De novo and recurrent metastatic breast cancer - A systematic review of population-level changes in survival since 1995.

BACKGROUND: Advances in breast cancer (BC) care have reduced mortality, but their impact on survival once diagnosed with metastasis is less well described. This systematic review aimed to describe population-level survival since 1995 for de novo metastatic BC (dnMBC) and recurrent MBC (rMBC). METHODS: We searched MEDLINE 01/01/1995-12/04/2021 to identify population-based cohort studies of MBC reporting overall (OS) or BC-specific survival (BCSS) over time. We appraised risk-of-bias and summarised survival descriptively for MBC diagnoses in 5-year periods from 1995 until 2014; and for age, hormone receptor and HER2 subgroups. FINDINGS: We identified 20 eligible studies (14 dnMBC, 1 rMBC, 5 combined). Potential sources of bias in these studies were confounding and shorter follow-up for the latest diagnosis period.For dnMBC, 13 of 14 studies reported improved OS or BCSS since 1995. In 2005-2009, the median OS was 26 months (range 24-30), a median gain of 6 months since 1995-1999 (range 0-9, 4 studies). Median 5-year OS was 23% in 2005-2009, a median gain of 7% since 1995-1999 (range -2 to 14%, 4 studies). For women ≥70 years, the median and 5-year OS was unchanged (1 study) with no to modest difference in relative survival (range: -1·9% (p = 0.71) to +2·1% (p = 0.045), 3 studies). For rMBC, one study reported no change in survival between 1998 and 2006 and 2007-2013 (median OS 23 months). For combined MBC, 76-89% had rMBC. Three of four studies observed no change in median OS after 2000. Of these, one study reported median OS improved for women ≤60 years (1995-1999 19·1; 2000-2004 22·3 months) but not >60 years (12·7, 11·6 months). INTERPRETATION: Population-level improvements in OS for dnMBC have not been consistently observed in rMBC cohorts nor older women. These findings have implications for counselling patients about prognosis, planning cancer services and trial stratification. FUNDING: SL was funded in part by a National Health and Medical Research Council (NHMRC) Project Grant ID: 1125433. NH was funded by the NBCF Chair in Breast Cancer Prevention grant (EC-21-001) and a NHMRC Investigator (Leader) grant (194410). BD and SAP were funded in part by the NHMRC Centre of Research Excellence in Medicines Intelligence (1196900).

The prognostic value of cancer stem-like cell markers SOX2 and CD133 in stage III colon cancer is modified by expression of the immune-related markers FoxP3, PD-L1 and CD3.

Cancer stem-like cells are highly tumourigenic cells that can repopulate entire tumours after apparent successful treatment. Recent evidence suggests they interact with other cells in the tumour microenvironment, including immune cell subsets, to enhance their survival. The aim of this study was to determine whether the expression of immune cell markers in primary colon cancer impacts the prognostic significance of cancer stem-like cell marker expression. Immunohistochemistry was used to assess the expression of putative stem cell markers (ALDH1, CD44v6, CD133, Lgr5, SOX2) and immune cell related markers (CD3, CD8, FoxP3, PD-L1) in 104 patients with stage III colon cancer. Associations of marker expression with overall and cancer-specific survival were determined using Kaplan-Meier analysis. High SOX2 expression in the central tumour area was found to be an independent factor for poor cancer-specific survival [hazard ratio (HR) 6.19; 95% confidence interval (CI) 2.24-17.14; p=0.001]. When immune-related factors were taken into account, patients categorised as SOX2low/FoxP3high had good outcome (HR 0.164; 95%CI 0.066-0.406; p<0.0001) whereas patients categorised as SOX2high/PD-L1low had poor outcome (HR 8.992; 95%CI 3.397-23.803; p<0.0001). The prognostic value of the SOX2 cancer stem-like cell marker in colon cancer is modified by expression of immune-cell related factors FoxP3 and PD-L1.

Objective analysis of cancer stem cell marker expression using immunohistochemistry.

Analysis of immunohistochemical expression is often a subjective and semiquantitative process that can lead to the inconsistent reporting of results. To assess the effect that region selection and quantification method have on results, five different cancer stem cell markers were used in this study to compare tissue scoring with digital analysis methods that used three different tissue annotation methods. Samples of tumour and normal mucosa were used from 10 consecutive stage II colon cancer patients and stained for the putative cancer stem cell markers ALDH1, CD44v6, CD133, Lgr5 and SOX2. Tissue scoring was found to have considerably different results to digital analysis with the three different digital methods harbouring concordant results overall. However, SOX2 on normal tissue and CD133 on tumour and normal tissue produced discordant results which could be attributed to the different regions of tissue that were analysed. It is important that quantification method and selection of analysis areas are considered as part of study design to ensure that reproducible and consistent results are reported in the literature.

Low stromal Foxp3+ regulatory T-cell density is associated with complete response to neoadjuvant chemoradiotherapy in rectal cancer.

BACKGROUND: Foxp3+ regulatory T cells (Tregs) play a vital role in preventing autoimmunity, but also suppress antitumour immune responses. Tumour infiltration by Tregs has strong prognostic significance in colorectal cancer, and accumulating evidence suggests that chemotherapy and radiotherapy efficacy has an immune-mediated component. Whether Tregs play an inhibitory role in chemoradiotherapy (CRT) response in rectal cancer remains unknown. METHODS: Foxp3+, CD3+, CD4+, CD8+ and IL-17+ cell density in post-CRT surgical samples from 128 patients with rectal cancer was assessed by immunohistochemistry. The relationship between T-cell subset densities and clinical outcome (tumour regression and survival) was evaluated. RESULTS: Stromal Foxp3+ cell density was strongly associated with tumour regression grade (P=0.0006). A low stromal Foxp3+ cell density was observed in 84% of patients who had a pathologic complete response (pCR) compared with 41% of patients who did not (OR: 7.56, P=0.0005; OR: 5.27, P=0.006 after adjustment for presurgery clinical factors). Low stromal Foxp3+ cell density was also associated with improved recurrence-free survival (HR: 0.46, P=0.03), although not independent of tumour regression grade. CONCLUSIONS: Regulatory T cells in the tumour microenvironment may inhibit response to neoadjuvant CRT and may represent a therapeutic target in rectal cancer.

Clinical outcomes of chronic hepatitis C patients related to baseline liver fibrosis stage: a hospital-based linkage study.

BACKGROUND AND AIMS: Rates of long-term clinical outcomes of chronic hepatitis C in patients with none, mild or severe liver fibrosis are required to determine benefits of anti-viral therapies. This study evaluated long-term outcomes for chronic hepatitis C stratified by all Metavir fibrosis stages. METHODS: Clinical outcomes were determined using population-based data linkage methodology for 880 hepatitis C patients who had a liver biopsy performed from 1992 to 2012. RESULTS: During 9386 person-years of follow up, 28 patients developed hepatocellular carcinoma, 58 developed liver decompensation and 122 died or underwent liver transplantation. There was no significant difference in liver-related death for those with F0-F2 with an 18-year survival probability >94%. Hazard ratio of liver-related death for F3 compared with F0-F2 was 4.24 (P = 0.003), with no significant difference in the first 13-year follow up. The 15-year decompensation-free survival for F0, F1 and F2 was 100%, 96% and 94% respectively and for hepatocellular carcinoma-free survival was 100%, 99% and 98%. Hazard ratio of liver complication (hepatocellular carcinoma or decompensation)-free survival for F3 compared with F0-F2 was 3.22 (P = 0.001), with no significant difference during the first 7-year follow up. F4 had significantly higher risk of liver-related death, decompensation and hepatocellular carcinoma than F3 (P < 0.001). CONCLUSIONS: Chronic hepatitis C patients with F2 or less had few liver complications after 15 years. For F3 patients, the significant increase in liver-related death occurred after 13 years and for liver complications after 7 years.

Hereditary hemochromatosis is characterized by a clinically definable arthropathy that correlates with iron load.

OBJECTIVE: To determine the frequency and character of arthropathy in hereditary hemochromatosis (HH) and to investigate the relationship between this arthropathy, nodal interphalangeal osteoarthritis, and iron load. METHODS: Participants were recruited from the community by newspaper advertisement and assigned to diagnostic confidence categories for HH (definite/probable or possible/unlikely). Arthropathy was determined by use of a predetermined clinical protocol, radiographs of the hands of all participants, and radiographs of other joints in which clinical criteria were met. RESULTS: An arthropathy considered typical for HH, involving metacarpophalangeal joints 2-5 and bilateral specified large joints, was observed in 10 of 41 patients with definite or probable HH (24%), all of whom were homozygous for the C282Y mutation in the HFE gene, while only 2 of 62 patients with possible/unlikely HH had such an arthropathy (P=0.0024). Arthropathy in definite/probable HH was more common with increasing age and was associated with ferritin concentrations>1,000 µg/liter at the time of diagnosis (odds ratio 14.0 [95% confidence interval 1.30-150.89], P=0.03). A trend toward more episodes requiring phlebotomy was also observed among those with arthropathy, but this was not statistically significant (odds ratio 1.03 [95% confidence interval 0.99-1.06], P=0.097). There was no significant association between arthropathy in definite/probable HH and a history of intensive physical labor (P=0.12). CONCLUSION: An arthropathy consistent with that commonly attributed to HH was found to occur in 24% of patients with definite/probable HH. The association observed between this arthropathy, homozygosity for C282Y, and serum ferritin concentrations at the time of diagnosis suggests that iron load is likely to be a major determinant of arthropathy in HH and to be more important than occupational factors.

Demographic, health and lifestyle factors associated with dental service attendance by young adults.

BACKGROUND: The aim of this study was to describe the demographic and health and lifestyle factors associated with dental service attendance in the previous 12 months by young Australian adults (18-24 years). METHODS: Population-based data from the 2001 Australian National Health Survey were analysed. Proportions and single associations between variables of interest and dental service attendance were calculated. A logistic regression analysis using significant single association variables was then conducted. RESULTS: Overall, 41 per cent of young adults in this study had visited a dental professional in the previous 12 months. Females, those in cities, those with private insurance, those who spoke languages other than English, those in the highest socioeconomic group and those with healthy behaviours were subgroups most likely to have visited a dental professional. With logistic regression, factors found to be associated with dental services attendance were being female, having private health insurance and low alcohol consumption. CONCLUSIONS: In this study, the proportion of young adults who had visited a dental professional in the previous 12 months was only 41 per cent. It is therefore suggested that oral health policy and promotion activities be encouraged for this group, paying attention to young adults in groups with low attendance.

A comparison of mental health hospital admissions in a cohort of heroin users prior to and after rapid opiate detoxification and oral naltrexone maintenance.

Mental health (MH) hospital admissions were investigated in a cohort (N=1184) of heroin dependent persons using linked health records. All MH in-patient admissions were extracted 36 months before to 36 months after commencing rapid opioid detoxification (ROD) and oral naltrexone. Results show that the incidence rate ratio (IRR) of drug-related and other MH admissions peaked in the 3 months immediately prior to treatment. All categories subsequently declined to baseline levels by 36 months following treatment. The authors conclude that treatment for heroin dependence reduces risk of MH admissions.

Domestic exposure to formaldehyde significantly increases the risk of asthma in young children.

Concern has arisen in recent years about indoor air pollution as a risk factor for asthma. Formaldehyde exposure was examined in relation to asthma among young children (between 6 months and 3 yrs old) in a population-based control study carried out in Perth, Western Australia, between 1997-1999. An association between exposure to formaldehyde and asthma in young children has been suggested. Cases (n=88), whose parents were recruited at Princess Margaret Hospital Accident and Emergency Dept (Perth, Western Australia), were children discharged with asthma as the primary diagnosis. Controls (n=104), who were children in the same age group without asthma diagnosed by a doctor, were identified from birth records through the Health Dept of Western Australia (Perth, Western Australia). Health outcomes for the children were studied using a respiratory questionnaire and skin-prick tests. Formaldehyde, average temperature and relative humidity were measured on two occasions, winter (July-September 1998) and summer (December 1998-March 1999) in the child's bedroom and in the living room. The study found seasonal differences in formaldehyde levels in the children's bedrooms and living rooms with significantly greater formaldehyde exposure during the summer period for case and control subjects. The generalised estimating equation model showed that children exposed to formaldehyde levels of > or = 60 microg x m(-3) are at increased risk of having asthma. The results suggest that domestic exposure to formaldehyde increases the risk of childhood asthma.

Predictors of low bone density in young adolescent females with anorexia nervosa and other dieting disorders.

OBJECTIVE: To compare the bone density of adolescent patients with anorexia nervosa with adolescent patients with other dieting disorders and to evaluate risk factors for low bone density in these patients. METHOD: Sixty-nine consecutive female patients referred to an adolescent eating disorders clinic were studied by interview, blood sampling, body composition, and lumbar spine bone density measurement using dual energy X-ray absorptiometry. RESULTS: Although patients with anorexia nervosa were more malnourished, their bone density was similar to other dieting patients. Patients were divided into a low and normal bone density group irrespective of psychiatric diagnosis. Patients with low bone density had dieted for longer, had lower lean body mass, more often had not achieved menarche, and had longer duration of secondary amenorrhea and lower estrogen levels. DISCUSSION: Irrespective of clinical diagnosis, adolescents with dieting disorders have increased risk of low bone density when malnutrition commences early in puberty and is associated with reduced lean body mass and impaired ovarian function.

Effect of hemochromatosis genotype and lifestyle factors on iron and red cell indices in a community population.

BACKGROUND: Heterozygotes for the C282Y mutation of the HFE gene may have altered hematology indices and higher iron stores than wild-type subjects. METHODS: We performed a cross-sectional analysis of 1488 females and 1522 males 20-79 years of age drawn from the Busselton (Australia) population study to assess the effects of HFE genotype, age, gender, and lifestyle on serum iron and hematology indices. RESULTS: Male C282Y heterozygotes had increased transferrin saturation compared with the wild-type genotype. Neither male nor female heterozygotes had significantly increased ferritin values compared with the wild-type genotype. Younger (20-29 years) wild-type males, but not heterozygous males, had significantly lower ferritin values than wild-type males in the older age groups. Compound heterozygous subjects had increased means for serum iron, transferrin saturation, corpuscular volume, and corpuscular hemoglobin compared with the wild-type genotype, and the males also had increased ferritin values (medians 323 vs 177 microg/L; P = 0.003). In both male and female wild-type subjects, an increased body mass index was associated with decreased serum iron and transferrin saturation and increased ferritin values. There was a significant increase in ferritin concentrations in both genders with increasing frequency of red meat consumption above a baseline of 1-2 times per week and alcohol intakes >10 g/day. CONCLUSIONS: Male C282Y heterozygotes had significantly increased transferrin saturation values. Compound heterozygous (C282Y/H63D) subjects formed a separate category of C282Y heterozygotes in whom both iron and red cell indices were significantly increased compared with the wild-type genotype.

Dose-response to inhaled aerosolized prostacyclin for hypoxemia due to ARDS.

STUDY OBJECTIVES: This study was carried out to determine the efficacy of and dose-response relationships to inhaled aerosolized prostacyclin (IAP), when used as a selective pulmonary vasodilator (SPV) in patients with severe hypoxemia due to ARDS. DESIGN: Unblinded, interventional, prospective clinical study. SETTING: A general ICU in a university-affiliated, tertiary referral center. PATIENTS: Nine adult patients with severe ARDS (lung injury score, > or = 2.5). INTERVENTIONS: All patients received IAP over the dose range 0 to 50 ng/kg/min. The IAP was delivered via a jet nebulizer placed in the ventilator circuit. Dose increments were 10 ng/kg/min every 30 min. MEASUREMENTS AND RESULTS: Cardiovascular parameters (cardiac index and mean pulmonary and systemic pressures), indexes of oxygenation (PaO(2)/fraction of inspired oxygen [FIO(2)] ratio and alveolar-arterial oxygen partial pressure difference [P(A-a)O(2)]) and shunt fraction were measured or calculated at each dose interval, as were platelet aggregation and systemic levels of prostacyclin metabolite (6-keto prostaglandin F1(alpha)). A generalized linear regression model was used to determine a dose effect of IAP on these parameters. The Wilcoxon rank sum test for related measures was used to compare the effects of various doses of IAP. IAP acted as an SPV, with a statistically significant dose-related improvement in PaO(2)/FIO(2) ratio (p = 0.003) and P(A-a)O(2) (p = 0.01). Systemic prostacyclin metabolite levels increased significantly in response to delivered IAP (p = 0.001). There was no significant dose effect on systemic or pulmonary arterial pressures, or on platelet function, as determined by platelet aggregation in response to challenge with adenosine diphosphate. CONCLUSIONS: IAP is an efficacious SPV, with marked dose-related improvement in oxygenation and with no demonstrable effect on systemic arterial pressures over the dose range 0 to 50 ng/kg/min. Despite significant systemic levels of prostacyclin metabolite, there was no demonstrable platelet function defect.

Age and secular trends in risk factors for cardiovascular disease in Busselton.

Mortality rates from heart disease and stroke in Australia have been falling for more than 20 years. No completely satisfactory explanations for this trend exist. However, it is believed to be due, at least in part, to changes in the incidence of cardiovascular disease arising from changes in the prevalence and severity of risk factors for cardiovascular disease. The adult community of Busselton in Western Australia participated in cross-sectional health surveys every three years from 1966 to 1981. This paper describes secular trends from 1966 to 1981 and age trends from 25 to 80 years for cardiovascular risk factors in Busselton men and women. Downwards secular trends were observed for mean blood pressure and smoking for men and women, upwards trends were observed for body mass index in men, and mean cholesterol was approximately constant over this period. The age and secular trends were consistent with other Australian studies conducted in the 1980s and with overseas studies. An estimated 67 per cent of the decline in cardiovascular mortality rates among Busselton men and 22 per cent of the decline among Busselton women may be attributed to changes in the prevalence of risk factors for cardiovascular disease.

Mortality trends, 1965 to 1989, in Busselton, the site of repeated health surveys and interventions.

The community of Busselton in Western Australia has participated in repeated cross-sectional health surveys and other health interventions since 1966. Health surveys of adults were conducted every three years from 1966 to 1981. Health interventions, including programs for high blood pressure, smoking, high blood cholesterol levels and obesity, were implemented in the community. Mortality rates for the Busselton area are compared with rates for the remainder of the southwest region of Western Australia in an attempt to determine if the surveys and associated interventions have had any impact on survival. Statistical comparisons via Poisson regression analysis showed that mortality rates for males over the period 1965 to 1989 in Busselton declined at a similar rate to the southwest. However, for females, especially those aged 45 to 74 years, mortality rates declined significantly faster in Busselton than in the southwest, suggesting a beneficial impact on survival of the surveys and associated interventions.

Reduction in prevalence, intensity of infection and morbidity due to Schistosoma mansoni infection in a community following treatment with praziquantel.

Five hundred and twenty-three individuals from an area endemic for Schistosoma mansoni infection were followed for a 16 month period in a population-based study in rural Zambia. Those found infected in each of five surveys were treated with praziquantel (40 mg kg-1 body weight). Data on prevalence, intensity of infection and morbidity (intestinal symptoms and liver and spleen enlargements) were also gathered. At the end of the study, prevalence had fallen from 64.8% to 11.5%, intensity of infection had dropped from 28.2 to 0.5 eggs per gram of stool (geometric means) and morbidity showed marked reduction.