[Retracted] Alteration of p53-binding protein 1 expression as a risk factor for local recurrence in patients undergoing resection for extrahepatic cholangiocarcinoma.

Following the publication of this paper, the Journal was alerted by an investigation committee of Niigata University to the fact that the paper had been identified as a duplicate publication, which had already been published. Therefore, in accordance with the rules of Niigata University Fraud Investigation committee, a request was made that the paper be retracted. After having been in contact with the authors, they agreed with the decision to retract the paper. The Editor apologizes to the readership for any inconvenience caused. [the original article was published in International Journal of Oncology 38: 1227-1236, 2011; DOI: 10.3892/ijo.2011.959].

[Selection of Chemotherapy Regimen on the Basis of Monitoring NLR and Soluble PD-L1 during CRC Chemotherapy].

AIM: It is known that the neutrophil-to-lymphocyte ratio(NLR)is associated with outcomes in patients with cancer. In this study, changes in the NLR and soluble programmed death-1 ligand-1(sPD-L1)levels were assessed in patients with metastatic colorectal cancer treated with chemotherapy. METHODOLOGY: Ten patients with unresectable metastatic colorectal cancer were administered chemotherapy from January 2005 to April 2017 at the Niitsu Medical Center Hospital. The NLR was calculated based on complete blood counts obtained prior to the administration of chemotherapy. Serum sPD-L1 levels were measured by enzyme-linked immunosorbent assay. NLR and sPD-L1 level changes from baseline were compared with tumor response and tumor markers. RESULTS: A relationship was found between sPD-L1 levels and NLR after the treatment of metastatic colorectal cancer(r=0.241, p=0.0459). Decreased sPD-L1 levels were associated with reduced NLR and tumor marker levels. Increased sPD-L1 levels were not related to elevated tumor marker levels. CONCLUSION: Changes in the NLR and sPD-L1 levels during chemotherapy may have a uniquely predictive value in patients with CRC treated with chemotherapy.

[The Changes in the Neutrophil-to-Lymphocyte Ratio Can Predict the Timing of Chemotherapeutic Regimen Alteration in Patients with Metastatic Colorectal Cancer].

AIM: In order to determine if the changes in the neutrophil-to-lymphocyte ratio(NLR)can predict the timingof regimen alteration, the outcome of chemotherapy for metastatic colorectal cancer was analyzed retrospectively. METHODOLOGY: Thirty patients with unresectable metastatic colorectal cancer were administered chemotherapy from January 2005 to December 2015 at the Niitsu Medical Center Hospital. The NLR was calculated from complete blood counts obtained prior to administration of chemotherapy and at the time of the best response. We defined the period with an NLR≤2.5 as the total interval of an NLR≤2.5. The role of the NLR in overall survival was determined by univariate and multivariate Cox regression models. RESULTS: The median overall survival was 27 months in patients with an NLR≤2.5(n=22)and 11 months in those with an NLR>2.5 (n=8)at the best response(p<0.001). The period with an NLR≤2.5 was found to correlate with overall survival(p<0.001). The patients who survived for more than 3 years were introduced to a second-line treatment prior to achievingan NLR>2.5. The period with an NLR≤2.5(p=0.001)and prechemotherapy CA19-9(p<0.0001)were independent, significant predictors of better survival in multivariate analysis. CONCLUSION: The introduction of a new chemotherapeutic regimen prior to achievingan NLR>2.5 predicted better survival in patients with mCRC.

[Change of Blood Neutrophil-to-Lymphocyte Ratio Predicts Survival in Patients with Metastatic Colorectal Cancer].

AIM: The impact of neutrophil-to-lymphocyte ratio(NLR)changes on the outcome of chemotherapy for metastatic colorectalcancer (mCRC)was analyzed retrospectively. METHODOLOGY: Twenty seven patients with unresectable mCRC were administered chemotherapy from January 2005 to December 2014 at the Niitsu Medical Center Hospital. The NLR was calculated from complete blood counts obtained prior to the administration of chemotherapy and at the best response. We defined the period with NLR≤2.5 as the totalintervalof NLR≤2.5. The impact of NLR on overallsurvivalwas determined using univariate and multivariate Cox regression models. RESULTS: The median overall survival was 26 months in patients with an NLR≤5(n= 22), and 11 months in those with an NLR>5(n=5)before chemotherapy(p=0.03). The median overall survival was 31 months in patients with an NLR≤2.5(n=19), and 11 months in those with an NLR>2.5(n=8)at the best response(p< 0.001). The period with an NLR≤2.5 was found to correlate with overall survival(p<0.001). The period with an NLR≤2.5 was the only independent, statistically significant predictor of better survival in multivariate analysis(p=0.001). CONCLUSION: The change of NLR may be a dynamic predictor of better survivalin patients with mCRC.

[Individual Dose Adjustment of 5-Fluorouracil Based on Pharmacokinetic Monitoring May Improve the Outcome of FOLFOX for Metastatic Colorectal Cancer].

AIM: The effect of individual dose adjustment of 5-fluorouracil (5-FU) based on pharmacokinetic monitoring on the outcome of FOLFOX for metastatic colorectal cancer was analyzed retrospectively. METHODOLOGY: Twenty patients with metastatic colorectal cancer underwent FOLFOX chemotherapy from January 2005 to December 2013 at the Niitsu Medical Center Hospital. The sample group included 11 patients in whom 5-FU doses were adjusted individually based on pharmacokinetic monitoring according to an algorithm to maintain the area under the curve (AUC) in the range of 20-25 mg·h/L (Group A) and 9 patients in whom 5-FU doses were adjusted conventionally based on body surface area (Group B). RESULTS: The objective response rate was 63% and 33% in Group A and Group B, respectively (p=0.174). The median overall survival was 34 months and 14 months in Group A and Group B, respectively (p=0.036). There were 4 cases of Grade 3 toxicity (2 in Group A, 2 in Group B; p=0.636) and no cases of Grade 4 toxicity or treatment-related death. CONCLUSION: Pharmacokinetically guided dose adjustment of 5-FU may improve the outcome of FOLFOX for metastatic colorectal cancer.

[Improved Response to 5-FU Using Dose Adjustment and Elastomeric Pump Selection Based on Monitoring of the 5-FU Level--A Case Report].

A 6 1-year-old man with unresectable multiple hepatic metastases after resection of sigmoid colon carcinoma was treated with irinotecan and infused 5-fluorouracil (5-FU) plus Leucovorin (FOLFIRI). Since the levels of tumor markers increased, the 5-FU dose was increased from 2,700 to 3,000 mg/m2 using a Jackson-type pump and an extended infusion time of 53 hours. The blood level of 5-FU was 507 ng/mL 16 hours after starting the infusion. The pump was then changed to a bottle-type pump with the same dose of 3,000 mg/m2. At 16 hours, the 5-FU level was 964.5 ng/mL. The areas under the concentration vs. time curve (AUC mg・h/L)were 21 and 44 mg・h/L for the Jackson- and bottle-type pumps, respectively. Owing to the development of Grade 3 stomatitis and hand-foot syndrome, 5-FU was reduced to 2,700 mg/m2 with a bottle-type pump. The AUC decreased to 27 mg・h/L, but the liver metastases were reduced and the adverse effects subsided to Grade 1. This case shows that individual dose adjustment of 5-FU to the appropriate AUC based on pharmacokinetic monitoring of the blood 5-FU level can improve the response, reduce adverse effects, and have a clinical benefit.

Early DNA damage response in residual carcinoma in situ at ductal stumps and local recurrence in patients undergoing resection for extrahepatic cholangiocarcinoma.

BACKGROUND/PURPOSE: The aim of this study was to clarify the association between the DNA damage response mediated by p53-binding protein 1 (53BP1) in residual carcinoma in situ at ductal stumps and local recurrence in patients undergoing resection for extrahepatic cholangiocarcinoma. METHODS: A retrospective analysis was conducted of 11 patients with positive ductal margins with carcinoma in situ. To evaluate the early DNA damage response, the nuclear staining pattern of 53BP1 was examined by immunofluorescence. TUNEL analysis was used to calculate the apoptotic index. RESULTS: Of the 11 tumor specimens of carcinoma in situ, seven showed diffuse localization of 53BP1 in nuclei (53BP1 inactivation) and four showed discrete nuclear foci of 53BP1 (53BP1 activation); the apoptotic index was significantly decreased in the seven tumor specimens with 53BP1 inactivation compared to the four with 53BP1 activation (median apoptotic index, 1 vs. 22 %; p = 0.003). The cumulative probability of local recurrence was significantly higher in patients with 53BP1 inactivation than in patients with 53BP1 activation (cumulative 5-year local recurrence rate, 60 vs. 0 %; p = 0.019). CONCLUSIONS: Clinically evident local recurrence of residual carcinoma in situ at ductal stumps is closely associated with 53BP1 inactivation and decreased apoptosis.

Risk of subsequent biliary malignancy in patients undergoing cyst excision for congenital choledochal cysts.

BACKGROUND AND AIM: The aim of this study was to elucidate the risk of subsequent biliary malignancy in patients undergoing cyst excision for congenital choledochal cysts. METHODS: A retrospective analysis of 94 patients who had undergone cyst excision for congenital choledochal cysts was conducted. The median age at the time of cyst excision and median follow-up time after cyst excision were 7 years and 181 months, respectively. RESULTS: Biliary tract cancer developed in four patients at 13, 15, 23, and 32 years after cyst excision. The cumulative incidences of biliary tract cancer at 15, 20, and 25 years after cyst excision were 1.6%, 3.9%, and 11.3%, respectively. The sites of biliary tract cancer were the intrahepatic (n = 2), hilar (n = 1), and intrapancreatic (n = 1) bile ducts. Of the four patients with biliary tract cancer after cyst excision, three patients underwent surgical resection and one patient received chemo-radiotherapy. The overall cumulative survival rates after treatment in the four patients with biliary tract cancer were 50% at 2 years and 25% at 3 years, with a median survival time of 15 months. CONCLUSIONS: The risk of subsequent biliary malignancy in patients undergoing cyst excision for congenital choledochal cysts seems to be relatively high in the long-term. The risk of biliary malignancy in the remnant bile duct increases more than 15 years after cyst excision. Despite an aggressive treatment approach for this condition, subsequent biliary malignancy following cyst excision for congenital choledochal cysts shows an unfavorable outcome.

Clinicopathological features of benign biliary strictures masquerading as biliary malignancy.

Discrimination between benign and malignant biliary strictures is difficult, with 5.2 to 24.5 per cent of biliary strictures proving to be benign after histological examination of the resected specimen. This study aimed to evaluate the clinicopathological features of benign biliary strictures in patients undergoing resection for presumed biliary malignancy. From January 1990 to August 2010, 5 of 153 (3.3%) patients who had undergone resection after a preoperative diagnosis of biliary malignancy had a final histological diagnosis of benign biliary stricture. The infiltration of immunoglobulin G4-positive plasma cells was evaluated by immunohistochemistry. None of the five patients had a history of trauma or earlier hepatobiliary surgery and all five underwent hemihepatectomy (combined with extrahepatic bile duct resection in three patients). Postoperative morbidity was recorded in two patients (transient cholangitis and biliary fistula), but there was no postoperative mortality. Histological re-examination identified immunoglobulin G4-related sclerosing cholangitis (n = 2) and nonspecific fibrosis/inflammation (n = 3). No preoperative clinical or radiographic features were identified that could reliably distinguish patients with benign biliary strictures from those with biliary malignancies. Although benign biliary strictures are rare, differentiating benign strictures from malignancy remains problematic. Thus, the treatment approach for biliary strictures should remain surgical resection for presumed biliary malignancy.

"Extended" radical cholecystectomy for gallbladder cancer: long-term outcomes, indications and limitations.

AIM: To delineate indications and limitations for "extended" radical cholecystectomy for gallbladder cancer: a procedure which was instituted in our department in 1982. METHODS: Of 145 patients who underwent a radical resection for gallbladder cancer from 1982 through 2006, 52 (36%) had an extended radical cholecystectomy, which involved en bloc resection of the gallbladder, gallbladder fossa, extrahepatic bile duct, and the regional lymph nodes (first- and second-echelon node groups). A retrospective analysis of the 52 patients was conducted including at least 5 years of follow up. Residual tumor status was judged as no residual tumor (R0) or microscopic/macroscopic residual tumor (R1-2). Pathological findings were documented according to the American Joint Committee on Cancer Cancer Staging Manual (7th edition). RESULTS: The primary tumor was classified as pathological T1 (pT1) in 3 patients, pT2 in 36, pT3 in 12, and pT4 in 1. Twenty-three patients had lymph node metastases; 11 had a single positive node, 4 had two positive nodes, and 8 had three or more positive nodes. None of the three patients with pT1 tumors had nodal disease, whereas 23 of 49 (47%) with pT2 or more advanced tumors had nodal disease. One patient died during the hospital stay for definitive resection, giving an in-hospital mortality rate of 2%. Overall survival (OS) after extended radical cholecystectomy was 65% at 5 years and 53% at 10 years in all 52 patients. OS differed according to the pT classification (P < 0.001) and the nodal status (P = 0.010). All of 3 patients with pT1 tumors and most (29 of 36) patients with pT2 tumors survived for more than 5 years. Of 12 patients with pT3 tumors, 8 who had an R1-2 resection, distant metastasis, or extensive extrahepatic organ involvement died soon after resection. Of the remaining four pT3 patients who had localized hepatic spread through the gallbladder fossa and underwent an R0 resection, 2 survived for more than 5 years and another survived for 4 years and 2 mo. The only patient with pT4 tumor died of disease soon after resection. Among 23 node-positive patients, 11 survived for more than 5 years, and of these, 10 had a modest degree of nodal disease (one or two positive nodes). CONCLUSION: Extended radical cholecystectomy is indicated for pT2 tumors and some pT3 tumors with localized hepatic invasion, provided that the regional nodal disease is limited to a modest degree (up to two positive nodes). Extensive pT3 disease, pT4 disease, or marked nodal disease appears to be beyond the scope of this radical procedure.

Histologic evaluation of intrahepatic micrometastases in patients treated with or without neoadjuvant chemotherapy for colorectal carcinoma liver metastasis.

In the present retrospective study, we tested the hypothesis that neoadjuvant chemotherapy (NAC) as a treatment for patients with colorectal carcinoma liver metastases (CRLM) may reduce intrahepatic micrometastases. The incidence and distribution of intrahepatic micrometastases were determined in specimens resected from 63 patients who underwent hepatectomy for CRLM (21 treated with NAC and 42 without). In addition, the therapeutic efficacy of NAC was evaluated histologically. Intrahepatic micrometastases were defined as microscopic lesions spatially separated from the gross tumor. The distance from these lesions to the border of the hepatic tumor was measured on histological specimens and the density of intrahepatic micrometastases (number of lesions/mm(2)) was determined in regions close to (<1 cm) the gross hepatic tumor. Of the 21 patients treated with NAC, 13 were identified as having a partial response according to the Response Evaluation Criteria in Solid Tumors (RECIST) guidelines; thus, the overall response rate was 62%. Histologic evaluation of the therapeutic efficacy of NAC was significantly associated with tumor response to NAC according to the RECIST guidelines (p=0.048). In all, 260 intrahepatic micrometastases were detected in 39 patients (62%). Intrahepatic micrometastases were less frequently detected in NAC-treated patients than in untreated patients (5/21 [24%] vs. 34/42 [81%], respectively; p<0.001). There were no significant differences in the distance and density of intrahepatic micrometastases between the two groups (p=0.313 and p=0.526, respectively). In conclusion, NAC reduces the incidence of intrahepatic micrometastases in patients with CRLM, but NAC has no significant effect on their distribution when intrahepatic micrometastases are present.

Regional lymphadenectomy for gallbladder cancer: rational extent, technical details, and patient outcomes.

AIM: To define the rational extent of regional lymphadenectomy for gallbladder cancer and to clarify its effect on long-term survival. METHODS: A total of 152 patients with gallbladder cancer who underwent a minimum of "extended" portal lymph node dissection (defined as en bloc removal of the first- and second-echelon nodes) from 1982 to 2010 were retrospectively analyzed. Based on previous studies, regional lymph nodes of the gallbladder were divided into first-echelon nodes (cystic duct or pericholedochal nodes), second-echelon nodes (node groups posterosuperior to the head of the pancreas or around the hepatic vessels), and more distant nodes. RESULTS: Among the 152 patients (total of 3352 lymph nodes retrieved, median of 19 per patient), 79 patients (52%) had 356 positive nodes. Among node-positive patients, the prevalence of nodal metastasis was highest in the pericholedochal (54%) and cystic duct (38%) nodes, followed by the second-echelon node groups (29% to 19%), while more distant node groups were only rarely (5% or less) involved. Disease-specific survival after R0 resection differed according to the nodal status (P < 0.001): most node-negative patients achieved long-term survival (median, not reached; 5-year survival, 80%), whereas among node-positive patients, 22 survived for more than 5 years (median, 37 mo; 5-year survival, 43%). CONCLUSION: The rational extent of lymphadenectomy for gallbladder cancer should include the first- and second-echelon nodes. A considerable proportion of node-positive patients benefit from such aggressive lymphadenectomy.

Assessment of lymph node status in gallbladder cancer: location, number, or ratio of positive nodes.

UNLABELLED: A BACKGROUND: Assessment of lymph node status is a critical issue in the surgical management of gallbladder cancer. The aim of this study was to compare the anatomical location of positive nodes, number of positive nodes, and lymph node ratio (LNR) as prognostic predictors in gallbladder cancer. METHODS: We conducted a retrospective analysis of 135 patients with gallbladder cancer who underwent a radical resection with regional lymphadenectomy. A total of 2,245 regional lymph nodes were retrieved (median, 14 per patient). The location of positive nodes was classified according to the AJCC staging manual (7th edition). 'Optimal' cutoff values were determined for the number of positive nodes and LNR based on maximal χ(2) scores calculated with the Cox proportional hazards regression model. RESULTS: Lymph node metastasis was found histologically in 59 (44%) patients. The 'optimal' cutoff values for the number of positive nodes and LNR were determined to be three nodes and 10%, respectively. Univariate analysis identified location of positive nodes (pN0, pN1, pN2; P<0.001), number of positive nodes (0, 1 to 3, ≥ 4; P <0.001), and LNR (0%, 0 to 10%, >10%; P<0.001) as significant prognostic factors. Multivariate analysis identified number of positive nodes as an independent prognostic factor ( P=0.004); however, location of positive nodes and LNR failed to remain as an independent variable. CONCLUSIONS: The number of positive lymph nodes better predicts patient outcome after resection than either the location of positive lymph nodes or LNR in gallbladder cancer. Dividing the number of positive lymph nodes into three categories (0, 1 to 3, or ≥ 4) is valid for stratifying patients based on the prognosis after resection.

Full-thickness cholecystectomy with limited lymphadenectomy for gallbladder cancer.

Aggressive radical resection is advocated for gallbladder cancer. However, this is a disease of the elderly and some patients have comorbid disease(s) and/or a debilitated condition that may preclude such an aggressive treatment strategy. Here, we describe a minimum radical procedure for gallbladder cancer, termed as "full-thickness cholecystectomy with limited lymphadenectomy". This procedure comprises full-thickness resection of the gallbladder (cholecystectomy combined with removal of the entire cystic plate) and removal of the first-echelon lymph nodes (the pericholedochal and cystic duct node groups). Since 1992, 12 consecutive patients underwent the described procedure for tumors confined to the gallbladder wall and with no gross evidence of distant metastases/nodal disease, resulting in no in-hospital mortality or recurrent disease. The median overall survival was 229 months with a cumulative 5-year survival of 100%. In conclusion, the minimal radical resection procedure is safe and effective for early-stage gallbladder cancer. This less invasive procedure can be applied to patients with advanced age and/or comorbid disease(s), provided that the tumor is apparently confined to the gallbladder wall and has no gross evidence of distant metastases/nodal disease.

Intraoperative assessment of the resectability of hilar cholangiocarcinoma.

Major hepatectomy combined with extrahepatic bile duct resection has gained acceptance as a standard radical procedure for hilar cholangiocarcinoma. Here, we describe an operative technique, "taping of the right hepatic artery behind Calot's triangle", for assessing the resectability of hilar lesions for which left-sided hepatectomy is planned. Briefly, after retracting the gall-bladder anteriorly, the lateral peritoneum of the hepatoduodenal ligament is incised longitudinally (3-4cm in length) behind Calot's triangle and just to the left of the fissure of Ganz. By dividing the adipose tissue, the distal portion of the right hepatic artery is identified and secured with tape. Any suspicious tissues around the right hepatic artery should be submitted to frozen-section analysis. If no cancer cells were found, the planned resection goes ahead. Conversely, if they were found, the resection should be abandoned. Since 2003, 14 patients for whom left-sided hepatectomy was planned for hilar cholangio-carcinoma involvement, underwent this technique. Three patients were judged to have irresectable tumors and the planned resection could be avoided. In conclusion, this simple technique, isolation of the right hepatic artery behind Calot's triangle before starting resection, should be applied to all hilar malignancies when a left-sided hepatectomy is planned.

Surgical outcomes of minor hepatectomy for locally advanced gallbladder carcinoma.

BACKGROUND/AIMS: This study aimed to evaluate whether wedge resection or S4bS5 resection was the more beneficial hepatectomy procedure for patients with locally advanced gallbladder carcinoma. METHODOLOGY: A retrospective analysis of 70 patients who underwent either wedge resection (n=58) or S4bS5 resection (n=12) for locally advanced gallbladder carcinoma without clinically evident liver metastases was conducted. Clinicopathological characteristics, histological features of hepatic invasion and surgical outcomes were analyzed. RESULTS: Sixteen patients had tumors with hepatic invasion. Of the 16 patients with hepatic invasion, 6 had direct liver invasion alone and 10 had portal tract invasion featuring intrahepatic stromal invasion (n=5), intrahepatic lymphatic invasion (n=4) and intrahepatic venous invasion (n=l). The hepatectomy procedure was not significantly associated with survival after resection (p=0.518) as patients who underwent wedge resection showed an overall cumulative 3-year survival rate of 74% compared with 60% for patients who underwent S4bS5 resection. The Cox proportional hazard regression analysis revealed that pT classification (p<0.001), pM classification (p=0.001) and resection of the extrahepatic bile duct (p=0.048) were independently significant factors associated with survival after resection. CONCLUSIONS: Hepatectomy procedure may not significantly affect surgical outcomes in patients with gallbladder carcinoma. Partial hepatectomy involving the gallbladder bed is critical due to possible tumor cells.

Morphological features of early gallbladder carcinoma.

BACKGROUND/AIMS: This study aimed to clarify the morphological features of early gallbladder carcinoma including tumors invading the lamina propria (pT1a) or muscular layer (pT1b). METHODOLOGY: This retrospective study involved 299 patients with early gallbladder carcinomas, identified from a surgical pathology database covering 29 years from 1982 through 2010. The macroscopic appearance of the tumor was classified as protruding (n=107, 36%) or superficial (n=192, 64%). Protruding tumors were subdivided into pedunculated or sessile, whereas superficial tumors were subdivided into elevated, flat or depressed. RESULTS: Eighty-four of 107 protruding tumors (79%) were detected preoperatively and/or intraoperatively, whereas only 47 of 192 superficial tumors (24%) were detected in this manner (p<0.001). Of the 107 protruding tumors, 21 were pedunculated and 86 were sessile; 76 of these sessile tumors (88%) were accompanied by superficial elevated and/or flat tumors. In total, 257 patients (86%) had pT1a tumors and 42 (14%) had pT1b tumors. No patient had evidence of lymphatic/blood vessel or perineural invasion or nodal metastasis on histology, except for lymphatic vessel invasion in one patient with a pT1b tumor. CONCLUSIONS: Two-thirds of early gallbladder carcinomas are classified as superficial. Most pT1b gallbladder carcinomas spread only locally.

Reduced NKG2D ligand expression in hepatocellular carcinoma correlates with early recurrence.

BACKGROUND & AIMS: The activating receptor natural killer group 2, member D (NKG2D) and its ligands play a crucial role in immune response to tumors. NKG2D ligand expression in tumors has been shown to be associated with tumor eradication and superior patient survival, but the involvement of NKG2D ligands in the immune response against hepatocellular carcinoma (HCC) still remains to be elucidated. METHODS: We investigated the expression of NKG2D ligands in HCC tissues collected from 54 patients and HCC cell lines. We also examined the proteasome expression and the effect of inhibition of proteasome activity on NKG2D ligand expression in HCC tissues and cell lines. RESULTS: In dysplastic nodules (DN), well-differentiated (well-HCC), and moderately-differentiated HCCs (mod-HCC), UL16-binding protein (ULBP) 1 was expressed predominantly in tumor cells, but not in poorly-differentiated HCCs (poor-HCC). Remarkably, recurrence-free survival of patients with ULBP1-negative HCC was significantly shorter than that of patients with ULBP1-positive HCC (p=0.006). Cox regression analysis revealed that loss of ULBP1 expression was an independent predictor of early recurrence (p=0.008). We confirmed that ULBP1 was expressed in the well- and mod-HCC cell lines, but not in the poor-HCC cell line KYN-2. However, inhibition of proteasome activity resulted in significant up-regulation of ULBP1 expression in KYN-2. Moreover, we found that 20S proteasome expression was more abundant in KYN-2 than that in the well- and mod-HCC cell lines. CONCLUSIONS: ULBP1 is prevalently expressed in DN to mod-HCC, but loss of its expression correlates with tumor progression and early recurrence.

Liver-intestine cadherin in intraepithelial neoplasia of intrahepatic cholangiocarcinoma.

BACKGROUND/AIMS: Liver-intestine cadherin (LI-cadherin) is a member of the cadherin superfamily and aberrant expression of LI-cadherin is associated with intestinal metaplasia. The aim of this study was to identify factors associated with LI-cadherin expression in biliary intraepithelial lesions of intrahepatic cholangiocarcinoma (ICC). METHODOLOGY: We evaluated the immunoreactivity of LI-cadherin, MUC2, CDX2, MUC5AC and HGM, according to the grade of biliary intraepithelial lesion in 16 resected specimens of ICC without hepatolithiasis. RESULTS: A total of 168 biliary intraepithelial lesions were classified into four grades: reactive change (42 lesions), biliary intraepithelial neoplasia (BilIN)-1 (10 lesions), BilIN-2 (40 lesions) and BilIN-3 (76 lesions). Biliary intraepithelial lesions were classified into three mucin phenotypes: null (46 lesions), gastric (97 lesions) and gastrointestinal phenotype (25 lesions). LI-cadherin expression was found in 45 (27%) of 168 biliary intraepithelial lesions. BilIN-2/3 (p<0.001), gastrointestinal phenotype (p=0.006) and CDX2 expression (p=0.002) were significantly associated with LI-cadherin expression. Logistic regression analysis revealed that BilIN-2/3 (p=0.002) was the only independently significant factor associated with LI-cadherin expression. CONCLUSIONS: The grade of BilIN independently correlates with LI-cadherin expression in biliary intraepithelial lesions of ICC without hepatolithiasis, whereas the mucin phenotype or CDX2 expression does not.