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- 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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- 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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- Hopewell, J W, et al.
(författare)
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Time factor for acute tissue reactions following fractionated irradiation: a balance between repopulation and enhanced radiosensitivity.
- 2003
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Ingår i: International journal of radiation biology. - 0955-3002. ; 79:7, s. 513-24
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Tidskriftsartikel (refereegranskat)abstract
- Experimental data for acute radiation-induced skin reactions are reviewed. These show that for dose fractionation schedules with gaps, repopulation is initiated after a lag period. After this lag period, the isoeffective dose for a given level of skin reaction first increases rapidly, but then slows. The timing of the lag period is related to the total turnover time of the tissue under investigation and, for example, is shorter in rodent skin than in pig or human skin. At the point when accelerated repopulation is initiated, there is a major shortening of the turnover time of the target cell population. At this time, there is evidence, for a short period, for an increase in radiosensitivity of the surviving stem cells in a number of acutely responding normal tissues. This effect is clearly illustrated by the results of experiments using sequential dose fractionation schedules. Prolongation of the schedule from 'short' to schedules that include irradiation over the period when the cell turnover is accelerated is associated with a marked increase in tissue radiosensitivity. Clinically, this is best illustrated by a comparison of the effects of accelerated fractionation schedules, involving multiple fractions/day, with daily fractionation schedules. The increase in radiosensitivity produced by the prolongation of the treatment from 2 to 4-5 weeks was equivalent to > or =1 Gy day(-1). Comparable findings were obtained from animal studies. In the oral mucosa of mice, the initiation of accelerated cell proliferation in surviving cells is associated with the loss of dose sparing by subsequent dose fractionation due to the loss of the capacity to repair sublethal damage. Studies in pig and human skin have indicated that increased radiosensitivity is associated with a loss of cells in the G1 phase of the cell cycle. A collation of these two sets of findings suggests that the repair of sublethal damage takes place over this phase of the cell cycle. One clinical implication of these findings is that the alpha/beta ratio for acute skin reaction changes with the length of the overall treatment time; it is approximately 4.0 Gy for 'short' fractionation schedules that avoid any shortening of the cell cycle time. This increases to 11.2-13.3 Gy for schedules given in 3-4 weeks and to approximately 35 Gy for schedules given in 5-6 weeks. Results for pig skin were in total agreement with those for human skin.
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- Isacsson, Ulf, et al.
(författare)
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A method to separate the rectum from the prostate during proton beam radiotherapy of prostate cancer patients
- 2010
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Ingår i: Acta Oncologica. - : Informa UK Limited. - 0284-186X .- 1651-226X. ; 49:4, s. 500-505
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Tidskriftsartikel (refereegranskat)abstract
- The use of protons for curative treatment of prostate cancer is increasing, either as a single treatment modality or in combination with conventional radiotherapy. The proximity between prostate (target) and rectum (organ at risk) often leads to a compromise between dose to target and organ at risk. Material and methods. The present study describes a method where the distance between prostate and rectum is increased by retraction of the rectum in dorsal direction. Comparative treatment plans with and without retraction of the rectum in the same patients have been studied. Nine patients with biopsy proven, localised adenocarcinoma of the prostate were studied. A cylindrical rod of Perspex was inserted into the rectum. This device allows the rectum to be retracted posteriorly. The patients were given a proton boost of 20 Gy in four fractions of 5 Gy in addition to a conventional photon beam treatment to a dose of 50 Gy in 25 fractions of 2 Gy. Results. Comparative treatment planning shows that the treatment plan with rectal retraction significantly reduces (p < 0.01) the volume of the rectal wall receiving high doses (equal to 70 Gy in 2 Gy fractions) in all patients. Conclusions. The proton boost treatment with retraction of rectum during treatment decreases the rectal dose substantially. This is expected to reduce rectal side effects.
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- Jebsen, Nina L., et al.
(författare)
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Five-year Results From A Scandinavian Sarcoma Group Study (SSG XIII) Of Adjuvant Chemotherapy Combined With Accelerated Radiotherapy In High-Risk Soft Tissue Sarcoma Of Extremities And Trunk Wall
- 2011
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Ingår i: International Journal of Radiation Oncology, Biology, Physics. - : Elsevier BV. - 0360-3016 .- 1879-355X. ; 81:5, s. 1359-1366
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: To evaluate adjuvant chemotherapy and interpolated accelerated radiotherapy (RT) for adult patients with high-risk soft tissue sarcoma in the extremities or trunk wall. Methods and Materials: High-risk soft tissue sarcoma was defined as high-grade malignancy and at least two of the following criteria: size >= 8 cm, vascular invasion, or necrosis. Six cycles of doxorubicin and ifosfamide were prescribed for all patients. RT to a total dose of 36 Gy (1.8 Gy twice daily) was inserted between two chemotherapy cycles after marginal margin resection regardless of tumor depth or after wide-margin resection for deep-seated tumors. RT was boosted to 45 Gy in a split-course design in the case of intralesional margin resection. Results: A total of 119 patients were eligible, with a median follow-up of 5 years. The 5-year estimate of the local recurrence, metastasis-free survival, and overall survival rate was 12%, 59%, and 68%, respectively. The group receiving RT to 36 Gy had a local recurrence rate of 10%. In contrast, the local recurrence rate was 29% in the group treated with RT to 45 Gy. The presence of vascular invasion and low chemotherapy dose intensity had a negative effect on metastasis-free and overall survival. Toxicity was moderate after both the chemotherapy and the RT. Conclusions: Accelerated RT interposed between chemotherapy cycles in a selected population of patients with high-risk soft tissue sarcoma resulted in good local and distant disease control, with acceptable treatment-related morbidity. The greater radiation dose administered after intralesional surgery was not sufficient to compensate for the poorer surgical margin. Vascular invasion was the most important prognostic factor for metastasis-free and overall survival. (C) 2011 Elsevier Inc.
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| 9. |
- 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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| 10. |
- Johansson, Silvia, et al.
(författare)
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Hypofractionated proton boost combined with external beam radiotherapy for treatment of localized prostate cancer
- 2012
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Ingår i: Prostate Cancer. - : Hindawi Limited. - 2090-3111 .- 2090-312X. ; 2012
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Tidskriftsartikel (refereegranskat)abstract
- Proton boost of 20 Gy in daily 5 Gy fractions followed by external beam radiotherapy (EBRT) of 50 Gy in daily 2 Gy fractions were given to 278 patients with prostate cancer with T1b to T4N0M0 disease. Fifty-three percent of the patients received neoadjuvant androgen deprivation therapy (N-ADT). The medium followup was 57 months. The 5-year PSA progression-free survival was 100%, 95%, and 74% for low-, intermediate-, and high-risk patients, respectively. The toxicity evaluation was supported by a patient-reported questionnaire before every consultant visit. Cumulative probability and actuarial prevalence of genitourinary (GU) and gastrointestinal (GI) toxicities are presented according to the RTOG classification. N-ADT did not influence curability. Mild pretreatment GU-symptoms were found to be a strong predictive factor for GU-toxicity attributable to treatment. The actuarial prevalence declined over 3 to 5 years for both GU and GI toxicities, indicating slow resolution of epithelial damage to the genitourinary and gastrointestinal tract. Bladder toxicities rather than gastrointestinal toxicities seem to be dose limiting. More than 5-year followup is necessary to reveal any sign of true progressive late side effects of the given treatment. Hypofractionated proton-boost combined with EBRT is associated with excellent curability of localized PC and acceptable frequencies of treatment toxicity.
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