Fulvestrant plus capivasertib versus placebo after relapse or progression on an aromatase inhibitor in metastatic, oestrogen receptor-positive, HER2-negative breast cancer (FAKTION): overall survival, updated progression-free survival, and expanded biomarker analysis from a randomised, phase 2 trial.

BACKGROUND: Capivasertib, an AKT inhibitor, added to fulvestrant, was previously reported to improve progression-free survival in women with aromatase inhibitor-resistant oestrogen receptor (ER)-positive, HER2-negative advanced breast cancer. The benefit appeared to be independent of the phosphoinositide 3-kinase (PI3K)/AKT/phosphatase and tensin homologue (PTEN) pathway alteration status of tumours, as ascertained using assays available at the time. Here, we report updated progression-free survival and overall survival results, and a prespecified examination of the effect of PI3K/AKT/PTEN pathway alterations identified by an expanded genetic testing panel on treatment outcomes. METHODS: This randomised, multicentre, double-blind, placebo-controlled, phase 2 trial recruited postmenopausal adult women aged at least 18 years with ER-positive, HER2-negative, metastatic or locally advanced inoperable breast cancer and an Eastern Cooperative Oncology Group performance status of 0-2, who had relapsed or progressed on an aromatase inhibitor, from across 19 hospitals in the UK. Participants were randomly assigned (1:1) to receive intramuscular fulvestrant 500 mg (day 1) every 28 days (plus a 500 mg loading dose on day 15 of cycle 1) with either capivasertib 400 mg or matching placebo, orally twice daily on an intermittent weekly schedule of 4 days on and 3 days off, starting on cycle 1 day 15. Treatment continued until disease progression, unacceptable toxicity, loss to follow-up, or withdrawal of consent. Treatment was allocated by an interactive web-response system using a minimisation method (with a 20% random element) and the following minimisation factors: measurable or non-measurable disease, primary or secondary aromatase inhibitor resistance, PIK3CA status, and PTEN status. The primary endpoint was progression-free survival in the intention-to-treat population. Secondary endpoints shown in this Article were overall survival and safety in the intention-to-treat population, and the effect of tumour PI3K/AKT/PTEN pathway status identified by an expanded testing panel that included next-generation sequencing assays. Recruitment is complete. The trial is registered with ClinicalTrials.gov, number NCT01992952. FINDINGS: Between March 16, 2015, and March 6, 2018, 183 participants were screened for eligibility and 140 (77%) were randomly assigned to receive fulvestrant plus capivasertib (n=69) or fulvestrant plus placebo (n=71). Median follow-up at the data cut-off of Nov 25, 2021, was 58·5 months (IQR 45·9-64·1) for participants treated with fulvestrant plus capivasertib and 62·3 months (IQR 62·1-70·3) for fulvestrant plus placebo. Updated median progression-free survival was 10·3 months (95% CI 5·0-13·4) in the group receiving fulvestrant plus capivasertib compared with 4·8 months (3·1-7·9) for fulvestrant plus placebo (adjusted hazard ratio [HR] 0·56 [95% CI 0·38-0·81]; two-sided p=0·0023). Median overall survival in the capivasertib versus placebo groups was 29·3 months (95% CI 23·7-39·0) versus 23·4 months (18·7-32·7; adjusted HR 0·66 [95% CI 0·45-0·97]; two-sided p=0·035). The expanded biomarker panel identified an expanded pathway-altered subgroup that contained 76 participants (54% of the intention-to-treat population). Median progression-free survival in the expanded pathway-altered subgroup for participants receiving capivasertib (n=39) was 12·8 months (95% CI 6·6-18·8) compared with 4·6 months (2·8-7·9) in the placebo group (n=37; adjusted HR 0·44 [95% CI 0·26-0·72]; two-sided p=0·0014). Median overall survival for the expanded pathway-altered subgroup receiving capivasertib was 38·9 months (95% CI 23·3-50·7) compared with 20·0 months (14·8-31·4) for those receiving placebo (adjusted HR 0·46 [95% CI 0·27-0·79]; two-sided p=0·0047). By contrast, there were no statistically significant differences in progression-free or overall survival in the expanded pathway non-altered subgroup treated with capivasertib (n=30) versus placebo (n=34). One additional serious adverse event (pneumonia) in the capivasertib group had occurred subsequent to the primary analysis. One death, due to atypical pulmonary infection, was assessed as possibly related to capivasertib treatment. INTERPRETATION: Updated FAKTION data showed that capivasertib addition to fulvestrant extends the survival of participants with aromatase inhibitor-resistant ER-positive, HER2-negative advanced breast cancer. The expanded biomarker testing suggested that capivasertib predominantly benefits patients with PI3K/AKT/PTEN pathway-altered tumours. Phase 3 data are needed to substantiate the results, including in patients with previous CDK4/6 inhibitor exposure who were not included in the FAKTION trial. FUNDING: AstraZeneca and Cancer Research UK.

Fulvestrant plus capivasertib versus placebo after relapse or progression on an aromatase inhibitor in metastatic, oestrogen receptor-positive breast cancer (FAKTION): a multicentre, randomised, controlled, phase 2 trial.

BACKGROUND: Capivasertib (AZD5363) is a potent selective oral inhibitor of all three isoforms of the serine/threonine kinase AKT. The FAKTION trial investigated whether the addition of capivasertib to fulvestrant improved progression-free survival in patients with aromatase inhibitor-resistant advanced breast cancer. METHODS: In this randomised, double-blind, placebo-controlled, phase 2 trial, postmenopausal women aged at least 18 years with an Eastern Cooperative Oncology Group performance status of 0-2 and oestrogen receptor-positive, HER2-negative, metastatic or locally advanced inoperable breast cancer who had relapsed or progressed on an aromatase inhibitor were recruited from 19 hospitals in the UK. Enrolled participants were randomly assigned (1:1) to receive intramuscular fulvestrant 500 mg (day 1) every 28 days (plus a loading dose on day 15 of cycle 1) with either capivasertib 400 mg or matching placebo, orally twice daily on an intermittent weekly schedule of 4 days on and 3 days off (starting on cycle 1 day 15) until disease progression, unacceptable toxicity, loss to follow-up, or withdrawal of consent. Treatment allocation was done using an interactive web-response system using a minimisation method (with a 20% random element) and the following minimisation factors: measurable or non-measurable disease, primary or secondary aromatase inhibitor resistance, PIK3CA status, and PTEN status. The primary endpoint was progression-free survival with a one-sided alpha of 0·20. Analyses were done by intention to treat. Recruitment is complete, and the trial is in follow-up. This trial is registered with ClinicalTrials.gov, number NCT01992952. FINDINGS: Between March 16, 2015, and March 6, 2018, 183 patients were screened for eligibility, of whom 140 (76%) were eligible and were randomly assigned to receive fulvestrant plus capivasertib (n=69) or fulvestrant plus placebo (n=71). Median follow-up for progression-free survival was 4·9 months (IQR 1·6-11·6). At the time of primary analysis for progression-free survival (Jan 30, 2019), 112 progression-free survival events had occurred, 49 (71%) in 69 patients in the capivasertib group compared with 63 (89%) of 71 in the placebo group. Median progression-free survival was 10·3 months (95% CI 5·0-13·2) in the capivasertib group versus 4·8 months (3·1-7·7) in the placebo group, giving an unadjusted hazard ratio (HR) of 0·58 (95% CI 0·39-0·84) in favour of the capivasertib group (two-sided p=0·0044; one-sided log rank test p=0·0018). The most common grade 3-4 adverse events were hypertension (22 [32%] of 69 patients in the capivasertib group vs 17 [24%] of 71 in the placebo group), diarrhoea (ten [14%] vs three [4%]), rash (14 [20%] vs 0), infection (four [6%] vs two [3%]), and fatigue (one [1%] vs three [4%]). Serious adverse reactions occurred only in the capivasertib group, and were acute kidney injury (two), diarrhoea (three), rash (two), hyperglycaemia (one), loss of consciousness (one), sepsis (one), and vomiting (one). One death, due to atypical pulmonary infection, was assessed as possibly related to capivasertib treatment. One further death in the capivasertib group had an unknown cause; all remaining deaths in both groups (19 in the capivasertib group and 31 in the placebo group) were disease related. INTERPRETATION: Progression-free survival was significantly longer in participants who received capivasertib than in those who received placebo. The combination of capivasertib and fulvestrant warrants further investigation in phase 3 trials. FUNDING: AstraZeneca and Cancer Research UK.

Identifying national health research priorities in Timor-Leste through a scoping review of existing health data.

Health research is crucial to understand a country's needs and to improve health outcomes. We conducted a scoping review and analysis of existing health data in Timor-Leste to identify the health research priorities of the country. Published and unpublished health research in Timor-Leste from 2001 to 2011 that reported objectives, methods and results were identified. Key findings were triangulated with data from national surveys and the Health Management Information System; 114 eligible articles were included in the analysis, the leading topics of which were communicable (malaria, tuberculosis, HIV and sexually transmitted diseases and dengue) and non-communicable (eye and mental health) diseases. There were 28 papers (25%) on safe motherhood, child health and nutrition, of which 20 (71%) were unpublished. The review of national indicators showed high infant, under-five and maternal mortality rates. Burden of disease is greatest in young children, with respiratory infections, febrile illnesses and diarrheal disease predominating. There is poor access to and utilization of health care. Childhood malnutrition is an important unresolved national health issue. There are several obstacles leading to under-utilization of health services. The following topics for future health research are suggested from the review: nutrition, safe motherhood, childhood illness (in particular identifying the causes and cause-specific burden of severe respiratory, febrile and diarrheal diseases) and access to and use of health services.

Looking Back, Looking Forward: A Study Protocol for a Mixed-Methods Multiple-Case Study to Examine Improvement Sustainability of Large-Scale Initiatives in Tertiary Hospitals.

Background Hospitals invest extensive resources in large-scale initiatives to improve patient safety and quality at an organizational level. However, initial success, if any, does not guarantee longer-term improvement. Empirical and theoretical knowledge that informs hospitals on how to attain sustained improvement from large-scale change is lacking. Aim The proposed study aims to examine improvement sustainability of two large-scale initiatives in an Australian tertiary hospital and translate the lessons into strategies for achieving sustained improvement from large-scale change in hospital settings. Design and Methods The study employs a single-site, multiple-case study design to evaluate the initiatives separately and comparatively using mixed methods. Semi-structured staff interviews will be conducted in stratified cohorts across the organizational hierarchy to capture different perspectives from various staff roles involved in the initiatives. The output and impact of the initiatives will be examined through organizational documents and relevant routinely collected organizational indicators. The obtained data will be analyzed thematically and statistically before being integrated for a synergic interpretation. Implications Capturing a comprehensive organizational view of large-scale change, the findings will have the potential to guide the practice and contribute to the theoretical understandings for achieving meaningful and longer-term organizational improvement in patient safety and quality.

Sustaining improvement of hospital-wide initiative for patient safety and quality: a systematic scoping review.

BACKGROUND: Long-term sustained improvement following implementation of hospital-wide quality and safety initiatives is not easily achieved. Comprehensive theoretical and practical understanding of how gained improvements can be sustained to benefit safe and high-quality care is needed. This review aimed to identify enabling and hindering factors and their contributions to improvement sustainability from hospital-wide change to enhance patient safety and quality. METHODS: A systematic scoping review method was used. Searched were peer-reviewed published records on PubMed, Scopus, World of Science, CINAHL, Health Business Elite, Health Policy Reference Centre and Cochrane Library and grey literature. Review inclusion criteria included contemporary (2010 and onwards), empirical factors to improvement sustainability evaluated after the active implementation, hospital(s) based in the western Organisation for Economic Co-operation and Development countries. Numerical and thematic analyses were undertaken. RESULTS: 17 peer-reviewed papers were reviewed. Improvement and implementation approaches were predominantly adopted to guide change. Less than 6 in 10 (53%) of reviewed papers included a guiding framework/model, none with a demonstrated focus on improvement sustainability. With an evaluation time point of 4.3 years on average, 62 factors to improvement sustainability were identified and emerged into three overarching themes: People, Process and Organisational Environment. These entailed, as subthemes, actors and their roles; planning, execution and maintenance of change; and internal contexts that enabled sustainability. Well-coordinated change delivery, customised local integration and continued change effort were three most critical elements. Mechanisms between identified factors emerged in the forms of Influence and Action towards sustained improvement. CONCLUSIONS: The findings map contemporary empirical factors and their mechanisms towards change sustainability from a hospital-wide initiative to improve patient safety and quality. The identified factors and mechanisms extend current theoretical and empirical knowledgebases of sustaining improvement particularly with those beyond the active implementation. The provided conceptual framework offers an empirically evidenced and actionable guide to assist sustainable organisational change in hospital settings.

Mainstreaming germline BRCA1/2 testing in non-mucinous epithelial ovarian cancer in the North West of England.

Poly(ADP-ribose) polymerase (PARP) inhibitors improve survival in BRCA-mutant high-grade serous ovarian carcinoma. As a result, germline and somatic BRCA1/2 testing has become standard practice in women diagnosed with ovarian cancer. We outline changes in testing and detection rates of germline BRCA1/2 pathogenic variants (PVs) in cases of non-mucinous epithelial ovarian cancer diagnosed during three eras, spanning 12 years, within the North West of England, and compare the uptake of cascade testing in families identified by oncology-led mainstreaming versus regional genetics clinics. Eras included: Period 1 (20% risk threshold for testing): between January 2007 and May 2013; Period 2 (10% risk threshold for testing): between June 2013 and October 2017 and; Period 3 (mainstream testing): between November 2017 and November 2019. A total of 1081 women underwent germline BRCA1/2 testing between January 2007 and November 2019 and 222 (20.5%) were found to have a PV. The monthly testing rate increased by 3.3-fold and 2.5-fold between Periods 1-2 and Periods 2-3, respectively. A similar incidence of germline BRCA1/2 PVs were detected in Period 2 (17.2%) and Period 3 (18.5%). Uptake of cascade testing from first-degree relatives was significantly lower in those women undergoing mainstream testing compared with those tested in regional genetics clinics (31.6% versus 47.3%, P = 0.038). Mainstream testing allows timely detection of germline BRCA1/2 status to select patients for PARP inhibitors, but shortfalls in the uptake of cascade testing in first-degree relatives requires optimisation to broaden benefits within families.

Measuring Transformational Leadership in Establishing Nursing Care Excellence.

Transformational leadership (TL) is known to be essential to achieving Magnet® recognition, an internationally prestigious status for nursing care excellence. Since its inception in the 1980s, empirical studies have identified benefits of implementing the Magnet® Model involving improved patient care and nursing workforce outcomes. However, little is known about the leadership styles of nurse managers (NMs) working in a regional Australian context, which may hinder achieving Magnet® status. To close the knowledge gap, a self-administered survey was conducted to measure leadership styles of NMs at a large health organization comprising hospitals with a wide range of service profiles in regional Australia using a validated tool-the Multifactor Leadership Questionnaire (MLQ-6S). One-way of variance (ANOVA) was used to identify statistical significance between respondents' demographic characteristics (e.g., age, education, gender) and their MLQ-6S scores. Respondents (n = 78) reported their leadership styles as more transformational, compared to transactional or passive/avoidant leadership styles. The findings indicated that NMs' higher education (p = 0.02) and older age (p = 0.03) were associated with TL styles, whereas passive/avoidant leadership was generally reported by female (p = 0.04) and younger (p = 0.06) respondents. This study has identified differences in reported leadership styles among NMs, providing a unique organizational insight into developing strategies to improve NMs' TL, which could help to facilitate the implementation of the Magnet® framework. Healthcare organizations in similar settings could benefit from replicating this study to identify a dominant leadership style and customize strategies to improve TL.

Effect of Standardized Handoff Curriculum on Improved Clinician Preparedness in the Intensive Care Unit: A Stepped-Wedge Cluster Randomized Clinical Trial.

Importance: Clinician miscommunication contributes to an estimated 250 000 deaths in US hospitals per year. Efforts to standardize handoff communication may reduce errors and improve patient safety. Objective: To determine the effect of a standardized handoff curriculum, UW-IPASS, on interclinician communication and patient outcomes. Design, Setting, and Participants: This cluster randomized stepped-wedge randomized clinical trial was conducted from October 2015 to May 2016 at 8 medical and surgical intensive care units at 2 hospital systems within an academic tertiary referral center. Participants included residents, fellows, advance-practice clinicians, and attending physicians (n = 106 clinicians, with 1488 handoff events over 8 months) and data were collected from daily text message-based surveys and patient medical records. Exposures: The UW-IPASS standardized handoff curriculum. Main Outcomes and Measures: The primary aim was to assess the effect of the UW-IPASS handoff curriculum on perceived adequacy of interclinician communication. Patient days of mechanical ventilation, intensive care unit length of stay, reintubations within 24 hours, and order workflow patterns were also analyzed. Mixed-effects logistic regression was used to compute odds ratios and confidence intervals with adjustment for location, time period, and clinician. Results: A total of 63 residents and advance practice clinicians, 13 fellows, and 30 attending physicians participated in the study. During the control period, clinicians reported being unprepared for their shift because of a poor-quality handoff in 35 of 343 handoffs (10.2%), while UW-IPASS-period residents reported being unprepared in 53 of 740 handoffs (7.2%) (odds ratio, 0.19; 95% CI, 0.03-0.74; P = .03). Compared with the control phase, the perceived duration of handoffs among clinicians using UW-IPASS was unchanged (+5.5 minutes; 95% CI, 0.34-9.39; P = .30). Early morning order entry decreased from 106 per 100 patient-days in the control phase to 78 per 100 patient-days in the intervention period (-28 orders; 95% CI, -55 to -4; P = .04). Overall, UW-IPASS was not associated with any changes in intensive care unit length of stay, duration of mechanical ventilation, or the number of reintubations. Conclusions and Relevance: The UW-IPASS standardized handoff curriculum was perceived to improve intensive care provider preparedness and workflow. IPASS-based curricula represent an important step forward in communication standardization efforts and may help reduce communication errors and omissions. Trial Registration: isrctn.org Identifier: ISRCTN14209509.

Group Therapy for Loss: Attachment, Intersubjectivity, and Healing.

Loss is a fundamental human experience that can impact a person's mental health in diverse ways. While this experience is potentially formative, harmful manifestations can fracture one's sense of self and undermine relational health. In this article, we present a rationale for process-oriented group therapy focused on healing relational injuries associated with loss. We draw on attachment, self-psychology, intersubjectivity, and Yalom & Leszcz's (2005) model of group psychotherapy to explore how group processes allow clients to work through losses and relational frustrations in the here-and-now. A case vignette and discussion offer practical insight on the ways in which loss manifests in the room and demonstrate the uniqueness of the group setting for reparative processing.

DNA recognition by the EcoRV restriction endonuclease probed using base analogues.

The EcoRV restriction endonuclease recognises palindromic GATATC sequences and cuts between the central T and dA bases in a reaction that has an absolute requirement for a divalent metal ion, physiologically Mg(2+). Use has been made of base analogues, which delete hydrogen bonds between the protein and DNA (or hydrophobic interactions in the case of the 5-CH(3) group of thymine), to evaluate the roles of the outer two base-pairs (GATATC) in DNA recognition. Selectivity arises at both the binding steps leading to the formation of the enzyme-DNA-metal ion ternary complex (assayed by measuring the dissociation constant in the presence of the non-reactive metal Ca(2+)) and the catalytic step (evaluated using single-turnover hydrolysis in the presence of Mg(2+)), with each protein-DNA contact contributing to recognition. With the A:T base-pair, binding was reduced by the amount expected for the simple loss of a single contact; much more severe effects were observed with the G:C base-pair, suggesting additional conformational perturbation. Most of the modified bases lowered the rate of hydrolysis; furthermore, the presence of an analogue in one strand of the duplex diminished cutting at the second, unmodified strand, indicative of communication between DNA binding and the active site. The essential metal ion Mg(2+) plays a key role in mediating interactions between the DNA binding site and active centre and in many instances rescue of hydrolysis was seen with Mn(2+). It is suggested that contacts between the GATATC site are required for tight binding and for the correct assembly of metal ions and bound water at the catalytic site, functions important in providing acid/base catalysis and transition state stabilisation.

Inactivation of Escherichia coli O157:H7, Salmonella enterica serotype enteritidis, and Listeria monocytogenes on lettuce by hydrogen peroxide and lactic acid and by hydrogen peroxide with mild heat.

Iceberg lettuce is a major component in vegetable salad and has been associated with many outbreaks of foodborne illnesses. In this study, several combinations of lactic acid and hydrogen peroxide were tested to obtain effective antibacterial activity without adverse effects on sensory characteristics. A five-strain mixture of Escherichia coli O157:H7, Salmonella enterica serotype Enteritidis, and Listeria monocytogenes was inoculated separately onto fresh-cut lettuce leaves, which were later treated with 1.5% lactic acid plus 1.5% hydrogen peroxide (H2O2) at 40 degrees C for 15 min, 1.5% lactic acid plus 2% H2O2 at 22 degrees C for 5 min, and 2% H2O2 at 50 degrees C for 60 or 90 s. Control lettuce leaves were treated with deionized water under the same conditions. A 4-log reduction was obtained for lettuce treated with the combinations of lactic acid and H2O2 for E. coli O157:H7 and Salmonella Enteritidis, and a 3-log reduction was obtained for L. monocytogenes. However, the sensory characteristics of lettuce were compromised by these treatments. The treatment of lettuce leaves with 2% H2O2 at 50 degrees C was effective not only in reducing pathogenic bacteria but also in maintaining good sensory quality for up to 15 days. A < or = 4-log reduction of E. coli O157:H7 and Salmonella Enteritidis was achieved with the 2% H2O2 treatment, whereas a 3-log reduction of L. monocytogenes was obtained. There was no significant difference (P > 0.05) between pathogen population reductions obtained with 2% H2O2 with 60- and 90-s exposure times. Hydrogen peroxide residue was undetectable (the minimum level of sensitivity was 2 ppm) on lettuce surfaces after the treated lettuce was rinsed with cold water and centrifuged with a salad spinner. Hence, the treatment of lettuce with 2% H2O2 at 50 degrees C for 60 s is effective in initially reducing substantial populations of foodborne pathogens and maintaining high product quality.

Ingesting a pre-workout supplement containing caffeine, B-vitamins, amino acids, creatine, and beta-alanine before exercise delays fatigue while improving reaction time and muscular endurance.

BACKGROUND: The purpose of this study was to determine the effects of the pre-workout supplement Assault™ (MusclePharm, Denver, CO, USA) on upper and lower body muscular endurance, aerobic and anaerobic capacity, and choice reaction time in recreationally-trained males. Subjective feelings of energy, fatigue, alertness, and focus were measured to examine associations between psychological factors and human performance. METHODS: Twelve recreationally-trained males participated in a 3-week investigation (mean +/- SD, age: 28 +/- 5 y, height: 178 +/- 9 cm, weight: 79.2 +/- 15.7 kg, VO2max: 45.7 +/- 7.6 ml/kg/min). Subjects reported to the human performance laboratory on three separate occasions. All participants completed a baseline/familiarization day of testing that included a maximal graded exercise test for the determination of aerobic capacity (VO2max), one-rep maximum (1-RM) for bench and leg press to determine 75% of 1-RM, choice reaction tests, and intermittent critical velocity familiarization. Choice reaction tests included the following: single-step audio and visual, one-tower stationary protocol, two-tower lateral protocol, three-tower multi-directional protocol, and three-tower multi-directional protocol with martial arts sticks. Subjects were randomly assigned to ingest either the supplement (SUP) or the placebo (PL) during Visit 2. Subjects were provided with the cross-over treatment on the last testing visit. Testing occurred 20 min following ingestion of both treatments. RESULTS: Significant (p < 0.05) main effects for the SUP were observed for leg press (SUP: 13 ± 6 reps, PL: 11 ± 3 reps), perceived energy (SUP: 3.4 ± 0.9, PL: 3.1 ± 0.8), alertness (SUP: 4.0 ± 0.7, PL: 3.5 ± 0.8), focus (SUP: 4.1 ± 0.6, PL: 3.5 ± 0.8), choice reaction audio single-step (SUP: 0.92 ± 0.10 s, PL: 0.97 ± 0.11 s), choice reaction multi-direction 15 s (SUP: 1.07 ± 0.12 s, PL: 1.13 ± 0.14 s), and multi-direction for 30 s (SUP: 1.10 ± 0.11 s, PL: 1.14 ± 0.13 s). CONCLUSIONS: Ingesting the SUP before exercise significantly improved agility choice reaction performance and lower body muscular endurance, while increasing perceived energy and reducing subjective fatigue. These findings suggest that the SUP may delay fatigue during strenuous exercise.

Role of prophylactic antibiotics in the prevention of infections after chemotherapy: a literature review.

Febrile neutropenia is a serious sequel of chemotherapy and can result in significant morbidity and mortality. The use of prophylactic antibiotics during neutropenia to reduce this complication has been widely investigated. Historical trials that tested a variety of approaches were generally small and reported mixed results. Because of the lack of compelling evidence and concerns over emergence of resistance, international guidance has continued to recommend against the routine use of antibiotic prophylaxis in this setting. The 2 recently published, large, randomized, double-blind, placebo-controlled trials of levofloxacin versus placebo have challenged the reluctance to adopt the policy of prophylaxis. The GIMEMA trial focused on patients receiving high-dose inpatient chemotherapy for hematologic and solid tumors. Levofloxacin prophylaxis significantly reduced febrile episodes and microbiologically documented infection and bacteremia. In contrast, the SIGNIFICANT trial randomized patients receiving cyclic, outpatient, standard-dose chemotherapy for a variety of solid tumors and lymphoma. Significant reductions in febrile neutropenia episodes and hospitalization for the treatment of infection were demonstrated with prophylaxis. A recent metaanalysis has conclusively demonstrated a reduction in mortality resulting from the use of prophylactic fluoroquinolones for the duration of neutropenia in patients with acute leukemia and after high-dose chemotherapy, and for the first cycle of standard-dose chemotherapy in patients with solid tumors and lymphomas. An inevitable consequence of antibiotic use is the development of resistance. Although there is no doubt this can occur in individual patients and in treatment centers using fluoroquinolone prophylaxis, there is little evidence that patients are harmed as a result. Nevertheless, the induction of bacterial resistance should be avoided in principle, and more work is needed to limit prescribing of antibacterial agents to situations supported by a secure evidence base. When a secure evidence base exists, as is the case now for prophylaxis after chemotherapy, further work is needed to identify subgroups of patients who benefit most from prophylaxis so that it can be applied rationally and efficiently.

Endocrine therapy and other targeted therapies for metastatic breast cancer.

The most important change in the treatment of advanced breast cancer that will emerge over the next 10 years is the shift from adjuvant tamoxifen to adjuvant aromatase inhibitors. This will mean an increasing proportion of tamoxifen-naive aromatase inhibitor-resistant breast cancer. Research of the most appropriate methods of optimizing remaining endocrine sensitivity in these patients is needed. The rapid expansion in the understanding of the molecular basis of breast cancer biology provides potential targets for novel therapies. Despite these pivotal developments, resistance to endocrine therapy remains a key limitation in the management of advanced breast cancer. Until recently, the only option following the development of resistance to an endocrine agent was to change endocrine therapy and, on exhaustion of endocrine sensitivity, to move to cytotoxic chemotherapy. Understanding of at least some of the mechanisms underlying the development of endocrine resistance is now emerging. We now have the tools that may allow us to both overcome resistance and restore sensitivity, or to pre-empt certain types of resistance from developing. These tools include the increasing array of signal transduction inhibitors in combination with standard endocrine agents. Correct clinical management strategy can be guided by preclinical modeling but can only be validated by carefully designed clinical trials. These will, at the very least, need to be conducted with correlative translational research elements that will track changes in tumors as resistance emerges and will allow us to select the most appropriate treatment strategy for individual patients. Amongst the myriad of promising drugs there will undoubtedly be some that fail to meet current hopes, but we can be optimistic that a handful will find a useful place in keeping advanced breast cancer at bay for longer than can be achieved at present. However, the holy grail of a cure is likely, in the medium term, to remain elusively at the end of the rainbow for most of these patients. Several other methods for the management of these patients are in development. These include strategies to overcome endocrine resistance and methods to target deregulated endocrine and growth factor signaling pathways using gene and immunotherapy approaches.