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1.  Clinicopathological Factors Affecting Survival and Recurrence after Initial Hepatectomy in Non-B Non-C Hepatocellular Carcinoma Patients with Comparison to Hepatitis B or C Virus 
BioMed Research International  2014;2014:975380.
We evaluated clinicopathological factors affecting survival and recurrence after initial hepatectomy in non-B non-C (NBNC) hepatocellular carcinoma (HCC) patients with comparison to hepatitis B or C virus, paying attention to relationship between alcohol consumption and histopathological findings. The medical records on the 201HCC patients who underwent initial hepatectomy between January 2000 and April 2013 were retrospectively reviewed. NBNC patients had higher prevalence of hypertension (47.4%), diabetes mellitus (35.5%), alcohol consumption (>20 g/day) (61.8%), and preserved liver function than hepatitis B or C patients. The 5-year survival rate of NBNC patients (74.1%) was significantly better than hepatitis B (49.1%) or C (65.0%) patients (NBNC versus B, P = 0.031). Among the NBNC patients, there was no relationship between alcohol consumption and clinicopathological findings including nonalcoholic fatty liver disease activity score (NAS). However, the 5-year OS and RFS rates in the alcohol-unrelated NBNC patients tend to be better than in the alcohol-related. By multivariate analysis, independent factors for OS in NBNC patients were Child-Pugh B/C, intrahepatic metastasis (im), and extrahepatic recurrence. NBNC patients, who were highly associated with lifestyle-related disease and preserved liver function, had significantly better prognosis compared to hepatitis B/C patients; however, there was no association between alcohol consumption and histopathological findings.
PMCID: PMC3972956  PMID: 24745029
2.  Immune Response following Liver Transplantation Compared to Kidney Transplantation: Usefulness of Monitoring Peripheral Blood CD4+ Adenosine Triphosphate Activity and Cytochrome P450 3A5 Genotype Assay 
Seventy living donor liver transplantation (LDLT) and 39 kidney transplantation (KT) patients were randomly screened by using the peripheral blood CD4+ adenosine triphosphate activity (ATP) assay (IMK assay). The patients were divided into 2 groups in each organ transplantation with low IMK ATP level (<225 ng/mL) or high (>225) (LT-L: n = 23, KT-L: n = 19, LT-H: n = 47, and KT-H: n = 20, resp.). The incidence of bacterial and/or viral infection was significantly higher in LT-L group than in LT-H group (74.0 versus 8.5%: P < 0.001). Occurrence of total viral infection in KT-L was also significantly higher than that in KT-H (36.8 versus 10%: P = 0.046). The sensitivity and specificity of the IMK assay for identifying risk of infection was 0.810 and 0.878 in LDLT patients and 0.727 and 0.607 in KT patients. The percentage of LDLT patients with cytochrome P450 3A5 (CYP3A5) *1/*1 or *1/*3 genotype (expressors) was significantly higher in LT-L group than in LT-H group (53.8 versus 20.7%: P = 0.032). In both LDLT and KT patients, the IMK assay can be useful for monitoring immunological aspects of bacterial and/or viral infection. CYP3A5 expressors in LT-L group are related to postoperative infections.
PMCID: PMC3886574  PMID: 24454479
3.  Dose-dependent effects of NY-ESO-1 protein vaccine complexed with cholesteryl pullulan (CHP-NY-ESO-1) on immune responses and survival benefits of esophageal cancer patients 
Cholesteryl pullulan (CHP) is a novel antigen delivery system for cancer vaccines. This study evaluated the safety, immune responses and clinical outcomes of patients who received the CHP-NY-ESO-1 complex vaccine, Drug code: IMF-001.
Patients with advanced/metastatic esophageal cancer were enrolled and subcutaneously vaccinated with either 100 μg or 200 μg of NY-ESO-1 protein complexed with CHP. The primary endpoints were safety and humoral immune responses, and the secondary endpoint was clinical efficacy.
A total of 25 patients were enrolled. Thirteen and twelve patients were repeatedly vaccinated with 100 μg or 200 μg of CHP-NY-ESO-1 with a median of 8 or 9.5 doses, respectively. No serious adverse events related to the vaccine were observed. Three out of 13 patients in the 100-μg cohort and 7 out of 12 patients in the 200-μg cohort were positive for anti-NY-ESO-1 antibodies at baseline. In the 100-μg cohort, an antibody response was observed in 5 out of 10 pre-antibody-negatives patients, and the antibody levels were augmented in 2 pre-antibody-positive patients after vaccination. In the 200-μg cohort, all 5 pre-antibody-negative patients became seropositive, and the antibody level was amplified in all 7 pre-antibody-positive patients. No tumor shrinkage was observed. The patients who received 200 μg of CHP-NY-ESO-1 survived longer than patients receiving 100 μg of CHP-NY-ESO-1, even those who exhibited unresponsiveness to previous therapies or had higher tumor burdens.
The safety and immunogenicity of CHP-NY-ESO-1 vaccine were confirmed. The 200 μg dose more efficiently induced immune responses and suggested better survival benefits. (Clinical trial registration number NCT01003808).
PMCID: PMC4015172  PMID: 24093426
Esophageal cancer; Cancer vaccine; NY-ESO-1; Cholesteryl pullulan (CHP)
4.  Immunological Aspects in Late Phase of Living Donor Liver Transplant Patients: Usefulness of Monitoring Peripheral Blood CD4+ Adenosine Triphosphate Activity 
Aim. To evaluate whether the combination of the peripheral blood CD4+ adenosine triphosphate activity (ATP) assay (ImmuKnow assay: IMK assay) and cytochrome P450 3A5 (CYP3A5) genotype assay is useful for monitoring of immunological aspects in the patient followup of more than one year after living donor liver transplantation (LDLT). Methods. Forty-nine patients, who underwent LDLT more than one year ago, were randomly screened by using IMK assay from January 2010 to December 2011, and the complete medical records of each patient were obtained. The CYP3A5 genotypes were examined in thirty-nine patients of them. Results. The mean ATP level of the IMK assay was significantly lower in the patients with infection including recurrence of hepatitis C (HCV) (n = 10) than in those without infection (n = 39): 185 versus 350 ng/mL (P < 0.001), while it was significantly higher in the patients with rejection (n = 4) than in those without rejection (n = 45): 663 versus 306 ng/mL (P < 0.001). The IMK assay showed favorable sensitivity/specificity for infection (0.909/0.842) as well as acute rejection (1.0/0.911). CYP3A5 genotypes in both recipient and donor did not affect incidence of infectious complications. Conclusions. In the late phase of LDLT patients, the IMK assay is very useful for monitoring immunological aspects including bacterial infection, recurrence of HCV, and rejection.
PMCID: PMC3803130  PMID: 24187567
5.  Quantifying longitudinal right ventricular dysfunction in patients with old myocardial infarction by using speckle-tracking strain echocardiography 
We investigated longitudinal right ventricular (RV) function assessed using speckle-tracking strain echocardiography in patient with myocardial infarction (MI), and identified the contributing factors for RV dysfunction.
We retrospectively studied 71 patients with old MI (the OMI group) and 45 normal subjects (the Control group) who underwent a transthoracic echocardiography. Global and free wall RV peak systolic strains (PSSs) in the longitudinal direction were measured by using speckle-tracking strain echocardiography. Left ventricular (LV) PSSs were measured in the longitudinal, radial and circumferential directions. Cardiac hemodynamics including peak systolic pulmonary artery pressure was also assessed non-invasively. Plasma brain natriuretic peptide (BNP) levels were measured in all patients.
In the OMI group, 73% of the patients had a normal estimated peak systolic pulmonary artery pressure of less than 35 mmHg. Global and free wall RV PSS were impaired in the OMI group compared with the Control group, and these RV systolic indices were significantly associated with heart rate, logarithmic transformed plasma BNP, greater than 1 year after onset of MI, Doppler-derived estimated pulmonary vascular resistance, LV systolic indices, LV mass index, infarcted segments within a territory of the left circumflex artery and residual total occlusion in the culprit right coronary artery. Multivariable linear regression analysis indicated that reduced longitudinal LV PSS in the 4-chamber view and BNP levels ≥500 pg/ml were independently associated with reduced global and free wall RV PSS. Moreover, when patients were divided into 3 groups according to plasma BNP levels (BNP <100 pg/ml; n = 31, 100 ≤BNP <500 pg/ml; n = 24, and BNP ≥500 pg/ml; n = 16), only patients with BNP ≥500 pg/ml had a strong correlation between RV PSS and longitudinal LV PSS in the 4-chamber view (r = 0.78 for global RV PSS and r = 0.71 for free wall RV PSS, p <0.05).
Longitudinal RV systolic strain depends significantly on longitudinal LV systolic strain especially in patients with high plasma BNP levels, but not on estimated peak systolic pulmonary artery pressure. These results indicate that process of RV myocardial dysfunction following MI may be governed by neurohormonal activation which causing ventricular remodeling rather than increased RV afterload.
PMCID: PMC3700756  PMID: 23802850
Echocardiography; Right Ventricle; Myocardial Infarction; Plasma Brain Natriuretic Peptide
6.  Regurgitation and remastication in the foregut-fermenting proboscis monkey (Nasalis larvatus) 
Biology Letters  2011;7(5):786-789.
Although foregut fermentation is often equated with rumination in the literature, functional ruminants (ruminants, camelids) differ fundamentally from non-ruminant foregut fermenters (e.g. macropods, hippos, peccaries). They combine foregut fermentation with a sorting mechanism that allows them to remasticate large particles and clear their foregut quickly of digested particles; thus, they do not only achieve high degrees of particle size reduction but also comparatively high food intakes. Regurgitation and remastication of stomach contents have been described sporadically in several non-ruminant, non-primate herbivores. However, this so-called ‘merycism’ apparently does not occur as consistently as in ruminants. Here, to our knowledge we report, for the first time, regurgitation and remastication in 23 free-ranging individuals of a primate species, the foregut-fermenting proboscis monkey (Nasalis larvatus). In one male that was observed continuously during 169 days, the behaviour was observed on 11 different days occurring mostly in the morning, and was associated with significantly higher proportions of daily feeding time than on days when it was not observed. This observation is consistent with the concept that intensified mastication allows higher food intake without compromising digestive efficiency, and represents an expansion of the known physiological primate repertoire that converges with a strategy usually associated with ruminants only.
PMCID: PMC3169055  PMID: 21450728
rumination; merycism; foregut fermentation; herbivory; food intake
7.  Echocardiographic estimation of pulmonary capillary wedge pressure using the combination of diastolic annular and mitral inflow velocities 
Journal of Echocardiography  2012;11(1):1-8.
We aimed to identify the clinical utility of a simple echocardiographic approach for estimating the pulmonary capillary wedge pressure (PCWP) on the basis of the combined assessment of mitral inflow and tissue Doppler mitral annular velocities.
We retrospectively enrolled 165 patients who underwent both echocardiographic examination and right heart catheterization, and determined the diagnostic accuracy of echocardiography-derived parameters for estimating PCWP >18 mmHg.
Eighty-three patients had preserved left ventricular (LV) ejection fraction ≥50% (the PEF group) and 82 patients had reduced LVEF <50% (the REF group). The PEF group had higher peak early mitral annular velocity (E′) compared with the REF group. Eight patients in the PEF group but none in the REF group had normal LV diastolic function, represented as E′ >8 cm/s, and all of these patients had normal inflow pattern. The mean PCWP had the strongest correlation with the ratio of the peak early mitral inflow velocity (E) to the peak late diastolic mitral inflow velocity during atrial contraction (E/A) in both groups, followed by the left atrial diameter and E/E′ in both patient groups. Receiver operating characteristic (ROC) analysis demonstrated that the combination of abnormal E′ ≤8 and elevated E/A had high diagnostic accuracy compared with E/E′ in both patient groups with different cutoff values of E/A (1.81 in the PEF group and 1.16 in the REF group) for predicting mean PCWP >18 mmHg.
After excluding patients with normal diastolic function using E′, conventional E/A is a reliable marker for predicting high PCWP and is superior to E/E′.
PMCID: PMC3611026  PMID: 23555178
Echocardiography; Displacement; Acute pulmonary embolism; Left ventricular function
8.  Risk factors for the incidence and progression of radiographic osteoarthritis of the knee among Japanese 
International Orthopaedics  2010;35(6):839-843.
This longitudinal study aimed to identify risk factors for the incidence and progression of radiographic knee osteoarthritis (OA). We examined the inhabitants of Miyagawa village aged ≥65 years every two years between 1997 and 2007. Anteroposterior radiographs of both knees were graded for OA using the Kellgren-Lawrence (K/L) grading system. Knee OA was defined as grade ≥2. We recorded the incidence of knee OA among participants in whom both knees changed from K/L grades 0 or 1 to ≥2 over a four-year follow-up period. We also recorded the progression of knee OA using this threshold among patients in whom one or both knees changed from K/L grades 2 or 3 to any higher grade over the follow-up period. Baseline data obtained from standard questionnaires, physical findings and X-rays included age, gender, body mass index (BMI), osteoporosis, Heberden’s nodes, knee range of motion (ROM), knee pain and cigarette smoking. The rates of incidence and progression of knee OA among 360 participants (241 women, 119 men) who fulfilled the study criteria were 4.0 and 6.0% per year, respectively. Female gender (odds ratio [OR] 2.849, 95% confidence interval [CI] 1.170–6.944) and high BMI (OR 1.243, 95% CI 1.095–1.411) were significantly associated with the incidence of knee OA, and restricted knee ROM (OR 0.941, 95% CI 0.892–0.992) was significantly associated with knee OA progression. Patients with a low knee ROM relative to grade of radiographic knee OA require more careful follow-up than those with a higher ROM.
PMCID: PMC3103966  PMID: 20559829
9.  Clinical significance of serum levels of vascular endothelial growth factor and its receptor in biliary disease and carcinoma 
AIM: To investigate the clinical significance of serum vascular endothelial growth factor (VEGF) and soluble VEGF receptor-1 (VEGFR1/Flt-1) (sVEGFR1) levels in biliary diseases.
METHODS: We analyzed the serum levels of these proteins in patients with acute cholangitis (group 1), biliary malignancies (group 2), and primary biliary cirrhosis or primary sclerosing cholangitis (group 3), and in healthy donors (group 4). The influence of inflammation was also analyzed. Serum VEGF levels were expressed as VEGF per platelet (VEGF/PLT, pg/106) in order to exclude the influence of platelet counts.
RESULTS: sVEGFR1 levels were significantly higher in groups 1 and 2 than in the control group, but did not correlate with inflammatory markers. VEGF/PLT levels were generally higher in patients with active inflammation than in those with carcinoma. C-reactive protein strongly correlated with the levels of serum VEGF independently of platelet and leukocyte counts, even in cancer patients. In cancer patients, VEGF/PLT and sVEGFR1 levels might be indicators for evaluating the effect of medical treatment or the disease progression.
CONCLUSION: Serum VEGF and VEGFR1 might be useful markers for gauging the clinical effect of various treatments on patients.
PMCID: PMC4250707  PMID: 15754398
VEGF; VEGFR1; Cholangiocarcinoma; Cholangitis
10.  Gemcitabine-Based Chemoradiotherapy Followed by Surgery for Borderline Resectable and Locally Unresectable Pancreatic Ductal Adenocarcinoma 
Pancreas  2014;43(3):350-360.
This study aimed to evaluate the efficacy of gemcitabine-based chemoradiotherapy followed by surgery (gem-CRTS) for pancreatic ductal adenocarcinoma (PDAC) for borderline resectable (BR) and locally unresectable (UR) tumors.
One hundred patients with PDAC who underwent the gem-CRTS protocol were classified into 3 groups, namely, resectable (R; 14), BR (44), and UR (42). After chemoradiotherapy, the patients were reassessed for curative-intent resection.
At reassessment, distant metastases became apparent in 27% of R patients, in 12% of BR patients, and in 18% of UR patients. The multivariate analysis of preoperative factors indicated that the CA19-9 reduction rate was an independent prognostic factor in the BR group. Among reassessed patients, the resection rate was 63.6% in R, 83.7% in BR, and 50.0% in UR patients. In 63 patients that underwent curative-intent resection, the 3-year survival rate was 83.3% in R, 33.0% in BR, and 7.8% in UR patients. Using multivariate analysis, the independent prognostic factor was found to be the surgical margin in BR patients and human equilibrative nucleoside transporter 1 expression in UR patients.
We consider that our gem-CRTS protocol, even for locally UR PDAC, allows for the identification of candidates for aggressive resection at the time of reassessment and improved prognosis in the patients with positive human equilibrative nucleoside transporter 1 expression.
PMCID: PMC4210173  PMID: 24622063
pancreatic cancer; preoperative chemoradiotherapy; resectabilty; gemcitabine; human equilibrative nucleoside transporter 1 expression; AC - adjuvant chemotherapy; BR - borderline resectable; CA - celiac artery; CRT - chemoradiotherapy; CT - computed tomography; DP - distal pancreatectomy; EMT - epithelial-mesenchymal transition; EUS-FNA - endoscopic ultrasonography–guided fine-needle aspiration; gem-CRTS - gemcitabine-based chemoradiotherapy followed by surgery; hENT-1 - human equilibrative nucleoside transporter-1; NCCN - National Comprehensive Cancer Network; NCRT - neoadjuvant chemoradiotherapy; MDCT - multidetector computed tomography; MSTs - median survival times; PD - pancreaticoduodenectomy; PDAC - pancreatic ductal adenocarcinoma; PV - portal vein; R - resectable; SMA - superior mesenteric artery; SMV - superior mesenteric vein; UICC - Union Internationale Contre le Cancer; UR - unresectable

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