Association of CD4-positive cell infiltration with response to vedolizumab in patients with ulcerative colitis.

Not all patients with ulcerative colitis (UC) respond initially to treatment with biologic agents, and predicting their efficacy prior to treatment is difficult. Vedolizumab, a humanized monoclonal antibody against alpha 4 beta 7 (α4ß7) integrin, suppresses immune cell migration by blocking the interaction between α4ß7 integrin and mucosal addressin cell adhesion molecule 1. Reports about histological features that predict vedolizumab efficacy are scarce. So, we examined the association between histological features and vedolizumab efficacy. This was a multicenter, retrospective study of patients with UC treated with vedolizumab. Biopsy specimens taken from the colonic mucosa prior to vedolizumab induction were used, and the areas positively stained for CD4, CD68, and CD45 were calculated. Clinical and histological features were compared between those with and without remission at week 22, and the factors associated with clinical outcomes were identified. We enrolled 42 patients. Patients with a high CD4+ infiltration showed a better response to vedolizumab [odds ratio (OR) = 1.44, P = 0.014]. The concomitant use of corticosteroids and high Mayo scores had a negative association with the vedolizumab response (OR = 0.11, P = 0.008 and OR = 0.50, P = 0.009, respectively). Histological evaluation for CD4+ cell infiltration may be helpful in selecting patients who can benefit from vedolizumab.

A novel fully covered metal stent for unresectable malignant distal biliary obstruction: results of a multicenter prospective study.

Background/Aims: Endoscopic self-expandable metal stent (SEMS) placement is currently the standard technique for treating unresectable malignant distal biliary obstructions (MDBO). Therefore, covered SEMS with longer stent patency and fewer migrations are required. This study aimed to assess the clinical performance of a novel, fully covered SEMS for unresectable MDBO. Methods: This was a multicenter single-arm prospective study. The primary outcome was a non-obstruction rate at 6 months. The secondary outcomes were overall survival (OS), recurrent biliary obstruction (RBO), time to RBO (TRBO), technical and clinical success, and adverse events. Results: A total of 73 patients were enrolled in this study. The non-obstruction rate at 6 months was 61%. The median OS and TRBO were 233 and 216 days, respectively. The technical and clinical success rates were 100% and 97%, respectively. Furthermore, the rate of occurrence of RBO and adverse events was 49% and 21%, respectively. The length of bile duct stenosis (<2.2 cm) was the only significant risk factor for stent migration. Conclusions: The non-obstruction rate of a novel fully covered SEMS for MDBO is comparable to that reported earlier but shorter than expected. Short bile duct stenosis is a significant risk factor for stent migration.

[A case of rectovaginal metastasis 6 years after initial resection of extra-gastrointestinal stromal tumor of vulvar origin].

A 53-year-old woman who had undergone excision of KIT-positive extra-gastrointestinal stromal tumor (EGIST) of the vulva 6 years ago presented to our hospital due to a positive fecal occult blood test. Colonoscopy revealed a submucosal tumor in the rectum ventral side. In addition, computed tomography and magnetic resonance imaging revealed a tumor in the rectovaginal septum. For diagnostic and therapeutic purposes, the tumor was resected via the perineal approach. The resected specimen analysis revealed a KIT-positive gastrointestinal stromal tumor (GIST). Following immunopathological and genetic mutation identifications, GIST of the rectovaginal septum from vulva EGIST metastasis was diagnosed. It is important to consider primary GIST and metastatic GIST as differential diagnoses in the case of a rectal submucosal tumor detected by endoscopy.

[Traumatic Neuroma Mimicking Lymph Node Metastasis of Pancreatic Neuroendocrine Neoplasms Developed after Pancreatoduodenectomy-A Case Report].

A traumatic neuroma is a benign tumor consisting of a non-neoplastic growth of injured nerves as a result of trauma or surgery. It is rarely found in an abdominal cavity, but some reports showed that it occurred around the bile duct. We report a case of a 72-year-old man who underwent subtotal stomach-preserving pancreatoduodenectomy for pancreatic neuroendocrine neoplasms 4 years ago. An abdominal contrast-enhanced CT follow-up examination revealed a growing nodule on the dorsal surface of the portal vein. The lesion showed a mild increase in fluorodeoxyglucose uptake in FDG-PET⊘CT. A lymph node metastasis of pancreatic neuroendocrine neoplasms was suspected. Nodule resection was performed for purpose of diagnosis and treatment. The final pathological diagnosis was traumatic neuroma with no evidence of recurrence. Traumatic neuromas developed after pancreatoduodenectomy have not been reported. Postoperative masses around the bile ducts should also be considered traumatic neuromas.

[Hematemesis due to rupture of splenic artery pseudoaneurysm in association with segmental arterial mediolysis:a case report].

A gastric ulcer was detected in a 54-year-old man who underwent upper gastrointestinal endoscopy for hematemesis. An abdominal contrasted computed tomography scan detected a splenic artery aneurysm adjacent to the gastric wall. Endoscopic hemostasis was thought to be risky owing to possible rupture of the aneurysm. Rupture of a splenic artery pseudoaneurysm due to segmental arterial mediolysis (SAM) was diagnosed by abdominal angiography, and subsequently transcatheter arterial embolization was performed. In cases of upper gastrointestinal hemorrhage, hemostasis is often performed during the emergency endoscopic examination. However, in cases of massive gastrointestinal bleeding, the possibility of a splenic artery aneurysm, in association with SAM, should be recognized. The risk of rupturing the aneurysm should be considered in selecting the most suitable treatment.

[Intraductal papillary neoplasm of bile duct developed in a patient with IgG4-related sclerosing cholangitis, autoimmune pancreatitis, and myasthenia gravis].

In the course of treatment for myasthenia gravis, enlargement of a cystic mass in the liver with peripheral bile duct dilation, diffuse pancreatic enlargement, and serum IgG4 level elevation was identified in a 65-year-old man. Following the diagnosis of autoimmune pancreatitis, a left hepatectomy was performed because of suspected malignancy of the cystic lesion. Analysis of the resected specimen revealed the cystic lesion to be a dilated bile duct. Intraductal papillary tumor comprising fibrovascular stalks covered by neoplastic epithelium was identified in the lesion. Infiltration of IgG4-positive plasma cells was discovered around the cystic lesion. Finally, a diagnosis of intraductal papillary neoplasm of bile duct with IgG4-related sclerosing cholangitis was made. Autoimmune diseases, including IgG4-related diseases, require careful observation because of their potential for malignancy.

[Successful resection of a gastric aberrant pancreas causing gastrointestinal bleeding by laparoscopy and endoscopy cooperative surgery].

A man in his 50s was admitted to our hospital for treatment of hematemesis. Endoscopy revealed arterial bleeding from a gastric submucosal tumor and endoscopic hemostasis was successful. However, surgical resection was contemplated to prevent recurrent bleeding and for making a definitive diagnosis. Surgical resection was eventually performed by laparoscopy and endoscopy cooperative surgery (LECS), and the tumor was pathologically diagnosed to be a gastric aberrant pancreas. We think that LECS is suitable for a gastric aberrant pancreas causing gastrointestinal bleeding, because the procedure is effective for tumor resection with minimal removal of the stomach wall.

Superficially elevated-type serrated hyperplastic lesion of the stomach with minute adenocarcinoma.

We report a case of gastric serrated hyperplastic lesion with minute adenocarcinoma. A 65-year-old Japanese man underwent endoscopic submucosal dissection to the superficially elevated-type (0-IIa) lesion located at the lesser curvature of the gastric angle. Histological observation revealed hyperplastic change of foveolar epithelium with serrated glandular structure as well as a minute tubular adenocarcinoma component. Immunohistochemically, the lesion demonstrated gastrointestinal, predominantly gastric, phenotype (MUC5AC++, MUC6+, MUC2+, CD10-). Positive p53 immunoreactivity was detected in the carcinoma component of the lesion with a point mutation (G877T; R209I) of the gene and microsatellite instability of the BAT-RII locus; however, immunoreactivity of the mismatch repair gene product hMLH1 was well preserved in the cancer as well as in the hyperplastic lesion. The hyperplastic lesion with serrated glandular pattern would be a precancerous lesion of adenocarcinoma of the stomach.

Observation of gastro-esophageal reflux by MRI: a feasibility study.

PURPOSE: To evaluate the feasibility of detecting and measuring gastro-esophageal reflux (GER) with esophageal MR fluoroscopy in patients suffering from heartburn. MATERIALS AND METHODS: Twenty patients with heartburn underwent esophageal MR fluoroscopy. The T1-FFE sequence was applied for MR imaging. We examined the frequency and the level of GER on MR images. Based on the MRI observations, patients were classified into four MRI grades (grade 1-4). Endoscopic findings were categorized into five grades (grade 0 to D). The overall MRI grade, Carlsson's questionnaire score, and endoscopic findings were compared. RESULTS: GER was observed with MR fluoroscopy in 19 of 20 patients. GER was observed only several times in three patients, and much more frequently in the remaining 16 patients. Elevated levels of GER reached the lower, middle-to-upper esophagus, and the hypopharynx. The observed MRI grades were grade 1 = 1 patient, grade 2 = 3 patients, grade 3 = 2 patients, and grade 4 = 13 patients. There was no statistical correlation between the questionnaire score and the MRI grade. Also, there was no correlation between the grade of endoscopic findings and MRI grade. Six patients demonstrated continuous reflux on MRI did not show mucosal injury at endoscopy. CONCLUSION: Esophageal MR fluoroscopy may be a useful diagnostic tool for GERD for its ability to show GER, even in patients with no mucosal injury, and for suggesting the cause of the reflux.

Role of metallothionein in Helicobacter pylori-positive gastric mucosa with or without early gastric cancer and the effect on its expression after eradication therapy.

BACKGROUND AND AIM: Metallothionein (MT) has a proven relationship with various kinds of cancer and reduces tissue damage. Helicobacter pylori (H. pylori) infection is associated with the alteration of gastric epithelial cell cycle events, a condition implicated in the initiation and development of gastric cancer. This study investigates the role of MT in H. pylori-induced gastritis with or without early gastric cancer (ECG) and evaluates the effect on MT expression after eradication therapy. METHODS: Gastric biopsy samples were immunohistochemically examined for MT expression in 36 H. pylori-negative patients without ECG and 98 positive patients with or without ECG. Real time polymerase chain reaction was performed in 14 antral biopsy samples with or without H. pylori. The severity of gastritis was also evaluated according to the updated Sydney System. In 31 successfully eradicated patients, the above assessment was repeated for two consecutive years. RESULTS: MT expression was higher in H. pylori-negative patients than in positive patients (P < 0.01). Moreover, in the corpus it was higher in H. pylori-positive patients without ECG compared to those with ECG (P < 0.05). The MT labeling index had a negative correlation with the severity of gastritis (P < 0.01). A positive correlation was shown between the MT labeling index and apoptosis: proliferation ratio (r = 0.41, P < 0.01). The MT labeling index in H. pylori-positive patients was gradually recovered after eradication (P < 0.05). CONCLUSION: The decrease of MT expression cannot prevent tissue damage in H. pylori-positive gastric mucosa and leads to more severe gastritis. This phenomenon may be attributed to gastric carcinogenesis. H. pylori eradication increases MT expression and may reduce the risk of ECG.

Relationship of BRAF mutation, morphology, and apoptosis in early colorectal cancer.

BACKGROUND AND AIMS: Many investigators have reported flat and depressed lesions as a new type of precursor of colorectal cancer. In our previous study, we determined that mutations in the BRAF gene may contribute to colorectal carcinogenesis by inhibiting apoptosis. However, the relationship among BRAF mutations, morphology and apoptosis in early colorectal cancer has not been clear. Therefore, gene alternation, morphology, and apoptosis in early colorectal cancer were investigated. MATERIALS AND METHODS: Forty-five flat and depressed early colorectal cancer samples and 43 polypoid early colorectal cancer samples were analyzed. Mutations in the BRAF gene and the K-ras gene were examined by direct sequence analysis, and proliferative activity and induction of apoptosis were evaluated using immunohistochemical examination. RESULTS FINDINGS: BRAF mutations were found in 5 (11.1%) of 45 flat and depressed early colorectal cancer samples. No BRAF alteration was found in polypoid early colorectal cancer samples. Mutations in the K-ras gene were detected in 13 (30.2%) of 43 polypoid early colorectal cancer samples. The rate of submucosal invasion of the samples with BRAF mutations was significantly higher than that of the samples with K-ras mutations (p<0.05). INTERPRETATION/CONCLUSIONS: BRAF and K-ras mutations were independent factors that influenced morphology in early colorectal cancer. In this study, the relationship between BRAF mutation and apoptosis is not so clear, but BRAF mutations and inhibition in apoptosis may play an important role in the developmental process of flat and depressed early colorectal cancer.

Helicobacter pylori VacA enhances prostaglandin E2 production through induction of cyclooxygenase 2 expression via a p38 mitogen-activated protein kinase/activating transcription factor 2 cascade in AZ-521 cells.

Treatment of AZ-521 cells with Helicobacter pylori VacA increased cyclooxygenase 2 (COX-2) mRNA in a time- and dose-dependent manner. A p38 mitogen-activated protein kinase (MAPK) inhibitor, SB203580, blocked elevation of COX-2 mRNA levels, whereas PD98059, which blocks the Erk1/2 cascade, partially suppressed the increase. Consistent with involvement of p38 MAPK, VacA-induced accumulation of COX-2 mRNA was reduced in AZ-521 cells overexpressing a dominant-negative p38 MAPK (DN-p38). Phosphatidylinositol-specific phospholipase C, which inhibits VacA-induced p38 MAPK activation, blocked VacA-induced COX-2 expression. In parallel with COX-2 expression, VacA increased prostaglandin E(2) (PGE(2)) production, which was inhibited by SB203580 and NS-398, a COX-2 inhibitor. VacA-induced PGE(2) production was markedly attenuated in AZ-521 cells stably expressing DN-p38. VacA increased transcription of a COX-2 promoter reporter gene and activated a COX-2 promoter containing mutated NF-kappaB or NF-interleukin-6 sites but not a mutated cis-acting replication element (CRE) site, suggesting direct involvement of the activating transcription factor 2 (ATF-2)/CREB-binding region in VacA-induced COX-2 promoter activation. The reduction of ATF-2 expression in AZ-521 cells transformed with ATF-2-small interfering RNA duplexes resulted in suppression of COX-2 expression. Thus, VacA enhances PGE(2) production by AZ-521 cells through induction of COX-2 expression via the p38 MAPK/ATF-2 cascade, leading to activation of the CRE site in the COX-2 promoter.

Favorable genetic polymorphisms predictive of clinical outcome of chemoradiotherapy for stage II/III esophageal squamous cell carcinoma in Japanese.

OBJECTIVES: This study was performed to find the genetic factors predictive of clinical outcome to a 5-fluorouracil (5-FU)/cisplatin (CDDP)-based chemoradiotherapy (CRT) in Japanese patients with locally advanced esophageal squamous cell carcinoma (ESCC). MATERIALS AND METHODS: Thirty-one patients with stage I-IVa ESCC (I/II/III/IVa = 7/7/14/3) were enrolled in this study. One course of treatment consisted of protracted venous infusions (PVIs) of 5-FU (400 mg/m2/24 hours for days 1-5 and 8-12), CDDP (40 mg/m2/3 hours on days 1 and 8) and radiation (2 Gy/d on days 1-5, 8-12, and 15-19), and a 2nd course was successively repeated after a 2-week interval. A total of 8 measurements of the plasma concentration of 5-FU were made using high performance liquid chromatography. Genetic polymorphisms examined herein included those in the genes coding thymidylate synthase (TS), glutathione S-transferase P1 (GSTP1), multidrug resistant transporter MDR1/P-glycoprotein, and intercellular adhesion molecule-1, and in a circadian rhythm-relating gene, CLOCK. RESULTS: The CR rate depended on stage (P = 0.001), but the analysis was not sufficiently powered to reach a level of statistical significance for the 2-year survival rate (P = 0.061). For stage II/III patients, to have 2 or 3 polymorphisms of 3R/3R of 5'-TSER, a 6 bp of 3'-TSUTR, and GSTP1-Ile105Val resulted in an extensively longer survival (P = 0.020), although no difference was found between 2 groups, with respect to the plasma concentrations of 5-FU and clinicopathologic characteristics. CONCLUSIONS: The prognostic index may allow predictions of the clinical outcome of a 5-FU/CDDP-based CRT in stage II/III ESCC patients.

The relationship between gastric emptying determined by the breath test and H. pylori.

BACKGROUND/AIMS: Helicobacter pylori infection has been implicated in atrophic gastritis and gastric ulcer disease. However, the relationship between gastric emptying and Helicobacter pylori infection is still unclear. METHODOLOGY: One hundred and two consecutive patients with functional dyspepsia were enrolled in this study (53 Helicobacter pylori positive and 49 negative). Gastric emptying was determined using both the 13C-octanoic acid breath test and the paracetamol absorption test. For grading gastric atrophy, the biopsy samples and serum pepsinogen I/II ratio were used. The relationship between gastric emptying, Helicobacter pylori infection and atrophy grade was investigated. RESULTS: There was no significant difference in all gastric emptying parameters between Helicobacter pylori positive and negative patients. However, in Helicobacter pylori positive subjects, pepsinogen I/II ratio correlated with atrophy grade, and it also correlated with all parameters of gastric emptying. Especially in the half-emptying time, an important parameter, there was significant correlation with the pepsinogen I/II ratio (R = -0.39, p < 0.01). This finding implies that gastric emptying is delayed according to the degree of gastric atrophy. CONCLUSIONS: Gastric emptying was not delayed simply according to advanced age, but according to the advance in gastric atrophy.

Diagnostic significance of gently sloping depression and irregular margin in superficial elevated colorectal tumors.

INTRODUCTION: Recently, superficial elevated colorectal tumors have been increasingly diagnosed after improvements in endoscopic instruments and techniques. However, their biological characteristics remain obscure and it is difficult to predict malignant potential. The aim of this study is to clarify the characteristics of superficial elevated tumors in endoscopic examination for the evaluation of malignant potential. MATERIALS AND METHODS: Sixty-three resected superficial elevated colorectal tumors more than 10 mm in diameter were analyzed with regard to their morphological characteristics and histological findings. The samples were classified according to the presence of a gently sloping depression and irregular margin at the edge. Their depth of vertical invasion and the degree of depression were examined. RESULTS: The rate of carcinoma in 27 lesions with a gently sloping depression was significantly higher than in 36 lesions with an even surface. The rate of carcinoma in 46 lesions with irregular margin was significantly higher than in 17 lesions without irregular margin. A multivariate analysis revealed that the coexistence of both IM and GSD was significantly associated with submucosal invasion. Statistical associations of age, tumor location, gender, and pathological grade with submucosal invasion were not observed. CONCLUSIONS: In superficial elevated colorectal tumors, a gently sloping depression and irregular margin at the edge when viewed endoscopically may be a predictor of malignant potential. These characteristics should be given priority when deciding on treatment.

Helicobacter pylori VacA and gastric ulcer.

VacA, the only protein toxin produced by Helicobacter pylori, vacuolates cultured cells. The presence of 2 VacA receptors has been demonstrated. One is the receptor-type protein tyrosine phosphatase (RPTP) zeta/beta (PTP zeta/beta), and the other is RPTP alpha. VacA binds to PTP zeta/beta, resulting in gastric epithelial detachment through the tyrosine phosphorylation of Git-1, which then leads to gastric ulceration by the direct action of gastric acid. Thus, disturbance of adhesion between gastric epithelial cells and the extracellular matrix due to an abnormal PTP zeta/beta signal is the main mechanism of gastric ulceration.

[A case of unknown primary cancer responding to TS-1].

A 65-year-old male showed elevated tumor marker and intra-abdominal lymph node (LN) swelling. PET revealed an accumulation of FDG at para-aortic LNs from the mediastinum to the inguinal region. Although many different examinations were performed to detect primary cancer, none was found. We diagnosed unknown primary cancer (UPC), and administered TS-1 (100 mg/day). Six months later, the tumor marker lowered and the LN swelling reduced. PET showed a little accumulation of FDG at intra-abdominal LN. An intra-abdominal LN biopsy was performed, and an adenocarcinoma was seen at a lymph vessel. Then, 15 months later, brain metastasis was recognized and 18 months later the patient died of systematic metastasis. Autopsy was not performed, and primary cancer was not seen till the end. TS-1 proved effective for the UPC.

Helicobacter pylori eradication therapy on histologic change in the distal esophagus.

BACKGROUND: Although cases of reflux esophagitis (RE) developing after treatment to eradicate Helicobacter pylori have been discussed in some detail, no reports are available concerning the histologic examination of RE both before and after eradication therapy. MATERIALS AND METHODS: Sixty-one patients and 111 specimens were investigated using endoscopic and histologic techniques. The histologic findings including basal zone height, papillar height, Ki-67 labeling index, and COX-2 expression before and after treatment for H. pylori infection were compared with those in normal controls and patients with endoscopic RE. RESULTS: Twelve months after eradication therapy, the incidence of newly developed endoscopic RE was 20% (5/25). Basal zone height and papillar height had increased at 1 month, but had returned to pretreatment levels after 12 months of eradication therapy. The Ki-67 labeling index was significantly increased 1 and 12 months after eradication therapy compared to values before treatment. COX-2 expression gradually increased after the treatment. The phenomena linked to esophagitis appeared after eradication therapy. However, the severity and extent of these signs were not so high after the treatment of H. pylori than those in patients with overt reflux esophagitis. Focusing on the patients with hiatal hernia, papillar height and Ki-67 labeling index increased significantly after eradication therapy, values being almost the same as those in the patients with endoscopic RE. CONCLUSIONS: Hiatal hernia plays an important role in the possible occurrence of hidden RE after treatment for a H. pylori infection.