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  • 1
    In: JMIR Research Protocols, JMIR Publications Inc., Vol. 10, No. 11 ( 2021-11-11), p. e32395-
    Abstract: Therapy for a first primary neoplasm (FPN) in childhood with high doses of ionizing radiation is an established risk factor for second primary neoplasms (SPN). An association between exposure to low doses and childhood cancer is also suggested; however, results are inconsistent. As only subgroups of children with FPNs develop SPNs, an interaction between radiation, genetic, and other risk factors is presumed to influence cancer development. Objective Therefore, the population-based, nested case-control study KiKme aims to identify differences in genetic predisposition and radiation response between childhood cancer survivors with and without SPNs as well as cancer-free controls. Methods We conducted a population-based, nested case-control study KiKme. Besides questionnaire information, skin biopsies and saliva samples are available. By measuring individual reactions to different exposures to radiation (eg, 0.05 and 2 Gray) in normal somatic cells of the same person, our design enables us to create several exposure scenarios for the same person simultaneously and measure several different molecular markers (eg, DNA, messenger RNA, long noncoding RNA, copy number variation). Results Since 2013, 101 of 247 invited SPN patients, 340 of 1729 invited FPN patients, and 150 of 246 invited cancer-free controls were recruited and matched by age and sex. Childhood cancer patients were additionally matched by tumor morphology, year of diagnosis, and age at diagnosis. Participants reported on lifestyle, socioeconomical, and anthropometric factors, as well as on medical radiation history, health, and family history of diseases (n=556). Primary human fibroblasts from skin biopsies of the participants were cultivated (n=499) and cryopreserved (n=3886). DNA was extracted from fibroblasts (n=488) and saliva (n=510). Conclusions This molecular-epidemiological study is the first to combine observational epidemiological research with standardized experimental components in primary human skin fibroblasts to identify genetic predispositions related to ionizing radiation in childhood and SPNs. In the future, fibroblasts of the participants will be used for standardized irradiation experiments, which will inform analysis of the case-control study and vice versa. Differences between participants will be identified using several molecular markers. With its innovative combination of experimental and observational components, this new study will provide valuable data to forward research on radiation-related risk factors in childhood cancer and SPNs. International Registered Report Identifier (IRRID) DERR1-10.2196/32395
    Type of Medium: Online Resource
    ISSN: 1929-0748
    Language: English
    Publisher: JMIR Publications Inc.
    Publication Date: 2021
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  • 2
    In: Molecular Medicine, Springer Science and Business Media LLC, Vol. 26, No. 1 ( 2020-12)
    Abstract: Exposure to ionizing radiation induces complex stress responses in cells, which can lead to adverse health effects such as cancer. Although a variety of studies investigated gene expression and affected pathways in human fibroblasts after exposure to ionizing radiation, the understanding of underlying mechanisms and biological effects is still incomplete due to different experimental settings and small sample sizes. Therefore, this study aims to identify the time point with the highest number of differentially expressed genes and corresponding pathways in primary human fibroblasts after irradiation at two preselected time points. Methods Fibroblasts from skin biopsies of 15 cell donors were exposed to a high (2Gy) and a low (0.05Gy) dose of X-rays. RNA was extracted and sequenced 2 h and 4 h after exposure. Differentially expressed genes with an adjusted p -value 〈  0.05 were flagged and used for pathway analyses including prediction of upstream and downstream effects. Principal component analyses were used to examine the effect of two different sequencing runs on quality metrics and variation in expression and alignment and for explorative analysis of the radiation dose and time point of analysis. Results More genes were differentially expressed 4 h after exposure to low and high doses of radiation than after 2 h. In experiments with high dose irradiation and RNA sequencing after 4 h, inactivation of the FAT10 cancer signaling pathway and activation of gluconeogenesis I , glycolysis I, and prostanoid biosynthesis was observed taking p -value ( 〈  0.05) and (in) activating z-score (≥2.00 or ≤ − 2.00) into account. Two hours after high dose irradiation, inactivation of small cell lung cancer signaling was observed. For low dose irradiation experiments, we did not detect any significant ( p   〈  0.05 and z-score ≥ 2.00 or ≤ − 2.00) activated or inactivated pathways for both time points. Conclusions Compared to 2 h after irradiation, a higher number of differentially expressed genes were found 4 h after exposure to low and high dose ionizing radiation. Differences in gene expression were related to signal transduction pathways of the DNA damage response after 2 h and to metabolic pathways, that might implicate cellular senescence, after 4 h. The time point 4 h will be used to conduct further irradiation experiments in a larger sample.
    Type of Medium: Online Resource
    ISSN: 1076-1551 , 1528-3658
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2020
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  • 3
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 80, No. 14_Supplement ( 2020-07-15), p. B60-B60
    Abstract: Childhood cancer therapies are known risk factors for the development of second primary cancers. They are also suggested risk factors for late adverse health effects. Until now, there is no established questionnaire to retrospectively assess exposure to cancer therapies in childhood among adults. Therefore, we aim to validate a new self-administered questionnaire. The study population consists of 438 former childhood cancer patients of the KiKme study. Participants are asked whether they had received cancer therapies and how often and with which dose they were treated. Used medications and affected body regions are inquired. Questionnaire data are used to compute cytotoxic drugs dose of chemotherapy, taking patients’ weight and height into account, and to reconstruct individual organ doses. For validation, self-reports are compared to data of cancer therapies of 178 patients from hospitals and clinical studies. Quality assessment for binary variables are performed by measuring sensitivity and specificity. AUC and ROC curve are used for graphical comparison. The validity is analyzed by the positive (PPV) and negative predictive value (NPV). Cohen’s Kappa (κ) is used to measure the concordance between the two assessments. Continuous variables are tested for validity by the intraclass correlation coefficient. A Bland-Altman plot is used to consider the patterns of disagreement between the measurements. Influencing factors (e.g., number of neoplasms, sex, sociodemographic factors, comorbidities, time since cancer treatment) on the dichotomous outcome variable “degree of agreement” are analyzed using logistic regression. If the questionnaire is reliable, logistic regression and mixed models will be used to estimate possible risk associations with cancer therapies. A perfect agreement between questionnaire and therapy data was found on whether a chemotherapy was received (κ = 1.00). The agreement for exposure to radiotherapy was lower, but in the upper substantial area (κ = 0.77). For radiotherapy, sensitivity (94%) and PPV (96%) of the questionnaire were at a very high level. Specificity (85%) and NPV (80%) were less precise. The agreement for exposure to radiotherapy was higher in participants with one cancer (κ = 0.82) compared to participants with more than one diagnosis (κ = 0.62). The odds ratios for agreement were 0.5 (0.1; 1.8) for participants with two vs. one diagnosis, 1.3 (0.3; 4.9) for men vs. women, 10.9 (1.7; 71.9) for age over 36.4 years (median) vs. younger participants, 2.2 (0.6; 9.0) for high vs. low education, 0.3 (0.1; 1.4) for over 26.5 years of follow-up (median) vs. less, 2.4 (0.6; 9.5) for existing vs. nonexisting comorbidities. In conclusion, the new developed questionnaire seems to be reliable for the retrospective assessment of binary exposure to cancer therapies in childhood, especially for chemotherapy. However, for radiotherapy older participants showed a significant higher agreement. All other tested variables showed no significant influence. Citation Format: Lara Kim Brackmann, Caine Lucas Grandt, Heike Schwarz, Irene Schmidtmann, Thomas Hankeln, Danuta Galetzka, Sebastian Zahnreich, Peter Scholz-Kreisel, Maria Blettner, Heinz Schmidberger, Manuela Marron. Exposure assessment among an adult population on radiation therapy, chemotherapy, and other cancer therapies in childhood [abstract]. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr B60.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
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