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J Overgaard

Publications and source records attributed to J Overgaard.

At least 271 records · Page 15Linked to original sources
PubMed1984

Formula to estimate the thermal enhancement ratio of a single simultaneous hyperthermia and radiation treatment.

An experimental model composed of a C3H mammary carcinoma and its surrounding skin has been exposed to simultaneous radiation and hyperthermia given with different combinations of heating time and temperature. Based on the thermal enhancement ratio (TER) values obtained in the temperature range 41.5 to 43.5 degrees C, a linear relationship between TER and the heating time was achieved at each temperature. The slopes of the curves drawn at each temperature were found to have a log-linear relationship with the treatment temperature. With these relationships it was possible to make a formula expressing the TER as a function of treatment temperature and time. This formula gives a crude but probably acceptable estimate of the TER following a single simultaneous radiation and heat treatment. Although subject to several limitations, the formula represents an attempt to describe a heat dose concept for the radiosensitizing effect of hyperthermia. This may be useful to establish the tolerance level of a given radiation treatment when combined with hyperthermia.

Animals↗
PubMed1983

The importance of thermotolerance for the clinical treatment with hyperthermia.

Thermotolerance (i.e. a temporary heat resistance following a prior heat treatment) is a general phenomenon occurring in both normal tissues and tumours. Besides affecting a fractionated heat treatment, thermotolerance may also influence the effect of fractionated combined heat and radiation. The importance of thermotolerance for fractionated clinical hyperthermia is discussed on the basis of a series of in vitro experiments in L1A2 cells and in vivo studies of a C3H mouse mammary carcinoma. If maximal tumour interaction is wanted, thermotolerance should be avoided, but it would be preferable in normal tissues in order to reduce the amount of damage. Unfortunately, there is a considerable variation in the kinetics and magnitude of thermotolerance between different tissues, and it is currently not possible to predict how thermotolerance will develop in a given tumour or normal tissue. However, both the magnitude and the kinetics appear to depend on the heat damage induced by the priming heat treatment. Thus, in a given tissue, thermotolerance will develop later, but will reach a higher maximum by a larger priming heat treatment. It follows that if a homogeneous temperature cannot be applied to a given tissue, different parts will develop thermotolerance at different kinetic patterns. Therefore, at the time of subsequent heat treatment, the tissue may express different heat sensitivities in different areas. With the current knowledge, the best way to overcome the problems of thermotolerance when heat is given alone or sequentially with radiotherapy will be by application of a single or few, but large heat fractions given with an interval that allows thermotolerance to develop and decay before the next hyperthermic treatment is given. With a simultaneous heat and radiation treatment which optimally requires heating in association with all radiation fractions, the fractionation interval should also be long, which is complicated by the fact that such long fractionation intervals may not result in an optimal radiation treatment.

Cell Line↗
PubMed1983

Studies of the pharmacokinetic properties of nimorazole.

The pharmacokinetics of the hypoxic radio-sensitizer nimorazole were studied in 19 individuals after single oral doses of between 0.5-3.5 g. HPLC measurements showed, after a rapid absorption, a linear relationship between peak plasma concentration and given dose. Mean elimination half life was 3.1 h. A tendency to a dose-dependent variation in the apparent volume of distribution, total body clearance and elimination half life suggest non-linear pharmacokinetics of nimorazole. Tumour concentrations measured in 5 patients gave tumour/plasma ratios between 0.8-1.3. No toxicity was observed. The results indicate that nimorazole may have potential as a clinically useful hypoxic radiosensitizer.

Adult↗
PubMed1983

Microcolony survival assay for jejunal crypt cells exposed to radiation alone and combined with cancer chemotherapeutic agents--methodological problems.

The effect of radiation alone or in combination with cyclophosphamide (CTX), methotrexate (MTX) and 5-fluorouracil (5-FU) on the jejunal crypt cells in C3D2F1/Bom mice was studied using the microcolony survival assay. In determination of survival curves, two sections per mouse and six mice per datum point were used in order to obtain a constant coefficient of variance of D0 (approximately 5 per cent). When CTX (250 mg/kg), MTX (150mg/kg), and 5-FU (150 mg/kg) were injected intraperitoneally 15 min before irradiation, the regeneration time for the surviving crypts increased. Thus, following radiation alone the regeneration time was 90 hours and when combined with the drugs, 96, 102, and 120 hours, respectively. At these hours the crypts were of an equivalent size. Scoring the crypt number at the regeneration times was found to be necessary, since the use of a constant assay time underestimated the crypt survival following the drug-radiation combinations. Neither was a constant assay time followed by a correction for different crypt sizes found sufficient to replace the use of different regeneration times. All three drugs significantly enhanced the radiation effect without changing the D0. The DEF values for CTX, MTX, and 5-FU were 1 . 05, 1 . 08 and 1 . 13, respectively.

Animals↗
PubMed1983

Influence of thermotolerance on the interaction between hyperthermia and radiation in a solid tumour in vivo.

The influence of thermotolerance (i.e. a temporary resistance to a subsequent heat treatment induced by prior heating) on the response of a C3H mouse mammary carcinoma to combined water-bath hyperthermia and radiation was investigated. Prior heating at 43.5 C for 30 min induced thermotolerance which was at a maximum 16 h later and had completely disappeared after 120 h. Prior heating reduced tumour response to simultaneous heat and radiation given 16 h later, as evidenced by a reduction from 5.1 to 3.3 in the thermal enhancement ratio (TER). The effect was lost by 120 h. This indicates that development of thermotolerance reduces the degree of thermal radiosensitisation. However, although the time course was the same, the prior heating effect on the combined treatment was smaller than on the resistance to heat alone. With sequential treatment, the tumours were treated with X rays (28 Gy) followed four hours later by a two-dose heat treatment at 43.5 degrees C, the first for 30 min and the second after an interval of 0, 16 or 120 h. With this treatment thermotolerance fully manifested itself. It was necessary to increase the duration of heating when applied 16 h after prior heating by a factor of 5.4 to cause a TER of 2.0, a value not significantly different from the expected value of 5.2, i.e., the thermotolerance ratio for heat alone.

Adaptation, Physiological↗
PubMed1983

Cerebral circulation after head injury. Part 4: Functional anatomy and boundary-zone flow deprivation in the first week of traumatic coma.

A considerable body of evidence suggests that posttraumatic disturbances of the cerebral circulation contribute to poor neurological outcome after blunt head injury, especially when regional cerebral blood flow (rCBF) falls to the ischemic range (below 17 ml/100 gm/min). Cerebral infarction concentrated in the arterial boundary regions has been described in patients who died. Since arterial boundary zones are the cortical areas most susceptible to cerebral ischemia, the authors have investigated the relationship between neurological outcome and the anatomic pattern of rCBF values in the acute phase. The bolus-injection xenon-133 washout technique was used to measure rCBF in 35 regions of the hemisphere during the 1st week after head injury. Eighty-eight hemispheres were studied in 80 patients whose Glasgow Coma Scale (GCS) score was less than 8 on admission to the neurosurgical department. A characteristic pattern of rCBF was found in patients who later died of neurological complications, or who survived in a persistent vegetative state, with low flows in regions conforming to the arterial boundary zones. These patients also had lower average global cerebral blood flow (CBF), GCS scores, and cerebral perfusion pressure compared with those who recovered, with or without neurological deficits; the latter group had an rCBF pattern similar to that of normal individuals. There was little change in the GCS score between the time of hospital admission and CBF measurement, suggesting that the major neurological injury had occurred prior to admission. It was not possible to determine whether boundary-zone ischemia preceded neurological deterioration, but the rCBF pattern of boundary-zone flow deprivation was clearly related to poor neurological outcome. These observations suggest that elevated intracranial pressure and arterial hypotension were important etiological factors. Measures to protect regional cerebral perfusion should be instituted as early as possible after injury, preferably before the patient reaches the hospital.

Arteries↗
PubMed1982

Postoperative radiotherapy in rectosigmoid cancer Dukes' B and C: interim report from a randomized multicentre study.

The design, and complications seen during the first 2 years, of a randomized trial of postoperative radiotherapy for rectosigmoid cancer Dukes' B and C are presented and discussed. It is concluded that the present complication rate-below 10% in 221 patients-permits continuation of the intake, which is planned to include 550 patients, to demonstrate a possible increase in crude 5-year survival by 15% (60-75% in Dukes' B and 25-40% in Dukes' C), on the basis of a 0·01 significance level and a probability that the experiment will be successful of 0·90.

Clinical Trials as Topic↗
PubMed1982

Importance of preheating temperature and time for the induction of thermotolerance in a solid tumour in vivo.

The importance of the priming heat treatment temperature and heating time for the degree and kinetics of thermotolerance was investigated in a C3H mammary carcinoma inoculated into the feet of CDF1 mice. A single heat treatment in the range 41.5-44.5 degrees C resulted in a linear relationship between heating time and tumour growth time (i.e. the time for tumours to reach a volume five times that of the first treatment day). An Arrhenius plot showed an inflection point at 42.5 degrees C with activation energies of 635 and 1508 kJ/mol, respectively, above and below 42.5 degrees C. The degree and kinetics of thermotolerance were independent of the preheating temperature, if the heating time was adjusted to give the same level of heat damage. A pretreatment at these temperatures with a tumour growth time of approximately 10 days, equivalent to 30 min at 43.5 degrees C, resulted in maximal thermotolerance at a 16-h interval with a thermotolerance ratio (TTRmax) of approximately 5.2. Preheating of the tumours at 43.5 degrees C for 3.5, 7.5, 15, 30, or 45 min, showed that if the preheating time was increased, both the TTRmax and the time interval necessary to develop TTRmax increased, both being linear functions of the duration of the preheating time. Maximal thermotolerance was obtained at intervals of 2, 4, 8, 16, and 28 h with TTRmax of 1.6, 2.2, 3.7, 5.2, and 7.7, respectively.

Animals↗
PubMed1982

A comparative investigation of nimorazole and misonidazole as hypoxic radiosensitizers in a C3H mammary carcinoma in vivo.

The hypoxic cell radiosensitizing properties of nimorazole have been investigated in a C3H mammary carcinoma transplanted to the feet of C3D2F1. The results have been compared with those obtained with misonidazole (MISO) in the same animal tumour system. For single-dose irradiation in air, nimorazole gives an enhancement ratio (ER) of approximately 1.4, independent of the dose of drug administered over the range 0.1-1.0 mg/g. MISO yields a similar ER at the 0.1 mg/g level but, unlike nimorazole, shows a steep dose-response curve with an ER of 2.2 when given in a concentration of 1.0 mg/g. No such dose-response relationship is seen with nimorazole despite the fact that tumour and plasma concentrations of the 2 drugs have an identical dose relationship. With irradiation given in 5 daily fractions, nimorazole and MISO at a dose of 0.3 mg/g per fraction both show an ER of approximately 1.3. The high drug doses used in single-fraction radiation experiments in animals bear little relation to those applicable to clinical practice since these would result in unacceptable toxicity. The results of the present studies are therefore of interest as nimorazole is potentially less toxic than MISO in humans but demonstrates similar radiosensitizing properties at clinically relevant dose levels.

Animals↗
PubMed1982

Development of thermotolerance during fractionated hyperthermia in a solid tumor in vivo.

The effect of 43.5 degrees water bath heating on a C3H mammary carcinoma inoculated into the foot of BALB/c x DBA F1 (hereafter called CD2F1 mice was investigated. A single heat treatment resulted in a linear dose-response relationship between heating time and tumor growth time (i.e., the time for tumors to reach 5 times the initial volume of the first treatment day). Recovery from hyperthermic damage, demonstrated by two-dose fractionation experiments (30 min + 60 min at 43.5 degrees), increased with increasing fractionation interval and reached its maximum at a 16-hr interval. Preheating for 30 min at 43.5 degrees induced thermal resistance to a second heat treatment at 43.5 degrees (thermotolerance) which was evidenced by a decrease in the slope of the dose-response curves. This thermotolerance gradually increased with increasing interval and reached a maximum at a 16-hr interval with a thermotolerance ratio of 5.2. Subsequently, the thermotolerance gradually decayed and completely disappeared at a 120-hr interval. No detectable repair of hyperthermic damage was found in this tumor. In principle, there data confirm the observations on thermotolerance reported previously for cell cultures in vitro and for several normal tissues in vivo.

Animals↗
PubMed1982

Influence of time and temperature on the kinetics of thermotolerance in L1A2 cells in vitro.

The overall importance of the primary heat treatment temperature and heating time for the degree and kinetics of thermotolerance was investigated in L1A2 cells in vitro. The degree and time course of thermotolerance developed following primary heating were independent of the priming temperature (in the range 41-44 degrees), if the heating time was adjusted to give identical survival levels. A pretreatment at these temperatures with a survival level of approximately 8%, equivalent to 90 min at 42 degrees, resulted in maximal thermotolerance at a 10-hr interval with a thermotolerance ratio (TTRmax) of approximately 4.3. This was also found irrespective of the temperature (in the range 41-45 degrees) of the second heat treatment. Preheating of cells at 42 degrees for 45, 90, 110, or 135 min corresponding to survival levels of approximately 40, 8, 3.2, and 1.8%, respectively, induced a subsequent delay of 0.8 to 5.8 hr in the onset of thermotolerance. In addition, with more severe primary heat treatments, the delay period, the TTRmax, and the time interval at 37 degrees necessary to develop TTRmax increased. Maximal thermotolerance was obtained at an interval of 6, 10, 13, and 16 hr, respectively, with TTRmax's of 2.9, 4.2, 5.3, and 5.9, respectively. In contrast, the rate of both development and decay of thermotolerance was independent of the primary heating time. These data indicate that the degree and kinetics of thermotolerance in L1A2 cells depend on the survival level following the primary heating irrespective of the treatment temperature and heating time used to obtain this survival level.

Acclimatization↗
PubMed1982

Influence of sequence and interval on the biological response to combined hyperthermia and radiation.

Experimental studies on the influence of sequence and interval between hyperthermia and radiation are reviewed. In general, experimental data in vitro and in tumor and normal tissues agree and indicate that maximal thermal enhancement occurs after simultaneous application of heat and radiation. However, such treatment is likely to enhance both tumor and normal tissue to the same degree and therefore does not increase the therapeutic effect. In normal tissue, sequential treatment with heat before radiation causes a higher and longer thermal enhancement than with the opposite sequence in which the thermal enhancement generally disappears with intervals greater than 4 hours. However, in most solid tumors, a moderate thermal enhancement exists with long intervals between the modalities independent of sequence and is probably a consequence of a direct hyperthermic destruction of the acidic and chronically hypoxic cells. Based on this biological conclusion, the clinical application of hyperthermia and radiation is discussed in the light of the technical problems related to the application of a homogeneous and selective local tumor heating.

Animals↗
PubMed1981

Fractionated radiation and hyperthermia: experimental and clinical studies.

The effect of fractionated radiation and hyperthermia was experimentally studied in a C3H mammary carcinoma and its surrounding skin. Simultaneous radiation and heat (42.5 C-60 minutes) with one or five fractions gave thermal enhancement ratios (TER) of approximately 2.5 in both tumor and surrounding skin, and no improved therapeutic effect was obtained. Five fractions of sequential treatment with heating four hours after radiation reduced the tumor TER to about 1.4, but when 72 hours were allowed between the fractions, no thermal enhancement of the skin was observed. Thus, an improved therapeutic ratio was observed. Clinically the combined treatment was studied in 12 patients with 49 metastases from malignant melanoma treated with different schedules of radiation and hyperthermia (approximately 43 C for 30 minutes). Simultaneous treatment with three fractions in eight days gave TER values in the skin between 1.2-1.4, but a similar effect was found in the tumor. Three fractions of sequential treatment in eight days did not produce any thermal enhancement of the skin response, but still presented an apparent gain of the tumor response, and so seemed to increase the therapeutic effect. Bases on these findings, the strategy for further clinical use of combined hyperthermia and radiation is discussed.

Animals↗