The Role of miRNAs in Diagnosis, Prognosis and Treatment Prediction in Cervical Cancer

Cervical cancer represents one of the major problems of health women worldwide, especially in the developing countries. If discovered in its earliest stages, cervical cancer is successfully treatable; however, due to lack of proper implementation of screening programs, the majority of cervical cancer patients are diagnosed in advanced stages, which dramatically influence their outcome. Almost a half of these patients will suffer recurrence or metastasis in the following 2 years after therapy. If there are no immediate prospects in terms of developing new or more effective therapies, identifying new tools for early diagnosis, prognosis and treatment prediction remains a big challenge for cervical cancer. miRNAs have been validated to be key players in cell physiology, alterations in miRNA expression being associated with cancer progression and response to therapy. Cervical cancer studies have showed that alterations of miRNA expression can be identified in tumor tissues, exfoliated cervical cells and patients serum and that their transcription pattern is regulated by the present HPV genotype. Furthermore, miRNAs have been associated with patients response to therapy, therefore suggesting their potential to be used as biomarkers for cervical cancer diagnosis, prognosis and treatment response

Evolutionary perspectives, heterogeneity and ovarian cancer: a complicated tale from past to present

Ovarian cancer is composed of a complex system of cells best described by features such as clonal evolution, spatial and temporal genetic heterogeneity, and development of drug resistance, thus making it the most lethal gynecologic cancer. Seminal work on cancer as an evolutionary process has a long history; however, recent cost-effective large-scale molecular profiling has started to provide novel insights coupled with the development of mathematical algorithms. In the current review, we have systematically searched for articles that focused on the clonal evolution of ovarian cancer to offer the whole landscape of research that has been done and highlight future research avenues given its characteristic features and connections to evolutionary biology. Keywords: Clonal evolution; Ovarian cancer; Spatial heterogeneity; Survival; Temporal heterogeneit

MiRNA-Based Therapeutics in Oncology, Realities, and Challenges

As master modulators of the human genome, miRNAs are involved in all cancer hallmarks, disrupting the normal function of their targets. By gaining or losing the function, miRNAs lead to the validation of tumor phenotype, its progression, and metastasis as well as to drug resistance. Increasing the evidence suggests that the modulation of miRNAs in cancer cells, by suppressing the oncogenic miRNAs (oncomiRs) and substituting the deficient tumor suppressive miRNAs (TS-miRNAs), could become a reliable tool for improving the cancer therapy. In this chapter, we will present an up-to-date overview of the role of miRNA-based therapeutics in oncology, highlighting their role in cancer management, how these therapies can be used, and which would be the future challenges related to miRNA-based therapies

Role of Folic Acid in the Therapeutic Action of Nanostructured Porous Silica Functionalized with Organotin(IV) Compounds against Different Cancer Cell Lines

The synthesis, characterization and cytotoxic activity against different cancer cell lines of various mesoporous silica-based materials containing folate targeting moieties and a cytotoxic fragment based on a triphenyltin(IV) derivative have been studied. Two different mesoporous nanostructured silica systems have been used: firstly, micronic silica particles of the MSU-2 type and, secondly, mesoporous silica nanoparticles (MSNs) of about 80 nm. Both series of materials have been characterized by different methods, such as powder X-ray diffraction, X-ray fluorescence, absorption spectroscopy and microscopy. In addition, these systems have been tested against four different cancer cell lines, namely, OVCAR-3, DLD-1, A2780 and A431, in order to observe if the size of the silica-based systems and the quantity of incorporated folic acid influence their cytotoxic action. The results show that the materials are more active when the quantity of folic acid is higher, especially in those cells that overexpress folate receptors such as OVCAR-3 and DLD-1. In addition, the study of the potential modulation of the soluble folate receptor alpha (FOLR1) by treatment with the synthesized materials has been carried out using OVCAR-3, DLD-1, A2780 and A431 tumour cell lines. The results show that a relatively high concentration of folic acid functionalization of the nanostructured silica together with the incorporation of the cytotoxic tin fragment leads to an increase in the quantity of the soluble FOLR1 secreted by the tumour cells. In addition, the studies reported here show that this increase of the soluble FOLR1 occurs presumably by cutting the glycosyl-phosphatidylinositol anchor of membrane FR-α and by the release of intracellular FR-α. This study validates the potential use of a combination of mesoporous silica materials co-functionalized with folate targeting molecules and an organotin(IV) drug as a strategy for the therapeutic treatment of several cancer cells overexpressing folate receptors.Spanish Government RTI2018-094322-B-I00 CTQ2017-90802-REDTMinistry of Research and Innovation, CNCS-UEFISCDI within PNCDI III PN-III-P4-ID-PCCF-2016-014

Adenosquamous carcinoma of the uterine cervix – impact of histology on clinical management

Introduction: Historically, the incidence rate of cervical cancer (CC) in Eastern Europe and particularly in Bulgaria has constantly been higher than that in the other European countries. Adenosquamous carcinoma (ASC) is a rare histological subtype of CC with incidence rate of less than 6 per 100,000. We aimed to analyze the epidemiology and prognosis of all Bulgarian patients with ASC, registered at the Bulgarian National Cancer Registry (BNCR), and to compare patients’ characteristics and outcomes with those of patients, treated at a large specialized institution – the Department of Gynecologic Oncology, University Hospital in Pleven, Bulgaria. Materials and Methods: This is a retrospective study of all cases of ASC, registered at the BNCR for a 10-year period of time. The Kaplan–Meier analysis with Log rank test was used to estimate the significant differences. Results: The incidence rate of ASC was calculated as 3.2% of all CC registered in BNCR and 4.97% of all stage I patients, treated in our department. The 5-year overall survival (OS) rate of all patients with ASC tumors from the registry was 50.5%. A total of 171 (48.4%) of the patients had T1 tumors and a 5-year OS of 67.1%. Lymph node status was a significant prognostic factor for OS (p=0.001). Thirty-one patients with T1 tumors and ASC histology were treated in our department for the same period of time. Lymph node metastases were found in 10 of them (32.2%). The 5-year observed OS in ASC group was 74.19%. Conclusion: The histological subtype of cancer of the uterine cervix has an impact on prognosis and should not be simply considered as a descriptive characteristic but a poor prognostic feature and should be an integral part of the decision-making in clinical management of patients.peer-reviewe

GYNOCARE Update: Modern Strategies to Improve Diagnosis and Treatment of Rare Gynecologic Tumors—Current Challenges and Future Directions

More than 50% of all gynecologic tumors can be classified as rare (defined as an incidence of ≤6 per 100, 000 women) and usually have a poor prognosis owing to delayed diagnosis and treatment. In contrast to almost all other common solid tumors, the treatment of rare gynecologic tumors (RGT) is often based on retrospective studies, expert opinion, or extrapolation from other tumor sites with similar histology, leading to difficulty in developing guidelines for clinical practice. Currently, gynecologic cancer research, due to distinct scientific and technological challenges, is lagging behind. Moreover, the overall efforts for addressing these challenges are fragmented across different European countries and indeed, worldwide. The GYNOCARE, COST Action CA18117 (European Network for Gynecological Rare Cancer Research) programme aims to address these challenges by creating a unique network between key stakeholders covering distinct domains from concept to cure: basic research on RGT, biobanking, bridging with industry, and setting up the legal and regulatory requirements for international innovative clinical trials. On this basis, members of this COST Action, (Working Group 1, “Basic and Translational Research on Rare Gynecological Cancer”) have decided to focus their future efforts on the development of new approaches to improve the diagnosis and treatment of RGT. Here, we provide a brief overview of the current state of-the-art and describe the goals of this COST Action and its future challenges with the aim to stimulate discussion and promote synergy across scientists engaged in the fight against this rare cancer worldwide

Ovarian Real-World International Consortium (ORWIC): A multicentre, real-world analysis of epithelial ovarian cancer treatment and outcomes

IntroductionMuch drug development and published analysis for epithelial ovarian cancer (EOC) focuses on early-line treatment. Full sequences of treatment from diagnosis to death and the impact of later lines of therapy are rarely studied. We describe the establishment of an international network of cancer centers configured to compare real-world treatment pathways in UK, Portugal, Germany, South Korea, France and Romania (the Ovarian Real-World International Consortium; ORWIC).Methods3344 patients diagnosed with EOC (2012-2018) were analysed using a common data model and hub and spoke programming approach applied to existing electronic medical records. Consistent definition of line of therapy between sites and an efficient approach to analysis within the limitations of local information governance was achieved.ResultsMedian age of participants was 53-67 years old and 5-29% were ECOG >1. Between 62% and 84% of patients were diagnosed with late-stage disease (FIGO III-IV). Sites treating younger and fitter patients had higher rates of debulking surgery for those diagnosed at late stage than sites with older, more frail patients. At least 21% of patients treated with systemic anti-cancer therapy (SACT) had recurrent disease following second-line therapy (2L); up to 11 lines of SACT treatment were recorded for some patients. Platinum-based SACT was consistently used across sites at 1L, but choices at 2L varied, with hormone therapies commonly used in the UK and Portugal. The use (and type) of maintenance therapy following 1L also varied. Beyond 2L, there was little consensus between sites on treatment choice: trial compounds and unspecified combinations of other agents were common.DiscussionSpecific treatment sequences are reported up to 4L and the establishment of this network facilitates future analysis of comparative outcomes per line of treatment with the aim of optimizing available options for patients with recurrent EOC. In particular, this real-world network can be used to assess the growing use of PARP inhibitors. The real-world optimization of advanced line treatment will be especially important for patients not usually eligible for involvement with clinical trials. The resources to enable this analysis to be implemented elsewhere are supplied and the network will seek to grow in coverage of further sites

Psycho-Oncology Structure and Profiles of European Centers Treating Patients With Gynecological Cancer

Objective: Psycho-oncological counseling should be an integrated part of modern cancer therapy. The aim of this study was to assess the structures and interests of psychooncology services within European Society of Gynecological Oncology (ESGO) centers. Methods: In 2010, a survey, which consisted of 15 questions regarding organization of psycho-oncological services and interests in training and research, was sent to all ESGO-accredited centers (n = 41). Results: The response rate was 65.8% (27 centers). 96.3% (n = 26) of the surveys came from universities, and 3.7% (n = 1) came from nonacademic institutions. Most of the institutions (92.6%, n = 25) offer psycho-oncological care, mainly by psychologists (64%, n = 16) or psycho-oncologists (48%, n = 12). Fifty-two percent of patients are evaluated for sexual dysfunction as sequelae of their disease or treatment-related adverse effects. Fifty-two percent (n = 14) of institutions offer psychological support for cancer care providers. Eighty-five percent (n = 23) of all centers are interested in psycho-oncological training, and the preferred teaching tools are educational workshops (87%). The main issues of interest are sexual problems in patients with cancer, communication and interpersonal skills, responses of patients and their families, anxiety and adjustment disorders, and palliative care. Eighty-five percent (n = 17) of the 20 institutions look for research in the field of psycho-oncology, and 55% (n = 11) of those are already involved in some kind of research. Conclusions: Although psycho-oncological care is provided in most of the consulted ESGO accredited centers, almost 50% of women lack information about sexual problems. The results of the survey show the need for and interest in psycho-oncology training and research, including sexual dysfunction. Furthermore, psychological support should be offered to all cancer care provider

Novel Phenothiazine-Bridged Porphyrin-(Hetero)aryl dyads: Synthesis, Optical Properties, In Vitro Cytotoxicity and Staining of Human Ovarian Tumor Cell Lines

We report here the synthetic procedure applied for the preparation of new AB3-type and trans-A2B2 type meso-halogenophenothiazinyl-phenyl-porphyrin derivatives, their metal core complexation and their peripheral modification using Suzuki–Miyaura cross coupling reactions with various (hetero)aryl (phenothiazinyl, 7-formyl-phenothiazinyl, (9-carbazolyl)-phenyl and 4-formyl-phenyl, phenyl) boronic acid derivatives. The meso-phenothiazinyl-phenyl-porphyrin (MPP) dyes family was thus extended by a series of novel phenothiazine-bridged porphyrin-(hetero)aryl dyads characterized by UV–Vis absorption/emission properties typical to the porphyrin chromophore, slightly modulated by increasing the size of peripheral substituents. Three phenothiazine-bridged porphyrin-heteroaryl dyads with fluorescence emission above 655 nm were selected as fluorophores in red spectral region for applications in cellular staining of human ovarian tumors. In vitro experiments of cell metabolic activity displayed a moderate toxicity on human ovarian tumor cell lines (OVCAR-3, cisplatin-sensitive A2780 and cisplatin-resistant A2780cis respectively). Visualization of the stained living cells was performed both by fluorescence microscopy imaging and by fluorescence lifetime imaging under two photon excitation (TPE-FLIM), confirming their cellular uptake and the capability of staining the cell nucleus