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The generation of thrombin–antithromin (AT) complex (TAT) or soluble fibrin (SF) was prospectively compared with prothrombin fragment 1 + 2 (F1 + 2) generation in patients with disseminated intravascular coagulation (DIC). The plasma levels of TAT, SF, and F1 + 2 were significantly higher in the DIC group than in the non-DIC group. The differences in these levels between the DIC group and non-DIC group were significantly related to infections and hematopoietic tumors. There were no significant differences in the TAT/F1 + 2 ratio between DIC and non-DIC patients, but the SF/F1 + 2 ratio was significantly higher in the DIC group than the non-DIC group. The plasma AT activity was significantly higher in patients with DIC with resolution than in those without resolution, and in survivors than in nonsurvivors. These findings suggest that the ratio of TAT/thrombin is constant between the patients with and without DIC but that the ratio of fibrin formation/thrombin might increase in DIC.

We identified a novel mechanism of hereditary thrombosis associated with antithrombin resistance, with a substitution of arginine for leucine at position 596 (p.Arg596Leu) in the gene encoding prothrombin (called prothrombin Yukuhashi). The mutant prothrombin had moderately lower activity than wild-type prothrombin in clotting assays, but the formation of thrombin-antithrombin complex was substantially impaired. A thrombin-generation assay revealed that the peak activity of the mutant prothrombin was fairly low, but its inactivation was extremely slow in reconstituted plasma. The Leu596 substitution caused a gain-of-function mutation in the prothrombin gene, resulting in resistance to antithrombin and susceptibility to thrombosis.

Background: Little information is available on the analysis of medical costs of acute pancreatitis hospitalizations. Aim: This study aimed to determine the factors affecting medical costs of patients with acute pancreatitis during hospitalization using a Japanese administrative database. Methods: A total of 7193 patients with acute pancreatitis were referred to 776 hospitals. We defined “patients with high medical costs” as patients whose medical costs exceeded the 90th percentile in medical costs during hospitalization and identified the independent factors for patients with high medical costs with and without controlling for length of stay. Results: Multiple logistic regression analysis demonstrated that necrosectomy was the most significant factor for medical costs of acute pancreatitis during hospitalization. The odds ratio of necrosectomy was 33.64 (95% confidence interval, 14.14–80.03; p < 0.001). Use of an intensive care unit was the most significant factor for medical costs after controlling for LOS. The OR of an ICU was 6.44 (95% CI, 4.72–8.81; p < 0.001). Conclusion: This study demonstrated that necrosectomy and use of an ICU significantly affected the medical costs of acute pancreatitis hospitalization. These results highlight the need for health care implementations to reduce medical costs whilst maintaining the quality of patient care, and targeting patients with severe acute pancreatitis.

Acute cholecystitis is one of the most frequently encountered conditions in daily practice in Japan. However, there is a shortage of detailed data about treatments that have been performed according to the clinical practice guidelines (CPGs) for acute cholecystitis. We therefore examined the management of acute cholecystitis for adherence to the appropriate CPGs using the Japanese administrative database associated with the Diagnosis Procedure Combination (DPC) system. We collected data from 6,070 patients with acute cholecystitis, examining for the application of four recommended treatments (administration of antimicrobial drugs and nonsteroidal anti-inflammatory drugs (NSAIDs) and performance of early and laparoscopic cholecystectomy). The patients were classified according to the procedures documented for each case: no gallbladder drainage (n = 4,333), gallbladder drainage without supportive care (ventilation or hemodiafiltration or the use of vasopressor) (n = 1,591) and gallbladder drainage and supportive care (n = 146). Multiple logistic regression models revealed that patients with gallbladder drainage without supportive care and those with gallbladder drainage and supportive care significantly higher received administration of antimicrobial drugs and NSAIDs, while these patients underwent less early or laparoscopic cholecystectomy than did patients without gallbladder drainage, after adjusting for potential confounding effects of the clinical variables. This study demonstrated that there were various differences with regard to the performance of recommended treatments between the levels of procedures required for acute cholecystitis. In addition, this administrative database was a feasible tool for the evaluation of care processes and will provide useful information contributing to improved quality of medical care.

To investigate the trends of antimicrobial resistance in pathogens isolated from surgical site infections (SSI), a Japanese surveillance committee conducted the first nationwide survey. Seven main organisms were collected from SSI at 27 medical centers in 2010 and were shipped to a central laboratory for antimicrobial susceptibility testing. A total of 702 isolates from 586 patients with SSI were included. Staphylococcus aureus (20.4 %) and Enterococcus faecalis (19.5 %) were the most common isolates, followed by Pseudomonas aeruginosa (15.4 %) and Bacteroides fragilis group (15.4 %). Methicillin-resistant S. aureus among S. aureus was 72.0 %. Vancomycin MIC 2μg/ml strains accounted for 9.7 %. In Escherichia coli, 11 of 95 strains produced extended-spectrum β-lactamase (Klebsiella pneumoniae, 0/53 strains). Of E. coli strains, 8.4 % were resistant to ceftazidime (CAZ) and 26.3 % to ciprofloxacin (CPFX). No P. aeruginosa strains produced metallo-β-lactamase. In P. aeruginosa, the resistance rates were 7.4 % to tazobactam/piperacillin (TAZ/PIPC), 10.2 % to imipenem (IPM), 2.8 % to meropenem, cefepime, and CPFX, and 0 % to gentamicin. In the B. fragilis group, the rates were 28.6 % to clindamycin, 5.7 % to cefmetazole, 2.9 % to TAZ/PIPC and IPM, and 0 % to metronidazole (Bacteroides thetaiotaomicron; 59.1, 36.4, 0, 0, 0 %). MIC90 of P. aeruginosa isolated 15 days or later after surgery rose in TAZ/PIPC, CAZ, IPM, and CPFX. In patients with American Society of Anesthesiologists (ASA) score ≥3, the resistance rates of P. aeruginosa to TAZ/PIPC and CAZ were higher than in patients with ASA ≤2. The data obtained in this study revealed the trend of the spread of resistance among common species that cause SSI. Timing of isolation from surgery and the patient’s physical status affected the selection of resistant organisms.

Fibrin-related markers (FRMs) such as fibrin and fibrinogen degradation products (FDPs), d-dimer, and soluble fibrin monomer complex (SFMC) were prospectively evaluated in 522 patients using the overt disseminated intravascular coagulation (DIC) diagnostic criteria. The differences in all FRMs between the DIC group and the non-DIC group, and those between the survivors and nonsurvivors were significant in the patients with infections. In an analysis of all patients, DIC score cutoff values of 2 and 3 points for FDP, d-dimer, and SFMC were recommended to be 8.3 and 42.0 μg/mL, 2.4 and 22.0 μg/mL, and 3.4 and 138.0 μg/mL, respectively. In conclusion, the adequate cutoff value is thus considered to be useful for both making a diagnosis of DIC and for predicting the outcome. Fibrin-related markers are therefore thought to be more useful for making a diagnosis of DIC based on infections than based on any other underlying disorders.

We describe a case of a 69-year-old woman who developed rapidly progressive hepatocellular carcinoma (HCC) associated with autoimmune hepatitis (AIH) after a 7-year follow-up. Markers for viral hepatitis were negative. Serum tumor markers including alpha-fetoprotein and prothrombin induced by vitamin K absence II rose suddenly, and a large tumor was detected in spite of regular surveillance for HCC. Surgical treatment was performed. The resected liver specimen revealed well to moderately differentiated HCC. Ki67 staining showed rapid proliferation of the HCC. Although the incidence of HCC in patients with AIH has been unclarified, the possible complication by HCC must not be overlooked.

Background Sepsis is a leading cause of death and long-term disability in developed countries. A comprehensive report on the incidence, clinical characteristics, and evolving management of sepsis is important. Thus, this study aimed to evaluate the characteristics, management, and outcomes of patients with severe sepsis in Japan. Methods This is a cohort study of the Focused Outcomes Research in Emergency Care in Acute Respiratory Distress Syndrome, Sepsis, and Trauma (FORECAST) study, which was a multicenter, prospective cohort study conducted at 59 intensive care units (ICUs) from January 2016 to March 2017. We included adult patients with severe sepsis based on the sepsis-2 criteria. Results In total, 1184 patients (median age 73 years, interquartile range (IQR) 64–81) with severe sepsis were admitted to the ICU during the study period. The most common comorbidity was diabetes mellitus (23%). Moreover, approximately 63% of patients had septic shock. The median Sepsis-related Organ Failure Assessment (SOFA) score was 9 (IQR 6–11). The most common site of infection was the lung (31%). Approximately 54% of the participants had positive blood cultures. The compliance rates for the entire 3-h bundle, measurement of central venous pressure, and assessment of central venous oxygen saturation were 64%, 26%, and 7%, respectively. A multilevel logistic regression model showed that closed ICUs and non-university hospitals were more compliant with the entire 3-h bundle. The in-hospital mortality rate of patients with severe sepsis was 23% (21–26%). Older age, multiple comorbidities, suspected site of infection, and increasing SOFA scores correlated with in-hospital mortality, based on the generalized estimating equation model. The length of hospital stay was 24 (12–46) days. Approximately 37% of the patients were discharged home after recovery. Conclusion Our prospective study showed that sepsis management in Japan was characterized by a high compliance rate for the 3-h bundle and low compliance rate for central venous catheter measurements. The in-hospital mortality rate in Japan was comparable to that of other developed countries. Only one third of the patients were discharged home, considering the aging population with multiple comorbidities in the ICUs in Japan. Trial registration UMIN-CTR, UMIN000019742. Registered on 16 November 2015. Electronic supplementary material The online version of this article (10.1186/s13054-018-2186-7) contains supplementary material, which is available to authorized users.

Disseminated intravascular coagulation (DIC) sometimes has a poor outcome, and therefore early diagnosis and treatment are required. This study prospectively evaluated the hemostatic abnormalities and the onset of DIC in 613 patients with underlying diseases to identify a useful marker for diagnosing Pre-DIC. Pre-DIC was defined as the condition of patients within a week before the onset of DIC. Initially, 34.4% of patients were diagnosed with DIC, and about 8.5% of the patients without DIC were diagnosed as DIC within a week after registration (pre-DIC). The mortality of DIC, Pre-DIC and "without DIC" was 35.3%, 32.4% and 17.2%, respectively. All hemostatic parameters were significantly worse in "DIC" than "without DIC" and the values of the prothrombin time ratio, platelet count and fibrin monomer complex could classify the three groups; "DIC", "pre-DIC" and "without DIC". No useful marker was identified that provided an adequate cutoff value to differentiate "pre-DIC" from "without DIC". A multivariate analysis identified clinical symptoms that were related to poor outcome. DIC must be treated immediately; there is no specific marker to identify pre-DIC.

The Japan Society of Clinical Oncology started implementing clinical practice guidelines for cancer in 2001. It created a Guideline Committee and has published cancer-related information in collaboration with individual subspecialty cancer societies. The society then established an Evaluation Committee to assess the quality of guidelines. The quality of development and general characteristics of guidelines were reviewed using the AGREE instrument. The six standardized domain scores and 23-item crude scores were described, and items with a low median score or a wide inter-quartile range were explored. Kappa statistics for inter-rater reproducibility were also described. Domains in which the median score was >50 points in 18 guidelines developed between March 2005 and May 2009 included “scope and purpose,” “rigor of development,” and “clarity and presentation.” Domains with a median score

金沢大学医薬保健研究域医学系, Islet transplantation for the treatment of type 1 diabetes mellitus is limited in its clinical application mainly due to early loss of the transplanted islets, resulting in low transplantation efficiency. NKT cell-dependent IFN-γ production by Gr-1+CD11b+ cells is essential for this loss, but the upstream events in the process remain undetermined. Here, we have demonstrated that high-mobility group box 1 (HMGB1) plays a crucial role in the initial events of early loss of transplanted islets in a mouse model of diabetes. Pancreatic islets contained abundant HMGB1, which was released into the circulation soon after islet transplantation into the liver. Treatment with an HMGB1-specific antibody prevented the early islet graft loss and inhibited IFN-γ production by NKT cells and Gr-1+CD11b + cells. Moreover, mice lacking either of the known HMGB1 receptors TLR2 or receptor for advanced glycation end products (RAGE), but not the known HMGB1 receptor TLR4, failed to exhibit early islet graft loss. Mechanistically, HMGB1 stimulated hepatic mononuclear cells (MNCs) in vivo and in vitro; in particular, it upregulated CD40 expression and enhanced IL-12 production by DCs, leading to NKT cell activation and subsequent NKT cell-dependent augmented IFN-γ production by Gr-1+CD11b+ cells. Thus, treatment with either IL-12- or CD40L-specific antibody prevented the early islet graft loss. These findings indicate that the HMGB1-mediated pathway eliciting early islet loss is a potential target for intervention to improve the efficiency of islet transplantation.

The present report from The Japanese Society of Thrombosis and Hemostasis provides an expert consensus for the treatment of disseminated intravascular coagulation (DIC) in Japan. Disseminated intravascular coagulation (DIC) may be classified as follows: asymptomatic type, marked bleeding type, and organ failure type. Although treatment of DIC is important, adequate treatment differs according to type of DIC. In asymptomatic DIC, low molecular weight heparin (LMWH), synthetic protease inhibitor (SPI), and antithrombin (AT) are recommended, although these drugs have not yet been proved to have a high degree of effectiveness. Unfractionated heparin (UFH) and danaparoid sodium (DS) are sometimes administrated in this type, but their usefulness is not clear. In the marked bleeding type, LMWH, SPI, and AT are recommended although these drugs do not have high quality of evidence. LMWH, UFH, and DS are not recommended in case of life threatening bleeding. In case of severe bleeding, SPI is recommended since it does not cause a worsening of bleeding. Blood transfusions, such as fresh frozen plasma and platelet concentrate, are also required in cases of life threatening bleeding. In the organ failure type, including sepsis, AT has been recommended based on the findings of several clinical trials. DIC is frequently associated with thrombosis and may thus require strong anticoagulant therapy, such as LMWH, UFH, and DS.

症例1は53歳，女性．他院にて，1996年肝細胞癌（hepatocellular carcinoma，以下HCCと略記）に対して，肝切除術施行した．2001年S5再発に対して経皮的ラジオ波焼灼療法（radiofrequency ablation，以下RFAと略記）を施行した．2006年10月AFP値の増加を認め，CT・MRI検査にて胸壁腫瘍および肝S5，S6，S7に再発腫瘍を認めたため当科紹介された．同年12月，肝S5・6・7開腹下マイクロターゼ凝固術，胸壁腫瘤摘出術施行し，中分化型肝細胞癌であり，胸壁穿刺経路播種と診断した．2007年2月胸壁播種再々発を認め，胸壁腫瘍，横隔膜・助骨合併切除術を施行した．症例2は65歳，男性．2003年前医にてS5のHCCに対してRFAを3回施行したが腫瘍のコントロールつかず，2006年2月当科紹介された．同年2月，肝右葉切除術施行した．同年11月CTにて胸壁の第9肋間にRFA穿刺部に一致して腫瘍を指摘され，同年12月開胸下に肋間腫瘍摘出術を施行した．病理組織学的検査では，中分化型肝細胞癌であった．比較的稀な経皮的RFA後の穿刺経路播種をきたした2症例を経験したので文献的考察を加え報告する．

Since it is well known that endothelial cells may be important targets during rejection after living-donor liver transplantation, in this study we investigated liver sinusoidal endothelial cell (SEC) damage during rejection by focusing on thrombomodulin (TM) and hyaluronic acid (HA) as plasma markers of SEC damage. We also examined tissue factor (TF) expression in SECs, because damage to endothelial cells leads to immediate activation of the coagulation system, with the damage being triggered mainly by TF. Living-donor liver transplantation was performed at Mie University Hospital between March 2002 and December 2007; there were 8 patients with rejection (4 with acute cellular rejection and 4 with chronic rejection) and 32 patients without rejection. Liver biopsy tissue was immunostained with an anti-TF antibody, and assessed for SEC damage. In addition, total RNA was extracted from liver biopsy tissue and tested for TF mRNA expression by reverse-transcription polymerase chain reaction (RT-PCR). The plasma TM level was significantly higher in the rejection group than in the non-rejection group. TF expression was observed in SECs, in infiltrating inflammatory cells, and in the vascular endothelium in the rejection group. TF mRNA expression was significantly higher in the rejection group than in the non-rejection group. We demonstrated that TF expression revealed severe SEC damage in grafted liver during both acute cellular rejection and chronic rejection.

Objective— High mobility group box 1 protein (HMGB1) was identified as a mediator of endotoxin lethality. We previously reported that thrombomodulin (TM), an endothelial thrombin-binding protein, bound to HMGB1, thereby protecting mice from lethal endotoxemia. However, the fate of HMGB1 bound to TM remains to be elucidated. Methods and Results— TM enhanced thrombin-mediated cleavage of HMGB1. N-terminal amino acid sequence analysis of the HMGB1 degradation product demonstrated that thrombin cleaved HMGB1 at the Arg10-Gly11 bond. Concomitant with the cleavage of the N-terminal domain of HMGB1, proinflammatory activity of HMGB1 was significantly decreased ( P Conclusions— TM not only binds to HMGB1 but also aids the proteolytic cleavage of HMGB1 by thrombin. These findings highlight the novel antiinflammatory role of TM, in which thrombin-TM complexes degrade HMGB1 to a less proinflammatory form.

SummaryThe Japanese Association for Acute Medicine (JAAM) disseminated intravascular coagulation (DIC) study group recently announced new diagnostic criteria for DIC. These criteria have been prospectively validated and demonstrated to progress to overt DIC as defined by the International Society on Thrombosis and Haemostasis (ISTH).Although an underlying condition is essential for the development of DIC, it has never been clarified if patients with different underlying disorders have a similar course. Among 329 patients with DIC diagnosed by the JAAM criteria, those with underlying sepsis (n=98) or trauma (n=95) were compared. The 28-day mortality rate was significantly higher in sepsis patients than trauma patients (34.7% vs. 10.5%, p

To survey the natural history of disseminated intravascular coagulation (DIC) in patients diagnosed according to the Japanese Association for Acute Medicine (JAAM) DIC scoring system in a critical care setting.Prospective, multicenter study during a 4-month period.General critical care center in a tertiary care hospital.All patients were enrolled when they were diagnosed as DIC by the JAAM DIC scoring system.None.Platelet counts, prothrombin time ratio, fibrinogen, and fibrin/fibrinogen degradation products were measured, and the systemic inflammatory response syndrome criteria met by the patients were determined following admission. Of 3,864 patients, 329 (8.5%) were diagnosed with DIC and the 28-day mortality rate was 21.9%, which was significantly different from that of the non-DIC patients (11.2%) (p.0001). The progression of systemic inflammation, deterioration of organ function, and stepwise increase in incidence of the International Society on Thrombosis and Haemostasis (ISTH) DIC and its scores all correlated with an increase in the JAAM DIC score as demonstrated by the patients on day 0. There were significant differences in the JAAM DIC score and the variables adopted in the scoring system between survivors and nonsurvivors. The logistic regression analyses showed the JAAM DIC score and prothrombin time ratio on the day of DIC diagnosis to be predictors of patient outcome. The patients who simultaneously met the ISTH DIC criteria demonstrated twice the incidence of multiple organ dysfunction (61.1 vs. 30.5%, p.0001) and mortality rate (34.4 vs. 17.2%, p = .0015) compared with those without the ISTH DIC diagnosis.This prospective survey demonstrated the natural history of DIC patients diagnosed by the JAAM DIC diagnostic criteria in a critical care setting. The study provides further evidence of a progression from the JAAM DIC to the ISTH overt DIC.

The changes in biomarkers of coagulation or fibrinolysis, anticoagulation, inflammation, and endothelial damage occur in patients with systemic inflammatory response syndrome (SIRS). The purpose of this study is to assess the prognostic value of these markers in patients with SIRS-associated hypercoagulopathy.Sixty-six SIRS patients with a platelet count less than 15.0 x 10(4)/mm3 in three university hospital intensive care units were enrolled in this prospective, comparative study. Blood samples were obtained on day 0 and day 2. Twelve hemostatic, inflammatory, and vascular endothelial indices were measured and the data were compared between the severe group (patients with a total maximum Sequential Organ Failure Assessment score of 10 or more and nonsurvivors; n = 25) and the less-severe group (Sequential Organ Failure Assessment score10; n = 41).Significant changes between the groups were observed in platelet count, fibrin or fibrinogen degradation products, interleukin-6, soluble thrombomodulin, antithrombin (AT) activity, and protein C activity, both on day 0 and on day 2. In contrast, the d-dimer, soluble fibrin, plasmin-[alpha]2-antiplasmin complex, and E-selectin levels were higher in the severe group only on day 2. No significant difference was seen regarding the thrombin-AT complex and total plasminogen activator inhibitor on both days. A comparison of the areas under the receiver operating characteristic curve revealed the AT activity to be the best predictor of a progression of organ dysfunction.The changes in some hemostatic molecular markers and vascular endothelial markers were conspicuous in patients with organ dysfunction. The AT activity is considered to be the most useful predictor of organ dysfunction.

Coagulopathy and thrombocytopenia often occur in critically ill patients, and disseminated intravascular coagulation (DIC) can lead to multiple organ dysfunction and a poor outcome. However, the relation between coagulopathy and systemic inflammatory response has not been thoroughly clarified. Thus, we evaluated coagulative activity, organ dysfunction, and systemic inflammatory response syndrome (SIRS) in critically ill patients with thrombocytopenia and examined the balance between coagulopathy and systemic inflammation.Two hundred seventy-three patients, who were admitted to 13 critical care centers in Japan and fulfilled the criteria of platelet count of less than 150*10(9)/L, were included. Coagulative variables (platelet count, fibrin/fibrinogen degradation products, and DIC scores), organ dysfunction index (Sequential Organ Failure Assessment [SOFA] score), and SIRS score in each patient were evaluated for 4 consecutive days after fulfilling the above entry criteria. The effect of SIRS on coagulopathy and organ dysfunction was evaluated in these patients.Both the maximum SIRS score and entry SIRS score had significant relation to the maximum SOFA score during the observation period. Coagulation disorders indicated by the minimum platelet count, maximum DIC scores, and positivity for DIC worsened gradually with increases in SIRS scores. Both the minimum platelet count and maximum DIC scores were significantly correlated with the maximum SOFA score, indicating that a relation exists between coagulopathy and organ dysfunction.In critically ill patients with thrombocytopenia, coagulopathy and organ dysfunction progress with significant mutual correlation, depending on the increase in SIRS scores. The SIRS-associated coagulopathy may play a critical role in inducing organ dysfunction after severe insult.

Previously, we have demonstrated that surgical stress rapidly induced transient hyporesponsiveness of blood cells to endotoxin and that monocyte mCD14 and HLA-DR expression decreased soon after the start of surgery under general anaesthesia. This study was designed to investigate the effects of epidural anaesthesia on surgical stress-induced immunosuppression in patients undergoing upper abdominal surgery.After having obtained informed consent, patients were randomly allocated to receive general anaesthesia (Group G) or general anaesthesia with epidural anaesthesia (Group E). Perioperative changes in neutrophil phagocytic activity, neutrophil respiratory burst activity, monocyte mCD14 and HLA-DR expression, plasma IL-10 concentration, and the LPS-induced TNF-alpha production in whole blood were measured.Surgical stress rapidly depressed neutrophil phagocytic activity, monocyte mCD14 and HLA-DR expression, and LPS-induced TNF-alpha production ex vivo (P0.05 vs preoperation) in both Group G and Group E. In contrast, the plasma IL-10 concentration increased significantly 2 h after the start of surgery (P0.05) in both groups. There were no significant differences between the two groups. The neutrophil respiratory burst activity did not change during the operation in either group.This study showed that the innate immune system is suppressed from the early period of upper abdominal surgery. Subgroup analysis suggested that epidural anaesthesia to T4 dermatome as well as general anaesthesia may not protect patients from this immunosuppression. These results in part explain the impairment of host-defense mechanisms seen in the perioperative period.

Sepsis is frequently complicated by coagulopathy and, in about 35 % of severe cases, by disseminated intravascular coagulation (DIC). In Japan, aggressive treatment of septic DIC is encouraged using antithrombin and recombinant thrombomodulin. The macrophages, monocytes, and neutrophils are a source of TF and participate in the direct activation of the coagulation cascade in the early phases of sepsis. And activated factor X (FXa), which is involved in hemostasis, thrombogenesis, inflammation, and cellular immune responses, induces TF expression in human peripheral monocytes and, conversely, that inhibition of FXa activity reduces TF expression. Both inflammation and coagulation play an important role in DIC due to sepsis. In addition to inflammatory cytokines (TNF-α, IL-1 and so on), HMGB1 has recently been shown to mediate the lethal late phase of sepsis and caused coagulopathy. TM not only binds HMGB1 but also aids the proteolytic cleavage of HMGB1 by thrombin. There have been many reports of the efficacy of recombinant TM and antithrombin for treatment of septic DIC from Japan. Further investigation of the efficacy of recombinant TM and AT in countries other than Japan, as well as the monitoring of medical costs incurred during hospitalization, will help validate the use of TM and AT for treatment of septic DIC.

This study investigated the time trends and hospital factors affecting the use of drugs for infectious disease-associated disseminated intravascular coagulation (DIC) based on a national administrative database. A total of 14 324 patients with infectious disease-associated DIC were referred to 1041 hospitals from 2010 to 2012 in Japan. Patients’ data were collected from the administrative database to determine time trends and hospital factors affecting the use of drugs for DIC. Three study periods were established, namely, the fiscal years 2010 (n = 3308), 2011 (n = 5403), and 2012 (n = 5613). The use of antithrombin, heparin, protease inhibitors, and recombinant human soluble thrombomodulin (rhs-TM) for DIC was evaluated. The frequency of use of antithrombin, heparin, and protease inhibitors decreased while that of rhs-TM significantly increased from 2010 to 2012 in Japan (25.1% in 2010, 43.1% in 2011, and 56.8% in 2012; P < .001, respectively). Logistic regression showed that the study period was associated with the use of rhs-TM in patients with DIC. The odds ratio (OR) for 2011 was 2.34 (95% confidence interval [CI], 2.12-2.58; P < .001) whereas that for 2012 was 4.34 (95% CI, 3.94-4.79; P < .001). A large hospital size was the most significant factor associated with the use of rhs-TM in patients with DIC (OR, 3.14; 95% CI, 2.68-3.66; P < .001). The use of rhs-TM has dramatically increased. A large hospital size was significantly associated with the increased use of rhs-TM in patients with DIC from 2010 to 2012 in Japan.

New Japanese diagnostic criteria were prepared for disseminated intravascular coagulation (DIC) in critically ill patients and their usefulness was compared with the criteria of the International Society of Thrombosis and Haemostasis (ISTH) and those of the Japan Ministry of Health and Welfare (JMHW). In a retrospective study of patients with platelet counts of less than 150 × 103/mL, 52 cases (33.3%), 66 cases (42.3%), and 101 cases (64.7%) were diagnosed as DIC by the ISTH, JMHW, and new Japanese DIC criteria, respectively. The DIC state as diagnosed by the new Japanese DIC criteria included both DIC states as diagnosed by ISTH or JMHW criteria. Some DIC states diagnosed by the JMHW criteria included those diagnosed by ISHT criteria but this was not universal. The mortality of DIC as diagnosed by the ISTH or JMHW criteria was markedly high, compared to that for DIC diagnosed by the new Japanese criteria. The mortality of patients without DIC by ISTH was also high when they were diagnosed as DIC by the new Japanese criteria. The frequency of DIC by each set of diagnostic criteria was significantly higher in patients with infection than in those without infection. The mortality of DIC by each set of diagnostic criteria was significantly higher in patients with infection than in those without infection, and the mortality of overt-DIC by ISTH diagnostic criteria was also high in patients without infection.

職業との関連が示唆されるStreptococcus intermediusを起炎菌とするガス壊疽の1例を経験した.症例は42歳,男性,歯科医.薬剤アレルギー歴あり. 2週間前より特に外傷なく右腋窩に疹痛と腫脹を生じ, 5日前より同部の自潰排膿があり,患者自ら歯科診療所の器具を用い自潰部を縫合した.右腋窩および胸部の痔痛と発熱を主訴に来院.来院時縫合部より出血および排膿がみられ,右腋窩および胸部の発赤熱発と触診上の握雪感を認めた.炎症反応も強く, X線検査でも筋層内に気泡を認めたため,ガス壊疽と診断し直ちに手術的にデブリードマン,ドレナージ施行.薬剤リンパ球刺激試験で陰性の抗生剤投与に加え高圧酸素療法も併用した.最終的に二次縫合し退院となった.本症例で分離されたS. intermediusは,以前はS. milleriグループに分類されており,口腔内特に歯科領域で分離される.今回の症例では感染巣の増悪に関与したものと考えられた.

BACKGROUND It is believed that midkine (MK), a heparin-binding growth factor, plays an important role in carcinogenesis. However, the biologic mechanism of MK in hepatocellular carcinoma has not been clarified to date. The objective of the current study was to investigate the antiapoptotic role of MK in a human hepatoma cell line. METHODS The human hepatoma cell line HepG2 was used to study the antiapoptotic effect of MK. Tumor necrosis factor–related apoptosis-inducing ligand (TRAIL)/actinomycin D (ActD)–induced apoptosis was detected using a 2-(2-methoxy-4-nitrophenyl)-3-(4-nitrophenyl)-5-(2,4-disulphophenyl)-2H-tetrazolium monosodium salt (WST-8) assay, a caspase-3 activity assay, a caspase-8 activity assay, and flow cytometric analysis. RESULTS TRAIL had a potent, dose-dependent inductive effect on cell death in HepG2 cells, for which viable cell counts decreased to 6.3% of the control count at a TRAIL concentration of 100 ng/mL in the presence of 500 ng/mL ActD. Flow cytometry was used to demonstrate that apoptosis induced by TRAIL/ActD was in fact the cause of cell death. According to the WST-8 assay, MK pretreatment resulted in the suppression of TRAIL/ActD-mediated apoptosis in HepG2 cells, although cell viability did not increase when HepG2 cells were treated with MK alone. Caspase-3 activity was down-regulated when MK was added, but caspase-8 activity was high in both the absence and presence of MK. CONCLUSIONS The results of the current study indicate that MK acts as an antiapoptotic factor in HepG2 cells through the down-regulation of caspase-3 activity. Cancer 2004. © 2004 American Cancer Society.

UNLABELLED We studied the effects of pneumoperitoneum on gastric submucosal perfusion metabolism during elective laparoscopic cholecystectomy (LASC) by measuring the PCO(2) gap, defined as the difference between intramucosal PCO(2) and arterial PCO(2), using gas tonometry in 20 patients. Furthermore, we examined whether thoracic epidural anesthesia (TEA) affects gastric submucosal perfusion metabolism during LASC. Patients were randomly allocated to receive general anesthesia (group G, n = 10) or general anesthesia combined with TEA (group E, n = 10). In both groups, the PCO(2) gap increased significantly during pneumoperitoneum and remained at this level until the end of surgery compared with the baseline value. There were no significant differences in PCO(2) gap values between the two groups at any time sampled. These results suggested that pneumoperitoneum significantly impaired gastric submucosal perfusion and metabolism and that TEA did not attenuate the impairment of gastric submucosal perfusion during or after pneumoperitoneum. IMPLICATIONS We investigated the effect of pneumoperitoneum on gastric submucosal perfusion by measuring PCO(2) gap with the use of gas tonometry. PCO(2) gap significantly increased during and after the pneumoperitoneum compared with the control level. Thoracic epidural anesthesia did not attenuate this inhibition.

We compared the criteria set by the International Society of Thrombosis and Hemostasis (ISTH) for the diagnosis of disseminated intravascular coagulation (DIC) with the criteria of the Japanese Ministry of Health and Welfare (JMHW) set for the diagnosis of overt DIC. We studied 1,284 Japanese patients with DIC. The rate of agreement in the diagnosis of DIC by the two diagnostic systems was 67.4%. In addition, only 2.0% of non-DIC patients by JMHW criteria were diagnosed with overt DIC by ISTH criteria, suggesting that ISTH for overt DIC includes typical cases of DIC. The concordance of diagnosis for DIC by ISTH and JMHW was significantly high in patients with trauma or acute promyelocytic leukemia. About 70% of DIC or overt DIC patients had more than 1 point in the scoring system for prothrombin time, but50% of those patients had 0 point for plasma fibrinogen level. Abnormal fibrin and fibrinogen degradation product (FDP) levels and platelet counts were observed in88% of DIC and overt DIC patients but were observed in50% of non-DIC patients, indicating that these parameters are sensitive markers but not specific markers for the diagnosis of DIC. Considered together, our results suggest that the diagnostic criteria for DIC and overt DIC could be improved by changing the cut-off values of the global coagulation tests.

Disseminated intravascular coagulation (DIC) associated with solid tumors (DIC-ST) is often encountered in clinical practice. Patients with DIC-ST are usually in poor condition and have bleeding diathesis due to advanced or metastatic diseases. Although some affected patients are treated with heparin, this strategy has not been prospectively studied. Recombinant human soluble thrombomodulin (thrombomodulin alfa, TM-α) is a new anticoagulant developed in Japan. We conducted a prospective study that evaluated the efficacy and safety of TM-α in patients with DIC-ST. A prospective one-arm study with TM-α was conducted for DIC-ST. TM-α (380 U/kg) was given for 30 min intravenously once daily for 6–14 days. The primary efficacy endpoint was the DIC resolution rate. Change in DIC scores and improvement in bleeding symptoms and outcomes were also evaluated. Safety endpoints included the incidence of bleeding-related adverse events. A total of 101 patients were treated with TM-α. The three main underlying malignant diseases were lung, stomach, and breast cancer, which accounted for 60 % of all patients. The DIC resolution rate was 34.0 % at the end of TM-α treatment. Improvement in DIC scores was seen in 55.2 % of patients, while only 22.9 % of patients had worsening of DIC scores. The overall survival rate was 55.4 % on day 28. The incidence of hemorrhage related to TM-α was 12.9 % until day 28. Cases of severe hemorrhage related to TM-α did not occur. TM-α is effective and safe for DIC-ST. This agent is the treatment of choice for the management of DIC-ST.

Background There have been no studies comparing the effects of antithrombin (AT-III) and recombinant human soluble thrombomodulin (rhs-TM) on outcomes in patients with disseminated intravascular coagulation (DIC) associated with infectious diseases. Objective The aim of this observational study is to compare AT-III and rhs-TM in terms of outcomes such as mortality, length of hospitalization, and medical costs in patients with DIC associated with infectious diseases based on a Japanese administrative database. Setting A total of 7,535 patients with DIC associated with infectious diseases in 886 hospitals from 2010 to 2012 in Japan. Methods We collected patients’ data from the administrative database to compare clinical and medical economic outcomes of patients with DIC. Patients were divided into two groups according to treatment of DIC: AT-III (n = 3,601) and rhs-TM (n = 3,934). Main outcomes measure In-hospital mortality (within 14 days, within 28 days, and overall mortality), length of stay (LOS), and medical costs during hospitalization. Results Multilevel logistic regression analysis showed that there were no significant differences with regard to in-hospital mortality between AT-III and rhs-TM within 14 days (odds ratio (OR) of rhs-TM 0.97, 95 % confidence interval (CI) 0.85–1.11, p = 0.744), within 28 days (OR 1.00, 95 % CI 0.89–1.13, p = 0.919), and overall (OR 0.95, 95 % CI 0.85–1.07, p = 0.470). However, multilevel linear regression analysis revealed that use of rhs-TM significantly decreased LOS and medical costs during hospitalization. The coefficient for LOS was −2.92 days (95 % CI −4.79 to −1.04 days; p = 0.002) whereas that for medical costs during hospitalization was −798.3 Euro (95 % CI −1,515.7 to −81.0 Euro; p = 0.029). Conclusion This study demonstrated no significant difference in in-hospital mortality between AT-III and rhs-TM. However, use of rhs-TM was significantly associated with decreased LOS and medical costs during hospitalization in patients with DIC associated with infectious diseases.

Heatstroke is a life-threatening illness and causes high mortality due to multiple organ injuries. Thrombomodulin (TM) is an endothelial anticoagulant cofactor that plays an important role in the regulation of intravascular coagulation. In this study, we investigated the effect of TM on the inflammatory process, liver function, coagulation status, and mortality in experimental heatstroke.Male C3H/HeN (8-10 weeks) mice were randomly assigned to the TM-treated group (TG-Pre) or nontreated heatstroke group (HS). In group TG-Pre, mice were treated with recombinant soluble TM (1 mg/kg, intraperitoneally) before heat exposure. In some experiments, recombinant soluble TM was administrated during heat exposure (TG-Delay). Heatstroke was induced by exposure to ambient temperature of 38°C for 4 hours. After heat exposure, the levels of tumor necrosis factor-α, interleukin-6, and plasma high-mobility group box 1 (HMGB1), liver function, plasma aspartate aminotransferase and alanine aminotransferase concentrations, and immunohistochemical and histopathological characteristics of the livers were determined. The coagulation status, plasma protein C levels, and thrombin-antithrombin complex levels were also measured.In group HS, plasma cytokines and HMGB1 concentrations increased after heat exposure. Plasma aspartate aminotransferase and alanine aminotransferase concentrations increased after heat exposure. In group HS livers, strong and extensive immunostaining for HMGB1 was observed. In addition, there was extensive hepatocellular necrosis and collapse of nuclei observed. In group HS, plasma protein C levels were suppressed and plasma thrombin-antithrombin complex levels increased. In group TG-Pre, plasma cytokines and HMGB1 concentrations were suppressed after heat exposure compared with group HS. Liver injury, coagulopathy, and mortality also improved in group TG-Pre. Furthermore, recombinant soluble TM treatment decreased mortality even with delayed treatment.This study demonstrated that recombinant soluble TM suppressed plasma cytokines and HMGB1 concentrations after heat exposure. Recombinant soluble TM also improved liver injury and coagulopathy. Recombinant soluble TM treatment improved mortality even with delayed treatment. Recombinant soluble TM may be a beneficial treatment for heatstroke patients.

Acute abdominal pain is one of the most frequent causes of admission to emergency departments. However, there is a shortage of detail information showing the difference of outcomes or etiology of acute abdominal pain according to age. We therefore conducted an epidemiological analysis to reveal the difference between age on outcomes and etiology of acute abdominal pain using an administrative database associated with the Diagnosis Procedure Combination (DPC) system. We obtained discharge data relating to 12,209 patients with acute abdominal pain from 931 DPC participation hospitals between 2009 and 2011 in Japan. We compared length of hospital stay (LOS), in-hospital mortality, and etiology of acute abdominal pain between age categories. Patients were divided into five age groups as follows: < 20 (n = 1,106), 20-39 (n = 3,353), 40-59 (n = 2,925), 60-79 (n = 3,144), and ≥ 80 years (n = 1,681). Longer LOS and higher in-hospital mortality were observed in patients aged ≥ 80 years (p < 0.001). Regarding etiologies of acute abdominal pain, intestinal infection or acute appendicitis were more frequent in patients aged < 20 or 20-39 years, while ileus or cholelithiasis were more frequent in patients aged 60-79 or ≥ 80 years in both male and female patients (p < 0.001). This study demonstrated the significant differences between age with regard to the patient outcomes and etiology of acute abdominal pain. The current findings highlight the importance of improving the quality of medical care for patients with acute abdominal pain.

A principal pathway of 2-methoxyethanol (ME) metabolism is to the toxic oxidative product, methoxyacetaldehyde (MALD). To assess the role of aldehyde dehydrogenase (ALDH) in MALD metabolism, in vitro MALD oxidation was examined with liver subcellular fractions from Japanese subjects who carried three different ALDH2 genotypes and Aldh2 knockout mice, which were generated in this study. The activity was distributed in mitochondrial fractions of ALDH2*1/*1 and wild type (Aldh2+/+) mice but not ALDH2*1/*2, *2/*2 subjects or Aldh2 homozygous mutant (Aldh2−/−) mice. These data suggest that ALDH2 is a key enzyme for MALD oxidation and ME susceptibility may be influenced by the ALDH2 genotype.

Background: Although tissue factor (TF) is involved in hemostasis, thrombogenesis, inflammation, and cellular immune response, its source in sepsis remains controversial. Recently, we found that, in addition to monocytes and endothelial cells, neutrophils may express TF in a rabbit model. The purpose of this study was to determine whether neutrophils could be a source of TF in a monkey model of sepsis. Methods: TF messenger RNA (mRNA) and protein in neutrophils were assayed by in situ hybridization and immunohistochemistry in tissues obtained from monkeys after injection of lipopolysaccharide (LPS) (n = 3) and after injection of saline as a control (n = 2). Coagulation parameters were measured before and at 1.5 and 3 hours after injections. Results: In LPS-treated monkeys, TF mRNA and protein were induced not only in monocytes and endothelial cells, but also in neutrophils accumulating in the liver 3 hours after LPS injection. Thrombin-antithrombin III complex and fibrin degradation products D-dimer levels were significantly increased at 3 and 1.5 hours after LPS injection compared with controls. Conclusions: Neutrophils are a source of TF and are implicated in direct activation of the coagulation cascade in the early phases of sepsis in the monkey. These results give important information for the treatment of sepsis. (Surgery 2000;127:209-16.)

Serum protein induced in vitamin K absence-II (PIVKA-II) is used as a tumor marker because it increases at a notably higher rate in patients with hepatocellular carcinoma. To clarify the mechanism causing the elevation of serum PIVKA-II, we measured the contents of vitamins K1 (phylloquinone, PK) and K2 (menaquinone, MK) (MK-4, MK-5, MK-6, MK-7, MK-8, MK-9, MK-10) in liver tissue resected from 21 hepatic cancer patients (12 patients with hepatocellular carcinoma and 9 patients with metastatic hepatic cancer), using HPLC combined with coulometric reduction and fluorometric detection. In the cancerous tissue of hepatocellular carcinoma patients, PK, MK-7, MK-8, and MK-10 were significantly lower than that found in the noncancerous tissue. Furthermore, MK-6, MK-7, MK-8, and MK-10 in the cancerous tissue of hepatocellular carcinoma patients were significantly lower than that in the cancerous tissue of metastatic hepatic cancer patients. These data suggested that one of the mechanisms of the elevation of serum PIVKA-II levels in hepatocellular carcinoma patients is a vitamin K deficiency in the local cancerous tissue.

The clinicopathological features and operative results were analyzed in 21 patients undergoing an operation for cancer of the remnant stomach between 1979 and 1997. The twenty-one patients were divided into two groups: Group A; n = 9: who had undergone a gastrectomy for benign gastric disease, Group B; n = 12: who had undergone the same operation for gastric cancer. In Group A, the interval between the first gastrectomy and the second was longer than in Group B. In both groups, a large number of advanced cancers (n = 16, 76.2%) and undifferentiated carcinomas (n = 15, 71.4%) were seen. Five-year-survival rates in Group A and Group B were 23.7%, 19.0%, respectively. The incidence of gastric stump cancer following partial gastrectomy was 80% in the patients on whom Billroth II reconstruction had been performed after gastrectomy. It is suggested that the residual stomach in the Billroth II reconstruction patients is susceptible to cancer development. Consideration of the reconstruction method and a systemic follow-up is needed to improve a prognosis.

A 45-year-old female presented at our hospital with a one-day history of upper abdominal pain. Abdominal computed tomography (CT) revealed that the root of the celiac artery was obstructed and that a large hematoma was present in the retroperitoneum. The patient was diagnosed with retroperitoneal hemorrhage associated with the rupture of an inferior pancreaticoduodenal artery aneurysm, which was caused by increased blood flow in the pancreaticoduodenal arterial arcade. Because the patient's general condition was stable, she was managed conservatively and discharged on achieving remission after a month. Follow-up CT revealed spontaneous resolution of the celiac artery obstruction and aneurysm. The celiac artery obstruction in this case was assumed to be caused by segmental arterial mediolysis.

Objective Disseminated intravascular coagulation (DIC) is often associated with infection and a poor outcome. In this study, useful markers for predicting poor outcomes were examined. Methods The frequency of DIC and organ failure, outcomes and hemostatic markers were prospectively evaluated in 242 patients with infections. Results Seventy-seven patients were diagnosed with DIC, 36 of whom recovered from the condition. The rate of DIC or resolution of DIC was highest in the patients with sepsis and lowest in the patients with respiratory infections. Mortality tended to be high in the patients with respiratory infections. The DIC score, sepsis-related organ failure assessment (SOFA) score, prothrombin time (PT) ratio and thrombin-antithrombin complex level were significantly high in the patients who did not recover from DIC. The age, DIC score, SOFA score, PT ratio and levels of thrombomodulin and plasminogen activator inhibitor (PAI)-I were significantly high in the non-survivors. Factors related to a poor outcome included resolution of DIC, the SOFA score, age and the PT ratio. Factors related to resolution of DIC included the SOFA score and age, while factors related to the SOFA score included the levels of PAI-I, leukocytes, fibrinogen, D-dimer and platelets. Conclusion The outcomes of septic patients primarily depend on the SOFA score and the resolution of DIC, which are related to organ failure.

Little information is available on the factors influencing length of stay (LOS) in hospital and medical costs during hospitalization associated with cholecystectomy for acute cholecystitis. We determined the independent factors affecting LOS and medical costs of patients who underwent cholecystectomy for acute cholecystitis based on data from the Diagnosis Procedure Combination (DPC) database. In 2008, a total of 2176 patients with acute cholecystitis were referred for cholecystectomy to 624 hospitals in Japan. We collected patient characteristics and data on treatments for acute cholecystitis using the DPC database and identified independent factors affecting LOS and medical costs during hospitalization using multiple linear regression models. Analysis revealed that early cholecystectomy was significantly associated with a decrease in LOS, whereas longer preoperative antimicrobial therapy was significantly associated with an increase of LOS: the standardized coefficient for early cholecystectomy was -0.372 and that for preoperative antimicrobial therapy was 0.353 (P < 0.001). These procedures were also significant independent factors with regard to medical costs during hospitalization: the standardized coefficient for early cholecystectomy was -0.391 and that for preoperative antimicrobial therapy was 0.335 (P < 0.001). Early cholecystectomy significantly reduces the LOS and medical costs of cholecystectomy for acute cholecystitis, while preoperative antimicrobial therapy increases LOS and medical costs during hospitalization. These results highlight the need for health care implementations such as promotion of early cholecystectomy, appropriate use of antimicrobial drugs, and centralization of patients with cholecystectomy for acute cholecystitis in Japan.

Little information is available on the analysis of chronological changes in medical economic outcomes of endoscopic submucosal dissection (ESD) for gastric cancer. This study aimed to investigate the recent time trend of medical economic outcomes of ESD for gastric cancer based on the Japanese administrative database.A total of 32,943 patients treated with ESD for gastric cancer were referred to 907 hospitals from 2009 to 2011 in Japan. We collected patients' data from the administrative database to compare ESD-related complications, risk-adjusted length of stay (LOS), and medical costs during hospitalization. The study periods were categorized into three groups: 2009 (n = 9,727), 2010 (n = 11,052), and 2011 (n = 12,164).No significant difference was observed in ESD-related complications between three study periods (p = 0.496). However, mean LOS and medical costs during hospitalization of patients with ESD were significantly lower in 2011 than in 2009 and 2010 (p0.001). Multiple linear regression analysis showed that patients who received ESD in 2011 had a significantly shorter LOS and lower medical costs during hospitalization compared with those in 2009. The unstandardized coefficient of patients with ESD in 2011 for LOS was -0.78 days [95 % confidence interval (CI), -0.89 to -0.65; p ≤ 0.001], while that of those for medical costs during hospitalization was -290.5 US dollars (95 % CI, -392.3 to -188.8; p ≤ 0.001).This study showed that the complication rate of ESD was stable, whereas the LOS and medical costs of patients were significantly reduced from 2009 to 2011.

Since the publication of the Tokyo Guidelines for the management of acute cholangitis and cholecystitis (TG07), diagnostic criteria and severity assessment criteria for acute cholangitis have been presented and extensively used as the primary standard all over the world. However, it has been found that there are crucial limitations in these criteria. The diagnostic criteria of TG07 do not have enough sensitivity and specificity, and its severity assessment criteria are unsuitable for clinical use. A working team for the revision of TG07 was organized in June, 2010, and these criteria have been updated through clinical implementation and its assessment by means of multi-center analysis. The diagnostic criteria of acute cholangitis have been revised as criteria to establish the diagnosis where cholestasis and inflammation demonstrated by clinical signs or blood test in addition to biliary manifestations demonstrated by imaging are present. The diagnostic criteria of the updated Tokyo Guidelines (TG13) have high sensitivity (87.6 %) and high specificity (77.7 %). TG13 has better diagnostic capacity than TG07. Severity assessment is classified as follows: Grade III: associated with organ failure; Grade II: early biliary drainage should be conducted; Grade1: others. As for the severity assessment criteria of TG07, separating Grade II and Grade I at the time of diagnosis was impossible, so they were unsuitable for clinical practice. Therefore, the severity assessment criteria of TG13 have been revised so as not to lose the timing of biliary drainage or treatment for etiology. Based on evidence, five predictive factors for poor prognosis in acute cholangitis––hyperbilirubinemia, high fever, leukocytosis, elderly patient and hypoalbuminemia––have been extracted. Grade II can be diagnosed if two of these five factors are present. Free full-text articles and a mobile application of TG13 are available via http://www.jshbps.jp/en/guideline/tg13.html .

In 2007, the Tokyo Guidelines for the management of acute cholangitis and cholecystitis (TG07) were first published in the Journal of Hepato-Biliary-Pancreatic Surgery. The fundamental policy of TG07 was to achieve the objectives of TG07 through the development of consensus among specialists in this field throughout the world. Considering such a situation, validation and feedback from the clinicians' viewpoints were indispensable. What had been pointed out from clinical practice was the low diagnostic sensitivity of TG07 for acute cholangitis and the presence of divergence between severity assessment and clinical judgment for acute cholangitis. In June 2010, we set up the Tokyo Guidelines Revision Committee for the revision of TG07 (TGRC) and started the validation of TG07. We also set up new diagnostic criteria and severity assessment criteria by retrospectively analyzing cases of acute cholangitis and cholecystitis, including cases of non-inflammatory biliary disease, collected from multiple institutions. TGRC held meetings a total of 35 times as well as international email exchanges with co-authors abroad. On June 9 and September 6, 2011, and on April 11, 2012, we held three International Meetings for the Clinical Assessment and Revision of Tokyo Guidelines. Through these meetings, the final draft of the updated Tokyo Guidelines (TG13) was prepared on the basis of the evidence from retrospective multi-center analyses. To be specific, discussion took place involving the revised new diagnostic criteria, and the new severity assessment criteria, new flowcharts of the management of acute cholangitis and cholecystitis, recommended medical care for which new evidence had been added, new recommendations for gallbladder drainage and antimicrobial therapy, and the role of surgical intervention. Management bundles for acute cholangitis and cholecystitis were introduced for effective dissemination with the level of evidence and the grade of recommendations. GRADE systems were utilized to provide the level of evidence and the grade of recommendations. TG13 improved the diagnostic sensitivity for acute cholangitis and cholecystitis, and presented criteria with extremely low false positive rates adapted for clinical practice. Furthermore, severity assessment criteria adapted for clinical use, flowcharts, and many new diagnostic and therapeutic modalities were presented. The bundles for the management of acute cholangitis and cholecystitis are presented in a separate section in TG13. Free full-text articles and a mobile application of TG13 are available via http://www.jshbps.jp/en/guideline/tg13.html.

We propose a management strategy for acute cholangitis and cholecystitis according to the severity assessment. For Grade I (mild) acute cholangitis, initial medical treatment including the use of antimicrobial agents may be sufficient for most cases. For non-responders to initial medical treatment, biliary drainage should be considered. For Grade II (moderate) acute cholangitis, early biliary drainage should be performed along with the administration of antibiotics. For Grade III (severe) acute cholangitis, appropriate organ support is required. After hemodynamic stabilization has been achieved, urgent endoscopic or percutaneous transhepatic biliary drainage should be performed. In patients with Grade II (moderate) and Grade III (severe) acute cholangitis, treatment for the underlying etiology including endoscopic, percutaneous, or surgical treatment should be performed after the patient's general condition has been improved. In patients with Grade I (mild) acute cholangitis, treatment for etiology such as endoscopic sphincterotomy for choledocholithiasis might be performed simultaneously, if possible, with biliary drainage. Early laparoscopic cholecystectomy is the first-line treatment in patients with Grade I (mild) acute cholecystitis while in patients with Grade II (moderate) acute cholecystitis, delayed/elective laparoscopic cholecystectomy after initial medical treatment with antimicrobial agent is the first-line treatment. In non-responders to initial medical treatment, gallbladder drainage should be considered. In patients with Grade III (severe) acute cholecystitis, appropriate organ support in addition to initial medical treatment is necessary. Urgent or early gallbladder drainage is recommended. Elective cholecystectomy can be performed after the improvement of the acute inflammatory process. Free full-text articles and a mobile application of TG13 are available via http://www.jshbps.jp/en/guideline/tg13.html.

重症敗血症では, エンドトキシンが様々なメディエータを介してその病態を形成している. 今回, 我々は重症敗血症に対して手術とエンドトキシン除去治療が有効であった2症例を経験したので報告する. 症例1は62歳の女性. 直腸穿孔による敗血症性ショックと3臓器障害を合併していた. 症例2は60歳の女性. 急性胆嚢炎, 急性閉塞性化膿性胆管炎による敗血症性ショックと6臓器障害を合併していた. これらの症例に対して術後2回にわたりエンドトキシン除去治療を行ったところ臓器障害の改善を認めた. また血中インターロイキン-6,-8値は低下し, 白血球数の正常化を認めた. 重症敗血症に対してエンドトキシン除去治療を行う時期および吸着治療の回数の決定には, 血中インターロイキン-6,-8値と末梢血中白血球数の変化が参考になると考えられた.