Nicholas A. Vick

A phase II study of temozolomide vs. procarbazine in patients with glioblastoma multiforme at first relapse.

A randomized, multicentre, open-label, phase II study compared temozolomide (TMZ), an oral second-generation alkylating agent, and procarbazine (PCB) in 225 patients with glioblastoma multiforme at first relapse. Primary objectives were to determine progression-free survival (PFS) at 6 months and safety for TMZ and PCB in adult patients who failed conventional treatment. Secondary objectives were to assess overall survival and health-related quality of life (HRQL). TMZ was given orally at 200 mg/m2/day or 150 mg/m2/day (prior chemotherapy) for 5 days, repeated every 28 days. PCB was given orally at 150 mg/m2/day or 125 mg/m2/day (prior chemotherapy) for 28 days, repeated every 56 days. HRQL was assessed using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30 [+3]) and the Brain Cancer Module 20 (BCM20). The 6-month PFS rate for patients who received TMZ was 21%, which met the protocol objective. The 6-month PFS rate for those who received PCB was 8% (P = 0.008, for the comparison). Overall PFS significantly improved with TMZ, with a median PFS of 12.4 weeks in the TMZ group and 8.32 weeks in the PCB group (P = 0.0063). The 6-month overall survival rate for TMZ patients was 60% vs. 44% for PCB patients (P = 0.019). Freedom from disease progression was associated with maintenance of HRQL, regardless of treatment received. TMZ had an acceptable safety profile; most adverse events were mild or moderate in severity.

Sensory neuropathy from pyridoxine abuse. A new megavitamin syndrome

We describe seven adults who had ataxia and severe sensory-nervous-system dysfunction after daily high-level pyridoxine (vitamin B6) consumption. Four were severely disabled; all improved after withdrawal. Weakness was not a feature of this condition, and the central nervous system was clinically spared. Although consumption of large doses of pyridoxine has gained wide public acceptance, this report indicates that it can cause sensory neuropathy or neuronopathy syndromes and that safe guidelines should be established for the use of this widely abused vitamin.

Effect of the Extent of Surgical Resection on Survival and Quality of Life in Patients with Supratentorial Glioblastomas and Anaplastic Astrocytomas

Thirty-one patients operated upon for supratentorial glioblastomas or anaplastic astrocytomas were studied to evaluate the effect of the extent of surgical resection on the length and quality of survival. The median age was 50 years and the median preoperative Karnofsky rate was 80. Twenty-one patients (68%) had glioblastoma multiforme, and 10 patients (32%) had anaplastic astrocytoma. Early postoperative enhanced computed tomography was used to determine the extent of tumor resection. Gross total tumor resection was accomplished in 19 patients (61%), and subtotal resection was performed in 12 patients (39%). The two groups were comparable regarding age, sex, pathological condition, preoperative Karnofsky rating, tumor location, postoperative radiation therapy, and postoperative chemotherapy (P greater than 0.05). The gross total resection group lived longer than the subtotal resection group by life table analysis (P less than 0.001; median survival of 90 and 43 weeks, respectively). Postoperatively, the mean functional ability measured by the Karnofsky rating was significantly increased in the gross total resection group (P = 0.006), but not in the subtotal resection group (P greater than 0.05). The difference in degree of change between preoperative and postoperative Karnofsky rating in the two groups was statistically significant (P = 0.002). The gross total resection group spent significantly more time after the operation in an independent status (Karnofsky rating greater than or equal to 80) compared to the subtotal resection group (P = 0.007; median time of 185 and 12.5 weeks, respectively). Gross total resection of supratentorial glioblastomas and anaplastic astrocytomas is feasible and is directly associated with longer and better survival when compared to subtotal resection.

Iodine-131-labeled antitenascin monoclonal antibody 81C6 treatment of patients with recurrent malignant gliomas : Phase I trial results

PURPOSE To determine the maximum-tolerated dose (MTD) of iodine 131 (131I)-labeled 81C6 monoclonal antibody (mAb) in brain tumor patients with surgically created resection cavities (SCRCs) and to identify any objective responses to this treatment. METHODS In this phase I trial, eligible patients were treated with a single injection of 131I-labeled 81C6. Cohorts of three to six patients were treated with escalating dosages of 131I (starting dose of 20 mCi with a 20-mCi escalation in subsequent cohorts) administered through an Ommaya reservoir in the SCRC. Patients were followed up for toxicity and response until death or for a minimum of 1 year after treatment. The SCRC patients, who were previously irradiated, were followed up without additional treatment unless progressive disease was identified. RESULTS We administered 36 treatments of 131I doses up to 120 mCi to 34 previously irradiated patients with recurrent or metastatic brain tumors. Dose-limiting toxicity was reached at 120 mCi and was limited to neurologic or hematologic toxicity. None of the patients treated with less than 120 mCi developed significant neurologic toxicity; one patient developed major hematologic toxicity (MHT). The estimated median survival for patients with glioblastoma multiforme (GBM) and for all patients was 56 and 60 weeks, respectively. CONCLUSION The MTD for administration of 131I-labeled 81C6 into the SCRCs of previously irradiated patients with recurrent primary or metastatic brain tumors was 100 mCi. The dose-limiting toxicity was neurologic toxicity. We are encouraged by the minimal toxicity and survival in this phase I trial. Radiolabeled mAbs may improve the current therapy for brain tumor patients.

Supratentorial Gliomas: Surgical Considerations and Immediate Postoperative Results Gross Total Resection versus Partial Resection

Forty-two patients with supratentorial gliomas not involving the basal ganglia (extraganglionic) were studied pre- and postoperatively with computed tomographic (CT) scans to evaluate the effect of the extent of surgical resection on the immediate postoperative results. Thirty-three patients (79%) had malignant astrocytic gliomas (glioblastoma or anaplastic astrocytoma), 4 patients (10%) had well-differentiated astrocytomas, and 5 (12%) had oligodendrogliomas. The median age was 58 years, and the median Karnofsky rating was 70. There was no operative mortality. Six patients (14%) had surgical complications. A gross total resection was defined as the absence of any abnormal enhancement on the postoperative CT scan. A nearly gross total resection had been accomplished when less than 10% of the preoperatively enhancing mass was still seen. A partial resection was indicated by the presence of more than 10% of the enhancing lesion on the postoperative CT scan. A gross total or nearly gross total resection was accomplished in 36 patients (86%), and an improved or stable postoperative neurological status was present in 35 of these patients (97%). In contrast, the rate of neurological morbidity after a partial resection was 40%. Supratentorial extraganglionic gliomas, regardless of their histological type, generally were well-circumscribed lesions except at the level of the ventricular wall, where glioblastomas and anaplastic astrocytomas blended with the subependymal white matter from which they seemed to arise.

Permeability of Different Experimental Brain Tumor Models to Horseradish Peroxidase

The permeability of different brain tumor models to horseradish peroxidase (HRP) was examined by determining the fraction of tumor that contained HRP after intravenous administration. The intracerebral tumor models studied were Avian Sarcoma Virus (ASV)-induced tumors and tumors from transplanted RG-2, S69-C1-5, and 9L cell lines. The average fraction of RG-2 tumors permeable to HRP was .95; of S69-C1-5 tumors, .699; of ASV-induced tumors, .63; and of 9L tumors, .52. Except for the RG-2 tumors, there was considerable regional variation in HRP permeability, which was most marked in the ASV-induced tumors. In ASV-induced tumors, HRP permeability did not correlate with tumor histo ogical classification, size, or anatomic location within the brain. The subcutaneous tumor models studied were RG-2-, S69-C1-5, and 9L-transplanted tumors in rats, and human glioblastoma cell lines transplanted into nude mice. All were completely permeable to HRP. These results indicate that significant differences in permeability to HRP exist among brain tumor models when the tumors are intracerebral, and that all subcutaneous tumors from transplanted glial cell lines are completely permeable to HRP. These variables must be considered in future studies of permeability in experimental brain tumors. Care must be exercised in extrapolating results about permeability from one brain tumor model to another

Influence of the type of surgery on the histologic diagnosis in patients with anaplastic gliomas

Stereotactic biopsy of CNS tumors provides a small amount of tissue for pathologic diagnosis. This potentially leads to inaccurate grading of gliomas because of their histologic heterogeneity. We compared histologic diagnoses in a consecutive series of 329 patients with newly diagnosed anaplastic gliomas whose diagnoses were established by either stereotactic biopsy or open resection. Of 262 patients undergoing resection, 214 (82%) had glioblastomas and 48 (18%) had anaplastic astrocytomas (AAs). Of 67 patients undergoing stereotactic biopsy, 33 (49%) had glioblastomas and 34 (51%) had AAs. This difference suggests that some AAs diagnosed by stereotactic biopsy are actually glioblastomas and has important implications for the design and interpretation of clinical trials.

Pleomorphic xanthoastrocytoma. Ultrastructural and immunohistochemical study of a case with a rapidly fatal outcome following surgery.

In 1979, researchers described a series of young patients with clinically and histologically distinctive supratentorial gliomas which were designated pleomorphic (meningocerebral) xanthoastrocytomas (PXA). Significantly, patients with these neoplasms were reported to have a relatively favorable prognosis. The authors present a new case of PXA in a 32‐year‐old man. This case is unique for two reasons: (1) a relatively rapid fatal outcome with death 21 months after diagnosis; and (2) the presence, at autopsy, of extensive recurrent tumor with features of a malignant astrocytoma. Detailed electron microscopic and immunohistochemical studies, supporting the proposed subpial astrocytic origin of PXA, are presented. Literature pertaining to PXA is reviewed. This report illustrates the unique features of PXA and demonstrates its potential for aggressive behavior. Cancer 52:2055‐2063, 1983.

Microvascular abnormalities in virally-induced canine brain tumors: Structural bases for altered blood-brain barrier function☆

Abstract The microvasculature of 17 autochthonous gliomas and intracranial sarcomas induced in 8 beagles by intracerebral inoculation of the Schmidt-Ruppin strain of the Rous Sarcoma Virus was studied by transmission electron microscopy. While many vessels, especially in the well-differentiated spongioblastomas and fibrillary astrocytomas, were similar to those of normal dog brain parenchyma, two types of distinctive endothelial alterations were found in the anaplastic gliomas and in the sarcomas. These were: 1. (a) Round 400-700A structures, always covered by a single leaflet of the adjacent endothelial cell unit membrane, which were virtually identical to the fenestrations which occur normally in choroid plexus, ciliary body of the eye, endocrine glands and intestinal villi; 2. (b) Small but complete gaps in the endothelial walls, similar in type to those which normally occur in the discontinuous capillaries of the liver, spleen and bone marrow. Fenestrated and discontinuous endothelium has not been observed by others in normal mammalian brain parenchyma save in certain regions lying outside the blood-brain barrier (e.g. area postrema); we have seen only typical continuous endothelium in control dog thalamus, frontal cortex and cerebellum. Unlike brain parenchymal endothelium, fenestrated and discontinuous capillaries have been shown to be permeable to a wide variety of substances. We believe that the heterotypical (metaplastic) endothelium observed in these virally-induced brain tumors provides a morphological basis for altered brain-barrier function, as demonstrated in some of these tumors with intravitally-administered cationic dyes. It is not yet clear whether the presence of heterotypical endothelium in these autochthonous brain tumors is intrinsic to the neoplastic transformation or if the vessel alterations are an epiphenomenon of the metabolic peculiarities of the surrounding neoplastic cells.

The role of the subependymal plate in glial tumorigenesis.

SummaryWe have studied the sequential morphological events of glial tumorigenesis in neonatal dogs, using high titer subgroup C Bratislava-77 Avian Sarcoma Virus, given as 0.01 ml by intraventricular inoculation. The cells of the subependymal plate are those which seem to form the gliomas; cytoplasmic alterations are evident within 24 h after inoculation and microfoci of gliomas, contigous with the subependymal plate of the lateral ventricles, are visible within 7 days. Independent tumors are present by the 10th post-inoculation day. These studies support the hypothesis of Globus and Kuhlenbeck, which implicates the cells of the subependymal plate in glial tumorigenesis.