Somatostatin enhances the chemosensitivity of GBC-SD cell line to doxorubicin through arresting the cell cycle to S phase rather than through the P53/Bax-depended apoptosis way in vitro.

BACKGROUND/AIMS: As one of the mostly aggressive and fatal malignancy, gallbladder carcinoma has been known to be resistant to many anticancer drugs. Although it is under active investigation, it is still difficult to achieve satisfactory effect for most chemo-drugs on this tumor. It has previously reported that somatostatin could increase the chemosensitivity of gallbladder carcinoma cells (GBC-SD) and reduce the therapeutic dose of Doxorubicin in killing GBC-SD cells. SST could enhance the chemosensitivity of gallbladder carcinoma to Doxorubincin (DOX) by transient arresting cell cycle to S phase. We tried to clarify the mechanism by which SST utilized to enhance the chemosensitivity of GBC-SD cells to DOX. We further investigated whether the enhanced chemosensitivity of GBC-SD cells to DOX in the presence of SST is via apoptosis or cell cycle regulation. In addition, we also looked into related factors involved in cell cycle regulation and apoptosis. METHODOLOGY: Twenty-four hours after somatostatin treatment, doxorubicin was gradually added and the growth curve of GBC-SD cells was determined according to MTT test. Cell apoptosis was measured by flow cytometry (FCM) using Annexin V/ Propidium Iodide Binding. Cell cycle was also examined by FCM. The somatostatin receptor (SSTR) subtypes in GBC-SD cells were identified using immunocytochemistry and RT-PCR assay. The expressions of p53, Bax and phosphorylated RB (pRB) protein were examined using western blotting assay. RESULTS: When GBC-SD cells were treated with SST alone, no significant cell growth inhibition and cell apoptosis were observed. SST could induce a transient S phase arrest in GBC-SD cells. The mRNA expression of SSTR1, 2, 3, 4, 5 were all detected in GBC-SD cells, whereas only SSTR1, 2, 3 were detected in GBC-SD cells using immunocytochemistry assay. After GBC-SD cells were treated with SST for 24h, the expression level of p53 and Bax protein in GBC-SD cells was similar to that of the control group, however up-regulated pRB protein expression was observed (p < 0.05). CONCLUSIONS: Our results suggested that the synergistic inhibitory effect of somatostatin and doxorubicin co-treatment on GBC-SD cells was not due to SST induced apoptosis concerning the expression of p53 and Bax protein. Our data clearly showed all 5 SST receptor subtypes expressed in GBC-SD cells by RT-PCR and 3 SST receptors by immunocytochemistry. Accumulated evidence has been proved the relationship between cell cycle regulation and RB protein phosphorylation. In the chemosensitized GBC-SD cell line treated with SST, phosphorylated RB and cell cycle arrest were simultaneously manifested. We reasoned that somatostatin might enhance the chemosensitivity of GBC-SD cells to doxorubin through arresting the cell cycle at S phase, but not P53 and Bax protein induced cell apoptosis.

Comprehensive treatment of biliary tract tumors:from the perspective of evolution / 肿瘤

Biliary tract tumors are a class of highly malignant digestive system tumors.Although surgical treatment,chemotherapy,and targeted therapy have achieved good therapeutic effects.However,due to its complex biological characteristics,it is easy to develop drug resistance,and recurrence is still inevitable.More than 99.9％of the species that had ever appeared on earth have become extinct,and these species possess resistance to external selection pressures similar to tumor cells.The comprehensive treatment of biliary tract tumors should be designed from the perspective of natural evolution and species extinction.We compared the causes of species extinction with existing cancer treatments,which are expected to provide new ideas for fundamental and clinical research.

Current situation and prospect in the clinical treatment of gallbladder cancer / 中华消化外科杂志

Gallbladder carcinoma is a tumor with poor prognosis and lack of effective comprehensive treatment. At present, surgical resection is still the main treatment for gallbladder carcinoma. Precise evaluation and adequate preparation before surgery, and safe, effective, standar-dized resection are the key points to successful treatment of gallbladder carcinoma. In clinic, there has been a growing appreciation of the prevention and reasonable treatment of incidental gallbladder carcinoma. Neoadjuvant and conversion therapy give full play to the effects of chemotherapy, targeted therapy, and immunotherapy agents on tumor cells, which can achieve the goal of downstage or conversion of tumors before surgery, increasing the radical resection rate, and improving the prognosis of patients.

The basis and current status of the clinical research on gallbladder cancer / 肿瘤

Gallbladder cancer is the most common biliary malignancy and has a poor prognosis.How to effectively improve the prognosis of gallbladder cancer patients is still an urgent problem for surgeons to solve.The solution to the problem depends on the early screening and intervention of gallbladder cancer,precise surgical treatment plan and effective comprehensive treatment measures.However,there are still many controversies in these aspects,and more high-quality clinical research,basic research and basic-clinical transformation research are still needed to improve the diagnosis and treatment system of gallbladder cancer in the future.

Progress in the research and theranostics of neurofibromatosis type Ⅰ / 肿瘤

Neurofibromatosis type 1 is a progressive autosomal dominant inherited disease caused by a mutation in neurofibromin 1(NF1)gene located on chromosome 1 7q1 1.2.NF1 can cause systemic peripheral neuropathy,but the clinical manifestations are varied due to the different onset times and lesion sites in different patients.The treatment of NF1 involves multiple disciplines due to different lesion sites.Clinical monitoring and symptomatic treatment are the main methods for NF1 management,while radical treatment is difficult.New drugs targeted at the pathogenic gene-related signaling pathways are expected to improve the therapeutic effect for NF1.This review summarizes the progress in the basic research and clinical diagnosis and treatment of NF1.

Analysis of long-term trend changes in breast cancer incidence and death among females in Shanghai,1973-2017 / 肿瘤

Objective:To describe the long-term characteristics and trend changes in the incidence and mortality of female breast cancer in Shanghai from 1 973 to 2017,aiming to provide references for exploring the etiology of breast cancer and formulating strategies and measures for prevention,intervention and control. Methods:Joinpoint software was used to analyze the trend changes in the incidence and mortality of female breast cancer in Shanghai from 1 973 to 2017,and an age-period-cohort model was constructed to explore the effects of age,year of diagnosis,and birth cohort on long-term trend changes. Results:From 1 973 to 2017,there were 68 192 new cases of female breast cancer in Shanghai,with a diagnosed rate of 31.72/100 000.The incidence rate continued to rise,and the risk of the disease continued to rise from the age of 20 years,and the rise rate accelerated significantly after the age of 40 years.There were 21 535 female breast cancer deaths from 1 973 to 2017.The mortality rate was stable,with a death rate of 8.62/100 000,and the risk of death increased significantly from the age of 45 years.The effects of age,period and cohort had a significant impact on the incidence of breast cancer(P＜0.01),while the increase in mortality rate was related to age and cohort effects(P＜0.01). Conclusion:The incidence rate of female breast cancer in Shanghai is still rising rapidly,and the mortality trend is generally stable,suggesting that the treatment is effective and the quality of life is improved.However,breast cancer is still the main malignant tumor among females in Shanghai.It should be continued to implement prevention and control strategies such as lifestyle intervention and screening of high-risk individuals to further strengthen the prevention and control of breast cancer.

Colorectal cancer incidence and mortality trends in urban Shanghai,China from 1973 to 2017:a Joinpoint regression and age-period-cohort analysis / 肿瘤

Objective:To describe the epidemiological features and temporal trends of colorectal cancer in urban Shanghai from 1973 to 2017. Methods:Data on colorectal cancer in urban Shanghai was obtained through Shanghai Cancer Registry and Vital Statistics System.Joinpoint analysis was used to describe the temporal trends and annual percent change(APC)and age-period-cohort analysis was used to estimate the association between age,period and birth cohort and colorectal cancer. Results:A total of 105 847 cases and 60 447 deaths of colorectal cancer were diagnosed in urban Shanghai over the 45-year study period.Both the number of new cases and the number of deaths showed an increasing trend.In the same period,the age-standardized incidence of colorectal cancer in urban areas of Shanghai increased significantly from 14.1/100 000 in 1973 to 27.7/100 000 in 2017,while the age-standardized mortality rate increased from 8.2/100 000 to 10.7/100 000.The overall average annual age-standardized incidence and mortality rates were 20.4/100 000 and 11.0/100 000,respectively.With the increase of age,the age-standardized morbidity and mortality of colorectal cancer showed an obvious upward trend.Taking 1993-1997 as reference,the risk of colorectal cancer in Shanghai reached the highest in 2013-2017,and the corresponding relative risk was 1.2(95％confidence interval:1.2-1.3),while the lowest was 0.9(95％confidence interval:0.8-1.0)during 1973-1977.Mortality risk,on the contrary,decreased with the increase of time.Before 1953-1957,the risk of colorectal cancer in urban Shanghai increased with the increase of birth cohort time,and then showed a downward trend.There was a corresponding decline in the risk of colorectal cancer death among people born after 1957. Conclusion:The incidence and mortality of colorectal cancer in Shanghai showed an increasing trend from 1973 to 2017,but the prevalence trend of colorectal cancer is still different among different populations.

Isoliquiritigenin induces HMOX1 and GPX4-mediated ferroptosis in gallbladder cancer cells / 中华医学杂志(英文版)

BACKGROUND@#Gallbladder cancer (GBC) is the most common malignant tumor of biliary tract. Isoliquiritigenin (ISL) is a natural compound with chalcone structure extracted from the roots of licorice and other plants. Relevant studies have shown that ISL has a strong anti-tumor ability in various types of tumors. However, the research of ISL against GBC has not been reported, which needs to be further investigated.@*METHODS@#The effects of ISL against GBC cells in vitro and in vivo were characterized by cytotoxicity test, RNA-sequencing, quantitative real-time polymerase chain reaction, reactive oxygen species (ROS) detection, lipid peroxidation detection, ferrous ion detection, glutathione disulphide/glutathione (GSSG/GSH) detection, lentivirus transfection, nude mice tumorigenesis experiment and immunohistochemistry.@*RESULTS@#ISL significantly inhibited the proliferation of GBC cells in vitro . The results of transcriptome sequencing and bioinformatics analysis showed that ferroptosis was the main pathway of ISL inhibiting the proliferation of GBC, and HMOX1 and GPX4 were the key molecules of ISL-induced ferroptosis. Knockdown of HMOX1 or overexpression of GPX4 can reduce the sensitivity of GBC cells to ISL-induced ferroptosis and significantly restore the viability of GBC cells. Moreover, ISL significantly reversed the iron content, ROS level, lipid peroxidation level and GSSG/GSH ratio of GBC cells. Finally, ISL significantly inhibited the growth of GBC in vivo and regulated the ferroptosis of GBC by mediating HMOX1 and GPX4 .@*CONCLUSION@#ISL induced ferroptosis in GBC mainly by activating p62-Keap1-Nrf2-HMOX1 signaling pathway and down-regulating GPX4 in vitro and in vivo . This evidence may provide a new direction for the treatment of GBC.

Controversies of abdominal drainage after pancreaticoduodenectomy / 中华肝胆外科杂志

Pancreaticoduodenectomy (PD) is an established surgical treatment for pancreatic and periampullary diseases. Abdominal drainage after PD has been routinely used for many years to early detect complications and to promote rapid recovery of patients. However, with the introduction of enhanced recovery after surgery, controversies exist on the safety and effectiveness of routine use of abdominal drainage after PD. This article reviewed the controversies on whether routine abdominal drainage are necessary after PD, how to place abdominal drains, and when to remove abdominal drains.

Mechanism study of neurofibromin 1 in gallbladder cancer / 中华消化外科杂志

Objective:To investigate the mechanism of neurofibromin 1 (NF1) in gallbla-dder cancer.Methods:The experimental study was conducted. Human gallbladder cancer cell lines, including GBC-SD, NOZ, SGC996, EH-GB1, ZJU0428, human embryonic kidneys cell line 293T and human cervical cancer cell line HELA, were cultured. The recombinant plasmids (mRFP-YAP1 FL-FLAG and eGFP-MYC-NF1 2650?2750-HA) were constructed for co-immunoprecipitation experiment. The truncated Yes associated protein 1(YAP1) and NF1 recombinant proteins were purified in vitro. The interaction between NF1 and YAP1 in vitro or in vivo were verified by isothermal titration calori-metry (ITC) assay, GST pull-down experiment, co-immunoprecipitation, immunofluorescence, laser confocal microscopy, and the expression of NF1 protein in different gallbladder cancer cell lines was verified by Western blot experiments. Observation indicators: (1) interaction between NF1 and YAP1 in vitro; (2) interaction between NF1 and YAP1 in cells; (3) expression of NF1 protein in different human gallbladder cancer cell lines. The dissociation constants were exported from ITC 200 software and represented as Mean± SD. Count data were represented as absolute numbers. Results:(1) Interaction between NF1 and YAP1 in vitro. ① Results of ITC assay showed that there was interac-tion between PPQY and YAP1-WW1, between PPQY and YAP1 (Amino acid residues 162?275), and the dissociation constants between PPQY and YAP1-WW1, between PPQY and YAP1(Amino acid residues 162?275) were (0.42±0.06)mmol/L, (0.69±0.14)mmol/L, respectively. ② GST pull-down results indicated that the target protein His-Sumo-YAP1 WW1 was obviouly observed in protein lane of reaction system between GST-PPQY recombinant protein and His-Sumo-YAP1 WW1, relative to the reaction system between GST protein and His-Sumo-YAP1 WW1. The target protein His-Sumo-YAP1 WW2 was obviouly observed in protein lane of reaction system between GST-PPQY recombinant protein and His-Sumo-YAP1 WW2, relative to the reaction system between GST protein and His-Sumo-YAP1 WW2. (2) Interaction between NF1 and YAP1 in cells. ① Co-immunoprecipitation results indica-ted that NF1 protein was observed in cell lysis solution which was incubated by FLAG gel beads and cotransfected with mRFP-YAP1 FL-FLAG and eGFP-MYC-NF1 2650?2750-HA. ② Immuno-fluorescence and laser confocal microscopy results indicated that YAP1 and NF1 with obvious fluorescence were co-localized in the cytoplasm of human gallbladder cancer NOZ cells. However, YAP1 with obvious fluorescence was localized in the nucleus of human gallbladder SGC996 cells and NF1 showed weak fluorescence. (3) Expression of NF1 protein in different human gallbladder cancer cell lines. Western blot results showed that with the expression level of NF1 protein in HELA cell line as the standard, the relative expression levels of NF1 protein in EH-GB1, GBC-SD, NOZ, SGC996, ZJU0428 cell lines were 1.28, 0, 1.01, 0, 0, respectively. Conclusion:NF1 affects the gallbladder cancer by directly acting on YAP1 protein.

Epidemiological characteristics, diagnosis, treatment and prognosis of gallbladder cancer in China: a report of 6 159 cases / 中华消化外科杂志

Objective:To investigate the epidemiological characteristics, diagnosis, treat-ment and prognosis of gallbladder cancer in China from 2010 to 2017.Methods:The single disease retrospective registration cohort study was conducted. Based on the concept of the real world study, the clinicopathological data, from multicenter retrospective clinical data database of gallbladder cancer of Chinese Research Group of Gallbladder Cancer (CRGGC), of 6 159 patients with gallbladder cancer who were admitted to 42 hospitals from January 2010 to December 2017 were collected. Observation indicators: (1) case resources; (2) age and sex distribution; (3) diagnosis; (4) surgical treatment and prognosis; (5) multimodality therapy and prognosis. The follow-up data of the 42 hospitals were collected and analyzed by the CRGGC. The main outcome indicator was the overall survival time from date of operation for surgical patients or date of diagnosis for non-surgical patients to the end of outcome event or the last follow-up. Measurement data with normal distribu-tion were represented as Mean±SD, and comparison between groups was conducted using the t test. Measurement data with skewed distribution were represented as M( Q1, Q3) or M(range), and com-parison between groups was conducted using the U test. Count data were described as absolute numbers or percentages, and comparison between groups was conducted using the chi-square test. Univariate analysis was performed using the Logistic forced regression model, and variables with P<0.1 in the univariate analysis were included for multivariate analysis. Multivariate analysis was performed using the Logistic stepwise regression model. The life table method was used to calculate survival rates and the Kaplan-Meier method was used to draw survival curves. Log-rank test was used for survival analysis. Results:(1) Case resources: of the 42 hospitals, there were 35 class A of tertiary hospitals and 7 class B of tertiary hospitals, 16 hospitals with high admission of gallbladder cancer and 26 hospitals with low admission of gallbladder cancer, respectively. Geographical distribution of the 42 hospitals: there were 9 hospitals in central China, 5 hospitals in northeast China, 22 hospitals in eastern China and 6 hospitals in western China. Geographical distribution of the 6 159 patients: there were 2 154 cases(34.973%) from central China, 705 cases(11.447%) from northeast China, 1 969 cases(31.969%) from eastern China and 1 331 cases(21.611%) from western China. The total average number of cases undergoing diagnosis and treatment in hospitals of the 6 159 patients was 18.3±4.5 per year, in which the average number of cases undergoing diagnosis and treatment in hospitals of 4 974 patients(80.760%) from hospitals with high admission of gallbladder cancer was 38.8±8.9 per year and the average number of cases undergoing diagnosis and treatment in hospitals of 1 185 patients(19.240%) from hospitals with low admission of gallbladder cancer was 5.7±1.9 per year. (2) Age and sex distribution: the age of 6 159 patients diagnosed as gallbladder cancer was 64(56,71) years, in which the age of 2 247 male patients(36.483%) diagnosed as gallbladder cancer was 64(58,71)years and the age of 3 912 female patients(63.517%) diagnosed as gallbladder cancer was 63(55,71)years. The sex ratio of female to male was 1.74:1. Of 6 159 patients, 3 886 cases(63.095%) were diagnosed as gallbladder cancer at 56 to 75 years old. There was a significant difference on age at diagnosis between male and female patients ( Z=-3.99, P<0.001). (3) Diagnosis: of 6 159 patients, 2 503 cases(40.640%) were initially diagnosed as gallbladder cancer and 3 656 cases(59.360%) were initially diagnosed as non-gallbladder cancer. There were 2 110 patients(34.259%) not undergoing surgical treatment, of which 200 cases(9.479%) were initially diagnosed as gallbladder cancer and 1 910 cases(90.521%) were initially diagnosed as non-gallbladder cancer. There were 4 049 patients(65.741%) undergoing surgical treatment, of which 2 303 cases(56.878%) were initially diagnosed as gallbladder cancer and 1 746 cases(43.122%) were initial diagnosed as non-gallbladder cancer. Of the 1 746 patients who were initially diagnosed as non-gallbladder cancer, there were 774 cases(19.116%) diagnosed as gallbladder cancer during operation and 972 cases(24.006%) diagnosed as gallbladder cancer after operation. Of 6 159 patients, there were 2 521 cases(40.932%), 2 335 cases(37.912%) and 1 114 cases(18.087%) undergoing ultrasound, computed tomography (CT) or magnetic resonance imaging (MRI) examination before initial diagnosis, respec-tively, and there were 3 259 cases(52.914%), 3 172 cases(51.502%) and 4 016 cases(65.205%) undergoing serum carcinoembryonic antigen, CA19-9 or CA125 examination before initially diagnosis, respectively. One patient may underwent multiple examinations. Results of univariate analysis showed that geographical distribution of hospitals (eastern China or western China), age ≥72 years, gallbladder cancer annual admission of hospitals, whether undergoing ultrasound, CT, MRI, serum carcinoembryonic antigen, CA19-9 or CA125 examination before initially diagnosis were related factors influencing initial diagnosis of gallbladder cancer patients ( odds ratio=1.45, 1.98, 0.69, 0.68, 2.43, 0.41, 1.63, 0.41, 0.39, 0.42, 95% confidence interval as 1.21-1.74, 1.64-2.40, 0.59-0.80, 0.60-0.78, 2.19-2.70, 0.37-0.45, 1.43-1.86, 0.37-0.45, 0.35-0.43, 0.38-0.47, P<0.05). Results of multivariate analysis showed that geographical distribution of hospitals (eastern China or western China), sex, age ≥72 years, gallbladder cancer annual admission of hospitals and cases undergoing ultrasound, CT, serum CA19-9 examination before initially diagnosis were indepen-dent influencing factors influencing initial diagnosis of gallbladder cancer patients ( odds ratio=1.36, 1.42, 0.89, 0.67, 1.85, 1.56, 1.57, 0.39, 95% confidence interval as 1.13-1.64, 1.16-1.73, 0.79-0.99, 0.57-0.78, 1.60-2.14, 1.38-1.77, 1.38-1.79, 0.35-0.43, P<0.05). (4) Surgical treatment and prognosis. Of the 4 049 patients undergoing surgical treatment, there were 2 447 cases(60.435%) with complete pathological staging data and follow-up data. Cases with pathological staging as stage 0, stage Ⅰ, stage Ⅱ, stage Ⅲa, stage Ⅲb, stage Ⅳa and stage Ⅳb were 85(3.474%), 201(8.214%), 71(2.902%), 890(36.371%), 382(15.611%), 33(1.348%) and 785(32.080%), respectively. The median follow-up time and median postoperative overall survival time of the 2 447 cases were 55.75 months (95% confidence interval as 52.78-58.35) and 23.46 months (95% confidence interval as 21.23-25.71), respectively. There was a significant difference in the overall survival between cases with pathological staging as stage 0, stage Ⅰ, stage Ⅱ, stage Ⅲa, stage Ⅲb, stage Ⅳa and stage Ⅳb ( χ2=512.47, P<0.001). Of the 4 049 patients undergoing surgical treatment, there were 2 988 cases(73.796%) with resectable tumor, 177 cases(4.371%) with unresectable tumor and 884 cases(21.833%) with tumor unassessable for resectabi-lity. Of the 2 988 cases with resectable tumor, there were 2 036 cases(68.139%) undergoing radical resection, 504 cases(16.867%) undergoing non-radical resection and 448 cases(14.994%) with operation unassessable for curative effect. Of the 2 447 cases with complete pathological staging data and follow-up data who underwent surgical treatment, there were 53 cases(2.166%) with unresectable tumor, 300 cases(12.260%) with resectable tumor and receiving non-radical resection, 1 441 cases(58.888%) with resectable tumor and receiving radical resection, 653 cases(26.686%) with resectable tumor and receiving operation unassessable for curative effect. There were 733 cases not undergoing surgical treatment with complete pathological staging data and follow-up data. There was a significant difference in the overall survival between cases not undergoing surgical treatment, cases undergoing surgical treatment for unresectable tumor, cases undergoing non-radical resection for resectable tumor and cases undergoing radical resection for resectable tumor ( χ2=121.04, P<0.001). (5) Multimodality therapy and prognosis: of 6 159 patients, there were 541 cases(8.784%) under-going postoperative adjuvant chemotherapy and advanced chemotherapy, 76 cases(1.234%) under-going radiotherapy. There were 1 170 advanced gallbladder cancer (pathological staging ≥stage Ⅲa) patients undergoing radical resection, including 126 cases(10.769%) with post-operative adjuvant chemotherapy and 1 044 cases(89.231%) without postoperative adjuvant chemo-therapy. There was no significant difference in the overall survival between cases with post-operative adjuvant chemotherapy and cases without postoperative adjuvant chemotherapy ( χ2=0.23, P=0.629). There were 658 patients with pathological staging as stage Ⅲa who underwent radical resection, including 66 cases(10.030%) with postoperative adjuvant chemotherapy and 592 cases(89.970%) without postoperative adjuvant chemotherapy. There was no significant difference in the overall survival between cases with postoperative adjuvant chemotherapy and cases without postoperative adjuvant chemotherapy ( χ2=0.05, P=0.817). There were 512 patients with pathological staging ≥stage Ⅲb who underwent radical resection, including 60 cases(11.719%) with postoperative adjuvant chemotherapy and 452 cases(88.281%) without postoperative adjuvant chemotherapy. There was no significant difference in the overall survival between cases with postoperative adjuvant chemo-therapy and cases without post-operative adjuvant chemo-therapy ( χ2=1.50, P=0.220). Conclusions:There are more women than men with gallbladder cancer in China and more than half of patients are diagnosed at the age of 56 to 75 years. Cases undergoing ultrasound, CT, serum CA19-9 examination before initial diagnosis are independent influencing factors influencing initial diagnosis of gallbladder cancer patients. Preoperative resectability evaluation can improve the therapy strategy and patient prognosis. Adjuvant chemotherapy for gallbladder cancer is not standardized and in low proportion in China.

Application progress of liquid biopsy in the diagnosis and treatment of biliary tract cancer / 中华肝胆外科杂志

With the development of precision medicine and individualized treatment, tissue biopsy in cancer patients diagnosis and therapy has been broadly used. However, because it’s hard to collect enough samples for biliary tract tumors, liquid biopsy was broadly applied for the diagnosis. In liquid biopsy, circulating tumor cells, circulating tumor DNA, and tumor-derived exosomes carrying tumor-specific information are released from tumor tissue into blood, bile, and other body fluids, which makes tumor biopsy samples easily to be obtained in a non-invasive way. At the same time, through a series of morphological and molecular measurements as well as genetic characterization, liquid biopsy can be used to look for the new early diagnostic markers, and therapeutic targets, monitoring progression and prognosis of diseases. This article outlined the current technology used to detect circulating tumor cells, circulating tumor DNA, and tumor-derived exosomes, and summarizes the latest advances in the clinical application of liquid biopsy in biliary tract cancers.

Key and difficult points in surgical treatment of hepatoli-thiasis / 中华消化外科杂志

Hepatolithiasis had diverse causes and complicated conditions with residual stones and recurrence after surgery, which is still a difficult point in surgical treatment. In this article, the authors focus on the timing of surgery for hepatolithiasis, preoperative imaging and precise assessment of important organs throughout the body, intraoperative technical points, progress in the application of minimally invasive techniques and endoscopic methods, surgical strategy for recurrent intrahepatic stones, application value of perihilar surgery technology and the treatment of patients combined with portal hypertension. This article aims to investigate the difficult problems that may be encountered in the surgical treatment of hepatolithiasis, improve the stone removal rate, reduce the recurrence rate, improve the patient′s prognosis and quality of life.

Problems and strategy in surgical treatment of biliary tract tumors / 中华消化外科杂志

Biliary tract tumor is a high degree malignancy,which presents with early metastasis and poor prognosis.However,the incidence keeps increasing in recent years compared with other digestive system tumors,the clinical and basic research started late.The biliary tract system is very complicated,it starts up to the liver,descending through the pancreas into the duodenum,involving these three organs,beside this,the portal vein and the hepatic artery are in close proximity.Thus,there are many problems to be solved in current surgical treatment,including how to assess accurately before surgery,whether to undergo preoperative biliary drainage,the extent of liver resection,the extent of lymph node dissection,whether venous involvement should be resected and constructed,whether liver transplantation is useful to these tumors,operation scope of early gallbladder carcinoma.

Clinical efficacy of GEMOX regimen combined with targeted therapy for advanced gallbladder cancer / 中华消化外科杂志

Objective To evaluate the clinical efficacy of gemcitabine-oxaliplatin (GEMOX) regimen combined with targeted therapy for advanced gallbladder cancer.Methods The retrospective descriptive study was conducted.The clinical data of 21 patients with advanced gallbladder cancer who were admitted to the Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine between January 2016 and December 2017 were collected,including 8 males and 13 females,aged from 28 to 80 years,with the age of (58± 12)years.Patients received GEMOX regimen combined with targeted therapy.According to the results of gene test,patients selected tageted therapy with Cetuximab,Herceptin or Apatinib.Observation indicators:(1) gene test situations;(2) situations of GEMOX regimen combined with targeted therapy;(3) adverse reactions of GEMOX regimen combined with targeted therapy.Measurement data with normal distribution were represented as Mean±SD,and measurement data with skewed distribution were described as M (range).Count data were represented as absolute number or percentage.The survival curve and rate were respectively drawn and calculated using the Kaplan-Meier method.The survival analysis was done using the Log-rank test.Results (1) Gene test situations:of 21 patients,19 were confirmed as K-ras wild type,including 13 of single K-ras wild type,4 of K-ras wild type combined with human epidermal growth factor receptor 2 (HER2),2 of K-ras wild type combined with vascular endothelial growth factor receptor 2 (VEGFR2);5 were detected positive HER2,including 1 of single positive HER2,4 of positive HER2 combined with K-ras wild type;3 were detected positive VEGFR2,including 1 of single positive VEGFR2,2 of positive VEGFR2 combined with K-ras wild type.Two and 19 patients had 0 and l of Eastern Cooperative Oncology Group score.(2) Situations of GEMOX regimen combined with targeted therapy:all the 21 patients underwent ≥ 2 courses of GEMOX regimen combined with targeted therapy.Among the 21 patients,0,4,9 and 8 were respectively detected in the complete remission (CR),partial remission (PR),stable disease (SD) and disease progression (PD).Fourteen patients (13 of single K-ras wild type and 1 of K-ras wild type combined with positive VEGFR2) received GEMOX regimen combined with Cetuximab therapy,including 0 with CR,4 with PR,5 with SD and 5 with PD;5 patients (1 of single positive HER2 and 4 of positive HER2 combined with K-ras wild type) received GEMOX regimen combined with Herceptin therapy,including 0 with CR,0 with PR,2 with SD and 3 with PD;2 patients (1 of single positive VEGFR2 and 1 of positive VEGFR2 combined with K-ras wild type) received GEMOX regimen combined with Apatinib therapy,including 0 with CR,0 with PR,2 with SD and 0 with PD.The objective response rate was 19.0％ (4/21) and disease control rate was 61.9％(13/21) in the 21 patients.The median onset time was 1.8 months in the 21 patients.The 3-,6-and 9-month progression free survival (PFS) rates and median PFS time were respectively 90.5％,71.4％,58.5％ and 10.7 months.The 6-and 12-month overall survival rates were respectively 90.2％ and 58.6％,and median overall survival (OS) time was 15.5 months in the 21 patients.The PFS and OS time were 8.4 months and 10.4 months in the 7 patients combined with jaundice,10.5 months and 14.8 months in the 14 patients without jaundice,with no statistically significant difference (x2 =0.868,0.774,P＞0.05).(3) Adverse reactions of GEMOX regimen combined with targeted therapy:the most common adverse events were skin rash and digestive tract reactions.No serious adverse event occurred during the therapy.All the adverse events were improved after symptomatic treatments.Conclusion GEMOX regimen combined with targeted therapy for advanced gallbladder cancer has good outcomes,less adverse reactions and higher safety.

The research situation and progress in the invasion and metastasis mechanism of intrahepatic cholangiocarcinoma / 中华消化外科杂志

Intrahepatic cholangiocarcinoma (ICC) is the second most common primary hepatic malignancy with an increasing incidence and mortality in recent years.Despite advanced improvements in its diagnosis and therapy,the prognosis for ICC patients remains poor.High heterogeneity and malignant biological behavior are the main factors determining the prognosis of ICC.An in-depth study of the mechanism of ICC invasion and metastasis is expected to help optimizing clinical decision-making.The application of advanced technologies such as next-generation sequencing has enhanced the researchers' understanding of heterogeneity of ICC and characteristics of invasion and metastasis.Studies have found that ICC gene expression abnormalities (gene mutations,fusion gene formation,and abnormalities in gene expression regulatory pathways) and microRNA expression disorders are closely related to ICC cell proliferation,invasion and metastasis.In addition,ICC is usually characterized by a dense desmoplastic stroma,in which cancer-associated myofibroblasts are the major cellular components and play an important role in inducing epithelial-mesenchymal transition,promoting malignant cell invasion and metastasis,and even accelerating ICC progression.

Diagnosis and treatment for unexpected gallbladder carcinoma(a retrospective study of 45 cases) / 中华外科杂志

Objective@#To investigate the rationale for appropriate diagnostic methods and treatment protocols for unexpected gallbladder carcinoma(UGC).@*Methods@#The clinical and pathological data of 45 patients with UGC admitted at Department of General Surgery, Xin Hua Hospital, Shanghai Jiao Tong University School of Medicine,from January 2008 to December 2017 were retrospectively collected and analyzed.There were 11 males(28.9%) and 34 females(71.1%),aged 68 years(range:27 to 68 years).And there were 20 cases who aged above 70 years. Twenty-four cases were diagnosed preoperatively as cholecystolithiasis plus chronic cholecystitis.Ten cases were diagnosed preoperatively as cholecystolithiasis plus actue cholecystitis.Six cases were diagnosed preoperatively as cholecystolithiasis plus choledocholith.Six cases were admitted because of gallbladder polyp and 1 case was admitted because of gallbladder adenomyomatosis.@*Results@#Thirty-four patients with UGC received radical surgery.Among them,11 patients experienced postoperative complication and no posterative mortality occoured during hospital stay.Thirteen patients were diagnosed with T1b UGC, the harvested lymph node of Nx, N0, N1 and N2 was 2, 9, 1 and 1, respectively.In addition, 2 cases were identified to have local-regional tumor recurrence during our rescue radical surgery.The median overall survival time of the patients who did not receive radical surgery was 7 months(range:2-56 months).Nevertheless,the median overall survival time for patients diagnosed with T1, T2 and T3 tumors who received radical surgery, was 41 months(range: 19-82 months), 33.5 months(range: 31-36 months) and 17 months(range: 7-46 months), respectively.@*Conclusions@#For patients with UGC, rescue radical surgery can achieve a better survival time.Furhtermore, our experience proved that rescue radical surgery for UGC is safe and feasible.Therefore,rescue radical surgery should be performed in patients with diagnose with UGC especially those T1b patients.

The new classifications of biliary tract diseases based on actual anatomy / 中华外科杂志

In order to facilitate the treatment strategies for biliary tract injury, hilar cholangiocarcinoma, bile duct tumor thrombus, cholangiocellular carcinoma and bile duct cystic dilatation, many classifications have been made, even more than 10 types for one disease. Each type is represented by numbers or English alphabet, which are not only confusing but also difficult to remember. The Academician Mengchao Wu divided the liver into five sections and four segments base on its anatomy, this classification is very direct and visual, thus had been using till now. In order to overcome those complicated problems, it is considered to develop a new classification based on actual anatomic location similar to that for liver cancer, which is easy to remember and to directly determine the treatment strategy. All kinds of classifications have their own characteristics and advantages and disadvantages. This practical classifications avoid the complexity and may be useful for clinicians.

Reconsideration of pancreatic reconstruction after pancreatoduodenectomy / 中华外科杂志

Pancreatic fistula is one of the most common and serious complications after digestive tract reconstruction.Grade A pancreatic fistula is defined as biochemical fistula only when the drainage fluid amylase level is elevated without affecting clinical decision-making.It is not a true pancreatic fistula, or a real surgical complication.Surgeons should pay more attention to the diagnosis and treatment of B and C pancreatic fistula, and it is more valuable to reduce the occurrence of B and C pancreatic fistula.Pancreatic fistula is not a purely surgical technical problem, but the quality of surgical reconstruction is very important.For pancreatic surgeons, the reconstruction of the pancreatic stump digestive tract after pancreaticoduodenectomy is accompanied by both opportunities and challenges.

Historical review of pancreatico-enteric reconstruction following pancreatoduodenectomy / 中华消化外科杂志

The pancreatico-enteric anastomisis has always been a great concern in pancreatoduodenectomy,even been called "Achilles heel".Pancreatic surgeons are interested in improving the anastomosis technique to prevent the pancreatic fistula rate.More than a hundred of anastomosis techniques were reported,authors reviewed the history of pancreatico-enteric anastomisis and divided it into three historical stages,as well as summarized the characteristics of each stage.At the same time,auhors introduced the most representative anastomotic techniques and conccpts in each period.