Published papers

The prognostic and predictive value of KRAS gene mutations in stage III colorectal cancer is controversial because many recent clinical trials have not involved a surgery-alone arm. Additionally, data on the significance of extended RAS (KRAS/NRAS) mutations in stage III cancer are not available. Hence, we undertook a combined analysis of two phase III randomized trials, in which the usefulness of adjuvant chemotherapy with tegafur-uracil (UFT) was evaluated, as compared with surgery alone. We determined the association of extended RAS and mismatch repair (MMR) status with the effectiveness of adjuvant chemotherapy. Mutations in KRAS exons 2, 3, and 4 and NRAS exons 2 and 3 were detected by direct DNA sequencing. Tumor MMR status was determined by immunohistochemistry. Total RAS mutations were detected in 134/304 (44%) patients. In patients with RAS mutations, a significant benefit was associated with adjuvant UFT in relapse-free survival (RFS) (hazard ratio = 0.49; P = 0.02) and overall survival (hazard ratio = 0.51; P = 0.03). In contrast, among patients without RAS mutations, there was no difference in RFS or overall survival between the adjuvant UFT group and surgery-alone group. We detected deficient DNA MMR in 23/304 (8%) patients. The MMR status was neither prognostic nor predictive for adjuvant chemotherapy. An interaction analysis showed that there was better RFS among patients treated with UFT with RAS mutations, but not for those without RAS mutations. Extended RAS (KRAS/NRAS) mutations are proposed as predictive indicators with respect to the efficacy of adjuvant UFT chemotherapy in patients with resected stage III colorectal cancer.

It remains unclear whether the immunologic status of cells in peripheral blood can be used as a prognostic indicator of response to treatment for patients with unresectable metastatic colorectal cancer (MCRC). We therefore investigated the relationship between the pretreatment immunologic status of 40 patients with MCRC who planned to receive the first-line chemotherapy and their progression-free survival. Twenty-five immune cell subsets, including monocytic myeloid-derived suppressor cells (M-MDSC) and effector memory T cells (TEM), were measured by multicolor-flow cytometry.Wedivided patients into high and low (above and below the median, respectively) groups based on the median value for each immune cell subset and compared progression-free survival of the two groups. Patients with high M-MDSC, low CD4 TEM, or low CD8 TEM quantities had significantly shorter progression-free survival (P = 0.004, 0.005, and 0.002, respectively). Patients were classified into two prognostic groups based on numbers of adverse factors; having two or three adverse factors (n =21, 52.5%) was correlated with significantly shorter progression-free survival compared with none or one (n = 19, 47.5%; P < 0.001). The presence of two or three adverse factors was an independent poor prognostic factor for progression-free survival (HR, 9.2; 95% confidence interval, 2.5-34.2; P < 0.001). These results provide evidence that pretreatment peripheral immune status can inform the outcome of patients with MCRC treated with first-line chemotherapy.

The purpose of this retrospective cohort study was to analyze the association between income level and health care access in Japan. Data from a total of 222,259 subjects (age range, 0-74 years) who submitted National Health Insurance claims in Chiba City from April 2012 to March 2014 and who declared income for the tax period from January 1 to December 31,2012 were integrated and analyzed. The generalized estimating equation, in which household was defined as a cluster, was used to evaluate the association between equivalent income and utilization and duration of hospitalization and outpatient care services. A significant positive linear association was observed between income level and outpatient visit rates among all age groups of both sexes; however, a significantly higher rate and longer period of hospitalization, and longer outpatient care, were observed among certain lower income subgroups. To control for decreased income due to hospitalization, subjects hospitalized during the previous year were excluded, and the data was then reanalyzed. Significant inverse associations remained in the hospitalization rate among 40-59-year-old men and 60-69-year-old women, and in duration of hospitalization among 40-59 and 60-69-year-olds of both sexes and 70-74-year-old women. These results suggest that low-income individuals in Japan have poorer access to outpatient care and more serious health conditions than their higher income counterparts.

Introduction: Nicorandil has vasodilatory effects on both the epicardial coronary arteries and the coronary microvasculature, thereby increasing coronary blood flow. Intravenous administration of nicorandil can be applicable for fractional flow reserve (FFR) measurement as a hyperaemic agent and a possible alternative to adenosine. However, the effectiveness of intravenous nicorandil infusion for FFR measurement is largely unclear. Methods and analysis: This crossover randomised study is being performed to investigate the efficacy of intravenous administration of nicorandil for FFR measurement. Patients with an intermediate coronary artery stenosis who satisfy the eligibility criteria undergo FFR measurement with a consecutive randomised order of patient-blind infusions of continuous intravenous administration of adenosine and a single bolus intravenous administration of nicorandil. The primary end point of the study is the agreement between the FFR values obtained by the intravenous nicorandil and those obtained by the intravenous adenosine. Recruitment of this trial started in November 2015 and will end in March 2017, or until a total of 50 participants have been recruited. Ethics and dissemination: The protocol was approved by the Institutional Review Board at Chiba University Hospital. Study findings will be published in peer-reviewed journals.

Background/Aim: Panitumumab and cetuximab are known to be effective treatments for KRAS wild-type metastatic colorectal cancer (mCRC). However, it remains unclear which of these two biologic agents confers the greatest benefit when combined with irinotecan in patients with KRAS wild-type mCRC previously treated with fluoropyrimidine, oxaliplatin and irinotecan. Patients and Methods: Data, from 139 patients who received panitumumab or cetuximab, in combination with irinotecan, for KRAS wild-type mCRC previously treated with fluoropyrimidine, oxaliplatin and irinotecan were analyzed. The efficacy and safety of panitumumab plus irinotecan was compared to that of cetuximab plus irinotecan. Results: Baseline characteristics of the panitumumab plus irinotecan (n=42) and cetuximab plus irinotecan (n=97) groups were similar. Among patients with measurable lesions, the response rate was 34% in the panitumumab plus irinotecan group and 20% in the cetuximab plus irinotecan group. Median progression-free survival (PFS) was 4.3 and 5.7 months in the panitumumab and cetuximab groups, respectively. Median overall survival was 13.6 months with panitumumab and 11.2 months with cetuximab. Conclusion: Panitumumab plus irinotecan was well-tolerated and displayed a similar level of efficacy to that of cetuximab plus irinotecan.

Background: In this study, differences in older patients between drug use as reported in clinical practice and in clinical trials for regulatory approval were examined. Methods: Electronic medical record (EMR) data such as patient background (age, sex), concomitant drugs, data on laboratory tests, and prescribed doses of drugs from outpatients with rheumatoid arthritis, diabetes, high blood pressure, or depression at Chiba University Hospital were obtained for the period from January 2003 to December 2012. These data were compared with data from relevant clinical trials for regulatory approval in order to examine differences in drug use. Results: There were 5134 eligible patients. The prescribed doses of drugs were lower than the standard approved doses for depression and rheumatoid arthritis but were generally within the approved dose range for type 2 diabetes mellitus and hypertension. When comparing the characteristics of older patients taking tacrolimus, 5.6% to 17.0% of those would not be able to participate in clinical trials because of liver or renal abnormality, and the incidence rates of some adverse drug events (ADEs) differed significantly between clinical practice and clinical trials. Conclusions: Appropriate doses of drugs for older patients may differ from approved doses in certain diseases. Complex situations such as a lot of polypharmacy, comorbidity, and functional impairment in older patients in clinical practice make it difficult to evaluate safety based on data from clinical trials. In the future, utilization of a database created from the EMR of older patients should be considered for assessment of drug safety in older patients in clinical practice.

Background: The prognostic significance of peripheral immune status in patients with advanced gastric cancer (AGC) remains unclear. Results: From July 2013 through December 2014, 37 patients were enrolled. Among patients with 25 subsets of immune cells, patients in the high group of granulocytic myeloid-derived suppressor cells (Gr-MDSCs) showed significantly shorter progression-free survival (PFS) than those in the low group (3.98 vs. 8.78 months; hazards ratio (HR), 2.61; p = 0.01). In multivariate analysis, the high Gr-MDSCs value was also associated with shorter PFS (HR, 4.60; 95% confidence interval (CI), 1.79-11.8; p = 0.001). Although significant difference was not found in univariate analysis, the high Gr-MDSCs group was associated with shorter overall survival (OS) (HR, 2.89; 95% CI, 1.23-6.80; p = 0.015) in multivariate analysis. Materials and Methods: In this explorative prospective study, peripheral blood samples were collected from AGC patients before initiating first-line cisplatin-based chemotherapy (S-1 + cisplatin or S-1 + cisplatin + docetaxel). Peripheral blood mononuclear cells were analyzed for 25 immune subsets by multicolor flow cytometry. PFS and OS were compared between the patients divided into high and low (≥ and < median, respectively) groups based on the median value for each immune cell subset. Conclusions: The peripheral immune status of Gr-MDSCs appears to affect the prognosis in AGC. Further research is needed to confirm the clinical value of the level of circulating Gr-MDSCs as a prognostic and/or predictive marker in AGC.

Purpose: To determine the time-dependent change in strain ratios (SRs) at the healing site of an Achilles tendon rupture in a rabbit model of tendon transection and to assess the correlation between SRs and the mechanical and histologic properties of the healing tissue. Materials and Methods: Experimental methods were approved by the institutional animal care and use committee. The Achilles tendons of 24 New Zealand white rabbits (48 limbs) were surgically transected. The SRs of Achilles tendons were calculated by using compression-based quantitative ultrasonographic elastography measurements obtained 2, 4, 8, and 12 weeks after transection. After in vivo elastography, the left Achilles tendon was harvested for mechanical testing of ultimate load, ultimate stress, elastic modulus, and linear stiffness, and the right tendons were harvested for tissue histologic analysis with the Bonar scale. Timedependent changes in SRs, mechanical parameters, and Bonar scale scores were evaluated by using repeated-measures analysis of variance. The correlation between SRs and each measured variable was evaluated by using the Spearman rank correlation coefficient. Results: Mean SRs and Bonar scale values decreased as a function of time after transection, whereas mechanical parameters increased (P<.001). SR correlated with ultimate stress (r = 0.68, P ,.001,) elastic modulus (r = 0.74, P ,.001), and the Bonar scale (r = 0.87, P ,.001). Conclusion: Quantitative elastography could be a useful method with which to evaluate mechanical and histologic properties of the healing tendon.

Background: Because standard chemotherapy for advanced gastric cancer consists of oral fluoropyrimidines plus platinum as first-line therapy, with paclitaxel plus ramucirumab as the second line, irinotecan is usually positioned as third-line chemotherapy in clinical practice in Japan. Methods: A retrospective evaluation was conducted to determine the efficacy and safety of irinotecan as third-line chemotherapy for advanced gastric cancer in patients refractory or intolerant to fluoropyrimidines, platinum, and taxanes. Results: Between February 2008 and December 2013, 52 patients received third-line irinotecan monotherapy. Among the 32 patients with measurable lesions, 1 patient achieved a confirmed partial response and 6 patients had stable disease. The overall response rate was 3% and the disease control rate was 22%. Median progression-free survival was 2.3 months [95% confidence interval (CI), 1.8–2.8] and median overall survival was 4.0 months (95% CI, 2.6–5.3). The most common adverse events of grade 3 severity or higher were neutropenia (27%), febrile neutropenia (12%), anorexia (12%), and diarrhea (6%). Although no treatment-related deaths occurred, 2 patients (4%) died of disease progression within 30 days after the last administration of irinotecan. Conclusion: Irinotecan monotherapy appears to be tolerated but was shown to have modest activity as third-line chemotherapy for advanced gastric cancer.

This study aims to compare the US Institute of Medicine (IOM) and Japanese guidelines proposed by the Ministry and the Japan Society for the Study of Obesity on gestational weight gain (GWG), and to explore the optimal GWG range in Japanese women. We investigated 8,152 Japanese women who had full-term singleton babies between 2010 and 2013 at a single center in Tokyo. Logistic regression models showed that GWG below the recommendation of the IOM and Japanese guidelines was similarly associated with an increased risk of light-for-date (LFD), whereas GWG above these guidelines was similarly associated with an increased risk of heavy-for-date (HFD) in pre-pregnancy body mass index categories of underweight (<18.5 kg/m , n = 1559), normal-weight (18.5-24.9 kg/m , n = 4998), overweight (25.0-29.9 kg/m , n = 270), and obese (30 ≤ kg/m , n = 60). The receiver-operating characteristic curve demonstrated that the optimal cutoffs for LFD and HFD were 9.7 and 10.4 kg, respectively in normal-weight mothers. The IOM and Japanese guidelines identified the risk of LFD or HFD equally well. The optimal GWG range in normal-weight women observed in this study was more close to Japanese guideline (i.e., 7-12 kg) compared to the IOM guideline (i.e., 11.5-16 kg). 2 2 2 2

Background: This study aimed to evaluate whether income-related inequalities in access to dental care services exist in Japan. Methods: The subjects included beneficiaries of the National Health Insurance (NHI) in Chiba City, Japan, who had been enrolled from 1 April 2014 to 31 March 2015. The presence or absence of dental visits and number of days spent on dental care services during the year were calculated using insurance claims submitted. Equivalent household income was calculated using individual income data from 1 January to 31 December 2013, declared for taxation. Results: Of the 216,211 enrolled subjects, 50.3% had dental care during the year. Among those with dental visits, the average number of days (standard deviation) spent on dental care services per year was 7.7 (7.1). Low income was associated with a decreased rate of dental care utilization regardless of age and sex. However, there was a significant inverse linear association between the number of days spent on dental care services and income levels for both sexes. Conclusions: There were income-related inequalities in access to dental care services, regardless of the age group or sex, within the Japanese universal health insurance system.

Although both geographic accessibility and socioeconomic status have been indicated as being important factors for the utilization of health care services, their combined effect has not been evaluated. The aim of this study was to reveal whether an income-dependent difference in the impact of geographic accessibility on the utilization of government-led annual health check-ups exists. Existing data collected and provided by Chiba City Hall were employed and analyzed as a retrospective cohort study. The subjects were 166,966 beneficiaries of National Health Insurance in Chiba City, Japan, aged 40 to 74 years. Of all subjects, 54,748 (32.8%) had an annual health check-up in fiscal year 2012. As an optimal index of geographic accessibility has not been established, five measures were calculated: travel time to the nearest health care facility, density of health care facilities (number facilities within a 30-min walking distance from the district of residence), and three indices based on the two-step floating catchment area method. Three-level logistic regression modeling with random intercepts for household and district of residence was performed. Of the five measures, density of health care facilities was the most compatible according to Akaike's information criterion. Both low density and low income were associated with decreased utilization of the health check-ups. Furthermore, a linear relationship was observed between the density of facilities and utilization of the health check-ups in all income groups and its slope was significantly steeper among subjects with an equivalent income of 0.00 yen than among those with equivalent income of 1.01-2.00 million yen (p = 0.028) or 2.01 million yen or more (p = 0.040). This result indicated that subjects with lower incomes were more susceptible to the effects of geographic accessibility than were those with higher incomes. Thus, better geographic accessibility could increase the health check-up utilization and also decrease the income-related disparity of utilization.

Purpose: First-line chemotherapy (Cx-1) in advanced gastric cancer (AGC) provides survival benefit. However, it is unclear who should proceed to second-line chemotherapy (Cx-2). Methods: We reviewed patients who received Cx-2 for AGC following progressive disease after Cx-1 from 2000 to 2005 at the National Cancer Center Hospital, Tokyo. To evaluate the prognostic factors in Cx-2, Cox regression multivariate analysis was performed. Results: Of 995 patients who received Cx-1 in this study period, 466 met the eligibility criteria. The median progression-free survival in Cx-1 (PFS-1) was 133 days. The median survival time from the date of starting second-line chemotherapy (MST-2) was 207 days. Multivariate analysis revealed that the factors affecting short survival time in Cx-2 were poor performance status (>2), low serum albumin level (<3.5 mg/dL), elevated C-reactive protein level (>1.0 mg/dL), patients with bone, liver or peritoneal metastasis, and patients without previous gastrectomy (p < 0.01). PFS-1 was an independent prognostic factor for survival (PFS-1 <120, MST-2 133 days, PFS-1 >120, MST-2 258 days, hazard ratio 0.71, 95% confidence interval 0.58-0.86, p < 0.01). The Cx-2 regimen (irinotecan vs. taxane) did not correlate with survival. Conclusion: PFS-1 is one of the prognostic factors of Cx-2 in patients with AGC. © 2010 Springer-Verlag.

Purpose: Taxane monotherapy is widely used for advanced gastric cancer (AGC) after failure of standard first-line chemotherapy with fluoropyrimidine and cisplatin. Triplet chemotherapy with docetaxel, cisplatin, and S-1 (DCS) is a promising regimen for first-line chemotherapy of AGC. The aim of this study was to evaluate the efficacy of taxane monotherapy in patients refractory to DCS. Methods: We retrospectively evaluated the efficacy and safety of taxane monotherapy in patients with AGC refractory to first-line therapy with DCS between January 2010 and April 2015. Selection criteria were as follows: ECOG PS of 0–2, treatment with taxane monotherapy in second-line or third-line therapy after failure of second-line irinotecan, absence of massive ascites, and adequate organ function. Results: A total of 30 patients were included in this study. Of these, 15 patients received paclitaxel while another 15 received nanoparticle albumin-bound paclitaxel in either second- or third-line treatment. Median age for the second/third-line group was 64.0/62.0 (range 27–75/42–75); 14/13 (93.3/86.7%) had ECOG PS of 0 or 1. No patients achieved complete or partial response and stable disease was observed in 37.5/35.7% of the patients in the second/third line. Median progression-free survival and overall survival were 3.4 and 5.8 months in the second-line group, and 2.0 and 4.5 months in the third-line group, respectively. The incidences of any grade ≥3 adverse events in the second-line group and the third-line group were 60.0 and 33.3%, respectively. There was no treatment-related death. Conclusions: Taxane monotherapy after DCS failure had acceptable toxicities but was ineffective in AGC patients.

Background: In the seventh edition of the Union for International Cancer Control (UICC) TNM classification, supraclavicular lymph node (SCLN) in regard to thoracic esophageal cancer (EC) is regarded as a distant organ, therefore, if resectable, SCLN metastasis is considered a candidate for systemic chemotherapy. The purpose of this study was to clarify the survival outcome in patients with resectable thoracic EC with SCLN metastases (M1LYM) treated with curative intent. Patients and Methods: Clinical outcomes in patients with resectable thoracic EC with SCLN metastases (M1LYM) treated by esophagectomy or definitive chemoradiotherapy (dCRT) were retrospectively analyzed. Results: A total of 102 patients were divided in three groups: Surgery with perioperative therapy, n=45; surgery alone, n=19; and dCRT, n=38. Overall, median progression-free survival and median survival time were 9.3 and 26.7 months, respectively. The median survival time was 27.5 months in the group treated with surgery with perioperative treatment, 50.6 months in those treated with surgery alone, and 22 months in the dCRT group. No significant survival difference was seen among the three groupS. Conclusion: Over 30% of patients with resectable M1LYM treated with curative intent achieved long-term survival.

Study Objectives: Although moderate to severe obstructive sleep apnea (OSA) is an independent risk factor for severe arteriosclerotic diseases such as cardiovascular disease (CVD) and stroke, the development of atherosclerosis-related diseases cannot yet be predicted in patients with OSA. In a pilot study, we identified autoantibodies against the coatomer protein complex, subunit epsilon [circulating anti-coatomer protein complex subunit epsilon autoantibody (COPE-Ab)], a cytosolic complex that mediates protein transport in the Golgi compartment, as a potential novel biomarker of atherosclerosis. This study aimed to evaluate whether COPE-Ab levels had an association with cardiovascular and cerebrovascular events in patients with OSA. Methods: Eighty-two adult patients with a diagnosis of OSA via polysomnography and 64 healthy donors were studied. Serum COPE-Ab levels were measured using an amplified luminescence proximity homogeneous assay. Then, clinical factors related to atherosclerosis were evaluated with respect to COPE-Ab levels. Results: Significant differences in COPE-Ab levels were observed in terms of OSA severity. COPE-Ab levels were significantly higher in patients with OSA and also CVD and/or stroke, hypertension, and a high body mass index. Univariate and multivariate logistic regression analyses of patients with OSA identified elevated COPE-Ab level as a significant predictor of CVD and/or stroke. Conclusions: An elevated COPE-Ab level may be a potential predictor of the risks of cardiovascular and cerebrovascular events in patients with OSA. Therefore, patients with higher COPE-Ab levels may require more careful and intensive treatment. Commentary: A commentary on this article appears in this issue on page 361.

Aim: Although several clinical trials demonstrated the benefits of platinum-combination adjuvant chemotherapy for stage II-IIIA lung adenocarcinoma, predictive biomarkers for the efficacy of such therapy have not yet been identified. We evaluated protein overexpression of actinin-4 as a predictive biomarker of the efficacy of adjuvant chemotherapy in resected lung adenocarcinoma. Materials & methods: We measured actinin-4 protein levels in patients with completely resected stage II-IIIA lung adenocarcinoma using immunohistochemistry and then retrospectively compared survival between adjuvant chemotherapy and observation groups. Results: A total of 148 eligible patients were classified into actinin-4 positive or negative cases by immunohistochemistry. In the former, patients with adjuvant chemotherapy survived significantly longer than those with observation (hazard ratio [HR]: 0.307; p = 0.028). But, no significant survival benefit was noted with adjuvant chemotherapy (HR: 0.926; p = 0.876) in the latter. Conclusion: This marker could predict the efficacy of adjuvant chemotherapy for resected lung adenocarcinoma patients.

Introduction In Japan, dipeptidyl peptidase-4 (DPP-4) inhibitors are frequently used as the treatment of choice for patients with type 2 diabetes. In some cases, however, poor glycaemic and body weight control issues persist despite treatment with DPP-4 inhibitors. Previous researchers have revealed that sodium-dependent glucose transporter-2 (SGLT-2) inhibitors reduce both plasma glucose levels and body weight in patients with type 2 diabetes. However, further investigation regarding the effects of SGLT-2 inhibitors on body composition, especially in the Asian population who tends to have relatively low-to-moderate body mass indices, is required. Therefore, we aim to determine the effects of treatment with SGLT-2 inhibitors or metformin for reducing visceral fat in 106 Asian patients with type 2 diabetes who were undergoing treatment with the DPP-4 inhibitor sitagliptin (50 mg daily) for poor glycaemic control. Methods and analysis A prospective, multicentre, blinded-endpoint phase IV randomised controlled study will be conducted to evaluate the safety and efficacy of a 24-week treatment with either an SGLT-2 inhibitor (ipragliflozin) or metformin for reducing visceral fat and plasma glucose levels in patients with type 2 diabetes. Patients who satisfy the eligibility criteria will be randomised (1:1) to receive ipragliflozin (50 mg daily) or metformin (1000 mg daily). The primary outcome is the rate of change in the total area of visceral fat for patients in both treatment groups, measured using CT, after 24 weeks of therapy. Two radiologists, blinded to the clinical information, will perform centralised analysis of the images in a unified measurement condition. Ethics and dissemination The protocol was approved by the institutional review board of each hospital. This study is ongoing and due to finish in April 2017. The findings of this study will be disseminated via peer-reviewed publications and conference presentations, and will also be disseminated to participants.

c-MET is implicated in the pathogenesis and growth of a wide variety of human malignancies, including colorectal cancer (CRC). The aim of the present study was to clarify the association between c-MET expression and tumor recurrence in CRC patients after curative liver resection, and to evaluate concordance in c-MET expression and various mutations of KRAS, BRAF and PIK3CA between primary CRC and paired liver metastases. A cohort of patients was tested for c-MET immunoreactivity (i.e. immunohistochemistry [IHC]) and KRAS, BRAF and PIK3CA mutations. Analyses were performed both on primary tumors and paired liver metastases, and the association between IHC and mutations results were assessed. A total of 108 patients were eligible. A total of 53% of patients underwent simultaneous resection of primary tumors and metastases, and the others underwent metachronous resection. Levels of concordance between primary tumors and metastases were 65.7%, 87.7%, 100% and 95.2% for c-MET, KRAS, BRAF and PIK3CA, respectively. High levels of c-MET expression (c-MET-high) in the primary tumors were observed in 52% of patients. Relapse-free survival was significantly shorter for patients with c-MET-high primary tumors (9.7 months) than for those with c-MET-low primary tumors (21.1 months) (P = 0.013). These results suggest that a high level of genetic concordance in KRAS, BRAF and PIK3CA between primary tumors and liver metastases, and c-MET-high in the primary tumors were associated with shorter relapse-free survival after hepatic metastasectomy. A high expression of c-MET in primary tumors was associated with worse RFS for patients who had undergone curative hepatectomy. © 2014 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association.