Lung Cancer Radiotherapy: Simulation and Analysis Based on a Multicomponent Mathematical Model.

BACKGROUND: Lung cancer has been one of the most deadly illnesses all over the world, and radiotherapy can be an effective approach for treating lung cancer. Now, mathematical model has been extended to many biomedical fields to give a hand for analysis, evaluation, prediction, and optimization. METHODS: In this paper, we propose a multicomponent mathematical model for simulating the lung cancer growth as well as radiotherapy treatment for lung cancer. The model is digitalized and coded for computer simulation, and the model parameters are fitted with many research and clinical data to provide accordant results along with the growth of lung cancer cells in vitro. RESULTS: Some typical radiotherapy plans such as stereotactic body radiotherapy, conventional fractional radiotherapy, and accelerated hypofractionated radiotherapy are simulated, analyzed, and discussed. The results show that our mathematical model can perform the basic work for analysis and evaluation of the radiotherapy plan. CONCLUSION: It will be expected that in the near future, mathematical model will be a valuable tool for optimization in personalized medical treatment.

Simulation analysis for tumor radiotherapy based on three-component mathematical models.

OBJECTIVE: To setup a three-component tumor growth mathematical model and discuss its basic application in tumor fractional radiotherapy with computer simulation. METHOD: First, our three-component tumor growth model extended from the classical Gompertz tumor model was formulated and applied to a fractional radiotherapy with a series of proper parameters. With the computer simulation of our model, the impact of some parameters such as fractional dose, amount of quiescent tumor cells, and α/ß value to the effect of radiotherapy was also analyzed, respectively. RESULTS: With several optimal technologies, the model could run stably and output a series of convergent results. The simulation results showed that the fractional radiotherapy dose could impact the effect of radiotherapy significantly, while the amount of quiescent tumor cells and α/ß value did that to a certain extent. CONCLUSIONS: Supported with some proper parameters, our model can simulate and analyze the tumor radiotherapy program as well as give some theoretical instruction to radiotherapy personalized optimization.

Prognostic impact of preoperative prognostic nutritional index in resected advanced gastric cancer: A multicenter propensity score analysis.

BACKGROUND: Advanced gastric cancer (AGC) causes debilitating malnutrition and leads to deterioration of the immune response. However, the concept of the prognostic nutritional index (PNI) is controversial when applied to patients with AGC. The aim of the present study was to evaluate the effect of the PNI after gastrectomy in patients with AGC. MATERIALS AND METHODS: A multicenter retrospective study was conducted using propensity score matching (PSM) in gastric adenocarcinoma patients who underwent resection via laparoscopic or open surgery between 2014 and 2017. To overcome selection bias, we performed 1:1 matching using 5 covariates. RESULTS: The resection margins (P < 0.001) and LNM (P = 0.004) were significantly different between the two groups. In univariate analysis, poor tumor differentiation (P = 0.038) (R1+R2, P = 0.004), vascular and neural invasion (P < 0.001), and a PNI<50 (P < 0.001) were associated with poor recurrence-free survival (RFS). In multivariate analysis, a PNI<50 (hazard ratio (HR), 12.993; P < 0.001) was a risk factor for RFS. Univariate analysis for overall survival (OS) revealed that a PNI<50 (P < 0.001) (R1+R2,P = 0.006) and vascular and neural invasion (P < 0.001) were risk factors. In subsequent multivariate analysis, a PNI<50 (HR, 24.501; P < 0.001) was a significant risk factor for OS. Clinical assessments performed during a 12.34 (±5.050) month follow-up revealed that OS (P < 0.001) and RFS (P < 0.001) were worse in patients with a low PNI (<50) than in matched patients with a high PNI. CONCLUSION: A low PNI is a strong predictor of unfavorable RFS and OS in patients with AGC.

The analysis of clinicopathologic predictors of lymph node metastasis and postoperative recurrence in patients with papillary thyroid microcarcinoma from Guangdong Province, China-a multicenter retrospective study.

PURPOSE: Currently the extent of lymph node dissection (LND) for papillary thyroid microcarcinoma (PTMC) remains controversial. The present study aims to investigate the clinicopathologic predictors of lymph node metastasis (LNM) and prognosis in PTMC patients from Guangdong to enable appropriate treatment and follow-up. METHODS: Data including demographics, tumor size, multifocality, extrathyroidal extension (ETE) and concomitant thyroiditis were collected from 374 untreated PTMC patients from Guangdong, China. Univariate and multivariate analyses were performed to identify clinicopathologic predictors of LNM and prognostic indicators in PTMC patients with LNM. RESULTS: During the follow-up period of 120 months, recurrence was significantly higher in patients with LNM than in patients without LNM (P<0.05). Age <45 years, larger tumor (>5 mm) and multifocality were predictors of LNM; age <45 years, larger tumor size and absence of concomitant thyroiditis were associated with central LNM (CLNM); male sex, ETE and multifocality were correlated with lateral LNM (LLNM) (P<0.05). There was no difference in recurrence between patients with CLNM and LLNM (P>0.05). LNM in PTMC primarily influenced disease-free survival. Age >45 years and male sex were risk factors of recurrence in PTMC patients with LNM. Male patients with CLNM and older patients with LLNM exhibited worse prognosis (P<0.05). CONCLUSIONS: PTMC easily metastasizes to cervical lymph nodes, which significantly influences prognosis. Prophylactic LND is recommended in PTMC patients from Guangdong, China, who have a high risk of CLNM and/or LLNM. More aggressive postoperative treatment and more frequent follow-up could be considered for older and/or male PTMC patients with LNM.

The prognostic value of regional lymph node metastases in patients of Guangdong Province, China with differentiated thyroid cancer: A multicenter retrospective clinical study.

Although the prognostic value of nodal metastases in differentiated thyroid cancer remains controversial, it is of interest to evaluate and understand the different characteristics of predictive outcomes.A multicenter retrospective study was conducted in 215 untreated patients with differentiated thyroid cancer from July 1997 to July 2015 in 4 medical centers of Guangdong Province. A total of 107 patients with nodal metastases (group A) were compared to 108 patients without metastases (group B). The 5-year disease-free survival (DFS), overall survival (OS), and postoperative complications in both groups were calculated. Variables predictive of DFS and OS were evaluated in group A.The group A had lower 5-year DFS (69.16%, 11 months) and shorter median time of recurrence than those in group B (87.96%, 8.5 months, respectively, P < 0.001). The incidence of temporary hypoparathyroidism in group A is lower; whereas higher incidence of temporary unilateral vocal cord palsy, permanent hypoparathyroidism, permanent unilateral vocal cord palsy, and bilateral vocal cord palsy in group A were observed. Both univariate and multivariate analyses in group A revealed that age, pathological tumor node metastasis (pTNM) stage, and histology were related to DFS (P < 0.05); while pTNM stage and histology were related to OS only in univariate analyses.Positive nodal metastases have significant prognostic value in patients with differentiated thyroid cancer in Guangdong, China and primarily reduce DFS. Moreover, patients with positive nodal metastases who are >45 years and have higher pTNM stage or follicular histology tend to have poor prognosis. Selective lymph node dissection with appropriate postoperative treatment and frequent follow-up should be accorded to these vulnerable groups of patients.

[Effects of Astragalus Membranaceus Injection on TNF-alpha-induced release of inflammatory factors from HUVECs and the molecular mechanisms].

OBJECTIVE: To investigate the protective effect of Astragalus Membranaceus Injection on human umbilical vein endothelial cells (HUVECs) against tumor necrosis factor alpha (TNF-alpha). METHODS: Cultured passage 2 HUVECs were stimulated with TNF-alpha with or without a 2-h Astragalus Membranaceus Injection treatment. The expression of nuclear factor-kappaB (NF-kappaB) subunit p65 were evaluated by immuncytochemistical method, and the levels of p65 in the nuclei and the protein Ikappabetaalpha in the cytoplasm were evaluated by Western blotting. The levels of interleukin-6 (IL-6) and soluble intracellular adhesion molecule-1 (sICAM-1) in the cell culture were determined with ELISA. RESULTS: TNF-alpha induced the activation of NF-kappaB and increased the expressions of IL-6 and sICAM-1 in HUVECs. The activation of NF-kappabeta by TNF-alpha was suppressed by Astragalus Membranaceus Injection in a dose-dependent manner. CONCLUSION: Astragalus Membranaceus Injection can inhibit the TNF-alpha-induced expression of IL-6 and sICAM-1 by suppressing NF-kappabeta activation, suggesting its protective effect on the endothelial function.

[Relationship of extrahepatic metastasis of primary hepatocellular carcinoma between circulative tumor cells in the blood of hepatoma patients].

OBJECTIVE: To study the relationship between extrahepatic metastasis of primary hepatocellular carcinoma and circulative tumor cells in the blood of hepatoma patients. METHODS: The immunomagnetic bead technique was employed to enrich and separate the hepatoma cells in the peripheral blood of preoperative and postoperative hepatoma patients. The relationship between postoperative extrahepatic metastasis and hepatoma cells in peripheral blood cancer cells were analyzed. The circulative tumor cells in the peripheral blood of hepatoma patients were enriched and separated by immunomagnetic bead technique. They were identified as hepatoma cells by AFP immunohistochemistry. Among 30 cases of hepatoma patients, the positive rate of hepatoma cells in the peripheral blood of preoperation and postoperation were 53.3% and 83.3% respectively. There was difference significantly in positive cases before operation and after operation (P<0.05). CONCLUSIONS: Extrahepatic metastasis of primary hepatocellular carcinoma is obviously correlated to the positive tumor cells and the concentration in the peripheral blood of preoperative patients.

[Study of mesenchymal stem cells transfected with oncogenes differentiate into hepatocellular carcinoma of rats].

OBJECTIVE: To investigate the effect of rat mesenchymal stem cells (MSCs) transfected with different oncogenes differentiate into hepatocellular carcinoma (HCC) in vitro. METHODS: MSCs, transfected with different oncogenes c-myc, K-ras, c-myc and K-ras and amplified in vitro, were infused into rats via vena portae. The recipient rats were divided into the hepatic impairment group, which were fed with tetrachloromethane and the healthy control group. At day 7, 14, 21, 28 and 42 following grafting, the complete livers were obtained and examined using fluorescence detection, conventional pathology and immunohistochemistry detection of GFP, c-kit and AFP to study the colonization and distribution of stem cells in rat liver. RESULTS: No immunological rejection occurred after grafting of allogenic MSCs. The infused MSCs colonized in the recipient rat liver. Liver tumors were present in 6 rats grafted with MSCs that were transfected with K-ras, K-ras and c-myc, and the protein expression of AFP was detected using immunocytochemistry at day 7. Rats grafted with MSCs that were transfected with c-myc gene had no obvious tuberosity or tumor. Small oval cells were found microscopically in the periphery of vena portae, and immunohistochemistry staining of AFP was negative. Immunohistochemical staining of c-kit was positive in all livers of rats that were transfected with MSCs. CONCLUSIONS: Hepatocellular carcinoma may derive from genetically mutated MSCs.

[Antisense oligonucleotide against survivin induces apoptosis and enhances adriamycin sensitivity of SMMC-7721/ADM cells].

OBJECTIVE: To explore the effects of survivin-specific antisense oligonucleotide (ASODN) delivered via liposome on the growth and apoptosis of drug-resistant human hepatic cancer cell line SMMC-7721/ADM and the sensitivity of the cells to adriamycin (ADM). METHODS: SMMC-7721/ADM cells were divided into 6 groups and treated with liposome, ADM, sense oligonucleotide (SODN), SODN+ADM, 400 ng/ml ASODN, and 400 ng/ml ASODN+ADM group, respectively. MTT assay was used to calculate the relative survival rates of the cells, and the changes in cell apoptosis and cycle were detected with flow cytometry. RT-PCR and Western blotting were performed to detect the expressions of survivin mRNA and protein, respectively. RESULTS: The apoptotic rate of ASODN-treated cells was much higher than that of the control cells. survivin protein expression showed no significant variation between cells treated with liposome, ADM, SODN, and SODN+ADM (P>0.05), whereas compared with these 4 groups, cells treated with 400 ng/ml ASODN and 400 ng/ml ASODN+ADM had significantly lowered survivin mRNA expression (P<0.05), without significant differences between the latter two groups (P>0.05). SMMC-7721/ADM cells cultured in the presence of ASODN and adriamycin showed significant growth inhibition in comparison with ASODN group and ADM group. CONCLUSION: survivin-specific ASODN can enhance the sensitivity of SMMC-7721/ADM cells to ADM by depressing survivin expression in the cells, thus improves the effect of ADM chemotherapy for liver cancer.

[A study of rat mesenchymal stem cells (MSCs) differentiating into liver cells when co-cultured with rat hepatocytes].

OBJECTIVE: To explore whether rat mesenchymal stem cells (MSCs) can be induced to develop into hepatocytes and the role of the microenvironment of hepatocytes growth in inducing MSCs differentiating into hepatocytes in vitro. METHODS: Mesenchymal stem cells were collected from the aspirates from femurs of SD rats by density gradient centrifugation and identified by flow cytometric analysis and alkaline phosphatase (ALP) staining. Rat hepatocytes were isolated by the modified two-step method described by Seglen. Two 6-well culture plates were piled up after the chambers' bottoms of the upper plate was removed. Then the upper and lower chambers were separated by a semi-permeable membrane. MSCs and hepatocytes of rats were plated separately in the upper and lower chambers of the two 6-well culture plates for co-culturing. MSCs cultured alone without co-culturing with hepatocytes served as controls. On days 1, 3, 7, 14, 21 and 28, mRNA of cytokeratin 18 (CK-18), alpha-fetoprotein (AFP) and albumin were detected by reverse transcriptase-polymerase chain reaction (RT-PCR), and immunocytochemistry staining of CK-18 AFP and albumin were also examined. RESULTS: The shapes of MSCs co-cultured with hepatocytes changed and their sizes and numbers increased in the course of the culturing. When MSCs were co-cultured with hepatocytes for 2 weeks, colonies composed of polygonal cells resembling mature hepatocytes were found. In the controls, shapes of cells also changed and their sizes and numbers increased, but colonies composed of polygonal cells resembling mature hepatocytes were not found. Of the MSCs co-cultured with hepatocytes, on day 7, the mRNA of AFP was detected by RT-PCR, and it increased on day 14, and then decreased on day 21. mRNA of albumin and CK-18 were detected by RT-PCR from day 14 to day 28 in the co-cultured cells, but mRNA of AFP and CK-18 and albumin were not detected in the controls in the course of the culturing. Immunocytochemical analysis for CK-18, albumin, and AFP, showed positive staining reaction for AFP on day 7, for CK-18 and AFP on day 14 in the co-cultured cells but not in the controls. CONCLUSIONS: Rat MSCs co-cultured with hepatocytes can differentiate into hepatocytes.

[A preliminary study of the homing capacity of allograft mesenchymal stem cells to rat liver].

OBJECTIVE: To study the homing capacity of allograft mesenchymal stem cells (MSCs) transfected with a green fluorescent protein (GFP) retroviral construct to the liver of rats. METHODS: MSCs were obtained from rat bone marrow and cultured in vitro in conditional DMEM medium supplemented with 10% fetal bovine serum. The MSCs were identified by the monoclonal antibodies of CD29, CD44, CD34, CD45, CD90, SH-2 and SH-3 followed by transfection with a GFP retroviral vector. After ex vivo expansion, the transfected MSCs were infused through the tail vein or portal veins of rats, some of which were subjected to treatment with carbon tetrachloride (CCl(4)) to induce centrolobular liver necrosis. On days 3 and 7 after transplantation, the liver was removed from each recipient and evaluated for the presence of GFP transgene in purified genomic DNA using sensitive real-time PCR. RESULTS: All the rats receiving GFP-labeled MSCs survived until the study had been completed. GFP transgene in purified genomic DNA were detected in the livers of all the rats with GFP-labeled MSC infusion by sensitive real-time PCR. DNA copy numbers of GFP in the liver were higher in rats with CCl(4) treatment than in those without the treatment. Infusion of the MSCs through the tail vein or the portal vein did not produce significant difference in the mean DNA copy number in the liver of CCl(4)-treated rats. In rats without CCl(4) treatment, the sites of MSC infusion, e.g. through the tail vein or the portal vein, produced significant difference in MSC homing to the liver, which was also related to the passage of time after MSC infusion. CONCLUSION: In rats with liver injuries induced CCl(4), the timing and number of MSCs homing to the liver might be closely related to the presence of liver injury, but not to the site of MSC infusion, e.g. through the tail vein or the portal vein. MSCs possess homing capacity to the liver in normal recipient rats, and number of homed MSCs is related to the site of infusion and post-transplantation time.

[Hepatocyte growth factor induces differentiation of adult rat mesenchymal stem cells into a hepatocyte lineage in vitro].

OBJECTIVE: To explore whether the mesenchymal stem cells (MSCs) of rats can be induced into hepatocytes and the condition of differentiation in vitro. METHODS: Mesenchymal stem cells were collected from the femora of SD rats by density gradient centrifugation and identified by flow cytometric analysis and alkaline phosphatase (AKP) staining. MSCs were divided into 4 groups to induce differentiation with the different concentration of hepatocyte growth factor (HGF) in culture medium. The concentration of each group was group A 0 ng/ml, group B 10 ng/ml, group C 20 ng/ml and group D 40 ng/ml, respectively. The morphological changes of MSCs were observed by phase-contrast microscope. On day 1, 3, 7, 14, 21 and 28, mRNA of albumin, AFP and CK18 of MSCs of each group were examined by reverse transcription polymerase chain reaction (RT-PCR), and the expressions of them were also detected with immunohistochemistry technique. RESULTS: Mesenchymal stem cells collected from the femora of SD rats expressed antigens of CD29, CD44 and CD90, but not CD34 and CD45. AKP staining was negative for all of MSCs. On day 7, AFP mRNA of MSCs in group C and D could be detected by RT-PCR, and increased on day 14, and then directed on day 21. Albumin and CK18 mRNA of MSCs in group C and D could also be detected from day 14 to day 28 by RT-PCR. On the contrary, mRNA of AFP, CK18 and albumin was not detected in group A and B of culture. Immunocytochemical analysis for CK18, albumin and AFP showed positive staining reaction for AFP on day 7, for CK18 and albumin on day 14 in group C and D, and negative staining reaction both in group A and B of culture. CONCLUSION: MSCs of adult rats cultured in high concentration of HGF can differentiate into hepatocytes.

Distribution of oval cells and c-myc mRNA expression in mouse hepatocarcinogenesis.

BACKGROUND: This study was designed to assess the roles of oval cells and c-myc mRNA in the process of hepatocarcinogenesis and to clarify the function of carcinogene c-myc in the development of hepatocellular carcinoma (HCC) and the mechanism of inhibitory function of uscharidin on HCC in mouse hepatocarcinogenesis. METHODS: A total of 120 clean SD mice were divided into normal group, cancer induction group, and intervention group. The normal group was fed with standard forage while the rest two groups were given p-dimethylaminoazobenzene (DAB) to induce cancer. Thirteen weeks after induction of cancer, the two groups were fed with standard forage and water. Once the pattern was set up, the intervention group was given uscharidin injection into the abdominal cavity from the first week to the 14th week. On the 2nd, 4th, 6th, 8th, 10th, 12th, 14th, 16th, 18th, 20th, 22nd, and 24th week, all mice were killed and biopsied from the liver lobe for pathological analysis. At the same time, the number of tumor nodes was counted and the expression of c-myc mRNA was tested by RT-PCR. RESULTS: Since the 2nd week after cancer induction, proliferated oval cells could be seen in the portal area. Initially, the oval cells appeared in the cortical layer of the portal area, then proliferated gradually and immigrated into the liver parenchyma. In the period of fibrosis after liver proliferation, proliferated heaps of oval cells were noted in both portal and peripheral areas. In the period of carcinomatous change, oval cells could be seen both outside and inside of cancer nodes, but most of them were distributed outside. The c-myc gene was expressed negatively in the liver tissue of mice. The quantity of the expression began to increase at the time of infection of the liver and tended to increase with the degree of hepatic injury. In the period of canceration, the expression level of c-myc mRNA increased gradually. The intervention of uscharidin could not inhibit but delay the increase of the expression of c-myc mRNA. CONCLUSION: Oval cells are closely related to hepatocarcinoma cells, which play an important role in the occurrence and development of hepatocarcinogenesis. Uscharidin can inhibit the occurrence of hepatocarcinogenesis or local spreading at the early stage of cancer induction by DAB, but it cannot inhibit the expression of c-myc.

[Study of three-dimensional computerized reconstruction and CT scanning with thin slice after filling hepatic duct system].

OBJECTIVE: To establish the modal of perfusing and casting in hepatic duct system and explore the methods of three dimensional reconstruction with CT scanning image after filling hepatic duct. METHODS: All canal of livers with integral porta hepatic were perfused with various filling material after pretreatment, then fixed and casted. Hepatic preparations that had been perfused were put into the model of modelling abdominal cavity and scanned with thin slice. The three dimensional duct structures of hepatic with three methods of MIP, SSD and computerized treatment. RESULTS: Fourteen hepatic samples were filled and casted. Nine hepatic samples were scanned with slice height 1.0 mm, all 2514 slice images and average 279 images. Five hepatic samples were scanned with slice height 3.0 mm, all 512 slice images and average 102 images. Intrahepatic vein and portal vein system of three dimensional reconstruction were seen clearly with MIP method. The three dimensional established three dimensional images with SSD method was shown much stronger than that of MIP method. The three dimensional images of hepatic solid and hepatic vein system were established with method of comperized treatment. Vary three dimensional shape of hepatic solid and hepatic vein was obtained through different direction rotational. CONCLUSIONS: The modal filled and casted hepatic duct system were practise. The images established three dimensional with methods of MIP, SSD and comperized treatment were seen clearly. The modal and images of thin slice CT scanning are a better method for researching hepatic duct system.

[Study of three-dimensional reconstruction of digitized virtual hepatic images].

OBJECTIVE: To study the methods of three-dimensional reconstruction of digitized virtual hepatic. METHODS: Images of DSCF 2511-2520 were taken from the database of digitized Virtual Chinese Human female No. 1 (VCH-F1). Method of insertion value algorithm of three-dimensional reconstruction was used to make three-dimensional block diagram. In ordering to auto-judge the position of hepatic solid and hepatic ducts, these images were shown with different colors according to the character of color and location of every spot. RESULTS: Stereo image of hepatic solid could be shown satisfactorily. Every shape of stereo image and the structure of hepatic duct could be shown by revolving the three-dimensional image with different direction. CONCLUSIONS: The image of hepatic database of digitized Virtual Chinese female No. 1 was exact. The three-dimensional image of the liver and hepatic duct made by insertion value algorithm of three-dimensional reconstruction were distinct, and it was a ideal method of three-dimensional reconstruction.

The expression of c-kit and proliferating cell nuclear antigen in oval cells of rats with hepatocellular carcinoma.

OBJECTIVE: To study the relationship between oval cells and primary hepatocarcinoma and the expression of c-kit and proliferating cell nuclear antigen (PCNA) in oval cells of rats with hepatocellular carcinoma. METHODS: A hundred and twenty clean SD rats were divided into three groups: normal group, cancer-induction group and intervention group. The normal group was fed with standard forage while the rest two groups were fed with 3'-methyl-2-methylamino-azobenzene (DAB) to induce carcinoma for 14 weeks and then fed with standard forage and water. Uscharidin was injected abdominally to the intervention group from the first week to the 14th week. All rats were killed and biopsy specimens were taken from the left and right liver lobes for immunohistochemical staining of c-kit and PCNA on the 2nd, 4th, 6th, 8th, 10th, 12th, 14th, 16th, 18th, 20th, 22nd, and 24th week. RESULTS: From the 2nd to 14th week after liver infection, c-kit positive cells, mainly oval cells were found in the portal area in the carcinoma-induction group and dotted positive pigmentations in liver lobules. In the 22nd week, a large number of cancerous nodes occurred and nuclei heteromorphism was apparent; the number of positive cell decreased but positive cells could be sparsely observed in cancerous nodes. In the 2nd week of the carcinoma-induction process, PCNA positive cells were oval cells in the portal area. In the 4th week, a lot of hepatic cells were positively stained, especially in the central vein area. In the 6th week, PCNA positive cells could be seen in the lobules of the liver. In the 8th week, the number of PCNA cells decreased comparatively. From the 10th to 14th week, oval cells in the portal area were still over-expressed. From the 16th to 24th week, a large number of cancerous nodes occurred and PCNA was over-expressed in some of them. In necrotic cancerous nodes, the para-cancerous PCNA positive cells were sparsely distributed and their number was less than that of PCNA positive cells of cancerous tissues. CONCLUSIONS: Hepatic stem cells originating from the terminal biliary plexus of the portal area are involved in the development of hepatocarcinoma because c-kit positive cells expressed in cancerous nodes, accompany the whole process of the development. In the middle inflammatory period of carcinoma-induction, the expression of PCNA in hepatic cells peaked, but the index decreased in the late inflammatory period and in the proliferated fibrosis stage. The expression of PCNA is a tortuous process, going up, down, then up again from normal tissues to cancerous tissues. Combined with pathological findings, PCNA can be considered as a warning index for carcinomatous cells.