Early Prediction of the Outcome Using Tumor Markers and mRECIST in Unresectable Hepatocellular Carcinoma Patients Who Underwent Transarterial Chemoembolization.

OBJECTIVE: We examined early predictors of the outcome in hepatocellular carcinoma (HCC) patients after transarterial chemoembolization (TACE). METHODS: We analyzed 116 patients with unresectable HCC treated with initial TACE. α-Fetoprotein (AFP) or des-γ-carboxy prothrombin (DCP) response was assessed in patients who had baseline AFP levels ≥200 ng/ml or DCP ≥60 mAU/ml; a positive response was defined as a reduction of >50% compared to baseline 1 month after TACE. RESULTS: A baseline AFP level ≥200 ng/ml was associated with a poor overall survival (OS) (29.4 vs. 6.1 months; p <0.0001). AFP response had no significantly prognostic effects on the OS. Conversely, although the baseline DCP did not influence the OS, DCP responders showed a significantly better OS than nonresponders (67.0 vs. 19.8 months, p = 0.020). The baseline AFP (p = 0.004) and initial tumor response evaluated by the modified Response Evaluation Criteria in Solid Tumors (mRECIST) (p = 0.012) were found to be independent predictors of the OS. The combination of the baseline AFP and initial assessment by mRECIST allowed stratification of the OS. CONCLUSIONS: The combination of the baseline AFP level and mRECIST is useful for the early prediction of the OS in HCC patients who underwent TACE.

Findings of the margin around lesions by magnifying endoscopy with narrow-band imaging in early gastric carcinoma and intestinal metaplasia.

OBJECTIVE: Many endoscopists have reported their own classifications of early gastric carcinoma (EGC) using magnifying narrow-band imaging (M-NBI). However, few reports on classifying the margin around lesions by M-NBI have been published. The aim of this study was to advocate the usefulness of the demarcation area classification for the diagnosis of EGC. METHODS: Altogether 197 lesions that could be investigated by M-NBI were included in this study, consisting of 115 EGC and 82 intestinal metaplasias (IM). We hypothesized that the changes in white zone (fusion and erasure signs) and blood vessel (extend and draw sign) were the indications of EGC and we retrospectively investigated this hypothesis. RESULTS: For the investigation of the white zone in the demarcation area, both fusion (P < 0.0001) and erasure signs (P < 0.0001) were observed more often in EGC than in IM, with an accuracy of 80.7%. For the investigation of blood vessel in the demarcation area, both the extend (P < 0.001) and the draw sign (P < 0.0001) were observed more often in EGC than in IM, with an accuracy of 59.9%. CONCLUSION: Estimations of the white zone and blood vessels in the demarcation area are useful for the diagnosis of EGC.

[Liver injury and hepatic encephalopathy induced by the herbal medicine Hochuekkito].

A 57-year-old man was admitted with pruritus and jaundice following treatment for fatigue with the herbal medicine Hochuekkito. The patient was prescribed prednisolone and ursodeoxycholic acid, but he developed progressive cholestasis that required intravenous methylprednisolone pulse therapy. After treatment with plasma exchange for prolonged prothrombin time, the patient recovered; however, his liver function deteriorated because of liver injury induced by trimethoprim-sulfamethoxazole for pneumocystis pneumonia. After reduction of trimethoprim-sulfamethoxazole, his liver function almost returned to normal by day 130 of admission. It has remained normal for 10 months since then. Therefore, when prescribing Hochuekkito, the possibility of drug-induced liver injury should be taken in account.

Standardized endoscopic reporting.

The need for standardized language is increasingly obvious, also within gastrointestinal endoscopy. A systematic approach to the description of endoscopic findings is vital for the development of a universal language, but systematic also means structured, and structure is inherently a challenge when presented as an alternative to the normal spoken word. The efforts leading to the "Minimal Standard Terminology" (MST) of gastrointestinal endoscopy offer a standardized model for description of endoscopic findings. With a combination of lesion descriptors and descriptor attributes, this system gives guidance to appropriate descriptions of lesions and also has a normative effect on endoscopists in training. The endoscopic report includes a number of items not related to findings per se, but to other aspects of the procedure, formal, technical, and medical. While the MST sought to formulate minimal lists for some of these aspects (e.g. indications), they are not all well suited for the inherent structure of the MST, and many are missing. Thus, the present paper offers a recommended standardization also of the administrative, technical, and other "peri-endoscopic" elements of the endoscopic report; important also are the numerous quality assurance initiatives presently emerging. Finally, the image documentation of endoscopic findings is becoming more obvious-and accessible. Thus, recommendations for normal procedures as well as for focal and diffuse pathology are presented. The recommendations are "minimal," meaning that expansions and subcategories will likely be needed in most centers. Still, with a stronger common grounds, communication within endoscopy will still benefit.

Helicobacter pylori infection and gastropathy: a comparison between Indonesian and Japanese patients.

AIM: To compare the effects of Helicobacter pylori (H. pylori) infection on gastropathy between Indonesian and Japanese patients. METHODS: Biopsy specimens were obtained during upper gastrointestinal endoscopy from 167 subjects (125 Indonesians and 42 Japanese) with uninvestigated symptoms of dyspepsia. The specimens were analyzed for the presence of H. pylori using urease analysis, histopathology, and cell culture. The grade and activity of gastritis was assessed using the updated Sydney system. RESULTS: The percentages of Indonesian and Japanese patients who were H. pylori-positive at the antrum or body of the stomach were similar (68% and 59.5%, respectively; P = 0.316). Of those who were H. pylori-positive, more Japanese patients than Indonesian patients had high levels of polymorphonuclear cells (P = 0.001), mononuclear cells (P = 0.013), glandular atrophy (P = 0.000), and intestinal metaplasia (P = 0.011) in both the antrum and body of the stomach. CONCLUSION: The grade of gastritis and prevalence of mucosal atrophy and intestinal metaplasia were higher in Japanese patients. The difference between Indonesian and Japanese patients was significant.

Terminology and global standardization of endoscopic information: Minimal Standard Terminology (MST).

Since 1994, following the leading efforts by the European Society for Gastrointestinal Endoscopy, Organisation Mondiale d'Endoscopie Digestive (OMED) has succeeded in compiling minimal number of terms required for computer generation of digestive endoscopy reports nicknamed MST (Minimal Standard Terminology). Though with some insufficiencies, and though developed only for digestive endoscopy, MST has been the only available terminology that is globally standardized in medicine. By utilizing the merits of a unified, structured terminology that can be used in multiple languages we can utilize the data stored in different languages as a common database. For this purpose, a standing, terminology-managing organization that manages and maintains and, when required, expands the terminology on a global level, is absolutely necessary. Unfortunately, however, the organization that performs version control of MST (OMED terminology, standardization and data processing committee) is currently suspending its activity. Medical practice of the world demands more and more specialization, with resultant needs for information exchange among specialized territories. As the cooperation between endoscopy and pathology has become currently the most important problem in the Endoscopy Working Group of Integrating Healthcare Enterprise-Japan (IHE-J,) the cooperation among different specialties is essential. There are DICOM or HL7 standards as the protocols for storage, and exchange (communication) of the data, but there is yet no organization that manages the terminology itself astride different specialties. We hereby propose to establish, within IEEE, for example, a system that promotes standardization of the terminology that can transversely describe a patient, and that can control different societies and groups, as far as the terminology is concerned.

Activities for endoscopy information systems standardization in Japan.

There are two activities for Japanese endoscopy information system. One is for a standard terminology (Minimal Standard Terminology: MST) for endoscopy reporting. Other is Integrating Healthcare Enterprise Japan (IHE-J) for an integration of hospital information system. In IHE-J activity, the members revealed specificities of an endoscopy workflow by making a comparison with a radiology workflow. The authors will propose a scheme for systematic standardization based on our experiences in the standardization activities.

[A case of systemic lupus erythematosus presenting with jaundice and lupus pneumonia].

A 27-year-old Japanese woman was referred to our hospital for acute hepatitis in April 2002. She had been suffering from low grade fever and fatigue for a week. She also presented with dyspnea. On admission, ALT and AST were 857 U/l and 473 U/l respectively. Urine protein was 2 g/day. Chest radiograph showed bilateral infiltrative shadow and pleural effusion. She developed jaundice and her level of total bilirubin was increased to 9.6 mg/dl on May 9. Antibodies to hepatitis viruses were not detected. Testing for antimitochondrial antibodies, antismooth muscle antibodies, and antiribosomal P antibodies showed all negative. However, antinuclear antibodies were positive at titer 1:160 and anti-double stranded DNA antibodies were 130 U/ml. A diagnosis of systemic lupus erythematosus was made and oral administration of 60 mg/day prednisolon was started on May 10. Serum levels of ALT, AST and bilirubin were reduced to within normal range and pulmonary lesions were also improved. We conclude that this is a rare case of systemic lupus erythematosus presenting with acute hepatitis and jaundice.

Isolation of novel mouse genes that were differentially expressed in W/W(V) mouse fundus.

BACKGROUND: Using cDNA microarray analysis that displays a total of 8734 mouse genes, we have identified 21 known and novel transcripts, including mouse expressed sequence tags (ESTs) that were consistently up- or downregulated in the fundus of wild-type mice and W/W(V) mice, where intramuscular interstitial cells of Cajal (ICC; IC-IM) are lost. METHODS: By using these tags as part of the full-length mRNA sequence of the murine genes, we screened a mouse-brain cDNA library and the FASTA database (http://www.ebi.ac.uk/fasta33/). RESULTS: Three of the queries were identified as novel mouse genes, whereas six transcripts had their human counterparts that were known to encode functional proteins. Four transcripts, DRIM (downregulated in metastasis), SLP8 (tumor antigen), PTK7/CCK4 (receptor protein tyrosine kinase-like molecule-7/colon carcinoma kinase-4), and a novel gene AWMS2 were increased in W/W(V) mice. Expression of another five genes was decreased in W/W(V) mice: BB1 (overexpressed in bladder and breast carcinoma), HTATIP/CPLA2 (HIV-1 TAT interactive protein/cytosolic phospholipase A2), Tenascin-receptor like (Hexabrachion, Cytotactin, Neuronectin, Myotendinous antigen), and two novel transcripts: DRWMS1 and DRWMS2. Molecular profiling generated by cDNA microarray analysis from the fundus of W/W(V) mice and its complete list of full-length cDNAs will be shown on our web site (http://www.yamanashi.ac.jp/). CONCLUSIONS: Differential gene comparisons between control and mutant animals with losses in specific populations of ICCs will contribute significantly to our understanding of motility disorders associated with the loss of these cells and electrical slow waves in the gastrointestinal tract.

Lipopolysaccharide induces CD25-positive, IL-10-producing lymphocytes without secretion of proinflammatory cytokines in the human colon: low MD-2 mRNA expression in colonic macrophages.

Despite the huge number of colonized Gram-negative bacteria in the colon, the normal colon maintains its homeostasis without any excessive immune response. To investigate the potential mechanisms involved, human colonic lamina propria mononuclear cells (LPMCs) obtained from uninflamed mucosa were cultured with lipopolysaccharide (LPS) prepared from Bacteroides vulgatus (BV-LPS) or Bacteroides fragilis (BF-LPS), as representatives of indigenous flora, or pathogenic Salmonella minnesota (SM-LPS). Colonic LPMCs failed to produce inflammatory cytokines in response to any type of LPS. Colonic macrophages barely expressed mRNA for MD-2, an essential association molecule for LPS signaling via Toll-like receptor 4. Further, BV-LPS induced CD25 and Foxp3 expression in lymphocytes and CD4(+)CD25(+) cells expressed IL-10 mRNA. Thus, the low expression of functioning LPS receptor molecules and induction of IL-10-producing CD4(+)CD25(+) lymphocytes by indigenous LPS may play a central role in the maintenance of colonic immunological homeostasis.

Novel human, mouse and xenopus genes encoding a member of the RAS superfamily of low-molecular-weight GTP-binding proteins and its downregulation in W/WV mouse jejunum.

BACKGROUND AND AIM: Interstitial cells of Cajal (ICC) are pacemakers and mediators of neurotransmission in gastroenteric smooth muscles. Interstitial cells of Cajal require cellular signaling via KIT, a receptor tyrosine kinase, for development and maintenance of cellular phenotype. Much of the evidence demonstrating the functions of ICC comes from studies of W/W V mutant mice, which have reduced KIT function. The aim of the present study was to differentially examine gene expression in the small intestines of wild-type and W/W V mice. METHODS: RNA from the jejunum of wild-type and W/W V mice was analyzed using a differential gene display method. RESULTS: One candidate gene, encoding a novel small GTPase of the RAS superfamily, was significantly suppressed both in fed and starved W/WV mice. The full-length clone of the murine gene and its human and xenopus counterparts were designated GTP-binding protein, 28 kDa (G28K). Human G28K cDNA encodes a protein of 258 amino acids with homology to the human cell division cycle 42/G25K protein. This gene is located at 1q42.11-q42.3. G28K was abundantly expressed in the human stomach and the small intestine. Semi-quantitative reverse transcription-polymerase chain reaction analysis revealed expression of G28K mRNA within single isolated ICC. CONCLUSIONS: Gene analysis showed that G28K was differentially expressed in the small intestines of wild-type and W/W V mice. Interstitial cells of Cajal within the small intestine expressed mRNA for G28K. The specific downregulation of G28K in the jejunum of W/W V mice, and high expression in human intestinal tissue suggest that the G28K gene might be associated with ICC function in mice and in humans.

L-Serine, D- and L-proline and alanine as respiratory substrates of Helicobacter pylori: correlation between in vitro and in vivo amino acid levels.

Helicobacter pylori whole cells showed high rates of oxygen uptake with L-serine and L-proline as respiratory substrates, and somewhat lower rates with D-alanine and D-proline. These respiratory activities were inhibited by rotenone and antimycin A at low concentrations. Since pyruvate was produced from L-serine and D- and L-alanine in whole cells, the respiratory activities with these amino acids as substrates occurred via pyruvate. Whole cells showed 2,6-dichlorophenolindophenol (DCIP)-reducing activities with D- and L-proline and D-alanine as substrates, suggesting that hydrogen removed from these amino acids also participated in oxygen uptake by the whole cells. High amounts of L-proline, D- and L-alanine, and L-serine were present in H. pylori cells, and these amino acids also predominated in samples of human gastric juice. H. pylori seems to utilize D- and L-proline, D-alanine and L-serine as important energy sources in its habitat of the mucous layer of the stomach.

Differential gene expression profile in the small intestines of mice lacking pacemaker interstitial cells of Cajal.

BACKGROUND: We previously identified eight known and novel genes differentially expressed in the small intestines of wild type and W/WV mice, which have greatly reduced populations of the interstitial cells of Cajal, that are responsible for the generation of electrical slow waves, by using a differential gene display method. METHODS: By using the same method we isolated additional candidate genes that were specifically down- or up-regulated in W/WV mice. Novel transcripts were designated as DDWMEST. RESULTS: We isolated seven candidates that were specifically down- or up-regulated in W/WV mice. Two novel transcripts, DDWMEST 1 and -91 were increased in both fed and fasted W/WV mice. Expression of another five genes was suppressed in W/WV mice: ARG2 (Arginase II), ONZIN (encoding leukemia inhibitory factor regulated protein), and three novel transcripts: DDWMEST62, -84, and -100. Together with the previous report, we identified fifteen differentially expressed genes in total in the small intestines of W/WV mice. Eight of these genes were reduced in the jejunums of W/WV mice compared to age matched wild type mice, whereas the other seven genes showed an increase in expression. Differential expression was the same in fasted and fed animals, suggesting that the differences were independent of the dietetic state of the animal. CONCLUSIONS: Several known and novel genes are differentially expressed in the small intestines of W/WV mice. Differential gene comparison might contribute to our understanding of motility disorders associated with the loss of the interstitial cells of Cajal.

Differential gene expression in the murine gastric fundus lacking interstitial cells of Cajal.

BACKGROUND: The muscle layers of murine gastric fundus have no interstitial cells of Cajal at the level of the myenteric plexus and only possess intramuscular interstitial cells and this tissue does not generate electric slow waves. The absence of intramuscular interstitial cells in W/WV mutants provides a unique opportunity to study the molecular changes that are associated with the loss of these intercalating cells. METHOD: The gene expression profile of the gastric fundus of wild type and W/WV mice was assayed by murine microarray analysis displaying a total of 8734 elements. Queried genes from the microarray analysis were confirmed by semi-quantitative reverse transcription-polymerase chain reaction. RESULTS: Twenty-one genes were differentially expressed in wild type and W/WV mice. Eleven transcripts had 2.0-2.5 fold higher mRNA expression in W/WV gastric fundus when compared to wild type tissues. Ten transcripts had 2.1-3.9 fold lower expression in W/WV mutants in comparison with wild type animals. None of these genes have ever been implicated in any bowel motility function. CONCLUSIONS: These data provides evidence that several important genes have significantly changed in the murine fundus of W/WV mutants that lack intramuscular interstitial cells of Cajal and have reduced enteric motor neurotransmission.

Novel human and mouse genes encoding a shank-interacting protein and its upregulation in gastric fundus of W/WV mouse.

BACKGROUND AND AIMS: A division of labor exists between different classes of interstitial cells of Cajal (ICC) in the gastrointestinal tract. In the stomach and small intestine, ICC at the level of the myenteric plexus (IC-MY) act as slow wave pacemaker cells, whereas intramuscular ICC (IC-IM) in the stomach act as intermediaries in enteric motor neurotransmission. The muscle layers of the gastric fundus do not have IC-MY, therefore electric slow waves are not generated. Intramuscular ICC are absent in the gastric fundus of W/WV mutant mice, and excitatory and inhibitory motor nerve responses are reduced in these tissues. The absence of IC-IM in W/WV mutants in the fundus provides a unique opportunity to study the molecular changes that are associated with the loss of these cells. METHODS: The tissue gene expression of wild-type and W/WV mice from gastric fundus was assayed using a murine microarray chip analysis displaying a total of 8734 elements. RESULTS: Twenty-one queries were differentially expressed in wild-type and W/WV mice. One candidate gene, encoding a novel protein homologous to rat Shank-interacting protein (Sharpin) was significantly upregulated in fed and starved W/WV mice. The full-length clone of the murine gene and its human counterpart were isolated and designated as Shank-interacting protein-like 1 (SIPL1). Human SIPL1 complementary DNA encodes a protein of 345 amino acids. This gene was localized to chromosome 8. SIPL1 was abundantly expressed in human stomach and small intestine, and scarcely expressed in cecum and rectum. CONCLUSIONS: Gene analysis showed that SIPL1 differentially express in the gastric fundus of normal and W/WV mice. The upregulation of SIPL1 in the fundus of W/WV mice, and expression in the upper gastrointestinal tract suggest that the SIPL1 gene could be associated with ICC function in mice and humans.

Characterization of the effects of pancreatic polypeptide in the regulation of energy balance.

BACKGROUND & AIMS: Pancreatic polypeptide (PP) belongs to a family of peptides including neuropeptide Y and peptide YY. We examined the role of PP in the regulation of body weight as well as the therapeutic potential of PP. METHODS: We measured food intake, gastric emptying, oxygen consumption, and gene expression of hypothalamic neuropeptides, gastric ghrelin, and adipocytokines in mice after administering PP intraperitoneally. Peptide gene expression was also examined in PP-overexpressing mice. Vagal and sympathetic nerve activities were recorded after intravenous administration in rats. Effects of repeated administrations of PP on energy balance and on glucose and lipid metabolism were examined in both ob/ob obese mice and fatty liver Shionogi (FLS)-ob/ob obese mice. RESULTS: Peripherally administered PP induced negative energy balance by decreasing food intake and gastric emptying while increasing energy expenditure. The mechanism involved modification of expression of feeding-regulatory peptides (decrease in orexigenic neuropeptide Y, orexin, and ghrelin along with an increase in anorexigenic urocortin) and activity of the vagovagal or vagosympathetic reflex arc. PP reduced leptin in white adipose tissue and corticotropin-releasing factor gene expression. The expression of gastric ghrelin and hypothalamic orexin was decreased in PP-overexpressing mice. Repeated administrations of PP decreased body weight gain and ameliorated insulin resistance and hyperlipidemia in both ob/ob obese mice and FLS-ob/ob obese mice. Liver enzyme abnormalities in FLS-ob/ob obese mice were also ameliorated by PP. CONCLUSIONS: These observations indicate that PP may influence food intake, energy metabolism, and the expression of hypothalamic peptides and gastric ghrelin.

Leptin treatment ameliorates anxiety in ob/ob obese mice.

We investigated whether or not administered leptin influences anxiety-like behavior in ob/ob mice. Repeated intraperitoneal administrations of leptin were continued for 5 days. Anxiety was assessed in the standard elevated plus maze. Body weight was measured daily. Repeated administrations of leptin significantly increased the percentage of the total number of entries in the open arms and the number of total entries. The body weight was significantly reduced by 13.2% after treatment. Leptin treatment ameliorated not only obesity but also anxiety in ob/ob mice. Our results indicate that the treatment of obesity may lead to the solution of psychological problems.

The association of fatty liver and diabetes risk.

We examined whether fatty liver, as diagnosed with abdominal ultrasonography, is an independent risk factor for diabetes mellitus during 10 years of follow-up. A total of 840 subjects (467 men and 373 women) were followed for the entire 10 years. The criteria for being non-diabetic were having no history of diabetes, having a fasting plasma glucose level of less than 110 mg/dl and a serum hemoglobin A1c level of 6.4% or less. We indicated that every examine received all examinations after 12 hours of fasting. Well-trained technicians performed abdominal ultrasonography. Although univariate analysis revealed that the presence of fatty liver was related to hyperglycemia 10 years later, multiple logistic regression analysis did not support this finding. In the multiple logistic regression analysis fasting plasma glucose levels at the baseline and age were significantly related to hyperglycemia (odds ratio [OR] = 1.16, 95% confidence interval [CI]: 1.11-1.21, OR = 1.07, 95% CI: 1.01-1.14, respectively). Fatty liver was not an independent risk factor for hyperglycemia in our follow-up study 10 years after the first diagnosis. The high fasting plasma glucose levels were a risk factor for diabetes, even in the normal range.

Ob/ob mice as a model of delayed gastric emptying.

Diabetic gastroparesis is a well-recognized delay of gastric emptying in diabetic patients. We assessed the gastric emptying rate in ob/ob mice, a genetic model of obesity and diabetes. The basal gastric emptying rate in 22- to 27-week-old ob/ob mice was significantly lower than that in 10- to 11-week-old ob/ob mice (P<.01). Our results indicate that the ob/ob mice are a useful model not only of glucose intolerance but also of delayed gastric emptying as a diabetic complication.