Accelerated versus standard epirubicin followed by cyclophosphamide, methotrexate, and fluorouracil or capecitabine as adjuvant therapy for breast cancer (UK TACT2; CRUK/05/19): quality of life results from a multicentre, phase 3, open-label, randomised, controlled trial.

BACKGROUND: Adjuvant chemotherapy for patients with early breast cancer improves outcomes but its toxicity affects patients' quality of life (QOL). The UK TACT2 trial investigated whether accelerated epirubicin improves time to recurrence and if oral capecitabine is non-inferior to cyclophosphamide, methotrexate, and fluorouracil (CMF) for efficacy with less toxicity. Results showed no benefit for accelerated epirubicin and capecitabine was non-inferior. As part of the QOL substudy, we aimed to assess the effect of chemotherapies on psychological distress, physical symptoms, and functional domains. METHODS: TACT2 was a multicentre, phase 3, open-label, parallel-group, randomised, controlled trial done in 129 UK centres. Participants were aged 18 years or older with histologically confirmed node-positive or high-risk node-negative invasive primary breast cancer, who had undergone complete excision, and due to receive adjuvant chemotherapy. Patients were randomly assigned (1:1:1:1) to four cycles of 100 mg/m2 epirubicin either every 3 weeks (standard epirubicin) or every 2 weeks with 6 mg pegfilgrastim on day 2 of each cycle (accelerated epirubicin), followed by four 4-week cycles of either CMF (600 mg/m2 cyclophosphamide intravenously on days 1 and 8 or 100 mg/m2 orally on days 1-14; 40 mg/m2 methotrexate intravenously on days 1 and 8; and 600 mg/m2 fluorouracil intravenously on days 1 and 8 of each cycle) or four 3-week cycles of 2500 mg/m2 capecitabine (1250 mg/m2 given twice daily on days 1-14 of each cycle). The randomisation schedule was computer generated in random permuted blocks, stratified by centre, number of nodes involved (none vs 1-3 vs ≥4), age (≤50 years vs >50 years), and planned endocrine treatment (yes vs no). QOL was one of the secondary outcomes and is reported here. All patients from a subset of 44 centres were invited to complete QOL questionnaires (Hospital Anxiety and Depression Scale [HADS] and European Organisation for Research and Treatment of Cancer [EORTC] Quality of Life Questionnaire 30-item core module [QLQ-C30] and Quality of Life Questionnaire breast module [QLQ-BR23]) at baseline, end of standard or accelerated epirubicin, end of CMF or capecitabine, and at 12 and 24 months after randomisation. The QOL substudy prespecified two coprimary QOL outcomes assessed in the intention-to-treat population: overall QOL (reported elsewhere) and HADS total score. Prespecified secondary QOL outcomes were EORTC QLQ-C30 subscales of physical function, role function, and fatigue and EORTC QLQ-BR23 subscales of sexual function and systemic therapy side-effects. This trial is registered with ISRCTN, ISRCTN68068041, and ClinicalTrials.gov, NCT00301925. FINDINGS: From Dec 16, 2005, to Dec 5, 2008, 4391 patients (20 [0·5%] of whom were male) were enrolled in TACT2; 1281 (85·8%) of 1493 eligible patients were included in the QOL substudy. Eight (0·6%) participants in the QOL substudy were male and 1273 (99·4%) were female. Median follow-up was 85·6 months (IQR 80·6-95·9). Analysis was performed on the complete QOL dataset (as of Sept 15, 2011) when all participants had passed the 24-month timepoint. Prerandomisation questionnaires were completed by 1172 (91·5%) patients and 1179 (92·0%) completed at least one postrandomisation questionnaire. End-of-treatment HADS depression score (p=0·0048) and HADS total change score (p=0·0093) were worse for CMF versus capecitabine. Accelerated epirubicin led to worse physical function (p=0·0065), role function (p<0·0001), fatigue (p=0·0002), and systemic side-effects (p=0·0001), but not sexual function (p=0·36), compared with standard epirubicin during treatment, but the effect did not persist. Worse physical function (p=0·0048), sexual function (p=0·0053), fatigue (p<0·0001), and systemic side-effects (p<0·0001), but not role functioning (p=0·013), were seen for CMF versus capecitabine at end of treatment; these differences persisted at 12 months and 24 months. INTERPRETATION: Accelerated epirubicin was associated with worse QOL than was standard epirubicin but only during treatment. These findings will help patients and clinicians make an informed choice about accelerated chemotherapy. CMF had worse QOL effects than did capecitabine, which were persistent for 24 months. The favourable capecitabine QOL compared with CMF supports its use as an adjuvant option after neoadjuvant chemotherapy in patients with triple-negative breast cancer. FUNDING: Cancer Research UK, Amgen, Pfizer, and Roche.

Effect of Predeparture Testing on Postarrival SARS-CoV-2-Positive Test Results Among International Travelers - CDC Traveler-Based Genomic Surveillance Program, Four U.S. Airports, March-September 2022.

Beginning December 6, 2021, all international air passengers boarding flights to the United States were required to show either a negative result from a SARS-CoV-2 viral test taken ≤1 day before departure or proof of recovery from COVID-19 within the preceding 90 days (1). As of June 12, 2022, predeparture testing was no longer mandatory but remained recommended by CDC (2,3). Various modeling studies have estimated that predeparture testing the day before or the day of air travel reduces transmission or importation of SARS-CoV-2 by 31%-76% (4-7). Postarrival SARS-CoV-2 pooled testing data from CDC's Traveler-based Genomic Surveillance program were used to compare SARS-CoV-2 test results among volunteer travelers arriving at four U.S. airports during two 12-week periods: March 20-June 11, 2022, when predeparture testing was required, and June 12-September 3, 2022, when predeparture testing was not required. In a multivariable logistic regression model, pooled nasal swab specimens collected during March 20-June 11 were 52% less likely to be positive for SARS-CoV-2 than were those collected during June 12-September 3, after adjusting for COVID-19 incidence in the flight's country of origin, sample pool size, and collection airport (adjusted odds ratio [aOR] = 0.48, 95% CI = 0.39-0.58) (p<0.001). These findings support predeparture testing as a tool for reducing travel-associated SARS-CoV-2 transmission and provide important real-world evidence that can guide decisions for future outbreaks and pandemics.

Hyperpolarised 13C MRI: a new horizon for non-invasive diagnosis of aggressive breast cancer.

Hyperpolarised 13C MRI (HP-MRI) is a novel imaging technique that allows real-time analysis of metabolic pathways in vivo.1 The technology to conduct HP-MRI in humans has recently become available and is starting to be clinically applied. As knowledge of molecular biology advances, it is increasingly apparent that cancer cell metabolism is related to disease outcomes, with lactate attracting specific attention. 2 Recent reviews of breast cancer screening programs have raised concerns and increased public awareness of over treatment. The scientific community needs to shift focus from improving cancer detection alone to pursuing novel methods of distinguishing aggressive breast cancers from those which will remain indolent. HP-MRI offers the opportunity to identify aggressive tumour phenotypes and help monitor/predict therapeutic response. Here we report one of the first cases of breast cancer imaged using HP-MRI alongside correlative conventional imaging, including breast MRI.

An observational study showed that explaining randomization using gambling-related metaphors and computer-agency descriptions impeded randomized clinical trial recruitment.

OBJECTIVES: To explore how the concept of randomization is described by clinicians and understood by patients in randomized controlled trials (RCTs) and how it contributes to patient understanding and recruitment. STUDY DESIGN AND SETTING: Qualitative analysis of 73 audio recordings of recruitment consultations from five, multicenter, UK-based RCTs with identified or anticipated recruitment difficulties. RESULTS: One in 10 appointments did not include any mention of randomization. Most included a description of the method or process of allocation. Descriptions often made reference to gambling-related metaphors or similes, or referred to allocation by a computer. Where reference was made to a computer, some patients assumed that they would receive the treatment that was "best for them". Descriptions of the rationale for randomization were rarely present and often only came about as a consequence of patients questioning the reason for a random allocation. CONCLUSIONS: The methods and processes of randomization were usually described by recruiters, but often without clarity, which could lead to patient misunderstanding. The rationale for randomization was rarely mentioned. Recruiters should avoid problematic gambling metaphors and illusions of agency in their explanations and instead focus on clearer descriptions of the rationale and method of randomization to ensure patients are better informed about randomization and RCT participation.

Correction to: IRIS study: a phase II study of the steroid sulfatase inhibitor Irosustat when added to an aromatase inhibitor in ER-positive breast cancer patients.

In the original publication of the article, a part of acknowledgement section was missed out. The omitted acknowledgement is given below: 'The study was coordinated by the Imperial Clinical Trials Unit-Cancer, Imperial College London and Sponsored by Imperial College London. The Imperial Clinical Trials Unit receives funding from the National Institute for Health (NIHR) Biomedical Research Centre based at Imperial College Healthcare NHS Trust and Imperial College London. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. This study was supported by Imperial Experimental Cancer Medicine Centre and Cancer Research UK Imperial Centre'.

Informed consent in randomised controlled trials: development and preliminary evaluation of a measure of Participatory and Informed Consent (PIC).

BACKGROUND: Informed consent (IC) is an ethical and legal prerequisite for trial participation, yet current approaches evaluating participant understanding for IC during recruitment lack consistency. No validated measure has been identified that evaluates participant understanding for IC based on their contributions during consent interactions. This paper outlines the development and formative evaluation of the Participatory and Informed Consent (PIC) measure for application to recorded recruitment appointments. The PIC allows the evaluation of recruiter information provision and evidence of participant understanding. METHODS: Published guidelines for IC were reviewed to identify potential items for inclusion. Seventeen purposively sampled trial recruitment appointments from three diverse trials were reviewed to identify the presence of items relevant to IC. A developmental version of the measure (DevPICv1) was drafted and applied to six further recruitment appointments from three further diverse trials to evaluate feasibility, validity, stability and inter-rater reliability. Findings guided revision of the measure (DevPICv2) which was applied to six further recruitment appointments as above. RESULTS: DevPICv1 assessed recruiter information provision (detail and clarity assessed separately) and participant talk (detail and understanding assessed separately) over 20 parameters (or 23 parameters for three-arm trials). Initial application of the measure to six diverse recruitment appointments demonstrated promising stability and inter-rater reliability but a need to simplify the measure to shorten time for completion. The revised measure (DevPICv2) combined assessment of detail and clarity of recruiter information and detail and evidence of participant understanding into two single scales for application to 22 parameters or 25 parameters for three-arm trials. Application of DevPICv2 to six further diverse recruitment appointments showed considerable improvements in feasibility (e.g. time to complete) with good levels of stability (i.e. test-retest reliability) and inter-rater reliability maintained. CONCLUSIONS: The DevPICv2 provides a measure for application to trial recruitment appointments to evaluate quality of recruiter information provision and evidence of patient understanding and participation during IC discussions. Initial evaluation shows promising feasibility, validity, reliability and ability to discriminate across a range of recruiter practice and evidence of participant understanding. More validation work is needed in new clinical trials to evaluate and refine the measure further.

IRIS study: a phase II study of the steroid sulfatase inhibitor Irosustat when added to an aromatase inhibitor in ER-positive breast cancer patients.

PURPOSE: Irosustat is a first-generation, orally active, irreversible steroid sulfatase inhibitor. We performed a multicentre, open label phase II trial of the addition of Irosustat to a first-line aromatase inhibitor (AI) in patients with advanced BC to evaluate the safety of the combination and to test the hypothesis that the addition of Irosustat to AI may further suppress estradiol levels and result in clinical benefit. EXPERIMENTAL DESIGN: Postmenopausal women with ER-positive locally advanced or metastatic breast cancer who had derived clinical benefit from a first-line AI and who subsequently progressed were enrolled. The first-line AI was continued and Irosustat (40 mg orally daily) added. The primary endpoint was clinical benefit rate (CBR). Secondary endpoints included safety, tolerability, and pharmacodynamic end points. RESULTS: Twenty-seven women were recruited, four discontinued treatment without response assessment. Based on local reporting, the CBR was 18.5% (95% CI 6.3-38.1%) on an intent to treat basis, increasing to 21.7% (95% CI 7.4-43.7%) by per-protocol analysis. In those patients that achieved clinical benefit (n = 5), the median (interquartile range) duration was 9.4 months (8.1-11.3) months. The median progression-free survival time was 2.7 months (95% CI 2.5-4.6) in both the ITT and per-protocol analyses. The most frequently reported grade 3/4 toxicities were dry skin (28%), nausea (13%), fatigue (13%), diarrhoea (8%), headache (7%), anorexia (7%) and lethargy (7%). CONCLUSIONS: The addition of Irosustat to aromatase inhibitor therapy resulted in clinical benefit with an acceptable safety profile. The study met its pre-defined success criterion by both local and central radiological assessments.

Conveying Equipoise during Recruitment for Clinical Trials: Qualitative Synthesis of Clinicians' Practices across Six Randomised Controlled Trials.

BACKGROUND: Randomised controlled trials (RCTs) are essential for evidence-based medicine and increasingly rely on front-line clinicians to recruit eligible patients. Clinicians' difficulties with negotiating equipoise is assumed to undermine recruitment, although these issues have not yet been empirically investigated in the context of observable events. We aimed to investigate how clinicians conveyed equipoise during RCT recruitment appointments across six RCTs, with a view to (i) identifying practices that supported or hindered equipoise communication and (ii) exploring how clinicians' reported intentions compared with their actual practices. METHODS AND FINDINGS: Six pragmatic UK-based RCTs were purposefully selected to include several clinical specialties (e.g., oncology, surgery) and types of treatment comparison. The RCTs were all based in secondary-care hospitals (n = 16) around the UK. Clinicians recruiting to the RCTs were interviewed (n = 23) to understand their individual sense of equipoise about the RCT treatments and their intentions for communicating equipoise to patients. Appointments in which these clinicians presented the RCT to trial-eligible patients were audio-recorded (n = 105). The appointments were analysed using thematic and content analysis approaches to identify practices that supported or challenged equipoise communication. A sample of appointments was independently coded by three researchers to optimise reliability in reported findings. Clinicians and patients provided full written consent to be interviewed and have appointments audio-recorded. Interviews revealed that clinicians' sense of equipoise varied: although all were uncertain about which trial treatment was optimal, they expressed different levels of uncertainty, ranging from complete ambivalence to clear beliefs that one treatment was superior. Irrespective of their personal views, all clinicians intended to set their personal biases aside to convey trial treatments neutrally to patients (in accordance with existing evidence). However, equipoise was omitted or compromised in 48/105 (46%) of the recorded appointments. Three commonly recurring practices compromised equipoise communication across the RCTs, irrespective of clinical context. First, equipoise was overridden by clinicians offering treatment recommendations when patients appeared unsure how to proceed or when they asked for the clinician's expert advice. Second, clinicians contradicted equipoise by presenting imbalanced descriptions of trial treatments that conflicted with scientific information stated in the RCT protocols. Third, equipoise was undermined by clinicians disclosing their personal opinions or predictions about trial outcomes, based on their intuition and experience. These broad practices were particularly demonstrated by clinicians who had indicated in interviews that they held less balanced views about trial treatments. A limitation of the study was that clinicians volunteering to take part in the research might have had a particular interest in improving their communication skills. However, the frequency of occurrence of equipoise issues across the RCTs suggests that the findings are likely to be reflective of clinical recruiters' practices more widely. CONCLUSIONS: Communicating equipoise is a challenging process that is easily disrupted. Clinicians' personal views about trial treatments encroached on their ability to convey equipoise to patients. Clinicians should be encouraged to reflect on personal biases and be mindful of the common ways in which these can arise in their discussions with patients. Common pitfalls that recurred irrespective of RCT context indicate opportunities for specific training in communication skills that would be broadly applicable to a wide clinical audience.

Gene and protein expression profiling of human ovarian cancer cells treated with the heat shock protein 90 inhibitor 17-allylamino-17-demethoxygeldanamycin.

The promising antitumor activity of 17-allylamino-17-demethoxygeldanamycin (17AAG) results from inhibition of the molecular chaperone heat shock protein 90 (HSP90) and subsequent degradation of multiple oncogenic client proteins. Gene expression microarray and proteomic analysis were used to profile molecular changes in the A2780 human ovarian cancer cell line treated with 17AAG. Comparison of results with an inactive analogue and an alternative HSP90 inhibitor radicicol indicated that increased expression of HSP72, HSC70, HSP27, HSP47, and HSP90beta at the mRNA level were on-target effects of 17AAG. HSP27 protein levels were increased in tumor biopsies following treatment of patients with 17AAG. A group of MYC-regulated mRNAs was decreased by 17AAG. Of particular interest and novelty were changes in expression of chromatin-associated proteins. Expression of the heterochromatin protein 1 was increased, and expression of the histone acetyltransferase 1 and the histone arginine methyltransferase PRMT5 was decreased by 17AAG. PRMT5 was shown to be a novel HSP90-binding partner and potential client protein. Cellular protein acetylation was reduced by 17AAG, which was shown to have an antagonistic interaction on cell proliferation with the histone deacetylase inhibitor trichostatin A. This mRNA and protein expression analysis has provided new insights into the complex molecular pharmacology of 17AAG and suggested new genes and proteins that may be involved in response to the drug or be potential biomarkers of drug action.

Internal dissension grows as CDC faces big threats to public health.

According to current and former CDC officials and several outside experts, the Centers for Disease Control and Prevention is being roiled by internal dissension as it faces such unprecedented threats as bioterrorism, a potential flu pandemic, and the obesity epidemic. The agency has been thrown into turmoil by a combination of factors, including a drawn-out restructuring, the departure of dozens of its most respected scientists, concerns about political interference, and a pending budget cut of nearly dollar 500 million. The impact remains a matter of debate, but the uproar is causing widespread alarm among public health authorities.

Activation of the ATPase activity of hsp90 by the stress-regulated cochaperone aha1.

Client protein activation by Hsp90 involves a plethora of cochaperones whose roles are poorly defined. A ubiquitous family of stress-regulated proteins have been identified (Aha1, activator of Hsp90 ATPase) that bind directly to Hsp90 and are required for the in vivo Hsp90-dependent activation of clients such as v-Src, implicating them as cochaperones of the Hsp90 system. In vitro, Aha1 and its shorter homolog, Hch1, stimulate the inherent ATPase activity of yeast and human Hsp90. The identification of these Hsp90 cochaperone activators adds to the complex roles of cochaperones in regulating the ATPase-coupled conformational changes of the Hsp90 chaperone cycle.