Peritoneum Of Patients Research Articles

Correlation Between the 8-hydroxy-2'-deoxyguanosine Levelin the Peritoneal Solution of Patients Undergoing PeritonealDialysis and the Peritoneal Equilibration Test, Kt/V, Ferritin,and Albumin Levels.

Peritoneal dialysis (PD) is an effective treatment modality for advanced kidney failure, offering patients a significant degree of independence. However, the long-term use of PD is limited due to the degeneration of the peritoneal membrane, resulting in reduced dialysis adequacy. Evaluating the peritoneal membrane condition in patients with advanced kidney failure who are undergoing PD is challenging with existing methods. Therefore, this study aimed to investigate the correlation between 8-hydroxy-2'-deoxyguanosine (8OHDG) levels in the peritoneal solution of patients undergoing PD and various factors, such as peritoneal equilibration test (PET), dialysis adequacy (Kt/V), underlying diseases, serum ferritin, and albumin levels. 8OHDG is a sensitive marker of oxidative stress caused by DNA damage. A total of 56 patients were included in this cross-sectional study. Five milliliters of PD fluid were collected from the patients, and 8-OHdG levels were measured using ELISA method. Then, they were compared with PET, Kt/V, albumin, and ferritin markers in the patients' files, and the results were analyzed by statistical tests. The study examined the correlation between 8OHDG and other markers. It was found that this index had significant associations with PET and underlying HTN (P < .05), whereas no significant associations were identified with the other markers. The results of the present study demonstrate that the level of 8OHDG, as one of the oxidative stress markers, could be used to evaluate the function of the peritoneum in patients undergoing PD. DOI: 10.52547/ijkd.7654.

Exosomes released from PD-L1+ tumor associated macrophages promote peritoneal metastasis of epithelial ovarian cancer by up-regulating T cell lipid metabolism

Epithelial ovarian cancer (EOC) tends to metastasize to the peritoneum, and the prognosis of patients is poor. In the peritoneum of patients with EOC, TAMs (tumor associated macrophages) regulate the imbalance of T cell ratio and promote the progression and metastasis of EOC. However, the mechanism of peritoneal metastasis in EOC patients remains unclear. Here, we confirmed that the percentages of PD-L1+ TAMs in EOC tissues increased significantly, and TAMs-derived PD-L1+ exosomes affected the transcription factor PPARα to up-regulate the expression of CPT1A in CD8+ T cells, promote fatty acid oxidation, and increase reactive oxygen species to cause cell damage. The apoptosis of CD8+ T cells was increased, and the expressions of their exhaustion markers LAG3, TIM-3, and PD-1 were also up-regulated. TAMs affect T cell function through lipid metabolism, leading to peritoneal immune imbalance and promoting peritoneal metastasis of EOC. This study reveals the mechanism by which TAMs in the peritoneal microenvironment regulate T cell lipid metabolism through exosome delivery of PD-L1, and the effect of lipid metabolism on T cell function, reveals the molecular mechanism of tumor immune microenvironment affecting EOC metastasis, and further explores related pathways whether molecular blockade can be used as a means to intervene in disease progression is expected to establish a new strategy for the diagnosis and treatment of EOC.

Peritoneal Expression of Membrane Complement Regulators Is Decreased in Peritoneal Dialysis Patients with Infected Peritonitis.

In peritoneal dialysis (PD) patients, fungi and Pseudomonas aeruginosa are considered important causative microorganisms for peritonitis with poor prognosis. Our objective was to explore expressions of membrane complement (C) regulators (CRegs) and tissue injuries in the peritoneum of patients with PD-related peritonitis, including fungal and Pseudomonas aeruginosa peritonitis. In peritoneal biopsy tissues obtained at PD catheter removal, we investigated the severity of peritonitis-associated peritoneal injuries and the expression of CRegs, CD46, CD55, and CD59 against peritoneal tissues without any episode of peritonitis. In addition, we evaluated peritoneal injuries among fungal and Pseudomonas aeruginosa-peritonitis (P1) and Gram-positive bacterial peritonitis (P2). We also observed deposition of C activation products such as activated C and C5b-9 and measured sC5b-9 in the PD fluid of patients. As a result, the severity of peritoneal injuries correlated inversely with the expression of peritoneal CRegs. Peritoneal CReg expression in peritonitis was significantly reduced compared to no peritonitis. Peritoneal injuries were more severe in P1 than in P2. CReg expression was further decreased and C5b-9 further increased in P1 than in P2. In conclusion, severe peritoneal injuries due to fungal and Pseudomonas aeruginosa-peritonitis decreased CReg expression and increased deposition of activated C3 and C5b-9 in the peritoneum, suggesting that peritonitis, particularly fungal and Pseudomonas aeruginosa-peritonitis, might induce susceptibility to further peritoneal injuries due to excessive C activation.

Surgical efficacy and quality of wide resection of the pelvic peritoneum in patients with epithelial ovarian cancer

PurposeThe aim of the study was to evaluate the impact of adding an extensive pelvic peritoneal stripping procedure, termed “wide resection of the pelvic peritoneum,” (WRPP) to standard surgery for epithelial ovarian cancer on survival effectiveness and to investigate the role of ovarian cancer stem cells (CSCs) in the pelvic peritoneum. MethodsA total of 166 patients with ovarian cancer undergoing surgical treatment at Kumamoto University Hospital between 2002 and 2018 were retrospectively analyzed. Eligible patients were divided into three groups based on the surgical approach: standard surgery (SS) group (n = 36), WRPP group (standard surgery plus WRPP, n = 100), and rectosigmoidectomy (RS) group (standard surgery plus RS, n = 30). Survival outcomes were compared between the three groups. CD44 variant 6 (CD44v6) and EpCAM expression, as markers of ovarian CSCs, in peritoneal disseminated tumors were evaluated using immunofluorescence staining. ResultsWith respect to patients with stage IIIA–IVB ovarian cancer, there were significant differences in overall and progression-free survival between the WRPP and SS groups, as revealed by univariate (hazard ratio [HR], 0.35; 95% confidence interval [CI], 0.17–0.69; P = 0.003 and HR, 0.54; 95% CI, 0.31–0.95; P = 0.032, respectively) and multivariate Cox proportional hazards models (HR, 0.35; 95% CI, 0.17–0.70; P = 0.003 and HR, 0.54; 95% CI, 0.31–0.95; P = 0.032, respectively). Further, no significant differences were observed in survival outcomes between the RS group and the SS or WRPP group. Regarding the safety of WRPP, no significant differences in major intraoperative and postoperative complications were found between the three groups. Immunofluorescence analysis revealed a high percentage of CD44v6/EpCAM double-positive ovarian cancer cells in peritoneal disseminated tumors. ConclusionThe present study demonstrates that WRPP significantly contributes to improved survival in patients with stage IIIA–IVB ovarian cancer. WRPP could result in eradicating ovarian CSCs and disrupting the CSC niche microenvironment in the pelvic peritoneum.

PATHOMORPHOLOGICAL CHANGES OF THE PERITONEUM IN PATIENTS WITH ACUTE ADHESIVE INTESTINAL OBSTRUCTION

Acute adhesive intestinal obstruction is a complex and often unpredictable pathology. Therefore, the study of the pathomorphological component of this problem is important for the selection of adequate surgical and conservative therapy of the disease.The aim of the study is to research the pathomorphological changes in the peritoneum in patients with acute adhesive intestinal obstruction and determine the basic patterns of adhesions.Material and methods. The study covered 117 operated patients with various acute diseases of the peritoneal cavity of an infl ammatory nature, which to varying degrees were accompanied by damage to the peritoneal mesothelium. Collection of material for morphological studies was performed according to standard requirements for the manufacture of histological specimens. Biopsies included areas of adhesive and peritoneal tissue.Results. Through the examination of peritoneal biopsy material in the event of local peritonitis was found that some mesotheliocytes developed pronounced dystrophic changes, in some cells with the transition to necrosis. The lumens of the vessels of the microcirculatory tract were moderately dilated, fi lled with erythrocytes, and stasis developed in some of them. The main component of the infl ammatory focus was the increase in catabolic processes that led to metabolic disorders in connective tissue, accumulation of breakdown products of fat and carbohydrate metabolism and the development of tissue acidosis.Summary. Adhesion disease is characterized by a great variety of pathomorphological picture, which is due to the phased development of infl ammatory and hyperproliferative processes, and that is fundamental in the pathogenesis of adhesive disease.

Baseline Peritoneal Membrane Transport Characteristics Are Associated with Peritonitis Risk in Incident Peritoneal Dialysis Patients.

The peritoneal equilibration test (PET) is a semi-quantitative measurement that characterizes the rate of transfer of solutes and the water transfer rate across the peritoneum in patients treated with peritoneal dialysis (PD). The results of the PET are used to maximize daily peritoneal ultrafiltration and solute clearances. Previous studies have shown that high transport status is associated with ultrafiltration failure, malnutrition, and reduced survival; however, the way in which peritoneum transport characteristics affect peritonitis risk is unknown. In the current cohort study, we recruited 898 incident-PD patients and used intention-to-treat analysis to test if baseline PET affected the subsequent 3-year peritonitis rate. Among all recruited PD patients, 308 (34.2%) developed peritonitis within three years. Multivariate Cox regression analysis showed that the high-transport group has the greatest peritonitis risk (HR 1.98, 95% CI: 1.08–3.62) even after an adjustment for demographics, comorbid diseases, and biochemical measurements. We concluded that a baseline high peritoneal membrane transport rate is an independent risk factor for peritonitis in incident PD patients.

Cytokine status in the omentum and peritoneum in metastatic gastric cancer.

e16557 Background: Gastric cancer (GC) is one of the most common malignant tumors and the second most common cause of cancer deaths in Russia. Many researchers note the ambiguous role of cytokines in the pathogenesis of tumor processes. The purpose of the study was to determine characteristics of the cytokine status in the omentum and peritoneum of patients with metastatic GC. Methods: The main group (Mgr) included 23 patients with T2-4N0-3M1 GC with metastases to the peritoneum and greater omentum, the mean age 58.9±9.7 years. The comparison group (Cgr) included 20 non-cancer patients, the mean age 55.9±9.7 years. Tissues of the omentum (OT) and peritoneum (PT) were obtained from all patients during cytoreductive and diagnostic surgeries. Ex tempore tissues were disintegrated using BD Medimachine (USA) with 0.9% NaCl; the cell suspension was centrifuged, and the supernatant was collected and aliquoted. Levels of cytokines IL-1β, IL-2, IL-6, IL-8, IL-18, TNF-α, IL-10 (Vektor-Best, Russia) and IL-1RA (eBioscience, Austria) were determined by ELISA. The results were expressed as the specific content per 1 g of protein evaluated by the biuret method (pg/mL/g of protein). Statisical analysis of the results was performed with the Statistica 10 program (StatSoft Inc., USA). Significance of differences was evaluated using the Mann-Whitney and Wilkinson tests; differences were considered significant at p &lt; 0.05. Results: In Cgr, levels of IL-6, IL-8, IL-18 and IL-1β in OT were 4.1±1.1, 3.4±0.7, 21.2±5.5 and 10.8±2.1, while in Mgr – 55.3±24.4, 32.5±13.8, 144.9±48.4 and 21.01±5.4 pg/mL/g of protein, i.e. 13.7, 9.5, 6.9 and 1.9 times (p≤0.05) higher than in Cgr, respectively. The specific content of IL-1RA in OT was 12.6 times higher, p≤0.05 (215.7±69.8 vs. 2723.1±730.1), and the IL-10 concentration did not differ significantly. In PT of Cgr, levels of IL-8, IL-18 and IL-6 were 9.8±7.3, 35.2±21.7, 7.5±3.7, and in Mgr – 250.7±21.4, 322.9±16.9, 61.1±27.6 pg/mL/g, i.e. 25.7, 9.2 and 8.2 times (p≤0.05) higher than in Cgr. IL-1RA in PT of Mgr was 24.4 times higher than in Cgr, p≤0.05 (7656.2±3160.3 vs. 357.69±180.86). Conclusions: A certain microenvironment is formed in OT and PT affected by metastases, with specific features in the ratio and concentrations of various cytokines, which undoubtedly contribute to the formation of a secondary tumor.

CYTOKINE TISSUE PROFILE IN NON-METASTATIC GASTRIC CANCER

The development of the tumor process involves the involvement of various functional elements of innate and adaptive immunity. A special role in the reorganization of tissues, changes and evolution of the properties of cancer cells is given to cytokines, the study of the role of which in these processes with various types of neoplasms and, in particular, with nonmetastatic gastric cancer is an urgent task. The aim of the work was to determine the characteristics of the cytokine status in the tissues of patients with non-metastatic gastric cancer. Materials and methods. In the extracts of tumor tissue, perifocal zone, omentum, peritoneum of patients with gastric cancer without metatstases (T3-4aN0-3M0, n = 20, 58.9 ± 9.7 years), the concentration of IL-1P, IL-2, IL -6, IL-8, IL-18, TNF-a, IL-10 and IL-1RA in tumor tissue, the perifocal zone, as well as in the omentum and peritoneum. Results and discussion. In the tumor tissue, an increase in the content of IL-1P, IL-8 and a decrease in IL-2, TNF-a and IL-10 were noted. In the perifocal zone, a decrease in the concentration of IL-1P, IL-6, IL-8 was revealed with an increased content of IL-2, IL-1RA, IL-10, TNF-a and IL-18. Against this background, the omentum and peritoneum compared with the tumor, the concentration of IL-1P, IL-18 and IL-1RA is reduced, against the background of an increase in the concentration of IL-2, IL-6, TNF-a and IL-10. Findings. It was shown that tumor tissue has some features in the cytokine profile compared with unaffected tissues, which can be used to further evaluate the development of the pathological process.

Levels of oncofetal proteins in pathological tissues of patients with gastric cancer.

449 Background: Spread to the peritoneal cavity and lymphatic system is the most important factor of gastric cancer prognosis. Successful implantation of cancer cells in a distant place is possible only when cancer cells accept a special kind of molecular invitation sent by some organs. Our purpose was to study levels of CA-19.9, CA-125, CA-72.4 and He-4 in tissues of tumors, peritoneum and omentum in patients with gastric cancer (GC) T3-4aN0-3M1 and T3-4aN0-3M0. Methods: Levels of CA-19.9, CA-125 and CA-72.4 were determined by ELISA in primary tumors, the omentum and peritoneum of patients from main groups 1 (M0) – GC T3-4aN0-3M0 (n = 24) and 2 (M1) – GC T3-4aN0-3M1 (n = 21) and in the stomach, omentum and peritoneum of non-cancer controls (n = 17). Results: Levels of CA-19.9, CA-125 and CA-72.4 were increased, compared to control values, in all studied samples from 1.6 times (CA-72.4) to 180.1 times (СA-19.9). Only CA-19.9 levels differed depending on the metastatic spread: 1.8 times (p˂0.05) higher in T3-4aN0-3M1 than in T3-4aN0-3M0. In the omentum tissues, CA-19.9 levels in T3-4aN0-3M1 exceeded the control values by 20 times; in 20 patients with T3-4aN0-3M0, the value was only 4.1 times higher than in controls and 4.8 times lower than in T3-4aN0-3M1, while in 4 patients it did not differed significantly from the value in T3-4aN0-3M1. In the peritoneal tissues, CA-19.9 levels in T3-4aN0-3M1 exceeded the control values by 19.2 times; in 21 patients with T3-4aN0-3M0, the value was only 2.2 times higher than in controls and 8.5 times lower than in T3-4aN0-3M1, while in 3 patients it did not differed significantly from the value in T3-4aN0-3M1. Conclusions: Saturation of peritoneal and omentum tissues with marker oncoproteins is one of the factors associated with metastatic characteristics of gastric cancer, while the CA-19.9 level can serve as informative laboratory tests to predict the nature of the further disease development.

Advanced glycation end products are associated with immature angiogenesis and peritoneal dysfunction in patients on peritoneal dialysis.

Deposition of advanced glycation end products (AGEs) is frequently found in the peritoneum of patients on peritoneal dialysis (PD). Angiogenesis is also observed in the peritoneum. However, the clinical significance of AGEs and angiogenesis in the peritoneum is not fully understood. We evaluated the maturation of capillary vessels and investigated whether AGEs are associated with angiogenesis and peritoneal function in the peritoneal membrane. Peritoneum obtained when PD catheters were removed from 61 patients with PD was analyzed. The peritoneum was immunohistochemically stained with anti-CD34 (for endothelial cells), anti-alpha smooth muscle actin (αSMA) (for pericytes), and anti-AGE antibodies. We defined CD34-positive and αSMA-negative vessels as immature capillary vessels in peritoneal membranes using serial sections. We evaluated the associations between vessel density, peritoneal function (dialysate-to-plasma ratio for creatinine (D/P creatinine)), and the degree of AGE deposition. AGE accumulation in the interstitium was positively associated with the duration of PD (p < 0.01). AGE accumulation in the interstitium and vascular wall was positively correlated with the use of acidic solution (p < 0.05) and the maximum value of D/P creatinine (p < 0.05). AGE accumulation in the vascular wall was significantly associated with immature capillary density (CD34+/αSMA-) in the peritoneum (p < 0.01). Vessel density was not significantly correlated with the last measurement of D/P creatinine (p = 0.126, r = 0.202), However, immature capillary density was positively correlated with the last measurement of D/P creatinine (p < 0.05, r = 0.278). AGE accumulation is significantly associated with immature angiogenesis and peritoneal dysfunction in patients undergoing PD.

Genetic or pharmacologic blockade of enhancer of zeste homolog 2 inhibits the progression of peritoneal fibrosis.

Dysregulation of histone methyltransferase enhancer of zeste homolog 2 (EZH2) has been implicated in the pathogenesis of many cancers. However, the role of EZH2 in peritoneal fibrosis remains unknown. We investigated EZH2 expression in peritoneal dialysis (PD) patients and assessed its role in peritoneal fibrosis in cultured human peritoneal mesothelial cells (HPMCs) and murine models of peritoneal fibrosis induced by chlorhexidine gluconate (CG) or high glucose peritoneal dialysis fluid (PDF) by using 3-deazaneplanocin A (3-DZNeP), and EZH2 conditional knockout mice. An abundance of EZH2 was detected in the peritoneum of patients with PD associated peritonitis and the dialysis effluent of long-term PD patients, which was positively correlated with expression of TGF-β1, vascular endothelial growth factor, and IL-6. EZH2 was found highly expressed in the peritoneum of mice following injury by CG or PDF. In both mouse models, treatment with 3-DZNeP attenuated peritoneal fibrosis and inhibited activation of several profibrotic signaling pathways, including TGF-β1/Smad3, Notch1, epidermal growth factor receptor and Src. EZH2 inhibition also inhibited STAT3 and nuclear factor-κB phosphorylation, and reduced lymphocyte and macrophage infiltration and angiogenesis in the injured peritoneum. 3-DZNeP effectively improved high glucose PDF-associated peritoneal dysfunction by decreasing the dialysate-to-plasma ratio of blood urea nitrogen and increasing the ratio of dialysate glucose at 2h after PDF injection to initial dialysate glucose. Moreover, delayed administration of 3-DZNeP inhibited peritoneal fibrosis progression, reversed established peritoneal fibrosis and reduced expression of tissue inhibitor of metalloproteinase 2, and matrix metalloproteinase-2 and -9. Finally, EZH2-KO mice exhibited less peritoneal fibrosis than EZH2-WT mice. In HPMCs, treatment with EZH2 siRNA or 3-DZNeP suppressed TGF-β1-induced upregulation of α-SMA and Collagen I and preserved E-cadherin. These results indicate that EZH2 is a key epigenetic regulator that promotes peritoneal fibrosis. Targeting EZH2 may have the potential to prevent and treat peritoneal fibrosis. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Distribution of urokinase-type plasminogen activator and its receptor in malignant tissues of gastric adenocarcinoma.

e15530 Background: Peritoneal metastases are the most common recurrence of gastric cancer, even after radical surgery. Urokinase-type plasminogen activator (uPA) system, including its receptor uPAR, is crucial in the proteolysis activation for the cleavage of the extracellular matrix and basement membrane. The purpose of the study was to determine the antigen form uPA-Ag, active form uPA-act and the uPAR receptor in tissues of adenocarcinoma of the stomach, its perifocal tissues (PT), greater omentum and peritoneum in patients with stomach cancer T3-4аN0-3M1 and T3-4аN0-3M0. Methods: Tissues of patients with gastric adenocarcinoma T3-4аN0-3M1 (n = 21: 10 men, 11 women) and T3-4аN0-3M0 (n = 24: 15 men, 9 women) aged 61.23±4.8 years were studied. Controls: non-cancer patients aged 39.1±3.2 years (n = 17: 6 men, 11 women). Levels of uPA-act, uPA-Ag and uPAR were determined by ELISA using standard test systems. Statistical analysis was performed using the SPSS 11.5 software package for Windows. Results: In T3-4аN0-3M1, the highest uPAR levels were observed in tissues of the tumor, greater omentum and peritoneum, compared to T3-4аN0-3M0 and controls (p &lt; 0.01). In PT of T3-4аN0-3M1, uPAR levels were lower than in tumor (p &lt; 0.01) but higher than in resection line tissues. Tumor levels of uPA-act in T3-4аN0-3M1 and T3-4аN0-3M0 were similar and in both cases higher than in PT. In the greater omentum in T3-4аN0-3M1, uPA-act levels were similar to tumor levels and exceeded the values in T3-4аN0-3M0 (p &lt; 0.01). Peritoneal uPA-act did not differ in T3-4аN0-3M1 and T3-4аN0-3M0 but was higher than in controls (p &lt; 0.05). Tumor levels of uPA-Ag in T3-4аN0-3M1 exceeded the levels in T3-4аN0-3M0 and in both PT (p &lt; 0.05). Levels of uPA-Ag in the greater omentum in T3-4аN0-3M1 were higher than in T3-4аN0-3M0 and lower than in controls (p &lt; 0.01). Comparable uPA-Ag levels in T3-4аN0-3M1 and T3-4аN0-3M0 were lower than in controls (p &lt; 0.01). Conclusions: Gastric adenocarcinoma secretes uPAR and uPA, and uPAR levels in the tumor are associated with omental or peritoneal metastases. Levels of uPAR and uPA-act in the greater omentum and peritoneum in T3-4аN0-3M1 are increased even higher than in T3-4аN0-3M0; uPAR can serve as a marker of a pre-metastatic niche in peritoneal tissues.

Mineralization of the Peritoneum — a New Target in the Treatment of Peritoneal Carcinomatosis

Introduction. This article presents data on the manifestations of changes in the microenvironment of the peritoneal cavity in patients with carcinomatosis, expressed by the mineralization of the peritoneum, which in turn leads to functional changes in drainage of the peritoneal cavity. Materials and methods . We examined autopsy tissue of the peritoneum with symptoms of carcinomatosis and intact peritoneum using comparative scanning electron microscopy. Results and discussion . The study of the ultrastructure of peritoneum in patients with PC, revealed the phenomenon of SLL mineralization. The resulting elemental composition profile showed a high content of Ca, P, Na. Conclusions . 1. Carcinomatosis is not a local, but rather a systemic process. Determining the role of mineralization in carcinomatosis is of fundamental importance in carcinogenesis. 2. The serous membranes mineralization in patients with carcinomatosis can become a new treatment target, the impact on which may increase life expectancy and improve the quality of life. 3. The serous membranes demineralization can serve as a part of a combination treatment that includes the subsequent endolymphatic anti-tumour drug therapy.

MiR-15a-5p suppresses inflammation and fibrosis of peritoneal mesothelial cells induced by peritoneal dialysis via targeting VEGFA.

Long-term peritoneal dialysis (PD) often ends up with ultrafiltration failure (UFF) which is partially caused by persistent inflammation and fibrosis of peritoneal tissues. However, the mechanism is still unclear. In the current study, the peritoneum from UFF patients demonstrated inflammation and fibrosis which were positively related to theexpression of vascular endothelial growth factor A (VEGFA). The in vitro model using human peritoneal mesothelial cells (HPMCs) stimulated by high glucose or advanced glycation end (AGE) product showed consistent changes of inflammation, fibrosis, and VEGFA. What's more, we showed that VEGFA was an instigator of inflammation and fibrosis. Several microRNAs (miRNAs) have been reported to regulate expression of VEGFA elsewhere. Five of them were selected to test the expression in the peritoneum ofpatients with PD. Results suggested that miR-15a-5p was the most significantly downregulated one. Also, in high glucose or AGE product-stimulated HPMCs, miR-15a-5p decreased. When miRNA mimic was used to restore the expression of miR-15a-5p, high glucose-induced VEGFA was repressed. The predicted binding site between these two molecules was confirmed by the dual-luciferase assay. Restoration of miR-15a-5p restrained inflammation and fibrosis of HPMCs. TGF-β1/Smad2 was shown to be the downstream signaling pathway and their activity was regulated by miR-15a-5p/VEGFA. In conclusion, our current study demonstrates that miR-15a-5p acts as a regulator of VEGFA mRNA and the following inflammation and fibrosis in peritoneal mesothelial cells. The miR-15a-5p/VEGFA pathway may be a potential target for preventing ultrafiltration failure in patients with PD.

Oxidative stress contributes to hepatocyte growth factor-dependent pro-senescence activity of ovarian cancer cells

The cancer-promoting activity of senescent peritoneal mesothelial cells (HPMCs) has already been well evidenced both in vitro and in vivo. Here we sought to determine if ovarian cancer cells may activate senescence in HPMCs. The study showed that conditioned medium (CM) from ovarian cancer cells (OVCAR-3, SKOV-3, A2780) inhibited growth and promoted the development of senescence phenotype (increased SA-β-Gal, γ-H2A.X, 53BP1, and decreased Cx43) in HPMCs. An analysis of tumors isolated from the peritoneum of patients with ovarian cancer revealed an abundance of senescent HPMCs in proximity to cancerous tissue. The presence of senescent HPMCs was incidental when fragments of peritoneum free from cancer were evaluated. An analysis of the cells' secretome followed by intervention studies with exogenous proteins and neutralizing antibodies revealed hepatocyte growth factor (HGF) as the mediator of the pro-senescence impact of the cancer cells. The activity of cancerous CM and HGF was associated with an induction of mitochondrial oxidative stress. Signaling pathways involved in the senescence of HPMCs elicited by the cancer-derived CM and HGF included p38 MAPK, AKT and NF-κB. HPMCs that senesced prematurely in response to the cancer-derived CM promoted adhesion of ovarian cancer cells, however this effect was effectively prevented by the cell protection against oxidative stress. Collectively, our findings indicate that ovarian cancer cells can elicit HGF-dependent senescence in HPMCs, which may contribute to the formation of a metastatic niche for these cells within the peritoneal cavity.

Senescent peritoneal mesothelium creates a niche for ovarian cancer metastases.

Although both incidence and aggressiveness of ovarian malignancy rise with age, the exact reason for this tendency, in particular the contribution of senescent cells, remains elusive. In this project we found that the patient's age determines the frequency of intraperitoneal metastases of ovarian cancer. Moreover, we documented that senescent human peritoneal mesothelial cells (HPMCs) stimulate proliferation, migration and invasion of ovarian cancer cells in vitro, and that this effect is related to both the activity of soluble agents released to the environment by these cells and direct cell-cell contact. The panel of mediators of the pro-cancerous activity of senescent HPMCs appeared to be cancer cell line-specific. The growth of tumors in a mouse peritoneal cavity was intensified when the cancer cells were co-injected together with senescent HPMCs. This effect was reversible when the senescence of HPMCs was slowed down by the neutralization of p38 MAPK. The analysis of lesions excised from the peritoneum of patients with ovarian cancer showed the abundance of senescent HPMCs in close proximity to the cancerous tissue. Collectively, our findings indicate that senescent HPMCs which accumulate in the peritoneum in vivo may create a metastatic niche facilitating intraperitoneal expansion of ovarian malignancy.

Ultrastructural Investigation of Pelvic Peritoneum in Patients With Chronic Pelvic Pain and Subtle Endometriosis in Association With Chromoendoscopy

Study ObjectiveTo evaluate the pelvic peritoneum under chromoendoscopy by scanning electron microscopy (SEM) as well as light microscopy with hematoxylin and eosin staining and immunohistochemistry (IHC) assays in patients with chronic pelvic pain (CPP) associated with subtle endometriosis. DesignCase series study (Canadian Task Force classification II). SettingA referral academic community tertiary medical center. PatientsThree women aged 29 to 37 years were referred to the obstetrics and gynecology clinic of the tertiary university hospital with CPP. They were suspicious for endometriosis, were not responding to medical treatments, and had undergone previous pelvic laparoscopy to determine the stage of endometriosis and preparation of peritoneal samples under the guidance of staining with methylene blue in 0.25% dilution. InterventionsComparison of stained and unstained pelvic peritoneal samples after the instillation of 0.25% methylene blue into the pelvic cavity. Measurements and Main ResultsIn 3 patients, laparoscopic examination showed minimal endometriosis. A total of 18 samples (9 stained and 9 unstained) from the 3 patients were prepared for SEM. Ten of the samples (55.6%) showed microstructural peritoneal destruction (7 of 9 stained [77.7%] and 3 of 9 [33.4%] unstained). Eighteen samples (9 stained and 9 unstained) from the 3 patients were also prepared for IHC. Six of these samples (33.3%) were S-100–positive, including 4 of 9 (44.4%) stained samples and 2 of 9 (22.2%) unstained samples. ConclusionsIn general, in the context of CPP and endometriosis, there is no established relationship between the severity of pain and stage of endometriosis. In the pathophysiology of CPP associated with endometriosis, ultrastructural changes can play a significant role. Under methylene blue staining, some destroyed areas were detected, but the stained areas do not necessarily correlate with increased microstructural peritoneal destruction.

Validation of Revised FIGO Staging Classification for Cancer of the Ovary, Fallopian Tube, and Peritoneum Based on a Single Histological Type.

This study aimed to evaluate the prognostic significance of revised International Federation of Gynecology and Obstetrics (FIGO2013) staging classification for cancer of the ovary, fallopian tube, and peritoneum in patients exhibiting high-grade serous histology. Clinical records of patients with high-grade serous carcinoma who underwent primary surgery between 2007 and 2012 were reviewed retrospectively. Patients were reclassified according to the FIGO2013 criteria. Progression-free survival (PFS) and overall survival (OS) were calculated for each stage using Kaplan-Meier estimates and compared with the log-rank test. In total, 125 patients were included in the analysis. The distribution of the study cohort according to the revised classification was as follows; stage I, 6 patients; stage II, 9 patients; stage III, 85 patients; and stage IV, 25 patients. Median follow-up time was 36 months (95% confidence interval [CI], 3-110). The median PFS and OS were 14 months (95% CI, 12.4-15.6) and 60 months (95% CI, 47.0-72.9), respectively. Both PFS and OS were significantly different among stages I, II, III, and IV (P < 0.01). Subgroup analyses for stage III disease also revealed significant differences in survival. The median PFS for stages IIIA1, IIIB, and IIIC was 56, 46, and 16 months, respectively (P < 0.01), and the median OS was 104, 95, and 60 months, respectively (P = 0.03). The outcomes of patients with stage IV disease differed slightly but nonsignificantly according to new substages. The median PFS for stages IVA and IVB was 12 and 6 months, respectively (hazard ratio, 1.16; 95% CI, 0.48-2.79; P = 0.72), and the median OS was 41 and 24 months, respectively (hazard ratio, 1.62; 95% CI, 0.58-4.55; P = 0.35). The study sample was insufficient in size for subgroup analyses in stages I and II. The revised FIGO2013 staging system is highly prognostic for discriminating outcomes of patients with high-grade serous carcinoma across stages I to IV, in subgroups of stage III, but not in subgroups of stage IV.

Morphological characteristics in peritoneum in patients with neutral peritoneal dialysis solution.

Peritoneal dialysis solution (PDS) plays a role in functional and morphological damage to the peritoneum. This study aimed to clarify the effect of neutral PDS in preventing morphological changes by assessing peritoneal damage and comparing morphological alterations between PD patients treated with neutral PDS and acidic PDS. Sixty-one patients participated from seven hospitals. All patients were treated with neutral PDS excluding icodextrin, during their entire PD treatment, and experienced no episode of peritonitis. The thickness of submesothelial compact (SMC) zone and the presence of vasculopathy in the anterior parietal abdominal peritoneum were assessed. The impact of icodextrin, hybrid therapy, and peritoneal rest and lavage in morphological alterations were determined. There was no significant difference in the average SMC thickness between neutral and acidic PDS. The vessel patency in patients using neutral PDS was significantly higher compared to that in acidic PDS at any time during PD. There were no significant suppressive effects from interventions or use of icodextrin with respect to peritoneal morphological injury. A monolayer of mesothelial cell was observed in approximately half the patients, especially in their receiving lavage patients. Neutral PDS, accompanied by other preventive approaches against peritoneal injury, might suppress the development of peritoneal morphological alterations.

Platelet-Derived Growth Factor Receptor-β Expression in Human Peritoneum

Introduction: Simple peritoneal fibrosis and encapsulating peritoneal sclerosis (EPS) are important lesions in the peritoneum of patients on peritoneal dialysis (PD). We have previously described a population of podoplanin-positive myofibroblasts in peritoneal biopsies from patients with EPS. Platelet-derived growth factor receptor-β (PDGFRβ) is a marker of pericytes, and PDGFs might be involved in the fibrotic response of the peritoneum. This study aimed to describe PDGFRβ in the human peritoneum. Methods: In this retrospective analysis, we localized PDGFRβ in peritoneal biopsies from patients with EPS (n = 6) and patients on PD without signs of EPS (n = 5), and compared them with normal peritoneum (n = 4) and peritoneum from uremic patients (n = 5). Consecutive sections were stained for smooth-muscle actin (SMA) and podoplanin. Slides were scored semiquantitatively by 2 observers blinded to the diagnosis. Results: PDGFRβ was expressed by cells of arterial walls in all biopsies. A prominent population of PDGFRβ-positive cells was present in the normal peritoneum, which were SMA negative on consecutive sections. In patients on PD, a high number of PDGFRβ were also positive for SMA. In EPS, the majority of podoplanin-positive cells were positive for PDGFRβ. In peritoneal biopsies from normal and uremic patients, the expression of SMA was mainly restricted to cells of arterial walls. Podoplanin expression was restricted to lymphatic vessels in normal peritoneum, in uremic patients, and in patients on PD without EPS. Conclusions: As podoplanin-positive myofibroblasts express PDGFRβ, these cells might be related to pericytes (rather than other sources of fibroblasts). PDGFRβ might turn out to be a therapeutic target in EPS.