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Background Zinc deficiency during long-term courses of chemotherapy and its related symptoms, including skin rash, taste disorder, and oral mucositis, has not been sufficiently investigated. Methods This prospective observational study enrolled patients with gastric and colorectal cancer who underwent standard first-line chemotherapy. According to the Practice Guideline for Zinc Deficiency, zinc deficiency is defined as a serum level of < 60 μg/dL. Serum zinc levels were measured before and after (1, 3, and 6 months) chemotherapy, and symptoms were assessed using the Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events version 1.0. Repeated measures were analyzed using a generalized linear mixed model. Results Of the 61 enrolled patients, we analyzed 48 patients who underwent standard first-line chemotherapy with fluoropyrimidine plus oxaliplatin. Zinc deficiency was observed in 18 patients (38 %) before chemotherapy. The least-square means of serum zinc levels significantly decreased at 3 and 6 months of chemotherapy in 30 patients without zinc deficiency at the start of chemotherapy (both p < 0.01) but not in 18 patients with zinc deficiency at the start. Changes in serum zinc levels during chemotherapy were negatively correlated with taste changes, rash, and itching (all p < 0.04) in patients without zinc deficiency before treatment initiation. Conclusions Serum zinc levels decreased during chemotherapy in zinc-non-deficient patients at the start of chemotherapy and were correlated with taste changes, skin rash, and itching. Therefore, it is necessary to investigate whether zinc supplementation can improve these symptoms.

Background Paclitaxel plus ramucirumab (PTX + RAM) is the standard second-line chemotherapy for unresectable advanced or recurrent gastric cancer (AGC). Nanoparticle albumin-bound paclitaxel (nab-PTX) is an improved, more convenient form of PTX and is non-inferior to PTX. Although some retrospective and single-arm phase II studies regarding nab-PTX + RAM have been reported, comparative studies are lacking. Here, we compared the efficacy and toxicity of nab-PTX + RAM and PTX + RAM using propensity score matching. Methods Clinical data of 265 patients treated for AGC with nab-PTX + RAM or PTX + RAM were retrospectively collected. Nab-PTX was administered at dosages of 100 mg/m2, replacing PTX in the standard PTX + RAM regimen. Progression-free survival (PFS), overall survival (OS), and toxicity were compared using 1:1 propensity score matching. Results In total, 190 (72%) patients were matched. The median PFS was 5.3 [95% confidence interval (CI) 4.4–6.3] and 4.7 (95% CI 3.2–5.3) months in the nab-PTX + RAM and PTX + RAM groups, respectively [hazard ratio (HR) = 0.76, 95% CI 0.56–1.03, p = 0.07]. The median OS was 11.5 (95% CI 9.2–15.0) and 9.9 (95% CI 8.0–12.7) months, respectively (HR = 0.78, 95% CI 0.56–1.07, p = 0.12). Grade 3 and 4 neutropenia was observed more frequently in the nab-PTX + RAM group (72% vs. 56%, p = 0.03). No treatment-related deaths occurred. Conclusions Nab-PTX + RAM exhibited more favorable trends in terms of PFS and OS but was more myelosuppressive than PTX + RAM. As neutropenia is commonly manageable toxicity, nab-PTX + RAM presents a treatment alternative for AGC. Further studies including randomized, controlled studies are warranted.

Soybean plants require a large amount of nitrogen either from nitrogen fixation in nodules or nitrogen absorption from roots. It is known that nitrate, a major inorganic nitrogen compound in upland soils, represses nodule growth and nitrogen fixation. Rapid and reversible inhibition of nodule growth and nitrogen fixation activity was found in the hydroponically cultivated soybeans after changing the nutrient solution with or without nitrate. Isotope tracer analysis revealed that the major cause of this inhibition depended on the changes in the partitioning of photo-assimilate between nodules and roots and was not directly related to the transported N compounds. Transcriptome and metabolome analyses supported that nitrate strongly promotes nitrogen and carbon metabolism in the roots but represses them in the nodules. The application of ammonium, glutamine, or urea also inhibited the nodule growth and nitrogen fixation like nitrate, although the inhibition was lower than that of nitrate. The degree of inhibition was related to the decrease in carbon isotope partitioning into the nodules, rather than the import of nitrogen isotope to nodules. Urea was detected in xylem sap and all parts of soybean, and some urea might be originated from ureide degradation.

Objective Uterine leiomyosarcoma (uLMS) is a rare gynecologic malignancy for which the currently available treatments do not consistently provide long-term disease control. This study aimed to reveal the current clinical status of uLMS to support future clinical trials. Methods This study enrolled patients with uLMS treated at 53 Japanese institutions from 2000 to 2012. Central pathological review (CPR) was performed. All cases were confirmed by CPR, and epidemiological features, treatment, and prognosis were analyzed statistically. Results A total of 307 patients were enrolled. A diagnosis of uLMS was confirmed in 266 patients (86.6%) of patients after CPR, of whom data for 259 were analyzed. Of these, 186 (71.8%) patients underwent complete gross resection as primary therapy. Ninety-eight patients received no additional adjuvant therapy, while docetaxel and gemcitabine was the most frequent regimen among 155 patients treated with adjuvant chemotherapy. In all cases, the median overall survival (OS) was 44.2 months. Multivariate analyses of prognostic factors in all cases identified stage III and IV disease, high serum lactate dehydrogenase level, and menopausal status as poor prognostic factors. However, in stage I cases, high serum lactate dehydrogenase level and no adjuvant treatment were identified as poor prognostic factors. The 5-year OS of patients with stage I uLMS treated with adjuvant chemotherapy was significantly better than that of those without adjuvant treatment (67.8% vs 46.7%, P = 0.0461). Conclusions Despite complete removal of the primary lesion, the clinical course of patients with uLMS was poor due to recurrence of distant metastasis. The application of a suitable biomarker and effective adjuvant chemotherapy are required to improve the prognosis of patients with uLMS.

Purpose Activated Notch receptor signaling has been implicated in tumor growth and progression in colorectal cancer (CRC). However, the pathogenic relevance of NOTCH gene alterations remains unclear. The aim of this study was to clarify mutational landscapes and assess their clinical significance in patients with metastatic CRC.Methods Pre-chemotherapy tumor tissues obtained from 1154 metastatic CRC patients in the Nationwide Cancer Genome Screening Project in Japan between April 2017 and March 2019 were studied using the Oncomine Comprehensive Assay.Results The frequencies of NOTCH1, NOTCH2, and NOTCH3 nonsynonymous sequence variants were 11.5%, 4.4%, and 10.4%, respectively. The majority of variants were missense of unknown significance that were distributed across all domains of all three NOTCH genes. The gain-of-function mutations in NOTCH reported in multiple malignancies were not identified. The NOTCH amplification rate was less than 1%. No NOTCH fusions were detected. In patients who were registered before, or within one year of, first-line chemotherapy, overall survival for 51 patients with only NOTCH3 variants was significantly longer than for 540 patients with no NOTCH variants (median, 40.2 months vs 27.7 months; P = 0.04). Multivariate analysis revealed that variant NOTCH3 was an independent prognostic factor for increased survival (hazard ratio 0.61, 95% confidence interval, 0.39-0.94; P = 0.03) besides poor prognostic factors associated with mutant TP53, KRAS, and BRAF, as well as amplified MYC.Conclusion NOTCH genes are unlikely to harbor driver mutations and amplifications in patients with metastatic CRC. NOTCH3 variants should be further investigated as a favorable prognostic marker.

To clarify the frequency of deficient mismatch repair (dMMR) in Japanese ovarian cancer patients, we examined microsatellite instability (MSI) status and immunohistochemistry (IHC) subtypes, including endometrioid carcinoma (EMC), clear cell carcinoma (CCC), or a mixture of both (Mix).We registered 390 patients who were diagnosed with EMC/CCC/Mix between 2006 and 2015 and treated at seven participating facilities. For 339 patients confirmed eligible by the Central Pathological Review Board, MSI, IHC, and MutL homolog 1 methylation analyses were conducted. The tissues of patients with Lynch syndrome (LS)-related cancer histories, such as colorectal and endometrial cancer, were also investigated.MSI-high (MSI-H) status was observed in 2/217 CCC (0.9%), 10/115 EMC (8.7%), and 1/4 Mix (25%). Additionally, loss of MMR protein expression (LoE-MMR) was observed in 5/219 (2.3%), 16/115 (14.0%), and 1/4 (25%) patients with CCC, EMC, and Mix, respectively. Both MSI-H and LoE-MMR were found significantly more often in EMC (p0.001). The median (range) ages of patients with MMR expression and LoE-MMR were 54 (30-90) and 46 (22-76) (p=0.002), respectively. In the multivariate analysis, advanced stage and histological type were identified as prognostic factors.The dMMR rate for EMC/CCC was similar to that reported in Western countries. In Japan, it is assumed that the dMMR frequency is higher because of the increased proportion of CCC.

Increasing use of zebrafish in biomedical, toxicological and developmental studies requires explicit knowledge of cytochrome P450 (CYP), given the central role of CYP in oxidative biotransformation of xenobiotics and many regulatory molecules. A full complement of CYP genes in zebrafish and their transcript expression during early development have already been examined. Here we established a comprehensive picture of CYP gene expression in the adult zebrafish liver using a RNA-seq technique. Transcriptional profiling of a full complement of CYP genes revealed that CYP2AD2, CYP3A65, CYP1A, CYP2P9 and CYP2Y3 are major CYP genes expressed in the adult zebrafish liver in both sexes. Quantitative real-time RT-PCR analysis for selected CYP genes further supported our RNA-seq data. There were significant sex differences in the transcript levels for CYP1A, CYP1B1, CYP1D1 and CYP2N13, with males having higher expression levels than those in females in all cases. A similar feature of gender-specific expression was observed for CYP2AD2 and CYP2P9, suggesting sex-specific regulation of constitutive expression of some CYP genes in the adult zebrafish liver. The present study revealed several "orphan" CYP genes as dominant isozymes at transcript levels in the adult zebrafish liver, implying crucial roles of these CYP genes in liver physiology and drug metabolism. The current results establish a foundation for studies with zebrafish in drug discovery and toxicology.

Zebrafish are used widely in biomedical, toxicological, and developmental research, but information on their xenobiotic metabolism is limited. Here, we characterized the expression of 14 xenobiotic cytochrome P450 (CYP) subtypes in whole embryos and larvae of zebrafish (4 to 144 h post-fertilization (hpf)) and the metabolic activities of several representative human CYP substrates. The 14 CYPs showed various changes in expression patterns during development. Many CYP transcripts abruptly increased at about 96 hpf, when the hepatic outgrowth progresses, however, the expression of some cyp1s (1b1, 1c1, 1c2, 1d1) and cyp2r1 peaked at 48 or 72 hpf, before full liver development. Whole-mount in situ hybridization revealed cyp2y3, 2r1, and 3a65 transcripts in larvae at 55 hpf after exposure to rifampicin, phenobarbital, or 2,3,7,8-tetrachlorodibenzo-p-dioxin from 30 hpf onward. Marked conversions of diclofenac to 4&prime, hydroxydiclofenac and 5-hydroxydiclofenac, and of caffeine to 1,7-dimethylxanthine, were detected as early as 24 or 50 hpf. The rate of metabolism to 4&rsquo, hydroxydiclofenac was more marked at 48 and 72 hpf than at 120 hpf, after the liver had become almost fully developed. These findings reveal the expression of various CYPs involved in chemical metabolism in developing zebrafish, even before full liver development.

BACKGROUND: The effectiveness of bevacizumab monotherapy in elderly patients with non-squamous non-small cell lung cancer (NSCLC) is unclear. The efficacy of the combinations for elderly patients was explored. METHODS: Untreated patients (≥75 years; performance status 0–1) with stage IIIB, IV, or recurrent non-squamous NSCLC were included. Patients with epidermal growth factor receptor (EGFR) mutation or anaplastic lymphoma kinase (ALK) gene rearrangements were eligible even if they received tyrosine kinase inhibitors. Patients were randomized 1:1 to receive docetaxel (50 mg/m(2)) (DB) or pemetrexed (500 mg/m(2)) (PB) with bevacizumab (15 m/kg). The primary endpoint was progression-free survival (PFS). Treatment was administered every 3 weeks until disease progression or unacceptable toxicity. RESULTS: Overall, 103 patients (DB: n=51; PB: n=52) were enrolled. In the DB and PB arms, median ages [range] were 78 [75–88] and 79 [75–94] years, respectively; median PFS were 6.1 and 4.6 months, respectively [hazard ratio (HR), 1.03; 95% confidence interval (CI), 0.66–1.61]; and response rates were 43%, and 40%, respectively (P=0.840). Grade ≥3 leukopenia, neutropenia, and fatigue incidences were significantly higher in the DB arm. Febrile neutropenia incidence did not differ significantly (16% vs. 12%, P=0.578). One patient in the PB arm died from a ruptured abdominal aortic aneurysm. Quality of life (QoL) analysis revealed less deterioration in the PB arm. CONCLUSIONS: In previously untreated elderly patients with non-squamous NSCLC, PB shows feasibility, better QoL, and promising efficacy in terms of PFS, and an objective response rate for further analysis (UMIN000012786).

OBJECTIVES: In clinical trials for dietary supplements and functional foods, the study population tends to be a mixture of healthy subjects and those who are not so healthy but are not definitely diseased (called “borderline subjects”). For such heterogeneous populations, the t-test and ANCOVA method often fail to provide the desired treatment efficacy. We propose an alternative approach for the efficacy evaluation of dietary supplements and functional foods based on a change-point linear regression model. METHODS: Suppose we are interested in analyzing data from a randomized controlled clinical trial of dietary supplements which was conducted under what is called pre-post design. We propose the change-point regression model (CPRM) as new analysis method. The model does not require the assumption of a constant treatment effect and provides clinically interpretable results. By employing the AIC-based profile likelihood method, inferences can be made easily using standard statistical software. RESULTS: CPRM method was applied to (-)-hydroxycitric acid (HCA) study data, and the merit of the method was demonstrated by comparing it with traditional methods those are ANCOVA or t-test. The AICs of CPRM, ANCOVA and t-test were 667.2, 685.9 and 685.0 respectively. Therefore, CPRM is well fit than traditional methods. Advantage of CPRM is that it can simultaneously provide information on effect appearance points and we succeeded estimation of the point in (-)-HCA study. CONCLUSIONS: We propose an alternative approach for the efficacy evaluation of dietary supplements and functional foods based on a CPRM. By employing the AIC-based profile likelihood method, inferences can be made easily using standard statistical software. The proposed method was applied to the Garcinia study data, and the merit of the method was demonstrated by comparing it with the ANCOVA models. FUNDING SOURCES: This research did not received any specific grant from funding agencies in the public. commercial, or not for-profit sectors.

Increasing use of zebrafish in biomedical, toxicological and developmental studies requires explicit knowledge of cytochrome P450 (CYP), given the central role of CYP in oxidative biotransformation of xenobiotics and many regulatory molecules. A full complement of CYP genes in zebrafish and their transcript expression during early development have already been examined. Here we established a comprehensive picture of CYP gene expression in the adult zebrafish liver using a RNA-seq technique. Transcriptional profiling of a full complement of CYP genes revealed that CYP2AD2, CYP3A65, CYP1A, CYP2P9 and CYP2Y3 are major CYP genes expressed in the adult zebrafish liver in both sexes. Quantitative real-time RT-PCR analysis for selected CYP genes further supported our RNA-seq data. There were significant sex differences in the transcript levels for CYP1A, CYP1B1, CYP1D1 and CYP2N13, with males having higher expression levels than those in females in all cases. A similar feature of gender-specific expression was observed for CYP2AD2 and CYP2P9, suggesting sex-specific regulation of constitutive expression of some CYP genes in the adult zebrafish liver. The present study revealed several "orphan" CYP genes as dominant isozymes at transcript levels in the adult zebrafish liver, implying crucial roles of these CYP genes in liver physiology and drug metabolism. The current results establish a foundation for studies with zebrafish in drug discovery and toxicology.

It has been reported that supply of nitrate to culture solution rapidly and reversibly inhibits nodule growth and nitrogen fixation activity of soybean. In this study, the effects of ammonium, urea, or glutamine on nodule growth and nitrogen fixation activity are compared with that for nitrate. Soybean plants were cultivated with a nitrogen-free nutrient solution, then 1 mM-N of nitrate, ammonium, glutamine, or urea were supplied from 12 DAP until 17 DAP. Repression of nodule growth and nitrogen fixation activity at 17 DAP were observed by ammonium, urea, and glutamine like nitrate, although the inhibitory effects were milder than nitrate. The removal of nitrogen from the culture solutions after nitrogen treatments resulted in a recovery of the nodule growth. It was found that the glutamine treatment followed by N-free cultivation gave highest nitrogen fixation activity about two times of the control. Tracer experiments with 15N and 13C were performed to evaluate the translocation of N and C to the different tissues. Culture solutions containing a 15N-labeled nitrogen source were supplied from 21 DAP, and the whole shoots were exposed to 13CO2 for 60 min on 23 DAP, and plants were harvested on 24 DAP. The percentage distribution of 15N in nodules was highest for ammonium (1.4%) followed by glutamine (0.78%), urea (0.32%) and nitrate (0.25%). The percentage distribution of 13C in the nodules was highest for the control (11.5%) followed by urea (5.8%), glutamine (2.6%), ammonium (2.3%), and nitrate (2.3%). The inhibitory effects of nitrogen compounds appeared to be related to a decrease in photoassimilate partitioning in the nodules, rather than 15N transport into the nodules. The free amino acid concentrations after nitrogen treatments were increased in the nodules and leaves by nitrate, in the roots by ammonium, in the stems by urea, and the roots, stems, and leaves by glutamine treatment. The concentrations of asparagine, aspartate, and glutamine were increased after nitrogen treatments. By the long-term supply of nitrogen for 2-weeks, nitrate significantly increased the lateral roots and leaf growth. The long-term supply of urea and glutamine also promoted the lateral roots and leaf growth, but ammonium suppressed them.

Background To evaluate the therapeutic outcomes in patients with bone metastases receiving radiotherapy (RT), it is important to use objective radiological response criteria. The aim of this study was to investigate the changes in pain and re-ossification after RT for painful vertebral bone metastases without paralysis by malignant spinal cord compression. Methods The participants included 55 patients who received RT for painful vertebral bone metastases without paralysis in our institution between 2012 and 2016. Bone modifying agents (BMAs) were administered in all patients. Follow-up assessments were done just before the start of RT and at 1, 2, 3, 4, and 6 months after RT. Radiological responses of irradiated vertebrae by RT were assessed by computed tomography (CT) using MD Anderson response classification criteria (MDA criteria) and the pain response was assessed by Numeric Rating Scale (NRS). Response was classified as complete response (CR), partial response (PR), progressive disease (PD), and stable disease (SD). Results The rates of CR were 2%, 7%, 20%, 30%, and 56% at 1, 2, 3, 4, and 6 months, respectively. The rates of CR or PR were 15%, 49%, 77%, 91%, and 91% at 1, 2, 3, 4, and 6 months, respectively. The rates of CR or PR were significantly higher in patients with breast cancer than in patients with lung cancer (p = 0.043). At one month, there was an association between the NRS and radiological response assessed by MDA criteria. There was a significant trend that, with a better response, there were more patients without pain (p = 0.021). Conclusions Under BMAs administration, successful RT for vertebral bone metastases decreased pain and caused re-ossification. The MD Anderson criteria could be useful for assessment of radiological responses of irradiated vertebrae.

IntroductionIn Japan, the age of patients with pancreatic cancer has increased. Combination chemotherapies such as 5-fluorouracil/leucovorin, oxaliplatin and irinotecan therapy and gemcitabine hydrochloride (GEM) +nab paclitaxel therapy have been developed as the standard treatments for young patients with advanced recurrent pancreatic cancer. However, both therapies produce toxicity and their administration is limited by the patients’ age or performance status. The efficacy and safety data obtained in the GEST study—a large-scale randomised controlled study conducted in patients with pancreatic cancer in Japan—suggested that GEM +S-1 (GS) combination therapy is a promising candidate for those aged between 75 and 80 years. However, for patients aged ≥80 years, no efficacy or safety data on GS therapy are currently available.Methods and analysisThis open-label, randomised phase II study will involve patients with advanced recurrent pancreatic cancer, aged ≥75 years, with favourable general conditions. Using the electronic data capture system, participants will be randomly allocated to groups with standard treatment (GEM therapy alone) and study treatment (GS therapy). The treatments will be administered until the conditions meet the discontinuation criteria. The primary endpoint is overall survival.Ethics and disseminationThis trial has been approved by the National Hospital Organisation’s Central Review Board (H28-NHOD-01).DiscussionThis study will reveal if GS therapy could be a standard treatment option for elderly patients with pancreatic cancer, by clarifying its efficacy and safety.Trial registration numberUMIN000025747; Pre-results.

Radiation therapy (RT) is the common treatment for painful vertebral bone metastases without paralysis by malignant spinal cord compression. However, no studies have focused on the time course of pain after RT. Then, we investigated the change of pain after RT for painful vertebral bone metastases without paralysis.Participants included 101 patients who received RT for painful vertebral bone metastases without paralysis in our institution between 2012 and 2016. All patients received RT and pain response was evaluated by Numeric Rating Scale (NRS). Follow-up assessments were performed just before the start of RT and every month for six months after RT. Pain response was classified as complete response (CR), partial response (PR), pain progression (PP), and indeterminate response (IR) based on the response criteria of International Bone Metastases Consensus Working Party. Responders were classified as either CR or PR, and non-responders as either PP or IR.Median NRS scores for pain were 5 before RT, decreasing to 0 by one month after RT and remaining zero until last follow-up, representing a significant decrease over time (P 0.001). The rate of responders at each month from one to six months was 93, 96, 95, 100, 98, and 96%, respectively. Multivariate analysis revealed that Spinal Instability Neoplastic Score (SINS) was the only risk factor for response to RT at one month. At one month pain disappeared in 88% of the patients with spinal stability (SINS 7), although pain disappeared 58% of the patients with spinal instability (SINS ≥ 7), which was significant (P = 0.002).Pain decreased significantly over time and 93% of patients were classified as responders as early as one month after RT in patients with painful vertebral bone metastases without paralysis. Pretreatment SINS could be a predictor of pain response to RT.

Background Atypical femoral fractures (AFFs) have been reported to occur in patients with bone metastases who received long-term bisphosphonate treatment. However, the incidence of AFFs in breast cancer patients with bone metastases who received intravenous bisphosphonate is unclear. The purpose of this study is to examine the incidence of AFFs in breast cancer patients with bone metastases who received intravenous bisphosphonate. In addition, we estimated the number of dose and duration of intravenous bisphosphonate at the time of occurrence of AFFs. Methods We identified 356 female breast cancer patients with bone metastases who received intravenous bisphosphonate between November 2004 and October 2013 in our institution. The median number of doses of intravenous bisphosphonate was 18 (range, 1–103). The median duration of intravenous bisphosphonate treatment was 16 months (range, 1–102 months). We estimated the incidence of AFFs in patients who received intravenous bisphosphonate and used Poisson regression model to obtain the incidence rates of AFFs. Results Three AFFs in two patients were identified and the estimated incidence of AFFs was 2.99 per 1000 person-years. At the time of occurrence of AFFs, the patients had received 41 and 83 doses of intravenous bisphosphonate, for 37 and 79 months, respectively. The patients underwent open reduction and internal fixation with intramedullary nail. The frequency and incidence of AFFs in patients who received intravenous bisphosphonate for at least 41 or 83 doses or for more than 37 or 79 months were 2/60 (3.3%), 1/7 (14.3%), 2/70 (2.9%), and 1/9 (11.1%), respectively. Conclusions The incidence of AFFs is low in breast cancer patients with bone metastases who received intravenous bisphosphonate. Careful observation is warranted and radiography should be performed to investigate AFFs when clinical signs such as thigh pain appear. Study design Clinical study.

Objective(s): The mortality of patients with locally advanced triple-negative breast cancer (TNBC) is high, and pathological complete response (pCR) to neoadjuvant chemotherapy (NAC) is associated with improved prognosis. This retrospective study was designed and powered to investigate the ability of 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG-PET/CT) to predict pathological response to NAC and prognosis after NAC. Methods: The data of 32 consecutive women with clinical stage II or III TNBC from January 2006 to December 2013 in our institution who underwent FDG-PET/CT at baseline and after NAC were retrospectively analyzed. The maximum standardized uptake value (SUVmax) in the primary tumor at each examination and the change in SUVmax (ΔSUVmax) between the two scans were measured. Correlations between PET parameters and pathological response, and correlations between PET parameters and disease-free survival (DFS) were examined. Results: At the completion of NAC, surgery showed pCR in 7 patients, while 25 had residual tumor, so-called non-pCR. Median follow-up was 39.0 months. Of the non-pCR patients, 9 relapsed at 3 years. Of all assessed clinical, biological, and PET parameters, N-stage, clinical stage, and ΔSUVmax were predictors of pathological response (p value of 0.0288, 0.0068, 0.0068 respectively; Fischer’s exact test). The cut-off value of ΔSUVmax to differentiate pCR evaluated by the receiver operating characteristic (ROC) curve analysis was 81.3%. Three-year disease-free survival (DFS) was lower in patients with non-pCR than in patients with pCR (p=0.328, log-rank test). The cut-off value of ΔSUVmax to differentiate 3-year DFS evaluated by the ROC analysis was 15.9%. In all cases, 3-year DFS was lower in patients with ΔSUVmax

この編年史料は、今出川キャンパス整備に伴う相国寺旧境内の発掘調査に関する事例(本山・鹿苑院・雲頂院)の造営・火災等を、史料から抄出し、編年により配列したものである。, ページは巻末(一)-(四三)

There could be covariates that are related to transition probabilities, but not related to duration times to the next event, or vice versa, in event history analyses. A method is proposed in this paper that estimates those relationships, separately, by using an accelerated failure time model. The method is applied to the data taken from individuals staying at home and having government care service, where different levels of care are provided to care need individuals based on their severities officially recognized. It is shown among others that family and disease are significantly related to duration times to the next event, but not related to transition probabilities.

This paper reports the synthesis of D-A polymers containing 1,2-dithienylethene (DTE) units via palladium-catalyzed direct arylation polymerization (DArP). The reaction of dibromoisoindigo (1-Br) and DTE (2-H), in the presence of Pd2(dba)3·CHCl3 (0.5 mol%), P(2-MeOC6H4)3 (L1) (2 mol%), pivalic acid (1 equiv) as catalyst precursors, and Cs2CO3 (3 equiv) as a base affords poly(1-alt-2) with a high molecular weight (Mn up to 44,900). Although, it has been known that monomers, with plural C–H bonds, tend to form insoluble materials via direct arylation at undesirable C–H positions; the reaction of 1-Br and 2-H cleanly proceeds without insolubilization. The resulting polymer has a well-controlled structure and exhibits good charge transfer characteristics in an organic field-effect transistor (OFET), compared to the polymer produced by Migita–Kosugi–Stille cross-coupling polymerization. The DArP product displays an ideal linear relationship in the current–voltage curve, whereas the Migita–Kosugi–Stille product shows a VG-dependent change in the charge mobility.

Background: Sleep pattern is an important factor in a child’s mental, behavioural and physical status. To evaluate the sleep patterns of children, subjective tools such as sleep logs and questionnaires are still widely used in addition to objective methods of sleep assessment. Despite the established correlation between subjective and objective sleep variables, the characteristic features of subjective assessment have not been elucidated.Methods: To investigate the characteristics of parental sleep assessment (daily sleep log and brief questionnaire) in preschool children, a 7-day actigraphic sleep study was conducted in 48 healthy 5-year-old children.Results: Sleep schedule variables in the parental reports generally correlated well with actigraphic assessment of sleep patterns; however, sleep periods were longer in parental reports than in actigraphic recordings. Although the daily sleep log was better correlated with actigraphy, the brief questionnaire showed a good correlation with sleep pattern on weekday actigraphic assessments. Parental reports recorded fewer than 10% of the night wakings recorded by actigraphy.Conclusions: Subjective sleep assessments remain useful, although their utility depends on the purpose and size of the study in question. However, knowledge of the potential biases and characteristics of such assessments is essential for correct interpretation of the data.

In clinical trials for dietary supplements and functional foods, the study population tends to be a mixture of healthy subjects and those who are not so healthy but are not definitely diseased (called "borderline subjects"). For such heterogeneous populations, the t-test and ANCOVA method often fail to provide the desired treatment efficacy. We propose an alternative approach for the efficacy evaluation of dietary supplements and functional foods based on a change-point linear regression model. The model does not require the assumption of a constant treatment effect and provides clinically interpretable results. By employing the AIC-based profile likelihood method, inferences can be made easily using standard statistical software. The proposed method was applied to the Garcinia study data, and the merit of the method was demonstrated by comparing it with traditional methods.

近世に二條家邸であった屋敷地は、明治維新後に、官家士族の子弟の救済を目的の一つとした学校「平安義校」として利用された。その後、明治24 年(1891)になると「平安義會」が発足し、義校を廃止して奨学事業が開始された。近代における官家士族救済活動の一端を示している。

Background HER2 testing for samples from recurrent or metastatic disease is recommended by the 2013 update of the American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) guidelines and cytological analysis can be applied to several types of metastatic lesions. However, the practical method to assess the HER2 testing of breast cancer cytology specimens has yet to be resolved. Therefore, we conducted the bright-field HER2 dual in situ hybridization (DISH) assay on cell blocks (CBs) prepared from breast cancer cell samples as a validation study before clinical use. Methods CBs were prepared from tumor cell samples collected from 54 surgically excised breast tumors. The cells were fixed in 10 % buffered formalin for 16–28 h, and embedded in paraffin. The INFORM HER2/neu Dual ISH DNA Probe Cocktail was used for the DISH assay on the Ventana BenchMark ULTRA (Roche Diagnostics). Results Successful results were obtained in 51 of 54 CB specimens, and the results from the CB specimens were in agreement with those from the histological sections in 48 of the 51 cases (concordance rate, 94 %; kappa, 0.846). The intraclass correlation coefficient (ICC) between the CB and histological specimens in the continuous HER2/CEP17 signal count ratio was 0.89 (95 % CI 0.81–0.93), and the Pearson’s CC was 0.91 (95 % CI 0.85–0.94). Conclusion The HER2 DISH assay, utilizing 10 % buffered formalin-fixed CB, would be a reliable and ideal method to assess the HER2 gene status of breast cancer cytological specimens.