-
JAMA May 2023Cirrhosis affects approximately 2.2 million adults in the US. From 2010 to 2021, the annual age-adjusted mortality of cirrhosis increased from 14.9 per 100 000 to 21.9... (Review)
Review
IMPORTANCE
Cirrhosis affects approximately 2.2 million adults in the US. From 2010 to 2021, the annual age-adjusted mortality of cirrhosis increased from 14.9 per 100 000 to 21.9 per 100 000 people.
OBSERVATIONS
The most common causes of cirrhosis in the US, which can overlap, include alcohol use disorder (approximately 45% of all cases of cirrhosis), nonalcoholic fatty liver disease (26%), and hepatitis C (41%). Patients with cirrhosis experience symptoms including muscle cramps (approximately 64% prevalence), pruritus (39%), poor-quality sleep (63%), and sexual dysfunction (53%). Cirrhosis can be diagnosed by liver biopsy but may also be diagnosed noninvasively. Elastography, a noninvasive assessment of liver stiffness measured in kilopascals, can typically confirm cirrhosis at levels of 15 kPa or greater. Approximately 40% of people with cirrhosis are diagnosed when they present with complications such as hepatic encephalopathy or ascites. The median survival time following onset of hepatic encephalopathy and ascites is 0.92 and 1.1 years, respectively. Among people with ascites, the annual incidence of spontaneous bacterial peritonitis is 11% and of hepatorenal syndrome is 8%; the latter is associated with a median survival of less than 2 weeks. Approximately 1% to 4% of patients with cirrhosis develop hepatocellular carcinoma each year, which is associated with a 5-year survival of approximately 20%. In a 3-year randomized clinical trial of 201 patients with portal hypertension, nonselective β-blockers (carvedilol or propranolol) reduced the risk of decompensation or death compared with placebo (16% vs 27%). Compared with sequential initiation, combination aldosterone antagonist and loop diuretics were more likely to resolve ascites (76% vs 56%) with lower rates of hyperkalemia (4% vs 18%). In meta-analyses of randomized trials, lactulose was associated with reduced mortality relative to placebo (8.5% vs 14%) in randomized trials involving 705 patients and reduced risk of recurrent overt hepatic encephalopathy (25.5% vs 46.8%) in randomized trials involving 1415 patients. In a randomized clinical trial of 300 patients, terlipressin improved the rate of reversal of hepatorenal syndrome from 39% to 18%. Trials addressing symptoms of cirrhosis have demonstrated efficacy for hydroxyzine in improving sleep dysfunction, pickle brine and taurine for reducing muscle cramps, and tadalafil for improving sexual dysfunction in men.
CONCLUSIONS AND RELEVANCE
Approximately 2.2 million US adults have cirrhosis. Many symptoms, such as muscle cramps, poor-quality sleep, pruritus, and sexual dysfunction, are common and treatable. First-line therapies include carvedilol or propranolol to prevent variceal bleeding, lactulose for hepatic encephalopathy, combination aldosterone antagonists and loop diuretics for ascites, and terlipressin for hepatorenal syndrome.
Topics: Adult; Humans; Male; Ascites; Carvedilol; Esophageal and Gastric Varices; Gastrointestinal Hemorrhage; Hepatic Encephalopathy; Hepatorenal Syndrome; Lactulose; Liver Cirrhosis; Liver Neoplasms; Muscle Cramp; Propranolol; Randomized Controlled Trials as Topic; Sodium Potassium Chloride Symporter Inhibitors; Terlipressin; United States
PubMed: 37159031
DOI: 10.1001/jama.2023.5997 -
Nature Medicine Aug 2020Malignant abdominal fluid (ascites) frequently develops in women with advanced high-grade serous ovarian cancer (HGSOC) and is associated with drug resistance and a poor...
Malignant abdominal fluid (ascites) frequently develops in women with advanced high-grade serous ovarian cancer (HGSOC) and is associated with drug resistance and a poor prognosis. To comprehensively characterize the HGSOC ascites ecosystem, we used single-cell RNA sequencing to profile ~11,000 cells from 22 ascites specimens from 11 patients with HGSOC. We found significant inter-patient variability in the composition and functional programs of ascites cells, including immunomodulatory fibroblast sub-populations and dichotomous macrophage populations. We found that the previously described immunoreactive and mesenchymal subtypes of HGSOC, which have prognostic implications, reflect the abundance of immune infiltrates and fibroblasts rather than distinct subsets of malignant cells. Malignant cell variability was partly explained by heterogeneous copy number alteration patterns or expression of a stemness program. Malignant cells shared expression of inflammatory programs that were largely recapitulated in single-cell RNA sequencing of ~35,000 cells from additionally collected samples, including three ascites, two primary HGSOC tumors and three patient ascites-derived xenograft models. Inhibition of the JAK/STAT pathway, which was expressed in both malignant cells and cancer-associated fibroblasts, had potent anti-tumor activity in primary short-term cultures and patient-derived xenograft models. Our work contributes to resolving the HSGOC landscape and provides a resource for the development of novel therapeutic approaches.
Topics: Ascites; Cell Line, Tumor; Cystadenoma, Serous; DNA Copy Number Variations; Drug Resistance, Neoplasm; Female; Fibroblasts; Gene Expression Regulation, Neoplastic; Heterografts; Humans; Janus Kinase 1; Neoplasm Grading; Neoplasm Proteins; Ovarian Neoplasms; Prognosis; STAT Transcription Factors; Sequence Analysis, RNA; Signal Transduction; Single-Cell Analysis
PubMed: 32572264
DOI: 10.1038/s41591-020-0926-0 -
Nature Cancer Aug 2023Ovarian cancer (OC) is an aggressive gynecological tumor usually diagnosed with widespread metastases and ascites. Here, we depicted a single-cell landscape of the OC...
Ovarian cancer (OC) is an aggressive gynecological tumor usually diagnosed with widespread metastases and ascites. Here, we depicted a single-cell landscape of the OC ecosystem with five tumor-relevant sites, including omentum metastasis and malignant ascites. Our data reveal the potential roles of ascites-enriched memory T cells as a pool for tumor-infiltrating exhausted CD8 T cells and T helper 1-like cells. Moreover, tumor-enriched macrophages exhibited a preference for monocyte-derived ontogeny, whereas macrophages in ascites were more of embryonic origin. Furthermore, we characterized MAIT and dendritic cells in malignant ascites, as well as two endothelial subsets in primary tumors as predictive biomarkers for platinum-based chemotherapy response. Taken together, our study provides a global view of the female malignant ascites ecosystem and offers valuable insights for its connection with tumor tissues and paves the way for potential markers of efficacy evaluation and therapy resistance in OC.
Topics: Female; Humans; Ascites; CD8-Positive T-Lymphocytes; Ecosystem; Ovarian Neoplasms; Single-Cell Analysis
PubMed: 37488416
DOI: 10.1038/s43018-023-00599-8 -
International Journal of Gynaecology... Oct 2021In 2014, FIGO's Committee for Gynecologic Oncology revised the staging of ovarian cancer, incorporating ovarian, fallopian tube, and peritoneal cancer into the same... (Review)
Review
In 2014, FIGO's Committee for Gynecologic Oncology revised the staging of ovarian cancer, incorporating ovarian, fallopian tube, and peritoneal cancer into the same system. Most of these malignancies are high-grade serous carcinomas (HGSC). Stage IC is now divided into three categories: IC1 (surgical spill); IC2 (capsule ruptured before surgery or tumor on ovarian or fallopian tube surface); and IC3 (malignant cells in the ascites or peritoneal washings). The updated staging includes a revision of Stage IIIC based on spread to the retroperitoneal lymph nodes alone without intraperitoneal dissemination. This category is now subdivided into IIIA1(i) (metastasis ≤10 mm in greatest dimension), and IIIA1(ii) (metastasis >10 mm in greatest dimension). Stage IIIA2 is now "microscopic extrapelvic peritoneal involvement with or without positive retroperitoneal lymph node" metastasis. This review summarizes the genetics, surgical management, chemotherapy, and targeted therapies for epithelial cancers, and the treatment of ovarian germ cell and stromal malignancies.
Topics: Fallopian Tube Neoplasms; Fallopian Tubes; Female; Humans; Neoplasm Staging; Ovarian Neoplasms; Peritoneum; Prognosis
PubMed: 34669199
DOI: 10.1002/ijgo.13878 -
Nature Communications Feb 2023Peritoneal metastasis is the leading cause of death for gastrointestinal cancers. The native and therapy-induced ascites ecosystems are not fully understood. Here, we...
Peritoneal metastasis is the leading cause of death for gastrointestinal cancers. The native and therapy-induced ascites ecosystems are not fully understood. Here, we characterize single-cell transcriptomes of 191,987 ascites cancer/immune cells from 35 patients with/without gastric cancer peritoneal metastasis (GCPM). During GCPM progression, an increase is seen of monocyte-like dendritic cells (DCs) that are pro-angiogenic with reduced antigen-presenting capacity and correlate with poor gastric cancer (GC) prognosis. We also describe the evolution of monocyte-like DCs and regulatory and proliferative T cells following therapy. Moreover, we track GC evolution, identifying high-plasticity GC clusters that exhibit a propensity to shift to a high-proliferative phenotype. Transitions occur via the recently described, autophagy-dependent plasticity program, paligenosis. Two autophagy-related genes (MARCKS and TXNIP) mark high-plasticity GC with poorer prognosis, and autophagy inhibitors induce apoptosis in patient-derived organoids. Our findings provide insights into the developmental trajectories of cancer/immune cells underlying GCPM progression and therapy resistance.
Topics: Humans; Ascites; Peritoneal Neoplasms; Peritoneum; Stomach Neoplasms
PubMed: 36788228
DOI: 10.1038/s41467-023-36310-9 -
British Journal of Cancer Jul 2020The build-up of fluid in the peritoneal cavity-ascites-is a hallmark of ovarian cancer, the most lethal of all gynaecological malignancies. This remarkable fluid, which... (Review)
Review
The build-up of fluid in the peritoneal cavity-ascites-is a hallmark of ovarian cancer, the most lethal of all gynaecological malignancies. This remarkable fluid, which contains a variety of cellular and acellular components, is known to contribute to patient morbidity and mortality by facilitating metastasis and contributing to chemoresistance, but remains largely under-researched. In this review, we will critically analyse the evidence associating ascites with metastasis and chemoresistance in ovarian cancer and provide an update on research in the field. We will argue the case for ascites as a unique and accessible substrate for tracking tumour progression and for translational research that will enhance our understanding of this cancer and lead to improvements in patient outcomes.
Topics: Ascites; Biomarkers, Tumor; Female; Humans; Ovarian Neoplasms; Ovary; Proteomics
PubMed: 32382112
DOI: 10.1038/s41416-020-0875-x -
Seminars in Cancer Biology Nov 2022Ovarian cancer encompasses a heterogeneous group of malignancies that involve the ovaries, fallopian tubes and the peritoneal cavity. Despite major advances made within... (Review)
Review
Ovarian cancer encompasses a heterogeneous group of malignancies that involve the ovaries, fallopian tubes and the peritoneal cavity. Despite major advances made within the field of cancer, the majority of patients with ovarian cancer are still being diagnosed at an advanced stage of the disease due to lack of effective screening tools. The overall survival of these patients has, therefore, not substantially improved over the past decades. Most patients undergo debulking surgery and treatment with chemotherapy, but often micrometastases remain and acquire resistance to the therapy, eventually leading to disease recurrence. Here, we summarize the current knowledge in epithelial ovarian cancer development and metastatic progression. For the most common subtypes, we focus further on the properties and functions of the immunosuppressive tumor microenvironment, including the extracellular matrix. Current and future treatment modalities are discussed and finally we provide an overview of the different experimental models used to develop novel therapies.
Topics: Female; Humans; Carcinoma, Ovarian Epithelial; Tumor Microenvironment; Neoplasm Recurrence, Local; Ovarian Neoplasms; Immunotherapy
PubMed: 35395389
DOI: 10.1016/j.semcancer.2022.03.027 -
Experimental & Molecular Medicine Dec 2020Gastric cancer (GC) patients develop malignant ascites as the disease progresses owing to peritoneal metastasis. GC patients with malignant ascites have a rapidly...
Gastric cancer (GC) patients develop malignant ascites as the disease progresses owing to peritoneal metastasis. GC patients with malignant ascites have a rapidly deteriorating clinical course with short survival following the onset of malignant ascites. Better optimized treatment strategies for this subset of patients are needed. To define the cellular characteristics of malignant ascites of GC, we used single-cell RNA sequencing to characterize tumor cells and tumor-associated macrophages (TAMs) from four samples of malignant ascites and one sample of cerebrospinal fluid. Reference transcriptomes for M1 and M2 macrophages were generated by in vitro differentiation of healthy blood-derived monocytes and applied to assess the inflammatory properties of TAMs. We analyzed 180 cells, including tumor cells, macrophages, and mesothelial cells. Dynamic exchange of tumor-promoting signals, including the CCL3-CCR1 or IL1B-IL1R2 interactions, suggests macrophage recruitment and anti-inflammatory tuning by tumor cells. By comparing these data with reference transcriptomes for M1-type and M2-type macrophages, we found noninflammatory characteristics in macrophages recovered from the malignant ascites of GC. Using public datasets, we demonstrated that the single-cell transcriptome-driven M2-specific signature was associated with poor prognosis in GC. Our data indicate that the anti-inflammatory characteristics of TAMs are controlled by tumor cells and present implications for treatment strategies for GC patients in which combination treatment targeting cancer cells and macrophages may have a reciprocal synergistic effect.
Topics: Ascites; Case-Control Studies; Cell Communication; Cell Plasticity; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; High-Throughput Nucleotide Sequencing; Humans; Macrophages; Peritoneal Neoplasms; Prognosis; Signal Transduction; Single-Cell Analysis; Stomach Neoplasms; Transcriptome; Tumor Microenvironment
PubMed: 33277616
DOI: 10.1038/s12276-020-00538-y -
Theranostics 2022Malignant ascites in peritoneal metastases is a lipid-enriched microenvironment and is frequently involved in the poor prognosis of epithelial ovarian cancer (EOC)....
Malignant ascites in peritoneal metastases is a lipid-enriched microenvironment and is frequently involved in the poor prognosis of epithelial ovarian cancer (EOC). However, the detailed mechanisms underlying ovarian cancer (OvCa) cells dictating their lipid metabolic activities in promoting tumor progression remain elusive. The omental conditioned medium (OCM) was established to imitate the omental or ascites microenvironment. Mass spectrometry, RT-qPCR, IHC, and western blot assays were applied to evaluate human fatty acid desaturases expressions and activities. Pharmaceutical inhibition and genetic ablation of SCD1/FADS2 were performed to observe the oncogenic capacities. RNA sequencing, lipid peroxidation, cellular iron, ROS, and Mito-Stress assays were applied to examine ferroptosis. OvCa patient-derived organoid and mouse model of peritoneal metastases were used to evaluate the combined effect of SCD1/FADS2 inhibitors with cisplatin. We found that two critical fatty acid desaturases, stearoyl-CoA desaturase-1 (SCD1) and acyl-CoA 6-desaturase (FADS2), were aberrantly upregulated, accelerating lipid metabolic activities and tumor aggressiveness of ascites-derived OvCa cells. Lipidomic analysis revealed that the elevation of unsaturated fatty acids (UFAs) was positively associated with SCD1/FADS2 levels and the oncogenic capacities of OvCa cells. In contrast, pharmaceutical inhibition and genetic ablation of SCD1/FADS2 retarded tumor growth, cancer stem cell (CSC) formation and reduced platinum resistance. Inhibition of SCD1/FADS2 directly downregulated GPX4 and the GSH/GSSG ratio, causing disruption of the cellular/mitochondrial redox balance and subsequently, iron-mediated lipid peroxidation and mitochondrial dysfunction in ascites-derived OvCa cells. Combinational treatment with SCD1/FADS2 inhibitors and cisplatin synergistically repressed tumor cell dissemination, providing a promising chemotherapeutic strategy against EOC peritoneal metastases.
Topics: Animals; Ascites; Carcinoma, Ovarian Epithelial; Cisplatin; Delta-5 Fatty Acid Desaturase; Fatty Acid Desaturases; Fatty Acids, Unsaturated; Female; Ferroptosis; Humans; Iron; Mice; Ovarian Neoplasms; Oxidation-Reduction; Peritoneal Neoplasms; Stearoyl-CoA Desaturase; Tumor Microenvironment
PubMed: 35547771
DOI: 10.7150/thno.70194 -
Journal For Immunotherapy of Cancer Dec 2022The immunogenic nature of metastatic colorectal cancer (CRC) with high microsatellite instability (MSI-H) underlies their responsiveness to immune checkpoint blockade...
BACKGROUND
The immunogenic nature of metastatic colorectal cancer (CRC) with high microsatellite instability (MSI-H) underlies their responsiveness to immune checkpoint blockade (ICB). However, resistance to ICB is commonly observed, and is associated with the presence of peritoneal-metastases and ascites formation. The mechanisms underlying this site-specific benefit of ICB are unknown.
METHODS
We created a novel model for spontaneous multiorgan metastasis in MSI-H CRC tumors by transplanting patient-derived organoids (PDO) into the cecum of humanized mice. Anti-programmed cell death protein-1 (PD-1) and anti-cytotoxic T-lymphocytes-associated protein 4 (CTLA-4) ICB treatment effects were analyzed in relation to the immune context of primary tumors, liver metastases, and peritoneal metastases. Immune profiling was performed by immunohistochemistry, flow cytometry and single-cell RNA sequencing. The role of B cells was assessed by antibody-mediated depletion. Immunosuppressive cytokine levels (interleukin (IL)-10, transforming growth factor (TGF)b1, TGFb2, TGFb3) were determined in ascites and serum samples by ELISA.
RESULTS
PDO-initiated primary tumors spontaneously metastasized to the liver and the peritoneum. Peritoneal-metastasis formation was accompanied by the accumulation of ascites. ICB completely cleared liver metastases and reduced primary tumor mass but had no effect on peritoneal metastases. This mimics clinical observations. After therapy discontinuation, primary tumor masses progressively decreased, but peritoneal metastases displayed unabated growth. Therapy efficacy correlated with the formation of tertiary lymphoid structures (TLS)-containing B cells and juxtaposed T cells-and with expression of an interferon-γ signature together with the B cell chemoattractant CXCL13. B cell depletion prevented liver-metastasis clearance by anti-CTLA-4 treatment. Peritoneal metastases were devoid of B cells and TLS, while the T cells in these lesions displayed a dysfunctional phenotype. Ascites samples from patients with cancer with peritoneal metastases and from the mouse model contained significantly higher levels of IL-10, TGFb1, TGFb2 and TGFb3 than serum samples.
CONCLUSIONS
By combining organoid and humanized mouse technologies, we present a novel model for spontaneous multiorgan metastasis by MSI-H CRC, in which the clinically observed organ site-dependent benefit of ICB is recapitulated. Moreover, we provide empirical evidence for a critical role for B cells in the generation of site-dependent antitumor immunity following anti-CTLA-4 treatment. High levels of immunosuppressive cytokines in ascites may underlie the observed resistance of peritoneal metastases to ICB.
Topics: Mice; Animals; Immune Checkpoint Inhibitors; Transforming Growth Factor beta3; Peritoneum; Ascites; Peritoneal Neoplasms; Cytokines; Liver Neoplasms; Colorectal Neoplasms
PubMed: 36543378
DOI: 10.1136/jitc-2022-005345