609 results on '"Combs SE"'
Search Results
2. Retrospektive Analyse klinischer Verläufe von 130 Patienten mit niedergradigen Gliomen (WHOII°)
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Ahmadi, R, Herold-Mende, MC, Combs, SE, Kremer, P, Unterberg, A, and Steiner, HH
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ddc: 610 - Published
- 2005
3. Chemoradiation in patients with unresectable extrahepatic and hilar cholangiocarcinoma or at high risk for disease recurrence after resection : Analysis of treatment efficacy and failure in patients receiving postoperative or primary chemoradiation.
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Habermehl D, Lindel K, Rieken S, Haase K, Goeppert B, Büchler MW, Schirmacher P, Welzel T, Debus J, Combs SE, Habermehl, D, Lindel, K, Rieken, S, Haase, K, Goeppert, B, Büchler, M W, Schirmacher, P, Welzel, T, Debus, J, and Combs, S E
- Abstract
Background: The purpose of this work was to determine efficacy, toxicity, and patterns of recurrence after concurrent chemoradiation (CRT) in patients with extrahepatic bile duct cancer (EHBDC) and hilar cholangiocarcinoma (Klatskin tumours) in case of incomplete resection or unresectable disease.Patients and Methods: From 2003-2010, 25 patients with nonmetastasized EHBDC and hilar cholangiocarcinoma were treated with radiotherapy and CRT at our institution in an postoperative setting (10 patients, 9 patients with R1 resections) or in case of unresectable disease (15 patients). Median age was 63 years (range 38-80 years) and there were 20 men and 5 women. Median applied dose was 45 Gy in both patient groups.Results: Patients at high risk (9 times R1 resection, 1 pathologically confirmed lymphangiosis) for tumour recurrence after curative surgery had a median time to disease progression of 8.7 months and an estimated mean overall survival of 23.2 months (6 of 10 patients are still under observation). Patients undergoing combined chemoradiation in case of unresectable primary tumours are still having a poor prognosis with a progression-free survival of 7.1 months and a median overall survival of 12.0 months. The main site of progression was systemic (liver, peritoneum) in both patient groups.Conclusion: Chemoradiation with gemcitabine is safe and can be applied safely in either patients with EHBDC or Klatskin tumours at high risk for tumour recurrence after resection and patients with unresectable tumours. Escalation of systemic and local treatment should be investigated in future clinical trials. [ABSTRACT FROM AUTHOR]- Published
- 2012
4. Polysomnographic abnormalities in succinic semialdehyde dehydrogenase (SSADH) deficiency.
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Pearl PL, Shamim S, Theodore WH, Gibson KM, Forester K, Combs SE, Lewin D, Dustin I, Reeves-Tyer P, Jakobs C, and Sato S
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- 2009
5. Long-term outcome after radiotherapy in patients with atypical and malignant meningiomas-clinical results in 85 patients treated in a single institution leading to optimized guidelines for early radiation therapy.
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Adeberg S, Hartmann C, Welzel T, Rieken S, Habermehl D, von Deimling A, Debus J, and Combs SE
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- 2012
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6. A Machine Learning Approach for Predicting Biochemical Outcome After PSMA-PET-Guided Salvage Radiotherapy in Recurrent Prostate Cancer After Radical Prostatectomy: Retrospective Study.
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Janbain A, Farolfi A, Guenegou-Arnoux A, Romengas L, Scharl S, Fanti S, Serani F, Peeken JC, Katsahian S, Strouthos I, Ferentinos K, Koerber SA, Vogel ME, Combs SE, Vrachimis A, Morganti AG, Spohn SK, Grosu AL, Ceci F, Henkenberens C, Kroeze SG, Guckenberger M, Belka C, Bartenstein P, Hruby G, Emmett L, Omerieh AA, Schmidt-Hegemann NS, Mose L, Aebersold DM, Zamboglou C, Wiegel T, and Shelan M
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- Humans, Male, Retrospective Studies, Aged, Middle Aged, Positron-Emission Tomography methods, Prostate-Specific Antigen blood, Antigens, Surface metabolism, Glutamate Carboxypeptidase II metabolism, Radiotherapy, Image-Guided methods, Nomograms, Prostatic Neoplasms radiotherapy, Prostatic Neoplasms surgery, Prostatic Neoplasms diagnostic imaging, Prostatic Neoplasms pathology, Prostatectomy methods, Salvage Therapy methods, Machine Learning, Neoplasm Recurrence, Local diagnostic imaging, Neoplasm Recurrence, Local radiotherapy
- Abstract
Background: Salvage radiation therapy (sRT) is often the sole curative option in patients with biochemical recurrence after radical prostatectomy. After sRT, we developed and validated a nomogram to predict freedom from biochemical failure., Objective: This study aims to evaluate prostate-specific membrane antigen-positron emission tomography (PSMA-PET)-based sRT efficacy for postprostatectomy prostate-specific antigen (PSA) persistence or recurrence. Objectives include developing a random survival forest (RSF) model for predicting biochemical failure, comparing it with a Cox model, and assessing predictive accuracy over time. Multinational cohort data will validate the model's performance, aiming to improve clinical management of recurrent prostate cancer., Methods: This multicenter retrospective study collected data from 13 medical facilities across 5 countries: Germany, Cyprus, Australia, Italy, and Switzerland. A total of 1029 patients who underwent sRT following PSMA-PET-based assessment for PSA persistence or recurrence were included. Patients were treated between July 2013 and June 2020, with clinical decisions guided by PSMA-PET results and contemporary standards. The primary end point was freedom from biochemical failure, defined as 2 consecutive PSA rises >0.2 ng/mL after treatment. Data were divided into training (708 patients), testing (271 patients), and external validation (50 patients) sets for machine learning algorithm development and validation. RSF models were used, with 1000 trees per model, optimizing predictive performance using the Harrell concordance index and Brier score. Statistical analysis used R Statistical Software (R Foundation for Statistical Computing), and ethical approval was obtained from participating institutions., Results: Baseline characteristics of 1029 patients undergoing sRT PSMA-PET-based assessment were analyzed. The median age at sRT was 70 (IQR 64-74) years. PSMA-PET scans revealed local recurrences in 43.9% (430/979) and nodal recurrences in 27.2% (266/979) of patients. Treatment included dose-escalated sRT to pelvic lymphatics in 35.6% (349/979) of cases. The external outlier validation set showed distinct features, including higher rates of positive lymph nodes (47/50, 94% vs 266/979, 27.2% in the learning cohort) and lower delivered sRT doses (<66 Gy in 57/979, 5.8% vs 46/50, 92% of patients; P<.001). The RSF model, validated internally and externally, demonstrated robust predictive performance (Harrell C-index range: 0.54-0.91) across training and validation datasets, outperforming a previously published nomogram., Conclusions: The developed RSF model demonstrates enhanced predictive accuracy, potentially improving patient outcomes and assisting clinicians in making treatment decisions., (©Ali Janbain, Andrea Farolfi, Armelle Guenegou-Arnoux, Louis Romengas, Sophia Scharl, Stefano Fanti, Francesca Serani, Jan C Peeken, Sandrine Katsahian, Iosif Strouthos, Konstantinos Ferentinos, Stefan A Koerber, Marco E Vogel, Stephanie E Combs, Alexis Vrachimis, Alessio Giuseppe Morganti, Simon KB Spohn, Anca-Ligia Grosu, Francesco Ceci, Christoph Henkenberens, Stephanie GC Kroeze, Matthias Guckenberger, Claus Belka, Peter Bartenstein, George Hruby, Louise Emmett, Ali Afshar Omerieh, Nina-Sophie Schmidt-Hegemann, Lucas Mose, Daniel M Aebersold, Constantinos Zamboglou, Thomas Wiegel, Mohamed Shelan. Originally published in JMIR Cancer (https://cancer.jmir.org), 20.09.2024.)
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- 2024
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7. Radiomics-based prediction of local control in patients with brain metastases following postoperative stereotactic radiotherapy.
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Buchner JA, Kofler F, Mayinger M, Christ SM, Brunner TB, Wittig A, Menze B, Zimmer C, Meyer B, Guckenberger M, Andratschke N, El Shafie RA, Debus J, Rogers S, Riesterer O, Schulze K, Feldmann HJ, Blanck O, Zamboglou C, Ferentinos K, Bilger-Zähringer A, Grosu AL, Wolff R, Piraud M, Eitz KA, Combs SE, Bernhardt D, Rueckert D, Wiestler B, and Peeken JC
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- Humans, Male, Female, Retrospective Studies, Middle Aged, Aged, Prognosis, Follow-Up Studies, Adult, Radiomics, Brain Neoplasms secondary, Brain Neoplasms surgery, Brain Neoplasms diagnostic imaging, Brain Neoplasms radiotherapy, Radiosurgery methods, Magnetic Resonance Imaging methods
- Abstract
Background: Surgical resection is the standard of care for patients with large or symptomatic brain metastases (BMs). Despite improved local control after adjuvant stereotactic radiotherapy, the risk of local failure (LF) persists. Therefore, we aimed to develop and externally validate a pre-therapeutic radiomics-based prediction tool to identify patients at high LF risk., Methods: Data were collected from A Multicenter Analysis of Stereotactic Radiotherapy to the Resection Cavity of BMs (AURORA) retrospective study (training cohort: 253 patients from 2 centers; external test cohort: 99 patients from 5 centers). Radiomic features were extracted from the contrast-enhancing BM (T1-CE MRI sequence) and the surrounding edema (T2-FLAIR sequence). Different combinations of radiomic and clinical features were compared. The final models were trained on the entire training cohort with the best parameter set previously determined by internal 5-fold cross-validation and tested on the external test set., Results: The best performance in the external test was achieved by an elastic net regression model trained with a combination of radiomic and clinical features with a concordance index (CI) of 0.77, outperforming any clinical model (best CI: 0.70). The model effectively stratified patients by LF risk in a Kaplan-Meier analysis (P < .001) and demonstrated an incremental net clinical benefit. At 24 months, we found LF in 9% and 74% of the low and high-risk groups, respectively., Conclusions: A combination of clinical and radiomic features predicted freedom from LF better than any clinical feature set alone. Patients at high risk for LF may benefit from stricter follow-up routines or intensified therapy., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.)
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- 2024
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8. Bone marrow toxicity in patients with locally advanced cervical cancer undergoing multimodal treatment with VMAT/IMRT: are there dosimetric predictors for toxicity?
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Hallqvist D, Kormann C, Pigorsch S, Kiechle M, Combs SE, and Habermehl D
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- Humans, Female, Middle Aged, Adult, Radiotherapy Dosage, Aged, Retrospective Studies, Chemoradiotherapy adverse effects, Chemoradiotherapy methods, Radiotherapy Planning, Computer-Assisted methods, Combined Modality Therapy, Uterine Cervical Neoplasms radiotherapy, Uterine Cervical Neoplasms pathology, Uterine Cervical Neoplasms therapy, Radiotherapy, Intensity-Modulated adverse effects, Radiotherapy, Intensity-Modulated methods, Bone Marrow radiation effects, Bone Marrow drug effects, Bone Marrow pathology
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Purpose: For women with locoregionally advanced cervical cancer, the standard of care treatment is the curatively intended chemoradiation therapy (CRT). A relationship between bone marrow (BM) dose-volume histograms (DVHs) and acute hematological toxicity (HT) has been debated recently. Aim of this study was the evaluation of BM dose constraints and HT in a contemporary patient cohort., Methods: Radiation treatment plans of 31 patients with cervical cancer (FIGO stage IIB-IVB) treated with intensity-modulated radiotherapy and simultaneous chemotherapy were explored retrospective. Pelvic bones (PB) and femoral heads (FH) were contoured and DVHs were correlated with white blood cells (WBC), hemoglobin levels and platelets., Results: Comparing the absolute blood levels with the dose volumes of both FH and PB the data showed a significant correlation between WBC and the median dose of the FH and the median dose, V
30Gy , V40Gy and V50Gy of the PB. A correlation between the toxicity grade of anemia and mean dose, maximum dose and V5Gy of the PB was found. Counting the highest grade of HT of all three blood levels of each patient, significant correlations were found for the mean and median dose, V30Gy , V40Gy and V50Gy of the PB., Conclusion: The results show that blood levels may correlate with distinct dosimetric subvolumes of critical bone marrow compartments with a potential impact on therapeutic outcome and treatment-related toxicity. The data presented are in line with the previous findings on the relevance of dosimetric exposure of pelvic bony subvolumes., (© 2024. The Author(s).)- Published
- 2024
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9. CT-based radiomics for predicting breast cancer radiotherapy side effects.
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Llorián-Salvador Ó, Windeler N, Martin N, Etzel L, Andrade-Navarro MA, Bernhardt D, Rost B, Borm KJ, Combs SE, Duma MN, and Peeken JC
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- Humans, Female, Middle Aged, Aged, Adult, Machine Learning, Breast diagnostic imaging, Breast pathology, Breast radiation effects, Radiomics, Breast Neoplasms radiotherapy, Breast Neoplasms diagnostic imaging, Breast Neoplasms pathology, Tomography, X-Ray Computed methods
- Abstract
Skin inflammation with the potential sequel of moist epitheliolysis and edema constitute the most frequent breast radiotherapy (RT) acute side effects. The aim of this study was to compare the predictive value of tissue-derived radiomics features to the total breast volume (TBV) for the moist cells epitheliolysis as a surrogate for skin inflammation, and edema. Radiomics features were extracted from computed tomography (CT) scans of 252 breast cancer patients from two volumes of interest: TBV and glandular tissue (GT). Machine learning classifiers were trained on radiomics and clinical features, which were evaluated for both side effects. The best radiomics model was a least absolute shrinkage and selection operator (LASSO) classifier, using TBV features, predicting moist cells epitheliolysis, achieving an area under the receiver operating characteristic (AUROC) of 0.74. This was comparable to TBV breast volume (AUROC of 0.75). Combined models of radiomics and clinical features did not improve performance. Exclusion of volume-correlated features slightly reduced the predictive performance (AUROC 0.71). We could demonstrate the general propensity of planning CT-based radiomics models to predict breast RT-dependent side effects. Mammary tissue was more predictive than glandular tissue. The radiomics features performance was influenced by their high correlation to TBV volume., (© 2024. The Author(s).)
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- 2024
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10. Deep learning for autosegmentation for radiotherapy treatment planning: State-of-the-art and novel perspectives.
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Erdur AC, Rusche D, Scholz D, Kiechle J, Fischer S, Llorián-Salvador Ó, Buchner JA, Nguyen MQ, Etzel L, Weidner J, Metz MC, Wiestler B, Schnabel J, Rueckert D, Combs SE, and Peeken JC
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The rapid development of artificial intelligence (AI) has gained importance, with many tools already entering our daily lives. The medical field of radiation oncology is also subject to this development, with AI entering all steps of the patient journey. In this review article, we summarize contemporary AI techniques and explore the clinical applications of AI-based automated segmentation models in radiotherapy planning, focusing on delineation of organs at risk (OARs), the gross tumor volume (GTV), and the clinical target volume (CTV). Emphasizing the need for precise and individualized plans, we review various commercial and freeware segmentation tools and also state-of-the-art approaches. Through our own findings and based on the literature, we demonstrate improved efficiency and consistency as well as time savings in different clinical scenarios. Despite challenges in clinical implementation such as domain shifts, the potential benefits for personalized treatment planning are substantial. The integration of mathematical tumor growth models and AI-based tumor detection further enhances the possibilities for refining target volumes. As advancements continue, the prospect of one-stop-shop segmentation and radiotherapy planning represents an exciting frontier in radiotherapy, potentially enabling fast treatment with enhanced precision and individualization., (© 2024. The Author(s).)
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- 2024
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11. Membrane-bound Heat Shock Protein mHsp70 Is Required for Migration and Invasion of Brain Tumors.
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Shevtsov M, Bobkov D, Yudintceva N, Likhomanova R, Kim A, Fedorov E, Fedorov V, Mikhailova N, Oganesyan E, Shabelnikov S, Rozanov O, Garaev T, Aksenov N, Shatrova A, Ten A, Nechaeva A, Goncharova D, Ziganshin R, Lukacheva A, Sitovskaya D, Ulitin A, Pitkin E, Samochernykh K, Shlyakhto E, and Combs SE
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- Humans, Animals, Mice, Cell Line, Tumor, Female, Cell Membrane metabolism, Male, Adult, Membrane Microdomains metabolism, Brain Neoplasms pathology, Brain Neoplasms metabolism, Cell Movement drug effects, Neoplasm Invasiveness, HSP70 Heat-Shock Proteins metabolism
- Abstract
Molecular chaperones, especially 70 kDa heat shock protein, in addition to their intracellular localization in cancer cells, can be exposed on the surface of the plasma membrane. We report that the membrane-associated chaperone mHsp70 of malignant brain tumors is required for high migratory and invasive activity of cancer cells. Live-cell inverted confocal microscopy of tumor samples from adult (n = 23) and pediatric (n = 9) neurooncologic patients showed pronounced protein expression on the membrane, especially in the perifocal zone. Mass spectrometry analysis of lipid rafts isolated from tumor cells confirmed the presence of the protein in the chaperone cluster (including representatives of other families, such as Hsp70, Hsc70, Hsp105, and Hsp90), which in turn, during interactome analysis, was associated with proteins involved in cell migration (e.g., Rac1, RhoC, and myosin-9). The use of small-molecule inhibitors of HSP70 (PES and JG98) led to a substantial decrease in the invasive potential of cells isolated from a tumor sample of patients, which indicates the role of the chaperone in invasion. Moreover, the use of HSP70 inhibitors in animal models of orthotopic brain tumors significantly delayed tumor progression, which was accompanied by an increase in overall survival. Data demonstrate that chaperone inhibitors, particularly JG98, disrupt the function of mHsp70, thereby providing an opportunity to better understand the diverse functions of this protein and offer aid in the development of novel cancer therapies., Significance: Membrane-bound mHsp70 is required for brain tumor cell migration and invasion and therefore could be employed as a target for anticancer therapies., (©2024 The Authors; Published by the American Association for Cancer Research.)
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- 2024
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12. Development and benchmarking of a Deep Learning-based MRI-guided gross tumor segmentation algorithm for Radiomics analyses in extremity soft tissue sarcomas.
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Peeken JC, Etzel L, Tomov T, Münch S, Schüttrumpf L, Shaktour JH, Kiechle J, Knebel C, Schaub SK, Mayr NA, Woodruff HC, Lambin P, Gersing AS, Bernhardt D, Nyflot MJ, Menze B, Combs SE, and Navarro F
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- Humans, Male, Female, Middle Aged, Adult, Aged, Radiotherapy Planning, Computer-Assisted methods, Soft Tissue Neoplasms diagnostic imaging, Soft Tissue Neoplasms radiotherapy, Soft Tissue Neoplasms pathology, Radiomics, Deep Learning, Sarcoma diagnostic imaging, Sarcoma radiotherapy, Sarcoma pathology, Magnetic Resonance Imaging methods, Benchmarking, Extremities diagnostic imaging, Algorithms
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Background: Volume of interest (VOI) segmentation is a crucial step for Radiomics analyses and radiotherapy (RT) treatment planning. Because it can be time-consuming and subject to inter-observer variability, we developed and tested a Deep Learning-based automatic segmentation (DLBAS) algorithm to reproducibly predict the primary gross tumor as VOI for Radiomics analyses in extremity soft tissue sarcomas (STS)., Methods: A DLBAS algorithm was trained on a cohort of 157 patients and externally tested on an independent cohort of 87 patients using contrast-enhanced MRI. Manual tumor delineations by a radiation oncologist served as ground truths (GTs). A benchmark study with 20 cases from the test cohort compared the DLBAS predictions against manual VOI segmentations of two residents (ERs) and clinical delineations of two radiation oncologists (ROs). The ROs rated DLBAS predictions regarding their direct applicability., Results: The DLBAS achieved a median dice similarity coefficient (DSC) of 0.88 against the GTs in the entire test cohort (interquartile range (IQR): 0.11) and a median DSC of 0.89 (IQR 0.07) and 0.82 (IQR 0.10) in comparison to ERs and ROs, respectively. Radiomics feature stability was high with a median intraclass correlation coefficient of 0.97, 0.95 and 0.94 for GTs, ERs, and ROs, respectively. DLBAS predictions were deemed clinically suitable by the two ROs in 35% and 20% of cases, respectively., Conclusion: The results demonstrate that the DLBAS algorithm provides reproducible VOI predictions for radiomics feature extraction. Variability remains regarding direct clinical applicability of predictions for RT treatment planning., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)
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- 2024
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13. Tumor Contact With Internal Mammary Perforator Vessels as Risk Factor for Gross Internal Mammary Lymph Node Involvement in Patients With Breast Cancer.
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Behzadi ST, Moser R, Kiesl S, Nano J, Peeken JC, Fischer JC, Fallenberg EM, Huber T, Haller B, Klein E, Kiechle M, Combs SE, and Borm KJ
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- Humans, Female, Middle Aged, Risk Factors, Aged, Adult, Aged, 80 and over, Mammary Arteries diagnostic imaging, Lymphatic Metastasis, Breast Neoplasms pathology, Breast Neoplasms radiotherapy, Magnetic Resonance Imaging, Lymph Nodes pathology, Lymph Nodes diagnostic imaging, Axilla
- Abstract
Purpose: The identification of internal mammary lymph node metastases and the assessment of associated risk factors are crucial for adjuvant regional lymph node irradiation in patients with breast cancer. The current study aims to investigate whether tumor contact with internal mammary perforator vessels is associated with gross internal mammary lymph node involvement., Methods and Materials: We included 297 patients with primary breast cancer and gross internal mammary (IMN+) and/or axillary metastases as well as 230 patients without lymph node metastases. Based on pretreatment dynamic contrast-enhanced magnetic resonance imaging, we assessed contact of the tumor with the internal mammary perforating vessels (IMPV)., Results: A total of 59 patients had ipsilateral IMN+ (iIMN+), 10 patients had contralateral IMN+ (cIMN+), and 228 patients had ipsilateral axillary metastases without IMN; 230 patients had node-negative breast cancer. In patients with iIMN+, 100% of tumors had contact with ipsilateral IMPV, with 94.9% (n = 56) classified as major contact. In iIMN- patients, major IMPV contact was observed in only 25.3% (n = 116), and 36.2% (n = 166) had no IMPV contact at all. Receiver operating characteristic analysis revealed that "major IMPV contact" was more accurate in predicting iIMN+ (area under the curve, 0.85) compared with a multivariate model combining grade of differentiation, tumor site, size, and molecular subtype (area under the curve, 0.65). Strikingly, among patients with cIMN+, 100% of tumors had contact with a crossing contralateral IMPV, whereas in cIMN- patients, IMPVs to the contralateral side were observed in only 53.4% (iIMN+) and 24.8% (iIMN-), respectively., Conclusions: Tumor contact with the IMPV is highly associated with risk of gross IMN involvement. Further studies are warranted to investigate whether this identified risk factor is also associated with microscopic IMN involvement and whether it can assist in the selection of patients with breast cancer for irradiation of the internal mammary lymph nodes., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)
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- 2024
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14. Incidental dose distribution to contralateral internal mammary nodes in breast cancer patients undergoing adjuvant radiotherapy.
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Behzadi ST, Duesberg M, Moser R, Duma MN, Oechsner M, Kiesl S, Nano J, Combs SE, and Borm KJ
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Background and Purpose: In a relevant number of primary breast cancer patients, lymphatic drainage to the contralateral internal mammary nodes (cIMN) is being observed. Nevertheless, so far lymphatic drainage pathway to the cIMN is largely neglected during adjuvant radiotherapy., Materials and Methods: This study evaluated the incidental dose to the cIMN for 120 volumetric modulated arc therapy (VMAT) treatment plans for node positive breast in dependence of internal mammary node irradiation (IMNI) and deep inspiration breath hold (DIBH). Additionally, incidental dose distribution to the cIMN based on the field design in the MA20, EORTC22922/10925 and AMAROS trials was assessed., Results: The incidental dose (Dmean ± SD) to the cIMN-CTV was 13.0 (±4.7) Gy with a maximum dose of < 30 Gy in 113/120 cases. If IMNI was included (n = 80), the Dmean to the cIMN-CTV was significantly higher compared to no IMNI, but still comparably low (n = 40; 14.3 Gy vs. 9.6 Gy; p = 0.0001). Furthermore, the dose in the cIMN during free breathing (n = 80) was higher compared to DIBH (n = 40; 13.9 Gy vs. 11.2 Gy; p = 0.002).Simulated treatment plans based on the randomized RNI trials revealed neglectable dose coverage of the cIMN (Dmean 1.0-1.8 Gy) for all protocols., Conclusion: Neither in the randomized RNI trials nor during contemporary treatment techniques clinically relevant dose distribution to the cIMN was observed. Further studies are warranted to assess the potential impact of intended irradiation of cIMN in high-risk patients., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: S.E.C. received third party funding from the German Research Foundation and the European Union as well as consulting fees from Icotec AG (Switzerland), HMG Systems Engineering GmbH (Germany), Bristol Myers Squibb BMS (Germany). Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events (most speaking appointments include reimbursement of travel costs − does not apply for virtual appointments): Roche, BMS, Brainlab, AstraZeneca, Accuray, Dr. Sennewald, Daiichi Sankyo, Elekta, Medac, med update GmbH. All other authors declare that they have no conflicts of interests., (© 2024 The Authors. Published by Elsevier B.V. on behalf of European Society for Radiotherapy and Oncology.)
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- 2024
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15. Exploring molecular glioblastoma: Insights from advanced imaging for a nuanced understanding of the molecularly defined malignant biology.
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Griessmair M, Delbridge C, Ziegenfeuter J, Jung K, Mueller T, Schramm S, Bernhardt D, Schmidt-Graf F, Kertels O, Thomas M, Zimmer C, Meyer B, Combs SE, Yakushev I, Wiestler B, and Metz MC
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Background: Molecular glioblastoma (molGB) does not exhibit the histologic hallmarks of a grade 4 glioma but is nevertheless diagnosed as glioblastoma when harboring specific molecular markers. MolGB can easily be mistaken for similar-appearing lower-grade astrocytomas. Here, we investigated how advanced imaging could reflect the underlying tumor biology., Methods: Clinical and imaging data were collected for 7 molGB grade 4, 9 astrocytomas grade 2, and 12 astrocytomas grade 3. Four neuroradiologists performed VASARI-scoring of conventional imaging, and their inter-reader agreement was assessed using Fleiss κ coefficient. To evaluate the potential of advanced imaging, 2-sample t test, 1-way ANOVA, Mann-Whitney U, and Kruskal-Wallis test were performed to test for significant differences between apparent diffusion coefficient (ADC) and relative cerebral blood volume (rCBV) that were extracted fully automatically from the whole tumor volume., Results: While conventional VASARI imaging features did not allow for reliable differentiation between glioma entities, rCBV was significantly higher in molGB compared to astrocytomas for the 5th and 95th percentile, mean, and median values ( P < .05). ADC values were significantly lower in molGB than in astrocytomas for mean, median, and the 95th percentile ( P < .05). Although no molGB showed contrast enhancement initially, we observed enhancement in the short-term follow-up of 1 patient., Discussion: Quantitative analysis of diffusion and perfusion parameters shows potential in reflecting the malignant tumor biology of molGB. It may increase awareness of molGB in a nonenhancing, "benign" appearing tumor. Our results support the emerging hypothesis that molGB might present glioblastoma captured at an early stage of gliomagenesis., Competing Interests: None declared., (© The Author(s) 2024. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)
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- 2024
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16. Liquid Biopsy in Whole Blood for Identification of Gene Expression Patterns (mRNA and miRNA) Associated with Recurrence of Glioblastoma WHO CNS Grade 4.
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Muhtadi R, Bernhardt D, Multhoff G, Hönikl L, Combs SE, Krieg SM, Gempt J, Meyer B, Barsegian V, Lindemann M, Kasper M, Stewart S, Port M, Abend M, Diehl CD, and Ostheim P
- Abstract
GBM WHO CNS Grade 4 represents a major challenge for oncology due to its aggressive behavior. Conventional imaging has restrictions in detecting tumor recurrence. This prospective study aims to identify gene-based biomarkers in whole blood instead of isolating exosomes for the early detection of tumor recurrence. Blood samples (n = 33) were collected from seven GBM patients at time points before and after surgery as well as upon tumor recurrence. Four tumor tissue samples were assessed in parallel. Next-generation sequencing (NGS), including mRNA-seq and small RNA-seq, was used to analyze gene expression profiles in blood samples and tumor tissues. A novel filtering pipeline was invented to narrow down potential candidate genes. In total, between 6-93 mRNA and 1-19 small RNA candidates could be identified among the seven patients. The overlap of genes between the patients was minimal, indicating significant inter-individual variance among GBM patients. In summary, this prospective study supports the applicability of gene expression measurements in whole blood for the detection of tumor recurrence. It might provide an alternative to the challenging workflow of liquid biopsy after laborious exosome isolation from whole blood.
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- 2024
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17. Tumor Dormancy and Reactivation: The Role of Heat Shock Proteins.
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Amissah HA, Combs SE, and Shevtsov M
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- Humans, Animals, Tumor Microenvironment, Neovascularization, Pathologic metabolism, Signal Transduction, Neoplasms pathology, Neoplasms metabolism, Heat-Shock Proteins metabolism
- Abstract
Tumors are a heterogeneous group of cell masses originating in various organs or tissues. The cellular composition of the tumor cell mass interacts in an intricate manner, influenced by humoral, genetic, molecular, and tumor microenvironment cues that dictate tumor growth or suppression. As a result, tumors undergo a period of a dormant state before their clinically discernible stage, which surpasses the clinical dormancy threshold. Moreover, as a genetically imprinted strategy, early-seeder cells, a distinct population of tumor cells, break off to dock nearby or extravasate into blood vessels to secondary tissues, where they form disseminated solitary dormant tumor cells with reversible capacity. Among the various mechanisms underlying the dormant tumor mass and dormant tumor cell formation, heat shock proteins (HSPs) might play one of the most important roles in how the dormancy program plays out. It is known that numerous aberrant cellular processes, such as malignant transformation, cancer cell stemness, tumor invasion, metastasis, angiogenesis, and signaling pathway maintenance, are influenced by the HSPs. An accumulating body of knowledge suggests that HSPs may be involved in the angiogenic switch, immune editing, and extracellular matrix (ECM) remodeling cascades, crucial genetically imprinted strategies important to the tumor dormancy initiation and dormancy maintenance program. In this review, we highlight the biological events that orchestrate the dormancy state and the body of work that has been conducted on the dynamics of HSPs in a tumor mass, as well as tumor cell dormancy and reactivation. Additionally, we propose a conceptual framework that could possibly underlie dormant tumor reactivation in metastatic relapse.
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- 2024
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18. Tissue-Speci fi c Quanti fi cation of Radiation-Induced Cervical Fibrosis and Correlation with Cervical Range of Motion.
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Dapper H, Waltenberger M, Pigorsch SU, Combs SE, Bauermeister K, and Bauermeister W
- Abstract
Background: Cervical fibrosis (CF) as a late consequence in patients after radiotherapy significantly impacts the long-term symptoms, functionality, and quality of life of these cancer patients due to a hardening process of different histological tissues. Modern Shear Wave Ultrasound Elastography now enables a differentiated analysis of the changes in various tissue types. In this study, tissue-specific changes in CF induced by radiation therapy in head and neck (ENT) cancer patients were quantified and correlated with cervical range of motion (CROM)., Materials and Methods: 16 patients after radiation of the cervical lymphatic drainage were selected as the observation group (OG). Further, 16 people without radiation in the head and neck region were matched by gender, age, and BMI as the control group (CG). Stiffness measurements in kilopascal (kPa; 1 Pa = 1 N m
-2 ) were performed using shear wave elastography (SWE) to assess the elasticity of muscle, fascia, and subcutaneous tissue within and surrounding the sternocleidomastoid muscle (SCM). Specific parameters of the OG were compared to the CG and correlated with functional parameters and quality of life (QoL)., Results: The OG exhibited significantly higher stiffness values (Emean, Emax, Emin) across all tissue types than the CG, suggesting a tangible effect of radiation therapy on tissue stiffness. Muscle compartment analysis revealed the most significant stiffness differences. Thickness measurements indicated changes in the muscle and skin but not in the subcutaneous tissue. CROM measurements within the OG fell within normal ranges, suggesting a possible homogenizing effect of radiation treatment on CROM variability. Strong correlations were observed between age and specific stiffness measures, particularly in the OG group, indicating a broader impact of aging or radiation therapy on physiological measures. Significant correlations between tissue stiffness and CROM were found., Conclusion: CF after radiotherapy occurs primarily in the muscle tissue and its fascia, with the hardening being about twice as pronounced as in the average population and becoming more pronounced with increasing age and correlates with CROM., Competing Interests: Competing interests: The author(s) declare no competing interests. Conflicts of interest: The authors declare they have no conflict of interest.- Published
- 2024
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19. Resolving spatial response heterogeneity in glioblastoma.
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Ziegenfeuter J, Delbridge C, Bernhardt D, Gempt J, Schmidt-Graf F, Hedderich D, Griessmair M, Thomas M, Meyer HS, Zimmer C, Meyer B, Combs SE, Yakushev I, Metz MC, and Wiestler B
- Abstract
Purpose: Spatial intratumoral heterogeneity poses a significant challenge for accurate response assessment in glioblastoma. Multimodal imaging coupled with advanced image analysis has the potential to unravel this response heterogeneity., Methods: Based on automated tumor segmentation and longitudinal registration with follow-up imaging, we categorized contrast-enhancing voxels of 61 patients with suspected recurrence of glioblastoma into either true tumor progression (TP) or pseudoprogression (PsP). To allow the unbiased analysis of semantically related image regions, adjacent voxels with similar values of cerebral blood volume (CBV), FET-PET, and contrast-enhanced T1w were automatically grouped into supervoxels. We then extracted first-order statistics as well as texture features from each supervoxel. With these features, a Random Forest classifier was trained and validated employing a 10-fold cross-validation scheme. For model evaluation, the area under the receiver operating curve, as well as classification performance metrics were calculated., Results: Our image analysis pipeline enabled reliable spatial assessment of tumor response. The predictive model reached an accuracy of 80.0% and a macro-weighted AUC of 0.875, which takes class imbalance into account, in the hold-out samples from cross-validation on supervoxel level. Analysis of feature importances confirmed the significant role of FET-PET-derived features. Accordingly, TP- and PsP-labeled supervoxels differed significantly in their 10th and 90th percentile, as well as the median of tumor-to-background normalized FET-PET. However, CBV- and T1c-related features also relevantly contributed to the model's performance., Conclusion: Disentangling the intratumoral heterogeneity in glioblastoma holds immense promise for advancing precise local response evaluation and thereby also informing more personalized and localized treatment strategies in the future., (© 2024. The Author(s).)
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- 2024
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20. Detecting Metastatic Patterns of Oligometastatic Breast Cancer: A Comparative Analysis of 18 F-FDG PET/CT and Conventional CT Imaging.
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Moser R, Pfeiffer S, Cala L, Klein E, Kiechle M, Behzadi ST, Fallenberg E, Combs SE, Weber W, and Borm KJ
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- Humans, Female, Middle Aged, Retrospective Studies, Aged, Adult, Tomography, X-Ray Computed, Aged, 80 and over, Fluorodeoxyglucose F18, Positron Emission Tomography Computed Tomography, Breast Neoplasms diagnostic imaging, Breast Neoplasms pathology, Neoplasm Metastasis
- Abstract
Metastasis-directed therapy has the potential to improve progression-free and overall survival in oligometastatic disease (OMD). For breast cancer, however, randomized trials have failed so far to confirm this finding. Because the concept of metastasis-directed therapy in OMD is highly dependent on the accuracy of the imaging modality, we aimed to assess the impact of
18 F-FDG PET/CT on the definition of OMD in breast cancer patients. Methods: Eighty patients with a total of 15018 F-FDG PET/CT images (between October 2006 and January 2022) were enrolled in this retrospective study at the Technical University of Munich. The inclusion criteria were OMD, defined as 1-5 distant metastases, at the time of18 F-FDG PET/CT. For the current study, we systemically compared the metastatic pattern on18 F-FDG PET/CT with conventional CT. Results: At the time of18 F-FDG PET/CT, 21.3% of patients ( n = 32) had a first-time diagnosis of metastatic disease, 40.7% ( n = 61) had a previous history of OMD, and 38% ( n = 57) had a previous history of polymetastatic disease. In 45.3% of cases, the imaging modality (18 F-FDG PET/CT vs. conventional CT) had an impact on the assessment of whether OMD was present. An identical metastatic pattern was observed in only 32% of cases.18 F-FDG PET/CT detected additional metastases in 33.3% of cases, mostly in the nonregional lymph node system. Conclusion: The use of18 F-FDG PET/CT had a substantial impact on the definition of OMD and detection of metastatic pattern in breast cancer. Our results emphasize the importance of establishing a standardized definition for imaging modalities in future trials and clinical practices related to metastasis-directed therapy in breast cancer patients., (© 2024 by the Society of Nuclear Medicine and Molecular Imaging.)- Published
- 2024
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21. A survey of cancer patients' interest in undertaking exercise to promote relaxation during radiotherapy for breast cancer and metastatic cancer.
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Moser R, Mayr NA, Nano J, Behzadi ST, Kiesl S, Combs SE, and Borm KJ
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- Humans, Female, Middle Aged, Male, Prospective Studies, Aged, Surveys and Questionnaires, Adult, Quality of Life, Aged, 80 and over, Anxiety etiology, Palliative Care, Bone Neoplasms secondary, Bone Neoplasms radiotherapy, Bone Neoplasms psychology, Exercise Therapy methods, Breast Neoplasms radiotherapy, Breast Neoplasms pathology, Breast Neoplasms psychology, Relaxation Therapy
- Abstract
Background: Approximately 25-50% of patients undergoing radiotherapy (RT) experience psychological distress and anxiety, which can detrimentally affect both their quality of life and treatment outcomes. While previous research has demonstrated that relaxation exercises can enhance the tolerability of RT and alleviate associated stress and anxiety, the specific needs for such therapies in radiation oncology remain under-explored. This study aims to investigate the demand for and preferences toward relaxation exercises among radiotherapy patients, addressing a critical gap in patient-centered care., Methods: A prospective pseudonymized survey study using a one-time paper-based questionnaire was conducted from 2022 to 2023 among patients undergoing curative-intent RT for breast cancer or patients undergoing palliative RT for bone metastases. Patients were asked in a 11-item questionnaire about their anxiety, pre-existing practice of relaxation exercises/interventions, their interest in relaxation exercises, and preferences on the type and format of instruction. Data were analyzed descriptively., Results: 100 patients (74 female and 26 male) responded, of whom 68 received curative-intent adjuvant RT and 32 palliative RT. Median age was 62 years. 78% of patients indicated a desire to be actively involved in their radiotherapy, but only 27% had used relaxation exercises prior to RT. 44.8% of both curatively and palliatively treated patients who wanted to be actively involved in their therapy desired to learn how to best relax. 56.4% of respondents were willing to spend extra time learning offered exercises., Conclusion: The survey indicates that patients undergoing RT, both for curative or palliative intent, desire relaxation exercises to relieve stress and anxiety from RT. It is therefore important to assess the need for relaxation interventions in individual patients and to develop suitable programs or collaborate with other healthcare professionals to meet these needs., (© 2024. The Author(s).)
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- 2024
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22. Imaging meningioma biology: Machine learning predicts integrated risk score in WHO grade 2/3 meningioma.
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Kertels O, Delbridge C, Sahm F, Ehret F, Acker G, Capper D, Peeken JC, Diehl C, Griessmair M, Metz MC, Negwer C, Krieg SM, Onken J, Yakushev I, Vajkoczy P, Meyer B, Zips D, Combs SE, Zimmer C, Kaul D, Bernhardt D, and Wiestler B
- Abstract
Background: Meningiomas are the most common primary brain tumors. While most are benign (WHO grade 1) and have a favorable prognosis, up to one-fourth are classified as higher-grade, falling into WHO grade 2 or 3 categories. Recently, an integrated risk score (IRS) pertaining to tumor biology was developed and its prognostic relevance was validated in a large, multicenter study. We hypothesized imaging data to be reflective of the IRS. Thus, we assessed the potential of a machine learning classifier for its noninvasive prediction using preoperative magnetic resonance imaging (MRI)., Methods: In total, 160 WHO grade 2 and 3 meningioma patients from 2 university centers were included in this study. All patients underwent surgery with histopathological workup including methylation analysis. Preoperative MRI scans were automatically segmented, and radiomic parameters were extracted. Using a random forest classifier, 3 machine learning classifiers (1 multiclass classifier for IRS and 2 binary classifiers for low-risk and high-risk prediction, respectively) were developed in a training set (120 patients) and independently tested in a hold-out test set (40 patients)., Results: Multiclass IRS classification had a test set area under the curve (AUC) of 0.7, mostly driven by the difficulties in clearly separating medium-risk from high-risk patients. Consequently, a classifier predicting low-risk IRS versus medium-/high-risk showed a very high test accuracy of 90% (AUC 0.88). In particular, "sphericity" was associated with low-risk IRS classification., Conclusion: The IRS, in particular molecular low-risk, can be predicted from imaging data with high accuracy, making this important prognostic classification accessible by imaging., Competing Interests: None declared., (© The Author(s) 2024. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)
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- 2024
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23. Adjuvant re-irradiation vs. no early re-irradiation of resected recurrent glioblastoma: pooled comparative cohort analysis from two tertiary centers.
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Straube C, Combs SE, Bernhardt D, Gempt J, Meyer B, Zimmer C, Schmidt-Graf F, Vajkoczy P, Grün A, Ehret F, Zips D, and Kaul D
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- Humans, Male, Female, Middle Aged, Aged, Adult, Cohort Studies, Radiotherapy, Adjuvant, Tertiary Care Centers, DNA Modification Methylases genetics, DNA Modification Methylases metabolism, DNA Repair Enzymes genetics, DNA Repair Enzymes metabolism, Tumor Suppressor Proteins genetics, Tumor Suppressor Proteins metabolism, Glioblastoma radiotherapy, Glioblastoma surgery, Glioblastoma mortality, Brain Neoplasms radiotherapy, Brain Neoplasms surgery, Brain Neoplasms mortality, Neoplasm Recurrence, Local pathology, Re-Irradiation methods
- Abstract
Background: The optimal management strategy for recurrent glioblastoma (rGBM) remains uncertain, and the impact of re-irradiation (Re-RT) on overall survival (OS) is still a matter of debate. This study included patients who achieved gross total resection (GTR) after a second surgery after recurrence, following the GlioCave criteria., Methods: Inclusion criteria include being 18 years or older, having histologically confirmed locally recurrent IDHwt or IDH unknown GBM, achieving MRI-proven GTR after the second surgery, having a Karnofsky performance status of at least 60% after the second surgery, having a minimum interval of 6 months between the first radiotherapy and the second surgery, and a maximum of 8 weeks from second surgery to the start of Re-RT., Results: A total of 44 patients have met the inclusion criteria. The median OS after the second surgery was 14 months. All patients underwent standard treatment after initial diagnosis, including maximum safe resection, adjuvant radiochemotherapy and adjuvant chemotherapy. Re-RT did not significantly impact OS. However, MGMT promoter methylation status and a longer interval (> 12 months) between treatments were associated with better OS. Multivariate analysis revealed the MGMT status as the only significant predictor of OS., Conclusion: Factors such as MGMT promoter methylation status and treatment interval play crucial roles in determining patient outcomes after second surgery. Personalized treatment strategies should consider these factors to optimize the management of rGBM. Prospective research is needed to define the value of re-RT after second surgery and to inform decision making in this situation., (© 2024. The Author(s).)
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- 2024
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24. Radiation therapy for cancer is potentially associated with reduced growth of concomitant abdominal aortic aneurysm.
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Becker von Rose A, Kobus K, Bohmann B, Lindquist-Lilljequist M, Eilenberg W, Kapalla M, Bassermann F, Reeps C, Eckstein HH, Neumayer C, Brostjan C, Roy J, von Heckel K, Hultgren R, Schwaiger BJ, Combs SE, Busch A, and Schiller K
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- Humans, Male, Retrospective Studies, Aged, Female, Middle Aged, Aged, 80 and over, Neoplasms radiotherapy, Dose-Response Relationship, Radiation, Disease Progression, Aortic Aneurysm, Abdominal radiotherapy
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Purpose: Co-prevalence of abdominal aortic aneurysm (AAA) and cancer poses a unique challenge in medical care since both diseases and their respective therapies might interact. Recently, reduced AAA growth rates were observed in cancer patients that received radiation therapy (RT). The purpose of this study was to perform a fine-grained analysis of the effects of RT on AAA growth with respect to direct (infield) and out-of-field (outfield) radiation exposure, and radiation dose-dependency., Methods: A retrospective single-center analysis identified patients with AAA, cancer, and RT. Clinical data, radiation plans, and aneurysm diameters were analyzed. The total dose of radiation to each aneurysm was computed. AAA growth under infield and outfield exposure was compared to patients with AAA and cancer that did not receive RT (no-RT control) and to an external noncancer AAA reference cohort., Results: Between 2003 and 2020, a total of 38 AAA patients who had received well-documented RT for their malignancy were identified. AAA growth was considerably reduced for infield patients (n = 18) compared to outfield patients (n = 20), albeit not significantly (0.8 ± 1.0 vs. 1.3 ± 1.6 mm/year, p = 0.28). Overall, annual AAA growth in RT patients was lower compared to no-RT control patients (1.1 ± 1.5 vs. 1.8 ± 2.2 mm/year, p = 0.06) and significantly reduced compared to the reference cohort (1.1 ± 1.5 vs. 2.7 ± 2.1 mm/year, p < 0.001). The pattern of AAA growth reduction due to RT was corroborated in linear regression analyses correcting for initial AAA diameter. A further investigation with respect to dose-dependency of radiation effects on AAA growth, however, revealed no apparent association., Conclusion: In this study, both infield and outfield radiation exposure were associated with reduced AAA growth. This finding warrants further investigation, both in a larger scale clinical cohort and on a molecular level., (© 2023. The Author(s).)
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- 2024
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25. Quantitative Assessment of Tumor Contact with Neurogenic Zones and Its Effects on Survival: Insights beyond Traditional Predictors.
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Jung K, Kempter J, Prokop G, Herrmann T, Griessmair M, Kim SH, Delbridge C, Meyer B, Bernhardt D, Combs SE, Zimmer C, Wiestler B, Schmidt-Graf F, and Metz MC
- Abstract
So far, the cellular origin of glioblastoma (GBM) needs to be determined, with prevalent theories suggesting emergence from transformed endogenous stem cells. Adult neurogenesis primarily occurs in two brain regions: the subventricular zone (SVZ) and the subgranular zone (SGZ) of the hippocampal dentate gyrus. Whether the proximity of GBM to these neurogenic niches affects patient outcome remains uncertain. Previous studies often rely on subjective assessments, limiting the reliability of those results. In this study, we assessed the impact of GBM's relationship with the cortex, SVZ and SGZ on clinical variables using fully automated segmentation methods. In 177 glioblastoma patients, we calculated optimal cutpoints of minimal distances to the SVZ and SGZ to distinguish poor from favorable survival. The impact of tumor contact with neurogenic zones on clinical parameters, such as overall survival, multifocality, MGMT promotor methylation, Ki-67 and KPS score was also examined by multivariable regression analysis, chi-square test and Mann-Whitney-U. The analysis confirmed shorter survival in tumors contacting the SVZ with an optimal cutpoint of 14 mm distance to the SVZ, separating poor from more favorable survival. In contrast, tumor contact with the SGZ did not negatively affect survival. We did not find significant correlations with multifocality or MGMT promotor methylation in tumors contacting the SVZ, as previous studies discussed. These findings suggest that the spatial relationship between GBM and neurogenic niches needs to be assessed differently. Objective measurements disprove prior assumptions, warranting further research on this topic., Competing Interests: The authors declare no conflicts of interest.
- Published
- 2024
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26. Neuroprotection in radiotherapy of brain metastases: A pattern-of-care analysis in Germany, Austria and Switzerland by the German Society for radiation Oncology - working group Neuro-Radio-Oncology (DEGRO AG-NRO).
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Gleim N, Rühle A, Heider S, Nägler F, Giordano FA, Combs SE, Becker J, Niyazi M, Grosu AL, Nicolay NH, and Seidel C
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Background and Purpose: Many patients with solid tumors develop brain metastases (BM). With more patients surviving long-term, preservation of neurocognitive function gains importance. In recent years, several methods to delay cognitive deterioration have been tested in clinical trials. However, knowledge on the extent to which these neuroprotective strategies have been implemented in clinical practice is missing., Materials and Methods: We performed an online survey regarding treatment patterns of BM in German-speaking countries, focused on the use of neuroprotective approaches. The survey was distributed among radiation oncologists (ROs) registered within the database of the German Society for Radiation Oncology (DEGRO)., Results: Physicians of 78 centers participated in the survey. Whole brain radiotherapy (WBRT) is still preferred by 70 % of ROs over stereotactic radiotherapy (SRT) in patients with 6-10 BM. For 4-5 BM WBRT is preferred by 23 % of ROs. The fraction of ROs using hippocampal sparing (HS) in WBRT has increased to 89 %, although the technique is used on a regular basis only by a minority (26 %). The drug memantine is not widely prescribed (14% of ROs). A trend was observed for university hospitals to implement neuroprotective approaches more frequently., Conclusion: There is considerable heterogeneity regarding the treatment of BM in German-speaking countries and a general standard of care is lacking. Neuroprotective strategies are not yet standard approaches in daily clinical routine, although usage is increasing. Further clinical trials, as well as improvement of technical opportunities and reimbursement, might further shift the treatment landscape towards neuroprotective radiation treatments in the future., (© 2024 The Authors. Published by Elsevier B.V. on behalf of European Society for Radiotherapy and Oncology.)
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- 2024
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27. Multicentric Assessment of Safety and Efficacy of Combinatorial Adjuvant Brain Metastasis Treatment by Intraoperative Radiation Therapy and Immunotherapy.
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Layer JP, Shiban E, Brehmer S, Diehl CD, de Castro DG, Hamed M, Dejonckheere CS, Cifarelli DT, Friker LL, Herrlinger U, Hölzel M, Vatter H, Schneider M, Combs SE, Schmeel LC, Cifarelli CP, Giordano FA, Sarria GR, and Kahl KH
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- Humans, Prospective Studies, Retrospective Studies, Combined Modality Therapy, Immunotherapy adverse effects, Necrosis, Neoplasm Recurrence, Local, Brain Neoplasms radiotherapy, Brain Neoplasms secondary
- Abstract
Purpose: After surgical resection of brain metastases (BMs), intraoperative radiation therapy (IORT) provides a promising alternative to adjuvant external beam radiation therapy by enabling superior organ-at-risk preservation, reduction of in-hospital times, and timely admission to subsequent systemic treatments, which increasingly comprise novel targeted immunotherapeutic approaches. We sought to assess the safety and efficacy of IORT in combination with immune checkpoint inhibitors (ICIs) and other targeted therapies (TTs)., Methods and Materials: In a multicentric approach incorporating individual patient data from 6 international IORT centers, all patients with BMs undergoing IORT were retrospectively assessed for combinatorial treatment with ICIs/TTs and evaluated for toxicity and cumulative rates, including wound dehiscence, radiation necrosis, leptomeningeal spread, local control, distant brain progression (DBP), and estimated overall survival., Results: In total, 103 lesions with a median diameter of 34 mm receiving IORT combined with immunomodulatory systemic treatment or other TTs were included. The median follow-up was 13.2 (range, 1.2-102.4) months, and the median IORT dose was 25 (range, 18-30) Gy prescribed to the applicator surface. There was 1 grade 3 adverse event related to IORT recorded (2.2%). A 4.9% cumulative radiation necrosis rate was observed. The 1-year local control rate was 98.0%, and the 1-year DBP-free survival rate was 60.0%. Median time to DBP was 5.5 (range, 1.0-18.5) months in the subgroup of patients experiencing DBP, and the cumulative leptomeningeal spread rate was 4.9%. The median estimated overall survival was 26 (range, 1.2 to not reached) months with a 1-year survival rate of 74.0%. Early initiation of immunotherapy/TTs was associated with a nonsignificant trend toward improved DBP rate and overall survival., Conclusions: The combination of ICIs/TTs with IORT for resected BMs does not seem to increase toxicity and yields encouraging local control outcomes in the difficult-to-treat subgroup of larger BMs. Time gaps between surgery and systemic treatment could be shortened or avoided. The definitive role of IORT in local control after BM resection will be defined in a prospective trial., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
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- 2024
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28. DEGRO guideline for personalized radiotherapy of brain metastases and leptomeningeal carcinomatosis in patients with breast cancer.
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Borm KJ, Behzadi ST, Hörner-Rieber J, Krug D, Baumann R, Corradini S, Duma MN, Dunst J, Fastner G, Feyer P, Fietkau R, Haase W, Harms W, Hehr T, Matuschek C, Piroth MD, Schmeel LC, Souchon R, Strnad V, Budach W, and Combs SE
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- Humans, Female, Cranial Irradiation adverse effects, Neoplasm Recurrence, Local etiology, Meningeal Carcinomatosis radiotherapy, Breast Neoplasms radiotherapy, Breast Neoplasms pathology, Brain Neoplasms secondary, Radiosurgery methods
- Abstract
Purpose: The aim of this review was to evaluate the existing evidence for radiotherapy for brain metastases in breast cancer patients and provide recommendations for the use of radiotherapy for brain metastases and leptomeningeal carcinomatosis., Materials and Methods: For the current review, a PubMed search was conducted including articles from 01/1985 to 05/2023. The search was performed using the following terms: (brain metastases OR leptomeningeal carcinomatosis) AND (breast cancer OR breast) AND (radiotherapy OR ablative radiotherapy OR radiosurgery OR stereotactic OR radiation)., Conclusion and Recommendations: Despite the fact that the biological subtype of breast cancer influences both the occurrence and relapse patterns of breast cancer brain metastases (BCBM), for most scenarios, no specific recommendations regarding radiotherapy can be made based on the existing evidence. For a limited number of BCBM (1-4), stereotactic radiosurgery (SRS) or fractionated stereotactic radiotherapy (SRT) is generally recommended irrespective of molecular subtype and concurrent/planned systemic therapy. In patients with 5-10 oligo-brain metastases, these techniques can also be conditionally recommended. For multiple, especially symptomatic BCBM, whole-brain radiotherapy (WBRT), if possible with hippocampal sparing, is recommended. In cases of multiple asymptomatic BCBM (≥ 5), if SRS/SRT is not feasible or in disseminated brain metastases (> 10), postponing WBRT with early reassessment and reevaluation of local treatment options (8-12 weeks) may be discussed if a HER2/Neu-targeting systemic therapy with significant response rates in the central nervous system (CNS) is being used. In symptomatic leptomeningeal carcinomatosis, local radiotherapy (WBRT or local spinal irradiation) should be performed in addition to systemic therapy. In patients with disseminated leptomeningeal carcinomatosis in good clinical condition and with only limited or stable extra-CNS disease, craniospinal irradiation (CSI) may be considered. Data regarding the toxicity of combining systemic therapies with cranial and spinal radiotherapy are sparse. Therefore, no clear recommendations can be given, and each case should be discussed individually in an interdisciplinary setting., (© 2024. The Author(s).)
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- 2024
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29. Association of Skin Microbiome Dynamics With Radiodermatitis in Patients With Breast Cancer.
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Hülpüsch C, Neumann AU, Reiger M, Fischer JC, de Tomassi A, Hammel G, Gülzow C, Fleming M, Dapper H, Mayinger M, Vogel M, Ertl C, Combs SE, Traidl-Hoffmann C, and Borm KJ
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- Aged, Aged, 80 and over, Female, Humans, Middle Aged, Prospective Studies, Radiotherapy, Adjuvant adverse effects, Skin pathology, Adult, Breast Neoplasms pathology, Radiodermatitis etiology, Radiodermatitis prevention & control
- Abstract
Importance: The interindividual differences in severity of acute radiation dermatitis are not well understood. To date, the pathomechanism and interplay of microbiome and radiodermatitis before and during treatment remain largely unknown., Objective: To assess the association of skin microbiome baseline composition and dynamics with severity of radiodermatitis in patients undergoing adjuvant radiotherapy for breast cancer., Design, Setting, and Participants: A longitudinal prospective pilot observational study was conducted between January 2017 and January 2019. Sequencing results were received in March 2021, and the data were analyzed from August 2021 to March 2023. This study was performed at an urban academic university cancer center. A total of 21 female patients with breast cancer after surgery were consecutively approached, of which 1 patient withdrew consent before the study started., Exposure: Adjuvant radiotherapy for breast cancer for 7 weeks., Main Outcomes and Measures: The main outcome was the association of baseline skin microbiome composition and its dynamics with the severity of radiodermatitis. A total of 360 skin microbiome samples from patients were analyzed, taken before, during, and after radiotherapy, from both the treated and contralateral healthy sides. The skin microbiome samples were analyzed using 16S (V1-V3) amplicon sequencing and quantitative polymerase chain reaction bacterial enumeration., Results: Twenty female patients with breast cancer after surgery who underwent radiotherapy enrolled in the study had a median (range) age of 61 (37-81) years. The median (range) body mass index of the patients was 24.2 (17.6-38.4). The 16S sequencing revealed that low (<5%) relative abundance of commensal skin bacteria (Staphylococcus epidermidis, Staphylococcus hominis, Cutibacterium acnes) at baseline composition was associated with the development of severe radiodermatitis with an accuracy of 100% (sensitivity and specificity of 100%, P < .001). Furthermore, in patients with severe radiodermatitis, quantitative polymerase chain reaction bacterial enumeration revealed a general non-species-specific overgrowth of skin bacterial load before the onset of severe symptoms. Subsequently, the abundance of commensal bacteria increased in severe radiodermatitis, coinciding with a decline in total bacterial load., Conclusions and Relevance: The findings of this observational study indicated a potential mechanism associated with the skin microbiome for the pathogenesis of severe radiodermatitis, which may be a useful biomarker for personalized prevention of radiodermatitis in patients undergoing adjuvant radiotherapy for breast cancer.
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- 2024
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30. Single brain metastases - prognostic factors and impact of residual tumor burden on overall survival.
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Baumgart L, Anetsberger A, Aftahy AK, Wiestler B, Bernhardt D, Combs SE, Meyer HS, Schneider G, Meyer B, and Gempt J
- Abstract
Background: Brain metastases (BM) are a common and challenging issue, with their incidence on the rise due to advancements in systemic therapies and increased patient survival. Most patients present with single BM, some of them without any further extracranial metastasis (i.e., solitary BM). The significance of postoperative intracranial tumor volume in the treatment of singular and solitary BM is still debated., Objective: This study aimed to determine the impact of resection and postoperative tumor burden on overall survival (OS) in patients with single BM., Methods: Patients with surgically treated single BM between 04/2007-01/2020 were retrospectively included. Residual tumor burden (RTB) was determined by manual segmentation of early postoperative brain MRI (72 h). Survival analyses were performed using Kaplan-Meier estimates for univariate analysis and Cox regression proportional hazards model for multivariate analysis, using preoperative Karnofsky performance status scale (KPSS), age, sex, RTB, incomplete resection and singular/solitary BM as covariates., Results: 340 patients were included, median age 64 years (54-71). 119 patients (35%) had solitary BM, 221 (65%) singular BM. Complete resection (RTB=0) was achieved in 73%, median preoperative tumor burden was 11.2 cm3 (5-25), and RTB 0 cm3 (0-0.2). Median OS of patients with singular BM was 13 months (4-33) vs 20 months (5-92) for solitary BM; p=0.062. Multivariate analysis revealed singular BM as independent risk factor for poorer OS: HR 1.840 (1.202-2.817), p=0.005. Complete vs. incomplete resection showed no significant OS difference (13 vs. 13 months, p=0.737). When focusing on solitary BM, complete resection led to a longer OS than incomplete resection (21 vs. 8 months), without statistical significance(p=0.250). Achieving RTB=0 resulted in higher OS for patients with solitary BM compared to singular BM (21 vs. 12 months, p=0.027). Patients who received postoperative radiotherapy (RT) had significantly longer OS compared to those without it (14 vs. 4 months, p<0.001), with favorable OS in those receiving stereotactic radiosurgery (SRS) (15 months (3-42), p<0.001) or hypofractionated stereotactic radiotherapy (HSRT)., Conclusion: When complete intracranial tumor resection RTB=0 is achieved, patients with solitary BM have a favorable outcome compared to singular BM. Singular BM was confirmed as independent risk factor. There is a strong presumption that complete resection leads to an improved oncological prognosis. Patients with solitary BM tend to benefit with a favorable outcome following complete resection. Hence, surgical resection should be considered as a treatment option for patients presenting with either no or minimal extracranial disease. Furthermore, the highly favorable impact of postoperative RT on OS was demonstrated and confirmed, especially with SRS or HSRT., Competing Interests: BM works as consultants for Brainlab Brainlab AG, Feldkirchen. In addition, BM works as a consultant for Medtronic, Spineart, Icotec, Relievant and Depuy/Synthes, as a member of their advisory boards. Furthermore, BM reports financial relationships with Medtronic, Ulrich Medical, Brainlab, Spineart, Icotec, Relievant and Depuy/Synthes. He received personal fees and research grants for clinical studies from Medtronic, Ulrich Medical, Brainlab, Icotec and Relievant. All of this happened independently of the submitted work. BM receives royalties from and holds a patent with Spineart. All of the named potential conflicts of interest are unrelated to this study. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Baumgart, Anetsberger, Aftahy, Wiestler, Bernhardt, Combs, Meyer, Schneider, Meyer and Gempt.)
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- 2024
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31. Novel Tumor Organoid-Based Mouse Model to Study Image Guided Radiation Therapy of Rectal Cancer After Noninvasive and Precise Endoscopic Implantation.
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Felchle H, Brunner V, Groll T, Walther CN, Nefzger SM, Zaurito AE, Silva MG, Gissibl J, Topping GJ, Lansink Rotgerink L, Saur D, Steiger K, Combs SE, Tschurtschenthaler M, and Fischer JC
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- Humans, Animals, Mice, Neoplasm Recurrence, Local pathology, Combined Modality Therapy, Chemoradiotherapy, Neoadjuvant Therapy, Neoplasm Staging, Radiotherapy, Image-Guided, Rectal Neoplasms pathology
- Abstract
Purpose: Preoperative (neoadjuvant) radiation therapy (RT) is an essential part of multimodal rectal cancer therapy. Recently, total neoadjuvant therapy (TNT), which combines simultaneous radiochemotherapy with additional courses of chemotherapy, has emerged as an effective approach. TNT achieves a pathologic complete remission in approximately 30% of resected patients, opening avenues for treatment strategies that avoid radical organ resection. Furthermore, recent studies have demonstrated that anti-programmed cell death protein 1 immunotherapy can induce clinical complete responses in patients with specific genetic alterations. There is significant potential to enhance outcomes through intensifying, personalizing, and de-escalating treatment approaches. However, the heterogeneous response rates to RT or TNT and strategies to sensitize patients without specific genetic changes to immunotherapy remain poorly understood., Methods and Materials: We developed a novel orthotopic mouse model of rectal cancer based on precisely defined endoscopic injections of tumor organoids that reflect tumor heterogeneity. Subsequently, we employed endoscopic- and computed tomography-guided RT and validated rectal tumor growth and response rates to therapy using small-animal magnetic resonance imaging and endoscopic follow-up., Results: Rectal tumor formation was successfully induced in all mice after 2 organoid injections. Clinically relevant RT regimens with 5 × 5 Gy significantly delayed clinical signs of tumor progression and significantly improved survival. Consistent with human disease, rectal tumor progression correlated with the development of liver and lung metastases. Notably, long-term survivors after RT showed no evidence of tumor recurrence, as demonstrated by in vivo radiologic tumor staging and histopathologic examination., Conclusions: Our novel mouse model combines orthotopic tumor growth via noninvasive and precise rectal organoid injection and small-animal RT. This model holds significant promise for investigating the effect of tumor cell-intrinsic aspects, genetic alterations of the host, and exogenous factors (eg, nutrition or microbiota) on RT outcomes. Furthermore, it allows for the exploration of combination therapies involving chemotherapy, immunotherapy, or novel targeted therapies., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)
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- 2024
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32. Carbon ion radiotherapy of hepatocellular carcinoma provides excellent local control: The prospective phase I PROMETHEUS trial.
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Hoegen-Saßmannshausen P, Naumann P, Hoffmeister-Wittmann P, Ben Harrabi S, Seidensaal K, Weykamp F, Mielke T, Ellerbrock M, Habermehl D, Springfeld C, Dill MT, Longerich T, Schirmacher P, Mehrabi A, Chang DH, Hörner-Rieber J, Jäkel O, Haberer T, Combs SE, Debus J, Herfarth K, and Liermann J
- Abstract
Background & Aims: Inoperable hepatocellular carcinoma (HCC) can be treated by stereotactic body radiotherapy. However, carbon ion radiotherapy (CIRT) is more effective for sparing non-tumorous liver. High linear energy transfer could promote therapy efficacy. Japanese and Chinese studies on hypofractionated CIRT have yielded excellent results. Because of different radiobiological models and the different etiological spectrum of HCC, applicability of these results to European cohorts and centers remains questionable. The aim of this prospective study was to assess safety and efficacy and to determine the optimal dose of CIRT with active raster scanning based on the local effect model (LEM) I., Methods: CIRT was performed every other day in four fractions with relative biological effectiveness (RBE)-weighted fraction doses of 8.1-10.5 Gy (total doses 32.4-42.0 Gy [RBE]). Dose escalation was performed in five dose levels with at least three patients each. The primary endpoint was acute toxicity after 4 weeks., Results: Twenty patients received CIRT (median age 74.7 years, n = 16 with liver cirrhosis, Child-Pugh scores [CP] A5 [n = 10], A6 [n = 4], B8 [n = 1], and B9 [n = 1]). Median follow up was 23 months. No dose-limiting toxicities and no toxicities exceeding grade II occurred, except one grade III gamma-glutamyltransferase elevation 12 months after CIRT, synchronous to out-of-field hepatic progression. During 12 months after CIRT, no CP elevation occurred. The highest dose level could be applied safely. No local recurrence developed during follow up. The objective response rate was 80%. Median overall survival was 30.8 months (1/2/3 years: 75%/64%/22%). Median progression-free survival was 20.9 months (1/2/3 years: 59%/43%/43%). Intrahepatic progression outside of the CIRT target volume was the most frequent pattern of progression., Conclusions: CIRT of HCC yields excellent local control without dose-limiting toxicity., Impact and Implications: To date, safety and efficacy of carbon ion radiotherapy for hepatocellular carcinoma have only been evaluated prospectively in Japanese and Chinese studies. The optimal dose and fractionation when using the local effect model for radiotherapy planning are unknown. The results are of particular interest for European and American particle therapy centers, but also of relevance for all specialists involved in the treatment and care of patients with hepatocellular carcinoma, as we present the first prospective data on carbon ion radiotherapy in hepatocellular carcinoma outside of Asia. The excellent local control should encourage further use of carbon ion radiotherapy for hepatocellular carcinoma and design of randomized controlled trials., Clinical Trials Registration: The study is registered at ClinicalTrials.gov (NCT01167374)., Competing Interests: PH and JL are funded by the Physician-Scientist Program of Heidelberg University, Faculty of Medicine. PH received fees for an advisory board from NovoCure GmbH. FW received speaker fees from AstraZeneca and Merck Sharp & Dohme. JD received grants from Accuray International Sàrl, Merck Serono GmbH, CRI – The Clinical Research Institute GmbH, View Ray Inc., Accuray Incorporated, RaySearch Laboratories AB, Vision RT limited, Astellas Pharma GmbH, Astra Zeneca GmbH, Solution Akademie GmbH, Ergomed PLC Surrey Research Park, Siemens Healthcare GmbH, Quintiles GmbH, NovoCure, Pharmaceutical Research Associates GmbH, Boehringer Ingelheim Pharma GmbH Co, PTW-Freiburg Dr Pychlau GmbH, Nanobiotix A.A. and IntraOP Medical outside the submitted work. JHR received speaker fees and travel reimbursement from ViewRay Inc., travel reimbursement from IntraOP Medical and Elekta Instrument AB, and a grant from IntraOP Medical outside the submitted work. Please refer to the accompanying ICMJE disclosure forms for further details., (© 2024 The Authors.)
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- 2024
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33. Influence of intestinal microbial metabolites on the abscopal effect after radiation therapy combined with immune checkpoint inhibitors.
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Felchle H, Gissibl J, Lansink Rotgerink L, Nefzger SM, Walther CN, Timnik VR, Combs SE, and Fischer JC
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Background: Most clinical studies failed to elicit a strong antitumor immune response and subsequent systemic tumor regression after radiation therapy (RT), even in combination with the immune checkpoint inhibitors (ICI) anti-CTLA4 or anti-PD1. Mechanistically, type I interferon (IFN-I) activation is essential for the development of such abscopal effects (AE); however, mechanisms driving or limiting IFN-I activation are ill defined. Groundbreaking discoveries have shown that antibiotics (ABx) can affect oncological outcomes and that microbiota-derived metabolites can modulate systemic antitumor immunity. Recent studies have demonstrated that the bacterial metabolites desaminotyrosine (DAT) and indole-3-carboxaldehyde (ICA) can enhance IFN-I activation in models of inflammatory diseases., Materials and Methods: The subcutaneous bilateral MC38 tumor model is a widely used experimental tool to study the AE in mice. We applied it to explore the influence of broad-spectrum ABx, DAT and ICA on the AE after radioimmunotherapy (RIT). We performed 1x8 Gy of the primary tumor ± anti-CTLA4 or anti-PD1, and ± daily oral application of ABx or metabolites., Result: Combinatory ABx had neither a significant effect on tumor growth of the irradiated tumor nor on tumor progression of the abscopal tumor after RIT with anti-CTLA4. Furthermore, DAT and ICA did not significantly impact on the AE after RIT with anti-CTLA4 or anti-PD1. Surprisingly, ICA even appears to reduce outcomes after RIT with anti-CTLA4., Conclusion: We did not find a significant impact of combinatory ABx on the AE. Experimental application of the IFN-I-inducing metabolites DAT or ICA did not boost the AE after combined RIT. Additional studies are important to further investigate whether the intestinal microbiota or specific microbiota-derived metabolites modulate the AE., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Author(s).)
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- 2024
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34. Dosiomics and radiomics-based prediction of pneumonitis after radiotherapy and immune checkpoint inhibition: The relevance of fractionation.
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Kraus KM, Oreshko M, Schnabel JA, Bernhardt D, Combs SE, and Peeken JC
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- Humans, Immune Checkpoint Inhibitors adverse effects, Radiomics, Lung Neoplasms drug therapy, Lung Neoplasms radiotherapy, Radiation Oncology, Pneumonia
- Abstract
Objectives: Post-therapy pneumonitis (PTP) is a relevant side effect of thoracic radiotherapy and immunotherapy with checkpoint inhibitors (ICI). The influence of the combination of both, including dose fractionation schemes on PTP development is still unclear. This study aims to improve the PTP risk estimation after radio(chemo)therapy (R(C)T) for lung cancer with and without ICI by investigation of the impact of dose fractionation on machine learning (ML)-based prediction., Materials and Methods: Data from 100 patients who received fractionated R(C)T were collected. 39 patients received additional ICI therapy. Computed Tomography (CT), RT segmentation and dose data were extracted and physical doses were converted to 2-Gy equivalent doses (EQD2) to account for different fractionation schemes. Features were reduced using Pearson intercorrelation and the Boruta algorithm within 1000-fold bootstrapping. Six single (clinics, Dose Volume Histogram (DVH), ICI, chemotherapy, radiomics, dosiomics) and four combined models (radiomics + dosiomics, radiomics + DVH + Clinics, dosiomics + DVH + Clinics, radiomics + dosiomics + DVH + Clinics) were trained to predict PTP. Dose-based models were tested using physical dose and EQD2. Four ML-algorithms (random forest (rf), logistic elastic net regression, support vector machine, logitBoost) were trained and tested using 5-fold nested cross validation and Synthetic Minority Oversampling Technique (SMOTE) for resampling in R. Prediction was evaluated using the area under the receiver operating characteristic curve (AUC) on the test sets of the outer folds., Results: The combined model of all features using EQD2 surpassed all other models (AUC = 0.77, Confidence Interval CI 0.76-0.78). DVH, clinical data and ICI therapy had minor impact on PTP prediction with AUC values between 0.42 and 0.57. All EQD2-based models outperformed models based on physical dose., Conclusions: Radiomics + dosiomics based ML models combined with clinical and dosimetric models were found to be suited best for PTP prediction after R(C)T and could improve pre-treatment decision making. Different RT dose fractionation schemes should be considered for dose-based ML approaches., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)
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- 2024
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35. Pencil beam kernel-based dose calculations on CT data for a mixed neutron-gamma fission field applying tissue correction factors.
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Sommer LB, Kampfer S, Chemnitz T, Breitkreutz H, Combs SE, and Wilkens JJ
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- Radiotherapy Dosage, Gamma Rays therapeutic use, Neutrons, Radiometry methods, Water, Tomography, X-Ray Computed, Monte Carlo Method, Algorithms, Phantoms, Imaging, Radiotherapy Planning, Computer-Assisted methods, Thromboplastin
- Abstract
Objective. For fast neutron therapy with mixed neutron and gamma radiation at the fission neutron therapy facility MEDAPP at the research reactor FRM II in Garching, no clinical dose calculation software was available in the past. Here, we present a customized solution for research purposes to overcome this lack of three-dimensional dose calculation. Approach. The applied dose calculation method is based on two sets of decomposed pencil beam kernels for neutron and gamma radiation. The decomposition was performed using measured output factors and simulated depth dose curves and beam profiles in water as reference medium. While measurements were performed by applying the two-chamber dosimetry method, simulated data was generated using the Monte Carlo code MCNP. For the calculation of neutron dose deposition on CT data, tissue-specific correction factors were generated for soft tissue, bone, and lung tissue for the MEDAPP neutron spectrum. The pencil beam calculations were evaluated with reference to Monte Carlo calculations regarding accuracy and time efficiency. Main results. In water, dose distributions calculated using the pencil beam approach reproduced the input from Monte Carlo simulations. For heterogeneous media, an assessment of the tissue-specific correction factors with reference to Monte Carlo simulations for different tissue configurations showed promising results. Especially for scenarios where no lung tissue is present, the dose calculation could be highly improved by the applied correction method. Significance. With the presented approach, time-efficient dose calculations on CT data and treatment plan evaluations for research purposes are now available for MEDAPP., (Creative Commons Attribution license.)
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- 2024
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36. Enhanced RBE of Particle Radiation Depends on Beam Size in the Micrometer Range.
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Ilicic K, Dollinger G, Dombrowsky A, Greubel C, Girst S, Sammer M, Siebenwirth C, Schmid E, Friedrich T, Kundrát P, Friedland W, Scholz M, Combs SE, Schmid TE, and Reindl J
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- Cricetinae, Humans, Animals, Relative Biological Effectiveness, CHO Cells, Cricetulus, Dose-Response Relationship, Radiation, Ions, Protons
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High-linear energy transfer (LET) radiation, such as heavy ions is associated with a higher relative biological effectiveness (RBE) than low-LET radiation, such as photons. Irradiation with low- and high-LET particles differ in the interaction with the cellular matter and therefore in the spatial dose distribution. When a single high-LET particle interacts with matter, it results in doses of up to thousands of gray (Gy) locally concentrated around the ion trajectory, whereas the mean dose averaged over the target, such as a cell nucleus is only in the range of a Gy. DNA damage therefore accumulates in this small volume. In contrast, up to hundreds of low-LET particle hits are required to achieve the same mean dose, resulting in a quasi-homogeneous damage distribution throughout the cell nucleus. In this study, we investigated the dependence of RBE from different spatial dose depositions using different focused beam spot sizes of proton radiation with respect to the induction of chromosome aberrations and clonogenic cell survival. Human-hamster hybrid (AL) as well as Chinese hamster ovary cells (CHO-K1) were irradiated with focused low LET protons of 20 MeV (LET = 2.6 keV/µm) beam energy with a mean dose of 1.7 Gy in a quadratic matrix pattern with point spacing of 5.4 × 5.4 µm2 and 117 protons per matrix point at the ion microbeam SNAKE using different beam spot sizes between 0.8 µm and 2.8 µm (full width at half maximum). The dose-response curves of X-ray reference radiation were used to determine the RBE after a 1.7 Gy dose of radiation. The RBE for the induction of dicentric chromosomes and cell inactivation was increased after irradiation with the smallest beam spot diameter (0.8 µm for chromosome aberration experiments and 1.0 µm for cell survival experiments) compared to homogeneous proton radiation but was still below the RBE of a corresponding high LET single ion hit. By increasing the spot size to 1.6-1.8 µm, the RBE decreased but was still higher than for homogeneously distributed protons. By further increasing the spot size to 2.7-2.8 µm, the RBE was no longer different from the homogeneous radiation. Our experiments demonstrate that varying spot size of low-LET radiation gradually modifies the RBE. This underlines that a substantial fraction of enhanced RBE originates from inhomogeneous energy concentrations on the µm scale (mean intertrack distances of low-LET particles below 0.1 µm) and quantifies the link between such energy concentration and RBE. The missing fraction of RBE enhancement when comparing with high-LET ions is attributed to the high inner track energy deposition on the nanometer scale. The results are compared with model results of PARTRAC and LEM for chromosomal aberration and cell survival, respectively, which suggest mechanistic interpretations of the observed radiation effects., (© 2024 by Radiation Research Society.)
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- 2024
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37. The value of subcutaneous xenografts for individualised radiotherapy in HNSCC: Robust gene signature correlates with radiotherapy outcome in patients and xenografts.
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Linge A, Patil S, Grosser M, Lohaus F, Gurtner K, Kemper M, Gudziol V, Haim D, Nowak A, Tinhofer I, Zips D, Guberina M, Stuschke M, Balermpas P, Rödel C, Schäfer H, Grosu AL, Abdollahi A, Debus J, Ganswindt U, Belka C, Pigorsch S, Combs SE, Boeke S, Gani C, Jöhrens K, Baretton GB, Löck S, Baumann M, and Krause M
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- Humans, Animals, Mice, Squamous Cell Carcinoma of Head and Neck genetics, Squamous Cell Carcinoma of Head and Neck radiotherapy, Heterografts, Retrospective Studies, Prognosis, Head and Neck Neoplasms genetics, Head and Neck Neoplasms radiotherapy
- Abstract
Purpose: To assess the robustness of prognostic biomarkers and molecular tumour subtypes developed for patients with head and neck squamous cell carcinoma (HNSCC) on cell-line derived HNSCC xenograft models, and to develop a novel biomarker signature by combining xenograft and patient datasets., Materials and Methods: Mice bearing xenografts (n = 59) of ten HNSCC cell lines and a retrospective, multicentre patient cohort (n = 242) of the German Cancer Consortium-Radiation Oncology Group (DKTK-ROG) were included. All patients received postoperative radiochemotherapy (PORT-C). Gene expression analysis was conducted using GeneChip Human Transcriptome Arrays. Xenografts were stratified based on their molecular subtypes and previously established gene classifiers. The dose to control 50 % of tumours (TCD50) was compared between these groups. Using differential gene expression analyses combining xenograft and patient data, a gene signature was developed to define risk groups for the primary endpoint loco-regional control (LRC)., Results: Tumours of mesenchymal subtype were characterized by a higher TCD50 (xenografts, p < 0.001) and lower LRC (patients, p < 0.001) compared to the other subtypes. Similar to previously published patient data, hypoxia- and radioresistance-related gene signatures were associated with high TCD50 values. A 2-gene signature (FN1, SERPINE1) was developed that was prognostic for TCD50 (xenografts, p < 0.001) and for patient outcome in independent validation (LRC: p = 0.007)., Conclusion: Genetic prognosticators of outcome for patients after PORT-C and subcutaneous xenografts after primary clinically relevant irradiation show similarity. The identified robust 2-gene signature may help to guide patient stratification, after prospective validation. Thus, xenografts remain a valuable resource for translational research towards the development of individualized radiotherapy., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Michael Baumann, CEO and Scientific Chair of the German Cancer Research Center (DKFZ, Heidelberg) is responsible for collaborations with a large number of companies and institutions worldwide. In this capacity, he has signed contracts for research funding and/or collaborations, including commercial transfers, with industry and academia on behalf of his institute(s) and staff. He is a member of several supervisory boards, advisory boards and boards of trustees. Michael Baumann confirms that there is no conflict of interest for this paper. In the past 5 years, Dr. Mechthild Krause received funding for her research projects by IBA (2016), Merck KGaA (2014-2018 for preclinical study; 2018-2020 for clinical study), Medipan GmbH (2014-2018). Dr. Mechthild Krause and Dr. Annett Linge are involved in an ongoing publicly funded (German Federal Ministry of Education and Research) project with the companies Medipan (2019-2022), Attomol GmbH (2019-2022), GA Generic Assays GmbH (2019-2022), Gesellschaft für medizinische und wissenschaftliche genetische Analysen (2019-2022), Lipotype GmbH (2019-2022) and PolyAn GmbH (2019-2022). Dr. Krause and Dr. Linge confirm that, to the best of their knowledge, none of the above-mentioned funding sources were involved in the preparation of this paper. The Department of Radiation Oncology Tübingen receives within the frame of research agreements financial and technical support as well as sponsoring for travels and scientific symposia from Elekta AB (Stockholm, Sweden), TheraPanacea (Paris, France), Philips GmbH (Best, The Netherlands); Dr. Sennewald Medizintechnik GmbH (München, Germany), PTW Freiburg (Germany). All other co-authors declare no conflicts of interests., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)
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- 2024
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38. Identification of the unfolded protein response pathway as target for radiosensitization in pancreatic cancer.
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Kern J, Schilling D, Schneeweis C, Schmid RM, Schneider G, Combs SE, and Dobiasch S
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- Humans, Animals, Mice, Endoribonucleases genetics, Endoribonucleases metabolism, Endoribonucleases pharmacology, Protein Serine-Threonine Kinases genetics, Protein Serine-Threonine Kinases metabolism, Protein Serine-Threonine Kinases pharmacology, Cell Line, Tumor, Unfolded Protein Response, Apoptosis, Cell Proliferation, Pancreatic Neoplasms radiotherapy, Carcinoma, Pancreatic Ductal radiotherapy, Carcinoma, Pancreatic Ductal drug therapy, Carcinoma, Pancreatic Ductal genetics, Radiation-Sensitizing Agents pharmacology, Radiation-Sensitizing Agents therapeutic use, Benzenesulfonamides, Naphthalenes
- Abstract
Background and Purpose: Due to the high intrinsic radioresistance of pancreatic ductal adenocarcinoma (PDAC), radiotherapy (RT) is only beneficial in 30% of patients. Therefore, this study aimed to identify targets to improve the efficacy of RT in PDAC., Materials and Methods: Alamar Blue proliferation and colony formation assay (CFA) were used to determine the radioresponse of a cohort of 38 murine PDAC cell lines. A gene set enrichment analysis was performed to reveal differentially expressed pathways. CFA, cell cycle distribution, γH2AX FACS analysis, and Caspase 3/7 SYTOX assay were used to examine the effect of a combination treatment using KIRA8 as an IRE1α-inhibitor and Ceapin-A7 as an inhibitor against ATF6., Results: The unfolded protein response (UPR) was identified as a pathway highly expressed in radioresistant cell lines. Using the IRE1α-inhibitor KIRA8 or the ATF6-inhibitor Ceapin-A7 in combination with radiation, a radiosensitizing effect was observed in radioresistant cell lines, but no substantial alteration of the radioresponse in radiosensitive cell lines. Mechanistically, increased apoptosis by KIRA8 in combination with radiation and a cell cycle arrest in the G1 phase after ATF6 inhibition and radiation have been observed in radioresistant cell lines., Conclusion: So, our data show evidence that the UPR is involved in radioresistance of PDAC. Increased apoptosis and a G1 cell cycle arrest seem to be responsible for the radiosensitizing effect of UPR inhibition. These findings are supportive for developing novel combination treatment concepts in PDAC to overcome radioresistance., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)
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- 2024
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39. Radiotherapy concepts for spinal metastases-results from an online survey among radiation oncologists of the German Society for Radiation Oncology.
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Waltenberger M, Vogel MME, Bernhardt D, Münch S, Dobiasch S, Redmond KJ, Lo SS, Acker G, Fehlings MG, Ringel F, Vajkoczy P, Meyer B, and Combs SE
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- Humans, Radiation Oncologists, Surveys and Questionnaires, Radiation Oncology, Spinal Neoplasms radiotherapy, Spinal Neoplasms secondary, Radiosurgery methods
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Purpose: Spinal metastases (SM) are a common radiotherapy (RT) indication. There is limited level I data to drive decision making regarding dose regimen (DR) and target volume definition (TVD). We aim to depict the patterns of care for RT of SM among German Society for Radiation Oncology (DEGRO) members., Methods: An online survey on conventional RT and Stereotactic Body Radiation Therapy (SBRT) for SM, distributed via e‑mail to all DEGRO members, was completed by 80 radiation oncologists between February 24 and April 29, 2022. Participation was voluntary and anonymous., Results: A variety of DR was frequently used for conventional RT (primary: n = 15, adjuvant: n = 14). 30 Gy/10 fractions was reported most frequently. TVD in adjuvant RT was heterogenous, with a trend towards larger volumes. SBRT was offered in 65% (primary) and 21% (adjuvant) of participants' institutions. A variety of DR was reported (primary: n = 40, adjuvant: n = 27), most commonly 27 Gy/3 fractions and 30 Gy/5 fractions. 59% followed International Consensus Guidelines (ICG) for TVD., Conclusion: We provide a representative depiction of RT practice for SM among DEGRO members. DR and TVD are heterogeneous. SBRT is not comprehensively practiced, especially in the adjuvant setting. Further research is needed to provide a solid data basis for detailed recommendations., (© 2023. The Author(s).)
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- 2024
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40. In Vivo Microbeam Radiation Therapy at a Conventional Small Animal Irradiator.
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Ahmed M, Bicher S, Combs SE, Lindner R, Raulefs S, Schmid TE, Spasova S, Stolz J, Wilkens JJ, Winter J, and Bartzsch S
- Abstract
Microbeam radiation therapy (MRT) is a still pre-clinical form of spatially fractionated radiotherapy, which uses an array of micrometer-wide, planar beams of X-ray radiation. The dose modulation in MRT has proven effective in the treatment of tumors while being well tolerated by normal tissue. Research on understanding the underlying biological mechanisms mostly requires large third-generation synchrotrons. In this study, we aimed to develop a preclinical treatment environment that would allow MRT independent of synchrotrons. We built a compact microbeam setup for pre-clinical experiments within a small animal irradiator and present in vivo MRT application, including treatment planning, dosimetry, and animal positioning. The brain of an immobilized mouse was treated with MRT, excised, and immunohistochemically stained against γH2AX for DNA double-strand breaks. We developed a comprehensive treatment planning system by adjusting an existing dose calculation algorithm to our setup and attaching it to the open-source software 3D-Slicer. Predicted doses in treatment planning agreed within 10% with film dosimetry readings. We demonstrated the feasibility of MRT exposures in vivo at a compact source and showed that the microbeam pattern is observable in histological sections of a mouse brain. The platform developed in this study will be used for pre-clinical research of MRT.
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- 2024
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41. The role of molecular tumor boards in neuro-oncology: a nationwide survey.
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Hönikl LS, Lange S, Butenschoen VM, Delbridge C, Meyer B, Combs SE, Illert AL, and Schmidt-Graf F
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- Humans, Surveys and Questionnaires, Medical Oncology methods, Hospitals, University, Germany, Neoplasms genetics, Neoplasms therapy
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Background: In neuro-oncology, the inclusion of tumor patients in the molecular tumor board has only become increasingly widespread in recent years, but so far there are no standards for indication, procedure, evaluation, therapy recommendations and therapy implementation of neuro-oncological patients. The present work examines the current handling of neuro-oncological patients included in molecular tumor boards in Germany., Methods: We created an online based survey with questions covering the handling of neuro-oncologic patient inclusion, annotation of genetic analyses, management of target therapies and the general role of molecular tumor boards in neuro-oncology in Germany. We contacted all members of the Neuro-Oncology working group (NOA) of the German Cancer Society (DKG) by e-mail., Results: 38 responses were collected. The majority of those who responded were specialists in neurosurgery or neurology with more than 10 years of professional experience working at a university hospital. Molecular tumor boards (MTB) regularly take place once a week and all treatment disciplines of neuro-oncology patients take part. The inclusions to the MTB are according to distinct tumors and predominantly in case of tumor recurrence. An independently MTB member mostly create the recommendations, which are regularly implemented in the tumor treatment. Recommendations are given for alteration classes 4 and 5. Problems exist mostly within the cost takeover of experimental therapies. The experimental therapies are mostly given in the department of medical oncology., Conclusions: Molecular tumor boards for neuro-oncological patients, by now, are not standardized in Germany. Similarities exists for patient inclusion and interpretation of molecular alterations; the time point of inclusion and implementation during the patient treatment differ between the various hospitals. Further studies for standardization and harmonisation are needed. In summary, most of the interviewees envision great opportunities and possibilities for molecular-based neuro-oncological therapy in the future., (© 2024. The Author(s).)
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- 2024
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42. Enhancing outcomes: neurosurgical resection in brain metastasis patients with poor Karnofsky performance score - a comprehensive survival analysis.
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Goldberg M, Mondragon-Soto MG, Altawalbeh G, Baumgart L, Gempt J, Bernhardt D, Combs SE, Meyer B, and Aftahy AK
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Background: A reduced Karnofsky performance score (KPS) often leads to the discontinuation of surgical and adjuvant therapy, owing to a lack of evidence of survival and quality of life benefits. This study aimed to examine the clinical and treatment outcomes of patients with KPS < 70 after neurosurgical resection and identify prognostic factors associated with better survival., Methods: Patients with a preoperative KPS < 70 who underwent surgical resection for newly diagnosed brain metastases (BM) between 2007 and 2020 were retrospectively analyzed. The KPS, age, sex, tumor localization, cumulative tumor volume, number of lesions, extent of resection, prognostic assessment scores, adjuvant radiotherapy and systemic therapy, and presence of disease progression were analyzed. Univariate and multivariate logistic regression analyses were performed to determine the factors associated with better survival. Survival > 3 months was considered favorable and ≤ 3 months as poor., Results: A total of 140 patients were identified. Median overall survival was 5.6 months (range 0-58). There was no difference in the preoperative KPS between the groups of > 3 and ≤ 3 months (50; range, 20-60 vs. 50; range, 10-60, p = 0.077). There was a significant improvement in KPS after surgery in patients with a preoperative KPS of 20% (20 vs 40 ± 20, p = 0.048). In the other groups, no significant changes in KPS were observed. Adjuvant radiotherapy was associated with better survival (44 [84.6%] vs. 32 [36.4%]; hazard ratio [HR], 0.0363; confidence interval [CI], 0.197-0.670, p = 0.00199). Adjuvant chemotherapy and immunotherapy resulted in prolonged survival (24 [46.2%] vs. 12 [13.6%]; HR 0.474, CI 0.263-0.854, p = 0.013]. Systemic disease progression was associated with poor survival (36 [50%] vs. 71 [80.7%]; HR 5.975, CI 2.610-13.677, p < 0.001]., Conclusion: Neurosurgical resection is an appropriate treatment modality for patients with low KPS. Surgery may improve functional status and facilitate further tumor-specific treatment. Combined treatment with adjuvant radiotherapy and systemic therapy was associated with improved survival in this cohort of patients. Systemic tumor progression has been identified as an independent factor for a poor prognosis. There is almost no information regarding surgical and adjuvant treatment in patients with low KPS. Our paper provides novel data on clinical outcome and survival analysis of patients with BM who underwent surgical treatment., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Goldberg, Mondragon-Soto, Altawalbeh, Baumgart, Gempt, Bernhardt, Combs, Meyer and Aftahy.)
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- 2024
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43. Toward image-based personalization of glioblastoma therapy: A clinical and biological validation study of a novel, deep learning-driven tumor growth model.
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Metz MC, Ezhov I, Peeken JC, Buchner JA, Lipkova J, Kofler F, Waldmannstetter D, Delbridge C, Diehl C, Bernhardt D, Schmidt-Graf F, Gempt J, Combs SE, Zimmer C, Menze B, and Wiestler B
- Abstract
Background: The diffuse growth pattern of glioblastoma is one of the main challenges for accurate treatment. Computational tumor growth modeling has emerged as a promising tool to guide personalized therapy. Here, we performed clinical and biological validation of a novel growth model, aiming to close the gap between the experimental state and clinical implementation., Methods: One hundred and twenty-four patients from The Cancer Genome Archive (TCGA) and 397 patients from the UCSF Glioma Dataset were assessed for significant correlations between clinical data, genetic pathway activation maps (generated with PARADIGM; TCGA only), and infiltration ( D
w ) as well as proliferation (ρ) parameters stemming from a Fisher-Kolmogorov growth model. To further evaluate clinical potential, we performed the same growth modeling on preoperative magnetic resonance imaging data from 30 patients of our institution and compared model-derived tumor volume and recurrence coverage with standard radiotherapy plans., Results: The parameter ratio Dw /ρ ( P < .05 in TCGA) as well as the simulated tumor volume ( P < .05 in TCGA/UCSF) were significantly inversely correlated with overall survival. Interestingly, we found a significant correlation between 11 proliferation pathways and the estimated proliferation parameter. Depending on the cutoff value for tumor cell density, we observed a significant improvement in recurrence coverage without significantly increased radiation volume utilizing model-derived target volumes instead of standard radiation plans., Conclusions: Identifying a significant correlation between computed growth parameters and clinical and biological data, we highlight the potential of tumor growth modeling for individualized therapy of glioblastoma. This might improve the accuracy of radiation planning in the near future., Competing Interests: M.M. and F.S. serve as part-time consultants for Novocure GmbH., (© The Author(s) 2023. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)- Published
- 2023
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44. SBRT of Spinal Metastases Using a Simultaneous Integrated Boost Concept in Oligometastatic Cancer Patients Is Safe and Effective.
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Waltenberger M, Strick C, Vogel MME, Diehl C, and Combs SE
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(1) Purpose: To assess the safety and effectivity of stereotactic body radiotherapy (SBRT) on spinal metastases utilizing a simultaneous integrated boost (SIB) concept in oligometastatic cancer patients. (2) Methods: 62 consecutive patients with 71 spinal metastases received SIB-SBRT between 01/2013 and 09/2022 at our institution. We retrospectively analyzed toxicity, local tumor control (LC), and progression-free (PFS) and overall survival (OS) following SIB-SBRT and assessed possible influencing factors (Kaplan-Meier estimator, log-rank test and Cox proportional-hazards model). (3) Results: SIB-SBRT was delivered in five fractions, mostly with 25/40 Gy ( n = 43; 60.56%) and 25/35 Gy ( n = 19, 26.76%). Estimated rates of freedom from VCF were 96.1/90.4% at one/two years. VCF development was significantly associated with osteoporosis ( p < 0.001). No ≥ grade III acute and one grade III late toxicity (VCF) were observed. Estimated LC rates at one/two years were 98.6/96.4%, and histology was significantly associated with local treatment failure ( p = 0.039). Median PFS/OS was 10 months (95% CI 6.01-13.99)/not reached. Development of metastases ≥ one year after initial diagnosis and Karnofsky Performance Score ≥ 90% were predictors for superior PFS ( p = 0.038) and OS ( p = 0.012), respectively. (4) Conclusion: Spinal SIB-SBRT yields low toxicity and excellent LC. It may be utilized in selected oligometastatic patients to improve prognosis. To the best of our knowledge, we provide the first clinical data on the toxicity and effectivity of SIB-SBRT in spinal metastases in a larger patient cohort.
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- 2023
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45. Towards more Diversity in Neuro-oncology Leadership-the DivINe Initiative.
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Kurz SC, Stammberger A, Rosahl SK, Abrey LE, Albert NL, von Baumgarten L, Gempt J, Grosu AL, Leidgens V, McLean A, Renovanz M, Schwarzenberger J, Sevenich L, Urbanic Purkart T, Combs SE, Tabatabai G, Hegi M, and Nowosielski M
- Subjects
- Humans, Leadership, Medical Oncology organization & administration, Neurology organization & administration
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- 2023
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46. Emergent radiotherapy for brain and leptomeningeal metastases: a narrative review.
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Barbour AB, Zaki P, McGranahan TM, Venur V, Vellayappan B, Palmer J, Halasz LM, Yang JT, Blau M, Tseng YD, Chao ST, Suh JH, Foote M, Redmond KJ, Combs SE, Chang EL, Sahgal A, and Lo SS
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- Humans, Brain, Meningeal Carcinomatosis secondary, Brain Neoplasms radiotherapy, Brain Neoplasms secondary
- Abstract
Background and Objective: As novel systemic therapies allow patients to live longer with cancer, the risk of developing central nervous system (CNS) metastases increases and providers will more frequently encounter emergent presentation of brain metastases (BM) and leptomeningeal metastases (LM). Management of these metastases requires appropriate work-up and well-coordinated multidisciplinary care. We set out to perform a review of emergent radiotherapy (RT) for CNS metastases, specifically focusing on BM and LM., Methods: We review the appropriate pathways for workup and initial management of BM and LM, while reviewing the literature supporting emergent treatment of these entities with surgery, systemic anti-cancer therapy, and RT. To inform this narrative review, literature searches in PubMed and Google Scholar were conducted, with preference given to articles employing modern RT techniques, when applicable. Due to the paucity of high-quality evidence for management of BM and LM in the emergent setting, discussion was supplemented by the authors' expert commentary., Key Content and Findings: This work highlights the importance of surgical evaluation, particularly for patients presenting with significant mass effect, hemorrhagic metastases, or increased intracranial pressure. We review the rare situations where emergent initiation of systemic anti-cancer therapy is indicated. When defining the role of RT, we review factors guiding selection of appropriate modality, treatment volume, and dose-fractionation. Generally, 2D- or 3D-conformal treatment techniques prescribed as 30 Gy in 10 fractions or 20 Gy in 5 fractions, should be employed in the emergent setting., Conclusions: Patients with BM and LM present from a diverse array of clinical situations, requiring well-coordinated multidisciplinary management, and there is a paucity of high-quality evidence guiding such management decisions. This narrative review aims to more thoroughly prepare providers for the challenging situation of emergent management of BM and LM.
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- 2023
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47. Identifying core MRI sequences for reliable automatic brain metastasis segmentation.
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Buchner JA, Peeken JC, Etzel L, Ezhov I, Mayinger M, Christ SM, Brunner TB, Wittig A, Menze BH, Zimmer C, Meyer B, Guckenberger M, Andratschke N, El Shafie RA, Debus J, Rogers S, Riesterer O, Schulze K, Feldmann HJ, Blanck O, Zamboglou C, Ferentinos K, Bilger A, Grosu AL, Wolff R, Kirschke JS, Eitz KA, Combs SE, Bernhardt D, Rueckert D, Piraud M, Wiestler B, and Kofler F
- Abstract
Background: Many automatic approaches to brain tumor segmentation employ multiple magnetic resonance imaging (MRI) sequences. The goal of this project was to compare different combinations of input sequences to determine which MRI sequences are needed for effective automated brain metastasis (BM) segmentation., Methods: We analyzed preoperative imaging (T1-weighted sequence ± contrast-enhancement (T1/T1-CE), T2-weighted sequence (T2), and T2 fluid-attenuated inversion recovery (T2-FLAIR) sequence) from 339 patients with BMs from seven centers. A baseline 3D U-Net with all four sequences and six U-Nets with plausible sequence combinations (T1-CE, T1, T2-FLAIR, T1-CE + T2-FLAIR, T1-CE + T1 + T2-FLAIR, T1-CE + T1) were trained on 239 patients from two centers and subsequently tested on an external cohort of 100 patients from five centers., Results: The model based on T1-CE alone achieved the best segmentation performance for BM segmentation with a median Dice similarity coefficient (DSC) of 0.96. Models trained without T1-CE performed worse (T1-only: DSC = 0.70 and T2-FLAIR-only: DSC = 0.73). For edema segmentation, models that included both T1-CE and T2-FLAIR performed best (DSC = 0.93), while the remaining four models without simultaneous inclusion of these both sequences reached a median DSC of 0.81-0.89., Conclusions: A T1-CE-only protocol suffices for the segmentation of BMs. The combination of T1-CE and T2-FLAIR is important for edema segmentation. Missing either T1-CE or T2-FLAIR decreases performance. These findings may improve imaging routines by omitting unnecessary sequences, thus allowing for faster procedures in daily clinical practice while enabling optimal neural network-based target definitions., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)
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- 2023
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48. Cytoreduction of Residual Tumor Burden Is Decisive for Prolonged Survival in Patients with Recurrent Brain Metastases-Retrospective Analysis of 219 Patients.
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Lin J, Kaiser Y, Wiestler B, Bernhardt D, Combs SE, Delbridge C, Meyer B, Gempt J, and Aftahy AK
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Background: Despite advances in treatment for brain metastases (BMs), the prognosis for recurrent BMs remains poor and requires further research to advance clinical management and improve patient outcomes. In particular, data addressing the impact of tumor volume and surgical resection with regard to survival remain scarce., Methods: Adult patients with recurrent BMs between December 2007 and December 2022 were analyzed. A distinction was made between operated and non-operated patients, and the residual tumor burden (RTB) was determined by using (postoperative) MRI. Survival analysis was performed and RTB cutoff values were calculated using maximally selected log-rank statistics. In addition, further analyses on systemic tumor progression and (postoperative) tumor therapy were conducted., Results: In total, 219 patients were included in the analysis. Median age was 60 years (IQR 52-69). Median preoperative tumor burden was 2.4 cm
3 (IQR 0.8-8.3), and postoperative tumor burden was 0.5 cm3 (IQR 0.0-2.9). A total of 95 patients (43.4%) underwent surgery, and complete cytoreduction was achieved in 55 (25.1%) patients. Median overall survival was 6 months (IQR 2-10). Cutoff RTB in all patients was 0.12 cm3 , showing a significant difference ( p = 0.00029) in overall survival (OS). Multivariate analysis showed preoperative KPSS (HR 0.983, 95% CI, 0.967-0.997, p = 0.015), postoperative tumor burden (HR 1.03, 95% CI 1.008-1.053, p = 0.007), and complete vs. incomplete resection (HR 0.629, 95% CI 0.420-0.941, p = 0.024) as significant. Longer survival was significantly associated with surgery for recurrent BMs ( p = 0.00097), and additional analysis demonstrated the significant effect of complete resection on survival ( p = 0.0027). In the subgroup of patients with systemic progression, a cutoff RTB of 0.97 cm3 ( p = 0.00068) was found; patients who had received surgery also showed prolonged OS ( p = 0.036). Single systemic therapy ( p = 0.048) and the combination of radiotherapy and systemic therapy had a significant influence on survival ( p = 0.036)., Conclusions: RTB is a strong prognostic factor for survival in patients with recurrent BMs. Operated patients with recurrent BMs showed longer survival independent of systemic progression. Maximal cytoreduction should be targeted to achieve better long-term outcomes.- Published
- 2023
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49. The importance of planning CT-based imaging features for machine learning-based prediction of pain response.
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Llorián-Salvador Ó, Akhgar J, Pigorsch S, Borm K, Münch S, Bernhardt D, Rost B, Andrade-Navarro MA, Combs SE, and Peeken JC
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- Humans, ROC Curve, Machine Learning, Pain, Retrospective Studies, Tomography, X-Ray Computed methods, Neoplasms radiotherapy
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Patients suffering from painful spinal bone metastases (PSBMs) often undergo palliative radiation therapy (RT), with an efficacy of approximately two thirds of patients. In this exploratory investigation, we assessed the effectiveness of machine learning (ML) models trained on radiomics, semantic and clinical features to estimate complete pain response. Gross tumour volumes (GTV) and clinical target volumes (CTV) of 261 PSBMs were segmented on planning computed tomography (CT) scans. Radiomics, semantic and clinical features were collected for all patients. Random forest (RFC) and support vector machine (SVM) classifiers were compared using repeated nested cross-validation. The best radiomics classifier was trained on CTV with an area under the receiver-operator curve (AUROC) of 0.62 ± 0.01 (RFC; 95% confidence interval). The semantic model achieved a comparable AUROC of 0.63 ± 0.01 (RFC), significantly below the clinical model (SVM, AUROC: 0.80 ± 0.01); and slightly lower than the spinal instability neoplastic score (SINS; LR, AUROC: 0.65 ± 0.01). A combined model did not improve performance (AUROC: 0,74 ± 0,01). We could demonstrate that radiomics and semantic analyses of planning CTs allowed for limited prediction of therapy response to palliative RT. ML predictions based on established clinical parameters achieved the best results., (© 2023. Springer Nature Limited.)
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- 2023
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50. Multitask Learning with Convolutional Neural Networks and Vision Transformers Can Improve Outcome Prediction for Head and Neck Cancer Patients.
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Starke S, Zwanenburg A, Leger K, Lohaus F, Linge A, Kalinauskaite G, Tinhofer I, Guberina N, Guberina M, Balermpas P, Grün JV, Ganswindt U, Belka C, Peeken JC, Combs SE, Boeke S, Zips D, Richter C, Troost EGC, Krause M, Baumann M, and Löck S
- Abstract
Neural-network-based outcome predictions may enable further treatment personalization of patients with head and neck cancer. The development of neural networks can prove challenging when a limited number of cases is available. Therefore, we investigated whether multitask learning strategies, implemented through the simultaneous optimization of two distinct outcome objectives (multi-outcome) and combined with a tumor segmentation task, can lead to improved performance of convolutional neural networks (CNNs) and vision transformers (ViTs). Model training was conducted on two distinct multicenter datasets for the endpoints loco-regional control (LRC) and progression-free survival (PFS), respectively. The first dataset consisted of pre-treatment computed tomography (CT) imaging for 290 patients and the second dataset contained combined positron emission tomography (PET)/CT data of 224 patients. Discriminative performance was assessed by the concordance index (C-index). Risk stratification was evaluated using log-rank tests. Across both datasets, CNN and ViT model ensembles achieved similar results. Multitask approaches showed favorable performance in most investigations. Multi-outcome CNN models trained with segmentation loss were identified as the optimal strategy across cohorts. On the PET/CT dataset, an ensemble of multi-outcome CNNs trained with segmentation loss achieved the best discrimination (C-index: 0.29, 95% confidence interval (CI): 0.22-0.36) and successfully stratified patients into groups with low and high risk of disease progression (p=0.003). On the CT dataset, ensembles of multi-outcome CNNs and of single-outcome ViTs trained with segmentation loss performed best (C-index: 0.26 and 0.26, CI: 0.18-0.34 and 0.18-0.35, respectively), both with significant risk stratification for LRC in independent validation (p=0.002 and p=0.011). Further validation of the developed multitask-learning models is planned based on a prospective validation study, which has recently completed recruitment.
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- 2023
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