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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.

BackgroundThe COVID-19 pandemic has reduced diagnosed cancer cases worldwide. This study aimed to elucidate the recovery of cancer care from the COVID-19 pandemic in Ehime Prefecture, Japan.MethodsThis study collected data from the hospital-based cancer registry (HBCR) as well as the number of outpatients, medical information provision fee payments (MIP2), and second opinion patients (SOP) from the Council of Ehime Cancer Care Hospitals (ECCH). Then cancer care and patient requests for hospital transfers before and during the COVID-19 pandemic were analyzed.ResultThe HBCR from the ECCH comprises >80% of cancer cases in Ehime Prefecture. In 2020, the numbers of all registered cases, first-line treatment cases, and cases detected by cancer screening in the HBCR decreased from those in 2018–2019. In 2021, they increased to almost the same levels as those in 2020. In contrast, the number of registered patients that changed hospitals (hospital-change cases) after first-line treatments, patients who lived outside the metropolitan area of Ehime but registered in metropolitan hospitals, MIP2, and SOP remained low in 2021 after decreasing in 2020. Furthermore, using the Wilcoxon rank sum test, the monthly numbers of hospital-change cases, MIP2, and SOP were significantly smaller in 2021 than in 2018–2019.ConclusionThe assessed indicators suggest that the willingness of cancer patients to improve and/or advance cancer care had not returned to pre-pandemic levels by 2021. Hence, psychological measures in society and support for patient caregivers are necessary to prevent self-restraint in patients receiving cancer care.Mini-abstractThe number of registered cases in hospital-based cancer registries returned to pre-COVID-19 levels by 2021, cancer patients’ willingness to further their care did not return to pre-pandemic levels.

Perioperative anaphylaxis (POA) is a severe complication with a low incidence and diverse risk factors. Its low incidence makes a detailed survey of POA challenging. Recent large-scale surveys in Japan have focused on identifying the causative agents using the basophil activation test. Only facilities, such as university hospitals, that can dispatch samples for this test participate, which may introduce bias. We surveyed the incidence of POA primarily in secondary hospitals, such as the Saiseikai hospitals, throughout Japan.We targeted data collection for the year 2021. Thirty-five facilities answered (Supplementary 1, 2); we excluded 1 reporting no surgeries. In total, 70,523 surgeries were performed, with POA diagnosed in 7 cases. For diagnosis, the skin test was used in 3 cases and quantification of histamine and tryptase in 1 case. In 3 cases, diagnosis was based on the time to onset of POA after drug use. Multiple tests are important to ensure patient safety. However, in this survey, no hospital performed in vitro tests to identify the cause. This is major limitation, however, as many hospitals do not have experimental laboratories, we believe that this study, which focuses on secondary care institutions, contributes to the literature significantly by presenting the current situation in clinical practice.

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.

Residents with limited experience of thoracic surgery have difficulty performing video-assisted thoracoscopic surgery (VATS) lobectomy. However, they can learn early in a stepwise training method to safely manage the pulmonary veins (PVs), which are relatively strong vessels. In this study, we investigated whether the time required to manage the PVs could serve as an indicator of technical skill acquisition in VATS lobectomy. To evaluate the acquisition of residents’ technical skills, we retrospectively assessed the PV management time of 5 residents at our institution who had performed more than 15 VATS lobectomies over an 8-year period (2012–2019). Their PV management time was determined from surgical video. We analyzed whether PV management time was affected by patient characteristics, operative factors, and experience of lobectomy. The 5 residents performed a total of 103 VATS lobectomies during the study period. Median PV management time was 9.6 min. The most frequently resected lobe was the right upper lobe (56.3%). Median PV management time for right middle lobe was 5.2 min, which was shorter than that for other lobes. We categorized the lobectomies according to whether PV management time was ≤10 min or > 10 min. Univariate analysis identified that shorter PV management time (≤10 min) was significantly associated with more right middle lobectomies performed (7.3% vs 0%, p = 0.02) and more lobectomies performed (14 vs 8, p = 0.01). Longer PV management time (>10 min) was significantly associated with lower lobectomies performed (18% vs 35%, p

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.

The safety of salvage lung resection after immune checkpoint inhibitor (ICI) therapy in patients with advanced non-small cell lung cancer (NSCLC) is not well understood.In this retrospective multicenter study, we reviewed perioperative morbidity and mortality rates in 11 patients (8 men, 3 women; median age 70 years) who underwent salvage lung resection for unresectable NSCLC after ICI therapy in the 4 years since 2017. Operative factors were also compared according to operating time ( 6 h, n = 7; 6 h, n = 4).The clinical stage at the time of diagnosis was IIIA in 2 patients, IIIB in 4, IVA in 2, and IVB in 3. Eight patients received pembrolizumab and 3 received durvalumab. Two patients received an ICI agent alone, 3 underwent chemoradiotherapy, and 6 received chemotherapy. Lobectomy was performed in 10 cases and bilobectomy in 1 case. All patients underwent complete resection. Median operating time was 429 (range 169-570) min with a median blood loss of 199 (range 10-5, 140) mL. The only intraoperative complication was damage to the pulmonary artery. The perioperative morbidity and mortality rates were 27% and 0%, respectively. The 90-day mortality rate was 9% (1 patient died of acute exacerbation of interstitial pneumonia). Patients in whom the operating time was 6 h more frequently had lymph node metastasis at the time of initial diagnosis (100% vs 25%, p = 0.02).Salvage lung resection was tolerated after ICI therapy in these patients. Lymph node metastasis at the time of initial diagnosis might make salvage surgery difficult.

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.

The effect of uniportal video-assisted thoracoscopic surgery (uni-VATS) versus that of conventional VATS on postoperative quality of life (QOL) is unclear. This prospective randomized controlled study compared uni-VATS and conventional 3-port VATS in terms of QOL and patient satisfaction. The subjects of this study were 84 patients with pulmonary nodules or bullous formation, randomized to undergo uniportal or conventional 3-port video-assisted thoracoscopic partial lung resection. The primary endpoint was postoperative pain, assessed using a numeric rating scale on postoperative day (POD) 1. No differences were found in the numeric rating scale on POD 1 after uni-VATS and conventional 3-port VATS. There were also no differences in blood loss, operative time, complication rate, surgical margin, analgesic requirement, vital capacity (VC), forced expiratory volume in 1 s (FEV1), the 6-min walk test (6MWT), C-reactive protein (CRP) levels, white blood cell count (WBC), or duration of chest tube drainage and hospital stay. Differences were found in the numeric rating scale on days 2, 3, 5, and 10 and in the patient satisfaction score on PODs 5 and 10. Uni-VATS is associated with less chest pain and better patient satisfaction in the short term but without differences in complication rates or surgical margins from the lesions. University Hospital Medical Information Network Clinical Trial Registry (UMIN000015340 http://www.umin.ac.jp/english/ ).

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).

Postoperative shoulder joint dysfunction has been observed at a certain rate after breast cancer surgery with axillary lymph node dissection. The purposes of this study were to verify the feasibility and effects of home-based exercise using a DVD and clarify the target of intensive intervention with physiotherapy by identifying the factors that cause postoperative shoulder dysfunction. The study comprised 237 female patients who underwent breast cancer surgery with axillary lymph node dissection, whose data were acquired until 3 months postoperatively. All patients were instructed to exercise at home using a DVD. Range of motion (ROM) of shoulder flexion and abduction and the disability of the arm, shoulder, and hand (DASH) score were measured before surgery, 1 week and 1, 2, and 3 months after surgery. As factors influencing the recovery of shoulder ROM at 3 months after surgery, the presence or absence of radiation and factors up to 1 month after surgery (age, body mass index, the relationship between operated side and dominant side of the hand, treatment modalities, and complications). Shoulder ROM and DASH scores had gradually recovered from 1 week to 3 months postoperatively. As the results of the multivariate analysis, the factors that were associated with the recovery of ROM of shoulder flexion at 3 months were the side of surgery corresponding to the dominant hand (negative factor) and the presence of paresthesia at 1 week postoperatively (positive factor) (p

Modulation of cardiac contractility by α-adrenoceptor is well known in several mammals. Mice are useful experimental animals, but α-adrenoceptor-mediated responses have been examined only in the ventricles. To determine function of α-adrenoceptors in the atrium, effects of α-adrenoceptor agonists on spontaneous contraction and electrical-field stimulation (EFS)-induced contraction were examined. In addition, expression of α1A, α1B, α1D and β1-adrenoceptor mRNAs were examined. In the right atrium, noradrenaline and phenylephrine caused positive inotropic and positive chronotropic actions. However, methoxamine, clonidine and xylazine caused positive inotropic actions, but contractile frequency was decreased at high concentrations. Phenylephrine-induced positive inotropic and chronotropic actions were partially decreased by propranolol, and both actions remained in the presence of propranolol were inhibited by phentolamine or prazosin. A low concentration of silodosin (

To evaluate the feasibility of image subtraction in late iodine enhancement CT (LIE-CT) for assessment of myocardial infarction (MI). A comprehensive cardiac CT protocol and late gadolinium enhancement MRI (LGE-MRI) was used to assess coronary artery disease in 27 patients. LIE-CT was performed after stress CT perfusion (CTP) and CT angiography. Subtraction LIE-CT was created by subtracting the mask volume of the left ventricle (LV) cavity from the original LIE-CT using CTP dataset. The %MI volume was quantified as the ratio of LIE to entire LV volume, and transmural extent (TME) of LIE was classified as 0%, 1–24%, 25–49%, 50–74% or 75–100%. These results were compared with LGE-MRI using the Spearman rank test, Bland-Altman method and chi-square test. One hundred twenty-five (29%) of 432 segments were positive on LGE-MRI. Correlation coefficients for original and subtraction LIE-CT to LGE-MRI were 0.79 and 0.85 for %MI volume. Concordances of the 5-point grading scale between original and subtraction LIE-CT with LGE-MRI were 75% and 84% for TME; concordance was significantly improved using the subtraction technique (p

Background The long-term outcomes of follow-up care for ground-glass opacity (GGO) lesions need to be clarified. Methods Between 2000 and 2005, a total of 226 patients with pure or mixed GGO lesions ≤ 3 cm in size were registered. The CT findings and changes in the findings during the follow-up period and the outcomes of the 226 patients were subsequently reviewed. Results Overall, 124 patients underwent resections, 57 did not receive follow-up examinations after 68 months because of stable disease or disease reduction, and 45 are continuing to receive follow-up examinations. Thirty-nine patients exhibited tumor growth during the follow-up period. Among the patients with a ratio of the diameter of consolidation relative to the tumor diameter (CTR) > 0, all cases with tumor growth were identified within 3 years; meanwhile, > 3 years were required to identify tumor growth in 16% of the patients with a CTR of 0. Aggressive cancer occurred in 4% of patients with a CTR of 0 and in 70% of patients with a CTR > 25%. Aggressive cancer was observed in 46% of the patients whose CTR increased during the follow-up period and in 8% of the patients whose tumors increased in size. Conclusions A higher CTR and an increase in CTR during follow-up were associated with invasive cancer. A follow-up period of 3 years is considered to be adequate for judging tumor growth in patients with a CTR > 0, whereas a longer follow-up period might be needed for patients with a CTR of 0.

The aim of this study is to assess the effect of blood pressure (BP) on coronary computed tomography angiography (CTA) derived computational fractional flow reserve (CTA-FFR). Twenty-one patients who underwent coronary CTA and invasive FFR were retrospectively identified. Ischemia was defined as invasive FFR ≤0.80. Using a work-in-progress computational fluid dynamics algorithm, CTA-FFR was computed with BP measured before CTA, and simulated BPs of 60/50, 90/60, 110/70, 130/80, 150/90, and 180/100 mmHg respectively. Correlation between CTA-FFR and invasive FFR was assessed using Pearson test. The repeated measuring test was used for multiple comparisons of CTA-FFR values by simulated BP inputs. Twenty-nine vessels (14 with invasive FFR ≤0.80) were assessed. The average CTA-FFR for measured BP (134 ± 20/73 ± 12 mmHg) was 0.77 ± 0.12. Correlation between CTA-FFR by measured BP and invasive FFR was good (r = 0.735, P

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.

Modulation of cardiac contractility by α-adrenoceptor is well known in several mammals. Mice are useful experimental animals, but α-adrenoceptor-mediated responses have been examined only in the ventricles. To determine function of α-adrenoceptors in the atrium, effects of α-adrenoceptor agonists on spontaneous contraction and electrical-field stimulation (EFS)-induced contraction were examined. In addition, expression of α

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.

Personalised breast cancer therapy requires pathological characterisation of tumours. The proliferative index, based on Ki67, is pivotal, but a standard method has not been established. Here we look for an easy and practical way to evaluate Ki67.Immunohistochemical staining of estrogen receptors, progesterone receptors, HER2 and Ki67 (MIB-1) was performed on resected specimens from 406 primary invasive ductal carcinomas. Ki67 labelling index (LI) from manual counting was compared with visual assessment using a 5-grade scale (Eye-5). Next, 10 pathologists evaluated 100 samples with marked hot spots by using Eye-5. Another 100 samples without marking were also assessed by eight pathologists. One year later, two pathologists reviewed 222 cases with Eye-5. Prognosis was analysed among estrogen receptor-positive cases with postoperative endocrine therapy.Eye-5 showed good correlation to LI. All 136 cases of score 4-5 had LI20% and all 56 cases of score 1 had LI20%, which means that manual counting was not necessary for about half of the cases. Interobserver and intraobserver variability was low even when a hot spot was not fixed. Eye-5 also correlated with histological grade and lymph node metastasis. Combining Eye-5 and histological grade created a new algorism to predict LI, which allows 80% of all cases (74% of luminal cases) without manual counting. Cases of Eye-5 score 1-2 had significantly better survival than score 3-5.Visual assessment of Ki67 by a 5-grade scale (Eye-5) is fast, easy, and reliable with acceptably low interobserver and intraobserver variability. Eye-5 can replace LI in many luminal tumours, and is a strong candidate as a standard method of evaluating Ki67.

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.

Background: One of surgical goals is decreasing of positive resection margin (PRM). In radical prostatectomy, PRM is important because of prognostic factor. We examine the relationship of PRM, cancer location and learning curve after laparoscopic radical prostatectomy (LRP). Methods: Between May, 2009 and May, 2015, 331 consecutive patients were treated with LRP. The resection margin status, Gleason score, pathological stage, cancer location and diameter were assessed in each surgical specimen, and the independent factors for PRM and prostate-specific antigen (PSA) failure were identified. The learning curve for PRM was calculated and the number of cases until the plateau was obtained. Results: PRM was found in 30.5% of all patients, with 27.7% in the pT2 patients and 39.0% in the pT3 patients. The most common site of PRM was in the apex-anterior. The 5-year PSA failure-free survival rate was 73.9%. In patients with a negative resection margin, the 5-year PSA failure-free survival rate was 81.6%, and in patients with PRM, it was 57.4%. The factors associated with PSA failure-free survival were PRM and elevated PSA. The tumor location was not associated with PSA failure-free survival. The factors associated with PRM were tumor location, nerve sparing procedure, and tumor diameter. When the tumor was localized in the apex-anterior, the rate of PRM was elevated 3-fold comparing the tumor in apex-posterior. The learning curve of all surgeons for obtaining a negative resection margin plateaus after 167 cases. The curve of a single surgeon was more improved than all surgeons and the rate of PRM was 16.7%. Conclusions: PRM was associated with both cancer location and diameter. The learning curve of PRM reached a plateau in about 170 cases. However, PRM can be further reduced. These findings related to LRP outcomes are useful for improvement in surgical techniques and for determining prognosis.

Background Patients with lung cancer often present with recurrence, even after resection. The identification of risk factors for recurrence after resection is useful. Methods Among 1,338 patients with lung cancer who underwent a complete resection, 277 developed recurrences post surgery. Data regarding the TNM factors, histologic subtype, and presence/absence of vessel invasion were analyzed retrospectively using the survival tree method to identify groups with a high risk of recurrence after resection. Results The results revealed that the T factor, the N factor, and lymphatic (ly) and blood (v) vessel invasion were related to the risk of recurrence, and six combinations of these factors were identified using the survival tree method: group A: v = 0, T ≤ 1b, ly = 0; group B: v = 0, T ≤ 1b, ly ≥ 1; group C: v = 0, T ≥ 2a; group D: v ≥ 1, N ≤ 1, T ≤ 2b; group E: v ≥ 1, N ≤ 1, T ≥ 3; and group F: v ≥ 1, N ≥ 2. The six groups were then further classified into three groups: a low-risk group (group A), a moderate-risk group (groups B, C, and D), and a high-risk group (groups E and F). The 5-year recurrence-free survival rate was approximately 98% for the low-risk group, 75% for the moderate-risk group, and 30% for the high-risk group. Conclusions Combining the T, N, v, and ly factors allowed the precise identification of a group with a high risk of recurrence after resection.

The Ki67 labeling index (LI) reflects the proliferative activity of breast cancers and defines luminal A and B tumors; however, no detailed method to measure Ki67 has been standardized. Here, we propose a fast and easy way to evaluate Ki67.Immunohistochemical staining of estrogen receptor (ER), progesterone receptor (PgR), HER2 and Ki67 (MIB-1) was performed on 235 primary invasive ductal carcinomas. For each sample, a hot spot with many Ki67+ cells was identified using a low-power field (40×, 4× objective). Three independent areas in high-power field (400×) were selected at the hot spot, and all cancer cells in the 3 areas were manually counted to calculate LI (% Ki67+ cells). Alternatively, micrographs taken at 100× and 200× fields including the hot spot were shown to 2 pathologists, who visually assessed percentages of Ki67+ cells in 10 % intervals at a glance (Eye-10).Eye-10 and LI were strongly correlated (r = 0.9412, P 0.0001). All cases of Eye-10 ≥ 30 % had LI 14 %; most of those10 % had LI 14 %. Of 170 ER+/HER2- tumors, Eye-10-based subtypes matched 87 % of LI-driven subtypes, and interobserver agreement was good (κ = 0.705).Eye-10 is far easier than counting many cancer cells and useful for classifying breast cancers. Eye-10 can exclude obviously high and low Ki67 cases, leaving a "gray zone" around a cutoff point. Combining Eye-10 and manual counting is a good candidate for a standard method to evaluate Ki67.

We evaluated the image quality and diagnostic performance of late iodine enhancement computed tomography (LIE-CT) with knowledge-based iterative model reconstruction (IMR) for the detection of myocardial infarction (MI) in comparison with late gadolinium enhancement magnetic resonance imaging (LGE-MRI). The study investigated 35 patients who underwent a comprehensive cardiac CT protocol and LGE-MRI for the assessment of coronary artery disease. The CT protocol consisted of stress dynamic myocardial CT perfusion, coronary CT angiography (CTA) and LIE-CT using 256-slice CT. LIE-CT scans were acquired 5 min after CTA without additional contrast medium and reconstructed with filtered back projection (FBP), a hybrid iterative reconstruction (HIR), and IMR. The signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) were assessed. Sensitivity and specificity of LIE-CT for detecting MI were assessed according to the 16-segment model. Image quality scores, and diagnostic performance were compared among LIE-CT with FBP, HIR and IMR. Among the 35 patients, 139 of 560 segments showed MI in LGE-MRI. On LIE-CT with FBP, HIR, and IMR, the median SNRs were 2.1, 2.9, and 6.1; and the median CNRs were 1.7, 2.2, and 4.7, respectively. Sensitivity and specificity were 56 and 93% for FBP, 62 and 91% for HIR, and 80 and 91% for IMR. LIE-CT with IMR showed the highest image quality and sensitivity (p

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)

Objectives: To examine the association between cancer location, resection margins and oncological outcome in patients undergoing radical prostatectomy. Methods: A total of 505 patients who underwent radical prostatectomy between 1993 and 2009 were included in this analysis. Cancer location, resection margins and pathological factors were assessed based on the 2010 General Rules for Clinical and Pathological Studies on Prostate Cancer. Biochemical recurrence was defined as prostate-specific antigen >0.2 ng/mL. Results: Positive resection margins were found in 38.4% of all cases, in 30.3% of pT2 cases and in 57.7% of pT3 cases. The cancer was distributed evenly among the apex-anterior, apex-posterior and middle lesions, which each accounted for approximately 30% of the whole lesion in the main tumor. A higher rate of positive resection margins (47.6%) was found in the apex-anterior lesions. In minor tumors, most cancer was located in the middle lesion and accounted for approximately 60% of the lesion. However, positive resection margins were detected significantly more frequently in the apex-anterior lesion of minor tumors. The 5-year and 10-year biochemical recurrence-free survival rates were 36.2% and 32.0%, respectively, in patients with a positive resection margin, and 82.7% and 77.4%, respectively, in those with a negative resection margin. Cancer location was an independent risk factor for biochemical recurrence and a positive resection margin. Recurrence-free survival was lower in pT2 cases with a positive resection margin compared with pT3 cases with a negative resection margin. Conclusions: Cancer location and occurrence of positive resection margins can have negative effects on recurrence-free survival. Thus, it is of utmost importance to avoid positive resection margins during radical prostatectomy.

1Urology, 2 Radiation Oncology, and 3 Objectives: To examine quality of life (QOL) for 3 years after radical retropubic prostatectomy (RRP) or permanent prostate brachytherapy (PPB) and to determine differences between the two procedures. Methods: In all 107 patients who underwent RRP and 91 who received PPB between October 2005 and July 2007 were included in this study. QOL surveys were performed using the international prostate symptom score (IPSS), the Medical Outcome Study 8-items short form health survey and the expanded prostate cancer index composite at baseline and 1, 3, 6, 12 and 36 months after treatment. Results: At 3 years, all parameters for general QOL and almost all for disease-specific QOL were similar to those at 12 months. Urinary continence after RRP slightly improved from 12 months to 3 years, but it was still significantly worse than that after PPB. Scores for urinary irritation or obstruction and for bowel function and bother at 3 years were similar between the two groups. Sexual function and bother did not change between 12 months and 3 years in either group. Sexual function at 3 years after RRP was worse than that after PPB. Recovery from urinary incontinence and sexual function after RRP with nerve sparing were similar to those after PPB. Urinary incontinence at 3 years correlated with the treatment method and patients’ age, whereas urinary irritation/obstruction and urinary bother correlated with the pretreatment IPSS. Conclusion: QOL assessment represents an important issue in prostate cancer management. Our findings are likely to be of aid in the development of a treatment plan for prostate cancer patients.

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.