CHD1L is associated with poor survival and promotes the proliferation and metastasis of intrahepatic cholangiocarcinoma.

Chromodomain helicase/ATPase DNA­binding protein 1­like gene (CHD1L) is a new oncogene which has been confirmed to be crucial to the progression of many solid tumors. In the present study, the expression of CHD1L was found to be upregulated in intrahepatic cholangiocarcinoma (ICC), which was significantly associated with histological differentiation (P=0.011), vascular invasion (P=0.002), lymph node metastasis (P=0.008) and TNM stage (P=0.001). Kaplan­Meier survival analysis revealed that ICC patients with positive CHD1L expression had shorter overall and disease­free survival than those with negative CHD1L expression. Functional study found that CHD1L exhibited strong oncogenic roles, including increased cell growth by CCK­8 assay, colony formation by plate colony formation assay, G1/S transition by flow cytometry and tumor formation in nude mice. In addition, RNAi­mediated silencing of CHD1L inhibited ICC invasion and metastasis by wound healing, Transwell migration and Matrigel invasion assays in vitro and in vivo. Collectively, our results show that CHD1L is upregulated and promotes the proliferation and metastasis of ICC cells. CHD1L acts as an oncogene and may be a prognostic factor or therapeutic target for patients with ICC.

A proposed severity classification system for hepatolithiasis based on an analysis of prognostic factors in a Japanese patient cohort.

BACKGROUND: Hepatolithiasis frequently results in severe complications. We conducted a cohort study to identify prognostic factors and to establish a hepatolithiasis severity classification system. METHODS: The study cohort comprised 396 patients who were identified through a 1998 nationwide survey and followed up for 18 years or until death. Cox regression analysis was used to identify prognostic factors. RESULTS: Median survival time of the patients was 308 (range 0-462) months. Of the 396 patients enrolled in the study, 118 (29.8%) died, most frequently from intrahepatic cholangiocarcinoma (25 patients, 21.2%). Age of ≥ 65 years at the time of initial diagnosis [hazard ratio (HR) 3.410], jaundice for ≥ 1 week during follow-up (HR 2.442), intrahepatic cholangiocarcinoma (HR 3.674), and liver cirrhosis (HR 5.061) were shown to be significant risk factors for death from any therapeutic course. The data led to a 3-grade disease severity classification system that incorporates intrahepatic cholangiocarcinoma and liver cirrhosis as major factors and age of ≥ 65 years and jaundice for ≥ 1 week during follow-up as minor factors. Survival rates differed significantly between grades. CONCLUSIONS: The proposed hepatolithiasis severity classification system can be used to assess prognosis and thereby improve patient outcomes.

Prognosis of Intrahepatic Cholangiocarcinomas with HBV Infection is Better than Those with Hepatolithiasis After R0 Liver Resection: A Propensity Score Matching Analysis.

BACKGROUND: The impact of different causative factors of intrahepatic cholangiocarcinoma (ICC) on disease outcome remains largely unknown. This study aimed to evaluate the prognosis of ICC patients with different pathogenic factors after hepatectomy. METHODS: Data of 731 consecutive patients undergoing R0 liver resection for ICC at The Eastern Hepatobiliary Surgery Hospital between 2004 and 2010 were analyzed. These patients were divided into the hepatitis B virus-related (HBV-ICC, n = 519), hepatolithiasis-related (stone-ICC, n = 87), HBV plus hepatolithiasis-related (HBV/stone-ICC, n = 45), and other etiologies-related (other-ICC, n = 80) ICC groups. Propensity score matching (PSM) was used to eliminate the baseline differences between these groups. RESULTS: In these four groups, the 5-year tumor recurrence and overall survival (OS) rates were 75.4, 90.3, 83.0 and 81.9%, and 32.7, 16.3, 17.7 and 22.6%, respectively. The significant differences in recurrence and OS were identified between the HBV- and stone-ICC groups (both p < 0.001). In these two groups, most of the independent prognostic predictors were similar, but tumor diameter >5 cm was demonstrated as a risk factor in the HBV-ICC patients only, and surgical margin <1 cm and human epidermal growth factor receptor 2-positive were demonstrated as risk factors in the stone-ICC patients only. With PSM, 75 patients in each of the HBV- and stone-ICC cohorts were created, and the 5-year recurrence and OS rates were 69.9 versus 88.6, and 34.6 versus 19.2%, respectively (p = 0.017, 0.027). CONCLUSION: Patients with HBV-ICC achieved better outcomes than those with stone-ICC. This prognostic difference was probably associated with biological malignant invasiveness rather than tumor stage.

Oddi sphincter preserved cholangioplasty with hepatico-subcutaneous stoma for hepatolithiasis.

AIM: To evaluate the long-term outcomes of Oddi sphincter preserved cholangioplasty with hepatico-subcutaneous stoma (OSPCHS) and risk factors for recurrence in hepatolithiasis. METHODS: From March 1993 to December 2012, 202 consecutive patients with hepatolithiasis underwent OSPCHS at our department. The Oddi sphincter preserved procedure consisted of common hepatic duct exploration, stone extraction, hilar bile duct plasty, establishment of subcutaneous stoma to the bile duct. Patients with recurrent stones can undergo stone extraction and/or biliary drainage via the subcutaneous stoma which can be incised under local anesthesia. The long-term results were reviewed. Cox regression model was employed to analyze the risk factors for stone recurrence. RESULTS: Ninety-seven (48.0%) OSPCHS patients underwent hepatic resection concomitantly. The rate of surgical complications was 10.4%. There was no perioperative death. The immediate stone clearance rate was 72.8%. Postoperative cholangioscopic lithotomy raised the clearance rate to 97.0%. With a median follow-up period of 78.5 mo (range: 2-233 mo), 24.8% of patients had recurrent stones, 2.5% had late development of cholangiocarcinoma, and the mortality rate was 5.4%. Removal of recurrent stones and/or drainage of inflammatory bile via subcutaneous stoma were conducted in 44 (21.8%) patients. The clearance rate of recurrent stones was 84.0% after subsequent choledochoscopic lithotripsy via subcutaneous stoma. Cox regression analysis showed that residual stone was an independent prognostic factor for stone recurrence. CONCLUSION: In selected patients with hepatolithiasis, OSPCHS achieves excellent long-term outcomes, and residual stone is an independent prognostic factor for stone recurrence.

Enterolithiasis.

Enterolithiasis or formation of gastrointestinal concretions is an uncommon medical condition that develops in the setting of intestinal stasis in the presence of the intestinal diverticula, surgical enteroanastomoses, blind pouches, afferent loops, incarcerated hernias, small intestinal tumors, intestinal kinking from intra-abdominal adhesions, and stenosing or stricturing Crohn's disease and intestinal tuberculosis. Enterolithiasis is classified into primary and secondary types. Its prevalence ranges from 0.3% to 10% in selected populations. Proximal primary enteroliths are composed of choleic acid salts and distal enteroliths are calcified. Clinical presentation includes abdominal pains, distention, nausea, and vomiting of occasionally sudden but often fluctuating subacute nature which occurs as a result of the enterolith tumbling through the bowel lumen. Thorough history and physical exam coupled with radiologic imaging helps establish a diagnosis in a patient at risk. Complications include bowel obstruction, direct pressure injury to the intestinal mucosa, intestinal gangrene, intussusceptions, afferent loop syndrome, diverticulitis, iron deficiency anemia, gastrointestinal hemorrhage, and perforation. Mortality of primary enterolithiasis may reach 3% and secondary enterolithiasis 8%. Risk factors include poorly conditioned patients with significant obstruction and delay in diagnosis. Treatment relies on timely recognition of the disease and endoscopic or surgical intervention. With advents in new technology, improved outcome is expected for patients with enterolithiasis.

3D Reconstruction Aids Surgery For Complicated Hepatolithiasis.

BACKGROUND/AIMS: Three-dimensional (3D) imaging may improve surgical interventions for complicated hepatolithiasis. METHODOLOGY: Between July 2008 and December 2012 a total of 131 patients with complicated hepatolithiasis underwent surgical therapy in the Department of Hepatobiliary Surgery Zhujiang Hospital, Southern Medical University. 77 patients received preoperative planning using a computed tomography (CT)-based 3D reconstruction technique, and 54 received treatment based on preoperative planning with traditional imaging (CT, ultrasonography, magnetic resonance imaging/magnetic resonance cholangiography). Perioperative and long-term outcomes were analyzed. RESULTS: 3D reconstruction facilitated significantly more accurate diagnosis of pathological morphology than conventional imaging methods, as confirmed during surgery. Patients that received 3D reconstruction preoperative planning had significantly better clinical outcomes. The immediate stone clearance rates were 92.2% and 61.1%, respectively. Additional postoperative choledochoscopic lithotripsy raised the clearance rates to 94.8% and 81.5%, respectively. The hospital mortality rates were 0% and 1.9%, respectively, and the complication rates were 33.8% and 44.4%, respectively. With a median follow-up of 28 months (5-38 months), the long-term overall asymptomatic survival rates were 80.5% and 46.3%, respectively. 3D reconstruction preoperative planning was a significant prognostic protective factor of long-term asymptomatic survival for the patients with complicated hepatolithiasis (Cox regression analysis, RR = 0.348, 95% confidence interval 0.185-0.657, p = 0.001). CONCLUSION: Surgical therapy conducted following preoperative planning using 3D reconstruction achieved better clinical outcomes than conventional imaging techniques. Whilst conventional imaging techniques accurately identify intrahepatic stones, they are less capable of identifying bile duct stricture.

Expression levels and significance of nuclear factor-κB and epidermal growth factor receptor in hepatolithiasis associated with intrahepatic cholangiocarcinoma.

BACKGROUND: An increasing incidence of cholangiocarcinoma (CCA) and CCA mortality rates has been observed around the world. Patients with intrahepatic biliary stones have a 10% risk of developing CCA, and up to 70% of patients with histologically confirmed CCA have hepatolithiasis. Few previous studies have addressed the associations between the expression of nuclear factor (NF)-κB and epidermal growth factor receptor (EGFR) and clinicopathological prognosis in patients with hepatolithiasis-associated intrahepatic CCA. AIMS: This study was designed to investigate the clinicopathological and prognostic significance of NF-κB and EGFR expression in hepatolithiasis-associated intrahepatic CCA and hepatolithiasis. METHODS: A total of 90 liver specimens were immunohistochemically stained for NF-κB and EGFR expression, and the characteristics of 90 individual patients were retrospectively reviewed. RESULTS: Differences in the positive rates of NF-κB and EGFR expression between the hepatolithiasis-associated intrahepatic CCA group, intrahepatic lithiasis group, and control group were found to be statistically significant. EGFR expression was closely associated with the degree of differentiation and depth of invasion (p < 0.05). The 1-, 3-, and 5-year overall survival rates were respectively 42.8, 21.0, and 10.3% in intrahepatic CCA groups. The survival rate of the EGFR-negative group was higher than in the EGFR-positive group (p < 0.01). Lymph node metastasis (HR 1.24, 95% CI 1.02-1.51) and EGFR positivity (HR 1.74, 95% CI 1.30-2.23) were associated with decreases in the survival rate. CONCLUSION: The expression of NF-κB may be an early step in intrahepatic cholangiocarcinogenesis. Overexpression of EGFR is associated with the degree of malignancy and with poor prognosis. NF-κB and EGFR may cooperate during intrahepatic cholangiocarcinogenesis and progression. Lymph node metastasis and EGFR positivity were associated with decreases in the survival rate.

Management hepatolithiasis with operative choledochoscopic FREDDY laser lithotripsy combined with or without hepatectomy.

BACKGROUND: Hepatolithiasis is very common in East Asia. It is benign in nature, but has a high recurrence rate. It is likely to lead to biliary cirrhosis and increase the risk of cholangiocarcinoma. Hence, the treatment of hepatolithiasis is difficult but vital. In this report, we present a novel approach to manage hepatolithiasis using the choledochoscopic Frequency-Doubled Double pulse Nd:YAG (FREDDY) laser lithotripsy combined with or without hepatectomy. METHODS: Between July 2009 and October 2012, 45 patients underwent choledochoscopic FREDDY laser lithotripsy combined with or without hepatectomy (laser lithotripsy group). Forty-eight patients underwent a traditional operation (traditional method group) from January 2009 to June 2009. Comparative analysis was made of demographic and clinical characteristics of the two groups. RESULTS: The final stone clearance rate of the laser lithotripsy group was 93.3%, whereas that of the traditional method group was 85.4% (P=0.22). In the laser lithotripsy group, 2 patients experienced hemobilia and 3 patients had acute cholangitis. In the traditional method group, 3 patients had intraoperative hemorrhage, 1 patient had bile leakage, 6 patients had acute cholangitis, and 1 patient died of liver failure. Moreover, the operative time in the traditional method group was significantly longer than that in the laser lithotripsy group (P=0.01). The mean hospital stay of the patients in the traditional method group was longer than that in the laser lithotripsy group (9.8 vs 8.2 days, P=0.17). Recurrent intrahepatic bile duct stones were not found during the follow-up period in the two groups. CONCLUSION: Operative choledochoscopic FREDDY laser lithotripsy combined with or without hepatectomy may be an effective and safe treatment for hepatolithiasis.

Diagnosis and cure experience of hepatolithiasis-associated intrahepatic cholangiocarcinoma in 66 patients.

BACKGROUND: The management of hepatolithiasis combined with intrahepatic cholangicarcinoma (IHHCC) remains a challenge due to poor prognosis. The aim of this study was to summarize our diagnosis and cure experience of IHHCC over the recent 10 years. METHODS: From January 1996 to January 2006, 66 patients with IHHCC were reviewed retrospectively. RESULTS: Of the 66 patients, 52 underwent surgical resection (radical resection in 38 and palliative in 14) and 8 patients abdominal exploration, while the other 6 cases received endoscopic retrograde biliary internal drainage and stent implantation. In this series, correct diagnosis of advanced stage was made during operation in 8 cases (8/60, 13.3%) and all of them (underwent unnecessary abdominal exploration, among them the positive rate of CA19-9 was 100%, and the positive rate of CEA was 87.6% (7/8), incidence rate of ascites was 100% and short-term significant weight loss was 100%, with median overall survival of only 4 months. CONCLUSION: Radical resection is mandatory for IHHCC patient to achieve long-term survival, the CT and MR imaging features of IHHCC being concentric enhancement. Patients with IHHCC have significant higher CA199 and significant higher CEA and short-term significant weight loss and ascites should be considered with advanced stage of IHHCC and unnecessary non-therapeutic laparotomies should be avoided.

Indocyanine green retention test avoiding liver failure after hepatectomy for hepatolithiasis.

BACKGROUND/AIMS: To investigate the role of indocyanine green (ICG) retention test in avoiding postoperative liver failure after hepatectomy for primary hepatolithiasis. METHODOLOGY: Between January, 2004 and December, 2010, 144 patients with primary hepatolithiasis undergoing hepatectomy were retrospectively selected for the study. Eighty-two of those (Group CP) were preoperatively evaluated only by Child-Pugh (CP) scoring to select candidates for hepatectomy before September, 2008. Since then ICG15 retention test was accepted for the same purpose in the remaining 62 cases (Group ICG). RESULTS: The immediate stone clearance rates were 79.27% and 80.65%, with final stone clearance rates 93.9% and 93.55% in the CP and ICG groups, respectively. Liver failure was observed significantly more in the CP (12.2%) than that in the ICG group (1.61%), (p<0.05). More hospital deaths occurred in the CP (4.88%) than in the ICG group (1.61%), although no significant difference was observed (p=0.548). The complication rate of the CP group (37.80%) was significantly higher than that of ICG group (17.74%), (p<0.05). CONCLUSIONS: ICG15 retention test is more effective to predict and avoid liver failure for patients with hepatolithiasis after hepatectomy than CP scoring system. It may also decrease the morbidity and mortality rate through strict selection, thus increasing operative safety.

Laparoscopic approach of surgical treatment for primary hepatolithiasis: a cohort study.

BACKGROUND: The aim of the current study was to evaluate the perioperative and long-term outcome of a laparoscopic approach for management of primary hepatolithiasis. METHODS: From January 1995 to June 2008, 55 consecutive patients with primary hepatolithiasis who underwent laparoscopic partial hepatectomy and laparoscopic bile duct exploration were analyzed. Immediate outcomes included stone clearance rate, operative morbidity, and mortality. Long-term outcomes included stone recurrence rate and hepatolithiasis-related mortality. RESULTS: Nineteen patients underwent laparoscopic left lateral sectionectomy and 36 patients underwent laparoscopic bile duct exploration. Twenty-five patients also underwent concomitant laparoscopic choledochoduodenostomy bypass. The operative morbidity and mortality rates were 25.5% and 1.8%, respectively. Four procedures needed open conversion. The immediate stone clearance rate was 90.9%, and the final stone clearance rate was 94.5% after subsequent choledochoscopic treatment. With a mean follow-up of 59 +/- 30 months, recurrent stones developed in 3 patients. One patient died of advanced cholangiocarcinoma. CONCLUSIONS: In selected patients with primary hepatolithiasis, a laparoscopic approach of definitive treatment is safe and effective with good immediate and long-term outcomes.

Outcomes of hepatic resection for hepatolithiasis.

BACKGROUND: Hepatic resection is main approach to treatment of hepatolithiasis, but the long-term follow-up results of hepatic resection for hepatolithiasis are rarely reported. METHODS: A retrospective study was conducted of 87 patients with hepatolithiasis who underwent hepatic resection. RESULTS: The final stone clearance rates were 95%. There was a significant difference in the incidence of recurrent stones between patients with and without remaining biliary strictures. On multivariate analysis, the presence of residual or recurrent stones was an independent risk factor associated with recurrent cholangitis. The 10-year overall survival rate was 80.3%. On multivariate analysis, the development of cholangiocarcinoma was an independent predictor of survival in patients who underwent hepatic resection for hepatolithiasis. CONCLUSIONS: The long-term outcomes after hepatic resection were satisfactory in patients whose intrahepatic stones and strictures were completely removed. Cholangiocarcinoma associated with hepatolithiasis was an independent prognostic factor in patients with hepatolithiasis who underwent hepatic resection.

Bile leakage after hepatectomy for hepatolithiasis: risk factors and management.

BACKGROUND: Bile leakage remains a major postoperative complication after liver resection. Bile leakage after hepatectomy for liver neoplasms has been well studied. However, the risk factors and management of this complication after liver resection for intrahepatic lithiasis has not been investigated. METHODS: From January 1992 to June 2004, 312 consecutive patients with intrahepatic lithiasis underwent hepatic resections Sun Yet-san University. Perioperative risk factors pertaining to the development of bile leakage were identified using univariate and multivariate analysis. The management and outcome of these patients with bile leakage were evaluated. RESULTS: Bile leakage developed in 23 (7.4%) of 312 patients. The multivariate logistic regression analysis identified that left hepatectomy (P=.024, odds ratio [OR]=3.695, 95% confidence interval [CI]: 1.185 to 11.517) and the period greater than 1 month between operative time and the latest acute cholangitis attack (P=.02, OR=4.144, 95% CI: 1.248 to 13.757) were the independent risk factors for development of bile leakage after hepatectomy for hepatolithiasis. The septic complications were higher in the patients with bile leakage than in those without bile leakage (ie, wound infection: 56.5% vs 13.5%, P=.001; subphrenic abscess: 21.7% vs 4.8%, P=.01; septicemia: 8.7% vs 0.7%, P=.029). Percutaneous drainage or combined endoscopic naso-biliary drainage was the first choice of treatment for bile leakage; 20 (87.0%) of 23 patients were treated by this method. One patient underwent re-operation for diffuse peritonitis due to withdrawal of T tube inadvertently at postoperative day 1. Two patients with bile leakage were re-operated due to uncontrollable hemobilia at postoperative day 5 and 12, respectively. CONCLUSIONS: Patients who underwent hepatectomy at the period less than 1 month after the latest attack of acute cholangitis carry high risk for the development of bile leakage. Preoperative cholangiography to identify the aberrant hepatic duct for high risk patients and avoidance of hepatectomy at the acute phase of cholangitis are of critical importance to prevent bile leakage after hepatectomy. Percutaneous drainage is the primary and effective treatment for bile leakage.