Unravelling the biological and clinical challenges of circulating tumour cells in epithelial ovarian carcinoma.

Epithelial ovarian carcinoma (EOC) is the eighth most common cancer in women and the leading cause of gynaecological cancer death, predominantly due to the absence of effective screening tools, advanced stage at diagnosis, and high rates of recurrence. Circulating tumour cells (CTCs), are a rare subset of tumour cells that disseminate from a tumour and migrate into the circulation, play a pivotal role in the metastatic cascade, and therefore hold promise as biomarkers for disease monitoring and prognostication. Exploring CTCs from liquid biopsies is an appealing approach for research and clinical practice, given it is minimally invasive, facilitates serial sampling and enables the capture of the entire spectrum of cancer cells circulating in the blood. The prognostic utility of CTC enumeration has been FDA-approved for clinical use in metastatic breast, prostate, and colorectal cancers. However, the unique biology of EOC, discussed herein, compounds the detection and characterisation complexities already inherent in CTC research, consequently hindering progress towards clinical applications. The aim of this review is to provide an overview of both the biological and clinical challenges encountered in harnessing the power of CTCs in EOC.

Social disconnection correlates of a "Wish to Die" among a large community-dwelling cohort of older adults.

Introduction: Social disconnection and deaths by suicide among older adults are both important public health concerns, particularly in the context of ageing populations. The association between death ideation and behaviours, and social disconnection is well established and both functional and structural social relationships have been identified as predictive of suicide-related thoughts and behaviours. The "Wish to Die" (WTD) involves thoughts of or wishes for one's own death or that one would be better off dead is a commonly used indicator to capture death ideation. It has been shown to be as predictive as active ideation of future suicide attempt. Methods: Data were from a large cohort of community-dwelling older adults aged 50+, The Irish Longitudinal Study on Ageing (TILDA). Cross-sectional analyses of the association between numerous markers of social disconnection (loneliness, social isolation, living alone, marital status, social participation, volunteering, and attending religious service) and WTD were conducted. Results: Multiple markers of social disconnection were associated with a "wish to die". However, loneliness was the strongest risk factor while attendance of religious services was an important protective behaviour. Discussion: There is a strong association between social disconnection and a WTD among older adults. There is also a strong association between depression and a WTD, while attending religious services or similarly prosocial settings may protect older adults from experiencing negative thoughts about dying.

A comparative study of circulating tumor cell isolation and enumeration technologies in lung cancer.

Circulating tumor cells (CTCs) have potential as diagnostic, prognostic, and predictive biomarkers in solid tumors. Despite Food and Drug Administration (FDA) approval of CTC devices in various cancers, the rarity and heterogeneity of CTCs in lung cancer make them technically challenging to isolate and analyze, hindering their clinical integration. Establishing a consensus through comparative analysis of different CTC systems is warranted. This study aimed to evaluate seven different CTC enrichment methods across five technologies using a standardized spike-in protocol: the CellMag™ (EpCAM-dependent enrichment), EasySep™ and RosetteSep™ (blood cell depletion), and the Parsortix® PR1 and the new design Parsortix® Prototype (PP) (size- and deformability-based enrichment). The Parsortix® systems were also evaluated for any differences in recovery rates between cell harvest versus in-cassette staining. Healthy donor blood (5 mL) was spiked with 100 fluorescently labeled EpCAMhigh H1975 cells, processed through each system, and the isolation efficiency was calculated. The CellMag™ had the highest recovery rate (70 ± 14%), followed by Parsortix® PR1 in-cassette staining, while the EasySep™ had the lowest recovery (18 ± 8%). Additional spike-in experiments were performed with EpCAMmoderate A549 and EpCAMlow H1299 cells using the CellMag™ and Parsortix® PR1 in-cassette staining. The recovery rate of CellMag™ significantly reduced to 35 ± 14% with A549 cells and 1 ± 1% with H1299 cells. However, the Parsortix® PR1 in-cassette staining showed cell phenotype-independent and consistent recovery rates among all lung cancer cell lines: H1975 (49 ± 2%), A549 (47 ± 10%), and H1299 (52 ± 10%). Furthermore, we demonstrated that the Parsortix® PR1 in-cassette staining method is capable of isolating heterogeneous single CTCs and cell clusters from patient samples. The Parsortix® PR1 in-cassette staining, capable of isolating different phenotypes of CTCs as either single cells or cell clusters with consistent recovery rates, is considered optimal for CTC enrichment for lung cancer, albeit needing further optimization and validation.

Switching from Dose-Intensified intravenous to SubCutaneoUS infliximab in Inflammatory Bowel Disease (DISCUS-IBD): protocol for a multicentre randomised controlled trial.

INTRODUCTION: A substantial proportion of patients with inflammatory bowel disease (IBD) on intravenous infliximab require dose intensification. Accessing additional intravenous infliximab is labour-intensive and expensive, depending on insurance and pharmaceutical reimbursement. Observational data suggest that subcutaneous infliximab may offer a convenient and safe alternative to maintain disease remission in patients requiring dose-intensified infliximab. A prospective, controlled trial is required to confirm that subcutaneous infliximab is as effective as dose-intensified intravenous infliximab, to identify predictors of disease flare and to establish the role of subcutaneous infliximab therapeutic drug monitoring. METHODS AND ANALYSIS: The DISCUS-IBD trial is an investigator-initiated, prospective, multicentre, randomised, open-label non-inferiority study comparing the rate of disease flares in participants randomised to continue dose-intensified intravenous infliximab to those switched to subcutaneous infliximab after 48 weeks. Participants are adult patients with IBD in sustained corticosteroid-free remission on any regimen of dose-intensified infliximab up to a maximum of 10 mg/kg 4-weekly intravenously. Participants allocated to intravenous infliximab will continue infliximab at the same dose-intensified regimen they were receiving at study enrolment. Subcutaneous infliximab dosing will be stratified by prior intravenous infliximab dosing. Clinical (Harvey-Bradshaw Index, partial Mayo score), biochemical (C reactive protein, faecal calprotectin), pharmacokinetic (drug-level±antidrug antibodies) and qualitative data are collected 12-weekly until study conclusion at week 48. 13 sites across Australia will participate in recruitment to reach a calculated sample size of 120 participants. ETHICS AND DISSEMINATION: Multisite ethics approval was obtained from the Health District Human Research Ethics Committee (HREC) at The Alfred Hospital under a National Mutual Acceptance (NMA) agreement (HREC/90559/Alfred-2022; Local Reference: Project 618/22, version 1.6, 2 March 2023). Findings will be reported at national and international gastroenterology meetings and published in peer-reviewed journals. DISCUS-IBD was prospectively registered with the Australian and New Zealand Clinical Trials Registry (ANZCTR) prior to commencing recruitment. TRIAL REGISTRATION NUMBER: ACTRN12622001458729.

Effects of Thiopurine Withdrawal on Vedolizumab-Treated Patients With Ulcerative Colitis: A Randomized Controlled Trial.

BACKGROUND & AIMS: The impact of thiopurine de-escalation while on vedolizumab versus continuing thiopurine therapy in ulcerative colitis (UC) is unclear. We aimed to determine the effect of thiopurine withdrawal for patients with UC in remission on vedolizumab. METHODS: This multicenter randomized controlled trial recruited UC patients on vedolizumab 300 mg intravenously every 8 weeks and a thiopurine. Patients in steroid-free clinical remission for ≥6 months and endoscopic remission/improvement (Mayo endoscopic subscore ≤1) were randomized 2:1 to withdraw or continue thiopurine. Primary outcome was comparing week 48 vedolizumab trough concentrations. Secondary outcomes were clinical relapse (partial Mayo score ≥3 and fecal calprotectin >150 µg/g or increase in Mayo endoscopic subscore ≥1 from baseline), fecal calprotectin remission (<150 µg/g), C-reactive protein remission (<5 mg/L), centrally read endoscopic remission (Mayo endoscopic subscore = 0), histologic remission (Nancy index = 0), histo-endoscopic remission, and adverse events. RESULTS: In total, 62 patients were randomized to continue (n = 20) or withdraw (n = 42) thiopurine. At week 48, vedolizumab trough concentrations were not significantly different between continue and withdrawal groups (14.7 µg/mL, interquartile rate [IQR], 12.3-18.5 µg/mL versus 15.9 µg/mL, IQR, 10.1-22.7 µg/mL, respectively, P = 0.36). The continue group had significantly higher fecal calprotectin remission (95.0%, 19/20 versus 71.4%, 30/42; P = .03), histologic remission (80.0%, 16/20 versus 48.6%, 18/37; P = .02), and histo-endoscopic remission (75.0%, 15/20 versus 32.4%, 12/37; P = .002) than the withdrawal group. Histologic activity (hazard ratio [HR], 15.5; 95% confidence interval [CI], 1.6-146.5; P = .02) and prior anti-tumor necrosis factor exposure (HR, 6.5; 95% CI, 1.3-33.8; P = .03) predicted clinical relapse after thiopurine withdrawal. CONCLUSIONS: Thiopurine withdrawal did not affect vedolizumab trough concentrations. However, it may increase fecal calprotectin, histologic, and histo-endoscopic activity. Histologic activity and prior anti-tumor necrosis factor exposure may predict disease relapse on thiopurine withdrawal for patients using vedolizumab for UC. Australian and New Zealand Trial Registry, number ACTRN12618000812291.

Frailty on the island of Ireland: evidence from the NICOLA and TILDA studies.

BACKGROUND: Aimed to compare the prevalence, characteristics, and associated mortality risk of frailty in Northern Ireland (NI) and the Republic of Ireland (ROI). METHODS: Secondary analysis of the first wave of two nationally representative cohorts, the Northern Ireland Cohort for the Longitudinal Study of Ageing or NICOLA study (N = 8504) and the Irish Longitudinal Study on Ageing or TILDA study (N = 8504). Frailty was assessed using a harmonized accumulation deficits frailty index (FI) containing 30 items. FI scores classified individuals as non-frail (<0.10), pre-frail (0.10-0.24) and frail (≥0.25). Linkage to respective administrative data sources provided mortality information with a follow-up time of 8 years. RESULTS: The prevalence of frailty was considerably higher in NI compared with the ROI (29.0% compared with 15.0%), though pre-frailty was slightly lower (35.8% and 37.3%, respectively). Age, female sex, and lower socio-economic status were consistently associated with a higher likelihood of both pre-frailty and frailty. In the pooled analysis, both frailty and pre-frailty were higher in NI (RR = 2.68, 95% CIs 2.45, 2.94 and RR = 1.30, 95% CIs 1.21, 1.40, respectively). Frailty was associated with an increased mortality risk in both cohorts, even after full adjustment for all other characteristics, being marginally higher in TILDA than in NICOLA (HR = 2.43, 95% CIs 2.03, 2.91 vs. HR = 2.31, 95% CIs 1.90, 2.79). CONCLUSIONS: Frailty is a major public health concern for both jurisdictions. Further research and monitoring are required to elucidate why there is a higher prevalence in NI and to identify factors in early life that may be driving these differences.

Plasminogen activator inhibitor 1 is associated with high-grade serous ovarian cancer metastasis and is reduced in patients who have received neoadjuvant chemotherapy.

Introduction: High-grade serous ovarian cancer (HGSOC) is the most prevalent and deadliest subtype of epithelial ovarian cancer (EOC), killing over 140,000 people annually. Morbidity and mortality are compounded by a lack of screening methods, and recurrence is common. Plasminogen-activator-inhibitor 1 (PAI-1, the protein product of SERPIN E1) is involved in hemostasis, extracellular matrix (ECM) remodeling, and tumor cell migration and invasion. Overexpression is associated with poor prognosis in EOC. Platelets significantly increase PAI-1 in cancer cells in vitro, and may contribute to the hematogenous metastasis of circulating tumor cells (CTCs). CTCs are viable tumor cells that intravasate and travel through the circulation-often aided by platelets - with the potential to form secondary metastases. Here, we provide evidence that PAI-1 is central to the platelet-cancer cell interactome, and plays a role in the metastatic cascade. Methods: SK-OV-3 cells where PAI-1 had been silenced, treated with healthy donor platelets, and treated with platelet-conditioned medium were used as an in vitro model of metastatic EOC. Gene expression analysis was performed using RNA-Seq data from untreated cells and cells treated with PAI-1 siRNA or negative control, each with and without platelets. Four cohorts of banked patient plasma samples (n = 239) were assayed for PAI-1 by ELISA. Treatment-naïve (TN) whole blood (WB) samples were evaluated for CTCs in conjunction with PAI-1 evaluation in matched plasma. Results and discussion: Significant phenotypic changes occurring when PAI-1 was silenced and when platelets were added to cells were reflected by RNA-seq data, with PAI-1 observed to be central to molecular mechanisms of EOC metastasis. Increased proliferation was observed in cells treated with platelets. Plasma PAI-1 significantly correlated with advanced disease in a TN cohort, and was significantly reduced in a neoadjuvant chemotherapy (NACT) cohort. PAI-1 demonstrated a trend towards significance in overall survival (OS) in the late-stage TN cohort, and correlation between PAI-1 and neutrophils in this cohort was significant. 72.7% (16/22) of TN patients with plasma PAI-1 levels higher than OS cutoff were CTC-positive. These data support a central role for PAI-1 in EOC metastasis, and highlight PAI-1's potential as a biomarker, prognostic indicator, or gauge of treatment response in HGSOC.

Adalimumab Drug Levels at Secondary Loss of Response Do Not Predict Response to Dose-intensification in Crohn's Disease: A Retrospective, International Multicenter Study.

BACKGROUND: The exposure-response relationship is less established for adalimumab (ADA) compared with infliximab in inflammatory bowel disease (IBD). Evidence supporting therapeutic drug monitoring post dose-intensification of ADA is limited. We aimed to explore the association between ADA drug levels and Crohn's disease (CD) activity at loss of response, and at 6 and 12 months post dose-intensification. METHODS: We performed a retrospective study of adult patients with CD receiving dose-intensified weekly ADA following secondary loss of response at 3 tertiary centers across 5 years. ADA trough levels were analyzed using a drug-sensitive enzyme-linked immunosorbent assay at loss of response, and 6 and 12 months after dose-intensification. Rates of clinical remission, objective remission (C-reactive protein <5 mg/L, fecal calprotectin <150 µg/g, or absence of inflammation at endoscopy or imaging), and ADA failure were investigated. RESULTS: A total of 131 CD patients were included, with a median disease duration of 9 (interquartile range, 4-17) years. 51% were biologic exposed prior to ADA and 50% received concomitant immunomodulators. Baseline drug levels measured at secondary loss of response did not discriminate between subsequent responders and non-responders at either 6 or 12 months post dose-intensification. However, both higher drug levels at 6 and 12 months and a higher increment from baseline were associated with improved outcomes. On receiver-operating characteristic analyses, post-escalation ADA drug levels >10.7 µg/mL (area under the receiver-operating characteristic curve [AUROC], 0.66; P = .013) and >10.9 µg/mL (AUROC, 0.67; P = .032) were associated with objective remission at 6 and 12 months, respectively. CONCLUSIONS: Drug levels following dose-intensification rather than at the time of secondary loss of response were associated with subsequent CD remission.

Literature supporting therapeutic drug monitoring at secondary loss of response and post dose-intensification of adalimumab is limited. Adalimumab drug levels following dose-intensification rather than at the time of secondary loss of response are associated with subsequent Crohn's disease remission.

You & Me: Test and Treat study protocol for promoting COVID-19 test and treatment access to underserved populations.

BACKGROUND: Infections and deaths from the COVID-19 pandemic have disproportionately affected underserved populations. A community-engaged approach that supports decision making around safe COVID-19 practices is needed to promote equitable access to testing and treatment. You & Me: Test and Treat (YMTT) will evaluate a systematic and scalable community-engaged protocol that provides rapid access to COVID-19 at-home tests, education, guidance on next steps, and information on local resources to facilitate treatment in underserved populations. METHODS: This direct-to-participant observational study will distribute at-home, self-administered, COVID-19 testing kits to people in designated communities. YMTT features a Public Health 3.0 framework and Toolkit prescribing a tiered approach to community engagement. We will partner with two large community organizations, Merced County United Way (Merced County, CA) and Pitt County Health Department (Pitt County, NC), who will coordinate up to 20 local partners to distribute 40,000 COVID tests and support enrollment, consenting, and data collection over a 15-month period. Participants will complete baseline questions about their demographics, experience with COVID-19 infection, and satisfaction with the distribution event. Community partners will also complete engagement surveys. In addition, participants will receive guidance on COVID-19 mitigation and health-promoting resources, and accessible and affordable therapeutics if they test positive for COVID-19. Data collection will be completed using a web-based platform that enables creation and management of electronic data capture forms. Implementation measures include evaluating 1) the Toolkit as a method to form community-academic partnerships for COVID-19 test access, 2) testing results, and 3) the efficacy of a YMTT protocol coupled with local resourcing to provide information on testing, guidance, treatment, and links to resources. Findings will be used to inform innovative methods to address community needs in public health research that foster cultural relevance, improve research quality, and promote health equity. DISCUSSION: This work will promote access to COVID-19 testing and treatment for underserved populations by leveraging a community-engaged research toolkit. Future dissemination of the toolkit can support effective community-academic partnerships for health interventions in underserved settings. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05455190 . Registered 13 July 2022.

Hospital-presenting self-harm among older adults living in Ireland: a 13-year trend analysis from the National Self-Harm Registry Ireland.

OBJECTIVES: To examine trends in rates of self-harm among emergency department (ED) presenting older adults in Ireland over a 13-year period. DESIGN: Population-based study using data from the National Self-Harm Registry Ireland. SETTING: National hospital EDs. PARTICIPANTS: Older adults aged 60 years and over presenting with self-harm to hospital EDs in Ireland between January 1, 2007 and December 31, 2019. MEASUREMENTS: ED self-harm presentations. RESULTS: Between 2007 and 2019, there were 6931 presentations of self-harm in older adults. The average annual self-harm rate was 57.8 per 100,000 among older adults aged 60 years and over. Female rates were 1.1 times higher compared to their male counterparts (61.4 vs 53.9 per 100,000). Throughout the study time frame, females aged 60-69 years had the highest rates (88.1 per 100,000), while females aged 80 years and over had the lowest rates (18.7 per 100,000). Intentional drug overdose was the most commonly used method (75.5%), and alcohol was involved in 30.3% of presentations. Between the austerity and recession years (2007-2012), self-harm presentations were 7% higher compared to 2013-2019 (incidence rate ratio (IRR): 1.07 95% CI 1.02-1.13, p = 0.01). CONCLUSIONS: Findings indicate that self-harm in older adults remains a concern with approximately 533 presentations per year in Ireland. While in younger age groups, females report higher rates of self-harm, this gender difference was reversed in the oldest age group (80 years and over), with higher rates of self-harm among males. Austerity/recession years (2007-2012) had significantly higher rates of self-harm compared to subsequent years.

Formal health care costs among older people in Ireland: methods and estimates using The Irish Longitudinal Study on Ageing (TILDA).

Background: Reliable data on health care costs in Ireland are essential to support planning and evaluation of services. New unit costs and high-quality utilisation data offer the opportunity to estimate individual-level costs for research and policy. Methods: Our main dataset was The Irish Longitudinal Study on Ageing (TILDA). We used participant interviews with those aged 55+ years in Wave 5 (2018) and all end-of-life interviews (EOLI) to February 2020. We weighted observations by age, sex and last year of life at the population level. We estimated total formal health care costs by combining reported usage in TILDA with unit costs (non-acute care) and public payer reimbursement data (acute hospital admissions, medications). All costs were adjusted for inflation to 2022, the year of analysis. We examined distribution of estimates across the population, and the composition of costs across categories of care, using descriptive statistics. We identified factors associated with total costs using generalised linear models. Results: There were 5,105 Wave 5 observations, equivalent at the population level to 1,207,660 people aged 55+ years and not in the last year of life, and 763 EOLI observations, equivalent to 28,466 people aged 55+ years in the last year of life. Mean formal health care costs in the weighted sample were EUR 8,053; EUR 6,624 not in the last year of life and EUR 68,654 in the last year of life. Overall, 90% of health care costs were accounted for by 20% of users. Multiple functional limitations and proximity to death were the largest predictors of costs. Other factors that were associated with outcome included educational attainment, entitlements to subsidised care and serious chronic diseases. Conclusions: Understanding the patterns of costs, and the factors associated with very high costs for some individuals, can inform efforts to improve patient experiences and optimise resource allocation.

Evaluation of a 3-Item Health Index in Predicting Mortality Risk: A 12-Year Follow-Up Study.

This study was carried out using a large cohort (N = 4265; 416 deceased) of older, community-dwelling adults from The Irish Longitudinal Study on Ageing (TILDA). The study compared the performance of a new 3-item health index (HI) with two existing measures, the 32-item frailty index (FI) and the frailty phenotype (FP), in predicting mortality risk. The HI was based on the objective measurement of resting-state systolic blood pressure sample entropy, sustained attention reaction time performance, and usual gait speed. Mortality data from a 12-year follow up period were analyzed using Cox proportional regression. All data processing was performed using MATLAB and statistical analysis using STATA 15.1. The HI showed good discriminatory power (AUC = 0.68) for all-cause mortality, similar to FI (AUC = 0.68) and superior to FP (AUC = 0.60). The HI classified participants into Low-Risk (84%), Medium-Risk (15%), and High-Risk (1%) groups, with the High-Risk group showing a significant hazard ratio (HR) of 5.91 in the unadjusted model and 2.06 in the fully adjusted model. The HI also exhibited superior predictive performance for cardiovascular and respiratory deaths (AUC = 0.74), compared with FI (AUC = 0.70) and FP (AUC = 0.64). The HI High-Risk group had the highest HR (15.10 in the unadjusted and 5.61 in the fully adjusted models) for cardiovascular and respiratory mortality. The HI remained a significant predictor of mortality even after comprehensively adjusting for confounding variables. These findings demonstrate the effectiveness of the 3-item HI in predicting 12-year mortality risk across different causes of death. The HI performed similarly to FI and FP for all-cause mortality but outperformed them in predicting cardiovascular and respiratory deaths. Its ability to classify individuals into risk groups offers a practical approach for clinicians and researchers. Additionally, the development of a user-friendly MATLAB App facilitates its implementation in clinical settings. Subject to external validation in clinical research settings, the HI can be more useful than existing frailty measures in the prediction of cardio-respiratory risk.

An investigation of what protective individual- and community-level factors are associated with life satisfaction in middle-aged and older family carers in Ireland.

Background: Family care plays an essential role in providing care in society. However, caring can cause stress, and mental and physical responses to caring vary widely. Different outcomes for carers may reflect different approaches or adaptability to caring and their ability to maintain or recover their mental health and wellbeing following an adverse event (psychosocial resilience). We aim to identify factors that may promote psychosocial resilience, conceptualized as maintaining or recovering subjective wellbeing and operationalized as satisfaction with life, among carers. Methods: Data were from 6 Waves (2009-2021) of The Irish Longitudinal Study on Aging (TILDA), a prospective biennial nationally representative longitudinal study of older adults aged ≥50 in Ireland. Family caregiving was assessed in Waves 3-6. Participants were asked if they cared for someone, their relationship to the recipient, and the number of hours per week that they provided care. We used growth mixture modeling to identify latent trajectories of satisfaction with life (SWL) before and after caring was initiated. Regression modeling was then used to identify protective factors (at the individual, family, and community levels) associated with resilient trajectories. Results: Overall, 731 (12.2%) participants became carers during follow-up. We identified three trajectories in SWL in carers following initiation of caring, namely, Resilient-Stable (81%), Resilient-Recovery (12%), and Non-recovery (6%). Membership in Resilient-Stable and Resilient-Recovery trajectories was associated with fewer depressive symptoms (OR = 0.86, 95% CI 0.78, 0.94) and chronic conditions (OR = 0.21, 95% CI 0.06, 0.74), larger social networks (OR = 2.03, 95% CI 1.06, 3.86), more close friends and relatives (OR = 1.15, 95% CI 1.01, 1.32), and caring for someone other than a child (OR = 0.19, 95% CI 0.07, 0.51) compared to the Non-recovery group. Conclusion: Becoming a family carer was associated with a decline in SWL over time in some carers. However, most carers either did not experience a decline in SWL or recovered their SWL over time. We found that both individual and community-level supports may be protective for carers' wellbeing. These results will inform the priorities for social and community-level services and support for older carers and contribute to the design of new projects and programs to meet these needs.

Dynamic interplay between sortilin and syndecan-1 contributes to prostate cancer progression.

Prostate cancer (PCa) development and progression relies on the programming of glucose and lipid metabolism, and this involves alterations in androgen receptor expression and signalling. Defining the molecular mechanism that underpins this metabolic programming will have direct significance for patients with PCa who have a poor prognosis. Here we show that there is a dynamic balance between sortilin and syndecan-1, that reports on different metabolic phenotypes. Using tissue microarrays, we demonstrated by immunohistochemistry that sortilin was highly expressed in low-grade cancer, while syndecan-1 was upregulated in high-grade disease. Mechanistic studies in prostate cell lines revealed that in androgen-sensitive LNCaP cells, sortilin enhanced glucose metabolism by regulating GLUT1 and GLUT4, while binding progranulin and lipoprotein lipase (LPL) to limit lipid metabolism. In contrast, in androgen-insensitive PC3 cells, syndecan-1 was upregulated, interacted with LPL and colocalised with ß3 integrin to promote lipid metabolism. In addition, androgen-deprived LNCaP cells had decreased expression of sortilin and reduced glucose-metabolism, but increased syndecan-1 expression, facilitating interactions with LPL and possibly ß3 integrin. We report a hitherto unappreciated molecular mechanism for PCa, which may have significance for disease progression and how androgen-deprivation therapy might promote castration-resistant PCa.

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.

Aortic Injury From High-Speed Deceleration Against a Lap Belt in a 10-year-Old.

Traumatic aortic injuries in children and adolescents are rare, and even more rare are blunt traumatic injury to the abdominal aorta in this population. Therefore, there are few reports discussing the presentation and repair of such injuries, especially within the pediatric population. We report the successful repair of traumatic abdominal aortic transection in a 10-year-old female after a high speed MVC. She arrived in extremis with a seatbelt sign and was taken emergently for damage control laparotomy with subsequent postoperative CT findings of aortic transection/dissection at L3 with active extravasation. She immediately underwent open thrombectomy of the bilateral iliac arteries, and repair of her aortic injury with a 12 × 7 mm Hemashield interposition graft extending just distal to the IMA and 1 cm proximal to the aortic bifurcation. There are little data regarding long-term outcomes of pediatric patients undergoing different aortic repair techniques, and further research is needed.