Novel paclitaxel formulations for oral application: a phase I pharmacokinetic study in patients with solid tumours.

PURPOSE: To explore the pharmacokinetics (PKs) of paclitaxel and two major metabolites after three single oral administrations of a novel drinking solution and two capsule formulations in combination with cyclosporin A (CsA) in patients with advanced cancer. Moreover, the tolerability and safety of the formulations was studied. In addition, single nucleotide polymorphisms in the multidrug resistance (MDR1) gene were determined. PATIENTS AND METHODS: Ten patients were enrolled and randomized to receive CsA 10 mg/kg followed by oral paclitaxel 180 mg given as (1) drinking solution (formulation 1), (2) capsule formulation 2B, and (3) capsule formulation 2C on day 1, 8, or 15. RESULTS: The median C (max) of paclitaxel was 0.42 (0.23-0.96), 0.48 (0.08-0.59), and 0.39 (0.11-1.03) microg/ml and the area under the plasma concentration-time curve was 2.83 (1.69-5.12), 2.01 (1.57-3.04), and 2.67 (1.05-3.61) mug h/ml following administration of formulations 1, 2B, and 2C, respectively. The novel formulations were tolerated after single oral dose without causing relevant gastrointestinal or haematological toxicity. CONCLUSIONS: The PK and metabolism of paclitaxel were comparable between the oral formulations co-administered with CsA.

Preirradiation paclitaxel in glioblastoma multiforme: efficacy, pharmacology, and drug interactions. New Approaches to Brain Tumor Therapy Central Nervous System Consortium.

PURPOSE: The purpose of this study was to determine the response rate of paclitaxel administered at maximal tolerated doses (MTD) in patients with newly diagnosed glioblastoma multiform. PATIENTS AND METHODS: All patients in this multicenter study were 45 years or older and had measurable residual tumor on postoperative MRI scans. Up to 3 cycles of paclitaxel were administered as a continuous 96-hour intravenous infusion prior to radiation, provided that the tumor did not enlarge on serial MRIs. The initial 10 patients were treated with the previously recommended phase II dose of 140 mg/m2. Less than anticipated toxicity led to the development of a phase I/II study in 24 patients in which paclitaxel doses were escalated separately in patients receiving (+EIAED) or not receiving (-EIAED), concomitant enzyme-inducing antiepileptic drugs. Paclitaxel plasma steady-state concentrations (Css) were measured during the first cycle of chemotherapy. Response was the primary efficacy endpoint for this study, although survival was also assessed. RESULTS: The MTD was 140 mg/m2 in the -EIAED, and 200 mg/m2 in the +EIAED patient groups. The mean Css for the -EIAED patients treated at 140 mg/m2 was 38 nM, whereas the mean Css for +EIAED patients were 17 nm at 140 mg/m2, 27 nM at 175 mg/m2, 46 nM at 200 mg/m2, and 51 nM at 230 mg/m2. One patient, who had a verified partial response, had his diagnosis changed to an anaplastic oligodendroglioma on subsequent central neuropathologic review. None of the 15 assessable glioblastoma patients treated at or above the MTD doses showed a radiographic response to paclitaxel. The median survival of eligible patients on this protocol was 355 days (95% CI, 255 to 485 days), which is similar to the survival of comparable patients treated with conventional therapy. CONCLUSIONS: These results suggest that (1) paclitaxel given as a 96-hour infusion at the MTD has minimal activity in patients with untreated glioblastoma, (2) the concomitant administration of EIAEDs alters the pharmacology of paclitaxel, resulting in a lower Css, reduced systemic toxicity, and higher dose requirements, (3) this study design, in which a new agent is given prior to radiation therapy (with serial monitoring of MRI), did not adversely affect survival in this patient population.

Intravenous recombinant interferon beta in patients with recurrent malignant gliomas: a phase I/II study.

A multicenter phase I/II trial of a human recombinant interferon beta (Betaseron; Triton Biosciences, Alameda, CA) was conducted in patients with recurrent glioblastoma and anaplastic astrocytoma in six centers between 1986 and 1988. Betaseron was given intravenously three times per week, starting at 90 x 10(6) IU per dose and escalating by 90 x 10(6) IU every 2 weeks up to a maximum dose of 540 x 10(6) per treatment. All patients had failed prior radiotherapy, and most had failed one or more courses of chemotherapy. Of the 72 patients entered into the protocol, 65 were considered assessable. Of 65 patients, 41 had glioblastoma, and 24 had anaplastic astrocytoma. Of the 65 assessable patients, 15 (23%) had an objective response (R), and 18 (28%) had stable disease (S), with a combined R and S rate of 51%. The Kaplan-Meier median time to progression was 24 weeks for the responders, 10 weeks for the nonresponders, and 23 weeks for the whole group. These results suggest that Betaseron has definite activity in recurrent gliomas, with an R + S rate of 51%. The maximum-tolerated dose (MTD) is between 180 and 360 x 10(6) IU, with neurotoxicity being the most troublesome toxicity at higher doses. Two patients died of treatment-related complication. Since most responders showed responses at the 180 x 10(6 IU dose range, further studies using a lower dose of Betaseron aimed at decreasing toxicity and allowing chronic maintenance therapy are merited.

Disparity in expression of protein kinase C alpha in human glioma versus glioma-derived primary cell lines: therapeutic implications.

Intracellular signal transduction by the protein kinase C (PKC) family of enzymes plays a critical role in carcinogenesis and cellular growth regulation. Recent studies have suggested that the PKC isoform alpha may be a critical target for antiglioma therapy in humans (G. H. Baltuch et al., Can. J. Neurol. Sci., 22: 264-271, 1995). We studied the expression and subcellular distribution of the PKC alpha isoform in human high- and low-grade gliomas and also in glioma-derived cell lines with immunoblot analyses. Cell lines derived from high-grade gliomas expressed higher levels of PKC alpha than did cell lines derived from low-grade gliomas. In glioblastoma-derived cell lines, PKC alpha was mainly expressed in the soluble (cytosolic) fraction, indicating an inactive state of the enzyme. When analyzed in freshly frozen samples from human gliomas, the expression of PKC alpha was at similar levels in high- and low-grade tumors and was also similar to the levels in normal brain tissue controls. The PKC partial antagonist bryostatin 1, currently undergoing Phase II testing in patients with malignant gliomas, was capable of specifically down-regulating PKC alpha in vitro in glioblastoma-derived cell lines. However, this was not associated with significant growth inhibition. We conclude that the observed overexpression of PKC alpha in glioblastoma-derived cell lines may be an artifact of in vitro growth. Furthermore, we conclude that expression of PKC alpha in glioma-derived cell lines is not essential for cellular growth in vitro because down-regulation of PKC alpha following treatment with bryostatin 1 was not associated with growth inhibition.

Immunocytochemistry of pineal astrocytes: species differences and functional implications.

Immunohistochemical demonstration of glial fibrillary acidic protein (GFAP) was performed in human, sheep, rat and guinea pig pineal bodies to determine if there were species differences. Specialized "basket-like" arrangements of many GFAP-positive astrocytic processes were shown around sheep pinealocytes. Human pineals contained scattered astrocytic cell bodies and a moderate number of GFAP-positive astrocytic processes which, as in sheep, also surrounded pinealocytes, but without the dense basket-like arrangements. In both species GFAP-positive fibers were concentrated at the periphery of pseudolobules and around blood vessels. Rat and guinea pig pineals contained only rare astrocytic cell bodies and few GFAP-positive fibers throughout the glands, but had a concentration of parallel GFAP-positive fibers at the stalk. GFAP-positive fibers in human and sheep pineals may be derived from both intra- and extraglandular sites, whereas in rodents only rare processes appear to be derived from within the gland. Astrocytes may play a role in modulation of pineal indoleamines and norepinephrine, and the species differences observed suggest that this effect may be important in sheep and human pineals but not in rodents.

Nevus of Ota and leptomeningeal melanocytic lesions.

Two patients with congenital nevus of Ota developed intracranial malignant melanocytic tumors. One had a localized tumor that resembled a melanocytoma, but the other had a more highly malignant tumor that diffusely seeded the leptomeninges. There are 10 prior cases in the world literature. These cases are contrasted with the other disorders in which melanotic skin lesions are associated with CNS melanocytic tumors, including neurocutaneous melanosis, cellular blue nevus, and metastatic malignant melanoma. Each disorder tends to involve particular sites of the CNS. The nevus of Ota can be considered a neurocristopathy and, rarely, may give rise to malignant CNS lesions.

Multiple paragangliomas in neurofibromatosis: a new neuroendocrine neoplasia.

A pheochromocytoma, a glomus jugulare tumor, and multiple pulmonary paragangliomas were found in a patient with neurofibromatosis. We review the literature and add this case to the growing number of case reports of neurocutaneous disease in association with neuroendocrine tumors.

Non-neoplastic pineal cysts.

We identified 53 patients with non-neoplastic cysts of the pineal gland. In contrast to patients with pineal neoplasms, pineal cysts are usually asymptomatic. They infrequently obstruct the aqueduct to cause hydrocephalus or compress the tectum to produce the neuro-ophthalmologic signs of dorsal midbrain dysfunction. Obstructive hydrocephalus was present in only five patients (9.4%); three of them showed clinical signs of Parinaud's syndrome. CT and MRI typically reveal a cystic mass that averages 1.6 cm in anteroposterior (A-P) diameter with calcification at the periphery and faint rim-like contrast enhancement. Sagittal MRI is the most useful diagnostic test because it shows the anatomic relationship of the cyst to the aqueduct. The mass may compress the tectum and distort the proximal aqueduct; occasionally a large cyst may occlude the aqueduct. All patients with obstructive hydrocephalus had cysts greater than 2.0 cm in A-P diameter. Nine patients had suboccipital craniotomy. In all of them, the cysts contained clear fluid and were easily removed. We advocate conservative management with clinical observation of these benign lesions that may be developmental variants of normal pineal gland.

Blind loop syndrome, vitamin E malabsorption, and spinocerebellar degeneration.

A 72-year-old man had severe malabsorption, progressive retinopathy, and spinocerebellar degeneration 32 years after gastric surgery, blind loop formation, and intestinal bacterial overgrowth. Clinical and pathologic features were typical of vitamin E deficiency; vitamin E was nearly undetectable in serum and profoundly low in adipose tissue. Vitamin E blood levels initially improved on treatment with antibiotics; after additional vitamin E supplementation, there was clinical improvement.

Neurolymphomatosis: a clinicopathologic syndrome re-emerges.

We describe a patient with sensorimotor peripheral neuropathy and cranial neuropathy due to autopsy-proven neurolymphomatosis defined by infiltration of peripheral nerves by tumor cells and review the findings in 39 previously reported patients. The cause of the neuropathy is not known. The association with immune-deficient states suggests virally mediated pathogenesis, possibly a retrovirus.

A pituitary adenoma with dilated ventricles.

It is generally accepted that postoperatively radiographic examinations be limited to the area of pathology. The patient presented here complained of visual difficulties two years after transphenoidal removal of a pituitary prolactinoma. His endocrinologist ordered what he believed to be the appropriate computed tomography study and the neuroradiologist did not correctly interpret the new finding of dilated ventricles. Subsequently, a second primary tumor was discovered, a pineal gland sarcoma. The patient had refused radiotherapy after removal of his prolactinoma. Had he not, his second tumor would probably have been attributed to radiation. It is interesting to speculate whether radiation scatter from treatment of the prolactinoma would have prevented the pineal gland sarcoma.

Thiotepa and etoposide treatment of recurrent malignant gliomas: phase I study.

PURPOSE: To determine: (1) the maximum tolerable dose (MTD) of thiotepa (TT) that can be administered with etoposide without stem cell support; (2) whether this regimen is active against recurrent malignant gliomas. BACKGROUND: Although several chemotherapeutic agents show minor activity against recurrent brain tumors, there is no consensus about the most effective regimen. The alkylating agent TT has excellent central nervous system (CNS) penetration and is synergistic with the topoisomerase II inhibitor etoposide. DESIGN/METHODS: Fifteen patients with recurrent malignant gliomas (14 glioblastomas, 1 anaplastic astrocytoma) received intravenous etoposide 100 mg/m2 on days 1, 2, and 3, and intravenous TT (40, 50, 60, or 70 mg/m2) on day 2. All had received irradiation, and eight BCNU. Chemotherapy was repeated every 3-4 weeks, with stepwise TT dose increments of 10 mg/m2, provided toxicity was less than grade III. RESULTS: The major toxicity was dose-limiting leukopenia. The MTD of TT in cycle 1 was 60 mg/m2. All patients died of progressive disease and none died of chemotherapy-related complications. CONCLUSIONS: The MTD of TT in this regimen for recurrent malignant gliomas is 60 mg/m2. Higher doses of TT would require colony-stimulating factors or stem cell support.

Patterns of spinal cord atrophy by metrizamide CT.

Forty patients with cervical myelopathy underwent high-resolution computed tomography (CT) with intrathecal administration of metrizamide for evaluation of cervical spinal cord atrophy. Thirty of them showed evidence of either focal atrophic distortion or generalized accentuation of the anatomic surface features of the spinal cord. Patients with a Chiari malformation or syringomyelia were excluded. The characteristic features in cervical spondylosis and canal deformity include flattening of the ventral surface of the cord, central infolding, beaking of the lateral funiculi, and wasting of the dorsal surface of the cord. Patients with motor neuron disease showed a combination of anterolateral and posterolateral atrophy reflecting underlying degeneration of the anterior horn cells and/or corticospinal tracts, respectively. Those with monomelic motor neuron disease had a striking ipsilateral hemiatrophy of the spinal cord. Among those presenting with spastic paraparesis, seven with clinically definite multiple sclerosis showed diffuse atrophy or focal degeneration due to a localized plaque of demyelination. Two cases of cord neoplasm showed atrophy secondary to ascending or descending degeneration of the long tracts.

Supratentorial ependymomas in adult patients.

OBJECTIVE: Ependymomas arise from different areas in the neuraxis and have variable outcomes that depend on tumor location and patient age at the time of presentation. The predictive value of histology for these tumors is unresolved. We report a series of adult patients with supratentorial ependymomas to characterize the roles of surgery, histology, ploidy, and proliferation index in tumor control. METHODS: Fourteen of the 23 supratentorial ependymomas were in the region of the third ventricle and the remainder were located in the hemispheres. Resections were gross total in 12 patients, subtotal in 8, and biopsy in 3. A single pathologist reviewed all slides and quantitated the deoxyribonucleic acid. The mean follow-up duration was 95 months (+/-75 mo). RESULTS: All of the malignant ependymomas were hemispheric (n = 4). Mortality occurred only in patients with third ventricular tumors; two patients died as a result of surgical complications and three as a result of tumor progression. Kaplan-Meier estimates of 5- and 10-year survival rates were 100% for hemispheric and 72.5% for third ventricular tumors (62.5% including the two perioperative deaths). The median time to recurrence was 53 months, with a 10-year progression-free survival rate of 27%. Univariate analysis revealed that recurrence was associated with malignant histology, including mitoses, cellularity, and aneuploidy. For nonmalignant ependymomas, recurrence was associated with subtotal resection and metastases. S-phase fraction did not correlate with recurrence. Only malignant histology correlated with recurrence on multivariate analysis. CONCLUSION: Although the numbers are too small to draw any definite conclusions, treatment of ependymomas that arise in the supratentorial compartment in adult patients results in excellent outcomes despite frequent recurrences. Association with the third ventricle and metastases seem to have a negative impact on survival, whereas malignant histology, subtotal resection, and metastases may be predictors of recurrence.

Reversible dementia due to macroprolactinoma. Case report.

Subfrontal tumors are an infrequent cause of dementia. Most of those that do cause dementia are meningiomas, and the symptoms may recede when the tumor is resected. A patient with a huge prolactinoma who came to medical attention because of dementia is described. The tumor shrank dramatically after bromocriptine therapy and the patient's mental status returned to normal.

Enhanced in vitro growth suppression of human glioblastoma cultures treated with the combination of recombinant fibroblast and immune interferons.

In the present study we have evaluated the effect of recombinant human fibroblast, IFN-beta ser, and immune, IFN-gamma, interferon, alone and in combination, on the proliferation of fifteen early passage human glioblastoma cell cultures. Explant cultures were established from glioblastoma tumor tissue obtained at the time of surgery. After sufficient outgrowth, cultures were dispersed with trypsin/versene and maintained as independent cell lines. IFN-beta ser induced a greater than or equal to 50% reduction in the 7 day growth of 6 of the 15 cultures. The majority of cultures, 9 of 15, displayed less than or equal to 50% growth suppression in comparison with control cultures after 7 days exposure to 2000 Units/ml of IFN-beta ser. When treated with 2000 Units/ml of IFN-gamma, only 1 of the 15 glioblastoma cultures exhibited a greater than or equal to 50% reduction in growth. In contrast, when treated with the combination of IFN-beta ser plus IFN-gamma, 1000 Units/ml of each interferon preparation, 12 of 15 cultures were inhibited by greater than or equal to 50% after 7 days growth. The combination of interferons was effective in suppressing glioblastoma growth both in cultures displaying relative sensitivity and those exhibiting innate resistance to either or both types of interferon when employed alone. One glioblastoma culture, G-7, was studied through 45 passages and displayed the same sensitivity at different passages to growth inhibition when exposed to IFN-beta ser, IFN-gamma or both interferons. Based on previous clinical studies indicating that IFN-beta or IFN-gamma when administered alone to patients do not generally alter the clinical progression of malignant gliomas, the present results suggest that the combination of IFN-beta plus IFN-gamma may prove more effective than either agent alone in the clinical treatment of patients with glioblastoma multiforme.

Neuroendocrine aspects of pineal tumors.

The evaluation and treatment of pineal region tumors has changed dramatically in the past decade. New imaging techniques result in earlier diagnosis. Surgical techniques now permit removal of benign tumors (about one third of cases). Pathologic diagnosis is obtained for the remainder, and postoperative therapy can be planned rationally. Germ cell tumors pose a particularly difficult problem for the pathologist because they often contain mixed germ cell elements. Biologic markers, beta HCG and AFP, aid diagnosis and can be monitored in serum and CSF to assess response to treatment. Only boys develop precocious puberty with pineal tumors. What appears to be puberty is actually pseudoprecocious puberty, due to ectopic production of HCG by their neoplasms (choriocarcinomas or germinomas with syncytiotrophoblastic giant cells). HCG can stimulate tests to produce testosterone, but FSH is necessary (together with LH or HCG) to stimulate ovaries to produce estrogen. Diabetes insipidus with pineal tumors is usually due to spread to the hypothalamus by ventricular seeding, but we report a case of aqueductal stenosis with diabetes insipidus resulting from a massively dilated third ventricle. Rarely, hydrocephalus may trigger true precocious puberty, a syndrome easily differentiated from pseudoprecocious puberty by endocrinologic tests. There are no biologic markers to diagnose pineal parenchymal tumors. Elevation of melatonin in plasma or CSF and increased tumor biosynthetic activity has been reported in isolated cases, but the range of melatonin values in normals is very wide, and melatonin levels do not correlate with specific pathologic tumor types. Both parenchymal and nonparenchymal tumors may increase melatonin nonspecifically by interfering with regulatory mechanisms of the normal pineal gland.

Therapeutic modalities for pineal region tumors.

Since there is no radiographic test that can definitely predict the histology of a pineal tumor, we believe all patients should be treated first with a surgical approach to the tumor. This usually is accomplished by the supracerebellar-suboccipital route. Hydrocephalus is best treated at the time of surgery with ventricular drainage. Sometimes, surgery can decompress the CSF obstruction, and the need for a shunt can be averted following surgery; if not, the ventricular drain is converted to a shunt several days later. If a pineal tumor is found to be benign and encapsulated, it is removed by surgery, and the patient requires no additional therapy. Meningiomas, cysts, and low grade cystic astrocytomas all fall into this category. Some germ cell tumors are well differentiated and can also be grossly excised, but one must exercise caution in assuming that the entire tumor is benign. Many seemingly well-differentiated teratomas contain admixtures, sometimes microscopic, of more malignant elements. Careful pathological evaluation of the operative specimen and analysis of biological markers (AFP and beta-HCG) can alert the clinician to the presence of malignant tumor. With germinomas, radiation therapy is initially effective, and chemotherapy has a proven role in treating recurrences. Spinal radiotherapy is withheld unless there is a strong suspicion of spinal seeding. Tumors of pineal cell origin are radiosensitive and should be treated with radiation therapy. Because these tumors are rare, there is little data to date to justify one particular form of chemotherapy over another for recurrent pineal cell malignancies. Likewise, whether chemotherapy is preferable to radiation therapy in the initial treatment of nongerminomatous germ cell malignancies is as yet unclear.