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Purpose: Tumor hypoxia is a paradigmatic negative prognosticator of treatment resistance in head and neck squamous cell carcinoma (HNSCC). The lack of robust and reliable hypoxia classifiers limits the adaptation of stratified therapies. We hypothesized that the tumor DNA methylation landscape might indicate epigenetic reprogramming induced by chronic intratumoral hypoxia. Experimental Design: A DNA-methylome–based tumor hypoxia classifier (Hypoxia-M) was trained in the TCGA (The Cancer Genome Atlas)-HNSCC cohort based on matched assignments using gene expression–based signatures of hypoxia (Hypoxia-GES). Hypoxia-M was validated in a multicenter DKTK-ROG trial consisting of human papillomavirus (HPV)–negative patients with HNSCC treated with primary radiochemotherapy (RCHT). Results: Although hypoxia-GES failed to stratify patients in the DKTK-ROG, Hypoxia-M was independently prognostic for local recurrence (HR, 4.3; P = 0.001) and overall survival (HR, 2.34; P = 0.03) but not distant metastasis after RCHT in both cohorts. Hypoxia-M status was inversely associated with CD8 T-cell infiltration in both cohorts. Hypoxia-M was further prognostic in the TCGA-PanCancer cohort (HR, 1.83; P = 0.04), underscoring the breadth of this classifier for predicting tumor hypoxia status. Conclusions: Our findings highlight an unexplored avenue for DNA methylation–based classifiers as biomarkers of tumoral hypoxia for identifying high-risk features in patients with HNSCC tumors.

Background Molecular brain tumor classification using DNA methylation profiling has revealed that the methylation-class of pleomorphic xanthoastrocytoma (mcPXA) comprised a substantial portion of divergent initial diagnoses, which had been established based on histology alone. This study aimed to characterize the survival outcome in patients with mcPXAs—in light of the diverse selected treatment regimes. Methods A retrospective cohort of adult mcPXAs were analyzed in regard to their progression-free survival following surgical resection and postoperative radiotherapy. Radiotherapy treatment plans were correlated with follow-up images to characterize the pattern of relapse. Treatment toxicities and molecular tumor characteristics were further analyzed. Results Divergent initial histological diagnoses were encountered in 40.7%. There was no significant difference in local progression-free (PFS) and overall survival (OS) following gross total or subtotal resection. Postoperative radiotherapy was completed in 81% (22/27) following surgical intervention. Local PFS was 54.4% (95% CI: 35.3–84.0%) and OS was 81.3% (95% CI: 63.8–100%) after 3 years following postoperative radiotherapy. Initial relapses post-radiotherapy were primarily located in the previous tumor location and/or the planning target volume (PTV) (12/13). All patients in our cohort demonstrated the prognostically favorable pTERT-wildtype mcPXA. Conclusion Our study demonstrated that adult patients with mcPXAs display a worse progression-free survival compared to the reported WHO grade 2 PXAs. Future matched-pair analyses are required with a non-irradiated cohort to elucidate the benefit of postoperative radiotherapy in adult patients with mcPXAs.

Purpose Proton beam radiotherapy (PRT) has been demonstrated to improve neurocognitive sequelae particularly. Nevertheless, following PRT, increased rates of radiation-induced contrast enhancements (RICE) are feared. How safe and effective is PRT for IDH-mutated glioma WHO grade 2 and 3? Methods We analyzed 194 patients diagnosed with IDH-mutated WHO grade 2 (n = 128) and WHO grade 3 (n = 66) glioma who were treated with PRT from 2010 to 2020. Serial clinical and imaging follow-up was performed for a median of 5.1 years. Results For WHO grade 2, 61% were astrocytoma and 39% oligodendroglioma while for WHO grade 3, 55% were astrocytoma and 45% oligodendroglioma. Median dose for IDH-mutated glioma was 54 Gy(RBE) [range 50.4–60 Gy(RBE)] for WHO grade 2 and 60 Gy(RBE) [range 54–60 Gy(RBE)] for WHO grade 3. Five year overall survival was 85% in patients with WHO grade 2 and 67% in patients with WHO grade 3 tumors. Overall RICE risk was 25%, being higher in patients with WHO grade 2 (29%) versus in patients with WHO grade 3 (17%, p = 0.13). RICE risk increased independent of tumor characteristics with older age (p = 0.017). Overall RICE was symptomatic in 31% of patients with corresponding CTCAE grades as follows: 80% grade 1, 7% grade 2, 13% grade 3, and 0% grade 3 + . Overall need for RICE-directed therapy was 35%. Conclusion These data demonstrate the effectiveness of PRT for IDH-mutated glioma WHO grade 2 and 3. The RICE risk differs with WHO grading and is higher in older patients with IDH-mutated Glioma WHO grade 2 and 3.

L'introduction de l’esthétique allemande joue un rôle important dans la constitution d’une esthétique métaphysique française. On retracera la réception des "Cours d’esthétique" de Hegel par le biais de sa traduction par le cousiniste Charles Bénard à partir de 1840. Après avoir indiqué les conditions institutionnelles et intellectuelles de ce projet d’envergure, on exposera les raisons philosophiques avancées par Bénard pour justifier cette traduction. L’importance accordée aux "Vorlesungen über die Ästhetik" publiées à partir de 1835 par Heinrich Gustav Hotho ne signifie pas l’adhésion pure et simple aux positions du philosophe allemand. Bénard assortit sa traduction de textes dans lesquels il souligne l’originalité, les qualités et aussi les limites de la philosophie hégélienne. Ils permettent de cerner avec quelle intention théorique Bénard fait passer Hegel en France. Enfin, on s’intéressera à la façon dont le traducteur a procédé pour assurer le tout premier passage des doctrines hégéliennes en français.

Tendon injuries can result in two major drawbacks. Adhesions to the surrounding tissue may limit the range of motion, while fibrovascular scar formation can lead to poor biomechanical outcomes. Prosthetic devices may help to mitigate those problems. Emulsion electrospinning was used to develop a novel three-layer tube based on the polymer DegraPol (DP), with incorporated insulin-like growth factor-1 (IGF-1) in the middle layer. Scanning electron microscopy was utilized to assess the fiber diameter in IGF-1 containing pure DP meshes. Further characterization was performed with Fourier Transformed Infrared Spectroscopy, Differential Scanning Calorimetry, and water contact angle, as well as through the assessment of mechanical properties and release kinetics from ELISA, and the bioactivity of IGF-1 by qPCR of collagen I, ki67, and tenomodulin in rabbit Achilles tenocytes. The IGF-1-containing tubes exhibited a sustained release of the growth factor up to 4 days and showed bioactivity by significantly upregulated ki67 and tenomodulin gene expression. Moreover, they proved to be mechanically superior to pure DP tubes (significantly higher fracture strain, failure stress, and elastic modulus). The novel three-layer tubes intended to be applied over conventionally sutured tendons after a rupture may help accelerate the healing process. The release of IGF-1 stimulates proliferation and matrix synthesis of cells at the repair site. In addition, adhesion formation to surrounding tissue can be reduced due to the physical barrier.

BACKGROUND: Inborn errors of immunity (IEI) are rare diseases, which makes diagnosis a challenge. A better description of the initial presenting manifestations should improve awareness and avoid diagnostic delay. Although increased infection susceptibility is a well-known initial IEI manifestation, less is known about the frequency of other presenting manifestations.OBJECTIVE: We sought to analyze age-related initial presenting manifestations of IEI including different IEI disease cohorts.METHODS: We analyzed data on 16,486 patients of the European Society for Immunodeficiencies Registry. Patients with autoinflammatory diseases were excluded because of the limited number registered.RESULTS: Overall, 68% of patients initially presented with infections only, 9% with immune dysregulation only, and 9% with a combination of both. Syndromic features were the presenting feature in 12%, 4% had laboratory abnormalities only, 1.5% were diagnosed because of family history only, and 0.8% presented with malignancy. Two-third of patients with IEI presented before the age of 6 years, but a quarter of patients developed initial symptoms only as adults. Immune dysregulation was most frequently recognized as an initial IEI manifestation between age 6 and 25 years, with male predominance until age 10 years, shifting to female predominance after age 40 years. Infections were most prevalent as a first manifestation in patients presenting after age 30 years.CONCLUSIONS: An exclusive focus on infection-centered warning signs would have missed around 25% of patients with IEI who initially present with other manifestations.

Introduction Re-irradiation is frequently performed in the era of precision oncology, but previous doses to organs-at-risk (OAR) must be assessed to avoid cumulative overdoses. Stereotactic magnetic resonance-guided online adaptive radiotherapy (SMART) enables highly precise ablation of tumors close to OAR. However, OAR doses may change considerably during adaptive treatment, which complicates potential re-irradiation. We aimed to compare the baseline plan with different dose accumulation techniques to inform re-irradiation. Patients & methods We analyzed 18 patients who received SMART to lung or liver tumors inside prospective databases. Cumulative doses were calculated inside the planning target volumes (PTV) and OAR for the adapted plans and theoretical non-adapted plans via (1) cumulative dose volume histograms (DVH sum plan) and (2) deformable image registration (DIR)-based dose accumulation to planning images (DIR sum plan). We compared cumulative dose parameters between the baseline plan, DVH sum plan and DIR sum plan using equivalent doses in 2 Gy fractions (EQD2). Results Individual patients presented relevant increases of near-maximum doses inside the proximal bronchial tree, spinal cord, heart and gastrointestinal OAR when comparing adaptive treatment to the baseline plans. The spinal cord near-maximum doses were significantly increased in the liver patients (D2% median: baseline 6.1 Gy, DIR sum 8.1 Gy, DVH sum 8.4 Gy, p = 0.04; D0.1 cm³ median: baseline 6.1 Gy, DIR sum 8.1 Gy, DVH sum 8.5 Gy, p = 0.04). Three OAR overdoses occurred during adaptive treatment (DIR sum: 1, DVH sum: 2), and four more intense OAR overdoses would have occurred during non-adaptive treatment (DIR sum: 4, DVH sum: 3). Adaptive treatment maintained similar PTV coverages to the baseline plans, while non-adaptive treatment yielded significantly worse PTV coverages in the lung (D95% median: baseline 86.4 Gy, DIR sum 82.4 Gy, DVH sum 82.2 Gy, p = 0.006) and liver patients (D95% median: baseline 87.4 Gy, DIR sum 82.1 Gy, DVH sum 81.1 Gy, p = 0.04). Conclusion OAR doses can increase during SMART, so that re-irradiation should be planned based on dose accumulations of the adapted plans instead of the baseline plan. Cumulative dose volume histograms represent a simple and conservative dose accumulation strategy.

Aims Reirradiation of prostate cancer (PC) local recurrences represents an emerging challenge for current radiotherapy. In this context, stereotactic body radiation therapy (SBRT) allows the delivery of high doses, with curative intent. Magnetic Resonance guided Radiation Therapy (MRgRT) has shown promising results in terms of safety, feasibility and efficacy of delivering SBRT thanks to the enhanced soft tissue contrast and the online adaptive workflow. This multicentric retrospective analysis evaluates the feasibility and efficacy of PC reirradiation, using a 0.35 T hybrid MR delivery unit. Methods Patients affected by local recurrences of PC and treated in five institutions between 2019 and 2022 were retrospectively collected. All patients had undergone previous Radiation Therapy (RT) in definitive or adjuvant setting. Re-treatment MRgSBRT was delivered with a total dose ranging from 25 to 40 Gy in 5 fractions. Toxicity according to CTCAE v 5.0 and treatment response were assessed at the end of the treatment and at follow-up. Results Eighteen patients were included in this analysis. All patients had previously undergone external beam radiation therapy (EBRT) up to a total dose of 59.36 to 80 Gy. Median cumulative biologically effective dose (BED) of SBRT re-treatment was 213,3 Gy (103,1-560), considering an α/β of 1.5. Complete response was achieved in 4 patients (22.2%). No grade ≥ 2 acute genitourinary (GU) toxicity events were recorded, while gastrointestinal (GI) acute toxicity events occurred in 4 patients (22.2%). Conclusion The low rates of acute toxicity of this experience encourages considering MRgSBRT a feasibile therapeutic approach for the treatment of clinically relapsed PC. Accurate gating of target volumes, the online adaptive planning workflow and the high definition of MRI treatment images allow delivering high doses to the PTV while efficiently sparing organs at risk (OARs).

(1) Background: Magnetic-resonance (MR)-guided stereotactic body radiotherapy (SBRT) allows for ablative, non-invasive treatment of liver metastases. However, long-term clinical outcome data are missing. (2) Methods: Patients received MR-guided SBRT with a MRIdian Linac between January 2019 and October 2021 and were part of an ongoing prospective observational registry. Local hepatic control (LHC), distant hepatic control (DHC), progression free survival (PFS) and overall survival (OS) were estimated with the Kaplan–Meier method. Toxicity was documented according to CTCAE (v.5.0). (3) Results: Forty patients were treated for a total of 54 liver metastases (56% with online plan adaptation). Median prescribed dose was 50 Gy in five fractions equal to a biologically effective dose (BED) (alpha/beta = 10 Gy) of 100 Gy. At 1 and 2 years, LHC was 98% and 75%, DHC was 34% and 15%, PFS was 21% and 5% and OS was 83% and 57%. Two-year LHC was higher in case of BED > 100 Gy (100% vs. 57%; log-rank p = 0.04). Acute grade 1 and 2 toxicity (mostly nausea) occurred in 26% and 7% of the patients, with no grade ≥ 3 event. (4) Conclusions: To our knowledge, this is the largest cohort of MR-guided liver SBRT. Long-term local control was promising and underscores the aim of achieving >100 Gy BED. Nonetheless, distant tumor control remains challenging.

Background The current CNS WHO classification of brain tumors distinguishes three malignancy grades in meningiomas, with increasing risk of recurrence from CNS WHO grade 1 to 3. Radiotherapy is recommended by current EANO guidelines for patients not safely amenable to surgery or after incomplete resection in higher grades. Despite adequately predicting recurrence probability for the majority of CNS WHO grade 2 meningioma patients, a considerable subset of patients demonstrates an unexpectedly early tumor recurrence following radiotherapy. Methods A retrospective cohort of 44 patients with CNS WHO grade 2 meningiomas was stratified into 3 risk groups (low, intermediate, high) using an integrated morphological, CNV- and methylation family-based classification. Local progression-free survival (lPFS) following radiotherapy (RT) was analyzed and total dose of radiation was correlated with survival outcome. Radiotherapy treatment plans were correlated with follow-up images to characterize the pattern of relapse. Treatment toxicities were further assessed. Results Risk stratification of CNS WHO grade 2 meningioma into integrated risk groups demonstrated a significant difference in 3-year lPFS following radiotherapy between the molecular low- and high-risk group. Recurrence pattern analysis revealed that 87.5 % of initial relapses occurred within the RT planning target volume or resection cavity. Conclusion Integrated risk scoring can identify CNS WHO grade 2 meningioma patients at risk or relapse and dissemination following radiotherapy. Therapeutic management of CNS WHO grade 2 meningiomas and future clinical trials should be adjusted according to the molecular risk-groups, and not rely on conventional CNS WHO grading alone.

Background Patients with locally-advanced non-small-cell lung cancer (LA-NSCLC) are often ineligible for surgery, so that definitive chemoradiotherapy (CRT) represents the treatment of choice. Nevertheless, long-term tumor control is often not achieved. Intensification of radiotherapy (RT) to improve locoregional tumor control is limited by the detrimental effect of higher radiation exposure of thoracic organs-at-risk (OAR). This narrow therapeutic ratio may be expanded by exploiting the advantages of magnetic resonance (MR) linear accelerators, mainly the online adaptation of the treatment plan to the current anatomy based on daily acquired MR images. However, MR-guidance is both labor-intensive and increases treatment times, which raises the question of its clinical feasibility to treat LA-NSCLC. Therefore, the PUMA trial was designed as a prospective, multicenter phase I trial to demonstrate the clinical feasibility of MR-guided online adaptive RT in LA-NSCLC. Methods Thirty patients with LA-NSCLC in stage III A-C will be accrued at three German university hospitals to receive MR-guided online adaptive RT at two different MR-linac systems (MRIdian Linac®, View Ray Inc. and Elekta Unity®, Elekta AB) with concurrent chemotherapy. Conventionally fractioned RT with isotoxic dose escalation up to 70 Gy is applied. Online plan adaptation is performed once weekly or in case of major anatomical changes. Patients are followed-up by thoracic CT- and MR-imaging for 24 months after treatment. The primary endpoint is twofold: (1) successfully completed online adapted fractions, (2) on-table time. Main secondary endpoints include adaptation frequency, toxicity, local tumor control, progression-free and overall survival. Discussion PUMA aims to demonstrate the clinical feasibility of MR-guided online adaptive RT of LA-NSCLC. If successful, PUMA will be followed by a clinical phase II trial that further investigates the clinical benefits of this approach. Moreover, PUMA is part of a large multidisciplinary project to develop MR-guidance techniques. Trial registration ClinicalTrials.gov: NCT05237453.

Supplementary Table S2. Treatment Information for the validation cohort (n=88, DKTK-ROG)

Supplementary Figure 4 (Top). CD8 T cell enrichment is prognostic for Overall Survival (OS), local recurrence (LR) and disease progression but not for distant metastasis (DM) in HPV negative HNSCC in the DKTK-ROG cohort (n=88). (Bottom) After adjusting for Immune cell Infiltration, Hypoxia-M remained an independent prognosticator for local recurrence (HR=3.06, p

Supplementary Table S3. Distribution of clinical and biomarker-related characteristics between Methylation Hypoxia High vs Low in the training cohort (TCGA-HNSCC)

Supplementary Table S7. Distribution of clinical and biomarker-related characteristics between Methylation Hypoxia High vs Low in the TCGA-pancancer cohort

Supplementary Table S6. Contingency Table of Hypoxia-M and CD8-immunohistochemistry (IHC) staining for CD8-T cells

Statistical Output

Supplementary Table S5. Distribution of clinical and biomarker-related characteristics between Methylation Hypoxia High vs Low in the validation cohort (DKTK-ROG)

Supplementary Figure S3. (Top) Hypoxia-M V2 is associated with decreased OS in the TCGApancancer cohort (p

Supplementary Figure S2. (Top) Hypoxia-M V2 is prognostic in the DKTK-ROG cohort. Patients predicted to have higher tumor hypoxia by Hypoxia-M V2 had higher rates of death (p=0.0097), local recurrence (p=0.0037), distant metastasis (p=0.027) and disease progression (p=0.00096). (Bottom) Hypoxia-M V2 remains an independent prognosticator of OS, LR and disease progression after adjusting for age, smoking status, GTV and anatomical site. Additionally, there is a trend towards higher rates of distant metastasis (HR=2.33, p=0.13)

Supplementary Methods, Results, Table of Contents

Purpose:Tumor hypoxia is a paradigmatic negative prognosticator of treatment resistance in head and neck squamous cell carcinoma (HNSCC). The lack of robust and reliable hypoxia classifiers limits the adaptation of stratified therapies. We hypothesized that the tumor DNA methylation landscape might indicate epigenetic reprogramming induced by chronic intratumoral hypoxia.Experimental Design:A DNA-methylome–based tumor hypoxia classifier (Hypoxia-M) was trained in the TCGA (The Cancer Genome Atlas)-HNSCC cohort based on matched assignments using gene expression–based signatures of hypoxia (Hypoxia-GES). Hypoxia-M was validated in a multicenter DKTK-ROG trial consisting of human papillomavirus (HPV)–negative patients with HNSCC treated with primary radiochemotherapy (RCHT).Results:Although hypoxia-GES failed to stratify patients in the DKTK-ROG, Hypoxia-M was independently prognostic for local recurrence (HR, 4.3; P = 0.001) and overall survival (HR, 2.34; P = 0.03) but not distant metastasis after RCHT in both cohorts. Hypoxia-M status was inversely associated with CD8 T-cell infiltration in both cohorts. Hypoxia-M was further prognostic in the TCGA-PanCancer cohort (HR, 1.83; P = 0.04), underscoring the breadth of this classifier for predicting tumor hypoxia status.Conclusions:Our findings highlight an unexplored avenue for DNA methylation–based classifiers as biomarkers of tumoral hypoxia for identifying high-risk features in patients with HNSCC tumors.

Supplementary Table S1. Multivariate Analysis for the Hypoxia-M and Brooks signature.

Many of the commonly used datasets for face recognition development are collected from the internet without proper user consent. Due to the increasing focus on privacy in the social and legal frameworks, the use and distribution of these datasets are being restricted and strongly questioned. These databases, which have a realistically high variability of data per identity, have enabled the success of face recognition models. To build on this success and to align with privacy concerns, synthetic databases, consisting purely of synthetic persons, are increasingly being created and used in the development of face recognition solutions. In this work, we present a three-player generative adversarial network (GAN) framework, namely IDnet, that enables the integration of identity information into the generation process. The third player in our IDnet aims at forcing the generator to learn to generate identity-separable face images. We empirically proved that our IDnet synthetic images are of higher identity discrimination in comparison to the conventional two-player GAN, while maintaining a realistic intra-identity variation. We further studied the identity link between the authentic identities used to train the generator and the generated synthetic identities, showing very low similarities between these identities. We demonstrated the applicability of our IDnet data in training face recognition models by evaluating these models on a wide set of face recognition benchmarks. In comparison to the state-of-the-art works in synthetic-based face recognition, our solution achieved comparable results to a recent rendering-based approach and outperformed all existing GAN-based approaches. The training code and the synthetic face image dataset are publicly available ( https://github.com/fdbtrs/Synthetic-Face-Recognition )., Accepted at CVPR Workshops

International audience

Rationale and Objectives Mobile mammography units provide preventive health care to patients facing barriers to annual screening. This study reviews the outcomes of a mobile mammography service during a recent 5-year period. Materials and Methods This retrospective study analyzed the examinations by mobile mammography during a 5-year period (9327 examinations). The patients recalled, biopsies performed, and cancers detected were tallied. The race, age, breast cancer size, lymph node involvement, and metastases were recorded. The positive predictive value (PPV) and cancer detection rate metrics were calculated as outlined by the American College of Radiology Breast Imaging Reporting and Data System Atlas. Results The program identified cancer in 14 cases (cancer detection rate = 1.5 per 1000 examinations [95% confidence interval [CI], 0.9–2.5]) with 11 being invasive. The majority of these cancers were small and of low stage. Lymph node status was determined in 11 of the 14 cases (1 as N1mi, 5 as N0, 4 as N1,1 as N2a). Abnormalities led to 1686 examinations recalled (Recall Rate = 17.8%; PPV 1 = 0.8% [95% CI, 0.5%–1.4%]). One hundred and one were recommended for biopsy (PPV 2 = 13.9% [95% CI, 8.4%–21.9%]), and 98 pursued biopsy (PPV 3 = 14.3% [95% CI, 8.7%–22.6%]). Patient age ranged from 41 to 67 years with an average of 50.6 years. Conclusion The program detected many cancers in an asymptomatic population facing barriers to breast cancer screening. These findings are underscored by the cancers detected at an early stage with a favorable prognosis and support the need for the development of similar programs.

IntroductionA very narrow therapeutic window exists when delivering curative chemoradiotherapy for inoperable locally advanced non-small cell lung cancer (NSCLC), particularly when large distances exist between areas of gross disease in the thorax. In the present study, we hypothesize that a novel technique of stereotactic body radiation therapy (SBRT) to the primary tumor in combination with volumetric arc therapy (VMAT) to the mediastinal lymph nodes (MLN) is a suitable approach for high-risk patients with large volume geographically distant locally advanced NSCLC.Patients and methodsIn this single institutional review, we identified high-risk patients treated between 2014 and 2017 with SBRT to the parenchymal lung primary as well as VMAT to the involved MLN using conventional fractionation. Dosimetrically, comparative plans utilizing VMAT conventionally fractionated delivered to both the primary and MLN were analyzed. Clinically, toxicity (CTCAE version 5.0) and oncologic outcomes were analyzed in detail.ResultsA total of 21 patients were identified, 86% (n=18) of which received chemotherapy as a portion of their treatment. As treatment phase was between 2014 and 2017, none of the patients received consolidation immunotherapy. Target volume (PTV) dose coverage (99 vs. 87%) and CTV volume (307 vs. 441 ml) were significantly improved with SBRT+MLN vs. for VMAT alone (pConclusionFor high risk patients, SBRT+MLN is dosimetrically feasible and can provide an alternative to dose reductions necessitated by otherwise very large target volumes.

Introduction The APROVE-trial investigated the tolerability of postoperative proton beam therapy in women with cervical or endometrial cancer. The present analysis evaluated the secondary endpoints of health-related quality of life (HRQOL) and patient-reported symptoms. Methods 25 patients were included in this prospective phase-II-trial and treated with postoperative radiotherapy using protons alone or in combination with chemotherapy. To attain general and gynecologic-specific HRQOL measures, the EORTC-QLQ-C30 questionnaires combined with -QLQ-CX24 for cervical and -QLQ-EN24 for endometrial cancer were assessed at baseline, at the end of RT and up to 2 years after radiotherapy. The results were compared to an age-matched norm reference population. Symptoms were assessed using Common Terminology Criteria for Adverse Events (CTCAE) and institutional patient-reported symptoms grading. Results Scores regarding global health status were markedly impaired at baseline (mean: 58.0 ± 20.1) compared to reference population data, but significantly (p = 0.036) improved and evened out to comparable norm values 2 years after proton therapy (mean: 69.9 ± 19.3). Treatment caused acute and long-term worsening of pain (p = 0.048) and gastrointestinal symptoms (p = 0.016) for women with endometrial cancer, but no higher-grade CTCAE ≥ 3° toxicity was observed. Dosimetric evaluation of rectum, sigmoid, large and small bowel showed no correlation with the reported gastrointestinal symptoms. After 2 years, fatigue had significantly improved (p = 0.030), whereas patients with cervical cancer experienced more often lymphedema (p = 0.017). Scores for endometrial cancer pertaining to sexual activity (p = 0.048) and body image (p = 0.022) had improved post treatment; in the latter this effect persisted after 2 years. Conclusion Proton beam therapy in the adjuvant setting was well tolerated with only low-grade side effects concerning gastrointestinal symptoms, lymphedema and pain. Overall quality of life was impaired at baseline, but patients were able to recover to values comparable to norm population 2 years after proton therapy. Larger studies are needed to confirm whether the benefit of proton therapy translates into a clinical effect. Sexual dysfunction remains an important issue. Trial registration: The trial was registered at https://clinicaltrials.gov (ClinicalTrials.gov Identifier: NCT03184350, 09th June 2017).

The connection between Pediatric Inflammatory Multisystem Syndrome (PIMS) and Kawasaki Disease (KD) is not yet fully understood. Using the same national registry, clinical features and outcome of children hospitalized in Germany, and Innsbruck (Austria) were compared. Reported to the registry were 395 PIMS and 69 KD hospitalized patients. Patient age in PIMS cases was higher than in KD cases (median 7 [IQR 4–11] vs. 3 [IQR 1–4] years). A majority of both PIMS and KD patients were male and without comorbidities. PIMS patients more frequently presented with organ dysfunction, with the gastrointestinal (80%), cardiovascular (74%), and respiratory (52%) systems being most commonly affected. By contrast, KD patients more often displayed dermatological (99% vs. 68%) and mucosal changes (94% vs. 64%), plus cervical lymph node swelling (51% vs. 34%). Intensive care admission (48% vs. 19%), pulmonary support (32% vs. 10%), and use of inotropes/vasodilators (28% vs. 3%) were higher among PIMS cases. No patients died. Upon patient discharge, potentially irreversible sequelae—mainly cardiovascular—were reported (7% PIMS vs. 12% KD). Despite differences in age distribution and disease severity, PIMS and KD cases shared many common clinical and prognostic characteristics. This supports the hypothesis that the two entities represent a syndrome continuum.

Supplementary Material 1

Deep Neural Networks (DNNs) have established themselves as powerful tools for a wide range of complex tasks, for example computer vision or natural language processing. DNNs are notoriously demanding on compute resources and as a result, dedicated hardware accelerators for all use cases are developed. Different accelerators provide solutions from hyper scaling cloud environments for the training of DNNs to inference devices in embedded systems. They implement intrinsics for complex operations directly in hardware. A common example are intrinsics for matrix multiplication. However, there exists a gap between the ecosystems of applications for deep learning practitioners and hardware accelerators. HowDNNs can efficiently utilize the specialized hardware intrinsics is still mainly defined by human hardware and software experts. Methods to automatically utilize hardware intrinsics in DNN operators are a subject of active research. Existing literature often works with transformationdriven approaches, which aim to establish a sequence of program rewrites and data-layout transformations such that the hardware intrinsic can be used to compute the operator. However, the complexity this of task has not yet been explored, especially for less frequently used operators like Capsule Routing. And not only the implementation of DNN operators with intrinsics is challenging, also their optimization on the target device is difficult. Hardware-in-the-loop tools are often used for this problem. They use latency measurements of implementations candidates to find the fastest one. However, specialized accelerators can have memory and programming limitations, so that not every arithmetically correct implementation is a valid program for the accelerator. These invalid implementations can lead to unnecessary long the optimization time. This work investigates the complexity of transformation-driven processes to automatically embed hardware intrinsics into DNN operators. It is explored with a custom, graph-based intermediate representation (IR). While operators like Fully Connected Layers can be handled with reasonable effort, increasing operator complexity or advanced data-layout transformation can lead to scaling issues. Building on these insights, this work proposes a novel method to embed hardware intrinsics into DNN operators. It is based on a dataflow analysis. The dataflow embedding method allows the exploration of how intrinsics and operators match without explicit transformations. From the results it can derive the data layout and program structure necessary to compute the operator with the intrinsic. A prototype implementation for a dedicated hardware accelerator demonstrates state-of-the art performance for a wide range of convolutions, while being agnostic to the data layout. For some operators in the benchmark, the presented method can also generate alternative implementation strategies to improve hardware utilization, resulting in a geo-mean speed-up of ×2.813 while reducing the memory footprint. Lastly, by curating the initial set of possible implementations for the hardware-in-the-loop optimization, the median timeto- solution is reduced by a factor of ×2.40. At the same time, the possibility to have prolonged searches due a bad initial set of implementations is reduced, improving the optimization’s robustness by ×2.35.

INTRODUCTION: Endothelial shear stress (ESS) is a local hemodynamic factor that is dependent on vessel geometry and influences the process of atherogenesis. As in vivo measurements of ESS are not possible, it must be calculated using computational fluid dynamics (CFD). In this feasibility study we explore CFD-models generated from coronary CT-angiography (CCTA) using an individualised blood viscosity and a pulsatile flow profile derived from in vivo measurements. MATERIALS AND METHODS: We retrospectively recruited 25 consecutive patients who received a CCTA followed by a coronary angiography including intravascular ultrasound (IVUS) and generated 3D models of the coronary arteries from the CT-datasets. We then performed CFD-simulations on these models. Hemodynamically non-relevant stenosis were identified in IVUS. They were isolated in the CFD-model and separated longitudinally into a half with atherosclerotic lesion (AL) and one without (NAL). ESS was measured and compared for both halves. RESULTS: After excluding vessels with no IVUS data or relevant stenosis we isolated 31 hemodynamically non-relevant excentric AL from a total of 14 vessels. AL segments showed consistently significantly lower ESS when compared to their corresponding NAL segments when regarding minimum (0.9 Pa, CI [0.6, 1.2] vs. 1.3 Pa, CI [0.9, 1.8]; p = 0.004), mean (5.0 Pa, CI [3.4, 6.0] vs. 6.7 Pa, CI [5.5, 8.4]; p = 0.008) and maximum ESS values (12.4 Pa, CI [8.6, 14.6] vs. 19.6 Pa, CI [12.4, 21.0]; p = 0.005). Qualitatively ESS was lower on the inside of bifurcations and curvatures. CONCLUSION: CFD simulations of coronary arteries from CCTA with an individualised flow profile and blood viscosity are feasible and could provide further prognostic information and a better risk stratification in coronary artery disease. Further prospective studies are needed to investigate this claim.

International audience; The paper discusses Ernst Cassirer’s and Erwin Panofsky’s conception of artistic space. The occasion for this comparison between the philosopher and the art historian is provided by a debate at the Kongress für Ästhetitk und Allgemeine Kunstwissenschaft (Congress for Aesthetics and the Science of Art) in Hamburg in 1933. The topic of the 4th Congress was the question of artistic space and time. Perspective, considered by Panofsky as a symbolic form, is a good case to understand the proximities and differences between the art historian and the philosopher of symbolic forms. Does the space of perspective correspond to the space of art that the philosopher defines as the space of representation (Darstellung)? This example of the perspective is often used to compare the two theorists, although often without much precision. The paper also discusses another, much more original example, namely the theory of proportions. Can we say that the theory of proportions, which also structures the space of the image, is, like perspective, a symbolic form? The answer allows us to clarify the way in which Cassirer and Panofsky see a relation between art, representation and subjectivity. Through this examination of the affinities and differences in their conception of art, we put at stake the possibility and limits of interdisciplinarity and the fruitful dialogue between philosophy and art history, as well as the question of whether a common theory of art was shared in Hamburg in those years around the Warburg Institute.; L’article discute les conceptions respectives que le philosophe Ernst Cassirer et l’historien de l’art Erwin Panofsky se font de l’espace artistique. L’occasion en est donnée par une discussion lors du Kongress für Ästhetitk und Allgemeine Kunstwissenschaft (Congrès d’esthétique et de science de l’art) organisé à Hambourg en 1933 sur la question de l’espace et du temps artistiques. La perspective, considérée par Panofsky comme une forme symbolique, constitue un bon cas pour saisir les proximités et différences entre l’historien de l’art et le philosophe des formes symboliques. L’espace de la perspective correspond-il à cet espace de l’art que le philosophe définit comme espace de la représentation (Darstellung) ? À cet exemple de la perspective, exemple classique quoique souvent évoqué sans grande précision pour comparer les deux théoriciens, l’article en ajoute un autre, inédit, à savoir celui de la théorie des proportions. Peut-on dire que la théorie des proportions qui structure elle aussi la surface de l’image est, comme la perspective, une forme symbolique ? La réponse permet de préciser la façon dont Cassirer et Panofsky construisent un lien entre art, représentation et subjectivité. À travers cette recherche des affinités et différences dans la conception de l’art, ce qui se joue en toile de fond, c’est, d’une part, la possibilité et les limites de l’interdisciplinarité et du dialogue fécond entre philosophie et histoire de l’art et, d’autre part, la question de savoir si une commune théorie de l’art était partagée à Hambourg dans ces années, autour de l’Institut Warburg.

Les peintures, gravures, sculptures et objets mobiliers découverts, en particulier depuis Altamira, célèbre grotte ornée d’Espagne et véritable chef-d’œuvre de l’art paléolithique, ne cessent d’interroger chercheurs, artistes et grand public. Comment penser cet « art avant l’art », ces œuvres des origines auxquelles nous attribuons une valeur esthétique mais dont la réalisation est antérieure et irréductible au concept d’art qui est le nôtre aujourd’hui ? Il convient pour cela de dégager les traits fondamentaux de ce paradigme préhistorique qui a paradoxalement résonné avec l’art moderne. On examinera quel traitement du geste, de la figuration, de l’espace et du mouvement a été source d’inspiration et de renouveau pour les artistes, de Picasso à Moore. L’ouvrage défend l’hypothèse que le Paléolithique force à reconsidérer notre définition de l’art, de ses fonctions et de ses significations, de ses débuts et de son histoire. Les réflexions inédites proposées par des spécialistes en philosophie, histoire, histoire de l’art et littérature s’adresseront à tous les passionnés de l’art et de ses théories. The paintings, engravings, sculptures and movable objects discovered, particularly since the discovery of Altamira, the famous decorated cave in Spain and a true masterpiece of Paleolithic art, never cease to question researchers, artists and the general public. How can we think about this ‘art before art’, these works of the origins to which we attribute an aesthetic value but whose realisation is prior and irreducible to the concept of art that we have today? In order to do so, we must identify the fundamental features of this prehistoric paradigm which paradoxically resonates with modern art. The treatment of gesture, figuration, space and movement will be examined as a source of inspiration and renewal for artists from Picasso to Moore. The book argues that the Paleolithic forces us to reconsider our definition of art, its functions and meanings, its beginnings and its history. The original reflections offered by specialists in philosophy, history, art history and literature will appeal to everyone who is passionate about art and its theories.

International audience

International audience

IntroductionStereotactic radiosurgery is a well-established treatment option in the management of brain metastases. Multiple prognostic scores for prediction of survival following radiotherapy exist, but are not disease-specific or validated for radiosurgery in women with primary pelvic gynecologic malignancies metastatic to the brain. The aim of the present study is to evaluate the feasibility, safety, outcomes, and impact of established prognostic scores.MethodsWe retrospectively identified 52 patients treated with radiotherapy for brain metastases between 2008 and 2021. Stereotactic radiosurgery was utilized in 31 patients for an overall number of 75 lesions; the remaining 21 patients received whole-brain radiotherapy. Kaplan-Meier survival analysis and the log-rank test were used to calculate and compare survival curves and univariate and multivariate Cox regression to assess the influence of cofactors on recurrence, local control, and prognosis.ResultsWith a median follow-up of 10.7 months, overall survival rates post radiosurgery were 65.3%, 51.3%, and 27.7% for 1, 2, and 5 years, respectively, which were significantly higher than post whole-brain radiotherapy (p=0.049). Five local failures (6.7%) were detected, resulting in 1 and 2 year local cerebral control rates of 97.4% and 94.0%, respectively. Univariate factors for prediction of superior overall survival were high performance status (p=0.030) and application of three prognostic scores, especially the Recursive Partitioning Analysis score (p=0.028). Uni- and multivariate analysis revealed that extracranial progression prior to radiosurgery was significant for inferior overall survival (pConclusionStereotactic radiosurgery for brain metastases from pelvic gynecologic malignancies appears to be safe and well tolerated, achieving promising local cerebral control. Prognostic scores were shown to be transferable and radiosurgery should be recommended as primary intracranial treatment, especially in women with no prior extracranial progression and Recursive Partitioning Analysis class I.