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Cancer Biology & Medicine Aug 2023Paclitaxel (P) is a standard second-line chemotherapy in the treatment of advanced gastric cancer. This study compared the clinical outcome of a paclitaxel plus... (Randomized Controlled Trial)
Randomized Controlled Trial
Comparing effectiveness and safety of paclitaxel plus raltitrexed paclitaxel alone in second-line palliative chemotherapy for metastatic gastric adenocarcinoma: A randomized phase II clinical trial.
OBJECTIVE
Paclitaxel (P) is a standard second-line chemotherapy in the treatment of advanced gastric cancer. This study compared the clinical outcome of a paclitaxel plus raltitrexed (RP) regimen as second-line treatment in metastatic gastric cancer (MGC) patients.
METHODS
An open, randomized, multi-center phase II clinical trial was conducted involving 148 patients who were randomly assigned and treated with RP [raltitrexed (3 mg/m on day 1) and paclitaxel (135 mg/m on day 1 every 3 weeks)] or P [paclitaxel (135 mg/m on day 1 every 3 weeks)] as 2-line chemotherapy. The primary endpoint was progression-free survival (PFS). The secondary endpoints were the overall response rate (ORR), overall survival (OS), and safety.
RESULTS
PFS had a tendency to be prolonged with RP compared to P (2.7 months 1.7 months; = 0.148). OS was also prolonged with RP compared to P (10.2 months 6.1 months; = 0.140). The ORR was equal in the RP and P groups (6.8% and 4.0%; = 0.72). The disease control rate (DCR) in the RP and P groups was 56.2% and 36.0%, respectively. Grade 3-4 treatment-related adverse events occurred in 36.2% (RP) and 28.2% (P) of patients. Frequent grade 3-4 toxicities for RP and P were neutropenia (11.0% and 4.0%), anemia (1.4% and 4.0%), and thrombocytopenia (1.4% and 5.3%), and all grades of peripheral neurotoxicity (12.3% 17.3%). All grades of hepatic toxicity were demonstrated for the RP and P groups based on elevated aminotransferase levels (27.4% and 14.1%). Subgroup analysis shows if MGC was combined with ascites or peritoneal involvement, the OS of the RP regimen was longer ( = 0.05).
CONCLUSIONS
Second-line palliative chemotherapy with RP was shown to prolong the PFS and OS, especially among patients with ascites or peritoneal involvement, which warrants confirmation using larger sample studies.
Topics: Humans; Paclitaxel; Stomach Neoplasms; Ascites; Adenocarcinoma
PubMed: 37653589
DOI: 10.20892/j.issn.2095-3941.2023.0112 -
PNAS Nexus Sep 2023Malignant ascites in hepatocellular carcinoma is usually a sign of advanced disease and poor prognosis and is also thought to be associated with chronic inflammation...
Malignant ascites in hepatocellular carcinoma is usually a sign of advanced disease and poor prognosis and is also thought to be associated with chronic inflammation mediated by neutrophil extracellular trap (NET) networks. Although ozone, a strong oxidant, has significant antibacterial and anti-inflammatory effects, its effectiveness in treating malignant liver ascites is unclear. We first measured the levels of NETs in the peripheral blood of patients with liver cancer and healthy individuals. Next, we constructed the H22 tumor-bearing mouse model and observed the abdominal girth, body weight, survival rate, and survival time in each group; we marked the proteins associated with NETs in mouse intestinal tissues by immunofluorescence; cf-DNA and cytokines in ascites such as: tumor necrosis factor alpha (TNF-α), vascular endothelial growth factor (VEGF), interleukin 6 (IL-6), matrix metalloprotein 9 (MMP-9), and interferon gamma (IFN-γ) levels in ascites were measured by enzyme-linked immunosorbent assay. The expression levels of phosphorylated adenylate-activated protein kinase (P-AMPK) and scavenger receptor-A (SR-A) were detected by immunocytochemistry in the intestinal tissues of each group of mice. We further examined the expression of P-AMPK and SR-A proteins in ascites deposits by Western blotting. The results show, the plasma levels of NETs were higher in patients with hepatocellular carcinoma than in normal subjects ( < 0.01). Abdominal girth and body weight were significantly reduced in the ozone-treated group compared with the model group, while survival and survival time were dose dependently increased (both < 0.05). NET-associated guanine histone H3 and myeloperoxidase were abundantly expressed at neutrophil aggregates in the intestinal tissues of the model mice, whereas their expression was significantly reduced in the ozone-treated group. The levels of cf-DNA, IL-6, IFN-γ, MMP-9, VEGF, and TNF-α were dose dependently increased in the ascites of H22 tumor-bearing mice in the ozone-treated group compared with the model group (all < 0.01), while the expression of P-AMPK and SR-A proteins was increased in the ozone-treated group compared with the model group. Ozone showed significant antiperitoneal fluid production properties in H22 tumor-bearing mice, and ozone reduced peritoneal fluid production by activating AMPK and up-regulating SR-A phagocytosis damage-associated molecular patterns to reduce the production of NETs. This suggests that ozone could be used as a new drug for the treatment of malignant ascites in hepatocellular carcinoma.
PubMed: 37693209
DOI: 10.1093/pnasnexus/pgad280 -
Frontiers in Pharmacology 2023Toxic (EK) is employed to treat malignant ascites effusion (MAE). EK stir-fried with vinegar (VEK) has been demonstrated to reduce toxicity due to its preserved...
Toxic (EK) is employed to treat malignant ascites effusion (MAE). EK stir-fried with vinegar (VEK) has been demonstrated to reduce toxicity due to its preserved water-expelling effect. This was demonstrated to be correlated with gut microbiota. Therein, bile acids (BAs) have a bidirectional relationship with the gut microbiota. Therefore, the aim of this study is to explore whether BA-mediated gut microbiota influences the water-expelling effect of VEK against MAE. The MAE rat model was established by intraperitoneal injection of Walker-256 tumor cells. A reliable simultaneous method for the determination of 15 bile acids in rat feces using ultra-high-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was established and applied to analyze the fecal BAs in rats treated with VEK. The screened BA was then administered to VEK-treated MAE rats. The water-expelling effect was evaluated using histopathological analysis, biochemical examination, inflammatory factors in ascites, urine volume, ascites amount, and intestinal aquaporin expression. The microbial composition was determined using 16S rRNA sequencing, and the contents of bile acids were finally measured. VEK decreased the content of fecal deoxycholic acid (DCA), lithocholic acid (LCA), and taurocholic acid (TCA) while increasing the content of ursodeoxycholic acid (UDCA). VEK alleviated liver, stomach, and intestinal injuries; oxidative damage; and inflammation, which were further ameliorated with UDCA intervention. VEK alleviated MAE by increasing the fecal water content, urine volume, and AQP3 protein expression and decreasing the urine levels of Na, K, and Cl. This was retained with the intervention of UDCA. UDCA and VEK regulated the BA metabolism disorder to a certain extent. Analysis of gut microbiota showed that VEK increased the abundance of and decreased that of in MAE rats. The combined administration of UDCA and VEK showed a better modulation of the microbiota structure than that of VEK alone, and the effect of this administration reached closer to the reference state. The water-expelling effect of VEK did not directly depend on the BA-mediated gut microbiota. However, VEK and BAs had a synergistic effect on malignant ascites effusion through the regulation of the gut microbiota. These results provided a scientific basis for the reasonable usage of VEK and the novel combination treatment strategy of VEK and UDCA.
PubMed: 38026948
DOI: 10.3389/fphar.2023.1249910 -
Cancer Research Communications Mar 2024High-grade serous carcinoma (HGSC) of the fallopian tube, ovary, and peritoneum is the most common type of ovarian cancer and is predicted to be immunogenic because the...
UNLABELLED
High-grade serous carcinoma (HGSC) of the fallopian tube, ovary, and peritoneum is the most common type of ovarian cancer and is predicted to be immunogenic because the presence of tumor-infiltrating lymphocytes conveys a better prognosis. However, the efficacy of immunotherapies has been limited because of the immune-suppressed tumor microenvironment (TME). Tumor metabolism and immune-suppressive metabolites directly affect immune cell function through the depletion of nutrients and activation of immune-suppressive transcriptional programs. Tryptophan (TRP) catabolism is a contributor to HGSC disease progression. Two structurally distinct rate-limiting TRP catabolizing enzymes, indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase 2 (TDO2), evolved separately to catabolize TRP. IDO1/TDO2 are aberrantly expressed in carcinomas and metabolize TRP into the immune-suppressive metabolite kynurenine (KYN), which can engage the aryl hydrocarbon receptor to drive immunosuppressive transcriptional programs. To date, IDO inhibitors tested in clinical trials have had limited efficacy, but those inhibitors did not target TDO2, and we find that HGSC cell lines and clinical outcomes are more dependent on TDO2 than IDO1. To identify inflammatory HGSC cancers with poor prognosis, we stratified patient ascites samples by IL6 status, which correlates with poor prognosis. Metabolomics revealed that IL6-high patient samples had enriched KYN. TDO2 knockdown significantly inhibited HGSC growth and TRP catabolism. The orally available dual IDO1/TDO2 inhibitor, AT-0174, significantly inhibited tumor progression, reduced tumor-associated macrophages, and reduced expression of immune-suppressive proteins on immune and tumor cells. These studies demonstrate the importance of TDO2 and the therapeutic potential of AT-0174 to overcome an immune-suppressed TME.
SIGNIFICANCE
Developing strategies to improve response to chemotherapy is essential to extending disease-free intervals for patients with HGSC of the fallopian tube, ovary, and peritoneum. In this article, we demonstrate that targeting TRP catabolism, particularly with dual inhibition of TDO2 and IDO1, attenuates the immune-suppressive microenvironment and, when combined with chemotherapy, extends survival compared with chemotherapy alone.
Topics: Female; Humans; Tryptophan Oxygenase; Tryptophan; B7-H1 Antigen; Interleukin-6; Kynurenine; Ovarian Neoplasms; Enzyme Inhibitors; Macrophages; Tumor Microenvironment
PubMed: 38451784
DOI: 10.1158/2767-9764.CRC-23-0513 -
Science Advances Apr 2024Slowing peritoneal spread in high-grade serous ovarian cancer (HGSOC) would improve patient prognosis and quality of life. HGSOC spreads when single cells and spheroids...
Slowing peritoneal spread in high-grade serous ovarian cancer (HGSOC) would improve patient prognosis and quality of life. HGSOC spreads when single cells and spheroids detach, float through the peritoneal fluid and take over new sites, with spheroids thought to be more aggressive than single cells. Using our in vitro model of spheroid collective detachment, we determine that increased substrate stiffness led to the detachment of more spheroids. We identified a mechanism where Piezo1 activity increased MMP-1/MMP-10, decreased collagen I and fibronectin, and increased spheroid detachment. Piezo1 expression was confirmed in omental masses from patients with stage III/IV HGSOC. Using OV90 and CRISPR-modified OV90 in a mouse xenograft model, we determined that while both genotypes efficiently took over the omentum, loss of Piezo1 significantly decreased ascitic volume, tumor spheroids in the ascites, and the number of macroscopic tumors in the mesentery. These results support that slowing collective detachment may benefit patients and identify Piezo1 as a potential therapeutic target.
Topics: Animals; Female; Humans; Mice; Cell Line, Tumor; Cystadenocarcinoma, Serous; Ion Channels; Mechanotransduction, Cellular; Neoplasm Grading; Ovarian Neoplasms; Spheroids, Cellular
PubMed: 38669327
DOI: 10.1126/sciadv.adl4463 -
BMC Medical Imaging Dec 2023To investigate the diagnostic value of computed tomography (CT) and magnetic resonance imaging (MRI) in ovarian malignant mesothelioma (OMM).
OBJECTIVE
To investigate the diagnostic value of computed tomography (CT) and magnetic resonance imaging (MRI) in ovarian malignant mesothelioma (OMM).
METHODS
The clinical and imaging data of 10 pathologically-confirmed OMM patients were analyzed retrospectively.
RESULT
(1) The patients were 27 years to 70 years old, with an average age of 57.2 ± 15.4 years. Seven patients reported abdominal distension and pain, 1 reported lower abdominal discomfort and decreased appetite, and 2 patients had no symptoms. (2) Two cases of localized OMM with incomplete semi-annular "capsule" observed around the localized OMM tumors were reported while 8 cases had diffuse OMM in which the tumor parenchyma showed isointense or slightly hypointense on T1WI, inhomogeneous hyperintense on T2WI, and obviously hyperintense on DWI, with obvious inhomogeneous enhancement after enhancement. Diffuse OMM was not mainly composed of ovarian masses and was mainly characterized by mild ovarian enlargement, nodular and irregular thickening of the peritoneum, cloudy omentum, unclear fat gap, and reticular or irregular thickening, which can fuse into a "cake-shape". (3) All 10 patients underwent surgery, while 9 patients underwent systemic chemotherapy or immunotherapy after surgery. All patients with localized OMM survived. Out of the 8 diffuse-type patients, 5 died, 1 was lost to follow-up, and 2 survived.
CONCLUSION
OMM has certain clinical and imaging characteristics. There is no liquefaction, calcification, or partition in the tumor. The ovarian enlargement in the diffuse lesion is not significant. The diffuse thickening of the peritoneum and omentum with early appearance of mural nodules and ascites in the upper abdomen, help the diagnosis of OMM.
Topics: Female; Humans; Adult; Middle Aged; Aged; Mesothelioma, Malignant; Retrospective Studies; Magnetic Resonance Imaging; Ovarian Neoplasms; Tomography, X-Ray Computed
PubMed: 38097964
DOI: 10.1186/s12880-023-01165-5 -
Clinical Endoscopy Mar 2024Endoscopic ultrasound (EUS)-guided hepaticogastrostomy (EUS-HGS) is useful for patients with biliary cannulation failure or inaccessible papillae. However, it can lead...
BACKGROUND/AIMS
Endoscopic ultrasound (EUS)-guided hepaticogastrostomy (EUS-HGS) is useful for patients with biliary cannulation failure or inaccessible papillae. However, it can lead to serious complications such as bile peritonitis in patients with ascites; therefore, development of a safe method to perform EUS-HGS is important. Herein, we evaluated the safety of EUS-HGS with continuous ascitic fluid drainage in patients with ascites.
METHODS
Patients with moderate or severe ascites who underwent continuous ascites drainage, which was initiated before EUS-HGS and terminated after the procedure at our institution between April 2015 and December 2022, were included in the study. We evaluated the technical and clinical success rates, EUS-HGS-related complications, and feasibility of re-intervention.
RESULTS
Ten patients underwent continuous ascites drainage, which was initiated before EUS-HGS and terminated after completion of the procedure. Median duration of ascites drainage before and after EUS-HGS was 2 and 4 days, respectively. Technical success with EUS-HGS was achieved in all 10 patients (100%). Clinical success with EUS-HGS was achieved in 9 of the 10 patients (90 %). No endoscopic complications such as bile peritonitis were observed.
CONCLUSION
In patients with ascites, continuous ascites drainage, which is initiated before EUS-HGS and terminated after completion of the procedure, may prevent complications and allow safe performance of EUS-HGS.
PubMed: 37743069
DOI: 10.5946/ce.2023.075 -
Diagnostics (Basel, Switzerland) Jul 2023Budd-Chiari syndrome (BCS) is a rare hepatic vascular disorder defined by the presence of partial or complete impairment of hepatic venous drainage in the absence of... (Review)
Review
Budd-Chiari syndrome (BCS) is a rare hepatic vascular disorder defined by the presence of partial or complete impairment of hepatic venous drainage in the absence of right heart failure or constrictive pericarditis. Several conditions can lead to BCS, from hypercoagulable states to malignancies. Primary BCS is the most common subtype, and usually bartends hypercoagulability states, while secondary BCS involves tumor invasion or extrinsic compression. A combination of clinical and imaging features leads to the diagnosis of BCS, including (1) direct signs: occlusion or compression of the hepatic veins and/or inferior vena cava, and the presence of venous collaterals; (2) indirect signs: morphological hepatic changes with caudate lobe enlargement; inhomogeneous enhancement, and hypervascular nodules. From a clinicopathological point of view, two forms of BCS can be distinguished: acute and subacute/chronic BCS, although asymptomatic and fulminant forms are also possible. Acute presentations are rare, and symptoms include hepatomegaly, ascites, and hepatic insufficiency. Subacute/chronic forms are the most common presentation, with dysmorphic liver and variable degrees of fibrosis deposition. Patients with chronic BCS can develop benign regenerative nodules (large regenerative nodules or FNH [Focal Nodular Hyperplasia]-like lesions), but are also at a higher risk of hepatocellular carcinoma (HCC). The radiologist role is therefore fundamental in both diagnosis and surveillance of BCS. The aim of this review is to present all clinical and imaging signs that can help to reach the diagnosis of BCS, with their clinical significance, providing tips and tricks for the cross-sectional diagnosis of this condition.
PubMed: 37443650
DOI: 10.3390/diagnostics13132256 -
Journal of Cachexia, Sarcopenia and... Oct 2023Skeletal muscle loss during treatment is associated with poor survival outcomes in patients with ovarian cancer. Although changes in muscle mass can be assessed on...
BACKGROUND
Skeletal muscle loss during treatment is associated with poor survival outcomes in patients with ovarian cancer. Although changes in muscle mass can be assessed on computed tomography (CT) scans, this labour-intensive process can impair its utility in clinical practice. This study aimed to develop a machine learning (ML) model to predict muscle loss based on clinical data and to interpret the ML model by applying SHapley Additive exPlanations (SHAP) method.
METHODS
This study included the data of 617 patients with ovarian cancer who underwent primary debulking surgery and platinum-based chemotherapy at a tertiary centre between 2010 and 2019. The cohort data were split into training and test sets based on the treatment time. External validation was performed using 140 patients from a different tertiary centre. The skeletal muscle index (SMI) was measured from pre- and post-treatment CT scans, and a decrease in SMI ≥ 5% was defined as muscle loss. We evaluated five ML models to predict muscle loss, and their performance was determined using the area under the receiver operating characteristic curve (AUC) and F1 score. The features for analysis included demographic and disease-specific characteristics and relative changes in body mass index (BMI), albumin, neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR). The SHAP method was applied to determine the importance of the features and interpret the ML models.
RESULTS
The median (inter-quartile range) age of the cohort was 52 (46-59) years. After treatment, 204 patients (33.1%) experienced muscle loss in the training and test datasets, while 44 (31.4%) patients experienced muscle loss in the external validation dataset. Among the five evaluated ML models, the random forest model achieved the highest AUC (0.856, 95% confidence interval: 0.854-0.859) and F1 score (0.726, 95% confidence interval: 0.722-0.730). In the external validation, the random forest model outperformed all ML models with an AUC of 0.874 and an F1 score of 0.741. The results of the SHAP method showed that the albumin change, BMI change, malignant ascites, NLR change, and PLR change were the most important factors in muscle loss. At the patient level, SHAP force plots demonstrated insightful interpretation of our random forest model to predict muscle loss.
CONCLUSIONS
Explainable ML model was developed using clinical data to identify patients experiencing muscle loss after treatment and provide information of feature contribution. Using the SHAP method, clinicians may better understand the contributors to muscle loss and target interventions to counteract muscle loss.
Topics: Humans; Female; Middle Aged; Muscle, Skeletal; Chemotherapy, Adjuvant; Ovarian Neoplasms; Albumins; Machine Learning
PubMed: 37435785
DOI: 10.1002/jcsm.13282 -
International Journal of Surgery Case... Nov 2023Ovarian fibrosarcoma is a rare cancer. In the literature, there have been very few occurrences of fibrosarcoma with ascites. The presence of ascites complicates the...
INTRODUCTION
Ovarian fibrosarcoma is a rare cancer. In the literature, there have been very few occurrences of fibrosarcoma with ascites. The presence of ascites complicates the diagnosis further, and is associated with a poor prognosis and has been linked to chemoresistance and metastasis. We present this case of an ovarian fibrosarcoma with ascites to provide a comprehensive overview of the clinical presentation, diagnostic evaluation and management of this pathology, which remains a challenge given the rarity of this entity.
PRESENTATION OF CASE
We report the case of a 60-year-old woman who was referred to our unit, because of abdominal bloating, sporadic pelvic pain and abdominal distension. Ultrasound showed a heterogeneous mass over the right adnexa with ascites. Serum tumour markers were within normal limits. During surgery, a total abdominal hysterectomy plus bilateral adnexectomy was performed. The final histopathological findings showed a well-differentiated fibrosarcoma. The patient was followed up regularly and no recurrence was seen 2 years after surgery.
DISCUSSION
Ovarian fibrosarcomas are uncommon cancers with no known risk factors. Diagnosis can be difficult, especially in the presence of ascites, and other diagnostic options should be considered. Pathological and immunohistochemistry investigations are required for a clear diagnosis. Early metastases and resistance to adjuvant chemotherapy characterize the prognosis of ovarian fibrosarcoma with ascites.
CONCLUSIONS
Ovarian fibrosarcoma with ascites is a rare and challenging ovarian disease, highlighting the need for postoperative pathology to make a clear diagnosis, complete cytoreductive surgery and individual consideration of adjuvant radiochemotherapy should be included in the management.
PubMed: 37871372
DOI: 10.1016/j.ijscr.2023.108938