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Ultrasound in Obstetrics & Gynecology :... Aug 2022The primary aim of this study was to describe the ultrasound features of various endometrial and other intracavitary pathologies in women without abnormal uterine... (Observational Study)
Observational Study
OBJECTIVES
The primary aim of this study was to describe the ultrasound features of various endometrial and other intracavitary pathologies in women without abnormal uterine bleeding (AUB) using the International Endometrial Tumor Analysis (IETA) terminology. The secondary aim was to compare our findings with published data on women with AUB.
METHODS
This was a prospective observational study of women presenting at one of seven centers specialized in gynecological ultrasonography, from 2011 until 2018, for indications unrelated to AUB. All patients underwent transvaginal ultrasound using the IETA examination and measurement techniques. Ultrasonography was performed as part of routine gynecological examination or follow-up of non-endometrial pathology, or as part of the work-up before undergoing treatment for infertility, uterine prolapse or ovarian pathology. Ultrasound findings were described using the IETA terminology. Endometrial sampling was performed after the ultrasound scan. The histological endpoints were endometrial atrophy, proliferative or secretory endometrium, endometrial hyperplasia without atypia, endometrial polyp, intracavitary leiomyoma, endometrial intraepithelial neoplasia (EIN), endometrial cancer (EC) and insufficient tissue. The findings in our cohort of women without AUB were compared with those in a published cohort of women with AUB who were examined with transvaginal ultrasound between 2012 and 2015 using the same IETA examination technique and terminology.
RESULTS
In this study (IETA3), we included 1745 women without AUB who underwent a standardized transvaginal ultrasound examination followed by either endometrial sampling with histological diagnosis (n = 1537) or at least 1 year of clinical and ultrasound follow-up (n = 208). Of these, 858 (49.2%) women were premenopausal and 887 (50.8%) were postmenopausal. Histology showed the presence of EC and/or EIN in 29 (1.7%) women, endometrial polyps in 1028 (58.9%), intracavitary myomas in 66 (3.8%), proliferative or secretory changes or hyperplasia without atypia in 144 (8.3%), endometrial atrophy in 265 (15.2%) and insufficient tissue in five (0.3%). Most cases of EC or EIN (25/29 (86.2%)) were diagnosed after menopause. The mean endometrial thickness in women with EC or EIN was 11.2 mm (95% CI, 8.9-13.6 mm), being on average 2.4 mm (95% CI, 0.3-4.6 mm) thicker than their benign counterparts. Women with malignant endometrial pathology manifested more frequently non-uniform echogenicity (22/29 (75.9%)) than did those with benign endometrial pathology (929/1716 (54.1%)) (difference, +21.8% (95% CI, +4.2% to +39.2%)). Moderate to abundant vascularization (color score 3-4) was seen in 31.0% (9/29) of cases with EC or EIN compared with 12.8% (220/1716) of those with a benign outcome (difference, +18.2% (95% CI, -0.5% to +36.9%)). Multiple multifocal vessels were recorded in 24.1% (7/29) women with EC or EIN vs 4.0% (68/1716) of those with a benign outcome (difference, +20.2% (95% CI, +4.6% to +35.7%)). A regular endometrial-myometrial junction was seen less frequently in women with EC or EIN (19/29 (65.5%)) vs those with a benign outcome (1412/1716 (82.3%)) (difference, -16.8% (95% CI, -34.2% to +0.6%)). In women with endometrial polyps without AUB, a single dominant vessel was the most frequent vascular pattern (666/1028 (64.8%)). In women with EC, both in those with and those without AUB, the endometrium usually manifested heterogeneous echogenicity, but the endometrium was on average 8.6 mm (95% CI, 5.2-12.0 mm) thinner and less intensely vascularized (color score 3-4: difference, -26.8% (95% CI, -52.2% to -1.3%)) in women without compared to those with AUB. In both pre- and postmenopausal women, asymptomatic endometrial polyps were associated with a thinner endometrium, and they manifested more frequently a bright edge, a regular endometrial-myometrial junction and a single dominant vessel than did polyps in symptomatic women, and they were less intensely vascularized.
CONCLUSIONS
We describe the typical ultrasound features of EC, polyps and other intracavitary histologies using IETA terminology in women without AUB. Our findings suggest that the presence of asymptomatic polyps or endometrial malignancy may be accompanied by thinner and less intensely vascularized endometria than their symptomatic counterparts. © 2022 International Society of Ultrasound in Obstetrics and Gynecology.
Topics: Atrophy; Endometrial Hyperplasia; Endometrial Neoplasms; Endometrium; Female; Humans; Male; Polyps; Ultrasonography; Uterine Diseases; Uterine Hemorrhage; Uterine Neoplasms
PubMed: 35385178
DOI: 10.1002/uog.24910 -
Nature Communications Sep 2022We have recently reported that some cancers induce accumulation of bone marrow (BM) B-cell precursors in the spleen to convert them into metastasis-promoting,...
We have recently reported that some cancers induce accumulation of bone marrow (BM) B-cell precursors in the spleen to convert them into metastasis-promoting, immunosuppressive B cells. Here, using various murine tumor models and samples from humans with breast and ovarian cancers, we provide evidence that cancers also co-opt differentiation of these B-cell precursors to generate macrophage-like cells (termed B-MF). We link the transdifferentiation to a small subset of CSF1R Pax5 cells within BM pre-B and immature B cells responding to cancer-secreted M-CSF with downregulation of the transcription factor Pax5 via CSF1R signaling. Although the primary source of tumor-associated macrophages is monocytes, B-MFs are phenotypically and functionally distinguishable. Compared to monocyte-derived macrophages, B-MFs more efficiently phagocytize apoptotic cells, suppress proliferation of T cells and induce FoxP3 regulatory T cells. In mouse tumor models, B-MFs promote shrinkage of the tumor-infiltrating IFNγ CD4 T cell pool and increase cancer progression and metastasis, suggesting that this cancer-induced transdifferentiation pathway is functionally relevant and hence could serve as an immunotherapeutic target.
Topics: Animals; B-Lymphocytes; Cell Differentiation; Humans; Macrophages; Mice; Monocytes; Neoplasms
PubMed: 36104343
DOI: 10.1038/s41467-022-33117-y -
International Journal of Molecular... Dec 2023Thrombocytes play an essential role in hemostasis and thrombosis. Moreover, the controlled activation of thrombocytes is required in reproduction and fertility. The... (Review)
Review
Thrombocytes play an essential role in hemostasis and thrombosis. Moreover, the controlled activation of thrombocytes is required in reproduction and fertility. The platelet-activating factor and the controlled activation of platelets have important roles in folliculogenesis, ovulation, placental development, implantation and embryo development. Activated platelets accumulate in the follicular vessels surrounding the follicle and, due to its released soluble molecules (factors, mediators, chemokines, cytokines, neurotransmitters), locally increase oocyte maturation and hormone secretion. Furthermore, activated platelets are involved in the pathogenesis of ovarian hyperstimulation syndrome (OHSS) and preeclampsia. Low-dose aspirin can prevent OHSS during ovulation induction, while intrauterine or intraovarian administration of platelet-rich plasma (PRP) increases the endometrium thickness and receptivity as well as oocyte maturation. Activated thrombocytes rapidly release the contents of intracellular granules and have multiple adhesion molecules and receptors on their surface. Considering the numerous homeostatic endocrine functions of thrombocytes, it is reasonable to suppose a platelet-associated regulatory system (PARS) in reproduction. Although we are far from a complete understanding of the regulatory processes, the results of PARS research and the therapeutic application of aspirin and PRP during in vitro fertilization are promising.
Topics: Pregnancy; Female; Humans; Blood Platelets; Placenta; Fertility; Fertilization in Vitro; Embryo Implantation; Ovarian Hyperstimulation Syndrome; Platelet-Rich Plasma; Aspirin
PubMed: 38139165
DOI: 10.3390/ijms242417336 -
Frontiers in Immunology 2023Ovarian cancer (OC) is an aggressive malignancy characterized by a complex immunosuppressive tumor microenvironment (TME). Immune checkpoint inhibitors have emerged as a... (Review)
Review
Ovarian cancer (OC) is an aggressive malignancy characterized by a complex immunosuppressive tumor microenvironment (TME). Immune checkpoint inhibitors have emerged as a breakthrough in cancer therapy by reactivating the antitumor immune response suppressed by tumor cells. However, in the case of OC, these inhibitors have failed to demonstrate significant improvements in patient outcomes, and existing biomarkers have not yet identified promising subgroups. Consequently, there remains a pressing need to understand the interplay between OC tumor cells and their surrounding microenvironment to develop effective immunotherapeutic approaches. This review aims to provide an overview of the OC TME and explore its potential as a therapeutic strategy. Tumor-infiltrating lymphocytes (TILs) are major actors in OC TME. Evidence has been accumulating regarding the spontaneous TILS response against OC antigens. Activated T-helpers secrete a wide range of inflammatory cytokines with a supportive action on cytotoxic T-cells. Simultaneously, mature B-cells are recruited and play a significant antitumor role through opsonization of target antigens and T-cell recruitment. Macrophages also form an important subset of innate immunity (M1-macrophages) while participating in the immune-stimulation context. Finally, OC has shown to engage a significant natural-killer-cells immune response, exerting direct cytotoxicity without prior sensitization. Despite this initial cytotoxicity, OC cells develop various strategies to induce an immune-tolerant state. To this end, multiple immunosuppressive molecules are secreted to impair cytotoxic cells, recruit regulatory cells, alter antigen presentation, and effectively evade immune response. Consequently, OC TME is predominantly infiltrated by immunosuppressive cells such as FOXP3 regulatory T-cells, M2-polarized macrophages and myeloid-derived suppressor cells. Despite this strong immunosuppressive state, PD-1/PD-L1 inhibitors have failed to improve outcomes. Beyond PD-1/PD-L1, OC expresses multiple other immune checkpoints that contribute to immune evasion, and each representing potential immune targets. Novel immunotherapies are attempting to overcome the immunosuppressive state and induce specific immune responses using antibodies adoptive cell therapy or vaccines. Overall, the OC TME presents both opportunities and obstacles. Immunotherapeutic approaches continue to show promise, and next-generation inhibitors offer exciting opportunities. However, tailoring therapies to individual immune characteristics will be critical for the success of these treatments.
Topics: Humans; Female; Programmed Cell Death 1 Receptor; Immunotherapy; T-Lymphocytes, Cytotoxic; Lymphocytes, Tumor-Infiltrating; Ovarian Neoplasms; Immunosuppressive Agents; Tumor Microenvironment
PubMed: 38164130
DOI: 10.3389/fimmu.2023.1328651 -
International Journal of Molecular... May 2023Ovarian cancer (OC) is one of the deadliest gynecological cancers, largely due to the fast development of metastasis and drug resistance. The immune system is a critical... (Review)
Review
Ovarian cancer (OC) is one of the deadliest gynecological cancers, largely due to the fast development of metastasis and drug resistance. The immune system is a critical component of the OC tumor microenvironment (TME) and immune cells such as T cells, NK cells, and dendritic cells (DC) play a key role in anti-tumor immunity. However, OC tumor cells are well known for evading immune surveillance by modulating the immune response through various mechanisms. Recruiting immune-suppressive cells such as regulatory T cells (Treg cells), macrophages, or myeloid-derived suppressor cells (MDSC) inhibit the anti-tumor immune response and promote the development and progression of OC. Platelets are also involved in immune evasion by interaction with tumor cells or through the secretion of a variety of growth factors and cytokines to promote tumor growth and angiogenesis. In this review, we discuss the role and contribution of immune cells and platelets in TME. Furthermore, we discuss their potential prognostic significance to help in the early detection of OC and to predict disease outcome.
Topics: Female; Humans; Blood Platelets; Myeloid Cells; Neoplasms; Ovarian Neoplasms; Prognosis; Tumor Microenvironment; Immune System; Receptor Cross-Talk
PubMed: 37298230
DOI: 10.3390/ijms24119279 -
Journal of Ovarian Research Aug 2023MUC16 (CA125) is a commonly used tumor marker for ovarian cancer screening and reported to be an immunosuppressive factor by acting on the sialic acid-binding...
BACKGROUND
MUC16 (CA125) is a commonly used tumor marker for ovarian cancer screening and reported to be an immunosuppressive factor by acting on the sialic acid-binding immunoglobulin-like lectin-9 (Siglec-9) on the surface of natural killer cells (NK cells), B cells, and monocytes. However, the role of MUC16 on neutrophils in the tumor microenvironment remains to be further explored.
METHODS
The correlation between the proportion and count of peripheral blood cells, serum inflammatory-related factors and serum MUC16 (CA125) level in patients was constructed based on clinical samples. RNAseq data was obtained from TCGA and sequencing of ovarian cancer tissues, followed by TIMER immune cell infiltration and correlation analysis. Ovarian cancer organoid was constructed to stimulate neutrophils with immunophenotype identification by qPCR and flow cytometry. MUC16 protein stimulation to neutrophils validated the role of MUC16 under the analysis of RNA sequencing and inhibition of NK cytotoxicity in vitro.
RESULTS
The serum MUC16 level was positively correlated with the proportion and count of peripheral blood neutrophils, neutrophil-to-lymphocyte ratio (NLR) and inflammatory factors IL-6, IL-8, IL-10 and IL-2R. Siglec-9, the receptor of MUC16, was expressed on neutrophils and was positively correlated to neutrophil infiltration in ovarian cancer. After the stimulation of ovarian cancer organoids and MUC16 respectively, the proportions of CD11b, CD66b, and ICAM-1 neutrophils were significantly increased, while the proportion of CXCR4 neutrophils was slightly decreased, with increasing of of inflammatory factors MMP9, IL-8, OSM, IL-1β, TNF-α, CXCL3, and ROS. RNA-sequencing analysis revealed that inflammatory response, TNFA signaling pathway, and IL6-related pathway were upregulated in MUC16-stimulated neutrophils, accompanied by high expression of immunosuppression-related factors HHLA2, IL-6, TNFRSF9, ADORA2A, CD274 (PD-L1), and IDO1. NK cytotoxicity was decreased when treated by supernanant of MUC16-stimulated neutrophils in vitro.
CONCLUSION
MUC16 acted on neutrophils by Siglec-9 leading to an inflammatory and immunosuppressive phenotype in ovarian cancer.
Topics: Female; Humans; Ovarian Neoplasms; Interleukin-6; Interleukin-8; Neutrophils; B-Lymphocytes; CA-125 Antigen; Tumor Microenvironment; Membrane Proteins; Immunoglobulins
PubMed: 37644468
DOI: 10.1186/s13048-023-01207-0 -
Cancer Biology & Therapy 2015The accumulation of tumor infiltrating lymphocytes (TILs) in ovarian cancer is prognostic for increased survival while increases in immunosuppressive regulatory T-cells... (Review)
Review
The accumulation of tumor infiltrating lymphocytes (TILs) in ovarian cancer is prognostic for increased survival while increases in immunosuppressive regulatory T-cells (Tregs) are associated with poor outcomes. Approaches that bolster tumor-reactive TILs may limit tumor progression. However, identifying tumor-reactive TILs in ovarian cancer has been challenging, though adoptive TIL therapy in patients has been encouraging. Other forms of TIL immunomodulation remain under investigation including Treg depletion, antibody-based checkpoint modification, activation and amplification using dendritic cells, antigen presenting cells or IL-2 cytokine culture, adjuvant cytokine injections, and gene-engineered T-cells. Many approaches to TIL manipulation inhibit ovarian cancer progression in preclinical or clinical studies as monotherapy. Here, we review the impact of TILs in ovarian cancer and attempts to mobilize TILs to halt tumor progression. We conclude that effective TIL therapy for ovarian cancer is at the brink of translation and optimal TIL activity may require combined methodologies to deliver clinically-relevant treatment.
Topics: Animals; Cancer Vaccines; Clinical Trials as Topic; Female; Humans; Immunomodulation; Immunotherapy, Adoptive; Lymphocyte Subsets; Lymphocytes, Tumor-Infiltrating; Ovarian Neoplasms; Prognosis; Treatment Outcome; Tumor Microenvironment
PubMed: 25894333
DOI: 10.1080/15384047.2015.1040960 -
Seminars in Oncology Jun 2014Growing understanding of the role of thrombocytosis, high platelet turnover, and the presence of activated platelets in the circulation in cancer progression and... (Review)
Review
Growing understanding of the role of thrombocytosis, high platelet turnover, and the presence of activated platelets in the circulation in cancer progression and metastasis has brought megakaryocytes into focus. Platelet biology is essential to hemostasis, vascular integrity, angiogenesis, inflammation, innate immunity, wound healing, and cancer biology. However, before megakaryocyte/platelet-directed therapies can be considered for clinical use, understanding of the mechanism and biology of paraneoplastic thrombocytosis in malignancy is required. Here, we provide an overview of the clinical implications, biological significance, and mechanisms of paraneoplastic thrombocytosis in the context of ovarian cancer.
Topics: Animals; Blood Platelets; Female; Humans; Ovarian Neoplasms; Paraneoplastic Syndromes; Thrombocytosis
PubMed: 25023353
DOI: 10.1053/j.seminoncol.2014.04.004 -
Frontiers in Immunology 2022Tissue-resident macrophages (TRMs) are highly heterogeneous and have a complex and important role in tissue support, homeostasis, and function. The heterogeneity,...
INTRODUCTION
Tissue-resident macrophages (TRMs) are highly heterogeneous and have a complex and important role in tissue support, homeostasis, and function. The heterogeneity, maintenance, and function of TRMs, as one of the major immune cells in the ovary, are not well understood.
METHODS
Application of flow cytometry, Parabiosis, Fate mapping, Macrophage depletion, etc.
RESULTS
Here, we described two distinct macrophage subsets, F4/80CD11b and F4/80CD11b, with different phenotypic characteristics in the ovary of mice. The F4/80CD11b population contained a distinct CD206 subgroup and highly expressed CD81, while the F4/80CD11b subset showed higher expression of CCR2 and TLR2. Notably, Ly6c macrophages were present almost exclusively in the F4/80CD11b subpopulation. Combining in vivo fate mapping and parabiotic mouse models, we characterized the longevity and replenishment of the two macrophage populations. We found that both the F4/80CD11b and F4/80CD11b subsets were ovary-resident. Importantly, the F4/80CD11b macrophages acted as a self-maintaining and long-lived population with a modest monocyte contribution at a steady state, and the F4/80CD11b subpopulation had a relatively short lifespan with a greater contribution from monocytes. After macrophage ablation, disturbance of estradiol secretion and ovarian hemorrhage due to damaged vascular integrity was observed in mice.
DISCUSSION
Our data provide critical insights into ovarian macrophage heterogeneity and highlight the strategic role of TRMs in ovarian homeostasis and physiology.
Topics: Female; Mice; Animals; Ovary; Macrophages; Monocytes; Disease Models, Animal
PubMed: 36605192
DOI: 10.3389/fimmu.2022.1007711 -
Journal of Ovarian Research May 2019Prognostic biomarkers are highly needed to properly manage patients with cancer and improve their clinical courses. The relationship between lymphocyte-to-monocyte ratio... (Meta-Analysis)
Meta-Analysis Review
INTRODUCTION
Prognostic biomarkers are highly needed to properly manage patients with cancer and improve their clinical courses. The relationship between lymphocyte-to-monocyte ratio (LMR) at diagnosis and ovarian cancer prognosis has been extensively studied, but little consensus has been reached regarding its utility as a biomarker of poor outcome. Thus, this study aimed to investigate the potential prognostic value of pretreatment LMR in such patients to shed light on this issue.
METHODS
We searched the scientific databases of MEDLINE, Embase, Cochrane Library, and WangFang for relevant studies about the inflammatory prognostic factor LMR in ovarian cancer, based on specific inclusion and exclusion criteria. The following parameters were analyzed among others: LMR values and respective cut-offs, patient's overall survival (OS) and progression-free survival (PFS), and clinicopathological features.
RESULTS
Eight studies, including 2259 patients, were eligible for inclusion in this meta-analysis. We found that low LMR was associated with both poor OS [Hazard ratio (HR): 1.92; 95% confidence interval (CI): 1.58-2.34; p < 0.001] and PFS (HR: 1.70; 95% CI: 1.54-1.88; p < 0.001). Moreover, our findings revealed that low LMR was correlated with high G2/G3 histological grade (OR: 1.67; 95% CI: 1.26-2.20; p < 0.001) and late III-IV FIGO stage tumors (OR: 3.55; 95% CI: 2.68-4.70; p < 0.001), high serum CA-125 level (OR: 2.18; 95% CI: 1.71-2.77; p < 0.001), and presence of malignant ascites (OR: 1.87; 95% CI: 1.11-3.14; p = 0.02) and lymph node metastases (OR: 1.70; 95% CI: 1.13-2.54; p = 0.01).
CONCLUSION
Pretreatment LMR is a potential prognostic marker of poor outcome in ovarian cancer patients and may thus be important in clinical care and disease control.
Topics: Biomarkers, Tumor; Female; Humans; Leukocyte Count; Lymphocytes; Monocytes; Ovarian Neoplasms; Prognosis; Progression-Free Survival; Survival Rate
PubMed: 31151469
DOI: 10.1186/s13048-019-0527-z