Solid,non-skin,post-liver transplant tumors:Key role oflifestyle and immunosuppression management

Liver transplantation has been the treatment of choice for end-stage liver disease since 1983.Cancer has emerged as a major long-term cause of death for liver transplant recipients.Many retrospective studies that have explored standardized incidence ratio have reported increased rates of solid organ cancers postliver transplantation;some have also studied risk factors.Liver transplantation results in a two to five-fold mean increase in the rate of solid organ cancers.Risk of head and neck,lung,esophageal,cervical cancers and Kaposi’s sarcoma is high,but risk of colorectal cancer is not clearly demonstrated.There appears to be no excess risk of developing breast or prostate cancer.Environmental risk factors such as viral infection and tobacco consumption,and personal risk factors such as obesity play a key role,but recent data also implicate the role of calcineurin inhibitors,whose cumulative and dose-dependent effects on cell metabolism might play a direct role in oncogenesis.In this paper,we review the results of studies assessing the incidence of non-skin solid tumors in order to understand the mechanisms underlying solid cancers in post-liver transplant patients and,ultimately,discuss how to prevent these cancers.Immunosuppressive protocol changes,including a calcineurin inhibitor-free regimen,combined with dietary guidelines and smoking cessation,are theoretically the best preventive measures.

HSP70 inhibitor combined with cisplatin suppresses the cervical cancer proliferation in vitro and transplanted tumor growth:An experimental study

Objective:To study the regulating effect of HSP70 inhibitor(PES) combined with cisplatin on cervical cancer proliferation in vitro and transplanted tumor growth.Methods:Cervical cancer Hela cell lines were cultured and divided into control group,cisplatin group,PES group and cisplatin+PES group that were treated with serum-free DMEM,cisplatin with final concentration of 10 μmol/L,PES 20 μmol/L and cisplatin 10 μmol/L combined with PES with 20 μmol/L,respectively;animal models with cervical cancer xenografts were established and divided into control group,cisplatin group,PES group and cisplatin+PES group who received intra-tumor injection of normal saline,10 μmol/L cisplatin,20 μmol/L PES as well as 10 μmol/L cisplatin+20 μmol/L PES,respectively.Cell proliferation activity,transplanted tumor volume and mitochondria apoptosis molecule expression were detected.Results:Cell viability value and Bcl-2 mRNA expression in cells of cisplatin group,PES group and cisplatin+PES group were significantly lower than those of control group while Bax,Caspase-3 and Caspase-9 mRNA expression in cells were significantly higher than those of control group;transplanted tumor volume and the Bcl-2 mRNA expression in transplanted tumor tissue of cisplatin group,PES group and cisplatin+PES group were significantly lower than those of control group while Bax,Caspase-3 and Caspase-9 m RNA expression in transplanted tumor tissue were significantly higher than those of control group.Conclusions:HSP70 inhibitor combined with cislatin can inhibit cervical cancer cell proliferation in vitro and transplanted tumor growth through mitochondrial apoptosis pathway.

Establishment of an orthotopic transplantation tumor model of hepatocellular carcinoma in mice

AIM:To improve the outcome of orthotopic transplantation in a mouse model,we used an absorbable gelatin sponge(AGS) in nude mice to establish an orthotopic implantation tumor model.METHODS:MHCC-97L hepatocellular carcinoma(HCC)cells stably expressing the luciferase gene were injected into the subcutaneous region of nude mice.One week later,the ectopic tumors were harvested and transplanted into the left liver lobe of nude mice.The AGS was used to establish the nude mouse orthotopic implantation tumor model.The tumor suppressor gene,paired box gene 5(PAX5),which is a tumor suppressor in HCC,was transfected into HCC cells to validate the model.Tumor growth was measured by bioluminescence imaging technology.Semi-quantitative reverse transcription polymerase chain reaction(RT-PCR) and histopathology were used to confirm the tumorigenicity of the implanted tumor from the MHCC-97L cell line.RESULTS:We successfully developed an orthotopic transplantation tumor model in nude mice with the use of an AGS.The success rate of tumor transplantation was improved from 60% in the control group to 100% in the experimental group using AGS.The detection of fluorescent signals showed that tumors grew in all live nude mice.The mice were divided into 3 groups:AGS-,AGS+/PAX5-and AGS+/PAX5 +.Tumor size was significantly smaller in PAX5 transfected nude mice compared to control mice(P < 0.0001).These fluorescent signal results were consistent with observations made during surgery.Pathologic examination further confirmed that the tissues from the ectopic tumor were HCC.Results from RT-PCR proved that the HCC originated from MHCC-97L cells.CONCLUSION:Using an AGS is a convenient and efficient way of establishing an indirect orthotopic liver transplantation tumor model with a high success rate.

Liver transplantation for hepatocellular carcinoma on cirrhosis:Strategies to avoid tumor recurrence

Hepatocellular carcinoma(HCC) is one of the most frequent neoplasms worldwide and in most cases it is associated with chronic liver disease.Liver transplantation(LT) is potentially the optimal treatment for those patients with HCC who have a poor functional hepatic reserve due to their underlying chronic liver disease.However,due to the limited availability of donors,only those patients whose oncologic profile is favorable can be considered for LT.Despite the careful selection of candidates based on strict rules,10 to 20%of liver transplant recipients who have HCC in the native cirrhotic liver develop tumor recurrence after transplantation.The selection criteria presently employed to minimize the risk of recurrence are based on gross tumor characteristics defined by imaging techniques;unfortunately,the accuracy of imaging is far from being optimal.Furthermore,microscopic tumor features that are strictly linked with prognosis can not be assessed prior to transplantation.Pre-transplantation tumor downstaging may allow transplantation in patients initially outside the selection criteria and seems to improve the prognosis;it also provides information on tumor biology.Themain peculiarity of the transplantation setting,when this is compared with other modalities of treatment,is the need for pharmacological immunosuppression:this is based on drugs that have been demonstrated to increase the risk of tumor development.As HCC is an aggressive malignancy,immunosuppression has to be handled carefully in patients who have HCC at the time of transplantation and new categories of immunosuppressive agents should be considered.Adjuvant chemotherapy following transplantation has failed to show any significant advantage.The aim of the present study is to review the possible strategies to avoid recurrence of HCC after liver transplantation based on the current clinical evidence and the more recent developments and to discuss possible future directions.

Plasma levels of tumor necrotic factor-alpha and interleukin-6, -8 during orthotopic liver transplantation and their relations to postoperative pulmonary complications

BACKGROUND: Pulmonary complications after orthoto- pic liver transplantation (OLT) include high morbidity and mortality. Experimental data have suggested hepatic ische- mia and reperfusion are induced by pro-inflammatory cyto- kines. The high level of inflammatory cytokines might ad- ditionally influence pulmonary cappillary fluid filtration. The objectives of this study were to measure the concentra- tions of tumor necrotic factor-alpha (TNF-α), interleukin- 6 (IL-6) and interleukin-8 (IL-8) during OLT and to in- vestigate the relationship between these cytokines and post- operative pulmonary complications. METHODS: Twenty-two patients undergoing OLT were divided into two groups according to whether they had postoperative pulmonary complications: group A consis- ting of 8 patients with postoperative pulmonary complica- tions , and group B consisting of 14 patients without post- operative pulmonary complications. Enzyme-linked im- munoassay (ELISA) was used to determine serum TNF-α, IL-6 and IL-8. Blood samples were taken at the beginning of operation (T0 ), clamping and cross-clamping of the in- ferior cava and portal vein (T1, T2 ), 90 minutes and 3 hours after reperfusion (T3 , T4 ) and 24 hours after opera- tion (T5). RESULTS: The level of PaO2/FiO2 in group A was lower than that in group B ( P <0. 05 ). The concentrations of TNF-α, IL-6 and IL-8 in the two groups increased rapidly at T2 , peaked at T3 , decreased rapidly after T3 until 24 hours after operation. The concentrations of TNF-α, IL-6 and IL-8 in group A were higher than those in group B at T2, T3, and T4(P<0.05). CONCLUSION: After un-clamping of the inferior cava and portal vein, the serum concentrations of TNF-α, IL-6 and IL-8 increased may be related to pulmonary injury after he- patic ischemic reperfusion.

Amniotic Membrane Transplantation for Conjunctival Tumor

Purpose: To evaluate the possibility of amniotic membrane transplantation (AMT) for the treatment of conjunctival tumor.Methods: Preserved AMT was performed in 26 patients (26 eyes) with conjunctival tumor, including 9 eyes (34.62%) with malignant tumor (conjunctival malignant melanoma,corneal and conjunctival squamous cell carcinoma, conjunctival lymphoma), 17 eyes(65.38%) with benign tumor(conjunctival papilloma, conjunctival dermoid tumor, conjunctival nevus, hemangioma etc.).Result: All the patients are followed up for 1 ～53 months. No acute rejection was observed after preserved AMT. Ideal healing was found in conjunctiva wound.Conclusion: Preserved AMT is a very effective method to repair wound after giant conjunctival tumor operation. Complete removal of tumor and perfect fixation are the key of ocular surface reconstruction.

Efficacy of intra- tumor injection of Kang-Lai-Te in treating transplanted hepatoma in rats

BACKGROUND: Non-operative therapy takes an impor- tant position in comprehensive therapy of liver cancer. De- spite some effects by using ethanol, acetic acid and heat sa- line for intra-tumor injection in the treatment of liver canc- er, it is difficult to attain a complete cure but bring about injury to the liver to some extent. Hence, searching for other drugs for the local treatment of liver tumor is an im- portant option. This study was designed to set up rat mo- dels of transplanted liver cancer, intra-tumor injection of Kang-Lai-Te (KLT), and negative control (saline) and positive control (ethanol). The effect of intra-tumor injec- tion of KLT in treating transplanted hepatoma in rats and its advantages and disadvantages were assessed and the pos- sibility of its use in treating patients with liver cancer was evaluated. METHODS: Forty rats were divided into 4 groups ( G1, G2, G3 and G4, 10 rats in each group). Different drugs were injected into their implanted hepatoma (G1 with 0.2 ml saline as control, G2 with 10 mg KLT, G3 with 20 mg KLT, G4 with 0.2 ml ethanol). After 3 and 8 days, the hepa- toma volume (HV), the serum levels of albumin, alanine aminotransferase(ALT), aspartate aminotransferase alkaline phosphatase( ALP) and creatinine, as well as the expression of proliferation cell nuclear antigen (PCNA) in hepatoma were detected. RESULTS: After 3 days, the HVs were smaller in G3 and G4 than in G1 (P <0.05), the serum levels of albumin were higher in G2 and G3 than in Gl and G4 (P <0.05), the se- rum levels of ALT and AST were lower in G2 and G3 than in G4 (P<0.05), the serum levels of ALP was lower in G2 and G3 than in Gl and G4 (P <0. 05), the PCNA labeling indexes (PCNA LI) were lower in G2 and G3 than in Gl and GA (P <0.05). After 8 days, the HVs were smaller in G2, G3 and G4 than in Gl (P <0.05), and the differences of HVs among G2, G3 and G4 were not significant. The serum levels of ALP were lower in G1, G2 and G3 than in G4 (P <0.05), and the PCNA LI were lower in G3 than in Gl andG4 (P<0.05). CONCLUSION: Intra-tumor injection of KLT into implan- ted hepatoma is evidently effective, but it is less effective than ethanol. The effect of KLT on liver function is markedly lower than that of ethanol.

Experimental Study of the Antitumor Activity of Polymetalacrylates against Animal Transplantable Tumors

The antitumor activity of the fourteen polymetalacrylates against two models of murine solid tumors (Lewis lung carcinoma and Acatol adenocarcinoma) as well as the acute toxicity of these compounds has been studied. It was shown that polyacrylates of noble metals (argent, aurum, platinum), namely argacryl (М = Ag), auracryl (М = Au) and platacryl (М = Pt) were the most effective agents among tested compounds against studied tumors. Thus, the tumor growth inhibitory effect of argacryl against Lewis lung carcinoma was equal to 90%, the life-span of treated by this compound animals has increased on 50% in comparison with control. Auracryl induced the inhibition of the Lewis lung carcinoma and Acatol adenocarcinoma development on 60 and 65%, correspondingly and the increasing of the mean life-span of animals with Lewis lung carcinoma on 20% in comparison with control. Platacryl inhibited the growth of Lewis lung carcinoma on 40% increasing the mean life-span of animals on 25% in comparison with control. In this way it was established that argacryl is the agent with the strongest antitumor activity among studied polymetalacrylates. On the basis of obtained data it seems possible to consider polymetalacrylates as a group of agents with the potential antitumor activity suitable for the further deep experimental investigation.

Orthotopic liver transplantation for patients with Klatskin tumor

BACKGROUND; It is not certain whether Klatskin tumor should be a routine indication for orthotopic liver trans- plantation (OLT). This study was to summarize the indi- cation and value of orthotopic liver transplantation for pa- tients with Klatskin tumor. METHODS; Forty patients with Klatskin tumors including 5 patients who had had liver transplantation ( LTx) and 35 patients who had not undergone LTx ( WLTx) from Janu- ary 1992 to December 2003 were analyzed retrospectively. Their TNM stages were comparable in both groups. In the LTx group, 4 patients had Klatskin tumor including recur- rent tumor after resection ( 1 ), and 1 cancerization from Carolis disease. Biliary duct anastomosis was made by Roux-en-Y choledochojejunostomy in 2, and end-to-end choledochocholedochostomy (C-C) in 3. RESULTS: In the LTx group, the total resection rate and radical resection rate were both 100%. Four patients have been surviving for 48, 38, 21 and 5 months, respectively, except one died from bile leakage at day 40 after transplan- tation. All 4 survivors enjoyed good life without tumors at local and distant sites, even though 2 of these patients de- veloped biliary stricture, which was soon resolved by radio- logical intervention. The 1-,3-year survival rates were both 80% in this group. The total resection rate and radical re- section rate in the WLTx group were 63.0% ( 17/27) and 40.7% (11/27 ) and, the 1-, 3-, 5-year survival rates were 32.2%, 8.0%, 0%, respectively. There were significant differences between the two groups in radical resection rates and survival rates( P =0.016).CONCLUSIONS: OLT is a good choice for patients with unresectable Klatskin tumor by routine modalities. The prognosis of patients undergoing OLT is encouraging.

Secondary non-resectable liver tumors:A single-center living-donor and deceased-donor liver transplantation case series

Background: During the last decades, deceased-donor liver transplantation (DDLT) has gained a place in the therapeutic algorithm of well-selected patients harbouring non-resectable secondary liver tumors. Living-donor LT (LDLT) might represent a valuable means to further expand this indication for LT. Methods: Between 1985 and 2016, twenty-two adults were transplanted because of neuroendocrine ( n = 18, 82%) and colorectal metastases ( n = 4, 18%);50% received DDLT and 50% LDLT. In LDLT, 4 (36%) right and 7 (64%) left grafts were used;the median graft-to-recipient-weight ratios (GRWR) were 1.03%(IQR 0.86%- 1.30%) and 0.59%(IQR 0.51%- 0.91%), respectively. Median post-LT follow-up was 64 months (IQR 17–107) in the DDLT group and 40 months (IQR 35–116) in the LDLT group. DDLT and LDLT recipients were compared in terms of overall survival, graft survival, postoperative complications and recurrence. Results: The 1- and 5-year actuarial patient survivals were 82% and 55% after DDLT, 100% and 100% after LDLT, respectively ( P < 0.01). One- and 5-year actuarial graft survivals were 73% and 36% after DDLT, 91% and 91% after LDLT ( P < 0.01). The outcomes of right or left LDLT were comparable. Donor hepatectomy proved safe, and one donor experienced a Clavien IIIb complication. Bilirubin peak was significantly lower after left hepatectomy compared with that after right hepatectomy [1.3 (IQR 1.2–2.2) vs. 3.3 (IQR 2.3–5.2) mg/dL;P = 0.02]. Conclusions: The more recent LDLT series compared favorably to our DDLT series in the treatment of secondary liver malignancies. The absence of portal hypertension and the use of smaller left grafts make recipient and donor surgeries safe. The safety of the procedures and lack of interference with the scarce allograft pool are expected to lead to a more frequent use of LDLT in the field of transplant oncology.

Effects of Ad-p27mt Gene Transfer on the Expression of Bax,Bcl-2,VEGF and MMP-9 in the Transplanted Liver Tumors in Nude Mice

In this study, the mechanism by which Ad-p27mt inhibits the growth, invasion and metastasis of transplanted liver tumor was studied by examining the effects of Ad-27mt gene transfer on the expression of Bax, Bcl-2, VEGF and MMP-9 in the transplanted liver tumors in nude mice.The model of transplanted hepatic tumor was established in nude mice.The mice were then divided into three groups, which were injected with PBS, Ad-LacZ and Ad-p27mt and the growth of the transplanted liver tumor was observed.The expressions of P27, Bax and Bcl-2 proteins were detected by Western blotting and the expressions of VEGF and MMP-9 were immunohistochemically determined.Our result showed that the tumor size, expressions of Bax, Bcl-2 proteins, VEGF and MMP-9 were all lower than those in PBS and Ad-LacZ groups and the differences were statistically significant (P【0.05).Our study suggested that Ad-p27mt could inhibit the growth, invasion and metastasis of hepatic cancer by lowering the expressions of VEGF and MMP-9.

Kanglaite combined Gemcitabine inhibits growth of nude mouse subcutaneous transplantation tumor of human PC-3 pancreatic cancer cell

Objective:To study the mechanisms of pancreatic cancer treatment with Kanglaite combined Gemcitabine by investigating the relationship between the apoptosis and the expression of bcl-2, Bax and VEGF in pancreatic cancer cells.Methods:Nude mouse subcutaneous transplantation tumor model of Human PC-3 pancreatic cancer was established; the expressions of bcl-2, Bax and VEGF of transplantation tumor cell were determined; the earlier apoptosis rate of pancreatic cancer cell and the gross tumor volume were determined. Results:Kanglaite combined Gemcitabine remarkably decreased the protein expression of bcl-2,raised the expression of Bax,increased the apoptosis rate of the pancreatic cancer and contract the gross tumor volume. Kanglaite greatly decreased the protein expression of VEGF of the tumor cell. Conclusion:Therapeutic efficacy of Kanglaite combined Gemcitabine is far better than separate use of the two medicines in the pancreatic cancer transplantation tumor treatment.

The Influence of Different Single Radiation Dose on Delayed Growth of Transplanted Tumor in Athymic Mouse

OBJECTIVE To reveal the biological effects and effective dosage in radiotherapy model which applies high single-dose irradiation by animal experiment. METHODS We inoculated subcutaneouly human pancreatic carcinoma cell line （MIA PaCa-2） in the lateral of the right lower extremity of the athymic mouse to grow transplantation tumor. While the median diameter of transplantation tumor reached 10 mm approximately, the animals were randomly divided into 7 groups （6 animals per group） and irradiation by different dose in one fixed with consciousness for fraction （0, 2, 5, 10, 17, 25, 35 Gy）. All were kept on to be bred for observation of the change in gross tumor volume, calculation of delayed growth time and delayed growth curve. RESULTS With increased dose per fraction, cutaneous reaction on the neoplasma surface of the animal, which was mainly moist yellow effusion was more and more severe. When dosage is less than 10 Gy, all animals showed similar effects, that＇s the delayed tumor growth was not obvious. Tumors receiving more than 10 Gy in one fraction showed very good biological effect and the delayed tumor growth was obviously related to dosage. The difference in delayed tumor growth between the 2 groups was statistically significant. The delayed tumor growth time in 10, 17, 25 Gy group was respectively 3 weeks, 6 weeks and more. CONCLUSION The biological effect of the model which applies high single-dose irradiation （more than 10 Gy in one fraction） was very good. The effect of delayed tumor growth was obviously related to the dosage after transplantation tumor was radiated. Because of its higher dose per fraction and biological effects, the model of high single-dose irradiation can get better clinical effects.

PERCUTANEOUS INJECTING ANTINEOPLASTIC AGENT INTO TRANSPLANTED TUMORS OF MICE BY CT－GUIDED

Antineoplastic agent and contrast medium were injected into transplanted tumors of mice under guidance with CT, site and range of the intratumoural drug were shown on CT image immediately. It was value of multipoint injections, concentration of 0.1 mg/0.l ml MMC every point, 1 cm interval of injection. After the injections, the tumor size of mice reduced and at last disappeared (ratio of inhibited tumor 59.32% in 0.05 mg MMC group, 43.86% in 0.1 mg MMC group).The pathologic examination showed coagulatic necrosis of the tumor tissues. The higher concentration of antineoplastic agent (0.2 mg MMC) could make the tumors enlarged (ratio of inhibited tumor -15.3%). The tissues and vessels around the tumors were not injured, if MMC overflow out off the tumor.

基于Nrf2/ROS信号通路探讨岩藻多糖对食管癌细胞增殖的抑制作用

目的:探讨岩藻多糖对食管癌增殖的影响,并分析其机制。方法:MTT法分析细胞增殖抑制率,Hoechst 33258染色和流式细胞术检测细胞凋亡,DCFH-DA探针检测ROS水平,Western blot法分析Nrf2、HO-1、NQO-1、Bcl-2、Bax、caspase-3水平,研究岩藻多糖对细胞增殖以及Nrf2/ROS信号通路的影响。裸鼠成瘤实验验证岩藻多糖对瘤体的瘤重、瘤体积及Nrf2、HO-1、NQO-1水平的影响。结果:1~16µg/mL岩藻多糖极显著抑制ECA109细胞增殖,48 h IC50为3.26µg/mL。与对照组(0.1%DMSO)相比,1、2、4µg/mL岩藻多糖处理后的ECA109细胞出现核凝聚、染色质不规则收缩、凋亡小体等明显的凋亡特征,(极)显著促进ECA109细胞凋亡,极显著下调Bcl-2表达水平,极显著上调Bax、Cleaved-caspase-3表达水平,极显著增加ROS水平,极显著降低Nrf2、HO-1、NQO-1蛋白水平(P<0.05,P<0.01);Nrf2过表达能显著下调岩藻多糖抑制ECA109细胞增殖效果,显著下调ROS水平,显著上调Nrf2、HO-1、NQO-1蛋白水平(P<0.05)。体内实验显示,50、100 mg/kg岩藻多糖极显著抑制瘤体体积、瘤体质量,下调瘤体Nrf2、HO-1、NQO-1水平(P<0.05)。结论:岩藻多糖抑制ECA109细胞增殖,对体内移植瘤抑瘤效果显著,其机制与调控Nrf2/ROS信号通路有关。

Mechanism of AiTongXiao granule in the treatment of hepatocellular carcinoma based on network pharmacology and rat transplanted liver cancer model

Objective:To investigate the mechanism of action and material basis of AiTongXiao granule in the treatment of hepatocellular carcinoma(HCC)based on network pharmacology and transplanted liver cancer rat model.Methods:TCMSP database was used to screen out effective components and its corresponding potential pharmaceutical targets,and databases including Gene Cards,OMIM,Drugbank and TTD were further used to collect HCC-related drug targets.The intersecting targets were obtained by mapping the drug and disease targets.The component-targets network was constructed and visualized by Cytoscape 3.8.2 software.Protein-protein interaction(PPI)network was built by STRING online platform,and the topological relationship and core targets was analyzed and screened by using CytoNCA software.In addition,Metascape database was used to perform gene ontology(GO)enrichment analysis and Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway analysis of the core targets.At last,rat liver transplanted liver cancer model was established by using Walker-256 cell line and treated by AiTongXiao granule for 15 days.Western blot was used to further compare the expression levels of AKT,pAKT,p53,p-p53,ERK1/2 and ERK1/2 in the tumor between treatment group and the control group.Results:257 active components were obtained from AiTongXiao granule,corresponding to 294 drug targets.Meanwhile,233 of the 7993 HCC disease targets were screened out between AiTongXiao granule drug and HCC disease targets.11 core targets including AKT1,IL6,TP53,MAPK3,TNF,JUN,CASP3,MAPK1,MYC,PTGS2,MMP9 were further obtained by median screening.GO and KEGG analysis results showed that these core targets enriched to HBV,TNF and cancer related pathways.The rat transplanted liver cancer model results indicated significant down regulation for AKT,p-AKT,pERK1/2,and significant up regulation of p-p53 after AiTongXiao granule treatment(P<0.05).Conclusion:AiTongXiao granule could act to multiple cancer related pathways,and AKT,p53 and ERK1/2 were validated to be regulated by ATXF in rat model.The mechanism may be through the regulation of the above signaling pathways to exert anti-liver cancer effect.

Liver re-transplantation for donor-derived neuroendocrine tumor: A case report

BACKGROUND Donor-origin cancer is a well-recognized but rare complication after liver transplantation (LT). The rise in the use of extended criteria donors due to the current shortage of organs increases the risk. Data on donor-origin neuroendocrine neoplasms (NENs) and the most appropriate treatment are scarce. Here, we report a case of a patient who developed a NEN confined to the liver after LT and was treated with liver re-transplantation (re-LT). CASE SUMMARY A 49-year-old man with no other medical co-morbidities underwent LT in 2013 for alcoholic liver cirrhosis. The donor was a 73-year-old female with no known malignancies. Early after LT, a hypoechogenic (15 mm) lesion was detected in the left hepatic lobe on abdominal ultrasound. The lesion was stable for next 11 mo, when abdominal magnetic resonance identified two hypovascular lesions (20 and 11 mm) with atypical enhancement pattern. Follow-up abdominal ultrasound revealed no new lesions for the next 2.5 years, when magnetic resonance showed a progression in size and number of lesions, also confirmed by abdominal computed tomography. Liver biopsy proved a well-differentiated NEN. Genetic analysis of the NEN confirmed donor origin of the neoplasm. As NEN was confined to liver graft only, in 2018, the patient underwent his second LT. At 12 mo after re-LT the patient is well with no signs of NEN dissemination. CONCLUSION The benefits of graft explantation should be weighed against the risks of re-LT and the likelihood of NEN dissemination beyond the graft.

4T1乳腺癌细胞株接种联合慢性束缚应激诱导乳腺癌合并抑郁小鼠模型构建探索

目的研究4T1乳腺癌细胞株接种联合慢性束缚应激方法构建乳腺癌合并抑郁症小鼠模型核心行为症状、生物学指标、病理学等改变。方法BABL/c小鼠随机分为正常(Control)组、束缚(Stress)组、移植瘤(Tumor)组和束缚移植瘤(Stress+Tumor,S+T)组,将4T1细胞株接种于Tumor和S+T组小鼠腋下,待成瘤后,给予Stress和S+T组小鼠束缚应激21 d。造模期间监测各组小鼠体重、摄食量。实验结束后,采用糖水偏好、旷场、高架十字迷宫、强迫游泳等试验评价各组小鼠抑郁样行为。小鼠处死后,测量小鼠瘤体重量和体积;采用ELISA方法检测各组小鼠血清肿瘤标志物糖类抗原(CA199)、癌胚抗原(CEA)、血管内皮生长因子(VEGF)以及相关神经递质5-羟色胺(5-HT)、去甲肾上腺素(NE)、皮质酮(CORT)的含量;运用HE染色法观察小鼠肿瘤和海马组织病理学改变。结果S+T组小鼠体重、摄食量显著降低,瘤体重量和体积明显增大,血清肿瘤标志物(CA199、CEA、VEGF)水平显著升高,快感和对新环境的探索欲望减弱,紧张和绝望行为显著增强,血清神经递质5-HT和NE水平显著降低,CORT水平显著升高;另外肿瘤组织细胞排列松散,间质减少,病理性核分裂象增多,海马CA3区神经元细胞排列和形态紊乱,核内空泡化样改变明显。结论4T1乳腺癌细胞株接种联合慢性束缚应激诱导的乳腺癌合并抑郁小鼠模型出现了乳腺癌和抑郁症双重典型症状和生物学指标改变,可为乳腺癌合并抑郁实验研究提供较好的模型参考。

白屈菜碱对小鼠肺癌细胞皮下移植瘤生长和血管生成的抑制作用及其机制

目的:探讨白屈菜碱对肺癌移植瘤小鼠肿瘤生长和血管生成的影响,并阐明其作用机制。方法:选取32只健康C57BL/6小鼠,制备Lewis肺癌移植瘤小鼠模型。将小鼠随机分为模型组(0.9%氯化钠)、低剂量白屈菜碱组(25 mg·kg^(-1)白屈菜碱)、高剂量白屈菜碱组(50 mg·kg^(-1)白屈菜碱)和阳性对照组(60 mg·kg^(-1)环磷酰胺),每组8只。称量各组小鼠移植瘤质量并计算抑瘤率,计算各组小鼠胸腺指数和脾脏指数,采用酶联免疫吸附测定(ELISA)法检测各组小鼠血清中白细胞介素2(IL-2)、γ干扰素(INF-γ)和肿瘤坏死因子α(TNF-α)水平,免疫组织化学法检测各组小鼠肿瘤组织中血管内皮生长因子(VEGF)蛋白表达情况并计算微血管密度(MVD)及VEGF蛋白表达评分,Westernblotting法检测各组小鼠肿瘤组织中核因子κB(NF-κB)和缺氧诱导因子1α(HIF-1α)蛋白表达水平。结果:与模型组比较,低和高剂量白屈菜碱组及阳性对照组小鼠移植瘤质量均降低(P<0.05);与低剂量白屈菜碱组比较,高剂量白屈菜碱组和阳性对照组小鼠移植瘤质量均降低(P<0.05),抑瘤率均升高(P<0.05);与高剂量白屈菜碱组比较,阳性对照组小鼠移植瘤质量均降低(P<0.05),抑瘤率升高(P<0.05)。与模型组比较,低和高剂量白屈菜碱组及阳性对照组小鼠脾脏指数和胸腺指数均升高(P<0.05);与低剂量白屈菜碱组比较,高剂量白屈菜碱组和阳性对照组小鼠脾脏指数及胸腺指数均升高(P<0.05);与高剂量白屈菜碱组比较,阳性对照组小鼠脾脏指数和胸腺指数均升高(P<0.05)。ELISA法,与模型组比较,低和高剂量白屈菜碱组及阳性对照组小鼠血清中IL-2、INF-γ和TNF-α水平均升高(P<0.05);与低剂量白屈菜碱组比较,高剂量白屈菜碱组和阳性对照组小鼠血清中IL-2、INF-γ和TNF-α水平均升高(P<0.05);与高剂量白屈菜碱组比较,阳性对照组小鼠血清中IL-2、INF-γ和TNF-α水平均升高(P<0.05)。与模型组比较,低和高剂量白屈菜碱组及阳性对照组小鼠肿瘤组织MVD降低(P<0.05);与低剂量白屈菜碱组比较,高剂量白屈菜碱组和阳性对照组小鼠肿瘤组织MVD降低(P<0.05);与高剂量白屈菜碱组比较,阳性对照组小鼠肿瘤组织中MVD降低(P<0.05)。与模型组比较,低和高剂量白屈菜碱组及阳性对照组小鼠肿瘤组织中VEGF蛋白表达量减少;与低剂量白屈菜碱组比较,高剂量白屈菜碱组和阳性对照组小鼠肿瘤组织中VEGF蛋白表达量减少;与高剂量白屈菜碱组比较,阳性对照组小鼠肿瘤组织中VEGF蛋白表达量减少;模型组、低剂量白屈菜碱组、高剂量白屈菜碱组和阳性对照组小鼠肿瘤组织VEGF蛋白表达评分比较差异有统计学意义(P<0.05)。Western blotting法,与模型组比较,低和高剂量白屈菜碱组及阳性对照组小鼠肿瘤组织中NF-κB和HIF-1α蛋白表达水平降低(P<0.05);与低剂量白屈菜碱组比较,高剂量白屈菜碱组和阳性对照组小鼠肿瘤组织中NF-κB和HIF-1α蛋白表达水平降低(P<0.05);与高剂量白屈菜碱组比较,阳性对照组小鼠肿瘤组织中NF-κB和HIF-1α蛋白表达水平降低(P<0.05)。结论:白屈菜碱能够抑制Lewis肺癌移植瘤小鼠肿瘤组织生长、保护免疫器官和抑制肿瘤血管生成,可能通过靶向NF-κB/HIF-1α信号通路和下调NF-κB及HIF-1α蛋白表达水平发挥治疗作用。

miR-551在甲状腺癌患者中的表达及靶向ERBB4对SW579细胞移植瘤生长的影响

目的 探讨miR-551在甲状腺癌患者中的表达及靶向ERBB4对SW579细胞移植瘤生长的影响。方法 选取2019年1月-2022年3月于我院病理科采集并保存的甲状腺乳头状癌组织及其配对的癌旁组织100例。将SW579细胞随机分为Control组、miR-NC组、miR-551组和miR-551+pcDNA-ERBB4组。RTPCR检测甲状腺癌组织和细胞中miR-551表达,分析甲状腺癌组织中miR-551表达和临床病理特征相关性;CCK-8、Transwell法、流式细胞仪分别检测细胞增殖、侵袭和凋亡率;蛋白质印迹法检测细胞中ERBB4蛋白表达;荧光素酶活性基因报告检测miR-551和ERBB4靶向关系。建立裸鼠皮下移植瘤模型,分为miR-NC组和miR-551组,比较两组裸鼠肿瘤体积;TUNEL检测肿瘤组织细胞凋亡率。结果 甲状腺癌组织中miR-551表达低于癌旁组织(P<0.05)。与甲状腺上皮细胞相比(1.00±0.10),甲状腺癌细胞中miR-551表达(0.32±0.04)明显降低(P<0.05)。与Control组相比,miR-551组细胞中miR-551表达(1.28±0.13)和细胞凋亡率(25.72±1.78)明显增加,24 h、48 h细胞活力(分别为52.38±5.46、32.29±3.17)、细胞侵袭数目(81.06±6.32)和细胞中ERBB4蛋白(0.46±0.05)表达明显降低(P<0.05);与miR-551组相比,miR-551+pcDNA-ERBB4组细胞中miR-551表达和细胞凋亡率(7.69±0.82)明显降低,24 h、48 h细胞活力(分别为85.11±7.61、71.56±6.82)、细胞侵袭数目(136.82±7.54)和细胞中ERBB4蛋白表达(0.84±0.08)明显增加(P<0.05);与miR-NC组(1.00±0.10)相比,转染野生型ERBB4(ERBB4-WT)时miR-551组荧光素酶活性明显降低(0.34±0.04)(P<0.05);与miR-NC组相比,miR-551组裸鼠肿瘤体积明显减少,肿瘤组织中细胞凋亡率(51.62±4.31)明显升高(P<0.05)。结论 甲状腺癌组织中miR-551呈低表达,过表达miR-551可靶向调控ERBB4抑制甲状腺癌细胞增殖和侵袭,诱导甲状腺癌细胞凋亡。