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Purpose: This study investigated whether the oral vasopressin V2 receptor antagonist tolvaptan has beneficial effects on mortality in real-world congestive heart failure (CHF) patients with hypoperfusion (i.e. the wet–cold pattern), from the viewpoint of cardiorenal syndrome.Data on 5511 consecutive CHF patients were extracted from the Tokyo CCU Network data registry. Congestion and hypoperfusion were defined by Nohria–Stevenson clinical profiles at the time of hospitalization. Propensity scores for tolvaptan use were calculated for each patient and used to assemble two matched cohorts of patients receiving tolvaptan or not in the CHF with and without hypoperfusion groups.Of the entire study cohort, 1073 patients (19%) had CHF with hypoperfusion (i.e. the wet–cold pattern). In-hospital mortality was significantly higher for CHF patients with than without hypoperfusion (log-rank, P < 0.001). The rate of tolvaptan use did not differ significantly between CHF patients with and without hypoperfusion (15% vs. 14%, respectively; P = 0.7848). In the propensity-matched CHF with hypoperfusion cohort, there was a significant association between the use of tolvaptan and a reduction in in-hospital mortality (log-rank, P = 0.0052). Conversely, in the matched CHF without hypoperfusion cohort, tolvaptan use was not associated with in-hospital mortality (log-rank, P = 0.4417).There was a significant association between the use of tolvaptan and a reduction in in-hospital mortality in CHF patients with, but not without, hypoperfusion. These findings hint at possible individualized therapies for patients with CHF.Methods: This study investigated whether the oral vasopressin V2 receptor antagonist tolvaptan has beneficial effects on mortality in real-world congestive heart failure (CHF) patients with hypoperfusion (i.e. the wet–cold pattern), from the viewpoint of cardiorenal syndrome.Data on 5511 consecutive CHF patients were extracted from the Tokyo CCU Network data registry. Congestion and hypoperfusion were defined by Nohria–Stevenson clinical profiles at the time of hospitalization. Propensity scores for tolvaptan use were calculated for each patient and used to assemble two matched cohorts of patients receiving tolvaptan or not in the CHF with and without hypoperfusion groups.Of the entire study cohort, 1073 patients (19%) had CHF with hypoperfusion (i.e. the wet–cold pattern). In-hospital mortality was significantly higher for CHF patients with than without hypoperfusion (log-rank, P < 0.001). The rate of tolvaptan use did not differ significantly between CHF patients with and without hypoperfusion (15% vs. 14%, respectively; P = 0.7848). In the propensity-matched CHF with hypoperfusion cohort, there was a significant association between the use of tolvaptan and a reduction in in-hospital mortality (log-rank, P = 0.0052). Conversely, in the matched CHF without hypoperfusion cohort, tolvaptan use was not associated with in-hospital mortality (log-rank, P = 0.4417).There was a significant association between the use of tolvaptan and a reduction in in-hospital mortality in CHF patients with, but not without, hypoperfusion. These findings hint at possible individualized therapies for patients with CHF.Results: This study investigated whether the oral vasopressin V2 receptor antagonist tolvaptan has beneficial effects on mortality in real-world congestive heart failure (CHF) patients with hypoperfusion (i.e. the wet–cold pattern), from the viewpoint of cardiorenal syndrome.Data on 5511 consecutive CHF patients were extracted from the Tokyo CCU Network data registry. Congestion and hypoperfusion were defined by Nohria–Stevenson clinical profiles at the time of hospitalization. Propensity scores for tolvaptan use were calculated for each patient and used to assemble two matched cohorts of patients receiving tolvaptan or not in the CHF with and without hypoperfusion groups.Of the entire study cohort, 1073 patients (19%) had CHF with hypoperfusion (i.e. the wet–cold pattern). In-hospital mortality was significantly higher for CHF patients with than without hypoperfusion (log-rank, P < 0.001). The rate of tolvaptan use did not differ significantly between CHF patients with and without hypoperfusion (15% vs. 14%, respectively; P = 0.7848). In the propensity-matched CHF with hypoperfusion cohort, there was a significant association between the use of tolvaptan and a reduction in in-hospital mortality (log-rank, P = 0.0052). Conversely, in the matched CHF without hypoperfusion cohort, tolvaptan use was not associated with in-hospital mortality (log-rank, P = 0.4417).There was a significant association between the use of tolvaptan and a reduction in in-hospital mortality in CHF patients with, but not without, hypoperfusion. These findings hint at possible individualized therapies for patients with CHF.Conclusion: This study investigated whether the oral vasopressin V2 receptor antagonist tolvaptan has beneficial effects on mortality in real-world congestive heart failure (CHF) patients with hypoperfusion (i.e. the wet–cold pattern), from the viewpoint of cardiorenal syndrome.Data on 5511 consecutive CHF patients were extracted from the Tokyo CCU Network data registry. Congestion and hypoperfusion were defined by Nohria–Stevenson clinical profiles at the time of hospitalization. Propensity scores for tolvaptan use were calculated for each patient and used to assemble two matched cohorts of patients receiving tolvaptan or not in the CHF with and without hypoperfusion groups.Of the entire study cohort, 1073 patients (19%) had CHF with hypoperfusion (i.e. the wet–cold pattern). In-hospital mortality was significantly higher for CHF patients with than without hypoperfusion (log-rank, P < 0.001). The rate of tolvaptan use did not differ significantly between CHF patients with and without hypoperfusion (15% vs. 14%, respectively; P = 0.7848). In the propensity-matched CHF with hypoperfusion cohort, there was a significant association between the use of tolvaptan and a reduction in in-hospital mortality (log-rank, P = 0.0052). Conversely, in the matched CHF without hypoperfusion cohort, tolvaptan use was not associated with in-hospital mortality (log-rank, P = 0.4417).There was a significant association between the use of tolvaptan and a reduction in in-hospital mortality in CHF patients with, but not without, hypoperfusion. These findings hint at possible individualized therapies for patients with CHF. [ABSTRACT FROM AUTHOR]

In recent years, most molecular target drugs have been administered orally, as prescribed at ambulatory services in hospitals and at patients’ homes. Telephone follow-up is increasingly being used in clinical practice for patients needing additional support post-discharge and for the prevention of hospital readmissions. The purpose of this study was to clarify the clinical benefits of telephone follow-up while administering oral anticancer drugs.This was a single-center, observational, retrospective study. We evaluated hepatocellular carcinoma patients who received sorafenib or lenvatinib between March 2010 and February 2018. The primary endpoint was the incidence of adverse events.From the total of 130 patients, 83 patients received telephone follow-up and 47 did not. The incidence of hand–foot skin reactions significantly reduced in patients with telephone follow-up (odds ratio (OR) 3.69, 95% confidence interval (CI) 1.16–11.8, p = 0.020). The median durations (ranges) of adherence to oral chemotherapy were 259 days (15−1730) for the telephone follow-up group and 121 days (14−1105) for the no-telephone follow-up group (p < 0.001). Moreover, the disease control rate was significantly higher in the telephone follow-up group (OR 2.52, 95% CI 1.15–5.53, p = 0.020).Remote interventions, such as telephone follow-up, are useful means of managing adverse events in patients receiving oral anticancer drugs and can lead to improved treatment results. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) hemorrhaging/rupture is a rare adverse effect of lenvatinib, and only limited pathological examinations have been reported. This report presents the case of a 69-year-old man who suffered from cardiac arrest and died 7 days after starting lenvatinib treatment for HCC, with an autopsy subsequently performed. Crack and coagulated blood were observed in the largest tumor. Pathologically, the hemorrhaging area was scattered in nearly all of the HCC lesions, regardless of tumor differentiation. This pathological feature is unusual in normal HCC. Thus, it is believed to have been the effect of lenvatinib.

Objective: Herein, we report a case of a patient with recurrent breast cancer who was diagnosed antemortem with pulmonary tumor thrombotic microangiopathy (PTTM) using wedge aspiration cytology of the pulmonary artery after breast cancer surgery., Case Summary: The patient was a 50-year-old woman who underwent mastectomy and axillary lymph node dissection for stage IIIA (T3N2M0) triple-negative left breast cancer. Postoperative follow-up was performed with radiotherapy and anticancer chemotherapy. Seventeen months after the surgery, the patient was hospitalized for right heart failure and diagnosed with pulmonary arterial hypertension. The patient was diagnosed with PTTM following the detection of malignant cells in the pulmonary artery using wedge aspiration cytology. Anti-pulmonary hypertension therapy was administered; however, the patient did not respond and died 26 days after admission. Autopsy revealed multiple microscopic tumor emboli in the pulmonary artery. In portions of the pulmonary artery without embolization, fibro-cellular intimal hyperplasia and stenosis were observed. Tumor embolism was expressed for CK7+/CK20-, consistent with the primary breast cancer., Discussion: Since the primary pathophysiology of PTTM entails narrowing due to fibro-cellular intimal hyperplasia rather than multiple tumor thrombi, the efficacy of chemotherapy combined with vasodilators is discussed.

The hydrostatic pressure dependent evolution of the electronic and magnetic structure of LaCo 5 and YCo 5 was investigated by means of x-ray emission spectroscopy, x-ray diffraction, and spin-polarized density functional theory (DFT) calculations. Using experimental lattice parameters the DFT correctly predicts the pressure of the magnetic transition in both compounds to be 26 GPa (La) and 22-23 GPa (Y). The transition was experimentally resolved in the changes of the electronic structure via the integrated absolute difference of the Co Kβ emission spectra. Comparison of theory and experiment confirm for the first time a common feature in both LaCo 5 and YCo 5 to be the source of the transition; the Fermi-level crossing of an up-spin polarized flat band driving the systems into a low spin configuration via a Lifshitz type transition of the Fermi surface. Another phase transition observed around 12 GPa in LaCo 5 was clarified to be caused by the change in the down-spin density of states at the Fermi level., (© 2022 IOP Publishing Ltd.)

Objectives: The transradial approach (TRA) is recommended in coronary catheterization due to the lower rate of bleeding complications compared with the transfemoral approach. However, a disadvantage of TRA is difficulty in puncturing under palpation of the radial pulse alone without arterial visibility. To overcome this limitation, a vessel visualization device using near-infrared rays, Art View (Forte Grow Medical Company), was used in the puncture of the radial artery (RA)., Methods: Patients who underwent coronary angiography via the right RA with Art View were retrospectively surveyed. According to the quality of RA visibility, the performance of the Art View was rated as follows: 5 = excellent; 4 = good; 3 = fair; 2 = not good; and 1 = poor. The primary endpoint was the procedural success of TRA using the Art View device. The secondary endpoints were procedural time (from injection of local anesthesia to successful crossing of the guidewire attached to the sheath), number of RA punctures, and change of puncture method or approach site., Results: The Art View device was used in 38 patients (mean age, 71 ± 11 years). Puncturing of the visualized RA was successful in 30 patients (79.0%). Among successful cases, the mean procedural time was 142 ± 87 seconds. The success rates of each visualization evaluation were 100%, 100%, 84.6%, 33.3%, and 0% from grades 5 to 1, respectively (P<.01). The mean procedural times were 92 ± 18 seconds, 102 ± 58 seconds, 180 ± 75 seconds, 306 ± 80 seconds, and not available from grades 5 to 1, respectively (P<.01)., Conclusion: The Art View RA visualization device is useful for RA puncture.

We examine electronic and crystal structures of iron-based superconductors Ln FeAsO 1- x H x ( Ln = La, Sm) under pressure by means of x-ray absorption spectroscopy (XAS), x-ray emission spectroscopy (XES), and x-ray diffraction. In LaFeAsO the pre-edge peak on high-resolution XAS at the Fe- K absorption edge gains in intensity on the application of pressure up to 5.7 GPa and it saturates in the higher pressure region. We found integrated-absolute difference values on XES for Ln = La, corresponding to a spin state, decline on the application of pressure, and then it is minimized when the T c approaches the maximum at around 5 GPa. In contrast, such the optimum value was not detected for Ln = Sm. We reveal that the superconductivity is closely related to the lower spin state for Ln = La unlike Sm case. We observed that As height from the Fe basal plane and As-Fe-As angle on the FeAs 4 tetrahedron for Ln = La deviate from the optimum values of the regular tetrahedron in superconducting (SC) phase, which has been widely accepted structural guide to SC thus far. In contrast, the structural parameters were held near the optimum values up to ∼15 GPa for Ln = Sm., (© 2021 IOP Publishing Ltd.)

A carrier doping by a hydrogen substitution in LaFeAsO 1- x H x is known to cause two superconducting (SC) domes with the magnetic order at both end sides of the doping. In contrast, SmFeAsO 1- x H x has a similar phase diagram but shows single SC dome. Here, we investigated the electronic and crystal structures for iron oxynitride Ln FeAsO 1- x H x ( Ln = La, Sm) with the range of x = 0-0.5 by using x-ray absorption spectroscopy, x-ray emission spectroscopy, and x-ray diffraction. For both compounds, we observed that the pre-edge peaks of x-ray absorption spectra near the Fe- K edge were reduced in intensity on doping. The character arises from the weaker As-Fe hybridization with the longer As-Fe distance in the higher doped region. We can reproduce the spectra near the Fe- K edge according to the Anderson impurity model with realistic valence structures using the local-density approximation (LDA) plus dynamical mean-field theory (DMFT). For Ln = Sm, the integrated-absolute difference (IAD) analysis from x-ray Fe- Kβ emission spectra increases significantly. This is attributed to the enhancement of magnetic moment of Fe 3 d electrons stemming from the localized picture in the higher doped region. A theoretical simulation implementing the self-consistent vertex-correction method reveals that the single dome superconducting phase for Ln = Sm arises from a better nesting condition in comparison with Ln = La., (© 2021 IOP Publishing Ltd.)

Background: The absence of high quality, large-scale data that indicates definitive mortality benefits does not allow for firm conclusions on the role of intravenous vasodilators in acute heart failure. We aimed to investigate the associations between intravenous vasodilators and clinical outcomes in acute heart failure patients, with a specific focus on patient profiles and type of vasodilators., Methods: Data of 26,212 consecutive patients urgently hospitalised for a primary diagnosis of acute heart failure between 2009 and 2015 were extracted from a government-funded multicentre data registration system. Propensity scores were calculated with multiple imputations and 1:1 matching performed between patients with and without vasodilator use. The primary endpoint was inhospital mortality., Results: On direct comparison of the vasodilator and non-vasodilator groups after propensity score matching, there were no significant differences in the inhospital mortality rates (7.5% vs. 8.8%, respectively; P =0.098) or length of intensive/cardiovascular care unit stay and hospital stay between the two groups. However, there was a substantial difference in baseline systolic blood pressure by vasodilator type; favourable impacts of vasodilator use on inhospital mortality were observed among patients who had higher systolic blood pressures and those who had no atrial fibrillation on admission. Furthermore, when compared to nitrates, the use of carperitide (natriuretic peptide agent) was significantly associated with worse outcomes, especially in patients with intermediate systolic blood pressures., Conclusions: In acute heart failure patients, vasodilator use was not universally associated with improved inhospital outcomes; rather, its effect depended on individual clinical presentation: patients with higher systolic blood pressure and no atrial fibrillation seemed to benefit maximally from vasodilators., Trial Registration: UMIN-CTR identifier, UMIN000013128.

Background: The Japan Society of Hepatology guidelines indicate that hepatitis C virus (HCV) protease inhibitor combination therapy with simeprevir (SMV), pegylated-interferon (Peg-IFN), and ribavirin (RBV) is a therapeutic option for patients who fail to respond to a direct direct-acting antiviral-containing regimen. However, treatment outcomes have room for improvement. Fluvastatin (FLV) add-on treatment in Peg-IFN and RBV combination therapy for HCV-infected patients significantly improved the sustained virologic response (SVR), but the add-on effect of FLV on SMV combination therapy is not well understood., Methods: This was a prospective, randomized, multicenter study in which a total of 61 HCV genotype 1b-infected patients were recruited and 60 eligible patients were randomly allocated to two groups that received 12 weeks of SMV/Peg-IFN/RBV followed by 12 weeks of Peg-IFN/RBV with or without 24 weeks of FLV. The SVR rate and adverse events were compared between the two groups., Results: Thirty-one patients were allocated to the FLV add-on group and 29 patients were allocated to the control group. Baseline clinical factors, including median age, baseline platelet count, alanine aminotransferase level, HCV RNA titer, Fibrosis-4 index, and rate of IL28B minor genotype, were all similar between the two groups. The rapid virologic response, end-of-treatment response rates, SVR rates at 24 weeks after treatment, and safety profiles were also similar between the two groups., Conclusions: This prospective, randomized, multicenter study indicated that FLV had no add-on effect when given with SMV/Peg-IFN/RBV combination therapy for genotype 1b HCV-infected patients., (© 2017 The Japan Society of Hepatology.)

A 50-year-old woman was diagnosed with dermatomyositis at the department of neurology in our hospital; she then received steroid pulse therapy. A positron emission computed tomography(PET-CT)revealed swollen lymph nodes near the aorta and in the left inguinal region. She presented at our institution for examination to determine the cause of her lymphadenopathy, but the primary site of the carcinoma was unknown. A histopathological examination of the lymph node specimen obtained using endoscopic ultrasonography-guided fine-needle aspiration(EUS-FNA)revealed a moderately to poorly differentiated adenocarcinoma. The patient underwent lymphadenectomy. After the surgery, a new lymph node metastasis appeared in the lower abdomen. We initiated a combination treatment with chemotherapy and radiotherapy. The patient died because of disease progression 31 months after her first visit.

We diagnosed distal cholangiocarcinoma in a 76-year-old woman who was then treated by subtotal stomach-preserving pancreaticoduodenectomy. Histopathological examination revealed a well-differentiated tubular adenocarcinoma on the side of the bile duct, and a neuroendocrine carcinoma in an area outside the bile duct where the tumor had infiltrated. Immunohistochemical staining identified homology between cytokeratins and MUC, indicating a similar origin. This report discusses problems associated with diagnosis and treatment by summarizing 22 patients who underwent curative resection and subsequently had a confirmed prognosis.

Background: Hepatitis C virus (HCV) infection is common in hemodialysis patients and worsens their prognosis, while antiviral therapy options are limited. Recently, clinical trial and real-world, small-scale studies have reported excellent responses to direct-acting antivirals in patients with advanced chronic kidney diseases. However, real-world, large-scale data were lacking. This large multicenter analysis included HCV-infected hemodialysis patients receiving combination therapy with a nonstructural protein 5A (NS5A) inhibitor, daclatasvir (DCV), and a protease inhibitor, asunaprevir (ASV)., Methods: Twenty-three centers in Japan participated in this study of 123 hemodialysis patients with genotype 1 HCV infection, who received DCV/ASV combination therapy between November 2014 and March 2016. We collected and analyzed data relating to treatment outcome, baseline clinical information, laboratory measurements (during and after the treatment), and adverse events., Results: Thirty-nine patients (31.7%) had advanced liver fibrosis, 12 (9.8%) had histories of hepatocellular carcinoma (HCC), and 18 (14.6%) had baseline resistance-associated variants (RAVs) of NS5A. The overall sustained virological response (SVR)12 rate was 95.9% (118/123). Notably, all patients with HCC and 94.4% (17/18) of those with NS5A RAVs achieved SVR12. Significant factors associated with non-SVR were advanced fibrosis and the interleukin-28B non-TT genotype at rs8099917. Four patients (3.3%) discontinued therapy because of adverse events including elevated serum alanine transaminase levels (n = 2), rash (n = 1), and HCC (n = 1); all of these achieved SVR12., Conclusions: This real-world, nationwide study revealed that DCV/ASV combination therapy was safe and highly effective for hemodialysis patients with genotype 1 HCV infections. This study was registered at the UMIN Clinical Trials Registry (UMIN000024227).

The purpose of this study is to study the usefulness of post-remission antiviral therapy in cases of HCV-RNA-positive diffuse large-cell lymphoma. Antiviral therapy against HCV was performed after remission using CHOP or CHOP-like chemotherapy in combination with rituximab in five successive cases of HCV-RNA-positive diffuse large-cell lymphoma. The control groups consisted of a group of HCV-RNA-positive diffuse large-cell lymphoma cases prior to this trial (control 1), and a group of cases that tested negative for HIV, HCV, and HBV (control 2). All the cases were in remission at the time of initial treatment. There were no significant differences between the three groups in terms of age, sex, treatment, stage, or International Prognosis Index (IPI). When HCV antiviral therapy was performed after treatment for diffuse large-cell lymphoma, we observed no recurrence or deaths, and the 2-year overall survival and progression-free survival rates were significantly greater than those in the control 1 group (P = 0.0246). It is possible that a better prognosis can be achieved by performing HCV antiviral therapy after achieving remission in cases of HCV-RNA-positive diffuse large-cell lymphoma through the use of R-CHOP or similar treatments.

Aim: Hepatitis C virus (HCV) infection is a risk factor for end-stage renal disease, renal graft failure, and hemodialysis patient mortality. However, the efficacy of direct-acting antiviral therapy for HCV-infected patients with renal impairment is unclear. Additionally, the promising NS5B inhibitor sofosbuvir has not been recommended for patients with severe renal impairment. In this prospective, multicenter study, we evaluated the efficacy and safety of daclatasvir and asunaprevir combination therapy, with a focus on patients with renal impairment., Methods: The study included 322 genotype 1 HCV-infected patients who received daclatasvir and asunaprevir combination therapy. The safety and sustained virological response was examined at 12 weeks after the end of treatment and safety was evaluated according to renal function., Results: Of 322 patients, 5% (16/322) and 2.5% (8/322) had chronic kidney disease stage G3b (estimated glomerular filtration rate [eGFR], 30-44 mL/min/1.73 m 2 ) and stage G4/5 (eGFR, 15-29/<15 mL/min/1.73 m 2 ), respectively. Baseline presence of the NS5A resistance-associated variant, previous simeprevir treatment, and HCV RNA titers, which were predictors of a sustained viral response, were similar between patients with eGFR <45 mL/min/1.73 m 2 and eGFR >45 mL/min/1.73 m 2 . Notably, the 12-week sustained viral response rate was comparable in patients with eGFR <45 mL/min/1.73 m 2 (100%, 24/24) and those with eGFR >45 mL/min/1.73 m 2 (88.9%, 265/298; P = 0.07). Treatment discontinuation rates and adverse events, including alanine aminotransferase elevation, anemia, and renal disorders, were similar between the two groups., Conclusion: Daclatasvir and asunaprevir combination therapy for patients with renal dysfunction was highly effective and safe., (© 2016 The Japan Society of Hepatology.)

Background: The optimal retreatment regimen for patients with hepatitis C virus (HCV) infection who failed interferon-free, direct-acting antiviral (DAA) therapy is undetermined. In this study, we aimed to evaluate the efficacy and safety of 12-week retreatment with ledipasvir (LDV) and sofosbuvir (SOF) with add-on ribavirin (RBV) for patients who previously failed to respond to HCV-NS5A inhibitor, daclatasvir (DCV), and HCV-NS3 inhibitor, asunaprevir (ASV), therapy., Methods: This multicenter, prospective study enrolled 15 patients with genotype-1 HCV infection who failed DCV/ASV combination therapy. They were retreated with SOF, LDV, and RBV for 12 weeks and underwent physical examinations and blood tests at baseline, during treatment, and after therapy. At baseline and relapse, NS3/NS5A and NS5B resistance-associated variants (RAVs) were evaluated., Results: Of the 15 enrolled patients, 73.3% (11/15), 86.7% (13/15), and 0% (0/15) had RAVs in NS3 D168A/V/T/E, NS5A L31I/M/F/V plus Y93H, and NS5B S282T, respectively. Overall, 86.7% (13/15) of patients achieved a sustained viral response, and all patients completed therapy. No patients experienced severe adverse events. Two patients who failed to respond to SOF, LDV, and RBV combination therapy were elderly women, had the IL28B non-TT genotype, and NS5A RAVs in L31I/Y93H or NS5A A92 K at baseline., Conclusions: This study revealed that SOF, LDV, and RBV combination therapy was effective and well-tolerated for patients with genotype-1 HCV infection who failed DCV and ASV combination therapy. Thus, RBV added to DAA therapy for difficult-to-treat patients might improve treatment outcomes.

Background and Aims: Sorafenib is the first molecular targeted drug approved for the treatment of advanced hepatocellular carcinoma (HCC) and is a potent small molecule inhibitor of multiple kinases. Combination therapy with sorafenib and other cytotoxic agents for HCC may result in additive anticancer activity. The purpose of this phase I study was to investigate the safety and tolerability of combination therapy with sorafenib and 5-fluorouracil (5-FU) and to determine the optimum dose of 5-FU for a phase II trial., Methods: This phase I study used a conventional 3 + 3 dose-escalation design. The primary endpoint was to determine the maximum tolerated dose (MTD) of 5-FU in combination with sorafenib and to determine the recommended dosage (RD) for phase II. The secondary endpoints evaluated were toxicity and the tumor response rate. All patients received 800 mg of sorafenib daily and three different dosages of 5-FU (250, 350, and 450 mg/m 2 /day) for 20 days by intravenous infusion in 1 month as one cycle., Results: Twelve patients with advanced HCC were evaluated. The MTD of 5-FU in combination with sorafenib was 450 mg/m 2 /day, and 350 mg/m 2 /day was selected as the RD for a phase II study. Thrombocytopenia, stomatitis, and hand-foot skin reaction were observed as grade 3 adverse events. Nine patients achieved stable disease (75%), and three patients (25%) were judged to have progressive disease. The disease control rate was 75%., Conclusions: Combination therapy with sorafenib and 5-FU appears to be well tolerated and may have the potential to be an option for advanced HCC.

A pressure-induced anomalous valence crossover without structural phase transition is observed in archetypal cubic YbCu 5 based heavy Fermion systems. The Yb valence is found to decrease with increasing pressure, indicating a pressure-induced crossover from a localized 4f 13 state to the valence fluctuation regime, which is not expected for Yb systems with conventional c-f hybridization. This result further highlights the remarkable singularity of the valence behavior in compressed YbCu 5 -based compounds. The intermetallics Yb 2 Pd 2 Sn, which shows two quantum critical points (QCP) under pressure and has been proposed as a potential candidate for a reentrant Yb 2+ state at high pressure, was also studied for comparison. In this compound, the Yb valence monotonically increases with pressure, disproving a scenario of a reentrant non-magnetic Yb 2+ state at the second QCP.

Obesity is known to be associated with the development of heart failure (HF). However, the relationship between the body mass index (BMI) and acute HF (AHF) remains to be elucidated. Eight hundred and eight AHF patients were enrolled in this study. The patients were assigned to four groups according to their BMI values: severely thin (n = 11, BMI <16), normal/underweight (n = 579, 16 ≤ BMI <25), overweight (n = 178, 25 ≤ BMI <30) and obese (n = 40, BMI ≥30). The patients in the severely thin group were more likely to be female, have systolic blood pressure (SBP) <100 mmHg and have valvular disease than normal/underweight patients. The patients in the overweight group were significantly younger than those in the normal/underweight, and those in the overweight group were more likely to have SBP ≥140 mmHg and hypertensive heart disease and less likely to have valvular disease than the patients in the normal/underweight group. The prognosis, including all-cause death, was significantly poorer among patients who were severely thin than those who were normal/underweight, overweight and significantly better among those who were overweight than those who were normal/underweight, severely thin and obese patients. A multivariate Cox regression model identified that severely thin [HR: 3.372, 95% confidence interval (CI) 1.362-8.351] and overweight (HR: 0.615, 95% CI 0.391-0.966) were independent predictors of 910-day mortality as the reference of normal/underweight. Overweight patients tended to have SBP ≥140 mmHg and be relatively young, while severely thin patients tended to have SBP <100 mmHg and be female. These factors were associated with a better prognosis of overweight patients and adverse outcomes in severely thin patients. These factors may contribute to the "obesity paradox" in severely decompensated AHF patients.

Atherosclerosis induces the elevation of uric acid (UA), and an elevated UA level is well known to lead to a poor prognosis in patients with acute heart failure (AHF). However, the prognostic value of atherosclerotic risk factors in hyperuricemic AHF patients remains to be elucidated. The data from 928 patients who were admitted to the intensive care unit (ICU) at Nippon Medical School Chiba Hokusoh Hospital between January 2001 and December 2014, and whose serum UA levels were measured were screened. A total of 394 AHF patients with hyperuricemia were enrolled in this study. The patients were assigned to a low-risk group (≤1 atherosclerosis risk factor) and a high-risk group (≥2 atherosclerosis risk factors) according to their number of risk factors. The patients in the low-risk group were more likely to have dilated cardiomyopathy, clinical scenario 3 than those in the high-risk group. The serum total bilirubin, blood urea nitrogen, C-reactive protein, and brain-type natriuretic peptide levels were significantly higher in the low-risk group than the high-risk group (p < 0.001, p = 0.005, p = 0.003, and p = 0.008, respectively). A multivariate Cox regression model revealed that the number of risk factors (number = 1, HR (hazard ratio) 0.243, 95 % CI 0.096-0.618, p = 0.003; number = 2, HR 0.253, 95 % CI 0.108-0.593, p = 0.002; number ≥3, HR 0.209, 95 % CI 0.093-0.472, p < 0.001), eGFR (per 1.0 mmol/l increase) (HR 0.977, 95 % CI 0.961-0.994, p = 0.007), and serum UA level (per 1 mg/dl increase) (HR 1.270, 95 % CI 1.123-1.435, p < 0.001) was an independent predictor of 1-year mortality. The prognosis, including all-cause death and HF events, was significantly poorer among the low-risk patients than among the high-risk patients. Atherosclerotic risk factors were not associated with a poor prognosis in patients with hyperuricemic AHF.

A 64-year-old woman was diagnosed with unresectable pancreatic cancer and underwent chemotherapy. However, the number of leukocytes significantly increased as the disease progressed. Serum G-CSF values also increased, and she eventually died on day 511 after diagnosis. Immediately after autopsy, immunohistochemical staining with an anti-G-CSF monoclonal antibody was positive in the poorly differentiated adenocarcinoma area of the primary pancreatic cancer and liver metastatic foci, but negative in the well-differentiated tubular adenocarcinoma part of the primary pancreatic cancer. During de-differentiation, invasive pancreatic ductal carcinoma appeared to have changed to a tumor that produced G-CSF.

Pressure dependence of the electronic and crystal structures of KxFe2-ySe2, which has pressure-induced two superconducting domes of SC I and SC II, was investigated by x-ray emission spectroscopy and diffraction. X-ray diffraction data show that compressibility along the c-axis changes around 12 GPa, where a new superconducting phase of SC II appears. This suggests a possible tetragonal to collapsed tetragonal phase transition. X-ray emission spectroscopy data also shows the change in the electronic structure around 12 GPa. These results can be explained by the scenario that the two SC domes under pressure originate from the change of Fermi surface topology. Our results here show the pronounced increase of the density of states near the Fermi surface under pressure with a structural phase transition, which can help address our fundamental understanding for the appearance of the SC II phase.

Background/aim: Intrahepatic cholangiocarcinoma (ICC) is one of the most aggressive malignant tumours, so the identification of molecular targets for ICC is an important issue. Zinc finger E-box binding homeobox 1 (ZEB1) is a key inducer of epithelial-mesenchymal transition (EMT). The aim of the present study was to clarify the clinical significance of ZEB1 in ICC and the associations between ZEB1 expression and EMT-related proteins., Methods: We immunohistochemically examined the expression of EMT-related proteins, namely ZEB1, vimentin and E-cadherin, in ICC specimens from 102 patients. The clinicopathological and prognostic values of these markers were evaluated., Results: ZEB1 and vimentin were expressed in 46.1% and 43.1% of tumours, respectively, and E-cadherin expression was lost in 44.1% of tumours. ZEB1 expression showed a significant inverse correlation with E-cadherin expression (p=0.004) and a positive correlation with vimentin expression (p=0.022). Altered expression of ZEB1 was associated with aggressive tumour characteristics, including advanced tumour stage (p=0.037), undifferentiated-type histology (p=0.017), lymph node metastasis (p=0.024) and portal vein invasion (p=0.037). Moreover, overall survival rates were significantly lower for patients with high ZEB1 expression than for patients with low ZEB1 expression (p=0.027). Kaplan-Meier analysis also identified E-cadherin expression (p=0.041) and vimentin expression (p=0.049) as prognostic indicators for overall survival., Conclusions: ZEB1 expression is associated with tumour progression and poor prognosis in patients with ICC through positive correlations with vimentin and negative correlations with E-cadherin. ZEB1 expression is associated with a poor prognosis and might be an attractive target for the treatment of ICC., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Background: HCV infection in chronic hemodialysis patients is high, has a poor prognosis and high risk of renal graft failure, and requires nosocomial infection control measures. However, options of anti-HCV therapy in such patients are limited and unsatisfactory. In this study, we report effectiveness and safety of HCV-NS5A-inhibitor daclatasvir (DCV) and protease-inhibitor asunaprevir (ASV) combination therapy for hemodialysis patients with HCV infection., Methods: This study was registered at the UMIN Clinical Trials Registry as UMIN000016355. Thirty-four dialysis patients were treated with DCV/ASV combination therapy between January 2015 and November 2015. Of those, 21 patients who were followed more than 12 weeks after treatment ended were included. We evaluated the 12-week sustained virologic response (SVR12) and adverse events during treatment., Results: Of the 21 patients, four had compensated liver cirrhosis and three had resistance-associated variant of NS5A (NS5A RAVs)-Y93H at baseline. Overall, total of 95.5 % (20/21) of the patients achieved SVR12. Of note, all patients with cirrhosis or NS5A RAVs achieved SVR12. One relapser patient at 4 weeks post-treatment had NS3 D168E RAVs at baseline. A total of 20 patients (95.5 %) completed the 24-week therapy. One patient discontinued treatment at week 12 due to ALT elevations and achieved SVR12., Conclusions: DAV and ASV combination therapy for chronic hemodialysis patients with HCV infection was highly effective and well tolerated, even in elderly patients and patients with liver cirrhosis and NS5A-RAVs.

A 61-year-old man was admitted to our hospital with extreme weight loss. Abdominal ultrasonography revealed an 8-cm tumor of the pancreatic head. Further investigation revealed orbital, pulmonary, pancreatic, colonic, and bone marrow lesions. A histopathological examination of the pancreatic tumor specimen obtained using endoscopic ultrasound-guided fine-needle aspiration revealed mucosa-associated lymphoid tissue (MALT) lymphoma. Monoclonal rearrangement of immunoglobulin heavy chain was found in the pulmonary, pancreatic, colonic, and bone marrow lesions. We diagnosed multi-organ disseminated MALT lymphoma, with the largest lesion located in the pancreatic head. Chemo-radiation therapy resulted in complete remission.

A 66-year-old female, under regular follow-up for 20 years after aortic valve replacement (19-mm Carbomedics), presented dyspnea on effort and hypotension during hemodialysis. A transthoracic echocardiogram showed elevation of transvalvular velocity up to 4 m/s, but the structure around the aortic prosthesis was difficult to observe due to artifacts. Fluoroscopy revealed normal motion of the leaflets of the mechanical valve. Intracardiac echocardiography (ICE) revealed a pannus-like structure in the left ventricular outflow tract. Transesophageal echocardiogram also revealed this structure. ICE can visualize structural abnormalities around a prosthetic valve after cardiac surgery even in patients in whom conventional imaging modalities failed.

A 73-year-old man with a hepatocellular carcinoma was admitted to our hospital. He suffered from recurrent severe hypoglycemia. An autopsy was performed after his death. Anti-insulin-like growth factor II (IGF-II) monoclonal antibody immunostaining of the hepatocellular carcinoma was positive. Western immunoblot analysis of the serum revealed highly elevated IGF-II. Therefore, we diagnosed this case as a non-islet cell tumor hypoglycemia caused by a big IGF-II-producing hepatocellular carcinoma.

Rituximab is currently used not only in the treatment of B-cell lymphoma but also for various other diseases, including autoimmune diseases, post-transplant graft vs host disease, and rejection following kidney transplants. Due to rituximab's widespread use, great progress has been made regarding research into complications that arise from its use, one of the most serious being the reactivation of hepatitis B virus (HBV), and efforts continue to establish guidelines for preventive treatment against this occurrence. This report discusses preventive measures against rituximab-induced HBV reactivation and future objectives.

Aim: Telaprevir-based therapy for chronic hepatitis C patients is effective; however, the high prevalence of dermatological reactions is an outstanding issue. The mechanism and characteristics of such adverse reactions are unclear; moreover, predictive factors remain unknown. Granulysin was recently reported to be upregulated in the blisters of patients with Stevens-Johnson syndrome (SJS). Therefore, we investigated the risk factors for severe telaprevir-induced dermatological reactions as well as the association between serum granulysin levels and the severity of such reactions., Methods: A total of 89 patients who received telaprevir-based therapy and had complete clinical information were analyzed. We analyzed the associations between dermatological reactions and clinical factors. Next, we investigated the time-dependent changes in serum granulysin levels in five and 14 patients with grade 3 and non-grade 3 dermatological reactions, respectively., Results: Of the 89 patients, 57 patients had dermatological reactions, including nine patients with grade 3. Univariate analysis revealed that grade 3 dermatological reactions were significantly associated with male sex. Moreover, serum granulysin levels were significantly associated with the severity of dermatological reactions. Three patients with grade 3 dermatological reaction had severe systemic manifestations including SJS, drug-induced hypersensitivity syndrome, and systemic lymphoid swelling and high-grade fever; all were hospitalized. Importantly, among the three patients, two patients' serum granulysin levels exceeded 8 ng/mL at onset and symptoms deteriorated within 6 days., Conclusion: Male patients are at high risk for severe telaprevir-induced dermatological reactions. Moreover, serum granulysin levels are significantly associated with the severity of dermatological reactions and may be a predictive factor in patients treated with telaprevir-based therapy., (© 2014 The Japan Society of Hepatology.)

There have been few reports discussing the clinical significance of the season of admission of acute heart failure (AHF) patients. The data of 661 patients with AHF admitted to the intensive care unit were analyzed. Patients were assigned to a summer admission (Group-S, n = 113, between July and September), a winter admission (Group-W, n = 214, between December and February), or to the other seasons admission group (Group-O, n = 334). We evaluated the relationships between the seasonal variations and the clinical profiles, and the long-term prognosis. There were significantly more patients with cardiomyopathy and New York Heart Association class 4, and the serum levels of total bilirubin were significantly higher in Group-S (85.8, 24.8 %, and 0.60 [0.50-0.90]) than in Group-W (75.2, 15.4 %, and 0.60 [0.40-0.78]). The left ventricular ejection fraction on admission was significantly reduced and intravenous administration of dobutamine was used more frequently in Group-S (30.0 [25.0-46.0], 31.9 %) than in Group-W (34.4 [25.2-48.0], 20.6 %) and Group-O (35.0 [25.0-46.0], 19.8 %). The multivariate Cox regression model found that summer admission was independently associated with cardiovascular death (HR: 1.58, 95 % CI 1.01-2.48; p = 0.044) and heart failure (HF) events (HR: 1.55, 95 % CI 1.05-2.28; p = 0.028). The Kaplan-Meier curves showed that the cardiovascular death rate was significantly higher in Group-S than in Group-W and Group-O, and the HF events were significantly higher in Group-S than in Group-O. The summer admission AHF patients included sicker patients, and the prognosis in these patients was worse than in the patients admitted at other times.

Background: Different mechanisms of acute kidney injury (AKI) may exist for acute heart failure (AHF) patients compared with other patients., Methods and Results: We analyzed data from 282 patients with AHF. The biomarkers were measured within 30 min of admission. Patients were assigned to a no-AKI (n=213) or AKI group (Class R (n=49), Class I (n=15) or Class F (n=5)) using the RIFLE classifications on admission. We evaluated the relationships between the biomarkers and AKI, in-hospital mortality, all-cause death and HF events (HF re-admission, all-cause death) within 90 days. The serum heart-type fatty acid-binding protein (s-HFABP) levels were significantly higher in the AKI than in the no-AKI group, and the predictive biomarker for AKI was s-HFABP (odds ratio: 6.709; 95% confidence interval: 3.362-13.391). s-HFABP demonstrated an optimal balance between sensitivity and specificity (71.0%, 79.3%; area under the receiver-operating characteristic curve [AUC]=0.790) at 22.8 ng/ml for AKI, at 22.8 ng/ml for Class I/F (90.0%, 71.4%; AUC=0.836) and at 21.0 ng/ml for in-hospital mortality (74.3%, 70.0%; AUC=0.726). The Kaplan-Meier survival curves showed a significantly poorer prognosis in the high s-HFABP group (≥22.9 ng/ml) than in other groups., Conclusions: The s-HFABP level can indicate AKI on admission, and a high s-HFABP level is associated with a poorer prognosis for AHF patients.

Background: Biomarkers predicting adverse outcomes in non-surgical intensive care patients have not been reported., Methods and Results: Data for 1,006 emergency department patients were prospectively analyzed. The serum heart-type fatty acid-binding protein (s-H-FABP) level was measured within 10 min of admission. The patients were assigned to intensive care (n = 835) or other departments (n = 171). The intensive care patients were divided into survivors (n = 745) and non-survivors (n = 90) according to the in-hospital mortality and assigned to four groups according to the quartiles of s-H-FABP (Q1, Q2, Q3 and Q4). The s-H-FABP levels were significantly higher in the intensive care patients (12.7 [6.1-38.8] ng/ml versus 5.3 [3.1-9.4] ng/ml) and in the non-survivors (44.9 [23.2-87.6] ng/ml versus 11.5 [5.6-32.6] ng/ml). A Kaplan-Meier curve showed a significantly higher survival rate in Q3 than in Q1 and Q2 and in Q4 than in the other groups. The multivariate Cox regression model identified Q3 (HR 4.646, 95 % CI 1.526-14.146) and Q4 (HR 9.483, 95 % CI 3.152-28.525) as independent predictors of 90-day mortality. The sensitivity and specificity of H-FABP for in-hospital mortality were 81.1 and 66.0 % (AUC 0.775) at 20.95 ng/ml. The in-hospitality rate was significantly higher in the high s-H-FABP patients than in the low s-H-FABP patients in each etiology group., Conclusions: The s-H-FABP level is an effective biomarker for risk stratification in non-surgical intensive care patients.

The prognosis for patients diagnosed with advanced colorectal cancer with liver metastases is poor. Chemotherapy should be administered with caution in such patients because of complications due to severe liver dysfunction. We report here the successful management of a case of advanced sigmoid colon cancer, with icterus due to severe liver metastases, treated with cetuximab as first-line therapy. A 72-year-old man presented at our institution with complaints of severe general fatigue, tarry stools, and abdominal distention. He was diagnosed with advanced sigmoid colon cancer with multiple liver metastases. Clinical examination revealed the presence of ascites. The patient had an Eastern Cooperative Oncology Group(ECOG) performance status(PS)score of 3. A biopsy specimen of the primary tumor showed well-moderately differentiated adenocarcinoma without KRAS mutation. He was diagnosed with advanced sigmoid colon cancer with multiple hepatic metastases. Cetuximab monotherapy was initiated as first-line treatment. After 4 courses of cetuximab monotherapy, results of laboratory tests showed an improvement, and a computed tomography(CT)scan revealed a regression in the size of the liver metastases. Because the results of liver function tests and the ECOG PS scores improved, we initiated combination chemotherapy with 5-fluorouracil, Leucovorin, oxaliplatin(FOLFOX), and cetuximab. This regimen was well tolerated up to 14 courses, during which the only adverse reaction reported was a rash of grade 2 toxicity. Thereafter, disease progression in the form of liver metastases resulted in a change in the combination therapy to irinotecan and S-1(IRIS)as second-line chemotherapy. Thereafter, irinotecan and panitumumab were administered as third-line therapy. The patient continued chemotherapy on an outpatient basis; however, he died due to disease progression 18 months after his first visit.

Background: There have been few reports about the clinical significance of the time of admission for acute heart failure (AHF)., Methods: Five hundred thirty-one patients with AHF admitted to the intensive care unit (ICU) were analyzed. The patients were assigned to either the daytime HF group (n=195, visited from 08:00 to 20:00, Group D) or nighttime HF group (n=336, visited from 20:00 to 08:00, Group N). The clinical findings and outcomes were compared between these groups., Results: The systolic blood pressure (SBP), the number of patients with clinical scenario (CS) 1, and the heart rate (HR) were significantly higher in group N (SBP, 171.0±38.9mmHg; CS 1, 80.9%; HR, 116.9±28.0beats/min) than in group D (SBP, 154.2±37.1mmHg; CS 1, 66.2%; HR, 108.6±31.4beats/min). The patients in group N were more likely to have orthopnea (91.1%) than those in group D (70.3%). A multivariate logistic regression model identified a SBP ≥164mmHg [odds ratio (OR): 2.043; 95% confidence interval (CI): 1.383-3.109], HR ≥114beats/min (OR: 1.490; 95%CI: 1.001-2.218), and orthopnea (OR: 2.257; 95%CI: 1.377-3.701) to be independently associated with Group N. The length of ICU stay was shorter in group N (5.8±10.5 days) than in group D (7.8±11.5 days)., Conclusion: The nighttime HF was characterized by high SBP, high HR, and orthopnea, and the length of ICU stay was shorter in the nighttime HF group., (Copyright © 2012 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

Background: Prediction and prevention of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) recurrence is an important clinical issue. We investigated whether HBV DNA level and antiviral therapy are associated with HCC recurrence., Methods: This retrospective study involved 103 patients who underwent hepatic resection or radiofrequency ablation for initial HCC. Patients were divided into four groups. Thirty had high serum HBV DNA levels (>4 log(10) copies/mL) and had not received antiviral therapy (high virus group; HVG). Thirty-four had low HBV DNA levels (< or =4 log(10) copies/mL) and had not received antiviral therapy (low virus group; LVG). Twenty received antiviral therapy after HCC developed (therapeutic group A, TG-A). Nineteen received antiviral therapy before HCC developed (therapeutic group B, TG-B)., Results: Cumulative HCC recurrence rates at 3 years in the HVG, LVG, TG-B, and TG-A were 71.1%, 42.2%, 42.3%, and 52.0%, respectively. Recurrence rates differed significantly between the HVG and LVG (P = 0.016) and between the HVG and TG-B (P = 0.008). Recurrence rate in the TG-A was marginally lower than in the HVG (P = 0.10). On multivariate analysis, high serum hepatitis B virus DNA levels (hazard ratio: HR 2.67; 95% CI 1.31-5.47; P = 0.007) and absence of antiviral therapy (HR 2.57; 95% CI 1.34-4.94; P = 0.005) were independent risk factors for hepatocellular carcinoma recurrence., Conclusion: HBV DNA level and antiviral therapy are associated with HCC recurrence. For patients with high HBV DNA levels, antiviral therapy before the development of HCC is important for prevention of recurrence.

To identify the genes responsible for carcinogenesis and progression of hepatocellular carcinoma (HCC), we screened differentially expressed genes in several human HCC cell lines. Among these genes, Gpr49 was up-regulated in PLC/PRF/5 and HepG2. Gpr49 is a member of the glycoprotein hormone receptor subfamily, which includes the thyroid-stimulating hormone receptor (TSHR). However, Gpr49 remains to be an orphan G-protein-coupled receptor. By real-time quantitative reverse transcriptase polymerase chain reaction (RT-PCR) analysis, overexpression (>3-fold increase compared with the corresponding noncancerous liver tissue) of Gpr49 mRNA was observed in 18 of 38 (47%) HCCs compared with corresponding noncancerous livers. Clinicopathologically, overexpression of Gpr49 was frequently observed in HCC with mutation in beta-catenin exon 3 (14 of 16 cases, 87.5%). Moreover, introduction of mutant beta-catenin into mouse hepatocytes in culture caused up-regulation of the Gpr49 mouse homologue. Therefore, Gpr49 is likely to be a target gene activated by Wnt-signaling in HCC. In conclusion, although much is still unknown, Gpr49 may be critically involved in the development of HCCs with beta-catenin mutations and has the potential to be a new therapeutic target in the treatment of HCC.