Abstract: Background Differential expression analysis is usually adjusted for variation. However, most studies that examined the expression variability (EV) have used computations affected by low expression levels and did not examine healthy tissue. This study aims to calculate and characterize an unbiased EV in primary fibroblasts of childhood cancer survivors and cancer-free controls (N0) in response to ionizing radiation. Methods Human skin fibroblasts of 52 donors with a first primary neoplasm in childhood (N1), 52 donors with at least one second primary neoplasm (N2 +), as well as 52 N0 were obtained from the KiKme case-control study and exposed to a high (2 Gray) and a low dose (0.05 Gray) of X-rays and sham- irradiation (0 Gray). Genes were then classified as hypo-, non-, or hyper-variable per donor group and radiation treatment, and then examined for over-represented functional signatures. Results We found 22 genes with considerable EV differences between donor groups, of which 11 genes were associated with response to ionizing radiation, stress, and DNA repair. The largest number of genes exclusive to one donor group and variability classification combination were all detected in N0: hypo-variable genes after 0 Gray (n = 49), 0.05 Gray (n = 41), and 2 Gray (n = 38), as well as hyper-variable genes after any dose (n = 43). While after 2 Gray positive regulation of cell cycle was hypo-variable in N0, (regulation of) fibroblast proliferation was over-represented in hyper-variable genes of N1 and N2+. In N2+, 30 genes were uniquely classified as hyper-variable after the low dose and were associated with the ERK1/ERK2 cascade. For N1, no exclusive gene sets with functions related to the radiation response were detected in our data. Conclusion N2+ showed high degrees of variability in pathways for the cell fate decision after genotoxic insults that may lead to the transfer and multiplication of DNA-damage via proliferation, where apoptosis and removal of the damaged genome would have been appropriate. Such a deficiency could potentially lead to a higher vulnerability towards side effects of exposure to high doses of ionizing radiation, but following low-dose applications employed in diagnostics, as well

Abstract: Introdution: We aimed to evaluate treatment outcome of combined radiotherapy (RT) including photon intensity modulated radiotherapy (IMRT) and carbon ion boost for adenoid cystic carcinomas (ACCs) of the major salivary glands, the currently available largest German collective for this cohort. Materials and Methods: Overall, 207 patients who were irradiated with combined RT between 2009 and 2019 at Heidelberg University Hospital were analyzed retrospectively for local control (LC), progression-free survival (PFS) and overall survival (OS) using Kaplan-Meier estimates. The majority of patients received postoperative RT (n=176/207, 85%) after previous surgery in large German hospitals mainly Mainz, Freiburg, Mannheim and Heidelberg University Hospitals and 15% received primary RT (n=31/207). Results: After a median follow-up time of 50 months, 84% of the patients were still alive (n=174/207). Disease progression occurred in 32% of the patients (n=66/207) while local recurrence was diagnosed in 12% (n=25/207), and distant relapse in 27% (n=56/207). Estimated 5-year LC, PFS and OS rates were 84%, 56% and 83% for OS, respectively. In multivariate analysis, we could identify two prognostic subgroups: one subgroup resulting in decreased LC, PFS and OS rates and another subgroup having an additional survival disadvantage in PFS and OS. Patients with a macroscopic tumor disease (yes vs. no; p0.001 for LC, p=0.010 for PFS and p=0.040 for OS) treated in a definitive setting (vs. postoperative setting; p=0.001 for LC, p=0.006 for PFS, p=0.049 for OS) and tumors of upper T stage (T1-4; p=0.004 for LC, p0.001 for PFS, p

Abstract: Background and purpose: To evaluate the tolerability and outcomes of chemoradiation in elderly patients with locally advanced esophageal squamous cell carcinoma (ESCC). Materials and methods: This multi-center retrospective analysis included 161 patients with SCC of the esophagus with a median age of 73 years (range 65-89 years) treated with definitive or neoadjuvant (chemo)radiotherapy between 2010 and 2019 at 3 large comprehensive cancer centers in Germany. Locoregional control (LRC), progression-free survival (PFS), distant metastasis-free survival (DMFS), overall survival (OS), and treatment-associated toxicities were analyzed, and parameters determining patient outcomes and treatment tolerance were assessed. Results: The delivery of radiotherapy without dose reduction was possible in 149 patients (93%). In 134 patients (83%), concomitant chemotherapy was initially prescribed; however, during the course of therapy, 41% of these patients (n = 55) required chemotherapy de-escalation due to treatment-related toxicities. Fifty-two patients (32%) experienced higher-grade acute toxicities, and 22 patients (14%) higher-grade late toxicities. The 2-year LRC, DMFS, PFS, and OS rates amounted to 67.5%, 33.8%, 31.4%, and 40.4%, respectively. Upon multivariate analysis, full-dose concomitant chemotherapy (vs. no or modified chemotherapy) was associated with significantly better DMFS (p=0.005), PFS (p=0.005) and OS (p=0.001). Furthermore, neoadjuvant chemoradiotherapy followed by tumor resection (vs. definitive chemoradiotherapy or definitive radiotherapy alone) significantly improved PFS (p=0.043) and OS (p=0.049). We could not identify any clinico-pathological factor that was significantly associated with LRC. Furthermore, definitive (chemo)radiotherapy, brachytherapy boost and stent implantation were significantly associated with higher-grade acute toxicities (p0.001, p=0.002 and p=0.04, respectively). The incidence of higher-grade late toxicities was also significantly associated with the choice of therapy, with a higher risk for late toxicities when treatment was switched from neoadjuvant to definitive (chemo)radiotherapy compared to primary definitive (chemo)radiotherapy (p0.001).