Exploring the significance of chemotherapy in the perioperative application of biliary tract carcinomas / 中华外科杂志

Biliary tract cancer is extremely malignant with a poor prognosis. At the moment, the only curative method available is radical resection. Targeted and immunotherapy are currently advancing quickly, but chemotherapy still holds a key role in the perioperative management of biliary cancer. Perioperative chemotherapy aims to decrease tumor volume before surgery so that patients can have their tumors surgically removed or have a higher radical resection rate. It also aims to remove any tumor cells that remain after surgery and prevent the growth of new tumors. Chemotherapy-based combination treatment techniques have been increasingly investigated in recent years to improve perioperative care and patient survival. From the standpoint of chemotherapy regimens and clinical trial success in the perioperative phase of radical surgery, the value of chemotherapy in the perioperative period of biliary tract cancer were explored in this paper.

Survival analysis of patients with intrahepatic cholangiocarcinoma treated with adjuvant chemotherapy after radical resection based on CoxPH model and deep learning algorithm / 中华外科杂志

Objective: To establish a predictive model for survival benefit of patients with intrahepatic cholangiocarcinoma (ICC) who received adjuvant chemotherapy after radical resection. Methods: The clinical and pathological data of 249 patients with ICC who underwent radical resection and adjuvant chemotherapy at 8 hospitals in China from January 2010 to December 2018 were retrospectively collected. There were 121 males and 128 females,with 88 cases>60 years old and 161 cases≤60 years old. Feature selection was performed by univariate and multivariate Cox regression analysis. Overall survival time and survival status were used as outcome indicators,then target clinical features were selected. Patients were stratified into high-risk group and low-risk group,survival differences between the two groups were analyzed. Using the selected clinical features, the traditional CoxPH model and deep learning DeepSurv survival prediction model were constructed, and the performance of the models were evaluated according to concordance index(C-index). Results: Portal vein invasion, carcinoembryonic antigen>5 μg/L,abnormal lymphocyte count, low grade tumor pathological differentiation and positive lymph nodes>0 were independent adverse prognostic factors for overall survival in 249 patients with adjuvant chemotherapy after radical resection (all P<0.05). The survival benefit of adjuvant chemotherapy in the high-risk group was significantly lower than that in the low-risk group (P<0.05). Using the above five features, the traditional CoxPH model and the deep learning DeepSurv survival prediction model were constructed. The C-index values of the training set were 0.687 and 0.770, and the C-index values of the test set were 0.606 and 0.763,respectively. Conclusion: Compared with the traditional Cox model, the DeepSurv model can more accurately predict the survival probability of patients with ICC undergoing adjuvant chemotherapy at a certain time point, and more accurately judge the survival benefit of adjuvant chemotherapy.

A nomogram for preoperative prediction of lymph node metastasis in patients with intrahepatic cholangiocarcinoma based on inflammation-related markers / 中华外科杂志

Objectives: To construct a nomogram for prediction of intrahepatic cholangiocarcinoma (ICC) lymph node metastasis based on inflammation-related markers,and to conduct its clinical verification. Methods: Clinical and pathological data of 858 ICC patients who underwent radical resection were retrospectively collected at 10 domestic tertiary hospitals in China from January 2010 to December 2018. Among the 508 patients who underwent lymph node dissection,207 cases had complete variable clinical data for constructing the nomogram,including 84 males,123 females,109 patients≥60 years old,98 patients<60 years old and 69 patients were pathologically diagnosed with positive lymph nodes after surgery. Receiver operating characteristic curve was drawn to calculate the accuracy of preoperative imaging examinations to determine lymph node status,and the difference in overall survival time was compared by Log-rank test. Partial regression squares and statistically significant preoperative variables were screened by backward stepwise regression analysis. R software was applied to construct a nomogram,clinical decision curve and clinical influence curve,and Bootstrap method was used for internal verification. Moreover,retrospectively collecting clinical information of 107 ICC patients with intraoperative lymph node dissection admitted to 9 tertiary hospitals in China from January 2019 to June 2021 was for external verification to verify the accuracy of the nomogram. 80 patients with complete clinical data but without lymph node dissection were divided into lymph node metastasis high-risk group and low-risk group according to the score of the nomogram among the 858 patients. Log-rank test was used to compare the overall survival of patients with or without lymph node metastasis diagnosed by pathology. Results: The area under the curve of preoperative imaging examinations for lymph node status assessment of 440 patients was 0.615,with a false negative rate of 62.8% (113/180) and a false positive rate of 14.2% (37/260). The median survival time of 207 patients used to construct a nomogram with positive or negative postoperative pathological lymph node metastases was 18.5 months and 27.1 months,respectively (P<0.05). Five variables related to lymph node metastasis were screened out by backward stepwise regression analysis,which were combined calculi,neutrophil/lymphocyte ratio,albumin,liver capsule invasion and systemic immune inflammation index,according to which a nomogram was constructed with concordance index(C-index) of 0.737 (95%CI: 0.667 to 0.806). The C-index of external verification was 0.674 (95%CI:0.569 to 0.779). The calibration prediction curve was in good agreement with the reference curve. The results of the clinical decision curve showed that when the risk threshold of high lymph node metastasis in the nomogram was set to about 0.32,the maximum net benefit could be obtained by 0.11,and the cost/benefit ratio was 1∶2. The results of clinical influence curve showed that when the risk threshold of high lymph node metastasis in the nomogram was set to about 0.6,the probability of correctly predicting lymph node metastasis could reach more than 90%. There was no significant difference in overall survival time between patients with high/low risk of lymph node metastasis assessed by the nomogram and those with pathologically confirmed lymph node metastasis or without lymph node metastasis (Log-rank test:P=0.082 and 0.510,respectively). Conclusion: The prediction accuracy of preoperative nomogram for ICC lymph node metastasis based on inflammation-related markers is satisfactory,which can be used as a supplementary method for preoperative diagnosis of lymph node metastasis and is helpful for clinicians to make personalized decision of lymph node dissection for patients with ICC.

Significance of combination of targeted therapy and immunotherapy in conversion therapy of biliary tract cancer / 中华外科杂志

Biliary tract cancer has insidious onset and high degree of malignancy, and radical resection is often impossible when it is diagnosed.Conversion therapy can achieve tumor downgrading, so that patients who were initially unresectable have a chance to achieve R0 resection.However, due to the high heterogeneity and complex immune microenvironment of biliary tract cancer, conversion therapy is still in the stage of active exploration.As a new type of conversion therapy, combination of targeted therapy and immunotherapy is of great significance to effectively improve the efficiency of conversion therapy.Further exploration of combination mechanism and improvement of immune microenvironment are expected to become the future direction of combination of targeted therapy and immunotherapy.

Application of perihilar surgical techniques in biliary tract surgery / 中国实用外科杂志

Perihilar biliary diseases have a wide spectrum of diseases including stones, inflammation, tumors, injuries and congenital malformations. Because of their characteristics such as anatomic variability, pathophysiological complexity, high operative difficulties, more postoperative complications and high operative risk, the perihilar biliary surgery is a high difficulty area in biliary surgery. For common clinical features ,common surgical methods and common technical difficulties of perihilar biliary diseases, the perihilar surgical technique system adequately evaluates hilar anatomy and its variations,liver function and volume of residual liver relying on threedimensional digital medical imaging technology, completely exposes hepatic hilum via combining anterograde and retrograde route from extra and intra-hepatic direction to hepatic hilum, then re-evaluates the relationship between the lesion and the hepatic artery and portal vein, and ultimately sets the surgical procedure . It is developed to improve the R0 resection rate, quality of cholangiojejunostomy, quality of vascular resection and reconstruction and safety of operation,eventually for the purpose of reducing postoperative complication rate and perioperative mortality and improving the prognosis. So surgeons should pay attention to the comprehensive system involving multiple disciplines in order to improve the effectiveness and safety in diagnosis and treatment of perihilar biliary diseases.

Downregulation of Notch-regulated Ankyrin Repeat Protein Exerts Antitumor Activities against Growth of Thyroid Cancer / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>The Notch-regulated ankyrin repeat protein (NRARP) is recently found to promote proliferation of breast cancer cells. The role of NRARP in carcinogenesis deserves extensive investigations. This study attempted to investigate the expression of NRARP in thyroid cancer tissues and assess the influence of NRARP on cell proliferation, apoptosis, cell cycle, and invasion in thyroid cancer.</p><p><b>METHODS</b>Thirty-four cases with thyroid cancer were collected from the Department of General Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine between 2011 and 2012. Immunohistochemistry was used to detect the level of NRARP in cancer tissues. Lentivirus carrying NRARP-shRNA (Lenti-NRARP-shRNA) was applied to down-regulate NRARP expression. Cell viability was tested after treatment with Lenti-NRARP-shRNA using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Apoptosis and cell cycle distribution were determined by flow cytometry. Cell invasion was tested using Transwell invasion assay. In addition, expressions of several cell cycle-associated and apoptosis-associated proteins were examined using Western blotting after transfection. Student's t-test, one-way analysis of variance (ANOVA), or Kaplan-Meier were used to analyze the differences between two group or three groups.</p><p><b>RESULTS</b>NRARP was highly expressed in thyroid cancer tissues. Lenti-NRARP-shRNA showed significantly inhibitory activities against cell growth at a multiplicity of infection of 10 or higher (P < 0.05). Lenti-NRARP-shRNA-induced G1 arrest (BHT101: 72.57% ± 5.32%; 8305C: 75.45% ± 5.26%) by promoting p21 expression, induced apoptosis by promoting bax expression and suppressing bcl-2 expression, and inhibited cell invasion by suppressing matrix metalloproteinase-9 expression.</p><p><b>CONCLUSION</b>Downregulation of NRARP expression exerts significant antitumor activities against cell growth and invasion of thyroid cancer, that suggests a potential role of NRARP in thyroid cancer targeted therapy.</p>

Comprehensive measures for improving the radical resection rate and safety of Bismuth-Corlette type III hilar cholangiocarcinoma / 中华外科杂志

<p><b>OBJECTIVE</b>To investigate the comprehensive measures for improving radical resection rate and safety of Bismuth-Corlette type III hilar cholangiocarcinoma.</p><p><b>METHODS</b>The clinical data of 15 patients with Bismuth-Corlette type III hilar cholangiocarcinoma who performed radical resection from June 2009 to December 2011 was analyzed retrospectively. There were 11 male and 4 female patients, aged from 45 to 74 years (mean 59 years). The preoperative evaluation were conducted by using magnetic resonance cholangiopancreatography (MRCP), dual source spiral CT combined with IQQA-Liver CT Imaging Analysis System providing three-dimensional reconstruction of tumor, bile duct, hepatic artery and portal vein, which could help to chose the appropriate treatment modality. All patients were treated with selective hemi-hepatic vascular control of removal liver, hemi-hepatectomy combined with whole caudate lobe resection and regional lymphadenectomy. The merits of each evaluation methods and measures of surgical treatment were analyzed thoroughly.</p><p><b>RESULTS</b>The preoperative evaluation modalities including the dual source spiral CT combined with IQQA-Liver CT Imaging Analysis System could clearly show the involvement of bile duct, hepatic artery and portal vein invaded by the tumor. The satisfactory postoperative recovery could be achieved by the remnant liver volume of > 40% after the hemi-hepatectomy combined with whole caudate lobe resection through the selective preoperative biliary drainage and hemihepatic vascular control. The mean complication was transient aggravated liver dysfunction. There was no death reported during perioperative period in the group.</p><p><b>CONCLUSIONS</b>The preoperative imaging evaluation modalities including MRCP, dual source spiral CT combined with IQQA-Liver CT Imaging Analysis System could do favor for the preoperative evaluation of invasion degree of hilar cholangiocarcinoma and the selection of appropriate surgical treatment. Hemi-hepatectomy combined with whole caudate lobe resection and regional lymphadenectomy could be an alternative management of Bismuth-Corlette type III hilar cholangiocarcinoma.</p>

The role of tissue factor pathway inhibitor-2 gene in gallbladder cancer / 中华外科杂志

<p><b>OBJECTIVE</b>To examine the expression of tissue factor pathway inhibitor-2 (TFPI-2) in gallbladder cancer (GBC) and to investigate the anti-cancer activities of TFPI-2 against the growth of GBC.</p><p><b>METHODS</b>TFPI-2 expression in gallbladder normal tissues, gallbladder polyp (GBP) tissues and GBC tissues were examined by reverse transcriptase polymerase chain reaction (RT-PCR), Western blot and immunohistochemical staining. Adenovirus carrying human TFPI-2 gene (Ad5-TFPI-2) were constructed and its anti-cancer effects were investigated in xenograft tumors. Xenograft tumors were constructed by injection of GBC-SD and SGC-996 cells into the flank of nude mice and the volume of xenograft tumors was measured every 3 days until the sacrifice of mice. The apoptosis index of xenograft tumors was examined by TUNEL assay. The status of Bax, Bcl-2 and caspase-3 was examined by Western blot assay.</p><p><b>RESULTS</b>TFPI-2 expression was profoundly lower in GBC tissues (87.0%) when compared to normal tissues (23.3%) and GBP tissues (52.2%; χ(2) = 21.104, P = 0.000). Ad-TFPI-2 significantly inhibited the growth of xenograft tumors in nude mice. Ad-TFPI-2 inhibited GBC-SD cell growth through the induction of apoptosis. The means of total apoptotic cells per field were much higher in Ad5-TFPI-2 group than those in PBS and Ad5-GFP groups. Ad5-TFPI-2 elevated the expression of Bax and cleaved caspase-3, while it decreased the expression of Bcl-2.</p><p><b>CONCLUSIONS</b>TFPI-2 gene and protein was down-regulated in GBC and the down-regulation of TFPI-2 may play a role in the tumorigenesis of GBC. Adenovirus-mediated TFPI-2 can inhibit GBC growth through the induction of apoptosis.</p>

Pharmacokinetics of photosensitizer m-THPC in rat models of liver cancer via orthotropic implantation using Walker-256 / 中华外科杂志

<p><b>OBJECTIVE</b>To study the pharmacokinetics, distribution and excretion of m-THPC in rat models of liver cancer via orthotropic implantation using Walker-256.</p><p><b>METHODS</b>After an intravenous injection of m-THPC with 0.3 mg/kg, the concentrations of m-THPC in biological specimens were determined by a fluorescence method. The data obtained were processed with PK-GRAPH pharmacokinetic procedure.</p><p><b>RESULTS</b>The disposition of m-THPC in rat models of liver cancer Walker-256 was conformed to a two compartment model with T(1/2)α = 1.18 h, T(1/2)β = 22.57 h at the dose of 0.3 mg/kg.m-THPC was shown to be widely distributed to the various tissues. There was a highest drug accumulation in liver and liver cancer, and lowest in skin and muscle. Ratio of m-THPC concentration in the Walker-256 tumor compared to normal tissue reach the peak 24 h after m-THPC administration.</p><p><b>CONCLUSIONS</b>m-THPC is distributed widely and eliminated at a rapid rate in Walker-256 rats. Twenty four hours after m-THPC administration may be the best time for photodynamic therapy of liver cancer.</p>

Mechanism research in somatostatin reverting the chemosensitivity of GBC-SD cell line / 中华外科杂志

<p><b>OBJECTIVE</b>To investigate the mechanism of increasing chemosensitivity of gallbladder carcinoma stimulated by somatostatin.</p><p><b>METHODS</b>GBC-SD cells were divided into four groups: SST-alone-treated group, Doxorubicin (DOX)-alone-treated group and co-treated group (co-treatment of SST and DOX). In the control group, the cells were cultivated by medium only. In SST-alone-treated group, the cells were cultivated by medium with SST in the concentration of 75 microg/ml. In DOX-alone-treated group, the cells were cultivated by medium with DOX in the gradient concentrations of 5, 10, 20 microg/ml. In the co-treated group, cells were first cultivated by medium with 75 microg/ml SST for 24 h, followed by the addition of DOX in the gradient concentrations mentioned above. Cell viability curve was measured by MTT assay at 24, 48, 72 and 96 h, respectively. Meanwhile, the alterations of protein expressions of ICBP90 and Topo IIalpha after treatment of SST were examined by Western blot.</p><p><b>RESULTS</b>The treatment of SST alone on GBC-SD cells did not exert significantly inhibitory effect compared to the control group (P > 0.05). However, 24 h after the treatment of SST, the protein expressions of ICBP90 and Topo IIalpha were both up-regulated (P < 0.05).</p><p><b>CONCLUSION</b>Up-regulated the expression of ICBP90 by somatostatin maybe the cause of overexpression of Topo IIalpha, which leads to the enhanced lethal effect of DOX.</p>

Role of dissection of secondary branches of splenic pedicle in portal hypertension cases undergoing splenectomy / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>It is well known that conventional splenectomy, which requires careful handling and ligation of tissue of the splenic hilum, can easily cause complications such as splenic fever and pancreatic fistula. Here, we use the technique of dissection of the secondary branches of the splenic pedicle to handle the hilum in the portal hypertension patients who are subjected to splenectomy.</p><p><b>METHODS</b>We retrospectively compared and analyzed the complications, postoperative hospital stay, operative time, and occurrence of hemorrhage in 121 patients with portal hypertension undergoing splenectomy and devascularization of the gastric cardia from January 1999 to December 2007. The selected cases consisted of 51 patients undergoing conventional splenectomy and 70 patients undergoing dissection of secondary branches of the splenic pedicle. In addition, we analyzed the relationship between size of the spleen and occurrence of complications.</p><p><b>RESULTS</b>The incidence of pancreatic fistula and splenic fever (0/70 and 9/70) was lower in patients undergoing dissection of secondary branches of the splenic pedicle as compared with that of the conventional group (5/51 and 18/51 respectively). In addition, there was no significant difference in operative time and volume of blood loss between two groups. The spleen thickness of those patients who had pancreatic fistula and splenic fever was significantly greater than those without complications.</p><p><b>CONCLUSIONS</b>These results indicate that dissection of secondary branches of the splenic pedicle in portal hypertension patients undergoing splenectomy can decrease the incidence of splenic fever and pancreatic fistula, and shorten the postoperative hospital stay, especially in the patients with a large spleen. So dissection of secondary branches of the splenic pedicle is a valuable technique for splenectomy.</p>

Expression of hTERT in liver of nude mice with human colon carcinoma liver metastases / 上海第二医科大学学报

Objective To develop the human colon carcinoma(HT-29) liver metastasis model in nude mice,and to detect the expression of human telomerase reverse transcriptases(hTERT) mRNA in liver of nude mice. Methods Liver metastases were established in 30 Balb/c nude mice by intrasplenic injection of colonic cancer cells(HT-29),and the spleens were resected.After being sacrificed,the tumor growth was observed,and the pathological examinations were performed.The expression of hTERT mRNA in the livers of nude mice was detected by RT-PCR technique. ResultsHuman colon carcinoma(HT-29) liver metastasis model was developed in all the 30 nude mice,with the liver metastasis rate of 100%.The pathological results revealed the occurrence of liver metastases,and the expression of hTERT mRNA was positive in the liver tissues. Conclusion Intrasplenic injection of HT-29 cell is a reliable way for producing colonic cancer liver metastasis model,and the positive expression of hTERT mRNA in liver tissues indicates the significance of hTERT in the early diagnosis and treatment of colon carcinoma liver metastasis.

Relationship between expression of syndecan-1 and prognosis in pancreatic cancer / 上海第二医科大学学报

Objective To explore the relationship between the expression of syndecan-1 and the prognosis in pancreatic cancer. Methods The data of 30 patients with pancreatic cancer who received radical operations were retrospectively analysed.Immunohistochemical staining was performed,and the expression of syndecan-1 in tumor epithelial cells and stroma was observed by light microscopy.The relationship between immunohistochemical findings and survival was analysed.Results For those with negative,weak positive,moderate positive and strong positive expression of synecan-1 in tumor epithelial cells and stroma,there were significant differences in the case numbers between those survived for 1 to 2 years and those survived for 2 to 4 years(P

Effects of postoperative immune-enhancing enteral nutrition on the immune system, inflammatory responses, and clinical outcome / 中华医学杂志(英文版)

<p><b>OBJECTIVE</b>This study was conducted to evaluate the effects of postoperative immune enhancing enteral nutrition on the immune system, inflammatory responses, and clinical outcome of patients undergoing major abdominal surgery.</p><p><b>METHODS</b>This study was designed as a multicenter, prospective, randomized and controlled clinical trial. One hundred twenty-four patients undergoing major abdominal surgery were randomly assigned to receive either an immune enhancing enteral diet or an isocaloric and isonitrogenous control enteral diet for seven days. Enteral feeding was initiated 24 hours after surgery. Host immunity was evaluated by measuring levels of IgG, IgM, IgA, CD4, CD8, and CD4/CD8, and the inflammatory response was determined by assessing IL-1alpha, IL-2, IL-6, IL-10, and TNF-alpha levels. Infectious complications were also recorded.</p><p><b>RESULTS</b>One hundred twenty patients completed the study and four patients were excluded. On postoperative day 9, among patients receiving an immune enhancing diet, IgG, IgA, CD4 and CD4/CD8 levels were significantly higher and TNF-alpha and IL-6 concentrations were significantly lower compared to the control group. Moreover, among patients receiving an immune enhancing diet, when comparing preoperation to day 9 postoperation levels, increases in IgA, CD4, and CD4/CD8 levels were significantly higher than in control patients and increases in TNF-alpha concentrations were significantly lower. No statistically significant differences were found between the two groups with regard to infectious complications.</p><p><b>CONCLUSIONS</b>Postoperative administration of immune enhancing enteral nutrition in patients undergoing major abdominal surgery can positively modulate postoperative immunosuppressive and inflammatory responses.</p>