Tomohiro Kodani

MAIT cells are activated and accumulated in the inflamed mucosa of ulcerative colitis

Ulcerative colitis (UC) is a chronic, relapsing and remitting, inflammatory disorder of the large intestine. Mucosal associated invariant T (MAIT) cells are a member of innate‐like lymphocytes found abundantly in the mucosal tissue. The contribution of MAIT cells in the pathogenesis of UC is still unclear; therefore, this study aimed at investigating the role of these cells in patients with UC.

Phase I clinical trial of peptide vaccination with URLC10 and VEGFR1 epitope peptides in patients with advanced gastric cancer

Peptide vaccine treatment has attracted attention in recent years as a new therapy option for chemotherapy-resistant, advanced, unresectable cancer. The safety of peptide vaccination with HLA-A*2402-restricted URLC10-A24-177 and VEGFR1-A12-9 1084 epitope peptides (fixed 2-mg dose) was investigated in a phase I clinical trial of patients with advanced gastric cancer who were refractory to chemotherapy. We determined the HLA genotype of the subjects after enrollment, results of which were held by the evaluation committee and kept from both patients and investigators until completion of the study. The primary end-point was safety of the peptide vaccination. The secondary end-points were immunological responses and clinical outcome, which were compared between the HLA-A*2402-positive and HLA-A*2402-negative groups. The peptides were subcutaneously administered on day 1, 8, 15 and 22 within a 28-day treatment cycle. A total of 14 patients was enrolled in this study; 12 of the 14 patients received 4 or more vaccinations (at least 1 course). No patient had a severe treatment-related adverse event. Findings from evaluation of clinical responses after a single course showed that 4 cases had stable disease and 8 cases had progressive disease. The median overall survival time (MST) for the 12 patients was 3.9 months. The MSTs in the HLA-A*2402-positive and HLA-A*2402-negative groups were, 4.2 and 3.6 months (p= 0.9164), respectively. The results of this study showed that vaccination with URLC10 and VEGFR1 peptides was a safe treatment for advanced gastric cancer. This trial was registered with University Hospital Medical Information Network (UMIN, no. 000002409).

Phase I study of Paclitaxel, Cisplatin and 5-fluorouracil combination chemotherapy for unresectable / recurrent gastric cancer

PURPOSE We investigated the safety of triple combination therapy by addition of Paclitaxel (PTX) to Cisplatin (CDDP) and 5-fluorouracil (5-FU) combination therapy, which was considered the conventional standard therapy for patients with unresectable / recurrent gastric cancer. MATERIAL AND METHODS The doses of PTX and CDDP were fixed at 80 and 50 mg/m2. They were administered on days 1 and 8, followed by a resting period of 20 days. 5-FU 300 mg/m2 at a maximum dose of 500 mg/m2 was administered at levels 0 and 2, respectively, and the dose was increased by 100 mg/m2 until the maximum tolerated dose (MTD). It was administered on days 1 - 5 and 8 - 12, followed by a resting period of 16 days. RESULTS Twelve patients enrolled in this study. Of them, three patients were excluded from evaluation because treatment continuation was not feasible. There were 4 leukopenia and 7 neutropenia cases with hematological toxicity at grade 3 or higher. They were observed at all dose levels, but no case showed infection. In terms of non-hematological toxicity at grade 3 or higher, there were two patients with nausea and vomiting and two patients with diarrhea, one patient with mucositis, one patient with anorexia. All patients with non-hematological toxicity at grade 3 or higher were at level 2. The dose-limiting toxicity (DLT) was observed at level 2, and 5-FU at 400 mg (level 1) was adopted. CONCLUSIONS We proved in this study that PTX, CDDP, and 5-FU combination chemotherapy was a safe treatment.

Continuation of antithrombotic therapy may be associated with a high incidence of colonic post-polypectomy bleeding

Post‐polypectomy bleeding (PPB) is the most common complication of endoscopic procedures. To reduce the risk of thromboembolic incidents, Japanese guidelines for gastroenterological endoscopy were revised to indicate that antithrombotic agents were not to be discontinued for endoscopic treatment. However, carrying out endoscopic procedures under antithrombotic medication potentially increases the incidence of hemorrhagic complications. The present study investigated the impact of the revised guidelines on the frequency of complications after colonoscopic procedures.

Phase I Clinical Trial of Peptide Vaccination with KIF20A and VEGFR1 Epitope Peptides in Patients with Advanced Pancreatic Cancer

We investigated the safety of peptide vaccination with HLA-A2402-restricted KIF20A and VEGFR1 epitope peptides in patients with advanced pancreatic cancer that was refractory to chemotherapy. This was a prospective nonrandomized, single-arm, phase I clinical trial with a fixed 2-mg dose of KIF20A and VEGFR1 peptides for patients with advanced unresectable pancreatic cancer. We determined the HLA genotype of the subjects after enrollment, results of which were held by the evaluative committee and kept from both patients and investigators until completion of the study. The primary endpoint was safety of the peptide vaccination with secondary endpoints being the immunological responses and clinical outcome. We compared study endpoints between the HLA-A*2402-positive and HLA-A*2402- negative groups. KIF20A and VEGFR1 peptides were subcutaneously administered on days 1, 8, 15, and 22 within a 28-day treatment cycle. Nineteen patients diagnosed with unresectable pancreatic cancer were enrolled from May 2009 to January 2010 at our Hospital. Twelve of the 19 patients received 4 or more vaccinations (at least one course). No patient had a severe adverse event in relation to this treatment. Findings from evaluation of clinical responses after one course showed that 2 cases had stable disease and 10 progressive disease. The median overall survival time (MST) for the 12 patients was 5.3 months. In the HLA-A*2402-positive group and HLA-A*2402-negative group, the MST was 6.0 months and 2.3 months (p=0.0373), respectively. Results of this study showed that vaccination with KIF20A and VEGFR1 peptides was a safe treatment, might be a promising treatment. This trial was registered with University Hospital Medical Information Network (UMIN) number UMIN000002022.

ENDOSCOPIC MUCOSAL RESECTION USING A CAP-FITTED PANENDOSCOPE AS A DIAGNOSTIC PROCEDURE IN A CASE OF SCIRRHOUS GASTRIC CARCINOMA

Dear Editor, A 75-year-old woman was admitted to our hospital complaining of upper abdominal pain, loss of appetite and bodyweight. Carcinoembryonic antigen and CA125 were normal, but CA19-9 and CA72-4 were abnormally elevated, 440 U/mL and 216.4 U/mL, respectively. Esophagogastroduodenoscopy (EGD) showed red and edematous mucosa, and poor stomach distensibility, but without any depressed area (Fig. 1a). Although scirrhous gastric cancer was highly indicated by EGD, upper gastrointestinal radiograph and computed tomography, histological evidence of malignancy was not obtained with both pinch biopsy and boring biopsy. Submucosal specimens were obtained by endoscopic mucosal resection (EMR) together with a capfitted panendoscope (EMRC). Two specimens were taken from the corpus and antrum (Fig. 1b). Poorly differentiated adenocarcinoma with signet ring cells were found in the submucosal layer (Fig. 2) leading to a definitive diagnosis. Because of carcinomatous peritonitis, radical resection was not an indication, instead the patient had been receiving chemotherapy. Follow-up EGD on post-EMRC day 80 showed scarring of the lesion without any complications. Scirrhous gastric carcinoma is known as poorly differentiating adenocarcinoma, typically diffusely sclerosing and infiltrating beneath the mucosal layer. Accordingly, it is often difficult to make the diagnosis of carcinoma with routine endoscopic pinch biopsies. Low sensitivity for endoscopic biopsy in scirrhous gastric carcinoma and a high falsenegative rate especially in a case with no depressive lesions have been reported. In such cases, a technique involving fine-needle aspiration or argon plasma coagulation has been described, but the specimens are often inadequate for pathological diagnosis. In contrast, specimens obtained using EMRC were approximately 20 mm in diameter, which are regarded as sufficient for making a definitive diagnosis. Further, unlike surgery or laparoscopy, the EMRC technique is less invasive and, in this case, it was effective and safe for concluding a diagnosis. Additional cases are needed to strengthen our impression.

Efficacy of cytapheresis for remission induction and dermatological manifestations of ulcerative colitis

In ulcerative colitis (UC) patients, cytapheresis depletes elevated and activated leucocytes, which are known to release inflammatory cytokines including tumor necrosis factor (TNF)‐α. Further, there are UC patients who develop erythema nodosum (EN) or pyoderma gangrenosum (PG) as extra‐intestinal manifestations of UC.

Successful remission of ulcerative colitis flare-up during pregnancy with adsorptive granulomonocytapheresis plus tacrolimus

Ulcerative colitis (UC) is 1 of the 2 major phenotypes of chronic inflammatory bowel disease (IBD), which afflicts millions of individuals throughout the world with debilitating symptoms that impair function and quality of life. Further, IBD often affects women during childbearing age. Indeed, UC activity frequently increases during pregnancy, and the medications used to induce remission may adversely affect the health of the mother and the unborn child. We report successful induction of a remission in a UC case who experienced a flare-up in the first trimester of pregnancy. Upon relapse, she was treated with steroids and adsorptive granulomonocytapheresis (GMA) with the Adacolumn plus tacrolimus. This combination therapy induced a stable remission that was maintained during her entire pregnancy. She gave birth to a healthy child at 36 weeks of pregnancy with no maternal or fetal complications. Our experience indicates that GMA, as a non-drug therapeutic intervention with a favorable safety profile, plus tacrolimus might be a relevant treatment option for patients with active IBD during pregnancy. A future study of a large cohort of pregnant patients should strengthen our findings.

Tu1716 A Novel Role for Fibroblast Growth Factor-Inducible Molecule 14 (Fn14) in Regulating Intestinal Injury and Colitis-Associated Tumorigenesis

of voltage-gated Ca2+ currents (VGCC) were performed with and without selective mu and delta agonists and antagonists (as a measure of functional activity of MOR and DOR at the plasma membrane). In 13 fast-blue labeled DRG neurons from controls, 54% expressed DORmRNA, 38% expressed MORmRNA and 23% expressed both. Patch clamp experiments revealed that the VGCC in DRG neurons incubated with chronic DSS supernatants were 68% smaller than those incubated with control supernatants (-63.6 ± 8.8 pA/pF vs -197.2 ± 22 pA/pF, n = 28 and 23 respectively, P = 0.0009, unpaired t test). To determine whether MOR and DOR were involved, neurons were incubated with supernatants from control or chronic DSS mice and 100 nM DADLE (delta agonist) or 100 nM DAMGO (mu agonist). DADLE inhibited 60% of voltage-gated Ca2+ in small DRG neurons incubated with control supernatants (-60.5 ± 14 pA/pF vs -197.2 ± 22 pA/pF , n = 11 and 28 respectively P = 0.007, unpaired t test). DAMGO had only a small effect (27% inhibition) in small DRG neurons (-135.3 ± 38 pA/pF vs -197.2 ± 22 pA/pF n = 11 and 28 respectively). In neurons incubated with chronic DSS supernatants neither DADLE nor DAMGO had an effect on VGCC. However, 1 μM CTOP, a selective antagonist of MOR reversed the inhibitory effects of chronic DSS supernatants on Ca2+ currents (-63.6 ± 8.8 pA/pF vs -224.8 ± 34 pA/pF, P = 0.0001), while 1 μM SDM25N, a selective antagonist of DOR, had no effect (-63.6 ± 8.8 pA/pF vs -88.7 ± 28 pA/pF). Our data suggest that chronic DSS inflammation enhanced mu opioid signalling and decreased delta opioid signalling. These changes underscore the importance of differences in opioid signalling during the evolution of inflammation in IBD.