| 1. |
- Turesson, I, et al.
(författare)
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Normal tissue response to low doses of radiotherapy assessed by molecular markers--a study of skin in patients treated for prostate cancer.
- 2001
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Ingår i: Acta oncologica (Stockholm, Sweden). - 0284-186X. ; 40:8, s. 941-51
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Tidskriftsartikel (refereegranskat)abstract
- The aim of this study was to evaluate normal tissue response by molecular markers to multifraction low doses of ionizing radiation, with the focus on changes in repopulation, estimated using Ki-67 as the proliferation marker, and on expressions of the p53 and p21 proteins, identified as key proteins in the DNA damage checkpoint. Repeated skin biopsies were taken from patients treated for prostate cancer with radiotherapy. The expressions of Ki-67, p53 and p21 of the keratinocytes in the basal cell layer of the epidermis were quantified immunohistochemically. The dose to the basal layer was 1.1 Gy per fraction, given five times per week for seven weeks. The indices of the three markers were determined over the whole period. A significant suppression of the Ki-67 index was observed during the first weeks, followed by a significant gradual increase in the Ki-67 index over the last weeks. The p53 and p21 protein levels were almost zero in the unirradiated skin. Upon irradiation, both the p53 and p21 index increased in a pattern very congruent to the Ki-67 index. In conclusion, daily fractions of about 1 Gy to the skin resulted in, for the keratinocytes in the basal layer, a cell growth arrest for a couple of weeks and a subsequent acceleration in repopulation during the following weeks of irradiation. The present findings also provided novel insights into the role of the p53/p21 pathway in the response of a normal epithelium to ionizing radiation as it is applied in radiotherapy.
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| 2. |
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| 3. |
- Burnet, N G, et al.
(författare)
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Describing patients' normal tissue reactions: concerning the possibility of individualising radiotherapy dose prescriptions based on potential predictive assays of normal tissue radiosensitivity. Steering Committee of the BioMed2 European Union Concerted Action Programme on the Development of Predictive Tests of Normal Tissue Response to Radiation Therapy.
- 1998
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Ingår i: International journal of cancer. Journal international du cancer. - 0020-7136. ; 79:6, s. 606-13
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Tidskriftsartikel (refereegranskat)abstract
- Clinical radiotherapeutic doses are limited by the tolerance of normal tissues. Patients given a standard treatment exhibit a range of normal tissue reactions, and a better understanding of this individual variation might allow for individualisation of radiotherapeutic prescriptions, with consequent improvement in the therapeutic ratio. At present, there is no simple way to describe normal tissue reactions, which hampers communication between clinic and laboratory and between groups from different centres. There is also no method for comparing the severity of reactions in different normal tissues. This arises largely because there is no definition of a "normal" reaction, an "extreme" reaction or the particular term "over-reactor" (OR). This report proposes definitions for these terms, as well as a simple terminology for describing normal tissue reactions in patients having radiotherapy. The "normal" range represents the individual variation in normal tissue reactions amongst large numbers of patients treated in the same way which is within clinically acceptable limits. The term "OR" is applied to an individual whose reaction is more severe than the normal range but also implies that this forced a major change in the radiotherapeutic prescription or that the reactions were very severe or fatal. A "severe OR" would develop serious problems with a typical radical dose, while an "extreme OR" would have such difficulties at a much lower dose. To describe the normal range, a numerical scale is suggested, from 1 to 5, resistant to sensitive. The term "highly radiosensitive" (HR) is suggested for category 5. An "informal" relative scale, as suggested here, is quick and simple. It should allow comparison between different hospitals, compensate for differences in radiotherapeutic dose and technique and allow comparison of reactions between different anatomical sites. It should be adequate for discriminating patients at the extremes of the normal range from those at the centre. It is hoped that the definitions and terminology proposed here will aid communication in the field of predictive testing of normal tissue radiosensitivity.
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| 4. |
- Burnet, N G, et al.
(författare)
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Prediction of normal-tissue tolerance to radiotherapy from in-vitro cellular radiation sensitivity.
- 1992
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Ingår i: Lancet. - 0140-6736. ; 339:8809, s. 1570-1
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Tidskriftsartikel (refereegranskat)abstract
- The success of radiotherapy depends on the total radiation dose, which is limited by the tolerance of surrounding normal tissues. Since there is substantial variation among patients in normal-tissue radiosensitivity, we have tested the hypothesis that in-vitro cellular radiosensitivity is correlated with in-vitro normal-tissue responses. We exposed skin fibroblast cell lines from six radiation-treated patients to various doses of radiation and measured the proportions surviving. There was a strong relation between fibroblast sensitivity in vitro and normal-tissue reactions, especially acute effects. Assessment of radiosensitivity could lead to improved tumour cure rates by enabling radiation doses to be tailored to the individual.
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| 5. |
- Burnet, N G, et al.
(författare)
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The relationship between cellular radiation sensitivity and tissue response may provide the basis for individualising radiotherapy schedules.
- 1994
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Ingår i: Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology. - 0167-8140. ; 33:3, s. 228-38
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Tidskriftsartikel (refereegranskat)abstract
- There is a wide variation in normal tissue reactions to radiotherapy and in many situations the severity of these reactions limits radiotherapy dose. Clinical fractionation studies carried out in Gothenburg have demonstrated that a large part of the spectrum of normal tissue reactions is due to differences in individual normal tissue sensitivity. If this variation in normal tissue reactions is due to differences in intrinsic cellular radiosensitivity, it should be possible to predict tissue response based on measurement of cellular sensitivity. Here we report the initial results of a study aimed at establishing whether a direct relationship exists between cellular radiosensitivity and tissue response. Ten fibroblasts strains, including four duplicates, were established from a group of patients in the Gothenburg fractionation trials who had received radiotherapy following mastectomy. Skin doses were measured and both acute and late skin changes were observed following radiotherapy. Right and left parasternal areas were treated with different dose fractionation schedules. Clonogenic assays were used to assess intrinsic cellular radiosensitivity, and all experiments were carried out without prior knowledge of the clinical response, or which strains were duplicates. Irradiation was carried out using 60Co gamma-rays at high dose-rate (HDR) of 1-2 Gy/min and low dose-rate (LDR) of 1 cGy/min. A spectrum of sensitivity was seen, with SF2 values of 0.17-0.28 at HDR and 0.25-0.34 at LDR, and values of D0.01 of 5.07-6.38 Gy at HDR and 6.43-8.12 Gy at LDR. Comparison of the in vitro results with the clinical normal tissue effects shows a correlation between cellular sensitivity and late tissue reactions, which is highly significant with p = 0.02. A correlation between cellular sensitivity and acute effects was noted in the left-sided parasternal fields, but not the right. This is thought to be coincidental, and without biological significance. Our results suggest that cellular sensitivity might form the basis for the development of an assay system capable of predicting late normal tissue effects to curative radiotherapy, which might allow dose escalation in some patients. Increased local control and cure, with unchanged or improved normal tissue complications, could result from such individualised radiotherapy prescriptions.
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| 6. |
- Carlomagno, F, et al.
(författare)
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Comparison of DNA repair protein expression and activities between human fibroblast cell lines with different radiosensitivities.
- 2000
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Ingår i: International journal of cancer. Journal international du cancer. - 0020-7136. ; 85:6, s. 845-9
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Tidskriftsartikel (refereegranskat)abstract
- In order to investigate the molecular basis of variation in response to ionising radiation (IR) in radiotherapy patients, we have studied the expression of several genes involved in DNA double-strand break repair pathways in fibroblast cell lines. Ten lines were established from skin biopsies of cancer patients with different normal-tissue reactions to IR, and 3 from a control individual. For all 10 test cell lines, the cellular radiosensitivity was also known. Using Western blots we measured, in non-irradiated cells, the basal expression levels of ATM, Rad1 and Hus1, involved in the control of cellular DNA damage checkpoints, together with DNA-PKcs, Ku70, Ku80; XRCC4, ligaseIV and Rad51, involved in radiation- induced DSB repair. We also analysed the in vitro enzymatic activities, under non-irradiated conditions, of the DNA-PK and XRCC4/ligaseIV complexes. The levels of expression of the different proteins were similar in all the cell lines, but the activities of the DNA-PK and XRCC4/ligaseIV complexes showed some differences. These differences did not correlate with either the normal tissue response of the patient in vivo or with cellular radiation sensitivity in vitro. The activity differences of these enzyme complexes, therefore, do not account for the variation of responses seen between patients.
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| 7. |
- Fessé, Per, et al.
(författare)
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Human cutaneous interfollicular melanocytes differentiate temporarily under genotoxic stress
- 2022
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Ingår i: Iscience. - : Elsevier BV. - 2589-0042. ; 25:10
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Tidskriftsartikel (refereegranskat)abstract
- DNA-damage response of cutaneous interfollicular melanocytes to fractionated radiotherapy was investigated by immunostaining of tissue sections from punch biopsies collected before, during, and after the treatment of patients for breast cancer. Our clinical assay with sterilized hair follicles, excluded the migration of immature melanocytes from the bulge, and highlighted interfollicular melanocytes as an autonomous self-renewing population. About thirty percent are immature. Surrounding keratinocytes induced and maintained melanocyte differentiation as long as treatment was ongoing. Concomitant with differentiation, melanocytes were protected from apoptosis by transient upregulation of Bcl-2 and CXCR2. CXCR2 upregulation also indicated the instigation of premature senescence, preventing proliferation. The stem cell factor BMI1 was constitutively expressed exclusively in interfollicular melanocytes and further upregulated upon irradiation. BMI1 prevents apoptosis, terminal differentiation, and premature senescence, allowing dedifferentiation post-treatment, by suppressing the p53/p21-and p16-mediated response and upregulating CXCR2 to genotoxic damage. The pre-treatment immature subset of interfollicular melanocytes was restored after the exposure ended.
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| 8. |
- Nyman, Jan, 1956, et al.
(författare)
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Basal cell density in human skin for various fractionation schedules in radiotherapy.
- 1994
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Ingår i: Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology. - 0167-8140. ; 33:2, s. 117-24
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Tidskriftsartikel (refereegranskat)abstract
- Changes in the epidermal basal cell density (BCD) in human skin were determined during and immediately after fractionate radiotherapy. The basal cells are one of the target cell types responsible for acute skin reactions and measuring the BCD is a histological method for studying the time course and degree of reaction. Thirty-two patients with breast cancer participated in this study. They received postmastectomy radiotherapy to the thoracic wall. A 3-mm punch biopsy was taken from the irradiation field once a week for 6-10 weeks and the linear basal cell density was determined. Standard fractionation at two different dose levels (40 and 50 Gy) as well as hypofractionation and accelerated treatment have been investigated. For the first 3 weeks we found a constant decline in the BCD (about 0.8%/day), independent of dose and fractionation schedule. Using the nadir value as endpoint we found a dose-response relationship between 40 and 50 Gy, and for total effect (TE)-values in the range 430-1015. Compared to standard fractionation, hypofractionation showed somewhat less effect and accelerated fractionation showed significantly less effect. The reduced effect of accelerated fractionation is interpreted as a result of lack of cell cycle redistribution of cells between the two daily fractions in this type of tissue. The removal rate of dead or doomed cells could also affect the results for schedules with different overall time. The results of BCD were also compared to erythema.(ABSTRACT TRUNCATED AT 250 WORDS)
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| 9. |
- Nyman, Jan, 1956, et al.
(författare)
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Changes in the basal cell density in pig skin after single radiation doses with different dose rates.
- 1991
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Ingår i: Acta oncologica (Stockholm, Sweden). - 0284-186X. ; 30:6, s. 753-9
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Tidskriftsartikel (refereegranskat)abstract
- Radiation-induced changes in the basal cell density (BCD) and the labelling index (LI) in the epidermis of pig skin were used to compare the effect of high and low dose rate irradiation. Single doses of 6, 12 and 24 Gy were applied at 1.5 and 0.02 Gy/min with two equal 137Cs sources. Punch biopsies were taken daily for 40 days. The linear BCD was calculated from histological sections. The LI was determined by an in vitro H3-thymidine labelling technique. We found a degenerative phase in the basal cell layer with a linear cell loss of 2% per day, independent of the dose and dose rate. The time and level of the minimum BCD were dose and dose rate dependent. The LI data indicated an increased proliferation rate after a 25% reduction in BCD, i.e. before the nadir was reached. From the BCD data an iso-effective dose factor of 1.8 was estimated for the two dose rates used, which was consistent with that determined from macroscopic scoring. The BCD can be used as an endpoint for comparison of different radiotherapy modalities and gives, together with the LI, further information on the time-course of the proliferation changes in the tissue.
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| 10. |
- Nyman, Jan, 1956, et al.
(författare)
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Does the interval between fractions matter in the range of 4-8 h in radiotherapy? A study of acute and late human skin reactions.
- 1995
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Ingår i: Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology. - 0167-8140. ; 34:3, s. 171-8
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Tidskriftsartikel (refereegranskat)abstract
- Accelerated radiotherapy has the potential to increase local control of rapidly growing tumours. To determine the necessary time interval for complete repair of sublethal damage in normal tissue in a clinical situation, we have compared the acute and late skin reactions with 8 and 24 h between fractions, using the same dose per fraction and total dose. Forty-nine breast cancer patients participated in this study, and received bilateral parasternal irradiation to 50 Gy with 2 Gy per fraction as part of their adjuvant postoperative radiotherapy. The time interval between daily fractions was always 8 h on the left field and 24 h on the right, and the total treatment time was 2.5 and 5 weeks, respectively. The acute endpoint was erythema, measured by reflectance spectrophotometry and an acute reaction score for erythema and desquamation. The late endpoint was telangiectasia, scored on an arbitrary scale. The results have also been compared with those in a previously treated group of patients with 4 and 24 h between fractions. The degree of acute reactions was decreased with an 8-h interval compared with 24 h between fractions with the peak acute score as endpoint; no difference was seen with the peak reflectance measurements. The maximal expression occurs approximately 1 week earlier with the accelerated schedule, possibly as a consequence of the reduction of the treatment time. The pattern of the acute reaction for 8 h between fractions is similar to that for 4 h.(ABSTRACT TRUNCATED AT 250 WORDS)
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