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J Overgaard

Publications and source records attributed to J Overgaard.

At least 109 records · Page 6Linked to original sources
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↗
PubMed1995

A century with hyperthermic oncology in Scandinavia.

The hyperthermic research during the last 100 years is reviewed with the aim to describe a research activity which has been performed in parallel to and associated with the development of radiation oncology. Basic and clinical research in several Scandinavian centres has made major international contributions to the establishment of a rationale for and implementation of hyperthermia as a combined modality treatment with chemotherapy or radiation in oncology. At the same time it has been demonstrated that collaboration and integration easily could be performed within the Scandinavian centres. Hyperthermic oncology is therefore a typical example of how research involving both biological, physical/engineering, and clinical skills in a proper environment can create valuable results.

History, 20th Century↗
PubMed1994

The in vivo interaction between vincristine and radiation in a C3H mammary carcinoma and the feet of CDF1 mice.

PURPOSE: Evaluation of the interaction between vincristine (VCR) and X rays in a murine tumor and its surrounding skin. METHODS AND MATERIALS: End points were local tumor control and moist desquamation using the C3H mammary carcinoma and the mouse foot skin in vivo. Cell cycle effects of VCR was studied by dual parameter flowcytometry. Vincristine was administered as a single IP injection at various time intervals from 4 days before to 4 days after irradiation. RESULTS: Flowcytometric studies of cell cycle distribution showed that VCR caused a temporary blockage of cells in the mitotic phase; the proportion of cells in G2M increased three-fold at intervals up to 48 h after VCR treatment. The radiation enhancement peaked when VCR was administered 24 h before X rays in tumors, and when given 15 min before X rays in skin. A significant therapeutic gain was observed at the 24 h preirradiation of postirradiation intervals--the therapeutic gain factors being 1.19 and 1.24, respectively (p < 0.005). Analysis of the tumor data suggested an additive cytotoxic effect rather than VCR radiosensitization. In contrast to what was expected from the single dose data, a significant loss of therapeutic effect was found for the addition of VCR administered at the first day of a fractionated irradiation regime with five fractions in 5 days (p < 0.025). CONCLUSION: The tumor control studies showed a lack of correlation between the VCR-induced accumulation of cells in G2M cell cycle phase and enhancement of tumor radiation response. Preirradiation VCR caused radiosensitization both in tumors and skin, whereas postirradiation VCR mostly resulted in responses equal to radiation only.

Animals↗
PubMed1994

Early and late radiotherapeutic morbidity in 442 consecutive patients with locally advanced carcinoma of the uterine cervix.

PURPOSE: to evaluate the early and late radiotherapeutic morbidity after combined external and intracavitary radiotherapy to the uterine cervix. METHODS AND MATERIALS: The morbidity in 442 consecutive cervical cancer patients FIGO Stage IIB (139), IIIA (10), IIIB (221) and IVA (72) treated from 1974 to 1984 were recorded retrospectively according to our own previously described system (18). This system is based on the assumption that radiotherapeutic morbidity progresses in severity with time wherefore successive morbidity scoring rather than recording the maximal damage alone is required to estimate the burden of complications for a group of patients. The early and late morbidity (within or beyond 3 months after the end of radiotherapy) was graded into mild, moderate, severe, and causing death depending on the symptoms and signs, and the requirement and type of therapy. The late morbidity was characterized by both the frequency and the actuarially corrected estimate. Also, the combined morbidity in two, three, four and five organs and the probability of surviving without tumor recurrence and/or significant late morbidity were evaluated. RESULTS: Early morbidity was most frequently seen in the rectosigmoideum (61%) and urinary bladder (27%). Medication for early morbidity was required in 68% and hospitalization in 10% of the patients. The frequencies of each late morbidity grade did not differ in relation to FIGO Stage while the actuarial estimates increased significantly with increasing stage. This reflects the poor prognosis in the more advanced stages, where few patients survived to develop late morbidity, and also points to the importance of latency in reporting late radiotherapeutic morbidity. In Stage IVA patients, the ratios between the actuarial estimate and the frequency of late severe rectosigmoid and urinary bladder morbidity were as high as 2.5 and 3, respectively. The highest 5-year risks (+/- 1 SE of the estimate) of late severe morbidity were found for the rectosigmoideum (28% +/- 3), small intestine (13% +/- 2) and urinary bladder (10% +/- 2). Rectosigmoid and urinary bladder complications constituted the most important part of the combined organ morbidity. Almost half of the patients developing late moderate rectosigmoid and one-third of those developing late moderate bladder complications, did so within one year after radiotherapy. Almost all complications were developed within 3 to 4 years after radiotherapy. The probability of surviving without recurrence and/or severe combined rectosigmoid and urinary bladder morbidity was low (23% +/- 2). CONCLUSION: Actuarial estimates rather than frequencies should be reported to avoid underestimation of the risk of late radiotherapeutic morbidity in long-term survivors.

Adult↗
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↗