P53 and TLR4 expression are prognostic markers informing progression free survival of advanced stage high grade serous ovarian cancer.

OBJECTIVE: New prognostic biomarkers, and bio-signatures, are urgently needed to facilitate a precision medicine-based approach to more effectively treat patients with high-grade serous ovarian cancer (HGSC). In this study, we analysed the expression patterns of a series of candidate protein biomarkers. METHODS: The panel of markers which included MyD88, TLR4, MAD2, PR, OR, WT1, p53, p16, CD10 and Ki67 was assessed using immunohistochemistry in a tissue microarray (TMA) cohort of n = 80 patients, composed of stage 3-4 HGSCs. Each marker was analysed for their potential to predict both overall survival (OS) and progression-free survival (PFS). RESULTS: TLR4 and p53 were found to be individually predictive of poorer PFS (Log Rank, p = 0.017, p = 0.030 respectively). Cox regression analysis also identified high p53 and TLR4 expression as prognostic factors for reduced PFS (p53; HR=1.785, CI=1.036-3.074, p = 0.037 and TLR4; HR=2.175, CI=1.112-4.253, p = 0.023). Multivariate forward conditional Cox regression analysis, examining all markers, identified a combined signature composed of p53 and TLR4 as prognostic for reduced PFS (p = 0.023). CONCLUSION: Combined p53 and TLR4 marker assessment may help to aid treatment stratification for patients diagnosed with advanced-stage HGSC.

Altered endosomal-lysosomal biogenesis in melanoma.

Cutaneous melanoma is the deadliest form of skin neoplasm and its high mortality rates could be averted by early accurate detection. While the detection of melanoma is currently reliant upon melanin visualisation, research into melanosome biogenesis, as a key driver of pathogenesis, has not yielded technology that can reliably distinguish between atypical benign, amelanotic and melanotic lesions. The endosomal-lysosomal system has important regulatory roles in cancer cell biology, including a specific functional role in melanosome biogenesis. Herein, the involvement of the endosomal-lysosomal system in melanoma was examined by pooled secondary analysis of existing gene expression datasets. A set of differentially expressed endosomal-lysosomal genes was identified in melanoma, which were interconnected by biological function. To illustrate the protein expression of the dysregulated genes, immunohistochemistry was performed on samples from patients with cutaneous melanoma to reveal candidate markers. This study demonstrated the dysregulation of Syntenin-1, Sortilin and Rab25 may provide a differentiating feature between cutaneous melanoma and squamous cell carcinoma, while IGF2R may indicate malignant propensity in these skin cancers.

Appl1, Sortilin and Syndecan-1 immunohistochemistry on intraductal carcinoma of the prostate provides evidence of retrograde spread.

The presence of intraductal carcinoma of the prostate (IDCP) correlates with late-stage disease and poor outcomes for patients with prostatic adenocarcinoma, but the accurate and reliable staging of disease severity remains challenging. Immunohistochemistry (IHC) has been utilised to overcome problems in assessing IDCP morphology, but the current markers have only demonstrated limited utility in characterising the complex biology of this lesion. In a retrospective study of a cohort of patients who had been diagnosed with IDCP, we utilised IHC on radical prostatectomy sections with a biomarker panel of Appl1, Sortilin and Syndecan-1, to interpret different architectural patterns and to explore the theory that IDCP occurs from retrograde spread of high-grade invasive prostatic adenocarcinoma. Cribriform IDCP displayed strong Appl1, Sortilin and Syndecan-1 labelling patterns, while solid IDCP architecture had high intensity Appl1 and Syndecan-1 labelling, but minimal Sortilin labelling. Notably, the expression pattern of the biomarker panel in regions of IDCP was similar to that of adjacent invasive prostatic adenocarcinoma, and also comparable to prostate cancer showing perineural and vascular invasion. The Appl1, Sortilin, and Syndecan-1 biomarker panel in IDCP provides evidence for the model of retrograde spread of invasive prostatic carcinoma into ducts/acini, and supports the inclusion of IDCP into the five-tier Gleason grading system.

Prediction of Prostate Cancer Biochemical and Clinical Recurrence Is Improved by IHC-Assisted Grading Using Appl1, Sortilin and Syndecan-1.

Gleason scoring is used within a five-tier risk stratification system to guide therapeutic decisions for patients with prostate cancer. This study aimed to compare the predictive performance of routine H&E or biomarker-assisted ISUP (International Society of Urological Pathology) grade grouping for assessing the risk of biochemical recurrence (BCR) and clinical recurrence (CR) in patients with prostate cancer. This retrospective study was an assessment of 114 men with prostate cancer who provided radical prostatectomy samples to the Australian Prostate Cancer Bioresource between 2006 and 2014. The prediction of CR was the primary outcome (median time to CR 79.8 months), and BCR was assessed as a secondary outcome (median time to BCR 41.7 months). The associations of (1) H&E ISUP grade groups and (2) modified ISUP grade groups informed by the Appl1, Sortilin and Syndecan-1 immunohistochemistry (IHC) labelling were modelled with BCR and CR using Cox proportional hazard approaches. IHC-assisted grading was more predictive than H&E for BCR (C-statistic 0.63 vs. 0.59) and CR (C-statistic 0.71 vs. 0.66). On adjusted analysis, IHC-assisted ISUP grading was independently associated with both outcome measures. IHC-assisted ISUP grading using the biomarker panel was an independent predictor of individual BCR and CR. Prospective studies are needed to further validate this biomarker technology and to define BCR and CR associations in real-world cohorts.

"There's a big tag on my head": exploring barriers to treatment seeking with women who use methamphetamine in Sydney, Australia.

BACKGROUND: Australia has a high prevalence of regular use of methamphetamine. While half of people who use methamphetamine regularly are women, they make up only one third of people seeking treatment for methamphetamine use disorder. There is a lack of qualitative research into the facilitators and barriers to treatment for women who use methamphetamine regularly. The study seeks a better understanding of the experiences and treatment preferences of women who use methamphetamine, to inform person-centred changes in practice and policy that break down barriers to treatment. METHODS: We conducted semi-structured interviews with 11 women who frequently use methamphetamine (at least once a week), and who are not engaged in treatment. Women were recruited from health services surrounding a stimulant treatment centre at an inner-city hospital. Participants were asked about their methapmhetamine use and health service needs and preferences. Thematic analysis was completed using Nvivo® software. RESULTS: Three themes were developed from participants' responses around experiences of regular methamphetamine use and treatment needs: 1. Resistance of stigmatised identity including dependence; 2. Interpersonal violence; 3. Institutionalised stigma. A fourth set of themes on service delivery preferences were also elicited, including continuity of care, integrated health care, and provision of non-judgmental services. CONCLUSION: Gender-inclusive health care services for people who use methamphetamine should actively work to address stigma, support a relational approach to assessment and treatment, and seek to provide structurally competent health care that is trauma and violence informed, and integrated with other services. Findings may also have application for substance use disorders other than methamphetamine.

Circulating tumour cells: The Good, the Bad and the Ugly.

This review is an overview of the current knowledge regarding circulating tumour cells (CTCs), which are potentially the most lethal type of cancer cell, and may be a key component of the metastatic cascade. The clinical utility of CTCs (the "Good"), includes their diagnostic, prognostic, and therapeutic potential. Conversely, their complex biology (the "Bad"), including the existence of CD45+/EpCAM+ CTCs, adds insult to injury regarding their isolation and identification, which in turn hampers their clinical translation. CTCs are capable of forming microemboli composed of both non-discrete phenotypic populations such as mesenchymal CTCs and homotypic and heterotypic clusters which are poised to interact with other cells in the circulation, including immune cells and platelets, which may increase their malignant potential. These microemboli (the "Ugly") represent a prognostically important CTC subset, however, phenotypic EMT/MET gradients bring additional complexities to an already challenging situation.

Aberrant protein expression of Appl1, Sortilin and Syndecan-1 during the biological progression of prostate cancer.

Diagnosis and assessment of patients with prostate cancer is dependent on accurate interpretation and grading of histopathology. However, morphology does not necessarily reflect the complex biological changes occurring in prostate cancer disease progression, and current biomarkers have demonstrated limited clinical utility in patient assessment. This study aimed to develop biomarkers that accurately define prostate cancer biology by distinguishing specific pathological features that enable reliable interpretation of pathology for accurate Gleason grading of patients. Online gene expression databases were interrogated and a pathogenic pathway for prostate cancer was identified. The protein expression of key genes in the pathway, including adaptor protein containing a pleckstrin homology (PH) domain, phosphotyrosine-binding (PTB) domain, and leucine zipper motif 1 (Appl1), Sortilin and Syndecan-1, was examined by immunohistochemistry (IHC) in a pilot study of 29 patients with prostate cancer, using monoclonal antibodies designed against unique epitopes. Appl1, Sortilin, and Syndecan-1 expression was first assessed in a tissue microarray cohort of 112 patient samples, demonstrating that the monoclonal antibodies clearly illustrate gland morphologies. To determine the impact of a novel IHC-assisted interpretation (the utility of Appl1, Sortilin, and Syndecan-1 labelling as a panel) of Gleason grading, versus standard haematoxylin and eosin (H&E) Gleason grade assignment, a radical prostatectomy sample cohort comprising 114 patients was assessed. In comparison to H&E, the utility of the biomarker panel reduced subjectivity in interpretation of prostate cancer tissue morphology and improved the reliability of pathology assessment, resulting in Gleason grade redistribution for 41% of patient samples. Importantly, for equivocal IHC-assisted labelling and H&E staining results, the cancer morphology interpretation could be more accurately applied upon re-review of the H&E tissue sections. This study addresses a key issue in the field of prostate cancer pathology by presenting a novel combination of three biomarkers and has the potential to transform clinical pathology practice by standardising the interpretation of the tissue morphology.

Pitfalls in Cutaneous Melanoma Diagnosis and the Need for New Reliable Markers.

Cutaneous melanoma is one of the most aggressive forms of skin cancer, with the development of advanced stage disease resulting in a high rate of patient mortality. Accurate diagnosis of melanoma at an early stage is essential to improve patient outcomes, as this enables treatment before the cancer has metastasised. Histopathologic analysis is the current gold standard for melanoma diagnosis, but this can be subjective due to discordance in interpreting the morphological heterogeneity in melanoma and other skin lesions. Immunohistochemistry (IHC) is sometimes employed as an adjunct to conventional histology, but it remains occasionally difficult to distinguish some benign melanocytic lesions and melanoma. Importantly, the complex morphology and lack of specific biomarkers that identify key elements of melanoma pathogenesis can make an accurate confirmation of diagnosis challenging. We review the diagnostic constraints of melanoma heterogeneity and discuss issues with interpreting routine histology and problems with current melanoma markers. Innovative approaches are required to find effective biomarkers to enhance patient management.

Evaluation of a mental health screening tool using cross-sectional surveys in a workplace setting.

OBJECTIVES: The Brief Health Check (BHC) is a health screener used by the Get Healthy at Work programme, which identifies workers with chronic disease risk and provides them with advice and referrals to support services. The BHC was revised to include mental health to provide a holistic approach to workplace health. This study aimed to evaluate the acceptability and appropriateness of the revised BHC by comparing the results around psychological distress and future risk with previous research, and a participant feedback survey. METHOD: Data collection took place between October 2018 and May 2019. The study used data that were collected as part of programme delivery, as well as a participant feedback survey that was administered after the health check was completed. RESULTS: BHCs were completed by n=912 workers, out of which, n=238 completed the feedback survey. The mean Distress Questionnaire 5 score was 10.5, and 10% of participants met the threshold for 'high' future risk. The feedback survey revealed that the majority of participants found the mental health advice to be useful (76%), agreed with their mental health distress and risk ratings (92%-94%) and most intended on using the referred services (62%-68%). CONCLUSION: The findings around mental health risk were comparable to previous findings in employed samples. The inclusion of mental health assessments, advice and referral pathways into the BHC was found to be acceptable and the subsequent referrals were appropriate, indicating that this approach could be scaled up and implemented to help address worker's mental ill health.

One-third of people who inject drugs are at risk of incomplete treatment for Staphylococcus aureus bacteraemia: a retrospective medical record review.

Staphylococcus aureus bacteraemia (SAB) is often a complication of injecting drug use, and is associated with high morbidity and mortality. This article reports the first audit of inpatient parenteral treatment of SAB completion among people who inject drugs (PWID) in Australia. Of 198 patients admitted with SAB, 106 were analysed. Twelve PWID had an inpatient stay <14 days compared with seven non-PWID (34% vs 10%; P=0.002). Sixteen PWID experienced discharge against medical advice compared with zero non-PWID (46% vs 0%; P<0.001). Re-admission to hospital within 28 days was 2.5 times greater among PWID than non-PWID (31% vs 15%; P=0.026). Methadone dose <60 mg/day was associated with premature discharge in opioid-dependent PWID receiving methadone (n=21, 100% vs 31%; P=0.012).

Novel and rare forms of oesophagitis.

Our understanding of inflammatory diseases of the gastrointestinal tract, including those of the oesophagus, has expanded in recent years. Once attributed almost exclusively to gastro-oesophageal reflux disease or infection, it is now recognised that oesophagitis may occur due to a variety of distinct disease entities. Many of these conditions cause debilitating and persistent symptoms, impacting upon quality of life and necessitating ongoing surveillance and treatment. This review will consider the clinical, endoscopic and histopathological features of these novel and rare forms of oesophagitis.

Smoke-free hospital grounds.

This study investigated whether the implementation of a multicomponent intervention project could improve compliance with the New South Wales (NSW) Health smoke-free healthcare policy. Environmental interventions were implemented on the hospital grounds for a 12-week period. Compliance was measured by a pre- and postintervention observational count of smokers on the hospital grounds. After implementation, there was a significant 73% reduction in people smoking on the hospital grounds, indicating improved compliance with the NSW smoke-free healthcare policy through the use of a non-punitive multicomponent intervention.

Continuous glucose monitoring guided insulin therapy is associated with improved clinical outcomes in cystic fibrosis-related diabetes.

INTRODUCTION: Continuous glucose monitoring (CGM) allows assessment of day to day glycaemic excursions and detects early glucose handling abnormalities that may not be apparent on oral glucose tolerance testing (OGTT). However, there is little published evidence as to whether these early dysglycaemic changes are amenable to treatment. We present outcomes following CGM guided insulin initiation at our centre. METHODS: Adults without a prior diagnosis of cystic fibrosis related diabetes (CFRD) whom underwent >72 h CGM at our adult CF centre were included in the study. Clinical outcomes including weight and pulmonary function changes over the next 12 months were compared between groups based on CGM results and subsequent management. RESULTS: CGM profiles for 59 patients were analysed. Insulin was commenced in 37 patients who had evidence of hyperglycaemia on CGM. Significant improvements in mean [95% confidence intervals] forced expiratory volume in 1 s (FEV1) (+4.3% predicted [1.06-7.48], p = 0.01) and weight (+1.2 kg [0.32-2.15], p = 0.01) were observed at 3 months in the insulin group. Annual rate of pulmonary function decline was also improved following insulin initiation. CONCLUSION: Insulin treatment targeted towards glycaemic excursions seen on CGM is associated with improvements in lung function and weight with subsequent reduced pulmonary function decline.