Overall survival in the OlympiA phase III trial of adjuvant olaparib in patients with germline pathogenic variants in BRCA1/2 and high-risk, early breast cancer

Publisher Copyright: © 2022 The AuthorsBackground: The randomized, double-blind OlympiA trial compared 1 year of the oral poly(adenosine diphosphate-ribose) polymerase inhibitor, olaparib, to matching placebo as adjuvant therapy for patients with pathogenic or likely pathogenic variants in germline BRCA1 or BRCA2 (gBRCA1/2pv) and high-risk, human epidermal growth factor receptor 2-negative, early breast cancer (EBC). The first pre-specified interim analysis (IA) previously demonstrated statistically significant improvement in invasive disease-free survival (IDFS) and distant disease-free survival (DDFS). The olaparib group had fewer deaths than the placebo group, but the difference did not reach statistical significance for overall survival (OS). We now report the pre-specified second IA of OS with updates of IDFS, DDFS, and safety. Patients and methods: One thousand eight hundred and thirty-six patients were randomly assigned to olaparib or placebo following (neo)adjuvant chemotherapy, surgery, and radiation therapy if indicated. Endocrine therapy was given concurrently with study medication for hormone receptor-positive cancers. Statistical significance for OS at this IA required P < 0.015. Results: With a median follow-up of 3.5 years, the second IA of OS demonstrated significant improvement in the olaparib group relative to the placebo group [hazard ratio 0.68; 98.5% confidence interval (CI) 0.47-0.97; P = 0.009]. Four-year OS was 89.8% in the olaparib group and 86.4% in the placebo group (Δ 3.4%, 95% CI −0.1% to 6.8%). Four-year IDFS for the olaparib group versus placebo group was 82.7% versus 75.4% (Δ 7.3%, 95% CI 3.0% to 11.5%) and 4-year DDFS was 86.5% versus 79.1% (Δ 7.4%, 95% CI 3.6% to 11.3%), respectively. Subset analyses for OS, IDFS, and DDFS demonstrated benefit across major subgroups. No new safety signals were identified including no new cases of acute myeloid leukemia or myelodysplastic syndrome. Conclusion: With 3.5 years of median follow-up, OlympiA demonstrates statistically significant improvement in OS with adjuvant olaparib compared with placebo for gBRCA1/2pv-associated EBC and maintained improvements in the previously reported, statistically significant endpoints of IDFS and DDFS with no new safety signals.Peer reviewe

Intraoperative ventilator settings and their association with postoperative pulmonary complications in neurosurgical patients : post-hoc analysis of LAS VEGAS study

Funding Information: LAS VEGAS was partly sponsored by the European Society of Anaesthesiology and the Amsterdam University Medical Centers, location ‘AMC’. It was also funded by a grant from the AAGBI via the NIAA in the UK. MFVM was supported by grant NIH-NHLBI UG3-HL140177. Funders provided support for logistic and study development. Funding Information: LAS VEGAS [8] was an international multicentre observational prospective study (registered at www. clini-caltrials.gov (study identifier NCT01601223)), endorsed and supported by the European Society of Anaesthesiology and the Amsterdam University Medical Centres, location AMC, Amsterdam, The Netherlands. Details about the LAS VEGAS study collaborators, participating centres and hospital characteristics of participating centres are reported in ESM Tables S2a, b and S3.Peer reviewedPublisher PD

The Association of Intraoperative driving pressure with postoperative pulmonary complications in open versus closed abdominal surgery patients : a posthoc propensity score–weighted cohort analysis of the LAS VEGAS study

Funding Information: G. Mazzinari: No interest declared; A. Serpa Neto: No interest declared; S.N.T. Hemmes: No interest declared; G. Hedenstierna: No interest declared; S. Jaber: No interest declared; M. Hiesmayr: No interest declared; M.W. Hollmann: Executive Section Editor Pharmacology with Anesthesia & Analgesia, Section Editor Anesthesiology with Journal of Clinical Medicine, and CSL Behring, no conflict of interest with the current work; G.H. Mills: No interest declared; M.F. Vidal Melo: is funded by NIH/NHLBI grant UH3-HL140177; R.M. Pearse: No interest declared; C. Putensen: No interest declared; W. Schmid: No interest declared; P. Severgnini: No interest declared; H.Wrigge: No interest declared; O. Diaz–Cambronero: had received a Merck Sharp & Dohme investigator–initiated grant (protocol code #53607). Sponsors and funders have no roles in study design, analysis of data or reporting. Also received speakers fees for lecture and medical advice from Merck Sharp & Dohme, no conflict of interest with the current work; L.Ball: No interest declared; M. Gama de Abreu: Ambu, GE Healthcare, ZOLL consulting fees, no conflict of interest with the current work; P.Pelosi: No interest declared; M.J.Schultz: No interest declared. Funding Information: The ethical committee of the Academic Medical Center, Amsterdam, the Netherlands, approved the LAS VEGAS study protocol (W12_190#12.17.0227). Each participating centre obtained approval from their institutional review board if needed, and patients were included after obtaining written informed consent when dictated by national or regional legislation. The LAS VEGAS study was partially funded and endorsed by the European Society of Anaesthesiology and registered at clinicaltrials.gov (study identifier NCT01601223, first posted date: 17/05/2012).Peer reviewedPublisher PD

Developing clinical decision tools to implement chronic disease prevention and screening in primary care: the BETTER 2 program (building on existing tools to improve chronic disease prevention and screening in primary care).

BackgroundThe Building on Existing Tools to Improve Chronic Disease Prevention and Screening in Family Practice (BETTER) trial demonstrated the effectiveness of an approach to chronic disease prevention and screening (CDPS) through a new skilled role of a 'prevention practitioner'(PP). The PP has appointments with patients 40-65 years of age that focus on primary prevention activities and screening of cancer (breast, colorectal, cervical), diabetes and cardiovascular disease and associated lifestyle factors. There are numerous and occasionally conflicting evidence-based guidelines for CDPS, and the majority of these guidelines are focused on specific diseases or conditions; however, primary care providers often attend to patients with multiple conditions. To ensure that high-level evidence guidelines were used, existing clinical practice guidelines and tools were reviewed and integrated into blended BETTER tool kits. Building on the results of the BETTER trial, the BETTER tools were updated for implementation of the BETTER 2 program into participating urban, rural and remote communities across Canada.MethodsA clinical working group consisting of PPs, clinicians and researchers with support from the Centre for Effective Practice reviewed the literature to update, revise and adapt the integrated evidence algorithms and tool kits used in the BETTER trial. These resources are nuanced, based on individual patient risk, values and preferences and are designed to facilitate decision-making between providers across the target diseases and lifestyle factors included in the BETTER 2 program. Using the updated BETTER 2 toolkit, clinicians 1) determine which CDPS actions patients are eligible to receive and 2) develop individualized 'prevention prescriptions' with patients through shared decision-making and motivational interviewing.ResultsThe tools identify the patients' risks and eligible primary CDPS activities: the patient survey captures the patient's health history; the prevention visit form and integrated CDPS care map identify eligible CDPS activities and facilitate decisions when certain conditions are met; and the 'bubble diagram' and 'prevention prescription' promote shared decision-making.ConclusionThe integrated clinical decision-making tools of BETTER 2 provide resources for clinicians and policymakers that address patients' complex care needs beyond single disease approaches and can be adapted to facilitate CDPS in the urban, rural and remote clinical setting.Trial registrationThe registration number of the original RCT BETTER trial was ISRCTN07170460

Morbidity and mortality after anaesthesia in early life: results of the European prospective multicentre observational study, neonate and children audit of anaesthesia practice in Europe (NECTARINE)

Cited by: 38; All Open Access, Green Open Access, Hybrid Gold Open AccessPeer reviewe

The value of 3D images in the aesthetic evaluation of breast cancer conservative treatment. Results from a prospective multicentric clinical trial

PURPOSE: BCCT.core (Breast Cancer Conservative Treatment. cosmetic results) is a software created for the objective evaluation of aesthetic result of breast cancer conservative treatment using a single patient frontal photography. The lack of volume information has been one criticism, as the use of 3D information might improve accuracy in aesthetic evaluation. In this study, we have evaluated the added value of 3D information to two methods of aesthetic evaluation: a panel of experts; and an augmented version of the computational model - BCCT.core3d. MATERIAL AND METHODS: Within the scope of EU Seventh Framework Programme Project PICTURE, 2D and 3D images from 106 patients from three clinical centres were evaluated by a panel of 17 experts and the BCCT.core. Agreement between all methods was calculated using the kappa (K) and weighted kappa (wK) statistics. RESULTS: Subjective agreement between 2D and 3D individual evaluation was fair to moderate. The agreement between the expert classification and the BCCT.core software with both 2D and 3D features was also fair to moderate. CONCLUSIONS: The inclusion of 3D images did not add significant information to the aesthetic evaluation either by the panel or the software. Evaluation of aesthetic outcome can be performed using of the BCCT.core software, with a single frontal image

Difficult tracheal intubation in neonates and infants. NEonate and Children audiT of Anaesthesia pRactice IN Europe (NECTARINE): a prospective European multicentre observational study

Cited by: 19; All Open Access, Green Open Access, Hybrid Gold Open AccessPeer reviewe

A prospective study to assess the value of MMP-9 in improving the appropriateness of urgent referrals for colorectal cancer

Background Bowel cancer is common and is a major cause of death. Most people with bowel symptoms who meet the criteria for urgent referral to secondary care will not be found to have bowel cancer, and some people who are found to have cancer will have been referred routinely rather than urgently. If general practitioners could better identify people who were likely to have bowel cancer or conditions that may lead to bowel cancer, the pressure on hospital clinics may be reduced, enabling these patients to be seen more quickly. Increased levels of an enzyme called matrix metalloproteinase 9 (MMP-9) have been found to be associated with such conditions, and this can be measured from a blood sample. This study aims to find out whether measuring MMP-9 levels could improve the appropriateness of urgent referrals for patients with bowel symptoms. Methods People aged 18 years or older referred to a colorectal clinic will be asked to complete a questionnaire about symptoms, recent injuries or chronic illnesses (these can increase the level of matrix metalloproteinases) and family history of bowel cancer. A blood sample will be taken from people who consent to take part to assess MMP-9 levels, and the results of examination at the clinic and/or investigations arising from the clinic visit will be collected from hospital records. The accuracy of MMP-9 will be assessed by comparing the MMP-9 level with the resulting diagnosis. The combination of factors (e.g. symptoms and MMP-9 level) that best predict a diagnosis of malignancy (invasive disease or polyps) will be determined. Discussion Although guidelines are in place to facilitate referrals to colorectal clinics, symptoms alone do not adequately distinguish people with malignancy from people with benign conditions. This study will establish whether MMP-9 could assist this process. If this were the case, measurement of MMP-9 levels could be used by general practitioners to assist in the identification of people who were most likely to have bowel cancer or conditions that may lead to bowel cancer, and who should, therefore, be referred most urgently to secondary car

Bortezomib, thalidomide, dexamethasone, and panobinostat for patients with relapsed multiple myeloma (MUK-six): a multicentre, open-label, phase 1/2 trial

Background Panobinostat (a pan histone deacetylase inhibitor) is approved in combination with bortezomib and dexamethasone for patients with relapsed multiple myeloma who have received two or more previous lines of therapy. We aimed to improve the safety of this combination and investigate efficacy by incorporating low-dose thalidomide, using sub-cutaneous weekly bortezomib, and determining the maximum tolerated dose of panobinostat in this regimen. Methods We did a phase 1/2, multicentre, open-label trial (MUK six) at four hospitals in the UK, enrolling patients with relapsed, or relapsed and refractory, multiple myeloma aged at least 18 years, with an Eastern Cooperative Oncology Group performance status of 2 or less who had previously received 1–4 lines of therapy. Exclusion criteria included any antimyeloma treatment within 28 days of study drugs (except dexamethasone 160 mg >48 h before treatment). We used a rolling six escalation design to determine the maximum tolerated dose of panobinostat, and allocated patients to receive subcutaneous bortezomib 1·3 mg/m2, and oral thalidomide 100 mg, dexamethasone 20 mg, and panobinostat 10, 15, or 20 mg (escalated to 20 mg according to the escalation schedule). Treatment was given during a 21-day cycle (bortezomib on days 1 and 8; thalidomide every day; dexamethasone on days 1, 2, 8, and 9; and panobinostat on days 1, 3, 5, 8, 10, and 12) for 16 cycles in the absence of disease progression or unacceptable toxicity. Patients were permitted to come off study for autologous stem cell transplantation. The primary objective was to determine the maximum tolerated dose and recommended dose of panobinostat, and to estimate the proportion of patients with an overall response that was equal to a partial response or greater within 16 cycles of treatment at the recommended panobinostat dose in the modified intention-to-treat population. We assessed safety in all patients who received a trial drug (ie, bortezomib, thalidomide, dexamethasone, or panobinostat). This trial is registered at ClinicalTrials.gov, number NCT02145715, and with the ISRCTN registry, number ISRCTN59395590 and is closed to recruitment. Findings Between Jan 31, 2013, and Oct 30, 2014, we enrolled 57 eligible patients who received at least one dose of trial medication or any drug. One dose-limiting toxicity was reported (grade 3 hyponatremia at the 20 mg dose), therefore the maximum tolerated dose was not reached, and 20 mg was deemed to be the recommended dose. 46 patients were treated with panobinostat 20 mg (the intention-to-treat population). 42 patients (91%, 80% CI 83·4–96·2) of 46 achieved the primary endpoint of an overall response that was equal to a partial response or greater. Most adverse events were grade 1–2 with few occurrences of grade 3–4 diarrhoea or fatigue. The most common adverse events of grade 3 or worse in the safety population (n=57) were reduced neutrophil count (15 [26%]), hypophosphatemia (11 [19%]), and decreased platelet count (8 [14%]). 46 serious adverse events were reported in 27 patients; of 14 suspected to be related to the trial medication, seven (50%) were gastrointestinal disorders. Interpretation Panobinostat 20 mg in combination with bortezomib, thalidomide, and dexamethasone is an efficacious and well tolerated regimen for patients with relapsed multiple myeloma

Variations in Treatment Delivery for Patients with Neovascular AMD in the UK: Results from an Ophthalmology Trainee Clinical Research Network Study

INTRODUCTION: The aim of this study was to determine treatment delivery patterns for patients with neovascular age-related macular degeneration (nAMD) across the UK through an ophthalmology trainee research network delivered observational study. METHODS: Data were collected via an online tool by potential research collaborators identified by the Ophthalmology Trainee Clinical Trial Network (OCTN). Collaborators were asked to comment on periprocedural practices of treatment of nAMD in their eye unit including treatment location and injectors, clinical assessment and routine observation in patients undergoing intravitreal treatment. RESULTS: Data were available from 26 units around the United Kingdom. Survey methodology refinement was approximately 3 months, and the average response time was 4.9 ± 2.4 days. The majority of responders confirmed that treatment was undertaken as a "one-stop" service (n = 15, 58%), delivered in a clean room (n = 23, 88%). In the majority of units, doctors administered injections (n = 24, 92%), but significant treatment was also given by nurse injectors (n = 21, 81%). All collaborators reported that patients underwent visual acuity testing and optical coherence tomography imaging at all visits, but other imaging including fundus fluorescein angiography (FFA) did not take place in all cases (n = 17, 65%) and only at baseline visit. CONCLUSIONS: These results demonstrate the feasibility of conducting ophthalmology trainee led and delivered observational studies. Our results show that FFA is not routinely used in the diagnosis of nAMD in the units sampled; most injections are carried out in a clean room, and ophthalmic nurses delivering injections is a highly prevalent model of care in the UK