Ryoko Sasaki

Significance of Ductal Margin Status in Patients Undergoing Surgical Resection for Extrahepatic Cholangiocarcinoma

ObjectivesThe objective of this study was to determine whether carcinoma in situ at the bile duct margin is prognostically different from residual invasive carcinoma in patients with extrahepatic cholangiocarcinoma.Summary Background DataAlthough there are many reports that the ductal margin status at bile duct resection stumps is a prognostic indicator in patients with extrahepatic cholangiocarcinoma, some patients who undergo resection with microscopic tumor involvement of the bile duct margin survive longer than expected.MethodsA retrospective clinicopathological analysis of 128 patients who had undergone surgical resection for extrahepatic cholangiocarcinoma was conducted. The status of the bile duct resection margin was classifiedas negative in 105 patients (82.0%), positive for carcinoma in situ in 12 patients (9.4%), and positive for invasive carcinoma in 11 patients (8.6%).ResultsDuctal margin status was an independent prognostic indicator by both univariate (p = 0.0022) and multivariate (p = 0.0105) analyses, along with lymph node metastasis. There was no significant difference between patients with a negative ductal margin and those with a positive ductal margin with carcinoma in situ (p = 0.5247). The 5-year survival rate of patients with a positive ductal margin with carcinoma in situ (22.2%) was significantly better (p = 0.0241) than with invasive carcinoma (0%). There was a significant relationship between local recurrence and ductal margin status (p = 0.0401).ConclusionsAmong patients undergoing surgical resection for extrahepatic cholangiocarcinoma, invasive carcinoma at the ductal resection margins appears to have a significant relation to local recurrence and also a significant negative impact on survival, whereas residual carcinoma in situ does not. Discrimination whether carcinoma in situ or invasive carcinoma is present is important in clinical setting in which the resection margin at the ductal stump is positive.

Activation of human liver sinusoidal endothelial cell by human platelets induces hepatocyte proliferation

BACKGROUND & AIMS We previously reported that platelets promote hepatocyte proliferation. In this study, we focused on the role of platelets in liver sinusoidal endothelial cells (LSECs) in addition to their role in hepatocyte in liver regeneration. METHODS Immortalized human LSECs (TMNK-1) were used. The LSECs were co-cultured with human platelets, and the proliferation of LSECs and the excretion of growth factors and interleukin-6 (IL-6) were subsequently measured. The main factor from platelets which induced the excretion of IL-6 from LSECs was determined using inhibitors of each component contained in the platelets. The need for direct contact between platelets and LSECs was investigated using cell culture inserts. The proliferation of human primary hepatocytes was measured after the addition of the supernatant of LSECs cultured with or without platelets. RESULTS The number of LSECs cocultured with platelets significantly increased. Excretion of IL-6 and vascular endothelial growth factor (VEGF) increased in LSECs with platelets. JTE-013, a specific antagonist for sphingosine 1-phosphate (S1P) 2 receptors, inhibited the excretion of IL-6 from LSECs after the addition of platelets. When the platelets and LSECs were separated by the cell culture insert, the excretion of IL-6 from LSECs was decreased. DNA synthesis was significantly increased in human primary hepatocytes cultured with the supernatant of LSECs with platelets. CONCLUSIONS Platelets promote LSEC proliferation and induce IL-6 and VEGF production. Direct contact between the platelets and LSECs and S1P, that are contained in platelets, were involved in the excretion of IL-6 from LSECs. IL-6 from LSECs induced proliferation of parenchymal hepatocytes.

Fatty acid synthase inhibitor cerulenin suppresses liver metastasis of colon cancer in mice

Fatty acid synthase (FAS) is highly expressed in many kinds of human cancers, including colorectal cancer (CRC), and we have investigated the potential use of FAS inhibitors for chemoprevention of liver metastasis of CRC in mice. Expression of FAS was evaluated in murine CRC cell lines Colon 26 and CMT 93. Cerulenin, a natural inhibitor of FAS, induced apoptosis in these cell lines. The ability of cerulenin to prevent development of liver metastatic lesions in Colon 26 was evaluated. The numbers and sizes of liver metastatic CRC tumors were significantly reduced by treating mice with cerulenin. Cerulenin treatment was associated with reduced levels of phosphorylated Akt in Colon 26 cells, suggesting that inhibition of this signal transduction pathway might be involved in the chemopreventive activity of this compound. Based on studies in mouse models, inhibiting FAS would be an effective strategy to prevent and retard growth of liver metastatic tumors of CRC that have high expression of this enzyme. (Cancer Sci 2010; 00: 000–000)

Significance of Extensive Surgery Including Resection of the Pancreas Head for the Treatment of Gallbladder Cancer—From the Perspective of Mode of Lymph Node Involvement and Surgical Outcome

The present study aimed to clarify the efficacy of extensive surgery, including pancreas head resection, for more complete lymphadenectomy in the treatment of gallbladder carcinoma. The study involved retrospective analyses of 65 consecutive patients with gallbladder carcinoma who underwent surgical resection between 1982 and 2003. Of these 65 patients, 41.5% displayed node-positive disease and among them 23.1% had positive para-aortic nodes. Of six node-positive 5-year survivors, five underwent pancreatoduodenectomy combined with S4aS5 hepatic subsegmentectomy. The 5-year survival rates were 76.2% for pN0, 30.0% for pN1, 45.8% for pN2, and 0% for pM1[lymph], respectively. Significant differences existed in survival rates. Postoperative recurrence was observed in 24.1% (13/54) of patients who underwent R0 resection. Of the four patients who displayed lymph node recurrence, two had pericholedocal and/or posterior pancreatoduodenal lymph node metastasis at the time of surgery and underwent pancreas-preserving regional lymphadenectomy. These results suggest that extensive resection, including resection of the pancreatic head, is effective in selected patients with up to pN2 lymph node metastasis, as long as complete removal of the cancer can be achieved. Pancreatoduodenectomy combined with S4aS5 hepatic subsegmentectomy should be considered when lymph node metastasis is obvious and the patient is in good condition.

Platelet-derived adenosine 5'-triphosphate suppresses activation of human hepatic stellate cell : In vitro study

Aim:  Activated hepatic stellate cells (HSC) play a critical role in liver fibrosis. Suppressing abnormal function of HSC or reversion from activated to quiescent form is a hopeful treatment for liver cirrhosis. The interaction between platelets and HSC remains unknown although platelets go through hepatic sinusoids surrounded by HSC. This study aimed at clarifying the hypothesis that platelets control activation of HSC.

Platelet adhesion in the sinusoid caused hepatic injury by neutrophils after hepatic ischemia reperfusion

Liver ischemia-reperfusion (I/R) injury is one of the most serious complications of hepatic surgery. In I/R, activated Kupffer cells cause platelet adhesion to sinusoidal endothelium as well as neutrophils and cause liver dysfunction. The aim of this study was to evaluate platelet dynamics in the hepatic microcirculation after I/R by intravital microscopy (IVM) and to clarify the relationship between platelet adhesion and neutrophil activation. Male Sprague-Dawley (SD) rats were divided into two groups: the control (administration of saline) group and the sivelestat group in which neutrophil activation was suppressed by sivelestat before I/R. The number of adherent platelets in sinusoid was observed up to 120 minutes after I/R by IVM. Samples of liver tissue and blood were taken for examination of histological findings, liver enzymes and inflammatory cytokines. The number of adherent platelets was significantly increased after I/R in both groups. Compared with the control group, the number of adherent platelets significantly decreased after hepatic I/R in the sivelestat group. Moreover, sivelestat improved changes of histological findings and elevation of liver enzymes. However, there was no significant difference in inflammatory cytokines of TNF-α, IL-1β or IL-6. Platelet adhesion in the sinusoid is associated with liver dysfunction after I/R as well as neutrophils. Activated neutrophils induce platelet adhesion in the sinusoid of the liver.

Impact of three-dimensional analysis of multidetector row computed tomography cholangioportography in operative planning for hilar cholangiocarcinoma.

BACKGROUND A detailed evaluation of portal triad structures, especially the biliary anatomy at the hepatic hilus, is essential to ensure curative resection for hilar cholangiocarcinoma. METHODS Patients underwent 3-dimensional analysis using multidetector row computed tomography cholangioportography preoperatively. The number of bile duct orifices in the cut end of the hilar plate was estimated and compared with the actual number of bile ducts. Furthermore, the estimated length of the surgical margin and its relationship to the pathological margin status was evaluated. RESULTS The number of bile duct orifices was correctly estimated in 14 of 19 patients. Of 18 hepatic ducts in which the estimated length of the hepatic side surgical margin was calculated 17 hepatic ducts (94.4%) were diagnosed pathologically as margin negative. CONCLUSIONS This investigatory technique has the advantages of precise visualization of anatomic structures and multidirectional assessment of biliary branches and vessels, allowing improved operative planning for the treatment of hilar cholangiocarcinoma.

Effective delivery of chemotherapeutic nanoparticles by depleting host Kupffer cells

Although chemotherapeutic nanoparticles would confer various advantages, the majority of administrated nanoparticles are known to be spoiled by the reticuloendothelial system (RES). Intending to more effectively deliver therapeutic nanoparticles to target regions in vivo, host RES, especially Kupffer cells in the liver, have been depleted ahead of drug administration. To demonstrate this hypothesis, clodronate liposomes were preinjected into BALB/c nude mice for depletion of Kupffer cells 2 days before, and pegylated liposomal doxorubicin (Doxil) at the doses of 1.25, 2.5 and 5.0 mg/kg was administered. As a result, doxorubicin accumulation in the liver was decreased from 36 to 26% injected dose/organ by the Kupffer cells depletion, and consequently, the plasma concentration of doxorubicin was significantly enhanced threefold (from 11 to 33 μg/mL) on day 1 at 1.25 mg/kg‐dose group. Doxorubicin accumulation in the tumor was increased from 0.78 to 3.0 μg/g‐tissue on day 3, and tumor growth inhibition by Doxil was significantly boosted (tumor volumes from 751 to 482 mm3 on day 24) by the Kupffer cells depletion. In conclusion, Kupffer cells depletion by clodronate liposomes enhanced the plasma concentration and antitumor effects of Doxil, and would be widely applicable for various clinical cancer chemotherapies using nanoparticles.

MR Imaging of Reactive Lymphoid Hyperplasia of the Liver

IntroductionReactive lymphoid hyperplasia, also known as pseudolymphoma or nodular lymphoid lesion of the liver, is a rare benign lesion. It is mainly detected in the lung, stomach, small intestine, orbit, pancreas, skin, and breast. It remains difficult to distinguish reactive lymphoid hyperplasia from malignant disease clinically when it develops in the liver.Case Report We have recently encountered a patient with liver reactive lymphoid hyperplasia who had undergone colon cancer surgery.ConclusionPreoperative MR imaging showed some useful findings indicating reactive lymphoid hyperplasia.

A novel preoperative fusion analysis using three-dimensional MDCT combined with three-dimensional MRI for patients with hilar cholangiocarcinoma

The purpose of the present study was to evaluate the anatomical relationship between the tumor, portal veins, hepatic arteries, and hilar hepatic ducts at the hepatic hilum using a novel preoperative fusion analysis for patients with hilar cholangiocarcinoma. This involved combining three-dimensional multidetector-row computed tomography with three-dimensional magnetic resonance imaging. This novel fusion imaging technique can play an important clinical role for patients undergoing surgery for hilar cholangiocarcinoma.