Purpose: To present results from the trial radiotherapy quality assurance (RTQA) programme of the centres involved in the randomised phase-III PROton versus photon Therapy for esophageal Cancer – a Trimodality strategy (PROTECT)-trial, investigating the clinical effect of proton therapy (PT) vs. photon therapy (XT) for patients with oesophageal cancer. Materials and methods: The pre-trial RTQA programme consists of benchmark target and organ at risk (OAR) delineations as well as treatment planning cases, a facility questionnaire and beam output audits. Continuous on-trial RTQA with individual case review (ICR) of the first two patients and every fifth patient at each participating site is performed. Patient-specific QA is mandatory for all patients. On-site visits are scheduled after the inclusion of the first two patients at two associated PT and XT sites. Workshops are arranged annually for all PROTECT participants. Results: Fifteen PT/XT sites are enrolled in the trial RTQA programme. Of these, eight PT/XT sites have completed the entire pre-trial RTQA programme. Three sites are actively including patients in the trial. On-trial ICR was performed for 22 patients. For the delineation of targets and OARs, six major and 11 minor variations were reported, and for six patients, there were no remarks. One major and four minor variations were reported for the treatment plans. Three site visits and two annual workshops were completed. Interpretation: A comprehensive RTQA programme was implemented for the PROTECT phase III trial. All centres adhered to guidelines for pre-trial QA. For on-trial QA, major variations were primarily seen for target delineations (< 30%), and no treatment plans required re-optimisation.

Purpose To introduce a new model formalism for the assessment of secondary cancer (SC) risk after proton therapy, accounting explicitly for the specific radiation quality of the beam, and to present results of a first application to two patient cohorts. Methods A dedicated adaptation of the microdosimetric kinetic model (MKM) model was combined with the Schneider model for excess absolute risk (EAR) calculation, extending its applicability from reference photon radiation to charged particles with different values of linear energy transfer. Plans for proton treatment of Lymphoma and Breast targets were recalculated with a Monte Carlo tool (TOPAS) to obtain voxel-by-voxel radiation quality distributions. To feed the model for computing an RBE for the specific endpoint of radiation-induced mutations, this information was joined with epidemiology-based parameterization to compute the EAR for the different patients, organs, and for different tentative α/β values of the involved tissues. Results A non-negligible impact of the explicit integration of RBE in the proposed model, as compared to estimates without (i.e. plain Schneider approach) is evident in all evaluated cases, with a strong impact of the α/β value for mutation induction. Lower levels of α/β ratio correlate with larger effects of the LET correction. Conclusions Accounting for the specific radiation quality of proton beams impacts EAR estimation, providing a more comprehensive picture in terms of SC risk prediction. Our analysis confirmed, however, that overall SC risk associated with modern proton treatments is not dramatically larger than that achievable by pure physical dose-based estimates for the most probable α/β values.

Halyomorpha halys (Heteroptera: Pentatomidae) is an insect pest native to Asia that has spread over the last two decades to most of the North America, parts of South America, Europe and North Africa. Its impact is significant as it can feed on more than 300 host plants, rendering affected fruits and vegetable crops unsellable or of lower quality. Various chemical and biological methods have been used to control this pest, with varying degrees of success. The sterile insect technique (SIT) is a pest control method involving the sterilization of insects via ionizing radiation and their subsequent mass release into the field. In the present contribution, the spermiogenesis of H. halys was studied from an ultrastructural point of view in both irradiated and non-irradiated adult males. In both cases, we observed ultrastructural characteristics typical of hemipteran sperm cells: bridges connecting the mitochondrial derivatives and the axonemal microtubules, the absence of accessory bodies, and the presence of two or three crystalline inclusions within the mitochondrial derivatives, an acrosome composed of tightly packed tubules, and an atypical, plaque-shaped microtubular organizing center (MTOC) in the centriolar region. Moreover, in the same region, we seldom observed the presence of two centrioles in the spermatids, one of which disappeared at a later stage of maturation. This feature is a novelty for insect spermiogenesis. The cysts of irradiated adults were not all uniformly affected by the radiation. However, irradiated cysts sometimes exhibited a general disorganization of sperm arrangement, incomplete divisions of sperm cells resulting in multiple copies of the same organelle within the same cell, failure to reabsorb the cytoplasm, and the lack of axonemes. Finally, rod-shaped viruses or virus-like particles were observed in vasa deferentia independently of irradiation.

Radiotherapy plays an essential role in the treatment of breast cancer (BC). Recent advances in treatment technology and radiobiological knowledge have a major impact in BC patients with locoregional disease as the majority are now long-term survivors.Over the last three decades, intensity-modulated radiotherapy (IMRT), volumetric-modulated arc therapy (VMAT) and deep inspiration breath-hold (DIBH) techniques, together with the increasing adoption of moderately hypofractionated and ultra-hypofractionated treatment schedules as well as the possibility to offer partial breast radiotherapy to a well-defined patient subset have significantly changed radiotherapy for BC patients.As dose-volume constraints (DVCs) have to be adapted to these new treatment paradigms we have reviewed available evidence-based data concerning dose-constraints for the main organs at risk (OARs) that apply to the treatment of whole breast/chest wall radiotherapy, whole breast/chest wall radiotherapy including regional nodal irradiation (RNI) and partial breast irradiation (PBI), for the most relevant fractionation schedules that have been introduced recently. This narrative review provides a comprehensive summary that may help to harmonize treatment planning strategies.

The brown marmorated stink bug, Halyomorpha halys, is a pentatomid bug of Eastern Asian origin that became an economically relevant pest in the Eurasian and American continents. Management of this species is limited to use of chemical insecticides: an inefficient method due to the strong adaptability of the target pest. The sterile insect technique (SIT) is potentially a valid tactic in the search for nontoxic alternatives. In this work, we investigated the suitability of mass-trapped overwintering males, collected during the aggregation phase before the winter diapause, for their release as competitive sterile males in an SIT programme. Differently from previous studies, irradiation was applied with a linear accelerator device that produced high-energy photons. Following a similar scientific protocol with newly emerged irradiated males, the effects of X-ray irradiation on physiological parameters (longevity, fecundity and fertility) were assessed. In addition, behavioural bioassays were carried out in no-choice conditions to evaluate if irradiation interferes with mating processes. The results are very encouraging; the effects of the irradiation at 32 Gy did not differ from the controls in the longevity or fecundity of the exposed overwintering adults. The hatching rate of the eggs laid by the fertile females that had mated with the irradiated males was less than 5%. The results of behavioural bioassays showed that the irradiation did not cause a significant impact on the quality of the sterile males. More research is warranted to evaluate the mating competitiveness of sterile males in semi-field and field conditions.

PURPOSE:Comparative outcome data after intraoperative radiation therapy and whole breast irradiation (WBI) for breast cancer at >10 years median follow-up are rare. We present a mature, single-institution, matched-pair comparison reporting survival and relapse rates in patients treated with either modality. METHODS AND MATERIALS:Complete data sets for 258 intraoperative electron radiation therapy (IOERT) patients treated between 2000 and 2010 were matched with 258 patients postoperatively treated with WBI by age/histology/tumor size, grading/lymph-node-status/hormone receptors/type of adjuvant therapy/surgical margins, and treatment date. Relapse at surgical intervention site was classified as true local recurrence (LR). All recurrences in the treated breast (any quadrant) were classified as ipsilateral recurrence (IR). RESULTS:Median follow-up was 157 months (12-251) for the IOERT group and 154 months (31-246) for the WBI group. Cumulative incidence of IR at 5, 10, and 15 years was 2.4%, 7.9%, and 12.7% for IOERT and 1.2%, 4.1%, and 5.0% for WBI (P = .02). Cumulative incidence of LR at 5, 10, and 15 years was 1.6%, 5.1%, and 8.3% for IOERT and 0.4%, 2.1%, and 2.5% for WBI (P = .02). No differences in overall survival, disease-free survival, second cancer incidence, or cardiac events were recorded in either treatment group. Outcome was better in the accelerated partial breast irradiation (APBI)-suitable group than in the APBI-unsuitable group (2009 criteria) (cumulative incidence of IR at 5, 10, and 15 years was 0% vs 7.3%, 6.1% vs 13.3%, and 7.3% vs 19.9% for IOERT and 0% vs 1.8%, 2.0% vs 3.9%, and 3.1% vs 3.9% for WBI) and in the revised APBI-suitable group than in the APBI-cautionary group (2017 criteria) (cumulative incidence of IR at 5, 10, and 15 years was 1.1% vs 6.4%, 6.2% vs 13.3%, and 7.8% vs 27.5% for IOERT and 1.7% vs 0%, 4.1% vs 4.4%, and 5.4% vs 4.4% for WBI). CONCLUSIONS:The IR and LR rate were higher after IOERT than after WBI for the American Society for Radiation Oncology suitable patient group, although without reaching statistical significance. Thus, IOERT could be an alternative to WBI upon stringent patient selection, but patients should be counseled carefully about the potential for increased IR rate with IOERT. Second cancer incidence and cardiac events did not differ between IOERT and WBI.

Abstract Funding Acknowledgements Type of funding sources: None. Background An increasing number of patients need cardiac implantable electronic devices (CIED) for bradycardia or to prevent sudden cardiac death. At the same time many patients require radiotherapy for oncologic reasons. Interaction between CIEDs and ionizing radiations may cause several dysfunctions: electromagnetic interferences due to oversensing, CIED reset, drainage of the battery, hardware damage to the pulse generator and to the lead-tissue interface. Purpose An adequate planning is expected to guarantee the safety of CIED patients, reducing the potential complications. We describe our protocol in use and its application. Methods In 2016 an internal protocol was written to standardize the approach to CIED patients undergoing radiotherapy. Cardiology Department, Radiotherapy Unit and Medical Physics were involved in the draft. We stratified patients in high and low risk groups according to the CIED characteristics (ICD vs pacemaker), electro-dependency (yes vs no), and the estimated radiation dose (< 2 Gy: 2-10 Gy, > 10 Gy). Low risk group: - Non pacemaker (PM) dependent patients, estimated dose < 10 Gy - PM dependent patients, estimated dose < 2 Gy High risk group: - PM dependent patients, estimated dose > 2 Gy - Non-PM dependent patients estimated dose >10 Gy - ICD patients Two EHRA certificated nurses followed up the patients before, during and after the radiotherapy. Low risk patients received weekly in office evaluation during radiotherapy course. High risk patients were scheduled for daily in office check plus monitoring during each radiotherapy session, ICD therapy was temporarily switched off during each radiotherapy session. An in office evaluation was planned 1, 3, 6 and 12 months after the end of radiotherapy course until 2019, since 2020 all patients were given remote monitoring for accurate follow up. Results Between 2016 and November 2022 101 patients with CIED underwent radiotherapy in our facility. Clinical characteristics of the patients are described in Table 1. EHRA certificated nurses managed 1282 radiotherapy sessions without any complication. A transient underestimation of ICD longevity was the only software error occurred. Conclusions The reported protocol assured a safe radiotherapy course for all our CIED patients. Given the limited data available about the interaction between the newest CIEDs and radiotherapy, we opted for a high safety profile. The EHRA certified nurse’s involvement allowed to optimize personnel resources.

Current follow-up policies for early breast cancer aim to detect loco-regional recurrences and manage treatment-related adverse effects. Their "one size fits all" approach does not take into account differences in subtypes at initial diagnosis, individual prognosis and treatments received. They are derived from clinical trials conducted when early detection means - other than mammography - and treatment options were limited. Herein, we address the arguments for re-evaluating current breast cancer follow-up strategies starting from recent advances in breast cancer local and systemic treatments and discussing individual risk of recurrence prediction models, time-adapted imaging and biomarker assessment for disease diagnostic anticipation. This change in perspective would transform breast cancer follow-up into an integrated, multidisciplinary team medical practice. Hence we discuss the important role of patient-centered approaches, but also of general practitioners and other health professionals, in the final promotion of personalized surveillance programs and patient education.

[This corrects the article DOI: 10.3389/fonc.2021.744956.].

Purpose A radiomics features classifier was implemented to evaluate segmentation quality of heart structures. A robust feature set sensitive to incorrect contouring would provide an ideal quantitative index to drive autocontouring optimization. Methods Twenty-five cardiac sub-structures were contoured as regions of interest in 36 CTs. Radiomic features were extracted from manually-contoured (MC) and Hierarchical-Clustering automatic-contouring (AC) structures. A robust feature-set was identified from correctly contoured CT datasets. Features variation was analyzed over a MC/AC dataset. A supervised-learning approach was used to train an Artificial-Intelligence (AI) classifier; incorrect contouring cases were generated from the gold-standard MC datasets with translations, expansions and contractions. ROC curves and confusion matrices were used to evaluate the AI-classifier performance. Results Twenty radiomics features, were found to be robust across structures, showing a good/excellent intra-class correlation coefficient (ICC) index comparing MC/AC. A significant correlation was obtained with quantitative indexes (Dice-Index, Hausdorff-distance). The trained AI-classifier detected correct contours (CC) and not correct contours (NCC) with an accuracy of 82.6% and AUC of 0.91. True positive rate (TPR) was 85.1% and 81.3% for CC and NCC. Detection of NCC at this point of the development still depended strongly on degree of contouring imperfection. Conclusions A set of radiomics features, robust on "gold-standard" contour and sensitive to incorrect contouring was identified and implemented in an AI-workflow to quantify segmentation accuracy. This workflow permits an automatic assessment of segmentation quality and may accelerate expansion of an existing autocontouring atlas database as well as improve dosimetric analyses of large treatment plan databases.

INTRODUCTION:For unresectable stage III non-small cell lung cancer (NSCLC), the standard therapy consists of chemoradiotherapy (CRT) followed by durvalumab maintenance for responding patients. The present study reports on the safety and outcome of durvalumab use after CRT in a real-world, multicenter, retrospective cohort.METHODS:Two hundred thirty-eight patients have been included. We collected data on systemic therapy, radiation therapy, the timing between CRT and durvalumab, number of durvalumab cycles, reasons for non-starting or discontinuation, incidence and grade of adverse events (AEs), and progression-free survival (PFS) and overall survival (OS).RESULTS:One hundred fifty-five patients out of 238 (65.1%) received at least one durvalumab dose: 91 (58.7%) after concomitant CRT (cCRT) and 64 (41.3%) after sequential CRT (sCRT). Programmed-death ligand 1 (PD-L1) status was unknown in 7/155 (4.5%), negative in 14 (9.1%), and positive ≥1% in 134/155 (86.4%). The main reasons for non-starting durvalumab were progression (10.1%), PD-L1 negativity (7.5%), and lung toxicity (4.6%). Median follow-up time was 14 months (range 2–29); 1-year PFS and OS were 65.5% (95%CI: 57.6-74.4) and 87.9% (95%CI: 82.26.6-93.9), respectively. No significant differences in PFS or OS were detected for cCRT vs. sCRT, but the median PFS was 13.5 months for sCRT vs. 23 months for cCRT. Potentially immune-related AEs were recorded in 76/155 patients (49.0%). Pneumonitis was the most frequent, leading to discontinuation in 11/155 patients (7.1%).CONCLUSIONS:Durvalumab maintenenace after concurrent or sequential chemoradiation for unresectable, stage III NSCLC showed very promising short-term survival results in a large, multicenter, restrospective, real-world study. Durvalumab was the first drug obtaining a survival benefit over CRT within the past two decades, and the present study contributes to validating its use in clinical practice.

4558 Background: The NIVES study represents the first prospective trial with NIVO in combination with SBRT in pre-treated mRCC patients. This study did not meet the primary endpoint in terms of objective response rate (ORR) as previously reported. However this combination showed a faster time to treatment response, a long progression free survival and median duration of response without increasing toxicities. Here we have tested with an exploratory analysis the correlation between PD-L1 expression and clinical outcomes in pts treated with NIVO plus SBRT. Methods: PD-L1 expression was assessed in archival collected tumour samples in our central laboratory using 4 commercial kits for immunoistochemical (ICH) analysis (clone 22C3 pharm DX Dako Agilent, 28.8 Abcam and SP142 and SP263 Ventana Medical System). A tumor cell was considered positive if any membranous staining was found regardless of the intensity. In particular the immunostaining was scored 0 when all tumor cells were unstained (PD-L1-negative), 1+ when < 1% positive tumor cells were counted, 2+ when the percentage was between 1% and 50%,3+ when the number of stained cells was more than 50%. ORR and overall survival (OS) were correlated with PD-L1 staining. Results: Formalin-fixed paraffin-embedded (FFPE) specimens were obtained from 44 of 69 pts enrolled in the NIVES study. Twenty-two pts of 44 (50%) were considered PD-L1-negative using all the 4 commercial kits for ICH analysis, while 14 of 44 pts (31,8%) were defined PD-L1 weakly positive (positive tumor cells < 1% at least in one kit for ICH). Eight of 44 pts (18.1%) were defined PD-L1 strong positive when at least one kit for ICH scored 2+ or 3+. About the correlation between ORR and PDL1 staining in the 42 pts (2/44 pts are not evaluable for ORR), ORR was 18.2% (95% CI, 5.2% to 40.3%) in the PD-L1-negative group vs 20% (95% CI, 5.7% to 43.7%) in weakly/strongly PD-L1 positive (p = 1.00). Among the 44 pts in the intention-to-treat population with available PD-L1 status, median OS was not significantly different between pts with PD-L1 negative (20.56 months, 95% CI, 7.16 to NR) and PD-L1 positive (18.33 months, 95% CI, 6.83 to NR) (p = 0.56). Conclusions: For the first time four commercial kits for ICH analysis were used to test PD-L1 expression in pretreated mRCC pts. Data from these small sample size seem to confirm that PD-L1 in pre-treated mRCC cancer is not a predictive biomarker for selecting pts to receive NIVO-based treatment. Clinical trial information: NCT03469713.

Background and purpose: Recurrent nasopharyngeal carcinoma (NPC) has limited curative treatment options. Reirradiation is the only potential definitive treatment in advanced stages at a cost of substantial severe and often life-threatening toxicity. Proton therapy (PT) reduces irradiated volume compared with X-ray radiotherapy and could be advantageous in terms of safety and efficacy in a population of heavily pretreated patients. We report the retrospective results of PT reirradiation in recurrent NPC patients treated at our Institution Methods: All recurrent NPC patients treated since the beginning of clinical activity entered the present analysis. Clinical target volume consisted of Gross Tumor volume plus a patient-specific margin depending on disease behavior, tumor location, proximity of organs at risk, previous radiation dose. No elective nodal irradiation was performed. Active scanning technique with the use of Single Field Optimization (SFO) or Multifield Optimization (MFO) was adopted. Cumulative X-ray -PT doses were calculated for all patients using a dose accumulation tool since 2016. Treatment toxicity was retrospectively collected. Results: Between February 2015, and October 2018, 17 recurrent NPC patients were treated. Median follow-up (FUP) was 10 months (range 2-41). Median PT reirradiation dose was 60 Gy RBE (range 30.6-66). The majority of patients (53%) underwent concomitant chemotherapy. Acute toxicity was low with no ≥ G3 adverse events. Late events ≥ G3 occurred in 23.5% of patients. Most frequent late toxicity was hearing impairment (17,6%). G2 soft tissue necrosis occurred in two patients. Fatal bleeding of uncertain cause (either tumor recurrence or G5 carotid blowout) occurred in one patient. Kaplan-Meier 18 months Overall Survival (OS) and Local control (LC) rates were 54.4% and 66.6%, respectively. Conclusions: Our initial results with the use of modern PT for reirradiation of recurrent NPC patients are encouraging. Favorable LC and OS rates were obtained at the cost of acceptable severe late toxicity.