Analysis of Expression of the ANG1, CaSR and FAK Proteins in Uterine Fibroids.

Understanding the molecular factors involved in the development of uterine myomas may result in the use of pharmacological drugs instead of aggressive surgical treatment. ANG1, CaSR, and FAK were examined in myoma and peripheral tissue samples taken from women after myoma surgery and in normal uterine muscle tissue samples taken from the control group. Tests were performed using tissue microarray immunohistochemistry. No statistically significant differences in ANG1 expression between the tissue of the myoma, the periphery, and the normal uterine muscle tissue of the control group were recorded. The CaSR value was reduced in the myoma and peripheral tissue and normal in the group of women without myomas. FAK expression was also lower in the myoma and periphery compared to the healthy uterine myometrium. Calcium supplementation could have an effect on stopping the growth of myomas.

Role of Vitamin E in Selected Malignant Neoplasms in Women.

Vitamin E, which is actually a mixture of eight isoforms (four tocopherols and four tocotrienols), is a powerful antioxidant that protects polyunsaturated fatty acids against oxidation and has the ability to break the chain lipid peroxidation, which is used in the treatment of heart disease, atherosclerosis, muscle disorders or infertility among men. Studies in-vitro show that one of the effects of tocopherol is the reduction of cancer stem cell activity which is connected to poor clinical course. In the scientific literature, reports on the participation of vitamin E not only in protection against the mutagenic effects of reactive oxygen species, but also in its anti-angiogenic activity and the ability to inhibit the invasion and metastasis of neoplastic cells are increasingly common. In this context, the role of vitamin E in preventing the neoplastic process and selected malignant neoplasms among women seems to be of particular interest. In this article, we present the results of research on the potential anticancer effects of vitamin E in the fight against breast, cervical, endometrial and ovarian cancer.

ESO-ESSO-ESTRO Multidisciplinary Course in Oncology for Medical Students: 4 Years of Experience (2016-2019).

The ESO-ESSO-ESTRO Multidisciplinary Course in Oncology is intended to fill the gap of the undergraduate fragmented oncology education, to provide insight into all theoretical and practical aspects of oncology, and to encourage future professional choices towards an oncology discipline. Students are exposed to (a) preclinical cancer topics; (b) natural history of the disease; (c) laboratory diagnostic tests; (d) medical, radiation, surgical, and palliative treatment; and (e) direct or through multidisciplinary patients' approach. Students are obliged to attend (i) all theoretical lectures, (ii) clinical case presentations, (iii) laboratories and ward visits, and (iv) to prepare and present a specific project under supervision. Participation is limited to 24 medical students who are selected through a competitive application process. Between 2016 and 2019, 96 students from 29 countries have attended. Data analysis derived from a given questionnaire demonstrates that most of the participants have declared that (1) they have achieved their expectations and objectives, (2) they have highly rated both clinical and non-clinical teaching oncological topics, and (3) they have been stimulated in developing a professional career in the field of oncology.

Dendritic cell-based immunotherapy (DCVAC/OvCa) combined with second-line chemotherapy in platinum-sensitive ovarian cancer (SOV02): A randomized, open-label, phase 2 trial.

OBJECTIVE: DCVAC/OvCa is an active cellular immunotherapy designed to stimulate an immune response against ovarian cancer. We explored the safety and efficacy of DCVAC/OvCa plus carboplatin and gemcitabine in platinum-sensitive ovarian cancer. METHODS: In this open-label, parallel-group, phase 2 trial (ClinicalTrials.gov number NCT02107950), patients with platinum-sensitive ovarian cancer relapsing after first-line chemotherapy were randomized to DCVAC/OvCa and chemotherapy or chemotherapy alone. DCVAC/OvCa was administered every 3-6 weeks (10 doses). Endpoints included safety, progression-free survival (PFS; primary efficacy endpoint) and overall survival (OS; secondary efficacy endpoint). RESULTS: Between November 2013 and May 2015, 71 patients were randomized to chemotherapy in combination with DCVAC/OvCa or to chemotherapy alone. Treatment-emergent adverse events related to DCVAC/OvCa, leukapheresis and chemotherapy occurred in six (16.2%), two (5.4%), and 35 (94.6%) patients in the DCVAC/OvCa group. Chemotherapy-related events occurred in all patients in the chemotherapy group. Seven patients in the DCVAC/OvCa group were excluded from primary efficacy analyses due to failure to receive ≥1 dose of DCVAC/OvCa. PFS was not improved (hazard ratio [HR] 0.73, 95% confidence interval [CI] 0.42-1.28, P = 0.274, data maturity 78.1%). Median OS was significantly prolonged (by 13.4 months) in the DCVAC/OvCa group (HR 0.38, 95% CI 0.20-0.74, P = 0.003; data maturity 56.3%). A signal for enhanced surrogate antigen-specific T-cell activity was seen with DCVAC/OvCa. CONCLUSIONS: DCVAC/OvCa combined with chemotherapy had a favorable safety profile in patients with platinum-sensitive ovarian cancer. DCVAC/OvCa did not improve PFS, but the exploratory analyses revealed OS prolongation and enhanced surrogate antigen-specific T-cell activity.

Doxycycline, salinomycin, monensin and ivermectin repositioned as cancer drugs.

Chemotherapy is one of the standard methods for the treatment of malignant tumors. It aims to cause lethal damage to cellular structures, mainly DNA. Noteworthy, in recent years discoveries of novel anticancer agents from well-known antibiotics have opened up new treatment pathways for several cancer diseases. The aim of this review article is to describe new applications for the following antibiotics: doxycycline (DOX), salinomycin (SAL), monensin (MON) and ivermectin (IVR) as they are known to show anti-tumor activity, but have not yet been introduced into standard oncological therapy. To date, these agents have been used for the treatment of a broad-spectrum of bacterial and parasitic infectious diseases and are widely available, which is why they were selected. The data presented here clearly show that the antibiotics mentioned above should be recognised in the near future as novel agents able to eradicate cancer cells and cancer stem cells (CSCs) across several cancer types.

Oral-genital human papillomavirus infection in Polish couples: frequent detection of HPV 42.

BACKGROUND: Human papillomavirus (HPV) contributes to the development of cervical and oropharyngeal tumors. The increased incidence of HPV associated oropharyngeal tumors is lately being observed also in Polish population. The worldwide distribution of HPV varies and the studies rarely combine analysis of virus genotypes in both: genital and oropharyngeal locations. Therefore, in our study, we investigated HPV distribution in both anatomical sites of females with previous history of cervical cancer or with pre-cancerous lesion and their partners to establish the dominant types in Polish couples in genital and oropharyngeal areas, as they can be easily sexually transmitted. METHODS: The study group consisted of 197 females and their partners. Each female had current or previous cervical pathology and HPV detected in gynecological swab with the use of Anyplex™ II HPV28 Detection system. This system is based on multiplexed real time PCR and enables detection of 19 high-risk and 9 low-risk HPVs. RESULTS: Beside women, the virus was found in 114/197 of men in their foreskin swabs. Additionally, HPV was detected in oropharyngeal swabs of 39/197 female and 56/197 male participants. HPV 16/31/42/39/54 dominated in female and HPV 66/42/16/31/53 in male genital locations. The incidence of HPV in oropharynx was lower, top five genotypes included: HPV 6/39/42/35/16 in women compared to HPV 39/6/42/40/33 in men. HPV16 was the most frequently detected virus type, found in 70/197 examined cervical swabs. It was significantly more prevalent as single infection in females, previously treated for the cervical cancer (p = 0.035). Moreover, regular presence of low risk type 42 was noticeable in both sexes, in both kind of swabs. There was a trend observed towards its prevalence as single infectious agent in women with previous history of cervical cancer (p = 0.069). CONCLUSIONS: Our results showed the distribution of HPV genotypes in Polish couples, in which each woman is HPV positive, indicating a common infection of HPV 42, regardless of sex and anatomical site. These findings shed new light on HPV 42 significance, however they should be verified on a larger group of Polish participants, followed regularly in 6 months intervals, in oral as well as in genital areas.

Ten years of anti-HPV vaccinations: what do we know?

Human papillomavirus (HPV) is one of the most important carcinogens in humans. Vaccines against HPV are now considered the first anti-cancer vaccinations. Since 2007, in many developed countries, there have been recommendations present for preventive vaccines against HPV. At present, the degree of implementation of these recommendations depends on a number of country-specific factors such as the health care system organization or the ways of funding. HPV vaccines are primarily to prevent the development of cervical cancer and other genital cancers. Therefore, only their long-term effectiveness can be measured, when a correspondingly large cohort of vaccinated teenagers reaches the age of the greatest incidence of these cancers. However, great care should be taken in assessing the results of vaccinations due to the possibility of misinterpretation and possible erroneous data. Undoubtedly, teenagers are the target population of HPV vaccines. However, vaccinating young sexually active women is also justified from an individual point of view. A 9-valent vaccine has been registered in the USA and in Europe - including Poland - as one of the three preventive vaccines. It is recommended to vaccinate women between 13 and 26 and men between 13 and 21, previously unvaccinated. It is also recommended to vaccinate men aged 26 years or less who have sexual relations with other men and people with reduced immunity, including HIV-positive people who have not been vaccinated previously.

Noble metals in oncology.

Worldwide research groups are searching for anticancer compounds, many of them are organometalic complexes having platinum group metals as their active centers. Most commonly used cytostatics from this group are cisplatin, carboplatin and oxaliplatin. Cisplatin was used fot the first time in 1978, from this time many platinum derivatives were created. In this review we present biological properties and probable future clinical use of platinum, gold, silver, iridium and ruthenium derivatives. Gold derivative Auranofin has been studied extensively. Action of silver nanoparticles on different cell lines was analysed. Iridium isotopes are commonly used in brachyterapy. Ruthenium compound new anti-tumour metastasis inhibitor (NAMI-A) is used in managing lung cancer metastases. Electroporation of another ruthenium based compound KP1339 was also studied. Most of described complexes have antiproliferative and proapoptotic properties. Further studies need to be made. Nevertheless noble metal based chemotherapheutics and compounds seem to be an interesting direction of research.

Evaluation of leptin serum concentrations during surgery and first-line chemotherapy in primary epithelial ovarian cancer patients.

AIM OF THE STUDY: The available data on serum leptin levels in ovarian cancer present contradictory results. The majority of authors report lower leptin levels in those patients in comparison to healthy individuals. However, there is no data regarding leptin concentrations during therapy in women with primary epithelial ovarian cancer. MATERIAL AND METHODS: Blood samples were collected at the time of diagnosis, after initial surgery, and after first-line chemotherapy. Leptin serum concentrations were analysed using ELISA technique. Additionally, parallel measurements of CA125 levels were performed. RESULTS: Fifty-three patients with primary epithelial ovarian cancer met the inclusion criteria and were included in our study. Our analysis revealed a significant difference in mean preoperative serum leptin concentrations between early and advanced ovarian cancer patients (p < 0.0001). We identified statistically significant elevation of mean serum leptin levels (p < 0.001) after complete macroscopic cytoreduction and after first-line chemotherapy in advanced ovarian cancer cases. DISCUSSION: In this cohort, a significant elevation of postoperative serum leptin levels after complete macroscopic cytoreduction were shown. Moreover, elevation of leptin levels corresponded with remission after chemotherapy. Further studies are needed to determine if leptin can be a potential marker of surgery completeness as well as a marker in chemotherapy response evaluation.

Signalling pathways in endometrial cancer.

Carcinogenesis is a multistage process, during which the activity of signalling pathways responsible for cell cycle regulation and division is disrupted which leads to inhibition of apoptosis and enhanced proliferation. Improper activation of Wnt/ß-catenin and PI3K. Akt pathways play essential role in endometrial cancers (EC), mainly type I. Mutations in APC, axin or CTNBB1 may lead to ß-catenin overactivation leading to excessive gene expression. PTEN inactivation, mutations in the PIK3CA or Akt result in increased transmission in the PI3K/Akt pathway, apoptosis inhibition, intensive cell division, mTOR excitation. In non-endometrioid cancers, key mutations include suppressor gene TP53 responsible for repairing damaged DNA or apoptosis initiation. Irregularities in gene P16, encoding a protein forming the p16-cyclinD/CDK-pRb have also been described. Understanding the complex relations between specific proteins taking part in signal transduction of the abovementioned pathways is key to research on drugs used in targeted therapy.

Gynotoxic Effects of Chemotherapy and Potential Protective Mechanisms.

Chemotherapy is one of the leading cancer treatments. Unfortunately, its use can contribute to several side effects, including gynotoxic effects in women. Ovarian reserve suppression and estrogen deficiency result in reduced quality of life for cancer patients and are frequently the cause of infertility and early menopause. Classic alkylating cytostatics are among the most toxic chemotherapeutics in this regard. They cause DNA damage in ovarian follicles and the cells they contain, and they can also induce oxidative stress or affect numerous signaling pathways. In vitro tests, animal models, and a few studies among women have investigated the effects of various agents on the protection of the ovarian reserve during classic chemotherapy. In this review article, we focused on the possible beneficial effects of selected hormones (anti-Müllerian hormone, ghrelin, luteinizing hormone, melatonin), agents affecting the activity of apoptotic pathways and modulating gene expression (C1P, S1P, microRNA), and several natural (quercetin, rapamycin, resveratrol) and synthetic compounds (bortezomib, dexrazoxane, goserelin, gonadoliberin analogs, imatinib, metformin, tamoxifen) in preventing gynotoxic effects induced by commonly used cytostatics. The presented line of research appears to provide a promising strategy for protecting and/or improving the ovarian reserve in the studied group of cancer patients. However, well-designed clinical trials are needed to unequivocally assess the effects of these agents on improving hormonal function and fertility in women treated with ovotoxic anticancer drugs.

Selected markers of ovarian cancer and their relation to targeted therapy (Review).

Despite advances in surgical treatment techniques and chemotherapy-including anti-angiogenic and immune poly (ADP-ribose) polymerase inhibitors, the 5-year survival rate in ovarian cancer (OC) remains low. The reasons for this are the diagnosis of cancer in advanced clinical stages, chemoresistance and cancer recurrence. New therapeutic approaches are being developed, including the search for new biomarkers that are also targets for targeted therapy. The present review describes new molecular markers with relevance to targeted therapy, which to date have been studied only in experimental research. These include the angiogenic protein angiopoietin-2, the transmembrane glycoprotein ectonucleotide pyrophosphatase/phosphodiesterase 1, the adhesion protein E-cadherin, the TIMP metallopeptidase inhibitor 1 and Kruppel-like factor 7. Drugs affecting cancer stem cells (CSCs) in OC, such as metformin and salinomycin, as well as inhibitors of CSCs markers aldehyde dehydrogenase 1 (with the drug ATRA) and the transcription factor Nanog homeobox (microRNA) are also discussed. A new approach to prevention and possible therapies under investigation such as development of vaccines containing a subpopulation of CD117(+) and CD44(+) stem cells with a promising option for use in women with OC was described.

Immunohistochemical Expression of the SERPINA3 Protein in Uterine Fibroids.

BACKGROUND: SERPINA3 (α-1-antichymotrypsin, AACT, ACT) is produced by the liver and released into plasma in an anti-inflammatory response and plays a role as a modulator of extracellular matrix (ECM) by inhibiting serine proteases. Numerous studies proved an increased level of SERPINA3 in many types of cancer, which could be linked to SERPINA3's anti-apoptotic function. AIM: In the context of progressive ECM fibrosis during the development of uterine fibroids, which are one of the most common hypertrophic changes within the uterus, it is interesting to describe the level of SERPINA3 protein in this type of lesion and the surrounding tissues. METHODS: We used immunohistochemical staining of the SERPINA3 protein and compared the intensity of the signal between the myoma tissue and the surrounding normal tissue. RESULTS: We showed a surprising reduction in the amount of the SERPINA3 protein within uterine fibroids compared to surrounding tissues. CONCLUSION: This observation sheds new light on the role of this protein in the formation of proliferative changes and suggests that understanding the mechanism of its action may become the basis for the development of new diagnostic and therapeutic tools.

Estrogen Receptor (ER) and Progesterone Receptor (PgR) Expression in Endometrial Cancer-An Immunohistochemical Assessment.

Endometrial cancer (EC) is one of the most common types of cancer in Poland and worldwide. Many risk factors lead to the pathogenesis of this disease, such as lifestyle choices, BMI, the medicines used in breast cancer therapy, and Lynch syndrome. EC cells show the expression of estrogen receptors (ERs) and progesterone receptors (PgR). These receptors occur in multiple isoforms and have a significant influence on the operation of cells. The loss of ER and PgR expression is associated with a poor prognosis. We assessed tissue slides that were obtained from 103 women with EC diagnoses of various grades, stages, and histological types. In this study, we used computer image analyses to increase the objectivity of the assessment. We proved that, in the tissue of patients with high-grade (G3) EC, the expression of PgR is significantly lower than that in the tissues of patients with low-grade EC. We also observed that PgR is significantly expressed in EC with a low FIGO stage and in the endometroid type of EC (which rarely becomes malignant compared to serous type). The expression of ERb1 was lower in patients with EC at the IV FIGO stage than in patients with stage III EC. These findings confirm that the loss of ER and PgR expression is connected with a poor prognosis.

A randomized phase II trial of maintenance therapy with Sorafenib in front-line ovarian carcinoma.

OBJECTIVES: Sorafenib, an oral multikinase inhibitor of the VEGFR/PDGFR/Raf/MEK/ERK pathway, has shown potential activity in patients with recurrent ovarian cancer (OC). One strategy to prolong disease control and survival in patients with OC is maintenance therapy after achieving a complete response. A double-blind, randomized, placebo-controlled, phase II study to assess the efficacy and safety of maintenance therapy with sorafenib in the treatment of OC is presented. METHODS: Patients with epithelial OC or primary peritoneal cancer in complete remission were randomized to sorafenib 400mg BID or matching placebo. The primary endpoint was progression-free survival (PFS). RESULTS: Of 246 randomized patients, 93% had OC; baseline characteristics were balanced between treatment arms. There was no significant difference between sorafenib and placebo arms for PFS (median 12.7 vs 15.7 months; hazard ratio 1.09; 95% CI 0.72-1.63), although there was a notable imbalance in early censoring. The most common ≥ grade 3 adverse events (AEs) were hand-foot skin reaction (39.0% vs 0.8%) and rash (14.6% vs 0%). More patients receiving sorafenib versus placebo required dose reductions (67.5% vs 30.1%), resulting in a lower than planned median daily dose (median 584.6 vs 800.0mg). Treatment with sorafenib was of shorter duration (median 17.6 vs 51.9 weeks) with more frequent discontinuations due to AEs (37.4% vs 6.5%). CONCLUSIONS: Sorafenib 400mg BID cannot be recommended as maintenance therapy for patients with OC in complete remission. Assessment of efficacy was limited by the high rate of dose reductions and early discontinuations.

Role of Hyaluronic Acid in Selected Malignant Neoplasms in Women.

Hyaluronic acid (HA) is a significant glycosaminoglycan component of the extracellular matrix, playing an essential role in cell localization and proliferation. However, high levels of HA may also correlate with multidrug resistance of tumor cells, an increased tendency to metastasize, or cancer progression, and thus represent a very unfavorable prognosis for cancer patients. The purpose of this review article is to summarize the results of studies describing the relationship between HA, the main ligand of the CD44 receptor, or other components of the HA signaling pathway. In addition, we review the course of selected female malignancies, i.e., breast, cervical, endometrial, and ovarian cancer, with the main focus on the mechanisms oriented to CD44. We also analyze reports on the beneficial use of HA-containing preparations in adjuvant therapy among patients with these types of cancer. Data from the literature suggest that HA and its family members may be critical prognostic biomarkers of selected malignancies among women. Nevertheless, the results of the available studies are inconclusive, and the actual clinical significance of HA expression analysis is still quite enigmatic. In our opinion, the HA-CD44 signaling pathway should be an attractive target for future research related to targeted therapy in gynecological cancers.

The Role of Selected Dietary Factors in the Development and Course of Endometriosis.

Endometriosis is a chronic disease with a complex, heterogeneous pathogenesis that affects about 10% of women of reproductive age, causing pain and leading to infertility. Treatment consists of administering pharmacological agents (resulting in a reduction of estrogen levels and inflammation), as well as the surgical removal of endometriotic lesions. Unfortunately, despite a wide range of available therapies, there is still a high recurrence rate after surgery. Consequently, it is necessary to improve the outcome of patients with endometriosis. In this context, there is growing interest in possible dietary modification to support or complement classic treatment options and even serve as a potential alternative to hormone therapy. In addition, a growing number of studies indicate positive effects of selected dietary factors on the development and course of endometriosis. This review article focuses on the potentially beneficial effects of compounds from the polyphenol group (curcumin, epigallocatechin gallate, quercetin, resveratrol), vitamins, and selected micronutrients on endometriosis. The results indicate the potential of the selected ingredients in fighting the disease. However, most of the studies have been performed on experimental animal models, with a smaller proportion looking at the actual effects of use among women. Therefore, well-designed studies are needed to assess the importance of a well-chosen diet and the effects of specific dietary factors on the health of women suffering from endometriosis.

Role of Fisetin in Selected Malignant Neoplasms in Women.

A promising therapeutic window and cost-effectiveness are just two of the potential advantages of using naturally derived drugs. Fisetin (3,3',4',7-tetrahydroxyflavone) is a natural flavonoid of the flavonol group, commonly found in fruit and vegetables. In recent years, fisetin has gained wide attention across the scientific community because of its broad spectrum of pharmacological properties, including cytotoxic activity against most abundant cancers. By stimulating or inhibiting selected molecular targets or biochemical processes, fisetin could affect the reduction of metastasis or cancer progression, which indicates its chemotherapeutic or chemopreventive role. In this review, we have summarized the results of studies on the anticancer effects of fisetin on selected female malignancies, both in in vitro and in vivo tests, i.e., breast, cervical, and ovarian cancer, published over the past two decades. Until now, no article dedicated exclusively to the action of fisetin on female malignancies has appeared. This review also describes a growing number of nanodelivery systems designed to improve the bioavailability and solubility of this natural compound. The reported low toxicity and activity of fisetin on cancer cells indicate its valuable potential, but large-scale clinical trials are urgently needed to assess real chemotherapeutic efficacy of this flavonoid.

Metastases and Recurrence Risk Factors in Endometrial Cancer-The Role of Selected Molecular Changes, Hormonal Factors, Diagnostic Methods and Surgery Procedures.

The presence of metastatic endometrial cancer (EC) is a key problem in treatment failure associated with reduced overall survival rates. The most common metastatic location is the pelvic lymph nodes, and the least common is the brain. The presence of metastasis depends on many factors, including the molecular profile of cancer (according to the TCGA-Genome Atlas), the activity of certain hormones (estrogen, prolactin), and pro-inflammatory adipocytokines. Additionally, an altered expression of microRNAs affecting the regulation of numerous genes is also related to the spread of cancer. This paper also discusses the value of imaging methods in detecting metastases; the primary role is attributed to the standard transvaginal USG with the tumor-free distance (uTFD) option. The influence of diagnostic and therapeutic methods on EC spread is also described. Hysteroscopy, according to the analysis discussed above, may increase the risk of metastases through a fluid medium, mainly performed in advanced stages of EC. According to another analysis, laparoscopic hysterectomy performed with particular attention to avoiding risky procedures (trocar flushing, tissue traumatization, preserving a margin of normal tissue) was not found to increase the risk of EC dissemination.

Role of Vitamin C in Selected Malignant Neoplasms in Women.

Since the first reports describing the anti-cancer properties of vitamin C published several decades ago, its actual effectiveness in fighting cancer has been under investigation and widely discussed. Some scientific reports indicate that vitamin C in high concentrations can contribute to effective and selective destruction of cancer cells. Furthermore, preclinical and clinical studies have shown that relatively high doses of vitamin C administered intravenously in 'pharmacological concentrations' may not only be well-tolerated, but significantly improve patients' quality of life. This seems to be particularly important, especially for terminal cancer patients. However, the relatively high frequency of vitamin C use by cancer patients means that the potential clinical benefits may not be obvious. For this reason, in this review article, we focus on the articles published mainly in the last two decades, describing possible beneficial effects of vitamin C in preventing and treating selected malignant neoplasms in women, including breast, cervical, endometrial, and ovarian cancer. According to the reviewed studies, vitamin C use may contribute to an improvement of the overall quality of life of patients, among others, by reducing chemotherapy-related side effects. Nevertheless, new clinical trials are needed to collect stronger evidence of the role of this nutrient in supportive cancer treatment.