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Tetsuhiro Chiba,1 Atsushi Hiraoka,2 Shigeru Mikami,3 Masami Shinozaki,4 Yukio Osaki,5 Masamichi Obu,6 Takamasa Ohki,7 Naoyuki Mita,8 Dianne Ledesma,8 Nariaki Yoshihara,8 Kathleen Beusterien,9 Kaitlan Amos,9 John FP Bridges,10 Osamu Yokosuka111Department of Gastroenterology and Nephrology, Chiba University Graduate School of Medicine, Chiba, Japan; 2Gastroenterology Center, Ehime Prefectural Central Hospital, Matsuyama, Ehime Prefecture, Japan; 3Department of Internal Medicine, Kikkoman General Hospital, Noda-shi, Chiba Prefecture, Japan; 4Department of Gastroenterology, Numazu City Hospital, Shizuoka, Japan; 5Department of Gastroenterology and Hepatology, Osaka Red Cross Hospital, Osaka, Japan; 6Department of Gastroenterology, Kimitsu Chuo Hospital, Kisarazu City, Chiba Prefecture, Japan; 7Department of Gastroenterology, Mitsui Memorial Hospital, Tokyo, Japan; 8Market Access, Bayer Yakuhin, Ltd., Tokyo, Japan; 9ORS Health, Washington DC, USA; 10Department of Biomedical Informatics and Department of Surgery, The Ohio State University College of Medicine, Columbus, OH, USA; 11Japan Community Health care Organization Funabashi Central Hospital, Funabashi, Chiba Prefecture, JapanPurpose: This study aimed to evaluate Japanese patient preferences regarding features of intermediate or advanced (Progressed) hepatocellular carcinoma (HCC) treatments: transarterial chemoembolization (TACE), hepatic arterial infusion chemotherapy (HAIC), and oral anti-cancer therapy.Methods: Patients with HCC, recruited from clinical sites and a patient panel in Japan, completed a cross-sectional web-based survey. Preferences were quantified using best–worst scaling, where patients identified the best and worst among 13 treatment features. Direct elicitation was used to identify preference for TACE, HAIC, or oral therapy, including the likelihood of trying each. Additional items asked for the willingness to try an oral medication that delays progression by six months but has an 8% or 21% risk of severe hand-foot skin reaction (HFSR).Results: The sample (N=119; 29 early stage; 90 Progressed) most preferred “oral medication”, “artery branches plugged”, and “prevents formation of new blood vessels”, and least preferred “risk of liver damage” and “risk of catheter-related complications”. Overall, 51%, 40%, and 8% preferred oral therapy, TACE, and HAIC, respectively (p

Renal carcinoid tumor is a rare neoplasm. In this article, we review this neoplasm with a focus on clinical and pathobiological aspects. The majority of patients present in the fourth to seventh decades, but there is no gender predilection. Clinically, patients with renal carcinoid tumor frequently present with abdominal, back or flank pain. This tumor is occassionally associated with horseshoe kidney and/or mature cystic teratoma located in the kidney. Macroscopically, these tumors are well demarcated with a lobulated appearance and yellow or tan-brown color cut surface. Microscopically, these tumors are composed of monomorphic round to polygonal cells with granular amphophilic to eosinophilic cytoplasm. Tumor cells are arranged in trabecular, ribbon-like, gyriform, insular, glandular and solid patterns. The nuclei are round to oval and with evenly distributed nuclear chromatin, frequently with a "salt and pepper"-pattern. Immunohistochemically, tumor cells demonstrate immuno-labeling for chromogranin A and synaptophysin. Ultrastructurally, the neoplastic cells contain abundant dense core neurosecretory granules. In previous genetic studies, abnormalities of chromosomes 3 or 13 have been reported. The clinical behavior of renal carcinoid tumors is variable, but is more indolent than most renal cell carcinomas. Further investigations are warranted in order to elucidate the critical genetic abnormalities responsible for the pathogenesis of this rare entity in renal neoplastic pathology.

Renal oncocytosis is a recently established disease entity characterized by numerous oncocytic tumors and diffuse involvement of oncocytic changes in renal parenchymal epithelia. In this article, we review this disease with a focus on its clinical and pathobiological aspects. Clinically, renal oncocytosis may occur in a sporadic form without any underlying disease or may be associated with chronic renal failure/long-term hemodialysis. However, Birt-Hogg- Dubé syndrome, characterized by skin tumors such as fibrofolliculoma or trichodiscoma, pulmonary lesions including bullae and spontaneous pneumothorax, and renal tumors should be evaluated in the differential diagnosis. The disease can develop either unilaterally or bilaterally. The involved renal parenchyma contains several to multiple brownish-colored nodules of varying size and is entirely replaced by lesions at the overt stage. Histologically, oncocytic tumors in both the dominant mass and smaller lesions encompass so-called hybrid tumor, chromophobe renal cell carcinoma (RCC), and renal oncocytoma (RO). Regarding renal parenchymal abnormalities, infiltrative growth of oncocytic cells, cortical cysts with oncocytic features, or extensive oncocytic change in non-neoplastic tubules can also be observed. Histochemical, immunohistochemical, and molecular genetic features of chromophobe RCC and RO arising in the setting of renal oncocytosis are generally identical to those in the sporadic type. However, hybrid tumors seem to be histologically distinct from chromophobe RCC and RO. In FISH analyses of some hybrid tumors, a gain of chromosomes 1, 2, 6, 10, and 17 was identified. In one tumor, no germ line mutation of folliculin gene was identified. Published data show that tumors follow a benign course. Further studies will be necesary to clarify the pathogenesis of renal oncocytosis.

The Thirteenth East Asia-Pacific Conference on Structural Engineering and Construction (EASEC-13), September 11-13, 2013, Sapporo, Japan.

Atherosclerotic arteries are well known to exhibit impaired endothelium-dependent relaxation (EDR), but the exact mechanism of this impairment remains unclear. Recently, endothelial constitutive nitric oxide synthase (ECNOS), which generates nitric oxide and mediates EDR, was cloned, and ECNOS mRNA expression was reported to be modified by various cytokines, lipoproteins, and shear stress. To investigate the expression of ECNOS mRNA and protein in atherosclerotic arteries with impaired EDR, thoracic aortas isolated from Watanabe heritable hyperlipidemic (WHHL) rabbits were examined by using in situ hybridization and immunohistochemistry. Compared with thoracic aortas from Japanese White rabbits, WHHL aortas exhibited significantly impaired EDRs, although both in situ hybridization and immunohistochemistry exhibited enhanced expression of ECNOS mRNA and protein in WHHL aortas. There was no significant relationship between expression of ECNOS mRNA and protein of endothelial cells and age of the examined WHHL aortas. These data suggest that the mechanism of impaired EDR in atherosclerotic arteries is not due to the decrease in ECNOS mRNA and protein.

Accurate first-trimester prenatal diagnosis was achieved in a Japanese haemophilia A family by the use of a restriction fragment length polymorphism (RFLP) located within the F.VIII gene. Since the pregnant woman's heterozygosity for BclI polymorphism in F.VIII/intron 18 (F8A) probe was informative, chorionic villus sampling (CVS) was performed at 9 weeks of gestation. Restriction analysis showed that the fetus was heterozygous for the BclI site and had received a normal paternal X chromosome (0.9 kb) and a normal maternal X (1.2 kb). Therefore, we concluded that the fetus was a non-carrier female. Pregnancy went to term and woman gave birth to an apparently healthy female. At one week after birth a coagulation study confirmed that the newborn infant is not a carrier. The first-trimester prenatal diagnosis of haemophilia A is possible by CVS due to a RFLP in the F.VIII gene.

3 young Japanese sisters with congenital α2-plasmin inhibitor (α2-PI) deficiency are reported. They have mild umbilical bleeding and/or repeated prolonged bleeding after minor trauma, but rarely spontaneous bleedings. The most characteristic hemostatic findings were shortened whole blood clot lysis time and euglobulin lysis time. Activities of all hemostatic factors except α2-PI were within normal range. Both functional and immunological absence of α2-PI were found in the plasma, and this failure to detect α2-PI was not corrected by the addition of the patient’s plasma of the first described case of α2-PI deficiency. Clinical and laboratory data revealed that these patients were probably homozygous for α2-PI deficiency and born of heterozygous parents, but not of consanguineous ones. Bleeding episodes due to deficiency of (α2-PI in these patients were well controlled by an antifibrinolytic agent, tranexamic acid.

SummaryPatterns of VIIIR:AG in the plasma and its fractions, cryoprecipitate and cryosupernatant, from various types of von Willebrand’s disease (vWd) were observed by SDS 1.5% polyacrylamide gel electrophoresis - crossed immunoelectrophoresis (SDS PAGE - CIE). VIIIR:AG in normal cryoprecipitate showed several precipitin peaks which correspond to molecular weights ranging from 8 X 105 to 1 X 10 7 daltons and are similar to those in normal plasma. Normal cryosupernatant VIIIR: AG gave smaller molecular weights from 8 X 10 5 to 2 X 10 6 daltons.VIIIR:AG in the plasma and cryoprecipitate from 2 patients with classical vWd gave low precipitin peaks with molecular weights in normal range. VIIIR:AG from 2 patients with subgroup A variant which showed fast anodal migration on the conventional CIE, presented 3 peaks with molecular weights of 8 X 105 to 3 X 106 which are similar to those in normal cryosupernatant. VIIIR: AG from 2 patients with subgroup B variant which showed normal migration on the CIE, gave normal patterns through all fractions.

SummaryThe nature of sugar chain of factor VTII/von Willebrand factor in plasma of normal subjects and patients with von Willebrand’s disease (vWd) was examined by crossed affinoimmunoelectrophoresis using anti-human factor VIII rabbit serum, with inserted Ricinus communis agglutinin-120 (RCA-120) agarose layer (RCA – CIE). Molecular weights of factor VlU-related antigen (VIIIR: Ag) were estimated by SDS polyacrylamide gel electrophoresis — crossed affinoimmunoelectrophoresis (SDS PAGE – RCA – CIE).VIIIR :Ag, in normal plasma and in classical form of vWd, showed two precipitin peaks on RCA – CIE. The slower moving component of VIIIR :Ag with molecular weights over 3×106 daltons from normal subjects and patients with classical form of vWd showed a high affinity for RCA-120. The faster moving component of VIIIR: Ag below 3×106 daltons from the abovementioned subjects and patients with a variant form (Type IIA) showed a very weak affinity for RCA-120.These results suggested that all of VIIIR: Ag in these variant cases may have a deficiency of galactose residues reactive with RCA, in addition to an incomplete polymerization of VIIIR: Ag, similar to that of the faster moving component of normal subjects.

Recently, the gene structure for human F.VIII protein was clarified, and F.VIII DNA probes have been used for carrier detection and prenatal diagnosis ofhaemophilia A. In order to make sure that the phenomena are universal, we have analysed the RFLPs of F.VIII gene in 16 Japanese families with haemophilia A, including a female haemophiliac case, using an intragenic F.VIII DNA probe(F8A) and an extragenic(linked) DNA probe(Stl4-1).The probe F8A revealed two variant bands after digestion by Bel I. Of normal 60 X chromosomes (females) examined, about 85% bore the 879-bp fragment and 15%the 1165-bp fragment. Five of sixteen mothers of hemophiliacs, definite carriers, were found to be heterozygous for Bel I polymorphism. Since the relationship between Bel I alleles and hemophilia gene has been identified in the 5 families in which the mothers were heterozygous, we could diagnose the carrier status of two women whose brothers are hemophiliacs. Onthe other hand, we could identify that one "haemophilic woman" with less than 10% of F.VIII:C was a carrier status when we analysed the Bel I alleles in theother members of the family.The probe DNA(ST 14-1) revealed seven variant bands ranging from 5.5 kb to 3.4 kb after digestion by Taq I. In 6 out of 16 families, the RFLPs of ST 14 locus were informative for carrier detection.From these data, it was concluded that the Bel I polymorphism of F.VIII gene and the Taq I polymorphism of ST 14 locus were informative for carrier detection in 8 out of 16 families with haemophilia A

The factor IX genes in four Japanese families with haemophilia B were analysed for the restriction fragment length polymorphisms (RFLPs) ofTaqI,XmnI andDdeI, using subcloned intragenic DNA fragments as probes (probes VIII and XIII). The factor IX genes in 12 patients with haemophilia B and three high-responder-inhibitor cases showed no size difference using a cDNA probe (cVII) when restricted byTaqI,EcoRI andHindIII. Complete gene deletions were observed in two other high-responder-inhibitor cases.

Carriers of haemophilia A were detected in 20 Japanese families with using the factor VIII gene probe (F8A) and the gene-linked ST 14-1 probe. Polymorphism by the use of theBclI and F8A probe detected the smaller allele (0.9 kb) in 86% and the larger allele (1.2 kb) in 14% of the 65 normal X chromosomes. The frequency ofBclI polymorphism was 30% in 30 normal fameles. In six out of 20 haemophilia A families, the haemophilia gene was identified byBclI allele polymorphism. The use ofTaqI and the ST 14-1 probe detected 11 carriers in 20 haemophilia A families. In 14 families (70%), either theBclI polymorphism in the factor VIII locus orTaqI polymorphisms in the ST 14 locus was useful for carrier detection.

A deletion mutation in the factor VIII gene of a severe haemophiliac patient was found along with a high level of factor VIII inhibitor in the blood plasma among seventy Japanese haemophilia A patients. The 6 kbp long deletion involved a region from somewhere betweenPstI andSstI sites at nucleotide positions 2659 and 2991 of exon 14 and intron 13, respectively (nucleotide positions were defined as in Woodet al., 1984).

Summary. Haemophilia B is extremely rare in females and so far 20 cases have been reported. A 9-year-old girl with severe haemophilia symptoms is described, who shows a very low level of factor IX activity (1.5%) and antigen (> 10%), normal XX female karyotype and negative family history of bleeding tendency or consanguinity. This case is probably the fourth report of sporadic female haemophilia B without chromosomal aberration and the first one with quantitative analysis by immunoradiometric assay and enzyme-linked immunosorbent assay of factor IX antigen. This very low factor IX level and severe bleeding tendency of the patient would be consistent with the homozygous state, but since a double mutation is extremely rare the patient's laboratory findings can be more easily explained by extreme lyonization of the normal X-chromosome of a heterozygous carrier.

The effects of several kinds of carbohydrate oxidase, SH-inhibitors and some other chemical reagents on the activities of von Willebrand factor, factor VIII procoagulant and factor VIII-related antigen were studied. Factor VIII procoagulant and von Willebrand factor activities were both inhibited by galactose oxidase, p-hydroxymercuribenzoic acid, 2,4,6-trinitrobenzensulfonic acid and sodium periodate. α-mannosidase, N-ethylmaleimide and phospholipase C inactivated factor VIII procoagulant but not von Willebrand factor activity. Dithiothreitol had little effect on factor VIII procoagulant activity but reduced significantly that of von Willebrand factor. It is suggested that galactose and the thiol and α-aminogroup groups of lysine may play an important role in both factor VIII procoagulant and von Willebrand factor activity. Mannose may be responsible for the factor VIII procoagulant activity but not for the von Willebrand factor activity. The Laurell rocket heights of factor VIII-related antigen rose with increasing concentration of galactose oxidase, 2,4,6-trinitrobenzenesulfonic acid or sodium periodate. Gel filtration experiments showed that factor VIII-related antigen may be dissociated into subunits by galactose oxidase but not by 2,4,6-trinitrobenzenesulfonic acid or sodium periodate.