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Biomedical subjects

J Overgaard

Publications and source records attributed to J Overgaard.

At least 235 records · Page 13Linked to original sources
PubMed1989

Photodynamic therapy of experimental intraocular retinoblastomas--dose-response relationships to light energy and photofrin II.

The destructive effect on tumour tissue and on normal eye tissue of photodynamic therapy has been investigated in rat eyes containing fast growing retinoblastoma-like tumours. Tumour response was described in terms of local control 90 days after treatment. The curability increased up to a maximum when large Photofrin II doses or light energy doses were administered. Early damage of conjunctiva or cornea also increased with large treatment doses and was an important limitation factor for improvement of the curability in the current model. The level of normal tissue damage decreased rapidly with increasing intervals between administration of Photofrin II and light, suggesting that conjunctival or corneal damage may not be a limitation factor 3-5 days after Photofrin II administration. A reciprocal relationship between light energy doses and Photofrin II doses was demonstrated both for curability and for the normal tissue damage. The results suggested that 2.5 mg/kg Photofrin II in combination with an extended light irradiation provoked less normal tissue damage than 10 mg/kg Photofrin II in combination with an equivalent shorter light exposure in order to obtain 15% curability of the animals.

Animals↗
PubMed1989

Mechanism for the reduction of tumour hypoxia by nicotinamide and the clinical relevance for radiotherapy.

Nicotinamide (1000 mg/kg; i.p.) enhanced the radiation response of the SCCVII tumour, producing an ER of almost 1.5 in a growth delay assay. Separating tumour cells as a function of fluorescent labelling with Hoechst 33342, suggested that this enhancement may be primarily a result of the elimination of acutely hypoxic cells in tumours. Nicotinamide also decreased mean arterial blood pressure in mice. These results are discussed with respect to their clinical applicability.

Animals↗
PubMed1988

Pharyngo-cutaneous fistulae after laryngectomy. Influence of previous radiotherapy and prophylactic metronidazole.

The development of a pharyngocutaneous fistulae is a major complication after total laryngectomy. In Denmark radiotherapy is the primary treatment for all laryngeal carcinomas. Based on the experience with conventional daily irradiation, a split-course radiation schedule was introduced in 1978. The charts of 106 consecutive patients laryngectomized for recurrence in the years 1975 to 1984 were examined. Thirty-four patients developed a fistula. An evaluation of the different radiotherapy schedules used during this period allowed a dose-response curve to be constructed. It showed a pronounced increase of fistulae with high doses of radiotherapy. Split-course radiotherapy caused a rise in late complications and did not improve tumor control. Large field sizes increased the number of fistulae. High-dose fractions showed a surprisingly high incidence of late complications. Prophylactic metronidazole (introduced in 1980) resulted in a highly significant decrease in the frequency of postoperative fistulae. Patients in whom fistula formed were hospitalized for an average of 54 days, patients without, for 22 days.

Fistula↗
PubMed1988

Misonidazole neuropathy. A prospective study.

The frequency with which polyneuropathy developed was investigated in patients with cancer of the larynx and pharynx who participated in a double-blind trial of the radiosensitizing drug misonidazole. Fourteen of 36 patients receiving misonidazole (total dose of about 11 g/m2) developed neuropathy, while this occurred in only 2 of 34 patients in the placebo group. Vibration perception threshold increased in all patients who developed neuropathy, but also in 12 (5 misonidazole and 7 placebo treated) without other symptoms or signs of neuropathy. Pharmacokinetic studies of misonidazole revealed a correlation between development of neuropathy and a high 'peak plasma concentration/g misonidazole in each fraction' and especially a high 'area under plasma concentration curve/g misonidazole in each fraction'.

Adult↗
PubMed1988

Effect of combined 5-fluorouracil and radiation on murine hematopoietic tissue.

The interaction of 5-fluorouracil (5-FU) and radiation in hematopoietic tissue was assessed as the survival of hematopoietic stem cells (CFUs) by means of the spleen colony assay. 5-FU was given intraperitoneally in the dose range 50-500 mg/kg body weight. In this dose range, stem cell survival decreased exponentially as a function of 5-FU dose. After 150 mg/kg of 5-FU alone (i.e. the maximum tolerated dose, MTD), the stem cell survival rapidly decreased, reaching a minimum after 1-2 days. The decrease was followed by a regeneration phase with a doubling time of about 28 h, with return to pretreatment values on day 7, and with an overshoot of survival on day 10-28. A similar regeneration was observed after 0.75 Gy radiation alone, but there was no evidence of an overshoot of stem cell number. 5-FU given 15 min before whole-body irradiation resulted in a pronounced reduction in stem cell survival due to an increase in the slope of the radiation survival curve by a factor of 2.1. After combined 5-FU and radiation, the survival rapidly decreased to a minimum at day 1, and it showed only a slight increase within the next 7 days. After this delay, the stem cells regenerated with a doubling time of about 30 h, reaching pretreatment values on day 15. The delayed stem cell regeneration was not seen following 3.5 Gy radiation alone or 225 mg/kg 5-FU alone, which resulted in the same nadir of CFUs survival as found after the combined treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

Effect of cancer chemotherapy on the hypoxic fraction of a solid tumor measured using a local tumor control assay.

The effect of mitomycin C (MMC), adriamycin (ADM), cyclophosphamide (CTX), cisplatinum (cis-DDP) and bleomycin (BLM) on the aerobic and hypoxic cells of a C3H mammary carcinoma in CDF1 mice was investigated using the tumor control assay. Hypoxic fractions (HF) were calculated by an indirect technique using the horizontal displacement of the TCD50 value from the dose-response curves of tumors irradiated under normal or clamped conditions. The HF and absolute number of tumor cells following a combined treatment was compared to that obtained with radiation alone. MMC, ADM and CTX had a significant enhancing effect on the unclamped TCD50. All three drugs caused a marked reduction in the proportion of hypoxic cells, decreasing the HF from 5.4% to about 1% of the total cell number. The surviving proportion of hypoxic cells were 11.1, 8.9 and 6.5% respectively. Killing of aerobic cells was also observed but the effect was less than that seen on the hypoxic cells, with the survival only being reduced to between 38 and 68% of the total number of aerobic cells. In contrast, cis-DDP and BLM were shown to produce major cell killing in the aerobic compartment but actually showed no cytotoxicity towards hypoxic cells. This would explain the lack of radiation enhancement observed for these two drugs. We conclude that the ability of adjuvant drugs to improve radiation response is dependent on the hypoxic cell killing by the drugs.

Animals↗
PubMed1988

Effect of step-down heating on hyperthermic radiosensitization in an experimental tumor and a normal tissue in vivo.

The effect of step-down heating (SDH) on the radiosensitization induced by simultaneous hyperthermia and radiation was investigated in a C3H mammary carcinoma inoculated into the feet of CDF1 mice and the skin of normal CDF1 feet. SDH consisted of a sensitizing treatment (ST) of 44.5 degrees C/10 min followed by a test treatment (TT) of 41.5 degrees C for 30, 60 or 120 min. Simultaneous administration of radiation and hyperthermia was achieved by delivering radiation in the middle of the TT. The endpoint selected was the radiation dose needed to achieve either tumor control or moist desquamation in 50% of the animals. The results were evaluated by the thermal enhancement ratio (TER), defined as dose of radiation needed to achieve endpoint in relation to dose of combined radiation and hyperthermia needed to achieve the endpoint. SDH of tumors increased the TER significantly compared with step-up heating (SUH). The ratios between TCD50 values for corresponding SDH and SUH increased with TT heating time and at 120 min a 2.5-fold increase in the radiosensitizing effect was achieved. It has previously been shown that SDH alone causes thermosensitization in tumors by decreasing the activation energy. However, the effect was too small to explain the increased radiosensitization observed with SDH. In the normal tissue studies SDH combined with radiation treatment gave a lower TER compared to the SDH tumor results, suggesting a possible therapeutic gain.

Animals↗
PubMed1988

Mechanism of action of the selective tumor radiosensitizer nicotinamide.

Nicotinamide has been shown to selectively enhance the radiation damage of tumors in preference to normal tissues. Our present study was an investigation into the mechanism responsible for this effect in the SCCVII/St tumor model grown on the backs of C3H/km mice. A large single injection of nicotinamide (1000 mg/kg), given intraperitoneally 60 minutes before whole body irradiation, significantly enhanced the radiation response of SCCVII tumors as measured by an in vivo/in vitro excision assay performed 24 hr following irradiation. It also gave rise to an almost 4-fold reduction in the binding of 14C-misonidazole, injected 1 hr after the nicotinamide and measured by scintillation counting of excised tumor material 24 hr later. This suggested that nicotinamide was decreasing the degree of tumor hypoxia. Attempts were made to correlate these results with nicotinamide-induced changes in tumor blood flow using the techniques of 133Xe clearance, 86RbCl extraction and Hoechst 33342 fluorescent labelling. Nicotinamide produced between a 30-40% increase in mean tumor cell fluorescence of Hoechst 33342, which was consistent with an increase in tumor blood flow. A similar response was obtained using the uptake of 86RbCl as the end point. However, no statistically significant difference was seen between the tumor blood flow of control and nicotinamide treated mice using the 133Xe clearance procedure. These results are discussed with respect to their clinical implications.

Animals↗
PubMed1988

A regression analysis of prognostic factors after resection of Dukes' B and C carcinoma of the rectum and rectosigmoid. Does post-operative radiotherapy change the prognosis?

The prognostic value of several clinical and histopathological characteristics has been evaluated in patients with Dukes' B and C carcinoma of the rectum and the rectosigmoid. Data on 260 Dukes' B and 208 Dukes' C tumours entered into a prospective, randomized clinical trial of post-operative radiotherapy (50 Gy given with 2 Gy/fraction in an overall time of 7 weeks) were analyzed by means of the Cox proportional hazards model. The Dukes' stages B and C were analyzed in two separate multivariate analyses. In patients with Dukes' B tumours, a poor prognosis was associated with age above 60, perineural and venous invasion, tumour located less than 10 cm from the anal verge and elevated pre-operative carcinoembryonic antigen (CEA) (greater than 3.2 ng ml-1). In patients with Dukes' C tumours, perineural and venous invasion, tumour located less than 10 cm from the anal verge, and elevated pre-operative CEA were associated with a poor prognosis. In addition, a large tumour diameter had a strong, negative influence on the prognosis. Males seemed to have a poorer prognosis than females among the Dukes' C patients. Resection of neighbouring organs was also associated with a poor prognosis in this stage. Post-operative radiotherapy as administered in the present series had no significant influence on prognosis. Based on the derived prognostic models patients with a hazard of death above the median in each stage were selected. A separate analysis of the survival in these high risk patients showed no survival benefit from radiotherapy. The proportional hazards model may be a useful tool in selecting patients for more aggressive adjuvant treatment.

Age Factors↗
PubMed1988

Predictive value of flow cytometric DNA-analysis on fresh retinoblastoma tissue.

The cellular DNA content and the distribution of tumour cells in different phases of the cell cycles has been analysed in 8 consecutive enucleated eyes with retinoblastoma. All tumours had abnormal ploidy levels. The analysis did not reveal any specific pattern in 2 tumours which had metastasized compared to 6 local tumours. The flow cytometric analysis alone or in combination with histopathology appeared not to improve the classification of large retinoblastomas.

Child, Preschool↗
PubMed1988

Some methodological problems in estimating radiobiological parameters from clinical data. Alpha/beta ratios and electron RBE for cutaneous reactions in patients treated with postmastectomy radiotherapy.

A number of biological, dosimetric, and statistical problems encountered in the determination of alpha/beta ratios and the relative biological efficiency (RBE) of high energy electrons are discussed. The analysis is based on isoeffect dose determination from logit analysis of dose-response data. Monte Carlo simulations of the logit analysis show that the estimated isoeffect dose may be treated as a normally distributed random variable. Under this assumption, formulae for the standard error of the derived radiobiological parameters are presented. The importance of specifying not only parameter estimates but also their confidence limits is emphasized. As a practical example, the dose-response relationships for severe erythema and subcutaneous fibrosis are discussed in two series of patients treated with postmastectomy irradiation with electrons and photons in two fractionation schedules. Because of a different dose per fraction in the electron and photon fields, a determination of RBE requires a fraction size correction. This is performed using the alpha/beta formalism. The present analysis suggests a high energy electron RBE for severe erythema of 0.93 (95% confidence limits 0.89 and 0.96) and for subcutaneous fibrosis of 0.84 (95% confidence limits 0.77 and 0.92).

Breast Neoplasms↗
PubMed1988

Comparison of conventional and split-course radiotherapy as primary treatment in carcinoma of the larynx.

Based on our experience with conventional, daily irradiation, a split-course radiation schedule was introduced in 1978. The schedule, which was based on Cohen's models for squamous cell carcinoma and vascular damage respectively, predicted an improved tumour control and a reduced rate of late complications, e.g. late oedema, if the conventional, daily treatment was replaced by a split-course schedule. The schedule has later been abandoned, but the experience gained from split-course treatment at various dose levels has been analysed and the results compared with those obtained by conventional radiation. The data allowed construction of dose-response curves and estimation of iso-effect doses. Split-course treatment was associated with a significantly reduced therapeutic ratio because, disappointingly, it did not improve tumour control, and the severity of late complications grew. No late complications were avoided by introducing a 3-week pause in the radiation therapy regimen, nor was the tumour response improved despite a 12-Gy increase in total dose. This indicates a significant repopulation corresponding to more than 0.5 Gy/day, equivalent to an up to 100-fold increase of the number of clonogenic tumour cells during the pause--an increase that occurred despite the decrease, clinically, of the tumours during this period.

Carcinoma, Squamous Cell↗
PubMed1987

Experimental studies of photodynamic therapy in a retinoblastoma-like tumour.

Combination therapy with a purified hematoporphyrin derivative, Photofrin II, and red light (photodynamic therapy) was investigated in a retinoblastoma-like tumour growing in the eyes of rats in vivo and in cell cultures. There was a marked dose-response relationship between Photofrin II and the light energy both in vitro and in vivo. Up to 33% of the tumours could be controlled in vivo. In vivo/in vitro assays indicated Photofrin II uptake in the tumour cells in vivo in relation to the administered doses. Studies of cell death kinetics suggested that the mechanisms of photodynamic therapy were both a primary cell kill effect and a secondary tissue destruction, probably as a consequence of vascular damage.

Animals↗