Satoshi Otsu

Transfer of Antigen-Pulsed Dendritic Cells Induces Specific T-Cell Proliferation and a Therapeutic Effect against Long-Term Helicobacter pylori Infection in Mice

ABSTRACT Helicobacter pylori causes persistent infection of the stomach and results in chronic gastritis and peptic ulcers. Jaws II cells, derived from mouse bone marrow, were pulsed with live or formalin-killed or whole-cell sonicates (WCS) of H. pylori. Representative cell surface molecules were expressed at substantial levels on Jaws II cells, indicating that appropriate maturation of the cells was achieved with the three H. pylori antigens without any significant differences. H. pylori WCS-pulsed Jaws II cells secreted a significant amount of tumor necrosis factor alpha into the culture supernatant. The naïve T cells exposed to the WCS-pulsed Jaws II cells showed significant proliferation and gamma interferon (IFN-γ) and interleukin-10 (IL-10) production in vitro. A 2-log reduction in the number of colonizing bacteria was observed in the mice treated with the WCS-pulsed Jaws II cells; however, no significant reductions were achieved in mice treated with Jaws II cells pulsed with other H. pylori antigens. Up-regulated production of IFN-γ and IL-10 was observed in the stomachs of the mice treated with the WCS-pulsed Jaws II cells, which is consistent with the result obtained in vitro. There were no differences in gastritis scores or H. pylori-specific antibody titers among the mice treated with Jaws II cells pulsed with the three different H. pylori antigens. The results suggest that Th1 cell-mediated immunity in combination with Th2 cell-mediated immunity plays a role in reducing colonizing bacterial numbers in mice with chronic H. pylori infections.

Comparison of amoxicillin-metronidazole plus famotidine or lansoprazole for amoxicillin-clarithromycin-proton pump inhibitor treatment failures for Helicobacter pylori infection

Background:  Proton pump inhibitor–amoxicillin–metronidazole is recommended as second‐line Helicobacter pylori therapy in Japan. The authors assessed the efficacy and safety of second‐line eradication using the H2‐receptor antagonist famotidine as a substitute for proton pump inhibitor.

Vesicocutaneous fistula formation during treatment with sunitinib malate: Case report

BackgroundThe oral multi-kinase inhibitor sunitinib malate improves the survival of patients with gastrointestinal stromal tumors (GIST) after the disease progresses or intolerance to imatinib mesylate develops. Urinary fistulae arising during treatment with sunitinib for GIST have not been described.Case presentationWe describe a 62-year-old female patient diagnosed with unresectable GIST that involved the abdominal wall, urinary bladder wall, bowel, mesentery and peritoneum in the pelvic cavity. Intestinocutaneous fistulae developed on a surgical lesion after orally administered imatinib was supplemented by an arterial infusion of 5-flurouracil. Sunitinib was started after the patient developed resistance to imatinib. On day 4 of the fourth course of sunitinib, a widely dilated cutaneous fistula discharged large amounts of fluid accompanied by severe abdominal pain. Urinary communication was indicated based on the results of an intravenous injection of indigo carmine. Computed tomography findings suggested a small opening on the anterior urinary bladder wall and fistulous communication between the bladder and abdominal walls bridged by a subcutaneous cavity. The fistula closed and the amount of discharge decreased when sunitinib was discontinued. Therefore, sunitinib might have been associated with the development of the vesicocutaneous fistula in our patient.ConclusionThis is the first description of a vesicocutaneous fistula forming while under sunitinib treatment. Clinicians should be aware of the possible complication of vesicocutaneous fistula formation during treatment with molecular targeting agents in patients with extravesical invasion and peritoneal dissemination of GIST.

Abstract A167: A phase I study of single-agent BEZ235 (SDS sachet), once- or twice-daily, in Japanese patients with advanced solid tumors.

Background: BEZ235 is an oral, ATP-competitive inhibitor that targets class l PI3K and downstream effectors mTORC1/2. In previous phase I studies in mainly Western patients, the maximum tolerated dose (MTD) of single-agent BEZ235 solid dispersion system (SDS) sachet once daily (QD) was declared as 1200 mg and the recommended dose (RD) as 1000 mg; the MTD of the same formulation of BEZ235 twice daily (BID) was declared as 400 mg (Rodon EORTC-NCI-AACR 2012, Arkenau ASCO 2012). Here we present the results of a phase I, multicenter, open-label, dose escalation study of single-agent BEZ235 SDS sachet, administered QD or BID, in adult Japanese patients with advanced solid tumors (NCT01195376). Methods: Patients with histologically confirmed, unresectable advanced solid tumors not amenable to standard therapy, received continuous oral BEZ235, QD or BID in 28-day cycles. The primary objective was to determine the MTD/RD of single-agent BEZ235 in adult Japanese patients, based on dose-limiting toxicity (DLT) using a standard 3+3 method for dose escalation. MTD was defined as the highest dose causing DLT in no more than 1/6 patients in Cycle 1. Secondary objectives included preliminary antitumor activity (RECIST v1), safety profiles (CTCAE v3), and pharmacokinetics (PK). Results: As of Feb 10, 2013, 32 patients (mean age 58 yrs) were treated with BEZ235 at 2 dosing schedules; 27 patients received BEZ235 QD at 5 dose levels: 400, 800, 1000, 1200, or 1400 mg; and 5 patients received BEZ235 BID at 400 mg. 2 DLTs were reported with QD dosing: Grade 2 allergic reaction (1200 mg) and Grade 4 thrombocytopenia (1400 mg). Although equivalent DLT ratios were recorded at 1200 mg and 1400 mg (1/6 evaluable patients each), clinical observation led to 1200 mg being declared as the maximum, clinically tolerable dose and 1000 mg being declared as the RD of single-agent BEZ235 QD. The primary reason for discontinuation was disease progression (63%). Common suspected BEZ235-related AEs (≥40%) were diarrhea, decreased appetite, nausea, stomatitis, fatigue, vomiting, and rash; no difference in AE profile was observed between QD and BID schedules. Three patients experienced serious suspected BEZ235-related AEs: infectious enterocolitis, pneumonia, and diarrhea. No death related to treatment was reported. Best overall response was stable disease in 15/27 evaluable patients (56% disease control rate). After Feb 10, 2013, 3 additional patients were enrolled at 400 mg BID (8 in total) and 1 DLT (Grade 2 liver dysfunction) out of 6 evaluable patients was observed. PK data revealed a slow rate of absorption, less than dose-proportional exposure, and large interpatient variability for single-agent BEZ235 SDS sachet. Conclusions: The maximum, clinically tolerable dose of BEZ235 QD was declared as 1200 mg and the RD was declared as 1000 mg, in agreement with previous studies in Western populations. In addition, the tolerability of 400 mg BEZ235 BID was confirmed. The findings of this first-in-Japanese study suggest no major difference in BEZ235 tolerability and PK profile between Japanese and Western populations. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A167. Citation Format: Koichiro Watanabe, Hironobu Minami, Satoshi Otsu, Yoshinori Hirashima, Ryotaro Morinaga, Kazuo Nishikawa, Yasushi Hisamatsu, Toru Mukohara, Naomi Kiyota, Naoko Chayahara, Masanori Toyoda, Yoshinori Imamura, Yutaka Fujiwara, Cornelia Quadt, Matthew Robson, Kazuto Natsume, Takuji Aoki, Kuniaki Shirao. A phase I study of single-agent BEZ235 (SDS sachet), once- or twice-daily, in Japanese patients with advanced solid tumors. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A167.

CD34-negative solitary fibrous tumour resistant to imatinib.

A 75-year-old man presented to our hospital with multifocal thickening of the left pleura and left pleural effusion. Histology of the pleura showed uniform and bipolar spindle cells with moderate mitosis in a collagenised stroma. It further showed abundant blood vessels in a haemangiopericytoma-like pattern. These findings were strongly suggestive of malignant solitary fibrous tumour (SFT). The tumour showed negative staining for CD34. The loss of CD34 expression could imply histologically high-grade tumour, as reported previously. Imatinib, a multityrosine kinase inhibitor with targets, including platelet-derived growth factor receptor (PDGFR)-α and PDGFR-β, has antitumour activity in some patients with SFT. Unfortunately, imatinib treatment failed to control disease progression in the present case that expressed PDGFR-β, but not PDGFR-α. This report described a case of CD34-negative SFT resistant to imatinib.