[Comparison of two cases of type 2 autoimmune pancreatitis].

We describe two cases of type 2 autoimmune pancreatitis (AIP). A 39-year-old man presented to our hospital with complaints of epigastric and back pain. Pancreatic enzyme levels were elevated, but serum levels of immunoglobulins G and G4 (IgG and IgG4) were normal. Computed tomography (CT) showed diffuse pancreatic enlargement, and endoscopic retrograde pancreatography revealed diffuse narrowing of the pancreatic duct. Endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) revealed granulocytic epithelial lesions and very few IgG4-positive cells. Colonoscopy revealed ulcerative colitis. Type 2 AIP was diagnosed, and 5-aminosalicylic acid (5-ASA) and prednisolone were administered. The clinical course has since been favorable, and the prednisolone dose is currently being reduced. A 47-year-old woman presented to our hospital with complaints of bloody stools. Colonoscopy revealed ulcerative colitis. CT depicted diffuse pancreatic enlargement with a capsule-like rim. Pancreatic enzyme levels were elevated, but serum levels of IgG and IgG4 were normal. On magnetic resonance cholangiopancreatography, the pancreatic duct could not be delineated. No pathological findings of type 2 AIP were obtained on EUS-FNA. Type 2 AIP was suspected, and 5-ASA and steroid enemas were administered. To date, recurrence has not been observed, and 5-ASA management continues. The two cases differed with regard to sex of patient, clinical course, pathological findings, and treatment.

M2 polarization of murine peritoneal macrophages induces regulatory cytokine production and suppresses T-cell proliferation.

Bone-marrow-derived macrophages are divided into two phenotypically and functionally distinct subsets, M1 and M2 macrophages. Recently, it was shown that adoptive transfer of M2-polarized peritoneal macrophages reduced the severity of experimental colitis in mice. However, it is still unclear whether peritoneal macrophages possess the same ability to be polarized to cells with functionally different phenotypes and cytokine production patterns as bone-marrow-derived macrophages. To address this question, we examined the ability of peritoneal macrophages to be polarized to the M1 and M2 phenotypes and determined the specific cytokine profiles of cells with each phenotype. We showed that peritoneal macrophages, as well as bone-marrow-derived macrophages, were differentiated into M1 and M2 phenotypes following stimulation with interferon-γ (IFN-γ) and interleukin-4 (IL-4)/IL-13, respectively. Following in vitro stimulation with lipopolysaccharide, M2-polarized peritoneal macrophages predominantly expressed T helper type 2 (Th2) cytokines and regulatory cytokines, including IL-4, IL-13, transforming growth factor-ß and IL-10, whereas M1-polarized peritoneal macrophages expressed negligible amounts of Th1 and pro-inflammatory cytokines. ELISA showed that M2-polarized peritoneal macrophages produced significantly more IL-10 than M1-polarized peritoneal macrophages. Notably, M2-polarized peritoneal macrophages contributed more to the suppression of T-cell proliferation than did M1-polarized peritoneal macrophages. The mRNA expression of Th2 cytokines, including IL-4 and IL-13, increased in T-cells co-cultured with M2-polarized macrophages. Hence, our findings showed that M2 polarization of peritoneal macrophages induced regulatory cytokine production and suppressed T-cell proliferation in vitro, and that resident peritoneal macrophages could be used as a new adoptive transfer therapy for autoimmune/inflammatory diseases after polarization to the regulatory phenotype ex vivo.

Prospective study of daily low-dose nedaplatin and continuous 5-fluorouracil infusion combined with radiation for the treatment of esophageal squamous cell carcinoma.

BACKGROUND: Protracted low-dose concurrent chemotherapy combined with radiation has been proposed for enhanced treatment results for esophageal cancer. We evaluated the efficacy and the toxicity of a novel regimen of daily low-dose nedaplatin (cis-diammine-glycolatoplatinum) and continuous infusion of 5-fluorouracil (5-FU) with radiation in patients with esophageal squamous cell carcinoma. METHODS: Between January 2003 and June 2008, 33 patients with clinical stage I to IVB esophageal squamous cell carcinoma were enrolled. Nedaplatin (10 mg/body/day) was administered daily and 5-FU (500 mg/body/day) was administered continuously for 20 days. Fractionated radiotherapy for a total dose of 50.4-66 Gy was administered together with chemotherapy. Additional chemotherapy with nedaplatin and 5-FU was optionally performed for a maximum of 5 courses after chemoradiotherapy. The primary end-point of this study was to evaluate the tumor response, and the secondary end-points were to evaluate the toxicity and the overall survival. RESULTS: Twenty-two patients (72.7%) completed the regimen of chemoradiotherapy. Twenty patients (60.6%) achieved a complete response, 10 patients (30.3%) a partial response. One patient (3.0%) had a stable disease, and 2 (6.1%) a progressive disease. The overall response rate was 90.9% (95% confidence interval: 75.7%-98.1%). For grade 3-4 toxicity, leukopenia was observed in 75.8% of the cases, thrombocytopenia in 24.2%, anemia in 9.1%, and esophagitis in 36.4%, while late grade 3-4 cardiac toxicity occurred in 6.1%. Additional chemotherapy was performed for 26 patients (78.8%) and the median number of courses was 3 (range, 1-5). The 1-, 2- and 3-year survival rates were 83.9%, 76.0% and 58.8%, respectively. The 1- and 2-year survival rates were 94.7% and 88.4% in patients with T1-3 M0 disease, and 66.2% and 55.2% in patients with T4/M1 disease. CONCLUSION: The treatment used in our study may yield a high complete response rate and better survival for each stage of esophageal squamous cell carcinoma. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00197444.

Cytokine responses of intraepithelial lymphocytes are regulated by histamine H(2) receptor.

BACKGROUND: Histamine participates in the immune regulation of several gastrointestinal diseases. However, the effect of histamine on intestinal intraepithelial lymphocytes (IELs), the front line of the intestinal mucosal immune system, is not well understood. We examined whether histamine has a direct effect on cytokine production by IELs and the involvement of histamine receptor subtypes. METHODS: Murine IELs were activated by PMA plus ionomycin with/without histamine. Secreted cytokines were measured and compared with those of splenocytes. Intracellular cytokines were detected by flow cytometry. Expression of histamine receptor subtypes in IELs was examined by RT-PCR. RESULTS: Histamine H(1) receptor (H(1)R), H(2)R, and H(4)R, but not H(3)R mRNA were expressed on IELs. Histamine significantly decreased Th1-cytokine (IFN-gamma, TNF-alpha, and IL-2) and also IL-4 production in IELs as well as splenocytes. The selective H(2)R antagonist famotidine, but not the H(1)R antagonist pyrilamine nor the H(3)R/H(4)R antagonist thioperamide, competes with the inhibitory effect of histamine on these cytokine production in IELs. These suppressive effects of histamine were mimicked by a selective H(2)R/H(4)R agonist dimaprit. Further, these suppressive effects of histamine for Th1-cytokine and IL-4 did not accompany the enhancement of IL-10 production or IL-10 mRNA level in IELs. Intracellular cytokine analysis revealed that the number of IFN-gamma-producing alphabeta T cells was significantly reduced by histamine in IELs. CONCLUSIONS: Histamine has a direct suppressive effect on IEL-derived cytokines via H(2)R, which would have a crucial role in the suppression of local immunoregulation in the intestinal epithelium.

[A case of elderly esophageal adenocarcinoma successfully treated with daily low-dose nedaplatin (CDGP) and continuous infusion of 5-FU combined with radiation].

We report an elderly patient with esophageal adenocarcinoma in whom a complete response (CR) was obtained by chemoradiotherapy using daily low-dose nedaplatin (CDGP) and continuous infusion of 5-FU. A 86-year-old man who had non-tuberculous mycobacterial infection was admitted for dysphagia, and diagnosed with Stage II A (T2N0M0) esophageal adenocarcinoma of the lower esophagus according to the TNM classification (sixth edition) of the International Union against Cancer (UICC). Chemoradiotherapy using daily low-dose CDGP and continuous infusion of 5- FU was performed, and thereafter one cycle of chemotherapy using CDGP and 5-FU was added. As the side effects of treatment, grade 3 leucopenia was observed while he was receiving chemoradiotherapy. A year later, he presented with grade 2 pericardial and pleural effusion and recovered with conservative treatment. CR was obtained and has been continued for two years. Definitive chemoradiotherapy using daily low-dose CDGP and continuous infusion of 5-FU is an effective choice for elderly and high-risk patients with esophageal adenocarcinoma.

Digoxin Attenuates Murine Experimental Colitis by Downregulating Th17-related Cytokines.

BACKGROUND: Digoxin, a cardiac glycoside used for the treatment of heart failure, was reported to inhibit the retinoid-related orphan receptor gamma t (RORγt) and attenuate the severity of experimental autoimmune encephalomyelitis and arthritis in mice. However, the effects of digoxin in a mice model of inflammatory bowel disease have not been elucidated. METHODS: Colitis was induced in severe combined immunodeficiency mice by adoptive transfer of CD45RB CD4 T cells. Digoxin or a vehicle was injected into mice with colitis intraperitoneally every other day and changes in body weight were evaluated. After 6 to 8 weeks, the treated mice were killed and evaluated for histological score, T-cell subset, and cytokine messenger RNA (mRNA) expression in the colonic tissue. RESULTS: Wasting disease and histological damage were significantly attenuated in digoxin-treated mice with colitis compared with those in the vehicle-treated mice. In addition, the mRNAs of Th17-related cytokines were downregulated, whereas those of interleukin-10 were upregulated in the colonic mucosa of digoxin-treated mice. However, unexpectedly, the mRNA expression level of tumor necrosis factor alpha did not decrease in the colonic mucosa of digoxin-treated mice with colitis. This observation suggests that digoxin may ameliorate colitis by a tumor necrosis factor alpha-independent pathway. CONCLUSIONS: This study has shown for the first time that treatment with digoxin can ameliorate murine experimental colitis. This finding suggests that the suppression of Th17 using reagents such as digoxin could be effective in treating Crohn's disease refractory to anti-tumor necrosis factor alpha therapy.

Inverted Meckel's diverticulum preoperatively diagnosed using double-balloon enteroscopy.

An inverted Meckel's diverticulum is a rare gastrointestinal congenital anomaly that is difficult to diagnose prior to surgery and presents with anemia, abdominal pain, or intussusception. Here, we report the case of 57-year-old men with an inverted Meckel's diverticulum, who was preoperatively diagnosed using double-balloon enteroscopy. He had repeatedly experienced epigastric pain for 2 mo. Ultrasonography and computed tomography showed intestinal wall thickening in the pelvis. Double-balloon enteroscopy via the anal route was performed for further examination, which demonstrated an approximately 8-cm, sausage-shaped, submucosal tumor located approximately 80 cm proximal to the ileocecal valve. A small depressed erosion was observed at the tip of this lesion. Forceps biopsy revealed heterotopic gastric mucosa. Thus, the patient was diagnosed with an inverted Meckel's diverticulum, and single-incision laparoscopic surgery was performed. This case suggests that an inverted Meckel's diverticulum should be considered as a differential diagnosis for a submucosal tumor in the ileum. Balloon-assisted enteroscopy with forceps biopsy facilitate a precise diagnosis of this condition.

Congenital absence of the portal vein complicating hepatic tumors.

Congenital absence of the portal vein (CAPV) is a rare malformation that is often accompanied by other anomalies such as cardiac and skeletal malformations and/or hepatic tumors. We describe here a case of CAPV complicating hepatic tumors in a 16-year-old Japanese girl. Abdominal ultrasonography revealed a hyperechoic tumor in the liver and dilatation of the portal vein that appeared to be connected directly with the inferior vena cava. Subsequent abdominal computed tomography (CT) revealed tumors and magnetic resonance angiography confirmed that the portal vein entered directly into the inferior vena cava just above the liver. In addition, there was absence of the right portal vein and the left intrahepatic branch except for the presence of left portal vein only within the porta hepatis. These findings led to a diagnosis of CAPV complicated hepatic tumors. Careful monitoring of these hepatic tumors is ongoing due to the possibility of malignant transformation.

Norepinephrine suppresses IFN-γ and TNF-α production by murine intestinal intraepithelial lymphocytes via the ß1 adrenoceptor.

We examined whether norepinephrine (NE) had direct effects on cytokine production by murine intestinal intraepithelial lymphocytes (IELs), compared with splenocytes. CD3⁺ IELs and CD3⁺ splenocytes expressed α(1B), α(1D), α(2C), ß1, ß2, and ß3 adrenoceptors (ARs). NE significantly suppressed IFN-γ and TNF-α production by IELs and splenocytes ex vivo. The suppressive effects of NE in IELs were reversed by ß1 AR antagonist CGP-20712A, whereas those in splenocytes were reversed by ß2 AR antagonist ICI118,551. In IELs, ß1 AR agonist xamoterol mimicked the suppressive effects of NE. These results indicated NE regulates intestinal mucosal immune responses mediated by IELs via ß1 AR.

A case of small bowel adenocarcinoma in a patient with Crohn's disease detected by PET/CT and double-balloon enteroscopy.

Small bowel adenocarcinoma (SBA) in patients with Crohn's disease (CD) is quite rare, difficult to diagnose without surgery, and has a poor prognosis. Here, we report a 48-year-old man with SBA and a 21-year history of CD who was diagnosed by a combination of positron emission tomography/computed tomography (PET/CT) and double-balloon enteroscopy (DBE). Since the age of 27 years, the patient had been treated for ileal CD and was referred to our hospital with persistent melena. Multiple hepatic tumors were found by CT. PET/CT detected an accumulation spot in the small bowel. DBE revealed an ulcerative tumor in the ileum about 100 cm from the ileocecal valve. An endoscopic forceps biopsy specimen showed poorly differentiated adenocarcinoma. There were some longitudinal ulcer scars near the tumor, and the chronic inflammation in the small bowel appeared to be associated with the cancer development. Previous reports suggest the risk of SBA in patients with CD is higher than in the overall population. Since early diagnosis is extremely difficult in these cases, novel techniques, such as PET/CT and DBE, may be expected to help in making a preoperative diagnosis of the development of SBA in CD.