Search

Abstract Aim The anti‐tumor effects of natural killer (NK) cells vary among individuals. Tumor necrosis factor‐related apoptosis‐inducing ligand (TRAIL) expressed on liver NK cells is a marker of anti‐tumor cytotoxicity against hepatocellular carcinoma (HCC) in immune cell therapy. This study aimed to develop a liver immune status index (LISI) that predicts low TRAIL expression and validates its ability to predict recurrence after initial hepatectomy for primary HCC. Methods A functional analysis of liver NK cells co‐cultured with interleukin‐2 for 3 days was performed of 40 liver transplant donors. The LISI, which predicted low TRAIL expression (25% quartile:

Abstract Background Non-invasive, prompt, and proper detection tools for kidney graft injuries (KGIs) are awaited to ensure graft longevity. We screened diagnostic biomarkers for KGIs following kidney transplantation using extracellular vesicles (EVs; exosomes and microvesicles) from the urine samples of patients. Methods One hundred and twenty-seven kidney recipients at 11 Japanese institutions were enrolled in this study; urine samples were obtained prior to protocol/episode biopsies. EVs were isolated from urine samples, and EV RNA markers were assayed using quantitative reverse transcription polymerase chain reaction. Diagnostic performance of EV RNA markers and diagnostic formulas comprising these markers were evaluated by comparison with the corresponding pathological diagnoses. Results EV CXCL9, CXCL10, and UMOD were elevated in T-cell-mediated rejection samples compared with other KGI samples, while SPNS2 was elevated in chronic antibody-mediated rejection (cABMR) samples. A diagnostic formula developed through Sparse Logistic Regression analysis using EV RNA markers allowed us to accurately (with an area under the receiver operator characteristic curve [AUC] of 0.875) distinguish cABMR from other KGI samples. EV B4GALT1 and SPNS2 were also elevated in cABMR, and a diagnostic formula using these markers was able to distinguish between cABMR and chronic calcineurin toxicity accurately (AUC 0.886). In interstitial fibrosis and tubular atrophy (IFTA) urine samples and those with high Banff chronicity score sums (BChS), POTEM levels may reflect disease severity, and diagnostic formulas using POTEM detected IFTA (AUC 0.830) and high BChS (AUC 0.850). Conclusions KGIs could be diagnosed with urinary EV mRNA analysis with relatively high accuracy.

Abstract Purpose The rate of postoperative morbidity, including infectious complications, is still high after major hepatobiliary pancreatic (HBP) surgery. Although surgery-related disseminated intravascular coagulation (DIC) occurs in some cases, its significance has not been elucidated in HBP surgery. This study aimed to evaluate the influence of surgery-related DIC on the complication severity after HBP surgery. Methods We analyzed the records of 100 patients with hepatectomy in two or more segments, hepatectomy with biliary tract reconstruction, and pancreaticoduodenectomy. The baseline characteristics and complications were compared between patients with and without surgery-related DIC on postoperative day 1 (POD1) after HBP surgery between 2010 and 2018. Complication severity was assessed using the Comprehensive Complication Index (CCI). Results The DIC group (surgery-related DIC on POD1) had predictive factors, such as larger bleeding volume and higher liver enzyme levels. The DIC group exhibited significantly elevated rates of surgical site infection, sepsis, prolonged intensive care unit stay, more frequent blood transfusions, and higher CCI. Furthermore, compared with and without adjustment of DIC, odds ratio (OR) of AST level and operation time for the risk of high CCI decreased (OR of AST level: 1.25 to 1.19 and OR of operation time: 1.30 to 1.23) and the significant differences had vanished. Conclusions Surgery-related DIC on POD1 could be a partial mediator between AST level, operation time and higher CCI. The prevention or proper management of surgery-related DIC on POD1 can be an important target to reduce the severity of postoperative complications.

Introduction The feasibility and efficacy of surgical resection following systemic therapy for intermediate-stage hepatocellular carcinoma (HCC) beyond the Up-to-7 criteria is unclear. The combination of lenvatinib (LEN) and transcatheter arterial chemoembolisation (TACE), termed LEN–TACE sequential therapy, has shown a high response rate and survival benefit in patients with intermediate-stage HCC. This trial aims to evaluate the efficacy and safety of LEN–TACE sequential therapy and the feasibility of surgical resection for intermediate-stage HCC beyond the Up-to-7 criteria.Methods and analysis This is a multicentre, single-arm, prospective clinical trial. Thirty patients with intermediate-stage HCC beyond the Up-to-7 criteria will be enrolled. Patients eligible for this study will undergo LEN–TACE sequential therapy in which LEN is administered for 4 weeks, followed by TACE, and then further LEN for another 4 weeks. Patients will be assessed for efficacy of LEN–TACE sequential therapy and resectability, and surgical resection will be performed if the HCC is considered radically resectable. The primary outcome of this study is the resection rate after LEN–TACE sequential therapy. The secondary outcomes are the objective response rate of LEN–TACE sequential therapy, safety, curative resection rate, overall survival and recurrence-free survival.Ethics and dissemination This trial was approved by the Institutional Review Board of Hiroshima University, Japan (approval no. CRB210003), and has been registered with the Japan Registry of Clinical Trials (jRCTs061220007). The results of this study will be submitted for publication in a peer-reviewed journal and shared with the scientific community at international conferences.Trial registration number jRCTs061220007 (https://jrct.niph.go.jp/latest-detail/jRCTs061220007).

Abstract Background and Objectives Hepatocellular carcinoma (HCC) has a high recurrence rate even after radical hepatectomy. More optimal biomarkers may help improve recurrence and prognosis. Methods We investigated whether the oncological properties of N‐glycolylneuraminic acid (NeuGc) can participate in the prognosis of HCC. We evaluated the NeuGc antigen (Ag) expression in the HCC tissues and measured the preoperative anti‐NeuGc IgG antibodies (Abs) in the sera of the patients with HCC. We compared the clinical characteristics and survival rate in the hepatectomized patients (initial; n = 66, recurrent; n = 34) with and without the NeuGc Ag or Abs. Results Multivariate analyses showed positive expression of NeuGc Ag in HCC tissues (Odds ratio; initial = 6.3, recurrent = 14.0) and higher titers of preoperative anti‐NeuGc Ab (Odds ratio; initial = 4.9; recurrent = 3.8), which could be the predictive factors related to early recurrence. Both the NeuGc Ag‐positive and Ab‐positive groups in the initial hepatectomized patients exhibited significantly shorter recurrent free survival compared to those in the negative groups. Conclusions Our findings suggested that anti‐NeuGc Ab titers and NeuGc Ag expression in the HCC tissues can be used as the predictive factors for the postoperative recurrence and prognosis of HCC.

Central-variant posterior reversible encephalopathy syndrome is an atypical subtype of posterior reversible encephalopathy syndrome that occurs during rapid fluctuations in blood pressure, leading to cerebrovascular autoregulatory failure and endothelial dysfunction. Few reports have described posterior reversible encephalopathy syndrome in infants. A 4-month-old girl, who was diagnosed a month before with hypoxic ischemic encephalopathy due to sudden cardiac arrest, showed persistent renovascular hypertension with a systolic blood pressure of 200 mmHg. Computed tomography of the head revealed a new-onset low-attenuation area in the bilateral basal ganglia, and computed tomography of the trunk revealed severe long-segment narrowing of the abdominal aorta encompassing the bilateral renal arteries. She was treated with antihypertensive drugs and peritoneal dialysis. Follow-up imaging after blood pressure stabilization showed resolution of the low-attenuation area in the bilateral basal ganglia. We diagnosed her basal ganglia lesions as central-variant posterior reversible encephalopathy syndrome. She suffered from neurological sequelae attributable to hypoxic ischemic encephalopathy but showed no evidence of basal ganglia dysfunction. Here, we report a case of infantile central-variant posterior reversible encephalopathy syndrome involving bilateral basal ganglia lesions with mid-aortic syndrome. The differential diagnosis of infantile symmetric bilateral basal ganglia lesions is broad and includes genetic, acquired metabolic or toxic, infectious, inflammatory, vascular, and neoplastic pathologies. Among them, central-variant posterior reversible encephalopathy syndrome is rare but important because neurological prognosis may be favorable, and specific treatment, such as administration of antihypertensive drugs or discontinuation of drugs that induce posterior reversible encephalopathy syndrome, is possible.

Abstract Background Rapidly progressive (RP) interstitial lung disease (ILD) is a life-threatening complication of juvenile dermatomyositis (JDM); however, it is generally refractory to treatment; to the best of our knowledge, no evidence-based treatment has been established for RP-ILD yet. We present the case of a 2-year-old girl with RP-ILD who showed resistance to treatment with methylprednisolone, cyclosporine A, cyclophosphamide, immunoglobulin, and plasma exchange (PE) and was finally treated with extracorporeal membrane oxygenation. We further present a literature review of 18 cases of JDM with RP-ILD. Case presentation A 2-year-old girl presented with malar rash, mild muscle weakness, and weight loss for a few months before admission. She had a history of dry cough and dyspnea for a few days, followed by rapid respiratory failure. The patient was diagnosed with JDM with RP-ILD through physical examination (malar rashes and Gottron’s sign) and based on the finding of myositis on femoral magnetic resonance imaging, elevated levels of serum muscle enzymes, positive anti-melanoma differentiation-association gene 5 (MDA5) antibody (> 7,500 index), elevated level of Krebs von den Lungen-6 glycoprotein (KL-6; 3,420 U/mL), and extensive ground-glass opacities with consolidation in the bilateral lungs on chest high-resolution computed tomography. She received combination therapy, including methylprednisolone pulse therapy, followed by oral prednisolone and intravenous cyclosporine A, cyclophosphamide, and immunoglobulin. On day 11 of hospitalization, she was placed on ventilation support and PE was initiated. However, her respiratory condition continued to deteriorate and veno-venous extracorporeal membrane oxygenation was started on day 24 of hospitalization. Rituximab was administered on day 28. After 2 weeks of rituximab therapy initiation, her respiratory condition showed gradual improvements. Eventually, on day 52 of hospitalization, the patient could be weaned off extracorporeal membrane oxygenation. Finally, she was discharged with minimal ventilation support and no neurological complications 11 months after admission. Conclusions Our literature review suggest that JDM with RP-ILD has a high mortality rate. In JDM, rituximab may be a promising treatment option for RP-ILD. In the future, the efficacy of rituximab in the early phases of ILD should be investigated.

Abstract Background Bloodstream infections (BSIs) are among the most lethal complications of liver transplantation (LT). Natural killer (NK) cells are an important component of innate immunity and play an essential role in infection and cancer. Adoptive transfer of activated NK cells has the potential to decrease post-LT infections, including BSIs. Methods In this prospective, single-center, interventional, single-arm, historical control, phase I/II study, 37 LT recipients will enroll. The patient will receive a single infusion of donor liver-derived NK cells 3−5 days after LT. Discussion The primary endpoint is the incidence of BSIs during the first month after LT. Secondary endpoints include overall survival, adverse events, immunological responses, hepatocellular or de novo malignancy, and incidence of infectious disease. Trial registration This study was prospectively registered with UMIN000019183 ( https://center6.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000022074 ) on November 1, 2015 and jRCTa060190036 on February 27, 2020.

Background. Second warm ischemic injury during vascular anastomosis not only adversely affects immediate posttransplant function but also affects long-term patient and graft survival. We developed a pouch-type thermal barrier bag (TBB) composed of a transparent, biocompatible insulation material suitably designed for kidneys and conducted the first-in-human clinical trial. Methods. A living-donor nephrectomy was performed using a minimum skin incision procedure. After back table preparation, the kidney graft was placed inside the TBB and preserved during vascular anastomosis. The graft surface temperature was measured before and after vascular anastomosis using a noncontact infrared thermometer. After completion of the anastomosis, the TBB was removed from the transplanted kidney before graft reperfusion. Clinical data, including patient characteristics and perioperative variables, were collected. The primary endpoint was safety, which was assessed by evaluating adverse events. The secondary endpoints were the feasibility, tolerability, and efficacy of the TBB in kidney transplant recipients. Results. Ten living-donor kidney transplant recipients with a median age of 56 y (range, 39–69 y) were enrolled in this study. No serious adverse events related to the TBB were observed. The median second warm ischemic time was 31 (27–39) min, and the median graft surface temperature at the end of anastomosis was 16.1 °C (12.8–18.7 °C). Conclusions. TBB can maintain transplanted kidneys at a low temperature during vascular anastomosis, which contributes to the functional preservation of transplanted kidneys and stable transplant outcomes.

Abstract Aim The clinical impact of abdominal aortic calcification (AAC) in patients who undergo hepatectomy for hepatocellular carcinoma (HCC) is unknown. Methods To evaluate the impact of AAC on clinical outcomes, we analyzed 203 patients who underwent hepatectomy for HCC between 2010 and 2013. Results Kaplan–Meier survival curve analysis showed significantly worse overall survival (OS) in the high AAC group than in the low AAC group. The recurrence‐free survival (RFS) was also significantly worse in the high AAC group. In the multivariate analysis, high AAC (hazard ratio [HR], 2.51; 95% confidence interval [CI], 1.24–5.09; P = .01) was an independent risk factor for poor OS after hepatectomy for HCC. High AAC was also an independent risk factor for poor RFS (HR, 1.69; 95% CI, 1.04–2.76; P = .04). Conclusions Abdominal aortic calcification had a strong relationship with poor OS and RFS after hepatectomy for HCC. We suggest that AAC had a relationship with smoking and diabetes; therefore, AAC could reflect a surrogate for older age, worse health status, and inflammatory score.

Introduction Hepatocellular carcinoma (HCC) remains a major clinical problem as more than half of these cases recur after radical resection. Natural killer (NK) cells are at the forefront of the innate immune system and attack microcarcinomas and circulating tumour cells. The objective of this study was to evaluate the feasibility and toxicity of peripheral blood CD34+ stem cell-derived NK cell infusion after radical hepatectomy for HCC.Methods and analysis This is an open-label, single-arm, single-centre phase I study. Patients who have undergone initial hepatectomy for HCC with three or more risk factors for recurrence (≥10 ng/mL of Alpha fetoprotein (AFP), ≥360 mAU/mL of PIVKA-II, multiple tumours and ≥3 peripheral blood circulating tumour cells) will be enrolled and be treated with three peripheral blood CD34+ stem cell-derived NK cell infusions every 3 months. The primary endpoint will be safety assessment including the type and severity of adverse events, frequency of occurrence and duration of occurrence. The secondary endpoints will include survival, effect of immune response and clinical laboratory test results.Ethics and dissemination Ethical approval of the trial was obtained from the Certified Committee for Regenerative Medicine Hiroshima University in Japan. The trial results will be shared with the scientific community at international conferences and by publication in a peer-reviewed journal.Trial registration number jRCTb060200020.

Abstract Background Liver cysts are common, with most cases being asymptomatic. In symptomatic cases, the disease is amenable to treatment. However, huge or multiple liver cysts with vascular narrowing and associated systemic symptoms are extremely rare. Furthermore, the performance of a reliable and effective surgery in such cases remains a major problem. Here, we report a case of multiple giant liver cysts with impaired blood flow surgically treated in a hybrid operating room. Case presentation A 73-year-old male presented to a previous doctor with leg edema and dyspnea on exertion; computed tomography revealed that the cause complaint was right lung and heart compression and inferior vena cava (IVC) stenosis due to huge liver cysts in the caudal lobe. The patient was referred to our hospital because of disease recurrence despite percutaneous aspiration of the cyst. Multiple liver cysts were observed in addition to the drained cysts, two of which were located on both sides of the IVC and caused IVC stenosis. We performed open surgery for the liver cysts and used the hybrid operating room for intraoperative IVC angiography and measuring the hepatic vein and portal vein (PV) pressure. We performed unroofing of the hepatic cyst and cauterization of the cyst wall on the hepatic side. Angiography was performed before and after unroofing of the liver cysts, and IVC stenosis release was confirmed. IVC pressure measured at the peripheral side of the stenosis and PV pressures were continuously measured during surgery and were confirmed to have decreased during the opening of the liver cysts. The patient had a good postoperative course and was discharged on the 10th postoperative day. No recurrence was observed 6 months postoperatively. Conclusions Cyst unroofing surgery using angiography in a hybrid operating room is a useful treatment for deep hepatic lesions in that vascular stenosis improvement can be intraoperatively confirmed. Moreover, in cases wherein the cyst compresses the vasculature, intraoperative monitoring of IVC and PV pressures can be used to prove that the liver cyst is hemodynamically involved.

Abstract Pretransplant desensitization with rituximab has been applied to preformed donor-specific anti-human leukocyte antigen antibody (DSA)-positive recipients for elimination of preformed DSA. We investigated the impact of pretransplant desensitization with rituximab on anti-donor T cell responses in DSA-positive transplant recipients. To monitor the patients’ immune status, mixed lymphocyte reaction (MLR) assays were performed before and after desensitization with rituximab. Two weeks after rituximab administration, the stimulation index (SI) of anti-donor CD4+ T cells was significantly higher in the DSA-positive recipients than in the DSA-negative recipients. To investigate the mechanisms of anti-donor hyper responses of CD4+ T cells after B cell depletion, highly sensitized mice models were injected with anti-CD20 mAb to eliminate B cells. Consistent with clinical observations, the SI values of anti-donor CD4+ T cells were significantly increased after anti-CD20 mAb injection in the sensitized mice models. Adding B cells isolated from untreated sensitized mice to MLR significantly inhibited the enhancement of anti-donor CD4+ T cell response. The depletion of the CD5+ B cell subset, which exclusively included IL-10-positive cells, from the additive B cells abrogated such inhibitory effects. These findings demonstrate that IL-10+ CD5+ B cells suppress the excessive response of anti-donor CD4+ T cells responses in sensitized recipients.

Abstract The Japanese Clinical Practice Guidelines for Management of Sepsis and Septic Shock 2020 (J-SSCG 2020), a Japanese-specific set of clinical practice guidelines for sepsis and septic shock created as revised from J-SSCG 2016 jointly by the Japanese Society of Intensive Care Medicine and the Japanese Association for Acute Medicine, was first released in September 2020 and published in February 2021. An English-language version of these guidelines was created based on the contents of the original Japanese-language version. The purpose of this guideline is to assist medical staff in making appropriate decisions to improve the prognosis of patients undergoing treatment for sepsis and septic shock. We aimed to provide high-quality guidelines that are easy to use and understand for specialists, general clinicians, and multidisciplinary medical professionals. J-SSCG 2016 took up new subjects that were not present in SSCG 2016 (e.g., ICU-acquired weakness [ICU-AW], post-intensive care syndrome [PICS], and body temperature management). The J-SSCG 2020 covered a total of 22 areas with four additional new areas (patient- and family-centered care, sepsis treatment system, neuro-intensive treatment, and stress ulcers). A total of 118 important clinical issues (clinical questions, CQs) were extracted regardless of the presence or absence of evidence. These CQs also include those that have been given particular focus within Japan. This is a large-scale guideline covering multiple fields; thus, in addition to the 25 committee members, we had the participation and support of a total of 226 members who are professionals (physicians, nurses, physiotherapists, clinical engineers, and pharmacists) and medical workers with a history of sepsis or critical illness. The GRADE method was adopted for making recommendations, and the modified Delphi method was used to determine recommendations by voting from all committee members. As a result, 79 GRADE-based recommendations, 5 Good Practice Statements (GPS), 18 expert consensuses, 27 answers to background questions (BQs), and summaries of definitions and diagnosis of sepsis were created as responses to 118 CQs. We also incorporated visual information for each CQ according to the time course of treatment, and we will also distribute this as an app. The J-SSCG 2020 is expected to be widely used as a useful bedside guideline in the field of sepsis treatment both in Japan and overseas involving multiple disciplines.

Abstract Hepatic epithelioid hemangioendothelioma is a rare neoplasm with a variable malignant potential and a high risk of recurrence. No general treatment guidelines have been established. Fortunately, we were able to minimize immunosuppressant after liver transplantation because of a full HLA‐matched case. There was no recurrence 1 year after treatment.

In organ transplantation, human leukocyte antigen (HLA)-mismatch grafts not only induce the activation of cellular mediated immune response but also the development of chronic antibody-mediated rejection due to the donor-specific anti-HLA antibody (DSA) produced by B cells and plasma cells interacting with the graft endothelium. Significant improvement in long-term survival after transplantation can be expected if antibody-mediated rejection due to the DSA can be overcome. However, the mechanism of producing or controlling the DSA remains to be elucidated. In recent decades, "humanized" mouse models have been widely used for the basic research of human immune systems, but a humanized mouse model to analyze the mechanism of DSA production has not been established yet. Thus, we aimed to create a humanized mouse using a severe immunodeficiency mouse (NSG mouse) administered with human peripheral blood mononuclear cells (PBMCs). Initially, we detected a very low level of human total-IgG and no anti-HLA antibodies (Abs) in these mice. In our next attempt, we mixed PBMCs of various HLA antigenic combinations with or without regulatory T cells and preconditioned them by culturing on feeder cells stably transfected with human CD40 ligand (h-CD40L) alone or with h-CD40L and human B cell activating factor (h-BAFF). They were subsequently co-cultured with the corresponding irradiated stimulator PBMCs, and all cells were administered into naïve NSG mice. Although all three humanized models had sufficient human total-IgG and anti-HLA antibody production, allospecific anti-HLA Ab production was prominently suppressed whereas non-specific anti-HLA Abs were sufficiently detected. Therefore, this novel humanized mouse model might be useful for analyzing the mechanism of anti-allogeneic human B cell tolerance induction.

The liver exhibits intrinsic immune regulatory properties that maintain tolerance to endogenous and exogenous antigens, and provide protection against pathogens. Such an immune privilege contributes to susceptibility to spontaneous acceptance despite major histocompatibility complex mismatch when transplanted in animal models. Furthermore, the presence of a liver allograft can suppress the rejection of other solid tissue/organ grafts from the same donor. Despite this immune privilege of the livers, to control the undesired alloimmune responses in humans, most liver transplant recipients require long-term treatment with immune-suppressive drugs that predispose to cardiometabolic side effects and renal insufficiency. Understanding the mechanism of liver transplant tolerance and crosstalk between a variety of hepatic immune cells, such as dendritic cells, Kupffer cells, liver sinusoidas endothelial cells, hepatic stellate cells and so on, and alloreactive T cells would lead to the development of strategies for deliberate induction of more specific immune tolerance in a clinical setting. In this review article, we focus on results derived from basic studies that have attempted to elucidate the immune modulatory mechanisms of liver constituent cells and clinical trials that induced immune tolerance after liver transplantation by utilizing the immune-privilege potential of the liver.

Abstract Background Portopulmonary hypertension (PPH) is a relatively rare but well-recognized complication of end-stage liver disease. Moderate or severe PPH (mean pulmonary artery pressure [mPAP] ≥ 35 mmHg) is usually a contraindication for liver transplantation due to high operation-related mortality. Here, we report on a patient with moderate PPH whose condition was successfully managed with a phosphodiesterase type 5 (PDE5) inhibitor (tadalafil) and prostaglandin E1, who experienced rapid improvement of PPH after living-donor liver transplantation (LDLT). Case presentation A 63-year-old woman with alcoholic decompensated cirrhosis was referred to our hospital for LDLT. She had mild dyspnea on exertion as well as fatigue. Echocardiography and subsequent cardiac catheterization revealed a high mPAP (35 mmHg), and she was diagnosed with moderate PPH. We commenced treatment with oral tadalafil for the PPH. A second preoperative echocardiography demonstrated improved PPH, and she underwent LDLT. An intravenous infusion of prostaglandin E1 was introduced instead of tadalafil during and after the operation. The mPAP value showed a rapid decrease in mPAP value to 22 mmHg in 2 days. After discontinuation of the prostaglandin E1, the mPAP value remained 23 mmHg. Postoperative catheterization 2 months after LDLT showed no exacerbation of PPH. She was discharged on foot 70 days after LDLT in good condition and has shown a good clinical condition more than 2 years after LDLT. Conclusion LDLT could be a radical treatment for PPH with careful management and adequate patient selection. PDE5 inhibitor and PGE1 is effective and feasible for perioperative management of the patient with moderate portopulmonary hypertension in LDLT.

Abstract Background and purpose The Japanese Clinical Practice Guidelines for Management of Sepsis and Septic Shock 2016 (J-SSCG 2016), a Japanese-specific set of clinical practice guidelines for sepsis and septic shock created jointly by the Japanese Society of Intensive Care Medicine and the Japanese Association for Acute Medicine, was first released in February 2017 and published in the Journal of JSICM, [2017; Volume 24 (supplement 2)] https://doi.org/10.3918/jsicm.24S0001 and Journal of Japanese Association for Acute Medicine [2017; Volume 28, (supplement 1)] http://onlinelibrary.wiley.com/doi/10.1002/jja2.2017.28.issue-S1/issuetoc. This abridged English edition of the J-SSCG 2016 was produced with permission from the Japanese Association of Acute Medicine and the Japanese Society for Intensive Care Medicine. Methods Members of the Japanese Society of Intensive Care Medicine and the Japanese Association for Acute Medicine were selected and organized into 19 committee members and 52 working group members. The guidelines were prepared in accordance with the Medical Information Network Distribution Service (Minds) creation procedures. The Academic Guidelines Promotion Team was organized to oversee and provide academic support to the respective activities allocated to each Guideline Creation Team. To improve quality assurance and workflow transparency, a mutual peer review system was established, and discussions within each team were open to the public. Public comments were collected once after the initial formulation of a clinical question (CQ) and twice during the review of the final draft. Recommendations were determined to have been adopted after obtaining support from a two-thirds (> 66.6%) majority vote of each of the 19 committee members. Results A total of 87 CQs were selected among 19 clinical areas, including pediatric topics and several other important areas not covered in the first edition of the Japanese guidelines (J-SSCG 2012). The approval rate obtained through committee voting, in addition to ratings of the strengths of the recommendation, and its supporting evidence were also added to each recommendation statement. We conducted meta-analyses for 29 CQs. Thirty-seven CQs contained recommendations in the form of an expert consensus due to insufficient evidence. No recommendations were provided for five CQs. Conclusions Based on the evidence gathered, we were able to formulate Japanese-specific clinical practice guidelines that are tailored to the Japanese context in a highly transparent manner. These guidelines can easily be used not only by specialists, but also by non-specialists, general clinicians, nurses, pharmacists, clinical engineers, and other healthcare professionals.

Abstract Background Despite the improvements of surgical techniques and postoperative management of patients with liver transplantation, biliary complications are one of the most common and important adverse events. We present a first case of choledochoduodenostomy using magnetic compression following a massive resection of the small intestine due to strangulated ileus after living donor liver transplantation. Case presentation The 54-year-old female patient had end-stage liver disease, secondary to liver cirrhosis, due to primary sclerosing cholangitis with ulcerative colitis. Five years earlier, she had received living donor liver transplantation using a left lobe graft, with resection of the extrahepatic bile duct and Roux-en-Y anastomosis. The patient experienced sudden onset of intense abdominal pain. An emergency surgery was performed, and the diagnosis was confirmed as strangulated ileus due to twisting of the mesentery. Resection of the massive small intestine, including choledochojejunostomy, was performed. Only 70 cm of the small intestine remained. She was transferred to our hospital with an external drainage tube from the biliary cavity and jejunostomy. We initiated total parenteral nutrition, and percutaneous transhepatic biliary drainage was established to treat the cholangitis. Computed tomography revealed that the biliary duct was close to the duodenum; hence, we planned magnetic compression anastomosis of the biliary duct and the duodenum. The daughter magnet was placed in the biliary drainage tube, and the parent magnet was positioned in the bulbus duodeni using a fiberscope. Anastomosis between the left hepatic duct and the duodenum was accomplished after 25 days, and the biliary drainage stent was placed over the anastomosis to prevent re-stenosis. Contributions to the successful withdrawal of parenteral nutrition were closure of the ileostomy in the adaptive period, preservation of the ileocecal valve, internal drainage of bile, and side-to-side anastomosis. Conclusions Choledochoduodenostomy with magnet compression could be a less invasive and safer method for treatment of biliary stricture that cannot be accessed by conventional surgery.

We encountered a case of a 73-year-old man with acute myeloid leukemia who developed Trichosporon asahii systemic infection while on itraconazole prophylaxis during severe neutropenia. Cryptococcal antigen was useful for diagnosis. Although itraconazole was ineffective in protecting against trichosporonosis, treatment was successful with voriconazole following liposomal amphotericin B. Keywords: Trichosporon asahii, Itraconazole, Liposomal amphotericin B, Voriconazole, Cryptococcal antigen

Patients who test positive for hepatitis C virus (HCV) antibody are not considered suitable living kidney donor candidates for HCV negative recipients. Here, we report a case of an HCV positive patient treated successfully with antiviral therapy, achieving sustained virologic response (SVR), who subsequently donated a kidney to an HCV negative recipient without viral transmission. This suggests that HCV positive patients who achieve SVR may safely donate kidneys. A 66-year-old male with end-stage renal disease had been on hemodialysis for 7 years. His 63-year-old wife was a candidate for living donation, but had a history of HCV infection. She had received interferon-beta treatment 12 years previously. After the treatment, SVR was achieved and her liver enzymes were normalized. The recipient received a preconditioning regimen comprising a single dose of rituximab combined with cyclosporine microemulsion and mycophenolate mofetil 2 weeks before the transplantation for the desensitization of anti-blood type antibody. The operation was performed with no adverse events. Protocol kidney biopsies at 3 and 12 months showed no signs of rejection. The recipient's liver function tests remained within the normal range, HCV antibody testing was negative, and HCV RNA was undetectable at the 1-year follow-up. At the time of this writing, the recipient is healthy with a serum creatinine level of 1.2 mg/dL. Likewise, the donor is healthy with follow up indicating SVR, normal liver enzymes, and normal renal function. In conclusion, only in selected cases, HCV antibody positive donors may be taken into consideration as a kidney donor.

We have previously proven that the interspecies incompatibility of CD47 is responsible for in vitro phagocytosis of xenogeneic cells by host macrophages. Utilizing an in vivo model in the present study, we investigated whether genetically engineered expression of mouse CD47 in rat insulinoma cells (INS-1E) could inhibit macrophage-mediated xenograft rejection. INS-1E cells transfected with the pRc/CMV-mouse CD47 vector (mCD47-INS-1E) induced SIRPα-tyrosine phosphorylation in mouse macrophages in vitro, whereas cells transfected with the control vector (cont-INS-1E) did not. When these cells were injected into the peritoneal cavity of streptozotocin-induced diabetic Rag2(-/-)γ chain (-/-) mice, which lack T, B, and NK cells, the expression of mouse CD47 on the INS-1E cells markedly reduced the susceptibility of these cells to phagocytosis by macrophages. Moreover, these mice became normoglycemic after receiving mCD47-INS-1E, whereas the mice that received cont-INS-1E failed to achieve normoglycemia. Furthermore, injection of an anti-mouse SIRPα blocking monoclonal antibody into the mouse recipients of mCD47-INS-1E cells prevented achievement of normoglycemia. These results demonstrate that interspecies incompatibility of CD47 significantly contributes to in vivo rejection of xenogeneic cells by macrophages. Thus, genetic induction of the expression of recipient CD47 on xenogeneic donor cells could provide inhibitory signals to recipient macrophages via SIPRα; this constitutes a novel approach for preventing macrophage-mediated xenograft rejection.

Signal regulatory protein α (SIRPα) is a critical immune inhibitory receptor on macrophages, and its interaction with CD47 prevents autologous phagocytosis. We have previously shown that pig CD47 does not interact with human SIRPα, and that human CD47 expression inhibits phagocytosis of porcine cells by human macrophages in vitro. In this study, we have investigated the potential of human CD47 expression to promote porcine cell survival in vivo. Human CD47-expressing and control porcine B-lymphoma cells were transplanted into T- and B-cell-deficient nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice that express SIRPα capable of interacting with human CD47. Only the human CD47-expressing porcine lymphoma cells survived and were able to form tumors in NOD/SCID mice; however, both the control and human CD47-expressing porcine cells survived in macrophage-depleted NOD/SCID mice. These results indicate that transgenic expression of human CD47 may provide an effective approach to inhibiting macrophage-mediated xenograft rejection in clinical xenotransplantation.

Patients requiring liver transplantation (LT) frequently experience renal insufficiency (RI), which affects their survival. Although calcineurin inhibitor-sparing immunosuppressive regimens (CSRs) are well known to prevent RI, the immune state in recipients receiving CSR remains to be intensively investigated. Among 60 cases of living-donor LT at our institute, 68% of the patients had none to mild RI (non-RI group) and 32% of the patients had moderate to severe RI (RI group). The RI group received a CSR comprising reduced dose of tacrolimus, methylprednisolone, and mycophenolate mofetil, while the non-RI group received a regimen comprising conventional dose of tacrolimus and methylprednisolone. One year after LT, the mean estimated glomerular filtration rate (eGFR) in the RI group had significantly improved, although it was still lower than that of the non-RI group. Serial mixed lymphocyte reaction assays revealed that antidonor T-cell responses were adequately suppressed in both groups. Thus, we provide evidence that CSR leads to improvement of eGFR after LT in patients with RI, while maintaining an appropriate immunosuppressive state.