Accumulation of blood-circulating PD-L1-expressing M-MDSCs and monocytes/macrophages in pretreatment ovarian cancer patients is associated with soluble PD-L1.

BACKGROUND: Previous studies have shown clinical relevance of programmed death-ligand 1 (PD-L1) and soluble PD-L1 (sPD-L1) in human cancers. However, still contradictory results exist. Our aim was evaluation of PD-L1-expressing monocytic myeloid-derived suppressor cells (M-MDSCs), monocytes/macrophages (MO/MA), tumour cells (TC) and immune/inflammatory cells (IC) as well as investigation of the sPD-L1 in ovarian cancer (OC) patients. METHODS: The group of 74 pretreatment women were enrollment to the study. The expression of PD-L1 on M-MDSCS and MO/MA was assessed by flow cytometry. The profile of sPD-L1 was examined with ELISA. The expression of PD-L1 in mononuclear cells (MCs) was analyzed using real time PCR. PD-L1 immunohistochemical analysis was prepared on TC and IC. An in silico validation of prognostic significance of PD-L1 mRNA expression was performed based microarray datasets. RESULTS: OC patients had significantly higher frequency of MO/MA versus M-MDSC in the blood, ascites and tumour (each p < 0.0001). In contrast, PD-L1 expression was higher on M-MDSCs versus MO/MA in the blood and ascites (each p < 0.0001), but not in the tumour (p > 0.05). Significantly higher accumulation of blood-circulating M-MDSC, MO/MA, PD-L1+M-MDSC, PD-L1+MO/MA and sPD-L1 was observed in patients versus control (p < 0.001, p < 0.05, p < 0.001, p < 0.001 and p < 0.0001, respectively). Accumulation of these factors was clinicopathologic-independent (p > 0.05). The expression of PD-L1 was significantly higher on IC versus TC (p < 0.0001) and was clinicopathologic-independent (p > 0.05) except higher level of PD-L1+TC in the endometrioid versus mucinous tumours. Interestingly, blood-circulating sPD-L1 positively correlated with PD-L1+M-MDSCs (p = 0.03) and PD-L1+MO/MA (p = 0.02) in the blood but not with these cells in the ascites and tumours nor with PD-L1+TC/IC (each p > 0.05). PD-L1 and sPD-L1 were not predictors of overall survival (OS; each p > 0.05). Further validation revealed no association between PD-L1 mRNA expression and OS in large independent OC patient cohort (n = 655, p > 0.05). CONCLUSIONS: Although PD-L1 may not be a prognostic factor for OC, our study demonstrated impaired immunity manifested by up-regulation of PD-L1/sPD-L1. Furthermore, there was a positive association between PD-L1+ myeloid cells and sPD-L1 in the blood, suggesting that sPD-L1 may be a noninvasive surrogate marker for PD-L1+myeloid cells immunomonitoring in OC. Overall, these data should be under consideration during future clinical studies/trials.

Correction to: Accumulation of blood-circulating PD-L1-expressing M-MDSCs and monocytes/macrophages in pretreatment ovarian cancer patients is associated with soluble PD-L1.

An amendment to this paper has been published and can be accessed via the original article.

Gemcitabine and Selected mTOR Inhibitors in Uterine Sarcomas and Carcinosarcoma Cells- an Isobolographic Analysis.

Introduction: mTOR inhibitors are anticancer agents affecting mTOR/AKT/PI3K pathway that is one of the most important in human cancer cells. Hyperactivation of mTOR/AKT/PI3K and overexpression of this pathway members are frequently reported in uterine sarcoma and carcinosarcoma. Present study is aimed to assess the activity of the two mTOR inhibitors (rapamycin - RAP and sapanisertib - MLN) as a single agent and combined with gemcitabine (GEM, one of substances commonly used in systemic anticancer treatment) in uterine sarcoma and carcinosarcoma in vitro models. Material and methods: SK-UT-1 and SK-UT1-B (uterine carcinosarcoma), MES-SA (leiomyosarcoma) and ESS-1 (endometrial stromal sarcoma) cell lines were used. An MTT assay was performed to examine the cytotoxicity of RAP, MLN and mixtures: RAP+MLN, RAP+GEM, MLN+GEM against these cells. The interactions between tested compounds were assessed in isobolographic analysis. Results and conclusions: Carcinosarcoma cell lines (both SK-UT-1 and SK-UT-1B) do not respond to RAP and respond relatively weakly to MLN treatment. Additive and supraadditive effects were noted for combined treatment with GEM and MLN. Endometrial stromal sarcoma cell line (ESS-1) occured to be sensitive to both RAP and MLN, but the response was stronger for MLN. Additive effect of all tested drug combinations was observed for ESS-1. Leiomyosarcoma cell line (MES-SA) was found sensitive to both mTOR inhibitors. Additive effects in combinations of GEM, RAP and MLN were observed, what makes them promising for future preclinical and clinical trials. Additivity with slight tendency towards antagonism between GEM and MLN observed in MES-SA cell line is unexpected finding and might prompt the mechanistic research aimed to explain this phenomenon.

Fucoidan Structure and Activity in Relation to Anti-Cancer Mechanisms.

Fucoidan is a natural derived compound found in different species of brown algae and in some animals, that has gained attention for its anticancer properties. However, the exact mechanism of action is currently unknown. Therefore, this review will address fucoidans structure, the bioavailability, and all known different pathways affected by fucoidan, in order to formulate fucoidans structure and activity in relation to its anti-cancer mechanisms. The general bioactivity of fucoidan is difficult to establish due to factors like species-related structural diversity, growth conditions, and the extraction method. The main pathways influenced by fucoidan are the PI3K/AKT, the MAPK pathway, and the caspase pathway. PTEN seems to be important in the fucoidan-mediated effect on the AKT pathway. Furthermore, the interaction with VEGF, BMP, TGF-ß, and estrogen receptors are discussed. Also, fucoidan as an adjunct seems to have beneficial effects, for both the enhanced effectiveness of chemotherapy and reduced toxicity in healthy cells. In conclusion, the multipotent character of fucoidan is promising in future anti-cancer treatment. However, there is a need for more specified studies of the structure⁻activity relationship of fucoidan from the most promising seaweed species.

Blood-based analyses of cancer: Circulating myeloid-derived suppressor cells - is a new era coming?

Progress in cancer treatment made by the beginning of the 21st century has shifted the paradigm from one-size-fits-all to tailor-made treatment. The popular vision, to study solid tumors through the relatively noninvasive sampling of blood, is one of the most thrilling and rapidly advancing fields in global cancer diagnostics. From this perspective, immune-cell analysis in cancer could play a pivotal role in oncology practice. This approach is driven both by rapid technological developments, including the analysis of circulating myeloid-derived suppressor cells (cMDSCs), and by the increasing application of (immune) therapies, the success or failure of which may depend on effective and timely measurements of relevant biomarkers. Although the implementation of these powerful noninvasive diagnostic capabilities in guiding precision cancer treatment is poised to change the ways in which we select and monitor cancer therapy, challenges remain. Here, we discuss the challenges associated with the analysis and clinical aspects of cMDSCs and assess whether the problems in implementing tumor-evolution monitoring as a global tool in personalized oncology can be overcome.

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.

[Characterization of chosen pro-angiogenic factors and anti-angiogenic therapies in ovarian cancer].

Ovarian cancer is a neoplasm characterized by notably malignancy. The poor results of treatment result not only from the lack of screening tests making diagnosis possible at an early stage, but also because of the insufficiently effective treatment methods. High hopes are placed in targeted therapies, using agents such as angiogenesis inhibitors, immune checkpoint inhibitors or anticancer vaccines. The aim of the work is to present the latest results of research on antiangiogenic drugs. Databases such as PubMed, Google Scholar and ClinicalTrials.gov were used. Antiangiogenic drugs are substances of various structure, the common feature of which is the influence on signaling pathways associated with such factors as VEGF, PDGF or Ang1 / 2. Bevacizumab is an antibody directed against VEGF-A. It is the first anti-angiogenic drug with proven efficacy, expressed in the extension of overall survival. This was demonstrated both in the group of patients with newly diagnosed advanced disease and in the situation of relapse. Other anti-angiogenic agents, such as trebananib, nintedanib or pazopanib, currently have not been proven to possess comparably high efficacy in the treatment of ovarian cancer. There are no known causes of disease progression despite maintenance therapy. The potential for combining bevacizumab with other targeted drugs such as PD-L1 inhibitors is currently being investigated.

[The sexuality of woman in puerperium].

After the birth various physical, hormonal and psychological changes affect women's emotional status. These significantly impact their family life including the quality of sexual relationships. Among these factors the method of birth, hormonal changes, breast feeding and incidence of postpartal depression are considered to affect relations with the partner. Unfortunately the sexuality in this special time in women's life is commonly avoided or underestimated both by woman and doctors.

Genetic analysis of uterine aspirates improves the diagnostic value and captures the intra-tumor heterogeneity of endometrial cancers.

Endometrial cancer is the most common cancer of the female genital tract in developed countries. Although the majority of endometrial cancers are diagnosed at early stages and the 5-year overall survival is around 80%, early detection of these tumors is crucial to improve the survival of patients given that the advanced tumors are associated with a poor outcome. Furthermore, correct assessment of the pre-clinical diagnosis is decisive to guide the surgical treatment and management of the patient. In this sense, the potential of targeted genetic sequencing of uterine aspirates has been assessed as a pre-operative tool to obtain reliable information regarding the mutational profile of a given tumor, even in samples that are not histologically classifiable. A total of 83 paired samples were sequenced (uterine aspirates and hysterectomy specimens), including 62 endometrioid and non-endometrioid tumors, 10 cases of atypical hyperplasia and 11 non-cancerous endometrial disorders. Even though diagnosing endometrial cancer based exclusively on genetic alterations is currently unfeasible, mutations were mainly found in uterine aspirates from malignant disorders, suggesting its potential in the near future for supporting the standard histologic diagnosis. Moreover, this approach provides the first evidence of the high intra-tumor genetic heterogeneity associated with endometrial cancer, evident when multiple regions of tumors are analyzed from an individual hysterectomy. Notably, the genetic analysis of uterine aspirates captures this heterogeneity, solving the potential problem of incomplete genetic characterization when a single tumor biopsy is analyzed.

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.

Management of uterine leiomyosarcoma.

The low incidence of uterine sarcomas requires many issues associated with its biology and clinical course to be followed with more research. Unsatisfactory surgical outcomes and a high risk of cancer dissemination make it worthwhile to consider the feasibility of supplementary systemic treatment. The currently employed chemo- and hormonal therapy is characterised by low efficacy. There is some hope in reports on targeted treatment. However, a comprehensive assessment of the efficacy of this kind of therapy is restricted by a small number of patients using it. Moreover, clinical studies using targeted therapies involve patients with a highly advanced disease, and the therapeutic results are assessed mainly via analysis of progression-free survival but not the clinical response.

[Decision-to-delivery interval (DDI) for emergency cesarean sections in Polish healthcare system]. / Czas od podjecia decyzji o wykonaniu ciecia cesarskiego do wydobycia dziecka (DDI) w warunkach polskiego systemu ochrony zdrowia.

Cesarean section is one of most common obstetric procedures, with the incidence of 33.9-43.1% of all labors in Poland. If the indication for cesarean section is 'immediate threat to maternal or fetal life', then the procedure must be performed without delay. The fact that time elapsed between decision to operate and delivery (decision-to-delivery interval, DDI) affects fetal outcome has been widely discussed. Poland lacks recommendations for optimal DDI in emergency cesarean section but some foreign scientific associations, universally recognized as an authority recommend DDI not to exceed 30 minutes in such cases. Our review attempts to determine the most significant factors affecting DDI, which can be divided according to the competence and responsibility of people involved in the functioning of the obstetrics department. Obstetrician-depending factors include appropriate diagnosis of indications for cesarean section and proficiency during procedure (incision-to-delivery interval). Midwives are responsible for preparation of the patient and the operating theater as well as transport of the patient. Anesthesiologists deem patients eligible for anesthesia and are also responsible for efficiency of its administration. Furthermore, few additional factors which seem to be fundamentally important in achieving optimal DDI have been identified and they depend on hospital management decisions, namely sufficient number of qualified staff, regular training in emergency procedures, availability of operating theaters, as well as fast and safe transportation of patients between the admission room, obstetrics department and operating theaters. In conclusion, we wish to emphasize that optimal DDI depends on proper collaboration of numerous teams, what may be important when discussing personal responsibility in obstetric failures.

[Expression of caspase 9 and p53 in uterine leiomyosarcomas]. / Ocena ekspresji kaspazy 9 i bialka p53 w miesakach macicy.

UNLABELLED: Uterine sarcomas are heterogeneous malignancies, both clinically and histologically. The process of oncogenesis depends on gene mutations and uncontrolled mitotic cell division that is promoted by blocking pathways of apoptosis. Caspase 9 and p53 protein play an important role in the process of cell apoptosis. OBJECTIVES: The aim of the study was to assess the expression of selected apoptosis proteins (caspase 9 and p53) using immunohistochemistry. MATERIAL AND METHODS: A total of 28 tissue samples diagnosed in postoperative histopathological examination as leiomyosarcoma were tested. Twenty eight samples of leiomyomas were used as the control group. Colorful reactions with appropriate antibodies were performed to assess the expression of caspase 9 and p53. From every section 5 fields on view were chosen, in each one 100 cells were assessed using 400x magnification. T-Student parametric test and U Mann-Whitney test were used for statistical analysis. RESULTS: Expression of caspase 9 was significantly lower (p < 0.05) in leiomyosarcoma tissues (33.2%) as compared to leiomyomas (60.4%). Expression of p53 protein was significantly lower in leiomyosarcoma tissues than in leiomyomas (30.1% vs. 51.3%, p < 0.001). CONCLUSIONS: Significantly lower expression of caspase 9 and p53 in leiomyosarcoma tissue samples suggests that impaired deregulation of apoptosis mechanisms plays a role in the development of these tumors.

Scientific and clinical relevance of non-cellular tumor microenvironment components in ovarian cancer chemotherapy resistance.

The tumor microenvironment (TME) components play a crucial role in cancer cells' resistance to chemotherapeutic agents. This phenomenon is exceptionally fundamental in patients with ovarian cancer (OvCa), whose outcome depends mainly on their response to chemotherapy. Until now, most reports have focused on the role of cellular components of the TME, while less attention has been paid to the stroma and other non-cellular elements of the TME, which may play an essential role in the therapy resistance. Inhibiting these components could help define new therapeutic targets and potentially restore chemosensitivity. The aim of the present article is both to summarize the knowledge about non-cellular components of the TME in the development of OvCa chemoresistance and to suggest targeting of non-cellular elements of the TME as a valuable strategy to overcome chemoresistance and to develop new therapeutic strategies in OvCA patients.

The Potential Influence of Residual or Recurrent Disease on Bevacizumab Treatment Efficacy in Ovarian Cancer: Current Evidence and Future Perspectives.

There were high hopes for the new antiangiogenic medicament, bevacizumab, which could inhibit the creation of new blood vessels through binding to isoform A of vascular endothelial growth factor (VEGF). However, it is not only blood vessels that are responsible for tumor cell spread. During the process of tumor growth, lymphangiogenesis is mediated by other members of the VEGF family, specifically VEGF-C and VEGF-D, which act independent to bevacizumab. Therefore, based on the mechanism of bevacizumab action and the processes of angio- and lymphangiogenesis, we formed three hypotheses: (1) if the lymph nodes in primary ovarian cancers are metastatic, the outcome of bevacizumab treatment is worsened; (2) concerning the second-line treatment, bevacizumab will act in a weakened manner if recurrence occurs in lymph nodes as opposed to a local recurrence; (3) patients treated by bevacizumab are more likely to have recurrences in lymph nodes. These hypotheses raise the issue of the existing knowledge gap, which concerns the effect of bevacizumab on metastatic lymph nodes.

Assessment of the Impact of SARS-CoV-2 Infection on the Sexual Function of Women, Levels of Oxytocin and Prolactin: A Prospective Cohort Study.

(1) Background: There is a lack of direct evidence on whether SARS-CoV-2 affects women's sexual function through a biological-organic mechanism. Existing studies on the topic are few and have produced contradictory results. This study aims to explore the possible relationship between sex hormones and sexual function in patients who have been infected with SARS-CoV-2. Moreover, we aimed to determine whether these changes are related to the clinical course of COVID-19 and whether they are temporary or long-lasting. (2) Methods: A study was conducted on 104 women, including 64 women infected with COVID-19 and a control group of 40 healthy women, between January 2021 and August 2022. Blood samples were collected to measure prolactin and oxytocin levels, and a clinical assessment was performed 3 and 6 months later. Sexual function self-assessment was captured based on the FSFI scale. (3) Results: Our study found that patients with severe COVID-19 had better sexual satisfaction scores one month after recovery but no discernible difference after six months. High levels of serum prolactin were observed in patients with active COVID-19 but became similar to a control group after one month and remained stable over time. Higher prolactin levels were significantly associated with increased arousal and hydration. Individuals with severe COVID-19 had notably low levels of plasma oxytocin, but there was no correlation between oxytocin levels and sexual satisfaction. (4) Conclusions: The gynecologic symptoms, as well as disturbances in oxytocin and prolactin levels, might be observed in a short time after infection. However, SARS-CoV-2 infection has no lasting effect on sexual function, oxytocin, and prolactin levels among women.

Perioperative Factors Affecting the Healing of Rectovaginal Fistula.

Rectovaginal fistula is rare, but a severe complication in gynecology, which despite the effort of clinicians is still not treated successfully in many cases. According to statistics, the healing rates of surgery in patients with RVF range from 20 to 100%. The treatment effectiveness depends on the etiology of fistula, the age of the patients, the presence of comorbidities, the type of surgery and many other factors. Considering the low efficiency of treatment and the high risk of recurrence, the question of possible methods to improve the results occurs. In our review, we analyzed both modifiable and non-modifiable factors which may influence the treatment, healing rate and future fate of the patients. Taking into account all analyzed risk factors, including age, comorbidities, smoking status, microbiology, medications, stoma and stool features, we are aware that rectovaginal fistula's treatment must be individualized and holistic. In cases of poorly healing RVF, the drainage of feces, the use of antibiotic prophylaxis or the implementation of estrogen therapy may be useful. Moreover, microbiome research in women with RVF and towards estrogen therapy should be performed in order to create treatment algorithms in women with fistulae. Those interventions, in our opinion, may significantly improve the outcome of the patients.

Preoperative Differentiation of Uterine Leiomyomas and Leiomyosarcomas: Current Possibilities and Future Directions.

The distinguishing of uterine leiomyosarcomas (ULMS) and uterine leiomyomas (ULM) before the operation and histopathological evaluation of tissue is one of the current challenges for clinicians and researchers. Recently, a few new and innovative methods have been developed. However, researchers are trying to create different scales analyzing available parameters and to combine them with imaging methods with the aim of ULMs and ULM preoperative differentiation ULMs and ULM. Moreover, it has been observed that the technology, meaning machine learning models and artificial intelligence (AI), is entering the world of medicine, including gynecology. Therefore, we can predict the diagnosis not only through symptoms, laboratory tests or imaging methods, but also, we can base it on AI. What is the best option to differentiate ULM and ULMS preoperatively? In our review, we focus on the possible methods to diagnose uterine lesions effectively, including clinical signs and symptoms, laboratory tests, imaging methods, molecular aspects, available scales, and AI. In addition, considering costs and availability, we list the most promising methods to be implemented and investigated on a larger scale.

Clinical Relevance and Immunosuppressive Pattern of Circulating and Infiltrating Subsets of Myeloid-Derived Suppressor Cells (MDSCs) in Epithelial Ovarian Cancer.

Myeloid-derived suppressor cells (MDSCs) expansion is a hallmark of cancer. Three major MDSC subsets defined as monocytic (M)-MDSCs, polymorphonuclear (PMN)-MDSCs and early stage (e)MDSCs can be revealed in human diseases. However, the clinical relevance and immunosupressive pattern of these cells in epithelial ovarian cancer (EOC) are unknown. Therefore, we performed a comprehensive analysis of each MDSC subset and immunosupressive factors in the peripheral blood (PB), peritoneal fluid (PF), and the tumor tissue (TT) samples from EOC and integrated this data with the patients' clinicopathological characteristic. MDSCs were analyzed using multicolor flow cytometry. Immunosuppressive factors analysis was performed with ELISA and qRT-PCR. The level of M-MDSCs in the PB/PF/TT of EOC was significantly higher than in healthy donors (HD); frequency of PMN-MDSCs was significantly greater in the TT than in the PB/PF and HD; while the level of eMDSCs was greater in the PB compared with the PF and HD. Elevated abundance of tumor-infiltrating M-MDSCs was associated with advanced stage and high grade of EOC. An analysis of immunosuppressive pattern showed significantly increased blood-circulating ARG/IDO/IL-10-expressing M- and PMN-MDSCs in the EOC patients compared with HD and differences in the accumulation of these subsets in the three tumor immune microenvironments (TIME). This accumulation was positively correlated with levels of TGF-ß and ARG1 in the plasma and PF. Low level of blood-circulating and tumor-infiltrating M-MDSCs, but neither PMN-MDSCs nor eMDSCs was strongly associated with prolonged survival in ovarian cancer patients. Our results highlight M-MDSCs as the subset with potential the highest clinical significance.