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Article, IFAC-PapersOnLine. 54(14): 66-71. (2021)

We investigate spatial distributions of iron Kα (Fe-Kα) lines in the cental 100 pc of the Seyfert 2 galaxy NGC 1068 observed with Chandra. The spatial distributions of Fe-Kα lines, neutral and highly ionized, around the center of the galactic nucleus are not isotropic, as consistently confirmed in both image and spectral analyses. The hydrogen number density of the gas clouds responsible for the neutral Fe-Kα line emission is estimated to be 102–103 cm−3 for the sampled regions near the galactic core. The photo-ionization model, where iron is assumed to be ionized by X-rays from the galactic nucleus, yields ionization parameters lower than 19 for these clouds. The range of this ionization parameter is two or three orders of magnitude lower than the theoretically expected value to produce the observed helium-like Fe-Kα line intensities. Therefore, the photo-ionization model is excluded from the explanation of the amount of highly ionized iron that is responsible for the observed Fe-Kα lines. Also, we find anti-correlation in the spatial distributions between the molecular cloud in the area observed with ALMA and that of the Fe-Kα lines, including that from neutral iron. We suggest that X-ray iron-line and radio molecular cloud observations are complementary to probe the distribution of matters in the central regions around the cores of active galactic nuclei.

A retrospective case–controlled analysis was performed to identify drug candidates in the current use that may prevent colorectal cancer, outside of aspirin. A total of 37,510 patients aged ≥20 years were assessed to identify subjects who had been diagnosed with colorectal cancer by colonoscopy without a previous diagnosis of colorectal cancer, inflammatory bowel disease (IBD), or gastrointestinal symptoms; 1,560 patients were identified who were diagnosed with colorectal cancer by colonoscopy. The patients with colorectal cancer were matched with 1,560 age, gender, family history of colorectal cancer and comorbidity-matched control patients who were not diagnosed with colorectal cancer at colonoscopy. The medication histories were compared between the two groups. Next, candidate drugs that were more frequently used by the control patients were selected and their effects on human colorectal cancer cell lines in vitro and an inflammation-induced mouse model of colorectal cancer were tested. Putative colorectal cancer preventative agents were identified, including aspirin, vitamin D, vitamin B, vitamin C, vitamin E, xanthine oxidase inhibitor, alpha-blockers, angiotensin receptor blocker, nateglinide, probiotics, thienopyridine, folic acid, nitrovasodilators, bisphosphonates, calcium channel blockers, steroids, and statins (P < 0.05). Alpha-blockers and xanthine oxidase inhibitors were selected for further study because these agents have not been analyzed previously as factors that may affect colorectal cancer outcomes. In vitro doxazosin (alpha-blocker), but not febuxostat (xanthine oxidase inhibitor), suppressed the proliferation of human colorectal cancer cells. Doxazosin also decreased tumorigenesis in an AOM/DSS mouse colorectal cancer model. Alpha-blockers may prevent colorectal cancer.

AIM Opportunities to treat older patients with hepatitis C virus infection have increased. We investigated the efficacy and safety of glecaprevir/pibrentasvir in patients with HCV infection aged ≥75 years. METHODS We retrospectively evaluated 131 patients with hepatitis C virus infection treated with glecaprevir/pibrentasvir at nine institutions in Japan. The patients were divided into two groups according to their age: the elderly group (n = 43, aged ≥75 years) and younger group (n = 88, aged

Background Rabeprazole at 10 or 20 mg twice daily (b.i.d.) has been reported to be highly effective in the treatment of proton pump inhibitor (PPI)-resistant reflux esophagitis (RE) that is refractory to the standard once-daily PPI regimen. We evaluated the efficacy and safety of rabeprazole maintenance therapy at 10 mg once daily (q.d.) or b.i.d. for longer than 8 weeks. Methods Patients with RE refractory to standard PPI regimens for at least 8 weeks were enrolled. They were treated with rabeprazole at 10 or 20 mg b.i.d. for 8 weeks during the open-label treatment period. After endoscopic examination, those with confirmed healing entered the subsequent double-blind maintenance therapy. During this period, the subjects were randomized to receive rabeprazole 10 mg q.d. (control) or 10 mg b.i.d. The primary endpoint was the endoscopic no-recurrence rate at Week 52. Results In total, 517 subjects entered the treatment, and 359 subjects continued on maintenance therapy. The full analysis set for central assessment included 343 subjects. The no-recurrence rate at Week 52 was significantly higher in the b.i.d. group (73.9%; p 2 test) than in the q.d. group (44.8%). In particular, the b.i.d. regimen was more effective in all subgroups with Los Angeles Classification Grade B to D at treatment entry. Conclusions In the maintenance treatment of PPI-resistant RE, rabeprazole at 10 mg b.i.d. exerted a stronger recurrence-preventing effect than 10 mg q.d. over 52 weeks. No particular safety issues were noted during long-term administration. ClinicalTrials.gov number: NCT02135107.

This study concerned the circular path-following control of a vehicle. For a circular path, two methods can be applied to the vehicle system, namely, rotational coordinate transformation and expansionary coordinate transformation. Via numerical simulations of the application of these two methods, we discovered that the former provides undershoot in its initial response; however, this does not appear if the latter method is also applied to the former. The undershoot phenomenon is undesirable for tracking control. In order to investigate the reason for the occurrence of the undershoot phenomenon, a condition for the undershoot was derived from an analysis of the first step response in the control system model. The obtained condition depended on the relationship between the initial value and the target value of the vehicle. As a result, we found that the former method satisfied the undershoot condition. Second, we analyzed the condition for the method which included expansionary coordinate transformation, and we found that this approach includes additional feedforward control input in comparison with the former method. Subsequently, we demonstrated that the feedforward input allowed the latter system to avoid undershoot.

Tacrolimus (TAC) combined with short-term methotrexate (MTX) is widely used to prevent graft-versus-host disease (GVHD) in cord blood transplantation (CBT). As short-term MTX aggravates mucositis and delays engraftment, we reduced the dose of MTX, as previously reported in the non-CBT setting. Here, we retrospectively analyze outcomes of 20 patients who received CBT from April 2017 to December 2018. All patients received TAC with mini-MTX as GVHD prophylaxis. Mini-MTX was administered at a dose of 5 mg/m2 of MTX on days 1, 3 and 6 after CBT. Median age was 54.5 years. Median follow-up time in surviving patients was 396 days. The primary disease was acute leukemia (n = 12) or malignant lymphoma (n = 8). Three patients and 17 patients received myeloablative and reduced-intensity conditioning, respectively. Rate and median time to engraftment of neutrophils were 90.0% and 20.5 days, respectively. Cumulative incidences of grade II–IV and grade III–IV acute GVHD were 35.0% and 5.0%, respectively. At one year after CBT, the overall survival rate was 80.5%, cumulative incidence of relapse/progression was 15.0%, and non-relapse mortality rate was 5.0%. In conclusion, TAC with mini-MTX may be a promising GVHD prophylaxis regimen in single-unit CBT.

AIM The present study aimed to determine the real-world efficacy and safety of the non-structural protein (NS)5A inhibitor elbasvir (EBR) combined with the NS3/4A protease inhibitor grazoprevir (GZR) in patients with hepatitis C virus (HCV) genotype 1 (GT1) infection. METHODS This study retrospectively evaluated the rate of sustained virologic response at 12 weeks post-treatment (SVR12) and the safety of EBR/GZR treatment in 159 men and 194 women with a median age of 72 years, and it assessed factors associated with the SVR12 rate. The attending physicians were responsible for selecting candidate patients for EBR/GZR in this retrospective study. RESULTS Treatment outcomes for EBR/GZR were good in direct-acting antiviral (DAA)-naive patients, of whom 99.4% achieved SVR. Of 353 patients, 10 (2.9%) had treatment failure. Of these patients, eight previously underwent DAA therapy, and the remaining two had NS5A-L31/Y93 double mutation. The SVR rate was 50% (8/16 patients) in patients who previously underwent DAA therapy, and 18.2% (2/11 patients) in patients with NS5A-L31/Y93 double mutation. On multivariate logistic regression analysis, NS5A-Y31/Y93 double mutation (odds ratio 356.3; 95% confidence interval, 23.91-16 940; P

Fatigue damage is a major topic in bridge maintenance. The fatigue damage to steel bridge deck has been dramatically increasing since the first fatigue damage was observed in Hanshin expressway in early 2000s. Insufficient knowledge of bridge fatigue design and unexpected increase of traffic demand and heavy vehicle could be the cause of the fatigue damage.Replacement of base pavement course to steel fiber reinforced concrete (SFRC) has been generally used for strengthening of steel decks; however, the countermeasure from the topside of the bridge deck could make serious traffic disruption. Therefore, reactive and proactive maintenance for such steel decks has not been well progressed so far.According to the background above, Hanshin expressway has been making an effort on developing new method by strengthening steel deck from the bottom side. The idea of the new method is to enhance fatigue resistance by improving the weld joint between deck plate and U-rib plate. Three potential methods were identified and the effectiveness of those methods was studied in field for making sure of not only fatigue resistance improvement but also field construction.This paper will introduce the new retrofit methods for steel deck and describe the effectiveness of those methods.

Duchenne muscular dystrophy (DMD) is caused by mutations in the DMD gene which encodes dystrophin protein. Dystrophin defect affects cardiac muscle as well as skeletal muscle. Cardiac dysfunction is observed in all patients with DMD over 18 years of age, but there is no curative treatment for DMD cardiomyopathy. To establish novel experimental platforms which reproduce the cardiac phenotype of DMD patients, here we established iPS cell lines from T lymphocytes donated from two DMD patients, with a protocol using Sendai virus vectors. We successfully conducted the differentiation of the DMD patient-specific iPS cells into beating cardiomyocytes. DMD patient-specific iPS cells and iPS cell-derived cardiomyocytes would be a useful in vitro experimental system with which to investigate DMD cardiomyopathy.

Early gastric cancer, especially cancer confined to the mucosa (stage T1a), is known to have a high cure rate with rare recurrence. We herein report the case of a 40-year-old female who initially presented with biliary tract dilatation, pancreatic duct dilatation and intestinal wall thickening 3 years after curative resection of pT1aN0 stage gastric cancer. The intestinal resection specimen revealed tumor cells spreading through the subserosa to the submucosa sparing mucosal membrane, which made exploratory laparotomy the only approach to confirm the diagnosis. It is always important to be aware of malignancy recurrence and clinicians should not hesitate to choose exploratory laparotomy to avoid any delay in the diagnosis and treatment.

A retrospective case-controlled analysis was performed to identify drug candidates in the current use that may prevent colorectal cancer, outside of aspirin. A total of 37,510 patients aged ≥20 years were assessed to identify subjects who had been diagnosed with colorectal cancer by colonoscopy without a previous diagnosis of colorectal cancer, inflammatory bowel disease (IBD), or gastrointestinal symptoms; 1,560 patients were identified who were diagnosed with colorectal cancer by colonoscopy. The patients with colorectal cancer were matched with 1,560 age, gender, family history of colorectal cancer and comorbidity-matched control patients who were not diagnosed with colorectal cancer at colonoscopy. The medication histories were compared between the two groups. Next, candidate drugs that were more frequently used by the control patients were selected and their effects on human colorectal cancer cell lines

Background and aim This study aimed to elucidate whether interferon (IFN)-free direct-acting antiviral (DAA) therapy for hepatitis C after curative treatment of hepatocellular carcinoma (HCC) promotes HCC recurrence in a real-world large-scale cohort. Methods This multicenter study was conducted by the Japanese Red Cross Hospital Liver Study Group. This retrospective study analyzed 516 patients who underwent antiviral treatment for hepatitis C with either IFN (n = 148) or IFN-free DAA (n = 368) after curative HCC treatment; 78 IFN-treated patients and 347 IFN-free DAA-treated patients achieved sustained virological response (SVR). The recurrence rate of HCC was compared between the antiviral therapies. Logistic analysis and Cox proportional hazards analysis identified factors associated with early recurrence of HCC within 24 weeks of antiviral therapy and recurrence throughout the observation period, respectively. Results AFP at the completion of antiviral therapy, clinical stage of HCC, and non-SVR were independent factors associated with early recurrence of HCC. Among patients who had achieved SVR, the clinical stage of HCC and the level of AFP at completion of antiviral therapy were independent factors associated with early recurrence of HCC. For recurrence throughout the observation period in SVR patients, AFP at completion of antiviral therapy, duration between last HCC treatment to antiviral therapy, and the number of treatments were independent factors. There was no significant difference in the rate of early recurrence of HCC or recurrence throughout the observation period between IFN and IFN-free DAA treated patients. Conclusions There were no differences in the early recurrence rate of HCC between patients who underwent IFN and those who underwent IFN-free DAA as antiviral therapies.

Keratin was extracted as a reduced form from wool, which was then subjected to acetamidation, carboxymethylation or aminoethylation at abundant free cysteine residues to give acetamidated keratin (AAK), carboxymethylated keratin (CMK) and aminoethylated keratin (AEK). Hydrogels were prepared from intact and three chemically modified keratins simply by concentrating their aqueous solution and subsequent cooling. The lowest concentration to form a hydrogel without fluidity was 110 mg/ml for AAK, 120 mg/ml for AEK, 130 mg/ml for keratin and 180 mg/ml for CMK. Comparing with a hydrogel just prepared (swelling ratio: 600-700), each hydrogel slightly shrank in an acidic solution. While AAK hydrogel little swelled in neutral and basic solutions, other hydrogels became swollen and CMK hydrogel reached to dissolution. Hydrogels of keratin, AAK and AEK were found to support cell proliferation, although cell elongation on AAK and AEK hydrogel was a little suppressed. On the other hand, CMK hydrogel did not seem to be suitable for a cell substrate because of its high swelling in culture medium. Evaluation of the hydrogels as a drug carrier showed that keratin and AAK hydrogels were good sustained drug release carriers, which showed the drug release for more than three days, while the release from AEK and CMK hydrogels completed within one day. Thus, keratin and chemically modified keratin hydrogels, especially keratin and AAK hydrogels, were promising biomaterials as a cell substrate and a sustained drug release carrier.

Coronary arterial complications associated with Kawasaki disease (KD), such as a giant coronary aneurysm, determine the relative risk of future cardiac events and require lifelong medical treatment. Here, we describe a 24-year-old man who developed myocardial infarction due to poor adherence to medical treatment for a giant coronary aneurysm in the chronic phase of KD. He was hospitalized two hours after the onset of chest pain. The presence of the giant coronary aneurysm made primary percutaneous coronary intervention (PCI) difficult. However, we were able to perform primary PCI successfully utilizing previous coronary computed tomography (CT) angiographic pictures as a reference. This case provides valuable insight for the management of coronary arterial complications associated with KD. Patients in the chronic phase of KD are usually asymptomatic, even in the presence of giant coronary aneurysms which have been reported to have a high risk of morbidity and mortality. Therefore, patient education is critical for preventing poor adherence to medical treatment for coronary arterial complications. In preparation for potential coronary intervention in the future, it is also useful to perform coronary CT angiography, coronary magnetic resonance (MR) angiography, and/or coronary angiography on a regular basis while patients remain free from serious cardiac events.

A 79-year-old Asian man was hospitalized because of progressive exertional dyspnea with decreasing left ventricular ejection fraction and frequent non-sustained ventricular tachycardia. Pre-procedure venography for implantable cardioverter defibrillator (ICD) implantation showed occlusion of the bilateral subclavian veins. In consideration of subcutaneous humps in the sterno-clavicular area and palmoplantar pustulosis, we diagnosed him as having synovitis, acne, pustulosis, hyperostosis, osteitis (SAPHO) syndrome and speculated that it induced peri-osteal chronic inflammation in the sterno-clavicular area, resulting in occlusion of the adjacent bilateral subclavian veins. An automatic external defibrillator (AED) was installed in the patient's house and total subcutaneous ICD was considered. Venous thrombosis in SAPHO syndrome is not frequent but has been reported. To the best of our knowledge, this is the first case of bilateral subclavian vein occlusion in a SAPHO syndrome patient who needs ICD implantation.

Background There are limited colonoscopy-based cohort data concerning the effectiveness of colonoscopy in reducing colorectal cancer deaths. The aim of this study was to clarify whether colonoscopy reduces colorectal cancer mortality. Methods A cohort of 18,816 patients who underwent colonoscopy without a diagnosis of colorectal cancer between 2001 and 2010 at high colonoscopy procedure volume centers was selected. Patient characteristics and colonoscopy findings were assessed. The main endpoint was colorectal cancer death (all, right-sided, and left-sided cancers), and data were censored at the time of the final visit or the final colonoscopy. The standardized all colorectal, colon, and rectal cancer mortality rates were estimated with reference to those of the general Japanese population. Additional outcome was all- cause death and the standardized all-cause mortality rate was also estimated. Results The total observed person-year mortality for colorectal cancer was 67,119. Of these, 4, 3, and 1 patients died from colorectal, colon, and rectal cancers, respectively; these values were significantly lower than the number of expected deaths in the general population, estimated to be 53.1, 34.0, and 19.1, respectively. The standardized mortalities for all colorectal, colon, and rectal cancers were 0.08 (95% confidence interval (CI), 0.02–0.17), 0.09 (95% CI, 0.02–0.22), and 0.05 (95% CI, 0.0002–0.21), respectively. There were 586 all-cause deaths (3.11%) during the observation period. The standardized all-cause mortality ratios were 0.22 (95% CI, 0.206–0.23). Conclusions The colorectal cancer mortality of patients who received colonoscopy without colorectal cancer diagnosis decreased significantly compared with that of individuals in the general population. These results were compatible even in patients with right-sided colon cancer.

Introduction: Indolent B-cell lymphoma is a type of non-Hodgkin's lymphoma that grows slowly and is not a curative disease. Yttrium-90 (90Y) iburitumomab tiuxetan is used in patients with relapsed/refractory indolent B-cell lymphoma, data is still limited in the rituximab era. In addition, previous studies did not assess the impact of early progression of disease within 2 years (POD24) which was reported to be associated with a poor prognosis in follicular lymphoma (Casulo et al, J Clin Oncol 2015) on the efficacy of 90Y iburitumomab tiuxetan. Thus, here we assessed the efficacy of 90Y iburitumomab tiuxetan in relapsed/refractory indolent B-cell lymphoma, and analyzed the impact of POD24 in this setting. Methods: We retrospectively analyzed the clinical outcomes of 51 patients with a relapsed/refractory indolent B-cell lymphoma who received 90Y iburitumomab tiuxetan at our institute from February 2009 to January 2018. POD24 was defined as progression within 24 months from the beginning of induction chemotherapy. Survival outcomes including overall survival (OS) and progression-free survival (PFS) were analyzed by Kaplan-Meier analysis and Cox proportional hazard models. Results: The median age was 64 years (range 37-88 years) at the time of receiving 90Y iburitumomab tiuxetan, and 29 (56.9%) were male. Disease subtypes were as follows: follicular lymphoma (n=44, 86.3%), mantle cell (n=4, 7.8%), marginal zone (n=2, 3.9%), and MALT lymphoma (n=1, 2.0%). The median number of previous regimens was 2 (range 1-9) and included rituximab-based therapy in all patients. Disease status at the time of receiving 90Y iburitumomab tiuxetan were as follows: complete remission (CR n=3, 5.9%), partial remission (PR n=13, 25.5%), stable disease (SD n=3, 5.9%), progression disease (PD n=32, 62.7%). The median follow-up time was 3.7 years (range 0.3-8.8 years) and overall response rate (ORR) was 94.1% (CR 56.9%, PR 37.3%). The ORR in patients with POD 24 was 95.0% (CR 60.0%, PR 35.0%), compared to 93.5% (CR 54.8%, PR 38.7%) with non-POD24. The 3-year OS and PFS rates for all patients receiving 90Y iburitumomab tiuxetan were 83.6% and 41.0%, respectively. POD24 was a significant prognostic factor for PFS in univariate analysis (1.2 years in patients with POD24 vs. 3.3 years in patients with non-POD24, (P=0.02) (Figure1). In multivariate analysis, POD24 was an independent prognostic marker of PFS (hazard ratio (HR) 0.43, 95% confidence interval (CI) 0.22-0.87, P=0.02). Conclusion: 90Y iburitumomab tiuxetan was highly effective in patients with relapsed/refractory indolent B-cell lymphoma patients. However, in patients with POD24, duration of response was short. Thus, another treatment strategy including hematopoietic stem cell transplantation should be considered. Disclosures No relevant conflicts of interest to declare.

Endoscopic ultrasound (EUS)-guided intervention has been established as a safe, effective and minimally invasive procedure for various diseases in adults, but there have been limited reports in pediatric patients. Herein, we report our experience with successful EUS-guided drainage of an intra-abdominal abscess in a 1-year-old infant concomitant with disseminated intravascular coagulation. The abscess was punctured via the stomach using a standard, convex-type echoendoscope, and the patient’s condition improved after naso-cystic catheter placement. Although the clinical course was complicated by delayed hemorrhage from the puncture site, the bleeding was successfully managed by endoscopic hemostasis using a standard forward-viewing endoscope.

Endoscopic retrograde cholangiopancreatography (ERCP) brushing cytology often cannot distinguish adenocarcinoma from reactive epithelial changes. We attempted to improve the diagnostic sensitivity of ERCP using the following methods: systematic cytological evaluation, immunocytochemical examination of minichromosome maintenance proteins (MCM) 2 and p53, and a combination of these methods. ERCP specimens from 53 patients (13 benign and 40 malignant cases) were studied. First, we reclassified the cases into three categories according to the systematic cytological evaluation: negative, suspicious, and positive. Secondly, immunocytochemistry was performed for MCM 2 and p53. The cut-off values were set at 25% labeling index (LI) for MCM 2 and 10% LI for p53, respectively. We evaluated the sensitivity, specificity, and diagnostic accuracy. The sensitivity of the systematic cytological evaluation alone did not improve significantly, compared with the original screening examination (77% vs. 68%). The sensitivity of immunocytochemistry for MCM 2 and p53 was 90% (P0.05) and 68%, respectively. Applying only the suspicious or positive categories, the sensitivity improved significantly to 93% for the combination of systematic cytological evaluation and immunocytochemistry for MCM 2 and p53 (P0.01). In conclusion, the combination of morphology and immunocytochemistry for MCM 2 and p53 may help to overcome the diagnostic cytological difficulties of pancreaticobiliary adenocarcinoma.

The role of preoperative biliary drainage (PBD) for periampullary and hilar malignancy is still controversial. We retrospectively studied consecutive 144 patients (92 periampullary and 52 hilar malignancy) undergoing surgical resection to evaluate the effects of PBD on surgical outcomes. The rate of PBD was 59% and 56%, and postoperative complications developed in 27% and 19% in periampullary and hilar malignancy, respectively. Risk factors for postoperative complications were overweight [odds ratio (OR), 7.6] and depression (OR, 8.5) in distal malignancy and American society of anesthesiologists score of 3 (OR, 6.6), depression (OR, 13.8), and portal vein embolization (OR, 6.1) in hilar malignancy. PBD was not associated with postoperative complications but reinterventions for PBD were necessary in 43% and 27% in distal and hilar biliary obstruction. In conclusion, PBD in pancreatobiliary surgery was not associated with postoperative complications, but the improvement of PBD is necessary given the high rate of reinterventions.

AIM: To investigate the safety and efficacy of the Cyberknife treatment for patients with advanced or terminal stage hepatocellular carcinoma (HCC). METHODS: Patients with HCC with extrahepatic metastasis or vascular or bile duct invasion were enrolled between May 2011 and June 2015. The Cyberknife was used to treat each lesion. Treatment response scores were based on Response Evaluation Criteria in Solid Tumors v1.1. The trends of tumor markers, including alpha fetoprotein (AFP) and proteins induced by vitamin K absence II (PIVKA II) were assessed. Prognostic factors for tumor response and tumor markers were evaluated with Fisher’s exact test and a logistic regression model. Survival was evaluated with the Kaplan-Meier method and multivariate analysis was performed using the Cox proportional hazards model. RESULTS: Sixty-five patients with 95 lesions were enrolled. Based on the Barcelona Clinic Liver Cancer classification, all patients were either in the advanced or terminal stage of the disease. The target lesions were as follows: 52 were bone metastasis; 9, lung metastasis; 7, brain metastasis; 9, portal vein invasion; 4, hepatic vein invasion; 4, bile duct invasion; and 10 other lesion types. The response rate and disease control rate were 34% and 53%, respectively. None of the clinical factors correlated significantly with tumor response. Fiducial marker implantation was associated with better control of both AFP (HR = 0.152; 95%CI: 0.026-0.887; P = 0.036) and PIVKA II (HR = 0.035; 95%CI: 0.003-0.342; P = 0.004). The median survival time was 9 mo (95%CI: 5-15 mo). Terminal stage disease (HR = 9.809; 95%CI: 2.589-37.17, P < 0.001) and an AFP of more than 400 ng/mL (HR = 2.548; 95%CI: 1.070-6.068, P = 0.035) were associated with worse survival. A radiation dose higher than 30 Gy (HR = 0.274; 95%CI: 0.093-0.7541, P = 0.012) was associated with better survival. In the 52 cases of bone metastasis, 36 patients (69%) achieved pain relief. One patient had cerebral bleeding and another patient had an esophageal ulcer after treatment. CONCLUSION: The Cyberknife can be safely administered to patients with advanced or terminal stage HCC. High AFP levels were associated with worse survival, but a higher radiation dose improved the survival.

Organic–inorganic hybrids with apatite-forming abilities in physiological environments offer possibilities for building flexible bone-bonding bioactive materials; several functional groups are known to induce apatite nucleation. Here, bioactive organic–inorganic hybrids from κ-carrageenan and λ-carrageenan containing sulfonic groups were prepared. Carrageenan hydrogels were made by cross-linking with CaCl2. The apatite-forming abilities of each kind of carrageenan hydrogel were examined using simulated body fluid (SBF); λ-carrageenan was found to be superior to κ-carrageenan for this purpose. The former swelled significantly in aqueous conditions, releasing a large amount of Ca2+ ions into the SBF, contributing to rapid apatite formation.

Coronary arterial complications associated with Kawasaki disease (KD), such as a giant coronary aneurysm, determine the relative risk of future cardiac events and require lifelong medical treatment. Here, we describe a 24-year-old man who developed myocardial infarction due to poor adherence to medical treatment for a giant coronary aneurysm in the chronic phase of KD. He was hospitalized two hours after the onset of chest pain. The presence of the giant coronary aneurysm made primary percutaneous coronary intervention (PCI) difficult. However, we were able to perform primary PCI successfully utilizing previous coronary computed tomography (CT) angiographic pictures as a reference. This case provides valuable insight for the management of coronary arterial complications associated with KD. Patients in the chronic phase of KD are usually asymptomatic, even in the presence of giant coronary aneurysms which have been reported to have a high risk of morbidity and mortality. Therefore, patient education is critical for preventing poor adherence to medical treatment for coronary arterial complications. In preparation for potential coronary intervention in the future, it is also useful to perform coronary CT angiography, coronary magnetic resonance (MR) angiography, and/or coronary angiography on a regular basis while patients remain free from serious cardiac events.

Endoscopic papillary balloon dilation has been accepted as a possible alternative to endoscopic sphincterotomy, especially in patients with impaired hemostasis. However, pancreatitis associated with endoscopic papillary balloon dilation has remained a controversial, serious issue. The aim of the study was to investigate the risk factors for postendoscopic papillary balloon dilation pancreatitis in a single-center study.A total of 304 patients who underwent endoscopic papillary balloon dilation for the management of common bile duct stones were enrolled. The risk of postendoscopic papillary balloon dilation pancreatitis was evaluated and the risk factors were analyzed by univariate and multivariate analysis. Definition and grade of the severity of postendoscopic papillary balloon dilation pancreatitis were based on the 1991 consensus guidelines.Common bile duct was cleared in 292 of 304 patients (96%). Procedure-related pancreatitis occurred in 15 patients (5.0%). The grade was mild in 8 and moderate in 7. Two risk factors, stone diameter and contrast medium injection to the pancreas, were identified by univariate analysis. Finally, only the contrast medium injection to the pancreas was statistically significant by multivariate analysis. Prior history of pancreatitis was identified as a risk factor for postendoscopic papillary balloon dilation pancreatitis in previous studies, but this factor was not identified as a risk factor in our series.Although the pathogenesis of pancreatitis after endoscopic papillary balloon dilation remains unresolved, the unnecessary injection of contrast medium to the pancreas can certainly be considered to be associated with the increased risk of pancreatitis.

Biliary strictures are a common complication of living donor liver transplantation (LDLT) with duct-to-duct reconstruction (1). Endoscopic stent insertion is considered to be the first-line treatment for this complication (2,3). To reduce duodenobiliary reflux, plastic stents are placed above the intact papilla (‘inside stent’) in some centers (2-4). Since the anastomosis of LDLT is more peripheral and more complex, compared with deceased donor liver transplantation, we have occasionally encountered technical difficulties in re-passing a guidewire through the anastomotic biliary stricture at the time of inside stent exchange. Here, we report a useful technique for the exchange of the inside stent in a patient with complex anastomotic biliary strictures after LDLT.

Background & Aims: The aim of this study was to define the bile duct changes associated with autoimmune pancreatitis. Methods: Eight patients with autoimmune pancreatitis were followed for a mean of 4 years. The clinical features of these patients, including extrapancreatic bile duct changes, were examined by using biochemical parameters and several imaging modalities. Pathologic features of the pancreas and liver were examined by using the biopsy specimens of 7 patients. Results: Diffuse or focal narrowing of the main pancreatic duct was observed in all patients. Histologic examination of the pancreas showed lymphoplasmacyte infiltration with severe fibrosis and acinar cell depletion. In 6 patients extrapancreatic bile duct changes such as stricture of the bile duct at hilus or intrahepatic area were observed. In 2 patients abnormalities in the bile duct and pancreas were detected simultaneously at diagnosis, and changes in the bile duct were observed later in 4 patients. Lymphoplasmacyte infiltration and fibrosis were observed in the portal area of all 7 liver biopsy samples. Five of the patients with bile duct changes received steroid therapy, and the pathological changes improved. Conclusions: Extrapancreatic bile duct changes are frequently associated with autoimmune pancreatitis. Similar pathogenic mechanism might produce the biliary tract and pancreatic abnormalities in autoimmune pancreatitis resulting in a similar histopathology in the liver and pancreas and response to steroid therapy.

Background: The efficacy of rabeprazole sodium 20 mg/d for the treatment of reflux esophagitis has been demonstrated in several studies in Japan. However, studies of rabeprazole sodium 10 mg/d are lacking. Objective: This study was conducted to assess the efficacy and tolerability of rabeprazole 10 mg/d for the treatment of reflux esophagitis. Methods: Patients diagnosed with reflux esophagitis in routine clinical practice were enrolled in this single-center, open-label, practice-based, post-marketing surveillance investigation. Patients were to receive 10 mg of rabeprazole once daily for 8 weeks. The efficacy of rabeprazole was assessed on the basis of symptoms and endoscopic findings in accordance with the modified Los Angeles classification. Tolerability was assessed using subjective symptoms recorded before, during, and after treatment. Results: Of a total of 61 patients enrolled in this study, 47 (77%; 29 men, 18 women; mean age, 63 years) were included in the efficacy and tolerability analyses. Fourteen (23%) patients, including 5 (8.2%) patients who were treated with rabeprazole 20 mg/d, were excluded from the analyses. Endoscopic examinations were performed before and after treatment in 32 of 47 (68.1%) patients; mucosal lesions were healed in 20 of 32 (62.5%) patients after rabeprazole treatment. In patients with mild mucosal lesions prior to treatment, complete remission was achieved in 17 of 24 (70.8%) patients after treatment. Rates of improvement of symptoms were as follows: epigastralgia, 76%; heartburn, 76.7%; dull pain in the esophagus, 86.7%; and belching, 72.2%. Rabeprazole was well tolerated throughout the study; no serious symptomatic adverse events were reported. Although 1 case each of elevated alkaline phosphatase and gamma-glutamyltranspeptidase levels were reported, these changes were mild and improved after continuous treatment with rabeprazole. Conclusion: In this study, rabeprazole 10 mg/d was well tolerated and was shown to have satisfactory efficacy in the healing of esophagitis and the relief of the symptoms of esophagitis.

A 6-year-old Japanese boy was admitted to our hospital because of right hypochondrial discomfort, which had started 6 h earlier. His medical history was unremarkable. A physical examination revealed rebound tenderness in the right upper quadrant associated with a low-grade fever (37.4 C). Laboratory tests at presentation showed an increased white cell count of 11,700/lL (normal range 3700–8000) and C-reactive protein 2.56 mg/dL (normal range 0.00–0.29). Liver and renal function tests were normal. Conventional gray-scale transabdominal ultrasonography (US) using the ProSound a10 (Hitachi-Aloca Medical Co., Tokyo, Japan) with a 3.5-MHz transducer demonstrated an enlarged gallbladder with a grossly thickened wall, and a small amount of pericholecystic fluid (Fig. 1). The sonographic Murphy’s sign was positive. There was no evidence of gallbladder stones. Based on the conventional US, our initial diagnosis was acute cholecystitis. However, the gallbladder wall was unusually thickened for typical acute cholecystitis, so we evaluated the blood flow of the gallbladder wall. Doppler imaging confirmed the flow in the cholecystic artery at the neck of the gallbladder, but no blood flow within the gallbladder wall was observed, which was inconsistent with acute cholecystitis [2]. Therefore, CEUS using Sonazoid (Daiichi-Sankyo, Tokyo, Japan) was performed to further assess the gallbladder vascularity, since CEUS is more sensitive in detecting the blood flow than nonenhanced color Doppler US [3]. Sonazoid diluted in 10 mL of saline solution was administered intravenously at 0.015 mL/kg over 3–5 s. Five seconds after administering the Sonazoid , the gallbladder wall was enhanced from the serosal side, and then the mucosal line was enhanced linearly a second later (Figs. 2, 3). Based on a preoperative diagnosis of acute cholecystitis due to incomplete gallbladder torsion, the boy underwent an emergency laparotomy. At surgery, the gallbladder was markedly swollen and the cystic duct had twisted 180 in a counter-clockwise manner around the mesentery (Fig. 4). Y. Yashima (&) T. Tsujino R. Nakata Department of Gastroenterology, Japanese Red Cross Medical Center, 4-1-22 Hiroo, Shibuya-ku, Tokyo 150-8935, Japan e-mail: y-yashima@umin.ac.jp

A 68-year-old woman was admitted to a nearby clinic because of worsening dyspnea with body weight gain and systemic edema. She had had exertional dyspnea for >10 years, and her body weight had increased by 20 kg over the past year. Administration of oral diuretics did not improve her overhydration state. She was referred to our hospital for further treatment. On admission, her heart rate was 66 bpm and blood pressure was 122/80 mm Hg. She showed orthopnea with severe systemic edema. Her arterial oxygen saturation was 88% with room air. An ECG showed 4:1 atrial flatter, and a chest x-ray showed marked cardiomegaly. Her brain natriuretic peptide was 2.718 pg/mL. A transthoracic echocardiogram demonstrated marked concentric hypertrophy of the left ventricle (Figure 1) with severe tricuspid valve regurgitation and preserved ejection fraction. Her estimated right ventricular systolic pressure was 110 mm Hg. An atrial septal defect was not detected. Her mother also had hypertrophic cardiomyopathy. Intravenous administration of diuretics was effective, and her body weight decreased by 10 kg. Subsequent catheterization of the right side of the heart showed pulmonary hypertension (systolic pulmonary artery pressure, 88 mm Hg), and blood gas oxymetry revealed an O2 step-up at the superior vena cava. Her coronary artery system was intact. Histopathology of a biopsy specimen of her left ventricular myocardium demonstrated hypertrophy and mild disarray of cardiomyocytes, which is compatible with hypertrophic cardiomyopathy. A contrast-enhanced dynamic computed tomography scan was useful for detecting the presence of abnormal venous connection and shunt flow. An anomalous left upper …

Infection after artificial joint replacement is a serious problem, which requires the re-implantation of prosthesis. To aim at developing bone filling materials having both osteoconductivity and ability as a sustained drug release carrier, composites of wool keratin or carboxymethylated (CM) keratin hydrogels with hydroxyapatite were prepared and evaluated as a sustained drug release carrier. CM-keratin was prepared by the reaction of keratin extracted from wool with iodoacetic acid. Hydrogels were obtained by dropping keratin or CM-keratin solution into CaCl2 solution. The composites were obtained by immersing hydrogels in simulated body fluid (SBF). The introduction of carboxymethyl groups to keratin facilitated the deposition of hydroxyapatite on hydrogel. After 7 days of immersion in SBF, a 4-5 times higher amount of hydroxyapatite was accumulated on CM-keratin hydrogel than that on keratin hydrogel. When salicylic acid was loaded on keratin and CM-keratin hydrogels, a good sustained release was observed; that is, 90% of a drug was released up to 14 days after 60 and 45% of the initial burst in 1 day. On the other hand, initial release within 1 day was suppressed by forming a composite with hydroxyapatite and the release was almost ceased at 3 days when 60% of the drug was released. Although further improvement to prolong drug release might be necessary, CaKHA and CaCMKHA are expected to be a promising novel type of bone filling materials which has both osteoconductivity and sustained drug release ability.

Adequate dosing of interferon (IFN) and its cost-effectiveness for sustained virological response were evaluated in relation to viral load and subtype. Prospective analysis of IFN therapy on 326 patients with chronic hepatitis C free from cirrhosis was performed using 9 or 6 million unit (MU) of IFN for six months daily and/or three times a week. Sustained virological response was achieved in 50–94% of patients with ≤2 × 104 copies/ml (competitive RT-PCR) or 200 × 103 copies/ml (Amplicor monitor), even with 468–1206 MU of IFN. A high sustained rate was demonstrated in patients with 100–200 × 103 copies/ml of HCV RNA by 901–1206 MU of IFN, in comparison to that with ≤900 MU of IFN. Multivariate analysis showed that IFN dose had a significant value for the efficacy of IFN therapy in patients presenting 100–200 × 103 copies/ml of HCV RNA. Cost efficacy analysis indicated that it cost approximately $10,000, $26,000, and $50,000–227,000 for one person-viral eradication in the patients with 200 × 103 copies/ml, respectively. High-dose IFN is only cost effective in patients with intermediate viral loads, and IFN therapy could be recommended in patients with

Virological sustained response (SR) is achieved in 31–49% of patients with chronic hepatitis C with combination therapy using interferon (IFN) -α and ribavirin for 24–48 weeks. However, as a period of 24–48 weeks is a burden for patients, we investigated the effect of daily intravenous administration of natural IFN-β for 12 weeks in this study. In all, 112 patients were enrolled and received a daily administration of 6 MU of natural IFN-β intravenously for 12 weeks. Serum HCV-RNA before treatment was assessed by the competitive reverse-transcription polymerase chain reaction assay. The patients were divided into two groups according to pretreatment viral load: the low viral load group (N = 25

Because interferon therapy exhibits low efficacy for cirrhotic patients infected with hepatitis C virus, this prospective study was conducted to determine effective interferon regimens tailored to treatment response by monitoring HCV RNA status. A total of 157 cirrhotic patients were enrolled to receive 9 million units (MU) of interferon three times a week. The HCV RNA values were drawn 8 weeks apart and the patients were randomized to a further 16 or 32 weeks of treatment after two sequential findings of negativity for HCV RNA. A total of 73 out of 157 patients (46%) proceeded to randomization to different durations of treatment, 37 short-course and 36 long-course (duration: 38 +/- 8 and 49 +/- 13 weeks; total amount of interferon: 940 +/- 240 and 1130 +/- 390 MU, respectively). The remaining 84 patients without two sequential negative serum HCV RNA determinations received 44.8 +/- 27.4 weeks of interferon (IFN) therapy with total amount of 993 +/- 633 MU. Of these 157 patients, sustained virological and biochemical response was shown in 32 (20%) and 37 patients (24%), respectively. Sustained virological and biochemical response rate in the randomized patients was significantly higher than in nonrandomized patients (41% vs. 2%, and 38% vs. 11%; each P.01). Of the 73 randomized patients, the rate of sustained virological response in patients with long-course treatment (50%) was significantly higher than that of patients with short-course treatment (32%) (P =.026: log-rank test), and in patients with early disappearance of HCV RNA especially within 8 weeks, in patients with low virus load (/=10(6.3) copies/mL) and with HCV 2a. Multivariate analysis revealed that HCV RNA level and subtypes were the most important factors contributing to sustained virological response. Interferon is effective even in cirrhotic patients with low viral load and HCV 2a, but requires a longer course of administration.

In an attempt to predict virological sustained responders among patients with chronic hepatitis C after interferon therapy, HCV-RNA in serum was measured by a one tube RT-PCR assay kit using the RNA corresponding to 5 microL serum (standard assay) or 300 microL serum (enhanced-sensitivity assay). Dilution analysis revealed that sensitivity of the 'enhanced-sensitivity assay' increased by 10-100-fold when compared with a 'standard assay'. Using these assays, prospective study of interferon therapy on 38 HCV-RNA seropositive cases with chronic hepatitis (total amount 702 MU; duration of treatment 5-6 months) was performed. At the end of treatment, six were still positive and 32 became negative by the "standard assay', whereas an additional eight cases became positive (total 14 cases positive; the remaining 24 cases negative) by the 'enhanced-sensitivity assay'. Hepatitis C viral RNA state at the end of treatment remained the same 6 months later in 23 cases (61%) by a 'standard assay' and in 31 (82%) by the 'enhanced-sensitivity assay'. Of importance was that all patients (14 cases) demonstrating HCV-RNA in serum at the end of therapy, even by the "enhanced-sensitivity assay', did not show the disappearance of HCV-RNA in serum despite the long follow up. From these results, in order to improve our treatment efficacy, we should try to modify our treatment protocol to the extent that at least HCV-RNA becomes undetectable. That can be only feasible during treatment by real-time monitoring of HCV-RNA.

To clarify the mechanism of neutrophil infiltration in the liver of acetaminophen-induced hepatic injury, chemotactic factor released from hepatocytes exposed to acetaminophen has been investigated. Hepatocytes exposed to acetaminophen release nondialyzable chemotactic factor, although acetaminophen in itself inhibits chemotaxis of neutrophils. Chemotactic activity of the nondialyzable chemotactic factor was reduced after treatment with heat (56 degrees C, 30 min) or trypsin. Chemotactic activity was demonstrated at the molecular weights of around 25 and 55 kDa. Chemotactic activity of the conditioned medium was not significantly reduced in the presence of antibody against rat KC/gro protein (interleukin-8-related cytokine in rodent). Chemotactic activity of a 25-kDa factor was reduced by the antibody against the antibody against KC/gro protein, but that of a 55-kDa factor was not reduced. Immunoblot analysis revealed that the peptide reacted with antibody against rat KC/gro protein was demonstrated at a molecular weight of around 20-25 kDa, but not around 55kDa, when the conditioned medium of acetaminophen-treated hepatocytes was electrophoresed. These results suggest that hepatocytes exposed to acetaminophen release two types of chemotactic factors for neutrophils and that a major part of the chemotactic factor could be different from a member of interleukin-8 family.

Percutaneous transhepatic biliary drainage (PTBD) is an established procedure for biliary obstruction. However, duodenobiliary or jejunobiliary reflux of the intestinal contents through a PTBD catheter sometimes causes recurrent catheter obstruction or cholangitis. A 64-year-old female patient with a history of choledochojejunostomy was referred to our department with acute cholangitis due to choledochojejunal anastomotic obstruction. Emergent PTBD was performed, but frequent obstructions of the catheter due to the reflux of intestinal contents complicated the post-PTBD course. We therefore introduced a catheter with an antireflux mechanism to prevent jejunobiliary reflux. A commercially available catheter was modified; side holes were made at 1 cm and 5 to 10 cm (1 cm apart) from the tip of the catheter, and the catheter was ligated with a nylon thread just proximal to the first side hole. Using this novel "antireflux PTBD technique," jejunobiliary reflux was prevented successfully, resulting in a longer patency of the catheter.

We recently developed a primary culture system for gastric epithelial cells from adult rabbits that allows the investigation of growth regulation at the cellular level. In this study, we demonstrated that epidermal growth factor (EGF), insulin, and dibutyryl adenosine 3',5'-cyclic monophosphate (dBcAMP) all stimulated cell proliferation. Insulin and dBcAMP potentiated the stimulation of cell proliferation by EGF, while transforming growth factor-beta 1 (TGF-beta 1) inhibited it. Expression of c-fos and c-myc was induced in response to the stimulation by these growth regulators, but the degree of expression did not necessarily correlate with the effects of these agents on cell proliferation. In conclusion, EGF, insulin, and dBcAMP were positive growth regulators, while TGF-beta 1 was a negative regulator in gastric epithelial cells. These growth modulators may exert their effects by distinct pathways from a standpoint of the expression of c-fos and c-myc.

A 78-year-old female was admitted to our hospital with acute abdomen (abdominal pain and bloody stool). Abdominal examination revealed mild rebound tenderness on the right side. The laboratory data revealed severe inflammation (WBC: 33100/microliters, CRP:35.5 mg/dl). Panperitonitis was suspected because of diffuse and severe abdominal pain and rebound tenderness on the next day. X-ray examination by gastrografin showed mucosal irregularity and tubular narrowing of the tubular narrowing of the ascending colon which indicated ischemic colitis, and an emergency operation was performed. Histological examination of the pathologic specimens revealed fibrinoid necrosis and destruction of the internal lamina in small and medium-size arteries. We report a case diagnosed as ischemic colitis due to polyarteritis nodosa by the findings of its pathologic specimens.