Efficacy of additional radiofrequency ablation after transcatheter arterial chemoembolization for intermediate hepatocellular carcinoma.

AIM: For intermediate hepatocellular carcinoma (HCC), transcatheter arterial chemoembolization (TACE) therapy is recommended in the guidelines as a monotherapy, although TACE is a non-curative therapy. The aims of the present study were to evaluate the efficacy of adding radiofrequency ablation (RFA) to TACE in patients with intermediate HCC, and to identify the factors that were associated with favorable survival in these patients. METHODS: Fifty-nine patients with intermediate HCC were enrolled in this retrospective study. Thirty-nine patients were treated with TACE alone and 20 patients were treated with additional RFA after TACE. RESULTS: The recurrence-free survival rates at 0.5, 1 and 2 years for the additional RFA group were 32%, 19% and 13%, respectively, and these were significantly higher than those of the TACE group (8%, 3% and 0%, respectively; log-rank test, P = 0.001). The cumulative survival rates of the additional RFA group were significantly higher than those of the TACE group (log-rank test, P = 0.002), although this significant difference was not found in the subgroup of treatment naive patients because of small sample size. Multivariate analysis indicated male sex, lower total bilirubin, lower α-fetoprotein, lower des-γ-carboxyprothrombin, newly recurrent HCC nodules within the last 12 months and additional RFA as independent factors that were significantly associated with favorable overall survival. CONCLUSION: Additional RFA of nodules insufficiently treated by TACE is effective therapy for obtaining favorable disease-free survival in patients with intermediate HCC, and leads to better overall survival particularly in recurrent patients.

Impaired induction of interleukin 28B and expression of interferon λ 4 associated with nonresponse to interferon-based therapy in chronic hepatitis C.

BACKGROUND AND AIM: Interferon (IFN) λ plays an important role in innate immunity to protect against hepatitis C viral (HCV) infection. Single nucleotide polymorphisms (SNPs) near IL28B (IFNλ3) are strongly associated with treatment response to IFNα therapy in chronic hepatitis C (CHC) patients. Recently, IFNλ4 related to IL28B-unfavorable allele was discovered. However, the impact of IFNλs on CHC is unknown. We aimed to investigate the mechanism underlying responsiveness to IFN-based therapy in CHC associated with SNPs near IL28B. METHODS: We evaluated the basal mRNA levels and ex-vivo induction of IFNλ expression including IFNλ4 in peripheral blood mononuclear cells (PBMCs) from 50 CHC patients treated with pegylated-IFNα/RBV. Furthermore, we investigated the effect of IFNλ4 on induction of IL28B in vitro. RESULTS: When PBMCs were stimulated with IFNα and polyinosinic-polycytidylic acid, IL28B induction was significantly lower in patients with IL28B-unfavorable genotype (rs12979860 CT/TT) than those with IL28B-favorable genotype (rs12979860 CC; P=0.049). IL28B induction was lower in nonresponders than in relapsers (P = 0.04), and it was also lower in nonsustained virological responder patients for triple therapy including NS3 protease inhibitors. IFNλ4 mRNA was detected in 12 of 26 patients with IL28B-unfavorable SNP, and IFNλ4 expression was associated with lower IL28B induction in patients with IL28B-unfavorable genotype (P=0.04) and nonresponse to IFNα therapy (P=0.003). Overexpression of IFNλ4 suppressed IL28B induction and promoter activation. CONCLUSIONS: Impaired induction of IL28B, related to IFNλ4 expression in PBMCs of IL28B-unfavorable patients, is associated with nonresponse to IFNα-based therapy for hepatitis C viral infection.

Adrenal infarction with latent myelodysplastic/myeloproliferative neoplasm, unclassifiable with JAK2V617F mutation.

Key Clinical Message: Hematopoietic neoplasms can cause adrenal infarction. In cases of thrombosis occurring at uncommon sites, it is necessary to consider evaluating for the JAK2V617F mutation, even in the absence of notable abnormalities in blood counts. Abstract: Adrenal infarction, a rare ailment, has been sporadically linked to hematopoietic neoplasms. A 46-year-old male encountered left adrenal infarction, which coincided with a progressive rise in platelet counts. Subsequent diagnosis revealed myelodysplastic/myeloproliferative neoplasm-unclassifiable, featuring a JAK2V617F mutation. Simultaneously, the patient manifested multiple arteriovenous thromboses, necessitating treatment with edoxaban, aspirin, and hydroxyurea. Following thrombosis resolution, he was transferred to a transplantation center. This report delves into the thrombogenicity linked to the JAK2V617F mutation, while also examining documented instances of adrenal infarction in myeloid neoplasms. We should consider evaluating for JAK2V617F mutation even in cases of thrombosis at unusual sites, including adrenal infarction, even if there are no considerable abnormalities in blood counts.

Comparing health care outcomes before and after employing nurse practitioners in cardiovascular hospitals in Japan: A retrospective chart review.

BACKGROUND: There are approximately 872 certified nurse practitioners (NPs) in Japan as of April 2024. However, research on the results of their specific activities is still scarce. PURPOSE: This study aimed to compare health care outcomes before (i.e., 2019) and after (i.e., 2021) employing NPs in cardiovascular hospitals in Japan. METHODOLOGY: We conducted a retrospective chart review and analyzed 114 patients who underwent cardiac surgery in Hospital A and 381 patients who received pacemaker implantation/replacement in Hospital B. Hospital A hired one NP for cardiac surgery service, and Hospital B hired one NP for pacemaker device service. The NPs assisted in the surgical procedures and provided postsurgical management. RESULTS: In Hospital A, the median length of hospitalization and intubation were shorter in 2021 than in 2019 (p = .02 and .01, respectively). In Hospital B, medical fee reimbursement was lower in 2021 (p < .001) than in 2019, and the median procedure duration was shorter (p = .01), which remained statistically significant after controlling for age, comorbidities, and device types. Some outcomes improved following the employment of NPs, whereas others remained unchanged. CONCLUSIONS: Nurse practitioners managed surgical patients well and contributed to the quality care of cardiovascular medicine. IMPLICATIONS: The employment of NPs in Japan is encouraged because even a single NP can have a positive, although not large, impact on patients and organizations.

[Nonspecific reacting materials that interferes tacrolimus assay by ACMIA].

We report two cases of falsely elevated levels of Tacrolimus (TAC) measured by affinity column mediated immunoassay (ACMIA). Potential reasons for this are herein explored. Patient 1, a post-renal transplantation patient, was treated by TAC, while patient 2, a patient with rheumatoid arthritis, was not. TAC levels measured by ACMIA of patients 1 and 2 were greater than 40 and 20 ng/ml, respectively. In patient 2, rheumatoid factor (RF) levels were constantly higher than 1,000 IU/ml, and levels of TAC were shown to be correlated with RF. Results of immunoglobulin adsorption tests and gel filtration suggested that the false positivities for TCA were induced by IgG of patient 1 and IgM of patient 2. After the addition of anti-TAC antibody, levels of TAC decreased to an undetectable range in both cases. TAC levels also became undetectable after the addition of MAK33-Framework IEP in patient 1 and IIR in patient 2. In patient 2, the addition of HBR-1 and MAK absorbent prevented the false positive phenomenon. In both cases, human anti mouse antibodies (HAMAs) reacted to anti-TAC mouse monoclonal antibodies within the reagent and produced falsely elevated results. These results were inhibited by MAK33-Framework IEP binding to the hyper-variable region of immunoglobulin; therefore, the causative agent of this phenomenon in patient 1 was likely an anti-idiotype antibody against the mouse monoclonal anti-TAC antibody used in the assay. Furthermore, a close relationship between measured levels of TAC and RF, along with the finding that the addition of HBR-1 and IRR prevents false positive results, suggests that RF produced false positive results through IgM-HAMA activity in patient 2. These data indicate that false positive results of TAC can be due to the presence of HAMAs with different specificities.

Hemoglobin-platelet index as a prognostic factor in patients with peripheral T-cell lymphoma.

Peripheral T-cell lymphoma (PTCL) is a heterogeneous group of aggressive lymphomas with a poor prognosis. The International Prognostic Index (IPI) and the Prognostic Index for PTCL-unspecified (PIT) is used to predict the prognosis of PTCL. The hemoglobin-platelet index (HPI), based on anemia and thrombocytopenia status, is associated with the prognosis of diffuse large B-cell lymphoma. However, its significance in terms of predicting the prognosis of PTCL has not been fully investigated. We herein retrospectively analyzed 100 patients with newly diagnosed PTCL in our department. At a median follow-up of 3.2 years, the median progression-free survival (PFS) and overall survival (OS) was 0.72 (95% confidence interval [CI]: 0.56-1.2) years and 2.0 (95% CI: 1.5-4.7) years, respectively. Multivariate analysis revealed that elevated lactic dehydrogenase (LDH) and hypoalbuminemia were independent adverse variables for PFS. The HPI showed significant predictive value for both PFS and OS. As a new prognostic model comprising the HPI, LDH, and albumin, the LA-HPI allowed the stratification of patients into four distinct risk subgroups: low risk (zero risk factors), low-intermediate risk (one risk factors), high-intermediate risk (two or three risk factors), or high risk (four risk factors). The PFS and OS differed significantly among the patients by the LA-HPI score. The LA-HPI demonstrated better predictive performance compared to the IPI, PIT, and HPI. Our data demonstrated the prognostic utility of the HPI in patients with PTCL. The LA-HPI, incorporating four readily obtainable parameters, exhibited superior performance compared to traditional indices.

Analysis of interferon signaling by infectious hepatitis C virus clones with substitutions of core amino acids 70 and 91.

Substitution of amino acids 70 and 91 in the hepatitis C virus (HCV) core region is a significant predictor of poor responses to peginterferon-plus-ribavirin therapy, while their molecular mechanisms remain unclear. Here we investigated these differences in the response to alpha interferon (IFN) by using HCV cell culture with R70Q, R70H, and L91M substitutions. IFN treatment of cells transfected or infected with the wild type or the mutant HCV clones showed that the R70Q, R70H, and L91M core mutants were significantly more resistant than the wild type. Among HCV-transfected cells, intracellular HCV RNA levels were significantly higher for the core mutants than for the wild type, while HCV RNA in culture supernatant was significantly lower for these mutants than for the wild type. IFN-induced phosphorylation of STAT1 and STAT2 and expression of the interferon-inducible genes were significantly lower for the core mutants than for the wild type, suggesting cellular unresponsiveness to IFN. The expression level of an interferon signal attenuator, SOCS3, was significantly higher for the R70Q, R70H, and L91M mutants than for the wild type. Interleukin 6 (IL-6), which upregulates SOCS3, was significantly higher for the R70Q, R70H, and L91M mutants than for the wild type, suggesting interferon resistance, possibly through IL-6-induced, SOCS3-mediated suppression of interferon signaling. Expression levels of endoplasmic reticulum (ER) stress proteins were significantly higher in cells transfected with a core mutant than in those transfected with the wild type. In conclusion, HCV R70 and L91 core mutants were resistant to interferon in vitro, and the resistance may be induced by IL-6-induced upregulation of SOCS3. Those mechanisms may explain clinical interferon resistance of HCV core mutants.

Creation of a questionnaire to measure stress among nurses engaged in palliative care on general wards.

PURPOSE: This study was conducted to create a questionnaire that measures stress among nurses engaged in palliative care on general wards. METHODS: Nurses with at least 3 years of experience involved in palliative care on a general ward in six facilities in Japan were the subjects from September 7 to October 4, 2004. A draft questionnaire on stress factors and conditions of stress in nurses engaged in end-of-life care was created, and question items and content meaning were revised to produce 32 question items, with a four-point Likert scale for the responses. Two pretests were conducted. Internal validity was investigated and resulted in 31 question items. Factor analysis using the principal factor method (Varimax rotation) was performed, and Cronbach's coefficient alpha was used to evaluate internal consistency and check reliability. RESULTS: The survey response rate was 94%, with a valid response rate of 98%. Analysis was conducted using responses from 269 participants, of whom 98.9% were female, with a mean age of 35.4 years. The mean length of experience as a nurse was 13.6 years, and the mean length of experience in cancer nursing was 8 years. Results of factor analysis produced eigenvalues of 5.260-1.558 and a cumulative proportion of 58.032%. After two items were deleted, six stress-related factors were identified; their alpha coefficients were 0.753 to 0.912, ensuring high reliability. CONCLUSIONS: The questionnaire developed had high internal validity and high reliability, and it can thus serve as a first stage in elucidating stress among nurses engaged in palliative care on general wards.

Inhibitory effect of a triterpenoid compound, with or without alpha interferon, on hepatitis C virus infection.

A lack of patient response to alpha interferon (α-IFN) plus ribavirin (RBV) treatment is a major problem in eliminating hepatitis C virus (HCV). We screened chemical libraries for compounds that enhanced cellular responses to α-IFN and identified a triterpenoid, toosendanin (TSN). Here, we studied the effects and mechanisms of action of TSN on HCV replication and its effect on α-IFN signaling. We treated HCV genotype 1b replicon-expressing cells and HCV-J6/JFH-infected cells with TSN, with or without α-IFN, and the level of HCV replication was quantified. To study the effects of TSN on α-IFN signaling, we detected components of the interferon-stimulated gene factor 3 (ISGF3), phosphorylated signal transducer and activator of transcription 1 (STAT1), and STAT2 by Western blotting analysis; expression levels of mRNA of interferon regulatory factor 9 using real-time reverse transcription-PCR (RT-PCR); and interferon-stimulated response element reporter activity and measured the expression levels of interferon-inducible genes for 2',5'-oligoadenylate synthetase, MxA, protein kinase R, and p56 using real-time RT-PCR. TSN alone specifically inhibited expression of the HCV replicon (50% effective concentration = 20.6 nM, 50% cytotoxic concentration > 3 µM, selectivity index > 146). Pretreatment with TSN prior to α-IFN treatment was more effective in suppressing HCV replication than treatment with either drug alone. Although TSN alone did not activate the α-IFN pathway, it significantly enhanced the α-IFN-induced increase of phosphorylated STATs, interferon-stimulated response element activation, and interferon-stimulated gene expression. TSN significantly increased baseline expression of interferon regulatory factor 9, a component of interferon-stimulated gene factor 3. Antiviral effects of treatment with α-IFN can be enhanced by pretreatment with TSN. Its mechanisms of action could potentially be important to identify novel molecular targets to treat HCV infection.

Cholestatic liver fibrosis and toxin-induced fibrosis are exacerbated in matrix metalloproteinase-2 deficient mice.

Matrix metalloproteinase (MMP) plays an important role in homeostatic regulation of the extracellular environment and degradation of matrix. During liver fibrosis, several MMPs, including MMP-2, are up-regulated in activated hepatic stellate cells, which are responsible for exacerbation of liver cirrhosis. However, it remains unclear how loss of MMP-2 influences molecular dynamics associated with fibrogenesis in the liver. To explore the role of MMP-2 in hepatic fibrogenesis, we employed two fibrosis models in mice; toxin (carbon tetrachloride, CCl4)-induced and cholestasis-induced fibrosis. In the chronic CCl4 administration model, MMP-2 deficient mice exhibited extensive liver fibrosis as compared with wild-type mice. Several molecules related to activation of hepatic stellate cells were up-regulated in MMP-2 deficient liver, suggesting that myofibroblastic change of hepatic stellate cells was promoted in MMP-2 deficient liver. In the cholestasis model, fibrosis in MMP-2 deficient liver was also accelerated as compared with wild type liver. Production of tissue inhibitor of metalloproteinase 1 increased in MMP-2 deficient liver in both models, while transforming growth factor ß, platelet-derived growth factor receptor and MMP-14 were up-regulated only in the CCl4 model. Our study demonstrated, using 2 experimental murine models, that loss of MMP-2 exacerbates liver fibrosis, and suggested that MMP-2 suppresses tissue inhibitor of metalloproteinase 1 up-regulation during liver fibrosis.

Antiviral effects of the interferon-induced protein guanylate binding protein 1 and its interaction with the hepatitis C virus NS5B protein.

UNLABELLED: Interferons (IFNs) and the interferon-stimulated genes (ISGs) play a central role in antiviral responses against hepatitis C virus (HCV) infection. We have reported previously that ISGs, including guanylate binding protein 1 (GBP-1), interferon alpha inducible protein (IFI)-6-16, and IFI-27, inhibit HCV subgenomic replication. In this study we investigated the effects of these ISGs against HCV in cell culture and their direct molecular interaction with viral proteins. HCV replication and virus production were suppressed significantly by overexpression of GBP-1, IFI-6-16, or IFI-27. Knockdown of the individual ISGs enhanced HCV RNA replication markedly. A two-hybrid panel of molecular interaction of the ISGs with HCV proteins showed that GBP-1 bound HCV-NS5B directly. A protein truncation assay showed that the guanine binding domain of GBP-1 and the finger domain of NS5B were involved in the interaction. Binding of NS5B with GBP-1 inhibited its guanosine triphosphatase GTPase activity, which is essential for its antiviral effect. Taken together, interferon-induced GBP-1 showed antiviral activity against HCV replication. CONCLUSION: Binding of the HCV-NS5B protein to GBP-1 countered the antiviral effect by inhibition of its GTPase activity. These mechanisms may contribute to resistance to innate, IFN-mediated antiviral defense and to the clinical persistence of HCV infection.

Pseudoaneurysm in a chronic pancreatitis patient: report of a case, with emphasis on contrast-enhanced sonograms.

The association between pseudoaneurysm of the splenic artery and pancreatitis is now established. Rupture of an aneurysm is a lethal condition, and early diagnosis and treatment are required to prevent this hazardous life-threatening complication. In our case, early detection of pseudoaneurysm of the splenic artery enabled us to start prompt embolization, which yielded good results. Splenic infarction is known to be an important and frequent complication of transarterial embolization of splenic artery aneurysms. Thus, when performing transarterial embolization of a splenic artery aneurysm, this complication must be kept in mind and it is absolutely necessary to confirm the presence or absence of this complication after embolization of the aneurysm. In our case of pseudoaneurysm of the splenic artery due to acute aggravation of chronic pancreatitis, contrast-enhanced ultrasonography confirmed the spleen to be free from infarction. Thus, this technique is strongly recommended in such instances.

Asymptomatic emphysematous cholecystitis.

Emphysematous cholecystitis (EC) is a life-threatening complication of acute cholecystitis. Its clinical manifestations are usually vague, but asymptomatic cases are very rare. We present such a case with an emphasis on sonographic (US) findings. In this case, detection of gas echoes in the gallbladder wall and the surrounding hepatic tissue led us to an appropriate treatment. US is now the technique of first choice for diagnosing gallbladder diseases, and knowledge of US findings encountered in this case can help prevent a hazardous delay in emergent treatment.

Portal gas in a diabetic patient under pharmacotherapy with an alpha-glucosidase inhibitor: report of a case with emphasis on US findings.

Portal gas is relatively rare, and its relation to ischemic bowel diseases has been emphasized. We report the case of a 56-year-old diabetic man under pharmacotherapy with an alpha-glucosidase inhibitor in which portal gas was incidentally detected by ultrasound (US). It showed multiple echo spots moving in the portal vein. Doppler signals confirmed them to be bidirectional and spiky, which immediately led to the diagnosis of portal gas. A change in oral antidiabetic drug caused the portal gas to disappear. We stress the usefulness of US and Doppler US for detecting and diagnosing portal gas. Although detailed analysis of a larger series of diabetic patients under this therapy is needed to draw a definitive conclusion, our observation merits attention. We also briefly review the literature.

Adult T-cell leukemia/lymphoma presenting multiple lymphomatous polyposis.

Multiple lymphomatous polyposis (MLP) is an unusual form of non-Hodgkin's lymphoma characterized by polyps throughout the gastrointestinal tract. It has been reported that most MLP are observed in cases with mantle cell lymphoma of B-cell type. We herein present a case of a 66-year-old man with adult T-cell leukemia/lymphoma (ATLL). Colonoscopy revealed MLP throughout the colon and histopathological findings of ATLL cell infiltration. The patient died despite combination of chemotherapy. The literature of manifestations of colonic involvement of ATLL is reviewed and the importance of endoscopic evaluation to differentiate ATLL intestinal lesions from opportunistic infectious enterocolitis is discussed.

Multiple anechoic hepatic nodules in a patient with malignant lymphoma: report of a case with an emphasis on B-mode sonograms.

We present a case of hepatic malignant lymphoma (ML) in which the hepatic ML nodules were imaged as round anechoic nodules with posterior echo enhancement, mimicking hepatic cysts on B-mode ultrasonography (US). However, the boundary echo between the nodules and the surrounding hepatic tissue seemed to be less distinct than that of a hepatic cyst. Contrast-enhanced US showed the nodules to be hypervascular, which ruled out the possibility of hepatic cysts. Our observation stresses the importance of boundary echo for the diagnosis of hepatic ML on B-mode US. We also offer a possible explanation for this phenomenon.

An inverse relationship between autoimmune liver diseases and Strongyloides stercoralis infection.

A case-control study was undertaken to describe the prevalence of Strongyloides stercoralis infection among patients with autoimmune liver diseases, such as primary biliary cirrhosis (PBC), autoimmune hepatitis (AIH), and primary sclerosing cholangitis (PSC). This study covered 4,117 patients who were admitted to hospitals in Okinawa, Japan, between 1988 and 2006. During this period, 538 patients had the following chronic liver diseases: PBC, AIH, PSC, chronic viral hepatitis group, and alcoholic liver disease. The other 3,579 patients who were hospitalized and underwent parasitologic tests served as controls. The frequency of S. stercoralis infection in the autoimmune liver diseases group (1.0%) was lower than that found in the control group (7.0%; P = 0.0063). None of the female patients with PBC born before 1955 had S. stercoralis infection, which was also statistically significant (P = 0.045). We hypothesized that immunomodulation by S. stercoralis infection may lower the incidence of autoimmune liver disease.

Different natural courses of chronic hepatitis B with genotypes B and C after the fourth decade of life.

AIM: To investigate the different impact of genotypes B and C on the development of liver cirrhosis (LC) among different age groups of patients with chronic hepatitis B (CH-B). METHODS: We examined the outcome of 121 patients with CH-B, divided by age and genotype. Univariate analyses were used to compare different groups. The Cox proportional hazard model was employed to evaluate factors affecting the development of LC. RESULTS: In patients < 30 years old, there were no significant predictors for development of LC. However, in patients > or = 30 years old, genotype C was the only significant predictor. In the genotype C group, 8 of 12 patients who progressed to LC were 30-49 years old at initial diagnosis of chronic hepatitis (7 patients were positive for HBeAg). In the genotype B group, 4 of 8 patients who developed LC were > or = 50 years old at initial diagnosis and were HBeAg-negative. CONCLUSION: The rate of development of LC was comparable in patients infected with genotypes B and C when CH-B occurred at < 30 years old. However, CH-B patients infected with genotype C showed poor prognosis if they were 30-49 years old and were positive for HBeAg. Age-specific natural course of CH-B should be considered when patients with CH-B are treated with antiviral drugs.

[Recurrent esophageal cancer with complete response to TS-1 chemotherapy].

An 80-year-old man was admitted to our hospital for treatment of recurrent esophageal cancer in December, 2004. He was diagnosed as having esophageal cancer of stage IVa (T2N4M0) in October, 2002, and he received chemoradiotherapy (nedaplatin (CDGP)/5-fluorouracil (5-FU) total 6 course+60 Gy). Afterwards, lymph nodes recurred, and two courses of CDGP/vindesine were given. Then, the primary lesion showed a complete response (CR), and lymph nodes a partial response (PR). In December, 2004, paraesophageal lymph nodes were enlarged to the size of 7 cm. On admission, because of renal disturbance and dementia with advanced age, we chose chemotherapy with TS-1 (100 mg/body/day, three weeks of administration, then two weeks of withdrawal). He had adverse effects of hematotoxicity of grade 3, and non-hematotoxicity of grade 1. He received 6 courses of this regimen and eventually showed CR. Serum SCC was decreased from 4.7 ng/mL to 0.9 ng/mL. At present,the lesions have not recurred during the follow-up for 18 months.

Portal gas in a patient with acute obstructive cholangitis: report of a case with emphasis on US findings.

Portal gas is relatively rare, and its relationship to ischemic bowel diseases has been emphasized. We report the case of a 70-year-old woman with acute obstructive cholangitis in whom portal gas was detected by ultrasonography (US) but not by computed tomography (CT). The former showed multiple echo spots moving in the portal vein. Doppler signals confirmed them to be bidirectional and spiky, which immediately led to the diagnosis of portal gas. Immediate appropriate antibiotic treatment and biliary drainage yielded the disappearance of the portal gas. We stress the usefulness of US and Doppler US for detecting and diagnosing portal gas. Our observation suggests that when portal gas is detected by US, the possibility of cholangitis should be included in the differential diagnosis.