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Background Despite advances in radiotherapeutic techniques, radiation-induced cardiovascular diseases (CVD) remain a leading but often underrecognized cause of morbidity and mortality in cancer survivors. Radiation exposure can trigger a broad spectrum of cardiotoxic effects yet clinical awareness and strategies for managing these long-term complications remain limited. Among emerging indicators of vascular dysfunction, measures of vascular flexibility offer key biomarkers for assessing vascular compliance and cardiovascular risk. Methods The present study hence investigated age- and dose-dependent effects of local irradiation on vascular function of the murine Arteria saphena in C57BL/6 wild-type and atherosclerosis-prone apolipoprotein E-knockout (ApoE −/− ) mice, a well established model for human CVD. Pathological effects of irradiation on vascular function of the A. saphena were assessed using in vivo Optical Coherence Tomography. Vascular flexibility in terms of arterial diameters and speed of diameter changes during vasoconstriction and vasodilation were recorded one day and 3, 6, 9, 12, or 18 months following irradiation with single doses of 2, 5, 8, 10, 16 Gy. Results Baseline arterial diameters declined with age in both strains, with earlier onset in ApoE −/− mice. Significant interactions with radiation dose indicate greater radiation sensitivity in ApoE −/− mice and additive effects of radiation and aging in both strains. Vasoconstriction halved arterial diameters in wild-type and more so in ApoE −/− mice, reflecting an enhanced vasoconstrictive response that diminished after 16 Gy. Contractility was found to be age-dependent, peaking between 6 and 12 months post-irradiation, while time to half-maximal constriction remained unchanged across conditions. Maximal vasodilation ranged from 1.2 to 2 × baseline, initially higher in ApoE −/− mice but declining earlier with age than in wildtype mice. ApoE −/− mice exhibited more sustained vasodilation, which progressively slowed with age and higher radiation doses in both strains. Conclusion Both mouse strains exhibited marked age-related vascular changes, with ApoE −/− mice showing greater radiation sensitivity. The combined effects of aging and radiation were most prominent in reduced arterial diameters at baseline and after vasoconstriction, along with slower vasodilation reflecting elevated vascular resistance linked to hypertension. Early blood pressure management is therefore essential to reduce the risk of radiation-induced CVD.

Radiation therapy treatment of breast cancer, Hodgkin's disease or childhood cancers expose the heart to high local radiation doses, causing an increased risk of cardiovascular disease in the survivors decades after the treatment. The mechanisms that underlie the radiation damage remain poorly understood so far. Previous data show that impairment of mitochondrial oxidative metabolism is directly linked to the development of cardiovascular disease. In this study, the radiation-induced in vivo effects on cardiac mitochondrial proteome and function were investigated. C57BL/6N mice were exposed to local irradiation of the heart with doses of 0.2 Gy or 2 Gy (X-ray, 200 kV) at the age of eight weeks, the control mice were sham-irradiated. After four weeks the cardiac mitochondria were isolated and tested for proteomic and functional alterations. Two complementary proteomics approaches using both peptide and protein quantification strategies showed radiation-induced deregulation of 25 proteins in total. Three main biological categories were affected: the oxidative phophorylation, the pyruvate metabolism, and the cytoskeletal structure. The mitochondria exposed to high-dose irradiation showed functional impairment reflected as partial deactivation of Complex I (32%) and Complex III (11%), decreased succinate-driven respiratory capacity (13%), increased level of reactive oxygen species and enhanced oxidation of mitochondrial proteins. The changes in the pyruvate metabolism and structural proteins were seen with both low and high radiation doses. This is the first study showing the biological alterations in the murine heart mitochondria several weeks after the exposure to low- and high-dose of ionizing radiation. Our results show that doses, equivalent to a single dose in radiotherapy, cause long-lasting changes in mitochondrial oxidative metabolism and mitochondria-associated cytoskeleton. This prompts us to propose that these first pathological changes lead to an increased risk of cardiovascular disease after radiation exposure.

U–Pb age spectra of detrital zircons related to the East European Platform could be traced in paragneiss through the whole Mid-German-Crystalline Zone (Variscides, Central Europe) from the Odenwald via the Spessart to the Ruhla crystalline forming an exotic unit between Armorica and Laurussia. The depositional ages of the paragneiss are defined by the youngest age of the detrital zircons and the oldest intrusion ages as Ordovician to Silurian. The Ediacaran dominated age spectrum of detrital zircons from the paragneiss of the East Odenwald suggests the latter to be derived from the shelf of the East European Platform (Baltica), which was influenced by the 1.5 Ga old detritus delivered from a giant intrusion (Mazury granitoid, Poland). The detrital zircon age spectrum of the lower Palaeozoic paragneiss of the East Odenwald and sandstone of the northern Holy Cross Mountains are identical. The pure Sveconorwegian spectrum of the lower Palaeozoic quartzite from the Spessart, (Kirchner and Albert Int J Earth Sci 2020) and the Ruhla (Zeh and Gerdes Gondwana Res 17:254–263, 2010) could be sourced from Bornholm and southern Sweden. A U–Pb age spectrum with 88% Palaeozoic detrital zircons from a volcano-sedimentary rock of the East Odenwald is interpreted to be derived from a Silurian magmatic arc (46%), which was probably generated during the drift of the Mid-German-Crystalline Zone micro-continent to the south. A tentative plate tectonic model of Mid-German-Crystalline Zone is presented taking into account (a) the East European Platform related age spectra of the detrital zircons (b) the Ordovician to Silurian depositional age of the metasediments (c) the Silurian and Early Devonian intrusion age of the plutonic and volcanic rocks and (d) the U–Pb ages of the Middle Devonian high-grade metamorphism. The East European Platform-related part of the Mid-German-Crystalline Zone is interpreted as a micro-continent, which drifted through the Rheic Ocean to the south and collided with the Saxothuringian (Armorican Terrane Assemblage) during the Early Devonian. Such large-scale tectonic transport from the northern continent to the southern continent is also known from the SW Iberia, where Laurussia-related metasediments of the Rheic suture zone are explained by a large scale tectonic escape (Braid et al. J Geol Soc Lond 168:383–392, 2011).

PurposeTo determine the effect of Cystus® tea (Naturprodukte Dr. Pandalis GmbH & Co. KG) as mouthwash compared to sage tea on oral mucositis in patients undergoing radio(chemo)therapy for head and neck cancer.MethodsIn this randomized, prospective phase III study, 60 head and neck cancer patients with primary or postoperative radio(chemo)therapy were included between 04/2012 and 06/2014. They received either sage or Cystus® tea for daily mouthwash under therapy. Mucositis was scored twice a week following the Radiation Therapy Oncology Group and the European Organization for Research and Treatment Cancer (RTOG/EORTC) scoring system. Dental parameters were also recorded. Statistical evaluation of the primary endpoint was performed using t‑test and log rank test.ResultsData from 57 patients could be evaluated. Patient characteristics showed no significant difference between the two groups (n = 27 sage; n = 30 Cystus®). A total of 55 patients received the prescribed dose (60–66 Gy postoperative; 70–76.8 Gy primary). Mucositis grade 3 was observed in 23 patients (n = 11 sage; n = 12 Cystus®) and occurred between day 16 and 50 after start of therapy. There was no significant difference between the two groups in latency (p = 0.75) and frequency (p = 0.85) of the occurrence of mucositis grade 3. The self-assessment of the oral mucosa and the tolerability of the tea also showed no significant differences. Occurrence of dental pathologies appeared to increase over time after radiotherapy.ConclusionCystus® and sage tea have a similar effect on the occurrence of radiation-induced mucositis regarding latency and incidence. Cystus® tea mouthwash solution is tolerated well and can be applied in addition to intensive oral care and hygiene along with the application of fluorides.

Investigating long-term cardiac effects of low doses of ionizing radiation is highly relevant in the context of interventional cardiology and radiotherapy. Epidemiological data report that low doses of irradiation to the heart can result in significant increase in the cardiovascular mortality by yet unknown mechanisms. In addition co-morbidity factor such as hypertension or/and atherosclerosis can enhance cardiac complications. Therefore, we explored the mechanisms that lead to long-term cardiac remodelling and investigated the interaction of radiation-induced damage to heart and cardiovascular systems with atherosclerosis, using wild-type and ApoE-deficient mice. ApoE-/- and wild-type mice were locally irradiated to the heart at 0, 0.2 and 2 Gy (RX). Twenty, 40 and 60 weeks post-irradiation, echocardiography were performed and hearts were collected for cardiomyocyte isolation, histopathological analysis, study of inflammatory infiltration and fibrosis deposition. Common and strain-specific pathogenic pathways were found. Significant alteration of left ventricular function (eccentric hypertrophy) occurred in both strains of mice. Low dose irradiation (0.2 Gy) induced premature death in ApoE-/- mice (47% died at 20 weeks). Acute inflammatory infiltrate was observed in scarring areas with accumulation of M1-macrophages and secretion of IL-6. Increased expression of the fibrogenic factors (TGF-β1 and PAI-1) was measured earlier in cardiomyocytes isolated from ApoE-/- than in wt animals. The present study shows that cardiac exposure to low dose of ionizing radiation induce significant physiological, histopathological, cellular and molecular alterations in irradiated heart with mild functional impairment. Atherosclerotic predisposition precipitated cardiac damage induced by low doses with an early pro-inflammatory polarization of macrophages.

PurposeTherapy response to neoadjuvant radiochemotherapy (nRCT) of locally advanced rectal cancer varies widely so that markers predicting response are urgently needed. Fibroblast growth factor (FGF) and FGF receptor (FGFR) signaling is involved in pro-survival signaling and thereby may result in radiation resistance.MethodsIn a cohort of 43 rectal cancer patients, who received nRCT, we analyzed protein levels of FGF 8 and its downstream target Survivin by immunohistochemistry to assess their impact on nRCT response. In vitro resistance models were created by exposing colorectal cancer cell lines to fractionated irradiation and selecting long-term survivors.ResultsOur findings revealed significantly higher FGF8 and Survivin staining scores in pre-treatment biopsies as well as in surgical specimens of non-responsive compared to responsive patients. Functional studies demonstrated dose-dependent induction of FGF8 mRNA expression in mismatch-incompetent DLD1 cells already after one dose of irradiation. Surviving clones after one or two series of radiation were more resistant to an additional radiation fraction than non-irradiated controls and showed a significant increase in expression of the FGF8 receptor FGFR3 and of Survivin on both the RNA and the protein levels.ConclusionThe results of this study suggest that FGF8 and Survivin contribute to radiation resistance in rectal cancer and may serve as markers to select patients who may not benefit from neoadjuvant radiotherapy.

In modern radiation oncology, tolerance dose-constraints for organs at risk (OAR) must be considered for treatment planning, but particularly in order to design clinical studies. Tolerance dose tables, however, only address one aspect of the therapeutic ratio of any clinical study, i.e., the limitation of adverse events, but not the desired potential improvement in the tumor effect of a novel treatment strategy. A sensible application of “tolerance doses” in a clinical situation requires consideration of various critical aspects addressed here: definition of tolerance dose, specification of an endpoint/symptom, consideration of radiation quality and irradiation protocol, exposed volume and dose distribution, and patient-related factors of radiosensitivity. The currently most comprehensive estimates of OAR radiation tolerance are in the QUANTEC compilations (2010). However, these tolerance dose values must only be regarded as a rough orientation and cannot answer the relevant question for the patients, i.e., if the study can achieve a therapeutic advantage; this can obviously be answered only by the final scientific analysis of the study results. Despite all limitations, the design of clinical studies should currently refer to the QUANTEC values for appreciation of the risk of complications, if needed supplemented by one’s own data or further information from the literature. The implementation of a consensus on the safety interests of the patients and on an application and approval process committed to progress in medicine, with transparent quality-assuring requirements with regard to the structural safeguarding of the study activities, plays a central role in clinical research in radiation oncology.

Detrital zircon age spectra of Ediacaran paragneiss from the Rheic suture between the Rhenohercynian Zone and Saxothuringian Zone suggest that they originated from different parts of peri-Gondwana. The paragneiss from the Northern Phyllite Belt displays an age spectrum of detrital zircons with a high amount of Neoproterozoic (82%) and Mesoproterozoic zircons (11%) typical for Amazonian provenance, whereas the spectrum from the metagreywacke of the Odenwald (Mid-German Crystalline Zone) shows a Mesoproterozoic age gap which is correlated with the West African Craton. The metagreywacke of the Odenwald contains 20% Paleoproterozoic and 32% Archean zircons, whereas the paragneiss of the Northern Phyllite Belt (Wartenstein Crystalline) contains only 6% Paleoproterozoic and no Archean zircons. The paleoposition of the basement of Northern Phyllite Belt was proximal to the Avalonian magmatic arc of the London–Brabant high. The Armorican metagreywacke of the Odenwald occupied a distal position to a Neoproterozoic magmatic arc, probably in a back-arc basin related to the West African Craton. Such a U–Pb age spectrum of detrital zircons together with a Mesoproterozoic age gap is typical for sediments of Armorica in Europe during the Ediacaran to Carboniferous. Neoproterozoic igneous rocks extruded at 566 ± 2 Ma forming a volcano-clastic sequence of the Cadomian magmatic arc which is the wall rock of the Silurian to Carboniferous plutons of the entire West Odenwald. This is the first occurrence of an extensive Cadomian crystalline basement in the Mid-German Crystalline Zone. Metagranite dykes crosscut the foliation of the Cadomian para- and orthogneiss at 542 ± 3 Ma. The deformation and migmatization of the Cadomian basement are bracketed between 566 and 542 Ma. A similar late Cadomian event is known from the Bohemian Massif and the Armorican Massif. Large Cadomian plutons with an age around 540 Ma, like that of the northern Odenwald, are common for Armorica. Silurian to Devonian granitoids (434 ± 4 Ma, 411 ± 5 Ma) are witness to an active margin along the northern boundary of Armorica. The Cadomian basement of the Odenwald together with the Palaeozoic granitoids is overprinted by a high-grade metamorphism at 384 ± 4 Ma (U–Pb on zircon) and cooled down below ca. 500 °C at 370 Ma (K–Ar ages of amphibole; U–Pb on titanite). Such a combination of late Cadomian and early Variscan ages could be correlated with the Münchberger Nappe, the Tepla–Barrandian Unit, Central Armorican Domain and the Massif Central.

This review summarizes information about modulation of radiation effects in tumor cells and tissues by selenium. In vitro, clonogenic survival to ionizing radiation was found to be reduced, depending on selenite concentration and duration of administration, by a factor of 1.5-4.4. In experimental animal tumors, a positive effect of selenium was observed with chemotherapy. The only available study in combination with irradiation did not show any benefit of selenium with clinically relevant radiotherapy protocols in R1H tumors. None of the investigations demonstrated a negative effect on the tumor response to therapy. The only study with fractionated irradiation was performed in a rat R1H tumor, which does not show accelerated repopulation. Therefore, interaction of selenium with such repopulation processes, potentially resulting in increased tumor tolerance, could not be detected. For local administration of normal tissues with selenium, potential tumor effects may be of less importance, but these may be relevant for systemic administration. Therefore, well-designed studies with relevant tumor models and endpoints, and with clinically relevant fractionation protocols are recommended.

Purpose: To evaluate the time course of late rectal mucosal changes after prostate cancer radiotherapy (RT). Patients and Methods: A rectosigmoidoscopy was performed at 12, 24, and 65 months after RT in 20 patients. Rectal mucosal changes (telangiectasia, congested mucosa, ulceration, stricture, and necrosis) were scored and documented according to the Vienna Rectoscopy Score (VRS, score 0–3). Results: VRS of 0 and 3, were found in 20% of patients (n = 4) and 5% of patients (n = 1), respectively at all time points. A shift of the VRS from 2 to 1 was found with incidence rates of 60% at 12 months and 20% at 65 months, which is equivalent to an improvement rate of 67%. Laser coagulation was required in 3 patients (15%) with rectal bleeding due to telangiectasia grade ≥2. Conclusion: Late rectal mucosal changes are frequent after pelvic RT. Generally only the incidence rates corresponding to the initial diagnosis of the complications, independent of subsequent recovery, are reported. The results reported in the present study show that complications often improve over time. Hence, the usual reports of complication rates overestimate the proportion of patients presenting with side effects of certain grades.