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Background Mesenchymal stem cells (MSCs), including adipose-derived mesenchymal stem cells (ADSCs), have been shown to attenuate organ damage in acute respiratory distress syndrome (ARDS) and sepsis; however, the underlying mechanisms are not fully understood. In this study, we aimed to explore the potential roles and molecular mechanisms of action of ADSCs in histone-induced endothelial damage. Methods Male C57BL/6 N mice were intravenously injected with ADSCs, followed by histones or a vehicle. The mice in each group were assessed for survival, pulmonary vascular permeability, and histological changes. A co-culture model with primary human umbilical vein endothelial cells (HUVECs) exposed to histones was used to clarify the paracrine effect of ADSCs. Overexpression and inhibition of miR-126 ADSCs were also examined as causative factors for endothelial protection. Results The administration of ADSCs markedly improved survival, inhibited histone-mediated lung hemorrhage and edema, and attenuated vascular hyper-permeability in mice. ADSCs were engrafted in the injured lung and attenuated histone-induced endothelial cell apoptosis. ADSCs showed endothelial protection (via a paracrine effect) and Akt phosphorylation in the histone-exposed HUVECs. Notably, increased Akt phosphorylation by ADSCs was mostly mediated by exosomes in histone-induced cytotoxicity and lung damage. Moreover, the expression of miR-126 was increased in exosomes from histone-exposed ADSCs. Remarkably, the inhibition of miR-126 in ADSCs failed to increase Akt phosphorylation in histone-exposed HUVECs. Conclusion ADSC-derived exosomes may exert protective effects on endothelial cells via activation of the PI3K/Akt pathway.

RATIONALE: In coronavirus disease 2019 (COVID-19) patients with acute respiratory distress syndrome refractory to optimal conventional management, we should consider the indication for veno-venous extracorporeal membrane oxygenation (V-V ECMO). Growing evidence indicates that COVID-19 frequently causes coagulopathy, presenting as hypercoagulation and incidental thrombosis. For these reasons, a multifactorial approach with several anticoagulant markers should be considered in the management of anticoagulation using heparin in COVID-19 patients on V-V ECMO. PATIENT CONCERNS: A 48-year-old man was infected with COVID-19 with a worsening condition manifesting as acute respiratory distress syndrome. DIAGNOSES: He was refractory to conventional therapy, thus we decided to introduce V-V ECMO. We used heparin as an anticoagulant therapy for V-V ECMO and adjusted the doses of heparin by careful monitoring of the activated clotting time (ACT) and activated partial thromboplastin time (APTT) to avoid both hemorrhagic and thrombotic complications. We controlled the doses of heparin in the therapeutic ranges of ACT and APTT, but clinical hemorrhaging and profound elevation of coagulant marker became apparent. INTERVENTIONS: Using thromboelastography (TEG; Haemonetics) in addition to ACT and APTT, we were able to clearly detect not only sufficient coagulability of COVID19 on V-V ECMO (citrated rapid thromboelastography-R 0.5 min, angle 75.5°, MA 64.0 mm, citrated functional fibrinogen-MA 20.7 mm) but also an excessive effect of heparin (citrated kaolin -R 42.7 min, citrated kaolin with heparinase 11.7 min). OUTCOMES: Given the TEG findings indicating an excessive heparin effect, the early withdrawal of ECMO was considered. After an evaluation of the patient's respiratory capacity, withdrawal from V-V ECMO was achieved and then anticoagulation was stopped. The hemorrhagic complications and elevated thrombotic marker levels dramatically decreased. LESSONS: TEG monitoring might be a useful option for managing anticoagulation in COVID-19 patients on V-V ECMO frequently showing a hypercoagulative state and requiring massive doses of heparin, to reduce both hemorrhagic and thrombotic complications.

Redox status influences the course of the inflammatory, metabolic, and proliferative liver diseases. Oxidative stress is thought to play a crucial and sustained role in the pathological progression of early steatosis to severe hepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma. Oxidative stress induced by reactive oxygen species which are generated in the mitochondria can lead to chronic organelle damage in hepatocytes. Currently, the diagnosis of liver disease requires liver biopsy, which is invasive and associated with complications. The present report describes the development of a novel molecular probe, EDA-PROXYL, with higher reactivity and mitochondrial selectivity than standard carboxyl-PROXYL and carbamoyl-PROXYL probes. The membrane permeability of our probe improved in aqueous environments which led to increased accumulation in the liver and interaction of EDA-PROXYL with the carnitine transporter via the amine (NH3+) group further increased accumulation. This increased mitochondrial sensitivity and enhanced accumulation highlight the potential of EDA-PROXYL as a molecular probe for determining metabolic reactions of the mitochondria. Thus, this novel probe could be a tool for the evaluation of redox status of the mitochondria to assess the degree of liver injury and, ultimately, the response to pharmacological therapy.

No effective treatment has been established for autoimmune hepatitis (AIH), except for liver transplantation in the fatal stage. Little is known about the roles and mechanisms of farnesyltransferase inhibitors (FTIs) in treating AIH. Thus, we investigated the specific role of the FTI, tipifarnib, in a Concanavalin A (Con A)-induced model of hepatitis. The effects of tipifarnib (10 mg/kg, intraperitoneal injection) were studied in Con A (20 mg/kg, intravenous injection)-challenged mice by histological, biochemical, and immunological analyses. Tipifarnib-treated mice were compared to phosphate-buffered saline (PBS)-treated mice. Con A caused liver injury characterized by increased plasma alanine aminotransferase (ALT) levels and marked histological changes. The increased serum ALT, interleukin-6, or interferon-γ (IFN-γ) levels were observed at 2 or 8 h; tumor necrosis factor-α levels at 2 h post-Con A administration decreased significantly in the tipifarnib group. Tipifarnib also suppressed Con A-induced activation of CD4+ cells (but not CD8+ T cells) in the liver and spleen, and also reversed the Con A-induced decrease of natural killer T (NKT) cells in the liver. Tipifarnib significantly inhibited IFN-γ production and STAT1 phosphorylation from CD4+ T cells (but not CD8+ T and NKT cells) in the liver at 2 h post-Con A administration. Tipifarnib significantly inhibited IFN-γ production by splenic CD4+ T cells at 48 h post-Con A injection in vitro. Tipifarnib also inhibited the expression of farnesylated proteins induced by Con A administration. In conclusion, tipifarnib inhibited IFN-γ derived from Con A-induced CD4+ T cell activation due to downregulated STAT1 phosphorylation, suggesting that Tipifarnib can protect against AIH.

Background Laparoscopic sleeve gastrectomy (LSG) is a well established treatment for severe obesity and type 2 diabetes. Although the gut microbiota is linked to the efficacy of LSG, the underlying mechanisms remain elusive. The effect of LSG for morbid obesity on the gut microbiota and bile acids was assessed here. Methods Severely obese subjects who were candidates for LSG were included and followed until 6 months after surgery. The composition and abundance of the microbiota and bile acids in faeces were assessed by 16S ribosomal RNA sequencing, quantitative PCR and liquid chromatography–mass spectrometry. Results In total, 28 patients with a mean(s.d.) BMI of 44·2(6·6) kg/m2 were enrolled. These patients had achieved excess weight loss of 53·2(19·0) per cent and showed improvement in metabolic diseases by 6 months after LSG, accompanied by an alteration in the faecal microbial community. The increase in α-diversity and abundance of specific taxa, such as Rikenellaceae and Christensenellaceae, was strongly associated with reduced faecal bile acid levels. These changes had a significant positive association with excess weight loss and metabolic alterations. However, the total number of faecal bacteria was lower in patients before (mean(s.d.) 10·26(0·36) log10 cells per g faeces) and after (10·39(0·29) log10 cells per g faeces) operation than in healthy subjects (10·83(0·27) log10 cells per g faeces). Conclusion LSG is associated with a reduction in faecal bile acids and greater abundance of specific bacterial taxa and α-diversity that may contribute to the metabolic changes.

Laparoscopic gastric devascularization(Lap GDS) and splenectomy (SPL) for gastric varices is technically challenging because of highly developed collateral vessels and bleeding tendency. We investigated the feasibility of customization of Lap GDS and SPL based on CT vascular anatomy. We analyzed 61 cirrhotic patients with gastric varices who underwent Lap GDS and SPL between 2006 and 2014. Lap GDS was customized according to the afferent feeding veins (left gastric vein (LGV) and/or posterior gastric vein (PGV)/short gastric vein (SGV)) and efferent drainage veins (gastrorenal shunt and/or gastrophrenic shunt, or numerous retroperitoneal veins) based on CT imaging. Thirty-four patients with efferent drainage veins suitable for balloon-occluded retrograde transvenous obliteration (B-RTO) underwent B-RTO instead of surgical GDS, with subsequent Lap SPL. Among 27 patients with gastric varices unsuitable for B-RTO, 15 patients with PGV/SGV underwent Lap GDS of the greater curvature and SPL, and 12 patients with LGV or LGV/PGV/SGV underwent Lap GDS of the greater and lesser curvature and SPL. The mean operation time was 294 min and mean blood loss was 198 g. There was no mortality or severe morbidity. Gastric varices were eradicated in all 61 patients, with no bleeding or recurrence during a mean follow-up of 55.9 months. The cumulative 3-, 5-, and 7-year survival rates were 92, 82, and 64%, respectively. Lap GDS and SPL customized based on CT vascular anatomy is a safe and effective procedure for treating gastric varices.

Introduction: Fat embolism syndrome (FES) is a known complication of long bone fracture and can affect multiple organs. The organ most commonly affected with FES is the lung. Severe cases of FES from long bone fracture can cause acute respiratory distress syndrome (ARDS). Although the treatment of ARDS remains challenging, it is reported that a lung protection strategy and prone positioning are effective. In addition, early fixation is reported to be beneficial in respiratory failure due to FES, though it may exacerbate respiratory failure during the perioperative period. We report the use of venovenous extracorporeal membrane oxygenation (VV-ECMO) for the successful perioperative management of a patient diagnosed with ARDS due to FES. Patient concerns: A 24-year-old man injured in a traffic accident was brought to our emergency department due to shock and consciousness disorder. Diagnosis: After examining the patient, we noted bilateral pneumothorax, liver and spleen injuries, and multiple long bone fractures. Four days after admission, he was diagnosed with FES due to a prolonged consciousness disorder, progressive hypoxia with diffuse lung damage, and cutaneous and mucosal petechiae. Intervention: As respiratory failure progressed, VV-ECMO was initiated on the 6th day. To improve the respiratory failure caused by ARDS, prone position therapy was necessary. Thus, we performed osteosynthesis on the 9th day under ECMO. Prone position therapy was started after surgery. Outcomes: Subsequently, his respiratory condition and chest radiographs improved steadily. VV-ECMO was discontinued on the 17th day and the ventilator was removed on the 28th day. His consciousness levels improved without residual central nervous system complications. Conclusion: Our study reveals the successful improvement of FES-induced ARDS by osteosynthesis and prone positioning under VV-ECMO. This strategy prioritizes supportive treatment over pharmacologic interventions.

Background This study aimed to determine the effect of fibrin glue and polyglycolic acid (PGA) felt on prevention of pancreatic fistula (PF) after laparoscopic splenectomy in patients with hypersplenism due to liver cirrhosis. Methods Fifty consecutive patients were enrolled in this prospective study. Twenty-three patients underwent laparoscopic splenectomy with a fibrin sheet (fibrin sheet group). The sealing ability of each treatment was evaluated by an ex vivo pressure test model. Based on the results from ex vivo experiments, 27 patients received prophylaxis using fibrin glue and PGA felt (PGA with fibrin group). The primary endpoint was the incidence of PF. Results Significantly more (5, 22%) patients developed PF in the fibrin sheet group than in the PGA with fibrin group (0%, P = .037). Conclusions Our new application of fibrin glue and PGA felt is an effective prophylactic procedure for preventing development of PF after laparoscopic splenectomy.

Aim Doxorubicin (DOX) induces dose-dependent cardiotoxicity due to reactive oxygen species (ROS)-mediated oxidative stress and subsequent apoptosis of cardiomyocytes. We aimed to assess whether sodium thiosulfate (STS), which has antioxidant and antiapoptotic properties, exerts cardioprotective effects on DOX-induced cardiomyopathy. Main methods Male C57BL/6N mice were divided into four groups, control, DOX, STS, and DOX + STS, and administered DOX (20 or 30 mg/kg) or normal saline intraperitoneally, followed by an injection of STS (2 g/kg) or normal saline 4 h later. Key findings The DOX group showed a poorer 6-day survival and decreased cardiac function than the DOX + STS group. The DOX group showed a marked increase in the plasma creatine kinase isoenzyme myocardial band (CK-MB) and lactate dehydrogenase (LDH) levels 10 h after DOX injection, while the DOX + STS group showed suppression of DOX-induced elevation of CK-MB and LDH levels. The DOX group showed increased 8-hydroxy-2′-deoxyguanosine (8-OHdG) levels in the heart, whereas the DOX + STS group showed increased catalase and superoxide dismutase (SOD) activities and decreased 8-OHdG levels in the heart compared with DOX group, suggesting that STS reduces DOX-induced DNA damage by improving antioxidant enzymes activities in cardiomyocytes. Additionally, the DOX + STS group showed attenuation of cleaved caspase-3 and DNA fragmentation in cardiomyocytes compared with the DOX group, suggesting that STS suppresses DOX-induced apoptosis in cardiomyocytes. Significance STS exerts cardioprotective effects against DOX-induced cardiac dysfunction partly by improving antioxidant defense and suppressing apoptosis, indicating the therapeutic potential of STS against DOX-induced cardiomyopathy.

Laparoscopic splenectomy (LS) is still challenging in patients with liver cirrhosis and portal hypertension. This study was designed to establish safe and less invasive LS in patients with liver cirrhosis and portal hypertension.We analyzed 390 patients with liver cirrhosis and portal hypertension, who underwent LS between 1993 and 2013. Patients were divided into 3 time periods; early (1993 to 2004, n = 106); middle (2005 to 2008, n = 159); and late (2008 to 2013, n = 125). During the middle time period, standardized technique for LS and selection criteria for hand-assisted LS were adopted. Patients with spleen volume ≥ 1,000 mL by CT volumetry, large perisplenic collateral vessels, and/or Child-Pugh score ≥ 9, underwent hand-assisted LS. During the late time period, the selection criteria were refined and patients with spleen volume ≥ 600 mL underwent hand-assisted LS.Conversion to open splenectomy decreased (10.4% in the early time period, 1.9% in the middle time period, and 3.2% in the late time period, p = 0.004), median blood loss decreased (300g, 87g, and 98g, respectively, p0.001), and the success rate of pure LS tended to improve (87.2%, 89.5%, and 98.0%, respectively, p = 0.110). Mortality was 0% in each time period, Clavien-Dindo grade IIIb or more complications tended to decrease (5.7%, 2.5%, and 0.8%, respectively, p = 0.081), and technique-related complications decreased significantly (10.4%, 3.8%, and 2.4%, respectively, p = 0.014).Laparoscopic splenectomy is now a safe and less invasive approach, even in patients with liver cirrhosis and portal hypertension, because of its technical standardization with the refined selection criteria for pure or hand-assisted LS.

Background : Bariatric surgical procedures are becoming a standard treatment for morbid obesity in many western countries and in some Asian countries. Aim : The aim of the current study was to evaluate the efficacy and safety of the initial 30 cases of bariatric surgical procedures performed for morbid obesity at a single institution in Japan. Materials and methods : From March 2012 until September 2014, 30 bariatric surgical procedures were performed for morbid obesity at a single medical center (Kyushu University Hospital) in Japan. Results : All of the operations procedures were planned laparoscopic procedures, and none required conversion to laparotomy. There were no perioperative or postoperative mortalities. Postoperative complications occurred in 3 patients : 1 patient developed an intra-abdominal abscess, 1 patient experienced temporary food intolerance, and 1 patient developed small bowel obstruction. The excessive body weight reduction rates after surgery at 1 month, 3 months, 6 months, and 1 year post-surgery were 26.1％, 39.2％, 41.7％, and 51.2％, respectively. The mean body mass index (BMI) at the same time points were 38.3％, 36.4％, 35.5％, and 31.4％, respectively. Eighteen patients had type II diabetes mellitus (T2DM). The mean preoperative fasting blood glucose levels were 169 ±37 mg/dL. Following surgery, the blood glucose levels at 3, 6 and 12 months were 113±12, 115 ±22, and 110 ± 19, mg/dL, respectively. The preoperative HbA1c percentage was 7.9 ± 0.5. Following surgery, the HbA1c percentages at 3, 6, and 12 months were 6.9 ± 0.5, 6.2 ± 0.9, and 5.9 ± 0.6, respectively. Conclusions : Bariatric surgical procedures are effective and safe for the treatment of morbid obesity. Our results indicate that the mechanism of improvement of diabetes and related diseases following bariatric surgical procedures is not simply as a result of calorie restriction and weight reduction., 海外では病的肥満に対して積極的に肥満外科手術が行われており，2008年の1年間には世界中で34 万例以上の腹腔鏡下肥満外科手術が行われている．世界的に腹腔鏡下肥満外科手術の代表的術式は，胃バイパス術とスリーブ状胃切除術である．一方，わが国では2014 年4 月スリーブ状胃切除術（LSG）が保険収載されたが，世界で最も肥満に関連した代謝性疾患に効果があるとされている胃バイパス術は保険収載されていない現状にある．当院においてこれまでおこなってきた病的肥満症に対する減量手術の術式の工夫と糖尿病，高脂血症に対する治療効果について検討した．2012 年3 月から2014 年11 月までに内科的治療に抵抗性のBMI35 以上の病的肥満症30 例に対して減量手術としての腹腔鏡下スリーブ状胃切除術を施行した．平均の術前体重は114.1kg，術前体重から身長による標準体重を引いた超過体重平均は55.5kg であった．平均の術前BMI は42.8で，BMI が50以上の症例を5例に認めた．肥満関連合併症として，糖尿病合併が18例，脂質異常症が13 例，高血圧症が20 例，睡眠時無呼吸が6例であった．開腹手術への移行例はなくlaparoscopic sleeve gastrectomy のoperation time は212 ± 57minで術中出血量は18 ± 39g であった．手術関連死亡例はなく，術後合併症は腹腔内膿瘍を1例，残胃狭窄を1例と小腸閉塞1 例に認めた．30 例の術後1ヶ月，6ヶ月後および1 年後の超過体重減少率は，26.1，39.2，41.7，51.2％であった．体重の減少に伴いBMI も38.3，36.4，35.5，31.4％と減少した．糖尿病合併18 例では術前の空腹時血糖（mg/dl）は169± 37 で術後3，6，12ヶ月には113± 12, 115 ± 22，110± 19 と変化した．HbA1c（％）は術前7.9± 0.5 で術後3，6，12ヶ月では6.9 ± 0.5，6.2 ± 0.9，5.9 ± 0.6 に減少した．BMI35〜75.8 の病的肥満症例に対して減量手術が安全に施行できた．術後1 年以上経過した症例は6 例のみであり，その長期的な有効性については結論は得ないが，明らかな体重減少に先行して糖尿病，高血圧，脂質異常症などの関連疾患の改善が認められた．肥満外科手術による糖尿病などの関連疾患改善のメカニズムは，単にカロリー制限や体重減少だけではないことを物語っていた．

Given the rising incidence of non-alcoholic fatty liver disease (NAFLD) in both adults and children, the development of a non-invasive diagnostic method for assessing disease progression to non-alcoholic steatohepatitis (NASH) has become an important research goal. Currently available non-invasive imaging technologies are only able to assess fat accumulation in the liver. Therefore, these methods are not suitable for a precise diagnosis of NASH. The standard diagnostic technique for NASH, liver biopsy, has several drawbacks, including the higher risk of complications that accompanies invasive procedures. Here, we demonstrated that in vivo mitochondrial redox metabolism was dramatically altered at an early stage, before histopathological changes, and NASH could be accurately diagnosed by in vivo dynamic nuclear polarization-magnetic resonance imaging, with carbamoyl-PROXYL as a molecular imaging probe. In addition, this technique was feasible for the diagnosis of NASH compared with histopathological findings from biopsies. Our data reveal a novel method for monitoring the dynamics of redox metabolic changes in NAFLD/NASH.

Esophageal perforation due to blunt trauma is a rare clinical condition, and the diagnosis is often difficult because patients have few specific symptoms. Delayed diagnosis may result in a fatal clinical course due to mediastinitis and subsequent sepsis. In this article, we describe a 26-year-old man with esophageal perforation due to blunt chest trauma resulting from a motor vehicle accident. Because a severe disturbance of consciousness masked the patient's trauma-induced thoracic symptoms, we required 11 h to diagnose the esophageal perforation. Therefore, the patient developed septic shock due to mediastinitis. However, his subsequent clinical course was good because of prompt combined therapy involving surgical repair and medical treatment after the diagnosis.

Background and purpose Accurate diagnosis of acute aortic dissection (AAD) is sometimes difficult because of accompanying central nervous system (CNS) symptoms. The purpose of this study was to investigate the clinical characteristics of Type A AAD (TAAAD) with CNS symptoms. Methods We retrospectively reviewed the medical records of 8403 patients ambulanced to our emergency and critical care center between April 2009 and May 2014. Results We identified 59 TAAAD patients for the analysis (mean age, 67.3 ± 10.5 years; 37 (62.0%) male). Eleven patients (18.6%) presented CNS symptoms at the onset of TAAAD, and these patients complained less frequently of typical chest and back pain than those without CNS symptoms ( p p = 0.003, and p = 0.049, respectively) and involvement of the supra-aortic artery was more frequent in patients with CNS symptoms ( p Conclusion Because CNS symptom can mask chest and back pain caused by TAAAD, physicians should always consider the possibility of TAAAD in patients with CNS symptoms in emergency medicine settings.

Background The effect of splenomegaly in patients with liver cirrhosis and portal hypertension is not fully understood. This study was designed to determine the effect of laparoscopic splenectomy on portal haemodynamics in these patients. Methods Patients with liver cirrhosis and portal hypertension who underwent laparoscopic splenectomy in Kyushu University Hospital from January 2006 to March 2009 were evaluated retrospectively. Correlations between splenic size and portal haemodynamics, and changes in portal haemodynamics and in levels of the vasoactive agents endothelin (ET) 1 and nitric oxide metabolites (NOx) before and 7–10 days after laparoscopic splenectomy were analysed. Results Portal venous (PV) blood flow, PV cross-sectional area and PV congestion index correlated significantly with splenic size (P < 0·050). All three were significantly reduced following splenectomy in 59 patients. The hepatic venous pressure gradient, measured in 18 patients, decreased by 25 per cent after splenectomy (P < 0·001). Portal vascular resistance was also reduced, by 21 per cent (P = 0·009). The peripheral blood concentration of ET-1 decreased from 2·95 to 2·11 pg/ml (P < 0·001), and that of NOx tended to decrease (from 29·2 to 25·0 pg/ml; P = 0·068). In hepatic venous blood, the level of ET-1 decreased from 2·37 to 1·83 pg/ml (P = 0·006), whereas NOx concentration tended to increase (from 24·5 to 30·9 pg/ml; P = 0·067). Conclusion In patients with liver cirrhosis and portal hypertension, splenectomy reduced portal venous pressure. A decrease in splanchnic blood flow, by eliminating splenic blood flow, and reduction in intrahepatic vascular resistance, by normalizing hepatic concentrations of ET-1 and NOx, may both have contributed.

Summary There is increasing interest in the role of T cell exhaustion and it is well known that the natural history of chronic hepatitis C virus infection (HCV) is modulated by CD8+ T cell immunobiology. There are many pathways that alter the presence of exhaustive T cells and, in particular, they are functionally impaired by inhibitory receptors, such as programmed death-1 (PD-1) and T cell immunoglobulin and mucin domain-containing protein 3 (Tim-3). We obtained spleen, liver and peripheral blood (before and after splenectomy) lymphoid cells from 25 patients with HCV-related cirrhosis undergoing liver transplantation for end-stage disease or splenectomy for portal hypertension. In all samples we performed an extensive phenotypic study of exhaustion markers [PD-1, Tim-3, interferon (IFN)-γ) and their ligands (PD-L1, PD-L2, galectin-9] in CD8+ T cell subpopulations (both total and HCV-specific) and in antigen-presenting cells (APC; monocytes and dendritic cells). In the spleen, total and HCV-specific CD8+ T cells demonstrated enhanced markers of exhaustion, predominantly in the effector memory subpopulation. Similarly, splenic APC over-expressed inhibitory receptor ligands when compared to peripheral blood. Finally, when peripheral blood CD8+ T cells were compared before and after splenectomy, markers of exhaustion were reduced in splenic CD8+ T cells and APC. Our data in HCV-related cirrhosis suggest that CD8+ T cells in the spleen manifest a significantly higher exhaustion compared to peripheral blood and may thus contribute to the failure to control HCV. Counteracting this process may contribute to inducing an effective immune response to HCV.

The purpose of our study was to evaluate the efficacy of balloon-occluded retrograde transvenous obliteration (B-RTO) in patients after living donor liver transplantation (LDLT). Five patients with gastric varices (GVx) and/or liver dysfunction who were treated with B-RTO from January 2001 to December 2007 were enrolled in this study (GVx, n = 2; liver dysfunction, n = 1; both, n = 2). The eradication rate of the GVx, portal vein hemodynamics and improvement of liver function were evaluated. B-RTO was performed successfully, and the GVx disappeared or decreased markedly in all patients. Recurrence of GVx was not observed during the follow-up. Significantly increased portal vein inflow and improved liver function were observed in all patients. B-RTO may be an effective treatment for patients after LDLT to prevent bleeding from GVx or to modulate portal vein inflow that is reduced by prolonged large portosystemic shunts.

Hepatic fibrosis is a chronic disorder caused by viral infection and/or metabolic, genetic and cholestatic disorders. A noninvasive procedure that enables the detection of liver fibrosis based on redox status would be useful for disease identification and monitoring, and the development of treatments. However, an appropriate technique has not been reported. This study describes a novel method for assessing the redox status of the liver using in vivo dynamic nuclear polarization-magnetic resonance imaging (DNP-MRI) with the nitroxyl radical carbamoyl-PROXYL as a molecular imaging probe, which was tested in dimethylnitrosamine-treated mice as a model of liver fibrosis. Based on the pharmacokinetics of carbamoyl-PROXYL in control livers, reduction rate mapping was performed in fibrotic livers. Reduction rate maps demonstrated a clear difference between the redox status of control and fibrotic livers according to the expression of antioxidants. These findings indicate that in vivo DNP-MRI with a nitroxyl radical probe enables noninvasive detection of changes in liver redox status.

We recently experienced 10 patients with cirrhosis who underwent laparoscopic splenectomy. A portion of these patients underwent dissection with a flexible endoscope in the peritoneal cavity. This pilot study mainly focused on the technical aspects and immediate results. From November 2009 to September 2010, 10 patients with cirrhosis and hypersplenism were entered into this pilot study. They were indicated to undergo laparoscopic splenectomy to treat portal hypertension and to facilitate initiation and completion of either interferon therapy for liver cirrhosis or anticancer therapy for hepatocellular carcinoma. To dissect the upper end of the gastrosplenic ligament and the marginal region between the left diaphragm and upper pole of the spleen, a flexible single-channel endoscope was introduced into the peritoneal cavity simultaneously with the use of a rigid laparoscope. Dissection with the flexible endoscope in the peritoneal cavity was performed using an insulation-tipped electrosurgical knife through the channel of the flexible endoscope. The flexible endoscope offered a magnified operative view, a water-jet lens cleaner, and a powerful lavage and suction capability. The upper end of the gastrosplenic ligament and the marginal region between the left diaphragm and upper pole of the spleen were easily seen, and dissection of these critical regions was smoothly conducted with articulation of the tip of the flexible endoscope, even in patients with splenomegaly. No patient experienced major intraoperative complications or required conversion to open surgery. Dissection with a flexible endoscope in the peritoneal cavity may be an effective tactic for laparoscopic megasplenectomy, and significant implications for pure natural orifice translumenal endoscopic surgery have been raised. Although future randomized controlled prospective studies are needed to confirm these findings, surgeons might find this to be a typical example of an appropriate strategy for high-risk patients.

Background Small intestinal variceal bleeding is an unusual cause of gastrointestinal hemorrhaging of portal hypertensive patients, but once it occurs it may lead to life-threatening bleeding because this problem is difficult to diagnose and treat. This study investigated the efficacy of balloon occluded retrograde transvenous obliteration (B-RTO) to treat small intestinal variceal bleeding. Methods From 2003 to 2007, 6 patients with small variceal bleeding were treated by B-RTO. The characteristics of the patients, B-RTO procedures, prognosis, and occurrence of risky esophageal and gastric varices were evaluated according to their medical records. Results Three-dimensional (3-D) angiography by MD-CT was useful for the diagnosis of small intestinal varices and the draining vessels. In all cases, variceal bleeding was controlled by B-RTO treatment, although rebleeding was recognized in one patient after 30 months (16.6%). All patients were alive throughout the follow-up except 1 patient who died of liver failure (6–44 months). Risky esophageal varices and gastric varices occurred in 2 patients (33.3%) after B-RTO. However, no variceal bleeding occurred. Conclusion B-RTO was found to be an effective treatment modality which provided good initial hemostasis, thereby eradicating ectopic small intestinal varices.

The outcomes of surgery for portal hypertensive patients at a single community hospital in the last two decades were retrospectively examined.From June 1989 to March 2008, 13 of 848 (1.5%) portal hypertensive patients admitted and treated at the community hospital underwent surgery. The types of surgery performed were a distal splenorenal shunt for 2 patients, gastric devascularization and splenectomy for 8, laparoscopic gastric devascularization and splenectomy for 1, distal gastrectomy for 1, and splenectomy alone for 1. This study reviewed the postoperative records of the endoscopic findings and additional treatments, and the perioperative records.No patient had bleeding from esophagogastric varices during the 75-month mean follow-up period after surgery. Five patients had one or two series of endoscopic treatment for recurrent likely-to-bleed esophageal varices. One patient needed interventional radiology for recurrent gastric varices. No patients died due to upper gastrointestinal bleeding. The survival rates were 87.5% after 5 years and 46.9% after 10 years.Surgery for portal hypertensive patients performed at a single community hospital is still safe and effective, and has been adequately incorporated into the late treatment strategy for portal hypertensive patients.

BackgroundPortal venous thrombosis (PVT) is a potentially fatal complication following splenectomy. Its mechanisms and risk factors are poorly understood, especially in patients with cirrhosis and portal hypertension. This study investigated risk factors for PVT following splenectomy in such patients.MethodsAll consecutive patients with cirrhosis who underwent splenectomy in Kyushu University Hospital between 1998 and 2004 were included in this retrospective study. They were divided into two groups based on the presence or absence of postoperative PVT. Preoperative and operative factors were compared, and the relationships between formation of PVT and its independent variables were analysed. In some cases, portal venous flow was measured before and after splenectomy using duplex Doppler ultrasonography.ResultsPVT developed after surgery in 17 (24 per cent) of 70 patients studied. Multivariable analysis showed that increased splenic vein diameter and low white cell count were significant independent risk factors for PVT. Portal venous flow after splenectomy was greatly reduced in the PVT group, but not in patients without PVT.ConclusionLarge splenic vein diameter and low white cell count are independent risk factors for PVT after splenectomy in patients with cirrhosis and portal hypertension.

The aim of this study was to determine the role of antithrombin III (AT-III) in portal vein thrombosis (PVT) after splenectomy in cirrhotic patients.There is no standard treatment for PVT after splenectomy in liver cirrhosis.A total of 50 consecutive cirrhotic patients who underwent laparoscopic splenectomy for hypersplenism were enrolled into this study. From January 2005 to December 2005, 25 cirrhotic patients received no prophylactic anticoagulation therapy after the operation (AT-III [-] group). From January 2006 to July 2006, 25 cirrhotic patients received prophylactic administration of AT-III concentrates (1500 U/d) on postoperative day (POD) 1, 2, and 3 (AT-III [+] group).In AT-III (-) group, 9 (36.0%) patients developed PVT up to POD 7, and risk factors for PVT were identified as: low platelet counts, low AT-III activity, and increased spleen weight. Although there were no significant differences in the clinical characteristics, including the above risk factors, between the 2 groups, only 1 (4.0%) patient developed PVT on POD 30 in AT-III (+) group, and the incidence of PVT was significantly lower than in AT-III (-) group (P = 0.01). In AT-III (-) group, AT-III activity was significantly decreased from POD 1 to POD 7, as compared with the preoperative level, whereas AT-III concentrates prevented the postoperative decrease in AT-III activity.These results demonstrate that low AT-III activity and further decreases in this activity are associated with PVT after splenectomy in cirrhotic patients, and that treatment with AT-III concentrates is likely to prevent the development of PVT in these patients.

We investigated the effects of thrombopoietin (TPO) on platelet counts and liver regeneration after partial hepatectomy in rats.We performed 70% partial hepatectomy on 60 rats given either TPO or a vehicle (controls). The rats were killed 6 h, 24 h, 72 h, or 168 h after the procedure, and we examined the platelet counts, weight of the regenerated liver, hepatocyte proliferation by bromodeoxyuridine (BrdU) labeling index, and expression of hepatocyte growth factor (HGF) mRNA by reverse transcription-polymerase chain reaction.In the controls, the platelet counts were significantly lower than the basal levels, by about 20%, at 6, 24, and 72 h; then recovered to the basal level at 168 h. Conversely, in the TPO-treated rats, the platelet counts increased significantly by 17%, 35%, and 60%, at 24, 72, and 168 h, respectively. The regenerated liver regained 80% of the pre-hepatectomy weight by 72 h in the controls, whereas reconstitution of the liver was accomplished by 72 h in the TPO-treated rats. Thrombopoietin significantly enhanced the BrdU labeling index of hepatocytes and expression of HGF mRNA 24 h post hepatectomy in TPO-treated rats versus controls.Thrombopoietin increased platelet counts; thereby accelerating liver regeneration after partial hepatectomy with enhanced induction of HGF.

A laparoscopic splenectomy in patients who previously underwent living-donor liver transplantation (LDLT) is thought to be technically difficult because of the presence of severe adhesions and splenomegaly. This report documents the efficacy and safety of a hand-assisted laparoscopic splenectomy (HALS) for hypersplenism in patients after LDLT.Five patients underwent HALS for hypersplenism after LDLT between 1999 and 2007. The medical records of those patients were retrospectively evaluated.The mean operative time was 237+/-12 minutes. The mean blood loss was 229+/-100 mL and the mean weight of excised spleen was 461+/-46 g. There was no conversion to open surgery. The number of platelets and leukocytes were significantly increased after surgery. No major complications were observed except for a patient who suffered paralytic ileus postoperatively. The mean hospital stay after the operation was 16.7+/-2.5 days.HALS for patients after LDLT is a feasible and safe procedure. This technique can thus become a standard procedure after LDLT.

This study aimed to evaluate whether laparoscopic splenectomy (Lap-Sp) contributes to the completion and curability of combined peginterferon and ribavirin (peg-IFN + RIB) therapy for cirrhotic patients with pancytopenia due to hypersplenism.From December 2004 to September 2007, 21 patients underwent Lap-Sp before treatment with peg-IFN + RIB. All the patients were Child-Pugh class A or B with a mean platelet count of 5.7 x 10(4)/mm(3) and a mean leukocyte count of 2,830/mm(3). The hepatitis C virus (HCV) genotype was 1b for 18 patients and 2b for 3 patients. Of the 21 patients, 17 had a viral load exceeding 100 KIU/ml, and 4 had a load of less than 100 KIU/ml.All the patients underwent Lap-Sp without severe complications. The average hospital stay was 12.7 days (range, 6-23 days). Platelet counts increased from a mean of 5.7 +/- 2.2 x 10(4)/mm(3) preoperatively to 19.6 +/- 7.6 x 10(4)/mm(3) postoperatively and remained above 7.0 x 10(4)/mm(3) during the subsequent peg-IFN + RIB therapy. The full course of therapy was completed for nine patients, with five obtaining a sustained virologic response and one obtaining a biologic response. The five patients who obtained a sustained virologic response had either HCV type 2b or 1b with a low viral load (100 KIU). At this writing, treatment is ongoing for the remaining 12 patients.Laparoscopic splenectomy allows patients with HCV cirrhosis and hypersplenism to receive full-dose peg-IFN + RIB therapy. Patients with HCV, genotype 2 or 1b and a low viral load, and hypersplenism may be good candidates for Lap-Sp.

Two-dimensional hyperspectral data systems with enhanced area detection and diagnostic abilities are now available in gastrointestinal endoscopy for colorectal cancer. We evaluated a new hyperspectral system for diagnosis of colorectal cancer.A resected-specimen spectrum observation module (stereoscopic macroscope, hyperspectral camera, and xenon lamp) was used to evaluate 21 resected colorectal cancer specimens (ex vivo experiment). A colonoscopy spectrum observation module (imaging fiberscope and hyperspectral camera) was used to perform 24 colonoscopic spectroscopy evaluations (in vivo experiment).An approximately 525-nm increase in spectral absorption occurred between normal mucosa and adenoma, with a tendency toward decreased absorption rates with aggravation of other tumor types. In vivo discrimination between tumorous and non-tumorous tissues showed 72.5% sensitivity and 82.1% specificity.This in vivo hyperspectral diagnostic system showed that reflectance spectra intensity may discriminate between normal and abnormal colonic mucosa.

Purpose : The aim of this study was to clarify the usefulness of two-stage operation for the patients with esophageal cancer who have liver dysfunction. Methods : Eight patients with esophageal cancer concomitant with liver dysfunction who underwent two-stage operation were analyzed. The patients initially underwent an esophagectomy, a cervical esophagostomy and a tube jejunostomy, and reconstruction with gastric tube was performed after the recovery of patients’ condition. Results : The average time of the 1st and 2nd stage operation was 410.0 min and 438.9 min, respectively. The average amount of blood loss in the 1st and 2nd stage operation was 433.5 ml and 1556.8 ml, respectively. The average duration between the operations was 29.8 days. The antesternal route was selected for 5 patients (62.5%) and the retrosternal route was for 3 patients (37.5%). In the 1st stage operation, no postoperative complications were observed, while, complications developed in 5 (62.5%) patients, including 4 anastomotic leakages, after the 2nd stage operation. Pneumonia was not observed through two-stage operation. No in-hospital death was experienced. Conclusion : A two-stage operation might prevent the occurrence of critical postoperative complications for the patients with esophageal cancer concomitant with liver dysfunction.

Stenotrophomonas maltophilia is an important nosocomial bacterial pathogen, as is Pseudomonas aeruginosa. Differentiation of these bacteria as bacteremic agents is critical in the clinical setting and to define a therapeutic strategy; however, the associated factors and prognosis for S. maltophilia bacteremia have not been fully evaluated to adequately characterize these factors. We first conducted a matched case-control study to clarify these questions. A total of 30 case patients with S. maltophilia bacteremia were compared with 30 control patients with P. aeruginosa bacteremia between January 2005 and August 2014, according to matching criteria based on underlying disease, age, and gender. The 30-day mortality rate for the case patients (53.3%) was significantly higher than that of the control group (30.0%) (P = 0.047, using the log-rank test). Conditional logistic regression analysis showed that the predisposing factors specific for the detection of S. maltophilia bacteremia were indwelling artificial products other than a central venous catheter, ICU stay, and previous use of anti-MRSA drugs. The high severity of illness was associated with mortality in both case and control patients. Interestingly, inappropriate antimicrobial treatment was an additional independent risk factor for mortality in only the case patients with S. maltophilia bacteremia (odds ratio = 13.64, P = 0.048). Monotherapy with fluoroquinolones inactive against the S. maltophilia isolates was mainly responsible for the inappropriate treatment. These results suggest that more precise prediction and more appropriate treatment might improve the prognosis of patients with S. maltophilia bacteremia.

Background & Aims Clinical studies suggest that splenectomy improves liver function in cirrhotic patients, but the influence of splenectomy on stem cell transplantation is poorly understood. This study investigated the effect of splenectomy on stem cell infusion and elucidated its mechanism. Methods Rat adipose tissue-derived mesenchymal stem cells were infused into cirrhosis rats with or without splenectomy, followed by the assessment of the in vivo distribution of stem cells and pathological changes. Stromal cell-derived factor-1 and hepatocyte growth factor expression were also investigated in splenectomized cirrhosis patients and rats. Results Splenectomy, prior to cell infusion, improved liver function and suppressed fibrosis progression more efficiently than cell infusion alone in the experimental cirrhosis model. Stromal cell-derived factor-1 and hepatocyte growth factor levels after splenectomy were increased in patients and rats. These upregulated cytokines significantly facilitated stem cell motility, migration and proliferation in vitro. C-X-C chemokine receptor type 4 neutralization weakened the promotion of cell migration by these cytokines. The infused cells integrated into liver fibrosis septa and participated in regeneration more efficiently in splenectomized rats. Direct coculture with stem cells led to inhibition of hepatic stellate cell proliferation. In addition, hepatocyte growth factor induced hepatic stellate cell apoptosis via the c-jun N-terminal kinase-p53 pathway. Conclusions Splenectomy prior to cell infusion enhanced the therapeutic effect of stem cells on cirrhosis, which involved upregulation of stromal cell-derived factor-1 and hepatocyte growth factor after splenectomy.

Background and Aim: In Japan, endoscopic injection sclerotherapy (EIS) is widely used to prevent first esophageal variceal bleeding, in contrast to pharmacological therapy which is the main treatment used in the rest of the world. The present study investigated if propranolol alone is acceptable to prevent first esophageal variceal bleeding in Japanese cirrhotic patients. This was compared with EIS. Methods: Twenty-five Japanese cirrhotic patients with endoscopically proven, likely to bleed esophageal varices were randomly assigned for propranolol administration (12 patients; group A) and EIS (13 patients; group B) to prevent first esophageal variceal bleeding. Complications, non-recurrence rate, bleeding rate and probability of survival were compared between the two groups. Results: One patient in group A had severe bradycardia with loss of consciousness that seriously worsened his quality of life. The cumulative non-recurrence rate of group A was significantly lower compared with that of group B (P

BACKGROUND The effect of the spleen on the cirrhotic liver is unknown. Transforming growth factor-beta 1 (TGF-beta 1), which plays a crucial role in the matrix production during liver fibrosis, is an inhibitory factor regarding the regeneration of hepatocytes. In this study, we investigated the TGF-beta 1 production in the spleen of cirrhotic rats and the effects of a splenectomy on the healing process from liver fibrosis. METHODS Thirty-six Wistar male rats were used. Thioacetamide (TAA) was administered intraperitoneally for 24 weeks. The rats underwent either a sham operation (TAA + Sham) or a splenectomy (TAA + SPL). The improvements in liver fibrosis and liver regeneration were investigated 10, 30 and 60 days after the operations in each group. The effect of a splenectomy on the plasma concentration of TGF-beta 1 in the portal vein was investigated by ELISA. The TGF-beta 1 expressions in the spleen were measured using immunohistochemical staining and the degree of such expression was measured using RT-PCR. The activity of TGF-beta 1 in the portal vein of TAA + Sham and TAA + SPL was assessed by the inhibiting effect of rat parenchymal hepatocyte proliferation in primary culture. RESULTS Liver regeneration (PCNA-labeling index) in the TAA + SPL rats was stimulated more at 10 and 30 days after the operation (P < 0.05) than in the TAA + Sham rats, and the improvement of liver fibrosis (fibrosis rate) in the TAA + SPL rats was higher at 60 days (P < 0.05) than in the TAA + Sham rats. The plasma concentration of TGF-beta1 of the portal vein in TAA + SPL rats was significantly lower than in the TAA + Sham rats for each period. Immunohistochemically, TGF-beta1-positive stained cells were recognized in the spleen macrophages in the red pulp of cirrhotic rats. The plasma of the TAA + Sham rats at 10 and 30 days after the operation was significantly stronger than that of the TAA + SPL rats in inhibiting the proliferation of rat hepatocytes of primary culture. Inhibitory effects were then dose-dependently neutralized by monoclonal TGF-beta 1 antibody. CONCLUSION Spleen-derived TGF-beta 1 may thus play an inhibitory role in the healing of liver cirrhosis by inhibiting the regeneration of the damaged liver.

Recent studies show that adipose tissue-derived mesenchymal stem cells have potential clinical applications. However, the mechanism has not been fully elucidated yet. Here, we investigated the effect of basic fibroblast growth factor-treated adipose tissue-derived mesenchymal stem cells infusion on a liver fibrosis rat model and elucidated the underlying mechanism.Adipose tissue-derived mesenchymal stem cells were infused into carbon tetrachloride-induced hepatic fibrosis rats through caudal vein. Liver functions and pathological changes were assessed. A co-culture model was used to clarify the potential mechanism.Basic fibroblast growth factor treatment markedly improved the proliferation, differentiation, and hepatocyte growth factor expression ability of adipose tissue-derived mesenchymal stem cells. Although adipose tissue-derived mesenchymal stem cells infusion alone slightly ameliorated liver functions and suppressed fibrosis progression, basic fibroblast growth factor-treatment significantly enhanced the therapeutic effect in association with elevated hepatocyte growth factor expression. Moreover, double immunofluorescence staining confirmed that the infused cells located in fibrosis area. Furthermore, co-culture with adipose tissue-derived mesenchymal stem cell led to induction of hepatic stellate cell apoptosis and enhanced hepatocyte proliferation. However, these effects were significantly weakened by knockdown of hepatocyte growth factor. Mechanism investigation revealed that co-culture with adipose tissue-derived mesenchymal stem cells activated c-jun N-terminal kinase-p53 signaling in hepatic stellate cell and promoted apoptosis.Basic fibroblast growth factor treatment enhanced the therapeutic effect of adipose tissue-derived mesenchymal stem cells, and secretion of hepatocyte growth factor from adipose tissue-derived mesenchymal stem cells plays a critical role in amelioration of liver injury and regression of fibrosis.

Recombinant thrombomodulin (rTM) has been available in Japan since 2008, but there is concern about its association with postoperative hemorrhage. The efficacy and safety of rTM were examined in patients with disseminated intravascular coagulation (DIC) caused by a septic condition after gastrointestinal surgery. Forty-two patients were emergently admitted to the intensive care unit after emergent gastrointestinal surgery in Kyushu University Hospital from May 2008 to April 2013. Of these patients, 22 had DIC (defined as an acute DIC score ≥4). All but three patients received treatment with gabexate mesylate (GM) (n = 9) or rTM (n = 10). The causes of sepsis were peritonitis with colorectal perforation, anastomotic leakage, and intestinal necrosis. Acute DIC score, sepsis-related organ failure assessment score, platelet count, and a variety of biochemical parameters were compared between rTM and GM recipients after treatment administration. There were no significant differences between the groups for any parameter except C-reactive protein levels. The CRP level tended to be lower in the rTM group than in the GM group. Acute DIC score in the rTM group resolved significantly earlier than that in the GM group. No patient stopped the administration of rTM because of postoperative bleeding. rTM may be an effective therapeutic drug for the treatment of septic patients with DIC following emergent gastrointestinal surgery.

Decreased antithrombin III (ATIII) activity and large splenic vein diameter (SVD) are risk factors for portal vein thrombosis (PVT) after splenectomy in liver cirrhosis with portal hypertension. Antithrombin III concentrates can prevent PVT. This study was designed to stratify risks for PVT after splenectomy in cirrhotic patients and to develop prophylactic protocols for PVT.In 53 patients (testing cohort), the cutoff level of preoperative ATIII activity (≤60%) was evaluated for administration of ATIII concentrates. Antithrombin III activity and SVD were re-evaluated as criteria for prophylaxis of PVT. In 57 patients (validation cohort), the risk stratification of PVT and prophylactic protocols were validated.In the testing cohort, 10 (19%) of 53 patients had PVT. Risk level of PVT was stratified and prophylactic protocols were developed. Patients at low risk (ATIII activity ≥70% and SVD10 mm) were not treated; those at high risk (ATIII activity70% or SVD ≥10 mm) received ATIII concentrates (1,500 U/day) for 3 days; and those at highest risk (SVD ≥15 mm) received ATIII concentrates for 3 days, followed by danaparoid sodium (2,500 U/day) for 14 days and warfarin. In the validation cohort, 0 of 14 low-risk and 2 of 32 high-risk patients had PVT. Although 8 of 11 patients at highest risk had temporary PVT, it disappeared within 3 months postoperatively. Finally, only 2 (3.5%) of 57 patients had PVT.Risk stratification of PVT after splenectomy and prophylaxis with ATIII concentrates and danaparoid sodium dramatically reduced the incidence of PVT.

Background Anastomotic leakage (AL) is a major complication after anterior resection. However, its therapeutic strategies and technical risk factors have not been well established. Therefore, we endoscopically evaluated anastomotic regions after laparoscopic colorectal anastomosis using a double-stapling technique (DST) for determination of treatment and investigation of technical factors. Methods In total, 191 consecutive patients underwent laparoscopic anterior resection with a DST from September 2008–January 2013. Anastomotic regions were endoscopically evaluated in patients suspected to have AL after surgery. Results Anastomotic dehiscence was observed in 19 patients, and AL was diagnosed in 18 (9.3%). Of the 19 patients, 12 were treated by creation of an intestinal stoma and 7 were treated conservatively based on their clinical status and endoscopic findings. Twenty-three dehiscences were observed among 19 anastomotic regions; all 23 were observed on the circular stapler anastomosis lines. Of these 23 dehiscences, 13 (56.5%) were located at the point at which the anastomosis lines of the circular and linear staplers overlapped, and 10 (43.5%) were located on the circumferential aspect between the overlapping points. Conclusions Endoscopic evaluation of anastomotic regions is safe and useful for the determination of therapeutic strategies. The DST anastomotic technique itself may be closely related to the development of AL.

Thrombocytopenia (TCP) of chronic hepatitis C patients with cirrhosis has a negative impact on the management of interferon-based treatment. The aim of this study is to evaluate the efficacy and safety of telaprevir-based triple therapy for patients who have undergone splenectomy (Spx).This prospective, multicenter study consisted of 80 patients, including 32 Spx and 48 non-Spx/TCP (platelet count: 60-99 × 10(9) /L) patients with advanced fibrosis infected with hepatitis C virus genotype 1b. All received 12 weeks of telaprevir in combination with 24 weeks of pegylated interferon (PEG-IFN) α2b and ribavirin.The sustained virological response (SVR) rate of the Spx group (75.0%) was significantly higher than that of the non-Spx/TCP group (52.1%) (P 0.05). Under favorable conditions such as treatment-naïve/prior relapse and interleukin-28B (IL28B) TT allele (rs8099917), the SVR rates of the Spx group were significantly higher than those of the non-Spx/moderate TCP (60-79 × 10(9) /L) groups (91.3% vs 50.0% and 93.8% vs 37.5%, respectively; both P 0.05). Adequate PEG-IFNα2b adherence was associated with SVR. However, the percentage of patients who achieved 80% adherence to PEG-IFNα2b in the non-Spx/moderate TCP (42.9%) group was significantly lower than that of the Spx (79.3%) and non-Spx/mild TCP (80-99 × 10(9) /L) (80.0%) groups. Treatment discontinuation due to adverse effects and the development of bacterial infection did not differ between the Spx and non-Spx/TCP groups.The increase of platelet count after Spx contributed to treatment success, especially for moderate to severe TCP patients who are treatment-naïve/prior relapse or IL28B TT allele.

Laparoscopic devascularization of the upper stomach and splenectomy (Dev+Sp), is technically difficult in patients with portal hypertension because of enlarged collateral vessels and spleen. This report presents the efficacy and safety of hand-assisted laparoscopic (HALS) Dev+Sp.Ten patients underwent HALS Dev+Sp as a treatment for esophagogastric varices between 2005 and 2012 (HALS group). A vessel-sealing system was used for devascularization of vessels. An autosuture device was applied to dissect the splenic hilum and the left gastric and enlarged short gastric vessels. The operative and postoperative data were compared between patients who previously underwent laparoscopic Dev+Sp (LAP group, n = 9) and conventional Dev+Sp (OP group, n = 10) between 2001 and 2008.The mean operative time was 328, 336, and 245 min (P 0.05) and the mean blood loss was 1786, 981, and 250 mL (P 0.05) in the OP, LAP, and HALS groups, respectively. Laparoscopic surgery was converted to HALS in one patient and to open surgery in three patients. There were no conversions in the HALS group. There was no significant difference in the cumulative recurrence rate and bleeding rate in the groups.HALS Dev+Sp is a feasible and effective surgery in patients with portal hypertension.

Superficial temporal artery (STA)—middle cerebral artery (MCA) bypass is an important technique for cerebrovascular reconstruction. Intraoperative hemodynamic imaging is needed to perform cerebrovascular reconstruction safely and effectively. Optical intrinsic signal (OIS) imaging is commonly used for assessing cerebral hemodynamics in experimental studies, because it can provide high-resolution mapping images. However, OIS is not used clinically due to algorithm, instrumentation and spectral resolution limitations. We tested the feasibility of a hyperspectral camera (HSC) for assessment of cortical hemodynamics with spectral imaging of the cerebral cortex in rats and in vivo humans. A hyperspectral camera (HSC) was tested in a rat model of cerebral ischemia (middle cerebral artery occlusion) and during human revascularization surgery (STA–MCA anastomosis). Changes in cortical oxygen saturation were derived from spectral imaging data (400–800 nm) collected by exposing the cortex to Xenon light. Reflected light was sampled using the HSC. The system was then tested intraoperatively during superficial temporal artery to middle cerebral artery anastomosis procedures. Comparison with single-photon emission computed tomography (SPECT) imaging data was done. During middle cerebral artery occlusion in rats, the HSC technique showed a significant decrease in cortical oxygen saturation in the ischemic hemisphere. In clinical cases, the cortical oxygen saturation was increased after STA–MCA anastomosis, which agreed with the SPECT imaging data. Continuous collection of imaging spectroscopic data is feasible and may provide reliable quantification of the hemodynamic responses in the brain. The HSC system may be useful for monitoring intraoperative changes in cortical surface hemodynamics during revascularization procedures in humans.

A 56-year-old male with alcohol-induced liver cirrhosis developed rectal varices. He had a prior history of treatment for esophageal varices with endoscopic variceal ligation. Despite the repeated treatment for rectal varices with endoscopic variceal ligation, endoscopic injection sclerotherapy, and surgery, the bleeding from the rectal varices could not be controlled. Multidetector-row computed tomography and 3D-angiography revealed the hemodynamic profile of the rectal varices. We next approached the rectal varices through the umbilical vein on the abdominal wall, and successfully embolized the varices continuing from the inferior mesenteric vein using coils and a 5% solution of ethanolamine oleate with iopamidol.

Several clinical studies of prophylactic therapy for esophageal varices have led to the conclusion that prophylactic therapy is of no value, and it is generally not accepted in the Western world. However, this is not the case in Japan. The present study evaluated the efficacy of prophylactic endoscopic injection sclerotherapy (EIS) in patients with unresectable hepatocellular carcinoma (HCC) and risky esophageal varices.Twenty-seven patients with 'likely-to-bleed' esophageal varices concomitant with unresectable HCC were randomly allocated to two groups. Thirteen patients underwent prophylactic EIS (EIS group), whereas the remaining 14 patients were observed conservatively (control group).No bleeding from esophageal varices occurred in the EIS group during the entire period of this study, whereas in thecontrol group the cumulative bleeding rate was 44.8% in 6 months. Cumulative survival rates of patients in the EIS group and in the control group were 48.8% and 7.7% in 2 years, respectively. There was a statistically significant difference between the two groups in cumulative bleeding rate and survival rate (P 0.01).This prospective study demonstrated that prophylactic EIS could prolong the survival of the patients with esophageal varices concomitant with unresectable HCC. Prophylactic EIS for patients with unresectable HCC may be, in part, justified according to the present study.

Background IL28B and ITPA genetic variants are associated with the outcome of pegylated-interferon and ribavirin (PEG-IFN/RBV) therapy. However, the significance of these genetic variants in cirrhotic patients following splenectomy has not been determined. Methods Thirty-seven patients with HCV-induced cirrhosis who underwent laparoscopic splenectomy (Spx group) and 90 who did not (non-Spx group) were genotyped for IL28B and ITPA. The outcome or adverse effects were compared in each group. Interferon-stimulated gene 15 (ISG15) and protein kinase R expression in the spleen was measured using total RNA extracted from exenterate spleen. Results Sustained virological response (SVR) rate was higher in patients carrying IL28B major genotype following splenectomy (50% vs 27.3%) and in patients carrying minor genotype in the Spx group compared to non-Spx group (27.3% vs 3.6%, P < 0.05). Pretreatment splenic ISG expression was higher in patients carrying IL28B major. There was no difference in progression of anemia or thrombocytopenia between patients carrying each ITPA genotype in the Spx group. Although splenectomy did not increase hemoglobin (Hb) level, Hb decline tended to be greater in the non-Spx group. In contrast, splenectomy significantly increased platelet count (61.1 × 103/μl vs 168.7 × 103/μl, P < 0.01), which was maintained during the course of PEG-IFN/RBV therapy. Conclusions IL28B genetic variants correlated with response to PEG-IFN/RBV following splenectomy. Splenectomy improved SVR rate among patients carrying IL28B minor genotype and protected against anemia and thrombocytopenia during the course of PEG-IFN/RBV therapy regardless of ITPA genotype.

The recent development of open magnetic resonance imaging (MRI) has provided an opportunity for the next stage of image-guided surgical and interventional procedures. The purpose of this study was to evaluate the feasibility of laparoscopic surgery under the pneumoperitoneum with the system of an open MRI operating theater. Five patients underwent laparoscopic surgery with a real-time augmented reality navigation system that we previously developed in a horizontal-type 0.4-T open MRI operating theater. All procedures were performed in an open MRI operating theater. During the operations, the laparoscopic monitor clearly showed the augmented reality models of the intraperitoneal structures, such as the common bile ducts and the urinary bladder, as well as the proper positions of the prosthesis. The navigation frame rate was 8 frames per min. The mean fiducial registration error was 6.88 ± 6.18 mm in navigated cases. We were able to use magnetic resonance–incompatible surgical instruments out of the 5-Gs restriction area, as well as conventional laparoscopic surgery, and we developed a real-time augmented reality navigation system using open MRI. Laparoscopic surgery with our real-time augmented reality navigation system in the open MRI operating theater is a feasible option.

In endoscopic surgery, limited views and lack of tactile sensation restrict the surgeon's abilities and cause stress to the surgeon. Therefore, an intra-operative navigation system is strongly recommended. We developed an augmented reality (AR) navigation system based on preoperative CT imaging. The purpose of this study is to evaluate the usefulness, feasibility, and accuracy of this system using laparoscopic splenectomy in children.Volume images were reconstructed by three-dimensional (3D) viewer application. We used an optical tracking system for registration between volume image and body surface markers. The AR visualization was superimposed preoperative 3D CT images onto captured laparoscopic live images. This system was applied to six cases of laparoscopic splenectomy in children. To evaluate registration accuracy, distances from the marker position to the volume data were calculated.The operator recognized the hidden vascular variation of the splenic artery and vein, accessory spleen, and pancreatic tail by overlaying an image onto a laparoscopic live image. The registration accuracy of six cases was 5.30 ± 0.08, 5.71 ± 1.70, 10.1 ± 0.60, 18.8 ± 3.56, 4.06 ± 1.71, and 7.05 ± 4.71.This navigation system provides real-time anatomical information, which cannot be otherwise visualized without navigation. The registration accuracy was acceptable in clinical operation.

We intended to determine whether laparoscopic splenectomy (Lap-Sp) contributes to treatment with interferon therapy in hepatitis C virus (HCV)-cirrhotic patients with thrombocytopenia caused by hypersplenism.From December 2004 to August 2008, 100 cirrhotic patients (54 men and 46 women) underwent Lap-Sp for a clinical application of interferon therapy. All the patients were Child-Pugh class A or B with thrombocytopenia (average platelet count, 56 × 10(3) /mm(3)). The HCV genotype was type 1 in 80 patients and type 2 in 20 patients.Pure laparoscopic or hand-assisted laparoscopy was performed in 78 and 22 patients, respectively, without mortality. Conversion to open surgery was not required in any of the patients. The platelet counts improved (mean platelet count 172 × 10(3) /mm(3) 1 month after surgery) and interferon (IFN) therapy was started in 97 patients. In this study period, 36 patients obtained a sustained virologic response. Eight patients discontinued IFN therapy because of depression, neutropenia or other reasons.Lap-Sp permits most patients with HCV cirrhosis and hypersplenism to receive sufficient IFN therapy. Therefore, Lap-Sp can become a strong supportive surgery for cirrhotic patients who require antiviral therapy.

Summary Dysfunction of T cells is a common feature in chronic persistent viral infections, including hepatitis C virus (HCV), and although hepatic and peripheral T cells have been studied extensively in chronic HCV hepatitis, the role of splenic T cell responses in such patients is poorly defined. This is an important issue, as thrombocytopenia is a complication of HCV-related liver cirrhosis (LC), due to splenic platelet sequestration and bone marrow suppression; splenectomy has been proposed to treat such patients. Herein, we studied peripheral blood mononuclear cells (PBMC) and splenic lymphoid subpopulations from a total of 22 patients, including 15 with HCV-related LC with marked thrombocytopenia treated with splenectomy, and seven controls. CD4+ T cells from peripheral blood and spleen were isolated and phenotype and function evaluated. Splenic CD4+ T cells in patients with LC expressed molecules associated with inhibitory signalling, including increased frequency of negative markers such as cytotoxic T lymphocyte associated antigen-4 (CTLA-4) and programmed death 1 (PD-1) and decreased production of cytokines. Patients with LC manifest higher levels of splenic CD4+ regulatory T cells and PD-L1- and PD-L2-expressing cells than controls. Blocking of PD-1/PD-1 ligand interaction reconstituted proliferative and cytokine responses of splenic mononuclear cells (SMC) from patients with LC. Splenectomy was followed by an increase in the ratio of interferon (IFN)-γ to interleukin (IL)-10 and a reduction of PD-1-expressing CD4+ T cells in peripheral blood. Our data suggest that peripheral tolerance is promoted by the spleen in LC via the up-regulated expression of PD-1 ligands.

Background/Aims: Recently, partial splenic arterial embolization (PSE) has become a supportive intervention for cirrhotic patients with hypersplenism in the administration of interferon therapy. However, relapsed thrombocytopenia is often observed in patients following PSE. This study aimed to report the clinical efficiency of laparoscopic splenectomy as a salvage treatment for relapsed thrombocytopenia following PSE. Methods: From 2005 to 2009, 6 patients with prior PSE treatment underwent laparoscopic splenectomy. We reviewed the surgical method of laparoscopic splenectomy and the peri- and postoperative outcomes. Results: Laparoscopic splenectomy effectively provided sufficient increases in patient platelet counts. In all patients, laparoscopic splenectomy was performed safely with no significant complications despite PSE-associated dense adhesion to the diaphragm and/or retroperitoneal attachments. Conclusion: Laparoscopic splenectomy provides a sufficient increase in patient platelet counts in relapsed thrombocytopenia following PSE. Therefore, laparoscopic splenectomy appears to be a superior supportive therapy for the treatment of thrombocytopenia in cirrhotic patients.

Background and Aims: To evaluate and compare laparoscopic splenectomy and partial splenic embolization as supportive intervention for cirrhotic patients with hypersplenism to overcome peripheral cytopenia before the initiation of and during interferon therapy or anticancer therapy for hepatocellular carcinoma. Methods: Between December 2000 and April 2008, 43 Japanese cirrhotic patients with hypersplenism underwent either laparoscopic splenectomy or partial splenic embolization as a supportive intervention to facilitate the initiation and completion of either interferon therapy or anticancer therapy for hepatocellular carcinoma. We reviewed the peri- and post-intervention outcomes and details of the subsequent planned main therapies. For interferon therapy, the rate of completion, the rate of treatment cessation and virological responses were evaluated. Anti-cancer therapies for hepatocellular carcinoma included liver resection, ablation therapy, intra-arterial chemotherapy, and transarterial chemoembolization. Results: All patients tolerated the operations well with no significant complications. The platelet count was significantly higher in the laparoscopic splenectomy group than in the partial splenic embolization group at 1 and 2 weeks after the intervention. Interferon therapy was stopped in two patients in the partial splenic embolization group due to recurrent thrombocytopenia whereas all patients in the laparoscopic splenectomy group completed interferon therapy. The planned anticancer therapies were performed in all patients, and were completed in all patients without any problems or major complications. Conclusion: Laparoscopic splenectomy may be superior to partial splenic embolization as a supportive intervention for cirrhotic patients with hypersplenism. Future prospective, randomized controlled patient studies are required to confirm these findings.

To evaluate the trends in the treatment outcomes for patients with colorectal cancer in Japan.We performed a retrospective analysis of patients undergoing surgery for primary colorectal cancer during a 16-year period (Group A [1992-2000, n = 258]; Group B [2001-2008, n = 258]) at Fukuoka City Hospital. Because no significant differences were found in the survival rates in stage 0, I, II, and III patients between the two groups, we concentrated on examining stage IV patients.The 3-year survival rate for stage IV patients in Group B (n = 26) was significantly higher than that in Group A (n = 31) (34.9% vs 3.9%, P0.05). The rate of curative resection for advanced liver metastases in Group B patients was also significantly higher than that of Group A patients (50.0% vs 13.3%, P0.05). As a result, the 2-year survival rate for the disease-free patients in Group B was significantly higher than that for the non-disease-free patients in Group B (46.0% vs 21.0%, P0.05). Group B had a greater proportion of patients receiving l-leucovorin/5-fluorouracil than Group A (8 patients vs none, P0.05).Recent advances in surgical innovations and the utilization of new chemotherapeutic agents may have led to significant improvements in the treatment outcomes for advanced colorectal cancer in Japan.

Aim: This study investigated the relationship between portal hypertensive gastropathy (PHG) and splenomegaly, and the effect of laparoscopic splenectomy on PHG in cirrhotic patients with portal hypertension. Methods: Seventy patients with liver cirrhosis and portal hypertension were prospectively studied. Indication for laparoscopic splenectomy was bleeding tendency in 10 patients, induction of interferon in 45, treatment of hepatocellular carcinoma in seven, and treatment for endoscopic injection sclerotherapy-resistant esophagogastric varices in eight. The severity of PHG was classified into none, mild, or severe according to the classification by McCormack et al. The severity of liver disease was classified using the Child–Pugh score. All patients underwent upper gastrointestinal endoscopy before and 1 month after the operation. Results: The prevalence of PHG was significantly correlated with the severity of liver disease using the Child–Pugh score. The severity of PHG was significantly correlated with the resected spleen volume. One month after the operation, PHG was improved in 16 of 17 patients with severe PHG and in 12 of 32 with mild PHG. The Child–Pugh score showed a significant improvement (6.8 ± 1.4 to 6.2 ± 1.2) at 3 months after laparoscopic splenectomy (P