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Article ; Online: Evolution of a Paradigm Switch in Diagnosis and Treatment of HPV-Driven Head and Neck Cancer—Striking the Balance Between Toxicity and Cure

Bouchra Tawk / Jürgen Debus / Amir Abdollahi

Frontiers in Pharmacology, Vol

2022 Volume 12

Abstract: More than a decade after the discovery of p16 immunohistochemistry (IHC) as a surrogate for human papilloma virus (HPV)-driven head and neck squamous cell carcinoma (HNSCC), p16-IHC has become a routinely evaluated biomarker to stratify oropharyngeal ... ...

Abstract	More than a decade after the discovery of p16 immunohistochemistry (IHC) as a surrogate for human papilloma virus (HPV)-driven head and neck squamous cell carcinoma (HNSCC), p16-IHC has become a routinely evaluated biomarker to stratify oropharyngeal squamous cell carcinoma (OPSCC) into a molecularly distinct subtype with favorable clinical prognosis. Clinical trials of treatment de-escalation frequently use combinations of biomarkers (p16-IHC, HPV-RNA in situ hybridization, and amplification of HPV-DNA by PCR) to further improve molecular stratification. Implementation of these methods into clinical routine may be limited in the case of RNA by the low RNA quality of formalin-fixed paraffin-embedded tissue blocks (FFPE) or in the case of DNA by cross contamination with HPV-DNA and false PCR amplification errors. Advanced technological developments such as investigation of tumor mutational landscape (NGS), liquid-biopsies (LBx and cell-free cfDNA), and other blood-based HPV immunity surrogates (antibodies in serum) may provide novel venues to further improve diagnostic uncertainties. Moreover, the value of HPV/p16-IHC outside the oropharynx in HNSCC patients needs to be clarified. With regards to therapy, postoperative (adjuvant) or definitive (primary) radiochemotherapy constitutes cornerstones for curative treatment of HNSCC. Side effects of chemotherapy such as bone-marrow suppression could lead to radiotherapy interruption and may compromise the therapy outcome. Therefore, reduction of chemotherapy or its replacement with targeted anticancer agents holds the promise to further optimize the toxicity profile of systemic treatment. Modern radiotherapy gradually adapts the dose. Higher doses are administered to the visible tumor bulk and positive lymph nodes, while a lower dose is prescribed to locoregional volumes empirically suspected to be invaded by tumor cells. Further attempts for radiotherapy de-escalation may improve acute toxicities, for example, the rates for dysphagia and feeding tube requirement, or ...
Keywords	head and neck (H&N) cancer ; human papilloma virus—HPV ; radiotherapy ; oropharyngeal cancer (OPC) ; precision medicine ; de-intensification trials ; Therapeutics. Pharmacology ; RM1-950
Subject code	610 ; 616
Language	English
Publishing date	2022-01-01T00:00:00Z
Publisher	Frontiers Media S.A.
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Do We Preserve Tumor Control Probability (TCP) in FLASH Radiotherapy? A Model-Based Analysis

Hans Liew / Stewart Mein / Thomas Tessonnier / Amir Abdollahi / Jürgen Debus / Ivana Dokic / Andrea Mairani

International Journal of Molecular Sciences, Vol 24, Iss 5118, p

2023 Volume 5118

Abstract: Reports of concurrent sparing of normal tissue and iso-effective treatment of tumors at ultra-high dose-rates (uHDR) have fueled the growing field of FLASH radiotherapy. However, iso-effectiveness in tumors is often deduced from the absence of a ... ...

Abstract	Reports of concurrent sparing of normal tissue and iso-effective treatment of tumors at ultra-high dose-rates (uHDR) have fueled the growing field of FLASH radiotherapy. However, iso-effectiveness in tumors is often deduced from the absence of a significant difference in their growth kinetics. In a model-based analysis, we investigate the meaningfulness of these indications for the clinical treatment outcome. The predictions of a previously benchmarked model of uHDR sparing in the “UNIfied and VERSatile bio response Engine” (UNIVERSE) are combined with existing models of tumor volume kinetics as well as tumor control probability (TCP) and compared to experimental data. The potential TCP of FLASH radiotherapy is investigated by varying the assumed dose-rate, fractionation schemes and oxygen concentration in the target. The developed framework describes the reported tumor growth kinetics appropriately, indicating that sparing effects could be present in the tumor but might be too small to be detected with the number of animals used. The TCP predictions show the possibility of substantial loss of treatment efficacy for FLASH radiotherapy depending on several variables, including the fractionation scheme, oxygen level, and DNA repair kinetics. The possible loss of TCP should be seriously considered when assessing the clinical viability of FLASH treatments.
Keywords	ionizing radiation ; FLASH ; UNIVERSE ; dose-rate ; DNA repair ; modeling ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
Subject code	660
Language	English
Publishing date	2023-03-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Cost-effectiveness analysis (CEA) of IMRT plus C12 boost vs IMRT only in adenoid cystic carcinoma (ACC) of the head and neck

A D Jensen / Jürgen Debus

Radiation Oncology, Vol 14, Iss 1, Pp 1-

2019 Volume 9

Abstract: Abstract Background Particle therapy provides steep dose gradients to facilitate dose escalation in challenging anatomical sites which has been shown not only to improve local control but also overall survival in patients with ACC. Cost-effectiveness of ... ...

Abstract	Abstract Background Particle therapy provides steep dose gradients to facilitate dose escalation in challenging anatomical sites which has been shown not only to improve local control but also overall survival in patients with ACC. Cost-effectiveness of intensity-modulated radiotherapy (IMRT) plus carbon ion (C12) boost vs IMRT alone was performed in order to objectivise and substantiate more widespread use of this technology in ACC. Methods Patients with pathologically confirmed ACC received a combination regimen of IMRT plus C12 boost. Patients presenting outside C12 treatment slots received IMRT only. Clinical results were published; economic analysis on patient-level data was carried out from a healthcare purchaser’s perspective based on costs of healthcare utilization. Cost histories were generated from resource use recorded in individual patient charts and adjusted for censoring using the Lin I method. Cost-effectiveness was measured as incremental cost-effectiveness ratio (ICER). Sensitivity analysis was performed regarding potentially differing management of recurrent disease. Results The experimental treatment increased overall costs by € 18,076 (€13,416 – €22,922) at a mean survival benefit of 0.86 years. Despite improved local control, following costs were also increased in the experimental treatment. The ICER was estimated to 26,863 €/LY. After accounting for different management of recurrent disease in the two cohorts, the ICER was calculated to 20,638 €/LY. Conclusion The combined treatment (IMRT+C12 boost) substantially increased initial and overall treatment cost. In view of limited treatment options in ACC, costs may be acceptable though. Investigations into quality of life measures may support further decisions in the future.
Keywords	Cost-effectiveness ; CEA ; IMRT ; C12 ; Adenoid cystic carcinoma ; ACC ; Medical physics. Medical radiology. Nuclear medicine ; R895-920 ; Neoplasms. Tumors. Oncology. Including cancer and carcinogens ; RC254-282
Subject code	616
Language	English
Publishing date	2019-11-01T00:00:00Z
Publisher	BMC
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: modelBuildR

Maximilian Knoll / Jennifer Furkel / Juergen Debus / Amir Abdollahi

PeerJ, Vol 9, p e

an R package for model building and feature selection with erroneous classifications

2021 Volume 10849

Abstract: Background Model building is a crucial part of omics based biomedical research to transfer classifications and obtain insights into underlying mechanisms. Feature selection is often based on minimizing error between model predictions and given ... ...

Abstract	Background Model building is a crucial part of omics based biomedical research to transfer classifications and obtain insights into underlying mechanisms. Feature selection is often based on minimizing error between model predictions and given classification (maximizing accuracy). Human ratings/classifications, however, might be error prone, with discordance rates between experts of 5–15%. We therefore evaluate if a feature pre-filtering step might improve identification of features associated with true underlying groups. Methods Data was simulated for up to 100 samples and up to 10,000 features, 10% of which were associated with the ground truth comprising 2–10 normally distributed populations. Binary and semi-quantitative ratings with varying error probabilities were used as classification. For feature preselection standard cross-validation (V2) was compared to a novel heuristic (V1) applying univariate testing, multiplicity adjustment and cross-validation on switched dependent (classification) and independent (features) variables. Preselected features were used to train logistic regression/linear models (backward selection, AIC). Predictions were compared against the ground truth (ROC, multiclass-ROC). As use case, multiple feature selection/classification methods were benchmarked against the novel heuristic to identify prognostically different G-CIMP negative glioblastoma tumors from the TCGA-GBM 450 k methylation array data cohort, starting from a fuzzy umap based rough and erroneous separation. Results V1 yielded higher median AUC ranks for two true groups (ground truth), with smaller differences for true graduated differences (3–10 groups). Lower fractions of models were successfully fit with V1. Median AUCs for binary classification and two true groups were 0.91 (range: 0.54–1.00) for V1 (Benjamini-Hochberg) and 0.70 (0.28–1.00) for V2, 13% (n = 616) of V2 models showed AUCs < = 50% for 25 samples and 100 features. For larger numbers of features and samples, median AUCs were 0.75 (range 0.59–1.00) for ...
Keywords	Feature selection ; Misclassification ; Model building ; Ground truth ; High dimensional data ; Glioblastoma multiforme ; Medicine ; R ; Biology (General) ; QH301-705.5
Subject code	519
Language	English
Publishing date	2021-02-01T00:00:00Z
Publisher	PeerJ Inc.
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Biosensor Cell-Fit-HD4D for correlation of single-cell fate and microscale energy deposition in complex ion beams

Julian Schlegel / Hans Liew / Katrin Rein / Oleh Dzyubachyk / Jürgen Debus / Amir Abdollahi / Martin Niklas

STAR Protocols, Vol 3, Iss 4, Pp 101798- (2022)

2022

Abstract: Summary: We present a protocol for the biosensor Cell-Fit-HD4D. It enables long-term monitoring and correlation of single-cell fate with subcellular-deposited energy of ionizing radiation. Cell fate tracking using widefield time-lapse microscopy is ... ...

Abstract	Summary: We present a protocol for the biosensor Cell-Fit-HD4D. It enables long-term monitoring and correlation of single-cell fate with subcellular-deposited energy of ionizing radiation. Cell fate tracking using widefield time-lapse microscopy is uncoupled in time from confocal ion track imaging. Registration of both image acquisition steps allows precise ion track assignment to cells and correlation with cellular readouts.For complete details on the use and execution of this protocol, please refer to Niklas et al. (2022). : Publisher’s note: Undertaking any experimental protocol requires adherence to local institutional guidelines for laboratory safety and ethics.
Keywords	Biophysics ; Biotechnology and bioengineering ; Cancer ; Microscopy ; Molecular biology ; Molecular/Chemical probes ; Science (General) ; Q1-390
Language	English
Publishing date	2022-12-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Cetuximab, gemcitabine and radiotherapy in locally advanced pancreatic cancer

Jakob Liermann / Marc Munter / Patrick Naumann / Amir Abdollahi / Robert Krempien / Juergen Debus

Clinical and Translational Radiation Oncology, Vol 34, Iss , Pp 15-

Long-term results of the randomized controlled phase II PARC trial

2022 Volume 22

Abstract: Purpose: Addressing the epidermal growth factor receptor (EGFR)-pathway by the competitive receptor ligand cetuximab is a promising strategy in pancreatic cancer. In the prospective randomized controlled phase II PARC-study (PARC: Pancreatic cancer ... ...

Abstract	Purpose: Addressing the epidermal growth factor receptor (EGFR)-pathway by the competitive receptor ligand cetuximab is a promising strategy in pancreatic cancer. In the prospective randomized controlled phase II PARC-study (PARC: Pancreatic cancer treatment with radiotherapy (RT) and cetuximab), we evaluated safety and efficacy of a trimodal treatment scheme consisting of cetuximab, gemcitabine and RT in locally advanced pancreatic cancer (LAPC). Methods: Between January 2005 and April 2007, 68 patients with inoperable pancreatic ductal adenocarcinoma were randomized in either trimodal therapy followed by gemcitabine maintenance (Arm A) or in trimodal therapy followed by gemcitabine plus cetuximab maintenance (Arm B). Intensity-modulated RT (IMRT) was performed with a total dose of 45 Gy in 25 fractions and with a simultaneous integrated boost to the gross tumor (54 Gy). Within the trimodal therapy, gemcitabine and cetuximab were administered weekly. Maintenance therapy consisted of gemcitabine only or gemcitabine plus cetuximab. Toxicity, overall survival (OS), secondary resection rate, local control and progression free survival (PFS) were evaluated. Results: With a median followup time of 13 months (range: 2 – 184 months), one patient is still alive and one patient is lost to follow-up. Nausea and gastrointestinal hemorrhage were the most important higher-graded (>°II) acute and late non-hematological toxicity (13% and 7%). Median OS was 13.1 months without significant difference between both treatment arms (Arm A: 11.9 months; Arm B: 14.2 months). Compared to historical data, cetuximab did not improve OS. One- and two-year local control rates were 76.6% and 68.9%. Local tumor control and secondary resection rate (Arm A: 4%; Arm B: 16%) were significantly improved in Arm B. Median PFS was 6.8 months with distant metastasis as main treatment failure. Conclusion: Trimodal therapy consisting of IMRT, gemcitabine and cetuximab can be considered safe and feasible. Compared to historical data, cetuximab does ...
Keywords	Pancreatic cancer ; Cetuximab ; Locally advanced pancreatic cancer ; Chemoradiation ; Pancreatic ductal adenocarcinoma ; Medical physics. Medical radiology. Nuclear medicine ; R895-920 ; Neoplasms. Tumors. Oncology. Including cancer and carcinogens ; RC254-282
Subject code	610
Language	English
Publishing date	2022-05-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: The Impact of Sub-Millisecond Damage Fixation Kinetics on the In Vitro Sparing Effect at Ultra-High Dose Rate in UNIVERSE

Hans Liew / Stewart Mein / Thomas Tessonnier / Amir Abdollahi / Jürgen Debus / Ivana Dokic / Andrea Mairani

International Journal of Molecular Sciences, Vol 23, Iss 2954, p

2022 Volume 2954

Abstract: The impact of the exact temporal pulse structure on the potential cell and tissue sparing of ultra-high dose-rate irradiation applied in FLASH studies has gained increasing attention. A previous version of our biophysical mechanistic model (UNIVERSE: ... ...

Abstract	The impact of the exact temporal pulse structure on the potential cell and tissue sparing of ultra-high dose-rate irradiation applied in FLASH studies has gained increasing attention. A previous version of our biophysical mechanistic model (UNIVERSE: UNIfied and VERSatile bio response Engine), based on the oxygen depletion hypothesis, has been extended in this work by considering oxygen-dependent damage fixation dynamics on the sub-milliseconds scale and introducing an explicit implementation of the temporal pulse structure. The model successfully reproduces in vitro experimental data on the fast kinetics of the oxygen effect in irradiated mammalian cells. The implemented changes result in a reduction in the assumed amount of oxygen depletion. Furthermore, its increase towards conventional dose-rates is parameterized based on experimental data from the literature. A recalculation of previous benchmarks shows that the model retains its predictive power, while the assumed amount of depleted oxygen approaches measured values. The updated UNIVERSE could be used to investigate the impact of different combinations of pulse structure parameters (e.g., dose per pulse, pulse frequency, number of pulses, etc.), thereby aiding the optimization of potential clinical application and the development of suitable accelerators.
Keywords	ionizing radiation ; FLASH ; UNIVERSE ; modeling ; ultra-high dose rate ; temporal pulse structure ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
Subject code	600
Language	English
Publishing date	2022-03-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Leaf-individual calibration for a double stack multileaf collimator in photon radiotherapy

Carolin Rippke / C. Katharina Renkamp / Charbel Attieh / Fabian Schlüter / Carolin Buchele / Jürgen Debus / Markus Alber / Sebastian Klüter

Physics and Imaging in Radiation Oncology, Vol 27, Iss , Pp 100477- (2023)

2023

Abstract: Background and Purpose: In online adaptive stereotactic body radiotherapy treatments, linear accelerator delivery accuracy is essential. Recently introduced double stack multileaf collimators (MLCs) have new facets in their calibration. We established a ... ...

Abstract	Background and Purpose: In online adaptive stereotactic body radiotherapy treatments, linear accelerator delivery accuracy is essential. Recently introduced double stack multileaf collimators (MLCs) have new facets in their calibration. We established a radiation-based leaf-individual calibration (LIMCA) method for double stack MLCs. Materials and Methods: MLC leaf positions were evaluated from four cardinal angles with test patterns at measurement positions throughout the radiation field on EBT3 radiochromic film for each single stack. The accuracy of the method and repeatability of the results were assessed. The effect of MLC positioning errors was characterized for a measured output factor curve and a clinical patient plan. Results: All positions in the motor step – position calibration file were optimized in the established LIMCA method. The resulting double stack mean accuracy for all angles was 0.2 ± 0.1 mm for X1 (left bank) and 0.2 ± 0.2 mm for X2 (right bank). The accuracy of the leaf position evaluation was 0.2 mm (95% confidence level). The MLC calibration remained stable over four months. Small MLC leaf position errors (e.g. 1.2 mm field size reduction) resulted in important dose errors (−5.8 %) for small quadratic fields of 0.83 × 0.83 cm2. Single stack position accuracy was essential for highly modulated treatment plans. Conclusions: LIMCA is a new double stack MLC calibration method that increases treatment accuracy from four angles and for all moving leaves.
Keywords	MR-Linac ; Adaptive radiotherapy ; Image guided radiotherapy ; MR-guided radiotherapy ; Quality assurance ; Quality control ; Medical physics. Medical radiology. Nuclear medicine ; R895-920 ; Neoplasms. Tumors. Oncology. Including cancer and carcinogens ; RC254-282
Subject code	620
Language	English
Publishing date	2023-07-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Modeling Direct and Indirect Action on Cell Survival After Photon Irradiation under Normoxia and Hypoxia

Hans Liew / Stewart Mein / Jürgen Debus / Ivana Dokic / Andrea Mairani

International Journal of Molecular Sciences, Vol 21, Iss 3471, p

2020 Volume 3471

Abstract: The demand for personalized medicine in radiotherapy has been met by a surge of mechanistic models offering predictions of the biological effect of ionizing radiation under consideration of a growing number of parameters. We present an extension of our ... ...

Abstract	The demand for personalized medicine in radiotherapy has been met by a surge of mechanistic models offering predictions of the biological effect of ionizing radiation under consideration of a growing number of parameters. We present an extension of our existing model of cell survival after photon irradiation to explicitly differentiate between the damage inflicted by the direct and indirect (radicals-mediated) action of ionizing radiation. Within our approach, we assume that the oxygenation status affects the indirect action. The effect of different concentrations of dimethyl sulfoxide (DMSO), an effective radical scavenger, has been simulated at different dose levels in normoxic and hypoxic conditions for various cell lines. Our model is found to accurately predict experimental data available in literature, validating the assumptions made in our approach. The presented extension adds further flexibility to our model and could act as basis for further developments of our model.
Keywords	ionizing radiation ; direct and indirect damage ; hypoxia ; modeling ; DMSO ; radicals ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
Language	English
Publishing date	2020-05-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Impact of DNA Repair Kinetics and Dose Rate on RBE Predictions in the UNIVERSE

Hans Liew / Stewart Mein / Thomas Tessonnier / Christian P. Karger / Amir Abdollahi / Jürgen Debus / Ivana Dokic / Andrea Mairani

International Journal of Molecular Sciences, Vol 23, Iss 6268, p

2022 Volume 6268

Abstract: Accurate knowledge of the relative biological effectiveness (RBE) and its dependencies is crucial to support modern ion beam therapy and its further development. However, the influence of different dose rates of the reference radiation and ion beam are ... ...

Abstract	Accurate knowledge of the relative biological effectiveness (RBE) and its dependencies is crucial to support modern ion beam therapy and its further development. However, the influence of different dose rates of the reference radiation and ion beam are rarely considered. The ion beam RBE-model within our “UNIfied and VERSatile bio response Engine” (UNIVERSE) is extended by including DNA damage repair kinetics to investigate the impact of dose-rate effects on the predicted RBE. It was found that dose-rate effects increase with dose and biological effects saturate at high dose-rates, which is consistent with data- and model-based studies in the literature. In a comparison with RBE measurements from a high dose in-vivo study, the predictions of the presented modification were found to be improved in comparison to the previous version of UNIVERSE and existing clinical approaches that disregard dose-rate effects. Consequently, DNA repair kinetics and the different dose rates applied by the reference and ion beams might need to be considered in biophysical models to accurately predict the RBE. Additionally, this study marks an important step in the further development of UNIVERSE, extending its capabilities in giving theoretical guidance to support progress in ion beam therapy.
Keywords	ionizing radiation ; ion beam therapy ; UNIVERSE ; dose rate ; DNA repair ; modeling ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
Subject code	616
Language	English
Publishing date	2022-06-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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