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Biomedical subjects

G C Howard

Publications and source records attributed to G C Howard.

At least 19 recordsLinked to original sources
PubMed2000

Pilot studies on the p53 gene in nipple aspirate fluid from patients with breast cancer.

Nipple Aspirate Fluid (NAF) from patients with breast cancer is a potential source of exfoliated tumour material amenable to molecular biological study, but few such data have been reported. In this study we demonstrate that polymerase chain reaction (PCR) amplification of p53 gene DNA is achievable in a proportion of NAF samples from breast cancer patients. Subsequently four NAF samples from patients whose primary tumours were identified as having a defined p53 mutation were studied by single stranded conformational polymorphism analysis (SSCP). Two samples yielded PCR product indistinguishable from wild type and two yielded no product. Whilst no cancer-related genetic mutations were demonstrated in NAF samples, further study is warranted.

Adult↗
PubMed2000

p53 mutations as a marker of malignancy in bladder washing samples from patients with bladder cancer.

The diagnosis and follow-up of patients with bladder cancer rely on invasive procedures (cystoscopy with biopsy). Polymerase chain reaction (PCR)-based technologies may allow the sensitive detection of cancer-related genetic mutations in exfoliated tumour material, potentially allowing the development of less invasive techniques. This pilot study investigated the feasibility of detecting mutations in exons 5-8 of the p53 gene using single-stranded conformational polymorphism (SSCP) analysis in bladder-washing specimens from patients with bladder cancer. Bladder-washing samples (31) were collected from patients (27) with bladder cancer. An abnormal additional SSCP band was detected in five samples from five different patients suggesting the presence of a p53 mutation. In all five cases the same abnormal SSCP pattern was demonstrated in samples of the corresponding bladder tumour. In one case bladder washings were available from the same patient on two separate occasions with one washing demonstrating a mutation and the other not. In two further cases a mutation was demonstrated in the bladder tumour but not in the corresponding washing. It is concluded that it is possible to detect and characterize p53 mutations in bladder-washing samples from patients with bladder cancer. Improved sensitivity in detecting mutations in a sample containing a mixture of normal and malignant cells may lead to the clinical applicability of molecular methods of disease monitoring.

Carcinoma, Squamous Cell↗
PubMed1999

Imaging of the thorax in the management of germ cell testicular tumours.

AIM: To evaluate role of chest computed tomography (CTC) and chest radiography (CXR) in management of patients with testicular germ cell tumours (GCT). PATIENTS AND METHODS: An analysis was undertaken of staging and re-assessment CTC and CXR examinations performed on patients with GCT over a 4.5-year period. Data were obtained on clinical presentation, tumour histology, tumour marker levels and clinical course. Consensus review interpretation was combined with these data to obtain a 'standard of reference'. Sensitivity, specificity and predictive values were derived by comparison of original imaging reports to 'standard of reference'. RESULTS: Six hundred and twenty-three CTC examinations on 207 patients with GCT were included. Intrathoracic metastases were identified in 1% of seminoma patients compared with 20% of non-seminoma (NSGCT) patients. CTC was more accurate than CXR in the detection of intrathoracic metastases at 0.97, 0.96-0.98 (95% CI) compared with 0.91, 0.89-0.93. The agreement between imaging techniques and the standard of reference (determined by Kappa statistic) was respectively 0.96 for CTC and 0.65 for CXR. In GCT patients undergoing re-assessment with both CXR and CTC, CXR never detected unknown intrathoracic metastatic disease. Abdominopelvic lymphadenopathy was associated with intrathoracic metastases (P < 0.001), however re-assessment CTC did identify intrathoracic metastases in 27 cases without concurrent abdominopelvic disease. CXR was negative in 19 of these. CONCLUSION: Routine interval CXRs are unnecessary in NSGCT patients undergoing regular re-assessment CTC due to the low additional yield and limited effect on management. Re-assessment should still include CTC. In low risk, pure seminoma patients (abdominal CT and marker negative) re-assessment CTC can be safely avoided. Baseline CTC is advocated with CXR alone for re-assessment.

False Negative Reactions↗
PubMed1999

In pursuit of excellence for patients with cancer: the Scottish Cancer Therapy Network model.

The Scottish Cancer Therapy Network (SCTN) was created against a background of rising concerns about perceived variation in the quality of care available to patients with cancer. SCTN has established itself as a major organization with the necessary recognition and infrastructure to provide leadership, support and impetus in the field of clinical guidelines, clinical audit and clinical trials of cancer therapy in Scotland. Since being formed in 1993, SCTN has been instrumental in the development of three evidence-based, clinical guidelines and in the completion of detailed, national, retrospective audits of the treatment of five major tumour sites. The infrastructure has been used successfully to support and encourage trial participation. Challenges for the future are a re-orientation towards prospective audit, widening the constituency and sense of ownership of SCTN as a resource for practising clinicians, and further increasing recruitment into clinical trials.

Clinical Trials as Topic↗
PubMed1999

Testicular seminoma in a patient with ataxia-telangiectasia.

The case history of a 27-year-old man with ataxia-telangiectasia (AT) and testicular seminoma is reported. This is the first documented description of such a malignancy in AT, a syndrome associated with a markedly increased risk of malignant disease. Furthermore, alpha-foetoprotein levels have limitations as a tumour marker in this situation because serum levels may be elevated as a biochemical manifestation of AT.

Adult↗
PubMed1998

Sexual function following radical radiotherapy for bladder cancer.

BACKGROUND AND PURPOSE: The effect of radical radiotherapy (RT) for bladder cancer on sexual function has not been previously investigated. The current study was designed as a pilot to assess sexual function in males pre- and post-radiotherapy. MATERIALS AND METHODS: An anonymous questionnaire was devised to examine the following sexual domains: libido, frequency of sexual function, erectile capacity, orgasm and ejaculation in the 6 months prior to radiotherapy and following treatment. Serum testosterone, FSH and LH were measured in 10 patients. RESULTS: Eighteen patients completed the questionnaire from 10 to 56 months following irradiation, 13 of whom were able to achieve an erection prior to RT. Over half of these patients noted a decline in the quality of erections after RT, with a similar proportion noting decreased libido and frequency of sexual activity. Three patients lost the ability to have any erections whatsoever. Of the 10 patients retaining erectile capacity, three noted reduced frequency of early morning erections suggesting a physical aetiology, five had decreased frequency of ejaculation and four had reduced intensity of orgasms. Seventy-one percent (12/17) felt their sex life was worse following RT but only 56% (9/16) were concerned about the deterioration. Testosterone levels were normal in all but one patient. CONCLUSIONS: Radical RT to the bladder can cause a decrease in sexual function in males.

Aged↗
PubMed1997

The role of computed tomographic examination of the pelvis in the management of testicular germ cell tumours.

AIM: To clarify the role of pelvic CT in the imaging of patients with germ cell testicular tumours (GCTT). PATIENTS AND METHODS: A retrospective analysis was undertaken of all CT examinations performed on patients with GCTT at a regional oncological centre over a 3-year-period. Patient notes were reviewed and data on histology, tumour marker levels, therapy and clinical course obtained. The review interpretation was combined with the original radiological report and clinical data to arrive at a consensus result. RESULTS: Four hundred and forty-three examinations on 167 patients were included. One hundred and nineteen examinations (27%) demonstrated abdominal and/or pelvic lymph node enlargement. Nodal metastasis was entirely or predominantly ipsilateral in 73/77 examinations from left-sided primary tumours (95%) and 35/42 examinations from right-sided tumours (83%). Pelvic nodal enlargement was identified in 37 examinations from 16 patients. Thirteen of these sixteen patients possessed an identifiable risk factor for pelvic nodal metastasis; the remaining three had unequivocal nodal metastases in the abdomen. Combined abdominopelvic CT increased the effective dose equivalent (EDE) by 2.6 mSv (74%) compared with abdominal examination alone. Three hundred pelvic CT examinations were performed on 117 patients without risk factors for pelvic nodal metastasis. For this cohort the radiation burden from pelvic CT was 0.78 manSv, giving a risk of induction of a single fatal cancer of 3.9%. CONCLUSION: We advocate pelvic CT only at the time of staging, except in patients with a risk factor for pelvic nodal metastasis. Any unequivocal abdominal lymph node enlargement should be regarded as a risk factor. Implementation of this policy would safely reduce pelvic CT examinations in patients with testicular tumours by nearly 50%, with a consequent reduction in patient radiation exposures and a resource saving.

Humans↗
PubMed1997

Pain relief and quality of life following radiotherapy for bone metastases: a randomised trial of two fractionation schedules.

BACKGROUND: The optimum dose and fractionation schedule for the palliative irradiation of painful bone metastases is controversial. PURPOSE: To compare the efficacy, side-effects and effect on quality of life of two commonly used radiotherapy schedules in the management of painful bone metastases. MATERIALS AND METHODS: In a prospective trial, 280 patients were randomised to receive either a single 10 Gy treatment or a course of 22.5 Gy in five daily fractions for the relief of localised metastatic bone pain. RESULTS: Response rates have been calculated from 240 assessable treated sites of pain. The overall response rates were 83.7% (single treatment) and 89.2% (five fractions). The complete response rates were 38.8% (single treatment) and 42.3% (five fractions). The median duration of pain control was 13.5 weeks (single treatment) and 14.0 weeks (five fractions). None of these differences was statistically significant. There were no differences between the groups in the effect of treatment on a variety of quality of life parameters. CONCLUSIONS: It is concluded that a single 10 Gy treatment is as effective as a course of 22.5 Gy in five fractions in the management of painful bone metastases.

Bone Neoplasms↗
PubMed1997

Identification of genetic polymorphisms at the glutathione S-transferase Pi locus and association with susceptibility to bladder, testicular and prostate cancer.

Two variant glutathione S-transferase cDNAs have been described at the GSTP1 locus, which differ by a single base pair (A-G) substitution at nucleotide 313 of the GSTP1 cDNA. This results in an amino acid substitution which alters the function of the enzyme. In this study, a novel PCR assay has been developed which demonstrates that these two variant cDNAs represent distinct GSTP1 alleles (GSTP1a and GSTP1b). In a study of individuals with different forms of cancer, the GSTP1b allele is found to be strongly associated with bladder cancer and testicular cancer. In controls 6.5% of individuals were homozygous for the GSTP1b allele. In bladder cancer cases, this rose to 19.7% [n = 71, odds ratio 3.6 (1.4-9.2), P = 0.006] and in testicular cancer to 18.7% [n = 155, odds ratio 3.3 (1.5-7.7), P = 0.002]. In addition, in prostate cancer a highly significant decrease in the frequency of the GSTP1a homozygotes was observed [control 51.0% versus 27.8% cancer cases, n = 36, odds ratio 0.4 (0.02-3.3), P = 0.008]. Increases in the frequency of GSTP1b homozygotes was also observed in lung cancer and chronic obstructive pulmonary disease. However, these were not statistically significant. No change in breast or colon cancer allele frequencies was observed.

Aged↗
PubMed1996

Identification of residues in alpha-macroglobulins involved in activation of the alpha 2-macroglobulin signaling receptor.

Site-directed mutagenesis of residues in the receptor binding fragment of rat alpha 1-macroglobulin identify residues 1377 and 1378 (human numbering) as crucial for interaction with the alpha 2M signaling receptor on murine macrophages. Secondary structure prediction and signaling studies with the mutant proteins suggest the alpha 2M signaling receptor binding site involves part of a loop-helix-loop motif comprised of residues 1372-1378.

Amino Acid Sequence↗
PubMed1996

Characterization of alpha 2-macroglobulin binding to human trabecular meshwork cells: presence of the alpha 2-macroglobulin signaling receptor.

Direct binding of receptor-recognized alpha 2-macroglobulin (alpha 2M*) or a cloned receptor binding fragment from rat alpha 1-macroglobulin (RBF) to human trabecular meshwork cells demonstrated two classes of cell surface binding sites. One class has an apparent Kd of 5.0 nM and a receptor number of 31,800 receptors/cell. The other class has an apparent Kd of 20 pM and a receptor number of 1600 receptors/cell. Binding studies of alpha 2M* or RBF in the presence of a competitor for binding to low-density-lipoprotein receptor-related protein/alpha 2M* receptor (LRP/alpha 2MR) called receptor-associated protein (RAP) show that only the lower affinity class of binding sites is susceptible to competition with RAP. Uptake studies demonstrate specific internalization and degradation of alpha 2M* which is inhibitable by RAP. Exposure of the cells to alpha 2M* and RBF (40 nM) is associated with mean increases of 171 and 210%, respectively, in the intracellular calcium concentration, which is not inhibitable by RAP or pertussis toxin. These studies present the first characterization of alpha 2M* and RBF signaling in a primary human cell type and suggest a role for alpha 2M* in the physiology of the eye.

Aged↗
PubMed1996

Selective mutations in cloned and expressed alpha-macroglobulin receptor binding fragment alter binding to either the alpha2-macroglobulin signaling receptor or the low density lipoprotein receptor-related protein/alpha2-macroglobulin receptor.

alpha2-Macroglobulin (alpha2M) activated with methylamine binds to two distinct cell-surface receptors: low density-lipoprotein receptor-related protein/alpha2M receptors and alpha2M signaling receptors. Binding to lipoprotein receptor-related protein/alpha2M receptor but not alpha2M signal receptor is inhibitable by another ligand, receptor-associated protein. Direct binding studies with a recombinant receptor binding fragment (RBF) from rat alpha1M and murine macrophages demonstrate two classes of binding sites of apparent Kd = 90 pM (1500 sites/cell) and 40 nM (60,400 sites/cell). Receptor-associated protein competes with RBF for binding to the lower but not the higher affinity site. Site-directed mutation of Lys-1374 (human numbering) in RBF to Arg or Ile residues almost completely abolishes signal transduction as compared to wild-type RBF. Direct binding studies with K1374R demonstrated no significant alteration in binding to the lower affinity site; however, binding to the high affinity site is reduced by 83%. Mutation of Lys-1370 to Ala resulted in a 4-5-fold increase in the Kd for binding to the lower affinity site with no significant alteration in binding to the high affinity site or signal transduction properties. Studies demonstrate comparable internalization and degradation of wild-type RBF and K1374R; however, internalization and degradation of K1370A is negligible. These studies suggest that regions around Lys-1370 and Lys-1374 are involved in lipoprotein receptor-related protein/alpha2M receptor and alpha2M signaling receptor binding, respectively.

Amino Acid Sequence↗
PubMed1996

Altered interaction of Cis-dichlorodiammineplatinum(II)--modified alpha 2-macroglobulin (alpha 2M) with the low density lipoprotein receptor-related protein/alpha 2M receptor but not the alpha 2M signaling receptor.

Receptor-recognized forms of alpha 2-macroglobulin (alpha 2M*) bind to two macrophage receptors: an endocytic receptor, the low density lipoprotein receptor-related protein/alpha 2M receptor (LRP/alpha 2MR), and a G protein-coupled receptor, the alpha 2M signaling receptor (alpha 2MSR). Binding of alpha 2M* to LRP/alpha 2MR but not alpha 2MSR is inhibited by receptor-associated protein. We now present binding characteristics of alpha 2MSR (kD approximately 50 pm; 1,530 sites/cell) using Scatchard analysis. We also demonstrate that chemical modification of alpha 2M* with cis-dichlorodiammineplatinum (cis-DDP) does not significantly alter binding to either receptor or signaling characteristics as compared with unmodified alpha 2M*. However, internalization by LRP/alpha 2MR is greatly affected. Cis-DDP-modified alpha 2M* (cis-DDP-alpha 2M*) and alpha 2M* show comparable internalization during a single round of endocytosis; however, cis-DDP modification of alpha 2M* results in a > or = 82% reduction in internalization involving receptor recycling and multiple rounds of endocytosis. Results from pH 5.0 dissociation and receptor recycling experiments suggest that the mechanism of decreased internalization of cis-DDP-alpha 2M* involves poor dissociation from the receptor in endosomes and a decrease in available surface receptors over the time of exposure to the ligand.

Amino Acid Sequence↗
PubMed1996

Split course radical radiotherapy for bladder cancer in the elderly: nonsense or commonsense? A report of 76 patients.

The role of split course radical radiotherapy in bladder cancer is controversial. We have pursued such a policy in elderly patients in view of the unpredictable toxicity of radical radiotherapy in this group. Between 1987 and 1992, 76 patients were treated in this way, with 2 weeks' treatment followed by a 3-week gap. Patients were then reassessed and, if considered fit enough, a further 2 weeks of treatment was given. Fifty-three patients (mean age 78.4 years) completed treatment and 23 (mean age 78 years) received phase 1 alone. Thirty-seven of 53 patients completing treatment has a follow-up cystoscopy at 6 months. Twenty-five percent of all patients, 36% of those completing treatment, and 51% of those undergoing cystoscopy, achieved a complete response. The reasons for not completing treatment and not being followed up cystoscopically are examined. We feel that this policy has a role in selected patients whose fitness to tolerate a conventional radical course of radiotherapy is in doubt.

Aged↗
PubMed1995

Referral patterns within Scotland to specialist oncology centres for patients with testicular germ cell tumours. The Scottish Radiological Society and the Scottish Standing Committee of the Royal College of Radiologists.

Details of 1123 patients registered in Scotland between 1983 and 1990 for testicular cancer under the Scottish Cancer Registration Scheme were obtained and compared with registrations within the five Scottish oncology centres. Some registration discrepancies were identified. Twenty-eight cancer registrations (2.5%) were coded to the wrong site, 29 patients seen at oncology centres had no cancer registration and 14 cancer registrations had the wrong histology. Five hundred and twenty-seven patients with testicular non-seminomatous germ cell tumours (NSGCT) and 567 with testicular seminoma were identified. Referral rates to specialist oncology centres for testicular germ cell tumours were measured by period and health board area of residence. For the whole study period 92% of NSGCT and 93% of seminoma patients were referred to specialist centres for treatment. Referral rates for different health board areas of residence were not significantly different. This study shows that within Scotland the majority of patients with testicular NSGCT and seminoma are referred to specialist centres, and suggests referral rates of around 92% are underestimates. Access is not related to area of residence.

Cancer Care Facilities↗
PubMed1995

A Scottish national audit of current patterns of management for patients with testicular non-seminomatous germ-cell tumours. The Scottish Radiological Society and the Scottish Committee of the Royal College of Radiologists.

A detailed casenote review was performed on all 65 patients registered with testicular non-seminomatous germ cell tumours (NSGCT) during 1989 under the Scottish Cancer Registration Scheme. Details of management at presentation and 2 years following diagnosis were recorded and analysed. In a small number of patients an unacceptable delay in diagnosis was noted. Variation was found in the frequency and type of investigations performed on patients placed on surveillance, types of chemotherapy regimens used and numbers of patients entered into trials. Three per cent of patients had a biopsy of the contralateral testis and 27% of patients defaulted from clinic attendance. Considerable variation in the management of testicular NSGCT in Scotland has been identified. The introduction of management guidelines should result in a more consistent approach to the care of these patients. Support, both financial and psychological, may reduce the unacceptable rate of default.

Adolescent↗
PubMed1995

A Scottish national mortality study assessing cause of death, quality of and variation in management of patients with testicular non-seminomatous germ-cell tumours. The Scottish Radiological Society and the Scottish Standing Committee of the Royal College of Radiologists.

A detailed casenote review was performed on 55 patients registered with testicular non-seminomatous germ cell tumours (NSGCT) between 1983 and 1988 under the Scottish Cancer Registration Scheme and who had died by 1992. Details of all aspects of clinical management relating to their NSGCT and death details were extracted and summarised. An assessment was made on whether the patients' management had been optimal. An analysis of 5 year survival rates by the five Scottish oncology centres demonstrated significant differences between centres (range 70.4-94.2; chi 2 = 14.46, d.f. = 4, P = 0.006). Some patients in all centres were assessed as having received suboptimal treatment, but two centres performed less well than the other three. There is a suggestion that the number of patients treated suboptimally decreases with increasing number of patients seen, but this does not reach statistical significance.

Adolescent↗