Oita University Hospital

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.

Renal anemia is a complication of chronic kidney disease. Guidelines for safe and effective treatment in patients with renal anemia are needed. The Japanese Society for Dialysis Therapy (JSDT) published guidelines for the treatment of renal anemia in chronic hemodialysis patients in 2004 and in hemodialysis, peritoneal dialysis, predialysis, and pediatric patients in 2008. These two publications provide excellent guidance with respect to clinical practice issues, including the definition and diagnosis of renal anemia, the criteria for the initiation of treatment, target hemoglobin levels, iron supplementation therapy, blood transfusion, and side effects. The guidelines significantly improved the treatment of renal anemia in Japan. However, since 2008, many studies have assessed the treatment of renal anemia, and erythropoiesis-stimulating agents (ESAs) are now available. Therefore, the Executive Board of the JSDT decided that it was time to revise the guidelines to make them more appropriate to the situation of chronic kidney disease patients in Japan. This is the third edition of the guidelines for renal anemia published by the JSDT. The purpose is to improve the prognosis of chronic kidney disease patients, including after renal transplantation, through the treatment of renal anemia. The intended users of the guidelines are all healthcare professionals engaged in the treatment of chronic kidney disease. Regarding the treatment of adult dialysis and predialysis patients, statements and commentary are provided in the context of answers to clinical questions in Chapter 2 (Target Hb level and criteria for starting renal anemia treatment) and Chapter 4 (Evaluation of iron status and iron therapy). Furthermore, the essential information is provided alongside the critical issues in Chapter 1 (Diagnosis of renal anemia), Chapter 3 (Administration of ESAs—administration route and dose), Chapter 5 (ESA hyporesponsiveness), Chapter 6 (Side effects and concomitant symptoms of ESAs), and Chapter 7 (Red blood cell transfusion). In addition, the treatment of pediatric patients and post-renal transplant patients is discussed in Chapter 8 and Chapter 9, respectively.

There has been a long-standing need for guidelines on the diagnosis and treatment of keloids and hypertrophic scars that are based on an understanding of the pathomechanisms that underlie these skin fibrotic diseases. This is particularly true for clinicians who deal with Asian and African patients because these ethnicities are highly prone to these diseases. By contrast, Caucasians are less likely to develop keloids and hypertrophic scars, and if they do, the scars tend not to be severe. This ethnic disparity also means that countries vary in terms of their differential diagnostic algorithms. The lack of clear treatment guidelines also means that primary care physicians are currently applying a hotchpotch of treatments, with uneven outcomes. To overcome these issues, the Japan Scar Workshop (JSW) has created a tool that allows clinicians to objectively diagnose and distinguish between keloids, hypertrophic scars, and mature scars. This tool is called the JSW Scar Scale (JSS) and it involves scoring the risk factors of the individual patients and the affected areas. The tool is simple and easy to use. As a result, even physicians who are not accustomed to keloids and hypertrophic scars can easily diagnose them and judge their severity. The JSW has also established a committee that, in cooperation with outside experts in various fields, has prepared a Consensus Document on keloid and hypertrophic scar treatment guidelines. These guidelines are simple and will allow even inexperienced clinicians to choose the most appropriate treatment strategy. The Consensus Document is provided in this article. It describes (1) the diagnostic algorithm for pathological scars and how to differentiate them from clinically similar benign and malignant tumors, (2) the general treatment algorithms for keloids and hypertrophic scars at different medical facilities, (3) the rationale behind each treatment for keloids and hypertrophic scars, and (4) the body site-specific treatment protocols for these scars. We believe that this Consensus Document will be helpful for physicians from all over the world who treat keloids and hypertrophic scars.

BACKGROUND: The epidemiology of human herpesvirus 6 (HHV-6) encephalitis after allogeneic hematopoietic cell transplantation (HCT) and its relationship with HHV-6 reactivation have not been sufficiently characterized. METHODS: This prospective, multicenter study of 230 allogeneic HCT recipients investigated the epidemiology of HHV-6 reactivation and HHV-6 encephalitis. Plasma HHV-6 DNA load was prospectively evaluated twice weekly until 70 days after HCT. RESULTS: Cumulative incidence of positive HHV-6 DNA and high-level HHV-6 reactivation (plasma HHV-6 DNA ≥10(4) copies/mL) at day 70 after HCT was 72.2% and 37.0%, respectively. Multivariate analysis identified myeloablative conditioning (hazard ratio [HR], 1.9; P = .004), umbilical cord blood transplantation (UCBT) (HR, 2.0; P = .003), and male sex (HR, 1.6; P = .04) as risk factors for displaying high-level HHV-6 reactivation. HHV-6 encephalitis occurred in 7 patients, and cumulative incidence at day 70 was 3.0%. None of the144 patients without high-level HHV-6 reactivation and 7 of 86 patients (8.1%) with high-level HHV-6 reactivation developed HHV-6 encephalitis (P = .0009). Prevalence of HHV-6 encephalitis was significantly higher among patients receiving UCBT than in patients with other sources (cumulative incidence at day 70, 7.9% vs 1.2%, P = .008). In each of 7 patients with HHV-6 encephalitis, central nervous system (CNS) symptoms developed concomitant with peak plasma HHV-6 DNA (range, 21 656-433 639 copies/mL). CONCLUSIONS: High levels of plasma HHV-6 DNA are associated with higher risk of HHV-6 encephalitis. UCBT is a significant risk factor for HHV-6 encephalitis. HHV-6 encephalitis should be considered if CNS dysfunction develops concomitant to high-level plasma HHV-6 DNA after allogeneic HCT.

BACKGROUND AND OBJECTIVES: Clinicopathological significance of colorectal mucinous carcinoma (MC) remains controversial. The aim of the current study was to investigate the clinicopathological characteristics of colorectal MC. METHODS: Eighteen patients with MC and 265 with moderately or well differentiated adenocarcinoma of the colon and rectum, were clinicopathologically compared. RESULTS: MCs occurred in the right colon significantly more frequently than did non-mucinous carcinomas (NMCs). The maximal size of the tumors in MCs (7.0 +/- 2.9 cm) was significantly larger than that in NMCs (5.1 +/- 2.1 cm) (P < 0.001). Although the ratio of patients with peritoneal metastasis in MCs (22.2%; 4/18) was significantly higher than that in NMCs (6.0%; 16/265) (P < 0.05), there was no significant difference regarding liver metastasis. The proportion of lymph node metastasis in MCs (72.2%; 13/18) was significantly higher than that in NMCs (44.9%; 119/265) (P < 0.05). There was no significant difference regarding the lymphatic and venous invasion. The 1-, 3-, and 5-year survival rates of patients with MCs were 77. 8%, 45.4%, and 30.3%, respectively, and were significantly lower than those in patients with NMCs, that were 88.9 %, 65.6%, and 60.8%, respectively (P < 0.05). CONCLUSIONS: As colorectal MCs proliferate and metastasize more rapidly than do NMCs, surgeons should realize that more aggressive surgical treatment should be occasionally administered to improve the postoperative prognosis of the patients with colorectal MCs.

This study analyses the evolutionary relatedness of 16 Japanese encephalitis virus (JEV) isolates (nine from Vietnam and seven from Japan) to previously published JEV strains using E gene sequence data. Vietnamese and Japanese strains isolated between 1986 and 1990 were found to cluster in genotype 3. However, more recent Vietnamese and Japanese strains isolated between 1995 and 2002 grouped within genotype 1, now a dominant though previously unreported genotype in Vietnam. In addition, in this study, strains isolated between 1995 and 2002 were more closely related to those isolated in the 1990s than to the older genotype 1 strains. Recently, the introduction of JEV genotype 1 into Japan and Korea has also been reported. Hence this genotype shift phenomenon may be occurring throughout all East Asia. Further studies on JEV ecology are needed to clarify the mechanism of JEV genotype 1 spread to new territories.

The gene encoding F-box protein FBXW7 is frequently mutated in many human cancers. Although most previous studies have focused on the tumor-suppressive capacity of FBXW7 in tumor cells themselves, we determined that FBXW7 in the host microenvironment also suppresses cancer metastasis. Deletion of Fbxw7 in murine BM-derived stromal cells induced accumulation of NOTCH and consequent transcriptional activation of Ccl2. FBXW7-deficient mice exhibited increased serum levels of the chemokine CCL2, which resulted in the recruitment of both monocytic myeloid-derived suppressor cells and macrophages, thereby promoting metastatic tumor growth. Administration of a CCL2 receptor antagonist blocked the enhancement of metastasis in FBXW7-deficient mice. Furthermore, in human breast cancer patients, FBXW7 expression in peripheral blood was associated with serum CCL2 concentration and disease prognosis. Together, these results suggest that FBXW7 antagonizes cancer development in not only a cell-autonomous manner, but also a non-cell-autonomous manner, and that modulation of the FBXW7/NOTCH/CCL2 axis may provide a potential approach to suppression of cancer metastasis.

BACKGROUND: High interdialytic weight gain (IDWG) is associated with adverse outcomes in hemodialysis (HD) patients. We identified temporal and regional trends in IDWG, predictors of IDWG, and associations of IDWG with clinical outcomes. STUDY DESIGN: Analysis 1: sequential cross-sections to identify facility- and patient-level predictors of IDWG and their temporal trends. Analysis 2: prospective cohort study to assess associations between IDWG and mortality and hospitalization risk. SETTING & PARTICIPANTS: 21,919 participants on HD therapy for 1 year or longer in the Dialysis Outcomes and Practice Patterns Study (DOPPS) phases 2 to 5 (2002-2014). PREDICTORS: Analysis 1: study phase, patient demographics and comorbid conditions, HD facility practices. Analysis 2: relative IDWG, expressed as percentage of post-HD weight (<0%, 0%-0.99%, 1%-2.49%, 2.5%-3.99% [reference], 4%-5.69%, and ≥5.7%). OUTCOMES: Analysis 1: relative IDWG as a continuous variable using linear mixed models; analysis 2: mortality; all-cause and cause-specific hospitalization using Cox regression, adjusting for potential confounders. RESULTS: From phase 2 to 5, IDWG declined in the United States (-0.29kg; -0.5% of post-HD weight), Canada (-0.25kg; -0.8%), and Europe (-0.22kg; -0.5%), with more modest declines in Japan and Australia/New Zealand. Among modifiable factors associated with IDWG, the most notable was facility mean dialysate sodium concentration: every 1-mEq/L greater dialysate sodium concentration was associated with 0.13 (95% CI, 0.11-0.16) greater relative IDWG. Compared to relative IDWG of 2.5% to 3.99%, there was elevated risk for mortality with relative IDWG≥5.7% (adjusted HR, 1.23; 95% CI, 1.08-1.40) and elevated risk for fluid-overload hospitalization with relative IDWG≥4% (HRs of 1.28 [95% CI, 1.09-1.49] and 1.64 [95% CI, 1.27-2.13] for relative IDWGs of 4%-5.69% and ≥5.7%, respectively). LIMITATIONS: Possible residual confounding. No dietary salt intake data. CONCLUSIONS: Reductions in IDWG during the past decade were partially explained by reductions in dialysate sodium concentration. Focusing quality improvement strategies on reducing occurrences of high IDWG may improve outcomes in HD patients.

ADAM proteases, defined by extracellular disintegrin and metalloprotease domains, are involved in protein processing and cell-cell interactions. Using wobbler (WR) mutant mice, we investigated the role of ADAMs in neurodegeneration and reactive glia activation in the CNS. We found that ADAM8 (CD 156), a suspected leukocyte adhesion molecule, is expressed in the CNS and highly induced in affected CNS areas of WR mice, in brainstem and spinal cord. ADAM8 mRNA and protein are found at low levels throughout the normal mouse CNS, in neurons and oligodendrocytes. In the WR CNS regions in which neurodegeneration occurs, ADAM8 is induced in neurons, reactive astrocytes, and activated microglia. Similarly, the proinflammatory cytokine tumor necrosis factor alpha (TNF-alpha) is upregulated and shows the same cellular distribution. In primary astrocytes from wild-type and WR mice, in primary cerebellar neurons, and in mouse motoneuron-like NSC19 cells, ADAM8 expression was induced up to 15-fold by mouse TNF-alpha, in a dose-dependent manner. In both cell types, ADAM8 was also induced by human TNF-alpha, indicating that TNF receptor type I (p55) is involved. Induction of ADAM8 mRNA was suppressed by treatment with an interferon-regulating factor 1 (IRF-1) antisense oligonucleotide. We conclude that IRF-1-mediated induction of ADAM8 by TNF-alpha is a signaling pathway relevant for neurodegenerative disorders with glia activation, proposing a role for ADAM8 in cell adhesion during neurodegeneration.

The cellular interactions in the tumor microenvironment of colorectal cancer (CRC) are poorly understood, hindering patient treatment. In the current study, we investigate whether events occurring at the invasion front are of particular importance for CRC treatment strategies. To this end, we analyze CRC tissues by combining spatial transcriptomics from patients with a public single-cell transcriptomic atlas to determine cell-cell interactions at the invasion front. We show that CRC cells are localized specifically at the invasion front. These cells induce human leukocyte antigen G (HLA-G) to produce secreted phosphoprotein 1 (SPP1)+ macrophages while conferring CRC cells with anti-tumor immunity, as well as proliferative and invasive properties. Taken together, these findings highlight the signaling between CRC cell populations and stromal cell populations at the cellular level.

The annual all-cause mortality in chronic dialysis patients in our country is within 10%, indicating that the outcome of dialysis therapy in Japan is one of the best in the world. It is nothing short of extraordinary to maintain favorable survival like this despite challenging conditions such as aging of the patients and increase in the proportion of patients on long-term dialysis and with diabetes mellitus. We can be proud of our achievement. Novel therapeutic strategies for dialysis patients have been developed, such as antihypertensive drugs (e.g. angiotensin II receptor blockers, calcium channel blockers and beta blockers), treatment of anemia (e.g. erythropoiesis stimulating agents), and management of chronic kidney disease-mineral and bone disorder (CKD-MBD) (e.g. activated vitamin D, calcimimetics, and new phosphate binders). While the beneficial effect of these new approaches is well acknowledged, we must not forget that the favorable outcome is also due to the considerable efforts and excellence in management of all the medical staff, including physicians, nurses, and clinical engineers, who are engaged in dialysis therapy in Japan. While mortality due to infectious diseases is increasing at present, about half of dialysis patients die from cardiovascular disease (CVD). Thus, the management of CVD has become the most challenging clinical issue in dialysis patients. With regard to CVD, the main focus has so far been on blood vessel diseases of the heart and brain; however, peripheral artery disease (PAD) is now also attracting attention because the number of patients with atherosclerotic obstruction of the peripheral arteries in the lower extremities has increased in recent years and endovascular catheter therapy has been introduced and developed. The number of specialists in the field of PAD has increased along with the development of new biomedical technology and expansion of their use. Endovascular catheter therapy is currently offered to patients with chronic dialysis and we expected an increase in the number of patients benefiting from this therapy. Evidence suggests that the pathological process of CVD is also involved in the aggravation of systemic atherosclerosis associated with renal dysfunction, prompting the use of potent anti-atherogenic agents, such as statins in dialysis patients similar to the general population. With regard to CVD in dialysis patients, unfortunately, there is little clinical evidence to justify the compilation of clinical guidelines. For example, the appropriate blood pressure level in such patients remains unknown, and the target blood pressure level for management of hypertension has not yet been defined even in the guidelines issued by Western countries. Although we discussed this issue in detail in several committee meetings, we only agreed on setting the target blood pressure though we presented this as an opinion rather than guideline by the committee. There is no doubt that we need to validate in the future whether the level is appropriate or not. In fact, we do not know whether any statement on the clinical guideline is right or not especially when evidence is insufficient, and any statement is nothing but "themes of clinical questions". We need to validate this issue by prospective high-evidence grade studies. The Japanese Society for Dialysis Therapy (JSDT) maintains a patient registry database kept with the standing committee responsible for statistics and investigation. We used the data stored in this database to generate the present guideline. We stress that we should continue to maintain this important registry system in order to revise the clinical guidelines in the future. The chapters on cardiac failure, ischemic heart disease, arrhythmia, valvular heart disease, cerebrovascular disease, and peripheral artery disease in the guideline are separated into those for "renal dialysis physicians" and "cardiologists (or strokologists)" in order to demonstrate the importance of cooperation between these two specialties. We think that the excellent outcome of dialysis therapy in Japan is in part attributed to the implementation of excellent daily clinical procedures, which are based on "evidence" and/or "experience" in each dialysis facility. We have to validate the daily procedures and present them as treatment guidelines. We hope this guideline is useful in daily clinical practice. We determined the grading evidence and recommendation levels according to the position statement from Kidney Disease: Improving Global Outcomes (1,2). In dialysis patients, dyslipidemia is an independent risk factor for cardiovascular diseases, particularly incident myocardial infarction (B). We recommend measurement of low-density lipoprotein cholesterol (LDL-C), non-high-density lipoprotein cholesterol (non-HDL-C), HDL-C, and triglyceride (TG) before dialysis (casual blood sampling) for routine evaluation (1B). We suggest the control target levels should be LDL-C < 120 mg/dL or non-HDL-C < 150 mg/dL for the primary prevention, and LDL-C < 100 mg/dL or non-HDL-C < 130 mg/dL for the secondary prevention of ischemic heart disease (2C). We suggest that administration of statin should be considered if lipid control cannot be achieved by dietary/exercise therapy (2B). We suggest that the evaluation and intervention of undernutrition should be considered if hypolipidemia is present. Observational studies in Japan have demonstrated a close relationship between dyslipidemia (hyper-LDL-cholesterolemia, hypo-HDL-cholesterolemia, hypertriglyceridemia, and/or hyper-non-HDL-cholesterolemia) and the severity of atherosclerosis (1,2) and also the risk of myocardial infarction (3) in dialysis patients. In addition, dyslipidemia is more closely related to coronary artery disease than cerebrovascular disorders. However, observational cohort studies of dialysis patients showed a higher risk of death due to all causes (4) or death due to cardiovascular disease (5) in patients with low total cholesterol (TC) level, reflecting a reverse tendency compared with epidemiological data in the general population. Such relationship is, however, not observed in dialysis patients who are free of inflammation or are not undernourished (as defined by the levels of C-reactive protein [CRP] and serum albumin, respectively) (4,6). In Western countries, the survival curve of dialysis patients who develop acute coronary syndrome is poorer in patients with low body mass index (BMI) than in those with high BMI (7). Similarly, in Japanese dialysis patients, old age, low BMI, and high CRP are reported to be factors that enhance the risk of death after a cardiovascular event (3). These reports suggest that undernutrition, represented by hypoalbuminemia, low BMI, and hypocholesterolemia, correlates with increased risk of death by increasing the risk of death after an event (fatality rate), although hypocholesterolemia per se is not considered to promote atherosclerosis (8). Dyslipidemia can be classified into primary and secondary dyslipidemia, depending on the cause. Primary dyslipidemia includes familial hypercholesterolemia (FH) and familial combined hyperlipidemia (FCHL), with a reported respective prevalence of each type of 1:500 and 1:100. Secondary dyslipidemia is caused by various conditions such as diabetes, endocrine (thyroid, adrenal) disorders, liver diseases, kidney diseases, and drugs. Hypercholesterolemia associated with nephrotic syndrome and hypertriglyceridemia and hypo-HDL-cholesterolemia associated with chronic kidney failure are well-known dyslipidemias caused by kidney diseases. Low lipoprotein lipase activity (high apo C-III levels), low hepatic lipase level, and low lecithin cholesterol acyltransferase (LCAT) activity contribute to dyslipidemia in patients with chronic renal failure. According to the Guidelines for Prevention of Atherosclerotic Cardiovascular Diseases by the Japan Atherosclerosis Society (9), hyper-LDL-cholesterolemia is defined as LDL-C ≥140mg/dL, hypo-HDL-cholesterolemia as HDL-C <40 mg/dL, and hypertriglyceridemia as TG ≥150 mg/dL in fasting blood samples. However, fasting blood samples are often difficult to obtain from dialysis patients. In general, post-prandial changes in TC or HDL-C level are very small, compared with the increase in TG levels. Thus, LDL-C level calculated by the Friedewald equation decreases while little change is observed in non-HDL-C level (TC minus HDL-C). Also, since non-HDL-C level is the sum of LDL-C and cholesterol present in TG-rich lipoproteins (Fig. 1), it is regarded as an integrated index of the atherogenic lipoprotein level. Therefore, for routine evaluation in dialysis patients, non-HDL-C level in a casual blood sample is considered acceptable in addition to the standard fasting LDL-C level. Serum total cholesterol and its components. Serum contains a mixture of lipoproteins of different densities (specific gravity), and the total sum of cholesterol in the various lipoproteins represents serum total cholesterol. Several methods are used to fractionate lipoproteins. HDL has an anti-atherosclerotic properties, and all other fractions apart from HDL (collectively called non-HDL) are atherogenic. The cholesterol present in non-HDL is expressed as non-HDL-C. Thus, non-HDL-C is the sum of cholesterol in atherogenic lipoproteins. In subjects with dyslipidemia in general, secondary dyslipidemia is usually excluded first, followed by recommendations for long-term dietary/exercise therapy. Drug treatment is also considered if the target level cannot be achieved. However, in patients with coronary artery disease, the first option should be drug treatment. A strict target lipid level is set in patients that have not developed coronary artery disease but are at high risk, while a stricter target is set for patients with established coronary artery disease (secondary prevention group). According to the recent epidemiological study of the Japanese Society for Dialysis Therapy (3), the risk of occurrence of acute myocardial infarction increases 1.24 times (95% confidence interval: 1.14–1.35) with every increase in non-HDL-C level of 1 mmol/L (38.7 mg/dL). Based on the results of this observational study, the present guidelines propose a target level of LDL-C <120 mg/dL or non-HDL-C <150 mg/dL for primary prevention, and LDL-C < 100 mg/dL or non-HDL-C level <130 mg/dL for secondary prevention. There are only a few randomized controlled trials in dialysis patients regarding whether lipid lowering therapy significantly reduces the risk of cardiovascular events. The 4D (Die Deutsche Diabetes Dialyse) study using atorvastatin (10) and AURORA Study using rosuvastatin (11) suggested that the risk of all cardiovascular diseases (including those not directly related to atherosclerosis such as heart failure and cerebral hemorrhage) can only be reduced slightly even by lipid lowering therapy using statins. However, the risk of ischemic cardiac accidents decreased significantly by 18% in the 4D Study. Taking these results and the results of the observational cohort study in Japan into consideration, it would be reasonable to treat dialysis patients with high LDL-C or non-HDL-C levels with statins to reduce the risk of ischemic heart disease. Furthermore, there is little medical basis for discontinuation of statins therapy, since statin use is reported to associate with better survival in both incident (12) and prevalent dialysis patients (13). In conducting drug therapy, statins are the first choice. Statins reduce LDL-C level by 25–40% although this effect varies with the drug and dose. In the above 4D (10) and AURORA (11) studies, the frequency of adverse effects were comparable between the statins and placebo groups, suggesting no safety problems with the use of statins. Excluding clinofibrate, fibrates available in Japan are contraindicated in patients with renal failure due to the high risk of rhabdomyolysis based on their excretion via the kidney. Bile acid-binding resins, eicosapentaenoic acid preparations, and intestinal cholesterol transporter inhibitors can also be used in dialysis patients. Niceritrol, a nicotinic acid derivative, reduces serum phosphate levels but could cause anemia and thrombocytopenia and must be administered with caution in dialysis patients. Many patients are treated with more than one drug. For safe treatment, one should monitor symptoms and laboratory tests including serum creatine kinase, aspartate aminotransferase and alanine aminotransferase, and also pay attention to drug interactions. If the patient develops hypolipidemia, a nutritional disorder should be suspected, and measures to improve the nutritional state should be considered. The following issues are proposed as topics of future studies; whether a very high TG level is a risk factor of acute pancreatitis in dialysis patients, and whether patients undergoing peritoneal dialysis and children with renal failure should be treated in a manner similar to that of adult hemodialysis patients. We expect further data from sub-analyses and meta-analysis of the 4D, AURORA, and Study of Heart and Renal Protection (SHARP) studies.* Papers on subanalyses of the 4D Study (14) and AURORA Study (15), and the original report of SHARP (16) appeared during the publication of the guidelines, on which the present simplified guidelines are based, and the preparation of this simplified version. The subanalyses of 4D and AURORA studies suggested that lipid lowering therapy prevents atherosclerotic cardiovascular events in diabetic patients on dialysis, and that it significantly prevents such events more effectively in patients with higher LDL-C levels before the treatment. SHARP also showed that lipid lowering therapy using the combination of simvastatin and ezetimibe significantly reduced the risk of atherosclerotic cardiovascular events and that such reduction showed no significant heterogeneity between the patient groups before and after the initiation of dialysis therapy. To evaluate the risk of cardiovascular death in dialysis patients, we recommend the inclusion of risk factors specific to renal failure (e.g. anemia, inflammation, undernutrition, abnormal mineral metabolism), in addition to classic risk factors (1C). The extent of arterial wall thickening, arterial wall stiffening, and vascular calcification may be used for the evaluation of cardiovascular risk (Opinion). In dialysis patients, the risk of death due to cardiovascular disease (CVD) such as ischemic heart disease, cerebrovascular diseases, and heart failure is markedly increased, and the relative risk compared to the general population is reported to be 10–30 (1). Dialysis patients are characterized by a high risk of CVD events and low survival rate after the onset (high fatality rate). Compared to the general population, dialysis patients show 2–5 times higher risk of incident acute myocardial infarction and poorer survival rate after acute myocardial infarction (2). This is also true for cerebrovascular diseases (3). The high incidence and high fatality rate are considered to synergistically increase the risk of death due to CVD (4). One of the reasons for the high risk of CVD in dialysis patients is advanced atherosclerosis before the initiation of dialysis. About half of the patients have significant coronary artery stenosis at the initiation of dialysis (5,6), and the presence or absence of coronary artery disease at the initiation of dialysis is a strong predictor of cardiovascular events after the initiation of dialysis (7). Vascular calcification is classified into atherosclerotic calcification affecting the intimal layer of the artery and Mönckeberg's sclerosis affecting the medial layer of the artery, especially the latter is more frequently observed in dialysis patients. Both types of calcification are significant predictors of death in dialysis patients. Abnormal mineral and bone metabolism including vascular calcification associated with chronic kidney diseases (CKD) has been integrated as a new concept named CKD-mineral and bone disorder (CKD-MBD) (8), and it is considered important in clinical practice of dialysis patients. Because the risk of CVD in dialysis patients is significantly high even after correction for classic risk factors such as old age, hypertension, dyslipidemia, and diabetes, factors specific to CKD are considered to be involved in the elevated risk of CVD (9). Sarnak et al. (10) noted many factors including anemia, inflammation, undernutrition, and abnormal mineral metabolism as non-classic risk factors. Among them, undernutrition (wasting) is diagnosed in daily clinical practice based on the presence of hypoalbuminemia or low BMI. According to reports from Japan, low BMI is a predictor of all-cause death (11,12) and CVD death (11), but not a predictor of future myocardial infarction (12). A report from the United States (13) observed that the survival curve after the onset of acute coronary syndrome was poorer in the low BMI group. In Japan, also, low BMI is independently related to the risk of death after CVD including myocardial infarction, cerebral infarction, and cerebral hemorrhage (12). Thus, certain non-classic risk factors are considered factors that enhance the fatality rate after the onset of CVD. Clinically, atherosclerosis-arteriosclerosis can be evaluated quantitatively and qualitatively by examination of the thickness and stiffness of the arterial wall and vascular calcification (Table 1). These measurements may serve as surrogate markers between risk factors and CVD events. Carotid artery intima-medial thickness is measured by B mode ultrasonography, which provides quantitative evaluation of arterial wall thickening, and is a predictor of the risk of CVD death and total death in dialysis patients (14). Aortic pulse wave velocity (cfPWV, hfPWV) is a representative index of arterial stiffness and a predictor of CVD death and total death in dialysis patients (15). While a high baPWV measured in the brachium and ankle is also a prognostic factor in dialysis patients (16), its value falsely decreases in patients with obstructive arteriosclerosis in the lower limbs. Therefore, caution is needed and simultaneous measurement of the ankle brachial pressure index (ABI) may be helpful. The Cardio-ankle vascular index (CAVI) and augmentation index (AI) have also been used as new indices of arterial stiffness. Various methods are available to evaluate vascular calcification. Among these, electron beam computed tomography (EBCT) has excellent temporal resolution and provides specific assessment of the heart and large blood vessels. Coronary artery calcification is usually evaluated using the coronary artery calcification score (CACS) calculated by Agatston's method. CACS has been reported to be a predictor of cardiovascular events (cardiac death, non-fatal myocardial infarction) in non-dialysis patients with coronary artery disease (17). However, while dialysis patients with high CACS have poor survival, CACS is not necessarily related to cardiovascular events (18). The sensitivity of multi-detector computed tomography (MDCT) has improved in recent years, and this modality has become the mainstay of coronary artery computed tomography (CT). Abdominal plain CT is used to measure the area of aortic calcification, using the aortic calcification index (ACI), which is determined in 10 slices at 1-cm intervals above the origin of the common iliac artery. In dialysis patients, there is a strong correlation between ACI and coronary artery calcification (19). The presence or absence of vascular calcification examined by thoracoabdominal CT (20,21) has also been shown to be an independent predictor of all-cause death and CVD death in dialysis patients and is considered to be useful in daily clinical practice. Although evaluation of these non-invasive surrogate indices may help estimate the individual CVD risk, the criteria used for their evaluation or appropriate frequency of their use have not been established. Longitudinal changes in these measures are not well known in dialysis patients. We propose that the evaluation method(s) should be selected taking into consideration the characteristics of individual patients and availability in the medical facilities, and to the measurement every if We do not the treatment for each risk factors and their effects on atherosclerosis-arteriosclerosis because are discussed in detail in for other including and at an appropriate for each patient are considered Furthermore, if treatment of CVD are particularly important in dialysis patients. In dialysis patients, we recommend blood pressure should be evaluated not only in the dialysis but also at (1B). In patients long-term dialysis with no of the cardiac we suggest the target of antihypertensive treatment should be blood pressure before dialysis at the of the (Opinion). We recommend should be set in the target blood pressure (1B). We recommend antihypertensive should be administered when the reduction in blood pressure is even after of (1B). According to reports on the present state of chronic dialysis therapy in Japan at the of of all dialysis patients were based on blood pressure measured at the initiation of dialysis and the criteria of the Japanese Society of (1). hypertension is a cause of ischemic heart disease, heart failure, and death, and the control of hypertension is important in dialysis patients (2). However, a in blood pressure during dialysis not only have effects on outcome (3), it may also the of or In dialysis patients, aortic calcification also has a on as pulse and and The outcome is poorer in patients with low pressure but pressure and also in patients with high pressure with pressure Also, the mortality rate is reported to significantly if the blood pressure of the pulse pressure measured before and after dialysis times a and at daily at and before to (7). This is also true for various other including the and blood blood pressure and blood pressure it is important to blood pressure in the evaluation It is more important to any clinical or therapeutic on the of measurements than a casual blood pressure measurement Many cohort studies demonstrated poorer of patients with high blood pressure compared with patients. This is due to the inclusion the of patients with or those with chronic heart failure reverse prospective studies are needed to further evaluate patients Many factors are to be responsible for hypertension in dialysis patients. blood pressure is reported to in more than of patients following strict management of body of is and the present guidelines propose should be of blood pressure measurement is for the of blood pressure of blood pressure pressure should be measured conditions although it can be measured in the or position depending on the at each facility. the of dialysis therapy, blood pressure should be measured after a of of at before the of dialysis. should from before the measurement and from during the pressure should be measured with the heart rate at every the of dialysis, the blood pressure should be measured in a similar manner before of blood and within after the of of and pressure measured before of blood at the of dialysis is called pressure at of setting or blood pressure should be measured also in the standing position at the of dialysis. blood pressure should be measured as by the guidelines of the Japanese Society of before to at and at in the are While has also been reported to be useful it cannot be due to the use of one for In dialysis patients with changes in body it is important to evaluate blood pressure not only in the dialysis but also at In dialysis patients, evaluation on a basis is because dialysis is after pressure decreases from the to the of the on the blood pressure should be evaluated or used are very The blood pressure represents the blood pressure measured before and after dialysis times a and daily blood in the and observational studies demonstrated that is a more significant predictor of and cardiovascular than casual or blood pressure measured at the of the pressure measured at on a non-dialysis in the of the could be also used since it correlates with In dialysis patients, a relationship is observed between blood pressure and However, this relationship that is, it is important to the subjects and when the target blood pressure of antihypertensive treatment. The of antihypertensive treatment is to reduce the long-term risk of cardiovascular diseases in patients on chronic dialysis, rather than reduce all-cause mortality Therefore, patients with cardiac dysfunction, for example, are The target level should be set after evaluation of cardiac in both patients with markedly reduced and those with reduced due to In since the outcome is reported to in patients with increased aortic stiffness due to aortic calcification, by in blood pressure and increase in pulse caution reduction in blood pressure is in consideration of the effects of the blood pressure on various conditions such as chronic heart failure and coronary blood For these the criteria for blood pressure control should not be to all patients but by patients with reduced cardiac for example, and further evaluated at While it is difficult to propose specific target blood pressure in the present guidelines due to the of a dialysis blood pressure than at the of the is as a However, a in blood pressure or in during dialysis and after dialysis are reported to and further studies are the other observational studies that blood pressure not with the effect of in blood pressure during dialysis The target blood pressure is set to reduce the long-term risk of cardiovascular diseases in patients on dialysis, and should not be to patients with cardiovascular disorders. In patients, the blood pressure during dialysis correlates significantly with the risk of death within years (3). One of antihypertensive treatment is appropriate of dialysis, and the conditions of dialysis such as blood and dialysis need to be should an appropriate be and This should be followed by administration of appropriate antihypertensive drugs when If a in blood pressure is observed during dialysis, antihypertensive should be or its the should be set the patient should be followed and antihypertensive if control of and of are the most important of during dialysis. To the target of antihypertensive treatment, the must be set first issue is discussed in a different It is to control changes in body between to any in blood pressure during

OBJECTIVE: Our objective was to evaluate the activity of cytochrome P4501A2 (CYP1A2), xanthine oxidase (XO), and N-acetyltransferase 2 (NAT2) from early to late pregnancy and after delivery. METHODS: Twelve women were studied on three occasions during pregnancy (early, 8-16 weeks' gestation; middle, 20-28 weeks' gestation; and late, 32-39 weeks' gestation) and about 1 month after delivery. Caffeine was used as a metabolic probe. After the women ingested a can or a bottle of caffeine-containing soft drink, urine samples were collected for 12 hours. The caffeine metabolites measured were 5-acetylamino-6-amino-3-methyluracil (AAMU), 1-methylxanthine (1X), 1-methyl-uric acid (1U), 1,7-dimethyl-uric acid (17U), and 1,7-dimethylxanthine (17X). The hepatic enzyme activities were estimated by the urinary caffeine metabolic ratios as follows: CYP1A2 = (AAMU + 1X + 1U)/17U; XO = 1U/(1X + 1U); NAT2 = AAMU/(AAMU + 1X + 1U). RESULTS: Statistically significant differences were found in CYP1A2 (P < .0001) and NAT2 (P < .01). The mean metabolic ratios for CYP1A2 during pregnancy (6.80, 5.18, and 4.97 for the early phase, middle phase, and late phase, respectively) were significantly lower than the ratio after delivery (10.39). The mean metabolic ratio for NAT2 in the early phase (0.57) was significantly lower than after delivery (0.66). There was no significant difference in metabolic ratios for XO during pregnancy and after delivery. CONCLUSION: The data demonstrate that pregnancy influences CYP1A2 and NAT2 activity. CYP1A2 activity decreases not only in late pregnancy but also in early and middle pregnancy.

BACKGROUND & AIMS: Platelet transfusion is used to prevent hemorrhagic events in patients with thrombocytopenia undergoing invasive procedures, but there are many disadvantages. We evaluated the efficacy and safety of lusutrombopag in patients with chronic liver disease and thrombocytopenia undergoing invasive procedures. METHODS: We performed a double-blind, parallel-group, phase 3 study of 96 patients with chronic liver disease and thrombocytopenia (platelet counts below 50,000/μL) undergoing invasive procedures from October 2013 to May 2014 at 81 centers in Japan. Patients were randomly assigned (1:1) to groups given once-daily lusutrombopag (3 mg) or placebo for up to 7 days. The primary efficacy endpoint was the proportion of patients not requiring platelet transfusion before the invasive procedure. The protocol-defined response (platelet count 50,000/μL or more with an increase of 20,000/μL or more from baseline) and the time course of the change in platelet count were also evaluated. Adverse events were recorded. RESULTS: The proportions of patients who did not require preoperative platelet transfusion were 79.2% (38/48) in the lusutrombopag group and 12.5% (6/48) in the placebo group (P < .0001). A response was observed in 77.1% (37/48) of patients in the lusutrombopag group and 6.3% (3/48) of patients in the placebo group (P < .0001). In the lusutrombopag group without platelet transfusion, the median platelet count was 50,000/μL or more after 5 days; the mean time to reach the maximum platelet count was 13.4 days; and the number of days (adjusted mean) during which the platelet count was 50,000/μL or more was 21.09 days. Adverse drug reactions were reported in 8.3% of patients in the lusutrombopag group and 2.1% of patients in the placebo group. Two patients (1 per group) had a thrombotic event, but neither were associated with an excessive increase in platelet count (200,000/μL or more). CONCLUSION: In a placebo-controlled trial, lusutrombopag was effective in achieving and maintaining the target platelet count in patients with chronic liver disease and thrombocytopenia undergoing invasive procedures. No significant safety concerns were raised. Japanese clinical trial registration no: JapicCTI-132323.

BACKGROUND: Classification of macroscopic appearance and standard operative procedures for intrahepatic cholangiocarcinoma (ICC) are still controversial. METHODS: The mode of spread of 12 resected ICCs was examined by light microscopy, and the appropriate operative procedures for the various tumours were considered. RESULTS: Macroscopically, nine tumours were classified as mass-forming type and three as periductal infiltrating type. All patients were treated by major hepatectomy; resection of the extrahepatic bile duct was included in two cases of the periductal infiltrating type. Microscopically, invasion into the portal vein, intrahepatic metastasis and perineural or lymphatic vessel invasion occurred in none, one and all of three tumours of the periductal infiltrating type and in eight, six and six of nine tumours of the mass-forming type. CONCLUSION: ICC of the periductal infiltrating type has a tendency to spread along Glisson's sheath via lymphatic vessels. By contrast, ICC of the mass-forming type tends to invade the liver via the portal vein system; such tumours begin to invade Glisson's sheath through the lymphatic vessels when the tumour has increased in size. Therefore, major hepatectomy with combined resection of the extrahepatic bile duct should be performed for all ICCs of the periductal infiltrating type and for those of the mass-forming type with invasion of Glisson's sheath.

Advanced colorectal cancer harbors extensive intratumor heterogeneity shaped by neutral evolution; however, intratumor heterogeneity in colorectal precancerous lesions has been poorly studied. We perform multiregion whole-exome sequencing on ten early colorectal tumors, which contained adenoma and carcinoma in situ. By comparing with sequencing data from advanced colorectal tumors, we show that the early tumors accumulate a higher proportion of subclonal driver mutations than the advanced tumors, which is highlighted by subclonal mutations in KRAS and APC. We also demonstrate that variant allele frequencies of subclonal mutations tend to be higher in early tumors, suggesting that the subclonal mutations are subject to selective sweep in early tumorigenesis while neutral evolution is dominant in advanced ones. This study establishes that the evolutionary principle underlying intratumor heterogeneity shifts from Darwinian to neutral evolution during colorectal tumor progression.

Mutations of CCAAT/enhancer-binding protein alpha (CEBPAmu) are found in 10% to 15% of de novo acute myeloid leukemia (AML) cases. Double-mutated CEBPA (CEBPAdm) is associated with a favorable prognosis; however, single-mutated CEBPA (CEBPAsm) does not seem to improve prognosis. We investigated CEBPAmu for prognosis in 1028 patients with AML, registered in the Multi-center Collaborative Program for Gene Sequencing of Japanese AML. It was found that CEBPAmu in the basic leucine zipper domain (bZIP) was strongly associated with a favorable prognosis, but CEBPAmu out of the bZIP domain was not. The presence of CEBPAmu in bZIP was a strong indicator of a higher chance of achieving complete remission (P < .001), better overall survival (OS; P < .001) and a lower risk of relapse (P < .001). The prognostic significance of CEBPAmu in bZIP was also observed in the subgroup with CEBPAsm (all patients: OS, P = .008; the cumulative incidence of relapse, P = .063; patients aged ≤70 years and with intermediate-risk karyotype: OS, P = .008; cumulative incidence of relapse, P = .026). Multivariate analysis of 744 patients aged ≤70 years showed that CEBPAmu in bZIP was the most potent predictor of OS (hazard ratio, 0.3287; P < .001). CEBPAdm was validated as a cofounding factor, which was overlapping with CEBPAmu in bZIP. In summary, these findings indicate that CEBPAmu in bZIP is a potent marker for AML prognosis. It holds potential in the refinement of treatment stratification and the development of targeted therapeutic approaches in CEBPA-mutated AML.

The root of the small-bowel mesentery (SBM) is an important peritoneal fold that is contiguous to other peritoneal ligaments and mesocolons. Several pathologic conditions can occur in the SBM itself, and diseases that spread through the connections from adjacent organs frequently involve it. The root of the SBM is contiguous to the hepatoduodenal ligament around the superior mesenteric vein (SMV) and contiguous to the right side of the transverse mesocolon around the gastrocolic trunk. The inferior mesenteric vein, which is a landmark of the descending mesocolon, runs along the left side of the root of the SBM. Malignant neoplasms can spread to the SBM by means of direct extension, extension along the neural plexus, extension along neighboring ligaments, or extension along lymphatic vessels. Inflammatory conditions such as pancreatitis and perforation of a jejunal diverticulum can also spread to the SBM. Anomalies that can occur in the SBM include rotation anomalies and internal hernia. Vascular lesions of the SBM include thrombosis of the superior mesenteric artery (SMA), acute SMV thrombosis, SMA dissection, arterioportal fistula, and portal venous gas. Other pathologic conditions that can occur in the SBM are edema or congestion, mesenteric tear, mesenteric panniculitis, and tumors or tumorlike lesions.

Background and Purpose— The purpose of this study is to compare the angiographic and clinical characteristics of spinal epidural arteriovenous fistulas (SEAVFs) and spinal dural arteriovenous fistulas (SDAVFs) of the thoracolumbar spine. Methods— A total of 168 cases diagnosed as spinal dural or extradural arteriovenous fistulas of the thoracolumbar spine were collected from 31 centers. Angiography and clinical findings, including symptoms, sex, and history of spinal surgery/trauma, were retrospectively reviewed. Angiographic images were evaluated, with a special interest in spinal levels, feeders, shunt points, a shunted epidural pouch and its location, and drainage pattern, by 6 readers to reach a consensus. Results— The consensus diagnoses by the 6 readers were SDAVFs in 108 cases, SEAVFs in 59 cases, and paravertebral arteriovenous fistulas in 1 case. Twenty-nine of 59 cases (49%) of SEAVFs were incorrectly diagnosed as SDAVFs at the individual centers. The thoracic spine was involved in SDAVFs (87%) more often than SEAVFs (17%). Both types of arteriovenous fistulas were predominant in men (82% and 73%) and frequently showed progressive myelopathy (97% and 92%). A history of spinal injury/surgery was more frequently found in SEAVFs (36%) than in SDAVFs (12%; P =0.001). The shunt points of SDAVFs were medial to the medial interpedicle line in 77%, suggesting that SDAVFs commonly shunt to the bridging vein. All SEAVFs formed an epidural shunted pouch, which was frequently located in the ventral epidural space (88%) and drained into the perimedullary vein (75%), the paravertebral veins (10%), or both (15%). Conclusions— SDAVFs and SEAVFs showed similar symptoms and male predominance. SDAVFs frequently involve the thoracic spine and shunt into the bridging vein. SEAVFs frequently involve the lumbar spine and form a shunted pouch in the ventral epidural space draining into the perimedullary vein.

We isolated the human osteopontin (hOP) gene and the 5' upstream region, and analysed its exon-intron structure and potential regulatory sequences of the promoter region in comparison with those of the mouse and porcine gene. The coding sequence is split into 7 exons which are similar to those of the mouse gene, although the hOP gene is longer than the mouse gene. The difference in length is mainly due to variations in intron 3, which is approximately 2.7-fold longer than that of the mouse OP gene. The 5' upstream region of the hOP, which is highly conserved up to nucleotide -250, contains a number of potential cis regulatory consensus sequences. A series of sequentially 5'-deleted chimeric clones was tested for the ability to stimulate chloramphenicol acetyltransferase (CAT). Initial CAT analysis demonstrated that nucleotides at positions -474 to -270, -124 to -80, and -55 to -39 contained cis-acting enhancing sequences in a human monocyte cell line, SCC-3, although the -124 to -80 region was much more active than other regions. Deletion of the sequences between -474 and -270 localized this cis region to the sequence at positions -439 to -410, whereas the deletion between -124 to -80 localized the regions to -124 to -115, and -94 to -80. Gel-shift analysis using as probes synthesized double-stranded DNA corresponding to the 10 and 15 bp region at positions -124 to -115 and -94 to -80 respectively revealed that each probe formed a major band complexed with nuclear proteins prepared from SCC-3 cells.

BACKGROUND: The once-daily, all oral, RBV-free, pangenotypic direct-acting anti-viral regimen consisting of co-formulated NS3/4A protease inhibitor glecaprevir and NS5A inhibitor pibrentasvir (G/P), demonstrated high rates of sustained virologic response (SVR) in phase 2 and 3 studies outside Japan. METHODS: CERTAIN-1 is a phase 3, open-label, multicenter study assessing the safety and efficacy of G/P (300/120 mg) once daily in Japanese patients with chronic HCV GT1 infection. Patients without cirrhosis received 8 weeks of G/P or 12 weeks of ombitasvir/paritaprevir/ritonavir (OBV/PTV/r, 25/150/100 mg); patients with cirrhosis received G/P for 12 weeks. The primary efficacy endpoint was non-inferiority of G/P compared to OBV/PTV/r by assessing SVR at post-treatment week 12 (SVR12) among non-cirrhotic patients without the NS5A Y93H polymorphism. RESULTS: SVR12 was achieved by 128/129 (99.2%; one patient lost to follow-up) non-cirrhotic patients in the 8-week G/P Arm (including 23/23 patients with the NS5A Y93H polymorphism) and 52/52 (100%) patients in the 12-week OBV/PTV/r Arm. No patients from the G/P Arm prematurely discontinued the study drug or experienced a treatment-emergent serious adverse event (TESAE). Three patients from the OBV/PTV/r Arm experienced five TESAEs and one of these patients discontinued the study drug due to TESAEs. All 38 (100%) patients with compensated cirrhosis achieved SVR12; in this group, no TESAEs were reported and one patient discontinued treatment due to an AE. CONCLUSIONS: CERTAIN-1 study results demonstrate high efficacy and favorable tolerability of G/P in GT1-infected Japanese patients including those with the NS5A Y93H polymorphism, with no virologic failures observed.