Efficacy and tolerability of 1 L polyethylene glycol plus ascorbic acid with senna versus 2 L polyethylene glycol plus ascorbic acid for colonoscopic bowel preparation: Prospective, randomized, investigator-blinded trial.

OBJECTIVES: Low-volume polyethylene glycol plus ascorbic acid (PEG-Asc) reduces the dosage of colonoscopic bowel preparation (BP) solution, but is still poorly tolerated. Adding laxatives to the BP solution reduces the volume of fluid required, without affecting quality. This study aimed to compare 1 L PEG-Asc plus 24 mg senna (1L-PEG/AS) and conventional 2 L PEG-Asc (2L-PEG/A) regimens on BP quality and patient tolerability. METHODS: A single-center, randomized, investigator-blinded, noninferiority trial was performed between June and August 2022. Outpatients scheduled for colonoscopy were randomized (1:1) to the 1L-PEG/AS or 2L-PEG/A group. The Boston Bowel Preparation Scale (BBPS) was used to evaluate BP quality. Adverse events and tolerability were surveyed using questionnaires. RESULTS: Overall, 344 patients received 1L-PEG/AS or 2L-PEG/A regimens. The baseline characteristics and adverse events of the two groups were comparable. The 1L-PEG/AS group showed noninferior adequate BP rates compared with the 2L-PEG/A group (88% vs. 89%, P = 1.00); overall BBPS was 7.1 ± 1.5 and 7.2 ± 1.5, respectively (P = 0.39). Higher willingness to repeat the BP was observed in the 1L-PEG/AS group (85% vs. 62%, P < 0.01). CONCLUSIONS: The 1L-PEG/AS regimen was comparable to the 2L-PEG/A regimen in terms of BP adequacy, requiring lower BP solution volumes, with better patient tolerance. Thus, it may be a suitable alternative to the conventional BP solution for colonoscopy. The Japan Registry of Clinical Trials (jRCT1051220043).

Cost-effectiveness of 12 months of capecitabine as adjuvant chemotherapy for stage III colon cancer: preplanned cost-effectiveness analysis of the JFMC37-0801 study.

OBJECTIVES: We evaluated the cost-effectiveness of a 12-month regimen of oral capecitabine versus a standard 6-month regimen as postoperative adjuvant chemotherapy for stage III colon cancer. METHODS: We utilized patient-level data from a multi-institutional randomized controlled trial (JFMC37-0801) that investigated prolonged oral fluoropyrimidine monotherapy. The analysis considered three health states: stable disease, post-metastasis, and death. A parametric statistical model with a cure model was used to estimate the survival curve. The analysis was conducted from the Japanese public healthcare payer's perspective, considering only direct medical costs. A lifetime horizon was used, with a discount rate of 2% for both cost and health outcomes. Health outcomes were evaluated in terms of quality-adjusted life-years (QALYs). RESULTS: The estimated cure rates for colon cancer were 0.726 [95% confidence interval (CI) 0.676-0.776] and 0.694 (95% CI 0.655-0.733) with the 12- and 6-month regimens, respectively; and the estimated 5-year relapse-free survival rates were 74.4% and 69.8%, respectively. The estimated lifetime cost for 12 months of capecitabine was JPY 3.365 million (USD 31,159), compared with JPY 3.376 million (USD 31,262) for 6 months. The estimated QALY were 12.48 and 11.77 for the 12- and 6-month regimens, respectively. Thus, the 12-month capecitabine regimen was dominant. Using a willingness-to-pay threshold of JPY 5 million per QALY, we determined a 97.4% probability that the 12-month capecitabine regimen is more cost-effective than the 6-month regimen. CONCLUSIONS: Twelve months of capecitabine is the favorable option for postoperative adjuvant chemotherapy for stage III colon cancer from the perspective of cost-effectiveness.

Chocolate as a food matrix reduces the bioavailability of galloylated catechins from green tea in healthy women.

In this study, we evaluated the food matrix effects of chocolate on the absorption of green tea catechins (GTCs), (-)-epicatechin (EC), (-)-epigallocatechin (EGC), (-)-epicatechin gallate (ECg), and (-)-epigallocatechin gallate (EGCg), in five healthy 22-year-old women. In the single-intake experiment, the plasma concentrations of ECg (P < 0.05, at 1.5 h) and EGCg (P < 0.05, at 6 h) but not those of EC and EGC were reduced by the chocolate matrix. Regardless of the chocolate matrix, ECg and EGCg were mainly present as their aglycones in the plasma, whereas EGC and EC were found mostly as conjugated metabolites. After daily intake of GTCs mixed with chocolate for 14 days followed by overnight fasting, ECg but not EGCg was detected in the plasma. To compare the plasma profiles of ECg and EGCg, a mixture containing approximately equal amounts of ECg and EGCg was administered to nine rats for 14 days. Following treatment and overnight food deprivation, the plasma content of ECg was higher than that of EGCg. After a single injection of the same mixture in seven rats, ECg levels were higher than those of EGCg, and a greater amount of conjugated metabolites of ECg than those of EGCg was detected in the plasma 10 h after administration. In conclusion, the chocolate matrix affects the plasma profiles of GTCs, particularly ECg. ECg appears to persist in the plasma for a longer period, regardless of the chocolate matrix.

Exploring the Application of Cost-Effectiveness Evaluation in the Japanese National Health Insurance System.

OBJECTIVES: Advances in health care due to the development and introduction of new drugs and medical devices have brought considerable benefits to people and patients in terms of upgraded quality of life and extended years of survival. However, some are concerned that the very advancement of health care would increase further the inflation of national healthcare costs. In response to these concerns, Japan's Central Social Insurance Medical Council ("Chuikyo") began in 2012 to examine how cost-effectiveness evaluation might be applied to the national health insurance system, and has been working toward establishing a system for its usage. METHODS: Cost-effectiveness evaluation was adopted on a trial basis in fiscal year (FY) 2016, targeting seven drugs and six medical devices. Analyses and re-analyses were performed by manufacturers and a public expert organization, respectively. Based on these analyses, a cost-effectiveness evaluation expert organization conducted an overall assessment ("appraisal"). Results of the evaluation were used to adjust the prices of the target items. RESULTS: Following the trial adoption of cost-effectiveness evaluation, price adjustments were performed for three items in April 2018. Meanwhile, a decision was also made to examine seven items for which technical requirements were identified due to differences in the understanding of analysis methods between involved parties. CONCLUSIONS: The Chuikyo will examine how to meet the newly identified technical requirements and discuss specific details with regard to establishing a system that incorporates cost-effectiveness evaluation. The Chuikyo plans to reach a conclusion by the end of FY 2018.

Patient-Reported Outcome Results from the Open-Label Randomized Phase III SELECT BC Trial Evaluating First-Line S-1 Therapy for Metastatic Breast Cancer.

OBJECTIVE: To evaluate the effects of S-1, an orally administered 5-FU agent, versus taxane on patient-reported outcomes (PROs) in the SELECT BC trial. METHODS: Patients with HER2-negative and endocrine treatment-resistant breast cancer with metastasis or recurrence after surgery were randomly assigned to receive first-line taxane or S-1. PROs (secondary endpoint) were assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) and Patient Neurotoxicity Questionnaire (PNQ) at baseline and at 3, 6, and 12 months. We conducted a responder analysis for the QLQ-C30 and PNQ and created cumulative distribution function (CDF) plots as a sensitivity analysis. RESULTS: The questionnaire response rates were over 80% from 386 patients, who completed at least one baseline questionnaire. S-1 was significantly superior to taxane with respect to 6 scales (physical functioning [p = 0.03], role functioning [p = 0.04], social functioning [p < 0.01], financial difficulties [p = 0.01], global health status [p = 0.02], and constipation [p < 0.01]) and sensory neuropathy (p = 0.01). The CDF plots partially supported the conclusions and their robustness. CONCLUSION: First-line S-1 therapy has clinical benefits with respect to many aspects of health-related quality of life for metastatic breast cancer patients.

Helvafuranone Produced by the Fungus Aspergillus nidulans BF0142 Isolated from Hot Spring-derived Soil.

The fungus, Aspergillus nidulans BFO 142, was isolated from hot spring-derived soil collected at Hell Valley in Noboribetsu, Hokkaido, Japan. A new furanone compound designated helvafuranone (1) was isolated along with microperfuranone (2), 9-hydroxymicroperfuranone (3), diorcinol (4), emestrin (5), and sterigmatocystin (6), from a culture broth of A. nidulans BF0142. The structure of 1 was elucidated as 5-hydroxy-4-(4-hydroxybenzyl)-3-(4- hydroxybenzyl)furanone based on various NMR experiments and chemical modifications.

Cost-effectiveness of adjuvant FOLFOX therapy for stage III colon cancer in Japan based on the MOSAIC trial.

OBJECTIVE: To evaluate the cost-effectiveness of adjuvant FOLFOX therapy versus 5-fluorouracil/leucovorin (FU/LV) for patients with stage III colorectal cancer. METHODS: We performed the cost-effectiveness of FOLFOX compared with standard FU/LV treatment by the retrospective analysis of patient-level data from the randomized controlled Multicenter International Study of Oxaliplatin, 5-Fluorouracil, and Leucovorin in the Adjuvant Treatment of Colon Cancer (MOSAIC) trial. Predicted mean time spent in each disease state was calculated by our statistical model, which takes into account the cure rate and treats death from causes other than colon cancer as a competing risk. We performed this analysis from the perspective of the health-care payer. Using a time horizon of 30 years, both cost and effectiveness were discounted by 3% per year. RESULTS: Estimated cure rates for colon cancer were 0.715 (FOLFOX) and 0.622 (FU/LV). Estimated medical costs of FOLFOX were JPY 3.1 million (USD 34,000) compared with JPY 1.9 million (USD 22,000) of FU/LV. The mean estimated quality-adjusted life-year was 9.83 with FOLFOX and 9.07 with that of FU/LV. The incremental cost-effectiveness ratio of FOLFOX was JPY 1.5 million (USD 17,000) per quality-adjusted life-year compared with FU/LV, which was supported by sensitivity analysis. Even if we assume that Japanese outcomes were better than those reported by the MOSAIC trial, which would reduce the difference between cure rates for each treatment to 5%, the incremental cost-effectiveness ratio remained below 5.0 million (USD 56,000) per quality-adjusted life-year. CONCLUSIONS: Adjuvant FOLFOX is a cost-effective treatment for stage III colon cancer in Japan compared with FU/LV therapy. Even when parameters were changed to reflect smaller improvements with FOLFOX, the conclusion is the same.

Search method for inhibitors of Staphyloxanthin production by methicillin-resistant Staphylococcus aureus.

Staphyloxanthin, a yellow pigment produced by methicillin-resistant Staphylococcus aureus (MRSA), is a virulent factor escaping from the host immune system. A new screening method for inhibitors of staphyloxanthin production by MRSA was established using paper disks. By this screening method, inhibitors of staphyloxanthin production were selected from the natural product library (ca. 300) and from actinomycete culture broths (ca. 1000). From the natural product library, four known inhibitors of lipid metabolism, cerulenin, dihydrobisvertinol, xanthohumol and zaragozic acid, were found to inhibit staphyloxanthin production; however, typical antibiotics used clinically, including vancomycin, had no effect on staphyloxanthin production. From actinomycete culture broths, two known anthraquinones, 6-deoxy-8-O-methylrabelomycin and tetrangomycin, were found to inhibit staphyloxanthin production by MRSA in the paper disk assay. These results suggested that this screening method is useful and effective to find compounds targeting staphyloxanthin production, leading to a new type of chemotherapeutics against MRSA infection.

Cost-effectiveness analysis of capecitabine compared with bolus 5-fluorouracil/l-leucovorin for the adjuvant treatment of colon cancer in Japan.

OBJECTIVE: A cost-effectiveness analysis of oral capecitabine versus intravenous bolus 5-fluorouracil/l-leucovorin (FU/LV) as adjuvant therapy in patients with stage 3 colon cancer was performed from a Japanese healthcare payer perspective. METHODS: Adjuvant therapy comprised 24 weeks of treatment with either oral capecitabine 1250 mg/m(2) twice daily on days 1-14 of a 21-day cycle or intravenous bolus FU 500 mg/m(2) and LV 250 mg/m(2) weekly for 6 weeks of an 8-week cycle (Roswell Park regimen). The analysis comprised short-term (1 year after initiation of adjuvant therapy) and long-term (up to 15 years) components. The long-term analysis involved a three-state (disease-free, recurrence and death) Markov model. Estimates for transition probabilities, costs and utilities were derived from the X-ACT trial, a Japanese phase II trial, and other published sources. Cost estimates were considered from the perspective of a healthcare payer. Costs were expressed in Japanese Yen (yen), year 2007 values. A discount rate of 3% was applied to costs and outcomes. Cost effectiveness was expressed as a cost per QALY. The effects of uncertainty were explored through one-way and probabilistic sensitivity analyses. RESULTS: In the 1-year analysis, direct costs were yen440,000 ($US4000) less per patient with capecitabine than with FU/LV. In the long-term analysis, differences between treatments in direct medical costs ranged from yen470,000 ($US4300) to yen580,000 ($US5300) depending on the time horizon used. Capecitabine was also projected to increase the number of QALYs compared with FU/LV. The sensitivity analysis suggested that the model outcome was robust. The probabilistic sensitivity analysis estimate of capecitabine being the dominant regimen was 96.6% at a zero willingness to pay. Direct costs remained lower with capecitabine if the price of generic LV was >OR=50% of the branded product. CONCLUSION: This analysis suggests that capecitabine improves health outcomes and lowers direct costs compared with bolus FU/LV (i.e. dominant treatment strategy) when used as adjuvant therapy in patients with stage 3 colon cancer in Japan.

Health utility scores of colorectal cancer based on societal preference in Japan.

PURPOSE: We measured health utility scores of colorectal cancer (CRC) patients from a societal perspective in Japan. METHODS: Twenty-five states of health were described: four metastatic states without severe adverse events (AEs), 16 metastatic states with Grade 3/4 AEs, four adjuvant states, and one terminal state. A total of 1,500 respondents stratified by age and gender were recruited randomly from the largest Web-panel in Japan. Respondents were allocated randomly to three of the 25 health states and answered questionnaires by standard gamble (SG) and time trade-off (TTO) methods. RESULTS: Although utility scores of metastatic CRC receiving XELOX (capecitabine plus oxaliplatin) chemotherapy were 0.48(SG and TTO) (with stoma) and 0.57(SG) or 0.59(TTO) (without stoma), utility scores of those receiving FOLFOX4 (5-fluorouracil/folinic acid and oxaliplatin) chemotherapy were 0.42(SG) or 0.43(TTO) (with stoma) and 0.52(SG) or 0.53(TTO) (without stoma). These differences between XELOX and FOLFOX4 were statistically significant (P = 0.0198 in SG and P = 0.0059 in TTO). Stage 3/4 AEs decreased utility scores to 0.35-0.4 and 0.4-0.45 in the presence and absence of stoma, respectively. CONCLUSIONS: XELOX was generally considered a significantly preferable chemotherapy regimen compared to FOLFOX4 for CRC in Japan. Almost all Grade 3/4 AEs and stoma significantly decreased utility scores. These differences are dependent on the accuracy of the health state description and to confirm these results. In future research, it would be preferable that preference-based HRQoL measures are used directly in patients if utility scores are practically measurable by such method.