Seiji Onogawa

Expression of VEGF‐C and VEGF‐D at the invasive edge correlates with lymph node metastasis and prognosis of patients with colorectal carcinoma

Vascular endothelial growth factor (VEGF)‐C and VEGF‐D are potent lymphangiogenic factors produced by tumor and stromal cells. The purpose of this study was to determine whether expression of VEGF‐C and/or VEGF‐D correlates with clinicopathological features of human colorectal carcinoma. Expression of mRNAs for VEGF‐C, VEGF‐D, and their receptor VEGFR‐3 was examined by reverse transcription‐polymerase chain reaction (RT‐PCR) in six colon carcinoma cell lines and in fresh endoscopic biopsy specimens from 20 patients with colorectal carcinoma. Expression of VEGF‐C and VEGF‐D protein was also examined immunohistochemically in 139 archival surgical specimens of human colorectal carcinoma. Of the six cell lines, one (Colo320D) constitutively expressed VEGF‐C and four (Colo320D, DLD‐1, km12sm, km12c) constitutively expressed VEGF‐D mRNA. Expression of VEGF‐D mRNA was increased under low oxygen conditions, and all six cell lines constitutively expressed VEGF‐D mRNA under hypoxic conditions. Of the 139 specimens of human colorectal carcinoma, 65 (46.8%) showed intense VEGF‐C immunoreactivity and 41 (29.5%) showed intense VEGF‐D immunoreactivity. In 49 (75.3%) of the 65 and 20 (48.8%) of the 41 cases, heterogeneous intratumoral staining was observed for VEGF‐C and VEGF‐D, respectively, with the highest levels of expression at the invasive edges. VEGF‐C expression correlated with the depth of tumor invasion, lymphatic involvement, venous involvement, lymph node metastasis, and liver metastasis, and VEGF‐D expression correlated with the depth of tumor invasion, lymph node metastasis, and liver metastasis. No correlation was observed between VEGF‐C and VEGF‐D expression in tumors. The survival time of patients with VEGF‐C‐positive tumors was significantly shorter than that of patients with VEGF‐C‐negative tumors, and the survival time of patients with VEGF‐D‐positive tumors was significantly shorter than that of patients with VEGF‐D‐negative tumors. The survival time of patients with both VEGF‐C‐ and VEGF‐D‐positive tumors was significantly shorter than that of patients with both VEGF‐C‐and VEGF‐D‐negative tumors. These results suggest that VEGF‐C and VEGF‐D may be independent and important prognostic factors in patients with human colorectal carcinoma. (Cancer Sci 2004; 95: 32–39)

Expression of hypoxia-inducible factor-1α is associated with tumor vascularization in human colorectal carcinoma

HIF‐1 is reported to transactivate expression of VEGF, which is an important angiogenic factor. To determine whether HIF‐1α plays a role in angiogenesis through its regulation of VEGF, we examined expression of HIF‐1α and its relation to clinicopathologic features, VEGF expression and prognosis of patients with colorectal carcinoma. Expression of HIF‐1α and VEGF was examined in 4 colorectal carcinoma cell lines (COLO320DM, COLO201, DLD‐1, WiDr) and 149 colorectal carcinoma tissues (10 fresh specimens, 139 archival, paraffin‐embedded specimens). HIF‐1α protein levels were increased by hypoxia in 3 of 4 colorectal carcinoma cell lines (COLO201, DLD‐1, WiDr), and VEGF mRNA levels were also increased by hypoxia in the same cell lines. In 8 of 10 patients with colorectal cancer, expression of HIF‐1α and VEGF was increased in tumor tissues compared to corresponding normal mucosa. Of 139 archival specimens of colorectal carcinoma, 81 (58.3%) expressed HIF‐1α protein at a high level. HIF‐1α expression was correlated with tumor invasion, tumor stage, lymphatic invasion, venous invasion and liver metastasis. Moreover, HIF‐1α expression was correlated significantly with VEGF expression and microvessel density. Although there was a tendency for poorer prognosis in patients with high HIF‐1α‐expressing tumors, this correlation was not statistically significant. These findings suggest that HIF‐1α may play a role in angiogenesis and tumor progression via regulation of VEGF in human colorectal carcinoma.

Evaluation of Individual Risk in Nonvariceal Gastrointestinal Bleeding Patients with NSAID Administration: A Multicenter Study in Japan

Backgrounds: Gastrointestinal (GI) toxicity is an undesirable effect of nonsteroidal anti-inflammatory drugs (NSAIDs). We conducted a multicenter study in Japan to clarify the GI risk grade in patients with NSAID-induced GI bleeding. Methods: Patients with emergent endoscopic hemostasis by nonvariceal bleeding were registered from 36 hospitals in Hiroshima. In cases with NSAID use, the GI risk grade (low, moderate, or high) was evaluated, and concomitant drugs were investigated. We asked 79 gastroenterologists and 234 orthopedists what concomitant drugs they would prescribe to 3 simulated patients. Results: A total of 1,350 patients were registered. NSAIDs were used in 278 cases (21%). Concerning the risk grade in each patient, the largest group was the moderate-risk group (203 patients; 73%), while the high-risk group comprised 10% of all NSAID users with bleeding. A proton pump inhibitor (PPI) or misoprostol was administrated to only 20 patients (7%). A small number of the gastroenterologists and orthopedists who responded to the questionnaire would prescribe PPI or misoprostol to simulated patients with short-term loxoprofen use. Conclusions: In NSAID users with GI bleeding, the moderate-risk group was the largest group for GI toxicity in Japan. In these cases, PPI or misoprostol was not commonly medicated in clinical practice.

Percutaneous transhepatic sclerotherapy for recurrent bleeding ileal varices diagnosed by capsule endoscopy and computed tomography during percutaneous transhepatic venography

We report a case of acute uncontrolled gastrointestinal bleeding in a patient with liver cirrhosis. A 64‐year‐old man was admitted to our hospital for further investigation of blood in stools. Preliminary examination by computed tomography (CT) as well as upper and lower endoscopy could not detect the bleeding source. Exploratory laparotomy was considered difficult due to potential easy bleeding and adhesions caused by past abdominal surgery. The hemoglobin level was normalized by blood transfusion. Capsule endoscopy (CE) identified ileal varices. The top of these ileal varices was red, prompting their identification as the source of bleeding. Percutaneous transhepatic venography (PTV) confirmed the presence of many varices in the branch of the superior mesenteric vein, although the bleeding source could not be identified. CT during PTV identified varices protruding into the ileal lumen, which were managed subsequently by percutaneous transhepatic sclerotherapy (PTS). The procedure stopped the bleeding completely. CE proved less invasive and effective in detecting obscure gastrointestinal bleeding. CT during PTV followed by PTS is suitable for diagnosis and treatment of bleeding varices in patients with portal hypertension.

Randomized study of lafutidine vs lansoprazole in patients with mild gastroesophageal reflux disease.

AIM To compare the clinical efficacy of the second-generation H2RA lafutidine with that of lansoprazole in Japanese patients with mild gastroesophageal reflux disease (GERD). METHODS Patients with symptoms of GERD and a diagnosis of grade A reflux esophagitis (according to the Los Angeles classification) were randomized to receive lafutidine (10 mg, twice daily) or lansoprazole (30 mg, once daily) for an initial 8 wk, followed by maintenance treatment comprising half-doses of the assigned drug for 24 wk. The primary endpoint was the frequency and severity of heartburn during initial and maintenance treatment. The secondary endpoints were the sum score of questions 2 and 3 in the Gastrointestinal Symptom Rating Scale (GSRS), and the satisfaction score. RESULTS Between April 2012 and March 2013, a total of 53 patients were enrolled, of whom 24 and 29 received lafutidine and lansoprazole, respectively. After 8 wk, the frequency and severity of heartburn was significantly reduced in both groups. However, lafutidine was significantly inferior to lansoprazole with regard to the severity of heartburn during initial and maintenance treatment (P = 0.016). The sum score of questions 2 and 3 in the GSRS, and satisfaction scores were also significantly worse in the lafutidine group than the lansoprazole group (P = 0.0068 and P = 0.0048, respectively). CONCLUSION The clinical efficacy of lafutidine was inferior to that of lansoprazole, even in Japanese patients with mild GERD.

A Trial of the Use of Patency Capsules in Combination with Overnight Capsule Endoscopy

Background: The PillCam® patency capsule (PPC) was developed to minimize the risk of capsule retention during capsule endoscopy (CE). Typically, the use of patency capsules prior to CE requires patients to be monitored over a period of time. To reduce the need for frequent outpatient visits during PPC examination and CE, we developed the overnight CE (ON-CE) procedure. Methods: Between October 2012 and January 2014, a total of 19 patients (15 males and 4 females, mean age 48.4 years) were administered PPC to assess the patency of the small intestine prior to ON-CE at JA Onomichi General Hospital in Hiroshima, Japan. Results: PPC confirmed patency of the small intestine in 15 of the 19 patients. Of these 15 patients, 14 proceeded to ON-CE. The CE was cancelled in 1 patient and the cecal intubation time exceeded 8 h in another patient. For the remaining 12 patients, the mean small intestine observation coverage was 92.3% and the mean cecal intubation time was 325 min. There were no adverse events and the discharge of the capsule was confirmed in all cases. Conclusion: When patency of the gastrointestinal tract was confirmed with the PPC, ON-CE was performed safely and effectively.

Clinical usefulness of transabdominal ultrasonography prior to patency capsule for suspected small-bowel strictures

Abstract Objective: Patency capsule (PC) examination has made it possible to perform capsule endoscopy (CE) in patients with a suspected small-bowel stricture. However, PC has some drawbacks, so we assessed the usefulness of transabdominal ultrasonography (TUS) prior to PC in patients with suspected small-bowel strictures to avoid unnecessary PC examination. Patients and methods: Fifty-two patients who underwent TUS prior to PC were enrolled in this study. TUS findings were classified as follows: intestinal narrowing and distension at the oral side (Type A); extensive bowel wall thickening (Type B); focal bowel wall thickening (Type C) or no abnormality detected (Type D). We evaluated the TUS and PC findings for the detection of small-bowel strictures. Results: Double-balloon endoscopy (DBE) revealed small-bowel strictures in 13 of 50 patients (26%). TUS yielded Type B or C findings in 12 of 13 patients (92%), while PC revealed strictures in all 13 patients. In Crohn’s disease (CD) patients with Type B TUS findings, 8 of 9 (89%) had small-bowel strictures on DBE. However, only two of six non-CD patients (33%) with Type B TUS findings had small-bowel strictures. The incidence of Type B strictures was significantly higher in CD patients. Conclusions: CD patients with Type B TUS findings should not undergo PC or CE because of the high rate of small-bowel strictures. Non-CD patients diagnosed with Type B TUS strictures, as well as patients diagnosed with Type C or D strictures should undergo CE after confirming small-bowel patency using PC.