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Cancer Medicine Nov 2022Given malignant ascites with a terrible prognosis and a unique immune microenvironment, our purpose is to evaluate whether oncolytic herpes simplex virus type 2(OH2) is...
BACKGROUND
Given malignant ascites with a terrible prognosis and a unique immune microenvironment, our purpose is to evaluate whether oncolytic herpes simplex virus type 2(OH2) is able to safely eliminate ascites of colon cancer and through which specific mechanism it exerts antitumor immunity.
METHODS
We established an ascites mice model through intraperitoneal injection of CT26 cells and obtained an appropriate dose range for in vivo tests. Efficacy and safety of OH2 were detected by weight of ascites, blood routine analysis, histopathological examination, and the survival time of mice. The specific mechanism underlying antitumor immunity was analyzed by cytometric bead array, flow cytometry, and single-cell RNA sequencing. Furthermore, anti-interleukin (IL)-6R antibody tocilizumab was synchronously or sequentially delivered with OH2 to explore the role of the regional cytokine storm, mainly IL-6 hypersecretion.
RESULTS
OH2 was able to eliminate ascites and significantly prolong the survival of mice-bearing CT26 tumor cells by intraperitoneal injection, without obvious systemic damage to the main organs even though a regional cytokine storm. Hypersecretion of pro-inflammatory cytokines, mainly IL-6, and increased infiltration of CD4+ and CD8+ T cells were observed in ascites mice treated by OH2, compared with those treated by 5-fluorouracil or nonresponders. Furthermore, the initial-stage blocking of the IL-6 pathway was able to considerably suppress antitumor immune responses driven by OH2. Surprisingly, we discovered upregulations of the immune checkpoint genes such as Cd274 and Pdcd1 by single-cell RNA sequencing.
CONCLUSIONS
OH2 could safely eliminate malignant ascites of colon cancer and convert the cold immune microenvironment by inducing a remarkably regional cytokine storm in ascites, mainly IL-6, in the early stage of antitumor immune responses beyond directed oncolytic virotherapy.
Topics: Mice; Animals; Oncolytic Viruses; Ascites; Cytokine Release Syndrome; Interleukin-6; Colonic Neoplasms; Peritoneal Neoplasms; Tumor Microenvironment
PubMed: 35510373
DOI: 10.1002/cam4.4772 -
Advanced Science (Weinheim,... Jul 2023Malignant ascites in advanced hepatocellular carcinoma (HCC) is a complex clinical problem that lacks effective treatments. Due to the insensitivity of advanced HCC...
Malignant ascites in advanced hepatocellular carcinoma (HCC) is a complex clinical problem that lacks effective treatments. Due to the insensitivity of advanced HCC cells to traditional chemotherapies, low drug accumulation, and limited drug residence time in the peritoneal cavity, the therapeutic effects of malignant ascites in HCC are not satisfactory. In this study, an injectable hydrogel drug delivery system based on chitosan hydrochloride and oxidized dextran (CH-OD) is designed to load sulfasalazine (SSZ), an FDA-approved drug with ferroptosis-inducing ability, for effective tumor-killing and activation of anti-tumor immunity. Compared to free SSZ, SSZ-loaded CH-OD (CH-OD-SSZ) hydrogel exhibits greater cytotoxicity and induces higher levels of immunogenic ferroptosis. In the preclinical model of hepatoma ascites, intraperitoneal administration of CH-OD-SSZ hydrogel can significantly suppress tumor progression and improve the immune landscape. Both in vitro and in vivo, CH-OD-SSZ hydrogel induces the repolarization of macrophages to an M1-like phenotype and promotes the maturation and activation of dendritic cells. Combination treatment with CH-OD-SSZ hydrogel and anti-programmed cell death protein 1 (PD-1) immunotherapy achieves more than 50% ascites regression and generates long-term immune memory. Collectively, CH-OD-SSZ hydrogel exhibits promising therapeutic potential in the treatment of peritoneal dissemination and malignant ascites in advanced HCC, especially when combined with anti-PD-1 immunotherapy.
Topics: Humans; Carcinoma, Hepatocellular; Hydrogels; Chitosan; Dextrans; Ascites; Ferroptosis; Liver Neoplasms; Sulfasalazine; Immunotherapy
PubMed: 37132587
DOI: 10.1002/advs.202300517 -
Cancer Research and Treatment Oct 2023Patient-derived tumor cells can be a powerful resource for studying pathophysiological mechanisms and developing robust strategies for precision medicine. However,...
PURPOSE
Patient-derived tumor cells can be a powerful resource for studying pathophysiological mechanisms and developing robust strategies for precision medicine. However, establishing organoids from patient-derived cells is challenging because of limited access to tissue specimens. Therefore, we aimed to establish organoids from malignant ascites and pleural effusions.
MATERIALS AND METHODS
Ascitic or pleural fluid from pancreatic, gastric, and breast cancer patients was collected and concentrated to culture tumor cells ex vivo. Organoids were considered to be successfully cultured when maintained for five or more passages. Immunohistochemical staining was performed to compare the molecular features, and drug sensitivity was assayed to analyze the clinical responses of original patients.
RESULTS
We collected 70 fluid samples from 58 patients (pancreatic cancer, n=39; gastric cancer, n=21; and breast cancer, n=10). The overall success rate was 40%; however, it differed with types of malignancy, with pancreatic, gastric, and breast cancers showing 48.7%, 33.3%, and 20%, respectively. Cytopathological results significantly differed between successful and failed cases (p=0.014). Immunohistochemical staining of breast cancer organoids showed molecular features identical to those of tumor tissues. In drug sensitivity assays, pancreatic cancer organoids recapitulated the clinical responses of the original patients.
CONCLUSION
Tumor organoids established from malignant ascites or pleural effusion of pancreatic, gastric, and breast cancers reflect the molecular characteristics and drug sensitivity profiles. Our organoid platform could be used as a testbed for patients with pleural and peritoneal metastases to guide precision oncology and drug discovery.
Topics: Humans; Female; Ascites; Precision Medicine; Pancreatic Neoplasms; Breast Neoplasms; Peritoneal Neoplasms; Organoids
PubMed: 37309112
DOI: 10.4143/crt.2022.1630 -
European Review For Medical and... Apr 2023Ascites is the pathological fluid accumulation in the peritoneal cavity and there are mainly two reasons for its etiology. These are malignant diseases such as hepatoma...
OBJECTIVE
Ascites is the pathological fluid accumulation in the peritoneal cavity and there are mainly two reasons for its etiology. These are malignant diseases such as hepatoma or pancreas cancer and benign diseases such as liver cirrhosis and heart failure. In this study, we investigated the diagnostic utility of arylesterase (ARES), paraoxonase (PON), stimulated paraoxonase (SPON), catalase (CAT) and myeloperoxidase (MPO) in the differential diagnosis of malignant and benign ascites.
PATIENTS AND METHODS
This study was conducted between February and September 2016. Patients with acute infection, those taking vitamin supplements and antioxidant medication, smoking, and drinking alcohol were excluded from the study.
RESULTS
The study population consisted of 60 patients: 36 had benign (60%) and 24 had malignant (40%) ascites. The mean age of the patients was 63.3 years. MPO levels (14.2 vs. 4.2; p=0.028) were found to be higher and PON (2.6 vs. 4.5; p<0.001), SPON (10.7 vs. 23.9; p<0.001), ARES (615.7 vs. 823.5, p<0.001) and CAT (13.3 vs. 36.8; p=0.044) were found to be lower in malignant patients compared to benign patients. There was a positive correlation between PON, SPON, and ARES levels, and a negative correlation between MPO levels and SPON, ARES, and CAT levels. MPO levels showed superior diagnostic performance compared to ARES and CAT levels (p<0.05) for predicting malignancy but showed no diagnostic superiority compared to PON and SPON levels (p>0.05).
CONCLUSIONS
PON, SPON, ARES, CAT, and MPO can be used with high sensitivity and specificity in the differential diagnosis of malignant and benign ascites.
Topics: Humans; Aryldialkylphosphatase; Ascites; Diagnosis, Differential; Oxidative Stress; Antioxidants
PubMed: 37070881
DOI: 10.26355/eurrev_202304_31912 -
The Cochrane Database of Systematic... Jan 2010Most patients with advanced ovarian cancer and some patients with advanced endometrial cancer need repeated drainage for malignant ascites. Guidelines to advise those... (Review)
Review
BACKGROUND
Most patients with advanced ovarian cancer and some patients with advanced endometrial cancer need repeated drainage for malignant ascites. Guidelines to advise those involved in the drainage of ascites are usually produced locally and are generally not evidence-based but mainly based on clinicians' anecdotal evidence and experience. To discover whether there are ways of managing drains that have been demonstrated to improve the efficacy and quality of the procedure is key in making recommendations which could improve the quality of life (QOL) for women at this critical period of their lives.
OBJECTIVES
To evaluate the benefit and harms of different practices in the management of drains for malignant ascites in the care of women with advanced or recurrent gynaecological cancer. The review aimed to evaluate the evidence regarding the following questions; How long should the drain stay in place? Should the volume of fluid drained be replaced intravenously? Should the drain be clamped to regulate the drainage of fluid? Should any particular vital observations be regularly recorded?
SEARCH STRATEGY
We searched the Cochrane Central Register of Controlled Trials (CENTRAL) Issue 1, 2009, Cochrane Gynaecological Cancer Group Trials Register, MEDLINE1950 to February Week 3 2009, Embase 1980 to 2009 Week 8 2009. We also searched registers of clinical trials, abstracts of scientific meetings, reference lists of review articles and contacted experts in the field.
SELECTION CRITERIA
We searched for randomised controlled trials (RCTs), quasi-RCTs and non-randomised studies that compared a range of interventions for management of multiple paracentesis in women with malignant ascites who had a confirmed histological diagnosis of gynaecological cancer.
DATA COLLECTION AND ANALYSIS
Two review authors independently assessed whether potentially relevant studies met the inclusion criteria. No trials were found and therefore no data were analysed.
MAIN RESULTS
The search strategy identified 1664 unique references of which 1646 were excluded on the basis of title and abstract. The remaining 18 articles were retrieved in full, but none satisfied the inclusion criteria.
AUTHORS' CONCLUSIONS
Since no relevant studies were identified, we are unable to make recommendations regarding the management of drains for malignant ascites in women with gynaecological cancer. Large, multi-centre RCTs are required to evaluate the efficacy and safety of the management of ascitic drains when in situ and their impact on QOL.
Topics: Ascites; Drainage; Female; Genital Neoplasms, Female; Humans
PubMed: 20091648
DOI: 10.1002/14651858.CD007794.pub2 -
Journal of Translational Medicine Dec 2022The poor prognosis of ovarian cancer patients is strongly related to peritoneal metastasis with the production of malignant ascites. However, it remains largely unclear...
BACKGROUND
The poor prognosis of ovarian cancer patients is strongly related to peritoneal metastasis with the production of malignant ascites. However, it remains largely unclear how ascites in the peritoneal cavity influences tumor metabolism and recurrence. This study is an explorative approach aimed at for a deeper molecular and physical-chemical characterization of malignant ascites and to investigate their effect on in vitro ovarian cancer cell proliferation.
METHODS
This study included 10 malignant ascites specimens from patients undergoing ovarian cancer resection. Ascites samples were deeply phenotyped by H-NMR based metabolomics, blood-gas analyzer based gas flow analysis and flow cytomertry based a 13-plex cytokine panel. Characteristics of tumor cells were investigated in a 3D spheroid model by SEM and metabolic activity, adhesion, anti-apoptosis, migratory ability evaluated by MTT assay, adhesion assay, flowcytometry and scratch assay. The effect of different pH values was assessed by adding 10% malignant ascites to the test samples.
RESULTS
The overall extracellular (peritoneal) environment was alkaline, with pH of ascites at stage II-III = 7.51 ± 0.16, and stage IV = 7.78 ± 0.16. Ovarian cancer spheroids grew rapidly in a slightly alkaline environment. Decreasing pH of the cell culture medium suppressed tumor features, metabolic activity, adhesion, anti-apoptosis, and migratory ability. However, 10% ascites could prevent tumor cells from being affected by acidic pH. Metabolomics analysis identified stage IV patients had significantly higher concentrations of alanine, isoleucine, phenylalanine, and glutamine than stage II-III patients, while stage II-III patients had significantly higher concentrations of 3-hydroxybutyrate. pH was positively correlated with acetate, and acetate positively correlated with lipid compounds. IL-8 was positively correlated with lipid metabolites and acetate. Glutathione and carnitine were negatively correlated with cytokines IL-6 and chemokines (IL-8 & MCP-1).
CONCLUSION
Alkaline malignant ascites facilitated ovarian cancer progression. Additionally, deep ascites phenotyping by metabolomics and cytokine investigations allows for a refined stratification of ovarian cancer patients. These findings contribute to the understanding of ascites pathology in ovarian cancer.
Topics: Humans; Female; Interleukin-8; Ascites; Ovarian Neoplasms; Peritoneal Neoplasms; Cell Proliferation; Cytokines; Lipids
PubMed: 36503580
DOI: 10.1186/s12967-022-03763-3 -
Drug Delivery Dec 2022Malignant ascites is a common complication of some advanced cancers. Although intraperitoneal (IP) administration of chemotherapy drugs is routinely used to treat...
Intraperitoneal administration of thermosensitive hydrogel Co-loaded with norcantharidin nanoparticles and oxaliplatin inhibits malignant ascites of hepatocellular carcinoma.
Malignant ascites is a common complication of some advanced cancers. Although intraperitoneal (IP) administration of chemotherapy drugs is routinely used to treat cancerous ascites, conventional drugs have poor retention and therefore need to be administered frequently to maintain a sustained anti-tumor effect. In this study, a thermosensitive hydrogel composite loaded with norethindrone nanoparticles (NPs) and oxaliplatin (N/O/Hydrogel) was developed to inhibit ascites of hepatocellular carcinoma (HCC) through IP injection. N/O/Hydrogel induced apoptosis in the H22 cells , and significantly inhibited ascites formation, tumor cell proliferation and micro-angiogenesis in a mouse model of advanced HCC with ascites, and prolonged the survival of tumor-bearing mice. Histological examination of the major organs indicated that the hydrogel system is safe. Taken together, the N/O/Hydrogel system is a promising platform for in-situ chemotherapy of malignant ascites.
Topics: Animals; Ascites; Bridged Bicyclo Compounds, Heterocyclic; Carcinoma, Hepatocellular; Cell Line, Tumor; Hydrogels; Liver Neoplasms; Mice; Nanoparticles; Oxaliplatin; Peritoneal Neoplasms
PubMed: 35975331
DOI: 10.1080/10717544.2022.2111480 -
Cancer Letters Aug 2022Ovarian cancer is mostly diagnosed at advantaged stages due to the lack of early diagnostic biomarkers. The common metastasis pattern is characterized by peritoneal...
Ovarian cancer is mostly diagnosed at advantaged stages due to the lack of early diagnostic biomarkers. The common metastasis pattern is characterized by peritoneal dissemination with a formation of malignant ascites. Extracellular vesicles (EVs) are emerging as promising clinical biomarkers in liquid biopsy. Here, we aimed to investigate robust liquid biopsy-based EV miRNA biomarkers for ovarian cancer diagnosis and metastasis regulation. EVs were isolated from malignant ascites and plasma of ovarian cancer patients as well as the benign control counterparts of patients with benign gynecologic diseases. EV small RNA sequencing identified a panel of eight miRNAs (miR-1246, miR-1290, miR-483, miR-429, miR-34b-3p, miR-34c-5p, miR-145-5p, miR-449a) based on dysregulated miRNAs overlapped in the ascites and plasma subset. The ovarian cancer EV miRNA (OCEM) signature developed based on these eight miRNAs demonstrated high diagnostic accuracy in our in-house dataset and multiple public datasets across diverse clinical samples (blood, tissue and urine). In addition, malignant ascites-derived EVs could significantly facilitate the aggressive property of ovarian cancer cells and boost the growth of ascites-derived organoids. Notably, miR-1246 and miR-1290 shuttled in malignant ascites-derived EVs were identified to promote the invasion and migration of ovarian cancer cells through regulating a common target RORα.
Topics: Ascites; Biomarkers, Tumor; Carcinoma, Ovarian Epithelial; Extracellular Vesicles; Female; Humans; MicroRNAs; Ovarian Neoplasms
PubMed: 35569696
DOI: 10.1016/j.canlet.2022.215735 -
PloS One 2017We performed post-marketing surveillance to evaluate the safety and efficacy of cell-free and concentrated ascites reinfusion therapy (CART). In total, 356 CART sessions...
We performed post-marketing surveillance to evaluate the safety and efficacy of cell-free and concentrated ascites reinfusion therapy (CART). In total, 356 CART sessions in 147 patients at 22 centers were performed. The most common primary disease was cancer (128 cases, 300 sessions). Mean amount of ascites collected was 3.7 L, and mean concentration ratio was 9.2. Mean amount of reinfused protein was 67.8 g (recovery rate, 72.0%). Performance status, dietary intake, urine volume, body weight and abdominal circumference were significantly improved after CART. Body temperature increased significantly, by 0.3°C on average. Concomitant steroids and/or NSAIDs use before reinfusion was significantly and negatively associated with increases in body temperature. Most adverse events were fever and chills. This study examined a large number of patients compared with previous studies, and showed that CART is an effective and relatively safe treatment for refractory ascites, such as malignant ascites.
Topics: Adult; Aged; Aged, 80 and over; Ascites; Ascitic Fluid; Blood Pressure; Body Temperature; Female; Fluid Therapy; Humans; Infusions, Parenteral; Male; Middle Aged; Product Surveillance, Postmarketing; Treatment Outcome; Young Adult
PubMed: 28510606
DOI: 10.1371/journal.pone.0177303 -
Cell Reports Jan 2024Malignant ascites accompanied by peritoneal dissemination contain various factors and cell populations as well as cancer cells; however, how the tumor microenvironment...
Malignant ascites accompanied by peritoneal dissemination contain various factors and cell populations as well as cancer cells; however, how the tumor microenvironment is shaped in ascites remains unclear. Single-cell proteomic profiling and a comprehensive proteomic analysis are conducted to comprehensively characterize malignant ascites. Here, we find defects in immune effectors along with immunosuppressive cell accumulation in ascites of patients with gastric cancer (GC) and identify five distinct subpopulations of CD45(-)/EpCAM(-) cells. Mesothelial cells with mesenchymal features in CD45(-)/EpCAM(-) cells are the predominant source of chemokines involved in immunosuppressive myeloid cell (IMC) recruitment. Moreover, mesothelial-mesenchymal transition (MMT)-induced mesothelial cells strongly express extracellular matrix (ECM)-related genes, including tenascin-C (TNC), enhancing metastatic colonization. These findings highlight the definite roles of the mesenchymal cell population in the development of a protumorigenic microenvironment to promote peritoneal dissemination.
Topics: Humans; Ascites; Epithelial Cell Adhesion Molecule; Proteomics; Peritoneum; Peritoneal Neoplasms; Cell Line, Tumor; Tumor Microenvironment
PubMed: 38232734
DOI: 10.1016/j.celrep.2023.113613