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Purpose Pre-treatment diagnostic magnetic resonance imaging (MRI) is used in prostate cancer detection and staging; however, little is known about its potential for radiotherapy treatment decision, or its prognostic value. We investigated the findings on pre-treatment MRI and its potential influence on treatment decisions, and its ability to predict biochemical recurrence in patients treated with radiotherapy. Methods Files of patients treated by radiotherapy from 2014 to 2022 were searched for if they had had an MRI within 12 months before radiotherapy. Prostate Imaging Reporting & Data System (PI-RADS) score, index lesion diameter and the presence of organ confined disease or extra-prostatic extension were correlated with their Cancer of the Prostate Risk Assessment (CAPRA) score. Distribution of radiological and clinical features between groups were estimated using a chi-squared test. Results Out of 1280 patients, 314 (24.5%) had an MRI. The distribution depended on the treatment received: 22.5% who received low-dose rate (LDR) brachytherapy as monotherapy, 24.0% treated with high-dose rate (HDR) boost and 32.0% treated with external-beam radiotherapy (EBRT) ( P = .017). The CAPRA score significantly correlated with the PI-RADS score (r = .342, P < .01) and the diameter of the index lesion (r = .473, P < .01). A clinically significant number of 22% patients with CAPRA ≤ 3 disease presented with lesions ≥15 mm and were less likely to be treated with LDR monotherapy ( P < .01). 39 patients had a recurrence, only 5 had an MRI: 4 had a lesion of ≥20 mm and 3 a seminal vesicle invasion. Conclusion More than twenty percent of patients with CAPRA ≤3 presented on MRI a ≥15 mm lesion. An MRI could potentially affect treatment choice, and although exploratory our results suggest an important prognostic potential.

Christian Voirol, 1– 3 Marie-France Pelland, 2 Julie Lajeunesse, 2 Jean Pelletier, 2 Rejean Duplain, 4 Josee Dubois, 5 Silvy Lachance, 6 Carole Lambert, 5 Julia Sader, 7 Marie-Claude Audetat 2, 7, 8 1Haute Ecole Arc Santé, HES-SO University of Applied Sciences and Arts Western Switzerland, Neuchâtel, Switzerland; 2Département de Médecine Familiale et de Médecine d’urgence, Faculté de Médecine, Université de Montréal, Montréal, Québec, Canada; 3Département de Psychologie, Faculté des Arts et des Sciences, Université de Montréal, Montréal, Québec, Canada; 4Academic Support, Campus de l’Université de Montréal en Mauricie, Trois-Rivières, Québec, Canada; 5Département de Radiologie, Radio-Oncologie et Médecine Nucléaire, Faculté de Médecine, Université de Montréal, Montréal, Québec, Canada; 6Département de Médecine, Faculté de Médecine, Université de Montréal, Montréal, Québec, Canada; 7Unité de Développement et de Recherche en Éducation Médicale (UDREM), Faculté de Médecine, Université de Genève, Genève, Switzerland; 8Institut Universitaire de Médecine de Famille et de l’Enfance (IuMFE), Faculté de Médecine, Université de Genève, Genève, SwitzerlandCorrespondence: Christian VoirolHE-Arc Santé, HES-SOUniversity of Applied Sciences and Arts Western Switzerland, Espace de l’Europe 11, Neuchâtel, 2000, SuisseTel +41 32 930 2554Fax +41 32 930 1213Email christian.voirol@he-arc.chAbstract: Due to the increasing complexity of medical education and practice, the training of healthcare professionals for leadership and management roles and responsibilities has become increasingly important. But gaps in physician leadership and management skills have been identified across a broad range of organizational and geographic settings. Many clinicians are inadequately prepared to meet their day-to-day clinical leadership responsibilities. Simultaneously, physicians’ leadership and management skills play a central role and yield superior outcomes for patients and health care delivery organizations. Currently, there is a tremendous variability in the amount of time, structure and resources dedicated to leadership/management training for physicians. Physicians who have completed such trainings seem to be pleased with the outcome. However, only a limited number of physicians enroll in these types of trainings. Several reasons can explain this fact, but it seems crucial to investigate what could increase the involvement of medical leaders and managers in these training programs. This paper offers a framework for addressing the barriers to training commitment and for designing initial training interventions for physicians. This framework is rooted in two well-known theoretical models used in social sciences. It aims to promote self-assessed knowledge and expertise amongst physicians about to embrace leader/manager careers. By developing the ability to explore and be curious about one’s own experience and actions, physicians may suddenly open up the possibilities of purposeful learning. The process we describe in this paper may be an essential step in fostering the involvement of physicians in leadership and management training processes. And this is essential to contribute to the advancement of medical discipline.Keywords: insight, self-consciousness, career path, assessment, training commitment, management, physicians, leadership

During aging, human skin is facing hyperpigmentation disorders: senile lentigo (chronobiologic aging) leads to loss of melanogenesis' control while solar lentigo (UV exposure) promotes an increase of oxidized proteins, melanogenesis, and lipofuscin.Stromal-cell-derived-factor-1 (SDF-1) was identified as key regulator of hyperpigmentation and its expression is reduced in senescent fibroblasts, highlighting this protein as new target for skin hyperpigmentation.We developed two skin explant models mimicking of senile and solar lentigo, based on HSDF-1 expression decreased in senile lentigo model, associated with hyperpigmentation. HEX application restored SDF-1 expression, leading to skin pigmentation decrease. For solar lentigo, we showed an impact of UVs on SDF-1 expression linked to hyperpigmentation, while the application of HEX restored SDF-1 expression and reduced skin pigmentation. On same model, HEX reduced oxidized proteins quantity and lipofuscin which increased after UV exposure. Clinically, HEX reduced dark spot pigmentation on Caucasian volunteers' hands and on Asian and African volunteers' face after 28 days.We have developed ex vivo models mimetic of senile and solar lentigo and showed for a very first time that SDF-1 can be also a key regulator for UV-induced hyperpigmentation.Our ex vivo and clinical studies highlighted the power of HEX with strong reduction of dark spots regardless of volunteers' ethnicities.

Skin lipids are essential in every compartment of the skin where they play a key role in various biological functions. Interestingly, their role is central in the maintenance of hydration which is related to skin barrier function and in the skin structure through adipose tissue. It is well described today that skin lipids are affected by ageing giving skin sagging, wrinkles and dryness. Thereby, developing cosmetic actives able to reactivate skin lipids would be an efficient ant-ageing strategy. Due to the strong commitment of our scientists to innovate responsibly and create value, they designed a high value active ingredient named here as Vetiver extract, using a ground-breaking upcycling approach. We evidenced that this unique extract was able to reactivate globally the skin lipids production, bringing skin hydration and plumping effect for mature skin.In order to demonstrate the global renewal of lipids, we evaluated the lipids synthesis on cutaneous cells that produce lipids such as keratinocytes, sebocytes and adipocytes then on Reconstructed Human Epidermis and skin explants. We evaluated the expression of proteins involved in ceramides transport and barrier cornification. We then evaluated hydration and sebaceous parameters on a panel of mature volunteers.We firstly demonstrated that Vetiver extract induced sebum production from human sebocytes cells lines but also improved its quality as observed by the production of specific antimicrobial lipids. Secondly, we demonstrated that Vetiver extract was able to restore skin barrier with the increase of skin lipids neosynthesis on Reconstructed Human Epidermis and skin explants. We also evidenced that Vetiver extract stimulated the lipids transport and epidermal cornification. Finally, Vetiver extract showed a significant effect on adipogenesis and maturation of adipocytes at in vitro and ex vivo models. We confirmed all these activities by showing that Vetiver extract improved sebum production and brought hydration through an increase of lipids content and their conformation. Vetiver extract induced an improvement of skin fatigue and a plumping effect by acting deeply on adipose tissue.In conclusion, we developed an active ingredient able to bring anti-ageing effect for mature skin by a global increase of skin lipids.Les lipides de la peau sont essentiels dans chaque compartiment de la peau où ils jouent un rôle clé dans diverses fonctions biologiques. Il est intéressant de noter que leur rôle est central dans le maintien de l'hydratation, liée à la fonction de barrière cutanée, mais aussi dans la structure même de la peau, par le biais du tissu adipeux. Il est bien décrit aujourd'hui que les lipides de la peau sont affectés par le vieillissement, ce qui entraîne un relâchement de la peau, des rides et une sécheresse. Ainsi, le développement d'actifs cosmétiques capables de réactiver les lipides de la peau serait une stratégie efficace de lutte contre le vieillissement. En raison de l'engagement fort de nos scientifiques à innover de manière responsable et à créer de la valeur, ils ont conçus un ingrédient actif à forte valeur ajoutée, appelé ici extrait de Vétiver, en utilisant une approche révolutionnaire de « up-cycling ». Nous avons démontré que cet extrait unique était capable de réactiver globalement la production de lipides de la peau, apportant une hydratation de la peau et un effet repulpant pour les peaux matures. MÉTHODES: Afin de démontrer le renouvellement global des lipides, nous avons évalué la synthèse des lipides sur les cellules cutanées qui produisent des lipides tels que les kératinocytes, les sébocytes et les adipocytes, puis sur un modèle d’Epiderme Humain Reconstruit et les explants de peau. Nous avons évalué l'expression des protéines impliquées dans le transport des céramides et la kératinisation de la barrière cutanée. Nous avons ensuite évalué l'hydratation et les paramètres sébacés sur un panel de volontaires matures. RÉSULTATS: Nous avons tout d'abord démontré que l'extrait de Vétiver induit la production de sébum à partir de lignées cellulaires de sébocytes humains mais améliore également sa qualité comme l'indique la production de lipides antimicrobiens spécifiques. Ensuite, nous avons démontré que l'extrait de Vétiver était capable de restaurer la barrière cutanée grâce à l'augmentation de la néosynthèse lipidique sur un modèle d’Epiderme Humain Reconstruit et sur des explants de peau. Nous avons également démontré que l'extrait de Vétiver stimulait le transport des lipides et la kératinisation de l'épiderme. Enfin, l'extrait de Vétiver a montré un effet significatif sur l'adipogenèse et la maturation des adipocytes dans des modèles in vitro et ex vivo. Nous avons confirmé à l’échelle clinique toutes ces activités en montrant que l'extrait de Vétiver améliorait la production de sébum et apportait une hydratation grâce à une augmentation de la teneur en lipides ainsi qu’une modification de leur conformation. L'extrait de Vétiver a induit une amélioration de la fatigue cutanée et un effet repulpant en agissant en profondeur sur le tissu adipeux.En conclusion, nous avons développé un ingrédient actif capable d'apporter un effet anti-âge aux peaux matures par une augmentation globale des lipides de la peau.

QTc prolongation is linked to Torsade de Pointes, sudden cardiac death, and overall cardiovascular mortality. 754 prostate cancer patients undergoing brachytherapy were analyzed, prolonged QTc was defined as ���450ms. A prolonged QTc was more frequent (10.1 vs. 5.1%, p = 0.040) in patients with high-risk cancer than in low to intermediate risk patients. The absolute QTc-time was correlated with age (r = 0.125), neutrophil count (r = 0.130) and negatively correlated with the testosterone level (r=���0.205). Treating physicians should be aware of this and monitor the QTc during ADT to possibly decrease cardiac morbidity/mortality in these patients who are more likely to require ADT.

Background Several studies evidenced significant increase of cortisol is the consequence of UV or emotional stress and leads to various deleterious effects in the skin. Aim The well-aging, a new concept of lifestyle, procures an alternative to the anti-aging strategy. We demonstrated that Tephrosia purpurea extract is able to stimulate well-being hormones while reducing cortisol release. Furthermore, we hypothesized that the extract could positively influence the global skin homeostasis. Method We evaluated the impact of the extract on cortisol, β-endorphin, and dopamine, released by normal human epidermal keratinocytes (NHEKs). A gene expression study was realized on NHEKs and NHDFs. The protein over-expression of HMOX1 and NQO1 was evidenced at cellular and tissue level. Finally, we conducted a clinical study on 21 women living in a polluted environment in order to observe the impact of the active on global skin improvement. Results The extract is able to reduce significantly the cortisol release while inducing the production of β-endorphin and dopamine. The gene expression study revealed that Tephrosia purpurea extract up-regulated the genes involved in antioxidant response and skin renewal. Moreover, the induction of HMOX and NQO1 expression was confirmed on NHDFs, NHEKs and in RHE. We clinically demonstrated that the extract improved significantly the skin by reducing dark circles, represented by an improvement of L*, a*, and ITA parameters. Conclusion Tephrosia purpurea extract has beneficial effects on skin homeostasis through control of the well-being state and antioxidant defenses leading to an improvement of dark circles, a clinical features particularly impacted by emotional and environmental stress.

Introduction We aimed to characterize the most influential radiation oncologists on Twitter, the correlation between their Twitter activity and their academic profiles as measured by the Scopus H-index as well as their activity around the American Society for Radiation Oncologists (ASTRO) 2018 meeting. Methods We defined radiation oncology influencers as any radiation oncologist with 500 or more followers on Twitter through the first two weeks of August 2019. We collected their available characteristics, their Scopus H-index, and Twitter metrics. We examined their general Twitter activity as well as their specific activity before, during, and after the 2018 ASTRO annual meeting. We identified the most frequent tweet content categories for each influencer. Results We identified 48 radiation oncologist influencers; 79% were male, 75% were based in the United States, and 94% were affiliated with an academic center. Among them, 44% had high H-indices of ≥21, an average value in academic faculty for full professors or department heads. There were no correlations between H-index and Twitter metrics such as the number of individuals the influencer was following (p = 0.58), the number of followers (p = 0.66), the number of tweets (p = 0.88), and the number of likes (p = 0.54). During the period around ASTRO 2018, the mean number of tweets per influencer was 4437 (range 87-93,000). Conclusion Current radiation oncology influencers are predominantly North American males from academic institutions. A correlation between academic productivity as measured by the H-index and Twitter metrics was not demonstrated. The fact that some influencers had a low H-index supports that a high academic profile as measured by traditional metrics is not necessary to have a voice in the Twitter radiation oncology community.

Purpose Volumetric arc therapy (VMAT) is a radiation therapy (RT) technique that spares normal tissues from high and intermediate RT doses but increases the volume of tissues receiving low doses of RT compared with 3-dimensional conformal RT (3DCRT). We hypothesized that palliative VMAT would reduce the detriment to patient quality of life (QOL) compared with palliative 3DCRT. Methods and Materials This phase 2 trial randomized patients to palliative RT using VMAT or 3DCRT to 1 painful site of metastatic disease in the trunk. Treating physicians could choose 8 Gy in 1 fraction or 20 Gy in 5 fractions to stratify randomization. The primary endpoint was the change in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Version 3.0 (EORTC QLQ-C30) global health status QOL subscale at 1 week after RT. Repeated measures analysis of variance was used to assess the relationship of patient QOL over time with other factors. Results From July 2014 to November 2017, 37 patients who underwent 3DCRT and 32 patients who underwent VMAT were randomized into the study. Median overall survival was 9 months. Overall pain responses to RT were equivalent (P = .53) between the techniques. Patient compliance in returning QOL questionnaires was 94%, 81%, and 69% at baseline, 1 week after RT, and 1 month after RT, respectively. At 1 week after RT, change in global QOL was not significantly (P = .31) different between VMAT versus 3DCRT. At 4 weeks after RT, VMAT induced significantly (P = .049) less global QOL deterioration than 3DCRT did. Patients who underwent VMAT maintained better physical (P = .012), role (P = .041), and social (P = .025) functioning, but they reported more diarrhea symptoms (P = .017) than in the 3DCRT group. Conclusions Palliative VMAT and 3DCRT did not differ in their ability to control pain; however, palliative VMAT induced fewer QOL detriments than 3DCRT did at 4 weeks after RT.

We investigated whether there is an association between testosterone levels and prostate cancer aggressiveness in patients treated with radiation therapy who underwent a prostatectomy or prostate radiotherapy (EBRT). A total of 380 patients who received primary or post-operative radiotherapy were identified. At the time of radiotherapy, baseline testosterone levels and body mass index (BMI) measurements were available. On multivariate analysis (MVA), higher prostate-specific antigen (PSA) levels were predictive of testosterone ≥10.4 (OR = 1.3, p = .04) and testosterone ≥12.0 nmol/L (OR = 1.3, p = .04). Patients with a Gleason score ≥8 were more likely to have testosterone

OBJECTIVE The objective of this study was to examine the correlation between Twitter mentions and the number of academic citations of radiation oncology articles. MATERIALS AND METHODS We reviewed all 178 clinical manuscripts of the 2 most important radiation oncology journals and "Brachytherapy," and all clinical manuscripts relating to radiation oncology from the top 10 impact factor oncology journals, published between January and February 2018. We collected the record of citations utilizing Scopus and Google Scholar platforms and the number of times an article was tweeted about using the "Altmetric Bookmarklet." χ test was used to compare distributions between groups and the Pearson coefficient was used for correlations between the Twitter metrics and academic citations. RESULTS Overall, 71% of all articles were tweeted about at least once. There was a significant correlation between the number of tweets and the number of citations in Google Scholar (r=0.55, P

Background Healthy skin is a delicate balance between skin renewal and microbiota homeostasis, and its imbalance promotes premature aging and dermatological disorders. Skin stem cells are key actors in this process but their sensitivity to aging and external stressors such as UV reduces the skin renewal power. The skin microbiota has been recently described as active in the healthy skin, and its imbalance could trigger some disorders. Aims We hypothesized that reactivation of stem cells and maintenance of microbiota could be a disruptive strategy for younger and healthier skin. We thus developed a new plant extract that restores the entire skin renewal process by sequential activation from stem cells stimulation to microbiota protection. Methods We studied stem cells comportment in the presence of Orobanche rapum extract by survivin immunocytochemistry and caspases 3 and 9 dosages. We also analyzed epidermal differentiation markers by immunohistochemistry and lipids organization by GC/MS At the clinical level, we investigated the impact of O. rapum extract on microbiota and on skin aspect. Results We demonstrated an active protection of skin stem cells through the maintenance of their clone-forming capacity and resistance to UV through the overexpression of survivin coupled to caspases inhibition. Furthermore, we showed the restoration of epidermal differentiation markers and ceramide biosynthesis favorable to orthorhombic organization. Clinical studies, including microbiota analysis, showed an active skin surface renewal coupled with microbiota protection. Conclusion We evidenced that our active ingredient is able to stimulate skin rejuvenation while protecting the cutaneous microbiota, creating healthier skin and thereby beauty.

Purpose The aim of this study was to compare early prostate-specific antigen (PSA) decline patterns and PSA nadirs between low-dose-rate seed prostate brachytherapy (LDR-PB) and different fractionations of external beam radiotherapy (EBRT) and their predictive importance for biochemical failure (bF). Methods and Materials Patients with D'Amico low- or intermediate-risk prostate cancer who underwent a single-modality treatment without androgen deprivation were included in this study. Three different treatment groups were compared: (1) normofractionation EBRT up to 70.2–79.2 Gy/1.8–2.0 Gy, (2) LDR-PB, and (3) EBRT with hypofractionation 60 Gy/3 Gy daily or 5–7.25 Gy once a week over 9–5 weeks, to a total dose of 45–36.25 Gy, respectively. The log-rank test, Cox regression analysis, and nonparametric tests were used. Results We analyzed 892 patients: the median followup for patients without bF was 84 months (interquartile range 60–102 months), with 12% of patients experiencing bF. The PSA decline within the first 15 months was generally exponential. LDR-PB showed a faster early exponential decline compared with EBRT treatments, but whether decline was fast or slow had no influence on recurrence. The only factors that were positive predictive factors in univariate and multivariate analyses were the time to nadir >48 months (median), PSA nadir Conclusions Although there are significant differences in early exponential PSA decline between different treatments, only the PSA nadir and longer time to nadir were predictive factors for bF.

Purpose/Objective Published preclinical and phase I clinical trial data suggest that fractionated lesional radiotherapy with 60 Gy in 10 fractions can serve as an alternative approach to single fraction radiosurgical boost for brain oligometastases. Methods and Materials A phase II clinical trial (NCT01543542) of a total of 60 Gy in 10 fractions of lesional (one to three) radiotherapy (given simultaneously with whole-brain helical tomotherapy with 30 Gy in 10 fractions) was conducted at five institutions. We hypothesized that fractionated radiotherapy would be considered unsuitable if the median overall survival (OS) was degraded by two months or if six-month intracranial control (ICC) and intracranial lesion (ILC) were inferior by 10% compared with the published RTOG 9508 results. Results A total of 87 patients were enrolled over a 4.5-year accrual period. Radiological lesion and extralesional central nervous system progression were documented in 15/87 (17%) and 11/87 (13%) patients, respectively. Median OS for all patients was 5.4 months. Six-month actuarial estimates of ICC and ILC were 78% and 89%, respectively. However, only the ILC estimate achieved statistical significance (p=0.02), demonstrating non-inferiority to the a priori historical controls (OS: p=0.09, ICC=0.31). Two patients developed suspected asymptomatic radionecrosis. Conclusions The phase II estimates of ILC were demonstrated to be non-inferior to the results of the RTOG 9508.

Purpose The progress of women in academic medicine appears to be curtailed. We evaluated gender differences in academia for residents in radiation oncology compared with 2 of its related specialties, radiology and medical oncology, across Canada. Methods and Materials We analyzed abstracts presented between 2013 and 2016 at the annual meetings of the Canadian Association of Radiation Oncologists and compared it to the corresponding data for the meetings of the Canadian Association of Radiologists and Canadian Association of Medical Oncology. We further evaluated gender composition of abstracts, presentations, and publications available on PubMed. Conversion rates according to gender and to medical specialties were assessed. Proportions were compared using Fisher exact test or the chi-squared test. Results Among the 198 presented abstracts, 103 (52%) were published. Radiation oncology had the highest publishing rate with 90% (oncology 56%, radiology 40%). The publication rate between the medical specialties was significantly different (P Fifty-seven percent of abstracts presented by women were published versus 48% of abstracts presented by men. Overall, there was no significant difference between genders in terms of subsequent conversions into a scientific publication within each specialty (P = .25-1.0). In radiation oncology, women presented 67% of abstracts and published 95% of their presented abstracts, and in medical oncology, 66% of abstracts were from women and 57% of the presented abstracts were published. Among the published abstracts, 83% had the same first author in the abstract and the publication. Among those who lost their first-authorship status, 59% were women. However, there was no statistically significant difference between specialties for loss of first-author status. Conclusions We observed that from 2013 to 2016, women had the highest presentation and publication rate in radiation oncology. More prospective data are needed to monitor the progress of women in all specialties and their specific needs.

Objective In hair care cosmetic products’ evaluation, one commonly used method is to evaluate the hair appearance as a gold standard in order to determine the effect of an active ingredient on the final state of the hair via visual appreciation. Although other techniques have been proposed for a direct analysis of the hair fibres, they give only surface or structural information, without any accurate molecular information. A different approach based on confocal Raman spectroscopy has been proposed for tracking in situ the molecular change in the keratin directly in the human hair fibres. It presents a high molecular specificity to detect chemical interactions between molecules and can provide molecular information at various depths at the cortex and cuticle levels. Methods To evaluate the potential of confocal Raman spectroscopy in testing the efficiency of cosmetic ingredients on keratin structure, we undertook a pilot study on the effectiveness of a smoothing shampoo on natural human hair, by analysing α‐helix and β‐sheet spectral markers in the Amide I band and spectral markers specific to the cystin sulfur content. Results We confirmed that an active proved to be effective on a gold standard decreases α‐helix keratin conformation and promotes β‐sheet keratin conformation in the hair fibres. We also showed that treatment with the effective active decreases the intensity of covalent disulfide (S–S at 510 cm‐1) cross‐linking bands of cysteine. These data confirm that the effective active also acts on the tertiary structure of keratin. Conclusion From these experiments, we concluded that the effective active has a smoothing effect on the human hair fibres by acting on α‐helix and β‐sheet keratin conformation and on the tertiary structure of keratin. Based on these results, confocal Raman spectroscopy can be considered a powerful technique for investigating the influence of hair cosmetic ingredients on keratin structure in human hair fibres. Moreover, this analytical technique has the advantage of being non‐destructive and label free; in addition, it does not require sample extraction or purification and it can be applied routinely in cosmetic laboratories., Confocal Raman spectroscopy can be considered as a powerful technique for investigating the influence of hair cosmetic ingredients on keratin structure in human hair fibres.

© 2016, Springer Science+Business Media New York. We examined functional outcomes and quality of life of whole brain radiotherapy (WBRT) with integrated fractionated stereotactic radiotherapy boost (FSRT) for brain metastases treatment. Eighty seven people with 1–3 brain metastases (54/87 lung primary, 42/87 single brain metastases) were enrolled on this Phase II trial of WBRT (30 Gy/10) + simultaneous FSRT, (60 Gy/10). Median overall follow-up and survival was 5.4 months, 6 month actuarial intra-lesional control was 78 %; only 1 patient exhibited grade 4 toxicity (worsened seizures); most treatment related toxicity was grade 1 or 2; 2/87 patients demonstrated asymptomatic radiation necrosis on follow-up imaging. Mean (Min–Max) baseline KPS, Mini Mental Status Exam (MMSE) and FACT-BR quality of life were 83 (70–100), 28 (21–30) and 143 (98–153). Lower baseline MMSE (but not KPS or FACT-Br) was associated with worse survival after adjusting for age, number of metastases, primary and extra-cranial disease status. Crude rates of deterioration (>10 points decrease from baseline for KPS and FACT-Br, MMSE fall to

From a large screening of microbial extracts for the discovery of proteasome modulating natural products, the fungal strain Cercospora sp. (CF-223709) was selected as the most promising for further investigation. Different liquid cultures of the strain were initially screened for their anti-oxidant activity (DPPH, ABTS) and for their cytotoxicity against the A2058, HepG2 and CCD25sk cell lines. A detailed chemical analysis and evaluation of the capacity to activate 26S-proteasome was followed for the most active extract. Three main polyketides were isolated and characterized by extensive analysis of NMR and HRMS spectra data as penialidine F (1), fulvic acid (2), and SB238569 (3). Fulvic acid showed the most significant anti-oxidant activity. Its IC50 value (8.16 μM) against the ABTS radical resulted 3-fold lower than the standard trolox. Fulvic acid also demonstrated a significant effect on proteasome by enhancing the chymotrypsin- and caspase-like activities of the 26S proteasome of human fibroblasts by 71.43% and 37.5% at 1 μM, respectively. Furthermore by scaling up the culture in a 30 L submerged bioreactor, Cercospora sp. produced up to 162.6 ± 1.3 mg of fulvic acid/L. Our findings suggest that CF-223709 can be a promising source of proteasome activating natural compounds.

In the course of a primary screening of 614 microbial actinomycete extracts for the discovery of tyrosinase inhibitors, the EtOAc extract of the fermentation broth of the strain Streptomyces sp. CA-129531 isolated from a Martinique sample, exhibited in cell free and cell-based assays the most promising activity (IC50 value of 63 μg/mL). Scaled-up production in a bioreactor led to the isolation of one new trichostatic acid analogue, namely trichostatic acid B (1), along with six known trichostatin derivatives (2–7), four diketopiperazines (8–11), two butyrolactones (12–13) and one hydroxamic acid siderophore (14). Among them, trichostatin A (4) showed a Ki value of 6.1 μM and six times stronger anti-tyrosinase activity (IC50 2.18 μΜ) than kojic acid (IC50 14.07 μΜ) used as a positive control. Deoxytrichostatin A (6) displayed also strong inhibitory activity against tyrosinase (IC50 19.18 μΜ). Trichostatin A production in bioreactor started together with the exponential phase of growth (day 4) and the maximum concentration was reached at day 9 (2.67 ± 0.13 μg/mL). Despite the cytotoxicity of some individual components, the EtOAc extract showed no cytotoxic effect on HepG2, A2058, A549, MCF-7 and MIA PaCa-2 cell lines, (IC50 >2.84 mg/mL) and against BG fibroblasts at the concentrations where the whitening effect was exerted, reassuring its safety and great tyrosinase inhibitory potential.

Conflicting data exists on the influence of metformin on prostate cancer. We investigated the importance of metformin in patients treated with radiotherapy or brachytherapy.All patients from a large institutionalized database, treated for primary localized prostate cancer with either brachytherapy or external-beam radiotherapy ± androgen deprivation therapy were identified. Groups were compared by Kaplan-Meier analyses and Cox regression models. Multivariate analysis was adjusted for CAPRA-Score, type of treatment and age.A total of 2441 patients with complete data was identified. Among the 382 patients (16% of total) were diabetic. Two-hundred and eighty-one of the 382 diabetics (74%) were treated with metformin and 101 were treated with other anti-diabetic medication. Median follow up was 48 months (interquartile range [IQR] 24-84). Two-hundred eighteen patients (9%) died and 150 (6%) experienced biochemical recurrence (BCR). On unadjusted univariate analysis for BCR-free survival, metformin users showed a 50% reduction in BCR compared to non-metformin users. The results remained significant on multivariate analysis comparing diabetic metformin users to non-metformin users (diabetics and non-diabetics combined) (hazard ratio [HR] 0.5-0.6, p = 0.03-0.04) but lost its significance when adjusting for cancer aggressiveness. On multivariate analysis, diabetics had worse overall survival (OS) than non-diabetics (HR 1.5, 95% confidence interval [CI] 1.08-2.06, p = 0.01), but diabetics on metformin fared better than diabetics not taking metformin (HR 0.5, 95% CI 0.26-0.86, p = 0.01).Metformin use in this analysis appears to be associated with better BCR and OS. Larger datasets and prospective trials are warranted to validate these results.

Introduction In a script concordance test (SCT), examinees are asked to judge the effect of a new piece of clinical information on a proposed hypothesis. Answers are collected using a Likert-type scale (ranging from −2 to +2, with ‘0’ indicating no effect), and compared with those of a reference panel of ‘experts’. It has been argued, however, that SCT may be susceptible to the influences of gaming and guesswork. This study aims to address some of the mounting concern over the response process validity of SCT scores. Method Using published datasets from three independent SCTs, we investigated examinee response patterns, and computed the score a hypothetical examinee would obtain on each of the tests if he 1) guessed random answers and 2) deliberately answered ‘0’ on all test items. Results A simulated random guessing strategy led to scores 2 SDs below mean scores of actual respondents (Z-scores −3.6 to −2.1). A simulated ‘all-0’ strategy led to scores at least 1 SD above those obtained by random guessing (Z-scores −2.2 to −0.7). In one dataset, stepwise exclusion of items with modal panel response ‘0’ to fewer than 10% of the total number of test items yielded hypothetical scores 2 SDs below mean scores of actual respondents. Discussion Random guessing was not an advantageous response strategy. An ‘all-0’ response strategy, however, demonstrated evidence of artificial score inflation. Our findings pose a significant threat to the SCT’s validity argument. ‘Testwiseness’ is a potential hazard to all testing formats, and appropriate countermeasures must be established. We propose an approach that might be used to mitigate a potentially real and troubling phenomenon in script concordance testing. The impact of this approach on the content validity of SCTs merits further discussion.

A prostate-specific antigen (PSA) nadir0.2 ng/mL is generally considered as tissue ablative and at low risk for recurrence. After attaining such a low PSA nadir, we analyzed risk factors for recurrence.We identified patients from our institutionalized database with either D'Amico low- or intermediate-risk prostate cancer that was treated with either low-dose-rate prostate brachytherapy or external beam radiotherapy as monotherapy. We compared patients who attained a nadir0.2 ng/mL and subsequently developed biochemical failure to patients who did not experience biochemical failure by using χOf 892 patients, 560 (63%) achieved a nadir0.2 ng/mL. Only 23 (4.1%) later developed a biochemical recurrence. The 7-year Kaplan-Meier biochemical recurrence-free survival after a PSA nadir of0.2 ng/mL was 96%. Patients who later experienced biochemical recurrence were more likely to have Cancer of the Prostate Risk Assessment Score intermediate- or high-risk cancer: (74% vs. 40%, p0.001). Patients were more likely to have a diagnostic PSA6.0 ng/mL: (66% vs. 43% p0.001) and have a Gleason score ≥ 3 + 4: (52% vs. 34%, p = 0.005). They were also more likely to be older (p = 0.003): mean (SD) 70.3 (6.4) vs. 66.2 (6.5) and have a time to PSA nadir that was significantly shorter (p = 0.013): mean (SD) 51.8 (29.6) vs. 65.2 (25.1).Biochemical recurrence after attaining a PSA nadir0.2 ng/mL is rare and more frequent in patients with intermediate risk cancer and older patients. These patients can benefit from a prolonged followup with specialized physicians.

International audience; The aim of the present study was to investigate the neuro-soothing activity of a water-soluble hydrolysate obtained from the red microalgae Rhodosorus marinus Geitler (Stylonemataceae). Transcriptomic analysis performed on ≈100 genes related to skin biological functions firstly revealed that the crude Rhodosorus marinus extract was able to significantly negatively modulate specific genes involved in pro-inflammation (interleukin 1α encoding gene, IL1A) and pain detection related to tissue inflammation (nerve growth factor NGF and its receptor NGFR). An in vitro model of normal human keratinocytes was then used to evaluate the ability of the Rhodosorus marinus extract to control the release of neuro-inflammation mediators under phorbol myristate acetate (PMA)-induced inflammatory conditions. The extract incorporated at 1% and 3% significantly inhibited the release of IL-1α and NGF secretion. These results were confirmed in a co-culture system of reconstructed human epithelium and normal human epidermal keratinocytes on which a cream formulated with the Rhodosorus marinus extract at 1% and 3% was topically applied after systemic induction of neuro-inflammation. Finally, an in vitro model of normal human astrocytes was developed for the evaluation of transient receptor potential vanilloid 1 (TRPV1) receptor modulation, mimicking pain sensing related to neuro-inflammation as observed in sensitive skins. Treatment with the Rhodosorus marinus extract at 1% and 3% significantly decreased PMA-mediated TRPV1 over-expression. In parallel with these biological experiments, the crude Rhodosorus marinus extract was fractionated by centrifugal partition chromatography (CPC) and chemically profiled by a recently developed 13C NMR-based dereplication method. The CPC-generated fractions as well as pure metabolites were tested again in vitro in an attempt to identify the biologically active constituents involved in the neuro-soothing activity of the Rhodosorus marinus extract. Two active molecules, namely, γ-aminobutyric acid (GABA) and its structural derivative GABA-alanine, demonstrated a strong capacity to positively regulate skin sensitization mechanisms related to the TRPV1 receptors under PMA-induced inflammatory conditions, therefore providing interesting perspectives for the treatment of sensitive skins, atopia, dermatitis, or psoriasis.

BACKGROUND In glioblastomas (GBM) patients the first post-radiation MRI is usually difficult to interpret given the post-radiotherapy enhancement and possible pseudo-progression which is present in almost 50% of the patients. METHODS We retrospectively analyzed all patients with GBM treated between 2006 and 2017 at the CHUM (SARDO database). If the first brain MRI done within 3 months after the systemic treatment showed progression of contrast, these patients were considered pseudoprogressors (PsP) while the patients who had stable or response to treatment were the non-progressors (nP). If progression persisted in subsequent MRI with a change of treatment within 6 months, they were considered early progressors (eP). If subsequent MRI improved or was stable, they were classified as nP (or true pseudo-progression). RESULTS In our cohort of 470 patients with GBM, 57.7% were nP and 42.3% were PsP after the first post-treatment imagery. The median follow-up was 10 months. The nP had a longer mOS 15.3m vs 11.3m, p < 0.001, regardless of subsequent evolution. After the second assessment, 67.8% of PsP patients were then considered as eP and 36.4% of nP patients also progressed within 6 months. The nP either after the first or second evaluation had the same mOS (19.9m vs 18.3m), just like the eP (9.3m vs 8.6m), independently of the subsequent treatment. No demographic, molecular or clinical factor predicted PsP, except for tumor size (> 5cm, p=0.024). PsP incidence was similar between 2006–2011 (PsP 57.8%) and 2012–2017 (42.2%). The 1y OS with pseudo progression at the first MRI was 39.7% vs 54.8% with no progression (p=0.001) which has a meaningful impact for the patient. CONCLUSION Pseudo-progression is frequent (42%) in glioblastoma and predicts a poorer prognosis with 1y OS of 39,7%. In fact, PsP patients have more than two-thirds chance to progress precociously.

International audience; A new in silico method is introduced for the dereplication of natural metabolite mixtures based on HMBC and HSQC spectra that inform about short-range and long-range H–C correlations occurring in the carbon skeleton of individual chemical entities. Starting from the HMBC spectrum of a metabolite mixture, an algorithm was developed in order to recover individualized HMBC footprints of the mixture constituents. The collected H–C correlations are represented by a network of NMR peaks connected to each other when sharing either a 1H or 13C chemical shift value. The network obtained is then divided into clusters using a community detection algorithm, and finally each cluster is tentatively assigned to a molecular structure by means of a NMR chemical shift database containing the theoretical HMBC and HSQC correlation data of a range of natural metabolites. The proof of principle of this method is demonstrated on a model mixture of 3 known natural compounds and then on a real-life bark extract obtained from the common spruce (Picea abies L.).

We tested different classification systems in order to separate intermediate-risk prostate cancers into prognostic groups. We then examined which groups were most suited for either prostate seed brachytherapy (PB) or external beam radiotherapy (EBRT).We selected patients with D'Amico intermediate-risk prostate cancer who were treated exclusively with either PB or EBRT. Patients were excluded if they had received androgen deprivation therapy in combination with EBRT or a follow up of30 months without recurrence. The Kaplan-Meier method was used to compare groups.Our sample consisted of 475 patients treated from July 2002-September 2013. Median follow up for patients without biochemical failure (BF) was 56 months (interquartile range 44-78); 222 patients (47%) were treated with PB exclusively (D90 interquartile range 145-176 Gy) and 253 (53%) with EBRT exclusively (dose interquartile range 76-80 Gy). The rate of BF was significantly lower in patients treated with PB (5.4%) than in patients treated with EBRT (14.2%) (p = 0.036, log-rank test). Upon univariate analysis, significant predictors of BF included the number of unfavorable intermediate-risk factors (0, 1, 2, 3) (p = 0.024) as well as the Cancer of the Prostate Risk Assessment (CAPRA) score (p = 0.002). After adjusting for the type of treatment, only the CAPRA score remained predictive (p = 0.025). For patients with a CAPRA score of 0-2, those with PB fared better than those treated with EBRT (p = 0.042). This difference disappeared in patients with a CAPRA score of 3-5 (p = 0.5).Using our current selection criteria for monotherapy, we found that PB or EBRT as monotherapy are equally effective treatment options for intermediate-risk prostate cancer.

Background Previous studies have examined testosterone levels after external beam radiation (EBRT) monotherapy, but since 2002 only sparse contemporary data have been reported. Aim To examine testosterone kinetics in a large series of contemporary patients after EBRT. Methods The study was conducted in 425 patients who underwent definitive EBRT for localized prostate cancer from 2002 through 2014. Patients were enrolled in several phase II and III trials. Exclusion criteria were neoadjuvant or adjuvant androgen-deprivation therapy or missing data. Testosterone was recorded at baseline and then according to each study protocol (not mandatory in all protocols). Statistical analyses consisted of means and proportions, Kaplan-Meier plots, and logistic and Cox regression analyses. Outcomes Testosterone kinetics after EBRT monotherapy and their influence on biochemical recurrence. Results Median follow-up of 248 assessable patients was 72 months. One hundred eighty-six patients (75.0%) showed a decrease in testosterone. Median time to first decrease was 6.4 months. Median percentage of decrease to the nadir was 30% and 112 (45.2%) developed biochemical hypogonadism (serum testosterone < 8 nmol/L). Of all patients with testosterone decrease, 117 (62.9%) recovered to at least 90% of baseline levels. Advanced age, increased body mass index, higher baseline testosterone level, and lower nadir level were associated with a lower chance of testosterone recovery. Subgroup analyses of 166 patients treated with intensity-modulated radiotherapy confirmed the results recorded for the entire cohort. In survival analyses, neither testosterone decrease nor recovery was predictive for biochemical recurrence. Clinical Implications EBRT monotherapy influences testosterone kinetics, and although most patients will recover, approximately 45% will have biochemical hypogonadism. Strengths and Limitations We report on the largest contemporary series of patients treated with EBRT monotherapy in whom testosterone kinetics were ascertained. Limitations are that testosterone follow-up was not uniform and the study lacked information on health-related quality-of-life data. Conclusion Our findings indicate that up to 75% of patients will have a profound testosterone decrease, with up to a 40% increase in rates of biochemical hypogonadism, although the latter events will leave biochemical recurrence unaffected.

BACKGROUND Before 2012, Temozolomide (TMZ) was used for low-grade gliomas (LGG) to avoid Lomustine toxicity. After 2012 RTOG data, Procarbazine, Lomustine and Vincristine (PCV) given sequentially with radiotherapy became standard treatment with the side effects burden associated. METHODS We retrospectively reviewed our SARDO clinical database of patients with low-grade glioma LGG grades 2 and 3 between 2006 and 2017 at CHUM University Health Center. Molecular profile for these tumors is reflex and standard in our institution since 2016. RESULTS A total of 123 patients were identified with grade 2 and grade 3 LGG; 37 (30%) treated with PCV and 86 (70%) received TMZ. Median follow up was 11mo for PCV 11mo vs 22mo TMZ. Both groups were balanced in terms of median age, sex, neurologic symptoms and surgery rate. 53% patients had tumor untested for IDH1-2 and codeletion1p19q because of diagnostic before 2016. Disparities were noted with a predominance of grade 3 in the TMZ group (74% vs 27%, p< 0.01). TMZ was the preferred regimen before 2012 (100% vs 43%) and PCV became the standard of care after 2012 (0% vs 57%). Radiation use as first line treatment was 90%. The 4y OS was not significantly longer for PCV 50% compared with TMZ 47% with mOS between both groups (PCV NR vs TMZ 39.9mo, p=0.158). When controlled for tumor grade, the 2y OS was 80% for PCV vs 64% for TMZ,p=0.542. The 4y PFS was trendly longer for PCV group 78% than TMZ group 45%, p=0.148. CONCLUSION As we are still waiting for the prospective ongoing prospective trials comparing these 2 regimens, PCV and radiation are still standard of care regimens for grade 2 and 3 LGG. This retrospective data is not reassuring for a replacement for PCV with TMZ.

Lambert, C., Khiook, I. L. K., Lucas, S., Telef-Micouleau, N., Merillon, J.-M., and Cluzet, S. 2013. A faster and a stronger defense response: One of the key elements in grapevine explaining its lower level of susceptibility to Esca? Phytopathology 103:1028-1034. Wood diseases like Esca are among the most damaging afflictions in grapevine. The defense mechanisms in this plant–pathogen interaction are not well understood. As some grapevine cultivars have been observed to be less susceptible to Esca than others, understanding the factors involved in this potentially stronger defense response can be of great interest. To lift part of this veil, we elicited Vitis vinifera plants of two cultivars less susceptible to Esca (‘Merlot’ and ‘Carignan’) and of one susceptible cultivar (‘Cabernet Sauvignon’), and monitored their defense responses at the leaf level. Our model of elicitation consisted in grapevine cuttings absorbing a culture filtrate of one causal agent of Esca, Phaemoniella chlamydospora. This model might reflect the early events occurring in Esca-affected grapevines. The two least susceptible cultivars showed an earlier and stronger defense response than the susceptible one, particularly with regard to induction of the PAL and STS genes, and a higher accumulation of stilbene compounds and some pathogenesis-related proteins.

Background:Stereotactic radiosurgery (SRS) is known to safely result in a high obliteration rate for small and medium sized arteriovenous malformations (AVM).Objective:To evaluate the long-term outcome of patients treated with SRS, with special emphasis given to obliteration and toxicity rates.Methods:We performed a review of 43 cerebral AVM patients, treated from 1998 to 2008 with a single SRS dose ranging from 21-25 Gy. Of these, 37 had a minimal follow-up of one year. Medical files were reviewed to assess patient and AVM characteristics, the SRS treatment, therapy prior to SRS, the obliteration rate and toxicities. Whenever necessary, outcome data was supplemented by telephone interviews with the patient or treating physician.Results:AVM size was ≥3cm in diameter in 21% of patients. Five patients (11.6%) underwent surgery prior to SRS and 31 patients (72.1%) received one or more embolizations prior to SRS. Of the patients followed with angiography ≥1 year post-SRS, 89% (33/37) had a complete obliteration of the nidus, after a median time of 24.7 months post-treatment. Embolization prior to SRS was not predictive of outcome. One patient suffered a non-fatal haemorrhage between treatment and obliteration. The rate of symptomatic radiation-induced radiological changes was 8.1%.Conclusion:Our study shows both obliteration and complication rates in the upper limit of those reported in the literature. SRS seems an attractive treatment option for small AVMs. Unlike other reports, the prior use of embolization did not impact negatively on obliteration rates.

To investigate the impact of 5‑alpha-reductase inhibitor (5-ARI) use on radiotherapy outcomes for localized prostate cancer. We included 203 patients on a 5-ARI from our institutional database comprising over 2500 patients who had been treated with either external beam radiotherapy (EBRT) or brachytherapy for localized prostate cancer. Patients received a 5-ARI for urinary symptoms or active surveillance. Cancer progressions at the time of definitive treatment were analyzed according to the following criteria: (a) progression of Gleason score or increase in cancer volume on biopsy, (b) first biopsy positive for cancer after being treated for urinary symptoms with a 5-ARI, and (c) prostate-specific antigen (PSA) progression with or without a previous cancer diagnosis. Biochemical failure (BF) was defined by the Phoenix definition. Log-rank test was used for survival analysis. At a median follow-up of 38.2 months (standard deviation 22.2 months), 10 (4.9%) patients experienced BF. Concerning prostate cancer progression criteria, 52% of men demonstrated none, 37% showed only one criterion, and 11% showed two. Using univariate analysis, PSA progression (p = 0.004) and appearance of a positive biopsy (p < 0.001) were significant predictive factors for BF, while Gleason progression (p = 0.3) was not. In multivariate analysis adjusted for cancer aggressiveness, rising PSA (hazard ratio, HR, 5.7; 95% confidence interval, CI, 1.1–28.8; p = 0.04) and the number of cancer progression factors (HR 2.9, 95% CI 1.2–7.0, p = 0.02) remained adverse risk factors. PSA progression experienced during 5‑ARI treatment before radiotherapy is predictive of worse biochemical outcome. Such details should be considered when counseling men prior to radiation therapy.