Increased Survival Benefit of Adjuvant Intra-arterial Infusion Chemotherapy in HCC Patients with Portal Vein Infiltration after Hepatectomy.

BACKGROUND: The role of adjuvant hepatic intra-arterial infusion chemotherapy (HAI) is considered to be a promising option. METHODS: We examined treatment effects of adjuvant HAI using cisplatin in 37 hepatocellular carcinoma (HCC) patients with portal vein infiltration (PVI) who underwent hepatectomy in comparison with those in 85 patients who did not. RESULTS: PVI in 89 patients. Increased levels of aspartate transaminase, tumor markers, size and microvessel tumor infiltration (MVI) or cirrhosis, poorly differentiation, non-adjuvant HAI was associated with lower overall survival (p = 0.09). Poor differentiation, MVI and HAI were independently risk factors associated with tumor-free and overall survivals by the multivariate analysis (p < 0.05). Adjuvant HAI tended to show longer survivals in comparison with no-HAI (p = 0.08) and the multivariate analysis revealed significant efficacy of HAI for better prognosis. CONCLUSION: Adjuvant HAI showed effectiveness on prolonging tumor-free and patient survival in HCC with PVI and is a promising option in the daily clinical practice.

Incidence of and risk factors for lymphocele formation after lateral pelvic lymph node dissection for rectal cancer: a retrospective study.

AIM: Pelvic lymphocele is a common complication that develops after pelvic lymph node dissection. The incidence of pelvic lymphocele formation has been reported to be 10.5-51% after gynaecological or urological procedures. However, no evidence has been reported thus far with regard to the development of pelvic lymphocele following lateral pelvic lymph node dissection (LPND) for low rectal cancer. The aim of this study was to investigate the incidence of and risk factors for lymphocele formation after LPND for low rectal cancer and to examine its clinical management. METHOD: We retrospectively analysed the incidence of and risk factors for pelvic lymphocele formation after LPND for rectal cancer in our hospital between January 2012 and December 2017. We also compared the size of the lymphocele between asymptomatic and symptomatic patients by using CT volumetry and examined its clinical management. RESULTS: A total of 30 out of 98 patients (30.8%) developed pelvic lymphocele after rectal LPND. The number of resected nodes was significantly higher in patients with a pelvic lymphocele (P < 0.01). The median volume was significantly higher in patients with symptomatic pelvic lymphocele (P = 0.011). Among the nine symptomatic patients, two underwent CT-guided drainage, one underwent transurethral ureteral stent placement and one underwent laparoscopic marsupialization. CONCLUSION: It is essential to keep in mind the possibility of pelvic lymphocele formation during follow-up of patients who undergo LPND, and to consider an appropriate treatment when these patients are symptomatic.

Obstruction is associated with perineural invasion in T3/T4 colon cancer.

AIM: Perineural invasion (PNI) is a risk factor for recurrence and metastasis and consequently leads to decreased survival in patients with various malignancies. Recent studies showed that stent placement in obstructive colon cancer increases the frequency of PNI. We hypothesized that mechanical stress including obstruction itself may be associated with PNI. METHOD: We retrospectively reviewed 496 patients with pathological T3 or T4 colon cancer who did not receive preoperative treatment. Data were collected from medical charts and pathological findings. The relationships between PNI and other clinicopathological factors were analysed using univariate and multivariate analyses. RESULTS: PNI was observed in 239 (48%) patients. Obstruction was markedly more frequent in PNI-positive cancer (39%) than in PNI-negative cancer (24%, P = 0.0003). Multivariate analyses identified obstruction as one of the significant factors associated with PNI (OR 1.68, P = 0.028). Moreover, in 414 patients without distant metastasis who underwent complete resection, PNI was an independent factor associated with poor recurrence-free survival (hazard ratio 2.35, P = 0.003). The coexistence of PNI and obstruction resulted in greater decreases in recurrence-free survival than PNI-negative and/or non-obstructive cases. CONCLUSION: Our results suggest that obstruction is associated with PNI and consequently contributes to an increased postoperative recurrence in colon cancer.

Influenza A virus infection of vascular endothelial cells induces GSK-3ß-mediated ß-catenin degradation in adherens junctions, with a resultant increase in membrane permeability.

Multiorgan failure with vascular hyperpermeability is the final outcome in the progression of seasonal influenza virus pneumonia and influenza-associated encephalopathy, and it is also common in infection with highly pathogenic avian influenza virus. However, the precise molecular mechanism by which influenza virus infection causes vascular endothelial cell hyperpermeability remains poorly defined. We investigated the mechanisms of hyperpermeability of human umbilical vein endothelial cells infected with influenza A virus (IAV)/Puerto Rico/8/34 (PR8) (H1N1). The levels of ß-catenin, a key regulatory component of the vascular endothelial-cadherin cell adhesion complex, were markedly decreased during infection for 28 h, with increments of vascular hyperpermeability measured by transendothelial electrical resistance. Lactacystin (at 2 µM), a proteasome inhibitor, inhibited the decrease in ß-catenin levels. Since the N-terminal phosphorylation of ß-catenin by glycogen synthase kinase (GSK)-3ß is the initiation step of proteasome-dependent degradation, we examined the effects of GSK-3ß suppression by RNA interference in endothelial cells. IAV-infection-induced ß-catenin degradation was significantly inhibited in GSK-3ß-knockdown cells, and transfection of cells with recombinant ß-catenin significantly suppressed IAV-induced hyperpermeability. These findings suggest that IAV infection induces GSK-3ß-mediated ß-catenin degradation in the adherens junctional complexes and induces vascular hyperpermeability. The in vitro findings of ß-catenin degradation and activation of GSK-3ß after IAV infection were confirmed in lungs of mice infected with IAV PR8 during the course of infection from day 0 to day 6. These results suggest that GSK-3ß-mediated ß-catenin degradation in adherens junctions is one of the key mechanisms of vascular hyperpermeability in severe influenza.

Abundant daily non-sedentary activity is associated with reduced prevalence of metabolic syndrome and insulin resistance.

BACKGROUND: Non-exercise activity thermogenesis has recently drawn attention because of its potential to prevent weight gain. AIM: This study evaluated the relationships between the duration of daily non-sedentary activities and the prevalence of metabolic syndrome and insulin resistance (IR) in the Japanese population. MATERIAL/SUBJECTS AND METHODS: A total of 518 eligible subjects (380 men and 138 women) who attended the Tokushima Prefectural General Health Checkup Center and participated in the baseline survey of a cohort study conducted in Tokushima Prefecture, Japan were analyzed. Information about lifestyle characteristics including leisure-time exercise and daily non-exercise activities was obtained from a questionnaire. Logistic and multiple linear regression analyses were performed to evaluate the associations between the duration of daily non-exercise non-sedentary activities (beyond sitting) and prevalence of metabolic syndrome (and its components) and IR. RESULTS: Subjects with longer duration of daily non-sedentary activities had significantly lower adjusted odds ratios for metabolic syndrome (p for trend =0.024), abdominal obesity (p for trend =0.023), and low HDLcholesterol levels (p for trend =0.002), after adjustment for sex, age, and other probable covariates including leisure-time exercise. Longer duration of daily non-sedentary activities was further associated with lower homeostasis model of assessment- IR (HOMA-IR) values (p for trend =0.009). CONCLUSIONS: Our results suggest that abundant daily non-sedentary activity might be associated with a lower prevalence of metabolic syndrome, especially for the components of central obesity and low HDL-cholesterol levels, and with a lower prevalence of IR, independent of leisure-time exercise.

Consumption of coffee, not green tea, is inversely associated with arterial stiffness in Japanese men.

BACKGROUND/OBJECTIVES: Studies on the associations between coffee and green tea consumption and arterial stiffness are rare. This study evaluated the possible relationships between coffee and green tea consumption and brachial-ankle pulse wave velocity (ba-PWV) values in Japanese men. SUBJECTS/METHODS: In total, 540 eligible men who enrolled in the baseline survey of a cohort study in Tokushima Prefecture, Japan, and who underwent ba-PWV measurement were analyzed. Information about lifestyle characteristics including coffee and green tea intake were obtained from a structural self-administered questionnaire. Multiple linear regression analyses were used to evaluate the associations between coffee and green tea consumption and ba-PWV. RESULTS: Subjects with greater coffee consumption were younger and showed higher proportions of current smoking and alcohol consumption. Subjects with greater green tea consumption were older and showed lower proportions of current smoking and alcohol consumption. Greater coffee consumption was significantly inversely associated with ba-PWV after the adjustment for probable covariates, including serum low-density lipoprotein cholesterol and high-density lipoprotein cholesterol (P for trend =0.031). After additional adjustment for serum triglycerides, this inverse association persisted, but was somewhat attenuated (P for trend =0.050). In contrast, green tea consumption was not associated with ba-PWV. CONCLUSIONS: Coffee consumption was inversely associated with arterial stiffness independent of known atherosclerotic risk factors, and this association was partly mediated by reduced circulating triglycerides. Further prospective or interventional studies are needed to confirm the causal association.

IL-34 and M-CSF share the receptor Fms but are not identical in biological activity and signal activation.

Macrophage colony-stimulating factor (M-CSF) regulates the production, survival and function of macrophages through Fms, the receptor tyrosine kinase. Recently, interleukin-34 (IL-34), which shares no sequence homology with M-CSF, was identified as an alternative Fms ligand. Here, we provide the first evidence that these ligands indeed resemble but are not necessarily identical in biological activity and signal activation. In culture systems tested, IL-34 and M-CSF showed an equivalent ability to support cell growth or survival. However, they were different in the ability to induce the production of chemokines such as MCP-1 and eotaxin-2 in primary macrophages, the morphological change in TF-1-fms cells and the migration of J774A.1 cells. Importantly, IL-34 induced a stronger but transient tyrosine phosphorylation of Fms and downstream molecules, and rapidly downregulated Fms. Even in the comparison of active domains, these ligands showed no sequence homology including the position of cysteines. Interestingly, an anti-Fms monoclonal antibody (Mab) blocked both IL-34-Fms and M-CSF-Fms binding, but another MAb blocked only M-CSF-Fms binding. These results suggested that IL-34 and M-CSF differed in their structure and Fms domains that they bound, which caused different bioactivities and signal activation kinetics/strength. Our findings indicate that macrophage phenotype and function are differentially regulated even at the level of the single receptor, Fms.

Circulating profiles of osteoprotegerin and soluble receptor activator of nuclear factor kappaB ligand in post-menopausal women.

OBJECTIVE: The aim of this study was to elucidate the detail profiles of circulating osteoprotegerin (OPG) and soluble receptor activator of nuclear factor kappaB ligand (sRANKL) in post-menopausal women. METHODS: Eighty Japanese post-menopausal women were enrolled in this cross-sectional study. Circulating OPG and free fraction of sRANKL (free sRANKL), PTH, calcium and phosphorus, age, years since menopause, body mass index, bone mineral density of the vertebral bodies (LBMD) and bone turnover markers were determined in each subject. RESULTS: In rank order correlation analysis, serum OPG concentrations had a significant positive correlation with age (r=0.291, p=0.024) and a marginal significant negative correlation with LBMD (r=-0.247, p=0.062). However they did not have correlations with LBMD or other parameters after adjustment for age. Serum free sRANKL concentrations had a significant positive correlation with age (r=0.332, p=0.010) and a significant negative correlation with LBMD (r=-0.608, p<0.001). This correlation with LBMD persisted after adjustment for age. In a multiple regression analysis with a stepwise model, the main determinants of LBMD were age and serum free sRANKL (p=0.015 and p=0.006, respectively). CONCLUSIONS: We found the increase in circulating OPG and sRANKL with age and a robust negative correlation between circulating free sRANKL and LBMD after adjustment for age. The increase in circulating free sRANKL may reflect directly or indirectly the conditions coexistent with bone loss in post-menopausal women.

Enhancement of oxidative damage to cultured cells and Caenorhabditis elegans by mitochondrial electron transport inhibitors.

The mechanisms that lead to mitochondrial damage under oxidative stress conditions were examined in primary and cultured cells as well as in the nematode Caenorhabditis elegans (C. elegans) treated simultaneously with electron transport inhibitors and oxygen gas. Oxygen loading enhanced the damage of PC 12 cells by thenoyltrifluoroacetone (TTFA, a complex II inhibitor), but did not by rotenone (a complex I inhibitor), antimycin (a complex III inhibitor), and sodium azide (a complex IV inhibitor). In primary hepatocytes, the enhancement was observed with the addition of sodium azide and rotenone, but not by TTFA or antimycin. In the nematode, only rotenone and TTFA enhanced the sensitivity under hyperoxia. These results demonstrate that highly specific inhibitors of electron transport can induce oxygen hypersensitivity in cell levels such as PC 12 cells and primary hepatocytes, and animal level of C. elegans. In addition the cell damage is different dependent on cell type and organism.

Detection of factor V Leiden in Thai patients with venous thrombosis.

The molecular defect underlying activated protein C resistance (APC-R) is caused by a G to A point mutation in the codon for arginine 506 in the factor V gene (factor V Leiden) which is a major risk factor for venous thrombosis, especially in Caucasian populations. This study is an analysis of the Thai population to determine the prevalence of the factor V Leiden mutation. Twenty-seven patients with apparent venous thrombosis were divided into two groups according to APC-R test. Thirteen patients were diagnosed as positive for n-APC-SR, ratio < 0.8 and fourteen patients were diagnosed as negative for n-APC-SR, ratio > 0.8. Two of thirteen APC-R positive patients and one of fourteen APC-R negative patients were found to have the heterozygous allele for the factor V Leiden mutation but the homozygous allele was not detected in these groups of patients. Neither the heterozygous nor homozygous Leiden mutation was detected in 200 healthy volunteer blood donors. In conclusion, our findings indicate that factor V Leiden mutation is related to venous thrombosis in Thai people. Moreover, a further study of other mutations at the activated protein C cleavage sites of factor V and factor VIII is recommended.

Which type of underlying disease facilitates cytomegalovirus infection? Comparison of benign disease, hematopoietic malignancy, and post-bone-marrow or renal transplantation status by using the first standardized objective PCR test for cytomegalovirus detection.

All immunocompromised hosts, such as infants, the elderly, patients with advanced cancer, and patients being treated with immunosuppressants, etc., are said to be more susceptible to cytomegalovirus (CMV) infection or CMV disease. However, we questioned the validity of this conclusion and attempted to detect CMV viremia in the plasma of subjects by using the AMPLICOR CMV test (Roche Diagnostics Systems, Branchburg, NJ), the first standardized PCR kit for CMV infection. One hundred healthy volunteers whose CMV IgG titer was < 4 and 100 healthy volunteers whose IgG titer for CMV was > or = 4 were studied. None of the subjects in either healthy group was positive for CMV viremia. Patients who were suspected of CMV infection were divided into four groups and tested: [1] 104 patients with benign disease, only one of whom was positive for CMV [2] 99 patients with hematopoietic malignancy who had not undergone bone marrow transplantation and all of whom were negative for CMV infection [3] 120 post-bone-marrow transplantation, 28 of whom were CMV positive, [4] 37 post-renal transplantation patients, 19 of whom were CMV positive. A statistically significant difference in CMV positivity was found by the non-parametric Kruskal-Wallis test (p < 0.0001) among the four disease group. CMV infection has been said to occur in all types of immunocompromised patients, however, based on our findings, we conclude that CMV infection tends to occur in post-transplantation status and does not tend to occur in patients with hematopoietic malignancy if they have not undergone transplantation.

Effects of glucocorticoids on bone mineral density in rheumatoid arthritis patients. A longitudinal study.

We carried out a comparative study in 78 post-menopausal women with rheumatoid arthritis (RA). Forty-four women with a mean disease duration of 17.5 years had been treated with low-dose glucocorticoid (prednisone at < 5 mg/day) for at least 12 months. They were studied for an average period of 3 years and 8 months. The remaining 34 women had been treated only with nonsteroidal anti-rheumatic drugs (NSAIDs) and served as the control group. Bone mineral density (BMD) in the lumbar spine (L2-4) and femoral neck was measured by dual-energy X-ray absorptiometry (DXA). Reduction of BMD in the lumbar spine was significant in both groups (P < 0.05 to approximately 0.01), but there was no statistically significant difference between the two groups. BMD of the femoral neck decreased significantly (P < 0.05) in the prednisone group, but again the difference was not significant between the two groups. Our data suggest that low-dose prednisone administration probably does not induce significant axial bone loss in female RA patients.

Evaluation of a new laboratory test measuring plasma (1-->3)-beta-D-glucan in the diagnosis of Candida deep mycosis: comparison with a serologic test.

We evaluated the effectiveness of the newly developed WAKO beta-glucan test which measures plasma (1-->3)-beta-D-glucan concentrations in the diagnosis of Candida deep mycosis. This test was compared to the Cand-Tec test. The WAKO beta-glucan test and Cand-Tec test were performed on 212 plasma specimens which were taken at 212 instances from 62 immunocompromised patients with serious diseases; i.e. hematopoietic malignancy, solid malignant tumor, etc. The sensitivities and specificities for the WAKO beta-glucan test were 84.8 and 85.9%, respectively, and 60.9 and 80.0% for the Cand-Tec test.

[A clinical evaluation of the new laboratory method that diagnoses bacterial infection, using silkworm larvae plasma].

Based upon the phenomenon that the peptidoglycan, a common component of Gram positive and negative bacteria, reacts specifically with silkworm larvae plasma (SLP), a new laboratory method named "SLP test" was developed to measure the reaction products in plasma quantitatively as SLP. This SLP test seems to be able to diagnose both Gram positive and negative bacterial infection. So we evaluated its usefulness in diagnosing clinical infectious diseases. This study included 14 patients with result to positive bacterial blood culture, 22 patients with bacterial local infection, 7 patients without any evidence of bacterial infection, and 19 healthy volunteers. It seemed that the cut-off value of this SLP test should be set at 0.6 ng/ml. The sensitivity and specificity of this SLP test were 57.1%, 100%, respectively. A significant difference was not detected statistically between SLP values of patients with Gram positive and Gram negative bacterial infectious diseases. So the SLP test did not appeared specific to either Gram positive or Gram negative bacteria. This test may become a new method diagnosing bacterial infectious disease.

Reduced susceptibility to collagen-induced arthritis in mice deficient in IFN-gamma receptor.

Collagen-induced arthritis (CIA) is an arthritic model that was developed after immunization with type II collagen (CII). Apparently, contradictory results have been reported regarding the role of IFN-gamma in the development of CIA. Therefore, we employed IFN-gamma R-deficient mice to study the role of IFN-gamma. To introduce the CIA susceptibility gene (H-2q), IFN-gamma R-deficient (H-2b/b/IFN-gamma R-/-) mice were mated with DBA/1 (H-2q/q/IFN-gamma R+/+) mice; next, the F1 mice were interbred to yield F2 offspring bearing different combinations of H-2 (H-2q/q, H-2q/b, and H-2b/b) and IFN-gamma R (IFN-gamma R+/+, IFN-gamma R+/-, and IFN-gamma R-/-) genes. Although the H-2q allele appeared to confer susceptibility to CIA, mice that were homozygous for the IFN-gamma R mutation showed a substantially decreased incidence and severity of CIA. The CII-specific IgG levels of serum samples, which are known to be involved in the development of CIA, were remarkably reduced in IFN-gamma R-/- mice. Furthermore, the anti-CII IgG2a levels controlled by IFN-gamma R were significantly reduced in IFN-gamma R-/- F2 mice compared with those seen in IFN-gamma R+/+ and IFN-gamma R+/- mice, although the levels of all IgG subclass Abs examined were lower in IFN-gamma R-/- mice than in IFN-gamma R+/+ mice. No clear evidence of the imbalance of Th1/Th2 cytokines was observed in CII-immunized, IFN-gamma R-deficient mice. Taken together, these results suggest that IFN-gamma exacerbates CIA by affecting, at least, levels of CII-specific IgG Ab rather than the imbalance of Th1/Th2 cells.

[Treatment of hepatosplenic candidiasis with liposomal amphotericin B in a patient with acute leukemia; a case report of the experience of use of liposomal amphotericin B].

We report a 26-year-old male patient with acute myelocytic leukemia and hepatosplenic candidiasis during his clinical course. His hepatosplenic candidiasis was refractoty to itraconazole and fluconazol. He developed serious side-effect such as renal dysfunction, when conventional amphotericin B was given. Then he was treated with liposomal amphotericin B (Abelcet). This therapy was safe and effective for him. He was able to be treated with 3075 mg of a liposomal amphotericin B. This was ten times as much as the dose of conventional amphotericin B which was given earlier until amphotericin B was stopped because of renal dysfunction. Liposomal amphotericin B seems to be a safe and effective therapy for systemic fungal infectin and should be considered more in Japan.