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J Overgaard

Publications and source records attributed to J Overgaard.

At least 55 records · Page 3Linked to original sources
PubMed2000

Combretastatins novel vascular targeting drugs for improving anti-cancer therapy. Combretastatins and conventional therapy.

Combretastatins are a new class of compounds that appear to have anti-tumour activity as a result of specifically targeting the vasculature of tumours. The aim of this study was to investigate the potential of combretastatin A-4 disodium phosphate (CA4DP) to induce vascular effects in a C3H mouse mammary carcinoma, and to see if the anti-tumour response could be improved by combining the drug with conventional anti-cancer therapies. It was found that CA4DP (250 mg/kg) significantly decreased tumour perfusion within 30 minutes after injection and maintained this decrease for several hours, although there was a return to normal by 24 hours. Similar changes were seen in the tumours bioenergetic and oxygenation status. The drug also significantly increased tumour necrosis and had a small inhibitory effect on tumour growth. It was also able to enhance the tumour response to radiation and hyperthermia, when given at the same time or 30 minutes after the radiation and hyperthermia, respectively. Giving the drug 1 hour after cisplatin injection only resulted in a tumour response that was no greater than additive. These results confirm the anti-vascular effects of CA4DP and demonstrate its potential to enhance the anti-tumour activity of conventional therapy.

Animals↗
PubMed1999

Morbidity and mortality of ischaemic heart disease in high-risk breast-cancer patients after adjuvant postmastectomy systemic treatment with or without radiotherapy: analysis of DBCG 82b and 82c randomised trials. Radiotherapy Committee of the Danish Breast Cancer Cooperative Group.

BACKGROUND: Radiotherapy in addition to systemic treatment after mastectomy prolongs survival in high-risk breast-cancer patients. However, adjuvant radiotherapy has a potential association with ischaemic heart disease. We assessed morbidity and mortality from ischaemic heart disease in patients treated with postmastectomy radiotherapy. METHODS: Between 1982 and 1990, we randomly assigned 3083 women at high risk of breast cancer, after mastectomy, adjuvant systemic treatment with (n=1538) or without (n=1545) radiotherapy. An anterior photon field was used against the periclavicular region and the axilla. The chest wall was treated through two anterior shaped electron fields, one including the internal mammary nodes. The intended dose was 48-50 Gy in 22-25 fractions, at four to five fractions per week. We obtained information on morbidity and mortality of ischaemic heart disease over a median of 10 years. Analysis was by intention to treat. FINDINGS: More women in the no-radiotherapy group than in the radiotherapy group died of breast cancer (799 [52.5%] vs 674 [44.2%]), whereas similar proportions of each group died from ischaemic heart disease (13 [0.9%] vs 12 [0.8%]). The relative hazard of morbidity from ischaemic heart disease among patients in the radiotherapy compared with the no-radiotherapy group was 0.86 (95% CI 0.6-1.3), and that for death from ischaemic heart disease was 0.84 (0.4-1.8). The hazard rate of morbidity from ischaemic heart disease in the radiotherapy group compared with the no-radiotherapy group did not increase with time from treatment. INTERPRETATION: Postmastectomy radiotherapy with this regimen does not increase the actuarial risk of ischaemic heart disease after 12 years.

Adult↗
PubMed1999

[Angiogenesis: prognostic marker in prostatic cancer].

Angiogenesis, the formation of new blood vessels, has been suggested to provide important prognostic information in prostate cancer. The aim of this study was to investigate, whether microvessel density (MVD) at diagnosis was correlated with disease-specific survival in a non-curative treated population of prostate cancer patients. MVD was immunohistochemically (factor VIII-related antigen) quantified in archival tumours obtained at diagnosis in 221 prostate cancer patients. The maximal MVD was quantified inside a 0.25 mm2 area of the tumour and the median MVD was 43 (range 16-151). MVD was statistically significantly correlated with clinicopathological characteristics and disease-specific survival. A multivariate analysis demonstrated that MVD was a significant predictor of disease-specific survival in the entire cancer population, as well as in the clinically localized cancer population. These findings suggest that quantitation of angiogenesis reflects the spontaneous clinical outcome of prostate cancer.

Antigens↗
PubMed1999

Postoperative radiotherapy in high-risk postmenopausal breast-cancer patients given adjuvant tamoxifen: Danish Breast Cancer Cooperative Group DBCG 82c randomised trial.

BACKGROUND: Postmastectomy radiotherapy is associated with a lower locoregional recurrence rate and improved disease-free and overall survival when combined with chemotherapy in premenopausal high-risk breast-cancer patients. However, whether the same benefits apply also in postmenopausal women treated with adjuvant tamoxifen for similar high-risk cancer is unclear. In a randomised trial among postmenopausal women who had undergone mastectomy, we compared adjuvant tamoxifen alone with tamoxifen plus postoperative radiotherapy. METHODS: Between 1982 and 1990, postmenopausal women with high-risk breast cancer (stage II or III) were randomly assigned adjuvant tamoxifen (30 mg daily for 1 year) alone (689) or with postoperative radiotherapy to the chest wall and regional lymph nodes (686). Median follow-up was 123 months. The endpoints were first site of recurrence (locoregional recurrence, distant metastases, or both), and disease-free and overall survival. FINDINGS: Locoregional recurrence occurred in 52 (8%) of the radiotherapy plus tamoxifen group and 242 (35%) of the tamoxifen only group (p<0.001). In total there were 321 (47%) and 411 (60%) recurrences, respectively. Disease-free survival was 36% in the radiotherapy plus tamoxifen group and 24% in the tamoxifen alone group (p<0.001). Overall survival was also higher in the radiotherapy group (385 vs 434 deaths; survival 45 vs 36% at 10 years, p=0.03). INTERPRETATION: Postoperative radiotherapy decreased the risk of locoregional recurrence and was associated with improved survival in high-risk postmenopausal breast-cancer patients after mastectomy and limited axillary dissection, with 1 year of adjuvant tamoxifen treatment. Improved survival in high-risk breast cancer can best be achieved by a strategy of both locoregional and systemic tumour control.

Antineoplastic Agents, Hormonal↗
PubMed1999

Localized in vivo 1H NMR spectroscopy of murine tumours: effect of blood flow reduction.

Single voxel 1H localized spectroscopy (PRESS at 300 MHz) was used to monitor physiological and biochemical changes induced by hydralazine (5 mg/kg, i.p.) in murine C3H mammary tumours. In addition to a significant increase (by 52%, maximal at 30 min) in the intensity of the 1.32 ppm signal (predominantly from lactate, consistent with a selective reduction in tumour blood supply by hydralazine), downfield shifts in the resonance frequencies of 1H signals were observed. In particular, the signal initially at 3.24 ppm (total choline, tCho) shifted by 0.050 ppm (maximal at 13 min), whereas water shifted by 0.086 ppm. Lactate intensity and water and tCho resonance frequencies returned to control values at approximately 100 min after treatment. No significant changes in the resonance frequencies of water or tCho were observed over this time period in the tumours of mice given saline. In vitro studies showed that, while the resonance frequency of water was temperature dependent, the main components of the tCho signal (choline, phosphorylcholine and glycerophosphorylcholine) were more than 30-fold less sensitive to temperature. It was concluded that the shift in the water resonance frequency was due to the combined effects of tumour temperature reduction and a paramagnetic shift from increased deoxyhaemoglobin levels, whereas the tCho signal was only affected by the paramagnetic shifts.

Animals↗
PubMed1999

Relationship between tumour cell in vitro radiosensitivity and clinical outcome after curative radiotherapy for squamous cell carcinoma of the head and neck.

BACKGROUND AND PURPOSE: Clinically, it is recognized that individual tumours respond differently to radiation treatment. Variation in tumour cell radiosensitivity is believed to be an important underlying factor. In the current study, cellular in vitro radiosensitivity was estimated as the fraction of surviving cells after a radiation dose of 2 Gy (SF2) and related to clinical outcome after curative radiotherapy. PATIENTS AND METHODS: Thirty-eight patients with squamous cell carcinoma of the head and neck were treated with curative radiotherapy alone. Pre-treatment biopsies were disaggregated to form a single-cell suspension and cells were cultured in the modified Courtenay-Mills soft agar clonogenic assay. Directly from this assay and with no respect to cell type, overall SF2 was assessed. By collecting the obtained colonies on a preparation slide using a colony-filter technique, and with immunocytochemical staining, it was possible to measure the surviving fraction of tumour cells selectively as tumour cell SF2. RESULTS: Experimentally, a broad inter-tumour variation was found for both tumour cell SF2 and overall SF2. Using weighted linear regression, it was demonstrated that tumour cell SF2 and overall SF2 were two independent measures of tumour radiosensitivity. In general, the measures of tumour radiosensitivity were independent of patient sex and age, T- and N-category, disease stage, tumour size and plating efficiency. Among the 38 patients grouped in loco-regional failures and patients with loco-regional control, respectively, sex, age, total radiation dose, overall treatment time and tumour grade were equally distributed. Advanced stage, lymph node involvement and tumour size correlated statistically significantly with poor loco-regional control. Neither tumour cell SF2, overall SF2, nor plating efficiency predicted loco-regional tumour control probability. In a multivariate analysis with respect to the risk of loco-regional tumour failure, only disease stage yielded independent prognostic significance. This significance suggests that this patient sample was representative for the patient population with head and neck cancer. CONCLUSION: In 38 patients with squamous cell carcinoma of the head and neck, the estimated tumour radiosensitivities were not statistically related to clinical outcome after curative radiotherapy alone.

Adult↗
PubMed1999

The value of pretreatment cell kinetic parameters as predictors for radiotherapy outcome in head and neck cancer: a multicenter analysis.

PURPOSE: The aim of this study was to assess the potential of pre-treatment cell kinetic parameters to predict outcome in head and neck cancer patients treated by conventional radiotherapy. MATERIALS AND METHODS: Data from 11 different centers were pooled. Inclusion criteria were such that the patients received radiotherapy alone, and that the radiotherapy was given in an overall time of at least 6 weeks with a dose of at least 60 Gy. All patients received a tracer dose of either iododeoxyuridine (IdUrd) or bromodeoxyuridine (BrdUrd) intravenously prior to treatment and a tumor biopsy was taken several hours later. The cell kinetic parameters labeling index (LI), DNA synthesis time (Ts) and potential doubling time (Tpot) were subsequently calculated from flow cytometry data, obtained on the biopsies using antibodies against I/BrdUrd incorporated into DNA. Each center carried out their own flow cytometry analysis. RESULTS: From the 11 centers, a total of 476 patients conforming to the inclusion criteria were analyzed. Median values for overall time and total dose were 49 days and 69 Gy, respectively. Fifty one percent of patients had local recurrences and 53% patients had died, the majority from their disease. Median follow-up was 20 months; being 30 months for surviving patients. Multivariate analysis revealed that T-stage, maximum tumor diameter, differentiation grade, N-stage, tumor localization and overall time correlated with locoregional control, in decreasing order of significance. For the cell kinetic parameters, univariate analysis showed that only LI was significantly associated with local control (P=0.02), with higher values correlating with a worse outcome. Ts showed some evidence that patients with longer values did worse, but this was not significant (P=0.06). Tpot showed no trend (P=0.8). When assessing survival in a univariate analysis, neither LI nor Tpot associated with outcome (P=0.4, 0.4, respectively). Surprisingly, Ts did correlate with survival, with longer values being worse (P=0.02). In the multivariate analysis of local control, LI lost its significance (P=0.16). CONCLUSIONS: The only pretreatment kinetic parameter for which some evidence was found for an association with local control (the best end-point for testing the present hypothesis) was LI, not Tpot, and this evidence disappeared in a multivariate analysis. It therefore appears that pretreatment cell kinetic measurements carried out using flow cytometry, only provide a relatively weak predictor of outcome after radiotherapy in head and neck cancer.

Analysis of Variance↗
PubMed1999

Respiratory consequences of feeding in the snake Python molorus.

Snakes can ingest large meals and exhibit marked increases in metabolic rate during digestion. Because postprandial oxygen consumption in some snakes may surpass that attained during exercise, studies of digestion offers an alternative avenue to understand the cardio-respiratory responses to elevated metabolic rate in reptiles. The effects of feeding on metabolic rate, arterial oxygen levels, and arterial acid-base status in the snake Python molorus are described. Four snakes (180-250 g) were cannulated in the dorsal aorta and blood samples were obtained during 72 h following ingestion of a meal (rat pups) exceeding 20% of body weight. Oxygen consumption increased from a fasting value of 1.71 +/- 0.08 to 5.54 +/- 0.42 ml kg-1 min-1 at 48 h following feeding, and the respiratory gas exchange ratio increased from 0.67 +/- 0.02 to a maximum of 0.92 +/- 0.03 at 32 h. Plasma lactate was always less than 0.5 mM, so the postprandial increase in metabolic rate was met by aerobic respiration. In fasting animals, arterial PO2 was 66 +/- 4 mmHg and haemoglobin-O2 saturation was 92 +/- 3%; similar values were recorded during digestion, but haematocrit decreased from 15.8 +/- 1.0 to 9.8 +/- 0.8 due to repeated blood sampling. Plasma [HCO3-] increased from a fasting level of 19.3 +/- 0.8 to 25.8 +/- 1.0 mmol l-1 at 24 h after feeding. However, because arterial PCO2 increased from 21.1 +/- 0.5 to 27.9 +/- 1.4 mmHg, there was no significant change in arterial pH from the fasting value of 7.52 +/- 0.01. Acid-base status returned to pre-feeding levels at 72 h following feeding. The increased arterial PCO2 is most likely explained by a reduction in ventilation relative to metabolism, but we predict that lung PO2 does not decrease below 115 mmHg. Although ingestion of large meals is associated with large metabolic changes in pythons, the attendant changes in blood gases are relatively small. In particular, the small changes in plasma [HCO3-] and stable pH show that pythons respond very differently to digestion than alligators where very large alkaline tides have been observed. It is unclear why pythons and alligators differ in the magnitude of their responses, but given these interspecific differences it seems worthwhile to describe arterial blood gases during digestion in other species of ectothermic vertebrates.

Acid-Base Imbalance↗
PubMed1999

Ku70/80 gene expression and DNA-dependent protein kinase (DNA-PK) activity do not correlate with double-strand break (dsb) repair capacity and cellular radiosensitivity in normal human fibroblasts.

The expression of the Ku70 and Ku80 genes as well as the activity of the DNA-dependent protein kinase (DNA-PK) were studied in 11 normal human fibroblast lines. The proteins studied are known to be part of a double-strand break (dsb) repair complex involved in non-homologous recombination, as was demonstrated for the radiosensitive rodent mutant cell lines of the complementation groups 5-7. The 11 fibroblast lines used in this study represent a typical spectrum of normal human radiosensitivity with the surviving fraction measured for a dose of 3.5 Gy, SF3.5 GY, ranging from 0.03 to 0.28. These differences in cell survival were previously shown to correlate with the number of non-repaired dsbs. We found that the mRNA signal intensities of both Ku70 and Ku80 genes were fairly similar for the 11 cell lines investigated. In addition, the DNA-PK activity determined by the pulldown assay was fairly constant in these fibroblast lines. Despite the correlation between cell survival and dsb repair capacity, there was no correlation between dsb repair capacity and DNA-PK activity in the tested normal human fibroblast lines. Obviously, in this respect, other proteins/pathways appear to be more relevant.

Antigens, Nuclear↗
PubMed1999

In vitro radiosensitivity of tumour cells and fibroblasts derived from head and neck carcinomas: mutual relationship and correlation with clinical data.

The aim was to characterize the variation in the cellular in vitro radiosensitivities in squamous cell carcinomas of the head and neck, and to test for a possible correlation between different measures of radiosensitivity and the clinical and histopathological data. Cellular in vitro radiosensitivities were assessed in tumour biopsies from 71 patients using the modified Courtenay-Mills soft agar clonogenic assay combined with an immunocytochemical analysis. Radiosensitivity was quantified as the surviving fraction after a radiation dose of 2 Gy irrespective of cell type (overall SF2), or based on identification of cell type (tumour cell SF2, fibroblast SF2). Sixty-three biopsies were from primary tumours, and eight were from recurrences. Overall plating efficiency ranged from 0.005 to 1.60% with a median of 0.052%. The majority of the colonies obtained from the biopsies were fibroblast marker-positive; the proportion of tumour marker-positive colonies ranged from 1 to 88% with a median of 15%. The median overall SF2 was 0.47 (range 0.24-0.96), the median tumour cell SF2 was 0.50 (range 0.11-1.0) and the median fibroblast SF2 was 0.49 (range 0.24-1.0). Comparing data from independent experiments, the overall SF2 was significantly correlated with the SF2 of fibroblasts (2P = 0.006) but not with the tumour cell SF2. The tumour cell and fibroblast radiosensitivities measured in the same individuals were not correlated (r= 0.06, 95% CI [-0.19, 0.30]):This finding seems to preclude a strong correlation between the radiosensitivity of tumour cells and fibroblasts. Concerning the clinical characteristics, neither of the measures of tumour radiosensitivity was correlated with T- and N-category, stage, tumour size, sex and age. However, the tumour cell radiosensitivity decreased with increasing grade of histopathological differentiation (2P = 0.012). The same tendency was found in two independent analyses of the same patient material. This correlation was not significant in case of the overall SF2 or the fibroblast SF2.

Adult↗
PubMed1998

The effect of combretastatin A-4 disodium phosphate in a C3H mouse mammary carcinoma and a variety of murine spontaneous tumors.

PURPOSE: To investigate the activity of combretastatin A-4 disodium phosphate in a transplanted C3H mouse mammary carcinoma and several murine spontaneous tumors. METHODS AND MATERIALS: The C3H mammary carcinoma was grown in the right rear foot of female CDF1 mice and treated when 200 mm3 in size. Spontaneous tumors (341-1437 mm3 in size) arose at different sites in female CDF1 mice that, 19-21 months earlier, had been irradiated. Oxygen partial pressure (pO2) distributions in the C3H tumors were measured with an Eppendorf oxygen electrode at various times after injecting combretastatin (100 mg/kg, i.p.) in restrained, nonanesthetized mice. Immediately after measurement, tumors were excised and necrotic fraction determined from histological sections. In the spontaneous tumors, pO2 was measured before and 3 h after giving combretastatin. The location of these spontaneous tumors required that measurements be made in anesthetised animals, achieved by injecting a mixture of hypnorm and diazepam. RESULTS: In untreated C3H tumors, the mean (+/- 1 SE) percentage of pO2 values < or = 2.5 mmHg was 32% (+/- 11). This was significantly (Student's t-test; p < 0.05) increased to 74% (+/- 4) within 1 h after injecting combretastatin, and remained at this level for at least 6 h, although some recovery was seen at 12 and 24 h. The necrotic fraction in control tumors was 1.9% (+/- 0.4) and this was significantly increased to 16.1% (+/- 3.7) 24 h after drug administration. In spontaneous tumors, the pO2 measurements indicated that 5 of 6 showed some response to combretastatin, although the degree of change was variable. CONCLUSIONS: Combretastatin increased tumor hypoxia and necrosis in the C3H mammary carcinoma, consistent with the induction of vascular damage. Drug-induced changes in pO2 were also found in spontaneous tumors, suggesting that the activity of this drug is not restricted to transplanted tumors alone.

Animals↗
PubMed1998

DNA ploidy and survival of patients with clinically localized prostate cancer treated without intent to cure.

BACKGROUND: The optimal approach to diagnosis and treatment of localized prostate cancer remains controversial. Deoxyribonucleic acid (DNA) ploidy has been suggested as an important predictor for outcome in prostate cancer. The purpose of this study was to correlate DNA ploidy with disease-specific survival in patients with clinically localized prostate cancer treated with no intent to cure. METHODS: DNA ploidy was determined by flow cytometry in archival formalin fixed, paraffin embedded tumor tissue obtained at diagnosis in 120 patients with clinically localized prostate cancer with a nearly complete follow-up. RESULTS: Ninety (75%) of the tumors were diploid, while only 11 (9%) tumors were categorized as tetraploid. Tumor DNA ploidy (diploid versus nondiploid) significantly associated with histopathological grade (P=0.002) and disease-specific survival (P=0.011), while there was no association with tumor stage (P=0.054). In a multivariate Cox analysis, histopathological grade (P=0.005) was the only significant predictor of disease-specific death, while analyzing the 96 low-grade tumors separately, DNA ploidy became significant (P= 0.024). CONCLUSIONS: Flow cytometric determined nondiploidy was associated with disease-specific death in patients with clinically localized prostate cancer, but DNA ploidy provided additional prognostic information in patients with low-grade tumors only.

Aged↗
PubMed1998

Allelic loss of 16q23.2-24.2 is an independent marker of good prognosis in primary breast cancer.

Allelic loss, detected as a loss of heterozygosity (LOH) on the long arm of chromosome 16, is an early and frequent event in breast cancer. Despite this, the clinical significance of LOH on 16q has been very poorly studied. In this study, corresponding blood and tumor samples from 199 clinically well-characterized primary breast cancer patients were analyzed for LOH with the highly polymorphic microsatellite marker D16S511, located at 16q23.2-24.2. 61% of 168 informative tumors showed LOH. Univariate and multivariate analysis found a highly significant association between LOH at 16q23.2-24.2 and freedom from distant metastases, disease-free survival, and overall survival, respectively. No association was found with other clinical parameters such as menopausal status, tumor size, lymph node status, histopathology, and lymph node capsule invasion. This makes allelic loss of 16q23.2-24.2 an independent marker of good prognosis for primary breast cancer.

Adult↗
PubMed1998

[DAHANCA (Danish Head and Neck Cancer)--20 years of cooperation].

A review of the DAHANCA-group's projects concerning cancer of the head and neck over 20 years is presented. Apart from the first, all projects were randomized trials. Two projects with neoadjuvant chemotherapy have not shown any notable tumour control or better survival. More than 1800 patients suffering from cancer of the head and neck treated in the five oncological centres of the country were included in the three projects concerning radiosensitizers and radiotherapy. The radiation has been accelerated during the years making it more effective. Each of the three projects has improved the local control rate by 11-15% and the survival is enhanced by 11-13% for each project. Cooperation between our five oncological centres has given good results and increased the survival for patients with head and neck cancer. It is now routine to give the radiosensitizer tablets Nimorazol 1 1/2 hours before radiation and to give six fractions weekly to patients with squamous cell cancer in the supraglottic region, pharynx and oral cavity.

Carcinoma, Squamous Cell↗
PubMed1998

Lack of predictive value of potential doubling time and iododeoxyuridine labelling index in radiotherapy of squamous cell carcinoma of the head and neck.

PURPOSE: To investigate the prognostic value of T(POT), S-phase time (TS), iododeoxyuridine (IdUrd) labelling index (LI) and DNA index with loco-regional tumour control as the end-point. MATERIALS AND METHODS: Iododeoxyuridine was given to 99 patients with squamous cell carcinomas of the head and neck before the start of radiotherapy. The analysis included FCM parameters (LI, TS, T[POT] and DNA index, n = 87) and LI determined by immunohistology (IHC, n = 45). A hybrid T(POT) was determined by combining the FCM TS and the IHC LI (n = 45). In diploid tumours (n = 39), the FCM LI was underestimated and the FCM T(POT) was overestimated because the flow cytometer was unable to distinguish between tumour and normal cells. The 'tumour LI' was defined as the IHC LI or the FCM LI of aneuploid tumours when a biopsy for IHC evaluation was not available and similarly the 'tumour T(POT)' was determined by the hybrid T(POT) or the FCM T(POT) of aneuploid tumours (n = 63). RESULTS: There was good agreement between the IHC LI and the FCM LI for aneuploid tumours, but there was disagreement for diploid tumours. The median tumour T(POT) was 4.1 days (range 0.6-19.5 days) and the median tumour LI was 12.9% (range 3.1-46.0%). In a univariate analysis there was no prediction of loco-regional tumour control by the LI, the TS or the T(POT) determined by either of the methods. T-classification, N-classification, clinical stage and tumour diameter were related with loco-regional tumour control, whereas clinical stage was the only parameter that yielded independent prognostic significance in a multivariate analysis. CONCLUSIONS: This study does not confirm the significant prognostic value of T(POT) as indicated in some previous reports. Larger clinical studies are needed to draw final conclusions.

Analysis of Variance↗
PubMed1998

A randomized double-blind phase III study of nimorazole as a hypoxic radiosensitizer of primary radiotherapy in supraglottic larynx and pharynx carcinoma. Results of the Danish Head and Neck Cancer Study (DAHANCA) Protocol 5-85.

PURPOSE: A multicenter randomized and balanced double-blind trial with the objective of assessing the efficacy and tolerance of nimorazole given as a hypoxic radiosensitizer in conjunction with primary radiotherapy of invasive carcinoma of the supraglottic larynx and pharynx. PATIENTS AND TREATMENT: Between January 1986 and September 1990, 422 patients (414 eligible) with pharynx and supraglottic larynx carcinoma were double-blind randomized to receive the hypoxic cell radiosensitizer nimorazole, or placebo, in association with conventional primary radiotherapy (62-68 Gy, 2 Gy per fraction, five fractions per week). The median observation time was 112 months. RESULTS: Univariate analysis showed that the outcome (5-year actuarial loco-regional tumor control) was significantly related to T-classification (T1-T2 48% versus T3-T4 36%, P = 0.0008), neck-nodes (N- 53% versus N+ 33%), pre-irradiation hemoglobin (Hb) concentration (high 46% versus low 37%, P = 0.02) and sex (females 51% versus males 38%, P = 0.03). Overall the nimorazole group showed a significantly better loco-regional control rate than the placebo group (49 versus 33%, P = 0.002). A similar significant benefit of nimorazole was observed for the end-points of final loco-regional control (including surgical salvage) and cancer-related deaths (52 versus 41%, P = 0.002). This trend was also found in the overall survival but to a lesser, non-significant extent (26 versus 16%, 10-year actuarial values, P = 0.32). Cox multivariate regression analysis showed the most important prognostic parameters for loco-regional control to be positive neck nodes (relative risk 1.84 (1.38-2.45)), T3-T4 tumor (relative risk 1.65 (1.25-2.17)) and nimorazole (relative risk 0.69 (0.52-0.90)). The same parameters were also significantly related to the probability of dying from cancer. The compliance to radiotherapy was good and 98% of the patients received the planned dose. Late radiation-related morbidity was observed in 10% of the patients, irrespective of nimorazole treatment. Drug-related side-effects were minor and tolerable with transient nausea and vomiting being the most frequent complications. CONCLUSION: Nimorazole significantly improves the effect of radiotherapeutic management of supraglottic and pharynx tumors and can be given without major side-effects.

Adult↗
PubMed1998

Differentiation state of skin fibroblast cultures versus risk of subcutaneous fibrosis after radiotherapy.

BACKGROUND AND PURPOSE: There is increasing evidence for patient-to-patient variation in the response of normal tissue to radiotherapy. Recently, it has been suggested that accumulation of functional fibrocytes may be a key step in the development of radiation-induced fibrosis. Therefore, we have examined a possible relationship between the differentiation state of untreated fibroblasts and the risk of radiation-induced subcutaneous fibrosis in individual patients. MATERIALS AND METHODS: We used skin fibroblast cultures isolated from eight postmastectomy radiotherapy patients whose individual clinical radiosensitivity was assessed by the mean excess risk of fibrosis. Different types of potentially mitotic progenitor fibroblasts (MF) and postmitotic functional fibrocytes (PMF) in the terminal differentiation lineage, MFI --> MFII --> MFIII --> PMF, were scored morphologically in clonal culture. Progression of differentiation was quantified by the ratio L/E of colony-forming late (MFIII and late MFII) and early (MFI and early MFII) progenitors. RESULTS: We observed a correlation between the ratio L/E and the mean risk of fibrosis (rs = 0.743, P = 0.03), indicating an approximately 10-fold increase in L/E with an increasing risk of fibrosis. This was paralleled by a decreasing trend in the absolute numbers of early progenitor types. By contrast, there was no significant correlation between the plating efficiency and the risk of fibrosis. CONCLUSIONS: The data suggest that the risk of fibrosis increases with the progression of the differentiation of untreated progenitor fibroblasts, indicating that the progression of fibroblast differentiation may be a co-factor in the development of radiation-induced fibrosis. If this hypothesis is validated, it provides a rationale for a novel predictive test to identify patients with an increased risk of subcutaneous fibrosis.

Adult↗