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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 -
Journal of Cachexia, Sarcopenia and... Oct 2023Malignant ascites is prevalent in advanced-stage ovarian cancer and may facilitate identification of the drivers of muscle loss. This study aimed to evaluate the...
BACKGROUND
Malignant ascites is prevalent in advanced-stage ovarian cancer and may facilitate identification of the drivers of muscle loss. This study aimed to evaluate the association of ascites with changes in systemic inflammation and muscle after treatment of advanced-stage ovarian cancer.
METHODS
We evaluated 307 patients with advanced-stage (III/IVA) ovarian cancer who underwent primary debulking surgery and adjuvant platinum-based chemotherapy between 2010 and 2019. The changes in skeletal muscle index (SMI) and radiodensity (SMD) were measured using pre-surgery and post-chemotherapy portal-venous phase contrast-enhanced computed tomography scans at L3. Systemic inflammation was measured using albumin levels, prognostic nutritional index (PNI), neutrophil-lymphocyte ratio (NLR), and platelet-lymphocyte ratio (PLR). Primary endpoint was the changes in SMI and SMD after treatment. Linear regression analysis was used to test associations between muscle change and other covariates. Mediation analysis was used to determine the mediator.
RESULTS
The median (range) age was 53 (23-83) years. The median duration (range) of follow-up was 5.2 (1.1-11.3) years. Overall, 187 (60.9%) patients had ascites. The changes in muscle and systemic inflammatory markers after treatment were significantly different between patients with and without ascites (SMI: -3.9% vs. 2.2%, P < 0.001; SMD: -4.0% vs. -0.4%, P < 0.001; albumin: -4.4% vs. 2.1%, P < 0.001; PNI: -8.4% vs. -0.1%, P < 0.001; NLR: 20.6% vs. -29.4%, P < 0.001; and PLR: 1.7% vs. -19.4%, P < 0.001). The changes in SMI and SMD were correlated with the changes in albumin, PNI, NLR, and PLR (all P < 0.001). In multiple linear regression, ascites and NLR changes were negatively while albumin change was positively correlated with SMI change (ascites: β = -3.19, P < 0.001; NLR change: β = -0.02, P = 0.003; albumin change: β = 0.37, P < 0.001). Ascites and NLR changes were negatively while PNI change was positively correlated with SMD change (ascites: β = -1.28, P = 0.02; NLR change: β = -0.02, P < 0.001; PNI change: β = 0.11, P = 0.04). In mediation analysis, ascites had a direct effect on SMI change (P < 0.001) and an indirect effect mediated by NLR change (indirect effects = -1.61, 95% confidence interval [CI]: -2.22 to -1.08) and albumin change (indirect effects = -2.92, 95% CI: -4.01 to -1.94). Ascites had a direct effect on SMD change (P < 0.001) and an indirect effect mediated by NLR change (indirect effects = -1.76, 95% CI: -2.34 to -1.22) and PNI change (indirect effects = -2.00, 95% CI: -2.79 to -1.36).
CONCLUSIONS
Malignant ascites was associated with enhanced systemic inflammation and muscle loss after primary debulking surgery and adjuvant chemotherapy in advanced-stage ovarian cancer. The association between ascites and muscle loss may be mediated by systemic inflammation.
Topics: Humans; Female; Middle Aged; Aged; Aged, 80 and over; Prognosis; Ascites; Inflammation; Muscle, Skeletal; Ovarian Neoplasms; Albumins
PubMed: 37503876
DOI: 10.1002/jcsm.13289 -
Current Oncology (Toronto, Ont.) Apr 2024This review of the palliation of various gastro-intestinal (GI) symptoms encountered in cancer patients is by no means exhaustive. Frequent symptoms such as... (Review)
Review
This review of the palliation of various gastro-intestinal (GI) symptoms encountered in cancer patients is by no means exhaustive. Frequent symptoms such as constipation, nausea and vomiting, bowel obstructions, ascites and bleeds will be discussed, focusing on their assessment and most importantly, how to control the associated symptoms. All of these symptoms and GI complications can significantly impact patients' quality of life (QOL) and should be treated as quickly and aggressively as possible.
Topics: Humans; Palliative Care; Quality of Life; Gastrointestinal Diseases; Neoplasms; Nausea; Vomiting; Constipation
PubMed: 38668077
DOI: 10.3390/curroncol31040174 -
Science Advances Nov 2023Gastric cancer (GC) with peritoneal metastases and malignant ascites continues to have poor prognosis. Exosomes mediate intercellular communication during cancer...
Gastric cancer (GC) with peritoneal metastases and malignant ascites continues to have poor prognosis. Exosomes mediate intercellular communication during cancer progression and promote therapeutic resistance. Here, we report the significance of exosomes derived from malignant ascites (EXO) in cancer progression and use modified exosomes as resources for cancer therapy. EXO from patients with GC stimulated invasiveness and angiogenesis in an ex vivo three-dimensional autologous tumor spheroid microfluidic system. EXO concentration increased invasiveness, and blockade of their secretion suppressed tumor progression. In -amplified GC, EXO contain abundant MET; their selective delivery to tumor cells enhanced angiogenesis and invasiveness. Exosomal MET depletion substantially reduced invasiveness; an additive therapeutic effect was induced when combined with MET and/or VEGFR2 inhibition in a patient-derived -amplified GC model. Allogeneic MET-harboring exosome delivery induced invasion and angiogenesis in a non-amplified GC model. -amplified patient tissues showed higher exosome concentration than their adjacent normal tissues. Manipulating exosome content and production may be a promising complementary strategy against GC.
Topics: Humans; Stomach Neoplasms; Exosomes; Ascites; Cell Line, Tumor; MicroRNAs
PubMed: 38000030
DOI: 10.1126/sciadv.adk1098 -
BMC Gastroenterology Nov 2023Transjugular intrahepatic portosystemic shunt (TIPS) is a well-validated treatment option for clinically significant portal hypertension (CSPH) in the context of liver... (Review)
Review
BACKGROUND
Transjugular intrahepatic portosystemic shunt (TIPS) is a well-validated treatment option for clinically significant portal hypertension (CSPH) in the context of liver cirrhosis. Its high efficacy and safety in the management of treatment-refractory ascites and variceal bleeding have been extensively proven. Contraindications for TIPS include severe right heart failure, hepatic encephalopathy, and sepsis. However, the role of liver malignancy in TIPS is debatable. Mostly, primary liver malignancies such as hepatocellular carcinoma (HCC) emerge from advanced liver diseases. Coexisting portal hypertension in HCC often results in limited treatment options and a poor prognosis. Previous studies have shown that TIPS implantation in patients with HCC is technically feasible and is usually not associated with major adverse events. Furthermore, TIPS may help in bridging the time to liver transplantation in early HCC and allow for locoregional treatment in advanced HCC. However, several studies suggest that seeding tumour cells to the lungs by TIPS placement might worsen the prognosis.
CONCLUSIONS
TIPS placement in patients with coexisting liver malignancy remains a case-by-case decision, and there is no profound evidence allowing general recommendations. This review aims to provide a state-of-the-art overview of the potential risks and benefits of TIPS placement in patients with liver malignancies.
Topics: Humans; Carcinoma, Hepatocellular; Liver Neoplasms; Esophageal and Gastric Varices; Portasystemic Shunt, Transjugular Intrahepatic; Treatment Outcome; Gastrointestinal Hemorrhage; Hypertension, Portal; Liver Cirrhosis; Risk Assessment; Ascites
PubMed: 37986043
DOI: 10.1186/s12876-023-03047-0 -
Journal of Extracellular Vesicles Jul 2023Ovarian cancer (OvCa) is the gynaecological disorder with the poorest prognosis due to the fast development of chemoresistance. We sought to connect chemoresistance and...
Ovarian cancer (OvCa) is the gynaecological disorder with the poorest prognosis due to the fast development of chemoresistance. We sought to connect chemoresistance and cancer cell-derived extracellular vesicles (EV). The mechanisms of how chemoresistance is sustained by EV remained elusive. One potentially contributing factor is A Disintegrin and Metalloprotease 17 (ADAM17)-itself being able to promote chemoresistance and inducing tumour cell proliferation and survival via the Epidermal Growth Factor Receptor (EGFR) pathway by shedding several of its ligands including Amphiregulin (AREG). We now demonstrate that upon chemotherapeutic treatment, proteolytically active ADAM17 is released in association with EV from OvCa cells. In terms of function, we show that patient-derived EV induce AREG shedding and restore chemoresistance in ADAM17-deficient cells. Confirming that ADAM17-containing EV transmit chemoresistance in OvCa, we propose that ADAM17 levels (also on EV) might serve as an indicator for tumour progression and the chemosensitivity status of a given patient.
Topics: Humans; Female; ADAM Proteins; ErbB Receptors; Extracellular Vesicles; Ovarian Neoplasms; Antineoplastic Agents; ADAM17 Protein
PubMed: 37408115
DOI: 10.1002/jev2.12338 -
Cancers Jul 2023The poor outcome of metastasized breast cancer (BC) stresses the need for reliable personalized oncology and the significance of models recapitulating the heterogeneous...
The poor outcome of metastasized breast cancer (BC) stresses the need for reliable personalized oncology and the significance of models recapitulating the heterogeneous nature of BC. Here, we cultured metastatic tumor cells derived from advanced BC patients with malignant ascites (MA) or malignant pleural effusion (MPE) using organoid technology. We identified the characteristics of tumor organoids by applying immunohistochemistry and mutation analysis. Tumor organoids preserved their expression patterns and hotspot mutations when compared to their original metastatic counterpart and are consequently a well-suited in vitro model for metastasized BC. We treated the tumor organoids to implement a reliable application for drug screenings of metastasized cells. Drug assays revealed that responses are not always in accord with expression patterns, pathway activation, and hotspot mutations. The discrepancy between characterization and functional testing underlines the relevance of linking IHC stainings and mutational analysis of metastasized BC with in vitro drug assays. Our metastatic BC organoids recapitulate the characteristics of their original sample derived from MA and MPE and serve as an invaluable tool that can be utilized in a preclinical setting for guiding therapy decisions.
PubMed: 37509265
DOI: 10.3390/cancers15143602 -
Journal of Experimental & Clinical... Sep 2023Malignant ascites commonly occurs in advanced or recurrent stages of epithelial ovarian cancer during peritoneal carcinomatosis and is correlated with poor prognosis....
BACKGROUND
Malignant ascites commonly occurs in advanced or recurrent stages of epithelial ovarian cancer during peritoneal carcinomatosis and is correlated with poor prognosis. Due to its complex composition of cellular and acellular components malignant ascites creates a unique tumor microenvironment, which mediates immunosuppression and promotes progression of disease. However, the immunosuppressive mechanisms remain poorly understood.
METHODS
In the present study, we explored the antitumor activity of healthy donor NK and T cells directed against ovarian cancer cells in presence of malignant ascites derived from patients with advanced or recurrent peritoneal carcinomatosis. A wide range of methods was used to study the effect of ascites on NK and T cells (FACS, ELISA, EliSpot, qPCR, Live-cell and confocal microscopy, Western blot and electrolyte flux assays). The ascites components were assessed using quantitative analysis (nephelometry, potentiometry and clinical chemistry) and separation methods (dialysis, ultracentrifugal filtration and lipid depletion).
RESULTS
Ascites rapidly inhibited NK cell degranulation, tumor lysis, cytokine secretion and calcium signaling. Similarly, target independent NK and T cell activation was impaired in ascites environment. We identified imbalanced electrolytes in ascites as crucial factors causing extensive immunosuppression of NK and T cells. Specifically, high sodium, low chloride and low potassium content significantly suppressed NK-mediated cytotoxicity. Electrolyte imbalance led to changes in transcription and protein expression of electrolyte channels and impaired NK and T cell activation. Selected inhibitors of sodium electrolyte channels restored intracellular calcium flux, conjugation, degranulation and transcript expression of signaling molecules. The levels of ascites-mediated immunosuppression and sodium/chloride/potassium imbalance correlated with poor patient outcome and selected molecular alterations were confirmed in immune cells from ovarian cancer patients.
CONCLUSION
Our data suggest a novel electrolyte-based mechanism of immunosuppression in malignant ascites of patients with peritoneal carcinomatosis. We show for the first time that the immunosuppression of NK cytotoxicity in coculture assays is correlated to patient poor survival. Therapeutic application of sodium channel inhibitors may provide new means for restoring immune cell activity in ascites or similar electrolyte imbalanced environments.
Topics: Humans; Female; Peritoneal Neoplasms; Ascites; Chlorides; T-Lymphocytes; Ovarian Neoplasms; Potassium; Tumor Microenvironment
PubMed: 37684704
DOI: 10.1186/s13046-023-02798-8 -
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 -
Journal For Immunotherapy of Cancer Sep 2023The potent immunosuppressive properties of sialic acid-binding immunoglobulin-like lectin-9 (Siglec-9) on myeloid cells and lymphocytes provide a strong rationale for...
BACKGROUND
The potent immunosuppressive properties of sialic acid-binding immunoglobulin-like lectin-9 (Siglec-9) on myeloid cells and lymphocytes provide a strong rationale for serving as a therapeutic target. However, the expression profile and critical role of Siglec-9 in high-grade serous ovarian cancer (HGSC) remain obscure. This study aimed to elucidate the prognostic significance of Siglec-9 expression and its predictive value for immunotherapy in HGSC.
METHODS
Study enrolled two cohorts, consisting of 120 tumor microarray specimens of HGSC for immunohistochemistry (IHC) and 40 fresh tumor specimens for flow cytometry (FCM). Expression profile of Siglec-9 in immune cells was analyzed by both bioinformatics analysis and FCM. Role of Siglec-9 was studied to identify that Siglec-9TAMs linked with an immunosuppressive phenotype by IHC and FCM, and block Siglec-9 was sensitive to immunotherapy by ex vivo and in vitro assays.
RESULTS
Siglec-9 is predominantly expressed on tumor-associated macrophages (TAMs). High Siglec-9TAMs were associated with inferior overall survival (OS). Both tumor-conditioned medium (TCM) and tumor ascites induced enrichment of Siglec-9TAMs with protumorigenic phenotypes. Siglec-9TAMs were associated with immunosuppressive tumor microenvironment (TME) characterized by exhausted CD8T cells and increased immune checkpoint expression. Blockade of Siglec-9 suppressed phosphorylation of the inhibitory phosphatase SHP-1 and repolarized TAMs to antitumorigenic phenotype and retrieved cytotoxic activity of CD8T cells in vitro and ex vivo. Responders toward antiprogrammed death receptor-1 (anti-PD-1) therapy present more Siglec-9TAMs than non-responders. Furthermore, blockade Siglec-9 synergized with anti-PD-1 antibody to enhance the cytotoxic activity of CD8T cells in tissues with higher Siglec-9TAMs.
CONCLUSIONS
Siglec-9TAMs may serve as an independent prognostic of poor survival but a predictive biomarker for anti-PD-1/antiprogrammed death ligand-1 immunotherapy in HGSC. In addition, the potential of immunosuppressive Siglec-9TAMs as a therapeutic target is worth further exploration.
Topics: Humans; Female; Tumor-Associated Macrophages; Immunosuppressive Agents; Immunotherapy; Antibodies; Ovarian Neoplasms; Tumor Microenvironment
PubMed: 37709296
DOI: 10.1136/jitc-2023-007099