Search PubMed⌕ Search

Biomedical subjects

I J Lewis

Publications and source records attributed to I J Lewis.

At least 19 recordsLinked to original sources
PubMed2004

Establishing long-term survival and cure in young patients with Ewing's sarcoma.

This paper investigates the potential for long-term survivorship for young patients diagnosed with Ewing's sarcoma. Data are examined from two successive UKCCSG Ewing's Tumour studies (ET-1 and ET-2). Patients have been followed for up to 20 years. These studies had suggested that better 5-year survival with ET-2 over the earlier ET-1 was achieved by replacing cyclophosphamide by ifosfamide and increasing the dose of doxorubicin in a four-drug chemotherapy regimen. The updated hazard ratio, stratified for metastatic status at diagnosis, of 0.39 (95% confidence interval 0.12-0.61) confirmed the advantage of the ET-2 regimen in terms of overall survival. Cure models, based on the Weibull distribution, suggested that factors for long-term survival in addition to presence of metastases were age, primary site of tumour and study. Modelling identified the proportion cured with the ET-2 protocol as best at 70% in those who are under 10 years with a nonpelvic primary site and without metastatic disease. This contrasts to only 13% cure in those with the corresponding adverse prognostic indicators. Additionally, the risk of death remains greatest but relatively constant over the first 2 years postdiagnosis, and then declines to a lower but constant value for the next 3 years before reaching the 'cure plateau' at about 5 years. This investigation suggests that 'cure' is possible for patients with Ewing's sarcoma. This is established at approximately 5 years post diagnosis and the proportion cured depends on the presence of metastases, pelvic site and age at diagnosis.

Adolescent↗
PubMed2004

Diagnosing childhood cancer in primary care--a realistic expectation?

The burden of childhood cancer for Primary Care Trusts (PCTs) is unknown. PCTs in Yorkshire are representative of England and Wales and show little heterogeneity in the incidence rates of childhood cancer. Each PCT will expect three to five newly diagnosed children per year. A single GP is likely to see an incident case once every 20 years.

Adolescent↗
PubMed2003

Patterns of childhood cancer by ethnic group in Bradford, UK 1974-1997.

The highly urbanised northern English city of Bradford contains a diverse population from different ethnic backgrounds, including a high proportion of south Asians. We aimed to identify the effect of ethnic group on the incidence and temporal trends of childhood cancer in Bradford. Children (0-14 years) from the district of Bradford, who were diagnosed with a malignancy between 1974 and 1997, were selected from a population-based register. Each child was classified as south Asian (Indian, Pakistani and Bangladeshi), or not, based on their full name using 2 computer algorithms and individual inspection. Mid-year population estimates were used to calculate incidence rates and differences were assessed using Poisson regression. The study included 318 children, of whom 81 (25%) were south Asian. The incidence of all cancers in south Asian children (14.9 per 100,000 person years, 95% CI 11.6-18.2) was higher than non-south Asian children (12.0, 10.5-13.5) although not significantly so (P=0.14). Comparisons by diagnostic subgroup showed no major differences apart from significantly higher rates of acute myeloid leukaemia (AML) in south Asian children (1.9 versus 0.7, P=0.02). The age-specific incidence peaks of all childhood cancers and leukaemias were present in south Asian children aged 5-9 years compared with 0-4 years olds in the non-south Asian population. Non-significant increases of 1.4 and 1.5% in the average annual incidence of all cancers were seen for south Asians and non-south Asians respectively, with a significant rise for non-south Asians with leukaemia of 3.0% (P=0.04). Our timely study shows patterns of occurrence of childhood cancer that differ with respect to ethnic group. Differences are particularly apparent in the excess of AML and incidence peak in 5-9 year olds in south Asian children.

Adolescent↗
PubMed2003

A systematic review of molecular and biological markers in tumours of the Ewing's sarcoma family.

The aims of this study were to perform the first systematic review of molecular and biological tumour markers in tumours of the Ewing's sarcoma family (ESFT), and evaluate the current evidence for their clinical use. A well-defined, reproducible search strategy was used to identify the relevant literature from 1966 to February 2000. Papers were independently assessed for tumour markers used in the screening, diagnosis, prognosis or monitoring of patients with ESFT. Eighty-four papers studying the use of 70 different tumour markers in ESFT's were identified. Low-quality, inconsistent reporting limited meta-analysis to that of prognostic data for 28 markers. Patients with tumours lacking S-100 protein expression have a better overall survival (OS) (hazard ratio (HR)=0.41, 95% confidence interval (CI) 0.19, 0.89) than those with expression; patients with high levels of serum LDH had a worse OS and disease-free survival (DFS) (OS: HR=2.92, CI 2.16, 3.94, DFS: HR=3.38, 95% CI 2.28, 4.99); patients with localised disease and tumours expressing type 1 EWS-FLI1 fusion transcripts had an improved DFS compared with those with other fusion transcript types (HR=0.17, 95% CI 0.079, 0.37). The knowledge base formed should facilitate more informative future research. Improved statistical reporting and large, multicentre prospective studies are advocated.

Biomarkers, Tumor↗
PubMed2002

Long-term survival after spontaneous rupture of a malignant rhabdoid tumor of the liver.

A 13-month-old girl presented with a large malignant rhabdoid liver tumor that ruptured soon after admission. Six years after an emergency right hepatectomy and subsequent chemotherapy (ifosfamide, vincristine, and actinomycin D), she remains well and disease free. Previously, these rare tumors invariably have been fatal and resistant to multimodal therapy. This is the first report of long-term survival of a patient with a malignant rhabdoid liver tumor.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2001

Circulating neuroblastoma cells detected by reverse transcriptase polymerase chain reaction for tyrosine hydroxylase mRNA are an independent poor prognostic indicator in stage 4 neuroblastoma in children over 1 year.

PURPOSE: In this prospective, multicenter study, the independent prognostic power of neuroblastoma cells detected by reverse transcriptase polymerase chain reaction (RT-PCR) for tyrosine hydroxylase (TH) mRNA was evaluated. PATIENTS AND METHODS: The clinical significance of disease detected by RT-PCR in peripheral blood from children at diagnosis was compared with established prognostic markers [ie, age, lactate dehydrogenase (LDH), neuron-specific enolase, ferritin, and MYCN gene amplification] by multivariate analysis. The value of disease detection by RT-PCR during treatment and follow-up was also examined. RESULTS: TH mRNA was detected in peripheral blood from 33 of 49 (67%) children with stage 4 neuroblastoma > 1 year old at diagnosis and was a significant predictive factor for overall survival [hazard ratio (HR) = 2.40, 95% confidence interval (CI) 1.19 to 4.84, P =.014) and event-free survival (HR = 2.09, 95% CI 1.06 to 4.17, P =.034) in a multivariate analysis. Detection of disease in blood from clinically disease-free children was related to increased risk of death (HR 2.54, 95% CI 1.42 to 4.55, P =.0014). CONCLUSION: TH mRNA in peripheral blood of children with neuroblastoma is a poor prognostic indicator, reflecting the propensity for dissemination via the bloodstream. When combined with a serum LDH > 1500 IU/L, this is the most powerful poor prognostic model at diagnosis for children > 1 year old with stage 4 disease. The detection of TH mRNA in peripheral blood from clinically disease-free children is related to increased risk of relapse and death.

Age Factors↗
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↗
PubMed2001

Minimal residual disease at the time of peripheral blood stem cell harvest in patients with advanced neuroblastoma.

BACKGROUND: Despite treatment with high-dose myeloblative chemotherapy and peripheral blood stem cell (PBSC) rescue, a high proportion of children with neuroblastoma relapse and die. Re-infusion of PBSC contaminated with tumour at the time of autologous transplantation may play a significant role in this relapse. In this study the frequency of tumour contamination in PB from children with neuroblastoma has been investigated. PROCEDURE: Minimal residual disease was measured using RT-PCR for tyrosine hydroxylase (TH) mRNA in PBSCs from patients with advanced neuroblastoma. PBSCs from 18 patients in complete clinical remission were studied. RESULTS: Studies in other cancers have suggested minimal contamination of PBSCs with tumour cells; TH mRNA was detected by RT-PCR in 50% (9/18) of PBSC harvests. Seventy-seven percent (7/9) of patients with TH mRNA in PBSC died of disease compared to 44% (4/9) who were TH mRNA-negative. CONCLUSIONS: Therefore, the presence of TH mRNA in PBSCs appeared to be associated with an unfavourable outcome, although this was not statistically significant. In summary, RT-PCR for TH mRNA is a sensitive method for the identification of tumour cells in PBSC harvest. The presence of TH mRNA in PBSC harvest may reflect disease status and be associated with an unfavourable outcome, although long-term clinical outcome studies in a larger patient cohort are required.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2001

OPEC/OJEC for stage 4 neuroblastoma in children over 1 year of age.

BACKGROUND: This paper reports the toxicity of OPEC/OJEC chemotherapy in stage 4 neuroblastoma patients over 1 year of age. PROCEDURE: Ninety-five patients with stage 4 neuroblastoma received alternating courses of OPEC/OJEC--vincristine 1.5 mg/m2 (O), cisplatin 80 mg/m2 (P), etoposide 200 mg/m2 (E), cyclophosphamide 600 mg/m2 (C), and carboplatin 500 mg/m2 (J), every 21 days if there was haematological recovery. RESULTS: Seventy out of ninety-five (74%) patients completed seven or more courses and were evaluable for toxicity. Of these 70 patients, 33% had more than three episodes of fever and sepsis, 35% required more than five blood or platelet transfusions, 36% had grade 2 or more gastrointestinal toxicity and 9% had neurotoxicity. There was a median reduction in GFR of 32 ml/min/1.73 m2 (-46 to 134) and there was one toxic death. CONCLUSIONS: OPEC/OJEC is a well-tolerated therapy for stage 4 neuroblastoma over 1 year of age.

3-Iodobenzylguanidine↗
PubMed2001

Survival from adolescent cancer in Yorkshire, UK.

The aim of this study was to investigate survival rates for adolescents with cancer and identify factors associated with differential long-term prognosis in Yorkshire, UK. A survival analysis of a population-based cohort of young adults aged 15-24 years, diagnosed with a malignancy in the former Yorkshire Regional Health Authority between 1985 and 1994 was carried out. The main outcome was death from all causes. Overall survival for the 1097 adolescents with a malignancy increased by 30% between 1985-1989 and 1990-1994 (P=0.004). This improvement was reflected in most subgroups of cancer. Large scale geographical differences in survival rates were observed across Yorkshire, with an increased risk of death in North Yorkshire and Humberside of 34% and 45%, respectively, compared with West Yorkshire. Small scale analyses showed reduced survival in areas of high population density, but no consistent trends were associated with socio-economic status. Improved survival from all cancers in young adults over the last decade is clearly seen. Reasons for differential survival by geographical area are unclear and warrant further investigation.

Adolescent↗
PubMed2001

Mitral regurgitation after anthracycline treatment for childhood malignancy.

OBJECTIVE: To investigate the new onset of mitral regurgitation in patients with otherwise normal echocardiograms after anthracycline treatment and to assess its relation to other selected indicators of myocardial damage. DESIGN: Prospective echocardiographic and electrocardiographic study. SETTING: Tertiary paediatric cardiac referral centre. PATIENTS: 305 patients, aged 2-33 years (median 14 years), treated with cumulative anthracycline doses of between 150-450 mg/m(2) (median 180 mg/m(2)) for childhood malignancy. MAIN OUTCOME MEASURES: Colour flow Doppler detection of mitral regurgitation and its relation to changes in echocardiographic indices of left ventricular function (systolic and diastolic dimensions, fractional shortening) and to changes in the 12 lead ECG; and the prevalence of mitral regurgitation in the anthracycline treated patients in comparison with previously studied normal volunteers of similar age. RESULTS: 34 patients (11.6%) developed ultrasound detectable mitral regurgitation, which was not apparent clinically, during or after anthracycline treatment, compared with only 1.8% of a normal population of similar age (p < 0.0001). Nine of the 34 also developed non-specific T wave abnormalities. All 34 patients had normal systolic function at the time of initial detection of mitral regurgitation, but four later developed impaired left ventricular function (5, 11, 20, and 27 months after the first detection of mitral regurgitation). CONCLUSIONS: Mitral regurgitation occurs much more often in patients treated with anthracyclines than in the normal population. Echocardiographic detection of new mitral regurgitation with or without ECG abnormalities may be an early predictor of anthracycline cardiomyopathy.

Adolescent↗
PubMed2000

Received dose and dose-intensity of chemotherapy and outcome in nonmetastatic extremity osteosarcoma. European Osteosarcoma Intergroup.

PURPOSE: To examine the relationship between received dose, received dose-intensity (RDI), and survival in patients with osteosarcoma. PATIENTS AND METHODS: Between 1983 and 1993, the European Osteosarcoma Intergroup (EOI) conducted two randomized trials involving patients with high-grade, nonmetastatic, biopsy-proven osteosarcoma of the extremity. These trials shared a common treatment arm of doxorubicin (DOX) 75 mg/m(2) and cisplatin (CDDP) 100 mg/m(2) planned for six cycles at 3-week intervals. Definitive surgery was scheduled at week 9, after three cycles. Survival time was calculated from 122 days, the scheduled end of chemotherapy. RESULTS: A total of 287 patients randomized to DOX/CDDP received at least one cycle of chemotherapy, and 232 (81%) received all six cycles. On average, 79% of the intended dose of DOX and 80% of the intended dose of CDDP was given. Mean time to completion of chemotherapy was 1.27 times that specified by the protocol. Mean RDI was 0.64 for DOX (SD = 0.19) and 0.65 for CDDP (SD = 0.18). Progression-free survival was lower for those who received one to five cycles compared with those who completed all six cycles (hazards ratio, 1.69; 95% confidence interval, 1.03 to 2.78). Survival and progression-free survival were lowest for patients with RDI less than 0.6, although these differences were not statistically significant at the 5% level. There was no clear evidence of preoperative dose or dose-intensity influencing histologic response. CONCLUSION: This analysis did not establish a clear survival benefit for increasing received dose or dose-intensity in the context of this two-drug regimen. The hypothesis that increasing dose-intensity may improve survival in osteosarcoma requires prospective evaluation.

Adolescent↗
PubMed2000

Induction of cell death by basic fibroblast growth factor in Ewing's sarcoma.

Ewing's sarcoma is thought to arise after developmental arrest of primitive neural cells during embryogenesis. Because basic fibroblast growth factor (bFGF) has a critical role in the regulation of cell survival, proliferation, and differentiation during embryogenesis, we have tested the hypothesis that bFGF and FGF receptors may contribute to the development of Ewing's sarcoma and may provide a mechanism for the modulation of their behavior. All four of the Ewing's sarcoma cell lines examined expressed bFGF and FGF receptors, which were detected by immunofluorescence and Western blotting. bFGF-induced a significant dose-dependent decrease in Ewing's sarcoma cell proliferation on plastic and reduced anchorage-independent growth in soft agar. Unexpectedly, this decrease in cell number reflected bFGF-induced apoptosis and necrosis, as demonstrated by electron microscopy, binding of annexin V, and staining with acridine orange. Induction of cell death was dependent on dosage of, and period of exposure to, bFGF. bFGF did not induce differentiation of Ewing's sarcoma cells in either the presence or the absence of serum or nerve growth factor. Treatment of NuNu mice with bFGF decreased growth of the highly tumorigenic Ewing's sarcoma cell lines. Histologically tumors grown in the NuNu mice treated with bFGF were less cellular than those in control mice, and showed an increased level of apoptotic nuclei. This is in contrast to the mitogenic effect bFGF has in most other cancer cells. In summary, bFGF decreases Ewing's sarcoma growth in vitro and in vivo by the induction of cell death. This novel observation may provide a new therapeutic strategy for Ewing's sarcomas.

Animals↗
PubMed2000

Ethnic group and survival from childhood cancer: report from the UK Children's Cancer Study Group.

Survival following cancer was analysed in relation to ethnic group among children diagnosed in Britain during 1981-1996 and treated at paediatric oncology centres by members of the UK Children's Cancer Study Group. Survival was analysed for 11 diagnostic groups: acute lymphoblastic leukaemia (ALL), acute non-lymphocytic leukaemia, Hodgkin's disease, non-Hodgkin's lymphoma, astrocytoma, primitive neuroectodermal tumour, neuroblastoma, Wilms' tumour, osteosarcoma, Ewing's sarcoma and rhabdomyosarcoma. There were no significant differences in survival between White and non-White children over the study period as a whole. Among children with ALL, however, the relative risk of death allowing for period of diagnosis, age and white blood count was 1.25 for those of South Asian ethnic origin compared with Whites (P = 0.057).

Adolescent↗
PubMed1999

A combined cytogenetic and molecular approach to diagnosis in a case of desmoplastic small round cell tumor with a complex translocation (11;22;21).

Desmoplastic small round cell tumor (DSRCT) has recently been described as a discrete tumor entity. It is distinguished from other small round cell tumors by its prominent desmoplastic quality, its preponderance in adolescent males, its almost exclusive intraabdominal location, a multi-immunophenotypic profile, and its aggressive nature. Diagnosis on histology alone is not always unequivocal. A recurrent t(11;22)(p13;q12) translocation has recently been described in this tumor, and a chimeric RNA fusion product formed from the WT1 and EWS genes is detectable by reverse transcriptase-polymerase chain reaction (RT-PCR). We describe the use of a multi-faceted approach using conventional G-banding, fluorescence in situ hybridization (FISH) and RT-PCR to assist the diagnosis of a case of DSRCT with a complex variant t(11;22;21)(p13;q12;q22.1) translocation and demonstrate the value of a combined approach to genetic investigation of solid tumors.

Abdominal Neoplasms↗
PubMed1999

Survival from childhood cancer in Yorkshire, U.K.: effect of ethnicity and socio-economic status.

The effect of ethnicity and socio-economic status on the survival of a population-based cohort of 1979 children diagnosed with cancer between 1974 and 1995 was investigated. Ethnicity was assigned by computer algorithms and visual inspection as south Asian (or not) for each child, based on their full name. Socio-economic status was measured using the Carstairs index, based on census areas of case residence at diagnosis. 15 children (0.8%) were lost to follow-up. Log-rank tests showed survival from all cancers did not differ between south Asians and other children and no increased risk was observed for south Asians in any diagnostic category, although numbers were small. Increasing levels of deprivation were associated with significant trends of poorer survival from all cancers, leukaemias and brain tumours. Risk of death was typically higher for children from the most deprived areas although differences were not statistically significant after accounting for other factors including ethnicity. Taking all children with malignant disease together, neither ethnicity nor socio-economic status appear to influence survival after taking other factors into consideration.

Adolescent↗