| 1. |
- Naylor, Andrew Stuart, 1977, et al.
(author)
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Voluntary running rescues adult hippocampal neurogenesis after irradiation of the young mouse brain.
- 2008
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In: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 1091-6490. ; 105:38, s. 14632-7
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Journal article (peer-reviewed)abstract
- Cranial radiation therapy is commonly used in the treatment of childhood cancers. It is associated with cognitive impairments tentatively linked to the hippocampus, a neurogenic region of the brain important in memory function and learning. Hippocampal neurogenesis is positively regulated by voluntary exercise, which is also known to improve hippocampal-dependent cognitive functions. In this work, we irradiated the brains of C57/BL6 mice on postnatal day 9 and evaluated both the acute effects of irradiation and the effects of voluntary running on hippocampal neurogenesis and behavior 3 months after irradiation. Voluntary running significantly restored precursor cell and neurogenesis levels after a clinically relevant, moderate dose of irradiation. We also found that irradiation perturbed the structural integration of immature neurons in the hippocampus and that this was reversed by voluntary exercise. Furthermore, irradiation-induced behavior alterations observed in the open-field test were ameliorated. Together, these results clearly demonstrate the usefulness of physical exercise for functional and structural recovery from radiation-induced injury to the juvenile brain, and they suggest that exercise should be evaluated in rehabilitation therapy of childhood cancer survivors.
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| 2. |
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| 3. |
- Alevronta, Eleftheria, et al.
(author)
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Dose-response relationships of intestinal organs and excessive mucus discharge after gynaecological radiotherapy
- 2021
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In: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203 .- 1932-6203. ; 16:4 April
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Journal article (peer-reviewed)abstract
- Background The study aims to determine possible dose-volume response relationships between the rectum, sigmoid colon and small intestine and the ‘excessive mucus discharge’ syndrome after pelvic radiotherapy for gynaecological cancer. Methods and materials From a larger cohort, 98 gynaecological cancer survivors were included in this study. These survivors, who were followed for 2 to 14 years, received external beam radiation therapy but not brachytherapy and not did not have stoma. Thirteen of the 98 developed excessive mucus discharge syndrome. Three self-assessed symptoms were weighted together to produce a score interpreted as ‘excessive mucus discharge’ syndrome based on the factor loadings from factor analysis. The dose-volume histograms (DVHs) for rectum, sigmoid colon, small intestine for each survivor were exported from the treatment planning systems. The dose-volume response relationships for excessive mucus discharge and each organ at risk were estimated by fitting the data to the Probit, RS, LKB and gEUD models. Results The small intestine was found to have steep dose-response curves, having estimated dose-response parameters: γ : 1.28, 1.23, 1.32, D : 61.6, 63.1, 60.2 for Probit, RS and LKB respectively. The sigmoid colon (AUC: 0.68) and the small intestine (AUC: 0.65) had the highest AUC values. For the small intestine, the DVHs for survivors with and without excessive mucus discharge were well separated for low to intermediate doses; this was not true for the sigmoid colon. Based on all results, we interpret the results for the small intestine to reflect a relevant link. Conclusion An association was found between the mean dose to the small intestine and the occurrence of ‘excessive mucus discharge’. When trying to reduce and even eliminate the incidence of ‘excessive mucus discharge’, it would be useful and important to separately delineate the small intestine and implement the dose-response estimations reported in the study.
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| 4. |
- Alevronta, Eleftheria, et al.
(author)
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Dose-response relationships of the sigmoid for urgency syndrome after gynecological radiotherapy.
- 2018
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In: Acta oncologica (Stockholm, Sweden). - 1651-226X .- 0284-186X. ; 57:10, s. 1352-1358
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Journal article (peer-reviewed)abstract
- To find out what organs and doses are most relevant for 'radiation-induced urgency syndrome' in order to derive the corresponding dose-response relationships as an aid for avoiding the syndrome in the future.From a larger group of gynecological cancer survivors followed-up 2-14years, we identified 98 whom had undergone external beam radiation therapy but not brachytherapy and not having a stoma. Of those survivors, 24 developed urgency syndrome. Based on the loading factor from a factor analysis, and symptom frequency, 15 symptoms were weighted together to a score interpreted as the intensity of radiation-induced urgency symptom. On reactivated dose plans, we contoured the small intestine, sigmoid colon and the rectum (separate from the anal-sphincter region) and we exported the dose-volume histograms for each survivor. Dose-response relationships from respective risk organ and urgency syndrome were estimated by fitting the data to the Probit, RS, LKB and gEUD models.The rectum and sigmoid colon have steep dose-response relationships for urgency syndrome for Probit, RS and LKB. The dose-response parameters for the rectum were D50: 51.3, 51.4, and 51.3Gy, γ50=1.19 for all models, s was 7.0e-09 for RS and n was 9.9×107 for LKB. For Sigmoid colon, D50 were 51.6, 51.6, and 51.5Gy, γ50 were 1.20, 1.25, and 1.27, s was 2.8 for RS and n was 0.079 for LKB.Primarily the dose to sigmoid colon as well as the rectum is related to urgency syndrome among gynecological cancer survivors. Separate delineation of the rectum and sigmoid colon in order to incorporate the dose-response results may aid in reduction of the incidence of the urgency syndrome.
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| 5. |
- Alin, Rebecca, 1989, et al.
(author)
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A Preparatory Study for a Randomized Controlled Trial of Dietary Fiber Intake During Adult Pelvic Radiotherapy
- 2021
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In: Frontiers in Nutrition. - : Frontiers Media SA. - 2296-861X. ; 8
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Journal article (peer-reviewed)abstract
- Background: Patients undergoing pelvic radiotherapy are often advised to omit fiber-rich foods from their diet to reduce the adverse effects of treatment. Scientific evidence supporting this recommendation is lacking, and recent studies on animals and humans have suggested that there is a beneficial effect of dietary fiber for the alleviation of symptoms. Randomized controlled studies on dietary fiber intake during pelvic radiotherapy of sufficient size and duration are needed. As preparation for such a large-scale study, we evaluated the feasibility, compliance, participation rate, and logistics and report our findings here in this preparatory study. Methods: In this preparatory study of a fiber intervention trial, Swedish gynecological cancer patients scheduled for radiotherapy were recruited between January 2019 and August 2020. During the intervention, the participants filled out questionnaires and used an application. They also consumed a fiber supplement at first in powder form, later in capsules. Blood- and fecal samples were collected. The study is registered in clinicaltrials.gov (https://clinicaltrials.gov/ct2/show/NCT04534075?cond=fidura&draw=2&rank=1). Results: Among 136 approached patients, 57 started the study and the participation rate for primary outcomes was 63% (third blood sample) and 65% (third questionnaire). Barely half of the participants provided fecal samples. Providing concise and relevant information to the patients at the right time was crucial in getting them to participate and stay in the study. The most common reasons for declining participation or dropping out were the expected burden of radiotherapy or acute side effects. Tailoring the ambition level to each patient concerning the collection of data beyond the primary endpoints was an important strategy to keep the dropout rate at an acceptable level. Using capsules rather than psyllium in powder form made it much easier to document intake and to create a control group. During the course of the preparatory study, we improved the logistics and for the last 12 participants included, the participation rate was 100% for the earliest primary outcome. Conclusion: A variety of adjustments in this preparatory study resulted in an improved participation rate, which allowed us to set a final protocol and proceed with the main study.
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| 6. |
- Boström, Martina, et al.
(author)
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A role for endothelial cells in radiation-induced inflammation
- 2018
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In: International Journal of Radiation Biology. - : Informa UK Limited. - 0955-3002 .- 1362-3095. ; 94:3, s. 259-271
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Journal article (peer-reviewed)abstract
- Purpose: To unravel the role of the vasculature in radiation-induced brain tissue damage.Materials and methods: Postnatal day 14 mice received a single dose of 10Gy cranial irradiation and were sacrificed 6h, 24h or 7 days post-irradiation. Endothelial cells were isolated from the hippocampus and cerebellum using fluorescence-activated cell sorting, followed by cell cycle analysis and gene expression profiling.Results: Flow cytometric analysis revealed that irradiation increased the percentage of endothelial cells, relative to the whole cell population in both the hippocampus and the cerebellum. This change in cell distribution indicates that other cell types are more susceptible to irradiation-induced cell death, compared to endothelial cells. This was supported by data showing that genes involved in endothelial cell-specific apoptosis (e.g. Smpd1) were not induced at any time point investigated but that genes involved in cell-cycle arrest (e.g. Cdkn1a) were upregulated at all investigated time points, indicating endothelial cell repair. Inflammation-related genes, on the other hand, were strongly induced, such as Ccl2, Ccl11 and Il6.Conclusions: We conclude that endothelial cells are relatively resistant to ionizing radiation but that they play an active, hitherto unknown, role in the inflammatory response after irradiation. In the current study, this was shown in both the hippocampus, where neurogenesis and extensive cell death after irradiation occurs, and in the cerebellum, where neurogenesis no longer occurs at this developmental age.
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| 7. |
- Bull, Cecilia, 1977, et al.
(author)
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A novel mouse model of radiation-induced cancer survivorship diseases of the gut
- 2017
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In: American journal of physiology. Gastrointestinal and liver physiology. - : American Physiological Society. - 1522-1547 .- 0193-1857. ; 313:5, s. G456-G466
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Journal article (peer-reviewed)abstract
- A deeper understanding of the radiation-induced pathophysiological processes that develop in the gut is imperative to prevent, alleviate, or eliminate cancer survivorship diseases after radiotherapy to the pelvic area. Most rodent models of high-dose gastrointestinal radiation injury are limited by high mortality. We therefore established a model that allows for the delivering of radiation in fractions at high doses while maintaining long-term survival. Adult male C57/BL6 mice were exposed to small-field irradiation, restricted to 1.5 cm of the colorectum using a linear accelerator. Each mouse received 6 or 8 Gy, two times daily in 12-h intervals in two, three, or four fractions. Acute cell death was examined at 4.5 h postirradiation and histological changes at 6 wk postirradiation. Another group was given four fractions of 8 Gy and followed over time for development of visible symptoms. Irradiation caused immediate cell death, mainly limited to the colorectum. At 6 wk postirradiation, several crypts displayed signs of radiation-induced degeneration. The degenerating crypts were seen alongside crypts that appeared perfectly healthy. Crypt survival was reduced after the fourth fraction regardless of dose, whereas the number of macrophages increased. Angiogenesis was induced, likely as a compensatory mechanism for hypoxia. Four months postirradiation, mice began to show radiation-induced symptoms, and histological examination revealed an extensive crypt loss and fibrosis. Our model is uniquely suitable for studying the long-term trajectory and underlying mechanisms of radiation-induced gastrointestinal injury. NEW & NOTEWORTHY A novel mouse model for studying the long-term trajectory of radiation-induced gut injury. The method allows for the use of high doses and multiple fractions, with minor impact on animal health for at least 3 mo. Crypt loss and a slow progression of fibrosis is observed. Crypt degeneration is a process restricted to isolated crypts. Crypt degeneration is presented as a convenient proxy endpoint for long-term radiation-induced gut injury.
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| 8. |
- Bull, Cecilia, 1977
(author)
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Brain Regeneration - in vitro and in vivo studies of exercise-related effects on brain plasticity
- 2008
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Doctoral thesis (other academic/artistic)abstract
- Neural stem and progenitor cells in the germinal regions of the adult brain, such as the hippocampus, are of great interest, because they provide the possibility for enhanced brain plasticity or can contribute to endogenous cell replacement after injury or disease. Voluntary exercise was recently shown to robustly induce cellular and structural plasticity, thereby contributing to overall brain health. This thesis focuses on exercise-related effects on cell genesis of neurons and oligodendrocytes in vitro and in vivo. In Paper I, we demonstrated that the exercise-induced, endogenously released opioid peptide ?-endorphin enhanced oligodendrogenesis in adult hippocampal progenitors in vitro. Results revealed a requirement for the helix-loop? helix transcriptional regulator ?Inhibitor of Differentiation? (Id) 1 in opioid-induced oligodendrogenesis. In Paper II, we studied the effects of voluntary exercise during adulthood on neurogenesis and behavior, subsequent to irradiation in the young mouse brain. Voluntary exercise following irradiation restored the hippocampal stem cell pool, increased neurogenesis, and ameliorated irradiation-induced alterations in behavior. Moreover, orientation of immature neurons in the hippocampal dentate gyrus was perturbed after irradiation; however, voluntary exercise restored proper orientation. In Paper III, we proceeded to investigate potential effects of voluntary exercise on oligodendrogenesis after irradiation to the immature brain. We demonstrate an efficient irradiation-induced reduction in the total number of Olig2-positive cells of the corpus callosum, considered to be mainly oligodendroglial cells, without affecting the number of newborn glial progenitor cells. Our results also reveal that, in contrast to the beneficial effects of exercise on neurogenesis in the hippocampus, voluntary running does not seem to affect cell proliferation or oligodendrogenesis in the corpus callosum. In conclusion, this thesis demonstrates the usefulness of physical exercise for functional and structural brain recovery, with special emphasis on insults to the juvenile brain. In addition, these results highlight the capacity of the adult brain to regenerate through activation of endogenous neural progenitors and stem cells.
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| 9. |
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| 10. |
- Bull, Cecilia, 1977, et al.
(author)
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Intra-abdominal Surgery and Intestinal Syndromes After Pelvic Radiation Therapy
- 2024
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In: ADVANCES IN RADIATION ONCOLOGY. - 2452-1094. ; 9:1
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Journal article (peer-reviewed)abstract
- Purpose: To determine the effects of intra-abdominal surgery on the intensities of 5 radiation -induced intestinal syndromes in survivors of pelvic cancer. Methods and Materials: The analysis included 623 women born in 1927 or later who had survived cancer. They all had received external radiation therapy toward the pelvic area to treat gynecologic cancers. Information from 344 women who did not undergo irradiation, matched for age and residency, was also included. Main outcome measures after the surgical procedures were the intensity scores for 5 radiation -induced intestinal syndromes: urgency-tenesmus syndrome, fecal -leakage syndrome, excessive mucus discharge, excessive gas discharge, and blood discharge. The scores were based on symptom frequencies obtained from patient -reported outcomes and on factor loadings obtained from a previously reported factor analysis. Follow-up was 2 to 15 years after radiation therapy. Results: Among survivors of cancer, intra-abdominal surgery increased the intensity of the urgency-tenesmus syndrome, the fecalleakage syndrome, excessive gas discharge, and blood discharge but had a negligible effect on mucus discharge. Intra-abdominal surgery had an especially negative effect on the urgency-tenesmus syndrome. Although the combination of appendectomy with 1 or more other intra-abdominal surgeries resulted in the highest score for all syndromes, appendectomy alone had weak to no effect. In women who did not undergo irradiation, a similar pattern was seen, albeit with much lower scores. Conclusions: We found intra-abdominal surgery to be a risk factor among survivors of gynecologic cancer, increasing the intensity score of 4 out of 5 radiation -induced intestinal syndromes. During radiation therapy, it may be worthwhile to pay extra attention to the dose of unwanted ionizing radiation to the intestines if the patient previously has undergone intra-abdominal surgery.
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| 11. |
- Bull, Cecilia, 1977, et al.
(author)
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Role of dietary fiber in safeguarding intestinal health after pelvic radiotherapy
- 2021
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In: Current Opinion in Supportive and Palliative Care. - : Ovid Technologies (Wolters Kluwer Health). - 1751-4258. ; 15:3, s. 180-187
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Journal article (peer-reviewed)abstract
- Purpose of review Damage to healthy bowel tissue during pelvic radiotherapy can produce devastating and life-long changes in bowel function. The surging interest in microbiota and its importance for our wellbeing has generated a bulk of research highlighting how the food we consume impacts bowel health and disease. Dietary fiber is known to promote bowel health, yet there is a limited number of studies on dietary fiber in connection to pelvic radiotherapy. Here, we review some of the literature on the subject and present the most recent publications in the field. Recent findings Advice given concerning dietary fiber intake during and after pelvic radiotherapy are inconsistent, with some clinics suggesting a decrease in intake and others an increase. Recent animal studies provide a solid support for a protective role of dietary fiber with regards to intestinal health after pelvic radiotherapy, mainly through its impact on the microbiota. No clinical study has yet provided unambiguous evidence for a similar function of dietary fiber in humans undergoing pelvic radiotherapy. There is a lack of evidence behind the dietary advice given to cancer survivors suffering from radiation-induced bowel dysfunction, and high-quality and well powered studies with long follow-up times are needed.
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| 12. |
- Devarakonda, Sravani, et al.
(author)
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Dietary Fiber and the Hippocampal Neurogenic Niche in a Model of Pelvic Radiotherapy
- 2021
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In: Neuroscience. - : Elsevier BV. - 0306-4522. ; 475, s. 137-147
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Journal article (peer-reviewed)abstract
- sought to determine whether radiation to the colorectum had an impact on parameters of hippocampal neurogenesis and, if so, whether it could be modulated by a fiber-rich diet. Male C57BL/6J mice were fed a diet containing bioprocessed oat bran or a fiber-free diet, starting two weeks before colorectal irradiation with 4 fractions of 8 Gray or sham-irradiation. Diets were then continued for 1, 6 or 18 weeks, whereafter parameters of hippocampal neurogenesis were analyzed and correlated to serum cytokine levels. No statistically significant changes in neuronal markers or cell proliferation were found at one week post-irradiation. Six weeks postirradiation there was a decreased cell proliferation in the subgranular zone that appeared slightly more pronounced in irradiated animals on a fiber-free diet and increased numbers of immature neurons per mm2 dentate gyrus in the irradiated mice, with a statistically significant increase in mice on a fiber-rich diet. Microglial abundancy was similar between all groups. 18 weeks post-irradiation, a fiber-free diet had reduced the number of immature neurons, whereas irradiation resulted in an increase. Despite this, the population of mature neurons was stable. Analysis of serum cytokines revealed a negative correlation between MIP1-a and the number of immature neurons one week after irradiation, regardless of diet. Our findings show that pelvic radiotherapy has the potential to cause a long-lasting impact on hippocampal neurogenesis, and dietary interventions may modulate this impact. More in-depth studies on the relationship between irradiation-induced intestinal injury and brain health are warranted. (c) 2021 The Authors. Published by Elsevier Ltd on behalf of IBRO. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
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| 13. |
- Devarakonda, Sravani, et al.
(author)
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Low-grade intestinal inflammation two decades after pelvic radiotherapy.
- 2023
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In: EBioMedicine. - 2352-3964. ; 94
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Journal article (peer-reviewed)abstract
- Radiotherapy is effective in the treatment of cancer but also causes damage to non-cancerous tissue. Pelvic radiotherapy may produce chronic and debilitating bowel symptoms, yet the underlying pathophysiology is still undefined. Most notably, although pelvic radiotherapy causes an acute intestinal inflammation there is no consensus on whether the late-phase pathophysiology contains an inflammatory component or not. To address this knowledge gap, we examined the potential presence of a chronic inflammation in mucosal biopsies from irradiated pelvic cancer survivors.We biopsied 24 cancer survivors two to 20 years after pelvic radiotherapy, and four non-irradiated controls. Using tandem mass tag (TMT) mass spectrometry and mRNA sequencing (mRNA-seq), we charted proteomic and transcriptomic profiles of the mucosal tissue previously exposed to a high or a low/no dose of radiation. Changes in the immune cell populations were determined with flow cytometry. The integrity of the protective mucus layers were determined by permeability analysis and 16S rRNA bacterial detection.942 proteins were differentially expressed in mucosa previously exposed to a high radiation dose compared to a low radiation dose. The data suggested a chronic low-grade inflammation with neutrophil activity, which was confirmed by mRNA-seq and flow cytometry and further supported by findings of a weakened mucus barrier with bacterial infiltration.Our results challenge the idea that pelvic radiotherapy causes an acute intestinal inflammation that either heals or turns fibrotic without progression to chronic inflammation. This provides a rationale for exploring novel strategies to mitigate chronic bowel symptoms in pelvic cancer survivors.This study was supported by the King Gustav V Jubilee Clinic Cancer Foundation (CB), The Adlerbertska Research Foundation (CB), The Swedish Cancer Society (GS), The Swedish State under the ALF agreement (GS and CB), Mary von Sydow's foundation (MA and VP).
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| 14. |
- Hedelin, Maria, 1964, et al.
(author)
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Intake of citrus fruits and vegetables and the intensity of defecation urgency syndrome among gynecological cancer survivors.
- 2019
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In: PloS one. - : Public Library of Science (PLoS). - 1932-6203. ; 14:1
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Journal article (peer-reviewed)abstract
- Despite the experimental evidence that certain dietary compounds lower the risk of radiation-induced damage to the intestine, clinical data are missing and dietary advice to irradiated patients is not evidence-based.We have previously identified 28 intestinal health-related symptoms among 623 gynaecological-cancer survivors (three to fifteen years after radiotherapy) and 344 matched population-based controls. The 28 symptoms were grouped into five radiation-induced survivorship syndromes: defecation-urgency syndrome, fecal-leakage syndrome, excessive mucus discharge, excessive gas discharge and blood discharge. The grouping was based on factor scores produced by Exploratory Factor Analysis in combination with the Variable Cutoff Method. Frequency of food intake was measured by a questionnaire. We evaluated the relationship between dietary intake and the intensity of the five syndromes.With the exception of excessive mucus discharge, the intensity of all syndromes declined with increasing intake of citrus fruits. The intensity of defecation-urgency and fecal-leakage syndrome declined with combined intake of vegetables and citrus fruits. The intensity of excessive mucus discharge was increased with increasing intake of gluten.In this observational study, we found an association between a high intake of citrus fruits and vegetables and a lower intensity of the studied radiation-induced cancer survivorship syndromes. Our data suggest it may be worthwhile to continue to search for a role of the diet before, during and after radiotherapy to help the cancer survivor restore her or his intestinal health after irradiation.
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| 15. |
- Malipatlolla, Dilip, 1990, et al.
(author)
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A fiber-rich diet and radiation-induced injury in the murine intestinal mucosa
- 2022
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In: International Journal of Molecular Sciences. - : MDPI AG. - 1661-6596 .- 1422-0067. ; 23:1
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Journal article (peer-reviewed)abstract
- Dietary fiber is considered a strong intestinal protector, but we do not know whether dietary fiber protects against the long-lasting mucosal damage caused by ionizing radiation. To evaluate whether a fiber-rich diet can ameliorate the long-lasting pathophysiological hallmarks of the irradiated mucosa, C57BL/6J mice on a fiber-rich bioprocessed oat bran diet or a fiber-free diet received 32 Gray in four fractions to the distal colorectum using a linear accelerator and continued on the diets for one, six or 18 weeks. We quantified degenerating crypts, crypt fission, cell proliferation, crypt survival, macrophage density and bacterial infiltration. Crypt loss through crypt degeneration only occurred in the irradiated mice. Initially, it was most frequent in the fiber-deprived group but declined to levels similar to the fiber-consuming group by 18 weeks. The fiber-consuming group had a fast response to irradiation, with crypt fission for growth or healing peaking already at one week post-irradiation, while crypt fission in the fiber-deprived group peaked at six weeks. A fiber-rich diet allowed for a more intense crypt cell proliferation, but the recovery of crypts was eventually lost by 18 weeks. Bacterial infiltration was a late phenomenon, evident in the fiber-deprived animals and intensified manyfold after irradiation. Bacterial infiltration also coincided with a specific proinflammatory serum cytokine profile. In contrast, mice on a fiber-rich diet were completely protected from irradiation-induced bacterial infiltration and exhibited a similar serum cytokine profile as sham-irradiated mice on a fiber-rich diet. Our findings provide ample evidence that dietary fiber consumption modifies the onset, timing and intensity of radiation-induced pathophysiological processes in the intestinal mucosa. However, we need more knowledge, not least from clinical studies, before this finding can be introduced to a new and refined clinical practice.
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| 16. |
- Malipatlolla, Dilip, 1990, et al.
(author)
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Long-term mucosal injury and repair in a murine model of pelvic radiotherapy
- 2019
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In: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 9
-
Journal article (peer-reviewed)abstract
- Chronic intestinal injury after pelvic radiotherapy affects countless cancer survivors worldwide. A comprehensive understanding of the long-term injury dynamics is prevented in available animal models. With linear accelerators that are used to treat cancer in patients, we irradiated a small volume encompassing the colorectum in mice with four fractions of 8 Gy per fraction. We then determined the long-term dynamics of mucosal injury, repair, and the duration of inflammation. We show that crypt fission, not cell proliferation, is the main long-term mechanism for rescuing crypt density after irradiation, and provides a potentially wide window for clinical interventions. Persisting macrophage aggregations indicate a chronic mucosal inflammation. A better understanding as to how crypt fission is triggered and why it fails to repair fully the mucosa may help restore bowel health after pelvic radiotherapy. Moreover, anti-inflammatory interventions, even if implemented long after completed radiotherapy, could promote bowel health in pelvic cancer survivors.
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| 17. |
- Patel, Piyush, et al.
(author)
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Dietary oat bran reduces systemic inflammation in mice subjected to pelvic irradiation
- 2020
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In: Nutrients. - : MDPI AG. - 2072-6643. ; 12:8
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Journal article (peer-reviewed)abstract
- Patients undergoing radiotherapy to treat pelvic-organ cancer are commonly advised to follow a restricted fiber diet. However, reducing dietary fiber may promote gastrointestinal inflammation, eventually leading to deteriorated intestinal health. The goal of this study was to evaluate the influence of dietary fiber on radiation-induced inflammation. C57BL/6J male mice were fed a High-oat bran diet (15% fiber) or a No-fiber diet (0% fiber) and were either irradiated (32 Gy delivered in four fractions) to the colorectal region or only sedated (controls). The dietary intervention started at 2 weeks before irradiation and lasted for 1, 6, and 18 weeks after irradiation, at which time points mice were sacrificed and their serum samples were assayed for 23 cytokines and chemokines. Our analyses show that irradiation increased the serum cytokine levels at all the time points analyzed. The No-fiber irradiated mice had significantly higher levels of pro-inflammatory cytokines than the High-oat irradiated mice at all time points. The results indicate that a fiber-rich oat bran diet reduces the intensity of radiation-induced inflammation, both at an early and late stage. Based on the results, it seems that the advice to follow a low-fiber diet during radiotherapy may increase the risk of decreased intestinal health in cancer survivors. © 2020 by the authors. Licensee MDPI, Basel, Switzerland.
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| 18. |
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| 19. |
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| 20. |
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| 21. |
- Sjöberg, Fei, et al.
(author)
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Elastase as a potential biomarker for radiation-induced gut wall injury of the distal bowel in an experimental mouse model
- 2018
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In: Acta Oncologica. - : Informa UK Limited. - 0284-186X .- 1651-226X. ; 57:8, s. 1025-1030
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Journal article (peer-reviewed)abstract
- Background and purpose: Traditionally, elastase has been used to study exocrine activity of the pancreas in patients with chronic pancreatitis and cystic fibrosis, and calprotectin as a marker for gut-wall inflammation in patients with inflammatory bowel disease. The aim of the study was to find out whether elastase and calprotectin could be used as inflammatory markers for radiation-induced gut wall injury of the distal bowel.Material and methods: Adult male mice were exposed to two, three, or four fractions of 6Gy or 8Gy irradiation to the sigmoid and rectum of the large bowel, using a linear accelerator. Fecal samples were collected from mice at 1, 3, and 6 weeks post-irradiation. The fecal levels of elastase and calprotectin were analyzed using ELISA.Results: Three and 6 weeks after irradiation, we found a dose-effect relationship between dose of ionizing radiation and the fecal level of elastase; that is significantly higher levels of elastase were observed in mice that had received a high irradiation dose. We also found that irradiated mice hosted in the same cage had a comparable level (either high or low) of elastase. No significant differences were observed from the calprotectin data.Conclusions: We found a clear association between the dose of ionizing radiation to the distal colon and the level of elastase in the fecal samples.
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| 22. |
- Steineck, Gunnar, 1952, et al.
(author)
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Contouring pudendal nerves.
- 2018
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In: Acta oncologica (Stockholm, Sweden). - 1651-226X. ; 57:4, s. 438-439
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Journal article (other academic/artistic)
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| 23. |
- Steineck, Gunnar, 1952, et al.
(author)
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Identifying radiation-induced survivorship syndromes affecting bowel health in a cohort of gynecological cancer survivors
- 2017
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In: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 12:2
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Journal article (peer-reviewed)abstract
- © 2017 Steineck et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Background: During radiotherapy unwanted radiation to normal tissue surrounding the tumor triggers survivorship diseases; we lack a nosology for radiation-induced survivorship diseases that decrease bowel health and we do not know which symptoms are related to which diseases. Methods: Gynecological-cancer survivors were followed-up two to 15 years after having undergone radiotherapy; they reported in a postal questionnaire the frequency of 28 different symptoms related to bowel health. Population-based controls gave the same information. With a modified factor analysis, we determined the optimal number of factors, factor loadings for each symptom, factor-specific factor-loading cutoffs and factor scores. Results: Altogether data from 623 survivors and 344 population-based controls were analyzed. Six factors best explain the correlation structure of the symptoms; for five of these a statistically significant difference (P< 0.001, Mann-Whitney U test) was found between survivors and controls concerning factor score quantiles. Taken together these five factors explain 42 percent of the variance of the symptoms. We interpreted these five factors as radiation-induced syndromes that may reflect distinct survivorship diseases. We obtained the following frequencies, defined as survivors having a factor loading above the 95 percent percentile of the controls, urgency syndrome (190 of 623, 30 percent), leakage syndrome (164 of 623, 26 percent), excessive gas discharge (93 of 623, 15 percent), excessive mucus discharge (102 of 623, 16 percent) and blood discharge (63 of 623, 10 percent). Conclusion: Late effects of radiotherapy include five syndromes affecting bowel health; studying them and identifying the underlying survivorship diseases, instead of the approximately 30 long-term symptoms they produce, will simplify the search for prevention, alleviation and elimination.
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| 24. |
- Steineck, Gunnar, 1952, et al.
(author)
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Late radiation-induced bowel syndromes, tobacco smoking, age at treatment and time since treatment - gynecological cancer survivors
- 2017
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In: Acta Oncologica. - : Informa UK Limited. - 0284-186X .- 1651-226X. ; 56:5, s. 682-691
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Journal article (peer-reviewed)abstract
- Background: It is unknown whether smoking; age at time of radiotherapy or time since radiotherapy influence the intensity of late radiation-induced bowel syndromes.Material and methods: We have previously identified 28 symptoms decreasing bowel health among 623 gynecological-cancer survivors (three to twelve years after radiotherapy) and 344 matched population-based controls. The 28 symptoms were grouped into five separate late bowel syndromes through factor analysis. Here, we related possible predictors of bowel health to syndrome intensity, by combining factor analysis weights and symptom frequency on a person-incidence scale.Results: A strong (p<.001) association between smoking and radiation-induced urgency syndrome was found with a syndrome intensity (normalized factor score) of 0.4 (never smoker), 1.2 (former smoker) and 2.5 (current smoker). Excessive gas discharge was also related to smoking (p=.001). Younger age at treatment resulted in a higher intensity, except for the leakage syndrome. For the urgency syndrome, intensity decreased with time since treatment.Conclusions: Smoking aggravates the radiation-induced urgency syndrome and excessive gas discharge syndrome. Smoking cessation may promote bowel health among gynecological-cancer survivors. Furthermore, by understanding the mechanism for the decline in urgency-syndrome intensity over time, we may identify new strategies for prevention and alleviation.
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| 25. |
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| 26. |
- Steineck, Gunnar, 1952, et al.
(author)
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Toward Restored Bowel Health in Rectal Cancer Survivors
- 2016
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In: Seminars in Radiation Oncology. - : Elsevier BV. - 1053-4296 .- 1532-9461. ; 26:3, s. 236-250
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Journal article (peer-reviewed)abstract
- As technology gets better and better, and as clinical research provides more and more knowledge, we can extend our ambition to cure patients from cancer with restored physical health among the survivors. This increased ambition requires attention to grade 1 toxicity that decreases quality of life. It forces us to document the details of grade 1 toxicity and improve our understanding of the mechanisms. Long-term toxicity scores, or adverse events as documented during clinical trials, may be regarded as symptoms or signs of underlying survivorship diseases. However, we lack a survivorship nosology for rectal cancer survivors. Primarily focusing on radiation-induced side effects, we highlight some important observations concerning late toxicity among rectal cancer survivors. With that and other data, we searched for a preliminary survivorship-disease nosology for rectal cancer survivors. We disentangled the following survivorship diseases among rectal cancer survivors: low anterior resection syndrome, radiation-induced anal sphincter dysfunction, gut wall inflammation and fibrosis, blood discharge, excessive gas discharge, excessive mucus discharge, constipation, bacterial overgrowth, and aberrant anatomical structures. The suggested survivorship nosology may form the basis for new instruments capturing long-term symptoms (patient-reported outcomes) and professional-reported signs. For some of the diseases, we can search for animal models. As an end result, the suggested survivorship nosology may accelerate our understanding on how to prevent, ameliorate, or eliminate manifestations of treatment-induced diseases among rectal cancer survivors.
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| 27. |
- Toft Morén, Amelie, 1994, et al.
(author)
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Remarkable effects of infliximab on severe radiation-induced side effects in a patient with uterine cervical cancer: a case report
- 2023
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In: Journal of International Medical Research. - 0300-0605 .- 1473-2300. ; 51:12
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Journal article (peer-reviewed)abstract
- Pelvic radiotherapy is a powerful treatment for a broad range of cancers, including gynecological, prostate, rectal, and anal cancers. Despite improvements in the delivery of ionizing beams, damage to non-cancerous tissue can cause long-term effects that are potentially severe, affecting quality of life and daily function. There is an urgent need for new strategies to treat and reverse the side effects of pelvic radiotherapy without compromising the antitumor effect. A woman with severe radiation-induced intestinal side effects was treated with the tumor necrosis factor-alpha inhibitor infliximab with a dose of 3 mg/kg every 4 to 6 weeks. With infliximab treatment, a remarkable improvement in her bowel health was observed. The patient’s late bowel toxicity was reduced from Grade 2 to Grade 0 (RTOG/EORTC Late Radiation Morbidity Scale). Although it is necessary to proceed cautiously because of the risk of serious side effects from immunosuppressants, our case suggests that infliximab can be used to treat symptoms of chronic bowel dysfunction after radiotherapy.
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| 28. |
- Voss, Ulrikke, et al.
(author)
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Irradiation Induces Tuft Cell Hyperplasia and Myenteric Neuronal Loss in the Absence of Dietary Fiber in a Mouse Model of Pelvic Radiotherapy
- 2022
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In: Gastroenterology Insights. - : MDPI AG. - 2036-7422. ; 13:1, s. 87-102
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Journal article (peer-reviewed)abstract
- Pelvic radiotherapy is associated with chronic intestinal dysfunction. Dietary approaches, such as fiber enrichment during and after pelvic radiotherapy, have been suggested to prevent or reduce dysfunctions. In the present paper, we aimed to investigate whether a diet rich in fermentable fiber could have a positive effect on radiation-induced intestinal damage, especially focusing on tuft cells and enteric neurons. Male C57BL/6 mice were fed either a purified non-fiber diet or the same purified diet with 5% or 15% oat fiber added, starting two weeks prior to sham-irradiation or irradiation with four fractions of 8 Gray. The animals continued on the diets for 1, 6 or 18 weeks, after which the gross morphology of the colorectum was assessed together with the numbers of enteric neurons, tuft cells and crypt-surface units. The results showed that dietary fiber significantly affected the intestinal morphometrics, both in the short and long-term. The presence of dietary fiber stimulated the re-emergence of crypt-surface unit structures after irradiation. At 18 weeks, the animals fed with the non-fiber diet displayed more myenteric neurons than the animals fed with the dietary fibers, but irradiation resulted in a loss of neurons in the non-fiber fed animals. Irradiation, but not diet, affected the tuft cell numbers, and a significant increase in tuft cells was found 6 and 18 weeks after irradiation. In conclusion, dietary fiber intake has the potential to modify neuronal pathogenesis in the colorectum after irradiation. The long-lasting increase in tuft cells induced by irradiation may reflect an as yet unknown role in the mucosal pathophysiology after pelvic irradiation. © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).
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| 29. |
- Åberg, N David, 1970, et al.
(author)
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Peripheral infusion of insulin-like growth factor-I increases the number of newborn oligodendrocytes in the cerebral cortex of adult hypophysectomized rats.
- 2007
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In: Endocrinology. - : The Endocrine Society. - 0013-7227 .- 1945-7170. ; 148:8, s. 3765-72
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Journal article (peer-reviewed)abstract
- We have previously shown that recombinant human (rh) IGF-I induces cell proliferation and neurogenesis in the hippocampus of hypophysectomized rats. In the current investigation, we determined the effects of rhIGF-I on proliferation and differentiation in the cerebral cortex. Adult hypophysectomized rats were injected with bromodeoxyuridine (BrdU) to label newborn cells (once a day for the first 5 d), and rhIGF-I was administered peripherally for 6 or 20 d. In the cerebral cortex, the number of BrdU-labeled cells increased after 20 d but not after 6 d of rhIGF-I infusion. This suggests that rhIGF-I enhances the survival of newborn cells in the cerebral cortex. Using BrdU labeling combined with the oligodendrocyte-specific markers myelin basic protein and 2',3'-cyclic nucleotide 3'-phosphodiesterase, we demonstrated an increase in oligodendrogenesis in the cerebral cortex. The total amount of myelin basic protein and 2',3'-cyclic nucleotide 3'-phosphodiesterase was also increased on Western blots of homogenates of the cerebral cortex, confirming the immunohistochemical findings. Also, we observed an increase in the number of capillary-associated BrdU-positive cells, although total capillary area was not increased. rhIGF-I treatment did not affect cortical astrogliogenesis and neurogenesis was not observed. The ability of rhIGF-I to induce cortical oligodendrogenesis may have implications for the regenerative potential of the cortex.
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