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Stereotactic Body Radiation Therapy (SBRT) is a standard of care for many localizations but the question of the optimal fractionation remains a matter of concern. If single fraction sessions are routinely used for intracranial targets, their utilization for mobile extracranial lesions is a source of debate and apprehension. Single session treatments improve patient comfort, provide a medico-economic benefit, and have proven useful in the context of the SARS-CoV 2 pandemic. However, both technical and radiobiological uncertainties remain. Experience from intracranial radiosurgery has shown that the size of the target, its proximity to organs at risk, tumor histology, and the volume of normal tissue irradiated are all determining factors in the choice of fractionation. The literature on the use of single fraction for extracranial sites is still scarce. Only primary and secondary pulmonary tumors have been evaluated in prospective randomized trials, allowing the integration of these fractionation schemes in daily practice, for highly selected cases and in trained teams. The level of evidence for the other organs is mainly based on dose escalation or retrospective trials and calls for caution, with further studies being needed before routine use in clinical practice.

Background: Immuno-radiotherapy may improve outcomes for patients with advanced solid tumors, although optimized combination modalities remain unclear. Here, we report the colorectal (CRC) cohort analysis from the SABR-PDL1 trial that evaluated the PD-L1 inhibitor atezolizumab in combination with stereotactic body radiation therapy (SBRT) in advanced cancer patients., Methods: Eligible patients received atezolizumab 1200 mg every 3 weeks until progression or unmanageable toxicity, together with ablative SBRT delivered concurrently with the 2nd cycle (recommended dose of 45 Gy in 3 fractions, adapted upon normal tissue tolerance constraint). SBRT was delivered to at least one tumor site, with at least one additional measurable lesion being kept from the radiation field. The primary efficacy endpoint was one-year progression-free survival (PFS) rate from the start of atezolizumab. Sequential tumor biopsies were collected for deep multi-feature immune profiling., Results: Sixty pretreated (median of 2 prior lines) advanced CRC patients (38 men [63%]; median age, 59 years [range, 20-81 years]; 77% with liver metastases) were enrolled in five centers (France: n = 4, Spain: n = 1) from 11/2016 to 04/2019. All but one (98%) received atezolizumab and 54/60 (90%) received SBRT. The most frequently irradiated site was lung (n = 30/54; 56.3%). Treatment-related G3 (no G4-5) toxicity was observed in 3 (5%) patients. Median OS and PFS were respectively 8.4 [95%CI:5.9-11.6] and 1.4 months [95%CI:1.2-2.6], including five (9%) patients with PFS > 1 year (median time to progression: 19.2 months, including 2/5 MMR-proficient). Best overall responses consisted of stable disease (n = 38; 64%), partial (n = 3; 5%) and complete response (n = 1; 2%). Immune-centric multiplex IHC and RNAseq showed that SBRT redirected immune cells towards tumor lesions, even in the case of radio-induced lymphopenia. Baseline tumor PD-L1 and IRF1 nuclear expression (both in CD3 + T cells and in CD68 + cells) were higher in responding patients. Upregulation of genes that encode for proteins known to increase T and B cell trafficking to tumors (CCL19, CXCL9), migration (MACF1) and tumor cell killing (GZMB) correlated with responses., Conclusions: This study provides new data on the feasibility, efficacy, and immune context of tumors that may help identifying advanced CRC patients most likely to respond to immuno-radiotherapy., Trial Registration: EudraCT N°: 2015-005464-42; Clinicaltrial.gov number: NCT02992912., (© 2024. The Author(s).)

Stereotactic Body Radiation Therapy (SBRT) is a standard of care for many localizations but the question of the optimal fractionation remains a matter of concern. If single fraction sessions are routinely used for intracranial targets, their utilization for mobile extracranial lesions is a source of debate and apprehension. Single session treatments improve patient comfort, provide a medico-economic benefit, and have proven useful in the context of the SARS-CoV 2 pandemic. However, both technical and radiobiological uncertainties remain. Experience from intracranial radiosurgery has shown that the size of the target, its proximity to organs at risk, tumor histology, and the volume of normal tissue irradiated are all determining factors in the choice of fractionation. The literature on the use of single fraction for extracranial sites is still scarce. Only primary and secondary pulmonary tumors have been evaluated in prospective randomized trials, allowing the integration of these fractionation schemes in daily practice, for highly selected cases and in trained teams. The level of evidence for the other organs is mainly based on dose escalation or retrospective trials and calls for caution, with further studies being needed before routine use in clinical practice., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 Published by Elsevier B.V. on behalf of European Society for Radiotherapy and Oncology.)

Background: Combining radiotherapy (RT) with immuno-oncology (IO) therapy (IORT) may enhance IO-induced antitumor response. Quantitative imaging biomarkers can be used to provide prognosis, predict tumor response in a non-invasive fashion and improve patient selection for IORT. A biologically inspired CD8 T-cells-associated radiomics signature has been developed on previous cohorts. We evaluated here whether this CD8 radiomic signature is associated with lesion response, whether it may help to assess disease spatial heterogeneity for predicting outcomes of patients treated with IORT. We also evaluated differences between irradiated and non-irradiated lesions., Methods: Clinical data from patients with advanced solid tumors in six independent clinical studies of IORT were investigated. Immunotherapy consisted of 4 different drugs (antiprogrammed death-ligand 1 or anticytotoxic T-lymphocyte-associated protein 4 in monotherapy). Most patients received stereotactic RT to one lesion. Irradiated and non-irradiated lesions were delineated from baseline and the first evaluation CT scans. Radiomic features were extracted from contrast-enhanced CT images and the CD8 radiomics signature was applied. A responding lesion was defined by a decrease in lesion size of at least 30%. Dispersion metrices of the radiomics signature were estimated to evaluate the impact of tumor heterogeneity in patient's response., Results: A total of 94 patients involving multiple lesions (100 irradiated and 189 non-irradiated lesions) were considered for a statistical interpretation. Lesions with high CD8 radiomics score at baseline were associated with significantly higher tumor response (area under the receiving operating characteristic curve (AUC)=0.63, p=0.0020). Entropy of the radiomics scores distribution on all lesions was shown to be associated with progression-free survival (HR=1.67, p=0.040), out-of-field abscopal response (AUC=0.70, p=0.014) and overall survival (HR=2.08, p=0.023), which remained significant in a multivariate analysis including clinical and biological variables., Conclusions: These results enhance the predictive value of the biologically inspired CD8 radiomics score and suggests that tumor heterogeneity should be systematically considered in patients treated with IORT. This CD8 radiomics signature may help select patients who are most likely to benefit from IORT., Competing Interests: Competing interests: RS received travel and accommodation expenses from AstraZeneca. NS reports travel grants from Merck Sharpe & Dohme, Astellas, Bayer and Bristol-Myers Squibb. MH declares consulting fees, research grants and travel expenses from Merck Serono, MSD, Novartis, BMS and Teva. PO reports research grants from Merck Sharpe & Dohme, Astellas and Janssen; travel grants from Ipsen and Ferring Pharmaceuticals and honorarium from Ferring and Bayer. CR received research grants from Therapanacea and Elekta. CF is a full-time employee of AstraZeneca since September 2017. NP reports grants from GE, Biogen and consulting fees from AstraZeneca and Ipsen. J-CS reports consultancy fees from AstraZeneca, Astex, Clovis, GSK, GamaMabs, Lilly, MSD, Mission Therapeutics, Merus, Pfizer, PharmaMar, Pierre Fabre, Roche-Genentech, Sanofi, Servier, Symphogen, Takeda. J-CS has been Full time employee for AstraZeneca (September 2017–December 2019) and is a shareholder of AstraZeneca, Gritstone. CF received travel, accommodations, expenses from Amgen; Genentech; GlaxoSmithKline; MedImmune. CM is an advisory board member, speaker, investigator at Amgen, Astellas, AstraZeneca, Bayer, Celgene, Genentech, Ipsen, Janssen, Eli Lilly, Novartis, Pfizer, Roche, Sanofi, Orion. USG received support for presentation activities for Dr Sennewald Medizintechnik GmbH, has received support for investigator initiated clinical studies (IITs) from MSD and AstraZeneca and contributed at Advisory Boards Meetings of AstraZeneca and Bristol-Myers Squibb. RF received grants/research support from MSD; AstraZeneca; Merck (Germany/Darmstadt); Novocure; honoraria/consultation fees: MSD; AstraZeneca; Merck (Germany/Darmstadt); Novocure; Fresenius and reports participation in a company sponsered speakers bureau: AstraZeneca; MSD; Merck (Germany/Darmstadt); Sennewald; Novocure; Brainlab; Roche. ED has declared consulting fees and support from Roche, BMS, Boehringer, AstraZeneca, Lilly Amgen and Merck-Serono., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.)

Background: Metastatic breast cancer (MBC) behaviour differs depending on hormone receptors (HR) and human epidermal growth factor receptor (HER2) statuses., Methods: The kinetics of central nervous system (CNS) metastases (CNS metastasis-free survival, CNSM-FS) and subsequent patient's prognosis (overall survival, OS) according to the molecular subtype were retrospectively assessed in 16703 MBC patients of the ESME nationwide multicentre MBC database (Kaplan-Meier method)., Results: CNS metastases occurred in 4118 patients (24.6%) (7.2% at MBC diagnosis and 17.5% later during follow-up). Tumours were HER2-/HR+ (45.3%), HER2+/HR+ (14.5%), HER2+/HR- (14.9%) and triple negative (25.4%). Median age at CNS metastasis diagnosis was 58.1 years (range: 22.8-92.0). The median CNSM-FS was 10.8 months (95% CI: 16.5-17.9) among patients who developed CNS metastases. Molecular subtype was independently associated with CNSM-FS (HR = 3.45, 95% CI: 3.18-3.75, triple-negative and HER2-/HR+ tumours). After a 30-month follow-up, median OS after CNS metastasis diagnosis was 7.9 months (95% CI: 7.2-8.4). OS was independently associated with subtypes: median OS was 18.9 months (HR = 0.57, 95% CI: 0.50-0.64) for HER2+/HR+ , 13.1 months (HR = 0.72, 95% CI: 0.65-0.81) for HER2+/HR-, 4.4 months (HR = 1.55, 95% CI: 1.42-1.69) for triple-negative and 7.1 months for HER2-/HR+ patients (p <0.0001)., Conclusions: Tumour molecular subtypes strongly impact incidence, kinetics and prognosis of CNS metastases in MBC patients., Clinical Trial Registration: NCT03275311.

As the prognosis of metastatic non-small cell lung cancer (NSCLC) patients is constantly improving with advances in systemic therapies (immune checkpoint blockers and new generation of targeted molecular compounds), more attention should be paid to the diagnosis and management of treatments-related long-term secondary effects. Brain metastases (BM) occur frequently in the natural history of NSCLC and stereotactic radiation therapy (SRT) is one of the main efficient local non-invasive therapeutic methods. However, SRT may have some disabling side effects. Brain radiation necrosis (RN) represents one of the main limiting toxicities, generally occurring from 6 months to several years after treatment. The diagnosis of RN itself may be quite challenging, as conventional imaging is frequently not able to differentiate RN from BM recurrence. Retrospective studies have suggested increased incidence rates of RN in NSCLC patients with oncogenic driver mutations [epidermal growth factor receptor (EGFR) mutated or anaplastic lymphoma kinase (ALK) positive] or receiving tyrosine kinase inhibitors. The risk of immune checkpoint inhibitors in contributing to RN remains controversial. Treatment modalities for RN have not been prospectively compared. Those include surveillance, corticosteroids, bevacizumab and local interventions (minimally invasive laser interstitial thermal ablation or surgery). The aim of this review is to describe and discuss possible RN management options in the light of the newly available literature, with a particular focus on NSCLC patients.

Objective: To study the prognostic value of neutrophil disorders in a retrospective cohort of high-grade glioma patients receiving definitive concurrent temozolomide and radiation., Materials and Methods: Clinical records of consecutive patients treated in our Institution between January 2005 and December 2010 with concurrent temozolomide (75 mg/m 2 daily) and radiation were collected. The prognostic value of pretreatment neutrophilia on survival, defined as a neutrophil count exceeding 7 G/L, was examined., Results: We identified 164 patients, all treated with concurrent temozolomide-based chemoradiotherapy. Initial surgery was achieved in most (75%), with resection > 90% in 55 patients (34%). Total 151 patients (92%) had glioblastoma, and 13 patients (8%) had WHO grade III glioma. Eighty-two patients (50%) displayed pretreatment neutrophilia. Neutrophilia was not associated with concurrent or adjuvant temodal discontinuation (p > 0.3). The 2-year actuarial overall survival was 45%. Steroid consumption, i.e. 60 mg or more of daily prednisolone, increased pretreatment neutrophil count (p = 0.005). In univariate analysis, neutrophilia was associated with worse overall survival (p = 0.019), as well as age ≥ 65 years (p = 0.009), surgical resection < 90% (p = 0.003) and prednisolone consumption ≥ 60 mg/day (p = 0.016). In multivariate analysis, neutrophilia (p = 0.013), age ≥ 65 (p = 0.001), and surgical tumor resection < 90% (p = 0.010) independently decreased overall survival, while, steroid consumption was not (p = 0.088)., Conclusion: In high-grade gliomas treated with concurrent temozolomide and radiation, pretreatment neutrophilia may be a significant prognosis factor for overall survival. In addition with previously available markers, this independent cost-effective biomarker could help identifying patients with worsened prognosis.

Fluctuation analysis is the standard experimental method for measuring mutation rates in micro-organisms. The appearance of mutants is classically described by a Luria-Delbrück distribution composed of two parameters: the number of mutations per culture (m) and the differential growth rate between mutant and wild-type cells (b). A precise estimation of these two parameters is a prerequisite to the calculation of the mutation rate. Here, we developed bz-rates, a Web tool to calculate mutation rates that provides three useful advances over existing Web tools. First, it allows taking into account b, the differential growth rate between mutant and wild-type cells, in the estimation of m with the generating function. Second, bz-rates allows the user to take into account a deviation from the Luria-Delbrück distribution called z, the plating efficiency, in the estimation of m. Finally, the Web site provides a graphical visualization of the goodness-of-fit between the experimental data and the model. bz-rates is accessible at http://www.lcqb.upmc.fr/bzrates., (Copyright © 2015 Gillet-Markowska et al.)

The recent discovery that DNA methylation survives in fossil material provides an opportunity for novel molecular approaches in palaeogenomics. Here, we apply to ancient DNA extracts the probe-independent Methylated Binding Domains (MBD)-based enrichment method, which targets DNA molecules containing methylated CpGs. Using remains of a Palaeo-Eskimo Saqqaq individual, woolly mammoths, polar bears and two equine species, we confirm that DNA methylation survives in a variety of tissues, environmental contexts and over a large temporal range (4,000 to over 45,000 years before present). MBD enrichment, however, appears principally biased towards the recovery of CpG-rich and long DNA templates and is limited by the fast post-mortem cytosine deamination rates of methylated epialleles. This method, thus, appears only appropriate for the analysis of ancient methylomes from very well preserved samples, where both DNA fragmentation and deamination have been limited. This work represents an essential step toward the characterization of ancient methylation signatures, which will help understanding the role of epigenetic changes in past environmental and cultural transitions.

Background: Large anatomical variations occur during the course of intensity-modulated radiation therapy (IMRT) for locally advanced head and neck cancer (LAHNC). The risks are therefore a parotid glands (PG) overdose and a xerostomia increase. The purposes of the study were to estimate: - the PG overdose and the xerostomia risk increase during a "standard" IMRT (IMRTstd); - the benefits of an adaptive IMRT (ART) with weekly replanning to spare the PGs and limit the risk of xerostomia., Material and Methods: Fifteen patients received radical IMRT (70 Gy) for LAHNC. Weekly CTs were used to estimate the dose distributions delivered during the treatment, corresponding either to the initial planning (IMRTstd) or to weekly replanning (ART). PGs dose were recalculated at the fraction, from the weekly CTs. PG cumulated doses were then estimated using deformable image registration. The following PG doses were compared: pre-treatment planned dose, per-treatment IMRTstd and ART. The corresponding estimated risks of xerostomia were also compared. Correlations between anatomical markers and dose differences were searched., Results: Compared to the initial planning, a PG overdose was observed during IMRTstd for 59% of the PGs, with an average increase of 3.7 Gy (10.0 Gy maximum) for the mean dose, and of 8.2% (23.9% maximum) for the risk of xerostomia. Compared to the initial planning, weekly replanning reduced the PG mean dose for all the patients (p<0.05). In the overirradiated PG group, weekly replanning reduced the mean dose by 5.1 Gy (12.2 Gy maximum) and the absolute risk of xerostomia by 11% (p<0.01) (30% maximum). The PG overdose and the dosimetric benefit of replanning increased with the tumor shrinkage and the neck thickness reduction (p<0.001)., Conclusion: During the course of LAHNC IMRT, around 60% of the PGs are overdosed of 4 Gy. Weekly replanning decreased the PG mean dose by 5 Gy, and therefore by 11% the xerostomia risk.

Paranasal sinus cancers are rare, aggressive tumours that are usually diagnosed at an advanced stage. They differ from other upper aerodigestive tract tumours in terms of risk factors (wood dust exposure) and premalignant lesions (inverted papillomas). The diagnosis should be suspected in the presence of unilateral and continuous nasal sinus symptoms or bone lysis or a heterogeneous opacity on imaging. The definitive positive diagnosis is based on histological examination. Staging must comprise face, brain, neck and chest CT as well as face and brain MRI. Tumours are stage T3-T4 in two-thirds of cases and are associated with cervical lymph node involvement in 10% of squamous cell carcinomas and 4% of adenocarcinomas. These tumours must be managed in reference centres experienced in all of the various treatment modalities. Treatment decisions must be based on a multidisciplinary approach comprising local, regional and national REFCOR expertise (French rare head and neck cancer network). Optimal treatment is surgical resection with clear margins associated with adjuvant intensity-modulated radiotherapy (IMRT). Although it has been improved over recent decades, the prognosis remains poor with local recurrences occurring in 38% of cases and a five-year overall survival of about 63%., (Copyright © 2013. Published by Elsevier Masson SAS.)

This dosimetric study investigated the impact of multileaf collimators (MLC) leaf width in volumetric-modulated arc therapy (VMAT) for head and neck cancers (HNC), either with a "standard" simultaneously integrated boost technique (S-SIB) or with a "dose painting" SIB technique (DP-SIB). HNC patients were planned either with an S-SIB comprising three dose levels, from 56 to 70 Gy (16 patients), or with a DP-SIB comprising five dose levels, from 56 to 84 Gy (8 patients), in 35 fractions. Two VMAT plans were calculated for each SIB technique using two Elekta MLCs: MLCi2 with 10 mm leaf width and Beam Modulator (BM) with 4 mm leaf width. Dose distributions were evaluated by comparing doses on PTVs, main OARs, and healthy tissue, and by comparing conformation indexes. Treatment efficiencies were evaluated by comparing the number of monitor units and the number of needed arcs. Comparisons of the two MLCs depending on the two SIB techniques showed: i) Regarding PTVs: Dmean and D2% on lower doses PTV decreased respectively by 0.5 Gy (p = 0.01) and 0.9 Gy (p = 0.01) with BM than with MLCi2 for S-SIB; no significant difference was found for DP-SIB;ii) Regarding OARs: for spinal cord and brainstem, D2% decreased respectively by 1.2 Gy (p = 0.03) and 4.2 Gy (p = 0.04) with BM than with MLCi2 for S-SIB; for controlateral parotid, D50% decreased by 1.5 Gy (p = 0.01) with BM than with MLCi2 for S-SIB; iii) Regarding treatment efficiency: the number of monitor units was 44% (p = 0.00) and 51% (p = 0.01) higher with BM for S-SIB and DP-SIB, respectively. Two arcs were more frequently needed with BM to reach an acceptable dose distribution. This study demonstrated that Beam Modulator (4 mm leaf width) and MLCi2 (10 mm leaf width) MLCs from Elekta provided satisfactory dose distributions for treatment delivery with VMAT technique for complex HNC cases with standard and dose painting prescriptions. OAR sparing was better with BM, mainly for brainstem and spinal cord. However, delivery efficiency of VMAT plans was better with MLCi2.

Background: The objective was to analyze locoregional (LR) failure patterns in patients with head-and-neck cancer (HNC) treated using intensity-modulated radiotherapy (IMRT) with whole salivary gland-sparing: parotid (PG), submandibular (SMG), and accessory salivary glands represented by the oral cavity (OC)., Methods: Seventy consecutive patients with Stage I-II (23%) or III/IV (77%) HNC treated by definitive IMRT were included. For all LR failure patients, the FDG-PET and CT scans documenting recurrence were rigidly registered to the initial treatment planning CT. Failure volumes (Vf) were delineated based on clinical, radiological, and histological data. The percentage of Vf covered by 95% of the prescription isodose (Vf-V95) was analyzed. Failures were classified as "in-field" if Vf-V95 ≥ 95%, "marginal" if 20% < Vf-V95 < 95%, and "out-of-field" if Vf-V95 ≤20%. Correlation between Vf-V95 and mean doses (Dmean) in the PG, SMG, and OC was assessed using Spearman's rank-order correlation test. The salivary gland dose impact on the LR recurrence risk was assessed by Cox analysis., Results: The median follow-up was 20 months (6-35). Contralateral and ipsilateral PGs were spared in 98% and 54% of patients, respectively, and contralateral and ipsilateral SMG in 26% and 7%, respectively. The OC was spared to a dose ≤40 Gy in 26 patients (37%). The 2-year LR control rate was 76.5%. One recurrence was "marginal", and 12 were "in-field". No recurrence was observed in vicinity of spared structures. Vf-V95 was not significantly correlated with Dmean in PG, SMG, and OC. The LR recurrence risk was not increased by lower Dmean in the salivary glands, but by T (p = 0.04) and N stages (p = 0.03)., Conclusion: Over 92% of LR failures occurred "in-field" within the high dose region when using IMRT with a whole salivary gland-sparing strategy. Sparing SMG and OC in addition to PG thus appears a safe strategy.