Preventing vaginal stenosis after brachytherapy for gynaecological cancer: an overview of Australian practices.

Despite advances in brachytherapy techniques in recent years, patients still experience a variety of treatment-related complications. Vaginal stenosis is a recognised toxicity of brachytherapy for the treatment of gynaecological cancer. It can result in long-term sexual dysfunction and painful vaginal examinations; however, it is generally accepted that it may be prevented by regular sexual intercourse or the use of vaginal dilators. The incidence of vaginal stenosis is variably reported in the literature, while preventative strategies and compliance are infrequently described and rarely evaluated. A telephone survey of radiation oncology centres in Australia was undertaken as a quality improvement activity to determine best practice for the use of vaginal dilators for the prevention of vaginal stenosis, by way of identifying similarities of practice. The results revealed a lack of consistency for all variables, including which patients are advised to use vaginal dilators, the time to initiate use, frequency of use, insertion time and duration of use. These findings suggest that current methods for preventing radiation-induced vaginal stenosis warrant formal evaluation in order to establish an evidence base for practice.     

Development of the Home Care Client Satisfaction Instrument

Abstract Client (patient) satisfaction has been studied extensively in the health care sector, yet those receiving home health care services have been the focus of few studies. The purpose of this study was to test the reliability and validity of the Home Care Client Satisfaction Instrument (HCCSI). A total of 400 clients, randomly selected from 20 randomly chosen home care agencies in one state, completed the HCCSI and demographic form. Most respondents were older adults with multiple health problems and their families or informal support systems. Since data were skewed, item analysis was used. The revised instrument (HCCSI-R) is unidimensional and includes 12 items rated on a 5-point Likert scale measuring specific aspects of care. In addition, there are three global measures of satisfaction rated on a 10-point scale. All items except one had significant item-total correlations greater than .59. The total score correlates with likeliness to recommend the agency to others (.37, p = .0001), showing some evidence for criterion-related validity.     

Pharmacodynamic Evaluation of CCI-779, an Inhibitor of mTOR, in Cancer Patients.

CCI-779 is an ester of rapamycin and inhibitor of mammalian target of rapamycin (mTOR) currently in Phase II clinical development for the treatment of patients with cancer. CCI-779 interacts with mTOR and inhibits its kinase activity, resulting in inhibition of the mTOR-regulated translational controllers p70(s6) kinase and 4E-BP1. Ultimately, CCI-779 decreases the translation of mRNAs involved in the control of the cell cycle, resulting in cell cycle arrest. The objective of this study was to develop a method to determine the pharmacodynamic effects of CCI-779 suitable for use in clinical trials. Exposure of Raji lymphoblastoid cells to increasing concentrations of rapamycin resulted in a linear concentration-dependent inhibition of p70(s6) kinase activity, suggesting that p70(s6) kinase activity could be an appropriate marker for mTOR-interacting agents. In subsequent experiments, treatment of nude mice bearing the CCI-779 susceptible breast cancer cell line MDA-468 with a single dose of 10 mg/kg CCI-779 resulted in a >80% inhibition of p70(s6) kinase activity in peripheral blood mononuclear cells (PBMCs) 72 h after treatment. Importantly, the degree of p70(s6) kinase inhibition was identical in PBMCs and simultaneously collected tumor tissue, suggesting that the PBMCs are an adequate surrogate tissue for p70(s6) kinase activity in vivo. The intrasubject coefficient of variation of p70(s6) kinase activity measured in PBMCs collected from five healthy volunteers on days 1, 4, and 8 was 14%, indicating that p70(s6) kinase activity in PBMCs remains relatively stable over time. Finally, p70(s6) kinase activity was measured in PBMCs from nine patients with renal cell cancer treated with a single dose of 25, 75, or 250 mg of CCI-779 i.v. (three patients each). PBMCs were collected on days 2, 4, and 8 after CCI-779 treatment. In this small data set, eight of the nine patients had evidence of p70(s6) kinase activity inhibition after treatment that was independent of the administered dose. There was a significant linear association between time to disease progression and inhibition of p70(s6) kinase activity 24 h after treatment. In conclusion, these results indicate that the pharmacodynamic effects of CCI-779 can be determined using a p70(s6) kinase assay in PBMCs. This assay is currently being incorporated in Phase I and II studies with CCI-779 to determine its relationship with dose and plasma concentration of the agent and its value as a predictor of treatment efficacy.     

Use of molecular tumor characteristics to prioritize mismatch repair gene testing in early-onset colorectal cancer.

PURPOSE: The relationships between mismatch repair (MMR) protein expression, microsatellite instability (MSI), family history, and germline MMR gene mutation status have not been studied on a population basis. METHODS: We studied 131 unselected patients with colorectal cancer diagnosed younger than age 45 years. For the 105 available tumors, MLH1, MSH2, MSH6, and PMS2 protein expression using immunohistochemistry (IHC) and MSI were measured. Germline DNA was screened for hMLH1, hMSH2, hMSH6, and hPMS2 mutations for the following patients: all from families fulfilling the Amsterdam Criteria for hereditary nonpolyposis colorectal cancer (HNPCC); all with tumors that were high MSI, low MSI, or that lacked expression of any MMR protein; and a random sample of 23 with MS-stable tumors expressing all MMR proteins. RESULTS: Germline mutations were found in 18 patients (nine hMLH1, four hMSH2, four hMSH6, and one hPMS2); all tumors exhibited loss of MMR protein expression, all but one were high MSI or low MSI, and nine were from a family fulfilling Amsterdam Criteria. Sensitivities of IHC testing, MSI (high or low), and Amsterdam Criteria for MMR gene mutation were 100%, 94%, and 50%, respectively. Corresponding positive predictive values were 69%, 50%, and 75%. CONCLUSIONS: Tumor IHC analysis of four MMR proteins and MSI testing provide a highly sensitive strategy for identifying MMR gene mutation-carrying, early-onset colorectal cancer patients, half of whom would have been missed using Amsterdam Criteria alone. Tumor-based approaches for triaging early-onset colorectal cancer patients for MMR gene mutation testing, irrespective of family history, appear to be an efficient screening strategy for HNPCC.     

Time in Parenting Activities in Dual‐Earner Families at the Transition to Parenthood

Time parenting was compared for new mothers and fathers in a sample of 182 dual‐earner families. Parenting domains included positive engagement, responsibility, routine child care, and accessibility. Time diaries captured parents' time use over a 24‐hour workday and nonworkday when infants were age 3 and 9 months. Parents were highly involved with their infants. Mothers were more involved than fathers in positive engagement and routine child care on days and at each assessment, and allocated more available time on workdays to these domains than fathers, with one exception. Fathers and mothers allocated similar shares of available workday time to positive engagement at 9 months. Greater equity in responsibility and accessibility was found; mothers spent more, and a greater share of, parenting time in responsibility than fathers on the 9‐month workday only, and were more accessible on the 3‐month workday only. Implications for parents in today's diverse families are discussed.     

Development of Doxycycline MIC and Disk Diffusion Interpretive Breakpoints and Revision of Tetracycline Breakpoints for Streptococcus pneumoniae

A study was performed to derive susceptibility testing interpretive breakpoints for doxycycline with Streptococcus pneumoniae and to reassess breakpoints for tetracycline using the requirements defined in Clinical and Laboratory Standards Institute (CLSI) document M23-A3. Tetracycline and doxycycline MICs and disk diffusion zone sizes were determined on 189 isolates selected from the 2009-2010 CDC Active Bacterial Core surveillance strain collection according to the testing methods described in CLSI documents M07-A8 and M02-A10. Tetracycline and doxycycline MICs and zones were compared to each other directly, and the reproducibility of MICs and zone diameters for both drugs was determined. Scattergrams of tetracycline MICs versus corresponding zone diameters and doxycycline MICs versus zones were prepared, and analysis indicated that the present CLSI tetracycline MIC and disk breakpoints did not fit the susceptibility data for doxycycline. Doxycycline was 1 to 3 dilutions more potent than tetracycline, especially in strains harboring the tetM resistance determinant. tetM was detected in ≥90% of isolates having tetracycline MICs of ≥4 μg/ml and in ≥90% with doxycycline MICs of ≥1. Limited pharmacokinetic/pharmacodynamic (PK/PD) data coupled with application of the error-rate bounded method of analysis suggested doxycycline-susceptible breakpoints of either ≤0.25 μg/ml or ≤0.5 μg/ml, with intermediate and resistant breakpoints 1 and 2 dilutions higher, respectively. The disk diffusion zone diameter correlates were susceptible at ≥28 mm, intermediate at 25 to 27 mm, and resistant at ≤24 mm. Revised lower tetracycline MIC breakpoints were suggested as susceptible at ≤1 μg/ml, intermediate at 2 μg/ml, and resistant at ≥4 μg/ml. Suggested tetracycline disk diffusion zones were identical to those of doxycycline.     

Evolving beyond antiracism: Reflections on the experience of developing a cultural safety curriculum in a tertiary education setting

There is an inextricable link between cultural and clinical safety. In Australia high-profile Aboriginal deaths in custody, publicised institutional racism in health services and the international Black Lives Matter movement have cemented momentum to ensure culturally safe care. However, racism within health professionals and health professional students remains a barrier to increasing the number of Aboriginal and Torres Strait Islander Health professionals. The Australian Health Practitioner Regulation Agency's Aboriginal and Torres Strait Islander Health Strategy's objective to ‘eliminate racism from the health system’, and the recent adoption of the Aboriginal and Torres Strait Islander peoples led cultural safety definition, has instigated systems level reflections on decolonising practice. This article explores cultural safety as the conceptual antithesis to racism, examining its origins, and contemporary evolution led by Aboriginal and Torres Strait Islander peoples in Australia, including its development in curriculum innovation. The application of cultural safety is explored using in-depth reflection, and the crucial development of integrating critical consciousness theory, as a precursor to culturally safe practice, is discussed. Novel approaches to university curriculum development are needed to facilitate culturally safe and decolonised learning and working environments, including the key considerations of non-Indigenous allyship and collaborative curriculum innovations and initiatives.     

Microsatellite instability markers for identifying early-onset colorectal cancers caused by germ-line mutations in DNA mismatch repair genes.

PURPOSE: Microsatellite instability (MSI) testing of colorectal cancer tumors is used as a screening tool to identify patients most likely to be mismatch repair (MMR) gene mutation carriers. We wanted to examine which microsatellite markers currently used to detect MSI best predict early-onset colorectal cancer caused by germ-line mutations in MMR genes. EXPERIMENTAL DESIGN: Invasive primary tumors from a population-based sample of 107 cases of colorectal cancer diagnosed before age 45 years and tested for germ-line mutations in MLH1, MSH2, MSH6, and PMS2 and MMR protein expression were screened for MSI using the National Cancer Institute panel and an expanded 10-microsatellite marker panel. RESULTS: The National Cancer Institute five-marker panel system scored 31 (29%) as (NCI)MSI-High, 13 (12%) as (NCI)MSI-Low, and 63 (59%) as (NCI)MS-Stable. The 10-marker panel classified 18 (17%) as (10)MSI-High, 17 (16%) as (10)MSI-Low, and 72 (67%) as (10)MS-Stable. Of the 26 cancers that lacked the expression of at least one MMR gene, 24 (92%) were positive for some level of MSI (using either microsatellite panel). The mononucleotide repeats Bat26, Bat40, and Myb were unstable in all (10)MSI-High cancers and all MLH1 and MSH2 mutation carriers (100% sensitive). Bat40 and Bat25 were unstable in all tumors of MSH6 mutation carriers (100% sensitive). Bat40 was unstable in all MMR gene mutation carriers (100% sensitive). By incorporating seven mononucleotide repeats markers into the 10-marker panel, we were able to distinguish the carriers of MSH6 mutations (all scored (10)MSI-Low) from the MLH1 and MSH2 mutation carriers (all scored (10)MSI-High). CONCLUSIONS: In early-onset colorectal cancer, a microsatellite panel containing a high proportion of mononuclear repeats can distinguish between tumors caused by MLH1 and MSH2 mutations from those caused by MSH6 mutations.