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Biomedical subjects

L Lashford

Publications and source records attributed to L Lashford.

13 recordsLinked to original sources
PubMed2002

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. From the 34 whose natural history was known, almost all (n = 31) were symptomatic, with mean ages of presentation of 4.5 and 5.1 years for NF1 and sporadic cases respectively. The majority (n = 22) presented with visual impairment, seven of whom were blind in at least one eye. Sporadic cases were over twice as likely as NF1 to have visual impairment. Recurrence occurred in 12 patients. Fewer NF1 patients died as a direct result of their optic glioma, but overall mortality and 5 and 10 year survival rates between the two groups were similar. All five primary (non-metastatic) second central nervous system (CNS) tumours occurred in NF1 cases, two of these following radiotherapy. CONCLUSIONS: Symptomatic sporadic optic gliomas presented with impaired vision more frequently and were more aggressive than NF1 optic gliomas. Only optic glioma cases with NF1 were at risk of developing a second CNS tumour. Aggressive treatment of sporadic optic gliomas and early surveillance of NF1 optic gliomas may be required. The use of radiotherapy in these children requires further clarification.

Adolescent↗
PubMed2001

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. In the 6 patients treated at 768 mg/m(2)24 h(-1), dose-limiting oral mucositis and myelosuppression were observed. Plasma nolatrexed concentrations and systemic exposure, measured in 14 patients, were dose related, with mean AUC values of 36 mg(-1)ml(-1)min(-1), 50 mg ml(-1)min(-1)and 80 mg ml(-1)min(-1)at the 3 dose levels studied. Whereas no toxicity was encountered if the nolatrexed AUC was <45 mg ml(-1)min(-1), Grade 3 or 4 toxicity was observed with AUC values of >60 mg ml(-1)min(-1). Elevated plasma deoxyuridine levels, measured as a surrogate marker of thymidylate synthase inhibition, were seen at all of the dose levels studied. One patient with a spinal primitive neuroectodermal tumour had stable disease for 11 cycles of therapy, and in two patients with acute lymphoblastic leukaemia a short-lived 50% reduction in peripheral lymphoblast counts was observed. Nolatrexed can be safely administered to children with cancer, and there is evidence of therapeutic activity as well as antiproliferative toxicity. Phase II studies of nolatrexed in children at the maximum tolerated dose of 640 mg/m(2)24 h(-1)are warranted.

Acute Disease↗
PubMed1999

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 = 0.047) and this effect was more significant in the presence of the ATase inactivator O6-beG (3. 5-fold, P = 0.001). The polychromatic erythrocytes were also significantly protected against BCNU-induced clastogenicity both in the presence (P < 0.001) and absence of O6-beG (P < 0.05). The primitive, multipotent spleen colony-forming cells (CFU-S) in these animals also showed moderate (1.6-fold, P = 0.034) protection in the absence of O6-beG but in the presence of the inactivator they remained as sensitive to BCNU toxicity as those in the control animals (P = 0.133). This result contrasts with previous findings demonstrating significant hATPA/GA-mediated, O6-beG-resistant protection against the toxicity and clastogenicity of a number of O6-alkylating agents, including temozolomide, fotemustine and chlorozotocin. The possibility that our strategy for protective gene therapy may be highly agent and cell-type specific is unexpected and has possible implications for clinical trials of this approach using BCNU or related agents.

Animals↗
PubMed1998

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. Myelosuppression was dose limiting, with Common Toxicity Criteria (CTC) grade 4 thrombocytopenia occurring in one of six patients receiving 1000 mg m(-2) per cycle, and two of four patients treated at 1200 mg m(-2) per cycle. Therefore, the maximum-tolerated dose (MTD) was 1000 mg m(-2) per cycle. The MTD was not defined for children with prior craniospinal irradiation because of poor recruitment. Plasma pharmacokinetic analyses showed temozolomide to be rapidly absorbed and eliminated, with linear increases in peak plasma concentrations and systemic exposure with increasing dose. Responses (CR and PR) were seen in two out of five patients with high-grade astrocytomas, and one patient had stable disease. One of ten patients with diffuse intrinsic brain stem glioma achieved a long-term partial response, and a further two patients had stable disease. Therefore, the dose recommended for phase II studies in patients who have not received prior craniospinal irradiation or nitrosoureas is 1000 mg m(-2) per cycle. Further evaluation in diffuse intrinsic brain stem gliomas and other high-grade astrocytomas is warranted.

Adolescent↗
PubMed1998

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. In 1997 diagnosis of Guillain-Barré syndrome should not be made without careful prior spinal imaging.

Child, Preschool↗
PubMed1996

Phase I trials in paediatric oncology--the European perspective. The New Agents Group of the United Kingdom Childrens Cancer Study Group.

The current recommendations for Phase I trials should allow more confident interpretation of the toxicity and efficacy of new agents by providing a framework for multicentre and international co-operation. An overview of the aims and designs of Phase I trials is presented, along with a summary of current and recently published United Kingdom Childrens Cancer Study Group Phase I trials, and a discussion of some of the difficulties faced in the methodology and evaluation of Phase I studies in children.

Antineoplastic Agents↗
PubMed1989

Monoclonal antibodies as targeting agents for cytotoxic compounds in vivo: a current assessment.

Monoclonal antibodies have proved useful in the in vitro diagnosis of tumour type. Radiolabelled antibodies have also been investigated as targeting agents for the in vivo diagnosis of tumour metastasis. These studies have revealed the potential of using 'targeting agents' to identify tumours, but in addition have exposed some of the problems associated with the technique. This review describes our experiences using radiolabelled antibodies for the identification and treatment of tumours arising from the neuro-ectoderm. Based on a small number of 4 patients studies, we conclude that there are limitations on the use of radiolabelled antibodies for targeting isotopes to primary tumour masses. In addition, we outline a possible important role for antibodies in targeting therapeutic agents to minimal residual disease and diffuse tumours presenting as micro-metastasis.

Animals↗
PubMed1987

Therapeutic application of radiolabeled monoclonal antibody UJ13A in children with disseminated neuroblastoma.

Dosimetric data from UJ13A scanning studies using 131I are presented for children with stage IV neuroblastoma and primary brain tumor. The data demonstrate a large variation among patients in dose delivery to vulnerable organs and tumors. Against this background, a phase I toxicity study is under way with escalating amounts of conjugate administered to patients who have stage IV neuroblastoma. Major toxicity has been confined to bone marrow aplasia and necessitates bone marrow harvest prior to therapy. Specific problems encountered include altered kinetics during therapy following tracer studies and adequate dose delivery in large tumor masses.

Antibodies, Monoclonal↗
PubMed1986

Autologous bone marrow transplantation in paediatric solid tumours.

Massive therapy with ABMT is now an established treatment modality in paediatric oncology. The technical aspects and most treatment-related complications have been clarified and many phase II studies have shown encouraging results. In advanced neuroblastoma the poor outlook with conventional chemotherapy has stimulated extensive investigation of forms of massive therapy. Current results from several centres indicate that although the median survival is increased, long-term survival in an unselected group of stage IV patients is unlikely to exceed 30% with current regimens. In the future, management of this disease may involve the use of more intensive induction regimens to improve the quality of remission at the time of ABMT, which remains the single most important prognostic factor. Improved purging procedures involve the possible use of double massive therapy regimens and a combination of immunological and chemical treatments. In other paediatric tumours, the relative rarity and limited indications for ABMT make the evaluation of its role more difficult. Preliminary results in advanced rhabdomyosarcoma and Ewing's sarcoma are none the less encouraging and justify further investigation. The value of purging procedures remains controversial and their assessment has been hampered by the lack of sensitive clonogenic assays to detect residual tumour cells. However, neuroblastoma has provided a useful model for the investigation of physical, immunological and chemical procedures. Massive therapy is expensive, time consuming, and carries a high cost in patient morbidity and stress to the families involved. As with any new treatment, it must be adequately assessed in phase III, randomized studies. The ENSG and SIOP trials are a beginning and the future of massive therapy in the paediatric patient will, we hope, be based on a rigorous and scientific comparison with other treatment modalities.

Alkylating Agents↗
PubMed1986

131-I coupled to monoclonal antibodies as therapeutic agents for neuroectodermally derived tumors: fact or fiction?

It has been suggested that monoclonal antibodies may be useful in targeting cytotoxic compounds to tumor cells. We have explored their use in targeting 131-I to highly radiosensitive primitive neural tumors such as neuroblastoma and pineoblastomas. Two routes of administration have been employed, intravenous and intrathecal. Our current experience in using radiolabelled antibodies is described, indicating toxicities seen and any therapeutic benefit observed. The results of the study suggest that if targeted radiation has a role in the treatment of these malignancies, it will be restricted to the eradication of small tumor masses from the body.

Animals↗