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Dès les premières grammaires du français apparaissent des considérations relatives à la complexité et à la simplicité de la langue : tout en célébrant la richesse de sa langue, le grammairien doit démontrer sa capacité à être réduite en règles et dégager ce qui fait son ordre propre. L’enjeu est également d’ordre pédagogique : il s’agit de dédramatiser l’apprentissage d’une langue réputée difficile. Le travail du grammairien sera d’atteindre cet ordre qui fonde l’intercompréhension, et que les auteurs désignent aussi par le nom de naïveté. La naïveté apparaît ainsi comme une notion mitoyenne, entre la simplicité et la complexité, qui définit l’objet et le but de l’activité grammaticale. Si la notion de naïveté endosse assez tôt une valeur esthétique, devenant une des perfections du style, elle désigne aussi le fonds commun de la langue, ce qui la caractérise et la distingue des autres idiomes. La recherche de la naïveté forme le socle de la norme d’usage. Cet article étudie le parcours de cette notion au xvie et au xviie siècles, la manière dont elle se situe dans le discours sur la langue française, et participe à l’évaluation de la langue française au regard du latin, des autres vernaculaires et des variétés régionales., {"references":["Pagani-Naudet, Cendrine & Nathalie Fournier. 2023. Éloge de la naïveté dans les grammaires du français (xvie-xviie s.). Du naïf de la langue à la naïveté du style. Simplicité et complexité des langues dans l'histoire des théories linguistiques, dir. par Chloé Laplantine, John E. Joseph & Émilie Aussant. Paris : SHESL (HEL Livres, 3). 105-136."]}

Novel molecules that directly target the neonatal Fc receptor (FcRn) and/or Fc gamma receptors (FcγRs) are emerging as promising treatments for immunoglobulin G (IgG)-dependent autoimmune pathologies. Mutated Fc regions and monoclonal antibodies that target FcRn are currently in clinical development and hold promise for reducing the levels of circulating IgG. Additionally, engineered structures containing multimeric Fc regions allow the dual targeting of FcRn and FcγRs; however, their tolerance needs to first be validated in phase I clinical studies. Here, for the first time, we have developed a modified monomeric recombinant Fc optimized for binding to all FcRns and FcγRs without the drawback of possible tolerance associated with FcγR cross-linking. A rational approach using Fc engineering allowed the selection of LFBD192, an Fc with a combination of six mutations that exhibits improved binding to human FcRn and FcγR as well as mouse FcRn and FcγRIV. The potency of LFBD192 was compared with that of intravenous immunoglobulin (IVIg), an FcRn blocker (Fc-MST-HN), and a trimeric Fc that blocks FcRn and/or immune complex-mediated cell activation through FcγR without triggering an immune reaction in several in vitro tests and validated in three mouse models of autoimmune disease.

This article reviews Les theories de l’enonce dans la grammaire generale 978-2-84788-697-9€ 24

Purpose To evaluate locoregional control and outcome after mastectomy in patients treated with postmastectomy highly conformal electron radiation therapy (PMERT) with bolus compared with patients treated by highly conformal photon radiation therapy (PMPhRT) without bolus in the adjuvant setting of nonmetastatic breast cancer. Methods and Materials We studied women undergoing PMRT without immediate reconstruction for breast cancer before 2012 in 2 sites of our hospital using 2 different techniques. All patients received 50 Gy in 25 fractions. Patients previously treated by neoadjuvant chemotherapy were excluded. Results Among the 807 patients, 583 received PMERT and 224 received PMPhRT. The median follow-up was 64 months. Patients in the PMERT group had a median age of 52.7 years (range, 26-91 years), 6.9% were triple-negative, 16.3% were HER2-positive, and 58.6% had multifocal lesions. Patients in the PMPhRT group had a median age of 56.4 years (28-89), 8.5% were triple negative, 12.9% were HER2-positive, and 55.8% had multifocal lesions. Lymph node involvement was observed in 66% and 72.8% of cases (P = .07) treated with PMERT and PMPhRT, respectively. No significant difference in overall survival was observed between the 2 groups (hazard ratio [HR], 1.2; 95% CI, 0.67-2.13; P = .54). The risk of locoregional recurrence, estimated using the Fine-Gray method, was significantly higher with PMPhRT than with PMERT (subdistribution HR, 3.62; 95% CI, 1.07-12.3; P = .04), corresponding to a 5-year LRR rate of 0.53% (95% CI, 0-1.12%) for PMERT and 2.52% (95% CI, 0.05%-4.6%) for PMPhRT. Conclusions A higher risk of local recurrence was observed in the PMPhRT without bolus group compared with the PMERT with bolus group. Prospective randomized trials are needed to confirm these findings.

The long serum t1/2 of IgGs is ensured by their interaction with the neonatal Fc receptor (FcRn), which salvages IgG from intracellular degradation. Fc glycosylation is thought not to influence FcRn binding and IgG longevity in vivo. In this article, we demonstrate that hypersialylation of asparagine 297 (N297) enhances IgG serum persistence. This polarized glycosylation is achieved using a novel Fc mutation, a glutamate residue deletion at position 294 (Del) that endows IgGs with an up to 9-fold increase in serum lifespan. The strongest impact was observed when the Del was combined with Fc mutations improving FcRn binding (Del-FcRn+). Enzymatic desialylation of a Del-FcRn+ mutant or its production in a cell line unable to hypersialylate reduced the in vivo serum t1/2 of the desialylated mutants to that of native FcRn+ mutants. Consequently, our study proves that sialylation of the N297 sugar moiety has a direct impact on human IgG serum persistence.

Purpose The purpose of this study was to evaluate locoregional control and describe the patterns of locoregional failure in women with breast cancer irradiated by a previously described post-mastectomy highly conformal electron beam radiotherapy technique. Material and methods We included all women irradiated by post-mastectomy highly conformal electron beam radiotherapy technique for non-metastatic breast cancer between 2007 and 2011 in our department. All cases of bilateral breast cancer were excluded. All patients who experienced locoregional recurrence have been studied. Mapping patterns of regional recurrences was also performed and compared with the European Society for Radiotherapy and Oncology (ESTRO) and Radiotherapy Oncology Group (RTOG) guidelines of volume definition and delineation guidelines. Results With a median follow-up of 64 months (range: 6-102 months), 5-year locoregional recurrence-free and overall survival probabilities were 90 % (95 % confidence interval [95 %CI]: 88.1-92.4) and 90.9 % (95 %CI: 88.9-93), respectively. Among the 796 patients included in the study, 23 patients (2.9 %) presented locoregional recurrences of them only 13 (1.6%) were presented with local recurrence. The majority of them presented aggressive biological features with grade III tumours in 17 patients (74 %) with high mitotic index in 16 cases (70 %) and triple negative tumours in 12 (52 %). Lymphovascular invasion was observed in 11 cases (48 %). In 14 cases the locoregional recurrences were diagnosed at the same time as the metastatic disease whereas 4 patients presented distant metastases secondarily. Locoregional recurrences occurred in 11 cases "in field" although adequate doses and volumes were used and in 12 cases "outfield", out of irradiated volume. Local recurrences occurred in 13 patients with 12 recurrences within the irradiated volumes. Regional recurrences occurred in 13 patients with 15 lymph nodes metastases identified. Four nodal recurrences occurred outside the ESTRO clinical target volume and within the RTOG clinical target volume and two occurred outside both RTOG and ESTRO clinical target volumes. Conclusion In presented series, the local recurrence resulted mostly from of biologic radio resistance whereas regional recurrences were caused by geographical miss. A number of nodal recurrences could occur outside the target volumes defined by ESTRO and RTOG.

Purpose Residual distal parametrial involvement after radiochemotherapy is a true challenge for brachytherapists since the width and asymmetry of high-risk clinical target volume (HR-CTV) are difficult to cover properly with a standard implant. Material and methods Dosimetric plans of five patients treated with Venezia advanced gynecological applicator at our institution were reviewed. For each patient, we compared the original plan with a new plan where oblique needles were removed and re-optimized manually. Optimization process was halted when EQD210 D90 HR-CTV reached 90 Gy, when one hard constraint to organs at risk (OARs) was reached according to the EMBRACE II protocol, or when dose-rate of one of OARs exceeded 0.6 Gy/h. Results Tumors were large; median HR-CTV volume was 64 cc and median distance between tandem and outer contour of HR-CTV was 40 mm. For the five patients, HR-CTV EQD210 D90 was superior in the plan using oblique needles, with a median difference of 6.5 Gy (range, 1.7-8.5 Gy). Median D90 HR-CTV and intermediate-risk CTV (IR-CTV) were significantly increased with oblique needles: 85.9 Gy (range, 83.2-90.3 Gy) vs. 81.5 Gy (range, 77.4-84 Gy), and 68.7 Gy (range, 66.3-72.3 Gy) vs. 67 Gy (range, 64.3-69.1 Gy), p = 0.006 for both. There were no significant differences in the dose to OARs. Plans with only parallel needles had less favorable dose distribution, with cold spots on the outer parametria and higher vaginal activation to compensate parametrial coverage in its inferior part. Conclusions VeneziaTM applicator permits reproducible application to increase CTV coverage in patients with distal parametrial tumor residue during brachytherapy, while maintaining acceptable dose to OARs.

BackgroundThe COVID-19 pandemic has aggressively reached the most vulnerable, not only the elderly but also patients with chronic conditions such as cancer. In this study, we present the outlines of ethical thinking and the measures implemented to try to respect our basic values of care, in the specific environment of an oncology hospital.MethodsOur ethics committee created an ethical watch system based on 24/7 shifts to assist practitioners in their daily decisions. We discuss the challenges faced by patients with cancer during the pandemic, such as access to critical care and ethical dilemmas in the context of resource scarcity, as well as the issue of isolation of patients. We also debate the restrictions in access to oncology care in a health context strongly ‘prioritised’ against COVID-19.ResultsIn all areas of an ethical dilemma, either for sorting out access to critical care or for the dramatic consequences of prolonged isolation of patients, our common thread was our attempt to protect, whenever possible, the principles of deontological ethics by strictly resisting utilitarian pressure. Respecting democratic health decision-making processes is a cornerstone of ethically relevant decisions, including in the context of a sanitary crisis.ConclusionThe role of an ethics committee related to real-life situations includes not only a reflexive perspective in respect of fundamental principles, but also the help to enlighten and resolve ethical dilemmas in complex clinical situations. This ethical watch team assists physicians in decision-making, promoting the supportive and palliative dimension of care with a holistic approach.

Therapeutic monoclonal antibodies (mAbs) represent one of the most important classes of pharmaceutical proteins to treat human diseases. Most are produced in cultured mammalian cells which is expensive, limiting their availability. Goats, striking a good balance between a relatively short generation time and copious milk yield, present an alternative platform for the cost-effective, flexible, large-scale production of therapeutic mAbs. Here, we focused on cetuximab, a mAb against epidermal growth factor receptor, that is commercially produced under the brand name Erbitux and approved for anti-cancer treatments. We generated several transgenic goat lines that produce cetuximab in their milk. Two lines were selected for detailed characterization. Both showed stable genotypes and cetuximab production levels of up to 10g/L. The mAb could be readily purified and showed improved characteristics compared to Erbitux. The goat-produced cetuximab (gCetuximab) lacked a highly immunogenic epitope that is part of Erbitux. Moreover, it showed enhanced binding to CD16 and increased antibody-dependent cell-dependent cytotoxicity compared to Erbitux. This indicates that these goats produce an improved cetuximab version with the potential for enhanced effectiveness and better safety profile compared to treatments with Erbitux. In addition, our study validates transgenic goats as an excellent platform for large-scale production of therapeutic mAbs.

Plasmacytoid dendritic cells (pDCs) play a central role for both innate and adaptive antiviral responses, as they direct immune responses through their unique ability to produce substantial concentrations of type I interferon (IFNs) upon viral encounter while also activating multiple immune cells, including macrophages, DCs, B, natural killer and T cells. Recent evidence clearly indicates that pDCs also play a crucial role in some cancers and several auto-immune diseases. Although treatments are currently available to patients with such pathologies, many are not fully efficient. We are proposing here, as a new targeted-based therapy, a novel chimeric monoclonal antibody (mAb) that mediates a strong cellular cytotoxicity directed against a specific human pDC marker, CD303. This antibody, ch122A2 mAb, is characterized by low fucose content in its human IgG1 constant (Fc) region, which induces strong in vitro and in vivo activity against human pDCs. We demonstrated that this effect relates in part to its specific Fc region glycosylation pattern, which increased affinity for CD16/FcγRIIIa. Importantly, ch122A2 mAb induces the down-modulation of CpG-induced IFN-α secretion by pDCs. Additionally, ch122A2 mAb shows in vitro high pDC depletion mediated by antibody-dependent cell-mediated cytotoxicity and antibody-dependent cellular phagocytosis. Remarkably, in vivo ch122A2 mAb efficacy is also demonstrated in humanized mice, resulting in significant pDC depletion in bloodstream and secondary lymphoid organs such as spleen. Together, our data indicates that ch122A2 mAb could represent a promising cytotoxic mAb candidate for pathologies in which decreasing type I IFNs or pDCs depleting may improve patient prognosis.

Radiochromic film is a very useful tool for 2D dosimetric measurements in radiotherapy because it is self-developing and has very high-spatial resolution. However, considerable care has to be taken in ion beam radiotherapy owing to the quenching effect of high-linear energy transfer (LET) radiation. In this study, the dose responses of GAFchromic EBT3 and EBT-XD films were experimentally investigated using the clinical carbon ion beam at the Heavy Ion Medical Accelerator in Chiba. Results showed that the relations between absorbed dose and net optical density could be expressed well using an equation proposed by Reinhardt (2015). The quenching effect was evaluated by determining their relative efficiencies for photon irradiation as a function of LET. A correction equation derived in this study allowed the absorbed dose to be determined in the small irradiation field used for carbon ion radiotherapy eye treatments. This study contributes to establishing an absolute dosimetry procedure for heavy ion beams using radiochromic film.

L'un des changements majeurs au cours de l'évolution du français est comme l'ont montré Christine Marchello-Nizia et Bernard Combettes, la grammaticalisation de l'ordre des mots et le passage de l'ordre informationnel Th V X de l'ancien français àl'ordre syntaxique S V G du français moderne. Cette évolution se caractérise par la dissymétrie entre le sujet et l'objet. L'objet se fixe plus tôt (XIIe-XIIIe siècles) à droite du verbe et de façon plus contrainteque le sujet à sa gauche,; intégré dans un groupe verbal hiérarchisé, il est soumis à de fortes contraintes d'expression et de position. En revanche, le sujet nominal, qui ne se fixe que tardivement devant le verbe (entre le XVe et le XVIIe siècle), garde une nette autonomie par rapport à celui-ci, dont Jtémoignent ses possibilités de postposition, d'ellipse et de disjonction. Le sujet nominal peut ainsi être disjoint du verbe par l'insertion de constituants de catégories diverses, ce qui contraste vivement avec les faibles possibilités d'insertion entre le verbe et l'objet et souligne fortement la dissymétrie entre les deux arguments majeurs du verbe.

Infectious mononucleosis, caused by infection with the human gamma-herpesvirus Epstein-Barr virus (EBV), manifests with one of the strongest CD8+ T-cell responses described in humans. The resulting T-cell memory response controls EBV infection asymptomatically in the vast majority of persistently infected individuals. Whether and how dendritic cells (DCs) contribute to the priming of this near-perfect immune control remains unclear. Here we show that of all the human DC subsets, plasmacytoid DCs (pDCs) play a central role in the detection of EBV infection in vitro and in mice with reconstituted human immune system components. pDCs respond to EBV by producing the interferon (IFN) subtypes α1, α2, α5, α7, α14, and α17. However, the virus curtails this type I IFN production with its latent EBV gene products EBNA3A and EBNA3C. The induced type I IFNs inhibit EBV entry and the proliferation of latently EBV-transformed B cells but do not influence lytic reactivation of the virus in vitro. In vivo, exogenous IFN-α14 and IFN-α17, as well as pDC expansion, delay EBV infection and the resulting CD8+ T-cell expansion, but pDC depletion does not significantly influence EBV infection. Thus, consistent with the observation that primary immunodeficiencies compromising type I IFN responses affect only alpha- and beta-herpesvirus infections, we found that EBV elicits pDC responses that transiently suppress viral replication and attenuate CD8+ T-cell expansion but are not required to control primary infection.

We present an original method using a low cost accelerometer and a Kalman-filter based algorithm to monitor cardiopulmonary resuscitation chest compressions (CC) depth. A three-axis accelerometer connected to a computer was used during CC. A Kalman filter was used to retrieve speed and position from acceleration data. We first tested the algorithm for its accuracy and stability on surrogate data. The device was implemented for CC performed on a manikin. Different accelerometer locations were tested. We used a classical inertial navigation algorithm to reconstruct CPR depth and frequency. The device was found accurate enough to monitor CPR depth and its stability was checked for half an hour without any drift. Average error on displacement was ±0.5mm. We showed that depth measurement was dependent on the device location on the patient or the rescuer. The accuracy and stability of this small low-cost accelerometer coupled to a Kalman-filter based algorithm to reconstruct CC depth and frequency, was found well adapted and could be easily implemented.

Second cancers and cardiovascular toxicities are long term radiation toxicity in locally advanced Hodgkin's lymphomas. In this study, we evaluate the potential reduction of dose to normal tissue with helical tomotherapy and proton therapy for Hodgkin's lymphoma involved-field or involved-site irradiation compared to standard 3D conformal radiation therapy.Fourteen female patients with supradiaphragmatic Hodgkin's lymphoma were treated at our institution with 3D conformal radiation therapy or helical tomotherapy to a dose of 30Gy in 15 fractions. A planning comparison was achieved including proton therapy with anterior/posterior passive scattered beams weighted 20Gy/10Gy.Mean doses to breasts, lung tissue and heart with proton therapy were significantly lower compared to helical tomotherapy and to 3D conformal radiation therapy. Helical tomotherapy assured the best protection of lungs from doses above 15Gy with the V20Gy equal to 16.4%, compared to 19.7% for proton therapy (P=0.01) or 22.4% with 3D conformal radiation therapy (P0.01). Volumes of lung receiving doses below 15Gy were significantly larger for helical tomotherapy than for proton therapy or 3D conformal radiation therapy, with respective lung doses V10Gy=37.2%, 24.6% and 27.4%. Also, in the domain of low doses, the volumes of breast that received more than 10Gy or more than 4Gy with helical tomotherapy were double the corresponding volumes for proton therapy, with V4Gy representing more than a third of one breast volume with helical tomotherapy.Helical tomotherapy achieved a better protection to the lungs for doses above 15Gy than passive proton therapy or 3D conformal radiation therapy. However, dose distributions could generally be improved by using protons even with our current passive-beam technology, especially allowing less low dose spreading and better breast tissue sparing, which is an important factor to consider when treating Hodgkin's lymphomas in female patients. Prospective clinical study is needed to evaluate the tolerance and confirm these findings.

Objective Wholesale China Water Storage Cistern Suppliers - Rongda, a new fractional skin resurfacing system based on thermo-OEM China Water Storage Cistern Manufacturers - Rongda. Tixel employs a hot (400°C) metallic tip consisting of 81 pyramids. Treatment is performed by rapidly advancing the tip to the skin for a preset tip-Supply China Water Bladder Storage Factory - Rongda.Wholesale China Rainwater Storage Containers Suppliers - Rongda-Wholesale China Water Bladder Storage Suppliers - Rongda. OEM China Rainwater Storage Containers Wholesaler - Rongda Wholesale China Water Storage Cistern Wholesaler - Rongda, D and S,Wholesale China Water Bladder Storage Factory - Rongda, were evaluated. Twenty-six subjects received three facial treatments, with 4-5-week intervals between treatments, without analgesia or cooling. In addition, histopathologies of Tixel and CO2 laser were performed. Wholesale China Water Storage Cistern Manufacturers - Rongda Wholesale China Water Storage Cistern Factory - Rongda.Supply China Water Storage Cistern Wholesaler - Rongda-Supply China Water Storage Cistern Factory - Rongda-Supply China Water Bladder Storage Wholesaler - Rongda-170 μm deep.Supply China Rainwater Storage Containers Wholesaler - Rongda-Wholesale China Water Bladder Storage Exporter - Rongda. Skin complexion improvement was achieved in all subjects; average treatment pain of 3.1/10,OEM China Stainless Steel Water Storage Containers Wholesaler - Rongda-1 days, and erythema clearance of 3.5 days. Subject's satisfaction was 75% and wrinkle attenuation was achieved in 75% of the cases. There was no incidence of bleeding, scarring, or post-inflammatory hyperpigmentation. Conclusions Supply China Water Storage Cistern OEM/ODM Quotes - Rongda-OEM China Rainwater Storage Containers Suppliers - Rongda,Wholesale China Rainwater Storage Containers Factory - Rongda,Supply China Rainwater Storage Containers Suppliers - Rongda.

PURPOSE The purpose of this study was to evaluate locoregional control and describe the patterns of failure in patients with breast cancer receiving whole breast radiotherapy in the isocentric lateral decubitus position technique. PATIENTS AND METHODS In a series of 832 consecutive female patients with early-stage breast cancer including invasive and in situ tumours treated by breast-conserving surgery followed by three-dimensional conformal whole breast irradiation in the isocentric lateral decubitus position between 2005 and 2010, all patients who experienced locoregional recurrence were studied. Five-year recurrence-free and overall survival rates were calculated. Regional recurrence mapping patterns were also determined. RESULTS The median age of this series of 832 women was 61.5 years (range: 29-90 years). Various types of fractionation were used: 50Gy in 25 fractions (17.9%), 66Gy in 33 fractions (50Gy in 25 fractions to breast followed by sequential boost to tumour bed to a total dose 66Gy in 33 fractions.) (46.5%), 40Gy in 15 fractions or 41.6Gy in 13 fractions (26.1%) and 30Gy in 5 fractions (9.5%). With a median follow-up of 6.4 years, only 36 patients experienced locoregional recurrence and no association with the fractionation regimen was identified (P=0.2). In this population of 36 patients, 28 (3.3%) had "in-breast" local recurrences (77.8%), two had local recurrences and regional lymph node recurrence (5.6%), and six had regional lymph node recurrence only (in non-irradiated areas; 16.6%). The median time to recurrence was 50 months. Complete mapping of patterns of recurrences was performed and, in most cases, local recurrences were situated adjacent to the primary tumour bed. Cases of local recurrences presented a significantly lower distant metastasis rate (P

Toutes les grammaires du XVIIe siecle, y compris celle qui a l'ambition theorique la plus haute, la Grammaire generale et raisonnee de Port-Royal, affichent des preoccupations pedagogiques et tous les grammairiens sont peu ou prou des praticiens, qui destinent leur ouvrage a un double public : francais desireux de perfectionner leur pratique de leur langue maternelle ou etrangers desireux d'apprendre le francais. Ainsi Maupas destine-t-il sa Grammaire et syntaxe francoise (1607) « A tous seig...

In the adjuvant breast cancer treatment, postoperative radiotherapy plays a principal part with an action against the microscopic residual disease in the lymph nodes after mastectomy as well as after breast conserving surgery. This positive effect is observed also in the case of small inner lesions in patients without lymph node involvement. At the same time, there is a recognized risk of cardiac toxicity directly related to the irradiation of internal mammary nodes. This paper is a report on the current available techniques to irradiate the internal mammary nodes, including promising new technology that may help limiting the risk of cardiac toxicity.

Introduction Secondary breast cancer (SBC) is a recognized late complication of radiation therapy, after treatment for Hodgkin lymphoma (HL), with reported relative risks as high as 50 with older techniques (Mantle Field). Within the past, it has been estimated that reduction in dose and volume will reduce the incidence of late complications such as secondary neoplasms and cardiovascular disease. We evaluate the impact of mediastinal proton therapy on potential limitation of SBC risk. Material & methods For 14 young female patients with early-stage, mediastinal HL, treated with chemotherapy and involved-field raditation therapy (IFRT), we simulated similar treatment plans with conformal radiotherapy (CRT), helical tomotherapy (HT) and proton therapy at the dose of 30 Gy. We report the respective doses to the breasts. Treatment plans were not specifically designed for breast sparing. Results Proton therapy significantly lowered the dose to the breasts, with mean doses of 2,76/1,53 Gy to the left and right breast respectively with proton therapy (vs. 4,95/3,88 Gy with HT and vs. 5,56/3,58 Gy with CRT). Proton therapy best limited lower doses (V4Gy and V10Gy) compared to CRT, while HT could limit the higher doses (V20Gy) at the expense of larger volume irradiated at low doses (V4Gy). Conclusion Relative reduction in mean doses to the left and right breasts was of 50 and 57% respectively with proton therapy compared to CRT. Relation between radiation dose and SBC seems to be linear, and reduction in SBC should be in such proportion with proton therapy. Proton therapy seems highly interesting for breast sparing after curative treatment for HL, but these results need to be confirmed by individualized risk estimations and prospective trials. Citation Format: Samy R Horn, Victor Pernin, Nathalie Fournier-Bidoz, Youlia Kirova. Can proton therapy for localized mediastinal Hodgkin's lymphoma reduce second breast cancer incidence? [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P6-09-08.

Radiochromic film is a very useful tool for 2D dosimetric measurements in radiotherapy because it is self-developing and has very high-spatial resolution. However, considerable care has to be taken in ion beam radiotherapy owing to the quenching effect of high-linear energy transfer (LET) radiation. In this study, the dose responses of GAFchromic EBT3 and EBT-XD films were experimentally investigated using the clinical carbon ion beam at the Heavy Ion Medical Accelerator in Chiba. Results showed that the relations between absorbed dose and net optical density could be expressed well using an equation proposed by Reinhardt (2015). The quenching effect was evaluated by determining their relative efficiencies for photon irradiation as a function of LET. A correction equation derived in this study allowed the absorbed dose to be determined in the small irradiation field used for carbon ion radiotherapy eye treatments. This study contributes to establishing an absolute dosimetry procedure for heavy ion beams using radiochromic film.

While glyco-engineered monoclonal antibodies (mAbs) with improved antibody-dependent cell-mediated cytotoxicity (ADCC) are reaching the market, extensive efforts have also been made to improve their pharmacokinetic properties to generate biologically superior molecules. Most therapeutic mAbs are human or humanized IgG molecules whose half-life is dependent on the neonatal Fc receptor FcRn. FcRn reduces IgG catabolism by binding to the Fc domain of endocytosed IgG in acidic lysosomal compartments, allowing them to be recycled into the blood. Fc-engineered mAbs with increased FcRn affinity resulted in longer in vivo half-life in animal models, but also in healthy humans. These Fc-engineered mAbs were obtained by alanine scanning, directed mutagenesis or in silico approach of the FcRn binding site. In our approach, we applied a random mutagenesis technology (MutaGen™) to generate mutations evenly distributed over the whole Fc sequence of human IgG1. IgG variants with improved FcRn-binding were then isolated from these Fc-libraries using a pH-dependent phage display selection process. Two successive rounds of mutagenesis and selection were performed to identify several mutations that dramatically improve FcRn binding. Notably, many of these mutations were unpredictable by rational design as they were located distantly from the FcRn binding site, validating our random molecular approach. When produced on the EMABling(®) platform allowing effector function increase, our IgG variants retained both higher ADCC and higher FcRn binding. Moreover, these IgG variants exhibited longer half-life in human FcRn transgenic mice. These results clearly demonstrate that glyco-engineering to improve cytotoxicity and protein-engineering to increase half-life can be combined to further optimize therapeutic mAbs.

Resume Objectif Evaluer les resultats cliniques et dosimetriques de la tomotherapie helicoidale adjuvante avec boost integre apres mastectomie partielle. Patientes et methodes Les dossiers de 20 patientes ayant recu une tomotherapie apres tumorectomie ont ete analyses. L’âge median etait de 49 ans. Les doses prescrites ont ete de 63,8 Gy par fraction de 2,2 Gy dans le lit operatoire, 52,2 Gy par fraction de 1,8 Gy dans le sein et 50,4 Gy par fractions de 1,74 dans les aires ganglionnaires, soit par 29 fractions. La reproductibilite a ete analysee en mesurant les decalages quotidiens dans les axes x, y, z et en rotation roll. La toxicite a ete decrite selon la Common Terminology Criteria of Adverse Effects v3.0. Resultats Vingt-deux tumeurs ont ete irradiees, 68 % etaient situees dans les quadrants internes, 90 % des patientes ont ete irradiees dans les aires sus-claviculaire et mammaire interne. Le volume recevant 107 % de la dose prescrite (V107 %) etait pour le volume cible previsionnel du boost de 0,3 % ± 0,50 (deviation standard), celui recevant 95 % (V95 %) de 98,4 % ± 1,9. Le volume cible previsionnel du sein recevant 107 % de la dose prescrite etait de 7,8 % ± 17,3, le V95 % de 96,8 % ± 2,2. Le volume cible previsionnel des aires ganglionnaires recevant 107 % de la dose prescrite etait de 2,5 % ± 4,2, le V95 % de 92,7 % ± 13,2. Le volume recevant 20 Gy (V20) du poumon homolateral etait de 18,9 % ± 3,5. Pour les lesions gauches, le volume moyen recevant 30 Gy (V30) du cœur etait de 0,9 % ± 0,8. Les volumes moyens recevant 5 Gy etaient pour le poumon homolateral de 73,1 % ± 11,8, pour le poumon controlateral de 38,9 % ± 21, pour le cœur (lesions gauches) de 57,3 % ± 21, et pour le sein controlateral de 15,5 % ± 9,6. Les decalages moyens ont ete pour l’axe x de –0,04 mm (intervalle de confiance a 95 % [IC95] : –0,40 +0,38), pour l’axe y de –0,37 mm (IC95 : −0,88 +0,14) et pour l’axe z de 2,90 mm (IC95 : 2,4–3,4), le rotation roll de 0,22° (IC95 : –0,10 +0,32). Le suivi median etait 9,7 mois. La tolerance a ete acceptable avec une seule interruption de traitement et trois arrets temporaires pour toxicite cutanee. Aucun cas de toxicite de grades 3–4 n’a ete observe, pour 95 % des patientes une toxicite cutanee de grade 2 pour 45 %. Il y a eu trois cas d’œsophagite. Conclusion La radiotherapie helicoidale permet un traitement bien tolere, qui autorise une couverture adequate des volumes cible en protegeant le cœur et le poumon homolateral. Cependant, les faibles doses dans les etudes suivantes doivent etre reduites.

The new world of safe aesthetic injectables has become increasingly popular with patients. Not only is there less risk than with surgery, but there is also significantly less downtime to interfere with patients' normal work and social schedules. Botulinum toxin (BoNT) type A (BoNTA) is an indispensable tool used in aesthetic medicine, and its broad appeal has made it a hallmark of modern culture. The key to using BoNTA to its best effect is to understand patient-specific factors that will determine the treatment plan and the physician's ability to personalize injection strategies.To present international expert viewpoints and consensus on some of the contemporary best practices in aesthetic BoNTA, so that beginner and advanced injectors may find pearls that provide practical benefits.Expert aesthetic physicians convened to discuss their approaches to treatment with BoNT. The discussions and consensus from this meeting were used to provide an up-to-date review of treatment strategies to improve patient results. Information is presented on patient management and assessment, documentation and consent, aesthetic scales, injection strategies, dilution, dosing, and adverse events.A range of product- and patient-specific factors influence the treatment plan. Truly optimized outcomes are possible only when the treating physician has the requisite knowledge, experience, and vision to use BoNTA as part of a unique solution for each patient's specific needs.

Background. We investigated the feasibility of helical tomotherapy (HT) for inoperable large breast tumors, after failing to achieve adequate treatment planning with conformal radiation techniques.Material and Methods. Five consecutive patients with locally advanced breast cancer (LABC) were treated by preoperative HT. All patients received up-front chemotherapy before HT. Irradiated volumes included breast and nodal areas (45–50 Gy) in 4 patients. One patient received a simultaneous integrated boost (55 Gy) to gross tumor volume (GTV) without lymph node irradiation. Acute toxicity was assessed with Common Toxicity Criteria for Adverse Events v.4. Patients were evaluated for surgery at the end of treatment.Results. Patients were staged IIB to IIIC (according to the AJCC staging system 2010). HT was associated in 4 patients with concomitant chemotherapy (5-fluorouracil and vinorelbine). Two patients were scored with grade 3 skin toxicity (had not completed HT) and one with grade 3 febrile neutropenia. One patient stopped HT with grade 2 skin toxicity. All patients were able to undergo mastectomy at a median interval of 43 days (31–52) from HT. Pathological partial response was seen in all patients.Conclusions. HT is feasible with acceptable toxicity profiles, potentially increased by chemotherapy. These preliminary results prompt us to consider a phase II study.

To evaluate locoregional control and survival after mastectomy, as well as toxicity, in patients irradiated by a previously described postmastectomy highly conformal electron beam radiation therapy technique (PMERT).We included all women irradiated by postmastectomy electron beam radiation therapy for nonmetastatic breast cancer between 2007 and 2011 in our department. Acute and late toxicities were retrospectively assessed using Common Terminology Criteria for Adverse Events version 3.0 criteria.Among the 796 women included, 10.1% were triple-negative, 18.8% HER2-positive, and 24.6% received neoadjuvant chemotherapy (CT). Multifocal lesions were observed in 51.3% of women, and 64.6% had at least 1 involved lymph node (LN). Internal mammary chain, supraclavicular, infraclavicular, and axillary LNs were treated in 85.6%, 88.3%, 77.9%, and 14.9% of cases, respectively. With a median follow-up of 64 months (range, 6-102 months), 5-year locoregional recurrence-free survival and overall survival were 90% (95% confidence interval 88.1%-92.4%) and 90.9% (95% confidence interval 88.9%-93%), respectively. Early skin toxicity was scored as grade 1 in 58.5% of patients, grade 2 in 35.9%, and grade 3 in 4.5%. Concomitant CT was associated with increased grade 3 toxicity (P.001). At long-term follow-up, 29.8% of patients presented temporary or permanent hyperpigmentation or telangiectasia or fibrosis (grade 1: 23.6%; grade 2: 5.2%; grade 3: 1%), with higher rates among smokers (P=.06); 274 patients (34.4%) underwent breast reconstruction. Only 24 patients (3%) had early esophagitis of grade 1. Only 3 patients developed ischemic heart disease: all had been treated by anthracycline-based CT with or without trastuzumab, all had been irradiated to the left chest wall and LN, and all presented numerous cardiovascular risk factors (2-4 factors).This study demonstrated the good efficacy of this technique in terms of locoregional control and survival, and good short-term and long-term safety. Longer follow-up is required to analyze chronic cardiac events.

In this chapter we present: I. The physical bases of proton therapy, going from microscopic concepts to macroscopic features II. The technology and the logistics, which evolve to more and more compact and cheaper facilities with the capability to perform adaptive radiation therapy III. The most usual clinical indications, moving toward (nearly) all indications of radiation therapy IV. Some research orientations, rediscovering physics, and radiation biology V. Basic elements to conceive and build a clinical center VI. Conclusions: The need to learn from others and also to innovate

Short pulse duration (∼0.1-5 milliseconds) CO2 lasers are perceived as excellent tools for vaporization of craters arrays in fractional skin resurfacing.To present a thermo-mechanical ablation technology, which affects tissue identically to fractional CO2 lasers, however at a fraction of the size and cost of a laser.The new technology is based on heating an oscillating array of thin metallic rods to a temperature of 400°C and advancing the rods into tissue down to a precise pre-selected depth for a duration of 0.1-5 milliseconds. As a result, an array of crater is vaporized with identical properties of those produced by CO2 lasers. An ex vivo test was performed with a thermo- metallic rod array prototype.Arrays of 10 × 10 vaporized micro-craters of 350 micron diameter, 200 micron depth have been produced with lateral thermal damage of 80 micron while thermal damage below craters was 80-250 micron.A resonating thermo-mechanical array of high temperature (350-400°C) rods is capable of producing an array of craters identical to those produced with pulsed CO2 lasers.

Purpose To assess the benefits of using cardiac gated images for treatment planning of breast and internal mammary nodes. Patients and methods Inspiration breath hold computed tomography (CT) series acquired at prospectively gated diastolic phase were used for planning. Three different techniques were compared. Technique A used tangents and an internal mammary nodes field covering the three first inter-rib spaces; technique B used an extended internal mammary nodes including part of the medial breast in junction with tangential fields; the 3 rd technique used helical tomotherapy. For each technique, two treatment plans were performed: one plan (plan-01) where mean dose and V 25 to the heart were considered for plan evaluation and a second plan (plan-02) where the irradiation of the left anterior descending artery was minimized. Results V 25 to the heart was found to be less than 5% for all six plans. Mean doses to the heart were within 4.8 to 7.2 Gy. By attempting to lower the dose to the left anterior descending artery, heart D mean was decreased by 20–30% for the two techniques A and B while being unchanged for tomotherapy. Regarding target coverage, there was no marked difference between plans where only heart dose was considered (plans-01) and plans where the left anterior descending artery dose was minimized (plans-02). When the left anterior descending artery dose was part of plan evaluation, D mean to the left anterior descending artery could be decreased by 24, 19 and 9% for techniques A, B and tomotherapy respectively. The three techniques exposed segments of the left coronary to different levels of dose. Conclusion This study showed that evaluation of the dose to the left anterior descending artery coronary may change the treatment strategy. Cardiac gated images without IV contrast permitted a good visualization of the coronaries in order to optimize the dose on these structures. In addition to heart V 25, the dose to the coronaries should be included in prospective studies on radiotherapy related heart toxicity in association with all additional risk factors.

Resume Objectif de l’etude L’indication d’une radiotherapie externe est parfois posee chez des patients porteurs d’un stimulateur cardiaque. Ce traitement peut occasionner des dysfonctionnements lies soit a l’effet ionisant des rayons, soit a des interferences electromagnetiques. Nous avons repris le cas de patientes atteintes d’un cancer du sein traitees par une irradiation mammaire ou parietale, parfois aussi des aires ganglionnaires de drainage, pour evaluer la tolerance et les repercussions de la radiotherapie par rapport au stimulateur cardiaque. Patientes et methodes Plus de 900 patientes ont ete traitees par irradiation externe pour un cancer du sein de novembre 2008 a decembre 2009 dans notre departement par un accelerateur lineaire de haute energie (par photons X de 4 a 6 MV et electrons). Parmi ces dernieres, sept etaient porteuses d’un stimulateur cardiaque. Toutes les patientes ont ete irradiees dans le sein, la paroi thoracique ou les aires ganglionnaires. La dose totale prescrite etait de 50 Gy en 25 fractions dans le sein ou la paroi thoracique et de 46 Gy en 23 fractions dans les aires ganglionnaires. Un boost de 16 Gy en huit fractions etait indique chez certaines patientes traitees par chirurgie conservatrice. Le rythme cardiaque de toutes les patientes etait monitore pendant les seances et surveille par un medecin oncologue radiotherapeute. Tous les stimulateurs cardiaques ont ete controles par le cardiologue des patientes avant et apres l’irradiation. Resultats Sept patientes ont ete adressees dans notre departement pour radiotherapie postoperatoire dans le cadre d’un cancer du sein. Parmi ces sept patientes, seule une finalement s’est vue recuser la radiotherapie et a beneficie d’une mastectomie. Dans quatre cas, le stimulateur cardiaque a ete repositionne avant le debut de la radiotherapie. Six patientes âgees de 48 a 84 ans ont ete traitees par irradiation pour leur cancer du sein. Quatre patientes ont ete traitees par chirurgie conservatrice suivie d’une irradiation mammaire et deux par mastectomie suivie d’une irradiation de la paroi thoracique et des aires ganglionnaires sus- et sous-claviculaire et mammaire interne. La dose au stimulateur cardiaque a ete calculee et etait toujours inferieure a 2 Gy. Il n’a ete observe aucun dysfonctionnement des stimulateurs cardiaques pendant la radiotherapie. Conclusion La prise en charge multidisciplinaire incluant un eventuel changement de positionnement du stimulateur cardiaque avant radiotherapie et le monitoring quotidien ont permis le deroulement sans incident de la radiotherapie pour nos patientes. Il est neanmoins necessaire de mettre a jour des recommandations precisant la dose maximale tolerable aux differents constituants du stimulateur cardiaque.

This study evaluated the efficacy and safety of a low-level, dual-wavelength laser energy and massage device for improving the appearance of cellulite and reducing thigh circumference.Subjects (n = 83) with mild to moderate cellulite enrolled in this IRB-approved, open-label, multicenter study. Their right or left thighs received eight treatments with a low-level, dual-wavelength laser and massage device. The untreated contralateral thigh served as a control. Circumferences of the upper, middle, and lower thighs (treated and untreated) were measured before the fifth and eighth treatments and 1 month after the final treatment.Reduction in thigh circumference of the treated areas exceeded those of the control areas for the upper, middle, and lower thigh in most subjects. The maximum reduction (-0.82 cm) occurred in the upper thigh at 1 month. The mean reduction of the upper, middle, and lower thigh circumferences was -0.64 cm for the treated thighs compared to -0.20 cm for untreated thighs. The difference was significant (p0.0001). Fifty-nine (71.1%) treatment thighs lost circumference compared to 44 (53.0%) control thighs. Resolution of adverse effects including erythema, swelling, and increased urination was seen within 30 minutes after treatment. All were resolved without sequelae and within the expected duration.The low-level, dual-wavelength laser energy and massage device safely improves the appearance of cellulite while reducing thigh circumference.

Purpose To evaluate the accuracy of a boost technique. Methods and Materials Twenty-two patients underwent tumorectomy with placement of two or more clips in the surgical cavity before breast remodeling. Preoperative and postoperative computed tomography scans, with match-point registration, were performed on all patients. The relationship between the location of the gross tumor volume (GTV), defined on the preoperative scan, and clip clinical target volume (CTV) (clips with a 5-mm margin on the postoperative scan) was then studied, by use of commercial volume analysis software. Results Of the patients, 4 had two clips, 2 had three clips, 8 had four clips, and 8 had five clips. The median GTV was 1.06 mL (range, 0.2–5.3 mL); clip CTV ranged from 2.4 to 21.5 mL. Volumetric analysis showed that in 7 cases (32%), there was no intersection between the GTV and the clip CTV, with the following distribution: 4 patients with two clips, 1 patient with three clips, 1 patient with four clips, and 1 patient with five clips. The common contoured volume was defined as the percent ratio between the intersection of the GTV and clip CTV and the GTV. It was found to be significantly increased if three or more clips were used vs. only two clips (common contoured volume, 35.45% vs. 0.73%; p = 0.028). Finally, the GTV and clip CTV volume relationship can be presented as follows: 12.5% to 33% overlap in 8 patients (36.4%), 50% to 75% in 5 patients (22.7%), and greater than 90% in 2 patients (9%). Conclusions The use of three or more clips during tumorectomy increases the accuracy of tumor bed delineation.

The aim of this study was to present the simplified rules of delineation of lymph node (LN) volumes in breast irradiation. Practical rules of delineation of LN areas were developed in the Department of Radiation Oncology of the Institut Curie. These practical guidelines of delineation were based on different specific publications in the field of breast and LN anatomy. The principal characteristic of these rules is their clearly established relationship with anatomical structure, which is easy to find on CT slices. The simplified rules of delineation have been published in pocket format as the illustrated atlas “Help of delineation for breast cancer treatment”. In this small pocket guide, delineation using the practical rules is illustrated, with examples from anatomical CT slices. It is shown that there is an improvement in delineation after the use of these simplified rules and the guide. In conclusion, this small guide is useful for improving everyday practice and decreasing the differences in target delineation for breast irradiation between institutions and observers.

To evaluate the dosimetry of helical tomotherapy (HT) and three-dimensional conformal radiotherapy (3D-CRT) in breast cancer patients undergoing whole breast radiation with simultaneous integrated boost (SIB) of the tumor bed.Thirteen patients with breast cancer treated by lumpectomy and requiring whole breast radiotherapy with tumor bed boost were planned using both HT and 3D-CRT using the field-in-field technique. The whole breast and tumor bed were prescribed 50.68 Gy and 64.4 Gy, respectively, in 28 fractions. Dosimetries for both techniques were compared.Coverage of the whole breast was adequate with both techniques (V(95%)=96.22% vs. 96.25%, with HT and 3D-CRT, respectively; p=0.64). Adequate tumor bed coverage was also achieved, although it was significantly lower with HT (V(95%)=97.18% vs. 99.72%; p0.001). Overdose of the breast volume outside the tumor bed was significantly lower with HT (V(54.23 Gy)=12.47% vs. 30.83%; p0.001). Ipsilateral lung V(20 Gy) (6.34% vs. 10.17%; p0.001), V(5 Gy) (16.54% vs. 18.53%; p0.05) and mean dose (4.05 Gy vs. 6.36 Gy; p0.001) were significantly lower with HT. In patients with left-sided tumors, heart V(30 Gy) (0.03% vs. 1.14%; p0.05) and mean dose (1.35 Gy vs. 2.22 Gy; p0.01) were significantly lower with HT, but not V(5 Gy). Contralateral breast V(5 Gy) (0.27% vs. 0.00%; p0.01) and maximum dose were significantly increased with HT.In breast cancer treated with SIB, both HT and 3D-CRT provided adequate target volume coverage and low heart doses. Tumor bed coverage was slightly lower with HT, but HT avoided unnecessary breast overdosage while improving ipsilateral lung dosimetry.

Any cutaneous damage triggers a cascade of biological effects in the skin responsible for re-establishing skin integrity. Wound healing is a complex biological process inducing dermal remodelling leading at least to a visible scar, and sometimes to hypertrophic or keloid scars. Recent studies suggest that using a laser generates a precisely defined thermal effect in the skin, improving the wound healing process and potentially opening the door to scarless healing.

Definition of nodal volumes in breast cancer treatment and segmentation guidelines. Purpose. To assist in the determination of breast and nodal volumes in the setting of radiotherapy for breast cancer and establish segmentation guidelines. Materials and methods. Contrast metarial enhanced CT examinations were obtained in the treatment position in 25 patients to clearly define the target volumes. The clinical target volume (CTV) including the breast, internal mammary nodes, supraclavicular and subclavicular regions and axxilary region were segmented along with the brachial plexus and interpectoral nodes. The following critical organs were also segmented : heart, lungs, contralateral breast, thyroid, esophagus and humeral head. Results. A correlation between clinical and imaging findings and meeting between radiation oncologists and breast specialists resulted in a better definition of irradiation volumes for breast and nodes with establishement of segmentation guidelines and creation of an anatomical atlas. Conclusion. A practical approach, based on anatomical criteria, is proposed to assist in the segmentation of breast and node volumes in the setting of breast cancer treatment along with a definition of irradiation volumes.

Purpose To describe a new procedure for breast radiotherapy that will improve tumor bed localization and radiotherapy treatment using a multidisciplinary approach. Patients and Methods This pilot study was conducted by departments of radiation oncology, surgery, and radiology. A new procedure has been implemented, summarized as eight steps: from pre-surgery contrast CT to surgery, tumor bed planning target volume (PTV) determination, and finally breast and tumor bed irradiation. Results Twenty patients presenting with T1N0M0 tumors were enrolled in the study. All patients underwent lumpectomy with the placement of surgical clips in the tumor bed region. During surgery, 1 to 5 clips were placed in the lumpectomy cavity before the plastic procedure. All patients underwent pre- and postoperative CT scans in the treatment position. The two sets of images were registered with a match-point registration. All volumes were contoured and the results evaluated. The PTV included the clips region, the gross tumor volume, and the surgical scar, with an overall margin of 5–10 mm in all directions, corresponding to localization and setup uncertainties. For each patient the boost PTV was discussed and compared with our standard forward-planned PTV. Conclusions We demonstrate the feasibility of a tumor bed localization and treatment procedure that seems adaptable to routine practice. Our study shows the advantages of a multidisciplinary approach for tumor bed localization and treatment. The use of more than 1 clip associated with pre- to postoperative CT image registration allows better definition of the PTV boost volume.

This article deals with syntactic and semantic representation of comparative structures in French. We propose an analysis of quantitative comparatives (plus, moins, aussi … que) and qualitative comparatives (comme) which highlights their common properties as well as their specificities. The first section (§ 1) offers a syntactic typology of matrix clause structures and (comparative) subordinate clause structures. The following sections consider the various aspects of semantic representations, as related to syntactic structures : we successively deal with (§ 2.) the type of parameter, (§ 3.) the type of differential constituant in the subordinate clause, (§ 4.) the type of parallel constituant in the matrix clause (with restitution of ellipses and anaphora), (§ 5.) the type of compared terms, by contrasting quantitative comparisons and qualitative comparison, and (§ 6.) the type of comparison, accounting for prototypical structures as well as for pragmatic effects induced by certain configurations.