Submucosal fibrosis and basic-fibroblast growth factor-positive neutrophils correlate with colonic stenosis in cases of ulcerative colitis.

BACKGROUND AND AIMS: The frequency of benign stenosis in ulcerative colitis (UC) is low, reported as being 3.2-11.2%, with fibrosis in the submucosa or deeper pointed out as one of the causes. The aim of the present study was to assess stenosis in UC cases using immunostaining and to analyze differences between stenotic and nonstenotic cases, focusing on basic-fibroblast growth factor (b-FGF) expression and myofibroblasts. METHODS: Totals of 9 stenotic and 17 nonstenotic UC cases were histopathologically examined and immunohistochemically stained for b-FGF, α-smooth muscle actin (α-SMA), CD34, CD68 and IL-6. To identify b-FGF-positive cells, double immunostaining for b-FGF and myeloperoxidase or CD68 was performed. RESULTS: In addition to submucosal fibrosis, a significant increase of b-FGF-positive inflammatory cells and myofibroblasts was observed in stenotic portions. Most b-FGF-positive cells were also positive for myeloperoxidase, and a correlation between b-FGF-positive and total neutrophil counts was found. CONCLUSIONS: One of the major causes of stenosis in long-standing UC is fibrosis in the bowel wall, possibly induced by infiltrating inflammatory neutrophils producing b-FGF.

Rectal granular-cell tumor difficult to distinguish from carcinoid tumor.

A 60-year-old man had a positive fecal occult-blood test on a medical check-up. Colonoscopy revealed a yellowish-white submucosal tumor 8 mm in diameter in the rectum. Endoscopic ultrasonography showed a well-demarcated mass with a homogeneous, low-level, internal echo in the second to third layers of the rectal wall. A carcinoid tumor was suspected, and the mass was resected endoscopically. Histopathological examination revealed a granular-cell tumor. Gastrointestinal granular-cell tumors rarely arise in the rectum, and the preoperative diagnosis of small lesions is often difficult. In our patient, granular-cell tumor was difficult to differentially diagnose because the endoscopic and endoscopic ultrasonographic findings closely resembled those of carcinoid tumor. Interestingly, the endoscopic characteristics of the rectal granular-cell tumor in our patient resembled those of a carcinoid tumor.

Eosinophilic gastroenteritis associated with giant folds.

We describe a 54-year-old man who presented with right subcostal pain. Minocycline had been prescribed to treat pruritus, and the symptoms resolved. Subsequently, the patient consulted a local physician because of right subcostal pain. Giant folds were found in the greater curvature of the gastric body, and he was referred to the Department of Gastroenterology, Kitasato University East Hospital. Upper gastrointestinal endoscopy revealed markedly enlarged folds in the greater curvature of the stomach, with redness and edematous mucosa in the lesser curvature. Biopsy showed marked inflammatory cell infiltration (mainly eosinophils), but no atypical cells. Blood tests showed marked eosinophilia and elevated immunoglobulin E levels in the serum. The results of various allergic examinations were negative, but the clinical course suggested drug-induced eosinophilic gastroenteritis, and treatment was started. Minocycline was withdrawn without adequate resolution of symptoms. Because the leukocyte and eosinophil counts continued to increase, the patient was given suplatast, an anti-allergic agent. The symptoms and hematological values improved promptly. The patient recovered uneventfully, with no recurrence.

Roles of prostaglandin E2-EP1 receptor signaling in regulation of gastric motor activity and emptying.

It is widely accepted that the inhibition of gastric motor activity as well as the maintenance of gastric mucosal blood flow and mucous secretion are important for the homeostasis of the gastric mucosa. The present study was performed to ascertain whether or not endogenous PGs, which can protect the stomach from noxious stimuli, affect gastric motor activity and emptying. The myoelectrical activity of rat gastric smooth muscle was increased at intragastric pressures of over 2 cmH(2)O. Replacement of intragastric physiological saline with 1 M NaCl solution significantly increased PGI(2) and PGE(2) in stomach and suppressed the myoelectrical activity under a pressure of 2 cmH(2)O by 70%. Indomethacin inhibited the suppression of myoelectrical activity by 1 M NaCl. The myoelectrical activity under a pressure of 2 cmH(2)O was suppressed by continuous infusion of a selective EP1 agonist (ONO-DI-004, 3-100 nmol·kg(-1)·min(-1)) into the gastric artery in a dose-dependent manner, but not by that of the PGI receptor agonist beraprost sodium (100 nmol·kg(-1)·min(-1)). Suppression of myoelectrical activity with 1 M NaCl was inhibited by continuous infusion of a selective EP1 antagonist (ONO-8711, 100 nmol·kg(-1)·min(-1)) into the gastric artery. Furthermore, gastric emptying was tested in EP1 knockout mice and their wild-type counterparts. Gastric emptying was strongly suppressed with intragastric 1 M NaCl in wild-type mice, but this 1 M NaCl-induced suppression was not seen in EP1 knockout mice. These results suggest that PGE(2)-EP1 signaling has crucial roles in suppression of myoelectrical activity of gastric smooth muscles and inhibition of gastric emptying and that EP1 is an obvious target for drugs that control gastric emptying.

Clinical significance of evaluating primary lesions in patients with gastric cancer who receive chemotherapy.

BACKGROUND: In Western countries, the response of gastric cancer to chemotherapy is evaluated by assessing measurable metastatic lesions (MMLs) according to the response evaluation criteria in solid tumors (RECIST). In Japan, the response of primary lesions is assessed according to local Japanese criteria. We compared the response to chemotherapy as evaluated by these two sets of criteria. METHODS: Patients with unresectable, advanced gastric cancer who had primary lesions and had received first-line chemotherapy were studied. Responses of MMLs were evaluated with RECIST. Responses of primary lesions were evaluated with the Japanese criteria. Median survival times (MSTs) were compared according to treatment response by each set of criteria. RESULTS: Data from 341 patients were analyzed. Of the 242 patients with MMLs, 108 were MML responders and 134 were MML nonresponders. MST was significantly longer in MML responders (293 days; 95% confidence interval [CI], 244-342) than in MML nonresponders (159 days; 95% CI, 127-191; P < 0.0001). According to the Japanese criteria, there were 128 primary-lesion responders and 213 primary-lesion nonresponders. MST was significantly longer in responders (304 days; 95% CI, 266-342) than in nonresponders (168 days; 95% CI, 143-193, P < 0.0001). Of the 99 patients without MMLs, 26 were primary-lesion responders and 73, primary-lesion nonresponders; MST was significantly longer in the former (300 days; 95% CI, 266-334) than in the latter group (173 days; 95% CI, 111-235; P = 0.019). CONCLUSION: The responses of primary lesions according to the Japanese criteria and the responses of MMLs according to the RECIST were both significantly related to the MST. Use of the RECIST alone might bias the evaluation of treatment response because response cannot be evaluated in patients without an MML.

Vulnerable sites and changes in mucin in the rat small intestine after non-steroidal anti-inflammatory drugs administration.

BACKGROUND AND AIMS: The location of mucosal damage and changes in mucin content in the rat small intestine following administration of non-steroidal anti-inflammatory drugs (NSAIDs) have not been well elucidated. METHODS: After subcutaneous administration of loxoprofen sodium (10-40 mg/kg), the small intestinal mucosa of male Wistar rats was evaluated macroscopically, histologically, and immunohistochemically by measuring the total mucin content and immunoreactivity for anti-mucin monoclonal antibody, HCM31, 1, 3, 7, and 14 days later. Changes in the number of enterobacteria invading the mucosa around the lesions were also determined. RESULTS: Loxoprofen sodium induced erosions and ulcers along the mesenteric margin of the distal jejunum. Early (≤6 h) mucosal lesions were small and round, located between the branches of the mesenteric arteries. In the jejunum, there was a transient increase in the total mucin content, and HCM31-positive mucin in the mucosa around the ulcers increased significantly on days 3 and 7, but in the ileum there were no marked changes and few ulcers. Bacterial translocation following loxoprofen sodium administration significantly increased, according to the site of the intestinal lesions. CONCLUSIONS: Vascularly compromised sites along the jejunal mesenteric margin are vulnerable to NSAIDs-induced damage and show increased numbers of enterobacteria in the NSAIDs-treated mucosa. Increased sialomucin content in the mucus around the lesions may play an important role in the healing of NSAIDs-induced intestinal lesions.

General rules for recording endoscopic findings of esophagogastric varices (2nd edition).

General rules for recording endoscopic findings of esophageal varices were initially proposed in 1980 and revised in 1991. These rules have widely been used in Japan and other countries. Recently, portal hypertensive gastropathy has been recognized as a distinct histological and functional entity. Endoscopic ultrasonography can clearly depict vascular structures around the esophageal wall in patients with portal hypertension. Owing to progress in medicine, we have updated and slightly modified the former rules. The revised rules are simpler and more straightforward than the former rules and include newly recognized findings of portal hypertensive gastropathy and a new classification for endoscopic ultrasonographic findings.

Fulminant amoebic colitis during chemotherapy for advanced gastric cancer.

A 52-year-old man had bloody stools during chemotherapy for gastric cancer. A colonoscopy revealed necrotizing ulcer-like changes. A biopsy confirmed the presence of amoebic trophozoites. Subsequently, peritonitis with intestinal perforation developed, and emergency peritoneal lavage and colostomy were performed. After surgery, endotoxin adsorption therapy was performed and metronidazole was given. Symptoms of peritonitis and colonitis resolved. However, the patient's general condition worsened with the progression of gastric cancer. The patient died 50 d after surgery. Fulminant amoebic colitis is very rarely associated with chemotherapy. Amoebic colitis should be considered in the differential diagnosis of patients who have bloody stools during chemotherapy.

Repeat radiofrequency ablation provides survival benefit in patients with intrahepatic distant recurrence of hepatocellular carcinoma.

OBJECTIVES: Intrahepatic distant recurrence (IDR) of hepatocellular carcinoma (HCC) after curative treatment occurs frequently and influences the prognoses. The aim of this study was to determine prognostic factors affecting survival after IDR and the optimum therapy for IDR. METHODS: A total of 115 patients with a single small primary HCC who had complete radiofrequency (RF) ablation were enrolled in this study. The prognostic factors and the optimum therapy affecting survival were statistically analyzed among patients with IDRs. RESULTS: IDRs were observed in 59 (51.3%) patients with the median observation period of 19.6 months. The cumulative rates of IDRs were 11.8, 53.9, and 75.8% at 1, 3, and 5 years, respectively. IDR nodules were present as a single nodule in 38 patients and as multiple nodules in 21 patients. In all, 23 patients died during the follow-up. A total of 30 patients were treated with RF ablation, and 27 were treated with transcatheter arterial chemoembolization (TACE). The overall cumulative survival rates after IDRs were 92.7, 55.4, and 43.7% at 1, 3, and 5 years, respectively. A multivariate analysis showed that treatment with RF ablation for IDR was a significant favorable prognostic factor after IDR (hazard ratio: 0.167, 95% confidence interval: 0.048-0.584, P=0.005). In a comparison of survival after IDR between patients treated with RF ablation and TACE, who were comparable with clinical and tumoral characteristics, the cumulative survival rate of patients treated with RF ablation was significantly higher than that of those treated with TACE (77.2 vs 28.5% at 3 years). The cumulative survival rates obtained from the initial RF ablation of the patients with IDRs treated with repeat RF ablation were similar to those of recurrence-free patients. CONCLUSIONS: Repeat RF ablation should be attempted for IDR as much as possible despite tumor multiplicity for survival benefit; by reducing the need, it will help solve the problem of the current shortage of donors for liver transplantations.

Therapeutic benefits of partial splenic embolization for thrombocytopenia in hepatocellular carcinoma patients treated with radiofrequency ablation.

AIM: Partial splenic embolization (PSE) is a non-surgical procedure developed to treat hypersplenism. The purpose of this study is to evaluate therapeutic benefits of PSE with follow-up radiofrequency ablation (RFA) treatment in hepatocellular carcinoma (HCC) patients with thrombocytopenia. METHODS: Between September 1999 and January 2007, a total of 20 patients with HCC who had a few lesions, each 3 cm or less in diameter, and liver function of Child-Pugh class A or B were enrolled into our study. The patients were diagnosed with marked thrombocytopenia (<50 x 10(3)/mm(3)), or mild thrombocytopenia (<80 x 10(3)/mm(3)) with decreased prothrombin activity. They were treated once or twice with PSE. RFA was given as a follow-up treatment 2 weeks after final PSE. The primary endpoint was a platelet-count increase and improvement of prothrombin activity, and the secondary endpoint was the initiation of RFA. RESULTS: PSE was performed successfully in 19 patients (95%). Two weeks after final PSE, platelet counts increased significantly (38 +/- 14 x 10(3)/mm(3) vs. 97 +/- 43 x 10(3)/mm(3); P < 0.0001), and prothrombin activity improved significantly (59.3 +/- 19.8% vs. 65.2 +/- 17.9%; P < 0.0001). No patients had major complications during the PSE procedure. The secondary endpoint was achieved in 18 of 19 patients (94.7%). The mean overall survival was 2257 days (95% confidence interval; range, 1659-2855 days). The Kaplan-Meier cumulative survival rate was estimated to be 61.9% at 5 years. CONCLUSIONS: PSE is a safe and effective treatment for thrombocytopenia and has adjuvant therapeutic benefits for the therapy of HCC.

Effects of indomethacin on the rat small intestinal mucosa: immunohistochemical and biochemical studies using anti-mucin monoclonal antibodies.

BACKGROUND: The luminal surface of the gastrointestinal tract is covered by a viscoelastic gel layer that acts as a protective barrier against the intraluminal environment. Because the situation of the small intestine has not been elucidated to the same degree as other sections, in this study, we investigated the effects of indomethacin on the rat small intestinal mucosa. METHODS: Male Wistar rats were given indomethacin 10 mg/kg s-c and sacrificed 1, 3, 7, or 14 days later. The small intestine was opened along the anti-mesenteric side, and examined macroscopically. Total mucin content in the small intestinal epithelium was measured and immunoreactivity was examined using anti-mucin monoclonal antibodies HCM31 and PGM34. RESULTS: Indomethacin caused punched out and linear ulcers located mostly along the mesenteric margin of the distal jejunum with sparing of the ileum. Histological examination showed sialomucin recognized by HCM31 increased on day 3 especially in the regenerating epithelium around the ulcer edge. Furthermore, the surface mucous gel layer displayed a multilaminated pattern, consisting of non-sulfated sialomucin-rich layers and sulfated mucin-rich layers, where both mucins had the common core protein, MUC2. Biochemical measurements also showed the total mucin content of the jejunum increased transiently and HCM31-positive mucin increased approximately 4 times greater than baseline on day 3, but no marked changes were observed in the ileum, with few ulcers observed. CONCLUSIONS: Indomethacin administration causes quantitative and qualitative change in jejunal mucin. In particular, sialomucin plays an important role in regenerating epithelium during the healing process following indomethacin-induced mucosal damage.

Tumor budding is predictive of lymphatic involvement and lymph node metastases in submucosal invasive colorectal adenocarcinomas and in non-polypoid compared with polypoid growths.

OBJECTIVE: Early colorectal carcinomas (submucosal invasive adenocarcinomas) can be classified into polypoid and non-polypoid growth types, the latter progressing more rapidly to advanced malignancy. The aim of this study was to investigate the differences between invasive features of the two types of carcinoma by focusing on tumor budding (isolated single cells or small cell clusters (up to four cells) scattered at invasive tumor margins). MATERIAL AND METHODS: The number of foci in the field with the most frequent tumor budding was regarded as "activity". Tumor budding was examined using anti-cytokeratin antibodies in 98 colorectal submucosal invasive adenocarcinomas and compared with the clinicopathological findings. In addition, the relationships between tumor budding and beta-catenin and laminin-5gamma2 expression were analyzed. RESULTS: Tumor budding activity was significantly higher in non-polypoid growth carcinomas compared with polypoid growth carcinomas (p = 0.0006) and values for left-sided lesions were higher than those for right-sided lesions of the colon (p = 0.0108). Positive links with tumor budding were evident for lymphatic involvement and lymph node metastasis in non-polypoid growth carcinomas, and with laminin-5gamma2 cytoplasmic expression in polypoid growth carcinomas. Multivariate logistic analysis revealed that the activity of tumor budding was an independent risk factor for lymphatic involvement. CONCLUSIONS: The results indicate that tumor budding makes a greater contribution to progression in non-polypoid than in polypoid growth carcinomas, with possible involvement of lymph node metastasis.

Changes in the mucus barrier of the rat during 5-fluorouracil-induced gastrointestinal mucositis.

OBJECTIVE: A frequent complication of antineoplastic chemotherapy (CT) is gastrointestinal (GI) mucositis. Although clinically this mucositis can be treated, data on the effect of CTon the mucosal defense mechanisms are scant, so the effects of 5-fluorouracil (5-FU) on mucin, one of the principal defense factors of the GI mucosa, were investigated. MATERIAL AND METHODS: 5-FU was administered orally to rats at a dose of 50 mg/kg once daily for 5 days. Using anti-mucin monoclonal antibodies, the immunoreactivity in different areas of the rats' GI tracts was compared, as well as the mucin content. Changes in the GI mucin during the process of recovery from the injury were also investigated. Immunohistochemical analysis of proliferating cell nuclear antigen (PCNA) was used to determine whether or not the effects of 5-FU on cell proliferation contributed to the changes in mucin. RESULTS: 5-FU caused significant alterations of the immunoreactivity and content of mucin in the rat GI mucosa, especially in the jejunum. The jejunal mucin content was most markedly reduced on day 1 after drug withdrawal, and increased thereafter. By day 7, the content had transiently but significantly increased approximately 1.5-fold, and returned to the basal level by day 13. The number of PCNA-positive cells strikingly decreased at day 1, but by day 7 had increased approximately 2-fold, compared with the control. CONCLUSION: The activation of mucus cells in the jejunum, if appropriately manipulated, could lead to more effective prevention of CT-induced GI mucositis.

A patient with stage IV type 4 advanced gastric cancer who had a complete pathological response to short-term treatment with S-1 alone.

An 81-year-old woman presented with dysphagia. Stage IV (cT3, cN3, cH0, cM1) type 4 advanced gastric cancer was diagnosed. The left adrenal gland and the paragastric, mediastinal, and abdominal para-aortic lymph nodes were enlarged. Ascites was present. The patient started to receive S-1 (100 mg/day), given orally for 4 weeks followed by 2 weeks of rest. During the first course of treatment, grade 2 anorexia, grade 2 vomiting, and grade 2 diarrhea developed. Treatment with S-1 was therefore discontinued on day 27. The tumor had shrunk and was severely deformed. There was marked narrowing of the pyloric antrum. Abdominal computed tomography revealed that ascites and enlargement of the left adrenal gland and paragastric lymph nodes had resolved. To ensure adequate oral intake and improve the patient's quality of life, a total gastrectomy with a limited (D1) lymph node dissection was performed. The primary gastric tumor, resected lymph nodes, and a peritoneal-lavage specimen were all negative for tumor. Histologically, the tumor had a complete pathological response to S-1. Two years after surgery, the patient is alive, with no evidence of metastasis or recurrence.

A multicenter, phase I dose-escalating study of docetaxel, cisplatin and S-1 for advanced gastric cancer (KDOG0601).

OBJECTIVE: This dose-escalation study of a combination of docetaxel, cisplatin and S-1 investigated the dose-limiting toxicity (DLT), maximum-tolerated dose (MTD), recommended dose (RD) and antitumor activity in advanced gastric cancer. PATIENTS AND METHODS: Patients received docetaxel (40 mg/m(2)), cisplatin (DIV on day 1) and S-1 (40 mg/m(2) p.o., twice daily, on days 1-14 every 28 days). The starting dose of cisplatin was 60 mg/m(2) (level 1); the dose was escalated to 70 (level 2) and 80 mg/m(2) (level 3) in a stepwise fashion. RESULTS: Fourteen patients were enrolled. The MTD of cisplatin was 80 mg/m(2) (level 3). DLT was grade 3 diarrhea, febrile neutropenia and delayed resumption of treatment. The RD of cisplatin was considered to be 70 mg/m(2) (level 2). DLT was liver dysfunction, occurring in only 1 patient at level 2. The response rate was 69.2% (9/13). CONCLUSIONS: For combined treatment with docetaxel, cisplatin and S-1 in patients with advanced gastric cancer, RD were docetaxel 40 mg/m(2), cisplatin 70 mg/m(2) and S-1 80 mg/m(2)/day. This regimen yields a high rate of tumor response and can be administered safely. Phase II studies of this regimen are under way.

Narrow band imaging for detecting metachronous superficial oropharyngeal and hypopharyngeal squamous cell carcinomas after chemoradiotherapy for head and neck cancers.

We present two cases of metachronous superficial squamous cell carcinomas at oropharyngeal and hypopharyngeal mucosal sites after chemoradiotherapy for head and neck cancers. These were detected by narrow band imaging combined with a magnifying gastrointestinal endoscopy. In one case, we successfully removed the tumor using endoscopic submucosal dissection. Narrow band imaging combined with magnifying gastrointestinal endoscopy illustrated well-demarcated brownish area and scattered foci of microvascular proliferation. Thus, it may serve as an ideal surveillance mode after chemoradiotherapy for head and neck cancers.

[Single-balloon enteroscopy].

Double-balloon enteroscope (DBE) requires a long preparation time and scope insertion is often confused because balloons have to be attached to both the endoscope and the overtube. Single-balloon enteroscope (SBE) is a new model endoscope produced by Olympus Medical Systems, and SBE does not require a balloon to be attached to the scope and has only sliding tube. Therefore, examination, preparations and scope insertion are easier than with DBE. SBE provides high-quality 'Q' type endoscopic images, and narrow-band-imaging can be performed. A prototype ultrasonic probe for SBE is now available. We underwent enteroscopy with SBE in 40 patients, and the total number of sessions was 50. Total enteroscopy was possible in 3 of 5 patients, in whom SBE was inserted deeply through both mouth and anus. There were no serious complications. This newly developed enteroscopy is useful for the diagnosis and treatment of small intestinal bleeding, intestinal stricture and protruding lesions. We believe that the single-balloon enteroscope will be more widely used clinically in the near future.

Impact of occult hepatitis B virus infection and prior hepatitis B virus infection on development of hepatocellular carcinoma in patients with liver cirrhosis due to hepatitis C virus.

OBJECTIVE: Although hepatitis B virus (HBV) DNA can be detected in liver or sera of patients without serum hepatitis B surface antigen (HBsAg), its clinical relevance in hepatocarcinogenesis remains controversial. This observational cohort study was conducted to clarify the risk factors, including the presence of serum HBV DNA and hepatitis B core antibody (anti-HBc), for hepatocellular carcinoma (HCC) in patients with hepatitis C virus (HCV)-related liver cirrhosis (LC). MATERIAL AND METHODS: The study comprised 123 patients with LC due to HCV, and negative for HBsAg. The risk factors for HCC development were analyzed by univariate and multivariate analysis. Serum samples were assayed for HBV DNA using real-time polymerase chain reaction. RESULTS: Serum HBV DNA was detectable in 14 patients (11.4%) and serum anti-HBc in 96 (78.0%). During the follow-up period (mean 53.3 months), 80 patients (65.0%) developed HCC. The cumulative HCC development rate was significantly higher in the anti-HBc-positive group than in the anti-HBc-negative group (p=0.0039), but did not differ between the serum HBV DNA-positive and -negative groups (p=0.8570). The multivariate analysis indicated that male gender, alpha-fetoprotein (AFP) 20 ng/ml or greater, average serum alanine aminotransferase (ALAT) 80 IU/l or greater and the presence of anti-HBc were independent risk factors for development of HCC (p=0.038, p=0.013, p=0.020 and p=0.001, respectively). CONCLUSIONS: Serum anti-HBc, which indicates a previous HBV infection, has clinical significance in hepatocarcinogenesis in patients with HCV-related LC, but serum HBV DNA does not. Therefore, anti-HBc in serum is a significant predictor for HCC.