The combination of docetaxel, cisplatin, and 5‐fluorouracil (DCF) as preoperative treatment for esophageal squamous cell carcinoma (ESCC) has not been investigated. We carried out a multicenter phase ...II feasibility study of preoperative chemotherapy with DCF for ESCC. Patients with clinical stage II/III ESCC (International Union Against Cancer TNM classification system, 6th edition) were eligible. Chemotherapy consisted of i.v. docetaxel (70–75 mg/m2) and cisplatin (70–75 mg/m2) on day 1, and continuous infusion of fluorouracil (750 mg/m2/day) on days 1–5. Antibiotic prophylaxis on days 5–15 was mandatory. This regimen was repeated every 3 weeks with a maximum of three cycles allowed. After completion of chemotherapy, esophagectomy with extended lymphadenectomy was carried out. The primary endpoint was the completion rate of protocol treatment. Forty‐two eligible patients were enrolled. During chemotherapy, the most common grade 3 or 4 toxicities were neutropenia (83%), anorexia (7%), and stomatitis (5%). Forty‐one (98%) patients underwent surgery. The completion rate of protocol treatment was 90.5% (38/42). No treatment‐related death was observed and the incidence of operative morbidity was tolerable. According to RECIST, the overall response rate after the completion of DCF was 64.3%. Pathological complete response was achieved in 17%. The estimated 2‐year progression‐free survival and overall survival were 74.5% and 88.0%, respectively. Although these data are preliminary, preoperative DCF was well tolerated. Antitumor activity was highly promising and warrants further investigation. This trial was registered with University Hospital Medical Information Network (no. UMIN000002396).
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
The central sensitization inventory (CSI) evaluates the central sensitization (CS)-related symptoms associated with increased pain sensitivity. However, the CSI includes items that are not directly ...related to pain. In this study, 146 patients with pain were classified into subgroups by k-means cluster analysis based on the short form of the central sensitization inventory (CSI9) and pain scores. In addition, inter-group and multiple comparisons were performed to examine the characteristics of each group. As a result of this study, there were three subgroups (clusters 1, 2, and 3) in which the CSI9 and pain intensity were both low, moderate, and high, and one subgroup (cluster 4) in which only CSI9 was high and pain intensity was low. Two subgroups with high CSI9 scores but contrasting pain intensities (clusters 3 and 4) were extracted; the pattern of CS-related symptoms in these two groups was very similar, with no differences in most of the non-pain factors. It is necessary to consider these points when interpreting the clinical condition of a patient with pain when using the assessment of CS-related symptoms.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Thiopurines, mercaptopurine, and azathioprine are used as immunosuppressants in the treatments of inflammatory bowel disease, rheumatoid arthritis, and organ transplantation and as chemotherapeutic ...drugs for the treatment of acute leukemia and chronic myeloid leukemia. This drug class sometimes causes severe adverse reactions, including bone marrow suppression and hair loss. Genetic polymorphisms of the metabolizing enzyme thiopurine S-methyltransferase have been used for predicting these reactions in Caucasians, but these allele frequencies are less frequently observed in Asian populations. Recently, nudix hydrolase 15 (NUDT15) polymorphisms have been shown to play an important role in thiopurine-induced adverse reactions in Asians. In this review, we summarize the NUDT15 studies, mainly in Asian countries, and their implementation in several countries.
We study low-energy transport through a quantum dot coupled to one normal and two superconducting (SC) leads in a Y-shaped junction. In this geometry a crossover between Kondo-dominated and ...Cooper-pairing-dominated states occurs by tuning parameters such as the quantized energy level epsilon sub(d) of the dot and the Josephson phase varphi, which induces a supercurrent flowing between the two SC leads through the dot. Furthermore, Andreev scattering takes place at the interface between the dot and normal lead. The low-lying energy states of this system can be described by a local Fermi-liquid theory for interacting Bogoliubov particles. In a description based on an Anderson impurity model, we calculate transport coefficients, renormalized parameters, and spectral function, using Wilson's numerical renormalization group approach, in the limit of a large SC gap. Our results demonstrate how the Andreev resonance level approaches the Fermi level in the crossover region between the Cooper-pairing singlet state and the strong-coupling situation as varepsilond or varphi are varied. The strong-coupling situation shows a Kondo effect with a significantly renormalized resonance width. The crossover is smeared when the coupling between the dot and the normal lead is large. Furthermore, asymmetry in the Josephson junction suppresses the cancellations of the SC proximity for finite 0, and it favors the SC singlet state rather than the Kondo singlet.
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CMK, CTK, FMFMET, IJS, NUK, PNG, UM
The impacts of polymorphic cytochrome P450 (P450 or CYP) 2C9 on drug interactions and the pharmacokinetics of cyclooxygenase inhibitors have attracted considerable attention. In this survey, the ...prescribed dosage was reduced or discontinued in 150 and 56 patients, respectively, receiving celecoxib and diclofenac prescribed alone, as recorded in a Japanese database of adverse drug events. Among the factors underlying adverse events, intrinsic drug clearance rates may be a contributing factor. The pharmacokinetically modeled plasma concentrations of celecoxib after an oral 200-mg dose increased in CYP2C9*3 homozygotes: the area under the plasma concentration curve was 4.7-fold higher than that in CYP2C9*1 homozygotes. In patients with CYP2C9*3/*3, the virtual hepatic concentrations of diclofenac after three daily 25-mg doses for a week were 11-fold higher than the plasma concentrations in subjects with CYP2C9*1/*1. The in vivo and in vitro fractions of the victim drug metabolized by a specific polymorphic P450 form is an important determining factor for estimating drug–drug interactions. Virtual hepatic and plasma exposures estimated by pharmacokinetic modeling in patients harboring the impaired CYP2C9*3 allele could represent a causal factor for adverse events induced by celecoxib or diclofenac in a manner similar to that for drug interactions.
The process of pain recovery varies and can include the recovery, maintenance, or worsening of symptoms. Many cases of patients with pain show a tendency of recovering as predicted; however, some do ...not. The characteristics of cases that do not fit the prediction of pain recovery remain unclear. We performed cluster and decision tree analyses to reveal the characteristics in cases that do not fit the prediction of pain recovery. A total of 43 patients with musculoskeletal pain (nonoperative: 22 patients, operative: 13 patients) and central pain (brain disease: 5 patients, spinal cord disease: 3 patients) were included in this longitudinal study. Central sensitivity syndrome (CSS) outcome measures (Central Sensitisation Inventory), pain intensity-related outcome measures (Short-Form McGill Pain Questionnaire-2 (SFMPQ-2)), and cognitive-emotional outcome measures (Hospital Anxiety and Depression Scale and Pain Catastrophising Scale-4) of all patients were assessed at baseline and after 1-2 months. Regression analysis was used to calculate pain recovery prediction values. A hierarchical cluster analysis based on the predicted change of SFMPQ-2 and the observed change of SFMPQ-2 was used to extract subgroups that fit and those that do not fit pain recovery prediction. To extract the characteristics of subgroups that do not fit the prediction of pain recovery, a decision tree analysis was performed. The level of significance was set at 5%. In the results of cluster analysis, patients were classified into three subgroups. Cluster 1 was characterised by worse pain intensity from baseline, cluster 2 by pain, having recovered less and mildly than the predicted value, and Cluster 3 by a marked recovery of pain. In the results of the decision tree analysis, the CSI change was extracted as an indicator related to the classification of all clusters. Our findings suggest that the poor improvement of CSS is characteristic in cases that do not fit the prediction of pain recovery.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
The significance of probabilistic risk assessments (PRAs) of nuclear power plants against external events was re-recognized after the Fukushima Daiichi Nuclear Power Plant accident. Regarding the ...seismic PRA, handling correlated failures of systems, components, and structures (SSCs) is very important because this type of failure negatively affects the redundancy of accident mitigation systems. The Japan Atomic Energy Research Institute initially developed a fault tree quantification methodology named the direct quantification of fault tree using Monte Carlo simulation (DQFM) to handle SSCs’ correlated failures in detail and realistically. This methodology allows quantifying the top event occurrence probability by considering correlated uncertainties related to seismic responses and capacities with Monte Carlo sampling. The usefulness of DQFM has already been demonstrated. However, improving its computational efficiency would allow risk analysts to perform several analyses such as uncertainty analysis efficiently. Therefore, we applied quasi-Monte Carlo and importance sampling to the DQFM calculation of simplified seismic PRA and examined their effects. Specifically, the conditional core damage probability of a hypothetical pressurized water reactor was analyzed with some assumptions. Applying the quasi-Monte Carlo sampling accelerates the convergence of results at intermediate and high ground motion levels by an order of magnitude over Monte Carlo sampling. The application of importance sampling allows us to obtain a statistically significant result at a low ground motion level, which cannot be obtained through Monte Carlo and quasi-Monte Carlo sampling. These results indicate that these applications provide a notable acceleration of computation and raise the potential for the practical use of DQFM in risk-informed decision-making.
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