Michael R. Fetell

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.

Prolonged partial complex status epilepticus EEG and behavioral observations

Four prolonged episodes of partial complex status epilepticus were observed in a teenaged girl. During each there was an “ictal” phase, in which her mental state frequently fluctuated between mildly clouded consciousness and almost total unresponsiveness; once, she was also blind during this phase of impaired consciousness. With therapy, the periods of unresponsiveness became less frequent and less prolonged until a second, “postictal,” phase occurred when she was alert, but with profound retrograde and anterograde amnesia that gradually resolved in several weeks. The “ictal” EEG pattern always consisted of lateral temporo-occipital fast and sharp waves continually alternating with slow activity. These cycled independently in the two hemispheres and correlated with the fluctuating behavioral state. During the “postictal” phase the EEG was diffusely slow with isolated bilaterally independent temporal spikes. The key to the diagnosis of partial complex status epilepticus may be the fluctuating mental state. Recognition and prompt treatment of this disorder are important since delay could result in prolonged or enduring memory impairment.

A randomized, double-blind, placebo-controlled, phase 2 study of RMP-7 in combination with carboplatin administered intravenously for the treatment of recurrent malignant glioma

RMP-7, a bradykinin analog, temporarily increases the permeability of the blood-brain tumor barrier to chemotherapy drugs like carboplatin. We conducted a randomized, controlled trial of carboplatin and RMP-7 versus carboplatin and placebo in patients with recurrent malignant glioma. The primary outcome measure was time to tumor progression (TTP). Adults with recurrent glioblastoma multiforme or anaplastic glioma were randomized in a 1:1 ratio to receive carboplatin and either RMP-7 or placebo. Radiation therapy had failed in all patients, and they may have received prior chemotherapy. Carboplatin (dosed to achieve an area under the curve of 5 mg/ml x time for patients who had received prior chemotherapy, or 7 mg/ml x time for those who had not) was given intravenously every 4 weeks, followed by intravenous infusion of either RMP-7 or placebo (300 ng/kg). TTP, tumor response, neuropsychological assessments, functional independence, and quality of life assessments were analyzed every 4 weeks. There were 122 patients enrolled, 62 in the RMP-7 and carboplatin group and 60 in the placebo and carboplatin group. Median TTP was 9.7 weeks (95% CI, 8.3-12.6 weeks) for the RMP-7 and carboplatin group and 8.0 weeks (95% CI, 7.4-12.6 weeks) for the placebo and carboplatin group. Median survival times were 26.9 weeks (95% CI, 21.3-37.6 weeks) for the RMP-7 group and 19.9 weeks (95% CI, 15.0-31.3 weeks) for the placebo group. No differences were noted for time to worsening of neuropsychological assessments, functional independence, or quality of life assessments. The use of RMP-7 had no effect on the pharmacokinetics or toxicity of carboplatin. At the dose and schedule used in this trial, RMP-7 did not improve the efficacy of carboplatin. Recent preclinical pharmacokinetic modeling of RMP-7 suggests that higher doses of RMP-7 may be required to increase carboplatin delivery to tumor.

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.

Multiple paragangliomas in neurofibrornatosis 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.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.

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.

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 Parinauds 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.

Randomized Study of Paclitaxel and Tamoxifen Deposition into Human Brain Tumors: Implications for the Treatment of Metastatic Brain Tumors

Purpose: Drug resistance in brain tumors is partially mediated by the blood-brain barrier of which a key component is P-glycoprotein, which is highly expressed in cerebral capillaries. Tamoxifen is a nontoxic inhibitor of P-glycoprotein. This trial assessed, in primary and metastatic brain tumors, the differential deposition of paclitaxel and whether tamoxifen could increase paclitaxel deposition. Experimental Design: Patients for surgical resection of their primary or metastatic brain tumors were prospectively randomized to prior paclitaxel alone (175 mg/m2/i.v.) or tamoxifen for 5 days followed by paclitaxel. Central and peripheral tumor, surrounding normal brain and plasma, were analyzed for paclitaxel and tamoxifen. Results: Twenty-seven patients completed the study. Based on a multivariate linear regression model, no significant differences in paclitaxel concentrations between the two study arms were found after adjusting for treatment group (tamoxifen versus control). However, in analysis for tumor type, metastatic brain tumors had higher paclitaxel concentrations in the tumor center (1.93-fold, P = 0.10) and in the tumor periphery (2.46-fold, P = 0.039) compared with primary brain tumors. Pharmacokinetic analyses showed comparable paclitaxel areas under the serum concentration between treatment arms. Conclusions: Paclitaxel deposition was not increased with this tamoxifen schedule as the low plasma concentrations were likely secondary to concurrent use of P-450-inducing medications. However, the statistically higher paclitaxel deposition in the periphery of metastatic brain tumors provides functional evidence corroborating reports of decreased P-glycoprotein expression in metastatic versus primary brain tumors. This suggests that metastatic brain tumors may respond to paclitaxel if it has proven clinical efficacy for the primary tumors histopathology.

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.

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.