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AIM: To assess population-level characteristics and post-metastasis survival of people with recurrent metastatic breast cancer (rMBC) during a period when new publicly-subsidised adjuvant and metastatic systemic therapies became available. METHODS: Record linkage study of females in NSW Cancer Registry (NSWCR) diagnosed with non-metastatic breast cancer (BC) in 2001-2002 (C1) and 2006-2007 (C2). We identified first rMBC from NSWCR, administrative hospital records, dispensed medicines and radiotherapy services (2001-2016). We used death registrations to estimate cumulative incidence of BC death. RESULTS: The analysis included 2267 women with rMBC (C1:1210, C2:1057). Compared to C1, C2 had access to adjuvant HER2-targeted therapy and were more likely to have received adjuvant chemotherapy (C1:38%, C2:47%) and aromatase inhibitors (C1:52%, C2:73%, of those dispensed endocrine therapy). Five-year probability of BC death was 65% (95%CI:62-68%) in C1 and 63% (95%CI:60-66%) in C2. Regional disease (T4 or N + ) at initial BC diagnosis (C1:62%, C2:68%), and age ≥ 70 years at first metastasis (C1:27%, C2:31%) were more common in C2 and had poorer prognosis. Five-year probability of BC death was lower in C2 than C1 for treatment-defined HER2-positive BC (C1:72% 95%CI:63-79%; C2:52% 95%CI 45-60%) and those dispensed chemotherapy alone (C1:76% 95%CI:69-82, C2:67% 95%CI:59-74%, p = 0.01), but not treatment-defined hormone receptor-positive HER2-negative BC (C1:60% 95%CI 56-63%, C2:64% 95%CI 60-68%). CONCLUSIONS: Despite less favourable prognostic characteristics in C2, BC-related survival following rMBC was similar between the two cohorts; and improved for women with HER2-positive tumours. These findings support the real-world benefits of newer treatments for rMBC.

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BACKGROUND: We investigated differences in cumulative incidence of first distant recurrence (DR) following non-metastatic breast cancer over a time period when new adjuvant therapies became available in Australia. METHODS: We conducted a health record linkage study of females with localized (T1-3N0) or regional (T4 or N+) breast cancer in the New South Wales Cancer Registry in 2001 to 2002 and 2006 to 2007. We linked cancer registry records with administrative records from hospitals, dispensed medicines, radiotherapy services, and death registrations to estimate the 9-year cumulative incidence of DR and describe use of adjuvant treatment. RESULTS: The study included 13,170 women (2001-2002 n = 6,338, 2006-2007 n = 6,832). The 9-year cumulative incidence of DR was 3.6% [95% confidence interval (CI), 2.3%-4.9%] lower for 2006-2007 diagnoses (15.0%) than 2001-2002 (18.6%). Differences in the annual hazard of DR between cohorts were largest in year two. DR incidence declined for localized and regional disease. Decline was largest for ages <40 years (absolute difference, 14.4%; 95% CI, 8.3%-20.6%), whereas their use of adjuvant chemotherapy (2001-2002 49%, 2006-2007 75%) and HER2-targeted therapy (2001-2002 0%, 2006-2007 16%) increased. DR did not decline for ages ≥70 years (absolute difference, 0.9%; 95% CI, -3.6%-1.8%) who had low use of adjuvant chemotherapy and HER2-targeted therapy. CONCLUSIONS: This whole-of-population study suggests that DR incidence declined over time. Decline was largest for younger ages, coinciding with changes to adjuvant breast cancer therapy. IMPACT: Study findings support the need for trials addressing questions relevant to older people and cancer registry surveillance of DR to inform cancer control programs.

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AIM: To develop a priority set of quality indicators (QIs) for use by colorectal cancer (CRC) multidisciplinary teams (MDTs). METHODS: The review search strategy was executed in four databases from 2009-August 2019. Two reviewers screened abstracts/manuscripts. Candidate QIs and characteristics were extracted using a tailored abstraction tool and assessed for scientific soundness. To prioritize candidate indicators, a modified Delphi consensus process was conducted. Consensus was sought over two rounds; (1) multidisciplinary expert workshops to identify relevance to Australian CRC MDTs, and (2) an online survey to prioritize QIs by clinical importance. RESULTS: A total of 93 unique QIs were extracted from 118 studies and categorized into domains of care within the CRC patient pathway. Approximately half the QIs involved more than one discipline (52.7%). One-third of QIs related to surgery of primary CRC (31.2%). QIs on supportive care (6%) and neoadjuvant therapy (6%) were limited. In the Delphi Round 1, workshop participants (n = 12) assessed 93 QIs and produced consensus on retaining 49 QIs including six new QIs. In Round 2, survey participants (n = 44) rated QIs and prioritized a final 26 QIs across all domains of care and disciplines with a concordance level > 80%. Participants represented all MDT disciplines, predominantly surgical (32%), radiation (23%) and medical (20%) oncology, and nursing (18%), across six Australian states, with an even spread of experience level. CONCLUSION: This study identified a large number of existing CRC QIs and prioritized the most clinically relevant QIs for use by Australian MDTs to measure and monitor their performance.

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OBJECTIVES: To estimate the long term risk of distant metastases (DM) for women with initial diagnoses of non-metastatic breast cancer; to estimate breast cancer-specific and overall survival for women with DM. DESIGN: Population-based health record linkage study. SETTING, PARTICIPANTS: Women diagnosed with localised or regional primary breast cancer recorded in the NSW Cancer Registry, 2001-2002. MAJOR OUTCOME MEASURES: Time from breast cancer diagnosis to first DM, time from first DM to death from breast cancer. SECONDARY OUTCOME: time to death from any cause. RESULTS: 6338 women were diagnosed with non-metastatic breast cancer (localised, 3885; regional, 2453; median age, 59 years [IQR, 49-69 years]). DM were recorded (to 30 September 2016) for 1432 women (23%; median age, 62 years [IQR, 51-73 years]). The 14-year cumulative DM incidence was 22.2% (95% CI, 21.1-23.2%; localised disease: 14.3% [95% CI, 13.2-15.4%]; regional disease: 34.7% [95% CI, 32.8-36.6%]). Annual hazard of DM was highest during the second year after breast cancer diagnosis (localised disease: 2.8%; 95% CI, 2.3-3.3%; regional disease: 9.1%; 95% CI, 7.8-10.3%); from year five it was about 1% for those with localised disease, from year seven about 2% for women with regional disease at diagnosis. Five years after diagnosis, the 5-year conditional probability of DM was 4.4% (95% CI, 3.7-5.1%) for women with localised and 10.4% (95% CI, 9.1-12.0%) for those with regional disease at diagnosis. Median breast cancer-specific survival from first DM record date was 28 months (95% CI, 25-31 months); the annual hazard of breast cancer death after the first DM record declined from 36% (95% CI, 33-40%) during the first year to 14% (95% CI, 11-18%) during the fourth year since detection. CONCLUSIONS: DM risk declines with time from diagnosis of non-metastatic breast cancer, and the annual risk of dying from breast cancer declines with time from initial DM detection. These findings can be used to inform patients at follow-up about changes in risk over time since diagnosis and for planning health services.

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Quality Indicators, based on clinical practice guidelines, have been used in medicine and within oncology to measure quality of care for over twenty years. However, radiation oncology quality indicators are sparse. This article describes the background to the development of current national and international, general and tumour site-specific radiation oncology quality indicators in use. We explore challenges and opportunities to expand their routine prospective collection and feedback to help drive improvements in the quality of care received by people undergoing radiation therapy.

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Slug (SNAI2), a member of the well-conserved Snail family of transcription factors, has multiple developmental roles, including in epithelial-to-mesenchymal transition (EMT). Here, we show that Slug is critical for the pathological angiogenesis needed to sustain tumor growth, and transiently necessary for normal developmental angiogenesis. We find that Slug upregulation in angiogenic endothelial cells (EC) regulates an EMT-like suite of target genes, and suppresses Dll4-Notch signaling thereby promoting VEGFR2 expression. Both EC-specific Slug re-expression and reduced Notch signaling, either by γ-secretase inhibition or loss of Dll4, rescue retinal angiogenesis in SlugKO mice. Conversely, inhibition of VEGF signaling prevents excessive angiogenic sprouting of Slug overexpressing EC. Finally, endothelial Slug (but not Snail) is activated by the pro-angiogenic factor SDF1α via its canonical receptor CXCR4 and the MAP kinase ERK5. Altogether, our data support a critical role for Slug in determining the angiogenic response during development and disease.

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The general paradigms that exist to guide measures in quality of care do not sufficiently deal with the changing needs of cancer management. The aim of this study was to review the literature regarding the quality of cancer care and develop a conceptual framework relevant to current practice. A textual narrative review of the literature was conducted by searching electronic databases from the last 10 years. Articles were then screened and included if they were both relevant to the management of cancer and standards in quality of care. Thematic analysis of the included articles was performed. Eighty-three articles were included and 12 domains identified and integrated with current models to develop a conceptual framework. These included: healthcare delivery system; timeliness; access; appropriateness of care; multidisciplinary and coordinated care; patient experience; technical aspects; safety; patient-centred outcomes; disease-specific outcomes; innovation and improvement and value. We propose a conceptual framework for the quality of cancer care based on relevant and current oncology practice. This presents a more practical and comprehensive approach than general models, and can be used by healthcare providers, managers and policy makers to guide and identify the need for metrics for quality improvements.

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AIM: To investigate adherence to clinical practice guidelines (CPGs) in cervical cancer and the correlation with clinical outcomes. METHODS: A retrospective analysis was conducted using patient information from a population-based cancer registry (2005-2011, n = 208). Compliance to 10 widely accepted CPGs was assessed. Univariate and multivariate analyses were performed to assess sociodemographic factors associated with CPG adherence. Multivariate Cox regression was performed to assess the relationship between CPG adherence and 5-year survival. RESULTS: Adherence to individual CPGs ranged from 47% to 100%. Compliance to all applicable CPGs was seen in 54% (n = 72) of patients, 62% of stage I and II patients and 22% of stage III and IV patients. Poorest adherence was seen with those with locally advanced disease receiving chemoradiotherapy. Patients who lived within 5 km of the treatment facility were more likely to be compliant. No difference was found for either age, country of birth or socioeconomic status group. Five-year survival was greater for stage I and II patients who received guideline adherent care (93.7% vs 69.7%, P = 0.002), and they had a significant lower risk of death on multivariate analysis (HR = 0.22, P = 0.015). There was no significant difference for those with stage III or IV disease. CONCLUSIONS: In this study, CPG adherence is variable between treatment modalities and only half complied to all applicable CPGs. There was better adherence in those with early-stage disease and this was associated with improved patient outcomes. CPG adherence may be a useful surrogate for quality of care.

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The purpose of this study was to review potential, physiological, hormonal and neuronal mechanisms that may mediate the sleep changes. This paper investigates the literatures regarding the activity of the hypothalamic-pituitary-adrenal (HPA) axis, one of the main neuroendocrine stress systems during sleep in order to identify relations between stress and sleep disorder and the treatment of stress-induced insomnia. Sleep and wakefulness are regulated by the aminergic, cholinergic brainstem and hypothalamic systems. Activation of the HPA and/or the sympathetic nervous systems results in wakefulness and these hormones including corticotropin-releasing hormone (CRH), adrenocorticotropic hormone (ACTH), cortisol or corticosterone, noradrenaline, and adrenaline, are associated with attention and arousal. Stress-related insomnia leads to a vicious circle by activating the HPA system. An awareness of the close interaction between sleep and stress systems is emerging and the hypothalamus is now recognized as a key center for sleep regulation, with hypothalamic neurontransmitter systems providing the framework for therapeutic advances. An updated understanding of these systems may allow researchers to elucidate neural mechanisms of sleep disorder and to develop effective intervention for sleep disorder.

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In this research the genotoxic effect of Polycan™ ß-glucans originated from Aureobasidium pullulans SM-2001, was evaluated using the mouse micronucleus test. Polycan™ was administered once a day for 2 days by oral gavage to male ICR mice at doses of 1000, 500 and 250 mg/kg. Cyclophosphamide was used as a known genotoxic agent in a positive control group. The appearance of a micronucleus is used as an index for genotoxic potential. The results obtained indicated that Polycan™ shows no genotoxicity effect up to 1000 mg/kg dosing levels. In addition, it is also considered that there were no problems from cytotoxicity of Polycan™ tested in this study because the polychromatic erythrocyte ratio was detected as > 0.47 in all tested groups.

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The effects of beta-glucan isolated from Aureobasidium pullulans were observed on acute xylene-induced inflammation. beta-glucan at a dose of 62.5, 125 or 250 mg/kg were administered once orally to xylene-treated mice (0.03 mL of xylene was applied on the anterior surface of the right ear to induce inflammation), and the body weight change, ear weight, histological profiles and histomorphometrical analyses of ear were conducted upon sacrifice. The xylene was topically applied 30 min after dosing with beta-glucan. The results were compared to those of diclofenac, indomethacin and dexamethasone (15 mg/kg injected once intraperitoneally). All animals were sacrificed 2 h after xylene application. Xylene application resulted in marked increases in induced ear weights compared to that of intact control ear; hence, the differences between intact and induced ear were also significantly increased. The histological characteristics of acute inflammation, such as severe vasodilation, edematous changes of skin and infiltration of inflammatory cells, were detected in xylene-treated control ears with marked increase in the thickness of the ear tissues. However, these xylene-induced acute inflammatory changes were significantly and dose-dependently decreased by beta-glucan treatment. We conclude that beta-glucan from A. pullulans has a somewhat favorable effect in the reduction of the acute inflammatory responses induced by xylene application in mice.

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A novel polyglucosamine polymer, PGB-2, was produced extracellularly from a new strain Citrobacter sp. BL-4 using pH-stat fed batch cultivation. It was composed of 97.3% glucosamine and 2.7% rhamnose; its average molecular weight, solubility in 2% acetic acid and viscosity were 20 kDa, 5 g l(-1) and 2.9 cps, respectively. FT-IR and 1H NMR spectra of PGB-2 revealed a close identity with chitosan from crab shells.

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