Koichi Taira

Phase I/II trial of 2‐weekly docetaxel combined with cisplatin plus fluorouracil in metastatic esophageal cancer (JCOG0807)

We carried out a phase I/II trial of adding 2‐weekly docetaxel to cisplatin plus fluorouracil (CF) therapy (2‐weekly DCF regimen) in esophageal cancer patients to investigate its safety and antimetastatic activity. Patients received 2‐weekly docetaxel (30 mg/m2 [dose level (DL)1] or 40 mg/m2 [DL2] with a 3 + 3 design in phase I, on days 1 and 15) in combination with fixed‐dose CF (80 mg/m2 cisplatin, day 1; 800 mg/m2 fluorouracil, days 1–5) repeated every 4 weeks. The primary endpoint was dose‐limiting toxicity (DLT) in phase I and central peer review‐based response rate in phase II. At least 22 responders among 50 patients were required to satisfy the primary endpoint with a threshold of 35%. Sixty‐two patients were enrolled in phase I and II. In phase I, 10 patients were enrolled with DLT of 0/3 at DL1 and 2/7 in DL2. Considering DLT and treatment compliance, the recommended phase II dose was determined as DL1. In phase II, the response rate was 62% (P < 0.0001; 95% confidence interval, 48–75%); median overall survival and progression‐free survival were 11.1 and 5.8 months, respectively. Common grade 3/4 adverse events were neutropenia (25%), anemia (36%), hyponatremia (29%), anorexia (24%), and nausea (11%). No febrile neutropenia was observed. Pneumonitis caused treatment‐related death in one patient. The 2‐weekly DCF regimen showed promising antimetastatic activity and tolerability. A phase III study comparing this regimen with CF therapy is planned by the Japan Clinical Oncology Group. This study was registered at the UMIN Clinical Trials Registry as UMIN 000001737.

Randomized phase III study of bevacizumab plus FOLFIRI and bevacizumab plus mFOLFOX6 as first-line treatment for patients with metastatic colorectal cancer (WJOG4407G)

BACKGROUND FOLFIRI and FOLFOX have shown equivalent efficacy for metastatic colorectal cancer (mCRC), but their comparative effectiveness is unknown when combined with bevacizumab. PATIENTS AND METHODS WJOG4407G was a randomized, open-label, phase III trial conducted in Japan. Patients with previously untreated mCRC were randomized 1:1 to receive either FOLFIRI plus bevacizumab (FOLFIRI + Bev) or mFOLFOX6 plus bevacizumab (mFOLFOX6 + Bev), stratified by institution, adjuvant chemotherapy, and liver-limited disease. The primary end point was non-inferiority of FOLFIRI + Bev to mFOLFOX6 + Bev in progression-free survival (PFS), with an expected hazard ratio (HR) of 0.9 and non-inferiority margin of 1.25 (power 0.85, one-sided α-error 0.025). The secondary end points were response rate (RR), overall survival (OS), safety, and quality of life (QoL) during 18 months. This trial is registered to the University Hospital Medical Information Network, number UMIN000001396. RESULTS Among 402 patients enrolled from September 2008 to January 2012, 395 patients were eligible for efficacy analysis. The median PFS for FOLFIRI + Bev (n = 197) and mFOLFOX6 + Bev (n = 198) were 12.1 and 10.7 months, respectively [HR, 0.905; 95% confidence interval (CI) 0.723-1.133; P = 0.003 for non-inferiority]. The median OS for FOLFIRI + Bev and mFOLFOX6 + Bev were 31.4 and 30.1 months, respectively (HR, 0.990; 95% CI 0.785-1.249). The best overall RRs were 64% for FOLFIRI + Bev and 62% for mFOLFOX6 + Bev. The common grade 3 or higher adverse events were leukopenia (11% in FOLFIRI + Bev/5% in mFOLFOX6 + Bev), neutropenia (46%/35%), diarrhea (9%/5%), febrile neutropenia (5%/2%), peripheral neuropathy (0%/22%), and venous thromboembolism (6%/2%). The QoL assessed by FACT-C (TOI-PFC) and FACT/GOG-Ntx was favorable for FOLFIRI + Bev during 18 months. CONCLUSION FOLFIRI plus bevacizumab was non-inferior for PFS, compared with mFOLFOX6 plus bevacizumab, as the first-line systemic treatment for mCRC. CLINICAL TRIALS NUMBER UMIN000001396.

Rebamipide Reduces Delay in Gastric Ulcer Healing in Cyclooxygenase-2-Deficient Mice

Rebamipide is an antiulcer drug capable of various actions including the induction of cyclooxygenase-2 (COX-2). In this study, we investigated the effect of rebamipide on gastric ulcer healing in COX-2-deficient mice. Wild-type (N = 34) and COX-2-deficient mice (N = 28) with gastric ulcers were administered 30 mg/kg of rebamipide or the vehicle. Ulcerous tissues were subjected to measurements of ulcer size, immunohistochemical staining of CD31 (an endothelial cell marker), and mRNA levels. COX-2 deficiency delayed ulcer healing and inhibited angiogenesis and bFGF mRNA expression in the granulation tissue. In wild-type mice, rebamipide accelerated ulcer healing and increased COX-2 mRNA expression. In COX-2-deficient mice, rebamipide prevented delayed ulcer healing and reversed the inhibition in angiogenesis and bFGF mRNA expression. The effect of rebamipide on the enhancement of ulcer healing, angiogenesis, and induction of bFGF expression was more prominent in wild-type mice than in COX-2-deficient mice. In conclusion, rebamipide may accelerate gastric ulcer healing through both COX-2-dependent and COX-2-independent mechanisms.

Multicenter Feasibility Study of Combination Therapy with Fluorouracil, Leucovorin and Paclitaxel (FLTAX) for Peritoneal Disseminated Gastric Cancer with Massive Ascites or Inadequate Oral Intake

OBJECTIVE Oral fluoropyrimidine plus cisplatin is a standard treatment for advanced gastric cancer, but patients with severe peritoneal metastasis often cannot tolerate this regimen. The aim of this study was to assess the feasibility of fluorouracil, l-leucovorin and paclitaxel therapy in such patients. METHODS In the first phase of the study, we investigated the maximum tolerated dose and recommended dose in Cycle 1 of fluorouracil, l-leucovorin and paclitaxel, at two dose levels [Level 1 (n = 6): 5-fluorouracil/l-leucovorin/paclitaxel = 500/250/60 mg/m(2); Level 2 (n = 6): 600/250/80 mg/m(2) on Days 1, 8 and 15, every 28 days]. Nineteen additional patients at the recommended dose level were enrolled in the second phase to investigate the feasibility of fluorouracil, l-leucovorin and paclitaxel therapy. The primary endpoint in the second phase was the completion rate of two cycles. RESULTS Dose-limiting toxicities were observed in a patient at Level 1 with Grade 4 gastrointestinal perforation (the site of primary tumor), and in two patients at Level 2 with Grade 3 febrile neutropenia and Grade 3 infection, respectively. In Cycle 2, treatment-related death occurred at Level 2 in one patient who had Grade 4 febrile neutropenia with pneumonia. The maximum tolerated dose was set at Level 2, and the recommended dose was determined as Level 1. In the second phase, the completion rate of two cycles was 92% and the ascites response was 44%. Median progression-free survival was 4.2 months and overall survival was 8.0 months. Grade 3/4 neutropenia was observed in 12% of patients. CONCLUSIONS Fluorouracil, l-leucovorin and paclitaxel at Level 1 is feasible as first-line treatment for peritoneal disseminated gastric cancer patients with massive ascites or inadequate oral intake.

Neutrophil-to-Lymphocyte Ratio for Predicting Loss of Response to Infliximab in Ulcerative Colitis

Objectives Neutrophil-to-lymphocyte ratio (NLR) has been used to determine the outcome in malignancies and coronary heart disease. Some reports considered the value of NLR as a predictor of response to infliximab in patients with Crohn’s disease or rheumatoid arthritis; however, no similar studies have been reported for ulcerative colitis (UC). This study aimed to evaluate the clinical significance of the baseline NLR in patients with UC treated by infliximab. Materials and Methods Patients with moderate-to-severe active UC who received the first infliximab infusion in our hospital between 2010 and 2015, who showed clinical response during the induction period, were retrospectively evaluated for long-term outcomes and risk factors for loss of response (LOR) during infliximab maintenance therapy. Baseline inflammatory markers including NLR were measured within one week before the initiation of infliximab. Results Fifty-nine patients with moderate-to-severe active UC started treatment with infliximab and 37 patients (62.7%) experienced clinical response after induction therapy. Fourteen of 37 patients on maintenance therapy lost the response during follow-up. Baseline NLR of patients with LOR was significantly higher than in patients with sustained response. The NLR cut-off value of 4.488 was predictive of LOR, using receiver operating characteristic analysis (sensitivity: 78.6%, specificity: 78.3%). A univariate analysis revealed a significant relationship between relapse-free survival and the NLR (P = 0.018). Multivariate analysis indicated the NLR as an independent prognostic factor for LOR (hazard ratio = 3.86, 95% confidence interval: 1.20–12.4, P = 0.023). Conclusions Baseline NLR is a useful prognostic marker in patients with moderate-to-severe active UC treated with infliximab, and may contribute to appropriate use of infliximab.

Roles of cyclooxygenase-2 and prostaglandin E receptors in gastric mucosal defense in Helicobacter pylori-infected mice

Abstract.Background/Aim:Helicobacter pylori (H. pylori) induces cyclooxygenase-2 (COX-2) expression. The aim of this study was to assess the roles of COX-2 and PGE2 receptors (EPs) in gastric defense in H. pylori-infected mice.Methods:Gastric lesions were induced by oral administration of 0.15 N HCl in 60 % ethanol (HCl/EtOH) to mice infected with H. pylori, and macroscopically evaluated 30 min later. Mice were administered NS-398 (COX-2 selective inhibitor) concomitantly with selective EP agonists 4 hours before HCl/EtOH challenge.Results:H. pylori infection prevented the gastric damage induced by HCl/EtOH, and this protective effect was abolished by NS-398. Selective agonists of EP1, EP2, and EP4, but not the EP3 agonist, reversed the inhibitory effect of NS-398 on prevention of damage by H. pylori infection. The EP4 agonist and EP2/EP4 agonists inhibited the increase in TNF-α mRNA expression and neutrophilic infiltration caused by NS-398, respectively.Conclusion:COX-2-derived PGE2 may play an important role in resistance to HCl/EtOH damage in H. pylori-infected mice by activating EP1, EP2, and EP4.

Clinical factors associated with positive capsule endoscopy findings in patients with obscure gastrointestinal bleeding: a single-center study

Abstract Background: Capsule endoscopy (CE) is a useful tool for patients with obscure gastrointestinal bleeding (OGIB), but positive finding rate differs among trials, which may be attributable to the difference in patients’ background. Objectives: To evaluate the predictive factors associated with positive findings on CE. Methods: Consecutive patients with OGIB who underwent CE between March 2004 and May 2015 at a single university hospital were enrolled. Patients’ clinical factors and CE data were reviewed retrospectively, and we evaluated the relationship between clinical factors and positive findings by univariate and multivariate logistic regression analyses. Results: Five hundred and seventy-eight patients were included in the analysis. Positive CE findings were obtained in 284 patients (49.1%). In multivariate analysis, low hemoglobin level (odds ratio (OR), 1.142 per 1 g/dL decrease; p < .001), Charlson comorbidity index (CCI) score (OR, 1.170 per 1 point increase; p = .002), and non-steroidal anti-inflammatory drug (NSAID) use (OR, 1.640; p = .044) were associated with an increased prevalence of positive findings. As for components of CCI, malignant tumor (OR, 1.839; p = .017) was associated with the positive findings. Conclusions: OGIB patient with a low-hemoglobin level, complex and severe comorbidities, and NSAID use should receive CE.

Results of a retrospective analysis of gemcitabine as a second-line treatment after chemoradiotherapy and maintenance chemotherapy using 5-fluorouracil in patients with locally advanced pancreatic cancer

BackgroundMany studies of concurrent chemoradiation therapy with 5-fluorouracil (5-FU) for locally advanced pancreatic cancer have been reported with a median survival time of approximately 10 months. Recently, gemcitabine (GEM) has been administered immediately after chemoradiation. The clinical outcome of chemoradiation therapy in conjunction with 5-FU and second-line chemotherapy with GEM after disease progression has not been clarified.MethodsPatients with locally advanced pancreatic cancer were treated with concurrent radiation therapy (1.8 Gy/fraction; total dose, 50.4 Gy) with 5-FU (200 mg/m2 every day) until disease progression, followed by GEM (1000 mg/m2, days 1, 8, 15, and every 4 weeks) as second-line therapy.ResultsOf the 18 patients with locally advanced pancreatic cancer who received chemoradiation therapy with 5-FU, there were three partial responses, giving a response rate of 17%. The median time to progression was 170 days. The median survival time was 443 days. During chemoradiation therapy, the incidences of grade 3 or 4 anorexia, nausea, mucositis, and gastric ulcer were 33%, 22%, 17%, and 17%, respectively. Sixteen patients received second-line chemotherapy with GEM, of whom one patient had a partial response. The median time to progression from the initiation of GEM was 113 days, and median overall survival time was 231 days. Major toxicities were hematological toxicities: grade 3 or 4 leukopenia in 75% and anemia in 31%.ConclusionsThe treatment strategy with concurrent chemoradiation and maintenance chemotherapy with 5-FU followed by second-line chemotherapy with GEM may be an option for locally advanced pancreatic cancer.

Efficacy of a concomitant elemental diet to reduce the loss of response to adalimumab in patients with intractable Crohn's disease

Secondary loss of response to adalimumab (ADA‐LOR) commonly occurs in patients with Crohns disease (CD) treated with adalimumab (ADA). We evaluated the efficacy of concomitant elemental diet (ED) therapy to reduce ADA‐LOR in adult CD patients.

A comparison of short-term therapeutic efficacy between infliximab and tacrolimus for moderate to severe ulcerative colitis.

Abstract Introduction. Both infliximab (IFX) and tacrolimus (Tac) are effective for inducing clinical remission in patients with ulcerative colitis (UC). However, no randomized study has addressed the relative efficacies of IFX and Tac for patients with moderate to severe UC. This study aimed to conduct a retrospective study on the relative efficacy of IFX and Tac in patients with moderate to severe UC, using an inverse probability of treatment weighting (IPTW) technique to adjust background factors statistically. Methods. Between July 2009 and March 2016, data obtained from 122 patients with moderate to severe UC who were treated with either IFX (n = 58) or Tac (n = 64) were analyzed retrospectively. We compared the short-term therapeutic efficacy between the IFX group and Tac group using IPTW technique. Results. The clinical remission rate at 14 weeks after treatment was 37.9% (22/58) in the IFX group and 50% (32/64) in the Tac group, respectively. The efficacy of IFX and Tac for clinical remission rate was not different according to univariate (Odds ratio [OR] 1.64, 95% confidence interval [CI] 0.80-3.37 P = 0.18) and multivariate analyses (OR 2.19, 95% CI 0.85-5.61, P = 0.10). After the background and confounders factors were adjusted by using IPTW based on propensity score, the efficacy of IFX and Tac for clinical remission rate was not differed statistically (OR, 1.483; 95% CI, 0.581-3.785; P = 0.409) Conclusion. IFX and Tac have equivalent short-term efficacies for induction in patients with moderate to severe UC.