Biomedical subjects

A J van der Kogel

Publications and source records attributed to A J van der Kogel.

At least 19 recordsLinked to original sources

PubMed2005

Recovery capacity of glial progenitors after in vivo fission-neutron or X irradiation: age dependence, fractionation and low-dose-rate irradiations.

Previous experiments on the radiosensitivity of O-2A glial progenitors determined for single-dose fission-neutron and X irradiation showed log-linear survival curves, suggesting a lack of accumulation of recovery of sublethal damage. In the present study, we addressed this question and further characterized the radiobiological properties of these glial stem cells by investigating the recovery capacity of glial stem cells using either fractionated or protracted whole-body irradiation. Irradiations were performed on newborn, 2-week-old or 12-week-old rats. Fractionated irradiations (four fractions) were performed with 24-h intervals, followed by cell isolations 16- 24 h after the last irradiation. Single-dose irradiations were followed by cell isolation 16-24 h after irradiation or delayed cell isolation (4 days after irradiation) of the O-2A progenitor cells from either spinal cord (newborns) or optic nerve (2- and 12-week-old rats). Results for neonatal progenitor cell survival show effect ratios for both fractionated fission-neutron and X irradiation of the order of 1.8 when compared with single-dose irradiation. A similar ratio was found after single-dose irradiation combined with delayed plating. Comparable results were observed for juvenile and adult optic nerve progenitors, with effect ratios of the order of 1.2. The present investigation clearly shows that fractionated irradiation regimens using X rays or fission neutrons and CNS tissue from rats of various ages results in an increase in O-2A progenitor cell survival while repair is virtually absent. This recovery of the progenitor pool after irradiation can be observed at all ages but is greatest in the neonatal spinal cord and can probably be attributed to repopulation.

Aging↗

PubMed2005

Modulation of hypoxia in murine liver metastases of colon carcinoma by nicotinamide and carbogen.

There is increasing evidence that modulation of tumor hypoxia may improve therapy outcome. However, most preclinical data are derived from subcutaneous rather than orthotopic tumor models. We investigated the effect of the hypoxia-modulating agents nicotinamide and carbogen on tumor hypoxia, tumor blood perfusion, and proliferative activity in liver metastases of the murine colon carcinoma line C26a. In untreated C26a liver metastases, we observed a considerable amount of hypoxia, similar to the amount in liver metastases of patients with colorectal cancer. Compared to untreated mice, we observed a significantly smaller hypoxic fraction in the liver metastases of mice treated with nicotinamide and carbogen breathing as single treatments or in combination. In the group of mice that underwent carbogen breathing, perfusion was significantly lower than in the untreated group, but the decrease was only marginal. The proliferative activity was similar in all groups. In C26a subcutaneous tumors, a similar effect on hypoxia has been observed that was, however, combined with a decrease in proliferative activity. The different effects of nicotinamide and carbogen on parameters of the tumor microenvironment in liver metastases and subcutaneous tumors suggest that the host tissue influences the mechanism by which nicotinamide and carbogen exert their effects. Since tumor hypoxia may be a clinical problem in colorectal liver metastases, our results open possibilities for further research on the effect of hypoxia modifiers on colorectal liver metastases to improve therapy outcome.

Animals↗

PubMed2004

Characterization of late radiation effects in the rat thoracolumbar spinal cord by MR imaging using USPIO.

The aim of this study was to detect late radiation effects in the rat spinal cord using MR imaging with ultra-small particles of iron oxide (USPIO) contrast agent to better understand the development of late radiation damage with emphasis on the period preceding neurological signs. Additionally, the role of an inflammatory reaction was assessed by measuring macrophages that internalized USPIO. T2-weighted spin echo MR measurements were performed at 7T in six rats before paresis was expected (130-150 days post-irradiation, early group), and in six paretic rats (150-190 days post-irradiation, late group). Measurements were performed before, directly after and, only in the early group, 40 h after USPIO administration and compared with histology. In the early group, MR images showed focal regions in grey matter (GM) and white matter (WM) with signal intensity reduction after USPIO injection. Larger lesions with contrast enhancement were located in and around edematous GM of three animals of the early group and five of the late group. Forty hours after injection, additional lesions in WM, GM and nerve roots appeared in animals with GM edema. In the late paretic group, MR imaging showed WM necrosis adjacent to areas with large contrast enhancement. In conclusion, detection of early focal lesions was improved by contrast administration. In the animals with extended radiation damage, large hypo-intense regions appeared due to USPIO, which might be attributed to blood spinal cord barrier breakdown, but the involvement of blood-derived iron-loaded macrophages could not be excluded.

Animals↗

PubMed2002

17beta-Oestradiol treatment modulates nitric oxide synthase activity in MDA231 tumour with implications on growth and radiation response.

The putative oestrogen receptor negative human breast cancer cell line MDA231, when grown as tumours in mice continually receiving 17beta-oestradiol, showed substantially increased growth rate when compared to control animals. Further, we observed that 17beta-oestradiol treatment could both increase the growth rate of established MDA231 tumours as well as decreasing the time taken for initiating tumour growth. We have also demonstrated that this increase in growth rate is accompanied by a four-fold increase in nitric oxide synthase activity, which was predominantly the inducible form. Inducible-nitric oxide synthase expression in these tumours was confirmed by immunohistochemical analysis and appeared localized primarily in areas between viable and necrotic regions of the tumour (an area that is presumably hypoxic). Prophylactic treatment with the nitric oxide synthase inhibitor nitro-L-arginine methyl ester resulted in significant reduction in this apparent 17beta-oestradiol-mediated growth promoting effect. Tumours derived from mice receiving 17beta-oestradiol-treatment were characterized by a significantly lower fraction of perfused blood vessels and an indication of an increased hypoxic fraction. Consistent with these observations, 17beta-oestradiol-treated tumours were less radio-responsive compared to control tumours when treated with a single radiation dose of 15 Gy. Our data suggests that long-term treatment with oestrogen could significantly alter the tumour oxygenation status during breast tumour progression, thus affecting response to radiotherapy.

Breast Neoplasms↗

PubMed2002

Oxygen-sensitive enzyme-prodrug gene therapy for the eradication of radiation-resistant solid tumours.

Overwhelming clinical and experimental data demonstrate that tumour hypoxia is associated with aggressive disease and poor treatment outcome as hypoxic cells are refractive to radiotherapy and some forms of chemotherapy. However, hypoxia is rare in physiologically normal tissues representing a tumour-specific condition. To selectively target this therapeutically refractive cell population, we have combined bioreductive chemotherapy with hypoxia-directed gene therapy. We have transfected the human fibrosarcoma cell line, HT1080, with a hypoxia-regulated expression vector encoding the human flavoprotein cytochrome c P450 reductase (HRE-P450R). This conferred hypoxia-dependent sensitivity to the alkylating nitroimidazole prodrug RSU1069 in vitro, with a greater than 30-fold increase in oxic/hypoxic cytotoxicity ratio compared with controls. Xenografts of both the HRE-P450R and empty vector transfectants had comparable hypoxic fractions and were refractive to single dose radiotherapy of up to 15 Gy. However, combining a prodrug of RSU1069 with a reduced radiotherapy dose of 10 Gy represents a curative regimen (50% tumour-free survival; day 100) in the HRE-P450R xenografts. In complete contrast, 100% mortality was apparent by day 44 in the empty vector control xenografts treated in the same way. Thus, an oxygen-sensitive gene-directed enzyme prodrug therapy approach may have utility when incorporated into conventional radiotherapy and/or chemotherapy protocols for loco-regional disease in any tissue where hypoxia is a contra-indication to treatment success. doi:10.1038/sj.gt.3301702

Animals↗

PubMed2001

Patterns of proliferation related to vasculature in human head-and-neck carcinomas before and after transplantation in nude mice.

PURPOSE: The predictive potential of tumor cell kinetic parameters may be improved when they are studied in relation to other microenvironmental parameters. The purpose of this investigation was to quantitatively categorize human tumor samples according to proliferation patterns. Second, it was examined whether these characteristics are retained after xenotransplantation. METHODS AND MATERIALS: Fifty tumor samples from head-and-neck cancer patients were immunohistochemically stained for Ki-67 and vessels. Also, parts of the samples were transplanted into nude mice. Tumors were categorized according to previously described patterns of proliferation. Vascular and proliferation patterns were analyzed using an image processing system. RESULTS: The 50 tumors were categorized into four patterns of proliferation by visual assessment: marginal (6), intermediate (10), random (21), and mixed (12). One tumor could not be classified. These patterns were quantified by calculating the Ki-67 labeling index in distinct zones at increasing distance from vessels yielding good discrimination and significant differences between patterns. The probability of growth after xenotransplantation was significantly higher for tumors with a labeling index and vascular density above the median value compared to tumors with both parameters below the median (82% vs. 35%). Fifty percent of the tumors retained their proliferation patterns after xenotransplantation. CONCLUSION: The categorization by proliferation pattern previously described by others was reproduced quantitatively and spatially related to the vascular network using a computerized image processing system. The combination of quantitative and architectural information of multiple microenvironmental parameters adds a new dimension to the study of treatment resistance mechanisms. Tumor models representative of the various patterns can be used to further investigate the relevance of these architectural patterns.

Animals↗

PubMed2001

Transcriptional response to hypoxia in human tumors.

BACKGROUND: The presence of hypoxic regions within solid tumors is associated with a more malignant tumor phenotype and worse prognosis. To obtain a blood supply and protect against cellular damage and death, oxygen-deprived cells in tumors alter gene expression, resulting in resistance to therapy. To investigate the mechanisms by which cancer cells adapt to hypoxia, we looked for novel hypoxia-induced genes. METHODS: The transcriptional response to hypoxia in human glioblastoma cells was quantified with the use of serial analysis of gene expression. The time course of gene expression in response to hypoxia in a panel of various human tumor cell lines was measured by real-time polymerase chain reaction. Hypoxic regions of human carcinomas were chemically marked with pimonidazole. Immunohistochemistry and in situ hybridization were used to examine gene expression in the tumor's hypoxic regions. RESULTS: From the 24 504 unique transcripts expressed, 10 new hypoxia-regulated genes were detected-all induced, to a greater extent than vascular endothelial growth factor, a hypoxia-induced mitogen that promotes blood vessel growth. These genes also responded to hypoxia in breast and colon cancer cells and were activated by hypoxia-inducible factor 1, a key regulator of hypoxic responses. In tumors, gene expression was limited to hypoxic regions. Induced genes included hexabrachion (an extracellular matrix glycoprotein), stanniocalcin 1 (a calcium homeostasis protein), and an angiopoietin-related gene. CONCLUSIONS: We have identified the genes that are transcriptionally activated within hypoxic malignant cells, a crucial first step in understanding the complex interactions driving hypoxia response. Within our catalogue of hypoxia-responsive genes are novel candidates for hypoxia-driven angiogenesis.

Blotting, Western↗

PubMed2001

Clinical implications of incomplete repair parameters for rat spinal cord: the feasibility of large doses per fraction in PDR and HDR brachytherapy.

PURPOSE: To evaluate the clinical implications of the repair parameters determined experimentally in rat spinal cord and to test the feasibility of large doses per fraction or pulses in daytime high-dose-rate (HDR) or pulsed-dose-rate (PDR) brachytherapy treatment schedules as an alternative to continuous low-dose-rate (CLDR) brachytherapy. METHODS AND MATERIALS: BED calculations with the incomplete repair LQ-model were performed for a primary CLDR-brachytherapy treatment of 70 Gy in 140 h or a typical boost protocol of 25 Gy in 50 h after 46-Gy conventional external beam irradiation (ERT) at 2 Gy per fraction each day. Assuming biphasic repair kinetics and a variable dose rate for the iridium-192- (192Ir) stepping source, the LQ-model parameters for rat spinal cord as derived in three different experimental studies were used: (a) two repair processes with an alpha/beta ratio = 2.47 Gy and repair half-times of 0.2 h (12 min) and 2.2 h (Pop et. al.); (b) two repair processes with an alpha/beta ratio = 2.0 Gy and repair half-times of 0.7 h (42 min) and 3.8 h (Ang et al.); and (c) two repair processes with an alpha/beta ratio = 2.0 Gy and repair half-times of 0.25 h (15 min) and 6.4 h (Landuyt et al.). For tumor tissue, an alpha/beta ratio of 10 Gy and a monoexponential repair half time of 0.5 h was assumed. The calculated BED values were compared with the biologic effect of a clinical reference dose of conventional ERT with 2 Gy/day and complete repair between the fractions. Subsequently, assuming a two-catheter implant similar to that used in our experimental study and with the repair parameters derived in our rat model, BED calculations were performed for alternative PDR- and HDR-brachytherapy treatment schedules, in which the irradiation was delivered only during daytime. RESULTS: If the repair parameters of the study of Pop et al., Ang et al., or Landuyt et al. are used, for a CLDR-treatment of 70 Gy in 140 h, the calculated BED values were 117, 193, or 216 Gy(sc) (Gy(sc) was used to express the BED value for the spinal cord), respectively. These BED values correspond with total doses of conventional ERT of 65, 96, or 104 Gy. The latter two are unrealistic high values and illustrate the danger of a straightforward comparison of BED values if repair parameters are used in situations quite different from those in which they were derived. For a brachytherapy boost protocol, the impact of the different repair parameters is less, due to the fact that the percentage increase in total BED value by the brachytherapy boost is less than 50%. If a primary treatment with CLDR brachytherapy delivering 70 Gy in 140 h has to be replaced, high doses per fraction or pulses (> 1 Gy) during daytime can only be used if the overall treatment time is prolonged with 3-4 days. The dose rate during the fraction or pulse should not exceed 6 Gy/h. For a typical brachytherapy boost protocol after 46 Gy ERT, it seems to be safe to replace CLDR delivering a total dose of 25 Gy in 50 h by a total dose of 24 Gy in 4 days with HDR or PDR brachytherapy during daytime only. Total dose per day should be limited to 6 Gy, and the largest time interval as possible between each fraction or pulse should be used. CONCLUSION: Extrapolations based on longer repair half-times in a CLDR reference scheme may lead to the calculation of unrealistically high BED values and dangerously high doses for alternative HDR and PDR treatment schedules. Based on theoretical calculations with the IR model and using the repair parameters derived in our rat spinal cord model, it is estimated that with certain restrictions, large doses per fraction or pulses can be used during daytime schedules of HDR or PDR brachytherapy as an alternative to CLDR brachytherapy, especially for those treatment conditions in which brachytherapy is used after ERT for only less than 50% of the total dose.

Animals↗

PubMed2001

Method for quantitative mapping of dynamic MRI contrast agent uptake in human tumors.

A method is presented for the acquisition and analysis of dynamic contrast-enhanced (DCE) MRI data, focused on the characterization of tumors in humans. Gadolinium (Gd) contrast was administered by bolus injection, and its effect was monitored in time by fast T1-weighted MRI. A simple algorithm was developed for automatic extraction of the arterial input function (AIF) from the DCE-MRI data. This AIF was used in the pixelwise pharmacokinetic determination of physiological vascular parameters in normal and tumor tissue. Maps were reconstructed to show the spatial distribution of parameter values. To test the reproducibility of the method 11 patients with different types of tumors were measured twice, and the rate of contrast agent uptake in the tumor was calculated. The results show that normalizing the DCE-MRI data using individual coregistered AIFs, instead of one common AIF for all patients, substantially reduces the variation between successive measurements. It is concluded that the proposed method enables the reproducible assessment of contrast agent uptake rates.

Algorithms↗

PubMed2001

Reirradiation of primary brain tumours: survival, clinical response and prognostic factors.

BACKGROUND AND PURPOSE: First, the aim was to determine the survival and quality of life after reirradiation of relapsing primary malignant brain tumours. The second aim was to assess the influence of a set of potentially prognostic factors on survival. MATERIALS AND METHODS: Forty-two patients received reirradiation for recurring primary brain tumours. The interval between the two consecutive treatments was at least 1 year. External beam irradiation for the initial and recurrent tumour was usually delivered with two opposing lateral fields or two wedged fields in orthogonal directions. The median physical doses of the first and second radiation course were 50 and 46 Gy, respectively. The median cumulative biological equivalent doses (BED) were 200.4 (alpha/beta = 2 Gy) and 115.2 Gy (alpha/beta = 10 Gy). During follow-up, corticosteroid medication and the WHO-performance were registered at regular intervals. The radiological response was assessed by reviewing all available CT- and MRI-films. Potentially prognostic factors with respect to survival were evaluated by both univariate and multivariate analyses. RESULTS: A clinical response (i.e. clinical improvement) was seen in 24% of the patients. Of the evaluable patients, nearly one-third showed a complete (8%) or partial (22%) radiological response. The median overall survival (OS) and progression-free survival (PFS) after retreatment were 10.9 and 8.6 months, respectively. By multivariate analysis, four independent prognostic factors for survival were identified: (1), the WHO-score before retreatment (P = 0.002); (2), the length of the interval between treatments (P = 0.008); (3), the tumour histology; and (4), the response to initial treatment (P values, 0.04). The median survival times for patients with WHO-scores of 0-1 and > or = 2 were 14.0 and 7.4 months, respectively. Patients with oligodendrogliomas had a median OS of 27.5 months, whereas patients with astrocytomas had a median OS of 6.9 months after retreatment. Long-term complications of retreatment were seen in three patients, all of whom had a cumulative BED(2) of > 204 Gy (with alpha/beta = 2 Gy). The quality of life after retreatment, however, was well preserved in the majority of patients. They remained ambulant and capable of self-care until the time of progression which occurred after 8.6 months (median PFS). CONCLUSIONS: After an initial treatment with radiation up to tolerance levels of normal brain tissue, reirradiation of recurring primary brain tumours seems feasible. During the time until clinical progression, patients remained independent with a reasonable quality of life.

Adrenal Cortex Hormones↗

PubMed2001

Impact of the tumour bed effect on microenvironment, radiobiological hypoxia and the outcome of fractionated radiotherapy of human FaDu squamous-cell carcinoma growing in the nude mouse.

PURPOSE: To investigate the impact of the tumour bed effect (TBE) on histological parameters of the micromilieu, radiobiological hypoxic fraction and local control after fractionated irradiation in FaDu squamous-cell carcinoma in the nude mouse. This tumour has previously shown a clear-cut TBE caused by increased necrotic cell loss at a constant cell production rate in the viable tumour compartment. MATERIALS AND METHODS: Human FaDu tumours were studied in the NMRI nude mouse. Tumours were transplanted either into unirradiated subcutaneous (s.c.) tissues (controls) or s.c. tissues pre-irradiated with 12.5 Gy (TBE group). In both groups we measured the volume doubling time (VDT), potential doubling time (T(pot)), relative necrotic area, and in the viable tumour compartment the relative vascular area (9F1 mAb), relative hypoxic area (NITP or pimonidazole), relative perfused area (Hoechst 33342), and the perfused fraction of vasculature. The tumour control dose 50% (TCD 50), radiobiological hypoxic fraction (rHF) and dose-modifying factors (DMF) for the comparison of tumours in the TBE and control groups were determined from local tumour control data after treatment with single doses under ambient conditions or under clamp hypoxia, and after irradiation with 30 fractions under ambient conditions within 6 weeks using maximum-likelihood analysis. RESULTS: A clear-cut TBE (VDT = 4.0 days (95%CI 2.9;4.4) for the control group versus 7.2 days (6.4;8.9) for the TBE group; p <0.0001) caused by increased necrosis (mean relative necrotic area of 12% (5;20)) versus 33% (10;41); p = 0.07) at a constant cell production rate (T(pot) = 2.2 days (1.4;2.3) versus 2.2 days (1.7;2.6); p = 0.30) was confirmed. Histological analysis of the micromilieu within the vital subarea revealed no systematic differences between the TBE and control groups. The rHF of 2% (0.1;27) for control tumours was lower than the 15% (95% CI 2;91) for the TBE group, but this difference was nonsignificant (p = 0.12). Compared with control tumours, the TCD50 for irradiation under clamped hypoxia was in a statistical trend lower for tumours in the TBE group (DMF 1.11 (0.98;1.28), p = 0.09). After fractionated irradiation, tumours of the TBE group were significantly more radiosensitive (TCD50 56.6 Gy (46;70) versus 78.7 Gy (63;100); p = 0.003). CONCLUSIONS: The results on FaDu tumours growing in pre-irradiated tissues indicate that increased necrosis caused by impairment of the vascular supply may increase the radiosensitivity of tumours treated by fractioned irradiation.

Animals↗

PubMed2001

Techniques for precision irradiation of the lateral half of the rat cervical spinal cord using 150 MeV protons [corrected].

Techniques for high precision irradiation experiments with protons, to investigate the volume dependence of the tolerance dose of the rat cervical spinal cord are described. In the present study, 50% of the lateral cross section of the spinal cord was irradiated. The diameter of the cross section of this part of the rat spinal cord is at maximum 3.5 mm. Therefore, a dedicated procedure was developed to comply with the needs for a very high positioning accuracy and high spatial resolution dosimetry. By using 150 MeV protons a steep dose gradient (20-80% = 1 mm) in the centre of the spinal cord was achieved. This yields a good dose contrast between the left and right halves of the cord. A home-made digital x-ray imager with a pixel resolution of 0.18 mm/pixel was used for position verification of the spinal cord. A positioning accuracy of 0.09 mm was obtained by using information of multiple pixels. The average position stability during the irradiation was found to be 0.08 mm (1 SD) without significant systematic deviations. Profiles of the dose distribution were measured with a 2D dosimetry system consisting of a scintillating screen and a CCD camera. Dose volume histograms of the whole spinal cord as well as separately of the white and grey matters were calculated using MRI imaging of the cross section of the rat cervical spinal cord. From the irradiation of 20 animals a dose-response curve has been established. MRI showed radiation-induced damage at the high dose side of the spinal cord. Analysis of the preliminary dose-response data shows a significant dose-volume effect. With the described procedure and equipment it is possible to perform high precision irradiations on selected parts of the spinal cord.

Animals↗

PubMed2000

Spatial relationship between hypoxia and the (perfused) vascular network in a human glioma xenograft: a quantitative multi-parameter analysis.

PURPOSE: To quantitatively study the spatial distribution of tumor hypoxia in relation to the perfused vasculature. METHODS AND MATERIALS: Using a human glioma xenograft model, nude mice were administered two different hypoxia markers (NITP or pimonidazole) and the perfusion marker Hoechst 33342. Frozen tumor sections were sequentially scanned for perfusion, hypoxia, and vasculature, respectively, to quantitate perfusion, vasculature, and hypoxia parameters in the same section. RESULTS: All tumors showed incomplete perfusion. Both NITP and pimonidazole stained the same hypoxic tumor areas. No statistically significant differences between the two markers were observed. The density of the perfused vessels was inversely related to the hypoxic fraction. At critical distances from perfused vessels, hypoxia occurred. These data suggest that predominantly diffusion-limited hypoxia was detected, based on the spatial distribution of nearby vessels. Also, the proportion of hypoxia distributed over arbitrary zones of 50 microm around perfused vessels was calculated. The largest proportion of hypoxia was found at distances beyond 100 microm from perfused vessels. CONCLUSION: With the multiple staining and functional microscopic imaging technique described here, the spatial relationship between perfused vessels and hypoxia was quantified in whole tumor cross-sections. The usefulness of this histologically-based method to quantitate morphological and physiological aspects of the tumor microenvironment was evaluated.

Animals↗

PubMed2000

Radiation tolerance of rat spinal cord to pulsed dose rate (PDR-) brachytherapy: the impact of differences in temporal dose distribution.

PURPOSE: To investigate the impact of a time-variable dose rate during a high dose rate (HDR-) or pulsed dose rate (PDR-) brachytherapy fraction with the HDR-microSelectron and to compare this with the biological effect of a constant dose rate treatment with the same average dose rate (as in the case of (192)Ir-wires). Moreover, the kinetics of repair in rat spinal cord are investigated using a wide spectrum of temporal dose distributions. MATERIALS AND METHODS: Two parallel catheters are inserted on each side of the vertebral bodies of the rat spinal column (Th(10)-L(4)) and connected to the HDR-microSelectron. Interstitial irradiation (IRT) is performed with a stepping (192)Ir-point source, varying the activity of the point source between 0.3 and 6.5 Ci. Three different groups of experiments are defined, varying the overall treatment time and average dose rates in the range of 3-8, 28-53 and 82-182 min and 312-489 Gy/h, 32-56 Gy/h and 13-15 Gy/h, respectively. Difference in temporal dose distribution (dose rate variation) during almost the same overall treatment time is obtained by varying the number of pulses per dwell position in either one or ten runs through the implant. For reasons of comparison, previously reported results of continuous irradiation at a constant dose rate obtained with two (192)Ir-wires in a fixed position are reanalyzed. Paralysis of the hindlegs after 5-6 months and histopathological examination of the spinal cord of each animal are used as experimental endpoints. RESULTS: During one run of the (192)Ir-point source, the peak dose rate is at least 25 times higher as compared with the minimum local dose rate and almost four times higher as compared with the average dose rate. For the three different groups of varying overall treatment times and average dose rates there is a significant difference in biological effect, with an ED(50)-value of 23.1-23.6 Gy (average dose rate 312-489 Gy/h), 25.4-27.9 Gy (average dose rate 312-489 Gy/h) and 29.3-33 Gy (average dose rate 13-15 Gy/h). For these range of single doses, difference in temporal dose distribution with either one or ten runs is only significant for treatment times less then 1 h. For the prolonged treatment times at lower average dose rates, the difference between one or ten run is no longer significant. However, the results with the (192)Ir-point source at an average dose rate/run of 13-15 Gy/h are significantly different from the ED(50)-value of 33 Gy using (192)Ir-wires at the same but constant dose rate. Using different types of analysis to estimate the repair parameters, the best fit of the data is obtained assuming biphasic repair kinetics and a variable dose rate (geometrically dependent) for the (192)Ir-point source. On the basis of the incomplete repair LQ model, two repair processes with an alpha/beta ratio=2.47 Gy and repair halftimes of 0.19 and 2.16 h are detected. The partition coefficient for the longer repair process is 0.98. This results in the proportion of total damage associated with the longer repair halftime being 0.495 for short sharp fractions with complete repair in between. CONCLUSIONS: Even in the range of high dose rates of 15-500 Gy/h, spinal cord radiation tolerance is significantly increased by a reduction in dose rate. For larger doses per fraction in PDR-brachytherapy dose rate variation is important, especially for tissues with very short repair half times (components). In rat spinal cord the repair of sublethal damage (SLD) is governed by a biphasic repair process with repair halftimes of 0.19 and 2.16 h.

Animals↗

PubMed2000

Effects of nicotinamide and carbogen on oxygenation in human tumor xenografts measured with luminescense based fiber-optic probes.

BACKGROUND AND PURPOSE: In head and neck cancer, addition of both carbogen breathing and nicotinamide to accelerated fractionated radiotherapy showed increased loco-regional control rates. An assay based on the measurement of changes in tumor pO(2) in response to oxygenation modification could be helpful for selecting patients for these new treatment approaches. MATERIALS AND METHODS: The fiber-optic oxygen-sensing device, OxyLite, was used to measure changes in pO(2), at a single position in tumors, after treatment with nicotinamide and carbogen in three human xenograft tumor lines with different vascular architecture and hypoxic patterns. Pimonidazole was used as a marker of hypoxia and was analyzed with a digital image processing system. RESULTS: At the position of pO(2) measurement, half of the tumors showed a local increase in pO(2) after nicotinamide administration. Steep increases in pO(2) were measured in most tumors during carbogen breathing although the increase was less pronounced in tumor areas with a low pre-treatment pO(2). A trend towards a faster local response to carbogen breathing for nicotinamide pre-treated tumors was found in all three lines. There were significant differences in hypoxic fractions, based on pimonidazole binding, between the three tumor lines. There was no correlation between hypoxic marker binding and the response to carbogen breathing. CONCLUSION: Temporal changes in local pO(2) can be measured with the OxyLite. This system was used to quantitate the effects of oxygen modifying treatments. Rapid increases in pO(2) during carbogen breathing were observed in most tumor areas. The locally measured response to nicotinamide was smaller and more variable. Bio-reductive hypoxic cell marker binding in combination with OxyLite pO(2) determination gives spatial information about the distribution patterns of tumor hypoxia at the microscopic level together with the possibility to continuously measure changes in pO(2) in specific tumor areas.

Analysis of Variance↗

PubMed2000

Clinical radiation doses for spinal cord: the 1998 international questionnaire.

BACKGROUND AND PURPOSE: Emmanuel van der Schueren gave a keynote lecture at the 1988 ASTRO annual conference pointing out that the spinal cord 'tolerance doses' then prescribed were probably unnecessarily cautious, resulting in probable underdosing of some tumours. This lecture was supported both by an international questionnaire which he and two of the present authors had conducted, and by animal experimental data. In 1997 he initiated a 10-year follow-up questionnaire, the results of which are summarised here. MATERIALS AND METHODS: The present report analyses the change in prescriptions from 1988 to 1998 and the variation in prescriptions among various regions of the World. RESULTS AND CONCLUSIONS: The main conclusion is that prescribed dose levels have increased significantly in this period. Large geographical variations still exist. Among responders who use a formula to correct for changed dose per fraction, 90% are now using the linear-quadratic model vs. 33% in 1988. The current status of clinically acceptable doses to spinal cord in 2-Gy fractions is discussed briefly. Further details from the responses to the 1998 questionnaire will be presented in another publication.

Dose Fractionation, Radiation↗

PubMed2000

Vascular architecture and hypoxic profiles in human head and neck squamous cell carcinomas.

Tumour oxygenation and vasculature are determinants for radiation treatment outcome and prognosis in patients with squamous cell carcinomas of the head and neck. In this study we visualized and quantified these factors which may provide a predictive tool for new treatments. Twenty-one patients with stage III-IV squamous cell carcinomas of the head and neck were intravenously injected with pimonidazole, a bioreductive hypoxic marker. Tumour biopsies were taken 2 h later. Frozen tissue sections were stained for vessels and hypoxia by fluorescent immunohistochemistry. Twenty-two sections of biopsies of different head and neck sites were scanned and analysed with a computerized image analysis system. The hypoxic fractions varied from 0.02 to 0.29 and were independent from T- and N-classification, localization and differentiation grade. No significant correlation between hypoxic fraction and vascular density was observed. As a first attempt to categorize tumours based on their hypoxic profile, three different hypoxia patterns are described. The first category comprised tumours with large hypoxic, but viable, areas at distances even greater than 200 micrometer from the vessels. The second category showed a typical band-like distribution of hypoxia at an intermediate distance (50-200 micrometer) from the vessels with necrosis at greater distances. The third category demonstrated hypoxia already within 50 micrometer from the vessels, suggestive for acute hypoxia. This method of multiparameter analysis proved to be clinically feasible. The information on architectural patterns and the differences that exist between tumours can improve our understanding of the tumour micro-environment and may in the future be of assistance with the selection of (oxygenation modifying) treatment strategies.

Aged↗

PubMed2000

Noninvasive assessment of the functional neovasculature in 9L-glioma growing in rat brain by dynamic 1H magnetic resonance imaging of gadolinium uptake.

Pathophysiologic parameters of the functional neovasculature and the blood-brain barrier of 9L-glioma in rat brain were measured noninvasively by dynamic 1H magnetic resonance imaging studies of gadolinium (Gd)-DTPA uptake. Changes of apparent [Gd-DTPA] uptake in time (CT[t]) were analyzed in a slice through the center of 10 9L-gliomas using fast T1 measurements. The distribution of the contrast agent was spatially correlated with the distribution of perfused microvessels as determined by immunohistochemical analysis. This method permits a distinction between perfused and nonperfused microvessels with a disrupted blood-brain barrier. In transverse slices of the whole tumor, a spatial correlation was observed between CT maps and the two-dimensional distribution of perfused microvessels. In the next step, Gd-DTPA uptake rates were spatially related to the perfused microvessel density (Np) or vascular surface area (Sp). In tumor voxels with perfused microvessels, a linear correlation was found between Gd-DTPA uptake rate constants (k values) and Np or Sp. No correlation was observed between k values and the total microvessel density. These are the first data that show a relation between Gd-DTPA uptake rates and parameters of the functional neovasculature in 9L-glioma growing in rat brain. Now that Gd-DTPA uptake studies can be related to parameters of the functional neovasculature, they may be used more efficiently as a prognostic tool before or during therapy.

Animals↗