Safety and efficacy of intraperitoneal perfusion with tumor vesicle-encapsulated methotrexate for the treatment of cancerous ascites - an open, randomized and controlled clinical trial

Background:Cancerous ascites is a common and severe complication that occurs in patients with late-stage malignant tumors.The prognosis of cancerous ascites is poor,clinical treatment is difficult and therapeutic outcome is disappointing.In the present study,tumor cell-derived vesicles were used as drug delivery vehicles that encapsulated a chemotherapeutic agent and were perfused into a patients’abdominal cavity to effectively kill the cancer cells in cancerous ascites.Pre-clinical data has demonstrated that tumor vesicles that carry low-dose chemotherapeutics can efficiently eliminate metastatic tumor cells in the abdominal cavity with minimal toxic or adverse effects.When combined,tumor cell-derived vesicles can sensitize tumor cells,which facilitates the entry of chemotherapeutics into tumor cells,thereby enhancing killing of tumor cells and limiting the risk of drug resistance.In this study,we designed a clinical trial to evaluate the safety and efficacy of intraperitoneal perfusion with tumor vesicle-encapsulated methotrexate for the treatment of cancerous ascites.Methods:Sixty patients with cancerous ascites were enrolled in this open,randomized and controlled clinical trial.Participants were randomly assigned a visit number and,according to their visiting order for which a random numerical table was used,were assigned to the trial group or the control group in a 1:1 ratio.The change in ascetic volume was used as the study outcome and adverse events were monitored during the entire length of the study.Conclusion:In this clinical trial,randomization and electronic case report forms were implemented.The trial indicated that tumor vesicle-encapsulated methotrexate was proposed to be a safe and effective method for treating malignant ascites.Our study may provide at the first time evidence for the clinical application of tumor vesicles in tumor therapy.

Use of ^(18)F-FDG PET/CT to locate primary malignancies in patients with hepatic cirrhosis and malignant ascites

Objective：Ascites in patients with hepatic cirrhosis is caused by cirrhosis in most cases.For most malignant ascites,the primary malignancy could be readily identified using conventional imaging methods,e.g.,computer tomography （CT） and magnetic resonance imaging （MRI）.However,in a small fraction of the patients,the primary malignancy remains occult even with these examinations.In this retrospective study,we assessed the usefulness of 18F-FDG PET/CT in patients with hepatic cirrhosis and malignant ascites of otherwise unknown origin.Methods：Twenty-eight patients with malignant ascites of unknown primary sites after CT,MRI and ultrasound during the period of five years between January 2008 and December 2012 had received 18F-FDG PET/CT.Medical records of these patients were reviewed and analyzed.Results：Elevated 18F-FDG absorption was found in 23 of 28 cases in the following sites：gastrointestinal tract （n=10,43.5％）,prostate （n=5,21.7％）,peritoneum （n=4,13.3％）,and ovary （n=4,13.3％）.Cancer was confirmed by pathology in 20 cases after open or laparoscopic surgeries.Five patients were found to have benign ascites,among which,3 were found to be false positive due to tuberculosis.SUV values were significantly higher for tumors than for benign lesions （mean values,6.95 vs.2.94; P=0.005）.Conclusions：The 18F-FDG PET/CT can be as a powerful imaging tool in identifying tissue origin in liver cirrhosis patients suspected of cancers or with cancers of unknown primary sites.

Effect of Qinggan Huayu granule on H22 liver ascitic tumor mice

Objective:To evaluate the therapeutic effect of Qinggan Huayu granule on mice with H22 liver cancer ascites tumor.Methods:A H22 liver cancer ascites mouse model was established by intraperitoneally injecting H22 liver cancer cells.Mice were randomly divided into the model group,the Ganfule group(1.35 g/kg),the fluorouracil group(50 mg/kg i.p),the Qinggan Huayu granule groups at low(0.67 g/kg),medium(1.34 g/kg),and high(2.68 g/kg)doses.Then the mice were administered continuously for 10 days and body weight and abdominal circumference were monitored every 3 days.On day 11,eight rats in each group were randomly selected for dissection to detect the amount of peritoneal water,peritoneal permeability and histopathological changes.The remaining mice were observed for survival.In addition,the vascular endothelial growth factor A(VEGFA)and vascular endothelial growth factor receptor 2(VEGFR2)were determined by Western blotting.Results:Compared with the model group,the weight growth of mice in the fluorouracil group and the medium-dose and high-dose Qinggan Huayu granule groups was slower(P<0.05).Moreover,the abdominal circumference of mice in each treatment group was increased slowly.There were significant differences in abdominal circumference between the fluorouracil group,the medium-dose group and the control group from day 6(P<0.05)while the abdominal circumference of the high dose group was significantly smaller than that of the control group from day 12(P<0.05).Moreover,compared with the model group,the amount of ascites in the medium-and high-dose Qinggan Huayu granule groups was decreased significantly(P<0.05).The optical density value of ascites supernatant in medium-and high-dose Qinggan Huayu granule group and the fluorouracil group decreased significantly(P<0.05)and the survival period of the medium-dose Qinggan Huayu granule group and the fluorouracil group was prolonged prominently(P<0.05).There was no significant difference in the low-dose Qinggan Huayu granule group and the Ganfule group.Peritoneal histopathological assay showed more complete peritoneal structure,less edema and less angiogenesis of the peritoneum in the fluorouracil group and the medium-and high-dose Qinggan Huayu granule group,which was better than that of the Ganfule group and the low-dose group.Compared with the model group,the expressions of VEGFA and VEGFR2 in the medium-dose Qinggan Huayu granule group decreased significantly(P<0.05,P<0.01).Conclusion:Qinggan Huayu granule can inhibit ascites production in the mice model with H22 liver cancer ascites tumor,prolong the survival of mice,and reduce peritoneal permeability and suppress the increase of peritoneal neovascularization.The mechanism may be related to the inhibition of VEGF/VEGFR pathway.

Study of the Effects of the Chinese Herbal Prescription Combinedwith Copper and Ferum on the Malignancy ot Cancer Cells

As compared with normal cells, cancer cells or malignant cells were morphologically abnor-mal : their contact inhibition and normal growth order were lost, the DNA content and ploid increased and suchkind of cells were transplantable. It the malignancy should be decreased or the malignant cells reversed, theabove abnormal changes could be reduced or disappear. BALB/c mice bearing ascites liver cancer wereused, Chinese herbal prescription combined with copper and ferrum (CHPCCF) was given by gavage for 10days, and then some cell-biological parameters were measured; further , the ascites cancer cells (controland treatment) were removed and retransptanted to another mice and observed. The results showed that inCHPCCF treatment group, DNA content of the cancer cells was decreased, and the proliferation index wasreduced (control : 83 . 4 ± 2 . 6, CHPCCF group : 78. 8 ± 1 . 5 ; or control : 67. 2 ± 1 . 3 , CHPCCF group : 64. 2 ±l . 6, P < 0. 02) , the number of the cancer cells in Gl phase increased obviously, but, those of S + G2Mphases decreased ( P < 0. 05 ￣ 0. 01 ) ; on the DNA histogram, the diploid peak became higher and bigger,but aneuploid or multiploid peaks became smaller. Furthermore, retransplanted experiments showed that in2/10 animals, the tumors did not grow, and in other 8/10 animals , the tumors grew, but the tumors' sizewere smaller than that of the control ; the growth inhibition rate was 71 . 7% ￣ 88. 3% ; and tumors ' grewslowly ; the growth curve of the tumors in CHPCCF group was considerably lower than that of the control ; thesurvival period of retransplanted animals was prolonged significantly (from 26. 1 ± 11 . 8 to 38. 1 ± 9. 6, or to39 . 6 ± 7 . 2 days, P<0 . 01 ); the increase in life span was 46% and 52% respectively. The results suggestedthat CHPCCF could reduce the malignancy of mice liver cancer cells.