Yasuyuki Shimahara

Chemokine receptor CXCR3 promotes colon cancer metastasis to lymph nodes.

Chemokines and their receptors are essential for leukocyte trafficking, and also implicated in cancer metastasis to specific organs. We have recently demonstrated that CXCR3 plays a critical role in metastasis of mouse melanoma cells to lymph nodes. Here, we show that some human colon cancer cell lines express CXCR3 constitutively. We constructed cells that expressed CXCR3 cDNA (‘DLD-1-CXCR3’), and compared with nonexpressing controls by rectal transplantation in nude mice. Although both cell lines disseminated to lymph nodes at similar frequencies at 2 weeks, DLD-1-CXCR3 expanded more rapidly than the control in 4 weeks. In 6 weeks, 59% of mice inoculated with DLD1-CXCR3 showed macroscopic metastasis in para-aortic lymph nodes, whereas only 14% of those with the control (P<0.05). In contrast, metastasis to the liver or lung was rare, and unaffected by CXCR3 expression. In clinical colon cancer samples, we found expression of CXCR3 in 34% cases, most of which had lymph node metastasis. Importantly, patients with CXCR3-positive cancer showed significantly poorer prognosis than those without CXCR3, or those expressing CXCR4 or CCR7. These results indicate that activation of CXCR3 with its ligands stimulates colon cancer metastasis preferentially to the draining lymph nodes with poorer prognosis.

Suppression of VEGFR-3 signaling inhibits lymph node metastasis in gastric cancer.

In gastric cancer, lymph node metastasis is one of the major prognostic factors and forms the basis for surgical removal of local lymph nodes. Recently, several studies have demonstrated that overexpression of lymphangiogenic growth factor VEGF‐C or VEGF‐D induces tumor lymphangiogenesis and promotes lymphatic metastasis in mouse tumor models. We examined whether these processes could be inhibited in naturally metastatic tumors by blocking of their cognate receptor VEGFR‐3 signaling pathway. Using a mouse orthotopic gastric cancer model which has a high frequency of lymph node metastasis, we estimated lymphatic vessels in gastric cancers by immunostaining for VEGFR‐3 and other specific lymphatic markers, LYVE‐1 and prox‐1. Then we systemically administered anti‐VEGFR‐3 blocking antibodies. This treatment resulted in the inhibition of regional lymph node metastasis and reduction of lymphatic vessel density in the primary tumors. In addition, increased density of LYVE‐1‐positive lymphatic vessels of primary tumors was closely correlated with lymph node metastasis in human samples of gastric cancer. Antilymphangiogenesis by inhibiting VEGFR‐3 signaling could provide a potential strategy for the prevention of lymph node metastasis in gastric cancer.

Surgical resection of hilar cholangiocarcinoma: analysis of survival and postoperative complications.

BackgroundSurgery is the only potentially curative treatment for hilar bile duct cancer. This study sought to evaluate the efficacy and feasibility of surgical management of hilar bile duct carcinoma, including radical hepatectomy, at a single institution.MethodsWe performed a retrospective review of 49 consecutive patients who underwent surgery at our hospital between 1990 and 2003.ResultsAltogether, 44 of 49 patients underwent radical hepatectomy combined with caudate lobectomy and lymphadenectomy. One and four patients underwent partial hepatectomy or bile duct resection, respectively. No patients underwent preoperative portal vein embolization. The 5-year survival rate was 39.7%, with a median survival time of 3.75 years. The postoperative morbidity and mortality rates were 46.8% and 2.0%, respectively. Cox’s proportional hazard model revealed that lymph node status and the residual tumor factor were independent prognostic factors. Multivariate analysis revealed that preoperative hyperbilirubinemia, postoperative complications, and extended surgical procedures were independently associated with postoperative hyperbilirubinemia. After potentially curative resection, 39.4% of patients suffered from disease recurrence. In 60% of the total cases, the sites of recurrence were distant metastases.ConclusionSurgery, including radical hepatectomy combined with caudate lobectomy and lymph node dissection, is a feasible, effective treatment for hilar bile duct cancer.

Safety of the donor in living-related liver transplantation-an analysis of 100 parental donors

The safety and lack of undue operative stress on the donor are documented from an analysis of 100 parental donors, whose children (3 months to 17 years old), received LRLTx at our institution between June 1992 and May 1994. Survival rate of recipients was 86%. No primary nonfunctioning liver was observed. The donors were 56 mothers and 44 fathers. Their ages ranged from 19 to 51 years and their weight ranged from 44 to 80 kg. They received partial liver resections to harvest the grafts. With regard to the liver graft, the left lobe was used in 24 cases (group L) and the left lateral segment was used in 75 cases (group S). The right lobe was used in one case. In the two groups, blood losses were 242 +/- 5 (S) and 312 +/- 14 ml (L); operation times were 6.22 +/- 0.11 (S) and 7.15 +/- 0.21 hr (L), respectively; in both groups, the postoperative hospital stay was 11 days (S, L). No significant differences between the two groups were observed in peripheral RBC and WBC count or serum AST. An increase in total bilirubin was not observed. In the exceptional case using the right lobe, blood loss of 2300 ml necessitated a blood transfusion of 1000 ml, and the total bilirubin increased up to 4.0 mg/dl on the third postoperative day, which prolonged the postoperative hospital stay to 17 days. These results conclusively suggest that safety is guaranteed when the left lobe or the left lateral segment is used as the liver graft for LRLTx.

An appraisal of pediatric liver transplantation from living relatives : initial clinical experiences in 20 pediatric liver transplantations from living relatives as donors

The authors performed 20 liver transplantations from living related donors between June 1990 and July 1991. The 20 pediatric patients (14 biliary atresia, two Budd-Chiari syndrome, one liver cirrhosis after hepatitis C viral infection (HCV hepatitis), 1 progressive intrahepatic cholestasis, 1 liver cirrhosis, 1 protoporphyria) were transplanted with 11 left lobes, eight left lateral segments, and one right lobe. The choice of donors was restricted to the parents of the recipients. The immunosuppressive treatment consisted of FK 506 and steroids. Seventeen recipients are alive, 15 of whom are well and at home. Two recipients, who underwent emergency transplantation, died of postoperative complications. Another recipient died of accidental asphyxia at 6 months after the transplantation. All 20 donors had uneventful postoperative courses and were able to resume their normal social lives. The arterial ketone body ratio (AKBR) increased to above 1.0 within 2 days after the transplantation in all cases. Relatively mild rejection episodes were encountered in only two cases transplanted with ABO-compatible grafts, and these were treated successfully with steroids and FK 506.

New Simple Technique for Hepatic Parenchymal Resection Using a Cavitron Ultrasonic Surgical Aspirator® and Bipolar Cautery Equipped with a Channel for Water Dripping

Abstract. We have developed a new technique to resect hepatic parenchyma without inflow occlusion by using the Cavitron Ultrasonic Surgical Aspirator (CUSA®) and bipolar cautery with a saline irrigation system. The significance of this method in hepatectomy was analyzed in comparison with historical control of hepatectomy using Pringles maneuver. An ordinary bipolar cautery was remodeled with an infusion line to bring saline droplets down the inner surface of one arm of the tweezers through an opening about 1.5 cm proximal to its tip. The optimal flow rate of saline was approximately one drop per second. The power of bipolar cautery was adjusted to 50 watts. When the tweezer blades were approximated to 1 or 2 mm, saline droplets were directed to the tip of tweezers and could be immediately evaporated. After sonicating parenchymal cells, the tissue of small branches of Glissons tree or small tributaries of the hepatic vein were coagulated by bipolar cautery. The coagulated cords were then easily cut by scissors. The impact of this technique on ordinary liver resections was evaluated by analyzing the postoperative clinical course in relation to the hepatic functional reserve necessary for major hepatectomy, duration of hepatectomy, and intraoperative blood loss. Hepatic resection without vascular occlusion using this technique could decrease the morbidity in patients who have less hepatic functional reserve. It could also decrease intraoperative blood loss. This new technique effectively decreased the surgical load of the remnant liver during parenchymal resection by avoiding ischemic stress. Consequently it extends the safety limits of major hepatectomy.

Implication of Frequent Local Ablation Therapy for Intrahepatic Recurrence in Prolonged Survival of Patients With Hepatocellular Carcinoma Undergoing Hepatic Resection: An Analysis of 610 Patients Over 16 Years Old

Objective:By comparing cohorts in 2 exclusive time frames, the factors that affected the surgical outcomes of patients with hepatocellular carcinoma (HCC) are presented. Summary Background Data:Reportedly, survival results of patients with HCC who underwent hepatectomy have improved in recent years. However, the major factors contributing to these favorable outcomes have not been fully explained. Methods:Between January 1985 and December 2000, 610 patients with HCC underwent liver resections as a primary and curative resection. They were categorized into 2 groups according to the year in which the surgeries were performed: before 1990 (n = 212; early group); and after 1991 (n = 398; late group). Clinicopathologic data, survival data, type of recurrence, and treatment of intrahepatic recurrence were compared between the 2 groups. Results:Clinicopathologic data were almost identical between the groups except for age, blood loss, and duration of surgery. The overall survival rate was significantly better in the late group compared with the early group (58.0% vs. 39.1% at 5 years, P < 0.0001). By contrast, disease-free survival remained unchanged (27.8% vs. 26.2% at 5 years, P = 0.2887). The most common type of recurrence was intrahepatic relapse, and there was no difference in the rate and the type of recurrence between the 2 groups. The 5-year survival rate after recurrence was increased in the late group (21.8% vs. 11.6%, P = 0.0002). Stratified analysis by the type of initial recurrence revealed that better survival in the late group was achieved only in solitary intrahepatic recurrences, not in multiple intrahepatic or extrahepatic recurrences. Changes in modality of treatment of recurrence were observed only in the management of solitary intrahepatic recurrences, where percutaneous ablation therapies were more frequently applied with new ablation techniques. Patients that had undergone ablation therapies in the late group had better postrecurrent survival than those in the early group. Multivariate analysis showed that presence of local ablation therapies was an independent favorable prognostic factor only in the late group. Conclusions:Significant improvements in outcomes were achieved in patients with HCC who underwent curative liver resections. Percutaneous ablation therapy for intrahepatic recurrence was considered to be a major contributory factor for improving survival after recurrence, as well as for overall survival.

Preoperative Positron Emission Tomography with Fluorine-18-Fluorodeoxyglucose is Predictive of Prognosis in Patients with Hepatocellular Carcinoma after Resection

Background:Hepatocellular carcinomas (HCCs) accumulate fluorine-18 fluorodeoxyglucose (FDG) to various degrees. The standardized uptake values (SUVs) of FDG-positron emission tomography (PET) in high-grade HCCs are significantly higher than those in low-grade HCCs.Aim:The aim of this study was to evaluate the possible usefulness of FDG-PET in predicting the prognosis of HCC patients after resection. We analyzed the relationship between the tumor to non-tumor SUV ratios (SUV ratio) and surgical outcome in 31 patients.Results:Of the 31 cases of HCC studied, seven (23%) exhibited SUV ratios greater than 2, as the cutoff value. The percentage of patients with poorly differentiated HCC was greater in the higher SUV ratio group (SUV ratio >2) than in the lower SUV ratio group (SUV ratio <2) (57 vs. 32%). The overall survival was significantly longer in the lower SUV ratio group than in the higher SUV ratio group (5-year-survival rate: 63 vs. 29% P = 0.006) (median survival time: 2310 vs.182 days).Conclusion:The SUV ratio was related significantly to disease-related death as well as other predictive factors, including the number of tumors, the size, stage, and involvement of vessels, and the involvement of the capsule. Consequently, we conclude that the SUV ratio provides information of prognostic relevance in patients with HCC before surgery.

Response of hepatic mitochondrial redox state to oral glucose load. Redox tolerance test as a new predictor of surgical risk in hepatectomy.

The redox tolerance test introduced in this article attempts to quantify the deterioration of hepatic mitochondrial energy metabolism by measuring the changes in arterial ketone body ratio in response to 75-g oral glucose loading, and is discussed in relation to its predictive value for assessing surgical risk in hepatectomy. The indicator, called redox tolerance index (RTI), represents a 100-fold cumulative enhancement of ketone body ratio relative to glucose level (100 x delta KBR/delta glucose). The redox tolerance index was significantly different between 31 liver cirrhotics and 10 normal volunteers (p less than 0.001). Subjects were divided into three classes (I: RTI greater than or equal to 1.0, II: 0.5 less than or equal to RTI less than 1.0, III: RTI less than 0.5). Postoperative mortality was significantly different among the three classes in 127 hepatic resections (chi 2 = 9.843, p less than 0.01). Of 97 hepatocellular carcinoma cases, major hepatic resections in class III showed significantly higher postoperative morbidity and mortality rates (p less than 0.05 and p less than 0.05, respectively). The present findings indicate that RTI based on redox theory is of potential value in predicting posthepatectomy outcome.

Results of hepatic resection for hepatocellular carcinoma invading major portal and/or hepatic veins

Nonsurgical therapy for patients with advanced hepatocellular carcinoma (HCC) has yielded poor long-term survival. This study evaluates the effects of surgical treatments for patients with HCC invading major portal and/or hepatic veins. The surgical results of 112 patients with HCC invading major portal and/or hepatic veins who underwent hepatic resection between 1985 and 2001 were studied to evaluate the feasibility of hepatic resection as a local treatment.