[Diagnostic utility of endoscopic ultrasonography elastography and contrast-enhanced harmonic endoscopic ultrasonography in a patient with type 2 autoimmune pancreatitis].

A referring hospital diagnosed a 57-year-old man with a pancreatic head mass. The initial endoscopic ultrasonography-guided fine needle aspiration (EUS-FNA) was inconclusive because of the small sample size. Endoscopic ultrasonography elastography (EUS-EG) and contrast-enhanced harmonic endoscopic ultrasonography (CE-EUS), conducted at our institute, raised the possibility of mass-forming pancreatitis or autoimmune pancreatitis (AIP). A repeat EUS-FNA revealed inflammatory changes, including a neutrophilic duct injury suggestive of type 2 AIP. The pancreatic lesion responded well to the steroid therapy. The present case suggests that EUS-EG and CE-EUS may be useful for diagnostic exclusion of pancreatic cancers, and the combined use of EUS-EG and CE-EUS, with EUS-FNA, may help characterize inflammatory pancreatic lesions.

Fistula Formation Secondary to Mucinous Appendiceal Adenocarcinoma May Be Related to a Favorable Prognosis: A Case Report and Literature Review.

A 90-year-old man was referred to our hospital because of a positive fecal occult blood test. Colonoscopy revealed a lesion with multiple nodules covered with abundant mucus at the hepatic flexure. Computed tomography showed a dilated appendix attached distally to the hepatic flexure. Right hemicolectomy was performed, and the pathological examination revealed a mucinous appendiceal adenocarcinoma infiltrating the hepatic flexure without pseudomyxoma peritonei. The patient is doing well without recurrence 12 months postoperatively. Extraperitoneal drainage of the malignant ascites caused by the fistula may allow for an early diagnosis, while also making it possible to successfully resect the lesion, thus resulting in a favorable outcome.

Diagnostic performance of a new endoscopic scraper for malignant biliary strictures: a multicenter prospective study.

BACKGROUND AND AIMS: The efficacy of ERCP for histologic diagnosis of malignant biliary strictures is disappointingly low. The aim of this study was to investigate the diagnostic performance of a newly developed endoscopic device with scraping loops in combination with conventional biopsy forceps. METHODS: We performed a multicenter single-arm prospective study. Between February 2013 and December 2014, 123 patients with suspected malignant biliary strictures were enrolled in the study. The new device and conventional biopsy forceps were applied for histologic diagnosis by ERCP. The primary outcome was to evaluate cancer detectability by biopsy forceps, the new device, and their combined use. RESULTS: Of the 123 patients, 119 were diagnosed with a malignant stricture. Sufficient samples were collected in 83.7% (103/123), 93.5% (115/123), and 95.9% (118/123) of patients using biopsy forceps, the new device, and their combination, respectively. Cancer detectability of forceps biopsy, the new device, and their combination were 51.3% (61/119), 64.7% (77/119), and 74.8% (89/119), respectively. The new device had a significantly higher sample yield and cancer detectability than biopsy forceps (P < .01 and P = .018, respectively, McNemar test). Complementary use of the new device with biopsy forceps demonstrated a significantly additive effect in both sample yield and cancer detection (P < .01 each, McNemar test). The new device detected 48.3% (28/58) of cancers that were not diagnosed as malignant by biopsy forceps. CONCLUSIONS: The new endoscopic scraper demonstrated a large sample yield and high cancer detectability. It could be a first-line tissue-sampling device for biliary strictures. (University Hospital Medical Information Network Clinical Trial Registry [UMIN-CTR] (http://www.umin.ac.jp/ctr/index.htm) registration number: UMIN000009895.).

Minimally invasive surgery for superior mesenteric artery syndrome: A case report.

Superior mesenteric artery (SMA) syndrome is defined as a compression of the third portion of the duodenum by the abdominal aorta and the overlying SMA. SMA syndrome associated with anorexia nervosa has been recognized, mainly among young female patients. The excessive weight loss owing to the eating disorder sometimes results in a reduced aorto-mesenteric angle and causes duodenal obstruction. Conservative treatment, including psychiatric and nutritional management, is recommended as initial therapy. If conservative treatment fails, surgery is often required. Currently, traditional open bypass surgery has been replaced by laparoscopic duodenojejunostomy as a curative surgical approach. However, single incision laparoscopic approach is rarely performed. A 20-year-old female patient with a diagnosis of anorexia nervosa and SMA syndrome was prepared for surgery after failed conservative management. As the patient had body image concerns, a single incision laparoscopic duodenojejunostomy was performed to achieve minimal scarring. As a result, good perioperative outcomes and cosmetic results were achieved. We show the first case of a young patient with SMA syndrome who was successfully treated by single incision laparoscopic duodenojejunostomy. This minimal invasive surgery would be beneficial for other patients with SMA syndrome associated with anorexia nervosa, in terms of both surgical and cosmetic outcomes.

[A case of gallbladder carcinoma following cholecystogastric fistula].

A 79-year-old woman with pneumobilia and liver dysfunction was admitted to our hospital. ERCP and gastrointestinal endoscopy revealed choledochal stones and a cholecystogastric fistula at the greater curvature of the gastric antrum. The risk of cholecystectomy and fistulectomy appeared to be extremely high for this patient because of her advanced age and low respiratory function due to interstitial pneumonia. Therefore, only an endoscopic lithotomy was performed, and the cholecystogastric fistula remained. However, after 2 years of follow-up, she developed an advanced gallbladder carcinoma. This finding suggests that cholecystogastric fistula is a risk factor for gallbladder carcinoma. Because of the difficulty of early detection of gallbladder carcinoma associated with cholecystogastric fistula, both fistulectomy and cholecystectomy are necessary when cholecystogastric fistula is diagnosed.

[Double esophageal carcinosarcomas showing rapid growth of a new polypoid tumor after sloughing of another polypoid tumor].

A 55-year-old man presented at our hospital with a large polypoid esophageal tumor. Initial upper gastrointestinal endoscopy revealed that this tumor had sloughed off to be replaced with ulceration in the thoracic esophagus. However, after the tumor at the thoracic esophagus sloughed off, a semi-circular, superficial, flat squamous cell carcinoma was observed adjacent to the ulceration. In addition, a separate carcinosarcoma, 2cm in diameter, was found at the esophagogastric junction. Approximately one month later, endoscopic re-examination revealed a new polypoid tumor approximately 4cm in diameter that was growing rapidly in the center of the superficial thoracic esophageal carcinoma lesion. Standard subtotal esophagectomy was performed. Histopathological examination revealed that both lesions were esophageal carcinosarcomas. This is a rare case of double esophageal carcinosarcoma associated with rapid polypoid tumor growth from a superficial squamous cell carcinoma lesion.

[Eosinophilic cholangitis from almost normal appearance to the bile duct sclerosis similar to primary sclerosing cholangitis].

A 48-year-old man was admitted to our hospital because of eosinophilia and liver dysfunction. Initial abdominal CT and MRI (MRCP) finding showed almost normal liver and bile duct. Liver biopsy demonstrated mild portal infiltration of lymphocytes and eosinophils. Definitive diagnosis was difficult, but we suspected autoimmune disease. Oral steroid administration was started, which led to a rapid improvement of eosinophilia and liver dysfunction. Dose reduction of steroid administration resulted in exacerbation of eosinophilia and liver dysfunction. Follow-up MRCP and ERCP study revealed biliary strictures similar to primary sclerosing cholangitis (PSC). A second liver biopsy revealed dense infiltration composed of lymphocytes and eosinophils in the portal area. Therefore we diagnosed eosinophilic cholangitis. This is the first case of eosinophilic cholangitis, observed after changes of the bile duct from an almost normal appearance to diffuse sclerosing and narrowing similar to PSC by imaging and pathological studies.

[A case of combined syndrome of juvenile polyposis and hereditary hemorrhagic telangiectasia associated with SMAD4 mutation].

A 47-year-old man was found to have abnormal findings on chest radiography. Chest computed tomography (CT) and magnetic resonance imaging (MRI) showed that he had a pulmonary arteriovenous malformation. He had experienced epistaxis when he was a junior high school student, and since then, the symptom had frequently recurred. Further, he had telangiectasia on the lips. Thus, he was given a diagnosis of hereditary hemorrhagic telangiectasia (HHT). Endoscopy revealed gastric telangiectasia, and in addition, his colon had many juvenile polyps. When he was 49 years of age, he underwent genetic analysis for HHT. A diagnosis of juvenile polyposis-HHT combined syndrome (JP-HHT) was made since a heterozygous germline 4-base deletion in exon 9 of SMAD4 was detected. To the best of our knowledge, this is the first case of JP-HHT associated with SMAD4 mutation in Japan.

SR-PSOX/CXCL16 plays a critical role in the progression of colonic inflammation.

BACKGROUND AND AIMS: Inflammatory bowel disease (IBD) is initiated and perpetuated by a dysregulated immune response to unknown environmental antigens such as luminal bacteria in genetically susceptible hosts. SR-PSOX/CXCL16, a scavenger receptor that binds phosphatidylserine and oxidised lipoprotein, has both phagocytic activity and chemotactic properties. The aim of this study was to investigate the role of SR-PSOX/CXCL16 in patients with IBD and experimental murine colitis. METHODS: The serum levels of SR-PSOX/CXCL16 were measured in patients with IBD. The roles of SR-PSOX/CXCL16 in phagocytosis of bacterial components and cytokine production by macrophages from wild-type (WT) and SR-PSOX/CXCL16 knockout (KO) mice were assessed. Colitis was induced by administering dextran sulfate sodium (DSS) to WT and SR-PSOX/CXCL16 KO mice. Colonic inflammation was analysed by clinical, histological and immunological parameters. Finally, the effect of a monoclonal antibody (mAb) to SR-PSOX/CXCL16 on DSS-induced colitis and trinitrobenzene sulfonic acid-induced colitis models was evaluated. RESULTS: Serum levels of SR-PSOX/CXCL16 correlated significantly with the disease activity of patients with IBD. Ex vivo experiments showed that SR-PSOX/CXCL16 was involved in both phagocytosis of bacterial antigens and the T helper 1 immune response through the production of interleukin 12 and interferon γ. In vivo murine experiments demonstrated the upregulated gene expression of SR-PSOX/CXCL16 in inflamed colonic tissues and the predominant expression of SR-PSOX/CXCL16 on macrophages. SR-PSOX/CXCL16 KO mice were less susceptible to colonic inflammation than were their WT littermates. Administration of SR-PSOX/CXCL16 mAb ameliorated the condition in the two different experimental colitis models. CONCLUSIONS: SR-PSOX/CXCL16 plays a critical role in colonic inflammation and could be a potential therapeutic target for patients with IBD.

CXCR4 is required for proper regional and laminar distribution of cortical somatostatin-, calretinin-, and neuropeptide Y-expressing GABAergic interneurons.

Cortical GABAergic interneurons are divided into various subtypes, with each subtype contributing to rich variety and fine details of inhibition. Despite the functional importance of each interneuron subtype, the molecular mechanisms that contribute to sorting them to their appropriate positions within the cortex remain unclear. Here, we show that the chemokine receptor CXCR4 regulates the regional and layer-specific distribution of interneuron subtypes. We removed Cxcr4 specifically in a subset of interneurons at a specific mouse embryonic developmental stage and analyzed the number of interneurons and their laminar distribution in 9 representative cortical regions comprehensively in adults. We found that the number of Cxcr4-deleted calretinin- and that of neuropeptide Y-expressing interneurons were reduced in most caudomedial and lateral cortical regions, respectively, and also in superficial layers. In addition, Cxcr4-deleted somatostatin-expressing interneurons showed a reduction in the number of superficial layers in certain cortical regions but of deep layers in others. These findings suggest that CXCR4 is required for proper regional and laminar distribution in a wider interneuron subpopulation than previously thought and may regulate the establishment of functional cortical circuitry in certain cortical regions and layers.

SDF1/CXCR4 signalling regulates two distinct processes of precerebellar neuronal migration and its depletion leads to abnormal pontine nuclei formation.

The development of mossy-fibre projecting precerebellar neurons (PCN) presents a classical example of tangential neuronal migration. PCN migrate tangentially along marginal streams beneath the pial surface from the lower rhombic lip to specific locations in the hindbrain, where they form precerebellar nuclei. Among them, the pontine neurons follow a stereotypic anteroventral-directed pathway to form the pontine nuclei in the pons. The guidance mechanisms that determine the marginal migration of PCN and the anterior migration of pontine neurons are poorly understood. Here, we report that a chemokine SDF1 (also known as CXCL12) derived from the meningeal tissue regulates the migratory pathways of PCN. PCN are chemoattracted by the meningeal tissue, an effect that is mimicked by an SDF1 source. Analysis of knockout mice for the Sdf1 receptor Cxcr4 shows that both the marginal migration of PCN and the anterior migration of pontine neurons are disrupted. We provide further evidence that SDF1/CXCR4 signalling regulates these two processes cell-autonomously. As a result of disrupted neuronal migration, pontine nuclei formation was highly abnormal, with the presence of multiple ectopic pontine clusters posteriorly. The ectopic pontine clusters led to ectopic collateral branch formation from the corticospinal tract. Our results together demonstrate crucial roles for SDF1/CXCR4 in multiple aspects of PCN migration and highlight the deleterious consequence of derailed migration on proper nuclei formation. Furthermore, we provide the first in vivo evidence that pontine neurons themselves induce collateral branching from the corticospinal axons.

Simultaneous occurrence of inflammatory bowel disease and myelodysplastic syndrome due to chromosomal abnormalities in bone marrow cells.

BACKGROUND/AIMS: Although chromosomal abnormalities in bone marrow (BM) cells, such as trisomy 8, are risk factors for the development of inflammatory bowel diseases (IBD) as well as myelodysplastic syndrome (MDS), the mechanisms of how these cytogenetic abnormalities cause intestinal inflammation are poorly understood. METHODS AND RESULTS: A 55-year-old man with a 3-month history of watery diarrhea, fever and abdominal pain was admitted. Blood examinations revealed pancytopenia. Pathological analysis and endoscopic images of the entire colon led to the diagnosis of IBD of unclassified type. BM examination showed that the pancytopenia was due to MDS and that his BM cells had dual chromosomal abnormalities: 47, XY, +1, der(1;7)(q10;p10), +8. Immunological studies using peripheral blood monocytes from this patient revealed that the dual chromosomal abnormalities of BM cells led to the development of colitogenic monocytes producing a large amount of pro-inflammatory cytokines and showing resistance to apoptosis upon stimulation with microbial antigens. CONCLUSION: An abnormal karyotype of BM cells is not only responsible for the development of MDS, but also for IBD in this case.

Random walk behavior of migrating cortical interneurons in the marginal zone: time-lapse analysis in flat-mount cortex.

Migrating neurons are thought to travel from their origin near the ventricle to distant territories along stereotypical pathways by detecting environmental cues in the extracellular milieu. Here, we report a novel mode of neuronal migration that challenges this view. We performed long-term, time-lapse imaging of medial ganglionic eminence (MGE)-derived cortical interneurons tangentially migrating in the marginal zone (MZ) in flat-mount cortices. We find that they exhibit a diverse range of behaviors in terms of the rate and direction of migration. Curiously, a predominant population of these neurons repeatedly changes its direction of migration in an unpredictable manner. Trajectories of migration vary from one neuron to another. The migration of individual cells lasts for long periods, sometimes up to 2 d. Theoretical analyses reveal that these behaviors can be modeled by a random walk. Furthermore, MZ cells migrate from the cortical subventricular zone to the cortical plate, transiently accumulating in the MZ. These results suggest that MGE-derived cortical interneurons, once arriving at the MZ, are released from regulation by guidance cues and initiate random walk movement, which potentially contributes to their dispersion throughout the cortex.

The effect of tacrolimus (FK-506) on Japanese patients with refractory Crohn's disease.

BACKGROUND: Recent evidence indicates that intravenous or oral therapy with tacrolimus (FK-506) is effective in treating patients with Crohn's disease. We evaluated the usefulness of tacrolimus therapy for Japanese patients with refractory Crohn's disease. METHODS: Fourteen adult Japanese patients with Crohn's disease that was refractory to conventional therapies, including prednisolone (n = 5), azathioprine (n = 6), and infliximab (n = 5), were enrolled. Treatment with tacrolimus was started orally or intravenously and aimed for serum trough levels of 10-15 ng/ml. After the patients achieved clinical improvement, tacrolimus maintenance therapy was administered to maintain the trough level at 5-10 ng/ml. RESULTS: All patients achieved remission or significant improvement 40 days after starting tacrolimus treatment. By 120 days after the start of therapy, 9 (64%) patients achieved remission, 2 patients (14%) achieved significant improvement, and only 3 patients (21%) relapsed. The relapsed patients were treated with infliximab therapy and achieved remission. Steroids were discontinued by the 5 patients who had taken steroids before the study began. Adverse effects of tacrolimus included a temporary increase in serum creatinine concentration (n = 1, 7%), hyperkalemia (n = 1, 7%), and tremor (n = 1, 7%). CONCLUSIONS: Tacrolimus therapy is effective and well tolerated in patients with Crohn's disease that is refractory to conventional therapies.

Blockade of CXCL12/CXCR4 axis ameliorates murine experimental colitis.

Recent studies indicate that the CXCL12/CXCR4 interaction is involved in several inflammatory conditions. However, it is unclear whether this interaction has a role in the pathophysiology of inflammatory bowel disease (IBD). We investigated the significance of this interaction in patients with IBD and in mice with dextran sulfate sodium (DSS)-induced colitis and the effect of a CXCR4 antagonist on experimental colitis. First, we measured CXCR4 expression on peripheral T cells in patients with IBD. Furthermore, we investigated CXCR4 expression on leukocytes and CXCL12 expression in the colonic tissue of mice with DSS-induced colitis, and we evaluated the effects of a CXCR4 antagonist on DSS-induced colitis and colonic inflammation of interleukin (IL)-10 knockout (KO) mice. Colonic inflammation was assessed both clinically and histologically. Cytokine production from mesenteric lymph node cells was also examined. CXCR4 expression on peripheral T cells was significantly higher in patients with active ulcerative colitis (UC) compared with normal controls, and CXCR4 expression levels of UC patients correlated with disease activity. Both CXCR4 expression on leukocytes and CXCL12 expression in colonic tissue were significantly increased in mice with DSS-induced colitis. Administration of a CXCR4 antagonist ameliorated colonic inflammation in DSS-induced colitis and IL-10 KO mice. CXCR4 antagonist reduced tumor necrosis factor-alpha and interferon-gamma production from mesenteric lymph node cells, whereas it did not affect IL-10 production. The percentage of mesenteric Foxp3+CD25+ T cells in DSS-induced colitis was not affected by CXCR4 antagonist. These results suggest that blockade of this chemokine axis might have potential as a therapeutic target for the treatment of IBD.

The effect of medical treatment on patients with fistulizing Crohn's disease: a retrospective study.

BACKGROUND: Fistulas are a major complication of Crohn's disease (CD), but the treatment strategy for fistulizing Crohn's disease is controversial. The aim of this study is to analyze the efficacy of medical therapy for fistulizing Crohn's disease. METHODS: Therapeutic regimens and clinical outcome of medical therapy were evaluated in 10 patients with fistulizing Crohn's disease (6 with external fistulas, 4 with internal fistulas). Complete response was defined as fistula closure with complete arrest of drainage in cases of external fistula, and disappearance of the fistula demonstrated by imaging studies in cases of internal fistula. Clinical remission was defined as a Crohn's disease activity index of less than 150 points. RESULTS: Complete responses were observed in all 6 patients with external fistulas (4 patients treated with a combination of antibiotics and immunomodulators, and 2 also treated with infliximab). In contrast, fistula closure was observed in only 1 of 4 patients with internal fistulas. Clinical remission of CD was achieved in all patients with external fistulas, whereas there was no significant difference in the CD activity index before and after medical therapy in patients with internal fistulas. CONCLUSIONS: External fistulas were more responsive to medical therapy than internal fistulas in patients with CD. Combined treatment with antibiotics and immunomodulators might be a suitable initial therapy for CD patients with external fistulas, and infliximab can be used as an additional therapy in cases refractory to this combination therapy. However, randomized controlled studies will be required to investigate what kinds of therapies are optimal for CD patients with fistulas.