor (the ring enhancing portion seen on the MRI) and the infiltrating portion than cannot be seen by any imaging method. Local control has improved over the past ten years, but control of the infiltrating portion is still lacking. It is likely that some form of biologic approach will be needed to seek out and kill these infiltrating cells that travel with such ease within the white matter tracts of the brain. Perhaps selective delivery of self-destruct genes to these cells will be possible. Perhaps the search and destroy potential of the immune system can be harnessed. If so, this incurable cancer may some day be brought under control. The effort involved will be extensive both in the laboratory and in the clinic.

Phase I study of weekly outpatient paclitaxel and concurrent cranial irradiation in adults with astrocytomas.

PURPOSE: Astrocytomas are extremely resistant to currently available treatments. Cranial irradiation is a mainstay of frontline therapy, but tumor recurrence is nearly universal. Paclitaxel has shown antitumor efficacy against astrocytoma cell lines, and is a potent radiosensitizer. For these reasons, we conducted a phase I study of weekly paclitaxel and concurrent cranial irradiation in patients with newly diagnosed astrocytomas. PATIENTS AND METHODS: Patients with astrocytomas were eligible for this study following initial surgery if they had a Karnofsky performance score (KPS) > or = 60%; normal hematologic, liver, and renal function; and could give informed consent. Beginning on day 1 of treatment, patients received paclitaxel by 3-hour infusion once weekly for 6 weeks, concurrent with standard cranial irradiation. Pharmacokinetic studies were performed on 10 patients. RESULTS: Sixty patients were enrolled; 56 were fully assessable. Forty-eight had glioblastomas (GBMs), 10 anaplastic astrocytomas (AAs), and two astrocytomas. Age ranged from 21 to 81 years (median, 55); KPS ranged from 60 to 100 (median, 70). The paclitaxel dose was escalated from 20 mg/m2 to 275 mg/m2. No clinically significant anemia or thrombocytopenia occurred. Only one patient (175 mg/m2) became neutropenic. Sensory neuropathy was dose-limiting. The maximum tolerated dose (MTD) was 250 mg/m2. Paclitaxel pharmacokinetic profiles in study patients were identical to those of previously reported patients with other solid tumors. CONCLUSION: The MTD of paclitaxel administered weekly for 6 weeks by 3-hour infusion is 250 mg/m2. Since patients with brain tumors often have preexisting neurologic deficits, we suggest 225 mg/m2 as the optimum dose for phase II trials in this group of patients.

Inhibition of angiotensin-converting enzyme with libenzapril in normotensive males.

The effect of intravenous (i.v.) libenzapril was studied in six healthy males by administering i.v. angiotensin I (AI) administered in stepwise increments of 20 ng/kg/5 min until the subjects' systolic blood pressure (SBP) had increased 20-30 mm Hg above baseline. The mean baseline infusion of 63 ng/kg/5 min resulted in a significant (P < 0.05) increase in the ratio of AII to AI plasma levels from 0.52 +/- 0.46 to 7.92 +/- 4.48 and a SBP increase of 120 +/- 7.1 to 147 +/- 5.6. Within 15 minutes of starting the 1-mg infusion of libenzapril over 1.5 hours, the AII/AI ratio decreased to baseline values, and the SBP had returned to baseline in 1 hour. Repeat AI challenges at 3.5 and 5 hours postdose did not increase SBP significantly. Even the 6.5-hour challenge demonstrated only a slight increase in SBP, with an AII/AI ratio of 0.26. At 24 hours, SBP was only 40% of the baseline response, demonstrating that libenzapril is a potent long-acting ACE inhibitor.

Pharmacodynamics of a continuous intravenous infusion of CGP-35126 recombinant human insulin-like growth factor-I (rhIGF-I) on glucose and insulin levels in healthy males.

Recombinant human insulin-like growth factor-I (rhIGF-I) was evaluated in 7 healthy males to determine the pharmacodynamics on glucose and insulin levels. Each subject received an initial intravenous infusion of normal saline and on the following day, rhIGF-I at a rate of 21.4 micrograms/kg/h over 7 hours. The subjects' fasting baseline glucose and insulin levels were not statistically different (p > 0.05) from their pre-dose levels. Compared to the saline (control) infusion, glucose levels were statistically lower (p < 0.05) 2 hours into the rhIGF-I infusion, and were suppressed until the subjects consumed a standard lunch (4 hours into the infusion). Insulin levels demonstrated a similar response to rhIGF-I, but decreases in insulin levels occurred after the rhIGF-I hypoglycemic effect. Therefore, suppression of insulin levels may be due to hypoglycemia rather than a direct action of rhIGF-I. This trial demonstrated the desired rhIGF-I effect of lowering subjects' glucose levels without clinically significant hypoglycemia. This finding suggests that rhIGF-I may have potential clinical utility in hyperglycemic or insulin resistant states.

Hydromyelia associated with a posterior fossa cyst.

There are rare reports of children with hydromyelia in association with arachnoid cysts at the foramen of Magendie, and these cases have uniformly been associated with hydrocephalus. We report a case of a 45-year-old woman with a posterior fossa cyst associated with hydromyelia and normal ventricles. This was successfully treated with a cystoperitoneal shunt. We believe this unusual condition is of interest in elucidating potential mechanisms of hydromyelia.

Long-term survival after central nervous system relapse in a patient with osteosarcoma.

BACKGROUND: Since the advent of multiagent adjuvant chemotherapy, survival among patients with localized osteosarcoma has improved to 60% or more. Pulmonary relapse, the most common cause of treatment failure, is associated with less than 25% long-term survival; central nervous system (CNS) metastasis, when it occurs, often presents as a catastrophic clinical event in preterminal patients. METHODS: The authors report a patient with osteosarcoma who had an isolated pulmonary relapse and a subsequent isolated CNS relapse. Complete surgical resection was accomplished on both occasions and followed in the initial instance by adjuvant chemotherapy and in the latter instance by adjuvant whole-brain irradiation. RESULTS: An isolated CNS metastasis was resected and adjuvant whole brain irradiation was administered; the patient is alive and relapse free more than 5 years later. CONCLUSIONS: Patients with osteosarcoma in whom isolated, resectable metastases develop can derive benefit from gross total resection followed by adjuvant chemotherapy or radiation therapy for microscopic residual disease.

Uricosuric effect of CGS-12970, a new thromboxane synthase inhibitor.

3-Methyl-2-(3-pyridyl)-1-indoleoctanoic acid (CGS-12970) is a reversible thromboxane synthase inhibitor that was noted to lower serum uric acid during preliminary trials in humans. Our clinical research unit studied 20 healthy male volunteers who received two doses of CGS-12970 12 hours apart (100, 200, 300, or 400 mg twice a day). Four subjects received placebo as a control. Serum uric acid concentrations decreased between 34% and 47%. Urinary excretion of uric acid increased between 28% and 134% within 12 hours of the first dose. Urinary excretion of uric acid returned to baseline within 24 hours after the last dose. In vitro study of bovine-creme xanthine oxidase inhibitor activity revealed minimal inhibition of xanthine oxidase by either CGS-12970 or its metabolite, CGS-12961. CGS-12970 appears to be a potent reversible uricosuric agent. We hypothesize that the uricosuric effect may be attributable to the acidic properties of CGS-12970 rather than to its inhibition of thromboxane synthase.

Hypoglycemic and insulin response to a continuous intravenous infusion of CGP-35126 recombinant human insulin-like growth factor-I (rhIGF-I) in healthy males.

Recombinant human insulin-like growth factor-I (rhIGF-I) produced by expression in a yeast vector was evaluated in seven normal men to determine effects on plasma glucose and insulin levels. Each subject received an initial intravenous infusion of normal saline and on the following day, rhIGF-I at a rate of 21.4 micrograms/kg/hour. Each infusion lasted for 7 hours. The subjects' fasting baseline glucose and insulin levels were not statistically different (P > .05) from their pre-dose levels. Compared with the saline (control) infusion, serum glucose levels were statistically lower (P < .05) 2 hours into the rhIGF-I infusion. These lower glucose levels were maintained until the subjects consumed a standard lunch (4 hours into the infusion). Insulin levels demonstrated a similar response to rhIGF-I, but decreases in insulin levels occurred after the rhIGF-I hypoglycemic effect. This observation suggests that suppression of insulin levels may be due to secondary hypoglycemia rather than to a direct rhIGF-I effect. This study demonstrated the desired rhIGF-I effect of lowering subjects' glucose levels without clinically significant hypoglycemia. This finding suggests that rhIGF-I may have potential clinical utility in hyperglycemic states.

The use of transdermal clonidine in the hypertensive patient with chronic renal failure.

The efficacy of transdermally administered clonidine was evaluated in twenty-four patients with mild-to-moderate hypertension (seated diastolic blood pressure 95-115 mmHg) and renal impairment. Patients were initially treated with oral clonidine; the dose was titrated until the seated diastolic pressure fell below 90 mmHg or a minimum 10% reduction in baseline was achieved. Oral clonidine produced a significant decrease in both systolic and diastolic blood pressure; mean seated diastolic blood pressure decreased 16.9 mmHg from baseline. When transdermal clonidine was substituted for twice daily dosage of oral clonidine, blood pressure decreases were fully maintained. Sixteen patients completed three months of stable-dose transdermal therapy. The results suggest that, in mild-to-moderate hypertensive patients with chronic renal impairment, blood pressure can be controlled with a once-weekly application of transdermal clonidine as effectively as with oral clonidine. Mean diastolic blood pressure was decreased approximately 17% during clonidine therapy independent of the severity of renal dysfunction or route of clonidine administration.

CT-guided stereotactic biopsy of nonenhancing brain lesions.

The majority of computer tomography stereotactic biopsy lesions enhance after administration of intravenous contrast, whereas patients with nonenhancing lesions are often followed conservatively or undergo craniotomies. There are few studies showing the effectiveness of stereotactic biopsies of nonenhancing cerebral lesions. Stereotactic biopsies were performed on 19 patients with lesions that did not enhance on CT after intravenous contrast. Pathological diagnoses were made in 90% (17/19) of patients. Four HIV-positive patients had progressive multifocal leukoencephalopathy, 11 patients had gliomas (4 astrocytomas, 6 anaplastic astrocytomas, and 1 ganglioma), 1 had multiple sclerosis, and 1 had herpes encephalitis. In 2 patients multiple biopsies revealed only gliosis. There was no morbidity or mortality. Stereotactic biopsies for nonenhancing brain lesions have a high diagnostic yield and can favorably alter the treatment course.

Boron neutron capture therapy for murine malignant gliomas.

Boron neutron capture therapy (BNCT) involves administration of a boron compound followed by neutron irradiation of the target organ. The boron atom captures a neutron, which results in the release of densely ionizing helium and lithium ions that are highly damaging and usually lethal to cells within their combined track length of approximately 12 microns. Prior to Phase I clinical trials for patients with malignant gliomas, mice with glioma 261 intracerebral tumors were fed D,L-3-(p-boronophenyl)alanine and irradiated with total tumor doses of 1000-5000 RBE-cGy of single fraction thermal neutrons to determine the maximum tolerated dose and effect on survival. These mice were compared to mice that received D,L-3-(p-boronophenyl)alanine alone, neutron irradiation alone, photon irradiation alone, or no treatment. Additional normal mice received escalating doses of neutron irradiation to determine its toxicity to normal brain. BNCT caused a dose-dependent, statistically significant prolongation in survival at 1000-5000 RBE-cGy. At 3000 RBE-cGy, median survival rates of the BNCT and untreated control groups were 68 and 22 days, respectively, with a long-term survival rate of 33%. At 4000 RBE-cGy, median survival was 72 and 21 days, respectively, with a long-term survival rate of 43%. At lower radiation doses, the extended survival was comparable between the BNCT and photon-irradiated mice; however, at 3000 and 4000 RBE-cGy the median survival of BNCT-treated mice was significantly greater than photon-irradiated mice. The maximum tolerated single fraction dose to normal brain was approximately 2000 RBE-cGy.

Treatment of murine primary brain tumors with systemic interleukin-2 and tumor-infiltrating lymphocytes.

Methods have recently been described for the isolation and expansion of lymphocytes that have trafficked into animal and human tumors. These CD8-positive tumor-infiltrating lymphocytes (TIL's) have exceptional trafficking ability to, and efficacy against, tumor targets in extracranial sites. Prior to Phase I clinical trials for patients with gliomas, adoptive immunotherapy with TIL's was studied in a mouse model of primary brain tumors to determine if intracerebral tumors have a similar response. Glioma 261 (GL261) tumors were grown in the subcutaneous space of C57BL/6 mice. After enzymatic digestion, the cells were incubated in vitro with interleukin-2 (IL-2) until a confluent population of T lymphocytes was present. The in vitro efficacy of these TIL's was tested against fresh GL261 targets with a chromium release assay; the in vivo efficacy was tested against GL261 tumors in the liver and against irradiated and nonirradiated GL261 tumors in the brain. Mice received one of the following: intraperitoneal saline; intraperitoneal IL-2 (7500 to 50,000 U three times daily for 5 days); IL-2 plus intravenous TIL's (1 to 3 x 10(7) cells); 10 Gy cranial irradiation; irradiation plus IL-2; or irradiation plus IL-2 plus TIL's. The TIL preparation killed 77% of tumor targets in 4 hours at an effector:target ratio of 100:1. In animals with GL261 tumors in the liver, at 2 weeks there were 93 +/- 37, 128 +/- 45, and 21 +/- 14 liver metastases in the control, IL-2, and IL-2 plus TIL groups, respectively. However, in animals with GL261 tumors in the brain, no treatment group had an increased survival rate compared to the control group. It is concluded that, although TIL and IL-2 immunotherapy can be used effectively to treat brain tumors in vitro and at sites outside the central nervous system, it is ineffective against the same type of tumor in the brain. Different methods of delivery or different combinations of these immunomodulators may be more effective; however, based on these findings, treatment of patients with IL-2 and TIL cannot be recommended until efficacy has been demonstrated in an animal model.

Expression and modulation of major histocompatibility antigens on murine primary brain tumor in vitro.

Lysis of tumor cells by activated cytotoxic lymphocytes requires their recognition of antigens associated with major histocompatibility complex molecules. The authors studied the constitutive expression of Class I and Class II major histocompatibility complex antigens on mouse brain-tumor cells and the capacity of different cytokines and cytokine combinations to alter this expression in vitro. Cells from the murine glioma 26 (GL26), glioma 261 (GL261), and ependymoblastoma A (EpA) cell lines were established in monolayer culture and treated for 48 hours with either alpha interferon, gamma interferon, tumor necrosis factor alpha, tumor necrosis factor alpha plus gamma interferon, or interleukin-2. They were then analyzed by flow cytometry for baseline and cytokine-altered major histocompatibility complex expression. All cell lines had a similar constitutive major histocompatibility complex pattern with low Class I antigen expression and no detectable Class II antigen expression. Alpha interferon substantially induced and up-regulated Class I antigen expression, but had no effect on Class II antigen expression. Gamma interferon also stimulated up-regulation of Class I antigen expression, generally doubling the anti-Class I antigen fluorescence of treated cells. Its effect on Class II antigen expression was more extensive. In the GL26 and GL261 cell lines the expression of Class II antigen determinants increased to 12 x and 14 x control values and as many as 75% of cells that had no detectable constitutive expression of Class II antigen expressed this antigen after priming with gamma interferon. The addition of tumor necrosis factor alpha to gamma interferon further increased Class II antigen expression on EpA tumor cells only. Interleukin-2 and tumor necrosis factor alpha alone had no effect on Class I or Class II antigen expression of any cell lines. It is concluded that Class I and Class II antigen expression in mouse glioma cell lines is induced and enhanced after treatment with certain cytokines in vitro. Use of these cell lines to create in situ primary brain tumors in C57BL/6 mice should provide an excellent animal system to study major histocompatibility complex modulation in brain tumor cells and to examine the potential impact of major histocompatibility complex up-regulation on the response of brain tumors to immunotherapy.

Intravascular streaming during carotid artery infusions. Demonstration in humans and reduction using diastole-phased pulsatile administration.

Intra-arterial carotid artery chemotherapy for malignant gliomas is limited by focal injuries to the eye and brain which may be caused by poor mixing of the drug with blood at the infusion site. This inadequate mixing can be eliminated in animal models with diastole-phased pulsatile infusion (DPPI) which creates 1-ml/sec spurts during the slow blood flow phase of diastole. Before treatment with intracarotid cisplatin, 10 patients with malignant gliomas were studied to determine whether intravascular streaming occurs after intracarotid infusion in humans, and if so, if it is reduced with DPPI. Regional cerebral blood flow (rCBF) studies were performed by intravenous injection of H2(15)O and positron emission tomography. This was followed by supra- or infraophthalmic internal carotid artery (ICA) injections of H2(15)O with either continuous infusion or DPPI. Local H2(15)O concentration in the brain was determined and the images of radiotracer distribution in the continuous infusion and DPPI studies were compared to the rCBF images. Intravascular streaming of the infusate was identified by a heterogeneous distribution of the infused H2(15)O in brain compared to rCBF. Extensive and variable intravascular streaming occurred in three patients who received infusions into the supraophthalmic segment of the ICA. Some brain areas received up to 11 times the expected radiotracer delivery, while other regions received as little as one-tenth. This streaming pattern was markedly reduced or eliminated by DPPI. In the five patients who received infraophthalmic infusions, a minimally heterogeneous distribution of the infusate was detected. The authors conclude that extensive intravascular streaming accompanies supraophthalmic ICA infusions in patients. The magnitude of streaming can be substantially reduced or eliminated with DPPI. Those who perform intra-arterial infusion should consider using DPPI to assure uniform drug delivery to brain.

Adoptive immunotherapy of intracerebral metastases in mice.

Lymphokine-activated killer (LAK) cells are a heterogeneous population of immune effector cells that nonspecifically destroy neoplastic cells but not normal cells. Although parenteral treatment with interleukin-2 (IL-2) alone or a combination of IL-2 and LAK cells reduces tumor load and prolongs survival in mice with pulmonary, peritoneal, or hepatic metastases, the effect of these treatments on brain metastases has not been studied. To determine in an animal model if intracerebral metastases would be protected by the immunologically privileged status of the brain, intracardiac and intravenous injections of 10(5) KHT sarcoma cells were performed in C3H mice to create brain and lung metastases, respectively. The mice were treated with adoptive immunotherapy to determine if efficacy seen in an extracerebral site could be reproduced in the brain, and if histological examination of these brains would reveal a significant degree of lymphocyte infiltration and cytolytic activity. Animals were treated with either parenteral IL-2 (7500 U three times daily on Days 3 to 7 after tumor injection), or IL-2 plus LAK cells (7500 U IL-2 times daily on Days 3 to 7, and 10(8) LAK cells intravenously on Days 3 and 6 after tumor injection), or IL-2 excipient (three times daily on Days 3 to 7 after tumor injection). As compared to control animals, pulmonary metastases on Day 14 after tumor injection were reduced or eliminated in animals treated with either IL-2 or IL-2 plus LAK cells (p less than 0.01). In these same animals, there was no reduction in the number of intracerebral metastases and no evidence of lymphocytic infiltration or cytolytic activity in the brain. This is the first study that reveals an organ-specific resistance to the treatment of metastases with adoptive immunotherapy, and affirms the concern that due to inadequate trafficking of endogenous or exogenous-activated lymphocytes or due to inadequate activation of in situ brain lymphoid precursors, there is no rejection of tumors in the brain. This information suggests that brain metastases in patients with systemic malignancies will not respond to intravenous treatment with LAK cells and IL-2, and that alternative forms of treatment are needed. Furthermore, this modification of a previously existing model of murine brain metastasis provides a method for concurrently evaluating the effectiveness of treatments for intra- and extracranial cancers.

The effect of intravenous interleukin-2 on brain water content.

Parenteral treatment with interleukin-2 (IL-2) is effective against certain advanced cancers outside the central nervous system. Prior to commencement of Phase II trials in patients with brain tumors, the neurological and neuroradiological features of 10 patients treated with intravenous administration of repeated doses of IL-2 were studied. Three patients had malignant gliomas, and seven patients had extracranial cancer without evidence of intracranial metastasis. All were treated with intravenous doses of 10(5) U/kg three times daily for up to 5 days. The patients with gliomas received cranial computerized axial tomography (CT) scans before IL-2 therapy was initiated and during the later stages of treatment. The patients with extracranial cancer underwent T2-weighted magnetic resonance (MR) imaging before and later during therapy. After two to 11 doses of IL-2, the patients with gliomas had marked neurological deterioration that was associated with a mild to marked increase in peritumoral edema and mass effect visible on CT scans. With cessation of treatment and appropriate supportive care, all returned to their pretreatment state. The patients with extracranial cancer were either neurologically unchanged or underwent minor transient changes in mental status (lethargy and confusion). In these patients, the MR signal intensity was quantified and compared in eight anatomic regions of interest. In six of the seven patients, there were increases in gray and white matter signal intensity consistent with increased cerebral water content. The percentage changes (means +/- standard error of the means) were 12.6% +/- 7.3% in the gray matter and 17.0% +/- 6.2% in the white matter. This study demonstrates that treatment with a high parenteral dose of IL-2 is not tolerated by patients with gliomas due to increased cerebral edema. In patients with extracranial cancer but no brain disease, parenteral IL-2 induces an increase in the cerebral water content of both gray and white matter.