Comparison of endoscopic gastritis based on Kyoto classification between diffuse and intestinal gastric cancer.

BACKGROUND: Gastric cancers can be categorized into diffuse- and intestinal-type cancers based on the Lauren histopathological classification. These two subtypes show distinct differences in metastasis frequency, treatment application, and prognosis. Therefore, accurately assessing the Lauren classification before treatment is crucial. However, studies on the gastritis endoscopy-based Kyoto classification have recently shown that endoscopic diagnosis has improved. AIM: To investigate patient characteristics including endoscopic gastritis associated with diffuse- and intestinal-type gastric cancers in Helicobacter pylori (H. pylori)-infected patients. METHODS: Patients who underwent esophagogastroduodenoscopy at the Toyoshima Endoscopy Clinic were enrolled. The Kyoto classification included atrophy, intestinal metaplasia, enlarged folds, nodularity, and diffuse redness. The effects of age, sex, and Kyoto classification score on gastric cancer according to the Lauren classification were analyzed. We developed the Lauren predictive background score based on the coefficients of a logistic regression model using variables independently associated with the Lauren classification. Area under the receiver operative characteristic curve and diagnostic accuracy of this score were examined. RESULTS: A total of 499 H. pylori-infected patients (49.6% males; average age: 54.9 years) were enrolled; 132 patients with gastric cancer (39 diffuse- and 93 intestinal-type cancers) and 367 cancer-free controls were eligible. Gastric cancer was independently associated with age ≥ 65 years, high atrophy score, high intestinal metaplasia score, and low nodularity score when compared to the control. Factors independently associated with intestinal-type cancer were age ≥ 65 years (coefficient: 1.98), male sex (coefficient: 1.02), high intestinal metaplasia score (coefficient: 0.68), and low enlarged folds score (coefficient: -1.31) when compared to diffuse-type cancer. The Lauren predictive background score was defined as the sum of +2 (age ≥ 65 years), +1 (male sex), +1 (endoscopic intestinal metaplasia), and -1 (endoscopic enlarged folds) points. Area under the receiver operative characteristic curve of the Lauren predictive background score was 0.828 for predicting intestinal-type cancer. With a cut-off value of +2, the sensitivity, specificity, and accuracy of the Lauren predictive background score were 81.7%, 71.8%, and 78.8%, respectively. CONCLUSION: Patient backgrounds, such as age, sex, endoscopic intestinal metaplasia, and endoscopic enlarged folds are useful for predicting the Lauren type of gastric cancer.

TGF-ß1 promotes lymphangiogenesis during peritoneal fibrosis.

Peritoneal fibrosis (PF) causes ultrafiltration failure (UFF) and is a complicating factor in long-term peritoneal dialysis. Lymphatic reabsorption also may contribute to UFF, but little is known about lymphangiogenesis in patients with UFF and peritonitis. We studied the role of the lymphangiogenesis mediator vascular endothelial growth factor-C (VEGF-C) in human dialysate effluents, peritoneal tissues, and peritoneal mesothelial cells (HPMCs). Dialysate VEGF-C concentration correlated positively with the dialysate-to-plasma ratio of creatinine (D/P Cr) and the dialysate TGF-ß1 concentration. Peritoneal tissue from patients with UFF expressed higher levels of VEGF-C, lymphatic endothelial hyaluronan receptor-1 (LYVE-1), and podoplanin mRNA and contained more lymphatic vessels than tissue from patients without UFF. Furthermore, mesothelial cell and macrophage expression of VEGF-C increased in the peritoneal membranes of patients with UFF and peritonitis. In cultured mesothelial cells, TGF-ß1 upregulated the expression of VEGF-C mRNA and protein, and this upregulation was suppressed by a TGF-ß type I receptor (TGFßR-I) inhibitor. TGF-ß1-induced upregulation of VEGF-C mRNA expression in cultured HPMCs correlated with the D/P Cr of the patient from whom the HPMCs were derived (P<0.001). Moreover, treatment with a TGFßR-I inhibitor suppressed the enhanced lymphangiogenesis and VEGF-C expression associated with fibrosis in a rat model of PF. These results suggest that lymphangiogenesis associates with fibrosis through the TGF-ß-VEGF-C pathway.

Atrial natriuretic peptide ameliorates peritoneal fibrosis in rat peritonitis model.

BACKGROUND: Atrial natriuretic peptide (ANP) was recently reported to ameliorate fibrosis in the heart and experimental renal diseases and vascular thickening after balloon injury. Peritoneal fibrosis is an important complication of long-term peritoneal dialysis, and peritonitis is a factor in its onset. In the present study, we investigated the effects of ANP in a rat peritonitis-induced peritoneal fibrosis model. METHODS: As pretreatment, an osmotic pump containing vehicle (saline) or ANP (0.15 or 0.3 µg/min) was inserted through the carotid vein in male Sprague-Dawley rats. ANP or saline was continuously infused using the osmotic pump. Three days after administration of ANP or saline, rats underwent peritoneal scraping in a blind manner and were sacrificed on Day 14. The effects of ANP were evaluated based on peritoneal thickness, immunohistochemistry and real-time polymerase chain reaction. In each experiment, we evaluated messenger RNA (mRNA) expression of the ANP receptor natriuretic peptide receptor A (NPR-A) in the peritoneum after scraping. The effects of ANP were also studied in cultured peritoneal fibroblasts and mesothelial cells. RESULTS: We observed a significant increase in NPR-A mRNA in the peritoneum. Peritoneal thickness increased with time and peaked on Day 14, but ANP significantly reduced peritoneal thickness. Parameters such as number of macrophages and CD-31-positive vessels and expression of type III collagen/transforming growth factor-ß/plasminogen activator inhibitor-1 (PAI-1)/connective tissue growth factor (CTGF) were significantly suppressed by ANP. In cultured peritoneal fibroblasts and mesothelial cells, ANP suppressed angiotensin II-induced upregulation of CTGF and PAI-1. CONCLUSIONS: Our results suggest that ANP is useful in preventing inflammation-induced peritoneal fibrosis.

Myoclonus after dextromethorphan administration in peritoneal dialysis.

OBJECTIVE: To report a case of myoclonus that developed after administration of dextromethorphan. CASE SUMMARY: A 64-year-old man was diagnosed with chronic renal failure due to diabetic nephropathy. The patient started on peritoneal dialysis 6 months before he was hospitalized. Two days before hospitalization, he developed cough and sputum and he visited an outpatient clinic, where dextromethorphan was prescribed. After taking a total of 30 mg of dextromethorphan, the patient developed myoclonus, tremor, agitation, slurred speech, and diaphoresis, which continued after he stopped taking the prescribed medicine. He visited an emergency department and was hospitalized for examination and treatment of myoclonus. DISCUSSION: As the patient's dialysis schedule was adequate, these symptoms were likely not due to uremia. The blood concentration of dextromethorphan (2.68 ng/mL) 60 hours after the 30-mg dose was higher than expected, and the blood concentration of dextrorphan, a metabolite, was lower than expected. We suspected that myoclonus was due to dextromethorphan-related symptoms induced by CYP2D6, which primarily metabolizes dextromethorphan. We analyzed the CYP2D6 gene for polymorphisms and identified CYP2D6 (*)1/(*)10. The patient had been taking metoprolol 40 mg/day for 2 years. The blood concentration of metoprolol 6 hours after administration was 13 ng/mL, which suggests that it was metabolized normally. Metoprolol has another metabolic pathway, via CYP2C19, and this may have led to its lack of accumulation. Moreover, metoprolol may have bound to active CYP2D6. Thus, affinity for CYP2D6, protein-binding rate, and lipid solubility may influence these drug interactions. Total scores for the Adverse Drug Reaction (ADR) probability scale and the Drug Interaction Probability Scale (DIPS) were 9 (highly probable) and 3 (possible), respectively. CONCLUSIONS: Myoclonus and other symptoms in this patient may have been caused by a prolonged high concentration of dextromethorphan due to CYP2D6 polymorphisms and drug interactions.