Fisetin induces DNA double-strand break and interferes with the repair of radiation-induced damage to radiosensitize triple negative breast cancer cells - Khozooei, Shayan; Lettau, Konstanze; Barletta, Francesca; Jost, Tina; Rebholz, Simone; Veerappan, Soundaram; Franz-Wachtel, Mirita; Macek, Boris; Iliakis, George; Distel, Luitpold; Zips, Daniel; Toulany, Mahmoud (Journal of Experimental & Clinical Cancer Research, 2022)
Background Triple-negative breast cancer (TNBC) is associated with aggressiveness and a poor prognosis. Besides surgery, radiotherapy serves as the major treatment modality for TNBC. However, response to radiotherapy is limited in many patients, most likely because of DNA damage response (DDR) signaling mediated radioresistance. Y-box binding protein-1 (YB-1) is a multifunctional protein that regulates the cancer hallmarks among them resisting to radiotherapy-induced cell death. Fisetin, is a plant flavonol of the flavonoid family of plant polyphenols that has anticancer properties, partially through inhibition of p90 ribosomal S6 kinase (RSK)-mediated YB-1 phosphorylation. The combination of fisetin with radiotherapy has not yet been investigated. Methods Activation status of the RSK signaling pathway in total cell lysate and in the subcellular fractions was analyzed by Western blotting. Standard clonogenic assay was applied to test post-irradiation cell survival. γH2AX foci assay and 3 color fluorescence in situ hybridization analyses were performed to study frequency of double-strand breaks (DSB) and chromosomal aberrations, respectively. The underlying repair pathways targeted by fisetin were studied in cells expressing genomically integrated reporter constructs for the DSB repair pathways via quantifying the expression of green fluorescence protein by flow cytometry. Flow cytometric quantification of sub-G1 cells and the protein expression of LC3-II were employed to measure apoptosis and autophagy, respectively. Kinase array and phosphoproteomics were performed to study the effect of fisetin on DDR response signaling. Results We showed that the effect of fisetin on YB-1 phosphorylation in TNBC cells is comparable to the effect of the RSK pharmacological inhibitors. Similar to ionizing radiation (IR), fisetin induces DSB. Additionally, fisetin impairs repair of IR-induced DSB through suppressing the classical non-homologous end-joining and homologous recombination repair pathways, leading to chromosomal aberration as tested by metaphase analysis. Effect of fisetin on DSB repair was partially dependent on YB-1 expression. Phosphoproteomic analysis revealed that fisetin inhibits DDR signaling, which leads to radiosensitization in TNBC cells, as shown in combination with single dose or fractionated doses irradiation. Conclusion Fisetin acts as a DSB-inducing agent and simultaneously inhibits repair of IR-induced DSB. Thus, fisetin may serve as an effective therapeutic strategy to improve TNBC radiotherapy outcome.<br

Fisetin induces DNA double-strand break and interferes with the repair of radiation-induced damage to radiosensitize triple negative breast cancer cells - Khozooei, Shayan; Lettau, Konstanze; Barletta, Francesca; Jost, Tina; Rebholz, Simone; Veerappan, Soundaram; Franz-Wachtel, Mirita; Macek, Boris; Iliakis, George; Distel, Luitpold; Zips, Daniel; Toulany, Mahmoud (Journal of Experimental & Clinical Cancer Research, 2022)
Background Triple-negative breast cancer (TNBC) is associated with aggressiveness and a poor prognosis. Besides surgery, radiotherapy serves as the major treatment modality for TNBC. However, response to radiotherapy is limited in many patients, most likely because of DNA damage response (DDR) signaling mediated radioresistance. Y-box binding protein-1 (YB-1) is a multifunctional protein that regulates the cancer hallmarks among them resisting to radiotherapy-induced cell death. Fisetin, is a plant flavonol of the flavonoid family of plant polyphenols that has anticancer properties, partially through inhibition of p90 ribosomal S6 kinase (RSK)-mediated YB-1 phosphorylation. The combination of fisetin with radiotherapy has not yet been investigated. Methods Activation status of the RSK signaling pathway in total cell lysate and in the subcellular fractions was analyzed by Western blotting. Standard clonogenic assay was applied to test post-irradiation cell survival. gamma H2AX foci assay and 3 color fluorescence in situ hybridization analyses were performed to study frequency of double-strand breaks (DSB) and chromosomal aberrations, respectively. The underlying repair pathways targeted by fisetin were studied in cells expressing genomically integrated reporter constructs for the DSB repair pathways via quantifying the expression of green fluorescence protein by flow cytometry. Flow cytometric quantification of sub-G1 cells and the protein expression of LC3-II were employed to measure apoptosis and autophagy, respectively. Kinase array and phosphoproteomics were performed to study the effect of fisetin on DDR response signaling. Results We showed that the effect of fisetin on YB-1 phosphorylation in TNBC cells is comparable to the effect of the RSK pharmacological inhibitors. Similar to ionizing radiation (IR), fisetin induces DSB. Additionally, fisetin impairs repair of IR-induced DSB through suppressing the classical non-homologous end-joining and homologous recombination repair pathways, leading to chromosomal aberration as tested by metaphase analysis. Effect of fisetin on DSB repair was partially dependent on YB-1 expression. Phosphoproteomic analysis revealed that fisetin inhibits DDR signaling, which leads to radiosensitization in TNBC cells, as shown in combination with single dose or fractionated doses irradiation. Conclusion Fisetin acts as a DSB-inducing agent and simultaneously inhibits repair of IR-induced DSB. Thus, fisetin may serve as an effective therapeutic strategy to improve TNBC radiotherapy outcome.
CRIS-Team WoS Importer:2022-09-02

Flow Induced Microvascular Network Formation of Therapeutic Relevant Arteriovenous (AV) Loop-Based Constructs in Response to Ionizing Radiation - Schmidt, Volker J.; Covi, Jennifer M.; Koepple, Christoph; Hilgert, Johannes; Polykandriotis, Elias; Bigdeli, Amir K.; Distel, Luitpold; Horch, Raymund E.; Kneser, Ulrich (Medical Science Monitor, 2017)
BACKGROUND The arteriovenous (AV) loop model enables axial vascularization to gain a functional microcirculatory system in tissue engineering constructs in vivo. These constructs might replace surgical flaps for the treatment of complex wounds in the future. Today, free flaps are often exposed to high-dose radiation after defect coverage, according to guideline-oriented treatment plans. Vascular response of AV loop-based constructs has not been evaluated after radiation, although it is of particular importance. It is further unclear whether the interposed venous AV loop graft is crucial for the induction of angiogenesis. MATERIAL AND METHODS We exposed the grafted vein to a single radiation dose of 2 Gy prior to loop construction to alter intrinsic and angio-inductive properties specifically within the graft. Vessel loops were embedded in a fibrin-filled chamber for 15 days and radiation-induced effects on flow-mediated vascularization were assessed by micro-CT and two-dimensional histological analysis. RESULTS Vessel amount was significantly impaired when an irradiated vein graft was used for AV loop construction. However, vessel growth and differentiation were still present. In contrast to vessel density, which was homogeneously diminished in constructs containing irradiated veins, vessel diameter was primarily decreased in the more peripheral regions. CONCLUSIONS Vascular luminal sprouts were significantly diminished in irradiated venous grafts, suggesting that the interposing vein constitutes a vital part of the AV loop model and is essential to initiate flow-mediate angiogenesis. These results add to the current understanding of AV loop-based neovascularization and suggest clinical implications for patients requiring combined AV loop-based tissue transfer and adjuvant radiotherapy.
EVALuna2:32850

FOLFIRINOX after Resection of Pancreatic Cancer sets new Standards - Systemic Therapy providing an Impulse for a Local Treatment in resectable Pancreatic Cancer - Semrau, Sabine; Lubgan, Dorota (Strahlentherapie und Onkologie, 2019)
CRIS-Team WoS Importer:2019-06-07

Four-dimensional patient dose reconstruction for scanned ion beam therapy of moving liver tumors - Richter, Daniel; Saito, Nami; Chaudhri, Naved; Haertig, Martin; Ellerbrock, Malte; Jaekel, Oliver; Combs, Stephanie E.; Habermehl, Daniel; Herfarth, Klaus; Durante, Marco; Bert, Christoph (International Journal of Radiation Oncology Biology Physics, 2014)
Estimation of the actual delivered 4-dimensional (4D) dose in treatments of patients with mobile hepatocellular cancer with scanned carbon ion beam therapy.Six patients were treated with 4 fractions to a total relative biological effectiveness (RBE)-weighted dose of 40 Gy (RBE) using a single field. Respiratory motion was addressed by dedicated margins and abdominal compression (5 patients) or gating (1 patient). 4D treatment dose reconstructions based on the treatment records and the measured motion monitoring data were performed for the single-fraction dose and a total of 17 fractions. To assess the impact of uncertainties in the temporal correlation between motion trajectory and beam delivery sequence, 3 dose distributions for varying temporal correlation were calculated per fraction. For 3 patients, the total treatment dose was formed from the fractional distributions using all possible combinations. Clinical target volume (CTV) coverage was analyzed using the volumes receiving at least 95% (V95) and 107% (V107) of the planned doses.4D dose reconstruction based on daily measured data is possible in a clinical setting. V95 and V107 values for the single fractions ranged between 72% and 100%, and 0% and 32%, respectively. The estimated total treatment dose to the CTV exhibited improved and more robust dose coverage (mean V95 > 87%, SD < 3%) and overdose (mean V107 < 4%, SD < 3%) with respect to the single-fraction dose for all analyzed patients.A considerable impact of interplay effects on the single-fraction CTV dose was found for most of the analyzed patients. However, due to the fractionated treatment, dose heterogeneities were substantially reduced for the total treatment dose. 4D treatment dose reconstruction for scanned ion beam therapy is technically feasible and may evolve into a valuable tool for dose assessment.
EVALuna2:18188

Fractionated LINAC-SBRT for Adrenal Gland Metatases: Dose-Dependence of Therapy Results - Knippen, S.; Burjakow, K.; Putz, Florian; Achterberg, N.; Lettmaier, S.; Fietkau, Rainer (2018)
EVALuna2:36502

Fractionated radiotherapy is the main stimulus for the induction of cell death and of Hsp70 release of p53 mutated glioblastoma cell lines - Rubner, Yvonne; Muth, Carolin; Strnad, Annedore; Derer, Anja; Sieber, Renate; Buslei, Rolf; Frey, Benjamin; Fietkau, Rainer; Gaipl, Udo (Radiation Oncology, 2014)
Glioblastoma multiforme (GBM) is the most common primary brain tumor in adults. Despite a multimodal therapy consisting of resection followed by fractionated radiotherapy (RT) combined with the chemotherapeutic agent (CT) temozolomide (TMZ), its recurrence is almost inevitable. Since the immune system is capable of eliminating small tumor masses, a therapy should also aim to stimulate anti-tumor immune responses by induction of immunogenic cell death forms. The histone deacetylase inhibitor valproic acid (VPA) might foster this.Reflecting therapy standards, we applied in our in vitro model fractionated RT with a single dose of 2Gy and clinically relevant concentrations of CT. Not only the impact of RT and/or CT with TMZ and/or VPA on the clonogenic potential and cell cycle of the glioblastoma cell lines T98G, U251MG, and U87MG was analyzed, but also the resulting cell death forms and release of danger signals such as heat-shock protein70 (Hsp70) and high-mobility group protein B1 (HMGB1).The clonogenic assays revealed that T98G and U251MG, having mutated tumor suppressor protein p53, are more resistant to RT and CT than U87MG with wild type (WT) p53. In all glioblastoma cells lines, fractionated RT induced a G2 cell cycle arrest, but only in the case of U87MG, TMZ and/or VPA alone resulted in this cell cycle block. Further, fractionated RT significantly increased the number of apoptotic and necrotic tumor cells in all three cell lines. However, only in U87MG, the treatment with TMZ and/or VPA alone, or in combination with fractionated RT, induced significantly more cell death compared to untreated or irradiated controls. While necrotic glioblastoma cells were present after VPA, TMZ especially led to significantly increased amounts of U87MG cells in the radiosensitive G2 cell cycle phase. While CT did not impact on the release of Hsp70, fractionated RT resulted in significantly increased extracellular concentrations of Hsp70 in p53 mutated and WT glioblastoma cells.Our results indicate that fractionated RT is the main stimulus for induction of glioblastoma cell death forms with immunogenic potential. The generated tumor cell microenvironment might be beneficial to include immune therapies for GBM in the future.
EVALuna2:7235

Fractionated SBRT for adrenal metastasis: contributing to local tumor control with modest toxicity - Knippen, S.; Burjakow, K.; Putz, Florian; Knippen, A.; Achterberg, N.; Lettmaier, S.; Fietkau, Rainer (2018)
EVALuna2:36514

Fractionated stereotactic radiation therapy for adrenal metastases: contributing to local tumor control with low toxicity - Burjakow, Kim; Fietkau, Rainer; Putz, Florian; Achterberg, Nils; Lettmaier, Sebastian; Knippen, Stefan (Strahlentherapie und Onkologie, 2019)
PurposeTo report on the Erlangen (UK-Er) experience with linear accelerator stereotactic body radiation therapy (LINAC SBRT) for adrenal metastasis from various primary tumors.Materials and methods33patients were treated. Primary sites included lung (n=19), melanoma (n=8), colorectal (n=2), hepatocellular (n=1), esophageal (n=2), and breast cancer (n=1). 14patients were treated palliatively, 19patients were treated with local curative intent.Radiation treatmentTreatment planning was done based on an exhale, mid-ventilation, and inspiration CT series. Further planning CTs were done to check for the correctness of the breathing pattern. Irradiation was performed using aNOVALIS (Varian, Palo Alto, CA, USA; Brainlab AG, Munchen, Germany) linear accelerator. The isocenter was verified before each treatment session using the BrainLab ExacTrac (R) (BrainlabAG, Munchen, Germany) system to minimize setup errors. Dose was prescribed to the planning target volume (PTV) surrounding 90% isodose.Follow-upDepending on their overall performance status and prognosis, patients received clinical check-ups and radiological imaging. Median follow-up was 11months.Statistical analysisIBM SPSS v.24 was used for univariate analysis using Kaplan-Meier curves, nonparametric Kruskal-Wallis test, and the chi-square test for frequency distributions. Toxicity was graded according to NCI CTCAE v4.0. Depending on radiologic imaging, patients were classified as stable, regression, and progression.ResultsMedian survival was 11months, median PFS was 5months. Median local failure-free survival was 21months. Patients who were treated with curative intent showed abetter survival curve (p<0.0001) and PFS (p=0.004). BED ranged from 42 to 108.8Gy, median BED was 67.2Gy. Three BED groups were formed. Overall survival curves differed significantly (p=0.046), favoring the high-dose group. 21patients were free from any adverse events or discomfort. In 7cases, agradeI toxicity was noted.
CRIS-Team WoS Importer:2019-03-06

Free Transplantation of a Tissue Engineered Bone Graft into an Irradiated, Critical-Size Femoral Defect in Rats - Rottensteiner-Brandl, Ulrike; Bertram, Ulf; Lingens, Lara; Köhn, Katrin; Distel, Luitpold; Fey, Tobias; Körner, Carolin; Horch, Raymund E.; Arkudas, Andreas (Cells, 2021)
Healing of large bone defects remains a challenge in reconstructive surgery, especially with impaired healing potential due to severe trauma, infection or irradiation. In vivo studies are often performed in healthy animals, which might not accurately reflect the situation in clinical cases. In the present study, we successfully combined a critical-sized femoral defect model with an ionizing radiation protocol in rats. To support bone healing, tissue-engineered constructs were transferred into the defect after ectopic preossification and prevascularization. The combination of SiHA, MSCs and BMP-2 resulted in the significant ectopic formation of bone tissue, which can easily be transferred by means of our custom-made titanium chamber. Implanted osteogenic MSCs survived in vivo for a total of 18 weeks. The use of SiHA alone did not lead to bone formation after ectopic implantation. Analysis of gene expression showed early osteoblast differentiation and a hypoxic and inflammatory environment in implanted constructs. Irradiation led to impaired bone healing, decreased vascularization and lower short-term survival of implanted cells. We conclude that our model is highly valuable for the investigation of bone healing and tissue engineering in pre-damaged tissue and that healing of bone defects can be substantially supported by combining SiHA, MSCs and BMP-2.
CRIS-Team WoS Importer:2021-10-01
Keywords: bone tissue engineering; critical size defect; irradiation; mesenchymal stem cells; hydroxyapatite

Frequent occurrence of therapeutically reversible CMV-associated encephalopathy during radiotherapy of the brain - Goerig, Nicole; Frey, Benjamin; Korn, Klaus; Fleckenstein, Bernhard; Überla, Klaus; Schmidt, Manuel; Dörfler, Arnd; Engelhorn, Tobias; Eyüpoglu, Ilker Yasin; Ruehle, Paul F.; Putz, Florian; Semrau, Sabine; et al. (Neuro-Oncology, 2016)
Neurological decline during radio(chemo)therapy of the brain is often attributed to disease progression or side effects of radiotherapy. Diagnosis of opportunistic neurotropic infections such as cytomegalovirus (CMV) infections is uncommon, even though high-grade gliomas and some brain metastases are known to contain CMV particles. We prospectively examined the frequency of CMV encephalopathy during radiotherapy of the brain.Fifty patients requiring whole-brain radiotherapy for brain metastases (n = 27) or local radio(chemo)therapy of the brain for high-grade gliomas (n = 23) were observed in the prospective observational GLIO-CMV-01 study. MRIs and blood samples were obtained before, halfway through, and at the end of radiotherapy. MRIs were screened for disease progression or increased intracranial pressure. Blood was tested for anti-CMV immunoglobulin (Ig)M, anti-CMV IgG, and CMV DNA.Thirty-two of 50 (64%) patients were positive for anti-CMV IgG before radio(chemo)therapy. Fifteen of those 32 (48%) developed viremia during or up to 28 days after treatment. Thirteen of those 15 (87%) required treatment for CMV-associated encephalopathy. MRIs were negative for disease progression, edema, or bleeding. None of the patients negative for anti-CMV IgG developed viremia, suggesting a reactivation rather than a primary infection.In the group at risk consisting of anti-CMV IgG+ patients, age >65 (P = .004) and the amount of dexamethasone taken during radio(chemo)therapy (P = .004) were associated with an increased risk for CMV-associated encephalopathy. One hundred and fifty days after the start of radio(chemo)therapy, survival was 74% (14/19) (no encephalopathy) versus 54% (7/13) (encephalopathy) (odds ratio, 0.42; 95% CI, 0.03-1.86; P = .25).CMV reactivation frequently causes encephalopathy during radio(chemo)therapy of the brain. The unexpected high incidence of this infection makes it highly clinically relevant for every treating physician.
EVALuna2:8306

FSRT versus SRS for Patients with large Brain Metastases: A volume-based Analysis of local Control and Radionecrosis - Putz, Florian; Oft, D.; Lettmaier, S.; Weissmann, T.; Fietkau, Rainer (STRAHLENTHERAPIE UND ONKOLOGIE, 2019)
CRIS-Team WoS Importer:2019-06-07

FSRT vs. SRS in Brain Metastases—Differences in Local Control and Radiation Necrosis—A Volumetric Study - Putz, Florian; Weissmann, Thomas; Oft, Dominik; Schmidt, Manuel; Roesch, Johannes; Siavooshhaghighi, Hadi; Filimonova, Irina; Schmitter, Charlotte; Mengling, Veit; Bert, Christoph; Frey, Benjamin; Lettmaier, Sebastian; et al. (Frontiers in Oncology, 2020)
Background: While the role of stereotactic radiotherapy for brain metastases is increasing, evidence on the comparative efficacy and safety of fractionated stereotactic radiotherapy (FSRT) and single-session radiosurgery (SRS) is scarce. Methods: Longitudinal volumetric analysis was performed in a consecutive cohort of 120 patients and 190 brain metastases (>0.065 cm3 in volume / > 5 mm in diameter) treated exclusively with FSRT (n = 98) and SRS (n = 92), respectively. A total of 972 tumor segmentations was used, averaging 5.1 time points per metastasis. Progression was defined using a volumetric extension of the RANO-BM criteria. Local control and radionecrosis were compared for lesions treated with FSRT and SRS, respectively. Results: Metastases treated with FSRT were significantly larger at baseline (mean, 4.66 vs. 0.40 cm3, p < 0.001). Biologically effective dose (BED) for metastases (α/β = 12, linear-quadratic-cubic model) was significantly associated with local control, whereas BED for normal brain (α/β = 2, linear-quadratic model) was significantly associated with radionecrosis. Median time to local progression was 22.9 months in the FSRT group compared to 14.5 months in the SRS group (p = 0.022). Overall radionecrosis rate at 12 months was 3.4% for FSRT and 14.8% for SRS (p = 0.010). Radionecrosis °IV requiring resection with histologic proof of radiation necrosis also was significantly reduced in the FSRT group (FSRT 0.0% vs. SRS 3.9%, p = 0.041). In multivariate analysis, FSRT was associated with reduced risk of progression (HR 0.47, p = 0.015) and reduced risk of radionecrosis (HR 0.18, p = 0.045). Conclusions: This volumetric study provides initial evidence that the improvements in therapeutic ratio expected for FSRT in larger brain metastases, might equally extend into the domain of smaller metastases, traditionally less considered for fractionated treatment. FSRT might constitute an important tool to further increase local control and reduce radionecrosis risk in stereotactic radiotherapy for brain metastases, that should be assessed in randomized intervention trials.
CRIS-Team Scopus Importer:2020-10-30
Keywords: brain metastases; fractionated stereotactic radiotherapy; radiobiological aspects; segmentation; stereotactic radiosurgery (SRS); stereotactic radiotherapy (SRT); volumetric analysis

Full field digital mammography (FFDM) versus cmos technology, specimen radiography system (SRS) and tomosynthesis (DBT) - Which system can optimise surgical therapy? - Schulz-Wendtland, Rüdiger; Dilbat, G.; Bani, Mayada; Fasching, Peter; Heusinger, K.; Lux, Michael P.; Löhberg, Christian; Brehm, Barbara; Hammon, Matthias; Saake, Marc; Dankerl, Peter; Jud, Sebastian; et al. (Geburtshilfe und Frauenheilkunde, 2013)
Aim: This prospective clinical study aimed to evaluate whether it would be possible to reduce the rate of re-excisions using CMOS technology, a specimen radiography system (SRS) or digital breast tomosynthesis (DBT) compared to a conventional full field digital mammography (FFDM) system. Material and Method: Between 12/2012 and 2/2013 50 patients were diagnosed with invasive breast cancer (BI-RADS™ 5). After histological verification, all patients underwent breast-conserving therapy with intraoperative imaging using 4 different systems and differing magnifications: 1. Inspiration™ (Siemens, Erlangen, Germany), amorphous selenium, tungsten source, focus 0.1 mm, resolution 85 m pixel pitch, 8 lp/mm; 2. BioVision™ (Bioptics, Tucson, AZ, USA), CMOS technology, photodiode array, flat panel, tungsten source, focus 0.05, resolution 50 m pixel pitch, 12 lp/mm; 3. the Trident™ specimen radiography system (SRS) (Hologic, Bedford, MA, USA), amorphous selenium, tungsten source, focus 0.05, resolution 70 m pixel pitch, 7.1 lp/mm; 4. tomosynthesis (Siemens, Erlangen, Germany), amorphous selenium, tungsten source, focus 0.1 mm, resolution 85 m pixel pitch, 8 lp/mm, angular range 50 degrees, 25 projections, scan time > 20 s, geometry: uniform scanning, reconstruction: filtered back projection. The 600 radiographs were prospectively shown to 3 radiologists. Results: Of the 50 patients with histologically proven breast cancer (BI-RADS™ 6), 39 patients required no further surgical therapy (re-excision) after breast-conserving surgery. A retrospective analysis (n = 11) showed a significant (p < 0.05) increase of sensitivity with the BioVision™, the Trident™ and tomosynthesis compared to the Inspiration™ at a magnification of 1.0: 2.0 or 1.0: 1.0 (tomosynthesis) (2.6, 3.3 or 3.6 %), i.e. re-excision would not have been necessary in 2, 3 or 4 patients, respectively, compared to findings obtained with a standard magnification of 1.0: 1.0. Conclusion: The sensitivity of the BioVision™, the Trident™ and tomosynthesis was significantly (p < 0.05) higher and the rate of re-excisions was reduced compared to FFDM using a conventional detector at a magnification of 2.0 but without zooming. © Georg Thieme Verlag KG Stuttgart New York.
CRIS-Team Scopus Importer:2023-03-08
Keywords: Breast; breast cancer; breast malignancy; mammography

Full Length Interleukin 33 Aggravates Radiation-Induced Skin Reaction - Kurow, Olga; Frey, Benjamin; Schuster, Louis; Schmitt, Verena; Adam, Susanne; Hahn, Madelaine; Gilchrist, Derek; Mcinnes, Iain B.; Wirtz, Stefan; Gaipl, Udo; Krönke, Gerhard; Schett, Georg; et al. (Frontiers in Immunology, 2017)
The interleukin (IL)-1 family member IL-33 has been described as intracellular alarmin with broad roles in wound healing, skin inflammation but also autoimmunity. Its dichotomy between full length (fl) IL-33 and the mature (m) form of IL-33 and its release by necrosis is still not fully understood. Here, we compare functional consequences of both forms in the skin in vivo, and therefore generated two lines of transgenic mice which selectively overexpress mmIL-33 and flmIL-33 in basal keratinocytes. Transgene mRNA was expressed at high level in skin of both lines but not in organs due to the specific K14 promoter. We could demonstrate that transgenic overexpression of mmIL-33 in murine keratinocytes leads to a spontaneous skin inflammation as opposed to flmIL-33. K14-mmIL-33 mice synthesize and secrete high amounts of mmIL-33 along with massive cutaneous manifestations, like increased epidermis and dermis thickness, infiltration of mast cells in the epidermis and dermis layers and marked hyperkeratosis. Using skin inflammation models such as IL-23 administration, imiquimod treatment, or mechanical irritation did not lead to exacerbated inflammation in the K14-flmIL-33 strain. As radiation induces a strong dermatitis due to apoptosis and necrosis, we determined the effect of fractionated radiation (12 Gy, 4 times). In comparison to wild-type mice, an increase in ear thickness in flmIL-33 transgenic mice was observed 25 days after irradiation. Macroscopic examination showed more severe skin symptoms in irradiated ears compared to controls. In summary, secreted mmIL-33 itself has a potent capacity in skin inflammation whereas fl IL-33 is limited due to its intracellular retention. During tissue damage, fl IL-33 exacerbated radiation-induced skin reaction.
EVALuna2:13432

Future prospects in radiation oncology from the perspective of innovative radiation biology - Rödel, Franz; Gaipl, Udo (Strahlentherapie und Onkologie, 2023)
CRIS-Team Scopus Importer:2023-12-08

Ga-68-FAPI-04 PET/CT for molecular assessment of fibroblast activation and risk evaluation in systemic sclerosis-related interstitial lung disease - Schmidkonz, Christian; Distler, Jörg; Treutlein, Christoph; Atzinger, Armin; Prante, Olaf; Ritt, Philipp; Goetz, T.; Bäuerle, Tobias; Cordes, Michael; Köhner, Markus; Kuwert, Torsten; Ramming, Andreas; et al. (European Journal of Nuclear Medicine and Molecular Imaging, 2021)
CRIS-Team WoS Importer:2022-01-07

Galectin-3 as a novel regulator of osteoblast-osteoclast interaction and bone homeostasis - Simon, Dominic; Derer, Anja; Andes, Fabian T.; Lezuo, Patrick; Bozec, Aline; Schett, Georg; Herrmann, Martin; Harre, Ulrike (Bone, 2017)
Bone tissue undergoes permanent and lifelong remodeling with a concerted action of bone-building osteoblasts and bone-resorbing osteoclasts. A precise cooperation between those two cell types is critical in the complex process of bone renewal. Galectin-3 is a member of the ?-galactoside-binding lectin family playing multiple roles in cell growth, differentiation and aggregation. As it has been described to be expressed in bone, galectin-3 might influence bone homeostasis by regulating the function and/or interplay of osteoblasts and osteoclasts. Here, we investigated the role of galectin-3 in osteoclastogenesis and osteoblast-osteoclast interactions. Bone histomorphometric analysis and ?CT measurements revealed a decreased trabecular bone volume and an increased osteoclast number in 12weeks old male galectin-3 knockout mice compared to wildtype littermates. Galectin-3 deficient bone marrow cells displayed a higher osteoclastogenic capacity in ex vivo differentiation assays, associated with elevated TRAF6 mRNA levels, suggesting an intrinsic inhibition of osteoclastogenesis by galectin-3 interfering with RANKL-mediated signaling. Furthermore, the addition of extracellular galectin-3 to murine or human osteoclastogenesis assays inhibited osteoclast formation and osteoclast numbers were higher in co-culture assays with galectin-3 deficient osteoblasts. In conclusion, our data suggest the secretion of galectin-3 as a novel mechanism for osteoblasts to control osteoclastogenesis and to maintain trabecular bone homeostasis independently of the RANKL/OPG-axis.
EVALuna2:13345

Galectin 3 expression in primary oral squamous cell carcinomas - Weber, Manuel; Buettner-Herold, Maike; Distel, Luitpold; Ries, Jutta; Möbius, Patrick; Preidl, Raimund; Geppert, Carol-Immanuel; Neukam, Friedrich Wilhelm; Wehrhan, Falk (BMC Cancer, 2017)
Immunologic factors can promote the progression of oral squamous cell carcinomas (oscc). The phylogenetic highly conserved protein Galectin 3 (Gal3) contributes to cell differentiation and immune homeostasis. There is evidence that Gal3 is involved in the progression of oscc and influences the regulation of macrophage polarization. Macrophage polarization (M1 vs. M2) in solid malignancies like oscc contributes to tumor immune-escape. However, the relationship between macrophage polarization and Gal3 expression in oscc is not yet understood. The current study analyzes the association between histomorphologic parameters (T-, N-, L- Pn-status, grading) and Gal3 expression resp. the ratio between Gal3 expressing cells and CD68 positive macrophages in oscc specimens.Preoperative diagnostic biopsies (n = 26) and tumor resection specimens (n = 34) of T1/T2 oscc patients were immunohistochemically analyzed for Gal3 and CD68 expression. The number of Gal3 expressing cells and the ratio between CD68 and Gal3 expressing cells was quantitatively assessed.In biopsy and tumor resection specimens, the number of Gal3 positive cells as well as the Gal3/CD68 ratio were significantly (p < 0.05) higher in T2 oscc compared to T1 cases. In biopsy specimens, a significantly (p < 0.05) increased Gal3 expression and Gal3/CD68 ratio was associated with the progression marker lymph vessel infiltration (L1). Tumor resection specimens of cases with lymph node metastases (N+) had a significantly (p < 0.05) increased Gal3 expression. Additionally, a high Gal3/CD68 ratio correlated significantly (p < 0.05) with higher grading (G3) in tumor resection specimens.High Gal3 expression in oscc is associated with tumor size (T-status) and parameters of malignancy (N-, L-status, grading). Gal3 might contribute to M2 macrophage mediated local immune tolerance. Gal3 expression shows association with prognosis in oscc and represent a potential therapeutic target.
EVALuna2:24446

Galectin 3 expression in regional lymph nodes and lymph node metastases of oral squamous cell carcinomas - Wehrhan, Falk; Büttner-Herold, Maike; Distel, Luitpold; Ries, Jutta; Möbius, Patrick; Preidl, Raimund; Geppert, Carol-Immanuel; Neukam, Friedrich Wilhelm; Kesting, Marco Rainer; Weber, Manuel (BMC Cancer, 2018)
BACKGROUND: Neck dissection is standard in surgical management of oral squamous cell carcinomas (oscc). However, the immunologic link between primary tumor and lymph nodes is insufficiently understood. Galectin 3 (Gal3) promotes M2 polarization of macrophages and contributes to immunosuppression. The current study analyzes the association between Gal3 expression in regional lymph nodes of oscc with histomorphologic parameters (T-, N-, L- Pn-stage, grading) of the primary tumor. Additionally, Gal3 expression is correlated with markers of macrophage polarization (M1 vs. M2). METHODS: Preoperative diagnostic biopsies (n = 26), tumor resection specimens (n = 34), tumor-free lymph nodes (n = 28) and lymph node metastases (n = 10) of T1/T2 oscc patients were immunohistochemically analyzed for Gal3 and macrophage marker (CD68, CD11c, CD163 and MRC1) expression. The number of positive cells and the expression ratios were quantitatively assessed. RESULTS: High Gal3 expression in tumor-free regional lymph nodes was significantly (p < 0.05) associated with increased tumor size. The epithelial compartment of lymph node metastases showed a significantly (p < 0.05) increased Gal3 expression compared to biopsies and tumor resection specimens. Cell density of M2 macrophages was significantly (p < 0.05) and positively correlated with the number of Gal3 expressing cells in lymph nodes and tumor specimens. CONCLUSION: Gal3 expression in regional lymph nodes might be associated with oscc progression. The increased Gal3 expression in regional lymph nodes of larger tumors underlines the need of immunomodulatory treatment concepts in early-stage oscc. Blocking of Gal3 might be a therapeutic option in oral cancer.
EVALuna2:34900

Gas plasma irradiation of breast cancers promotes immunogenicity, tumor reduction, and an abscopal effect in vivo - Mahdikia, Hamed; Saadati, Fariba; Freund, Eric; Gaipl, Udo; Majidzadeh-a, Keivan; Shokri, Babak; Bekeschus, Sander (OncoImmunology, 2021)
While many new and emerging therapeutic concepts have appeared throughout the last decades, cancer still is fatal in many patients. At the same time, the importance of immunology in oncotherapy is increasingly recognized, not only since the advent of checkpoint therapy. Among the many types of tumors, also breast cancer has an immunological dimension that might be exploited best by increasing the immunogenicity of the tumors in the microenvironment. To this end, we tested a novel therapeutic concept, gas plasma irradiation, for its ability to promote the immunogenicity and increase the toxicity of breast cancer cells in vitro and in vivo. Mechanistically, this emerging medical technology is employing a plethora of reactive oxygen species being deposited on the target cells and tissues. Using 2D cultures and 3D tumor spheroids, we found gas plasma-irradiation to drive apoptosis and immunogenic cancer cell death (ICD) in vitro, as evidenced by an increased expression of calreticulin, heat-shock proteins 70 and 90, and MHC-I. In 4T1 breast cancer-bearing mice, the gas plasma irradiation markedly decreased tumor burden and increased survival. Interestingly, non-treated tumors injected in the opposite flank of mice exposed to our novel treatment also exhibited reduced growth, arguing for an abscopal effect. This was concomitant with an increase of apoptosis and tumor-infiltrating CD4+ and CD8+ T-cells as well as dendritic cells in the tissues. In summary, we found gas plasma-irradiated murine breast cancers to induce toxicity and augmented immunogenicity, leading to reduced tumor growth at a site remote to the treatment area.
CRIS-Team Scopus Importer:2021-01-15
Keywords: ICD; immunogenic cancer cell death; leukocytes; medical technology; oncology; plasma medicine; reactive oxygen species; ros

Gastrointestinal Brachytherapy - Strnad, Vratislav (Brachytherapy, 2023)
Brachytherapy is a sophisticated and proven treatment technique of different GI localizations. Here the development of GI– brachytherapy of last 20 years, current position and the perspectives for next years are discussed. In summary: The GI–brachytherapy of different localizations is very effective, in experienced hands a safe technique and should be part of armamentarium of every radiation oncologist.
CRIS-Team Scopus Importer:2023-02-10

GEC-ESTRO multicenter phase 3-trial: Accelerated partial breast irradiation with interstitial multicatheter brachytherapy versus external beam whole breast irradiation: Early toxicity and patient compliance - Ott, Oliver J.; Strnad, Vratislav; Hildebrandt, Guido; Kauer-Dorner, Daniela; Knauerhase, Hellen; Major, Tibor; Lyczek, Jaroslaw; Luis Guinot, Jose; Dunst, Juergen; Gutierrez Miguelez, Cristina; Slampa, Pavel; Allgaeuer, Michael; et al. (Radiotherapy and Oncology, 2016)
To compare early side effects and patient compliance of accelerated partial breast irradiation (APBI) with multicatheter brachytherapy to external beam whole breast irradiation (WBI) in a low-risk group of patients with breast cancer.Between April 2004 and July 2009, 1328 patients with UICC stage 0-IIA breast cancer were randomized to receive WBI with 50Gy and a boost of 10Gy or APBI with either 32.0Gy/8 fractions, or 30.1Gy/7 fractions (HDR-brachytherapy), or 50Gy/0.60-0.80Gy per pulse (PDR-brachytherapy). This report focuses on early side-effects and patient compliance observed in 1186 analyzable patients. ClinicalTrials.gov identifier: NCT00402519.Patient compliance was excellent in both arms. Both WBI and APBI were well tolerated with moderate early side-effects. No grade 4 toxicity had been observed. Grade 3 side effects were exclusively seen for early skin toxicity (radiation dermatitis) with 7% vs. 0.2% (p<0.0001), and breast infection with 0% vs. 0.2% (p=n.s.) for patients treated with WBI and APBI. The incidence of grades 1-2 early side effects for WBI and APBI was 86% vs. 21% (p<0.0001) for skin toxicity, 2% vs. 20% (p<0.0001) for mild hematoma, and 2% vs. 5% (p=0.01) for mild breast infection rates, respectively. No differences had been found regarding grades 1-2 early breast pain (26% vs. 29%, p=0.23).APBI with interstitial multicatheter brachytherapy was tolerated very well and dramatically reduced early skin toxicity in comparison to standard WBI.
EVALuna2:5544

Genomic EWSR1 Fusion Sequence as Highly Sensitive and Dynamic Plasma Tumor Marker in Ewing Sarcoma - Krumbholz, Manuela; Hellberg, Julia; Steif, Benedikt; Bäuerle, Tobias; Gillmann, Clarissa; Fritscher, Torsten; Agaimy, Abbas; Frey, Benjamin; Juengert, Joerg; Wardelmann, Eva; Hartmann, Wolfgang; Juergens, Heribert; et al. (Clinical Cancer Research, 2016)
The application of the tumor-specific genomic fusion sequence as noninvasive biomarker for therapy monitoring in Ewing sarcoma (EwS) has been evaluated.EwS xenograft mouse models were used to explore detectability in small plasma volumes and correlation of genomic EWSR1-FLI1 copy numbers with tumor burden. Furthermore, 234 blood samples from 20 EwS patients were analyzed before and during multimodal treatment. EWSR1 fusion sequence levels in patients' plasma were quantified using droplet digital PCR and compared with tumor volumes calculated from MRI or CT imaging studies.Kinetics of EWSR1 fusion sequence copy numbers in the plasma are correlated with changes of the tumor volume in patients with localized and metastatic disease. The majority of patients showed a fast reduction of cell-free tumor DNA (ctDNA) during initial chemotherapy. Recurrence of increasing ctDNA levels signalized relapse development.Genomic fusion sequences represent promising noninvasive biomarkers for improved therapy monitoring in EwS. Until now, response assessment is largely based on MRI and CT imaging, implying restrictions on closely repeated performance and limitations on the differentiation between vital tumor and reactive stromal tissue. Particularly in patients with prognostic unfavorable disseminated disease, ctDNA is a valuable addition for the assessment of therapy response. Clin Cancer Res; 22(17); 4356-65. ©2016 AACR.
EVALuna2:6851

GILT - A randomised phase III study of oral vinorelbine and cisplatin with concomitant radiotherapy followed by either consolidation therapy with oral vinorelbine and cisplatin or best supportive care alone in stage III non-small cell lung cancer - Flentje, Michael; Huber, Rudolf M.; Engel-Riedel, Walburga; Andreas, Stefan; Kollmeier, Jens; Staar, Susanne; Dickgreber, Nicolas; Vaissiere, Nathalie; De Almeida, Cecilia; Edlich, Birgit; Fietkau, Rainer (Strahlentherapie und Onkologie, 2016)
Concurrent chemoradiotherapy (CRT) is considered standard for inoperable stage III non-small cell lung cancer (NSCLC). Consolidation chemotherapy (CC) following CRT is intended to further improve outcomes, yet studies have shown discordant results. This phase III study assessed CRT followed by best supportive care (BSC) or consolidation with oral vinorelbine and cisplatin.Patients received two cycles of oral vinorelbine (50 mg/m(2) days 1, 8 and 15) + cisplatin (20 mg/m(2) days 1-4) q4w + radiotherapy (RT; 66 Gy). Patients with at least stable disease (SD) were randomised to either two cycles oral vinorelbine (60-80 mg/m(2) days 1 and 8) + cisplatin (80 mg/m(2) day 1) q3w + BSC or BSC alone. Primary endpoint was progression-free survival (PFS).A total of 279 patients were enrolled for CRT and 201 patients were randomised to CC or BSC. Both CRT and CC were well tolerated, with limited radiation-mediated grade 3/4 toxicities (CRT/CC/BSC: oesophagitis-related events 12.9 %/3.1 %/0 %; grade 3 pneumonitis 0 %/0 %/2 %) and chemotherapy-mediated grade 3/4 toxicities (CRT/CC: neutropenia 11.2 %/22.1 %; leukopenia 18.3 %/26.7 %; grade 3 nausea 5.0 %/2.3 %, grade 3 vomiting 3.2 %/3.5 %). Median PFS from randomisation was 6.4 (5.0-8.7) and 5.5 (3.8-7.4) months in the CC and BSC arms (hazard ratio, HR = 0.93 [0.69-1.26]; p = 0.63), respectively; median overall survival (OS) 20.8 (13.5-25.3) and 18.5 (13.6-24.7) months, respectively.Consolidation chemotherapy after concurrent CRT did not prolong PFS or OS. Concurrent RT with oral vinorelbine and cisplatin demonstrated a favourable safety profile and represents a suitable treatment regimen for inoperable stage III NSCLC.
EVALuna2:18353

GLIO-CMV-01: Identification of immune biomarkers for CMV-related encephalitis during radiotherapy of the brain - Donaubauer, Anna-Jasmina; Becker, I.; Rühle, Paul-Friedrich; Goerig, Nicole; Pohn, A.; Winkler, Thomas; Korn, Klaus; Überla, Klaus; Fietkau, Rainer; Gaipl, Udo; Frey, Benjamin (2018)
EVALuna2:36498

GLIO-CMV-01: Identification of immune biomarkers for CMV related encephalitis during standard brain radiotherapy - Rühle, Paul-Friedrich; Goerig, Nicole; Korn, Klaus; Überla, Klaus; Wunderlich, Roland; Fietkau, Rainer; Gaipl, Udo; Frey, Benjamin (2017)
EVALuna2:32892

Good outcome of brain stem progressive multifocal leukoencephalopathy in an immunosuppressed renal transplant patient: Importance of early detection and rapid immune reconstitution - Sauer, Rolf; Gölitz, Philipp; Jacobi, Johannes; Schwab, Stefan; Linker, Ralf; Lee, De-Hyung (Journal of the Neurological Sciences, 2017)
Progressive multifocal leukoencephalopathy (PML) is a rare, opportunistic and often fatal disease of the CNS which may occur under immunosuppression in transplant patients. Brain stem PML is associated with a particularly bad prognosis. Here, we present a case of a renal transplant patient treated with mycophenolate mofetil (MMF) and tacrolimus who developed brain stem PML with limb ataxia, dysarthria and dysphagia. Diagnosis was established by typical MRI features and detection of JCV-DNA in the CSF. Immune reconstitution after stopping MMF and tacrolimus led to a complete and sustained remission of symptoms with improvement of the brain stem lesion over a follow-up over 20months. In summary, early detection of PML and consequent treatment may improve neurological outcomes even in brain stem disease with a notorious bad prognosis.
EVALuna2:22499

Graphene-Induced Hyperthermia (GIHT) Combined With Radiotherapy Fosters Immunogenic Cell Death - Podolska, Malgorzata; Shan, Xiaomei; Janko, Christina; Boukherroub, Rabah; Gaipl, Udo; Szunerits, Sabine; Frey, Benjamin; Munoz, Luis Enrique (Frontiers in Oncology, 2021)
Radiotherapy and chemotherapy are the standard interventions for cancer patients, although cancer cells often develop radio- and/or chemoresistance. Hyperthermia reduces tumor resistance and induces immune responses resulting in a better prognosis. We have previously described a method to induce tumor cell death by local hyperthermia employing pegylated reduced graphene oxide nanosheets and near infrared light (graphene-induced hyperthermia, GIHT). The spatiotemporal exposure/release of heat shock proteins (HSP), high group mobility box 1 protein (HMGB1), and adenosine triphosphate (ATP) are reported key inducers of immunogenic cell death (ICD). We hypothesize that GIHT decisively contributes to induce ICD in irradiated melanoma B16F10 cells, especially in combination with radiotherapy. Therefore, we investigated the immunogenicity of GIHT alone or in combination with radiotherapy in melanoma B16F10 cells. Tumor cell death in vitro revealed features of apoptosis that is progressing fast into secondary necrosis. Both HSP70 and HMGB1/DNA complexes were detected 18 hours post GIHT treatment, whereas the simultaneous release of ATP and HMGB1/DNA was observed only 24 hours post combined treatment. We further confirmed the adjuvant potential of these released DAMPs by immunization/challenge experiments. The inoculation of supernatants of cells exposed to sole GIHT resulted in tumor growth at the site of inoculation. The immunization with cells exposed to sole radiotherapy rather fostered the growth of secondary tumors in vivo. Contrarily, a discreet reduction of secondary tumor volumes was observed in mice immunized with a single dose of cells and supernatants treated with the combination of GIHT and irradiation. We propose the simultaneous release of several DAMPs as a potential mechanism fostering anti-tumor immunity against previously irradiated cancer cells.
CRIS-Team Scopus Importer:2021-09-17
Keywords: hyperthermia; immunogenic cell death; melanoma; multimodal; radiotherapy; reduced graphene oxide

Graphene Oxide Nanosheets for Localized Hyperthermia-Physicochemical Characterization, Biocompatibility, and Induction of Tumor Cell Death - Podolska, Malgorzata; Barras, Alexandre; Alexiou, Christoph; Frey, Benjamin; Gaipl, Udo; Boukherroub, Rabah; Szunerits, Sabine; Janko, Christina; Munoz, Luis Enrique (Cells, 2020)
Background: The main goals of cancer treatment are not only to eradicate the tumor itself but also to elicit a specific immune response that overcomes the resistance of tumor cells against chemo- and radiotherapies. Hyperthermia was demonstrated to chemo- and radio-sensitize cancerous cells. Many reports have confirmed the immunostimulatory effect of such multi-modal routines. Methods: We evaluated the interaction of graphene oxide (GO) nanosheets; its derivatives reduced GO and PEGylated rGO, with components of peripheral blood and evaluated its thermal conductivity to induce cell death by localized hyperthermia. Results: We confirmed the sterility and biocompatibility of the graphene nanomaterials and demonstrated that hyperthermia applied alone or in the combination with radiotherapy induced much more cell death in tumor cells than irradiation alone. Cell death was confirmed by the release of lactate dehydrogenase from dead and dying tumor cells. Conclusion: Biocompatible GO and its derivatives can be successfully used in graphene-induced hyperthermia to elicit tumor cell death.
CRIS-Team WoS Importer:2020-05-15

Guideline development GEC ESTRO - Strnad, Vratislav; Perez-Calatayud, J.; Jurgenliemk-Schulz, I. (RADIOTHERAPY AND ONCOLOGY, 2021)
CRIS-Team WoS Importer:2021-11-26

Head and neck tumor cells treated with hypofractionated irradiation die via apoptosis and are better taken up by M1-like macrophages - Wedekind, Hanna; Walz, Kristina; Buchbender, Mayte; Rieckmann, Thorsten; Strasser, Erwin; Grottker, Fridolin; Fietkau, Rainer; Frey, Benjamin; Gaipl, Udo; Rückert, Michael (Strahlentherapie und Onkologie, 2021)
Purpose: The incidence of head and neck squamous cell carcinomas (HNSCC) is increasing worldwide, especially when triggered by the human papilloma virus (HPV). Radiotherapy has immune-modulatory properties, but the role of macrophages present in HNSCC and having contact with irradiated tumor cells remains unclear. The influence of irradiated (2 × 5Gy) HNSCC cells on the (re-)polarization and phagocytosis of human macrophages, either non-polarized or with a more M1 or M2 phenotype, was therefore investigated. Methods: Human monocytes were differentiated with the hematopoietic growth factors M‑CSF (m) or GM-CSF (g) and additionally pre-polarized with either interleukin (IL)-4 and IL-10 or interferon (IFN)-γ and lipopolysaccharides (LPS), respectively. Subsequently, they were added to previously irradiated (2 × 5Gy) and mock-treated HPV-positive (UD-SCC-2) and HPV-negative (Cal33) HNSCC cells including their supernatants. Results: The HNSCC cells treated with hypofractionated irradiation died via apoptosis and were strongly phagocytosed by M0m and M2 macrophages. M0g and M1 macrophages phagocytosed the tumor cells to a lesser extent. Irradiated HNSCC cells were better phagocytosed by M1 macrophages compared to mock-treated controls. The polarization status of the macrophages was not significantly changed, except for the expression of CD206 on M2 macrophages, which was reduced after phagocytosis of irradiated HPV-negative cells. Further, a significant increase in the uptake of irradiated HPV-positive cells by M0g macrophages when compared to HPV-negative cells was observed. Conclusion: HNSCC cells treated with hypofractionated irradiation foster phagocytosis by anti-tumorigenic M1 macrophages. The data provide the first evidence on the impact of the HPV status of HNSCC cells on the modulation of the macrophage response to irradiated tumor cells.
CRIS-Team Scopus Importer:2021-10-29
Keywords: Head and neck cancer; Human papilloma virus; Macrophage polarization; Phagocytosis; Radiotherapy

Heart-sparing radiotherapy techniques in breast cancer patients: a recommendation of the breast cancer expert panel of the German society of radiation oncology (DEGRO) - Duma, Marciana Nona; Baumann, René; Budach, Wilfried; Dunst, Jürgen; Feyer, Petra; Fietkau, Rainer; Haase, Wulf; Harms, Wolfgang; Hehr, Thomas; Krug, David; Piroth, Marc D.; Sedlmayer, Felix; et al. (Strahlentherapie und Onkologie, 2019)
Purpose: The aim of this review was to analyze the respective efficacy of various heart-sparing radiotherapy techniques. Material and methods: Heart-sparing can be performed in three different ways in breast cancer radiotherapy: by seeking to keep the heart out of treated volumes (i.e. by prone position or specific breathing techniques such as deep inspiration breath-hold [DIBH] and/or gating), by solely irradiating a small volume around the lumpectomy cavity (partial breast irradiation, PBI), or by using modern radiation techniques like intensity-modulated radiation therapy (IMRT), volumetric modulated arc therapy (VMAT) or protons. This overview presents the available data on these three approaches. Results: Studies on prone position are heterogeneous and most trials only refer to patients with large breasts; therefore, no definitive conclusion can be drawn for clinical routine. Nonetheless, there seems to be a trend toward better sparing of the left anterior descending artery in supine position even for these selected patients. The data on the use of DIBH for heart-sparing in breast cancer patients is consistent and the benefit compared to free-breathing is supported by several studies. In comparison with whole breast irradiation (WBI), PBI has an advantage in reducing the heart dose. Of note, DIBH and PBI with multicatheter brachytherapy are similar with regard to the dose reduction to heart structures. WBI by IMRT/VMAT techniques without DIBH is not an effective strategy for heart-sparing in breast cancer patients with “standard” anatomy. A combination of DIBH and IMRT may be used for internal mammary radiotherapy. Conclusion: Based on the available findings, the DEGRO breast cancer expert panel recommends the use of DIBH as the best heart-sparing technique. Nonetheless, depending on the treatment volume and localization, other techniques may be employed or combined with DIBH when appropriate.
CRIS-Team Scopus Importer:2019-07-26
Keywords: Breast cancer; DEGRO; Heart toxicities; Radiotherapy; Technique

Heart toxicity from breast cancer radiotherapy : Current findings, assessment, and prevention - Piroth, Marc D.; Baumann, Rene; Budach, Wilfried; Dunst, Juergen; Feyer, Petra; Fietkau, Rainer; Haase, Wulf; Harms, Wolfgang; Hehr, Thomas; Krug, David; Roeser, Arnd; Sedlmayer, Felix; et al. (Strahlentherapie und Onkologie, 2019)
BACKGROUND: Late cardiac toxicities caused by (particularly left-sided) breast radiotherapy (RT) are now recognized as rare but relevant sequelae, which has prompted research on risk structure identification and definition of threshold doses to heart subvolumes. The aim of the present review was to critically discuss the clinical evidence on late cardiac reactions based on dose-dependent outcome reports for mean heart doses as well as doses to cardiac substructures. METHODS: A literature review was performed to examine clinical evidence on radiation-induced heart toxicities. Mean heart doses and doses to cardiac substructures were focused upon based on dose-dependent outcome reports. Furthermore, an overview of radiation techniques for heart protection is given and non-radiotherapeutic aspects of cardiotoxicity in the multimodal setting of breast cancer treatment are discussed. RESULTS: Based on available findings, the DEGRO breast cancer expert panel recommends the following constraints: mean heart dose <2.5 Gy; DmeanLV (mean dose left ventricle) < 3 Gy; V5LV (volume of LV receiving ≥5 Gy) < 17%; V23LV (volume of LV receiving ≥23 Gy) < 5%; DmeanLAD (mean dose left descending artery) < 10 Gy; V30LAD (volume of LAD receiving ≥30 Gy) < 2%; V40LAD (volume of LAD receiving ≥40 Gy) < 1%. CONCLUSION: In addition to mean heart dose, breast cancer RT treatment planning should also include constraints for cardiac subvolumes such as LV and LAD. The given constraints serve as a clinicians' aid for ensuring adequate heart protection. The individual decision between sufficient protection of cardiac structures versus optimal target volume coverage remains in the physician's hand. The risk of breast cancer-specific mortality and a patient's cardiac risk factors must be individually weighed up against the risk of radiation-induced cardiotoxicity.
EVALuna2:36455

Heat Shock Protein 70 (Hsp70) Peptide Activated Natural Killer (NK) Cells for the Treatment of Patients with Non-Small Cell Lung Cancer (NSCLC) after Radiochemotherapy (RCTx) - From Preclinical Studies to a Clinical Phase II Trial - Specht, Hanno M.; Ahrens, Norbert; Blankenstein, Christiane; Duell, Thomas; Fietkau, Rainer; Gaipl, Udo; Guenther, Christine; Gunther, Sophie; Habl, Gregor; Hautmann, Hubert; Hautmann, Matthias; Huber, Rudolf Maria; et al. (Frontiers in Immunology, 2015)
Heat shock protein 70 (Hsp70) is frequently overexpressed in tumor cells. An unusual cell surface localization could be demonstrated on a large variety of solid tumors including lung, colorectal, breast, squamous cell carcinomas of the head and neck, prostate and pancreatic carcinomas, glioblastomas, sarcomas and hematological malignancies, but not on corresponding normal tissues. A membrane (m)Hsp70-positive phenotype can be determined either directly on single cell suspensions of tumor biopsies by flow cytometry using cmHsp70.1 monoclonal antibody or indirectly in the serum of patients using a novel lipHsp70 ELISA. A mHsp70-positive tumor phenotype has been associated with highly aggressive tumors, causing invasion and metastases and resistance to cell death. However, natural killer (NK), but not T cells were found to kill mHsp70-positive tumor cells after activation with a naturally occurring Hsp70 peptide (TKD) plus low dose IL-2 (TKD/IL-2). Safety and tolerability of ex vivo TKD/IL-2 stimulated, autologous NK cells has been demonstrated in patients with metastasized colorectal and non-small cell lung cancer (NSCLC) in a phase I clinical trial. Based on promising clinical results of the previous study, a phase II randomized clinical study was initiated in 2014. The primary objective of this multicenter proof-of-concept trial is to examine whether an adjuvant treatment of NSCLC patients after platinum-based radiochemotherapy (RCTx) with TKD/IL-2 activated, autologous NK cells is clinically effective. As a mHsp70-positive tumor phenotype is associated with poor clinical outcome only mHsp70-positive tumor patients will be recruited into the trial. The primary endpoint of this study will be the comparison of the progression-free survival of patients treated with ex vivo activated NK cells compared to patients who were treated with RCTx alone. As secondary endpoints overall survival, toxicity, quality-of-life, and biological responses will be determined in both study groups.
EVALuna2:18287

Hemicorporal paresthesias in a parvovirusinfection - Baltas, Dimos; Ladd, Mark E.; Fiebich, Martin; Bert, Christoph; Heufelder, Jens (Zeitschrift für Medizinische Physik, 2020)
CRIS-Team WoS Importer:2021-01-29

HIBCH deficiency in a patient with phenotypic characteristics of mitochondrial disorders - Reuter, Miriam; Sass, Joern Oliver; Leis, Thomas; Koehler, Julia; Mayr, Johannes A.; Feichtinger, Rene G.; Rauh, Manfred; Schanze, Ina; Baehr, Luzy; Trollmann, Regina; Uebe, Steffen; Ekici, Arif Bülent; et al. (American Journal of Medical Genetics Part A, 2014)
HIBCH (3-hydroxyisobutyryl-CoA hydrolase) deficiency (MIM #250620) is a rare autosomal recessive inborn error of metabolism, leading to a block in the catabolic pathway of the amino acid valine and presumably to accumulation of toxic valine metabolites in mitochondria. Only three families with HIBCH deficiency and biallelic HIBCH mutations have been described. We report on a further patient, first child of healthy consanguineous parents, with severe developmental delay, seizures, hyperintensities of the basal ganglia on magnetic resonance imaging (MRI), progressive brain atrophy, optic nerve atrophy, repeatedly elevated blood lactate, and respiratory chain complexes I, I + III and cytochrome c oxidase deficiencies with borderline depletion of mitochondrial DNA in muscle tissue. Laboratory findings in blood and skeletal muscle were inconsistent and did not allow a definite diagnosis, but supported the hypothesis of mitochondrial dysfunction. Homozygosity mapping and whole-exome sequencing revealed a homozygous one-base pair insertion in HIBCH. Deficiency of enzyme activity was confirmed in cultured fibroblasts. Although relatively unspecific, the clinical features were similar to those of the previously reported cases. Given the clinical variability and large number of differential diagnoses, the prevalence of HIBCH deficiency is probably underestimated. Next-generation sequencing approaches are an effective tool for identifying the underlying genetic basis in patients suspected of mitochondrial disorders. © 2014 Wiley Periodicals, Inc.
EVALuna2:9220

High Detection Accuracy of an optimized 3D Convolutional Neural Network for Auto Detection and Auto Segmentation of Brain Metastases - Putz, Florian; Weissmann, Thomas; Mansoorian, Sina; Schmitter, Charlotte; Semrau, Sabine; Lettmaier, Sebastian; Masitho, Siti; Grigo, Johanna; Schmidt, Manuel; Heiß, Rafael; Frey, Benjamin; Bert, Christoph; et al. (STRAHLENTHERAPIE UND ONKOLOGIE, 2021)
CRIS-Team WoS Importer:2021-07-16

High-grade histology as predictor of early distant metastases and decreased disease-free survival in salivary gland cancer irrespective of tumor subtype - Haderlein, Marlen; Scherl, Claudia; Semrau, Sabine; Lettmaier, Sebastian; Uter, Wolfgang; Neukam, Friedrich Wilhelm; Iro, Heinrich; Agaimy, Abbas; Fietkau, Rainer (Head and Neck-Journal For the Sciences and Specialties of the Head and Neck, 2016)
The purpose of this study was to evaluate risk factors that influence overall survival (OS)/disease-free survival (DFS)/locoregional recurrence-free survival (LRFS), and distant metastases-free survival (DMFS) in patients with high-risk primary salivary gland carcinoma who underwent surgery and postoperative (chemo)radiotherapy with curative intention.We reviewed data of 63 patients with high-risk primary salivary gland carcinoma in a retrospective single-center audit.At a median follow-up of 31 months (range, 5-145 months), cumulative OS and DFS were 91.7%, 77.6%, and 62.9%, and 82.1%, 65.6%, and 57.7%, respectively, after 1, 2, and 5 years. LRFS and DMFS were 92%, 86%, and 86%, and 83.4%, 70.4%, and 62.3% after 1, 2, and 5 years, respectively. Of all patient-related, tumor-related, and treatment-related factors, high-grade histology (G3) was the only factor in univariate and multivariate analysis that was predictive for a shorter DMFS (low/intermediate vs high-grade: 100%, 100%, and 89.4% vs 72.9%, 54.3%, and 42.8% after 1, 2, and 5 years, respectively) and a shorter DFS (low/intermediate vs high-grade: 100%, 90%, and 84.4% vs 71.2%, 50.1%, and 39.4% after 1, 2, and 5 years, respectively) and OS (low/intermediate vs high-grade: 100%, 100%, and 86.5% vs 86.5%, 63.2%, and 46.5% after 1, 2, and 5 years, respectively).High-grade tumor histology is a highly significant predictor of a shorter DMFS, OS, and DFS in salivary gland carcinoma, irrespective of histological subtype. © 2016 Wiley Periodicals, Inc. Head Neck 38: E2041-E2048, 2016.
EVALuna2:5539

High-grade salivary gland cancer: is surgery followed by radiotherapy an adequate treatment to reach tumor control? Results from a tertiary referral centre focussing on incidence and management of distant metastases - Freitag, Viola; Lettmaier, Sebastian; Semrau, Sabine; Hecht, Markus; Mantsopoulos, Konstantinos; Müller-Hübner, Sarina; Traxdorf, Maximilian; Iro, Heinrich; Agaimy, Abbas; Fietkau, Rainer; Haderlein, Marlen (European Archives of Oto-Rhino-Laryngology, 2021)
Purpose: Salivary Gland cancer (SGC) is a rare and heterogenous group of tumors. Standard therapeutic options achieve high local but poor distant control rates, especially in high-grade SGC. The aim of this monocentric study was to evaluate patterns of recurrence and its treatment options (local ablative vs. systemic) in a homogenously treated patient population with high-grade SGC after surgery and radio(chemo)therapy. Methods: Monocentric, retrospective study of patients with newly diagnosed high-grade salivary gland cancer. We retrospectively reviewed clinical reports from 69 patients with high-grade salivary gland cancer in a single-center audit. Survival rates were calculated using the Kaplan–Meier method and prognostic variables were analyzed (univariate analysis: log-rank test; multivariate analysis: Cox regression analysis). Results: The median time of follow-up was 31 months. After 5 years, the cumulative overall survival was 65.2%, cumulative incidence of local recurrence was 7.2%, whereas the cumulative incidence of distant metastases was 43.5% after 5 years. 30 of 69 patients developed distant metastases during the time of follow-up, especially patients with adenoid cystic carcinoma, salivary duct carcinoma, adenocarcinoma NOS and acinic cell carcinoma with high-grade transformation. The most common type of therapy therefore was chemotherapy (50%). 85.7% of patients with local ablative therapy of distant metastases show disease progression during follow-up afterwards. Conclusion: With surgery and radio-chemotherapy, a high rate of loco-regional control is reached, but over 40% of patients develop distant metastases in the further follow-up which usually present a diffuse pattern involving in a diffuse metastases. Therefore, in the future, intensified interdisciplinary combination therapies even in the first-line treatment in certain subtypes of high-grade SGC should be investigated.
CRIS-Team Scopus Importer:2021-09-10
Keywords: Chemotherapy; Distant metastases; High-grade; Radiotherapy; Salivary gland cancer

High Intensity Resistance Exercise Training vs. High Intensity (Endurance) Interval Training to Fight Cardiometabolic Risk Factors in Overweight Men 30-50 Years Old. - Tuttor, Michael; von Stengel, Simon; Kohl, Matthias; Lell, Michael; Scharf, Michael; Uder, Michael; Wittke, Andreas; Kemmler, Wolfgang (Frontiers in Sports and Active Living, 2020)
Cardiovascular and cardiometabolic diseases are leading causes of death worldwide. Exercise favorably affects this problem, however only few invest (enough) time to favorably influence cardiometabolic risk-factors and cardiac morphology/performance. Time-effective, high-intensity, low-volume exercise protocols might increase people's commitment to exercise. To date, most research has focused on high-intensity interval training (HIIT), the endurance type of HIT, while corresponding HIT-resistance training protocols (HIT-RT) are rarely evaluated. In this study we compared the effect of HIIT vs. HIT-RT, predominately on cardiometabolic and cardiac parameters in untrained, overweight-obese, middle-aged men. Eligible, untrained men aged 30-50 years old in full-time employment were extracted from two joint exercise studies that randomly assigned participants to a HIIT, HIT-RT or corresponding control group. HIIT predominately consisted of interval training 90 s-12 min, (2-4 sessions/week), HIT-RT (2-3 sessions/week) was applied as a single set resistance training to muscular failure. Core intervention length of both protocols was 16 weeks. Main inclusion criteria were overweight-obese status (BMI 25-35 kg/m2) and full employment (occupational working time: ≥38.5 h/week). Primary study-endpoint was the Metabolic Syndrome (MetS) Z-Score, secondary study-endpoints were ventricular stroke volume index (SVI) and myocardial mass index (MMI) as determined by Magnetic Resonance Imaging. The Intention to treat (ITT) principle was applied to analyze the summarized data set. Twenty-seven eligible men of the HIT-RT and 30 men of the HIIT group were included in the ITT. Both interventions significantly (p < 0.001) improve the MetS Z-Score, however the effect of HIIT was superior (p = 0.049). In parallel, HIT-RT and HIIT significantly affect SVI and MMI, with the effect of HIIT being much more pronounced (p < 0.001). Although HIIT endurance exercise was superior in favorably affecting cardiometabolic risk and particularly cardiac performance, both exercise methods positively affect cardiometabolic risk factors in this overweight to obese, middle-aged cohort of males with low time resources. Thus, the main practical application of our finding might be that in general overweight-obese people can freely choose their preferred exercise type (HIIT-END or HIT-RT) to improve their cardiometabolic health, while investing an amount of time that should be feasible for everybody. Trial Registrations: NCT01406730, NCT01766791.
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Highlights from the 2021 ASCO and ESMO annual meetings on radiotherapy of head and neck cancer Highlights der ASCO- und ESMO-Jahrestagungen 2021 zur Strahlentherapie von Kopf-Hals-Tumoren - Hecht, Markus; von der Grün, Jens; Semrau, Sabine; Müller, Susanna; Weissmann, Thomas; Gaipl, Udo; Iro, Heinrich; Fietkau, Rainer; Gostian, Antoniu-Oreste (HNO, 2022)
At this year’s annual meetings of the American Society of Clinical Oncology (ASCO) and the European Society for Medical Oncology (ESMO), several studies on radiotherapy of locally advanced head and neck cancer were presented. For the indication of definitive radiochemotherapy, particularly the administration of immune checkpoint inhibitors concomitant to radiotherapy was investigated. In the phase III GORTEC-REACH trial, combined inhibition of epidermal growth factor receptor (EGFR) and programmed death-ligand (PD-L1) concomitant to radiotherapy of locally advanced head and neck cancer was inferior to platinum-based chemoradiotherapy. However, this therapeutic approach may be more efficient than radiotherapy with simultaneous EGFR inhibition alone. The concept of the phase II CheckRad-CD8 trial with induction chemoimmunotherapy followed by chemotherapy-free radioimmunotherapy after appropriate patient selection also proved to be highly efficient. In initial phase II trials, dose de-escalation of radiotherapy seems feasible for HPV-positive oropharyngeal cancer after appropriate patient selection both postoperatively (ECOG-ACRIN E3311 trial) and after induction therapy (Optima II trial). However, dose de-escalation should currently not be performed outside of clinical trials. In addition, first studies indicate a benefit of functional imaging (diffusion-weighted magnetic resonance imaging [MRI] or F‑fluoromisonidazole positron-emission tomography [FMISO-PET]) to establish personalized dose concepts in radiotherapy.
CRIS-Team Scopus Importer:2022-03-25
Keywords: Chemoradiotherapy; Head and neck squamous cell carcinoma; Human papillomavirus; Immunotherapy; Oropharyngeal cancer

High locoregional Control Rates after Radio (chemo) Therapy in anaplastic Thyroid Carcinoma - a monocentric Analysis - Schmied, M.; Semrau, Sabine; Hecht, Markus; Lettmaier, Sebastian; Mantsopoulos, K.; Traxdorf, Maximilian; Iro, Heinrich; Denz, Axel; Grützmann, Robert; Fietkau, Rainer; Haderlein, Marlen (STRAHLENTHERAPIE UND ONKOLOGIE, 2020)
CRIS-Team WoS Importer:2020-10-02

High stroma T-cell infiltration is associated with better survival in stage pT1 bladder cancer - Hülsen, Sabine; Lippolis, Eleonora; Ferrazzi, Fulvia; Otto, Wolfgang; Distel, Luitpold; Fietkau, Rainer; Denzinger, Stefan; Breyer, Johannes; Burger, Maximilian; Bertz, Simone; Eckstein, Markus; Ebner, Annette; et al. (International Journal of Molecular Sciences, 2020)
Stage pT1 bladder cancer (BC) shows highly diverse outcomes. Predictive markers are required to stratify patients for personalized treatment. The present study aimed to validate immune response quantification as a prognostic marker. Patients with pT1 BC (n = 167) treated by transurethral resection of the bladder (TURB) were enrolled. Formaldehyde-fixed paraffin-embedded material was stained for CD3 and CD8. Corresponding T cells were counted in three regions with the highest immune response. Numbers of tertiary lymphoid structures (TLS) and lymphocyte aggregates (LA) were quantified. High CD3+ stroma T-cell infiltration was associated with improved survival (p = 0.045), especially in the G3 subgroup (p = 0.01). Cluster with higher immune response showed less recurrence (p = 0.034) and favorable overall survival (OS) (p = 0.019). In contrast, higher CD3+ and CD8+ tumor T-cell infiltration seemed to have a negative impact on prognosis. TLS and LA were more frequently observed in G3 tumors, indicating an increased antitumoral immune response. We proved the role of immune cell infiltration and showed that higher infiltration numbers of CD3+ (not CD8+) lymphocytes in the stroma are associated with favorable outcome. Immune cell quantification could be used as a marker to help stratify patients’ risk and therefore, to optimize patients’ management and follow-up examination as well as possible therapies.
CRIS-Team Scopus Importer:2020-11-20
Keywords: CD8; Immunoscore; Progression; PT1 bladder cancer; Survival; Tumor-infiltrating lymphocytes (TILs); CD3

Histology-Depended Pattern of Patho-Histological Response After Induction Therapy in Locally Advanced Non-Small Cell Lung Cancer - Schreiner, Waldemar; Dudek, Wojciech; Rieker, Ralf; Fietkau, Rainer; Sirbu, Horia (JOURNAL OF THORACIC ONCOLOGY, 2019)
CRIS-Team WoS Importer:2019-11-08

How nescience may obscure evidence - Sautter-Bihl, M. -L.; Sedlmayer, F.; Budach, W.; Dunst, Juergen; Feyer, P.; Fietkau, Rainer; Haase, W.; Harms, W.; Piroth, M. D.; Souchon, R.; Wenz, F.; Sauer, Rolf (Strahlentherapie und Onkologie, 2014)
EVALuna2:18199

How Octogenarians with Bladder Cancer Are Treated in a Maximum-Care Hospital: The Real-Life Experience - Sikic, Danijel; Wach, Sven; Taubert, Helge; Richterstetter, Mario; Kunath, Frank; Lieb, Verena; Krause, F. Steffen; Merten, Ricarda; Ott, Oliver; Fietkau, Rainer; Wullich, Bernd; Keck, Bastian (Urologia Internationalis, 2016)
With increasing life expectancy, curative treatment of octogenarians with urothelial carcinoma of the bladder (UCB) becomes more important.The treatment modalities of 276 octogenarians with UCB who were treated at the University Hospital of Erlangen between 1982 and 2011 were assessed retrospectively.One hundred forty-six patients had non-muscle invasive bladder cancer (NMIBC) while 71 had muscle invasive bladder cancer (MIBC). No data was available for 59 patients. Eighty-five (58.2%) of the 146 patients with NMIBC received transurethral resection of the bladder tumor (TURBT) only, another 38 patients (26%) underwent additional intravesical therapy; and 8.9% were treated with radiochemotherapy (RCT), 4.1% with radiotherapy (RT), 1.4% with systemic chemotherapy and 1.4% with radical cystectomy (RC). Of the 71 patients suffering from MIBC, 39 (54.9%) received TURBT alone. A potentially curative therapy was performed on 31 of the 71 patients with MIBC (43.7%). Of these, 16 patients (51.6%) received RCT, 9 patients (29.0%) RT and 6 patients (19.4%) RC. In Kaplan-Meier analysis, patients with MIBC had better median overall survival with curative treatment compared to TURBT alone (28 vs. 9 months; p < 0.001, log-rank test).By offering a wide range of treatment options, over 43% of octogenarians with MIBC received a curative therapy at a maximum care hospital.
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Hydrostatic High Pressure generated Whole Cell Tumor Vaccines in combination with Radiotherapy produce an immunogenic Tumor Microenvironment - Rueckert, M.; Seitz, C.; Weiss, E. -M; Utz, S.; Izydor, Marika; Ebel, Nina; Schlücker, Eberhard; Fietkau, Rainer; Gaipl, Udo; Frey, Benjamin; Deloch, Lisa (STRAHLENTHERAPIE UND ONKOLOGIE, 2019)
CRIS-Team WoS Importer:2019-06-07

Hyperthermia with 44 degrees C enhances danger signal-mediated activation of dendritic cells, while immune cell infiltration into tumors is particularly fostered by hyperthermia with lower temperatures - Vogl, P.; Frey, Benjamin; Rueckert, M.; Maueröder, Christian; Fietkau, Rainer; Gaipl, Udo; Derer, Anja (2017)
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Hypofractionated Irradiation Has Immune Stimulatory Potential and Induces a Timely Restricted Infiltration of Immune Cells in Colon Cancer Tumors - Frey, Benjamin; Rueckert, Michael; Weber, Julia; Mayr, Xaver; Derer, Anja; Lotter, Michael; Bert, Christoph; Roedel, Franz; Fietkau, Rainer; Gaipl, Udo (Frontiers in Immunology, 2017)
In addition to locally controlling the tumor, hypofractionated radiotherapy (RT) particularly aims to activate immune cells in the RT-modified microenvironment. Therefore, we examined whether hypofractionated RT can activate dendritic cells (DCs), induce immune cell infiltration in tumors, and how the chronology of immune cell migration into tumors occurs to gain knowledge for future definition of radiation breaks and inclusion of immunotherapy. Colorectal cancer treatments offer only limited survival benefit, and immunobiological principles for additional therapies need to be explored with preclinical models. The impact of hypofractionated RT on CT26 colon cancer tumor cell death, migration of DCs toward supernatants (SN) of tumor cells, and activation of DCs by SN were analyzed. The subcutaneous tumor of a BALB/c-CT26 mouse model was locally irradiated with 2 × 5 Gy, the tumor volume was monitored, and the infiltration of immune cells in the tumor was determined by flow cytometry daily. Hypofractionated RT induced a mixture of apoptotic and necrotic CT26 cells, which is known to be in particular immunogenic. DCs that migrated toward SN of CT26 cells particularly upregulated the activation markers CD80 and CD86 when in contact with SN of irradiated tumor cells. After hypofractionated RT, the tumor outgrowth was significantly retarded and in the irradiated tumors an increased infiltration of macrophages (CD11bhigh/F4-80+) and DCs (MHC-II+), but only between day 5 and 10 after the first irradiation, takes place. While CD4+T cells migrated into non-irradiated and irradiated tumors, CD8+T cells were only found in tumors that had been irradiated and they were highly increased at day 8 after the first irradiation. Myeloid-derived suppressor cells and regulatory T cells show regular turnover in irradiated and non-irradiated tumors. Tumor cell-specific anti-IgM antibodies were enhanced in the serum of animals with irradiated tumors. We conclude that hypofractionated RT suffices to activate DCs and to induce infiltration of innate and adaptive immune cells into solid colorectal tumors. However, the presence of immune cells in the tumor which are beneficial for antitumor immune responses is timely restricted. These findings should be considered when innovative multimodal tumor treatment protocols of distinct RT with immune therapies are designed and clinically implemented.
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Hypofractionated Irradiation increases the Expression of the Immune Checkpoint Molecule HVEM on TS/A, 4T1-luc and E0771 Breast Carcinoma Cells - Flohr, Ann-Sophie; Fietkau, Rainer; Rückert, Michael; Gaipl, Udo (STRAHLENTHERAPIE UND ONKOLOGIE, 2022)
CRIS-Team WoS Importer:2022-06-03

Hypofractionated Radiation increases the Expression of the Immune Checkpoint-Molecule HVEM on TS/A Breast Cancer- and B16 Melanoma Cells - Flohr, Ann-Sophie; Grün, A; Fietkau, Rainer; Rückert, Michael; Gaipl, Udo (STRAHLENTHERAPIE UND ONKOLOGIE, 2021)
CRIS-Team WoS Importer:2021-07-16

Hypofractionated Radiotherapy Upregulates Several Immune Checkpoint Molecules in Head and Neck Squamous Cell Carcinoma Cells Independently of the HPV Status While ICOS-L Is Upregulated Only on HPV-Positive Cells - Wimmer, Sebastian; Deloch, Lisa; Hader, Michael; Derer, Anja; Grottker, Fridolin; Weissmann, Thomas; Hecht, Markus; Gostian, Antoniu-Oreste; Fietkau, Rainer; Frey, Benjamin; Gaipl, Udo (International Journal of Molecular Sciences, 2021)
While the treatment of squamous cell carcinoma of the head and neck (HNSCC) with radiotherapy (RT) is complemented more and more by immunotherapy in clinical trials, little is known about the impact of the human papillomavirus (HPV) status or the applied RT scheme on the immune phenotype of the tumor cells. Therefore, we aimed to examine the impact of the HPV status of four human HNSCC cell lines on cell death and the expression of immune checkpoint molecules (ICMs) after RT with either hypofractionation irradiation (5x3.0Gy) or a high single dose (1x19.3Gy) via multicolor flow cytometry and quantitative PCR at an early time point after therapy. In our study, 5x3.0Gy RT induced high numbers of early and late apoptotic cells independent of the HPV status, but necrosis was only increased in the HPV-positive UM-Scc-47 cells. Generally, the immune stimulatory ICMs (CD70, CD137-L, ICOS-L) were less affected by RT compared to the immune suppressive ones (PD-L1, PD-L2, and the herpesvirus entry mediator (HVEM)). A significant higher surface expression of the analyzed ICMs was found after hypofractionated RT compared to a single high dose; however, regardless of the HPV status, with the exception of ICOS-L. Here, HPV-positive HNSCC tumor cells showed a stronger response to 5x3.0Gy than HPV-negative ones. On the RNA level, only minor alterations of ICMs were observed following RT, with the exception of the HPV negative cell line CAL33 treated with 5x3.0Gy, where PD-L2, HVEM and CD70 were significantly increased. We conclude that the HPV status may not distinctly predict immunological responses following RT, and thus cannot be used as a single predictive marker for therapy responses in HNSCC. In contrast, the patient-specific individual expression of ICMs following RT is preferable for the targeted patient selection for immune therapy directed against distinct ICM.
CRIS-Team WoS Importer:2021-09-17

Idelalisib may have the potential to increase radiotherapy side effects - Gryc, Thomas; Putz, Florian; Goerig, Nicole; Ziegler, Sonia; Fietkau, Rainer; Distel, Luitpold; Schuster, Barbara (Radiation Oncology, 2017)
INTRODUCTION: Idelalisib is approved for the treatment of relapsed chronic lymphocytic leukemia together with Rituximab and for monotherapy of follicular B-cell non-Hodgkin's lymphoma and small lymphocytic lymphoma. It is a potent and selective phosphatidylinositol 3-kinase-δ (PI3K-δ) inhibitor. PI3K-δ primarily is expressed in B-cells and prevents effectively proliferation in malignant B-cells. METHODS: We provide a detailed report on treatment history and photo documentation of acute adverse effects of radiation therapy with simultaneous Idelalisib medication in one case of B-CLL. Radiosensitivity tests were performed for the index patient under Idelalisib and after the addition of Idelalisib to healthy individuals' blood. Radiosensitivity in human lymphocytes was analyzed with a three color in situ hybridization assay. Primary skin fibroblasts were studied after a treatment with Idelalisib for apoptosis, necrosis and cell cycle using flow cytometry. DNA double-strand break repair was analyzed by γH2AX immunostaining. RESULTS: The index patient presented a strong grade 2 radiodermatitis and grade 3 mucositis after irradiation with 20 Gy and a simultaneous intake of Idelalisib. Irradiations without Idelalisib medication were well tolerated and resulted in not more than grade 1 radiodermatitis. The index patient under Idelalisib had a radiosensitivity of 0.62 B/M which is in the range of clearly radiosensitive patients. A combined treatment of lymphocytes with 2 Gy and 10 nmol/l Idelalisib showed a tendency to an increased radiosensitivity. We found a clear increase of apoptosis as a result of the combined treatment in the Idelalisib dose range of 1 to 100 nmol/l compared to solely irradiated cells or solely Idelalisib treated cells (p = 0.05). CONCLUSION: A combined Idelalisib radiotherapy treatment has an increased risk of side effects. However, combined therapy seems to be feasible when patients are monitored closely.
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Identification and characterization of circular RNAs as novel putative biomarkers to predict anti-PD-1 monotherapy response in metastatic melanoma patients – Knowledge from two independent international studies - Zhou, Jian Guo; Liang, Rui; Wang, Hai Tao; Jin, Su Han; Hu, Wei; Frey, Benjamin; Fietkau, Rainer; Hecht, Markus; Ma, Hu; Gaipl, Udo (Neoplasia, 2023)
Melanoma is the most aggressive skin malignancy with high morbidity. Anti-programmed cell death protein 1 (PD-1) monotherapy has been applied in metastatic melanoma. However, still most of the patients do not respond to anti-PD-1 and the availability of the present approved biomarkers therefore is limited. Here we combined the transcriptomic and clinical data of 163 advanced melanoma patients receiving anti-PD-1 from NIH Melanoma Genome Sequencing Project (phs000452, 122 patients) as the training and internal validation cohort, and Melanoma Institute Australia cohort (PRJEB23709, 41 patients) as the external validation cohort, respectively. Circular RNAs (circRNAs) are an evolutionarily conserved novel class of noncoding endogenous RNAs (ncRNAs) found in the eukaryotic transcriptome and were used based on RNAseq data for our analyses. 74,243 circular RNAs (circRNAs) were identified with NCLscan and CIRCexplorer2. Thereof, 70 circRNAs significantly associated with progression-free survival and overall survival. Further, a prognostic circRNAs signature consisting of HSA_CIRCpedia_1497, HSA_CIRCpedia_12559, HSA_CIRCpedia_43640, HSA_CIRCpedia_43070, and HSA_CIRCpedia_21660 could be determined with LASSO regression. This signature was a prognostic factor of overall survival and progression-free survival among the analyzed advanced melanoma patients. The concordance indexes (C-index of OStraining: 0.61, C-index of PFStraining: 0.68) also confirmed its credibility and accuracy. First enrichment analysis indicated that immune response and pathways related to tumor immune microenvironment were enriched. In conclusion, we succeeded to construct and validate novel prognostic circRNAs signature for advanced melanoma patients treated with anti-PD-1 immunotherapy.
CRIS-Team Scopus Importer:2023-02-03
Keywords: Advanced melanoma; Anti-PD-1; circRNAs; Predictor; Survival benefit

Identification of 15 lncRNAs Signature for Predicting Survival Benefit of Advanced Melanoma Patients Treated with Anti-PD-1 Monotherapy - Zhou, Jian Guo; Liang, Bo; Liu, Jian Guo; Jin, Su Han; He, Si Si; Frey, Benjamin; Gu, Ning; Fietkau, Rainer; Hecht, Markus; Ma, Hu; Gaipl, Udo (Cells, 2021)
The blockade of programmed cell death protein 1 (PD-1) as monotherapy has been widely used in melanoma, but to identify melanoma patients with survival benefit from anti-PD-1 monotherapy is still a big challenge. There is an urgent need for prognostic signatures improving the prediction of immunotherapy responses of these patients. We analyzed transcriptomic data of pre-treatment tumor biopsies and clinical profiles in advanced melanoma patients receiving only anti-PD-1 monotherapy (nivolumab or pembrolizumab) from the PRJNA356761 and PRJEB23709 data sets as the training and validation cohort, respectively. Weighted gene co-expression network analysis was used to identify the key module, then least absolute shrinkage and selection operator was conducted to determine prognostic-related long noncoding RNAs (lncRNAs). Subsequently, the differentially expressed genes between different clusters were identified, and their function and pathway annotation were performed. In this investigation, 92 melanoma patients with complete survival information (51 from training cohort and 41 from validation cohort) were included in our analyses. We initiallyidentified the key module (skyblue) by weighted gene co-expression network analysis, and then identified a 15 predictive lncRNAs (AC010904.2, LINC01126, AC012360.1, AC024933.1, AL442128.2, AC022211.4, AC022211.2, AC127496.5, NARF-AS1, AP000919.3, AP005329.2, AC023983.1, AC023983.2, AC139100.1, and AC012615.4) signature in melanoma patients treated with anti-PD-1 monotherapy by least absolute shrinkage and selection operator in the training cohort. These results were then validated in the validation cohort. Finally, enrichment analysis showed that the functions of differentially expressed genes between two consensus clusters were mainly related to the immune process and treatment. In summary, the 15 lncRNAs signature is a novel effective predictor for prognosis in advanced melanoma patients treated with anti-PD-1 monotherapy.
CRIS-Team Scopus Importer:2021-05-28
Keywords: advanced melanoma; immune checkpoint inhibitor; LASSO; lncRNA; PD-1; predictor; survival benefit; WGCNA

Identification of an endogenous retroviral signature to predict anti-PD1 response in advanced clear cell renal cell carcinoma: an integrated analysis of three clinical trials - Zhou, Jianguo; Zeng, Yu; Wang, Haitao; Jin, Su-Han; Wang, Yun-Jia; He, Sisi; Frey, Benjamin; Fietkau, Rainer; Hecht, Markus; Ma, Hu; Zhang, Wenchuan; Gaipl, Udo (Therapeutic Advances in Medical Oncology, 2022)
Background: Endogenous retrovirus (ERV) elements are genomic footprints of ancestral retroviral infections within the human genome. Previous studies have demonstrated that dysregulated ERV transcription level is associated with immune cell infiltration in cancers, but the association between ERV expression and programmed cell death protein 1 (PD-1) blockade response is currently unraveled for solid cancers, such as advanced clear cell renal cell carcinoma (ccRCC). Methods: ERV mRNA profiles were obtained from three clinical trials of ccRCC where the patients were treated with anti-PD-1 (CM-009, CM-010, CM-025, and TCGA-KIRC data). Patients treated with nivolumab were divided into training and test cohort, while the TCGA-KIRC cohort was used as an external validation. Univariate Cox regression analysis and least absolute shrinkage and selection operator regression were used to establish the signature. Immune cell infiltration analysis and gene set enrichment analysis were performed to explore potential biological mechanisms. Results: An ERV signature was established based on nine ERV expression patterns. In the training cohort, the median overall survival in the low- and high-risk group was 45.2 and 19.6 months [hazard ratio (HR) = 0.49, 0.32-0.75, p < 0.001], respectively. The results were confirmed in the test (HR = 0.41, 0.20-0.83, p = 0.013), and in the TCGA-KIRC cohort (HR = 0.55, 0.34-0.90, p = 0.017). Moreover, in the CM-025 cohort, the low-risk group that received nivolumab had a more favorable survival compared with those that received the mTOR inhibitor everolimus, while no significant differences were observed in the high-risk group. CD8+ T cells were enriched in the low-risk group, while immune suppressive pathways were suppressed. Conclusion: The newly identified ERV signature is not only a prognostic, but also a predictive biomarker for advanced ccRCC patients who received anti-PD-1 therapy, which can guide personalized treatment in cancer patients in the future.
CRIS-Team WoS Importer:2022-10-14

Identification of an endogenous retroviral signature to predict PD-1 blockade response in advanced clear cell renal cell carcinoma: Integrated analysis of three clinical trials - Zhou, J-G.; Wang, H.; Ma, H.; Gaipl, Udo (ANNALS OF ONCOLOGY, 2021)
CRIS-Team WoS Importer:2021-12-31

Identification of High-risk Metastases in MRI Follow-up after Stereotaxic by using Radiomics and Delta Radiomics - Sommer, Phillip; Huang, Yixing; Fischer, Stefan; Srinivasan, Aishwarya Lakshmi; Dörfler, Arnd; Schmidt, M.; Frey, Benjamin; Maier, Andreas; Fietkau, Rainer; Bert, Christoph; Putz, Florian (STRAHLENTHERAPIE UND ONKOLOGIE, 2022)
CRIS-Team WoS Importer:2022-06-03

Identification of nine lncRNAs signature for predicting survival benefit of melanoma patients treated with immune checkpoint inhibitors - Zhou, J-G.; Ma, H.; Gaipl, Udo (ANNALS OF ONCOLOGY, 2020)
CRIS-Team WoS Importer:2021-01-15

IGF-I and Hyaluronic Acid Mitigate the Negative Effect of Irradiation on Human Skin Keratinocytes - Sörgel, Celena; Schmid, Rafael; Stadelmann, Nina; Weisbach, Volker Günter; Distel, Luitpold; Horch, Raymund E.; Kengelbach-Weigand, Annika (Cancers, 2022)
Ionizing radiation has become an integral part of modern cancer therapy regimens. Various side effects, such as radiation dermatitis, affect patients in acute and chronic forms and decrease therapy compliance significantly. In this study, primary keratinocytes were irradiated in a 2-dimensional (2D) culture as well as on a 3-dimensional (3D) collagen-elastin matrix with doses of 2 and 5 Gy. The effect of different concentrations of IGF-I, KGF, platelet lysate (PL), high and low molecular weight hyaluronic acid (H-HA, L-HA), and adipose-derived stem cell (ADSC) conditioned medium was analyzed in respect to cell viability (WST-8), wound closure (migration), and the gene expression (quantitative real-time PCR) of 2D cultures. The 3D culture was evaluated by WST-8. A mixture of H-HA and L-HA, as well as IGF-I, could significantly stimulate the keratinocyte viability and migration which were severely reduced by irradiation. The MKI67and IL6 gene expression of irradiated keratinocytes was significantly higher after H-HA/L-HA treatment. The stimulating effects of H-HA/L-HA and IGF-I were able to be confirmed in 3D culture. A positive influence on cell viability, migration, and gene expression was achieved after the treatment with H-L-HA and IGF-I. These results open the possibility of a novel therapeutic method for both the prevention and the treatment of radiation dermatitis.
CRIS-Team Scopus Importer:2022-02-25
Keywords: Dermatitis; Hyaluronic acid; IGF-I; Irradiation; Keratinocytes; Wound healing

Imaging Hepatocellular Carcinoma with Dynamic CT Before and After Transarterial Chemoembolization: Optimal Scan Timing of Arterial Phase - Saake, Marc; Lell, Michael; Eller, Achim; Wüst, Wolfgang; Heinz, Marco; Uder, Michael; Schmid, Axel (Academic Radiology, 2015)
The aim of this study was to determine the optimal arterial phase delay for computed tomography imaging of hepatocellular carcinoma (HCC) before and after transarterial chemoembolization (TACE) using a low iodine dose protocol.A total of 39 patients with known HCC were imaged with dynamic computed tomography of the liver (40-second scan duration, 60 mL of contrast medium), both on the same day before TACE and 1 day after TACE. Time attenuation curves of vessels, nonmalignant liver parenchyma, and 62 HCCs were normalized to a uniform aortic contrast arrival and analyzed.Maximal arterial phase HCC to liver contrast was reached between 13 and 17 seconds after aortic contrast arrival, both before and after TACE.Using our low iodine dose protocol, arterial phase imaging of HCC should be performed between 13 and 17 seconds after aortic contrast arrival, both before and after TACE.
EVALuna2:14493

Imaging the Parasinus Region with a Third-Generation Dual-Source CT and the Effect of Tin Filtration on Image Quality and Radiation Dose - Lell, Michael; May, Matthias; Brand, Michael; Eller, A.; Buder, Thomas; Hofmann, Eva Maria; Uder, Michael; Wüst, Wolfgang (American Journal of Neuroradiology, 2015)
CT is the imaging technique of choice in the evaluation of midface trauma or inflammatory disease. We performed a systematic evaluation of scan protocols to optimize image quality and radiation exposure on third-generation dual-source CT.CT protocols with different tube voltage (70-150 kV), current (25-300 reference mAs), prefiltration, pitch value, and rotation time were systematically evaluated. All images were reconstructed with iterative reconstruction (Advanced Modeled Iterative Reconstruction, level 2). To individually compare results with otherwise identical factors, we obtained all scans on a frozen human head. Conebeam CT was performed for image quality and dose comparison with multidetector row CT. Delineation of important anatomic structures and incidental pathologic conditions in the cadaver head was evaluated.One hundred kilovolts with tin prefiltration demonstrated the best compromise between dose and image quality. The most dose-effective combination for trauma imaging was Sn100 kV/250 mAs (volume CT dose index, 2.02 mGy), and for preoperative sinus surgery planning, Sn100 kV/150 mAs (volume CT dose index, 1.22 mGy). "Sn" indicates an additional prefiltration of the x-ray beam with a tin filter to constrict the energy spectrum. Exclusion of sinonasal disease was possible with even a lower dose by using Sn100 kV/25 mAs (volume CT dose index, 0.2 mGy).High image quality at very low dose levels can be achieved by using a Sn100-kV protocol with iterative reconstruction. The effective dose is comparable with that of conventional radiography, and the high image quality at even lower radiation exposure favors multidetector row CT over conebeam CT.
EVALuna2:14481

Immediate changes of angiosome perfusion during tibial angioplasty - Rother, Ulrich; Krenz, Katrin; Lang, Werner; Horch, Raymund E.; Schmid, Axel; Heinz, Marco; Meyer, Alexander; Regus, Susanne (Journal of Vascular Surgery, 2017)
In recent years, a controversial discussion about the clinical relevance of the angiosome concept during tibial angioplasty has developed. Therefore, we conducted a prospective study to evaluate the angiosome concept on the level of microcirculation during tibial vascular interventions.Thirty patients with isolated tibial angioplasty were examined prospectively. Macrocirculation was evaluated by measurement of the ankle-brachial index (ABI). For the assessment of microcirculation, a combined method of laser Doppler flowmetry and tissue spectrometry (O2C; LEA Medizintechnik GmbH, Giessen, Germany) was applied. Microcirculatory parameters were measured continuously during the procedures. Measuring points were located over different angiosomes of the index foot; a control probe was placed on the contralateral leg.Cumulated microcirculation parameters (sO2, flow) as well as the ABI showed a significant improvement postinterventionally (ABI, P < .001; sO2, P < .001; flow, P < .001). Assessment of the separate angiosomes of the index leg and the comparison of the directly revascularized (DR) and indirectly revascularized (IR) angiosomes showed no significant difference concerning the microperfusion postinterventionally (DR - IR: sO2, P = .399; flow, P = .909) as well as during angioplasty. Even a further subdivision of the collective into patients with diabetes (sO2, P = .445; flow, P =.758) and renal insufficiency (sO2, P = .246; flow, P = .691) could not demonstrate a superiority of the direct revascularization at the level of microcirculation in these patients (comparison DR - IR).There is a significant overall improvement in tissue perfusion of the foot immediately after tibial angioplasty. The effect shown in this study, however, was found to be global and was not restricted to certain borders, such as defined by angiosomes.
EVALuna2:14616

Immobilization for carbon ion beam ablation of cardiac structures in a porcine model - Prall, Matthias; Eichhorn, Anna; Richter, Daniel; Lehmann, H. Immo; Constantinescu, Anna; Kaderka, Robert; Lugenbiel, Patrick; Thomas, Dierk; Bert, Christoph; Packer, Douglas L.; Durante, Marco; Graeff, Christian (Physica Medica, 2017)
INTRODUCTION: Whereas hadron therapy of static targets is clinically established, treatment of moving organs remains a challenge. One strategy is to minimize motion of surrounding tissue mechanically and to mitigate residual motion with an appropriate irradiation technique. In this technical note, we present and characterize such an immobilization technique for a novel noncancerous application: the irradiation of small targets in hearts with scanned carbon ion beams in a porcine model for elimination of arrhythmias. MATERIAL AND METHODS: A device for immobilization was custom-built. Both for the treatment planning 4D-CT scan and for irradiation, breath-hold at end-exhale was enforced using a remotely-controlled respirator. Target motion was thus reduced to heartbeat only. Positioning was verified by orthogonal X-rays followed by couch shift if necessary. Reproducibility of bony anatomy, diaphragm, and heart position after repositioning and between repeated breath-hold maneuvers was evaluated on X-rays and cardiac-gated 4D-CTs. Treatment was post hoc simulated on sequential 4D-CTs for a subset of animals, after immediate repositioning and after a delay of one week, similar to the delay between imaging and irradiation. RESULTS: Breath-hold without repositioning was highly reproducible with an RMS deviation of at most one millimeter. 4D-CTs showed larger deformations in soft tissue, but treatment simulation on sequential images resulted in full target coverage (V95 >95%). CONCLUSION: The method of immobilization permitted reproducible positioning of mobile, thoracic targets for range-sensitive particle therapy. The presented immobilization strategy could be a reasonable approach for future animal investigations with the ultimate goal of translation to therapy in men.
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IMMO-LDRT01: Immunophenotyping of patients suffering from chronic degenerative joint diseases and receiving local low-dose radiation therapy - Harrer, A.; Rühle, Paul-Friedrich; Gryc, Thomas; Ott, O. J.; Fietkau, Rainer; Gaipl, Udo; Frey, Benjamin (2017)
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IMMO-LDRT01 TRIAL: IMMUNOMODULATORY EFFECTS OF LOW DOSE RADIATION THERAPY OF CHRONIC DEGENERATIVE AND INFLAMMATORY DISEASES - Donaubauer, Anna-Jasmina; Gryc, Thomas; Becker, I.; Ott, O. J.; Fietkau, Rainer; Gaipl, Udo; Frey, Benjamin (ANNALS OF THE RHEUMATIC DISEASES, 2019)
CRIS-Team WoS Importer:2019-05-17

Immune biological rationales for the design of combined radio- and immunotherapies - Hader, Michael; Frey, Benjamin; Fietkau, Rainer; Hecht, Markus; Gaipl, Udo (Cancer Immunology, Immunotherapy, 2020)
Cancer immunotherapies are promising treatments for many forms of cancer. Nevertheless, the response rates to, e.g., immune checkpoint inhibitors (ICI), are still in low double-digit percentage. This calls for further therapy optimization that should take into account combination of immunotherapies with classical tumor therapies such as radiotherapy. By designing multimodal approaches, immune modulatory properties of certain radiation schemes, additional immune modulation by immunotherapy with ICI and hyperthermia, as well as patient stratification based on genetic and immune constitutions have to be considered. In this context, both the tumor and its microenvironment including cells of the innate and adaptive immune system have to be viewed in synopsis. Knowledge of immune activation and immune suppression by radiation is the basis for well-elaborated addition of certain immunotherapies. In this review, the focus is set on additional immune stimulation by hyperthermia and restoration of an immune response by ICI. The impact of radiation dose and fractionation on immune modulation in multimodal settings has to be considered, as the dynamics of the immune response and the timing between radiotherapy and immunotherapy. Another big challenge is the patient stratification that should be based on matrices of biomarkers, taking into account genetics, proteomics, radiomics, and "immunomics". One key aim is to turn immunological "cold" tumors into "hot" tumors, and to eliminate barriers of immune-suppressed or immune-excluded tumors. Comprehensive knowledge of immune alterations induced by radiation and immunotherapy when being applied together should be utilized for patient-adapted treatment planning and testing of innovative tumor therapies within clinical trials.
CRIS-Team WoS Importer:2020-01-31

Immune-modulating properties of ionizing radiation: rationale for the treatment of cancer by combination radiotherapy and immune checkpoint inhibitors - Derer, Anja; Frey, Benjamin; Fietkau, Rainer; Gaipl, Udo (Cancer Immunology Immunotherapy, 2016)
Radiotherapy (RT) utilizes the DNA-damaging properties of ionizing radiation to control tumor growth and ultimately kill tumor cells. By modifying the tumor cell phenotype and the tumor microenvironment, it may also modulate the immune system. However, out-of-field reactions of RT mostly assume further immune activation. Here, the sequence of the applications of RT and immunotherapy is crucial, just as the dose and fractionation may be. Lower single doses may impact on tumor vascularization and immune cell infiltration in particular, while higher doses may impact on intratumoral induction and production of type I interferons. The induction of immunogenic cancer cell death seems in turn to be a common mechanism for most RT schemes. Dendritic cells (DCs) are activated by the released danger signals and by taking up tumor peptides derived from irradiated cells. DCs subsequently activate T cells, a process that has to be tightly controlled to ensure tolerance. Inhibitory pathways known as immune checkpoints exist for this purpose and are exploited by tumors to inhibit immune responses. Cytotoxic T lymphocyte antigen 4 (CTLA-4) and programmed cell death protein 1 (PD-1) on T cells are two major checkpoints. The biological concepts behind the findings that RT in combination with anti-CTLA-4 and/or anti-PD-L1 blockade stimulates CD8+ T cell-mediated anti-tumor immunity are reviewed in detail. On this basis, we suggest clinically significant combinations and sequences of RT and immune checkpoint inhibition. We conclude that RT and immune therapies complement one another.
EVALuna2:18336

Immune modulation by low dose radiation therapy-results from 70 patients followed up in the IMMO-LDRT01 study - Donaubauer, Anna-Jasmina; Gryc, Thomas; Becker, I.; Harrer, A.; Rühle, Paul-Friedrich; Ott, O. J.; Fietkau, Rainer; Gaipl, Udo; Frey, Benjamin (2018)
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Immune modulation during anti-cancer radio(immuno)therapy - Irianto, Teresa Tamara; Gaipl, Udo; Rückert, Michael (International Review of Cell and Molecular Biology, 2023)
Cancer can affect all human organs and tissues and ranks as a prominent cause of death as well as an obstruction to increasing life expectancy. A notable breakthrough in oncology has been the inclusion of the immune system in fighting cancer, potentially prolonging life and providing long-term benefits. The concept of “immunotherapy” has been discussed from the 19th and early 20th centuries by Wilhelm Busch, William B. Coley and Paul Ehrlich. This involves distinct approaches, including vaccines, non-specific cytokines and adoptive cell therapies. However, despite the advances made in recent years, questions on how to select the best therapeutic options or how to select the best combinations to improve clinical outcomes are still relevant for scientists and clinicians. More than half of cancer patients receive radiotherapy (RT) as part of their treatment. With the advances in RT and immunotherapy approaches, it is reasonable to consider how to enhance immunotherapy with radiation and vice versa, and to investigate whether combinations of these therapies would be beneficial. In this chapter, we will discuss how the immune system responds to cancer cells and different cancer therapies with a focus on combination of RT and immunotherapy (radioimmunotherapy, RIT).
CRIS-Team Scopus Importer:2023-08-11
Keywords: Immune checkpoint molecules; Immune editing; Immunogenic cell death; Radioimmunotherapies; Radiotherapy

Immune modulatory effects of radiotherapy as basis for well-reasoned radioimmunotherapies - Rueckert, Michael; Fietkau, Rainer; Frey, Benjamin; Hecht, Markus; Gaipl, Udo; Deloch, Lisa (Strahlentherapie und Onkologie, 2018)
BACKGROUND: Radiotherapy (RT) has been known for decades as a local treatment modality for malign and benign disease. In order to efficiently exploit the therapeutic potential of RT, an understanding of the immune modulatory properties of ionizing radiation is mandatory. These should be used for improvement of radioimmunotherapies for cancer in particular. METHODS: We here summarize the latest research and review articles about immune modulatory properties of RT, with focus on radiation dose and on combination of RT with selected immunotherapies. Based on the knowledge of the manifold immune mechanisms that are triggered by RT, thought-provoking impulse for multimodal radioimmunotherapies is provided. RESULTS: It has become obvious that ionizing radiation induces various forms of cell death and associated processes via DNA damage initiation and triggering of cellular stress responses. Immunogenic cell death (ICD) is of special interest since it activates the immune system via release of danger signals and via direct activation of immune cells. While RT with higher single doses in particular induces ICD, RT with a lower dose is mainly responsible for immune cell recruitment and for attenuation of an existing inflammation. The counteracting immunosuppression emanating from tumor cells can be overcome by combining RT with selected immunotherapies such as immune checkpoint inhibition, TGF-β inhibitors, and boosting of immunity with vaccination. CONCLUSION: In order to exploit the full power of RT and thereby develop efficient radioimmunotherapies, the dose per fraction used in RT protocols, the fractionation, the quality, and the quantity of certain immunotherapies need to be qualitatively and chronologically well-matched to the individual immune status of the patient.
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Immune suppressive properties of Glioblastoma cells might result in part from radiation-induced increased expression of inhibitory immune checkpoint molecules - Langenfelder, E.; Derer, Anja; Fietkau, Rainer; Gaipl, Udo; Frey, Benjamin (2018)
EVALuna2:36504

Immunological Aspects of intraoperative Radiotherapy in Breast Cancer after breast conserving Surgery - Tiefenthaller, A.; Brix, N.; Escudero, Pazos M.; Kost, B.; Rack, B.; Bodungen Von,; Weissenbacher, T.; Wuerstlein, R.; Rühle, Paul-Friedrich; Gaipl, Udo; Harbeck, N.; Belka, C.; et al. (2017)
EVALuna2:32928

Immunological aspects of radiotherapy - Scheithauer, Heike; Belka, Claus; Lauber, Kirsten; Gaipl, Udo (Radiation Oncology, 2014)
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Immunological basis of abscopal antitumor responses induced with radio-immunotherapy - Rueckert, M.; Frey, Benjamin; Fietkau, Rainer; Gaipl, Udo (2017)
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Immunological basis of local and abscopal antitumor responses induced with radio-immunotherapy - Rueckert, M.; Frey, Benjamin; Fietkau, Rainer; Gaipl, Udo (2017)
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Immunomodulation by ionizing radiation-impact for design of radio-immunotherapies and for treatment of inflammatory diseases - Frey, Benjamin; Rueckert, Michael; Rühle, Paul-Friedrich; Derer, Anja; Fietkau, Rainer; Gaipl, Udo; Deloch, Lisa (Immunological Reviews, 2017)
Ionizing radiation is often regarded as an element of danger. But, danger responses on the cellular and molecular level are often beneficial with regard to the induction of anti-tumor immunity and for amelioration of inflammation. We outline how in dependence of radiation dose and fraction, radiation itself-and especially in combination with immune modulators-impacts on the innate and adaptive immune system. Focus is set on radiation-induced changes of the tumor cell phenotype and the cellular microenvironment including immunogenic cancer cell death. Mechanisms how anti-tumor immune responses are triggered by radiotherapy in combination with hyperthermia, inhibition of apoptosis, the adjuvant AnnexinA5, or vaccination with high hydrostatic pressure-killed autologous tumor cells are discussed. Building on this, feasible multimodal radio-immunotherapy concepts are reviewed including overcoming immune suppression by immune checkpoint inhibitors and by targeting TGF-β. Since radiation-induced tissue damage, inflammation, and anti-tumor immune responses are interconnected, the impact of lower doses of radiation on amelioration of inflammation is outlined. Closely meshed immune monitoring concepts based on the liquid biopsy blood are suggested for prognosis and prediction of cancer and non-cancer inflammatory diseases. Finally, challenges and visions for the design of cancer radio-immunotherapies and for treatment of benign inflammatory diseases are given.
EVALuna2:32867

Immunomodulatory and analgesic Effects of serial Radon-Baths in Patients with musculoskeletal Diseases: Investigations in the RAD-ON02 Study - Donaubauer, Anna-Jasmina; Becker, Ina; Weikl, Lena; Klein, Gerhart; Fietkau, Rainer; Gaipl, Udo; Frey, Benjamin (Strahlentherapie und Onkologie, 2021)
CRIS-Team WoS Importer:2021-07-16

Immunophanotype modulating Properties of Ferrous Clathrochelates and Irradiation in Lung Cancer Cells - Alomo, Jannik; Becker, I.; Roessel, T.; Denzler, M.; Heim, L.; Mokhir, Andriy; Klemt, Insa; Voloshin, Y.; Selin, R.; Fietkau, Rainer; Gaipl, Udo; Frey, Benjamin (STRAHLENTHERAPIE UND ONKOLOGIE, 2022)
CRIS-Team WoS Importer:2022-06-03

Impact of age on the efficacy of oxaliplatin in the preoperative chemoradiotherapy and adjuvant chemotherapy of rectal cancer: a post hoc analysis of the CAO/ARO/AIO-04 phase III trial - Hofheinz, R. -D.; Arnold, D.; Fokas, E.; Kaufmann, M.; Hothorn, T.; Folprecht, G.; Fietkau, Rainer; Hohenberger, Werner; Ghadimi, M.; Liersch, T.; Grabenbauer, G. G.; Sauer, Rolf; et al. (Annals of Oncology, 2018)
Background: The German rectal cancer trial CAO/ARO/AIO-04 has shown a significant benefit in 3-year disease-free survival (DFS) of adding oxaliplatin to a standard preoperative 5-fluorouracil (5-FU)-based chemoradiotherapy (CRT) and adjuvant chemotherapy in patients with locally advanced rectal cancer. The use of oxaliplatin as adjuvant treatment in elderly patients with colon cancer is controversial. We therefore investigated the impact of age on clinical outcome in the CAO/ARO/AIO-04 phase III trial. Patients and methods: We carried out a post hoc analysis of the CAO/ARO/AIO-04 phase III trial evaluating primary and secondary end points according to age. Patient and tumor characteristics, NCI CTC adverse events grades 3-4 (version 3.0), dose intensities as well as survival and recurrence data were analyzed in three specified age groups (<60, 60-70, and ≥70 years). The influence of age as a continuous variable on DFS was modeled using a subpopulation treatment effect pattern plot (STEPP) analysis. Results: A total of 1232 patients were assessable. With the exception of Eastern Cooperative Oncology Group status (P < 0.001), no differences in patient and tumor characteristics were noticed between age groups. Likewise, toxicity pattern, dose intensities of CRT and surgical results were similar in all age groups. After a median follow-up of 50 months, in patients aged <60 years a significant benefit of adding oxaliplatin to 5-FU-based CRT and adjuvant chemotherapy was observed for local (P = 0.013) and systemic recurrences (P = 0.023), DFS (P = 0.011), and even overall survival (OS; P = 0.044). The STEPP analysis revealed improved hazard ratios for DFS in patients aged 40-70 years compared with elderly patients treated with oxaliplatin. Conclusion: The addition of oxaliplatin significantly improved DFS and OS in younger patients aged <60 years with advanced rectal cancer. Patients aged ≥70 years had no benefit. Clinical Trials Number: NCT00349076.
EVALuna2:36460

Impact of Citrate-stabilized superparamagnetic Iron Oxide-Nanoparticles on Head and Neck Tumor Cell Lines in Combination Therapy with ionizing Radiation - Schreiber, C.; Franzen, T.; Fietkau, Rainer; Tietze, Rainer; Stein, René; Friedrich, Bernhard; Distel, Luitpold (STRAHLENTHERAPIE UND ONKOLOGIE, 2021)
CRIS-Team WoS Importer:2021-07-16

Impact of COVID-19 on Quality of Life in Long-Term Advanced Rectal Cancer Survivors - Blasko, Daniel; Schweizer, Claudia; Fitz, Tim; Schröter, Christoph; Sörgel, Christopher; Kallies, Annett; Fietkau, Rainer; Distel, Luitpold (Healthcare, 2023)
Colorectal cancer remains one of the most commonly diagnosed cancers. Advanced rectal cancer patients receive neoadjuvant radiochemotherapy as well as surgery and suffer from reduced health-related quality of life due to various side effects. We were interested in the role of the COVID-19 pandemic and how it affected those patients’ quality of life. A total of 489 advanced rectal cancer patients from the University Hospital Erlangen in Germany were surveyed between May 2010 and March 2022 and asked to fill out the EORTC QLQ-C30 and QLQ-CR38 questionnaires over eight different time points: at the beginning, during and after radiochemotherapy, right before surgery, and in yearly intervals after surgery for up to four years. Answers were converted to scores to compare the COVID-19 period to the time before March 2020, focusing on the follow-ups, the developments over time—including by sex and age—and the influence of the TNM cT-stage. Overall, a trend of impaired functional and symptom scores was found across all surveys with few significances (body image −10.6 percentage points (pp) after one year; defecation problems +13.5 pp, insomnia +10.2 pp and weight loss +9.8 pp after three years; defecation problems +11.3 pp after four years). cT4-stage patients lost significantly more weight than their cT1-3-stage counterparts (+10.7 to 13.7 pp). Further studies should be conducted to find possible causes and develop countermeasures for future major infectious diseases.
CRIS-Team Scopus Importer:2023-08-11
Keywords: COVID-19; pandemic; quality of life; radiochemotherapy; rectal cancer

Impact of fractionation and number of fields on dose homogeneity for intra-fractionally moving lung tumors using scanned carbon ion treatment - Woelfelschneider, Jens; Friedrich, Thomas; Luechtenborg, Robert; Zink, Klemens; Scholz, Michael; Dong, Lei; Durante, Marco; Bert, Christoph (Radiotherapy and Oncology, 2016)
Scanned particle beam therapy may result in over and under dosages within the target volume. This study quantifies how CTV dose coverage improves with number of fractions and fields.Based on 4DCTs of nine lung tumor patients, treatment plans were optimized separately for four different fields using an ITV approach. 4D RBE-weighted dose distributions were calculated for varying motion parameters and fraction numbers. The total RBE-weighted dose was determined for one and four-field application per fraction. DVHs were analyzed for the tumor and interpreted based on statistical modeling.Dose homogeneity within the CTV increased with the fraction number, but depends significantly on the tumor motion amplitude. For single-field schedules and amplitudes >6mm, the dose coverage indices (V95min=90.7% and V107max=0.4%) differed to the stationary case even after 40 fractions. Target coverage for a four-field approach followed a proposed model and homogeneous dose distributions could be achieved 6-times faster than single-field treatments.Fractionated delivery improves dose homogeneity in scanned ion beam therapy of moving targets. The achievable homogeneity depends mainly on tumor volume and motion amplitude. The outcome of multiple-field irradiations can be predicted based on single-field results and accelerates the achievement of homogeneous dose distributions.
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Impact of hypo- and normofractionated radiation on cell death and senescence of HNSCC-cells of different HPV-Status - Wild, Kristina; Peitz, L.; Rieckmann, T.; Fietkau, Rainer; Frey, Benjamin; Gaipl, Udo (2018)
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Impact of inter- and intra-observer variabilities of catheter reconstruction on multi-catheter interstitial brachytherapy of breast cancer patients - Kallis, Karoline; Kaltsas, Theodoros; Kreppner, Stephan; Lotter, Michael; Strnad, Vratislav; Fietkau, Rainer; Bert, Christoph (Radiotherapy and Oncology, 2019)
Purpose: The aim of this study was to evaluate inter- and intra-observer variabilities of catheter reconstruction and its dosimetric impact for multi-catheter interstitial breast cancer patients. Methods and materials: In order to evaluate inter-observer variabilities (IOV) three medical physicists reconstructed the catheter traces of 13 patients. These manual reconstructions were further compared to the automatic reconstruction algorithm integrated into the planning system and one on purpose imprecise manual reconstruction. For intra-observer variabilities (IAV) repeated reconstructions of two physicists were compared for 13 patients. In total 426 catheters were considered. Keeping dwell times, dwell positions, the optimization and the normalization relative points constant the geometrical deviations between the corresponding dwell positions of the reference data set and the investigated reconstructions were evaluated. Also, the effect on the quality indices, such as coverage index (CI), dose non-uniformity ratio (DNR) or conformal index (COIN), and the exposure of the organs at risk were analyzed. Results: Over all patients and all different catheter reconstructions considered for IOV a mean deviation between the corresponding dwell positions of 0.60 ± 0.35 mm was detected. The first observer had a mean deviation of 0.54 ± 0.32 mm, whereas the second observer yielded a mean deviation of 0.58 ± 0.37 mm. The length of the catheter traces varied in the mean by 0.51 ± 0.45 mm. The mean relative deviation of the CI, DNR, COIN, mean heart dose and mean lung dose varied by 0.27 ± 0.31%, 0.0027 ± 0.0025, 0.0036 ± 0.0033, 0.024 ± 0.019%, 0.05 ± 0.11%, respectively. The skin dose (D 0.2ccm ) changed in the maximum 8.52%. On average IAV reached a deviation between the corresponding dwell positions of 0.49 ± 0.30 mm. IOVs and IAVs proved to be significantly different (Wilcoxon's test p < 0.01). Conclusions: The study proved that a repeated reconstruction of the catheter traces does not lead to large geometrical deviations or to a significant change in the dose exposure. But the lack of ground truth makes the estimation of the quality of the reconstruction challenging. A precise reconstruction mapping the reality is a necessity for the planned dose delivery. With all considered reconstruction techniques reliable quality indices for the target and the organs at risk could be obtained.
CRIS-Team Scopus Importer:2019-05-02
Keywords: Breast cancer; Inter-observer variability; Interstitial multi-catheter brachytherapy

Impact of patient positioning on interstitial multicatheter HDR brachytherapy of the breast - Abu-Hossin, N.; Kallis, Karoline; Strnad, Vratislav; Fietkau, Rainer; Bert, Christoph (RADIOTHERAPY AND ONCOLOGY, 2021)
CRIS-Team WoS Importer:2021-06-18

Impact of postoperative radiotherapy and HER2/new overexpression in salivary duct carcinoma : A monocentric clinicopathologic analysis - Haderlein, Marlen; Scherl, Claudia; Semrau, Sabine; Lettmaier, Sebastian; Hecht, Markus; Erber, Ramona; Iro, Heinrich; Agaimy, Abbas; Fietkau, Rainer (Strahlentherapie und Onkologie, 2017)
Retrospective Investigation of the prognostic relevance of clinicopathologic parameters in patients with salivary duct carcinoma (SDC).An experienced pathologist reviewed 67 patients with de novo SDC or SDC ex pleomorphic adenoma. Paraffin-embedded tumor samples were examined by immunohistochemistry for expression of HER2/neu, androgen (AR), progesterone (PR), estrogen (ER), epidermal growth factor (EGFR) and programmed death ligand 1 (PD-L1-R) receptor. In 45 patients who had cM0 and follow-up data available, survival rates were calculated (Kaplan-Meier method) and prognostic variables were analyzed (univariate analysis: log-rank test; multivariate analysis: Cox-regression analysis).Overexpression of HER2/neu, AR, ER, PR, EGFR, PD-L1-R was found in 25.4%, 84%, 0%, 0%, 17.9%, 16.4% of patients. Overall (OS), disease-free (DFS), distant-metastases-free survival (DMFS) and locoregional control (LRC) were 92.3/72.4/56.9%, 78.2/58.1/58.1%, 85.4/65.2/65.2% and 89.7/81.9/81.9% after 1/3/5 years (medial follow-up 26 months). In univariate analysis a positive resection margin (p = 0.008) and no postoperative radiotherapy (p = 0.001) predict an increased locoregional recurrence rate. In multivariate analysis only postoperative radiotherapy is statistically significant (p = 0.004). Presence of lymph node metastases, a lymph node density >4 and HER2/neu overexpression predict decreased DFS and DMFS. In multivariate HER2/neu overexpression was the only significant predictor for reduced DFS (p = 0.04) and DMFS (p = 0.02).Postoperative radiotherapy is the only significant predictor for LRC. HER2/neu receptor expression is an independent prognostic factor for decreased DFS and DMFS in patients with SDC. In addition to radio(chemo)therapy, intensified first-line treatment regimens should also be evaluated in the future.
EVALuna2:6895

Impact of radio(chemo)therapy on expression of immune checkpoint ligands PD-L1 and PD-L2 on murine and human melanoma cells - Riegel, Dania; Bäumler, Monika; Spiljar, Martina; Rückert, Michael; Frey, Benjamin; Fietkau, Rainer; Derer, Anja; Gaipl, Udo (DEGRO - Deutsche Gesellschaft für Radioonkologie e.V., 2017)
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Impact of radiotherapy and chemotherapy on PD-L1 and EGF-R expression in melanoma and glioblastoma cells - Bäumler, Monika; Spiljar, Martina; Frey, Benjamin; Fietkau, Rainer; Gaipl, Udo; Derer, Anja (DEGRO - Deutsche Gesellschaft dür Radioonkologie e.V., 2016)

Impact of radon and combinatory radon/carbon dioxide spa on pain and hypertension: Results from the explorative RAD-ON01 study - Rühle, Paul-Friedrich; Klein, Gerhart; Rung, Tatiana; Phan, Hong Tiep; Fournier, Claudia; Fietkau, Rainer; Gaipl, Udo; Frey, Benjamin (Modern Rheumatology, 2019)
OBJECTIVES: Therapies with low doses of radon have beneficial effects on patients suffering from chronic painful degenerative and inflammatory diseases. We already showed that this is accompanied by systemic immune modulations. We here focus on pain-reducing effects of very low doses of radon by adding carbon dioxide water and its impact on heart rate variability (HRV), blood pressure and free radicals. METHODS: 97 of 103 patients receiving radon spa (1.200 Bq/l at 34 °C or 600 Bq/l, 1 g/l CO2 at 34 °C) were monitored before and at three different time points after therapy. Individual pain perception was analyzed and the capability to process radicals. At each time point, the hypertensive patients (n = 46) were examined over 24 h for blood pressure and HRV. RESULTS: Long-term pain reduction was observed in the majority of patients. A modulation of superoxide dismutase was identified, presumably representing a priming effect for lowering radiation stress. Further, lowering of blood pressure, especially in those patients who additionally received carbon dioxide, was seen. Radon did in particular impact on HRV implying lasting relaxation effects. CONCLUSION: Radon/carbon dioxide spa efficiently reduces pain. In particular, patients simultaneously suffering from painful and cardiovascular diseases should be treated by combination of radon and CO2.
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IMPACT OF RADON SPA ON PAIN AND THE IMMUNE SYSTEM OF PATIENTS WITH MUSCULOSKELETAL DISORDERS - Becker, I.; Donaubauer, Anna-Jasmina; Klein, G.; Fournier, C.; Fietkau, Rainer; Frey, Benjamin; Gaipl, Udo (ANNALS OF THE RHEUMATIC DISEASES, 2019)
CRIS-Team WoS Importer:2019-05-17

Impaired renal function in stroke patients with atrial fibrillation - Sauer, Eva-Maria; Sauer, Rolf; Kallmuenzer, Bernd; Blinzler, Christian; Breuer, Lorenz; Huttner, Hagen; Schwab, Stefan; Köhrmann, Martin (Journal of Stroke and Cerebrovascular Diseases, 2014)
Stroke patients with atrial fibrillation (AF) are prone to have comorbidities such as impaired renal function. Because poly-pharmacotherapy is often required in those patients, renal function is important to consider in light of renally cleared medications such as direct oral anticoagulants. In this study, we analyzed frequency and predictors for impaired renal function and its impact on functional outcome in stroke patients with underlying AF.We analyzed 272 patients with acute ischemic stroke and AF of our prospective, observational stroke database. Estimated glomerular filtration rate (eGFR) was calculated on admission and during hospitalization from the equation of the Modification Diet for Renal Disease. Outcome measures included mortality and functional outcome at 90 days, assessed as modified Rankin Scale (mRS) score.On admission, impaired renal function was found in 41.5% (n = 113) and was associated with worse 90-day outcome (mRS score <= 2: 26.5% versus 45.9%, P = .001) and a higher mortality rate (23.9% versus 14.5%, P = .043). Multivariate logistic regression identified older age and history of myocardial infarction as independent predictors of renal dysfunction on admission (P < .05). Normalization of eGFR during hospitalization was achieved in 55.8%.In patients with acute ischemic stroke and AF, impaired renal function on admission is frequent and associated with worse outcome. Normalization of eGFR can often be achieved during hospitalization, but in everyday life, fluctuations of renal function because of infection or dehydration have to be considered. Careful monitoring of renal status is indispensable and should influence drug treatment decisions.
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Implant-based CT estimation towards adaptive breast brachytherapy - Dürrbeck, Christopher; Pflaum, L.; Schulz, M.; Kallis, Karoline; Geimer, Tobias; Abu-Hossin, N.; Strnad, Vratislav; Maier, Andreas; Fietkau, Rainer; Bert, Christoph (RADIOTHERAPY AND ONCOLOGY, 2021)
CRIS-Team WoS Importer:2021-06-18

Implementation and validation of 2-D-array based tests in routine linac quality assurance - Valenta, Jiří; Schmidt, Manfred; Bert, Christoph (Zeitschrift für Medizinische Physik, 2024)
Purpose: In medical linac quality assurance (QA), to replace film dosimetry with low-resolution 2-D ionization chamber array measurements, to validate the procedures, and to perform a comprehensive sensitivity analysis. Methods: A 2-D ionization chamber array with a spatial resolution of 7.62 mm was deployed to perform the following tests: Junction tests, MLC transmission test, beam profile constancy vs. gantry angle test, beam profile constancy vs. low dose delivery test, and beam energy constancy vs. low dose delivery test. Test validation and sensitivity analyses based on short- and long-term statistics of the test results were performed. Results: All selected mechanical and dosimetry tests could be successfully performed with a 2-D array. Considering the tolerance limits recommended by the AAPM Task Group 142 report (2009), sensitivities of 99.0% or better and specificities ranging from 99.5% to 99.9% could be achieved in all tests when the proper metrics were chosen. Conclusions: The results showed that a low-resolution 2-D ionization chamber array could replace film dosimetry without having to sacrifice high test sensitivity. Its implementation in the routine clinical linac QA program may involve considerable QA time savings.
CRIS-Team Scopus Importer:2024-03-22
Keywords: 2-D array; Linear accelerator quality assurance; Test sensitivity; Test specificity

Implementation of a dedicated 1.5 T MR scanner for radiotherapy treatment planning featuring a novel high-channel coil setup for brain imaging in treatment position - Mengling, Veit; Bert, Christoph; Perrin, Rosalind; Masitho, Siti; Weissmann, Thomas; Mansoorian, Sina; Siavooshhaghighi, Hadi; Janka, Rolf Matthias; Doussin, Sylvain; Habatsch, Melanie; Fietkau, Rainer; Putz, Florian (Strahlentherapie und Onkologie, 2020)
Purpose: To share our experiences in implementing a dedicated magnetic resonance (MR) scanner for radiotherapy (RT) treatment planning using a novel coil setup for brain imaging in treatment position as well as to present developed core protocols with sequences specifically tuned for brain and prostate RT treatment planning. Materials and methods: Our novel setup consists of two large 18-channel flexible coils and a specifically designed wooden mask holder mounted on a flat tabletop overlay, which allows patients to be measured in treatment position with mask immobilization. The signal-to-noise ratio (SNR) of this setup was compared to the vendor-provided flexible coil RT setup and the standard setup for diagnostic radiology. The occurrence of motion artifacts was quantified. To develop magnetic resonance imaging (MRI) protocols, we formulated site- and disease-specific clinical objectives. Results: Our novel setup showed mean SNR of 163 ± 28 anteriorly, 104 ± 23 centrally, and 78 ± 14 posteriorly compared to 84 ± 8 and 102 ± 22 anteriorly, 68 ± 6 and 95 ± 20 centrally, and 56 ± 7 and 119 ± 23 posteriorly for the vendor-provided and diagnostic setup, respectively. All differences were significant (p > 0.05). Image quality of our novel setup was judged suitable for contouring by expert-based assessment. Motion artifacts were found in 8/60 patients in the diagnostic setup, whereas none were found for patients in the RT setup. Site-specific core protocols were designed to minimize distortions while optimizing tissue contrast and 3D resolution according to indication-specific objectives. Conclusion: We present a novel setup for high-quality imaging in treatment position that allows use of several immobilization systems enabling MR-only workflows, which could reduce unnecessary dose and registration inaccuracies.
CRIS-Team Scopus Importer:2020-10-30
Keywords: Immobilization; MR-only treatment planning; Prostate; Simulation; Stereotactic radiosurgery

Implementation of an analytical model for leakage neutron equivalent dose in a proton radiotherapy planning system - Eley, John; Newhauser, Wayne; Homann, Kenneth; Howell, Rebecca; Schneider, Christopher; Durante, Marco; Bert, Christoph (Cancers, 2015)
Equivalent dose from neutrons produced during proton radiotherapy increases the predicted risk of radiogenic late effects. However, out-of-field neutron dose is not taken into account by commercial proton radiotherapy treatment planning systems. The purpose of this study was to demonstrate the feasibility of implementing an analytical model to calculate leakage neutron equivalent dose in a treatment planning system. Passive scattering proton treatment plans were created for a water phantom and for a patient. For both the phantom and patient, the neutron equivalent doses were small but non-negligible and extended far beyond the therapeutic field. The time required for neutron equivalent dose calculation was 1.6 times longer than that required for proton dose calculation, with a total calculation time of less than 1 h on one processor for both treatment plans. Our results demonstrate that it is feasible to predict neutron equivalent dose distributions using an analytical dose algorithm for individual patients with irregular surfaces and internal tissue heterogeneities. Eventually, personalized estimates of neutron equivalent dose to organs far from the treatment field may guide clinicians to create treatment plans that reduce the risk of late effects.
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Implementation of double immune checkpoint blockade increases response rate to induction chemotherapy in head and neck cancer - Semrau, Sabine; Gostian, Antoniu Oreste; Traxdorf, Maximilian; Eckstein, Markus; Rutzner, Sandra; von der Grün, Jens; Illmer, Thomas; Hautmann, Matthias; Klautke, Gunther; Laban, Simon; Brunner, Thomas; Tamaskovics, Bálint; et al. (Cancers, 2021)
To determine whether a single dose of double immune checkpoint blockade (induction chemoimmunotherapy (ICIT)) adds benefit to induction single-cycle platinum doublet (induction chemotherapy (IC)) in locally advanced head and neck squamous cell carcinoma (HNSCC), patients treated with cisplatin 30 mg/m2 d1-3 and docetaxel 75 mg/m2 d1 combined with durvalumab 1500 mg fixed dose d5 and tremelimumab 75 mg fixed dose d5 (ICIT) within the CheckRad-CD8 trial were compared with a retrospective cohort receiving the same chemotherapy (IC) without immunotherapy. The endpoint of this analysis was the complete response rate (CR). A total of 53 patients were treated with ICIT and 104 patients with IC only. CR rates were 60.3% for ICIT and 40.3% for IC (p = 0.018). In the total population (n = 157), the most important predictor to achieve a CR was treatment type (OR: 2.21 for ICIT vs. IC; p = 0.038, multivariate analysis). The most diverse effects in CR rates between ICIT and IC were observed in younger (age ≤ 60) patients with HPV-positive OPSCCs (82% vs. 33%, p = 0.176), while there was no difference in older patients without HPV-positive OPSCCs (53% vs. 48%). The analysis provides initial evidence that ICIT could result in higher CR rates than IC. Young patients with HPV-positive OPSCCs may have the greatest benefit from additional immune checkpoint inhibitors.
CRIS-Team Scopus Importer:2021-04-30
Keywords: Combined modality therapy; Double immune checkpoint inhibition; Head and neck neoplasms; HPV-positive OPSCC; Immunotherapy; Induction therapy; Organ preservation

Implementation of registration quality assurance - Anderle, K.; Brandt, Tobias; Wölfelschneider, Jens; Bert, Christoph; Graeff, C. (2018)
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Implementation of Whole Skin Therapy: Dosimetry, Optimization and FMEA Analysis - Shariff, Maya; Lotter, M.; Stillkrieg, W.; Bert, Christoph (STRAHLENTHERAPIE UND ONKOLOGIE, 2021)
CRIS-Team WoS Importer:2021-07-16

Improved outcome of adult Burkitt lymphoma/leukemia with rituximab and chemotherapy: report of a large prospective multicenter trial - Hoelzer, Dieter; Walewski, Jan; Doehner, Hartmut; Viardot, Andreas; Hiddemann, Wolfgang; Spiekermann, Karsten; Serve, Hubert; Duehrsen, Ulrich; Huettmann, Andreas; Thiel, Eckhard; Dengler, Jolanta; Kneba, Michael; et al. (Blood, 2014)
This largest prospective multicenter trial for adult patients with Burkitt lymphoma/leukemia aimed to prove the efficacy and feasibility of short-intensive chemotherapy combined with the anti-CD20 antibody rituximab. From 2002 to 2011, 363 patients 16 to 85 years old were recruited in 98 centers. Treatment consisted of 6 5-day chemotherapy cycles with high-dose methotrexate, high-dose cytosine arabinoside, cyclophosphamide, etoposide, ifosphamide, corticosteroids, and triple intrathecal therapy. Patients >55 years old received a reduced regimen. Rituximab was given before each cycle and twice as maintenance, for a total of 8 doses. The rate of complete remission was 88% (319/363); overall survival (OS) at 5 years, 80%; and progression-free survival, 71%; with significant difference between adolescents, adults, and elderly patients (OS rate of 90%, 84%, and 62%, respectively). Full treatment could be applied in 86% of the patients. The most important prognostic factors were International Prognostic Index (IPI) score (0-2 vs 3-5; P = .0005), age-adjusted IPI score (0-1 vs 2-3; P = .0001), and gender (male vs female; P = .004). The high cure rate in this prospective trial with a substantial number of participating hospitals demonstrates the efficacy and feasibility of chemoimmunotherapy, even in elderly patients. This trial was registered at www.clinicaltrials.gov as #NCT00199082.
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Improved survival for elderly married glioblastoma patients : Better treatment delivery, less toxicity, and fewer disease complications - Putz, Florian; Putz, Tobias; Goerig, Nicole; Knippen, Stefan; Gryc, Thomas; Eyüpoglu, Ilker Yasin; Roessler, Karl; Semrau, Sabine; Lettmaier, Sebastian; Fietkau, Rainer (Strahlentherapie und Onkologie, 2016)
OBJECTIVES: Marital status is a well-described prognostic factor in patients with gliomas but the observed survival difference is unexplained in the available population-based studies. METHODS: A series of 57 elderly glioblastoma patients (≥70 years) were analyzed retrospectively. Patients received radiotherapy or chemoradiation with temozolomide. The prognostic significance of marital status was assessed. Disease complications, toxicity, and treatment delivery were evaluated in detail. RESULTS: Overall survival was significantly higher in married than in unmarried patients (median, 7.9 vs. 4.0 months; p = 0.006). The prognostic significance of marital status was preserved in the multivariate analysis (HR, 0.41; p = 0.011). Married patients could receive significantly higher daily temozolomide doses (mean, 53.7 mg/m² vs. 33.1 mg/m²; p = 0.020), were more likely to receive maintenance temozolomide (45.7 % vs. 11.8 %; p = 0.016), and had to be hospitalized less frequently during radiotherapy (55.0 % vs. 88.2 %; p = 0.016). Of the patients receiving temozolomide, married patients showed significantly lower rates of hematologic and liver toxicity. Most complications were infectious or neurologic in nature. Complications of any grade were more frequent in unmarried patients (58.8 % vs. 30.0 %; p = 0.041) with the incidence of grade 3-5 complications being particularly elevated (47.1 % vs. 15.0 %; p = 0.004). CONCLUSION: We found poorer treatment delivery as well as an unexpected severe increase in toxicity and disease complications in elderly unmarried glioblastoma patients. Marital status may be an important predictive factor for clinical decision-making and should be addressed in further studies.
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Improvement of albuminuria after renal denervation - Ott, Christian; Mahfoud, Felix; Schmid, Axel; Ditting, Tilmann; Veelken, Roland; Ewen, Sebastian; Ukena, Christian; Uder, Michael; Boehm, Michael; Schmieder, Roland (International Journal of Cardiology, 2014)
The primary objective of this study was the effect of renal denervation (RDN) on elevated urinary albumin-to-creatinine ratio (UACR) in treatment-resistant hypertensive patients. In addition, patients were stratified according their UACR at baseline into micro- (30-300 mg/g, n=37) and macroalbuminuria (>= 300 mg/g, <2,200 mg/g, n=22).Increased albuminuria indicates cardiovascular and renal damage in hypertension. RDN emerged as an innovative interventional approach to reduce blood pressure (BP) and may thus reduce albumin urinary excretion.Fifty-nine treatment-resistant hypertensive patients with elevated UACR at baseline underwent catheter-based RDN using the Symplicity Flex(TM) catheter (Medtronic Inc., Santa Rosa, CA).In the whole and pre-specified subgroups both office and 24-h ambulatory BP were significantly reduced 6 months after RDN. In parallel, a significant reduction in UACR occurred in all patients (160 (65-496) versus 89 (29-319) mg/g creatinine, p<0.001) and in both subgroups (microalbuminuria: 83 (49-153) versus 58 (17-113) mg/g creatinine, p=0.001; macroalbuminuria: (536 (434-1483) versus 478 (109-1080) mg/g creatinine, p<0.001). In accordance, the prevalence of micro- and macroalbuminuria decreased significantly. Regression analysis revealed a modest positive relationship between the decrease of UACR and the fall of systolic BP (?=0.340, p=0.039) independent of renal function. Renal function remained unchanged after RDN.In summary, following RDN, the magnitude of albuminuria as well as the prevalence of micro- and macroalbuminuria decreased in treatment-resistant hypertensive patients. Since albuminuria is an independent renal and cardiovascular risk factor, our findings suggest a reduction of renal and cardiovascular risk in these patients.
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Improvement of Deep Learning-based Auto-detection of Brain Metastases by Integrating previous MRI Images - Dörfler, Arnd; Huang, Yixing; Bert, Christoph; Sommer, Philipp; Frey, Benjamin; Gaipl, Udo; Distel, Luitpold; Weissmann, Thomas; Uder, Michael; Schmidt, Manuel; Maier, Andreas; Fietkau, Rainer; et al. (STRAHLENTHERAPIE UND ONKOLOGIE, 2022)
CRIS-Team WoS Importer:2022-06-03

Improving diagnostic accuracy in assessing pulmonary edema on bedside chest radiographs using a standardized scoring approach - Hammon, Matthias; Dankerl, Peter; Voit-Hoehne, Heinz Leonhard; Sandmair, Martin; Kammerer, Ferdinand Josef; Uder, Michael; Janka, Rolf Matthias (BMC Anesthesiology, 2014)
To assess the value of a score-based system which allows standardized evaluation of pulmonary edema on bedside chest radiographs (CXRs) under routine clinical conditions.Seven experienced readers assessed bedside CXRs of ten patients with an extravascular lung water (EVLW)-value of <= 8 mL/kg (range: 4-8 mL/kg; indicates no pulmonary edema) and a series of ten patients with an EVLW-value of >= 15 mL/kg (range: 15-21 mL/kg; = indicates a pulmonary edema) with and without customized software which would permit a standardized assessment of the various indications of pulmonary edema. The software provides a score that identifies patients with and without pulmonary edema. EVLW-values were measured instantly after bedside CXR imaging using a pulse contour cardiac output (PiCCO) system and served as a reference standard. The patients were non-traumatic and not treated with diuretics or dobutamine during bedside CXR imaging and the PiCCO measurements. Mean sensitivity, specificity, positive and negative predictive value, the percentage of overall agreement and the free-marginal multirater kappa value was calculated for both the standard and the standardized score-based approach. The net reclassification index was calculated for each reader as well as for all readers.Evaluation of bedside CXRs by means of the score-based approach took longer (23 ± 12 seconds versus 7 ± 3 seconds without the use of the software) but improved radiologists' sensitivity (from 57 to 77%), specificity (from 90 to 100%) and the free-marginal multirater kappa value (from 0.34 to 0.68). The positive predictive value was raised from 85 to 100% and the negative predictive value from 68 to 81%. A net reclassification index of 0.3 (all readers) demonstrates an improvement in prediction performance gained by the score-based approach. The percentage of overall agreement was 67% with the standard approach and 84% with the software-based approach.The diagnostic accuracy of bedside CXRs to discriminate patients with elevated EVLW-values from those with a normal value can be improved with the use of a standardized score-based approach. The investigated system is freely available as a web-based application (accessible via: http://www.radiologie.uk-erlangen.de/aerzte-und-zuweiser/edema).
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Inactivation of tankyrases reduces experimental fibrosis by inhibiting canonical Wnt signalling - Akhmetshina, Alfiya; Deloch, Lisa; Huang, Jingang; Dees, Clara; Lin, Neng-Yu; Palumbo-Zerr, Katrin; Beyer, Christian; Weidemann, Alexander; Distler, Oliver; Schett, Georg; Distler, Jörg (Annals of the Rheumatic Diseases, 2013)

Increased growth-inhibitory and cytotoxic activity of arsenic trioxide in head and neck carcinoma cells with functional p53 deficiency and resistance to EGFR blockade - Boyko-Fabian, Mariya; Niehr, Franziska; Distel, Luitpold; Budach, Volker; Tinhofer, Ingeborg (PLoS ONE, 2014)
Mutations in the p53 gene are frequently observed in squamous cell carcinoma of the head and neck region (SCCHN) and have been associated with drug resistance. The potential of arsenic trioxide (ATO) for treatment of p53-deficient tumor cells and those with acquired resistance to cisplatin and cetuximab was determined.In a panel of 10 SCCHN cell lines expressing either wildtype p53, mutated p53 or which lacked p53 by deletion the interference of p53 deficiency with the growth-inhibitory and radiosensitizing potential of ATO was determined. The causal relationship between p53 deficiency and ATO sensitivity was evaluated by reconstitution of wildtype p53 in p53-deficient SCCHN cells. Interference of ATO treatment with cell cycle, DNA repair and apoptosis and its efficacy in cells with acquired resistance to cisplatin and cetuximab was evaluated.Functional rather than structural defects in the p53 gene predisposed tumor cells to increased sensitivity to ATO. Reconstitution of wt p53 in p53-deficient SCCHN cells rendered them less sensitive to ATO treatment. Combination of ATO with irradiation inhibited clonogenic growth in an additive manner. The inhibitory effect of ATO in p53-deficient tumor cells was mainly associated with DNA damage, G2/M arrest, upregulation of TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) receptors and apoptosis. Increased activity of ATO was observed in cetuximab-resistant SCCHN cells whereas cisplatin resistance was associated with cross-resistance to ATO.Addition of ATO to treatment regimens for p53-deficient SCCHN and tumor recurrence after cetuximab-containing regimens might represent an attractive strategy in SCCHN.
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Increased malignancy of oral squamous cell carcinomas (oscc) is associated with macrophage polarization in regional lymph nodes - an immunohistochemical study - Wehrhan, Falk; Buettner-Herold, Maike; Hyckel, Peter; Moebius, Patrick; Preidl, Raimund; Distel, Luitpold; Ries, Jutta; Amann, Kerstin Ute; Schmitt, Christian; Neukam, Friedrich Wilhelm; Weber, Manuel (BMC Cancer, 2014)
It is largely accepted that specific immunological parameters in solid malignancies are associated with patient's prognosis. Recently a correlation of macrophage polarization with histomorphological parameters could also be shown in oral squamous cell carcinoma (oscc). The observed tumor derived peripheral immune tolerance could be associated with the macrophage polarization in regional tumor draining lymph nodes.So far there are no studies analyzing the macrophage polarization in cervical lymph nodes of oscc patients. In the present study we aimed to correlate macrophage polarization in different anatomical lymph node compartments of patients diagnosed with oscc with histopathologic parameters of the primary tumor (T-, N-, L-, V-, Pn-status, grading).Tumor free (n = 37) and metastatic (n = 17) lymph nodes of T1 and T2 oscc patients were processed for immunohistochemistry to detect CD68, CD11c, CD163 and MRC1 positive cells. Samples were digitized using whole slide imaging and the number of cells expressing the aforementioned markers in the region of interest quantitatively analyzed.The malignancy of the primary tumor (defined by T-, L-, Pn-status, grading) correlated with the lymph node macrophage polarization. L1 and Pn1 tumor cases displayed a significantly (p < 0.05) decreased M1 and increased M2 polarization in the sinus of the lymph nodes. G3 cases presented a significantly (p < 0.05) increased M2 polarization in the sinus compared to G2 cases. T2 tumors had significantly (p < 0.05) increased M2 polarization in the interfollicular zone of regional lymph nodes compared to T1 tumors. Metastatic and non-metastatic lymph nodes did not differ regarding their macrophage polarization.The current study revealed for the first time an influence of oscc on the macrophage polarization in regional lymph nodes. Markers of malignant behavior in the primary tumor were associated with a shift of macrophage polarization in lymph nodes from the anti-tumoral M1 type to the tumor-promoting M2 type. As tumor free and metastatic lymph nodes did not differ in terms of their macrophage polarization pattern, there must be other factors influencing the location for lymph node metastasis formation.
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Increased Radiation Sensitivity in Patients with Phelan-McDermid Syndrome - Jesse, Sarah; Kuhlmann, Lukas; Hildebrand, Laura; Magelssen, Henriette; Schmaus, Martina; Timmermann, Beate; Andres, Stephanie; Fietkau, Rainer; Distel, Luitpold (Cells, 2023)
Phelan-McDermid syndrome is an inherited global developmental disorder commonly associated with autism spectrum disorder. Due to a significantly increased radiosensitivity, measured before the start of radiotherapy of a rhabdoid tumor in a child with Phelan-McDermid syndrome, the question arose whether other patients with this syndrome also have increased radiosensitivity. For this purpose, the radiation sensitivity of blood lymphocytes after irradiation with 2Gray was examined using the G0 three-color fluorescence in situ hybridization assay in a cohort of 20 patients with Phelan-McDermid syndrome from blood samples. The results were compared to healthy volunteers, breast cancer patients and rectal cancer patients. Independent of age and gender, all but two patients with Phelan-McDermid syndrome showed significantly increased radiosensitivity, with an average of 0.653 breaks per metaphase. These results correlated neither with the individual genetic findings nor with the individual clinical course, nor with the respective clinical severity of the disease. In our pilot study, we saw a significantly increased radiosensitivity in lymphocytes from patients with Phelan-McDermid syndrome, so pronounced that a dose reduction would be recommended if radiotherapy had to be performed. Ultimately, the question arises as to the interpretation of these data. There does not appear to be an increased risk of tumors in these patients, since tumors are rare overall. The question, therefore, arose as to whether our results could possibly be the basis for processes, such as aging/preaging, or, in this context, neurodegeneration. There are no data on this so far, but this issue should be pursued in further fundamentally based studies in order to better understand the pathophysiology of the syndrome.
CRIS-Team Scopus Importer:2023-03-24
Keywords: atypical teratoid rhabdoid tumor; chromosomal aberrations; Phelan McDermid syndrome; radiation sensitivity; SHANK3 deficiency

Increased skin and mucosal toxicity in the combination of vemurafenib with radiation therapy - Merten, Ricarda; Hecht, Markus; Haderlein, Marlen; Distel, Luitpold; Fietkau, Rainer; Heinzerling, Lucie; Semrau, Sabine (Strahlentherapie und Onkologie, 2014)
Palliative radiotherapy is often required for patients with metastatic malignant melanoma in the case of bone or brain metastases. Since BRAF inhibitor therapy is highly efficient in V600-mutated melanomas, there is hesitation to stop it during radiotherapy. Consequently, radiotherapy under simultaneous vemurafenib treatment is frequently needed.We report the case of a patient receiving palliative radiotherapy of spinal bone metastases before and during vemurafenib therapy. The skin reactions were quantitatively scored using computer-assisted digital image evaluation.Radiotherapy without vemurafenib was tolerated very well, whereas radiotherapy under simultaneous vemurafenib treatment resulted in accentuated skin reactions. Furthermore, the patient developed dysphagia and had to be hospitalized for parenteral nutrition. In the quantitative analysis, there was a twofold increase in pigmentation and erythema of the irradiated skin area of the thoracic spine when vemurafenib was combined with radiotherapy compared with radiotherapy treatment alone. This is the first reported case of a patient showing no complications during radiotherapy without vemurafenib but remarkable skin and mucosal toxicity under concurrent vemurafenib therapy. Thus, a genetically conditioned individually elevated radiosensitivity can definitely be excluded. Compared with other reported cases, radiosensitization was not limited to the skin, but also affected the esophageal mucosa.Vemurafenib is a strong radiosensitizer. Patients receiving radiotherapy under simultaneous vemurafenib treatment should be monitored very closely.
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Increase in non-professional phagocytosis during the progression of cell cycle - Hofmann, Alexander; Putz, Florian; Büttner-Herold, Maike; Hecht, Markus; Fietkau, Rainer; Distel, Luitpold (PLoS ONE, 2021)
Homotypic or heterotypic internalization of another, either living or necrotic cell is currently in the center of research interest. The active invasion of a living cell called entosis and cannibalism of cells by rapidly proliferating cancers are prominent examples. Additionally, normal healthy tissue cells are capable of non-professional phagocytosis. This project studied the relationship between non-professional phagocytosis, individual proliferation and cell cycle progression. Three mesenchymal and two epithelial normal tissue cell lines were studied for homotypic non-professional phagocytosis. Homotypic dead cells were co-incubated with adherent growing living cell layers. Living cells were synchronized by mitotic shake-off as well as Aphidicolin-treatment and phagocytotic activity was analyzed by immunostaining. Cell cycle phases were evaluated by flow cytometry. Mesenchymal and epithelial normal tissue cells were capable of internalizing dead cells. Epithelial cells had much higher non-professional phagocytotic rates than mesenchymal cells. Cells throughout the entire cell cycle were able to phagocytose. The phagocytotic rate significantly increased with progressing cell cycle phases. Mitotic cells regularly phagocytosed dead cells, this was verified by Nocodazole and Colcemid treatment. Taken together, our findings indicate the ability of human tissue cells to phagocytose necrotic neighboring cells in confluent cell layers. The origin of the cell line influences the rate of cell-in-cell structure formation. The higher cell-in-cell structure rates during cell cycle progression might be influenced by cytoskeletal reorganization during this period or indicate an evolutionary anchorage of the process. Recycling of nutrients during cell growth might also be an explanation. ?2021 Hofmann 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.
CRIS-Team Scopus Importer:2021-02-19

Individualization of post-mastectomy radiotherapy and regional nodal irradiation based on treatment response after neoadjuvant chemotherapy for breast cancer : A systematic review - Krug, David; Baumann, Rene; Budach, Wilfried; Dunst, Juergen; Feyer, Petra; Fietkau, Rainer; Haase, Wulf; Harms, Wolfgang; Hehr, Thomas; Piroth, Marc D.; Sedlmayer, Felix; Souchon, Rainer; et al. (Strahlentherapie und Onkologie, 2018)
PURPOSE: To review the evidence regarding post-mastectomy radiotherapy (PMRT) and regional nodal irradiation (RNI) after neoadjuvant chemotherapy (NACT) for breast cancer, with a special focus on individualization of adjuvant radiotherapy based on treatment response. METHODS: A systematic literature search using the PubMed/Medline database was performed. We included prospective and retrospective reports with a minimum of 10 patients that had been published since 1st January 2000, and provided clinical outcome data analyzed by treatment response and radiotherapy. RESULTS: Out of 763 articles identified via PubMed/Medline and hand search, 68 full text-articles were assessed for eligibility after screening of title and abstract. 13 studies were included in the systematic review, 9 for PMRT and 5 for RNI. All included studies were retrospective reports. CONCLUSIONS: There is a considerable lack of evidence regarding the role of adjuvant radiotherapy and its individualization based on treatment response after NACT. Results of prospective randomized trials such as NSABP B‑51/RTOG 1304 and Alliance A11202 are eagerly awaited.
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Individual Radiation Sensitivity of Tumor Patients with Rheumatoid Arthritis - Rzepka, Dinah; Schuster, Barbara; Geinitz, H.; Fietkau, Rainer; Distel, Luitpold (STRAHLENTHERAPIE UND ONKOLOGIE, 2021)
CRIS-Team WoS Importer:2021-07-16

Induction chemoimmunotherapy followed by CD8+ immune cell-based patient selection for chemotherapy-free radioimmunotherapy in locally advanced head and neck cancer - Hecht, Markus; Eckstein, Markus; Rutzner, Sandra; Von Der Grun, Jens; Illmer, Thomas; Klautke, Gunther; Laban, Simon; Hautmann, Matthias G.; Brunner, Thomas B.; Tamaskovics, Balint; Hinke, Axel; Zhou, Jianguo; et al. (Journal for ImmunoTherapy of Cancer, 2022)
Purpose The first aim of the trial is to study feasibility of combined programmed death protein ligand 1/cytotoxic T-lymphocyte-associated protein 4 inhibition concomitant to radiotherapy. In addition, efficacy of the entire treatment scheme consisting of induction chemoimmunotherapy followed by chemotherapy-free radioimmunotherapy (RIT) after intratumoral CD8 +immune cell-based patient selection will be analyzed. Methods Patients with stage III-IVB head and neck squamous cell carcinoma were eligible for this multicenter phase II trial. Treatment consisted of a single cycle of cisplatin 30 mg/m² days 1-3, docetaxel 75 mg/m² day 1, durvalumab 1500 mg fix dose day 5 and tremelimumab 75 mg fix dose day 5. Patients with increased intratumoral CD8 +immune cell density or pathological complete response (pCR) in the rebiopsy entered RIT up to a total dose of 70 Gy. Patients received further three cycles of durvalumab/tremelimumab followed by eight cycles of durvalumab mono (every 4 weeks). The intended treatment for patients not meeting these criteria was standard radiochemotherapy outside the trial. Primary endpoint was a feasibility rate of patients entering RIT to receive treatment until at least cycle 6 of immunotherapy of ≥80%. Results Between September 2018 and May 2020, 80 patients were enrolled (one excluded). Out of these, 23 patients had human papilloma virus (HPV)-positive oropharyngeal cancer. Median follow-up was 17.2 months. After induction chemoimmunotherapy 41 patients had pCR and 31 had increased intratumoral CD8 +immune cells. Of 60 patients entering RIT (primary endpoint cohort), 10 experienced imiting toxic (mainly hepatitis) and four discontinued for other reasons, resulting in a feasibility rate of 82%. The RIT cohort (n=60) had a progression-free survival (PFS) rate at one and 2 years of 78% and 72%, respectively, and an overall survival rate at one and 2 years of 90% and 84%, respectively. Patients with HPV-positive oropharyngeal cancers had greater benefit from RIT with a 2-year PFS rate of 94% compared with 64% for HPV-negative oropharyngeal cancers and other locations. In the entire study cohort (n=79) the 2-year PFS rate was 68% (91% for HPV-positive oropharynx vs 59% for others). Toxicity grade 3-4 mainly consisted of dysphagia (53%), leukopenia (52%) and infections (32%). Conclusions The trial met the primary endpoint feasibility of RIT. Induction chemo-immunotherapy followed by chemotherapy-free RIT after intratumoral CD8 +immune cell-based patient selection has promising PFS. Trial registration number The trial was registered with ClinicalTrials.gov (identifier: NCT03426657). The trial was conducted as investigator-sponsored trial (IST).
CRIS-Team Scopus Importer:2022-02-11
Keywords: radioimmunotherapy

Induction of Senescence in Head and Neck Tumor Cells by Combination of Irradiation and DNA Repair Inhibitors - Dobler, Clara; Jost, Tina; Hecht, Markus; Fietkau, Rainer; Distel, Luitpold (STRAHLENTHERAPIE UND ONKOLOGIE, 2020)
CRIS-Team WoS Importer:2020-10-02

Inflammatory cells infiltrating HPV positive and negative head and neck squamous cell carcinoma - Distel, Luitpold; Farhoumand, D.; Haderlein, Marlen; Fietkau, Rainer (2018)
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Inflammatory Cells in HPV positive and negative Head and Neck Tumors - Distel, Luitpold; Haderlein, Marlen; Farhoumand, D.; Fietkau, Rainer; Hecht, Markus (2018)
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Influence and compensation of patient motion in electromagnetic tracking based quality assurance in interstitial brachytherapy of the breast - Dürrbeck, Christopher; Gulde, Sarah; Abu-Hossin, Nadin; Fietkau, Rainer; Strnad, Vratislav; Bert, Christoph (Medical Physics, 2022)
Purpose: Electromagnetic tracking (EMT) is a versatile and viable technique for various quality assurance (QA) tasks in interstitial brachytherapy (iBT). As the duration of EMT measurements in iBT is on the order of minutes, they can be strongly affected by patient motion, especially breathing, which gives rise to motion artefacts. Since the centrepiece of EMT-related QA in iBT is to assess the geometry of the iBT implant or applicator, the absence of adequate motion compensation techniques could impede the use of EMT for QA purposes. A common way to compensate for this is to reference the data to either external or internal reference sensors (ERS, IRS) which are fixated on the patient's body or inside the applicator and therefore move with the patient. The purpose of the presented study is to provide a quantitative and in-depth analysis on the use of reference sensors for motion compensation. Methods: First, the need for adequate motion compensation is identified both qualitatively and quantitatively using a phantom subjected to simulated breathing motion. An evaluation routine is developed to assess the influence of motion compensation using reference sensors on the acquired EMT data. The evaluation metric is based on the observed displacement of the EMT sensor from its mean position while dwelling at a dwell position (DP) for a dwell time of 1 s. After that, the routine is applied to a cohort of 54 breast cancer patients treated with iBT, and the quality of an ERS based compensation approach is assessed. In a subgroup of four patients, an IRS is inserted into the iBT implant and IRS-based compensation is compared to the ERS-based approach. Moreover, a correlation analysis of the ERS and IRS approach is performed, also including respiratory signals derived from the trajectories of the different reference sensors. Results: It was found that motion compensation with ERS effectively reduced the mean sensor displacement per DP to median values as low as 0.11 mm in both phantom and patient measurements, which is below the precision of the EMT system (0.48 mm). Compensation using the IRS yielded comparable results and was as good as compensation with ERS. The results obtained from both approaches showed a strong correlation. Also the respiratory signals calculated from the different reference sensors were well correlated in most cases. Conclusion: These results indicate that motion compensation with ERS can effectively remove motion artefacts in EMT data. While compensation with an IRS leads to comparable results, the IRS occupies one catheter whose geometry hence cannot be assessed. The use of ERS has proven to be both effective and practical in clinical routine.
CRIS-Team Scopus Importer:2022-03-04
Keywords: breast cancer; breathing motion; electromagnetic tracking; interstitial brachytherapy; quality assurance

Influence and mechanistic principles of radio(chemo) therapy on PD-L1 and EGF-R expression on melanoma and glioblastoma cells - Baeumler, M.; Spiljar, M.; Frey, Benjamin; Fietkau, Rainer; Gaipl, Udo; Derer, Anja (DEGRO - Deutsche Gesellschaft für Radioonkologie e.V., 2017)
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Influence of alectinib and crizotinib on ionizing radiation - in vitro analysis of ALK/ROS1-wildtype lung tissue cells - Jost, Tina; Schultz, Ann Kristin; Frey, Benjamin; Vu, Jennifer; Fietkau, Rainer; Distel, Luitpold; Hecht, Markus (Neoplasia, 2022)
(1) Background: Just little is known about the interaction of ALK/ROS1-targeting kinase inhibitors with ionizing radiation (IR), particularly regarding side effects. We investigated the toxicity in two different lung cell lines both ALK/ROS1 wildtype (healthy and tumor origin) as representatives for normal lung tissue; (2) Methods: Human lung cell line BEAS-2B and malignant A549 lung cancer cells (ALK/ROS1 wt) were treated with alectinib or crizotinib, 2 Gy irradiation or a combination of KI and IR. Cell toxicity was analyzed by cell death (Annexin, 7AAD), colony forming, migration assay and live-cell imaging (TMRM, DRAQ7, Caspase3/7). Cell cycle (Hoechst) were analyzed by flow cytometry; (3) Results: Crizotinib led to higher cell death rates than alectinib, when cells were treated with 10 µM KI. Alectinib induced a more intense growth inhibition of colonies. Both inhibitors showed additive effects in combination with irradiation. Combination treatment (IR + KI) does not lead to synergistic effect on neither cell death nor colony forming; (4) Conclusions: The influence of simultaneous KI and IR was studied in non-mutated ALK/ROS1 cell lines. Both KIs seems to be well tolerated in combination with thoracic radiotherapy and lacked synergistic reinforcement in cellular toxicity. This supports the feasibility of ALK/ROS1 inhibition in combination with thoracic irradiation in future clinical trials.
CRIS-Team Scopus Importer:2022-03-18
Keywords: Alectinib; Crizotinib; Lung cells; Normal tissue; Radiotherapy; Side effects

Influence of CDK4/6 Inhibitors and Ionizing Radiation on Senescence in Breast Cancer Cells - Quarz, L.; Jost, Tina; Fietkau, Rainer; Distel, Luitpold (STRAHLENTHERAPIE UND ONKOLOGIE, 2021)
CRIS-Team WoS Importer:2021-07-16

Influence of CT metal artifact reduction on SPECT/CT quantification of bone scintigraphy - Retrospective study for selected types of metal implants - Kugler, Amelie; Kuwert, Torsten; Ritt, Philipp; Grings, Andreas (Nuklearmedizin-Nuclear Medicine, 2022)
Aim Implanted metal prostheses can cause severe artifacts in reconstructed computed tomography (CT) images. To reduce the diagnostic impact of these artifacts and improve attenuation correction in single photon emission computed tomography (SPECT), an algorithm of iterative metal artifact reduction (iMAR) for SPECT/CT systems was developed. The aims of this study were (a) to assess the difference in visual image quality by comparing CT and SPECT images reconstructed with and without iMAR and (b) to determine the influence of iMAR on quantitative (99m) Tc-uptake in SPECT/CT. Methods This retrospective study includes 21 patients with implanted metal prostheses who underwent SPECT/CT bone scintigraphy. CT data were reconstructed with iMAR and without (noMAR) and were used for attenuation correction of SPECT data for xSPECT Quant and xSPECT Bone reconstruction. The effect of iMAR on image quality was evaluated by visual analysis and the effect on quantitative SPECT/CT was assessed by measuring HU values and absolute uptake values (kBq/mL) in volumes of interest (VOIs). Results There was a significant reduction of visible metal artifacts with iMAR (p<0.01) in the CT images, but visual differences in the SPECT images were minor. The values of quantitative tracer uptake in VOIs near metal implants were lower for iMAR vs. noMAR xSPECT Quant (p<0.01). Only VOIs near metal showed significant differences in HU values, which were 14.6% lower for iMAR CT (p<0.01). Conclusion The use of iMAR reduces metal artifacts in CT and improves the perceived image quality. Although in some cases a significant difference in the quantitative evaluation of SPECT/CT was observed, the influence of iMAR can be considered small in relation to other factors in the clinical setting.
CRIS-Team WoS Importer:2022-08-19

Influence of ex vivo Hyperthermia caused by Warm Water or Microwave Irradiation in a Circulatory System and/or Irradiation on the immunogenic Potential of B16 Melanoma and MCF-7 / MDA-MB-231 Breast Cancer Cells - Hader, Michael; Savcigil, D. P.; Rosin, A.; Gekle, S.; Wadepohl, M.; Fietkau, Rainer; Frey, Benjamin; Gaipl, Udo (STRAHLENTHERAPIE UND ONKOLOGIE, 2020)
CRIS-Team WoS Importer:2020-10-02

Influence of fractional Radio(chemo)therapy on the Expression Patterns of immunocheckpoint Molecules on Glioblastoma Cell Lines - Ladinig, A.; Schatz, Johannes; Fischer, R.; Fietkau, Rainer; Frey, Benjamin; Gaipl, Udo; Derer, Anja (STRAHLENTHERAPIE UND ONKOLOGIE, 2020)
CRIS-Team WoS Importer:2020-10-02

Influence of gender on radiosensitivity during radiochemotherapy of advanced rectal cancer - Schuster, Barbara; Hecht, Markus; Schmidt, Manfred; Haderlein, Marlen; Jost, Tina; Büttner-Herold, Maike; Weber, Klaus; Denz, Axel; Grützmann, Robert; Hartmann, Arndt; Geinitz, Hans; Fietkau, Rainer; et al. (Cancers, 2022)
Gender is increasingly recognized as an important factor in medicine, although it has long been neglected in medical research in many areas. We have studied the influence of gender in advanced rectal cancer with a special focus on radiosensitivity. For this purpose, we studied a cohort of 495 men (84.1% ≥ T3, 63.6% N1, 17.6%, M1) and 215 women (84.2% ≥ T3, 56.7% N1, 22.8%, M1) who all suffered from advanced rectal cancer and were treated with radiochemotherapy. The energy deposited, DNA double-strand break (dsb) repair, occurrence of chromosomal aberrations, duration of therapy, tumor regression and tumor-infiltrating lymphocytes, laboratory parameters, quality of life and survival were assessed. The residual DNA dsb damage 24 h after irradiation in lymphocytes was identical in both sexes. Furthermore, chromosomal aberrations accurately reflecting radiosensitivity, were similar in both sexes. There were no gender-dependent differences in tumor regression, tumor-infiltrating lymphocytes and outcome indicating no differences in the radiosensitivity of cancer cells. The irradiated tumor volume in women was slightly lower than in men, related to body weight, no difference was observed. However, when the total energy deposited was calculated and related to the body weight, women were exposed to higher amounts of ionizing radiation. During radiochemotherapy, decreases in blood lymphocyte counts and albumin and several quality-of-life parameters such as nausea and vomiting, loss of appetite, and diarrhea were significantly worse in women. There is no difference in radiation sensitivity between men and women in both normal tissue and tumors. During radiochemotherapy, the quality of life deteriorates more in women than in men. However, women also recover quickly and there are no long-term differences in quality of life.
CRIS-Team Scopus Importer:2022-01-07
Keywords: Blood values; Deposited energy; DNA double-strand breaks; Gender; Quality of life; Radiochemotherapy; Radiosensitivity; Radiosensitivity; Rectal cancer

Influence of marital status on overall survival in patients with ovarian serous carcinoma: Finding from the surveillance epidemiology and end results (SEER) database - Luo, Pei; Zhou, Jianguo; Jin, Su Han; Qing, Ming Song; Ma, Hu (Journal of Ovarian Research, 2019)
Objective: This study is to investigate the relationship between marital status and prognosis of patients with ovarian serous carcinoma. Results: We performed data analysis from 19,276 patients identified from the SEER database of the National Cancer Center of the United States. 57.8% of the patients were married, 13.0% unmarried, and 29.2% separated/ divorced/widowed (SDW). The median overall survival time ofthe unmarried group and the married group are 48 months and 52 months respectively. Univariate Cox regression analysis showed that the patients with serous ovarian cancer in the unmarried group resulted in a hazard ratio (HR) of 1.14 (95% CI: 1.08-1.19%; P < 0.001), comparing to SDW group with a HR of 1.02 (95% CI: 0.98-1.19%; P = 0.26). However, the SDW group was not statistically significantly different from the married group. (median 32 vs 52 months). Multivariate Cox regression analysis presented the unmarried group leading to a HR of 1.05 (95% CI: 1.00-1.11%; P = 0.05), and the SDW group was not significant with a HR of 0.99 (95% CI: 0.95-1.03%; P = 0.57). Conclusion: Unmarried patients with ovarian serous carcinoma have higherHRof overall survival. After controlling age, race, grade, radiation and year of diagnosis, unmarried patients were found to have a significantly higher risk of OS. Consequently, these patients are suggested to obtain more focused healthcare for the management of ovarian serous carcinoma.
CRIS-Team Scopus Importer:2020-02-21
Keywords: Marital status; Ovarian serous carcinoma; Overall survival; SEER

Influence of MRI Distortion Correction on the local Control of stereotactically irradiated Brain Metastases - Putz, Florian; Siavooshhaghighi, Hadi; Grigo, Johanna; Masitho, Siti; Huang, Yixing; Weissmann, Thomas; Mansoorian, Sina; Schmidt, Manfred; Semrau, Sabine; Bert, Christoph; Fietkau, Rainer (STRAHLENTHERAPIE UND ONKOLOGIE, 2022)
CRIS-Team WoS Importer:2022-06-03

Influence of neoadjuvant Radiation Therapy on the Quality of Life in Patients with advanced Rectal Cancer over a Period of 5 Years - Sörgel, Celena; Fietkau, Rainer; Distel, Luitpold (STRAHLENTHERAPIE UND ONKOLOGIE, 2020)
CRIS-Team WoS Importer:2020-10-02

Influence of p16 status on indication and outcome of salvage neck dissection in oropharyngeal cancer - Mueller, Sarina K.; Mantsopoulos, Konstantinos; Semrau, Sabine; Agaimy, Abbas; Eckstein, Markus; Traxdorf, Maximilian; Gostian, Antoniu Oreste; Goncalves, Miguel; Sievert, Matti; Haderlein, Marlen; Grundtner, Philipp; Hecht, Markus; et al. (Acta Oto-Laryngologica, 2020)
Background: Human papillomavirus (HPV)+ and HPV– oropharyngeal squamous cell carcinomas (OPSCC) are separate tumor entities. Aims/Objectives: The aim of this study was to examine if the p16 status influences the need and outcome of a salvage neck dissection (SND) after primary radiochemotherapy (pRCT). Material and methods: Retrospective study of 164 patients (n = 108 p16–, n = 56 p16+) who underwent pRCT for OPSCC between 2009 and 2016. HPV status was defined via p16 immunohistochemical staining. Clinical nodal status was assessed using ultrasound and computed tomography of the neck with contrast. Results: Of the 56 p16+ patients, 17 (30.4%) patients were given an indication for a SND after pRCT with 4 (23.5%) patients showing persistent malignant nodes. Of the 108 p16– patients, 24 (22.2%) patients underwent a SND with 8 (33.3%) patients showing persistent malignant nodes. There was no significant association of the p16 status and neither the indication for SND (p(Chi2(two-sided)-Test) = 0.25, ϕ = 0.34) nor the occurrence of positive nodes (p(Chi2(two-sided)-Test) = 0.74, ϕ = 0.50). The probability for persistence of the ypN + nodal status independent of HPV-status was 29.2%(12/41). Conclusions and significance: There was neither a significant association between the p16 status and the indication for a SND nor for persistent malignant nodal disease after pRCT.
CRIS-Team Scopus Importer:2020-11-06
Keywords: de-escalation; HPV; Oropharyngeal cancer; p16; radiochemotherapy

Influence of patient mispositioning on SAR distribution and simulated temperature in regional deep hyperthermia - Aklan, Bassim; Gierse, Pia; Hartmann, Josefin; Ott, Oliver J.; Fietkau, Rainer; Bert, Christoph (Physics in Medicine and Biology, 2017)
Patient positioning plays an important role in regional deep hyperthermia to obtain a successful hyperthermia treatment. In this study, the influence of possible patient mispositioning was systematically assessed on specific absorption rate (SAR) and temperature distribution. With a finite difference time domain approach, the SAR and temperature distributions were predicted for six patients at 312 positions. Patient displacements and rotations as well as the combination of both were considered inside the Sigma-Eye applicator. Position sensitivity is assessed for hyperthermia treatment planning -guided steering, which relies on model-based optimization of the SAR and temperature distribution. The evaluation of the patient mispositioning was done with and without optimization. The evaluation without optimization was made by creating a treatment plan for the patient reference position in the center of the applicator and applied for all other positions, while the evaluation with optimization was based on creating an individual plan for each position. The parameter T90 was used for the temperature evaluation, which was defined as the temperature that covers 90% of the gross tumor volume (GTV). Furthermore, the hotspot tumor quotient (HTQ) was used as a goal function to assess the quality of the SAR and temperature distribution. The T90 was shown considerably dependent on the position within the applicator. Without optimization, the T90 was clearly decreased below 40 °C by patient shifts and the combination of shifts and rotations. However, the application of optimization for each positon led to an increase of T90 in the GTV. Position inaccuracies of less than 1 cm in the X-and Y-directions and 2 cm in the Z-direction, resulted in an increase of HTQ of less than 5%, which does not significantly affect the SAR and temperature distribution. Current positioning precision is sufficient in the X (right-left)-direction, but position accuracy is required in the Y-and Z-directions.
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Influence of radiotherapy-induced reactive oxygen species on the immunogenic potential of HPV+ in comparison to HPV- HNSCC - Peitz, L.; Frey, Benjamin; Rieckmann, T.; Fietkau, Rainer; Gaipl, Udo (2017)
EVALuna2:32888

Influence of radiotherapy-induced reactive oxygen species on the immunogenic potential of HPV plus in comparison to HPV-HNSCC - Peitz, L.; Frey, Benjamin; Rieckmann, T.; Fietkau, Rainer; Gaipl, Udo (2018)
EVALuna2:36505

Influence of the ALK Kinase Inhibitors Crizotinib and Alectinib on healthy and malignant Lung Cell Lines in a Combination Therapy with ionizing Radiation - Schultz, A. -K; Jost, Tina; Hecht, Markus; Fietkau, Rainer; Distel, Luitpold (STRAHLENTHERAPIE UND ONKOLOGIE, 2020)
CRIS-Team WoS Importer:2020-10-02

Influence of the ATR and ATM Kinase Inhibitors VE822 and AZD0156 on Melanoma Cell Lines in Combination Therapy with ionizing Radiation - Scheper, J. S. S.; Jost, Tina; Faulhaber, E. -M; Hecht, Markus; Fietkau, Rainer; Distel, Luitpold (STRAHLENTHERAPIE UND ONKOLOGIE, 2020)
CRIS-Team WoS Importer:2020-10-02

Influence of the Kinase Inhibitor Palbociclib on the Migration of malignant and non-malignant Cells under Irradiation - Jost, Tina; Hecht, Markus; Fietkau, Rainer; Distel, Luitpold (STRAHLENTHERAPIE UND ONKOLOGIE, 2019)
CRIS-Team WoS Importer:2019-06-07

Infrared camera based thermometry for quality assurance of superficial hyperthermia applicators - Müller, Johannes; Hartmann, Josefin; Bert, Christoph (Physics in Medicine and Biology, 2016)
The purpose of this work was to provide a feasible and easy to apply phantom-based quality assurance (QA) procedure for superficial hyperthermia (SHT) applicators by means of infrared (IR) thermography. The VarioCAM hr head (InfraTec, Dresden, Germany) was used to investigate the SA-812, the SA-510 and the SA-308 applicators (all: Pyrexar Medical, Salt Lake City, UT, USA). Probe referencing and thermal equilibrium procedures were applied to determine the emissivity of the muscle-equivalent agar phantom. Firstly, the disturbing potential of thermal conduction on the temperature distribution inside the phantom was analyzed through measurements after various heating times (5-50 min). Next, the influence of the temperature of the water bolus between the SA-812 applicator and the phantom's surface was evaluated by varying its temperature. The results are presented in terms of characteristic values (extremal temperatures, percentiles and effective field sizes (EFS)) and temperature-area-histograms (TAH). Lastly, spiral antenna applicators were compared by the introduced characteristics. The emissivity of the used phantom was found to be ? = 0.91 ± 0.03, the results of both methods coincided. The influence of thermal conduction with regard to heating time was smaller than expected; the EFS of the SA-812 applicator had a size of (68.6 ± 6.7) cm(2), averaged group variances were ±3.0 cm(2). The TAHs show that the influence of the water bolus is mostly limited to depths of <3 cm, yet it can greatly enhance or reduce heat generation in this regime: at a depth of 1 cm, measured maximal temperature rises were 14.5 °C for T Bolus = 30 °C and 8.6 °C for T Bolus = 21 °C, respectively. The EFS was increased, too. The three spiral antenna applicators generated similar heat distributions. Generally, the procedure proved to yield informative insights into applicator characteristics, thus making the application of an IR camera a very useful tool in SHT technical QA.
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In head and neck cancer the number of dissected lymph nodes predicts mortality - Haderlein, Marlen; Fietkau, Rainer (Strahlentherapie und Onkologie, 2017)
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Inhibition of bone remodeling in young mice by bisphosphonate displaces the plasma cell niche into the spleen - Teufel, Stefan; Groetsch, Bettina; Luther, Julia; Derer, Anja; Schinke, Thorsten; Amling, Michael; Schett, Georg; Mielenz, Dirk; David, Jean-Pierre (Journal of Immunology, 2014)
The bone marrow provides niches for early B cell differentiation and long-lived plasma cells. Therefore, it has been hypothesized that perturbing bone homeostasis might impact B cell function and Ab production. This hypothesis is highly relevant for patients receiving long-term treatment with antiresorptive drugs. We therefore analyzed the humoral immune response of mice chronically treated with ibandronate, a commonly used bisphosphonate. We confirmed the increased bone mass caused by inhibition of osteoclast activity and also the strongly reduced bone formation because of decreased osteoblast numbers in response to ibandronate. Thus, bisphosphonate drastically inhibited bone remodeling. When ibandronate was injected into mice after a primary immunization to mimic common antiosteoporotic treatments, the generation of the various B cell populations, the response to booster immunization, and the generation of plasma cells were surprisingly normal. Mice also responded normally to immunization when ibandronate was applied to naive mice. However, there, ibandronate shunted the homing of bone marrow plasma cells. Interestingly, ibandronate reduced the numbers of megakaryocytes, a known component of the bone marrow plasma cell niche. In line with normal Ab responses, increased plasma cell populations associated with increased megakaryocyte numbers were then observed in the spleens of the ibandronate-treated mice. Thus, although inhibition of bone remodeling disturbed the bone marrow plasma cell niche, a compensatory niche may have been created by relocating the megakaryocytes into the spleen, thereby allowing normal B cell responses. Therefore, megakaryocytes may act as a key regulator of plasma cell niche plasticity.
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In memory of Professor Dr. György Nemeth (1935-2014) - Loevey, Jozsef; Sauer, Rolf (Strahlentherapie und Onkologie, 2014)
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Innovative radiation oncology Together - Precise, Personalized, Human Vision 2030 for radiotherapy & radiation oncology in Germany - Krug, David; Hecht, Markus; Ebert, Nadja; Maeurer, Matthias; Fleischmann, Daniel F.; Fokas, Emmanouil; Straube, Christoph; Nicolay, Nils Henrik; Hoerner-Rieber, Juliane; Schmitt, Daniela; Von Neubeck, Clare; Zamboglou, Constantinos; et al. (Strahlentherapie und Onkologie, 2021)
Purpose Scientific and clinical achievements in radiation, medical, and surgical oncology are changing the landscape of interdisciplinary oncology. The German Society for Radiation Oncology (DEGRO) working group of young clinicians and scientists (yDEGRO) and the DEGRO representation of associate and full professors (AKRO) are aware of the essential role of radiation oncology in multidisciplinary treatment approaches. Together, yDEGRO and AKRO endorsed developing a German radiotherapy & radiation oncology vision 2030 to address future challenges in patient care, research, and education. The vision 2030 aims to identify priorities and goals for the next decade in the field of radiation oncology. Methods The vision development comprised three phases. During the first phase, areas of interest, objectives, and the process of vision development were defined jointly by the yDEGRO, AKRO, and the DEGRO board. In the second phase, a one-day strategy retreat was held to develop AKRO and yDEGRO representatives' final vision from medicine, biology, and physics. The third phase was dedicated to vision interpretation and program development by yDEGRO representatives. Results The strategy retreat's development process resulted in conception of the final vision "Innovative radiation oncology Together - Precise, Personalized, Human." The first term "Innovative radiation oncology" comprises the promotion of preclinical research and clinical trials and highlights the development of a national committee for strategic development in radiation oncology research. The term "together" underpins collaborations within radiation oncology departments as well as with other partners in the clinical and scientific setting. "Precise" mainly covers technological precision in radiotherapy as well as targeted oncologic therapeutics. "Personalized" emphasizes biology-directed individualization of radiation treatment. Finally, "Human" underlines the patient-centered approach and points towards the need for individual longer-term career curricula for clinicians and researchers in the field. Conclusion The vision 2030 balances the ambition of physical, technological, and biological innovation as well as a comprehensive, patient-centered, and collaborative approach towards radiotherapy & radiation oncology in Germany.
CRIS-Team WoS Importer:2021-09-24

Inosine Released from Dying or Dead Cells Stimulates Cell Proliferation via Adenosine Receptors - Chen, Jin; Chaurio, Ricardo A.; Maueröder, Christian; Derer, Anja; Rauh, Manfred; Kost, Andriy; Liu, Yi; Mo, Xianming; Hueber, Axel; Bilyy, Rostyslav; Herrmann, Martin; Zhao, Yi; et al. (Frontiers in Immunology, 2017)
Many antitumor therapies induce apoptotic cell death in order to cause tumor regression. Paradoxically, apoptotic cells are also known to promote wound healing, cell proliferation, and tumor cell repopulation in multicellular organisms. We aimed to characterize the nature of the regenerative signals concentrated in the micromilieu of dead and dying cells.Cultures of viable melanoma B16F10 cells, mouse fibroblasts, and primary human fibroblast-like synoviocytes (FLS) in the presence of dead and dying cells, their supernatants (SNs), or purified agonists and antagonists were used to evaluate the stimulation of proliferation. Viable cell quantification was performed by either flow cytometry of harvested cells or by crystal violet staining of adherent cells. High-performance liquid chromatography and liquid chromatography coupled with mass spectrometry of cell SNs were deployed to identify the nature of growth-promoting factors. Coimplantation of living cells in the presence of SNs collected from dead and dying cells and specific agonists was used to evaluate tumor growth in vivo.The stimulation of proliferation of few surviving cells by bystander dead cells was confirmed for melanoma cells, mouse fibroblasts, and primary FLS. We found that small soluble molecules present in the protein-free fraction of SNs of dead and dying cells were responsible for the promotion of proliferation. The nucleoside inosine released by dead and dying cells acting via adenosine receptors was identified as putative inducer of proliferation of surviving tumor cells after irradiation and heat treatment.Inosine released by dead and dying cells mediates tumor cell proliferation via purinergic receptors. Therapeutic strategies surmounting this pathway may help to reduce the rate of recurrence after radio- and chemotherapy.
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In Regard to Rahimi et al. - Hannoun-Levi, Jean Michel; Guinot, José Luis; Gutierrez, Cristina; Polgar, Csaba; Strnad, Vratislav (International Journal of Radiation Oncology Biology Physics, 2022)
CRIS-Team Scopus Importer:2022-05-20

In regard to “The Italian association of radiotherapy and oncology recommendation for breast tumor recurrence: grades of recommendation, assessment, development and evaluation criteria” - Hannoun-Levi, Jean-Michel; Gutierrez, Cristina; Polgar, Csaba; Strnad, Vratislav (Journal of Breast Cancer, 2021)
CRIS-Team Scopus Importer:2021-07-16

In regard to Van den Bruele AB et al. Management of ipsilateral breast tumor recurrence following breast conservation surgery: a comparative study of re-conservation vs mastectomy. Breast Cancer Res Treat. 2021 May;187(1):105-112. doi:10.1007/s10549-020-06080-9. Epub 2021 Jan 12. PMID: 33433775; PMCID: PMC8068641 - Hannoun-Levi, Jean-Michel; Polgar, Csaba; Strnad, Vratislav (Breast Cancer Research and Treatment, 2021)
CRIS-Team WoS Importer:2021-08-20

In Reply - Raptis, Dimitrios; Schneider, Ignaz Hans Friedrich; Matzel, Klaus E.; Hohenberger, Werner; Ott, Oliver; Fietkau, Rainer (Deutsches Ärzteblatt international, 2015)
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Insights into the infiltrative behavior of adamantinomatous craniopharyngioma in a new xenotransplant mouse model - Stache, Christina; Hoelsken, Annett; Schlaffer, Sven-Martin; Heß, Andreas; Metzler, Markus; Frey, Benjamin; Fahlbusch, Rudolf; Flitsch, Joerg; Buchfelder, Michael; Buslei, Rolf (Brain Pathology, 2015)
Adamantinomatous craniopharyngiomas (adaCP) cause hypothalamic pituitary dysfunction. Elucidation of pathomechanisms underlying tumor progression is essential for the development of targeted chemotherapeutic treatment options. In order to study the mechanisms of tumor outgrowth, we implanted human primary adaCP tissue from three different surgical specimens stereotactically into the brain of immunodeficient mice (n = 20). Three months after tumor inoculation, magnetic resonance imaging and histology confirmed tumor engraftment in all 20 mice (100%) that obtained tissue transplants. The lesions invaded adjoining brain tissue with micro finger-shaped protrusions. Immunohistochemical comparison of the primary tumor and xenotransplants revealed a similar amount of proliferation (Mib-1) and cytokeratin expression pattern (KL-1). Whole tumor reconstruction using serial sections confirmed whirl-like cell clusters with nuclear ?-catenin accumulations at the tumor brain border. These whirls were surrounded by a belt of Claudin-1 expressing cells, showed an activated epidermal growth factor receptor (EGFR) and distinct CD133 as well as p21(WAF1/Cip1) positivity, indicating a tumor stem cell phenotype. Consistent with our previous in vitro studies, intracranial xenotransplants of adaCP confirmed cells with nuclear ?-catenin and activated EGFR being the driving force of tumor outgrowth. This model provides the possibility to study in vivo tumor cell migration and to test novel treatment regimens targeting this tumor stem cell niche.
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'In situ' high pressure confocal Ca2+-fluorescence microscopy in skeletal muscle: A new method to study pressure limits in mammalian cells - Friedrich, Oliver; von Wegner, Frederic; Hartmann, M.; Frey, Benjamin; Sommer, Karl; Ludwig, Horst; Fink, Rainer (Undersea & Hyperbaric Medicine, 2006)
We combined 'in situ' high pressure microscopy with confocal laser scanning microscopy to directly study Ca2+ homeostasis in intact mammalian (murine) skeletal muscle fibres during high pressure exposure up to 35 MPa. Cytosolic Fluo-4 and mitochondrial Rhod-2 Ca2+ fluorescence were simultaneously monitored. To separate changes in Ca2+ and direct/indirect effects of pressure on the dye, experiments in permeabilized ('skinned') muscle fibres were performed at a fixed Ca2+ concentration. Normalized Fluo-4 fluorescence sharply declined up to 10 MPa but showed a plateau between 10 MPa and -35 MPa. In the intact fibre, Fluo-4 fluorescence exponentially decreased during pressurization to 35 MPa with a pressure constant of pi-5 MPa whereas mitochondrial Rhod-2 fluorescence exponentially increased with a four-fold larger pi. Holding the pressure at 35 MPa almost did not change Fluo-4 fluorescence. However, Rhod-2 fluorescence started to decrease after -40 min. Upon decompression, Rhod-2 and Fluo-4 fluorescence increased exponentially with similar pi. However, initial Fluo-4 fluorescence values were not restored. Our results are in agreement with pressure induced Ca2+ leakage from the sarcoplasmic reticulum. Ca2+ might then be taken up in large amounts by mitochondria preventing cytosolic increase in Ca2+. Prolonged pressure applications (-40 min at 35 MPa) seem to destabilize mitochondrial function with release of Ca2+ from mitochondria back into the cytosol and eventually mechanical activation resulting in irreversible contractures. The pressure induced disturbance of Ca2+ homeostasis might have important implications for the pressure exposure limits and/or dive profiles of deep sea mammal

Integrating Loco-Regional Hyperthermia Into the Current Oncology Practice: SWOT and TOWS Analyses - Datta, Niloy R.; Kok, H. Petra; Crezee, Hans; Gaipl, Udo; Bodis, Stephan (Frontiers in Oncology, 2020)
Moderate hyperthermia at temperatures between 40 and 44°C is a multifaceted therapeutic modality. It is a potent radiosensitizer, interacts favorably with a host of chemotherapeutic agents, and, in combination with radiotherapy, enforces immunomodulation akin to “in situ tumor vaccination.” By sensitizing hypoxic tumor cells and inhibiting repair of radiotherapy-induced DNA damage, the properties of hyperthermia delivered together with photons might provide a tumor-selective therapeutic advantage analogous to high linear energy transfer (LET) neutrons, but with less normal tissue toxicity. Furthermore, the high LET attributes of hyperthermia thermoradiobiologically are likely to enhance low LET protons; thus, proton thermoradiotherapy would mimic 12C ion therapy. Hyperthermia with radiotherapy and/or chemotherapy substantially improves therapeutic outcomes without enhancing normal tissue morbidities, yielding level I evidence reported in several randomized clinical trials, systematic reviews, and meta-analyses for various tumor sites. Technological advancements in hyperthermia delivery, advancements in hyperthermia treatment planning, online invasive and non-invasive MR-guided thermometry, and adherence to quality assurance guidelines have ensured safe and effective delivery of hyperthermia to the target region. Novel biological modeling permits integration of hyperthermia and radiotherapy treatment plans. Further, hyperthermia along with immune checkpoint inhibitors and DNA damage repair inhibitors could further augment the therapeutic efficacy resulting in synthetic lethality. Additionally, hyperthermia induced by magnetic nanoparticles coupled to selective payloads, namely, tumor-specific radiotheranostics (for both tumor imaging and radionuclide therapy), chemotherapeutic drugs, immunotherapeutic agents, and gene silencing, could provide a comprehensive tumor-specific theranostic modality akin to “magic (nano)bullets.” To get a realistic overview of the strength (S), weakness (W), opportunities (O), and threats (T) of hyperthermia, a SWOT analysis has been undertaken. Additionally, a TOWS analysis categorizes future strategies to facilitate further integration of hyperthermia with the current treatment modalities. These could gainfully accomplish a safe, versatile, and cost-effective enhancement of the existing therapeutic armamentarium to improve outcomes in clinical oncology.
CRIS-Team Scopus Importer:2020-07-10
Keywords: chemotherapy; clinical trials; hyperthermia; hyperthermia treatment planning; immunotherapy; radiation therapy; radiosensitizer; SWOT analysis

Integration of a Halcyon Accelerator with ARIA in a Mosaiq - Environment - Risk Analysis Procedure - Shariff, Maya; Lotter, M.; Lambrecht, U.; Bert, Christoph (STRAHLENTHERAPIE UND ONKOLOGIE, 2022)
CRIS-Team WoS Importer:2022-06-03

Integration of radiation oncology teaching in medical studies by German medical faculties due to the new licensing regulations: An overview and recommendations of the consortium academic radiation oncology of the German Society for Radiation Oncology (DEGRO) - Dapper, H.; Belka, C.; Bock, F.; Budach,; Budach, W.; Christiansen, H.; Debus, J.; Distel, Luitpold; Dunst, J.; Eckert, F.; Eich, H.; Eicheler, W.; et al. (Strahlentherapie und Onkologie, 2021)
The new Medical Licensing Regulations 2025 (Ärztliche Approbationsordnung, ÄApprO) will soon be passed by the Federal Council (Bundesrat) and will be implemented step by step by the individual faculties in the coming months. The further development of medical studies essentially involves an orientation from fact-based to competence-based learning and focuses on practical, longitudinal and interdisciplinary training. Radiation oncology and radiation therapy are important components of therapeutic oncology and are of great importance for public health, both clinically and epidemiologically, and therefore should be given appropriate attention in medical education. This report is based on a recent survey on the current state of radiation therapy teaching at university hospitals in Germany as well as the contents of the National Competence Based Learning Objectives Catalogue for Medicine 2.0 (Nationaler Kompetenzbasierter Lernzielkatalog Medizin 2.0, NKLM) and the closely related Subject Catalogue (Gegenstandskatalog, GK) of the Institute for Medical and Pharmaceutical Examination Questions (Institut für Medizinische und Pharmazeutische Prüfungsfragen, IMPP). The current recommendations of the German Society for Radiation Oncology (Deutsche Gesellschaft für Radioonkologie, DEGRO) regarding topics, scope and rationale for the establishment of radiation oncology teaching at the respective faculties are also included.
CRIS-Team Scopus Importer:2021-11-26
Keywords: Medical studies; New licensing regulations; Radiation oncology teaching

Integrative evaluation of primary and metastatic lesion spectrum to guide anti-PD-L1 therapy of non-small cell lung cancer: results from two randomized studies - Ma, Si-Cong; Tang, Xin-Ran; Long, Li-Li; Bai, Xue; Zhou, Jianguo; Duan, Zhi-Jiao; Wang, Jian; Fu, Qiang John; Zhu, Hong-Bo; Guo, Xue-Jun; Zhang, Yan-Pei; Guo, Ze-Qin; et al. (OncoImmunology, 2021)
Objectives: Clinical benefits of immune-checkpoint blockade (ICB) versus standard chemotherapy have been established in unselected non-small cell lung cancer (NSCLC). However, the response to ICB therapy among patients is heterogeneous in clinical practice.
CRIS-Team WoS Importer:2021-05-14

Interaction of Radiotherapy and Hyperthermia with the Immune System: a Brief Current Overview - Sengedorj, Azzaya; Hader, Michael; Frey, Benjamin; Fietkau, Rainer; Ott, Oliver; Gaipl, Udo; Rückert, Michael (Current Stem Cell Reports, 2022)
Purpose of Review This review focuses on the opposing effects on the immune system of radiotherapy (RT) and the consequences for combined cancer treatment strategies of RT with immunotherapies, including hyperthermia (HT). How RT and HT might affect cancer stem cell populations is also briefly outlined in this context.
CRIS-Team WoS Importer:2022-07-29

Interactions between radiotherapy and immunotherapy - Rueckert, Michael; Fietkau, Rainer; Frey, Benjamin; Gaipl, Udo; Deloch, Lisa (Onkologe, 2017)
Background. Radiotherapy (RT) acts not only locally on cells but is also capable of inducing systemic reactions. What are the immunological foundations for radiation-induced systemic reactions and how can this knowledge be exploited for the design of multimodal radioimmunotherapy? Ionizing radiation can induce many forms of tumor cell death via DNA damage responses, which have different influences on the immune system. Immunogenic cancer cell death (ICD) is mainly characterized by the release of immune-activating danger signals. Particularly RT with higher single doses induces ICD and thereby triggers anti-tumor immune responses. Lower doses of ionizing radiation foster immune cell infiltration into the tumor; however, RT also ameliorates inflammation and has immune suppressive properties in that the release of transforming growth factor beta (TGF-beta) is increased after RT and immune checkpoint molecules, such as PD-L1 are upregulated. This calls for additional immunotherapies to exploit the properties of RT to act as an in situ vaccine and to subsequently induce local and systemic, abscopal, anti-tumor immune reactions. For the development of efficient radioimmunotherapies, a timely well-reasoned combination of the individual therapies based on knowledge of the immune-modulating modes of action of ionizing radiation has to be worked out. It might be inevitable in the future to develop radiation concepts with differing single doses in one therapy setting to exploit the maximum anti-tumor effect of the immune system.
EVALuna2:32869

Interaktionen von Strahlen- und Immuntherapie - Rueckert, Michael; Fietkau, Rainer; Frey, Benjamin; Gaipl, Udo; et al. (Onkologe, 2017)
Background: Radiotherapy (RT) acts not only locally on cells but is also capable of inducing systemic reactions. Objective: What are the immunological foundations for radiation-induced systemic reactions and how can this knowledge be exploited for the design of multimodal radioimmunotherapy? Results: Ionizing radiation can induce many forms of tumor cell death via DNA damage responses, which have different influences on the immune system. Immunogenic cancer cell death (ICD) is mainly characterized by the release of immune-activating danger signals. Particularly RT with higher single doses induces ICD and thereby triggers anti-tumor immune responses. Lower doses of ionizing radiation foster immune cell infiltration into the tumor; however, RT also ameliorates inflammation and has immune suppressive properties in that the release of transforming growth factor β (TGF-β) is increased after RT and immune checkpoint molecules, such as PD-L1 are upregulated. This calls for additional immunotherapies to exploit the properties of RT to act as an in situ vaccine and to subsequently induce local and systemic, abscopal, anti-tumor immune reactions. Conclusion: For the development of efficient radioimmunotherapies, a timely well-reasoned combination of the individual therapies based on knowledge of the immune-modulating modes of action of ionizing radiation has to be worked out. It might be inevitable in the future to develop radiation concepts with differing single doses in one therapy setting to exploit the maximum anti-tumor effect of the immune system.
Created from Fastlane, Scopus look-up
Keywords: Immune checkpoint inhibition; Immunogenic cancer cell death; In situ vaccine; Inflammation; Radioimmunotherapy

Interconnection between DNA damage, senescence, inflammation, and cancer - Wunderlich, Roland; Rühle, Paul-Friedrich; Unger, Kristian; Hess, Julia; Zitzelsberger, Horst; Lauber, Kirsten; Frey, Benjamin; Gaipl, Udo; Deloch, Lisa (Frontiers in Bioscience, 2017)
In order to deal with endogenous and exogenous factors, including radiation or pathogens, cells evolved different strategies. This includes highly complex processes such as DNA damage response, senescence, cell death, and inflammatory reactions. Recent research indicates an interconnection between the mentioned cellular pathways whilst all of them seem to play a role in induction and progression, but also the prevention of cancerous diseases and therefore qualify for potential prevention and treatment strategies. On the basis of their pivotal functions in cancer biology in general, each of the cellular processes represents promising single therapeutic targets. Further, due to their strong interconnection, targeting all of them in a multimodal approach could be another promising strategy to treat cancer. We, therefore, review the mechanisms of DNA damage induction, detection and repair as well as the induction of cell death. Further, features of senescence and mechanism of inflammation induction and abrogation are outlined. A special focus is set on how senescence and inflammation are related to diseases and how targeting them could contribute to improvement of cancer therapies.
EVALuna2:33313

Interleukin-36 receptor mediates the crosstalk between plasma cells and synovial fibroblasts - Schmitt, Verena; Hahn, Madelaine; Kästele, Verena; Wagner, Olga; Wiendl, Maximilian; Derer, Anja; Taddeo, Adriano; Hahne, Stefanie; Radbruch, Andreas; Jäck, Hans-Martin; Schuh, Wolfgang; Mielenz, Dirk; et al. (European Journal of Immunology, 2017)
The IL-1 family member IL-36? has proinflammatory and pathogenic properties in psoriasis. IL-36? binds to the IL-36 receptor leading to nuclear factor kappa B/mitogen activated protein kinase mediated cytokine release. The IL-36R antagonist prevents recruitment of IL-1 receptor accessory protein and therefore IL-36-dependent cell activation. In inflamed human tissue, we previously could show that resident B cells and plasma cells (PC) express IL-36?. Further, fibroblast-like synoviocytes (FLS) produced proinflammatory cytokines upon IL-36?-stimulation. We hypothesize an IL-36-specific crosstalk between B cells/PCs and FLS permitting a proinflammatory B cell niche. Here, we firstly demonstrated that B cell lines and B cells from healthy donors express IL-36? and stimulation increased IL-36? in B cells and primary plasmablasts/PCs. Moreover, FLS respond specifically to IL-36? by proliferation and production of matrix metalloproteinases via p38/HSP27 signaling. Importantly, IL-36R-deficiency abrogated IL-36?-induced production of inflammatory mediators in FLS and changed the intrinsic FLS-phenotype. Using an in vitro co-culture system, we could show that IL-36R-deficient FLS had a limited capacity to support PC survival compared to wild-type FLS. Hence, we demonstrated an IL-36R-dependent crosstalk between B cells/PCs and FLS. Our data support the concept of initiation and maintenance of a proinflammatory niche by B cells in the joints. This article is protected by copyright. All rights reserved.
EVALuna2:13406

INTERNATIONAL EXPERT DELPHI CONSENSUS GUIDELINES FOR THE USE OF BOLUS IN POST MASTECTOMY RADIATION THERAPY - Dahn, Hannah; Boersma, Liesbeth; De Ruysscher, Dirk; Meattini, Icro; Offersen, Birgitte; Pignol, Jean-Philippe; Aristei, Cynthia; Benjamin, Dori; Bese, Nuran; Coles, Charlotte; Franco, Pierfrancesco; Ho, Alice; et al. (RADIOTHERAPY AND ONCOLOGY, 2021)
CRIS-Team WoS Importer:2021-12-10

Interstitial brachytherapy as a boost to patients with anal carcinoma and poor response to chemoradiation: Single-institution long-term results - Gryc, Thomas; Ott, Oliver; Putz, Florian; Knippen, Stefan; Raptis, Dimitrios; Fietkau, Rainer; Strnad, Vratislav (Brachytherapy, 2016)
To analyze the efficacy of a protocol-based brachytherapy (BT) boost after external beam radiation therapy (EBRT) with simultaneous chemotherapy in patients with anal carcinoma.About 190 patients have been analyzed. Around 143 patients were identified with a good clinical response at the end of EBRT. Another 47 patients received an additional BT boost to the residual tumor at 6 weeks after end of chemoradiation.The 5-year incidence of local recurrence was 24% in patients with BT boost and 19% in patients without BT boost (p = 0.238). The 5-year disease-free survival rate, overall survival rate, and colostomy-free survival rate were 64% and 75% and 76.1% in the BT group and 69% (p = 0.212), 72% (p = 0.924), and 82.7% (p = 0.488) in the non-BT group. We found no differences in late toxicity between the groups.For patients with anal cancer with not a good response to 50-59 Gy EBRT with simultaneous chemotherapy, the further dose escalation using the BT boost up to a mean of 67.5 Gy seems to improve the clinical outcome to the same level as observed in patients with a good response to ERBT, without an increase in late side effects.
EVALuna2:15265

Interstitial PDR-brachytherapy alone or in combination with EBRT for malignancies of the vulvar area: the UK Erlangen experience - Knippen, S.; Kreppner, Stephan; Lotter, M.; Fietkau, Rainer; Strnad, Vratislav (STRAHLENTHERAPIE UND ONKOLOGIE, 2020)
CRIS-Team WoS Importer:2020-10-02

In the Case of Radiochemotherapy of advanced Rectal Cancer, there is only slight gender-related Differences, none in terms of Radiation Sensitivity! - Schuster, Barbara; Hecht, Markus; Schmidt, Manfred; Haderlein, Marlen; Jost, Tina; Geinitz, H.; Fietkau, Rainer; Distel, Luitpold (STRAHLENTHERAPIE UND ONKOLOGIE, 2022)
CRIS-Team WoS Importer:2022-06-03

Intra-abdominal ALK-positive anaplastic large cell lymphoma in a patient with neurofibromatosis type 1 - Agaimy, Abbas; Semrau, Sabine; Heinz, Marco (Histopathology, 2016)
EVALuna2:6768

Intra-and Early Postoperative Evaluation of Malperfused Areas in an Irradiated Random Pattern Skin Flap Model Using Indocyanine Green Angiography and Near-Infrared Reflectance-Based Imaging and Infrared Thermography - Müller-Seubert, Wibke; Ostermaier, Patrick; Horch, Raymund E.; Distel, Luitpold; Frey, Benjamin; Cai, Aijia; Arkudas, Andreas (Journal of Personalized Medicine, 2022)
Background: Assessment of tissue perfusion after irradiation of random pattern flaps still remains a challenge. Methods: Twenty-five rats received harvesting of bilateral random pattern fasciocutaneous flaps. Group 1 served as nonirradiated control group. The right flaps of the groups 2–5 were irradiated with 20 Gy postoperatively (group 2), 3 × 12 Gy postoperatively (group 3), 20 Gy preoperatively (group 4) and 3 × 12 Gy preoperatively (group 5). Imaging with infrared thermography, indocyanine green angiography and near-infrared reflectance-based imaging were performed to detect necrotic areas of the flaps. Results: Analysis of the percentage of the necrotic area of the irradiated flaps showed a statistically significant increase from day 1 to 14 only in group 5 (p < 0.05). Indocyanine green angiography showed no differences (p > 0.05) of the percentage of the nonperfused area between all days in group 1 and 3, but a decrease in group 2 in both the left and the right flaps. Infrared thermography and near-infrared reflectance-based imaging did not show evaluable differences. Conclusion: Indocyanine green angiography is more precise in prediction of necrotic areas in random pattern skin flaps when compared to hyperspectral imaging, thermography or clinical impression. Preoperative fractional irradiation with a lower individual dose but a higher total dose has a more negative impact on flap perfusion compared to higher single stage irradiation.
CRIS-Team Scopus Importer:2022-02-25
Keywords: Imaging; Irradiation; Malperfusion

Intraluminal brachytherapy in oesophageal cancer: defining its role and introducing the technique - Lettmaier, Sebastian; Strnad, Vratislav (Journal of Contemporary Brachytherapy, 2014)
Intraluminal brachytherapy plays an important role in the treatment of oesophageal tumours. This article aims to define this role in the curative as well as in the palliative treatment settings drawing on data from the literature, and also emphasizing its potential for harm when used inexpertly. It also provides a short introduction to practical aspects of the treatment procedure and treatment planning.
EVALuna2:18192

Introduction of a hybrid treatment delivery system used for quality assurance in multi-catheter interstitial brachytherapy - Kallis, Karoline; Kreppner, Stephan; Lotter, Michael; Fietkau, Rainer; Strnad, Vratislav; Bert, Christoph (Physics in Medicine and Biology, 2018)
Multi-catheter interstitial brachytherapy (iBT) is a treatment option for breast cancer patients after breast conserving surgery. Typically, only a few additional quality interventions after the first irradiation have been introduced to ensure the planned treatment delivery. Therefore, the purpose of this study is to show the possibilities of an electromagnetic tracking (EMT) system integrated into the afterloader for quality assurance (QA) in high-dose rate (HDR) iBT of patients with breast cancer. The hybrid afterloader system equipped with an electromagnetic sensor was used for all phantom and patient measurements. Phantom measurements were conducted to estimate the quality of different evaluation schemes. After a coherent point drift registration of the EMT traces to the reconstructed catheters based on computed tomograms the dwell positions (DP) were defined. Different fitting and interpolation methods were analyzed for the reconstruction of DPs. All estimated DPs were compared to the DPs defined in treatment planning. Until now, the implant geometry of 20 patients treated with HDR brachytherapy was acquired and explored. Regarding the reconstruction techniques, both fitting and interpolation were able to detect manually introduced shifts and swaps. Nonetheless, interpolation showed superior results (RMSE = 1.27 mm), whereas fitting seemed to be more stable to distortion and motion. The EMT system proved to be beneficial for QA in brachytherapy and furthermore, clinical feasibility was proven.
EVALuna2:36464

Investigating a Correlation between Chemoradiotherapy Schedule Parameters and Overall Survival in a real-life LD SCLC Patient Cohort - Manapov, Farkhad; Eze, Chukwuka; Niyazi, Maximilian; Roengvoraphoj, Olarn; Li, Minglun; Hegemann, Nina-Sophie; Hildebrandt, Guido; Fietkau, Rainer; Belka, Claus (Journal of Cancer, 2016)
Background : Chemoradiotherapy (CRT) is a treatment standard in limited disease (LD) small cell lung cancer (SCLC). Currently, the timing of thoracic radiation therapy (TRT) remains the subject of randomised trials and meta-analyses. To investigate a correlation between CRT schedule parameters and overall survival (OS) in a real-life patient cohort, a temporal analysis was performed.Methods: 182 LD SCLC patients successfully treated with definitive CRT were retrospectively reviewed. TRT was applied concurrently or sequentially. Impact of the treatment mode and interval of simultaneous treatment (IST) (an interval in days when chemotherapy and TRT were applied simultaneously, including time between chemotherapy cycles and weekends) on OS was analysed.Results: 71 (39%) patients were treated with concurrent and 111 (61%) with sequential CRT. Median overall survival (MS) for the entire cohort was 534 days (95%CI 461 - 607) without any significant difference between the concurrent and sequential groups (589: 95%CI 358 - 820 vs. 533: 95%CI 446 - 620 days, p=0.746, log-rank test). IST was 0 days in 111 (61%) patients treated sequentially whereas in the concurrent group, 20 (11%) and 51 (28%) patients showed an IST < 35 and > 35 days, respectively. Patients with IST > 0 and < 35 days demonstrated a trend to improved overall survival (MS: IST 0 vs. > 35 vs. < 35 was 533 vs. 448 vs. 1169 days, p=0.109, log-rank test). When patients treated with sequential CRT (IST 0) were excluded from the analysis, statistical difference in overall survival according to the IST subgroups (IST > 35 vs. < 35) became significant (p=0.021, log-rank test). On multivariate analysis of patients treated with concurrent CRT, IST > 0 and < 35 days remained a variable that significantly correlated with better overall survival (p=0.039, HR 0.38).Conclusion: In this real-life LD SCLC patient cohort, improved overall survival was achieved in patients treated with CRT schedule according to the IST > 0 and < 35-day concept. By exceeding the 35-day interval, we have seen deterioration in survival.
EVALuna2:32925

Investigating the impact of breast positioning control on physical treatment parameters in multi-catheter breast brachytherapy - Karius, Andre; Strnad, Vratislav; Lotter, Michael; Kreppner, Stephan; Fietkau, Rainer; Bert, Christoph (Strahlentherapie und Onkologie, 2023)
Purpose: To assess the effects of a workflow for reproducible patient and breast positioning on implant stability during high-dose-rate multi-catheter breast brachytherapy. Methods: Thirty patients were treated with our new positioning control workflow. Implant stability was evaluated based on a comparison of planning-CTs to control-CTs acquired halfway through the treatment. To assess geometric stability, button–button distance variations as well as Euclidean dwell position deviations were evaluated. The latter were also quantified within various separated regions within the breast to investigate the location-dependency of implant alterations. Furthermore, dosimetric variations to target volume and organs at risk (ribs, skin) as well as isodose volume changes were analyzed. Results were compared to a previously treated cohort of 100 patients. Results: With the introduced workflow, the patient fraction affected by button–button distance variations > 5 mm and by dwell position deviations > 7 mm were reduced from 37% to 10% and from 30% to 6.6%, respectively. Implant stability improved the most in the lateral to medial breast regions. Only small stability enhancements were observed regarding target volume dosimetry, but the stability of organ at risk exposure became substantially higher. D0.2ccm skin dose variations > 12.4% and D0.1ccm rib dose variations > 6.7% were reduced from 11% to 0% and from 16% to 3.3% of all patients, respectively. Conclusion: Breast positioning control improved geometric and dosimetric implant stability for individual patients, and thus enhanced physical plan validity in these cases.
CRIS-Team Scopus Importer:2023-09-15
Keywords: Adaptive brachytherapy; Computed tomography; Implant stability; Treatment quality; Treatment re-planning

Investigation of a radioprotective Effect of the Kinase Inhibitor Palbociclib on Melanoma Cells in a 3D Cell Culture Model - Jost, Tina; Buerkel, F.; Proebstle, Stephanie; Hecht, Markus; Fietkau, Rainer; Distel, Luitpold (2018)
EVALuna2:36487

Investigation of daily Activity, Sleep and neurocognitive Function in Glioblastoma Patients using TTFields Therapy in Routine clinical Care in Germany - the TIGER PRO-Active Study - Glas, M.; Tabatabai, G.; Fietkau, Rainer; Goldbrunner, R.; Baehr, O. (STRAHLENTHERAPIE UND ONKOLOGIE, 2022)
CRIS-Team WoS Importer:2022-06-03

Investigation of Long Term Survival in Metastatic NSCLC with Driver Mutations under Molecular Targeted Therapy and Local Radiotherapy of all Tumor Manifestations - Weissmann, T.; Semrau, S.; Lettmaier, S.; Fietkau, Rainer; Putz, Florian (STRAHLENTHERAPIE UND ONKOLOGIE, 2019)
CRIS-Team WoS Importer:2019-06-07

In Vitro Analysis of Superparamagnetic Iron Oxide Nanoparticles Coated with APTES as Possible Radiosensitizers for HNSCC Cells - Emer, Clara; Hildebrand, Laura; Friedrich, Bernhard; Tietze, Rainer; Fietkau, Rainer; Distel, Luitpold (Nanomaterials, 2023)
Superparamagnetic iron oxide nanoparticles (SPION) are being investigated for many purposes, e.g., for the amplification of ionizing radiation and for the targeted application of therapeutics. Therefore, we investigated SPIONs coated with (3-Aminopropyle)-Triethoxysilane (SPION-APTES) for their influence on different head and neck squamous cell carcinoma (HNSCC) cell lines, as well as for their suitability as a radiosensitizer. We used 24-well microscopy and immunofluorescence microscopy for cell observation, growth curves to determine cytostatic effects, and colony formation assays to determine cytotoxicity. We found that the APTES-SPIONs were very well taken up by the HNSCC cells. They generally have a low cytotoxic effect, showing no significant difference in clonogenic survival between the control group and cells treated with 20 µg Fe/mL (p > 0.25) for all cell lines. They have a cytostatic effect on some cell lines cells (e.g., Cal33) that is visible across different radiation doses (1, 2, 8 Gy, p = 0.05). In Cal33, e.g., SPION-APTES raised the doubling time at 2 Gy from 24.53 h to 41.64 h. Importantly, these findings vary notably between the cell lines. However, they do not significantly alter the radiation effect: only one out of eight cell lines treated with SPION-APTES showed a significantly reduced clonogenic survival after ionizing radiation with 2 Gy, and only two showed significantly reduced doubling times. Thus, although the APTES-SPIONs do not qualify as a radiosensitizer, we were still able to vividly demonstrate and analyze the effect that the APTES-SPIONs have on various cell lines as a contribution to further functionalization.
CRIS-Team Scopus Importer:2023-02-03
Keywords: cell survival; doubling time; head and neck cancer cell lines; HNSCC; nanoparticles; SPION; time lapse

In Vitro Examinations of Cell Death Induction and the Immune Phenotype of Cancer Cells Following Radiative-Based Hyperthermia with 915 MHz in Combination with Radiotherapy - Hader, Michael; Streit, Simon; Rosin, Andreas; Gerdes, Thorsten; Wadepohl, Martin; Bekeschus, Sander; Fietkau, Rainer; Frey, Benjamin; Schlücker, Eberhard; Gekle, Stephan; Gaipl, Udo (Cells, 2021)
Multimodal tumor treatment settings consisting of radiotherapy and immunomodulating agents such as immune checkpoint inhibitors are more and more commonly applied in clinics. In this context, the immune phenotype of tumor cells has a major influence on the anti-tumor immune response as well as the composition of the tumor microenvironment. A promising approach to further boost anti-tumor immune responses is to add hyperthermia (HT), i.e., heating the tumor tissue between 39 degrees C to 45 degrees C for 60 min. One key technique is the use of radiative hyperthermia systems. However, knowledge is limited as to how the frequency of the used radiative systems affects the immune phenotype of the treated tumor cells. By using our self-designed in vitro hyperthermia system, we compared cell death induction and expression of immune checkpoint molecules (ICM) on the tumor cell surface of murine B16 melanoma and human MDA-MB-231 and MCF-7 breast cancer cells following HT treatment with clinically relevant microwaves at 915 MHz or 2.45 GHz alone, radiotherapy (RT; 2 x 5 Gy or 5 x 2 Gy) alone or in combination (RHT). At 44 degrees C, HT alone was the dominant cell death inductor with inactivation rates of around 70% for B16, 45% for MDA-MB-231 and 35% for MCF-7 at 915 MHz and 80%, 60% and 50% at 2.45 GHz, respectively. Additional RT resulted in 5-15% higher levels of dead cells. The expression of ICM on tumor cells showed time-, treatment-, cell line- and frequency-dependent effects and was highest for RHT. Computer simulations of an exemplary spherical cell revealed frequency-dependent local energy absorption. The frequency of hyperthermia systems is a newly identified parameter that could also affect the immune phenotype of tumor cells and consequently the immunogenicity of tumors.
CRIS-Team WoS Importer:2021-07-09

Ion beam tracking using ultrasound motion detection - Prall, M.; Kaderka, R.; Saito, N.; Graeff, Christian; Bert, Christoph; Durante, Marco; Parodi, K.; Schwaab, J.; Sarti, C.; Jenne, J. (Medical Physics, 2014)
The use of motion mitigation techniques such as tracking and gating in particle therapy requires real-time knowledge of tumor position with millimeter precision. The aim of this phantom-based study was to evaluate the option of diagnostic ultrasound (US) imaging (sonography) as real-time motion detection method for scanned heavy ion beam irradiation of moving targets.For this pilot experiment, a tumor surrogate was moved inside a water bath along two-dimensional trajectories. A rubber ball was used for this purpose. This ball was moved by a robotic arm in two dimensions lateral to the heavy ion beam. Trajectories having a period of 3 s and peak to peak amplitude of 20 mm were used. Square radiation fields of[Formula: see text] were irradiated on radiosensitive films with a 200 MeV/u beam of calcium ions having a FWHM of 6 mm. Pencil beam scanning and beam tracking were employed. The films were attached on the robotic arm and thus moved with the rubber ball. The position of the rubber ball was continuously measured by a US tracking system (Mediri GmbH, Heidelberg) and sent to the GSI therapy control system (TCS). This position was used as tracking vector. Position reconstruction from the US tracking system and data communication introduced a delay leading to a position error of several millimeters. An artificial neural network (ANN) was implemented in the TCS to predict motion from US measurements and thus to compensate for the delay.Using ANN delay compensation and large motion amplitudes, the authors could produce irradiation patterns with a few percent inhomogeneity and about 1 mm geometrical conformity.This pilot experiment suggests that diagnostic US should be further investigated as dose-free, high frame-rate, and model-independent motion detection method for scanning heavy ion beam irradiation of moving targets.
EVALuna2:18309

IONISING RADIATION INHIBITS INFLAMMATION IN PATIENTS WITH MUSCULOSKELETAL DISEASES: RADON TREATMENT VS LOW-DOSE RADIATION THERAPY - Shreder, K.; Cucu, A.; Kraft, D.; Lehrian, S.; Kondol, J.; Klein, G.; Frey, Benjamin; Gaipl, Udo; Fournier, C. (2018)
EVALuna2:36523

Ionizing radiation reduces the capacity of activated macrophages to induce T-cell proliferation, but does not trigger dendritic cell-mediated non-targeted effects - Wunderlich, Roland; Rühle, Paul-Friedrich; Roedel, Franz; Fietkau, Rainer; Gaipl, Udo; Frey, Benjamin; Deloch, Lisa (International Journal of Radiation Biology, 2019)
PURPOSE: Previous investigations revealed influences of irradiation up to 2Gy on the cytokine secretion profile of inflammatory and peritoneal mouse macrophages (pMФ). This raised the question if those alterations impact on dendritic cells and consecutive T-cell responses. Further, the impact of irradiation directly on pMФ capacity to induce T-cell responses was analyzed. MATERIALS AND METHODS: pMФ were LPS-activated, irradiated and the expression of activation markers was assessed. Treated pMФ were co-incubated with T-cells to investigate proliferation. To verify modulating properties of pMФ supernatants isolated 24 h after irradiation, bone marrow-derived dendritic cells (BMDC) were co-incubated with supernatants and activation markers as well as the BMDC-induced proliferation of T-cells were measured. RESULTS: pMФ showed a highly significantly decreased major histocompatibility complexII (MHCII) expression within a dose range from 0.7-2Gy. Further, the proliferation rate of cluster of differentiation 4+ (CD4+) T-cells was decreased after co-incubation particularly with 2 Gy irradiated pMФ. The co-incubation of BMDC with supernatants of activated, irradiated pMФ significantly reduced the CD40 expression, but did not impact on the BMDC-derived induction of T-cell proliferation. CONCLUSIONS: Inflammatory macrophages being exposed to irradiation have the potential to modulate consecutive adaptive immune reactions. But supernatants of irradiated macrophages do not influence the dendritic cells (DC)-mediated induction of T cell proliferation.
EVALuna2:36459

Ion therapy of prostate cancer: daily rectal dose reduction by application of spacer gel - Rucinski, Antoni; Brons, Stephan; Richter, Daniel; Habl, Gregor; Debus, Juergen; Bert, Christoph; Haberer, Thomas; Jaekel, Oliver (Radiation Oncology, 2015)
Ion beam therapy represents a promising approach to treat prostate cancer, mainly due to its high conformity and radiobiological effectiveness. However, the presence of prostate motion, patient positioning and range uncertainties may deteriorate target dose and increase exposure of organs at risk. Spacer gel injected between prostate and rectum may increase the safety of prostate cancer (PC) radiation therapy by separating the rectum from the target dose field. The dosimetric impact of the application of spacer gel for scanned carbon ion therapy of PC has been analyzed at Heidelberg Ion-Beam Therapy Center (HIT).The robustness of ion therapy treatment plans was investigated by comparison of two data sets of patients treated with and without spacer gel. A research treatment planning system for ion therapy was used for treatment plan optimization and calculation of daily dose distributions on 2 to 9 Computed Tomography (CT) studies available for each of the 19 patients. Planning and daily dose distributions were analyzed with respect to target coverage, maximal dose to the rectum (excluding 1 ml of the greatest dose; Dmax-1 ml) and the rectal volume receiving dose greater than 90% of prescribed target dose (V90Rectum), respectively.The application of spacer gel did substantially diminish rectum dose. Dmax-1 ml on the treatment planning CT was on average reduced from 100.0 ± 1.0% to 90.2 ± 4.8%, when spacer gel was applied. The robustness analysis performed with daily CT studies demonstrated for all analyzed patient cases that application of spacer gel results in a decrease of the daily V90Rectum index, which calculated over all patient cases and CT studies was 10.2 ± 10.4 [ml] and 1.1 ± 2.1 [ml] for patients without and with spacer gel, respectively.The dosimetric benefit of increasing the distance between prostate and rectum using spacer gel for PC treatment with carbon ion beams has been quantified. Application of spacer gel substantially reduced rectal exposure to high treatment dose and, therefore, can reduce the hazard of rectal toxicity in ion beam therapy of PC. The results of this study enable modifications of the PC ion therapy protocol such as dose escalation or hypofractionation.
EVALuna2:18312

iPad-based patient briefing for radiological examinations-a clinical trial - Schlechtweg, Philipp; Hammon, Matthias; Giese, David Andreas; Heberlein, Christian; Uder, Michael; Schwab, Siegfried (Journal of Digital Imaging, 2014)
To analyze if an iPad-based patient briefing can serve as a digital alternative to conventional documentations prior to radiological examinations. One hundred one patients referred for routine MRI were randomized into two groups, who underwent iPad-based and classic written briefing in opposite order. For each briefing completion time, completeness and correctness were noted. Patient's knowledge about the content of either briefing modality was subsequently tested. The influence of patient-related factors on the performance of the electronic briefing (EB) was analyzed. Finally, the patient's subjective impression of the EB was assessed. The mean durations were 4.4 ± 2.2 min for EB and 1.7 ± 1.3 min for the classic briefing (p < 0.01). All iPad briefings were returned entirely filled out, whereas 11 % of the classic forms were returned with missing data. No significant differences in memorization of the briefing's information were objectified. There was a positive correlation between the duration of EB and age (r = 0.53; p < 0.01), whereas a negative correlation was found between computer skills and patient's age (r = -0.55; p < 0.01) or duration of EB (r = -0.62; p < 0.01). More than half of the study patients would prefer EB in the future; another 29 % had no preference at all. Patient briefing on iPads transfers the information for the patients equally well compared to the classic written approach. Although iPad briefing took patients longer to perform, the majority would prefer it to written consent briefings in the future. Nevertheless, measures have to be undertaken to improve the overall acceptance and performance.
EVALuna2:14372

Irradiated HPV+ head and neck cancer cells induce an interferon related gene expression in various innate immune cell subtypes - Wunderlich, R.; Unger, K.; Hess, J.; Lauber, K.; Frey, Benjamin; Gaipl, Udo; Zitzelsberger, H. (2017)
EVALuna2:32929

Irradiation of the locoregional Lymphatic Drainage Pathways of Breast Cancer: Is the prescribed Dose actually applied? A Planning Study by the DEGRO Breast Cancer Working Group - Duma, M. N.; Piroth, M.; Fastner, G.; Baumann, R.; Combs, S.; Dunst, J.; Feyer, P.; Fietkau, Rainer; Haase, W.; Harms, W.; Hehr, T.; Krug, D.; et al. (STRAHLENTHERAPIE UND ONKOLOGIE, 2022)
CRIS-Team WoS Importer:2022-06-03

Is adaptive treatment planning in multi-catheter interstitial breast brachytherapy necessary? - Kallis, Karoline; Ziegler, Marc; Lotter, Michael; Kreppner, Stephan; Strnad, Vratislav; Fietkau, Rainer; Bert, Christoph (Radiotherapy and Oncology, 2019)
Purpose: For 55 patients treated with interstitial multi-catheter breast brachytherapy the need for adaptive treatment planning was assessed. Methods and materials: For all patients a treatment planning computed tomography (CT) and a follow-up CT were acquired and used for the retrospective evaluation. Keeping dwell time and dwell positions constant, the treatment plan assessed directly after catheter implantation was compared to the situation 48 h after implantation. Both manual catheter reconstructions, based on the planning and follow-up CT, were rigid registered to each other and the resulting deviations analyzed, like the difference between corresponding dwell positions (ΔDP) or the discrete Fréchet distance. Further, the dosimetric changes, e.g., coverage index (ΔCI), conformal index (ΔCOIN) and dose non-uniformity ratio (ΔDNR) were considered for a deformed planning target volume (PTV) and the rigid warped PTV structure. The PTV was deformed according to the vector field estimated between the two acquired CTs. Results: Over all patients with rigid aligned CTs a mean ΔDP, ΔCI, ΔCOIN and ΔDNR were determined to 2.41 ± 1.73 mm, 3.10 ± 3.17%, 0.009 ± 0.007 and 0.036 ± 0.040, respectively. Considering the deformed PTV ΔCI was estimated to 5.05 ± 4.14 %. Conclusion: In conclusion, in 4% of the cases re-planning would have been beneficial to ensure the planned dose delivery. Large PTV changes or large DP deviations were found to be the main reasons for dosimetric variations.
CRIS-Team Scopus Importer:2019-09-24
Keywords: Adaptive treatment planning; Breast cancer; Deformable image registration; Interstitial brachytherapy

Is elective irradiation of lymph node levels IV and Vb necessary in nasopharyngeal carcinoma? - Semrau, Sabine; Haderlein, Marlen (Strahlentherapie und Onkologie, 2022)
CRIS-Team WoS Importer:2022-08-26

Is in vivo and ex vivo irradiation equally reliable for individual Radiosensitivity testing by three colour fluorescence in situ hybridization? - Mayo, Theresa; Haderlein, Marlen; Schuster, Barbara; Wiesmueller, Anna; Hummel, Christian; Bachl, Maximilian; Schmidt, Manfred; Fietkau, Rainer; Distel, Luitpold (Radiation Oncology, 2019)
Background Individual radiosensitivity is influencing the outcome of radiation therapy. A general ex vivo testing is very work-intensive. It is of interest to see if a significant prediction concerning the sensitivity can be made by in vivo irradiation during radiation treatment. Methods Blood samples of 274 patients with rectal cancer and 43 lung cancer patients receiving radiotherapy were examined after 2 Gy ex vivo and in vivo ionizing radiation. Chromosomes # 1, 2 and 4 were stained by the 3-color-fluorescence in situ hybridization. Chromosomal aberrations were analyzed as breaks per metaphase (B/M). The deposited energy per session was calculated for each patient. Results Weak correlation could be found between the chromosomal aberrations ex and in vivo. Though receiving significantly smaller deposited energy during radiation therapy (RT) the lung cancer cohort displayed B/M values similar to the rectal cancer cohort. Considering the individual deposit energy differences improved slightly the correlation. Conclusions As various factors influence the induction of chromosomal aberrations it seems not feasible to estimate individual radiosensitivity via in vivo irradiation. An ex vivo estimation of individual radiosensitivity should be preferred.
CRIS-Team WoS Importer:2020-01-10

Is it time to redefine the role of low-dose radiotherapy for benign disease? - Montero, Angel; Sabater, Sebastia; Roedel, Franz; Gaipl, Udo; Ott, Oliver; Seegenschmiedt, Michael Heinrich; Arenas, Meritxell (Annals of the Rheumatic Diseases, 2020)
CRIS-Team WoS Importer:2020-03-27

Is There Any Evidence of Monocytes Involvement in Alzheimer's Disease? A Pilot Study on Human Postmortem Brain - Monoranu, Camelia-Maria; Hartmann, Tim; Strobel, Sabrina; Heinsen, Helmut; Riederer, Peter; Distel, Luitpold; Bohnert, Simone (Journal of Alzheimer's Disease Reports, 2021)
Background: The role of neuroinflammation has become more evident in the pathogenesis of neurodegenerative diseases. Increased expression of microglial markers is widely reported in Alzheimer's disease (AD), but much less is known about the role of monocytes in AD pathogenesis. In AD animal models, bone marrow-derived monocytes appear to infiltrate the parenchyma and contribute to the phagocytosis of amyloid-beta depositions, but this infiltration has not been established in systematic studies of the human brain postmortem.
CRIS-Team WoS Importer:2022-01-07

Is there a patient population with squamous cell carcinoma of the head and neck region who might benefit from de-intensification of postoperative radiotherapy? - Onbasi, Yonca; Lettmaier, Sebastian; Hecht, Markus; Semrau, Sabine; Iro, Heinrich; Kesting, Marco Rainer; Fietkau, Rainer; Haderlein, Marlen (Strahlentherapie und Onkologie, 2019)
Purpose: The aim of this retrospective study was to evaluate the clinical outcome of a previously defined low-risk patient population with completely resected (R0) squamous cell carcinoma of the oral cavity, oropharynx, larynx (pT1–3, pN0–pN2b), hypopharynx (pT1–2, pN0–pN1), and the indication for postoperative radio(chemo)therapy. Patients and methods: According to predefined criteria, 99 patients with head and neck squamous cell carcinoma (SCC) who were treated at our institution from January 1, 2005 to December 31, 2014, were available for analysis. The Kaplan–Meier method was used for calculating survival and incidence rates. For univariate comparative analysis, the log-rank test was used for analyzing prognostic clinicopathologic parameters. Results: Median follow-up was 67 months. Cumulative overall (OS) and disease-free survival (DFS) were 97.9%/94.7%/88.0% and 96.9%/92.6%/84.7% after 1, 2, and 5 years, respectively. Cumulative incidence of loco-regional recurrence (LRR), distant metastases (DM), and second cancer (SC) were 1.0%/1.0%/4.9%, 0.0%/3.4%/5.8%, and 2.1%/4.2%/13.1%, respectively. In univariate comparative analysis, location of the primary tumor in the oropharynx was a significant predictor for increased OS (p = 0.043) and DFS (p = 0.048). Conclusion: Considering the low disease relapse rates and high rates of therapy-induced late side effects, as well as the increased risk of developing SC, a prospective multicentric trial investigating de-escalation of radiotherapy in this clearly defined low-risk patient population was started and is still recruiting patients (DIREKHT-Trial, NCT02528955).
CRIS-Team Scopus Importer:2019-06-04
Keywords: Disease-free survival; Late side effect; Overall survival; Radio(chemo)therapy; Second cancer

Is there a patient population with squamous cell carcinoma of the head and neck region who might benefit from de-intensification of postoperative radiotherapy? - Onbasi, Yonca; Lettmaier, Sebastian; Hecht, Markus; Semrau, Sabine; Iro, Heinrich; Kesting, Marco Rainer; Fietkau, Rainer; Haderlein, Marlen (Strahlentherapie und Onkologie, 2019)
PURPOSE: The aim of this retrospective study was to evaluate the clinical outcome of a previously defined low-risk patient population with completely resected (R0) squamous cell carcinoma of the oral cavity, oropharynx, larynx (pT1-3, pN0-pN2b), hypopharynx (pT1-2, pN0-pN1), and the indication for postoperative radio(chemo)therapy. PATIENTS AND METHODS: According to predefined criteria, 99 patients with head and neck squamous cell carcinoma (SCC) who were treated at our institution from January 1, 2005 to December 31, 2014, were available for analysis. The Kaplan-Meier method was used for calculating survival and incidence rates. For univariate comparative analysis, the log-rank test was used for analyzing prognostic clinicopathologic parameters. RESULTS: Median follow-up was 67 months. Cumulative overall (OS) and disease-free survival (DFS) were 97.9%/94.7%/88.0% and 96.9%/92.6%/84.7% after 1, 2, and 5 years, respectively. Cumulative incidence of loco-regional recurrence (LRR), distant metastases (DM), and second cancer (SC) were 1.0%/1.0%/4.9%, 0.0%/3.4%/5.8%, and 2.1%/4.2%/13.1%, respectively. In univariate comparative analysis, location of the primary tumor in the oropharynx was a significant predictor for increased OS (p = 0.043) and DFS (p = 0.048). CONCLUSION: Considering the low disease relapse rates and high rates of therapy-induced late side effects, as well as the increased risk of developing SC, a prospective multicentric trial investigating de-escalation of radiotherapy in this clearly defined low-risk patient population was started and is still recruiting patients (DIREKHT-Trial, NCT02528955).
EVALuna2:184476

Kill and spread the word: stimulation of antitumor immune responses in the context of radiotherapy - Gaipl, Udo; Multhoff, Gabriele; Scheithauer, Heike; Lauber, Kirsten; Hehlgans, Stefanie; Frey, Benjamin; Roedel, Franz (Immunotherapy, 2014)
Besides the direct, targeted effects of ionizing irradiation (x-ray) on cancer cells, namely DNA damage and cell death induction, indirect, nontargeted ones exist, which are mediated in large part by the immune system. Immunogenic forms of tumor cell death induced by x-ray, including immune modulating danger signals like the heat shock protein 70, adenosine triphosphate, and high-mobility group box 1 protein are presented. Further, antitumor effects exerted by cells of the innate (natural killer cells) as well as adaptive immune system (T cells activated by dendritic cells) are outlined. Tumor cell death inhibiting molecules such as survivin are introduced as suitable target for molecularly tailored therapies in combination with x-ray. Finally, reasonable combinations of immune therapies with radiotherapy are discussed.
EVALuna2:18189

Kinase Inhibitor Palbociclib shows differential Effects upon Irradiation on Normal Tissue and Cancer Cell Lines - Jost, Tina; Proebstle, Stephanie; Buerkel, F.; Hecht, Markus; Fietkau, Rainer; Distel, Luitpold (2018)
EVALuna2:36486

Kinase inhibitors increase individual radiation sensitivity in normal cells of cancer patients - Jost, Tina; Schuster, Barbara; Heinzerling, Lucie; Weissmann, Thomas; Fietkau, Rainer; Distel, Luitpold; Hecht, Markus (Strahlentherapie und Onkologie, 2022)
Purpose Kinase inhibitors (KI) are known to increase radiosensitivity, which can lead to increased risk of side effects. Data about interactions of commonly used KI with ionizing radiation on healthy tissue are rare. Patients and methods Freshly drawn blood samples were analyzed using three-color FISH (fluorescence in situ hybridization) to measure individual radiosensitivity via chromosomal aberrations after irradiation (2 Gy). Thresholds of 0.5 and 0.6 breaks/metaphase (B/M) indicate moderate or clearly increased radiosensitivity. Results The cohorts consisted of healthy individuals (NEG, n = 219), radiosensitive patients (POS, n = 24), cancer patients (n = 452) and cancer patients during KI therapy (n = 49). In healthy individuals radiosensitivity (>= 0.6 B/M) was clearly increased in 5% of all cases, while in the radiosensitive cohort 79% were elevated. KI therapy increased the rate of sensitive patients (>= 0.6 B/M) to 35% significantly compared to 19% in cancer patients without KI (p = 0.014). Increased radiosensitivity of peripheral blood mononuclear cells (PBMCs) among patients occurred in six of seven KI subgroups. The mean B/M values significantly increased during KI therapy (0.47 +/- 0.20 B/M without compared to 0.50 +/- 0.19 B/M with KI, p = 0.047). Conclusions Kinase inhibitors can intensify individual radiosensitivity of PBMCs distinctly in 85% of tested drugs.
CRIS-Team WoS Importer:2022-05-13

Kinase Inhibitors increase the individual Radiation Sensitivity of Normal Tissue in Cancer Patients - Jost, Tina; Schuster, Barbara; Heinzerling, L.; Weissmann, Thomas; Fietkau, Rainer; Distel, Luitpold; Hecht, Markus (Strahlentherapie und Onkologie, 2022)
CRIS-Team WoS Importer:2022-06-03

Kinase Inhibitors of DNA-PK, ATM and ATR in Combination with Ionizing Radiation Can Increase Tumor Cell Death in HNSCC Cells While Sparing Normal Tissue Cells - Faulhaber, Eva-Maria; Jost, Tina; Symank, Julia-Alice; Scheper, Julian; Burkel, Felix; Fietkau, Rainer; Hecht, Markus; Distel, Luitpold (Genes, 2021)
(1) Kinase inhibitors (KI) targeting components of the DNA damage repair pathway are a promising new type of drug. Combining them with ionizing radiation therapy (IR), which is commonly used for treatment of head and neck tumors, could improve tumor control, but could also increase negative side effects on surrounding normal tissue. (2) The effect of KI of the DDR (ATMi: AZD0156; ATRi: VE-822, dual DNA-PKi/mTORi: CC-115) in combination with IR on HPV-positive and HPV-negative HNSCC and healthy skin cells was analyzed. Cell death and cell cycle arrest were determined using flow cytometry. Additionally, clonogenic survival and migration were analyzed. (3) Studied HNSCC cell lines reacted differently to DDRi. An increase in cell death for all of the malignant cells could be observed when combining IR and KI. Healthy fibroblasts were not affected by simultaneous treatment. Migration was partially impaired. Influence on the cell cycle varied between the cell lines and inhibitors; (4) In conclusion, a combination of DDRi with IR could be feasible for patients with HNSCC. Side effects on healthy cells are expected to be limited to normal radiation-induced response. Formation of metastases could be decreased because cell migration is impaired partially. The treatment outcome for HPV-negative tumors tends to be improved by combined treatment.
CRIS-Team WoS Importer:2021-07-09

Kinase Inhibitors of DNA-PK, ATM and ATR in Combination with Ionizing Radiation Can Increase Tumor Cell Death in HNSCC Cells While Sparing Normal Tissue Cells - Jost, Tina; Faulhaber, Eva-Maria; Symank, Julia-Alice; Scheper, Julian; Bürkel, Felix; Fietkau, Rainer; Hecht, Markus; Distel, Luitpold (ONCOLOGY RESEARCH AND TREATMENT, 2022)
CRIS-Team WoS Importer:2022-12-16

Kleinst-Produktionslinie zur Fertigung hochpräziser faseroptischer Mikroteile - Zimmermann, M.; Weber, Manuel; Wolf, W.; Junker, S.; Menschig, A. (LEF 2006, Laser in der Elektronik- & Feinwerkproduktion, 2006)
LFT Import::2019-08-05 (1296)

Late side-effects and cosmetic results of accelerated partial breast irradiation with interstitial brachytherapy versus whole-breast irradiation after breast-conserving surgery for low-risk invasive and in-situ carcinoma of the female breast: 5-year results of a randomised, controlled, phase 3 trial - Polgar, Csaba; Ott, Oliver J.; Hildebrandt, Guido; Kauer-Dorner, Daniela; Knauerhase, Hellen; Major, Tibor; Lyczek, Jaroslaw; Guinot, Jose Luis; Dunst, Jurgen; Miguelez, Cristina Gutierrez; Slampa, Pavel; Allgaeuer, Michael; et al. (Lancet Oncology, 2017)
BACKGROUND: We previously confirmed the non-inferiority of accelerated partial breast irradiation (APBI) with interstitial brachytherapy in terms of local control and overall survival compared with whole-breast irradiation for patients with early-stage breast cancer who underwent breast-conserving surgery in a phase 3 randomised trial. Here, we present the 5-year late side-effects and cosmetic results of the trial. METHODS: We did this randomised, controlled, phase 3 trial at 16 centres in seven European countries. Women aged 40 years or older with stage 0-IIA breast cancer who underwent breast-conserving surgery with microscopically clear resection margins of at least 2 mm were randomly assigned 1:1, via an online interface, to receive either whole-breast irradiation of 50 Gy with a tumour-bed boost of 10 Gy or APBI with interstitial brachytherapy. Randomisation was stratified by study centre, menopausal status, and tumour type (invasive carcinoma vs ductal carcinoma in situ), with a block size of ten, according to an automated dynamic algorithm. Patients and investigators were not masked to treatment allocation. The primary endpoint of our initial analysis was ipsilateral local recurrence; here, we report the secondary endpoints of late side-effects and cosmesis. We analysed physician-scored late toxicities and patient-scored and physician-scored cosmetic results from the date of breast-conserving surgery to the date of onset of event. Analysis was done according to treatment received (as-treated population). This trial is registered with ClinicalTrials.gov, number NCT00402519. FINDINGS: Between April 20, 2004, and July 30, 2009, we randomly assigned 1328 women to receive either whole-breast irradiation (n=673) or APBI with interstitial brachytherapy (n=655); 1184 patients comprised the as-treated population (551 in the whole-breast irradiation group and 633 in the APBI group). At a median follow-up of 6·6 years (IQR 5·8-7·6), no patients had any grade 4 toxities, and three (<1%) of 484 patients in the APBI group and seven (2%) of 393 in the whole-breast irradiation group had grade 3 late skin toxicity (p=0·16). No patients in the APBI group and two (<1%) in the whole-breast irradiation group developed grade 3 late subcutaneous tissue toxicity (p=0·10). The cumulative incidence of any late side-effect of grade 2 or worse at 5 years was 27·0% (95% CI 23·0-30·9) in the whole-breast irradiation group versus 23·3% (19·9-26·8) in the APBI group (p=0·12). The cumulative incidence of grade 2-3 late skin toxicity at 5 years was 10·7% (95% CI 8·0-13·4) in the whole-breast irradiation group versus 6·9% (4·8-9·0) in the APBI group (difference -3·8%, 95% CI -7·2 to 0·4; p=0·020). The cumulative risk of grade 2-3 late subcutaneous tissue side-effects at 5 years was 9·7% (95% CI 7·1-12·3) in the whole-breast irradiation group versus 12·0% (9·4-14·7) in the APBI group (difference 2·4%; 95% CI -1·4 to 6·1; p=0·28). The cumulative incidence of grade 2-3 breast pain was 11·9% (95% CI 9·0-14·7) after whole-breast irradiation versus 8·4% (6·1-10·6) after APBI (difference -3·5%; 95% CI -7·1 to 0·1; p=0·074). At 5 years' follow-up, according to the patients' view, 413 (91%) of 454 patients had excellent to good cosmetic results in the whole-breast irradiation group versus 498 (92%) of 541 patients in the APBI group (p=0·62); when judged by the physicians, 408 (90%) of 454 patients and 503 (93%) of 542 patients, respectively, had excellent to good cosmetic results (p=0·12). No treatment-related deaths occurred, but six (15%) of 41 patients (three in each group) died from breast cancer, and 35 (85%) deaths (21 in the whole-breast irradiation group and 14 in the APBI group) were unrelated. INTERPRETATION: 5-year toxicity profiles and cosmetic results were similar in patients treated with breast-conserving surgery followed by either APBI with interstitial brachytherapy or conventional whole-breast irradiation, with significantly fewer grade 2-3 late skin side-effects after APBI with interstitial brachytherapy. These findings provide further clinical evidence for the routine use of interstitial multicatheter brachytherapy-based APBI in the treatment of patients with low-risk breast cancer who opt for breast conservation. FUNDING: German Cancer Aid.
EVALuna2:32911

LDRT induces long-lasting Pain and Immunomodulating Effects in chronic degenerative and inflammatory Diseases - Results from the IMMO-LDRT01 Study - Donaubauer, Anna-Jasmina; Weissmann, Thomas; Fröhlich, Birgitta; Becker, Ina; Ott, Oliver; Fietkau, Rainer; Gaipl, Udo; Frey, Benjamin (STRAHLENTHERAPIE UND ONKOLOGIE, 2022)
CRIS-Team WoS Importer:2022-06-03

Left breast irradiation with tangential intensity modulated radiotherapy (t-IMRT) versus tangential volumetric modulated arc therapy (t-VMAT): Trade-offs between secondary cancer induction risk and optimal target coverage - Karpf, Daniel; Sakka, Mazen; Metzger, Martin; Grabenbauer, Gerhard G. (Radiation Oncology, 2019)
Background: Adjuvant radiotherapy is the standard treatment after breast-conserving surgery. According to meta-analyses, adjuvant 3d-conventional irradiation reduces the risk of local recurrence and thereby improves long-term survival by 5-10%. However, there is an unintended exposure of organs such as the heart, lungs and contralateral breast. Irradiation of the left breast has been related to long-term effects like increased rates of coronary events as well as second cancer induction. Modern radiotherapy techniques such as tangential intensity modulated radiotherapy (t-IMRT) and tangential volumetric modulated arc therapy (t-VMAT) and particularly deep inspiration breath hold (DIBH) technique have been developed in order to improve coverage of target volume and to reduce dose to normal tissue. The aim of this study was to compare t-IMRT-plans with t-VMAT-plans in DIBH position for left-sided breast irradiation in terms of normal tissue exposure, i.e. of lungs, heart, left anterior descending coronary artery (LADCA), as well as homogeneity (HI) and conformity index (CI) and excess absolute risk (EAR) for second cancer induction for organs at risk (OAR) after irradiation. Methods: Twenty patients, diagnosed with left-sided breast cancer and treated with breast-preserving surgery, were included in this planning study. For each patient DIBH-t-IMRT plan using 5 to 7 beams and t-VMAT plan using four rotations were generated to achieve 95% dose coverage to 95% of the volume. Data were evaluated on the basis of dose-volume histograms: Cardiac dose and LADCA (mean and maximum dose, D25% and D45%), dose to ipsilateral and contralateral lung (mean, D20%, D30%), dose to contralateral breast (mean dose), total monitor units, V5% of total body and normal tissue integral dose (NTID). In addition, homogeneity index and conformity index, as well as the excess absolute risk (EAR) to estimate the risk of second malignancy were calculated. Results: T-IMRT showed a significant reduction in mean cardiac dose of 26% (p = 0.002) compared to t-VMAT, as well as a significant reduction in the mean dose to LADCA of 20% (p = 0.03). Following t-IMRT, mean dose to the left lung was increased by 5% (p = 0.006), whereas no significant difference was found in the mean dose to the right lung and contralateral breast between the two procedures. Monitor units were 31% (p = 0.000004) lower for t-IMRT than for t-VMAT. T-IMRT technique significantly reduced normal tissue integral dose (NTID) by 19% (p = 0.000005) and the V5% of total body by 24% (p = 0.0007). In contrast, t-VMAT improved CI and HI by 2% (p = 0.001) and 0.4% (p = 0.00001), respectively. EAR with t-IMRT was significantly lower, especially for contralateral lung and contralateral breast (2-5/10,000 person years) but not for ipsilateral lung. Conclusion: Compared to t-VMAT, t-IMRT in left-sided breast irradiation significantly reduced dose to organs at risk as well as normal tissue integral dose, and V5% total body. EAR with t-IMRT was significantly lower for contralateral lung and contralateral breast. T-VMAT, however, achieved better homogeneity and conformity. This may be relevant in individual cases where sufficient coverage of medial lymphatic target volumes is warranted.
CRIS-Team Scopus Importer:2019-09-17
Keywords: Breast cancer; Cardiac dose; Deep inspiration breath hold; Homogeneity index (HI) and conformity index (CI); Tangential intensity modulated radiotherapy (t-IMRT); Tangential volumetric modulated arc therapy (t-VMAT). Normal tissue integral dose (NTID)

Lessons learned after one year of COVID-19 from a urologist and radiotherapist view: A German survey on prostate cancer diagnosis and treatment - Harke, Nina N.; Wagner, Christian; Hermann, Robert M.; Hadaschik, Boris A.; Radtke, Jan Philipp; Altay-Langguth, Alev; Aufderklamm, Stefan; Bach, Christian; Becker-Schiebe, Martina; Blana, Andreas; Bruns, Frank; Buse, Stephan; et al. (PLoS ONE, 2022)
Introduction
CRIS-Team WoS Importer:2022-09-09

Lethal outcome after pelvic salvage radiotherapy in a patient with prostate cancer due to increased radiosensitivity : Case report and literature review - Fahrig, Antje; Koch, T.; Lenhart, M.; Rieckmann, P.; Fietkau, Rainer; Distel, Luitpold; Schuster, Barbara (Strahlentherapie und Onkologie, 2018)
BACKGROUND: In general, late side effects after salvage radiotherapy (RT) for prostate cancer are below 10%. Patients with impaired DNA repair ability and genetic instability can have significantly increased reactions after RT. CASE, CLINICAL FOLLOW-UP, AND EXAMINATION: We present a patient who experienced severe side effects after additive RT for prostate cancer and died from the complications 25 months after RT. Imaging (MR) is shown as well as three-color fluorescence in situ hybridization. The blood sample testing revealed that radiosensitivity was increased by 35-55%. We undertook a review of the literature to give an overview over the tests established that are currently considered useful. CONCLUSION: This case highlights that the identification of patients with increased radiosensitivity is an important task in radiation protection. Groups of patients who should be screened have to be found and corresponding research facilities have to be set up.
EVALuna2:32861

Letter comments on: The impact of isolated local recurrence on long-term outcome in early-breast cancer patients after breast-conserving therapy - Hannoun-Levi, Jean Michel; Gutierrez, Cristina; Polgar, Csaba; Strnad, Vratislav (European Journal of Cancer, 2021)
CRIS-Team Scopus Importer:2021-11-19

Leukocytosis and Neutrophilia as independent prognostic Biomarkers for clinical Outcome in the randomized Phase III CAO/ARO/AIO-04 Rectal Cancer Study - Diefenhardt, M.; Hofheinz, R-D; Martin, D.; Beissbarth, T.; Arnold, D.; Hartmann, Arndt; Von Der Grun, J.; Grützmann, Robert; Liersch, T.; Stroebel, P.; Grabenbauer, G. G.; Rieger, M.; et al. (STRAHLENTHERAPIE UND ONKOLOGIE, 2019)
CRIS-Team WoS Importer:2019-06-07

Leukocytosis and neutrophilia as independent prognostic immunological biomarkers for clinical outcome in the CAO/ARO/AIO-04 randomized phase 3 rectal cancer trial - Diefenhardt, Markus; Hofheinz, Ralf Dieter; Martin, Daniel; Beißbarth, Tim; Arnold, Dirk; Hartmann, Arndt; von der Grün, Jens; Grützmann, Robert; Liersch, Torsten; Ströbel, Philipp; Grabenbauer, Gerhard G.; Rieger, Michael; et al. (International Journal of Cancer, 2019)
Peripheral blood leukocytosis and neutrophilia reflect cancer inflammation and have been proposed as prognostic immunological biomarkers in various malignancies. However, previous studies were limited by their retrospective nature and small patient numbers. Baseline peripheral blood leukocytes, neutrophils, hemoglobin, platelets, lactate dehydrogenase and carcinoembryonic antigen (CEA) were correlated with clinicopathologic characteristics, and clinical outcome in 1236 patients with rectal cancer treated with 5-FU-based preoperative chemoradiotherapy (CRT) alone or with oxaliplatin followed by surgery and adjuvant chemotherapy within the CAO/ARO/AIO-04 randomized phase 3 trial. Multivariable analyses were performed using Cox regression models. After a median follow-up of 50 months, baseline leukocytosis remained an independent adverse prognostic factor for disease-free survival (DFS; HR 1.457; 95% CI 1.163–1.825; p = 0.001), distant metastasis (HR 1.696; 95% CI 1.266–2.273; p < 0.001) and overall survival (OS; HR 1.716; 95% CI 1.264–2.329; p = 0.001) in multivariable analysis. Similar significant findings were observed for neutrophilia and high CEA levels. Conversely, treatment-induced leukopenia correlated with favorable DFS (p = 0.037), distant metastasis (p = 0.028) and OS (p = 0.012). Intriguingly, addition of oxaliplatin to 5-FU CRT resulted in a significant DFS improvement only in patients with neutrophilia and leukocytosis (p = 0.028 and p = 0.002). Our findings have important clinical implications and provide high-level evidence on the adverse prognostic role of leukocytes and neutrophils, and the impact of chemotherapy in the context of these biomarkers. These data could help guide patient stratification and should be further validated within prospective studies.
CRIS-Team Scopus Importer:2019-05-07
Keywords: clinical radiotherapeutic studies; clinical trials; colorectal cancer; molecular markers of metastasis and progression; radiochemotherapy