[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.

[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.

[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.

[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.

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.

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.

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.

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.

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.

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.

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.

Assessment of the nodal status in ampullary carcinoma: the number of positive lymph nodes versus the lymph node ratio.

BACKGROUND: This study was intended to compare the prognostic power of the number of positive lymph nodes with that of the lymph node ratio in patients with ampullary carcinoma. METHODS: A retrospective analysis was conducted of the medical records of 71 consecutive patients with ampullary carcinoma who underwent pancreaticoduodenectomy with regional lymph node dissection. A total of 2151 lymph nodes were dissected (median: 28 nodes per patient) and examined histologically. Cutoff points were determined for both the number of positive nodes and the lymph node ratio using χ(2) scores calculated with the Cox proportional hazards regression model. RESULTS: Lymph node metastasis was found in 34 patients. The best cutoff point for the number of positive nodes was identified as three nodes, and that for the lymph node ratio was identified as 10%. Univariate analysis revealed both the number of positive nodes (0, 1-3, or ≥ 4; P < 0.0001) and the lymph node ratio (0%, 0-10%, or >10%; P < 0.0001) as significant prognostic factors. Multivariate analysis identified the number of positive nodes as an independent prognostic factor (P < 0.001), whereas the lymph node ratio failed to remain as an independent variable. The cumulative 5-year survival rates were 85% for patients with 0 positive nodes, 63% for patients with 1-3 positive nodes, and 0% for patients with ≥ 4 positive nodes (P < 0.0001). CONCLUSIONS: The number of positive lymph nodes better predicts the outcome after resection than the lymph node ratio in patients with ampullary carcinoma.

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.

Intraepithelial ductal spread in colorectal carcinoma liver metastasis.

BACKGROUND/AIMS: This study aimed to evaluate the usefulness of immunohistochemical combinations for discrimination between intraepithelial ductal spread of colorectal carcinoma liver metastasis (CRLM) and that of intrahepatic cholangiocarcinoma (ICC). METHODOLOGY: A retrospective analysis of resected specimens from 151 patients with CRLM and 28 patients with ICC was conducted. Intraepithelial ductal spread along the bile ducts was judged positive when tumor cells spreading along the intact basement membranes of intrahepatic bile ducts. We evaluated immunoreactivity of cytokeratin (CK) 7, CK20, CDX2, MUC2, MUC5AC and human gastric mucin (HGM). RESULTS: Of the 151 patients with CRLM, 21 had intrahepatic bile duct involvement verified histologically. Intraepithelial ductal spread was detected in 17 of 21 (81%) patients with CRLM with bile duct involvement, whereas it was detected in 22 of 28 (79%) patients with ICC. CK20-positive/ CK7-negative immunophenotype demonstrated a high accuracy of 95% for evaluation of intraepithelial ductal spread from CRLM. CK7-positive/ CK20-negative immunophenotype demonstrated the highest accuracy of 85% for evaluation of intraepithelial ductal spread from ICC. CONCLUSION: Intraepithelial ductal spread is a common feature of CRLM with bile duct involvement. Immunohistochemical combination of CK7 and CK20 is useful for discrimination between intraepithelial ductal spread of CRLM and that of ICC.

Ribonucleotide reductase M1 expression in intrahepatic cholangiocarcinoma.

BACKGROUND/AIMS: Ribonucleotide reductase M1 (RRM1) is a key molecule for gemcitabine resistance. This study evaluated the immunohistochemical expression of RRM1 in resected specimens of intrahepatic cholangiocarcinoma (ICC) and investigated the efficacy of gemcitabine-based neoadjuvant chemotherapy in relation to RRM1 expression in tumors. METHODOLOGY: A retrospective analysis was conducted on 34 consecutive Japanese patients who underwent resection of ICC. Of the 34 patients, 2 were treated with neoadjuvant chemotherapy consisting of gemcitabine 800mg/m2 every 2 weeks to address extrahepatic tumor extension. Expression of RRM1 in tumor specimens was assessed using immunohistochemistry and was classified as either positive or negative. RESULTS: RRM1-positive expression was detected in 19/34 (56%) tumor specimens. Two patients were treated with gemcitabine-based neoadjuvant chemotherapy; one had a tumor specimen showing RRM1-positive expression and showed a 14% tumor reduction rate (stable disease); another patient had a tumor showing RRM1-negative expression and showed a 68% tumor reduction rate (partial response). Surgical procedures planned before administration of neoadjuvant chemotherapy were performed in both patients. CONCLUSIONS: Neoadjuvant chemotherapy with gemcitabine for locally advanced ICC was well tolerated and did not impair planned surgical resections. Tumor expression of RRM1 may determine the efficacy of gemcitabine-based chemotherapy for patients with ICC.

[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].

Number of positive lymph nodes independently determines the prognosis after resection in patients with gallbladder carcinoma.

BACKGROUND: This study was designed to compare the prognostic power of the location of positive lymph nodes with that of the number of positive lymph nodes in gallbladder carcinoma. METHODS: A retrospective analysis was conducted of 116 consecutive patients who underwent an R0 radical resection for gallbladder carcinoma. A total of 2,406 lymph nodes taken from the patients were examined histologically. The location of positive regional nodes was classified according to the Japanese staging system. The number of positive regional nodes was recorded for each patient. RESULTS: Nodal disease was found in 49 patients, of whom 19 survived for more than 5 years after resection. Univariate analysis revealed that both the location (P < 0.0001) and the number (P < 0.0001) of positive nodes were significant prognostic factors. Multivariate analysis revealed that the number of positive nodes was an independent prognostic factor (P < 0.001), whereas the location of positive nodes failed to remain as an independent variable. The cumulative 5-year survival rates were 81% for patients without regional nodal disease, 62% for patients with a single positive node, 43% for patients with 2-3 positive nodes, and 15% for patients with > or =4 positive nodes (P < 0.0001). CONCLUSIONS: The number, not the location, of positive lymph nodes independently determines the prognosis after resection in gallbladder carcinoma. No nodal disease or a single positive node indicates a favorable outcome after resection, whereas radical lymph node dissection is effective for selected patients with multiple positive nodes, provided that an R0 resection is feasible.

Histological evaluation of intracapsular venous invasion for discrimination between portal and hepatic venous invasion in hepatocellular carcinoma.

BACKGROUND AND AIM: Histological criteria for intracapsular venous invasion (IVI) that would allow its discrimination between portal and hepatic venous invasion in hepatocellular carcinoma (HCC) have not been established. METHODS: We evaluated IVI immunohistochemically to discriminate between portal and hepatic venous invasion in 89 resected specimens from patients with HCC. IVI was defined as the microscopic involvement of the vessels within the fibrous capsule of HCC. The hepatic venous system was subdivided into the central vein and the sublobular/hepatic vein. Immunohistochemical analysis with the D2-40 monoclonal antibody revealed lymphatic vessels. RESULTS: In non-neoplastic liver tissues, the portal veins (n = 4355) were accompanied by lymphatic vessels (99.7%), bile ductules (100%) and arteries (96%), whereas the central veins (n = 3932) and sublobular/hepatic veins (n = 662) were rarely accompanied by lymphatic vessels (0% and 17%, respectively) and bile ductules (12% and 33%, respectively). In total, 29 IVI foci were detected; three foci were clearly visible within vessels that contained a distinct layer of connective tissue fibers, signifying sublobular/hepatic venous invasion. As the remaining 26 foci were accompanied by lymphatic vessels (26/26 [100%]), bile ductules (21/26 [81%]) and arteries (10/26 [38%]), these foci were considered to reflect intracapsular portal venous invasion rather than venous invasion of the central vein. Intracapsular portal venous invasion was significantly associated with extratumoral portal venous invasion (P < 0.001). CONCLUSIONS: D2-40 immunoreactivity for the histological evaluation of IVI in HCC allows discrimination between portal and hepatic venous invasion for cases in which portal venous invasion predominates.

Fucosylated fraction of alpha-fetoprotein as a predictor of prognosis in patients with hepatocellular carcinoma after curative treatment.

AIM: The aim of this study was to evaluate the clinical usefulness of measuring the Lens culinaris agglutinin-reactive fraction of alpha-fetoprotein (AFP-L3) for prognostic predictor in patients with hepatocellular carcinoma (HCC). METHODS: A total of 477 HCC patients who underwent percutaneous ablative therapy or hepatectomy were enrolled. Overall survival and recurrence-free survival were respectively evaluated retrospectively and prospectively. Multivariate analyses of clinical prognostic factors were performed by Cox's stepwise proportional hazard model. RESULTS: AFP-L3 status was a statistically significant independent prognostic factor of long-term survival (P = 0.013) and recurrence-free survival (P = 0.006) in patients who underwent percutaneous ablative therapy. In contrast, AFP-L3 did not affect prognosis in patients who underwent hepatectomy. CONCLUSIONS: AFP-L3 had different impacts on prognosis in patients with HCC who underwent percutaneous ablative therapy and hepatectomy. Our results suggest that AFP-L3 positivity (>or=15%) might be a promising indicator for choosing therapeutic modalities in HCC patients.