Longitudinal surveillance of three biomarkers to predict recurrence of hepatocellular carcinoma after radical resection.

BACKGROUND: Radical resection is a curative treatment for patients with hepatocellular carcinoma (HCC), but the incidence of recurrence remains high. We aimed to explore the performance of predicting HCC recurrence by longitudinal surveillance of the protein induced by vitamin K absence (PIVKA-II), alpha- fetoprotein (AFP), and lectin-reactive AFP (AFP-L3) during postoperative follow-up. METHODS: Patients who underwent radical resection for HCC at the Ningbo Medical Centre Lihuili Hospital between January 2015 and December 2020 were included. All enrolled patients regularly monitor PIVKA-II, AFP, AFP-L3 every 3 months during postoperative follow-up. The surveillance performance of PIVKA-II, AFP, AFP-L3 during follow-up for the prediction of HCC recurrence was compared in patients. The generalized estimation equation (GEE) was used to analyze the trends of the tumor biomarkers and interactions with time. Area under the receiver operator characteristic (AUROC) curves, the optimal cut-off value, the sensitivity and specificity were calculated to evaluate the performance of the three biomarkers. The recurrence-free survival (RFS) and overall survival (OS) of patients with any of the elevated biomarkers was analyzed by Kaplan-Meier curves and the log-rank test. Multivariate logistic regression models were used to analyze potential risk factors for recurrence. RESULTS: The GEE analysis indicated that PIVKA-II, AFP, AFP-L3 in the recurrence patients were higher than the no recurrence patients during follow-up, PIVKA-II and AFP showed increasing trends from 6 months before recurrence. In predicting recurrence, the AUROCs for PIVKA-II, AFP, AFP-L3 and their combination were 0.885, 0.754, 0.781 and 0.885 respectively, the optimal cut-off value for PIVKA-II, AFP, AFP-L3 was 29.5 mAU/ml, 10.7 ng/L, 1.5% respectively. The sensitivity in predicting recurrence for PIVKA-II, AFP, AFP-L3 and combination were 75.0, 54.7, 57.8 and 79.7% respectively. The RFS and the OS of patients with any of the biomarkers elevated during the follow-up was significantly shorter than that without elevated biomarkers ( P  < 0.001). Multivariate analysis showed that any of the biomarkers elevated was the independent risk factor of recurrence. CONCLUSION: Longitudinal surveillance of PIVKA-II, AFP and AFP-L3 can effectively predict recurrence of HCC after operation.

MTM-HCC at Previous Liver Resection as a Predictor of Overall Survival in Salvage Liver Transplantation.

OBJECTIVES: Salvage liver transplantation (sLT) is considered an effective method to treat hepatocellular carcinoma (HCC) recurrence. This multicenter research aimed to identify the prognostic factors associated with recurrence-free survival (RFS) and overall survival (OS) after sLT. MATERIAL AND METHODS: A retrospective analysis of 114 patients who had undergone sLT for recurrent HCC between February 2012 and September 2020 was performed. The baseline and clinicopathological data of the patients were collected. RESULTS: The 1-, 3-, and 5-year RFS rates after sLT were 88.9%, 75.2%, and 69.2%, respectively, and the OS rates were 96.4%, 78.3%, and 70.8%. A time from liver resection (LR) to recurrence < 1 year, disease beyond the Milan criteria at sLT and macrotrabecular massive (MTM)-HCC were identified as risk factors for RFS and were further identified as independent risk factors. A time from LR to recurrence < 1 year, disease beyond the Milan criteria at sLT and MTM-HCC were also risk factors for OS and were further identified as independent risk factors. CONCLUSIONS: Compared with primary liver transplantation (pLT), more prognostic factors are available from patients who had undergone LR. We suggest that in cases of HCC recurrence within 1 year after LR, disease beyond the Milan criteria at sLT and MTM-HCC patients, sLT should be used with caution.

Predictive Value of the TP53 p.G245S Mutation Frequency for the Short-Term Recurrence of Hepatocellular Carcinoma as Detected by Pyrophosphate Sequencing.

Aims: We explored the relationship between the mutation at the p.G245S site in TP53 and the short-term recurrence of hepatocellular carcinoma (HCC). Materials and Methods: 101 HCC patients were included in this study. The TP53 p.G245S mutation frequency spectrum was examined by direct sequencing of genomic DNA from tissue specimens of HCC patients. Univariate and multivariate Cox regression analyses were performed to evaluate the independent prognostic factors of tumor recurrence. ROC curve analysis was applied to determine the cut-off value for the p.G245S mutation frequency and to verify the predictive ability of the Cox model compared with single risk factor indices. Results: A multivariate Cox regression analysis showed that TP53 p.G245S mutation frequency (HR = 1.231, 95% CI: 1.006-1.505, p = 0.043), AFP (HR = 2.432, 95% CI: 1.297-4.561, p = 0.006), MTM (HR = 2.656, 95% CI: 0.930-7.583, p = 0.068), and PVTT (HR = 14.297, 95% CI: 3.085-66.243, p = 0.001) were independent prognostic factors for short-term recurrence. The cut-off value for the TP53 p.G245S mutation frequency (18.5%) was determined by ROC analysis. A predictive model integrating the TP53 p.G245S mutation frequency with PVTT, MTM, and AFP values appears to an excellent predictive indicator of short-term recurrence in HCC patients (AUC = 0.849, 95% CI = 0.748-0.950, p = 0.000001). Survival analysis indicated that the probability of short-term recurrence-free survival was significantly different among different TP53 p.G245S mutation frequency, MTM, PVTT, and AFP risk groups (p < 0.05). Conclusion: The mutation frequency of the p.G245S site is a novel prognostic risk factor for the short-term recurrence of HCC.

Efficacy and safety of sirolimus early conversion protocol in liver transplant patients with hepatocellular carcinoma: A single-arm, multicenter, prospective study.

Mammalian target of rapamycin (mTOR) inhibitor as an attractive drug target with promising antitumor effects has been widely investigated. High quality clinical trial has been conducted in liver transplant (LT) recipients in Western countries. However, the pertinent studies in Eastern world are paucity. Therefore, we designed a clinical trial to test whether sirolimus can improve recurrence-free survival (RFS) in hepatocellular carcinoma (HCC) patients beyond the Milan criteria after LT. This is an open-labeled, single-arm, prospective, multicenter, and real-world study aiming to evaluate the clinical outcomes of early switch to sirolimus-based regimens in HCC patients after LT. Patients with a histologically proven HCC and beyond the Milan criteria will be enrolled. The initial immunosuppressant regimens are center-specific for the first 4-6 weeks. The following regimens integrated sirolimus into the regimens as a combination therapy with reduced calcineurin inhibitors based on the condition of patients and centers. The study is planned for 4 years in total with a 2-year enrollment period and a 2-year follow-up. We predict that sirolimus conversion regimen will provide survival benefits for patients particular in the key indicator RFS as well as better quality of life. If the trial is conducted successfully, we will have a continued monitoring over a longer follow-up time to estimate indicator of overall survival. We hope that the outcome will provide better evidence for clinical decision-making and revising treatment guidelines based on Chinese population data. Trial register: Trial registered at http://www.chictr.org.cn: ChiCTR2100042869.

Comparison of the short-term outcomes of open and laparoscopic hepatectomy in the treatment of recurrent hepatocellular carcinoma: a single-center retrospective study.

Background: To retrospectively analyze the short-term outcomes between open hepatectomy (OH) and laparoscopic hepatectomy (LH) in the treatment of recurrent hepatocellular carcinoma (HCC). The objective is to develop the optimal surgical method for patients with recurrent liver cancer after operation. Methods: We retrospectively reviewed the data of 165 HCC patients whose cancer recurred after hepatectomy between January 2015 and March 2021 at our medical center. According to the inclusion and exclusion criteria, a total of 74 patients were eventually enrolled in this study. Results: Tumors located in S1, S7, or S8 and larger tumor diameters were more frequent in the OH group, and the difference was statistically significant. Furthermore, there were notable differences between the LH and OH groups in terms of intraoperative blood loss (140.00 vs. 348.68 mL, P<0.001), mean operation time (150.95 vs. 203.28 min, P=0.024), and mean postoperative hospital stay (6.76 vs. 11.28 days, P=0.014). There were no statistically significant differences in the remaining characteristics between the two groups. There was no significant difference in recurrence-free survival and overall survival between the two groups. Conclusions: Compared with OH, LH can significantly reduce the amount of intraoperative blood loss and shorten the operation time and postoperative hospital stay. At the same time, laparoscopic surgery may be a better surgical approach for patients with tumors of smaller diameter located in segments 2 to 6.

Surgical Treatment of Postoperative Abdominal Metastases of Hepatocellular Carcinoma: 10-Year Experience in a Single Center.

OBJECTIVE: The significance of surgical treatment was analyzed by retrospectively collecting data on the re-resection of intra-abdominal metastases after hepatocellular carcinoma (HCC) surgery in our center over the past 10 years. METHODS: The clinical and pathological data of 15 patients who developed intra-abdominal metastases after HCC resection and underwent re-resection from January 2010 to January 2020 were collected to analyze the patients' characteristics and prognosis. RESULTS: Of the 15 cases of abdominal metastasis, the majority (8 cases) had greater omental metastasis. There were 4 cases of mesenteric metastases, 1 case of abdominal wall metastasis, 1 case of mesenteric plus rectal wall metastasis, and 1 case of colon and mesenteric metastasis. The 1-year, 3-year, and 5-year disease-free survival (DFS) rates were 31.1%, 23.3%, and 11.7%, respectively. The 1-year, 3-year, and 5-year overall survival rates were 93.3%, 28.7%, and 19.1%, respectively. Three patients are currently surviving disease-free, with survival times of 130.4 months, 43.3 months, and 9.4 months, respectively. CONCLUSION: Although the current guidelines do not recommend surgical resection as the preferred treatment for postoperative abdominal metastases of HCC, surgical resection is recommended for patients with limited or solitary metastasis in the abdominal cavity.

Laparoscopic versus open radical antegrade modular pancreatosplenectomy for pancreatic cancer: a single-institution comparative study.

BACKGROUND: Laparoscopic distal pancreatosplenectomy is an effective and safe surgical modality for treating benign and borderline distal pancreatic tumors, but rarely for pancreatic cancer. This study aimed to compare the feasibility and safety of laparoscopic and open radical antegrade modular pancreatosplenectomy for pancreatic cancer. METHODS: Fifty-one patients with pancreatic cancer who underwent radical antegrade modular pancreatosplenectomy at Ningbo Medical Center Lihuili Hospital between January 2014 and July 2018 were enrolled. 20 patients underwent laparoscopic radical antegrade modular pancreatosplenectomy and 31 patients received open radical antegrade modular pancreatosplenectomy. Postoperative and short-term outcomes of the two groups of patients were analyzed. RESULTS: The mean operation time, length of postoperative hospital stay, and overall postoperative morbidity were similar in the two groups (P>0.05). The laparoscopic radical antegrade modular pancreatosplenectomy group lost less blood (252.5±198.3 vs. 472.6±428.0 mL, P=0.037) and had lower transfusion rates (10.0% vs. 35.4%, P=0.041) than the open radical antegrade modular pancreatosplenectomy group. The laparoscopic group also had statistically significantly earlier passing of first flatus (2.5±0.8 vs. 3.2±1.2 days, P=0.028) and first oral intake (2.9±1.0 vs. 3.7±1.6 days, P=0.042). Furthermore, the rates of postoperative pancreatic fistula (45.0% vs. 32.3%) and overall complications (70.0% vs. 74.2%) were not statistically difference between the two groups. The survival rates at 6 months, 1 year, and 2 years after surgery were not statistically difference between the laparoscopic and open groups (94.4% vs. 93.5, 67.0% vs. 78.0%, and 50.2% vs. 38.3%, respectively). CONCLUSIONS: The results of this study show that laparoscopic radical antegrade modular pancreatosplenectomy is feasible and safe for the treatment of pancreatic cancer.

Risk Factors for Clinically Relevant Postoperative Pancreatic Fistula (CR-POPF) after Distal Pancreatectomy: A Single Center Retrospective Study.

Objectives: Clinically relevant postoperative pancreatic fistula (CR-POPF) is the considerable contributor to major complications after pancreatectomy. The purpose of this study was to evaluate the potential risk factor contributing to CR-POPF following distal pancreatectomy (DP) and discuss the risk factors of pancreatic fistula in order to interpret the clinical importance. Methods: In this retrospective study, 263 patients who underwent DP at Ningbo Medical Center Li Huili Hospital between January 2011 and January 2020 were reviewed in accordance with relevant guidelines and regulations. Patients' demographics and clinical parameters were evaluated using univariate and multivariate analyses to identify the risk factors contributing to CR-POPF. P < 0.05 was considered statistically significant. Results: In all of the 263 patients with DP, pancreatic fistula was the most common surgical complication (19.0%). The univariate analysis of 18 factors showed that the patients with a malignant tumor, soft pancreas, and patient without ligation of the main pancreatic duct were more likely to develop pancreatic fistula. However, on multivariate analysis, the soft texture of the pancreas (OR = 2.381, 95% CI = 1.271-4.460, P=0.001) and the ligation of the main pancreatic duct (OR = 0.388, 95% CI = 0.207-0.726, P=0.002) were only an independent influencing factor for CR-POPF. Conclusions: As a conclusion, pancreatic fistula was the most common surgical complication after DP. The soft texture of the pancreas and the absence of ligation of the main pancreatic duct can increase the risk of CR-POPF.

Quantitative analysis of three-dimensional reconstruction data to guide the selection of methods for laparoscopic distal pancreatectomy.

BACKGROUND/PURPOSE: To explore the risk factors of splenic vessel preservation in laparoscopic distal pancreatectomy (LDP) and to guide with the appropriate selection of surgical methods through three-dimensional (3D) reconstruction. METHODS: Patients suffering from benign or low-grade malignant tumors of pancreatic body and tail having undergone LDP in Ningbo Medical Center Lihuili Hospital from January 2014 to September 2019 were selected for quantitative analysis of the anatomical data of patients' pancreas, tumors, splenic vessels and spleens by 3D reconstruction. According to the final surgical methods, the patients were divided into the laparoscopic spleen-preserving distal pancreatectomy with splenic vessel preservation (lap-SVP) group and the non-lap-SVP group. Clinical data of the two groups were compared to assess the risk factors for surgical failure of lap-SVP and logistic regression model was applied to predict the choice of surgical methods. RESULTS: A total of 218 patients were included in the study, including 144 in the lap-SVP group and 74 in the non-lap-SVP group. Multivariate analysis confirms that large tumor volume, large contact area between the pancreas to be resected and the splenic vein, and large maximum ratio of the circumference of the splenic vessel embedded in the pancreas to be resected to the circumference of the splenic vessel are independent risk factors for surgical failure of lap-SVP (OR > 1, P < .05). The prediction accuracy of lap-SVP operation by the logistic regression reaches up to 80.9%. CONCLUSIONS: 3D reconstruction can provide essential basis for the surgical method selection of laparoscopic distal pancreatectomy.

Options for the treatment of intrahepatic recurrent hepatocellular carcinoma: Salvage liver transplantation or rehepatectomy?

OBJECTIVE: To explore prognostic factors by comparing the efficacy of salvage liver transplantation (sLT) and rehepatectomy (RH) for the treatment of recurrent hepatocellular carcinoma after hepatectomy. METHODS: Clinical data were collected for 124 patients treated at our center from January 2012 to August 2018. The median follow-up time for the patients was 39 months. By analyzing the clinical data between the sLT group (46 cases) and RH group (78 cases), the factors affecting the prognosis of patients were compared. RESULTS: The proportion of alpha-fetoprotein (AFP) ≥ 100 µg/L in the recurrence group was significantly higher than that in the recurrence-free group (70.0% vs 22.2%, P = .014). The postoperative overall survival (OS) and recurrence-free survival (RFS) were better in the sLT group than in the RH group (81.2% vs 36.9%, P < .01; 77.1% vs 55.6%, P = .019). In the sLT group, the OS and RFS in the AFP < 100 µg/L group were superior to those in the AFP ≥ 100 µg/L group (P = .046 and P = .002). CONCLUSION: The sLT group had achieved better efficacy than RH group, but when AFP ≥ 100 µg/L, sLT did not achieve better efficacy than RH.

DNA damage-induced activation of ATM promotes ß-TRCP-mediated ARID1A ubiquitination and destruction in gastric cancer cells.

BACKGROUND: AT-rich interactive domain-containing protein 1A (ARID1A) is a subunit of the mammary SWI/SNF chromatin remodeling complex and a tumor suppressor protein. The loss of ARID1A been observed in several types of human cancers and associated with poor patient prognosis. Previously, we have reported that ARID1A protein was rapidly ubiquitinated and destructed in gastric cancer cells during DNA damage response. However, the ubiquitin e3 ligase that mediated this process remains unclear. MATERIALS AND METHODS: The interaction between ARID1A and ß-TRCP was verified by co-immunoprecipitation (Co-IP) assay. The degron site of ARID1A protein was analyzed by bioinformatics assay. Short hairpin RNAs (shRNAs) were used to knockdown (KD) gene expression. RESULTS: Here we show that DNA damage promotes ARID1A ubiquitination and subsequent destruction via the ubiquitin E3 ligase complex SCFß-TRCP. ß-TRCP recognizes ARID1A through a canonical degron site (DSGXXS) after its phosphorylation in response to DNA damage. Notably, genetic inactivation of the Ataxia Telangiectasia Mutated (ATM) kinase impaired DNA damage-induced ARID1A destruction. CONCLUSIONS: Our studies provide a novel molecular mechanism for the negative regulation of ARID1A by ß-TRCP and ATM in DNA damaged gastric cancer cells.

Portal vein/superior mesenteric vein resection in pancreatic cancer treatment in the elderly.

There is an increased interest in extending surgical criteria for pancreatic cancer by performing pancreaticoduodenectomy (PD) combined with portal vein (PV) or superior mesenteric vein (SMV) resection and reconstruction for borderline resectable patients. However, whether this procedure suitable for elderly patients remains unclear. Here, we studied cases of pancreatic cancer treatment in our medical center to evaluate feasibility and safety of this procedure in the elderly.Eighty-three patients 65 years of age or older who underwent PD from January 2009 to March 2014 were divided into 2 groups: PD only (Group A, 52 cases), and PD combined with PV/SMV resection and reconstruction (Group B, 31 cases). Surgical outcomes and survival rates were compared between groups. Information regarding preoperative, intraoperative and postoperative conditions, and follow-up visits were provided. The outcomes of postoperative complications and survival rates were investigated.No difference in the preoperative data was detected between 2 groups with the exception that the serum albumin level was significantly lower in Group B (P = .013), indicating more deteriorating health conditions in this group. Although intraoperative time and blood loss were higher in Group B (P < .001 and P = .048, respectively), the overall postoperative complications and survival curve showed no statistical differences between 2 groups with one exception in that there was higher incidence of intractable diarrhea in Group B (P = .034). The symptoms, however, resolved later on with conservative treatment. The median survival time for patients in this study was comparable to other reported PD treatments. There was zero postoperative mortality in both groups.PD combined with PV/SMV treatment did not lead to increased morbidity and motility in elderly patients 65 years of age and above. This procedure could provide a promising opportunity for borderline resectable elderly pancreatic cancer patients.

Risk factors, treatment and impact on outcomes of bile leakage after hemihepatectomy.

BACKGROUND: Risk factors for bile leakage after hemihepatectomy are unknown. METHODS: A prospectively maintained database review identified patients undergoing hemihepatectomy between 1 January 2009 and 30 September 2014. Patients were divided into B/C and non-B/C bile leakage groups. Risk factors for bile leakage were predicted and assessments of their impact on patients were made. RESULTS: Bile leakage occurred in 91 of the 297 patients (30.6%); 64 cases were classified as grade B bile leakage (21.5%) and three cases as grade C bile leakage (1.0%). Multivariate analysis confirmed that elevated preoperative alanine transaminase (ALT), positive bile culture during surgery, hilar bile duct plasty, bilioenteric anastomosis and laparoscopic surgery were risk factors for B/C grade bile leakage (P < 0.05). Percutaneous transhepatic biliary drainage (PTBD) and endoscopic nasobiliary drainage (ENBD) were protective factors for B/C grade bile leakage (P < 0.05). PTBD, ENBD and Kehr's T-tube drainage could reduce the drainage volume and duration of drainage after bile leakage (P < 0.05). The incidence of wound infection, abdominal infection, major complications and the Clavien classification system score in the B/C bile leakage group were higher than those in the non-B/C bile leakage group (P < 0.05). Patients in the B/C bile leakage group also required prolonged hospitalization (P < 0.05). The mortality of two groups was similar (P > 0.05). CONCLUSION: Patient with elevated preoperative ALT, positive bile cultures during surgery, hilar bile duct plasty, bilioenteric anastomosis and laparoscopic surgery are more likely to complicate bile leakage. We should use biliary drainage such as preoperative PTBD, ENBD or intraoperative Kehr's T-tube drainage to reduce and treat bile leakage in patients with high risk of bile leakage.

A novel technique of inserting pancreaticogastrostomy with duct-to-mucosa anastomosis can potentially reduce postoperative pancreatic fistula.

BACKGROUND: We describe our novel technique of inserting pancreaticogastrostomy (IPG) after pancreaticoduodenectomy. In our technique, the seromuscular and mucosal layers of the posterior gastric wall are separated to create a mucosal pouch. A duct-to-mucosa anastomosis is performed through a small incision in the mucosal layer. An inner suture at the seromuscular-mucosal margin incorporating the pancreatic parenchyma and an outer suture on the exterior margin of the seromuscular layer to wrap the pouch around the pancreas are placed to complete the IPG. MATERIALS AND METHODS: We examined the clinicopathological features and outcomes of 259 patients who underwent pancreaticoduodenectomy between January 2010 and April 2014. RESULTS: One hundred forty-three (55.2%) patients underwent IPG, while 116 (44.8%) had conventional pancreaticojejunostomy. Most preoperative and intraoperative parameters were comparable. Overall morbidity in the IPG group was 28.7%. The rate of grade A postoperative pancreatic fistula (POPF) was 7.0%, and the rates of grade B and C POPF were 0.7% and 0.0%, respectively. The corresponding rates of grade A, B, and C fistulae were 5.2%, 8.6%, and 5.2%, respectively. CONCLUSIONS: In selected patients, our novel technique can be performed safely and may reduce the rates of POPF.

Vitamin C Intake and Pancreatic Cancer Risk: A Meta-Analysis of Published Case-Control and Cohort Studies.

BACKGROUND: Observational studies inconsistently reported the relationship between vitamin C intake and risk of pancreatic cancer. We conducted a meta-analysis of published case-control and cohort studies to quantify the association. METHODS: Potentially eligible studies were found on PubMed and EMBASE databases through May 31, 2015. A random-effects model was assigned to compute summary point estimates with corresponding 95% confidence intervals (CIs). Subgroup and meta-regression analyses were also performed to explore sources of heterogeneity. RESULTS: Our final analyses included 20 observational studies comprising nearly 5 thousand cases of pancreatic cancer. When comparing the highest with the lowest categories of vitamin C intake, the summary odds ratio/relative risk for case-control studies (14 studies), cohort studies (6 studies) and all studies combined was 0.58 (95% CI: 0.52-0.66), 0.93 (95% CI: 0.78-1.11) and 0.66 (95% CI: 0.58-0.75), respectively. The difference in the findings between case-control and cohort studies was statistically significant (P < .001). Possible publication bias was shown in the meta-analysis of case-control studies. CONCLUSION: There is insufficient evidence to conclude any relationship between vitamin C intake and risk of pancreatic cancer. The strong inverse association observed in case-control studies may be affected by biases (eg, recall and selection biases) that particularly affect case-control studies and/or potential publication bias. Future prospective studies of vitamin C intake and pancreatic cancer are needed.

Mucin-producing intrahepatic biliary papillomatosis.

PURPOSE: Mucin-producing intrahepatic biliary papillomatosis (MPIBP) is an uncommon tumor. The purpose of this study was to evaluate the clinical, radiological, and histopathological characteristics of MPIBP, and its prognosis. METHODS: A retrospective analysis was conducted of 11 patients who underwent surgery for MPIBP. The clinical features and radiological, pathological, and operative findings were reviewed, and the survival rates were determined. RESULTS: Repeated episodes of fever and epigastric pain with or without jaundice were the common clinical manifestations. Radiologically, all patients showed diffuse bile duct dilatation with cystic change in intrahepatic bile duct. All patients underwent a hepatic resection with or without an extrahepatic bile duct resection. No in-hospital mortality occurred. All patients survived without any signs of recurrence (median 12 +/- 7 months); three patients, including two patients who underwent a palliative resection, had an attack of cholangitis, which was effectively treated with antibiotics. CONCLUSIONS: A diagnosis of MPIBP is usually made in patients with biliary dilatation following a radiologic study. Magnetic resonance cholangiopancreatography is more valuable than other modalities in diagnosis. Mucin-producing intrahepatic biliary papillomatosis is a premalignant disease with high malignant potential. The prognosis of MPIBP is excellent if an aggressive resection is performed. A combination of cholangioscopy and frozen sections during the operation is beneficial for a radical successful surgical resection.

Chemoresponse to docetaxel correlates with expression of the survivin splicing variants in patients with gastric cancer.

BACKGROUND/AIMS: Survivin, a potential predictive marker to chemotherapeutic drugs, reduces the susceptibility of tumor cells to proapoptotic stimuli, thereby promoting tumor cell survival during tumor treatment with anticancer agents. In the present study, we examined the correlation between drug-response and expression of survivin in gastric cancer. METHODOLOGY: Drug-response was performed by histoculture drug-response assay (HDRA) in 42 patients with advanced gastric cancer. Survivin variants was studied by real-time RT-PCR at mRNA levels. RESULTS: In our data, twenty-one cases (50%) were sensitive to at least one of drugs tested in the HDRA and 80% (16/20) were positively confirmed clinically, with 100% sensitivity and 83.3% specificity. The diagnostic efficacy of the HDRA were calculated as the area under the receiver operating characteristic (AUC-ROC) curve and showed a value of 0.917. More importantly, significant statistical differences (p=0.012) in chemoresponse to docetaxel were revealed depending on the mRNA level of wild-type survivin. CONCLUSIONS: These clinical data demonstrated, for the first time, that wild-type survivin is useful for evaluating the docetaxel-response in patients with gastric cancer. Moreover, the HDRA is an excellent clinical useful drug-response assay for patients to individualize their chemotherapy.

[Prognostic significance of survivin splicing variants in expression gastric cancer].

OBJECTIVE: To study the expression and associations of three survivin splicing variants in gastric cancer and normal gastric mucosa, and to evaluate the prognostic significance. METHODS: Real time quantitative RT-PCR was used to detect the expression of three survivin splicing variants in tumor and matched normal gastric mucosa specimens from 77 cases with gastric cancer. RESULTS: The expression of three survivin splicing variants than upregulated significantly in gastric cancer than those in normal mucosas (P< 0.01). In cancer tissues, the expression rates of survivin, survivin-2B, survivin-deltaEx3 were 100%, 79.8% (61/77), 64.9% (50/77) respectively. The survival rate was significantly lower in the patients with high survivin expression than those with low survivin expression (P< 0.01). CONCLUSION: Among three survivin splicing variants, the expression level of wild-type survivin mRNA is an important predictor for prognosis.

[Effect of inhibiting survivin expression with antisense oligodeoxynucleotides on sensitivity of hepatocellular carcinoma cell lines HepG2 and HepG2/ADM to adriamycin].

BACKGROUND & OBJECTIVE: Survivin deserves attention as a selective target for cancer therapy because it is silenced in differentiated adult tissues, but is expressed in a variety of human tumors, and is involved in tumorigenesis and chemoresistance. Antisense oligodeoxynucleotides (ASODN) can be used to inhibit the expression of survivin to induce apoptosis or enhance chemosensitivity of tumor cells. This study was to investigate the effect of inhibiting survivin expression with ASODN on sensitivity of hepatocellular carcinoma cell lines HepG2 and HepG2/ADM to Adriamycin (ADM). METHODS: The expression of survivin in HepG2 and HepG2/ADM cells was detected by reverse transcription-polymerase chain reaction (RT-PCR) and Western blot. Sensitivities of HepG2 and HepG2/ADM cells to ASODN and ADM were detected by MTT assay. ASODN was transfected into HepG2 and HepG2/ADM cells; expression of survivin was detected by RT-PCR. Synergetic effects of low concentrations of ASODN and subtoxic concentrations of ADM on HepG2 and HepG2/ADM cells were detected by isobolography. The expression of active Caspase-3 and cell apoptosis were evaluated by flow cytometry. RESULTS: mRNA level of survivin in HepG2/ADM cells was 15 folds as that in HepG2 cells; protein level of Survivin in HepG2/ADM cells was 18 folds as that in HepG2 cells. Both HepG2 and HepG2/ADM cells were sensitive to ASODN-mediated cytotoxicity in a concentration-dependent manner. The 50% inhibitory concentration (IC(50)) of ASODN was 317.90 nmol/L for HepG2 cells, and 480.74 nmol/L for HepG2/ADM cells. The maximal cytotoxicity was observed at 500 nmol/L of ASODN; the inhibitory rate was 71.10% in HepG2 cells, and 53.67% in HepG2/ADM cells. The IC(50) of ADM was 0.36 microg/ml for HepG2 cells, and 2.12 microg/ml for HepG2/ADM cells; the resistance index was 6. ASODN efficiently down-regulated mRNA level of survivin in both cell lines in a concentration-dependent manner. For HepG2 cells, with the IC(50) of 271.93 nmol/L, the maximal effect of ASODN was achieved at a concentration of 400 nmol/L, at which mRNA level of survivin was down-regulated by 69.12%; for HepG2/ADM cells, with the IC(50) of 365.72 nmol/L, its maximal effect was achieved at a concentration of 400 nmol/L, at which mRNA level of survivin was down-regulated by 60.01%. ASODN in combination with ADM synergetically enhanced sensitivity of HepG2 cells to ADM by 6 folds, and HepG2/ADM cells by 4 folds. Combination treatment of ASODN and ADM gradually enhanced activity of Caspase-3 and cell apoptosis in a concentration-dependent manner, and resulted in caspase-dependent cell death in HepG2/ADM cells. CONCLUSION: Inhibiting survivin expression with ASODN could sensitize hepatocellular carcinoma cells to ADM, and the combination of ASODN and ADM may be a reasonable approach for clinical treatment of ADM-resistant hepatocellular carcinoma.