Individual Optimization of Contrast Media Injection Protocol at Hepatic Dynamic Computed Tomography Using Patient-Specific Contrast Enhancement Optimizer.

OBJECTIVE: We developed a patient-specific contrast enhancement optimizer (p-COP) that can exploratorily calculate the contrast injection protocol required to obtain optimal enhancement at target organs using a computer simulator. Appropriate contrast media dose calculated by the p-COP may minimize interpatient enhancement variability. Our study sought to investigate the clinical utility of p-COP in hepatic dynamic computed tomography (CT). METHODS: One hundred thirty patients (74 men, 56 women; median age, 65 years) undergoing hepatic dynamic CT were randomly assigned to 1 of 2 contrast media injection protocols using a random number table. Group A (n = 65) was injected with a p-COP-determined iodine dose (developed by Higaki and Awai, Hiroshima University, Japan). In group B (n = 65), a standard protocol was used. The variability of measured CT number (SD) between the 2 groups of aortic and hepatic enhancement was compared using the F test. In the equivalence test, the equivalence margins for aortic and hepatic enhancement were set at 50 and 10 Hounsfield units (HU), respectively. The rate of patients with an acceptable aortic enhancement (250-350 HU) for the diagnosis of hypervascular liver tumors was compared using the χ test. RESULTS: The mean ± SD values of aortic and hepatic enhancement were 311.0 ± 39.9 versus 318.7 ± 56.5 and 59.0 ± 11.5 versus 58.6 ± 11.8 HU in groups A and B, respectively. Although the SD for aortic enhancement was significantly lower in group A (P = 0.006), the SD for hepatic enhancement was not significantly different (P = 0.871). The 95% confidence interval for the difference in aortic and hepatic enhancement between the 2 groups was within the range of the equivalence margins. The number of patients with acceptable aortic enhancement was significantly greater in group A than in group B (P < 0.01). CONCLUSIONS: The p-COP software reduced interpatient variability in aortic enhancement and obtained acceptable aortic enhancement at a significantly higher rate compared with the standard injection protocol for hepatic dynamic CT.

Contrast Material Injection Protocol With the Dose Determined According to Lean Body Weight at Hepatic Dynamic Computed Tomography: Comparison Among Patients With Different Body Mass Indices.

OBJECTIVE: The objective of this study was to compare enhancement of the aorta and liver on hepatic dynamic computed tomography scans acquired with contrast material doses based on the lean body weight (LBW) or the total body weight (TBW). METHODS: We randomly divided 529 patients (279 men, 250 women; median age, 66 years) scheduled for hepatic dynamic computed tomography into 2 groups. The LBW patients (n = 278) were injected with 679 mg iodine/kg (men) or 762 mg iodine/kg (women). The TBW group (n = 251) was injected with 600 mg iodine/kg TBW. Each group was subdivided into the 3 classes based on the body mass index (BMI; low, normal, high). Aortic enhancement during the hepatic arterial phase and hepatic enhancement during the portal venous phase was compared. The aortic and hepatic equivalence margins were 100 and 20 Hounsfield units, respectively. RESULTS: Comparison of the median iodine dose in patients with a normal or high BMI showed that it was significantly lower under the LBW protocol than the TBW protocol (558.2 and 507.0 mg iodine/kg, P < 0.001, respectively). However, in patients with a low BMI, the LBW protocol delivered a significantly higher dose than the TBW protocol (620.7 vs 600.0 mg iodine/kg, P < 0.001). The 95% confidence interval for the difference in aortic and hepatic enhancement between the 2 protocols was within the range of the predetermined equivalence margins in all BMI subgroups. CONCLUSIONS: Contrast enhancement was equivalent under both protocols. The LBW protocol can avoid iodine overdosing, especially in patients with a high BMI.

Advanced liver fibrosis effects on the response to sofosbuvir-based antiviral therapies for chronic hepatitis C.

BACKGROUND: Sustained virological response (SVR) rates for the treatment of chronic hepatitis C virus (HCV)-infected patients have drastically improved with the use of direct-acting antiviral (DAA) therapies; however, a small minority of patients still fails to eradicate the virus. We analyzed factors associated with SVR in DAA therapy and the effect of age and liver fibrosis on treatment response. METHODS: Nine hundred and eighteen patients with chronic HCV infection were treated with 24 weeks of daclatasvir plus asunaprevir (DCV + ASV) or 12 weeks of sofosbuvir plus ledipasvir (SOF + LDV), ombitasvir, paritaprevir plus ritonavir (OMB + PTV + r) or sofosbuvir plus ribavirin (SOF + RBV). Multivariate logistic regression analysis was used to identify factors associated with SVR. The effect of age and liver fibrosis on SVR was analyzed. RESULTS: The overall SVR rate was 95.4% (876 of 918 patients), and rates by DAA regimen were 93.4%, 95.7%, 100%, and 95.0% in DCV + ASV-treated, SOF + LDV-treated, OMB + PTV + r-treated, and SOF + RBV-treated patients, respectively. Patients older than 75 years achieved a similar SVR rate with those aged 75 years or younger (96.4% and 94.8%, respectively). Multivariate logistic regression analysis identified absence of DAA therapy history (odds ratio [OR], 3.868 for presence; P = 0.002) and FIB-4 index of less than 3.25 (OR, 5.042 for ≥3.25; P = 0.001) as independent predictors for SVR. SVR rates were significantly lower in patients with FIB4 index of 3.25 or more compared with those with less than 3.25, especially in sofosbuvir-based therapies such as SOF + LDV-treated or SOF + RBV-treated patients. CONCLUSION: Both older and younger patients respond similarly to DAA therapy. Advanced liver fibrosis affects the virological response to sofosbuvir-based therapy.

A Case of Ulcerative Colitis During Pregnancy and Childbirth at an Older Age While on Biologic Therapy.

There is considerable uncertainty regarding the safety and efficacy of biological therapies during pregnancy. We report a case of a 46-year-old female, diagnosed with ulcerative colitis over 30 years ago, who was successfully managed with infliximab and ustekinumab. She experienced no exacerbation of her condition during two pregnancies, demonstrating the safety of biologic therapy in maintaining disease remission during pregnancy. This case report highlights successful outcomes despite the uncertainties associated with biologic therapy during pregnancy and includes a brief review of the relevant literature.

Benign Lymphoid Polyp of the Rectum Diagnosed and Treated With Endoscopic Submucosal Resection With a Ligation Device.

Benign lymphoid polyps of the rectum, also termed "Rectal tonsil" or "Pseudolymphoma," are submucosal tumor-like growths with localized hyperplasia of the lymphoid follicles and are often discovered incidentally during colonoscopy. Its diagnosis and differentiation from other submucosal tumors pose challenges owing to their similar endoscopic features. A 72-year-old woman presented with a positive fecal occult blood test, which led to the discovery of a 10-mm lower rectal tumor resembling a neuroendocrine tumor during colonoscopy. Upon closer examination, the lesion had a yellow submucosal appearance with dilated capillaries. Endoscopic submucosal resection with a ligation device (ESMR-L) was performed because the patient preferred immediate removal. Histopathological examination revealed lymphocytic infiltration with germinal center-containing lymphoid follicles, confirming the diagnosis of benign lymphoid polyp. Benign lymphoid polyps are often difficult to differentiate from carcinoid tumors and malignant lymphomas because the endoscopic findings are similar. Although preoperative endoscopic ultrasonography aids localization and characterization, definitive differentiation remains elusive and necessitates complete lesion resection. ESMR-L is a viable approach for diagnostic accuracy and therapeutic intervention, offering advantages in terms of procedural efficiency and patient care, particularly in cases involving submucosal rectal lesions.

Circulating microRNA-22 correlates with microRNA-122 and represents viral replication and liver injury in patients with chronic hepatitis B.

Hepatitis B virus (HBV) infection is associated with increased expression of microRNA-122. Serum microRNA-122 and microRNA-22 levels were analyzed in 198 patients with chronic HBV who underwent liver biopsy and were compared with quantitative measurements of HBsAg, HBeAg, HBV DNA, and other clinical and histological findings. Levels of serum microRNA-122 and microRNA-22 were determined by reverse transcription-TaqMan PCR. Serum levels of microRNA-122 and microRNA-22 were correlated (R(2) = 0.576; P < 0.001), and both were elevated in chronic HBV patients. Significant linear correlations were found between microRNA-122 or microRNA-22 and HBsAg levels (R(2) = 0.824, P < 0.001 and R(2) = 0.394, P < 0.001, respectively) and ALT levels (R(2) = 0.498, P < 0.001 and R(2) = 0.528, P < 0.001, respectively). MicroRNA-122 levels were also correlated with HBV DNA titers (R(2) = 0.694, P < 0.001 and R(2) = 0.421, P < 0.001). Levels of these microRNAs were significantly higher in HBeAg-positive patients compared to HBeAg-negative patients (P < 0.001 and P < 0.001). MicroRNA-122 levels were also lower in patients with advanced liver fibrosis (P < 0.001) and lower inflammatory activity (P < 0.025). These results suggest that serum micro-RNA levels are significantly associated with multiple aspects of HBV infection. The biological meaning of the correlation between microRNA-122 and HBsAg and should be investigated further.

Efficacy of Lusutrombopag for Thrombocytopenia in Patients with Chronic Liver Disease Scheduled to Undergo Invasive Procedures.

Objective Lusutrombopag is a thrombopoietin receptor agonist that improves thrombocytopenia in patients with chronic liver disease scheduled to undergo invasive procedures. However, information on the efficacy of repeated lusutrombopag treatment and factors associated with the treatment is scarce. We analyzed the efficacy of repeated lusutrombopag treatment and the factors associated with a response to lusutrombopag. Methods Thirty-nine patients with chronic liver disease who received lusutrombopag treatment before undergoing invasive procedures were enrolled in this retrospective study. Of the 39 patients, 10 received lusutrombopag treatment multiple times for a total of 53 regimens of lusutrombopag treatment. Changes in platelet counts, the effects of repeated lusutrombopag treatment, and factors associated with response to lusutrombopag were analyzed. Results The median platelet count increased significantly from 4.5×104/µL before lusutrombopag treatment to 7.2×104/µL before the invasive procedure (p<0.01), and patients undergoing 49 of the 53 (92%) treatment regimens succeeded in undergoing invasive procedures without needing platelet transfusions. In patients who received lusutrombopag treatment repeatedly, the median platelet count significantly increased following the second administration of lusutrombopag, and the effects of lusutrombopag were similar between the first and second administration. A multivariate analysis identified the absence of diabetes mellitus (odds ratio, 5.56 for presence; p=0.04) as a significant and independent predictor of a response to lusutrombopag. Conclusion Lusutrombopag treatment significantly increased platelet counts in patients with chronic liver disease, making it possible to receive invasive procedures. The treatment produced identical effects when it was repeated. The efficacy of lusutrombopag might be decreased in patients with diabetes mellitus.

Efficacy and safety of ledipasvir/sofosbuvir with ribavirin in chronic hepatitis C patients who failed daclatasvir/asunaprevir therapy: pilot study.

BACKGROUND: In Japan, daclatasvir (DCV) and asunaprevir (ASV) therapy was the first IFN-free treatment to be approved, and thousands of patients have since been successfully treated, with an SVR rate of around 90%. The converse, however, is that around 10% of patients fail to achieve viral eradication and must be retreated using a different approach. This study is to evaluate treatment efficacy of ledipasvir/sofosbuvir and ribavirin in patients who failed to respond to DCV and ASV therapy. METHODS: Thirty patients were treated with 12 weeks of ledipasvir/sofosbuvir and ribavirin. We evaluated the rate of sustained virological response 12 weeks after the end of treatment (SVR12) and examined the incidence of adverse events during ledipasvir/sofosbuvir and ribavirin treatment. NS5A and NS5B resistance-associated variants (RAVs) in treatment failure cases were examined. RESULTS: The overall SVR12 rate was 86.7% (26/30). Large decreases in mean log10 HCV RNA levels were observed in patients without cirrhosis, and the SVR12 rate for these patients was 100% (12/12). In cases of cirrhosis, SVR12 rate was 72.2% (13/18). The common factors in treatment failure cases were the presence of liver cirrhosis and both NS5A L31M/I and Y93H RAVs. The frequency of RAVs did not change before and after treatment among patients who relapsed. CONCLUSION: Ledipasvir/sofosbuvir with ribavirin is an effective retreatment option for patients with chronic hepatitis C who failed to respond to prior daclatasvir and asunaprevir therapy.

Daclatasvir and asunaprevir in hemodialysis patients with hepatitis C virus infection: a nationwide retrospective study in Japan.

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).

Liver disease in hepatitis C virus carriers identified at blood donation and their outcomes with or without interferon treatment: Study on 1019 carriers followed for 5-10 years.

AIM: To portray liver disease and project outcomes in carriers of hepatitis C virus (HCV) in the general population. METHODS: Liver disease was evaluated in 1019 individuals who were found with HCV infection at blood donation, and they were followed for 5-10 years with or without receiving interferon (IFN). RESULTS: At baseline, chronic hepatitis was detected in 529 (51.9%) HCV carriers and more frequently in men than in women (62.6% [299/478]vs 42.5% [230/541], P < 0.01); cirrhosis was diagnosed in five (0.5% [three men included]) and hepatocellular carcinoma (HCC) in one (0.1% [man]). Of the carriers who were followed for 5 years or longer, loss of HCV-RNA from serum was achieved in 61 (31.0%) of the 197 treated with interferon (IFN) and only one of the 211 (0.5%) without IFN (P < 0.0001). HCC developed in 14 carriers including six ofthe 211 (2.8%) without IFN and eight of the 197 (4.1%) with IFN (six non-responders included). Follow ups of the 949 carriers identified age (P < 0.002), male gender (P < 0.01) and cirrhosis at the baseline (P < 0.0001) as factors contributing to the development of HCC. Cumulative incidence rates of HCC during 10 years among carriers found with chronic hepatitis increased in parallel with the age at the baseline. CONCLUSION: Identification of HCV carriers in the general population and treating those indicated with IFN would help decrease the development of HCC and lift its medical, as well as economic, burdens off society.

ITPA polymorphism effects on decrease of hemoglobin during sofosbuvir and ribavirin combination treatment for chronic hepatitis C.

BACKGROUND: Polymorphisms in the inosine triphosphatase (ITPA) gene is associated with anemia induced by peg-interferon (PEG-IFN) plus ribavirin (RBV) treatment for patients with chronic hepatitis C virus (HCV) infection. However, the effect of ITPA polymorphism on sofosbuvir plus RBV treatment is unknown. METHODS: Two hundred and forty-four patients with chronic HCV genotype 2 infection without decompensated liver cirrhosis were treated with sofosbuvir plus RBV for 12 weeks. The effects of ITPA polymorphism on hemoglobin levels and RBV dose reduction and treatment response were analyzed. ITPA (rs1127354) was genotyped using the Invader assay. Multivariate regression analysis was performed to identify factors associated with sustained virological response (SVR). RESULTS: Overall, SVR12 was achieved in 231 (94.7%) patients, based on intention to treat analysis. During the therapy, reduction of hemoglobin levels was significantly greater in ITPA genotype CC patients than CA/AA patients. Therefore, the cumulative proportion of patients with RBV dose reduction was significantly higher and total dose of RBV was significantly lower in patients with CC genotype compared to CA/AA genotypes. SVR12 rates were similar between ITPA genotypes CC and CA/AA (94.7 and 94.4%, respectively, P = 0.933). Multivariate logistic regression analysis identified FIB4 index <3.25 (odds ratio [OR], 9.388 for ≥3.25; P = 0.005) and low body weight (OR, 1.059, for high body weight; P = 0.017) as independent predictors for SVR12. CONCLUSIONS: ITPA polymorphism influences hemoglobin levels and incidence of RBV dose reduction during sofosbuvir plus RBV therapy. However, ITPA genotype CC patients can expect a curative effect equivalent to CA/AA patients for chronic HCV genotype 2 infection.

A serious clinical course of a very elderly patient with takotsubo cardiomyopathy.

An 86-year-old woman was admitted to our hospital because of vomiting and anorexia. Although serum cardiac markers, an electrocardiogram, and echocardiography suggested acute myocardial infarction, emergency cardiac catheterization revealed akinesis of the left ventricular apex without significant coronary artery stenosis. She was diagnosed as having takotsubo cardiomyopathy. The left ventricular dysfunction was considered transient and reversible but did not improve at all, contrary to our expectations. She died of worsening heart failure on day 14. We discuss this serious clinical course of a very elderly patient with takotsubo cardiomyopathy.

Primary hepatic carcinoid tumor (a case report).

A primary hepatic carcinoid tumor arising in a 77-year-old woman is reported. The patient was admitted with a huge tumor in the right lobe of the liver and treated by an extended right lobectomy of the liver. Light microscopic findings showed that the tumor cells had small oval-shaped nuclei and eosinophilic cytoplasm with small granules forming trabecular, glandular, and rosette patterns. Immunohistochemically, tumor cells were stained positive with neuron-specific enolase and synaptophysin and were stained slightly positive with chromogranin and carcinoembryonic antigen. Careful examination before and after the operation revealed no other origin of the tumor. Based on the findings, the liver tumor was diagnosed as a primary carcinoid. The clinical features and diagnosis of this rare tumor are discussed in this report.

A case of fulminant hepatic failure caused by hepatitis E virus.

Recent studies reported finding hepatitis E virus (HEV) in sera of domestic animals in Japan and also that HEV is a causative agent of non-A, non-B, non-C acute hepatitis and fulminant hepatitis. To clarify the incidence and severity of the disease caused by HEV in Hiroshima, Japan, we studied 97 patients with acute sporadic hepatitis. Stored serum samples were analysed for markers of hepatitis viruses. Only one patient, who developed fulminant hepatitis that was indistinguishable from acute exacerbation of autoimmune hepatitis (AIH), and died of liver failure, was positive for IgM and IgG antibodies against HEV by enzyme-linked immunosorbent assay and for HEV RNA by reverse transcription-polymerase chain reaction. Nucleotide sequence analyses of cDNA showed that the isolate, HA-Hir1, belongs to genotype III of HEV. A careful study of the life style of the patient failed to identify the infectious route. Although the incidence was not high, we considered that HEV was an important causative agent of severe hepatitis and the clinical features of acute hepatitis E were sometimes indistinguishable from those of acute exacerbation of AIH.

Establishment of an infectious genotype 1b hepatitis C virus clone in human hepatocyte chimeric mice.

The establishment of clonal infection of hepatitis C virus (HCV) in a small-animal model is important for the analysis of HCV virology. A previous study developed models of molecularly cloned genotype 1a and 2a HCV infection using human hepatocyte-transplanted chimeric mice. This study developed a new model of molecularly cloned genotype 1b HCV infection. A full-length genotype 1b HCV genome, HCV-KT9, was cloned from a serum sample from a patient with severe acute hepatitis. The chimeric mice were inoculated intrahepatically with in vitro-transcribed HCV-KT9 RNA. Inoculated mice developed viraemia at 2 weeks post-infection, and this persisted for more than 6 weeks. Passage experiments indicated that the sera of these mice contained infectious HCV. Interestingly, a similar clone, HCV-KT1, in which the poly(U/UC) tract was 29 nt shorter than in HCV-KT9, showed poorer in vivo infectivity and replication ability. An in vitro study showed that no virus was produced in the culture medium from HCV-KT9-transfected cells. In conclusion, this study developed a genetically engineered genotype 1b HCV-infected mouse. This mouse model will be useful for the study of HCV virology, particularly the mechanism underlying the variable resistance of HCV genotypes to interferon therapy.

Evolution of hepatitis C virus quasispecies during ribavirin and interferon-alpha-2b combination therapy and interferon-alpha-2b monotherapy.

OBJECTIVE: Ribavirin and interferon combination therapy is more effective than interferon monotherapy in patients with chronic hepatitis C virus (HCV) infection. To test the hypothesis that ribavirin induces nucleotide substitutions in the viral genome and reduces viral load by forcing it into error catastrophe in the combination therapy, we investigated the molecular evolution of HCV quasispecies in 3 patients who received combination therapy and 2 patients who received interferon monotherapy. METHODS: The quasispecies were analyzed before and after therapy by sequencing at least 8 clones in five regions of the HCV genome; 5' untranslated region, EI, E2, NS5A and NS5B. RESULTS: Marked genetic drift was observed in the NS5A and NS5B regions in patients treated with combination therapy. However, genetic distances between clones obtained after therapy were closer than those obtained before therapy. CONCLUSION: Our results suggest that the combination therapy modified HCV quasispecies, but that this did not reflect the induction of error catastrophe by ribavirin. Modification of quasispecies by this therapy requires further investigation in a larger number of patients to elucidate the possible mechanism of viral resistance against the combination therapy.

Ventricular septal perforation in a patient with takotsubo cardiomyopathy.

An 84-year-old woman was admitted with anorexia and because the serum cardiac markers, electrocardiogram and echocardiography suggested acute myocardial infarction she underwent emergency cardiac catheterization. Coronary angiography revealed no significant coronary artery stenosis, but left ventriculography revealed akinesis of the left ventricular apex with shunt flow to the right ventricle. The diagnosis was a rare case of takotsubo cardiomyopathy complicated by ventricular septal perforation. The patient died of cardiogenic shock on the day of admission day.

Catheter interventional therapy in an elderly patient with deep vein thrombosis and a brain tumor.

A 92-year-old woman with a brain tumor developed swelling of the left lower extremity. Venography showed considerable thrombi from the left common iliac vein to the femoral vein. Following implantation of a temporary inferior vena cava filter, catheter aspiration therapy and catheter-directed thrombolysis were performed. Venography after 3 days showed disappearance of the thrombi and an improvement in vein flow. A permanent inferior vena cava filter was implanted. Local intensive thrombectomy and thrombolysis by catheter together with a temporary inferior vena cava filter were effective treatments in this elderly patient with deep vein thrombosis.