Clinical implementation of deep-learning based auto-contouring tools-Experience of three French radiotherapy centers.

Deep-learning (DL)-based auto-contouring solutions have recently been proposed as a convincing alternative to decrease workload of target volumes and organs-at-risk (OAR) delineation in radiotherapy planning and improve inter-observer consistency. However, there is minimal literature of clinical implementations of such algorithms in a clinical routine. In this paper we first present an update of the state-of-the-art of DL-based solutions. We then summarize recent recommendations proposed by the European society for radiotherapy and oncology (ESTRO) to be followed before any clinical implementation of artificial intelligence-based solutions in clinic. The last section describes the methodology carried out by three French radiation oncology departments to deploy CE-marked commercial solutions. Based on the information collected, a majority of OAR are retained by the centers among those proposed by the manufacturers, validating the usefulness of DL-based models to decrease clinicians' workload. Target volumes, with the exception of lymph node areas in breast, head and neck and pelvic regions, whole breast, breast wall, prostate and seminal vesicles, are not available in the three commercial solutions at this time. No implemented workflows are currently available to continuously improve the models, but these can be adapted/retrained in some solutions during the commissioning phase to best fit local practices. In reported experiences, automatic workflows were implemented to limit human interactions and make the workflow more fluid. Recommendations published by the ESTRO group will be of importance for guiding physicists in the clinical implementation of patient specific and regular quality assurances.

Automation in radiotherapy treatment planning: Examples of use in clinical practice and future trends for a complete automated workflow.

Modern radiotherapy treatment planning is a complex and time-consuming process that requires the skills of experienced users to obtain quality plans. Since the early 2000s, the automation of this planning process has become an important research topic in radiotherapy. Today, the first commercial automated treatment planning solutions are available and implemented in a growing number of clinical radiotherapy departments. It should be noted that these various commercial solutions are based on very different methods, implying a daily practice that varies from one center to another. It is likely that this change in planning practices is still in its infancy. Indeed, the rise of artificial intelligence methods, based in particular on deep learning, has recently revived research interest in this subject. The numerous articles currently being published announce a lasting and profound transformation of radiotherapy planning practices in the years to come. From this perspective, an evolution of initial training for clinical teams and the drafting of new quality assurance recommendations is desirable.

[Implementing new technology in radiation oncology: The French agency for nuclear safety (ASN) report]. / Conditions de mise en œuvre des « nouvelles techniques et pratiques ¼ en radiothérapie. Synthèse du rapport du groupe de travail issu du groupe permanent d'experts en radioprotection médicale de l'Autorité de sûreté nucléaire.

In August 2013, the French nuclear safety agency (ASN) requested the permanent group of experts in radiation protection in medicine (GPMED) to propose recommendations on the implementation of new technology and techniques in radiation oncology. These recommendations were finalized in February 2015 by the GPMED. In April 2015, the ASN sent a letter to the French ministry of health (DGS/DGOS), and its national health agencies (ANSM, INCa, HAS). In these letters, ASN proposed that, from the 12 recommendations made by the GPMED, an action plan should be established, whose control could be assigned to the French national cancer institute (INCa), as a pilot of the national committee for radiotherapy and that this proposal has to be considered at the next meeting of the national committee of radiotherapy.

[Impact of dynamic IMRT and tomotherapy in pelvic cancers: a prospective dosimetric study with 51 patients]. / Apport de la RCMI rotationnelle et de la tomothérapie hélicoïdale dans les cancers pelviens : étude dosimétrique prospective sur 51 patients.

PURPOSE: To compare the dosimetric results of different techniques of dynamic intensity modulated radiation therapy (IMRT) in patients treated for a pelvic cancer with nodal irradiation. PATIENTS AND METHODS: Data of 51 patients included prospectively in the Artpelvis study were analyzed. Thirty-six patients were treated for a high-risk prostate cancer (13 with helical tomotherapy, and 23 with Rapid'Arc(®)) and 15 patients were treated for a localized anal cancer (nine with helical tomotherapy and six with Rapid'Arc(®)). Plan quality was assessed according to several different dosimetric indexes of coverage of planning target volume and sparing of organs at risk. RESULTS: Although some dosimetric differences were statistically significant, helical tomotherapy and Rapid'Arc provided very similar and highly conformal plans. Regarding organs at risk, Rapid'Arc(®) provided better pelvic bone sparing with a lower non-tumoral integral dose. CONCLUSION: In pelvis cancer with nodal irradiation, Rapid'Arc and helical tomotherapy provided very similar plans. The clinical evaluation of Artpelvis study will verify this equivalence hypothesis.

Clinical results of an EPID-based in-vivo dosimetry method for pelvic cancers treated by intensity-modulated radiation therapy.

The purpose of our work was to investigate the feasibility of using an EPID-based in-vivo dosimetry method initially designed for conformal fields on pelvic dynamic IMRT fields. The method enables a point dose delivered to the patient to be calculated from the transit signal acquired with an electronic portal imaging device (EPID). After defining a set of correction factors allowing EPID pixel values to be converted into absolute doses, several tests on homogeneous water-equivalent phantoms were performed to estimate the validity of the method in reference conditions. The effects of different treatment parameters, such as delivered dose, field size dependence and patient thickness were also studied. The model was first evaluated on a group of 53 patients treated by 3D conformal radiotherapy (3DCRT) and then on 92 patients treated by IMRT, both for pelvic cancers. For each measurement, the dose was reconstructed at the isocenter (DREC) and compared with the dose calculated by our treatment planning system (DTPS). Excellent agreement was found between DREC and DTPS for both techniques. For 3DCRT treatments, the mean deviation between DREC and DTPS for the 211 in-vivo dose verifications was equal to -1.0  ±  2.2% (1SD). Concerning IMRT treatments, the averaged deviation for the 418 fields verified was equal to -0.3 ± 2.6% (1SD) proving that the method is able to reconstruct a dose for dynamic IMRT pelvic fields. Based on these results, tolerance criteria and action levels were established before its implementation in clinical routine.

[Benefit of intensity modulated and image-guided radiotherapy in prostate cancer]. / Apports de la radiothérapie avec modulation d'intensité guidée par l'image dans les cancers prostatiques.

External beam radiotherapy (RT) is used to treat all stages of localized prostate cancer. Using a 3D conformal RT (3DCRT) without any androgen deprivation, a clear dose-effect relationship has been shown in terms of both biochemical control and also unfortunately of rectal and urinary toxicity. Compared to a "standard" 3DCRT, intensity modulated RT (IMRT) improves the dose distribution by mainly providing concave dose distribution and tight dose gradients. Based on large clinical experiences for at least one decade, IMRT is widely used to increase the dose in the prostate and therefore local control, without increasing toxicity. Indeed, toxicity rates observed after high dose delivered in the prostate (80Gy) with IMRT appear no different than those observed after a standard dose (70Gy) delivered by a standard 3DCRT. Arc IMRT appears a new promising IMRT modality, decreasing dramatically treatment duration. However, this IMRT-based dosimetric benefit may not be translated into a full clinical benefit, if intra-pelvic prostate motion is not taken in account. Image-guided radiotherapy (IGRT) should be therefore associated with IMRT for a maximal clinical benefit. This article is a literature review showing the interest of both combined approaches.

Cell investigation by Terahertz BioMEMS.

Quite recently, it was found that metal wires can effectively guide terahertz radiation. We report in this communication an original planar excitation of surface wave on a single wire transmission line. This configuration is well suited for the design of THz BioMEMS dedicated to cell investigation. We show that we can deal with a micrometer spatial resolution.

Lactoferrin: a modulator of immune and inflammatory responses.

Lactoferrin is an iron-binding glycoprotein of the transferrin family. Abundant expression and secretion of lactoferrin, in particular in milk and fluids of the digestive tract, are related to its implication in the first line of host defense. Lactoferrin is also a prominent component of the secondary granules of neutrophils (PMNs) and is released in infected tissues and blood during the inflammatory process. In addition to its direct antimicrobial properties, the abilities of lactoferrin to regulate the immune response and to protect against infection and septic shock have been described in numerous in vitro and in vivo studies. Although the cellular and molecular mechanisms that account for the modulation of the inflammatory and immune responses by lactoferrin are not yet totally elucidated, many are now established. At the cellular level, lactoferrin modulates the migration, maturation and function of immune cells. At the molecular level and in addition to iron binding, interactions of lactoferrin with a plethora of compounds, either soluble or membrane molecules, account for its modulatory properties. This paper reviews our current understanding of the cellular and molecular mechanisms that explain the regulatory properties of lactoferrin in host defence.

2-APB inhibits volume-regulated anion channels independently from intracellular calcium signaling modulation.

It has previously been suggested that volume-regulated anion channels (VRACs) and store-operated channels (SOCs) interact with each other according to their expected colocalization in the plasma membrane of LNCaP cells. In order to study interactions between these two channels, we used 2-aminoethoxydiphenyl borate (2-APB) as a regular SOC inhibitor. Surprisingly 2-APB reduced VRAC activity in a dose-dependent manner (IC(50)=122.8 microM), but not 2,2-diphenyltetrahydrofuran (a structural analog of 2-APB). This effect was also present in keratinocytes. We conclude that 2-APB is an inhibitor of the VRAC family, and is also a potent tool to study the SOC-VRAC interaction in LNCaP cells.

[Preliminary results of the assessment of intensity modulated radiotherapy (IMRT) for prostatic and head and neck tumors (STIC 2001)]. / Résultats préliminaires de l'évaluation de la radiothérapie conformationnelle avec modulation d'intensité (RCMI) pour le traitement des cancers prostatiques et ORL (STIC 2001).

INTRODUCTION: Between May 2002 and May 2004, eight French comprehensive cancer centres did a prospective nonrandomized study including 200 patients, 100 with cancer of the prostate and 100 with head and neck cancers. Half of each patient group was treated by IMRT and the others by RTC 3D. This clinical study was associated with an economic study and a physics study. We report here the first results. PATIENTS AND METHODS: For the clinical study, the analysis of the data of the first 88 patients irradiated for a prostatic cancer shows that 39 received RTC and 49 IMRT with a mean dose of 78 Gy at the ICRU point at 2 Gy per fraction. For H&N tumours, the preliminary analysis was done on the 87 first patients with a mean follow-up of 11.5 months (2 to 25 months) and a median of 8.4 months for the IMRT groups and 13.2 months for the RTC group. The economic study was done on the first 157 patients included during the first 18 months: 71 treated by RTC (35 for H&N and 36 for prostate) and 86 treated by IMRT (38 for H&N and 48 for prostate). The assessment of the direct costs was realized by a micro-costing technique. The physical study compared dose distributions for both techniques and has created quality control recommendations. RESULTS: Clinical studies of the acute reactions do not show any difference between groups, but we want to point out the short follow-up and the relatively high dose delivered to cancers of the prostate. The physics study demonstrates that IMRT is technically feasible in good clinical conditions with high quality assurance, a good reproducibility and precision. Dosimetric data show that IMRT could certainly spare organs at risk more than RTC for H&N tumours. The direct costs of "routine" treatments for H&N tumours were 4922 euros for IMRT versus 1899 euros for RTC and for the prostatic cancers 4911 euros for IMRT versus 2357 for RTC.

[External ionizing radiation on the prosthesis-arterial anastomosis for the prevention of intimal hyperplasia and study of biomechanical resistance. Experiments and results]. / Radiations ionisantes délivrées par voie externe sur l'anastomose prothéto-artérielle pour limiter l'hyperplasie intimale et étude de la résistance biomécanique. Expérimentations et résultats.

PURPOSE: To evaluate the use of external ionizing radiation for the prevention of intimal hyperplasia in anastomosis between PTFE and artery. METHODS: Bypass using a 6 mm PTFE was performed on a swine subrenal aorta with a distal conventional anastomosis (N = 35) associated (test group; N = 17) or not (control group; N = 18) with post-operative external radiation (20 Gy) on this anastomosis. At 45 days, histological studies and morphometric studies were performed on the aorta receiving the anastomosis. Two protocols were performed, the first protocol with standard analysis and the animals were randomly assigned to either group (test group; N = 11 and control group; N = 13) and the second protocol with test of extraction comparing the biomechanical resistance between the irradiated group (N = 6) and the control group (N = 5). RESULTS: Twenty-one animals survived the procedure in the first protocol, 11 in the second. The endothelium was restored in either group. Histological recasting was observed in the media after radiation with fibrosis and areas of necrosis. Intimal thickness was significantly lower after irradiation in the heel (P < 0.01), the head (P < 0.01) and the suture line (P < 0.001) of the artery in the first protocol. The intimal thickness was also significantly lower in the second protocol after radiation in the heel (P < 0.05) and the head of the artery (P < 0.05). There was no difference between the two groups comparing the resistance. CONCLUSION: After external irradiation, the thickness parameter of the intima decreased significantly in comparison with the control group with similar resistance. Media fibrosis and necrosis need to be confirmed by further investigation.

[High-dose external ionizing radiation prevents intimal hyperplasia and limits secretion of growth factors PDGFbb, bFGF, and TGFb1. Experiments and results]. / Les radiations ionisantes externes à doses élevées limitent l'hyperplasie intimale et diminuent la sécrétion des facteurs de croissance PDGF-bb, bFGF et TGFb1. Expérimentation et résultats.

PURPOSE: To evaluate the ionizing radiation for intimal hyperplasia prevention and to assess the production of growth factors. METHODS: An oversized injury using an embolectomy catheter was performed on a rabbit distal aorta (N=23), associated (test group; N=12) or not (control group; N=11) with a post-operative external radiation (25 Gy). At t=45 days, histological studies and morphometric studies were performed on the aorta. Smooth muscular cells and endothelial cells were stained using immuno-histologic revelation. Immuno-histological analysis was performed on arteries for growth factors PDGFbb, bFGF and TGFb1. RESULTS: Twenty-one animals survived the procedure, 11 were in the test group and 10 in the control group. Intimal thickness and ratio intima/media were significantly lower after radiation (respectively p=0.008, p=0.008). There was no difference for the medial thickness (p=0.155). Immuno-histochemical positive staining for PDGF and TGFb1 was lower after radiation (respectively 18.44 +/- 2.963% versus 47.64 +/- 6.86%, p<0.001 and 10.11 +/- 3.18% versus 29.45 +/- 4.156%, p<0.001). There was no difference for the expression of bFGF growth factor. After radiation, the media was found to be reduced and replaced by interstitial fibrosis. CONCLUSION: After external radiation the thickness parameter of the intima and the ratio intima/media decreased significantly in comparison with the control group. PDGF and TGFb1 were also less expressed in the artery irradiated. Fibrosis recasting needs to be confirmed by further investigation.

[In vivo dosimetry and radiation therapy of breast cancer]. / Dosimétrie in vivo et radiothérapie des cancers du sein.

INTRODUCTION: Verification of absorbed dose in target volume is a key factor for quality assurance in radiotherapy. In vivo measurements allow evaluation of the variations in dose with time and variations between measured doses and calculated doses by TPS. The aim of this work were to evaluate reproducibility of patient positioning and to compare calculated doses by 2 different TPS. PATIENTS AND METHODS: Twenty patients were divided in 2 groups according to the thickness of their breast (mean SSD = 92.9 cm). In vivo measurement was performed within the first two sessions. RESULTS: Reproducibility of SSD evaluation was made on 12 beams between 2 fractions. With a tolerance margin of 0.5 cm, positioning errors were present in 33% (4/12). The 2 TPS were in agreement in 75% (30/40). CONCLUSION: In vivo dosimetry can be a very interesting tool to assess patients positioning variations and TPS dose calculation.

[Quality control of intensity modulated treatments in radiotherapy]. / Contrôle de qualité dans la mise en oeuvre de la modulation d'intensité en radiothérapie.

Since January 2001, radiotherapy treatments with modulated intensity beams (IMRT) have started at the Centre Oscar-Lambret. This paper presents the tests and measurements made before the clinical implementation as well the quality control performed before each routine treatment. We use the treatment planning system Helax-TMS (MDS-Nordion) and the Primus accelerator (Siemens) linked to the Lantis network with Primeview and Simtec modules (Siemens) allowing to deliver intensity modulated beams with Step-and-Shoot technique. A prostate case and a head and neck case have been studied and have permitted to evaluate the benefit of IMRT compared to a "classical" conformal radiotherapy. In a second time, we have tested the accelerator's capabilities to deliver these intensity modulated beams, id-est, the accuracy of the leaf positions and the linearity of the monitor chamber. The third step has been the verification of the dose distributions calculated by Helax-TMS, id-est, the dose for different segment sizes, the dose profiles for an intensity modulated beam and the dose distribution for all the traitment beams. The used phantom has been especially developed at the Centre Oscar-Lambret for IMRT. The results have allowed to start clinical treatments and to establish a quality control set for this technique. The next step is the real time dosimetry with a portal imager.

[Probabilities of controlling tumors and complications (TCP/NTCP) after radiotherapy: methodologic, physical, and biological aspects]. / Probabilités de contrôle tumoral et de complications (TCP/NTCP) après radiothérapie: aspects méthodologiques, physiques et biologiques.

Radiotherapy is aimed at getting the best possible therapeutic ratio (tumor local control versus morbidity). Physicists and radiation oncologists have to evaluate explicitly or implicitly the probability of induced complications to normal surrounding tissues. This is based on published data and clinician's experience. Quantitative methods have been introduced with different models in order to predict the impact of partial or global irradiation on a normal organ. These models correspond to the Tumor Control Probability (TCP) and Normal Tissue Complication Probability (NTCP). These biological models may be useful to evaluate the quality of a treatment planning or for the optimization process. The methodologies used and the clinical data are developed and discussed.

Recognition of Lewis x derivatives present on mucins by flagellar components of Pseudomonas aeruginosa.

Pseudomonas aeruginosa binds to human respiratory mucins by mechanisms involving flagellar component-receptor interactions. The adhesion of P. aeruginosa strain PAK is mediated by the flagellar cap protein, FliD, without the involvement of flagellin. Two distinct types of FliD proteins have been identified in P. aeruginosa: A type, found in strain PAK, and B type, found in strain PAO1. In the present work, studies performed with the P. aeruginosa B-type strain PAO1 indicate that both the FliD protein and the flagellin of this strain are involved in the binding to respiratory mucins. Using polyacrylamide-based fluorescent glycoconjugates in a flow cytometry assay, it was previously demonstrated that P. aeruginosa recognizes Le(x) (or Lewis x) derivatives found at the periphery of human respiratory mucins. The aim of the present work was therefore to determine whether these carbohydrate epitopes (or glycotopes) are receptors for FliD proteins and flagellin. The results obtained by both flow cytometry and a microplate adhesion assay indicate that the FliD protein of strain PAO1 is involved in the binding of glycoconjugates bearing Le(x) or sialyl-Le(x) determinants, while the binding of flagellin is restricted to the glycoconjugate bearing Le(x) glycotope. In contrast, the type A cap protein of P. aeruginosa strain PAK is not involved in the binding to glycoconjugates bearing Le(x), sialyl-Le(x), or sulfosialyl-Le(x) glycotopes. This study demonstrates a clear association between a specific Pseudomonas adhesin and a specific mucin glycotope and demonstrates that fine specificities exist in mucin recognition by P. aeruginosa.

Calculation of perturbation correction factors for some reference dosimeters in high-energy photon beams with the Monte Carlo code PENELOPE.

The BNM-LNHB (formerly BNM-LPRI, the French national standard laboratory for ionizing radiation) is equipped with a SATURNE 43 linear accelerator (GE Medical Systems) dedicated to establishing national references of absorbed dose to water for high-energy photon and electron beams. These standards are derived from a dose measurement with a graphite calorimeter and a transfer procedure to water using Fricke dosimeters. This method has already been used to obtain the reference of absorbed dose to water for cobalt-60 beams. The correction factors rising from the perturbations generated by the dosimeters were determined by Monte Carlo calculations. To meet these applications, the Monte Carlo code PENELOPE was used and user codes were specially developed. The first step consisted of simulating the electron and photon showers produced by primary electrons within the accelerator head to determine the characteristics of the resulting photon beams and absorbed dose distributions in a water phantom. These preliminary computations were described in a previous paper. The second step, described in this paper, deals with the calculation of the perturbation correction factors of the graphite calorimeter and of Fricke dosimeters. To point out possible systematic biases, these correction factors were calculated with another Monte Carlo code, EGS4, widely used for years in the field of dose metrology applications. Comparison of the results showed no significant bias. When they were possible, experimental verifications confirmed the calculated values.

Human lactoferrin interacts with soluble CD14 and inhibits expression of endothelial adhesion molecules, E-selectin and ICAM-1, induced by the CD14-lipopolysaccharide complex.

Lipopolysaccharides (LPS), either in the free form or complexed to CD14, a LPS receptor, are elicitors of the immune system. Lactoferrin (Lf), a LPS-chelating glycoprotein, protects animals against septic shock. Since optimal protection requires administration of Lf prior to lethal doses of LPS, we hypothesized that interactions between Lf and soluble CD14 (sCD14) exist. In a first step, human sCD14 and human Lf (hLf) were used to determine the kinetic binding parameters of hLf to free sCD14 in an optical biosensor. The results demonstrated that hLf bound specifically and with a high affinity (K(d) = 16+/-7 nM) to sCD14. Affinity chromatography studies showed that hLf interacted not only with free sCD14 but also, though with different binding properties, with sCD14 complexed to LPS or lipid A-2-keto-3-deoxyoctonic acid-heptose. In a second step, we have investigated whether the capacity of hLf to interact with sCD14 could modulate the expression of endothelial-leukocyte adhesion molecule 1 (E-selectin) or intercellular adhesion molecule 1 (ICAM-1) induced by the sCD14-LPS complex on human umbilical vein endothelial cells (HUVEC). Our experiments show that hLf significantly inhibited both E-selectin and ICAM-1 expressions at the surface of HUVEC. In conclusion, these observations suggest that the anti-inflammatory effects of hLf are due not only to the ability of the molecule to chelate LPS but also to its ability to interact with sCD14 and with the sCD14 complexed to LPS, thus modifying the activation of endothelial cells.

Lactoferrin upregulates the expression of CD4 antigen through the stimulation of the mitogen-activated protein kinase in the human lymphoblastic T Jurkat cell line.

The main biological properties of lactoferrin are thought to concern inflammation and immunomodulation processes, including maturation of immature B and T cells. Lactoferrin accelerates T-cell maturation by inducing the expression of the CD4 surface marker. In this report, using the Jurkat T-cell line, we have shown that lactoferrin upregulates the expression of CD4 antigen through the activation of a transduction pathway. Using an anti-phosphotyrosine antibody, lactoferrin was demonstrated to induce a cascade of phosphorylation of numerous proteins on their tyrosine residues. This tyrosine-phosphorylation was transient, reaching maxima between 5 and 10 min. We also identified the mitogen-activated protein kinase (MAP kinase) which presented an enhanced catalytic activity, reaching a maximum at 10 min of incubation with lactoferrin. Moreover, the use of inhibitors such as genistein and PD98059, tyrosine kinases and MAP kinase kinase (or MEK) inhibitors respectively, allowed us to correlate the activation of MAP kinase with the upregulation of CD4 expression. Finally, using Lck-defective Jurkat cells, our results showed that the p56(lck) (Lck) kinase is necessary for MAP kinase activity and CD4 expression. This paper demonstrates that lactoferrin activates transduction pathway(s) in lymphoblastic T-cells, and that Lck and the Erk2 isoform of MAP kinase are implicated in the upregulation of CD4, induced by lactoferrin in these cells.

Lactoferrin inhibits the binding of lipopolysaccharides to L-selectin and subsequent production of reactive oxygen species by neutrophils.

The activation of leukocytes by lipopolysaccharides (LPS), resulting in the oxidative burst, contributes to the pathogenesis of septic shock. The binding of LPS to L-selectin, which was reported as a serum-independent LPS receptor on neutrophils, induces the production of oxygen free radicals. Human lactoferrin (hLf), an anti-inflammatory glycoprotein released from neutrophil granules during infection, binds to LPS. In this study, we investigated the capacity of hLf to inhibit the L-selectin-mediated activation of neutrophils. Our experiments revealed that hLf prevents the binding of LPS to L-selectin in a concentration-dependent manner. Inhibition was maximum (87.7+/-0.5%) at a concentration of 50 microg/ml of hLf. Furthermore, hLf inhibited up to 55.4+/-0.5% of the intracellular hydrogen peroxide production induced by LPS in neutrophils. These findings suggest that the anti-inflammatory properties of hLf are due, at least in part, to their ability to prevent the binding of LPS to neutrophil L-selectin.