Investigating the impact of breast positioning control on physical treatment parameters in multi-catheter breast brachytherapy.

PURPOSE: To assess the effects of a workflow for reproducible patient and breast positioning on implant stability during high-dose-rate multi-catheter breast brachytherapy. METHODS: Thirty patients were treated with our new positioning control workflow. Implant stability was evaluated based on a comparison of planning-CTs to control-CTs acquired halfway through the treatment. To assess geometric stability, button-button distance variations as well as Euclidean dwell position deviations were evaluated. The latter were also quantified within various separated regions within the breast to investigate the location-dependency of implant alterations. Furthermore, dosimetric variations to target volume and organs at risk (ribs, skin) as well as isodose volume changes were analyzed. Results were compared to a previously treated cohort of 100 patients. RESULTS: With the introduced workflow, the patient fraction affected by button-button distance variations > 5 mm and by dwell position deviations > 7 mm were reduced from 37% to 10% and from 30% to 6.6%, respectively. Implant stability improved the most in the lateral to medial breast regions. Only small stability enhancements were observed regarding target volume dosimetry, but the stability of organ at risk exposure became substantially higher. D0.2ccm skin dose variations > 12.4% and D0.1ccm rib dose variations > 6.7% were reduced from 11% to 0% and from 16% to 3.3% of all patients, respectively. CONCLUSION: Breast positioning control improved geometric and dosimetric implant stability for individual patients, and thus enhanced physical plan validity in these cases.

Initial needle tracking with the first standalone combined infrared camera - CT system for brachytherapy-analysis of tracking accuracy and uncertainties.

PURPOSE: A prototype infrared camera - cone-beam computed tomography (CBCT) system for tracking in brachytherapy has recently been developed. We evaluated for the first time the corresponding tracking accuracy and uncertainties, and implemented a tracking-based prediction of needles on CBCT scans. METHODS: A marker tool rigidly attached to needles was 3D printed. The precision and accuracy of tool tracking was then evaluated for both static and dynamic scenarios. Euclidean distances between the tracked and CBCT-derived markers were assessed as well. To implement needle tracking, ground truth models of the tool attached to 200 mm and 160 mm needles were matched to the tracked positions in order to project the needles into CBCT scans. Deviations between projected and actual needle tips were measured. Finally, we put our results into perspective with simulations of the system's tracking uncertainties. RESULTS: For the stationary scenario and dynamic movements, we achieved tool-tracking precision and accuracy of 0.04 ± 0.06 mm and 0.16 ± 0.18 mm, respectively. The tracked marker positions differed by 0.52 ± 0.18 mm from the positions determined via CBCT. In addition, the predicted needle tips in air deviated from the actual tip positions by only 1.62 ± 0.68 mm (200 mm needle) and 1.49 ± 0.62 mm (160 mm needle). The simulated tracking uncertainties resulted in tip variations of 1.58 ± 0.91 mm and 1.31 ± 0.69 mm for the 200 mm and 160 mm needles, respectively. CONCLUSION: With the innovative system it was possible to achieve a high tracking and prediction accuracy of marker tool and needles. The system shows high potential for applicator tracking in brachytherapy.

Protocol-based CT-guided brachytherapy for patients with prostate cancer and previous rectal extirpation-a curative approach.

OBJECTIVE: There are numerous curative treatment possibilities for prostate cancer. In patients who have undergone rectal extirpation for rectal cancer treatment, curative options are limited due to anatomic changes and previous irradiation of the pelvis. In this analysis, we validate the feasibility of CT-guided transperineal interstitial brachytherapy for this specific scenario. PATIENTS AND METHODS: We analyzed the treatment procedures and outcomes of 5 patients with metachronic nonmetastatic prostate cancer. Ultrasound-guided brachytherapy was not possible in any of the patients. Of these 5 patients, 3 were treated for prostate cancer using temporary brachytherapy with Ir-192 only, and 2 were treated with external-beam radiation therapy and temporary brachytherapy as a boost. CT-guided brachytherapy was performed in all patients. We analyzed the feasibility, efficacy, treatment-related toxicity, and quality of life (EORTC-30, IEFF, IPSS, and ICIQ questionnaires) of the treatments. RESULTS: Median follow-up was 35 months. Two out of five patients received boost irradiation (HDR 2â€¯× 9 Gy, PDR 30 Gy). Three out of five patients were treated with PDR brachytherapy in two sessions up to a total dose of 60 Gy. Dosimetric parameters were documented as median values as follows: V100 94.7% (94.5-98.4%), D2bladder 64.3% (50.9-78.3%), D10urethra 131.05% (123.2%-141.2%), and D30urethra 122.45% (116.2%-129.5%). At the time of analysis, no biochemical recurrence had been documented. Furthermore, neither early nor late side effects exceeding CTCAE grade 2 were documented. CONCLUSION: CT-guided transperineal brachytherapy of the prostate in patients with previous rectal surgery and radiation therapy is safe and represents a possible curative treatment option. Brachytherapy can be considered for patients with metachronic prostate cancer in this specific scenario, albeit preferably in experienced high-volume centers.

Principles of artificial intelligence in radiooncology.

PURPOSE: In the rapidly expanding field of artificial intelligence (AI) there is a wealth of literature detailing the myriad applications of AI, particularly in the realm of deep learning. However, a review that elucidates the technical principles of deep learning as relevant to radiation oncology in an easily understandable manner is still notably lacking. This paper aims to fill this gap by providing a comprehensive guide to the principles of deep learning that is specifically tailored toward radiation oncology. METHODS: In light of the extensive variety of AI methodologies, this review selectively concentrates on the specific domain of deep learning. It emphasizes the principal categories of deep learning models and delineates the methodologies for training these models effectively. RESULTS: This review initially delineates the distinctions between AI and deep learning as well as between supervised and unsupervised learning. Subsequently, it elucidates the fundamental principles of major deep learning models, encompassing multilayer perceptrons (MLPs), convolutional neural networks (CNNs), recurrent neural networks (RNNs), transformers, generative adversarial networks (GANs), diffusion-based generative models, and reinforcement learning. For each category, it presents representative networks alongside their specific applications in radiation oncology. Moreover, the review outlines critical factors essential for training deep learning models, such as data preprocessing, loss functions, optimizers, and other pivotal training parameters including learning rate and batch size. CONCLUSION: This review provides a comprehensive overview of deep learning principles tailored toward radiation oncology. It aims to enhance the understanding of AI-based research and software applications, thereby bridging the gap between complex technological concepts and clinical practice in radiation oncology.

Successful implementation of online educational lectures of the German Society for Radiation Oncology (DEGRO).

PURPOSE: Modern digital teaching formats have become increasingly important in recent years, in part due to the COVID-19 pandemic. In January 2021, an online-based webinar series was established by the German Society for Radiation Oncology (DEGRO) and the young DEGRO (yDEGRO) working group. In the monthly 120-minute courses, selected lecturers teach curricular content as preparation for the board certification exam for radiation oncology. METHODS: The evaluation of the 24 courses between 01.2021 and 12.2022 was performed using a standardized questionnaire with 21 items (recording epidemiological characteristics of the participants, didactic quality, content quality). A Likert scale (1-4) was used in combination with binary and open-ended questions. RESULTS: A combined total of 4200 individuals (1952 in 2021 and 2248 in 2022) registered for the courses, and out of those, 934 participants (455 in 2021 and 479 in 2022) later provided evaluations for the respective courses (36% residents, 35% specialists, 21% medical technicians for radiology [MTR], 8% medical physics experts [MPE]). After 2 years, 74% of the DEGRO Academy curriculum topics were covered by the monthly webinars. The overall rating by participants was positive (mean 2021: 1.33 and 2022: 1.25) and exceeded the curriculum offered at each site for 70% of participants. Case-based learning was identified as a particularly well-rated method. CONCLUSION: The DEGRO webinar expands the digital teaching opportunities in radiation oncology. The consistently high number of participants confirms the need for high-quality teaching and underlines the advantages of e­learning methods. Optimization opportunities were identified through reevaluation of feedback from course participants. In its design as a teaching format for a multiprofessional audience, the webinar series could be used as a practice model of online teaching for other disciplines.

Quality requirements for MRI simulation in cranial stereotactic radiotherapy: a guideline from the German Taskforce "Imaging in Stereotactic Radiotherapy".

Accurate Magnetic Resonance Imaging (MRI) simulation is fundamental for high-precision stereotactic radiosurgery and fractionated stereotactic radiotherapy, collectively referred to as stereotactic radiotherapy (SRT), to deliver doses of high biological effectiveness to well-defined cranial targets. Multiple MRI hardware related factors as well as scanner configuration and sequence protocol parameters can affect the imaging accuracy and need to be optimized for the special purpose of radiotherapy treatment planning. MRI simulation for SRT is possible for different organizational environments including patient referral for imaging as well as dedicated MRI simulation in the radiotherapy department but require radiotherapy-optimized MRI protocols and defined quality standards to ensure geometrically accurate images that form an impeccable foundation for treatment planning. For this guideline, an interdisciplinary panel including experts from the working group for radiosurgery and stereotactic radiotherapy of the German Society for Radiation Oncology (DEGRO), the working group for physics and technology in stereotactic radiotherapy of the German Society for Medical Physics (DGMP), the German Society of Neurosurgery (DGNC), the German Society of Neuroradiology (DGNR) and the German Chapter of the International Society for Magnetic Resonance in Medicine (DS-ISMRM) have defined minimum MRI quality requirements as well as advanced MRI simulation options for cranial SRT.

DEGRO guideline for personalized radiotherapy of brain metastases and leptomeningeal carcinomatosis in patients with breast cancer.

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.

Brachytherapy in vaginal cancer for organ preservation: Clinical outcome and safety from a single center experience.

BACKGROUND: Interstitial and/or intracavitary brachytherapy is an integral part of the treatment of vaginal cancer Brachytherapy (BT) has shown to improve local control, overall survival (OS) and disease-free survival (DFS). The aim of our study was to analyze the efficacy and safety of brachytherapy in patients with vaginal cancer. MATERIALS AND METHODS: Between 2000 and 2023, 27 patients with vaginal cancer in stage FIGO I-III were treated with brachytherapy with or without external beam radiotherapy (EBRT) and simultaneous chemotherapy. Brachytherapy has been performed either as PDR-brachytherapy alone with a median cumulative dose up to 62.5 Gy (EQD2 = 63.9 Gy) or with PDR-BT boost with median dose of 30.9 Gy (EQD2 = 30.4 Gy). HDR-BT was administered solely as boost with a median dose of 25.5 Gy (EQD2 = 47.8 Gy). The median dose of EBRT was 48.7 Gy and 49.4 Gy for primary and for pelvic lymph nodes. RESULTS: Median follow-up was 39 months (2-120). 5/27 patients developed local recurrences and the 5-year cumulative local recurrence rate for whole patient population was 18.5%. 5-year OS and DFS was 90% and 68%. 5-year DFS for Stage I-II was 72% and for Stage III 65% (p = 0.933). Grade 3 late side effects of brachytherapy were documented in 3/22 patients (13.6%), one patient experienced Grade 4 toxicity (4.5%). CONCLUSION: Brachytherapy with or without EBRT and concomitant chemotherapy for vaginal cancer is a safe and effective treatment option with excellent local control and overall survival and acceptable toxicity.

The course of tumor-related epilepsy in glioblastoma patients: A retrospective analysis.

PURPOSE: Many patients with glioblastoma suffer from tumor-related seizures. However, there is limited data on the characteristics of tumor-related epilepsy achieving seizure freedom. The aim of this study was to characterize the course of epilepsy in patients with glioblastoma and the factors that influence it. METHODS: We retrospectively analyzed the medical records of glioblastoma patients treated at the University Hospital Erlangen between 01/2006 and 01/2020. RESULTS: In the final cohort of patients with glioblastoma (n = 520), 292 patients (56.2 %) suffered from tumor-related epilepsy (persons with epilepsy, PWE). Levetiracetam was the most commonly used first-line antiseizure medication (n = 245, 83.9 % of PWE). The onset of epilepsy was preoperative in 154/292 patients (52.7 %). 136 PWE (46.6 %) experienced only one single seizure while 27/292 PWE (9.2 %) developed drug-resistant epilepsy. Status epilepticus occurred in 48/292 patients (16.4 %). Early postoperative onset (within 30 days of surgery) of epilepsy and total gross resection (compared with debulking) were independently associated with a lower risk of further seizures. We did not detect dose-dependent pro- or antiseizure effects of radiochemotherapy. CONCLUSION: Tumor-related epilepsy occurred in more than 50% of our cohort, but drug-resistant epilepsy developed in less than 10% of cases. Epilepsy usually started before tumor surgery.

First implementation of an innovative infra-red camera system integrated into a mobile CBCT scanner for applicator tracking in brachytherapy-Initial performance characterization.

PURPOSE: To enable a real-time applicator guidance for brachytherapy, we used for the first time infra-red tracking cameras (OptiTrack, USA) integrated into a mobile cone-beam computed tomography (CBCT) scanner (medPhoton, Austria). We provide the first description of this prototype and its performance evaluation. METHODS: We performed assessments of camera calibration and camera-CBCT registration using a geometric calibration phantom. For this purpose, we first evaluated the effects of intrinsic parameters such as camera temperature or gantry rotations on the tracked marker positions. Afterward, calibrations with various settings (sample number, field of view coverage, calibration directions, calibration distances, and lighting conditions) were performed to identify the requirements for achieving maximum tracking accuracy based on an in-house phantom. The corresponding effects on camera-CBCT registration were determined as well by comparing tracked marker positions to the positions determined via CBCT. Long-term stability was assessed by comparing tracking and a ground-truth on a weekly basis for 6 weeks. RESULTS: Robust tracking with positional drifts of 0.02 ± 0.01 mm was feasible using the system after a warm-up period of 90 min. However, gantry rotations affected the tracking and led to inaccuracies of up to 0.70 mm. We identified that 4000 samples and full coverage were required to ensure a robust determination of marker positions and camera-CBCT registration with geometric deviations of 0.18 ± 0.03 mm and 0.42 ± 0.07 mm, respectively. Long-term stability showed deviations of more than two standard deviations from the initial calibration after 3 weeks. CONCLUSION: We implemented for the first time a standalone combined camera-CBCT system for tracking in brachytherapy. The system showed high potential for establishing corresponding workflows.

Effective Radiosensitization of HNSCC Cell Lines by DNA-PKcs Inhibitor AZD7648 and PARP Inhibitors Talazoparib and Niraparib.

(1) Head and neck squamous cell carcinoma (HNSCC) is common, while treatment is difficult, and mortality is high. Kinase inhibitors are promising to enhance the effects of radiotherapy. We compared the effects of the PARP inhibitors talazoparib and niraparib and that of the DNA-PKcs inhibitor AZD7648, combined with ionizing radiation. (2) Seven HNSCC cell lines, including Cal33, CLS-354, Detroit 562, HSC4, RPMI2650 (HPV-negative), UD-SCC-2 and UM-SCC-47 (HPV-positive), and two healthy fibroblast cell lines, SBLF8 and SBLF9, were studied. Flow cytometry was used to analyze apoptosis and necrosis induction (AnnexinV/7AAD) and cell cycle distribution (Hoechst). Cell inactivation was studied by the colony-forming assay. (3) AZD7648 had the strongest effects, radiosensitizing all HNSCC cell lines, almost always in a supra-additive manner. Talazoparib and niraparib were effective in both HPV-positive cell lines but only consistently in one and two HPV-negative cell lines, respectively. Healthy fibroblasts were not affected by any combined treatment in apoptosis and necrosis induction or G2/M-phase arrest. AZD7648 alone was not toxic to healthy fibroblasts, while the combination with ionizing radiation reduced clonogenicity. (4) In conclusion, talazoparib, niraparib and, most potently, AZD7648 could improve radiation therapy in HNSCC. Healthy fibroblasts tolerated AZD7648 alone extremely well, but irradiation-induced effects might occur. Our results justify in vivo studies.

FEN1 Inhibition as a Potential Novel Targeted Therapy against Breast Cancer and the Prognostic Relevance of FEN1.

To improve breast cancer treatment and to enable new strategies for therapeutic resistance, therapeutic targets are constantly being studied. Potential targets are proteins of DNA repair and replication and genomic integrity, such as Flap Endonuclease 1 (FEN1). This study investigated the effects of FEN1 inhibitor FEN1-IN-4 in combination with ionizing radiation on cell death, clonogenic survival, the cell cycle, senescence, doubling time, DNA double-strand breaks and micronuclei in breast cancer cells, breast cells and healthy skin fibroblasts. Furthermore, the variation in the baseline FEN1 level and its influence on treatment prognosis was investigated. The cell lines show specific response patterns in the aspects studied and have heterogeneous baseline FEN1 levels. FEN1-IN-4 has cytotoxic, cytostatic and radiosensitizing effects, expressed through increasing cell death by apoptosis and necrosis, G2M share, senescence, double-strand breaks and a reduced survival fraction. Nevertheless, some cells are less affected by the cytotoxicity and fibroblasts show a rather limited response. In vivo, high FEN1 mRNA expression worsens the prognosis of breast cancer patients. Due to the increased expression in breast cancer tissue, FEN1 could represent a new tumor and prognosis marker and FEN1-IN-4 may serve as a new potent agent in personalized medicine and targeted breast cancer therapy.

Multicenter clinical trial on functional evaluation of transoral laser microsurgery for supraglottic laryngeal carcinomas.

BACKGROUND: Transoral laser microsurgery (TLM) is an accepted and effective treatment strategy for supraglottic carcinomas. Data on oncologic and to a lesser extent functional outcomes have been published by mainly European specialized single institutions. TLM for supraglottic carcinomas has never been tested in a multicenter trial on its applicability as surgical standard at every hospital. OBJECTIVES: To test the efficacy of TLM supraglottic laryngectomy (TLM-SGL) in terms of swallowing function, oncologic outcome parameters, morbidity, complications of treatment, and quality of life in a multicenter setting. METHODS: The study is designed as a multicenter (approximately 25 centers), non-randomized, single-arm study with a targeted number of 200 previously untreated patients with squamous cell carcinomas (SCC) of the supraglottic larynx T2/T3 N0-3 M0; UICC stage II-IVa. The surgical treatment consists of TLM-SGL and elective or therapeutic uni- or bilateral selective neck dissection (SND). After pathologic risk stratification adjuvant radio- (RT) or radiochemotherapy (RCT) is indicated. Patients are followed-up for 2 years post surgically. Swallowing function is assessed by fibreoptic endoscopic evaluation of swallowing (FEES). The primary endpoint is aspiration-free swallowing at 12 months as established using FEES and defined as grade < 6 of penetration-aspiration scale (PAS). Secondary endpoints include local control, larynx preservation, overall and disease-free survival, complications and side effects of treatment, prevalence of tracheostomy and percutaneous endoscopic gastrostomy (PEG)-tube-feeding, and dysphagia-specific quality of life (QoL) assessed by the MD Anderson Dysphagia Inventory (MDADI) as well as voice-related QoL assessed by the Voice Handicap Index (VHI).

Accelerated partial breast irradiation using sole interstitial multicatheter brachytherapy compared with whole-breast irradiation with boost for early breast cancer: 10-year results of a GEC-ESTRO randomised, phase 3, non-inferiority trial.

BACKGROUND: Several randomised, phase 3 trials have investigated the value of different techniques of accelerated partial breast irradiation (APBI) for patients with early breast cancer after breast-conserving surgery compared with whole-breast irradiation. In a phase 3 randomised trial, we evaluated whether APBI using multicatheter brachytherapy is non-inferior compared with whole-breast irradiation. Here, we present the 10-year follow-up results. METHODS: We did a randomised, phase 3, non-inferiority trial at 16 hospitals and medical centres in Austria, Czech Republic, Germany, Hungary, Poland, Spain, and Switzerland. Patients aged 40 years or older with early invasive breast cancer or ductal carcinoma in situ treated with breast-conserving surgery were centrally randomly assigned (1:1) to receive either whole-breast irradiation or APBI using multicatheter brachytherapy. Whole-breast irradiation was delivered in 25 daily fractions of 50 Gy over 5 weeks, with a supplemental boost of 10 Gy to the tumour bed, and APBI was delivered as 30·1 Gy (seven fractions) and 32·0 Gy (eight fractions) of high-dose-rate brachytherapy in 5 days or as 50 Gy of pulsed-dose-rate brachytherapy over 5 treatment days. Neither patients nor investigators were masked to treatment allocation. The primary endpoint was ipsilateral local recurrence, analysed in the as-treated population; the non-inferiority margin for the recurrence rate difference (defined for 5-year results) was 3 percentage points. The trial is registered with ClinicalTrials.gov, NCT00402519; the trial is complete. FINDINGS: Between April 20, 2004, and July 30, 2009, 1328 female patients were randomly assigned to whole breast irradiation (n=673) or APBI (n=655), of whom 551 in the whole-breast irradiation group and 633 in the APBI group were eligible for analysis. At a median follow-up of 10·36 years (IQR 9·12-11·28), the 10-year local recurrence rates were 1·58% (95% CI 0·37 to 2·8) in the whole-breast irradiation group and 3·51% (1·99 to 5·03) in the APBI group. The difference in 10-year rates between the groups was 1·93% (95% CI -0·018 to 3·87; p=0·074). Adverse events were mostly grade 1 and 2, in 234 (60%) of 393 participants in the whole-breast irradiation group and 314 (67%) of 470 participants in the APBI group, at 7·5-year or 10-year follow-up, or both. Patients in the APBI group had a significantly lower incidence of treatment-related grade 3 late side-effects than those in the whole-breast irradiation group (17 [4%] of 393 for whole-breast irradiation vs seven [1%] of 470 for APBI; p=0·021; at 7·5-year or 10-year follow-up, or both). At 10 years, the most common type of grade 3 adverse event in both treatment groups was fibrosis (six [2%] of 313 patients for whole-breast irradiation and three [1%] of 375 patients for APBI, p=0·56). No grade 4 adverse events or treatment-related deaths have been observed. INTERPRETATION: Postoperative APBI using multicatheter brachytherapy after breast-conserving surgery in patients with early breast cancer is a valuable alternative to whole-breast irradiation in terms of treatment efficacy and is associated with fewer late side-effects. FUNDING: German Cancer Aid, Germany.

Ex Vivo Chromosomal Radiosensitivity Testing in Patients with Pathological Germline Variants in Breast Cancer High-Susceptibility Genes BReast CAncer 1 and BReast CAncer 2.

BACKGROUND: Individual radiosensitivity is an important factor in the occurrence of undesirable consequences of radiotherapy. The potential for increased radiosensitivity has been linked to highly penetrant heterozygous mutations in DNA repair genes such as BRCA1 and BRCA2. By studying the chromosomal radiosensitivity of BRCA1/2 mutation carriers compared to the general population, we study whether increased chromosomal radiation sensitivity is observed in patients with BRCA1/2 variants. METHODS: Three-color-fluorescence in situ hybridization was performed on ex vivo-irradiated peripheral blood lymphocytes from 64 female patients with a heterozygous germline BRCA1 or BRCA2 mutation. Aberrations in chromosomes #1, #2 and #4 were analyzed. Mean breaks per metaphase (B/M) served as the parameter for chromosomal radiosensitivity. The results were compared with chromosomal radiosensitivity in a cohort of generally healthy individuals and patients with rectal cancer or breast cancer. RESULTS: Patients with BRCA1/2 mutations (n = 64; B/M 0.47) overall showed a significantly higher chromosomal radiosensitivity than general healthy individuals (n = 211; B/M 0.41) and patients with rectal cancer (n = 379; B/M 0.44) and breast cancer (n = 147; B/M 0.45) without proven germline mutations. Chromosomal radiosensitivity varied depending on the locus of the BRCA1/2 mutation. CONCLUSIONS: BRCA1/2 mutations result in slightly increased chromosomal sensitivity to radiation. A few individual patients have a marked increase in radiation sensitivity. Therefore, these patients are at a higher risk for adverse therapeutic consequences.

Prerequisites for the clinical implementation of a markerless SGRT-only workflow for the treatment of breast cancer patients.

PURPOSE: A markerless workflow for the treatment of breast cancer patients has been introduced and evaluated retrospectively. It includes surface-guided radiation therapy (SGRT)-only positioning for patients with small cone beam CT (CBCT) position corrections during the first five fractions. Prerequisites and the frequency of its clinical application were evaluated, as well as potential benefits in terms of treatment time and dose savings, the frequency of CBCT scans, and the accuracy of the positioning. METHODS: A group of 100 patients treated with the new workflow on two Versa HD linacs has been compared to a matched control group of patients treated with the former workflow, which included prepositioning with skin markings and lasers, SGRT and daily CBCT. The comparison was based on the evaluation of logfiles. RESULTS: Of the patients treated with the new workflow, 40% did not receive daily CBCT scans. This resulted in mean time savings of 97 s, 166 s and 239 s per fraction for the new workflow, for patients treated without daily CBCT and for SGRT-only fractions, respectively, when compared to the old workflow. Dose savings amounted to a weighted computed tomography dose index reduction of CTDIW = 2.56 cGy on average for normofractionated treatment and weekly CBCTs, while for patients not treated with daily CBCT, SGRT-based positioning accuracy was 5.2 mm for the mean translational magnitude, as evaluated by CBCT. CONCLUSION: For 40% of the patients, after five fractions with small CBCT corrections, the workflow could be changed to SGRT-only positioning with weekly CBCT. This leads to imaging dose and time savings and thus also reduced intrafraction motion, potentially increased patient throughput and patient comfort, while assuring appropriate positioning accuracy.

Normofractionated irradiation and not temozolomide modulates the immunogenic and oncogenic phenotype of human glioblastoma cell lines.

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

Synthetic CTs for MRI-only brain RT treatment: integration of immobilization systems.

PURPOSE: Auxiliary devices such as immobilization systems should be considered in synthetic CT (sCT)-based treatment planning (TP) for MRI-only brain radiotherapy (RT). A method for auxiliary device definition in the sCT is introduced, and its dosimetric impact on the sCT-based TP is addressed. METHODS: T1-VIBE DIXON was acquired in an RT setup. Ten datasets were retrospectively used for sCT generation. Silicone markers were used to determine the auxiliary devices' relative position. An auxiliary structure template (AST) was created in the TP system and placed manually on the MRI. Various RT mask characteristics were simulated in the sCT and investigated by recalculating the CT-based clinical plan on the sCT. The influence of auxiliary devices was investigated by creating static fields aimed at artificial planning target volumes (PTVs) in the CT and recalculated in the sCT. The dose covering 50% of the PTV (D50) deviation percentage between CT-based/recalculated plan (∆D50[%]) was evaluated. RESULTS: Defining an optimal RT mask yielded a ∆D50[%] of 0.2 ± 1.03% for the PTV and between -1.6 ± 3.4% and 1.1 ± 2.0% for OARs. Evaluating each static field, the largest ∆D50[%] was delivered by AST positioning inaccuracy (max: 3.5 ± 2.4%), followed by the RT table (max: 3.6 ± 1.2%) and the RT mask (max: 3.0 ± 0.8% [anterior], 1.6 ± 0.4% [rest]). No correlation between ∆D50[%] and beam depth was found for the sum of opposing beams, except for (45°â€¯+ 315°). CONCLUSION: This study evaluated the integration of auxiliary devices and their dosimetric influence on sCT-based TP. The AST can be easily integrated into the sCT-based TP. Further, we found that the dosimetric impact was within an acceptable range for an MRI-only workflow.

Tumor-specific radiosensitizing effect of the ATM inhibitor AZD0156 in melanoma cells with low toxicity to healthy fibroblasts.

PURPOSE: Despite new treatment options, melanoma continues to have an unfavorable prognosis. DNA damage response (DDR) inhibitors are a promising drug class, especially in combination with chemotherapy (CT) or radiotherapy (RT). Manipulating DNA damage repair during RT is an opportunity to exploit the genomic instability of cancer cells and may lead to radiosensitizing effects in tumors that could improve cancer therapy. METHODS: A panel of melanoma-derived cell lines of different origin were used to investigate toxicity-related clonogenic survival, cell death, and cell cycle distribution after treatment with a kinase inhibitor (KI) against ATM (AZD0156) or ATR (VE-822, berzosertib), irradiation with 2 Gy, or a combination of KI plus ionizing radiation (IR). Two fibroblast cell lines generated from healthy skin tissue were used as controls. RESULTS: Clonogenic survival indicated a clear radiosensitizing effect of the ATM inhibitor (ATMi) AZD0156 in all melanoma cells in a synergistic manner, but not in healthy tissue fibroblasts. In contrast, the ATR inhibitor (ATRi) VE-822 led to additive enhancement of IR-related toxicity in most of the melanoma cells. Both inhibitors mainly increased cell death induction in combination with IR. In healthy fibroblasts, VE-822 plus IR led to higher cell death rates compared to AZD0156. A significant G2/M block was particularly induced in cancer cells when combining AZD0156 with IR. CONCLUSION: ATMi, in contrast to ATRi, resulted in synergistic radiosensitization regarding colony formation in melanoma cancer cells, while healthy tissue fibroblasts were merely affected with respect to cell death induction. In connection with an increased number of melanoma cells in the G2/M phase after ATMi plus IR treatment, ATMi seems to be superior to ATRi in melanoma cancer cell treatments when combined with RT.

Clinical application of breathing-adapted 4D CT: image quality comparison to conventional 4D CT.

PURPOSE: 4D CT imaging is an integral part of 4D radiotherapy workflows. However, 4D CT data often contain motion artifacts that mitigate treatment planning. Recently, breathing-adapted 4D CT (i4DCT) was introduced into clinical practice, promising artifact reduction in in-silico and phantom studies. Here, we present an image quality comparison study, pooling clinical patient data from two centers: a new i4DCT and a conventional spiral 4D CT patient cohort. METHODS: The i4DCT cohort comprises 129 and the conventional spiral 4D CT cohort 417 4D CT data sets of lung and liver tumor patients. All data were acquired for treatment planning. The study consists of three parts: illustration of image quality in selected patients of the two cohorts with similar breathing patterns; an image quality expert rater study; and automated analysis of the artifact frequency. RESULTS: Image data of the patients with similar breathing patterns underline artifact reduction by i4DCT compared to conventional spiral 4D CT. Based on a subgroup of 50 patients with irregular breathing patterns, the rater study reveals a fraction of almost artifact-free scans of 89% for i4DCT and only 25% for conventional 4D CT; the quantitative analysis indicated a reduction of artifact frequency by 31% for i4DCT. CONCLUSION: The results demonstrate 4D CT image quality improvement for patients with irregular breathing patterns by breathing-adapted 4D CT in this first corresponding clinical data image quality comparison study.