Biomechanical strain imposed by age-related thickening of the basal lamina and augmented tissue stiffness in the prostate gland coincides with increased cancer risk. Here we hypothesized that the structural alterations in the basal lamina associated with age can induce mechanotransduction pathways in prostate epithelial cells (PECs) to promote invasiveness and cancer progression. To demonstrate this, we developed a 3D model of PEC acini in which thickening and stiffening of basal lamina matrix was induced by advanced glycation end-product (AGE)-dependent non-enzymatic crosslinking of its major components, collagen IV and laminin. We used this model to demonstrate that antibody targeted blockade of CTLD2, the second of eight C-type lectin-like domains in Endo180 (CD280, CLEC13E, KIAA0709, MRC2, TEM9, uPARAP) that can recognize glycosylated collagens, reversed actinomyosin-based contractility [myosin-light chain-2 (MLC2) phosphorylation], loss of cell polarity, loss of cell-cell junctions, luminal iniltration and basal invasion induced by AGE-modiied basal lamina matrix in PEC acini. Our in vitro results were concordant with luminal occlusion of acini in the prostate glands of adult Endo180 Ex2-6/ Ex2-6 mice, with constitutively exposed CTLD2 and decreased survival of men with early (non-invasive) prostate cancer with high epithelial Endo180 expression and levels of AGE. These indings indicate that AGE-dependent modiication of the basal lamina induces invasive behaviour in non-transformed PECs via a molecular mechanism linked to cancer progression. This study provides a rationale for targeting CTLD2 in Endo180 in prostate cancer and other pathologies in which increased basal lamina thickness and tissue stiffness are driving factors.

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Nuclear grading system for epithelioid malignant pleural mesothelioma (MPM) has been proposed but 2 it remains uncertain if they could be applied in a biopsy-heavy setting. Using the proposed system, we 3 conducted an independent, external validation study using 563 consecutive cases of epithelioid MPM 4 diagnosed at our institution between 2003 and 2017, of which 87% of patients underwent biopsies 5 only. The median number of sites sampled was 1, with median maximum tissue dimension of 17mm 6 (Biopsy) and 150mm (Resection). The median overall survival (OS) was 14.7 months. The 7 frequencies of Grade I, II and III tumors were 31% (132/563), 52% (292/563) and 17% (94/563). 8Grade I tumors were associated with the most favorable median OS (24.7 months) followed by grade 9 II (12.7 months) and III (7.2 months). 2-tier nuclear grade separated tumors into low grade (19.3 10 months) and high grade (8.9 months). In multivariate analysis, 3-tier nuclear grade, 2-tier nuclear 11 grade and mitosis-necrosis score predicted OS independent of age, procedural type, solid-predominant 12 growth pattern, necrosis and atypical mitosis (all p<0.001 except 2-tier nuclear grade, p=0.001). In the 13 scenario of a single site biopsy with tissue dimension less than or equal to 10mm, none but age 14 (p=0.002) were independently predictive. Our data also suggested sampling 3 sites or a maximum 15 tissue dimension of at least 20mm from a single site is optimal for nuclear grade assessment. In 16 conclusion our study confirmed the utility of nuclear grade in epithelioid MPM using a biopsy-heavy 17 cohort provided the tissue sample met minimum dimensional criteria.

Antibiotic usage and increasing antimicrobial resistance (AMR) mount significant challenges to patient safety and management of the critically ill on intensive care units (ICU). Antibiotic stewardship programmes (ASPs) aim to optimise appropriate antibiotic treatment whilst minimising antibiotic resistance. Different models of ASP in intensive care setting, include "standard" control of antibiotic prescribing such as "de-escalation strategies" through to interventional approaches utilising biomarkerguided antibiotic prescribing. A systematic review of outcomes related studies for ASPs in an ICU setting was conducted. Forty three studies were identified from MEDLINE between 1996 and 2014. Of 34 nonprotocolised studies, [1 randomised control trial (RCT), 22 observational and 11 case series], 29 (85%) were positive with respect to one or more outcome: These were the key outcome of reduced antibiotic use, or ICU length of stay, antibiotic resistance, or prescribing cost burden. Limitations of non-standard antibiotic initiation triggers, patient and antibiotic selection bias or baseline demographic variance were identified. All 9 protocolised studies were RCTs, of which 8 were procalcitonin (PCT) guided antibiotic stop/start interventions. Five studies addressed antibiotic escalation, 3 de-escalation and 1 addressed both. Six studies reported positive outcomes for reduced antibiotic use, ICU length of stay or antibiotic resistance. PCT based ASPs are effective as antibiotic-stop (de-escalation) triggers, but not as an escalation trigger alone. PCT has also been effective in reducing antibiotic usage without worsening morbidity or mortality in ventilator associated pulmonary infection. No study has demonstrated survival benefit of ASP. Ongoing challenges to infectious disease management, reported by the World Health Organisation global report 2014, are high AMR to newer antibiotics, and regional knowledge gaps in AMR surveillance. Improved AMR surveillance data, identifying core aspects of successful ASPs that are transferable, and further well-conducted trials will be necessary if ASPs are to be an effective platform for delivering desired patient outcomes and safety through best antibiotic policy.

Objectives The prognostic significance of pathologic features and invasive size has not been well studied for invasive mucinous adenocarcinoma (IMA). This study evaluates the significance of pathologic features and invasive size in relation to clinical outcome. Methods We reviewed the pathologic features in 84 IMAs, including histologic pattern, nuclear atypia, mitosis, necrosis, and lymphovascular invasion. The invasive size was calculated from the total size using the percentage of invasive components. Cases were subdivided into two pathologic grades based on five pathologic features, and the pathologic grade and adjusted T (aT) stage were correlated with disease-free and overall survival (OS). Results Necrosis and N stage were significantly associated with aT stage, and a significant association was noted between OS and aT stage. Nuclear atypia, mitosis, and lymphovascular and pleural invasion also showed a significant association with OS. High-grade tumors showing a significantly worse OS compared with low-grade tumors, as well as pathologic grade (hazard ratio [HR], 2.337; P = .043) and aT stage (HR, 1.875; P = .003), were independent prognostic factors in multivariate analysis. Conclusions The pathologic grading system stratified IMAs into high- and low-grade tumors with significant differences in OS. Invasive size may provide a better prognostic stratification for OS.

Pleural mesothelioma is an aggressive malignancy with limited effective therapies. In order to identify therapeutic targets, we integrated SNP genotyping, sequencing and transcriptomics from tumours and low-passage patient-derived cells. Previously unrecognised deletions of SUFU locus (10q24.32), observed in 21% of 118 tumours, resulted in disordered expression of transcripts from Hedgehog pathways and the T-cell synapse including VISTA. Co-deletion of Interferon Type I genes and CDKN2A was present in half of tumours and was a predictor of poor survival. We also found previously unrecognised deletions in RB1 in 26% of cases and show sub-micromolar responses to downstream PLK1, CHEK1 and Aurora Kinase inhibitors in primary mesothelioma cells. Defects in Hippo pathways that included RASSF7 amplification and NF2 or LATS1/2 mutations were present in 50% of tumours and were accompanied by micromolar responses to the YAP1 inhibitor Verteporfin. Our results suggest new therapeutic avenues in mesothelioma and indicate targets and biomarkers for immunotherapy.

Objectives Numerous studies on malignant mesothelioma (MM) highlight the prognostic importance of histologic subtype, nuclear grade, and necrosis. This study compares these parameters in paired biopsy and resection specimens of pleural MM. Methods Histologic subtype, percentage of epithelioid morphology, nuclear grade, and the presence or absence of necrosis were compared in 429 paired biopsies and resection specimens of pleural MM from 19 institutions. Results Histologic subtype was concordant in 81% of cases (κ = 0.58). When compared with resection specimens, epithelioid morphology at biopsy had a positive predictive value (PPV) of 78.9% and a negative predictive value (NPV) of 93.5%; sarcomatoid morphology showed high PPV (92.9%) and NPV (99.3%), and biphasic morphology PPV was 89.7% and NPV was 79.7%. Agreement of the percentage of epithelioid morphology was fair (κ = 0.27). Nuclear grade and necrosis were concordant in 75% (κ = 0.59) and 81% (κ = 0.53) of cases, respectively. Nuclear grade showed moderate (κ = 0.53) and substantial (κ = 0.67) agreement from patients with and without neoadjuvant therapy, respectively, and necrosis showed moderate (κ = 0.47 and κ = 0.60) agreement, respectively, in the same subsets of paired specimens. Conclusions Paired biopsy-resection specimens from pleural MM show overall moderate agreement in pathologic parameters. These findings may help guide postbiopsy management and triage of patients with MM.