Results of the c-TRAK TN trial: a clinical trial utilising ctDNA mutation tracking to detect molecular residual disease and trigger intervention in patients with moderate- and high-risk early-stage triple-negative breast cancer.

BACKGROUND: Post-treatment detection of circulating tumour DNA (ctDNA) in early-stage triple-negative breast cancer (TNBC) patients predicts high risk of relapse. c-TRAK TN assessed the utility of prospective ctDNA surveillance in TNBC and the activity of pembrolizumab in patients with ctDNA detected [ctDNA positive (ctDNA+)]. PATIENTS AND METHODS: c-TRAK TN, a multicentre phase II trial, with integrated prospective ctDNA surveillance by digital PCR, enrolled patients with early-stage TNBC and residual disease following neoadjuvant chemotherapy, or stage II/III with adjuvant chemotherapy. ctDNA surveillance comprised three-monthly blood sampling to 12 months (18 months if samples were missed due to coronavirus disease), and ctDNA+ patients were randomised 2 : 1 to intervention : observation. ctDNA results were blinded unless patients were allocated to intervention, when staging scans were done and those free of recurrence were offered pembrolizumab. A protocol amendment (16 September 2020) closed the observation group; all subsequent ctDNA+ patients were allocated to intervention. Co-primary endpoints were (i) ctDNA detection rate and (ii) sustained ctDNA clearance rate on pembrolizumab (NCT03145961). RESULTS: Two hundred and eight patients registered between 30 January 2018 and 06 December 2019, 185 had tumour sequenced, 171 (92.4%) had trackable mutations, and 161 entered ctDNA surveillance. Rate of ctDNA detection by 12 months was 27.3% (44/161, 95% confidence interval 20.6% to 34.9%). Seven patients relapsed without prior ctDNA detection. Forty-five patients entered the therapeutic component (intervention n = 31; observation n = 14; one observation patient was re-allocated to intervention following protocol amendment). Of patients allocated to intervention, 72% (23/32) had metastases on staging at the time of ctDNA+, and 4 patients declined pembrolizumab. Of the five patients who commenced pembrolizumab, none achieved sustained ctDNA clearance. CONCLUSIONS: c-TRAK TN is the first prospective study to assess whether ctDNA assays have clinical utility in guiding therapy in TNBC. Patients had a high rate of metastatic disease on ctDNA detection. Findings have implications for future trial design, emphasising the importance of commencing ctDNA testing early, with more sensitive and/or frequent ctDNA testing regimes.

'I know it's not normal but it's normal to me, and that's all that matters': experiences of young adults conceived through egg donation, sperm donation, and surrogacy.

STUDY QUESTION: What are thoughts and feelings of young adults born following egg donation, sperm donation, and surrogacy? SUMMARY ANSWER: Young adults felt either unconcerned or positive about the method of their conception. WHAT IS KNOWN ALREADY: Much of what we know about adults born to heterosexual couples following anonymous donation has come from samples of donor conceived people who had found out about their origins during adulthood. There have been no studies of how young adults born through surrogacy feel about their conception and towards their surrogate. STUDY DESIGN, SIZE, DURATION: Thirty-five young adults were interviewed as part of the seventh phase of a larger multi-method, multi-informant longitudinal study of assisted conception families in the UK. Adults were conceived using either egg donation, sperm donation, gestational surrogacy, or genetic surrogacy and were raised in households headed by heterosexual couples. PARTICIPANTS/MATERIALS, SETTING, METHODS: Participants had a mean age of 20 years and were born following traditional surrogacy (n = 10), gestational surrogacy (n = 5), egg donation (n = 11), or sperm donation (n = 9). All young adults born following sperm donation and most (n = 10) born from egg donation had an anonymous donor. In all surrogacy arrangements, the parents had met the surrogate prior to treatment. The majority of young adults were told about their conception by the age of 4 years. Participants were interviewed over the internet using a semi-structured interview. Interviews were transcribed verbatim and analysed using qualitative content analysis to understand young adults' thoughts and experiences related to their conception and whether they were interested in meeting their donor or surrogate. MAIN RESULTS AND THE ROLE OF CHANCE: Fourteen (40%) young adults felt their conception made them feel special or unique, with the remainder feeling either neutral or unconcerned (n = 21, 60%). A higher proportion of young adults conceived using egg donation (n = 8, 73%) felt unique/special compared to young adults born following sperm donation and surrogacy. For 10 of the young adults, their feelings about their conception had changed over time, with most becoming more positive (n = 9, 26%). For most young adults (n = 22, 63%), conception was rarely or infrequently discussed with others. However, when it was, these conversations were largely conducted with ease. Most (n = 25, 71%) did not know other individuals born through the same method of conception as themselves, and the vast majority (n = 34, 97%) were not members of any support groups. For the 25 young adults not in contact with their donor or surrogate, 11 wished to meet them, 8 did not want to have contact, and 6 were unsure. Young adults in contact with their donor or surrogate had varying levels of closeness to them. Only one young adult had searched for the identity of their donor. LIMITATIONS, REASONS FOR CAUTION: Of the 47 young adults invited to participate in the present study, 35 agreed to take part resulting in a response rate of 74%. It is therefore not known how those who did not take part felt about their conception. Given that the families reported here had been taking part in this longitudinal study from when the target child was aged 1 year, they may have been more likely to discuss the child's conception than other families. The study also utilized self-report measures, which may have been prone to social desirability, with donor conceived young adults wanting to present their experiences in a positive light. WIDER IMPLICATIONS OF THE FINDINGS: The findings suggest that young adults born through surrogacy and donor conception do not feel negatively about their birth and this may be a consequence of the young age at which they found out about their conception. Although some young adults said they wished to meet their donor, this did not necessarily mean they were actively searching for them. STUDY FUNDING/COMPETING INTEREST(S): The study was funded by the Wellcome Trust [grant number 208013/Z/17/Z]. The authors have no conflicts of interest to declare. TRIAL REGISTRATION NUMBER: N/A.

Value of ultrasound in assessing response to neoadjuvant chemotherapy in breast cancer.

AIM: To analyse the utility of ultrasound in assessing response to neoadjuvant chemotherapy (NAC) and predicting residual cancer burden (RCB) index and pathological complete response (pCR) MATERIALS AND METHODS: This was a retrospective study with 417 patients over 7 years. The difference in longest diameter (LD) of the index lesion from baseline to end, baseline to mid, and mid to end was evaluated with respect to RCB class using logistic regression and ordered logistic regression. RESULTS: Change in LD measurements from baseline to end, baseline to mid, and mid to end of chemotherapy as a predictor of RCB class show a negative relationship with a statistically significant association. This would suggest that a smaller change in LD measurements would be associated with an eventual higher RCB class. Change in LD measurements from baseline to end and baseline to mid chemotherapy as a predictor of pCR class show a negative relationship with a statistically significant association (p<0.05). This similarly indicates an inversely proportional relationship between changes in LD measurements and RCB class 0 for baseline to end and baseline to mid. CONCLUSION: This study has shown significance in reducing LD measurements on ultrasound as a predictor of PCR and RCB class. This adds weight to the current practice of using ultrasound at the start, mid and end of chemotherapy cycles to monitor NACT responses.

An international, open-label, randomised trial comparing a two-step approach versus the standard three-step approach of the WHO analgesic ladder in patients with cancer.

BACKGROUND: Worldwide, cancer pain management follows the World Health Organization (WHO) three-step analgesic ladder. Using weak opioids (e.g. codeine) at step 2 is debatable with low-dose strong opioids being potentially better, particularly in low- and middle-income countries where weak opioids are expensive. We wanted to assess the efficiency, safety and cost of omitting step 2 of the WHO ladder. PATIENTS AND METHODS: We carried out an international, open-label, randomised (1 : 1) parallel group trial. Eligible patients had cancer, pain ≥4/10 on a 0-10 numerical rating scale, required at least step 1 (paracetamol) of the WHO ladder and were randomised to the control arm (weak opioid, step 2 of the WHO ladder) or the experimental arm (strong opioid, step 3). Primary outcome was time to stable pain control (3 consecutive days with pain ≤3). Secondary outcomes included distress, opioid-related side-effects and costs. The primary outcome analysis was by intention to treat and the follow-up was for 20 days. RESULTS: One hundred and fifty-three patients were randomised (76 control, 77 experimental). There was no statistically significant difference in time to stable pain control between the arms, P = 0.667 (log-rank test). The adjusted hazard ratio for the control arm was 1.03 (95% confidence interval 0.72-1.49). In the control arm, 38 patients (53%) needed to change to a strong opioid due to ineffective analgesia. The median time to change was day 6 (interquartile range 4-11). Compared to the control arm, patients in the experimental arm had less nausea (P = 0.009) and costs were less. CONCLUSION: This trial provides some evidence that the two-step approach is an alternative option for cancer pain management.

CYP2D6 genotype predicts tamoxifen discontinuation and drug response: a secondary analysis of the KARISMA trial.

BACKGROUND: Guidelines regarding whether tamoxifen should be prescribed based on women's cytochrome P450 2D6 (CYP2D6) genotypes are conflicting and have caused confusion. This study aims to investigate if CYP2D6 metabolizer status is associated with tamoxifen-related endocrine symptoms, tamoxifen discontinuation, and mammographic density change. PATIENTS AND METHODS: We used data from 1440 healthy women who participated the KARISMA dose determination trial. Endocrine symptoms were measured using a modified Functional Assessment of Cancer Therapy - Endocrine Symptoms (FACT-ES) questionnaire. Change in mammographic density was measured and used as a proxy for tamoxifen response. Participants were genotyped and categorized as poor, intermediate, normal, or ultrarapid CYP2D6 metabolizers. RESULTS: The median endoxifen level per mg oral tamoxifen among poor, intermediate, normal and ultrarapid CYP2D6 metabolizers were 0.18 ng/ml, 0.38 ng/ml, 0.56 ng/ml and 0.67 ng/ml, respectively. Ultrarapid CYP2D6 metabolizers were more likely than other groups to report a clinically relevant change in cold sweats, hot flash, mood swings, being irritable, as well as the overall modified FACT-ES score, after taking tamoxifen. The 6-month tamoxifen discontinuation rates among poor, intermediate, normal, and ultrarapid CYP2D6 metabolizers were 25.7%, 23.6%, 28.6%, and 44.4%, respectively. Among those who continued and finished the 6-month tamoxifen intervention, the mean change in dense area among poor, intermediate, normal, and ultrarapid CYP2D6 metabolizers were -0.8 cm2, -4.5 cm2, -4.1 cm2, and -8.0 cm2 respectively. CONCLUSIONS: Poor CYP2D6 metabolizers are likely to experience an impaired response to tamoxifen, measured through mammographic density reduction. In contrast, ultrarapid CYP2D6 metabolizers are at risk for exaggerated response with pronounced adverse effects that may lead to treatment discontinuation.

Technological readiness and implementation of genomic-driven precision medicine for complex diseases.

The fields of human genetics and genomics have generated considerable knowledge about the mechanistic basis of many diseases. Genomic approaches to diagnosis, prognostication, prevention and treatment - genomic-driven precision medicine (GDPM) - may help optimize medical practice. Here, we provide a comprehensive review of GDPM of complex diseases across major medical specialties. We focus on technological readiness: how rapidly a test can be implemented into health care. Although these areas of medicine are diverse, key similarities exist across almost all areas. Many medical areas have, within their standards of care, at least one GDPM test for a genetic variant of strong effect that aids the identification/diagnosis of a more homogeneous subset within a larger disease group or identifies a subset with different therapeutic requirements. However, for almost all complex diseases, the majority of patients do not carry established single-gene mutations with large effects. Thus, research is underway that seeks to determine the polygenic basis of many complex diseases. Nevertheless, most complex diseases are caused by the interplay of genetic, behavioural and environmental risk factors, which will likely necessitate models for prediction and diagnosis that incorporate genetic and non-genetic data.

Tanzanian men's engagement in household chores is associated with improved antenatal care seeking and maternal health.

BACKGROUND: Male support for partners' antenatal care (ANC) has the potential to improve women's care-seeking and maternal health outcomes. This study describes factors that are associated with men's involvement in household tasks and explores the relationship between men's help with tasks and women's ANC-seeking, diet and workload during pregnancy as well as other health behaviors. METHODS: This study was conducted in five Lake Zone regions of Tanzania. Cross-sectional surveys were carried out among approximately 10,000 households that had children under the age of 2 years. Surveys were administered to mothers of children less than 2 years and where available, their male partners. Data were collected between December 2015 and May 2020, in conjunction with a large-scale campaign aimed at reducing childhood stunting by changing the behavior of mothers, caregivers, and decision makers. Data analysis included bivariate analysis and logistic regression modeling. RESULTS: Men's engagement in household activities was significantly associated with living in an urban setting, being younger, having at least some formal schooling, early verbal interactions with their children, and male involvement in healthcare decisions. Additionally, mothers of male partners that were engaged in household activities were significantly older and more likely to have at least some secondary school education. Relative to households where men only infrequently helped out with chores or not at all, women from households where men frequently helped were significantly more likely to have taken iron tablets during pregnancy, report having eaten more than usual, lessening their household workload during their most recent pregnancy, and more likely to have played with their child in the week prior to the survey. CONCLUSION: Male's participation in household tasks is associated with a general improvement in mother's ANC behaviors. Implicit in these findings is that general primary education for both men and women has health benefits that transcend socioeconomic class and that future interventions aimed to engage males in household tasks may target older males with less education living in rural areas.

Understanding female and male empowerment in Burkina Faso using the project-level Women's Empowerment in Agriculture Index (pro-WEAI): a longitudinal study.

BACKGROUND: Achieving gender equality and women's empowerment is a major global priority. The purpose of this study was to determine whether the Building the Resilience of Vulnerable Communities in Burkina Faso (BRB) project, an agricultural development program, improved women's empowerment, as measured by the project-level Women's Empowerment in Agriculture Index (pro-WEAI). METHODS: This study used a longitudinal, quasi-experimental study design. Participants included both treatment and comparison groups (total N = 751) comprising female members of savings groups and their husbands or main male household member in Burkina Faso. All participants completed the pro-WEAI questionnaire at both baseline and endline. The treatment group received a comprehensive intervention package consisting of agriculture loans and services, microenterprise loans, and education, nutrition education, and women's empowerment programs including gender-based discussions designed to facilitate personalized changes in gender relations. RESULTS: The proportion of the treatment group achieving empowerment did not change from baseline for women, but improved substantially for men. Women from the comparison group saw an increase in empowerment at endline while men saw a substantial decrease. Gender parity was high for women in both groups at baseline and increased slightly at endline. Women were more likely to have adequate empowerment in input in productive decisions, group membership, and membership in influential groups than men while men were more likely to have adequate empowerment in attitudes about domestic violence, control over use of income, and work balance than women. Participants from the treatment group reported an increase in the average number of empowerment indicators that they were adequate in while the comparison group saw a decrease in average adequacy over time (p = 0.002) after controlling for age, sex, and level of education. CONCLUSION: Despite starting at an empowerment disadvantage, the treatment group experienced gains in individual indicators of empowerment while the comparison group men and women experienced mixed results, with the women gaining, and the men losing empowerment. This research suggests that the BRB intervention may have provided some protection for the treatment group when they faced an economic down-turn prior to the endline, indicative of household resilience. Future research should consider and strengthen relationships between resilience and empowerment.

Interpersonal communication campaign promoting knowledge, attitude, intention, and consumption of iron folic acid tablets and iron rich foods among pregnant Indonesian women.

BACKGROUND AND OBJECTIVES: Indonesia's community health delivery system offers services such as prenatal care and supplementation. Despite accessibility to these services, compliance with supplementation is low, and childhood stunting rates remain high. To address undernutrition, a National Nutrition Communication Campaign (NNCC) - using interpersonal communication (IPC) strategies - was implemented to promote consumption of iron-folic acid (IFA) supplements and iron-rich foods (ATIKA). The purpose of this study was to understand how participation in IPC activities influenced knowledge, attitude/intention, and consumption of IFA supplements and ATIKA among pregnant Indonesian women. METHODS AND STUDY DESIGN: Cross-sectional data came from 766 pregnant women that participated in a survey that was based on the constructs from the Theory of Planned Behavior and Health Belief Model. Adjusted linear and logistic regression models were conducted to analyze the differences between self-reported IPC participants and non-IPC participants. Approximately 20% of women were exposed to the IFA portion of the IPC campaign, and 18% were exposed to the ATIKA portion. RESULTS: Women that were exposed to the campaign reported significantly higher knowledge of IFA tablets and ATIKA, and improved attitudes/intentions towards IFA, compared to non-exposed women. Exposure was not associated with actual consumption behaviors. CONCLUSIONS: These findings suggest that exposure to a low-intensity intervention can increase knowledge but may not be sufficient to impact behavior. As such, future efforts to reduce stunting through improved maternal nutrition should seek to increase exposure, address barriers, understand perceived susceptibility, and improve self-efficacy in order to expand intervention reach in Indonesia.

Real-world treatment in patients with HER2+ metastatic breast cancer : Treatment decisions in HER2+ mBC.

PURPOSE: The landscape of HER2+ metastatic breast cancer (mBC) treatment is changing due to the availability of new anti-HER2 drugs. The purpose of this study was to assess the current treatment patterns and sequences used in HER2+ mBC in the real-world setting. Secondary objectives were to describe the factors that influence the decision to prescribe a first and second-line antitumour treatment. METHODS: Retrospective chart review of 3068 cases in Spain, Italy, the Netherlands and the UK. RESULTS: First and second-line treatments and regimens are consistent with the clinical guidelines, especially for recently initiated treatments. Age and performance status (PS) of patients impact treatment patterns: younger patients received more innovative treatments than elderly patients. In addition, while most patients received a first antitumor treatment, the rate of patients who continue to subsequent lines of therapy is low (55% transitioning from 1st to 2nd line; 58% from 2nd to 3rd line). Age and PS are key factors in the decision to prescribe further antitumor treatment. CONCLUSION: Fewer HER2+ mBC patients than expected receive a second and third line therapy. Guidelines should make specific recommendations for older patients or those with a poor PS.

Risk of recurrence and death in patients with breast cancer after delayed deep inferior epigastric perforator flap reconstruction.

BACKGROUND: Postmastectomy reconstruction using a deep inferior epigastric perforator (DIEP) flap is increasingly being performed in patients with breast cancer. The procedure induces extensive tissue trauma, and it has been hypothesized that the release of growth factors, angiogenic agonists and immunomodulating factors may reactivate dormant micrometastasis. The aim of the present study was to estimate the risk of breast cancer recurrence in patients undergoing DIEP flap reconstruction compared with that in patients treated with mastectomy alone. METHODS: Each patient who underwent delayed DIEP flap reconstruction at Karolinska University Hospital, Sweden, between 1999 and 2013, was compared with up to four controls with breast cancer who did not receive a DIEP flap. The control patients were selected using incidence density matching with respect to age, tumour and nodal status, neoadjuvant therapy and year of mastectomy. The primary endpoint was breast cancer-specific survival. Survival analysis was carried out using Kaplan-Meier survival estimates and Cox proportional hazard regression analysis. RESULTS: The analysis included 250 patients who had 254 DIEP flap reconstructions and 729 control patients. Median follow-up was 89 and 75 months respectively (P = 0·053). Breast cancer recurrence developed in 50 patients (19·7 per cent) in the DIEP group and 174 (23·9 per cent) in the control group (P = 0·171). The 5-year breast cancer-specific survival rate was 92·0 per cent for patients with a DIEP flap and 87·9 per cent in controls (P = 0·032). Corresponding values for 5-year overall survival were 91·6 and 84·7 per cent (P < 0·001). After adjustment for tumour and patient characteristics and treatment, patients without DIEP flap reconstruction had significantly lower overall but not breast cancer-specific survival. CONCLUSION: The present findings do not support the hypothesis that patients with breast cancer undergoing DIEP flap reconstruction have a higher rate of breast cancer recurrence than those who have mastectomy alone.

New horizons in systemic anti-cancer therapy in older people.

Cancer is a disease associated with ageing. Increased life expectancy means that cancer in older adults is becoming an increasingly common problem. There are unique issues to consider when making decisions about cancer treatment in older populations. Unfortunately, however, this group is still under-represented in clinical trials for new cancer therapies meaning there are less evidence-based data to guide management. This article aims to look at how we can optimise the cancer treatment for older patients with a focus on systemic anti-cancer therapy and addressing particular issues around patient selection, improving treatment tolerance and use of newer agents with different toxicity profiles.

A randomised phase II trial and feasibility study of palliative chemotherapy in frail or elderly patients with advanced gastroesophageal cancer (321GO).

BACKGROUND: Elderly patients are commonly under-represented in cancer clinical trials. The 321GO was undertaken in preparation for a definitive phase three trial assessing different chemotherapy regimens in a frail and/or elderly population with advanced gastroesophageal (GO) cancer. METHODS: Patients with advanced GO cancer considered unfit for conventional dose chemotherapy were randomly assigned in a 1 : 1 : 1 ratio to: epirubicin, oxaliplatin and capecitabine (EOX); oxaliplatin and capecitabine (OX); and capecitabine alone (X) (all 80% of full dose and unblinded). The primary end point was patient recruitment over an 18-month period. A registration study recorded treatment choice for all patients with advanced GO cancer at trial centres. RESULTS: A total of 313 patients were considered for palliative chemotherapy for GO cancer over the 18-month period: 115 received full dose treatment, 89 less than standard treatment or entered 321GO and 111 no treatment. Within 321GO, 55 patients were randomly assigned (19 to OX and X; 17 to EOX). Progression-free survival (PFS) for all patients was 4.4 months and by arm 5.4, 5.6 and 3.0 months for EOX, OX and X, respectively. The number of patients with a good overall treatment utility (OTU), a novel patient-centred endpoint, at 12 weeks was 3 (18%), 6 (32%) and 1 (6%) for EOX, OX and X, respectively. At 6 weeks, 22 patients (41%) had experienced a non-haematologic toxicity ⩾grade 3, most commonly lethargy or diarrhoea. The OTU was prognostic for overall survival in patients alive at week 12 (logrank test P=0.0001). CONCLUSIONS: It is feasible to recruit elderly and/or frail patients with advanced GO cancer to a randomised clinical trial. The OX is the preferred regimen for further study. Overall treatment utility shows promise as a comparator between treatment regimens for feasibility and randomised trials in the elderly and/or frail GO cancer population.

Final efficacy and updated safety results of the randomized phase III BEATRICE trial evaluating adjuvant bevacizumab-containing therapy in triple-negative early breast cancer.

BACKGROUND: The purpose of this analysis was to assess the long-term impact of adding bevacizumab to adjuvant chemotherapy for early triple-negative breast cancer (TNBC). METHODS: Patients eligible for the open-label randomized phase III BEATRICE trial had centrally confirmed triple-negative operable primary invasive breast cancer (pT1a-pT3). Investigators selected anthracycline- and/or taxane-based chemotherapy for each patient. After definitive surgery, patients were randomized 1:1 to receive ≥4 cycles of chemotherapy alone or with 1 year of bevacizumab (5 mg/kg/week equivalent). Stratification factors were nodal status, selected chemotherapy, hormone receptor status, and type of surgery. The primary end point was invasive disease-free survival (IDFS; previously reported). Secondary outcome measures included overall survival (OS) and safety. RESULTS: After 56 months' median follow-up, 293 of 2591 randomized patients had died. There was no statistically significant difference in OS between treatment arms in either the total population (hazard ratio 0.93, 95% confidence interval [CI] 0.74-1.17; P = 0.52) or pre-specified subgroups. The 5-year OS rate was 88% (95% CI 86-90%) in both treatment arms. Updated IDFS results were consistent with the primary IDFS analysis. Five-year IDFS rates were 77% (95% CI 75-79%) with chemotherapy alone versus 80% (95% CI 77-82%) with bevacizumab. From 18 months after first study dose to study end, new grade ≥3 adverse events occurred in 4.6% and 4.5% of patients in the two arms, respectively. CONCLUSION: Final OS results showed no significant benefit from bevacizumab therapy for early TNBC. Late-onset toxicities were rare in both groups. Five-year OS and IDFS rates suggest that the prognosis for patients with TNBC is better than previously thought. CLINICALTRIALS.GOV: NCT00528567.

A randomized, double-blind phase II study evaluating cediranib versus cediranib and saracatinib in patients with relapsed metastatic clear-cell renal cancer (COSAK).

BACKGROUND: Preclinical work suggests SRC proteins have a role in the development of resistance to vascular endothelial growth factor (VEGF) targeted therapy in metastatic clear-cell renal cancer (mRCC). This hypothesis was tested in this trial using the SRC inhibitor saracatinib and the VEGF inhibitor cediranib. PATIENTS AND METHODS: Patients with disease progression after ≥1 VEGF-targeted therapy were eligible to participate in this double-blind, randomized (1:1) phase II study. The study compared the combination cediranib 30 mg once daily (o.d.) and saracatinib 175 mg o.d. (CS) (n = 69) or cediranib 45 mg o.d. and placebo o.d. (C) (n = 69). Archived tissue was used for biomarker analysis [SRC, focal adhesion kinase (FAK), von Hippel-Lindau, protein tyrosine phosphatase 1b and hypoxia-inducible factor 2α : n = 86]. The primary end point was progression-free survival (PFS) by RECIST v1.1. RESULTS: Between 2010 and 2012, 138 patients were randomized across 16 UK sites. The characteristics of the two groups were well balanced. Partial responses were seen in 13.0% for C and 14.5% for CS (P > 0.05). There was no significant difference in PFS [5.4 months (3.6-7.3 months) for C and 3.9 (2.4-5.3 months) for CS; hazard ratio (HR) 1.18 (0.94-1.48)] or overall survival (OS) [14.2 months (11.2-16.8 months) for C and 10.0 (6.7-13.2 months) for CS; HR 1.28 (1.00-1.63)]. There was no significant difference in the frequency of key adverse events, dose reductions or drug discontinuations. None of the biomarkers were prognostic for PFS or OS. FAK overexpression correlated with an OS benefit [HR 2.29 (1.09-4.82), P > 0.05], but not PFS, for CS. CONCLUSIONS: Saracatinib did not increase the efficacy of a VEGF-targeted therapy (cediranib) in this setting. Biomarker analysis did not identify consistent predictive biomarkers. CLINICALTRIALSGOV: NCT00942877.

Patient behaviour at the time of stroke onset: a cross-sectional survey of patient response to stroke symptoms.

BACKGROUND AND PURPOSE: Revascularisation treatment with thrombolysis must be initiated within 4.5 h following ischaemic stroke symptom onset. Despite its proven benefits, thrombolysis therapy is underused, with patient delay in presenting to hospital with symptoms identified as the leading barrier. This study aimed to examine help-seeking behaviour at stroke onset, in order to understand delays in accessing acute medical care for stroke symptoms. METHODS: 149 consecutive patients hospitalised with ischaemic stroke were interviewed at 72 h poststroke with the Stroke Awareness Questionnaire and the Response to Symptoms Questionnaire. RESULTS: Sixty per cent of stroke cases presented to the ED within 3.5 h of stroke onset. Knowledge of stroke symptoms and risk factors was poor, with 40% unable to correctly define a stroke. Bystander recognition of symptoms (p=0.03) and bystander initiation of Emergency Medical Services was associated with ED presentation within 3.5 h (p=0.03). CONCLUSIONS: This study provides insights into patient response when a stroke occurs, with the presence and action of others highlighted as critical in fast response to stroke symptoms. Knowledge of stroke warning signs and risk factors was low among stroke survivors. Findings highlight the complexity of changing help-seeking behaviour during stroke onset, and provide directions for public education efforts to reduce prehospital delay.

Considerations of prescription opioid abuse and misuse among older adults in West Virginia--An Under-Recognized Population at Risk.

Opioid abuse, misuse and overdose is now a public health epidemic receiving political, medical, and media attention at all levels. Despite the fact that many people know someone suffering from addiction, there is very little research focusing on this issue in older adults. Chronic pain, a highly prevalent affliction for the aging population, has been accompanied by a significant increase in opioid use. This, along with some unique aspects of older adults (increased susceptibility to illness, higher likelihood of altered presentation of illness, and impaired recovery), means that great care needs to be taken when considering opioids for treatment. Prudent prescribing is possible, but universal precautions should be taken to reduce the risk of opioid abuse, misuse, and addiction. This review provides education, summarizes current literature, and gives guidance in universal precautions for prescribing opioids.

Background risk of breast cancer influences the association between alcohol consumption and mammographic density.

BACKGROUND: Alcohol consumption has been suggested to increase risk of breast cancer through a mechanism that also increases mammographic density. Whether the association between alcohol consumption and mammographic density is modified by background breast cancer risk has, however, not been studied. METHODS: We conducted a population-based cross-sectional study of 53 060 Swedish women aged 40-74 years. Alcohol consumption was assessed using a web-based self-administered questionnaire. Mammographic density was measured using the fully-automated volumetric Volpara method. The Tyrer-Cuzick prediction model was used to estimate risk of developing breast cancer in the next 10 years. Linear regression models were used to evaluate the association between alcohol consumption and volumetric mammographic density and the potential influence of Tyrer-Cuzick breast cancer risk. RESULTS: Overall, increasing alcohol consumption was associated with higher absolute dense volume (cm(3)) and per cent dense volume (%). The association between alcohol consumption and absolute dense volume was most pronounced among women with the highest (⩾5%) Tyrer-Cuzick 10-year risk. Among high-risk women, women consuming 5.0-9.9, 10.0-19.9, 20.0-29.9, and 30.0-40.0 g of alcohol per day had 2.6 cm(3) (95% confidence interval (CI), 0.2-4.9), 2.9 cm(3) (95% CI, -0.6 to 6.3), 4.6 cm(3) (95% CI, 1.5-7.7), and 10.8 cm(3) (95% CI, 4.8-17.0) higher absolute dense volume, respectively, as compared with women abstaining from alcohol. A trend of increasing alcohol consumption and higher absolute dense volume was seen in women at low (⩽3%) risk, but not in women at moderate (3.0-4.9%) risk. CONCLUSION: Alcohol consumption may increase breast cancer risk through increasing mammographic density, particularly in women at high background risk of breast cancer.

Costs of cancer care for use in economic evaluation: a UK analysis of patient-level routine health system data.

BACKGROUND: The rising financial burden of cancer on health-care systems worldwide has led to the increased demand for evidence-based research on which to base reimbursement decisions. Economic evaluations are an integral component of this necessary research. Ascertainment of reliable health-care cost and quality-of-life estimates to inform such studies has historically been challenging, but recent advances in informatics in the United Kingdom provide new opportunities. METHODS: The costs of hospital care for breast, colorectal and prostate cancer disease-free survivors were calculated over 15 months from initial diagnosis of cancer using routinely collected data within a UK National Health Service (NHS) Hospital Trust. Costs were linked at patient level to patient-reported outcomes and registry-derived sociodemographic factors. Predictors of cost and the relationship between costs and patient-reported utility were examined. RESULTS: The study population included 223 breast cancer patients, 145 colorectal and 104 prostate cancer patients. The mean 15-month cumulative health-care costs were £12 595 (95% CI £11 517-£13 722), £12 643 (£11 282-£14 102) and £3722 (£3263-£4208), per-patient respectively. The majority of costs occurred within the first 6 months from diagnosis. Clinical stage was the most important predictor of costs for all cancer types. EQ-5D score was predictive of costs in colorectal cancer but not in breast or prostate cancer. CONCLUSION: It is now possible to evaluate health-care cost using routine NHS data sets. Such methods can be utilised in future retrospective and prospective studies to efficiently collect economic data.