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Notes: Abstract Cerebral sparganosis, a parasitic disease, rarely produces a chronic active inflammatory response in the brain. Clinically and radiographically the process may mimic a neoplasm. We report a 30-year-old man who underwent surgical exploration for a mass in the insular cortex. Histology revealed a densely fibrotic mass heavily infiltrated with plasma cells and lymphocytes, in which were embedded parasitic forms consistent with sparganosis. We describe the MRI appearances and pathologic features. Intracranial mass lesions secondary to sparganosis must be considered in patients with a history of travel to endemic areas, especially Asia.

Notes: Abstract  The prognosis for patients with malignant gliomas continues to be dismal. The high degree of resistance of gliomas to nitrosourea-based chemotherapy is one major factor in poor treatment outcome. The identification of O 6-alkylguanine-DNA alkyltransferase (AGAT) as a major determinant of nitrosourea resistance has resulted in the development of several agents to inactivate this repair protein and counteract tumor cell resistance. However, a major problem in preclinical trials has been the marked nitrosourea dose limitations imposed by the prior administration of AGAT-depleting agents. We investigated the AGAT depletion and selective enhancement of BCNU activity of intraarterial (i.a.) O 6-benzylguanine (O 6BG) in the human malignant glioma xenograft D-456 MG growing intracranially (i.c.) in athymic rats. Whereas i.a. O 6BG at 2.5 mg/kg produced 100% inhibition of D-456 MG AGAT i.c. activity 8 h after administration, intraperitoneal (i.p.) O 6BG at this dose produced only 40% inhibition, requiring dose escalation to 10 mg/kg to produce 100% AGAT depletion. Prior administration of i.p. O 6BG (10 mg/kg) and i.a. O 6BG (2.5 mg/kg) limited maximum tolerated intravenous (i.v.) BCNU doses (37.5 mg/kg when given alone) to 6.25 and 25 mg/kg, respectively. Higher doses of BCNU alone or in combination with O 6BG produced histopathologic evidence of cerebral and hepatic toxicity. Therapy experiments revealed a significantly improved median survival for rats treated with O 6BG i.a. (2.5 mg/kg) plus BCNU i.v. (25 mg/kg, days 61 and 59 in duplicate experiments) compared with saline (day 21, P=0.001), O 6BG i.a. or i.p. (days 22 and 23, P=0.001), BCNU i.v. (37.5 mg/kg, day 29, P=0.001), and O 6BG i.p. (10 mg/kg) plus BCNU i.v. (6.25 mg/kg, day 37, P〈0.001). Therefore, O 6BG i.a., by virtue of rapid AGAT depletion and selective uptake into i.c. tumors, offers significant potential for regional chemomodulation of AGAT-mediated nitrosourea resistance in malignant human gliomas with concomitant reduction of systemic toxicity.

Notes: [Auszug] Ionizing radiation represents the most effective therapy for glioblastoma (World Health Organization grade IV glioma), one of the most lethal human malignancies, but radiotherapy remains only palliative because of radioresistance. The mechanisms underlying tumour radioresistance have remained ...

Notes: Abstract The current study was designed to evaluate the toxicity and activity of Spartaject™ Busulfan, a microcrystalline preparation of busulfan, following its intrathecal administration into a nude rat model of human neoplastic meningitis. Animals were treated through permanent indwelling subarachnoid catheters. Human glioma D-456 MG growing in the subarachnoid space was treated with 8.1 µmol of intrathecal Spartaject™ Busulfan. Single-dose therapy was also subsequently compared with 4 doses of 8.1 and 2.0 µmol busulfan, respectively, against D-456 MG neoplastic meningitis. Additional experiments evaluated a saline control versus 8.1 µmol×1, 6.2 µmol×4 and 4.1 µmol×4, respectively, against D-456 MG. A single dose of 8.1 µmol of intrathecal Spartaject™ Busulfan resulted in an increase in median survival of 61.7% compared with the saline control. In experiment 2, all busulfan treatments showed increases in median survival of 142.8% (8.1 µmol×1), 52.3% (2.0 µmol×4), and 23% (8.1 µmol×4) (p〈0.001 for all groups) compared with the saline control. These results suggest that a narrow therapeutic dose range for both toxicity and activity has been defined for intrathecal busulfan in the treatment of human neoplastic meningitis in athymic nude rats. Although busulfan has only limited activity against solid tumors, the high doses achievable in the CSF following intrathecal administration coupled with the steep dose–response relationships of alkylating agents, provide rationale for further evaluation of this agent.

Notes: Summary The advent of monoclonal antibody (MAb) technology has made Ehrlich's postulate of the ‘magic bullet’ an attainable goal. Although specific localization of polyvalent antibodies to human gliomas was demonstrated in the 1960s, the lack of specific, high affinity antibody populations and of defined target antigens of sufficient density precluded therapeutic applications. Not until the identification of operationally specific tumor-associated antigens (present in tumor tissue but not normal central nervous system tissue); production of homogeneous, high affinity MAbs to such antigens; and the use of compartmental administration (intrathecal or intracystic), has the promise of passive immunotherapy of primary and metastatic central nervous system neoplasms been recognized. We report here preliminary data from Phase I studies of the compartmental administration of the anti-tenascin MAb 81C6 and F(ab2)2 fragments of MAb Mel-14, which recognizes the proteoglycan chondroitin sulfate-associated protein of gliomas and melanomas, to patients with primary central nervous system tumors or tumors metastatic to the central nervous system. Phase I dose escalation studies of intracystically administered131I-labeled anti-tenascin MAb 81C6 to either spontaneous cysts of recurrent gliomas or surgically created cystic resection cavities have resulted in striking responses. Of five patients with recurrent cystic gliomas treated, four had partial responses, clinically or radiographically. Similarly, in patients with surgically created resection cavities, a partial response at the treatment site and extended stable disease status has been obtained following intracystic administration of131I-labeled 81C6. No evidence of hematologie or neurologic toxicity has been observed in either patient population, with the exception of transient exacerbation of a pre-existing seizure disorder in a single patient. Dosimetry calculations indicated high intracystic retention for four to six weeks with little or no systemic dissemination; estimated total doses intracystically ranged from 12,700–70,290 rad. Intrathecal administration of labeled MAbs to patients with neoplastic meningitis is more difficult to assess in terms of clinical responsiveness. Of patients so treated with either131I-labeled 81C6 or131I-labeled Mel-14 F(ab)2, cerebrospinal fluid and radiographie responses have been achieved, and survival prolongation through maintenance of stable disease has been observed in several cases. Initial results from Phase I dose escalation trials are encouraging in terms of the proportion of cases of disease stabilization and partial and complete responses obtained. Importantly, neurotoxicity has been virtually nonexistent, and hematologie toxicity rare and rapidly responsive to treatment. In the intracompartmental setting, then, the promise of chimerized MAb molecules or of dimeric or monomeric single-fragment chains, either radiolabeled or drug- or toxin-conjugated, is great. The possibilities of MAb-mediated, targeted therapy for tumors of the central nervous system are many and promising. Future work will be with newly defined antigens of exquisite tumor specificity, such as the variant epidermal growth factor receptor III molecule. New labeling technology will allow halogens such as131I and211At to be used for internalized or membrane-localized antigens. Internalized MAbs will be able to be used as immunotoxins or labeled with chemotherapeutic agents.

Notes: Abstract DNA derived from medulloblastoma biopsies was analyzed to determine if deletions of the 17p region, mutations of theTP53 gene, or amplification of the c-myc, N-myc, EGFR (epidermal growth factor receptor), orMDM2 (murine double-minute-2) genes was indicative of a poor prognosis. Loss of heterozygosity for 17p, observed in 8/28 (29%) paired samples, was associated with a shortened survival period (p=0.045 by the logrank test).TP53 mutations occurred in 2/46 (4.3%) tumor samples. c-myc Amplification was seen in 3/43 (6.9%) cases, while none of the tumors contained amplified N-myc, EGFR, orMDM2 genes. These results demonstrate that, while only rare medulloblastomas containTP53 gene mutations or amplification of the c-myc gene, loss of heterozygosity on chromosome 17p is indicative of a significantly worse prognosis among patients with these tumors. Further, these results provide a strong impetus for a prospective analysis of loss of heterozygosity in a cooperative group setting, which would include tumor staging, a selection of treatment modalities, and multivariate analyses.

Notes: Abstract The biologic behavior of ependymomas is highly variable, and its correlation with histologic features is at best imprecise. This retrospective study attempted to correlate the malignant histologic characteristics of ependymomas with MIB-1 proliferation index and survival. Biopsy and resection specimens taken from 34 patients who received treatment 1972 to 1996 were histologically examined. The patients' ages range was 1 to 59 years. The histologic specimens were assessed for anaplastic features (necrosis, mitosis, vascular proliferation, cellular pleomorphism, and overlapping of nuclei) and an MIB-1 (Ki-67 antigen) proliferation index was also determined. The overall median MIB-1 proliferation index was 7.8% (range 0.1 – 62.5%). An MIB-1 of 20% was significant for a decrease in survival (RR=5.7) (p=0.0013). The median MIB-1 for patients 〈 20 years old was 20.6% with range (0.1, 43%), while that for patients 〉 20 years was 5.1% (range 0.2, 9.4%) (KW p=0.055). Three of 5 histological features evaluated were significantly associated with outcome: 〉 5 mitotic figures per high-power field, necrosis, and vascular proliferation, but not nuclear overlap or pleomorphism. All pathologic factors except pleomorphism were significantly related to the MIB-1 proliferation index. In brief, our data support the association of poor prognoses in ependymomas with young age, the presence of three to four anaplastic histologic features, and an MIB-1 proliferation index 〉 20%.