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Biomedical subjects

M I Saunders

Publications and source records attributed to M I Saunders.

At least 55 records · Page 3Linked to original sources
PubMed1996

Effect of carbogen breathing on tumour microregional blood flow in humans.

BACKGROUND AND PURPOSE: Carbogen is currently being re-evaluated as a radiosensitiser. It acts primarily by increasing tissue pO2, although there is evidence to suggest that enhanced tumour blood flow may also be a component of its action. MATERIALS AND METHODS: Ten tumours in eight patients with advanced malignant disease were studied. Up to six microprobes, each with an estimated sampling volume of 10(-2) mm3, were inserted into the tumours. Ten min of baseline readings were taken prior to a 10 min carbogen (95% O2/5% CO2) breathing period, measurements were continued for a further 10 min. RESULTS: The results show that in 34 microregions analysed no overall change in tumour perfusion was seen with carbogen breathing. Individual tumour analysis demonstrated variation in response between patients to carbogen-after 6 min of carbogen four tumours showed an increase in blood flow by more than 10% of the pre-breathing value, two a decrease and four no change. The magnitude of change was small, with only two tumours fluctuating by more than 25%. CONCLUSIONS: These findings confirm the presence of transient fluctuations in microregional blood flow in human tumours but suggest that the radiosensitising action of carbogen lies primarily in its effect on increasing the oxygen capacity of blood. This supports the addition of agents such as nicotinamide with carbogen in order to overcome both diffusion and perfusion limited hypoxia.

Administration, Inhalation↗
PubMed1996

Randomised multicentre trials of CHART vs conventional radiotherapy in head and neck and non-small-cell lung cancer: an interim report. CHART Steering Committee.

While radiotherapy is proceeding, tumour cells may proliferate. The use of small individual doses reduces late morbidity. Continuous hyperfractionated accelerated radiation therapy (CHART), which reduces overall treatment from 6-7 weeks to 12 days and gives 36 small fractions, has now been tested in multicentre randomised controlled clinical trials. The trial in non-small-cell lung cancer included 563 patients and showed improvement in survival; 30% of the CHART patients were alive at 2 years compared with 20% in the control group (P = 0.006). In the 918 head and neck cases, there was only a small, non-significant improvement in the disease-free interval. In this interim analysis there was a trend for those with more advanced disease (T3 and T4) to show advantage; this will be subject to further analysis when the data are more mature. The early mucosal reactions appeared sooner and were more troublesome with CHART, however they quickly settled; so far no difference in long-term morbidity has emerged. These results support the hypothesis that tumour cell repopulation can occur during a conventional course of radiotherapy and be a cause of treatment failure.

Adult↗
PubMed1996

The effect of radiotherapy on urethral obstruction from carcinoma of the prostate.

OBJECTIVE: To assess the impact of radiotherapy on the relief of complete bladder outlet obstruction requiring catheterization secondary to prostatic carcinoma. PATIENTS AND METHODS: From a consecutive series of 151 patients treated with radiotherapy for localized carcinoma of the prostate, 19 (12.6%; median age 72 years, range 59-83) who had an indwelling catheter in situ at the time of irradiation because of urinary retention, were analysed retrospectively and grouped according to the stage and grade of tumour and the irradiation dose delivered. RESULTS: The catheter was removed following radiotherapy in all but two patients, who both had stage 4 tumours, and normal urinary function was restored. The grade and stage of tumour did not influence the duration of catheterization. The median time from completion of radiotherapy to catheter removal was 10 weeks (range 0-46). Recatheterization was required in two patients at 3 and 64 months after radiotherapy and three patients, including these two, required transurethral prostatectomy (TURP) to relieve outlet obstruction. CONCLUSION: Prostatic radiotherapy is effective in relieving bladder neck obstruction caused by prostate cancer. Most patients will achieve normal urinary function without requiring TURP after treatment.

Aged↗
PubMed1996

Time course from first symptom to treatment in patients with non-small cell lung cancer referred for radiotherapy: a report by the CHART Steering Committee.

BACKGROUND: Only a small proportion of patients with non-small cell lung cancer (NSCLC) attending radiotherapy centres were suitable for inclusion in a randomised trial which compared continuous hyperfractionated accelerated radiotherapy (CHART) with conventional radical radiotherapy. As this was thought to be partly due to delays in the referral of patients to clinical oncologists, a prospective study was performed to determine the interval between first report of symptoms and first radiotherapy treatment in patients with NSCLC. METHODS: The time course from first symptom to treatment was determined in all patients with NSCLC attending 10 cancer centres for radiotherapy to a primary tumour in a three month period. RESULTS: Only 5% of 484 patients were suitable for the trial of radical radiotherapy. The principal causes for exclusion were poor general condition (37%), too large a tumour (27%), and extrathoracic metastases (19%). The median time from first symptom to diagnosis was 13 weeks, from first symptom to first treatment 19 weeks, and from diagnosis to first treatment five weeks. In a quarter of the patients these intervals were greater than 25,33 weeks, and nine weeks, respectively. CONCLUSION: The reason for these long intervals needs investigation since earlier diagnosis and more immediate referral for consideration of treatment might increase the number of patients with NSCLC suitable for radical radiotherapy.

Aged↗
PubMed1996

Short communication: a technique for delivering carbogen with high dose rate intraluminal brachytherapy in carcinoma of the oesophagus; early results and toxicity.

A technique to deliver carbogen with high dose rate afterloading therapy to the oesophagus is described. Treatment is given using a standard high dose rate (HDR) afterloading catheter which is passed through the tumour-bearing area of the oesophagus within a nasogastric tube. In order to achieve a gas-tight seal, a standard "oxygen" mask used for delivery of carbogen is modified to incorporate the nasogastric tube allowing the treatment catheter to pass through the mask and be connected to the afterloading machine. The technique has proven to be feasible and well tolerated during treatment in four patients treated in this way. Severe acute radiation toxicity, possibly attributable to the carbogen, has been encountered in these patients receiving 1500 cGy at 1 cm via the HDR catheter after 4050 cGy in 27 fractions in 9 days using CHART external beam. Modifications to the radiation scheduling is recommended to enable carbogen to be incorporated in this way.

Brachytherapy↗
PubMed1996

Nicotinamide pharmacokinetics in normal volunteers and patients undergoing palliative radiotherapy.

The influence of nicotinamide formulation on absorption characteristics and incidence of adverse side-effects has been studied in normal volunteers and in patients undergoing radiotherapy. Escalating single or repeated oral doses of nicotinamide were administered in tablet or liquid form under fasting or non-fasting conditions. Drug absorption was slowed both by the presence of food in the stomach and by the administration of nicotinamide in tablet form compared with when it was dissolved in orange juice. Peak concentrations were generally slightly higher following the liquid preparation, but the incidence of adverse side-effects (chiefly nausea) was increased. A single dose of 9 g (88-97 mg/kg) nicotinamide in tablet form was well tolerated in two fasting normal volunteers, and in patients, doses of up to 133 mg/kg as tablets were tolerated twice/week for three weeks. Daily administration of 80 mg/kg nicotinamide was tolerated when given as tablets, but not in a liquid formulation. Neither the peak concentration nor the area under the concentration/time curve (AUC) of nicotinamide, nor the main metabolites of nicotinamide appeared to correlate with the incidence of toxicity.

Administration, Oral↗
PubMed1996

Direct comparison of bromodeoxyuridine and Ki-67 labelling indices in human tumours.

Direct comparison of bromodeoxyuridine (BrdUrd) and Ki-67 labelling indices was achieved by selecting similar areas from serial sections of human tumours. Fifteen patients were selected who had been administered BrdUrd in vivo and both proliferation markers were assessed by immunohistochemistry. The data show a good correlation between both BrdUrd LI and MIB-1 LI and Tpot (calculated using the flow cytometry derived duration of S phase) and MIB-1 LI. The contribution of BrdUrd LI to growth fraction varied as a function of proliferation characteristics. In tumours with a high LI, the number of DNA synthesizing cells represented half the growth fraction, whilst in tumours with lower LI's ( < 10%) the ratio of DNA precursor labelled cells as a function of growth fraction fell to between 10% and 20%. Tpot showed a linear correlation with MIB-1/BrdUrd ratio with a slope approaching unity. It was apparent that both intra- and interpatient variation in proliferation index was greater for BrdUrd labelling than for MIB-1 expression.

Antibody Specificity↗
PubMed1996

Microregional blood flow in murine and human tumours assessed using laser Doppler microprobes.

A multichannel laser Doppler system has been used to measure microregional fluctuations in perfusion in the HT29 human tumour xenograft and in patients with advanced malignant disease. A comparison is made with previously obtained data for the SaF, a transplantable murine tumour. The 300 microns diameter probes recorded fluctuations in erythrocyte flux in tumour microregions with an estimated volume of 10(-2) mm3. Of the 66 human tumour microregions sampled, 26% showed a change in erythrocyte flux by a factor of 2 or more over the 60 min measurement period, compared with 37% of HT29 and 48% of SaF microregions. In each of the studies more than 50% of changes were completed within 20 min, although slower changes were more common in the human tumours than in the experimental systems. Within the 1 h monitoring period at least 30% of the changes were reversed (human tumours 30%, HT29 45%, SaF 31%). These findings demonstrate that microregional changes in erythrocyte flux, consistent with transient, perfusion-driven changes in oxygenation, are a feature of human malignancies as well as experimental transplanted tumours.

Aged↗
PubMed1995

Administration of nicotinamide during chart: pharmacokinetics, dose escalation, and clinical toxicity.

PURPOSE: To determine nicotinamide pharmacokinetics in patients undergoing accelerated radiotherapy with the CHART regimen (continuous, hyperfractionated, accelerated radiotherapy) and given nicotinamide on a daily basis. The aim was to establish the pharmacokinetic profiles and their reproducibility during repeated administration, the maximum tolerated dose with fractionated radiotherapy, whether such a dose achieves sufficiently high plasma levels for radiosensitization, the optimal time interval between nicotinamide and irradiation, and toxic side effects. METHODS AND MATERIALS: Nicotinamide plasma concentrations were determined using high performance liquid chromatography in 11 patients with advanced carcinomas of the head and neck and rectum being treated with CHART (36 fractions in 12 days). Kinetic profiles on the first day of radiotherapy and residual 24-h values were obtained in 10 patients; in four of these, full profiles were repeated two or three times during the course of treatment. In one other, a single sample per day was taken four times over the 12-day period. Doses of 80, 90, or 100 mg/kg/day were given 90 min prior to the second radiotherapy fraction on each day. RESULTS: A dose of 80 mg/kg/day was well tolerated by all the patients. However, an increase of 10-25% in dose led to significant drug accumulation and major clinical toxicity, and none of the patients in the dose-escalation arm completed the planned regimen. Large interpatient variations in absolute peak concentrations were seen from 0.4 to 1.4 mumol/ml (mean 0.9 +/- 0.3; standard deviation (SD)). Of the five samples with the lowest peak levels, four were obtained from one patient. The time taken to peak concentration was also very variable from 0.8 to 4 h (mean 2.1 +/- 1.3 h; SD). In 70% of the samples, absolute plasma levels > or = 0.7 mumol/ml were reached within 1-2 h after administration and maintained for up to 6 h (mean 2.8 +/- 1.8 h; SD). There was a small but nonsignificant increase in the half-life of nicotinamide when the dose was increased from 80 to 90 or 100 mg/kg (7.1 h and 8.6 h, respectively). CONCLUSIONS: In an accelerated regimen such as CHART, 80 mg/kg/day of oral nicotinamide is feasible and clinically tolerated, giving no or few side effects, and a 2-h interval between its oral administration and radiotherapy should achieve effective plasma levels in most patients.

Aged↗
PubMed1995

Studies with bromodeoxyuridine in head and neck cancer and accelerated radiotherapy.

Using bromodeoxyuridine (BrdUrd), tumour cell proliferation was assessed, by flow cytometric (FCM) and immunohistochemical methods, in patients treated by the CHART regime of radiotherapy. Of 115 cases studied, data were complete in 90 using both methods. No cell kinetic-related parameter predicted the outcome of patients treated by CHART, in keeping with the view that, with this regime, cellular proliferation had been minimised as a cause of failure. Histological evaluation of the labelling index (LI) revealed a trend for higher LI is in diploid tumours (16.2%) than in aneuploid (13.8%), contrasting to that found by FCM (5.0 and 9.3% respectively). When the Tpot was calculated using a combination of histology LI and FCM TS, diploid tumours showed more rapid proliferation (Tpot 1.8 days) than aneuploid tumours (Tpot 3.2 days); this finding was significant (p < 0.02). A novel parameter, termed proliferation pattern, unique to these studies with BrdUrd in vivo, was assessed. Both proliferation pattern and histological grading had predictive power to discriminate the outcome in univariate analysis (p = < 0.031 and 0.037, respectively). In a Cox multivariate analysis, proliferation pattern was the more important predictor. The studies reported highlight the extra information that can be gained from combining immunohistochemistry with flow cytometry to study the cellular proliferation of human tumours.

Bromodeoxyuridine↗
PubMed1995

Where exactly does failure occur after radiation in head and neck cancer?

Loco-regional recurrence in squamous cell carcinoma of the head and neck can occur at the site of the original primary tumour or in the marginal zone at its periphery. While nodal recurrence may occur in previously involved nodes or in uninvolved nodes within or outside the treatment volume. The exact site of failure was determined in 89 patients treated with radical radiotherapy for carcinoma of the head and neck. Of 73 patients who failed at the primary site 71 (97%) did so within the site of the original tumour; only two patients developed a marginal recurrence. Of the 30 (93%) patients with N1-3 disease who later showed failure in the lymph nodes, 28 (93%) did so at their original site of disease. These results support the view that when radiation fails it usually does so in the centre of the tumour. In order to improve our results we need to deal with radioresistance at the site of mass disease. Ways of approaching this include the combination of surgery with radiotherapy, the addition of a sensitiser or an increase in the dose to the tumour mass by boosting a 'mini' volume using conformal techniques.

Adult↗
PubMed1995

Quality assurance in the CHART clinical trial.

As part of the clinical trial of CHART (continuous hyperfractionated accelerated radiotherapy) a quality assurance programme was included. The technical part of this--which is reported in this paper--is a series of tests designed to check all aspects of treatment planning and delivery. The results of visits to the 13 participating centres--and repeat visits to some of these centres--are discussed. The main areas tested were as follows. The linear accelerator: mechanical, and optical, scales and indicators; radiation field size; flatness and symmetry. DOSIMETRY: output; wedge factor; beam energy; phantom measurements against a plan calculated by the centre. SIMULATOR: mechanical, optical scales and indicators. The results show these centres work within the tolerances chosen for most parameters. Flatness, wedge factor and energy were areas of weakness in some centres. This must be partly the cause of the spread of phantom measurements which, after removal of variations in output, still range from -7 to +6% between calculated and measured values.

Bronchial Neoplasms↗
PubMed1995

Continuous hyperfractionated accelerated radiotherapy in the treatment of carcinoma of the columella and vestibule of the nose.

Twenty-one patients with squamous cell carcinoma of the nasal columella and vestibule were treated at the Mount Vernon Centre for Cancer Treatment between March 1986 and January 1994. Tumours ranged from 15 to 55 mm in maximum dimension (median 25 mm). All patients were treated with radical intent with continuous hyperfractionated accelerated radiotherapy (CHART). This group was analysed with respect to tumour control, tumour cell kinetics and radiation-induced morbidity at a median time to last follow-up of 40 months. Particular attention was paid to the detailed evaluation of late radiation changes. Patients who were still alive were assessed as to the satisfaction with the cosmesis of their treated nose. Four patients had relapse of disease either at the primary site alone (2), in neck nodes (1) or in both regions (1). One patient was successfully salvaged with surgery. Cell kinetic studies showed that cancers at this site may have potential for rapid cellular repopulation similar to cancers developing at other head and neck sites. CHART was well tolerated by patients. Late skin changes were remarkedly slight (despite full skin dose) and overall cosmesis excellent with this radiotherapy schedule.

Adult↗
PubMed1995

p53 status of head and neck cancer: relation to biological characteristics and outcome of radiotherapy.

p53 status was investigated in 99 patients with squamous cell carcinoma of the head and neck region uniformly treated with accelerated radiotherapy and in whom tumour cell proliferation and DNA aneuploidy were assessed using bromodeoxyuridine (BrdUrd) incorporation and flow cytometry (FCM). Seventy-six percent of tumours were immunohistochemically positive for p53 protein, but heterogeneity was noticed both in the percentage of cells positive for p53 and in their level of expression. However, tumours which were either essentially all positive or all negative or showed sporadic positivity for p53 protein showed no differences in their level of aneuploidy, proliferation rate, tissue organisation or outcome with radiotherapy. There was a trend for those p53-positive tumours with the strongest expression to have more DNA aneuploidy and deregulation of proliferation organisation than weaker expressors; but there were no differences in proliferation rate or outcome of radiotherapy. These studies suggest that p53 protein stabilisation as assessed by immunohistochemistry does not have any major relationship with the biological characteristics and outcome of squamous cell cancer treated by accelerated radiotherapy.

Aneuploidy↗
PubMed1995

Short communication: the addition of carbogen and nicotinamide to a palliative fractionation schedule for locally advanced breast cancer.

Tumour cell hypoxia is a recognized cause of resistance to radiotherapy. Using clinically relevant dose-fractionation schedules in a mouse tumour model, the addition of carbogen and nicotinamide to overcome chronic and acute hypoxia results in a marked increase in radioresponsiveness with a lower degree of sensitization in normal tissue. Carbogen and nicotinamide were added to the palliative radiation treatment given to six patients with locally advanced breast cancer. The aim of the pilot study was to determine if patients tolerated the addition of carbogen and nicotinamide and to assess if there was any increase in radiosensitivity of the skin. Patients received 30 Gy prescribed to the intersection dose in six fractions over 17/18 days with full skin bolus to the tumour. All patients were given 6 g of nicotinamide orally 90 min before radiation treatment. Carbogen breathing was started 5 min prior to treatment and continued during it. Patients tolerated the treatment well, with vomiting in one patient being the only side effect that could be related to the nicotinamide, and this settled with an anti-emetic. No increase in skin reaction was noted with the addition of carbogen and nicotinamide, and good tumour regression was achieved.

Aged↗
PubMed1994

Predictive testing of radiosensitivity in non-small cell carcinoma of the lung.

The paper reviews the prognostic factors which influence the radiosensitivity of non-small cell lung cancer. The clonogenic cell numbers, hypoxic fraction, tumour cell kinetics and inherent radiosensitivity are considered. In the future the measurement of these factors may play an important role in decision making as to the best management for patients with non-small cell lung cancer.

Carcinoma, Non-Small-Cell Lung↗