Hirofumi Kamachi

Number of lymph node metastases is a significant prognostic factor in intrahepatic cholangiocarcinoma.

Intrahepatic cholangiocarcinoma (IHCC) is a rare primary hepatic tumor. Outcomes after resection and the use of lymph node dissection have not been well described. From a prospective database, we identified 53 patients with IHCC who underwent exploration between April 1983 and March 2004. Hepatic resection was performed in 44 patients, 30 of whom underwent lymph node dissection. Clinicopathological features and outcomes were analyzed. The actuarial 1-year survival was 66.2% in resected patients, compared to 0% in unresectable patients (p < 0.0001), with a 50% overall survival of 21.5 months and 3.1 months, respectively. The actuarial 3-year and 5-year overall survival rates in resected patients were 38.3% and 26.3%, respectively. Univariate analysis revealed that factors associated with poor overall survival included multiple tumors, extrahepatic bile duct involvement, noncurative resection, and involvement of lymph nodes. Multivariate analysis in resected patients revealed that multiple tumors (p < 0.0074) and non-curative resection (p = 0.0068) were significant risk factors for poor overall survival. The survival rate in patients with three or more positive nodes was significantly lower than in those with fewer than three (p < 0.0001). Three patients with solitary tumors and one or two involved lymph nodes have survived beyond 4 years after extended lobectomy with systemic lymphadenectomy. Curative resection, single tumor, and fewer than two lymph node metastases were prognostic factors for good outcome. Curative resection with lymph node dissection improved survival in patients with no more than two positive lymph nodes.

Perioperative Management of Hepatic Resection Toward Zero Mortality and Morbidity: Analysis of 793 Consecutive Cases in a Single Institution

BACKGROUND The mortality rates associated with hepatectomy are still not zero. Our aim was to define the risk factors for complications and to evaluate our perioperative management. STUDY DESIGN Between 2001 and 2008, 793 consecutive patients (547 men and 246 women; mean age ± SD, 56.1 ± 14.9 years) underwent hepatectomy without gastrointestinal resection and choledocojejunostomy at our center. Of these patients, 354 (44.6%) were positive for the hepatitis B virus surface antigen and/or the hepatitis C virus antibody. We categorized 783 (98.7%) patients as Child-Pugh class A. Major resection (sectionectomy, hemihepatectomy, and extended hemihepatectomy), was performed in 535 patients (67.5%) and re-resection in 81 patients (10.2%). RESULTS The median operative time was 345.5 minutes and median blood loss was 360 mL. The rate of red blood cell transfusion was 6.8%. The morbidity rate was 15.6%. Reoperations were performed in 19 patients (2.4%). The mean postoperative hospital stay was 18.4 ± 10.4 days. The in-hospital mortality rate was 0.1% (1 of 793 patients; caused by hepatic failure). The independent relative risk for morbidity was influenced by an operative time of more than 360 minutes, blood loss of more than 400 mL, and serum albumin levels of less than 3.5 g/dL, as determined using multivariate logistic regression analysis. CONCLUSIONS Shorter operative times and reduced blood loss were obtained by improving the surgical technique and using new surgical devices and intraoperative management, including anesthesia. Additionally, decision making using our algorithm and perioperative management according to CDC guidelines reduced the morbidity and mortality associated with hepatectomy.

Identification of novel serum biomarkers of hepatocellular carcinoma using glycomic analysis.

The altered N‐glycosylation of glycoproteins has been suggested to play an important role in the behavior of malignant cells. Using glycomics technology, we attempted to determine the specific and detailed N‐glycan profile for hepatocellular carcinoma (HCC) and investigate the prognostic capabilities. From 1999 to 2011, 369 patients underwent primary curative hepatectomy in our facility and were followed up for a median of 60.7 months. As normal controls, 26 living Japanese related liver transplantation donors were selected not infected by hepatitis B and C virus. Their mean age was 40.0 and 15 (57.7%) were male. We used a glycoblotting method to purify N‐glycans from preoperative blood samples from this cohort (10 μL serum) which were then identified and quantified using mass spectrometry (MS). Correlations between the N‐glycan levels and the clinicopathologic characteristics and outcomes for these patients were evaluated. Our analysis of the relative areas of all the sugar peaks identified by MS, totaling 67 N‐glycans, revealed that a proportion had higher relative areas in the HCC cases compared with the normal controls. Fourteen of these molecules had an area under the curve of greater than 0.80. Analysis of the correlation between these 14 N‐glycans and surgical outcomes by univariate and multivariate analysis identified G2890 (m/z value, 2890.052) as a significant recurrence factor and G3560 (m/z value, 3560.295) as a significant prognostic factor. G2890 and G3560 were found to be strongly correlated with tumor number, size, and vascular invasion. Conclusion: Quantitative glycoblotting based on whole serum N‐glycan profiling is an effective approach to screening for new biomarkers. The G2890 and G3560 N‐glycans determined by tumor glycomics appear to be promising biomarkers for malignant behavior in HCCs. (HEPATOLOGY 2013;)

Co-expression of mesothelin and CA125 correlates with unfavorable patient outcome in pancreatic ductal adenocarcinoma.

Objectives: Recent studies have shown that the high affinity of mesothelin-CA125 interaction might cause intracavitary tumor metastasis. We examined the clinicopathologic significance and prognostic implication of mesothelin and CA125 expression in pancreatic ductal adenocarcinoma. Methods: Tissue samples from 66 pancreatic ductal adenocarcinomas were immunohistochemically examined. Proportion and intensity of constituent tumor cells with mesothelin and CA125 expression were analyzed and classified as high-level expression, defined as expression by more than 50% of tumor cells and/or moderate to strong staining, or low-level expression otherwise. Results: A high level of mesothelin was correlated with a higher histological grade (P = 0.049) and the level of blood vessel permeation (P = 0.0006), whereas a high level of CA125 expression was correlated with a higher recurrence rate (P = 0.015). The expression of mesothelin was strongly correlated with that of CA125 (P = 0.0041). Co-expression of mesothelin and CA125 were associated with an unfavorable patient outcome (P = 0.0062). Conclusions: This is the first report showing that co-expression of mesothelin and CA125 were in pancreatic ductal adenocarcinoma, and such co-expression is associated with a poor prognosis. Our finding suggests that co-expression of these two factors plays a significant role in the acquisition of aggressive clinical behavior.

ASKP1240, a fully human anti-CD40 monoclonal antibody, prolongs pancreatic islet allograft survival in nonhuman primates.

A strategy for inhibiting CD40 has been considered as an alternative approach for immunosuppression because of undesirable effects of anti‐CD154 monoclonal antibodies (mAbs). Previously, we demonstrated that ASKP1240, which is a fully human anti‐CD40 mAb, significantly prolonged kidney and liver allograft survival in cynomolgus monkeys without causing thromboembolic complications. Herein, we evaluated the effect of ASKP1240 on pancreatic islet transplantation (PITx) in cynomolgus monkeys. Diabetes was induced by total pancreatectomy, and islet allografts were transplanted into the liver. Following PITx (8201–12 438 IEQ/kg), blood glucose levels normalized promptly in all animals. Control islet allografts were rejected within 9 days (n = 3), whereas ASKP1240 (10 mg/kg) given on postoperative days 0, 4, 7, 11 and 14 (induction treatment, n = 5) significantly prolonged graft survival time (GST) to >15, >23, 210, 250 and >608 days, respectively. When ASKP1240 (5 mg/kg) was administered weekly thereafter up to post‐PITx 6 months (maintenance treatment, n = 4), GST was markedly prolonged to >96, >115, 523 and >607 days. During the ASKP1240 treatment period, both anti‐donor cellular responses and development of anti‐donor antibodies were abolished, and no serious adverse events were noted. ASKP1240 appears to be a promising candidate for immunosuppression in clinical PITx.

The impact of anatomical resection for hepatocellular carcinoma that meets the milan criteria

The aim of this study was to analyze the impact of anatomical resection for hepatocellular carcinoma (HCC) that meets the Milan criteria.

Analysis of the risk factors for early death due to disease recurrence or progression within 1 year after hepatectomy in patients with hepatocellular carcinoma

BackgroundLiver resection for hepatocellular carcinoma (HCC) has the highest local controllability among all local treatments and results in a good survival rate. However, the recurrence rates of HCC continue to remain high even after curative hepatectomy Moreover, it has been reported that some patients with HCC have an early death due to recurrence. We analyzed the preoperative risk factors for early cancer death.MethodsBetween 1997 and 2009, 521 consecutive patients who underwent hepatectomy for HCC at our center were assigned to group ED (death due to HCC recurrence or progression within 1 year after hepatectomy) and group NED (alive over 1 year after hepatectomy). Risk factors for early cancer death were analyzed.ResultsGroup ED included 48 patients, and group NED included 473 patients. The cause of death included cancer progression (150; 78.1%), operation-related (1; 0.5%), hepatic failure (15; 7.8%), and other (26; 13.5%). Between the ED and NED groups, there were significant differences in albumin levels, Child-Pugh classifications, anatomical resections, curability, tumor numbers, tumor sizes, macroscopic vascular invasion (portal vein and hepatic vein), alpha-fetoprotein (AFP) levels, AFP-L3 levels, protein induced by vitamin K absence or antagonism factor II (PIVKA-II) levels, differentiation, microscopic portal vein invasion, microscopic hepatic vein invasion, and distant metastasis by univariate analysis. Multivariate analysis identified specific risk factors, such as AFP level > 1,000 ng/ml, tumor number ≥ 4, tumor size ≥ 5 cm, poor differentiation, and portal vein invasion. With respect to the preoperative risk factors such as AFP level, tumor number, and tumor size, 3 (1.1%) of 280 patients with no risk factors, 12 (7.8%) of 153 patients with 1 risk factor, 24 (32.9%) of 73 patients with 2 factors, and 9 (60.0%) of 15 patients with 3 risk factors died within 1 year of hepatectomy (p < 0.0001).ConclusionsHepatectomy should be judiciously selected for patients with AFP level > 1,000 ng/ml, tumor number ≥ 4, and tumor size ≥ 5 cm, because patients with these preoperative risk factors tend to die within 1 year after hepatectomy; these patients might be better treated with other therapy.

Efficacy of preoperative radiotherapy to portal vein tumor thrombus in the main trunk or first branch in patients with hepatocellular carcinoma

BackgroundThe prognosis of hepatocellular carcinoma (HCC) with portal vein tumor thrombus (PVTT) in the main trunk or the first branch is very poor.MethodsRadiotherapy (RT) to PVTT was followed by hepatectomy within 2 weeks. The dose used was 30–36 Gy, in 10–12 fractions, for 15–20 days. The efficacy of preoperative RT to PVTT in the main trunk or first branch was evaluated by comparing results in patients who underwent hepatectomy (group R; n = 15) with preoperative RT and those without preoperative RT (group N; n = 28).ResultsThe 1-, 3-, and 5-year survival rates in group R were 86.2%, 43.5%, and 34.8%, respectively, while these values in group N were 39.0%, 13.1%, and 13.1%, respectively. The survival curve of group R was significantly better than that of group N (P = 0.0359). In group R, five (83.3%) of six patients whose tumor thrombus was completely necrosed (based on pathological examination) and whose follow-up period was over 2 years survived for more than 2 years. Female sex (P = 0.0066), multiple tumors (P = 0.0369), and absence of preoperative RT (P = 0.0359) were ranked as significant factors for a poor prognosis by univariate analysis. Multivariate analysis revealed absence of preoperative RT and female sex to be significant factors for a poor prognosis.ConclusionPreoperative RT to PVTT in the main trunk or first branch improved the prognosis of patients with HCC with PVTT, and could be a promising new modality in the treatment of these patients.

Preoperative Evaluation of Hepatic Vasculature by Three-Dimensional Computed Tomography in Patients Undergoing Hepatectomy

BackgroundHepatectomy is particularly difficult when the tumor is large, close to the inferior vena cava or the main trunk of the hepatic or portal vein, or in the caudate lobe, as well as when the operation is a re-hepatectomy, because two-dimensional computed tomography (CT) often does not clearly show tumor location relative to blood vessels.Study DesignTo evaluate the efficacy of three-dimensional computed tomography (3D-CT), reconstructed from multidetector-row computed tomography (MD-CT) with contrast, MD-CT was performed in 17 patients before hepatectomy.ResultsThe third-order branches of the hepatic artery and the portal vein were clearly shown in all cases. Both the hepatic vein, which drained the same segment that the portal vein fed, and the portal vein were also clearly shown. These vessels could be visualized from any perspective. In 2 patients who underwent hemihepatectomy, large tumors (23.0 and 17.0 cm) displaced the vasculature, but the positions of tumor and vessels could be precisely evaluated by 3D-CT. In patients who required replacement of the vena cava with synthetic grafts, the distance and direction of pressure to IVC by tumor was accurately estimated by 3D-CT. In patients who were limited to segmentectomy or partial hepatectomy because of prior hepatectomy or tumor position, evaluation of the glissons was facilitated by 3D-CT.ConclusionsThree-dimensional-CT was extremely useful for preoperative simulation because it provided important information that could not be obtained with 2D-CT.

AFP mRNA detected in bone marrow by real-time quantitative RT-PCR analysis predicts survival and recurrence after curative hepatectomy for hepatocellular carcinoma.

Objective:To determine whether detection of hepatocellular carcinoma (HCC) cells by real-time quantitative RT-PCR targeting of alpha-fetoprotein mRNA (AFP mRNA) before or after curative hepatectomy predicts HCC recurrence and patient survival. Summary Background Data:The presence of cancer cells in peripheral blood and/or bone marrow in patients with malignant disease has been reported to correlate with outcome. Methods:Between July 2000 and June 2005, 136 consecutive HCC patients underwent primary curative hepatectomy. Bone marrow aspirated preoperatively, and peripheral blood samples collected before and after operation were subjected to real-time quantitative RT-PCR analysis using AFP mRNA as a target molecule. Median follow-up was 23 months (range, 6–54 months). Patient survival (PS), disease-free survival (DFS), and clinicopathologic features were compared between patients with positive and negative AFP mRNA. Results:Twenty-four patients died (22 from HCC). HCC recurred in 66 patients (hepatic in 37 [56.1%]; hepatic and remote in 17 [25.8%], and remote alone in 12 [18.2%]). Bone marrow was positive for AFP mRNA in 38 patients (27.9%) and negative in 98 (72.1%). One- and 3-year PS was 96.6% and 91.4%, respectively, with negative AFP mRNA versus 86.2% and 55.5%, respectively, with positive AFP mRNA (P < 0.0001). One- and 3-year DFS were 73.2% and 44.8%, respectively, with negative AFP mRNA versus 54.5% and 25.8%, respectively, with positive AFP mRNA (P = 0.0399). Portal vascular invasion, tumor size, multiple tumors, and tumor differentiation correlated with inferior PS and DFS on univariate analysis. On multivariate analysis, positive AFP mRNA was the most important risk factor for PS (P = 0.001) and DFS (P = 0.0165). In addition, positive AFP mRNA in peripheral blood after operation tended to predict reduced DFS. Conclusion:AFP mRNA in the bone marrow and systemic circulation during the perioperative period predicts patient survival and recurrence after curative hepatic resection for HCC.