The Association of Death Receptors and TGF-ß1 Expression in Urothelial Bladder Cancer and Their Prognostic Significance.

Death receptor signalization that triggers the extrinsic apoptotic pathway and TGF-ß1 have important roles in urothelial carcinogenesis, with a complex interplay between them. The aim of this research was to assess the association of death receptors DR4, DR5, and FAS as well as TGF-ß1 immunohistochemical expression with the clinicopathological characteristics of urothelial bladder cancer (UBC) and to evaluate their prognostic significance. The decrease or loss of death receptors' expression was significantly associated with muscle-invasive tumors, while non-invasive UBC often retains the expression of death receptors, which are mutually strongly linked. High DR4 expression is a marker of low-grade tumors and UBC associated with exposition to known carcinogens. Conversely, TGF-ß1 was significantly associated with high tumor grade and advanced stage. High expression of DR4 and FAS indicates longer overall survival. High TGF-ß1 signifies an inferior outcome and is an independent predictor of adverse prognosis in UBC patients. This study reveals the expression profile of death receptors in UBC and their possible interconnection with TGF-ß1 and indicates independent prognostic significance of high FAS and TGF-ß1 expression in UBC, which may contribute to deciphering the enigma of UBC heterogeneity in light of the rapid development of novel and effective therapeutic approaches, including targeting of the TRAIL-induced apoptotic pathway.

Bevacizumab with Chemotherapy as a First-Line Treatment for Advanced Ovarian Cancer in a Serbian Cohort.

Background and Objectives: For stage IIIb-IV ovarian cancer, bevacizumab-containing treatment is considered the standard of care. The purpose of this study was to evaluate the efficacy of bevacizumab in combination with carboplatin and paclitaxel as a first-line treatment for advanced ovarian cancer. Materials and Methods: Eligible patients had stage IIIc-IV ovarian cancer according to the International Federation of Gynecology and Obstetrics with no clinical signs or symptoms of gastrointestinal obstruction or a history of abdominal fistulae, gastrointestinal perforation, or intra-abdominal abscess or evidence of rectosigmoid involvement by pelvic examination, bowel involvement on computed tomography, or clinical symptoms of bowel obstruction in the previous 6 months. After debulking surgery, the patients received 175 mg/m2 paclitaxel and carboplatin (AUC 6) for the first six cycles and 7.5 mg/kg bevacizumab every three weeks up to 17 cycles until disease progression, unacceptable toxicity, or consent withdrawal. The primary endpoint was progression-free survival. The secondary endpoint was overall survival. Results: Between April 2017 and March 2020, 35 patients began study treatment. Bevacizumab was administered at 7.5 mg/kg in all the patients and for more than 7.5 months in 70% of them. The median progression-free survival was 20 months (95% CI: 16-23). The median overall survival was not reached. Conclusions: This was, to our knowledge, the first trial in Serbia to show progression-free survival and overall survival of combination regimens in advanced ovarian cancer. Based on the observed progression-free survival, bevacizumab combined with chemotherapy should be considered as a standard option in advanced ovarian cancer.

Risk Factors and Predictive Value of Depression and Anxiety in Cervical Cancer Patients.

Background and Objectives: Women with cervical cancer may experience depression or anxiety, influencing their quality of life and even their adherence to cancer treatments. This study aimed to explore and measure the levels of anxiety and depression in patients suffering from cervical cancer and to identify the possible predictors among known risk factors such as age, cancer stage, smoking status, number of partners, use of contraceptives, and annual gynecological visits. Materials and Methods: In total, 59 patients with cervical cancer were included. A consecutive sampling method was used to select participants in this research. Depression and anxiety were assessed using the Zung Anxiety Scale (SAS) and Zung Depression Scale (SDS). The subjects were divided into three groups, according to the stage of cancer. Results: Scores of depression and anxiety were increased in all recruited cervical cancer patients. A significant correlation was found between disease stage and the scores of depression (p = 0.002) and anxiety (p = 0.016). More severe depressive symptoms correlated to a more advanced stage of the disease. A multiple linear regression showed that disease stage and annual visits to the gynecologist are the risk factors associated with higher depression scores. Conclusions: Patients diagnosed with cervical cancer are a vulnerable group for the development of the psychiatric disorders and they require screening programs, which could potentially detect candidates for co-psychiatric and/or psychotherapeutic treatment. They demand particular attention because anxiety and depression are associated with the significant burden of the underlying disease and unfavorable survival rates.

Prognostic Impact of Canonical TGF-ß Signaling in Urothelial Bladder Cancer.

Background and objectives: Dysregulation of TGF-ß signaling plays multiple roles in cancer development and progression. In the canonical TGF-ß pathway, TGF-ß regulates the expression of hundreds of target genes via interaction with Smads, signal transducers and transcriptional modulators. We evaluated the association of TGF-ß1, Smad2, and Smad4, the key components of canonical TGFß pathway, with clinicopathologic characteristics of urothelial bladder cancer, and assessed their prognostic value in prediction of patients' outcome. Materials and Methods: Immunohistochemical analysis of TGF-ß1, Smad2, and Smad4 expression was performed on 404 urothelial bladder cancer samples, incorporated in tissue microarrays. Expression status was correlated with clinicopathological and follow-up data. The median follow-up was 61 months. Results: High expression of TGF-ß1, Smad2, and Smad4 was detected in 68.1%, 31.7% and 45.2% of the tumors, respectively. TGF-ß1 overexpression was significantly associated with high tumor grade, and advanced pathologic stage (p < 0.001, respectively). Conversely, high Smad2 and Smad4 expression was linked to low tumor grade (p = 0,003, p = 0.048, respectively), and low tumor stage (p < 0.001, p = 0.003, respectively). Smad2 showed an inverse correlation with variant morphology and divergent differentiation of urothelial tumors (p = 0.014). High TGF-ß1 correlated directly, while Smad2 and Smad4 correlated inversely to cancer-specific death (p = 0.043, p = 0.003, and p = 0.022, respectively). There was a strong relationship between Smad2 and Smad4 expression (p < 0.001). Survival analyses showed that high Smad2 and Smad4 expression was associated with longer overall survival (p = 0.003, p = 0.034, respectively), while in multivariate regression analysis TGF-ß1 manifested as an independent predictor of poor outcome. Conclusions: Unraveling the complex roles and significance of TGF-ß signaling in urothelial bladder cancer might have important implications for therapy of this disease. Assessment of TGF-ß pathway status in patients with urothelial bladder cancer may provide useful prognostic information, and identify patients that could have the most benefit from therapy targeting TGF-ß signaling cascade.

Epithelial ovarian cancer with CD117 phenotype is highly aggressive and resistant to chemotherapy.

AIM: CD117 expression has a pathogenic role in many malignancies, including ovarian carcinoma. The aim of the present study was to examine the correlation of stemness-associated marker CD117 with the clinicopathologic features of epithelial ovarian cancer and patient survival. MATERIAL AND METHODS: The analysis included 240 primary ovarian carcinomas (OC) diagnosed during the period from 2005 to 2011 in the region of South Serbia. Age, pathohistological characteristics, presence and size of residual tumor, choice of therapy and response to the therapy were studied. RESULTS: Residual tumors were more frequently present in the patients with positive CD117 expression (18.1% vs 8.0%; P < 0.05). Chemotherapy according to paclitaxel/carboplatin protocol was more frequent in the patients with positive CD117 expression (70.9% vs 54.2%; P < 0.05), while carboplatin monotherapy was more frequent in the patients with negative CD117 expression (18.0% vs 6.4%; P < 0.05). Median survival time in patients with CD117-positive mucinous and endometrioid OC was significantly shorter, at 20 and 26.8 months, respectively. Median survival in serous OC was not related to CD117 expression. CONCLUSION: Residual tumors and chemotherapy treatment were more frequent in patients with positive CD117 expression. The outcome was dependent on the type of OC; a worse outcome, including a shorter survival, was documented in the mucinous and endometrioid OC cases.

Prognostic significance of mucin expression in urothelial bladder cancer.

Urothelial bladder cancer (UBC) is a common genitourinary malignancy, accounting for more than 160.000 deaths per year worldwide. Overexpression and aberrant glycosylation of mucins are frequent traits of many human cancers derived from epithelial cells, and are found to have prognostic significance in various carcinomas. The aim of this study was to further elucidate the features and significance of mucin expression in UBC. We investigated the relationship between mucin expression and clinicopathological characteristics in 539 cases of UBC by immunohistochemical analysis of MUC1, MUC2, MUC4, MUC5AC and MUC6 expression profiles. MUC1 stained 61.8% of the tumors and correlated with high tumor grade (P = 0.013). The expression of MUC2 and MUC6 was associated with low tumor grade (P < 0.000 and P < 0.022, respectively), and low pathologic stage (P < 0.001 and P = 0.001, respectively). MUC2 negative tumors were more frequently associated with the finding of carcinoma in situ in tumor surroundings (P = 0.019). UBC with divergent differentiation correlated with MUC1, MUC4 and MUC5AC staining. MUC4 expression was directly linked to cancer specific death (P = 0.027), while MUC2 and MUC6 showed inverse correlation to cancer-specific death (P < 0.001 and P = 0.005, respectively). Kaplan-Meier analyses showed that expression of MUC2 and MUC6 in UBC was significantly associated with better overall survival of the patients (P < 0.001, respectively). In Cox regression model, the absence of MUC6 expression emerged as independent predictor of death outcome. In conclusion, this study identifies MUC2 and MUC6 expression as markers of UBC with less aggressive behavior and useful predictors of better survival.

Ovarian epithelial cancer stem cells.

The last decade witnessed an explosion of interest in cancer stem cells (CSCs). The realization of epithelial ovarian cancer (EOC) as a CSC-related disease has the potential to change approaches in the treatment of this devastating disease dramatically. The etiology and early events in the progression of these carcinomas are among the least understood of all major human malignancies. Compared to the CSCs of other cancer types, the identification and study of EOC stem cells (EOCSCs) is rather difficult due to several major obstacles: the heterogeneity of tumors comprising EOCs, unknown cells of origin, and lack of knowledge considering the normal ovarian stem cells. This poses a major challenge for urgent development in this research field. This review summarizes and evaluates the current evidence for the existence of candidate normal ovarian epithelial stem cells as well as EOCSCs, emphasizing the requirement for a more definitive laboratory approach for the isolation, identification, and enrichment of EOCSCs. The present review also revisits the ongoing debate regarding other cells and tissues of origin of EOCs, and discusses early events in the pathogenesis of this disease. Finally, this review discusses the signaling pathways that are important regulators of candidate EOCSC maintenance and function, their potential role in the distinct pathogenesis of different EOC subtypes, as well as potential mechanisms and clinical relevance of EOCSC involvement in drug resistance.

Glioblastoma multiforme stem cells.

Glioblastoma multiforme (GBM) is an aggressive, malignant, and lethal brain tumor, resistant to all current forms of treatment. The rapidly emerging focus on cancer stem cells embodies a paradigm shift in our understanding of tumor pathogenesis, while the development of powerful genome-wide screening techniques has provided cause for optimism related to the development of more reliable therapies primarily targeting GBM stem cells (GBMSCs). There are promising mounting data on providing new molecular targets and predictive markers of response, leading to more effective therapies of GBM, guided by patient-specific genetic and epigenetic profiling. However, the achievement of efficient GBMSC targeting also requires an adequate understanding of the unique microenvironment, and the relationship with the immune system in the central nervous system (CNS) and CNS tumors. The endogenous immune regulation is likely to limit or abrogate the efficacy of the host's immune response, as well as the developed immunotherapeutic strategies at present. Therefore, a comprehensive understanding of the mechanisms underlying the GBM-induced immunosuppression is indispensable. This review presents a summary of the present knowledge both on GBMSCs and the GBM, and/or GBMSC-related mechanisms of developing both local and systemic immunosuppression, of which an understanding may lead to the development of the novel and effective therapeutic strategies.