Search PubMed⌕ Search

Biomedical subjects

J Overgaard

Publications and source records attributed to J Overgaard.

At least 37 records · Page 2Linked to original sources
PubMed2002

Validity of breast cancer in the Danish Cancer Registry. A study based on clinical records from one county in Denmark.

Cancer registries are essential in order to monitor the incidence of cancer and, with proper follow-up, survival in a population. However, the usefulness of the registry depends upon the data quality. To validate the Danish Cancer Registry concerning breast cancer in female residents of Aarhus county 1983-1989, registry records were compared with clinical records. Completeness was validated in 2062 patients and correctness was determined for pathologically proven primary invasive breast cancer in 1949 patients. Incidence data were complete with no tumours missing. Data were coded according to ICD-7 and correctness of registry data in terms of basis of diagnosis and tumour malignancy was 99%. Information on extent of disease (stage) was not complete and there was a high disconcordance, in particular for bilateral breast tumours and cases with distant metastasis. Even crude staging into local and regional disease was inconsistent for 13% of cases, which probably hampered survival analysis by stage. The quality of registry data should be addressed when using variables, such as stage, not routinely reported by registries.

Adult↗
PubMed2001

Combretastatin A-4 disodium phosphate: a vascular targeting agent that improves that improves the anti-tumor effects of hyperthermia, radiation, and mild thermoradiotherapy.

PURPOSE: To investigate the effect of combining the vascular targeting drug combretastatin A-4 disodium phosphate (CA4DP) with hyperthermia, radiation, or mild thermoradiotherapy in a transplanted C3H mouse mammary carcinoma. METHODS AND MATERIALS: The C3H mammary carcinoma was grown on the rear foot of female CDF1 mice and treated when at 200 mm(3) in size. CA4DP was dissolved in saline and injected i.p. Hyperthermia and/or radiation were locally given to tumors in restrained nonanesthetized mice. Tumor response was assessed using either a tumor growth or a tumor control assay. Mouse foot skin was used to assess normal tissue damage. RESULTS: CA4DP significantly enhanced thermal damage in this tumor model. This effect was independent of drug doses between 25-400 mg/kg, but was strongly dependent on the time interval between drug injection and heating, with the greatest improvement seen when CA4DP preceded the heating by 1 h or less. There was also a suggestion of a temperature dependency with a 1.9-fold increase in heat damage at 42.5 degrees C and a 2.6-fold increase at 41.5 and 40.5 degrees C. Heat-induced normal tissue damage was also enhanced by combining CA4DP with heat, but the degree of enhancement was less than that seen in tumors. CA4DP (25 mg/kg) significantly increased radiation-induced local tumor control and this was further enhanced by combining CA4DP with mild temperature (41.5 degrees C, 60 min) heating. CONCLUSIONS: CA4DP improved the anti-tumor effect of hyperthermia, especially at mild temperatures. More importantly, it also increased the tumor response to mild hyperthermia and radiation, which suggests that CA4DP may ultimately have an important application in clinical thermoradiotherapy.

Animals↗
PubMed2001

The charge density distribution in a model compound of the catalytic triad in serine proteases.

Combined low temperature (28(1) K) X-ray and neutron diffraction measurements were carried out on the co-crystallised complex of betaine, imidazole, and picric acid (1). The experimental charge density was determined and compared with ab initio theoretical calculations at the B3LYP/6-311G(d,p) level of theory. The complex serves as a model for the active site in, for example, the serine protease class of enzymes, the so-called catalytic triad. The crystal contains three short strong N-H...O hydrogen bonds (HBs) with dN...O < 2.7 A. The three HBs have energies above 13 kcalmol(-1), although the hydrogen atoms are firmly localized in the "nitrogen wells". This suggests that low-barrier hydrogen bonding in catalytic enzyme reactions may be a sufficient, but not a necessary, condition for obtaining transition-state stabilization. Structural analysis (e.g., covalent N-H bond lengthening) indicates that the hydrogen bond between H3A and 08 of imidazole and betaine respectively (HB2) is slightly stronger than the bond between H1A and O1A of imidazole and picric acid (HB1), although HB1 is shorter than HB2: (dN...O(HB1)= 2.614(1) A, dN...O(HB2) = 2.684(1) A, dH...O(HB1) = 1.630(1) A, dH...O(HB2)= 1.635(1) A, dN-H(HB1) = 1.046(1) A, dN-H(HB2) = 1.057(1) A). Furthermore, the charge density analysis reveals that HB2 has a larger covalent character than HB1, with considerable polarization of the density towards the acceptor atom. The Gatti and Bader source function (S) is introduced to the analysis of strong HBs. The source function is found to be a sensitive measure for the nature of a hydrogen bond, and comparison with low-barrier and single-well hydrogen bonding systems (e.g., benzoylacetone and nitromalonamide) shows that the low-barrier hydrogen bond (LBHB) state is characterized by an enormously increased hydrogen atom source contribution to the bond critical point in the HB. In this context, HB2 can be characterized as intermediate between localized HBs and delocalized LBHBs.

Binding Sites↗
PubMed2001

Effect of changing tumor oxygenation on glycolytic metabolism in a murine C3H mammary carcinoma assessed by in vivo nuclear magnetic resonance spectroscopy.

The rate of conversion of D-[1-(13)C]glucose into [3-(13)C]lactate (apparent glycolytic rate) has been determined in C3H murine mammary carcinomas in vivo using tumor-selective (13)C nuclear magnetic resonance spectroscopy with (1)H-(13)C cross-polarization. Under conditions of acute hypoxia induced by breathing carbon monoxide at 660 ppm, the apparent glycolytic rate was 0.0239 +/- 0.0019 min(-1). The proportion of (13)C label incorporated into [4-(13)C]glutamate (measured in tumor extracts) was 25-fold lower than that incorporated into [3-(13)C]lactate, reflecting a very limited oxidative metabolism during this hypoxic episode. For animals breathing air or carbogen (95% O(2) + 5% CO(2)), the calculated glycolytic rates were correspondingly lower (0.0160 +/- 0.0021 min(-1) and 0.0050 +/- 0.0011 min(-1), respectively). Although (13)C labeling of glutamate at C4 was still an order of magnitude lower than that for lactate at C3 (11-fold for air and 9-fold for carbogen), these ratios did show a greater degree of oxidative metabolism than that seen in animals breathing carbon monoxide at 660 ppm. The marked difference in apparent glycolytic rate for this tumor model between well-oxygenated and hypoxic conditions demonstrates a substantial Pasteur effect (inhibition of glycolysis by oxygen). Dynamic (13)C nuclear magnetic resonance spectroscopy provides a noninvasive estimate of tumor glycolysis that can be used to evaluate the relationship between oxygenation and energy metabolism, and this has potential consequences for the sensitivity of hypoxic cells to treatment and their ability to promote angiogenesis.

Animals↗
PubMed2001

Hypoxia in human soft tissue sarcomas: adverse impact on survival and no association with p53 mutations.

Clinical and experimental studies have suggested that tumour hypoxia is associated with poor treatment outcome and that loss of apoptotic potential may play a role in malignant progression of neoplastic cells. The tumour suppressor gene p53 induces apoptosis under certain conditions and microenvironmental tumour hypoxia may select for mutant tumour cells with diminished apoptotic potential due to lack of p53 function. The aim of this study was to evaluate the prognostic relevance of oxygenation status for treatment outcome and to compare pre-treatment tumour oxygenation measurements were done in 31 of those by PCR using DNA extracted from paraffin-embaedded sections (n = 2) or frozen biopsies (n = 29). The overall median of the tumour median pO(2)was 19 mmHg (range 1-58 mmHg). Only 6 tumours had functional p53 mutations and no association was found between mutant p53 and tumour hypoxia. Five out of 6 STS with lower histopathological grade were well-oxygenated whereas high-grade STS were both hypoxic and well-oxygenated. At a median follow-up of 74 months, 16 patients were still alive among 28 available for survival analysis. When stratifying into hypoxic and well-oxygenated tumours patients with the most hypoxic tumours has a statistically poorer disease-specific and overall survival at 5 years. In conclusion hypoxia was an indicator for both a poorer disease specific and overall survival in human STS but hypoxic tumours were not characterized by mutations in the p53 gene.

Adult↗
PubMed2001

Patterns of angiogenesis in nonsmall-cell lung carcinoma.

BACKGROUND: Tumor angiogenesis plays a pivotal role in tumor growth, maintenance, and metastasis. The objective of the current study was to evaluate the prognostic value of estimates of tumor angiogenesis and vascular endothelial growth factor (VEGF) status in 143 primary tumors from patients who underwent radical surgery for nonsmall-cell lung carcinoma (NSCLC). METHODS: Tumor sections were stained by immunohistochemistry for CD34 and VEGF. Angiogenesis was estimated both by a modification of the method described by Weidner and by the use of a 25-point Chalkley eyepiece graticule. VEGF intensity was evaluated semiquantitatively in three groups of patients. The vascular data were correlated with histopathologic tumor type and grade, TNM classification, patient age, and the endpoint (death). RESULTS: The estimates of vascular score did not reveal any prognostic information. In 35 patients (24%), invasive tumor growth was identified with a highly ordered alveolar microvessel pattern. In parallel sections, the intensity of VEGF staining was weak in tumors that exhibited an alveolar microvessel pattern only, and it was more intense in tumors that demonstrated a mixed alveolar and diffuse angiogenic pattern. The 35 patients with alveolar microvessel pattern had a significantly better survival (P = 0.007). In a Cox multivariate analysis, the results demonstrated an independent bad prognostic value of high disease stage (P < 0.0001), adenocarcinoma (P = 0.004), greater age (P = 0.01), and angiogenic microvessel pattern (P = 0.01). CONCLUSIONS: The authors believe that the alveolar vascular pattern represented preexisting alveolar vessels, that is, the alveoli were filled up by tumor cells that exploited the existing highly vascular bed of the lungs. Therefore, this subgroup was characterized by tumor progression without the induction of angiogenesis. The current data do not support a significant prognostic role for tumor angiogenesis in patients who are diagnosed with NSCLC. This may have implications for therapy aimed at inhibiting tumor growth by the inhibition of angiogenesis.

Adult↗
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

TP53 mutation is related to poor prognosis after radiotherapy, but not surgery, in squamous cell carcinoma of the head and neck.

BACKGROUND AND METHODS: TP53 gene-mutation and expression of p53 have been described to influence the radiosensitivity of tumour cells from head and neck carcinomas. The present study was performed to evaluate whether TP53 mutation may influence the clinical outcome of head and neck cancer patients treated with radiotherapy or surgery. MATERIALS AND METHODS: DNA was extracted from formalin-fixed paraffin-embedded tissue sections from primary biopsies taken before radiotherapy. Gene mutations (in exons 5-9) were identified using denaturing gradient gel electrophoresis (DGGE) as the initial scanning procedure and characterized by sequencing. Patients were treated with primary radiotherapy or surgery alone. Treatment was given according to the DAHANCA schedules with 5 or 6 weekly fractions (2 Gy) of radiotherapy (66-68 Gy). Most patients were also treated with the hypoxic radiosensitizer Nimorazole. The results are reported as 5-year actuarial values, and differences estimated by log-rank analysis. RESULTS: The present analysis is based on 114 patients with squamous cell carcinoma of the larynx, pharynx and oral cavity diagnosed between March 1992 and October 1996. Ninety patients received primary radiotherapy alone and 21 were treated with surgery. TP53 mutations were found in 45 patients (39%) and in patients receiving radiotherapy, TP53 mutation was highly associated with poor prognosis. Loco-regional control rates (5-year actuarial values) for TP53 mutation was 29 vs. 54% for TP53 wildtype (P < 0.01). For disease-free survival the corresponding values were 13 and 38% (P < 0.01), respectively. The correlations were not found to be related to specific subtypes of mutations (e.g. missense mutations affecting DNA-contact or Zn-binding regions) but rather to the presence of any mutation at all. In contrast, TP53 mutation did not influence the response to surgery. CONCLUSIONS: A strong relationship was observed between TP53 mutation and poor prognosis (increased risk of loco-regional failure and death) in head and neck cancer patients given primary radiotherapy but not surgery.

Carcinoma, Squamous Cell↗
PubMed2001

Interaction between combretastatin A-4 disodium phosphate and radiation in murine tumors.

BACKGROUND AND PURPOSE: The ability of combretastatin A-4 disodium phosphate (CA4DP) to induce vascular damage and enhance the radiation response of murine tumors was investigated. MATERIALS AND METHODS: A C3H mouse mammary carcinoma transplanted in the foot of CDF1 mice and the KHT mouse sarcoma growing in the leg muscle of C3H/HeJ mice were used. CA4DP was dissolved in saline and injected intraperitoneally. Tumor blood perfusion was estimated using 86RbCl extraction and Hoechst 33342 fluorescent labelling. Necrotic fraction was determined from histological sections. Tumors were locally irradiated in non-anaesthetised mice and response assessed by local tumor control for the C3H mammary carcinoma and in vivo/in vitro clonogenic cell survival for the KHT sarcoma. RESULTS: CA4DP decreased tumor blood perfusion and increased necrosis in a dose-dependent fashion in the C3H mammary carcinoma, which was maximal at 250 mg/kg. The decrease in perfusion and induction of necrosis by CA4DP was more extensive in the KHT sarcoma. CA4DP enhanced radiation damage in both tumor types. In the KHT sarcoma this enhancement was independent of whether the drug was given before or after irradiating, whereas for C3H mammary carcinoma the enhancement was only significant when administered at the same time or after the radiation, with no enhancement seen if CA4DP was given before. These effects were drug-dose dependent. CA4DP did not enhance radiation damage in normal skin. CONCLUSIONS: CA4DP enhanced radiation damage in the two tumor models without enhancing normal tissue damage. These radiation effects were clearly consistent with the anti-vascular action of CA4DP.

Animals↗
PubMed2001

Squamous cell carcinoma of the nasopharynx--an analysis of treatment results in 149 consecutive patients.

The purpose of this study was to evaluate the outcome of primary treatment and treatment of recurrences in patients with nasopharyngeal carcinoma. The material included 149 consecutive patients seen at the Aarhus University Hospital from 1963 to 1991 (49 females and 100 males). The stage distribution was: Stage I-9%, II-3%, III-28%, and IV-60%. Primary treatment was delivered with curative intent in 145 patients (97%). Persistent or recurrent disease after primary radical treatment was observed in 82 of the patients; 54% at the T-level, 40% at the N-level, and 33% at the M-level. A curative salvage attempt was carried out in 14 patients only, all with nodal recurrence: surgery in 8 patients (4 controlled) and radiotherapy in 6 patients (2 controlled). The 5-year local tumour control, locoregional tumour control, disease-specific survival rate and the overall survival rate for the patients treated with curative intent were 66%, 53%, 50% and 43%, respectively. Most of the patients (88%) had poorly differentiated tumours and these patients had the best prognosis. A major complication in three patients was radiation-induced myelopathy due to high-dose radiation delivered to the brain stem. Significant positive prognostic factors for treatment outcome in univariate analyses were early T-classification, small clinical stage, poor differentiation and low age. The Cox multivariate analysis showed that early T-categories, low N-categories and poor differentiation were independent, positive prognostic factors. Nasopharyngeal carcinoma is curable with primary radiotherapy; patients with poorly differentiated tumours have the best prognosis. Only a few patients were salvaged after recurrence. The factor most essential for success is primary control of the disease at the T- and N-levels.

Adolescent↗
PubMed2001

Improving local tumor control by combining vascular targeting drugs, mild hyperthermia and radiation.

Improvement in local control in a foot-implanted (200 mm3) C3H mouse mammary carcinoma by combining vascular targeting drugs, mild hyperthermia and radiation was investigated. The vascular targeting drug was flavone acetic acid (FAA; 150 mg/kg) intraperitoneally injected either 3 h before local tumor water-bath heating or 1 h after local tumor irradiation. For untreated tumors, the average (+/- 1 S.E.) tumor growth time (TGT; time to reach 5 x treatment volume) was 7.1 days (+/- 0.4). This was increased to 9.2 days (+/- 0.7) by using FAA. Heating also increased TGT, the effect being temperature and time dependent, and this heat response was further increased by FAA. The radiation dose (+/- 95% confidence interval) to control 50% of tumors (TCD50) 90 days after irradiation was 52 Gy (50-55) for radiation alone. This was decreased to 42 Gy (39-45) by FAA, 47 Gy (45-50) by heating (41.5 degrees C; 60 min) 4 h after irradiation, and to 28 Gy (22-35) by combining FAA and heat. Thus, vascular targeting drugs can improve the efficacy of mild hyperthermia and radiation.

Animals↗
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

Improved tumor response by combining radiation and the vascular-damaging drug 5,6-dimethylxanthenone-4-acetic acid.

The interaction between 5,6-dimethylxanthenone-4-acetic acid (DMXAA) and radiation was investigated in two different mouse tumor models and a normal mouse tissue. C3H mouse mammary carcinomas transplanted in the feet of CDF1 mice and KHT mouse sarcomas growing in the leg muscles of C3H/HeJ mice were used. DMXAA was dissolved in saline and injected intraperitoneally. Tumors were irradiated locally in nonanesthetized mice, and response was assessed using tumor growth for the C3H mammary carcinoma and in vivo/in vitro clonogenic cell survival for the KHT sarcoma. DMXAA alone had an antitumor effect in both tumor types, but only at doses above 15 mg/kg. DMXAA also enhanced radiation damage, and again there was a threshold dose. No enhancement was seen in the C3H mammary carcinoma at 10 mg/kg and below, while in the KHT sarcoma, doses above 15 mg/kg were necessary. This enhancement of radiation damage was also dependent on the sequence of and interval between the treatments with DMXAA and radiation. Combining radiation with DMXAA at the maximum tolerated dose (i.e., the highest dose that could be injected without causing any lethality) of either 20 mg/kg (CDF1 mice) or 17.5 mg/kg (C3H/HeJ mice) gave an additive response when the two agents were administered simultaneously. Even greater antitumor effects were achieved when DMXAA was administered 1-3 h after irradiation. However, when administration of DMXAA preceded irradiation, the effect was similar to that seen for radiation alone, suggesting that appropriate timing is essential to maximize the utility of this agent. When such conditions were met, DMXAA was found to increase the tumor response significantly in the absence of an enhancement of radiation damage in normal skin, thus giving rise to therapeutic gain.

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↗