BACKGROUND: Distal radius (wrist) fractures are the second most common fracture admitted to hospital. The anatomical pattern of these types of injuries is diverse, with variation in clinical management, guidelines for management remain inconclusive, and the uptake of findings from clinical trials into routine practice limited. Robust predictive modelling, which considers both the characteristics of the fracture and patient, provides the best opportunity to reduce variation in care and improve patient outcomes. This type of data is housed in unstructured data sources with no particular format or schema. The "Predicting fracture outcomes from clinical Registry data using Artificial Intelligence (AI) Supplemented models for Evidence-informed treatment (PRAISE)" study aims to use AI methods on unstructured data to describe the fracture characteristics and test if using this information improves identification of key fracture characteristics and prediction of patient-reported outcome measures and clinical outcomes following wrist fractures compared to prediction models based on standard registry data. METHODS AND DESIGN: Adult (16+ years) patients presenting to the emergency department, treated in a short stay unit, or admitted to hospital for >24h for management of a wrist fracture in four Victorian hospitals will be included in this study. The study will use routine registry data from the Victorian Orthopaedic Trauma Outcomes Registry (VOTOR), and electronic medical record (EMR) information (e.g. X-rays, surgical reports, radiology reports, images). A multimodal deep learning fracture reasoning system (DLFRS) will be developed that reasons on EMR information. Machine learning prediction models will test the performance with/without output from the DLFRS. DISCUSSION: The PRAISE study will establish the use of AI techniques to provide enhanced information about fracture characteristics in people with wrist fractures. Prediction models using AI derived characteristics are expected to provide better prediction of clinical and patient-reported outcomes following distal radius fracture.

Whilst some of the diversity in management of women with ductal carcinoma in situ (DCIS) may be explained by tumour characteristics, the role of patient preference and the factors underlying those preferences have been less frequently examined. We have used a descriptive qualitative study to explore treatment decisions for a group of Australian women diagnosed with DCIS through mammographic screening. Semi-structured telephone interviews were performed with 16 women diagnosed with DCIS between January 2012 and December 2018, recruited through the LifePool dataset (a subset of BreastScreen participants who have agreed to participate in research). Content analysis using deductive coding identified three themes: participants did not have a clear understanding of their diagnosis or prognosis; reported involvement in decision making about management varied; specific factors including the psychosexual impact of mastectomy and perceptions of radiotherapy, could act as barriers or facilitators to specific decisions about treatment. The treatment the women received was not simply determined by the characteristics of their disease. Interaction with the managing clinician was pivotal, however many other factors played a part in individual decisions. Recognising that decisions are not purely a function of disease characteristics is important for both women with DCIS and the clinicians who care for them.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal solid malignancies. While immortalized cancer cell lines and genetically engineered murine models have increased our understanding of PDAC tumorigenesis, they do not recapitulate inter- and intra-patient heterogeneity. PDAC patient derived organoid (PDO) biobanks have overcome this hurdle, and provide an opportunity for the high throughput screening of potential new therapies. This review provides a summary of the PDAC PDO biobanks established to date, and discusses how they have advanced our understanding of PDAC biology. Looking forward, the development of coculturing techniques for specific immune or stromal cell populations will enable a better understanding of the crosstalk that occurs within the tumor microenvironment, and the impact of this crosstalk on treatment response.

BACKGROUND: Research on the possible association between shiftwork and breast cancer is complicated because there are many different shiftwork factors, which might be involved including: light at night, phase shift, sleep disruption and changes in lifestyle factors while on shiftwork (diet, physical activity, alcohol intake and low sun exposure). METHODS: We conducted a population-based case-control study in Western Australia from 2009 to 2011 with 1205 incident breast cancer cases and 1789 frequency age-matched controls. A self-administered questionnaire was used to collect demographic, reproductive, and lifestyle factors and lifetime occupational history and a telephone interview was used to obtain further details about the shiftwork factors listed above. RESULTS: A small increase in risk was suggested for those ever doing the graveyard shift (work between midnight and 0500 hours) and breast cancer (odds ratio (OR)=1.16, 95% confidence interval (CI)=0.97-1.39). For phase shift, we found a 22% increase in breast cancer risk (OR=1.22, 95% CI=1.01-1.47) with a statistically significant dose-response relationship (P=0.04). For the other shiftwork factors, risks were marginally elevated and not statistically significant. CONCLUSION: We found some evidence that some of the factors involved in shiftwork may be associated with breast cancer but the ORs were low and there were inconsistencies in duration and dose-response relationships.

PURPOSE: Despite evidence supporting at least five years of endocrine therapy for early breast cancer, many women discontinue therapy early. We investigated the impact of initial therapy type and specific comorbidities on discontinuation of endocrine therapy in clinical practice. METHODS: We identified women in a population-based cohort with a diagnosis of early breast cancer and an incident dispensing of anastrozole, letrozole or tamoxifen from 2003-2008 (N = 1531). Pharmacy and health service data were used to determine therapy duration, treatment for pre-existing and post-initiation comorbidities (anxiety, depression, hot flashes, musculoskeletal pain, osteoporosis, vaginal atrophy), demographic and other clinical characteristics. Time to discontinuation of initial, and any, endocrine therapy was calculated. Cox regression determined the association of different characteristics on early discontinuation. RESULTS: Initial endocrine therapy continued for a median of 2.2 years and any endocrine therapy for 4.8 years. Cumulative probability of discontinuing any therapy was 17% after one year and 58% by five years. Initial tamoxifen, pre-existing musculoskeletal pain and newly-treated anxiety predicted shorter initial therapy but not discontinuation of any therapy. Early discontinuation of any therapy was associated with newly-treated hot flashes (HR = 2.1, 95% CI = 1.3-3.3), not undergoing chemotherapy (HR = 1.4, 95% CI = 1.1-1.8) and not undergoing mastectomy (HR = 1.5, 95% CI = 1.2-1.8). CONCLUSIONS: Less than half of women completed five years of endocrine therapy. Women at greatest risk of stopping any therapy early were those with newly-treated hot flashes, no initial chemotherapy, or no initial mastectomy. This suboptimal use means that the reductions in recurrence demonstrated in clinical trials may not be realised in practice.

BACKGROUND: Australian clinical guidelines recommend endocrine therapy for all women with hormone-dependent early breast cancer. Guidelines specify tamoxifen as first-line therapy for pre-menopausal women, and tamoxifen or an aromatase inhibitor (AI) for post-menopausal women depending on the risk of recurrence based on tumour characteristics including size. Therapies have different side effect profiles; therefore comorbidity may also influence choice. We examined comorbidity, and the clinical and demographic characteristics of women commencing different therapies. PATIENTS AND METHODS: We identified the first dispensing of tamoxifen, anastrozole or letrozole for women diagnosed with invasive breast cancer in the 45 and Up Study from 2004-2009 (N = 1266). Unit-level pharmacy and medical service claims, hospital, Cancer Registry, and self-reported data were linked to determine menopause status at diagnosis, tumour size, age, comorbidities, and change in subsidy restrictions. Chi-square tests and generalised regression models were used to compare the characteristics of women commencing different therapies. RESULTS: Most pre-menopausal women commenced therapy with tamoxifen (91%). Anastrozole was the predominant therapy for post-menopausal women (57%), followed by tamoxifen (28%). Women with osteoporosis were less likely to commence anastrozole compared with tamoxifen (anastrozole RR = 0.7, 95% CI = 0.5-0.9). Women with arthritis were 1.6-times more likely to commence letrozole than anastrozole (95% CI = 1.1-2.1). Tamoxifen was more often initiated in women with tumours >1 cm, who were also ≥75 years. Subsidy restriction changes were associated with substantial increases in the proportion of women commencing AIs (anastrozole RR = 4.3, letrozole RR = 8.3). CONCLUSIONS: The findings indicate interplay of comorbidity and therapy choice for women with invasive breast cancer. Most post-menopausal women commenced therapy with anastrozole; however, letrozole and tamoxifen were more often initiated for women with comorbid arthritis and osteoporosis, respectively. Tamoxifen was also more common for women with tumours >1 cm and aged ≥75 years. Subsidy restrictions appear to have strongly influenced therapy choice.

BACKGROUND: Statutory State-based cancer registries are considered the 'gold standard' for researchers identifying cancer cases in Australia, but research using self-report or administrative health datasets (e.g. hospital records) may not have linkage to a Cancer Registry and need to identify cases. This study investigated the validity of administrative and self-reported data compared with records in a State-wide Cancer Registry in identifying invasive breast cancer cases. METHODS: Cases of invasive breast cancer recorded on the New South Wales (NSW) Cancer Registry between July 2004 and December 2008 (the study period) were identified for women in the 45 and Up Study. Registry cases were separately compared with suspected cases ascertained from: i) administrative hospital separations records; ii) outpatient medical service claims; iii) prescription medicines claims; and iv) the 45 and Up Study baseline survey. Ascertainment flags included diagnosis codes, surgeries (e.g. lumpectomy), services (e.g. radiotherapy), and medicines used for breast cancer, as well as self-reported diagnosis. Positive predictive value (PPV), sensitivity and specificity were calculated for flags within individual datasets, and for combinations of flags across multiple datasets. RESULTS: Of 143,010 women in the 45 and Up Study, 2039 (1.4%) had an invasive breast tumour recorded on the NSW Cancer Registry during the study period. All of the breast cancer flags examined had high specificity (>97.5%). Of the flags from individual datasets, hospital-derived 'lumpectomy and diagnosis of invasive breast cancer' and '(lumpectomy or mastectomy) and diagnosis of invasive breast cancer' had the greatest PPV (89% and 88%, respectively); the later having greater sensitivity (59% and 82%, respectively). The flag with the highest sensitivity and PPV ≥ 85% was 'diagnosis of invasive breast cancer' (both 86%). Self-reported breast cancer diagnosis had a PPV of 50% and sensitivity of 85%, and breast radiotherapy had a PPV of 73% and a sensitivity of 58% compared with Cancer Registry records. The combination of flags with the greatest PPV and sensitivity was '(lumpectomy or mastectomy) and (diagnosis of invasive breast cancer or breast radiotherapy)' (PPV and sensitivity 83%). CONCLUSIONS: In the absence of Cancer Registry data, administrative and self-reported data can be used to accurately identify cases of invasive breast cancer for sample identification, removing cases from a sample, or risk adjustment. Invasive breast cancer can be accurately identified using hospital-derived diagnosis alone or in combination with surgeries and breast radiotherapy.

BACKGROUND: The germ cell supranetwork multidisciplinary team (SMDT) for the Anglian Network covers a population of 7.5 million. METHODS: We reviewed 10 years of SMDT discussion and categorised them into five domains ((1) overall outcome, (2) chemotherapy regimens-untreated disease and salvage therapy, (3) radiology, (4) pathology and (5) complex cases) to assess the impact of the SMDT. RESULTS: A total of 2892 new cases were reviewed. In the first 5 years, patients with good prognosis disease had poorer survival in low-volume vs high-volume centres (87.8 vs 95.3, p = 0.02), but the difference was no longer significant in the last 5 years (93.3 vs 95.1, p = 0.30). Radiology review of 3206 scans led to rejection of the diagnosis of progression in 26 cases and a further 10 cases were down-staged. There were 790 pathology reviews by two specialised uropathologists, which lead to changes in 75 cases. 18F-fluorodeoxyglucose (18FDG) PET-CT was undertaken during this time period but did not help to predict who would have viable cancer. A total of 26 patients with significant mental health issues who were unable to give informed consent were discussed. CONCLUSION: SMDT working has led to an improvement in outcomes and refining of treatment in patients with germ cell tumours.

[This corrects the article DOI: 10.1371/journal.pgen.1009497.].

Optical elastography is undergoing extensive development as an imaging tool to map mechanical contrast in tissue. Here, we present a new platform for optical elastography by generating sub-millimetre-scale mechanical contrast from a simple digital camera. This cost-effective, compact and easy-to-implement approach opens the possibility to greatly expand applications of optical elastography both within and beyond the field of medical imaging. Camera-based optical palpation (CBOP) utilises a digital camera to acquire photographs that quantify the light intensity transmitted through a silicone layer comprising a dense distribution of micro-pores (diameter, 30-100 µm). As the transmission of light through the micro-pores increases with compression, we deduce strain in the layer directly from intensity in the digital photograph. By pre-characterising the relationship between stress and strain of the layer, the measured strain map can be converted to an optical palpogram, a map of stress that visualises mechanical contrast in the sample. We demonstrate a spatial resolution as high as 290 µm in CBOP, comparable to that achieved using an optical coherence tomography-based implementation of optical palpation. In this paper, we describe the fabrication of the micro-porous layer and present experimental results from structured phantoms containing stiff inclusions as small as 0.5 × 0.5 × 1 mm. In each case, we demonstrate high contrast between the inclusion and the base material and validate both the contrast and spatial resolution achieved using finite element modelling. By performing CBOP on freshly excised human breast tissue, we demonstrate the capability to delineate tumour from surrounding benign tissue.

Despite the high prevalence of prostate cancer in older men, the predictive value of a polygenic risk score (PRS) remains uncertain in men aged ≥70 years. We used a 6.6 million-variant PRS to predict the risk of incident prostate cancer in a prospective study of 5701 men of European descent aged ≥70 years (mean age 75 years) enrolled in the ASPirin in Reducing Events in the Elderly (ASPREE) clinical trial. The study endpoint was prostate cancer, including metastatic or non-metastatic disease, confirmed by an expert panel. After excluding participants with a history of prostate cancer at enrolment, we used a multivariable Cox proportional hazards model to assess the association between the PRS and incident prostate cancer risk, adjusting for covariates. Additionally, we examined the distribution of Gleason grade groups by PRS group to determine if a higher PRS was associated with higher grade disease. We tested for interaction between the PRS and aspirin treatment. Logistic regression was used to independently assess the association of the PRS with prevalent (pre-trial) prostate cancer, reported in medical histories. During a median follow-up time of 4.6 years, 218 of the 5701 participants (3.8%) were diagnosed with prostate cancer. The PRS predicted incident risk with a hazard ratio (HR) of 1.52 per standard deviation (SD) (95% confidence interval (CI) 1.33-1.74, p < 0.001). Men in the top quintile of the PRS distribution had an almost three times higher risk of prostate cancer than men in the lowest quintile (HR = 2.99 (95% CI 1.90-4.27), p < 0.001). However, a higher PRS was not associated with a higher Gleason grade groups. We found no interaction between aspirin treatment and the PRS for prostate cancer risk. The PRS was also associated with prevalent prostate cancer (odds ratio = 1.80 per SD (95% CI 1.65-1.96), p < 0.001).While a PRS for prostate cancer is strongly associated with incident risk in men aged ≥70 years, the clinical utility of the PRS as a biomarker is currently limited by its inability to select for clinically significant disease.

Appropriate soft tissue tension in total knee replacement (TKR) is an important factor for a successful outcome. The purpose of our study was to assess both the reproducibility of a modern intraoperative pressure sensor (IOP) and if a surgeon could unconsciously influence measurement. A consecutive series of 80 TKRs were assessed with an IOP between January 2018 and December 2020. In the first scenario, two blinded sequential measurements in 48 patients were taken; in a second scenario, an initial blinded measurement and a subsequent unblinded measurement in 32 patients were taken while looking at the sensor monitor screen. Reproducibility was assessed by intraclass correlation coefficients (ICCs). In the first scenario, the ICC ranged from 0.83 to 0.90, and in the second scenario it ranged from 0.80 to 0.90. All ICCs were 0.80 or higher, indicating reproducibility using a IOP and that a surgeon may not unconsciously influence the measurement. The use of a modern IOP to measure soft tissue tension in TKRs is a reproducible technique. A surgeon observing the measurements while performing IOP may not significantly influence the result. An IOP gives additional information that the surgeon can use to optimize outcomes in TKR.

Glioblastoma (GBM) is the most common primary central nervous system tumor in adults, accounting for approximately 80% of all brain-related malignancies [...].

INTRODUCTION: ACOSOG-Z0011(Z11) trial showed that axillary node clearance (ANC) may be omitted in women with ≤2 positive nodes undergoing breast conserving surgery (BCS) and whole breast radiotherapy (RT). A confirmatory study is needed to clarify the role of axillary treatment in women with ≤2 macrometastases undergoing BCS and groups that were not included in Z11 for example, mastectomy and those with microscopic extranodal invasion. The primary objective of POsitive Sentinel NOde: adjuvant therapy alone versus adjuvant therapy plus Clearance or axillary radiotherapy (POSNOC) is to evaluate whether for women with breast cancer and 1 or 2 macrometastases, adjuvant therapy alone is non-inferior to adjuvant therapy plus axillary treatment, in terms of 5-year axillary recurrence. METHODS AND ANALYSIS: POSNOC is a pragmatic, multicentre, non-inferiority, international trial with participants randomised in a 1:1 ratio. Women are eligible if they have T1/T2, unifocal or multifocal invasive breast cancer, and 1 or 2 macrometastases at sentinel node biopsy, with or without extranodal extension. In the intervention group women receive adjuvant therapy alone, in the standard care group they receive ANC or axillary RT. In both groups women receive adjuvant therapy, according to local guidelines. This includes systemic therapy and, if indicated, RT to breast or chest wall. The UK Radiotherapy Trials Quality Assurance Group manages the in-built radiotherapy quality assurance programme. Primary endpoint is 5-year axillary recurrence. Secondary outcomes are arm morbidity assessed by Lymphoedema and Breast Cancer Questionnaire and QuickDASH questionnaires; quality of life and anxiety as assessed with FACT B+4 and State/Trait Anxiety Inventory questionnaires, respectively; other oncological outcomes; economic evaluation using EQ-5D-5L. Target sample size is 1900. Primary analysis is per protocol. Recruitment started on 1 August 2014 and as of 9 June 2021, 1866 participants have been randomised. ETHICS AND DISSEMINATION: Protocol was approved by the National Research Ethics Service Committee East Midlands-Nottingham 2 (REC reference: 13/EM/0459). Results will be submitted for publication in peer-reviewed journals. TRIAL REGISTRATION NUMBER: ISRCTN54765244; NCT0240168Cite Now.

Studies show conflicting results on whether exercise interventions to improve outcomes for women with breast cancer are cost-effective. We modelled the long-term cost-effectiveness of the Exercise for Health intervention compared with usual care. A lifetime Markov cohort model for women with early breast cancer was constructed taking a societal perspective. Data were obtained from trial, epidemiological, quality of life, and healthcare cost reports. Outcomes were calculated from 5000 Monte Carlo simulations, and one-way and probabilistic sensitivity analyses. Over the cohort's remaining life, the incremental cost for the exercise versus usual care groups were $7409 and quality-adjusted life years (QALYs) gained were 0.35 resulting in an incremental cost per QALY ratio of AU$21,247 (95% Uncertainty Interval (UI): Dominant, AU$31,398). The likelihood that the exercise intervention was cost-effective at acceptable levels was 93.0%. The incremental cost per life year gained was AU$8894 (95% UI Dominant, AU$11,769) with a 99.4% probability of being cost effective. Findings were most sensitive to the probability of recurrence in the exercise and usual care groups, followed by the costs of out-of-pocket expenses and the model starting age. This exercise intervention for women after early-stage breast cancer is cost-effective and would be a sound investment of healthcare resources.

BACKGROUND: Ductal carcinoma in situ (DCIS) is an in-situ (pre-cancerous) breast malignancy whereby malignant cells are contained within the basement membrane of the breast ducts. Increasing awareness that some low-risk forms of DCIS might remain indolent for many years has led to concern about overtreatment, with at least 3 clinical trials underway internationally assessing the safety of active monitoring for low-risk DCIS. This study aimed to understand healthcare professionals' (HCPs) views on the management options for patients with DCIS. METHODS: Qualitative study using semi-structured interviews with HCPs involved in the diagnosis and management of DCIS in Australia and New Zealand. Interviews were audio-recorded, transcribed and analysed thematically using Framework Analysis method. RESULTS: Twenty-six HCPs including 10 breast surgeons, 3 breast physicians, 6 radiation oncologists, and 7 breast care nurses participated. There was a strong overall consensus that DCIS requires active treatment. HCPs generally felt uncomfortable recommending active monitoring as a management option for low-risk DCIS as they viewed this as outside current standard care. Overall, HCPs felt that active monitoring was an unproven strategy in need of an evidence base; however, many acknowledged that active monitoring for low-risk DCIS could be appropriate for patients with significant co-morbidities or limited life expectancy. They believed that most patients would opt for surgery wherever possible. CONCLUSIONS: This study highlights the important need for robust randomised controlled trial data about active monitoring for women with low-risk DCIS, to provide HCPs with confidence in their management recommendations and decision-making.

BACKGROUND: Few studies have specifically assessed the scope, nature and challenges of palliative and end-of-life care in rural general practice. These knowledge gaps limit the development of evidence-based policies and services for patients in the last months of life. This study aimed to explore the perspectives of general practitioners (GPs) and other stakeholders on rural GPs' involvement and challenges in providing palliative and end-of-life care in regional Australia. METHODS: A qualitative study involving five focus groups with 26 GPs based in rural/regional Western Australia together with 15 individual telephone interviews with four GPs and 11 other stakeholders involved in end-of-life care across Australia. RESULTS: The rural GPs' central role in end-of-life care was recognized by the majority of participants but multiple challenges were also identified. Some challenges were comparable to those found in urban settings but others were more pronounced, including resource limitations and lack of training. Inappropriate payment models discouraged GPs' involvement in some aspects of end-of-life care, such as case conferences and home visits. Compared to GPs in urban settings, those in rural/regional communities often reported closer doctor-patient relationships and better care integration and collaboration. These positive aspects of care could be further developed to enhance service provision. Our study highlighted the importance of regular interactions with other professionals and patients in providing end-of-life care, but many GPs and other stakeholders found such interactions more challenging than the more "technical" aspects of care. CONCLUSIONS: Rural/regional GPs appear to be disproportionately affected by inappropriate payment models and limited resources, but may benefit from closer doctor-patient relationships and better care integration and collaboration relative to urban GPs. Systematic collection of empirical data on GP management at end-of-life is required to build on these strengths and address the challenges.

BACKGROUND: Mammographic density (MD) is an established risk factor for breast cancer. There are significant ethnic differences in MD measures which are consistent with those for corresponding breast cancer risk. This is the first study investigating the distribution and determinants of MD measures within Aboriginal women of Western Australia (WA). METHODS: Epidemiological data and mammographic images were obtained from 628 Aboriginal women and 624 age-, year of screen-, and screening location-matched non-Aboriginal women randomly selected from the BreastScreen Western Australia database. Women were cancer free at the time of their mammogram between 1989 and 2014. MD was measured using the Cumulus software. Kolmogorov-Smirnov tests were used to compare distributions of absolute dense area (DA), precent dense area (PDA), non-dense area (NDA) and total breast area between Aboriginal and non-Aboriginal women. General linear regression was used to estimate the determinants of MD, adjusting for age, NDA, hormone therapy use, family history, measures of socio-economic status and remoteness of residence for Aboriginal and non-Aboriginal women separately. RESULTS: Aboriginal women were found to have lower DA and PDA and higher NDA than non-Aboriginal women. Age (p <  0.001) was negatively associated and several socio-economic indices (p <  0.001) were positively associated with DA and PDA in Aboriginal and non-Aboriginal women. Remoteness of residence was associated with both mammographic measures but for non-Aboriginal women only. CONCLUSIONS: Aboriginal women have, on average, less MD than non-Aboriginal women but the factors associated with MD are similar for both sample populations. Since reduced MD is associated with improved sensitivity of mammography, this study suggests that mammographic screening is a particularly good test for Australian Indigenous women, a population that suffers from high breast cancer mortality.

OBJECTIVE: TARGIT-A randomised women with early breast cancer to receive external beam radiotherapy (EBRT) or intraoperative radiotherapy (TARGIT-IORT). This study aimed to identify what extra risk of recurrence patients would accept for perceived benefits and risks of different radiotherapy treatments. METHODS: Patient preferences were determined by self-rated trade-off questionnaires in two studies: Stage (1) 209 TARGIT-A participants (TARGIT-IORTn = 108, EBRTn = 101); Stage (2) 123 non-trial patients yet to receive radiotherapy (pre-treatment group), with 85 also surveyed post-radiotherapy. Patients traded-off risks of local recurrence in preference selection between TARGIT-IORT and EBRT. RESULTS: TARGIT-IORT patients were more accepting of IORT than EBRT patients with 60% accepting the highest increased risk presented (4%-6%) compared to 12% of EBRT patients, and 2% not accepting IORT at all compared to 43% of EBRT patients. Pre-treatment patients were more accepting of IORT than post-treatment patients with 23% accepting the highest increased risk presented compared to 15% of post-treatment patients, and 15% not accepting IORT at all compared to 41% of pre-treatment patients. CONCLUSIONS: Breast cancer patients yet to receive radiotherapy accept a higher recurrence risk than the actual risk found in TARGIT-A. Measured patient preferences are highly influenced by experience of treatment received. This finding challenges the validity of post-treatment preference studies.

Globally, an increasing and aging population is contributing to the prevalence of cancer. To be effective, cancer care needs to involve the coordination of multidisciplinary specialties, and also needs to be affordable, accessible, and capable of producing optimal patient outcomes. Porter and Teisberg (2006) have postulated that shifting current healthcare strategies from volume-based to patient-centric care redirects economic competition to providing treatments which promote the best patient outcomes while driving down costs. Therefore, the value in value-based healthcare (VBH) is defined as patient outcome per currency spent on providing care. Based on the experiences of healthcare organizations currently transitioning to the value-based system, this review details actionable guidelines to transition current cancer care practices to the value-based system in four main steps: by defining universal clinical and patient-reported measures, creating cancer-specific units that provide the full care cycle, establishing a data capture model to routinely determine the value of the care delivered, and continually improving treatment strategies through research. As healthcare providers in more developed countries move to value-based care, those located in less developed countries should also be assisted in their transition to relieve the cancer burden globally.

INTRODUCTION: Physically active cancer survivors have substantially less cancer recurrence and improved survival compared with those who are inactive. However, the majority of survivors (70%-90%) are not meeting the physical activity (PA) guidelines. There are also significant geographic inequalities in cancer survival with poorer survival rates for the third of Australians who live in non-metropolitan areas compared with those living in major cities. The primary objective of the trial is to increase moderate-to-vigorous PA (MVPA) among cancer survivors living in regional and remote Western Australia. Secondary objectives are to reduce sedentary behaviour and in conjunction with increased PA, improve quality of life (QoL) in non-metropolitan survivors. Tertiary objectives are to assess the effectiveness of the health action process approach (HAPA) model variables, on which the intervention is based, to predict change in MVPA. METHODS AND ANALYSIS: Eighty-six cancer survivors will be randomised into either the intervention or control group. Intervention group participants will receive a Fitbit and up to six telephone health-coaching sessions. MVPA (using Actigraph), QoL and psychological variables (based on the HAPA model via questionnaire) will be assessed at baseline, 12 weeks (end of intervention) and 24 weeks (end of follow-up). A general linear mixed model will be used to assess the effectiveness of the intervention. ETHICS AND DISSEMINATION: Ethics approval has been obtained from St John of God Hospital Subiaco (HREC/#1201). We plan to submit a manuscript of the results to a peer-reviewed journal. Results will be presented at conferences, community and consumer forums and hospital research conferences. TRIAL REGISTRATION NUMBER: ACTRN12618001743257; pre-results, U1111-1222-5698.

BACKGROUND: Carcinoma of unknown primary (CUP) is a metastatic epithelial malignancy in the absence of an identifiable primary tumour. Prognosis for patients with CUP is poor because treatment options are generally limited to broad spectrum chemotherapy. A shift towards personalised cancer management based on mutation profiling offers the possibility of new treatment paradigms. This study has explored whether actionable, oncogenic driver mutations are present in CUP that have potential to better inform treatment decisions. METHODS: Carcinoma of unknown primary cases (n = 21) were selected and DNA was isolated from formalin-fixed paraffin embedded sections prior to amplification and sequencing. Two distinct yet complementary targeted gene panels were used to assess variants in up to 76 known cancer-related genes for the identification of biologically relevant and actionable mutations. RESULTS: Variants were detected in 17/21 cases (81%) of which 11 (52%) were potentially actionable with drugs currently approved for use in known primary cancer types or undergoing clinical trials. The most common variants detected were in TP53 (47%), KRAS (12%), MET (12%) and MYC (12%). Differences at the molecular level were seen between common CUP histological subtypes. CUP adenocarcinomas and poorly differentiated carcinomas harboured the highest frequency of variants in genes involved in signal transduction pathways (e.g. MET, EGFR, HRAS, KRAS, and BRAF). In contrast, squamous cell carcinoma exhibited a higher frequency of variants in cell cycle control and DNA repair genes (e.g. TP53, CDKN2A and MLH1). CONCLUSION: Taken together, mutations in biologically relevant genes were detected in the vast majority of CUP tumours, of which half provided a potentially novel treatment option not generally considered in CUP.

BACKGROUND: The purpose of this research was to assess agreement between four rating systems of cosmetic outcome measured in a subset of patients with early breast cancer participating in the randomised TARGIT-A trial. TARGIT-A compared risk-adapted single-dose intra-operative radiotherapy (TARGIT-IORT) to whole breast external beam radiotherapy (EBRT). METHODS: Patients, their Radiation Oncologist and Research Nurse completed a subjective cosmetic assessment questionnaire before radiotherapy and annually thereafter for five years. Objective data previously calculated by the validated BCCT.core software which utilizes digital photographs to score symmetry, colour and scar was also used. Agreement was assessed by the Kappa statistic and longitudinal changes were assessed by generalized estimating equations. RESULTS: Overall, an Excellent-Good (EG) cosmetic result was scored more often than a Fair-Poor (FP) result for both treatment groups across all time points, with patients who received TARGIT-IORT scoring EG more often than those who received EBRT however this was statistically significant at Year 5 only. There was modest agreement between the four rating systems with the highest Kappa score being moderate agreement which was between nurse and doctor scores at Year 1 with Kappa = 0.46 (p < 0.001), 95% CI (0.24, 0.68). CONCLUSION: Despite similar overall findings between treatment groups and rating systems, the inter-rater agreement was only modest. This suggests that the four rating systems utilized may not necessarily be used interchangeably and it is arguable that for an outcome such as cosmetic appearance, the patient's point of view is the most important. TRIAL REGISTRATION: TARGIT-A ISRCTN34086741 , Registered 21 July 2004, retrospectively registered.

Background: The clinical effectiveness of treating ipsilateral multifocal (MF) and multicentric (MC) breast cancers using breast-conserving surgery (BCS) compared with the standard of mastectomy is uncertain. Inconsistencies relate to definitions, incidence, staging and intertumoral heterogeneity. The primary aim of this systematic review was to compare clinical outcomes after BCS versus mastectomy for MF and MC cancers, collectively defined as multiple ipsilateral breast cancers (MIBC). Methods: Comprehensive electronic searches were undertaken to identify complete papers published in English between May 1988 and July 2015, primarily comparing clinical outcomes of BCS and mastectomy for MIBC. All study designs were included, and studies were appraised critically using the Newcastle-Ottawa Scale. The characteristics and results of identified studies were summarized. Results: Twenty-four retrospective studies were included in the review: 17 comparative studies and seven case series. They included 3537 women with MIBC undergoing BCS; breast cancers were defined as MF in 2677 women, MC in 292, and reported as MIBC in 568. Six studies evaluated MIBC treated by BCS or mastectomy, with locoregional recurrence (LRR) rates of 2-23 per cent after BCS at median follow-up of 59·5 (i.q.r. 56-81) months. BCS and mastectomy showed apparently equivalent rates of LRR (risk ratio 0·94, 95 per cent c.i. 0·65 to 1·36). Thirteen studies compared BCS in women with MIBC versus those with unifocal cancers, reporting LRR rates of 2-40 per cent after BCS at a median follow-up of 64 (i.q.r. 57-73) months. One high-quality study reported 10-year actuarial LRR rates of 5·5 per cent for BCS in 300 women versus 6·5 per cent for mastectomy among 887 women. Conclusion: The available studies were mainly of moderate quality, historical and underpowered, with limited follow-up and biased case selection favouring BCS rather than mastectomy for low-risk patients. The evidence was inconclusive, weakening support for the St Gallen consensus and supporting a future randomized trial.

Breast magnetic resonance imaging (MRI) now has an accepted place in screening younger women at high risk of breast cancer, and is increasingly used in a number of other settings including assessment of response to neo-adjuvant therapy and local staging of cancer. Although the evidence for its general use in these settings is very limited, in highly selected patients, especially where discordance with conventional measurements occurs, MRI can have a place in assessing extent of disease, both whether operable and how operable, and guiding surgery. These scenarios and future indications and alternative technologies are explored in this paper.

BACKGROUND: While weight gain following breast cancer is considered common, results supporting these findings are dated. This work describes changes in body weight following breast cancer over 72 months, compares weight with normative data and explores whether weight changes over time are associated with personal, diagnostic, treatment or behavioral characteristics. METHODS: A population-based sample of 287 Australian women diagnosed with early-stage invasive breast cancer was assessed prospectively at six, 12, 18 and 72 months post-surgery. Weight was clinically measured and linear mixed models were used to explore associations between weight and participant characteristics (collected via self-administered questionnaire). Those with BMI changes of one or more units were considered to have experienced clinically significant changes in weight. RESULTS: More than half (57%) of participants were overweight or obese at 6 months post-surgery, and by 72 months post-surgery 68% of women were overweight or obese. Among those who gained more weight than age-matched norms, clinically significant weight gain between 6 and 18 months and 6 and 72 months post-surgery was observed in 24% and 39% of participants, respectively (median [range] weight gain: 3.9 kg [2.0-11.3 kg] and 5.2 kg [0.6-28.7], respectively). Clinically-significant weight losses were observed in up to 24% of the sample (median [range] weight loss between 6 and 72 months post-surgery: -6.4 kg [-1.9--24.6 kg]). More extensive lymph node removal, being treated on the non-dominant side, receiving radiation therapy and lower physical activity levels at 6 months was associated with higher body weights post-breast cancer (group differences >3 kg; all p < 0.05). CONCLUSIONS: While average weight gain among breast cancer survivors in the long-term is small, subgroups of women experience greater gains linked with adverse health and above that experienced by age-matched counterparts. Weight change post-breast cancer is a contemporary public health issue and the integration of healthy weight education and support into standard breast cancer care has potential to significantly improve the length and quality of cancer survivorship.

BACKGROUND: Evaluation of lymph node involvement is an important factor in detecting metastasis and deciding whether to perform axillary lymph node dissection (ALND) in breast cancer surgery. As ALND is associated with potentially severe long term morbidity, the accuracy of lymph node assessment is imperative in avoiding unnecessary ALND. The mechanical properties of malignant lymph nodes are often distinct from those of normal nodes. A method to image the micro-scale mechanical properties of lymph nodes could, thus, provide diagnostic information to aid in the assessment of lymph node involvement in metastatic cancer. In this study, we scan axillary lymph nodes, freshly excised from breast cancer patients, with optical coherence micro-elastography (OCME), a method of imaging micro-scale mechanical strain, to assess its potential for the intraoperative assessment of lymph node involvement. METHODS: Twenty-six fresh, unstained lymph nodes were imaged from 15 patients undergoing mastectomy or breast-conserving surgery with axillary clearance. Lymph node specimens were bisected to allow imaging of the internal face of each node. Co-located OCME and optical coherence tomography (OCT) scans were taken of each sample, and the results compared to standard post-operative hematoxylin-and-eosin-stained histology. RESULTS: The optical backscattering signal provided by OCT alone may not provide reliable differentiation by inspection between benign and malignant lymphoid tissue. Alternatively, OCME highlights local changes in tissue strain that correspond to malignancy and are distinct from strain patterns in benign lymphoid tissue. The mechanical contrast provided by OCME complements the optical contrast provided by OCT and aids in the differentiation of malignant tumor from uninvolved lymphoid tissue. CONCLUSION: The combination of OCME and OCT images represents a promising method for the identification of malignant lymphoid tissue. This method shows potential to provide intraoperative assessment of lymph node involvement, thus, preventing unnecessary removal of uninvolved tissues and improving patient outcomes.

Probing the mechanical properties of tissue on the microscale could aid in the identification of diseased tissues that are inadequately detected using palpation or current clinical imaging modalities, with potential to guide medical procedures such as the excision of breast tumours. Compression optical coherence elastography (OCE) maps tissue strain with microscale spatial resolution and can delineate microstructural features within breast tissues. However, without a measure of the locally applied stress, strain provides only a qualitative indication of mechanical properties. To overcome this limitation, we present quantitative micro-elastography, which combines compression OCE with a compliant stress sensor to image tissue elasticity. The sensor consists of a layer of translucent silicone with well-characterized stress-strain behaviour. The measured strain in the sensor is used to estimate the two-dimensional stress distribution applied to the sample surface. Elasticity is determined by dividing the stress by the strain in the sample. We show that quantification of elasticity can improve the ability of compression OCE to distinguish between tissues, thereby extending the potential for inter-sample comparison and longitudinal studies of tissue elasticity. We validate the technique using tissue-mimicking phantoms and demonstrate the ability to map elasticity of freshly excised malignant and benign human breast tissues.

BACKGROUND: Attributions of causality are common for many diseases, including breast cancer. The risk of developing breast cancer can be reduced by modifications to lifestyle and behaviours to minimise exposure to specific risk factors, such as obesity. However, these modifications will only occur if women believe that certain behaviours/lifestyle factors have an impact on the development of breast cancer. METHOD: The Breast Cancer, Environment and Employment Study is a case-control study of breast cancer conducted in Western Australia between 2009 and 2011. As part of the study 1109 women with breast cancer and 1633 women without the disease completed a Risk Perception Questionnaire in which they were asked in an open-ended question for specific cause/s to the development of breast cancer in themselves or in others. The study identified specific causal beliefs, and assessed differences in the beliefs between women with and without breast cancer. RESULTS: The most common attributions in women without breast cancer were to familial or inherited factors (77.6%), followed by lifestyle factors, such as poor diet and smoking (47.1%), and environmental factors, such as food additives (45.4%). The most common attributions in women with breast cancer were to mental or emotional factors (46.3%), especially stress, followed by lifestyle factors (38.6%) and physiological factors (37.5%), particularly relating to hormonal history. CONCLUSIONS: While the majority of participants in this study provided one or more causal attributions for breast cancer, many of the reported risk factors do not correspond to those generally accepted by the scientific community. These misperceptions could be having a significant impact on the success of prevention and early detection programs that seek to minimise the pain and suffering caused by this disease. In particular, women who have no family history of the disease may not work to minimise their exposure to the modifiable risk factors.

BACKGROUND: The randomized TARGIT trial comparing experimental intra-operative radiotherapy (IORT) to up to 7 weeks of daily conventional external beam radiotherapy (EBRT) recruited participants in Western Australia between 2003 and 2012. We aimed to understand preferences for this evolving radiotherapy treatment for early breast cancer (EBC) in health professionals, and how they changed over time and in response to emerging data. Preferences for single dose IORT or EBRT for EBC were elicited in 2004 and 2011, together with factors that may be associated with these preferences. METHODS: Western Australian health professionals working with breast cancer patients were invited to complete a validated, self-administered questionnaire. The questionnaire used hypothetical scenarios and trade-off methodology to determine the maximum increase in risk of local recurrence health professionals were willing to accept in order to have a single dose of IORT in the place of EBRT if they were faced with this decision themselves. RESULTS: Health professional characteristics were similar across the two time points although 2011 included a higher number of nurse (49% vs. 36%) and allied health (10% vs. 4%) participants and a lower number of radiation therapists (17% vs. 32% ) compared to 2004.Health professional preferences varied, with 7.5% and 3% judging IORT unacceptable at any risk, 18% and 21% judging IORT acceptable only if offering an equivalent risk, 56% and 59% judging IORT acceptable with a low maximum increase in risk (1-3%) and 19% and 17% judging a high maximum increase in risk acceptable (4-5%), in 2004 and 2011 respectively. A significantly greater number of nurses accepted IORT as a treatment option in 2011. CONCLUSIONS: Most Western Australian health professionals working with breast cancer patients are willing to accept an increase in risk of local recurrence in order to replace EBRT with IORT in a hypothetical setting. This finding was consistent over two time points spanning 7 years despite the duration of clinical experience with IORT and the publication of the early clinical results of IORT in 2010. These results need to be compared with preferences elicited from patient groups, and further investigation into the impact of personal preferences on health professionals' advice to patients is warranted.

To identify novel cancer therapies, the tumor microenvironment (TME) has received a lot of attention in recent years in particular with the advent of clinical successes achieved by targeting immune checkpoint inhibitors (ICIs). The TME consists of multiple cell types that are embedded in the extracellular matrix (ECM), including immune cells, endothelial cells and cancer associated fibroblasts (CAFs), which communicate with cancer cells and each other during tumor progression. CAFs are a dominant and heterogeneous cell type within the TME with a pivotal role in controlling cancer cell invasion and metastasis, immune evasion, angiogenesis and chemotherapy resistance. CAFs mediate their effects in part by remodeling the ECM and by secreting soluble factors and extracellular vesicles. Exosomes are a subtype of extracellular vesicles (EVs), which contain various biomolecules such as nucleic acids, lipids, and proteins. The biomolecules in exosomes can be transmitted from one to another cell, and thereby affect the behavior of the receiving cell. As exosomes are also present in circulation, their contents can also be explored as biomarkers for the diagnosis and prognosis of cancer patients. In this review, we concentrate on the role of CAFs-derived exosomes in the communication between CAFs and cancer cells and other cells of the TME. First, we introduce the multiple roles of CAFs in tumorigenesis. Thereafter, we discuss the ways CAFs communicate with cancer cells and interplay with other cells of the TME, and focus in particular on the role of exosomes. Then, we elaborate on the mechanisms by which CAFs-derived exosomes contribute to cancer progression, as well as and the clinical impact of exosomes. We conclude by discussing aspects of exosomes that deserve further investigation, including emerging insights into making treatment with immune checkpoint inhibitor blockade more efficient.

BACKGROUND: Premenopausal women with early hormone-receptor positive (HR+) breast cancer receive 5-10 years of adjuvant endocrine therapy (ET) during which pregnancy is contraindicated and fertility may wane. The POSITIVE study investigates the impact of temporary ET interruption to allow pregnancy. METHODS: POSITIVE enrolled women with stage I-III HR + early breast cancer, ≤42 years, who had received 18-30 months of adjuvant ET and wished to interrupt ET for pregnancy. Treatment interruption for up to 2 years was permitted to allow pregnancy, delivery and breastfeeding, followed by ET resumption to complete the planned duration. FINDINGS: From 12/2014 to 12/2019, 518 women were enrolled at 116 institutions/20 countries/4 continents. At enrolment, the median age was 37 years and 74.9 % were nulliparous. Fertility preservation was used by 51.5 % of women. 93.2 % of patients had stage I/II disease, 66.0 % were node-negative, 54.7 % had breast conserving surgery, 61.9 % had received neo/adjuvant chemotherapy. Tamoxifen alone was the most prescribed ET (41.8 %), followed by tamoxifen + ovarian function suppression (OFS) (35.4 %). A greater proportion of North American women were <35 years at enrolment (42.7 %), had mastectomy (59.0 %) and received tamoxifen alone (59.8 %). More Asian women were nulliparous (81.0 %), had node-negative disease (76.2%) and received tamoxifen + OFS (56.0 %). More European women had received chemotherapy (69.3 %). INTERPRETATION: The characteristics of participants in the POSITIVE study provide insights to which patients and doctors considered it acceptable to interrupt ET to pursue pregnancy. Similarities and variations from a regional, sociodemographic, disease and treatment standpoint suggest specific sociocultural attitudes across the world.

BACKGROUND: Palliative care improves the quality of lives of patients and families affected by advanced illnesses through the prevention and relief of suffering. While palliative care is well established in developed countries, it is inadequate or non-existent in most developing countries. Palliative care is an emerging concept in Bhutan, a tiny Himalayan Kingdom. A small community palliative care service is available in the national referral hospital with three dedicated inpatient palliative care beds. This study explored the needs for palliative care among patients diagnosed with advanced illnesses and is a component of a larger project aimed to inform a suitable palliative care model for the country. METHODS: This is a cross-sectional descriptive study. A survey, using a structured questionnaire including the EORTC QLQ-C30, was carried out among patients with advanced illness in hospitals, primary care units and communities across the country. Purposeful and snowball sampling strategies were used to recruit study participants. RESULTS: Seventy (76%), out of 93 eligible patients, agreed to participate in the survey. Participants reported low to moderate scores on physical, role, emotional, cognitive and social functioning, a moderate score for the global health/ quality of life scale and moderately high (worse) scores in symptoms including fatigue, pain, insomnia, loss of appetite and the financial impact from the disease. CONCLUSIONS: The symptom burden experienced by patients affected by advanced illnesses demonstrates the need for palliative care in Bhutan. These findings will help inform the development of a public health-focused palliative care model, modified to the Bhutanese context, as recommended by the World Health Organization.

Mammographic breast density (MBD) is a strong and highly heritable predictor of breast cancer risk and a biomarker for the disease. This study systematically assesses MBD as an endophenotype for breast cancer-a quantitative trait that is heritable and genetically correlated with disease risk. Using data from the family-based kConFab Study and the 1994/1995 cross-sectional Busselton Health Study, participants were divided into three status groups-cases, relatives of cases and controls. Participant's mammograms were used to measure absolute dense area (DA) and percentage dense area (PDA). To address each endophenotype criterion, linear mixed models and heritability analysis were conducted. Both measures of MBD were significantly associated with breast cancer risk in two independent samples. These measures were also highly heritable. Meta-analyses of both studies showed that MBD measures were higher in cases compared to relatives (β = 0.48, 95% CI = 0.10, 0.86 and β = 0.41, 95% CI = 0.06, 0.78 for DA and PDA, respectively) and in relatives compared to controls (β = 0.16, 95% CI = -0.24, 0.56 and β = 0.16, 95% CI = -0.21, 0.53 for DA and PDA, respectively). This study formally demonstrates, for the first time, that MBD is an endophenotype for breast cancer.