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Contains fulltext : 241226.pdf (Publisher’s version ) (Closed access) BACKGROUND: Olaparib, a poly (ADP-ribose) polymerase (PARP) inhibitor, has previously been shown to extend progression-free survival versus placebo when given to patients with relapsed high-grade serous or endometrioid ovarian cancer who were platinum sensitive and who had a BRCA1 or BRCA2 (BRCA1/2) mutation, as part of the SOLO2/ENGOT-Ov21 trial. The aim of this final analysis is to investigate the effect of olaparib on overall survival. METHODS: This double-blind, randomised, placebo-controlled, phase 3 trial was done across 123 medical centres in 16 countries. Eligible patients were aged 18 years or older, had an Eastern Cooperative Oncology Group performance status at baseline of 0-1, had histologically confirmed, relapsed, high-grade serous or high-grade endometrioid ovarian cancer, including primary peritoneal or fallopian tube cancer, and had received two or more previous platinum regimens. Patients were randomly assigned (2:1) to receive olaparib tablets (300 mg in two 150 mg tablets twice daily) or matching placebo tablets using an interactive web or voice-response system. Stratification was by response to previous chemotherapy and length of platinum-free interval. Treatment assignment was masked to patients, treatment providers, and data assessors. The primary endpoint of progression-free survival has been reported previously. Overall survival was a key secondary endpoint and was analysed in all patients as randomly allocated. Safety was assessed in all patients who received at least one treatment dose. This trial is registered with ClinicalTrials.gov, NCT01874353, and is no longer recruiting patients. FINDINGS: Between Sept 3, 2013 and Nov 21, 2014, 295 patients were enrolled. Patients were randomly assigned to receive either olaparib (n=196 [66%]) or placebo (n=99 [34%]). One patient, randomised in error, did not receive olaparib. Median follow-up was 65·7 months (IQR 63·6-69·3) with olaparib and 64·5 months (63·4-68·7) with placebo. Median overall survival was 51·7 months (95% CI 41·5-59·1) with olaparib and 38·8 months (31·4-48·6) with placebo (hazard ratio 0·74 [95% CI 0·54-1·00]; p=0·054), unadjusted for the 38% of patients in the placebo group who received subsequent PARP inhibitor therapy. The most common grade 3 or worse treatment-emergent adverse event was anaemia (which occurred in 41 [21%] of 195 patients in the olaparib group and two [2%] of 99 patients in the placebo group). Serious treatment-emergent adverse events were reported in 50 (26%) of 195 patients receiving olaparib and eight (8%) of 99 patients receiving placebo. Treatment-emergent adverse events with a fatal outcome occurred in eight (4%) of the 195 patients receiving olaparib, six of which were judged to be treatment-related (attributed to myelodysplastic syndrome [n=3] and acute myeloid leukaemia [n=3]). INTERPRETATION: Olaparib provided a median overall survival benefit of 12·9 months compared with placebo in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation. Although statistical significance was not reached, these findings are arguably clinically meaningful and support the use of maintenance olaparib in these patients. FUNDING: AstraZeneca and Merck.

Background: Although most patients with epithelial ovarian cancer respond to frontline platinum-based chemotherapy, around 70% will relapse within 3 years. The phase 3 JAVELIN Ovarian 100 trial compared avelumab (anti-PD-L1 monoclonal antibody) in combination with chemotherapy followed by avelumab maintenance, or chemotherapy followed by avelumab maintenance, versus chemotherapy alone in patients with treatment-naive epithelial ovarian cancer. Methods: JAVELIN Ovarian 100 was a global, open-label, three-arm, parallel, randomised, phase 3 trial run at 159 hospitals and cancer treatment centres in 25 countries. Eligible women were aged 18 years and older with stage III–IV epithelial ovarian, fallopian tube, or peritoneal cancer (following debulking surgery, or candidates for neoadjuvant chemotherapy), and had an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients were randomly assigned (1:1:1) via interactive response technology to receive chemotherapy (six cycles; carboplatin dosed at an area under the serum-concentration-time curve of 5 or 6 intravenously every 3 weeks plus paclitaxel 175 mg/m2 every 3 weeks or 80 mg/m2 once a week [investigators' choice]) followed by avelumab maintenance (10 mg/kg intravenously every 2 weeks; avelumab maintenance group); chemotherapy plus avelumab (10 mg/kg intravenously every 3 weeks) followed by avelumab maintenance (avelumab combination group); or chemotherapy followed by observation (control group). Randomisation was in permuted blocks of size six and stratified by paclitaxel regimen and resection status. Patients and investigators were masked to assignment to the two chemotherapy groups without avelumab at the time of randomisation until completion of the chemotherapy phase. The primary endpoint was progression-free survival assessed by blinded independent central review in all randomly assigned patients (analysed by intention to treat). Safety was analysed in all patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, NCT02718417. The trial was fully enrolled and terminated at interim analysis due to futility, and efficacy is no longer being assessed. Findings: Between May 19, 2016 and Jan 23, 2018, 998 patients were randomly assigned (avelumab maintenance n=332, avelumab combination n=331, and control n=335). At the planned interim analysis (data cutoff Sept 7, 2018), prespecified futility boundaries were crossed for the progression-free survival analysis, and the trial was stopped as recommended by the independent data monitoring committee and endorsed by the protocol steering committee. Median follow-up for progression-free survival for all patients was 10·8 months (IQR 7·1–14·9); 11·1 months (7·0–15·3) for the avelumab maintenance group, 11·0 months (7·4–14·5) for the avelumab combination group, and 10·2 months (6·7–14·0) for the control group. Median progression-free survival was 16·8 months (95% CI 13·5–not estimable [NE]) with avelumab maintenance, 18·1 months (14·8–NE) with avelumab combination treatment, and NE (18·2 months–NE) with control treatment. The stratified hazard ratio for progression-free survival was 1·43 (95% CI 1·05–1·95; one-sided p=0·99) with the avelumab maintenance regimen and 1·14 (0·83–1·56; one-sided p=0·79) with the avelumab combination regimen, versus control treatment. The most common grade 3–4 adverse events were anaemia (69 [21%] patients in the avelumab maintenance group, 63 [19%] in the avelumab combination group, and 53 [16%] in the control group), neutropenia (91 [28%], 99 [30%], and 88 [26%]), and neutrophil count decrease (49 [15%], 45 [14%], and 59 [18%]). Serious adverse events of any grade occurred in 92 (28%) patients in the avelumab maintenance group, 118 (36%) in the avelumab combination group, and 64 (19%) in the control group. Treatment-related deaths occurred in one (

Treatment approaches for relapsed ovarian cancer have evolved over the past decade from a calendar-based decision tree to a patient-oriented biologically driven algorithm. Nowadays, platinum-based chemotherapy should be offered to all patients with a reasonable chance of responding to this therapy. The treatment-free interval for platinum is only one of many factors affecting patients' eligibility for platinum re-treatment. Bevacizumab increases the response to chemotherapy irrespective of the cytotoxic regimen and can be valuable in patients with an urgent need for symptom relief (e.g. pleural effusion, ascites). For patients with recurrent high-grade ovarian cancer, which responds to platinum-based treatment, maintenance therapy with a poly(ADP-ribose) polymerase inhibitor can be offered, regardless of the BRCA mutation status. Here we review contemporary decision-making processes in the systemic treatment of relapsed ovarian cancer.

Cytoreductive surgery is the mainstay of treatment for high-grade epithelial ovarian cancer. Although for early stage disease outcomes following surgery alone are good, the risk of recurrence necessitates adjuvant chemotherapy for the majority of patients. Post-operative chemotherapy in advanced-stage disease, or neoadjuvant chemotherapy followed by surgery has improved progression-free survival (PFS) and overall survival (OS). However, despite the use of chemotherapy, the rate of recurrence remains high. In recent years, there has been considerable increase in knowledge regarding the biology of ovarian cancer, which has led to a journey of drug discovery, facilitating the use of novel targeted agents such as VEGF inhibitors and, more recently, PARP inhibitors in the first-line treatment of ovarian cancer. Here, we outline the current evidence-based guidance for systemic therapies in ovarian cancer and highlight the ongoing research to improve patient outcomes.

During the COVID-19 pandemic, pressures on clinical services required adaptation to how care was prioritised and delivered for women with gynecological cancer. This document discusses potential ‘salvage’ measures when treatment has deviated from the usual standard of care. The British Gynaecological Cancer Society convened a multidisciplinary working group to develop recommendations for the onward management and follow-up of women with gynecological cancer who have been impacted by a change in treatment during the pandemic. These recommendations are presented for each tumor type and for healthcare systems, and the impact on gynecological services are discussed. It will be important that patient concerns about the impact of COVID-19 on their cancer pathway are acknowledged and addressed for their ongoing care.

Background There is limited evidence that fractional flow reserve (FFR) is effective in guiding therapeutic strategy in multivessel coronary artery disease (CAD) beyond prespecified percutaneous coronary intervention or coronary graft surgery candidates. Objectives The FUTURE (FUnctional Testing Underlying coronary REvascularization) trial aimed to evaluate whether a treatment strategy based on FFR was superior to a traditional strategy without FFR in the treatment of multivessel CAD. Methods The FUTURE trial is a prospective, randomized, open-label superiority trial. Multivessel CAD candidates were randomly assigned (1:1) to treatment strategy based on FFR in all stenotic (≥50%) coronary arteries or to a traditional strategy without FFR. In the FFR group, revascularization (percutaneous coronary intervention or surgery) was indicated for FFR ≤0.80 lesions. The primary endpoint was a composite of major adverse cardiac or cerebrovascular events at 1 year. Results The trial was stopped prematurely by the data safety and monitoring board after a safety analysis and 927 patients were enrolled. At 1-year follow-up, by intention to treat, there were no significant differences in major adverse cardiac or cerebrovascular events rates between groups (14.6% in the FFR group vs 14.4% in the control group; hazard ratio: 0.97; 95% confidence interval: 0.69-1.36; P = 0.85). The difference in all-cause mortality was nonsignificant, 3.7% in the FFR group versus 1.5% in the control group (hazard ratio: 2.34; 95% confidence interval: 0.97-5.18; P = 0.06), and this was confirmed with a 24 months’ extended follow-up. FFR significantly reduced the proportion of revascularized patients, with more patients referred to exclusively medical treatment (P = 0.02). Conclusions In patients with multivessel CAD, we did not find evidence that an FFR-guided treatment strategy reduced the risk of ischemic cardiovascular events or death at 1-year follow-up. (Functional Testing Underlying Coronary Revascularisation; NCT01881555 )

Background After an acute myocardial infarction (MI 2 ), patients may develop posttraumatic stress disorder (PTSD 3 ). There is evidence for alterations in the hypothalamic–pituitary–adrenal axis in PTSD. An association between patients` cortisol level after experiencing an MI and subsequent PTSD symptoms has not been investigated yet. Therefore, the aim of this study was to examine whether serum cortisol measured in patients admitted to hospital for acute coronary care after MI is predictive of PTSD symptoms at three and 12 months post-MI, respectively. Methods Patients (N=106) with a verified MI and high risk for the development of MI-induced PTSD symptoms were included in the study within 48 hours of hospital admission for acute coronary intervention. Serum cortisol was measured from fasting venous blood samples the next morning. Hierarchical regression analysis was used to test for an independent contribution of cortisol levels from admission to the Clinician-Administered PTSD Scale sum score three and 12 months after discharge from the coronary care unit. Results Hierarchical regression analysis showed that lower serum cortisol levels were significantly associated with more severe PTSD symptoms three months (B=-0.002, p=0.042) and 12 months (B=-0.002, p=0.043) post-MI. Limitations The generalizability of the findings is limited to patients with high acute peri-traumatic distress and without an acute severe depressive episode. The study does not provide any information about the diurnal cortisol pattern. Conclusion Lower serum cortisol measured during MI hospitalization may predict more severe MI-induced PTSD symptoms three and 12 months after hospital discharge.

Background The impact of maintenance therapy with PARP inhibitors (PARPi) on progression-free survival (PFS) in patients with BRCA mutations and platinum-sensitive recurrent ovarian cancer (PSROC) varies widely. Individual prognostic factors do not reliably distinguish patients who progress early from those who have durable benefit. We developed and validated a prognostic nomogram to predict PFS in these patients. Methods The nomogram was developed using data from a training patient cohort with BRCA mutations and high-grade serous PSROC on the placebo arm of two maintenance therapy trials, Study 19 and SOLO2/ENGOT-ov21. We performed multivariable Cox regression analysis based on pre-treatment characteristics to develop a nomogram that predicts PFS. We assessed the discrimination and validation of the nomogram in independent validation patient cohorts treated with maintenance olaparib. Results The nomogram includes four PFS predictors: CA-125 at randomisation, platinum-free interval, presence of measurable disease and number of prior lines of platinum therapy. In the training (placebo) cohort (internal validation C-index 0.64), median PFS in the model-predicted good, intermediate and poor-risk groups was: 7.7 (95% CI 5.3–11.3), 5.4 (4.8–5.8) and 2.9 (2.8–4.4) months, respectively. In the validation (olaparib) cohort (C-index 0.71), median PFS in the model-predicted good, intermediate and poor-risk groups was: not reached, 16.6 (13.1–22.4) and 8.3 (7.1–10.8) months, respectively. The nomogram showed good calibration in the validation cohort (calibration plot). Conclusions This nomogram can be used to predict PFS and counsel patients with BRCA mutations and PSROC prior to maintenance olaparib and for stratification of patients in trials of maintenance therapies.

Summary Background Most patients with ovarian cancer will relapse after receiving frontline platinum-based chemotherapy and eventually develop platinum-resistant or platinum-refractory disease. We report results of avelumab alone or avelumab plus pegylated liposomal doxorubicin (PLD) compared with PLD alone in patients with platinum-resistant or platinum-refractory ovarian cancer. Methods JAVELIN Ovarian 200 was an open-label, parallel-group, three-arm, randomised, phase 3 trial, done at 149 hospitals and cancer treatment centres in 24 countries. Eligible patients were aged 18 years or older with epithelial ovarian, fallopian tube, or peritoneal cancer (maximum of three previous lines for platinum-sensitive disease, none for platinum-resistant disease) and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients were randomly assigned (1:1:1) via interactive response technology to avelumab (10 mg/kg intravenously every 2 weeks), avelumab plus PLD (40 mg/m2 intravenously every 4 weeks), or PLD and stratified by disease platinum status, number of previous anticancer regimens, and bulky disease. Primary endpoints were progression-free survival by blinded independent central review and overall survival in all randomly assigned patients, with the objective to show whether avelumab alone or avelumab plus PLD is superior to PLD. Safety was assessed in all patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov , NCT02580058 . The trial is no longer enrolling patients and this is the final analysis of both primary endpoints. Findings Between Jan 5, 2016, and May 16, 2017, 566 patients were enrolled and randomly assigned (combination n=188; PLD n=190, avelumab n=188). At data cutoff (Sept 19, 2018), median duration of follow-up for overall survival was 18·4 months (IQR 15·6–21·9) for the combination group, 17·4 months (15·2–21·3) for the PLD group, and 18·2 months (15·8–21·2) for the avelumab group. Median progression-free survival by blinded independent central review was 3·7 months (95% CI 3·3–5·1) in the combination group, 3·5 months (2·1–4·0) in the PLD group, and 1·9 months (1·8–1·9) in the avelumab group (combination vs PLD: stratified HR 0·78 [repeated 93·1% CI 0·59–1·24], one-sided p=0·030; avelumab vs PLD: 1·68 [1·32–2·60], one-sided p>0·99). Median overall survival was 15·7 months (95% CI 12·7–18·7) in the combination group, 13·1 months (11·8–15·5) in the PLD group, and 11·8 months (8·9–14·1) in the avelumab group (combination vs PLD: stratified HR 0·89 [repeated 88·85% CI 0·74–1·24], one-sided p=0·21; avelumab vs PLD: 1·14 [0·95–1·58], one-sided p=0·83]). The most common grade 3 or worse treatment-related adverse events were palmar-plantar erythrodysesthesia syndrome (18 [10%] in the combination group vs nine [5%] in the PLD group vs none in the avelumab group), rash (11 [6%] vs three [2%] vs none), fatigue (ten [5%] vs three [2%] vs none), stomatitis (ten [5%] vs five [3%] vs none), anaemia (six [3%] vs nine [5%] vs three [2%]), neutropenia (nine [5%] vs nine [5%] vs none), and neutrophil count decreased (eight [5%] vs seven [4%] vs none). Serious treatment-related adverse events occurred in 32 (18%) patients in the combination group, 19 (11%) in the PLD group, and 14 (7%) in the avelumab group. Treatment-related adverse events resulted in death in one patient each in the PLD group (sepsis) and avelumab group (intestinal obstruction). Interpretation Neither avelumab plus PLD nor avelumab alone significantly improved progression-free survival or overall survival versus PLD. These results provide insights for patient selection in future studies of immune checkpoint inhibitors in platinum-resistant or platinum-refractory ovarian cancer. Funding Pfizer and Merck KGaA, Darmstadt, Germany.

In recent years emotional labor (EL) and its relationship with organizational outcomes such as job satisfaction and job performance has become an area of burgeoning research interest in work and organizational psychology manifesting in a growth of published articles (Grandey, Diefendorff, & Rupp, 2013, p. 5). In the 80s, Hochschild coined the differentiation between the strategies deep acting and surface acting (Hochschild, 1983). On the one hand, there is the assumption that deep acting, as a strategy that actually modifies the way of feeling, is rather adaptive for organizational outcomes while surface acting, as a strategy that focuses only on the modification of the facial expression, is maladaptive (Chi, Grandey, Diamond, & Krimmel, 2011; Humphrey, Ashforth, & Diefendorff, 2015). On the other hand, recent metanalytical findings indicate that the direct relationship between both EL strategies and job performance is low (Hülsheger & Schewe, 2011; Kammeyer‐Mueller et al., 2013; Mesmer-Magnus, DeChurch, & Wax, 2012). Taking these heterogenous findings as an indicator for a more complex relationship between EL and organizational outcomes, Grandey (2000) suggested to consider supplementing the EL findings by the findings of the emotion regulation (ER) research. ER research is coined by Gross in the 90’s (Gross, 1998) and has in common with EL research that it investigates how individuals take influence on their emotions triggered at an event-level. The research fields complement one another in so far as EL focusses on the relationships to constructs at a work context-level (e.g. job performance, autonomy) while ER focusses on relationships to constructs at a person-level (e.g. wellbeing) (Grandey & Melloy, 2017). Assuming that there is an overlap between EL and ER and an interaction between these levels, Grandey and Melloy (2017) postulated a model integrating EL and ER research findings that considers personal-level, work context-level and event-level constructs. To become precisely, the model describes a relationship between EL (event-level) and job satisfaction (personal level) and between EL and job performance (work context-level) moderated by autonomy (work context-level) and social support (work context-level) and mediated by goal achievement. Goal achievement as a mediator is assumed to represent the immediate success of the regulation process at an event level (Wong, Tschan, & Semmer, 2017). The immediate success can be either a result of achieving a hedonic goal by feeling the desired emotional state or it can be a result of achieving an instrumental goal by expressing the desired emotional state with regard to interpersonal interactions (Tamir, 2016). Work context factors such as autonomy and social support are assumed to moderate the relationship EL and goal achievement in such a way that the positive relationship will be stronger for employees perceiving more autonomy and social support (Grandey & Diamond, 2010). Furthermore, Grandey and Melloy (2017) postulate there is a relationship between the selected EL strategy and the type of the triggering event. This relationship is focused in ER research by investigating the concept of emotion regulation flexibility (ERF) (Bonanno, Papa, Lalande, Westphal, & Coifman, 2004; Cheng, Lau, & Chan, 2014). ERF means to adapt the selection of emotion regulation strategies (ERS) to situational demands and it is recommended to measure it ambulatory using the ecological momentary assessment (EMA) method (Aldao, Sheppes, & Gross, 2015; Doré, Silvers, & Ochsner, 2016). Considering as well the research questions resulting from the theoretical framework of Grandey and Melloy (2017) as the method recommended by Aldao et al. (2015), provides an innovative perspective for investigating the relationship between EL and organizational outcomes. However, to our knowledge, the combination of the described research question and study design has not been investigated, yet. So, the present study represents a pilot study in this field and aims to investigate the relationship between flexible EL and job satisfaction as well as the relationship between flexible EL and job performance postulating a mediating effect of goal achievement and a moderating effect of work context factors (autonomy and social support) by the use of EMA method. Research Questions 1. To what extent does goal achievement mediate the relationship between flexible emotional labor and students’ satisfaction and is the relationship between flexible emotional labor und students’ satisfaction moderated by autonomy and social support? 2. To what extent does goal achievement mediate the relationship between flexible emotional labor and students’ performance and is the relationship between flexible emotional labor und students’ performance moderated by autonomy and social support?

The aim of this study was to analyse the rates of metastatic events and clinical outcomes of patients with adenoid cystic carcinoma (ACC) of the minor salivary glands and to critically evaluate the role of surgical therapy. A retrospective cohort study was designed including all patients with ACC of the oral minor salivary glands treated in the study department during the years 2010-2017. Relevant clinicopathological data were analysed to determine factors with an impact on overall survival (OS) and progression-free survival (PFS). Forty-one patients with primary ACC of the oral cavity and the oropharynx were included. Cervical metastases were found in 14 patients (34.1%) and were shown to have a significant negative impact on OS (P=0.009) and PFS (P=0.03). Sixteen patients developed disease recurrence during follow-up (39.0%) and most patients exhibited local disease recurrence with or without regional or distant metastases (14/16, 87.5%). Local recurrence was treated successfully with surgery in five cases. We recommend surgical therapy for patients with ACC of the minor salivary glands, including elective neck dissection and microvascular reconstruction, to optimize the planning of adjuvant therapy.

The Chilean Abbe Ignacio Molina (1740-1829) developed a brilliant career as naturalist in the University of Bologna, where he arrived when the Jesuit Order was expelled from the Spanish colonies in 1767, until he was accused of heresy because some ideas about evolution expressed in one of his late works, at the same time with Lamarck and 44 years before Darwin. In his youth Molina was affected in a severe way by smallpox, leaving us in two poems a vivid story of his suffering, not only by the disease itself but also for the useless therapeutic measures, some disagreeable, like enemas; other injurious, as bleeding and topic vinegar of the four thieves. A handful of the more significant verses from the two Latin Elegies "De peste variolarum" and "De peste variolis vulgo dicta" is analyzed: its literary value is scarce, its reading is bored, and its real merit only historic.

We investigated the safety and efficacy of a combination of the oral tyrosine kinase inhibitor, nintedanib (BIBF 1120) with oral cyclophosphamide in patients with relapsed ovarian cancer.Patients with relapsed ovarian, fallopian tube or primary peritoneal cancer received oral cyclophosphamide (100 mg o.d.) and were randomised (1,1) to also have either oral nintedanib or placebo. The primary endpoint was overall survival (OS). Secondary endpoints included progression free survival (PFS), response rate, toxicity, and quality of life.117 patients were randomised, 3 did not start trial treatment, median age 64 years. Forty-five (39%) had received ≥5 lines chemotherapy. 30% had received prior bevacizumab. The median OS was 6.8 (nintedanib) versus 6.4 (placebo) months (hazard ratio 1.08; 95% confidence interval 0.72-1.62; P = 0.72). The 6-month PFS rate was 29.6% versus 22.8% (P = 0.57). Grade 3/4 adverse events occurred in 64% (nintedanib) versus 54% (placebo) of patients (P = 0.28); the most frequent G3/4 toxicities were lymphopenia (18.6% nintedanib versus 16.4% placebo), diarrhoea (13.6% versus 0%), neutropenia (11.9% versus 0%), fatigue (10.2% versus 9.1%), and vomiting (10.2% versus 7.3%). Patients who had received prior bevacizumab treatment had 52 days less time on treatment (P 0.01). 26 patients (23%) took oral cyclophosphamide for ≥6 months. There were no differences in quality of life between treatment arms.This is the largest reported cohort of patients with relapsed ovarian cancer treated with oral cyclophosphamide. Nintedanib did not improve outcomes when added to oral cyclophosphamide. Although not significant, more patients than expected remained on treatment for ≥6 months. This may reflect a higher proportion of patients with more indolent disease or the higher dose of cyclophosphamide used.Clinicaltrials.govNCT01610869.

Background Homologous recombination repair deficiency (HRD) is a frequent feature of high-grade serous ovarian, fallopian tube and peritoneal carcinoma (HGSC) and is associated with sensitivity to PARP inhibitor (PARPi) therapy. HRD testing provides an opportunity to optimise PARPi use in HGSC but methodologies are diverse and clinical application remains controversial. Materials and methods To define best practice for HRD testing in HGSC the ESMO Translational Research and Precision Medicine Working Group launched a collaborative project that incorporated a systematic review approach. The main aims were to (i) define the term 'HRD test'; (ii) provide an overview of the biological rationale and the level of evidence supporting currently available HRD tests; (iii) provide recommendations on the clinical utility of HRD tests in clinical management of HGSC. Results A broad range of repair genes, genomic scars, mutational signatures and functional assays are associated with a history of HRD. Currently, the clinical validity of HRD tests in ovarian cancer is best assessed, not in terms of biological HRD status per se, but in terms of PARPi benefit. Clinical trials evidence supports the use of BRCA mutation testing and two commercially available assays that also incorporate genomic instability for identifying subgroups of HGSCs that derive different magnitudes of benefit from PARPi therapy, albeit with some variation by clinical scenario. These tests can be used to inform treatment selection and scheduling but their use is limited by a failure to consistently identify a subgroup of patients who derive no benefit from PARPis in most studies. Existing tests lack negative predictive value and inadequately address the complex and dynamic nature of the HRD phenotype. Conclusions Currently available HRD tests are useful for predicting likely magnitude of benefit from PARPis but better biomarkers are urgently needed to better identify current homologous recombination proficiency status and stratify HGSC management.

Background The efficacy and safety of rucaparib maintenance treatment in ARIEL3 were evaluated in subgroups based on best response to most recent platinum‐based chemotherapy and baseline disease. Methods Patients were randomized 2:1 to receive either oral rucaparib at a dosage of 600 mg twice daily or placebo. Investigator‐assessed PFS was assessed in prespecified, nested cohorts: BRCA‐mutated, homologous recombination deficient (HRD; BRCA mutated or wild‐type BRCA/high loss of heterozygosity), and the intent‐to‐treat (ITT) population. Results Median PFS for patients in the ITT population with a complete response to most recent platinum‐based chemotherapy was 11.1 months in the rucaparib arm (126 patients) versus 5.6 months in the placebo arm (64 patients) (HR, 0.33 [95% CI, 0.23–0.48]), and in patients with a partial response (249 vs. 125), it was 9.0 versus 5.3 months (HR, 0.38 [0.30–0.49]). In subgroups of the ITT population based on baseline disease, median PFS was 8.2 versus 5.3 months (HR, 0.40 [0.28–0.57]) in patients with measurable disease (141 rucaparib vs. 66 placebo), 10.4 versus 4.5 months (HR, 0.31 [0.20–0.48]) in those with nonmeasurable but evaluable disease (104 vs. 56), and 14.1 versus 7.3 months (HR, 0.35 [0.24–0.51]) in those with no residual disease (130 vs. 67). Across subgroups, significantly longer median PFS was observed with rucaparib versus placebo in the BRCA‐mutated and HRD cohorts. Objective responses were reported in patients with measurable disease and in patients with nonmeasurable but evaluable baseline disease. Safety was consistent across subgroups. Conclusion Rucaparib maintenance treatment provided clinically meaningful efficacy benefits across subgroups based on response to last platinum‐based chemotherapy or baseline disease., The efficacy and safety of the PARP inhibitor rucaparib as maintenance treatment for recurrent ovarian cancer were similar regardless of whether patients had a complete or partial response to their last platinum‐based chemotherapy or according to whether they had measurable, nonmeasurable but evaluable, or no residual disease at baseline. Rucaparib also reduced the disease burden in patients who had measurable or nonmeasurable but evaluable disease at baseline.

IntroductionIn ARIEL3 (NCT01968213), the poly(adenosine diphosphate-ribose) polymerase inhibitor rucaparib significantly improved progression-free survival versus placebo regardless of biomarker status when used as maintenance treatment for recurrent ovarian cancer. The aim of the current analyses was to evaluate the efficacy and safety of rucaparib in subgroups based on progression-free interval following penultimate platinum, number of prior chemotherapies, and prior use of bevacizumab.MethodsPatients were randomized 2:1 to rucaparib 600 mg twice daily or placebo. Within subgroups, progression-free survival was assessed in prespecified, nested cohorts: BRCA-mutant, homologous recombination deficient (BRCA-mutant or wild-type BRCA/high genomic loss of heterozygosity), and the intent-to-treat population.ResultsIn the intent-to-treat population, median investigator-assessed progression-free survival was 8.2 months with rucaparib versus 4.1 months with placebo (n=151 vs n=76; HR 0.33, 95% CI 0.24 to 0.46, p12 months. Median progression-free survival was 10.4 versus 5.4 months (n=231 vs n=124; HR 0.42, 95% CI 0.32 to 0.54, pBRCA-mutant and homologous recombination deficient cohorts. Safety was consistent across subgroups.ConclusionsRucaparib maintenance treatment significantly improved progression-free survival versus placebo irrespective of progression-free interval following penultimate platinum, number of lines of prior chemotherapy, and previous use of bevacizumab.

BACKGROUND:The PORTEC-3 trial investigated the benefit of combined adjuvant chemotherapy and radiotherapy versus pelvic radiotherapy alone for women with high-risk endometrial cancer. We updated the analysis to investigate patterns of recurrence and did a post-hoc survival analysis.METHODS:In the multicentre randomised phase 3 PORTEC-3 trial, women with high-risk endometrial cancer were eligible if they had International Federation of Gynaecology and Obstetrics (FIGO) 2009 stage I, endometrioid grade 3 cancer with deep myometrial invasion or lymphovascular space invasion, or both; stage II or III disease; or stage I-III disease with serous or clear cell histology; were aged 18 years and older; and had a WHO performance status of 0-2. Participants were randomly assigned (1:1) to receive radiotherapy alone (48·6 Gy in 1·8 Gy fractions given on 5 days per week) or chemoradiotherapy (two cycles of cisplatin 50 mg/m2 given intravenously during radiotherapy, followed by four cycles of carboplatin AUC5 and paclitaxel 175 mg/m2 given intravenously), by use of a biased coin minimisation procedure with stratification for participating centre, lymphadenectomy, stage, and histological type. The co-primary endpoints were overall survival and failure-free survival. Secondary endpoints of vaginal, pelvic, and distant recurrence were analysed according to the first site of recurrence. Survival endpoints were analysed by intention-to-treat, and adjusted for stratification factors. Competing risk methods were used for failure-free survival and recurrence. We did a post-hoc analysis to analyse patterns of recurrence with 1 additional year of follow-up. The study was closed on Dec 20, 2013; follow-up is ongoing. This study is registered with ISRCTN, number ISRCTN14387080, and ClinicalTrials.gov, number NCT00411138.FINDINGS:Between Nov 23, 2006, and Dec 20, 2013, 686 women were enrolled, of whom 660 were eligible and evaluable (330 in the chemoradiotherapy group, and 330 in the radiotherapy-alone group). At a median follow-up of 72·6 months (IQR 59·9-85·6), 5-year overall survival was 81·4% (95% CI 77·2-85·8) with chemoradiotherapy versus 76·1% (71·6-80·9) with radiotherapy alone (adjusted hazard ratio [HR] 0·70 [95% CI 0·51-0·97], p=0·034), and 5-year failure-free survival was 76·5% (95% CI 71·5-80·7) versus 69·1% (63·8-73·8; HR 0·70 [0·52-0·94], p=0·016). Distant metastases were the first site of recurrence in most patients with a relapse, occurring in 78 of 330 women (5-year probability 21·4%; 95% CI 17·3-26·3) in the chemoradiotherapy group versus 98 of 330 (5-year probability 29·1%; 24·4-34·3) in the radiotherapy-alone group (HR 0·74 [95% CI 0·55-0·99]; p=0·047). Isolated vaginal recurrence was the first site of recurrence in one patient (0·3%; 95% CI 0·0-2·1) in both groups (HR 0·99 [95% CI 0·06-15·90]; p=0·99), and isolated pelvic recurrence was the first site of recurrence in three women (0·9% [95% CI 0·3-2·8]) in the chemoradiotherapy group versus four (0·9% [95% CI 0·3-2·8]) in the radiotherapy-alone group (HR 0·75 [95% CI 0·17-3·33]; p=0·71). At 5 years, only one grade 4 adverse event (ileus or obstruction) was reported (in the chemoradiotherapy group). At 5 years, reported grade 3 adverse events did not differ significantly between the two groups, occurring in 16 (8%) of 201 women in the chemoradiotherapy group versus ten (5%) of 187 in the radiotherapy-alone group (p=0·24). The most common grade 3 adverse event was hypertension (in four [2%] women in both groups). At 5 years, grade 2 or worse adverse events were reported in 76 (38%) of 201 women in the chemoradiotherapy group versus 43 (23%) of 187 in the radiotherapy-alone group (p=0·002). Sensory neuropathy persisted more often after chemoradiotherapy than after radiotherapy alone, with 5-year rates of grade 2 or worse neuropathy of 6% (13 of 201 women) versus 0% (0 of 187). No treatment-related deaths were reported.INTERPRETATION:This updated analysis shows significantly improved overall survival and failure-free survival with chemoradiotherapy versus radiotherapy alone. This treatment schedule should be discussed and recommended, especially for women with stage III or serous cancers, or both, as part of shared decision making between doctors and patients. Follow-up is ongoing to evaluate long-term survival.FUNDING:Dutch Cancer Society, Cancer Research UK, National Health and Medical Research Council, Project Grant, Cancer Australia Grant, Italian Medicines Agency, and the Canadian Cancer Society Research Institute.

OBJECTIVE: Niraparib is a poly(ADP-ribose) polymerase (PARP) inhibitor approved for use in heavily pretreated patients and as maintenance treatment in patients with newly-diagnosed or recurrent ovarian cancer following a response to platinum-based chemotherapy. We present long-term safety data for niraparib from the ENGOT-OV16/NOVA trial. METHODS: This multicenter, double-blind, randomized, controlled phase III trial evaluated the efficacy and safety of niraparib for the treatment of recurrent ovarian cancer. Patients were randomly assigned 2:1 to receive either once-daily niraparib 300 mg or placebo. Two independent cohorts were enrolled based on germline BRCA mutation status. The primary endpoint was progression-free survival, reported previously. Long-term safety data were from the most recent data cutoff (September 2017). RESULTS: Overall, 367 patients received niraparib 300 mg once daily. Dose reductions due to TEAEs were highest in month 1 (34%) and declined every month thereafter. Incidence of any-grade and grade ≥ 3 hematologic and symptomatic TEAEs was also highest in month 1 and subsequently declined. Incidence of grade ≥ 3 thrombocytopenia decreased from 28% (month 1) to 9% and 5% (months 2 and 3, respectively), with protocol-directed dose interruptions and/or reductions. Acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) were reported in 2 and 6 niraparib-treated patients, respectively, and in 1 placebo patient each. Treatment discontinuations due to TEAEs were

The SARS-CoV-2 infection (COVID-19), originally reported in Wuhan, China, has rapidly proliferated throughout several continents and the first case in the United States was reported on January 19, 2020. According to the ACR guidelines issued shortly after this disease was declared a pandemic, radiologists are expected to familiarize themselves with the CT appearance of COVID-19 infection in order to be able to identify specific findings of this entity. This case report discusses the relevant imaging findings of one of the first cases in the mid-western United States. It involves a 60-year-old man who presented with fever, dyspnea, and cough for 1 week and subsequently tested positive for COVID-19. The utility of the noncontrast CT chest in the diagnosis of COVID-19 has been controversial, but there are specific imaging findings that have been increasingly associated with this virus in the appropriate clinical context. The stages of imaging findings in COVID-19 are considered along with the implications of fibrosis throughout the stages. Future considerations include using artificial intelligence algorithms to distinguish between community acquired pneumonias and COVID-19 infection.

Summary Background The ICON8 study reported no significant improvement in progression-free survival (a primary endpoint) with weekly chemotherapy compared with standard 3-weekly treatment among patients with epithelial ovarian cancer. All ICON8 patients were eligible to take part in the accompanying health-related quality-of-life study, which measured the effect of treatment on self-reported wellbeing, reported here. Methods In this open-label, randomised, controlled, phase 3, three-arm, Gynecologic Cancer Intergroup (GCIG) trial done at 117 hospital sites in the UK, Australia, New Zealand, Mexico, South Korea, and Republic of Ireland, women (aged at least 18 years) with newly diagnosed, histologically confirmed International Federation of Gynecology and Obstetrics stage IC–IV ovarian cancer and an Eastern Cooperative Oncology Group performance status of 0–2 were randomly assigned (1:1:1) centrally using minimisation to group 1 (intravenous carboplatin area under the curve [AUC]5 or AUC6 and 175 mg/m2 intravenous paclitaxel every 3 weeks), group 2 (carboplatin AUC5 or AUC6 every 3 weeks and 80 mg/m2 paclitaxel weekly), or group 3 (carboplatin AUC2 weekly and 80 mg/m2 paclitaxel weekly). Randomisation was stratified by GCIG group, disease stage, and outcome and timing of surgery. Patients and clinicians were not masked to treatment assignment. Patients underwent immediate or delayed primary surgery according to clinicians' choice. Patients were asked to complete European Organisation for Research and Treatment of Cancer QLQ-C30 and QLQ-OV28 questionnaires at enrolment, before each chemotherapy cycle, then 6-weekly up to 9 months, 3-monthly up to 2 years, and 6-monthly up to 5 years. Quality of life was a prespecified secondary outcome of the ICON8 study. Within the quality-of-life study, the co-primary endpoints were QLQ-C30 global health score at 9 months (cross-sectional analysis) and mean QLQ-C30 global health score from randomisation to 9 months (longitudinal analysis). Data analyses were done on an intention-to-treat basis. The trial is registered on ClinicalTrials.gov , NCT01654146 and ISRCTN Registry, ISRCTN10356387, and is currently in long-term follow up. Findings Between June 6, 2011, and Nov 28, 2014, 1566 patients were recruited into ICON8 (522 were included in group 1, 523 in group 2, and 521 in group 3). Baseline quality-of-life questionnaires were completed by 1438 (92%) of 1566 patients and 9-month questionnaires by 882 (69%) of 1280 patients. We observed no significant difference in global health score at 9 months (cross-sectional analysis) between study groups (group 2 vs group 1, difference in mean score 2·3, 95% CI −0·4 to 4·9, p=0·095; group 3 vs group 1, −0·8, −3·8 to 2·2, p=0·61). Using longitudinal analysis, we found lower global health scores for those receiving weekly paclitaxel than for those receiving 3-weekly chemotherapy (group 2 vs group 1, mean difference −1·8, 95% CI −3·6 to −0·1, p=0·043; group 3 vs group 1, −2·9, −4·7 to −1·1, p=0·0018). Interpretation We found no evidence of a difference in global quality of life between treatment groups at 9 months; however, patients receiving weekly treatment reported lower mean quality of life across the 9-month period after randomisation. Taken together with the lack of progression-free survival benefit, these findings do not support routine use of weekly paclitaxel-containing regimens in the management of newly diagnosed ovarian cancer. Funding Cancer Research UK, Medical Research Council, Health Research Board Ireland, Irish Cancer Society, and Cancer Australia.

BackgroundImprovement in clinical outcomes of patients with platinum-resistant disease is an unmet medical need and trials in this population are urgently needed. Checkpoint-inhibitors have already shown activity in multiple other tumor entities and ovarian cancer, especially in the combination with anti-angiogenic treatment.Primary objectiveTo test if the activity of non-platinum-based chemotherapy and bevacizumab could be improved by the addition of atezolizumab.Study hypothesisThe addition of atezolizumab to standard non-platinum combination of chemotherapy and bevacizumab improves median overall survival from 15 to 20 months.Trial designPatients are randomized to chemotherapy (paclitaxel weekly or pegylated liposomal doxorubicin) + bevacizumab + placebo vs chemotherapy + bevacizumab + atezolizumab. Stratification factors are: number of prior lines, planned type of chemotherapy, prior use of bevacizumab, and tumor programmed death-ligand 1 (PD-L1) status.Major inclusion/exclusion criteriaRecurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer with up to three prior therapies and a treatment-free interval after platinum of less than 6 months. Patients with three prior lines of chemotherapy are eligible irrespective of the platinum free-interval. A de novo tumor tissue sample biopsy for determination of PD-L1 status prior to randomization for stratification is mandatory. Major exclusion criteria consider bevacizumab-specific and immunotherapy-specific criteria.Primary endpointOverall survival and progression-free survival are co-primary endpoints.Sample sizeIt is planned to randomize 664 patients.Trial registrationNCT03353831.

CNES develops its spacecraft-oriented tool named PAMPERO since 2013. PAMPERO aims to simulate the complete atmospheric reentry of a spacecraft including the fragmentation and ablation processes. One of its objectives is to provide a support to experts using current certification tools such as DEBRISK, in which the user needs to pre-fragment the space vehicle. The purpose of this paper is to describe the rebuilding of two destructive tests of aluminium honeycomb sandwich panels performed at TsAGI. A detailed analysis of modelling simplifications of honeycomb structures is presented.

A interferência do ser humano sobre o meio ambiente, tem causado impactos negativos, aumentando as discussões acerca de ações que visem o equilíbrio da preservação ambiental, melhoria das condições sociais e a manutenção do desempenho econômico e financeiro positivo, buscando não comprometer a qualidade de vida da população atual e futura do planeta. Com isso objetiva-se verificar o comportamento de uma indústria metal mecânica com relação as condutas econômicas, ambientais e sociais adotadas com base no modelo ECT-Triplo de Abreu et al., (2008). Para tanto tem-se uma pesquisa descritiva, estudo de campo e quantitativa. Para a realização dessa pesquisa utilizou-se para a coleta de dados coletados o questionários com questões fechadas e abertas com 32 colaboradores (funcionários) de uma indústria metal mecanica. Os resultados indicam que a empresa analisada apresenta desempenho triplo , prosposto por Abreu et al. (2008), decorrente de suas atividades econômicas, ambientais e sociais, sendo que a análise desses indicadores possibilitaram identificar o posicionamento estratégico com relação as ações sócio ambientais da empresa, verificando o efeito de suas ações estratégicas no resultado econômico financeiro. Palavras chaves: Gestão. Sustentabilidade. Social e Ambiental. ECP-Triplo. Desenvolvimento Sustentável.

The National Cancer Survivorship Initiative through the National Health Service (NHS) improvement in the UK started the implementation of stratified pathways of patient-initiated follow-up (PIFU) across various tumor types. Now the initiative is continued through the Living With and Beyond Cancer program by NHS England. Evidence from non-randomized studies and systematic reviews does not demonstrate a survival advantage to the long-established practice of hospital-based follow-up regimens, traditionally over 5 years. Evidence shows that patient needs are inadequately met under the traditional follow-up programs and there is therefore an urgent need to adapt pathways to the needs of patients. The assumption that hospital-based follow-up is able to detect cancer recurrences early and hence improve patient prognosis has not been validated. A recent survey demonstrates that follow-up practice across the UK varies widely, with telephone follow-up clinics, nurse-led clinics and PIFU becoming increasingly common. There are currently no completed randomized controlled trials in PIFU in gynecological malignancies, although there is a drive towards implementing PIFU. PIFU aims to individualize patient care, based on risk of recurrence and holistic needs, and optimizing resources. The British Gynaecological Cancer Society wishes to provide the gynecological oncology community with guidance and a recommendations statement regarding the value, indications, and limitations of PIFU in endometrial, cervical, ovarian, and vulvar cancers in an effort to standardize practice and improve patient care. [Abstract copyright: © IGCS and ESGO 2020. No commercial re-use. See rights and permissions. Published by BMJ.]

Marzipan is a mixture of almonds, sugar, and water. Almonds can be replaced by apricot kernels, which results in a similar product called persipan. Depending on the prices of almonds, profit can be maximized using apricot kernels instead of almonds. If not specified on the product, this kind of substitution is illegal and is prosecuted by official food control authorities. Likewise, also commercial buyers would like to know which product they bought. Real-time PCR systems for the determination of apricot DNA are already available, however, real-time PCR requires the use of external standards, which have a direct impact on the accuracy of the measurement. Currently, such standards are not available. In contrast to real-time PCR, digital PCR does not require external standards and exhibits a smaller measurement uncertainty as shown in recent publications. Therefore, we developed a duplex droplet digital PCR system to measure the proportion of apricot in marzipan without the use of external standards. We present validation data and results of an international proficiency test, underlining the applicability of this system.

INTRODUCTION The ultimate goal for any surgical simulation program is to prove the capability of transferring the skills learned to real-life surgical scenarios. We designed an arthroscopic partial meniscectomy (APM) training program and sought to determine its ability to transfer skills to real patients. METHODS Eleven junior orthopaedic residents and three expert knee surgeons were included. A low-fidelity knee simulator was used. Trainees had two baseline assessments of completing APM on a supervised real patient and on the simulator, measured using the Arthroscopic Surgical Skill Evaluation Tool (ASSET). After baseline, the trainees completed an APM training program and had a final evaluation of proficiency on the simulator and in real patients. Experts were also assessed for comparison. Statistical analysis was performed, assuming nonparametric behavior of variables. RESULTS All trainees improved from a base score of 14 points in real patients and 10 points on the simulator to a final score of 39 points and 36 points, respectively (P < 0.01). The final trainee simulator score did not differ from experts on the simulator and was lower in real patients (36 versus 39 points, respectively, P ≤ 0.01), which resulted in a 92% transfer ratio for the simulator. DISCUSSION Simulated training of APM in orthopaedic residents using a low-fidelity knee simulator proved to not only improve simulated proficiency but also successfully transfer skills to a real clinical scenario with a high model transfer ratio. LEVEL OF EVIDENCE Level II (Prospective Cohort Study).

Highlights • Japanese encephalitis (JE) is largely preventable through vaccination. • Several JE vaccines prequalified by World Health Organization are available. • Hospital-based surveillance were conducted in Bangladesh to describe JE epidemiology. • JE cases were identified each year, among all age groups, and from a widespread geographical area. • Routine childhood immunization program or mass vaccination need to be examined., Background Japanese encephalitis (JE) virus is recognized as a major cause of encephalitis in Bangladesh. The World Health Organization (WHO) recommends human immunization as the most effective means to control JE. Several WHO-prequalified vaccines are available to prevent JE but no vaccination program has been implemented in Bangladesh. Methods We conducted hospital-based surveillance for acute meningitis-encephalitis syndrome (AMES) to describe JE epidemiology and help inform policy decisions about possible immunization strategies for Bangladesh. Results During 2007–2016, a total of 6543 AMES patients were identified at four tertiary hospitals. Of the 6525 patients tested, 548 (8%) were classified as JE cases. These 548 patients resided in 36 (56%) out of 64 districts of Bangladesh, with the highest proportion of JE cases among AMES patients (12% and 7%) presenting at two hospitals in the northwestern part of the country. The median age of JE cases was 30 years, and 193 (35%) were aged ≤15 years. The majority of JE cases (80%) were identified from July through November. Conclusions Surveillance results suggest that JE continues to be an important cause of meningo-encephalitis in Bangladesh. Immunization strategies including JE vaccine introduction into the routine childhood immunization program or mass vaccination in certain age groups or geographic areas need to be examined, taking into consideration the cost-effectiveness ratio of the approach and potential for decreasing disease burden.

Contains fulltext : 232064.pdf (Publisher’s version ) (Open Access) PURPOSE: The survival results of the PORTEC-3 trial showed a significant improvement in both overall and failure-free survival with chemoradiation therapy versus pelvic radiation therapy alone. The present analysis was performed to compare long-term adverse events (AE) and health-related quality of life (HRQOL). METHODS AND MATERIALS: In the study, 660 women with high-risk endometrial cancer were randomly assigned to receive chemoradiation therapy (2 concurrent cycles of cisplatin followed by 4 cycles of carboplatin/paclitaxel) or radiation therapy alone. Toxicity was graded using Common Terminology Criteria for Adverse Events, version 3.0. HRQOL was measured using EORTC QLQ-C30 and CX24/OV28 subscales and compared with normative data. An as-treated analysis was performed. RESULTS: Median follow-up was 74.6 months; 574 (87%) patients were evaluable for HRQOL. At 5 years, grade ≥2 AE were scored for 78 (38%) patients who had received chemoradiation therapy versus 46 (24%) who had received radiation therapy alone (P = .008). Grade 3 AE did not differ significantly between the groups (8% vs 5%, P = .18) at 5 years, and only one new late grade 4 toxicity had been reported. At 3 and 5 years, sensory neuropathy toxicity grade ≥2 persisted after chemoradiation therapy in 6% (vs 0% after radiation therapy, P < .001) and more patients reported significant tingling or numbness at HRQOL (27% vs 8%, P < .001 at 3 years; 24% vs 9%, P = .002 at 5 years). Up to 3 years, more patients who had chemoradiation therapy reported limb weakness (21% vs 5%, P < .001) and lower physical (79 vs 87, P < .001) and role functioning (78 vs 88, P < .001) scores. Both treatment groups reported similar long-term global health/quality of life scores, which were better than those of the normative population. CONCLUSIONS: This study shows a long-lasting, clinically relevant, negative impact of chemoradiation therapy on toxicity and HRQOL, most importantly persistent peripheral sensory neuropathy. Physical and role functioning impairments were seen until 3 years. These long-term data are essential for patient information and shared decision-making regarding adjuvant chemotherapy for high-risk endometrial cancer.

Background:\ud Carboplatin and paclitaxel administered every 3 weeks is standard-of-care first-line chemotherapy for epithelial ovarian cancer. The Japanese JGOG3016 trial showed a significant improvement in progression-free and overall survival with dose-dense weekly paclitaxel and 3-weekly carboplatin. In this study, we aimed to compare efficacy and safety of two dose-dense weekly regimens to standard 3-weekly chemotherapy in a predominantly European population with epithelial ovarian cancer.\ud Methods:\ud In this phase 3 trial, women with newly diagnosed International Federation of Gynecology and Obstetrics stage IC–IV epithelial ovarian cancer were randomly assigned to group 1 (carboplatin area under the curve [AUC]5 or AUC6 and 175 mg/m2 paclitaxel every 3 weeks), group 2 (carboplatin AUC5 or AUC6 every 3 weeks and 80 mg/m2 paclitaxel weekly), or group 3 (carboplatin AUC2 and 80 mg/m2 paclitaxel weekly). Written informed consent was provided by all women who entered the trial. The protocol had the appropriate national research ethics committee approval for the countries where the study was conducted. Patients entered the trial after immediate primary surgery, or before neoadjuvant chemotherapy with subsequent planned delayed primary surgery. The trial coprimary outcomes were progression-free survival and overall survival. Data analyses were done on an intention-to-treat basis, and were powered to detect a hazard ratio of 0·75 in progression-free survival. The main comparisons were between the control group (group 1) and each of the weekly research groups (groups 2 and 3).\ud Findings:\ud Between June 6, 2011, and Nov 28, 2014, 1566 women were randomly assigned to treatment. 72% (365), completed six protocol-defined treatment cycles in group 1, 60% (305) in group 2, and 63% (322) in group 3, although 90% (454), 89% (454), and 85% (437) completed six platinum-based chemotherapy cycles, respectively. Paclitaxel dose intensification was achieved with weekly treatment (median total paclitaxel dose 1010 mg/m2 in group 1; 1233 mg/m2 in group 2; 1274 mg/m2 in group 3). By February, 2017, 1018 (65%) patients had experienced disease progression. No significant progression-free survival increase was observed with either weekly regimen (restricted mean survival time 24·4 months [97·5% CI 23·0–26·0] in group 1, 24·9 months [24·0–25·9] in group 2, 25·3 months [23·9–26·9] in group 3; median progression-free survival 17·7 months [IQR 10·6–not reached] in group 1, 20·8 months [11·9–59·0] in group 2, 21·0 months [12·0–54·0] in group 3; log-rank p=0·35 for group 2 vs group 1; group 3 vs 1 p=0·51). Although grade 3 or 4 toxic effects increased with weekly treatment, these effects were predominantly uncomplicated. Febrile neutropenia and sensory neuropathy incidences were similar across groups.\ud Interpretation:\ud Weekly dose-dense chemotherapy can be delivered successfully as first-line treatment for epithelial ovarian cancer but does not significantly improve progression-free survival compared with standard 3-weekly chemotherapy in predominantly European populations.\ud Funding:\ud Cancer Research UK, Medical Research Council, Health Research Board in Ireland, Irish Cancer Society, Cancer Australia.

Antiplatelet therapy is the cornerstone of coronary artery disease treatment and prevention. Combination of aspirin and P2Y12 inhibitor is recommended after acute coronary syndrome and after elective percutaneous coronary intervention. The optimal duration of dual antiplatelet therapy depends on the individual ischemic and bleeding risk of the patient. Bleeding on dual anti platelet therapy remains the most frequent complication of antiplatelet therapy even is mostly minimal or moderate. Beyond individualized evaluation of patients' bleeding risk, management of patients with severe bleeding complications is a challenging situation and requires general and specific recommendations with interruption of the dual antiplatelet therapy in the vast majority of the cases.

A European consensus conference on endometrial carcinoma was held in 2014 to produce multidisciplinary evidence-based guidelines on selected questions. Given the large body of literature on the management of endometrial carcinoma published since 2014, the European Society of Gynaecological Oncology (ESGO), the European SocieTy for Radiotherapy & Oncology (ESTRO) and the European Society of Pathology (ESP) jointly decided to update these evidence-based guidelines and to cover new topics in order to improve the quality of care for women with endometrial carcinoma across Europe and worldwide. ESGO/ESTRO/ESP nominated an international multidisciplinary development group consisting of practicing clinicians and researchers who have demonstrated leadership and expertise in the care and research of endometrial carcinoma (27 experts across Europe). To ensure that the guidelines are evidence-based, the literature published since 2014, identified from a systematic search was reviewed and critically appraised. In the absence of any clear scientific evidence, judgment was based on the professional experience and consensus of the development group. The guidelines are thus based on the best available evidence and expert agreement. Prior to publication, the guidelines were reviewed by 191 independent international practitioners in cancer care delivery and patient representatives. The guidelines comprehensively cover endometrial carcinoma staging, definition of prognostic risk groups integrating molecular markers, pre- and intra-operative work-up, fertility preservation, management for early, advanced, metastatic, and recurrent disease and palliative treatment. Principles of radiotherapy and pathological evaluation are also defined.

IMPORTANCE: A total of 1% to 3% of patients treated with a poly(adenosine diphosphate–ribose) polymerase inhibitor for high-grade ovarian cancer (HGOC) develop therapy-related myeloid neoplasms (t-MNs), which are rare but often fatal conditions. Although the cause of these t-MNs is unknown, clonal hematopoiesis of indeterminate potential (CHIP) variants can increase the risk of primary myeloid malignant neoplasms and are more frequent among patients with solid tumors. OBJECTIVES: To examine whether preexisting CHIP variants are associated with the development of t-MNs after rucaparib treatment and how these CHIP variants are affected by treatment. DESIGN, SETTING, AND PARTICIPANTS: This retrospective genetic association study used peripheral blood cell (PBC) samples collected before rucaparib treatment from patients in the multicenter, single-arm ARIEL2 (Study of Rucaparib in Patients With Platinum-Sensitive, Relapsed, High-Grade Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer) (n = 491; between October 30, 2013, and August 9, 2016) and the multicenter, placebo-controlled, double-blind ARIEL3 (Study of Rucaparib as Switch Maintenance Following Platinum-Based Chemotherapy in Patients With Platinum-Sensitive, High-Grade Serous or Endometrioid Epithelial Ovarian, Primary Peritoneal or Fallopian Tube Cancer) (n = 561; between April 7, 2014, and July 19, 2016), which tested rucaparib as HGOC therapy in the treatment and maintenance settings, respectively. The follow-up data cutoff date was September 1, 2019. Of 1052 patients in ARIEL2 and ARIEL3, PBC samples from 20 patients who developed t-MNs (cases) and 44 randomly selected patients who did not (controls) were analyzed for the presence of CHIP variants using targeted next-generation sequencing. Additional longitudinal analysis was performed on available ARIEL2 samples collected during treatment and at the end of treatment. MAIN OUTCOMES AND MEASURES: Enrichment analysis of preexisting variants in 10 predefined CHIP-associated genes in cases relative to controls; association with clinical correlates. RESULTS: Among 1052 patients (mean [SE] age, 61.7 [0.3] years) enrolled and dosed in ARIEL2 and ARIEL3, 22 (2.1%) developed t-MNs. The t-MNs were associated with longer overall exposure to prior platinum therapies (13.2 vs 9.0 months in ARIEL2, P = .04; 12.4 vs 9.6 months in ARIEL3, P = .003). The presence of homologous recombination repair gene variants in the tumor, either germline or somatic, was associated with increased prevalence of t-MNs (15 [4.1%] of 369 patients with HGOC associated with an HRR gene variant vs 7 [1.0%] of 683 patients with wild-type HGOC, P = .002). The prevalence of preexisting CHIP variants in TP53 but not other CHIP-associated genes at a variant allele frequency of 1% or greater was significantly higher in PBCs from cases vs controls (9 [45.0%] of 20 cases vs 6 [13.6%] of 44 controls, P = .009). TP53 CHIP was associated with longer prior exposure to platinum (mean 14.0 months of 15 TP53 CHIP cases vs 11.1 months of 49 non-TP53 CHIP cases; P = .02). Longitudinal analysis showed that preexisting TP53 CHIP variants expanded in patients who developed t-MNs. CONCLUSIONS AND RELEVANCE: The findings of this genetic association study suggest that preexisting TP53 CHIP variants may be associated with t-MNs after rucaparib treatment.

Objectives This study determined the knowledge of clinicians on the evidence for, and application of, PARP inhibitors (PARPi) in newly diagnosed ovarian cancer. Methods A 27-question, online, continuing medical education (CME) self-assessment was developed that included demographic, knowledge, confidence and practice-based multiple-choice questions. Activity was launched for clinicians practising outside of the USA in July 2020 and data collected to October 2020. Results 104 oncologists, 46 obstetricians/gynaecologists (obs/gyn) and 21 other physicians completed the assessment. Participants were divided evenly between academic and community practice, but only 20% specialized in ovarian cancer. Only 33% were moderately/very confident (across a 5-point Likert scale) in their ability to select an appropriate PARPi maintenance regimen. Knowledge of key trials was low. 56% identified the population of the SOLO 1 trial, 37% patient characteristics, 29% correct PFS outcome and 43% most common AEs. 56% identified the outcome of the PRIMA trial, 33% patient characteristics, 28% efficacy in key subpopulations, and 43% most common G3/4 AEs. 49% identified the outcome of the PAOLA-1 trial, 44% efficacy in key subpopulations, and 44% the AE profile. Only 32% identified the appropriate PARPi maintenance regimen for a patient with HRD-ve/BRCA-ve disease following carboplatin/paclitaxel, whilst 77% identified the appropriate PARPi maintenance strategy following chemotherapy + bevacizumab for BRCA+ve disease. Obs/gyns and other physicians generally performed worse than oncologists in terms of knowledge and confidence. Conclusions The knowledge and confidence gaps revealed indicate there is a significant need for education to facilitate optimal application of PARPi maintenance strategies in newly diagnosed ovarian cancer.

Introduction/Background* In the randomized phase 3 JAVELIN Ovarian 200 trial (N=566), avelumab alone or combined with pegylated liposomal doxorubicin (PLD) did not significantly prolong progression-free survival (PFS; blinded independent central review) or overall survival (OS) vs PLD alone in patients with platinum-resistant/refractory ovarian cancer (PRROC). Here, we report exploratory biomarker analyses associated with outcomes in the avelumab alone arm. Methodology Biomarkers analyzed in tumour tissue or blood were somatic and germline mutations by whole-exome sequencing and whole-transcriptomic profiling by RNAseq. Associations were assessed using the Cox proportional hazards model. For continuous biomarkers, hazard ratios (HRs) and 95% CIs were reported using a median cutoff. Result(s)* Within the avelumab alone arm, higher expression of CD8+ T-cell signature correlated with longer PFS (HR, 0.61 [95% CI 0.43-0.87]), and higher tumour mutational burden (>0.6 mut/Mb) and presence of the high-affinity FCGR2A allele correlated with longer OS (HR [95% CI], 0.63 [0.42-0.96] and 0.53 [0.34-0.83], respectively), while presence of APOBEC and homologous recombination deficiency (HRD) mutational signatures were associated with shorter OS (HR [95% CI], 2.17 [1.22-3.89] and 1.68 [1.07-2.62], respectively). In patients with PFS of Conclusion* Although JAVELIN Ovarian 200 did not meet its primary endpoints, these analyses indicate potential subgroups of patients who could have improved outcomes with immunotherapy alone and provide insights into the biology of PRROC that may inform future trials.

Introduction/Background* In the randomized phase 3 JAVELIN Ovarian 200 trial (N=566), avelumab alone or combined with pegylated liposomal doxorubicin (PLD) did not significantly prolong progression-free survival (PFS; blinded independent central review) or overall survival (OS) vs PLD alone in patients with platinum-resistant/refractory ovarian cancer (PRROC). Here, we report exploratory biomarker analyses associated with outcomes in the avelumab alone arm. Methodology Biomarkers analyzed in tumour tissue or blood were somatic and germline mutations by whole-exome sequencing and whole-transcriptomic profiling by RNAseq. Associations were assessed using the Cox proportional hazards model. For continuous biomarkers, hazard ratios (HRs) and 95% CIs were reported using a median cutoff. Result(s)* Within the avelumab alone arm, higher expression of CD8+ T-cell signature correlated with longer PFS (HR, 0.61 [95% CI 0.43-0.87]), and higher tumour mutational burden (>0.6 mut/Mb) and presence of the high-affinity FCGR2A allele correlated with longer OS (HR [95% CI], 0.63 [0.42-0.96] and 0.53 [0.34-0.83], respectively), while presence of APOBEC and homologous recombination deficiency (HRD) mutational signatures were associated with shorter OS (HR [95% CI], 2.17 [1.22-3.89] and 1.68 [1.07-2.62], respectively). In patients with PFS of Conclusion* Although JAVELIN Ovarian 200 did not meet its primary endpoints, these analyses indicate potential subgroups of patients who could have improved outcomes with immunotherapy alone and provide insights into the biology of PRROC that may inform future trials.

Introduction/Background* This study determined whether online continuing medical education (CME) could improve the competence of obstetricians/gynaecologists (obs/gyns) and oncologists (oncs) regarding the selection and application of PARP inhibitor maintenance strategies for patients with newly diagnosed advanced ovarian cancer Methodology A 30-minute online video discussion between four expert faculty was launched for physicians outside the USA December 2020 with data collected to May 2021. Educational effect assessed with repeated-pairs pre-/post-activity- individual participants serving as their own control. 3 multiple-choice, knowledge questions and 1 self-efficacy, 5-point Likert scale confidence question were analysed. McNemar’s test assessed pre- to post-activity change (5% significance level, P .80=Large. Result(s)* 216 obs/gyns and 80 oncs completed pre- and post-activity questions. Positive educational effect was observed for obs/gyns (small effect, Cohen’s d=.34, P Conclusion* This on-demand, online video panel discussion had a positive educational impact. However, significant education gaps were evident pre-activity that remained post-activity in a high proportion of participants. There is a need for further education to increase the competence and confidence of clinicians in application of PARP inhibitor maintenance regimens in real world practice

Introduction/Background* ARIEL3 is a placebo-controlled randomized trial of the PARP inhibitor rucaparib as maintenance treatment in high-grade ovarian cancer (HGOC) patients who responded to the latest line of platinum therapy (NCT01968213). Rucaparib improved progression-free survival (PFS) across all predefined subgroups. Here, we present an exploratory analysis of characteristics associated with exceptional benefit from rucaparib. Methodology Between 7 April 2014, and 19 July 2016, 564 patients were randomized 2:1 to rucaparib 600 mg BID or placebo. As of 31 December 2019 (data cutoff), 33/375 (9%) and 1/189 (0.5%) patients were still ongoing and receiving rucaparib or placebo. Molecular features (genomic alterations and BRCA1 promoter methylation) and baseline clinical characteristics were compared between patients who derived exceptional benefit (PFS ≥2 years), and those with disease progression on first scan (≈12 weeks; the short-term subgroup) within each treatment arm. Result(s)* Of 564 patients, a greater percentage of rucaparib vs placebo patients showed exceptional benefit: 79/375 (21%) in the rucaparib arm and 4/189 (2%) in the placebo arm (including 26/375 [7%] patients in the rucaparib arm and 1/189 [0.5%] patient in the placebo arm with PFS >4 years as of the data cutoff date). Within the rucaparib arm, exceptional benefit patients had more favourable clinical prognostic factors at baseline versus the short-term subgroup (table 1). Although BRCA (BRCA1 or BRCA2) mutations were enriched in the rucaparib exceptional benefit subgroup, 33/79 (42%) of these patients were BRCA wild type. Patterns of enrichment varied among other biomarkers. Overall trends were similar in the placebo arm. Conclusion* Exceptional benefit in ARIEL3 was more common in, but not exclusive to, patients with favourable clinical characteristics and known mechanisms of sensitivity to a PARP inhibitor. Our results suggest rucaparib can deliver exceptional benefit to a diverse set of patients with HGOC.

Pathological studies have revealed spontaneous recanalized coronary thrombi as a frequent evolution of coronary occlusions; however, they are poorly recognized on coronary angiography, and the optimal therapeutic strategy for clinical evolution is unknown. We report the role of optical coherence tomography in identifying a recanalized coronary thrombus causing myocardial ischemia after 11 years of follow-up. (Level of Difficulty: Intermediate.).

Pacients d'edat avançada; Càncer d'ovaris; Inhibidor de la PARP Pacientes de edad avanzada; Cáncer de ovarios; Inhibidor de PARP Elderly patients; Ovarian cancer; PARP inhibitor Background In the phase 3 trial ARIEL3, maintenance treatment with the poly(ADP-ribose) polymerase (PARP) inhibitor rucaparib provided clinical benefit versus placebo for patients with recurrent, platinum-sensitive ovarian cancer. Here, we evaluate the impact of age on the clinical utility of rucaparib in ARIEL3. Methods Patients with platinum-sensitive, recurrent ovarian carcinoma with ≥2 prior platinum-based chemotherapies who responded to their last platinum-based therapy were enrolled in ARIEL3 and randomized 2:1 to rucaparib 600 mg twice daily or placebo. Exploratory, post hoc analyses of progression-free survival (PFS), patient-centered outcomes (quality-adjusted PFS [QA-PFS] and quality-adjusted time without symptoms or toxicity [Q-TWiST]), and safety were conducted in three age subgroups (

The rapid spread of severe acute respiratory syndrome coronavirus 2 infection and its related disease (COVID-19) has required an immediate and coordinate healthcare response to face the worldwide emergency and define strategies to maintain the continuum of care for the non-COVID-19 diseases while protecting patients and healthcare providers. The dimension of the COVID-19 pandemic poses an unprecedented risk especially for the more vulnerable populations. To manage patients with cancer adequately, maintaining the highest quality of care, a definition of value-based priorities is necessary to define which interventions can be safely postponed without affecting patients’ outcome. The European Society for Medical Oncology (ESMO) has endorsed a tiered approach across three different levels of priority (high, medium, low) incorporating information on the value-based prioritisation and clinical cogency of the interventions that can be applied for different disease sites. Patients with gynaecological cancer are at particular risk of COVID-19 complications because of their age and prevalence of comorbidities. The definition of priority level should be based on tumour stage and histology, cancer-related symptoms or complications, aim (curative vs palliative) and magnitude of benefit of the oncological intervention, patients’ general condition and preferences. The decision-making process always needs to consider the disease-specific national and international guidelines and the local healthcare system and social resources, and a changing situation in relation to COVID-19 infection. These recommendations aim to provide guidance for the definition of deferrable and undeferrable interventions during the COVID-19 pandemic for ovarian, endometrial and cervical cancers within the context of the ESMO Clinical Practice Guidelines.

Carcinoma d'ovari recurrent; Rucaparib Carcinoma de ovario recurrente; Rucaparib Recurrent Ovarian Carcinoma; Rucaparib PURPOSE To investigate quality-adjusted progression-free survival (QA-PFS) and quality-adjusted time without symptoms or toxicity (Q-TWiST) in a post hoc exploratory analysis of the phase III ARIEL3 study of rucaparib maintenance treatment versus placebo. PATIENTS AND METHODS Patients with platinum-sensitive, recurrent ovarian carcinoma were randomly assigned to rucaparib (600 mg twice per day) or placebo. QA-PFS was calculated as progression-free survival function × the 3-level version of the EQ-5D questionnaire (EQ-5D-3L) index score function. Q-TWiST analyses were performed defining TOX as the mean duration in which a patient experienced grade ≥ 3 treatment-emergent adverse events (TEAEs) or the mean duration in which a patient experienced grade ≥ 2 TEAEs of nausea, vomiting, fatigue, and asthenia. Q-TWiST was calculated as μTOX × TOX + TWiST, with μTOX calculated using EQ-5D-3L data. RESULTS The visit cutoff was Apr 15, 2017. Mean QA-PFS was significantly longer with rucaparib versus placebo in the intent-to-treat (ITT) population (375 randomly assigned to rucaparib v 189 randomly assigned to placebo; difference, 6.28 months [95% CI, 4.85 to 7.47 months]); BRCA-mutant cohort (130 rucaparib v 66 placebo; 9.37 months [95% CI, 6.65 to 11.85 months]); homologous recombination deficient (HRD) cohort (236 rucaparib v 118 placebo; 7.93 months [95% CI, 5.93 to 9.53 months]); and BRCA wild-type/loss of heterozygosity (LOH) low patient subgroup (107 rucaparib v 54 placebo; 2.71 months [95% CI, 0.31 to 4.44 months]). With TOX defined using grade ≥ 3 TEAEs, the difference in mean Q-TWiST (rucaparib v placebo) was 6.88 months (95% CI, 5.71 to 8.23 months), 9.73 months (95% CI, 7.10 to 11.94 months), 8.11 months (95% CI, 6.36 to 9.49 months), and 3.35 months (95% CI, 1.66 to 5.40 months) in the ITT population, BRCA-mutant cohort, HRD cohort, and BRCA wild-type/LOH low patient subgroup, respectively. Q-TWiST with TOX defined using select grade ≥ 2 TEAEs also consistently favored rucaparib. CONCLUSION The significant differences in QA-PFS and Q-TWiST confirm the benefit of rucaparib versus placebo in all predefined cohorts. Supported by Clovis Oncology. Additional support was provided in part by the Ann Rife Cox Chair in Gynecology and the Judy Reis/Albert Pisani, MD, Ovarian Cancer Research Fund (to R.L.C.) and by the National Institute of Health Research Biomedical Research Centre at University College London (to J.A.L.). C.A. is supported in part by Memorial Sloan Kettering Cancer Center Support Grant P30 CA008748. Funding was also provided by US Department of Defense Ovarian Cancer Research Program OC120506, a V Foundation Translational Award, and a Stand Up To Cancer–Ovarian Cancer Research Fund Alliance–National Ovarian Cancer Coalition Dream Team Translational Research Grant (Grant No. SU2C-AACR-DT16–15; all to E.M.S.). Stand Up to Cancer is a program of the Entertainment Industry Foundation; research grants are administered by the American Association for Cancer Research, a scientific partner of Stand Up To Cancer.

Background: In ARIEL3, rucaparib maintenance treatment significantly improved progression-free survival versus placebo. Here, we report prespecified, investigator-assessed, exploratory post-progression endpoints and updated safety data. Methods: In this ongoing (enrolment complete) randomised, placebo-controlled, phase 3 trial, patients aged 18 years or older who had platinum-sensitive, high-grade serous or endometrioid ovarian, primary peritoneal, or fallopian tube carcinoma and an Eastern Cooperative Oncology Group performance status of 0 or 1 who had received at least two previous platinum-based chemotherapy regimens and responded to their last platinum-based regimen were randomly assigned (2:1) to oral rucaparib (600 mg twice daily) or placebo in 28-day cycles using a computer-generated sequence (block size of six with stratification based on homologous recombination repair gene mutation status, progression-free interval following penultimate platinum-based regimen, and best response to most recent platinum-based regimen). Patients, investigators, site staff, assessors, and the funder were masked to assignments. The primary endpoint of investigator-assessed progression-free survival has been previously reported. Prespecified, exploratory outcomes of chemotherapy-free interval (CFI), time to start of first subsequent therapy (TFST), time to disease progression on subsequent therapy or death (PFS2), and time to start of second subsequent therapy (TSST) and updated safety were analysed (visit cutoff Dec 31, 2017). Efficacy analyses were done in all patients randomised to three nested cohorts: patients with BRCA mutations, patients with homologous recombination deficiencies, and the intention-to-treat population. Safety analyses included all patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, NCT01968213. Findings: Between April 7, 2014, and July 19, 2016, 564 patients were enrolled and randomly assigned to rucaparib (n=375) or placebo (n=189). Median follow-up was 28·1 months (IQR 22·0–33·6). In the intention-to-treat population, median CFI was 14·3 months (95% CI 13·0–17·4) in the rucaparib group versus 8·8 months (8·0–10·3) in the placebo group (hazard ratio [HR] 0·43 [95% CI 0·35–0·53]; p

International audience; Background: Percutaneous coronary intervention (PCI)-related myonecrosis is frequent and can affect the long-term prognosis of patients. To our knowledge, ticagrelor has not been evaluated in elective PCI and could reduce periprocedural ischaemic complications compared with clopidogrel, the currently recommended treatment. The aim of the ALPHEUS study was to examine if ticagrelor was superior to clopidogrel in reducing periprocedural myocardial necrosis in stable coronary patients undergoing high-risk elective PCI.Methods: The ALPHEUS study, a phase 3b, randomised, open-label trial, was done at 49 hospitals in France and Czech Republic. Patients with stable coronary artery disease were eligible for the study if they had an indication for PCI and at least one high-risk characteristic. Eligible patients were randomly assigned (1:1) to either ticagrelor (180 mg loading dose, 90 mg twice daily thereafter for 30 days) or clopidogrel (300-600 mg loading dose, 75 mg daily thereafter for 30 days) by use of an interactive web response system, and stratified by centre. The primary outcome was a composite of PCI-related type 4 (a or b) myocardial infarction or major myocardial injury and the primary safety outcome was major bleeding, both of which were evaluated within 48 h of PCI (or at hospital discharge if earlier). The primary analysis was based on all events that occurred in the intention-to-treat population. The trial was registered with ClinicalTrials.gov, NCT02617290.Findings: Between Jan 9, 2017, and May 28, 2020, 1910 patients were randomly assigned at 49 sites, 956 to the ticagrelor group and 954 to the clopidogrel group. 15 patients were excluded from the ticagrelor group and 12 from the clopidogrel group. At 48 h, the primary outcome was observed in 334 (35%) of 941 patients in the ticagrelor group and 341 (36%) of 942 patients in the clopidogrel group (odds ratio [OR] 0·97, 95% CI 0·80-1·17; p=0·75). The primary safety outcome did not differ between the two groups, but minor bleeding events were more frequently observed with ticagrelor than clopidogrel at 30 days (105 [11%] of 941 patients in the ticagrelor group vs 71 [8%] of 942 patients in the clopidogrel group; OR 1·54, 95% CI 1·12-2·11; p=0·0070).Interpretation: Ticagrelor was not superior to clopidogrel in reducing periprocedural myocardial necrosis after elective PCI and did not cause an increase in major bleeding, but did increase the rate of minor bleeding at 30 days. These results support the use of clopidogrel as the standard of care for elective PCI.Funding: ACTION Study Group and AstraZeneca.

Background Limited evidence exists to support CA-125 as a valid surrogate biomarker for progression in patients with ovarian cancer on maintenance PARP inhibitor (PARPi) therapy. We aimed to assess the concordance between CA-125 and Response Evaluation Criteria in Solid Tumours (RECIST) criteria for progression in patients with BRCA mutations on maintenance PARPi or placebo. Methods We extracted data on progression as defined by Gynecologic Cancer InterGroup CA-125, investigator- and independent central-assessed RECIST from the SOLO2/ENGOT-ov21(NCT01874353) trial. We excluded those with progression other than by RECIST, progression on date of randomisation, and no repeat CA-125 beyond baseline. We evaluated the concordance between CA-125 progression and RECIST progression, and assessed the negative (NPV) and positive predictive value (PPV). Results Of 295 randomised patients, 275 (184 olaparib, 91 placebo) were included. 171 patients had investigator-assessed RECIST progression. Of 80 patients with CA-125 progression, 77 had concordant RECIST progression (PPV 96%, 95% confidence interval 90–99%). Of 195 patients without CA-125 progression, 94 had RECIST progression (NPV 52%, 45–59%). Within treatment arms, PPV was similar (olaparib: 95% [84–99%], placebo: 97% [87–100%]) but NPV was lower in patients on placebo (olaparib: 60% [52–68%], placebo: 30% [20–44%]). Of 94 patients with RECIST but without CA-125 progression, 64 (68%) had CA-125 that remained within normal range. We observed similar findings using independent-assessed RECIST. Conclusions Almost half the patients without CA-125 progression had RECIST progression, and most of these had CA-125 within the normal range. Regular computed tomography imaging should be considered as part of surveillance in patients treated with or without maintenance olaparib rather than relying on CA-125 alone.

Numerous retrospective studies have demonstrated that the density of intra-tumoral immune cell infiltration is prognostic in epithelial ovarian cancer (OC). These observations together with reports of programmed death ligand-1 (PD-L1) expression in advanced OC provided the rationale for investigating the benefit of programmed death-1 (PD1) or PD-L1 inhibition in OC. Unfortunately clinical trials to date evaluating PD1/PD-L1 inhibition in patients with relapsed OC have been disappointing. In this review we will discuss early results from single agent PD1/PD-L1 inhibitors and the strategies to enhance benefit from immune-oncology agents in OC, including proposing anti-PD-L1 in combination with other agents (cytotoxics, anti-angiogenics, poly(ADP-ribose) polymerase. (PARP) inhibitors, targeted therapies or other immunotherapies), as well as evaluating these agents earlier in the disease course, or in biomarker selected patients.

This study examined how individual pretreatment symptoms (depression and anxiety) predicted longitudinal, relational processes in couples therapy (the therapeutic alliance and couple satisfaction). This study included 99 heterosexual couples receiving systemic couples therapy. Partners reported their individual pretreatment symptoms of depression and anxiety before intake. Each member reported their therapeutic alliance with the therapist at the end of sessions 2-8, as well as their couple satisfaction before intake and at the end of sessions 4 and 8. A Latent Profile Analysis revealed four profiles characterizing couples on their pretreatment psychological symptoms, namely both higher (where both members of the couple had higher depressive and anxiety symptoms), female higher, male higher, and both lower profiles. Furthermore, longitudinal, dyadic multilevel models revealed that men in male higher, female higher, and both higher profiles had higher initial alliance levels, compared to men in the both lower profile. In contrast, only female partners in the both higher profile had a higher initial therapeutic alliance than those in the both lower profile. Men in the both higher profile had faster reductions in their alliance, whereas other profiles did not predict changes in male or female alliance. Additionally, the male higher and both higher profiles predicted a lower initial level of couple satisfaction in males but not females. The profiles did not predict changes in couple satisfaction, which may be a result of lowered power due to missing data. Findings were discussed in the context of systemic family theory, with clinical implications for distressed couples.En este estudio se analizó como los síntomas individuales previos al tratamiento (depresión y ansiedad) predijeron procesos longitudinales y relacionales en la terapia de pareja (la alianza terapéutica y la satisfacción con la pareja). En este estudio participaron 99 parejas heterosexuales que recibían terapia sistémica de pareja. Antes de la admisión, las parejas informaron sus síntomas individuales de depresión y ansiedad previos al tratamiento. Cada miembro informó su alianza terapéutica con el terapeuta al final de las sesiones 2-8, así como su satisfacción con la pareja antes de la admisión y al final de las sesiones 4 y 8. Un análisis de perfiles latentes indicó cuatro perfiles que caracterizaron a las parejas en sus síntomas psicológicos previos al tratamiento, por ejemplo, los perfiles ambos más altos (donde ambos miembros de la pareja tenían síntomas más altos de depresión y ansiedad), mujeres más altos, hombres más altos y ambos más bajos. Además, los modelos multinivel longitudinales y diádicos revelaron que los hombres de los perfiles hombres más altos, mujeres más altas y ambos más altos tuvieron niveles iniciales de alianza más altos en comparación con los hombres del perfil ambos más bajos. Por el contrario, solo las mujeres del perfil ambos más altos tuvieron una alianza terapéutica inicial más alta que los del perfil ambos más bajos. Los hombres del perfil ambos más altos tuvieron reducciones más rápidas en su alianza, mientras que otros perfiles no predijeron cambios en la alianza masculina o femenina. Además, los perfiles hombres más altos y ambos más altos predijeron un nivel inicial más bajo de satisfacción con la pareja en los hombres, pero no en las mujeres. Los perfiles no predijeron cambios en la satisfacción con la pareja, lo cual puede ser un resultado de la reducción del poder debido a datos faltantes. Se comentaron los resultados en el contexto de la teoría sistémica familiar, con consecuencias clínicas para las parejas con distrés.

Background: (FM). Fibromyalgia (FM) is a very prevalent and debilitating chronic pain disorder that is difficult to treat. Mindfulness-based techniques are regarded as a very promising approach for the treatment of chronic pain and in particular FM. The Mindfulness-Oriented Recovery Enhancement (MORE) intervention, a mindfulness-based group intervention, has shown beneficial effects in opioid-treated chronic pain patients, including reduced pain severity, functional interference, and opioid dosing, by restoring neurophysiological and behavioral responses to reward. First evidence for a hypodopaminergic state and impaired reward processing in FM have been reported. However, little is known about its impact on dopamine (DA) function and in particular with regard to DA responses to monetary reward in FM. The aim of the present study protocol is to evaluate if MORE is able to restore the DA function in FM patients, in particular with regard to the DA responses to reward, and to reduce pain and mood complaints in FM.Methods/design: The present study is a multi-center RCT with 3 time points: before the intervention, after completion of the intervention and 3-months after completion of the intervention. Eighty FM patients will be randomly assigned to either the MORE intervention (N=40) or to a wait-list control group (N=40). Additionally a comparison group of healthy women (N=20) will be enrolled. The MORE intervention consists of eight 2-hour long group sessions administered weekly over a period of 8 weeks. Before and after the intervention, FM participants will undergo [18F] DOPA Positron Emission Tomography (PET) and functional MR imaging while performing a monetary reward task. The primary outcome will be endogeneous DA changes measured with [18F] DOPA PET at baseline, after the intervention (after 8 weeks for control group), and at 3 months’ follow-up. Secondary outcomes will be (1) clinical pain measures and FM symptoms using standardized clinical scales 2) functional brain changes 3) measures of negative and positive affect, stress and reward experience in daily life using the Experience Sampling method (ESM) 4) biological measures of stress including cortisol and alpha-amylase.Design: If the findings of this study confirm the effectiveness of MORE in restoring DA function, reducing pain and improving mood symptoms, MORE can be judged to be a promising means to improve quality of life in FM patients. The findings of this trial may inform health care providers about the potential use of the MORE intervention as a possible non-pharmacological intervention for FM.Trial registration: ClinicalTrials.gov NCT 04451564. Registered on 3 July 2020. The trial was prospectively registered.

Purpose of Review Advanced epithelial ovarian cancer remains the most lethal gynaecological cancer. Most patients with advanced disease will relapse within 3 years after primary treatment with surgery and chemotherapy. Recurrences become increasing difficult to treat due to the emergence of drug resistance and 5-year survival has changed little over the last decade. Maintenance treatment, here defined as treatment given beyond primary chemotherapy, can both consolidate the response and prolong the control of disease which is an approach to improve survival. Recent Findings Here we review maintenance strategies such as targeting angiogenesis, interference of DNA repair through inhibition of PARP, combinations of targeting agents, and immunotherapy and hormonal therapy. Summary Much has been learnt from the success and challenges of these treatments that have in the last few years which led to significant reduction in disease recurrence, changed the guidelines for treatment, and established a new paradigm for the treatment of ovarian cancer.