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J Overgaard

Publications and source records attributed to J Overgaard.

At least 145 records · Page 8Linked to original sources
PubMed1994

Relationship between radiobiological hypoxia in tumors and electrode measurements of tumor oxygenation.

PURPOSE: To determine whether electrode measurements of tumor oxygenation, made in a variety of murine tumor models, correlate with estimates of radiobiological hypoxia in the same tumor systems. METHODS AND MATERIALS: The tumor models used were a C3H mammary carcinoma grown in the feet of CDF1 mice; the SCCVII, KHT and RIF-1 tumors grown in the feet or flanks of C3H/Km mice; and the CaNT and SaF tumors grown on the backs of CBA mice. All treatments were performed when tumors were about 200 mm3 in size. Radiobiological hypoxic fractions were determined using either a paired survival curve assay, with survival measured 0-24 h after irradiation, or using a clamped tumor control assay, with percent local tumor control estimated 90 days after treatment. Measurements of tumor oxygen partial pressure (pO2) distributions were performed using Eppendorf oxygen electrodes. RESULTS: The hypoxic fractions determined from the radiation response data were about 1% in RIF-1 and SCCVII, 12% in C3H and KHT, 28% in CaNT and up to 38% in SaF tumors. When this data was compared with the tumor oxygenation measurements it was found that as hypoxic fraction increased the mean, median, and the percentage of pO2 values < or = 5 mmHg showed a trend towards poorer oxygenation status. However, none of these pO2 changes were significantly correlated with hypoxia. Moreover, the pO2 values < or = 2.5 mmHg indicated an improvement in oxygen status with increasing hypoxic fraction. CONCLUSION: Electrode measurements of tumor oxygenation alone may, therefore, not be a good indicator of tumor hypoxia across different tumor cell lines.

Animals↗
PubMed1994

Effect of carbon monoxide breathing on hypoxia and radiation response in the SCCVII tumor in vivo.

PURPOSE: To study the influence of a clinically relevant concentration of carbon monoxide (CO) on tumor oxygenation and response to irradiation. METHODS AND MATERIALS: The murine tumor model was the SCCVII squamous cell carcinoma transplanted to the feet of C3H/Km mice. RESULTS: Sixty minutes of breathing CO at 200 ppm resulted in a carboxyhemoglobin level of 15%. This resulted in a reduction in p50 (the oxygen partial pressure at which hemoglobin is 50% saturated) to 78% of the control value, and a decrease in tumor blood perfusion to 73% of the control value. The combined effect of a decrease in effective hemoglobin and blood perfusion resulted in a reduction in tumor oxygen supply to 62% of the control value. In agreement with this, intratumoral pO2 measurements showed a significant increase in tumor hypoxia, such that the percentage of measurements with low pO2 (< or = 5 mmHg) increased from 33% to 62%. The fraction of clonogenic hypoxic cells, measured radiobiologically by paired cell survival curves, similarly increased from 0.2% to 3.8%. Radiation sensitivity, evaluated from in vivo-in vitro excision assay, was significantly decreased by CO breathing with both single dose and fractionated irradiation. The observed enhancement ratios for radiation given in 1, 4, 8, and 12 fractions were 0.71, 0.77, 0.83, and 0.71, respectively. CONCLUSION: The present SCCVII tumor data confirm the general experimental observation that CO breathing significantly increases tumor hypoxia and reduces the effectiveness of ionizing irradiation.

Animals↗
PubMed1994

Importance of nicotinamide dose on blood pressure changes in mice and humans.

PURPOSE: The importance of nicotinamide dose on inducing blood pressure changes in mice and humans was investigated. METHODS AND MATERIALS: Blood pressure measurements in human volunteers were made using an inflated cuff procedure after oral ingestion of 3 or 6 g nicotinamide. Animal blood pressure measurements were performed in fully awake nonanesthetized female CDF1 mice, 24 h after cannulation of the carotid artery. RESULTS: In humans, the average (+/- 1 SE) resting systolic and diastolic pressures were 122.8 mmHg (+/- 2.5) and 80.6 mmHg (+/- 2.1), respectively. They were unchanged during the first 3 h after ingestion of either 3 g or 6 g nicotinamide. The resting value (+/- 1 SE) in mice was 115.1 mmHg (+/- 4.0) and this was significantly reduced following intraperitoneal injection of 400-1000 mg/kg nicotinamide. This decrease was maximal within 15-30 min after injection and was linearly dependent on drug dose. At doses of 200 mg/kg or less, no significant effect on blood pressure was observed. CONCLUSION: Doses between 100-200 mg/kg in mice are known to be equivalent to 6 g in man and can also produce maximal radiosensitization in murine tumors. Our results, therefore, not only show that the mouse and human data are entirely consistent, but also suggest that nicotinamide-induced decreases in blood pressure are not necessary for radiosensitization.

Adult↗
PubMed1994

Influence of sampling time on assessment of potential doubling time.

Potential doubling time (Tpot), S-phase transit time (Ts), and labeling index were determined in three experimental rodent tumors by in vivo incorporation of bromodeoxyuridine and flow cytometry. The kinetic parameters were derived from the relative movement method at varying sampling times (time between injection of bromodeoxyuridine and tumor excision). Ts and Tpot were close to the expected (extrapolated) values of the two parameters with sampling time within the range 60-100% of the expected Ts. With short sampling time, Ts and Tpot were considerably over- or underestimated. By use of the original method by (Begg et al., Cytometry 6:620-626, 1985), the Tpot came out with a twofold overestimation with a short sampling time. Generally, modified methods for calculation of Ts did not improve the results. When Tpot is measured in human tumors, there is no a priori knowledge of the kinetic parameters. Consequently, the sampling time must be based on the general experience of tumor cell kinetics in the specific tumor type measured. A relatively long sampling time should be aimed for when measuring Tpot in human tumors. With proper sampling time, Tpot assessed by flow cytometry was found to be a precise and reproducible parameter.

Adenocarcinoma↗
PubMed1994

Introduction.

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Journal Article↗
PubMed1994

The relationship between carbon monoxide breathing, tumour oxygenation and local tumour control in the C3H mammary carcinoma in vivo.

The effect of acute carbon monoxide (CO) breathing on blood oxygenation and tumour hypoxia was related to the radiation response of the C3H/Tif mammary carcinoma. Blood gas analysis showed that CO breathing caused a time- and dose-dependent formation of carboxyhaemoglobin (HbCO), a significant left shift of the oxygen dissociation curve and a reduction in tumour blood perfusion. These factors all contributed to a marked drop in tumour oxygen supply. In agreement with this, tumour hypoxia was found to be significantly increased: Microelectrode PO2 measurements showed a clear relationship between CO concentration and the proportion of low PO2 measurements (< or = 5 mmHg). The fraction of clonogenic hypoxic cells increased from 8% in air-breathing animals to 13%, 18% and 54% with 75,220 and 660 p.p.m. CO respectively. The tumour hypoxia resulted in significant radiation modification. The local tumour control after single-dose and fractionated irradiation gave TCD50 enhancement ratios (relative to air-breathing controls) of 0.90, 0.85 and 0.89 for single dose and five or ten fractions given in 5 days (P < 0.005 for all values). For 15 fractions in 5 days with 6- 6- and 12 h intervals, the TCD50 was similar in CO- and air-breathing mice, presumably as a consequence of insufficient reoxygenation during the short inter-fraction intervals. It is concluded that elevated HbCO levels to increased tumour hypoxia and that the induced hypoxia has a significant impact on the local tumour control also after fractionated irradiation.

Animals↗
PubMed1994

Patient-to-Patient Variability in the Expression of Radiation-Induced Normal Tissue Injury.

Radiotherapy is associated with a board spectrum of early and late normal tissue injury. It is a basic clinical observation that even within a group of identically treated patients large variability exists in the incidence and severity of radiation sequelae. Although this is partly a result of the random nature of radiation-induced cell killing, there are at least two additional phenomena involved. One is that certain cofactors influence the expression of radiation damage. These include for example, age of the patient, hemoglobin level, and smoking habits. Another type of predisposing factors are related to coexisting morbidity, like collagen vascular disease, diabetes mellitus, hypertension, and infections. The influence of these factors on the expression of normal tissue injury is critically reviewed and some of the methodological problems involved in this field are discussed. The other phenomenon, that probably contributes to the patient-to-patient variability in the expression of normal tissue reactions, is the variability in intrinsic cellular radiosensitivity that has been shown among individuals. Clinical studies have shown that patients who express a given type of normal tissue injury in one treated area are more likely also to express this injury in another treated area. On the other hand, different normal tissue reactions seem to have a very limited, if any, intrapatient correlation. A number of genetic syndromes are associated with hypersensitivity to radiation, both clinically and in vitro. Also, studies have shown that highly selected patients who express an unusually strong response to radiotherapy, are likely to have in vitro radiosensitivities in the lower normal range. Recently, two studies on otherwise unselected patients support the hypothesis that in vitro radiosensitivity of normal human skin fibroblasts correlated with clinical normal tissue reactions.

Journal Article↗
PubMed1994

Evidence for a positive correlation between in vitro radiosensitivity of normal human skin fibroblasts and the occurrence of subcutaneous fibrosis after radiotherapy.

A colony-forming assay of human skin fibroblast radiosensitivity was established in our laboratory and applied to primary skin biopsies from 12 women belonging to an unselected group of patients who received postmastectomy radiotherapy 10-12 years prior to this study. The aim was to investigate the relationship between in vitro radiosensitivity and the occurrence of subcutaneous fibrosis after radiotherapy. Early generations of normal skin fibroblasts in exponential growth were irradiated at room temperature at a high dose-rate to estimate the surviving fraction of colony-forming cells after single doses ranging from 1 to 8 Gy. A linear-quadratic cell survival curve was fitted to the data and from these fits the surviving fraction at 3.5 Gy (SF3.5) was estimated. Replicate experiments of different cell generations were made to validate the assay, and the between-patients variability was significantly larger than the assay variability for both SF2(p = 0.002) and SF3.5 (p = 0.04). Patients were treated in the period 1978-1982 with a dose per fraction between 2.7 and 3.9 Gy, a total of 12 fractions at two fractions per week. They were evaluated with respect to the occurrence of marked subcutaneous fibrosis in a total of 36 independent treatment fields. In each treatment field the total dose and dose per fraction at the relevant dosimetric reference depth as well as the length of follow-up were recorded. A previously derived LQ mixture model was applied to these data in order to determine the probability of marked fibrosis in that particular field. From this probability and the actually observed fibrosis, the excess risk of fibrosis was calculated, and this was averaged over the three treatment fields to obtain a single measure of clinical radiosensitivity. Increasing values of SF3.5 were statistically significantly correlated with decreasing probabilities of developing subcutaneous fibrosis (p = 0.014, Spearman's rank correlation test). Thus, this pilot study has demonstrated a positive correlation between in vivo radiosensitivity and normal skin fibroblasts and the clinical expression of subcutaneous fibrosis.

Breast Neoplasms↗
PubMed1994

Quantitative magnetic resonance for assessment of radiation fibrosis after post-mastectomy radiotherapy.

Subcutaneous fibrosis is a serious complication of post-mastectomy radiotherapy with a pronounced influence on skin conditions, shoulder movement and arm oedema. To establish safer radiotherapy schedules, precise evaluation of the tissue damage is required. A feasibility study was performed to assess the value of calculated relaxation times from magnetic resonance (MR) images for quantitative characterization of different degrees of subcutaneous fibrosis after post-mastectomy radiotherapy. A surface coil was applied to the irradiated area, as well as to unirradiated skin, to obtain appropriate MR coronal slices for acquisition of calculated values using a mixed imaging sequence technique. 14 patients with clinically diagnosed subcutaneous fibrosis were examined, 10 of whom had severe fibrosis. The mean T2 values of the treated and untreated side were 53.0 and 56.7, respectively. A statistically significant decrease of the calculated T2 values on the treated side was observed. No correlation was found between the clinically assessed fibrosis and the calculated relaxation times. The findings indicate that despite a general decrease of T2 calculated values, the large variation in the relaxation times restricts the value of MR, as applied in this study, in differentiating between different degrees of fibrosis in normal tissues after radiotherapy.

Aged↗
PubMed1994

Continuous or split-course combined external and intracavitary radiotherapy of locally advanced carcinoma of the uterine cervix.

From 1974 to 1984, 442 consecutive patients with carcinoma of the uterine cervix (FIGO IIB: 139, IIIA:10, IIIB:221, IVA:72) were referred for combined intracavitary (IRT) and external radiotherapy (ERT). To improve local control and reduce late rectosigmoid morbidity the treatment strategy was changed from continuous (CRT) to split-course radiotherapy (SCRT) in 1978. Stage by stage the 5-year actuarial estimates of survival, local control, and late morbidity did not differ in relation to strategy. In the patients with tumours larger than 8 cm, the SCRT involved an increased dose in point B, a reduced dose in point A from the IRT, a lower total dose in point A, and a 34 days' prolongation of the total treatment time (TTT). The resulting 5-year actuarial local control rates were significantly lower compared with those after CRT. No difference of late severe morbidity was found except in IVA patients. In the patients with tumours between 4 and 8 cm, the SCRT involved a reduced dose in point A from the IRT, an increased total dose in point A and B, and a 50 days' prolongation of the TTT. In patients with stage IIB, the 5-year actuarial central local control rate was lower (p = 0.06), and the 5-year estimate of late severe morbidity significantly higher after SCRT compared with CRT. It is concluded that the increase of the dose in point B in the SCRT was insufficient to prevent the deleterious effect on local tumour control of either the lower dose from IRT in point A, or the prolonged TTT. The increase of the total dose in the SCRT may explain why the late morbidity was not reduced, and may suggest that the TTT is of no significant importance for the risk of late normal tissue damage.

Adult↗
PubMed1994

Reducing acute and chronic hypoxia in tumours by combining nicotinamide with carbogen breathing.

The ability of nicotinamide and carbogen breathing to improve the radiation response of a C3H mammary carcinoma by reducing both acute and chronic hypoxia was investigated. Using a tumour growth delay assay the response of 200 mm3 foot tumours to local irradiation was found to be increased by either injecting nicotinamide (100-1,000 mg/kg) 20 min prior to irradiation, or by allowing mice to breathe carbogen for 10 min before and during the radiation treatment. The greatest radiosensitization occurred when nicotinamide and carbogen were combined. With a histological fluorescent staining technique nicotinamide was shown to prevent transient stoppages in microregional blood flow, and also appeared to improve tumour oxygenation as measured with an Eppendorf oxygen electrode, both effects being consistent with its ability to decrease perfusion limited acute hypoxia. Carbogen had no effect on vessel closure, but it significantly improved tumour oxygenation, which was indicative of it reducing diffusion limited chronic hypoxia.

Animals↗
PubMed1994

Measurement of human tumour oxygenation status by a polarographic needle electrode. An analysis of inter- and intratumour heterogeneity.

Tumour oxygenation status was measured by a polarographic needle electrode in 31 patients with lymph node metastasis of squamous cell carcinoma of the head and neck and 18 patients with primary soft tissue sarcoma. Two oxygenation parameters, the median pO2 and the proportion of measured values less than 5 mm Hg, were used in comparing the inter- and intrasubject heterogeneity in tumour and subcutaneous tissue. Results of the analysis may be summarized as follows: 1) the variation in oxygenation between tumours was significantly greater than that within tumours, 2) the variation in oxygenation of subcutaneous tissue between patients was significantly greater than the variation within patients, 3) oxygenation of tumour was significantly lower than that of subcutaneous tissue, 4) no significant difference in the distribution of the oxygenation parameters in the two tumour types, and 5) both oxygenation parameters correlated. In conclusion, measurements by oxygen electrodes were able to distinguish intratumour heterogeneity from intertumour heterogeneity provided that several electrode tracks were done. The method therefore appears to be feasible for differentiation of tumour oxygenation clinically.

Adult↗
PubMed1994

Deep heating using a movable applicator phased array hyperthermia system. A preclinical feasibility study.

A preclinical evaluation of the 'movable applicator phased array hyperthermia system' was performed. The system employs four coherent applicators enabling power steering by amplitude and phase control. This concept has already been used in other systems, but the combination with a compact applicator design and easy movement of applicators has not been used before. The paper contains a description of the system and a verification of its performance using quality assurance tests with scanned E-field measurements. A clinical simulation was performed in pig to address the clinical feasibility of the system. The target volume was the left kidney. Two heating sessions, with and without occluded blood-flow to the kidney, were performed. In the low-flow experiments a temperature of 48 degrees C and 46 degrees C was obtained in the upper and lower pole of the kidney respectively. For the high-flow experiment the temperature in the upper pole was 48 degrees C.

Animals↗
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↗