The Effect of Three-Dimensional Preoperative Simulation on Liver Surgery.

BACKGROUND: In the past decade, three-dimensional (3D) simulation has been commonly used for liver surgery. However, few studies have analyzed the usefulness of this 3D simulation. The aim of this study was to evaluate the effect of 3D simulation on the outcome of liver surgery. METHODS: We retrospectively analyzed 240 consecutive patients who underwent liver resection. The patients were divided into two groups: those who received 3D preoperative simulation ("3D group", n = 120) and those who did not undergo 3D preoperative simulation ("without 3D group", n = 120). The perioperative outcomes, including operation time, blood loss, maximum aspartate transaminase level, length of postoperative stay, postoperative complications and postoperative mortality, were compared between the two groups. The predicted resected liver volume was compared with the actual resected volume. RESULTS: The median operation time for the 3D group was 36 min shorter than that for the without 3D group (P = 0.048). There were no significant differences in other outcomes between the two groups. A subgroup analysis revealed that the operation time of repeated hepatectomy and segmentectomy for the 3D group was shorter than that for the without 3D group (P = 0.03). There was a strong correlation between the predicted liver volume and the actual resected liver weight (r = 0.80, P < 0.001). CONCLUSION: These findings demonstrate that 3D preoperative simulation may reduce the operation time, particularly for repeated hepatectomy and segmentectomy.

Three-dimensional simulation of pancreatic surgery showing the size and location of the main pancreatic duct.

PURPOSE: We performed three-dimensional (3D) surgical simulation of pancreatic surgery, including the size and location of the main pancreatic duct on the resected pancreatic surface. METHODS: The subjects of this retrospective analysis were 162 patients who underwent pancreatic surgery. This cohort was sequentially divided into a "without-3D" group (n = 81) and a "with-3D" group (n = 81). We compared the pancreatic duct diameter and its location, using nine sections in a grid pattern, with the intraoperative findings. The perioperative outcomes were also compared between patients who underwent pancreaticoduodenectomy (PD) and those who underwent distal pancreatectomy (DP). RESULTS: There were no significant differences in the main pancreatic duct diameter between the 3D-simulated values and the operative findings. The 3D-simulated main pancreatic duct location was consistent with its actual location in 80 % of patients (65/81). In comparing the PD and DP groups, the intraoperative blood loss was 1174 ± 867 and 817 ± 925 ml in the without-3D group, and 828 ± 739 and 307 ± 192 ml in the with-3D group, respectively (p = 0.024, 0.026). CONCLUSION: The 3D surgical simulation provided useful information to promote our understanding of the pancreatic anatomy, including details on the size and location of the main pancreatic duct.

High expression of EPB41L5, an integral component of the Arf6-driven mesenchymal program, correlates with poor prognosis of squamous cell carcinoma of the tongue.

BACKGROUND: Squamous cell carcinoma of the tongue (tongue SCC) is a major subtype of head and neck squamous cell carcinoma (HNSCC), which is an intractable cancer under current therapeutics. ARF6 and its effector AMAP1 are often overexpressed in different types of cancers, such as breast cancer and renal cancer, and in these cancers, AMAP1 binds to EPB41L5 to promote invasion, metastasis, and drug resistance. EPB41L5 is a mesenchymal-specific protein, normally induced during epithelial-mesenchymal transition (EMT) to promote focal adhesion dynamics. Similarly to breast cancer and renal cancer, the acquisition of mesenchymal phenotypes is the key process that drives the malignancy of HNSCC. We previously showed that the overexpression of AMAP1 in tongue SCC is statistically correlated with the poor outcome of patients. In this study, we examined whether tongue SCC also expresses EPB41L5 at high levels. RESULTS: Immunohistochemical staining of clinical specimens of tongue SCC demonstrated that high expression levels of EPB41L5 statistically correlate with poor disease-free survival and poor overall survival rates of patients. The tongue SCC cell line SCC-9, which overexpress Arf6 and AMAP1, also expressed EPB41L5 at high levels to promote invasiveness, whereas the weakly invasive SCC-25 cells did not express EPB41L5 at notable levels. Among the different EMT-associated transcriptional factors, ZEB1 was previously found to be most crucial in inducing EPB41L5 in breast cancer and renal cancer. In contrast, expression levels of ZEB1 did not correlate with the expression levels of EPB41L5 in tongue SCC, whereas KLF8 and FOXO3 levels showed positive correlations with EPB41L5 levels. Moreover, silencing of EPB41L5 only marginally improved the drug resistance of SCC-9 cells, even when coupled with ionizing radiation. CONCLUSION: Our results indicate that activation of the cancer mesenchymal program in tongue SCC, which leads to EPB41L5 expression, closely correlates with the poor prognosis of patients. However, ZEB1 was not the major inducer of EPB41L5 in tongue SCC, unlike in breast cancer and renal cancer. Thus, processes that trigger the mesenchymal program of tongue SCC, which drives their malignancies, seem to be substantially different from those of other cancers.

Protecting liver sinusoidal endothelial cells suppresses apoptosis in acute liver damage.

AIM: Apoptosis is associated with various types of hepatic disorders. We have developed a novel cell-transfer drug delivery system (DDS) using a multifunctional envelope-type nano device that targets liver sinusoidal endothelial cells (LSECs). The purpose of this study was to determine the efficacy of the novel DDS containing siRNA at suppressing apoptosis in LSECs. METHODS: Bax siRNA was transfected into a sinusoidal endothelial cell line (M1) to suppress apoptosis induced by an anti-Fas antibody and staurosporine. C57BL/6J mice were divided into three groups: (i) a control group, only intravenous saline; (ii) a nonselective group, injections of siRNA sealed in the nonselective DDS; and (iii) an LSEC-transfer efficient group, injections of siRNA sealed in an LSEC-transfer efficient DDS. Hepatic cell apoptosis was induced by an anti-Fas antibody. RESULTS: Bax siRNA had an anti-apoptotic effect on M1 cells. Serum alanine aminotransferase was reduced in the LSEC-transfer efficient group, as were cleaved caspase-3 and the number of terminal deoxynucleotidyl transferase dUTP nick end labeling positive hepatocytes. Silver impregnation staining indicated that the sinusoidal space was maintained in the LSEC-transfer efficient group but not in the other groups. Electron microscopy showed that the LSECs were slightly impaired, although the sinusoidal structure was maintained in the LSEC-transfer efficient group. CONCLUSION: Hepatocyte apoptosis was reduced by the efficient suppression of LSEC apoptosis with a novel DDS. Protecting the sinusoidal structure by suppressing LSEC damage will be an effective treatment for acute liver failure.

Postoperative Decrease in Platelet Counts Is Associated with Delayed Liver Function Recovery and Complications after Partial Hepatectomy.

Peripheral platelet counts decrease after partial hepatectomy; however, the implications of this phenomenon are unclear. We assessed if the observed decrease in platelet counts was associated with postoperative liver function and morbidity (complications grade ≤ II according to the Clavien-Dindo classification). We enrolled 216 consecutive patients who underwent partial hepatectomy for primary liver cancers, metastatic liver cancers, benign tumors, and donor hepatectomy. We classified patients as either low or high platelet percentage (postoperative platelet count/preoperative platelet count) using the optimal cutoff value calculated by a receiver operating characteristic (ROC) curve analysis, and analyzed risk factors for delayed liver functional recovery and morbidity after hepatectomy. Delayed liver function recovery and morbidity were significantly correlated with the lowest value of platelet percentage based on ROC analysis. Using a cutoff value of 60% acquired by ROC analysis, univariate and multivariate analysis determined that postoperative lowest platelet percentage ≤ 60% was identified as an independent risk factor of delayed liver function recovery (odds ratio (OR) 6.85; P < 0.01) and morbidity (OR, 4.90; P < 0.01). Furthermore, patients with the lowest platelet percentage ≤ 60% had decreased postoperative prothrombin time ratio and serum albumin level and increased serum bilirubin level when compared with patients with platelet percentage ≥ 61%. A greater than 40% decrease in platelet count after partial hepatectomy was an independent risk factor for delayed liver function recovery and postoperative morbidity. In conclusion, the decrease in platelet counts is an early marker to predict the liver function recovery and complications after hepatectomy.

Sphingosine 1-phosphate has anti-apoptotic effect on liver sinusoidal endothelial cells and proliferative effect on hepatocytes in a paracrine manner in human.

AIM: Sphingosine 1-phosphate (S1P) is a bioactive sphingolipid metabolite released from erythrocytes and platelets, and is a potent stimulus for endothelial cell proliferation. However, the role of S1P on human liver sinusoidal endothelial cells (LSEC) remains unclear. The proliferation and inhibition of apoptosis in LSEC are involved in the promotion of liver regeneration and the suppression of liver injury after liver resection and transplantation. The aim of this study is to investigate the role of S1P on human LSEC and the interaction between S1P and LSEC in hepatocyte proliferation in vitro. METHODS: Immortalized human LSEC were used. LSEC were cultured with S1P, and the cell proliferation, anti-apoptosis, signal transductions and production of cytokines and growth factors were subsequently examined. To investigate the interaction between S1P and LSEC in hepatocyte proliferation, primary human hepatocytes were cultured with the supernatants of LSEC with and without S1P. DNA synthesis and signal transductions in hepatocytes were examined. RESULTS: S1P induced LSEC proliferation through activation of Akt and extracellular signal-related kinase pathways and suppressed LSEC apoptosis by affecting the expression levels of Bcl-2, Bax and cleaved caspase-3. S1P promoted interleukin-6 (IL-6) and vascular endothelial growth factor (VEGF) production in LSEC. The supernatants of LSEC cultured with S1P enhanced hepatocyte DNA synthesis more strongly than the supernatants of LSEC cultured without S1P through activation of the signal transducer and activator of transcription-3 pathway. CONCLUSION: S1P has proliferative and anti-apoptotic effects and promotes the production of IL-6 and VEGF in human LSEC, thereby promoting hepatocyte proliferation.

The Tight Adaptation at Pancreatic Anastomosis Without Parenchymal Laceration: An Institutional Experience in Introducing and Modifying the New Procedure.

BACKGROUND: Among the types of pancreatic anastomosis used after pancreatoduodenectomy (PD), Blumgart type reconstruction has rapidly been distributed for its theoretical reasonableness, including secure tight adaptation of jejunal wall and pancreatic parenchyma without cause of parenchymal laceration. The clinical appropriateness of our modified Blumgart method was demonstrated by comparing to that of Kakita method. METHODS: Retrospective analysis of 156 patients underwent elective open PD, reconstructed former 78 patients with the Kakita method, utilizing a full-thickness penetrating suture for tight stump adhesion. The later 78 patients were treated with the modified Blumgart method, which involved clamping the pancreatic parenchymal stump by the jejunal seromuscular layers with horizontal mattress-type penetration sutures. Evaluated variables were the rate of pancreatic fistula (PF) and the length of postoperative hospital stay (POHS). RESULTS: The rate of ISGPF grade B+C PF was 29/78 (37.2%) in the Kakita group and 16/78 (20.5%) in the Blumgart group (P=0.033). The median POHS for the Kakita group was 23 days, whereas that for the Blumgart group was 16 days (P<0.001), one of the shortest value among Japanese high-volume centers. There was no perioperative intensive hemorrhage or deaths in either group. CONCLUSION: A unique concept of Blumgart pancreatic anastomosis, i.e., utilizing the jejunum as an interstitial cushion to prevent pancreatic laceration at the knot site, has become realistic through a simple "one step" modification. This technique, also providing flexible handling space at main pancreatic duct anastomosis, should contribute to the improved PF prevention and shortening the POHS.

Role of platelets in chronic liver disease and acute liver injury.

Platelets contain not only hemostatic factors but also many growth factors that play important roles in wound healing and tissue repair. Platelets have already been used for the promotion of tissue regeneration in the clinical setting, such as dental implantation and plastic surgery. Thrombocytopenia, which is frequently found in patients with chronic liver disease and cirrhosis, is due to various causes such as decreased thrombopoietin production and accelerated platelet destruction caused by hypersplenism. However, the relationship between thrombocytopenia and hepatic pathogenesis and the role of platelets in chronic liver disease are poorly understood. In acute liver injury, it is reported that platelets are recruited to the liver and contribute to liver damage by promoting the induction of chemotactic factors and the accumulation of leukocytes in the liver, whereas platelets or mediators released by platelets can have a protective effect against liver injury. In this review, we highlight the recent accumulated knowledge concerning the role of platelets in chronic liver disease and acute liver injury.

Current treatment status of polycystic liver disease in Japan.

AIM: Polycystic liver disease (PLD) is a genetic disorder characterized by the progressive development of multiple liver cysts. No standardized criteria for the selection of treatment exist because PLD is a rare condition and most patients are asymptomatic. We here aimed to clarify the status of treatment and to present a therapeutic strategy for PLD in Japan. METHODS: From 1 June 2011 to 20 December 2011, we administered a questionnaire to 202 PLD patients from 86 medical institutions nationwide. RESULTS: The patients included 45 men and 155 women, and the median age was 63 years. Two hundred and eighty-one treatments were performed for these patients, as follows: cyst aspiration sclerotherapy (AS) in 152 cases, cyst fenestration (FN) in 53, liver resection (LR) in 44, liver transplantation (LT) in 13 and other treatments in 19. For cases of type I PLD (mild form) according to Gigot's classification, the therapeutic effects of AS, FN and LR were similar. For type II (moderate form), LT demonstrated the best therapeutic effects, followed by LR and FN. For type III (severe form), the effects of LT were the best. The incidences of complications were 23.0% in AS, 28.4% in FN, 31.8% in LR and 61.5% in LT. CONCLUSION: Considering the therapeutic effects and complications, AS, LR and LT showed good results for type I, type II and type III PLD, respectively. However, LT for PLD was performed in a small number of patients. In Japan, the transplantation therapy is expected to be common in the future.

Interaction of kupffer cells and platelets determines the severity of ischemia-reperfusion injury in steatosis.

Liver steatosis increases the risk of postoperative complications following major liver resection, since the steatotic liver is susceptible to ischemia-reperfusion (IR) injury. However, it is unclear how IR injury changes in relation to the degree of hepatic steatosis. Previously, we reported that interaction between Kupffer cells (KCs) and platelets induced hepatic IR injury. The aim of our present study was to evaluate the relationship between the degree of liver steatosis and IR injury by focusing on the interaction of KCs and platelets. Mild and moderate steatotic liver models were generated in Wistar rats by feeding a choline-deficient diet for 2 and 4 weeks, respectively. The intensity of steatosis was defined based on the proportion of hepatocytes with fatty infiltration: normal (less than 5%), a mild steatosis (5-30%), and moderate steatosis (30-60%). All groups were subjected to 20 min of warm ischemia followed by 120 min of reperfusion. The number of adhesion of KCs to platelets in sinusoids was observed by intravital microscopy. IR injury was evaluated with serum alanine aminotransferase levels, histological findings, and sinusoidal perfusion. Compared to the normal liver, mild steatosis reduced the adhesion of KCs to platelets, inducing the attenuation of IR injury. In contrast, moderate steatosis increased the adhesion of KCs to platelets, aggravating IR injury relative to the normal liver. IR injury in the steatotic liver was not simply proportional to the degree of steatosis. Mild steatosis ameliorates IR injury compared to the normal liver, whereas moderate steatosis increases IR injury.

Prognostic Impact of Preoperative Assessment of Muscle Mass and Strength in Surgically Resected Lung Cancer.

BACKGROUND/AIM: The association between resected non-small cell lung cancer (NSCLC) and long-term outcomes of muscle mass depletion and muscle weakness has also not been well documented. This study evaluated whether muscle mass depletion assessed by bioelectrical impedance analysis (BIA) and low muscle strength assessed by the peak expiratory flow rate as a percentage of predicted value (%PEFR) were associated with surgical outcomes in patients with resected NSCLC. PATIENTS AND METHODS: This retrospective study included 219 patients with resected NSCLC between 2016 and 2021. The cutoff value for muscle mass depletion was according to guidelines, for low muscle strength, we defined by receiver operating characteristics analysis for recurrence-free survival (RFS). Survival analysis was performed, and postoperative outcomes were compared. RESULTS: A total of 76 patients (34.7%) had muscle mass depletion, and 114 patients (52.1%) had low muscle strength. Muscle mass depletion and low muscle strength were independent poor prognostic factors for overall survival [hazard ratio (HR)=2.631, p=0.003; HR=1.983, p=0.044] and RFS (HR=3.120, p<0.001; HR=1.857, p=0.028) in multivariate analysis. Postoperative complication was associated with low muscle strength (p=0.009). Postoperative recurrence was associated with muscle mass depletion (p=0.03). CONCLUSION: Preoperative muscle mass depletion assessed by BIA and low muscle strength determined by %PEFR are worse prognostic factors after surgical resection for NSCLC. Our results may provide some important information for preoperative management.

Histological and prognostic importance of CD44(+) /CD24(+) /EpCAM(+) expression in clinical pancreatic cancer.

CD44(+) /CD24(+) /EpCAM(+) cells have been reported to be cancer stem cells in pancreatic cancer; however, the histological and clinical importance of these cells has not yet been investigated. Here we clarified the characteristics of CD44(+) /CD24(+) /EpCAM(+) cells in clinical specimens of pancreatic cancer using immunohistochemical assay. We used surgical specimens of pancreatic ductal adenocarcinoma from 101 patients. In view of tumor heterogeneity, we randomly selected 10 high-power fields per case, and triple-positive CD44(+) /CD24(+) /EpCAM(+) expression was identified using our scoring system. The distribution, histological characteristics, and prognostic importance of CD44(+) /CD24(+) /EpCAM(+) cells were then analyzed. As a result, the distribution of CD44(+) /CD24(+) /EpCAM(+) cells varied widely among the 101 cases examined, and CD44(+) /CD24(+) /EpCAM(+) expression was correlated with poor glandular differentiation and high proliferation. Survival analysis showed that CD44(+) /CD24(+) /EpCAM(+) expression was not correlated with patient outcome; however, CD44(+) /CD24(+) expression appeared to be correlated with poor prognosis. In conclusion, CD44(+) /CD24(+) /EpCAM(+) expression overlapped with poorly differentiated cells and possessed high proliferative potential in clinical pancreatic cancer. In particular, the presence of double-positive CD44(+) /CD24(+) expression seemed to have clinical relevance, associating with poor prognosis.

Human platelets promote liver regeneration with Kupffer cells in SCID mice.

BACKGROUND: Platelets contain several growth factors, including vascular endothelial growth factor (VEGF) and insulin-like growth factor. We examined the role of human platelets in liver regeneration with a focus on Kupffer cells (KCs). MATERIALS AND METHODS: Severe combined immunodeficiency mice were subjected to 70% hepatectomy and phosphate-buffered saline administration (PBS); 70% hepatectomy and human platelet transfusion (hPLT); 70% hepatectomy, KC depletion, and PBS administration (KD + PBS); 70% hepatectomy, KC depletion, and human platelet transfusion (KD + hPLT); or a sham operation and human platelet transfusion (sham). The groups were evaluated for liver regeneration, accumulation and activation of human platelets in the liver, and/or co-localization of platelets and KCs. RESULTS: The liver-to-body weight ratio was significantly higher 48 h post-transfusion in the hPLT group compared with the PBS, KD + PBS, and KD + hPLT groups. Human VEGF concentrations were higher in liver tissues from the hPLT group, whereas VEGF was not detected in the other groups. Hepatic levels of KC-derived cytokines were elevated in the hPLT group compared with the PBS group. Molecules in signaling cascades downstream of these cytokines were phosphorylated earlier and more robustly in the hPLT group than in the PBS group. Activated human platelets accumulated in livers in the hPLT group, whereas fewer platelets accumulated and many were not activated in the sham and KD + hPLT groups. In the hPLT group, most human platelets were attached to KCs. CONCLUSIONS: Human platelet transfusion promoted liver regeneration in severe combined immunodeficiency mice. Together, human platelets and KCs resulted in growth factor release and enhanced liver regeneration.

Effects of thrombopoietin on growth of hepatocellular carcinoma: Is thrombopoietin therapy for liver disease safe or not?

AIM: Liver cirrhosis (LC) is the end stage of chronic liver disease. No definitive pharmacological treatment is currently available. We previously reported that thrombopoietin (TPO) promoted liver regeneration and improved liver cirrhosis by increasing platelet count. TPO is therefore considered to be a therapeutic agent for LC; however, it is unclear whether TPO has proliferative effects on hepatocellular carcinoma (HCC), which arises frequently in cirrhotic livers. In this study, we examined the effects of TPO on growth of HCC. METHODS: Expression of the TPO receptor, myeloproliferative leukemia virus oncogene (MPL) was examined in various liver tumor cell lines and liver cell types. In an in vitro study, the effects of TPO on signal transduction, cell proliferation, migration and invasion were examined in Huh7 cells, in which MPL is highly expressed. In an in vivo study, we subcutaneously transplanted Huh7 cells into nude mice that were divided into a TPO-treated group and a control group, and the tumor volume of each group was measured. RESULTS: MPL was expressed strongly in hepatocytes but not in other cell types. Among liver tumor cell lines, Huh7 showed the highest expression of MPL. In Huh7, the addition of TPO activated Akt phosphorylation but not cell proliferation, migration or invasion. In the mouse experiment, there was no significant difference in tumor volume between the two groups. CONCLUSION: TPO had no proliferative effect on HCC in vitro or in vivo, and could therefore be useful in the treatment of liver cirrhosis.

Protective effect of heme oxygenase-1 on hepatic ischemia-reperfusion injury through inhibition of platelet adhesion to the sinusoids.

BACKGROUND AND AIM: Heme oxygenase-1 (HO-1) acts as a protector against hepatic inflammatory injury. HO-1 catalyzes the conversion of heme protein to biliverdin, free iron, and carbon monoxide. Pro-inflammatory responses play critical roles in hepatic ischemia-reperfusion (I/R) injury, and carbon monoxide effectively downregulates I/R injury. The aim of this study was to evaluate the mechanism by which HO-1 reduces warm I/R injury. METHODS: Sprague-Dawley rats were divided into two groups: the 20-min ischemia group (control group; n = 6) and the 20-min ischemia with cobalt protoporphyrin (CoPP group; n = 6). CoPP is an inducer of HO-1 in the sinusoids. Kupffer cells were labeled using the liposome entrapment method, and platelets were labeled with rhodamine-6G. The adherent platelets were observed for up to 120 min after reperfusion by intravital microscopy. RESULTS: In the control group, the number of adherent platelets significantly increased than in the CoPP group. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling-positive cells were observed after 120 min of reperfusion in the control group. They were not observed in the CoPP group. In the CoPP group, serum alanine transaminase and interleukin-6 levels reduced after reperfusion. Moreover, the flow velocity of platelets in the hepatic sinusoid markedly increased. CONCLUSIONS: This study suggests that HO-1 inhibits platelet adhesion to sinusoids. Such inhibition leads to the prevention of hepatic I/R injury.

Platelet transfusion improves liver function in patients with chronic liver disease and cirrhosis.

Chronic liver disease (CLD), such as hepatitis C, is a progressive disease consisting of the destruction and regeneration of the liver parenchyma, leading to fibrosis and cirrhosis. Platelets contain various growth factors and may play important roles in liver regeneration. Thus, to investigate whether platelet transfusion improves liver function in patients with CLD and cirrhosis, we conducted an exploratory clinical trial. The study included 10 patients with CLD and cirrhosis (Child-Pugh class A or B), who all presented thrombocytopenia (platelet counts between 50,000 and 100,000 /µl). The subjects received 10 units of platelet concentrate once a week for 12 weeks. They were followed up for 9 months after the last transfusion. One patient discontinued platelet transfusion because of pruritus, and 2 patients discontinued because of platelet transfusion refractoriness. One patient was excluded from the analysis for receiving a procedural treatment after 12 platelet transfusions. Thus, the remaining 6 patients were analyzed. The platelet count did not increase significantly after the last transfusion. Significant improvement of serum albumin was observed at 1 month and 3 months after the last transfusion. Serum cholinesterase improved significantly at 1 week, 3 months, and 9 months after the last transfusion. Serum hyaluronic acid showed a tendency toward improvement after the last transfusion. In conclusion, platelet transfusion improved some of the indicators of liver function in patients with CLD and cirrhosis, though adverse events related to platelet transfusion were observed in some patients. Platelet increment therapy could be a new strategy for treating CLD and cirrhosis.

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 mm(3) 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.

Interaction between Kupffer cells and platelets in the early period of hepatic ischemia-reperfusion injury--an in vivo study.

BACKGROUND: Hepatic ischemia-reperfusion (I/R) leads to activation of Kupffer cells (KCs). The activated KCs cause platelet and leukocyte adhesion to the sinusoidal endothelium. Previously, we reported that platelet-endothelium interactions occur earlier than leukocyte responses. The aim of this study was to evaluate the interaction between platelets and KCs in the hepatic microcirculation after I/R. MATERIALS AND METHODS: Sprague-Dawley rats were divided into three groups: the no-ischemia group (control group; n = 6); the 20-min ischemia group (I/R group; n = 6); and the 20-min ischemia + anti-rat platelet serum group (APS group; n = 6). KCs were labeled using the liposome entrapment method. The number of adherent platelets was observed for up to 120 min after reperfusion by intravital microscopy. To investigate the effects of platelets on I/R injury, rats were injected intravenously with rabbit APS for platelet depletion. RESULTS: In the I/R group, the number of adherent platelets increased significantly after I/R. More than 50% of the adherent platelets adhered to KCs. Electron microscopy indicated that the platelets attached to the KCs after hepatic ischemia. The histologic findings indicated liver damage and apoptosis of hepatocytes in zone 1. In the I/R group, but not in the control and APS groups, serum ALT increased immediately after reperfusion. CONCLUSIONS: We succeeded in visualizing the dynamics of both KCs and platelets in the hepatic sinusoids. Liver ischemia induced the adhesion of platelets to KCs in the early period, which could play a key role in reperfusion injury of the liver.

Invasion of the hepatic artery is a crucial predictor of poor outcomes in gallbladder carcinoma.

BACKGROUND: In the present study we undertook a retrospective analysis of gallbladder carcinoma to assess whether histologically determined hepatic artery (HA) invasion and portal vein (PV) invasion can be considered prognostic factors. METHODS: Seventy-one patients who had undergone radical resection for gallbladder carcinoma between 1995 and 2008 at University of Tsukuba were selected from the database for analysis. Patients who required extended surgery for para-aortic lymph node metastasis were also included. Correlation between invasion of the HA and the PV and prognosis and other clinicopathologic factors were analyzed. RESULTS: There were two postoperative deaths among the 71 patients. Pathological invasion of the HA was confirmed in 16 (22.5%) cases and PV invasion was confirmed in 15 patients. Patients with invasion of the HA had a significantly poorer prognosis than those without HA invasion (P < 0.0001). Additionally, in univariate analysis, gender (male), positive para-aortic lymph node metastasis, PV invasion, and HA invasion were identified as significant poor prognostic factors. In multivariate analysis, only HA invasion was an independent prognostic factor (Odds Ratio 0.323; P = 0.029). CONCLUSIONS: Invasion of the HA is a crucial prognostic factor in patients with gallbladder carcinoma.

Recognition of other organ involvement might assist in the differential diagnosis of IgG4-associated sclerosing cholangitis without apparent pancreatic involvement: report of two cases.

IgG4-associated sclerosing cholangitis (IAC) was recently defined as biliary involvement of IgG4-related systemic disease. It is frequently associated with autoimmune pancreatitis, characterized by pancreatic enlargement and irregular narrowing of the pancreatic duct. However, a few cases of IAC with no apparent pancreatic involvement have been described, the characteristics of which may mimic those of cholangiocarcinoma. We report two rare cases of IgG4-associated sclerosing cholangitis at the hepatic hilum, mimicking hilar cholangiocarcinoma. When trying to establish the diagnosis, we should consider other organs that could be involved, such as the pancreas, salivary glands, retroperitoneum, lymph nodes, and kidneys, as well as chronic inflammatory changes. By recognizing these lesions and measuring serum IgG4, IAC can be diagnosed correctly, thereby avoiding unnecessary major surgery for a condition that is treated effectively by steroid therapy.