AHRR and SFRP2 in primary versus recurrent high-grade serous ovarian carcinoma and their prognostic implication.

BACKGROUND: The aim of this study was to analyse transcriptomic differences between primary and recurrent high-grade serous ovarian carcinoma (HGSOC) to identify prognostic biomarkers. METHODS: We analysed 19 paired primary and recurrent HGSOC samples using targeted RNA sequencing. We selected the best candidates using in silico survival and pathway analysis and validated the biomarkers using immunohistochemistry on a cohort of 44 paired samples, an additional cohort of 504 primary HGSOCs and explored their function. RESULTS: We identified 233 differential expressed genes. Twenty-three showed a significant prognostic value for PFS and OS in silico. Seven markers (AHRR, COL5A2, FABP4, HMGCS2, ITGA5, SFRP2 and WNT9B) were chosen for validation at the protein level. AHRR expression was higher in primary tumours (p < 0.0001) and correlated with better patient survival (p < 0.05). Stromal SFRP2 expression was higher in recurrent samples (p = 0.009) and protein expression in primary tumours was associated with worse patient survival (p = 0.022). In multivariate analysis, tumour AHRR and SFRP2 remained independent prognostic markers. In vitro studies supported the anti-tumorigenic role of AHRR and the oncogenic function of SFRP2. CONCLUSIONS: Our results underline the relevance of AHRR and SFRP2 proteins in aryl-hydrocarbon receptor and Wnt-signalling, respectively, and might lead to establishing them as biomarkers in HGSOC.

LRP1B-a prognostic marker in tubo-ovarian high-grade serous carcinoma.

Low-density lipoprotein (LDL) receptor-related protein 1B (LRP1B) is a member of the LDL receptor family and has often been discussed as a tumor suppressor gene, as its down-regulation is correlated with a poor prognosis in multiple carcinoma entities. Due to the high metastasis rate into the fatty peritoneal cavity and current research findings showing a dysregulation of lipid metabolism in tubo-ovarian high-grade serous carcinoma (HGSC), we questioned the prognostic impact of the LRP1B protein expression. We examined a well-characterized large cohort of 571 patients with primary HGSC and analyzed the LRP1B protein expression via immunohistochemical staining (both in tumor and stroma cells separately), performed precise bioimage analysis with QuPath, and calculated the prognostic impact using SPSS. Our results demonstrate that LRP1B functions as a significant prognostic marker for overall survival (OS) and progression-free survival (PFS) in HGSC on the protein level. High cytoplasmic expression of LRP1B in tumor, stroma, and combined tumor and stroma cells has a significantly positive association with a mean prolongation of the OS by 42 months (P = .005), 29 months (P = .005), and 25 months (P = .001), respectively. Additionally, the mean PFS was 18 months longer in tumor (P = .002), 19 months in stroma (P = .004), and 19 months in both cell types combined (P = .01). Our results remained significant in multivariate analysis. We envision LRP1B as a potential prognostic tool that could help us understand the functional role of lipid metabolism in advanced HGSC, especially regarding liposomal medications.

Prognostic value of regulatory T cells and T helper 17 cells in high grade serous ovarian carcinoma.

PURPOSE: In recent years the tumor microenvironment and its interaction with the tumor has emerged into research focus with increased attention to the composition of Tumor-infiltrating lymphocytes. We wanted to quantify the composition of Regulatory T cells (Tregs) and T helper 17 cells (Th17 cells) and their prognostic impact in high-grade serous tubo-ovarian carcinoma. METHODS: Tregs and Th17 cells were determined by immunohistochemical analysis of CD25 FoxP3 and RORγt, respectively on tissue microarrays of a cohort of 222 patients with reviewed histology and available clinical data. Expression was analyzed with Qupath for quantification and integration with clinical data enabled calculation of prognostic impact. For validation FOXP3 and RORC mRNA expression levels from 502 patients with HGSC in publicly available datasets were evaluated. RESULTS: An average percentage of 0.93 Tregs and of 0.06 Th17 cells was detected per cells in overall tissue. Optimal cut-offs were determined and higher Tregs were associated with a better overall survival in stroma (p = 0.006), tumor area (p = 0.0012) and overall tissue (p = 0.02). After accounting for well-known prognostic factors age at diagnosis, residual tumor and FIGO stage, this association remained significant for stromal Tregs with overall survival (p = 0.02). Survival analysis for Th17 cells revealed no significant association with survival rates. Moreover, lower Th17/Treg ratios had a positive impact on patient overall survival (p = 0.025 tumor, p = 0.049 stroma and p = 0.016 overall tissue). CONCLUSION: Our results outline a positive prognostic effect for higher Tregs but not for Th17 in high grade serous tubo-ovarian carcinoma.

Patients' and GPs' duties and responsibilities in long-term care after myocardial infarction: a qualitative study of patients' perspectives.

BACKGROUND: Cardiovascular disease is one of the main causes of death in Europe and around the world. Effective and individualized long-term treatment of patients with chronic diseases such as cardiovascular disease and myocardial infarction reduces mortality and the risk of recurrence and prevents secondary disease. However, there is little data on patients' views. OBJECTIVE: To examine patients' perspectives on long-term care after myocardial infarction. METHODS: A qualitative interview study with patients after myocardial infarction in Berlin and Brandenburg, Germany. Fifteen episodic interviews were conducted, transcribed, coded, and analyzed using framework analysis. RESULTS: Participants consistently emphasized major functions fulfilled by general practitioners: monitoring, advice, diagnosis, referral, coordination. Furthermore, other functions such as empathy and feeling emotionally valued. Major patient roles emerged such as information sharing, lifestyle change, and coping. Responsibility toward doctors was expressed in terms of active participation in describing their symptoms, following the doctor's directions, and sharing in decision-making. Self-responsibility in participants showed 2 contrasting approaches. On the one hand, a passive attitude (acceptance, helplessness), and on the other, active resistance and taking action. CONCLUSION: The study underlines the importance of communication and awareness of the patient's perspective. General practitioners must address patients' aims and fears, encourage their initiative, and focus on empathy and education.

A Model for Design and Implementation of a Laboratory Information-Management System Specific for Molecular Pathology Laboratory Operations.

The Molecular Pathology Section, Cleveland Clinic (Cleveland, OH), has undergone enhancement of its testing portfolio and processes. An Excel 2013- and paper-based data-management system was replaced with a commercially available laboratory information-management system (LIMS) software application, a separate bioinformatics platform, customized test-interpretation applications, a dedicated sample-accessioning service, and a results-releasing software application. The customized LIMS solution manages complex workflows, large-scale data packets, and process automation. A customized approach was required because, in a survey of commercially available off-the-shelf software products, none met the diverse and complex needs of this molecular diagnostics service. The project utilized the expertise of clinical laboratorians, pathologists, genetics counselors, bioinformaticians, and systems analysts in partnering with software-engineering consultants to design and implement a solution. Concurrently, Agile software-building best practices were formulated, which may be emulated for scalable and cost-effective laboratory-authored software.