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Background: Meningiomas are one of the most common benign primary brain tumors; however, there is a paucity of literature on potential preventability. This comprehensive review aimed to explore the existing evidence for the potential risk factors that may contribute to meningioma development and to discuss early prevention strategies., Methods: Literature search was conducted via MEDLINE, Embase, Web of Science, and Cochrane Database to retrieve existing literature on various environmental exposures and lifestyle behaviors that are potential risk factors for the development of meningiomas., Results: Significant risk factors included exposure to ionizing radiation and certain environmental chemicals. Notably, this study also identified that cigarette smoking and obesity are associated with the development of meningiomas. To date, wireless phone usage, hormonal exposures, dietary factors, and traumatic brain injury remain inconclusive. Early prevention strategies should primarily be family-driven, community-based, and public health-endorsed strategies. Targeting unhealthy behaviors through healthcare organizations could execute a pivotal role in the maintenance of an optimum lifestyle, reducing the development of risk factors pertinent to meningiomas., Conclusions: To our knowledge, this is the first study that offers a perspective on prevention of meningiomas. A causal relationship of risk factors in developing meningiomas cannot be directly established with the current evidence. We are aware of the limitations of the hypothesis, but we believe that this study will raise more awareness and our findings could potentially be endorsed by organizations promoting health across the globe. Further prospective and retrospective studies will shed more light on this topic and help establish a definitive relationship., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Several studies through the years have proven how an unhealthy nutrition, physical inactivity, sedentary lifestyle, obesity, and smoking represent relevant risk factors in cancer genesis. This study aims to provide an overview about the relationship between meningiomas and food assumption in the Mediterranean diet and whether it can be useful in meningioma prevention or it, somehow, can prevent their recurrence. The authors performed a wide literature search in PubMed and Scopus databases investigating the presence of a correlation between Mediterranean diet and meningiomas. The following MeSH and free text terms were used: "Meningiomas" AND "Diet" and "Brain tumors" AND "diet." Databases' search yielded a total of 749 articles. After duplicate removal, an abstract screening according to the eligibility criteria has been performed and 40 articles were selected. Thirty-one articles were excluded because they do not meet the inclusion criteria. Finally, a total of 9 articles were included in this review. It is widely established the key and protective role that a healthy lifestyle and a balanced diet can have against tumorigenesis. Nevertheless, studies focusing exclusively on the Mediterranean diet are still lacking. Thus, multicentric and/or prospective, randomized studies are mandatory to better assess and determine the impact of food assumptions in meningioma involvement., (© 2023. The Author(s).)

Epidemiological studies reported in 2016 and 2019 demonstrated that breast cancer patients under tamoxifen treatment had significantly reduced risks of meningioma development. Tamoxifen treatment duration longer than 1500 days or with cumulative dosage higher than 26 320 mg have especially lowered risk of meningioma. Clinical long-term anticancer efficacy of tamoxifen shall associate with simultaneous suppression of estrogen receptor and downregulation of certain growth factor pathways, which may associate with - but not limited to - protein kinase-C (PKC) signaling. In this study, we will put the evidence together and indicate that tamoxifen may be effective in meningioma treatment in some patients who do not express estrogen receptor but expresses PKC, yet much higher doses of tamoxifen will be needed to treat meningiomas than those applied to treat breast cancer. We underline the fact that immunohistochemical analysis of both estrogen receptor and PKC (especially α, δ, λ and ι isoenzymes) may guide in patient stratification for selective benefitting from tamoxifen in management of meningiomas. Lastly, it would also be logical to test individual responses of meningiomas to tamoxifen in primary monolayer and spheroid cultures before starting treatment in each patient as the differential distribution of PCK isoenzymes may cause also untoward effects., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Leptomeningeal metastasis (LM) is a severe complication of advanced non-small cell lung cancer (NSCLC). This retrospective study aimed to investigate the potential use of osimertinib for preventing LM in patients with advanced epidermal growth factor receptor (EGFR)-mutated NSCLC., Methods: Patients with advanced NSCLC harboring EGFR mutations who underwent tyrosine kinase inhibitors (TKIs) therapy for at least 8 weeks between September 2016 and September 2019 were eligible for this study. All included patients were divided into two groups based on whether they received osimertinib, the osimertinib group (patients treated with osimertinib) and the control group (patients not treated with osimertinib). Propensity score matching (PSM, ratio of 1:1) was used to account for differences in baseline characteristics. The cumulative incidence of LM and the overall survival (OS) were evaluated., Results: A total of 304 patients were included in the study population. Among them, 116 patients received osimertinib, and 188 did not. A total of 112 patients remained in each group after PSM, and the baseline characteristics were not significantly different between the two cohorts. LM developed in 11 patients (9.82%) in the osimertinib group and 24 patients (21.42%) in the control group (hazard ratio [HR] 0.38, 95% confidence interval [CI] 0.19-0.79, p = 0.009). Multivariate analysis indicated that osimertinib was an independent, statistically significant predictor for determining the risk for LM, with an HR of 0.33 (p = 0.042). At present, the OS rate data are too immature for statistical analysis., Conclusion: Real-world data demonstrate that osimertinib can significantly reduce the incidence of LM in patients with advanced NSCLC harboring common EGFR mutations. Given this result, osimertinib should be encouraged in clinical practice for specific patient populations., (© 2021. The Author(s).)

Objective: Glioma and meningioma are the most common primary brain tumors in adults. Epidemiologic studies of the relationship between female hormone exposure and exogenous hormone use and the risk of meningioma and glioma in females have yielded inconsistent results., Methods: Two investigators comprehensively searched 3 electronic databases, including PubMed, Embase, and Cochrane Library. A total of 11 case-control studies were enrolled for meta-analysis. Dose-response meta-analyses were conducted., Results: Compared with the non-oral contraceptives (OCs) female users, the female OC users might have reduced risk of glioma (risk ratio [RR], 0.87; 95% confidence interval [CI], 0.77-0.97; I 2  = 42.6%). However, there was no obvious evidence of an association between OC use and the risk of meningioma in females (RR, 0.99; 95% CI, 0.87-1.13; I 2  = 42.7%). Using OCs for >10 years in females may significantly decrease the risk of glioma to 30% (RR, 0.7; 95% CI, 0.6-0.81; I 2  = 0%). The dose-response meta-analyses indicated that the risk of glioma in females significantly decreased when the duration of oral OC use was >7.5 years., Conclusions: OC use may not increase the risks of glioma and meningioma in females. Instead, the long-term use of OCs may significantly decrease the risk of glioma, and the benefits are even more pronounced when the time window is >7.5 years. Nonetheless, the pooled results in this study suggest that OC use may not increase the risk of meningioma. Therefore, our conclusion should be validated and supplemented in future larger studies., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Previous studies suggest that hormone therapy may play an important role in the development of meningioma. However, it is unclear whether medication with tamoxifen can prevent meningioma. Our study cohort included all women who were diagnosed with breast cancer between 1961 and 2010, and a total of 227 535 women were identified with breast cancer with a median age at diagnosis of 63 years. Women diagnosed with breast cancer after 1987 were defined as tamoxifen exposed; those diagnosed with breast cancer before or during 1987 were defined as not exposed to tamoxifen. Standardized incidence ratios (SIRs) were used to calculate the risk of subsequent meningioma. Of these women, 223 developed meningioma. For women without tamoxifen exposure, the risk of meningioma was significantly increased, with an SIR of 1.54 (95% confidence interval 1.30-1.81); the risk was not increased in those with tamoxifen exposure (SIR=1.06, 95% confidence interval 0.84-1.32). The increased risk of meningioma in women without tamoxifen exposure persisted during 10 years of follow-up. In this historical cohort study, we found that women diagnosed with breast cancer but not treated with tamoxifen had an increased incidence of meningioma, whereas the incidence was close to that of the general population in patients treated with tamoxifen. This suggests that tamoxifen may prevent the development of meningioma.

Purpose: The relationship between hormone replacement therapy (HRT) and the incidence of meningioma in women has been investigated in several epidemiologic studies, but their results were not entirely consistent. Here, we performed a meta-analysis of case-control and cohort studies to analyze this association., Methods: The PubMed database was searched from inception to 30 September 2012 to identify relevant studies that met pre-stated inclusion criteria. We also reviewed reference lists from the retrieved articles. Two researchers evaluated study eligibility and extracted the data independently. Odds ratios (ORs) or relative risks and 95 % confidence intervals (CIs) were extracted and pooled using the fixed-effect or random-effects models., Results: A total of 11 studies (six case-control and five cohort studies) were included in this meta-analysis, involving 1,820,954 participants, of whom 3,249 had meningioma. When compared to never users of HRT, the pooled OR with ever users for meningioma was 1.29 (95 % CI 1.03-1.60). Sensitivity analyses restricted to postmenopausal women yielded similar results (OR: 1.22; 95 % CI 1.02-1.46). Subgroup analyses showed that the pooled ORs were 1.27 (95 % CI 1.08-1.49, p < 0.05) and 1.12 (95 % CI 0.95-1.32) for current and past users of HRT, respectively., Conclusion: Hormone replacement therapy use is associated with an increased risk of meningioma in women, as well as in postmenopausal women. Besides, the significant risk elevation is present in current users but not in past users. Future research should attempt to establish whether this association is causal and to clarify its mechanisms.

Background: CD163 is a 130-kDa transmembrane protein expressed in human monocytes and macrophages, and the aberrant expression of CD163 in breast and colorectal cancer associated with patients' poor prognosis was reported. Here, we analyzed the expression of CD163 in meningioma, a common intracranial tumor, and its molecular mechanism in association with meningioma progression., Methods: First, we performed immunohistochemical analysis using 50 human meningioma specimens. Next, we established CD163-overexpressing human meningioma cell lines and investigated its roles in tumor progression in vitro and in vivo., Results: Immunohistochemically, 26 of 50 human meningioma specimens (52.0%) were positive for CD163 in tumor cells, including benign grade I (48.5%) and grade II (71.4%) cases. Furthermore, CD163 expression was correlated with histological atypical parameters that directly predict the prognosis of meningioma. CD163-overexpressing meningioma cells showed significant suppression of apoptosis and accelerated tumor growth in nude mice. In addition, unexpected splenomegaly affiliated with the xenograft predicted tumor-derived granulocyte colony-stimulating factor (G-CSF) production, which was confirmed by reverse-transcription polymerase chain reaction and enzyme-linked immunosorbent assay., Conclusions: To our knowledge, this is the first report that demonstrates CD163 expression in meningioma not only by immunohistochemistry but also by reverse-transcription polymerase chain reaction, using primary culture cells, and provides the novel molecular function of CD163 to prevent apoptosis through the production of G-CSF in meningioma.

Purpose: To evaluate the mTORC1 (mammalian target of rapamycin complex 1) pathway in meningiomas and to explore mTORC1 as a therapeutic target in meningioma cell lines and mouse models., Experimental Design: Tissue microarrays (53 meningiomas of all WHO grades) were stained for phosphorylated polypeptides of mTOR, Akt, and the mTORC1 targets 4EBP1 and p70S6K, the latter being the consensus marker for mTORC1 activity. Expression of proteins and mRNAs was assessed by Western blotting and real-time PCR in 25 tumors. Cell lines Ben-Men-1 (benign), IOMM-Lee and KT21 (malignant), and pairs of merlin-positive or -negative meningioma cells were used to assess sensitivity toward mTORC1 inhibitors in methyl-tetrazolium and bromodeoxyuridine (BrdUrd) assays. The effect of temsirolimus (20 mg/kg daily) on tumor weight or MRI-estimated tumor volume was tested by treatment of eight nude mice (vs. 7 controls) carrying subcutaneous IOMM-Lee xenografts, or of eight (5) mice xenotransplanted intracranially with IOMM-Lee (KT21) cells in comparison to eight (5) untreated controls., Results: All components of the mTORC1 pathway were expressed and activated in meningiomas, independent of their WHO grade. A significant dosage-dependent growth inhibition by temsirolimus and everolimus was observed in all cell lines. It was slightly diminished by merlin loss. In the orthotopic and subcutaneous xenograft models, temsirolimus treatment resulted in about 70% growth reduction of tumors (P < 0.01), which was paralleled by reduction of Ki67 mitotic index (P < 0.05) and reduction of mTORC1 activity (p70S6K phosphorylation) within the tumors., Conclusion: mTORC1 inhibitors suppress meningioma growth in mouse models, although the present study did not measure survival., (©2012 AACR.)

Objective: To introduce a kind of method for skull base reconstruction after resecting anterior skull base tumors involving paranasal sinuses., Method: A retrospective analysis was carried out on 13 patients who underwent anterior skull base reconstruction. Pericranial flap were detached with integrity from the frontal bone during craniotomy, after the tumor had been resected partitionedly, the cribriform plate of ethmoid bone which was involved by tumor was resected. Using the fat tissue to fill the skull-base defects and sutured the pedicled pericranial flap with surrounding normal dura mater. Then reinforced at the junction of pericranial flap and dura mater with biogel., Result: The pathogenic diagnosis of all cases were meningioma. I grade resection was acquired in 12 cases and II grade in 1 case according to Simpson grading standard of meningioma resection. The postoperative complications were 3 cases aseptic meningitis, 3 cases frontal syndrome. No CSF leakage, intracranial infection, nor death occurred. An average of 3. 4-year follow-up was achieved in all the cases from 9 months to 8 years, no tumor relapse., Conclusion: CSF leakage can be effectively prevented by filling the skull-base defects with the fat tissue, suturing the pedicled pericranial flap with surrounding normal dura mater, and reinforcing at the junction of pericranial flap and dura mater with biogel.

Background and Purpose: Some CNS tumours present leptomeningeal dissemination. Craniospinal radiotherapy is complex and recurrences may occur at sites of target volume underdosage. IMRT, being highly conformal to the target, could theoretically underdose the optic nerves if they are not specifically targeted leading to optic nerve recurrences. We analyzed optic nerve dosimetry when they are not specifically targeted., Materials and Methods: We designed 3D-conformal and tomotherapy plans for our last five patients treated to the craniospinal axis, not including the optic nerves in the target volume. We analyzed the dose delivered to the optic nerves, to the anterior and posterior half of the optic nerves, and to a theoretical optic nerve-PTV., Results: The dose delivered to the optic nerves was similar for both plans in all patients (V95% close to 100%) except one in whom tomotherapy considerably underdosed the anterior optic nerves. The dose to the optic nerve-PTV was lower with tomotherapy in all patients., Conclusion: Despite not intentionally targeting the optic nerves, the dose to the optic nerves with IMRT was similar to 3D-conformal plans in most cases but left no margin for setup error. In individual cases the anterior half of the optic nerves could be significantly underdosed., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

The current WHO 2007 classification divides meningiomas into a 3-grade prognostic hierarchy. Recent literature evokes two pathways to disease progression in meningiomas akin to a comparable paradigm in gliomas, but without similar prognostic connotation: de novo anaplastic meningioma (better prognosis), and transformed meningioma (worse prognosis). We present two adult cases of transformed meningiomas that display a spectrum of morphologic progression. Case 1 at presentation showed a random admixture of meningothelial, atypical and anaplastic meningioma. The tumor recurred as anaplastic meningioma. Case 2 presented as a chordoid meningioma, but recurred as anaplastic meningioma mainly at the invasive front in transition with residual chordoid pattern. Of interest, portions of tumor also showed papillary configuration. In accordance with the dire prognosis for anaplastic meningioma, both patients succumbed to their disease within 2 months of recurrence. The present study highlights two main points: First, that proper recognition of focal high-grade areas in a heterogeneous low-grade meningioma (case 1) provides critical morphologic clues to spatial histologic progression and predicts aggressive biologic behavior, as evidenced by progression to frankly anaplastic meningioma at recurrence. Second, the presence of papillary in addition to anaplastic areas, in the recurrence of a previously diagnosed chordoid meningioma supports the ostensibly heightened transforming potential of grade II meningiomas, but also reflects on the morphologic heterogeneity of high-grade meningiomas, and their potentially diverse pathways of progression. We propose that grading of meningiomas as outlined by WHO is of more critical prognostic import than histologic sub-typing, and must include a thorough survey of the tumor-brain interface. Future molecular genetic correlates, akin to those characterized in gliomas, could help stratify prognostic subcategories to refine meningioma grading, and govern optimal therapeutic strategies.

Central nervous system (CNS) recurrence continues to be a significant complication in the treatment of adult patients with acute lymphoblastic leukemia (ALL). Preventing CNS recurrence has been a therapeutic challenge and has not been addressed critically in many clinical trials. Adult studies modeled on childhood ALL studies have used multiple treatment modalities, including radiation therapy, systemic therapy, intrathecal therapy, and combinations thereof. Cranial irradiation is effective but is offset by substantial toxicity, including neurologic sequelae. Systemic chemotherapy, especially with cytarabine (AraC) and methotrexate, has demonstrated promise in decreasing CNS recurrence, but therapeutic levels of drugs in the cerebrospinal fluid (CSF) are not maintained. Intrathecal chemotherapy with or without high-dose systemic therapy is the most common approach to CNS prophylaxis. Liposomal AraC recently has become available and confers prolonged levels of free AraC in the CSF, a critical requirement for CNS prophylactic therapy. This review discusses the various modalities used for CNS prophylaxis in patients with ALL and the emerging trends, with specific emphasis on the outcome in terms of event-free survival and toxicity., ((c) 2010 American Cancer Society.)

We report a case of a 57-year-old African American male patient with standard risk (IIIA) IgA kappa multiple myeloma. This patient presented with neurologic complaints (manifesting as generalized muscle weakness and swallowing dysfunction associated with a poor cough reflex) 10 months after achieving a very good partial remission and without evidence of systemic progression. Examination of the cerebrospinal fluid revealed leptomeningeal involvement. Very little is known about the mechanisms of myelomatous spread to the leptomeninges, a very rare event, and the presentation of this case could raise awareness of this rare complication in those involved in caring for patients with multiple myeloma.

Background: Somatostatin receptors, especially the sst2A subtype, are present on most meningiomas. The addition of somatostatin inhibits meningioma growth in vitro in some studies. There have been anecdotal reports of octreotide inhibiting growth in meningiomas., Objectives: A prospective pilot trial of sustained-release somatostatin (Sandostatin LAR) in 16 patients with recurrent meningiomas was conducted with a primary study objective of progression-free survival at 6 months., Methods: Sixteen patients (11 women, 5 men; median age 58) with recurrent meningioma were treated prospectively with long-acting somatostatin. Patients had progressed radiographically after prior therapy with surgery (14/16; complete resection in 5; subtotal in 7; biopsy only in 2), radiotherapy (13/16), and chemotherapy (12/16). All patients had confirmation of the presence of somatostatin receptors in their tumor using (111)In-octreotide, a long-acting somatostatin agonist, SPECT scanning., Results: Patients received 2 to 15 cycles (median 4.5) of somatostatin with minimal toxicity. Five [corrected] partial responses, five stable disease, and six [corrected] progressive disease patterns were seen. Duration of response ranged from 2 to 20+ months (median 5.0 months). Median survival was 7.5 months (range 3 to 20+). The overall progression-free survival was 44% (seven patients) at 6 months., Conclusions: In this small trial of patients with recurrent meningiomas shown to overexpress somatostatin receptors by octreotide scintigraphy, long-acting somatostatin (Sandostatin LAR) was administered on a monthly schedule. Thirty-one percent of patients demonstrated a partial radiographic response and 44% achieved progression-free survival at 6 months. Toxicity was minimal, suggesting somatostatin analogues may offer a novel, relatively nontoxic alternative treatment for recurrent meningiomas.

Background: Treatments for recurrent meningiomas are limited. We previously demonstrated universal expression of COX-2 in meningiomas and dose-dependent growth inhibition in vitro with celecoxib, a COX-2 inhibitor. We therefore tested the effects of celecoxib on meningioma growth in a mouse xenograft model., Methods: Meningioma cell lines (IOMM-Lee, CH157-MN, WHO grade I primary cultured tumor) were transplanted into flanks of nude mice fed mouse chow with celecoxib at varying concentrations (0, 500, 1000, 1500 ppm) ad libitum. Tumors were measured biweekly and processed for MIB-1, Factor VIII, COX-2, and VEGF, and assayed with transferase-mediated dUTP-biotin nick-end labeling (TUNEL)., Results: Celecoxib reduced growth of mean tumor volume by 66% (P < .05), 25% (P > .05), and 65% (P < .05) compared with untreated controls in IOMM-Lee, CH157-MN, and benign tumors, respectively. IOMM-Lee tumors removed from celecoxib treatment regained a growth rate similar to the control. Blood vessel density decreased and apoptotic cells increased in treated flank tumors. Diminished COX-2 expression and VEGF were observed in treated IOMM-Lee tumors. Mean plasma celecoxib levels were 845, 1540, and 2869 ng/mL, for low-, medium-, and high-dose celecoxib, respectively., Conclusions: Celecoxib inhibits meningioma growth in vivo at plasma levels achievable in humans. Celecoxib-treated tumors were less vascular with increased apoptosis. IOMM-Lee tumors treated with celecoxib showed decreased COX-2 and VEGF expression. COX-2 inhibitors may have a role in the treatment of recurrent meningiomas., ((c) 2007 American Cancer Society.)

Although CD20- relapses of B-cell lymphoma following rituximab therapy have increasingly been reported recently, coexistence of both the original and selected clones on relapse in a single patient have not been described. We experienced such a case with rare CD5+ intravascular lymphomatosis (IVL). A 46-year-old woman was admitted because of IVL complicated with cauda equina syndrome and pulmonary infarction. Complete remission was successfully achieved with multidrug chemotherapy in combination with rituximab. However, the disease recurred after 8 months with leukemic progression and meningeal involvement. The phenotype of the abnormal lymphocytes in the peripheral blood was fundamentally the same (CD20+CD5+CD10-CD19+CD23-sIglambda+) as that of the cells in the cerebrospinal fluid (CSF). However, CD20 expression was decreased remarkably compared with that in the CSF and that in the bone marrow before therapy. The targeting of CD20 molecules on the tumor cell surface by rituximab may have provided a selective pressure on lymphoma cells. The escape phenomenon of the lymphoma cells from rituximab was observed by simultaneously comparing the CD20 expression of cells in the peripheral blood and in a site of sanctuary from rituximab, the CSF.

Purpose: The toxicity and antitumor activity of regional intrathecal delivery of an oncolytic recombinant poliovirus, PVS-RIPO, was evaluated in rodent models of glioblastoma multiforme neoplastic meningitis., Experimental Design: To evaluate for toxicity, PVS-RIPO was administered into the spinal cord of transgenic mice that express the human poliovirus receptor, CD155, and into the intrathecal space of athymic rats without tumor. To evaluate efficacy, two different doses of PVS-RIPO were administered intrathecally 3 days after athymic rats were inoculated intrathecally with an aggressive human glioblastoma multiforme xenograft., Results: No clinical or histologic evidence of toxicity was found. In efficacy studies, median survival was increased by 174.47% from 8.5 days in the group treated with UV light-inactivated virus to 15 days in the rats treated with 1.0 x 10(7) plaque-forming units (pfu) of PVS-RIPO (P < 0.0001). A similar increase in median survival was seen in the group receiving 1.0 x 10(9) pfu PVS-RIPO (P < 0.0001); however, there was no statistically significant dose-response relationship (P = 0.345). In addition, 1 of 10 rats in lower-dose PVS-RIPO-treated group and 3 of 10 rats in higher-dose PVS-RIPO-treated group survived >60 days after tumor cell inoculation and had no evidence of residual tumor at autopsy., Conclusion: These results suggest that intrathecal treatment with PVS-RIPO may be useful for treatment of neoplastic meningitis in patients with glioblastoma multiforme and provides a rationale for clinical trials in this area.

Medulloblastoma (MB), the most common pediatric brain tumor, is a highly malignant disease with a 5-year survival rate of only 60%. Tumor cells invade surrounding tissue and disseminate through cerebral spinal fluid, making treatment difficult. Human reovirus type 3 exploits an activated Ras pathway in tumor cells to support productive infection as an oncolytic virus. Here, we examined the ability of human reovirus to kill MB cells lines and surgical specimens in vitro and inhibit tumor growth/metastases in vivo. Most human MB cell lines tested (five of seven = 71.4%), two MB cell lines derived from spontaneously arising tumors in Patched-1(+/-) mice (two of two = 100%) and three MB primary cultures derived from surgical specimens, were susceptible to reovirus infection. Reovirus was internalized and transcribed in both susceptible and resistant cell lines. However, viral protein synthesis was restricted to cell lines with higher levels of activated Ras, suggesting that Ras plays a critical role in reovirus oncolysis in MB. Using an in vivo Daoy orthotopic animal model, we found that a single i.t. injection of reovirus dramatically prolonged survival compared with controls (160 versus 70 days, respectively; P = 0.0003). Repeating this experiment with GFP-labeled Daoy cells and multiple i.t. administrations of reovirus, we again found prolonged survival and a dramatic reduction in spinal and leptomeningeal metastases (66.7% in control injections versus 0.0% in the live virus group). These data suggest that this oncolytic virus may be a potentially effective novel therapy against human MB. Its ability to reduce metastases to the spinal cord could allow a reduction in the dose/field of total neuroaxis cerebral-spinal radiotherapy currently used to treat/prevent cerebral spinal fluid dissemination.

The authors present four patients with a history of high dose cranial irradiation, who were diagnosed years later to have symptomatic meningiomas requiring surgical management. Relevant literature pertaining to these rare tumours is reviewed and their unusual characteristics highlighted. Their aetio-pathogenesis and management strategies are discussed.

Objective: To evaluate clinicopathological features associated with leptomeningeal disease in systemic AIDS-related non-Hodgkin's lymphoma (NHL) and to compare outcomes to those without leptomeningeal disease. In addition to evaluate intrathecal chemoprophylaxis for patients with good immunological parameters and high risk of meningeal relapse (bone marrow, paraspinal or paranasal involvement or Burkitt's lymphoma histology)., Design and Methods: Prospective data, which has been collected on our cohort of 8640 HIV seropositive patients treated at the Chelsea and Westminster Hospital includes 176 patients with systemic AIDS-related NHL, was analysed., Results: At presentation, 18 (10%) patients had meningeal involvement. There were significant associations between meningeal disease and both Burkitt's lymphoma and paraspinal or paranasal involvement. There was no difference in the overall survival between patients with or without meningeal involvement at presentation (Kaplan-Meier log-rank, P = 0.35) and the 1-year actuarial survivals are 25% [95% confidence interval (CI), 3-47%] for patients with meningeal involvement and 33% (95% CI, 26-41%) for those without. Prophylactic intrathecal chemotherapy was administered to 21 high-risk patients and four (19%) relapsed with meningeal disease., Conclusions: This single-centre experience of a large cohort has demonstrated that meningeal involvement at presentation correlates with Burkitt's lymphoma histology and paraspinal or paranasal space disease, but not with bone marrow lymphoma. It also documents that long-term survival is achievable rarely in patients who present with meningeal disease and in patients with isolated meningeal relapse.

After initial treatment, a 54-year-old male with plasma cell leukaemia developed extramedullary relapse in the testis and meninges without evidence of bone marrow involvement. We postulate that the central nervous system (CNS) and testis may have served as sanctuary sites for the disease during initial treatment. A role for CNS prophylaxis in plasma cell leukaemia is suggested.

An unforeseen consequence of improved disease-free survival in many hematologic and solid tumor malignancies has been an increase in the incidence of disease recurrence in the leptomeninges. The recognition of the central nervous system (CNS) as a unique 'sanctuary' site has resulted in the development of therapeutic strategies specifically directed at the leptomeninges. Although therapeutic strategies have been successful in the prevention and treatment of CNS leukemia, there are still a paucity of therapeutic options for patients with neoplastic meningitis due to solid tumors or recurrent CNS leukemia. This article provides an overview of the pharmacology and toxicity of intrathecal agents that are commonly employed in the treatment and prevention of leptomeningeal disease, and describes new agents that are in the early stages of clinical development.

Leptomeningeal (LM) neoplastic metastases are painful, debilitating and inevitably lethal. Intrathecal (IT) anti-tumor antibodies may have therapeutic potential. We evaluated 3F8, an anti-G(D2) murine IgG(3) monoclonal antibody (MAb) in the treatment of human melanoma (SKMEL-1) and neuroblastoma (NMB7) xenografts in athymic rats. Both tumors were lysed efficiently in vitro by 3F8 in the presence of rat neutrophils or rat complement. Antibody-dependent cellular cytotoxicity (ADCC) was not augmented by recombinant human GM-CSF (rhGM-CSF), rhG-CSF, recombinant rat MIP-2 (rrMIP-2) or lipopolysaccharide (LPS). In vivo, continuous intraventricular administration of 3F8 and LPS prevented tumor engraftment, retarded tumor growth and eradicated 3-day-old established xenografts whereas 3F8 alone, LPS alone or F(ab)'(2) plus LPS had no or only marginal effects. Tumor establishment in brain was completely prevented in 36% of animals implanted with SKMEL-1 and 65% of animals implanted with NMB7. Twenty percent of established xenografts around the brain were eradicated but all animals had persistent tumor in the lumbosacral meninges despite treatment. Continuous intraventricular infusion of LPS produced a variable polymorphonuclear (PMN) pleocytosis that was dose-dependent. Continuous intraventricular infusion of 3F8 produced immunohistochemically detectable attachment to 86% of persistent brain deposits of tumor but <1% of spinal lumbosacral deposits. We conclude that regional therapy with anti-G(D2) MAb could target neutrophils to inhibit LM tumor growth. However, optimal activation and mobilization of neutrophils into the cerebrospinal fluid (CSF) and improved penetration of MAb to tumor sites remain critical variables., (Copyright 1999 Wiley-Liss, Inc.)

The outcome of children less than 3 years of age with medulloblastoma has been poor in comparison to older children. The cure rates were below 30%, and the quality of life for cured children was frequently reduced by a complex syndrome of long-term sequelae including intellectual retardation and growth hormone deficiency. Due to the deleterious side-effects of radiotherapy in very young children chemotherapy has played an important role in this group of patients. Firstly, chemotherapy should improve their survival rate. Secondly, it should allow dose reduction of craniospinal irradiation and a smaller involved field. With the goal of improving quality of life radiotherapy should be delayed or even replaced by postoperative chemotherapy. The EFS of low-risk patients steadily improved and is now as high as at least 50%. Since most patients of this group do not need radiation, treatment-related long-term sequelae are minimal. High-risk patients, by contrast, with metastatic disease or measurable postoperative tumor still have a very disappointing progression-free survival in a range below 30% at 3 to 4 years in all large studies. Therefore prevention and effective therapy of meningosis, as well as a good response to induction chemotherapy, are essential for the outcome. Strategies to increase the efficacy of conventional treatment modalities in high-risk patients are under investigation. Recently, interesting results have been published on high-dose chemotherapy followed by autologous stem cell rescue and intraventricular administration of the alkylating agent mafosfamide.

Neoplastic meningitis (NM) occurs in approximately 8% of all cancer patients. To confirm a clinical impression that NM is relatively common in patients who undergo surgical resection of an isolated cerebellar metastasis (ICM), a retrospective study was performed. All patients who underwent a surgical resection of an isolated CNS metastasis at The Johns Hopkins Hospital between January 1991 and June 1993 were identified. Their charts, laboratory and pathologic data, radiologic studies, survival and cause of death were reviewed. A total of 66 patients were identified fifty-five patients underwent a surgical resection of a supratentorial metastasis while 11 patients (6 females and 5 males) underwent a surgical resection of an isolated cerebellar metastasis. The ages of patients with cerebellar metastases ranged from 23 to 74 years at the time of diagnosis with a median age of 49 years. All 11 patients had stable systemic disease and an excellent performance status. Five patients had tumors from lung, 2 from breast, and 4 from other sites. Each was expected to have a long survival. However, 4 of the 11 patients (36%) developed unequivocal NM at 1, 3, 6, and 7 months following surgical resection and all died within 1 month from the diagnosis of NM. Two patients had a positive CSF cytology and the other two had multiple enhancing leptomeningeal metastases on MRI. Two additional patients died of progressive neurological disease without evidence of local recurrence, yet were never formally evaluated for NM and two were lost to follow-up. Thus, the incidence of NM in this patient population is at least 36%. In the 55 patients who had resections of supratentorial metastases, only 1 patient (2%) developed NM. This study suggests that NM following surgical resection of an ICM may be common and may result in the premature demise of patients with excellent performance status, minimal systemic disease, and a reasonable life expectancy. Further studies are needed to determine if prophylactic intrathecal chemotherapy administered perioperatively could diminish the incidence of clinically apparent NM in this patient population.

The influence of the intrathecal methotrexate (IT MTX) prophylaxis on frequency and intensity of lymphomatous infiltrates within the leptomeninges and spinal roots in adults with non-Hodgkin's lymphomas (HGNHL) of high grade malignancy was evaluated. The effect of selected risk factors on the central nervous system (CNS) involvement by infiltrates was also analysed. Based on the results, indications for the prophylactic management were discussed. The post-mortem neuropathological investigations have been performed on 42 deceased patients having the NHL of high grade malignancy, treated and suffered in the Department of Haematology of the Pomeranian Medical Academy between 1980-1994. In all patients, neither apparent neurological complications nor changes in the cerebrospinal fluid during the disease were noted. Generally, lymphomatous infiltrates within the leptomeninges and spinal roots were observed in 64 per cent of cases. They were usually observed as variously sized foci: from single small to large, diffused in many regions. The study group of 21 patients subjected to IT MTX prophylaxis were compared with 21 patients without "CNS prophylaxis" (control group). Frequency and intensity of lymphomatous infiltrates decreased significantly after more than 3 IT MTX injections (Tab. 1) within spinal leptomeninges only (Tab. 2, 3). No benefits of this kind of treatment within cerebellar leptomeninges were noted. A poor penetration of the MTX (given by lumbar injection) into this region, could be a possible explanation of such result. It was disclosed that high white blood cells (WBC) count was the most important risk factor of the CNS involvement by lymphomatous infiltrates. Frequency of lymphomatous infiltrates diminished after IT MTX prophylaxis only in patients with WBC count less than 50 G/1 during the disease (Tab. 4). It was also found that lymphomatous infiltrates within the leptomeninges and spinal roots occurred in high percentage in both groups, and were independent of histological type of the HGNHL (Tab. 5) as well as of patients' age. From the neuropathological point of view, IT MTX prophylaxis seems to be ineffective in patients with the HGNHL, who did not reach a complete heamatological remission. A complete elimination of lymphomatous cells from the intracranial leptomeninges is particularly difficult to achieve. Considering the fact that it is hard to foresee response to polychemotherapy, especially at the beginning of the treatment, and--as present study shows--the lymphomatous infiltrates in the CNS are frequently found soon after the onset of the disease, "CNS prophylaxis" should be initiated simultaneously with the induction of remission. However, the continuation of the prophylaxis without haematological control of the disease seems to be aimless.

A multicenter prospective study was conducted in 114 children with acute lymphoblastic leukemia receiving 4 intravenous methotrexate (MTX) courses (5 g/m2 as a 24 hour-infusion) to determine the diffusion of MTX in cerebrospinal fluid (CSF) and to correlate the drug levels to central nervous system (CNS) relapse occurrence. Serum and CSF levels were measured at the end of 446 MTX courses. A significant correlation was found between CSF and serum MTX concentration. CSF MTX level was greater than 1 mumol/l in 66% of the courses. Twelve patients (11%) failed to achieve this potentially cytotoxic drug level at the end of the 4 consecutive MTX courses: only one CNS relapse was observed and the mean age of these children was lower than that of the others. To date 9 (7.8%) children had CNS relapse and no difference was observed in terms of CSF MTX levels when compared to data of children free of CNS relapse. With a median follow up of 32 months, pharmacokinetic data during high-dose MTX therapy do not seem to be an exclusive predictive factor of CNS relapse.

Purpose: Childrens Cancer Group 123 was a trial of intensive multidrug chemotherapy as well as cranial irradiation and bulk disease irradiation in children with acute lymphoblastic leukemia with lymphomatous presentation (bulk disease and either T-cell phenotype, high white blood count, or absence of anemia), a poor prognostic group with an increased risk of central nervous system (CNS) and other extramedullary recurrence., Methods and Materials: Three hundred eight patients without CNS disease were randomized among three regimens: A--BFM chemotherapy (designed for high risk ALL patients) with 1800 cGy cranial irradiation; B--LSA2L2 chemotherapy (designed for non-Hodgkins lymphoma patients) with 1800 cGy cranial irradiation and 1500 cGy to nonabdominal bulk disease; C--Reg B without cranial irradiation. All patients received intrathecal methotrexate throughout therapy. Radiation treatment records were reviewed., Results: With a minimum 52-month follow-up, Regimen B and C patients had 5-year actuarial CNS relapses of 7% and 17% (p = 0.01) and event-free survivals of 53% and 39% (p = 0.04). Patients with white blood count < 50,000/mm3 did not benefit from cranial irradiation. Regimen A patients had the same CNS relapse rate as Regimen B patients but an improved event-free survival. Regimen B and C patients with large mediastinal masses who received their assigned chest radiation had a lower event rate than those who did not (p = 0.06). Patients whose cranial fields did or did not encompass the entire meningeal surface had equivalent CNS relapse rates., Conclusion: Patients treated with LSA2L2 chemotherapy, a less than optimal regimen, benefited from cranial and mediastinal irradiation. Compliance with radiation volume guidelines was not essential for patients to receive the benefit of cranial irradiation.

The prognosis of non-Hodgkin's lymphoma (NHL) in childhood has improved steadily in the last 2 decades. This is primarily the result of increasingly effective chemotherapy regimens tailored to defined and relatively homogeneous prognostic categories and tested in prospective clinical trials. Surgical excision remains of prognostic benefit only when near-total resection can be performed without delay of chemotherapy. The role of radiation therapy is now limited to the treatment of overt central nervous system (CNS) lymphoma, disease unresponsive to chemotherapy, and certain emergencies. Effective 'prophylactic' treatment of the CNS has been achieved in most series by intrathecal and systemic chemotherapy alone. The most relevant modality of treatment is chemotherapy and a very large number of protocols have been published. The origins of current multi-agent regimens stem both from early experience with cyclophosphamide in endemic Burkitt's lymphoma and from therapeutic studies of acute lymphoblastic leukaemia. Sub-stratification of non-localized NHL has produced protocols designed for either lymphoblastic (mostly T cell) or non-lymphoblastic (mostly B cell) categories. While the cure rate for lymphoblastic lymphoma now exceed 70%, the non-localized non-lymphoblastic disease remains a major obstacle to cure. These patients frequently present with large abdominal primaries and are prone to regional as well as hematogenous dissemination. In particular, involvement of the CNS is now considered to be the most adverse prognostic variable in this group. Recently, highly intensive regimens are addressing these obstacles. On the other hand, NHL defined as localized has been shown to be curable in up to 95% of children with the use of simple chemotherapy regimens as short as 6 months in duration. Salvage of patients who relapse during or after chemotherapy remains bleak but cures are possible with regimens incorporating bone marrow transplantation from either an autologous or allogeneic source. Experimental methods, including biologic and immune response modifiers may also offer future promise.

Using the CCLSG-S811 protocol for children with standard-risk acute lymphoblastic leukemia (ALL), late intensification therapy (LIT) with high-dose methotrexate (HD-MTX) was conducted without randomization. Of 118 eligible patients, 114 attained complete remission and 82 maintained continuous complete remission (CCR) for at least 3 years, completing the entire S811 regimen. Among the latter, 74 patients received LIT with HD-MTX between 2-3 years after CCR onset. MTX (2,000 mg/m2 per dose per week) was administered by 24 h infusion and three doses were given every 12 weeks. Leucovorin rescue (15 mg/m2 i.v.) every 6 h was initiated 12 h after the end of MTX infusion for seven doses. As regular maintenance chemotherapy, intermittent (Regimen A) or continuous (Regimen B) MTX plus 6-mercaptopurine (6MP) combined with pulses of prednisolone and vincristine was administered (Koizumi S, Fujimoto T, Takeda T, et al. Cancer 1988; 61: 1292-1300). Retrospective analysis revealed that patients on Regimen A who started LIT earlier (within 2 years of CCR onset (n = 23)) showed a higher rate of event-free survival (EFS) at 8 years (95.5% +/- 4.4%, mean +/- S.E.) than patients who started LIT later (2.5 years after CCR onset (n = 18, 66.2% +/- 11.3%, p less than 0.01)). In addition, the superiority of four or five courses of the LIT (n = 39) as compared to 2 or 3 courses (n = 35) was noted for both regimens. The data suggest that early and aggressive LIT with HD-MTX may improve the long-term survival of childhood ALL patients.

We report a boy with acute lymphoblastic leukaemia (ALL) treated with chemotherapy and prophylactic cranial irradiation to a dose of 24 Gy. Six years after diagnosis he developed a glioma and died. Prior to 1979, four cases of second malignant neoplasm (SMN) of the brain had been reported in children treated for ALL. These SMNs occurred within 2 years of the original diagnosis (median 1.3 years) and at least two of four patients had not received prior radiotherapy. Since 1979, 28 cases of SMN of the brain have been reported including nine of 468 (1.9%) long-term survivors in one study. All occurred more than 3.7 years from diagnosis (median 6.5 years; range 4-13 years) and all received cranial irradiation (median 24 Gy; range 20-48 Gy). These data indicate a change in the pattern of SMNs which is most likely due to the introduction of cranial irradiation. As well, the frequency of SMNs in children treated for ALL appears to have increased, although it is still no greater than the risk of SMNs developing following the treatment of any other primary childhood neoplasm.

In 1971, Cancer and Leukemia Group B (CALGB) mounted a study of acute lymphocytic leukemia (ALL) that compared the effects of the two steroid hormones dexamethasone and prednisone. Six-hundred-forty-six children and adolescents with ALL were randomized to receive either prednisone or dexamethasone as part of their remission induction therapy. The 493 evaluable patients who achieved complete remission received the same steroid as pulses throughout remission. Specific central nervous system (CNS) therapy was randomized to either six injections of intrathecal methotrexate (IT MTX) alone or to six injections of IT MTX with cranial radiation (2,400 cGy). Both cranial radiation and dexamethasone offered increased protection against CNS relapse as the first site of failure over IT MTX alone. There were 30 CNS relapses among 238 patients (12.6%) receiving cranial radiation plus IT MTX, whereas there were 70 CNS relapses among 225 (P less than 0.001) (22.5%) in those who received IT MTX alone. Similarly, there were 33 CNS relapses among 231 (14.3%) children treated with dexamethasone, whereas there were 67 CNS relapses among 262 (25.6%) treated with prednisone (P = 0.017). Both steroids appeared equal in protecting the bone marrow. Recent national studies have shown significant improvements in preventing CNS relapse over the results in the present report. However, this finding warrants further investigation and, with further documentation, could lead to the substitution of prednisone by dexamethasone to aid further in preventing CNS relapse. This may be particularly important in patients at higher risk for CNS relapse.

Investigation of the bioelectrical activity of the brain (EEG, echoEG) in 60 patients aged 8 to 20 years with a long relapse-free course of acute lymphoblastic leukemia (6-10 years) made it possible to distinguish 3 groups of patients in accordance with the changes seen on the EEG. A reverse relationship was noted between the characteristics of the leukemic process during disease diagnosis and neurophysiological disorders after intensive therapy including chemoradiation prophylaxis of neuroleukemia. It is recommended that the dose of radiation of the brain of children with acute lymphoblastic leukemia may be reduced, if there are no risk factors of the development of disease relapses.

The follow-up of 318 children with acute lymphoblastic leukemia given program therapy that included different treatments including chemo- and radioprevention of neuroleukemia demonstrated the high efficacy of the measures carried out, which reduced the incidence of neuroleukemia to 5.6%. No gross changes on the part of the neuropsychic status were revealed in the course of the follow-up of children who received the combined prophylaxis of neuroleukemia. The derangement of the CNS was recorded in 17 patients and ran its course in the form of leukemic meningitis and meningoencephalitis.

A series of 15 consecutive children with head and neck nonorbital rhabdomyosarcoma (RMSA) with meningeal extension were prospectively treated with chemotherapy consisting of Adriamycin (doxorubicin; Adria Laboratory, Columbus, OH) (ADM), vincristine (VCR), cyclophosphamide (CPM), and dactinomycin (DACT) followed by radiotherapy (60 Gy) to the primary tumor volume, along with intrathecal methotrexate (IT MTX). Thirteen of 15 responded to preradiation chemotherapy. Four of 13 relapsed. Relapse occurred at the level of the primary tumor in three of four. The 3-year progression-free survival (PFS) was 59%, similar to that achieved in a previous series treated with a comparable therapeutic approach that also included whole-brain radiotherapy as a prophylaxis of possible occult meningeal seeding. It is concluded that CNS prophylaxis with radiotherapy is questionable in the management of childhood RMSA with meningeal extension.

By use of prophylactic CNS therapy, the incidence of meningeal relapse has been dramatically reduced and the length of the initial bone marrow remission has been greatly prolonged in children with acute lymphoblastic leukemia. Pinkel performed a controlled study in which 94 patients were randomized to one of two regimens of presymptomatic CNS therapy, or received no prophylactic CNS therapy. This crucial study showed that prophylactic CNS therapy was very useful both in preventing meningeal relapse and in prolonging the duration of complete remission. Then, many additional regimens for prophylactic CNS therapy were tried on thousands of children worldwide in an effort to improve upon these results. Among the many CNS therapy regimens that were tried, none gave results better than the original St. Jude regimen. Our knowledge of CNS leukemia in general has greatly increased, but the last 20 years have brought us no further significant progress as to improved results in preventing meningeal leukemia. The many novel and innovative CNS therapy regimens that have been tried have yielded essentially the same results as to prevention of meningeal leukemia and as to duration of disease-free survival. Five to ten percent, or fewer in patients at low risk, still show meningeal relapse, and nearly one half of children with ALL still have hematologic relapse within the first 5 years following initiation of therapy. The goal now is to reduce neurotoxicity. Thus, progress has been stymied and we now await some new addition to therapy that will dramatically improve our results. Nonetheless, there are still many promising avenues of research yet to be explored. Meningeal leukemia remains a fascinating and satisfying field of clinical research.

A prospective study was conducted to investigate the possibility of osteoporosis after treatment for childhood acute lymphoblastic leukemia (ALL). Forty-two survivors of ALL had the trabecular bone density of the spine evaluated by quantitative computed tomography, 6 to 98 months (mean 42 months) after completion of chemotherapy. The ALL survivors had significantly lower bone density than age-, gender-, and race-matched nonleukemic control subjects had (10% less, p less than 0.001); this decrease was accounted for solely by the subset of patients who had received cranial irradiation (n = 30; p less than 0.001). The relative reduction in bone density in ALL survivors was unrelated to age at the time of diagnosis or time without therapy. The effects on bone density of 18 Gy and of 22.5 to 25.2 Gy were indistinguishable. We conclude that survivors of ALL commonly have reduced bone density in the lumbar spine and suggest that the diminution is related to nervous system irradiation, not to the disease or to chemotherapy.

A 14-year-old boy, suffering from acute lymphoblastic leukemia with meningeal involvement, was treated with intraventricular methotrexate and cytosine arabinoside, administered via an Ommaya reservoir (OR). Three months later, right occipital headache, vomiting, and lethargy appeared. Cerebrospinal fluid specimens showed increased proteins and a right frontal slow-wave focus was evident on the EEG recording. The computed tomography scan revealed white matter hypodensity within the right frontal and rolandic regions. After injection of medium contrast, an abscesslike hyperdensity appeared, surrounding both a well-placed cannula tip and the right frontal horn of the lateral ventricle. Brain swelling and shift signs were also evident. Nine cases of focal methotrexate leukoencephalopathy have been previously reported, and in six of these there was a misplaced OR cannula tip. The focal methotrexate leukoencephalopathy seems to be related to the neurotoxicity of the drugs administered, and may also exist with a well-placed OR cannula tip. Immediate removal of the catheter may be associated with a benign evolution.

We have analyzed 60 cases of intra-axial brain tumors associated with antecedent radiation therapy. These include four new cases. The patients had originally received radiation therapy for three reasons: (a) cranial irradiation for acute lymphoblastic leukemia (ALL), (b) definitive treatment of CNS neoplasia, and (c) treatment of benign disease (mostly cutaneous infections). The number of cases reported during the past decade has greatly increased as compared to previous years. Forty-six of the 60 intra-axial tumors have been reported since 1978. The relative risk of induction of an intra-axial brain tumor by radiation therapy is estimated to be more than 100, as compared to individuals who have not had head irradiation.

Two cases of Ph1-positive acute lymphoblastic leukemia (ALL) and one case of lymphoid blast crisis (LyBc) of chronic granulocytic leukemia (CGL) treated with standard chemotherapy for ALL are presented. Hematologic remissions lasting 6, 12, and 15 months were achieved in all cases. Meningeal relapse occurred in all three, terminating remission in two cases and occurring immediately after systemic relapse in the third. No CNS-prophylaxis was given to the patient who relapsed at six months. Methotrexate (MTX) alone or combined with cranial irradiation formed the prophylaxis given in the other cases. Experience of these patients together with an analysis of reported cases of Ph1 ALL and CGL-LyBc suggests CNS-prophylaxis may prolong first remission. A large scale trial of this appears indicated.

Twenty-one children with acute nonlymphoblastic leukemia (ANLL) were treated with a combination regimen consisting of arabinosyl cytosine (Ara-C), 6-thioguanine (TG), and Adriamycin, The incidence of complete remission was 74%. For consolidation, addition courses of Ara-C and TG were given, followed by L-asparaginase. The maintenance program was the same as that for the lymphoblastic type (L-2) including intrathecal methotrexate for prophylaxis of meningeal leukemia. Of the 16 who were evaluable for the duration of complete remission, six developed bone marrow relapse, one meningeal leukemia within 3-14 months after entering complete remission and one was lost to follow-up. Eight remain in complete remission for 9-72 months. In five of eight, chemotherapy has been terminated after 3 years, and all continue in remission for 11-32 months post-treatment. Although the results do not compare well to those of the lymphoblastic morphology, long-term disease-free survival can be achieved with multiple-drug intensive treatment in childhood ANLL.