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- Fessé, Per, et al.
(författare)
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UV-Radiation Response Proteins Reveal Undifferentiated Cutaneous Interfollicular Melanocytes with Hyperradiosensitivity to Differentiation at 0.05 Gy Radiotherapy Dose Fractions.
- 2019
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Ingår i: Radiation research. - 1938-5404 .- 0033-7587. ; 191:1, s. 93-106
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Tidskriftsartikel (refereegranskat)abstract
- To date, the response activated in melanocytes by repeated genotoxic insults from radiotherapy has not been explored. We hypothesized that the molecular pathways involved in the response of melanocytes to ionizing radiation and ultraviolet radiation (UVR) are similar. Skin punch biopsies, not sun-exposed, were collected from prostate cancer patients before, as well as at 1 and 6.5 weeks after daily doses of 0.05-1.1 Gy. Interfollicular melanocytes were identified by ΔNp63- and eosin-periodic acid Schiff staining. Immunohistochemistry and immunofluorescence were performed to detect molecular markers of the melanocyte lineage. Melanocytes were negative for ΔNp63, and the number remained unchanged over the treatment period. At radiation doses as low as 0.05 Gy, melanocytes express higher protein levels of microphthalmia-associated transcription factor (MITF) and Bcl-2. Subsets of MITF- and Bcl-2-negative melanocytes were identified among interfollicular melanocytes in unexposed skin; the cell number in both subsets was reduced after irradiation in a way that indicates low-dose hyperradiosensitivity. A corresponding increase in MITF- and Bcl-2-positive cells was observed. PAX3 and SOX10 co-localized to some extent with MITF in unexposed skin, more so than after radiotherapy. Low doses of ionizing radiation also intensified c-KIT and DCT staining. Nuclear p53 and p21 were undetectable in melanocytes. Apoptosis and proliferation could not be observed. In conclusion, undifferentiated interfollicular melanocytes were identified, and responded with differentiation in a hypersensitive manner at 0.05 Gy doses. Radioresistance regarding cell death was maintained up to fractionated doses of 1.1 Gy, applied for 7 weeks. The results suggest that the initial steps of melanin synthesis are common to ionizing radiation and UVR, and underline the importance of keratinocyte-melanocyte interaction behind hyperpigmentation and depigmentation to radiotherapy.
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| 2. |
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| 3. |
- Johansson, Silvia, et al.
(författare)
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High efficacy of hypofractionated proton therapy with 4 fractions of 5 Gy as a boost to 50 Gy photon therapy for localized prostate cancer
- 2019
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Ingår i: Radiotherapy and Oncology. - : ELSEVIER IRELAND LTD. - 0167-8140 .- 1879-0887. ; 141, s. 164-173
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: We report the outcome of hypofractionated proton boost as an alternative to high dose-rate brachytherapy boost, aimed at an equivalent dose exceeding 86 Gy in 2 Gy fractions, for patients with localized prostate cancer and all risk groups.Methods: Proton boost of 20 Gy given in 4 daily fractions to the prostate was followed after a one-week rest by photon therapy to 50 Gy in 2 Gy fractions. Outcomes are presented per risk group according to both NCCN and ISUP classifications. Advanced imaging was performed for adequate staging, and at an early stage of rising PSA, to identify the relapse site. Endpoints were PSA relapse-free-, locoregional relapse-free-, and distant metastasis-free- survival. Prostate cancer-specific-, metastasis-free-, and overall survival were also estimated. Genitourinary (GU) and gastrointestinal (GI) toxicity were based on patients' questionnaires and physicians' records.Results: We treated 531 patients between 2002 and 2015; 504 had localized disease. The cohort included 180 patients with T3/T4 disease (36%). The majority of the 50% with high-/very high-risk disease received ADT, 9-24 months; 92 had adjuvant pelvic node treatment. Median follow-up was 113 months (43-193). For low-, intermediate-, high-, and very high-risk patients, the 5-year PSA relapse-free survival was 100%, 94%, 82%, and 72%, respectively. Prolonged ADT improved biochemical control and nodal treatment regional control. The NCCN classification had higher predictive discrimination than the ISUP classification. The 5-year prevalence grade 3+ was 2% for GU and 0% for GI toxicity in pre-treatment symptom-free patients, and not worsened by nodal treatment.Conclusion: Dose escalation with hypofractionated proton boost was as effective as reported with high dose-rate brachytherapy boost, and the GU and GI toxicity profile was very similar. The proton boost was also appropriate for patients with larger prostate volume, higher T-stage, and high-risk disease encompassing elective regional node photon therapy.
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| 4. |
- Qvarnström, Fredrik, et al.
(författare)
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Double strand break induction and kinetics indicate preserved hypersensitivity in keratinocytes to subtherapeutic doses for 7 weeks of radiotherapy
- 2017
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Ingår i: Radiotherapy and Oncology. - : Elsevier BV. - 0167-8140 .- 1879-0887. ; 122:1, s. 163-169
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Tidskriftsartikel (refereegranskat)abstract
- Background and purpose Previously we reported that hyper-radiosensitivity (HRS) was evidenced by quantifying DNA double strand break (DSB) foci in epidermis biopsies collected after delivering radiotherapeutic one and five dose fractions. The aim of this study was to determine whether HRS was preserved throughout a 7-week radiotherapy treatment, and also to examine the rate of foci decline and foci persistence between dose fractions. Materials and methods 42 patients with prostate cancer received 7-week fractionated radiotherapy treatment (RT) with daily dose fractions of 0.05–1.10 Gy to the skin. Before RT, and at several times throughout treatment, skin biopsies (n = 452) were collected at 30 min, and 2, 3, 24, and 72 h after dose fractions. DSB-foci markers, γH2AX and 53BP1, were labelled in epidermal keratinocytes with immunofluorescence and immunohistochemical staining. Foci were counted both with digital image analysis and manually. Results HRS in keratinocytes was evidenced by the dose–response relationships of DSB foci, observed throughout the treatment course, independent of sampling time and quantification method. Foci observed at 24 h after dose fractions indicated considerable DSB persistence. Accordingly, foci significantly accumulated after 5 consecutive dose fractions. For doses below 0.3 Gy, persistent foci could be observed even at 72 h after damage induction. A comparison of γH2AX and 53BP1 quantifications in double-stained biopsies showed similar HRS dose–response relationships. Conclusions These results represented the first evidence of preserved HRS, assessed by γH2AX- and 53BP1-labelled DSB foci, throughout a 7-week treatment course with daily repeated subtherapeutic dose fractions. © 2016 Elsevier Ireland Ltd
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| 5. |
- Åström, Lennart, et al.
(författare)
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Two decades of high dose rate brachytherapy with external beam radiotherapy for prostate cancer
- 2018
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Ingår i: Radiotherapy and Oncology. - : Elsevier BV. - 0167-8140 .- 1879-0887. ; 127:1, s. 81-87
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Tidskriftsartikel (refereegranskat)abstract
- Background: High-dose-rate brachytherapy (HDR-BT) has optimal prerequisites in radiotherapy of prostate cancer (PC) with a conformal dose distribution and high doses per fraction giving a biological dose escalation. We report the outcome after HDR-BT and external beam radiotherapy (EBRT) after 20 years of experience.Material and methods: The study includes 623 patients, median age of 66 years, treated from 1995 to 2008 and a median follow up of 11 years (range 2–266 months). Androgen deprivation therapy was given to 429 patients (69%). The HDR-BT was given with two 10 Gy fractions and the EBRT with 2 Gy fractions to 50 Gy.Results: The 10-year PC-specific survival was 100%, 92%, 91%, and 75% for low-, intermediate-, high- and very high-risk patients respectively, and the 10-year probability of PSA relapse was 0%, 21%, 33%, and 65% respectively. The 10-year actuarial prevalence for ≥grade 2 GU- and GI-toxicities were 28% and 12% respectively and for ≥grade 3, 4% and 1% respectively. Urethral stricture was the most frequent GU complication with a 10-year actuarial incidence of 10%. Treatment without dose constraints for the urethra conferred a higher incidence 18%, compared to 5% after 2003 (p < 0.001). Sixteen patients experienced grade 4 GU toxicity, of which 13 were treated before 2003. No grade 4 rectal toxicity was seen.Conclusion: The combination of EBRT and HDR-BT with adequate dose constraints to risk organs provides satisfactory long-term tumour control even in high-risk patients. GI toxicity stabilised but GU toxicity progressed during the 10-year follow up.
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