Primary postoperative chemotherapy without radiotherapy for intracranial ependymoma in children: the UKCCSG/SIOP prospective study.

Background: Over half of childhood intracranial ependymomas occur in children younger than 5 years. As an adjuvant treatment, radiotherapy can be effective, but has the potential to damage the child's developing nervous system at a crucial time-with a resultant reduction in IQ and cognitive impairment, endocrinopathy, and risk of second malignancy. We aimed to assess the role of a primary chemotherapy strategy in avoiding or delaying radiotherapy in children younger than 3 years with intracranial ependymoma.

Analysis of patients with supratentorial primitive neuro-ectodermal tumours entered into the SIOP/UKCCSG PNET 3 study.

The SIOP PNET 3 study was designed to determine whether 10 weeks of moderately intensive chemotherapy given after surgery and before radiotherapy (RT) would improve the outcome for patients with primitive neuroectodermal tumours (PNETs) compared with RT alone. Patients with a histological diagnosis of supratentorial PNET (StPNET) and no radiological evidence of metastatic disease were initially eligible for randomisation to either chemotherapy followed by craniospinal RT 35 Gy in 21 fractions with a boost of 20 Gy in 12 fractions to the primary site, or RT alone. In respect of the increasing recognition that StPNET were high-risk tumours, randomisation for this group closed in November 1999.

Outcome for patients with metastatic (M2-3) medulloblastoma treated with SIOP/UKCCSG PNET-3 chemotherapy.

The aim of this study was to determine the outcome for patients with Chang stage M2-3 medulloblastoma (MB) treated with surgery and pre-radiotherapy (RT) chemotherapy (CT). Between 1992 and 2000, 68 patients aged 2.8-16.

Impact of radiotherapy parameters on outcome in the International Society of Paediatric Oncology/United Kingdom Children's Cancer Study Group PNET-3 study of preradiotherapy chemotherapy for M0-M1 medulloblastoma.

Purpose: To analyze the impact of radiotherapy (RT) parameters on outcome in a randomized study of pre-RT chemotherapy for M0-M1 medulloblastoma.

Methods And Materials: Patients were randomized to RT alone or RT preceded by chemotherapy with vincristine, etoposide, carboplatin, and cyclophosphamide. RT consisted of craniospinal RT, 35 Gy in 21 fractions, followed by a posterior fossa (PF) boost of 20 Gy in 12 fractions.

New perspectives for cancer chemotherapy by genetic protection of haematopoietic cells.

The effectiveness of anti-cancer chemotherapy can be limited by acute suppression of the bone marrow (myelosuppression). There is also a risk of therapy-related secondary haematopoietic malignancy as well as acute and longer term effects in other tissues. Clinical strategies have been established to address some of these problems, particularly toxic effects on the bone marrow (acute myelotoxicity); however, there is still substantial scope for improving the management of chronic toxicity and mutagenicity to haematopoietic cells and collateral damage to non-haematopoietic cells during chemotherapy.

Results of a randomized study of preradiation chemotherapy versus radiotherapy alone for nonmetastatic medulloblastoma: The International Society of Paediatric Oncology/United Kingdom Children's Cancer Study Group PNET-3 Study.

Purpose: To determine whether preradiotherapy (RT) chemotherapy would improve outcome for Chang stage M0-1 medulloblastoma when compared with RT alone. Chemotherapy comprised vincristine 1.5 mg/m2 weekly for 10 weeks and four cycles of etoposide 100 mg/m2 daily for 3 days, and carboplatin 500 mg/m2 daily for 2 days alternating with cyclophosphamide 1.

Temozolomide in malignant gliomas of childhood: a United Kingdom Children's Cancer Study Group and French Society for Pediatric Oncology Intergroup Study.

Purpose: To determine the response rate of the malignant gliomas of childhood to an oral, daily schedule of temozolomide.

Patients And Methods: A multicenter, phase II evaluation of an oral, daily schedule of temozolomide (200 mg/m(2) on 5 consecutive days) was undertaken in children with relapsed or progressive, biopsy-proven, high-grade glioma (arm A) and progressive, diffuse, intrinsic brainstem glioma (arm B). Evidence of activity was defined by radiologic evidence of a sustained reduction in tumor size on serial magnetic resonance imaging scans.

Neurofibromatosis type 1 and sporadic optic gliomas.

Aims: To compare the natural history of sporadic optic glioma with those associated with neurofibromatosis type 1 (NF1).

Methods: Optic glioma cases were identified using both the Manchester Children's Tumour Registry (CTR) and the North West Regional NF1 Database (NF1DB), with detailed information on natural history available from the former (in 34 of 36 cases identified).

Results: A total of 52 cases over a period of 41 years were identified.

Assays to predict the genotoxicity of the chromosomal mutagen etoposide -- focussing on the best assay.

The topoisomerase II inhibitor etoposide is used routinely to treat a variety of cancers in patients of all ages. As a result of its extensive use in the clinic and its association with secondary malignancies it has become a compound of great interest with regard to its genotoxic activity in vivo. This paper describes a series of assays that were employed to determine the in vivo genotoxicity of etoposide in a murine model system.

A phase I study of nolatrexed dihydrochloride in children with advanced cancer. A United Kingdom Children's Cancer Study Group Investigation.

A phase I study of nolatrexed, administered as a continuous 5 day intravenous infusion every 28 days, has been undertaken for children with advanced malignancy. 16 patients were treated at 3 dose levels; 420, 640 and 768 mg/m(2)24 h(-1). 8 patients were evaluable for toxicity.

The effects of dose, route of administration, drug scheduling and MDR-1 gene transfer on the genotoxicity of etoposide in bone marrow.

We have used the bone marrow micronucleus assay (BMMN) as a measure of clastogenicity, in response to etoposide exposure in murine bone marrow. Oral delivery of etoposide resulted in a reduced number of micronucleated polychromatic erythrocytes (MPE) relative to the same dose delivered intraperitoneally (P < 0.001).

Engineering drug resistance in human cells.

Many of the problems with current anti-tumour therapies stem from a lack of specificity for tumour as opposed to normal tissues. To address the problem of collateral toxicity during anti-tumour chemotherapy we have been developing a gene therapy approach to protect normal tissues from the toxic and potentially mutagenic effects of chemotherapeutic agents. As a paradigm for this we have been examining the potential of the DNA repair protein O6-alkylguanine-DNA-alkyltransferase (ATase) to confer genetic chemoprotection to the bone marrow.

A radiation-controlled molecular switch for use in gene therapy of cancer.

Ionising radiation induces the expression of a number of radiation-responsive genes and there is current interest in exploiting this to regulate the expression of exogenous therapeutic genes in gene therapy strategies for cancer. However, the radiation-responsive promoters used in these approaches are often associated with low and transient levels of therapeutic gene expression. We describe here a novel radiation-triggered molecular switching device based on promoter elements from the radiation-responsive Egr-1 gene and the cre-LoxP site-specific recombination system of the P1 bacteriophage.

The expression of full length Gp91-phox protein is associated with reduced amphotropic retroviral production.

Background And Objective: As a single gene defect in mature bone marrow cells, chronic granulomatous disease (X-CGD) represents a disorder which may be amenable to gene therapy by the transfer of the missing subunit into hemopoietic stem cells. In the majority of cases lack of Gp91-phox causes the disease. So far, studies involving transfer of Gp91-phox cDNA, including a phase I clinical trial, have yielded disappointing results.

Enhancing hemopoietic drug resistance: a rationale for reconsidering the clinical use of mitozolomide.

Retroviral gene transfer was used to achieve expression in mouse bone marrow of a mutant form of the DNA repair protein O6-alkylguanine-DNA alkyltransferase (hATPA/GA), which exhibits resistance to inactivation by O6-benzylguanine (O6-beG). After reconstitution of mice with transduced bone marrow, approximately 50% of the bipotent granulocyte-macrophage colony-forming cell (GM-CFC) and multipotent spleen colony-forming unit (CFU-S) hemopoietic populations showed expression of the transgene; this expression was associated with resistance to either mitozolomide or to a combination of O6-beG and mitozolomide, relative to mock-transduced controls. Thus, at a dose of mitozolomide in vivo that allowed only 70% and 62% survival of mock-transduced GM-CFC and CFU-S, respectively, the hATPA/GA CFC were totally resistant to the same dose of mitozolomide (P < .

Development of synthetic promoters for radiation-mediated gene therapy.

Exposure of cells to ionising radiation results in the activation of specific transcriptional control (CArG) elements within the early growth response 1 (Egr1) gene promoter, leading to increased gene expression. As part of a study investigating the potential use of these elements in radiation-controlled gene therapy vectors, we have incorporated their sequences into a synthetic gene promoter and assayed for the ability to induce expression of a downstream reporter gene following irradiation. In vector-transfected MCF-7 breast adenocarcinoma cells, the synthetic promoter was more effective than the wild-type Egr1 counterpart in up-regulating expression of the reporter gene after exposure to a single 5 Gy dose, and equally effective as the wild-type in U87-MG glioma cells.

Protection of committed murine haemopoietic progenitors against BCNU toxicity does not predict protection of primitive, multipotent spleen colony-forming cells - implications for chemoprotective gene therapy.

The effect of expression of an O6-benzylguanine (O6-beG)-resistant mutant (hATPA/GA) of human O6-alkylguanine-DNA alkyltransferase (ATase) on the in vivo toxicity and clastogenicity of the anti-tumour agent N,N'-bis(2-chloroethyl)-N-nitrosourea (BCNU) to murine bone marrow has been investigated. When compared with control animals, the bipotent granulocyte-macrophage colony-forming (GM-CFC) progenitor population of the hATPA/GA transduced mice were somewhat more resistant to BCNU (1.4-fold, P = 0.

A novel dual function retrovirus expressing multidrug resistance 1 and O6-alkylguanine-DNA-alkyltransferase for engineering resistance of haemopoietic progenitor cells to multiple chemotherapeutic agents.

Following transduction with a retrovirus (SF1MIH) expressing both the multidrug resistance 1 (MDR1) and O6-alkylguanine-DNA-alkyltransferase (ATase) proteins, human erythroleukaemic progenitor (K562) cells were isolated which were resistant to killing by the MDR1 substrate, colchicine. In colony-forming survival assays, K562-SF1MIH cells exhibited resistance to colchicine and doxorubicin, as well as to the O6-alkylating agents N-Methyl-N-nitrosourea (MNU) and temozolomide. Furthermore, the resistance to doxorubicin was abolished by preincubation with the MDR1 inhibitor verapamil while resistance to MNU was ablated by the specific ATase inactivator, O6-benzylguanine (O6-beG) confirming that resistance to doxorubicin and MNU was conferred by MDR1 and ATase, respectively.

Leptomeningeal melanoma in childhood.

Background: Malignant melanoma (MM) is one of the least common types of childhood cancer, accounting for less than 1% of all pediatric malignancies. Neurocutaneous melanosis (NCM) is a rare phakomatosis consisting of congenital abnormal pigmentation of the skin and meninges. The meningeal lesions are particularly prone to malignant change.

Ifosfamide/etoposide alternating with high-dose methotrexate: evaluation of a chemotherapy regimen for poor-risk osteosarcoma.

Fifteen patients with relapsed osteosarcoma were treated with an intensive combination chemotherapy schedule. Ifosfamide 2.5 g m(-2) daily and etoposide 150 mg m(-2) daily coincidentally for 3 days and high-dose methotrexate 8 g m(-2) (with folinic acid rescue) on days 10-14 in a planned 21 -day cycle.

Chemoprotective gene transfer II: multilineage in vivo protection of haemopoiesis against the effects of an antitumour agent by expression of a mutant human O6-alkylguanine-DNA alkyltransferase.

Murine bone marrow cells were transduced ex vivo with a retrovirus encoding an O6-benzylguanine (O6-beG) insensitive, double mutant form of the human DNA repair protein O6-alkylguanine-DNA alkyltransferase (hATPA/GA). In animals reconstituted with the transduced bone marrow, about 50% of cells in the multipotent spleen colony-forming cells (CFU-S) and lineage restricted granulocyte-macrophage (GM-CFC) haemopoietic progenitor populations were found to be carrying the transgene and this correlated with the frequency of bone marrow cells and spleen colonies which stained positive for hATPA/GA by immunocyto-chemistry. Expression of hATPA/GA was associated with significant in vivo protection of both CFU-S (P = 0.

Chemoprotective gene transfer I: transduction of human haemopoietic progenitors with O6-benzylguanine-resistant O6-alkylguanine-DNA alkyltransferase attenuates the toxic effects of O6-alkylating agents in vitro.

Retroviral transduction was used to introduce cDNAs encoding two mutants of human O6-alkylguanine-DNA alkyltransferase (hAT), one of which (hATPA) is 16 times more resistant to O6-benzylguanine (O6-beG), and the other (hATPA/GA) which is almost totally refractory to inactivation relative to the wild-type protein, into K562 human erythroleukaemic cells. A colony-forming assay was used to demonstrate significant protection (P < 0.001) against mitozolomide or temozolomide toxicity in K562 clones expressing either hAT mutant, as determined from an in vitro assay of activity.

Phase I study of temozolomide in paediatric patients with advanced cancer. United Kingdom Children's Cancer Study Group.

A phase I study of temozolomide administered orally once a day, on 5 consecutive days, between 500 and 1200 mg m(-2) per 28-day cycle was performed. Children were stratified according to prior craniospinal irradiation or nitrosourea therapy. Sixteen of 20 patients who had not received prior craniospinal irradiation or nitrosourea therapy were evaluable.

Spinal cord compression--do we miss it?

Four children with spinal cord compression due to malignant tumours are presented. The severity of the condition was not initially recognized by parents, or the nature of the likely cause by the initial physicians. Lower limb asymmetrical weakness, clear-cut sensory levels, and marked pain indicate need for urgent imaging and exclusion of a space occupying lesion.