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Biomedical subjects

J Overgaard

Publications and source records attributed to J Overgaard.

At least 217 records · Page 12Linked to original sources
PubMed1989

Cystometric evaluation of early and late irradiation damage to the mouse urinary bladder.

The present study reports a simple, non-invasive, in vivo method for detecting early and late radiation damage to the mouse urinary bladder using transurethral bladder filling. The study also describes a useful experimental model for irradiation of mouse urinary bladder without any concomitant irradiation of the rectum and bony structures and maximal shielding of the small intestine. Within 30 days after single fraction bladder irradiation at 5-30 Gy, repeated cystometric investigations reveal a change in the reservoir function of the bladder illustrated by a considerable dose-dependent decrease in the compliance of the bladder wall. The changes in the reservoir function is reversible hence the bladder function is restored after another month. At various time intervals after the irradiation, however, the late radiation damage appears, the time of manifestation being dose-dependent. This final change is irreversible and consistent with the clinically known contracted bladder.

Animals↗
PubMed1989

Radiosensitization by nicotinamide in tumors and normal tissues: the importance of tissue oxygenation status.

Nicotinamide induced radiosensitization of tumors has been suggested to be a consequence of a reduction in tumor hypoxia. We have investigated the possibility that nicotinamide may produce significant radiosensitization in a normal tissue in which the radiation response is also influenced by hypoxia. The normal tissue studied was testis and radiation damage was assessed by measuring survival of spermatogonial stem cells. The radiosensitizing action of nicotinamide in testis was compared to that observed in a C3H mammary carcinoma when assayed by both regrowth delay and local tumor control. Our results show that nicotinamide (1000 mg/kg; i.p.) enhanced radiation damage in both tissue types when the radiation was given up to at least 3 hr after drug injection. Enhancement ratios obtained when the drug and radiation were separated by a 1 hr time interval were between 1.1 to 1.2 for the testis and 1.0 to 1.5 for the tumor. The results suggest that nicotinamide will produce radiosensitization in testis, but the effect is small and less than that observed in tumors.

Animals↗
PubMed1989

The current and potential role of hyperthermia in radiotherapy.

Current clinical experience strongly suggests that hyperthermia will become an important modality as an adjuvant to radiotherapy in the treatment of locally advanced solid tumors. Hyperthermia must therefore be considered a topic of general interest. Biologically, hyperthermia has two different types of interactions with radiation. Firstly, heat has a radiosensitizing effect. This is most prominent with simultaneous application, but is of the same magnitude in both tumor and normal tissue and will not improve the therapeutic ratio unless the tumor is heated to a higher temperature than the normal tissue. Secondly, hyperthermia exhibits a direct cytotoxic effect, and a moderate heat treatment alone can almost selectively destroy tumor cells in a nutritionally deprived chronically hypoxic and acidic environment. Because such cells are the most radioresistant, a smaller radiation dose is needed to control the remaining more radiosensitive cells. If critical, irradiated normal tissues are also heated, the cytotoxicity is best utilised if heat is given at least 3-4 hours after irradiation. The magnitude of both the sensitizing and the cytotoxic effect depends on temperature and heating time. Clinically, heating of superficial tumors (e.g. breast, neck nodes and malignant melanoma) has confirmed the biological rationale for using hyperthermia as an adjuvant to radiotherapy. An overview of available data gives thermal enhancement ratios of approximately 1.5 in several superficial tumor sites after external heating. From a practical point of view, true simultaneous treatment is almost impossible using external heating, and the major effect of the combined treatment will have to rely on hyperthermic cytotoxicity. This makes the design of clinical schedules less complicated since only a few heat fractions may be needed to achieve an optimal effect. On this basis, several randomized clinical trials have been activated with the aim to evaluate the role of adjuvant hyperthermia in the primary treatment of advanced (superficial) tumors. In addition, studies are underway to specifically elucidate the clinical relevance of thermotolerance and other biological issues. So far, the clinical evaluation has almost solely been limited to superficial tumors, or to situations where interstitial heating is feasible. External heating of "deep" seated tumors is still preliminary, and most studies are in Phase I-II, with emphasis on toxicity and feasibility. The initial results are promising with regard to improved tumor control and acceptable toxicity.

Combined Modality Therapy↗
PubMed1989

Misonidazole combined with split-course radiotherapy in the treatment of invasive carcinoma of larynx and pharynx: report from the DAHANCA 2 study.

Between October 1979 and May 1985, 626 patients with pharynx and larynx carcinoma were randomized to two different split-course radiation regimens and given either misonidazole (MISO; 11 g/m2) or placebo during the initial 4 weeks of treatment. Patients in the different treatment groups were evenly distributed among stages. The small number of females (136) gave an uneven distribution, thus making analysis difficult. The results show that females had a statistically better loco-regional control (45 vs. 33%; 5-year actuarial value). Overall, the MISO treated group did not have a significantly better control rate than the placebo groups (37 vs. 34%). However, a difference was found in patients with pharynx carcinomas (38 vs. 27%; p less than 0.05). The pre-irradiation hemoglobin (Hb) concentration was found to be a prognostic parameter. In females, loco-regional control for IIb values below or above 8 mmol/l were 37 and 47%, respectively. In males, the same values were below or above 9 mmol/l 26 and 38%. Hb influence on local control was only seen in supraglottic and pharynx tumors. This effect was independent of tumor size, which also was of prognostic value. In addition Hb concentration and MISO had an apparent additive effect. Thus in the male pharynx group, placebo patients with low Hb had a 14% disease rate compared to 40% in MISO treated patients with Hb above 9 mmol/l. MISO induced significant peripheral neuropathy in 26% of the treated patients, whereas other drug related side effects were minimal and tolerable.

Carcinoma, Squamous Cell↗
PubMed1989

Misonidazole combined with radiotherapy in the treatment of carcinoma of the uterine cervix.

Between April 1979 and January 1982, 331 patients were included in a study to establish whether misonidazole (MISO) had any effect as an adjuvant to radiotherapy in the treatment of squamous cell carcinoma of the uterine cervix (FIGO Stage IIb, III, and IVa). Patients were randomized to receive either MISO (12 g/m2 applied within 6 weeks) or placebo. This was given in conjunction with each institution's normal radiotherapy schedule and thus varied with regard to external and intracavitary irradiation. The analysis was performed based on patients' status at January 1986, with all patients observed for at least 4 years. One hundred and sixty-four patients received MISO and 167 placebo. Compliance to radiotherapy was good and MISO was well tolerated. The overall rates for MISO vs. placebo were as follows: local tumour control, 50 vs. 54%; disease-free survival, 47 vs. 46%, and crude survival, 39 vs. 45%. A similar lack of MISO effect was found in the individual stages. However, patients in all stages with hemoglobin concentrations below 7 mmol/l had a significantly lower local control probability (overall 24 vs. 47%), whereas the incidence of distant metastases was unaffected. We conclude that the addition of MISO did not influence the radiation response in advanced uterine carcinoma. The reasons for this ineffectiveness are yet to be clarified.

Carcinoma, Squamous Cell↗
PubMed1989

Sensitization of hypoxic tumour cells--clinical experience.

There is substantial evidence for the presence of hypoxia in human tumours. This is documented by histopathological demonstration of vascular insufficiency, direct oxygen measurements in tumours, as well as by physiological imaging and mapping of hypoxic areas. As a consequence, clinical trials have focused on the hypoxia problem for more than 30 years. This includes the use of hyperbaric oxygen, hypoxic cell radiosensitizers, and, more recently, modification of the oxygen-unloading capacity of haemoglobin. Agents directed towards destruction of hypoxic cells have also been applied, such as hyperthermia and bio-reductive drugs. Despite decades of clinical trials, the results are still inconclusive, and although some trials have shown significant benefit, it has become apparent that hypoxia is a complex problem. Hypoxia appears to be especially a problem in certain tumour types (e.g. squamous cell carcinoma), but even within tumours of the same type, site, and stage, hypoxia does not occur to the same extent. Furthermore, there are increasing suggestions that hypoxia may occur in two principally different ways, namely acutely and chronically, yielding varying responses to modifying agents. Although improvement in hypoxic cell radiosensitizers and other agents is under way, a definitive solution to the hypoxia problem will not be found until the tumours in which hypoxia occurs can be identified. This will require detailed analysis of individual tumours and patients' parameters, and better knowledge of the mechanisms of reoxygenation in clonogenic tumour cells.

Cell Hypoxia↗
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↗