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J Overgaard

Publications and source records attributed to J Overgaard.

At least 19 recordsLinked to original sources
PubMed2001

Interaction between potential doubling time and TP53 mutation: predicting radiotherapy outcome in squamous cell carcinoma of the head and neck.

PURPOSE: To investigate the correlation between tumor potential doubling time, Tpot, and mutations in the p53 gene, TP53, and the potential of these parameters to predict outcome of head and neck cancer patients treated with radiotherapy. METHODS AND MATERIALS: Data from two independent studies on Tpot and TP53 mutations were combined, including 58 patients with squamous cell carcinoma of the head and neck. Tpot was estimated on biopsies obtained 6-9 h after infusion of iododeoxyuridine by combined flow cytometry and immunohistology. TP53 mutations were detected using DGGE and sequenced. All patients received primary radiotherapy alone. RESULTS: The predictive value of Tpot alone was of borderline significance. However, in TP53 wild-type tumors, Tpot was a strong predictor of outcome, whereas Tpot in TP53 mutant tumors failed to provide any information. Tpot and TP53 were not associated with nodal control; however, there was a strong relationship with control in the T-position, disease-specific survival, and overall survival. CONCLUSION: Tpot can to be a relevant parameter for predicting outcome of radiotherapy in head and neck cancer but only in the subset of patients without mutations in the p53 gene.

Adult↗
PubMed2001

Invasive oxygen measurements and pimonidazole labeling in human cervix carcinoma.

PURPOSE: This study was designed to compare tumor hypoxia assessed by invasive O2 sensitive electrodes and pimonidazole labeling in primary human cervix carcinomas. METHODS AND MATERIALS: Twenty-eight patients with primary cervix carcinomas (FIGO Stage Ib-IVa) were investigated. Both invasive pO2 measurements and pimonidazole labeling were obtained in all patients. Before treatment, patients were given pimonidazole as a single injection (0.5 g/m2 i.v.). Ten to 24 h later, oxygenation measurements were done by Eppendorf histography, and after this procedure biopsies were taken for pimonidazole-binding analysis. Tumor oxygen partial pressure (pO2) was evaluated as the median tumor pO2 and the fraction of pO2 values < or = 10 mmHg (HF10). Biopsies were formalin fixed and paraffin embedded, and hypoxia was detected by immunohistochemistry using monoclonal antibodies directed against reductively activated pimonidazole. Pimonidazole binding was evaluated by a semiquantitative scoring system. RESULTS: Both Eppendorf measurements and pimonidazole binding showed large intra-and intertumor variability. A comparison between pimonidazole binding expressed as the fraction of fields at the highest score and HF10 showed a trend for the most well-oxygenated tumors having a low fraction of fields; however, the correlation did not reach statistical significance (p = 0.43, r = 0.165; Spearman's rank correlation test). CONCLUSION: Hypoxia measured in human uterine cervix carcinomas is heterogeneously expressed both within and between tumors when assessed by either invasive pO2 measurements or pimonidazole binding. Despite a trend that tumors with high pO2 values expressed less pimonidazole binding, no correlation was seen between the two assays in this preliminary report.

Adult↗
PubMed2001

Comparative effects of combretastatin A-4 disodium phosphate and 5,6-dimethylxanthenone-4-acetic acid on blood perfusion in a murine tumour and normal tissues.

PURPOSE: To compare the ability of combretastatin A-4 disodium phosphate (CA4DP) and 5,6-dimethylxanthenone-4-acetic acid (DMXAA) to change tissue blood perfusion. MATERIALS AND METHODS: The tissues were a C3H mouse mammary carcinoma and various murine normal tissues, with perfusion measured using the 86RbCl extraction technique. RESULTS: CA4DP (250mg/kg; i.p.) reduced tumour perfusion to 34% of that seen in controls within 1 h of injection. It was maintained at this for at least 6 h, returning to control levels by 24 h. This decrease was dose-dependent. DMXAA (25mg/kg; i.p.) caused a 79% reduction in tumour perfusion 6h after injection; no recovery was observed even after 24 h. DMXAA showed no changes at doses below 10 mg/kg. Both CA4DP and DMXAA increased perfusion in the gut, kidney, bladder and lung, while decreasing splenic perfusion. CA4DP tended to decrease perfusion in muscle, while DMXAA increased liver perfusion. These changes in normal tissue perfusion were generally less than those changes seen in tumours. No significant changes were seen in skin. CONCLUSIONS: CA4DP and DMXAA produced a selective and significant reduction in tumour perfusion, but the pattern of change was different. These results suggest how these vascular targeting drugs should be combined with more conventional therapies.

Animals↗
PubMed2001

The respiratory consequences of feeding in amphibians and reptiles.

Many ectothermic vertebrates ingest very large meals at infrequent intervals. The digestive processes associated with these meals, often coupled with an extensive hypertrophy of the gastrointestinal organs, are energetically expensive and metabolic rate, therefore, increases substantially after feeding (specific dynamic action, SDA). Here, we review the cardio-respiratory consequences of SDA in amphibians and reptiles. For some snakes, the increased oxygen uptake during SDA is of similar magnitude to that of muscular exercise, and the two physiological states, therefore, exert similar and profound demands on oxygen transport by the cardiorespiratory systems. In several species, SDA is attended by increases in heart rate and overall systemic blood flows, but changes in blood flow distribution remain to be investigated. In snakes, the regulation of heart rate appears to involve a non-adrenergic-non-cholinergic mechanism, which may be a regulatory peptide released from the gastrointestinal system during digestion. Digestion is also associated with a net acid secretion to the stomach that causes an increase in plasma HCO3- concentration (the 'alkaline tide'). Experiments on chronically cannulated amphibians and reptiles, show that this metabolic alkalosis is countered by an increased P(CO2), so that the change in arterial pH is reduced. This respiratory compensation of arterial pH is accomplished through a reduction in ventilation relative to metabolism, but the estimated reductions in lung P(O2) are relatively small. The SDA response is also associated with haematological changes, but large interspecific differences exist. The studies on cardiorespiratory responses to digestion may allow for a further understanding of the physiological and structural constraints that limits the ability of reptiles and amphibians to sustain high metabolic rates.

Amphibians↗
PubMed2000

Relationship between DNA double-strand breaks, cell killing, and fibrosis studied in confluent skin fibroblasts derived from breast cancer patients.

PURPOSE: To investigate the relationship between DNA double-strand breaks (dsbs), cell killing, and fibrosis using skin fibroblasts derived from breast cancer patients who received postmastectomy radiotherapy. METHODS AND MATERIALS: Experiments were performed with 12 lines of normal skin fibroblasts derived from recurrence-free breast cancer patients. Cells were irradiated in confluence and cell survival was determined either after immediate or delayed (14 h) plating using a colony-forming assay. Dsbs were measured by constant-field gel electrophoresis. The "excess risk of fibrosis" was previously scored by Johansen et al. (IJRB 1994;66:407-412). RESULTS: The 12 cell lines showed a typical spectrum of radiosensitivity. The mean value of surviving fraction after 3.5 Gy (SF3.5) was 0.063 for immediate and 0.174 for delayed plating with a coefficient of variation (CV) of 44 and 39%, respectively. There was also a broad variation in the extent of recovery from potentially lethal damage (RPLD), which was not correlated with the immediate sensitivity. The number of initial dsbs as well as the half-times of dsb repair showed little variation, whereas there were considerable differences in the number of residual dsbs (CV = 29%). The number of residual dsbs after 100 Gy was correlated significantly only with SF3.5 after delayed (r2 = O.59; p = 0.006) but not after immediate plating (r2 = 0.21, p = 0.16). There was also no significant relationship between residual dsbs and the "excess risk of fibrosis" determined for the respective patients. CONCLUSION: It is shown that the number of residual dsbs measured in confluent human fibroblast lines can be used to predict the cellular radiosensitivity after delayed but not after immediate plating and also not to predict the excess risk of fibrosis of the respective breast cancer patients.

Breast Neoplasms↗
PubMed2000

A confirmatory prognostic study on oxygenation status and loco-regional control in advanced head and neck squamous cell carcinoma treated by radiation therapy.

INTRODUCTION: In a previous report of 35 patients we suggested that pretreatment tumour pO(2) measured by Eppendorf electrodes was predictive of loco-regional control after primary radiotherapy in advanced head and neck squamous cell carcinomas. Radiother Oncol 41 (1996) 31. MATERIALS AND METHODS: The aim of the present study was to test this hypothesis. Therefore, pretreatment tumour pO(2) was measured using the same assay in a new cohort of 35 patients that received an identical treatment being primary radiation along with a total dose of 66-68 Gy as 2 Gy per fraction over 5.5 or 6.5 weeks. Treatment outcome was evaluated as loco-regional control probability at 2 years using the same oxygenation parameter and applying the cut-off value from the first study. RESULTS: In agreement with the hypothesis generating study we found that the loco-regional tumour control probability was significantly higher (90%) among well oxygenated tumours as compared with the hypoxic subgroup (45%) (P=0. 04). CONCLUSION: This study confirmed that pretreatment tumour oxygenation status was prognostic of loco-regional tumour control after primary radiation alone in advanced head and neck squamous cell carcinoma.

Adult↗
PubMed2000

Histopathological and morphometric analyses of late rectal injury after irradiation.

The aim of the present study was to assess and quantify changes in the structural components of the rectal wall after irradiation with varying single doses of x-rays. A total of 70 CDF1/Bom male mice were irradiated at a selective 1.5 cm of the distal rectum with varying single doses of 0-30 Gy. At 32 weeks postirradiation the mice were sacrificed and the rectum was removed. Sampling of the specimens was based on unbiased stereological principles using systematic random sampling. Vertical tissue sections were used to estimate mucosal surface area density and to measure the thickness and volume fraction of the different intestinal wall layers. The surface area density decreased with increasing dose (p<0.02) due to pronounced injury of the crypts and mucosal morphology. The thickness and the volume fraction of the submucosa were significantly increased in the 20, 25 and 30 Gy treatment groups (p<0.0001 and p<0.0001), whereas the thicknesses of the mucosa, the lamina muscularis propria and the serosa did not change after irradiation. It is concluded that irradiation causes histopathological changes in the rectal mucosa and submucosa, and changes in the thickness of the submucosal intestinal layer. These changes were found to be dose-dependent.

Animals↗
PubMed2000

Time course of radiological lung density changes after postmastectomy radiotherapy.

The purpose of this study was to quantify the time course of radiological lung changes in patients after postmastectomy radiotherapy assessed from routine follow-up chest x-rays. Radiological density changes in the apex of the irradiated lung were quantified by a recent lung densitometry assay. Lung changes were expressed as the so-called Relative change in Equivalent Absorber Thickness (REAT). The clinical series comprised 329 patients treated with postmastectomy radiotherapy between 1978 and 1982. Of these patients 100 were treated with chemotherapy (CTX or CMF) and 41 were given tamoxifen as an additional adjuvant treatment; 290 patients (88.2%) had pretreatment x-rays and at least one x-ray after completion of radiotherapy and these were included in the study. A total of 2,209 chest x-rays was taken during follow-up, and among these 1921 x-rays (86.9%) were judged to be assessable. Late changes were defined as changes occurring more than a year after radiotherapy. A total of 280 patients had at least one chest x-ray taken more than one year after radiotherapy and these were evaluable with respect to late changes. There were 1,390 follow-up x-rays in these patients and 207 patients (73.9%) had three or more follow-up x-rays. Linear regression of REAT vs. observation time was used to identify three patterns of time changes: progressive, regressive, and stable. The results were as follows. Two phases of lung changes were observed. The early phase peaks around 6 months and the density changes may subsequently resolve, completely or in part. In most cases (173 patients or 84%), the lung density changes reached a stable level 12 months after irradiation. Yet, in 16 patients (7.7%) the lung changes progressed for five or more years. Regression of the density changes was seen in 18 patients (8.7%), and in some cases there were signs that this apparent regression was caused by contraction of the fibrotic tissue. We conclude that two phases of lung response can be distinguished and can be graded according to severity using this assay. Early lung changes reach a maximum around 6 months after RT. Late reactions reach a plateau in most patients after one year, but progress in some cases for five or more years.

Adult↗
PubMed2000

Squamous cell carcinoma of the oropharynx--an analysis of treatment results in 289 consecutive patients.

In this retrospective study the results of primary and salvage treatment of oropharyngeal carcinoma were evaluated. A total of 289 consecutive patients (103 females and 186 males) were included in the study. Most tumours originated in the tonsil area (58%) and comprised stages I 8%, II 19%, III 46% and IV 28%. The primary treatment was delivered with curative intent in 276 cases (96%). Of these, 266 received primary radiotherapy. The median radiation dose was 62 Gy, given as laterally opposed fields to the primary tumour and bilateral neck. Eight patients were treated with primary surgery and two with chemotherapy as part of a curatively intended treatment programme including radiotherapy. Six patients received palliative treatment, and seven were not treated at all. Out of 276 tumours treated with curative intent, 173 reappeared; 72% recurred in T position, 38% in N position, and 12% at distant metastatic sites, some in combination. Salvage surgery was possible in 52 patients, and 24 treatments were successful. Salvage radiotherapy or cryotherapy was used in 22 patients and 4 were controlled. For the entire group, the 5-year locoregional tumour control, disease-specific survival and overall survival rates were 38%, 44% and 31%, respectively. For patients treated with curative intent, clinical T- and N-stage, stage, tumour size, gender, age, and pretreatment haemoglobin were significant prognostic parameters in a univariate analysis. The Cox multivariate analysis showed that T-stage, N-stage and gender were independent prognostic factors. It is concluded that T-stage, N-stage and gender are significant independent prognostic factors. The primary control of the carcinoma in the T-position is crucial for overall success, but salvage surgery is found to have a favourable success rate in patients suitable for relapse treatment.

Adult↗
PubMed2000

TP53 mutation is an independent prognostic marker for poor outcome in both node-negative and node-positive breast cancer.

TP53 gene-mutation and protein expression of p53 are described as being of prognostic importance for the outcome of breast cancer. The present study was therefore carried out to evaluate whether TP53 mutation would be a feasible prognostic marker in the routine diagnostic evaluation of breast cancer, and, in particular, to analyse the relationship between TP53 mutation and nodal status. Tumour material was obtained from women with sporadic early breast cancer. Gene mutations in exon 2-11 were identified using denaturing gradient gel electrophoresis (DGGE) as the initial scanning procedure and characterized by sequencing. All patients were treated according to the guidelines of the Danish Breast Cancer Cooperative Group for the DBCG 89 protocols. The results were correlated with clinico-pathological parameters and the prognosis evaluated by uni- and multivariate analysis using local control, freedom from distant metastasis, disease-free survival, and overall survival as endpoints. The study included 294 patients. TP53 mutations were found in 23% of cases. Mutations were significantly more frequent in tumours from patients who were node-positive and with tumours characterized as being ductal, large of size, with a high degree of anaplasia, and oestrogen receptor negative. Using univariate analysis, it was found that distant metastasis, disease-free, and overall survival were correlated to tumour size, nodal status, degree of anaplasia, oestrogen receptor status, and TP53 mutation. In addition, overall survival was also correlated to age and menopausal status. When analysed according to nodal status, TP53 mutation was found to have a significantly poor survival probability in each of the subgroups. A Cox proportional hazard analysis, including all 294 patients, demonstrated that positive nodal status and TP53 mutation were the only parameters that had an independent poor influence on the risk of developing distant metastasis and reduced recurrence-free survival. The same factors together with postmenopausal status were found to be significantly associated with increased risk of death. TP53 mutation is a strong marker for the prediction of overall and disease-free survival in breast cancer, irrespective of nodal status. A better understanding of the role of the p53 pathway, including analysis of different types of TP53 mutations, is required in order further to investigate the prognostic potential of this marker.

Adult↗
PubMed2000

Treatment of morbidity associated with the management of the axilla in breast-conserving therapy.

The purpose of this study was to determine the impact of surgery and radiotherapy on late morbidity associated with the management of the axilla in breast cancer patients. Two hundred and sixty-six patients from a randomized breast conservation trial (DBCG-82TM protocol) were called in for a single follow-up interview and clinical examination of several functional outcome measures after a median of 6.6 years (3.5-10.5). All the patients were treated with lumpectomy and axillary dissection, followed by external beam radiotherapy to the residual breast. High-risk patients were given additional radiation to the regional lymph nodes plus adjuvant systemic treatment. Twenty-eight patients (11%) had arm edema (> or = 2 cm), which was associated with the extent of axillary node dissection as well as with age and radiotherapy (relative risk, RR = 4.5 (1.8-11.2, p = 0.001)). Impaired shoulder movement of any degree (7%) was associated with radiotherapy (RR = 4.0 (1.5-13.8, p = 0.007)) and advanced age (p = 0.002), while the extent of axillary dissection as described by the number of nodes retrieved was the only factor that predicted pain on logistic regression analysis (p = 0.02). A moderate to severe change in arm/shoulder strength and working ability was observed in 7% and 5% of patients, respectively, but no independent predisposing factor was discerned for these endpoints. It is concluded that the level of late functional morbidity several years after breast-conserving treatment is relatively low and clearly relates to age, extension of surgery, irradiation of the axilla or a combination of these factors, depending on the specific clinical outcome measure.

Adult↗
PubMed2000

Late treatment-related morbidity in breast cancer patients randomized to postmastectomy radiotherapy and systemic treatment versus systemic treatment alone.

Late treatment-related morbidity after mastectomy and adjuvant systemic treatment with and without postoperative irradiation was assessed in 84 patients randomized in the Danish Breast Cancer Cooperative Group Trials 82b and c. A structured interview and physical examination, using a standardized assessment sheet, constructed on the basis of the late effects normal tissues (LENT) scoring system, was used. The median length of follow-up from mastectomy was 9 years (range 6-13 years). Lymphedema was measured in 14%, of the irradiated patients versus 3% of the non-irradiated patients (NS). Slightly decreased shoulder morbidity was measured in 45% of the irradiated women versus 15% of the non-irradiated patients, but moderate or more severe impairment was seen in only 5% of the irradiated patients and in none of the non-irradiated patients (p = 0.004). Seventeen percent of the irradiated patients and 2% of the non-irradiated patients found that impairment of shoulder movement caused symptoms (p = 0.001).

Adult↗
PubMed2000

Fibroblast differentiation in subcutaneous fibrosis after postmastectomy radiotherapy.

In order to acquire a better understanding of the mechanism of radiation-induced fibrosis, we studied the differentiation of normal skin fibroblasts cultured from breast cancer radiotherapy patients with different risk of fibrosis. The differentiation state of fibroblasts was characterized in clonal cultures using established cytomorphological criteria. Collagen synthesis was determined by 3H-proline incorporation into pepsin-resistant protein. Radiation-induced inactivation of fibroblasts was paralleled by an increase in terminally differentiated fibrocytes, demonstrating that premature terminal differentiation is an important response to irradiation of fibroblasts from radiotherapy patients. Surviving colony-forming fibroblasts showed a change in differentiation with an increase in the ratio L:E of progenitor fibroblasts in late (L) compared to early (E) differentiation states. Furthermore, increased collagen production was observed after irradiation. The results provide evidence supporting a role of terminal fibroblast differentiation in radiation-induced fibrosis and imply that the progenitor population surviving radiotherapy might be more prone to terminal differentiation than before radiotherapy.

Breast Neoplasms↗
PubMed2000

Risk factors of arm lymphedema in breast cancer patients.

Chronic lymphedema is a life-long, potential complication of axillary treatment for breast cancer patients. In this article we focus on risk factors in the development of arm lymphedema and also discuss definition, type and stage, and incidence of arm edema.

Arm↗