The PD-1/PD-L1 Gateway: Peripheral Immune Regulation in the Pathogenesis of Endometriosis.

Endometriosis is a chronic inflammatory disease characterized by the presence of endometrial-like tissue outside the uterine cavity, causing pain and infertility. Despite the rather unclear etiopathogenesis, recent studies suggest the involvement of the immune system in the development and progression of endometriosis. The role of the PD-1/PD-L1 axis in the modulation of the immune response in this disease seems to be particularly interesting. This preliminary study aimed to investigate the expression of PD-1 and PD-L1 on T and B lymphocytes in peripheral blood in patients with endometriosis to assess their potential impact on disease progression. Our study involved peripheral blood samples from 80 patients diagnosed with endometriosis and 20 healthy women as a control group were analyzed. Flow cytometry was used to assess the expression of PD-1 and PD-L1 on T and B lymphocytes, and enzyme-linked immunosorbent assays were used to assess their soluble forms in serum and peritoneal fluid.in our research we observe significantly higher expression of PD-1 and PD-L1 on T and B lymphocytes was found in patients with endometriosis compared to the control group. Higher expression of both tested molecules correlated with the stage of endometriosis. The results of our preliminary studies indicate a potential role of the PD-1/PD-L1 axis in the modulation of the immune response in endometriosis. Modified expression of these proteins may contribute to immune evasion by ectopic tissues, supporting their survival and proliferation. These findings suggest that targeting PD-1/PD-L1 could be explored as a therapeutic option for the treatment of endometriosis, though further research with larger sample sizes is necessary to confirm these results and clarify the role of PD-1/PD-L1 in the pathogenesis of the disease.

The Role of Microbiota in the Immunopathogenesis of Endometrial Cancer.

The female reproductive tract hosts a specific microbiome, which plays a crucial role in sustaining equilibrium and good health. In the majority of reproductive women, the microbiota (all bacteria, viruses, fungi, and other single-celled organisms within the human body) of the vaginal and cervical microenvironment are dominated by Lactobacillus species, which benefit the host through symbiotic relationships, in comparison to the uterus, fallopian tubes, and ovaries, which may contain a low-biomass microbiome with a diverse mixture of microorganisms. Although disruption to the balance of the microbiota develops, the altered immune and metabolic signaling may cause an impact on diseases such as cancer. These pathophysiological modifications in the gut-uterus axis may spark gynecological cancers. New information displays that gynecological and gastrointestinal tract dysbiosis (disruption of the microbiota homeostasis) can play an active role in the advancement and metastasis of gynecological neoplasms, such as cervical, endometrial, and ovarian cancers. Understanding the relationship between microbiota and endometrial cancer is critical for prognosis, diagnosis, prevention, and the development of innovative treatments. Identifying a specific microbiome may become an effective method for characterization of the specific microbiota involved in endometrial carcinogenesis. The aim of this study was to summarize the current state of knowledge that describes the correlation of microbiota with endometrial cancer with regard to the formation of immunological pathologies.

Toll-like Receptor 2 as a Marker Molecule of Advanced Ovarian Cancer.

Ovarian cancer is a global problem that affects women of all ages. Due to the lack of effective screening tests and the usually asymptomatic course of the disease in the early stages, the diagnosis is too late, with the result that less than half of the patients diagnosed with ovarian cancer (OC) survive more than five years after their diagnosis. In this study, we examined the expression of TLR2 in the peripheral blood of 50 previously untreated patients with newly diagnosed OC at various stages of the disease using flow cytometry. The studies aimed at demonstrating the usefulness of TLR2 as a biomarker in the advanced stage of ovarian cancer. In this study, we showed that TLR2 expression levels were significantly higher in women with more advanced OC than in women in the control group. Our research sheds light on the prognostic potential of TLR2 in developing new diagnostic approaches and thus in increasing survival in patients with confirmed ovarian cancer.

Toll-Like Receptor 2 Expression as a New Hallmark of Advanced Endometriosis.

Recent evidence suggests that immunological aspects play a pivotal role in this disorder. Toll-like receptor 2 (TLR2) is crucial in recognizing microbial infections and mediating innate immune response. The objective of our study was to rate with flow cytometry the levels of several subsets of dendritic cells, monocytes, and basic peripheral blood lymphocytes expressing TLR2, aiming at the determination of a possible correlation between the expression of TLR2 and the clinical outcomes of endometriosis in 40 patients and 40 age-matched healthy women. Our study showed the importance of TLR2 expression, mainly on myeloid dendritic cells (mDCs) and B cells in patients with endometriosis. Both mDCs BDCA1+CD19-TLR2+ and B lymphocytes CD19+TLR-2+ proved useful in the differentiation of affected individuals with stages 3-4 of the disease (area under the receiver operating characteristic curve /AUC/ = 0.96, p < 0.0001 for mDCs; AUC = 0.78, p = 0.0001 for B lymphocytes), and those presenting adhesion (AUC = 0.92, p < 0.0001 for mDCs; AUC = 0.82, p < 0.0001 for B lymphocytes) or infertility (AUC = 0.83, p < 0.0001 for mDCs; AUC = 0.73, p = 0.006 for B lymphocytes). Our findings suggest that the levels of TLR2-expressing cells, particularly mDCs and B lymphocytes, may be an effective biomarker of endometriosis, because the disease currently lacks clinically useful noninvasive biomarkers enabling early and cost-effective diagnosis.

Current Possibilities of Gynecologic Cancer Treatment with the Use of Immune Checkpoint Inhibitors.

Despite the ongoing progress in cancer research, the global cancer burden has increased to 18.1 million new cases and 9.6 million deaths in 2018. Gynecological cancers, such as ovarian, endometrial, and cervical cancers, considerably contribute to global cancer burden, leading to $5,862.6, $2,945.7, and $1,543.9 million of annual costs of cancer care, respectively. Thus, the development of effective therapies against gynecological cancers is still a largely unmet medical need. One of the novel therapeutic approaches is to induce anti-cancer immunity by the inhibition of the immune checkpoint pathways using monoclonal antibodies. The molecular targets for monoclonal antibodies are cytotoxic T lymphocyte-associated protein-4 (CTLA-4), programmed cell death protein-1 (PD-1), and programmed death-ligand 1 (PD-L1). The rationale for the use of immune checkpoint inhibitors in patients with gynecological cancers was based on the immunohistological studies showing high expression levels of PD-1 and PD-L1 in those cancers. Currently available immune checkpoint inhibitors include nivolumab, pembrolizumab, atezolizumab, avelumab, durvalumab, and ipilimumab. The efficacy and safety of these inhibitors, used as monotherapy and with combination with chemotherapy, is being currently evaluated in several clinical studies. As the results are promising, more clinical trials are being planned, which may lead to the development of efficient therapies for gynecological cancer patients.

Neuropilin 1 in uterine leiomyosarcoma. Clinical and pathological analysis.

OBJECTIVES: The role of angiogenesis in leiomyosarcomas still remains unclear. The aim of this study was to evaluate the NRP1 expression in the leiomyosarcoma tissues and to find the relations between its expression and the clinical features. MATERIAL AND METHODS: The study group consisted of 50 patients with diagnosis of the uterine leiomyosarcoma. Clinical and follow up data were collected. Using immunohistochemical methods the expression of NRP1 was detected. RESULTS: The lack of NRP1 expression was found in 14 cases, positive (weak or moderate) expression was noted in 36 cases. The significantly higher expression of NRP1 was observed in more severe clinical stages in comparison to lower stages of the disease. The significantly shorter survival of patients with the positive expression of NRP1 in leiomyosarcoma was observed. CONCLUSIONS: The expression of NRP1 is associated with clinical advancement and worse prognosis in uterine LMS. Neuropilin 1 can be widely used as a postoperative survival predictor for the patients suffering from uterine LMS.

Does the patients age at cancer diagnosis affect microvessels density in uterine sarcoma tissues?

OBJECTIVES: The objective of the study was to retrospectively evaluate the density of vessels exhibiting positive glycoprotein CD34 expression in the uterine leiomyosarcoma tissues and their correlation with the age of patients at the time of tumor diagnosis. MATERIAL AND METHODS: The archival paraffin blocks with the cancer tissues collected from 50 patients suffering from uterine leiomyosarcoma were used together with their clinical and demographic data. The immunohistochemical peroxidase-de-pendent methods were used to detect microvessels with positive CD34 expression. The glycoprotein CD34 expression was evaluated as a density of microvessel showing the positive immunohistochemical reaction (MVDCD34). RESULTS: The negative, statistically significant correlation between the age of patients (at the moment diagnosis) and the MVDCD34+ (R = -0.289, p = 0.042) was found. CONCLUSIONS: The study's findings may suggest that the tissues of younger people constitute a permissive environment for pro-angiogenic factors.

Microtissue density prognostic factor evaluation based on antigens CD34 and CD 105 in ovarian cancer patients.

Uncontrollable cell division and disorders of the apoptotic processes constitute the key phenomena in cancer transformation. The theory that the tumour growth above critical density is possible due to creation of the new blood vessels during angiogenesis process was put forward in 1971 by Folkman. The panendotelial antibodies targeted against such markers as CD34 are used most frequently in cancer vessel evaluation. The anti-CD34 reacts with the largest number of endoepithelial cells. The second group constitutes the antibodies that agglomerate with the antigens characteristic for proliferous endoepithelial cells. The most popular marker used for functional endothelial tissues is endoglin called CD105. The subject of this publication is to find the answer to a question whether the practical usage of the CD34 and CD 105 as a prognostic factor in predicting failure of a planned treatment, determining expected remission and the total survival rate is possible. 74 patients with the diagnosed ovarian cancer, treated in the I Clinic of Gynecology Oncology and Gynecology, Medical University in Lublin, between years 1999-2004 were included into the analysis. Representative paraffin blocks with the embedded ovarian cancer fragments were used for immunohistochemical research. Density of the microvessels was being evaluated basing on the expression of the antigen CD34 and CD105. Evaluation of the microvessel density with CD34 and CD105 markers is not useful in forecasting survival rate and disease recurrence in patients with ovary cancer.

[Expression of lymphangiogenesis marker neuropilin-1 in different types of ovarian cancer]. / Ekspresja markera limfangiogenezy neuropiliny-1 w róznych typach raka jajnika.

BACKGROUND: Neuropilin (NRP) may be used as a marker of lymphangiogenesis in malignant tumors. Significant correlations of the expression of NRP with tumor progression and overall survival prognosis were found in several cancer types. However; its potential role in epithelial ovarian cancer (EOC) has not been clarified. AIMS: The aim of the work was to study a possible correlation of neuropilin-1 (NRP-1) expression with selected clinical and histological features of EOC. MATERIAL AND METHODS: The study included 53 women (aged 23 to 81, mean 56.6 +/- 14.4 yrs), 38 of which were postmenopausal (71.7%). Immunohistochemical staining with a specific anti-NRP-1 antibody was performed in representative tumor tissue samples of patients with EOC. Both, percentage of stained lymphatic cells and intensity of staining were assessed under 200x magnification. The results were correlated with the menopausal status, FIGO stage, histological type and histological grade of EOC. RESULTS: Histological examination revealed that there were 27 cases of serous cancers (50%), 15 cases of mucinous cancer (28.3%) and 11 endometrioid cancers (20.7%). In 41.5% (n = 22) cases of EOC no NRP-1 staining was found, a weak (+) or strong (++) staining were found in 13 (24.5%) and 18 tumors, respectively There were no significant differences between neuropilin-1 expression and both menopausal status of women and histological type of EOC. Except for stage II, clinical EOC patients' FIGO stage was not correlated with the lack of expression (38.8% for stage I, 71.4% for stage II and 35.7% for stage III). CONCLUSION: We believe that neuropilin-1 expression is probably not related to clinical and histological features of epithelial ovarian cancer:

Fertility following laparoscopic uterine myomectomy in an infertile patient treated for 10 years. Case report.

The presence of myomas in the uterus is a relevant factor in infertility cases. Myomas may reduce contractility of the uterus, hinder migration of sperm and vascular changes within myomas themselves interfere with embryo implantation. The paper presents the case of a patient with over 10-year-history of infertility treatment diagnosed with numerous myomas of the uterus. The medical records revealed that the patient had undergone laparoscopy and laparotomy due to the left ovarian cyst and had been subjected to hysteroscopic removal of the uterine partition twice. The patient took part in the IVF programme twice--without success. At our Department the patient underwent laparoscopic myomectomy during which 5 myomas were removed: 4 subserous ones, 1.5-2 cm in diameter and an intramural one, 6 cm in diameter. The sites of the biggest myoma were laparoscopically sewn putting in 3 single sutures. In her next cycle the patient spontaneously conceited. The pregnancy was without serious complications and at 38 weeks was terminated by Caesarian section. The infant was delivered in good general condition (10 Apgar points) and weighted 3,360 g. On Caesarian section no uterine dehiscence following laparoscopic myomectomy was observed.