Growth rate of non-operated meningiomas.

INTRODUCTION: Meningiomas are dural-based brain tumors that are typically histologically benign. Some meningiomas grow slowly or seemingly not at all with planimetric measurement. Volumetric measurement may be more accurate because tumors may grow in different directions than the planimetric axes. METHODS: Twenty-one patients (with 22 tumors) had serial MRI brain scans available for review. We reviewed the charts and measured tumor dimensions on the MRI scans. Relative growth rates were calculated for volume and maximum initial diameter using published formulas. Patient demographics, tumor location, and special radiologic characteristics (calcification, T2 hypointensity, dural tail, mass effect, and midline shift) were compared to the volumetric growth rate. RESULTS: Patients included 17 females and 4 males; age at diagnosis 36 to 74 years (mean 61). Follow-up was 2.08 to 10.83 years (mean 3.64). Most tumors were located in the convexity (27.27 %), sphenoid wing (27.27 %), or cerebellopontine angle (13.04 %). Two meningiomas (9.09 %) demonstrated no growth. The mean relative volumetric growth rate was 5.82 %/year, and planimetric was 2.00 %/year (difference 3.82 %/year, p-value < 0.0001). Convexity location had near significant association with slower relative volumetric growth. There were no significant associations between other tumor locations, age, gender, or radiologic characteristics and volumetric growth. CONCLUSIONS: The mean volumetric growth rate was significantly greater than the planimetric growth rate, suggesting that volumetric measurement conveys more information and is superior in assessing tumor growth. This information could have clinical value in determining the frequency of follow-up imaging and the urgency of surgical intervention.

Spatial distribution of proliferating cells in avian sarcoma virus-induced gliomas.

We studied the regional distribution of proliferating tumor cells in five avian sarcoma virus-induced gliomas. The labeling index and spatial distribution of [3H]thymidine (dThd)-labeled tumor cells were determined in serial sections of each tumor with a computer-assisted digitizing system. The density of [3H]dThd-labeled cells showed marked regional variation in each tumor, and the ratio of the density of [3H]dThd-labeled cells in tumor periphery to tumor center varied from 0.86 to 1.38. The labeling index generally, but not always, reflected [3H]dThd-labeled cell density. This study indicates that proliferating pools of glioma tumor cells exhibit regional variability in concentration and that the highest numbers of proliferating cells may be predominantly located in central regions of tumor and not in tumor periphery as assumed previously. In all tumors, large numbers of proliferating cells were present in all parts of the tumor.

Regional measurements of blood flow in experimental RG-2 rat gliomas.

Regional measurements of blood flow (F) were performed in transplanted intracerebral RG-2 rat gliomas using [14C]iodoantipyrine, Kety-Schmidt blood flow equations, and quantitative autoradiography. Twenty-nine intracranial tumors in ten rats were analyzed by location; 18 intraparenchymal, seven meningeal, two third-ventricular, and two fourth-ventricular tumors were studied. For all tumors, averaged mean F was 91 +/- 33 (S.D.) ml/hg/min. In all but one tumor, mean F was intermediate between normal cortex and corpus callosum values. There was moderate regional variation: averaged mean F was lower in tumor center (78 +/- 47 ml/hg/min) than in tumor periphery (93 +/- 30 ml/hg/min). Within individual tumors, F showed moderate variation which correlated to some extent with histological features; a regional F of less than 10 ml/hg/min was observed in only one tumor within an area of necrosis. F in regions of brain immediately surrounding the tumor was higher than in tumor periphery. Blood flow to RG-2 tumors seems unlikely to limit drug delivery any more than to normal brain, and the consistent levels from tumor to tumor and within individual tumors make the RG-2 model an excellent one with which to study drug delivery in experimental brain tumors.

Regional measurements of blood-to-tissue transport in experimental RG-2 rat gliomas.

Regional measurements of blood-to-tissue transport were performed in transplanted RG-2 rat gliomas using [alpha- 14C]aminoisobutyric acid (AIB), quantitative autoradiography, and equations to express a unidirectional transfer constant. Thirty-eight intracranial tumors in ten rats were analyzed according to location; 23 intraparenchymal tumors, eight meningeal tumors, six fourth-ventricular tumors, and one third-ventricular tumor were studied. Except for the small third-ventricular tumor, the transfer constant (K) for AIB was similar in all groups and ranged from 0.031 to 0.038 ml/g/min. Within individual tumors, regional variation of K was also small, although some local variation could be correlated with histological features. The K for AIB decreased in brain around tumor and, at a distance of 300 microns from tumor edge, had returned to values similar to those of normal cortex (0.002 ml/g/min). An average extraction fraction (E) of 0.09 was calculated for AIB in the RG-2 tumors. The low E suggests that delivery of water-soluble chemotherapeutic drugs to RG-2 tumors should be limited more by capillary permeability or surface area than by blood flow. RG-2 is an ideal experimental tumor with which to test drug delivery and the methods that attempt to increase drug delivery in brain tumors.

Randomized comparison of diaziquone and carmustine in the treatment of adults with anaplastic glioma.

PURPOSE: We conducted a phase III trial comparing intravenous (IV) diaziquone (AZQ) and carmustine (BCNU) as single agents in patients with cerebral anaplastic gliomas who had received surgery and radiotherapy. Its purpose was to compare the efficacy of AZQ with that of BCNU, the standard agent for brain tumor chemotherapy. PATIENTS AND METHODS: Randomization between the two regimens occurred 8 weeks after completion of radiotherapy. A total of 251 patients were randomized to receive either AZQ or BCNU, and there were no significant differences between the two treatment arms in any of the known prognostic variables, including age, histologic grade, and Karnofsky performance status (KPS). RESULTS: There was no significant difference in either time to tumor progression or survival between the two treatment arms. Age and histology were strong predictors of outcome, whereas KPS had relatively less effect. Three groups of patients with distinctly different outcomes could be identified: (1) older age (45+) and glioblastoma/gliosarcoma (GBM/GS) patients had a median survival of 37 weeks after randomization; (2) patients with either older age or GBM/GS had a median survival of 61 weeks; and (3) younger age (< 45) and non-GBM/GS (usually anaplastic astrocytoma) patients had a median survival of 147 weeks. Toxicity was primarily hematologic, although acute gastrointestinal toxicity and chronic pulmonary toxicity were more common with BCNU. Patients randomized to AZQ who had significant hematologic toxicity that required dose reduction after the first treatment cycle had significantly longer time to tumor progression and survival than those who did not require dose reduction (P = .011 and .016, respectively). CONCLUSION: There was no significant difference in efficacy between AZQ and BCNU in patients with anaplastic gliomas as tested in this study, although AZQ was somewhat better tolerated.

Phase II diaziquone-based chemotherapy trials in patients with anaplastic supratentorial astrocytic neoplasms.

We treated 103 patients with histologically confirmed anaplastic supratentorial astrocytic neoplasms with either diaziquone (AZQ) and carmustine (BCNU) or AZQ and procarbazine. There were 74 patients with glioblastoma multiforme (GBM) and 29 patients with anaplastic astrocytoma (AA). AZQ plus BCNU produced partial (PR) or unequivocal responses in seven of 32 (21.9%) patients with GBMs and three of ten (30%) patients with AAs. Two patients with GBMs (6.3%) and five patients with AAs (50%) showed stable disease (SD). AZQ plus procarbazine produced PRs or unequivocal responses in five of 42 (11.9%) patients with GBMs and nine of 19 (47.4%) patients with AAs. Eight patients with GBMs (19%) and one patient with an AA (5.2%) showed SD. In addition to histologic diagnosis, only the Karnofsky performance-status (KPS) rating independently influenced response and survival. Differences in response rates between the two regimens were not significant, although estimated median survival after adjusting for performance status was slightly better with AZQ plus BCNU than with AZQ plus procarbazine (P = .031). Neither age nor prior chemotherapy were significant independent risk factors. Toxicity was mild and primarily hematologic. We conclude that these AZQ-based regimens have activity in patients with recurrent anaplastic gliomas, but that they are not clearly superior to other agents in current use. The histologic diagnosis of GBM is associated with a significantly worse prognosis than AA, and we believe that this important distinction must be recognized in phase II as well as phase III trials.

Phase II treatment of medulloblastoma and pineoblastoma with melphalan: clinical therapy based on experimental models of human medulloblastoma.

We conducted a phase II study of intravenous (IV) melphalan in the treatment of children with recurrent medulloblastoma and in the initial treatment of children with poor-prognosis medulloblastoma and pineoblastoma. There was one complete response (CR) and two partial responses (PRs) among the 12 children with recurrent medulloblastoma. There were three PRs in the four patients initially treated with melphalan for poor-prognosis medulloblastoma or pineoblastoma. Toxicity was limited to severe myelosuppression with marked neutropenia and thrombocytopenia. These results support our laboratory studies demonstrating melphalan activity in human medulloblastoma, suggest that similar activity may be demonstrated against pineoblastoma, and support further trials with this agent (administered prior to radiotherapy) in the treatment of patients with newly diagnosed poor-prognosis medulloblastoma.

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.

Intrathecal 131I-labeled antitenascin monoclonal antibody 81C6 treatment of patients with leptomeningeal neoplasms or primary brain tumor resection cavities with subarachnoid communication: phase I trial results.

We aimed to determine the maximum tolerated dose (MTD) of 131I-labeled 81C6 in patients with leptomeningeal neoplasms or brain tumor resection cavities with subarachnoid communication and to identify any objective responses. 81C6 is a murine IgG monoclonal antibody that reacts with tenascin in gliomas/carcinomas but does not react with normal adult brain. 131I-labeled 81C6 delivers intrathecal (IT) radiation to these neoplasms. This study was a Phase I trial in which patients were treated with a single IT dose of 131I-labeled 81C6. Cohorts of three to six patients were treated with escalating doses of 131I (starting dose, 40 mCi; 20 mCi escalations) on 10 mg 81C6. MTD is defined as the highest dose resulting in serious toxicity in no more than two of six patients. Serious toxicity is defined as grade III/IV nonhematological toxicity or major hematological toxicity. We treated 31 patients (8 pediatric and 23 adult). Eighteen had glioblastoma multiforme. Patients were treated with 131I doses from 40 to 100 mCi. Hematological toxicity was dose limiting and correlated with the administered 131I dose. No grade III/IV nonhematological toxicities were encountered. A partial response occurred in 1 patient and disease stabilization occurred in 13 (42%) of 31 patients. Twelve patients are alive (median follow-up, > 320 days); five are progression free >409 days median posttreatment. The MTD of a single IT administration of 131I-labeled 81C6 in adults is 80 mCi 131I-labeled 81C6. The MTD in pediatric patients was not reached at 131I doses up to 40 mCi normalized for body surface area.

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 histological 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.

Bilateral superior laryngeal neuralgia: its successful treatment with carbamazepine.

A patient had bilateral superior laryngeal neuralgia. After an extensive search for thyroid and laryngeal disease, his condition was successfully treated with carbamazepine.

Dominantly inherited pseudohypertrophic muscular dystrophy with internalized capillaries.

We describe two families with a father and son with the phenotypic appearance of benign (Becker's) muscular dystrophy. Other family members were normal, though in one kindred the paternal grandfather probably had the same disorder of muscle. Muscle histology resembled that seen in Becker's muscular dystrophy with, in addition, central cores and internalized capillaries in type I fibers. These capillaries seemed to be due to an unexplained ingrowth from vessels normally located outside muscle fibers and could not be ascribed to the phenomenon of fiber splitting. The internalized capillaries were histologically normal. They may be a histologic marker for dominantly inherited pseudohypertrophic muscular dystrophy, since they have not been described in other dystrophies. We suggest that fathers and paternal relatives be evaluated, in addition to the customary screening of female family members, in all instances of apparently benign (Becker's) pseudohypertrophic muscular dystrophy.

Acute transverse myelitis due to Mycoplasma pneumoniae infection.

We examined a woman who had acute transverse myelopathy (ATM) associated with respiratory illness due to Mycoplasma pneumoniae. To our knowledge, only one previously described case documented this relationship with serologic studies of spinal fluid. Since 16% to 35% of ATM patients experience antecedent respiratory illness, evidence of M pneumoniae infection should be sought in all cases.

Basilar artery migraine 12 patients, with an attack recorded electroencephalographically.

Basilar artery migraine is distinctive disorder characterized by symptoms referable to dysfunction of brainstem structures in conjunction with more typical migrainous phenomena. Our experience with 12 cases, seen in a period of 10 years, is reviewed. In one instance, an attack of basilar artery migraine was captured by EEG, and appeared as a typical photoconvulsive response. More than half of our patients responded well to anticonvulsant drugs.

Meningiomas: the decision not to operate.

In a consecutive series of 100 patients diagnosed with meningiomas, we advised 12 patients not to have surgery, and followed them from 3.3 to 12.8 years (mean, 8.8 years). The two determinants of this decision were either absence of related neurologic symptoms or signs and concern about high operative risk of neurologic impairment. Serial imaging studies showed meningioma growth in only one of the 12 unoperated patients and only one had convincing progression of neurologic impairment.

'Glioblastoma'. Induction of a reproducible autochonous tumor in rats with murine sarcoma virus.

Inoculation of 0.02 ml of high-titer Kirsten strain Murine Sarcoma Virus into the brains of 10-day-old Wistar/Furth rats yields, with 100 percent incidence, a uniform glioblastoma-like tumor within 16 days. Light and electronmicroscopy confirmed the neuroectodermal origin of the parenchymal cells. The remarkable vascular component was studied with extracellular tracers. The permeability of the abnormal endothelium to constituents of the blood vascular compartment was confirmed. Accessory vascular channels, and blood channels devoid of endothelium entirely, were observed. This reporducible system should provide a useful model for further studies of the biology of brain tumors.

Reoperation for malignant astrocytoma.

We evaluated 15 consecutive patients with malignant astrocytomas who were reoperated for functional status and survival. Their Karnovsky Performance Status (KPS) was not changed by surgery. None suffered perioperative death, wound infection, or complications. Patients with glioblastoma maintained KPS unchanged for a mean of 13 weeks (median, 10 weeks); with anaplastic astrocytoma, mean, 37.2 weeks (median, 24 weeks). Life spans were approximately twice that of non-reoperated historical controls. Reoperation for patients with recurrent malignant astrocytoma should be seriously considered when a gross total re-resection can be the goal in a patient whose tumor is in an accessible brain region.

Experimental gliomas: an autoradiographic study of the endothelial component.

Autochthonous gliomas were induced in rats by intracerebral inoculation of avian of avian sarcoma virus and studied by 3H-thymidine autoradiography. Parenchymal glial tumor cells had a 3H-labeling index (LI) of 3.0 to 13.6%. Endothelial cells in tumor blood vessels had an LI of 2.6 to 34.3%, independent of and in most instances higher than the LI of the glial tumor. Endothelial cells of normal blood vessels had an average LI of 0.3%. This study documents the high proliferative rate of the endothelial cells in anaplastic experimental gliomas, and emphasizes the necessity for seeking direct, incontrovertible evidence to determine whether or not the rapidly proliferating endothelial cells are malignant.

Neoadjuvant procarbazine, CCNU, and vincristine for anaplastic and aggressive oligodendroglioma.

The authors reviewed the results of neoadjuvant (preradiation) procarbazine, CCNU, and vincristine chemotherapy for anaplastic oligodendrogliomas because, increasingly, chemotherapy is prescribed before radiation for oligodendroglial neoplasms. The data indicate that 70% of patients respond to neoadjuvant chemotherapy, whereas 30% require early radiation because they either have chemoresistant tumors or experience unacceptable chemotoxicity.

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.