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Objective: Although doctor-patient communication has been the focus of numerous studies, there is a lack of empirical evidence on which to base a curriculum for teaching effective communication skills for use in an oncology setting. Research within the general practice area identifies patient-centred and doctor-centred behaviours as the most important dimensions of doctor-patient communication. This study examined patients and their relatives/friends' preferences for and satisfaction with patient-centred and doctor-centred consulting styles. It was argued that by determining patient preferences for consulting styles, specific recommendations for improving communication in the oncology setting could be formulated.Participants and Methods: One hundred and thirteen women who had been treated for breast cancer and 48 of their relatives or friends watched videotaped scenarios of an oncology consultation, using professional actors. Viewers were randomly allocated to either a good prognosis or poor prognosis video, in which the oncologist discussed the patient's diagnosis, treatment and prognosis. These segments were presented in both styles to allow viewers to directly compare and contrast the patient-centred and doctor-centred approach. Outcomes included style preference and satisfaction. Demographic details, information and involvement preferences, anxiety and depression levels were also obtained.Results: Both patients and their relatives or friends significantly preferred a patient-centred consulting style across all aspects of the consultation (p<0.0001), except within the treatment segment of the good prognosis video where there was no significant difference. One third of the viewers preferred a doctor-centred style for the treatment and prognosis segments. Predictors of a patient-centred style preference in the treatment and prognosis segments included watching a poor prognosis video (OR=2.45, 95% CI 1.04-5.81, p=0.04; OR=3.22, 95% CI 1.22-8.50, p=0.02, respectively), and being employed in a professional occupation (OR=2.38, 95% CI 1.02-5.53, p=0.04 for the treatment segment only). Satisfaction ratings varied within and across videos.Conclusion: Despite some methodological limitations, this study provides empirical data indicating that patients and their relatives or friends prefer a patient-centred approach to the consultation, particularly when the patient has a poor prognosis. The fact that a substantial minority of patients preferred a doctor-centred style emphasizes the need to enhance physicians' abilities to recognize different patient needs throughout the consultation. [ABSTRACT FROM AUTHOR]

Background: Refinement of the risk classification for localized prostate cancer is warranted to aid in clinical decision making. A systematic analysis was undertaken to evaluate the prognostic ability of three genomic classifiers, Decipher, GPS, and Prolaris, for biochemical recurrence, development of metastases and prostate cancer-specific mortality in patients with localized prostate cancer., Methods: Data sources: MEDLINE, Embase, and Web of Science were queried for reports published from January 2010 to April 2022., Study Selection: prospective or retrospective studies reporting prognosis for patients with localized prostate cancer., Data Extraction: relevant data were extracted into a customized database by one researcher with a second overreading. Risk of bias was assessed using a validated tool for prognostic studies, Quality in Prognosis Studies (QUIPS). Disagreements were resolved by consensus or by input from a third reviewer. We assessed the certainty of evidence by GRADE incorporating adaptation for prognostic studies., Results: Data synthesis: a total of 39 studies (37 retrospective) involving over 10,000 patients were identified. Twenty-two assessed Decipher, 5 GPS, and 14 Prolaris. Thirty-four studies included patients who underwent prostatectomy. Based on very low to low certainty of evidence, each of the three genomic classifiers modestly improved upon the prognostic ability for biochemical recurrence, development of metastases, and prostate cancer-specific mortality compared to standard clinical risk-classification schemes., Limitations: downgrading of confidence in the evidence stemmed largely from bias due to the retrospective nature of the studies, heterogeneity in treatment received, and era in which patients were treated (i.e., prior to the 2000s)., Conclusions: Genomic classifiers provide a small but consistent improvement upon the prognostic ability of clinical classification schemes, which may be helpful when treatment decisions are uncertain. However, evidence from current management-era data and of the predictive ability of these tests is needed., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Tissue-based genomic classifiers (GCs) have been developed to improve prostate cancer (PCa) risk assessment and treatment recommendations., Purpose: To summarize the impact of the Decipher, Oncotype DX Genomic Prostate Score (GPS), and Prolaris GCs on risk stratification and patient-clinician decisions on treatment choice among patients with localized PCa considering first-line treatment., Data Sources: MEDLINE, EMBASE, and Web of Science published from January 2010 to August 2024., Study Selection: Two investigators independently identified studies on risk classification and treatment choice after GC testing for patients with localized PCa considering first-line treatment., Data Extraction: Relevant data extracted by 1 researcher and overread by a second. Risk of bias (ROB) was assessed in duplicate., Data Synthesis: Ten studies reported risk reclassification after GC testing. In low ROB observational studies, very low- or low-risk patients with PCa were more likely to have their risk levels classified as the same or lower (GPS, 100% to 88.1%; Decipher, 87.2% to 82.9%; Prolaris, 76.9%). However, 1 randomized trial found that GC testing with GPS reclassified 34.5% of very low-risk and 29.4% of low-risk patients to a higher risk category. Twelve observational studies indicated that treatment decisions after GC testing either remained unchanged or slightly favored active surveillance. In contrast, analyses from a single randomized trial found fewer choices for active surveillance after GPS testing., Limitations: Heterogeneity in screening patterns, risk-determination cutoffs, pathology, and clinical practices. Studies on treatment choice were moderate to high ROB., Conclusion: Although GC tests do not consistently influence risk classification or treatment decisions, the differences observed between observational and randomized studies highlight a need for well-designed trials to explore the role of GC tests in patients with newly diagnosed PCa considering first-line treatment., Primary Funding Source: U.S. Department of Veterans Affairs. (PROSPERO: CRD42022347950)., Competing Interests: Disclosures: Disclosure forms are available with the article online.

Introduction: The JAVELIN Lung 101 phase 1b/2 trial evaluated avelumab (immune checkpoint inhibitor) combined with lorlatinib or crizotinib (tyrosine kinase inhibitors) in ALK -positive or ALK -negative advanced NSCLC, respectively., Methods: Starting doses of lorlatinib 100 mg once daily or crizotinib 250 mg twice daily were administered with avelumab 10 mg/kg every 2 weeks. Primary objectives were assessment of maximum tolerated dose (MTD) and recommended phase 2 dose in phase 1 and objective response rate in phase 2. Primary end points were dose-limiting toxicity (DLT) and confirmed objective response per Response Evaluation Criteria in Solid Tumors, version 1.1., Results: In the avelumab plus lorlatinib group ( ALK -positive; n = 31; 28 in phase 1b; three in phase 2), two of 28 assessable patients (7%) had DLT, and the MTD and recommended phase 2 dose was avelumab 10 mg/kg every 2 weeks plus lorlatinib 100 mg once daily. In the avelumab plus crizotinib group ( ALK -negative; n = 12; all phase 1b), five of 12 assessable patients (42%) had DLT, and the MTD was exceeded with avelumab 10 mg/kg every 2 weeks plus crizotinib 250 mg twice daily; alternative crizotinib doses were not assessed. Objective response rate was 52% (95% confidence interval, 33%-70%) with avelumab plus lorlatinib (complete response, 3%; partial response, 48%) and 25% (95% confidence interval, 6%-57%) with avelumab plus crizotinib (all partial responses)., Conclusions: Avelumab plus lorlatinib treatment in ALK -positive NSCLC was feasible, but avelumab plus crizotinib treatment in ALK -negative NSCLC could not be administered at the doses tested. No evidence of increased antitumor activity was observed in either group., Clinicaltrialsgov Identifier: NCT02584634., Competing Interests: Dr. Solomon reports providing a consulting or advisory role for Amgen, AstraZeneca, BeiGene, Bristol Myers Squibb, Cancer Council of Victoria, D3 Bio, Janssen, Lilly, the healthcare business of Merck KGaA, Darmstadt, Germany, Pfizer, Roche/Genentech, Takeda, and Thoracic Oncology Group of Australasia; has provided speaker services for Amgen, AstraZeneca, Pfizer, and Roche/Genentech; and has received institutional research funding from 10.13039/100017239BeiGene, 10.13039/100002491Bristol Myers Squibb, 10.13039/100020536Lilly, 10.13039/100004336Novartis, Nuvalent, 10.13039/100004319Pfizer, 10.13039/100004337Roche/10.13039/100004328Genentech, and 10.13039/100004339Sanofi. Prof. Dagogo-Jack reports providing a consulting or advisory role for AstraZeneca, Bayer, Boehringer Ingelheim, BostonGene, Catalyst Pharmaceuticals, Genentech, Janssen, Novocure, Pfizer, Sanofi, Syros Pharmaceuticals, and Xcovery; has received travel, accommodations, or expenses from Array BioPharma, Creative Educational Concepts, DAVA Oncology, Medscape, OncLive/MJH Life Sciences, Pfizer, The ASCO Post, and Total Health Conferencing; and has received institutional research funding from 10.13039/100007174Array BioPharma, 10.13039/100017658Calithera Biosciences, Genentech, Pfizer, 10.13039/100004336Novartis, and Vivace Therapeutics. Prof. Lee reports providing a consulting or advisory role for AstraZeneca/MedImmune, Bristol Myers Squibb, and Novartis; has received honoraria from AstraZeneca/MedImmune, the healthcare business of Merck KGaA, Darmstadt, Germany, and Roche; and has received travel, accommodations, or expenses from Novartis. Prof. Boyer reports providing a consulting or advisory role for AstraZeneca/MedImmune, Bristol Myers Squibb, and Merck & Co., Kenilworth, NJ; has received institutional research funding from 10.13039/100002429Amgen, 10.13039/100019621Ascentage Pharma, 10.13039/100004325AstraZeneca, 10.13039/100017239BeiGene, Boehringer Ingelheim, Bristol Myers Squibb, Lilly, 10.13039/100004334Merck & Co., Kenilworth, NJ, OncoMed, 10.13039/100012742Peregrine Pharmaceuticals, Pfizer, and Roche/Genentech; and has received travel, accommodations, or expenses from Boehringer Ingelheim, Bristol Myers Squibb, Merck & Co., Kenilworth, NJ, and Roche/Genentech. Prof. Ramalingam reports providing a consulting or advisory role for AbbVie, Amgen, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Lilly/ImClone, Roche/Genentech, Takeda, and the healthcare business of Merck KGaA, Darmstadt, Germany. Dr. Carcereny has no relationships to disclose. Prof. Felip reports providing a consulting or advisory role for AbbVie, Amgen, AstraZeneca, Bayer, Blueprint Medicines, Boehringer Ingelheim, Bristol Myers Squibb, Lilly, GlaxoSmithKline, Janssen, Merck & Co., Kenilworth, NJ, Novartis, Pfizer, Puma Biotechnology, Roche, Sanofi, Genzyme, Takeda, and the healthcare business of Merck KGaA, Darmstadt, Germany; has provided speaker services for AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Lilly, Medscape, Merck & Co., Kenilworth, NJ, Novartis, PeerVoice, Pfizer, Prime Oncology, Roche, Springer, Takeda, touchIME, and CME Outfitters; has received research funding from grant for Oncology Innovation, Fundación Merck Salud, Madrid, Spain, an affiliate of Merck KGaA, Darmstadt, Germany; and is an independent member of the board of Grifol. Dr. Han reports providing a consulting or advisory role for Merck & Co., Kenilworth, NJ; has received honoraria from Novartis; and has received institutional research funding from Roche. Dr. Hida has received honoraria from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Chugai Pharma, Clovis Oncology, Kissei Pharmaceutical, Lilly, Merck & Co., Kenilworth, NJ, Novartis, Ono Pharmaceutical, Pfizer, and Taiho Pharmaceutical; and has received institutional research funding from 10.13039/100006483AbbVie, 10.13039/501100004948Astellas, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Chugai Pharma, Clovis Oncology Daiichi Sankyo, 10.13039/501100002975Dainippon Sumitomo Pharma, 10.13039/501100003769Eisai, 10.13039/100014584Ignyta, 10.13039/100016288Kissei Pharmaceutical, 10.13039/501100004095Kyowa Hakko Kirin, 10.13039/100004334Merck & Co., Kenilworth, NJ, Novartis, Ono Pharmaceutical, Pfizer, Servier, 10.13039/100009954Taiho Pharmaceutical, Takeda, and the healthcare business of Merck KGaA, Darmstadt, Germany. Dr. Hughes reports providing a consulting or advisory role for AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Eisai, Pfizer, Merck & Co., Kenilworth, NJ, and Roche. Dr. Kim has no relationships to disclose. Dr. Nishio has received lecture fees from Chugai Pharmaceutical, Pfizer, Novartis, and Takeda. Dr. Seto has received honoraria from Astellas Pharma, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Chugai Pharma, Kissei Pharmaceutical, Kyowa Hakko Kirin, Lilly Japan, Merck & Co., Kenilworth, NJ, Nippon Kayaku, Ono Pharmaceutical, Pfizer, Roche Singapore, Taiho Pharmaceutical, Takeda, and Yakult Honsha; and has received institutional research funding from Astellas Pharma, AstraZeneca, 10.13039/100015731Bayer Yakuhin, Boehringer Ingelheim, Chugai Pharma, Daiichi Sankyo, Eisai, Kissei Pharmaceutical, Lilly, Merck & Co., Kenilworth, NJ, Novartis, Pfizer, and the healthcare business of Merck KGaA, Darmstadt, Germany. Dr. Okamoto has received honoraria from AstraZeneca, Bristol Myers Squibb, Chugai Pharmaceutical, Eli Lilly, Johnson & Johnson, Merck & Co., Kenilworth, NJ, Boehringer Ingelheim, Nippon Kayaku, Novartis, Ono Pharmaceutical, and Taiho Pharmaceutical; and has received institutional research funding from AnHeart Therapeutics, AstraZeneca, Bristol Myers Squibb, Chugai Pharmaceutical, Covidien Japan, Daiichi Sankyo, Lilly, KM Biologics, the healthcare business of Merck KGaA, Darmstadt, Germany, Merck & Co., Kenilworth, NJ, Boehringer Ingelheim, Nippon Kayaku, Novartis, Pfizer, and Taiho Pharmaceutical. Dr. Zhang is an employee of Pfizer and owns stock and has other ownership interests in Pfizer. Dr. Martini is an employee of Pfizer and owns stock and has other ownership interests in Pfizer. Dr. Wang was an employee of Pfizer at the time this study was conducted. Dr. De Beukelaer was an employee of Pfizer at the time this study was conducted and owns stock and has other ownership interests in Pfizer. Dr. Bauer reports providing a consulting or advisory role for AstraZeneca, Bayer, Lilly, and Pfizer; has provided speaker services for Bayer, Bristol Myers Squibb, Lilly, and Pfizer; and has received institutional research funding from AstraZeneca, Bayer, Bristol Myers Squibb, Lilly, and Pfizer., (© 2024 by the International Association for the Study of Lung Cancer.)

Purpose: Chat Generative Pre-Trained Transformer (ChatGPT), an artificial intelligence program that uses natural language processing to generate conversational-style responses to questions or inputs, is increasingly being used by both patients and health care professionals. This study aims to evaluate the accuracy and comprehensiveness of ChatGPT in radiation oncology-related domains, including answering common patient questions, summarizing landmark clinical research studies, and providing literature reviews with specific references supporting current standard-of-care clinical practice in radiation oncology., Methods and Materials: We assessed the performance of ChatGPT version 3.5 (ChatGPT3.5) in 3 areas. We evaluated ChatGPT3.5's ability to answer 28 templated patient-centered questions applied across 9 cancer types. We then tested ChatGPT3.5's ability to summarize specific portions of 10 landmark studies in radiation oncology. Next, we used ChatGPT3.5 to identify scientific studies supporting current standard-of-care practice in clinical radiation oncology for 5 different cancer types. Each response was graded independently by 2 reviewers, with discordant grades resolved by a third reviewer., Results: ChatGPT3.5 frequently generated inaccurate or incomplete responses. Only 39.7% of responses to patient-centered questions were considered correct and comprehensive. When summarizing landmark studies in radiation oncology, 35.0% of ChatGPT3.5's responses were accurate and comprehensive, improving to 43.3% when provided the full text of the study. ChatGPT3.5's ability to present a list of studies related to standard-of-care clinical practices was also unsatisfactory, with 50.6% of the provided studies fabricated., Conclusions: ChatGPT should not be considered a reliable radiation oncology resource for patients or providers at this time, as it frequently generates inaccurate or incomplete responses. However, natural language programming-based artificial intelligence programs are rapidly evolving, and future versions of ChatGPT or similar programs may demonstrate improved performance in this domain., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: While moderately hypofractionated radiotherapy (MHRT) for prostate cancer (PC) is commonly delivered by intensity modulated radiation therapy, IMRT has not been prospectively compared to three-dimensional conformal radiotherapy (3D-CRT) in this context. We conducted a secondary analysis of the phase III RTOG 0415 trial comparing survival and toxicity outcomes for low-risk PC following MHRT with IMRT versus 3D-CRT., Methods: RTOG 0415 was a phase III, non-inferiority trial randomizing low-risk PC patients to either MHRT or conventionally fractionated radiation with stratification by RT technique. A secondary analysis for differences in overall survival (OS), biochemical recurrence free survival (BRFS), or toxicity by EPIC scores and Common Terminology Criteria for Adverse Events (CTCAE) was performed., Results: 1079 patients received the allocated intervention with a median follow up of 5.8 years. 79.1% of patients were treated with IMRT and radiation technique was balanced between arms. Across all patients, RT technique was not associated with significant differences in BRFS, OS, or rates of acute and late toxicities. For patients completing MHRT, there was a difference in the late GU toxicity distribution between 3D-CRT and IMRT but no difference in late grade 2 or greater GU or GI toxicity. Stratifying patients by RT technique and fractionation, no significant differences were observed in the minimal clinically important difference (MCID) in EPIC urinary and bowel scores following RT., Conclusions: RT technique did not impact clinical outcomes following MHRT for low-risk PC. Despite different late GU toxicity distributions in patients treated with MHRT by IMRT or 3D-CRT, there was no difference in late Grade 2 or greater GU or GI toxicity or patient reported toxicity. Increases in late GU and GI toxicity following MHRT compared to CFRT, as demonstrated in the initial publication of RTOG 0415, do not appear related to a 3D-CRT treatment technique., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Risks of maternal morbidity are known to be reduced in pregnancies resulting from frozen embryo transfer (FET) compared to fresh-embryo transfer ( fresh -ET), except for the risk of pre-eclampsia, reported to be higher in FET pregnancies compared to fresh -ET or natural conception. Few studies have compared the risk of maternal vascular morbidities according to endometrial preparation for FET, either with ovulatory cycle (OC-FET) or artificial cycle (AC-FET). Furthermore, maternal pre-eclampsia could be associated with subsequent vascular disorders in the offspring., Methods: A 2013-2018 French nationwide cohort study comparing maternal vascular morbidities in 3 groups of single pregnancies was conducted: FET with either OC or AC preparation, and fresh -ET. Data were extracted from the French National Health System database. Results were adjusted for maternal characteristics and infertility (age, parity, smoking, obesity, history of diabetes or hypertension, endometriosis, polycystic ovary syndrome and premature ovarian insufficiency)., Results: A total of 68025 single deliveries were included: fresh -ET (n=48152), OC-FET (n=9500), AC-FET (n=10373). The risk of pre-eclampsia was higher in AC-FET compared to OC-FET and fresh -ET groups in univariate analysis (5.3% vs. 2.3% and 2.4%, respectively, P <0.0001). In multivariate analysis the risk was significantly higher in AC-FET compared to fresh -ET: aOR=2.43 [2.18-2.70], P <0.0001). Similar results were observed for the risk of other vascular disorders in univariate analysis (4.7% vs . 3.4% and 3.3%, respectively, P =0.0002) and in multivariate analysis (AC-FET compared to fresh -ET: aOR=1.50 [1.36-1.67], P <0.0001). In multivariate analysis, the risk of pre-eclampsia and other vascular disorders were comparable in OC-FET and fresh -ET: aOR=1.01 [0.87-1.17, P = 0.91 and aOR=1.00 [0.89-1.13], P =0.97, respectively).Within the group of FET, the risks of pre-eclampsia and other vascular disorders in multivariate analysis were higher in AC-FET compared to OC-FET (aOR=2.43 [2.18-2.70], P <0.0001 and aOR=1.5 [1.36-1.67], P <0.0001, respectively)., Conclusion: This nationwide register-based cohort study highlights the possibly deleterious role of prolonged doses of exogenous estrogen-progesterone supplementation on gestational vascular pathologies and the protective role of the corpus luteum present in OC-FET for their prevention. Since OC-FET has been demonstrated not to strain the chances of pregnancy, OC preparation should be advocated as first-line preparation in FET as often as possible in ovulatory women., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Epelboin, Labrosse, De Mouzon, Devaux, Gervoise-Boyer, Hesters, Jonveaux, Levy, Sermondade, Fauque and Pessione.)

Research Question: What part do maternal context and medically assisted reproduction (MAR) techniques play in the risk of fetal growth disorders?, Design: This retrospective nationwide cohort study uses data available in the French National Health System database and focuses on the period from 2013 to 2017. Fetal growth disorders were divided into four groups according to the origin of pregnancy: fresh embryo transfer (n = 45,201), frozen embryo transfer (FET, n = 18,845), intrauterine insemination (IUI, n = 20,179) and natural conceptions (n = 3,412,868). Fetal growth disorders were defined from the percentiles of the weight distribution according to gestational age and sex: small and large for gestational age (SGA and LGA) if <10th and >90th percentiles, respectively. Analyses were performed using univariate and multivariate logistic models., Results: Compared with births following natural conception, multivariate analysis showed that the risk of SGA was higher for births following fresh embryo transfer and IUI (adjusted odds ratio [aOR] 1.26 [1.22-1.29] and 1.08 [1.03-1.12], respectively) and significantly lower following FET (aOR 0.79 [0.75-0.83]). The risk of LGA was higher for births following FET (aOR 1.32 [1.27-1.38]), especially in artificial cycles when compared with ovulatory cycles (aOR 1.25 [1.15-1.36]). In the subgroup of births without any obstetrical or neonatal morbidity, the same increased risk of SGA and LGA were observed following fresh embryo transfer or IUI and FET (aOR 1.23 [1.19-1.27] or 1.06 [1.01-1.11] and aOR 1.36 [1.30-1.43], respectively)., Conclusions: An effect of MAR techniques on the risks for SGA and LGA is suggested independently from maternal context and obstetrical or neonatal morbidities. Pathophysiological mechanisms remain poorly understood and should be further evaluated, as well as the influence of embryonic stage and freezing techniques., (Copyright © 2023 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.)

Research Question: What are the risk factors for prematurity other than intrauterine growth restriction in singletons after IVF?, Design: Data were collected from a national registry, based on an observational prospective cohort of 30,737 live births after assisted reproductive technology (fresh embryo transfers: n = 20,932 and frozen embryo transfer [FET] n = 9805) between 2014 and 2015. A population of not-small for gestational age singletons conceived after fresh embryo transfers and FET, and their parents, was selected. Data on a number of variables were collected, including type of infertility, number of oocytes retrieved and vanishing twins., Results: Preterm birth occurred in 7.7% (n = 1607) of fresh embryo transfers and 6.2% (n = 611) of frozen-thawed embryo transfers (P < 0.0001; adjusted odds ratio [aOR] = 1.34 [1.21-1.49]). Endometriosis and vanishing twin increased the risk of preterm birth after fresh embryo transfer (P < 0.001; aOR 1.32 and 1.78, respectively). Polycystic ovaries or more than 20 oocytes retrieved also increased preterm birth risk (aOR 1.31 and 1.30; P = 0.003 and P = 0.02, respectively); large oocyte cohort (>20) was no longer associated with the risk of prematurity in FET., Conclusion: Endometriosis remains a risk for prematurity even in the absence of intrauterine growth retardation, which suggests a dysimmune effect. Large oocyte cohorts obtained by stimulation, without clinical polycystic ovary syndrome diagnosed before attempts, do not affect FET outcomes, reinforcing the idea of a phenotypic difference in the clinical presentation of polycystic ovary syndrome., (Copyright © 2023 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.)

Purpose: The Oncotype DX Genomic Prostate Score (GPS) assay has been validated as a strong prognostic indicator of adverse pathology, biochemical recurrence, distant metastasis (DM), and prostate cancer (PCa)-related death (PCD) in men with localized PCa after radical prostatectomy. However, it has yet to be tested in men undergoing external beam radiation therapy (EBRT), for whom assessing PCa progression risk could inform decisions on treatment intensity. We analyzed whether GPS results are associated with time to biochemical failure (BCF), DM, and PCD after EBRT in men with localized PCa and whether the association is modified by race., Methods and Materials: We conducted a retrospective study of men with localized PCa treated with EBRT at the VA Health Care System in Durham, NC from 2000 to 2016. Study endpoints were time to BCF per the Phoenix criteria, DM, and PCD. The association of GPS results, per 20-unit increase or dichotomous variable (0-40 vs 41-100), was evaluated with each endpoint using univariable and multivariable Cox proportional hazards models. Results were then stratified by race., Results: A total of 238 patients (69% Black) met the eligibility criteria. Median follow-up for patients who did not experience BCF was 7.6 years. GPS results per 20-unit increase were significantly associated with BCF (hazard ratio [HR], 3.62; 95% confidence interval [CI], 2.59-5.02), DM (HR, 4.48; 95% CI, 2.75-7.38), and PCD (HR, 5.36; 95% CI, 3.06-9.76) in univariable analysis. GPS results remained significant in multivariable models adjusted for baseline clinical and pathological factors, with HRs being similar to the univariable analysis. There was no significant interaction between the GPS assay and race (P = .923). HRs for BCF were similar in Black men (HR, 3.88; 95% CI, 2.40-6.24) versus non-Black men (HR, 4.01; 95% CI, 2.42-6.45)., Conclusions: Among men treated with EBRT, the GPS assay is a strong, independent prognostic indicator of time to BCF, DM, and PCD, and performs similarly in Black and non-Black men., (Published by Elsevier Inc.)

Purpose: We previously reported on the clinical outcomes of treating oligometastases with radiation using an elective simultaneous integrated boost technique (SIB), delivering higher doses to known metastases and reduced doses to adjacent bone or nodal basins. Here we compare outcomes of oligometastases receiving radiation targeting metastases alone (MA) versus those treated via an SIB., Methods: Oligometastatic patients with ≤5 active metastases treated with either SIB or MA radiation at two institutions from 2013 to 2019 were analyzed retrospectively for treatment-related toxicity, pain control, and recurrence patterns. Tumor metastasis control (TMC) was defined as an absence of progression in the high dose planning target volume (PTV). Marginal recurrence (MR) was defined as recurrence outside the elective PTV but within the adjacent bone or nodal basin. Distant recurrence (DR) was defined as any recurrence that is not within the PTV or surrounding bone or nodal basin. The outcome rates were estimated using the Kaplan-Meier method and compared between the two techniques using the log-rank test., Results: 101 patients were treated via an SIB to 90 sites (58% nodal and 42% osseous) and via MA radiation to 46 sites (22% nodal and 78% osseous). The median follow-up among surviving patients was 24.6 months (range 1.4-71.0). Of the patients treated to MA, the doses ranged from 18 Gy in one fraction (22%) to 50 Gy in 10 fractions (50%). Most patients treated with an SIB received 50 Gy to the treated metastases and 30 Gy to the elective PTV in 10 fractions (88%). No acute grade ≥3 toxicities occurred in either cohort. Late grade ≥3 toxicity occurred in 3 SIB patients (vocal cord paralysis and two vertebral body compression), all related to the high dose PTV and not the elective volume. There was similar crude pain relief between cohorts. The MR-free survival rate at 2 years was 87% (95% CI: 70%, 95%) in the MA group and 98% (95% CI: 87%, 99%) in the SIB group ( p = 0.07). The crude TMC was 89% (41/46) in the MA group and 94% (85/90) in the SIB group. There were no significant differences in DR-free survival (65% (95% CI: 55-74%; p = 0.24)), disease-free survival (60% (95% CI: 40-75%; p = 0.40)), or overall survival (88% (95% CI: 73-95%; p = 0.26)), between the MA and SIB cohorts., Conclusion: Both SIB and MA irradiation of oligometastases achieved high rates of TMC and similar pain control, with a trend towards improved MR-free survival for oligometastases treated with an SIB. Further investigation of this technique with prospective trials is warranted.

Background: To the best of our knowledge, no study has exhaustively evaluated the association between maternal morbidities and Coronavirus Disease 2019 (COVID-19) during the first wave of the pandemic in pregnant women. We investigated, in natural conceptions and assisted reproductive technique (ART) pregnancies, whether maternal morbidities were more frequent in pregnant women with COVID-19 diagnosis compared to pregnant women without COVID-19 diagnosis during the first wave of the COVID-19 pandemic., Methods and Findings: We conducted a retrospective analysis of prospectively collected data in a national cohort of all hospitalizations for births ≥22 weeks of gestation in France from January to June 2020 using the French national hospitalization database (PMSI). Pregnant women with COVID-19 were identified if they had been recorded in the database using the ICD-10 (International Classification of Disease) code for presence of a hospitalization for COVID-19. A total of 244,645 births were included, of which 874 (0.36%) in the COVID-19 group. Maternal morbidities and adverse obstetrical outcomes among those with or without COVID-19 were analyzed with a multivariable logistic regression model adjusted on patient characteristics. Among pregnant women, older age (31.1 (±5.9) years old versus 30.5 (±5.4) years old, respectively, p < 0.001), obesity (0.7% versus 0.3%, respectively, p < 0.001), multiple pregnancy (0.7% versus 0.4%, respectively, p < 0.001), and history of hypertension (0.9% versus 0.3%, respectively, p < 0.001) were more frequent with COVID-19 diagnosis. Active smoking (0.2% versus 0.4%, respectively, p < 0.001) and primiparity (0.3% versus 0.4%, respectively, p < 0.03) were less frequent with COVID-19 diagnosis. Frequency of ART conception was not different between those with and without COVID-19 diagnosis (p = 0.28). When compared to the non-COVID-19 group, women in the COVID-19 group had a higher frequency of admission to ICU (5.9% versus 0.1%, p < 0.001), mortality (0.2% versus 0.005%, p < 0.001), preeclampsia/eclampsia (4.8% versus 2.2%, p < 0.001), gestational hypertension (2.3% versus 1.3%, p < 0.03), postpartum hemorrhage (10.0% versus 5.7%, p < 0.001), preterm birth at <37 weeks of gestation (16.7% versus 7.1%, p < 0.001), <32 weeks of gestation (2.2% versus 0.8%, p < 0.001), <28 weeks of gestation (2.4% versus 0.8%, p < 0.001), induced preterm birth (5.4% versus 1.4%, p < 0.001), spontaneous preterm birth (11.3% versus 5.7%, p < 0.001), fetal distress (33.0% versus 26.0%, p < 0.001), and cesarean section (33.0% versus 20.2%, p < 0.001). Rates of pregnancy terminations ≥22 weeks of gestation, stillbirths, gestational diabetes, placenta praevia, and placenta abruption were not significantly different between the COVID-19 and non-COVID-19 groups. The number of venous thromboembolic events was too low to perform statistical analysis. A limitation of this study relies in the possibility that asymptomatic infected women were not systematically detected., Conclusions: We observed an increased frequency of pregnant women with maternal morbidities and diagnosis of COVID-19 compared to pregnant women without COVID-19. It appears essential to be aware of this, notably in populations at known risk of developing a more severe form of infection or obstetrical morbidities and in order for obstetrical units to better inform pregnant women and provide the best care. Although causality cannot be determined from these associations, these results may be in line with recent recommendations in favor of vaccination for pregnant women., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: JG reports personal fees from Merck, grants and personal fees from ViiV healthcare, grants and personal fees from Gilead Sciences, personal fees from Roche, personal fees from AstraZeneca, personal fees from Janssen, outside the submitted work. All other authors have declared that no competing interests exist.

What is the perception of health and well-being of adolescents from an assisted reproductive technology (ART) cohort? We conducted a survey, from September 2015 to June 2016, through self-completion questionnaires, on 487 singleton or twin ART-conceived 11- to 15-year-old adolescents, followed up since 1994, as part of an ART cohort. Collected data concerned perinatal characteristics, health indicators and perception, eating habits, behavior, and living standards. A total of 60.6% of the questionnaires were returned and could therefore be analyzed. This concerned 295 adolescents who were representative of the 788 remaining adolescents of our cohort, in terms of type of ART, maternal and perinatal characteristics, but not gender (sex ratio = 0.77). Overall, 15.3% reported chronic diseases, and only 13.3% of them considered that their chronic disease had an impact on their school life. Moreover, 94.2% of adolescents perceived that their health was "excellent" or "good"; 97.3% adolescents had normal weight or were underweight; onset of menstruation was 12 years old (± 1) for girls, age usually reported for puberty in girls; 51.9% declared having regular physical activity, boys more frequently than girls. Moreover, 70.6% of the boys had a sedentary behavior compared to 44.8% of the girls. A total of 73.5% of the adolescents were stressed at school, but school demand was considered high only in 12.2% of cases. Finally, 90% declared to have high life satisfaction. Overall, ART does not appear to have particular effect on the health indicators and behavior of adolescents who participated in the survey except for higher family affluence scale.

Purpose: In vitro developing embryos may apparently show no developmental progress during 24 h and resume their development up to the blastocyst stage. The present study was conducted to assess their ability to implant and to give rise to a live birth when replaced at day 5 (fresh or vitrified/warmed) as compared to continuously developing embryos., Methods: Embryo development follow-up and grade were prospectively recorded in a photo database. The studied period was from April 2011 to July 2017. The studied embryos included transient arrested embryos (TAE) that showed the same developmental stage at two subsequent observations, i.e. between day 2 and day 3 (d2 and d3), between day 3 and day 4 (d3 and d4) and between day 4 and day 5 (d4 and d5). TAE were compared to continuously developing embryos (CDE). Elective day 5 embryo transfers were performed., Results: Woman age was higher in TAE (34.3±3.9) than in CDE (32.9±4.8) (p<0.01). TAE were more frequently (63.1%) observed after ICSI than after conventional IVF (55.9%) (p<0.01). Implantation rate was reduced in TAE as compared to CDE, after both fresh (10.0% vs 23.8% [p<0.01]) and vitrified/warmed (12.9% vs 19.0% [p<0.01]) embryo transfers. Delivery rate was also lower after the transfer of fresh (8.3% vs 19.4% [p<0.01]) and vitrified/warmed (8.5% vs 14.1% [p<0.01]) TAE as compared to CDE. Implantation and delivery rates were not statistically different whether embryo arrested between day 2 and day 3 (d2 and d3), between day 3 and day 4 (d3 and d4) or between day 4 and day 5 (d4 and d5)., Conclusion: TAE may be considered for transfer at a lower priority than CDE and associated with inferior prognosis than CDE.

Research Question: Does endometriosis increase obstetric and neonatal complications, and does assisted reproductive technology (ART) cause additional risk of maternal or fetal morbidity?, Design: A nationwide cohort study (2013-2018) comparing maternal and perinatal morbidities in three groups of single pregnancies: spontaneous pregnancies without endometriosis; spontaneous pregnancies with endometriosis; and ART pregnancies in women with endometriosis., Results: Mean maternal ages were 30.0 (SD = 5.3), 31.7 (SD = 4.8) and 33.1 years (SD = 4.0), for spontaneous conceptions, spontaneous conceptions with endometriosis and ART pregnancies with endometriosis groups, respectively (P < 0.0001). Comparison of spontaneous conceptions with endometriosis and spontaneous conceptions: endometriosis independently increased the risk of venous thrombosis (adjusted OR [aOR] 1.51, P < 0.001), pre-eclampsia (aOR 1.29, P < 0.001), placenta previa (aOR 2.62, P < 0.001), placental abruption (aOR 1.54, P < 0.001), premature birth (aOR 1.37, P < 0.001), small for gestational age (aOR 1.05, P < 0.001) and malformations (aOR 1.06, P = 0.049). Comparison of ART pregnancies with endometriosis and spontaneous conceptions with endometriosis: ART increased the risk of placenta previa (aOR 2.43, 95% CI 2.10 to 2.82, P < 0.001), premature birth (aOR 1.42, 95% CI 1.29 to 1.55, P < 0.001) and small for gestational age (aOR 1.18, 95% CI 1.10 to 1.27, P < 0.001), independently from the effect of endometriosis. Risk of pre-eclampsia, placental abruption or congenital malformations was not increased with ART., Conclusion: Endometriosis is an independent risk factor for mother and child morbidities. Maternal morbidity and perinatal morbidity were significantly increased by ART in addition to endometriosis; however, some perinatal and maternal morbidity risks were increasingly linked to pathologies related to infertility., (Copyright © 2020 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.)

Study Question: Do IVF, IUI or female infertility (i.e. endometriosis, polycystic ovary syndrome [PCOS] and primary ovarian insufficiency [POI]) lead to an increased risk of congenital anomalies in singletons?, Summary Answer: After multivariable adjustments, the increased risks of congenital defects associated with IUI were no longer significant, but the underlying maternal infertility presented a potential emental risk, in addition to the risk associated with IVF., What Is Known Already: Most epidemiological studies suggest that singletons born from ART have a higher risk of birth defects, specifically musculoskeletal, cardiovascular and urogenital disorders. However, most of these studies were established on data obtained at birth or in the neonatal period and from relatively small populations or several registries. Moreover, to our knowledge, female infertility, which is a potential confounder, has never been included in the risk assessment., Study Design, Size, Duration: Using data from the French National Health System database, we conducted a comparative analysis of all singleton births (deliveries ≥22 weeks of gestation and/or >500 g of birthweight) in France over a 5-year period (2013-2017) resulting from fresh embryo or frozen embryo transfer (fresh-ET or FET from IVF/ICSI cycles), IUI and natural conception (NC). Data were available for this cohort of children at least up to early childhood (2.5 years old)., Participants/materials, Setting, Methods: A total of 3 501 495 singleton births were included (3 417 089 from NC, 20 218 from IUI, 45 303 from fresh-ET and 18 885 from FET). Data were extracted from national health databases and used to identify major birth defects. Malformations were classified according to the 10th revision of the International Classification of Disease. To analyse the effect of mode of conception, multivariable analyses were performed with multiple logistic regression models adjusted for maternal age, primiparity, obesity, smoking, history of high blood pressure or diabetes and female infertility., Main Results and the Role of Chance: In our cohort of children, the overall prevalence of congenital malformations was 3.78% after NC, 4.53% after fresh-ET, 4.39% after FET and 3.91% after IUI (132 646 children with major malformations). Compared with infants conceived naturally, children born after fresh-ET and after FET had a significantly higher prevalence of malformations, with an adjusted odds ratio (aOR) of 1.15 [95% CI 1.10-1.20, P < 0.0001] and aOR of 1.13 [95% CI 1.05-1.21, P = 0.001], respectively. Among the 15 relevant subgroups of malformations studied, we observed a significantly increased risk of eight malformations in the fresh-ET group compared with the NC group (i.e. musculoskeletal, cardiac, urinary, digestive, neurological, cleft lip and/or palate and respiratory). In the FET group, this increased risk was observed for digestive and facial malformations. The overall risk of congenital malformations, and the risk by subtype, was similar in the IUI group and the NC group (overall risk: aOR of 1.01 [95% CI 0.94-1.08, P = 0.81]). In addition, there was an overall independent increase in the risk of congenital defects when the mothers were diagnosed with endometriosis (1.16 aOR [95% CI 1.10-1.22], P < 0.0001), PCOS (1.20 aOR [95% CI 1.08-1.34], P = 0.001) or POI (1.52 aOR [95% CI 1.23-1.88], P = 0.0001). Chromosomal, cardiac and neurological anomalies were more common in the three maternal infertility groups., Limitations, Reasons for Caution: Male infertility, the in vitro fertilization method (i.e. in vitro fertilization without or with sperm injection: conventional IVF vs ICSI) and embryo stage at transfer could not be taken into account. Furthermore, residual confounding cannot be excluded as well as uncertainties regarding the diagnostic criteria used for the three female infertilities. Findings for specific malformations should be interpreted with caution because the number of cases was small in some sub-groups (potentially due to the Type I error or multiple testing)., Wider Implications of the Findings: In this large study, after multivariable maternal adjustments, a moderately increased risk of defects subsisted after IVF, while those associated with IUI were no longer significant. In addition, our results showed that underlying maternal infertility could contribute to the increased risk of defects associated with IVF. These novel findings highlight the importance of taking into account the ART treatment methods and the type of infertility., Study Funding/competing Interest(s): This work was supported by the National Agency of Biomedicine. The authors have no competing interests to disclose., Trial Registration Number: NA., (© The Author(s) 2021. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Our objective was to describe and discuss management of recent cases of drug hypersensitivity in children reported in a pharmacovigilance center. Two pediatric allergy units conducted a collaborative retrospective analysis of 101 adverse drug reactions reported to a regional pharmacovigilance center between January 2016 and July 2019. Time lapse between hypersensitivity reaction onset and allergy consultation varied from 1 month to 12 years. Sixty-two patients (61.4%) presented with immediate reactions, 11 (10.9%) with non-immediate reactions, and 28 (27.7%) had reactions impossible to classify through medical interview. Overall, 92 children (91%) were explored for simultaneously administered drugs. All 113 prick tests were negative, and 2 were uncertain. Among 108 intradermal tests, 2 were positive to penicillin and to an iodinated contrast medium, 105 were negative, and 1 was uncertain. Overall, 129 drug provocation tests were proposed. Nine provocation tests among 80 were positive (11.25%): 6 to penicillin, 1 to sulfonamide antibiotics, and 2 to non-steroidal anti-inflammatory drugs; the remaining 71 were negative. No severe reaction was observed during these tests. Finally, drug allergy was only retained in 11 reported cases (10.9%).Conclusion: These pharmacovigilance reports show the difficulty in defining drug allergy in children only by anamnesis, and that explorations, particularly provocation tests, should take place at a reasonable time lapse after drug hypersensitivity reaction onset. What is Known: • True drug allergy is rarely observed in children. • Absence of full workup leads to falsely labeling children as "allergic." What is New: • Short time lapse between hypersensitivity onset and consultation improves classification of pediatric allergy. • Timely allergy consultations are essential, and tests are useful to confirm or exclude pediatric allergy.

Background: Epidemiological studies suggest that singletons born from assisted reproductive technologies (ART) have a high risk of adverse perinatal outcomes, specifically for imprinting disorders. Because ART processes take place at times when epigenetic reprogramming/imprinting are occurring, there is concern that ART can affect genomic imprints. However, little is currently known about the risk of imprinting defects according to the type of ART or the type of underlying female infertility. From the French national health database, a cohort of 3,501,495 singletons born over a 5-year period (2013-2017) following fresh embryo or frozen embryo transfers (fresh-ET or FET from in vitro fertilization), intrauterine insemination, or natural conception was followed up to early childhood. Based on clinical features, several syndromes/diseases involving imprinted genes were monitored. The effects of ART conception and the underlying cause of female infertility were assessed., Results: Compared with infants conceived naturally, children born after fresh-ET had a higher prevalence of imprinting-related diseases, with an aOR of 1.43 [95% CI 1.13-1.81, p = 0.003]. Namely, we observed an increased risk of neonatal diabetes mellitus (1.96 aOR [95% CI 1.43-2.70], p < 0.001). There was an overall independent increase in risk of imprinting diseases for children with mothers diagnosed with endometriosis (1.38 aOR [95% CI 1.06-1.80], p = 0.02). Young and advanced maternal age, primiparity, obesity, smoking, and history of high blood pressure or diabetes were also associated with high global risk., Conclusions: This prospective epidemiological study showed that the risk of clinically diagnosed imprinting-related diseases is increased in children conceived after fresh embryo transfers or from mothers with endometriosis. The increased perturbations in genomic imprinting could be caused by controlled ovarian hyperstimulation and potentially endometriosis through the impairment of endometrial receptivity and placentation, leading to epigenetic feto-placental changes. Further studies are now needed to improve understanding of the underlying molecular mechanisms (i.e. genetic or epigenetic causes).

Since its discovery in 2007, we have seen the lives of patients diagnosed with advanced anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancers (NSCLC) transform with the advent of molecular therapies with first-, second-, and third-generation ALK inhibitors now available in the clinic. Despite great gains in patient survival now measured in years and preserved quality of life with targeted therapies, drug resistance is unfortunately inevitably encountered in this rare and unique molecular subset of lung cancer, and patients will eventually succumb to the disease. As these patients are often young, fit, and never smokers, the clinical and scientific communities have aligned to expedite drug development and access. Drug resistance profiling and further strategies are being explored through clinical trials, including the evaluation of specific drug sequencing and combinations to overcome such resistance and promote patient longevity. The cases of this report focus on precision medicine and aim to portray the pertinent aspects to consider when treating ALK-rearranged NSCLC in 2020, an ever-shifting space. By way of case examples, this report offers valuable information to the treating clinician, including the evolution of systemic treatments and the management of oligo-progression and multisite drug resistance. With the maturation of real-world data, we are fortunate to be experiencing quality and length of life for patients with this disease surpassing prior expectations in advanced lung cancer. KEY POINTS: This report focuses on the importance of genetic analysis of serial biopsies to capture the dynamic therapeutic vulnerabilities of a patient's tumor, providing a perspective on the complexity of ALK tyrosine kinase inhibitor (ALKi) treatment sequencing. These case examples contribute to the literature on ALK-rearranged and oncogene addicted non-small cell lung cancer (NSCLC), providing a framework for care in the clinic. In oligo-progressive disease, local ablative therapy and continuation of ALKi postprogression should be considered with potential for sustained disease control. ALK G1202R kinase domain mutations (KDM), highly prevalent at resistance to second-generation ALKi resistances, may emerge in non-EML4-ALK variant 3 cases and is sensitive to third-generation lorlatinib. When in compound with one or more ALK KDMs, resistance to lorlatinib is expected. In the case of rampantly progressive disease, rebiopsy and redefining biology in a timely manner may be informative., (© AlphaMed Press 2020.)

Endothelial inflammation and mitochondrial dysfunction have been implicated in cardiovascular diseases, yet, a unifying mechanism tying them together remains limited. Mitochondrial dysfunction is frequently associated with mitochondrial fission/fragmentation mediated by the GTPase Drp1 (dynamin-related protein 1). Nuclear factor (NF)-κB, a master regulator of inflammation, is implicated in endothelial dysfunction and resultant complications. Here, we explore a causal relationship between mitochondrial fission and NF-κB activation in endothelial inflammatory responses. In cultured endothelial cells, TNF-α (tumor necrosis factor-α) or lipopolysaccharide induces mitochondrial fragmentation. Inhibition of Drp1 activity or expression suppresses mitochondrial fission, NF-κB activation, vascular cell adhesion molecule-1 induction, and leukocyte adhesion induced by these proinflammatory factors. Moreover, attenuations of inflammatory leukocyte adhesion were observed in Drp1 heterodeficient mice as well as endothelial Drp1 silenced mice. Intriguingly, inhibition of the canonical NF-κB signaling suppresses endothelial mitochondrial fission. Mechanistically, NF-κB p65/RelA seems to mediate inflammatory mitochondrial fission in endothelial cells. In addition, the classical anti-inflammatory drug, salicylate, seems to maintain mitochondrial fission/fusion balance against TNF-α via inhibition of NF-κB. In conclusion, our results suggest a previously unknown mechanism whereby the canonical NF-κB cascade and a mitochondrial fission pathway interdependently regulate endothelial inflammation.

The vascular endothelium and smooth muscle form adjacent cellular layers that comprise part of the vascular wall. Each cell type can regulate the other's structure and function through a variety of paracrine effectors. Extracellular vesicles (EVs) are released from and transit between cells constituting a novel means of cell-cell communication. Here, we characterized the proteome of EVs released from each vascular cell type and examined the extent to which these vesicles participate in endothelial-vascular smooth muscle cell (VSMC) communication. EVs were collected by ultracentrifugation from media of rat aortic endothelial and smooth muscle cells cultured under serum-free conditions. Vesicle morphology, size and concentration were evaluated by transmission electron microscopy and nanoparticle tracking analysis. Western blot as well as shot gun proteomic analyses revealed sets of proteins common to both endothelial- and smooth muscle-derived EVs as well as proteins unique to each vascular cell type. Functionally, endothelial-derived EVs stimulated vascular cell adhesion molecule-1 (VCAM-1) expression and enhanced leukocyte adhesion in VSMCs while smooth muscle EVs did not elicit similar effects in endothelial cells (ECs). EVs from ECs also induced protein synthesis and senescence in VSMCs. Proteomic analysis of VSMCs following exposure to EC-derived EVs revealed upregulation of several proteins including pro-inflammatory molecules, high-mobility group box (HMGB) 1 and HMGB2. Pharmacological blockade HMGB1 and HMGB2 and siRNA depletion of HMGB1 in smooth muscle cells attenuated VCAM-1 expression and leukocyte adhesion induced by EC EVs. These data suggest that EC-derived EVs can enhance signalling pathways which influence smooth muscle cell phenotype., Competing Interests: No potential conflict of interest was reported by the author(s)., (© 2020 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group on behalf of The International Society for Extracellular Vesicles.)

Adenoviral vectors are useful tools in manipulating a gene of interest in vitro and in vivo, including in the vascular system. The transduction efficiencies of adenoviral vectors in vascular cells such as endothelial cells (ECs) and vascular smooth muscle cells (VSMCs) are known to be lower than those in epithelial cell types. The effective entry for adenoviral vectors is primarily mediated through the coxsackievirus and adenovirus receptor (CAR), which has been shown to be expressed in both cell types. Cationic liposomes have been used to enhance adenovirus transduction efficiency in nonepithelial cells. Accordingly, the aim of this study is to obtain new information regarding differences in transduction efficiencies, cationic liposome sensitivity, and CAR expression between ECs and VSMCs. Using cultured rat aortic ECs and VSMCs, here, we have compared transduction efficiency of adenoviruses with or without inclusion of liposomes and CAR expression. A significant increase in basal transduction efficiency was observed in ECs compared with VSMCs. Cationic liposome polybrene enhanced transduction efficiency in VSMCs, whereas decreased efficiency was observed in ECs. Western blotting demonstrated expression of the CAR in ECs but not in VSMCs. Proteomic analysis and mouse aorta immunostaining further suggests significant expression of the CAR in ECs but not in VSMCs. In conclusion, adenoviruses can effectively transduce the gene of interest in aortic ECs likely because of abundant expression of the CAR, whereas cationic liposomes such as polybrene enhance the transduction efficiency in VSMCs lacking CAR expression.

Angiotensin II (AngII) has a crucial role in cardiovascular pathologies, including endothelial inflammation and premature vascular aging. However, the precise molecular mechanism underlying aging-related endothelial inflammation induced by AngII remains elusive. Here, we have tested a hypothesis in cultured rat aortic endothelial cells (ECs) that the removal of AngII-induced senescent cells, preservation of proteostasis, or inhibition of mitochondrial fission attenuates the pro-inflammatory EC phenotype. AngII stimulation in ECs resulted in cellular senescence assessed by senescence-associated β galactosidase activity. The number of β galactosidase-positive ECs induced by AngII was attenuated by treatment with a senolytic drug ABT737 or the chemical chaperone 4-phenylbutyrate. Monocyte adhesion assay revealed that the pro-inflammatory phenotype in ECs induced by AngII was alleviated by these treatments. AngII stimulation also increased mitochondrial fission in ECs, which was mitigated by mitochondrial division inhibitor-1. Pretreatment with mitochondrial division inhibitor-1 attenuated AngII-induced senescence and monocyte adhesion in ECs. These findings suggest that mitochondrial fission and endoplasmic reticulum stress have causative roles in endothelial senescence-associated inflammatory phenotype induced by AngII exposure, thus providing potential therapeutic targets in age-related cardiovascular diseases., Competing Interests: The authors declare no conflict of interest.

Objectives: The objective of this study was to quantify the risk of maternal and perinatal morbidity with in vitro fertilization (IVF) technology compared to non-IVF pregnancies in a recent French national cohort., Method: The data was extracted from the hospital information data system, including all pregnancies with a delivery from 2013 to 2016. The risks of preterm birth, maternal morbidity (venous and arterial thrombosis, gestational diabetes, vascular disorders, placenta previa, placenta abruption), hypotrophy and congenital malformation were compared in both groups in univariate and multivariate analysis after adjustment on the characteristics of women (age, parity, obesity, tobacco dependence, history of diabetes or high blood pressure), multiple deliveries and sex of children., Results: In all, 2,875,662 pregnancies and 2,922,712 births were analyzed, of which 49,224 were derived from IVF (1.7%). In multivariate analysis, all risks were significantly higher in IVF: premature deliveries (OR ajusted =1.28; CI 95% =1.24-1.32), maternal morbidity (OR ajusted =1.24; CI 95% =1.21-2.28), (mainly for thrombosis venous, placenta previa and placenta abruption). The risks of hypotrophy (OR ajusted =1.13; CI 95% =1.10-1.16) and congenital malformations (OR ajusted =1.11; CI 95% =1.05-1.17) were slightly increased., Conclusion: The results of this study on a large cohort of recent births in France confirm that there was an increased risk of maternal and perinatal morbidities in IVF. These risks were similar to those published in the international literature. This study is the starting point for a forthcoming surveillance., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

Background: Adjuvant chemotherapy (AC) after chemoradiation (CRT) and surgery for locoregionally advanced rectal cancer (LARC) is a standard of care in the United States. This study examined the role, optimal regimen, and duration of AC using data from the largest integrated health system in the United States., Patients and Methods: Using the Veterans Affairs Central Cancer Registry, patients with stage II-III rectal cancer diagnosed in 2001 through 2011 who received neoadjuvant CRT and surgery with or without AC were identified. Kaplan-Meier analysis, log-rank tests, and propensity score (PS) adjustment analysis were used to assess survival., Results: A total of 866 patients were identified; 417 received AC and 449 did not (observation [OBS] group). Median follow-up was 109 months. Median disease-specific survival (DSS) was not reached. Six-year DSS was 73.7%; 79.5% for the AC group versus 68.0% for the OBS group. PS-matched analysis for DSS favored AC (P=.0002). Median overall survival (OS) was 90.8 months. Six-year OS was 56.7%; 64.3% for AC versus 49.6% for OBS. In PS-matched analysis, median OS was 117.4 months for AC and 74.3 months for OBS (P<.0001). A DSS advantage was seen when comparing ≥4 months with <4 months of AC (P=.023). No difference in DSS or OS was seen with single-agent versus multiagent AC., Conclusions: In this population of patients with LARC treated with neoadjuvant CRT and surgery, OS and DSS were improved among those treated with AC versus OBS. DSS benefits were seen with ≥4 months of AC. No additional benefit was observed with multiagent therapy. In the absence of phase III data, these findings support the use of AC for LARC.

Research Question: Does fresh embryo transfer after IVF with or without intracytoplasmic sperm injection (ICSI) increase the small for gestational age (SGA) rate, and frozen embryo transfer (FET) after IVF with or without ICSI increase the large for gestational age (LGA) rate versus natural conception?, Design: Retrospective comparison of an exposed historical group/cohort involving singletons conceived after fresh embryo transfer and after FET with an unexposed group/cohort involving singletons conceived after a natural conception., Results: A total of 1961 fresh embryo transfer babies and 366 FET babies were compared with 6981 natural conception babies. The SGA rate in fresh embryo transfer babies was not significantly different to natural conception babies (6.9% versus 6.8%, P = 0.856). This outcome was not influenced by the fresh embryo transfer (adjusted odds ratio [aOR] 1.0; 95% confidence interval [CI] 0.8-1.3), but rather by a low rate of multiparity (aOR 0.5; 95% CI 0.3-0.7), advanced maternal age (aOR 1.1; 95% CI 1.0-1.2), maternal underweight (aOR 1.5; 95% CI 1.1-2.1), maternal smoking or cessation during pregnancy (aOR 1.8; 95% CI 1.4-2.3), pre-existing hypertension (aOR 2.3; 95% CI 1.3-4.1) and pregnancy-induced hypertension (aOR 2.5; 95% CI 1.7-3.7). The LGA rate in FET babies was significantly different from natural conception babies (6.6% versus 3.2%, P = 0.012). This outcome was influenced by the transfer of frozen embryos (aOR 2.2; 95% CI 1.3-3.8) and by a high maternal weight (aOR 1.9; 95% CI 1.1-3.6)., Conclusions: Maternal background and obstetric parameters are more likely to influence the SGA rate than fresh embryo transfer conception. FET conception could be associated with an increase in LGA rate., (Copyright © 2019 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.)

Formation of the solid electrolyte interphase (SEI) at the anode surface during the initial charge cycles is critical to lithium ion battery operability. Reduction of electrolyte components must ultimately result in the formation of this ionically conducting and electronically insulating layer to compensate for the limited electrochemical stability window of conventional liquid electrolytes. One important reaction in SEI formation is the bimolecular combination of radical anions to form more stable products. Molecular dynamics simulations illustrate the nature and dynamics of the intermolecular interactions between the reactive intermediates produced from one-electron reduction in ethylene carbonate-based electrolytes. A clear concentration dependence is shown for this interaction, and its ramifications for SEI formation are discussed.

Purpose: In the phase III FLAURA study, third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) osimertinib significantly improved progression-free survival (PFS) versus standard-of-care (SoC) EGFR-TKI (gefitinib or erlotinib) in patients with previously untreated EGFR (exon 19 deletion or L858R) mutation-positive advanced non-small cell lung cancer (NSCLC). Interim overall survival (OS) data were encouraging, but not formally statistically significant at current maturity (25%). Here we report exploratory postprogression outcomes., Patients and Methods: Patients were randomized 1:1 to receive osimertinib (80 mg orally, once daily) or SoC EGFR-TKI (gefitinib 250 mg or erlotinib 150 mg, orally, once daily). Treatment beyond disease progression was allowed if the investigator judged ongoing clinical benefit. Patients receiving SoC EGFR-TKI could cross over to receive osimertinib after independently confirmed objective disease progression with documented postprogression T790M-positive mutation status., Results: At data cutoff (June 12, 2017), 138 of 279 (49%) and 213 of 277 (77%) patients discontinued osimertinib and SoC EGFR-TKI, respectively, of whom 82 (59%) and 129 (61%), respectively, started a subsequent treatment. Median time to discontinuation of any EGFR-TKI or death was 23.0 months [95% confidence interval (CI), 19.5-not calculable (NC)] in the osimertinib arm and 16.0 months (95% CI, 14.8-18.6) in the SoC EGFR-TKI arm. Median second PFS was not reached (95% CI, 23.7-NC) in the osimertinib arm and 20.0 months (95% CI, 18.2-NC) in the SoC EGFR-TKI arm [hazard ratio (HR), 0.58; 95% CI, 0.44-0.78; P = 0.0004]., Conclusions: All postprogression endpoints showed consistent improvement with osimertinib versus SoC EGFR-TKI, providing further confidence in the interim OS data., (©2019 American Association for Cancer Research.)