Relationship between the GH-IGFs axis and the proliferation of bile duct cancer cell line QBC939 in vitro

BACKGROUND: In recent years, recombined human growth hormone (rhGH) has been increasingly used in patients to help them recover from operation. But GH, as a mitogen, can promote cell renewal and increase malignant transformation. In the current study, we assessed the proliferation of a bile duct cancer cell line (QBC939) in vitro with GH and explored the possible relationship with the axis of GH-IGFs (insulin-like growth factors). METHODS: QBC939 cells in the exponential growth stage were harvested and divided into an experimental group (GH group) and a control group (NS group). The GH group was divided into four sub-groups according to the dose of GH and culture time (50 mu g/L for 2 hours, 50 mu g/L for 24 hours, 100 mu g/L for 2 hours, 100 mu g/L for 24 hours). The NS group was divided into two sub-groups (NS for 2 hours and NS for 24 hours). After 2 or 24 hours, IGF-1 and IGF-2 were detected using the enzyme-linked immunosorbent assay. The QBC939 cells cultured for 24 hours with two GH concentrations were made into single cell suspensions and samples underwent subsequent cell cycle evaluation. Messenger RNA of IGF-1 and IGF-2 receptor (IGF-1RmRNA and IGF-2RmRNA) were tested with the method of in situ hybridization. RESULTS: There was no statistically significant difference between the GH and NS groups after 2 hours of culture (P>0.05). But after 24 hours of culture, GH stimulated cell growth in vitro and also elevated the percentage in S phase and the proliferation index (P<0.05). IGF-1RmRNA and IGF-2RmRNA were expressed in QBC939 in contrast to the blank group. The expression of IGF-1RmRNA increased with the dose of GH, but IGF-2RmRNA did not. CONCLUSION: GH can stimulate QBC939 cell growth and proliferation in vitro and the mechanism is most likely by the GH-IGF-1-IGF-1R axis.

Effect of external beam radiotherapy on patency of uncovered metallic stents in patients with inoperable bile duct cancer

BACKGROUND： Although biliary decompression with metallic stenting is the preferred treatment for inoperable bile duct cancer（BDC）, maintenance of patency is still unsatisfactory.We tried to assess the effectiveness and safety of external beam radiotherapy（EBRT） for prolonging stent patency in patients having uncovered metallic stents.METHOD： We retrospectively reviewed 50 patients who received endoscopic stenting, of whom 18 received EBRT（RT group） and 32 did not（non-RT group）.RESULTS： No difference was found in baseline characteristics between the two groups. Although stent patency was longer in the RT group than that in the non-RT group（140.7±51.3 vs136.4±34.9 days, P=0.94）, the difference was not statistically significant. There were a lower rate of stent occlusion（27.8% vs50.0% of patients, P=0.12） and a longer overall survival（420.1 ±73.2 vs 269.1±41.7 days, P=0.11） in the RT group than in the non-RT group, and the difference again was not statistically significant. The development of adverse reactions did not differ（55.6% vs 53.1% of patients, P=0.91）. There was no serious adverse reaction in both groups（P=0.99）.CONCLUSIONS： EBRT did not significantly improve stent patency in patients with inoperable BDC having uncovered metallic stents. However, EBRT was safe. Future trials withrefined protocols for better efficacy are expected.

Diagnostic accuracy of administrative database for bile duct cancer by ICD-10 code in a tertiary institute in Korea

Background:Administrative database provides valuable information for large cohort studies,especially when tissue diagnosis is rather difficult such as the diagnosis for bile duct cancer(BDC).The aim of this study was to evaluate the diagnostic accuracy of administrative database for BDC by International Classification of Diseases(ICD)-10 codes in a tertiary institute.Methods:BDC and control groups were collected from 2003 to 2016 at Seoul National University Bundang Hospital.Cases of BDC were identified in the National Health Insurance Service(NHIS)database by ICD 10-code supported by V code.The control group was selected from cases without ICD-10 codes for BDC.A definite or possible diagnosis was defined according to pathologic reports.Medical records,images,and pathology reports were analyzed to evaluate ICD-10 codes for BDC.Sensitivity,specificity,positive predictive value,and negative predictive value for BDC were analyzed according to diagnostic criteria and cancer locations.Results:A total of 1707 patients with BDC and 1707 controls were collected.Among those with BDC,1320(77.3%)were diagnosed by definite criteria.Most(99.4%)of them had adenocarcinoma.Rate of definite diagnosis was the highest for ampulla of Vater(88.9%),followed by that for extrahepatic(84.9%)and intrahepatic(68.3%)BDCs.False positive cases commonly had hepatocellular carcinomas.For overall diagnosis of BDC,sensitivity,specificity,positive predictive value,and negative predictive value were 99.94%,98.33%,98.30%,and 99.94%,respectively.Diagnostic accuracies were similar regardless of diagnostic criteria or tumor locations.Conclusions:Administrative database for BDC collected according to ICD-10 code with V code shows good accuracy.

Current surgical treatment for bile duct cancer

Since extrahepatic bile duct cancer is difficult to diagnose and to cure,a safe and radical surgical strategy is needed.In this review,the modes of infiltration and spread of extrahepatic bile duct cancer and surgical strategy are discussed.Extended hemihepatectomy,with or without pancreatoduodenectomy(PD),plus extrahepatic bile duct resection and regional lymphadenectomy has recently been recognized as the standard curative treatment for hilar bile duct cancer.On the other hand,PD is the choice of treatment for middle and distal bile duct cancer.Major hepatectomy concomitant with PD(hepatopancreatoduodenectomy)has been applied to selected patients with widespread tumors.Preoperative biliary drainage(BD)followed by portal vein embolization(PVE)enables major hepatectomy in patients with hilar bile duct cancer without mortality.BD should be performed considering the surgical procedure,especially,in patients with separated intrahepatic bile ducts caused by hilar bile duct cancer.Right or left trisectoriectomy are indicated according to the tumor spread and biliary anatomy.As a result,extended radical resection offers a chance for cure of hilar bile duct cancer with improved resectability,curability,and a 5-year survival rate of 40%.A 5-year survival rate has ranged from 24% to 39% after PD for middle and distal bile duct cancer.

Effect of preoperative biliary drainage on surgical results after pancreaticoduodenectomy in patients with distal common bile duct cancer:Focused on the rate of decrease in serum bilirubin

AIM: To examine if the rate of decrease in serum bilirubin after preoperative biliary drainagecan be used as a predicting factor for surgical complications and postoperative recovery after pancreaticoduodenectomy in patients with distal common bile duct cancer.METHODS: A retrospective study was performed in 49 consecutive patients who underwent pancrea-ticoduodenectomy for distal common bile duct cancer. Potential risk factors were compared between the complicated and uncomplicated groups. Also, the rates of decrease in serum bilirubin were compared pre- and postoperatively. RESULTS: Preoperative biliary drainage (PBD) was performed in 40 patients (81.6%). Postoperative morbidity and mortality rates were 46.9% (23/49) and 6.1% (3/49), respectively. The presence or absence of PBD was not different between the complicated and uncomplicated groups. In patients with PBD, neither the absolute level nor the rate of decrease in serum bilirubin was significantly different. Patients with rapid decrease preoperatively showed faster decrease during the first postoperative week (5.5 ± 4.4 μmol/L vs -1.7 ± 9.9 μmol/L, P = 0.004).CONCLUSION: PBD does not affect the surgical outcome of pancreaticoduodenectomy in patients with distal common bile duct cancer. There is a certain group of patients with a compromised hepatic excretory function, which is represented by the slow rate of decrease in serum bilirubin after PBD.

Early bile duct cancer

Bile duct cancers are frequently diagnosed as advanced diseases. Over half of patients with advanced bile duct cancer present with unresectable malignancies and their prognosis has been very poor even after curative resections. Although there has been a need to diagnose bile duct cancer at its early stage, it has been a diffi cult goal to achieve due to our lack of knowledge regarding this disease entity. Early bile duct cancer may be defi ned as a carcinoma whose invasion is confined within the fibromuscular layer of the extrahepatic bile duct or intrahepatic large bile duct without distant metastasis irrespective of lymph node involvement. Approximately 3%-10% of resected bile duct cancers have been reported to be early cancers in the literature. The clinicopathological features of patients with early bile duct cancer differ from those of patients with advanced bile duct cancer, with more frequent asymptomatic presentation, characteristic histopathological findings, and excellent prognosis. This manuscript is organized to emphasize the need for convening an international consensus to develop the concept of early bile duct cancer.

Prognostic factors in patients with middle and distal bile duct cancers

AIM:To identify the influence of the surgery type and prognostic factors in middle and distal bile duct cancers.METHODS:Between August 1990 and June 2011,data regarding the clinicopathological factors of 194patients with surgical and pathological confirmation were collected.A total of 133 patients underwent resections(R0,R1,R2;n=102,24,7),whereas 61patients underwent nonresectional surgery.Either pancreaticoduodenectomy(PD)or bile duct resection(BDR)was selected according to the sites of tumors and comorbidities of the patients after confirming resectionmargin by the frozen histology in all cases.Univariate and multivariate analyses of clinicopathologic factors were performed,utilizing the Kaplan-Meyer method and Cox hazard regression analysis.RESULTS:The overall 5-year survival rate for the 133patients who underwent resection(R0,R1,and R2)was 41.2%,whereas no patients survived longer than3 years among the 61 patient who underwent nonresectional surgeries.The 5-year survival rate of the patients who underwent a PD(n=90)was higher than the rate of those who underwent BDR(n=43),although the difference was not statistically significant(46.6%vs 30.0%P=0.105).However,PD had a higher rate of R0 resection than BDR(90.0%vs 48.8%,P<0.0001).If R0 resection was achieved,PD and BDR showed similar survival rates(49.4%vs 46.5%P=0.762).The 5-year survival rates of R0 and R1 resections were not significantly different(49.0%vs 21.0%P=0.132),but R2 resections had lower survival(0%,P=0.0001).Although positive lymph node,presence of perineural invasion,presence of lymphovascular invasion(LVI),7th AJCC-UICC tumor node metastasis(TNM)stage,and involvement of resection margin were significant prognostic factors in univariate analysis,multivariate analysis identified only TNM stage and LVI as independent prognostic factors.CONCLUSION:PD had a greater likelihood of curative resection and R1 resection might have some positive impact.The TNM stage and LVI were independent prognostic factors.

CD24 expression predicts distant metastasis in extrahepatic bile duct cancer

AIM: To evaluate the prognostic significance of CD24 expression in patients undergoing adjuvant chemoradiotherapy for extrahepatic bile duct (EHBD) cancer. METHODS: Eighty-four patients with EHBD cancer who underwent curative resection followed by adjuvant chemoradiotherapy were enrolled in this study. Postoperative radiotherapy was delivered to the tumor bed and regional lymph nodes up to a median of 40 Gy (range: 40-56 Gy). All patients also received fluoropyrimidine chemotherapy for radiosensitization during radiotherapy. CD24 expression was assessed with immunohistochemical staining on tissue microarray. Clinicopathologic factors as well as CD24 expression were evaluated in multivariate analysis for clinical outcomes including loco-regional recurrence, distant metastasisfree and overall survival. RESULTS: CD24 was expressed in 36 patients (42.9%). CD24 expression was associated with distant metastasis, but not with loco-regional recurrence nor with overall survival. The 5-year distant metastasis-free survival rates were 55.1% and 29.0% in patients with negative and positive expression, respectively (P=0.0100). On multivariate analysis incorporating N stage, histologic differentiation and CD24 expression, N stage was the only significant factor predicting distant metastasis-free survival (P=0.0089), while CD24 expression had borderline significance (P=0.0733). In subgroup analysis, CD24 expression was significantly associated with 5-year distant metastasis-free survival in node-positive patients (38.4% with negative expression vs 0% with positive expression, P=0.0110), but not in nodenegative patients (62.0% with negative expression vs 64.0% with positive expression,P=0.8599). CONCLUSION: CD24 expression was a significant predictor of distant metastasis for patients undergoing curative resection followed by adjuvant chemoradiotherapy especially for node-positive EHBD cancer.

Metachronous bile duct cancer nine years after resection of gallbladder cancer

We report a rare case of a 74-year-old man with metachronous gallbladder cancer and bile duct cancer who underwent curative resection twice, with the operations nine years apart. At the age of 65 years, the patient underwent a cholecystectomy and resection of the liver bed for gallbladder cancer. This was a well-differentiated adenocarcinoma, with negative resection margins (T2N0M0, stageB). Nine years later,during a follow-up examination, abdominal computed tomography and MRCP showed an enhanced 1.7 cm mass in the hilum that extended to the second branch of the right intrahepatic bile duct. We diagnosed thislesion as a perihilar bile duct cancer, Bismuth type.

Diagnostic-therapeutic management of bile duct cancer

Biliary tract cancer, or cholangiocarcinoma, comprises a heterogeneous group of malignant tumors that can emerge at any part of the biliary tree. This group is the second most common type of primary liver cancer. Diagnosis is usually based on symptoms, which may be heterogeneous, and nonspecific biomarkers in serum and biopsy specimens, as well as on imaging techniques. Endoscopy-based diagnosis is essential, since it enables biopsy specimens to be taken. In addition, it can help with locoregional staging of distal tumors. Endoscopic retrograde cholangiopancreatography is a key technique for the evaluation and treatment of malignant biliary tumors. Correct staging of cholangiocarcinoma is essential in order to be able to determine the degree of resectability and assess the results of treatment. The tumor is staged based on the TNM classification of the American Joint Committee on Cancer. The approach will depend on the classification of the tumor. Thus, some patients with early-stage disease could benefit from surgery;complete surgical resection is the cornerstone of cure. However, only a minority of patients are diagnosed in the early stages and are suitable candidates for resection. In the subset of patients diagnosed with locally advanced or metastatic disease, chemotherapy has been used to improve outcome and to delay tumor progression. The approach to biliary tract tumors should be multidisciplinary, involving experienced endoscopists, oncologists, radiologists, and surgeons.

Radiation therapy for extrahepatic bile duct cancer: Current evidences and future perspectives

Extrahepatic bile duct cancer (EBDC) is a rare malignancy that involves neoplastic changes extending from both hepatic ducts to the common bile duct. The treatment of choice is surgical resection, but the predominant pattern of initial treatment failure is locoregional recurrence. Accordingly, adjuvant radiotherapy has been administered after surgical resection based on these rationales. At this time, there is minimal evidence supporting adjuvant radiotherapy, because there have been no phase III trials evaluating its benefit. Relatively small retrospective studies have tried to compare outcomes associated with EBDC treated with or without radiotherapy. We aimed to review studies investigating adjuvant radiotherapy for resected EBDC. Because less than onethird of EBDC cases are amenable to curative resection at diagnosis, other locoregional treatment modalities need to be considered, including radiotherapy. The next aim of this review was to summarize reports of definitive radiotherapy for unresectable EBDC. Patients with advanced EBDC often experience biliary obstruction, which can lead to jaundice and progress to death. Biliary stent insertion is an important palliative procedure, but stents are prone to occlusion after subsequent ingrowth of the EBDC. Radiotherapy can be effective for maintaining the patency of inserted stents. We also reviewed the benefit of palliative radiotherapy combined with the biliary stent insertion. Lastly, we discuss the existing gaps in the evidence supporting radiotherapy in the management of EBDC.

Synchronous double cancers of the common bile duct

We report an extremely rare case of synchronous double cancers of the common bile duct without pancreaticobiliary maljunction.Only two similar cases have been reported in the English literature.Endoscopic retrograde cholangiopancreatography showed a tuberous filling defect in the middle and superior parts of the common bile duct,and mild stenosis in the inferior duct.Computed tomography(CT) showed a well enhanced mass in the middle and superior parts of the common bile duct.A single cancer of the middle and superior bile duct was suspected and extra-hepatic bile duct resection was performed.CT eleven months after surgery revealed enhanced inferior bile duct wall and a slightly enhanced tumor within it.Retrospective review of the CT images taken before first surgery showed enhanced inferior bile duct wall without intrabiliary tumor only on the delayed phase.The inferior bile duct tumor was suspected to have originally co-existed with the middle and superior bile duct tumor.Pancreaticoduodenectomy was performed subsequently.Histopathological examination revealed that the middle and superior bile duct tumor was a moderately differentiated tubular adenocarcinoma while the inferior bile duct tumor was a papillary adenocarcinoma.The two tumors were separated and had different histological findings and growth patterns,further suggesting that they were two primary cancers.

Intraductal endoscopic radiofrequency ablation for the treatment of hilar non-resectable malignant bile duct obstruction

AIM: To evaluate the safety and technical success of endoscopic radiofrequency ablation(RFA) for palliative treatment of malignant hilar bile duct obstruction. METHODS: In this study, a recently CE and FDA-approved endoscopic RFA catheter was first tested in an ex vivo pig liver model to study the effect of electrosurgical variables on the extent of the area of induced necrosis. Subsequently, a retrospective analysis was conducted of all patients treated with endoscopic RFA for malignant biliary obstruction at our center between February 2012 and April 2013. All patients received an additional plastic stent implantation into the biliary tree following RFA. RESULTS: In the pig model, ablation time of 60-90 seconds using the bipolar soft coagulation mode at 8-10 watts with an effect of 8 was found to be the most feasible setting. Twelve patients(5 females, 7 males; mean age, 70 years) underwent 19 endoscopic RFA(range, 1-5) sessions. Deployment of RFA was successful in all patients. Systemic chemotherapy was administered in four patients. We observed biliary bleeding 4-6 wk after the intervention in three cases and two of these patients died: in one patient, spontaneous hemobilia occurred, whereas bleeding started during stent extraction in the other. In the third patient, bleeding was stopped by insertion of a non-covered self-expanding metal stent. Another three patients developed cholangitis during follow-up. Seven patients died during follow-up and median survival was 6.4 mo(95%CI: 0.05-12.7) from the time of the first RFA. CONCLUSION: Endoscopic RFA is an easy to perform and technically highly successful procedure. However, hemobilia possibly associated with RFA occurred in three of our patients. Therefore, larger prospective studies are needed to further evaluate the safety and efficacy of this promising new method.

Carcinoma of the middle bile duct:Is bile duct segmental resection appropriate?

AIM:To compare survival between bile duct segmental resection(BDSR)and pancreaticoduodenectomy(PD) for treating distal bile duct cancers. METHODS:Retrospective analysis was conducted for 45 patients in a BDSR group and for 149 patients in a PD group. RESULTS:The T-stage(P<0.001),lymph node invasion (P=0.010)and tumor differentiation(P=0.005)were significant prognostic factors in the BDSR group.The 3-and 5-year overall survival rates for the BDSR group and PD group were 51.7%and 36.6%,respectively and 46.0%and 38.1%,respectively(P=0.099).The BDSR group and PD group did not show any significant difference in survival when this was adjusted for the TNM stage.The 3-and 5-year survival rates were: stageⅠa[BDSR(100.0%and 100.0%)vs PD(76.9% and 68.4%)(P=0.226)];stageⅠb[BDSR(55.8% and 32.6%)vs PD(59.3%and 59.3%)(P=0.942)]; stageⅡb[BDSR(19.2%and 19.2%)vs PD(31.9%and 14.2%)(P=0.669)]. CONCLUSION:BDSR can be justified as an alternative radical operation for patients with middle bile duct inselected patients with no adjacent organ invasion and resection margin is negative.

Intraoperative frozen section diagnosis of bile duct margin for extrahepatic cholangiocarcinoma

AIM To evaluate the usefulness of frozen section diagnosis(FSD) of bile duct margins during surgery for extrahepatic cholangiocarcinoma(CCA). METHODS We retrospectively analyzed 74 consecutive patients who underwent surgery for extrahepatic CCA from 2012 to 2017, during which FSD of bile duct margins was performed. They consisted of 40 distant and 34 perihilar CCAs(45 and 55 bile duct margins, respectively). The diagnosis was classified into three categories: negative, borderline(biliary intraepithelial neoplasia-1 and 2, and indefinite for neoplasia), or positive. FSD in the epithelial layer, subepithelial layer, and total layer was compared with corresponding permanent section diagnosis(PSD) postoperatively.Then, association between FSD and local recurrence was analyzed with special reference to borderline.RESULTS Analysis of 100 duct margins revealed that concordance rate between FSD and PSD was 68.0% in the total layer, 69.0% in the epithelial layer, and 98.0% in the subepithelial layer. The extent of remaining biliary epithelium was comparable between FSD and PSD, and more than half of the margins lost > 50% of the entire epithelium, suggesting low quality of the samples. In FSD, the rate of negative margins decreased and that of borderline and positive margins increased according to the extent of the remaining epithelium. Diagnostic discordance between FSD and PSD was observed in 31 epithelial layers and two subepithelial layers. Alteration from borderline to negative was the most frequent(20 of the 31 epithelial layers). Patients with positive margin in the total and epithelial layers by FSD demonstrated a significantly worse local recurrence-free survival(RFS) compared with patients with borderline and negative margins, which revealed comparable local RFS. Patients with borderline and negative margins in the epithelial layer by PSD also revealed comparable local RFS. These results suggested that epithelial borderline might be regarded substantially as negative. When classifying the status of the epithelial layer either as negative or positive, concordance rates between FSD and PSD in the total, epithelial, and subepithelial layers were 95.0%, 93.0%, and 98.0%, respectively.CONCLUSION During intraoperative assessment of bile duct margin, borderline in the epithelial layer can be substantially regarded as negative, under which condition FSD is comparable to PSD.

Classifying extrahepatic bile duct metachronous carcinoma by de novo neoplasia site

Extrahepatic bile duct(EHBD)cancer may occur metachronously,and these cancers are resectable with a favorable prognosis.We aimed to identify the pattern of metachronous EHBD cancer.We classified the cases of metachronous EHBD cancer reported in the literature thus far and investigated two new cases of metachronous EHBD cancer.A 70-year-old female underwent R0 bile duct resection for a type 1 Klatskin tumor(pT-1N0M0).A 70-year-old male patient underwent R0 bile duct resection for a middle bile duct cancer(pT2N1M0).Imaging studies of both patients taken at 14 and 24mo after first surgery respectively revealed a metachronous cholangiocarcinoma that required pancreaticoduodenectomy(PD).Histopathology of the both tumors after PD revealed cholangiocarcinoma invading the pancreas(pT3N0M0).Both patients have been free from recurrence for 6 years and 16 mo respectively after the second surgery.Through a review of the literature on these cases,we classified the pattern of metachronous EHBD cancer according to the site of de novo neoplasia.The proximal remnant bile duct was most commonly involved.Metachronous EHBD cancer should be distinguished from an unresectable recurrent tumor.Classifying metachronous EHBD cancer may be helpful in identifying rare metachronous tumors.

Outcomes of liver resection in hepatitis C virus-related intrahepatic cholangiocarcinoma:A systematic review and meta-analysis

BACKGROUND Cholangiocarcinoma is the second most common primary liver malignancy.Its incidence and mortality rates have been increasing in recent years.Hepatitis C virus(HCV)infection is a risk factor for development of cirrhosis and cholan-giocarcinoma.Currently,surgical resection remains the only curative treatment option for cholangiocarcinoma.We aim to study the impact of HCV infection on outcomes of liver resection(LR)in intrahepatic cholangiocarcinoma(ICC).AIM To study the outcomes of curative resection of ICC in patients with HCV(i.e.,HCV+)compared to patients without HCV(i.e.,HCV-).METHODS We conducted a systematic review and meta-analysis of randomized controlled trials(RCTs)and observational studies to assess the outcomes of LR in ICC in HCV+patients compared to HCV-patients in tertiary care hospitals.PubMed,EMBASE,The Cochrane Library and Scopus were systematically searched from inception till August 2023.Included studies were RCTs and non-RCTs on patients≥18 years old with a diagnosis of ICC who underwent LR,and compared outcomes between patients with HCV+vs HCV-.The primary outcomes were overall survival(OS)and recurrence-free survival.Secondary outcomes include perioperative mortality,operation duration,blood loss,intrahepatic and extrahepatic recurrence.RESULTS Seven articles,published between 2004 and 2021,fulfilled the selection criteria.All of the studies were retrospective studies.Age,incidence of male patients,albumin,bilirubin,platelets,tumor size,incidence of multiple tumors,vascular invasion,bile duct invasion,lymph node metastases,and stage 4 disease were comparable between HCV+and HCV-group.Alanine transaminase[MD 22.20,95%confidence interval(CI):13.75,30.65,P<0.00001]and aspartate transaminase levels(MD 27.27,95%CI:20.20,34.34,P<0.00001)were significantly higher in HCV+group compared to HCV-group.Incidence of cirrhosis was significantly higher in HCV+group[odds ratio(OR)5.78,95%CI:1.38,24.14,P=0.02]compared to HCV-group.Incidence of poorly differentiated disease was significantly higher in HCV+group(OR 2.55,95%CI:1.34,4.82,P=0.004)compared to HCV-group.Incidence of simultaneous hepatocellular carcinoma lesions was significantly higher in HCV+group(OR 8.31,95%CI:2.36,29.26,P=0.001)compared to HCV-group.OS was significantly worse in the HCV+group(hazard ratio 2.05,95%CI:1.46,2.88,P<0.0001)compared to HCV-group.CONCLUSION This meta-analysis demonstrated significantly worse OS in HCV+patients with ICC who underwent curative resection compared to HCV-patients.

基于关键免疫细胞亚群的胆管癌患者外周血早期诊断标志物的研究

目的基于关键免疫细胞亚群探究胆管癌患者外周血早期诊断标志物。方法于2021年5月至2023年5月选取在本院确诊为CCA的患者75例即为CCA组,同期在本院收治的75例胆管炎患者即为对照组。同期在本院体检健康的志愿者75例为健康组。采用流式细胞仪检测CD3^(+)、CD4^(+)、CD8^(+)、CD4^(+)/CD8^(+)水平;采用酶联免疫吸附试验(ELISA)法检测肿瘤坏死因子(TNF-α)、白细胞介素-2(IL-2)、γ干扰素(IFN-γ)水平。采用Pearson法分析CCA患者CD3^(+)、CD4^(+)、CD4^(+)/CD8^(+)水平与TNF-α、IL-2、IFN-γ水平的相关性;ROC曲线分析外周血免疫细胞亚群对CCA发生的诊断价值。多因素Logistic回归分析CCA发生的影响因素。结果与健康组相比,对照组、CCA组患者CD3^(+)、CD4^(+)、CD4^(+)/CD8^(+)水平显著升高;与对照组相比,CCA组患者CD3^(+)、CD4^(+)、CD4^(+)/CD8^(+)水平显著升高(P<0.05)。与健康组相比,对照组、CCA组患者IL-2、IFN-γ水平显著降低,TNF-α水平显著升高;与对照组相比,CCA组患者IL-2、IFN-γ水平显著降低,TNF-α水平显著升高(P<0.05)。相关性分析显示,CCA患者CD3^(+)、CD4^(+)、CD4^(+)/CD8^(+)水平与IL-2、IFN-γ呈负相关关系,与TNF-α呈正相关关系(P<0.05)。外周血免疫细胞亚群(CD3^(+)、CD4^(+)、CD4^(+)/CD8^(+)、TNF-α、IL-2、IFN-γ)联合检测对CCA发生诊断的AUC显著高于单一指标诊断的AUC的值(Z_(CD3^(+)vs联合)=4.424,P<0.001;Z_(CD4^(+)vs联合)=3.425,P=0.001;Z_(CD4^(+)/CD8^(+)vs联合)=4.502,P<0.001;Z_(TNF-αvs联合)=3.322,P<0.001;Z_(IL-2^(+)vs联合)=7.473,P=0.001;Z_(IFN-γ^(+)vs联合)=3.166,P=0.001)。多因素Logistic回归分析显示,CD3^(+)、CD4^(+)、CD4^(+)/CD8^(+)、IL-2、IFN-γ水平是影响CCA发生的影响因素(P<0.05)。结论CCA患者外周血免疫细胞亚群水平显著升高,联合检测能够提高对CCA发生的诊断效能。

Cytotoxic effects of Thai noni juice product ethanolic extracts against cholangiocarcinoma cell lines

Objective:To investigate the cytotoxic activity and molecular mechanism(s)of two Thai noni juice(TNJ)products ethanolic extracts against cholangiocarcinoma(CCA)cell lines and non-cancerous cells,and to explore phenolic acid compositions of TNJ products.Methods:Phenolic acid profiles of TNJ Chiangrai(TNJ-Cr)and TNJ Buasri(TNJ-Bs)ethanolic extracts were determined by HPLC.The cytotoxicity of TNJ ethanolic extracts on cancer and non-cancerous cells was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide and trypan blue assays.Mechanism(s)underlying the anti-CCA activity of TNJ ethanolic extracts were determined by cell cycle,apoptosis,and reactive oxygen species(ROS)generation assays.The expression levels of proteins involved in apoptosis and ERK signaling were evaluated by Western blot analysis.Results:Phenolic acid profiles of both TNJ ethanolic extracts showed that the p-hydroxybenzoic,vanillic,and protocatechuic acids were the major phenolic acids in TNJ products.Cytotoxicity assays revealed that the TNJ-Cr and TNJ-Bs ethanolic extracts reduced viability of CCA cell lines through induction of apoptosis by up-regulation of p53 and Bax proapoptotic proteins.Both TNJ ethanolic extracts promoted ROS generation by activating the ERK1/2 signaling in well-differentiated CCA cells KKU-213B.Meanwhile,TNJ ethanolic extracts did not induce ROS production in poorly differentiated CCA cells KKU-100.Both TNJ ethanolic extracts showed no toxicity to human peripheral blood mononuclear cells.Conclusions:TNJ ethanolic extracts could inhibit CCA cell proliferation by inducing ROS generation and apoptosis and may be applicable for combination therapies in CCA treatment.

Circulating tumour DNA in gastrointestinal cancer in clinical practice:Just a dream or maybe not?

The evaluation of circulating tumor DNA(ctDNA)is increasingly integrated into the management of diagnosis and treatment of gastrointestinal cancer as it represents an innovative and minimally invasive biomarker that could allow us to reach clinical needs not met yet in randomized clinical trials.Recent research provided an interesting overview of the role of circulating tumor DNA in gastric,biliary,liver,pancreatic,and colorectal cancer.Data regarding upper gastrointestinal tumors are currently not practice changing.Tumor detection rates are low in the early stages,while in advanced stages ctDNA is useful for molecular tracking evaluation.Most of the evidence comes from colorectal cancer studies,where ctDNA was evaluated both in the early and advanced stages with the postsurgery minimal residual disease assessment and the response assessment,respectively.ctDNA qualifies as a promising tool in the era of precision medicine,with potential applications in the entire management of gastrointestinal cancer patients.Further evidence is needed to establish which setting may be influenced greatly by liquid biopsy in clinical practice.