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PARTNER is a prospective, phase II–III, randomized controlled clinical trial that recruited patients with triple-negative breast cancer 1 , 2 , who were germline  BRCA 1 and BRCA2 wild type 3 . Here we report the results of the trial. Patients ( n  = 559) were randomized on a 1:1 basis to receive neoadjuvant carboplatin–paclitaxel with or without 150 mg olaparib twice daily, on days 3 to 14, of each of four cycles (gap schedule olaparib, research arm) followed by three cycles of anthracycline-based chemotherapy before surgery. The primary end point was pathologic complete response (pCR) 4 , and secondary end points included event-free survival (EFS) and overall survival (OS) 5 . pCR was achieved in 51% of patients in the research arm and 52% in the control arm ( P  = 0.753). Estimated EFS at 36 months in the research and control arms was 80% and 79% (log-rank P  > 0.9), respectively; OS was 90% and 87.2% (log-rank P  = 0.8), respectively. In patients with pCR, estimated EFS at 36 months was 90%, and in those with non-pCR it was 70% (log-rank P  < 0.001), and OS was 96% and 83% (log-rank P  < 0.001), respectively. Neoadjuvant olaparib did not improve pCR rates, EFS or OS when added to carboplatin–paclitaxel and anthracycline-based chemotherapy in patients with triple-negative breast cancer who were germline BRCA1 and BRCA2 wild type. ClinicalTrials.gov ID: NCT03150576 . A study details the results of the PARTNER trial, a prospective, randomized controlled trial of the use of neoadjuvant olaparib with carboplatin–paclitaxel chemotherapy in patients with triple-negative breast cancer who were germline BRCA1 and BRCA2  wild type.

Adjuvant trastuzumab significantly improves outcomes for patients with HER2-positive early breast cancer. The standard treatment duration is 12 months but shorter treatment could provide similar efficacy while reducing toxicities and cost. We aimed to investigate whether 6-month adjuvant trastuzumab treatment is non-inferior to the standard 12-month treatment regarding disease-free survival. This study is an open-label, randomised phase 3 non-inferiority trial. Patients were recruited from 152 centres in the UK. We randomly assigned patients with HER2-positive early breast cancer, aged 18 years or older, and with a clear indication for chemotherapy, by a computerised minimisation process (1:1), to receive either 6-month or 12-month trastuzumab delivered every 3 weeks intravenously (loading dose of 8 mg/kg followed by maintenance doses of 6 mg/kg) or subcutaneously (600 mg), given in combination with chemotherapy (concurrently or sequentially). The primary endpoint was disease-free survival, analysed by intention to treat, with a non-inferiority margin of 3% for 4-year disease-free survival. Safety was analysed in all patients who received trastuzumab. This trial is registered with EudraCT (number 2006–007018–39), ISRCTN (number 52968807), and ClinicalTrials.gov (number NCT00712140). Between Oct 4, 2007, and July 31, 2015, 2045 patients were assigned to 12-month trastuzumab treatment and 2044 to 6-month treatment (one patient was excluded because they were double randomised). Median follow-up was 5·4 years (IQR 3·6–6·7) for both treatment groups, during which a disease-free survival event occurred in 265 (13%) of 2043 patients in the 6-month group and 247 (12%) of 2045 patients in the 12-month group. 4-year disease-free survival was 89·4% (95% CI 87·9–90·7) in the 6-month group and 89·8% (88·3–91·1) in the 12-month group (hazard ratio 1·07 [90% CI 0·93–1·24], non-inferiority p=0·011), showing non-inferiority of the 6-month treatment. 6-month trastuzumab treatment resulted in fewer patients reporting severe adverse events (373 [19%] of 1939 patients vs 459 [24%] of 1894 patients, p=0·0002) or stopping early because of cardiotoxicity (61 [3%] of 1939 patients vs 146 [8%] of 1894 patients, p<0·0001). We have shown that 6-month trastuzumab treatment is non-inferior to 12-month treatment in patients with HER2-positive early breast cancer, with less cardiotoxicity and fewer severe adverse events. These results support consideration of reduced duration trastuzumab for women at similar risk of recurrence as to those included in the trial. UK National Institute for Health Research, Health Technology Assessment Programme.

PARTNER is a prospective, phase II-III, randomised controlled clinical trial, which recruited patients with Triple Negative Breast Cancer (TNBC) , who were gBRCA wild type (gBRCAwt) . Patients (n=559) were randomised on a 1:1 basis to neoadjuvant carboplatin with paclitaxel +/- olaparib 150mg twice daily, days 3 to 14, for 4 cycles (gap schedule olaparib, research arm) followed by 3 cycles of anthracycline chemotherapy before surgery. The primary endpoint was pathological complete response (pCR) , and secondary endpoints included event-free survival (EFS), and overall survival (OS) . pCR was achieved in 51% in the research arm and 52% in the control arm (p=0.753). Estimated EFS at 36 months in research and control arms were 80% and 79% (log-rank p>0.9); OS were 90% and 87.2% (log-rank p=0.8) respectively. In patients with pCR, estimated EFS at 36 months was 90%, and with non-pCR was 70% (log-rank p < 0.001) and OS was 96% and 83% (log-rank p < 0.001) respectively. Neo-adjuvant olaparib did not improve pCR rates, EFS or OS when added to carboplatin/paclitaxel and anthracycline chemotherapy in patients with TNBC (gBRCAwt). This is in marked contrast to the major benefit of olaparib (gap schedule) in those with gBRCA pathogenic variants (gBRCAm) which is reported separately (gBRCAm article). ClinicalTrials.gov ID NCT03150576.

Tamoxifen-resistance, both acquired and primary (de novo), is a major clinical problem in the management of breast cancer. One potential mechanism for resistance is for the effector pathways, via which activated oestrogen receptor leads to proliferation of the cell, to become independent of the oestrogen receptor (ER) and function autonomously. There is good experimental evidence to implicate growth factors and growth factor receptors as elements of these effector pathways. This project was designed to test this hypothesis in clinical material from patients who had developed tamoxifen-resistance. In vitro the erbB family of growth factors/receptors play an important role in the hormonal regulation of breast cancer cell growth. They have also been implicated in the mechanism of action of anti-oestrogens and also in the development of hormone-independence and tamoxifen-resistance in breast cancer cell lines. Clinically there is some supportive evidence for the importance of these pathways, but the data are very limited. The project involved the collection of pre-treatment and relapse material from patients identified as having tamoxifen-resistance. Wherever possible paired pre-treatment and relapse specimens were collected from each patient. Expression of growth factors of the erbB and TGFβ families was assessed immunohistochemically and compared between relapse and pre-treatment samples, looking for evidence of changes which might have caused the development of resistance. Overall the results did not find evidence to implicate the EGFR family in acquired tamoxifen-resistance, though TGFβ1 expression was reduced in relapse samples from these patients and may have played a role in the development of resistance. In the de novo resistant-tumours, results confirmed previous findings that expression of either of the receptors EGFR or c-erbB2 resulted in an increased likelihood of de novo resistance and may have been responsible for this resistance in a proportion of cases. TGFβ expression was increased during tamoxifen therapy in those de novo-resistant tumours expressing EGFR and may have been the mechanism for progression in those cases. However in the receptor-negative cases, which were the majority even in this group of patients, acquisition of receptor expression did not account for resistance. A secondary aim of the project was to look for clinical evidence to support the in vitro data showing effects of anti-oestrogen treatment on expression of these growth factors and thereby providing clinical data to support the initial hypothesis. Small clinical studies have supported these findings previously. No such evidence was found for either of the ligands TGFβ or amphiregulin in this study. However, evidence was found to link TGFβ expression to the presence of functional ER (i.e. PgR expression) in the pre-treatment samples from initially responsive cases, the first time such an association has been demonstrated in vivo. Prediction of response to first and second-line endocrine therapy was not aided by assessing the expression of these growth factors/receptors, except in ER-negative cases, where expression of EGFR or c-erbB2 resulted in a complete lack of response to tamoxifen. Second-line endocrine responses occurred in the face of EGFR and c-erbB2 expression.

Background Healthcare systems data (HCSD) could improve the efficiency of clinical trials, but their accuracy and validity are uncertain. Our objective was to assess the accuracy of HCSD as the sole method of outcome detection in the REstart or STop Antithrombotics Randomised Trial (RESTART; ISRCTN71907627) compared with adjudicated questionnaire follow-up and compare estimates of treatment effect. Methods RESTART was a prospective, open, assessor-blind, parallel-group randomised controlled trial (RCT) of antiplatelet therapy after intracerebral haemorrhage (ICH) in the UK. We included 496 (92%) of 537 RESTART participants, who were resident in England or Scotland at randomisation. Computerised randomisation incorporating minimisation allocated participants (1:1) to start or avoid antiplatelet therapy. RESTART used annual questionnaires to detect its primary outcome (recurrent ICH) and secondary outcome (a composite of haemorrhagic or ischemic major adverse cardiovascular events [MACE]) over a median of 2.0 years; an independent adjudication committee verified outcomes using medical records and brain imaging. We obtained ICD10-coded HCSD on hospital admissions and deaths in England and Scotland to identify primary and secondary outcomes. We compared HCSD with a reference standard of adjudicated outcomes. We estimated the effects of antiplatelet therapy using HCSD alone in a Cox proportional hazards model adjusted for minimisation variables. Results In the original RESTART trial, 31 people experienced a primary outcome event. HCSD had sensitivity of 84% (95% CI 66 to 95%) and positive predictive value of 68% (51 to 82%) for recurrent ICH. HCSD estimated an effect of antiplatelet therapy (adjusted hazard ratio [aHR] 0.51, 95% CI 0.27 to 0.98; p  = 0.044) that was almost identical to adjudicated outcomes (aHR 0.51, 95% CI 0.25 to 1.03; p  = 0.060). HCSD had sensitivity of 84% (76 to 91%) and positive predictive value of 78% (69 to 85%) for MACE, on which HCSD estimated an effect of antiplatelet therapy (aHR 0.81, 95% CI 0.56 to 1.16; p  = 0.247) that was similar to adjudicated outcomes (aHR 0.65, 95% CI 0.44 to 0.95; p  = 0.025). Conclusions In a RCT of antiplatelet therapy for people with ICH, HCSD was reasonably accurate and provided similar estimates of treatment effect compared with adjudicated outcomes. Trial registration ISRCTN71907627 . Registered on 25 April 2013.

Even as progress has been made in extending access to safe water and sanitation under the Sustainable Development Goals (SDGs), substantial disparities in water, sanitation, and hygiene (WASH) services persist in high-income countries around the world. These gaps in service occur disproportionately among historically marginalized, rural, informal, and Indigenous communities. This paper synthesizes results from a side session convened at the 2020 University of North Carolina, Chapel Hill, Water and Health conference focused on knowledge gaps, challenges, and approaches to achieve SDG 6 among marginalized communities in high-income countries. We provide approaches and next steps to advance sustainable WASH services in communities that have often been overlooked.

Background In the treatment of phenylketonuria (PKU), there was disparity between UK dietitians regarding interpretation of how different foods should be allocated in a low phenylalanine diet (allowed without measurement, not allowed, or allowed as part of phenylalanine exchanges). This led to variable advice being given to patients. Methodology In 2015, British Inherited Metabolic Disease Group (BIMDG) dietitians ( n  = 70) were sent a multiple-choice questionnaire on the interpretation of protein from food-labels and the allocation of different foods. Based on majority responses, 16 statements were developed. Over 18-months, using Delphi methodology, these statements were systematically reviewed and refined with a facilitator recording discussion until a clear majority was attained for each statement. In Phase 2 and 3 a further 7 statements were added. Results The statements incorporated controversial dietary topics including: a practical ‘scale’ for guiding calculation of protein from food-labels; a general definition for exchange-free foods; and guidance for specific foods. Responses were divided into paediatric and adult groups. Initially, there was majority consensus (≥86%) by paediatric dietitians ( n  = 29) for 14 of 16 statements; a further 2 structured discussions were required for 2 statements, with a final majority consensus of 72% ( n  = 26/36) and 64% ( n  = 16/25). In adult practice, 75% of dietitians agreed with all initial statements for adult patients and 40% advocated separate maternal-PKU guidelines. In Phase 2, 5 of 6 statements were agreed by ≥76% of respondents with one statement requiring a further round of discussion resulting in 2 agreed statements with a consensus of ≥71% by dietitians in both paediatric and adult practice. In Phase 3 one statement was added to elaborate further on an initial statement, and this received 94% acceptance by respondents. Statements were endorsed by the UK National Society for PKU. Conclusions The BIMDG dietitians group have developed consensus dietetic statements that aim to harmonise dietary advice given to patients with PKU across the UK, but monitoring of statement adherence by health professionals and patients is required.