Background: Recent technical innovation enhances progresses in liver surgery. Now, for example, a preoperative 3D-simulation of the liver is indispensable for liver surgery. Detailed 3D-image revealed that portal perfusion area in cranial side of anterior segment sometimes surrounded superior right hepatic vein (SRHV). In such patients with HCC, SRHV should be resected for systematic resection. The aim of this presentation is to introduce various kinds of progresses in preoperative simulation and propose a new hepatectomy based on a hybrid concept of portal perfusion of anterior segment and hepatic venous drainage area of SRHV. A next generation simulation: 1) One-stop shopping of 3D-simulation of the liver: We newly developed 3D-simulation using a software of SYNAPSE VINCENT Ver. 3.1 (Fujifilm Medical, Tokyo, Japan), in which biliary system and hepatic vasculature are simultaneously reconstructed in one dynamic MD-CT. This technique can avoid incorrect positional relationship when separately depicted DIC–CT or MRCP is fused on 3D-image by MD-CT, as well as unnecessary radiation exposure. Recently, we applied 3D-printer to a preoperative simulation of hepatic resection to better understand the 3D-anatomy 2) Assessment of partial functional reserve: We have reported new methods to estimate regional hepatic functional reserve using hepatocyte-phase of EOB-MRI (J Gastroenterol 2012), (and fusion image of 3D-CT and asialoscintigraphy using 99m-Tc galactosyl human albumin). The method of EOB-MRI utilized character of hepatocyte-uptake of EOB through membrane transporters on hepatocytes. Fusion of both acialoscintigram of hepatic functional reserve and 3D-simulation by the above-mentioned software also well determines regional liver functional reserve. Those techniques provided accurate estimation of partial functional volume, and help surgeons’ decision making for resection volume of the liver. A new anatomical resection: SRHV-involvement was observed in 17 out of 66 patients (26%). The large IRHV (more than 5 mm in diameter) was found in 16 out of 66 patients (24%). In patients with SRHV-involvement, the incidence of a large IRHV (8 of 17: 48%) was significantly higher, compared to that in those without SRHV-involvement (8 of 49: 16%). The procedures are as follows: 1) encircling of anterior Glissonian pedicle, SRHV and inferior right hepatic vein (IRHV), 2) confirmation of demarcation line of anterior segment by occluding Glissonian pedicle and demarcation (congested) line by clamping proper hepatic artery and SRHV, and 3) IRHV-preserved complete resection of portal perfusion area plus drainage area of SRHV, combined with SRHV resection. Two patients having a large IRHV and HCC near the root of SRHV underwent a IRHV-preserved hepatectomy combined with SRHV resection (S8 + SRHVdrainage area in 1 and anterior segment + SRHV-drainage area in 1). Postoperative CT scan revealed complete resection of drainage area of SRHV and no congestion in the remnant posterior segment after hepatectomy due to excellent drainage through a large IR. Conclusions: Various advancements, such as preoperative 3D-simulation including partial functional reserve estimation and 3D-printer, enabled surgeons to perform hepatic resection easily and safely. In such HCC patients having a large IRHV, our new hepatectomy based on a hybrid concept of portal perfusion of anterior segment and venous drainage area of SRHV, combined with SRHV resection, is a promising option from the viewpoint of systematic resection (curability) and functional reserve of the future remnant liver in selected patients.

Background: Recent technical innovation enhances progresses in liver surgery.Now, for example, a preoperative 3D-simulation of the liver is indispensable forliver surgery. Detailed 3D-image revealed that portal perfusion area in cranial sideof anterior segment sometimes surrounded superior right hepatic vein (SRHV). Insuch patients with HCC, SRHV should be resected for systematic resection.The aim of this presentation is to introduce various kinds of progresses inpreoperative simulation and propose a new hepatectomy based on a hybridconcept of portal perfusion of anterior segment and hepatic venous drainage areaof SRHV.A next generation simulation:1) One-stop shopping of 3D-simulation of the liver: We newly developed3D-simulation using a software of SYNAPSE VINCENT Ver. 3.1 (Fujifilm Medical,Tokyo, Japan), in which biliary system and hepatic vasculature are simultaneouslyreconstructed in one dynamic MD-CT. This technique can avoid incorrectpositional relationship when separately depicted DIC–CT or MRCP is fused on3D-image by MD-CT, as well as unnecessary radiation exposure. Recently, weapplied 3D-printer to a preoperative simulation of hepatic resection to betterunderstand the 3D-anatomy2) Assessment of partial functional reserve: We have reported new methods toestimate regional hepatic functional reserve using hepatocyte-phase of EOB-MRI(J Gastroenterol 2012), (and fusion image of 3D-CT and asialoscintigraphy using99m-Tc galactosyl human albumin). The method of EOB-MRI utilized characterof hepatocyte-uptake of EOB through membrane transporters on hepatocytes.Fusion of both acialoscintigram of hepatic functional reserve and 3D-simulationby the above-mentioned software also well determines regional liver functionalreserve. Those techniques provided accurate estimation of partial functionalvolume, and help surgeons’ decision making for resection volume of the liver.A new anatomical resection: SRHV-involvement was observed in 17 out of 66patients (26%). The large IRHV (more than 5 mm in diameter) was found in 16 outof 66 patients (24%). In patients with SRHV-involvement, the incidence of a largeIRHV (8 of 17: 48%) was significantly higher, compared to that in those withoutSRHV-involvement (8 of 49: 16%).The procedures are as follows: 1) encircling of anterior Glissonian pedicle, SRHVand inferior right hepatic vein (IRHV), 2) confirmation of demarcation line ofanterior segment by occluding Glissonian pedicle and demarcation (congested)line by clamping proper hepatic artery and SRHV, and 3) IRHV-preserved completeresection of portal perfusion area plus drainage area of SRHV, combined withSRHV resection.Two patients having a large IRHV and HCC near the root of SRHV underwenta IRHV-preserved hepatectomy combined with SRHV resection (S8 + SRHVdrainagearea in 1 and anterior segment + SRHV-drainage area in 1). PostoperativeCT scan revealed complete resection of drainage area of SRHV and no congestionin the remnant posterior segment after hepatectomy due to excellent drainagethrough a large IR.Conclusions: Various advancements, such as preoperative 3D-simulationincluding partial functional reserve estimation and 3D-printer, enabled surgeonsto perform hepatic resection easily and safely.In such HCC patients having a large IRHV, our new hepatectomy based on ahybrid concept of portal perfusion of anterior segment and venous drainagearea of SRHV, combined with SRHV resection, is a promising option from theviewpoint of systematic resection (curability) and functional reserve of the futureremnant liver in selected patients.

Cancer stem cells (CSCs) play an important role in cancer development, its main functions are self-renewing capacity, chemoresistance and tumorigenic capacity. The aim of this study is to clarify the possible role of Shh signaling in regulation of CSCs. METHODS: Normal cancer cells (HCT-116) were cultured with serum medium and cancer stem-like cells (CSCs) were obtained from serum-free medium after incubation for 14 days. After cell culturing was done RNA extraction and cDNA transcription of NCs and CSCs (HCT-116). The expressions mRNA of surface markers (CD44, EpCAM), stemness genes (Oct-4, Nanog), Shh signaling (Ptch1, SMO), and shh pathway downstream gene (Gli1), EMT markers (E-Cadherin, Vimentin) and TJ genes (Claudin-4, Occludin) were determined by real time RT-PCR before and after administration of cyclopamine (2, 5 μM). RESULTS: The expressions of surface markers (CD44, EpCAM) and stemness genes (Oct-4, Nanog) were significantly highly expressed in CSCs. Shh signaling pathway Ptch1, SMO and downstream gene Gli1 were significantly higher in CSCs than in NCs. Epithelial marker E-Cadherin was reduced in CSCs, mesenchymal marker Vimentin was up-regulated in CSCs. The expressions of Claudin-4 and Occludin were significantly higher in CSCs compared with NCs. SMO, Gli1 and Vimnetin were significantly inhibited after administration of cyclopamine (2, 5μM), but E-Cadherin was up-regulated in CSCs. Tight junction proteins were significantly inhibited by cyclopamine (2, 5μM). Although CD-44, Oct-4 and Nanog were inhibited in CSCs after administration of cyclopamine, these alterations were statistically significant in different genes respectively, but EpCAM was not inhibited. CONCLUSION: EMT, TJ and CSCs markers were affected by Shh signaling pathway in CSCs. Shh signaling pathway may play in an important role of regulation of CSCs.

Cancer stem cells (CSCs) play an important role in cancer development, its main functions are self-renewing capacity, chemoresistance and tumorigeniccapacity. The aim of this study is to clarify the possible role of Shh signaling in regulation of CSCs.METHODS:Normal cancer cells (HCT-116) were cultured with serum medium and cancer stem-like cells (CSCs) were obtained from serum-free medium after incubation for14 days. After cell culturing was done RNA extraction and cDNA transcription of NCs and CSCs (HCT-116). The expressions mRNA of surface markers (CD44,EpCAM), stemness genes (Oct-4, Nanog), Shh signaling (Ptch1, SMO), and shh pathway downstream gene (Gli1), EMT markers (E-Cadherin, Vimentin) and TJgenes (Claudin-4, Occludin) were determined by real time RT-PCR before and after administration of cyclopamine (2, 5 μM).RESULTS:The expressions of surface markers (CD44, EpCAM) and stemness genes (Oct-4, Nanog) were significantly highly expressed in CSCs. Shh signaling pathwayPtch1, SMO and downstream gene Gli1 were significantly higher in CSCs than in NCs. Epithelial marker E-Cadherin was reduced in CSCs, mesenchymal markerVimentin was up-regulated in CSCs. The expressions of Claudin-4 and Occludin were significantly higher in CSCs compared with NCs. SMO, Gli1 and Vimnetin were significantly inhibited after administration of cyclopamine (2, 5μM), but E-Cadherin was up-regulated in CSCs. Tight junction proteins were significantly inhibited by cyclopamine (2, 5μM). Although CD-44, Oct-4 and Nanog were inhibited in CSCs after administration of cyclopamine, these alterations were statistically significant in different genes respectively, but EpCAM was not inhibited.CONCLUSION:EMT, TJ and CSCs markers were affected by Shh signaling pathway in CSCs. Shh signaling pathway may play in an important role of regulation of CSCs.

Background: The technique of pancreatoduodenectomy (PD) has evolved, and artery first’ approach was considered for the intraoperative early determination of resectability for borderline resectable cases before the ‘point of no return’ and avoidance of blood congestion resulted in the reduction of blood loss. Also, active application of energy device was useful for the reduced operative time and blood loss. Recently, 3D simulation for hepatobiliary pancreatic surgery has been useful and mandatory. In this presentation, we introduced our recent refinements and advances for PD. ‘Artery first’ approach and vessel sealing system for PD: ‘Artery first’ approach were considered as six different methods as follows; 1) Superior approach, 2) Anterior approach, 3) Posterior approach, 4) Left posterior approach, 5) Right/ medial uncinate approach and 6) Mesenteric approach. A while ago, we preferably applied the mesenteric approach to PD, and also the combination of this approach with vessel sealing system (VSS) significantly reduced intraoperative blood loss (Mesenteric approach with VSS, n=21 vs. non-‘Artery first’ approach without VSS, n=78; 320±174ml vs. 486±263ml, p<0.01). Modified de-rotation method as complete ‘Artery first’ approach: Most recently, for further refinement of operative procedure, we refined a right/medial uncinate and posterior approach as modified de-rotation method. Point of view in this method was the complete clockwise rotation of small intestinal mesentery including ascending colon, in order to linearize from duodenum to jejunum and look at the direct front of superior mesenteric artery (SMA), vein (SMV) and some branched jejunal vessels originated from SMA and SMV (Fig.). Thereby, in the posterior view, the easy dissection of all pancreatic branch originated from SMA can be done. This modified de-rotation method was possible to achieve the complete ‘Artery first’ approach. Preoperative 3D simulation of arterial and venous anatomy: Until now, we applied 3D volumetery software (SYNAPSE VINCENT®) as preoperative simulation for hepatic resection. And recently, for evaluation of the position relationship between arteries and veins surround pancreas head, we adopted this software before PD. As first step, arteries and veins are automatically identified, and small vessels are manually traced on the axial CT view. After that, 3D arterial and venous simulations are combined. Grasp of detailed vessel anatomy and its relationship using preoperative 3D simulation enable to safely perform PD, even in young surgeons (operative time; young 512±49 vs. senior 445±41 min, p<0.01), (blood loss; young 353±203 vs. senior 246±109 ml, p=0.16). Conclusion: Those refinements and advances are possible to safely and easily perform pancreatoduodenectomy.

Background: The technique of pancreatoduodenectomy (PD) has evolved, andartery first’ approach was considered for the intraoperative early determinationof resectability for borderline resectable cases before the ‘point of no return’and avoidance of blood congestion resulted in the reduction of blood loss. Also,active application of energy device was useful for the reduced operative time andblood loss. Recently, 3D simulation for hepatobiliary pancreatic surgery has beenuseful and mandatory. In this presentation, we introduced our recent refinementsand advances for PD.‘Artery first’ approach and vessel sealing system for PD: ‘Artery first’ approachwere considered as six different methods as follows; 1) Superior approach, 2)Anterior approach, 3) Posterior approach, 4) Left posterior approach, 5) Right/medial uncinate approach and 6) Mesenteric approach. A while ago, wepreferably applied the mesenteric approach to PD, and also the combination ofthis approach with vessel sealing system (VSS) significantly reduced intraoperativeblood loss (Mesenteric approach with VSS, n=21 vs. non-‘Artery first’ approachwithout VSS, n=78; 320±174ml vs. 486±263ml, p<0.01).Modified de-rotation method as complete ‘Artery first’ approach: Most recently,for further refinement of operative procedure, we refined a right/medial uncinateand posterior approach as modified de-rotation method. Point of view in thismethod was the complete clockwise rotation of small intestinal mesenteryincluding ascending colon, in order to linearize from duodenum to jejunumand look at the direct front of superior mesenteric artery (SMA), vein (SMV) andsome branched jejunal vessels originated from SMA and SMV (Fig.). Thereby, inthe posterior view, the easy dissection of all pancreatic branch originated fromSMA can be done. This modified de-rotation method was possible to achieve thecomplete ‘Artery first’ approach.Preoperative 3D simulation of arterial and venous anatomy:Until now, we applied 3D volumetery software (SYNAPSE VINCENT®) aspreoperative simulation for hepatic resection. And recently, for evaluation of theposition relationship between arteries and veins surround pancreas head, weadopted this software before PD. As first step, arteries and veins are automaticallyidentified, and small vessels are manually traced on the axial CT view. Afterthat, 3D arterial and venous simulations are combined. Grasp of detailed vesselanatomy and its relationship using preoperative 3D simulation enable to safelyperform PD, even in young surgeons (operative time; young 512±49 vs. senior445±41 min, p<0.01), (blood loss; young 353±203 vs. senior 246±109 ml,p=0.16).Conclusion: Those refinements and advances are possible to safely and easilyperform pancreatoduodenectomy.

BACKGROUND/AIMS: The role of uncoupling protein-2 (UCP2) in the liver is currently unclear. Emerging evidence suggests a relationship between UCP2 and oxidative stress. In the present study, we tested the hypothesis that UCP2 expression in the liver might change during warm ischemia-reperfusion (I/R) according to oxidative stress. METHODS: Wistar rats were subjected to 40 (short ischemia) or 90 (long ischemia) minutes of partial lobar ischemia followed by 4 hours of reperfusion. UCP2 expression in the ischemic and nonischemic lobes was assessed using reverse transcription-polymerase chain reaction and immunohistochemistry. Malondialdehyde concentrations in the liver tissue were also compared. RESULTS: Malondialdehyde concentrations in the ischemic lobes were significantly higher in the long ischemia group. In the ischemic lobes of the short ischemia group, UCP2 protein expression was induced in hepatocytes, which did not express the protein prior to treatment, and the expression levels were higher than in the long ischemia group. The intralobular distribution of UCP2 seemed to correlate inversely with that of the necrotic area. UCP2 expression was observed, even in nonischemic lobes with similar intralobular heterogeneity. CONCLUSIONS: UCP2 was induced in hepatocytes after warm I/R. Although the primitive role of UCP2 expression may be cytoprotective in nature, its actual protective effect in hepatic I/R may be minimal
Animals ; Hepatocytes ; Immunohistochemistry ; Ion Channels ; Ischemia ; Liver ; Malondialdehyde ; Mitochondrial Proteins ; Oxidative Stress ; Rats ; Rats, Wistar ; Reperfusion

INTRODUCTION: Recent technical innovation in liver surgery is remarkable. Now, for example, a preoperative 3D-simulation of the liver is a routine modality, and indispensable (or essential) for liver surgery. The aim of this presentation is to clarify various kinds of progresses and future perspective in liver surgery. PREOPERATIVE MODALITIES 1) One-stop shopping of 3D-simulation of the liver: We newly developed 3D-simulation using a software of SYNAPSE VINCENT Ver. 3.1 (Fujifilm Medical, Tokyo, Japan), in which biliary system is simultaneously reconstructed in one dynamic MD-CT. This technique avoids position error which occurred in 3D fusion image using another modality such as DIC–CT or MRCP, as well as unnecessary radiation exposure. 2) Assessment of partial functional reserve: We have reported new methods to astimate regional hepatic functional reserve using hepatocyte-phase of EOB-MRI (J Gastroenterol 2012), and fusion image of 3D-CT and asialoscintigraphy using 99m-Tc galactosyl human albumin. The method of EOB-MRI utilized character of hepatocyte-uptake of EOB through membrane transporters on hepatocytes. The other used fusion of both asialoscintigram of hepatic functional reserve and 3D-simulation by the above-mentioned software. Those techniques provided accurate estimation of partial functional volume, and help surgeons’ decision making of resection volume. INTRAOPERATIVE MODALITIES: 1) Navigation using iPad: navigation using iPad in which preoperative 3D-image data are uploaded in advance, tumor location, accurate and anatomical orientation can confirm in the operative field during operation. This technique enable not only operators also assistants or students to better understand precise anatomy. 2) Indocyanine green (ICG) fluorescent image-guided navigation: this technique using HyperEye Medical System (MIZUHO IKAKOGYO Co., Ltd. Tokyo, Japan) help us to confirm tattooing of target segment and parenchymal intersegmental plane, and detect hepatic tumors (metastatic and HCC) near liver surface as well as invisible tumor inside the liver. CONCLUSIONS: Various advancements such as preoperative 3D-simulation including partial functional reserve estimation and intraoperative navigation techniques enabled surgeons to easily and safely perform hepatic resection.

Background: The glissonean pedicle approach was introduced by Couinaud and Takasaki in the early 1980s. The key of the glissonean pedicle approach is clamping the pedicle first, secondly confirming the territory, and finally dissecting the liver parenchyma. In this presentation, we introduced our recent refinements of glissonean pedicle approach for liver resection. “Approach to the glissonean pedicles at the hepatic hilus” Couinaud described three approaches to the hepatic hilus. 1) Intra-fascial access (Control method): The conventional dissection at the hilus or within the sheath is referred to as intrafascial access However, dissection performed under the hilar plate is dangerous and surgeons have to consider any variations of the hepatic artery and bile ducts. 2) Extra-fascial access (Glissonean pedicle approach): The glissonean pedicle is dissected from the liver parenchyma at the hepatic hilus before dissecting the liver parenchyma. This procedure prevents intrahepatic metastasis of HCC, which spreads along the portal vein and improves the overall survival after surgery. 3) Extra-fascial and transfissural access: If the main portal fissure or the left suprahepatic fissure is opened after dissecting the liver parenchyma, the surgeon can confirm the pedicles that arise from the hilar plate or the umbilical plate. “Operative techniques” 1) Preoperative 3D simulation of the precise anatomy of portal vein, hepatic artery and bile duct at hepatic hilus should be performed. 2) Right glissonean pedicle: The hilar plate is detached from the quadrate lobe. The assistant pulls the liver parenchyma cranially and the operator conversely pulls the hepatoduodenal ligament caudally. Mayo scissors are inserted along the liver parenchyma between the liver parenchyma and glissonean capsule (Fig.1). Then forceps are inserted in the same way and the right main pedicle is taped (Fig.2). The right anterior and posterior glissonean pedicles are taped as well. 3) Left glissonean pedicle: The hilar plate is detached from the liver parenchyma. Then, the Arantius duct is confirmed and the left pedicle is dissected along the left pedicle at the ventral side of the Arantius duct. “Pitfall of glissonean pedicle approach” The right pedicle should be dissected in the liver side as much as possible to prevent the injury of left hepatic duct. If possible, the right pedicle is recommended to be dissected at the level of the second branches separately (Fig.3). The right posterior hepatic duct sometimes branches from the left hepatic duct and the Arantius duct is confirmed and the left pedicle should be dissected along the left pedicle at the ventral side of the Arantius duct because the right posterior hepatic duct branches from the left hepatic duct at the dorsal side of Arantius’ duct. In addition, the intraoperative cholangiogram should be used in the case with the abnormal anatomy of bile duct. Conclusions: Any anatomical hepatectomy can be performed using “glissonean pedicle approach” which allows simple, safe and easy liver resection.

Kampo medicine is well known to play an important role in cancer therapy, especially as a supportive therapy. We literally investigated the significance of Kampo medicine on antitumor effect including our data in the era that cancer immunotherapy using immune checkpoint inhibitors is a main stream. Up to now, many reports have been published regarding the mechanism of Kampo medicine on augmentation of immunity, particularly innate immunity. Regarding the effect of Kampo medicine on cancel of immune suppression by cancer, a few reports have been published including our data that juzentaihoto reduced regulatory T cell ratio in advanced pancreas cancer patients. Interestingly, a certain kind of Kampo medicine has possibility to induce immune tolerance in murine cardiac transplant model through increased regulatory T cells, and to suppress intestinal inflammation by anticancer drug by functioning immune checkpoint (PD-1). We hope that Kampo medicine would be proved to possibly regulate immune function from the viewpoint of immune checkpoint in the near future.