Clinicopathological features of narrow-band imaging endoscopy and immunohistochemistry in ultraminute esophageal squamous neoplasms.

To reveal clinicopathological features of narrow-band imaging (NBI) endoscopy and immunohistochemistry in ultraminute esophageal squamous neoplasms. If a lesion diameter was smaller or same compared with a width of closed biopsy forceps, a lesion was defined to be an ultraminute lesion. Twenty-five consecutive patients with 33 ultraminute esophageal lesions that were removed by endoscopic mucosal resection were included in the present study. We conducted two questionnaire surveys of six endoscopists by their retrospective review of endoscopic still images. The six endoscopists evaluated the endoscopic findings of the ultraminute lesions on still images taken by conventional white-light imaging endoscopy and non-magnified NBI endoscopy in the first questionnaire, and taken by magnified NBI endoscopy in the second questionnaire. An experienced pathologist who was unaware of any endoscopic findings made histological diagnosis and evaluated immunoexpression of p53 and Ki67. The 33 ultraminute lesions were all determined to be either 11 high-grade intraepithelial neoplasias (HGIENs) or 22 low-grade intraepithelial neoplasias (LGIENs). The tumor diameters were histologically confirmed to be <3 mm. All of the ultraminute tumors were visualized as unstained areas and brownish areas by real-time endoscopy with Lugol dye staining and non-magnified NBI endoscopy, respectively. All of the ultraminute IENs were visualized as brownish areas by real-time non-magnified NBI endoscopy. Three of the 25 patients with the ultraminute IENs (12%) had multiple brownish areas (more than several areas) in the esophagus on real-time non-magnified NBI endoscopy. All of the ultraminute IENs were visualized as unstained areas by real-time Lugol chromoendoscopy. Twenty of the 25 patients (80%) had multiple unstained areas (more than several areas) in the esophagus on real-time Lugol chromoendoscopy. The first questionnaire survey revealed that a significantly higher detection rate of the ultraminute IENs on non-magnified NBI endoscopy images compared with conventional white-light imaging endoscopy ones (100% vs. 72%, respectively: P < 0.0001). The second questionnaire survey revealed that presence rates of any magnified NBI endoscopy findings were not significantly different between HGIENs and LGIENs. Proliferation, dilation, and various shapes of intrapapillary capillary loops indicated remarkably high presence rates of more than 90% in both HGIENs and LGIENs. Six of 22 LGIENs (27%) and 3 of 11 HGIENs (27%) show a positive expression for p53. None of peri-IEN epithelia was positive for p53. A mean of Ki67 labeling index of LGIENs was 33% and that of HGIENs 36%. Ki67 labeling index was significantly greater in the LGIENs and HGIENs compared with that in the peri-IEN epithelia. There were no significant differences in p53 expression and Ki67 labeling index between the HGIENs and LGIENs. Non-magnified/magnified NBI endoscopy could facilitate visualization and characterization of ultraminute esophageal squamous IENs. The ultraminute HGIENs and LGIENs might have comparable features of magnified NBI endoscopy and immunohistochemistry.

Can mechanical balloon dissection be applied to cleave fibrotic submucosal tissues? A pilot study in a porcine model.

BACKGROUND AND STUDY AIMS: Removal of a lesion containing an ulcer scar is one of the most challenging applications of endoscopic submucosal dissection (ESD). The present study examined whether a novel balloon dissector could cleave fibrotic submucosal tissue beneath ulcer scars. METHODS: Six pigs were studied. Endoscopic mucosal resection (EMR) with ligation was performed at 7 or 8 sites in the stomach for each animal; 4 weeks later, 23 sites with a visible scar were selected for submucosal dissection. The procedure involved first creating a submucosal fluid cushion (SFC) by injecting either saline mixed with mesna or pure saline. A slender, compliant balloon with a diameter of 8, 13, or 18 mm was inserted into the SFC. The balloon was unfolded and thrust forward to cleave the fibrotic submucosa over approximately 5 cm. RESULTS: Fibrotic submucosa was dissected within 90 seconds in 17 of 23 attempts. Isolating the ulcer scar from the muscularis with the SFC prior to balloon dissection and using a thinner balloon catheter both ensured a better dissection. CONCLUSIONS: The fibrotic submucosa underlying post-EMR scars can be dissected with the novel balloon dissector, although the technique is less effective in cases with no sign of lifting.

Comparison of the prognostic value of inflammation-based prognostic scores in patients with hepatocellular carcinoma.

BACKGROUND: Inflammation-based prognostic scores including the Glasgow Prognostic Score (GPS), neutrophil to lymphocyte ratio (NLR), and Prognostic Nutritional Index (PNI) are associated with survival in patients with hepatocellular carcinoma (HCC). The aim of this study was to investigate the prognostic value of these inflammation-based prognostic scores in patients with HCC. METHODS: In total, 150 patients with newly diagnosed HCC were prospectively evaluated. Patients were divided according to the GPS, modified GPS, NLR, platelet to lymphocyte ratio (PLR), Prognostic Index (PI), and PNI. The area under the receiver operating characteristics curve (AUC) was calculated to compare the predictive ability of each of the scoring systems. A univariate and multivariate analysis were performed to identify the clinicopathological variables associated with overall survival. RESULTS: The GPS consistently had a higher AUC value at 6 months (0.768), 12 months (0.787), and 24 months (0.758) in comparison with other inflammation-based prognostic scores. A multivariate analysis showed that the GPS was independently associated with overall survival. CONCLUSION: This study demonstrates that the GPS, an inflammation-based prognostic score, is an independent marker of poor prognosis in patients with HCC and is superior to the other inflammation-based prognostic scores in terms of prognostic ability.

Activated natural killer T cells producing interferon-gamma elicit promoting activity to murine dendritic cell-based autoimmune hepatic inflammation.

As natural killer (NK) T cells play an important role in the development of autoimmune diseases, they should have significant roles for the pathogenesis of autoimmune liver disease. Implication of the NK T cells in the generation of autoimmune-related hepatic inflammation was investigated using a novel mouse model. Immunization of mice with dendritic cells (DCs) loaded with hepatocyte-mimicking hepatocellular carcinoma cells (DC/Hepa1-6) induces cytotoxic T lymphocytes (CTL) capable of killing hepatocytes. Subsequent administration of interleukin (IL)-12, a potent interferon-gamma (IFN-γ) inducer, to the immunized mice generates autoimmune hepatic inflammation (AHI), as reported previously. Upon onset of the AHI response, the number of intrahepatic CD3(+) NK1 · 1(+) NK T cells increased markedly, along with a decrease in the number of splenic NK T cells, augmented expression of CXCR6 on intrahepatic NK T cells and CXCL16 in hepatic tissue, suggesting that NK T cells were recruited into the inflamed liver. The NK T cells were strongly positive for CD69 and produced IFN-γ, but not IL-4. AHI activity was attenuated markedly in CD1d(-/-) NK T cell-deficient mice, indicating that NK T cells play a pivotal role in the development of AHI. Mice treated with DC/Hepa1-6 and alpha-galactosylceramide, a potent NK T cell activator, also exhibited similar hepatic inflammation, in which activated NK T cells producing IFN-γ and CD8(+) T cells cytotoxic to hepatocytes were induced in liver-infiltrating mononuclear cells. Activated NK T cells producing IFN-γ potentiate DC-based AHI in the mouse model.

Initial evaluation of a novel multibending backward-oblique viewing duodenoscope in endoscopic retrograde cholangiopancreatography.

A novel multibending backward-oblique viewing duodenoscope was developed to overcome the difficult technical aspect of deep cannulation into the bile duct during endoscopic retrograde cholangiopancreatography (ERCP). The aim of the present study was to evaluate the initial experience of a novel multibending backward-oblique viewing duodenoscope (M-D scope) for ERCP. This was a retrospective review of 23 patients with native papilla who received biliary ERCP with the M-D scope between April and December 2010. The procedures were performed by two well-experienced endoscopists. In all patients, biliary cannulation and therapeutic procedure were successfully completed. In two patients with Billroth I gastrectomy, ERCP were initially attempted with a conventional single-bending duodenoscope, but biliary cannulations were unsuccessful. However, with the use of the M-D scope, biliary cannulation and therapeutic procedures were successfully completed. A novel multibending backward-oblique viewing duodenoscope is safe and feasible for therapeutic and diagnostic ERCP.

Colon capsule endoscopy: European Society of Gastrointestinal Endoscopy (ESGE) Guideline.

PillCam colon capsule endoscopy (CCE) is an innovative noninvasive, and painless ingestible capsule technique that allows exploration of the colon without the need for sedation and gas insufflation. Although it is already available in European and other countries, the clinical indications for CCE as well as the reporting and work-up of detected findings have not yet been standardized. The aim of this evidence-based and consensus-based guideline, commissioned by the European Society of Gastrointestinal Endoscopy (ESGE) is to furnish healthcare providers with a comprehensive framework for potential implementation of this technique in a clinical setting.

Cytokine and chemokine response in children with the 2009 pandemic influenza A (H1N1) virus infection.

We report the systemic cytokine and chemokine response in children with the 2009 pandemic influenza A (H1N1) virus infection. In patients with pneumonia, the serum levels of IFN-γ and IL-5 were significantly higher than those in patients without pneumonia. This tendency was also present for IL-6, IL-8, IL-10, IL-13, and MCP-1 in patients with pneumonia. Among patients with pneumonia, the levels of MCP-1 were significantly higher in the group of patients with pneumonia with severe respiratory failure than patients with mild pneumonia.

Feasibility of stomach exploration with a guided capsule endoscope.

BACKGROUND AND STUDY AIMS: Video capsule endoscopy has been established in diagnosis of small-bowel disease and has been evaluated for esophageal pathology and recently for colorectal diagnostics. Gastric capsule endoscopy has not hitherto been feasible due to the stomach's large surface area and volume. We present the first application of a magnetically navigated capsule in the human stomach. PATIENTS AND METHODS: 29 volunteers and 24 patients (men 42, women 11; mean age 47.5 years) were included in a feasibility study. Low-level magnetic fields were used to maneuver the double-sensor video capsule within the human stomach with an air-water interface provided by ingestion of 1300 ml water within 1 hour before examination. Visualization of all parts of the stomach was attempted; time for visualization was recorded, and a subjective assessment of completeness of visualization was documented. RESULTS: There was technical failure in one individual; thus technical success rate was 98 %. In the 52 remaining cases, examiners assessed that the antrum, body, fundus, and cardia were fully visualized in 98 %, 96 %, 73 % and 75 %, respectively. Mean duration of examinations was 30 minutes (range 8 - 50), with a longer time (mean 37 minutes) for volunteers for study reasons. In total, 30 findings were identified: 14 were detected by both gastroscopy and capsule, 10 lesions were identified by guided capsule examination only, 6 by gastroscopy only. No significant capsule-related adverse events occurred. CONCLUSION: Magnetically navigated video capsule endoscopy appears to be feasible and sufficiently accurate for gastric examination. It may permit endoscopic examinations that are more patient-friendly and without sedation. Comparative studies are under way.

Chemically assisted submucosal injection facilitates endoscopic submucosal dissection of gastric neoplasms.

BACKGROUND AND STUDY AIMS: A randomized in vivo animal study previously demonstrated that topical injection of mesna solution (sodium-2-mercaptoethanesulfonate) chemically softened submucosal connective tissues and facilitated mechanical dissection of the submucosal tissue plane. The present study evaluated the technical feasibility and safety of chemically assisted endoscopic submucosal dissection (CA-ESD) using mesna in 20 consecutive patients who underwent endoscopic excision of gastric neoplasm. MATERIALS AND METHODS: Following the margination of the lesion with a mucosal circumcision, 4 - 12 mL of 10 % mesna solution was injected into the submucosal layer. Mechanical submucosal dissection was then performed by bluntly cleaving the chemically treated submucosal layer with the tip of a cap-fitted gastroscope. The use of cautery was restricted to prophylactic hemostasis, dissection of the coagulated vessels and persistent submucosal tissues, and the final snare resection. Post-therapeutic ulceration repair and adverse events were followed up during a 1-week hospitalization and by repeat endoscopies at 1 day, 1 week, and 1 month after the procedure. RESULTS: Sixteen gastric cancers and four adenomas were treated in this study. The sampled tissue measured 38.25 +/- 14.53 mm, with an en bloc resection rate of 100 %. Mean operation time was 21.17 +/- 11.6 minutes. The time spent using cautery was limited to 26.1 % of the total submucosal dissection time. Ulcerations healed normally without complications. CONCLUSIONS: This preliminary study demonstrates that submucosal injection of mesna facilitates and expedites mechanical submucosal dissection. The major limitations in this study include the single-arm study design and a small patient population.

Antigenic stimulation with cytochrome P450 2J expressed in mouse hepatocellular carcinoma cells regulates host anti-tumour immunity.

Cytochrome P450 2J subfamily (CYP2J) enzymes expressed in mouse hepatocellular carcinoma (HCC) cells were identified as an antigen recognized by specific CD4(+) T cells and the structure of its T cell epitope was determined by proteomics-based exploration. The major histocompatibility complex (MHC) class II binding peptides were isolated from I-A(k)/peptide complex of dendritic cells (DCs) loaded or unloaded with MIH-2 mouse HCC cells. MHC class II-binding peptides found in MIH-2-loaded DCs but not in unloaded DCs were determined by tandem mass spectrometric analysis. The peptide, consisting of amino acid 276-290 (DFIDAFLKEMTKYPE) of mouse CYP2J enzymes, was identified as an antigenic peptide presented in the context of MHC class II. Preventive treatment of mice with CYP2J peptide stimulated interferon (IFN)-gamma production of splenocytes and suppressed the growth of implanted CYP2J-positive MIH-2 cells but not CYP2J-negative murine bladder tumour cells. However, continuous treatment of MIH-2-bearing mice with CYP2J peptide significantly suppressed IFN-gamma production of splenocytes and accelerated the growth of implanted MIH-2 tumours in vivo. Increased frequencies of CD4(+)forkhead box P3 regulatory T cells and CD11b(+)Gr-1(+) myeloid suppressor cells were observed in splenocytes from the continuously immunized mice. These results indicate that antigenecity of CYP2J isoforms expressed in HCC cells activate host anti-tumour immunity at an initial stage of HCC, but suppress host anti-tumour immunity with excessive antigenic stimulation at an advanced stage.

Magnifying endoscopy combined with narrow-band imaging for differential diagnosis of superficial depressed gastric lesions.

BACKGROUND AND AIM: Magnifying endoscopy combined with narrow-band imaging (ME-NBI) has been used for differential diagnosis of various focal lesions. The aim of our study was to evaluate ME-NBI criteria for cancer diagnosis in superficial depressed gastric lesions in comparison to conventional white light endoscopy (WLE). PATIENTS AND METHODS: ME-NBI and WLE images of 100 superficial gastric depressions (55 depressed cancers, 45 benign depressions) were independently evaluated by 11 endoscopists blinded to the diagnosis in each case. The presence or absence of predefined ME-NBI findings relating to microvasculature and fine mucosal structure (FMS) was recorded. A general diagnosis of benign or malignant also had to be given on the basis of a general assessment of features of color and shape as shown in the ME-NBI and WLE images, respectively, without regard to any prespecified criteria. RESULTS: Multivariate and ROC analysis demonstrated that the triad of FMS disappearance, microvascular dilation, and heterogeneity appeared to be the best combination for diagnosis of gastric cancer. ME-NBI diagnosis with the triad attained a good specificity (85 %, theoretically calculated if all of the triad were positive), which was significantly ( P < 0.001) superior to WLE general diagnosis (65 %), and comparable with ME-NBI general diagnosis (80 %). The sensitivities of the three diagnoses (ME-NBI with the triad 69 %, WLE general diagnosis 71 %, ME-NBI general diagnosis 72 %) were comparably moderate. The kappa values (interobserver concordance) for ME-NBI diagnosis with the triad (0.47) and ME-NBI general diagnosis (0.48) were superior to the kappa value for WLE diagnosis (0.34). CONCLUSION: The triad of FMS disappearance, microvascular dilation, and heterogeneity has good specificity for the diagnosis of superficial depressed gastric carcinoma, but the sensitivity needs to be improved.

A pilot study of EUS-guided hot saline injection for induction of pancreatic tissue necrosis.

BACKGROUND AND STUDY AIMS: Hot saline may be potentially useful for inducing necrosis of pancreatic tissue. However, the local and systemic effects are largely unknown. This pilot study aimed to evaluate the feasibility and safety of EUS-guided injection of hot saline into the pancreas in the porcine model. METHODS: Boiling hot saline was injected into the tail of normal porcine pancreas under EUS guidance in six pigs via a transgastric approach. Three pigs were killed 4 hours later to study the acute effect of the hot saline injection (acute study). The remaining three pigs were killed after 7 days of clinical observation (survival study). RESULT: Injection of 5 mL, 2 mL and 1 mL of hot saline produced localized necrosis (7 - 10 mm) of pancreatic tissue in the acute study. However, there was pooling of hot saline on the surface of the pancreas when 5mL was injected. On the basis of the results of the acute study, the volume of hot saline injected in the survival study was 1 mL. One milliliter of hot saline produced localized or sporadic necrosis of pancreatic tissue without any signs of pancreatitis in all three pigs in the survival study; hot saline was observed to pool on the pancreatic surface of one pig. There was no histological evidence of necrosis in the pancreatic tissue adjacent to the pooled hot saline in either the acute or the survival study. CONCLUSION: EUS-guided hot saline injection of pancreatic tissue in the porcine model was technically successful and led to localized necrosis of pancreatic tissue without any sign of pancreatitis.

Assessment of novel endoscopic techniques for visualizing superficial esophageal squamous cell carcinoma: autofluorescence and narrow-band imaging.

Lugol chromoendoscopy (LCE) is a useful technique for visualizing superficial esophageal squamous cell carcinoma (SESCC), but the stimulating effect of the Lugol solution can sometimes cause clinical problems. Newly developed techniques such as narrow-band imaging (NBI) and autofluorescence imaging (AFI) enable SESCC to be easily visualized without LCE. This study aimed to assess the visualizing power of white-light imaging (WLI), NBI, and AFI, compared with LCE. Sixteen patients with 16 SESCCs underwent LCE and endoscopy with NBI and AFI before endoscopic or surgical treatment. Twenty sets of endoscopic SESCC images were prepared, each of which contained still images from WLI, NBI, AFI, and LCE. The image sets were shown to 25 endoscopists, who then each completed a questionnaire about the ease-of-detection of the SESCCs, scoring WLI, NBI, and AFI images with reference to a perfect score for LCE; mean scores were compared. Overall, significantly higher scores were given for NBI than for WLI and AFI, with no significant difference between WLI and AFI. Stratification by endoscopist characteristics indicated that younger or less experienced endoscopists gave significantly higher scores for AFI than WLI. Stratification by lesion characteristics revealed that AFI had significantly higher scores than WLI for flat/elevated lesions or those with diameter >or=20 mm; scores were significantly lower for depressed lesions or those with diameter <20 mm. For SESCC, the visualizing power of NBI seems more similar to that of LCE than AFI or WLI: NBI might be more useful than AFI or WLI in detecting SESCC. AFI seems to have both superior and inferior visualizing power to WLI depending on characteristics of endoscopists or SESCC lesions.

Magnifying endoscopy with narrow band imaging for predicting the invasion depth of superficial esophageal squamous cell carcinoma.

The invasion depth of superficial esophageal squamous cell carcinoma is important in determining therapeutic strategy. The aim of this study was to prospectively investigate the clinical utility of magnifying endoscopy with narrow band imaging compared with that of non-magnifying high-resolution endoscopy or high-frequency endoscopic ultrasonography in predicting the depth of superficial esophageal squamous cell carcinoma. The techniques were carried out in 72 patients with 101 superficial esophageal squamous cell carcinomas, which were then resected by either endoscopic mucosal resection or esophagectomy. The histological invasion depth was divided into two: mucosal or submucosal carcinoma. We investigated the relationship between endoscopic staging and histology of tumor depth. Non-magnifying high-resolution endoscopy, magnifying endoscopy with narrow band imaging, and high-frequency endoscopic ultrasonography had overestimation/underestimation rates of 7/5, 4/4 and 8/3%, respectively. The sensitivity rates for the three techniques were 72, 78, and 83%, respectively, and the specificity rates were 92, 95, and 89%, respectively. There were no statistically significant differences among the three endoscopic techniques. Clinical utility of magnifying endoscopy with narrow band imaging does not seem to be significantly different from that of non-magnifying high-resolution endoscopy or high-frequency endoscopic ultrasonography in predicting the depth of superficial esophageal squamous cell carcinoma. Magnifying endoscopy with narrow band imaging may have potential to reduce overestimation risks of non-magnifying high-resolution endoscopy or high-frequency endoscopic ultrasonography.

Autofluorescence endoscopy versus conventional white light endoscopy for the detection of superficial gastric neoplasia: a prospective comparative study.

BACKGROUND AND STUDY AIMS: Preliminary studies have suggested autofluorescence endoscopy (AFE) to be accurate in the diagnosis of gastric tumors. Our prospective blinded study systematically compared AFE with white light endoscopy (WLE) for the detection of superficial gastric neoplasia. PATIENTS AND METHODS: An enriched population included 33 patients with superficial gastric neoplasia referred for endoscopic submucosal dissection (ESD), and 18 control patients undergoing follow-up endoscopy after curative ESD. At the direction of a study coordinator, two endoscopists who were blinded to the patient's history and to each other's findings, performed WLE followed by AFE or performed AFE alone, in random order. Both endoscopists independently recorded the presence of lesions seen at AFE and WLE. All lesions identified in either test were biopsied and the pathological results were used as the gold standard. RESULTS: 39 gastric neoplasias were histologically confirmed and 52 non-neoplastic lesions were found to be either WLE- and/or AFE-positive. Sensitivities of WLE and AFE alone were 74 % vs. 64 % (n. s.) and specificities were 83 % vs. 40 % ( P = 0.0003), respectively. WLE followed by AFE had a sensitivity of 69 % (n. s.) and a specificity of 64 % ( P = 0.046 compared with WLE alone). Of all neoplasias finally diagnosed, 13 % (or in the case of elevated neoplasias, 23 %) were detected by AFE but not by WLE. CONCLUSIONS: Although one quarter of elevated gastric neoplasias were detected only by AFE, its specificity is poor; therefore its clinical value is limited.

Clinical outcome after endoscopic mucosal resection for esophageal squamous cell carcinoma invading the muscularis mucosae--a multicenter retrospective cohort study.

BACKGROUND AND STUDY AIMS: Endoscopic mucosal resection (EMR) is now commonly indicated for esophageal squamous cell carcinoma (ESCC) within the lamina propria mucosa. However, EMR for ESCC that has invaded the muscularis mucosa is controversial because the risk of lymph node metastasis is not negligible. We conducted a multicenter retrospective cohort study to investigate the incidence of lymph node metastasis and survival after EMR for ESCC invading the muscularis mucosa. PATIENTS AND METHODS: A total of 104 patients with 111 lesions invading the muscularis mucosa, were retrospectively studied at eight institutes. No patients exhibited evidence of metastasis of lymph nodes or distant organs prior to EMR. Overall and cause-specific survival rates were calculated from the date of EMR to the date of death or the most recent follow-up visit. Survival curves were plotted according to the Kaplan-Meier method. RESULTS: In total, 86 patients (82.7%) who did not receive further treatment such as chemotherapy, irradiation therapy, chemoradiotherapy, or esophagectomy after EMR were followed up. Only two patients (1.9%) developed lymph node metastasis after EMR. With a median follow-up period of 43 months (range, 8-134 months), overall and cause-specific survival rates at 5 years after EMR were 79.5% and 95.0%, respectively. CONCLUSIONS: EMR for ESCC that invades the muscularis mucosa has curative potential as a minimally invasive treatment option.

Induction of vascular endothelial growth factor by nitric oxide in human glioblastoma and hepatocellular carcinoma cells.

We evaluated the effect of nitric oxide (NO) on vascular endothelial growth factor (VEGF) gene expression in human A-172 glioblastoma cells and human HepG2 hepatocellular carcinoma cells. The mRNA level of VEGF increased in response to S-Nitroso-N-acetyl-D,L-penicillamine (SNAP) in both cell lines, and increased in mRNA level well coincided with VEGF protein production in A-172 cells. SNAP at 0.5 mM induced maximal stimulation of 4.4 and 3.7 kb VEGF mRNA expression after 6 h about 11 and 8 fold increase, respectively above control level. Similar VEGF mRNA accumulation was observed also with NOR3, another chemical NO generator. To evaluate the effect of SNAP on VEGF mRNA stability, half-lives of VEGF mRNA were measured in A-172 cells cultured with or without 0.5 mM SNAP and treated with actinomycin D (25 microg/ml). Half-life for VEGF mRNA was found to be prolonged about 2.4 fold by SNAP. VEGF expression induced by SNAP was inhibited by guanylate cyclase inhibitors, methylene blue (10 microM) and LY-83583 (1 microM), and by the protein synthesis inhibitor, cycloheximide (25 microg/ml). These results suggest that induction of VEGF gene expression by NO is mediated through guanylate cyclase activity and requires on-going protein synthesis.

Biological markers as a predictor for response and prognosis of unresectable gastric cancer patients treated with 5-fluorouracil and cis-platinum.

We investigated the utility of examining biological markers to predict chemoresponse and survival. The subjects consisted of 39 unresectable gastric cancer patients treated with a combination of 5-fluorouracil and cis-platinum. The expression of p53, bcl-2, thymidylate synthase (TS), glutathione S-transferase pi (GST-pi), and vascular endothelial growth factor (VEGF) in the formalin-fixed biopsy samples of primary tumors before chemotherapy was examined immunohistochemically. The positive rate for VEGF, bcl-2, TS, p53, and GST-pi was 51, 10, 46, 38, and 69%, respectively. VEGF-positive cases showed a higher response rate than did negative cases (11 of 20 versus 2 of 19 cases; P = 0.0057). The cases that were negative for p53, TS, bcl-2, and GST-pi were more likely to respond to chemotherapy than the cases that were positive for these markers. The 10 cases having 4 or 5 favorable phenotypes (VEGF positive, p53 negative, bcl-2 negative, TS negative, and GST-pi negative) survived longer than the remaining 29 cases (P = 0.0069). Multivariate analysis revealed that the number of favorable phenotypes (> or = 4 versus < or = 3) had a greater impact on survival than performance status (0 versus 1 or 2), age (> 60 years versus < or = 60 years), macroscopic type (scirrhous versus nonscirrhous), histological type (intestinal versus diffuse), or tumor extent (locally advanced versus metastatic). Immunohistochemical examination of biological markers in biopsy samples may be useful in predicting the clinical outcome of unresectable gastric cancer patients treated with 5-fluorouracil and cis-platinum.

Hypophosphatemic rickets accompanying congenital microvillous atrophy.

This report concerns an 11-year-old boy who manifested hypophosphatemic rickets associated with congenital microvillous atrophy (CMA). He had been suffering from vomiting and severe diarrhea from the first day of life and had been treated with total parenteral nutrition (TPN) since he was 67 days old. At 4 years of age, intestinal biopsy resulted in a diagnosis of CMA. He was admitted to our hospital complaining of leg pain at the age of 11. Laboratory data revealed hypophosphatemia, elevated serum 1, 25-dihydroxyvitamin D (1,25(OH)2D) levels, and hypercalciuria. A roentgenogram showed rickets in the extremities. A balance study of phosphate in urine and stool indicated that the amount of phosphate leaking into the stool was greater than that into the urine. Moreover, the total amount of phosphate leaking from both the intestine and kidney exceeded the amount of phosphate intake from TPN. The rickets was healed by increasing the phosphate concentration in TPN. This case is different from X-linked hypophosphatemic rickets but similar to hereditary hypophosphatemic rickets with hypercalciuria (HHRH) in terms of hypercalciuria and elevated serum 1,25(OH)2D levels. The effectiveness of phosphate treatments used here is also similar to that used for HHRH. However, this type of hypophosphatemic rickets is unique in that phosphate leaking into the intestine plays an important role in its pathogenesis.