Using hospital registries in Australia to extend data availability on vulval cancer treatment and survival.

BACKGROUND: The value of hospital registries for describing treatment and survival outcomes for vulval cancer was investigated. Hospital registry data from four major public hospitals in 1984-2016 were used because population-based data lacked required treatment and outcomes data. Unlike population registries, the hospital registries had recorded FIGO stage, grade and treatment. METHODS: Unadjusted and adjusted disease-specific survival and multiple logistic regression were used. Disease-specific survivals were explored using Kaplan-Meier product-limit estimates. Hazards ratios (HRs) were obtained from proportional hazards regression for 1984-1999 and 2000-2016. Repeat analyses were undertaken using competing risk regression. RESULTS: Five-year disease-specific survival was 70%, broadly equivalent to the five-year relative survivals reported for Australia overall (70%), the United Kingdom (70%), USA (72%), Holland (70%), and Germany (Munich) (68%). Unadjusted five-year survival tended to be lower for cancers diagnosed in 2000-2016 than 1984-1999, consistent with survival trends reported for the USA and Canada, but higher for 2000-2016 than 1984-1999 after adjusting for stage and other covariates, although differences were small and did not approach statistical significance (p ≥ 0.40). Surgery was provided as part of the primary course of treatment for 94% of patients and radiotherapy for 26%, whereas chemotherapy was provided for only 6%. Less extensive surgical procedures applied in 2000-2016 than 1984-1999 and the use of chemotherapy increased over these periods. Surgery was more common for early FIGO stages, and radiotherapy for later stages with a peak for stage III. Differences in treatment by surgery and radiotherapy were not found by geographic measures of remoteness and socioeconomic status in adjusted analyses, suggesting equity in service delivery. CONCLUSIONS: The data illustrate the complementary value of hospital-registry data to population-registry data for informing local providers and health administrations of trends in management and outcomes, in this instance for a comparatively rare cancer that is under-represented in trials and under-reported in national statistics. Hospital registries can fill an evidence gap when clinical data are lacking in population-based registries.

Sociodemographic disparities in survival from colorectal cancer in South Australia: a population-wide data linkage study.

BACKGROUND: Inequalities in survival from colorectal cancer (CRC) across socioeconomic groups and by area of residence have been described in various health care settings. Few population-wide datasets which include clinical and treatment information are available in Australia to investigate disparities. This study examines socio-demographic differences in survival for CRC patients in South Australia (SA), using a population-wide database derived via linkage of administrative and surveillance datasets. METHODS: The study population comprised all cases of CRC diagnosed in 2003-2008 among SA residents aged 50-79 yrs in the SA Central Cancer Registry. Measures of socioeconomic status (area level), geographical remoteness, clinical characteristics, comorbid conditions, treatments and outcomes were derived through record linkage of central cancer registry, hospital-based clinical registries, hospital separations, and radiotherapy services data sources. Socio-demographic disparities in CRC survival were examined using competing risk regression analysis. RESULTS: Four thousand six hundred and forty one eligible cases were followed for an average of 4.7 yrs, during which time 1525 died from CRC and 416 died from other causes. Results of competing risk regression indicated higher risk of CRC death with higher grade (HR high v low =2.25, 95% CI 1.32-3.84), later stage (HR C v A = 7.74, 95% CI 5.75-10.4), severe comorbidity (HR severe v none =1.21, 95% CI 1.02-1.44) and receiving radiotherapy (HR = 1.41, 95% CI 1.18-1.68). Patients from the most socioeconomically advantaged areas had significantly better outcomes than those from the least advantaged areas (HR =0.75, 95% 0.62-0.91). Patients residing in remote locations had significantly worse outcomes than metropolitan residents, though this was only evident for stages A-C (HR = 1.35, 95 % CI 1.01-1.80). These disparities were not explained by differences in stage at diagnosis between socioeconomic groups or area of residence. Nor were they explained by differences in patient factors, other tumour characteristics, comorbidity, or treatment modalities. CONCLUSIONS: Socio-economic and regional disparities in survival following CRC are evident in SA, despite having a universal health care system. Of particular concern is the poorer survival for patients from remote areas with potentially curable CRC. Reasons for these disparities require further exploration to identify factors that can be addressed to improve outcomes.

Dose-intense capecitabine, oxaliplatin and bevacizumab as first line treatment for metastatic, unresectable colorectal cancer: a multi-centre phase II study.

BACKGROUND: Dose intense chemotherapy may improve efficacy with acceptable toxicity. A phase II study was conducted to determine the feasibility of a dose-intense two weekly schedule of capecitabine, oxaliplatin, and bevacizumab in metastatic colorectal cancer (mCRC). METHODS: 49 patients with previously untreated mCRC were recruited. Nineteen received capecitabine (1750 mg/m(2) oral BD days 1-7)oxaliplatin (85 mg/m(2)i.v. day 1) and bevacizumab (5 mg/kg i.v. day 1) using a 14-day cycle (C1750). Following toxicity concerns capecitabine was reduced to 1500 mg/m2oral BD (C1500) and 30 further patients recruited. RESULTS: Over 80% of patients received at least 75% of planned chemotherapy doses over the first two cycles. At C1750 Grade 3 or higher toxicity occurred in 74% (95% CI 49% to 91%) and on C1500 in 70% (95% CI 51% to 85%). The median progression-free survival was 6.9 months (95% CI 4.7 to 8.7) for C1750 dose and 8.9 months (95% CI 4.1 to 12.4) for C1500. 3 treatment-related deaths occurred. CONCLUSIONS: Dose intense capecitabine and oxaliplatin with bevacizumab does not show additional efficacy and has potentially significant toxicity. Its use outside of clinical trials is not recommended. TRIAL REGISTRATION: ISRCTN41540878.

Association of fertility with group mating behavior in ewes.

It was hypothesized that values for fertility variables would vary with number of rams ewes mated with in a group mating management system. In Experiment 1, for adult ewes (n = 872) joined with rams for 35-38 days, 19.0 ± 2.2 %, 19.2 ± 3.5 %, 34.4 ± 1.3 % and 27.4 ± 3.3 % were marked by zero, one, two or three rams during the first 17 days, respectively. In general, as number of rams with which ewes mated increased, number of lambs born (NLB) increased, however, ovulation rate (OR) did not. In mated ewes, embryo survival (ES) increased (P < 0.05) as number of rams with which ewes mated increased. In Experiment 2, ewes that mated with zero or one ram had lesser concentrations of estradiol than ewes that mated with two or three rams when evaluated 30 h after initiation of the follicular phase. Following breeding on the subsequent estrus, number of fetuses at mid-gestation was less in ewes that had mated, in the previous estrus, with zero or one ram compared to two or three rams. In summary, ewes mating with a larger number of rams had greater values for the fertility variables that were evaluated compared with those mating with fewer rams. When ewes mated with fewer rams during the estrous period there were lesser concentrations of estradiol, potentially associated with the decreased ES.

Patient experiences of continuity of cancer care: development of a new medical care questionnaire (MCQ) for oncology outpatients.

OBJECTIVES: To adapt the Components of Primary Care Index (CPCI) to be applicable to oncology outpatients and to assess the reliability and validity of the adapted instrument (renamed the Medical Care Questionnaire [MCQ]). METHODS: The development and validation of the MCQ took place in four phases. Phase 1 reviewed the literature and examined existing measures. In Phase 2, the selected instrument (CPCI) was reviewed by a panel of experts using a stepwise consensus procedure. In Phase 3, the adapted 21-item MCQ was administered to 200 outpatients attending oncology appointments. The instrument was refined to 15 items and in Phase 4, it was completed by 477 oncology outpatients. The psychometric properties of the new instrument were assessed using exploratory factor analysis (EFA), confirmatory factor analysis, multitrait scaling analysis, and by comparing MCQ scores between known groups. RESULTS: EFA of the 15-item MCQ suggested three subscales with acceptable to good reliability: "Communication"alpha = 0.69; "Coordination"alpha = 0.84; and "Preferences"alpha = 0.75. Comparing known groups showed that patients who saw fewer doctors during their clinic visits reported stronger "Preferences" to see their usual doctor and rated "Communication" with their doctors as better than patients who saw more doctors during their clinic visits. CONCLUSION: The MCQ demonstrates good psychometric properties in the target population. It is a brief and simple-to-use instrument, which provides a valid perspective on patients' experiences of communicating with doctors and their perceptions of the continuity and coordination of their cancer care.

Exploring the added value of hospital-registry data for showing local service outcomes: cancers of the ovary, fallopian tube and peritoneum.

OBJECTIVES: To explore the added value of hospital-registry data on invasive epithelial ovarian, tubal and peritoneal cancers. DESIGN: Historic cohort analyses. METHODS: Unadjusted and adjusted regression. SETTING: Major South Australian hospitals. PARTICIPANTS: 1596 women (1984-2015 diagnoses). RESULTS: 5-Year and 10-year survival was 48% and 41%, respectively, equivalent to relative survival for Australia and the USA. After adjusting for age, clinical and geographic factors, risk of ovarian cancer death was 25% lower in 2010-2015 than 1984-1989. Women generally had surgical treatment (87%) in their first round of care. This was more common for younger patients (adjusted OR (95% CIs) 0.17 (0.04 to 0.65) for 80+ vs <40 years) and earlier International Federation of Gynecology and Obstetrics stages (adjusted OR 0.48 (0.13 to 1.78) for stage IIIB/C and 0.13 (0.04 to 0.45) for stage IV vs stage IA). Most (74%) had systemic therapy, which was more common for advanced stages (adjusted ORs >15.0 for stages III and IV vs stage IA). Few (9%) had radiotherapy. Women generally had systemic therapy (74%), without difference by service accessibility and socioeconomic disadvantage, suggesting equity. However, surgery was less common for residents of the most compared with least remote areas (adjusted OR 0.49 (0.24 to 0.99)); and more common prior to adjustment in the highest versus lowest socioeconomic category (unadjusted OR 1.55 (1.01 to 2.39)), but this elevation did not apply after adjustment (adjusted OR 0.19 (0.63 to 2.25)), with the difference largely explained by stage. CONCLUSIONS: Hospital-registry data add value for assessing local service delivery. Equivalent survival to Australia-wide and USA survival, and temporal gains after adjusting for stage and other patient characteristics are reassuring. Survival gains may reflect therapeutic benefits of more extensive surgery and improved chemotherapy regimens.

Loss of heterozygosity analysis and DNA copy number measurement on 8p in bladder cancer reveals two mechanisms of allelic loss.

Many epithelial tumors show deletion of the short arm of chromosome 8 that is related to aggressive disease or adverse prognosis. In undissected samples of urothelial cell carcinoma of the bladder, at least two regions of loss of heterozygosity (LOH) were identified previously within a small region of 8p11-p12. LOH analysis on a panel of pure tumor DNA samples confirmed this and identified tumors with allelic imbalance, some with clear breakpoints in 8p12. This suggests either that these samples contained genetically distinct subclones or that breakpoints in 8p12 may confer a selective advantage without LOH. To assess the mechanism of LOH and to map breakpoints precisely, a panel of bladder cancer cell lines was examined. Microsatellite analysis of 8p markers identified regions of contiguous homozygosity that coincided with regions of LOH in tumors. Fluorescence in situ hybridization analysis was carried out on seven cell lines predicted to have 8p LOH using a chromosome 8 paint, a chromosome 8 centromeric probe, and a series of single-copy genomic probes. This revealed overall underrepresentation of 8p and overrepresentation of 8q. Several breakpoints and one interstitial deletion were identified in 8p12. Two cell lines with extensive interstitial regions of homozygosity showed no reduction in DNA copy number by fluorescence in situ hybridization analysis, indicating that, in addition to large deletions and rearrangements of 8p, small regions of interstitial LOH on 8p12 may be generated by mitotic recombination. This implicates both major DNA double-strand break repair mechanisms in the generation of 8p alterations.

Breast cancer screening-opportunistic use of registry and linked screening data for local evaluation.

RATIONALE: Screening has been found to reduce breast cancer mortality at a population level in Australia, but these studies did not address local settings where numbers of deaths would generally have been too low for evaluation. Clinicians, administrators, and consumer groups are also interested in local service outcomes. We therefore use more common prognostic and treatment measures and survivals to gain evidence of screening effects among patients attending 4 local hospitals for treatment. AIMS AND OBJECTIVES: To compare prognostic, treatment, and survival measures by screening history to determine whether expected screening effects are occurring. METHODS: Employing routine clinical registry and linked screening data to investigate associations of screening history with these measures, using unadjusted and adjusted analyses. RESULTS: Screened women had a 10-year survival from breast cancer of 92%, compared with 78% for unscreened women; and 79% of screened surgical cases had breast conserving surgery compared with 64% in unscreened women. Unadjusted analyses indicated that recently screened cases had earlier tumor node metastasis stages, smaller diameters, less nodal involvement, better tumor differentiation, more oestrogen and progesterone receptor positive lesions, more hormone therapy, and less chemotherapy. Radiotherapy tended to be more common in screening participants. More frequent use of adjunctive radiotherapy applied when breast conserving surgery was used. CONCLUSIONS: Results confirm the screening effects expected from the scientific literature and demonstrate the value of opportunistic use of available registry and linked screening data for indicating to local health administrations, practitioners, and consumers whether local screening services are having the effects expected.

Female breast cancer management and survival: The experience of major public hospitals in South Australia over 3 decades-trends by age and in the elderly.

BACKGROUND: Clinical registry data from major South Australian public hospitals were used to investigate trends in invasive breast-cancer treatment and survival by age. METHODS: Disease-specific survival was calculated for the 1980 to 2013 diagnostic period using Kaplan-Meier product-limit estimates, with a censoring of live cases on December 31, 2014. Cox proportional hazards regression was used to examine differences in survival by age and tumour characteristic. First-round treatments following diagnosis were analysed, using multiple logistic regression to adjust for confounding. RESULTS: Five-year survival increased from 75% in the 1980s to 87% in 2000 to 2013, consistent with national trends, and with increases occurring irrespective of age. There was an increased use of breast conserving surgery, radiotherapy, chemotherapy, and hormone treatments. Five-year survival was lower for women aged 80+ years, increasing from 65% in the 1980s to 74% in 2000 to 2013. Lower survival in these older women persisted after adjusting for TNM stage, other clinical variables, and diagnostic year, without evidence of a reduced disparity over time. Older women were less likely to have surgery, radiotherapy, and chemotherapy throughout 1980 to 2013. By comparison, their use of hormone therapy was elevated. The adjusted relative odds of mastectomy (as opposed to breast conserving surgery) were lower for the 80+ year age range. CONCLUSIONS: Breast-cancer survival increases applied to all ages, including 80+ years, but poorer outcomes persisted in this older group and the gap did not reduce. A key question is whether the best trade-off now exists between optimally therapeutic cancer treatment and accommodations for frailty and co-morbidity in the aged, or whether opportunities exist for better trade-offs and better survival. Local registry data are important for describing local service activity and outcomes by age for local service providers, health administrations and consumer groups; monitoring disparities; and indicating effects of local initiatives.

Infrequent mutation of TRAIL receptor 2 (TRAIL-R2/DR5) in transitional cell carcinoma of the bladder with 8p21 loss of heterozygosity.

Loss of heterozygosity (LOH) on 8p is a frequent event in many cancers and is often associated with more aggressive disease. Tumour necrosis factor-related apoptosis inducing ligand (TRAIL) receptor 2 (TRAIL-R2) also known as TNFRSF10B (tumour necrosis factor receptor (TNFR) super family 10b) or KILLER/DR5, a member of the TNFR family, is a promising candidate tumour suppressor gene at 8p21-22. Mutations in this gene have been identified in non-small cell lung cancer, head and neck cancer, breast cancer and non-Hodgkin's lymphoma. We carried out mutation analysis of TRAIL-R2 in bladder cancer cell lines and in primary bladder tumours. One novel protein truncating mutation was identified in a bladder cancer cell line. Our results suggest that if TRAIL-R2 is the target of LOH events in these cancers, inactivation of the remaining allele is by a mechanism other than mutation.

Systematic application of multiplex PCR enhances the detection of bacteria, parasites, and viruses in stool samples.

OBJECTIVES: To determine whether systematic testing of faecal samples with a broad range multiplex PCR increases the diagnostic yield in patients with diarrhoea compared with conventional methods and a clinician initiated testing strategy. METHODS: 1758 faecal samples from 1516 patients with diarrhoea submitted to two diagnostic laboratories were tested for viral, bacterial, and parasitic pathogens by Fast-Track Diagnostics multiplex real-time PCR kits and conventional diagnostic tests. RESULTS: Multiplex PCR detected pathogens in 530 samples (30%): adenovirus (51, 3%), astrovirus (95, 5%), norovirus (172, 10%), rotavirus (3, 0.2%), Campylobacter jejuni/coli (85, 5%), Salmonella spp. (22, 1%), Clostridium difficile (72, 4%), entero-haemorrhagic Escherichia coli (21, 1%), Cryptosporidium spp. (3, 0.2%), Entamoeba histolytica (1, 0.1%), and Giardia lamblia (59, 3%). In contrast, conventional testing detected a pathogen in 324 (18%) samples. CONCLUSIONS: Using a systematic approach to the diagnosis of gastroenteritis improved diagnostic yield. This enhanced detection with PCR was achieved by a combination of improved detection of individual pathogens and detection of pathogens not requested or unable to be tested by conventional tests. This approach also allowed earlier identification for most pathogens and created a workflow which is likely to adapt well for many diagnostic laboratories.

Chemotherapy prescription patterns in colon cancer: a patterns-of-care survey in New Zealand.

Colorectal cancer is the second most common site of cancer for both men and women in New Zealand (NZ). Survival, especially with metastatic disease, has improved considerably over the last decade with the introduction of new chemotherapeutic agents. A questionnaire-based survey was conducted to document variations in chemotherapy prescription patterns throughout NZ. Out of 25 medical oncologists, responses were obtained from 22 (88%). The patient with stage III colon cancer was offered either 5-fluorouracil/leucovorin, most commonly on the weekly bolus schedule, or capecitabine monotherapy. Chemotherapy was also offered by the majority (65%) of respondents to the patient with 'high-risk' stage II colon cancer. Several chemotherapy combinations are available in NZ in the metastatic setting, with the most popular being oxaliplatin/capecitabine combination (CAPOX) (35%) or irinotecan/5-FU combination (FOLFIRI) (23%). None of the respondents would commence chemotherapy solely on the basis of a rising carcinoembryonic antigen (CEA). Two-thirds of respondents would recommend chemotherapy for the patient with resectable liver metastases, either before or after surgery. Our survey indicates that chemotherapy prescriptions for patients with colon cancer in NZ, though not uniform, are mostly in line with international recommendations.

Assessment by M-FISH of karyotypic complexity and cytogenetic evolution in bladder cancer in vitro.

We carried out multiplex fluorescence in situ hybridization (M-FISH) and follow-up FISH studies on a large series of transitional cell carcinoma (TCC) cell lines and 2 normal urothelium-derived cell lines, several of which have not had karyotypes reported previously. M-FISH analysis, with appropriate follow-up, complements conventional cytogenetic analysis and array CGH studies, allowing a more accurate definition of karyotype. The detailed karyotypic data obtained will assist in choosing suitable cell lines for functional studies and identifies common losses, gains, breakpoints and potential fusion gene sites in TCC. We have shown changes in cell lines RT112 and DSH1 following prolonged culture, and differences in karyotype, between RT112 cultures obtained from different sources. We propose a model for the evolutionary changes leading to these differences. A comparison with the literature found other examples of differences in cell-line karyotypes between different sources. Nevertheless, several karyotypic changes were preserved between different sources of the same cell line and were also seen in more than one cell line. These may be the most important changes and include -8p, +20, 4q-, 10p-, 16p- and breaks in 8p21. We carried out a more detailed follow-up of some regions, which showed involvement of 8p breaks and losses in 15 of 16 TCC cell lines but in neither of the normal urothelium-derived cell lines. Some changes represented distal loss, whereas others were small deletions. Further study of this region is warranted.