Cancer stem cells (CSC) are a distinct subpopulation within a tumor. They are able to self-renew and differentiate and possess a high capability to repair DNA damage, exhibit low levels of reactive oxygen species (ROS), and proliferate slowly. These features render CSC resistant to various therapies, including radiation therapy (RT). Eradication of all CSC is a requirement for an effective antineoplastic treatment and is therefore of utmost importance for the patient. This makes CSC the prime targets for any therapeutic approach. Albeit clinical data is still scarce, experimental data and first clinical trials give hope that CSC-targeted treatment has the potential to improve antineoplastic therapies, especially for tumors that are known to be treatment resistant, such as glioblastoma. In this review, we will discuss CSC in the context of RT, describe known mechanisms of resistance, examine the possibilities of CSC as biomarkers, and discuss possible new treatment approaches.

The immune system is affected by the aging process and undergoes significant age-related changes, termed immunosenescence. Different T cell subsets are affected by this process. Alterations within the bone marrow and thymus lead to a shift in the composition of the T cell repertoire from naïve to antigen-experienced T cells, thereby compromising the diversity of the T cell pool. Additional infection with latent pathogens such as cytomegalovirus aggravates this process. In this review, we focus on the major age-related changes that occur in the naïve and the antigen-experienced T cell population. We discuss the mechanisms responsible for the generation and maintenance of these subsets and how age-related changes can be delayed or prevented by clinical interventions.

The life-long homeostasis of memory CD8+ T cells as well as persistent viral infections have been shown to facilitate the accumulation of highly differentiated CD8+CD28− T cells, a phenomenon that has been associated with an impaired immune function in humans. However, the molecular mechanisms regulating homeostasis of CD8+CD28− T cells have not yet been elucidated. In this study, we demonstrate that the miR-23∼24∼27 cluster is up-regulated during post-thymic CD8+ T-cell differentiation in humans. The increased expression of miR-24 in CD8+CD28− T cells is associated with decreased expression of the histone variant H2AX, a protein that plays a key role in the DNA damage response (DDR). Following treatment with the classic chemotherapeutic agent etoposide, a topoisomerase II inhibitor, apoptosis was increased in CD8+CD28− when compared to CD8+CD28+ T cells and correlated with an impaired DDR in this cell type. The reduced capacity of CD8+CD28− T cell to repair DNA was characterized by the automated fluorimetric analysis of DNA unwinding (FADU) assay as well as by decreased phosphorylation of H2AX at Ser139, of ATM at Ser1981, and of p53 at Ser15. Interleukin (IL)-15 could prevent etoposide-mediated apoptosis of CD8+CD28− T cells, suggesting a role for IL-15 in the survival and the age-dependent accumulation of CD8+CD28− T cells in humans.

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The immune system undergoes profound age-related changes, including a gradual increase in the production and circulation of proinflammatory cytokines. Despite the known capacity of fibroblasts to produce cytokines, little is known so far about the inflammatory response of fibroblasts to cellular stress such as viral and/or bacterial infection in the context of aging. Therefore the aim of this study was to analyze the levels of IL6 and IL8 secretion in supernatants of human skin fibroblasts from young and elderly persons. Cytokine and chemokine secretion was analyzed before and after in vitro infection of the cells with Cytomegalovirus (CMV) and/or stimulation with Lipopolysaccharide (LPS). The exposure of fibroblasts to these agents caused inflammatory changes, reflected by the secretion of both the cytokine IL6 and the chemokine IL8 by fibroblasts from young as well as elderly persons. The cytokine/chemokine production induced by either agent alone could be further increased by co-stimulation of the cells with both stimuli. The level of protein secretion was dependent on the chronological age of the fibroblasts. Stimulated human skin fibroblasts from elderly donors produced higher amounts of IL6 as well as IL8 than fibroblasts from young donors. These differences were more pronounced for IL6 than for IL8. The inflammatory response of fibroblasts to stimulation differed among donors and did not correspond to the responsiveness of whole blood derived from the same person.In summary lifelong CMV-infection may act as an in vivo trigger for inflammatory changes by increasing the inflammatory response to bacterial products such as LPS. It may thus contribute to age-related inflammatory processes, referred to as ‘inflamm-aging’.

Aimof this study is to determine the temporal resolution of therapy-induced pneumonitis, and to assess promoting factors in adjuvant treated patients with unilateral mammacarcinoma.Patients and methodsA total of 100 post-surgery patients were recruited. The cohort was treated by 2 field radiotherapy (2FRT; breast and chest wall, N = 75), 3 field radiotherapy (3FRT; + supraclavicular lymphatic region, N = 8), or with 4 field radiotherapy (4FRT; + parasternal lymphatic region, N = 17). Ninety-one patients received various systemic treatments prior to irradiation. Following an initial screening visit post-RT, two additional visits after 12 and 25 weeks were conducted including radiographic examination. In addition, general anamnesis and the co-medication were recorded. The endpoint was reached as soon as a pneumonitis was developed or at maximum of six months post-treatment.ResultsA pneumonitis incidence of 13% was determined. Of 91 patients with prior systemic therapy, 11 patients developed pneumonitis. Smoking history and chronic obstructive pulmonary disease (COPD) appeared to be positive predictors, whereas past pneumonia clearly promoted pneumonitis. Further pneumonitis-promoting predictors are represented by the applied field extensions (2 field radiotherapy [2FRT] < 3 field radiotherapy [3FRT] < 4 field radiotherapy [4FRT]) and the type of combined initial systemic therapies. As a consequence, all of the three patients in the study cohort treated with 4FRT and initial chemotherapy combined with anti-hormone and antibody protocols developed pneumonitis. A combination of the hormone antagonists tamoxifen and goserelin might enhance the risk for pneumonitis. Remarkably, none of the 11 patients co-medicated with statins suffered from pneumonitis.ConclusionsThe rapidly increasing use of novel systemic therapy schedules combined with radiotherapy (RT) needs more prospective studies with larger cohorts. Our results indicate that contribution to pneumonitis occurrence of various (neo)adjuvant therapy approaches followed by RT is of minor relevance, whereas mean total lung doses of >10 Gy escalate the risk of lung tissue complications. The validity of potential inhibitors of therapy-induced pneumonitis as observed for statin co-medication should further be investigated in future trials.

BackgroundThe present study investigates the intrafractional accuracy of a frameless thermoplastic mask used for head immobilization during stereotactic radiotherapy. Non-invasive masks cannot completely prohibit head movements. Previous studies attempted to estimate the magnitude of intrafractional inaccuracy by means of pre- and postfractional measurements only. However, this might not be sufficient to accurately map also intrafractional head movements.Materials and methodsIntrafractional deviation of mask-fixed head positions was measured in five patients during a total of 94 fractions by means of close-meshed repeated ExacTrac measurements (every 1.4 min) conducted during the entire treatment session. A median of six (range: 4 to 11) measurements were recorded per fraction, delivering a dataset of 453 measurements.ResultsRandom errors (SD) for the x, y and z axes were 0.27 mm, 0.29 mm and 0.29 mm, respectively. Median 3D deviation was 0.29 mm. Of all 3D intrafractional motions, 5.5 and 0.4% exceeded 1 mm and 2 mm, respectively. A moderate correlation between treatment duration and mean 3D displacement was determined (rs = 0.45). Mean 3D deviation increased from 0.21 mm (SD = 0.26 mm) in the first 2 min to a maximum of 0.53 mm (SD = 0.31 mm) after 10 min of treatment time.ConclusionPre- and post-treatment measurement is not sufficient to adequately determine the range of intrafractional head motion. Thermoplastic masks provide both reliable interfractional and intrafractional immobilization for image-guided stereotactic hypofractionated radiotherapy. Greater positioning accuracy may be obtained by reducing treatment duration (< 6 min) and applying intrafractional correction.Trial registrationClinicaltrials.gov, NCT03896555, Registered 01 April 2019 - retrospectively registered.

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