Real-world treatment patterns and outcomes of abemaciclib for the treatment of HR + , HER2- metastatic breast cancer patients in Japan.

INTRODUCTION: This study described, in routine clinical practice in Japan, the patient characteristics, treatment patterns, and outcomes of female patients with HR + /HER2- metastatic breast cancer (MBC) who started abemaciclib treatment. METHODS: Clinical charts were reviewed for patients starting abemaciclib in 12/2018-08/2021 with a minimum of 3 months follow-up data post-abemaciclib initiation regardless of abemaciclib discontinuation. Patient characteristics, treatment patterns, and tumor response were descriptively summarized. Kaplan-Meier curves estimated progression-free survival (PFS). RESULTS: 200 patients from 14 institutions were included. At abemaciclib initiation, median age was 59 years, and the Eastern Cooperative Oncology Group performance status score was 0/1/2 for 102/68/5 patients (58.3/38.9/2.9%), respectively. Most had an abemaciclib starting dose of 150 mg (92.5%). The percentage of patients receiving abemaciclib as 1st, 2nd, or 3rd line treatment was 31.5%, 25.8%, and 25.2%, respectively. The most frequent endocrine therapy drugs used with abemaciclib were fulvestrant (59%) and aromatase inhibitors (40%). Evaluation of tumor response was available for 171 patients, 30.4% of whom had complete/partial response. Median PFS was 13.0 months (95% CI 10.1-15.8 months). CONCLUSIONS: In a routine clinical practice setting in Japan, patients with HR + , HER2- MBC appear to benefit from abemaciclib treatment in terms of treatment response and median PFS, with the results broadly reflecting the evidence demonstrated in clinical trials.

Significance of Granulocyte Colony-Stimulating Factor-Combined High-Dose Cytarabine, Cyclophosphamide, and Total Body Irradiation in Allogeneic Hematopoietic Cell Transplantation for Myeloid Malignant Neoplasms.

Allogeneic hematopoietic cell transplant (HCT) is a curative procedure for myeloid malignant neoplasms, but relapse after HCT remains critical. A conditioning regimen involving granulocyte colony-stimulating factor-combined high-dose cytarabine, cyclophosphamide, and total body irradiation (G-CSF-combined high-dose cytarabine/cyclophosphamide/total-body irradiation [HDCA/CY/TBI]) was reported to improve outcomes after cord blood transplant (CBT) for myeloid malignant neoplasms, but this regimen was not previously evaluated among patients undergoing bone marrow transplant (BMT) or peripheral blood stem cell transplant (PBSCT). METHODS: We retrospectively analyzed 28 patients who underwent allogeneic HCT including BMT from a related (1 patient) or unrelated donor (9 patients), PBSCT from a related donor (7 patients), or single-unit CBT from an unrelated donor (11 patients) after a G-CSF-combined HDCA/CY/TBI regimen. RESULTS: All patients achieved neutrophil and platelet engraftment, which were significantly more rapid in the BMT/PBSCT group than in the CBT group. Eighteen patients were alive at a median follow-up of 54.3 months. The 3-year relapse and nonrelapse mortality rates were 28.6% and 7.1%, respectively, which were similar between the BMT/PBSCT and CBT groups. Overall survival and disease-free survival at 5 years after HCT were 62.6% and 64.3%, respectively, which were also similar between the BMT/PBSCT and CBT groups. Only disease status at HCT had a significant impact on overall survival and disease-free survival (86.7% with standard risk vs 38.5% with high risk and 86.7% with standard risk vs 38.5% with high risk, respectively). CONCLUSION: A G-CSF-combined HDCA/CY/TBI regimen is a promising conditioning in patients with myeloid malignant neoplasms who undergo not only CBT but also BMT or PBSCT.

Factors predicting early postpartum glucose intolerance in Japanese women with gestational diabetes mellitus: decision-curve analysis.

AIMS: To identify factors predicting early postpartum glucose intolerance in Japanese women with gestational diabetes mellitus, using decision-curve analysis. METHODS: A retrospective cohort study was performed. The participants were 123 Japanese women with gestational diabetes who underwent 75-g oral glucose tolerance tests at 8-12 weeks after delivery. They were divided into a glucose intolerance and a normal glucose tolerance group based on postpartum oral glucose tolerance test results. Analysis of the pregnancy oral glucose tolerance test results showed predictive factors for postpartum glucose intolerance. We also evaluated the clinical usefulness of the prediction model based on decision-curve analysis. RESULTS: Of 123 women, 78 (63.4%) had normoglycaemia and 45 (36.6%) had glucose intolerance. Multivariable logistic regression analysis showed insulinogenic index/fasting immunoreactive insulin and summation of glucose levels, assessed during pregnancy oral glucose tolerance tests (total glucose), to be independent risk factors for postpartum glucose intolerance. Evaluating the regression models, the best discrimination (area under the curve 0.725) was obtained using the basic model (i.e. age, family history of diabetes, BMI ≥25 kg/m2 and use of insulin during pregnancy) plus insulinogenic index/fasting immunoreactive insulin <1.1. Decision-curve analysis showed that combining insulinogenic index/fasting immunoreactive insulin <1.1 with basic clinical information resulted in superior net benefits for prediction of postpartum glucose intolerance. CONCLUSIONS: Insulinogenic index/fasting immunoreactive insulin calculated using oral glucose tolerance test results during pregnancy is potentially useful for predicting early postpartum glucose intolerance in Japanese women with gestational diabetes.

Quantum key distribution with hacking countermeasures and long term field trial.

Quantum key distribution's (QKD's) central and unique claim is information theoretic security. However there is an increasing understanding that the security of a QKD system relies not only on theoretical security proofs, but also on how closely the physical system matches the theoretical models and prevents attacks due to discrepancies. These side channel or hacking attacks exploit physical devices which do not necessarily behave precisely as the theory expects. As such there is a need for QKD systems to be demonstrated to provide security both in the theoretical and physical implementation. We report here a QKD system designed with this goal in mind, providing a more resilient target against possible hacking attacks including Trojan horse, detector blinding, phase randomisation and photon number splitting attacks. The QKD system was installed into a 45 km link of a metropolitan telecom network for a 2.5 month period, during which time the system operated continuously and distributed 1.33 Tbits of secure key data with a stable secure key rate over 200 kbit/s. In addition security is demonstrated against coherent attacks that are more general than the collective class of attacks usually considered.

Enhanced recovery after surgery for gastric cancer and an assessment of preoperative carbohydrate loading.

BACKGROUND: We previously reported on the feasibility of enhanced recovery after surgery (ERAS) protocol for gastric cancer with a prospective phase II study, but the superiority of this approach over non-ERAS perioperative management remains unclear. Preoperative carbohydrate loading, an important element of the ERAS protocol, has been shown to reduce insulin resistance, but its effects on clinical endpoints in gastric cancer surgery remain controversial. The aim of this study was to clarify the efficacy of the ERAS protocol for gastric cancer surgery, with particular focus on preoperative carbohydrate loading. METHODS: In this ERAS case-control study, we enrolled 121 patients as a case group and 259 patients undergoing gastrectomy for gastric cancer with our conventional perioperative management as a control group. Matched-pair analysis was performed to balance the patients' characteristics for comparison analysis. RESULTS: After matching, 108 patients were included in each group. Postoperative hospital stay was significantly shorter in the ERAS group than in the control group (8 days vs. 9 days, p < 0.001), while the incidence of Clavien-Dindo classification grade II or more postoperative complication was similar between the groups (11.1% vs. 15.7%, p = 0.325). No significant differences were found in serum albumin level, body weight, or grip strength between the groups before surgery and at 1 week and 1 month after surgery. CONCLUSION: Use of the ERAS protocol for gastric cancer shortened the length of postoperative hospital stay without increasing complications. Preoperative carbohydrate loading didn't improve the postoperative nutritional status or maintain the muscle strength postoperatively.

Efficacy and safety of once-weekly dulaglutide in combination with sulphonylurea and/or biguanide compared with once-daily insulin glargine in Japanese patients with type 2 diabetes: a randomized, open-label, phase III, non-inferiority study.

AIMS: To evaluate 0.75 mg of dulaglutide, a once-weekly glucagon-like peptide-1 receptor agonist, compared with once-daily insulin glargine for glycaemic control in Japanese patients with type 2 diabetes (T2D). METHODS: In this phase III, randomized, open-label, parallel-group, 26-week study, 361 patients with inadequately controlled T2D receiving sulphonylureas and/or biguanides, aged ≥20 years, with glycated haemoglobin (HbA1c) levels 7.0-10.0% (53-86 mmol/mol), inclusive, were randomized (1 : 1) to receive dulaglutide or glargine. Participants and investigators were not masked to treatment allocation. The primary measure was change from baseline in HbA1c at 26 weeks, analysed using a mixed-effects model for repeated measures, with a predefined non-inferiority margin of 0.4%. RESULTS: At week 26, least-squares (LS) mean (standard error) reductions in HbA1c were -1.44 (0.05)% [-15.74 (0.55) mmol/mol] in the dulaglutide group and -0.90 (0.05)% [-9.84 (0.55) mmol/mol] in the glargine group. The mean between-group treatment difference in HbA1c was -0.54% (95% CI -0.67, -0.41) [-5.90 mmol/mol (95% CI -7.32, -4.48)]; p < 0.001. Dulaglutide significantly reduced body weight compared with glargine at week 26 (LS mean difference -1.42 kg, 95% CI -1.89, -0.94; p < 0.001). The most frequent adverse events with dulaglutide treatment were nasopharyngitis and gastrointestinal symptoms. The incidence of hypoglycaemia was significantly lower with dulaglutide [47/181 (26%)] compared with glargine [86/180 (48%)], p < 0.001. CONCLUSION: In Japanese patients with T2D uncontrolled on sulphonylureas and/or biguanides, once-weekly dulaglutide was superior to once-daily glargine for reduction in HbA1c at 26 weeks. Although dulaglutide increased gastrointestinal symptoms, it was well tolerated, with an acceptable safety profile.

High speed prototype quantum key distribution system and long term field trial.

Securing information in communication networks is an important challenge in today's world. Quantum Key Distribution (QKD) can provide unique capabilities towards achieving this security, allowing intrusions to be detected and information leakage avoided. We report here a record high bit rate prototype QKD system providing a total of 878 Gbit of secure key data over a 34 day period corresponding to a sustained key rate of around 300 kbit/s. The system was deployed over a standard 45 km link of an installed metropolitan telecommunication fibre network in central Tokyo. The prototype QKD system is compact, robust and automatically stabilised, enabling key distribution during diverse weather conditions. The security analysis includes an efficient protocol, finite key size effects and decoy states, with a quantified key failure probability of ε = 10⁻¹°.

Long-term treatment with empagliflozin as add-on to oral antidiabetes therapy in Japanese patients with type 2 diabetes mellitus.

AIMS: To evaluate the safety and efficacy of empagliflozin for 52 weeks as add-on to one other oral antidiabetes therapy in Japanese patients with type 2 diabetes mellitus (T2DM). METHODS: Patients on biguanide (n = 133), thiazolidinedione (n = 273), α-glucosidase inhibitor (n = 139), dipeptidyl-peptidase-4 inhibitor (n = 139) or glinide (n = 140) were randomized 1 : 1 to receive empagliflozin 10 or 25 mg double-blind as add-on therapy for 52 weeks. Patients on sulphonylurea (SU; n = 336) were randomized 2 : 2 : 1 to receive empagliflozin 10 or 25 mg double-blind or open-label metformin as add-on therapy for 52 weeks. The primary objective was to evaluate safety. Change from baseline in glycated haemoglobin (HbA1c) at week 52 was a secondary endpoint. RESULTS: Adverse events (AEs) were reported in 67.6-84.6% of patients receiving empagliflozin. Confirmed hypoglycaemic AEs (plasma glucose ≤70 mg/dl and/or requiring assistance) were reported in 4.4 and 6.6%, respectively, of patients receiving empagliflozin 10 and 25 mg as add-on to SU and in 0.0 to 2.9%, respectively, of patients receiving empagliflozin 10 and 25 mg as add-on to other therapies. Baseline mean ± standard deviation HbA1c ranged from 7.51 ± 0.73 to 8.06 ± 0.76% across background therapy groups. At week 52, adjusted mean ± standard error changes from baseline in HbA1c ranged from -0.77 ± 0.06 to -1.00 ± 0.06% in patients receiving empagliflozin. CONCLUSIONS: In Japanese patients with T2DM, empagliflozin 10 and 25 mg as add-on to one other oral antidiabetes therapy for 52 weeks were well tolerated and were associated with clinically meaningful reductions in HbA1c.

Cytomegalovirus ventriculoencephalitis in a reduced- intensity conditioning cord blood transplant recipient.

Cytomegalovirus (CMV) encephalitis most commonly occurs in patients with advanced human immunodeficiency virus infection and profound CD4 cell depletion and is rare in transplant recipients. We describe a patient with pathologically proven CMV ventriculoencephalitis that occurred after human herpesvirus-6 limbic encephalitis, following reduced-intensity conditioning cord blood transplantation (CBT). At approximately day 150 after CBT, the patient became acutely confused after steroid therapy for grade III acute graft-versus-host disease. Fluid-attenuated inversion recovery magnetic resonance imaging of the brain revealed a communicating hydrocephalus with abnormal periventricular hyperintensity. Neuropathologic examination of the brain at autopsy revealed necrotizing CMV ventriculoencephalitis, limbic encephalitis, and multifocal necrotizing leukoencephalopathy. This case represents the first report of CMV encephalitis following CBT and serves to highlight the interrelationship between viruses in transplant recipients.

Distinct thermal migration behaviors in response to different thermal gradients in Caenorhabditis elegans.

The nematode Caenorhabditis elegans exhibits a complex behavior called thermotaxis in response to temperature. This behavior is defined as a form of associative learning, in which temperature pairs with the presence or absence of food. Different interpretations have been drawn from the diverse results obtained by several groups, mainly because of the application of different methodologies for the analysis of thermotaxis. To clarify the discrepancies in behavioral observations and subsequent interpretations by different laboratories, we attempted to systematize several parameters to observe thermotaxis behavior as originally defined by Hedgecock and Russell in 1975. In this study, we show clearly how C. elegans can show a conditioned migration toward colder or warmer areas on a thermal gradient, given certain criteria necessary for the observation of thermotaxis. We thus propose to distinguish thermotaxis from other temperature-related behaviors, such as the warm avoidance response displayed at temperature gradients of 1 degrees C/cm and steeper.

Increased insulin demand promotes while pioglitazone prevents pancreatic beta cell apoptosis in Wfs1 knockout mice.

AIMS/HYPOTHESIS: The WFS1 gene encodes an endoplasmic reticulum (ER) membrane-embedded protein called Wolfram syndrome 1 protein, homozygous mutations of which cause selective beta cell loss in humans. The function(s) of this protein and the mechanism by which the mutations of this gene cause beta cell death are still not fully understood. We hypothesised that increased insulin demand as a result of obesity/insulin resistance causes ER stress in pancreatic beta cells, thereby promoting beta cell death. METHODS: We studied the effect of breeding Wfs1 ( -/- ) mice on a C57BL/6J background with mild obesity and insulin resistance, by introducing the agouti lethal yellow mutation (A ( y ) /a). We also treated the mice with pioglitazone. RESULTS: Wfs1 ( -/- ) mice bred on a C57BL/6J background rarely develop overt diabetes by 24 weeks of age, showing only mild beta cell loss. However, Wfs1 ( -/- ) A ( y ) /a mice developed selective beta cell loss and severe insulin-deficient diabetes as early as 8 weeks. This beta cell loss was due to apoptosis. In Wfs1 ( +/+ ) A ( y ) /a islets, levels of ER chaperone immunoglobulin-binding protein (BiP)/78 kDa glucose-regulated protein (GRP78) and phosphorylation of eukaryotic translation initiation factor 2, subunit alpha (eIF2alpha) apparently increased. Levels of both were further increased in Wfs1 ( -/- ) A ( y ) /a murine islets. Electron micrography revealed markedly dilated ERs in Wfs1 (-/-) A ( y ) /a murine beta cells. Interestingly, pioglitazone treatment protected beta cells from apoptosis and almost completely prevented diabetes development. CONCLUSIONS/INTERPRETATION: Wfs1-deficient beta cells are susceptible to ER stress. Increased insulin demand prompts apoptosis in such cells in vivo. Pioglitazone, remarkably, suppresses this process and prevents diabetes. As common WFS1 gene variants have recently been shown to confer a risk of type 2 diabetes, our findings may be relevant to the gradual but progressive loss of beta cells in type 2 diabetes.

Reaction characteristics of a tooth-bleaching agent containing H2O2 and NaF: in vitro study of crystal structure change in treated hydroxyapatite and chemical states of incorporated fluorine.

This in vitro study was performed to elucidate the reaction mechanism of sodium fluoride (NaF), which is added to tooth-bleaching agents to lessen the adverse effect of hydrogen peroxide (H2O2) on teeth. Both hydroxyapatite (HAP) and dihydrated dicalcium phosphate (DCPD), model substances for dental hard tissues, dissolved easily in a simple H2O2 solution. In the H2O2/NaF solutions, however, fluorine compounds that could not be identified by X-ray diffraction (XRD) due to the smallness of the products were formed on the surface of the HAP. X-ray photoelectron spectroscopy (XPS) studies demonstrated that fluoridated hydroxyapatite (FHAP) was formed on HAP, and that calcium fluoride (CaF2) formation was accelerated by increasing the concentrations of fluorine and H2O2 along with the partial dissolution of HAP. In H2O2/NaF solution, DCPD also transformed easily to FHAP and CaF2, which are favorable to the remineralization process on the tooth surface. Thus, the mechanism of NaF was elucidated, and its use together with H2O2 for tooth bleaching was proved to be effective. Methodologically, the XPS two-dimensional plot made it possible for the first time to directly estimate the ratio of FHAP and CaF2 in the reaction products, in contrast to the conventional wet-analytical method, which is simply based on the difference in solubility of the two components.

Salivary films on hydroxyapatite studied by an in vitro system for investigating the effect of metal ions and by a quartz-crystal microbalance system for monitoring layer-by-layer film formation.

The salivary film or the acquired pellicle is a protein film formed initially on the enamel surface of teeth. Such a film plays an important role in enamel protection, but is also an initial substructure for the formation of plaque and the cosmetically undesirable colored stain. The composition and the structure of the film are still essentially unknown because of the difficulty of its isolation for characterization. The purpose of this study was to investigate the effect of some metal cations on the salivary film or the pellicle formation, and also to clarify the mechanism of development. First, using infrared spectroscopy (IR) and X-ray photoelectron spectroscopy (XPS), the in situ-formed film in the mouth was confirmed to contain selectively adsorbed well-known proteins. Then, in vitro studies have demonstrated that Ca2+ ions enhance film formation at the initial stage in virtue of Ca bridging and, interestingly, that Mg2+ ions oppositely inhibit the formation. Furthermore, the quartz-crystal microbalance (QCM), utilized successfully for the first time to study the salivary film, has shown the possibility of an alternate accumulation mechanism by which the surface charges on the film are effectively reversed by the opposite charged proteins.

Role of urotensin II gene in genetic susceptibility to Type 2 diabetes mellitus in Japanese subjects.

AIM/HYPOTHESIS: Urotensin II is a potent vasoactive hormone and the urotensin II gene (UTS2) is localized to 1p36-p32, one of the regions reported to show possible linkage with Type 2 diabetes in Japanese subjects. The aim of this study is to investigate a possible contribution of SNPs in the UTS2 gene to the development of Type 2 diabetes. METHODS: We surveyed SNPs in the UTS2 gene in 152 Japanese subjects with Type 2 diabetes mellitus and two control Japanese cohorts: one consisting of 122 elderly subjects who met stringent criteria for being non-diabetic, including being older than 60 years of age with no evidence of diabetes (HbA(1c)<5.6%), and another 268 subjects with normal glucose tolerance. RESULTS: We identified two SNPs with amino acid substitutions, designated T21M and S89N. The allele frequency of 89N was higher in Type 2 diabetic patients than in both elderly normal subjects (p=0.0018) and subjects with normal glucose tolerance (p=0.0011), whereas the allele frequency of T21M was essentially identical in these three groups. Furthermore, in the subjects with normal glucose tolerance, 89N was associated with higher insulin concentrations on oral glucose tolerance test, suggesting reduced insulin sensitivity in subjects with 89N. CONCLUSION/INTERPRETATION: These results strongly suggest that the S89N polymorphism in the UTS2 gene is associated with the development of Type 2 diabetes, via insulin sensitivity, in Japanese subjects.

Leptin increases the viability of isolated rat pancreatic islets by suppressing apoptosis.

To test the hypothesis that leptin secreted from adipose tissue is a mediator linking obesity and pancreatic islet hypertrophy, we examined the effects of leptin on proliferative and apoptotic responses in rat islet cells. Rat pancreatic islets were isolated and incubated with 0, 1, 5, or 75 nM leptin for 24 h under serum-deprived conditions. Cell viability was assessed with 2,5-diphenyltetrazolium bromide and trypan blue dye exclusion tests. Cell proliferation and apoptosis were evaluated with 5-bromo-2'-deoxyuridine incorporation into DNA and DNA ladder formation, respectively. Incubation for 24 h with 1 and 5 nM leptin, the concentrations observed in obese subjects, increased the viability of isolated pancreatic islet cells. Five nanomolar concentrations of leptin did not stimulate 5-bromo-2'-deoxyuridine incorporation into incubated islet cells, indicating no influence on cell proliferation, but did inhibit DNA ladder formation, a hallmark of cell apoptosis. Moreover, 5 nM leptin reduced the triglyceride content and suppressed inducible nitric oxide synthase mRNA expression in incubated islets. These results suggest that leptin increased viable cell numbers via suppression of apoptosis in isolated pancreatic islet cells under these experimental conditions. This mechanism might account at least in part for an obesity-induced increase in pancreatic beta-cell mass.

Development of an in situ polarization-dependent total-reflection fluorescence XAFS measurement system.

An in situ polarization-dependent total-reflection fluorescence X-ray absorption fine structure (PTRF-XAFS) spectroscopy system has been developed, which enables PTRF-XAFS experiments to be performed in three different orientations at various temperatures (273-600 K) and pressures (10(-10) approximately 760 torr). The system consists of a measurement chamber and a preparation chamber. The measurement chamber has a high-precision six-axis goniometer and a multielement solid-state detector. Using a transfer chamber, also operated under ultra-high-vacuum conditions, the sample can be transferred to the measurement chamber from the preparation chamber, which possesses low-energy electron diffraction, Auger electron spectroscopy and X-ray photoelectron spectroscopy facilities, as well as a sputtering gun and an annealing system. The in situ PTRF-EXAFS for Cu species on TiO2 (110) has been measured in three different orientations, revealing anisotropic growth of Cu under the influence of the TiO2 (110) surface.