Immunotherapy and Antivascular Targeted Therapy in Patients' Treatment with Concurrent Malignant Tumors after Organ Transplantation: Opportunity or Challenge.

Objective: To analyze the therapeutic effects and organ rejection of anti-PD-1 immunotherapy or antivascular targeting therapy on patients with combined malignancies after organ transplantation. Methods: We collected retrospective studies on "post-transplantation, cancer, immunotherapy, and vascular targeting therapy" in Embase, Wanfang database, Cochrane Library, VIP databases, CNKI, and PubMed, and the case data were organized and analyzed. Results: Data from only 40 papers met our requirements, which included 2 literature reviews, 4 original researches, and 34 case reports from 2016 to 2020. A total of 40 studies involving 66 patients were included, who were divided into 3 groups (patients using CTLA-4 inhibitors, group 1; patients who received sequential or concurrent anti-PD-1 and anti-CTLA-4 therapy, group 2; and patients using PD-1/PD-L1 inhibitors, group 3). There was no statistical difference in patients' DCR between the three groups (P > 0.05). Also, compared with group 2, there was no statistically significant difference in recipient organ rejection in group 1 and group 3 (P > 0.05). The DCR rate for antivascular targeted therapy is approximately 60%. Conclusions: Immunotherapy should be carefully selected for patients with combined malignancies after organ transplantation. Antivascular targeted therapy is one of the options worth considering; the risk of side effects of drug therapy is something that needs to be closely monitored when combined with immunotherapy.

CRABP2 accelerates epithelial mesenchymal transition in serous ovarian cancer cells by promoting TRIM16 methylation via upregulating EZH2 expression.

Recently, it was covered that cellular retinoic acid-binding protein 2 (CRABP2) is upregulated in ovarian cancer and participates in tumor progression, however, the specific mechanism remains to be explored. The pcDNA-CRABP2 or si-CRABP2 was transfected into SKOV3 and OVCAR3 ovarian cancer cells, respectively, and we observed that overexpression of CRABP2 inhibited cell apoptosis, promoted cell invasion and expression of epithelial mesenchymal transition (EMT) marker proteins, and transfection of si-CRABP2 had the opposite effect. Furthermore, we predicted that EZH2 interacted with CRABP2, and overexpression of CRABP2 promoted EZH2 expression, knockdown of CRABP2 inhibited EZH2 expression, and co-immunoprecipitation assay confirmed their binding relationship. The SKOV3 and OVCAR3 cells were then incubated with pcDNA-CRABP2 alone together with si-EZH2, and we found that si-EZH2 reversed the effect of pcDNA-CRABP2 on promotion of EZH2 expression, cell invasion and EMT maker protein levels. Next, we found that EZH2 could bind to DNMT1, and overexpression of EZH2 inhibited TRIM16 expression and knockdown of EZH2 promoted TRIM16 expression. Moreover, the promoter of TRIM16 contains the CpG island, and ChIP assay observed enriched DNMT1 on the promoter of TRIM16, and overexpression of EZH2 increased the promoter methylation level of TRIM16 and knockdown of EZH2 suppressed the methylation. The SKOV3 cells were incubated with si-EZH2 alone or combined with si-TRIM16, and we found that si-TRIM16 reversed the effect of si-EZH2. In vivo studies showed that knockdown of CRABP2 inhibited tumor volume and weight, suppressed the expression of EZH2 and EMT related proteins vimentin and snail, and increased the expression of TRIM16 and E-cadherin.

The Meta-Analysis of Bevacizumab Combined with Platinum-Based Treatment of Malignant Pleural Effusions by Thoracic Perfusion.

OBJECTIVE: To evaluate the safety of bevacizumab combined with platinum-based thoracic perfusion for treating lung cancer-related malignant pleural effusion (MPE) through meta-analysis. METHODS: The CNKI, PubMed, Cochrane Library, Embase, Chinese Science and Technology Journal Database (VIP), and Wanfang Databases were searched for randomized controlled trials (RCTs) of bevacizumab combined with platinum-based thoracic perfusion for the treatment of MPE. The references included in the articles were manually searched for additional studies. A meta-analysis of the RCTs was conducted using the RevMan 5.3 application. RESULTS: A total of 8 studies involving 540 patients (271 cases in the test group and 269 cases in the control group) were included in the meta-analysis. The test group had a significantly greater risk of elevated blood pressure as well as a higher rate of complete remission (CR) compared to the control group (P < 0.05). In contrast, the incidence of partial remission (PR) was only slightly higher in the test group (P > 0.05), and the risks of leukopenia, vomiting or nausea, rhinorrhea, diarrhea, gastrointestinal bleeding or hemoptysis, proteinuria, abnormal kidney and liver function, arrhythmia, and rashes were not significantly different between the test and control groups (P > 0.05). CONCLUSION: Bevacizumab combined with platinum-based thoracic perfusion can achieve CR of MPE in patients with advanced lung cancer without significantly increasing the risk of adverse effects. The rate of PR was similar for the combination treatment and platinum-based infusion.

Current Status of Malignant Tumors after Organ Transplantation.

OBJECTIVE: To analyze the diagnosis and treatment of patients with concomitant malignant tumors after organ transplantation by compiling data from organ transplantation patients. METHODS: By searching CNKI and PubMed databases, we made a systematic analysis of the studies of postorgan transplantation complicating malignant tumors in the last decade. RESULTS: There were 10 articles on malignant tumors after renal transplantation, 8 articles on liver transplantation, 2 articles on heart transplantation, and 1 article on lung transplantation. The incidence of malignant tumors complicating renal transplantation is 10.4% in Europe, with skin cancer and Kaposi's sarcoma being common; the incidence in the United States is 3.4%, with PTLD having the highest incidence; the incidence of malignant tumors is relatively lowest in Asia, with gastrointestinal malignancies being the main ones. The mean time to complication of malignancy after renal transplantation is 3.83 years. The incidence of concurrent malignancies after liver transplantation is 8.8% in Europe, where skin cancer and Kaposi's sarcoma are common; 5.6% in Asia, where gastrointestinal tract tumors are prevalent; and 4.5% in the United States, where gastrointestinal tract tumors, PTLD, and hematologic diseases are predominant. The mean time to complication of malignancy after liver transplantation is 4.79 years. The incidence of malignancy after heart transplantation is 6.8-10.7%. The incidence of malignancy after lung transplantation is about 10.1%. Minimization of immunosuppression or modification of immunosuppression regimens may be a key component of cancer prevention. mTOR inhibitors and phenolate (MMF) reduce the incidence of de novo malignancies in patients after solid organ transplantation. Surgical treatment improves survival in patients with early malignancies. The use of external beam radiation therapy in the treatment of hepatocellular carcinoma is limited due to the risk of radiation liver disease. CONCLUSIONS: The risk of concomitant malignancy needs to be guarded for 5 years of immunosuppressive therapy after organ transplantation surgery. Adjusting the immunosuppressive treatment regimen is an effective way to reduce concurrent malignancies. Systemic chemotherapy or radiotherapy requires vigilance against the toxic effects of drug metabolism kinetics on the transplanted organ.

Association between the effect of controlled fluid resuscitation on massive hemorrhage and expression of human neutrophil lipocalin.

The present study was designed to investigate the association between the effect of controlled fluid resuscitation on massive hemorrhage and expression of human neutrophil lipocalin (HNL). A total of 112 patients confirmed with traumatic hemorrhage were enrolled as study subjects and were randomly divided into the control group (n=56) and observation group (n=56). The control group was treated with rapid fluid resuscitation, and the observation group was treated with controlled fluid resuscitation. The success rate of resuscitation, incidence rate of complications, and HNL levels were compared both before and after resuscitation at multiple time intervals. The success rate of resuscitation showed a significant improvement while the incidence rate of complications were decreased. The HNL levels in both groups revealed increase after resuscitation at 3-10 h, thereby, they showed decline following peak point. However, the peak reduction in the observation group appeared earlier, while the HNL levels at 24 and 72 h were significantly lower than those in the control group. The study concluded that the effect of controlled fluid resuscitation on massive hemorrhage was superior to that of rapid fluid resuscitation. Moreover, controlled fluid resuscitation was also able to decrease the level of HNL as well as inflammatory response.

[Clinical research of laparoscopic bundled fastigiated mesh in repairing inguinal hernia].

OBJECTIVE: To explore the method and effectiveness of laparoscopic bundled fastigiated mesh in repairing inguinal hernia. METHODS: Between January 2003 and December 2009, 1 215 patients (1 363 sides) with inguinal hernia were treated. There were 1 132 males (1 268 sides) and 83 females (95 sides), aged from 18 to 89 years (median, 58 years). The cases included 1 187 cases (1 329 sides) of primary hernia and 28 cases (34 sides) of recurrent hernia. There were indirect inguinal hernia in 728 cases (786 sides), direct inguinal hernia in 416 cases (499 sides), femoral hernia in 43 cases (45 sides), and unusual hernia in 28 cases (33 sides). According to the hernia classification criteria, there were 31 cases (38 sides) in type I, 683 cases (754 sides) of type II, 403 cases (452 sides) of type III, and 98 cases (119 sides) of type IV. The disease duration was 1 to 9 days with an average of 3.8 days. To repair the hernia, the bundled fastigiated mesh was patched through the internal inguinal ring and fixed on the internal inguinal fascia by three-point fixation. The mesh would be wrapped in the peritoneum by purse-string suture. RESULTS: The surgeries were performed successfully. The operative time ranged from 18-32 minutes (mean, 22 minutes). Postoperative tractional pain in the inguinal region occurred in 19 cases (21 sides), acute uroschesis in 8 cases, and far-end hernial sac effusion in 2 cases (2 sides); all were cured after symptomatic treatment. All incisions healed by first intention, and no complications of fever, infection, or hematoma occurred. A total of 1 095 cases (1 182 sides) were followed up 1 to 7 years (median, 3 years and 9 months). Five patients died of medical illnesses at 1-3 years after operation. Three cases recurred and then were cured by a second surgery. No intestinal adhesion or obstruction occurred. CONCLUSION: The bundled fastigiated mesh in laparoscopic inguinal hernia repair has the advantages of minimal invasiveness, easy-to-operate, less complications, and lower recurrence rate.

[Impact of fragile histidine triad gene transfection on the proliferation and apoptosis of human colorectal cancer cell].

OBJECTIVE: To investigate the effect of fragile histidine triad (FHIT) gene transfection on human colorectal cancer cell line SW480 through up-regulation of caspase-8 expression. METHODS: The eukaryotic expression plasmid containing FHIT, pRc/CMV2-FHIT was prepared and purified, and then identified by restrictive enzyme digestion. pRc/CMV2-FHIT was transfected into SW480 cells, and positive cell clones (SW480-FHIT, study group) were selected and amplified. Empty plasmid-transfected SW480 cells(SW480-pRc/CMV2, negative control) and normal SW480 cells (bland control) were used as control. Methyl thiazolyl tetrazolium (MTT) assay was used to test the changes in the proliferation of SW480 cells. Cell-cycle kinetics and apoptosis were analyzed by flow cytometry (FCM). The changes of pro-caspase-8, caspase-8 mRNA and caspase-8 relative activity were analyzed by Western blot, semi-quantitative RT-PCR and colorimetric assay with pan labeled substrate, respectively. RESULTS: At 96 hours after transfection, cell inhibition rates of the study group and the negative control group were 71.7% and 16.9%. G0/G1 ratio was (63.2±3.5)% and (50.6±2.1)%, optical density of caspase-8 mRNA band 107 and 41, and relative activity of caspase-8 0.43 and 0.25, respectively. All the differences above were statistically significant (P<0.05). When FHIT inhibitor was added, the relative activity of caspase-8 decreased to 0.22, comparable to that in the control group. CONCLUSIONS: FHIT gene transfection can significantly inhibit the proliferation and induce G0/G1 arrest in human colon cancer cell line SW480. The mechanism is related to the up-regulation of caspase-8 expression.

[Inhibition of activator protein 4 gene expression by RNA interference in human colon carcinoma cell line SW480].

OBJECTIVE: To construct an expression plasmid of siRNA against activator protein 4(AP-4) gene and to investigate its biological behavioral effect on human colon carcinoma cell line SW480. METHODS: The specific siRNA target exon 7 of AP-4 gene was constructed and transfected into SW480 cells by liposome. Expression levels of AP-4 mRNA and protein from SW480 after transfection were examined by RT-PCR and Western blot respectively. Cell proliferation was detected by cell counting and MTT assay. Flow cytometry(FCM) and Western blot were used to detect cell apoptosis and cell cycle. The invasiveness of SW480 cells in vitro was measured quantitatively by the matrigel invasion assay. RESULTS: After AP-4 siRNA transfection into SW480 cells for 96 hours, the cell AP-4 mRNA reduced by 57.8% and the AP-4 protein concentration in culture supernatant decreased by 75.2%. The cell growth was significantly inhibited by 61%-78%. The apoptosis rate of SW480 cells was significantly higher in AP-4 siRNA group than that in negative control group[(21.7 +/- 2.51)% vs. (2.31 +/- 0.14)%, P<0.01]. Cells in G0-G1 phase increased by 22.43% and in G2-M phase decreased by 14.52% (P<0.05). AP-4 siRNA significantly inhibited AP-4-induced invasion of SW480 cells to matrigel (P<0.05). CONCLUSIONS: Silencing AP-4 gene by the siRNA technology can actively suppress the expression of AP-4 gene, and then inhibit the growth and proliferation of SW480 cell, and induce apoptosis of SW480 cell. The successful application of AP-4 siRNA extends the list of available therapeutic modalities in the treatment of human colon cancer.