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Objective: Electronic Patient-Reported Outcome Measures (ePROMs) could be used to monitor patients' symptoms after treatment. However, ePROM implementation in clinical practice has been challenging, especially in (palliative) radiation oncology. The aim of this study was to explore the opinions of healthcare providers (HCP) active in radiation oncology in Belgium on the use of ePROMs for symptom follow-up after palliative radiotherapy. Methods: An anonymous online survey was conducted with different HCP in radiation oncology in Belgium. Participants were recruited through several professional organizations with approximately 390 members actively working in the field of radiation oncology. The survey used was a self-developed questionnaire, based on existing literature on implementation of (e)PROMs in cancer care, our previous research on this topic as well as our personal experience in the field of oncology and palliative care. Results: Of the 128 respondents, 26% had experience with ePROMs in clinical practice. Eighty-four percent considered ePROMs beneficial for patients' health and symptom knowledge, symptom self-management and active participation in care. ePROMs could help HCP to focus on detection of relevant symptoms and improve their management. Almost 75% were willing to implement and use ePROMs. Assigning ePROM introduction and follow-up to a dedicated person, such as a nurse navigator, was suggested to promote ePROM implementation and use in clinical practice. Conclusion: Despite limited experience with ePROMs in clinical care for palliative radiotherapy patients, the majority of respondents is willing to implement and use ePROMs for this particular patient population. Innovation: This is one of the first studies specifically focusing on experiences and opinions of HCP in radiation oncology on the use of ePROMs for symptom follow-up in palliative radiotherapy. HCP should be actively involved in implementation of ePROMs after palliative radiotherapy, to translate their vision of their ideals in practice.

Purpose: To report on the accuracy of automated delineation, treatment plan quality, and duration of an in-silico “scan-(pre)plan-treat” (SPT) workflow for vertebral bone metastases using a 1 × 8 Gy regimen. Method and Materials: The cloud-based emulator system of the Ethos therapy system was used to adapt an organ-at-risk-sparing preplan created on the diagnostic CT to the anatomy-of-the-day using the cone beam CT made before treatment. Results: SPT using the Ethos emulator system resulted in relatively good coverage of the PTV and acceptable dose to the OAR. Delivery time and plan homogeneity was the best for 7-field IMRT plan template. Conclusions: A SPT workflow formula results in a highly conformal treatment delivery while maintaining an acceptable timeframe for the patient on the treatment couch.

Purpose: To report on organ preservation following chemoradiotherapy (CRT) in a prospective cohort of locally advanced rectal cancer patients. Methods and materials: Fifty-two patients received CRT. MRI and 18F-FDG-PET/CT were performed prior to CRT. Response assessment was done 6 and 12 weeks after CRT using digital rectal examination, MRI, 18F-FDG-PET/CT and endoscopy. For clinical complete response or minimal residual disease, a watch-and-wait (W&W) protocol was started.Regrowth-free survival (ReFS), Total Mesorectal Excision-free disease-free survival, distant metastasis-free survival (DMFS) and overall survival (OS) were evaluated using Kaplan-Meier method. Functional outcome was compared with the Wilcoxon signed-rank test using EORTC QLQ-C30, MSKCC BFI, LARS and IIEF-5/FSFI-5 questionnaires. A previously developed prediction model performance was tested using receiver operating characteristic analysis. Results: 29/52 patients entered a W&W protocol. There was no difference in two-year DMFS (81.1 % vs 78.8 %, p = 0.82), two-year OS (96.4 % vs 100 %, p = 0.38) and two-year DFS (77.5 % vs 78.8 %, p = 0.87) between W&W patients and those who underwent surgery at 12 weeks after CRT. Two-year DMFS differed between W&W with local regrowth, W&W with sustained response and patients who had surgery (66.7 % vs 88.0 % vs 78.8 %; p = 0.04). At 6 and 12 months, W&W patients reported good QoL and bowel function. The model validation reached an AUC of 0.627. Conclusion: Good functional outcome in patients with rectal cancer allocated to surveillance after CRT needs to be balanced against potentially worse DMFS in a subset of patients without sustained clinical complete response. Reliable prediction of patients eligible for surveillance programs needs further investigation.

Objectives: To provide an overview of the impact of the pandemic on the clinical activity and take a snapshot of the contingent challenges that European particle therapy centers are called to face, we surveyed the members of the European Particle Therapy Network (EPTN). Material and methods: A 52-question survey was conducted from 4th April 2021 to 30th July 2021 using the Google Forms platform. Three dedicated sections analysed the clinical context of each participating institution, the staff management, and the clinical changes in the oncological workflow. Results: Out of the 23 contacted European hubs of particle radiotherapy, a total of 9 (39%) responded to the survey. The number of in-person first evaluations and follow-up visits decreased, but telemedicine was implemented. Multidisciplinary tumour board discussions continued during the outbreak using web-based solutions. A delay in cancer diagnosis and oncological staging leading to an increment in more advanced diseases at first presentation was generally observed. Even if the total number of treatments (photons and particles) in the responding institutions showed a trend of decrease, there was or a stable situation or slight increase in particle treatments. The clinical treatment choices followed the national and international scientific recommendations and were patient/disease-oriented. Hypofractionation and short-schedule of chemotherapy, when applicable, were preferred. Conclusions: Our findings show a rapid and effective reaction of European particle RT hubs to manage the healthcare crisis. Considering the new waves and virus variants, the vaccination campaign will hopefully reduce the oncological impacts and consequences of the prolonged outbreak.

Purpose: Recently, ultrahigh-dose-rate radiation therapy (UHDR-RT) has emerged as a promising strategy to increase the benefit/risk ratio of external RT. Extensive work is on the way to characterize the physical and biological parameters that control the so-called “Flash” effect. However, this healthy/tumor differential effect is observable in in vivo models, which thereby drastically limits the amount of work that is achievable in a timely manner. Methods and Materials: In this study, zebrafish embryos were used to compare the effect of UHDR irradiation (8-9 kGy/s) to conventional RT dose rate (0.2 Gy/s) with a 68 MeV proton beam. Viability, body length, spine curvature, and pericardial edema were measured 4 days postirradiation. Results: We show that body length is significantly greater after UHDR-RT compared with conventional RT by 180 µm at 30 Gy and 90 µm at 40 Gy, while pericardial edema is only reduced at 30 Gy. No differences were obtained in terms of survival or spine curvature. Conclusions: Zebrafish embryo length appears as a robust endpoint, and we anticipate that this model will substantially fasten the study of UHDR proton-beam parameters necessary for “Flash.”

IntroductionWe hypothesized that increasing the pelvic integral dose (ID) and a higher dose per fraction correlate with worsening fatigue and functional outcomes in localized prostate cancer (PCa) patients treated with external beam radiotherapy (EBRT).MethodsThe study design was a retrospective analysis of two prospective observational cohorts, REQUITE (development, n=543) and DUE-01 (validation, n=228). Data were available for comorbidities, medication, androgen deprivation therapy, previous surgeries, smoking, age, and body mass index. The ID was calculated as the product of the mean body dose and body volume. The weekly ID accounted for differences in fractionation. The worsening (end of radiotherapy versus baseline) of European Organisation for Research and Treatment of Cancer EORTC) Quality of Life Questionnaire (QLQ)-C30 scores in physical/role/social functioning and fatigue symptom scales were evaluated, and two outcome measures were defined as worsening in ≥2 (WS2) or ≥3 (WS3) scales, respectively. The weekly ID and clinical risk factors were tested in multivariable logistic regression analysis.ResultsIn REQUITE, WS2 was seen in 28% and WS3 in 16% of patients. The median weekly ID was 13.1 L·Gy/week [interquartile (IQ) range 10.2-19.3]. The weekly ID, diabetes, the use of intensity-modulated radiotherapy, and the dose per fraction were significantly associated with WS2 [AUC (area under the receiver operating characteristics curve) =0.59; 95% CI 0.55-0.63] and WS3 (AUC=0.60; 95% CI 0.55-0.64). The prevalence of WS2 (15.3%) and WS3 (6.1%) was lower in DUE-01, but the median weekly ID was higher (15.8 L·Gy/week; IQ range 13.2-19.3). The model for WS2 was validated with reduced discrimination (AUC=0.52 95% CI 0.47-0.61), The AUC for WS3 was 0.58,ConclusionIncreasing the weekly ID and the dose per fraction lead to the worsening of fatigue and functional outcomes in patients with localized PCa treated with EBRT.

Abstract Background Detection of the site of recurrence using PSMA-PET/CT is important to guide treatment in patients with biochemical recurrence of prostate cancer (PCa). The aim of this study was to evaluate the positivity rate of [18F]PSMA-1007-PET/CT in patients with biochemically recurrent PCa and identify parameters that predict scan positivity as well as the type and number of detected lesions. This monocentric retrospective study included 137 PCa patients with biochemical recurrence who underwent one or more [18F]PSMA-1007-PET/CT scans between August 2018 and June 2019. PET-positive malignant lesions were classified as local recurrence, lymph node (LN), bone or soft tissue lesions. The association between biochemical/paraclinical parameters, as PSA value, PSA doubling time, PSA velocity, Gleason score (GS) and androgen deprivation therapy (ADT), and scan positivity as well as type and number of detected lesions was evaluated using logistic regression analysis (binary outcomes) and Poisson models (count-type outcomes). Results We included 175 [18F]PSMA-1007-PET/CT scans after radical prostatectomy (78%), external beam radiation therapy (8.8%), ADT (7.3%), brachytherapy (5.1%) and high intensity focused ultrasound (0.7%) as primary treatment (median PSA value 1.6 ng/ml). Positivity rate was 80%. PSA value and PSA velocity were significant predictors of scan positivity as well as of the presence of bone and soft tissue lesions and number of bone, LN and soft tissue lesions, both in uni- and/or multivariable analysis. Multivariable analysis also showed prior ADT as predictor of bone and soft tissue lesions, GS as predictor of the number of bone lesions and ongoing ADT as predictor of the number of LN lesions. Conclusion [18F]PSMA-1007-PET/CT showed a high positivity rate in patients with biochemically recurrent PCa. PSA value and PSA velocity were significant predictors of scan positivity as well as of the presence and number of bone and soft tissue lesions and the number of LN lesions. Our findings can guide clinicians in optimal patient selection for [18F]PSMA-1007-PET/CT and support further research leading to the development of a prediction nomogram.

Purpose: To prospectively evaluate the feasibility of solid gold marker placement in oesophageal cancer patients and to quantify inter-fractional and intra-fractional (baseline shift) marker motion during radiation treatment. Radiotherapy target margins and matching strategies were investigated. Materials/methods: Thirty-four markers were implanted by echo-endoscopy in 10 patients. Patients received a planning 4D CT, daily pre-treatment cone-beam CT (CBCT) and a post-treatment CBCT for at least five fractions. For fractions with both pre- and post-treatment CBCT, marker displacement between planning CT and pre-treatment CBCT (inter-fractional) and between pre-treatment and post-treatment CBCT (intra-fractional; only for fractions without rotational treatment couch correction) were calculated in left–right (LR), cranio-caudal (CC) and anterior-posterior (AP) direction after bony-anatomy and soft-tissue matching. Systematic/random setup errors were estimated; treatment margins were calculated. Results: No serious adverse events occurred. Twenty-three (67.6%) markers were visible during radiotherapy (n = 3 middle oesophagus, n = 16 distal oesophagus, n = 4 proximal stomach). Margins for inter-fractional displacement after bony-anatomy match depended on the localisation of the primary tumour and were 11.2 mm (LR), 16.4 mm (CC) and 8.2 mm (AP) for distal markers. Soft-tissue matching reduced the CC margin for these markers (16.4 mm to 10.5 mm). The mean intra-fractional shift of 12 distal markers was 0.4 mm (LR), 2.3 mm (CC) and 0.7 mm (AP). Inclusion of this shift resulted in treatment margins for distal markers of 12.8 mm (LR), 17.3 mm (CC) and 10.4 mm (AP) after bony-anatomy matching and 12.4 mm (LR), 11.4 mm (CC) and 9.7 mm (AP) after soft-tissue matching. Conclusion: This study demonstrated that the implantation of gold markers was safe, albeit less stable compared to other marker types. Inter-fractional motion was largest cranio-caudally for markers in the distal oesophagus, which was reduced after soft-tissue compared to bony-anatomy matching. The impact of intra-fractional baseline shifts on margin calculation was rather small.

While proton therapy offers an excellent dose conformity and sparing of organs at risk, this can be compromised by uncertainties, e.g. organ motion. This study aimed to investigate the influence of cardiac motion on the contoured oesophagus using electrocardiogram-triggered imaging and to assess the impact of this motion on the robustness of proton therapy plans in oesophageal cancer patients. Limited cardiac-induced motion of the oesophagus was observed with a negligible impact on the robustness of proton therapy plans. Therefore, our data suggest that cardiac motion may be safely ignored in the robust optimisation strategy for proton planning in oesophageal cancer.

The key goal and main challenge of radiation therapy is the elimination of tumors without any concurring damages of the surrounding healthy tissues and organs. Radiation doses required to achieve sufficient cancer‐cell kill exceed in most clinical situations the dose that can be tolerated by the healthy tissues, especially when large parts of the affected organ are irradiated. High‐precision radiation oncology aims at optimizing tumor coverage, while sparing normal tissues. Medical imaging during the preparation phase, as well as in the treatment room for localization of the tumor and directing the beam, referred to as image‐guided radiotherapy (IGRT), is the cornerstone of precision radiation oncology. Sophisticated high‐resolution real‐time IGRT using X‐rays, computer tomography, magnetic resonance imaging, or ultrasound, enables delivery of high radiation doses to tumors without significant damage of healthy organs. IGRT is the most convincing success story of radiation oncology over the last decades, and it remains a major driving force of innovation, contributing to the development of personalized oncology, for example, through the use of real‐time imaging biomarkers for individualized dose delivery.

Abstract Background Patients diagnosed with metastatic castration-refractory prostate cancer (mCRPC) rely on a limited number of therapeutic agents resulting in a median survival of 2–3 years. A subgroup of those patients with mCRPC presents with oligoprogressive disease, with a limited number of progressive lesions while other metastases are still controlled by ongoing systemic treatment. Methods In this single arm prospective phase II trial, we aim to include 18 patients with oligoprogressive mCRPC (1–3 metastases and/or local recurrence) who will be treated with metastasis-directed therapy to all visible progressive lesions. Progression is based on conventional imaging, as the use of PSMA PET-CT is considered investigational. However all patients will undergo PSMA PET-CT and the images will be blinded until progression. Primary endpoint is the postponement of the start of next-line systemic treatment (NEST) and the additional clinical value of PSMA PET-CT. Recruitment of patients for this trial started in January 2020 and will be completed approximately by December 2020. Discussion In this phase 2 trial on oligoprogressive mCRPC, we will investigate the benefit of progression-directed therapy while continuing ongoing systemic treatment. We hypothesize that progression-directed therapy (PDT) with surgery or stereotactic body radiation therapy for these oligoprogressive lesions will postpone the start of next-line systemic treatment and therefore serve as a new or add-on therapy in the spectrum of treatments available for mCRPC. The results of this trial will serve as guidance for a later randomized phase 3 trial. All participants are given an information sheet and are required to give written informed consent. Results will be published in a peer-reviewed journal. Trial registration This study is registered at ClinicalTrials.gov: NCT04222634 (December 18th 2019).

Background and purpose: Recently, intermediate and high-risk prostate cancer patients have been treated in a multicenter phase II trial with extremely hypofractionated prostate radiotherapy (hypo-FLAME trial). The purpose of the current study was to investigate whether a 1.5 T magnetic resonance imaging guided linear accelerator (MRI-linac) could achieve complex dose distributions of a quality similar to conventional linac state-of-the-art prostate treatments. Materials and methods: The clinically delivered treatment plans of 20 hypo-FLAME patients (volumetric modulated arc therapy, 10 MV, 5 mm leaf width) were included. Prescribed dose to the prostate was 5 × 7 Gy, with a focal tumor boost up to 5 × 10 Gy. MRI-linac treatment plans (intensity modulated radiotherapy, 7 MV, 7 mm leaf width, fixed collimator angle and 1.5 T magnetic field) were calculated. Dose distributions were compared. Results: In both conventional and MRI-linac treatment plans, the V35Gy to the whole prostate was >99% in all patients. Mean dose to the gross tumor volume was 45 Gy for conventional and 44 Gy for MRI-linac plans, respectively. Organ at risk doses were met in the majority of plans, except for a rectal V35Gy constraint, which was exceeded in one patient, by 1 cc, for both modalities. The bladder V32Gy and V28Gy constraints were exceeded in two and one patient respectively, for both modalities. Conclusion: Planning of stereotactic radiotherapy with focal ablative boosting in prostate cancer on a high field MRI-linac is feasible with the current MRI-linac properties, without deterioration of plan quality compared to conventional treatments. Keywords: MRI-linac, Prostate cancer, Stereotactic body radiotherapy, Hypofractionation, Focal boost

Abstract Background Neoadjuvant treatment followed by esophagectomy is standard practice in locally advanced esophageal cancer. However, not all patients who started neoadjuvant treatment will undergo esophageal resection. The purpose of our study was to investigate the group of patients, scheduled for neoadjuvant treatment followed by esophagectomy, who never made it to esophageal resection. Methods We retrospectively analyzed patients treated between 2002 and 2015 for locally advanced esophageal cancer, who did not undergo esophagectomy after neoadjuvant treatment. Subanalysis was performed according to time period (2002–2010 versus 2011–2015) and histology (adenocarcinoma versus squamous cell carcinoma). Results In 114 of 679 patients (16.8%), surgery was not performed after neoadjuvant treatment. Reasons for cancelation were disease progression (50 patients, 43.9%), poor general condition (26 patients, 22.8%), irresectability (14 patients, 12.3%), patients’ own decision (15 patients, 13.2%), and death during neoadjuvant treatment (9 patients, 7.9%). In the second time period, there were less irresectable tumors (17.7% versus 5.8%; p = 0.044). Median overall survival was not different over time (9.2 versus 12.5 months; p = 0.937). Irresectability (p = 0.032), patients’ refusal (p = 0.012), and poor general condition (p = 0.002) were more frequent as reasons for cancelation in squamous cell carcinoma patients. Median overall survival was, respectively, 12.5 and 9.9 months for adenocarcinoma and squamous cell carcinoma patients (p = 0.441). The majority of patients refusing surgery had a clinical complete response (73.3%). They had a median overall survival of 33.2 months. Conclusions One in six patients starting neoadjuvant treatment for locally advanced esophageal cancer never made it to esophagectomy, more than half of them for oncological reasons, but also 1.3% because of death during treatment. Over time, irresectability as reason decreased. As a result, the relative weight of medical inoperability increased, indicating the importance of upfront testing of medical operability. Cancelation of surgery was significantly more common in patients with a squamous cell carcinoma, and this histology seems to represent a more complex oncological and functional entity. Refusal of esophagectomy based on clinical complete response showed a significant survival benefit compared to those who did not undergo esophagectomy because of other reasons.

Background: Acute skin toxicity is a common and usually transient side-effect of breast radiotherapy although, if sufficiently severe, it can affect breast cosmesis, aftercare costs and the patient's quality-of-life. The aim of this study was to develop predictive models for acute skin toxicity using published risk factors and externally validate the models in patients recruited into the prospective multi-center REQUITE (validating pREdictive models and biomarkers of radiotherapy toxicity to reduce side-effects and improve QUalITy of lifE in cancer survivors) study.Methods: Patient and treatment-related risk factors significantly associated with acute breast radiation toxicity on multivariate analysis were identified in the literature. These predictors were used to develop risk models for acute erythema and acute desquamation (skin loss) in three Radiogenomics Consortium cohorts of patients treated by breast-conserving surgery and whole breast external beam radiotherapy (n = 2,031). The models were externally validated in the REQUITE breast cancer cohort (n = 2,057).Results: The final risk model for acute erythema included BMI, breast size, hypo-fractionation, boost, tamoxifen use and smoking status. This model was validated in REQUITE with moderate discrimination (AUC 0.65), calibration and agreement between predicted and observed toxicity (Brier score 0.17). The risk model for acute desquamation, excluding the predictor tamoxifen use, failed to validate in the REQUITE cohort.Conclusions: While most published prediction research in the field has focused on model development, this study reports successful external validation of a predictive model using clinical risk factors for acute erythema following radiotherapy after breast-conserving surgery. This model retained discriminatory power but will benefit from further re-calibration. A similar model to predict acute desquamation failed to validate in the REQUITE cohort. Future improvements and more accurate predictions are expected through the addition of genetic markers and application of other modeling and machine learning techniques.

Background: REQUITE (validating pREdictive models and biomarkers of radiotherapy toxicity to reduce side effects and improve QUalITy of lifE in cancer survivors) is an international prospective cohort study. The purpose of this project was to analyse a cohort of patients recruited into REQUITE using a deep learning algorithm to identify patient-specific features associated with the development of toxicity, and test the approach by attempting to validate previously published genetic risk factors.Methods: The study involved REQUITE prostate cancer patients treated with external beam radiotherapy who had complete 2-year follow-up. We used five separate late toxicity endpoints: ≥grade 1 late rectal bleeding, ≥grade 2 urinary frequency, ≥grade 1 haematuria, ≥ grade 2 nocturia, ≥ grade 1 decreased urinary stream. Forty-three single nucleotide polymorphisms (SNPs) already reported in the literature to be associated with the toxicity endpoints were included in the analysis. No SNP had been studied before in the REQUITE cohort. Deep Sparse AutoEncoders (DSAE) were trained to recognize features (SNPs) identifying patients with no toxicity and tested on a different independent mixed population including patients without and with toxicity.Results: One thousand, four hundred and one patients were included, and toxicity rates were: rectal bleeding 11.7%, urinary frequency 4%, haematuria 5.5%, nocturia 7.8%, decreased urinary stream 17.1%. Twenty-four of the 43 SNPs that were associated with the toxicity endpoints were validated as identifying patients with toxicity. Twenty of the 24 SNPs were associated with the same toxicity endpoint as reported in the literature: 9 SNPs for urinary symptoms and 11 SNPs for overall toxicity. The other 4 SNPs were associated with a different endpoint.Conclusion: Deep learning algorithms can validate SNPs associated with toxicity after radiotherapy for prostate cancer. The method should be studied further to identify polygenic SNP risk signatures for radiotherapy toxicity. The signatures could then be included in integrated normal tissue complication probability models and tested for their ability to personalize radiotherapy treatment planning.

Background: Cancer-specific survival (CSS) within high-risk non-metastatic prostate cancer varies dramatically. It is likely that within this heterogenous population there are subgroup(s) at extraordinary risk, burdened with an exaptational poor prognosis. Establishing the characteristics of these group(s) would have significant clinical implications since high quality preoperative risk stratification remains the cornerstone of therapeutic decision making to date.Objective: To stratify high-risk prostate cancer based on preoperative characteristics and evaluate cancer specific survival after radical prostatectomy.Method: The EMPaCT multi-center database offers an international population of non-metastatic high-risk prostate cancer. Preoperative characteristics such as age, biopsy Gleason score, PSA and clinical stage were subcategorized. A multivariate analysis was performed using predictors showing significant survival heterogeneity after stratification, as observed by a univariate analysis. Based upon the hazard ratios of this multivariate analysis, a proportional score system was created. The most ideal group distribution was evaluated trough different score cut-off's. The predictive value was tested by the herald C index.Results: An overall 5-years CSS of 94% was noted within the entire high-risk cohort (n = 4,879). Except for age, all preoperative risk factors showed a significantly differing CSS. Multivariate analysis indicated, T4 stage as being the strongest predictor of CSS (HR: 3.31), followed by ISUP grade 5 group (HR 3,05). A score system was created by doubling the hazard ratios of this multivariate analysis and rounding off to the nearest complete number. Multivariate analysis suggested 0, 4, 8, and 12 pts as being the most optimal group distribution (p-value: 0.0015). Five-years CSS of these groups were 97, 93, 87, and 70%, respectively. The calculated Herald C-index of the model was 0.77.Conclusion: An easy-to-use pre-operative model for risk stratification of newly diagnosed high-risk prostate cancer is presented. The heterogeneous CSS of high-risk non-metastatic prostate cancer after radical prostatectomy is illustrated. The model is clinically accessible through an online calculator, presenting cancer specific survival based on individualized patient characteristics.

Abstract Background Recent retrospective data suggest that neoadjuvant androgen deprivation therapy can improve the prognosis of high-risk prostate cancer (PCa) patients. Novel androgen receptor pathway inhibitors are nowadays available for treatment of metastatic PCa and these compounds are promising for early stage disease. Apalutamide is a pure androgen antagonist with a very high affinity with the androgen receptor. The combination of apalutamide with degarelix, an LHRH antagonist, could increase the efficacy compared to degarelix alone. Objective The primary objective is to assess the difference in proportions of minimal residual disease at prostatectomy specimen between apalutamide + degarelix vs placebo + degarelix. Various secondary endpoints are assessed: variations of different biomarkers at the tumour level (tissue microarrays to evaluate DNA-PKs, PARP, AR and splice variants, PSMA, etc.), whole transcriptome sequencing, exome sequencing and clinical (PSA and testosterone kinetics, early biochemical recurrence free survival, quality of life, safety, etc.) and radiological endpoints. Methods ARNEO is a single centre, phase II, randomized, double blind, placebo-controlled trial. The plan is to include at least 42 patients per each of the two study arms. Patients with intermediate/high-risk PCa and who are amenable for radical prostatectomy with pelvic lymph node dissection can be included. After signing an informed consent, every patient will undergo a pelvic 68Ga -PSMA-11 PSMA PET/MR and receive degarelix at standard dosage and start assuming apalutamide/placebo (60 mg 4 tablets/day) for 12 weeks. Within thirty days from the last study medication intake the same imaging will be repeated. Every patient will undergo PSA and testosterone testing the day of randomization, before the first drug intake, and after the last dose. Formalin fixed paraffin embedded tumour samples will be collected and used for transcriptome analysis, exome sequencing and immunohistochemistry. Discussion ARNEO will allow us to answer, first, whether the combined treatment can result in an increased proportion of patients with minimal residual disease. Secondly, It will enable the study of the molecular consequences at the level of the tumour. Thirdly, what the consequences are of new generation androgen receptor pathway inhibitors on 68Ga -PSMA-11 PET/MR. Finally, various clinical, safety and quality of life data will be collected. Trial Registration EUDRaCT number: 2016–002854-19 (authorization date 3rd August 2017). clinicalTrial.gov: NCT03080116.

Abstract Background Prostate cancer (PCa) is a heterogeneous disease with a variable natural history, genetics, and treatment outcome. The Hedgehog (Hh) signaling pathway is increasingly recognized as being potentially important for the development and progression of PCa. In this retrospective study, we compared the activation status of the Hh signaling pathway between benign and tumor tissue, and evaluated the clinical significance of Hh signaling in PCa. Methods In this tissue microarray (TMA) study, the protein expression of several Hh signaling components and Hh target proteins, along with microvessel density, were compared between benign (n = 64) and malignant (n = 170) prostate tissue, and correlated with PCa clinicopathological characteristics and biochemical recurrence (BCR). Results The Hh signaling pathway appeared to be more active in PCa than in benign prostate tissue, as demonstrated by lower expression of the negative regulators PTCH1 and GLI3 in the tumor tissue compared to benign. In addition, high epithelial GLI2 expression correlated with higher pathological Gleason score. Overall, higher epithelial GLI3 expression in the tumor was shown to be an independent marker of a favorable prognosis. Conclusion Hh signaling activation might reflect aggressive tumoral behavior, since high epithelial GLI2 expression positively correlates with a higher pathological Gleason score. Moreover, higher epithelial GLI3 expression is an independent marker of a more favorable prognosis.

Due to the advantages of charged particles compared to conventional radiotherapy, a vast increase is noted in the use of particle therapy in the clinic. These advantages include an improved dose deposition and increased biological effectiveness. Metastasis is still an important cause of mortality in cancer patients and evidence has shown that conventional radiotherapy can increase the formation of metastasizing cells. An important pathway involved in the process of metastasis is the Hedgehog (Hh) signaling pathway. Recent studies have demonstrated that activation of the Hh pathway, in response to X-rays, can lead to radioresistance and increased migratory, and invasive capabilities of cancer cells. Here, we investigated the effect of X-rays, protons, and carbon ions on cell survival, migration, and Hh pathway gene expression in prostate cancer (PC3) and medulloblastoma (DAOY) cell lines. In addition, the potential modulation of cell survival and migration by the Hh pathway inhibitor GANT61 was investigated. We found that in both cell lines, carbon ions were more effective in decreasing cell survival and migration as well as inducing more significant alterations in the Hh pathway genes compared to X-rays or protons. In addition, we show here for the first time that the Hh inhibitor GANT61 is able to sensitize DAOY medulloblastoma cells to particle radiation (proton and carbon ion) but not to conventional X-rays. This important finding demonstrates that the results of combination treatment strategies with X-ray radiotherapy cannot be automatically extrapolated to particle therapy and should be investigated separately. In conclusion, combining GANT61 with particle radiation could offer a benefit for specific cancer types with regard to cancer cell survival.

Aim: To determine the impact of the extent of lymph node invasion (LNI), on long-term oncological outcomes after radical prostatectomy (RP). Material and methods: In this retrospective study we examined the data of 1249 high-risk, non-metastatic PCa patients treated with RP and pelvic lymph node dissection (PLND) between 1989 and 2011 at 8 different tertiary institutions. We fitted univariate and multivariate cox models to assess independent predictors of cancer specific survival (CSS) and overall survival (OS). The number of positive LN was dichotomized according to the most informative cut-off predicting CSS. Kaplan-Meier curves assessed CSS and OS rates. Only patients with at least 10 LNs removed at PLND were included. This cut-off was chosen as a surrogate for a well performed PNLD.Results: Mean age was 65 years (median: 66, IQR 60-70). Positive surgical margins were present in 53.7% (n=671). Final Gleason score was 2-6 in 12.7% (n=158), 7 in 52% (n=649) and 8-10 in 35.4% (n=442). The median number of LNs removed during PLND was 15 (IQR 12-17). Of all patients, 1128 (90.3%) had 0-3 positive LNs, while 126 (9.7%) had ≥4 positive LNs. Patients with 0-3 positive LNs had significantly better CSS outcome at 10-year follow-up compared to patients with ≥4 positive LNs (87% vs. 50%; p < 0.0001). Similar results were obtained for OS, with a 72% vs. 37% (p

BackgroundProstate cancer (PCa) is a very heterogeneous disease with respect to clinical outcome. This study explored differential DNA methylation in a priori selected genes to diagnose PCa and predict clinical failure (CF) in high-risk patients.MethodsA quantitative multiplex, methylation-specific PCR assay was developed to assess promoter methylation of the APC, CCND2, GSTP1, PTGS2 and RARB genes in formalin-fixed, paraffin-embedded tissue samples from 42 patients with benign prostatic hyperplasia and radical prostatectomy specimens of patients with high-risk PCa, encompassing training and validation cohorts of 147 and 71 patients, respectively. Log-rank tests, univariate and multivariate Cox models were used to investigate the prognostic value of the DNA methylation.ResultsHypermethylation of APC, CCND2, GSTP1, PTGS2 and RARB was highly cancer-specific. However, only GSTP1 methylation was significantly associated with CF in both independent high-risk PCa cohorts. Importantly, trichotomization into low, moderate and high GSTP1 methylation level subgroups was highly predictive for CF. Patients with either a low or high GSTP1 methylation level, as compared to the moderate methylation groups, were at a higher risk for CF in both the training (Hazard ratio [HR], 3.65; 95% CI, 1.65 to 8.07) and validation sets (HR, 4.27; 95% CI, 1.03 to 17.72) as well as in the combined cohort (HR, 2.74; 95% CI, 1.42 to 5.27) in multivariate analysis.ConclusionsClassification of primary high-risk tumors into three subtypes based on DNA methylation can be combined with clinico-pathological parameters for a more informative risk-stratification of these PCa patients.