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H McDowell

Publications and source records attributed to H McDowell.

At least 19 recordsLinked to original sources
PubMed2001

Detection of the PAX3-FKHR fusion gene in paediatric rhabdomyosarcoma: a reproducible predictor of outcome?

Rhabdomyosarcoma has 2 major histological subtypes, embryonal and alveolar. Alveolar histology is associated with the fusion genes PAX3-FKHR and PAX7-FKHR. Definition of alveolar has been complicated by changes in terminology and subjectivity. It is currently unclear whether adverse clinical behaviour is better predicted by the presence of these fusion genes or by alveolar histology. We have determined the presence of the PAX3/7-FKHR fusion genes in 91 primary rhabdomyosarcoma tumours using a combination of classical cytogenetics, FISH and RT-PCR, with a view to determining the clinical characteristics of tumours with and without the characteristic translocations. There were 37 patients with t(2;13)/PAX3-FKHR, 8 with t(1;13) PAX7-FKHR and 46 with neither translocation. One or other of the characteristic translocations was found in 31/38 (82%) of alveolar cases. Univariate survival analysis revealed the presence of the translocation t(2;13)/PAX3-FKHR to be an adverse prognostic factor. With the difficulties in morphological diagnosis of alveolar rhabdomyosarcoma on increasingly used small needle biopsy specimens, these data suggest that molecular analysis for PAX3-FKHR will be a clinically useful tool in treatment stratification in the future. This hypothesis requires testing in a prospective study. Variant t(1;13)/PAX7-FKHR appears biologically different, occurring in younger patients with more localised disease.

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↗
PubMed2001

Ovarian adenocarcinoma in premenarchal girls.

Ovarian neoplasms are unusual in the paediatric age group; the majority of them are of germ cell origin. Malignant epithelial tumours of the ovary occur infrequently in adolescent girls. Ovarian carcinoma in particular is extremely rare before puberty. The authors describe 3 cases of adenocarcinoma of the ovary in premenarchal girls and highlight the unique characteristics of this tumour in this age group.

Adenocarcinoma↗
PubMed1999

Agriculture sector resource and environmental policy analysis: an economic and biophysical approach.

Agricultural pollution of the environment is jointly determined by economic decisions driving land use, production practices, and stochastic biophysical processes associated with agricultural production, land and climate characteristics. It follows that environmental and economic statistics, traditionally collected independently of each other, offer little insight into non-point pollutant loadings. We argue that effective policy development would be facilitated by integrating environmental and economic data gathering, combined with simulation modelling linking economic and biophysical components. Integrated data collection links economics, land use, production methods and environmental loadings. An integrated economic/biophysical modelling framework facilitates policy analysis because monetary incentives to reduce pollution can be evaluated in the context of market costs and returns that influence land use and production activity. This allows prediction of environmental and economic outcomes from alternative policies to solve environmental problems. We highlight steps taken to merge economic and biophysical modelling for policy analysis within the Economic Research Service of the United States Department of Agriculture. An example analysis of a policy to reduce agricultural nitrogen pollution is presented, with the economic and environmental results illustrating the value of linked economic and biophysical analysis.

Agriculture↗
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

Predicting the effect of carotid artery occlusion during carotid endarterectomy: comparing transcranial doppler measurements and cerebral angiography.

BACKGROUND AND PURPOSE: We correlated the mean transcranial Doppler blood flow velocity (FVm) during carotid endarterectomy with the functional collateral pathway(s) documented by angiography. METHODS: Three patient groups were established: group 1 was dependent on the anterior communicating artery, group 2 on the anterior communicating artery and ipsilateral posterior communicating artery, and group 3 on the ipsilateral posterior communicating artery. Continuous middle cerebral artery FVm and electroencephalographic monitoring were performed in 45 patients during carotid endarterectomy. RESULTS: Clamped FVm was lowest in group 3 at 17+/-9 cm/s versus 36+/-16 and 33+/-11 cm/s for groups 1 and 2 (P<0.01). FVm values in groups 1 and 2 were similar. There was significant cerebral arterial vasodilation in group 3 patients on the basis of a pulsatility index of 0.38+/-0.15. The maximum FVm after clamp release was similar among the 3 groups. Normalized blood flow velocity 1 minute before release of the clamp was increased from the minimum flow velocity after clamping only in group 1 and 2 patients. CONCLUSIONS: The ipsilateral posterior communicating artery is a minor collateral pathway during acute carotid occlusion that contributes little to the collateral flow if there is a functional anterior communicating artery. Collateral flow through the middle cerebral artery is not recruited during occlusion in group 3 patients. The reperfusion FVm transient is independent of the primary collateral pathway. Documentation of functional collateral pathways on the basis of Doppler or angiographic examination may be advantageous in future studies since it can provide the basis for comparison among studies.

Arterial Occlusive Diseases↗
PubMed1998

Endometroid adenocarcinoma of the cervix in a 9-year-old girl.

We present the first reported case of endometroid adenocarcinoma of the uterine cervix in a young girl. The differential diagnosis of a vaginal mass in this age group is usually rhabdomyosarcoma, although other, rarer tumours also occur.

Adenocarcinoma↗
PubMed1998

[Oncogenic factors of metastatic dissemination in neuroblastoma].

Disseminated neuroblastoma frequently show a very poor prognosis. N-myc gene amplification, 1p deletion and lack of CD44 gene expression, are all genetic factors associated with the disease's dissemination. Human neuroblastoma xenografts in nude mice has permitted to characterize, in disseminated neuroblasts, oncogenes overexpression, inactivation of tumor suppressor genes as well as detoxifying genes activation which contributes to increase cellular resistance to chemotherapy. These genetic abnormalities permit to propose a nosology of this very aggressive pediatric solid tumor. Hopefully, this genetic classification could be of great value for new therapeutic approaches.

Animals↗
PubMed1997

Immunohistochemical detection of p140trkA and p75LNGFR neurotrophin receptors in neuroblastoma.

In neuroblastoma, high levels of mRNA for p140trkA and p75LNGFR neurotrophin receptors are predictive of favorable outcome. Their evaluation by Northern blot, however, requires substantial amounts of tissue and this prevents their routine evaluation as well as the possibility for multicenter studies to be easily carried out. In an attempt to overcome these limitations, the feasibility and reliability of determining both neurotrophin receptors on cryostat sections by immunohistochemistry were assessed, and these findings were compared to those obtained from Northern blot analysis. Primary tumor samples from 28 untreated patients at all stages were evaluated by using H10 anti-p140trkA and ME20.4 anti-p75LNGFR mAbs. Although weak, positive immunostaining was found in 9 of 28 tumors for p140trkA and in 5 of 28 tumors for p75LNGFR. As compared to Northern blot, the concordance rate was 79% (22 of 28 cases) for p140trkA (p < 0.05) and 71% (20 of 28 cases) for p75LNGFR (p < 0.05). No case negative for Northern blot was found to be positive with immunohistochemistry. Since only high mRNA levels for both receptors have been shown to be clinically relevant, their immunohistochemical detection, although less sensitive than Northern blot, can be just as sufficient and reliable as a prognostic tool, and possibly with a better cost-benefit ratio.

Antibodies, Monoclonal↗
PubMed1995

Immunohistochemical detection of high-affinity nerve growth factor receptor in neuroblastoma.

High levels of mRNA (as assessed by northern blot) for the high-affinity nerve growth factor receptor (p140TRK) are predictive of favourable outcome in neuroblastoma. The feasibility of determining p140trk on frozen sections using a recently developed monoclonal antibody was evaluated, and immunohistochemical findings were compared to those obtained from northern blot analysis. Primary tumour samples from 28 untreated patients were quick frozen and an indirect immunofluorescence assay was performed on 4-microns acetone-fixed cryostat sections. 9 cases were positive with immunohistochemistry, and these were among the 15 cases also positive by northern blot. None of the cases negative by northern blot were positive with immunohistochemistry. The concordance rate was 79% (P < 0.03), with a sensitivity of 60% and a specificity of 100%. Immunohistochemistry can thus be rather reliable for assessing p140trk expression, even when only very small amounts of tissue are available, such as with needle biopsy.

Biomarkers, Tumor↗
PubMed1995

Vaginal rhabdomyosarcoma in a patient with Noonan syndrome.

This is the first report of a Noonan syndrome patient who has had a vaginal rhabdomyosarcoma. Recent reports of Noonan syndrome patients with leukaemia have prompted speculation that there may be a slightly increased malignancy risk associated with this syndrome.

DNA Mutational Analysis↗
PubMed1992

Readmissions to a geriatric medical unit: is prevention possible?

Of the 622 patients admitted to a geriatric medical unit during the period November 1985 to October 1986, 211 (33.9%) had been discharged from hospital within the previous year. Of these, 117 (55.5%) had previously been admitted to the geriatric medical unit (18.8% of all admissions). The reasons for readmission were deterioration of existing disease (47.4%), new medical events (33.2%), poor management of previous discharge (9.5%), and social problems (5.7%). Age was not a significant factor influencing readmission. Readmission was judged preventable by better management of the previous admission and discharge in only 33 cases (15.6% of readmissions). A prospective study of the patients discharged in the same year revealed that 19.3% were readmitted in the following year, and of these readmissions 2.3% were considered to be preventable. There was no difference in medical causes for readmission in the two years. A significant number of the patients readmitted in both years studied was categorized as "high dependency". The figures suggest that although unplanned readmission is common, it is generally not preventable by better management of the previous admission, and often reflects a highly dependent and medically frail group of patients, in whom early intervention with readmission is appropriate.

Aged↗
PubMed1991

Long-term follow-up of ifosfamide renal toxicity in children treated for malignant mesenchymal tumors: an International Society of Pediatric Oncology report.

The renal function of 74 children with malignant mesenchymal tumors in complete remission and who have received the same ifosfamide chemotherapy protocol (International Society of Pediatric Oncology Malignant Mesenchymal Tumor Study 84 [SIOP MMT 84]) were studied 1 year after the completion of treatment. Total cumulative doses were 36 or 60 g/m2 of ifosfamide (six or 10 cycles of ifosfamide, vincristine, and dactinomycin [IVA]). None of them had received cisplatin chemotherapy. Ages ranged from 4 months to 17 years; 58 patients were males and 42 females. The most common primary tumor site was the head and neck. Renal function was investigated by measuring plasma and urinary electrolytes, glucosuria, proteinuria, aminoaciduria, urinary pH, osmolarity, creatinine clearance, phosphate tubular reabsorption, beta 2 microglobulinuria, and lysozymuria. Fifty-eight patients (78%) had normal renal tests, whereas 16 patients (22%) had renal abnormalities. Two subsets of patients were identified from this latter group: the first included four patients (5% of the total population) who developed major toxicity resulting in Fanconi's syndrome (TDFS); and the second group included five patients with elevated beta 2 microglobulinuria and low phosphate reabsorption. The remaining seven patients had isolated beta 2 microglobulinuria. Severe toxicity was correlated with the higher cumulative dose of 60 g/m2 of ifosfamide, a younger age (less than 2 1/2 years old), and a predominance of vesicoprostatic tumor involvement. This low percentage (5%) of TDFS must be evaluated with respect to the efficacy of ifosfamide in the treatment of mesenchymal tumors in children.

Acute Kidney Injury↗
PubMed1991

N-myc genomic content and DNA ploidy in stage IVS neuroblastoma.

DNA ploidy and N-myc genomic content were analyzed in a series of stage IVS neuroblastomas by flow cytometry and Southern blot hybridization, respectively. Of the 12 stage IVS neuroblastomas studied, nine were aneuploid (DNA index [DI] greater than 1), two were diploid (DI = 1), and one was not assessable for DNA content due to insufficient tumor material. N-myc gene amplification was present in two of 12 tumors. None of the aneuploid tumors exhibited N-myc amplification. Among the aneuploid neuroblastomas, the DIs were between 1.27 and 1.60, ie, in the near-triploid range. The follow-up from diagnosis ranged from 1 to 41 months (mean, 20 months). The nine neuroblastomas with near-triploid DNA content were free of disease at the end of the follow-up period. In contrast, a rapid and fatal tumor progression was observed for the three neuroblastomas with N-myc amplification and/or diploidy. Although involving only a limited series, these results strongly suggest that the combined analysis of DNA ploidy and N-myc genomic content could predict clinical outcome in stage IVS neuroblastoma and should help to identify patients for whom a more aggressive therapy is required.

Aneuploidy↗