Studies using Australia's Pharmaceutical Benefits Scheme data for pharmacoepidemiological research: a systematic review of the published literature (1987-2013).

PURPOSE: Research using dispensing claims is used increasingly to study post-market medicines use and outcomes. The purpose of this review is to catalogue more than 25 years of published literature using Australia's Pharmaceutical Benefits Scheme (PBS) dispensing records. METHODS: We searched MEDLINE, PreMEDLINE and Embase and conducted author searches for studies published from 1987 to 2013. Independent reviewers screened abstracts of 3209 articles and reviewed 264 full-text manuscripts. Included studies used PBS dispensing data to measure patterns and/or outcomes of prescribed medicines use or dispensing claims to derive a proxy for a specific disease cohort or health outcome. RESULTS: Of the 228 studies identified, 106 used PBS claims only (56 using claims-level data and 50 using individual-level data) and 63 studies linked individual-level PBS claims to other health data. Most commonly, studies examined trends in drug utilisation (33%), clinician and patient practices (26%), drug use and outcomes (18%) and evaluations of intervention impacts (17%). Sixty-two percent of studies using individual-level data were based on a subset of elderly Australians. Most studies focused on drug classes acting on the nervous system (36%), cardiovascular system (15%) and alimentary tract (11%). Few studies examined prescribed medicines use in children and pregnant women. CONCLUSIONS: Pharmaceutical Benefits Scheme claims represent a significant resource to examine Australia's billion-dollar annual investment in prescribed medicines. The body of research is growing and has increased in complexity over time. Australia has great potential to undertake world-class, whole-of-population pharmacoepidemiological studies. Recent investment in data linkage infrastructure will significantly enhance these opportunities.

Chemotherapy administration: modelling the costs of alternative protocols.

BACKGROUND AND OBJECTIVE: The increasing cost of chemotherapy is placing greater pressures on limited healthcare budgets. A potentially important, but often overlooked, aspect of chemotherapy is the cost associated with administration. This study aims to develop a better understanding of these costs, and in doing so, develop a model to estimate the comparative cost of administering alternative chemotherapy protocols for economic evaluation or local decision making. METHODS: We identified the potential tasks and choices related to administering intravenous chemotherapy, grouped tasks according to anticipated resource use, and allocated costs to each task using data from an evidence-based collection of cancer protocols or from primary data collection. The resources were costed from a healthcare system perspective using standard data sources within Australia. The model was applied to alternative protocols used in the treatment of three different cancers: locally advanced and metastatic non-small-cell lung cancer, adjuvant colorectal cancer and adjuvant breast cancer. RESULTS: For the three cancer types examined, the cost of completed administration ranged from 1274 Australian dollars ($A) to $A3015 (year 2009 values) for 13 different protocols potentially used for the initial treatment of locally advanced and metastatic non-small-cell lung cancer; $A5175-8445 for seven protocols for adjuvant colorectal cancer treatment; and $A1494-4074 for seven protocols for adjuvant breast cancer treatment. CONCLUSIONS: The results are of practical significance to those undertaking economic evaluations and to decision makers who use this information within the area of chemotherapy. The examples used suggest that administration costs per visit varied inversely with the number of visits. The results provide information where little has previously been available and may allow decisions about costs and resource allocation to be made with more certainty. Although our model uses costs from the public health system within an Australian state (New South Wales), it can be adapted for use in other jurisdictions.

Nursing takes time: workload associated with administering cancer protocols.

New medicines and therapeutic combinations are tested and marketed every year. Healthcare decision makers have to make explicit choices about adopting new treatments and deal with the resource consequences of their choices. The aim of this article is to examine the nursing workload of administering alternative chemotherapy protocols as a driver of costs. Data collection (focus groups with chemotherapy nurses and a survey of nurse unit managers) was conducted to ascertain the time required to undertake chemotherapy-related tasks and the sources of variability in six chemotherapy centers in New South Wales, Australia. Four task types (patient education, patient assessment, administration, and patient communication) were identified as being associated with administering chemotherapy. On average, patient education required 48 minutes during the first visit and 18.5 minutes thereafter, patient assessment took 20.3 minutes, administration averaged 23 minutes, and patient communication required 24.2 minutes. Each center treated an average of 14 patients per day. Each patient received 3.3 hours of staff time (1.7 hours of direct contact time and 1.6 hours of noncontact time). The result of this research will allow healthcare decision makers and evaluators to predict the amount of nursing time required to administer chemotherapy based on the characteristics of a wide range of chemotherapy protocols.

DNA of mouse mammary tumor virus-like virus is present in human tumors influenced by hormones.

Mouse mammary tumor virus (MMTV) is a hormonally regulated, oncogenic virus of mice. MMTV-like virus DNA has previously been detected in human breast cancers, liver disease, and liver cancers. It is hypothesized that local hormonal effects might be of primary importance in determining MMTV-like virus detection in human tumors. MMTV-like virus envelope (env) DNA was determined using nested PCR in 89 ovarian, 147 prostate, 50 endometrial, 141 skin, and 51 lung cancers. Viral-positive sequences were compared with published MMTV-like viral sequences from human breast cancer, liver cancer and MMTV. Immunohistochemistry for estrogen receptor (ER-alpha) and progesterone receptor (PgR) was performed on a subset of tumors. MMTV-like virus env DNA was detected in ovarian cancers (14/89; 16%), prostate cancers (53/147; 36%), endometrial cancers (5/50; 10%), skin cancers (13/141; 9%) but not in lung cancers (0/51). Phylogenetic analysis of the viral-positive sequences showed no clustering of the isolates according to tissue type. A significant association was observed between the presence of hormone receptors and detection of MMTV-like virus in the human cancers screened (P = 0.01). A significant association between MMTV-like virus and PgR was noted in skin cancers (P = 0.003). Therefore, unlike the mouse model, the detection of MMTV-like env sequences in human cancers in addition to breast indicates that MMTV-like viral expression is not breast cancer-specific and may relate to hormone-dependent viral expression.

Prevalence of mouse mammary tumor virus (MMTV) in wild house mice (Mus musculis) in southeastern Australia.

We determined the prevalence of mouse mammary tumor virus (MMTV) in introduced, free-roaming, wild house mice (Mus musculus domesticus) [corrected] and compared envelope (env) and long terminal repeat (LTR) nucleotide sequences of viruses from wild mice and other sources. Mice were trapped on two occasions, in October (spring) and the following May (autumn) of 2003-2004 in the Mallee region of northwestern Victoria, Australia. Animals were assigned to three cohorts (subadult, young, and old adults) based on their body length. The DNA from salivary glands (62 of 62 mice) and mammary glands (19 of 32 female mice) was screened for the MMTV envelope (env) gene, and the long terminal repeat (LTR) region including the superantigen (SAg) sequence was amplified from a subset. Positive polymerase chain reaction (PCR) results for the MMTV env PCR were detected from salivary gland tissues from 60 of 62 (97%) mice and from mammary gland tissues from 19 of 19 (100%) female mice. All but two mice were positive for MMTV env across both sexes and the three cohorts. Similarity of the SAg carboxy-terminal nucleotide sequence between free-roaming wild house mice varied from 64% to 99%, although most of this variation was due to DNA sequences from two mice (M4 and M5). Phylogenetic analysis of the LTR region did not result in distinct grouping of sequences derived from mice when comparisons were made among sequences from mice in the US, Europe, and Australia, and MMTV-like virus (MMTV-LV) env sequences derived from human hosts. We report a high prevalence of the MMTV env sequence during a sampling period when peak mouse density was low. This indicates that MMTV is an enzootic virus in a population of wild, free-ranging mice in northwestern Victoria, in Australia. Phylogenetic analysis, based upon env and LTR sequence data, indicated minor variation among all isolates. This represents the first report on the prevalence of MMTV in mouse populations in Australia.

Mouse mammary tumor virus-like RNA transcripts and DNA are found in affected cells of human breast cancer.

Identifiable risk factors for the development of breast cancer include age, diet, family history, and lifetime estrogen exposure. An infectious agent (mouse mammary tumor virus; MMTV) is known to cause murine breast tumors and may be involved in the pathogenesis of human disease. Multiple studies have detected MMTV-like sequences in 30 to 60% of breast cancer samples and up to 1.8% of samples from normal breast. Using in situ PCR of MMTV-like sequences of formalin-fixed, paraffin-embedded breast tissue, viral sequences have been located in cancerous epithelial cells in breast acini of male and female breast tumors, but not in adjacent nonmalignant cells. MMTV-like sequences were also located in the epithelial cells of male gynecomastia samples. Using reverse transcriptase in situ PCR, RNA transcripts from the env gene were also detected within cancerous epithelial cells of 78% of DNA-positive tumors, 80% of gynecomastia samples, and 0% of normal tissues screened. This suggests the virus may be replicating in these cells. The epidemiologic and histopathological data are consistent with the association of an MMTV-like virus with breast cancers in men and women. The association with gynecomastia, a benign, possibly premalignant condition suggests hormonal influences, rather than cancer per se, may be the dominant factor in determining viral presence and replication.

Low genetic diversity among isolates of the nematode-trapping fungus Duddingtonia flagrans: evidence for recent worldwide dispersion from a single common ancestor.

The genetic variation of Duddingtonia flagrans, which has become a promising biocontrol agent of animal parasitic nematodes, was investigated in a worldwide collection of 22 isolates. We analysed the sequence variation in four nuclear genes, tubA (beta-tubulin), CMD1 (calmodulin), EF1alpha (translation elongation factor 1alpha), and PII (extracellular serine protease). 1428 aligned base pairs (bp) were analysed from the four genes, including 709 bp of introns. In addition, the variations in three anonymous genomic regions comprising 1155 bp were examined. Three single nucleotide polymorphisms (SNPs) were detected in the seven loci, none of them in the protein encoding genes. The genetic variation was significantly higher in the nematode-trapping fungus Arthrobotrys oligospora, the closest evolutionary relative to D. flagrans. Analysis of 12 isolates of A. oligospora revealed 30 SNPs in tubA, CMD1, EF1alpha and PII. The genetic variation in the isolates of D. flagrans was further examined using AFLP analysis. Five primer combinations were used to detect 159 bands, of which 94 (59.1%) were polymorphic. A neighbour-joining tree based on the AFLP data showed no clear association between genotype and geographical origin. Furthermore, the AFLP data suggest that D. flagrans is mainly clonal and no recombination could be detected, not even within the same country. The low genetic variation in D. flagrans suggests that this fungus has recently diverged from a single progenitor. Based on estimations of mutation rates, it was calculated that this most recent common ancestor lived about 16,000-23,000 years ago.

Progression from normal breast pathology to breast cancer is associated with increasing prevalence of mouse mammary tumor virus-like sequences in men and women.

Mouse mammary tumor virus (MMTV)-like sequences have been found in up to 40% of breast cancer samples but in <2% of normal breast tissue samples from Australian women studied by our group. Screening of a larger and more diverse cohort of female breast cancer samples has now shown a correlation of MMTV-like sequences with the severity (grade) of breast cancer. Thirty-two percent (43 of 136) of female breast cancer samples were positive for MMTV-like sequences when screened using PCR. A significant gradient of MMTV positivity was observed with increasing severity of cancer from 23% of infiltrating ductal carcinoma (IDC) grade I tumors to 34% of IDC grade II tumors (P = 0.00034) and 38% of IDC grade III tumors (P = 0.00002). We also report for the first time the detection of MMTV-like sequences in 62% (8 of 13) of male breast cancer samples and 19% (10 of 52) of male gynecomastia samples screened. MMTV-like sequences were demonstrated in various premalignant breast lesions of females, including fibroadenoma (20%) and fibrocystic disease (28%) samples, at a significantly higher prevalence than that seen in normal breast tissue (1.8%; P = 0.00001). Study of a longitudinal cohort of female breast cancer patients indicated that MMTV was co-incident with tumor but was not present when tumor was absent on histology. These results support the association of MMTV-like sequences with development of breast tumors in men and women and suggest association of MMTV with increasing severity of cancer.

Mouse mammary tumor-like virus is associated with p53 nuclear accumulation and progesterone receptor positivity but not estrogen positivity in human female breast cancer.

PURPOSE: The purpose is to compare the presence of proteins with known associations with breast cancer-progesterone receptor (PgR), estrogen receptor, and p53, with the prevalence of mouse mammary tumor virus (MMTV)-like DNA sequences in human female breast cancers. EXPERIMENTAL DESIGN: A cohort of 128 Australian female breast cancers were screened for MMTV-like DNA sequences using PCR. The presence of PgR, estrogen receptor, and nuclear accumulation of p53 protein was assessed in the same samples using immunohistochemical staining. RESULTS: Nuclear accumulation of p53 was significantly more prevalent (P = 0.05) in archival human breast cancers containing MMTV-like DNA sequences. The presence of progesterone receptor was significantly higher in MMTV-positive than MMTV-negative breast cancers (P = 0.01). No correlation between estrogen receptor and MMTV-like DNA sequences was found. CONCLUSIONS: MMTV causes breast cancer in mice, and hormones up-regulate expression of virus in mice mammary tissue. It is unknown if this is the case in human breast cancers shown to contain DNA of MMTV-like viruses. The positive association between MMTV-like DNA sequences and PgR indicates hormones and MMTV may play a role in human breast cancer. Mutations of the tumor suppressor gene p53 are common in human breast cancer and are associated with higher grades of cancer. The association of MMTV-like DNA sequences with higher grades of cancer, and the positive association between p53 and MMTV-like DNA sequences clearly warrant additional investigation.