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In this study, different assortments of 2-arylquinolines and 2,6-diarylquinolines have been developed. Recently, we have developed a new series of 6,7-dimethoxy-4-alkoxy-2-arylquinolines as Topoisomerase I (TOP1) inhibitors with potent anticancer activity. Utilising the SAR outputs from this study, we tried to enhance anticancer and TOP1 inhibitory activities. Though target quinolines demonstrated potent antiproliferative effect, specifically against colorectal cancer DLD-1 and HCT-116, they showed weak TOP1 inhibition which may be attributable to their non-coplanarity. Thereafter, screening against kinase panel revealed their dual inhibitory activity against EGFR and FAK. Quinolines 6f, 6h, 6i, and 20f were the most potent EGFR inhibitors (IC50s = 25.39, 20.15, 22.36, and 24.81 nM, respectively). Meanwhile, quinolines 6f, 6h, 6i, 16d, and 20f exerted the best FAK inhibition (IC50s = 22.68, 14.25, 18.36, 17.36, and 15.36 nM, respectively). Finally, molecular modelling was employed to justify the promising EGFR/FAK inhibition. The study outcomes afforded the first reported quinolines with potent EGFR/FAK dual inhibition., Graphical Abstract

The evolution of patients hospitalized with coronavirus disease 2019 (COVID-19) is still hard to predict, even after several months of dealing with the pandemic.To develop and validate a score to predict outcomes in patients hospitalized with COVID-19.All consecutive adults hospitalized for COVID-19 from February to April 2020 were included in a nationwide observational study. Primary composite outcome was transfer to an intensive care unit from an emergency department or conventional ward, or in-hospital death. A score that estimates the risk of experiencing the primary outcome was constructed from a derivation cohort using stacked LASSO (Least Absolute Shrinkage and Selection Operator), and was tested in a validation cohort.Among 2873 patients analysed (57.9% men; 66.6±17.0 years), the primary outcome occurred in 838 (29.2%) patients: 551 (19.2%) were transferred to an intensive care unit; and 287 (10.0%) died in-hospital without transfer to an intensive care unit. Using stacked LASSO, we identified 11 variables independently associated with the primary outcome in multivariable analysis in the derivation cohort (n=2313), including demographics (sex), triage vitals (body temperature, dyspnoea, respiratory rate, fraction of inspired oxygen, blood oxygen saturation) and biological variables (pH, platelets, C-reactive protein, aspartate aminotransferase, estimated glomerular filtration rate). The Critical COVID-19 France (CCF) risk score was then developed, and displayed accurate calibration and discrimination in the derivation cohort, with C-statistics of 0.78 (95% confidence interval 0.75-0.80). The CCF risk score performed significantly better (i.e. higher C-statistics) than the usual critical care risk scores.The CCF risk score was built using data collected routinely at hospital admission to predict outcomes in patients with COVID-19. This score holds promise to improve early triage of patients and allocation of healthcare resources.

Here, we report the management of a catastrophic COVID-19 Delta variant surge, which overloaded ICU capacity, using crisis standards of care (CSC) based on a multiapproach protocol.Retrospective observational study.University Hospital of Guadeloupe.This study retrospectively included all patients who were hospitalized for COVID-19 pneumonia between August 11, 2021, and September 10, 2021, and were eligible for ICU admission.Based on age, comorbidities, and disease severity, patients were assigned to three groups: Green (ICU admission as soon as possible), Orange (ICU admission after the admission of all patients in the Green group), and Red (no ICU admission).Among the 328 patients eligible for ICU admission, 100 (30%) were assigned to the Green group, 116 (35%) to the Orange group, and 112 (34%) to the Red group. No patient in the Green group died while waiting for an ICU bed, whereas 14 patients (12%) in the Orange group died while waiting for an ICU bed. The 90-day mortality rates were 24%, 37%, and 78% in the Green, Orange, and Red groups, respectively. A total of 130 patients were transferred to the ICU, including 79 from the Green group, 51 from the Orange group, and none from the Red group. Multivariate analysis revealed that among patients admitted to the ICU, death was independently associated with a longer time between ICU referral and ICU admission, the Sequential Organ Failure Assessment score, and the number of comorbidities, but not with triage group.CSC based on a multiapproach protocol allowed admission of all patients with a good prognosis. Higher mortality was associated with late admission, rather than triage group.

Background: Alzheimer’s disease (AD) is a neurodegenerative pathology that disrupts processing of facial expressions of emotion. The impairment was demonstrated for negative emotions in tasks of matching, discriminating, and labeling facial expressions but no study has included the expression of pain in its protocol. Objective: The objective was to study the processing of emotional facial expressions in AD with a particular interest in pain expression. Methods: Twenty-seven controls, 15 mild AD patients, and 15 moderate AD patients had to perform four emotional tasks: identification of facial expressions, matching pain expressions, discriminating the intensity of pain expressions, and judging pain intensity. Results: Some emotions were less efficiently recognized by AD patients compared to controls (p

Postoperative pancreatic fistula (POPF) is a feared complication in pancreatic resection. Gravity drainage (GD) is hypothesized to reduce POPF versus closed-suction drainage (CSD). We sought to evaluate this theory.Six-hundred-twenty-nine patients undergoing pancreatic resection between 2013 and 2020 were analyzed with multivariable logistic regression for the outcomes of POPF and clinically-relevant POPF (crPOPF).Three-hundred-ninety-seven patients (63.1%) underwent pancreaticoduodenectomy and 232 (36.9%) underwent distal pancreatectomy. Suction drains were placed in 588 patients (93.5%) whereas 41 (6.5%) had GDs. One-hundred-twenty-five (27.6%) experienced a POPF; 49 (10%) crPOPFs. On multivariable analysis, suction drainage was not associated with increased risk of POPF (OR 0.76, 95% CI 0.30-1.93, P = 0.57) or crPOPF (OR 0.99, 95% CI 0.30-3.26, P = 0.98).Suction drainage does not promote POPF when compared to GDs. Drain type should be determined by surgeon preference, while taking into account nursing and patient-specific considerations especially when patients are discharged with drains.

International audience; Purpose: To evaluate the cost-effectiveness of moderate Hypofractionated Radiotherapy (H-RT) compared to Conventional Radiotherapy (C-RT) for intermediate-risk prostate caner (PCa).Methods: A prospective randomized clinical trial including 222 patients from six French cancer centers was conducted as an ancillary study of the international PROstate Fractionated Irradiation Trial (PROFIT). We carried-out a cost-effectiveness analysis (CEA) from the payer's perspective, with a time horizon of 48 months. Patients assigned to the H-RT arm received 6000 cGy in 20 fractions over 4 weeks, or 7800 cGy in 39 fractions over 7 to 8 weeks in the C-RT arm. Patients completed quality of life (QoL) questionnaire: Expanded Prostate Cancer Index Composite (EPIC) at baseline, 24 and 48 months, which were mapped to obtain a EuroQol five-dimensional questionnaire (EQ-5D) equivalent to generate Quality Adjusted Life Years (QALY). We assessed differences in QALYs and costs between the two arms with Generalized Linear Models (GLMs). Costs, estimated in euro (€) 2020, were combined with QALYs to estimate the Incremental Cost-effectiveness ratio (ICER) with non-parametric bootstrap.Results: Total costs per patien were lower in the H-RT arm compared to the C-RT arm €3,062 (95 % CI: 2,368 to 3,754) versus €4,285 (95 % CI: 3,355 to 5,215), (p < 0.05). QALY were marginally higher in the H-RT arm, however this difference was not significant: 0.044 (95 % CI: - 0.016 to 0.099).Conclusions: Treating localized prostate cancer with moderate H-RT could reduce national health insurance spending. Adopting such a treatment with an updated reimbursement tariff would result in improving resource allocation in RT management.

Postoperative pancreatic fistulas (POPFs) remain common; POPFs frequently require intervention, termed clinically-relevant POPFs (crPOPFs). Pasireotide is increasingly used to prevent POPF, however, risk factors for POPF in this population remain unexplored.Patients undergoing pancreatectomy with perioperative pasireotide from 2013 to 2020 were identified from our institutional National Surgical Quality Improvement Project database. Logistic regression was utilized to identify risk factors associated with POPF.One-hundred patients were identified; 26 (26%) underwent distal pancreatectomy with the remainder undergoing pancreaticoduodenectomy. Thirty (30%) experienced POPF, with 21 crPOPFs. Only current smoking was significantly associated with crPOPF (OR 3.79, p = 0.04). Of 30 patients with a firm gland, none experienced crPOPF. Twenty-five received a partial course of pasireotide; 7/25 (28%) crPOPFs occurred versus 14/75 (19%) in patients receiving a full course (p = 0.38).Shortened courses of pasireotide do not increase crPOPF risk; selective discontinuation may be suitable in low-risk patients. Smoking cessation should be encouraged.

Small cell lung cancers (SCLC) are highly aggressive, and currently there are no available targeted therapies. To identify clinically actionable drug combinations, we analyzed our previously reported chemogenomics screens and identified a synergistically cytotoxic combination of the topoisomerase I (TOP1) inhibitor topotecan and cycle-dependent kinase 7 (CDK7) inhibitor THZ1. Topotecan causes cell death by generating TOP1-induced DNA breaks and DNA-protein cross-links (TOP1-DPC) that require proteolysis by the ubiquitin-proteasome pathway for their repair. We find that inhibition of the transcriptional kinase CDK7 by THZ1 induces ubiquitin-mediated proteasomal degradation of RNA polymerase II and prevents the proteasomal degradation of TOP1-DPCs. We provide a mechanistic basis for combinatorial targeting of transcription using selective inhibitors of CDK7 and TOP1 in clinical trials to advance SCLC therapeutics.

Epithelial-to-mesenchymal transition (EMT) is associated with tumor aggressiveness, drug resistance, and poor survival in non-small cell lung cancer (NSCLC) and other cancers. The identification of immune-checkpoint ligands (ICPLs) associated with NSCLCs that display a mesenchymal phenotype (mNSCLC) could help to define subgroups of patients who may benefit from treatment strategies using immunotherapy.We evaluated ICPL expression in silico in 130 NSCLC cell lines. In vitro, CRISPR/Cas9-mediated knockdown and lentiviral expression were used to assess the impact of ZEB1 expression on CD70. Gene expression profiles of lung cancer samples from the TCGA (n = 1018) and a dataset from MD Anderson Cancer Center (n = 275) were analyzed. Independent validation was performed by immunohistochemistry and targeted-RNA sequencing in 154 NSCLC whole sections, including a large cohort of pulmonary sarcomatoid carcinomas (SC, n = 55).We uncover that the expression of CD70, a regulatory ligand from the tumor necrosis factor ligand family, is enriched in mNSCLC in vitro models. Mechanistically, the EMT-inducer ZEB1 impacted CD70 expression and fostered increased activity of the CD70 promoter. CD70 overexpression was also evidenced in mNSCLC patient tumor samples and was particularly enriched in SC, a lung cancer subtype associated with poor prognosis. In these tumors, CD70 expression was associated with decreased CD3Our results provide evidence on the pivotal roles of CD70 and ZEB1 in immune escape in mNSCLC, suggesting that EMT might promote cancer progression and metastasis by not only increasing cancer cell plasticity but also reprogramming the immune response in the local tumor microenvironment.

International audience; Background: COVID-19 triggered an unprecedented crisis affecting society at every level. Research in pediatric and congenital cardiology is currently in full development and may have been disrupted. The aim of the study was to determine the impact of COVID-19 on pediatric and congenital cardiology clinical research and to analyze decision-making and adaptation processes, from a panel of ongoing academic and industry-sponsored research at the time of the pandemic.Methods: This observational study was carried out in April 2020, from a CHD clinical research network involving five tertiary care pediatric and congenital cardiology centers. Investigators and clinical research assistants from each participating research center completed an online survey questionnaire, and each principal investigator underwent a 1-h web-based videoconference interview.Results: A total of 34 study questionnaires were collected, reporting that 18 studies were totally suspended. Upon the investigator's decision, after discussion on ethical issues and with facilitating support from health authorities, 16 studies were resumed. The rate of study suspension in interventional research (53%) was similar to that in non-interventional research (56%). Logistical problems were predominantly reported in both continued and suspended trials. Research protocols were adapted, largely thanks to telemedicine, which in some cases even improved the course of the study.Conclusion: The impact of the COVID-19 pandemic on clinical research in pediatric and congenital cardiology has been limited by a rapid adaptation of all research structures and an extensive use of telemedicine at all stages of the studies.

Indications of adjuvant radiotherapy (RT) for high-risk cutaneous squamous cell carcinoma (cSCC) are not clearly defined. We aimed to identify factors predicting relapse in cSCC patients treated with surgery or RT alone and to assess in which clinical setting adjuvant RT was beneficial in term of progression free survival (PFS).This retrospective analysis included patients with resectable primary cSCC treated with surgery and/or RT in curative intent, managed at Centre Léon Bérard (Lyon, France) from April 2010 to September 2020.A total of 303 patients with 529 cSCC were included. 31 (5.9%) cSCC were treated with surgery and adjuvant RT. With a median follow-up of 54 (0.2-126) months, 103 (19.5%) cSCC relapsed. In multivariate analysis, the highest predictive factor of relapse in cSCC was the number of risk factors (HR = 15.110 [95% CI: 3.91-58.40] for ≥3 risk factors p 0.001), followed by poor differentiation (HR = 4.930 [95% CI: 2.47-9.86], p 0.001) and perineural invasion (HR = 2.442 [95% CI: 1.11-5.38], p = 0.027). For cSCC with ≥3 risk factors, PFS was significantly higher in cSCC treated with surgery and adjuvant RT compared to those treated with surgery or RT alone (the 36-month PFS was 74% [95% CI: 43-90%] and 31% [95% CI: 10-54%] respectively, p = 0.008).An increased number of risk factors was identified as being the highest predictive factor of relapse in cSCC. Adjuvant RT improved PFS for high-risk cSCC with ≥3 risk factors.

Human topoisomerases comprise a family of six enzymes: two type IB (TOP1 and mitochondrial TOP1 (TOP1MT), two type IIA (TOP2A and TOP2B) and two type IA (TOP3A and TOP3B) topoisomerases. In this Review, we discuss their biochemistry and their roles in transcription, DNA replication and chromatin remodelling, and highlight the recent progress made in understanding TOP3A and TOP3B. Because of recent advances in elucidating the high-order organization of the genome through chromatin loops and topologically associating domains (TADs), we integrate the functions of topoisomerases with genome organization. We also discuss the physiological and pathological formation of irreversible topoisomerase cleavage complexes (TOPccs) as they generate topoisomerase DNA-protein crosslinks (TOP-DPCs) coupled with DNA breaks. We discuss the expanding number of redundant pathways that repair TOP-DPCs, and the defects in those pathways, which are increasingly recognized as source of genomic damage leading to neurological diseases and cancer.

Prostate brachytherapy techniques are described, concerning both permanent seed implant and high dose rate brachytherapy. The following guidelines are presented: brachytherapy indications, implant procedure for permanent low dose rate implants and high dose rate with source projector, as well as dose and dose-constraints objectives, immediate postoperative management, post-treatment evaluation, and long-term follow-up.

We present the update of the recommendations of the French society of oncological radiotherapy on external radiotherapy of prostate cancer. External radiotherapy is intended for all localized prostate cancers, and more recently for oligometastatic prostate cancers. The irradiation techniques are detailed. Intensity-modulated radiotherapy combined with prostate image-guided radiotherapy is the recommended technique. A total dose of 74 to 80Gy is recommended in case of standard fractionation (2Gy per fraction). Moderate hypofractionation (total dose of 60Gy at a rate of 3Gy per fraction over 4 weeks) in the prostate has become a standard of therapy. Simultaneous integrated boost techniques can be used to treat lymph node areas. Extreme hypofractionation (35 to 40Gy in five fractions) using stereotactic body radiotherapy can be considered a therapeutic option to treat exclusively the prostate. The postoperative irradiation technique, indicated mainly in case of biological recurrence and lymph node involvement, is detailed.

Penile cancers are uncommon and should be treated in expert center. Radiotherapy indications are mainly limited to exclusive brachytherapy for early stage penile glans cancer. Brachytherapy yields to excellent outcome for disease control and organ and function preservation. Only scarce data are available for external beam radiation therapy. It could be considered as palliative setting for irradiation of the primary tumor. For lymph node irradiation, external beam radiation therapy (with or without chemotherapy) could be discussed either as neoadjuvant approach prior to surgery for massive inguinal lymph node invasion or as adjuvant approach in case of high-risk of relapse. However, these cases should be discussed on an individual basis, as the level of evidence is poor. We present the recommendations of the French Society of Oncological Radiotherapy on the indications and techniques for external beam radiotherapy and brachytherapy for penile glans cancer.

Background The 8th edition AJCC Staging for small bowel neuroendocrine tumors created a novel N2 classification. This study investigates if it is independently prognostic. Methods Records of patients from 2008 to 2019 were reviewed. Survival rates were estimated by Kaplan-Meier method and compared by log-rank. The Cox Proportional Hazards model was used to determine factors associated with overall survival (OS) via multivariate analysis. Results Among 300 patients, 225 were N2 and 60 were N1. No differences were seen in pathologic markers for N1 compared to N2. N2 were more likely to have liver metastases (LM) (p = 0.048) but rates of resectability were similar. Median OS for N1 with >70% liver cytoreduction was not yet reached compared to 121 months for N2 (p = 0.005). On multivariate analysis, LM was associated with shorter survival (p = 0.028), but nodal status was not. Conclusions Unlike LM, N2 status is not independently prognostic, but a marker for aggressive LM.

Background Oligorecurrent pelvic nodal relapse in prostatic cancer is a challenge for regional salvage treatments. Androgen depriving therapies (ADTs) are a mainstay in metastatic prostate cancer, and salvage pelvic radiotherapy may offer long ADT-free intervals for patients harboring regional nodal relapses. Objective To assess the efficacy of the combination of ADT and salvage radiotherapy in men with oligorecurrent pelvic node relapses of prostate cancer. Design, setting, and participants We performed an open-label, phase II trial of combined high-dose intensity-modulated radiotherapy and ADT (6 mo) in oligorecurrent (five or fewer) pelvic node relapses in prostate cancer, detected by fluorocholine positron-emission tomography computed tomography imaging. Outcome measurements and statistical analysis The primary endpoint was 2-yr progression-free survival defined as two consecutive prostate-specific antigen levels above the level at inclusion and/or clinical evidence of progression as per RECIST 1.1 and/or death from any cause. Results and limitations Between August 2014 and July 2016, 67 patients were recruited in 15 centers. Half of the patients had received prior prostatic irradiation. The median age was 67.7 yr. After a median follow-up of 49.4 mo, 2- and 3-yr progression-free survival rates were 81% and 58%, respectively. Median progression-free survival was 45.3 mo. The median biochemical relapse–free survival (BRFS) was 25.9 mo. At 2 and 3 yr, the BRFS rates were 58% and 46%, respectively. Grade 2 + 2-yr genitourinary and gastrointestinal toxicities were 10% and 2%, respectively. Conclusions Combined high-dose salvage pelvic radiotherapy and ADT appeared to prolong tumor control in oligorecurrent pelvic node relapses in prostate cancer with limited toxicity. After 3 yr, nearly half of patients were in complete remission. Our study showed initial evidence of benefit, but a randomized trial is required to confirm this result. Patient summary In this report, we looked at the outcomes of combined high-dose salvage pelvic radiotherapy and 6-mo-long hormone therapy in oligorecurrent pelvic nodal relapse in prostatic cancer. We found that 46% of patients presenting with oligorecurrent pelvic node relapses in prostate cancer were in complete remission after 3 yr following combined treatment at the cost of limited toxicity.

Background Encephalitis is a worldwide public health issue, with a substantially high burden among children in southeast Asia. We aimed to determine the causes of encephalitis in children admitted to hospitals across the Greater Mekong region by implementing a comprehensive state-of-the-art diagnostic procedure harmonised across all centres, and identifying clinical characteristics related to patients’ conditions. Methods In this multicentre, observational, prospective study of childhood encephalitis, four referral hospitals in Cambodia, Vietnam, Laos, and Myanmar recruited children (aged 28 days to 16 years) who presented with altered mental status lasting more than 24 h and two of the following minor criteria: fever (within the 72 h before or after presentation), one or more generalised or partial seizures (excluding febrile seizures), a new-onset focal neurological deficit, cerebrospinal fluid (CSF) white blood cell count of 5 per mL or higher, or brain imaging (CT or MRI) suggestive of lesions of encephalitis. Comprehensive diagnostic procedures were harmonised across all centres, with first-line testing was done on samples taken at inclusion and results delivered within 24 h of inclusion for main treatable causes of disease and second-line testing was done thereafter for mostly non-treatable causes. An independent expert medical panel reviewed the charts and attribution of causes of all the included children. Using multivariate analyses, we assessed risk factors associated with unfavourable outcomes (ie, severe neurological sequelae and death) at discharge using data from baseline and day 2 after inclusion. This study is registered with ClinicalTrials.gov, NCT04089436, and is now complete. Findings Between July 28, 2014, and Dec 31, 2017, 664 children with encephalitis were enrolled. Median age was 4·3 years (1·8–8·8), 295 (44%) children were female, and 369 (56%) were male. A confirmed or probable cause of encephalitis was identified in 425 (64%) patients: 216 (33%) of 664 cases were due to Japanese encephalitis virus, 27 (4%) were due to dengue virus, 26 (4%) were due to influenza virus, 24 (4%) were due to herpes simplex virus 1, 18 (3%) were due to Mycobacterium tuberculosis, 17 (3%) were due to Streptococcus pneumoniae, 17 (3%) were due to enterovirus A71, 74 (9%) were due to other pathogens, and six (1%) were due to autoimmune encephalitis. Diagnosis was made within 24 h of admission to hospital for 83 (13%) of 664 children. 119 (18%) children had treatable conditions and 276 (42%) had conditions that could have been preventable by vaccination. At time of discharge, 153 (23%) of 664 children had severe neurological sequelae and 83 (13%) had died. In multivariate analyses, risk factors for unfavourable outcome were diagnosis of M tuberculosis infection upon admission (odds ratio 3·23 [95% CI 1·04–10·03]), coma on day 2 (2·90 [1·78–4·72]), supplementary oxygen requirement (1·89 [1·25–2·86]), and more than 1 week duration between symptom onset and admission to hospital (3·03 [1·68–5·48]). At 1 year after inclusion, of 432 children who were discharged alive from hospital with follow-up data, 24 (5%) had died, 129 (30%) had neurological sequelae, and 279 (65%) had completely recovered. Interpretation In southeast Asia, most causes of childhood encephalitis are either preventable or treatable, with Japanese encephalitis virus being the most common cause. We provide crucial information that could guide public health policy to improve diagnostic, vaccination, and early therapeutic guidelines on childhood encephalitis in the Greater Mekong region. Funding Institut Pasteur, Institut Pasteur International Network, Fondation Merieux, Aviesan Sud, INSERM, Wellcome Trust, Institut de Recherche pour le Développement (IRD), and Fondation Total. Translations For the Khmer, Lao, Vietnamese and Burmese translation of the abstract see Supplementary Materials section.

Adrenocortical carcinoma (ACC) is a rare endocrine malignancy of the adrenal gland with an unfavorable prognosis. It is rare in the pediatric population, with an incidence of 0.2-0.3 patients per million in patients under 20 years old. It is primarily associated with Li-Fraumeni and Beckwith-Wiedemann tumor predisposition syndromes in children. The incidence of pediatric ACC is 10-15fold higher in southern Brazil due to a higher prevalence of TP53 mutation associated with Li-Fraumeni syndrome in that population. Current treatment protocols are derived from adult ACC and consist of surgery and/or chemotherapy with etoposide, doxorubicin, and cisplatin (EDP) with mitotane. Limited research has been reported on other treatment modalities for pediatric ACC, including mitotane, pembrolizumab, cabozantinib, and chimeric antigen receptor autologous cell (CAR-T) therapy.

Introduction Neuroendocrine tumors (NETs) metastatic to the ovary are traditionally considered rare, but data are lacking. This study seeks to better characterize the prevalence and outcomes of patients with neuroendocrine ovarian metastases (NOM). Methods Women with well-differentiated lung and gastroenteropancreatic NETs 2007–2017 were identified by medical record query. Clinicopathologic data were reviewed among patients with and without NOM. Results Of 242 patients, 27 (11.2%) developed NOM. NOM developed in 24.8% of SBNET patients and 65.7% of patients with carcinomatosis and intact ovaries. 33.3% had associated small bowel obstructions; 11.1% had ureteral obstruction. NOM were not apparent on imaging in 29.6% nor visible intraoperatively in 8.3%. Five-year survival rate was 61.5%. Those who underwent oophorectomy had a lower rate of subsequent ureteral obstruction (p Conclusions NOM are more prevalent than previously reported and associated with significant morbidity. Empiric oophorectomy may be considered for SBNET patients and strongly advised in carcinomatosis.

Background There is a paucity of randomized data regarding the safety and efficacy of the use of intracardiac echocardiography (ICE) from the left atrium (LA) to guide left atrial appendage occlusion (LAAO) procedures under local anesthesia using either of the available devices. Hypothesis The aim of this study was to compare the efficacy and safety of ICE from the LA with transesophageal echocardiography (TEE) for guidance during transcatheter LAAO procedures. Methods Single‐center, cohort study of patients undergoing LAAO with the Amplatzer Cardiac Plug or Watchman device. Procedures were guided by ICE from the LA with local anesthesia (n = 175) or TEE under general anesthesia (n = 49). Efficacy outcomes were procedural success and peri‐device leaks 6 weeks after LAAO. The safety outcome was a composite of procedure‐related complications. Results Procedural success was similar between groups: 100% in the TEE‐guided group, and 98% in the ICE‐guided group. Procedure‐related complications such as death, embolism, migration, or major vascular complications occurred similarly between groups (p = 0.590). The rate and degree of peri‐device leaks or presence of a thrombus on the device did not differ between groups on follow‐up CT. Turnover time in the catheter laboratory and use of contrast agent were reduced with ICE. Conclusions ICE in the left atrium to guide LAAO procedures appears to be as effective and safe as TEE. There was no increase in procedure‐related complications, whatever the device used. ICE resulted in similar procedural success while decreasing procedure time and requiring only local anesthesia.

Summary Purpose Lacking a standard technique, the surgical management of aphakia without capsular support remains to be optimized. The goal of this study is to analyze results for the Carlevale FIL-SSF intraocular lens and propose surgical recommendations. Patients and methods The P1.5 Collective performed a retrospective analysis, with a minimum follow-up of 6 months, of the records of 72 implantations of the Carlevale FIL-SSF intraocular lens, specifically designed for sutureless scleral fixation in the ciliary sulcus. Results The most common indication was exchange of a posterior chamber intraocular lens (70.8%). The surgery lasted a mean of 53.4 minutes due to the creation of scleral flaps. The implant was damaged in 12.5% of cases. Visual acuity was improved in 83.3% of cases. The postoperative spherical equivalent was −0.3 diopters, with no change in corneal astigmatism. The implant was centered and stable in all cases. Two cases (2.8%) of cystoid macular edema were observed and resolved over six months. Discussion A number of advantages of the Carlevale FIL-SSF intraocular lens make it a safe and effective solution for correction of aphakia in the absence of capsular support. It requires a longer than usual surgical procedure, and the implant must be handled with care. From their experience, the authors propose 7 recommendations to accelerate the learning curve. Conclusion In light of the results of this study, we propose the Carlevale FIL-SSF intraocular lens as the new standard for the correction of aphakia without capsular support, but other studies are necessary to determine its exact place within the heirarchy of other available techniques.

Lung cancer in never smokers (LCINS) is a common cause of cancer mortality but its genomic landscape is poorly characterized. Here high-coverage whole-genome sequencing of 232 LCINS showed 3 subtypes defined by copy number aberrations. The dominant subtype (piano), which is rare in lung cancer in smokers, features somatic UBA1 mutations, germline AR variants and stem cell-like properties, including low mutational burden, high intratumor heterogeneity, long telomeres, frequent KRAS mutations and slow growth, as suggested by the occurrence of cancer drivers' progenitor cells many years before tumor diagnosis. The other subtypes are characterized by specific amplifications and EGFR mutations (mezzo-forte) and whole-genome doubling (forte). No strong tobacco smoking signatures were detected, even in cases with exposure to secondhand tobacco smoke. Genes within the receptor tyrosine kinase-Ras pathway had distinct impacts on survival; five genomic alterations independently doubled mortality. These findings create avenues for personalized treatment in LCINS.

International audience; Parenting is a central life experience that could promote recovery in people with Serious Mental Illness (SMI). It could also be challenging for parents with SMI and result in poor recovery-related outcomes. Parenting is often overlooked in psychiatric rehabilitation. The objectives of the present study were to identify the characteristics and needs for care of mothers and fathers with SMI enrolled in a multicentric non-selected psychiatric rehabilitation SMI sample. We consecutively recruited 1436 outpatients from the French National Centers of Reference for Psychiatric Rehabilitation cohort (REHABase). The evaluation included standardized scales for clinical severity, psychosocial function, quality of life and satisfaction with life, wellbeing, personal recovery and a broad cognitive battery. We found that parenting was associated to suicidal history in mothers and fathers with SMI. In the multivariate analysis, being mother was best explained by insight (p

Repairing bone defects generated by craniectomy is a major therapeutic challenge in terms of bone consolidation as well as functional and cognitive recovery. Furthermore, these surgical procedures are often grafted with complications such as infections, breaches, displacements and rejections leading to failure and thus explantation of the prosthesis.To evaluate cumulative explantation and infection rates following the implantation of a tailored cranioplasty CUSTOMBONE prosthesis made of porous hydroxyapatite. One hundred and ten consecutive patients requiring cranial reconstruction for a bone defect were prospectively included in a multicenter study constituted of 21 centres between December 2012 and July 2014. Follow-up lasted 2 years.Mean age of patients included in the study was 42±15 years old (y.o), composed mainly by men (57.27%). Explantations of the CUSTOMBONE prosthesis were performed in 13/110 (11.8%) patients, significantly due to infections: 9/13 (69.2%) (p0.0001), with 2 (15.4%) implant fracture, 1 (7.7%) skin defect and 1 (7.7%) following the mobilization of the implant. Cumulative explantation rates were successively 4.6% (SD 2.0), 7.4% (SD 2.5), 9.4% (SD 2.8) and 11.8% (SD 2.9%) at 2, 6, 12 and 24 months. Infections were identified in 16/110 (14.5%): 8/16 (50%) superficial and 8/16 (50%) deep. None of the following elements, whether demographic characteristics, indications, size, location of the implant, redo surgery, co-morbidities or medical history, were statistically identified as risk factors for prosthesis explantation or infection.Our study provides relevant clinical evidence on the performance and safety of CUSTOMBONE prosthesis in cranial procedures. Complications that are difficulty incompressible mainly occur during the first 6 months, but can appear at a later stage (1 year). Thus assiduous, regular and long-term surveillances are necessary.

Objective To compare the impact of two radiation modalities on loco-regional control, survival and tumour emergence, after node dissection for an unilateral head and neck carcinoma of unknown primary (HNCUP). Materials and methods This is a multicentric retrospective study of 138 patients with unilateral HNCUP treated between 2002 and 2017. The absence of primary tumour was assessed by a systematic panendoscopy and positron emission tomography. Neck dissection was initially performed for all patients. Radiation Therapy was delivered on ipsilateral lymph node areas in 62 cases (44%: UL-RT group) and on bilateral lymph node areas and the entire pharyngeal mucosa in 77 cases (56%: COMP-RT group). Impact of radiation modalities on locoregional control and overall survival was assessed using propensity score matching method in order to balance baseline characteristics between the two groups. Results The population included 80.4% men, 80.4% smokers, 32.6% P16 positive tumours and 71.0% extracapsular extension. After a median follow-up of 5 years, the locoregional control rate was 80.3% in the UL-RT group and 75.3% in the COMP-RT group (p = 0.688). The corresponding rate of contralateral lymph node recurrence was 0% versus 2.6% (p = 0.503) and the rate of tumour emergence was 11.5% versus 9.1% (p = 0.778). No significant difference was observed between the UL-RT and the COMP-RT groups for overall survival (p = 0.9516), specific survival (p = 0.4837) or tumour emergence (p = 0.9034). Conclusion UL-RT seems to provide similar outcomes as COMP-RT in unilateral HNCUP post-operative management.

PURPOSE To assess the relevance of virtual reality distraction (VR) during uterovaginal brachytherapy applicators’ removal, as an alternative to nitrous oxide (N2O) conscious sedation, to decrease anxiety and pain perception. METHODS AND MATERIALS We prospectively evaluated 35 patients treated with cervical brachytherapy for locally or locally advanced cervical cancer. Brachytherapy applicators were removed in the patient's room at the end of the treatment. Patients were assigned to N2O conscious sedation (reference group) or VR (experimental group). Anxiety and pain were evaluated with the STAI-E score and with Visual Analogical Scales (VAS). RESULTS Fourteen patients were treated with VR and 21 with N2O. STAI-E baselines scores were 35 in the VR group and 38 in the reference group and declined to 30 and 28, respectively after procedure. The mean VAS-anxiety was 2.9 before and 2.7 at the peak in the VR group versus 4.1 and 1.6, respectively in the reference group. The mean VAS-pain was 1.0 before, 3.1 at the peak and 0.4 after the procedure in the experimental group, versus 1.8, 2.0, and 0.6 respectively in the N2O group. Four patients in the VR group experienced mild nausea/vomiting or dizziness during the procedure. The preparation duration was higher in the VR group, with a similar duration for the removal itself. CONCLUSIONS Replacing a medical gas by a virtual reality device was feasible and led to acceptable levels of pain and anxiety. Prospective randomized trials are needed to confirm efficacy and to determine which patients could benefit the most from this approach.

We investigated the efficacy and safety of afatinib maintenance therapy in patients with head and neck squamous cell carcinoma (HNSCC) with macroscopically complete resection and adjuvant radiochemotherapy (RCT).This French multicentric randomised phase III double-blind placebo-controlled study included adult patients with ECOG-PS≤2, normal haematological, hepatic and renal functions, and non-metastatic, histologically confirmed HNSCC of the oral cavity, oropharynx, larynx or hypopharynx, with macroscopically complete resection and adjuvant RCT (≥2 cycles of cisplatin 100 mg/m2 J1, J22, J43 and 66Gy (2Gy/fraction, 5 fractions/week, conventional or intensity modulated radiotherapy ≥60Gy). Randomised patients were planned to receive either afatinib (afa arm) or placebo (control arm (C)) as maintenance therapy for one year. Primary endpoint was disease free survival (DFS). A 15% improvement in DFS was expected at 2 years with afatinib (from 55 to 70%).Among the 167 patients with resected HNSCC included in 19 cancer centres and hospitals from Dec 2011, 134 patients were randomised to receive one-year maintenance afatinib or placebo (afa:67; C:67). Benefit/risk ratio was below assumptions and independent advisory committee recommended to stop the study in Feb 2017, the sponsor decided premature study discontinuation, with a 2-year follow-up for the last randomised patient. 2y-DFS was 61% (95% CI 0.48-0.72) in the afatinib group and 64% (95% CI 0.51-0.74) in the placebo group (HR 1.12, 95% CI 0.70-1.80).Maintenance therapy with afatinib compared with placebo following post-operative RCT in patients with HNSCC did not significantly improve 2y-DFS and should not be recommended in this setting outside clinical trials.gov identifier NCT01427478.

Exatecan and deruxtecan are antineoplastic camptothecin derivatives in development as tumor-targeted-delivery warheads in various formulations including peptides, liposomes, polyethylene glycol nanoparticles, and antibody–drug conjugates. Here, we report the molecular pharmacology of exatecan compared with the clinically approved topoisomerase I (TOP1) inhibitors and preclinical models for validating biomarkers and the combination of exatecan with ataxia telangiectasia and Rad3-related kinase (ATR) inhibitors. Modeling exatecan binding at the interface of a TOP1 cleavage complex suggests two novel molecular interactions with the flanking DNA base and the TOP1 residue N352, in addition to the three known interactions of camptothecins with the TOP1 residues R364, D533, and N722. Accordingly, exatecan showed much stronger TOP1 trapping, higher DNA damage, and apoptotic cell death than the classical TOP1 inhibitors used clinically. We demonstrate the value of SLFN11 expression and homologous recombination (HR) deficiency (HRD) as predictive biomarkers of response to exatecan. We also show that exatecan kills cancer cells synergistically with the clinical ATR inhibitor ceralasertib (AZD6738). To establish the translational potential of this combination, we tested CBX-12, a clinically developed pH-sensitive peptide–exatecan conjugate that selectively targets cancer cells and is currently in clinical trials. The combination of CBX-12 with ceralasertib significantly suppressed tumor growth in mouse xenografts. Collectively, our results demonstrate the potency of exatecan as a TOP1 inhibitor and its clinical potential in combination with ATR inhibitors, using SLFN11 and HRD as predictive biomarkers.

Although several ATR inhibitors are in development, there are unresolved questions regarding their differential potency, molecular signatures of patients with cancer for predicting activity, and most effective therapeutic combinations. Here, we elucidate how to improve ATR-based chemotherapy with the newly developed ATR inhibitor, M4344 using in vitro and in vivo models. The potency of M4344 was compared with the clinically developed ATR inhibitors BAY1895344, berzosertib, and ceralasertib. The anticancer activity of M4344 was investigated as monotherapy and combination with clinical DNA damaging agents in multiple cancer cell lines, patient-derived tumor organoids, and mouse xenograft models. We also elucidated the anticancer mechanisms and potential biomarkers for M4344. We demonstrate that M4344 is highly potent among the clinically developed ATR inhibitors. Replication stress (RepStress) and neuroendocrine (NE) gene expression signatures are significantly associated with a response to M4344 treatment. M4344 kills cancer cells by inducing cellular catastrophe and DNA damage. M4344 is highly synergistic with a broad range of DNA-targeting anticancer agents. It significantly synergizes with topotecan and irinotecan in patient-derived tumor organoids and xenograft models. Taken together, M4344 is a promising and highly potent ATR inhibitor. It enhances the activity of clinical DNA damaging agents commonly used in cancer treatment including topoisomerase inhibitors, gemcitabine, cisplatin, and talazoparib. RepStress and NE gene expression signatures can be exploited as predictive markers for M4344.

Background: The coronavirus disease 2019 (COVID-19) pandemic has led to a public health crisis. Only limited data are available on the characteristics and outcomes of patients hospitalized for COVID-19 in France. Aims: To investigate the characteristics, cardiovascular complications and outcomes of patients hospitalized for COVID-19 in France. Methods: The Critical COVID-19 France (CCF) study is a French nationwide study including all consecutive adults with a diagnosis of severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2) infection hospitalized in 24 centres between 26 February and 20 April 2020. Patients admitted directly to intensive care were excluded. Clinical, biological and imaging parameters were systematically collected at hospital admission. The primary outcome was in-hospital death. Results: Of 2878 patients included (mean ± SD age 66.6 ± 17.0 years, 57.8% men), 360 (12.5%) died in the hospital setting, of which 7 (20.7%) were transferred to intensive care before death. The majority of patients had at least one (72.6%) or two (41.6%) cardiovascular risk factors, mostly hypertension (50.8%), obesity (30.3%), dyslipidaemia (28.0%) and diabetes (23.7%). In multivariable analysis, older age (hazard ratio [HR] 1.05, 95% confidence interval [CI] 1.03−1.06; P < 0.001), male sex (HR 1.69, 95% CI 1.11−2.57; P = 0.01), diabetes (HR 1.72, 95% CI 1.12−2.63; P = 0.01), chronic kidney failure (HR 1.57, 95% CI 1.02−2.41; P = 0.04), elevated troponin (HR 1.66, 95% CI 1.11−2.49; P = 0.01), elevated B-type natriuretic peptide or N-terminal pro-B-type natriuretic peptide (HR 1.69, 95% CI 1.0004−2.86; P = 0.049) and quick Sequential Organ Failure Assessment score ≥ 2 (HR 1.71, 95% CI 1.12−2.60; P = 0.01) were independently associated with in-hospital death. Conclusions: In this large nationwide cohort of patients hospitalized for COVID-19 in France, cardiovascular comorbidities and risk factors were associated with a substantial morbi-mortality burden.

Carcinoid heart disease (CHD) is a sequela of carcinoid liver metastases (LM). The true prevalence of CHD is unknown due to infrequent screening by transthoracic echocardiography (TTE). Octreotide is believed to protect against new and recurrent CHD, but supporting data are scant. This study determined CHD prevalence and outcomes in patients screened by TTE and treated with octreotide.Records of carcinoid patients from 2001 to 2021 were reviewed. Survival was estimated by Kaplan-Meyer curves and compared by log-rank.Among 282 patients screened by TTE, overall survival was lower in CHD (n = 40) versus non-CHD (n = 242) patients (p 0.001). Despite octreotide therapy, 21 patients developed CHD. Among patients with inoperable LM, survival was lower in CHD patients without valve replacement (VR) (p 0.001), but similar between CHD patients with VR and non-CHD patients. CHD patients with VR and hepatic cytoreduction had survival similar to CHD patients without VR.VR improves survival in CHD patients with inoperable LM. Hepatic cytoreduction after VR should be reserved for carefully selected cases. Our data do not support a protective effect of octreotide.

Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are the most common form of neuroendocrine neoplasia, but there is no current consensus for the sequencing of approved therapies, particularly with respect to peptide receptor radionuclide therapy (PRRT). This comprehensive review evaluates the data supporting approved therapies for GEP-NETs and recommendations for therapeutic sequencing with a focus on how PRRT currently fits within sequencing algorithms. The current recommendations for PRRT sequencing restrict its use to metastatic, inoperable, progressive midgut NETs; however, this may change with emerging data to suggest that PRRT might be beneficial as neoadjuvant therapy for inoperable tumors, is more tolerable than other treatment modalities following first-line standard dose somatostatin analogs, and can be used as salvage therapy after disease relapse following prior successful cycles of PRRT. PRRT has also been shown to reduce tumor burden, improve quality of life, and prolong the time to disease progression in a broad spectrum of patients with GEP-NETs. As the various potential benefits of PRRT in GEP-NET therapy continues to expand, it is necessary to review and critically evaluate our treatment algorithms for GEP-NETs.

Introduction Contaminated drinking and recreational waters account for most of the reported Cryptosporidium spp. exposures in high-income countries. In June 2017, two successive cryptosporidiosis outbreaks occurred among service members in a military training camp located in Southwest France. Several other gastroenteritis outbreaks were previously reported in this camp, all among trainees in the days following their arrival, without any causative pathogen identification. Epidemiological, microbiological and environmental investigations were carried out to explain theses outbreaks. Material and methods Syndromic diagnosis using multiplex PCR was used for stool testing. Water samples (100 L) were collected at 10 points of the drinking water installations and enumeration of Cryptosporidium oocysts performed. The identification of Cryptosporidium species was performed using real-time 18S SSU rRNA PCR and confirmed by GP60 sequencing. Results A total of 100 human cases were reported with a global attack rate of 27.8%. Cryptosporidium spp. was identified in 93% of stool samples with syndromic multiplex PCR. The entire drinking water network was contaminated with Cryptosporidium spp. The highest level of contamination was found in groundwater and in the water leaving the treatment plant, with >1,000 oocysts per 100 L. The same Cryptosporidium hominis isolate subtype IbA10G2 was identified in patients’ stool and water samples. Several polluting activities were identified within the protection perimeters of the water resource. An additional ultrafiltration module was installed at the outlet of the water treatment plant. After several weeks, no Cryptosporidium oocysts were found in the public water supply. Conclusions After successive and unexplained gastroenteritis outbreaks, this investigation confirmed a waterborne outbreak due to Cryptosporidium hominis subtype IbA10G2. Our study demonstrates the value of syndromic diagnosis for gastroenteritis outbreak investigation. Our results also highlight the importance of better assessing the microbiological risk associated with raw water and the need for sensitive and easy-to-implement tools for parasite detection.

Nature has been always a great source of possible lead compounds to develop new drugs against several diseases. Here we report the identification of a natural compound, membranoid G, derived from the Antarctic sponge

Background Some cancers such as sarcomas (bone and soft tissue sarcomas) and adenoid cystic carcinomas are considered as radioresistant to low linear energy transfer radiation (including photons and protons) and may therefore beneficiate from a carbon ion therapy. Despite encouraging results obtained in phase I/II trials compared to historical data with photons, the spread of carbon ions has been limited mainly because of the absence of randomized medical data. The French health authorities stressed the importance of having randomized data for carbon ion therapy. Methods The ETOILE study is a multicenter prospective randomized phase III trial comparing carbon ion therapy to either advanced photon or proton radiotherapy for inoperable or macroscopically incompletely resected (R2) radioresistant cancers including sarcomas and adenoid cystic carcinomas. In the experimental arm, carbon ion therapy will be performed at the National Center for Oncological Hadrontherapy (CNAO) in Pavia, Italy. In the control arm, photon or proton radiotherapy will be carried out in referent centers in France. The primary endpoint is progression-free survival (PFS). Secondary endpoints are overall survival and local control, toxicity profile, and quality of life. In addition, a prospective health-economic study and a radiobiological analysis will be conducted. To demonstrate an absolute improvement in the 5-year PFS rate of 20% in favor of carbon ion therapy, 250 patients have to be included in the study. Discussion So far, no clinical study of phase III has demonstrated the superiority of carbon ion therapy compared to conventional radiotherapy, including proton therapy, for the treatment of radioresistant tumors. Trial registration ClinicalTrials.gov identifier: NCT02838602. Date of registration: July 20, 2016. The posted information will be updated as needed to reflect protocol amendments and study progress.

International audience; Rationale: Whether COVID patients may benefit from extracorporeal membrane oxygenation (ECMO) compared with conventional invasive mechanical ventilation (IMV) remains unknown.Objectives: To estimate the effect of ECMO on 90-Day mortality vs IMV only Methods: Among 4,244 critically ill adult patients with COVID-19 included in a multicenter cohort study, we emulated a target trial comparing the treatment strategies of initiating ECMO vs. no ECMO within 7 days of IMV in patients with severe acute respiratory distress syndrome (PaO2/FiO2

In metazoans, topoisomerase 3β (TOP3B) regulates R-loop dynamics and mRNA translation, which are critical for genome stability, neurodevelopment and normal aging. As a Type IA topoisomerase, TOP3B acts by general acid-base catalysis to break and rejoin single-stranded DNA. Passage of a second DNA strand through the transient break permits dissipation of hypernegative DNA supercoiling and catenation/knotting. Additionally, hsTOP3B was recently demonstrated as the human RNA topoisomerase, required for normal neurodevelopment and proposed to be a potential anti-viral target upon RNA virus infection. Here we elucidate the biochemical mechanisms of human TOP3B. We delineate the roles of divalent metal ions, and of a conserved Lysine residue (K10) in the differential catalysis of DNA and RNA. We also demonstrate that three regulatory factors fine-tune the catalytic performance of TOP3B: the TOP3B C-terminal tail, its protein partner TDRD3, and the sequence of its DNA/RNA substrates.