Tolvaptan (TLV) is a diuretic agent administrated for heart failure (HF) only in Japan. Many clinical findings have been obtained from the accumulation of clinical experience, and the administration of TLV reportedly avoids causing a reduction in the renal function. In addition, TLV has been reported to exert effects other than diuresis. The early start of TLV after hospitalization shortens the length of the hospital stay, and continuous TLV after discharge extends the period until re-hospitalization of HF patients. TLV is thought to function via vasopressin V2 receptor antagonism. However, no significant differences in the long-term prognosis were noted between the group using TLV and not using TLV in the Endovascular Valve Edge-to-Edge Repair Study (EVEREST) trial, and effects other than diuresis are not useful for all HF patients. Therefore, it is necessary to identify patients who may experience effects other than diuresis with TLV administration. The accumulation of more patients and findings from further large-scale clinical trials will be necessary in order to clarify these points.

Objective Regional disparities were observed in the outcomes of interferon (IFN)-based therapy for chronic hepatitis C virus (HCV) infection in a Japanese nationwide study. However, whether or not these regional disparities are observed in the outcomes of direct-acting antiviral drugs, including sofosbuvir (SOF) plus ribavirin (RBV) therapy, remains unclear.

Methods We conducted a multicenter study to assess the efficacy of SOF plus RBV therapy for HCV genotype 2 infection in Tochigi Prefecture and its vicinity, in which IFN-based therapy yielded a low sustained virologic response (SVR) rate. In addition, we divided Tochigi Prefecture into six regions to examine regional disparities in the SVR.

Patients We enrolled patients with chronic HCV genotype 2 infection.

Results Of the 583 patients enrolled, 569 (97.6%) completed the treatment, and 566 (97.1%) also complied with post-treatment follow-up for 12 weeks. The overall SVR12 rate was 96.1% by per protocol and 93.7% by intention-to-treat analyses. No marked differences were observed in the SVR12 between subjects ≥65 and <65 years of age. Although large gaps were observed in the characteristics of patients and accessibility to medical resources, there was no significant difference in the SVR12 rate among the six regions in Tochigi Prefecture.

Conclusion SOF plus RBV therapy was effective for HCV genotype 2 infection in an area where IFN-based therapy had previously shown unsatisfactory results. In addition, no regional disparities in the SVR12 were observed in Tochigi Prefecture.

Objective The aim of this study was to identify patients with a high risk of early mortality after acute esophageal variceal bleeding by measuring the C-reactive protein (CRP) level.

Methods We retrospectively evaluated 154 consecutive cirrhotic patients admitted with acute esophageal variceal bleeding. Differences between categorical variables were assessed by the chi-square test. Continuous variables were compared using the Mann-Whitney U-test. Multivariate logistic regression analyses consisting of clinical laboratory parameters were performed to identify risk factors associated with the 6-week mortality. The discriminative ability and the best cut-off value were assessed by a receiver-operating characteristic (ROC) curve analysis.

Results Child-Pugh C patients showed a significantly higher 6-week mortality than Child-Pugh A or B patients (38% vs. 6%, p<0.0001). The 6-week mortality in Child-Pugh C patients was associated with the age (p<0.0001), etiology of cirrhosis (p=0.003), hepatocellular carcinoma (p=0.0003), portal vein thrombosis (p=0.005), baseline creatinine (p=0.0001), albumin (p=0.001), white blood cell count (p=0.038), baseline CRP [p=0.0004; area under the ROC (AUROC)=0.765; optimum cut-off value at 1.30 mg/dL] and bacterial infection (p=0.019). We determined that CRP ≥1.30 mg/dL was an independent predictor for 6-week mortality in Child-Pugh C patients [odds ratio (OR)=8.789; 95% confidence interval (CI): 2.080-47.496; p=0.003], along with a creatinine level of 0.71 mg/dL (OR=17.628; 95% CI: 2.349-384.426; p=0.004) (73% mortality if CRP ≥1.30 mg/dL vs. 19% if CRP<1.30 mg/dL, p<0.0001).

Conclusion In Child-Pugh C patients with esophageal variceal bleeding, a baseline CRP ≥1.30 mg/dL can help identify patients with an increased risk of mortality.

Objective The association of primary aldosteronism (PA) with thyroid disease has already been suggested. The aim of this study was to examine the presence of PA in patients with papillary thyroid carcinoma (PC) and to characterize such PC patients with PA.

Methods We examined the presence of PA in 81 consecutive patients with PC, whose random sitting blood pressure (BP) was ≥140/90 mmHg in the office (n= 68), who had an incidental adrenal tumor or adrenal enlargement (n=9), or who showed hypokalemia (n=4). Thirty-one of these 81 patients had been treated with anti-hypertensive drugs. The plasma aldosterone concentration (PAC) and plasma renin activity (PRA) were first measured before operation in 16 patients and after operation in 65 patients. PA was diagnosed according to the guidelines of the Japan Endocrine Society.

Results Forty patients with PC with a random PAC/PRA ratio of over 200 were subjected to a further study (12 of these patients had been treated with anti-hypertensive drugs). Ultimately, 15 patients with PC were diagnosed with PA. Adrenal venous sampling was done in 9 out of 15 patients with PC associated with PA. No patients were diagnosed as having unilateral lesions. Among the 15 patients, white-coat hypertension was observed in 5 patients, and normotension was observed in 1 patient.

Conclusion These findings suggest that the prevalence of PA may be high among patients with PC. An active examination is needed to detect PA, as its signs and symptoms may be mild in patients with PC associated with hypertension.

Objective Skeletal muscle is the main target organ for glycemic control, and the serum creatinine level is a convenient indicator of the skeletal muscle mass. This study aimed to assess the potential relationship between the serum creatinine level and the onset of impaired fasting glucose (IFG).

Methods In this large, community-based, retrospective longitudinal cohort study, we examined the records of 7,905 Japanese participants (3,863 men, 4,042 women) of 18-80 years of age who underwent annual health checkups at a single center between April 2003 and August 2013. After applying the exclusion criteria, 6,490 participants were reviewed to identify those with the onset of IFG, defined as a fasting plasma glucose ≥6.11 mM. Among the participants, 278 met the criterion for the onset of IFG during the observation period.

Results Creatinine levels were higher in male subjects who exercised periodically and were exercise conscious in comparison to those who did not exercise, and were higher in female subjects who exercised periodically in comparison to female subjects who did not exercise and who were not exercise conscious. Additionally, the serum creatinine level was negatively associated with the onset of IFG in both men [adjusted hazard ratio, 0.98; 95% confidence interval (CI), 0.96-0.99; p=0.008] and women (adjusted hazard ratio, 0.94; 95% CI, 0.91-0.97; p<0.001) after adjustment for variables previously reported to be risk factors for the onset of glucose intolerance and factors associated with chronic kidney disease.

Conclusion A low creatinine level might be associated with the onset of IFG. Moreover, the fact that serum creatinine levels increase with exercise might demonstrate the importance of exercise therapy.

Objectives The present study was performed with the aim of analyzing the biological disease-modifying antirheumatic drug (bDMARD)-free (Bio-free) condition of adalimumab (ADA)-treated rheumatoid arthritis (RA) patients in a real-world setting.

Methods ADA was used in the treatment of 130 (male, n=21; female, n=109 females) RA patients. Among them, 26 patients (20.0%) discontinued ADA due to a good response. We analyzed 20 patients who were followed up for more than 6 months after the discontinuation of ADA. The Disease Activity Score 28 based on C-reactive protein (DAS28-CRP) and modified health assessment questionnaires (mHAQs) were evaluated.

Results The mean age of the patients was 53.4±11.1 years. The mean disease duration was 4.5±4.3 years. Sixteen patients were bDMARD-naïve, while 4 switched from bDMARDs to ADA. At 6 months after the discontinuation ADA, 19 patients had achieved a clinical remission, and 1 had achieved a low disease activity. The Bio-free period was 26.4±15.5 months. The dose of prednisolone was significantly reduced from baseline (3.45±3.17 mg/day) at 6 months after the discontinuation of ADA (2.63±2.78 mg/day). The dose of methotrexate was unchanged. The number of conventional synthetic DMARDs (csDMARDs) was significantly increased (0.8±0.6 to 1.4±1.06). The mHAQ values were significantly ameliorated by ADA and remained good in patients with a Bio-free condition. A multivariate analysis showed that the dose of methotrexate (MTX) was an important factor for achieving a Bio-free condition.

Conclusion A sustainable Bio-free condition in a real clinical setting can be achieved and may be a suitable way of reducing medical costs. The dose of MTX and the additional administration of csDMARDs is therefore thought to be important for ensuring a good outcome in these patients.

Objective The standard anti-tuberculosis (TB) regimen occasionally causes acute kidney injury (AKI). The major etiology is rifampicin-induced acute interstitial nephritis. However, the standard management of AKI induced by anti-TB drugs has yet to be established.

Methods We retrospectively reviewed patients with TB who developed AKI after starting standard anti-TB treatment between 2006 and 2016 at a single TB center. The clinical characteristics and the management are described.

Results Among 1,430 patients with active TB, 15 (1.01%) developed AKI. The mean age (standard deviation) was 61 years (18). The median (interquartile range) time to AKI development was 45 days (21-54 days). The median serum creatinine level before anti-TB treatment was 0.7 mg/dL (0.5-1.4 mg/dL), whereas the median peak serum creatinine level after AKI onset was 4.0 mg/dL (3.08-5.12 mg/dL). Five patients (33.3%) were pathologically confirmed as having acute interstitial nephritis (AIN), and 7 patients (46.7%) had a clinical diagnosis of the disease. All anti-TB drugs were stopped, and steroids were administered to 5 (100%) patients with pathologically confirmed AIN and 3 (42.8%) patients with clinically diagnosed AIN. The renal function was normalized in 12 patients (80.0%) after restarting anti-TB treatment without rifampicin (n=12) or isoniazid (n=1). Two patients died due to severe renal failure after restarting rifampicin.

Conclusion Rifampicin is the leading cause of AKI. Levofloxacin may be an alternative to rifampicin thanks to its safety and potency. Restarting anti-TB treatment without rifampicin and short-term steroid administration may be a feasible management for AKI.

Fanconi anemia (FA) is a disorder of chromosomal fragility characterized by progression to aplastic anemia, myelodysplastic syndrome, and leukemia. FA patients are also predisposed to solid cancers. A case of FA in an adult patient who developed tongue and superficial esophageal cancers following hematopoietic stem cell transplantation is reported. This case was considered significant because it is the first reported case of superficial esophageal cancer in an FA patient that was treated successfully by endoscopic submucosal resection.

Midventricular obstructive hypertrophic cardiomyopathy (MVOHCM) is a rare form of hypertrophic cardiomyopathy (HCM). An 80-year-old man was administered bisoprolol and warfarin therapies as treatment for MVOHCM with an apex aneurysm due to myocardial damage and intra-aneurysmal thrombus not complicated by atrial fibrillation. The pressure gradient in the midventricle successfully improved from 53.9 to 21.8 mmHg, and the intra-aneurysmal thrombus disappeared.

Peripartum cardiomyopathy (PPCM) is rare but life-threatening. We herein report the case of a 48-year-old woman with PPCM after oocyte donation and delivery of twins. Two weeks after delivery, she suffered from severe symptoms of heart failure [orthopnea, New York Heart Association (NYHA) class IV, pulmonary edema and a reduced left ventricular ejection fraction of 18%]. Although standard heart failure therapy was effective for diminishing the congestion, it was not sufficient to improve her symptoms or left ventricular systolic dysfunction. During admission, we added bromocriptine. A year later after the onset, she was in a good state with an improved left ventricular systolic function.

Diffuse pulmonary ossification (DPO) is an uncommon diffuse lung disease characterized by metaplastic bone formation in the lung parenchyma and is rarely diagnosed in life. While DPO usually occurs as a secondary disease, idiopathic cases are extremely rare. We describe three cases of idiopathic DPO, two of which were definitively diagnosed by surgical lung biopsy. One case was observed in a 43-year-old man with a history of recurrent pneumothorax who developed pneumothorax after the surgical biopsy. Few reports have described cases of DPO with recurrent pneumothorax; however, pneumothorax should be considered as a potential complication when such patients are encountered.

Yellow nail syndrome (YNS) is a rare clinical syndrome characterized by a triad of yellow thick nail, lymphedema and respiratory diseases. We experienced 2 cases of YNS with diffuse panbronchiolitis (DPB)-like pulmonary manifestation. Since YNS might be hidden to those who have been diagnosed with DPB, physicians should be alert to recognize nail signs of YNS in case of DPB refractory to macrolide therapy. We hereby review previous case reports of YNS and discuss its pulmonary manifestations.

We herein report a case involving a 64-year-old Japanese woman with a pulmonary Mycobacterium abscessus infection complicated by reactive AA amyloidosis, which, to our knowledge, has not been reported to date. The patient underwent gastrointestinal endoscopy for diarrhea during the treatment of pulmonary M. abscessus infection and was diagnosed with AA amyloidosis according to the histopathological findings from the endoscopic specimen. She died four months later. The prognosis of AA amyloidosis associated with pulmonary M. abscessus infection may be very poor, and physicians should pay attention to this rare condition when difficult-to-treat diarrhea occurs in patients with pulmonary M. abscessus infection.

Large cell neuroendocrine carcinoma (LCNEC) is a highly malignant cancer originally found in lung in 1991. In extremely rare occasions, primary LCNEC is found in the mediastinum; approximately 40 of such cases have been reported. Due to the limited number of reported cases, a standardized treatment protocol has yet to be established. We report a case of a 66-year-old woman with primary mediastinal LCNEC who presented with superior vena cava syndrome. Emergent radiotherapy was performed, followed by systemic chemotherapy with cisplatin and etoposide, which resulted in a dramatic tumor reduction. This is the first report describing the achievement of a complete response after systemic chemotherapy in a patient with primary LCNEC.

A 34-year-old woman experiencing shortness of breath was referred to our hospital. The patient was diagnosed with sporadic lymphangioleiomyomatosis based on the observation of bilateral diffuse multiple thin-walled cysts on computed tomography of the chest, chylous effusion, elevated serum vascular endothelial growth factor-D levels and transbronchial biopsy findings. This patient was a hepatitis B virus (HBV) carrier. Treatment with 1 mg daily of sirolimus was started after HBV DNA was brought below the cut-off level using entecavir. Sirolimus was effective, as the chylous effusion resolved completely and the dyspnea improved. The sirolimus dosage was increased to 2 mg daily without causing HBV reactivation.

A 61-year-old woman exhibited right inguinal lymphadenopathy and right lower limb edema approximately 1 month prior to hospitalization. She was diagnosed with high grade B-cell lymphoma, and a lymph node biopsy and fluorescence in situ hybridization indicated MYC, BCL2, and BCL6 rearrangements (triple-hit lymphoma). She had progressive disease that was CD20-negative after two courses of rituximab, cyclophosphamide, doxorubicin, vincristine, methotrexate/ifosfamide, etoposide, high-dose cytarabine (R-CODOX-M/IVAC) therapy. Subsequent etoposide, prednisolone, vincristine, cyclophosphamide, doxorubicin (EPOCH) therapy was not effective. However, after two cycles of gemcitabine, dexamethasone, and cisplatin (GDP) therapy, she achieved a complete response and was able to undergo autologous peripheral blood stem cell transplantation. GDP therapy may be effective as salvage therapy for chemotherapy-resistant triple-hit lymphoma.

Foix-Chavany-Marie syndrome (FCMS) is a rare cortical type of pseudobulbar palsy characterized by the loss of voluntary control of the facial, pharyngeal, lingual, and masticatory muscles with preserved reflexive and autonomic functions. FCMS is generally associated with cerebrovascular diseases affecting the bilateral opercular regions. We herein report the clinical features of an 84-year-old right-handed Japanese man with FCMS due to a unilateral brain abscess. The patient's symptoms were resolved after treating the brain abscess. The present clinical results suggest that a unilateral brain abscess in the temporal operculum with a persistent old lesion in the contralateral insular cortex can induce FCMS.

Chronic active Epstein-Barr virus (CAEBV) T-cell type infection, systemic form, is characterized by persistent infectious mononucleosis-like symptoms, high Epstein-Barr virus (EBV) DNA levels in the peripheral blood, organ damage, and a poor prognosis. The association between CAEBV and rheumatoid arthritis (RA) is unclear. We report a case of fatal CAEBV T-cell type infection in an RA patient undergoing treatment with cytotoxic T-lymphocyte-associated antigen 4 immunoglobulin fusion protein (abatacept, ABT). CAEBV can rapidly worsen in RA patients receiving ABT. Thus, we should try to establish an early diagnosis in patients with CAEBV infection.

Rheumatoid vasculitis is a rare etiology for pulmonary hypertension (PH) in patients with connective tissue disease. We encountered a case of acute PH crisis in a case with rheumatoid vasculitis eight months after undergoing adalimumab reduction. Since no repetition of arthralgia occurred after the adalimumab reduction, we decided to not increase the dose of adalimumab. However, hemodynamic collapse thereafter developed and even though steroid pulse therapy was administered, the patient nevertheless died. The autopsy showed clusters of acute and chronic inflammation around the remodeled pulmonary arteries along with micro-thrombi in the vessel lumen. We should consider the possibility of critical worsening of PH as a phenotype of vasculitis related to immunosuppressive therapy reduction.

Anderson-Fabry disease (AFD) is a rare X-linked disorder caused by deficient activity of the lysosomal enzyme α-galactosidase A (α-GAL A). We herein report 10 cases of AFD in 5 families (3 men and 7 women) that were found to have a specific common mutation in R301Q [G-to-A transition in exon 6 (codon 301) resulting in the replacement of a glutamine with an arginine residue]. We evaluated their clinical characteristics, residual enzymatic activity, and plasma concentrations of globotriaosylsphingosine (Lyso-Gb3). Although all 10 cases had cardiac and renal manifestations in common, their clinical manifestations were markedly divergent despite the same genetic abnormality.

In 1982, we reported a case of retroperitoneal fibrosis (RPF) exhibiting various clinical manifestations. Our current understanding of immunoglobulin G4 (IgG4)-related disease led us to consider it as a possible diagnosis because all of the patient's clinical features could be explained by this disease entity. To confirm our hypothesis, were investigated the histopathological findings of resected specimens that had been stored for 35 years postoperatively. Typical pathological findings together with predominant IgG4⁺ plasma cell infiltration confirmed a potential diagnosis of IgG4-related RPF. Furthermore, we observed positive immunohistochemical staining for several molecules associated with T regulatory and T follicular helper cells.