PubMed Health⌕ Search

Biomedical subjects

J Overgaard

Publications and source records attributed to J Overgaard.

At least 19 recordsLinked to original sources
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

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

The importance of determining necrotic fraction when studying the effect of tumour volume on tissue oxygenation.

The relationship between tumour tissue oxygenation and necrosis at different tumour sizes was investigated in a C3H mammary carcinoma implanted in the feet of female CDF1 mice. Experiments were performed using tumours that ranged in size from 80 to 800 mm3. Necrosis was estimated histologically. Tumour tissue oxygenation (pO2) was estimated with an Eppendorf electrode. Our results showed that as tumour volume increased there was a corresponding increase in necrotic fraction ranging from 1% in small tumours up to 51% in large tumours. The percentage of pO2 values < or = 5 mmHg increased from 2% up to 79%, in small and large tumours respectively. After correcting for necrosis, the apparent, significant increase in the % of pO2 values < or = 5 mmHg was lost. We conclude that correcting for necrotic fraction in this tumour model is necessary when attempting to measure tumour oxygenation using electrodes.

Animals↗
PubMed1995

Reoxygenation in a C3H mouse mammary carcinoma. The importance of chronic rather than acute hypoxia.

The role that chronic and acute hypoxia play in tumour reoxygenation after irradiation was investigated in a C3H mouse mammary carcinoma grown in the feet of female CDF1 mice. Tumours at 200 mm3 in size were locally irradiated with a priming dose of 20 Gy and then at various times after given a range of radiation doses under normal or clamped conditions. Local tumour control was determined 90 days later from which the tumour hypoxic fractions were calculated. Untreated tumours contained 23% hypoxic cells. Immediately after 20 Gy this increased to 52% and by 24 h had fallen to 10%. These reoxygenation experiments were repeated, giving either nicotinamide (1000 mg/kg; i.p. injected 30 min before each irradiation) to remove acute hypoxia, or carbogen breathing (for 5 min before and during irradiation) to decrease chronic hypoxia. With nicotinamide the normal hypoxic fraction was reduced to 7%, but after irradiation it had risen to 46% and by 24 h there was full reoxygenation with a value of 5% being observed. Carbogen breathing also decreased the normal hypoxic fraction to 6%, and immediately after irradiation this was increased to 38%. However, by 24 h it was still elevated at around 23%. These results suggest that chronic rather than acute hypoxia is necessary for reoxygenation in this tumour.

Animals↗
PubMed1995

Relationship between tumour oxygenation, bioenergetic status and radiobiological hypoxia in an experimental model.

Tumour oxygenation and bioenergetic status were measured in the same tumour and these results related to radiobiological hypoxia. A C3H mouse mammary carcinoma grown in the feet of CDF1 mice was used. Bioenergetic status was assessed by 31P MRS using a SISCO 7 Tesla magnet, oxygen measurements were done by a polarographic electrode and the hypoxic fraction was determined from direct analysis of the radiation dose-response data. During all examinations restrained, non-anaesthetized mice were allowed to breathe either 100% oxygen, carbogen, normal air, carbon monoxide (CO) at 75, 220, or 660 ppm or had blood flow occluded by clamping. Results showed a significant correlation between the radiobiological hypoxic fraction and % pO2 < or = 5 mmHg under the different treatment conditions, whereas no correlation was found between beta nucleosidetriphosphate/inorganic phosphate (beta-NTP/Pi) ratio and either the hypoxic fraction or the % of pO2 values < or = 5 mmHg under the different treatment conditions. In conclusion, oxygen electrode measurements were sensitive to changes in tumour hypoxia whereas the bioenergetic status alone seemed to be a less precise measure of hypoxia in this tumour model. Furthermore, the present study demonstrated that tumour cells in vivo can actually maintain the bioenergetic status during a period of severe hypoxia.

Animals↗
PubMed1995

The ability of nicotinamide to inhibit the growth of a C3H mouse mammary carcinoma.

Experimental studies have suggested that nicotinamide and its analogs may inhibit the growth of murine tumours. We have now investigated this using a C3H mouse mammary carcinoma implanted into the right rear foot of female CDF1 mice. From days 1 to 30 after implantation mice were intraperitoneally (i.p.) injected with either 100, 200, 500 or 1,000 mg/kg nicotinamide. The tumour volume (+/- 1 S.E.) after 30 days in saline-treated mice had reached 1540 mm3 (+/- 260). No change in tumour growth was seen at that time with daily doses of up to 500 mg/kg nicotinamide, but at 1,000 mg/kg tumour volume was reduced to 904 mm3 (+/- 233). However, this large dose of nicotinamide was also toxic to the mice with some 16% of animals dying during the 30-day treatment period. A similar growth inhibition was seen with daily i.p. injections of 5 mg/kg fumagillin (tumour volume at 30 days = 821 +/- 191 mm3), a known inhibitor of angiogenesis, but whether this mechanism also explains the nicotinamide effect is not clear.

Animals↗
PubMed1995

Prognostic value of pretreatment factors in patients with locally advanced carcinoma of the uterine cervix treated by radiotherapy alone.

The prognostic effect of pretreatment patient- and tumor characteristics, and the influence of radiotherapy schedule on local control, distant metastases, and crude survival were analyzed in 424 consecutive patients with FIGO stage IIB (n = 137), IIIA (n = 10), IIIB (n = 211) and IVA (n = 66) cancer of the uterine cervix. All patients were given radiotherapy alone. From 1974 and through 1977, the external and intracavitary combined radiotherapy was given continuously in 4 to 6 weeks. From 1978 and through 1983, the treatment policy was changed to split-course radiotherapy by introducing planned pauses, resulting in an overall treatment time of 10 to 12 weeks. The results were estimated by univariate actuarial- and Cox multivariate regression analyses. Multivariate analysis showed that significant adverse variables for local control were large lateral tumor diameter, young age, low hemoglobin at time of admission, many pregnancies, split-course strategy, and high FIGO stage. Risk of metastases increased with decreasing hemoglobin, increasing malignancy grade and split-course treatment. Poor survival probability were related to large lateral tumor diameter, high malignancy grade and FIGO stage, low hemoglobin, split-course therapy, and adeno/adenosquamous tumor type.

Actuarial Analysis↗
PubMed1994

Clinical evaluation of nitroimidazoles as modifiers of hypoxia in solid tumors.

Hypoxic modification by nitroimidazoles has been explored in a large number of clinical studies. Nine different drugs (misonidazole, metronidazole, benznidazole, desmethylmisonidazole, etanidazole, pimonidazole, nimorazole, ornidazole, and RSU 1069) have reached clinical evaluation. Phase I and II trials have demonstrated a relationship between drug tolerance and expected hypoxic modification. Thus, the most tolerable drugs, viz., 5-nitroimidazoles, are those with the smallest preclinical activity. However, they may be the most clinically active, due to higher plasma and tumor concentrations. The clinical evaluation of hypoxic modification is difficult, since clinically important hypoxia can be observed only indirectly. There is, however, indirect evidence of substantial hypoxia in human tumors, although with considerable heterogeneity among individual tumors. More than 7000 patients have been included in 50 randomized trials. A meta-analysis showed that modification of tumor hypoxia significantly improved the loco-regional tumor control after radiotherapy with an odds ratio of 1.17 (95% confidence limits 1.06 to 1.28). The treatment benefit could mostly be related to an improved response in head and neck with odds ratio 1.23 (95% confidence limits 1.09 to 1.37), and to a lesser extent in bladder tumors; no significant effect was observed in other tumor sites (cervix, lung, central nervous system, and esophagus). Similarly to the local control benefit, the overall survival rate was improved with an overall odds ratio of 1.13 (95% confidence limits 1.03 to 1.23). The clinical trials showed no evidence of significant chemosensitization or direct bioreductive effect. Although 50 randomized clinical trials were evaluated, the median number of patients was only 97 (range 17-620). Clinical trials of this size are not likely to detect the observed differences, which may explain the lack of significant improvement in most of the individual studies. However, the overall results indicate that the biological issue related to hypoxia appears to be a sound rationale, especially with regard to head and neck and bladder carcinoma. Future studies related to the hypoxic problem should therefore preferably be aimed towards such tumors.

Antineoplastic Agents↗
PubMed1992

Auditory brain stem responses in patients after radiation therapy for nasopharyngeal carcinoma.

BACKGROUND: The study evaluated the incidence and severity of brain stem myelopathy occurring after radiation exposure in a cohort of patients who received external radiation exposure for nasopharyngeal carcinoma (NPC). METHODS: Brain stem function was investigated by auditory brain stem responses (ABR). RESULTS: Four of 21 patients who could be examined had aberrations in ABR. Three patients showed highly abnormal ABR, with no distinctive patterns or peaks. Two of these patients also showed clinical symptoms of brain stem dysfunction, including multiple palsies in cranial and peripheral nerves, whereas the third patient had no clinical signs of brain stem disorders. The fourth patient had minor conduction delays in ABR. The remaining group of 17 patients who could be examined had ABR latency and transmission times similar to those of the control group. None of these patients had neurologic symptoms. Dose-response analysis showed that patients who received radiation doses of 59 Gy or less to the brain stem had normal ABR, whereas four of six patients who received a dose of 68 Gy had manifest or subclinical brain stem dysfunction. CONCLUSIONS: The results emphasize the importance of protecting the brain stem from high-dose radiation when possible. The results also demonstrate the usefulness of ABR as a supplement to the clinical examination of patients with possible myelopathy occurring after radiation exposure.

Adult↗
PubMed1992

Stereologic, histopathologic, flow cytometric, and clinical parameters in the prognostic evaluation of 74 patients with intraoral squamous cell carcinomas.

BACKGROUND AND METHODS: A consecutive series of all 78 incident cases of intraoral squamous cell carcinoma occurring during a 2-year period in a population of 1.4 million inhabitants were evaluated by histologic score (the modified classification of Jacobsson et al.), flow cytometry, stereology, tumor size, and the TNM classification. RESULTS: The investigation showed a significant difference between the volume-weighted mean nuclear volume (nuclear vv) of oral leukoplakia (n = 29) and oral squamous cell carcinomas (P = 0.001). The value of the parameters as prognostic indicators of survival and recurrence was tested with Kaplan-Meier plots and Cox multiple hazard regression analysis. Tumor size, T-stage, stereologically estimated nuclear vv, and mean nuclear profile area were all of significant prognostic value in single factor analysis with reference to both survival and recurrence. The histologic parameters of mitotic activity, morphologic nuclear dedifferentiation, and histologic mean malignancy score and the DNA ploidy level had no prognostic value. A prognostic index based on the results of the Cox analysis that included T-stage and nuclear vv was correlated highly with survival (P = 0.00001) and recurrence (P = 0.002). CONCLUSION: These findings may contribute to optimal and individualized therapy.

Adult↗
PubMed1992

Effect of etoposide, carmustine, vincristine, 5-fluorouracil, or methotrexate on radiobiologically oxic and hypoxic cells in a C3H mouse mammary carcinoma in situ.

The effect of etoposide (VP16), carmustine (BCNU), vincristine (VCR), methotrexate (MTX), and 5-fluorouracil (5-FU) on the oxic and hypoxic cells in a C3H mammary carcinoma in CDF1 mice was investigated using an in situ local-tumor-control (TCD50) assay. The surviving fraction (SF) was calculated from the size of the radiation dose needed to inactivate the surviving tumor cells in drug-treated tumors relative to untreated controls. Preferential drug cytotoxicity towards oxic and hypoxic cells was evaluated from the difference in the response to irradiation under ambient and clamped conditions, respectively. Three drugs caused a significant (P less than 0.05) reduction in the survival of hypoxic cells, the SFs being 0.31 (VP-16), 0.13 (BCNU) and 0.16 (VCR). VCR was also toxic towards oxic cells (SF, 0.17), whereas VP16 and BCNU had no significant effect on these cells (SF, 0.5 and 0.76, respectively). Two drugs produced significant killing of cells in the oxic compartment: 5-FU (SF, 0.10) and MTX (SF, 0.22); these two drugs had no effect on hypoxic cells (SF, 0.78 and 1.11, respectively).

Animals↗
PubMed1992

BW12C-induced changes in haemoglobin-oxygen affinity in mice and its influence on the radiation response of a C3H mouse mammary carcinoma.

The effect of the substituted benzaldehyde BW12C on haemoglobin-oxygen binding affinity, tumour radiation response and blood perfusion were investigated in a C3H mouse mammary carcinoma grown in the feet of CDF1 mice. Mouse P50 (partial pressure of oxygen at half saturation) was estimated using an ABL blood gas analyzer; radiation response determined from tumour regrowth and local tumour control assays; and tumour blood perfusion measured with a 86RbCl extraction procedure. A single intravenous injection of BW12C substantially decreased mouse P50. This effect was dependent on the time after injection with the nadir observed within 15 min and only returning to normal after several hours. It was also dependent on drug dose, the decrease becoming larger with increasing concentration, reaching a maximum 50% reduction at 70 mg/kg. The decrease in P50 could be maintained for at least 6 h following injection of 70 mg/kg, if mice were also given 25 mg/kg at hourly intervals. However, no changes in radiation response or tumour blood perfusion were observed with either single or multiple administrations of BW12C. These results suggest that BW12C induced changes in tumour hypoxia reported by several groups of workers, may not be entirely the result of a change in haemoglobin-oxygen affinity.

Animals↗