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Biomedical subjects

J Overgaard

Publications and source records attributed to J Overgaard.

At least 109 records · Page 6Linked to original sources
PubMed1996

Pretreatment oxygenation predicts radiation response in advanced squamous cell carcinoma of the head and neck.

BACKGROUND AND PURPOSE: Hypoxic tumor cells are known to be relatively radioresistant. The aim of the study was to correlate oxygenation status and radiation response in advanced squamous cell carcinomas of head and neck. METHODS AND PATIENTS: Pretreatment oxygenation status was measured in 34 lymph nodes and one primary tumor neck using oxygen electrodes. The primary oxygenation endpoint was the fraction of pO2 values less than 2.5 mmHg. Patients received standardized, conventional, external radiotherapy 66-68 Gy in 33-34 fractions. RESULTS: Sixteen patients had loco-regional failure. Among these 16 patients the median of the fraction of pO2 values less than 2.5 mmHg was 22% (range 0-95%) as compared to 6% (range 0-51%) among patients with loco-regional tumor control. When separating all 35 patients by the median of the fraction of pO2 values less than 2.5 mmHg and comparing the 2 years actuarial tumor control probability using Kaplan-Meier estimates, the most hypoxic subgroup had significantly lower loco-regional tumor control (P = 0.013, Logrank test). By univariate regression analysis the fraction of pO2 values less than 2.5 mmHg was found to be significant as continuous variable (P = 0.010). Finally, by Cox multiple regression analysis the fraction of pO2 values less than 2.5 mmHg was found to be the strongest independent variable in predicting radiation response when using tumor control in the site of pO2 assessment as treatment endpoint (P = 0.018). CONCLUSION: These results suggest that pretreatment tumor oxygenation status is predictive of radiation response, when using the fraction of pO2 values less than 2.5 mmHg as endpoint.

Carcinoma, Squamous Cell↗
PubMed1996

Modification of Hypoxia-Induced Radioresistance in Tumors by the Use of Oxygen and Sensitizers.

It is now well established that most animal solid tumors contain oxygen-deficient hypoxic cells and that these cells will influence the response of those tumors to radiation. Identifying hypoxic cells in human tumors has proven more difficult, primarily because most of the direct procedures used in animals are not applicable to humans. However, substantial indirect evidence, which goes back to as early as 1909, clearly indicates the presence of hypoxia in human tumors, although with a considerable heterogeneity among individual tumors. Experimental studies during the last 30 years have shown that this source of radiation resistance can be effectively eliminated by a variety of procedures that include high oxygen-content gas breathing, nitrometric radiation sensitizers, blood transfusions, hemoglobin-oxygen affinity modifiers, and nicotinamide. A number of these procedures have also been tested clinically such that by 1995 over 10,000 patients in 83 randomized trials had undergone treatment designed to modify tumor hypoxia before radiation therapy. Although a number of these trials showed no benefit, an overview analysis showed that modification of tumor hypoxia significantly improved the locoregional tumor control after radiotherapy with an odds ratio of 1.21 (95% confidence interval 1.12-1.30). The treatment benefit could mostly be related to an improved response in head and neck with odds ratio 1.31 (1.19-1.43) and to a lesser extent in bladder tumors; no significant effect was observed in other tumor sites (cervix, lung and esophagus). Similar to the local control benefit, the overall survival rate improved with an overall odds ratio of 1.13 (1.05-1.21). The overall results thus showed that the biological issue related to hypoxia appears to be a sound rationale, which may impact the outcome of radiotherapy, especially with head and neck carcinoma. However, despite this wealth of positive data, "hypoxic modification" still has no impact on general clinical practice.

Journal Article↗
PubMed1996

A comparison of the physiological effects of RSU1069 and RB6145 in the SCCVII murine tumour.

The physiological and therapeutic effects of the bioreductive agent RSU1069 (80 mg/kg i.p.) and its prodrug RB6145 (240 mg/kg i.p.) were investigated in the SCCVII tumour. Using laser Doppler flowmetry it was found that RSU1069 produced a significant 30% reduction in tumour blood flow 30 min after administration, while RB6145 had no effect. Tumour oxygenation, measured with an Eppendorf oxygen electrode, was unchanged by either agent except for a reduction in values less than 2.5 mmHg at 30 min after injection. Neither agent significantly altered tumour energy metabolism, assessed by 31P magnetic resonance spectroscopy. Both agents significantly increased tumour glucose content by a factor of 1.6-1.7 at 30 min after injection, but had no effect on glucose-6-phosphate or lactate levels. Tumour growth was significantly delayed by heating (42.5 degrees C, 60 min), and although neither RSU1069 nor RB6145 alone had any effect on tumour growth they produced a similar enhancement of the tumour response to heat. The therapeutic effects are consistent with the known conversion in vivo of one third of the pro-drug RB6145 to its active product RSU1069, however the physiological effects of the two agents in the SCCVII tumour are not identical.

Animals↗
PubMed1996

Proliferative response of mouse spermatogonial stem cells after irradiation: a quantitative model analysis of experimental data.

The testes of CDF1 mice were irradiated with single doses of X-rays ranging from 2-16 Gy. The number of haploid cells in the testis at different times after irradiation (42-350 days) was determined by one-parameter flow cytometry both for irradiated animals and for age-matched controls. Based on literature data on the kinetics of the spermatogenesis in mice, a mathematical model of the (hierarchical) germ tissue was developed. Using this model, the processes of radiation-induced cell loss and subsequent recovery were simulated and free parameters of the model were estimated by fitting the model prediction to the experimental data. One of the aims of the study was to investigate the kinetic behaviour of spermatogonial stem cells and the corresponding control mechanisms. In order to fit the data, the model has to include the following features: (i) A preferential self-repopulation of spermatogonial stem cells following tissue injury. The model-estimated probability of a self-renewing division rises from 50% (the steady-state value) to 95% if the stem-cell population is reduced to 10% of its normal size. (ii) A relatively low, almost constant turnover rate of the stem-cell compartment. It is suggested by the analysis that less than 10% of the spermatogonial stem cells present in the testis divide per day, regardless of the degree of cellular depletion. (iii) A mechanism responsible for incomplete recovery. The observed incomplete recovery of spermatogenesis after single doses exceeding 10 Gy can be described quantitatively assuming that the stem cells are organized into discrete proliferative structures, the number of cells per structure being about 60.

Animals↗
PubMed1996

Growth of vestibular schwannomas: in situ model employing the monoclonal antibody Ki-67 and DNA flow cytometry.

Vestibular schwannoma (VS) growth potentials were studied in an in situ model, in which the cycling cellular fraction was determined immunohistochemically by applying the mouse monoclonal Ki-67 antibody, and the tumor ploidy was estimated by DNA flow cytometry in a consecutive series of 124 VSs. The tumors were classified according to the average number of positively stained nuclei in 10 high-power fields into three groups: 28 highly (> 10), 33 moderately (> 5-10) and 63 low proliferating (< or = 5). The intratumoral proliferative variation was studied in 10 tumors. Only slight variation in the number of the positively stained nuclei were observed. Six of seven tumors removed because of macroscopically documented growth by computed tomography (CAT) scan were moderately or highly proliferative. Proliferation of VS was correlated to prospectively registered clinical data. A statistically significant relation was found between VS proliferation and the prediagnostic duration of symptoms (p = 0.0001). The proliferative status was unrelated to age, sex, and tumor size. Flow-cytometric determination of DNA index of the 124 tumors revealed 12 tetraploid (DNA index = 2), 110 diploid (DNA) index = 1) and two nondiploid tumors. A statistically significant relation was noted between tumor ploidy and proliferation status expressed by Ki-67 (p = 0.024). The tetraploid tumors showed significantly lower proliferation compared with the diploid tumors. Tumor ploidy was statistically unrelated to age, sex, tumor size, and duration of symptoms. The results of this study provide a link between the immunohistochemical, flow cytometric findings, and clinical data, which could probably be relevant in identifying patients at risk for rapid tumor growth and tumor recurrences, because a rapid test for cell proliferation is now available.

Adult↗
PubMed1996

Effect of nitro-L-arginine on blood flow, oxygenation and the activity of hypoxic cell cytotoxins in murine tumours.

This study was an investigation into the ability of nitro-L-arginine to change blood flow, oxygenation status and the activity of hypoxic cell cytotoxic agents in two different transplanted murine tumours. The tumour models were the C3H mammary carcinoma grown in the feet of female CDF1 mice and the SaF grown on the backs of CBA mice. Treatments were carried out in restrained non-anaesthetised animals when tumours were about 100 to 200 mm3 in size. Blood flow was monitored using laser Doppler flowmetry; oxygen partial pressure (pO2) distributions were obtained with an Eppendorf oxygen electrode; and response to treatment with hyperthermia (43.5 degrees C; 30 min) and RB6145 (250 mg kg-1;i.p.) assessed using a tumour growth delay assay. Nitro-L-arginine (10 mg kg-1; i.v.) significantly reduced blood flow by around 40-60% within 15 min after injection in C3H tumour and by 30 min in the SaF. However, nitro-L-arginine had absolutely no effect on tumour pO2 measured at the time of maximal blood flow reduction in both tumour types. It also failed to enhance the response of the C3H tumour to heat, but did produce a small yet significant increase in the response of the SaF tumour to RB6145.

Animals↗
PubMed1996

Effect of hydralazine in spontaneous tumours assessed by oxygen electrodes and 31P-magnetic resonance spectroscopy.

Hydralazine can substantially decrease the blood flow, oxygen status and energy metabolism of transplanted tumours. In spontaneous tumours, two recent studies reported no effects of hydralazine on energy metabolism measured by 31P-magnetic resonance spectroscopy (31P-MRS), although another study saw changes in oxygen partial pressure (pO2) distributions measured with electrodes. We have now performed 31P-MRS and pO2 measurements in the same T138 spontaneous tumours, before and after intravenously (i.v.) injecting anaesthetised mice with 5 mg kg-1 hydralazine. Tumour pO2 was measured with an Eppendorf oxygen electrode and 31P-MRS spectra obtained with a 7-tesla SISCO magnet. Of 12 tumours all showed an increase in the percentage of pO2 values < or = 5 mmHg after hydralazine treatment and 10/12 showed a decrease in median pO2. The average (+/-1 s.e.) values for the percentage < or = 5 mmHg went from 45% (+/-9) to 79% (+/-5) and the median from 9 mmHg (+/-2) to 2 mmHg (+/-1). With the 31P-MRS 8/12 tumours showed an increase in the ratio of the peaks of inorganic phosphate to beta-nucleoside triphosphate with the average (+/-1 s.e.) values going from 1.1 (+/-0.2) to 2.4 (+/-0.9). Thus spontaneous tumours can respond to hydralazine and do so in a way consistent with that reported for transplanted tumours.

Animals↗
PubMed1996

Is there a radiobiologic basis for improving the treatment of advanced stage cervical cancer?

The success of radiotherapy in eradicating the primary tumor in patients with locally advanced cervical cancer is limited by normal tissue tolerance. Systematic recording of morbidity and treatment parameters is therefore very important for radiobiologic treatment optimization and clinical decision making. There is substantial evidence that fractionation schedules employing large doses per fraction lead to a loss of therapeutic ratio. A similar argument could be used for high-dose-rate (HDR) brachytherapy that should also be administered in small dose fractions. However, HDR brachytherapy might convey some advantage to physical dose distribution that should be weighed against the radiobiologic advantages of low-dose-rate (LDR) continuous irradiation. Increasing overall treatment time reduces local control probability, whereas a shorter overall treatment time by accelerated fractionation may improve the therapeutic ratio, at least in fast-growing tumors. Hypoxia and reduced oxygen delivery are associated with poor radiation response. Anemia should be compensated, if necessary. The role of hypoxic modification needs to be further explored. In the future, the therapeutic ratio may also be improved by the use of chemical and biologic response modifiers. Tumors are heterogeneous with respect to intrinsic radiosensitivity, proliferation parameters, and extent of hypoxia. Until a detailed prognostic profile can be obtained for each patient, optimal curative radiotherapy must aim for a sufficient dose, short overall treatment time, hypoxic modification, and LDR or low dose per fraction.

Brachytherapy↗
PubMed1995

Randomised trial of hyperthermia as adjuvant to radiotherapy for recurrent or metastatic malignant melanoma. European Society for Hyperthermic Oncology.

The value of hyperthermia as an adjuvant to radiotherapy in patients with malignant melanoma was studied in a European multicentre trial. 134 metastatic or recurrent lesions of malignant melanoma in 70 patients were randomly assigned to receive radiotherapy (three fractions of 8 Gy or 9 Gy in 8 days) alone or followed by hyperthermia (43 degrees C for 60 min). Overall, the 2-year actuarial local tumour control was 37 (SE 5)%. Univariate analysis showed a beneficial effect of hyperthermia (radiation alone 28% vs combined treatment 46%, p = 0.008) and radiation dose (24 Gy 25% vs 27 Gy 56%, p = 0.02), but no effect of tumour size (< or = 4 cm 42% vs > 4 cm 29%, p = 0.21). Cox multivariate regression analysis showed the most important prognostic variables to be hyperthermia (odds ratio for 2-year local control 1.73 [95% CI 1.07-2.78], p = 0.023), tumour size (0.91 [0.85-0.99], p = 0.05), and radiation dose (1.17 [1.01-1.36], p = 0.05). Addition of heat did not significantly increase acute or late radiation reactions. Heating was well tolerated, but because of difficulties with equipment only 14% of treatments achieved the protocol objective. The overall 5-year survival rate was 19%, but 38% of the patients for whom all known disease was controlled survived 5 years. Adjuvant hyperthermia significantly improved local tumour control when applied in association with radiation in treatment of malignant melanoma. Successful local treatment of patients with a single or a few metastatic malignant melanoma lesions has significant curative potential.

Adult↗
PubMed1995

Renal damage after total body irradiation in a mouse model for bone marrow transplantation: effect of radiation dose rate.

Late renal damage after total body irradiation (TBI) and bone marrow transplantation (BMT) is a recently recognised morbidity. We have tested the effect of single fraction TBI given at two different dose rates on late kidney damage in a mouse model. TBI was given at either high dose rate (HDR; 0.71 Gy/min) or low dose rate (LDR; 0.08 Gy/min). Transplantation with syngeneic marrow cells was done 4-6 h after TBI. Kidney damage was tested using 51CrEDTA residual activity, blood urea nitrogen (BUN) and percentage haematocrit (Hct). TBI alone given at HDR or LDR caused progressive renal damage with no evidence of recovery or plateau. The time latency before the expression of damage was dependent on both dose and the end point used. It was shorter the higher the dose. 51CrEDTA detected renal damage at the same doses as BUN but earlier in time, while %Hct showed evidence of renal damage at doses lower than both BUN and 51CrEDTA. Using the 51CrEDTA the dose-response curves for renal damage were steep and continuously shifting towards lower doses as follow-up time after treatment increased. There was a sparing effect of reducing the dose rate that was more evident at follow-up times of less than a year than at 66 weeks after TBI. Thus, the dose modifying ratio (DMF), defined as the dose needed to cause renal damage in 50% of irradiated animals (ED50) using LDR divided by the ED50 using HDR, was dependent on the time of evaluation.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Quality assurance in radiotherapy. European Society for Therapeutic Radiology and Oncology Advisory Report to the Commission of the European Union for the 'Europe Against Cancer Programme'.

This document is now in the process of being endorsed by all National Scientific Societies of Radiotherapy and Medical Physics of the European countries. It can therefore not be formally considered as the definitive version and is still susceptible to benefit from further alterations or improvements.

Clinical Competence↗
PubMed1995

Selective assessment of in vitro radiosensitivity of tumour cells and fibroblasts from single tumour biopsies using immunocytochemical identification of colonies in the soft agar clonogenic assay.

The assumed selective growth of tumour cells has formed the basis for the use of the soft agar clonogenic assay to test in vitro radio- and chemosensitivity of tumours. However, recent studies have demonstrated that fibroblasts proliferate in soft agar in addition to tumour cells. The present study was initiated to quantify the contaminating growth of non-malignant cells in the modified form of the Courtenay-Mills soft agar assay, in order to establish a reliable assay for estimating tumour cell radiosensitivity in squamous cell carcinomas of the head and neck. DNA flow cytometry analysis confirmed that 'tumour fibroblasts' (fibroblasts obtained from tumour biopsies) grow in soft agar. In contrast, white blood cells did not form colonies. Different media were tested with soft agar, but a selective medium for tumour cells was not found. Therefore, a colony filter-technique combined with an immunocytochemical analysis was developed to quantify the number of tumour cell and fibroblast colonies. In 12 tumour biopsies, 2-33% of the colonies were Cytokeratin AE1-3 positive, whereas 83-100% of the colonies were 5B5 fibroblast antibody positive. The parameter normally reported, the overall SF2 (surviving cell fraction at 2 Gy) based on colonies in agar, was found to be statistically significantly correlated to the fibroblast SF2, but not to the tumour cell SF2. The overall SF2 was significantly different from the tumour cell SF2 in half of the tumours. Furthermore, the tumour cell SF2 was not correlated to fibroblast SF2. In consequence of our findings, correcting for fibroblast contamination is a necessity, when studying in vitro sensitivity of tumour cells. Combining the soft agar clonogenic assay with the new colony filter-technique and the immunocytochemical analysis appear to be useful for making this routine correction and for measuring the in vitro radiosensitivity of both tumour cells and fibroblasts from single tumour biopsies, which is of interest in future clinical studies on predictive assays.

Biopsy↗
PubMed1995

Late renal damage after total body irradiation and bone marrow transplantation in a mouse model: effect of radiation fractionation.

In response to the accumulating evidence that renal damage is now becoming an important late complication after total body irradiation (TBI) and bone marrow transplantation (BMT), we have tested the effect of fractionated and hyperfractionated TBI on late kidney damage in a mouse model. TBI was given as fractionated (three fractions in 3 days, Fx 3), or hyperfractionated (nine fractions in 3 days, Fx 9) treatment. Kidney damage was evaluated using [51Cr]EDTA residual activity, blood urea nitrogen (BUN) and percentage haematocrit (%Hct) as end-points. We were able to detect progressive renal damage with no evidence of recovery or plateau in the Fx 3 and Fx 9 schedules. The time latency before the expression of renal damage was dependent on both total dose and end-point and it was shorter the higher the dose. [51Cr]EDTA detected renal damage at the same doses as BUN but earlier in time whereas %Hct detected renal damage at doses lower than both BUN and [51Cr]EDTA. Reducing the dose per fraction spared the kidney from TBI damage. The dose-response curves for renal damage (using the [51Cr]EDTA end-point) were steep, and tended to shift towards lower doses with longer follow-up times. The dose-modifying factors defined as the dose needed to cause renal damage in 50% of the animals (ED50) using single fraction TBI divided by the ED50 using fractionated TBI were 1.3 and 1.9 for the Fx 3 and Fx 9, respectively. These results may indicate that patients treated with TBI and BMT should be assessed for late kidney damage and that fractionation and particularly hyperfractionation may protect the kidneys from TBI-induced renal damage.

Animals↗
PubMed1995

Direct evidence that hydralazine can induce hypoxia in both transplanted and spontaneous murine tumours.

Hydralazine can substantially decrease blood flow and increase hypoxia in transplanted tumours. Previous indirect studies have suggested that hydralazine does not induce such effects in spontaneous tumours. We have now directly investigated the ability of hydralazine to increase hypoxia in both transplanted and spontaneous murine tumours by measuring tumour oxygen partial pressure (pO2) distributions using an Eppendorf oxygen electrode. Spontaneous tumours arose at different sites in CDF1 mice, while transplanted tumours were produced by implanting a C3H mouse mammary carcinoma on the backs of the same mouse strain. Measurements of pO2 were made in anaesthetised mice immediately before and 45 min after an intravenous injection of 5 mg kg-1 hydralazine. In the transplanted tumours hydralazine significantly decreased tumour oxygenation, such that the percentage of pO2 values < or = 5 mmHg increased from 45% to 87%, and median pO2 decreased from 5 to 3 mmHg. Similar significant changes were induced by hydralazine in the spontaneous tumours, the percentage of pO2 values < or = 5 mmHg increasing from 60% to 94% while the median pO2 values decreased from 8 to 2 mmHg. These results clearly show that there is no difference in the response of transplanted and spontaneous mouse tumours to hydralazine.

Adenocarcinoma↗