Active vitamin D treatment in the prevention of sarcopenia in adults with prediabetes (DPVD ancillary study): a randomised controlled trial.

BACKGROUND: Observational studies show inverse associations between serum 25-hydroxyvitamin D concentrations and sarcopenia incidence; however, it remains unclear whether treatment with vitamin D prevents its development. We aimed to assess whether treatment with active vitamin D (eldecalcitol [0·75 µg per day]) can reduce the development of sarcopenia among adults with prediabetes. METHODS: This randomised, double-blind, placebo-controlled, multicenter trial as an ancillary study was conducted at 32 clinics and hospital sites in Japan. Participants were assigned (1:1) by using a central randomisation method in which a randomisation list was made for each hospital separately using a stratified permuted block procedure. The primary endpoint was sarcopenia incidence during 3 years in the intention-to-treat population defined as weak handgrip strength (<28 kg for men and <18 kg for women) and low appendicular skeletal muscle index (<7·0 kg/m2 for men and <5·7 kg/m2 for women in bioelectrical impedance analysis). Although the usual criterion of hypercalcaemia was 10·4 mg/dL (2·6 mmol/L) or higher, hypercalcaemia that was enough to discontinue the study was defined as 11·0 mg/dL or higher. This study is registered with the UMIN clinical trials registry, UMIN000005394. FINDINGS: A total of 1094 participants (548 in the eldecalcitol group and 546 in the placebo group; 44·2% [484 of 1094] women; mean age 60·8 [SD 9·2] years) were followed up for a median of 2·9 (IQR 2·8-3·0) years. Eldecalcitol treatment as compared with placebo showed statistically significant preventive effect on sarcopenia incidence (25 [4·6%] of 548 participants in the eldecalcitol group and 48 [8·8%] of 546 participants in the placebo group; hazard ratio 0·51; 95% CI 0·31 to 0·83; p=0·0065). The incidence of adverse events did not differ between the two groups. INTERPRETATION: We found that treatment with eldecalcitol has the potential to prevent the onset of sarcopenia among people with prediabetes via increasing skeletal muscle volume and strength, which might lead to a substantial risk reduction of falls. FUNDING: Kitakyushu Medical Association. TRANSLATION: For the Japanese translation of the abstract see Supplementary Materials section.

Effect of active vitamin D treatment on development of type 2 diabetes: DPVD randomised controlled trial in Japanese population.

OBJECTIVE: To assess whether eldecalcitol, an active vitamin D analogue2, can reduce the development of type 2 diabetes among adults with impaired glucose tolerance. DESIGN: Double blinded, multicentre, randomised, placebo controlled trial. SETTING: Three hospitals in Japan, between June 2013 and August 2019. PARTICIPANTS: People aged 30 years and older who had impaired glucose tolerance defined by using a 75 g oral glucose tolerance test and glycated haemoglobin level. INTERVENTIONS: Participants were randomised to receive active vitamin D (eldecalcitol 0.75 µg per day; n=630) or matching placebo (n=626) for three years. MAIN OUTCOMES: The primary endpoint was incidence of diabetes. Prespecified secondary endpoints were regression to normoglycaemia and incidence of type 2 diabetes after adjustment for confounding factors at baseline. In addition, bone densities and bone and glucose metabolism markers were assessed. RESULTS: Of the 1256 participants, 571 (45.5%) were women and 742 (59.1%) had a family history of type 2 diabetes. The mean age of participants was 61.3 years. The mean serum 25-hydroxyvitamin D concentration at baseline was 20.9 ng/mL (52.2 nmol/L); 548 (43.6%) participants had concentrations below 20 ng/mL (50 nmol/L). During a median follow-up of 2.9 years, 79 (12.5%) of 630 participants in the eldecalcitol group and 89 (14.2%) of 626 in the placebo group developed type 2 diabetes (hazard ratio 0.87, 95% confidence interval 0.67 to 1.17; P=0.39). Regression to normoglycaemia was achieved in 145 (23.0%) of 630 participants in the eldecalcitol group and 126 (20.1%) of 626 in the placebo group (hazard ratio 1.15, 0.93 to 1.41; P=0.21). After adjustment for confounding factors by multivariable fractional polynomial Cox regression analysis, eldecalcitol significantly lowered the development of diabetes (hazard ratio 0.69, 0.51 to 0.95; P=0.020). In addition, eldecalcitol showed its beneficial effect among the participants with the lower level of basal insulin secretion (hazard ratio 0.41, 0.23 to 0.71; P=0.001). During follow-up, bone mineral densities of the lumbar spine and femoral neck and serum osteocalcin concentrations significantly increased with eldecalcitol compared with placebo (all P<0.001). No significant difference in serious adverse events was observed. CONCLUSIONS: Although treatment with eldecalcitol did not significantly reduce the incidence of diabetes among people with pre-diabetes, the results suggested the potential for a beneficial effect of eldecalcitol on people with insufficient insulin secretion. TRIAL REGISTRATION: UMIN Clinical Trials Registry UMIN000010758.

Component with abundant immune-related cells in combined hepatocellular cholangiocarcinoma identified by cluster analysis.

Combined hepatocellular cholangiocarcinoma (cHCC-CCA) is a heterogeneous tumor sharing histological features with hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA). The tumor immune microenvironment (TIME) of cHCC-CCA is unclear. We compared the TIME of cHCC-CCA with that of HCC and iCCA. Twenty-three patients with cHCC-CCA after hepatectomy were evaluated in this study. Twenty-three patients with iCCA and HCC were also included. iCCA was matched for size, and HCC was matched for size and hepatitis virus infection with cHCC-CCA. Immune-related cells among the iCCA-component of cHCC-CCA (C-com), HCC-component of cHCC-CCA (H-com), iCCA, and HCC were assessed using multiplex fluorescence immunohistochemistry. Among C-com, H-com, iCCA, and HCC, multiple comparisons and cluster analysis with k-nearest neighbor algorithms were performed using immunological variables. Although HCC had more T lymphocytes and lower PD-L1 expression than iCCA (P < 0.05), there were no significant differences in immunological variables between C-com and H-com. C-com tended to have more T lymphocytes than iCCA (P = 0.09), and C-com and H-com had fewer macrophages than HCC (P < 0.05). In cluster analysis, all samples were classified into two clusters: one cluster had more immune-related cells than the other, and 12 of 23 H-com and eight of 23 C-com were identified in this cluster. The TIME of C-com and H-com may be similar, and some immunological features in these components were different from those in HCC and some iCCA. Cluster analysis identified components with abundant immune-related cells in cHCC-iCCA.

Efficacy of immunotherapy targeting the neoantigen derived from epidermal growth factor receptor T790M/C797S mutation in non-small cell lung cancer.

Lung cancer is the leading cause of cancer-related deaths worldwide. Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKI) often have good clinical activity against non-small cell lung cancer (NSCLC) with activating EGFR mutations. Osimertinib, which is a third-generation EGFR-TKI, has a clinical effect even on NSCLC harboring the threonine to methionine change at codon 790 of EGFR (EGFR T790M) mutation that causes TKI resistance. However, most NSCLC patients develop acquired resistance to osimertinib within approximately 1 year, and 40% of these patients have the EGFR T790M and cysteine to serine change at codon 797 (C797S) mutations. Therefore, there is an urgent need for the development of novel treatment strategies for NSCLC patients with the EGFR T790M/C797S mutation. In this study, we identified the EGFR T790M/C797S mutation-derived peptide (790-799) (MQLMPFGSLL) that binds the human leukocyte antigen (HLA)-A*02:01, and successfully established EGFR T790M/C797S-peptide-specific CTL clones from human PBMC of HLA-A2 healthy donors. One established CTL clone demonstrated adequate cytotoxicity against T2 cells pulsed with the EGFR T790M/C797S peptide. This CTL clone also had high reactivity against cancer cells that expressed an endogenous EGFR T790M/C797S peptide using an interferon-γ (IFN-γ) enzyme-linked immunospot (ELISPOT) assay. In addition, we demonstrated using a mouse model that EGFR T790M/C797S peptide-specific CTL were induced by EGFR T790M/C797S peptide vaccine in vivo. These findings suggest that an immunotherapy targeting a neoantigen derived from EGFR T790M/C797S mutation could be a useful novel therapeutic strategy for NSCLC patients with EGFR-TKI resistance, especially those resistant to osimertinib.

Peptide vaccine as an adjuvant therapy for glypican-3-positive hepatocellular carcinoma induces peptide-specific CTLs and improves long prognosis.

There is no established postoperative adjuvant therapy for hepatocellular carcinoma (HCC), and improvement of patient prognosis has been limited. We conducted long-term monitoring of patients within a phase II trial that targeted a cancer antigen, glypican-3 (GPC3), specifically expressed in HCC. We sought to determine if the GPC3 peptide vaccine was an effective adjuvant therapy by monitoring disease-free survival and overall survival. We also tracked GPC3 immunohistochemical (IHC) staining, CTL induction, and postoperative plasma GPC3 for a patient group that was administered the vaccine (n = 35) and an unvaccinated patient group that underwent surgery only (n = 33). The 1-y recurrence rate after surgery was reduced by approximately 15%, and the 5-y and 8-y survival rates were improved by approximately 10% and 30%, respectively, in the vaccinated group compared with the unvaccinated group. Patients who were positive for GPC3 IHC staining were more likely to have induced CTLs, and 60% survived beyond 5 y. Vaccine efficacy had a positive relationship with plasma concentration of GPC3; high concentrations increased the 5-y survival rate to 75%. We thus expect GPC3 vaccination in patients with HCC, who are positive for GPC3 IHC staining and/or plasma GPC3 to induce CTL and have significantly improved long-term prognosis.

Usefulness of plasma full-length glypican-3 as a predictive marker of hepatocellular carcinoma recurrence after radial surgery.

Predicting the risk of hepatocellular carcinoma (HCC) recurrence before treatment is necessary for developing subsequent treatment policies. Several tumor markers found in blood, such as alpha-fetoprotein (AFP) and protein induced by vitamin K absence or antagonist-II (PIVKA-II), are presently used to determine the occurrence and recurrence of HCC and to predict patient prognosis. However, these markers are insufficient for these purposes as certain patients have HCC recurrence despite exhibiting negative AFP and PIVKA-II. The present study identified glypican-3 (GPC3), an embryonal carcinoma antigen that is expressed specifically in HCC and is secreted into blood. Although the N-terminal domain of GPC3 in sera may be a potential prognostic factor for HCC, its biological role remains unclear. By contrast, full-length GPC3 (FL-GPC3) is reported to serve important roles in cell differentiation, proliferation and signaling events that cause HCC. Given the biological roles of FL-GPC3 in HCC progression, the present study evaluated its potential as a predictive marker of HCC recurrence. In the present study, a novel measurement system was constructed to specifically measure plasma FL-GPC3. Subsequently, its ability to predict recurrence after radical surgery in 39 HCC patients was evaluated. The results revealed that preoperative FL-GPC3 levels in patients with recurrence were significantly higher than those in patients without recurrence, suggesting that FL-GPC3 could be a better predictive maker of risk of recurrence than AFP or PIVKA-II. Furthermore, it was determined that the combination of FL-GPC3, AFP and PIVKA-II could predict recurrence within one year of radical surgery with high sensitivity and specificity. Based on these results, the validation of FL-GPC3 as a predictive marker of HCC recurrence in a larger population is warranted.

Plasma and tumoral glypican-3 levels are correlated in patients with hepatitis C virus-related hepatocellular carcinoma.

Glypican-3 (GPC3) is a cancer antigen expressed in approximately 80% of hepatocellular carcinomas (HCC) and is secreted into the blood. To confirm the effectiveness of GPC3 as a biomarker in HCC, we analyzed the relationship between GPC3 expression levels in cancer cells and in blood in 56 patients with HCC. Preoperative plasma GPC3 levels were determined with an immunoassay, and expression of GPC3 in resected tumors was analyzed by immunohistochemical staining. Median plasma GPC3 level in all HCC cases was 4.6 pg/mL, and tended to be higher in patients with hepatitis C virus (HCV)-related HCC (HCV group) (9.9 pg/mL) than in patients with hepatitis B virus (HBV)-related HCC (HBV group) (2.6 pg/mL) or in those without virus infection (None group) (3.0 pg/mL), suggesting that the virus type most likely influences GPC3 secretion. Median percentage of GPC3+ cells in tumors was also higher in the HCV (26.2%) and HBV (11.1%) groups than in the None group (4.2%). In the HCV group, there was a positive correlation between the two parameters (r = 0.66, P < .01). Moreover, receiver operating characteristic analysis predicted >10% GPC3+ cells in a tumor if the cut-off value was 6.8 pg/mL (sensitivity 80%, specificity 100%; area under the curve 0.875, 95% confidence interval 0.726-1) in the HCV group. Plasma concentration of GPC3 could be a predictive marker of tumoral GPC3 expression in patients with HCV-related HCC, suggesting a useful biomarker for immunotherapies targeting GPC3, although larger-scale validations are needed.

Efficacy of the NCCV Cocktail-1 vaccine for refractory pediatric solid tumors: A phase I clinical trial.

Pediatric refractory solid tumors are aggressive malignant diseases, resulting in an extremely poor prognosis. KOC1, FOXM1, and KIF20A are cancer antigens that could be ideal targets for anticancer immunotherapy against pediatric refractory solid tumors with positive expression for these antigens. This nonrandomized, open-label, phase I clinical trial evaluated the safety and efficacy of the NCCV Cocktail-1 vaccine, which is a cocktail of cancer peptides derived from KOC1, FOXM1, and KIF20A, in patients with pediatric refractory solid tumors. Twelve patients with refractory pediatric solid tumors underwent NCCV Cocktail-1 vaccination weekly by intradermal injections. The primary endpoint was the safety of the NCCV Cocktail-1 vaccination, and the secondary endpoints were the immune response, as measured by interferon-r enzyme-linked immunospot assay, and the clinical outcomes including tumor response and progression-free survival. The NCCV Cocktail-1 vaccine was well tolerated. The clinical response of this trial showed that 4 patients had stable disease after 8 weeks and 2 patients maintained remission for >11 months. In 4, 8, and 5 patients, the NCCV Cocktail-1 vaccine induced the sufficient number of peptide-specific CTLs for KOC1, FOXM1, and KIF20A, respectively. Patients with high peptide-specific CTL frequencies for KOC1, FOXM1, and KIF20A had better progression-free survival than those with low frequencies. The findings of this clinical trial showed that the NCCV Cocktail-1 vaccine could be a novel therapeutic strategy, with adequate effects against pediatric refractory solid tumors. Future large-scale trials should evaluate the efficacy of the NCCV Cocktail-1 vaccination.

Heat shock protein 105 peptide vaccine could induce antitumor immune reactions in a phase I clinical trial.

Heat shock protein 105 (HSP105) is overexpressed in many cancers, including colorectal cancer (CRC) and esophageal cancer (EC). We carried out a phase I clinical trial of HLA-A24- and HLA-A2-restricted HSP105 peptide vaccines in patients with CRC or EC. In this additional study of the trial, we examined the immunological efficacy of the novel vaccine. Thirty patients with advanced CRC or EC underwent HSP105 peptide vaccination. Immunological responses were evaluated by ex vivo and in vitro γ-interferon enzyme-linked immunospot assays and their correlation with patients' prognosis was analyzed. The HSP105 peptide vaccines induced peptide-specific CTLs in 15 of 30 patients. Among HLA-A24 patients (n = 15), 7 showed induction of CTLs only ex vivo, whereas among HLA-A2 patients (n = 15), 4 showed the induction ex vivo and 6 in vitro. Heat shock protein 105-specific CTL induction correlated with suppression of cancer progression and was revealed as a potential predictive biomarker for progression-free survival (P = .008; hazard ratio = 3.03; 95% confidence interval, 1.34-6.85) and overall survival (P = .025; hazard ratio = 2.72; 95% confidence interval, 1.13-6.52). Production of cytokines by HSP105 peptide-specific CTLs was observed at the injection sites (skin) and tumor tissues, suggesting that HSP105-specific CTLs not only accumulated at vaccination sites but also infiltrated tumors. Furthermore, we established 2 HSP105 peptide-specific CTL clones, which showed HSP105-specific cytokine secretion and cytotoxicity. Our results suggest that the HSP105 peptide vaccine could induce immunological effects in cancer patients and improve their prognosis.

Usefulness of serum microRNA as a predictive marker of recurrence and prognosis in biliary tract cancer after radical surgery.

Biliary tract cancer (BTC) is an aggressive type of malignant tumour. Even after radical resection, the risk of recurrence is still high, resulting in a poor prognosis. Here, we investigated the usefulness of serum miRNAs as predictive markers of recurrence and prognosis for patients with BTC after radical surgery using 66 serum samples that were collected at three time points from 22 patients with BTC who underwent radical surgery. Using microarray analysis, we successfully identified six specific miRNAs (miR-1225-3p, miR-1234-3p, miR1260b, miR-1470, miR-6834-3p, and miR-6875-5p) associated with recurrence and prognosis of BTC after radical surgery. In addition, using a combination of these miRNAs, we developed a recurrence predictive index to predict recurrence in patients with BTC after operation with high accuracy. Patients having higher index scores (≥ cut-off) had significantly worse recurrence-free survival (RFS) and overall survival (OS) than those with lower index scores (

Higher human lymphocyte antigen class I expression in early-stage cancer cells leads to high sensitivity for cytotoxic T lymphocytes.

Human lymphocyte antigen (HLA) class I molecules play a central role in cytotoxic T lymphocytes (CTL)-based antitumor immunity. However, the expression rate of HLA class I in cancer cells remains a topic of discussion. We compared HLA class I expression levels between cancer cells and surrounding non-tumorous hepatocytes in 20 early-stage hepatocellular carcinoma (HCC) patients by immunohistochemistry using EMR 8-5. The expression levels of HLA class I were classified as negative, incomplete positive or complete positive. Similarly, for various types of solid cancers, HLA class I expression was examined. For the HLA class I expression in cancer cells, among 20 HCC patients, 13 were complete positive, 3 were incomplete positive, and 4 were negative. In addition, 15 (75.0%) had higher expression levels of HLA class I in cancer cells compared with that in surrounding non-tumorous hepatocytes. An interferon-γ (IFN-γ) enzyme-linked immunospot (ELISPOT) assay indicated that cancer cells with positive expression of HLA class I had strong sensitivity to antigen-specific CTL. We suggested that HLA class I expression in cancer cells could be involved in the clinical prognosis of HCC patients. Similarly, 66.7%, 100.0%, 66.7% and 62.5% of patients with early-stage pancreatic, gallbladder, esophageal and breast cancers, respectively, had higher expression levels of HLA class I in cancer cells than in surrounding normal tissue cells. We suggest that in several early-stage solid cancers, including HCC, HLA class I expression levels in cancer cells are higher than that in surrounding normal tissue cells, which could result in the anti-tumor effect of CTL-based cancer immunotherapy.

Corrigendum: direct adjustment for confounding by smoking reduces radiation-related cancer risk estimates of mortality among male nuclear workers in Japan, 1999-2010.

We found some trivial errors which might confuse reader. The errors can be identified as the following two types. (1) The one is that misuse of "ERR" and "ERR/Sv". We denoted "Table 4 shows ERRs/Sv and 90% CIs ..." in line 7 of page 366. While we denoted "ERR and 90% CI for all cancers, excluding leukaemia, by dose category ..." in title of Table 4. The values described in Table 4 were ERR by dose category and not ERR/Sv. In addition, the explanation about the model that derived ERR by dose category is better to be added. Therefore, the description mentioned above should be changed as follows. (Misprinted) Table 4 shows ERRs/Sv and 90% CIs for all cancers excluding leukaemia by dose category. (Corrected) Table 4 shows ERRs which were defined as follow equation and 90% CIs for all cancers excluding leukaemia by dose category. λ=λ0 (a,c,y,r,s)exp(α1z1+α2z2+α3z3) (1+ßi di) where di is the dose category, and ßi is the ERR by dose category. The lowest dose category was set as reference. (2) The other were errors in surface caput of several tables. We described "ERR without adjustment for smoking" and "ERR with adjustment for smoking" in Table 4. These are correct description. However, "ERR with adjustment for smoking" was described as "For smoking" in Table 2. In addition, "Without adjustment" and "With adjustment" denoted in the surface caput of Table 5, 6, 7 should be denoted as "Without adjustment for smoking" and "With adjustment for smoking". The author wishes to apologies for the errors. .

Direct adjustment for confounding by smoking reduces radiation-related cancer risk estimates of mortality among male nuclear workers in Japan, 1999-2010.

A causal relationship between protracted exposure to low-dose rate radiation and health effects remains unclear despite extensive international studies of nuclear workers. One potential reason is that radiation epidemiological studies that adjust for tobacco smoking, which heavily influences mortality, have been limited. In the present study, we examined radiation-related cancer risk by directly assessing the possible confounding effect of smoking, using data from two questionnaire surveys performed among Japanese nuclear workers in 1997 and 2003. Mortality follow-up was carried out for 71 733 male respondents for an average of 8.2 years during the observation period of 1999-2010. The mean cumulative dose was 25.5 mSv at the end of the follow-up period. Estimates of excess relative risk per Sv (ERRs/Sv) were obtained by Poisson regression. By adjusting for smoking directly on the basis of a linear dose-response model, we quantified the confounding effects of smoking on radiation risks. Statistically significant ERRs/Sv were found for all causes, all diseases, all non-cancer diseases, and liver cancer: 0.97 (90% confidence interval: 0.23, 1.78), 1.32 (0.40, 2.34), 1.87 (0.47, 3.49), and 4.78 (0.09, 11.68), respectively, without adjustment for smoking. However, the ERRs/Sv were no longer statistically significant after adjustment for smoking: 0.45 (-0.22, 1.19), 0.77 (-0.08, 1.72), 1.28 (-0.03, 2.79), and 3.89 (-0.46, 10.34), respectively. The ERRs/Sv for all cancers excluding leukaemia and lung cancer were not significant before adjustment for smoking, but declined after adjustment for smoking. The present study demonstrates that in this cohort of workers, smoking heavily distorts radiation risk estimates of mortality. The possibility of confounding by smoking depends on how strongly smoking is correlated with radiation exposure. If a correlation between smoking and radiation dose is suggested, smoking is an important confounder when assessing the radiation and health risks.

Immunological efficacy of glypican-3 peptide vaccine in patients with advanced hepatocellular carcinoma.

We have previously conducted a phase I trial to test the efficacy of a glypican-3 (GPC3) peptide vaccine in patients with advanced hepatocellular carcinoma (HCC); however, its immunological mechanism of action remains unclear. Here, we report a pilot study conducted to evaluate the immunological mechanisms of action of this GPC3 peptide vaccine (UMIN-CTR number 000005093). Eleven patients with advanced HCC were vaccinated with the GPC3 peptide in this trial. The primary end point was GPC3 peptide-specific immune response induced by the GPC3 peptide vaccination. The secondary endpoints were clinical and biologic outcomes. We demonstrated that the present vaccine induced GPC3 peptide-specific cytotoxic T lymphocytes (CTLs), which were found to infiltrate into the tumor. Moreover, we established GPC3 peptide-specific CTL clones from a biopsy specimen: these cells exhibited GPC3 peptide-specific cytokine secretion and cell cytotoxicity. The plasma GPC3 level tended to decrease temporarily at least once during the follow-up period. The GPC3-specific CTL frequency after vaccination was correlated with overall survival. The degree of skin reactions at the injection site correlated with the GPC3 peptide-specific CTLs. Furthermore, we sequenced the T cell receptors (TCRs) of tumor-infiltrating lymphocyte (TIL) clones, and confirmed the existence of this TCR repertoire in both tumor tissue and PBMCs. In response to these data, we are developing TCR-engineered T cell therapy using TCR sequences obtained from GPC3 peptide-specific CTL clones for improved efficacy in patients with advanced HCC.

Phase I study of glypican-3-derived peptide vaccine therapy for patients with refractory pediatric solid tumors.

The carcinoembryonic antigen glypican-3 (GPC3) is a good target of anticancer immunotherapy against pediatric solid tumors expressing GPC3. In this non-randomized, open-label, phase I clinical trial, we analyzed the safety and efficacy of GPC3-peptide vaccination in patients with pediatric solid tumors. Eighteen patients with pediatric solid tumors expressing GPC3 underwent GPC3-peptide vaccination (intradermal injections every 2 weeks), with the primary endpoint being the safety of GPC3-peptide vaccination and the secondary endpoints being immune response, as measured by interferon (IFN)-γ enzyme-linked immunospot assay and Dextramer staining, and the clinical outcomes of tumor response, progression free survival (PFS), and overall survival (OS). Our findings indicated that GPC3 vaccination was well tolerated. We observed disease-control rates [complete response (CR)+partial response+stable disease] of 66.7% after 2 months, and although patients in the progression group unable to induce GPC3-peptide-specific cytotoxic T lymphocytes (CTLs) received poor prognoses, patients in the partial-remission and remission groups or those with hepatoblastoma received good prognoses. The GPC3-peptide vaccine induced a GPC3-specific CTL response in seven patients, with PFS and OS significantly longer in patients with high GPC3-specific CTL frequencies than in those with low frequencies. Furthermore, we established GPC3-peptide-specific CTL clones from a resected-recurrent tumor from one patient, with these cells exhibiting GPC3-peptide-specific cytokine secretion. The results of this trial demonstrated that the GPC3-peptide-specific CTLs induced by the GPC3-peptide vaccine infiltrated tumor tissue, and use of the GPC3-peptide vaccine might prevent the recurrence of pediatric solid tumors, especially hepatoblastomas, after a second CR.

Rationale and design of Diabetes Prevention with active Vitamin D (DPVD): a randomised, double-blind, placebo-controlled study.

INTRODUCTION: Recent research suggests that vitamin D deficiency may cause both bone diseases and a range of non-skeletal diseases. However, most of these data come from observational studies, and clinical trial data on the effects of vitamin D supplementation on individuals with pre-diabetes are scarce and inconsistent. The aim of the Diabetes Prevention with active Vitamin D (DPVD) study is to assess the effect of eldecalcitol, active vitamin D analogue, on the incidence of type 2 diabetes among individuals with pre-diabetes. METHODS AND ANALYSIS: DPVD is an ongoing, prospective, multicentre, randomised, double-blind and placebo-controlled outcome study in individuals with impaired glucose tolerance. Participants, men and women aged ≥30 years, will be randomised to receive eldecalcitol or placebo. They will also be given a brief (5-10 min long) talk about appropriate calorie intake from diet and exercise at each 12-week visit. The primary end point is the cumulative incidence of type 2 diabetes. Secondary endpoint is the number of participants who achieve normoglycaemia at 48, 96 and 144 weeks. Follow-up is estimated to span 144 weeks. ETHICS AND DISSEMINATION: All protocols and an informed consent form comply with the Ethics Guideline for Clinical Research (Japan Ministry of Health, Labour and Welfare). The study protocol has been approved by the Institutional Review Board at Kokura Medical Association and University of Occupational and Environmental Health. The study will be implemented in line with the CONSORT statement. TRIAL REGISTRATION NUMBER: UMIN000010758; Pre-results.

Phase II study of the GPC3-derived peptide vaccine as an adjuvant therapy for hepatocellular carcinoma patients.

The recurrence rates of Hepatocellular carcinoma (HCC) are high, necessitating novel and effective adjuvant therapies. Therefore, we conducted a phase II study of glypican-3 (GPC3) peptide vaccine as an adjuvant therapy for HCC patients. Forty-one patients with initial HCC who had undergone surgery or radiofrequency ablation (RFA) were analyzed in this phase II, open-label, single-arm trial. Ten vaccinations were performed for 1 y after curative treatment. We also investigated case-control subjects, where selected patients treated surgically during the same period were analyzed. The expression of GPC3 in the available primary tumors was determined by immunohistochemical analysis. Six patients received RFA therapy while 35 received surgery. The recurrence rate tended to be lower in the 35 patients treated with surgery plus vaccination compared to 33 patients who underwent surgery alone (28.6% vs. 54.3% and 39.4% vs. 54.5% at 1 and 2 y, respectively; p = 0.346, 0.983). Twenty-five patients treated with surgery and vaccination had GPC3-positive tumors; the recurrence rate in this group was significantly lower compared to that in 21 GPC3-positive patients who received surgery only (24% vs. 48% and 52.4% vs. 61.9% at 1 and 2 y, respectively; p = 0.047, 0.387). The GPC3 peptide vaccine improved the 1-y recurrence rate in patients with GPC3-positive tumors. This study demonstrated that GPC3 expression by the primary tumor may be used as a biomarker in a putative larger randomized clinical trial to determine the efficacy of the GPC3-derived peptide vaccine.

What factors were important for dietary improvement in emergency shelters after the Great East Japan Earthquake?

The Great East Japan Earthquake of 2011 left many evacuees with insufficient food and emergency shelter. However, there is no evidence concerning the factors affecting dietary circumstances in emergency shelters after disasters. To clarify the factors that influenced the provision of meals, we reanalyzed a data set from a dietary survey conducted in emergency shelters one month after the Great East Japan Earthquake (2011). Among the 69 shelters in "city A," 53 (79.1%) had food shortages. The possibility of cooking in the emergency shelter improved the provision of meals to evacuees. When comparing emergency shelters with and without cooking equipment, the shelters with cooking equipment provided more meals, as well as more dishes containing grains and vegetables. When there was a gas supply, the twice per day provision of "balanced" meals (containing grains, vegetables, and meat/fish) was more frequent than when there was no gas supply. Interestingly, neither the water supply nor the electricity supply affected the provision of balanced meals. Further, emergency shelters with larger numbers of evacuees had a lower possibility of cooking and lower availability of gas supply. Our results demonstrate that early improvements to post-disaster meal provision may maintain the health of evacuees. Such improvements could be achieved by 1) the speedy restoration of the gas supply to enable cooking, and 2) limiting the number of evacuees per emergency shelter.