Comparison of the efficacy and tolerability of elobixibat plus sodium picosulfate with magnesium citrate and split-dose 2-L polyethylene glycol with ascorbic acid for bowel preparation before outpatient colonoscopy: a study protocol for the multicentre, randomised, controlled E-PLUS trial.

BACKGROUND: Sodium picosulfate (SP)/magnesium citrate (MC) and polyethylene glycol (PEG) plus ascorbic acid are recommended by Western guidelines as laxative solutions for bowel preparation. Clinically, SP/MC has a slower post-dose defaecation response than PEG and is perceived as less cleansing; therefore, it is not currently used for major bowel cancer screening preparation. The standard formulation for bowel preparation is PEG; however, a large dose is required, and it has a distinctive flavour that is considered unpleasant. SP/MC requires a small dose and ensures fluid intake because it is administered in another beverage. Therefore, clinical trials have shown that SP/MC is superior to PEG in terms of acceptability. We aim to compare the novel bowel cleansing method (test group) comprising SP/MC with elobixibat hydrate and the standard bowel cleansing method comprising PEG plus ascorbic acid (standard group) for patients preparing for outpatient colonoscopy. METHODS: This phase III, multicentre, single-blind, noninferiority, randomised, controlled, trial has not yet been completed. Patients aged 40-69 years will be included as participants. Patients with a history of abdominal or pelvic surgery, constipation, inflammatory bowel disease, or severe organ dysfunction will be excluded. The target number of research participants is 540 (standard group, 270 cases; test group, 270 cases). The primary endpoint is the degree of bowel cleansing (Boston Bowel Preparation Scale [BBPS] score ≥ 6). The secondary endpoints are patient acceptability, adverse events, polyp/adenoma detection rate, number of polyps/adenomas detected, degree of bowel cleansing according to the BBPS (BBPS score ≥ 8), degree of bowel cleansing according to the Aronchik scale, and bowel cleansing time. DISCUSSION: This trial aims to develop a "patient-first" colon cleansing regimen without the risk of inadequate bowel preparation by using both elobixibat hydrate and SP/MC. TRIAL REGISTRATION: Japan Registry of Clinical Trials (jRCT; no. s041210067; 9 September 2021; https://jrct.niph.go.jp/ ), protocol version 1.5 (May 1, 2023).

Maternal Metals Exposure and Infant Weight Trajectory: The Japan Environment and Children's Study (JECS).

BACKGROUND: To our knowledge, the association of maternal exposure to metallic elements with weight trajectory pattern from the neonatal period has not been investigated. OBJECTIVES: The goals of this study were to identify infant growth trajectories in weight in the first 3 y of life and to determine the associations of maternal blood levels of lead, cadmium, mercury, selenium, and manganese with growth trajectory. METHODS: This longitudinal study, part of the Japan Environment and Children Study, enrolled 103,099 pregnant women at 15 Regional Centres across Japan between 2011 and 2014. Lead, cadmium, mercury, selenium, and manganese levels were measured in blood samples collected in the second (14-27 wk gestational age) or third trimester (≥28wk). Growth trajectory of 99,014 children was followed until age 3 y. Raw weight values were transformed to age- and sex-specific weight standard deviation (SD) scores, and latent-class group-based trajectory models were estimated to determine weight trajectories. Associations between maternal metallic element levels and weight trajectory were examined using multinomial logistic regression models after confounder adjustment. RESULTS: We identified 5 trajectory patterns based on weight SD score: 4.74% of infants were classified in Group I, very small to small; 31.26% in Group II, moderately small; 21.91% in Group III, moderately small to moderately large; 28.06% in Group IV, moderately large to normal; and 14.03% in Group V, moderately large to large. On multinomial logistic regression, higher maternal lead and selenium levels tended to be associated with increased odds ratios (ORs) of poor weight SD score trajectories (Groups I and II), in comparison with Group III. Higher levels of mercury were associated with decreased ORs, whereas higher levels of manganese were associated with increased ORs of "moderately large" trajectories (Groups IV and V). DISCUSSION: Maternal lead, mercury, selenium, and manganese blood levels affect infant growth trajectory pattern in the first 3 y of life. https://doi.org/10.1289/EHP10321.

No Significant Effect of Daikenchuto (TJ-100) on Peritoneal IL-9 and IFN-γ Levels After Pancreaticoduodenectomy.

AIM AND BACKGROUND: TJ-100 is a traditional Japanese medicine that affects inflammation and gastrointestinal motility, and is used as a preventive and treatment for paralytic ileus. This study aims at determining the effect of TJ-100 on the peritoneal levels of IFN-γ/IL-9, cytokines related to ileus, after pancreaticoduodenectomy (PD) in a clinical setting. METHODS: This was a subsidiary study of the clinical trial investigating the effect of TJ-100 on postoperative bowel function. Ascites was collected from 180 patients using an abdominal drainage tube on postoperative day 1 and 3 after PD (POD 1 or POD 3) and used to measure 27 cytokines. We performed univariate and multivariate analyses using several perioperative variables and administration of TJ-100/placebo to determine the effect of TJ-100 on the levels of IFN-γ and IL-9. RESULTS: Peritoneal levels of IL-9 and IFN-γ decreased between POD 1 and 3 (Wilcoxon signed-rank test p<0.001). Multivariate analysis was performed after univariate analysis to select the variables and patients with a body mass index of ≥22 kg/m2, older age, use of epidural anesthesia, and longer surgery correlated with the levels of IL-9 and IFN-γ. However, we could not detect a correlation between the use of TJ-100 and cytokine levels in ascites either on POD 1 or 3. CONCLUSION: TJ-100 did not affect peritoneal IL-9 and IFN-γ levels after PD. This was in accordance with published clinical findings showing no improvement in bowel function after PD and TJ-100 treatment.

The effect of TJ-28 (Eppikajutsuto) on the prevention of hand-foot syndrome using Capecitabine for colorectal cancer: The Yokohama Clinical Oncology Group Study (YCOG1102).

BACKGROUND: Eppikajututo (TJ-28, a Kampo medicine) is effective against rheumatoid arthritis and eczema. We conducted a randomized comparative trial to assess the efficacy of TJ-28 for preventing hand-foot syndrome (HFS) as a complication of adjuvant chemotherapy using capecitabine. METHODS: The present study was a multi-institutional randomized-controlled trial (UMIN000005899). Colorectal cancer patients scheduled to receive capecitabine chemotherapy as adjuvant therapy were randomly assigned to receive TJ-28 (7500 mg/day) or oral pyridoxine (60 mg/day). Patients were monitored for the development of grade ≥ 2 HFS according to the National Cancer Institute Common Toxicity Criteria until chemotherapy completion. RESULTS: Twenty-two patients were enrolled in this study. The relative dose intensity of capecitabine was 76.2% in the TJ-28 group and 68.2% in the pyridoxine group. Grade ≥ 2 HFS developed in 6 (50.0%) of 12 TJ-28 patients and in 4 (40.0%) of 10 pyridoxine patients. Chemotherapy treatment failure was observed in seven patients, mainly due to HFS, liver dysfunction, diarrhea, and neutropenia. Chemotherapy treatment failure due to HFS occurred in none of the TJ-28 group and 2 patients (20.0%) in the pyridoxine group (p = 0.114). CONCLUSION: Capecitabine-associated HFS was not markedly prevented by TJ-28 compared with pyridoxine. However, TJ-28 might support the continuation of chemotherapy with capecitabine. Further studies are warranted to clarify the benefits of TJ-28.

Neoadjuvant Chemotherapy With Anthracycline-Based Regimen for BRCAness Tumors in Triple-Negative Breast Cancer.

BACKGROUND: A subgroup of triple-negative breast cancer (TNBC) shows impaired BRCA1 function owing to causes other than mutation, which is called "BRCAness." DNA-damaging agents are known to have more efficacy in BRCA1-mutant tumors than mitotic poisons. We conducted a prospective single-arm clinical trial of neoadjuvant chemotherapy (NAC) using an anthracycline-based regimen without taxanes for BRCAness TNBCs. MATERIALS AND METHODS: BRCAness was examined using the multiplex ligation-dependent probe amplification (MLPA) method in TNBC cases. For BRCAness cases, NAC was performed with anthracycline-based regimens without additional taxanes. RESULTS: A total of 30 patients with TNBC were enrolled. MLPA was successfully performed in 25 patients. Eighteen patients (72%) showed BRCAness. Twenty-three patients received NAC as per the protocol. On analysis, the clinical response rate (complete response plus partial response) was 76.4%, and the pathological complete response rate was 35.3%. CONCLUSIONS: The interim analysis revealed that the pathological complete response rate was lower than estimated. Therefore, BRCAness by MLPA was not sufficient to predict the therapeutic response to anthracycline-based regimens in TNBC.

Anthracycline could be essential for triple-negative breast cancer: A randomised phase II study by the Kanagawa Breast Oncology Group (KBOG) 1101.

BACKGROUND: It is important to determine whether anthracycline-containing regimens or taxane-containing regimens are more effective in individual patients. The present study compared the efficacy of six cycles of docetaxel and cyclophosphamide (TC6) with that of three cycles of 5-fluorouracil, epirubicin and cyclophosphamide followed by docetaxel (FEC-D) in Japanese patients with hormone receptor (HR)-negative breast cancer (BC) to identify subtypes requiring anthracycline treatment. METHODS: The study included 103 patients with operable HR-negative BC. Of these patients 53 received FEC-D and 50 received TC6. The primary endpoint was pathological complete response (pCR). The secondary endpoints were safety, breast-conserving surgery, disease-free survival (DFS) and overall survival (OS). The predictive factors for each regimen were evaluated. RESULTS: Of the 103 patients, 97 completed the study (FEC-D, 50 patients; TC6, 47 patients). The pCR rate was higher with FEC-D (36%) than with TC6 (25.5%); however, the difference was not significant (P = 0.265). TC6 was safer than FEC-D, as the adverse events with docetaxel in the FEC-D regimen were similar to those with the TC6 regimen. Among patients with basal BC, the pCR rate was significantly higher with FEC-D (42.9%) than with TC6 (13.6%; P = 0.033). Among patients with triple-negative breast cancer (TNBC), the DFS and OS were significantly better with FEC-D than with TC6 (P = 0.016 and P = 0.034, respectively). CONCLUSION: TC6 was not as effective as FEC-D for treating HR-negative BC, as TC6 was not sufficient to treat TNBC, particularly the basal subtype. Our findings suggest that anthracyclines are better treatment options than taxanes for basal BC.

Transition of serum cytokines following pancreaticoduodenectomy: A subsidiary study of JAPAN-PD.

Our previous study aimed to examine the effect of TJ-100, a widely used herbal medicine, on intestinal function following pancreaticoduodenectomy (PD) in a multicenter, randomized, double-blinded, placebo-controlled manner (JAPAN-PD study). This concomitant study investigated the effect of TJ-100 on serum cytokine levels in patients who underwent PD. Due to the fact that several clinical variables can affect the absolute values of baseline serum cytokine levels, the ratios of the cytokine levels on postoperative day (POD)3 to those on POD1 were also used for analysis. The present study enrolled 180/224 randomized patients, of whom 91 received TJ-100 and 89 received placebo. As the main findings of the analysis, Wilcoxon signed-rank test revealed no significant difference in the levels of serum cytokines between the groups; however, patients in the TJ-100 group without severe inflammatory complications exhibited significantly higher ratios of interleukin (IL)-4 (n=123), IL-9 (n=72), IL-10 (n=97), PDGF-BB (n=143) and tumor necrosis factor-α (n=135), compared with patients in the Placebo Group (P<0.05). According to the results of the present study, TJ-100 has an effect on the change in serum cytokine levels from POD1 to POD3 following PD. However, the role of different transition pattern of cytokines in postoperative recovery following PD has to be investigated by further mechanical studies focusing on these extracted cytokines (ClinicalTrials.gov; no. NCT01607307; May 30, 2012).

Evaluation of the efficacy of daikenchuto (TJ -100) for the prevention of paralytic ileus after pancreaticoduodenectomy: A multicenter, double-blind, randomized, placebo-controlled trial.

BACKGROUND: We assessed the efficacy of TJ-100 taken perioperatively to recovery among patients with periampullary tumor or tumor of the head of the pancreas who underwent pancreaticoduodenectomy (PD). PATIENTS AND METHODS: In this multicenter, randomized, double-blinded, placebo-controlled, phase II trial (JAPAN-PD Study), patients were assigned randomly in a 1:1 ratio to receive TJ-100 or placebo. The coprimary endpoints were (1) incidence of postoperative paralytic ileus lasting >72 hours after surgery and (2) time to occurrence of postoperative paralytic ileus. This trial is registered at the UMIN Clinical Trials Registry (000007975) and at ClinicalTrials.gov (NCT01607307). RESULTS: From August 2012 through July 2013, we assessed 273 patients for eligibility, and 224 underwent randomization; 112 patients received TJ-100, and 112 patients received placebo. The population for analysis consisted of 104 patients who received TJ-100 and 103 who received placebo. Paralytic ileus occurred 35 (33.7%) in the TJ-100 group and 38 (36.9%) in the placebo group (P = .626). Time to first flatus was 2.25 (2.00-2.50) days in the TJ-100 group and 2.50 (1.50-2.50) days in the placebo group (P = .343). Among 23 patients who underwent a pylorus ring-preserving PD, time to first flatus was lower in the TJ-100 group than in the placebo group: 0.50 (0.50-1.00) days versus 1.50 (0.50-3.00) days (P = .034). CONCLUSION: Our findings suggest that use of TJ-100 did not improve recovery from paralytic ileus after PD, and may preclude the routine use of TJ-100 in clinical practice after PD operation.

Effects of melatonin premedication to prevent emergence agitation after general anaesthesia in children: A systematic review and meta-analysis with trial sequential analysis.

BACKGROUND: Emergence agitation is a common phenomenon in children recovering from general anaesthesia. An emergence agitation reaction increases the risk of injuring the surgical repair, the patient and the caregivers. OBJECTIVE: The objective of this study is to examine the efficacy of melatonin premedication in emergence agitation prevention. DESIGN: A systematic review and meta-analysis of randomised controlled trials (RCTs) with trial sequential analysis (TSA) and meta-regression analysis. DATA SOURCES: We searched MEDLINE, the Cochrane Central Register of Controlled Trials, Embase, Web of Science, clinicaltrials.gov and UMIN Clinical Trials Registry up to 4 April 2014. ELIGIBILITY CRITERIA: RCTs reporting effects of melatonin on the incidence of emergence agitation in children who underwent general anaesthesia were included. RESULTS: Four studies (358 participants) were analysed. A conventional random-effects meta-analysis showed that compared with placebo, melatonin premedication may be effective in emergence agitation prevention [risk ratio 0.31, 95% confidence interval (CI) 0.16 to 0.60; I2 = 0%]. However, TSA corrected the 95% CI to 0.07 to 1.47 and showed that 22.5% of the required information size (RIS) was achieved. The effect of melatonin compared with that of midazolam was not statistically significant (risk ratio 0.48, 95% CI 0.15 to 1.52) with significant heterogeneity (I2 = 36.8%). TSA-adjusted 95% CI could not be calculated because of the small information size (4% of RIS). Meta-regression showed that, compared with midazolam, melatonin dose was significantly correlated with the effect (P = 0.024). The risk ratios (95% CI) of low and high-dose melatonin were 1.02 (0.39 to 2.65) and 0.22 (0.08 to 0.58), respectively. There was no effect of melatonin compared with dexmedetomidine (risk ratio 1.0, 95% CI 0.15 to 6.55). TSA-adjusted 95% CI could not be calculated (0.9% of RIS). CONCLUSION: Compared with placebo, melatonin premedication may be effective in preventing emergence agitation in children (GRADE: low). This TSA suggests that further studies are required to confirm the results. Compared with midazolam, high-dose melatonin might have a significant effect in preventing emergence agitation (GRADE: very low). The study protocol was registered in the UMIN Clinical Trials Registry (registration number: UMIN000011841).

Double-blind, placebo-controlled, randomized phase II study of TJ-14 (hangeshashinto) for gastric cancer chemotherapy-induced oral mucositis.

BACKGROUND: Hangeshashinto (TJ-14, a Kampo medicine), which reduces the level of prostaglandin E2 and affects the cyclooxygenase activity, alleviates chemotherapy-induced oral mucositis (COM). We conducted a randomized comparative trial to investigate whether TJ-14 prevents and controls COM in patients with gastric cancer. METHODS: We randomly assigned patients with gastric cancer who developed moderate-to-severe oral mucositis (CTCAE v4.0 grade ≧1) during any cycle of chemotherapy to receive either TJ-14 or a placebo as a double-blind trial. The patients received a placebo or TJ-14 for 2-6 weeks according to the chemotherapy regimen from the beginning of the next course of chemotherapy. The primary end point was the incidence of grade ≧2 oral mucositis in the protocol treatment course, and the secondary end points were the time to disappearance of oral mucositis and the incidence of adverse events. RESULTS: Following the key opening of the blinding protocol, we analyzed 91 eligible patients (TJ-14: 45, placebo: 46) using a "per protocol set" analysis. The incidence of ≧grade 2 COM was 40.0 % in the TJ-14 group and 41.3 % in the placebo group (p = 0.588). The median duration of ≧grade 2 COM was 14 days in the TJ-14 group and 16 days in the placebo group (p = 0.894). Meanwhile, the median duration of any grade of COM was 9 days in the TJ-14 group and 17 days in the placebo group among the patients who developed grade 1 symptoms during the screening cycle [hazard ratio 0.60; 95 % CI (0.23-1.59), p = 0.290]. CONCLUSIONS: Although TJ-14 treatment did not reduce the incidence of ≥2 COM in the patients who developed mucositis during chemotherapy for gastric cancer, a trend was observed in which TJ-14 reduced the risk of COM in the patients who developed grade 1 COM during the screening cycle. Further, phase III studies with a larger sample size are needed to clarify the protective effects of TJ-14 for COM.