Presurgical and intraoperative mapping of the motor system in congenital truncation of the precentral gyrus.

A 43-year-old man presented with a grade II astrocytoma in the left postcentral gyrus and superior parietal lobule. Preoperative functional MR imaging and diffusion tensor imaging mapped distal upper-extremity primary motor cortex and white matter, respectively, adjacent to the tumor, within a congenitally truncated precentral gyrus. Because of the congenital anomaly, this region of primary motor cortex was inaccessible to direct visualization or intraoperative electrocortical stimulation. The integration of preoperative and intraoperative mapping data facilitated resection of the tumor while avoiding a postoperative motor deficit.

Transferrin toxin but not transferrin receptor immunotoxin is influenced by free transferrin and iron saturation.

BACKGROUND: Cytotoxic agents can be targeted successfully to cancer cells. The efficacy of such novel and potent anticancer strategies may be influenced by variables of iron metabolism. METHODS: The in vitro cytotoxicity against glioma cells of transferrin (Tf)-based targeted toxins was compared with that of alpha-transferrin receptor (TfR)-immunotoxin. RESULTS: Of four Tf-based targeted toxins, Tf-gelonin, Tf-pokeweed antiviral protein, Tf-momordin and Tf-saporin, inhibitory concentration 50% values against glioma-derived cell lines HS683 and U251, ranged from [4.8 +/- 1.5] x 10(-10) m for Tf-saporin to [26.9 +/- 15.3] x 10(-10) m for Tf-gelonin in [(3)H]-leucine incorporation assays. Tf-saporin and alpha-TfR-saporin-immunotoxin had similar efficacy, even in the more quantitative clonogenic assay (4-5 log kill with 1 x 10(-9) m) using the myeloma cell line RPMI 8226 and glioma cell line U251. However, on RPMI 8226, the efficacy of Tf-saporin 1 x 10(-9) m was reduced by 90% in the presence of 150 microg mL(-1)(=20% of normal plasma value) competing diferric transferrin, whereas the efficacy of the corresponding immunotoxin was affected only marginally. In addition, the efficacy of Tf-based conjugates will depend on their iron saturation state. Iron desaturation of Tf-saporin was demonstrated by [(59)Fe]-labelling, subsequent CM-Sepharose chromatography and SDS-PAGE. Desaturation led to virtually complete loss of affinity for the transferrin receptor, as determined by flow cytometry, which could be largely restored upon resaturation. CONCLUSION: Transferrin-based toxin conjugates are strongly influenced by the presence of free transferrin and the iron saturation state. The corresponding alpha-transferrin receptor-immunotoxin does not show these disadvantages, has similar efficacy and should be preferred for further experiments.

Utility of simultaneously acquired gradient-echo and spin-echo cerebral blood volume and morphology maps in brain tumor patients.

An interleaved gradient-echo (GE) / spin-echo (SE) EPI sequence was used to acquire images during the first pass of a susceptibility contrast agent, in patients with brain tumors. Maps of 1) GE (total) rCBV (relative cerebral blood volume), 2) SE (microvascular) rCBV, both corrected for T(1) leakage effects, and 3) (DeltaR(2)*/DeltaR(2)), a potential marker of averaged vessel diameter, were determined. Both GE rCBV and DeltaR(2)*/DeltaR(2) correlated strongly with tumor grade (P = 0.01, P = 0.01, n = 15), while SE rCBV did not (P = 0.24, n = 15). When the GE rCBV data were not corrected for leakage effects, the correlation with tumor grade was no longer significant (P = 0.09, n = 15). These findings suggest that MRI measurements of total blood volume fraction (corrected for agent extravasation) and DeltaR(2)*/DeltaR(2), as opposed to maps of microvascular volume, may prove to be the most appropriate markers for the evaluation of tumor angiogenesis (the induction of new blood vessels) and antiangiogenic therapies. Magn Reson Med 43:845-853, 2000.

Management of seizures in brain tumor patients at the end of life.

Few data exist on the management of seizures in brain tumor patients near the end of life. This article provides information on the epidemiology and phenomenology of seizures, as well as on differential diagnostic considerations. Based largely on empirical data from the pediatric epilepsy literature, guidelines for management of seizures near the end of life are given, with emphasis on the use of rectal antiepileptic drugs.

Single-voxel proton MR spectroscopy of nonneoplastic brain lesions suggestive of a neoplasm.

BACKGROUND AND PURPOSE: MR spectroscopy is used to characterize biochemical components of normal and abnormal brain tissue. We sought to evaluate common histologic findings in a diverse group of nonneoplastic diseases in patients with in vivo MR spectroscopic profiles suggestive of a CNS neoplasm. METHODS: During a 2-year period, 241 patients with suspected neoplastic CNS lesions detected on MR images were studied with MR spectroscopy. Of these, five patients with a nonneoplastic diagnosis were identified retrospectively; a sixth patient without tissue diagnosis was added. MR spectroscopic findings consistent with a neoplasm included elevated choline and decreased N-acetylaspartate and creatine, with or without detectable mobile lipid and lactate peaks. RESULTS: The histologic specimens in all five patients for whom tissue diagnoses were available showed significant WBC infiltrates, with both interstitial and perivascular accumulations of lymphocytes, macrophages, histiocytes, and (in one case) plasma cells. Reactive astrogliosis was also prominent in most tissue samples. This cellular immune response was an integral component of the underlying disorder in these patients, including fulminant demyelination in two patients, human herpesvirus 6 encephalitis in one patient, organizing hematoma from a small arteriovenous malformation in one patient, and inflammatory pseudotumor in one patient. Although no histologic data were available in the sixth patient, neoplasm was considered unlikely on the basis of ongoing clinical and neuroradiologic improvement without specific therapy. CONCLUSION: Nonneoplastic disease processes in the CNS may elicit a reactive proliferation of cellular elements of the immune system and of glial tissue that is associated with MR spectroscopic profiles indistinguishable from CNS neoplasms with current in vivo MR spectroscopic techniques. Such false-positive findings substantiate the need for histologic examination of tissue as the standard of reference for the diagnosis of intracranial mass lesions.

Response rate and prognostic factors of recurrent oligodendroglioma treated with procarbazine, CCNU, and vincristine chemotherapy. Dutch Neuro-oncology Group.

OBJECTIVES: To determine the response rate and factors correlated with response of oligodendroglial tumors to procarbazine, lomustine (CCNU), and vincristine (PCV) chemotherapy. DESIGN: Retrospective, observational multicenter study. METHODS: Patients treated with PCV or intensified PCV chemotherapy for a recurrent oligodendroglial tumor after surgery and radiation therapy with measurable disease were retrospectively evaluated for response. A 50% reduction in cross-sectional enhancing tumor area was considered a partial response. Stabilized or responding patients received six cycles of PCV unless unacceptable toxicity occurred. RESULTS: Fifty-two patients were included; median time to progression (MTP) for the entire group was 10 months. In 17% of patients a complete response (MTP, 25 months) was obtained, and in 46% a partial response (MTP, 12 months) was obtained. Median overall survival was 20 months. Although treatment was discontinued for toxicity in seven patients, it was generally well tolerated. The intensified PCV regimen was more toxic. Patients initially presenting with seizures and patients with tumor necrosis in histologic specimens had a better response rate in contrast to patients who had their first relapse within 1 year of first treatment (surgery and radiation therapy). CONCLUSIONS: Oligodendroglial tumors are chemosensitive, but most patients will have relapsed after 12 to 16 months. New studies must aim at improving initial treatment and second-line chemotherapy.

Current therapy and new perspectives in the treatment of medulloblastoma.

Medulloblastoma, a malignant tumor arising from the medullary velum, is the most common malignant brain tumor of childhood. Local extension into the cerebellar hemisphere, infiltration of the floor of the fourth ventricle, and seeding into the subarachnoid space are common. Early diagnosis and improved treatment consisting of surgery followed by radiation and chemotherapy for selected high-risk patients has contributed to a dramatic change in survival. This article reviews current treatment strategies and describes new therapies that have the potential to improve the outlook of children with medulloblastoma.

Radiation therapy and hydroxyurea followed by the combination of 6-thioguanine and BCNU for the treatment of primary malignant brain tumors.

PURPOSE: This study was designed to evaluate a combined modality treatment for malignant gliomas using radiation therapy with a radiosensitizer and an adjuvant chemotherapy regimen designed to modify resistance to BNCU. METHODS AND MATERIALS: Patients were eligible if they were 15 years of age or older, and had newly diagnosed glioblastoma multiforme (GBM), or anaplastic glioma (AG). Treatment consisted of external beam radiotherapy given to a dose of 60 Gy using a single daily fraction Monday to Friday. Concurrent hydroxyurea at a dose of 300 mg/m2 every 6 h every other day was given during radiation. Following radiotherapy, patients were then treated with BCNU and 6-Thioguanine (6TG). The 6-TG was given by mouth every 6 h for 12 doses prior to BCNU. Patients were initially treated with 60 mg/m2/dose of 6TG, with escalation to a maximum dose of 100 mg/m2/dose. The primary study end points were time to tumor progression and survival. RESULTS: A total of 245 eligible patients were enrolled from 1/18/88 to 12/26/91. The histologic subtypes included 135 GBM, and 110 with AG (103 with anaplastic astrocytoma, 7 with high-grade mixed oligoastrocytoma). For the GBM group, the median time to tumor progression (TTP) and median survival were 33 (95% CI 26, 39) and 56 (95% CI 49, 69) weeks, respectively. For the AG group the median TTP was 282 weeks (95% lower confidence bound = 155 weeks). Median survival for this group has not been reached (95% lower confidence bound = 284 weeks) with a median follow-up for surviving patients of 298 weeks. A proportional hazards model was used to look at potential prognostic factors for survival, including initial Karnofsky Performance Scale (KPS), age, and extent of surgery, as well as dose of 6TG. Higher KPS, and lower age, predicted for longer survival (p < 0.01, < 0.001) in GBM patients; lower age was significant (p = 0.05) for AG cases. A higher (greater than 95 mg/m2) or lower dose of 6TG was not statistically significant in this model. CONCLUSIONS: This therapy was no more effective in patients with GBM than other reported series. In patients with malignant gliomas other than GBM, prolonged progression-free and overall survival is noted, without a median survival reached at the time of this report. In this subset of AG patients, survival is comparable to recent studies using halogenated prymidines during radiation and Procarbazine, CCNU, and Vincristine (PCV) as adjuvant chemotherapy.

Oligoastrocytomas: a clinicopathological study of 52 cases.

Oligoastrocytomas form a poorly defined subgroup of glial tumors, and few clinical series have been reported. We performed a retrospective study to elucidate the histopathological features of these tumors and to relate the clinical signs and symptoms and proliferative potential to survival. Oligoastrocytomas were defined as glial tumors with at least 10% neoplastic astrocytes and 10% neoplastic oligodendrocytes; tumors were graded with the St. Anne-Mayo criteria for astrocytomas and oligodendrogliomas. Proliferative potential was estimated with antibodies against proliferating cell nuclear antigen (PCNA). Median survival of 52 patients (median age, 42 years) was 75 weeks (range 2-703 weeks). Actuarial 1-, 2-, 3-, and 5-year survival rates were 67%, 43%, 40%, and 29%, respectively. For 15 patients with grade 3 and 33 with grade 4 lesions (St. Anne-Mayo astrocytoma classification), median survival was 217 and 55 weeks, respectively. For 19 patients with grade 2 and 33 with grade 3 lesions (St. Anne-Mayo oligodendroglioma classification), median survival was 305 and 55 weeks, respectively. Interobserver agreement between three experienced neuropathologists on identification of astrocytes, oligodendrocytes, and unclassifiable cells was low, indicating considerable subjectivity in the histopathological diagnosis. Median PCNA labeling indices correlated with tumor grade, but individual values varied so widely within grades that they had no predictive value for survival. In a multivariate analysis, symptoms of increased intracranial pressure and microvascular proliferation were independently associated with poor prognosis. The biological behavior of subgroups appeared to be distinctly less aggressive than that of 'pure' astrocytomas of similar grade. Better histopathological definition of oligoastrocytomas and improved assessment of percentages of constituent cell types may allow more accurate prognosis.

Transient cranial neuropathy in prostatic cancer with bone metastases after rhenium-186-HEDP treatment.

Rhenium-186 (tin) hydroxyethylidene diphosphonate (186Re-HEDP), a bone-seeking radiopharmaceutical, has been successfully used in the treatment of patients with painful bone metastases. Toxicity is usually limited to reversible thrombocytopenia. An infrequent but clinically significant side effect is the occurrence of transient cranial neuropathy. We report on two prostatic cancer patients with metastatic bone cancer. Both patients developed transient cranial neuropathy shortly after treatment with 186Re-HEDP. Transient neuropathy of cranial nerves needs to be distinguished from neurological abnormalities caused by disease progression.

Infiltrative astrocytomas of the thalamus.

Clinical characteristics and outcome in 57 patients with infiltrative thalamic astrocytomas were analyzed retrospectively. The median patient age was 22 years (range 1 to 69 years). Fourteen patients had no surgery, 37 had biopsy, and six had subtotal resection. The histological diagnosis was astrocytoma in 14 patients, anaplastic astrocytoma in 25, and glioblastoma multiforme in two; two specimens were nondiagnostic. The initial treatment was conventional radiation therapy (RT) in 20 patients (one also received interstitial brachytherapy), RT followed by chemotherapy in 18, hyperfractionated RT in 17 (one also received chemotherapy), and chemotherapy alone in two. The median time to tumor progression was 47 weeks (range 5 to 388 weeks); median survival was 73 weeks (range 11 to 502 weeks). Actuarial 1-, 2-, 3-, and 5-year survival rates were 67%, 35%, 24%, and 20%, respectively. Tumor progression was usually treated with chemotherapy. The assessed treatment failure was within 2 months after RT in 12 patients in whom the findings of the neurological and radiological examinations did not correspond. This assessment showed false-negative diagnosis of radiation-induced changes in five patients (42%); false-positive diagnosis of tumor progression could not be ascertained. In univariate Cox proportional-hazards analysis, histological diagnosis of astrocytoma, age under 18 years, and open biopsy were prognostically favorable features; in multivariate analysis, only open biopsy was favorable. Infiltrative astrocytomas of the thalamus carry a dismal prognosis, regardless of the type of treatment. Hyperfractionated RT does not increase toxicity but its benefit over conventional RT remains unproven.

Gangliogliomas: a clinicopathological study of 25 cases and review of the literature.

The histopathological, clinical, and radiological findings in 25 patients (median age 20.5 years; range 1.7-64.2 years) with gangliogliomas were assessed to correlate degree of astrocytic anaplasia and proliferative potential with recurrence or survival. Most patients (64%) presented with seizures (median Karnofsky Performance Score 90%; range 70-100%). Computerized tomography and magnetic resonance imaging showed nonspecific abnormalities. Neoplastic ganglion cells were defined as heterotopic, irregularly grouped, or having more than one nucleus of bizarre shape or size. The astrocytic component was moderately anaplastic in 15 cases and highly anaplastic (HAA) in 10. Eight patients had gross total resection, 11 had subtotal resection, and six underwent biopsy. Ten patients (five gross total resection, three subtotal resection, two biopsy) had no further treatment, 15 underwent external irradiation, and five had adjuvant chemotherapy. Twenty-four patients are alive 15-394 weeks (median 203.5 weeks) postoperatively; one with ganglioglioma-HAA died at 65 weeks. No tumor recurred after gross total resection. Duration of preoperative symptoms < 1 year, greater anaplasia, and age > 30 years at diagnosis may have increased the risk of recurrence after subtotal resection or biopsy by four, three, and two times, respectively (not significant). Bromodeoxyuridine labeling index (BUdR LI) was < 1% in eight non-recurring tumors and 1.3% in another recurring twice (second recurrence LI = 1.6%). Most patients with ganglioglioma have a good prognosis. After gross total resection, only observation is required. After subtotal resection or biopsy, recurrence is possible. BUdR labeling may guide further therapy.

Proliferative potential and outcome in pediatric astrocytic tumors.

In 43 pediatric patients (29 male, 14 female) with primary astrocytic tumors of the central nervous system (CNS), the correlation was evaluated between outcome and proliferative potential, measured by the bromodeoxyuridine (BrdU) labeling index (LI). Twenty-five patients had low-grade gliomas, 13 had anaplastic gliomas, and 5 had glioblastomas multiforme (GBM). All patients underwent surgery; 37 also had chemotherapy, radiation therapy, or both. The median BrdU LIs were less than 1% (range 0-9.3%) in low-grade gliomas, 2.3% (range 0-21.2%) in anaplastic gliomas, and 7.7% (range 0-21.3%) in GBM. Seven of eight patients with BrdU LI greater than 5% have died (median survival 29 weeks). Median survival has not been reached in patients with BrdU LI less than 1% (19/22 alive) or between 1% and 5% (12/13 alive) after median follow-up periods of 165 and 120 weeks, respectively. A high BrdU LI correlated with short survival (p = 0.0001); the association between malignant histology and short survival was weaker (p = 0.019). BrdU LI is therefore a significant predictor of outcome in patients with primary CNS astrocytomas and appears to be a stronger predictor than histology in patients with low-grade and anaplastic gliomas. More patients need to be studied to confirm these preliminary observations.

A comparison of CT contrast enhancement and BUDR labeling indices in moderately and highly anaplastic astrocytomas of the cerebral hemispheres.

Contrast enhancement on computerized tomography (CT) scans has been used in directing therapy for presumed intracranial gliomas. However, for moderately anaplastic astrocytomas (MOAAS) and highly anaplastic astrocytomas (HAAS), it provides no information about proliferative potential. The bromodeoxyuridine (BUDR) labeling index (LI), however, indicates proliferative potential, correlating with histologic malignancy and survival. An LI less than 1% is a favorable indicator; LI greater than 5% suggests more aggressiveness. To determine the correlation, if any, between BUDR LI and contrast enhancement, CT scans of 71 patients with cerebral hemisphere tumors labeled with BUDR were retrospectively reviewed. Among 36 MOAAS, the BUDR LI was less than 1% in 77% of enhanced tumors and 61% of unenhanced tumors. Among 35 HAAS, it was less than 5% in 56% of enhanced tumors and 90% of unenhanced tumors. Therefore, contrast enhancement on CT scans does not always correctly predict proliferative potential in these tumors, and biopsy and labeling studies are recommended before therapy.

Desmoplastic medulloblastoma metastatic to the pancreas: case report.

A case is reported in which a desmoplastic medulloblastoma metastasized to the pancreas and to the surrounding soft tissues but did not recur locally or disseminate within the central nervous system. Multidrug chemotherapy and local radiation therapy resulted in a complete remission. In all four previously reported cases of medulloblastoma metastasizing to the pancreas, the diagnosis was not made until the postmortem examination, and all of these patients also had extensive metastases in other organ systems. Modification of the Weiss criteria defining extraneural metastases from tumors of the central nervous system is suggested.

A three-dimensional micro-organ culture system optimized for in vitro growth of human malignant brain tumors.

A brain tumor is composed not only of tumor cells, but also of normal glial, mesenchymal, endothelial, and microglial cells, as well as lymphocytes and macrophages. Therefore, homogeneous cultures of tumor cells, currently used for chemosensitivity testing, do not accurately model in situ tumors. We have developed an in vitro growth assay for brain tumors that includes normal host cells and is potentially useful for studies of chemotherapy and biological response modifiers. Human glioblastoma xenografts (U251-MG) were resected from mice, minced, and explanted into agarose-coated culture wells. After 5 to 7 days, microtumors emerged as expanding spheroids, which grew most efficiently in minimum essential medium supplemented with 20% fetal calf serum, 90% of which was replaced on alternate days. The growth rate and bromodeoxyuridine labeling index were similar in the microtumors and the xenografts, and light microscopy revealed highly cellular, pleomorphic tumors with high mitotic activity in both. Immunohistochemical studies also demonstrated the persistence of macrophages in both xenografts and microtumors. Microtumors treated for 2 hours with 75 mumol/L 1,3-bis-(2-chloroethyl)-1-nitrosourea showed a growth delay of 1.5 days; no effects were observed after treatment with lower doses. This in vitro system for brain tumor culture may provide a useful technique for the study of new therapies as an alternative to in vivo xenograft studies using immunodeficient animals.

Gemistocytic astrocytomas: a reappraisal.

Although gemistocytic astrocytomas are considered slow-growing astrocytomas, they often behave aggressively. To clarify the biological and clinical behavior of these rare tumors, the authors retrospectively identified 59 patients with gemistocytic astrocytoma whose tumors were diagnosed and treated between June, 1976, and July, 1989. Three patients who were lost to follow-up review were excluded, as were two whose original slides could not be obtained and three whose tumors were diagnosed at recurrence or at autopsy. The pathological material of the remaining 51 patients was reviewed using two sets of histological criteria. Thirteen patients (Group A) had "pure" gemistocytic astrocytoma, defined as a glial tumor with more than 60% gemistocytes/high-power field and a background of fibrillary astrocytes. Fifteen patients (Group B) had "mixed" gemistocytic astrocytoma, defined as a glial tumor with 20% to 60% gemistocytes/high-power field and a background of anaplastic astrocytes. Twenty-three tumors did not meet these criteria and were excluded from analysis. The median age of the patients was 48.5 years in Group A and 38.3 years in Group B (p less than 0.05). In both groups, the median Karnofsky Performance Scale score was greater than 90%. All patients underwent surgical procedures (four total and 19 partial resections, and five biopsies) and postoperative radiation therapy. The majority also had interstitial brachytherapy, chemotherapy, or both. Ten patients had one reoperation for tumor recurrence and one had two reoperations; other treatments for recurrence included brachytherapy, chemotherapy, and repeat irradiation. All four patients who originally underwent gross total resection are still alive; all five who had a biopsy have died. There was no significant difference in median survival times between groups: 136.5 weeks in Group A (range 10 to 310+ weeks) and 135.6 weeks in Group B (range 31 to 460+ weeks). Analysis of all 28 patients showed a better prognosis for patients less than 50 years of age (185 vs. 36 weeks survival time; p less than 0.001), patients with preoperative symptoms lasting for more than 6 months (228.1 vs. 110.2 weeks survival time; p less than 0.05), and patients with seizures as the first symptom (185.7 vs. 80 weeks survival time; p less than 0.01). Survival time did not correlate with the presence of perivascular lymphocytic infiltration. The authors conclude that the presence of at least 20% gemistocytes in a glial neoplasm is a poor prognostic sign, irrespective of the pathological background. It is proposed that gemistocytic astrocytomas be classified with anaplastic astrocytomas and treated accordingly.