The autopsy is in decline, despite the fact that accurate mortality statistics remain essential for public health and health service planning. The falling autopsy rate combined with the Coroners Review and Human Tissue Act have contributed to this decline, and to a falling use of autopsy histology, with potential impact on clinical audit and mortality statistics. At a time when the need for reform and improvement in the death certification process is so prominent, we felt it important to assess the value of the autopsy and autopsy histology. We carried out a meta-analysis of discrepancies between clinical and autopsy diagnoses and the contribution of autopsy histology. There has been little improvement in the overall rate of discrepancies between the 1960s and the present. At least a third of death certificates are likely to be incorrect and 50% of autopsies produce findings unsuspected before death. In addition, the cases which give rise to discrepancies cannot be identified prior to autopsy. Over 20% of clinically unexpected autopsy findings, including 5% of major findings, can be correctly diagnosed only by histological examination. Although the autopsy and particularly autopsy histology are being undermined, they are still the most accurate method of determining the cause of death and auditing accuracy of clinical diagnosis, diagnostic tests and death certification.

SUMMARY Bladder cancer incurs a higher lifetime treatment cost than other cancers due to frequent recurrence of non-invasive disease. Improved prognostic biomarkers and localised therapy are needed for this large patient group. We defined two major genomic subtypes of primary stage Ta tumors that showed differential risk of recurrence. The higher risk subtype was characterised by loss of 9q including TSC1, increased KI67 labelling index, upregulated glycolysis, DNA repair, mTORC1 signaling, features of the unfolded protein response and altered cholesterol homeostasis. Comparison with muscle-invasive bladder cancer mutation profiles revealed lower overall mutation rates and more frequent mutations in RHOB and chromatin modifier genes. More mutations in the histone-lysine demethylase KDM6A were present in non-invasive tumors from females than males.

The nuclear matrix protein Cip1-interacting zinc finger protein 1 (CIZ1) promotes DNA replication in association with cyclins and has been linked to adult and pediatric cancers. Here we show that CIZ1 is highly enriched on the inactive X chromosome (Xi) in mouse and human female cells and is retained by interaction with the RNA-dependent nuclear matrix. CIZ1 is recruited to Xi in response to expression of X inactive-specific transcript (Xist) RNA during the earliest stages of X inactivation in embryonic stem cells and is dependent on the C-terminal nuclear matrix anchor domain of CIZ1 and the E repeats of Xist. CIZ1-null mice, although viable, display fully penetrant female-specific lymphoproliferative disorder. Interestingly, in mouse embryonic fibroblast cells derived from CIZ1-null embryos, Xist RNA localization is disrupted, being highly dispersed through the nucleoplasm rather than focal. Focal localization is reinstated following re-expression of CIZ1. Focal localization of Xist RNA is also disrupted in activated B and T cells isolated from CIZ1-null animals, suggesting a possible explanation for female-specific lymphoproliferative disorder. Together, these findings suggest that CIZ1 has an essential role in anchoring Xist to the nuclear matrix in specific somatic lineages.

Background:Bone metastases in prostate cancer (CaP) result in CaP-related morbidity/mortality. The omega-6 polyunsaturated fatty acid (PUFA) arachidonic acid (AA) and lipophilic statins affect metastasis-like behaviour in CaP cells, regulating the critical metastatic step of CaP migration to the bone marrow stroma.Methods:Microscopic analysis and measurement of adhesion and invasion of CaP cells through bone marrow endothelial cells (BMEC) was undertaken with AA stimulation and/or simvastatin (SIM) treatment. Amoeboid characteristics of PC-3, PC3-GFP and DU-145 were analysed by western blotting and Rho assays.Results:The CaP cell lines PC-3, PC3-GFP and DU-145 share the ability to migrate across a BMEC layer. Specific amoeboid inhibition decreased transendothelial migration (TEM). AA stimulates amoeboid characteristics, driven by Rho signalling. Selective knock-down of components of the Rho pathway (RhoA, RhoC, Rho-associated protein kinase 1 (ROCK1) and ROCK2) showed that Rho signalling is crucial to TEM. Functions of these components were analysed, regarding adhesion to BMEC, migration in 2D and the induction of the amoeboid phenotype by AA. TEM was reduced by SIM treatment of PC3-GFP and DU-145, which inhibited Rho pathway signalling.Conclusions:AA-induced TEM is mediated by the induction of a Rho-driven amoeboid phenotype. Inhibition of this cell migratory process may be an important therapeutic target in high-risk CaP.

Summary Understanding the molecular determinants that underpin the clinical heterogeneity of non-muscle-invasive bladder cancer (NMIBC) is essential for prognostication and therapy development. Stage T1 disease in particular presents a high risk of progression and requires improved understanding. We present a detailed multi-omics study containing gene expression, copy number, and mutational profiles that show relationships to immune infiltration, disease recurrence, and progression to muscle invasion. We compare expression and genomic subtypes derived from all NMIBCs with those derived from the individual disease stages Ta and T1. We show that sufficient molecular heterogeneity exists within the separate stages to allow subclassification and that this is more clinically meaningful for stage T1 disease than that derived from all NMIBCs. This provides improved biological understanding and identifies subtypes of T1 tumors that may benefit from chemo- or immunotherapy.

Prostate cancer (CaP) cells preferentially metastasise to the bone marrow, a microenvironment that plays a substantial role in the sustenance and progression of the CaP tumour. Here we use a combination of FTIR microspectroscopy and histological stains to increase molecular specificity and probe the biochemistry of metastatic CaP cells in bone marrow tissue derived from a limited source of paraffin-embedded biopsies of different patients. This provides distinction between the following dominant metabolic processes driving the proliferation of the metastatic cells in each of these biopsies: glycerophospholipid synthesis from triacylglyceride, available from surrounding adipocytes, in specimen 1, through significantly high (p < or = 0.05) carbohydrate (8.23 +/- 1.44 cm(-1)), phosphate (6.13 +/- 1.5 cm(-1)) and lipid hydrocarbon (24.14 +/- 5.9 cm(-1)) signals compared with the organ-confined CaP control (OC CaP), together with vacuolation of cell cytoplasm; glycolipid synthesis in specimen 2, through significantly high (p < or = 0.05) carbohydrate (5.51 +/- 0.04 cm(-1)) and high lipid hydrocarbon (17.91 +/- 2.3 cm(-1)) compared with OC CaP, together with positive diastase-digested periodic acid Schiff staining in the majority of metastatic CaP cells; glycolysis in specimen 3, though significantly high (p < or = 0.05) carbohydrate (8.86 +/- 1.78 cm(-1)) and significantly lower (p < or = 0.05) lipid hydrocarbon (11.67 +/- 0.4 cm(-1)) than OC CaP, together with negative diastase-digested periodic acid Schiff staining in the majority of metastatic CaP cells. Detailed understanding of the biochemistry underpinning the proliferation of tumour cells at metastatic sites may help towards refining chemotherapeutic treatment.

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Activating mutations of FGFR3 are a common and early event in bladder cancer. Ectopic expression of mutant FGFR3 in normal urothelial cells has both pro-proliferative and antiapoptotic effects at confluence, suggesting that mutant cells are insensitive to cell-cell contact inhibition. Herein, detailed analysis revealed that these cells have reduced cell-cell adhesion, with large intercellular spaces observable at confluence, and diminished cell-substrate adhesion to collagen IV, collagen I, and fibronectin. These phenotypic alterations are accompanied by changes in the expression of genes involved in cell adhesion and extracellular matrix remodeling. Silencing of endogenous mutant FGFR3 in bladder cancer cells induced converse changes in transcript levels of CDH16, PLAU, MMP10, EPCAM, TNC, and HAS3, confirming them as downstream gene targets of mutant FGFR3. Overexpression of EPCAM, HAS3, and MMP10 transcripts was found in a large fraction of primary bladder tumors analyzed, supporting their key role in bladder tumorigenesis in vivo. However, no correlation was found between their protein and/or mRNA expression and FGFR3 mutation status in tumor specimens, indicating that these genes may be targeted by several converging oncogenic pathways. Overall, these results indicate that mutant FGFR3 favors the development and progression of premalignant bladder lesions by altering key genes regulating the cell-cell and cell-matrix adhesive properties of urothelial cells. Implications:The ability of mutant FGFR3 to drive transcriptional expression profiles involved in tumor cell adhesion suggests a mechanism for expansion of premalignant urothelial lesions. Mol Cancer Res; 13(1); 138-48. Ó2014 AACR.