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Emergency Radiology Jun 2024The goal of our study was to better characterize new CT diagnoses of peritoneal carcinomatosis (PC) in the ED, and to evaluate how to best identify the primary lesion....
PURPOSE
The goal of our study was to better characterize new CT diagnoses of peritoneal carcinomatosis (PC) in the ED, and to evaluate how to best identify the primary lesion. Prompt identification of the source of the carcinomatosis may allow for the patient to receive early initial care from the correct clinical service.
METHODS
All new CT cases of PC-like appearance identified on CT in the ED from January 2017 through July 2020. Each report and corresponding medical record were manually reviewed. Patient demographics, presence/absence of intravenous contrast, source organ predicted by the radiologist in the CT scan report, pathologic diagnosis, and amount of ascites were tabulated. Chi-tests were used to test the statistical significance of differences between groups.
RESULTS
Of the 131 CT cases of new PC-like appearance which received workup, 108 cases had pathologically proven PC and 23 cases had no underlying malignancy yielding a positive predictive value for actual PC of 82%. The most common cause of new PC in women was gynecological (66%), and in men was of GI tract origin (57%). Concordance between radiologist prediction and final pathology was higher with intravenous contrast (58%) compared to without contrast (40%); although this difference was not statistically significant (p = 0.19). A moderate or large amount of ascites was found in more than half of GYN primaries and in adenocarcinoma of unknown primary and there was a statistically significant difference in amount of ascites between cancer primaries (p = 0.01).
CONCLUSION
A PC-like appearance on CT in the ED will likely be in patients with known malignancy, but of the new cases, there is a high PPV for it to represent new peritoneal carcinomatosis. Gynecological and GI malignancies are the most common cause in women and men, respectively, and this may help in focusing the radiologist's search pattern. Usage of intravenous contrast may help in identifying a primary lesion, and the presence of high-volume ascites should suggest a GYN primary or adenocarcinoma of unknown primary when there is no other obvious primary lesion.
PubMed: 38836936
DOI: 10.1007/s10140-024-02238-w -
Small Methods Jan 2024Basic and clinical cancer research requires tumor models that consistently recapitulate the characteristics of prima tumors. As ex vivo 3D cultures of patient tumor... (Review)
Review
Basic and clinical cancer research requires tumor models that consistently recapitulate the characteristics of prima tumors. As ex vivo 3D cultures of patient tumor cells, patient-derived tumor organoids possess the biological properties of primary tumors and are therefore excellent preclinical models for cancer research. Patient-derived organoids can be established using primary tumor tissues, peripheral blood, pleural fluid, ascites, and other samples containing tumor cells. Circulating tumor cells acquired by non-invasive sampling feature dynamic circulation and high heterogeneity. Circulating tumor cell-derived organoids are prospective tools for the dynamic monitoring of tumor mutation evolution profiles because they reflect the heterogeneity of the original tumors to a certain extent. This review discusses the advantages and applications of patient-derived organoids. Meanwhile, this work highlights the biological functions of circulating tumor cells, the latest advancement in research of circulating tumor cell-derived organoids, and potential application and challenges of this technology.
Topics: Humans; Neoplastic Cells, Circulating; Precision Medicine; Organoids
PubMed: 37882328
DOI: 10.1002/smtd.202301009 -
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 -
Diagnostic and Interventional Imaging Oct 2023
Topics: Humans; Lymphography; Chylous Ascites; Lymphocele; Ethiodized Oil; Contrast Media
PubMed: 37349173
DOI: 10.1016/j.diii.2023.06.004 -
Annals of Palliative Medicine Apr 2024Malignant ascites (MA) is common in patients with advanced cancer, and about 60% of patients with MA experience distressing symptoms. In addition, MA has been identified...
BACKGROUND AND OBJECTIVE
Malignant ascites (MA) is common in patients with advanced cancer, and about 60% of patients with MA experience distressing symptoms. In addition, MA has been identified as a poor prognostic factor, therefore, making the management of MA an important issue. We aimed to review literature describing MA provide a narrative synthesis of relevant studies.
METHODS
A literature search of articles published between 1971 and May 2023 was performed in PubMed, and Cochrane library using the words "ascites/malignant ascites" and the theme of each section. Authors independently selected the articles used and summarized. Finally, this manuscript was obtained consensus through discussed among all authors.
KEY CONTENT AND FINDINGS
The pathophysiological mechanism of ascites formation involves increased vascular permeability and impaired fluid drainage through the lymphatic system, which explain the occurrence of peritoneal carcinomatosis, portal hypertension due to liver tumors, liver cirrhosis in the background of hepatocellular carcinoma, and Budd-Chiari syndrome caused by tumor occlusion of the hepatic vein. The efficacy and safety of various treatments and procedures have been investigated previously; however, no treatment guidelines have been established yet. Diuretics and paracentesis are often selected as the first lines of treatment. Intraperitoneal drug administration (catumaxomab, bevacizumab, aflibercept, hyperthermic intraperitoneal chemotherapy, triamcinolone), indwelling peritoneal catheters, peritoneovenous shunting, and cell-free and concentrated ascites reinfusion therapy are commonly used to manage refractory ascites. A new device for this purpose is alfapump, which transfers ascites fluid from the peritoneum into the urinary bladder. In addition, thoracic epidural analgesia may be effective for managing ascites-related symptoms.
CONCLUSIONS
Despite these options, no standard treatment for MA has been established yet because few trials have been conducted in this area. There are many issues to be investigated, and future research and treatment development are expected.
PubMed: 38644553
DOI: 10.21037/apm-23-554 -
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 -
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 -
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 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 -
Oncogene Sep 2023PG545 (Pixatimod) is a highly sulfated small molecule known for its ability to inhibit heparanase and disrupt signaling mediated by heparan-binding-growth factors...
PG545 (Pixatimod) is a highly sulfated small molecule known for its ability to inhibit heparanase and disrupt signaling mediated by heparan-binding-growth factors (HB-GF). Previous studies indicated that PG545 inhibits growth factor-mediated signaling in ovarian cancer (OC) to enhance response to chemotherapy. Here we investigated the previously unidentified mechanisms by which PG545 induces DNA damage in OC cells and found that PG545 induces DNA single- and double-strand breaks, reduces RAD51 expression in an autophagy-dependent manner and inhibits homologous recombination repair (HRR). These changes accompanied the ability of PG545 to inhibit endocytosis of the heparan-sulfate proteoglycan interacting DNA repair protein, DEK, leading to DEK sequestration in the tumor microenvironment (TME) and loss of nuclear DEK needed for HRR. As a result, PG545 synergized with poly (ADP-ribose) polymerase inhibitors (PARPis) in OC cell lines in vitro and in 55% of primary cultures of patient-derived ascites samples ex vivo. Moreover, PG545/PARPi synergy was observed in OC cells exhibiting either de novo or acquired resistance to PARPi monotherapy. PG545 in combination with rucaparib also generated increased DNA damage, increased antitumor effects and increased survival of mice bearing HRR proficient OVCAR5 xenografts compared to monotherapy treatment in vivo. Synergistic antitumor activity of the PG545/rucaparib combination was likewise observed in an immunocompetent syngeneic ID8F3 OC model. Collectively, these results suggest that targeting DEK-HSPG interactions in the TME through the use of PG545 may be a novel method of inhibiting DNA repair and sensitizing cells to PARPis.
Topics: Animals; Female; Humans; Mice; Angiogenesis Inhibitors; Cell Line, Tumor; DNA Repair; Ovarian Neoplasms; Poly(ADP-ribose) Polymerase Inhibitors; Rad51 Recombinase; Tumor Microenvironment; Saponins
PubMed: 37550562
DOI: 10.1038/s41388-023-02785-5