Long-term outcomes of hemostatic therapy for variceal bleeding and the challenge pending in the post-direct-acting antivirals era.

Background and study aims: This study evaluated the longterm outcomes of mainly endoscopic hemostatic therapy for gastrointestinal variceal bleeding and of the transition of hemostatic therapy. Patients and methods: Among 1,163 patients treated for gastrointestinal varices between April 2006 and June 2020, a total of 125 patients who underwent emergency hemostatic therapy were enrolled. Survival rates and secondary evaluation points were analyzed. Additionally, patients were classified into two groups: the previous and latter term. Patients' background, therapeutic method, and treatment results were compared between the groups. Results: 94.4% had cirrhosis. The average Child-Pugh score was 8.90. Successful primary hemostasis rate was 98.4%, and 5.6% died within 2 weeks, all with a Child-Pugh score ≥9. The respective 1- and 5-year survival rates for Child-Pugh grade A/B were 81.3% and 55.4%, while those for Child-Pugh grade C were 58.1% and 17.8%. Child-Pugh grade C or hepatocellular carcinoma was significantly associated with poor prognosis. In total, 21.6% experienced variceal re-bleeding; 62.9% of these cases were triggered by continued alcohol consumption. There was no significant difference in survival between patients with and without variceal re-bleeding and in post-treatment survival between the previous and latter terms. In the latter term, the number of cases caused by continued alcohol consumption significantly increased. Conclusions: Multidisciplinary treatment and continuation of proper management after hemostatic therapy for variceal bleeding are crucial. Continued alcohol consumption leads to variceal bleeding and re-bleeding; its proper management, including alcohol abstinence, is one of the major challenges left in the post-directacting antivirals era.

Evaluation of risk factors for nephrotoxicity associated with high-dose vancomycin in Japanese patients.

Introduction: Considering the physique of the Japanese population, the standard daily vancomycin dose of 2 g/day and doses ≥ 3 g/day are high in terms of dose per body weight. Studies have reported that administering high-dose vancomycin to achieve a high target trough concentration has been associated with nephrotoxicity. The risk of high-dose vancomycin-associated nephrotoxicity is believed to be exceptionally high for Japanese patients because of their relatively low body weights, but data on the population is lacking. In this retrospective study, we aimed to evaluate risk factors associated with nephrotoxicity in Japanese patients treated with vancomycin. Methods: We examined the medical records of 107 Japanese patients who received vancomycin (3 to 4 g/day). They were divided into two groups based on the presence or absence of nephrotoxicity, and their demographics and clinical characteristics were compared. Results : The incidence of nephrotoxicity in patients receiving high-dose vancomycin was 13%. Age (≥ 60 years) and concurrent use of piperacillin/tazobactam were independent risk factors for vancomycin-associated nephrotoxicity (P = 0.027 and 0.017, respectively). Conclusions : We conclude that the nephrotoxicity risk of high-dose vancomycin in Japanese patients is not excessively high when administered within the confines of a therapeutic drug-monitoring program. However, special care must be taken with patients who are older or on concurrent piperacillin/tazobactam therapy.

High hepatitis B virus screening rate among patients receiving systemic anticancer treatment in Japan.

BACKGROUND: Patients with hepatitis B virus (HBV) infection have a risk of reactivation after chemotherapy. All patients undergoing chemotherapy should be screened for HBV infection. No large-scale studies have been conducted to examine HBV screening practice in Japan. METHODS: We analyzed health insurance claims equivalent data linked with a nationwide hospital-based cancer registry. Patients diagnosed with cancer in 2014, who were aged 20 years and older and those who underwent systemic anticancer treatment in 2014-15 were included. We assessed the HBV screening rates by the HBsAg or anti-HBc tests, HBV-DNA tests, and entecavir prescriptions. Multiple logistic regression models were used to identify factors related to the receipt of screening. RESULTS: Of 177,597 patients (mean [SD] age, 65.6 [12.2] years), 82.6% and 12.9% patients had a solid tumor and hematologic malignancy, respectively. Among them, 88.1%, 6.3%, and 5.5% received cytotoxic chemotherapy, targeted therapy, and anti-CD20 antibodies, respectively. Overall, 70.6% of patients were screened. The positive predictor of HBV screening was receiving anti-CD20 antibodies [odds ratio (OR); 2.23, 95% confidence interval (CI) 2.06-2.41, p < 0.001] and negative predictors were age ≥ 85 (OR 0.76, 95% CI 0.71-0.81), age 75-84 (OR 0.77, 95% CI 0.75-0.79) and targeted therapy (OR 0.69, 95% CI 0.67-0.72). Among the screened patients, 13.2% were tested for HBV-DNA, and 1.49% were prescribed entecavir. CONCLUSIONS: The HBV screening rate in Japan is higher than in other countries. Further improvement of the HBV screening rate is needed to prevent reactivation and avoidable deaths of patients with HBV infection.

The clinical impact of preoperative body composition differs between male and female colorectal cancer patients.

AIM: Patient body composition is an important indicator of metabolic status and is associated with cancer progression. Because body composition varies between men and women, we aimed to examine the difference in clinical impact of preoperative body composition according to sex. METHOD: We used an integrated dataset of 559 colorectal cancer (CRC) patients. The association between preoperative body composition indices [body mass index (BMI), visceral to subcutaneous fat area ratio (VSR) and skeletal muscle index (SMI)] and patient outcome, clinicopathological factors and preoperative inflammation and nutritional status was analysed, comparing men and women. RESULTS: Preoperative low BMI and low SMI in men was significantly associated with unfavourable overall survival (OS) [BMI: hazard ratio (HR) 2.22, 95% CI 1.28-4.14, P = 0.004; SMI: HR 2.54, 95% CI 1.61-4.07, P < 0.001] and high VSR in women was significantly associated with unfavourable OS (HR 1.79, 95% CI 1.03-3.02, P = 0.040). Additionally, low SMI in men was significantly associated with deeper tumour invasion and greater distant metastasis and high VSR in women was significantly associated with advanced age, right-sided tumour, lower total lymphocyte count and lower albumin levels. Interestingly, low BMI in men was significantly associated with deeper tumour invasion, but also with favourable inflammation and nutritional status (lower C-reactive protein and higher albumin). CONCLUSION: The clinical impact of preoperative body composition differed between men and women: SMI in men and VSR in women were good prognosticators. Our findings may provide a novel insight for CRC treatment strategies.

The impact of preoperative anaemia and anaemic subtype on patient outcome in colorectal cancer.

AIM: Preoperative anaemia is associated with adverse outcomes in colorectal cancer (CRC). To clarify the reason for this we aimed to comprehensively assess the association of preoperative anaemia with tumour characteristics, host systemic inflammation and nutrition status, and perioperative blood transfusion. METHOD: We used an integrated database of 592 CRC patients. The association of preoperative anaemic subtype, calculated from haemoglobin and erythrocyte mean corpuscular volume levels, with patient outcome, preoperative serum data relating to systemic inflammation and nutrition and perioperative blood transfusion was analysed. RESULTS: Preoperative anaemia was significantly associated with poorer overall survival and relapse-free survival (RFS); in particular microcytic anaemia had a trend to poorer RFS than other forms of anaemia (P = 0.0648). In addition, preoperative anaemia was significantly correlated with right-sided tumours, greater depth of tumour invasion, use of neoadjuvant chemotherapy, poorer prognostic nutritional index and higher modified Glasgow Prognostic Score (mGPS). Microcytic anaemia in particular had a strong association with a greater depth of tumour invasion (P = 0.0072) and higher mGPS (P = 0.0058) than other causes of anaemia. Perioperative blood transfusion for CRC patients with anaemia was associated with adverse outcomes. CONCLUSIONS: Preoperative anaemia, especially microcytic anaemia, was associated with poor patient outcomes, possibly due to poor systemic inflammatory and nutritional status, and it was not improved by perioperative blood transfusion. Our data suggest that preoperative anaemia and the anaemic subtype may serve as an easily available predictor of outcome in CRC.

Progressive Cortical Neuronal Damage and Extracranial-Intracranial Bypass Surgery in Patients with Misery Perfusion.

BACKGROUND AND PURPOSE: Misery perfusion may cause selective neuronal damage in atherosclerotic ICA or MCA disease. Bypass surgery can improve misery perfusion and may prevent neuronal damage. On the other hand, surgery conveys a risk for neuronal damage. The purpose of this retrospective study was to determine whether progression of cortical neuronal damage in surgically treated patients with misery perfusion is larger than that in surgically treated patients without misery perfusion or medically treated patients with misery perfusion. MATERIALS AND METHODS: We evaluated the distribution of benzodiazepine receptors twice by using PET and 11C-labeled flumazenil in 18 surgically treated patients with atherosclerotic ICA or MCA disease (9 with misery perfusion and 9 without) and no perioperative stroke before and after bypass surgery; in 8 medically treated patients with misery perfusion and no intervening ischemic event; and in 7 healthy controls. We quantified abnormal decreases in the benzodiazepine receptors of the cerebral cortex within the MCA distribution and compared changes in the benzodiazepine receptor index among the 3 groups. RESULTS: The change in the benzodiazepine receptor index in surgically treated patients with misery perfusion (27.5 ± 15.6) during 7 ± 5 months was significantly larger than that in surgically treated patients without misery perfusion (-5.2 ± 9.4) during 6 ± 4 months (P < .001) and in medically treated patients with misery perfusion (3.2 ± 15.4) during 16 ± 6 months (P < .01). CONCLUSIONS: Progression of cortical neuronal damage in surgically treated patients with misery perfusion and no perioperative stroke may occur and may be larger than that in medically treated patients with misery perfusion and no intervening ischemic event.

miR-9-3p plays a tumour-suppressor role by targeting TAZ (WWTR1) in hepatocellular carcinoma cells.

BACKGROUND: The inactivation of the Hippo pathway lead to TAZ (PDZ-binding motif)/YAP (yes-associated protein) overexpression, and is associated with worse prognostic outcomes in various cancers including hepatocellular carcinoma (HCC). Although there are several reports of microRNA (miR) targeting for YAP, miR targeting for TAZ remains unclear. The aim of this study is to identify the miR targeting TAZ expression in HCC. METHODS: MicroRNA expression was analysed using the Human miFinder 384HC miScript miR PCR array, and was compared between low and high TAZ expression cell lines. Then, we extracted miR-9-3p as a tumour-suppressor miR targeting TAZ. We examined the functional role of miR-9-3p using miR-9-3p mimic and inhibitor in HCC cell lines). RESULTS: In HCC cell lines and HCC clinical samples, there was the inverse correlation between miR-9-3p and TAZ expressions. TAZ expression was induced by treatment of miR-9-3p inhibitor and was downregulated by treatment of miR-9-3p mimic. Treatment of miR-9-3p mimic inhibited cell proliferative ability with downregulated phosphorylations of Erk1/2, AKT, and ß-catenin in HLF. Inversely, treatment of miR-9-3p inhibitor accelerated cell growth compared with control in HuH1. CONCLUSIONS: MicroRNA-9-3p was identified as the tumour-suppressor miR targetting TAZ expression in HCC cells.

Effect of LSKL peptide on thrombospondin 1-mediated transforming growth factor ß signal activation and liver regeneration after hepatectomy in an experimental model.

BACKGROUND: A strategy for accelerating liver regeneration after hepatectomy would offer great benefits in preventing postoperative liver failure and improving surgical outcomes. Transforming growth factor (TGF) ß is a potent inhibitor of hepatocyte proliferation. Recently, thrombospondin (TSP) 1 has been identified as a negative regulator of liver regeneration by activation of local TGF-ß signals. This study aimed to clarify whether the LSKL (leucine-serine-lysine-leucine) peptide, which inhibits TSP-1-mediated TGF-ß activation, promotes liver regeneration after hepatectomy in mice. METHODS: Mice were operated on with a 70 per cent hepatectomy or sham procedure. Operated mice received either LSKL peptide or normal saline intraperitoneally at abdominal closure and 6 h after hepatectomy. Perioperative plasma TSP-1 levels were measured by enzyme-linked immunosorbent assay in patients undergoing hepatectomy. RESULTS: Administration of LSKL peptide attenuated Smad2 phosphorylation at 6 h. S-phase entry of hepatocytes was accelerated at 24 and 48 h by LSKL peptide, which resulted in faster recovery of the residual liver and bodyweight. Haematoxylin and eosin tissue staining and blood biochemical examinations revealed no significant adverse effects following the two LSKL peptide administrations. In the clinical setting, plasma TSP-1 levels were lowest on the first day after hepatectomy. However, plasma TSP-1 levels at this stage were significantly higher in patients with subsequent liver dysfunction compared with levels in those without liver dysfunction following hepatectomy. CONCLUSION: Only two doses of LSKL peptide during the early period after hepatectomy can promote liver regeneration. The transient inhibition of TSP-1/TGF-ß signal activation using LSKL peptide soon after hepatectomy may be a promising strategy to promote subsequent liver regeneration. Surgical relevance Although the mechanisms of liver regeneration after hepatectomy have been explored intensively in vivo, no therapeutic tools are thus far available to accelerate liver regeneration after hepatectomy in the clinical setting. Recently, the matricellular protein thrombospondin (TSP) 1, a major activator of latent transforming growth factor (TGF) ß1, has been identified as a negative regulator of liver regeneration after hepatectomy. In this study, the inhibition of TSP-1-mediated TGF-ß signal activation by LSKL (leucine-serine-lysine-leucine) peptide in the early period after hepatectomy accelerated liver regeneration without any adverse effects. In addition, continuous high plasma TSP-1 levels after hepatectomy were associated with liver damage in humans. The transient inhibition of TSP-1/TGF-ß signal activation using LSKL peptide in the early period after hepatectomy could be a novel therapeutic strategy to accelerate liver regeneration after hepatectomy.

A cohort study of toner-handling workers on inflammatory, allergic, and oxidative stress markers: cross-sectional and longitudinal analyses from 2003 to 2008.

OBJECTIVES: This study examines the relationship between toner exposure and its health effects in terms of biomarkers which are known to assess the damages to humans caused by toxic material exposure. METHODS: The subjects were 1504 male workers aged below 50 in 2003 in a Japanese toner and photocopier manufacturing company. Personal exposure measurements, pulmonary function tests, chest X-ray examinations, biomarker measurement, and a questionnaire about respiratory symptoms were conducted. We will report about biomarker measurement in this study. Cross-sectional survey studies and a longitudinal study from 2003 to 2008 were conducted. RESULTS: Few significant findings were associated with the toner exposure in both the cross-sectional and the longitudinal studies. The higher toner exposure concentrations did not induce effects on increasing biomarkers. CONCLUSION: There was no evidence of excessive inflammatory, allergic, or oxidative stress reaction in toner-handling workers as compared to non-handling workers, despite some sporadically significant findings. There are no other reports of a longitudinal epidemiological study with regard to toner exposure; this report significantly contributes to toner exposure literature. Although in the current well-controlled working environment, the toner exposure concentrations are quite low; further studies are needed to completely understand the health effects toner may have, however small they may be.

A cohort study using pulmonary function tests and x-ray examination in toner-handling workers: cross-sectional and longitudinal analyses from 2003 to 2008.

OBJECTIVES: This study uses pulmonary function tests and chest x-ray examinations to examine the relationship between toner-handling work and its health effects. METHODS: The subjects were 1504 male workers in a Japanese toner and photocopier manufacturing company, in the age range from 19 to 50 years in 2003. Personal exposure measurements, pulmonary function tests, chest x-ray examinations, biomarker measurements, and a questionnaire about respiratory symptoms were conducted. The present study reports the results of pulmonary function tests and chest x-ray examinations conducted in the subjects, which includes a cross-sectional study on the toner handling and non-handling workers and a longitudinal study from 2003 to 2008. RESULTS: Few significant findings were suspected to be caused by toner exposure found in pulmonary function indices in both the cross-sectional and longitudinal studies. Any obvious fibrotic findings in chest x-ray findings related to the toner exposure could not be found out. CONCLUSION: No evidence of adverse effects on pulmonary function indices and chest x-rays was present in the toner-handling workers as compared to the nonspecifically exposed workers. Although the toner exposure concentration is quite low in the current well-controlled working environment, even among the toner-handling workers, we would like to continue this study in the future to verify the toner exposure health effects.

Validation experiment of a numerically processed millimeter-wave interferometer in a laboratory.

We propose a new interferometer system for density profile measurements. This system produces multiple measurement chords by a leaky-wave antenna driven by multiple frequency inputs. The proposed system was validated in laboratory evaluation experiments. We confirmed that the interferometer generates a clear image of a Teflon plate as well as the phase shift corresponding to the plate thickness. In another experiment, we confirmed that quasi-optical mirrors can produce multiple measurement chords; however, the finite spot size of the probe beam degrades the sharpness of the resulting image.

A study of the behavior and mechanism of thermal conduction in the skin under moist and dry heat conditions.

PURPOSE: We analyzed skin heat conduction under moist and dry heat conditions to confirm the influence of moist heat on the skin and subcutaneous region. METHODS: Six healthy subjects placed their forearms in moist and dry heat air chambers, and the thickness of and moisture levels in the stratum corneum were measured. Skin surface temperatures, heat flux, and skin blood flow were measured in 11 healthy subjects. RESULTS: Within 10 min, the stratum corneum in skin exposed to moist heat reached a thickness of about 150%, and water content in the stratum corneum increased to about 200%. In contrast, the thickness of water content in the stratum corneum did not change in the dry heat condition. Skin surface temperatures of skin exposed to moist heat were significantly higher after 0.5 min of exposure (P < 0.01), the skin surface heat flux was greater, and blood flow was significantly higher (P < 0.05) after 10 min than that of skin exposed to dry heat. CONCLUSION: Stratum corneum moisture levels and skin surface heat conductivity were higher in the moist heat condition and skin blood flow was significantly greater than that in skin exposed to dry heat. Therefore, moist heat is more efficient at warming the body than dry heat.

Chronic hemodynamic compromise and cerebral ischemic events in asymptomatic or remote symptomatic large-artery intracranial occlusive disease.

BACKGROUND AND PURPOSE: In asymptomatic or remote symptomatic LAICOD, the risk of ischemic events is low in general, but there may be a subgroup of higher risk patients who require aggressive medical management. The purpose of this study was to determine whether chronic hemodynamic compromise is a predictor of ischemic events in asymptomatic or remote symptomatic LAICOD. MATERIALS AND METHODS: We prospectively studied 51 asymptomatic, 19 coexistent asymptomatic, and 19 remote (>6 months) symptomatic patients with atherosclerotic intracranial internal carotid artery or middle cerebral artery disease by using (15)O-PET. MP was defined as decreased CBF, increased OEF, and a decreased CBF/CBV ratio. All patients were followed up for 2 years or until occurrence of stroke or TIA or death. RESULTS: Bypass surgery was performed in 4 patients (2 with MP). Three cerebral ischemic events (1 TIA in an asymptomatic patient, 1 stroke, and 1 TIA in a remote symptomatic patient) occurred in the vascular territory ipsilateral to LAICOD. Kaplan-Meier analysis with censoring at the time of bypass surgery revealed that the incidence of ipsilateral ischemic events in patients with MP (2/5) was significantly higher than that in patients without MP (1/84) (log-rank test; P < .0001). The relative risk conferred by MP was 83.1 (95% confidence interval, 6.8-1017.4; P < .001). The incidence of ipsilateral ischemic events in patients with decreased CBF/CBV (2/9) was also significantly higher than that of patients without it (1/80) (P = .0001). CONCLUSIONS: Chronic hemodynamic compromise may be a predictor of ischemic events in both asymptomatic and remote symptomatic LAICOD.