@article{Prieto‐GarciaHartmannReisslandetal.2020, author = {Prieto-Garcia, Cristian and Hartmann, Oliver and Reissland, Michaela and Braun, Fabian and Fischer, Thomas and Walz, Susanne and Sch{\"u}lein-V{\"o}lk, Christina and Eilers, Ursula and Ade, Carsten P. and Calzado, Marco A. and Orian, Amir and Maric, Hans M. and M{\"u}nch, Christian and Rosenfeldt, Mathias and Eilers, Martin and Diefenbacher, Markus E.}, title = {Maintaining protein stability of ∆Np63 via USP28 is required by squamous cancer cells}, series = {EMBO Molecular Medicine}, volume = {12}, journal = {EMBO Molecular Medicine}, number = {4}, doi = {10.15252/emmm.201911101}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-218303}, year = {2020}, abstract = {The transcription factor ∆Np63 is a master regulator of epithelial cell identity and essential for the survival of squamous cell carcinoma (SCC) of lung, head and neck, oesophagus, cervix and skin. Here, we report that the deubiquitylase USP28 stabilizes ∆Np63 and maintains elevated ∆NP63 levels in SCC by counteracting its proteasome-mediated degradation. Impaired USP28 activity, either genetically or pharmacologically, abrogates the transcriptional identity and suppresses growth and survival of human SCC cells. CRISPR/Cas9-engineered in vivo mouse models establish that endogenous USP28 is strictly required for both induction and maintenance of lung SCC. Our data strongly suggest that targeting ∆Np63 abundance via inhibition of USP28 is a promising strategy for the treatment of SCC tumours.}, language = {en} } @phdthesis{Warm2023, author = {Warm, Tobias Dominik}, title = {Einstellung von Pflegeheimbewohnenden zur vorausschauenden Versorgungsplanung}, doi = {10.25972/OPUS-32373}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-323739}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2023}, abstract = {Hintergrund: Aufgrund des demographischen Wandels nimmt der Anteil der Pflegebed{\"u}rftigen in Deutschland zu. Aktuelle Erhebungen zeigen, dass der Einzug in station{\"a}re Pflegeeinrichtungen erst in h{\"o}herem Lebensalter und bei steigenden Komorbidit{\"a}ten erfolgt, womit ein erh{\"o}hter Bedarf an medizinischer und pflegerischer Versorgung einhergeht. Ziele der Studie: Durch die Befragung der Pflegeheimbewohnenden sollten Erkenntnisse {\"u}ber eine bereits erfolgte Vorsorgedokumentation und deren Versorgungsw{\"u}nsche am Lebensende gewonnen werden. Methodik: Es wurde eine multizentrische, explorative Beobachtungsstudie als Vollerhebung in elf bayerischen Pflegeeinrichtungen durchgef{\"u}hrt. Die Datenerhebung erfolgte vor Ort durch den Promovierenden mittels eines standardisierten Fragebogens im Zeitraum von April 2018 bis Mai 2019. Im Zuge der statistischen Auswertung wurden deskriptive Statistiken erstellt, Gruppenunterschiede wurden zweiseitig mittels Fisher-Exakt-Test auf Unabh{\"a}ngigkeit hin {\"u}berpr{\"u}ft und paarweise Gruppenvergleiche durch bin{\"a}re logistische Regression durchgef{\"u}hrt. Ergebnisse: Von 1207 wurden 269 (22,3 \%) Pflegeheimbewohnende in die Studie eingeschlossen. Von den Studienteilnehmenden hatten sich 55 \% bereits intensiver mit dem eigenen Sterben auseinandergesetzt. 50,9 \% der Pflegeheimbewohnenden w{\"u}nschten im Falle einer zum Tode f{\"u}hrenden Erkrankung eine alleinige pflegerische und medizinische Versorgung in der Einrichtung. 19,7 \% w{\"u}nschten in diesem Fall eine Klinikeinweisung, aber den Verzicht auf Anwendung invasiver Therapiemaßnahmen. Ein Wunschsterbeort lag bei 65,4 \% der Pflegeheimbewohnenden vor. Von diesen w{\"u}nschten 76,7 \% in der Pflegeeinrichtung zu versterben. 71,7 \% der Pflegeheimbewohnenden w{\"u}nschten, nicht allein zu versterben. {\"U}ber ihre Versorgungsw{\"u}nsche hatten bereits 45,7 \% aller Studienteilnehmenden eine andere Person, mehrheitlich die eigenen Angeh{\"o}rigen, informiert. 49,1 \% der Pflegeheimbewohnenden w{\"u}nschten sich eine Erfassung der Versorgungsw{\"u}nsche direkt bei Einzug in die Einrichtung. In 63,6 \% der F{\"a}lle lag mindestens ein schriftliches Vorsorgedokument vor. Eine Patientenverf{\"u}gung hatten 45,5 \%, eine Vorsorgevollmacht 46,5 \% der Pflegeheimbewohnenden verfasst. Schlussfolgerungen: Pflegeheimbewohnende haben mehrheitlich konkrete Vorstellungen f{\"u}r ihre Versorgung am Lebensende. Die vorhandenen Versorgungsw{\"u}nsche sollten auf Wunsch der Pflegeheimbewohnenden erfasst werden, um eine entsprechende Versorgung auch im Falle einer eintretenden Einwilligungsunf{\"a}higkeit zu erm{\"o}glichen. Der Zeitpunkt der Erfassung der Versorgungsw{\"u}nsche sollte im Hinblick auf das steigende Lebensalter bei Einzug in deutsche Pflegeeinrichtungen und auf die altersbedingt steigende Rate an kognitiven Einschr{\"a}nkungen m{\"o}glichst fr{\"u}hzeitig gew{\"a}hlt werden. Hierbei stellen Konzepte der vorausschauenden Versorgungsplanung eine M{\"o}glichkeit dar, um einen Dialog zwischen den beteiligten Akteuren zu erm{\"o}glichen.}, subject = {Versorgungsplanung}, language = {de} } @article{WegenerSauer2018, author = {Wegener, Sonja and Sauer, Otto A.}, title = {Electrometer offset current due to scattered radiation}, series = {Journal of Applied Clinical Medical Physics}, volume = {19}, journal = {Journal of Applied Clinical Medical Physics}, number = {6}, doi = {10.1002/acm2.12458}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-176137}, pages = {274-281}, year = {2018}, abstract = {Relative dose measurements with small ionization chambers in combination with an electrometer placed in the treatment room ("internal electrometer") show a large dependence on the polarity used. While this was observed previously for percent depth dose curves (PDDs), the effect has not been understood or preventable. To investigate the polarity dependence of internal electrometers used in conjunction with a small-volume ionization chamber, we placed an internal electrometer at a distance of 1 m from the isocenter and exposed it to different amounts of scattered radiation by varying the field size. We identified irradiation of the electrometer to cause a current of approximately -1 pA, regardless of the sign of the biasing voltage. For low-sensitivity detectors, such a current noticeably distorts relative dose measurements. To demonstrate how the current systematically changes PDDs, we collected measurements with nine ionization chambers of different volumes. As the chamber volume decreased, signal ratios at 20 and 10 cm depth (M20/M10) became smaller for positive bias voltage and larger for negative bias voltage. At the size of the iba CC04 (40 mm\(^{3}\)) the difference of M20/M10 was around 1\% and for the smallest studied chamber, the iba CC003 chamber (3 mm\(^{3}\)), around 7\% for a 10 × 10 cm² field. When the electrometer was moved further from the source or shielded, the additional current decreased. Consequently, PDDs at both polarities were brought into alignment at depth even for the 3 mm\(^{3}\) ionization chamber. The apparent polarity effect on PDDs and lateral beam profiles was reduced considerably by shielding the electrometer. Due to normalization the effect on output values was low. When measurements with a low-sensitivity probe are carried out in conjunction with an internal electrometer, we recommend careful monitoring of the particular setup by testing both polarities, and if deemed necessary, we suggest shielding the electrometer.}, language = {en} } @article{RabevanOorschotJentschke2020, author = {Rabe, A. and van Oorschot, B. and Jentschke, E.}, title = {Suizidalit{\"a}t bei Krebspatienten}, series = {Der Onkologe}, volume = {26}, journal = {Der Onkologe}, issn = {Suizidalit{\"a}t bei Krebspatienten}, doi = {10.1007/s00761-020-00712-x}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-232401}, pages = {163-168}, year = {2020}, abstract = {Hintergrund Die Diagnose Krebs und ihre Behandlung kann eine große Belastung f{\"u}r die Betroffenen darstellen. Neben k{\"o}rperlichen Beschwerden kann auch die Psyche in Mitleidenschaft gezogen werden. Fehlt es an entsprechenden Bew{\"a}ltigungsstrategien, kann der selbstbestimmte Tod als einziger Ausweg erscheinen. Ziel und Fragestellung Die vorliegende {\"U}bersichtsarbeit zur Suizidalit{\"a}t bei Krebspatienten befasst sich mit einem Thema, das in der Forschung und Praxis in Deutschland nur wenig Aufmerksamkeit findet. Material und Methoden Eine themenbezogene Literaturrecherche stellt die Basis der Arbeit dar. Ergebnisse Todesw{\"u}nsche unter Krebspatienten sind nicht selten und k{\"o}nnen Suizidgedanken/-absichten beinhalten. Psychische Beschwerden, insbesondere Hoffnungslosigkeit und Depression, sind ernstzunehmende Risikofaktoren. Das Erkennen einer hohen psychischen Belastung/von Todesw{\"u}nschen ist ein wichtiger Aspekt f{\"u}r die Suizidpr{\"a}vention. F{\"u}r die Praxis empfiehlt sich zun{\"a}chst die Verwendung von Frageb{\"o}gen. Bei auff{\"a}lligen Werten muss die Suizidalit{\"a}t proaktiv in einem pers{\"o}nlichen Gespr{\"a}ch exploriert werden. Betroffene sind meist ambivalent bez{\"u}glich ihrer Entscheidung f{\"u}r oder gegen das Leben. Dies stellt eine große Chance f{\"u}r Interventionen dar. Schlussfolgerungen Suizidalit{\"a}t kann verhindert werden, wenn die hohe Belastung erkannt wird. Bereits das Gespr{\"a}ch zwischen Arzt und Patient {\"u}ber Todesw{\"u}nsche kann eine erste Entlastung darstellen.}, language = {de} } @phdthesis{Zehner2024, author = {Zehner, Leonie Constanze}, title = {Evaluierung der Rezidivbestrahlung des Prostatakarzinoms}, doi = {10.25972/OPUS-35123}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-351230}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {Es erfolgte eine Evaluierung von Bestrahlungsdaten aus der Strahlentherapie der Universit{\"a}tsklinik W{\"u}rzburg von 435 Patienten mit biochemischen oder klinischen Rezidiv des Prostatakarzinoms. Der prim{\"a}re Endpunkt war das biochemisch rezidivfreie {\"U}berleben. Sekund{\"a}re Endpunkte waren das Auftreten von Fernmetastasen und das Versterben der Patienten. Zudem wurde der Einfluss patienten-, tumor-, und behandlungsspezifischer Faktoren {\"u}berpr{\"u}ft.}, subject = {Prostata}, language = {de} } @article{DietzschBraesigkSeideletal.2022, author = {Dietzsch, Stefan and Braesigk, Annett and Seidel, Clemens and Remmele, Julia and Kitzing, Ralf and Schlender, Tina and Mynarek, Martin and Geismar, Dirk and Jablonska, Karolina and Schwarz, Rudolf and Pazos, Montserrat and Weber, Damien C. and Frick, Silke and Gurtner, Kristin and Matuschek, Christiane and Harrabi, Semi Ben and Gl{\"u}ck, Albrecht and Lewitzki, Victor and Dieckmann, Karin and Benesch, Martin and Gerber, Nicolas U. and Obrecht, Denise and Rutkowski, Stefan and Timmermann, Beate and Kortmann, Rolf-Dieter}, title = {Types of deviation and review criteria in pretreatment central quality control of tumor bed boost in medulloblastoma—an analysis of the German Radiotherapy Quality Control Panel in the SIOP PNET5 MB trial}, series = {Strahlentherapie und Onkologie}, volume = {198}, journal = {Strahlentherapie und Onkologie}, number = {3}, issn = {0179-7158}, doi = {10.1007/s00066-021-01822-0}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-307812}, pages = {282-290}, year = {2022}, abstract = {Purpose In Germany, Austria, and Switzerland, pretreatment radiotherapy quality control (RT-QC) for tumor bed boost (TB) in non-metastatic medulloblastoma (MB) was not mandatory but was recommended for patients enrolled in the SIOP PNET5 MB trial between 2014 and 2018. This individual case review (ICR) analysis aimed to evaluate types of deviations in the initial plan proposals and develop uniform review criteria for TB boost. Patients and methods A total of 78 patients were registered in this trial, of whom a subgroup of 65 patients were available for evaluation of the TB treatment plans. Dose uniformity was evaluated according to the definitions of the protocol. Additional RT-QC criteria for standardized review of target contours were elaborated and data evaluated accordingly. Results Of 65 initial TB plan proposals, 27 (41.5\%) revealed deviations of target volume delineation. Deviations according to the dose uniformity criteria were present in 14 (21.5\%) TB plans. In 25 (38.5\%) cases a modification of the RT plan was recommended. Rejection of the TB plans was rather related to unacceptable target volume delineation than to insufficient dose uniformity. Conclusion In this analysis of pretreatment RT-QC, protocol deviations were present in a high proportion of initial TB plan proposals. These findings emphasize the importance of pretreatment RT-QC in clinical trials for MB. Based on these data, a proposal for RT-QC criteria for tumor bed boost in non-metastatic MB was developed.}, language = {en} } @article{LisowskiHartrampfHasenaueretal.2023, author = {Lisowski, Dominik and Hartrampf, Philipp E. and Hasenauer, Natalie and Nickl, Vera and Monoranu, Camelia-Maria and Tamihardja, J{\"o}rg}, title = {Complete loss of E-cadherin expression in a rare case of metastatic malignant meningioma: a case report}, series = {BMC Neurology}, volume = {23}, journal = {BMC Neurology}, doi = {10.1186/s12883-023-03450-w}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-357996}, year = {2023}, abstract = {Background Hematogenous tumor spread of malignant meningiomas occurs very rarely but is associated with very poor prognosis. Case presentation We report an unusual case of a patient with a malignant meningioma who developed multiple metastases in bones, lungs and liver after initial complete resection of the primary tumor. After partial hepatic resection, specimens were histologically analyzed, and a complete loss of E-cadherin adhesion molecules was found. No oncogenic target mutations were found. The patient received a combination of conventional radiotherapy and peptide receptor radionuclide therapy (PRRT). Due to aggressive tumor behavior and rapid spread of metastases, the patient deceased after initiation of treatment. Conclusions E-cadherin downregulation is associated with a higher probability of tumor invasion and distant metastasis formation in malignant meningioma. Up to now, the efficacy of systemic therapy, including PRRT, is very limited in malignant meningioma patients.}, language = {en} } @article{DiefenhardtMartinLudmiretal.2022, author = {Diefenhardt, Markus and Martin, Daniel and Ludmir, Ethan B. and Fleischmann, Maximilian and Hofheinz, Ralf-Dieter and Ghadimi, Michael and Kosmala, Rebekka and Polat, B{\"u}lent and Friede, Tim and Minsky, Bruce D. and R{\"o}del, Claus and Fokas, Emmanouil}, title = {Development and validation of a predictive model for toxicity of neoadjuvant chemoradiotherapy in rectal cancer in the CAO/ARO/AIO-04 phase III trial}, series = {Cancers}, volume = {14}, journal = {Cancers}, number = {18}, issn = {2072-6694}, doi = {10.3390/cancers14184425}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-288081}, year = {2022}, abstract = {Background: There is a lack of predictive models to identify patients at risk of high neoadjuvant chemoradiotherapy (CRT)-related acute toxicity in rectal cancer. Patient and Methods: The CAO/ARO/AIO-04 trial was divided into a development (n = 831) and a validation (n = 405) cohort. Using a best subset selection approach, predictive models for grade 3-4 acute toxicity were calculated including clinicopathologic characteristics, pretreatment blood parameters, and baseline results of quality-of-life questionnaires and evaluated using the area under the ROC curve. The final model was internally and externally validated. Results: In the development cohort, 155 patients developed grade 3-4 toxicities due to CRT. In the final evaluation, 15 parameters were included in the logistic regression models using best-subset selection. BMI, gender, and emotional functioning remained significant for predicting toxicity, with a discrimination ability adjusted for overfitting of AUC 0.687. The odds of experiencing high-grade toxicity were 3.8 times higher in the intermediate and 6.4 times higher in the high-risk group (p < 0.001). Rates of toxicity (p = 0.001) and low treatment adherence (p = 0.007) remained significantly different in the validation cohort, whereas discrimination ability was not significantly worse (DeLong test 0.09). Conclusion: We developed and validated a predictive model for toxicity using gender, BMI, and emotional functioning. Such a model could help identify patients at risk for treatment-related high-grade toxicity to assist in treatment guidance and patient participation in shared decision making.}, language = {en} } @article{TamihardjaZehnerHartrampfetal.2022, author = {Tamihardja, J{\"o}rg and Zehner, Leonie and Hartrampf, Philipp and Lisowski, Dominik and Kneitz, Susanne and Cirsi, Sinan and Razinskas, Gary and Flentje, Michael and Polat, B{\"u}lent}, title = {Salvage nodal radiotherapy as metastasis-directed therapy for oligorecurrent prostate cancer detected by positron emission tomography shows favorable outcome in long-term follow-up}, series = {Cancers}, volume = {14}, journal = {Cancers}, number = {15}, issn = {2072-6694}, doi = {10.3390/cancers14153766}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-286064}, year = {2022}, abstract = {Simple Summary Patients, who suffer from oligorecurrent prostate cancer with limited nodal involvement, may be offered positron emission tomography (PET)-directed salvage nodal radiotherapy to delay disease progression. This current analysis aimed to access salvage radiotherapy for nodal oligorecurrent prostate cancer with simultaneous integrated boost to PET-involved lymph nodes as metastasis-directed therapy. A long-term oncological outcome was favorable after salvage nodal radiotherapy and severe toxicity rates were low. Androgen deprivation therapy plays a major role in recurrent prostate cancer management and demonstrates a positive influence on the rate of biochemical progression in patients receiving salvage nodal radiotherapy. The present long-term analysis may help clinicians identify patients who would benefit from salvage nodal radiotherapy and androgen deprivation therapy, as a multimodal treatment strategy for oligorecurrent prostate cancer. Abstract Background: The study aimed to access the long-term outcome of salvage nodal radiotherapy (SNRT) in oligorecurrent prostate cancer. Methods: A total of 95 consecutive patients received SNRT for pelvic and/or extrapelvic nodal recurrence after prostate-specific membrane antigen (PSMA) or choline PET from 2010 to 2021. SNRT was applied as external beam radiotherapy with simultaneous integrated boost up to a median total dose of 62.9 Gy (EQD2\(_{1.5Gy}\)) to the recurrent lymph node metastases. The outcome was analyzed by cumulative incidence functions with death as the competing risk. Fine-Gray regression analyses were performed to estimate the relative hazards of the outcome parameters. Genitourinary (GU)/gastrointestinal (GI) toxicity evaluation utilized Common Toxicity Criteria for Adverse Events (v5.0). The results are as follows: the median follow-up was 47.1 months. The five-year biochemical progression rate (95\% CI) was 50.1\% (35.7-62.9\%). Concomitant androgen deprivation therapy (ADT) was adminstered in 60.0\% of the patients. The five-year biochemical progression rate was 75.0\% (42.0-90.9\%) without ADT versus 35.3\% (19.6-51.4\%) with ADT (p = 0.003). The cumulative five-year late grade 3 GU toxicity rate was 2.1\%. No late grade 3 GI toxicity occured. Conclusions: Metastasis-directed therapy through SNRT for PET-staged oligorecurrent prostate cancer demonstrated a favorable long-term oncologic outcome. Omittance of ADT led to an increased biochemical progression.}, language = {en} } @article{LisowskiLutyjAbazarietal.2023, author = {Lisowski, Dominik and Lutyj, Paul and Abazari, Arya and Weick, Stefan and Traub, Jan and Polat, B{\"u}lent and Flentje, Michael and Kraft, Johannes}, title = {Impact of Radiotherapy on Malfunctions and Battery Life of Cardiac Implantable Electronic Devices in Cancer Patients}, series = {Cancers}, volume = {15}, journal = {Cancers}, number = {19}, issn = {2072-6694}, doi = {10.3390/cancers15194830}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-358008}, year = {2023}, abstract = {Purpose: This study analyses a large number of cancer patients with CIEDs for device malfunction and premature battery depletion by device interrogation after each radiotherapy fraction and compares different guidelines in regard to patient safety. Methods: From 2007 to 2022, a cohort of 255 patients was analyzed for CIED malfunctions via immediate device interrogation after every RT fraction. Results: Out of 324 series of radiotherapy treatments, with a total number of 5742 CIED interrogations, nine device malfunctions (2.8\%) occurred. Switching into back-up/safety mode and software errors occurred four times each. Once, automatic read-out could not be performed. The median prescribed cumulative dose at planning target volume (PTV) associated with CIED malfunction was 45.0 Gy (IQR 36.0-64.0 Gy), with a median dose per fraction of 2.31 Gy (IQR 2.0-3.0 Gy). The median maximum dose at the CIED at time of malfunction was 0.3 Gy (IQR 0.0-1.3 Gy). No correlation between CIED malfunction and maximum photon energy (p = 0.07), maximum dose at the CIED (p = 0.59) nor treatment localization (p = 0.41) could be detected. After excluding the nine malfunctions, premature battery depletion was only observed three times (1.2\%). Depending on the national guidelines, 1-9 CIED malfunctions in this study would have been detected on the day of occurrence and in none of the cases would patient safety have been compromised. Conclusion: Radiation-induced malfunctions of CIEDs and premature battery depletion are rare. If recommendations of national safety guidelines are followed, only a portion of the malfunctions would be detected directly after occurrence. Nevertheless, patient safety would not be compromised.}, language = {en} } @article{HuflageKunzHendeletal.2023, author = {Huflage, Henner and Kunz, Andreas Steven and Hendel, Robin and Kraft, Johannes and Weick, Stefan and Razinskas, Gary and Sauer, Stephanie Tina and Pennig, Lenhard and Bley, Thorsten Alexander and Grunz, Jan-Peter}, title = {Obesity-related pitfalls of virtual versus true non-contrast imaging — an intraindividual comparison in 253 oncologic patients}, series = {Diagnostics}, volume = {13}, journal = {Diagnostics}, number = {9}, issn = {2075-4418}, doi = {10.3390/diagnostics13091558}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-313519}, year = {2023}, abstract = {Objectives: Dual-source dual-energy CT (DECT) facilitates reconstruction of virtual non-contrast images from contrast-enhanced scans within a limited field of view. This study evaluates the replacement of true non-contrast acquisition with virtual non-contrast reconstructions and investigates the limitations of dual-source DECT in obese patients. Materials and Methods: A total of 253 oncologic patients (153 women; age 64.5 ± 16.2 years; BMI 26.6 ± 5.1 kg/m\(^2\)) received both multi-phase single-energy CT (SECT) and DECT in sequential staging examinations with a third-generation dual-source scanner. Patients were allocated to one of three BMI clusters: non-obese: <25 kg/m\(^2\) (n = 110), pre-obese: 25-29.9 kg/m\(^2\) (n = 73), and obese: >30 kg/m\(^2\) (n = 70). Radiation dose and image quality were compared for each scan. DECT examinations were evaluated regarding liver coverage within the dual-energy field of view. Results: While arterial contrast phases in DECT were associated with a higher CTDI\(_{vol}\) than in SECT (11.1 vs. 8.1 mGy; p < 0.001), replacement of true with virtual non-contrast imaging resulted in a considerably lower overall dose-length product (312.6 vs. 475.3 mGy·cm; p < 0.001). The proportion of DLP variance predictable from patient BMI was substantial in DECT (R\(^2\) = 0.738) and SECT (R\(^2\) = 0.620); however, DLP of SECT showed a stronger increase in obese patients (p < 0.001). Incomplete coverage of the liver within the dual-energy field of view was most common in the obese subgroup (17.1\%) compared with non-obese (0\%) and pre-obese patients (4.1\%). Conclusion: DECT facilitates a 30.8\% dose reduction over SECT in abdominal oncologic staging examinations. Employing dual-source scanner architecture, the risk for incomplete liver coverage increases in obese patients.}, language = {en} } @article{MemmelSisarioZimmermannetal.2020, author = {Memmel, Simon and Sisario, Dmitri and Zimmermann, Heiko and Sauer, Markus and Sukhorukov, Vladimir L. and Djuzenova, Cholpon S. and Flentje, Michael}, title = {FocAn: automated 3D analysis of DNA repair foci in image stacks acquired by confocal fluorescence microscopy}, series = {BMC Bioinformatics}, volume = {21}, journal = {BMC Bioinformatics}, doi = {10.1186/s12859-020-3370-8}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-229023}, year = {2020}, abstract = {Background Phosphorylated histone H2AX, also known as gamma H2AX, forms mu m-sized nuclear foci at the sites of DNA double-strand breaks (DSBs) induced by ionizing radiation and other agents. Due to their specificity and sensitivity, gamma H2AX immunoassays have become the gold standard for studying DSB induction and repair. One of these assays relies on the immunofluorescent staining of gamma H2AX followed by microscopic imaging and foci counting. During the last years, semi- and fully automated image analysis, capable of fast detection and quantification of gamma H2AX foci in large datasets of fluorescence images, are gradually replacing the traditional method of manual foci counting. A major drawback of the non-commercial software for foci counting (available so far) is that they are restricted to 2D-image data. In practice, these algorithms are useful for counting the foci located close to the midsection plane of the nucleus, while the out-of-plane foci are neglected. Results To overcome the limitations of 2D foci counting, we present a freely available ImageJ-based plugin (FocAn) for automated 3D analysis of gamma H2AX foci in z-image stacks acquired by confocal fluorescence microscopy. The image-stack processing algorithm implemented in FocAn is capable of automatic 3D recognition of individual cell nuclei and gamma H2AX foci, as well as evaluation of the total foci number per cell nucleus. The FocAn algorithm consists of two parts: nucleus identification and foci detection, each employing specific sequences of auto local thresholding in combination with watershed segmentation techniques. We validated the FocAn algorithm using fluorescence-labeled gamma H2AX in two glioblastoma cell lines, irradiated with 2 Gy and given up to 24 h post-irradiation for repair. We found that the data obtained with FocAn agreed well with those obtained with an already available software (FoCo) and manual counting. Moreover, FocAn was capable of identifying overlapping foci in 3D space, which ensured accurate foci counting even at high DSB density of up to similar to 200 DSB/nucleus. Conclusions FocAn is freely available an open-source 3D foci analyzer. The user-friendly algorithm FocAn requires little supervision and can automatically count the amount of DNA-DSBs, i.e. fluorescence-labeled gamma H2AX foci, in 3D image stacks acquired by laser-scanning microscopes without additional nuclei staining.}, language = {en} } @article{TamihardjaZehnerHartrampfetal.2022, author = {Tamihardja, J{\"o}rg and Zehner, Leonie and Hartrampf, Philipp E. and Cirsi, Sinan and Wegener, Sonja and Buck, Andreas K. and Flentje, Michael and Polat, B{\"u}lent}, title = {Dose-escalated salvage radiotherapy for macroscopic local recurrence of prostate cancer in the prostate-specific membrane antigen positron emission tomography era}, series = {Cancers}, volume = {14}, journal = {Cancers}, number = {19}, issn = {2072-6694}, doi = {10.3390/cancers14194956}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-290302}, year = {2022}, abstract = {Simple Summary Prostate cancer often relapses after initial radical prostatectomy, and salvage radiotherapy offers a second chance of cure for relapsed patients. Modern imaging techniques, especially prostate-specific membrane antigen positron emission tomography/computed tomography (PSMA PET/CT), enable radiation oncologists to target radiotherapy at the involved sites of disease. In a group of patients, PSMA PET/CT imaging can detect a macroscopic local recurrence with or without locoregional lymph node metastasis. In these cases, an escalation of the radiotherapy dose is often considered for controlling the visible tumor mass. As the evidence for dose-escalated salvage radiotherapy for macroscopic recurrent prostate cancer after PSMA PET/CT imaging is still limited, we address this topic in the current analysis. We found that the outcome of patients with dose-escalated salvage radiotherapy for macroscopic prostate cancer recurrence is encouragingly favorable, while the toxicity is very limited. Abstract Background: The purpose of this study was to access the oncological outcome of prostate-specific membrane antigen positron emission tomography (PSMA PET/CT)-guided salvage radiotherapy (SRT) for localized macroscopic prostate cancer recurrence. Methods: Between February 2010 and June 2021, 367 patients received SRT after radical prostatectomy. Out of the 367 screened patients, 111 patients were staged by PSMA PET/CT before SRT. A total of 59 out of these 111 (53.2\%) patients were treated for PSMA PET-positive macroscopic prostatic fossa recurrence. Dose-escalated SRT was applied with a simultaneous integrated boost at a median prescribed dose of 69.3 Gy (IQR 69.3-72.6 Gy). The oncological outcome was investigated using Kaplan-Meier and Cox regression analyses. The genitourinary (GU)/gastrointestinal (GI) toxicity evaluation utilized Common Toxicity Criteria for Adverse Events (version 5.0). Results: The median follow-up was 38.2 months. The three-year biochemical progression-free survival rate was 89.1\% (95\% CI: 81.1-97.8\%) and the three-year metastasis-free survival rate reached 96.2\% (95\% CI: 91.2-100.0\%). The cumulative three-year late grade 3 GU toxicity rate was 3.4\%. No late grade 3 GI toxicity occurred. Conclusions: Dose-escalated PSMA PET/CT-guided salvage radiotherapy for macroscopic prostatic fossa recurrence resulted in favorable survival and toxicity rates.}, language = {en} } @article{LisowskiTroemelLutyjetal.2022, author = {Lisowski, Dominik and Tr{\"o}mel, Jannik and Lutyj, Paul and Lewitzki, Victor and Hartrampf, Philipp E. and Polat, B{\"u}lent and Flentje, Michael and Tamihardja, J{\"o}rg}, title = {Health-related quality of life and clinical outcome after radiotherapy of patients with intracranial meningioma}, series = {Scientific Reports}, volume = {12}, journal = {Scientific Reports}, doi = {10.1038/s41598-022-24192-8}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-301233}, year = {2022}, abstract = {This retrospective, single-institutional study investigated long-term outcome, toxicity and health-related quality of life (HRQoL) in meningioma patients after radiotherapy. We analyzed the data of 119 patients who received radiotherapy at our department from 1997 to 2014 for intracranial WHO grade I-III meningioma. Fractionated stereotactic radiotherapy (FSRT), intensity modulated radiotherapy (IMRT) or radiosurgery radiation was applied. The EORTC QLQ-C30 and QLQ-BN20 questionnaires were completed for assessment of HRQoL. Overall survival (OS) for the entire study group was 89.6\% at 5 years and 75.9\% at 10 years. Local control (LC) at 5 and 10 years was 82.4\% and 73.4\%, respectively. Local recurrence was observed in 22 patients (18.5\%). Higher grade acute and chronic toxicities were observed in seven patients (5.9\%) and five patients (4.2\%), respectively. Global health status was rated with a mean of 59.9 points (SD 22.3) on QLQ-C30. In conclusion, radiotherapy resulted in very good long-term survival and tumor control rates with low rates of severe toxicities but with a deterioration of long-term HRQoL.}, language = {en} } @article{TamihardjaSchortmannLawrenzetal.2021, author = {Tamihardja, J{\"o}rg and Schortmann, Max and Lawrenz, Ingulf and Weick, Stefan and Bratengeier, Klaus and Flentje, Michael and Guckenberger, Matthias and Polat, B{\"u}lent}, title = {Moderately hypofractionated radiotherapy for localized prostate cancer: updated long-term outcome and toxicity analysis}, series = {Strahlentherapie und Onkologie}, volume = {197}, journal = {Strahlentherapie und Onkologie}, issn = {0179-7158}, doi = {10.1007/s00066-020-01678-w}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-232509}, pages = {124-132}, year = {2021}, abstract = {Purpose Evaluation of long-term outcome and toxicity of moderately hypofractionated radiotherapy using intensity-modulated radiotherapy (IMRT) with simultaneous integrated boost treatment planning and cone beam CT-based image guidance for localized prostate cancer. Methods Between 2005 and 2015, 346 consecutive patients with localized prostate cancer received primary radiotherapy using cone beam CT-based image-guided intensity-modulated radiotherapy (IG-IMRT) and volumetric modulated arc therapy (IG-VMAT) with a simultaneous integrated boost (SIB). Total doses of 73.9 Gy (n = 44) and 76.2 Gy (n = 302) to the high-dose PTV were delivered in 32 and 33 fractions, respectively. The low-dose PTV received a dose (D95) of 60.06 Gy in single doses of 1.82 Gy. The pelvic lymph nodes were treated in 91 high-risk patients to 45.5 Gy (D95). Results Median follow-up was 61.8 months. The 5‑year biochemical relapse-free survival (bRFS) was 85.4\% for all patients and 93.3, 87.4, and 79.4\% for low-, intermediate-, and high-risk disease, respectively. The 5‑year prostate cancer-specific survival (PSS) was 94.8\% for all patients and 98.7, 98.9, 89.3\% for low-, intermediate-, and high-risk disease, respectively. The 5‑year and 10-year overall survival rates were 83.8 and 66.3\% and the 5‑year and 10-year freedom from distant metastasis rates were 92.2 and 88.0\%, respectively. Cumulative 5‑year late GU toxicity and late GI toxicity grade ≥2 was observed in 26.3 and 12.1\% of the patients, respectively. Cumulative 5‑year late grade 3 GU/GI toxicity occurred in 4.0/1.2\%. Conclusion Moderately hypofractionated radiotherapy using SIB treatment planning and cone beam CT image guidance resulted in high biochemical control and survival with low rates of late toxicity.}, language = {en} } @article{RichterWegenerBreueretal.2021, author = {Richter, Anne and Wegener, Sonja and Breuer, Kathrin and Razinskas, Gary and Weick, Stefan and Exner, Florian and Bratengeier, Klaus and Flentje, Michael and Sauer, Otto and Polat, B{\"u}lent}, title = {Comparison of sliding window and field-in-field techniques for tangential whole breast irradiation using the Halcyon and Synergy Agility systems}, series = {Radiation Oncology}, volume = {16}, journal = {Radiation Oncology}, doi = {10.1186/s13014-021-01942-y}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-265704}, year = {2021}, abstract = {Background To implement a tangential treatment technique for whole breast irradiation using the Varian Halcyon and to compare it with Elekta Synergy Agility plans. Methods For 20 patients two comparable treatment plans with respect to dose coverage and normal tissue sparing were generated. Tangential field-in-field treatment plans (Pinnacle/Synergy) were replanned using the sliding window technique (Eclipse/Halcyon). Plan specific QA was performed using the portal Dosimetry and the ArcCHECK phantom. Imaging and treatment dose were evaluated for treatment delivery on both systems using a modified CIRS Phantom. Results The mean number of monitor units for a fraction dose of 2.67 Gy was 515 MUs and 260 MUs for Halcyon and Synergy Agility plans, respectively. The homogeneity index and dose coverage were similar for both treatment units. The plan specific QA showed good agreement between measured and calculated plans. All Halcyon plans passed portal dosimetry QA (3\%/2 mm) with 100\% points passing and ArcCheck QA (3\%/2 mm) with 99.5\%. Measurement of the cumulated treatment and imaging dose with the CIRS phantom resulted in lower dose to the contralateral breast for the Halcyon plans. Conclusions For the Varian Halcyon a plan quality similar to the Elekta Synergy device was achieved. For the Halcyon plans the dose contribution from the treatment fields to the contralateral breast was even lower due to less interleaf transmission of the Halcyon MLC and a lower contribution of scattered dose from the collimator system.}, language = {en} } @article{BratengeierHerzogWegeneretal.2017, author = {Bratengeier, Klaus and Herzog, Barbara and Wegener, Sonja and Holubyev, Kostyantyn}, title = {Finer leaf resolution and steeper beam edges using a virtual isocentre in concurrence to PTV-shaped collimators in standard distance - a planning study}, series = {Radiation Oncology}, volume = {12}, journal = {Radiation Oncology}, number = {88}, doi = {10.1186/s13014-017-0826-8}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-157543}, year = {2017}, abstract = {Purpose: Investigation of a reduced source to target distance to improve organ at risk sparing during stereotactic irradiation (STX). Methods: The authors present a planning study with perfectly target-volume adapted collimator compared with multi-leaf collimator (MLC) at reduced source to virtual isocentre distance (SVID) in contrast to normal source to isocentre distance (SID) for stereotactic applications. The role of MLC leaf width and 20-80\% penumbra was examined concerning the healthy tissue sparing. Several prescription schemes and target diameters are considered. Results: Paddick's gradient index (GI) as well as comparison of the mean doses to spherical shells at several distances to the target is evaluated. Both emphasize the same results: the healthy tissue sparing in the high dose area around the planning target volume (PTV) is improved at reduced SVID ≤ 70 cm. The effect can be attributed more to steeper penumbra than to finer leaf resolution. Comparing circular collimators at different SVID just as MLC-shaped collimators, always the GI was reduced. Even MLC-shaped collimator at SVID 70 cm had better healthy tissue sparing than an optimal shaped circular collimator at SID 100 cm. Regarding penumbra changes due to varying SVID, the results of the planning study are underlined by film dosimetry measurements with Agility™ MLC. Conclusion: Penumbra requires more attention in comparing studies, especially studies using different planning systems. Reduced SVID probably allows usage of conventional MLC for STX-like irradiations.}, language = {en} } @article{DjuzenovaFischerKatzeretal.2021, author = {Djuzenova, Cholpon S. and Fischer, Thomas and Katzer, Astrid and Sisario, Dmitri and Korsa, Tessa and Streussloff, Gudrun and Sukhorukov, Vladimir L. and Flentje, Michael}, title = {Opposite effects of the triple target (DNA-PK/PI3K/mTOR) inhibitor PI-103 on the radiation sensitivity of glioblastoma cell lines proficient and deficient in DNA-PKcs}, series = {BMC Cancer}, volume = {21}, journal = {BMC Cancer}, doi = {10.1186/s12885-021-08930-1}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-265826}, year = {2021}, abstract = {Background: Radiotherapy is routinely used to combat glioblastoma (GBM). However, the treatment efficacy is often limited by the radioresistance of GBM cells. Methods: Two GBM lines MO59K and MO59J, differing in intrinsic radiosensitivity and mutational status of DNA-PK and ATM, were analyzed regarding their response to DNA-PK/PI3K/mTOR inhibition by PI-103 in combination with radiation. To this end we assessed colony-forming ability, induction and repair of DNA damage by gamma H2AX and 53BP1, expression of marker proteins, including those belonging to NHEJ and HR repair pathways, degree of apoptosis, autophagy, and cell cycle alterations. Results: We found that PI-103 radiosensitized MO59K cells but, surprisingly, it induced radiation resistance in MO59J cells. Treatment of MO59K cells with PI-103 lead to protraction of the DNA damage repair as compared to drug-free irradiated cells. In PI-103-treated and irradiated MO59J cells the foci numbers of both proteins was higher than in the drug-free samples, but a large portion of DNA damage was quickly repaired. Another cell line-specific difference includes diminished expression of p53 in MO59J cells, which was further reduced by PI-103. Additionally, PI-103-treated MO59K cells exhibited an increased expression of the apoptosis marker cleaved PARP and increased subG1 fraction. Moreover, irradiation induced a strong G2 arrest in MO59J cells (similar to 80\% vs. similar to 50\% in MO59K), which was, however, partially reduced in the presence of PI-103. In contrast, treatment with PI-103 increased the G2 fraction in irradiated MO59K cells. Conclusions: The triple-target inhibitor PI-103 exerted radiosensitization on MO59K cells, but, unexpectedly, caused radioresistance in the MO59J line, lacking DNA-PK. The difference is most likely due to low expression of the DNA-PK substrate p53 in MO59J cells, which was further reduced by PI-103. This led to less apoptosis as compared to drug-free MO59J cells and enhanced survival via partially abolished cell-cycle arrest. The findings suggest that the lack of DNA-PK-dependent NHEJ in MO59J line might be compensated by DNA-PK independent DSB repair via a yet unknown mechanism.}, language = {en} } @article{TamihardjaCirsiKessleretal.2021, author = {Tamihardja, J{\"o}rg and Cirsi, Sinan and Kessler, Patrick and Razinskas, Gary and Exner, Florian and Richter, Anne and Polat, B{\"u}lent and Flentje, Michael}, title = {Cone beam CT-based dose accumulation and analysis of delivered dose to the dominant intraprostatic lesion in primary radiotherapy of prostate cancer}, series = {Radiation Oncology}, volume = {16}, journal = {Radiation Oncology}, doi = {10.1186/s13014-021-01933-z}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-265656}, year = {2021}, abstract = {Background Evaluation of delivered dose to the dominant intraprostatic lesion (DIL) for moderately hypofractionated radiotherapy of prostate cancer by cone beam computed tomography (CBCT)-based dose accumulation and target coverage analysis. Methods Twenty-three patients with localized prostate cancer treated with moderately hypofractionated prostate radiotherapy with simultaneous integrated boost (SIB) between December 2016 and February 2020 were retrospectively analyzed. Included patients were required to have an identifiable DIL on bi-parametric planning magnetic resonance imaging (MRI). After import into the RayStation treatment planning system and application of a step-wise density override, the fractional doses were computed on each CBCT and were consecutively mapped onto the planning CT via a deformation vector field derived from deformable image registration. Fractional doses were accumulated for all CBCTs and interpolated for missing CBCTs, resulting in the delivered dose for PTV\(_{DIL}\), PTV\(_{Boost}\), PTV, and the organs at risk. The location of the index lesions was recorded according to the sector map of the Prostate Imaging Reporting and Data System (PIRADS) Version 2.1. Target coverage of the index lesions was evaluated and stratified for location. Results In total, 338 CBCTs were available for analysis. Dose accumulation target coverage of PTV\(_{DIL}\), PTV\(_{Boost}\), and PTV was excellent and no cases of underdosage in D\(_{Mean}\), D_95\%, D_02\%, and D_98\% could be detected. Delivered rectum D\(_{Mean}\) did not significantly differ from the planned dose. Bladder mean DMean was higher than planned with 19.4 ± 7.4 Gy versus 18.8 ± 7.5 Gy, p < 0.001. The penile bulb showed a decreased delivered mean DMean with 29.1 ± 14.0 Gy versus 29.8 ± 14.4 Gy, p < 0.001. Dorsal DILs, defined as DILs in the posterior medial peripheral zone of the prostate, showed a significantly lower delivered dose with a mean DMean difference of 2.2 Gy (95\% CI 1.3-3.1 Gy, p < 0.001) compared to ventral lesions. Conclusions CBCT-based dose accumulation showed an adequate delivered dose to the dominant intraprostatic lesion and organs at risk within planning limits. Cautious evaluation of the target coverage for index lesions adjacent to the rectum is warranted to avoid underdosage.}, language = {en} } @article{FischerHartmannReisslandetal.2022, author = {Fischer, Thomas and Hartmann, Oliver and Reissland, Michaela and Prieto-Garcia, Cristian and Klann, Kevin and Pahor, Nikolett and Sch{\"u}lein-V{\"o}lk, Christina and Baluapuri, Apoorva and Polat, B{\"u}lent and Abazari, Arya and Gerhard-Hartmann, Elena and Kopp, Hans-Georg and Essmann, Frank and Rosenfeldt, Mathias and M{\"u}nch, Christian and Flentje, Michael and Diefenbacher, Markus E.}, title = {PTEN mutant non-small cell lung cancer require ATM to suppress pro-apoptotic signalling and evade radiotherapy}, series = {Cell \& Bioscience}, volume = {12}, journal = {Cell \& Bioscience}, issn = {2045-3701}, doi = {10.1186/s13578-022-00778-7}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-299865}, year = {2022}, abstract = {Background Despite advances in treatment of patients with non-small cell lung cancer, carriers of certain genetic alterations are prone to failure. One such factor frequently mutated, is the tumor suppressor PTEN. These tumors are supposed to be more resistant to radiation, chemo- and immunotherapy. Results We demonstrate that loss of PTEN led to altered expression of transcriptional programs which directly regulate therapy resistance, resulting in establishment of radiation resistance. While PTEN-deficient tumor cells were not dependent on DNA-PK for IR resistance nor activated ATR during IR, they showed a significant dependence for the DNA damage kinase ATM. Pharmacologic inhibition of ATM, via KU-60019 and AZD1390 at non-toxic doses, restored and even synergized with IR in PTEN-deficient human and murine NSCLC cells as well in a multicellular organotypic ex vivo tumor model. Conclusion PTEN tumors are addicted to ATM to detect and repair radiation induced DNA damage. This creates an exploitable bottleneck. At least in cellulo and ex vivo we show that low concentration of ATM inhibitor is able to synergise with IR to treat PTEN-deficient tumors in genetically well-defined IR resistant lung cancer models.}, language = {en} }