Methods of Detecting Medication Administration Point-of-Care Errors in Acute Adult Inpatient Settings: A Scoping Review Protocol.

Medication administration is recognized as a risk-prone activity where errors and near misses have multiple opportunities to occur along the route from manufacturing, through transportation, storage, prescription, dispensing, point-of-care administration, and post-administration documentation. While substantial research, education, and tools have been invested in the detection of medication errors on either side of point-of-care administration, less attention has been placed on this finite phase, leaving a gap in the error detection process. This protocol proposes to undertake a scoping review of the literature related to the detection of medication errors at the point-of-care to understand the potential size, nature, and extent of available literature. The aim is to identify research evidence to guide clinical practice and future research at the medication and patient point-of-care intersection. The search strategy will review literature from PubMed, CINAHL, Cochrane Collaboration, Embase, Scopus, PsychInfo, Web of Science, TRIP, TROVE, JBI Systematic Reviews, Health Collection (Informit), Health Source Nursing Academic, Prospero, Google Scholar, and graylit.org dated 1 January 2000-31 December 2021. Two independent reviewers will screen the literature for relevancy to the review objective, and critically appraise the citations for quality, validity, and reliability using the Joanna Briggs scoping review methodology and System for Unified Management, Assessment and Review of Information (SUMARI) tool. The data will be systematically synthesized to identify and compare the medication error administration detection method findings. A descriptive narrative discussion will accompany the findings.

PI3K/AKT/mTOR inhibitors for advanced or recurrent endometrial cancer.

BACKGROUND: Endometrial cancer is one of the most common gynaecological cancers in developed countries. Treatment of advanced endometrial cancer usually involves radiotherapy, chemotherapy, endocrine therapy or a combination of these. However, survival outcomes are poor in advanced or metastatic disease. Better systemic treatment options are needed to improve survival and safety outcomes for these women. The PI3K/AKT/mTOR pathway is a frequently altered signalling pathway in endometrial cancer. Single-arm studies have reported some encouraging results of the PI3K/AKT/mTOR inhibition in advanced or recurrent endometrial cancer. OBJECTIVES: To assess the efficacy and safety of PI3K/AKT/mTOR inhibitor-containing regimens in women with locally-advanced, metastatic or recurrent endometrial cancer. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials, MEDLINE and Embase to 16 January 2019; and the World Health Organization's International Clinical Trials Registry Platform (WHO ICTRP) and ClinicalTrials.gov in July 2018. We also reviewed reference lists from included studies and endometrial cancer guidelines. SELECTION CRITERIA: We included randomised controlled trials (RCTs) comparing a regimen with a PI3K/AKT/mTOR inhibitor (either alone or in combination with other treatments, such as chemotherapy or hormonal therapy) versus a comparator regimen without a PI3K/AKT/mTOR inhibitor. There were no restrictions on which comparator(s) were included. DATA COLLECTION AND ANALYSIS: We extracted data independently, and assessed risks of bias and the certainty of the evidence. The primary outcome measures were progression-free survival and toxicity (grade 3/4 where available). We derived hazard ratios (HRs) for time-to-event outcomes and risk ratios (RRs) for dichotomous outcomes. Secondary outcomes included overall survival, objective tumour response rate, quality of life and treatment-related death. We used GRADEproGDT to assess the certainty of the evidence for the most important outcomes (by first-line and second/third-line therapy for progression-free survival and overall survival). MAIN RESULTS: We included two RCTs involving 361 women. One study assessed the effects of the mTOR inhibitor temsirolimus, in combination with carboplatin/paclitaxel versus carboplatin/paclitaxel and bevacizumab in treatment-naïve women with advanced or recurrent endometrial cancer. The second study compared the mTOR inhibitor ridaforolimus alone versus progestin or investigator choice of chemotherapy in women who had received prior treatment for metastatic or recurrent endometrial cancer. We identified five ongoing studies on the effects of PI3K and AKT inhibitors, metformin and dual mTOR inhibitors.For first-line therapy, an mTOR inhibitor-containing regimen may worsen progression-free survival (HR 1.43, 95% CI 1.06 to 1.93; 1 study, 231 participants; low-certainty evidence), while for second/third-line therapy, an mTOR inhibitor probably improves progression-free survival compared to chemotherapy or endocrine therapy (HR 0.53, 95% CI 0.31 to 0.91; 1 study, 95 participants; moderate-certainty evidence). Data on toxicity were available from both studies: administering an mTOR inhibitor regimen may increase the risk of grade 3/4 mucositis (RR 10.42, 95% CI 1.34 to 80.74; 2 studies, 357 participants; low-certainty evidence), but may result in little to no difference in risk of anaemia or interstitial pneumonitis (low-certainty evidence for both toxicities). Overall, event rates were low. For first-line therapy, an mTOR inhibitor-containing regimen may result in little to no difference in overall survival compared to chemotherapy (HR 1.32, 95% CI 0.98 to 1.781 study, 231 participants; low-certainty evidence). The finding was similar for second/third-line therapy (HR 1.06, 95% CI 0.70 to 1.61; 1 study, 130 participants; low-certainty evidence). Administering mTOR inhibitor-containing regimens may result in little to no difference in tumour response compared to chemotherapy or hormonal therapy in first-line or second/third-line therapy (first line: RR 0.93, 95% CI 0.75 to 1.17; 1 study, 231 participants; second/third line: RR 0.22, 95% CI 0.01 to 4.40; 1 study, 61 participants; low-certainty evidence).Neither study collected or reported quality-of-life data. AUTHORS' CONCLUSIONS: Two RCTs have been reported to date, with low certainty of evidence. In a recurrent disease setting, mTOR inhibitors may result in improved progression-free survival, but we found no clear benefit in overall survival or tumour response rate. We await the publication of at least five ongoing studies investigating the role of PI3K/AKT/mTOR inhibitors in advanced or recurrent endometrial cancer before any conclusions can be drawn on their use.

The safe administration of medication: Nursing behaviours beyond the five-rights.

This paper discusses the findings from the observation phase of a more extensive, appreciative inquiry qualitative study exploring registered nurses' experiences of administering medications. The observations aimed to explore the participants' application of the five-rights of medication administration in practice. Twenty registered nurses working in inpatient medical/surgical units at a regional Australian hospital were observed administering medications from the commencement to the completion of their shift. A data collection tool based on the five-rights of medication administration was used. The findings indicated that medication administration was not as routine as the rights framework suggests. Indeed, what was observed rarely reflected all the criteria of the rights framework. Notably, in practice, some of the rights were unable to be observed because the critical thinking that underpins the rights are implicit. However, the participants were observed to implement strategies beyond those described by the rights framework that ensured safe and timely medication administration. In brief, medication administration in contemporary healthcare settings is more complicated than the linear process suggested by the rights framework. So more attention is warranted, to the safe practice strategies of nurses who, to deal with complex clinical contexts. Their person-centred strategies respond to patient circumstances and maintain safety.

Perspectives from practice: complexities of personal care workers.

Personal care workers (PCWs) make up the bulk of the workforce in residential and community care services. The knowledge and skill set needed for safe and effective practice in care settings is extensive. A diverse range of registered training organisations (RTOs) offering Certificate III and IV in Individual Support (aging, home and community) are tasked with producing job-ready PCWs. However, the curricula of these programs vary. Additionally, a national code of conduct for healthcare workers became effective in October 2015 as a governance framework for PCWs. The language of the code statements is ambiguous making it unclear how this framework should be translated by RTOs and applied in the preservice practice preparation of PCWs. Employers of PCWs need to feel confident that the content of the preservice education of PCWs satisfactorily prepares them for the diverse contexts of their practice. Likewise, the health professionals who supervise PCWs must be assured about the knowledge and skills of the PCW if they are to safely delegate care activities. The perspectives presented in this discussion make it clear that investigation into the nebulous nature of PCW education, regulation and practice is needed to identify the shortcomings and enable improved practice.

Combining participatory action research and appreciative inquiry to design, deliver and evaluate an interdisciplinary continuing education program for a regional health workforce.

Objective Continuing education (CE) is essential for a healthcare workforce, but in regional areas of Australia there are challenges to providing and accessing relevant, reliable and low-cost opportunities. The aim of the present study was to collaborate with the local regional healthcare workforce to design, deliver and evaluate an interdisciplinary CE (ICE) program. Methods A participatory action research (PAR) model combined with an appreciative inquiry (AI) framework was used to design, deliver and evaluate an ICE program. A focus group of 11 health professionals developed an initial program. Evaluation data from 410 program participants were analysed using AI. Results The ICE program addressed the CE barriers for the regional healthcare workforce because the locally derived content was delivered at a reasonable cost and in a convenient location. Program participants identified that they most valued shared experiences and opportunities enabling them to acquire and confirm relevant knowledge. Conclusion ICE programs enhance interdisciplinary collaboration. However, attendance constraints for regional healthcare workforce include location, cost, workplace and personal factors. Through community engagement, resource sharing and cooperation, a local university and the interdisciplinary focus group members successfully designed and delivered the local education and research nexus program to address a CE problem for a regional healthcare workforce. What is known about the topic? Participation in CE is mandatory for most health professionals. However, various barriers exist for regional health workers to attending CE. Innovative programs, such as webinars and travelling workshops, address some of the issues but create others. Bringing various health workers together for the simultaneous education of multiple disciplines is beneficial. Collectively, this is called ICE. What does this paper add? Using PAR combined with AI to design an ICE program will focus attention on the enablers of the program and meet the diverse educational needs of the healthcare workforce in regional areas. Engaging regional health professionals with a local university to design and deliver CE is one way to increase access to quality, cost-effective education. What are the implications for practitioners? Regional healthcare workers' CE needs are more likely to be met when education programs are designed by them and developed for them. ICE raises awareness of the roles of multiple healthcare disciplines. Learning together strengthens healthcare networks by bolstering relationships through a greater understanding of each other's roles. Enriching communication between local health workers has the potential to enhance patient care.

Safe medication administration: Perspectives from an appreciative inquiry of the practice of registered nurses in regional Australia.

Registered Nurses (RNs) are regulated health professionals who are educated and accountable for safe medication administration (MA). Binding their practice are standards, policies, procedure and legislation. MA competence is taught and assessed during professional pre-registration education programs. However, different philosophies, theories and models are used by education providers making curriculum content disparate and competency frameworks diverse. Additionally, healthcare contexts are increasingly complex and clinical environments unpredictable. Competency models must respect contemporary practice. This paper focusses on the outcomes of Australian PhD research that combined Appreciative Inquiry (AI) principles with a qualitative study to identify MA safety strategies. In this 2-phase descriptive study, twenty RNs were observed then interviewed about their MA experiences. This paper discusses the interview findings. The participants explained how they assessed patient's needs and implemented strategies to administer medications safely. They presented their actions as being underpinned by a desire to do 'the right thing for the patient' despite their practice going beyond traditional procedural frameworks and not reflecting organisational protocols. Instead, they developed common strategies to enhance safe MA. The participants' described using clinical reasoning and patient-centredness during MA. This study contributes to the knowledge needed for future practice development by highlighting what works.

Phase I study of BNC105P, carboplatin and gemcitabine in partially platinum-sensitive ovarian cancer patients in first or second relapse (ANZGOG-1103).

PURPOSE: The primary objective of this study was to determine the recommended dose of the vascular disrupting agent, BNC105P, in combination with gemcitabine and carboplatin in patients with ovarian cancer in first or second relapse with a minimum 4 month progression-free interval after last platinum. METHODS: Patients received carboplatin AUC4 on day 1 in combination with escalating doses of 800 or 1000 mg/m2 gemcitabine on days 1 and 8 and escalating doses of 12 or 16 mg/m2 BNC105P on days 2 and 9 every 21 days for a maximum for six cycles. Maintenance treatment with 16 mg/m2 BNC105P treatment continued for a maximum of six additional cycles. Patients were followed for safety and anti-tumor activity. RESULTS: Fifteen patients were enrolled in the study. Adverse events were most commonly of hematological origin. Dose-limiting toxicities (thrombocytopenia and neutropenia) occurred in two patients at the dose level of 800 mg/m2 gemcitabine, carboplatin AUC4 and 16 mg/m2 BNC105P. No dose-limiting toxicities were observed at a dose level of gemcitabine 1000 mg/m2, carboplatin AUC4 and BNC105P 12 mg/m2. BNC105P as a single agent was well tolerated at a dose of 16 mg/m2 in maintenance treatment. Ten patients (67%) achieved a complete or partial response according to CA125 and/or RECIST response criteria, four of 13 (31%) responded by RECIST alone. The median progression-free survival was 5.9 months. CONCLUSIONS: We have established that BNC105P 12 mg/m2 with gemcitabine 1000 mg/m2 and carboplatin AUC4 is the recommended dose level and has an acceptable toxicity profile. Further exploration of BNC105P in the ovarian cancer setting is planned.

Paragon (ANZGOG-0903): Phase 2 Study of Anastrozole in Women With Estrogen or Progesterone Receptor-Positive Platinum-Resistant or -Refractory Recurrent Ovarian Cancer.

BACKGROUND: There is some evidence that a subset of patients with recurrent ovarian cancer may benefit from antiestrogen therapy. The Paragon study is a basket protocol that includes a series of phase 2 trials investigating the activity of anastrozole in patients with estrogen or progesterone receptor-positive recurrent gynecological cancers. We report the results of treatment in patients with platinum-resistant or -refractory recurrent epithelial ovarian cancer. METHODS: Postmenopausal women who had estrogen and/or progesterone receptor-positive platinum-resistant or platinum-refractory recurrent ovarian cancer and disease measurable by Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1 or GCIG (Gynecologic Cancer InterGroup) CA-125 criteria were eligible. Patients received anastrozole 1 mg daily until progression or unacceptable toxicity. The study was prospectively registered (ACTRN12610000796088). RESULTS: There were 49 evaluable patients, and clinical benefit was observed in 13 (27%; 95% confidence interval [CI], 16%-40%). There were no complete or partial RECIST version 1.1 responses. Clinical benefit was associated with higher global quality-of-life scores. Median progression-free survival was 2.7 months (95% CI, 2.0-2.8 months). The median duration of clinical benefit was 2.8 months (95% CI, 2.6-5.7 months). Most patients (83%) progressed within 6 months. Seven patients continued on treatment for longer than 6 months. Anastrozole was well tolerated in most patients. Subgroup analysis suggested greater clinical benefit in patients with tumors with estrogen-receptor histoscore of more than 200, but this difference was not statistically significant. CONCLUSIONS: A subset of patients with estrogen- or progesterone-positive platinum-resistant or platinum-refractory recurrent epithelial ovarian cancers derives clinical benefit from anastrozole, with acceptable toxicity. The challenge remains how to identify them.

Symptom burden and outcomes of patients with platinum resistant/refractory recurrent ovarian cancer: a reality check: results of stage 1 of the gynecologic cancer intergroup symptom benefit study.

BACKGROUND: The aim of chemotherapy in patients with platinum resistant ovarian cancer is palliation. Patients' experience of symptoms is not well documented, and the impact of treatment on symptoms has not been evaluated in clinical trials. We report symptom burden and treatment outcomes from stage 1 of the Gynecological Cancer Intergroup (GCIG) Symptom Benefit Study. METHODS: One hundred twenty-six patients receiving palliative chemotherapy completed 5 validated health-related quality-of-life questionnaires before starting treatment and before each cycle. They also reported their expected and perceived benefits from treatment. Physicians documented the reasons for treatment and adverse events including symptoms at baseline and estimated the number of cycles of treatment that patients would receive. RESULTS: Palliation was the major reason for chemotherapy. At baseline, all patients were symptomatic (almost 70% had ≥9 symptoms). Patients had high expectation of benefit from treatment. Only 41% of patients received the predicted number of cycles with most stopping early (≤2 cycles) due to progression, death, or adverse effects. Treatment was associated with significant toxicity, with discordance between patient report and physician grading. Although RECIST response rates were low (8.5%), 40% of the patients were reported to have had a clinical benefit and almost 50% of symptomatic patients also reported symptom improvement. CONCLUSIONS: Patients had a complex array of symptoms and significant symptom burden, which was commonly the reason for treatment. Although chemotherapy improved symptoms in about half of the patients, many did not benefit and progressed rapidly. Our findings support research into the use of patient reported outcome measures to document symptoms, adverse events, and subjective benefit, both in clinical trials and in clinical practice, in this patient population. Our findings highlight the need to develop prognostic models to better select patients for treatment, and this is an aim of stage 2 of the GCIG Symptom Benefit Study.

Development of the measure of ovarian symptoms and treatment concerns: aiming for optimal measurement of patient-reported symptom benefit with chemotherapy for symptomatic ovarian cancer.

OBJECTIVE: The aim of this study was to determine the optimal patient-reported outcome measure (PROM) for assessing symptom benefit in trials of palliative chemotherapy for women with symptomatic ovarian cancer. METHODS: Candidate PROMs were EORTC QLQ-C30 plus ovarian-specific QLQ-OV28, Functional Assessment of Cancer Therapy-Ovarian (FACT-O), FACT Ovarian Symptom Index (FOSI), and gynecologic cancer-specific Symptom Representation Questionnaire. Predefined optimality criteria were inclusion of all symptoms necessary for the specified purpose, recall period covering typical length of palliative chemotherapy, numerical item rating scales, and all necessary symptoms included in a single symptom index. Qualitative and quantitative methods were applied to data from stage 1 of the Gynecologic Cancer Intergroup Symptom Benefit Study to determine the set of necessary symptoms and to objectively assess candidate PROMs against the optimality criteria. RESULTS: Ten necessary symptoms were identified: pain, fatigue, abdominal bloating/discomfort, sleep disturbance, bowel disturbance, nausea and vomiting, shortness of breath, poor appetite, urinary symptoms, and weight changes. Although QLQ-C30 and QLQ-OV28 together cover all these symptoms, they split them into numerous scales, dissipating potential symptom-benefit signal. Conversely, FACT-O does not cover all necessary symptoms and contains many other HRQoL-related items and treatment side effects, diluting potential symptom-benefit signal when summed into scales. Item response scales and composite scoring of all candidate PROMs were suboptimal to our specific purpose. We therefore developed a new PROM, the Measure of Ovarian Symptoms and Treatment (MOST) concerns, to provide optimal measurement for the specified purpose. CONCLUSIONS: This article documents the development of the MOST, a new PROM designed to assess patient-reported benefits and burden as end points in clinical trials of palliative chemotherapy for women with symptomatic ovarian cancer. The validity, reliability, and statistical efficiency of the MOST, relative to the best candidate scales of existing PROMs, will be assessed in the stage 2 of Gynecologic Cancer Intergroup Symptom Benefit Study.

Distance and devices - potential barriers to use of wireless handheld devices.

This paper reports the findings of a research project investigating the use of iPods by student nurses to enhance their interactions with content, instructors and peers while located at a distance from their university campus. Wireless handheld devices (WHD) are an important tool in nursing environments that are undergoing rapid technological change. Preferred treatments, drug dosages, postsurgical care, and preventive healthcare regimens continually change and such devices allow students to rapidly confirm information while in the clinical area, thus fostering active learning and safe practice. A case study approach was adopted with each participating student cohort comprising a case. Multiple data collection methods were used to enable rich descriptions of each case. This paper focusses on factors, relating to the use of iPods, which influenced student learning in distance courses at two regional Queensland universities. It furthermore highlights a range of creative interventions reported by students and educators in resolving issues with their devices. The study found that connectivity difficulties, technology literacy level, compatibility of study resources with the WHDs, and small screen size were all factors that impacted negatively on the use of iPods in distance courses. The paper describes the responses of students and educators to the use of iPods for learning. This study concluded that nursing students and nursing educators alike may experience problems when WHD's are introduced to courses as a platform for learning. However, both students and educators can be innovative and resourceful in managing these problems and, when access to course resources that were enabled for viewing on the WHDs were available, the learning experience of the students and the teaching experience for the educators were enhanced.

Exploring the relationships between teaching, approaches to learning and critical thinking in a problem-based learning foundation nursing course.

Undergraduate nursing programmes are responsible for providing teaching and learning that develops students' knowledge, skills and attitudes in alignment with contemporary nursing standards and healthcare demands. Problem-based learning (PBL) as a pedagogy uses authentic artefacts reflecting real-world situations for students to practice problem-solving skills through collaboration with their peers. PBL was introduced in a foundation nursing course delivered in a regional university in Queensland, Australia. This paper presents the findings of a study exploring the relationships between nursing students' individual characteristics and perceptions of learning environments, teaching in PBL mode, approaches to learning, and critical thinking skill readiness. The study was guided by an ecological perspective designed to examine nursing students' ecological environments and the influences of those environments on their approaches to learning, and on critical thinking skill readiness. The results, through hierarchical linear modelling, revealed that aspects of the PBL approach to teaching influenced the approaches to learning students adopt, and thus their critical thinking skill readiness. Implications for teaching in undergraduate nursing programmes are discussed.

Hope, quality of life, and benefit from treatment in women having chemotherapy for platinum-resistant/refractory recurrent ovarian cancer: the gynecologic cancer intergroup symptom benefit study.

Chemotherapy for platinum-resistant/refractory ovarian cancer is motivated by the hope of benefit. We sought to determine the relationships between: (a) trait hope, expectation of symptom benefit from chemotherapy, and anxiety and depression; (b) hope and perceived efficacy of chemotherapy; and (c) unfulfilled hope (where expectations for benefit are not fulfilled) and depression. Methods. Adult patients enrolled within stage 1 of the Gynecologic Cancer Intergroup Symptom Benefit Study were included. Patient. Reported outcomes were collected from 126 women with predominantly platinum-resistant ovarian cancer at baseline, prior to the first four treatment cycles (12-16 weeks), and four weeks after completing chemotherapy or at disease progression, whichever came first. Associations were assessed with Spearman rank correlation coefficient (r) and odds ratio. Results. Trait hope and expectation of symptom benefit from chemotherapy were weakly correlated with each other (r = 0.25). Trait hope, but not expectation of symptom benefit, was negatively correlated with anxiety (r = -0.43) and depression (r = -0.50). The smaller the discrepancy between perceived and expected symptom benefit, the less likely the patient was to have scores indicative of depression (odds ratio: 0.68; 95% confidence interval: 0.49-0.96; p = .026). Conclusion. Trait hope and expectation of symptom benefit from chemotherapy appear to be distinct and independent of the aspects of quality of life and scores for depression. Hope did not appear to affect perceived efficacy of chemotherapy in alleviating symptoms, but women whose expectation of symptom benefit from chemotherapy was not fulfilled were more likely to have scores indicative of depression. It may be preferable to encourage hope toward achievable goals rather than toward benefits from chemotherapy.

Feasibility, acceptability and preferences for intraperitoneal chemotherapy with paclitaxel and cisplatin after optimal debulking surgery for ovarian and related cancers: an ANZGOG study.

OBJECTIVE: Intraperitoneal (IP) chemotherapy in women with optimally debulked stage III ovarian cancer has been reported to prolong overall survival, but has not been widely adopted due to concerns about its toxicity, inconvenience and acceptability to patients. The purposes of this study were to determine the regimen's feasibility, adverse events, catheter-related complications, progression-free survival, health-related quality of life (HRQL), and patients' preferences for IP versus intravenous (IV) chemotherapy. METHODS: We conducted a single arm, multi-center study of IP chemotherapy with IV paclitaxel 135 mg/m(2) (D1) over 3 hours, IP cisplatin 75 mg/m(2) (D2), and IP paclitaxel 60 mg/m(2) (D8) for 6 cycles in women with optimally debulked stage III ovarian or related cancers. RESULTS: Thirty-eight eligible patients were recruited from 12 sites between July 2007 and December 2009. Seventy-one percent (n=27) completed at least 4 cycles and 63% (n=24) completed all 6 cycles. Grade 3 or 4 adverse events included nausea (n=2), vomiting (n=2), abdominal pain (n=2), and diarrhea (n=1), but not febrile neutropenia, neurotoxicity, or nephropathy. There were no treatment-related deaths. Catheter-related complications were the most frequent cause of early discontinuation of treatment (16 patients, 21%). Apart from neurotoxicity HRQL which worsened over time, HRQL was stable or improved with time. Most patients (≥50%) judged moderate benefits (e.g., an extra 6 months survival time or a 5% improvement in survival rates) necessary to make IP chemotherapy worthwhile. CONCLUSION: IP chemotherapy was feasible, tolerable, and most participants considered moderate survival benefits sufficient to warrant the adverse effects and inconvenience.

The role of hormonal therapy in gynecological cancers-current status and future directions.

Many gynecological cancers, including epithelial and stromal ovarian cancers; endometrial carcinomas; and some gynecological sarcomas, in particular endometrial stromal sarcomas, express estrogen and/ or progesterone receptors. Hormonal therapy, typically progestogens or tamoxifen, is commonly prescribed to patients with potentially hormone-sensitive recurrent or metastatic gynecological cancers with very variable response rates and clinical benefit reported. Aromatase inhibitors are now widely used to treat postmenopausal women with hormone receptor-positive breast cancers as they have greater activity than tamoxifen and are generally better tolerated. The role of aromatase inhibitors in gynecological cancers is uncertain and has not been well studied, although they do appear to be active. The current evidence to support the use of hormonal therapies including aromatase inhibitors in gynecological cancers is reviewed, and the gaps in our knowledge highlighted.

Symptom control in patients with recurrent ovarian cancer: measuring the benefit of palliative chemotherapy in women with platinum refractory/resistant ovarian cancer.

Most women with advanced ovarian cancer will relapse and subsequently develop platinum-resistant/refractory ovarian cancer. The benefit of treatment is currently based on objective response rates, which are a crude measure of benefit. It would be clinically meaningful if we were better able to measure the benefit of palliative therapy and, in particular, ascertain whether cancer-related symptoms improve with treatment and how this impacts on quality of life. This paper reviews the management of patients with platinum-resistant/refractory ovarian cancer and highlights the gaps in our knowledge and shortcomings with the current approaches to measure the benefit of treatment. The ultimate objective is to describe and encourage recruitment to the Gynecologic Cancer Intergroup study that has recently opened. This study will recruit a large number of patients from around the world in an effort to develop more robust instruments to measure the benefit of chemotherapy and to understand the impact of chemotherapy on symptom control and quality of life. In addition, this study will give us an insight into how all patients are managed rather than a select minority who are treated in clinical trials.

Skeletal muscle development in normal and double-muscled cattle.

This study examined the effect of genotype on prenatal muscle development in both normal-muscled (NM) animals and in double-muscled (DM) animals harboring a mutation in the gene for myostatin that results in the production of a functionally inactive protein. The following muscle development parameters were analyzed at four gestational ages: muscle weight, fiber type, by both enzyme histochemistry and myosin heavy-chain (MHC) immunocytochemistry, and average fiber area. The weights of both M. vastus lateralis and M. vastus medialis were greater throughout prenatal development in the DM animals compared to NM. The percentage of type 1 muscle fibers initially declined with gestational age and subsequently increased in both NM and DM. The percentage of type 1 fibers was consistently lower in DM than in NM. A pattern of MHC isoform localization was shown in DM muscle that is indicative of a delay in muscle development relative to NM. Muscle fiber size was differentially regulated in NM and DM, depending on fiber type. Type 1 fibers were smaller in DM than NM in late gestation, while type 2 fibers were smaller throughout gestation. This study suggests that the inactivating myostatin mutation in DM animals may be associated with changes in both skeletal muscle fiber type and fiber size during bovine muscle development.

Apoptotic adaptations from exercise training in skeletal and cardiac muscles.

The effect of exercise on apoptosis in postmitotic tissues is not known. In this study, we investigated the effect of regular moderate physical activity (i.e., exercise training) on the extent of apoptosis in rat skeletal and cardiac muscles. Adult Sprague Dawley rats were trained (TR) 5 days weekly for 8 wk on treadmill. Sedentary rats served as controls (CON). An ELISA was used to detect mono- and oligonucleosome fragmentation as an indicator of apoptosis. Bcl-2, Bax, Apaf-1, AIF, cleaved PARP, cleaved caspase-3, cleaved/active caspase-9, heat shock protein (HSP)70, Cu/Zn-SOD, and Mn-SOD protein levels were determined by Western analyses. Bcl-2 and Bax transcript contents were estimated by RT-PCR. A spectrofluorometric assay was used to determine caspase-3 activity. DNA fragmentation in ventricles of the TR group decreased by 15% whereas that in soleus of the TR group tended to decrease (P=0.058) when compared with CON group. Protein contents of Bcl-2, HSP70, and Mn-SOD increased in both soleus and ventricle muscles of TR animals when compared with CON animals. Apaf-1 protein content in the soleus of TR animals was lower than that of CON animals. Bcl-2 mRNA levels increased in both ventricle and soleus muscles of TR animals, and Bax mRNA levels decreased in the soleus of TR animals when compared with CON animals. Furthermore, HSP70 protein content was negatively correlated to Bax mRNA content and was positively correlated to Bcl-2 protein and mRNA contents. Mn-SOD protein content was negatively correlated to the apoptotic index, and caspase-3 activity and was positively correlated to Bcl-2 transcript content and HSP70 protein content. These data suggest that exercise training attenuates the extent of apoptosis in cardiac and skeletal muscles.

Id2 expression during apoptosis and satellite cell activation in unloaded and loaded quail skeletal muscles.

Inhibitor of differentiation-2 (Id2) is a basic helix-loop-helix protein that acts as a negative regulator of the myogenic regulatory transcription factor family, but Id2 has also been implicated in apoptosis in several cell lines. In this study, we tested the hypothesis that Id2 has a role in both apoptosis-associated muscle atrophy and muscle hypertrophy. A weight corresponding to 12% of the body weight was attached to one wing of Japanese quail to induce hypertrophy in the patagialis (PAT) muscle. Birds in group 1 were killed after 5 (n = 8), 7 (n = 10), or 14 days (n = 10) of loading. The left wing was loaded for 14 days in group 2 birds, and then the weight was removed and the PAT was examined after 7 (n = 10), 14 (n = 10), or 21 (n = 5) days of unloading. A time-released bromodeoxyuridine (BrdU) pellet was implanted subcutaneously with wing weighting to identify activated satellite cells during loading. The left wing was loaded for 14 days, unloaded for 14 days, and then the weight was reattached for a subsequent 7 (n = 10) or 14 days (n = 10) in group 3 birds. BrdU was implanted on the second loading phase in this group. Id2 mRNA as measured by kinetic PCR increased by 3.9-, 2.7-, and 1.6-fold, relative to control levels after 7, 14, and 21 days of unloading (group 2). Id2 protein as estimated by Western blots increased by 1.5-, 1.4-, and 0.75-fold after 7, 14, and 21 days of unloading (group 2). Muscle unloading induced apoptosis, because poly(ADP-ribose) polymerase-(PARP)-positive nuclei increased and caspase 8 levels increased by 2.6- and 1.7-fold after 7 or 14 days of unloading, respectively (group 2). Although BrdU-positive nuclei increased during loading (groups 1 and 3), 50% failed to survive during unloading (group 2). Id2 mRNA increased by 2.2- and 1.8-fold after 5 and 7 days of loading, respectively, but decreased to control levels by 14 days of loading in group 1. Id2 protein levels increased 2.1-fold after 5 days of loading (group 1). In contrast, Id2 did not increase in reloaded muscles of group 3 birds. These data suggest that Id2 may have a role in apoptosis-associated atrophy of skeletal muscles, but its role in muscle hypertrophy is less clear.

The myostatin gene is a downstream target gene of basic helix-loop-helix transcription factor MyoD.

Myostatin is a negative regulator of myogenesis, and inactivation of myostatin leads to heavy muscle growth. Here we have cloned and characterized the bovine myostatin gene promoter. Alignment of the upstream sequences shows that the myostatin promoter is highly conserved during evolution. Sequence analysis of 1.6 kb of the bovine myostatin gene upstream region revealed that it contains 10 E-box motifs (E1 to E10), arranged in three clusters, and a single MEF2 site. Deletion and mutation analysis of the myostatin gene promoter showed that out of three important E boxes (E3, E4, and E6) of the proximal cluster, E6 plays a significant role in the regulation of a reporter gene in C(2)C(12) cells. We also demonstrate by band shift and chromatin immunoprecipitation assay that the E6 E-box motif binds to MyoD in vitro and in vivo. Furthermore, cotransfection experiments indicate that among the myogenic regulatory factors, MyoD preferentially up-regulates myostatin promoter activity. Since MyoD expression varies during the myoblast cell cycle, we analyzed the myostatin promoter activity in synchronized myoblasts and quiescent "reserve" cells. Our results suggest that myostatin promoter activity is relatively higher during the G(1) phase of the cell cycle, when MyoD expression levels are maximal. However, in the reserve cells, which lack MyoD expression, a significant reduction in the myostatin promoter activity is observed. Taken together, these results suggest that the myostatin gene is a downstream target gene of MyoD. Since the myostatin gene is implicated in controlling G(1)-to-S progression of myoblasts, MyoD could be triggering myoblast withdrawal from the cell cycle by regulating myostatin gene expression.