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Retrospective studies provide conflicting interpretations of the effect of inherited genetic factors on the prognosis of patients with breast cancer. The primary aim of this study was to determine the effect of a germline BRCA1 or BRCA2 mutation on breast cancer outcomes in patients with young-onset breast cancer. We did a prospective cohort study of female patients recruited from 127 hospitals in the UK aged 40 years or younger at first diagnosis (by histological confirmation) of invasive breast cancer. Patients with a previous invasive malignancy (except non-melanomatous skin cancer) were excluded. Patients were identified within 12 months of initial diagnosis. BRCA1 and BRCA2 mutations were identified using blood DNA collected at recruitment. Clinicopathological data, and data regarding treatment and long-term outcomes, including date and site of disease recurrence, were collected from routine medical records at 6 months, 12 months, and then annually until death or loss to follow-up. The primary outcome was overall survival for all BRCA1 or BRCA2 mutation carriers (BRCA-positive) versus all non-carriers (BRCA-negative) at 2 years, 5 years, and 10 years after diagnosis. A prespecified subgroup analysis of overall survival was done in patients with triple-negative breast cancer. Recruitment was completed in 2008, and long-term follow-up is continuing. Between Jan 24, 2000, and Jan 24, 2008, we recruited 2733 women. Genotyping detected a pathogenic BRCA mutation in 338 (12%) patients (201 with BRCA1, 137 with BRCA2). After a median follow-up of 8·2 years (IQR 6·0–9·9), 651 (96%) of 678 deaths were due to breast cancer. There was no significant difference in overall survival between BRCA-positive and BRCA-negative patients in multivariable analyses at any timepoint (at 2 years: 97·0% [95% CI 94·5–98·4] vs 96·6% [95·8–97·3]; at 5 years: 83·8% [79·3–87·5] vs 85·0% [83·5–86·4]; at 10 years: 73·4% [67·4–78·5] vs 70·1% [67·7–72·3]; hazard ratio [HR] 0·96 [95% CI 0·76–1·22]; p=0·76). Of 558 patients with triple-negative breast cancer, BRCA mutation carriers had better overall survival than non-carriers at 2 years (95% [95% CI 89–97] vs 91% [88–94]; HR 0·59 [95% CI 0·35–0·99]; p=0·047) but not 5 years (81% [73–87] vs 74% [70–78]; HR 1·13 [0·70–1·84]; p=0·62) or 10 years (72% [62–80] vs 69% [63–74]; HR 2·12 [0·82–5·49]; p= 0·12). Patients with young-onset breast cancer who carry a BRCA mutation have similar survival as non-carriers. However, BRCA mutation carriers with triple-negative breast cancer might have a survival advantage during the first few years after diagnosis compared with non-carriers. Decisions about timing of additional surgery aimed at reducing future second primary-cancer risks should take into account patient prognosis associated with the first malignancy and patient preferences. Cancer Research UK, the UK National Cancer Research Network, the Wessex Cancer Trust, Breast Cancer Now, and the PPP Healthcare Medical Trust Grant.

Biologically distinct subtypes of diffuse large B-cell lymphoma can be identified using gene-expression analysis to determine their cell of origin, corresponding to germinal centre or activated B cell. We aimed to investigate whether adding bortezomib to standard therapy could improve outcomes in patients with these subtypes. In a randomised evaluation of molecular guided therapy for diffuse large B-cell lymphoma with bortezomib (REMoDL-B), an open-label, adaptive, randomised controlled, phase 3 superiority trial, participants were recruited from 107 cancer centres in the UK (n=94) and Switzerland (n=13). Eligible patients had previously untreated, histologically confirmed diffuse large B-cell lymphoma with sufficient diagnostic material from initial biopsies for gene-expression profiling and pathology review; were aged 18 years or older; had ECOG performance status of 2 or less; had bulky stage I or stage II–IV disease requiring full-course chemotherapy; had measurable disease; and had cardiac, lung, renal, and liver function sufficient to tolerate chemotherapy. Patients initially received one 21-day cycle of standard rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP; rituximab 375 mg/m2, cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, and vincristine 1·4 mg/m2 [to a maximum of 2 mg total dose] intravenously on day 1 of the cycle, and prednisolone 100 mg orally once daily on days 1–5). During this time, we did gene-expression profiling using whole genome cDNA-mediated annealing, selection, extension, and ligation assay of tissue from routine diagnostic biopsy samples to determine the cell-of-origin subtype of each participant (germinal centre B cell, activated B cell, or unclassified). Patients were then centrally randomly assigned (1:1) via a web-based system, with block randomisation stratified by international prognostic index score and cell-of-origin subtype, to continue R-CHOP alone (R-CHOP group; control), or with bortezomib (RB-CHOP group; experimental; 1·3 mg/m2 intravenously or 1·6 mg/m2 subcutaneously) on days 1 and 8 for cycles two to six. If RNA extracted from the diagnostic tissues was of insufficient quality or quantity, participants were given R-CHOP as per the control group. The primary endpoint was 30-month progression-free survival, for the germinal centre and activated B-cell population. The primary analysis was on the modified intention-to-treat population of activated and germinal centre B-cell population. Safety was assessed in all participants who were given at least one dose of study drug. We report the progression-free survival and safety outcomes for patients in the follow-up phase after the required number of events occurred. This study was registered at ClinicalTrials.gov, number NCT01324596, and recruitment and treatment has completed for all participants, with long-term follow-up ongoing. Between June 2, 2011, and June 10, 2015, 1128 eligible patients were registered, of whom 918 (81%) were randomly assigned to receive treatment (n=459 to R-CHOP, n=459 to RB-CHOP), comprising 244 (26·6%) with activated B-cell disease, 475 (51·7%) with germinal centre B cell disease, and 199 (21·7%) with unclassified disease. At a median follow-up of 29·7 months (95% CI 29·0–32·0), we saw no evidence for a difference in progression-free survival in the combined germinal centre and activated B-cell population between R-CHOP and RB-CHOP (30-month progression-free survival 70·1%, 95% CI 65·0–74·7 vs 74·3%, 69·3–78·7; hazard ratio 0·86, 95% CI 0·65–1·13; p=0·28). The most common grade 3 or worse adverse event was haematological toxicity, reported in 178 (39·8%) of 447 patients given R-CHOP and 187 (42·1%) of 444 given RB-CHOP. However, RB-CHOP was not associated with increased haematological toxicity and 398 [87·1%] of 459 participants assigned to receive RB-CHOP completed six cycles of treatment. Grade 3 or worse neuropathy occurred in 17 (3·8%) patients given RB-CHOP versus eight (1·8%) given R-CHOP. Serious adverse events occurred in 190 (42·5%) patients given R-CHOP, including five treatment-related deaths, and 223 (50·2%) given RB-CHOP, including four treatment-related deaths. This is the first large-scale study in diffuse large B-cell lymphoma to use real-time molecular characterisation for prospective stratification, randomisation, and subsequent analysis of biologically distinct subgroups of patients. The addition of bortezomib did not improve progression-free survival. Janssen-Cilag, Bloodwise, and Cancer Research UK.

Background PREDICT is a breast cancer prognostic and treatment benefit model implemented online. The overall fit of the model has been good in multiple independent case series, but PREDICT has been shown to underestimate breast cancer specific mortality in women diagnosed under the age of 40. Another limitation is the use of discrete categories for tumour size and node status resulting in ‘step’ changes in risk estimates on moving between categories. We have refitted the PREDICT prognostic model using the original cohort of cases from East Anglia with updated survival time in order to take into account age at diagnosis and to smooth out the survival function for tumour size and node status. Methods Multivariable Cox regression models were used to fit separate models for ER negative and ER positive disease. Continuous variables were fitted using fractional polynomials and a smoothed baseline hazard was obtained by regressing the baseline cumulative hazard for each patients against time using fractional polynomials. The fit of the prognostic models were then tested in three independent data sets that had also been used to validate the original version of PREDICT. Results In the model fitting data, after adjusting for other prognostic variables, there is an increase in risk of breast cancer specific mortality in younger and older patients with ER positive disease, with a substantial increase in risk for women diagnosed before the age of 35. In ER negative disease the risk increases slightly with age. The association between breast cancer specific mortality and both tumour size and number of positive nodes was non-linear with a more marked increase in risk with increasing size and increasing number of nodes in ER positive disease. The overall calibration and discrimination of the new version of PREDICT (v2) was good and comparable to that of the previous version in both model development and validation data sets. However, the calibration of v2 improved over v1 in patients diagnosed under the age of 40. Conclusions The PREDICT v2 is an improved prognostication and treatment benefit model compared with v1. The online version should continue to aid clinical decision making in women with early breast cancer.

Background Chronic kidney disease (CKD) is a very common long-term condition and powerful risk factor for cardiovascular disease (CVD). Low-dose aspirin is of proven benefit in the secondary prevention of myocardial infarction (MI) and stroke in people with pre-existing CVD. However, in people without CVD, the rates of MI and stroke are much lower, and the benefits of aspirin in the primary prevention of CVD are largely balanced by an increased risk of bleeding. People with CKD are at greatly increased risk of CVD and so the absolute benefits of aspirin are likely to be greater than in lower-risk groups, even if the relative benefits are the same. Post hoc evidence suggests the relative benefits may be greater in the CKD population but the risk of bleeding may also be higher. A definitive study of aspirin for primary prevention in this high-risk group, recommended by the National Institute for Health and Care Excellence (NICE) in 2014, has never been conducted. The question has global significance given the rising burden of CKD worldwide and the low cost of aspirin. Methods ATTACK is a pragmatic multicentre, prospective, randomised, open-label, blinded endpoint adjudication superiority trial of aspirin 75 mg daily vs. standard care for the primary prevention of CVD in 25,210 people aged 18 years and over with CKD recruited from UK Primary Care. Participants aged 18 years and over with CKD (GFR category G1-G4) will be identified in Primary Care and followed up using routinely collected data and annual questionnaires for an average of 5 years. The primary outcome is the time to first major vascular event (composite of non-fatal MI, non-fatal stroke and cardiovascular death [excluding confirmed intracranial haemorrhage and other fatal cardiovascular haemorrhage]). Deaths from other causes (including fatal bleeding) will be treated as competing events. The study will continue until 1827 major vascular events have occurred. The principal safety outcome is major intracranial and extracranial bleeding; this is hypothesised to be increased in those randomised to take aspirin. The key consideration is then whether and to what extent the benefits of aspirin from the expected reduction in CVD events exceed the risks of major bleeding. Discussion This will be the first definitive trial of aspirin for primary CVD prevention in CKD patients. The research will be of great interest to clinicians, guideline groups and policy-makers, in the UK and globally, particularly given the high and rising prevalence of CKD that is driven by population ageing and epidemics of obesity and diabetes. The low cost of aspirin means that a positive result would be of relevance to low- and middle-income countries and the impact in the developed world less diluted by any inequalities in health care access. Trial registration ISRCTN: ISRCTN40920200 . EudraCT: 2018-000644-26 . ClinicalTrials.gov: NCT03796156

Background Mesothelioma is an incurable, apoptosis-resistant cancer caused in most cases by previous exposure to asbestos and is increasing in incidence. It represents a growing health burden but remains under-researched, with limited treatment options. Early promising signals of activity relating to both PD-L1- and PD-1-targeted treatment in mesothelioma implicate a dependency of mesothelioma on this immune checkpoint. There is a need to evaluate checkpoint inhibitors in patients with relapsed mesothelioma where treatment options are limited. Methods The addition of 12 months of nivolumab (anti-PD1 antibody) to standard practice will be conducted in the UK using a randomised, placebo-controlled phase III trial (the Cancer Research UK CONFIRM trial). A total of 336 patients with pleural or peritoneal mesothelioma who have received at least two prior lines of therapy will be recruited from UK secondary care sites. Patients will be randomised 2:1 (nivolumab:placebo), stratified according to epithelioid/non-epithelioid, to receive either 240 mg nivolumab monotherapy or saline placebo as a 30-min intravenous infusion. Treatment will be for up to 12 months. We will determine whether the use of nivolumab increases overall survival (the primary efficacy endpoint). Secondary endpoints will include progression-free survival, objective response rate, toxicity, quality of life and cost-effectiveness. Analysis will be performed according to the intention-to-treat principle using a Cox regression analysis for the primary endpoint (and for other time-to-event endpoints). Discussion The outcome of this trial will provide evidence of the potential benefit of the use of nivolumab in the treatment of relapsed mesothelioma. If found to be clinically effective, safe and cost-effective it is likely to become the new standard of care in the UK. Trial registration EudraCT Number: 2016–003111-35 (entered on 21 July 2016); ClinicalTrials.gov, ID: NCT03063450 . Registered on 24 February 2017.

The objective of this study is to compare the efficacy and cost of specialised individually delivered parent training (PT) for preschool children with attention-deficit/hyperactivity disorder (ADHD) against generic group-based PT and treatment as usual (TAU). This is a multi-centre three-arm, parallel group randomised controlled trial conducted in National Health Service Trusts. The participants included in this study were preschool children (33–54 months) fulfilling ADHD research diagnostic criteria. New Forest Parenting Programme (NFPP)—12-week individual, home-delivered ADHD PT programme; Incredible Years (IY)—12-week group-based, PT programme initially designed for children with behaviour problems were the interventions. Primary outcome—Parent ratings of child’s ADHD symptoms (Swanson, Nolan & Pelham Questionnaire—SNAP-IV). Secondary outcomes—teacher ratings (SNAP-IV) and direct observations of ADHD symptoms and parent/teacher ratings of conduct problems. NFPP, IY and TAU outcomes were measured at baseline (T1) and post treatment (T2). NFPP and IY outcomes only were measured 6 months post treatment (T3). Researchers, but not therapists or parents, were blind to treatment allocation. Analysis employed mixed effect regression models (multiple imputations). Intervention and other costs were estimated using standardized approaches. NFPP and IY did not differ on parent-rated SNAP-IV, ADHD combined symptoms [mean difference − 0.009 95% CI (− 0.191, 0.173), p = 0.921] or any other measure. Small, non-significant, benefits of NFPP over TAU were seen for parent-rated SNAP-IV, ADHD combined symptoms [− 0.189 95% CI (− 0.380, 0.003), p = 0.053]. NFPP significantly reduced parent-rated conduct problems compared to TAU across scales (p values < 0.05). No significant benefits of IY over TAU were seen for parent-rated SNAP, ADHD symptoms [− 0.16 95% CI (− 0.37, 0.04), p = 0.121] or parent-rated conduct problems (p > 0.05). The cost per family of providing NFPP in the trial was significantly lower than IY (£1591 versus £2103). Although, there were no differences between NFPP and IY with regards clinical effectiveness, individually delivered NFPP cost less. However, this difference may be reduced when implemented in routine clinical practice. Clinical decisions should take into account parental preferences between delivery approaches.

Background Women with acute uncomplicated urine infection are usually treated with antibiotics. One trial has demonstrated that delayed antibiotic treatment offered without symptom relief results in a modest reduction in antibiotic use. There is some evidence that ibuprofen provides symptom relief and reduces antibiotic use. Uva-ursi, a herbal product, has a traditional use for urinary infection symptom relief. We set out to test: in adult women with suspected UTI who accept the delayed prescription strategy: Do NSAIDs or uva-ursi (a herbal product) provide relief from urinary symptoms and reduce antibiotic use. Methods/design Adult women with suspected urinary tract infection presenting to primary care will be randomised using a factorial trial design in which patients will be randomised to one of two interventions as below: Group 1 – Uva-ursi + advice to take ibuprofen Group 2 – Placebo + advice to take ibuprofen Group 3 – Uva-ursi + no advice to take ibuprofen Group 4 – Placebo + no advice to take ibuprofen Patients and physicians will be blinded to the randomised group for the herb. The main outcome is symptom severity at days 2–4 recorded in a validated, self-report diary used in previous studies. Secondary outcomes include antibiotic use and symptom duration. In total the trial will require 328 patients in order to achieve at least 90% power for the primary endpoint and 80% for the secondary endpoint. In accordance with CONSORT guidelines all comparative analyses will be conducted on an intention-to-treat basis using SPSS or similar package. Discussion The outcomes from this trial have the potential to modify the current approach to the management of acute urinary symptoms with less dependence on the use of antibiotics. Trial registration ISRCTN registry, ID: ISRCTN43397016 . Registered on 11 February 2015.

Background Women who have been treated for breast cancer may identify vasomotor symptoms, such as hot flushes and night sweats (HFNS), as a serious problem. HFNS are unpleasant to experience and can have a significant impact on daily life, potentially leading to reduced adherence to life saving adjuvant hormonal therapy. It is known that Cognitive Behavioural Therapy (CBT) is effective for the alleviation of hot flushes in both well women and women who have had breast cancer. Most women with breast cancer will see a breast care nurse and there is evidence that nurses can be trained to deliver psychological treatments to a satisfactory level, whilst also maintaining treatment fidelity. The research team will assess whether breast care nurses can effectively deliver a CBT intervention to alleviate hot flushes in women with breast cancer. Methods This study is a multi-centre phase III individually randomised controlled trial of group CBT versus usual care to reduce the impact of hot flushes in women with breast cancer. 120–160 women with primary breast cancer experiencing seven or more problematic HFNS a week will be randomised to receive either treatment as usual (TAU) or participation in the group CBT intervention plus TAU (CBT Group). A process evaluation using May’s Normalisation Process Theory will be conducted, as well as practical and organisational issues relating to the implementation of the intervention. Fidelity of implementation of the intervention will be conducted by expert assessment. The cost effectiveness of the intervention will also be assessed. Discussion There is a need for studies that enable effective interventions to be implemented in practice. There is good evidence that CBT is helpful for women with breast cancer who experience HFNS, yet it is not widely available. It is not yet known whether the intervention can be effectively delivered by breast care nurses or implemented in practice. This study will provide information on both whether the intervention can effectively help women with hot flushes and whether and how it can be translated into routine clinical practice. Trial registration ISRCTN 12824632 . Registered 25–01-2017.

Background: The addition of cetuximab (CTX) to perioperative chemotherapy (CT) for operable colorectal liver metastases resulted in a shorter progression-free survival. Details of disease progression are described to further inform the primary study outcome. Methods: A total of 257 KRAS wild-type patients were randomised to CT alone or CT with CTX. Data regarding sites and treatment of progressive disease were obtained for the 109 (CT n =48, CT and CTX n =61) patients with progressive disease at the cut-off date for analysis of November 2012. Results: The liver was the most frequent site of progression (CT 67% (32/48); CT and CTX 66% (40/61)). A higher proportion of patients in the CT and group had multiple sites of progressive disease (CT 8%, 4/48; CT and CTX 23%, 14/61 P =0.04). Further treatment for progressive disease is known for 84 patients of whom 69 received further CT, most frequently irinotecan based. Twenty-two patients, 11 in each arm, received CTX as a further line agent. Conclusions: Both the distribution of progressive disease and further treatment are as expected for such a cohort. The pattern of disease progression seen is consistent with failure of systemic micrometastatic disease control rather than failure of local disease control following liver surgery.

Background The New Forest Parenting Programme (NFPP) is a home-delivered, evidence-based parenting programme to target symptoms of attention-deficit/hyperactivity disorder (ADHD) in preschool children. It has been adapted for use with ‘hard-to-reach’ or ‘difficult-to-treat’ children. This trial will compare the adapted-NFPP with a generic parenting group-based programme, Incredible Years (IY), which has been recommended for children with preschool-type ADHD symptoms. Methods/design This multicentre randomized controlled trial comprises three arms: adapted-NFPP, IY and treatment as usual (TAU). A sample of 329 parents of preschool-aged children with a research diagnosis of ADHD enriched for hard-to-reach and potentially treatment-resistant children will be allocated to the arms in the ratio 3:3:1. Participants in the adapted-NFPP and IY arms receive an induction visit followed by 12 weekly parenting sessions of 1½ hours (adapted-NFPP) or 2½ hours (IY) over 2.5 years. Adapted-NFPP will be delivered as a one-to-one home-based intervention; IY, as a group-based intervention. TAU participants are offered a parenting programme at the end of the study. The primary objective is to test whether the adapted-NFPP produces beneficial effects in terms of core ADHD symptoms. Secondary objectives include examination of the treatment impact on secondary outcomes, a study of cost-effectiveness and examination of the mediating role of treatment-induced changes in parenting behaviour and neuropsychological function. The primary outcome is change in ADHD symptoms, as measured by the parent-completed version of the SNAP-IV questionnaire, adjusted for pretreatment SNAP-IV score. Secondary outcome measures are: a validated index of behaviour during child’s solo play; teacher-reported SNAP-IV (ADHD scale); teacher and parent SNAP-IV (ODD) Scale; Eyberg Child Behaviour Inventory - Oppositional Defiant Disorder scale; Revised Client Service Receipt Inventory - Health Economics Costs measure and EuroQol (EQ5D) health-related quality-of-life measure. Follow-up measures will be collected 6 months after treatment for participants allocated to adapted-NFPP and IY. Discussion This trial will provide evidence as to whether the adapted-NFPP is more effective and cost-effective than the recommended treatment and TAU. It will also provide information about mediating factors (improved parenting and neuropsychological function) and moderating factors (parent and child genetic factors) in any increased benefit. Trial registration Current Controlled Trials, ISRCTN39288126 .