Lipiodol injections for optimization of target volume delineation in a patient with a second tumor of the oropharynx: A case report - Haderlein, Marlen; Merten, Ricarda; Stojanovic, Andrea; Speer, Stefan; Scherl, Claudia; Fietkau, Rainer; Ott, Oliver J. (Strahlentherapie und Onkologie, 2015)
Lipiodol injections were administered in the head and neck area to improve gross tumor volume (GTV) definition for small-volume re-irradiation of a 63-year-old previously irradiated patient with a second tumor of the oropharynx in the posterior wall with longitudinal ligament infiltration (cT4cN0cM0).The patient had dialysis-depending renal failure. On diagnostic computed tomography (CT), which was performed with intravenous contrast agent, the tumor in the oropharynx was not detectable. Because of dialysis-depending renal failure comorbidity, no contrast agent was applied in the planning CT and in the diagnostic magnetic resonance imaging (MRI) study. In each cross-sectional imaging study performed, the GTV, especially in craniocaudal extensions, was not safely delineable. Therefore, craniocaudal tumor margins were pharyngoscopically marked with Lipiodol injections, an iodine-containing contrast agent.In a second planning CT, the GTV could be defined with the help of the Lipiodol marks and small-volume re-irradiation was performed. No Lipiodol-associated side effects occurred in the patient.In the present case, the use of Lipiodol injections at the tumor margins facilitated the definition of the GTV.
EVALuna2:18277

Local and systemic immunological Effects of intraoperative Radiotherapy (IORT) for Breast Cancer - Tiefenthaller, A.; Brix, N.; Hennel, R.; Pazos, M.; Kost, B.; Rack, B.; Von Bodungen,; Weissenbacher, T.; Wuerstlein, R.; Rühle, Paul-Friedrich; Gaipl, Udo; Harbeck, N.; et al. (STRAHLENTHERAPIE UND ONKOLOGIE, 2020)
CRIS-Team WoS Importer:2020-10-02

Local hyperthermia combined with radiotherapy and-/or chemotherapy: recent advances and promises for the future - Datta, N. R.; Ordonez, S. Gomez; Gaipl, Udo; Paulides, M. M.; Crezee, H.; Gellermann, J.; Marder, D.; Puric, E.; Bodis, S. (Cancer Treatment Reviews, 2015)
Hyperthermia, one of the oldest forms of cancer treatment involves selective heating of tumor tissues to temperatures ranging between 39 and 45°C. Recent developments based on the thermoradiobiological rationale of hyperthermia indicate it to be a potent radio- and chemosensitizer. This has been further corroborated through positive clinical outcomes in various tumor sites using thermoradiotherapy or thermoradiochemotherapy approaches. Moreover, being devoid of any additional significant toxicity, hyperthermia has been safely used with low or moderate doses of reirradiation for retreatment of previously treated and recurrent tumors, resulting in significant tumor regression. Recent in vitro and in vivo studies also indicate a unique immunomodulating prospect of hyperthermia, especially when combined with radiotherapy. In addition, the technological advances over the last decade both in hardware and software have led to potent and even safer loco-regional hyperthermia treatment delivery, thermal treatment planning, thermal dose monitoring through noninvasive thermometry and online adaptive temperature modulation. The review summarizes the outcomes from various clinical studies (both randomized and nonrandomized) where hyperthermia is used as a thermal sensitizer of radiotherapy and-/or chemotherapy in various solid tumors and presents an overview of the progresses in loco-regional hyperthermia. These recent developments, supported by positive clinical outcomes should merit hyperthermia to be incorporated in the therapeutic armamentarium as a safe and an effective addendum to the existing oncological treatment modalities.
EVALuna2:18302

Localization of reference points in electromagnetic tracking data and their application for treatment error detection in interstitial breast brachytherapy - Dürrbeck, Christopher; Schuster, Sabrina; Sauer, Birte; Abu-Hossin, Nadin; Strnad, Vratislav; Fietkau, Rainer; Bert, Christoph (Medical Physics, 2023)
Background: Electromagnetic tracking (EMT) is a promising technology that holds great potential to advance patient-specific pre-treatment verification in interstitial brachytherapy (iBT). It allows easy determination of the implant geometry without line-of-sight restrictions and without dose exposure to the patient. What it cannot provide, however, is a link to anatomical landmarks, such as the exit points of catheters or needles on the skin surface. These landmarks are required for the registration of EMT data with other imaging modalities and for the detection of treatment errors such as incorrect indexer lengths, and catheter or needle shifts. Purpose: To develop an easily applicable method to detect reference points in the positional data of the trajectory of an EMT sensor, specifically the exit points of catheters in breast iBT, and to apply the approach to pre-treatment error detection. Methods: Small metal objects were attached to catheter fixation buttons that rest against the breast surface to intentionally induce a local, spatially limited perturbation of the magnetic field on which the working principle of EMT relies. This perturbation can be sensed by the EMT sensor as it passes by, allowing it to localize the metal object and thus the catheter exit point. For the proof-of-concept, different small metal objects (magnets, washers, and bushes) and EMT sensor drive speeds were used to find the optimal parameters. The approach was then applied to treatment error detection and validated in-vitro on a phantom. Lastly, the in-vivo feasibility of the approach was tested on a patient cohort of four patients to assess the impact on the clinical workflow. Results: All investigated metal objects were able to measurably perturb the magnetic field, which resulted in missing sensor readings, that is two data gaps, one for the sensor moving towards the tip end and one when retracting from there. The size of the resulting data gaps varied depending on the choice of gap points used for calculation of the gap size; it was found that the start points of the gaps in both directions showed the smallest variability. The median size of data gaps was ⩽8 mm for all tested materials and sensor drive speeds. The variability of the determined object position was ⩽0.5 mm at a speed of 1.0 cm/s and ⩽0.7 mm at 2.5 cm/s, with an increase up to 2.3 mm at 5.0 cm/s. The in-vitro validation of the error detection yielded a 100% detection rate for catheter shifts of ≥2.2 mm. All simulated wrong indexer lengths were correctly identified. The in-vivo feasibility assessment showed that the metal objects did not interfere with the routine clinical workflow. Conclusions: The developed approach was able to successfully detect reference points in EMT data, which can be used for registration to other imaging modalities, but also for treatment error detection. It can thus advance the automation of patient-specific, pre-treatment quality assurance in iBT.
CRIS-Team Scopus Importer:2023-07-28
Keywords: brachytherapy; electromagnetic tracking; error detection; quality assurance

LOCAL LOW DOSE RADIATION INDUCES SYSTEMIC IMMUNE ALTERATIONS IN TWO EXPERIMENTAL MODELS OF INFLAMMATORY ARTHRITIS - Deloch, Lisa; Rückert, Michael; Seeling, Michaela; Nimmerjahn, Falk; Fietkau, Rainer; Frey, Benjamin; Gaipl, Udo (ANNALS OF THE RHEUMATIC DISEASES, 2019)
CRIS-Team WoS Importer:2019-05-17

Local tumor control probability modeling of primary and secondary lung tumors in stereotactic body radiotherapy - Guckenberger, Matthias; Klement, Rainer J.; Allgaeuer, Michael; Andratschke, Nicolaus; Blanck, Oliver; Boda-Heggemann, Judit; Dieckmann, Karin; Duma, Marciana; Ernst, Iris; Ganswindt, Ute; Hass, Peter; Henkenberens, Christoph; et al. (Radiotherapy and Oncology, 2016)
To evaluate whether local tumor control probability (TCP) in stereotactic body radiotherapy (SBRT) varies between lung metastases of different primary cancer sites and between primary non-small cell lung cancer (NSCLC) and secondary lung tumors.A retrospective multi-institutional (n=22) database of 399 patients with stage I NSCLC and 397 patients with 525 lung metastases was analyzed. Irradiation doses were converted to biologically effective doses (BED). Logistic regression was used for local tumor control probability (TCP) modeling and the second-order bias corrected Akaike Information Criterion was used for model comparison.After median follow-up of 19 months and 16 months (n.s.), local tumor control was observed in 87.7% and 86.7% of the primary and secondary lung tumors (n.s.), respectively. A strong dose-response relationship was observed in the primary NSCLC and metastatic cohort but dose-response relationships were not significantly different: the TCD90 (dose to achieve 90% TCP; BED of maximum planning target volume dose) estimates were 176 Gy (151-223) and 160 Gy (123-237) (n.s.), respectively. The dose-response relationship was not influenced by the primary cancer site within the metastatic cohort.Dose-response relationships for local tumor control in SBRT were not different between lung metastases of various primary cancer sites and between primary NSCLC and lung metastases.
EVALuna2:18346

Local X-ray Therapy induces systemic Immune Modulations in an experimental Model of rheumatoid Arthritis - Deloch, Lisa; Rueckert, M.; Seeling, Michaela; Nimmerjahn, Falk; Fietkau, Rainer; Frey, Benjamin; Gaipl, Udo (STRAHLENTHERAPIE UND ONKOLOGIE, 2020)
CRIS-Team WoS Importer:2020-09-25

Locoregional recurrence in anal cancer: risk factors and management strategies - Gryc, Thomas; Putz, Florian; Merten, Ricarda; Goerig, Nicole; Fietkau, Rainer; Strnad, Vratislav (2017)
EVALuna2:32883

Longitudinal C-reactive protein (CRP) as an individualized dynamic predictor for metastatic cancer patients treated with immune checkpoint inhibitors: Findings from the prospective ST-ICI cohort. - Zhou, Jian-Guo; Ma, Hu; Gaipl, Udo; Frey, Benjamin; Hecht, Markus; Fietkau, Rainer (CANCER RESEARCH, 2021)
CRIS-Team WoS Importer:2021-09-03

Longitudinal Spread Analysis of Patients with Glioblastoma: high Prevalence of discontinuous Tumor Foci with no strong Relation to the Fibrous Tract System - Schmitter, Charlotte; Weissmann, Thomas; Mansoorian, Sina; Lettmaier, Sebastian; Semrau, Sabine; Schmidt, Manfred; Heiß, Rafael; Frey, Benjamin; Bert, Christoph; Fietkau, Rainer; Putz, Florian (STRAHLENTHERAPIE UND ONKOLOGIE, 2021)
CRIS-Team WoS Importer:2021-07-16

Long-term control with chemoradiation of initially metastatic mixed adenoneuroendocrine carcinoma of the rectum: A case report - Semrau, S.; Agaimy, Abbas; Pavel, Marianne Ellen; Lubgan, Dorota; Schmidt, Daniela; Golcher, H.; Grützmann, Robert; Fietkau, Rainer; Cavallaro, Alexander Josef (Journal of Medical Case Reports, 2019)
Background: Mixed adenoneuroendocrine carcinomas are highly malignant tumors with both adenocarcinomatous and neuroendocrine components. They can originate in any organ but are more common in the rectum. Due to their rarity, current treatment recommendations for mixed adenoneuroendocrine carcinoma are based on limited data and follow general guidelines for the management of adenocarcinomas and neuroendocrine neoplasms. Uncertainty regarding the efficacy of the available local and systemic treatment strategies is a compounding issue. Even those patients with locally limited disease have a relatively short life expectancy. In this report, we describe a case of deep rectal mixed adenoneuroendocrine carcinoma with long survival after chemoradiation. Case presentation: A 48-year-old Caucasian woman was diagnosed with a grade 3 rectal adenocarcinoma combined with a poorly differentiated large cell neuroendocrine carcinoma component and synchronous metastases (cT3cN1cM1) in both lobes of the liver in 2012. She received concomitant chemoradiotherapy followed by four additional cycles of cisplatin plus irinotecan. Initial treatment induced complete remission of the rectal tumor and liver metastases. Consequently, it was not necessary to surgically resect the primary tumor or any of the metastases. Three months after the end of treatment, one metastasis in the first segment of the liver showed regrowth, and stereotactic body radiotherapy of the metastasis and chemotherapy resulted in a clinical complete response. The patient has been recurrence-free for more than 5 years. Conclusions: Extended long-term control of a poorly differentiated metastatic (stage IV) mixed adenoneuroendocrine carcinoma is rare. The multimodal first- and second-line regimens of radiotherapy and chemotherapy described in this case report represent a new therapeutic approach. Encouraged by the results in this case, we compiled a review of the literature on mixed adenoneuroendocrine carcinoma.
CRIS-Team Scopus Importer:2019-05-14
Keywords: Chemoradiation; MANEC; Rectum; SBRT

Long-term durability of Starr-Edwards disk mitral valve prosthesis over 46 years - Strecker, Thomas; Agaimy, Abbas; Roesch, Johannes; Jasinski, Dominik (Journal of Cardiac Surgery, 2020)
CRIS-Team Scopus Importer:2020-05-08
Keywords: cardiac surgery; computed tomography; echocardiography; long-term durability; mechanical mitral valve prosthesis

Long-Term Experience of Chemoradiotherapy Combined with Deep Regional Hyperthermia for Organ Preservation in High-Risk Bladder Cancer (Ta, Tis, T1, T2) - Merten, Ricarda; Ott, Oliver; Haderlein, Marlen; Bertz, Simone; Hartmann, Arndt; Wullich, Bernd; Keck, Bastian; Kühn, Reinhard; Rödel, Claus Michael; Weiss, Christian; Gall, Christine; Uter, Wolfgang; et al. (Oncologist, 2019)
Background: The aim of this study was to evaluate the efficacy and safety of chemoradiotherapy (RCT) combined with regional deep hyperthermia (RHT) of high-risk bladder cancer after transurethral resection of bladder tumor (TUR-BT). Materials and methods: Between 1982 and 2016, 369 patients with pTa, pTis, pT1, and pT2 cN0–1 cM0 bladder cancer were treated with a multimodal treatment after TUR-BT. All patients received radiotherapy (RT) of the bladder and regional lymph nodes. RCT was administered to 215 patients, RCT + RHT was administered to 79 patients, and RT was used in 75 patients. Treatment response was evaluated 4–6 weeks after treatment with TUR-BT. Results: Complete response (CR) overall was 83% (290/351), and in treatment groups was RT 68% (45/66), RCT 86% (178/208), and RCT + RHT 87% (67/77). CR was significantly improved by concurrent RCT compared with RT (odds ratio [OR], 2.32; 95% confidence interval [CI], 1.05–5.12; p =.037), less influenced by hyperthermia (OR, 2.56; 95% CI, 0.88–8.00; p =.092). Overall survival (OS) after RCT was superior to RT (hazard ratio [HR], 0.7; 95% CI, 0.50–0.99; p =.045). Five-year OS from unadjusted Kaplan-Meier estimates was RCT 64% versus RT 45%. Additional RHT increased 5-year OS to 87% (HR, 0.32; 95% CI, 0.18–0.58; p =.0001). RCT + RHT compared with RCT showed a significantly better bladder-preservation rate (HR, 0.13; 95% CI, 0.03–0.56; p =.006). Median follow-up was 71 months. The median number of RHT sessions was five. Conclusion: The multimodal treatment consisted of a maximal TUR-BT followed by RT; concomitant platinum-based chemotherapy combined with RHT in patients with high-grade bladder cancer improves local control, bladder-preservation rate, and OS. It offers a promising alternative to surgical therapies like radical cystectomy. Implications for Practice: Radical cystectomy with appropriate lymph node dissection has long represented the standard of care for muscle-invasive bladder cancer in medically fit patients, despite many centers reporting excellent long-term results for bladder preserving strategies. This retrospective analysis compares different therapeutic modalities in bladder-preservation therapy. The results of this study show that multimodal treatment consisting of maximal transurethral resection of bladder tumor followed by radiotherapy, concomitant platinum-based chemotherapy combined with regional deep hyperthermia in patients with Ta, Tis, T1–2 bladder carcinomas improves local control, bladder-preservation rate, and survival. More importantly, these findings offer a promising alternative to surgical therapies like radical cystectomy. The authors hope that, in the future, closer collaboration between urologists and radiotherapists will further improve treatments and therapies for the benefit of patients.
CRIS-Team Scopus Importer:2019-08-13
Keywords: Bladder cancer; Bladder preservation; Chemoradiotherapy; Hyperthermia; Radiotherapy

Long‐term follow‐up of patients receiving neoadjuvant treatment modalties for soft tissue sarcomas of the extremities - Rauch, Miriam; Agaimy, Abbas; Semrau, Sabine; Willner, Alexander; Ott, Oliver; Fietkau, Rainer; Hohenberger, Werner; Croner, Roland S.; Grützmann, Robert; Fechner, Katja; Vassos, Nikolaos (Cancers, 2021)
Background: Neoadjuvant treatment modalities in soft tissue sarcoma (STS) of the extremities have become more popular in recent years, but because of the rarity and heterogeneity of STS, there are yet few studies on the long‐term impact of neoadjuvant treatment modalities, especially in terms of neoadjuvant radiochemotherapy. Methods: The study enrolled 136 patients with primary STS of the extremities who underwent surgery with curative intent or neoadjuvant therapy, followed by surgery in a 15‐year period. Neoadjuvant treatment consisted of radiotherapy (RT) with 60 Gy and in most cases simultaneous chemotherapy (CTx) with ifosfamide (1.5 g/m2/d, d1–5, q28) and doxorubicine (50 mg/m2/d, d3, q28). We investigated the clinical, (post)‐operative and histopathological data and the oncological follow‐up as well. The median follow‐up period was 82 months (range 6–202). Results: A total of 136 patients (M:F = 73:63) with a mean age of 62 years (range; 21–93) was observed. Seventy‐four patients (54.4%) received neoadjuvant therapy (NT), 62 patients (45.6%) received primary surgery (PS). When receiving NT, patients with high‐risk STS had a lower risk to develop distant metastasis (p = 0.025). Age, histological type, tumor size and surgical margins (R0 vs. R1) had no influence on any survival rates. There was an association between NT and the occurrence of postoperative complications (p = 0.001). The 5‐year local recurrence free survival (LRFS), metastasis free survival (MFS), disease free survival (DFS) and overall survival (OS) rate of the whole cohort was 89.9%, 77.0%, 70.6% and 72.6%; whereas the 5‐year LRFS, MFS, DFS and OS rate was 90.5%, 67.2%, 64.1% and 62.8% for the NT group and 89.5%, 88.3%. 78.4% and 83.8% for the PS group. Conclusion: Multimodal treatment strategies in patients with STS of extremities lead to excellent oncological outcomes. Patients with high‐risk STS had a significantly better MFS when receiving NT than patients with low‐risk STS. NT was associated with a higher probability of postoperative but well‐manageable complications.
CRIS-Team Scopus Importer:2021-10-29
Keywords: Extremity; Neoadjuvant therapy; Radiation; Radiochemotherapy; Soft tissue sarcoma

Long-term prognostic impact of surgical complications in the German Rectal Cancer Trial CAO/ARO/AIO-94 - Sprenger, T.; Beissbarth, T.; Sauer, Rolf; Tschmelitsch, J.; Fietkau, Rainer; Liersch, T.; Hohenberger, Werner; Staib, L.; Gaedcke, J.; Raab, H. -R.; Roedel, C.; Ghadimi, M. (British Journal of Surgery, 2018)
BACKGROUND: The influence of postoperative complications on survival in patients with locally advanced rectal cancer undergoing combined modality treatment is debatable. This study evaluated the impact of surgical complications on oncological outcomes in patients with locally advanced rectal cancer treated within the randomized CAO/ARO/AIO-94 (Working Group of Surgical Oncology/Working Group of Radiation Oncology/Working Group of Medical Oncology of the Germany Cancer Society) trial. METHODS: Patients were assigned randomly to either preoperative chemoradiotherapy (CRT) followed by total mesorectal excision (TME) or postoperative CRT between 1995 and 2002. Anastomotic leakage and wound healing disorders were evaluated prospectively, and their associations with overall survival, and distant metastasis and local recurrence rates after a long-term follow-up of more than 10 years were determined. Medical complications (such as cardiopulmonary events) were not analysed in this study. RESULTS: A total of 799 patients were included in the analysis. Patients who had anterior or intersphincteric resection had better 10-year overall survival than those treated with abdominoperineal resection (63·1 versus 51·3 per cent; P < 0·001). Anastomotic leakage was associated with worse 10-year overall survival (51 versus 65·2 per cent; P = 0·020). Overall survival was reduced in patients with impaired wound healing (45·7 versus 62·2 per cent; P = 0·009). At 10 years after treatment, patients developing any surgical complication (anastomotic leakage and/or wound healing disorder) had impaired overall survival (46·6 versus 63·8 per cent; P < 0·001), a lower distant metastasis-free survival rate (63·2 versus 72·0 per cent; P = 0·030) and more local recurrences (15·5 versus 6·4 per cent; P < 0·001). In a multivariable Cox regression model, lymph node metastases (P < 0·001) and surgical complications (P = 0·008) were the only independent predictors of reduced overall survival. CONCLUSION: Surgical complications were associated with adverse oncological outcomes in this trial.
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Long-term results of a protocol-based ultrasound-guided salvage brachytherapy as re-irradiation for local recurrent prostate cancer - Schönle, Nicole; Strnad, Vratislav; Lotter, Michael; Kreppner, Stephan; Fietkau, Rainer (Radiotherapy and Oncology, 2020)
Background and purpose: To assess the long-term results of protocol-based ultrasound-guided salvage pulsed-dose rate brachytherapy in locally recurrent prostate cancer following previous radiation therapy. Materials and methods: A total of 82 patients (median age 69 years) with locally recurrent prostate cancer after previous external beam radiation therapy (43/82, 52.4%), prostatectomy and adjuvant radiation therapy (24/82, 29.3%) or brachytherapy (15/82, 18.3%) were treated with sole salvage interstitial pulsed-dose rate brachytherapy (PDR-BT). The treatment regimen consisted of two PDR-BT sections with 30 Gy (single pulse dose 0.6 Gy/h, 24 h per day) each up to a total reference dose of 60 Gy (EQD2 = 71.5 Gy-eq). The endpoints of the present analysis are cumulative local recurrence-rate, PSA-free survival, overall survival and the treatment-associated late toxicity according to the “Common Toxicity Criteria” with a median follow-up of 49 months (range, 12–129 months). Results: The 5-y. overall cumulative local recurrence rate was 17.7% with no significant differences between low, intermediate and high-risk groups. Differences in PSA-free survival were marginally non-significant, at 67.3%, 70.4% and 63.8% for low, intermediate and high risk group, respectively. No grade 3 gastrointestinal late side effects have been observed. The most common late side effect was urinary incontinence grade 1–3 and urinary frequency/urgency grade 1–3 in 18.3% (15/82) and 17.1% (14/82) of patients, respectively. Conclusion: PDR salvage brachytherapy in local recurrent previously irradiated prostate cancer is efficient with low late toxicity. Salvage-brachytherapy represents a valuable therapeutic option for the treatment of previously irradiated locally recurrent prostate cancer.
CRIS-Team Scopus Importer:2020-07-24
Keywords: Prostate cancer; Re-irradiation; Salvage-brachytherapy

Long-term Results of oligometastatic Head and Neck Tumors after local Treatment of all Metastases - Weissmann, T.; Höfler, Daniel; Semrau, S.; Lettmaier, S.; Fietkau, Rainer; Putz, Florian (STRAHLENTHERAPIE UND ONKOLOGIE, 2019)
CRIS-Team WoS Importer:2019-06-07

Long-Term Results of the TARGIT-A Trial: More Questions than Answers - Piroth, Marc D.; Strnad, Vratislav; Krug, David; Fastner, Gerd; Baumann, Rene; Combs, Stephanie E.; Duma, Marciana Nona; Dunst, Juergen; Feyer, Petra; Fietkau, Rainer; Haase, Wulf; Harms, Wolfgang; et al. (Breast Care, 2021)
Background: During the last decade, partial breast irradiation (PBI) has gained traction as a relevant treatment option for patients with early-stage low-risk breast cancer after breast-conserving surgery. The TARGIT-A prospective randomized trial compared a "risk-adapted" intraoperative radiotherapy (IORT) approach with 50-kv X-rays (INTRABEAM (R)) as the PBI followed by optional whole-breast irradiation (WBI) and conventional adjuvant WBI in terms of observed 5-year in-breast recurrence rates. Recently, long-term data were published. Since the first publication of the TARGIT-A trial, a broad debate has been emerged regarding several uncertainties and limitations associated with data analysis and interpretation. Our main objective was to summarize the data, with an emphasis on the updated report and the resulting implications. Summary: From our point of view, the previously unresolved questions still remain and more have been added, especially with regard to the study design, a change in the primary outcome measure, the significant number of patients lost to follow-up, and the lack of a subgroup analysis according to risk factors and treatment specifications. Key Message: Taking into account the abovementioned limitations of the recently published long-term results of the TARGIT-A trial, the German Society of Radiation Oncology (DEGRO) Breast Cancer Expert Panel adheres to its recently published recommendations on PBI: "the 50-kV system (INTRABEAM) cannot be recommended for routine adjuvant PBI treatment after breast-conserving surgery."
CRIS-Team WoS Importer:2021-04-23

Long-Term Survival after Salvage Surgery for Local Failure after Definitive Chemoradiation Therapy for Locally Advanced Non-small Cell Lung Cancer - Schreiner, Waldemar; Dudek, Wojciech; Lettmaier, Sebastian; Fietkau, Rainer; Sirbu, Horia (Thoracic and Cardiovascular Surgeon, 2018)
BACKGROUND: The incidence of local failure and residual tumor after definitive chemoradiation therapy (dCRT) for locally advanced non-small-cell lung cancer remains high, irrespective of applied radiation dose (>59 Gy). So-called salvage surgery has been suggested as a feasible treatment option after failure of definitive chemoradiation for locally advanced non-small cell lung cancer (NSCLC). Experience with salvage lung surgery (SLS) is limited, and long-term survival is rarely reported. Patient selection criteria for surgical lung salvage are not defined. The aim of this study was to assess postoperative survival and perioperative morbidity/mortality to identify prognostic factors and to define patient selection criteria. PATIENTS AND METHODS: Records of 13 consecutive patients with locally advanced NSCLC, who underwent SLS at a single institution between March 2011 and November 2016, were reviewed. Descriptive statistics were applied for patient characteristics and surgical and oncological outcome. Survival rates were calculated using the Kaplan-Meier method and were compared with the long-rank test. RESULTS: All patients initially received curative-intent definitive chemoradiation with median radiation doses of 66 Gy (range 59.4-72) and concurrent platinum-based chemotherapy. Clinical tumor stage before definitive chemoradiation was IIIA in 9, IIIB in 3, IV in 1 patients. Median interval between definitive chemoradiation and salvage surgery was 6.7 months. Perioperative morbidity and 30-days-mortality was 38% and 7.7%, respectively. The median postoperative survival and estimated 5-year survival rate were 29.7 months and 46%, respectively. CONCLUSION: SLS in patients with locally advanced non-small cell lung surgery following dCRT is feasible, prolongs long-term survival and allows local tumor control. Selection criteria remain undefined and patients should be considered surgical candidates during multidisciplinary team conference.
EVALuna2:35734

Low and moderate doses of ionizing radiation up to 2 Gy modulate transmigration and chemotaxis of activated macrophages, provoke an anti-inflammatory cytokine milieu, but do not impact upon viability and phagocytic function - Wunderlich, Roland; Ernst, A.; Roedel, F.; Fietkau, Rainer; Ott, O.; Lauber, K.; Frey, Benjamin; Gaipl, Udo (Clinical and Experimental Immunology, 2015)
Benign painful and inflammatory diseases have been treated for decades with low/moderate doses of ionizing radiation (LD-X-irradiation). Tissue macrophages regulate initiation and resolution of inflammation by the secretion of cytokines and by acting as professional phagocytes. Having these pivotal functions, we were interested in how activated macrophages are modulated by LD-X-irradiation, also with regard to radiation protection issues and carcinogenesis. We set up an ex-vivo model in which lipopolysaccharide pre-activated peritoneal macrophages (pM?) of radiosensitive BALB/c mice, mimicking activated macrophages under inflammatory conditions, were exposed to X-irradiation from 0·01 Gy up to 2 Gy. Afterwards, the viability of the pM?, their transmigration and chemotaxis, the phagocytic behaviour, the secretion of inflammatory cytokines and underlying signalling pathways were determined. Exposure of pM? up to a single dose of 2 Gy did not influence their viability and phagocytic function, an important fact regarding radiation protection. However, significantly reduced migration, but increased chemotaxis of pM? after exposure to 0·1 or 0·5 Gy, was detected. Both might relate to the resolution of inflammation. Cytokine analyses revealed that, in particular, the moderate dose of 0·5 Gy applied in low-dose radiotherapy for inflammatory diseases results in an anti-inflammatory cytokine microenvironment of pM?, as the secretion of the proinflammatory cytokine interleukin (IL)-1? was reduced and that of the anti-inflammatory cytokine transforming growth factor (TGF)-? increased. Further, the reduced secretion of IL-1? correlated with reduced nuclear translocation of nuclear factor (NF)-?B p65, starting at exposure of pM? to 0·5 Gy of X-irradiation. We conclude that inflammation is modulated by LD-X-irradiation via changing the inflammatory phenotype of macrophages.
EVALuna2:18185

Low cytoplasmic and nuclear KPNA2 expression in radiotherapy-treated head and neck squamous cell cancer is associated with an adverse outcome - Erben, Pia; Brunner, Kathrin; Hecht, Markus; Haderlein, Marlen; Buettner-Herold, Maike; Agaimy, Abbas; Fietkau, Rainer; Hartmann, Arndt; Distel, Luitpold (International Journal of Clinical and Experimental Pathology, 2015)
KPNA2 has effects on carcinogenesis, cell differentiation and transcriptional regulation. KPNA2 has been linked to DNA damage repair by its role to import the DNA double strand break repair complex MRN into the nucleus. The aim of our study was to evaluate the prognostic value of KPNA2 expression in both cytoplasmic and nuclear location in patients with HNSCC treated with radio(chemo)therapy.225 patients with HNSCC treated with neoadjuvant, definitive or adjuvant radio(chemo)therapy were included. Immunohistochemical staining was performed on tissue micro arrays to evaluate nuclear and cytoplasmic KPNA2 expression.The median fraction of tumor cells with nuclear KPNA2 expression was 15%. 47% of tumor samples showed positive cytoplasmic staining. Patients with low nuclear as well as negative cytoplasmic expression tended to have an unfavorable prognosis. There was no correlation between nuclear and cytoplasmic KPNA2 expression. Low nuclear combined with negative cytoplasmic KPNA2 had a clearly unfavorable prognostic effect in local failure-free survival (P=0.014), metastasis-free survival (P=0.001) and no evidence of disease (P=0.008). A combination of low nuclear/negative cytoplasmic with high nuclear/high cytoplasmic KPNA2 expression was prognostically unfavorable with regard to tumor specific survival (P=0.021) and to a lower extent to overall survival (P=0.18). In multivariate analysis low nuclear/negative cytoplasmic versus any high KPNA2 (P=0.008) and T-category (P=0.002) proved as independent prognostic variables.The combination of nuclear and cytoplasmic KPNA2 expression is a potential excellent prognostic parameter in HNSCC treated with radio(chemo)therapy.
EVALuna2:6796

LOW-DOSE IONISING RADIATION INHIBITS ADIPOKINE INDUCED INFLAMMATION IN RHEUMATOID ARTHRITIS - Shreder, K.; Cucu, A.; Deloch, Lisa; Frey, Benjamin; Gaipl, Udo; Durante, M.; Fournier, C. (2016)
EVALuna2:32936

Low dose ionising radiation leads to a NF-?B dependent decreased secretion of active IL-1? by activated macrophages with a discontinuous dose-dependency - Lödermann, Barbara; Wunderlich, Roland; Frey, Silke; Schorn, Christine; Stangl, Sonja; Roedel, Franz; Keilholz, Ludwig; Fietkau, Rainer; Gaipl, Udo; Frey, Benjamin (International Journal of Radiation Biology, 2012)
Therapy with low doses of ionising radiation (X-rays) exerts anti-inflammatory effects. Little is known about whether and how low doses of X-ray treatment modulate the inflammatory phenotype of macrophages, especially the secretion of Interleukin-1beta (IL-1?).Macrophages were differentiated from human THP-1 monocytes, activated with lipopolysaccharide (LPS), treated with distinct low doses of X-rays, and co-activated with monosodium urate crystals (MSU) to induce inflammasome activation. Secretion of IL-1? was analysed by an enzyme-linked immunosorbent assay (ELISA) and Western blot. Furthermore, we analysed the intracellular amounts of the serine/threonine protein kinase B (named: Akt), mitogen-activated protein kinase p38 (p38), the v-rel reticuloendotheliosis viral oncogene homolog A (RelA), and pro- and cleaved IL-1?.Low dose X-rays led to decreased secretion of active IL-1? in a manner discontinuous with dose which was most pronounced after 0.5 or 0.7 Gy. Passive release of lactate dehydrogenase (LDH) was not influenced by X-rays. The decreased secretion of IL-1? correlated with reduced translocation of RelA, being part of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-?B) complex, into the nucleus. After 0.5 or 0.7 Gy of X-rays, the intracellular protein amounts of up (p38) and downstream molecules (Akt) of NF-?B were reduced in activated macrophages, as were the pro- and cleaved forms of IL-1?.Distinct low doses of X-rays induce an anti-inflammatory phenotype of activated macrophages by lowering the amount of secreted IL-1? in a NF-?B dependent manner.
EVALuna2:12777

Low-Dose Irradiation Differentially Impacts Macrophage Phenotype in Dependence of Fibroblast-Like Synoviocytes and Radiation Dose - Fuchs, Jana; Rueckert, Michael; Fietkau, Rainer; Frey, Benjamin; Gaipl, Udo; Deloch, Lisa (Journal of Immunology Research, 2019)
Rheumatoid arthritis (RA) is a multifactorial autoimmune disease whose main hallmark is inflammation and destruction of the joints. Two cell types within the synovium that play an important role in RA are fibroblast-like synoviocytes (FLS) and macrophages. The latter innate immune cells show a high plasticity in their phenotype and are central in inflammatory processes. Low-dose radiotherapy (LD-RT) with particularly a single dose of 0.5 Gy has been demonstrated to have a positive impact on pain, inflammation, and bone in inflamed joints. We now examined for the first time how LD-RT influences FLS and bone marrow-derived macrophages in co-culture systems of an experimental model of RA to reveal further mechanisms of immune modulatory effects of low and intermediate dose of ionizing radiation. For this, the bone marrow of hTNF-alpha tg mice was differentiated either with cytokines to obtain key macrophage phenotypes (M0, M1, and M2) or with supernatants (SN) of untreated or irradiated FLS. Flow cytometry analyses were used to analyse the impact of radiation (0.1, 0.5, 1.0, and 2.0 Gy) on the phenotype of macrophages in the presence or absence of SN of FLS. LD-RT had no impact on cytokine-mediated macrophage polarization in M0, M1, or M2 macrophages. However, SN of irradiated FLS particularly reduced CD206 expression on macrophages. Macrophage phenotype was stable when being in contact with SN of nonirradiated FLS, but significantly increased surface expression of CD206 and slightly decreased CD80 and CD86 expression were observed when macrophage themselves were irradiated with 0.5 Gy under these microenvironmental conditions, again highlighting discontinuous dose dependencies in the low and intermediate dose range. One can conclude that FLS-dependent microenvironmental conditions have a slight influence on the modulation of macrophage phenotype under radiation exposure conditions. Future studies are needed to reveal the impact of radiation exposure on the functions of treated macrophages under such microenvironmental conditions.
CRIS-Team WoS Importer:2019-09-13

Low-dose irradiation has an impact on bone metabolism as well as on local and systemic immune cell-mediated inflammation - Deloch, Lisa; Rückert, Michael; Seeling, Michaela; Nimmerjahn, Falk; Fietkau, Rainer; Frey, Benjamin; Gaipl, Udo (2018)
EVALuna2:36495

Low-dose irradiation reduces fibroblast-like synoviocytes and impacts on bone metabolism in dependence of the inflammatory state - Liberg, J.; Fietkau, Rainer; Frey, Benjamin; Gaipl, Udo; Deloch, Lisa (2017)
EVALuna2:32878

Low-dose irradiation shifts macrophages to a more immune suppressive phenotype in a clinically relevant setting together with inflammatory fibroblast-like synoviocytes - Liberg, J.; Rueckert, M.; Fietkau, Rainer; Frey, Benjamin; Gaipl, Udo; Deloch, Lisa (2017)
EVALuna2:32887

Low dose radiation alters the inflammatory phenotype of fibroblast-like synoviocytes and impacts on bone metabolism - Frey, Benjamin; Liberg, J.; Derer, Anja; Fietkau, Rainer; Gaipl, Udo; Deloch, Lisa (2017)
EVALuna2:32862

LOW DOSE RADIATION ALTERS THE INFLAMMATORY PHENOTYPE OF FIBROBLAST-LIKE SYNOVIOCYTES AND MACROPHAGES AND STIMULATES OSTEOBLASTS - Deloch, Lisa; Liberg, Jana; Rückert, Michael; Hueber, Axel; Fietkau, Rainer; Frey, Benjamin; Gaipl, Udo (2017)
EVALuna2:32907

LOW DOSE RADIATION HAS A POSITIVE IMPACT ON BONE METABOLISM IN AN EXPERIMENTAL MODEL OF INFLAMMATORY ARTHRITIS - Deloch, Lisa; Rückert, Michael; Hueber, Axel; Herrmann, Martin; Fietkau, Rainer; Frey, Benjamin; Gaipl, Udo (2018)
EVALuna2:36516

Low-dose radiation therapy for COVID-19 pneumopathy: what is the evidence? - Roedel, Franz; Arenas, Meritxell; Ott, Oliver; Fournier, Claudia; Georgakilas, Alexandros G.; Tapio, Soile; Trott, Klaus-Ruediger; Gaipl, Udo (Strahlentherapie und Onkologie, 2020)
In the current dismal situation of the COVID-19 pandemic, effective management of patients with pneumonia and acute respiratory distress syndrome is of vital importance. Due to the current lack of effective pharmacological concepts, this situation has caused interest in (re)considering historical reports on the treatment of patients with low-dose radiation therapy for pneumonia. Although these historical reports are of low-level evidence per se, hampering recommendations for decision-making in the clinical setting, they indicate effectiveness in the dose range between 0.3 and 1 Gy, similar to more recent dose concepts in the treatment of acute and chronic inflammatory/degenerative benign diseases with, e.g., a single dose per fraction of 0.5 Gy. This concise review aims to critically review the evidence for low-dose radiation treatment of COVID-19 pneumopathy and discuss whether it is worth investigating in the present clinical situation.
CRIS-Team Scopus Importer:2020-05-22
Keywords: Anti-inflammatory; COVID-19; Low-dose radiation therapy; Pneumonia; SARS-CoV-2

Low Dose Radiation Therapy Induces Long-Lasting Reduction of Pain and Immune Modulations in the Peripheral Blood - Interim Analysis of the IMMO-LDRT01 Trial - Donaubauer, Anna-Jasmina; Becker, Ina; Weissmann, Thomas; Fröhlich, Birgitta; Munoz, Luis Enrique; Gryc, Thomas; Denzler, Manuel; Ott, Oliver; Fietkau, Rainer; Gaipl, Udo; Frey, Benjamin (Frontiers in Immunology, 2021)
The treatment of chronic inflammatory and degenerative diseases by low dose radiation therapy (LDRT) is promising especially for patients who were refractory for classical therapies. LDRT aims to reduce pain of patients and to increase their mobility. Although LDRT has been applied since the late 19th century, the immunological mechanisms remain elusive. Within the prospective IMMO-LDRT01 trial (NCT02653079) the effects of LDRT on the peripheral blood immune status, as well as on pain and life quality of patients have been analyzed. Blood is taken before and after every serial irradiation with a single dose per fraction of 0.5Gy, as well as during follow-up appointments in order to determine a detailed longitudinal immune status by multicolor flow cytometry. Here, we report the results of an interim analysis of 125 patients, representing half the number of patients to be recruited. LDRT significantly improved patients' pain levels and induced distinct systemic immune modulations. While the total number of leukocytes remained unchanged in the peripheral blood, LDRT induced a slight reduction of eosinophils, basophils and plasmacytoid dendritic cells and an increase of B cells. Furthermore, activated immune cells were decreased following LDRT. Especially cells of the monocytic lineage correlated to LDRT-induced improvements of clinical symptoms, qualifying these immune cells as predictive biomarkers for the therapeutic success. We conclude that LDRT improves pain of the patients by inducing systemic immune modulations and that immune biomarkers could be defined for prediction by improved patient stratification in the future.
CRIS-Team WoS Importer:2021-11-12

Low dose radiation therapy, particularly with 0.5 gy, improves pain in degenerative joint disease of the fingers: Results of a retrospective analysis - Donaubauer, Anna-Jasmina; Zhou, Jianguo; Ott, Oliver J.; Putz, Florian; Fietkau, Rainer; Keilholz, Ludwig; Gaipl, Udo; Frey, Benjamin; Weissmann, Thomas (International Journal of Molecular Sciences, 2020)
Low-dose radiation therapy (LDRT) has been successfully established for decades as an alternative analgesic treatment option for patients suffering from chronic degenerative and inflammatory diseases. In this study, 483 patients were undergoing LDRT for degenerative joint disease of the fingers and thumb at the University Hospital Erlangen between 2004 and 2019. Radiotherapy was applied according to the German guidelines for LDRT. Several impact factors on therapeutic success, such as the age and gender, the number of affected fingers, the single and cumulative dose, as well as the number of series, were investigated. In summary, 70% of the patients showed an improvement of their pain following LDRT. No significant impact was found for the factors age, gender, the number of series or the cumulative dosage. Patients with an involvement of the thumb showed a significantly worse outcome compared to patients with an isolated affection of the fingers. In this cohort, patients receiving a single dose of 0.5 Gy reported a significantly better outcome than patients receiving 1.0 Gy, strongly suggesting a reduction in the total dose. In summary, LDRT is a good alternative treatment option for patients suffering from degenerative and inflammatory joint disease of the fingers.
CRIS-Team Scopus Importer:2020-08-28
Keywords: Chronic degenerative and inflammatory diseases; Degenerative joint disease of the fingers; LDRT; Low-dose radiation therapy; Osteoarthritis; Subjective pain level

Low-Dose Radiotherapy Ameliorates Advanced Arthritis in hTNF-α tg Mice by Particularly Positively Impacting on Bone Metabolism - Deloch, Lisa; Derer, Anja; Hueber, Axel; Herrmann, Martin; Schett, Georg; Wölfelschneider, Jens; Hahn, Jonas; Rühle, Paul-Friedrich; Stillkrieg, Willy; Fuchs, Jana; Fietkau, Rainer; Frey, Benjamin; et al. (Frontiers in Immunology, 2018)
Inflammation and bone erosion are central in rheumatoid arthritis (RA). Even though effective medications for control and treatment of RA are available, remission is only seen in a subset of patients. Treatment with low-dose radiotherapy (LD-RT) which has been already successfully used for amelioration of symptoms in benign diseases should be a promising approach to reduce pain, inflammation, and particularly bone erosion in patients with RA. Even though anti-inflammatory effects of LD-RT are already described with non-linear dose response relationships, and pain-reducing effects have been clinically observed, the underlying mechanisms are widely unknown. Besides immune cells many other cell types, such as fibroblast-like synoviocytes (FLS), osteoclasts, and osteoblast are present in the affected joint and might be modulated by LD-RT. For this study, these cell types were obtained from human tumor necrosis factor-α transgenic (hTNF-α tg) mice and were consecutively exposed to different doses of ionizing radiation (0.1, 0.5, 1.0, and 2.0 Gy, respectively) in vitro. In order to study the in vivo effects of LD-RT within the arthritic joint, hind paws of arthritic hTNF-α tg mice were locally irradiated with 0.5 Gy, a single dose per fraction that is known for good clinical responses. Starting at a dose of 0.5 Gy, proliferation of FLS was reduced and apoptosis significantly enhanced with no changes in necrosis. Further, expression of RANK-L was slightly reduced following irradiation with particularly 0.5 Gy. Starting from 0.5 Gy, the numbers of differentiated osteoclasts were significantly reduced, and a lower bone resorbing activity of treated osteoclasts was also observed, as monitored via pit formation and Cross Laps presence. LD-RT had further a positive effect on osteoblast-induced mineralization in a discontinuous dose response relationship with 0.5 Gy being most efficient. An increase of the gene expression ratio of OPG/RANK-L at 0.1 and 0.5 Gy and of production of OPG at 0.5 and 1.0 Gy was observed. In vivo, LD-RT resulted in less severe arthritis in arthritic hTNF-α tg mice and in significant reduction of inflammatory and erosive area with reduced osteoclasts and neutrophils. Locally applied LD-RT can, therefore, induce a beneficial micro-environment within arthritic joints by predominantly positively impacting on bone metabolism.
EVALuna2:34663
Keywords: rheumatoid arthritis; inflammation; low-dose radiotherapy; bone metabolism; synovial-like fibroblasts; osteoclasts; osteoblasts

Low-dose Radiotherapy for painful Finger Joint Arthrosis - Weissmann, T.; Ott, Oliver; Putz, Florian; Becker, Ina; Fietkau, Rainer; Donaubauer, Anna-Jasmina; Frey, Benjamin (STRAHLENTHERAPIE UND ONKOLOGIE, 2020)
CRIS-Team WoS Importer:2020-09-25

Low-Dose Radiotherapy Has No Harmful Effects on Key Cells of Healthy Non-Inflamed Joints - Deloch, Lisa; Rückert, Michael; Fietkau, Rainer; Frey, Benjamin; Gaipl, Udo (International Journal of Molecular Sciences, 2018)
Low-dose radiotherapy (LD-RT) for benign inflammatory and/or bone destructive diseases has been used long. Therefore, mechanistic investigations on cells being present in joints are mostly made in an inflammatory setting. This raises the question whether similar effects of LD-RT are also seen in healthy tissue and thus might cause possible harmful effects. We performed examinations on the functionality and phenotype of key cells within the joint, namely on fibroblast-like synoviocytes (FLS), osteoclasts and osteoblasts, as well as on immune cells. Low doses of ionizing radiation showed only a minor impact on cytokine release by healthy FLS as well as on molecules involved in cartilage and bone destruction and had no significant impact on cell death and migration properties. The bone resorbing abilities of healthy osteoclasts was slightly reduced following LD-RT and a positive impact on bone formation of healthy osteoblasts was observed after in particular exposure to 0.5 Gray (Gy). Cell death rates of bone-marrow cells were only marginally increased and immune cell composition of the bone marrow showed a slight shift from CD8⁺ to CD4⁺ T cell subsets. Taken together, our results indicate that LD-RT with particularly a single dose of 0.5 Gy has no harmful effects on cells of healthy joints.
EVALuna2:36453

Low-Dose Radiotherapy is highly effective in the Treatment of painful Finger Polyarthrosis - Weissmann, Thomas; Gaipl, Udo; Putz, Florian; Hecht, Markus; Donaubauer, Anna-Jasmina; Zhou, Jianguo; Fietkau, Rainer; Ott, Oliver; Frey, Benjamin (STRAHLENTHERAPIE UND ONKOLOGIE, 2021)
CRIS-Team WoS Importer:2021-07-16

Low-dose Radiotherapy is highly effective in the Treatment of Patients with painful Ankle Arthrosis - Weissmann, Thomas; Putz, Florian; Hecht, Markus; Zhou, Jianguo; Donaubauer, Anna-Jasmina; Fietkau, Rainer; Gaipl, Udo; Ott, Oliver; Frey, Benjamin (STRAHLENTHERAPIE UND ONKOLOGIE, 2021)
CRIS-Team WoS Importer:2021-07-16

Low-Dose Radiotherapy Leads to a Systemic Anti-Inflammatory Shift in the Pre-Clinical K/BxN Serum Transfer Model and Reduces Osteoarthritic Pain in Patients - Weissmann, Thomas; Rückert, Michael; Zhou, Jianguo; Seeling, Michaela; Lettmaier, Sebastian; Donaubauer, Anna-Jasmina; Nimmerjahn, Falk; Ott, Oliver; Hecht, Markus; Putz, Florian; Fietkau, Rainer; Frey, Benjamin; et al. (Frontiers in Immunology, 2022)
Osteoarthritis (OA) is the leading degenerative joint disease in the western world and leads, if left untreated, to a progressive deterioration of joint functionality, ultimately reducing quality of life. Recent data has shown, that especially OA of the ankle and foot are among the most frequently affected regions. Current research in OA points towards a complex involvement of various cell and tissue types, often accompanied by inflammation. Low-dose radiotherapy (LDRT) is widely used for the treatment of degenerative and inflammatory diseases. While the reported analgesic effects are well known, the underlying molecular mechanisms are only poorly understood. We therefore correlated a clinical approach, looking at pain reduction in 196 patients treated with LDRT with a pre-clinical approach, utilizing the K/BxN serum transfer mouse model using flow cytometry and multiplex ELISA for analysis. While an improvement of symptoms in the majority of patients was found, patients suffering from symptoms within the tarsi transversa show a significantly lower level of improvement. Further, a significant impact of therapy success was detected depending on whether only one or both feet were affected. Further, patients of younger age showed a significantly better outcome than older ones while needing fewer treatment series. When looking on a cellular level within the mouse model, a systemic alteration of immune cells namely a shift from CD8+ to CD4+ T cells and reduced numbers of DCs was observed. A general reduction of inflammatory cytokines was detected, with significant alterations in IL-4 and IL-17 levels, all of which could potentially be responsible for the highly effective clinical improvement in patients. Taken together our data indicate that LDRT can be regarded as a highly effective treatment option for patients suffering from OA of the foot and ankle, in terms of analgesic effects, especially in younger patients. Furthermore, the observed effects are mediated by an interplay of cellular and soluble immune factors, as observed in the K/BxN serum transfer model. With this interdisciplinary approach we aim to encourage the usage of LDRT as an additive treatment strategy not only as a last resort, but also earlier in the course of disease.
CRIS-Team Scopus Importer:2022-01-28
Keywords: foot; K/BxN serum transfer; low-dose radiotherapy; mouse model; osteoarthritis; pain; rheumatoid arthritis; X-rays

Low-dose radiotherapy: Mayday, mayday. We've been hit! - Ott, Oliver J.; Micke, Oliver; Muecke, Ralph; Niewald, Marcus; Roedel, Franz; Schaefer, Ulrich; Seegenschmiedt, M. H.; Arenas, Meritxell; Frey, Benjamin; Gaipl, Udo (Strahlentherapie und Onkologie, 2019)
CRIS-Team WoS Importer:2019-04-09

Low-dose radiotherapy of osteoarthritis: from biological findings to clinical effects-challenges for future studies - Weissmann, Thomas; Rückert, Michael; Putz, Florian; Donaubauer, Anna-Jasmina; Hecht, Markus; Schnellhardt, Sören; Schubert, Philipp; Roesch, Johannes; Höfler, Daniel; Ott, Oliver; Haderlein, Marlen; Lettmaier, Sebastian; et al. (Strahlentherapie und Onkologie, 2023)

Low-dose Radiotherapy with X-rays and Radon leads to different immunological Changes in a Mouse Model for Rheumatoid Arthritis - Deloch, Lisa; Rückert, Michael; Maier, A.; Hinrichs, A.; Weissmann, T.; Seeling, Michaela; Nimmerjahn, Falk; Flohr, A. -S.; Eckert, D.; Fournier, C.; Fietkau, Rainer; Frey, Benjamin; et al. (STRAHLENTHERAPIE UND ONKOLOGIE, 2022)
CRIS-Team WoS Importer:2022-06-03

Low-dose-rate Prostate Brachytherapy: Characterization of Seeds Dynamics within the Prostate - Karius, Andre; Lotter, M.; Kreppner, Stephan; Lubgan, Dorota; Grigo, Johanna; Fietkau, Rainer; Strnad, Vratislav; Bert, Christoph (STRAHLENTHERAPIE UND ONKOLOGIE, 2022)
CRIS-Team WoS Importer:2022-06-03

Low-dose X-Rays influence the Macrophage Polarization interacting with Synovial Fibroblasts in an anti-inflammatory Manner - Fuchs, J.; Rueckert, M.; Fietkau, Rainer; Frey, Benjamin; Gaipl, Udo; Deloch, Lisa (STRAHLENTHERAPIE UND ONKOLOGIE, 2019)
CRIS-Team WoS Importer:2019-06-07

Low-grade (polymorphous) adenocarcinoma of the middle ear mimicking a jugulotympanic paraganglioma - Mantsopoulos, Konstantinos; Fietkau, Rainer; Hornung, Joachim; Agaimy, Abbas; Iro, Heinrich; Taha, Lava (HNO, 2021)
A 64-year-old female patient presented with otalgia and hearing loss in the right ear. On otoscopy, the right tympanic membrane was highly vascularized and bulged into the anteroinferior quadrant. High-resolution computed tomography revealed an osteolytic lesion with occupation of the hypotympanum extending into the petrous apex and right parapharyngeal space as well as infiltration of the wall of the right internal carotid artery. MRI strengthened the suspicion of a jugulotympanic paraganglioma. The biopsy material obtained through exploratory tympanotomy was assessed as a low-grade polymorphic adenocarcinoma. The tumor was treated with definitive chemoradiotherapy. Posttherapeutic imaging after 4 months did not show any evidence of tumor progression.
CRIS-Team WoS Importer:2021-06-18

Low-grade (polymorphous) adenocarcinoma of the middle ear mimicking a jugulotympanic paraganglioma. German version - Mantsopoulos, Konstantinos; Fietkau, Rainer; Hornung, Joachim; Agaimy, Abbas; Iro, Heinrich; Taha, Lava (HNO, 2021)
A 64-year-old female patient presented with otalgia and hearing loss in the right ear. On otoscopy, the right tympanic membrane was highly vascularized and bulged into the anteroinferior quadrant. High-resolution computed tomography revealed an osteolytic lesion with occupation of the hypotympanum extending into the petrous apex and right parapharyngeal space as well as infiltration of the wall of the right internal carotid artery. MRI strengthened the suspicion of a jugulotympanic paraganglioma. The biopsy material obtained through exploratory tympanotomy was assessed as a low-grade polymorphic adenocarcinoma. The tumor was treated with definitive chemoradiotherapy. Posttherapeutic imaging after 4 months did not show any evidence of tumor progression.
CRIS-Team WoS Importer:2021-05-07

Low- vs. high-dose radiotherapy in Graves’ ophthalmopathy: a retrospective comparison of long-term results - Weissmann, Thomas; Lettmaier, Sebastian; Donaubauer, Anna-Jasmina; Bert, Christoph; Schmidt, Manfred; Kruse, Friedrich; Ott, Oliver; Hecht, Markus; Fietkau, Rainer; Frey, Benjamin; Putz, Florian (Strahlentherapie und Onkologie, 2021)
Purpose: Radiotherapy represents an effective treatment option in Graves’ ophthalmopathy (GO), leading to palliation of clinical symptoms. However, there are only a limited number of trials comparing the effectiveness of low- vs. high-dose radiotherapy. Methods: We analyzed 127 patients treated with radiotherapy for stage 3/4 GO (NOSPECS classification). Patients were treated with single doses of 2.0 Gy (cumulative dose 20 Gy) until 2007, afterwards a single dose of 0.8 Gy (cumulative dose 4.8 Gy) was applied. With a median follow-up-time of 9.0 years, the treatment efficacy (overall improvement, sense of eye pressure, lid edema, ocular motility, exophthalmos, subjective vision, and diplopia) and adverse effects were analyzed by a standardized survey. Results: Overall, 63.8% described improvement of symptoms after radiotherapy. No significant differences in overall treatment response and improvement of main outcome measures between low- or high-dose radiotherapy treatments are detectable, while low-dose radiotherapy leads significantly more often to retreatment (13.1% vs. 1.7%, p = 0.016). The main independent predictor of treatment response is the presence of lid edema (odds ratio, OR, 3.53; p = 0.006). Conclusion: At long-term follow-up, the majority of patients reported palliation of symptoms with limited adverse effects, suggesting clinical effectiveness of radiotherapy for amelioration of GO symptoms independent of low- or high-dose radiotherapy.
CRIS-Team Scopus Importer:2021-05-07
Keywords: Exophthalmos; Graves’ ophthalmopathy; Low dose radiation therapy; Radiotherapy; Thyroid eye disease

Lung Resection after Definitive and Neo-Adjuvant Chemoradiation for Stage IIIA/B Locally Advanced Non-Small Cell Lung Cancer: a Retrospective Analysis - Schreiner, Waldemar; Gavrychenkova, Sofiia; Dudek, Wojciech; Lettmaier, Sebastian; Rieker, Ralf; Fietkau, Rainer; Sirbu, Horia (Zentralblatt für Chirurgie, 2018)
BACKGROUND: The outcomes of so called "salvage" resections after definitive chemoradiation vs. curative resections after neoadjuvant chemoradiation therapy (IT-resection) in patients with stage IIIA/B locally advanced non-small cell lung cancer have rarely been compared. The aim of our study was to compare perioperative results, postoperative and recurrence-free survival and to identify relevant prognostic survival factors for both therapy strategies. PATIENTS AND METHODS: Between June 2008 and May 2017, 43 patients underwent pulmonary resection following induction therapy (group 1) and 14 patients underwent salvage resection after definitive chemoradiation (group 2). Retrospective analysis was performed of demographic factors, tumour stage and location, initial therapy, preoperative regression status, perioperative morbidity and mortality, postoperative and recurrence-free survival. RESULTS: In group 2, significantly higher radiation dose was applied (p < 0.001) and the interval between chemoradiation and lung resection was significantly longer (p = 0.02). In addition, significantly higher perioperative blood loss and more frequent blood transfusions were noted (p = 0.003 and 0.005, respectively). Perioperative morbidity and mortality were statistically comparable in the two groups (p = 0.72 and 0.395, respectively). Postoperative 5 year survival in group 1 was 55%, in group 2 48% (log-rank p = 0.353). Five year recurrence-free survival in group 1 was 53%, in group 2 42% (log-rank p = 0.180). Diffuse metastasis occurred mostly in group 2, whereas in group 1 oligometastasis was more frequently noted. CONCLUSION: Postoperative outcome after salvage resection seems statistically comparable to results following curative resection after induction therapy. Diffuse distant metastasis is frequently noted. Careful patient selection is required.
EVALuna2:35732

Machine Learning-assisted immunophenotyping of peripheral blood identifies innate immune cells as best predictor of response to induction chemo-immunotherapy in head and neck squamous cell carcinoma – knowledge obtained from the CheckRad-CD8 trial - Hecht, Markus; Frey, Benjamin; Gaipl, Udo; Tianyu, Xie; Eckstein, Markus; Donaubauer, Anna-Jasmina; Klautke, Gunther; Illmer, Thomas; Fleischmann, Maximilian; Laban, Simon; Hautmann, Matthias G.; Tamaskovics, Bálint; et al. (Neoplasia, 2024)
Purpose: Individual prediction of treatment response is crucial for personalized treatment in multimodal approaches against head-and-neck squamous cell carcinoma (HNSCC). So far, no reliable predictive parameters for treatment schemes containing immunotherapy have been identified. This study aims to predict treatment response to induction chemo-immunotherapy based on the peripheral blood immune status in patients with locally advanced HNSCC. Methods: The peripheral blood immune phenotype was assessed in whole blood samples in patients treated in the phase II CheckRad-CD8 trial as part of the pre-planned translational research program. Blood samples were analyzed by multicolor flow cytometry before (T1) and after (T2) induction chemo-immunotherapy with cisplatin/docetaxel/durvalumab/tremelimumab. Machine Learning techniques were used to predict pathological complete response (pCR) after induction therapy. Results: The tested classifier methods (LDA, SVM, LR, RF, DT, and XGBoost) allowed a distinct prediction of pCR. Highest accuracy was achieved with a low number of features represented as principal components. Immune parameters obtained from the absolute difference (lT2-T1l) allowed the best prediction of pCR. In general, less than 30 parameters and at most 10 principal components were needed for highly accurate predictions. Across several datasets, cells of the innate immune system such as polymorphonuclear cells, monocytes, and plasmacytoid dendritic cells are most prominent. Conclusions: Our analyses imply that alterations of the innate immune cell distribution in the peripheral blood following induction chemo-immuno-therapy is highly predictive for pCR in HNSCC.
CRIS-Team Scopus Importer:2024-01-26
Keywords: Chemotherapy; HNSCC; Immune phenotyping; Immunotherapy; Induction therapy

Machine learning based on blood biomarkers predicts fast progression in advanced NSCLC patients treated with immunotherapy - Zhou, J-G.; Yang, J.; Wang, H.; Wong, A. H-H.; Tan, F.; Chen, X.; He, S.; Shen, G.; Wang, Y-J.; Frey, B.; Fietkau, Rainer; Hecht, Markus; et al. (ANNALS OF ONCOLOGY, 2022)
CRIS-Team WoS Importer:2022-04-29

Macrophages and dendritic cells as actors in the immune reaction of classical hodgkin lymphoma - Tudor, Christiane; Bruns, Heiko; Daniel, Christoph; Distel, Luitpold; Hartmann, Arndt; Gerbitz, Armin; Büttner, Maike (PLoS ONE, 2014)
The inflammatory infiltrate plays a pivotal role in classical Hodgkin lymphoma (cHL). Here, we focussed on the role of macrophages (M?) and dendritic cells (DC).M? and DC infiltration was investigated in 106 cHL specimens using immunohistochemistry and cytokine expression was analyzed in a subset by real-time PCR. Human peripheral blood-derived monocytes, DC, M? stimulated with GM-CSF (M?GM-CSF, pro-inflammatory M?-1-model) or M-CSF (M?M-CSF, immunomodulatory M?-2-model) were incubated with cHL cell line (L1236, HDLM2) supernatants (SN). DC maturation or M? polarization were investigated by flow cytometry. Furthermore, the impact of DC or M? on cHL cell proliferation was analyzed by BrdU/CFSE assay.In cHL tissues mature myeloid (m)DC and M? predominated. High numbers of CD83+ mDC and low numbers of CD163+ M? were associated with improved disease specific survival. In numerous cHL specimens increased levels of both pro- and anti-inflammatory cytokines and of IL13 and GM-CSF were observed compared to reactive lymphadenopathies. Maturation of DC and induction and maintenance of an immunomodulatory M? phenotype were promoted by SN derived from cHL cell lines. TNF? neutralization in SN resulted in a significant inhibition of mDC maturation. DC and pro-inflammatory M? inhibited the proliferation of cHL cells.Adopting an immunomodulatory phenotype is a potential mechanism for how M? promote immune evasion in cHL. Mature DC, in contrast, might participate in antitumoral immunit
EVALuna2:6630

Magnetic resonance cinematography of the fingers: a 3.0 Tesla feasibility study with comparison of incremental and continuous dynamic protocols - Bayer, Thomas; Adler, Werner; Janka, Rolf Matthias; Uder, Michael; Roemer, Frank (Skeletal Radiology, 2017)
To study the feasibility of magnetic resonance cinematography of the fingers (MRCF) with comparison of image quality of different protocols for depicting the finger anatomy during motion.MRCF was performed during a full flexion and extension movement in 14 healthy volunteers using a finger-gating device. Three real-time sequences (frame rates 17-59 images/min) and one proton density (PD) sequence (3 images/min) were acquired during incremental and continuous motion. Analyses were performed independently by three readers. Qualitative image analysis included Likert-scale grading from 0 (useless) to 5 (excellent) and specific visual analog scale (VAS) grading from 0 (insufficient) to 100 (excellent). Signal-to-noise calculation was performed. Overall percentage agreement and mean absolute disagreement were calculated.Within the real-time sequences a high frame-rate true fast imaging with steady-state free precession (TRUFI) yielded the best image quality with Likert and overall VAS scores of 3.0 ± 0.2 and 60.4 ± 25.3, respectively. The best sequence regarding image quality was an incremental PD with mean values of 4.8 ± 0.2 and 91.2 ± 9.4, respectively. Overall percentage agreement and mean absolute disagreement were 47.9 and 0.7, respectively. No statistically significant SNR differences were found between continuous and incremental motion for the real-time protocols.MRCF is feasible with appropriate image quality during continuous motion using a finger-gating device. Almost perfect image quality is achievable with incremental PD imaging, which represents a compromise for MRCF with the drawback of prolonged scanning time.
EVALuna2:14720

Magnetic resonance imaging for brain stereotactic radiotherapy - A review of requirements and pitfalls - Putz, Florian; Mengling, Veit; Perrin, Rosalind; Masitho, Siti; Weissmann, Thomas; Roesch, Johannes; Bäuerle, Tobias; Janka, Rolf Matthias; Uder, Michael; Amarteifio, Patrick; Doussin, Sylvain; Schmidt, Manuel; et al. (Strahlentherapie und Onkologie, 2020)
Due to its superior soft tissue contrast, magnetic resonance imaging (MRI) is essential for many radiotherapy treatment indications. This is especially true for treatment planning in intracranial tumors, where MRI has a long-standing history for target delineation in clinical practice. Despite its routine use, care has to be taken when selecting and acquiring MRI studies for the purpose of radiotherapy treatment planning. Requirements on MRI are particularly demanding for intracranial stereotactic radiotherapy, where accurate imaging has a critical role in treatment success. However, MR images acquired for routine radiological assessment are frequently unsuitable for high-precision stereotactic radiotherapy as the requirements for imaging are significantly different for radiotherapy planning and diagnostic radiology. To assure that optimal imaging is used for treatment planning, the radiation oncologist needs proper knowledge of the most important requirements concerning the use of MRI in brain stereotactic radiotherapy. In the present review, we summarize and discuss the most relevant issues when using MR images for target volume delineation in intracranial stereotactic radiotherapy.
CRIS-Team WoS Importer:2020-04-10

Magnetic Resonance thermometry images of hyperthermia treatments of sarcomas for prediction of therapy responses-need of data reprocessing and cleaning - Khatun, Rupali; Hader, Michael; Schmidt, Manfred; Bert, Christoph; Wadepohl, Martin; Fietkau, Rainer; Ott, Jessica; Gaipl, Udo; Frey, Benjamin (STRAHLENTHERAPIE UND ONKOLOGIE, 2022)
CRIS-Team WoS Importer:2022-06-03

Major Pathologic Response after Induction Therapy Has a Long-Term Impact on Survival and Tumor Recurrence in Stage IIIA/B Locally Advanced NSCLC - Schreiner, Waldemar; Dudek, Wojciech; Rieker, Ralf; Lettmaier, Sebastian; Fietkau, Rainer; Sirbu, Horia (Thoracic and Cardiovascular Surgeon, 2019)
BACKGROUND: Major pathologic response (MPR) determines favorable outcome in locally advanced non-small cell lung cancer after induction therapy (IT) followed by lung resection. The aim of this retrospective study was to identify the prognostic relevance of MPR in long-term interval. METHODS: In 55 patients, the survival rate according to MPR and non-MPR was estimated by Kaplan-Meier method and compared using log-rank, Breslow, and Tarone-Ware tests. RESULTS: The IT included chemoradiation with 50.4 Gy (range: 45-56.4 Gy) combined with platinum-based chemotherapy in 52 patients (94.5%) and platinum-based chemotherapy in 3 patients (5.5%). Perioperative morbidity and 30-day mortality were 36 and 3.6%, respectively. The estimated 5-year postoperative and progressive-free survivals were statistically significantly improved in MPR versus non-MPR with 53.5 versus 18% and 49.4 versus 18.5%, respectively. According to the log-rank, Breslow, and Tarone-Ware tests, the MPR demonstrates prognostic significance in early, long-term, and whole postoperative interval. CONCLUSION: MPR is associated with a robust correlation to long-term postoperative and recurrence-free survival improvement, and can potentially simplify the multidisciplinary debate and allow further stratification of adjuvant treatment in multimodality therapy.
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Management of advanced hypopharyngeal and laryngeal cancer with and without cartilage invasion - Scherl, Claudia; Mantsopoulos, Konstantinos; Semrau, Sabine; Fietkau, Rainer; Kapsreiter, Markus; Koch, Michael; Traxdorf, Maximilian; Grundtner, Philipp; Iro, Heinrich (Auris Nasus Larynx, 2016)
To compare efficacy, in terms of disease control/survival in advanced hypopharyngeal and laryngeal lesions, according to treatment strategy (primary surgery, PS or primary chemoradiotherapy, CRT) and invasion pattern (cartilage, CAI or soft tissue involvement, STI).Records from 463 patients with T3 and T4a carcinoma with CAI (n=221) or STI (n=242) treated at a university clinic over 18 years were retrospectively reviewed.Disease-specific survival (DSS) for the CAI group was 70.1% (PS) and 38.4% (CRT), and 76.6% and 46% for the STI group, respectively. Overall survival (OS) for STI was 56.4% (PS) and 30.6% (CRT), and for CAI 51.1% (PS) and 28.5% (CRT) respectively. Positive resection margins and regional neck metastases reduced survival. T3 lesions treated non-operatively still had significantly improved survival versus T4a by >20%.Surgery remains an indispensable part of treatment in local advanced hypopharyngeal and laryngeal cancer with high survival results. It should be part of a concept that includes adjuvant (C)RT. For T3 lesions, primary CRT is also acceptable and CAI is not a contraindication for primary CRT. Regional disease is a strong prognostic factor. In spite of adjuvant treatment, DSS deteriorates by about 20% in cases with positive resection margins.
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Management of organ motion in scanned ion beam therapy - Bert, Christoph; Herfarth, Klaus (Radiation Oncology, 2017)
Scanned ion beam therapy has special demands for treatment of intra-fractionally moving tumors such as lesions in lung or liver. Interplay effects between beam and organ motion can in those settings lead to under-dosage of the target volume. Dedicated treatment techniques such as gating or abdominal compression are required. In addition 4D treatment planning should be used to determine strategies for patient specific treatment planning such as an increased beam focus or the use of internal target volumes incorporating range changes.Several work packages of the Clinical Research Units 214 and 214/2 funded by the German Research Council investigated the management of organ motion in scanned ion beam therapy. A focus was laid on 4D treatment planning using TRiP4D and the development of motion mitigation strategies including their quality assurance. This review focuses on the activity in the second funding period covering adaptive treatment planning strategies, 4D treatment plan optimization, and the application of motion management in pre-clinical research on radiation therapy of cardiac arrhythmias.
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Measures of infection prevention and incidence of SARS-CoV-2 infections in cancer patients undergoing radiotherapy in Germany, Austria and Switzerland - Matuschek, Christiane; Fischer, Johannes C.; Combs, Stephanie E.; Fietkau, Rainer; Corradini, Stefanie; Zaenker, Kurt; Boelke, Edwin; Djiepmo-Njanang, Freddy-Joel; Tamaskovics, Balint; Fischer, Joachim E.; Stuschke, Martin; Poettgen, Christoph; et al. (Strahlentherapie und Onkologie, 2020)
Purpose: COVID-19 infection has manifested as a major threat to both patients and healthcare providers around the world. Radiation oncology institutions (ROI) deliver a major component of cancer treatment, with protocols that might span over several weeks, with the result of increasing susceptibility to COVID-19 infection and presenting with a more severe clinical course when compared with the general population. The aim of this manuscript is to investigate the impact of ROI protocols and performance on daily practice in the high-risk cancer patients during this pandemic. Methods: We addressed the incidence of positive COVID-19 cases in both patients and health care workers (HCW), in addition to the protective measures adopted in ROIs in Germany, Austria and Switzerland using a specific questionnaire. Results: The results of the questionnaire showed that a noteworthy number of ROIs were able to complete treatment in SARS-CoV‑2 positive cancer patients, with only a short interruption. The ROIs reported a significant decrease in patient volume that was not impacted by the circumambient disease incidence, the type of ROI or the occurrence of positive cases. Of the ROIs 16.5% also reported infected HCWs. About half of the ROIs (50.5%) adopted a screening program for patients whereas only 23.3% also screened their HCWs. The range of protective measures included the creation of working groups, instituting home office work and protection with face masks. Regarding the therapeutic options offered, curative procedures were performed with either unchanged or moderately decreased schedules, whereas palliative or benign radiotherapy procedures were more often shortened. Most ROIs postponed or cancelled radiation treatment for benign indications (88.1%). The occurrence of SARS-CoV‑2 infections did not affect the treatment options for curative procedures. Non-university-based ROIs seemed to be more willing to change their treatment options for curative and palliative cases than university-based ROIs. Conclusion: Most ROIs reported a deep impact of SARS-CoV‑2 infections on their work routine. Modification and prioritization of treatment regimens and the application of protective measures preserved a well-functioning radiation oncology service and patient care.
CRIS-Team Scopus Importer:2020-09-25
Keywords: COVID-19; Oncology; Pandemic; Patient care; Radiation oncoloy

Measuring the systemic immune-modulating effects of radiation - Frey, Benjamin; Gaipl, Udo (2018)
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Mechanism of necrotic Cell Clearance by non-professional Phagocytes - Hofmann, Andrea; Seeberg, J.; Fietkau, Rainer; Distel, Luitpold (2018)
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Medication safety in patients treated with new oral antitumor agents: A prospective, randomized investigation on the impact of intensified clinical pharmaceutical/clinical pharmacological care on patient safety, patient knowledge and patient well-being (AMBORA). Supported by the German Cancer Aid within the Comprehensive Cancer Center Erlangen-EMN - Schlichtig, Katja; Lechner, P.; Grafe, Carolin; Ferstl, B.; Fuchs, F.; Hein, Alexander; Meidenbauer, N.; Sell, C.; Semrau, S.; Pavel, Marianne Ellen; Wullich, Bernd; Neurath, Markus; et al. (2018)
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Metabolic Response of Short-term Induction Chemotherapy (IC) for Therapy Selection as well as Prediction of long-term local and systemic Therapy Success for Head and Neck cancer. The Results of 100 Patients - Semrau, S.; Haderlein, Marlen; Schmidt, Daniela; Waldfahrer, F.; Scherl, C.; Lettmaier, S.; Kuwert, Torsten; Iro, Heinrich; Fietkau, Rainer (2017)
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Metal-conscious Embedding for CBCT Projection Inpainting - Fan, Fuxin; Wang, Yangkong; Ritschl, Ludwig; Biniazan, Ramyar; Beister, Marcel; Kreher, Björn W.; Huang, Yixing; Kappler, Steffen; Maier, Andreas (2023 IEEE 20th International Symposium on Biomedical Imaging (ISBI), 2023)
The existence of metallic implants in projection images for cone-beam computed tomography (CBCT) introduces undesired artifacts which degrade the quality of reconstructed images. In order to reduce metal artifacts, projection in-painting is an essential step in many metal artifact reduction algorithms. In this work, a hybrid network combining the shift window (Swin) vision transformer (ViT) and a convolutional neural network is proposed as a baseline network for the inpainting task. To incorporate metal information for the Swin ViT-based encoder, metal-conscious self-embedding and neighborhood-embedding methods are investigated. Both methods have improved the performance of the baseline network. Furthermore, by choosing appropriate window size, the model with neighborhood-embedding could achieve the lowest mean absolute error of 0.079 in metal regions and the highest peak signal-to-noise ratio of 42.346 in CBCT projections. At the end, the efficiency of metal-conscious embedding on both simulated and real cadaver CBCT data has been demonstrated, where the inpainting capability of the baseline network has been enhanced.<br

Method for a motion model based automated 4D dose calculation - Ziegler, Marc; Brandt, Tobias; Lettmaier, Sebastian; Fietkau, Rainer; Bert, Christoph (Physics in Medicine and Biology, 2019)
The Vero system can treat intra-fractionally moving tumors with gimbaled dynamic tumor tracking (DTT) by rotating the treatment beam so that it follows the motion of the tumor. However, the changes in the beam geometry and the constant breathing motion of the patient influence the dose applied to the patient. This study aims to perform a full 4D dose reconstruction for thirteen patients treated with DTT at the Vero system at the Universitätsklinikum Erlangen and investigates the temporal resolution required to perform an accurate 4D dose reconstruction. For all patients, a 4DCT was used to train a 4D motion model, which is able to calculate pseudo-CT images for arbitrary breathing phases. A new CT image was calculated for every 100 ms of treatment and a dose calculation was performed according to the current beam geometry (i.e. the rotation of the treatment beam at this moment in time) by rotating according to the momentary beam rotation, which is extracted from log-files. The resulting dose distributions were accumulated on the planning CT and characteristic parameters were extracted and compared. [Formula: see text]-evaluations of dose accumulations with different spatial-temporal resolutions were performed to determine the minimal required resolution. In total 173 700 dose calculations were performed. The accumulated 4D dose distributions show a reduced mean GTV dose of 0.77% compared to the static treatment plan. For some patients larger deviations were observed, especially in the presence of a poor 4DCT quality. The [Formula: see text]-evaluation showed that a temporal resolution of 500 ms is sufficient for an accurate dose reconstruction. If the tumor motion is regarded as well, a spatial-temporal sampling of 1400 ms and 2 mm yields accurate results, which reduces the workload by 84%.
CRIS-Team Scopus Importer:2019-11-26

Micropapillary morphology is an indicator of poor prognosis in patients with urothelial carcinoma treated with transurethral resection and radiochemotherapy - Bertz, Simone; Wach, S.; Taubert, Helge; Merten, Ricarda; Krause, F. S.; Schick, S.; Ott, O. J.; Weigert, E.; Dworak, O.; Roedel, C.; Fietkau, Rainer; Wullich, Bernd; et al. (Virchows Archiv, 2016)
Purpose of this study was to evaluate prognostic impact of rare variants of urothelial bladder cancer (BC) after treatment with combined radiochemotherapy (RCT). To this end tumour tissue of 238 patients with urothelial carcinoma (UC) treated with transurethral resection of the bladder (TUR-B) and RCT with curative intent was collected. Histomorphological analysis included re-evaluation and semi-quantitative assessment of rare UC subtypes. Additionally, human epidermal growth factor receptor 2 (HER2) chromogenic in situ hybridisation (CISH) was performed in tumours with a micropapillary component exceeding 30 %. Long-term follow-up was available for 200 patients (range 3-282 months). Variant UC histology was found in 45 of 238 tumours, most frequently micropapillary UC (N = 17) including cases with a small fraction of tumour with micropapillary morphology. The mere presence of micropapillary morphology did not affect prognosis. In tumours with extensive (>=30 %) micropapillary morphology (N = 8) Kaplan-Meier analysis revealed significantly worse cancer specific survival (CSS) (P = 0.002) compared to conventional UC (mean survival times 97 months and 229 months, respectively). Univariate Cox regression analysis of cases with >=30 % micropapillary morphology revealed a hazard ratio of 4.726 (95 % CI 1.629-13.714) for CSS (P = 0.004). CISH revealed HER2 gene amplification in 3/10 tumours with >=30 % micropapillary component. In conclusion, for BC treated with TUR-B and RCT, the presence of micropapillary morphology in more than 30 % of the tumour is an adverse prognostic factor. Further studies are needed to evaluate a potential benefit of different, especially multimodal treatment strategies for micropapillary UC and also other subtypes of UC. Her2 represents a promising therapeutic target in a subset of micropapillary UC.
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Minutes of the General Meeting of the German Society for Medical Physics e.V. 2019 - Ladd, Mark E.; Bert, Christoph (Zeitschrift für Medizinische Physik, 2019)
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Mitoxantrone-loaded nanoparticles for magnetically controlled tumor therapy–induction of tumor cell death, release of danger signals and activation of immune cells - Ratschker, Teresa; Egenberger, Laura; Alev, Magdalena; Zschiesche, Lisa; Band, Julia; Schreiber, Eveline; Frey, Benjamin; Derer, Anja; Alexiou, Christoph; Janko, Christina (Pharmaceutics, 2020)
Stimulating the patient`s immune system represents a promising therapeutic strategy to fight cancer. However, low immunogenicity of the tumor cells within an immune suppressive milieu often leads to weak anti-tumor immune responses. Additionally, the immune system may be impaired by accompanying aggressive chemotherapies. We show that mitoxantrone, bound to superparamagnetic iron oxide nanoparticles (SPIONs) as the transport system, can be magnetically accumulated in adherent HT-29 colon carcinoma cells, thereby inducing the same cell death phenotype as its soluble counterpart, a chemotherapeutic agent and prototypic inductor of immunogenic cell death. The nanoparticle-loaded drug induces cell cycle stop, apoptosis and secondary necrosis in a dose-and time-dependent manner comparable to the free drug. Cell death was accompanied by the release of interleukin-8 and damage-associated molecular patterns (DAMPs) such as HSP70 and ATP, which fostered chemotactic migration of monocytes and maturation of dendritic cells. We furthermore ensured absence of endotoxin contaminations and compatibility with erythrocytes and platelets and investigated the influence on plasma coagulation in vitro. Summarizing, with magnetic enrichment, mitoxantrone can be accumulated at the desired place, sparing healthy peripheral cells and tissues, such as immune cells. Conserving immune competence in cancer patients in the future might allow combined therapeutic approaches with immune therapies (e.g. checkpoint inhibitors).
CRIS-Team Scopus Importer:2020-10-09
Keywords: Cell death; Chemotherapy; Iron oxide nanoparticles; Magnetic drug targeting; Nanomedicine

Mobile Image Interpretation: Diagnostic Performance of CT Exams Displayed on a Tablet Computer in Detecting Abdominopelvic Hemorrhage - Schlechtweg, Philipp; Kammerer, Ferdinand J.; Seuß, Hannes; Uder, Michael; Hammon, Matthias (Journal of Digital Imaging, 2015)
To investigate whether abdominopelvic hemorrhage shown on computed tomography (CT) images can be diagnosed with the same accuracy on a tablet computer as on a dedicated reading display. One hundred patients with a clinical suspicion of abdominopelvic hemorrhage that underwent biphasic CT imaging were retrospectively read by two readers on a dedicated reading display (reference standard) and on a tablet computer (iPad Air). Reading was performed in a dedicated reading room with ambient light conditions. Image evaluation included signs of an active hemorrhage (extravasation of contrast media) and different signs indicating a condition after abdominopelvic hemorrhage (hematoma, intestinal clots, vessel stump, free abdominopelvic fluid with a mean Hounsfield unit value >20, and asymmetric muscle volume indicating intramuscular hemorrhage). Sensitivity, specificity, and positive and negative predictive values (PPV/NPV) were calculated for the tablet-based reading. Active abdominopelvic hemorrhage (n = 72) was diagnosed with the tablet computer with a sensitivity of 0.96, a specificity of 0.93, a PPV of 0.97, and an NPV of 0.90. The results for the detection of the signs indicating a condition after abdominopelvic hemorrhage range from 0.83 to 1.00 in the case of sensitivity, from 0.95 to 1.00 in the case of specificity, from 0.94 to 1.00 in the case of the PPV, and from 0.96 to 1.00 in the case of the NPV. Abdominopelvic hemorrhage shown on CT images can be diagnosed on a tablet computer with a high diagnostic accuracy allowing mobile on-call diagnoses. This may be helpful because an early and reliable diagnosis at any time is crucial for an adequate treatment strategy.
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Moderate hypofractionation remains the standard of care for whole-breast radiotherapy in breast cancer: Considerations regarding FAST and FAST-Forward - Krug, David; Baumann, René; Combs, Stephanie E.; Duma, Marciana Nona; Dunst, Jürgen; Feyer, Petra; Fietkau, Rainer; Haase, Wulf; Harms, Wolfgang; Hehr, Thomas; Piroth, Marc D.; Sedlmayer, Felix; et al. (Strahlentherapie und Onkologie, 2021)
Moderate hypofractionation is the standard of care for adjuvant whole-breast radiotherapy after breast-conserving surgery for breast cancer. Recently, 10-year results from the FAST and 5‑year results from the FAST-Forward trial evaluating adjuvant whole-breast radiotherapy in 5 fractions over 5 weeks or 1 week have been published. This article summarizes recent data for moderate hypofractionation and results from the FAST and FAST-Forward trial on ultra-hypofractionation. While the FAST trial was not powered for comparison of local recurrence rates, FAST-Forward demonstrated non-inferiority for two ultra-hypofractionated regimens in terms of local control. In both trials, the higher-dose experimental arms resulted in elevated rates of late toxicity. For the lower dose experimental arms of 28.5 Gy over 5 weeks and 26 Gy over 1 week, moderate or marked late effects were similar in the majority of documented items compared to the respective standard arms, but significantly worse in some subdomains. The difference between the standard arm and the 26 Gy of the FAST-Forward trial concerning moderate or marked late effects increased with longer follow-up in disadvantage of the experimental arm for most items. For now, moderate hypofractionation with 40–42.5 Gy over 15–16 fractions remains the standard of care for the majority of patients with breast cancer who undergo whole-breast radiotherapy without regional nodal irradiation after breast-conserving surgery.
CRIS-Team Scopus Importer:2021-02-05
Keywords: Breast cancer; Hypofractionation; Late toxicity; Local recurrence; Radiotherapy

Modern Radiotherapy Concepts and the Impact of Radiation on Immune Activation - Derer, Anja; Hartmann, Josefin; Frey, Benjamin; Fietkau, Rainer; Gaipl, Udo; Deloch, Lisa (Frontiers in Oncology, 2016)
Even though there is extensive research carried out in radiation oncology, most of the clinical studies focus on the effects of radiation on the local tumor tissue and deal with normal tissue side effects. The influence of dose fractionation and timing particularly with regard to immune activation is not satisfactorily investigated so far. This review, therefore, summarizes current knowledge on concepts of modern radiotherapy (RT) and evaluates the potential of RT for immune activation. Focus is set on radiation-induced forms of tumor cell death and consecutively the immunogenicity of the tumor cells. The so-called non-targeted, abscopal effects can contribute to anti-tumor responses in a specific and systemic manner and possess the ability to target relapsing tumor cells as well as metastases. The impact of distinct RT concepts on immune activation is outlined and pre-clinical evidence and clinical observations on RT-induced immunity will be discussed. Knowledge on the radiosensitivity of immune cells as well as clinical evidence for enhanced immunity after RT will be considered. While stereotactic ablative body radiotherapy seem to have a beneficial outcome over classical RT fractionation in pre-clinical animal models, in vitro model systems suggest an advantage for classical fractionated RT for immune activation. Furthermore, the optimal approach may differ based on the tumor site and/or genetic signature. These facts highlight that clinical trials are urgently needed to identify whether high-dose RT is superior to induce anti-tumor immune responses compared to classical fractionated RT and in particular how the outcome is when RT is combined with immunotherapy in selected tumor entities.
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Modulation of Differentiation and Bone Resorbing Activity of Human (Pre-) Osteoclasts After X-Ray Exposure - Eckert, Denise; Rapp, Felicitas; Tsedeke, Ayele Taddese; Kraft, Daniela; Wente, Isabell; Molendowska, Jessica; Basheer, Sidra; Langhans, Markus; Meckel, Tobias; Friedrich, Thomas; Donaubauer, Anna-Jasmina; Becker, Ina; et al. (Frontiers in Immunology, 2022)
Low-dose radiotherapy (LD-RT) is a local treatment option for patients with chronic degenerative and inflammatory diseases, in particular musculoskeletal diseases. Despite reported analgesic and anti-inflammatory effects, cellular and molecular mechanisms related to osteoimmunological effects are still elusive. Here we test the hypothesis that X-irradiation inhibits the differentiation of precursor osteoclasts into mature osteoclasts (mOC) and their bone resorbing activity. Circulating monocytes from healthy donors were isolated and irradiated after attachment with single or fractionated X-ray doses, comparable to an LD-RT treatment scheme. Then monocytes underwent ex vivo differentiation into OC during cultivation up to 21 days, under conditions mimicking the physiological microenvironment of OC on bone. After irradiation, apoptotic frequencies were low, but the total number of OC precursors and mOC decreased up to the end of the cultivation period. On top, we observed an impairment of terminal differentiation, i.e. a smaller fraction of mOC, reduced resorbing activity on bone, and release of collagen fragments. We further analyzed the effect of X-irradiation on multinucleation, resulting from the fusion of precursor OC, which occurs late during OC differentiation. At 21 days after exposure, the observation of smaller cellular areas and a reduced number of nuclei per mOC suggest an impaired fusion of OC precursors to form mOC. Before, at 14 days, the nuclear translocation of Nuclear Factor Of Activated T Cells 1 (NFATc1), a master regulator of osteoclast differentiation and fusion, was decreased. In first results, obtained in the frame of a longitudinal LD-RT study, we previously reported a pain-relieving effect in patients. However, in a subgroup of patients suffering from Calcaneodynia or Achillodynia, we did not observe a consistent decrease of established blood markers for resorption and formation of bone, or modified T cell subtypes involved in regulating these processes. To assess the relevance of changes in bone metabolism for other diseases treated with LD-RT will be subject of further studies. Taken together, we observed that in vitro X-irradiation of monocytes results in an inhibition of the differentiation into bone-resorbing OC and a concomitant reduction of resorbing activity. The detected reduced NFATc1 signaling could be one underlying mechanism.
CRIS-Team WoS Importer:2022-06-03

Modulation of inflammation by low and high doses of ionizing radiation: Implications for benign and malign diseases - Frey, Benjamin; Hehlgans, Stephanie; Rödel, Franz; Gaipl, Udo (Cancer Letters, 2015)
Inflammation is a homeostatic mechanism aiming to maintain tissue integrity. The underlying immunological mechanisms and the interrelationship between ionizing radiation and inflammation are complex and multifactorial on cellular and chemical levels. On the one hand, radiation with single doses exceeding 1 Gy might initiate inflammatory reactions and thereby impact on tumor development. On the other hand, radiation is capable of attenuating an established inflammatory process, which is clinically used for the treatment of inflammatory and degenerative diseases with low-dose radiotherapy (single dose <1 Gy). At higher doses, ionizing radiation, especially in combination with additional immune stimulation, fosters the induction of immunogenic forms of tumor cell death and shifts the tumor microenvironment as well as the infiltration of immune cells from an anti- to a pro-inflammatory state. Distinct tumor infiltrating immune cells predict the response to radiochemotherapy in a multitude of tumor entities. While a high tumor infiltration of these adaptive immune cells mostly predicts a favorable disease outcome, a high infiltration of tumor-associated macrophages predicts an unfavorable response. Pro-inflammatory events should dominate over anti-inflammatory ones in this scenario. This review focuses on how ionizing radiation modulates inflammatory events in benign inflammatory and in malign diseases. A special focus is set on the role of tumor infiltrating lymphocytes and macrophages as biomarkers to predict treatment response and anti-tumor immunity and on mechanisms implicated in the anti-inflammatory effects of low-dose radiation therapy.
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Modulation of the peripheral immune system after low-dose radon spa therapy: Detailed longitudinal immune monitoring of patients within the RAD-ON01 study - Rühle, Paul-Friedrich; Wunderlich, Roland; Fournier, Claudia; Maier, Andreas; Klein, Gerhart; Fietkau, Rainer; Gaipl, Udo; Frey, Benjamin; Deloch, Lisa (Autoimmunity, 2017)
The pain-relieving effects of low-dose radon therapies on patients suffering from chronic painful inflammatory diseases have been described for centuries. Even though it has been suggested that low doses of radiation may attenuate chronic inflammation, the underlying mechanisms remain elusive. Thus, the RAD-ON01 study was initiated to examine the effects of radon spa therapy and its low doses of alpha radiation on the human immune system. In addition to an evaluation of pain parameters, blood was drawn from 100 patients suffering from chronic painful degenerative musculoskeletal diseases before as well as 6, 12, 18, and 30 weeks after the start of therapy. We verified significant long-term pain reduction for the majority of patients which was accompanied by modulations of the peripheral immune cells. Detailed immune monitoring was performed using a multicolor flow cytometry-based whole blood assay. After therapy, the major immune cells were only marginally affected. Nevertheless, a small but long-lasting increase in T cells and monocytes was observed. Moreover, neutrophils, eosinophils and, in particular, dendritic cells were temporarily modulated after therapy. Regarding the immune cell subsets, cytotoxic T and NK cells, in particular, were altered. However, the most prominent effects were identified in a strong reduction of the activation marker CD69 on T, B, and NK cells. Simultaneously, the percentage of HLA-DR+T cells was elevated after therapy. The RAD-ON01 study showed for the first time a modulation of the peripheral immune cells following standard radon spa therapy. These modulations are in line with attenuation of inflammation.
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Modulations in the Peripheral Immune System of Glioblastoma Patient Is Connected to Therapy and Tumor Progression-A Case Report from the IMMO-GLIO-01 Trial - Rühle, Paul-Friedrich; Goerig, Nicole; Wunderlich, Roland; Fietkau, Rainer; Gaipl, Udo; Strnad, Annedore; Frey, Benjamin (Frontiers in Neurology, 2017)
Immune responses are important for efficient tumor elimination, also in immune privileged organs such as the brain. Fostering antitumor immunity has therefore become an important challenge in cancer therapy. This cannot only be achieved by immunotherapies as already standard treatments such as radiotherapy and chemotherapy modify the immune system. Consequently, the understanding of how the tumor, the tumor microenvironment, and immune system are modulated by cancer therapy is required for prognosis, prediction, and therapy adaption. The prospective, explorative, and observational IMMO-GLIO-01 trial was initiated to examine the detailed immune status and its modulation of about 50 patients suffering from primary glioblastoma multiforme (GBM) or anaplastic astrocytoma during standard therapy. Prior to the study, a flow cytometry-based assay was established allowing the analysis of 34 immune cell subsets and their activation state. Here, we present the case of the first and longest accompanied patient, a 53-year-old woman suffering from GBM in the front left lobe. In context of tumor progression and therapy, we describe the modulation of the peripheral immune status over 17 months. Distinct immune modulations that were connected to therapy response or tumor progression were identified.Inter alia, a shift of CD4:CD8 ratio was observed that correlated with tumor progression. Twice we observed a unique composition of peripheral immune cells that correlated with tumor progression. Thus, following up these immune modulations in a closely-meshed manner is of high prognostic and predictive relevance for supporting personalized therapy and increasing therapy success.Clinical Trial registration: ClinicalTrials.gov, identifier NCT02022384 (registered retrospectively on 13th of December, 2013).
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Molecular and Translational Classifications of DAMPs in Immunogenic Cell Death - Garg, Abhishek D.; Galluzzi, Lorenzo; Apetoh, Lionel; Baert, Thais; Birge, Raymond B.; Bravo-San Pedro, Jose Manuel; Breckpot, Karine; Brough, David; Chaurio, Ricardo; Cirone, Mara; Coosemans, An; Coulie, Pierre G.; et al. (Frontiers in Immunology, 2015)
The immunogenicity of malignant cells has recently been acknowledged as a critical determinant of efficacy in cancer therapy. Thus, besides developing direct immunostimulatory regimens, including dendritic cell-based vaccines, checkpoint-blocking therapies, and adoptive T-cell transfer, researchers have started to focus on the overall immunobiology of neoplastic cells. It is now clear that cancer cells can succumb to some anticancer therapies by undergoing a peculiar form of cell death that is characterized by an increased immunogenic potential, owing to the emission of the so-called "damage-associated molecular patterns" (DAMPs). The emission of DAMPs and other immunostimulatory factors by cells succumbing to immunogenic cell death (ICD) favors the establishment of a productive interface with the immune system. This results in the elicitation of tumor-targeting immune responses associated with the elimination of residual, treatment-resistant cancer cells, as well as with the establishment of immunological memory. Although ICD has been characterized with increased precision since its discovery, several questions remain to be addressed. Here, we summarize and tabulate the main molecular, immunological, preclinical, and clinical aspects of ICD, in an attempt to capture the essence of this phenomenon, and identify future challenges for this rapidly expanding field of investigation.
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Monte Carlo Dose Simulation for In-Vivo X-Ray Nanoscopy - Wagner, Fabian; Thies, Mareike; Karolczak, Marek; Pechmann, Sabrina; Huang, Yixing; Gu, Mingxuan; Kling, Lasse; Weidner, Daniela; Aust, Oliver; Schett, Georg; Christiansen, Silke; Maier, Andreas (Informatik aktuell, 2022)
CRIS-Team Scopus Importer:2022-05-06

MRI-Based Treatment of Rectal Cancer: Is Prognostication of the Recurrence Risk Solid Enough to Render Radiation Redundant? - Sautter-Bihl, Marie-Luise; Hohenberger, Werner; Fietkau, Rainer; Roedel, Claus; Schmidberger, Heinz; Sauer, Rolf (Annals of Surgical Oncology, 2014)
Most current guidelines recommend neoadjuvant short course radiotherapy (sRT) or radio-chemotherapy (nRCT) for rectal cancer stage II and III. After the introduction of total mesorectal excision (TME) and magnetic resonance imaging (MRI), this proceeding has been questioned and omission of neoadjuvant treatment according to preoperative MRI-criteria has been propagated. Aim of the present paper is to review the state of evidence regarding MRI-based treatment decision depending on the predicted width of the circumferential resection margin (CRM).A comprehensive survey of the literature was performed using the search terms "rectal cancer", "radiotherapy", "radio-chemotherapy", "MRI-based therapy", "circumferential resection margin". Data from lately published observational studies were compared to results from randomized trials and outcome analyses of the Norwegian national cancer registry.Only one observational study using MRI-based treatment according to the anticipated CRM provided 5 year local recurrence data, however only for 65 patients. The second study did not yet evaluate recurrence rates. Two randomized trials comparing sRT to primary TME showed significantly worse outcome for non-irradiated patients. Data from the Norwegian rectal cancer registry demonstrate that TME alone is associated with higher LRR than achievable with preoperative RT.Current evidence does not support the omission of neoadjuvant treatment for stage II-III rectal cancer on the basis of an MRI-predicted negative CRM. Randomized studies are warranted to clarify whether and for which subgroups TME alone is safe in terms of local recurrences.
EVALuna2:15138

Mri of finger pulleys at 7t—direct characterization of pulley ruptures in an ex vivo model - Heiß, Rafael; Librimir, Alexander; Lutter, Christoph; Janka, Rolf Matthias; Kuerten, Stefanie; Roemer, Frank; Nagel, Armin Michael; Uder, Michael; Bayer, Thomas (Diagnostics, 2021)
The aim of this study was to evaluate 7 Tesla (7T) magnetic resonance imaging (MRI) for direct visualization and specific characterization of the finger flexor pulleys A2, A3, and A4 before and after ex vivo pulley rupture. Thirty fingers of human cadavers were examined before and after pulley disruption with a 26 min clinical 7T pulse sequence protocol. Images were assessed by two experienced radiologists for the presence of pulley rupture. Injury characterization included definition of rupture location, morphology, and complications. Image quality was evaluated according to a 4-point Likert-type scale from “not evaluable” to “excellent”. Macroscopic preparations were used as the reference standard. Direct characterization of intact A2, A3, and A4 pulleys and the corresponding pulley lesions was possible in all cases. The rupture location was distributed equally at the radial, ulnar, and central parts of the pulleys. A dislocation and intercalation of the pulley stump between the flexor tendon and finger phalanges was observed as a complication in 62.5% of cases. The average Likert score for direct visualization of pulleys was 2.67 before rupture and 2.79 after rupture creation, demonstrating adequate image quality for routine application. 7T MRI enables a direct characterization of A2, A3, and A4 pulleys before and after artificial disruption, including the definition of rupture morphology and location as well as the detection of rupture complications. This promises a precise presurgical evaluation of pulley injuries and complicated pulley stump dislocations.
CRIS-Team Scopus Importer:2021-07-30
Keywords: Climbing; Finger flexor pulleys; Imaging; Injury classification; Ultra-high-field MRI

Multicenter quality assurance evaluation of MR-guided deep hyperthermia systems - Curto, S.; Mulder, T.; Aklan, B.; Mils, O.; Schmidt, Manfred; Lamprecht, U.; Peller, M.; Wessalowski, R.; Lindern, L.; Fietkau, Rainer; Zips, D.; Paulides, M.; et al. (2018)
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Multigating, a 4D optimized beam tracking in scanned ion beam therapy - Graeff, Christian; Constantinescu, Anna; Luechtenborg, Robert; Durante, Marco; Bert, Christoph (Technology in Cancer Research & Treatment, 2014)
The treatment of moving tumors with a scanned ion beam is challenging due to interplay effects and changing beam range. We propose multigating, as a method for 4D-treatment optimization and delivery. In 3D beam tracking, tracking vectors are added during delivery to beam spot positions based on the detected motion phase. This has the disadvantage of dose errors in case of complex motion patterns and an uncertain out-of-target dose distribution. In multigating, the motion phase for each beam spot is predefined, which allows to add the tracking vector prior to beam weight optimization on all motion phases. The synchronization of delivery and target motion is assured by fast gating. The feasibility of the delivery was shown in a film experiment and required only minor software modification to the treatment planning system. In a treatment planning study in 4 lung cancer patients, target coverage could be restored to the level of a static reference plan by multigating (V95 > 99%) but not by standard beam tracking (V95 < 95%). The conformity of the multigating plans was only slightly lower than those of the static plan, with a conformity number of 72.0% (median, range 64.6-76.6%) compared to 75.8% (70.8-81.5%) in spite of target motion of up to 22 mm. In conclusion, we showed the technical feasibility of multigating, a 4D-optimization and delivery method using scanned beams that allows for conformal and homogeneous dose delivery to moving targets also in case of complex motion.
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MyCases-a portable application for radiologic case collections - Kammerer, Ferdinand Josef; Janka, Rolf Matthias; Kramer, Manuel; Hammon, Matthias; Uder, Michael; Schlechtweg, Philipp (Journal of Digital Imaging, 2014)
Radiologists come across interesting patient cases almost every day. This work proposes a novel case database server for quick and easy storage of such cases including whole image series, patient data, and annotations. Cases can be added to the database by saving DICOM images into a predefined directory on the local network. The application automatically extracts patient and study data from the DICOM header and saves it in the database while images are stored as anonymized JPEG files. Users can mark their cases as private or public (visible to all users). Different data fields for annotations and categorization of a case are available. The user frontend also provides several retrieval mechanisms allowing for browsing the cases and performing different kinds of search queries. The stored series can be scrolled interactively in the form of scrollable image stacks. The project is realized as a web-based application using a portable web and database server software package (XAMPP). This makes the system very lightweight and easy to run on almost any desktop computer, even from a USB flash drive, without the need for deeper IT knowledge and administrative rights.
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Myeloperoxidase Modulates Inflammation in Generalized Pustular Psoriasis and Additional Rare Pustular Skin Diseases - Haskamp, Stefan; Bruns, Heiko; Hahn, Madelaine; Hoffmann, Markus; Gregor, Anne; Löhr, Sabine; Hahn, Jonas; Ringer, Mark; Flamann, Cindy; Frey, Benjamin; Lesner, Adam; Thiel, Christian; et al. (American Journal of Human Genetics, 2020)
Generalized pustular psoriasis (GPP) is a severe multi-systemic inflammatory disease characterized by neutrophilic pustulosis and triggered by pro-inflammatory IL-36 cytokines in skin. While 19%–41% of affected individuals harbor bi-allelic mutations in IL36RN, the genetic cause is not known in most cases. To identify and characterize new pathways involved in the pathogenesis of GPP, we performed whole-exome sequencing in 31 individuals with GPP and demonstrated effects of mutations in MPO encoding the neutrophilic enzyme myeloperoxidase (MPO). We discovered eight MPO mutations resulting in MPO -deficiency in neutrophils and monocytes. MPO mutations, primarily those resulting in complete MPO deficiency, cumulatively associated with GPP (p = 1.85E−08; OR = 6.47). The number of mutant MPO alleles significantly differed between 82 affected individuals and >4,900 control subjects (p = 1.04E−09); this effect was stronger when including IL36RN mutations (1.48E−13) and correlated with a younger age of onset (p = 0.0018). The activity of four proteases, previously implicated as activating enzymes of IL-36 precursors, correlated with MPO deficiency. Phorbol-myristate-acetate-induced formation of neutrophil extracellular traps (NETs) was reduced in affected cells (p = 0.015), and phagocytosis assays in MPO-deficient mice and human cells revealed altered neutrophil function and impaired clearance of neutrophils by monocytes (efferocytosis) allowing prolonged neutrophil persistence in inflammatory skin. MPO mutations contribute significantly to GPP's pathogenesis. We implicate MPO as an inflammatory modulator in humans that regulates protease activity and NET formation and modifies efferocytosis. Our findings indicate possible implications for the application of MPO inhibitors in cardiovascular diseases. MPO and affected pathways represent attractive targets for inducing resolution of inflammation in neutrophil-mediated skin diseases.
CRIS-Team Scopus Importer:2020-09-11
Keywords: ACH; acrodermatitis continua suppurativa Hallopeau; activation of IL-36 precursors; acute generalized 4 exanthematous pustulosis; AGEP; efferocytosis; generalized pustular psoriasis; GPP; impaired NETosis; MPO deficiency; myeloperoxidase; oligogenic inheritance

Myocardial adaptation to high-intensity (interval) training in previously untrained men with a longitudinal cardiovascular magnetic resonance imaging study (Running Study and Heart Trial) - Scharf, Michael; Schmid, Axel; Kemmler, Wolfgang; von Stengel, Simon; May, Matthias; Wüst, Wolfgang; Achenbach, Stephan; Uder, Michael; Lell, Michael (Circulation: Cardiovascular Imaging, 2015)
To prospectively evaluate whether short-term high-intensity (interval) training (HI(I)T) induces detectable morphological cardiac changes in previously untrained men in cardiovascular magnetic resonance imaging.Eighty-four untrained volunteers were randomly assigned to a HI(I)T group (n=42; 44.1±4.7 years) or an inactive control group (n=42; 42.3±5.6 years). HI(I)T focused on interval runs (intensity: 95%-105% of individually calculated heart rate at the anaerobic threshold). Before and after 16 weeks, all subjects underwent physiological examination, stepwise treadmill test with blood lactate analysis, and contrast-enhanced cardiovascular magnetic resonance imaging (cine, tagging, and delayed enhancement). Indexed left ventricular (LV) and right ventricular (RV) volume (LV, 77.1±8.5-83.9±8.6; RV, 80.5±8.5-86.6±8.1) and mass (LV, 58.2±6.4-63.4±8.1; RV, 14.8±1.7-16.1±2.1) significantly increased with HI(I)T. Changes in LV and RV morphological parameters with HI(I)T were highly correlated with an increase in maximal aerobic capacity (VO2max) and a decrease in blood lactate concentration at the anaerobic threshold. Mean LV and RV remodeling index of HI(I)T group did not alter with training (0.76 ±0.09 and 0.24±0.10 g/mL, respectively [P=0.97 and P=0.72]), indicating balanced cardiac adaptation. Myocardial circumferential strain decreased after HI(I)T within all 6 basal segments (anteroseptal, P=0.01 and anterolateral, P<0.001). There was no late gadolinium enhancement in any of the participants before or post HI(I)T.Sixteen weeks of HI(I)T lead to measurable changes in cardiac atrial and ventricular morphology and function in previously untrained men. This correlates with improvements in parameters of endurance capacity.URL: http://www.clinicaltrials.gov. Unique identifier: NCT01406730.
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NAR score as surrogate for disease-free survival in the CAO/ARO/AIO-04 phase 3 rectal cancer trial - Fokas, E.; Fietkau, Rainer; Hartmann, Arndt; Hohenberger, Werner; Grützmann, Robert; Ghadimi, M.; Liersch, T.; Stroebel, P.; Grabenbauer, G.; Wittekind, C.; Sauer, Rolf; Kaufmann, M.; et al. (2018)
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Neoadjuvant chemoradiation combined with regional hyperthermia in locally advanced or recurrent rectal cancer - Ott, Oliver; Gani, Cihan; Lindner, Lars H.; Schmidt, Manfred; Lamprecht, Ulf; Abdel-Rahman, Sultan; Hinke, Axel; Weissmann, Thomas; Hartmann, Arndt; Issels, Rolf D.; Zips, Daniel; Belka, Claus; et al. (Cancers, 2021)
Background: To prospectively analyze feasibility and pathological complete response (pCR) rates of neoadjuvant chemoradiotherapy combined with regional hyperthermia (RHT) in patients with locally advanced (LARC) or recurrent (LRRC) rectal cancer. Methods: between 2012 and 2018, 111 patients with UICC stage IIB-IV or any locally recurrent rectal cancer were included (HyRec-Trial, ClinicalTrials.gov Identifier: NCT01716949). Patients received radiotherapy with concurrent 5-Fluororuracil (5-FU)/Capecitabine and Oxaliplatin, and RHT. Stage 1 feasibility analysis evaluated dose-limiting toxicities (DLT) after 19 patients, stage 2 after 59 evaluable patients. Analysis of the pCR rate was based on histopathological reports. Results: the feasibility rates for stages 1 and 2 were 90% (17/19) and 73% (43/59), respectively. In the intention-to-treat population the pCR rate was 19% (20/105; 90% confidence interval (CI) 13.0–26.5). In the per-protocol-analysis, complete tumor regression was seen in 28% (18/64) and 38% (3/8) of the patients with LARC and LRRC, respectively. Complete resection rates (R0) among patients with LARC and LRRC who received surgery were 99% (78/84) and 67% (8/12). Conclusions: the intensified neoadjuvant and multimodality treatment schedule was feasible and led to comparable early toxicity rates as described by other trials that used the similar chemoradiation protocol. The presented treatment regimen resulted in a very high pCR rate and appears as a promising option for patients with LRRC.
CRIS-Team Scopus Importer:2021-03-19
Keywords: Complete remission rate; Concurrent chemoradiation; Locally advanced rectal cancer; Locally recurrent rectal cancer; Regional hyperthermia; Tumor regression grading

Neoadjuvant chemoradiation therapy with gemcitabine/cisplatin and surgery versus immediate surgery in resectable pancreatic cancer : Results of the first prospective randomized phase II trial - Golcher, Henriette; Brunner, Thomas; Witzigmann, Helmut; Marti, Lukas; Bechstein, Wolf-Otto; Bruns, Christiane; Jungnickel, Henry; Schreiber, Stefan; Grabenbauer, Gerhard; Meyer, Thomas; Merkel, Susanne; Fietkau, Rainer; et al. (Strahlentherapie und Onkologie, 2015)
In nonrandomized trials, neoadjuvant treatment was reported to prolong survival in patients with pancreatic cancer. As neoadjuvant chemoradiation is established for the treatment of rectal cancer we examined the value of neoadjuvant chemoradiotherapy in pancreatic cancer in a randomized phase II trial. Radiological staging defining resectability was basic information prior to randomization in contrast to adjuvant therapy trials resting on pathological staging.Patients with resectable adenocarcinoma of the pancreatic head were randomized to primary surgery (Arm A) or neoadjuvant chemoradiotherapy followed by surgery (Arm B), which was followed by adjuvant chemotherapy in both arms. A total of 254 patients were required to detect a 4.33-month improvement in median overall survival (mOS).The trial was stopped after 73 patients; 66 patients were eligible for analysis. Twenty nine of 33 allocated patients received chemoradiotherapy. Radiotherapy was completed in all patients. Chemotherapy was changed in 3 patients due to toxicity. Tumor resection was performed in 23 vs. 19 patients (A vs. B). The R0 resection rate was 48 % (A) and 52 % (B, P = 0.81) and (y)pN0 was 30 % (A) vs. 39 % (B, P = 0.44), respectively. Postoperative complications were comparable in both groups. mOS was 14.4 vs. 17.4 months (A vs. B; intention-to-treat analysis; P = 0.96). After tumor resection, mOS was 18.9 vs. 25.0 months (A vs. B; P = 0.79).This worldwide first randomized trial for neoadjuvant chemoradiotherapy in pancreatic cancer showed that neoadjuvant chemoradiation is safe with respect to toxicity, perioperative morbidity, and mortality. Nevertheless, the trial was terminated early due to slow recruiting and the results were not significant. ISRCTN78805636; NCT00335543.
EVALuna2:15177

Neoadjuvant chemotherapy for breast cancer-background for the indication of locoregional treatment - 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)
Neoadjuvant chemotherapy (NACT) has been widely adopted into the multidisciplinary management of breast cancer. The prognostic impact of treatment response has been clearly demonstrated. However, the impact of treatment response on the indication for adjuvant radiotherapy is unclear. This review summarizes important implications of NACT and treatment response on the risk of recurrence and locoregional multidisciplinary management from the standpoint of radiation oncology.
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Neoadjuvant concurrent chemoradiotherapy with and without hyperthermia in retroperitoneal sarcomas: feasibility, efficacy, toxicity, and long-term outcome - Willner, Alexander; Fechner, Katja; Agaimy, Abbas; Haller, Florian; Eckstein, Markus; Ott, Oliver; Putz, Florian; Gaipl, Udo; Kersting, S.; Meidenbauer, Norbert; Grützmann, Robert; Fietkau, Rainer; et al. (Strahlentherapie und Onkologie, 2021)
Purpose Retroperitoneal (RPS) sarcomas are associated with poor local and abdominal tumor control. However, the benefit of preoperative radio- or chemotherapy alone for these entities is currently unclear. Moreover, as intermediate- and high-grade sarcomas have a tendency toward early metastasis, exploration of neoadjuvant strategies is of high importance. This analysis reports the results of our 20-year single-institution experience with preoperative neoadjuvant concurrent chemoradiation. Methods From 2000-2019, 27 patients with intermediate- or high-grade RPS (12 dedifferentiated liposarcoma, 10 leiomyosarcoma, 5 others) were treated with radiotherapy (median dose: 50.4 Gy; range 45-75 Gy) and two cycles of chemotherapy (doxorubicin 50 mg/m(2) BSA/d3 q28 and ifosfamide 1.5 g/m(2) BSA/d1-5 q28) in neoadjuvant intent. Chemotherapy consisted of doxorubicin alone in two cases and ifosfamide alone in one case. Fifteen patients (56%) additionally received deep regional hyperthermia. Results The median follow-up time was 53 months (+/- 56.7 months). 92% of patients received two cycles of chemotherapy as planned and 92% underwent surgery. At 5 and 10 years, abdominal-recurrence-free survival was 74.6% (+/- 10.1%) and 66.3% (+/- 11.9%), distant metastasis-free survival was 67.2% (+/- 9.7%) and 59.7% (+/- 11.1%), and overall survival was 60.3% (+/- 10.5%) and 60.3% (+/- 10.5%), respectively. CTC grade III and IV toxicities were leukocytopenia (85%), thrombocytopenia (33%), and anemia (11%). There were no treatment-related deaths. Conclusion Neoadjuvant chemoradiotherapy with and without hyperthermia for retroperitoneal sarcomas is feasible and provided high local control of intermediate- and high-grade sarcoma.
CRIS-Team WoS Importer:2021-11-12

Neoadjuvant Immunotherapy of Oral Squamous Cell Carcinoma: Case Report and Assessment of Histological Response - Olmos, Manuel; Glajzer, Jacek; Büntemeyer, Tjark-Ole; Frohwitter, Gesche; Ries, Jutta; Eckstein, Markus; Hecht, Markus; Lutz, Rainer; Kesting, Marco Rainer; Weber, Manuel (Frontiers in Oncology, 2021)
Background: The treatment of oral cancer remains challenging due to its infiltrative nature and a high tendency for tumour relapse leading to an overall poor prognosis. In the case of early recurrence, the patient’s prognosis deteriorates dramatically, with survival rate dropping to below 30%. Minimal improvements in survival trends in recurrent and advanced stage tumours have been reported in recent decades. Neoadjuvant immunotherapy may represent a new therapeutic approach changing the standard of care in advanced oral cancer therapy. Case Presentation: We describe the case of a woman in her late 30’s who presented in mid-2019 with oral squamous cell carcinoma (OSCC) localized to the floor of the mouth. After initial R0 resection, selective neck dissection, and adjuvant brachytherapy, an early recurrence of OSCC located between the hyoid bone and the mandible was diagnosed at the end of 2019. An off-label treatment regimen was performed with neoadjuvant use of Pembrolizumab 19 days prior to salvage surgery. Radiological and histological assessment of T-cell and programmed cell death protein 1 ligand 1 (PD-L1) expression was performed before and after checkpoint inhibitor application. Neoadjuvant immunotherapy resulted in increased T-cell infiltration and PD-L1 expression, as well as a significant tumour necrosis rate. One cycle of Pembrolizumab led to significant regressive tumour changes with increases in immune infiltration, sclerosis, and necrosis of 75% of the tumour mass with only 25% vital tumour cells remaining. By June 2020, the patient remained without recurrence. Conclusions: The case presented outlines the potential effects of neoadjuvant immunotherapy in recurrent or advanced OSCC prior to definitive surgical tumour treatment. The benefit of additional adjuvant treatment after histologic response will be discussed. The case is also analysed considering ongoing clinical trials of neoadjuvant immunotherapy for head and neck malignancies.
CRIS-Team Scopus Importer:2021-08-13
Keywords: case report; immune checkpoint inhibitors; immunotherapy; neoadjuvant; oral cancer; OSCC; PD-1 - PD-L1 axis; pembrolizumab

Neoadjuvant Radiochemotherapy Alters the Immune and Metabolic Microenvironment in Oral Cancer—Analyses of CD68, CD163, TGF-β1, GLUT-1 and HIF-1α Expressions - Weber, Manuel; Ries, Jutta; Braun, Kristina; Wehrhan, Falk; Distel, Luitpold; Geppert, Carol-Immanuel; Lutz, Rainer; Kesting, Marco Rainer; Trumet, Leah (Cells, 2024)
Background: The first-line treatment of oral squamous cell carcinoma (OSCC) involves surgical tumor resection, followed by adjuvant radio(chemo)therapy (R(C)T) in advanced cases. Neoadjuvant radio- and/or chemotherapy has failed to show improved survival in OSCC. Recently, neoadjuvant immunotherapy has shown promising therapeutic efficacy in phase 2 trials. In this context, the addition of radio- and chemotherapy is being reconsidered. Therefore, a better understanding of the tumor-biologic effects of neoadjuvant RCT would be beneficial. The current study was conducted on a retrospective cohort of patients who received neoadjuvant RCT for the treatment of oral cancer. The aim of the study was to evaluate the influence of neoadjuvant RCT on the immunological tumor microenvironment (TME) and hypoxic and glucose metabolisms. Methods: A cohort of 45 OSSC tissue samples from patients were analyzed before and after RCT (total 50.4 Gy; 1.8 Gy 5× weekly; Cisplatin + 5-Fluorouracil). Immunohistochemistry for CD68, CD163, TGF-β, GLUT-1 and HIF-1α was performed using tissue microarrays and automated cell counting. Differences in expression before and after RCT and associations with histomorphological parameters (T-status, N-status) were assessed using the Mann–Whitney U test. Results: Tumor resection specimens after neoadjuvant RCT showed a significant decrease in CD68 infiltration and a significant increase in CD163 cell density. The CD68/CD163 ratio was significantly lower after RCT, indicating a shift toward M2 polarization. The GLUT-1 and HIF-1α expressions were significantly lower after RCT. Larger tumors (T3/T4) showed a lower GLUT-1 expression. Other biomarkers were not associated with the T- and N-status. Conclusions: Neoadjuvant RCT with 50.4 Gy induced a shift toward the M2 polarization of macrophages in the TME. This change in immune composition is not favorable and may be prognostically negative and counteract immunotherapeutic approaches. In addition, the decreased expressions in GLUT-1 and HIF-1α indicate reductions in the glucose metabolism and hypoxic energy metabolism in response to “high dose” neoadjuvant RCT, which may be therapeutically desirable.
CRIS-Team Scopus Importer:2024-03-22
Keywords: head and neck squamous cell carcinoma; HNSCC; hypoxia; immune tolerance; induction therapy; macrophage polarization; metabolism; oral squamous cell carcinoma; OSCC; RCT

Neoadjuvant Radiochemotherapy Followed by Curative Resection in Patients with Advanced Non-Small Cell Lung Cancer in Stage IIIA/IIIB: Prognostic Factors and Results - Schreiner, Waldemar; Dudek, Wojciech; Lettmaier, S.; Gavrychenkova, S.; Rieker, R.; Fietkau, Rainer; Sirbu, Horia (Zentralblatt für Chirurgie, 2016)
The role of surgical lung resection following neo-adjuvant radio-chemotherapy (RCT) in patients with locally advanced non-small cell lung cancer (NSCLC) is yet not clearly defined. The aim of our study was to analyze the postoperative survival and to identify relevant prognostic factors. 46 patients underwent curative resections after neo-adjuvant RCT for locally advanced NSCLC (IIIA/IIIB) between February 2008 and February 2015. A retrospective data analysis regarding preoperative regression status, perioperative mortality, postoperative survival, patho-histological remission, relapse pattern and other prognostic factors was performed. A neo-adjuvant RCT with a median radiation dose of 50.4 [range, 45-60] Gy was performed in 44 (96 %) patients. Partial and/or complete regression was observed in 32 (70 %) patients. R0-resection was achieved in 44 (96 %) patients. The 30-day mortality was 4 % and the perioperative morbidity was 37 %. The overall and progression free 5-year survival rate was 47 % and respectively 45 % [in median 58 months]. The 5-year survival rate of 64 % in the "responder"-group was significantly better when compared with 24 % in the "non-responder"-group (p = 0.038). The tri-modality therapy improved the prognosis in patients with locally advanced NSCLC (stage IIIA/IIIB). The complete patho-histological remission is an important prognostic factor for better long term survival. Dividing the patients in "responder" and "non-responder" after neo-adjuvant RCT may have large therapeutically consequences in the future.
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Neoadjuvant rectal score as individual-level surrogate for disease-free survival in rectal cancer in the CAO/ARO/AIO-04 randomized phase III trial - Fokas, E.; Fietkau, Rainer; Hartmann, Arndt; Hohenberger, Werner; Grützmann, Robert; Ghadimi, M.; Liersch, T.; Stroebel, P.; Grabenbauer, G. G.; Graeven, U.; Hofheinz, R-D; Koehne, C-H; et al. (Annals of Oncology, 2018)
Background: Surrogate end points in rectal cancer after preoperative chemoradiation are lacking as their statistical validation poses major challenges, including confirmation based on large phase III trials. We examined the prognostic role and individual-level surrogacy of neoadjuvant rectal (NAR) score that incorporates weighted cT, ypT and ypN categories for disease-free survival (DFS) in 1191 patients with rectal carcinoma treated within the CAO/ARO/AIO-04 phase III trial. Patients and methods: Cox regression models adjusted for treatment arm, resection status, and NAR score were used in multivariable analysis. The four Prentice criteria (PC1-4) were used to assess individual-level surrogacy of NAR for DFS. Results: After a median follow-up of 50 months, the addition of oxaliplatin to fluorouracil-based chemoradiotherapy (CRT) significantly improved 3-year DFS [75.9% (95% confidence interval [CI] 72.30% to 79.50%) versus 71.3% (95% CI 67.60% to 74.90%); P = 0.034; PC 1) and resulted in a shift toward lower NAR groups (P = 0.034, PC 2) compared with fluorouracil-only CRT. The 3-year DFS was 91.7% (95% CI 88.2% to 95.2%), 81.8% (95% CI 78.4% to 85.1%), and 58.1% (95% CI 52.4% to 63.9%) for low, intermediate, and high NAR score, respectively (P < 0.001; PC 3). NAR score remained an independent prognostic factor for DFS [low versus high NAR: hazard ratio (HR) 4.670; 95% CI 3.106-7.020; P < 0.001; low versus intermediate NAR: HR 1.971; 95% CI 1.303-2.98; P = 0.001] in multivariable analysis. Notwithstanding the inherent methodological difficulty in interpretation of PC 4 to establish surrogacy, the treatment effect on DFS was captured by NAR, supporting satisfaction of individual-level PC 4. Conclusion: Our study validates the prognostic role and individual-level surrogacy of NAR score for DFS within a large randomized phase III trial. NAR score could help oncologists to speed up response-adapted therapeutic decision, and further large phase III trial data sets should aim to confirm trial-level surrogacy.
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Neoadjuvant short-course radiotherapy followed by chemotherapy or simultaneous radiochemotherapy for local unresectable rectal cancer - Klautke, G.; Sauer, Rolf (Strahlentherapie und Onkologie, 2014)
EVALuna2:18203

Neoadjuvant Therapy for Resectable Pancreatic Cancer A New Standard of Care. Pooled Data From 3 Randomized Controlled Trials - Birrer, Dominique L.; Golcher, Henriette; Casadei, Riccardo; Haile, Sarah R.; Fritsch, Ralph; Hussung, Saskia; Brunner, Thomas B.; Fietkau, Rainer; Meyer, Thomas; Grützmann, Robert; Merkel, Susanne; Ricci, Claudio; et al. (Annals of Surgery, 2021)
Objective: The aim of this study was to pool data from randomized controlled trials (RCT) limited to resectable pancreatic ductal adenocarcinoma (PDAC) to determine whether a neoadjuvant therapy impacts on disease-free survival (DFS) and surgical outcome. Summary Background Data: Few underpowered studies have suggested benefits from neoadjuvant chemo (+/- radiation) for strictly resectable PDAC without offering conclusive recommendations. Methods: Three RCTs were identified comparing neoadjuvant chemo (+/- radio) therapy vs. upfront surgery followed by adjuvant therapy in all cases. Data were pooled targeting DFS as primary endpoint, whereas overall survival (OS), postoperative morbidity, and mortality were investigated as secondary endpoints. Survival endpoints DFS and OS were compared using Cox proportional hazards regression with study-specific baseline hazards. Results: A total of 130 patients were randomized (56 in the neoadjuvant and 74 in the control group). DFS was significantly longer in the neoadjuvant treatment group compared to surgery only [hazard ratio (HR) 0.6, 95% confidence interval (CI) 0.4-0.9] (P = 0.01). Furthermore, DFS for the subgroup of R0 resections was similarly longer in the neoadjuvant treated group (HR 0.6, 95% CI 0.35-0.9, P = 0.045). Although postoperative complications (Comprehensive Complication Index, CCI(R)) occurred less frequently (P = 0.008), patients after neoadjuvant therapy experienced a higher toxicity, but without negative impact on oncological or surgical outcome parameters. Conclusion: Neoadjuvant therapy can be offered as an acceptable standard of care for patients with purely resectable PDAC. Future research with the advances of precision oncology should now focus on the definition of the optimal regimen.
CRIS-Team WoS Importer:2022-02-11

Neuropilin-2 and its ligand VEGF-C predict treatment response after transurethral resection and radiochemotherapy in bladder cancer patients - Keck, Bastian; Wach, S.; Taubert, Helge; Zeiler, S.; Ott, O. J.; Kunath, F.; Hartmann, Arndt; Bertz, Simone; Weiss, C.; Hoenscheid, P.; Schellenburg, S.; Roedel, C.; et al. (International Journal of Cancer, 2015)
The standard treatment for invasive bladder cancer is radical cystectomy. In selected patients, bladder-sparing therapy can be performed by transurethral resection (TURBT) and radio-chemotherapy (RCT) or radiotherapy (RT). Our published in vitro data suggest that the Neuropilin-2 (NRP2)/VEGF-C axis plays a role in therapy resistance. Therefore, we studied the prognostic impact of NRP2 and VEGF-C in 247 bladder cancer patients (cN0M0) treated with TURBT and RCT (n = 198) or RT (n = 49) and a follow-up time up to 15 years. A tissue microarray was analyzed by immunohistochemistry. NRP2 expression emerged as a prognostic factor in overall survival (OS; HR: 3.42; 95% CI: 1.48 - 7.86; p = 0.004) and was associated with a 3.85-fold increased risk of an early cancer specific death (95% CI: 0.91 - 16.24; p = 0.066) in multivariate analyses. Cancer specific survival (CSS) dropped from 166 months to 85 months when NRP2 was highly expressed (p = 0.037). Patients with high VEGF-C expression have a 2.29-fold increased risk of shorter CSS (95% CI: 1.03-5.35; p = 0.043) in univariate analysis. CSS dropped from 170 months to 88 months in the case of high VEGF-C expression (p = 0.041). Additionally, NRP2 and VEGF-C coexpression is a prognostic marker for OS in multivariate models (HR: 7.54; 95% CI: 1.57-36.23; p = 0.012). Stratification for muscle invasiveness (T1 vs. T2-T4) confirmed the prognostic role of NRP2 and NRP2/VEGF-C co-expression in patients with T2-T4 but also with high risk T1 disease. In conclusion, immunohistochemistry for NRP2 and VEGF-C has been determined to predict therapy outcome in bladder cancer patients prior to TURBT and RCT.
EVALuna2:6641

Neutrophilia as prognostic factor for outcome in the CAO/ARO/ALO-04 phase 3 rectal cancer trial - Diefenhardt, M.; Hofheinz, R.; Beissbarth, T.; Arnold, D.; Von Den Gruen, J. Mueller; Liersch, T.; Stroebel, P.; Grabenbauer, G.; Fietkau, Rainer; Weitz, J.; Ghadimi, M.; Roedel, C.; et al. (RADIOTHERAPY AND ONCOLOGY, 2019)
CRIS-Team WoS Importer:2019-06-18

Neutrophils seeking new neighbors: radiotherapy affects the cellular framework and the spatial organization in a murine breast cancer model - Reichardt, Clara; Munoz Becerra, Marco; Rius Rigau, Aleix; Rückert, Michael; Fietkau, Rainer; Schett, Georg; Gaipl, Udo; Frey, Benjamin; Munoz Becerra, Luis (Cancer Immunology, Immunotherapy, 2024)
Neutrophils are known to contribute in many aspects of tumor progression and metastasis. The presence of neutrophils or neutrophil-derived mediators in the tumor microenvironment has been associated with poor prognosis in several types of solid tumors. However, the effects of classical cancer treatments such as radiation therapy on neutrophils are poorly understood. Furthermore, the cellular composition and distribution of immune cells in the tumor is of increasing interest in cancer research and new imaging technologies allow to perform more complex spatial analyses within tumor tissues. Therefore, we aim to offer novel insight into intra-tumoral formation of cellular neighborhoods and communities in murine breast cancer. To address this question, we performed image mass cytometry on tumors of the TS/A breast cancer tumor model, performed spatial neighborhood analyses of the tumor microenvironment and quantified neutrophil-extracellular trap degradation products in serum of the mice. We show that irradiation with 2 × 8 Gy significantly alters the cellular composition and spatial organization in the tumor, especially regarding neutrophils and other cells of the myeloid lineage. Locally applied radiotherapy further affects neutrophils in a systemic manner by decreasing the serum neutrophil extracellular trap concentrations which correlates positively with survival. In addition, the intercellular cohesion is maintained due to radiotherapy as shown by E-Cadherin expression. Radiotherapy, therefore, might affect the epithelial–mesenchymal plasticity in tumors and thus prevent metastasis. Our findings underscore the growing importance of the spatial organization of the tumor microenvironment, particularly with respect to radiotherapy, and provide insight into potential mechanisms by which radiotherapy affects epithelial–mesenchymal plasticity and tumor metastasis.
CRIS-Team Scopus Importer:2024-03-15
Keywords: Cancer; Cellular neighborhood; Image mass cytometry; Neutrophil; Radiotherapy

Newly Synthesized Melphalan Analogs Induce DNA Damage and Mitotic Catastrophe in Hematological Malignant Cancer Cells - Poczta, Anastazja; Krzeczynski, Piotr; Ionov, Maksim; Rogalska, Aneta; Gaipl, Udo; Marczak, Agnieszka; Lubgan, Dorota (International Journal of Molecular Sciences, 2022)
Myeloablative therapy with highdoses of the cytostatic drug melphalan (MEL) in preparation for hematopoietic cell transplantation is the standard of care for multiple myeloma (MM) patients. Melphalan is a bifunctional alkylating agent that covalently binds to nucleophilic sites in the DNA and effective in the treatment, but unfortunately has limited therapeutic benefit. Therefore, new approaches are urgently needed for patients who are resistant to existing standard treatment with MEL. Regulating the pharmacological activity of drug molecules by modifying their structure is one method for improving their effectiveness. The purpose of this work was to analyze the physicochemical and biological properties of newly synthesized melphalan derivatives (EE-MEL, EM-MEL, EM-MOR-MEL, EM-I-MEL, EM-T-MEL) obtained through the esterification of the carboxyl group and the replacement of the the amino group with an amidine group. Compounds were selected based on our previous studies for their improved anticancer properties in comparison with the original drug. For this, we first evaluated the physicochemical properties using the circular dichroism technique, then analyzed the zeta potential and the hydrodynamic diameters of the particles. Then, the in vitro biological properties of the analogs were tested on multiple myeloma (RPMI8226), acute monocytic leukemia (THP1), and promyelocytic leukemia (HL60) cells as model systems for hematological malignant cells. DNA damage was assessed by immunostaining γH2AX, cell cycle distribution changes by propidium iodide (PI) staining, and cell death by the activation of caspase 2. We proved that the newly synthesized derivatives, in particular EM-MOR-MEL and EM-T-MEL, affected the B-DNA conformation, thus increasing the DNA damage. As a result of the DNA changes, the cell cycle was arrested in the S and G2/M phases. The cell death occurred by activating a mitotic catastrophe. Our investigations suggest that the analogs EM-MOR-MEL and EM-T-MEL have better anti-cancer activity in multiple myeloma cells than the currently used melphalan.
CRIS-Team Scopus Importer:2022-12-09
Keywords: blood cancer; DNA damage γH2AX; drug structure modification; melphalan; mitotic catastrophe

New, mobile CBCT-System (ImagingRing m) for image-guided Brachytherapy - Quality Assurance - Karius, Andre; Strnad, Vratislav; Bert, Christoph (STRAHLENTHERAPIE UND ONKOLOGIE, 2021)
CRIS-Team WoS Importer:2021-07-16

NNRTI-based antiretroviral therapy may increase risk of radiation induced side effects in HIV-1-infected patients - Keller, Ulrike; Hecht, Markus; Harrer, Thomas; Harrer, Ellen; Schuster, Barbara; Fietkau, Rainer; Distel, Luitpold (Radiotherapy and Oncology, 2015)
As the incidence of cancer is rising in HIV-1-infected patients, radiotherapy is used more frequently in this patient group. Strong radiation induced side effects have been reported in single patients on antiretroviral therapy. Thus we investigated whether HIV-1 itself or antiretroviral drugs could enhance radiosensitivity in patients.Radiosensitivity after in vitro irradiation of blood lymphocytes was tested in 196 individuals (80 HIV-1-infected patients and 116 healthy controls and cancer patients) using a three color fluorescence in situ hybridization approach to analyze chromosomal aberrations (B/M). Additionally, the NNRTI efavirenz and the NRTIs tenofovir and emtricitabine were tested for radiosensitizing effects in vitro.Lymphocytes from HIV-1-infected patients in the NNRTI + NRTI group were significantly more sensitive to ionizing radiation than in the other groups (patients without treatment or with NRTI + PI or HIV-negative controls). In vitro the triple medication efavirenz, tenofovir and emtricitabine leads to a reduced survival fraction and an increased activation of the DNA repair proteins H2AX, Nbs, Atm and 53BP1 in combination with ionizing radiation.HIV-1 treatment with NNRTI containing therapy regimes possibly sensitizes a subgroup of patients to ionizing radiation. Individual radiosensitivity of HIV-1-infected patients on HAART including NNRTI should be tested before starting radiotherapy.
EVALuna2:13258

No abscopal effects in combination of immunotherapy and stereotactic radiotherapy in Merkel cell carcinomas - Schnellhardt, Soeren; Gaipl, Udo; Hecht, Markus (Strahlentherapie und Onkologie, 2023)
CRIS-Team WoS Importer:2023-05-12

NOBF4-Functionalized Au-Fe3O4 Nanoheterodimers for Radiation Therapy: Synergy Effect Due to Simultaneous Reactive Oxygen and Nitrogen Species Formation - Klein, Stefanie; Harreiß, Christina; Menter, Christina; Hümmer, Julian; Distel, Luitpold; Meyer, Karsten; Hock, Rainer; Kryschi, Carola (ACS Applied Materials and Interfaces, 2018)
Snowman-shaped Au-Fe3O4 nanoheterodimers were synthesized by thermal decomposition of iron oleate on presynthesized Au nanoparticles. Subsequently performed ligand exchange with nitrosyl tetrafluoroborate provided water solubility and enabled X-ray-induced NO release. These Au-Fe3O4 nanoheterodimers combine high-Z material with catalytically active Fe3O4 surfaces and, moreover, plasmonic properties with superparamagnetic performance. We could establish synergetic interactions between X-radiation and both the Au and Fe3O4 surfaces, which resulted in the simultaneous production of the nitric oxide radical at the Fe3O4 surface and the superoxide radical at the Au surface. The surface-confined reaction between these radicals generated peroxynitrite. This highly reactive species may cause nitration of mitochondrial proteins and lipid peroxidation and induce DNA strand breaks. Therefore, high concentrations of peroxynitrite are expected to give rise to severe cellular energetic derangements and thereupon entail rapid cell death. As providing a common platform for X-ray-induced formation of the highly superoxide, and peroxynitrite, nitrosyl tetrafluoroborate functionalized Au-Fe3O4 nanosnowmen were shown to exhibit excellent performance as X-ray-enhancing agents in radiation therapy.
Keywords: Au-Fe3O4 nanoheterodimers; nitrosyl tetrafluoroborate coating; radiation therapy; reactive oxygen species; reactive nitrogen species

No gender-specific Differences in the Radiation Sensitivity of Rectal Cancer Patients - Schuster, B.; Geinitz, H.; Fietkau, Rainer; Distel, Luitpold (STRAHLENTHERAPIE UND ONKOLOGIE, 2021)
CRIS-Team WoS Importer:2021-07-16

Noncurated Data Lead to Misinterpretation of Treatment Outcomes in Patients With Prostate Cancer After Salvage or Palliative Radiotherapy - Rutzner, Sandra; Ganslandt, Oliver Thomas; Fietkau, Rainer; Prokosch, Hans-Ulrich; Lubgan, Dorota (JCO Clinical Cancer Informatics, 2019)
PURPOSE: Clinical data warehouses (cDWHs) and cancer registry databases have enabled researchers to conduct clinical analytics with structured electronic health record data. However, these secondary electronic health record sources are often limited in scope because they do not capture the clinical information needed to understand complex clinical questions. Thus, we evaluated the effect of additional curation of data. MATERIALS AND METHODS: Clinical data sets of 149 patients with prostate cancer with biochemical recurrence after radical prostatectomy treated with salvage or palliative radiotherapy between 2008 and 2017 from our institutional cDWH and Gießener Tumor Documentation System (GTDS) were linked (data warehouse [DWH] population) for analyzing treatment outcomes. The linked data sets were manually curated (manual postprocessing [MPP], eg, incorporate data from established urologists). The primary outcomes were the impact on data quality of treatment outcomes and the time spent on data curation. RESULTS: We obtained significantly more information on disease progression and patient survival (nonsignificant) when using curated data; the biochemical progression-free survival rate at 5 years for the DWH and DWH plus MPP populations was 63% v 30% (P ≤ .001) and the overall survival rate was 84% v 81% (P = .479), respectively. The median deviation of completeness and the median concordance of clinical data values were 21.47% (range, 55.38%-100%) and 95.00% (range, 63.40%-100%), respectively. We spent 121 hours, 42 minutes on data curation, with most time required for laboratory values, accounting, for a total of 45 hours, 20 minutes (37.26%). CONCLUSION: Our analysis indicates that time-to-event outcomes for patients with prostate cancer cannot be extracted using secondary data sources (cDWH plus GTDS) only. Outcomes data differed between the electronic data (DWH) and the second manual extraction (DWH plus MPP) because of a lack of follow-up data. When using such unique database resources, only baseline characteristics can reliably be extracted.
EVALuna2:209482

Noninvasive cardiac arrhythmia ablation with particle beams - Graeff, Christian; Bert, Christoph (Medical Physics, 2018)
Cardiac arrhythmias are a major health burden, associated with reduced quality of life and substantial morbidity and mortality. Current therapy includes moderately effective medication and catheter-based ablation of arrhythmogenic substrates in the heart. Catheter interventions frequently have to be repeated due to recurrent arrhythmia, can have rare but severe side-effects and are less suited especially for potentially lethal left ventricular tachycardia. Noninvasive alternatives are therefore warranted. Photon and ion beam radiotherapy has been studied in animal models and first patient cases have been reported using photons. Ion beams might offer the possibility to greatly reduce dose to surrounding healthy tissue, including critical cardiac substructures. Based on a recently conducted animal study, we report advantages and disadvantages of 4D-ion beam therapy, and strategies necessary for a clinical transition. Motion management of both respiration and heartbeat are discussed, as well as range uncertainty resulting from both regular motion and interfractional anatomic changes. Image guidance both in 3D and 4D has to be employed for a safe irradiation, but also population-based data on motion variability and time behavior of interfractional changes are necessary. Range verification could play a crucial role at least during development of clinical protocols. For clinical realization, it appears necessary to suppress or conformally mitigate the large respiratory motion to avoid normal tissue complications. Cardiac motion has to be incorporated into treatment planning, either through adequate range-considering internal margins or through more conformal strategies such as ECG-based gating or even 4D-optimization. The latter strategies would necessitate online 4D image guidance.
EVALuna2:36472

Non-Invasive Characterization of Experimental Bone Metastasis in Obesity Using Multiparametric MRI and PET/CT - Gregoric, Gasper; Gaculenko, Anastasia; Nagel, Lisa; Popp, Vanessa; Maschauer, Simone; Prante, Olaf; Saake, Marc; Schett, Georg; Uder, Michael; Ellmann, Stephan; Bozec, Aline; Bäuerle, Tobias (Cancers, 2022)
The growth of primary tumors and metastases is associated with excess body fat. In bone metastasis formation, the bone marrow microenvironment, and particularly adipocytes, play a pivotal role as growth mediators of disseminated tumor cells in the bone marrow. The aim of the present study is to non-invasively characterize the pathophysiologic processes in experimental bone metastasis resulting from accelerated tumor progression within adipocyte-rich bone marrow using multimodal imaging from magnetic resonance imaging (MRI) and positron emission tomography/computed tomography (PET/CT). To achieve this, we have employed small animal models after the administration of MDA-MB 231 breast cancer and B16F10 melanoma cells into the bone of nude rats or C57BL/6 mice, respectively. After tumor cell inoculation, ultra-high field MRI and mu PET/CT were used to assess functional and metabolic parameters in the bone marrow of control animals (normal diet, ND), following a high-fat diet (HFD), and/or treated with the peroxisome proliferator-activated receptor-gamma (PPAR gamma) antagonist bisphenol-A-diglycidylether (BADGE), respectively. In the bone marrow of nude rats, dynamic contrast-enhanced MRI (DCE-MRI) and diffusion-weighted imaging (DWI), as well as [F-18]fluorodeoxyglucose-PET/CT([F-18]FDG-PET/CT), was performed 10, 20, and 30 days after tumor cell inoculation, followed by immunohistochemistry. DCE-MRI parameters associated with blood volume, such as area under the curve (AUC), were significantly increased in bone metastases in the HFD group 30 days after tumor cell inoculation as compared to controls (p < 0.05), while the DWI parameter apparent diffusion coefficient (ADC) was not significantly different between the groups. [F-18]FDG-PET/CT showed an enhanced glucose metabolism due to increased standardized uptake value (SUV) at day 30 after tumor cell inoculation in animals that received HFD (p < 0.05). BADGE treatment resulted in the inversion of quantitative DCE-MRI and [F-18]FDG-PET/CT data, namely a significant decrease in AUC and SUV in HFD-fed animals as compared to ND-fed controls (p < 0.05). Finally, immunohistochemistry and qPCR confirmed the HFD-induced stimulation in vascularization and glucose activity in murine bone metastases. In conclusion, multimodal and multiparametric MRI and [F-18]FDG-PET/CT were able to derive quantitative parameters in bone metastases, revealing an increase in vascularization and glucose metabolism following HFD. Thus, non-invasive imaging may serve as a biomarker for assessing the pathophysiology of bone metastasis in obesity, opening novel options for therapy and treatment monitoring by MRI and [F-18]FDG-PET/CT.
CRIS-Team WoS Importer:2022-06-10

Non-professional Phagocytes can phagocytize Necrotic Cells at any Stage of the Cell Cycle - Hofmann, Andrea; Seeberg, Jacob; Fietkau, Rainer; Distel, Luitpold (STRAHLENTHERAPIE UND ONKOLOGIE, 2020)
CRIS-Team WoS Importer:2020-10-02

Non-professional phagocytosis: a general feature of normal tissue cells - Seeberg, Jacob; Loibl, Monika; Moser, Fabian; Schwegler, Manuela; Büttner-Herold, Maike; Daniel, Christoph; Engel, Felix; Hartmann, Arndt; Schlötzer-Schrehardt, Ursula; Goppelt-Strübe, Margarete; Schellerer, Vera; Naschberger, Elisabeth; et al. (Scientific Reports, 2019)
Non-professional phagocytosis by cancer cells has been described for decades. Recently, non-professional phagocytosis by normal tissue cells has been reported, which prompted us to take a closer look at this phenomenon. Non-professional phagocytosis was studied by staining cultured cells with live-cell staining dyes or by staining paraffin-embedded tissues by immunohistochemistry. Here, we report that each of 21 normal tissue cell lines from seven different organs was capable of phagocytosis, including ex vivo cell cultures examined before the 3rd passage as well as the primary and virus-transformed cell lines. We extended our analysis to an in vivo setting, and we found the occurrence of non-professional phagocytosis in healthy skin biopsies immediately after resection. Using dystrophin immunohistochemistry for membrane staining, human post-infarction myocardial tissue was assessed. We found prominent signs of non-professional phagocytosis at the transition zone of healthy and infarcted myocardia. Taken together, our findings suggest that non-professional phagocytosis is a general feature of normal tissue cells.
CRIS-Team Scopus Importer:2019-08-27

Non-Professional Phagocytosis Increases in Melanoma Cells and Tissues with Increasing E-Cadherin Expression. - Unseld, Luzie Helene; Hildebrand, Laura; Putz, Florian; Büttner-Herold, Maike; Daniel, Christoph; Fietkau, Rainer; Distel, Luitpold (Current Oncology, 2023)
Non-professional phagocytosis in cancer has been increasingly studied in recent decades. In malignant melanoma metastasis, cell-in-cell structures have been described as a sign of cell cannibalism. To date, only low rates of cell-in-cell structures have been described in patients with malignant melanoma. To investigate these findings further, we examined twelve primary melanoma cell lines in both adherent and suspended co-incubation for evidence of engulfment. In addition, 88 malignant melanoma biopsies and 16 healthy tissue samples were evaluated. E-cadherin levels were determined in the cell lines and tissues. All primary melanoma cell lines were capable of phagocytosis, and phagocytosis increased when cells were in suspension during co-incubation. Cell-in-cell structures were also detected in most of the tissue samples. Early T stages and increasingly advanced N and M stages have correspondingly lower rates of cell-in-cell structures. Non-professional phagocytosis was also present in normal skin tissue. Non-professional phagocytosis appears to be a ubiquitous mechanism in malignant melanoma. The absence of phagocytosis in metastases may be one reason for the high rate of metastasis in malignant melanoma.
EVALuna2:539840

Norm- and hypo-fractionated radiotherapy is capable of activating human dendritic cells - Kulzer, Lorenz; Rubner, Yvonne; Deloch, Lisa; Allgäuer, Andrea; Frey, Benjamin; Fietkau, Rainer; Dörrie, Jan; Schaft, Niels; Gaipl, Udo (Journal of Immunotoxicology, 2014)
Abstract Despite the transient immunosuppressive properties of local radiotherapy (RT), this classical treatment modality of solid tumors is capable of inducing immunostimulatory forms of tumor-cell death. The resulting 'immunotoxicity' in the tumor, but not in healthy tissues, may finally lead to immune-mediated destruction of the tumor. However, little is known about the best irradiation scheme in this setting. This study examines the immunological effects of differently irradiated human colorectal tumor cells on human monocyte-derived dendritic cells (DC). Human SW480 tumor cells were irradiated with a norm-fractionation scheme (5 × 2 Gy), a hypo-fractionated protocol (3 × 5 Gy), and with a high single irradiation dose (radiosurgery; 1 × 15 Gy). Subsequently, human immature DC (iDC) were co-incubated with supernatants (SN) of these differently treated tumor cells. Afterwards, DC were analyzed regarding the expression of maturation markers, the release of cytokines, and the potential to stimulate CD4(+) T-cells. The co-incubation of iDC with SN of tumor cells exposed to norm- or hypo-fractionated RT resulted in a significantly increased secretion of the immune activating cytokines IL-12p70, IL-8, IL-6, and TNF?, compared to iDC co-incubated with SN of tumor cells that received a high single irradiation dose or were not irradiated. In addition, DC-maturation markers CD80, CD83, and CD25 were also exclusively elevated after co-incubation with the SN of fractionated irradiated tumor cells. Furthermore, the SN of tumor cells that were irradiated with norm- or hypo-fractionated RT triggered iDC to stimulate CD4(+) T-cells not only in an allogenic, but also in an antigen-specific manner like mature DC. Collectively, these results demonstrate that norm- and hypo-fractionated RT induces a fast human colorectal tumor-cell death with immunogenic potential that can trigger DC maturation and activation in vitro. Such findings may contribute to the improvement of irradiation protocols for the most beneficial induction of anti-tumor immunity.
EVALuna2:18178

Normofractionated irradiation and not temozolomide modulates the immunogenic and oncogenic phenotype of human glioblastoma cell lines - Schatz, Julia; Ladinig, Alexandra; Fietkau, Rainer; Putz, Florian; Gaipl, Udo; Frey, Benjamin; Derer, Anja (Strahlentherapie und Onkologie, 2022)
Purpose Glioblastoma multiforme (GBM) is the most aggressive primary brain tumor, with an overall poor prognosis after diagnosis. Conventional treatment includes resection, chemotherapy with temozolomide (TMZ), and concomitant radiotherapy (RT). The recent success of immunotherapy approaches in other tumor entities, particularly with immune checkpoint inhibitors, could not be clinically transferred to GBM treatment so far. Therefore, preclinical analyses of the expression of both immune-suppressive and immune-stimulatory checkpoint molecules following treatment of human glioblastoma cells with RT and/or temozolomide is needed to design feasible radio(chemo)immunotherapy trials for GBM in the future. Methods Five human glioblastoma cell lines (H4, HROG-06, U118, U138, U251) were analyzed regarding their clonogenic survival and cell death forms after chemotherapy (CT) with TMZ and/or normofractionated RT (5 x 2 Gy) via multicolor flow cytometry. Further, the tumor cell surface expression of immune-activating (OX40L, CD137L, CD70, and ICOSL) and immune-suppressive (PD-L1, PD-L2, HVEM) checkpoint molecules and of an oncogenic molecule (EGFR) were measured via multicolor flow cytometry after CT and RT alone or after RCT. Results Normofractionated RT and not TMZ was the trigger of induction of predominantly necrosis in the glioblastoma cells. Notably, clonogenicity did not correlate with cell death induction by RT. The basal expression level of immune-suppressive PD-L1, PD-L2, and HVEM varied in the analyzed glioblastoma cells. RT, but not TMZ, resulted in a significant upregulation of PD-L1 and PD-L2 in all tumor cells investigated. Also, the expression of HVEM was increased after RT in most of the GBM cell lines. In contrast, normofractionated RT individually modulated expression of the stimulating immune checkpoint molecules CD70, CD137L, OX40L, and ICOSL1. The oncogenic factor EGFR was significantly increased by irradiation in all examined cell lines, albeit to a different extent. None of the investigated molecules were downregulated after the treatments. Conclusion Normofractionated radiotherapy modulates the immunogenic as well as the oncogenic phenotype of glioblastoma cells, partly individually. Therefore, not only PD-L1 and PD-L2, but also other immunogenic molecules expressed on the surface of glioblastoma cells could serve as targets for immune checkpoint blockade in combination with RT in the future.
CRIS-Team WoS Importer:2022-12-23

Novel technique for high-precision stereotactic irradiation of mouse brains - Hartmann, Josefin; Wölfelschneider, Jens; Stache, Christina; Buslei, R.; Derer, Anja; Schwarz, Martin; Bäuerle, Tobias; Fietkau, Rainer; Gaipl, Udo; Bert, Christoph; Hoelsken, A.; Frey, Benjamin (Strahlentherapie und Onkologie, 2016)
Small animal irradiation systems were developed for preclinical evaluation of tumor therapy closely resembling the clinical situation. Mostly only clinical LINACs are available, so protocols for small animal partial body irradiation using a conventional clinical system are essential. This study defines a protocol for conformal brain tumor irradiations in mice.CT and MRI images were used to demarcate the target volume and organs at risk. Three 6 MV photon beams were planned for a total dose of 10 fractions of 1.8 Gy. The mouse position in a dedicated applicator was verified by an X-ray patient positioning system before each irradiation. Dosimetric verifications (using ionization chambers and films) were performed. Irradiation-induced DNA damage was analyzed to verify the treatment effects on the cellular level.The defined treatment protocol and the applied fractionation scheme were feasible. The in-house developed applicator was suitable for individual positioning at submillimeter accuracy of anesthetized mice during irradiation, altogether performed in less than 10 min. All mice tolerated the treatment well. Measured dose values perfectly matched the nominal values from treatment planning. Cellular response was restricted to the target volume.Clinical LINAC-based irradiations of mice offer the potential to treat orthotopic tumors conformably. Especially with respect to lateral penumbra, dedicated small animal irradiation systems exceed the clinical LINAC solution.
EVALuna2:7317

Olanzapine combined with 5-hydroxytryptamine type 3 receptor antagonist (5-HT3 RA) plus dexamethasone for prevention and treatment of chemotherapy-induced nausea and vomiting in high and moderate emetogenic chemotherapy: a systematic review and meta-analysis of randomised controlled trials - Zhou, Jian Guo; Huang, Lang; Jin, Su Han; Xu, Cheng; Frey, Benjamin; Ma, Hu; Gaipl, Udo (ESMO Open, 2020)
We performed a pooled analysis to evaluate the efficacy and adverse events (AEs) of olanzapine combined with dexamethasone plus 5-hydroxytryptamine type 3 receptor antagonist (5-HT3 RA) compared with 5-HT3 RA plus dexamethasone for the prevention and treatment of chemotherapy-induced nausea and vomiting (CINV) in high and moderate emetogenic chemotherapy based on randomised controlled trials (RCTs). PubMed, EMBASE, Web of Science, the Cochrane Library, China Biomedical Literature database (CBM), WanFang Database, China National Knowledge Infrastructure (CNKI), and Chinese Science and Technology Periodical Database (VIP) (from their inception to April 2019) were searched to capture relevant articles. Relative risk with 95% confidence intervals for CINV and AEs were all extracted or calculated. Eleven studies with 1107 cancer patients were involved in this review. The pooled RR of delayed CINV (RR 0.50, 95% CI 0.38 to 0.66; p<0.01) were significantly decreased in the olanzapine group. The occurrence of insomnia was also statistically decreased, as was the rate of acute CINV (RR 0.60, 95% CI 0.48 to 0.75; p<0.01). However, only the percentages of CINV III and CINV IV were significantly decreased in the acute and delayed phases. Subgroup analysis demonstrated that the efficacy was not statistically significantly different between 5 mg and 10 mg olanzapine. Olanzapine significantly decreased the occurrence of CINV III and IV and insomnia in high and moderately emetogenic chemotherapy. Compared with 10 mg per day, 5 mg oral olanzapine may be more appropriate for patients with cancer.
CRIS-Team Scopus Importer:2020-03-06
Keywords: 5-HT3 RA; chemotherapy-induced nausea and Vomiting; dexamethasone; meta-analysis; olanzapine

Older Patients Are Less Affected by Radiochemotherapeutic Treatment than Younger - Welling, Max J.; Losensky, Wencke; Wächter, Katharina; Schilling, Teresa; Frank, Friedrich; Haas, Matthias; Fietkau, Rainer; Distel, Luitpold; Weiß, Stephanie (BioMed Research International, 2018)
Purpose: The general assumption is that cancer therapy impairs the quality of life in elderly patients more than in younger ones. We were interested in the effects of radiochemotherapeutic treatment on the quality of life of elderly patients compared to younger patients and compared to normative data of a general German population. Methods and Materials: A total of 465 patients completed the EORTC QLQ-C30 questionnaire. Repetitive completion of the questionnaire over time led to 1407 datasets. Our patient cohort contained 197 (42.4%) patients with colorectal cancer followed by 109 (23.4%) patients with head and neck cancer, 43 (9.2%) patients with lung cancer, and 116 (25%) with other types of cancer. Patients were categorized into five age groups, the respective cut-offs being 40, 50, 60, and 70 years. Normative data were drawn from a population study of a general German population. Results: Functional scores and symptom scores were approximately stable between the different age groups. Our data does not suggest a significant difference between the investigated age groups. Advancing age evened out the differences between the normative data of the general German population and the cancer patients in 11 of 15 scores. Conclusions: The general belief about younger patients having fewer physical and psychological problems related to radiochemotherapy needs to be reconsidered. Overall resilience of older patients is apparently underestimated.
EVALuna2:36461

Older patients with inoperable non-small cell lung cancer: long-term survival after concurrent chemoradiotherapy - Semrau, Sabine; Zettl, Heike; Hildebrandt, Guido; Klautke, Gunther; Fietkau, Rainer (Strahlentherapie und Onkologie, 2014)
Considering the various comorbidities associated with aging, the feasibility and usefulness of concurrent chemoradiotherapy (CRT) in older patients with inoperable non-small cell lung cancer (NSCLC) is a controversial issue. Here, we compared the feasibility of CRT and the effects of various comorbidities on the prognosis of a minimally selected population of inoperable NSCLC patients aged 60-77 years.The study comprised 161 patients with inoperable NSCLC who received CRT with a target radiation dose greater than 60 Gy and platinum-based chemotherapy from 1998 to 2007. The total population included 69 patients aged 60-69 years and 53 aged 70-77 years. These two age cohorts were included in the study with a follow-up of a median 14.5 months.The two groups showed no differences in long-term survival, as reflected by the 5-year survival rates of 13.0 ± 4.1 % (60- to 69-year-olds) and 14.4 ± 4.9 % (70- to 77-year-olds). During the treatment phase, the groups were comparable in terms of toxicity and the feasibility of chemotherapy. Compared to patients in their 60s, the septuagenarians had more pulmonary comorbidities (p = 0.02), diabetes mellitus (p = 0.04), cardiac comorbidities (p = 0.08), and previous cancer disease (p = 0.08) that exerted a negative effect on survival. In patients without comorbidities, there were no differences between the age groups.Age is not a contraindication for concurrent CRT per se, because elderly patients do not have a worse long-term prognosis than younger seniors. However, "elderly patients" (>= 70-77 years) have more concomitant diseases associated with shorter survival than "moderately aged patients" (>= 60-69 years).
EVALuna2:18190

Oligometastasis in breast cancer—current status and treatment options from a radiation oncology perspective - Piroth, Marc D.; Krug, David; Feyer, Petra; Baumann, Rene; Combs, Stephanie; Duma, Marciana-Nona; Dunst, Juergen; Fastner, Gerd; Fietkau, Rainer; Guckenberger, Matthias; Haase, Wulf; Harms, Wolfgang; et al. (Strahlentherapie und Onkologie, 2022)
Evidence from a few small randomized trials and retrospective cohorts mostly including various tumor entities indicates a prolongation of disease free survival (DFS) and overall survival (OS) from local ablative therapies in oligometastatic disease (OMD). However, it is still unclear which patients benefit most from this approach. We give an overview of the several aspects of stereotactic body radiotherapy (SBRT) in extracranial OMD in breast cancer from a radiation oncology perspective. A PubMed search referring to this was conducted. An attempt was made to relate the therapeutic efficacy of SBRT to various prognostic factors. Data from approximately 500 breast cancer patients treated with SBRT for OMD in mostly in small cohort studies have been published, consistently indicating high local tumor control rates and favorable progression-free (PFS) and overall survival (OS). Predictors for a good prognosis after SBRT are favorable biological subtype (hormone receptor positive, HER2 negative), solitary metastasis, bone-only metastasis, and long metastasis-free interval. However, definitive proof that SBRT in OMD breast cancer prolongs DFS or OS is lacking, since, with the exception of one small randomized trial (n = 22 in the SBRT arm), none of the cohort studies had an adequate control group. Further studies are needed to prove the benefit of SBRT in OMD breast cancer and to define adequate selection criteria. Currently, the use of local ablative SBRT should always be discussed in a multidisciplinary tumor board.
CRIS-Team Scopus Importer:2022-05-20
Keywords: Breast cancer; Oligometastases; OMD; Radiotherapy; Stereotactic body radiotherapy

Oligometastatic head and neck cancer: Which patients benefit from radical local treatment of all tumour sites? - Weissmann, Thomas; Höfler, Daniel; Hecht, Markus; Semrau, Sabine; Haderlein, Marlen; Filimonova, Irina; Frey, Benjamin; Bert, Christoph; Lettmaier, Sebastian; Mantsopoulos, Konstantinos; Iro, Heinrich; Fietkau, Rainer; et al. (Radiation Oncology, 2021)
Background: There is a large lack of evidence for optimal treatment in oligometastatic head and neck cancer and it is especially unclear which patients benefit from radical local treatment of all tumour sites. Methods: 40 patients with newly diagnosed oligometastatic head and neck cancer received radical local treatment of all tumour sites from 14.02.2008 to 24.08.2018. Primary endpoint was overall survival. Time to occurrence of new distant metastases and local control were evaluated as secondary endpoints as well as prognostic factors in univariate und multivariate Cox’s regression analysis. To investigate the impact of total tumour volume on survival, all tumour sites were segmented on baseline imaging. Results: Radical local treatment included radiotherapy in 90% of patients, surgery in 25% and radiofrequency ablation in 3%. Median overall survival from first diagnosis of oligometastatic disease was 23.0 months, 2-year survival was 48%, 3-year survival was 37%, 4-year survival was 24% and 5-year survival was 16%. Median time to occurrence of new distant metastases was 11.6 months with freedom from new metastases showing a tail pattern after 3 years of follow-up (22% at 3, 4- and 5-years post-treatment). In multivariate analysis, better ECOG status, absence of bone and brain metastases and lower total tumour volume were significantly associated with improved survival, whereas the number of metastases and involved organ sites was not. Conclusions: Radical local treatment in oligometastatic head and neck cancer shows promising outcomes and needs to be further pursued. Patients with good performance status, absence of brain and bone metastases and low total tumour volume were identified as optimal candidates for radical local treatment in oligometastatic head and neck cancer and should be considered for selection in future prospective trials.
CRIS-Team Scopus Importer:2021-04-16
Keywords: Head and neck cancer; Local treatment; Oligometastatic disease; Radiotherapy; SBRT

Oligometastatic non-small cell lung cancer–surgical options and therapy strategies - Schreiner, Waldemar; Semrau, S.; Fietkau, Rainer; Sirbu, Horia (Zentralblatt für Chirurgie, 2014)
The therapeutic strategies for oligometastatic non-small cell lung cancer have changed over the last decade from palliative to curative intent. The role of surgery in this multimodal treatment in selected patients remains a subject for open discussion.Data of 34 patients with one or two metastases treated from January 1998 to January 2013 were retrospectively analysed.The mean age was 59.7 (± 10.1) years. The male vs. female ratio was 20 vs. 14. Adenocarcinoma was the most common histological type (58.8 %). The synchronous metastases were present in 15 patients, the metachronous in 19 patients. Single metastases were present in 27 patients, two metastases in 7 patients. The most frequently involved organs were brain (58.8 %) and the lungs (23.6 %). The primary tumour resection was achievable in 20 patients as R0 and in 2 patients as R1. The median overall survival, the local and the systemic disease-free survivals in the entire group were 40, 38 and 25 months, respectively. The 5 year overall survival, the 5 year local and systemic disease-free survivals were 29.2, 26.9 and 16.5 %, respectively. The treatment strategies including surgery for primary tumour as well as for pulmonary metastases site, combined with the lymph node dissection and the resection of the extracerebral and cerebral metastases, were identified as independent prognostic factors for long-term survival.Surgery in oligometastatic non-small cell lung carcinoma is feasible for primary tumour and for metastases. It is an effective option in the multimodal treatment in highly selected patients. The lymph node dissection should remain an important integral part of the surgical treatment.
EVALuna2:18244

Oncological Patients with systemic Lupus Erythematosus have a clear risk of increased Radiation Sensitivity - Schenker, Hannah; Schuster, B.; Hecht, Markus; Fietkau, Rainer; Distel, Luitpold (STRAHLENTHERAPIE UND ONKOLOGIE, 2020)
CRIS-Team WoS Importer:2020-10-02

One-tube multicolor flow cytometry assay (OTMA) for comprehensive immunophenotyping of peripheral blood - Donaubauer, Anna-Jasmina; Rühle, Paul-Friedrich; Becker, Ina; Fietkau, Rainer; Gaipl, Udo; Frey, Benjamin (Human Monoclonal Antibodies, 2019)
Recent improvements in the flow cytometry technology allow the determination of the general immune status through the development of multicolor immunofluorescence panels. The one-tube multicolor flow cytometry assay (OTMA) that is presented here identifies 20 different, clinically relevant immune cell subsets and three common activation markers. Thereby, a comprehensive immune status that covers all major immune cells is easily obtained. The assay is suitable for every common three lasers and 10 color flow cytometer and includes the application of 15 different antibodies. Furthermore, the assay requires only 100 μL of EDTA-treated whole-blood and less than 40 min for sample preparation. By being easily adaptable to individual requirements and by additionally determining absolute cell counts, the assay is well-suited for translational research in clinical trials.
CRIS-Team Scopus Importer:2019-07-09
Keywords: Absolute cell count; Antibody; Gating strategy; Human whole-blood; Immune status; Immunophenotyping; Multicolor flow cytometry; One-tube measurement

One year survival of brain tumor patients is closely linked to symptomatic CMV-encephalopathy - Goerig, Nicole; Frey, Benjamin; Korn, Klaus; Fleckenstein, Bernhard; Überla, Klaus; Schmidt, Manuel; Dörfler, Arnd; Engelhorn, Tobias; Eyüpoglu, Ilker Yasin; Merkel, Andreas; Rühle, Paul-Friedrich; Putz, Florian; et al. (2017)
EVALuna2:32882

On PTV definition for glioblastoma based on fiber tracking of diffusion tensor imaging data - Witulla, Barbara; Goerig, Nicole; Putz, Florian; Frey, Benjamin; Engelhorn, Tobias; Dörfler, Arnd; Uder, Michael; Fietkau, Rainer; Bert, Christoph; Laun, Frederik Bernd (PLoS ONE, 2020)
Radiotherapy (RT) is commonly applied for the treatment of glioblastoma multiforme (GBM). Following the planning target volume (PTV) definition procedure standardized in guidelines, a 20% risk of missing non-local recurrences is present. Purpose of this study was to evaluate whether diffusion tensor imaging (DTI)-based fiber tracking may be beneficial for PTV definition taking into account the prediction of distant recurrences. 56 GBM patients were examined with magnetic resonance imaging (MRI) including DTI performed before RT after resection of the primary tumor. Follow-up MRIs were acquired in three month intervals. For the seven patients with a distant recurrence, fiber tracking was performed with three algorithms and it was evaluated whether connections existed from the primary tumor region to the distant recurrence. It depended strongly on the used tracking algorithm and the used tracking parameters whether a connection was observed. Most of the connections were weak and thus not usable for PTV definition. Only in one of the seven patients with a recurring tumor, a clear connection was present. It seems unlikely that DTI-based fiber tracking can be beneficial for predicting distant recurrences in the planning of PTVs for glioblastoma multiforme.
CRIS-Team Scopus Importer:2020-01-21

On the Death of our Honorary Member, Prof. Seymour Levitt MD, has works published, Radiologist in Minneapolis - Sauer, Rolf (Strahlentherapie und Onkologie, 2017)
EVALuna2:33029

On the implant stability in adaptive multi-catheter breast brachytherapy: Establishment of a decision-tree for treatment re-planning - Karius, Andre; Szkitsak, Juliane; Strnad, Vratislav; Lotter, Michael; Kreppner, Stephan; Schubert, Philipp; Fietkau, Rainer; Bert, Christoph (Radiotherapy and Oncology, 2023)
Background and purpose: To assess implant stability and identify causes of implant variations during high-dose-rate multi-catheter breast brachytherapy. Materials and methods: Planning-CTs were compared to control-CTs acquired halfway through the treatment for 100 patients. For assessing geometric stability, Fréchet-distance and button-to-button distance changes of all catheters as well as variations of Euclidean distances and convex hulls of all dwell positions were determined. The CTs were inspected to identify the causes of geometric changes. Dosimetric effects were evaluated by target volume transfers and re-contouring of organs at risk. The dose non-uniformity ratio (DNR), 100% and 150% isodose volumes (V100 and V150), coverage index (CI), and organ doses were calculated. Correlations between the examined geometric and dosimetric parameters were assessed. Results: Fréchet-distance and dwell position deviations >2.5 mm as well as button-to-button distance changes >5 mm were detected for 5%, 2%, and 6.3% of catheters, but for 32, 17, and 37 patients, respectively. Variations occurred enhanced in the lateral breast and close to the ribs, e.g. due to different arm positions. Only small dosimetric effects with median DNR, V100, and CI variations of −0.01 ± 0.02, (−0.5 ± 1.3)ccm, and (–1.4 ± 1.8)% were observed in general. Skin dose exceeded recommended levels for 12 of 100 patients. Various correlations between geometric and dosimetric implant stability were found, based on which decision-tree regarding treatment re-planning was established. Conclusion: Multi-catheter breast brachytherapy shows a high implant stability in general, but considering skin dose changes is important. To increase implant stability for individual patients, we plan to investigate patient immobilization aids during treatments.
CRIS-Team Scopus Importer:2023-04-07
Keywords: Adaptive brachytherapy; CT imaging; Imaging-based treatment planning; Implant stability; Multi-catheter breast brachytherapy; Treatment quality assurance

On the use of multi-dimensional scaling and electromagnetic tracking in high dose rate brachytherapy - Goetz, Th I.; Ermer, M.; Salas-Gonzalez, Diego; Kellermeier, Markus; Strnad, Vratislav; Bert, Christoph; Hensel, Bernhard; Tome, A. M.; Lang, E. W. (Physics in Medicine and Biology, 2017)
High dose rate brachytherapy affords a frequent reassurance of the precise dwell positions of the radiation source. The current investigation proposes a multi-dimensional scaling transformation of both data sets to estimate dwell positions without any external reference. Furthermore, the related distributions of dwell positions are characterized by uni-or bi-modal heavy-tailed distributions. The latter are well represented by α-stable distributions. The newly proposed data analysis provides dwell position deviations with high accuracy, and, furthermore, offers a convenient visualization of the actual shapes of the catheters which guide the radiation source during the treatment.
EVALuna2:33032

On the use of particle filters for electromagnetic tracking in high dose rate brachytherapy - Goetz, Th I.; Lahmer, Godehard; Brandt, Tobias; Kallis, Karoline; Strnad, Vratislav; Bert, Christoph; Hensel, Bernhard; Tome, A. M.; Lang, E. W. (Physics in Medicine and Biology, 2017)
Modern radiotherapy of female breast cancers often employs high dose rate brachytherapy, where a radioactive source is moved inside catheters, implanted in the female breast, according to a prescribed treatment plan. Source localization relative to the patient's anatomy is determined with solenoid sensors whose spatial positions are measured with an electromagnetic tracking system. Precise sensor dwell position determination is of utmost importance to assure irradiation of the cancerous tissue according to the treatment plan. We present a hybrid data analysis system which combines multi-dimensional scaling with particle filters to precisely determine sensor dwell positions in the catheters during subsequent radiation treatment sessions. Both techniques are complemented with empirical mode decomposition for the removal of superimposed breathing artifacts. We show that the hybrid model robustly and reliably determines the spatial positions of all catheters used during the treatment and precisely determines any deviations of actual sensor dwell positions from the treatment plan. The hybrid system only relies on sensor positions measured with an EMT system and relates them to the spatial positions of the implanted catheters as initially determined with a computed x-ray tomography.
EVALuna2:33033

Optimization of Single Voxel MR Spectroscopy Sequence Parameters and Data Analysis Methods for Thermometry in Deep Hyperthermia Treatments - Hartmann, Josefin; Gellermann, J.; Brandt, Tobias; Schmidt, M.; Pyatykh, S.; Hesser, J.; Ott, O.; Fietkau, Rainer; Bert, Christoph (Technology in Cancer Research & Treatment, 2016)
The difference in the resonance frequency of water and methylene moieties of lipids quantifies in magnetic resonance spectroscopy the absolute temperature using a predefined calibration curve. The purpose of this study was the investigation of peak evaluation methods and the magnetic resonance spectroscopy sequence (point-resolved spectroscopy) parameter optimization that enables thermometry during deep hyperthermia treatments.Different Lorentz peak-fitting methods and a peak finding method using singular value decomposition of a Hankel matrix were compared. Phantom measurements on organic substances (mayonnaise and pork) were performed inside the hyperthermia 1.5-T magnetic resonance imaging system for the parameter optimization study. Parameter settings such as voxel size, echo time, and flip angle were varied and investigated.Usually all peak analyzing methods were applicable. Lorentz peak-fitting method in MATLAB proved to be the most stable regardless of the number of fitted peaks, yet the slowest method. The examinations yielded an optimal parameter combination of 8 cm(3) voxel volume, 55 millisecond echo time, and a 90° excitation pulse flip angle.The Lorentz peak-fitting method in MATLAB was the most reliable peak analyzing method. Measurements in homogeneous and heterogeneous phantoms resulted in optimized parameters for the magnetic resonance spectroscopy sequence for thermometry.
EVALuna2:18362

Oral cavity carcinomas as primary manifestation of telomere maintenance disorders (telomeropathies) - Beier, F.; Schmitt, K.; Bouillon, A. -S; Hasenbank, C.; Vankann, L.; Ambrosch, P.; Hoffmann, T.; Fietkau, Rainer; Panse, J.; Bruemmendorf, T. H. (2016)
EVALuna2:32921

Organ-sparing treatment of penile cancer with interstitial pulsed-dose-rate brachytherapy - Seibold, Johannes; Strnad, Vratislav; Fietkau, Rainer (Strahlentherapie und Onkologie, 2016)
To assess the efficacy and toxicity profile of protocol-based interstitial pulsed-dose-rate (PDR) brachytherapy for penile carcinoma.From August 2002 to February 2014, 13 men with penile cancer were treated by interstitial brachytherapy. The tumor stage was T1 for eight patients, T2 for four patients, and T3 for one patient. The tumor grade was well differentiated for five patients and moderately differentiated for seven patients, while it was unknown for one patient. Lymph node staging was positive for three of 13 patients. All patients were treated using interstitial PDR brachytherapy with dose specifications according to the Paris system. For data collection of erectile dysfunction, the International Index of Erectile Function questionnaire was used, supplemented by the follow-up data.The median follow-up was 54.0 months (range, 13-155 months). Only one patient (1/13, 7.7 %) with local failure was documented. At 5 and 10 years, the local cumulative recurrence rate, disease-free survival, and the cancer-specific survival rates were 12.5 % (95 % CI, 80.4-119.6), 80.8 % (95 % CI, 75.2-124.8), and 77.9 % (95 % CI, 74.3-125.7), respectively. At the time of analysis, nine of 13 men were alive; two of 13 men died of distant metastases from the tumor and two for other reasons with no sign of cancer disease. Serious late side effects such as soft tissue necrosis occurred in four of 13 patients (30 %) and all were successfully treated with medication. Mutilating salvage surgery was not necessary in any of the cases. Urethral stenosis was documented for two of 13 (15.4 %) and dysuria occurred in four of 13 patients (30.8 %). Eight of 11 men (72.7 %) never or only sometimes had erectile dysfunction.In selected patients, interstitial PDR brachytherapy of penile cancer is effective as an organ-sparing treatment. It yields satisfactory results for the conservation of sexual function.
EVALuna2:18347

Orofacial clefts lead to increased pro-inflammatory cytokine levels on neonatal oral mucosa - Seidel, Corinna L.; Percivalle, Elena; Tschaftari, Marco; Weider, Matthias; Strobel, Karin; Willershausen, Ines; Unertl, Christoph; Schmetzer, Helga M.; Weber, Manuel; Schneider, Michael; Frey, Benjamin; Gaipl, Udo; et al. (Frontiers in Immunology, 2022)
Orofacial clefts (OFC) are frequent congenital malformations characterized by insufficient separation of oral and nasal cavities and require presurgical infant orthopedics and surgical interventions within the first year of life. Wound healing disorders and higher prevalence of gingivitis and plaque levels are well-known challenges in treatment of children with OFC. However, oral inflammatory mediators were not investigated after birth using non-invasive sampling methods so far. In order to investigate the impact of OFC on oral cytokine levels, we collected tongue smear samples from 15 neonates with OFC and 17 control neonates at two time points (T), T0 at first consultation after birth, and T1, 4 to 5 weeks later. The samples were analyzed using multiplex immunoassay. Overall, we found significantly increased cytokine levels (TNF, IL-1β/-2/-6/-8/-10) in tongue smear samples from neonates with OFC compared to controls, especially at T0. The increase was even more pronounced in neonates with a higher cleft severity. Further, we detected a significant positive correlation between cleft severity score and distinct pro-inflammatory mediators (GM-CSF, IL-1β, IL-6, IL-8) at T0. Further, we found that breast-milk (bottle) feeding was associated with lower levels of pro-inflammatory cytokines (IL-6/-8) in neonates with OFC compared to formula-fed neonates. Our study demonstrated that neonates with OFC, especially with high cleft severity, are characterized by markedly increased inflammatory mediators in tongue smear samples within the first weeks of life potentially presenting a risk for oral inflammatory diseases. Therefore, an inflammatory monitoring of neonates with (severe) OFC and the encouragement of mother to breast-milk (bottle) feed might be advisable after birth and/or prior to cleft surgery.
CRIS-Team Scopus Importer:2022-12-16
Keywords: cleft lip and palate; cytokines; mucosal homeostasis; mucosal immunity; neonates; oral; oral inflammation; orofacial clefts

Osteoimmunological Effects of Radon Therapy on Patients with chronic degenerative and/or inflammatory Diseases - Becker, I.; Donaubauer, Anna-Jasmina; Klein, G.; Cheremina, O.; Fournier, C.; Cucu, A.; Rapp, F.; Kraft, D.; Fietkau, Rainer; Frey, Benjamin; Gaipl, Udo (STRAHLENTHERAPIE UND ONKOLOGIE, 2019)
CRIS-Team WoS Importer:2019-06-07

Osteo-immunological impact of radon spa treatment: due to radon or spa alone? Results from the prospective, thermal bath placebo-controlled RAD-ON02 trial. - Eckert, Denise; Evic, Megi; Schang, Jasmin; Isbruch, Maike; Er, Melissa; Dörrschuck, Lea; Rapp, Felicitas; Donaubauer, Anna-Jasmina; Gaipl, Udo; Frey, Benjamin; Fournier, Claudia (Frontiers in Immunology, 2024)
Musculoskeletal disorders (MSDs) are associated with pain and lead to reduced mobility and quality of life for patients. Radon therapy is used as alternative or complementary to pharmaceutical treatments. According to previous reports, radon spa leads to analgesic and anti-inflammatory effects, but the cellular and molecular mechanisms are widely unknown. A previous study (RAD-ON01) revealed, that bone erosion markers like collagen fragments (C-terminal telopeptide, CTX) are reduced after radon spa treatment in serum of patients with degenerative MSDs. Within the scope of the prospective, placebo-controlled RAD-ON02 trial presented here, we analyzed the influence of radon and thermal spa treatment on osteoclastogenesis. From patient blood, we isolate monocytes, seeded them on bone slices and differentiated them in the presence of growth factors into mature osteoclasts (mOCs). Subsequent analysis showed a smaller fraction of mOCs after both treatments, which was even smaller after radon spa treatment. A significantly reduced resorbed area on bone slices reflects this result. Only after radon spa treatment, we detected in the serum of patients a significant decrease of receptor activator of NF-κB ligand (RANKL), which indicates reduced differentiation of OCs. However, other markers for bone resorption (CTX) and bone formation (OPG, OCN) were not altered after both treatments. Adipokines, such as visfatin and leptin that play a role in some MSD-types by affecting osteoclastogenesis, were not changed after both treatments. Further, also immune cells have an influence on osteoclastogenesis, by inhibiting and promoting terminal differentiation and activation of OCs, respectively. After radon treatment, the fraction of Treg cells was significantly increased, whereas Th17 cells were not altered. Overall, we observed that both treatments had an influence on osteoclastogenesis and bone resorption. Moreover, radon spa treatment affected the Treg cell population as well as the Th17/Treg ratio were affected, pointing toward a contribution of the immune system after radon spa. These data obtained from patients enrolled in the RAD-ON02 trial indicate that radon is not alone responsible for the effects on bone metabolism, even though they are more pronounced after radon compared to thermal spa treatment.
EVALuna2:557909

Outcome and management of rare high-grade “salivary” adenocarcinoma: the important role of adjuvant (chemo)radiotherapy - Scherl, Claudia; Haderlein, Marlen; Agaimy, Abbas; Mantsopoulos, Konstantinos; Koch, Michael; Traxdorf, Maximilian; Fietkau, Rainer; Grundtner, Philipp; Iro, Heinrich (Strahlentherapie und Onkologie, 2019)
Purpose: To determine survival and management strategies for high-grade adenocarcinoma of salivary glands (ASG). Methods: A retrospective analysis of cases diagnosed between 1998 and 2015 from our single tertiary referral center was performed. Multivariable logistic regression was used to determine factors associated with survival. Results: Thirty-eight cases of high-grade ASG were identified. Most patients were men (68.4%) with a median age of 65.5 years (range 23–84 years). Most tumors were T3 and T4 (65.8%). Regional metastases were common (55.2%), and 42.1% developed distant metastases. The mean follow-up was 60.5 months. All patients received surgery as primary treatment, with 84.2% of patients receiving adjuvant radiation therapy or chemoradiotherapy ([C]RT). Cumulative overall survival was 89.1%, 50.9%, and 20.7% after 1, 5, and 10 years, respectively. Disease-specific survival was 94.4%, 69.8%, and 42.8%, and distant-metastases-free survival (DMFS) was 80.5%, 50.1%, and 40.1% after 1, 5, and 10 years. On multivariable analysis, advanced T status correlated with DMFS (hazard ratio 2.75, 95% CI 0.93–8.16). Postsurgical (C)RT reduced the locoregional recurrence rate by 23.9%, and it improved the locoregional-recurrence-free survival by 39% (p = 0.094). Conclusion: High-grade ASG is considered to have an unfavorable prognosis. Adjuvant (C)RT reduces the rate of locoregional recurrences. Distant metastases are common, and an advanced T stage has increased prognostic value for development of early distant lesions.
CRIS-Team Scopus Importer:2019-08-06
Keywords: Head and neck cancer; Salivary gland cancer; Salivary gland malignancy; Survival salivary gland cancer; Treatment salivary gland cancer

Oxaliplatin added to fluorouracil-based preoperative chemoradiotherapy and postoperative chemotherapy of locally advanced rectal cancer (the German CAO/ARO/AIO-04 study): final results of the multicentre, open-label, randomised, phase 3 trial - Roedel, Claus; Graeven, Ullrich; Fietkau, Rainer; Hohenberger, Werner; Hothorn, Torsten; Arnold, Dirk; Hofheinz, Ralf-Dieter; Ghadimi, Michael; Wolff, Hendrik A.; Lang-Welzenbach, Marga; Raab, Hans-Rudolf; Wittekind, Christian; et al. (Lancet Oncology, 2015)
Preoperative chemoradiotherapy with infusional fluorouracil, total mesorectal excision surgery, and postoperative chemotherapy with fluorouracil was established by the German CAO/ARO/AIO-94 trial as a standard combined modality treatment for locally advanced rectal cancer. Here we compare the previously established regimen with an investigational regimen in which oxaliplatin was added to both preoperative chemoradiotherapy and postoperative chemotherapy.In this multicentre, open-label, randomised, phase 3 study we randomly assigned patients with rectal adenocarcinoma, clinically staged as cT3-4 or any node-positive disease, to two groups: a control group receiving standard fluorouracil-based combined modality treatment, consisting of preoperative radiotherapy of 50·4 Gy in 28 fractions plus infusional fluorouracil (1000 mg/m(2) on days 1-5 and 29-33), followed by surgery and four cycles of bolus fluorouracil (500 mg/m(2) on days 1-5 and 29); or to an investigational group receiving preoperative radiotherapy of 50·4 Gy in 28 fractions plus infusional fluorouracil (250 mg/m(2) on days 1-14 and 22-35) and oxaliplatin (50 mg/m(2) on days 1, 8, 22, and 29), followed by surgery and eight cycles of oxaliplatin (100 mg/m(2) on days 1 and 15), leucovorin (400 mg/m(2) on days 1 and 15), and infusional fluorouracil (2400 mg/m(2) on days 1-2 and 15-16). Randomisation was done with computer-generated block-randomisation codes stratified by centre, clinical T category (cT1-3 vs cT4), and clinical N category (cN0 vs cN1-2) without masking. The primary endpoint was disease-free survival, defined as the time between randomisation and non-radical surgery of the primary tumour (R2 resection), locoregional recurrence after R0/1 resection, metastatic disease or progression, or death from any cause, whichever occurred first. Survival and cumulative incidence of recurrence analyses followed the intention-to-treat principle; toxicity analyses included all patients treated. Enrolment of patients in this trial is completed and follow-up is ongoing. This study is registered with ClinicalTrials.gov, number NCT00349076.Of the 1265 patients initially enrolled, 1236 were assessable (613 in the investigational group and 623 in the control group). With a median follow-up of 50 months (IQR 38-61), disease-free survival at 3 years was 75·9% (95% CI 72·4-79·5) in the investigational group and 71·2% (95% CI 67·6-74·9) in the control group (hazard ratio [HR] 0·79, 95% CI 0·64-0·98; p=0·03). Preoperative grade 3-4 toxic effects occurred in 144 (24%) of 607 patients who actually received fluorouracil and oxaliplatin during chemoradiotherapy and in 128 (20%) of 625 patients who actually received fluorouracil chemoradiotherapy. Of 445 patients who actually received adjuvant fluorouracil and leucovorin and oxaliplatin, 158 (36%) had grade 3-4 toxic effects, as did 170 (36%) of 470 patients who actually received adjuvant fluorouracil. Late grade 3-4 adverse events in patients who received protocol-specified preoperative and postoperative treatment occurred in 112 (25%) of 445 patients in the investigational group, and in 100 (21%) of 470 patients in the control group.Adding oxaliplatin to fluorouracil-based neoadjuvant chemoradiotherapy and adjuvant chemotherapy (at the doses and intensities used in this trial) significantly improved disease-free survival of patients with clinically staged cT3-4 or cN1-2 rectal cancer compared with our former fluorouracil-based combined modality regimen (based on CAO/ARO/AIO-94). The regimen established by CAO/ARO/AIO-04 can be deemed a new treatment option for patients with locally advanced rectal cancer.German Cancer Aid (Deutsche Krebshilfe).
EVALuna2:15201

Oxidized silicon nanoparticles and iron oxide nanoparticles for radiation therapy - Klein, Stefanie; Kizaloglu, Melek; Dell'Acriprete, M. L.; Neuhuber, Winfried; Distel, Luitpold; Gonzales, M. C.; Kryschi, Carola (2016)
EVALuna2:33050

Oxidized silicon nanoparticles for radiosensitization of cancer and tissue cells - Klein, Stefanie; Dell'Arciprete, Maria L.; Wegmann, Marc; Distel, Luitpold; Neuhuber, Winfried; Gonzalez, Monica C.; Kryschi, Carola (Biochemical and Biophysical Research Communications, 2013)
The applicability of ultrasmall uncapped and aminosilanized oxidized silicon nanoparticles (SiNPs and NH-SiNPs) as radiosensitizer was studied by internalizing these nanoparticles into human breast cancer (MCF-7) and mouse fibroblast cells (3T3) that were exposed to X-rays at a single dose of 3Gy. While SiNPs did not increase the production of reactive oxygen species (ROS) in X-ray treated cells, the NH-SiNPs significantly enhanced the ROS formation. This is due to the amino functionality as providing positive surface charges in aqueous environment. The NH-SiNPs were observed to penetrate into the mitochondrial membrane, wherein these nanoparticles provoked oxidative stress. The NH-SiNPs induced mitochondrial ROS production was confirmed by the determination of an increased malondialdehyde level as representing a gauge for the extent of membrane lipid peroxidation. X-ray exposure of NH-SiNPs incubated MCF-7 and 3T3 cells increased the ROS concentration for 180%, and 120%, respectively. Complementary cytotoxicity studies demonstrate that these silicon nanoparticles are more cytotoxic for MCF-7 than for 3T3 cells. © 2013 Elsevier Inc.

P22-2-jD Mit hydrostatischem Hochdruck generierte Ganzzell- Tumorvakzine erzeugen in Kombination mit Strahlentherapie ein immunogenes Tumor-Mikromilieu - Rückert, Michael; Seitz, Christoph; Deloch, Lisa; Weiss, Eva-Maria; Utz, S; Izydor, Marika; Ebel, Nina; Schlücker, Eberhard; Fietkau, Rainer; Gaipl, Udo; Frey, Benjamin (2019)

PACIFIC-R: First real-world study of patients with unresectable, stage III NSCLC treated with durvalumab after chemoradiotherapy - Girard, N.; Mornex, F.; Christoph, D. C.; Fietkau, Rainer; Filippi, A. R.; Field, J.; Garrido Lopez, P.; Mcdonald, F.; Peters, S.; Klein, A. B.; Licour, M.; Garassino, M. C. (ANNALS OF ONCOLOGY, 2019)
CRIS-Team WoS Importer:2019-08-13

PACIFIC-R real-world study: Treatment duration and interim analysis of progression-free survival in unresectable stage III NSCLC patients treated with durvalumab after chemoradiotherapy - Girard, N.; Smit, H. J. M.; Sibille, A.; Mcdonald, F.; Mornex, F.; Garassino, M. C. C.; Filippi, A. R.; Peters, S.; Field, J. K.; Christoph, D. C.; Fietkau, Rainer; Haakensen, V. D.; et al. (ANNALS OF ONCOLOGY, 2021)
CRIS-Team WoS Importer:2021-10-15

Paediatric and adult soft tissue sarcomas with NTRK1 gene fusions: a subset of spindle cell sarcomas unified by a prominent myopericytic/haemangiopericytic pattern - Haller, Florian; Knopf, Jasmin; Ackermann, Andreas; Bieg, Matthias; Kleinheinz, Kortine; Schlesner, Matthias; Moskalev, Evgeny; Will, Rainer; Satir, Ali Abdel; Abdelmagid, Ibtihalat E.; Giedl, Josef; Carbon, Roman; et al. (Journal of Pathology, 2016)
Neoplasms with a myopericytomatous pattern represent a morphological spectrum of lesions encompassing myopericytoma of the skin and soft tissue, angioleiomyoma, myofibromatosis/infantile haemangiopericytoma and putative neoplasms reported as malignant myopericytoma. Lack of reproducible phenotypic and genetic features of malignant myopericytic neoplasms have prevented the establishment of myopericytic sarcoma as an acceptable diagnostic category. Following detection of a LMNA-NTRK1 gene fusion in an index case of paediatric haemangiopericytoma-like sarcoma by combined whole-genome and RNA sequencing, we identified three additional sarcomas harbouring NTRK1 gene fusions, termed 'spindle cell sarcoma, NOS with myo/haemangiopericytic growth pattern'. The patients were two children aged 11 months and 2 years and two adults aged 51 and 80 years. While the tumours of the adults were strikingly myopericytoma-like, but with clear-cut atypical features, the paediatric cases were more akin to infantile myofibromatosis/haemangiopericytoma. All cases contained numerous thick-walled dysplastic-like vessels with segmental or diffuse nodular myxohyaline myo-intimal proliferations of smooth muscle actin-positive cells, occasionally associated with thrombosis. Immunohistochemistry showed variable expression of smooth muscle actin and CD34, but other mesenchymal markers, including STAT6, were negative. This study showed a novel variant of myo/haemangiopericytic sarcoma with recurrent NTRK1 gene fusions. Given the recent introduction of a novel therapeutic approach targeting NTRK fusion-positive neoplasms, recognition of this rare but likely under-reported sarcoma variant is strongly encouraged.
EVALuna2:6792

Palbociclib Induces Senescence in Melanoma and Breast Cancer Cells and Leads to Additive Growth Arrest in Combination With Irradiation - Jost, Tina; Heinzerling, Lucie; Fietkau, Rainer; Hecht, Markus; Distel, Luitpold (Frontiers in Oncology, 2021)
Introduction: Several kinase inhibitors (KI) bear the potential to act as radiosensitizers. Little is known of the radiosensitizing effects of a wide range of other KI like palbociclib, which is approved in ER+/HER2- metastatic breast cancer. Method: In our study, we used healthy donor fibroblasts and breast cancer and skin cancer cells to investigate the influence of a concomitant KI + radiation therapy. Cell death and cell cycle distribution were studied by flow cytometry after Annexin-V/7-AAD and Hoechst staining. Cellular growth arrest was studied in colony-forming assays. Furthermore, we used C12-FDG staining (senescence) and mRNA expression analysis (qPCR) to clarify cellular mechanisms. Results: The CDK4/6 inhibitor palbociclib induced a cell cycle arrest in the G0/G1 phase. Cellular toxicity (cell death) was only slightly increased by palbociclib and not enhanced by additional radiotherapy. As the main outcome of the colony formation assays, we found that cellular growth arrest was induced by palbociclib and improved by radiotherapy in an additive manner. Noticeably, palbociclib treatment clearly induced senescence not only in breast cancer and partly in melanoma cells, but also in healthy fibroblasts. According to these findings, the downregulation of senescence-related FOXM1 might be an involved mechanism of the senescence-induction potential of palbociclib. Conclusion: The effect on cellular growth arrest of palbociclib and radiotherapy is additive. Palbociclib induces permanent G0/G1 cell cycle arrest by inducing senescence in fibroblasts, breast cancer, and melanoma cells. Direct cell death induction is only a minor secondary mechanism of action. Concomitant KI and radiotherapy is a strategy worth studying in clinical trials.
CRIS-Team Scopus Importer:2021-11-12
Keywords: breast cancer; kinase inhibitor; melanoma; palbociclib; radiotherapy; senescence

Panniculitis under successful targeted inhibition of the MAPK/ERK signaling pathway in a patient with BRAF V600E-mutated spindle cell oncocytoma of the pituitary gland - Sollfrank, Lukas; Lettmaier, Sebastian; Erdmann, Michael; Uslu, Ugur (Anticancer Research, 2019)
Background: Spindle cell oncocytoma (SCO) is a rare non-neuroendocrine neoplasm of the pituitary gland. In general, surgical excision and radiation therapy is performed. However, local recurrences are frequently seen, requiring repeated surgical and radio-oncological interventions. Thus, mutational analysis of the tumor and targeted therapy may represent a valuable therapy option in these patients. Case Report: A 38-year-old female patient with past medical history of 6 surgeries (two transsphenoidal and four transcranial), radiation therapy, and chemoradiation therapy due to several recurrences of a SCO, presented for follow-up imaging. MRI of the brain showed growth of a tumor in the right parasellar region consistent with a new local recurrence, which due to its size and location was considered to be not resectable. Molecular analysis of a previously surgically removed tumor showed a BRAF V600E mutation and thus, combined targeted inhibition of the MAPK/ERK signaling pathway using a BRAF inhibitor and a MEK inhibitor was started. Due to drug-induced panniculitis, MEK inhibitor had to be stopped and BRAF inhibitor only was continued, which was well tolerated by the patient. Subsequent imaging revealed tumor regression already four weeks after therapy initiation and no disease progression has been observed to date. Conclusion: A SCO patient with BRAF V600E mutation was successfully treated using targeted inhibition of the MAPK/ERK signaling pathway. Under therapy, tumor regression was observed and the patient has been free of progressive disease for more than two years now. Thus, mutational analysis and targeted inhibition may offer an effective treatment option for SCO patients, while potential side-effects to this therapy, like observed in our case, can occur and needs to be adequately treated.
CRIS-Team Scopus Importer:2019-07-12
Keywords: Adenoma; BRAF; Cobimetinib; Dabrafenib; MEK; Panniculitis; Pituicytoma; Targeted therapy; Trametinib; Vemurafenib

Paragangliomas of the Head and Neck: Local Control and Functional Outcome Following Fractionated Stereotactic Radiotherapy - Weissmann, Thomas; Lettmaier, Sebastian; Roesch, Johannes; Mengling, Veit; Bert, Christoph; Iro, Heinrich; Hornung, Joachim; Janka, Rolf Matthias; Semrau, Sabine; Fietkau, Rainer; Putz, Florian (American Journal of Clinical Oncology-Cancer Clinical Trials, 2019)
Objectives: To investigate local control and functional outcome following state-of-the-art fractionated stereotactic radiotherapy (FSRT) for paragangliomas of the head and neck. Methods: In total, 40 consecutive patients with paragangliomas of the head and neck received conventionally FSRT from 2003 to 2016 at the Department of Radiation Oncology of the University Hospital Erlangen. Local control, toxicities, and functional outcome were examined during follow-up. In total, 148 magnetic resonance imaging studies were subjected to longitudinal volumetric analysis using whole tumor segmentation in a subset of 22 patients. Results: A total of 80.0% (32/40) of patients received radiotherapy as part of their primary treatment. In 20.0% (8/40) of patients, radiation was used as salvage treatment after tumor recurrence in patients initially treated with surgery alone. The median dose applied was 54.0 Gy (interdecile range, 50.4 to 56.0 Gy) in single doses of 1.8 or 2 Gy. Local control was 100% after a median imaging follow-up of 52.2 months (range, 0.8 to 152.9 mo). The volumetric analysis confirmed sustained tumor control in a subset of 22 patients and showed transient enlargement (range, 129.6% to 151.2%) in 13.6% of cases (3/22). After a median volumetric follow-up of 24.6 months mean tumor volume had diminished to 86.1% compared with initial volume. In total, 52.5% (21/40) of patients reported improved symptoms after radiotherapy, 40% (16/40) observed no subjective change with only 7.5% (3/40) reporting significant worsening. Conclusions: State-of-the-art FSRT provides excellent control and favorable functional outcome in patients with paragangliomas of the head and neck. The volumetric analysis provides improved evidence for sustained tumor control.
CRIS-Team Scopus Importer:2019-10-22
Keywords: fractionated stereotactic radiotherapy; functional outcomes; paraganglioma; tumor control; volumetric analysis

Paragangliomas of the head and neck-local control and functional outcomes following stereotactic radiotherapy - Weissmann, T.; Semrau, S.; Fietkau, Rainer; Putz, Florian (2018)
EVALuna2:36509

PARP inhibitors combined with ionizing radiation induce different effects in melanoma cells and healthy fibroblasts - Weigert, Verena; Jost, Tina; Hecht, Markus; Knippertz, Ilka; Heinzerling, Lucie; Fietkau, Rainer; Distel, Luitpold (BMC Cancer, 2020)
BACKGROUND: PARP inhibitors niraparib and talazoparib are FDA approved for special cases of breast cancer. PARP is an interesting repair protein which is frequently affected in cancer cells. We studied the combined action of talazoparib or niraparib with ionizing radiation in melanoma cells and healthy fibroblasts. METHODS: Homologous recombination (HR) status in six different melanoma cell lines and healthy fibroblasts was assessed. Cell cultures were treated with PARP inhibitors talazoparib or niraparib and ionizing radiation (IR). Apoptosis, necrosis and cell cycle distribution was analyzed via flow cytometry. Cell migration was studied by scratch assays. RESULTS: Studied melanoma cell cultures are HR deficient. Studied healthy fibroblasts are HR proficient. Talazoparib and niraparib have congruent effects within the same cell cultures. In all cell cultures, combined treatment increases cell death and G2/M arrest compared to IR. Combined treatment in melanoma cells distinctly increases G2/M arrest. Healthy fibroblasts are less affected by G2/M arrest. Treatment predominantly decelerates or does not modify migration. In two cell cultures migration is enhanced under the inhibitors. CONCLUSIONS: Although the two PARP inhibitors talazoparib and niraparib appear to be suitable for a combination treatment with ionizing radiation in our in vitro studies, a combination treatment cannot generally be recommended. There are clear interindividual differences in the effect of the inhibitors on different melanoma cells. Therefore, the effect on the cancer cells should be studied prior to a combination therapy. Since melanoma cells increase more strongly than fibroblasts in G2/M arrest, the fractional application of combined treatment should be further investigated.
CRIS-Team Scopus Importer:2020-08-28
Keywords: Cell cycle; Cell death; Homologous recombination; Ionizing radiation; Kinase inhibitor; PARP1/PARP2; Radiosensitivity

PARP Inhibitors Talazoparib and Niraparib Sensitize Melanoma Cells to Ionizing Radiation - Jonuscheit, Stephanie; Jost, Tina; Gajdošová, Fritzi; Wrobel, Maximilian; Hecht, Markus; Fietkau, Rainer; Distel, Luitpold (Genes, 2021)
(1) Background: Niraparib and Talazoparib are poly (ADP-ribose) polymerase (PARP) 1/2 inhibitors. It is assumed that combining PARP inhibitors with radiotherapy could be beneficial for cancer treatment. In this study, melanoma cells were treated with Niraparib and Talazoparib in combination with ionizing radiation (IR). (2) Methods: The effects of Talazoparib and Niraparib in combination with IR on cell death, clonogenicity and cell cycle arrest were studied in healthy primary fibroblasts and primary melanoma cells. (3) Results: The melanoma cells had a higher PARP1 and PARP2 content than the healthy fibroblasts, and further increased their PARP2 content after the combination therapy. PARP inhibitors both sensitized fibroblasts and melanoma cells to IR. A clear supra-additive effect of KI+IR treatment was detected in two melanoma cell lines analyzing the surviving fraction. The cell death rate increased in the healthy fibroblasts, but to a larger extent in melanoma cells after combined treatment. Finally, a lower percentage of cells in the radiosensitive G2/M phase is present in the healthy fibroblasts compared to the melanoma cells. (4) Conclusions: Both PARP inhibitors sensitize melanoma cells to IR. Healthy tissue seems to be less affected than melanoma cells. However, the great heterogeneity of the results suggests prior testing of the tumor cells in order to personalize the treatment.
CRIS-Team Scopus Importer:2021-06-18
Keywords: ionizing radiation; kinase inhibitors; PARP

Particle radiosurgery: a new frontier of physics in medicine - Bert, Christoph; Durante, Marco (Physica Medica, 2014)
Radiosurgery was introduced over half a century ago for treatment of intracranial lesions. In more recent years, stereotactic radiotherapy has rapidly advanced and is now commonly used for treatments of both cranial and extracranial lesions with high doses delivered in a few, down to a single fraction. The results of a workshop on Particle radiosurgery: A new frontier of physics in medicine held at Obergurgl, Austria during August 25-29 2013 are summarized in this issue with an overview presented in this paper. The focus was laid on particle radiosurgery but the content also includes current practice in x-ray radiosurgery and the overarching research in radiobiology and motion management for extracranial lesions. The results and discussions showed that especially research in radiobiology of high-dose charged-particles and motion management are necessary for the success of particle radiosurgery.
EVALuna2:18241

Pathologic complete response after induction therapy and surgery is an independed long-term survival prognostic factor in locally advanced non-small cell lung cancer - Schreiner, Waldemar; Dudek, Wojciech; Lettmaier, S.; Rieker, Ralf; Fietkau, Rainer; Sirbu, Horia (2018)
EVALuna2:35736

Pathologic complete response after induction therapy-the role of surgery in stage IIIA/B locally advanced non-small cell lung cancer - Schreiner, Waldemar; Gavrychenkova, Sofiia; Dudek, Wojciech; Rieker, Ralf; Lettmaier, Sebastian; Fietkau, Rainer; Sirbu, Horia (Journal of Thoracic Disease, 2018)
Background: Pathologic complete response (pCR) is dominant prognostic factor determining favorable outcome in locally advanced non-small cell lung cancer (NSCLC) after induction therapy (IT). There is no non-operative diagnostics that adequately estimates the pCR. Aim of this retrospective study was to assess the correlation between clinical and pathological factors in patients with pCR. Methods: Twenty-five patients with pCR after curative lung resection following IT were assessed using univariate and multivariate Cox regression and descriptive analysis. The survival rate was estimated by Kaplan-Meier method. Results: The IT included chemoradiation with median doses of 50.4 Gy (range, 45-59.4 Gy) combined with platinum-based chemotherapy in 23 patients (92%) and induction platinum-based chemotherapy in 2 patients (8%). Clinical tumor stage before IT was IIIA in 21, IIIB in 4 patients. Mean interval between IT and surgery was 8.1±3.0 weeks. Perioperative morbidity and 30-day mortality was 32% and 4%, respectively. There was no significant correlation of pCR and different clinical and pathological factors. The estimated 5-year long-term survival (LTS) and progressive-free survival (PFS) was 57% and 54%, respectively. The median LTS and PFS was not reached. Conclusions: pCR in patients with locally advanced NSCLC following IT is an independent prognostic factor, without correlation with pathological and clinical factors. Non-operative accurate assessment of pCR is currently impossible. Surgical resection enables secure identification of pCR and might improve the patient stratification for additive therapy.
EVALuna2:35733

Pathologic response after induction chemo-immunotherapy with single or double immune checkpoint inhibition in locally advanced head and neck squamous cell carcinoma (HNSCC): Expansion cohorts of the CheckRad-CD8 trial. - Hecht, Markus; Eckstein, Markus; Kallies, Annett; Klautke, Gunther; Illmer, Thomas; von der Grün, Jens; Laban, Simon; Hautmann, Matthias; Tamaskovics, Bálint; Hinke, Axel; Brunner, Thomas; Frey, Benjamin; et al. (JOURNAL OF CLINICAL ONCOLOGY, 2022)
CRIS-Team WoS Importer:2022-11-04

Patient-reported treatment satisfaction with Rivaroxaban in cancer patients with acute venous thromboembolism - Results from the CONKO-011 trial - Sinn, M.; Juehling, A.; Hellmann, M.; Omar, M.; Suedhoff, T.; Stahl, M.; Krziwanie, A.; Schlenska-Lange, A.; Rutzner, Sandra; Heinz, J.; Ettrich, T.; Trappe, R.; et al. (ONCOLOGY RESEARCH AND TREATMENT, 2021)
CRIS-Team WoS Importer:2022-03-25

Patient-specific brain phantom SPECT database of cerebral perfusion analysed with the 3D-data analysis platform Scenium - Grings, Andreas; Vija, Alexander Hans; Reymann, Maximilian; Kuwert, Torsten; Brand, Johann (JOURNAL OF NUCLEAR MEDICINE, 2022)
CRIS-Team WoS Importer:2023-01-27

Patients with Lupus Erythematosus often have increased Radiosensitivity - Schuster, Barbara; Schenker, Hannah; Fietkau, Rainer; Distel, Luitpold (STRAHLENTHERAPIE UND ONKOLOGIE, 2019)
CRIS-Team WoS Importer:2019-06-07

Patterns of care analysis for salivary gland cancer: a survey within the German Society of Radiation Oncology (DEGRO) and recommendations for daily practice - Von Der Gruen, Jens; Roedel, Claus; Semrau, Sabine; Balermpas, Panagiotis; Martin, Daniel; Fietkau, Rainer; Haderlein, Marlen (Strahlentherapie und Onkologie, 2021)
Background Salivary gland cancer (SGC) is rare and a heterogeneous type of cancer. Prospective randomized trials are lacking. No guideline focusing on standard procedures of radiotherapy (RT) in the treatment of SGC exists. Therefore, we surveyed the members of the German Society of Radiation Oncology (DEGRO) to gain information about current therapeutic strategies of SGC. Methods An anonymous questionnaire was designed and made available on the online platform umfrageonline.com. The corresponding link was sent to all DEGRO members who provided their user data for contact purposes. Alternatively, a PDF printout version was sent. Frequency distributions of responses for each question were calculated. The data were also analyzed by type of institution. Results Sixty-seven responses were received, including answers from 21 university departments, 22 non-university institutions, and 24 radiation oncology practices. Six participants reported that their departments (practice: n = 5, non-university hospital: n = 1) did not treat SGC, and therefore the questionnaire was not completed. Concerning radiation techniques, target volume definition, and concomitant chemotherapy, treatment strategies varied greatly among the participants. Comparing university vs. non-university institutions, university hospitals treat significantly more patients with SGC per year and initiated more molecular pathological diagnostics. Conclusion SGC represents a major challenge for clinicians, as reflected by the inhomogeneous survey results regarding diagnostics, RT approaches, and systemic therapy. Future prospective, multicenter clinical trials are warranted to improve and homogenize treatment of SGC and to individualize treatment according to histologic subtypes and risk factors.
CRIS-Team WoS Importer:2021-09-03

Patterns of lymph node involvement in prostate cancer patients presenting for pelvic and paraaortic stereotactic radiotherapy of nodal metastases - Filimonova, Irina; Weissmann, T.; Mansoorian, S.; Bert, Christoph; Frey, Benjamin; Fietkau, Rainer; Putz, Florian (STRAHLENTHERAPIE UND ONKOLOGIE, 2020)
CRIS-Team WoS Importer:2020-10-02

PD-1 and PD-L1 expression predict regression and prognosis following neoadjuvant radiochemotherapy of oesophageal adenocarcinoma - Göbel, Holger H.; Distel, Luitpold; Aigner, Thomas; Büttner-Herold, Maike; Grabenbauer, Gerhard G. (Clinical and Translational Radiation Oncology, 2022)
Background and purpose: PD-1 and PD-L1 are involved in anticancer immunosurveillance, and their expression may be predictive for therapeutic effectiveness of specific antibodies. Their influence on response to neoadjuvant radiochemotherapy (RCT) and prognosis in patients with oesophageal adenocarcinoma (OAC) remains to be defined. Materials and methods: Between 10/2004 and 06/2018, complete pre-RCT biopsy-specimens were available from 76 patients with locally advanced, non-metastatic OAC scheduled for trimodality therapy. We evaluated intra- and peritumoural expression of CD8, PD-1 and PD-L1 in pre-treatment specimens to determine their influence on tumour regression grade and survival. PD-1 and PD-L1 expression were considered positive (+) if ≥1% of all cells were stained positive, otherwise negative (-); densities of CD8+ cells were categorized as being high (Hi) or low (Lo) according to the median. Results: A negative PD-L1 expression in peritumoural cells predicted a poor tumour regression (RD 0.24 [95% CI 0.03–0.44], p = 0.023). A positive PD-1 expression in intra- as well as peritumoural cells was identified as an unfavourable prognostic factor (HR 0.52 [95% CI 0.29–0.93], p = 0.028; HR 0.50 [0.25–0.99], p = 0.047, respectively). With respect to CD8+ infiltration, positive PD-1 and PD-L1 expressions attenuated its favourable prognostic effect in intratumoural area (LoCD8/PD1 + vs. HiCD8/PD1-: HR 0.25 [0.09–0.69], p = 0.007; LoCD8/PDL1+ vs. HiCD8/PDL1-: HR 0.32 [0.12–0.89], p = 0.028) and were associated with negative outcome when seen in peritumoural area (HiCD8/PD1+ vs. LoCD8/PD1-: HR 0.29 [0.11–0.74], p = 0.010); HiCD8/PDL1+ vs. LoCD8/PDL1-: HR 0.33 [0.12–0.90], p = 0.031). Conclusions: PD-1 and PD-L1 expression were identified to be of predictive and prognostic value in patients with OAC, particularly when considering CD8+ infiltration. Further validation by a large size dataset is required.
CRIS-Team Scopus Importer:2022-04-15
Keywords: CD8+; Esophageal adenocarcinoma; PD-1; PD-L1; Radiochemotherapy

PD-L1 is upregulated by radiochemotherapy in rectal adenocarcinoma patients and associated with a favourable prognosis - Hecht, Markus; Buettner-Herold, Maike; Erlenbach-Wuensch, Katharina; Haderlein, Marlen; Croner, Roland; Grützmann, Robert; Hartmann, Arndt; Fietkau, Rainer; Distel, Luitpold (European Journal of Cancer, 2016)
The influence of neoadjuvant radiochemotherapy (RCT) on programmed death-ligand 1 (PD-L1) expression, a predictive marker for programmed cell death protein 1 (PD-1) inhibitor therapy, was studied on tumour and inflammatory cells in rectal adenocarcinoma patients along with its prognostic value.PD-L1 immunohistochemistry was performed on tissue microarrays of 103 pre-RCT biopsies and 159 post-RCT surgical specimens (central tumour, invasive front and normal tissue) of 199 patients. In 63 patients, both samples were available. Proportion and maximum intensity of PD-L1-positive (PD-L1+) cells were evaluated.RCT increased the proportion of PD-L1-expressing cancer cells from 2.1% to 7.8% in the central tumour (p < 0.001) or 9.3% in the invasive front (p < 0.001). Cancer cell PD-L1 on its own could not predict prognosis. High PD-L1 expression on pre-RCT inflammatory cells (maximum intensity: p = 0.048) and post-RCT invasive front inflammatory cells (p = 0.010) correlated with improved no evidence of disease survival. In multivariate analysis, the combination of low PD-L1 in cancer and inflammatory cells was an independent negative prognostic marker for overall survival (OS) pre-RCT (Cox's proportional hazard ratio 0.438, p = 0.045) and in the invasive front post-RCT (Cox's proportional hazard ratio 0.257, p = 0.030).Neoadjuvant RCT is associated with an increased PD-L1 expression in rectal adenocarcinoma patients, which should prompt clinical trials combining radiotherapy and PD-1/PD-L1 pathway blockade. Combined low PD-L1 expression on tumour and inflammatory cells is an independent negative prognostic marker for OS in RCT of rectal adenocarcinoma.
EVALuna2:6814

Pediatric cardiac MRI: automated left-ventricular volumes and function analysis and effects of manual adjustments - Hammon, Matthias; Janka, Rolf Matthias; Dankerl, Peter; Glöckler, Martin; Kammerer, Ferdinand J.; Dittrich, Sven; Uder, Michael; Rompel, Oliver (Pediatric Radiology, 2015)
Cardiac MRI is an accurate and reproducible technique for the assessment of left ventricular volumes and function. The accuracy of automated segmentation and the effects of manual adjustments have not been determined in children.To evaluate automated segmentation and the effects of manual adjustments for left ventricular parameter quantification in pediatric cardiac MR images.Left ventricular parameters were evaluated in 45 children with suspected myocarditis (age 13.4 ± 3.5 years, range 4-17 years) who underwent cardiac MRI. Dedicated software was used to automatically segment and adjust the parameters. Results of end-diastolic volume, end-systolic volume, stroke volume, myocardial mass, and ejection fraction were documented before and after apex/base adjustment and after apex/base/myocardial contour adjustment.The software successfully detected the left ventricle in 42 of 45 (93.3%) children; failures occurred in the smallest and youngest children. Of those 42 children, automatically segmented end-diastolic volume (EDV) was 151 ± 47 ml, and after apex/base adjustment it was 146 ± 45 ml, after apex/base/myocardial contour adjustment 146 ± 45 ml. The corresponding results for end-systolic volume (ESV) were 66 ± 32 ml, 63 ± 29 ml and 64 ± 28 ml; for stroke volume (SV) they were 85 ± 25 ml, 83 ± 23 ml and 83 ± 23 ml; for ejection fracture (EF) they were 57 ± 10%, 58 ± 9% and 58 ± 9%, and for myocardial mass (MM) they were 104 ± 31 g, 95 ± 31 g and 94 ± 30 g. Statistically significant differences were found when comparing the EDV/ESV/MM results, the EF results after apex/base adjustment and after apex/base/myocardial contour adjustment and the SV results (except for comparing the SVs after apex/base adjustment and after apex/base/myocardial contour adjustment).Automated segmentation for the evaluation of left ventricular parameters in pediatric MR images proved to be feasible. Automated segmentation + apex/base adjustment provided clinically acceptable parameters for the majority of cases.
EVALuna2:14344

Peer review analysis in the field of radiation oncology: results from a web-based survey of the Young DEGRO working group - Käsmann, Lukas; Schröder, Annemarie; Frey, Benjamin; Fleischmann, Daniel F.; Gauer, Tobias; Ebert, Nadja; Hecht, Markus; Krug, David; Niyazi, Maximilian; Mäurer, Matthias (Strahlentherapie und Onkologie, 2020)
Purpose: To evaluate the reviewing behaviour in the German-speaking countries in order to provide recommendations to increase the attractiveness of reviewing activity in the field of radiation oncology. Methods: In November 2019, a survey was conducted by the Young DEGRO working group (jDEGRO) using the online platform “eSurveyCreator”. The questionnaire consisted of 29 items examining a broad range of factors that influence reviewing motivation and performance. Results: A total of 281 responses were received. Of these, 154 (55%) were completed and included in the evaluation. The most important factors for journal selection criteria and peer review performance in the field of radiation oncology are the scientific background of the manuscript (85%), reputation of the journal (59%) and a high impact factor (IF; 40%). Reasons for declining an invitation to review include the scientific background of the article (60%), assumed effort (55%) and a low IF (27%). A double-blind review process is preferred by 70% of respondents to a single-blind (16%) or an open review process (14%). If compensation was offered, 59% of participants would review articles more often. Only 12% of the participants have received compensation for their reviewing activities so far. As compensation for the effort of reviewing, 55% of the respondents would prefer free access to the journal’s articles, 45% a discount for their own manuscripts, 40% reduced congress fees and 39% compensation for expenses. Conclusion: The scientific content of the manuscript, reputation of the journal and a high IF determine the attractiveness for peer reviewing in the field of radiation oncology. The majority of participants prefer a double-blind peer review process and would conduct more reviews if compensation was available. Free access to journal articles, discounts for publication costs or congress fees, or an expense allowance were identified to increase attractiveness of the review process.
CRIS-Team Scopus Importer:2020-12-25
Keywords: Impact factor; Peer review; Publication; Radiation oncology; Scientific publishing

Penile bulb sparing in prostate cancer radiotherapy: Dose analysis of an in-house MRI system to improve contouring - Boeckelmann, F.; Hammon, Matthias; Lettmaier, S.; Fietkau, Rainer; Bert, Christoph; Putz, Florian (Strahlentherapie und Onkologie, 2019)
ObjectiveThis study aimed to assess the reduction in dose to the penile bulb (PB) achieved by MRI-based contouring following drinking and endorectal balloon (ERB) instructions.Patients and methodsA total of 17prostate cancer patients were treated with intensity-modulated radiation therapy (IMRT) and interstitial brachytherapy (IBT). CT and MRI datasets were acquired back-to-back based on a65cm(3) air-filled ERB and drinking instructions. After rigid co-registration of the imaging data, the CT-based planning target volume (PTV) used for treatment planning was retrospectively compared to an MRI-based adaptive PTV and the dose to the PB was determined in each case. The adapted PTV encompassed acaudally cropped CT-based PTV which was defined on the basis of the MRI-based prostate contour plus an additional 5mm safety margin.ResultsIn the seven-field IMRT treatment plans, the MRI-based adapted PTV achieved mean (D-mean) and maximum (D-max) doses to the PB which were significantly lower (by 7.6Gy and 10.9Gy, respectively; p<0.05) than those of the CT-contoured PTV. For 6patients, the estimated PB D-max (seven-field IMRT and IBT) for the adapted PTV was <70Gy, whereas only 1patient fulfilled this criterium with the CT-based PTV.ConclusionMRI-based contouring and seven-field IMRT-based treatment planning achieved dose sparing to the PB. Whereas the comparison of MRI and CT contouring only relates to external beam radiotherapy (EBRT) sparing, considering EBRT and IBT shows the improvement in PB sparing for the total treatment. ZusammenfassungZielZiel war es, eine Dosisreduktion an der Peniswurzel auf Grundlage einer Magnetresonanztomographie-(MRT-)unterstutzten Konturierung unter Einhaltung eines Trink- und Rektalballonprotokolls (ERB) zu erreichen.Patienten und MethodenInsgesamt wurden 17Patienten mit Prostatakrebs intensitatsmoduliert bestrahlt (IMRT) und erhielten anschlie ss end eine interstitielle Brachytherapie (IBT). Computertomographie- (CT) und MRT-Datensatze wurden kurz nacheinander auf Basis eines 65-cm(3)-ERB- und Trinkprotokolls akquiriert und danach rigide registriert. In beiden Datensatzen wurde jeweils die Peniswurzeldosis bestimmt. Ein CT-basiertes Planungszielvolumen (PTV) wurde fur die Bestrahlungsplanung verwendet und retrospektiv mit einem MRT-basierten adaptiven PTV verglichen. Das adaptive PTV umfasst ein kaudal gekurztes CT-basiertes PTV, welches auf Grundlage einer MRT-basierten Prostatakontur und einem zusatzlichen 5-mm-Sicherheitsraum definiert wurde.ErgebnisseDas MRT-basierte adaptive PTV erzielte bei der 7-Felder-IMRT-Planung 7,6Gy (D-mean) und 10,9Gy (D-max) weniger Dosis an der Peniswurzel als das CT-konturierte PTV. Fur 6Patienten, geplant mit dem adaptiven PTV, war die abgeschatzte Maximaldosis D-max (7-Felder-IMRT+IBT) an der Peniswurzel <70Gy, wohingegen beim CT-basierten PTV nur 1Patient das Kriterium erfullte.SchlussfolgerungDie MRT-basierte Konturierung und die 7-Felder-IMRT-Planung reduzierte die Peniswurzeldosis. Die Gesamtdosis der Peniswurzel bestehend aus der 7-Felder-IMRT- und IBT-Planung zeigte sich reduziert, wobei die MRT- und CT- Konturierungsanalyse nur auf die externe 7-Felder-Bestrahlungsplanung basiert.
CRIS-Team WoS Importer:2019-02-21

Percent mammographic density and dense area as risk factors for breast cancer - Rauh, C.; Hack, Caroline; Häberle, Lothar; Hein, Alexander; Engel, Anne; Schrauder, Michael G.; Fasching, Peter; Jud, Sebastian; Ekici, Arif Bülent; Loehberg, C. R.; Meier-Meitinger, Martina; Ozan-Mergner, Sevil Julia; et al. (Geburtshilfe und Frauenheilkunde, 2012)
Purpose: Mammographic characteristics are known to be correlated to breast cancer risk. Percent mammographic density (PMD), as assessed by computer-assisted methods, is an established risk factor for breast cancer. Along with this assessment the absolute dense area (DA) of the breast is reported as well. Aim of this study was to assess the predictive value of DA concerning breast cancer risk in addition to other risk factors and in addition to PMD. Methods: We conducted a case control study with hospital-based patients with a diagnosis of invasive breast cancer and healthy women as controls. A total of 561 patients and 376 controls with available mammographic density were included into this study. We describe the differences concerning the common risk factors BMI, parital status, use of hormone replacement therapy (HRT) and menopause between cases and controls and estimate the odds ratios for PMD and DA, adjusted for the mentioned risk factors. Furthermore we compare the prediction models with each other to find out whether the addition of DA improves the model. Results: Mammographic density and DA were highly correlated with each other. Both variables were as well correlated to the commonly known risk factors with an expected direction and strength, however PMD (ρ = 0.56) was stronger correlated to BMI than DA (ρ = 0.11). The group of women within the highest quartil of PMD had an OR of 2.12 (95 % CI: 1.25-3.62). This could not be seen for the fourth quartile concerning DA. However the assessment of breast cancer risk could be improved by including DA in a prediction model in addition to common risk factors and PMD. Conclusions: The inclusion of the parameter DA into a prediction model for breast cancer in addition to established risk factors and PMD could improve the breast cancer risk assessment. As DA is measured together with PMD in the process of computer-assisted assessment of PMD it might be considered to include it as one additional breast cancer risk factor that is obtained from breast imaging. © Georg Thieme Verlag KG Stuttgart · New York.
CRIS-Team Scopus Importer:2021-07-19
Keywords: breast cancer; mammographic density; risk

Percutaneous renal transplant biopsy: is the safety profile adequate for short-term postprocedure monitoring? - Schmid, Axel (Transplant International, 2016)
EVALuna2:14655

Performance of gimbal-based dynamic tumor tracking for treating liver carcinoma - Ziegler, Marc; Brandt, Tobias; Lettmaier, Sebastian; Fietkau, Rainer; Bert, Christoph (Radiation Oncology, 2018)
BACKGROUND: Since the introduction of tumor tracking in radiotherapy, it is possible to ensure a precise irradiation of moving targets. To follow the tumor movement, most systems rely on the detection of implanted markers and correlation models between the internal and external patient movement. This study reports the clinical workflow and first results of the dynamic tumor tracking (DTT) performance for patients with liver carcinoma at the Vero SBRT system of the University Hospital Erlangen regarding the detection of the internal marker and the changes of the determined correlation models. METHODS: So far 13 liver patients were treated with DTT. For each patient, two fiducial markers (FM), which are monitored with X-rays during treatment, were implanted in the vicinity of the tumor. All patients received a fraction dose of 4-6 Gy with 8 to 12 fractions. Treatment and patient data is evaluated by processing the acquired log-files of the DTT treatment. Based on this, the marker detection and the changes of the correlation model between the internal and external movement is investigated. RESULTS: The median treatment time was 19:42 min. During treatment a median of 173 X-ray stereoscopic images were acquired. The marker detection was successful in 64.6% of the images. The FM detection is independent of the relative angle between the marker and the imager, but shows a dependency on the average intensity surrounding the FM position within the kV images. The number of correlation models needed during treatment increases in the presence of baseline shifts. The comparison of the correlation models shows large differences in the internal-external correlation between the different models acquired for one patient. CONCLUSION: Thirteen liver patients were treated with DTT at the Vero SBRT system and the marker detection was analyzed. Furthermore, the importance of regularly monitoring the internal target motion could be shown, since the correlation between the internal and external motion changes considerably over the course of the treatment.
EVALuna2:36448

Performance of Makerless Tracking for Gimbaled Dynamic Tumor Tracking - Ziegler, Marc; Lettmaier, Sebastian; Fietkau, Rainer; Bert, Christoph (Zeitschrift für Medizinische Physik, 2019)
Background and Purpose: The purpose of this work is to report the workflow and the accuracy of the new markerless dynamic tumor tracking (MLDTT) method of the Vero 4DRT system introduced with ExacTrac 3.6.1. Material and Methods: Phantom measurements were performed to assess the accuracy of the MLDTT algorithm by using the QA-tool which is provided by the vendor. A patient breathing curve was used as the motion trajectory of the phantom and the target positions detected by the MLDTT algorithm were compared to the defined positions. Furthermore, eight patients have been treated with MLDTT between May 2018 and July 2019. A log-file analysis is used to evaluate MLDTT treatment data. Results: The accuracy of the MLDTT detection is 0.12 mm ± 0.12 mm, 0.12 mm ± 0.11 mm, 0.20 mm ± 0.21 mm for the x-, y-, z-direction, respectively. These values are comparable to the accuracy of marker based DTT at the Vero system. The median treatment time was 21 min 34 seconds and 175 kV images were acquired during treatment for monitoring the target motion. Conclusion: The accuracy of the MLDTT algorithm is comparable to the marker based approach and the accuracy reported for the XSight Lung of the CyberKnife. Eight patients were treated successfully using MLDTT and the treatment times are comparable to a standard DTT treatment.
CRIS-Team Scopus Importer:2019-12-27
Keywords: NSCLC; Real-time monitoring; Stereotactic body radiation therapy; Tumor Tracking

Performance of Marker-less Tracking for Gimbaled Dynamic Tumor Tracking - Ziegler, Marc; Lettmaier, S.; Fietkau, Rainer; Bert, Christoph (RADIOTHERAPY AND ONCOLOGY, 2019)
CRIS-Team WoS Importer:2019-06-18

Performance of Photon-Counting Breast Computed Tomography, Digital Mammography, and Digital Breast Tomosynthesis in Evaluating Breast Specimens - Rößler, Ann-Christin; Kalender, Willi Alfred; Kolditz, Daniel; Steiding, Christian; Ruth, Veikko; Preuss, Caroline; Peter, Sandra Christina; Brehm, Barbara; Hammon, Matthias; Schulz-Wendtland, Rüdiger; Wenkel, Evelyn (Academic Radiology, 2017)
This study compared a novel photon-counting breast computed tomography (pcBCT) system with digital mammography (DM) and digital breast tomosynthesis (DBT) systems. For this reason, surgical specimens were examined with all three techniques and rated by three observers.A total of 30 surgical specimens were investigated with DM, DBT, and pcBCT; the associated images were shown to three experienced radiologists. Findings (22 microcalcifications and 23 mass lesions) were recorded and compared to the results of the pathological examination. Sensitivity and specificity for detection of microcalcifications and lesions were calculated and displayed using receiver operating characteristic curves.Sensitivity for microcalcifications was 82% for DM, 70% for DBT, and 85% for pcBCT. Specificity for microcalcifications was 71% for DM, 75% for DBT, and 83% for pcBCT. Sensitivity for lesions was 45% for DM, 62% for DBT, and 65% for pcBCT. Specificity for lesions was 76% for DM, 62% for DBT, and 76% for pcBCT.pcBCT showed a comparable or superior performance compared to the clinically approved DM and DBT systems. Mass lesion detectability can be increased further by the use of contrast media.
EVALuna2:14619

Permanent LDR prostate brachytherapy: Comprehensive characterization of seed-dynamics within the prostate on a seed-only level - Karius, Andre; Lotter, Michael; Kreppner, Stephan; Schaller, Verena; Lubgan, Dorota; Grigo, Johanna; Fietkau, Rainer; Strnad, Vratislav; Bert, Christoph (Brachytherapy, 2022)
PURPOSE: Seed brachytherapy is a well-established treatment modality for prostate cancer. However, there is still a lack of profound characterizations of seed motions within the prostate. We assessed these dynamics between day 0 and day 30 of brachytherapy. METHODS: We considered 45 patients with 2408 implanted seeds, and performed a 1:1 assignment between their positions on post-plan CT (nominal day 30) and intraoperative ultrasound (day 0). Geometric seed arrangement changes were measured for each patient and the entire collective. The impact of seed strand-lengths and implant regions was investigated. Correlations with patient characteristics were evaluated. We determined corresponding dosimetric effects by calculating common dose metrics. RESULTS: We found a median seed displacement of 4.3 mm [interquartile range: 3.1–6.9 mm], occurring preferentially in superior-inferior direction. Single and double strands moved significantly stronger than strands of higher lengths. Seed dynamics was more pronounced in base (5.6 mm [3.7–10.7 mm]) and apex (6.5 mm [4.1–15.0 mm]) than in the mid-gland (3.8 mm [2.7–5.0 mm]), and less pronounced in peripheral (4.3 mm [3.0–6.7 mm]) than in urethra-near (5.5 mm [3.5–10.7 mm]) regions. Correlations of seed dynamics with prostate volume changes and the number of implanted seeds and needles were found. D90 (dose that 90% of the prostate receives) varied by a median of 3 Gy [-6 to 15 Gy] between treatment plan and post-plan, but >40 Gy for individual patients. CONCLUSIONS: Reducing seed dynamics is important to ensure a high treatment quality. For this, strands containing ≥3 seeds may be useful, implantations in base-, apex-, and urethra-near zone should be avoided, and the number of needles and seeds may be minimized where possible.
CRIS-Team Scopus Importer:2022-09-16
Keywords: Adaptive Brachytherapy; Low-dose-rate prostate brachytherapy; Prostate Cancer; Seed brachytherapy; Seed displacements

Phagocytosis by non-professional Phagocytes - Seeberg, J. C.; Loibl, Monika; Fietkau, Rainer; Distel, Luitpold (2017)
EVALuna2:32894

Phase II Study: Accelerated Partial Breast Irradiation (APBI) on a Linear Accelerator - Ott, Oliver; Schweizer, Claudia; Strnad, Vratislav; Stillkrieg, W.; Lambrecht, U.; Fietkau, Rainer (STRAHLENTHERAPIE UND ONKOLOGIE, 2022)
CRIS-Team WoS Importer:2022-06-03

Physical Fitness in Combination with Age is an overwhelming prognostic Factor in Patients with advanced Rectal Cancer - Fitz, Tim; Sörgel, Christopher; Rutzner, Sandra; Fietkau, Rainer; Distel, Luitpold (STRAHLENTHERAPIE UND ONKOLOGIE, 2021)
CRIS-Team WoS Importer:2021-07-16

Pilot Project for App-based Patient Connection in outpatient Tumor Therapy - Hecht, Markus; Goldbrunner, L.; Kaul, F.; Winkler, S.; Ploner, N.; Lettmaier, Sebastian; Haderlein, Marlen; Kallies, Annett; Pirschel, Wiebke; Fietkau, Rainer; Distel, Luitpold (STRAHLENTHERAPIE UND ONKOLOGIE, 2022)
CRIS-Team WoS Importer:2022-06-03

Plan robustness analysis for threshold determination of SGRT-based intrafraction motion control in 3DCRT breast cancer radiation therapy - Sauer, Tim-Oliver; Stillkrieg, Willy; Ott, Oliver; Fietkau, Rainer; Bert, Christoph (Radiation Oncology, 2023)
Purpose: The goal of this study was to obtain maximum allowed shift deviations from planning position in six degrees of freedom (DOF), that can serve as threshold values in surface guided radiation therapy (SGRT) of breast cancer patients. Methods: The robustness of conformal treatment plans of 50 breast cancer patients against 6DOF shifts was investigated. For that, new dose distributions were calculated on shifted computed tomography scans and evaluated with respect to target volume and spinal cord dose. Maximum allowed shift values were identified by imposing dose constraints on the target volume dose coverage for 1DOF, and consecutively, for 6DOF shifts using an iterative approach and random sampling. Results: Substantial decreases in target dose coverage and increases of spinal cord dose were observed. Treatment plans showed highly differing robustness for different DOFs or treated area. The sensitivity was particularly high if clavicular lymph nodes were irradiated, for shifts in lateral, vertical, roll or yaw direction, and showed partly pronounced asymmetries. Threshold values showed similar properties with an absolute value range of 0.8 mm to 5 mm and 1.4° to 5°. Conclusion: The robustness analysis emphasized the necessity of taking differences between DOFs and asymmetrical sensitivities into account when evaluating the dosimetric impact of position deviations. It also highlighted the importance of rotational shifts, especially if clavicular lymph nodes were irradiated. A practical approach of determining 6DOF shift limits was introduced and a set of threshold values applicable for SGRT based patient motion control was identified.
CRIS-Team Scopus Importer:2023-10-06
Keywords: Intrafraction motion; Probabilistic dose evaluation; Surface guided radiation therapy; Treatment plan robustness

PML-nuclear bodies decrease with age and their stress response is impaired in aged individuals - Wenger, Barbara; Schwegler, Manuela; Brunner, Michaela; Daniel, Christoph; Schmidt, Manfred; Fietkau, Rainer; Distel, Luitpold (BMC Geriatrics, 2014)
Promyelocytic leukemia nuclear bodies (PML-NBs) have been depicted as structures which are involved in processing cell damages and DNA double-strand break repairs. The study was designed to evaluate differences in patients' PML-NBs response to stress factors like a cancerous disease and ionizing radiation exposure dependent on age.In order to clarify the role of PML-NBs in the aging process, we examined peripheral blood monocytes of 134 cancer patients and 41 healthy individuals between 22 and 92 years of age, both before and after in vitro irradiation. Additionally, we analyzed the samples of the cancer patients after in vivo irradiation. Cells were immunostained and about 1600 cells per individual were analyzed for the presence of PML- and ?H2AX foci.The number of existing PML-NBs per nucleus declined with age, while the number of ?H2AX foci increased with age. There was a non-significant trend that in vivo irradiation increased the number of PML-NBs in cells of young study participants, while in older individuals PML-NBs tended to decrease. It can be assumed that PML-NBs decrease in number during the process of aging.The findings suggest that there is a dysfunctional PML-NBs stress response in aged cells.
EVALuna2:18179

Positive factors on survival of head and neck cancer of unknown primary: what the clinician can do - Khalil, Firas; Koch, Michael; Iro, Heinrich; Sievert, Matti; Haderlein, Marlen; Semrau, Sabine; Fietkau, Rainer; Agaimy, Abbas; Scherl, Claudia (Acta Oto-Laryngologica, 2023)
Background: Management of patients with head and neck cancer of unknown primary (HNCUP) is challenging. Aims/Objectives: To provide a long-term analysis focusing on protective survival factors for clinical decision-making. Furthermore, the prognostic value of the current N classification system was evaluated. Material and methods: We retrospectively analyzed patients with HNCUP between 2003 and 2016. Univariate and multivariate analyses were used to investigate predictors of overall survival (OS). Results: A primary tumor was found in 67 of 290 patients with suspected HNCUP, leaving after exclusion 141 HNCUP cases for analysis, who received multi-step therapy (MST) (n = 108) or single therapy (n = 28). Chemotherapy (CT) (n = 101), curative MST, ≤3 positive lymph nodes (LN) (n = 33), squamous cell carcinoma (SCC) (n = 123), HPV+ (n = 21), M0 (n = 70) increased OS by 21.8%, 24.4%, 12.7%, 6.8%, 18.7%, 29.6%, respectively. 5- and 10-year OS was 78.1%/66.6%. The number of metastatic LNs predicted OS is better than N classification. Conclusion and significance: Aspects for clinical decision-making: Curative MST and SCC histology were the most significant predictors for improved OS. Categorizing LN into 1, 2-3, and >3 LNs was more significant than the traditional N classification. The addition of CT to curative MST has a stronger impact on survival than HPV and N classifications.
CRIS-Team Scopus Importer:2023-10-27
Keywords: cancer; cancer of unknown primary; CUP; head and neck; hNCUP; hNSCC; squamous cell carcinoma; survival

Positron emission tomography-computed tomography versus positron emission tomography-magnetic resonance imaging for diagnosis of oral squamous cell carcinoma: A pilot study - Schlittenbauer, Tilo; Zeilinger, Martin; Nkenke, Emeka; Kreißel, Sebastian; Wurm, Matthias; Lell, Michael; Kuwert, Torsten; Beck, Michael (Journal of Cranio-Maxillofacial Surgery, 2015)
Diagnostic imaging of head and neck cancer has made enormous progress during recent years. Next to morphological imaging modalities (computed tomography [CT] and magnetic resonance imaging [MRI]), there are also hybrid imaging systems that combine functional and morphological information (positron emission tomography [PET]/CT and PET/MRI). The aim of this study was to compare the diagnostic accuracy of PET/MRI in the diagnosis of head and neck cancer with other imaging modalities (MRI, CT, PET/CT). Ten patients (nine male and one female) with histologically proven oral squamous cell carcinoma participated in an 18 F-FDG-PET/CT scan and an additional 18 F-FDG PET/MRI scan prior to surgery. The morphological and functional results were compared with the histological results. Inclusion criteria were histologically proven oral squamous cell carcinoma and no prior surgical intervention, medical therapy, or local external radiation. There was no significant correlation between tumor differentiation and maximum standard uptake values. Functional imaging showed a slightly better correlation with the measurement of the maximal tumor diameter, whereas pure morphological imaging showed a better correlation with the measurement of infiltration depth. Only with PET/MRI could correct lymph node staging be reached; the other imaging tools showed false-negative or false-positive results. In conclusion, we showed in our limited patient cohort that PET/MRI is superior to the morphological imaging modalities, especially for lymph node staging.
EVALuna2:13832

Possibilities of a Seed Control after the Implantation by using MRI and Deep Learning-based QSM Reconstruction - Grigo, Johanna; Karius, Andre; Hanspach, Jannis; Weissmann, Thomas; Laun, Frederik Bernd; Strnad, Vratislav; Putz, Florian; Bert, Christoph (STRAHLENTHERAPIE UND ONKOLOGIE, 2022)
CRIS-Team WoS Importer:2022-06-03

Post-neoadjuvant treatment with capecitabine and trastuzumab emtansine in breast cancer patients—sequentially, or better simultaneously? - Piroth, Marc D.; Krug, David; Sedlmayer, Felix; Duma, Marciana Nona; Baumann, René; Budach, Wilfried; Dunst, Jürgen; Feyer, Petra; Fietkau, Rainer; Haase, Wulf; Harms, Wolfgang; Hehr, Thomas; et al. (Strahlentherapie und Onkologie, 2020)
Purpose: Following neoadjuvant chemotherapy for breast cancer, postoperative systemic therapy, also called post-neoadjuvant treatment, has been established in defined risk settings. We reviewed the evidence for sequencing of postoperative radiation and chemotherapy, with a focus on a capecitabine and trastuzumab emtansine (T-DM1)-based regimen. Methods: A systematic literature search using the PubMed/MEDLINE/Web of Science database was performed. We included prospective and retrospective reports published since 2015 and provided clinical data on toxicity and effectiveness. Results: Six studies were included, five of which investigated capecitabine-containing regimens. Of these, four were prospective investigations and one a retrospective matched comparative analysis. One randomized prospective trial was found for T‑DM1 and radiotherapy. In the majority of these reports, radiation-associated toxicities were not specifically addressed. Conclusion: Regarding oncologic outcome, the influence of sequencing radiation therapy with maintenance capecitabine chemotherapy in the post-neoadjuvant setting is unclear. Synchronous administration of capecitabine is feasible, but reports on possible excess toxicities are partially conflicting. Dose reduction of capecitabine should be considered, especially if normofractionated radiotherapy is used. In terms of tolerance, hypofractionated schedules seem to be superior in terms of toxicity in concurrent settings. T‑DM1 can safely be administered concurrently with radiotherapy.
CRIS-Team Scopus Importer:2020-08-07
Keywords: Breast cancer; Capecitabine; Radiochemotherapy; Radiotherapy; T‑DM1

Postponements in Use of Radiotherapy during the first Wave of the COVID-19 Pandemic? An Analysis of Hospital Data - Kapsner, Lorenz; Brunner, T.; Christiansen, H.; Kisser, U.; Mansoorian, Sina; Prokosch, Hans-Ulrich; Seuchter, S.; Vordermark, D.; Medenwald, D. (STRAHLENTHERAPIE UND ONKOLOGIE, 2022)
CRIS-Team WoS Importer:2022-06-03

Practicability of hygienic wrapping of touchscreen operated mobile devices in a clinical setting - Hammon, Matthias; Kunz, Hans Bernd; Dinzl, Veronika; Kammerer, Ferdinand J.; Schwab, Siegfried; Bogdan, Christian; Uder, Michael; Schlechtweg, Philipp (PLoS ONE, 2014)
To prove effectiveness of wrapping tablet computers in order to reduce microbiological contamination and to evaluate whether a plastic bag-covered tablet leads to impaired user satisfaction or touchscreen functionality.Within a period of 11 days 115 patients were provided with a tablet computer while waiting for their magnetic resonance imaging examination. Every day the contamination of the surface of the tablet was determined before the first and after the final use. Before the device was handed over to a patient, it was enclosed in a customized single-use plastic bag, which was analyzed for bacterial contamination after each use. A questionnaire was applied to determine whether the plastic bag impairs the user satisfaction and the functionality of the touchscreen.Following the use by patients the outside of the plastic bags was found to be contaminated with various bacteria (657.5 ± 368.5 colony forming units/day); some of them were potentially pathogenic. In contrast, the plastic bag covered surface of the tablet was significantly less contaminated (1.7 ± 1.9 colony forming units/day). Likewise, unused plastic bags did not show any contamination. 11% of the patients reported problems with the functionality of the touchscreen. These patients admitted that they had never used a tablet or a smartphone before.Tablets get severely contaminated during usage in a clinical setting. Wrapping with a customized single-use plastic bag significantly reduces microbiological contamination of the device, protects patients from the acquisition of potentially pathogenic bacteria and hardly impairs the user satisfaction and the functionality of the touchscreen.
EVALuna2:7657

Pradictive Character of Immunophenotyping in peripheral Blood in Patients treated with PD-1 Immunocheckpoint Inhibitors with and without Radiotherapy (Prospective Phase IV Study ST-ICI) - Hecht, Markus; Donaubauer, Anna-Jasmina; Harrer, A.; Rutzner, Sandra; Becker, I.; Lettmaier, S.; Haderlein, Marlen; Wolf, W.; Fietkau, Rainer; Gaipl, Udo; Frey, Benjamin (2018)
EVALuna2:36500

Prädiktion der pathologischen Komplettremission beim Ösophaguskarzinom nach neoadjuvanter Radiochemotherapie mittels FDG-PET/CT und diffusionsgewichteter MRT - Hecht, Markus; Semrau, Sabine (Strahlentherapie und Onkologie, 2021)
CRIS-Team Scopus Importer:2021-10-01

Precautionary documents in patients with head and neck cancer - status quo and factors influencing their creation - Allner, Moritz; Gostian, M.; Balk, Matthias; Rupp, Robin; Hecht, Markus; Ostgathe, Christoph; Mueller, Sarina K.; Iro, Heinrich; Gostian, Antoniu-Oreste (ORAL ONCOLOGY, 2021)
CRIS-Team WoS Importer:2021-07-16

Predicting survival in melanoma patients treated with concurrent targeted- or immunotherapy and stereotactic radiotherapy : Melanoma brain metastases prognostic score - Schaule, Jana; Kroeze, Stephanie G.C.; Blanck, Oliver; Stera, Susanne; Kahl, Klaus H.; Roeder, Falk; Combs, Stephanie E.; Kaul, David; Claes, An; Schymalla, Markus M.; Adebahr, Sonja; Eckert, Franziska; et al. (Radiation Oncology, 2020)
BACKGROUND: Melanoma patients frequently develop brain metastases. The most widely used score to predict survival is the molGPA based on a mixed treatment of stereotactic radiotherapy (SRT) and whole brain radiotherapy (WBRT). In addition, systemic therapy was not considered. We therefore aimed to evaluate the performance of the molGPA score in patients homogeneously treated with SRT and concurrent targeted therapy or immunotherapy (TT/IT). METHODS: This retrospective analysis is based on an international multicenter database (TOaSTT) of melanoma patients treated with TT/IT and concurrent (≤30 days) SRT for brain metastases between May 2011 and May 2018. Overall survival (OS) was studied using Kaplan-Meier survival curves and log-rank testing. Uni- and multivariate analysis was performed to analyze prognostic factors for OS. RESULTS: One hundred ten patients were analyzed. 61, 31 and 8% were treated with IT, TT and with a simultaneous combination, respectively. A median of two brain metastases were treated per patient. After a median follow-up of 8 months, median OS was 8.4 months (0-40 months). The molGPA score was not associated with OS. Instead, cumulative brain metastases volume, timing of metastases (syn- vs. metachronous) and systemic therapy with concurrent IT vs. TT influenced OS significantly. Based on these parameters, the VTS score (volume-timing-systemic therapy) was established that stratified patients into three groups with a median OS of 5.1, 18.9 and 34.5 months, respectively (p = 0.001 and 0.03). CONCLUSION: The molGPA score was not useful for this cohort of melanoma patients undergoing local therapy for brain metastases taking into account systemic TT/IT. For these patients, we propose a prognostic VTS score, which needs to be validated prospectively.
CRIS-Team Scopus Importer:2020-06-16
Keywords: Brain metastases; Immunotherapy; Melanoma; molGPA; Stereotactic; Targeted therapy

Prediction of response to Certolizumab-Pegol in rheumatoid arthritis (PreCePRA) by functional MRI of the brain – Study protocol for a randomized double-blind controlled study - Schenker, Hannah; Tascilar, Koray; Konerth, Laura; Sergeeva, Marina; Prade, Jutta; Strobelt, Sandra; Kleyer, Arnd; Simon, David; Mendez, L.; Hagen, Melanie; Schönau, V.; Hueber, A.; et al. (Contemporary Clinical Trials Communications, 2021)
Background: Tumor necrosis factor inhibitors (TNFi) signify a major advance in the treatment of rheumatoid arthritis (RA). However, treatment success initially remains uncertain as approximately half of the patients do not respond adequately to TNFi. Thus, an unmet need exists to better predict therapeutic outcome of biologicals. Objectives: We investigated whether brain activity associated with arthritis measured by functional magnetic resonance imaging (fMRI) of the brain can serve as a predictor of response to TNFi in RA patients. Methods: PreCePRA is a multi-center, randomized, double-blind, placebo-controlled fMRI trial on patients with RA [1] [2]. Active RA patients failing csDMARDs therapy with a DAS28 > 3.2 and at least three tender and/or swollen joints underwent a brain BOLD (blood-oxygen-level dependent) fMRI scan upon joint compression at screening. Patients were then randomized into a 12-week double-blinded treatment phase with 200 mg Certolizumab Pegol (CZP) every two weeks (arm 1: fMRI BOLD signal activated volume > 2000 voxel, i.e. 2 cm3; arm 2: fMRI BOLD signal activated volume <2000 voxel) or placebo (arm 3). DAS28 low disease activity at 12 weeks was assigned as primary endpoint. A 12-week follow-up phase in which patients were switched from the placebo to the treatment arm followed the blinded phase. fMRI was carried out at screening as well as after 12 and 24 weeks of receiving CZP or placebo. Conclusion: We hypothesize that high-level central nervous representation of pain in patients with rheumatoid arthritis predicts response to the TNFi CZP which we further investigate in the PreCePRA trial.
CRIS-Team Scopus Importer:2021-06-04
Keywords: functional MRI; Neuroimaging; Rheumatoid arthritis; TNF inhibition

Predictive character of peripheral blood immunophenotype before and during treatment with PD-1 immune checkpoint inhibitors (interim analysis of the prospective phase IV ST-ICI trial) - Hecht, Markus; Harrer, A.; Rutzner, Sandra; Lettmaier, S.; Wolf, W.; Fietkau, Rainer; Frey, Benjamin; Gaipl, Udo (2018)
EVALuna2:33777

Predictive Value of Multiparametric MRI for Response to Single-Cycle Induction Chemo-Immunotherapy in Locally Advanced Head and Neck Squamous Cell Carcinoma - Hellwig, Konstantin; Ellmann, Stephan; Eckstein, Markus; Wiesmüller, Marco; Rutzner, Sandra; Semrau, Sabine; Frey, Benjamin; Gaipl, Udo; Hartmann, Arndt; Iro, Heinrich; Fietkau, Rainer; Uder, Michael; et al. (Frontiers in Oncology, 2021)
Objectives
CRIS-Team WoS Importer:2021-11-19

Predictors for occlusion of cerebral AVMs following radiation therapy : Radiation dose and prior embolization, but not Spetzler-Martin grade - Knippen, Stefan; Putz, Florian; Semrau, Sabine; Lambrecht, Ulrike; Knippen, Arzu; Buchfelder, Michael; Schlaffer, Sven-Martin; Struffert, Tobias; Fietkau, Rainer (Strahlentherapie und Onkologie, 2017)
BACKGROUND: Intracranial arteriovenous malformations (AVMs) may show a harmful development. AVMs are treated by surgery, embolization, or radiation therapy. OBJECTIVE: This study investigated obliteration rates and side effects in patients with AVMs treated by radiation therapy. METHODS: A total of 40 cases treated between 2005 and 2013 were analyzed. Single-dose stereotactic radiosurgery (SRS) was received by 13 patients and 27 received hypofractionated stereotactic radiation therapy (HSRT). In 20 patients, endovascular embolization had been performed prior to irradiation and 24 patients (60 %) had a history of previous intracranial hemorrhage. RESULTS: Treatment resulted in complete obliteration (CO) in 23/40 cases and partial obliteration in 8/40. CO was achieved in 85 % of patients receiving SRS compared to 44 % of those receiving HSRT. In the HSRT group, a first indication of an influence of AVM volume on obliteration rate was found. Equivalent 2 Gy fraction doses (EQD2) >70 Gy showed an obliteration rate of 50 %. Prior embolization was significantly associated with a higher portion of CO (p = 0.032). Median latency period (24.2 vs. 26 months) until CO was similar in both groups (SRS vs. HSRT). The rate of intracranial hemorrhage in patients with no prior bleeding events was 0 %. CONCLUSION: Excellent obliteration rates were achieved by SRS. Consistent with the literature, this data analysis suggests that the results of HSRT are volume-dependent. Furthermore, regimens with EQD2 doses >70 Gy appear more likely to achieve obliteration than schemes with lower doses. The findings indicate that radiation therapy does not increase the risk of bleeding. Prior embolization may have a good prognostic impact.
EVALuna2:32909

Predictors of long-term survival following radical treatment of oligometastatic NSCLC with cerebral metastases - Hirschmann, Eva; Zoske, Hanno; Weissmann, T.; Lettmaier, S.; Filimonova, I.; Fietkau, Rainer; Putz, Florian (2018)
EVALuna2:36501

Prenatal Correction of X-Linked Hypohidrotic Ectodermal Dysplasia - Schneider, Holm; Faschingbauer, Florian; Schuepbach-Mallepell, Sonia; Koerber, Iris; Wohlfart, Sigrun; Dick, Angela; Wahlbuhl, Mandy; Kowalczyk-Quintas, Christine; Vigolo, Michele; Kirby, Neil; Tannert, Corinna; Rompel, Oliver; et al. (New England Journal of Medicine, 2018)
Genetic deficiency of ectodysplasin A (EDA) causes X-linked hypohidrotic ectodermal dysplasia (XLHED), in which the development of sweat glands is irreversibly impaired, an condition that can lead to life-threatening hyperthermia. We observed normal development of mouse fetuses with Eda mutations after they had been exposed in utero to a recombinant protein that includes the receptor-binding domain of EDA. We administered this protein intraamniotically to two affected human twins at gestational weeks 26 and 31 and to a single affected human fetus at gestational week 26; the infants, born in week 33 (twins) and week 39 (singleton), were able to sweat normally, and XLHED-related illness had not developed by 14 to 22 months of age. (Funded by Edimer Pharmaceuticals and others.).
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Preoperative assessment of the aortic arch in children younger than 1 year with congenital heart disease: utility of low-dose high-pitch dual-source computed tomography. A single-centre, retrospective analysis of 62 cases - Glöckler, Martin; Halbfass, Julia; Koch, Andreas; Dittrich, Sven; Achenbach, Stephan; Rueffer, Andre; Ihlenburg, Katharina Susanne; Cesnjevar, Robert; May, Matthias; Uder, Michael; Rompel, Oliver (European Journal of Cardio-Thoracic Surgery, 2014)
To evaluate the feasibility, image quality and impact of 3D imaging in low-dose high-pitch dual-source computed tomography (DSCT) to assess arbitrary anatomical malformations of the aortic arch in children <1 year of age with congenital heart disease (CHD).Between January 2010 and May 2013, DSCT was performed to assess the aortic arch anatomy in a total of 62 consecutive patients with CHD (aged 0-348 days). DSCT was used whenever conventional echocardiography was not sufficient to display the complex anatomy entirely. Image data acquisition was realized within a single cardiac cycle using prospective ECG triggering. 3D reconstruction for surgical planning was performed. Image quality was assessed retrospectively, using a 4-point scale from '1 = no artefacts' to '4 = uninterpretable'. The accuracy and impact of the 3D reconstructions was compared with intraoperative findings using a 5-point scale (from '1 = essential' to '5 = misleading'). Administered radiation exposure was evaluated.Imaging was successful in all patients, image quality was rated 1.34 on the 4-point scale and the impact of the 3D reconstructions for surgical planning was 2.05 on the 5-point scale. Mean dose-length product was 6.8 ± 2.6 mGy cm, and the effective dose was 0.45 ± 0.13 mSv (0.21-0.74).DSCT is a fast and appropriate imaging modality in the preoperative assessment of the aortic arch for surgical planning in CHD.
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Preoperative chemoradiotherapy and postoperative chemotherapy with fluorouracil and oxaliplatin versus fluorouracil alone in locally advanced rectal cancer: initial results of the German CAO/ARO/AIO-04 randomised phase 3 trial - Roedel, Claus; Liersch, Torsten; Becker, Heinz; Fietkau, Rainer; Hohenberger, Werner; Hothorn, Torsten; Graeven, Ullrich; Arnold, Dirk; Lang-Welzenbach, Marga; Raab, Hans-Rudolf; Suelberg, Heiko; Wittekind, Christian; et al. (Lancet Oncology, 2012)
BACKGROUND: Preoperative chemoradiotherapy, total mesorectal excision surgery, and adjuvant chemotherapy with fluorouracil is the standard combined modality treatment for rectal cancer. With the aim of improving disease-free survival (DFS), this phase 3 study (CAO/ARO/AIO-04) integrated oxaliplatin into standard treatment. METHODS: This was a multicentre, open-label, randomised, phase 3 study in patients with histologically proven carcinoma of the rectum with clinically staged T3-4 or any node-positive disease. Between July 25, 2006, and Feb 26, 2010, patients were randomly assigned to two groups: a control group receiving standard fluorouracil-based combined modality treatment, consisting of preoperative radiotherapy of 50·4 Gy plus infusional fluorouracil (1000 mg/m(2) days 1-5 and 29-33), followed by surgery and four cycles of bolus fluorouracil (500 mg/m(2) days 1-5 and 29; fluorouracil group); and an experimental group receiving preoperative radiotherapy of 50·4 Gy plus infusional fluorouracil (250 mg/m(2) days 1-14 and 22-35) and oxaliplatin (50 mg/m(2) days 1, 8, 22, and 29), followed by surgery and eight cycles of adjuvant chemotherapy with oxaliplatin (100 mg/m(2) days 1 and 15), leucovorin (400 mg/m(2) days 1 and 15), and infusional fluorouracil (2400 mg/m(2) days 1-2 and 15-16; fluorouracil plus oxaliplatin group). Randomisation was done with computer-generated block-randomisation codes stratified by centre, clinical T category (cT1-4 vs cT4), and clinical N category (cN0 vs cN1-2) without masking. DFS is the primary endpoint. Secondary endpoints, including toxicity, compliance, and histopathological response are reported here. Safety and compliance analyses included patients as treated, efficacy endpoints were analysed according to the intention-to-treat principle. This study is registered with ClinicalTrials.gov, number NCT00349076. FINDINGS: Of the 1265 patients initially enrolled, 1236 were evaluable (613 in the fluorouracil plus oxaliplatin group and 623 in the fluorouracil group). Preoperative grade 3-4 toxic effects occurred in 140 (23%) of 606 patients who actually received fluorouracil and oxaliplatin during chemoradiotherapy and in 127 (20%) of 624 patients who actually received fluorouracil chemoradiotherapy. Grade 3-4 diarrhoea was more common in those who received fluorouracil and oxaliplatin during chemoradiotherapy than in those who received fluorouracil during chemoradiotherapy (73 patients [12%] vs 52 patients [8%]), as was grade 3-4 nausea or vomiting (23 [4%] vs nine [1%]). 516 (85%) of the 606 patients who received fluorouracil and oxaliplatin-based chemoradiotherapy had the full dose of chemotherapy, and 571 (94%) had the full dose of radiotherapy; as did 495 (79%) and 601 (96%) of 624 patients who received fluorouracil-based chemoradiotherapy, respectively. A pathological complete response was achieved in 103 (17%) of 591 patients who underwent surgery in the fluorouracil and oxaliplatin group and in 81 (13%) of 606 patients who underwent surgery in the fluorouracil group (odds ratio 1·40, 95% CI 1·02-1·92; p=0·038). In the fluorouracil and oxaliplatin group, 352 (81%) of 435 patients who began adjuvant chemotherapy completed all cycles (with or without dose reduction), as did 386 (83%) of 463 patients in the fluorouracil group. INTERPRETATION: Inclusion of oxaliplatin into modified fluorouracil-based combined modality treatment was feasible and led to more patients achieving a pathological complete response than did standard treatment. Longer follow-up is needed to assess DFS. FUNDING: German Cancer Aid (Deutsche Krebshilfe).
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Preoperative Radiochemotherapy in Rectal Cancer: Is There an Impact of Oxaliplatin on Pathologic Complete Response and Survival Rates under “Real World“ Conditions? - Grabenbauer, Alexander; Aigner, Thomas; Göbel, Holger; Leibl, Bernhard J.; Lamberti, Christof; Grabenbauer, Gerhard G.; Distel, Luitpold (Cells, 2023)
This study aimed to evaluate the benefit of additional administration of oxaliplatin during fluorouracil-based neoadjuvant radiochemotherapy (nRCT) in terms of pathologic complete remission (pCR), disease-free survival (DFS), and overall survival (OS) in patients with advanced rectal cancer. Between 2006 and 2021, 669 patients (pts) were diagnosed with locally advanced rectal cancer, of whom a total of 414 pts with nRCT were identified and included in the study. A total of 283 pts were treated by nRCT using concurrent chemotherapy with fluorouracil or capecitabine; 131 pts were treated using a combination of fluorouracil or capecitabine and oxaliplatin. Propensity score matching analyses (PSM) with 114 pts in each group were used to balance the patients’ characteristics. OS, DFS, pCR-rate, and potential prognostic factors were compared between the two groups. The median follow-up time was 59.5 weeks in the fluorouracil-group and 43 weeks in the fluorouracil/oxaliplatin group (p = 0.003). After PSM, the pCR-rate (including sustained clinical complete remission) was 27% (31/114 pts) in the fluorouracil/oxaliplatin group and 16% (18/114 pts) in the fluorouracil-group (p = 0.033). There was no difference between these two groups for both 10-year OS and DFS neither before nor after PSM, respectively (OS: 72.6% vs. 55.4%, p = 0.066, and 67.8% vs. 55.1%, p = 0.703, and DFS: 44.8% vs. 46.8%, p = 0.134, and 44.7% vs. 42.3%, p = 0.184). Multivariate analysis identified regression grading according to Dworak grade 4 (HR: 0.659; CI: 0.471–0.921; p = 0.015) and age over 60 years (HR: 2.231; CI: 1.245–4.001; p = 0.007) as independent predictors for OS. In conclusion, the addition of oxaliplatin to fluorouracil during nRCT significantly improved pCR-rate without having an impact on survival.
CRIS-Team Scopus Importer:2023-02-24
Keywords: locally advanced rectal cancer; neoadjuvant radiochemotherapy; oxaliplatin; pathological complete remission; survival; total neoadjuvant radiochemotherapy

Prerequisites for the clinical implementation of a markerless SGRT-only workflow for the treatment of breast cancer patients - Sauer, Tim-Oliver; Ott, Oliver; Lahmer, Godehard; Fietkau, Rainer; Bert, Christoph (Strahlentherapie und Onkologie, 2022)
Purpose: A markerless workflow for the treatment of breast cancer patients has been introduced and evaluated retrospectively. It includes surface-guided radiation therapy (SGRT)-only positioning for patients with small cone beam CT (CBCT) position corrections during the first five fractions. Prerequisites and the frequency of its clinical application were evaluated, as well as potential benefits in terms of treatment time and dose savings, the frequency of CBCT scans, and the accuracy of the positioning. Methods: A group of 100 patients treated with the new workflow on two Versa HD linacs has been compared to a matched control group of patients treated with the former workflow, which included prepositioning with skin markings and lasers, SGRT and daily CBCT. The comparison was based on the evaluation of logfiles. Results: Of the patients treated with the new workflow, 40% did not receive daily CBCT scans. This resulted in mean time savings of 97 s, 166 s and 239 s per fraction for the new workflow, for patients treated without daily CBCT and for SGRT-only fractions, respectively, when compared to the old workflow. Dose savings amounted to a weighted computed tomography dose index reduction of CTDIW = 2.56 cGy on average for normofractionated treatment and weekly CBCTs, while for patients not treated with daily CBCT, SGRT-based positioning accuracy was 5.2 mm for the mean translational magnitude, as evaluated by CBCT. Conclusion: For 40% of the patients, after five fractions with small CBCT corrections, the workflow could be changed to SGRT-only positioning with weekly CBCT. This leads to imaging dose and time savings and thus also reduced intrafraction motion, potentially increased patient throughput and patient comfort, while assuring appropriate positioning accuracy.
CRIS-Team Scopus Importer:2022-07-15
Keywords: Breast neoplasms; Interfraction motion management; Intrafraction motion management; Markerless radiation therapy; Surface-guided radiation therapy

Pretreatment vitamin D levels are associated with improved overall survival following combined chemoradiotherapy - Putz, Florian; Distel, Luitpold; Lettmaier, S.; Weissmann, T.; Filimonova, I.; Fietkau, Rainer (2018)
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Prevention of activated brown adipose tissue in F-18-FDG-PET-imaging in children and adolescents - Which measures are effective? - Poetzsch, C.; Naumann, S.; Kurch, L.; Georgi, T. W.; Weckesser, M.; Klutmann, S.; Schmidt, D.; Herrmann, K.; Sciuk, J.; Hasenclever, D.; Mauz-Koerholz, C.; Korhoelz, D.; et al. (EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING, 2019)
CRIS-Team WoS Importer:2019-11-19

Primary glioblastoma multiforme tumors and recurrence : Comparative analysis of the danger signals HMGB1, HSP70, and calreticulin - Muth, Carolin; Ruebner, Yvonne; Semrau, Sabine; Rühle, Paul-Friedrich; Frey, Benjamin; Strnad, Annedore; Buslei, Rolf; Fietkau, Rainer; Gaipl, Udo (Strahlentherapie und Onkologie, 2016)
Glioblastoma multiforme (GBM) is the most common and aggressive brain tumor. Despite improved multimodal therapies, the tumor recurs in most cases. Diverging patient survival suggests great tumor heterogeneity and different therapy responses. Danger signals such as high-mobility group box protein 1 (HMGB1), heat shock protein 70 (HSP70), and calreticulin (CRT) are biomarker candidates, due to their association with tumor progression versus induction of antitumor immune responses. Overexpression of these danger signals has been reported for various types of tumors; however, their role in GBM is still elusive. A direct comparison of their expression in the primary tumor versus the corresponding relapse is still lacking for most tumor entities.We therefore performed an expression analysis by immunohistochemistry of the danger signals HMGB1, HSP70, and CRT in primary tumors and the corresponding relapses of 9 patients with de novo GBM.HMGB1 was highly expressed in primary tumors with a significant reduction in the respective relapse. The extracellular HSP70 expression was significantly increased in the relapse compared to the primary tumor. CRT was generally highly expressed in the primary tumor, with a slight increase in the relapse.The combination of a decreased expression of HMGB1, an increased expression of extracellular HSP70, and an increased expression of CRT in the relapse seems to be beneficial for patient survival. HMGB1, extracellular HSP70, and CRT could be taken into concerted consideration as potential biomarkers for the prognosis of patients with GBM.
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Primary Results of the phase II CheckRad-CD8 Trial: First-Line Treatment of locally advanced Head and Neck Tumors with double Checkpoint Blockade and Radiotherapy dependent on intratumoral CD8+T-Cell Infiltration - Hecht, Markus; Eckstein, Markus; Rutzner, Sandra; Von Der Gruen, J.; Illmer, T.; Klautke, G.; Laban, S.; Hautmann, M.; Brunner, T.; Tamaskovics, B.; Hinke, A.; Frey, Benjamin; et al. (STRAHLENTHERAPIE UND ONKOLOGIE, 2021)
CRIS-Team WoS Importer:2021-07-16

Priming of Anti-tumor Immune Mechanisms by Radiotherapy Is Augmented by Inhibition of Heat Shock Protein 90 - Ernst, Anne; Hennel, Roman; Krombach, Julia; Kapfhammer, Heidi; Brix, Nikko; Zuchtriegel, Gabriele; Uhl, Bernd; Reichel, Christoph A.; Frey, Benjamin; Gaipl, Udo; Winssinger, Nicolas; Shirasawa, Senji; et al. (Frontiers in Oncology, 2020)
Radiotherapy is an essential part of multi-modal cancer therapy. Nevertheless, for certain cancer entities such as colorectal cancer (CRC) the indications of radiotherapy are limited due to anatomical peculiarities and high radiosensitivity of the surrounding normal tissue. The development of molecularly targeted, combined modality approaches may help to overcome these limitations. Preferably, such strategies should not only enhance radiation-induced tumor cell killing and the abrogation of tumor cell clonogenicity, but should also support the stimulation of anti-tumor immune mechanisms – a phenomenon which moved into the center of interest of preclinical and clinical research in radiation oncology within the last decade. The present study focuses on inhibition of heat shock protein 90 (HSP90) whose combination with radiotherapy has previously been reported to exhibit convincing therapeutic synergism in different preclinical cancer models. By employing in vitro and in vivo analyses, we examined if this therapeutic synergism also applies to the priming of anti-tumor immune mechanisms in model systems of CRC. Our results indicate that the combination of HSP90 inhibitor treatment and ionizing irradiation induced apoptosis in colorectal cancer cells with accelerated transit into secondary necrosis in a hyperactive Kras-dependent manner. During secondary necrosis, dying cancer cells released different classes of damage-associated molecular patterns (DAMPs) that stimulated migration and recruitment of monocytic cells in vitro and in vivo. Additionally, these dying cancer cell-derived DAMPs enforced the differentiation of a monocyte-derived antigen presenting cell (APC) phenotype which potently triggered the priming of allogeneic T cell responses in vitro. In summary, HSP90 inhibition – apart from its radiosensitizing potential – obviously enables and supports the initial steps of anti-tumor immune priming upon radiotherapy and thus represents a promising partner for combined modality approaches. The therapeutic performance of such strategies requires further in-depth analyses, especially for but not only limited to CRC.
CRIS-Team Scopus Importer:2020-09-25
Keywords: anti-tumor immunity; cancer immunology; colorectal cancer; DAMPs; HSP90 inhibition; immune priming; radiotherapy; secondary necrosis

Process failure mode and effects analysis for external beam radiotherapy: Introducing a literature-based template and a novel action priority - Kornek, Dominik; Bert, Christoph (Zeitschrift für Medizinische Physik, 2024)
Purpose: The first aim of the study was to create a general template for analyzing potential failures in external beam radiotherapy, EBRT, using the process failure mode and effects analysis (PFMEA). The second aim was to modify the action priority (AP), a novel prioritization method originally introduced by the Automotive Industry Action Group (AIAG), to work with different severity, occurrence, and detection rating systems used in radiation oncology. Methods and materials: The AIAG PFMEA approach was employed in combination with an extensive literature survey to develop the EBRT-PFMEA template. Subsets of high-risk failure modes found through the literature survey were added to the template where applicable. Our modified AP for radiation oncology (RO AP) was defined using a weighted sum of severity, occurrence, and detectability. Then, Monte Carlo simulations were conducted to compare the original AIAG AP, the RO AP, and the risk priority number (RPN). The results of the simulations were used to determine the number of additional corrective actions per failure mode and to parametrize the RO AP to our department's rating system. Results: An EBRT-PFMEA template comprising 75 high-risk failure modes could be compiled. The AIAG AP required 1.7 additional corrective actions per failure mode, while the RO AP ranged from 1.3 to 3.5, and the RPN required 3.6. The RO AP could be parametrized so that it suited our rating system and evaluated severity, occurrence, and detection ratings equally to the AIAG AP. Conclusions: An adjustable EBRT-PFMEA template is provided which can be used as a practical starting point for creating institution-specific templates. Moreover, the RO AP introduces transparent action levels that can be adapted to any rating system.
CRIS-Team Scopus Importer:2024-03-29
Keywords: Action priority (AP); External beam radiation therapy (EBRT); Process failure mode and effects analysis (PFMEA); Prospective risk assessment; Template

Prof. Dr. med. Thomas G. Wendt Director of the Department of Radiation Oncology at the University Hospital Jena on his 65th birthday - Wiezorek, Tilo; Grabenbauer, Gerhard G.; Sauer, Rolf (Strahlentherapie und Onkologie, 2014)
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