BRCA loss of function including BRCA1 DNA-methylation, but not BRCA-unrelated homologous recombination deficiency, is associated with platinum hypersensitivity in high-grade ovarian cancer.

Background: In high-grade ovarian cancer (HGOC), determination of homologous recombination deficiency (HRD) status is commonly used in routine practice to predict response to platinum-based therapy or poly (ADP-ribose) polymerase inhibitors (PARPi). Here we tested the hypothesis that BRCA loss of function (LOF) due to epigenetic or genetic aberrations is a better predictor for the clinical outcome than HRD. One hundred thirty-one HGOC tissues were tested for BRCA DNA-methylation, BRCA mutations, HRD and BRCA1 mRNA expression, followed by a comprehensive survival analysis.

Stratification of Homologous Recombination Deficiency-Negative High-Grade Ovarian Cancer by the Type of Peritoneal Spread into Two Groups with Distinct Survival Outcomes.

Background: Homologous recombination deficiency (HRD) has evolved into a major diagnostic marker in high-grade ovarian cancer (HGOC), predicting the response to poly (adenosine diphosphate-ribose) polymerase inhibitors (PARPi) and also platinum-based therapy. In addition to HRD, the type of peritoneal tumor spread influences the treatment response and patient survival; miliary type tumor spread has a poorer predicted outcome than non-miliary type tumor spread.

Methods: Known methods for HRD assessment were adapted for our technical requirements and the predictive-value integrated genomic instability score (PIGIS) for HRD assessment evolved as an outcome.

Multifunctional Hybrid Material for Endoprosthetic Implants Based on Alumina-Toughened Zirconia Ceramics and Additively Manufactured TiNbTa Alloys.

Aseptic implant loosening after a total joint replacement is partially influenced by material-specific factors when cobalt-chromium alloys are used, including osteolysis induced by wear and corrosion products and stress shielding. Here, we aim to characterize a hybrid material consisting of alumina-toughened zirconia (ATZ) ceramics and additively manufactured Ti-35Nb-6Ta (TiNbTa) alloys, which are joined by a glass solder. The structure of the joint, the static and fatigue shear strength, the influence of accelerated aging, and the cytotoxicity with human osteoblasts are characterized.

An angiogenic tumor phenotype predicts poor prognosis in ovarian cancer.

Objective: Epithelial ovarian cancer (OC) is the deadliest gynecological malignancy worldwide. Blocking angiogenesis with bevacizumab, an antibody targeting vascular endothelial growth factor (VEGF), shows efficacy in different lines of OC therapy. This study investigates the clinical impact of tumoral expression of angiogenesis-related genes and their association with bevacizumab response in OC in retrospective analysis of three independent cohorts.

Clinical impact of EZH2 and its antagonist SMARCA4 in ovarian cancer.

SMARCA4 and EZH2 are two functional key players of their respective antagonizing chromatin remodeling complexes SWI/SNF and PRC2. EZH2 inhibitory drugs may abrogate pro-oncogenic features of PRC2 and turn the balance to cell differentiation via SWI/SNF activity in cancers. SMARCA4 and EZH2 expression was assessed by RT-PCR in 238 epithelial ovarian cancers (OCs) and put in relation to clinico-pathological parameters and patients' outcome.

Enlarged cardiophrenic lymph nodes predict disease involvement of the upper abdomen and the outcome of primary surgical debulking in advanced ovarian cancer.

Introduction: The outcome of ovarian cancer patients is highly dependent on the success of primary debulking surgery in terms of postoperative residual disease. This study critically evaluates the clinical impact of preoperative radiologic assessment of the cardiophrenic lymph node (CPLN) status in advanced ovarian cancer.

Material And Methods: Baseline CT scans of 178 stage III and IV ovarian cancer patients were retrospectively reviewed by two independent radiologists.

High RIG-I expression in ovarian cancer associates with an immune-escape signature and poor clinical outcome.

Ovarian cancer (OC) is the most lethal gynecological malignancy, with platinum-based chemotherapy remaining the mainstay for adjuvant treatment after surgery. The lack of indication for immunotherapy may at least in part result from the lack of suitable biomarkers allowing stratification of potentially responding patients. In this monocentric study of 141 cases with OC, we used real-time quantitative PCR to assess the expression of retinoic acid-inducible gene-I (RIG-I) in primary tumor and healthy ovarian control tissues.

Ovarian Cancer Stem Cell Heterogeneity.

Ovarian carcinoma features pronounced clinical, histopathological, and molecular heterogeneity. There is good reason to believe that parts of this heterogeneity can be explained by differences in the respective cell of origin, with a self-renewing fallopian tube secretory cell being likely responsible for initiation of an overwhelming majority of high-grade serous ovarian carcinomas (i.e.

Calgranulin A (S100A8) Immunostaining: A Future Candidate for Risk Assessment in Patients with Non-Muscle-Invasive Bladder Cancer (NMIBC).

Introduction: There is an urgent need to identify patients with bladder cancer (BC) who are at high risk of recurrence or progression. Calgranulin A is a strong marker for muscle-invasive or advanced BC and recent studies have shown its potential for identifying patients at risk even in non-muscle-invasive bladder cancer (NMIBC). The present study examines risks of recurrence and progression dependent on immunostaining with calgranulin A in NMIBC.

Evaluation of Vav3.1 as prognostic marker in endometrial cancer.

Purpose: Vav3 is a guanine nucleotide exchange factor that regulates the activity of Rho/Rac family GTPases. In a study on ovarian cancer, we recently demonstrated pronounced prognostic and predictive value of Vav3.1, a specific truncation variant of the parental Vav3 gene.

(Iso-)form Matters: Differential Implication of Vav3 Variants in Ovarian Cancer.

This commentary discusses recent results on the role of Vav3 in malignancy, in an effort to begin to define the underlying mechanisms and tissue context by which Vav3 proteins, in particular Vav3.1, promote the progression of malignant diseases and further modulate the response to clinically relevant drugs.

Truncated isoform Vav3.1 is highly expressed in ovarian cancer stem cells and clinically relevant in predicting prognosis and platinum-response.

Vav3 is a key modulator of GTP-hydrolases of the Rho/Rac family, which are crucially involved in cell proliferation. Vav3 is alternatively spliced in full-length Vav3-alpha and N-terminal truncated Vav3.1 lacking its self-regulatory domains.

Prognostic role of plasma fibrinogen in patients with uterine leiomyosarcoma - a multicenter study.

Fibrinogen has an important pathophysiological role in tumor cell progression and development of metastases in different types of cancer. The present study aimed to evaluate the role of pre-treatment fibrinogen plasma concentrations as a biomarker for tumor biology and prognosis in patients with uterine leiomyosarcoma (ULMS). Clinical data of patients with ULMS were assessed in this multi-center study Pre-therapeutic fibrinogen plasma concentrations were evaluated.

Meeting evolving workforce needs: Preparing psychologists for leadership in the patient-centered medical home.

Behavioral health integration in the patient-centered medical home (PCMH) offers opportunities for psychologists to play leadership roles. Widespread practice transition to PCMH models of care are expected to substantially impact the psychology workforce. Conservative estimates suggest that approximately 90% of the 93,000 clinically trained psychologists would be required to meet projected need in these settings.

Evaluating L1CAM expression in human endometrial cancer using qRT-PCR.

Background: Management of endometrial carcinoma (EC) still needs improvement of risk assessment. Recently, L1CAM immunohistochemical (IHC) evaluation showed a unique value to predict the outcome of early EC. However IHC results are often conflicting for lack of inter-laboratory standardisation.

Heterogeneity of Cancer Stem Cells: Rationale for Targeting the Stem Cell Niche.

Malignancy is fuelled by distinct subsets of stem-like cells which persist under treatment and provoke drug-resistant recurrence. Eradication of these cancer stem cells has therefore become a prime objective for the development and design of novel classes of anti-cancer therapeutics with improved clinical efficacy. Here, we portray potentially clinically-relevant hallmarks of cancer stem cells and focus on their recently appreciated properties of cell variability and plasticity, both of which make them elusive targets for cancer therapies.

Evaluation of folate receptor 1 (FOLR1) mRNA expression, its specific promoter methylation and global DNA hypomethylation in type I and type II ovarian cancers.

Background: In this retrospective study we evaluated the respective correlations and clinical relevance of FOLR1 mRNA expression, FOLR1 promoter specific methylation and global DNA hypomethylation in type I and type II ovarian cancer.

Methods: Two hundred fifty four ovarian cancers, 13 borderline tumours and 60 samples of healthy fallopian epithelium and normal ovarian epithelium were retrospectively analysed for FOLR1 expression with RT-PCR. FOLR1 DNA promoter methylation and global DNA hypomethylation (measured by means of LINE1 DNA hypomethylation) were evaluated with MethyLight technique.

Clinical impact of L1CAM expression measured on the transcriptome level in ovarian cancer.

Background: High expression of L1 cell adhesion molecules (L1CAM) has been repeatedly shown to be associated with aggressive disease behavior, which translates in poor clinical outcome in various cancer entities. However, in ovarian cancer results based either on immunohistochemistry or cytosolic protein quantifications remained conflicting regarding clinical behavior. In the present work we assessed L1CAM expression on the transcriptome level with the highly sensitive quantitative real-time PCR (qRT-PCR) to define its relevance in ovarian cancer biology.

Expression and promotor hypermethylation of miR-34a in the various histological subtypes of ovarian cancer.

Background: An increasing body of evidence shows that miR-34 family has tumor suppressive properties mediating apoptosis, cell cycle arrest and senescence. In ovarian cancer, miR34 family members were found to be under expressed. Particularly miR-34a has been revealed to be a direct transcriptional target of p53 which is frequently mutated in epithelial ovarian carcinomas especially in high grade serous cancer.

The side population of ovarian cancer cells defines a heterogeneous compartment exhibiting stem cell characteristics.

Cancer stem cells (CSC) are believed to be involved in tumor evasion of classical antitumor therapies and have thus become an attractive target for further improvement of anticancer strategies. However, the existence and identity of CSC are still a matter of controversy. In a systematic screen of 13 ovarian cancer cell lines we show that cells with stem cell properties are reliably detectable as a minor population, characterized by ABC transporter expression resulting in the side population (SP) phenotype.

L1CAM in early-stage type I endometrial cancer: results of a large multicenter evaluation.

Background: Despite the excellent prognosis of Fédération Internationale de Gynécologie et d'Obstétrique (FIGO) stage I, type I endometrial cancers, a substantial number of patients experience recurrence and die from this disease. We analyzed the value of immunohistochemical L1CAM determination to predict clinical outcome.

Methods: We conducted a retrospective multicenter cohort study to determine expression of L1CAM by immunohistochemistry in 1021 endometrial cancer specimens.

DyeCycle Violet used for side population detection is a substrate of P-glycoprotein.

Cancer stem cells (CSC) are increasingly recognized as key target cells for cancer therapy because they are both tumorigenic and chemoresistant and, therefore, can give rise to recurrent disease. Side population (SP) sorting using an ultraviolet (UV) laser is an established method to isolate CSC based on ABC drug transporter-dependent (e.g.

The N-terminally truncated p53 isoform Δ40p53 influences prognosis in mucinous ovarian cancer.

Objective: The tumor suppressor p53 generates the N-terminally truncated isoforms Δ40p53 and Δ133p53 that possess the ability to modulate p53 function in vitro. The aim of the present study was to evaluate the clinical relevance of p53 isoforms in the main histological subtypes of ovarian cancer.

Methods: Δ40p53, Δ133p53, and full-length p53 (FLp53) expression was determined in 45 mucinous, 30 endometrioid, and 91 serous ovarian cancer specimens as well as 42 normal ovarian tissues using reverse transcriptase-quantitative polymerase chain reaction.

MDM2 SNP309 modifies the prognostic significance of the p53 mutational status in patients with ovarian cancer.

A single nucleotide polymorphism (SNP309) of MDM2 causes elevated MDM2 levels and an attenuation of p53 function. The aim of the present study was to examine the clinical relevance of the MDM2 SNP309 in ovarian cancer.MDM2 SNP309 genotype was analyzed in 198 patients with primary ovarian cancer.

Clinical relevance of TAp73 and ΔNp73 protein expression in ovarian cancer: a series of 83 cases and review of the literature.

The p73 gene gives rise to the full-length transactivation competent TAp73 and the N-terminally truncated isoform ΔNp73, which inhibits TAp73 and wild-type p53. The clinical relevance of TAp73 and ΔNp73 protein expression has not yet been evaluated in ovarian cancer. TAp73 and ΔNp73 expression was examined using immunohistochemistry and reverse transcription-polymerase chain reaction in 83 and 64 ovarian cancer specimens, respectively.