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Biomedical subjects

C Brock

Publications and source records attributed to C Brock.

At least 19 recordsLinked to original sources
PubMed2006

The place of VEGF inhibition in the current management of renal cell carcinoma.

Vascular endothelial growth factor (VEGF) is overexpressed in around 80% of patients with clear cell carcinoma of the kidney owing to the inactivation of von Hippel Lindau gene activity. VEGF stimulates angiogenesis and acts as an autocrine growth factor. A number of different agents are now available which target VEGF and its signalling pathways. A significant body of evidence has accumulated demonstrating that antagonism of VEGF and its downstream pathways is clinically useful in a significant proportion of patients with metastatic clear cell carcinoma of the kidney. Enough data is now available to recommend that patients with metastatic clear cell carcinoma of the kidney should at some point during the course of their disease be offered entry into a clinical trial enabling exposure to a targeted inhibitor of VEGF or its signalling pathways. Assuming early clinical trial data is substantiated by ongoing registration studies, efforts should be made to minimise the time taken between licensing and general availability of these active agents.

Antibodies, Monoclonal↗
PubMed2004

Phase I and pharmacokinetic study of XR11576, an oral topoisomerase I and II inhibitor, administered on days 1-5 of a 3-weekly cycle in patients with advanced solid tumours.

XR11576 is an oral topoisomerase I and II inhibitor. The objectives of this phase I study were to assess the dose-limiting toxicities (DLTs), to determine the maximum tolerated dose (MTD) and to describe the pharmacokinetics (PKs) of XR11576 when administered orally on days 1-5 every 3 weeks to patients with advanced solid tumours. Patients were treated with escalating doses of XR11576 at doses ranging from 30 to 180 mg day(-1). For PK analysis, plasma sampling was performed during the first and second courses of treatment and XR11576 concentrations were assayed using a validated high-performance liquid chromatographic assay with mass spectrometric detection. In all, 21 patients received a total of 47 courses. The MTD was reached at 180 mg day(-1), with diarrhoea and fatigue as DLT. Nausea and vomiting, although not qualifying for DLT, was ubiquitous. Only in combination with an extensive prophylactic antiemetic regimen consisting of a combination of both dexamethasone and a 5HT3 antagonist was treatment with XR11576 at 120 mg day(-1) tolerable. The systemic exposure of XR11576 increased more than proportionally with increasing dose, with a large interpatient variability. No objective responses were seen; four patients experienced stable disease for periods of 12-30 weeks. In this study, the DLTs of XR11576 were diarrhoea and fatigue. The recommended dose for phase II studies of XR11576 is 120 mg administered orally, on days 1-5 every 21 days. Alternative regimens are currently being explored.

Administration, Oral↗
PubMed2003

Impact of naled on honey bee Apis mellifera L. survival and productivity: aerial ULV application using a flat-fan nozzle system.

A study was conducted to evaluate the impact of naled on honey bees as a result of their exposure to aerial ULV applications of this insecticide during three routine mosquito spray missions by Manatee County Mosquito Control District in Florida during the summer of 1999. Naled deposits were collected on filter paper and subsequently analyzed by gas chromatography. Mortality of adult honey bees Apis mellifera L. was estimated based on numbers from dead bee collectors placed in front of the entrance of the beehives. We found that honey bees clustering outside of the beehives were subject to naled exposure. Bee mortality increased when higher naled residues were found around the hives. The highest average naled deposit was 6,227 +/- 696 microg/m2 at the site 1 forest area following the mosquito spray mission on July 15, 1999. The range of naled deposition for this application was 2,818-7,101 microg/m2. The range of dead bees per hive was 0-39 prior to spraying and 9-200 within 24 h following this spray mission. The average yield of honey per hive was significantly lower (p < 0.05) for naled-exposed hives compared with unexposed hives. Because reduction of honey yield also may be affected by other factors, such as location of the hives relative to a food source and vigor of the queen bee, the final assessment of honey yield was complicated.

Agriculture↗
PubMed2002

Nephrotoxicity in survivors of Wilms' tumours in the North of England.

One aspect of concern for survivors of Wilms' tumour has been the late outcome in terms of renal function. Previous studies have documented low glomerular filtration rate and high blood pressure in some patients. Furthermore, disorders in tubular function (especially urinary concentration defects) have been suggested but not confirmed in small studies. The aim of this study was to determine the prevalence and nature of subclinical and overt glomerular, proximal and distal renal tubular toxicity in a population based cohort of survivors of Wilms' tumour. Forty patients (24 female) with a median age of 4.3 years (3 months-11.8 years) at diagnosis were studied. Median follow-up was 8.8 (range 0.06-27.5) years. Glomerular filtration rate was measured by (51)Cr-EDTA plasma clearance, proximal tubular function by electrolyte fractional excretions, urine excretion of low molecular weight proteins (retinol-binding protein) and renal tubular enzymes (alanine aminopeptidase; N-acetylglucosaminidase) and distal tubular function by the osmolality of the first two urines of the day on 3 consecutive days. Renal size (ultrasound) and blood pressure were also measured. Mean (range) glomerular filtration rate was 100 (61-150) ml min(-1) 1.73 m(-2). Nine were below the reference range for healthy individuals with two kidneys. Most serum electrolyte concentrations (sodium, potassium, chloride, calcium, magnesium and phosphate) fell within the normal range for age, as did the fractional excretions. The values that fell outside the normal range were only marginally abnormal. Subclinical measures of tubular toxicity (retinal-binding protein, alanine aminopeptidase, N-acetylglucosaminidase) were abnormal in only four patients. Thirty-seven patients achieved maximal urine osmolalities > or =800 mOsm kg(-1), but three failed to achieve this value even after DDAVP administration. Two patients had evidence of increased urinary albumin excretion. Compensatory renal hypertrophy was seen in all but two patients, but blood pressure was within normal limits in all patients. Current and past treatment for Wilms' tumour does not have any clinically important nephrotoxic effect in the majority of patients. This finding will enable paediatric oncologists to reassure patients and parents that treatment for Wilms' tumour rarely causes long-term renal impairment.

Age Factors↗
PubMed2000

NCCN Practice Guidelines for Cancer Pain.

The overall approach to pain management encompassed in these guidelines is comprehensive. It is based on objective pain assessments, utilizes both pharmacologic and nonpharmacologic interventions, and requires continual reevaluation of the patient. The NCCN Cancer Pain Practice Guidelines Panel believes that cancer pain can be well controlled in the vast majority of patients if the algorithms presented are systematically applied, carefully monitored, and tailored to the needs of the individual patient.

Acetaminophen↗
PubMed1999

Loss of chromosome 10 is an independent prognostic factor in high-grade gliomas.

Loss of heterozygosity (LOH) for chromosome 10 is the most frequent genetic abnormality observed in high-grade gliomas. We have used fluorescent microsatellite markers to examine a series of 83 patients, 34 with anaplastic astrocytoma (grade 3) and 49 with glioblastoma multiforme (grade 4), for LOH of chromosome 10. Genotype analysis revealed LOH for all informative chromosome 10 markers in 12 (35%) of patients with grade 3 and 29 (59%) grade 4 tumours respectively, while partial LOH was found in a further eight (24%) grade 3 and ten (20%) grade 4 tumours. Partial LOH, was confined to the long arm (10q) in six and the short arm (10p) in three cases, while alleles from both arms were lost in four cases. Five tumours (one grade 3 and four grade 4) showed heterogeneity with respect to loss at different loci. There was a correlation between any chromosome 10 loss and poorer performance status at presentation (chi2 P = 0.005) and with increasing age at diagnosis (Mann-Whitney U-test P = 0.034) but not with tumour grade (chi2 p= 0.051). A Cox multivariate model for survival duration identified age (proportional hazards (PH), P= 0.004), grade (PH, P= 0.012) and any loss of chromosome 10 (PH, P= 0.009) as the only independent prognostic variables. Specifically, LOH for chromosome 10 was able to identify a subgroup of patients with grade 3 tumours who had a significantly shorter survival time. We conclude that LOH for chromosome 10 is an independent, adverse prognostic variable in high-grade glioma.

Brain Neoplasms↗
PubMed1998

New synthetic non-peptide ligands for classical major histocompatibility complex class I molecules.

Poly-N-acylated amines, as a new class of synthetic non-peptide ligands for the murine major histocompatibility complex (MHC) class I molecule H-2Kb, were developed on the basis of the ovalbumin-derived peptide epitope SIINFEKL. Non-peptidic structural elements were introduced at the C-terminal part of the ligand and include the two dominant anchors at positions 5 and 8. Several oligomers and five different combinatorial libraries were synthesized and tested for their H-2Kb-binding capacities in an MHC stabilization assay. First, the optimal spacing and geometry of the side chains were determined using a series of oligomers with different main chain modifications. Then, based on the structure with the highest binding efficiency, randomized libraries were designed that contain 26 different aromatic, heteroaromatic, or pseudoaromatic side chains for the dominant anchor at position 5, which is deeply buried inside the MHC peptide-binding groove and is crucial for the conformational stability of the entire peptide-MHC complex. Similarly, a series of aliphatic side chains were tested for the second dominant anchor at position 8. MHC-binding and MHC-stabilizing oligomers with defined structures were derived from these libraries by deconvolution.

Amines↗
PubMed1998

The management of high-risk gestational trophoblastic tumours (GTT).

Between 1979 and 1995 we have treated 272 consecutive women with high-risk (GTT including 121 previously treated patients who were treated with the weekly EMA/CO (etoposide, methotrexate, actinomycin D alternating with cyclophosphamide and vincristine). The median follow-up is 4.5 years (range 1-16 years). The cumulative 5 year survival is 86.2% (95% confidence interval 81.9-90.5%). No deaths from GTT occurred later than 2 years after starting EMA/CO. In a multivariate analysis, adverse prognostic factors were the presence of liver metastases (p < 0.0001), interval from antecedent pregnancy > 24 months (p < 0.0001), brain metastases (p=0.0008) and term delivery of antecedent pregnancy (p=0.045). There were 11 (4%) early deaths while 213 (78%) achieved complete remission. 47 (17%) developed drug resistance to EMA/CO of whom 33 (70%) were salvaged by further cisplatinum based chemotherapy and surgery. 2 women developed acute myeloid leukaemia after treatment with EMA/CO. 56% of women who have been in remission for at least 2 years and had fertility conserving surgery have achieved pregnancy since completing EMA/CO and there have been 112 live births including 3 babies with congenital abnormalities. EMA/CO is an effective, easy to administer and well tolerated regimen for treating patient with high-risk GTT. More than half of these women will retain their fertility. However, there is a small but significant increase in second malignancies.

Adolescent↗
PubMed1997

POMB/ACE chemotherapy for mediastinal germ cell tumours.

Mediastinal germ cell tumours (MGCT) are rare and most published series reflect the experiences of individual institutions over many years. Since 1979, we have treated 16 men (12 non-seminomatous germ cell tumours and 4 seminomas) with newly diagnosed primary MGCT with POMB/ACE chemotherapy and elective surgical resection of residual masses. This approach yielded complete remissions in 15/16 (94%) patients. The median follow-up was 6.0 years and no relapses occurred more than 2 years after treatment. The 5 year overall survival in the non-seminomatous germ cell tumours (NSGCT) is 73% (95% confidence interval 43-90%). One patient with NSGCT developed drug-resistant disease and died without achieving remission and 2 patients died of relapsed disease. In addition, 4 patients with bulky and/or metastatic seminoma were treated with POMB/ACE. One died of treatment-related neutropenic sepsis in complete remission and one died of relapsed disease. Finally, 4 patients (2 NSGCT and 2 seminomas) referred at relapse were treated with POMB/ACE and one was successfully salvaged. The combination of POMB/ACE chemotherapy and surgery is effective management for MGCT producing high long-term survival rates.

Adolescent↗
PubMed1997

EMA/CO for high-risk gestational trophoblastic tumors: results from a cohort of 272 patients.

PURPOSE: To evaluate the results of etoposide, methotrexate, and dactinomycin alternating with cyclophosphamide and vincristine (EMA/CO) chemotherapy in women with high-risk gestational trophoblastic tumors (GTT) and to document the middle- and long-term toxicity of the regimen. PATIENTS AND METHODS: A total of 272 consecutive women with high-risk GTT, including 121 previously treated patients, were treated with weekly EMA/CO. The median follow-up duration is 4.5 years (range, 1 to 16). RESULTS: The cumulative 5-year survival rate is 86.2% (95% confidence interval, 81.9% to 90.5%). No deaths from GTT have occurred later than 2 years after the end [corrected] of EMA/CO. In a multivariate model, adverse prognostic factors were the presence of liver metastases (P < .0001), interval from antecedent pregnancy (P < .0001), brain metastases (P = .0008), and term delivery of antecedent pregnancy (P = .045). There were 11 (4%) early deaths, while 213 patients (78%) achieved a complete remission. Forty-seven (17%) developed drug resistance to EMA/CO, of whom 33 (70%) were salvaged by further cisplatin-based chemotherapy and surgery. Two women developed acute myeloid leukemia, two cervical malignancy, and one gastric adenocarcinoma after EMA/CO. More than half (56%) of the women who had fertility-conserving surgery and who have been in remission at least 2 years have become pregnant since the completion of EMA/CO, with 112 live births, including three infants with congenital abnormalities. CONCLUSION: EMA/CO is an effective and well-tolerated regimen for high-risk GTT. More than half of the women will retain their fertility; however, there is a small but significant risk of second malignancy.

Adolescent↗
PubMed1996

A weekly alternating chemotherapy regimen with low toxicity for the treatment of aggressive lymphoma.

A total of 50 consecutive adult patients with newly diagnosed aggressive non-Hodgkin's lymphoma were treated with a weekly alternating combination chemotherapy schedule, BEMOP/CA, including bleomycin, etoposide, methotrexate, vincristine, cyclophosphamide and Adriamycin. Two-thirds of the patients were over 60 years old or had stage 4 disease. Clinical remission was achieved in 56% of cases. The 3-year survival is 53% (95% confidence interval, 39-66%). The presence of B symptoms and a serum albumin value of <33 g/l at presentation were poor prognostic indicators for survival in a multivariate proportional-hazards model. Overall, the response rate and survival for this group of patients with intermediate- and high-grade lymphomas is similar to results previously reported. The BEMOP/CA treatment was brief (16 weeks) and associated with a low fatal toxicity (one early death and one late fatality from Pneumocystis pneumonia), and the drug costs are equivalent to those for eight cycles of CHOP.

Adolescent↗
PubMed1996

The Charing Cross Hospital experience with temozolomide in patients with gliomas.

Temozolomide, a new oral cytotoxic agent, was given to 75 patients with malignant gliomas. The schedule used was for the first course 150 mg/m2 per day for 5 days (i.e. total dose 750 mg/m2), escalating, if no significant myelosuppression was noted on day 22, to 200 mg/m2 per day for 5 days (i.e. total dose 1000 mg/m2) for subsequent courses at 4-week intervals. There were 27 patients with primary disease treated with two courses of temozolomide prior to their radiotherapy and 8 (30%) fulfilled the criteria for an objective response. There were 48 patients whose disease recurred after their initial surgery and radiotherapy and 12 (25%) fulfilled the criteria for an objective response. This gave an overall objective response rate of 20 (27%) out of 75 patients. Temozolomide was generally well tolerated, with little subjective toxicity and predictable myelosuppression. However, the responses induced with this schedule were of short duration and had relatively little impact on overall survival. In conclusion, temozolomide given in this schedule has activity against high grade glioma. However, studies evaluating chemotherapy in primary brain tumours should include a quality-of-life/performance status evaluation in addition to CT or MRI scanning assessment.

Adult↗
PubMed1996

Whole body protein metabolism in children with cancer.

Whole body protein synthesis and catabolism were measured using the [ring-2H5]phenylalanine and [1-13C]leucine primed constant infusion technique in 32 paediatric patients with cancer at different stages of treatment. Rates of synthesis (S) and catabolism (C) derived from the [ring-2H5]phenylalanine and [1-13C]leucine models were 4.7 (SD 1.3) (S) and 6.0 (1.5) (C) g/d/kg, and 5.5 (0.8) (S) and 6.8 (1.2) (C) g/d/kg, respectively. These results show that these two tracer techniques give similar results in this study population. Comparison of these values with results previously reported for groups of control children using the [ring-2H5]phenylalanine model (S = 3.69 and 3.93; C = 4.09 and 4.28 g/d/kg) and the [1-13C]leucine model (S = 4.32; C = 4.85 g/d/kg) show that rates of synthesis and catabolism were higher in cancer patients than in controls. Thus whole body protein turnover is increased in children under treatment for cancer. Other indices of metabolism such as plasma amino acids and intermediary metabolites were also measured and showed that, although subjects were in isotopic steady state, there were significant metabolic changes during the course of the primed constant infusions used to measure protein turnover.

Adolescent↗