Pembrolizumab monotherapy for previously untreated, PD-L1-positive, metastatic triple-negative breast cancer: cohort B of the phase II KEYNOTE-086 study.

BACKGROUND: Standard first-line treatment of metastatic triple-negative breast cancer (mTNBC) is chemotherapy. However, outcomes are poor, and new treatment options are needed. In cohort B of the phase II KEYNOTE-086 study, we evaluated pembrolizumab as first-line therapy for patients with PD-L1-positive mTNBC. PATIENTS AND METHODS: Eligible patients had centrally confirmed mTNBC, no prior systemic anticancer therapy for metastatic disease, measurable disease at baseline per RECIST v1.1 by central review, no radiographic evidence of central nervous system metastases, and a tumor PD-L1 combined positive score ≥1. Patients received pembrolizumab 200 mg intravenously every 3 weeks for up to 2 years. The primary end point was safety. Secondary end points included objective response rate, disease control rate (percentage of patients with complete or partial response or stable disease for ≥24 weeks), duration of response, progression-free survival and overall survival. RESULTS: All 84 patients enrolled were women, and 73 (86.9%) received prior (neo)adjuvant therapy. Fifty-three (63.1%) patients had treatment-related adverse events (AEs), including 8 patients (9.5%) with grade 3 severity; no patients experienced grade 4 AEs or died because of treatment-related AEs. Four patients had a complete response and 14 had a partial response, for an objective response rate of 21.4% (95% CI 13.9-31.4). Of the 13 patients with stable disease, 2 had stable disease lasting ≥24 weeks, for a disease control rate of 23.8% (95% CI 15.9-34.0). At data cut-off, 8 of 18 (44.4%) responses were ongoing, and median duration of response was 10.4 months (range 4.2 to 19.2+). Median progression-free survival was 2.1 months (95% CI 2.0-2.2), and median overall survival was 18.0 months (95% CI 12.9-23.0). CONCLUSIONS: Pembrolizumab monotherapy had a manageable safety profile and showed durable antitumor activity as first-line therapy for patients with PD-L1-positive mTNBC. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT02447003.

Stress-induced birefringence in the isotropic phases of lyotropic mixtures.

In this work, the frequency dependence of the known mechano-optical effect which occurs in the micellar isotropic phases (I) of mixtures of potassium laurate (KL), decanol (DeOH), and water is investigated in the range from 200mHz to 200Hz. In order to fit the experimental data, a model of superimposed damped harmonic oscillators is proposed. In this phenomenological approach, the micelles (microscopic oscillators) interact very weakly with their neighbors. Due to shape anisotropy of the basic structures, each oscillator i (i=1,2,3,...,N) remains in its natural oscillatory rotational movement around its axes of symmetry with a frequency ω_{0i}. The system will be in the resonance state when the frequency of the driving force ω reaches a value near ω_{0i}. This phenomenological approach shows excellent agreement with the experimental data. One can find f∼2.5, 9.0, and 4.0Hz as fundamental frequencies of the micellar isotropic phases I, I_{1}, and I_{2}, respectively. The different micellar isotropic phases I, I_{1}, and I_{2} that we find in the phase diagram of the KL-DeOH-water mixture are a consequence of possible differences in the intermicellar correlation lengths. This work reinforces the possibilities of technological applications of these phases in devices such as mechanical vibration sensors.

MR Imaging of the Superior Cervical Ganglion and Inferior Ganglion of the Vagus Nerve: Structures That Can Mimic Pathologic Retropharyngeal Lymph Nodes.

BACKGROUND AND PURPOSE: The superior cervical ganglion and inferior ganglion of the vagus nerve can mimic pathologic retropharyngeal lymph nodes. We studied the cross-sectional anatomy of the superior cervical ganglion and inferior ganglion of the vagus nerve to evaluate how they can be differentiated from the retropharyngeal lymph nodes. MATERIALS AND METHODS: This retrospective study consists of 2 parts. Cohort 1 concerned the signal intensity of routine neck MR imaging with 2D sequences, apparent diffusion coefficient, and contrast enhancement of the superior cervical ganglion compared with lymph nodes with or without metastasis in 30 patients. Cohort 2 used 3D neurography to assess the morphology and spatial relationships of the superior cervical ganglion, inferior ganglion of the vagus nerve, and the retropharyngeal lymph nodes in 50 other patients. RESULTS: All superior cervical ganglions had homogeneously greater enhancement and lower signal on diffusion-weighted imaging than lymph nodes. Apparent diffusion coefficient values of the superior cervical ganglion (1.80 ± 0.28 × 10-3mm2/s) were significantly higher than normal and metastatic lymph nodes (0.86 ± 0.10 × 10-3mm2/s, P < .001, and 0.73 ± 0.10 × 10-3mm2/s, P < .001). Ten and 13 of 60 superior cervical ganglions were hypointense on T2-weighted images and had hyperintense spots on both T1- and T2-weighted images, respectively. The latter was considered fat tissue. The largest was the superior cervical ganglion, followed in order by the retropharyngeal lymph node and the inferior ganglion of the vagus nerve (P < .001 to P = .004). The highest at vertebral level was the retropharyngeal lymph nodes, followed, in order, by the inferior ganglion of the vagus nerve and the superior cervical ganglion (P < .001 to P = .001). The retropharyngeal lymph node, superior cervical ganglion, and inferior ganglion of the vagus nerve formed a line from anteromedial to posterolateral. CONCLUSIONS: The superior cervical ganglion and the inferior ganglion of the vagus nerve can be almost always differentiated from retropharyngeal lymph nodes on MR imaging by evaluating the signal, size, and position.

Long-term health status as measured by EQ-5D among patients with metastatic breast cancer: comparison of first-line oral S-1 and taxane therapies in the randomized phase III SELECT BC trial.

PURPOSE: The goal of chemotherapy for metastatic breast cancer (MBC) is to prolong survival and maintain health-related quality of life. This study aimed to evaluate long-term health status of patients with MBC who participated in the phase III randomized SELECT BC trial. METHODS: In the SELECT BC trial, patients were randomly allocated to the S-1 or taxane (paclitaxel or docetaxel) arm. Health status was assessed by EQ-5D at pre-treatment, 3 and 6 months after randomization, and every 6 months thereafter to the extent possible. Least square mean scores were assessed to compare EQ-5D index values between groups. Time to deterioration analysis was also performed by defining the minimally important difference of EQ-5D as 0.05 or 0.1. RESULTS: The number of patients for EQ-5D analysis was 175 and 208 in the taxane and S-1 arms, respectively. Least square mean EQ-5D index values up to 60 months were 0.741 (95 % CI [0.713-0.769]) in the taxane arm and 0.748 [0.722-0.775] in the S-1 arm. The EQ-5D index value during PFS up to 12 months in the S-1 was superior to the corresponding index value in the taxane (0.812 [0.789-0.834] vs. 0.772 [0.751-0.792], P = 0.009). Time to deterioration analysis also revealed that S-1 significantly delayed the deterioration of EQ-5D index value during the period before progression (P = 0.002 and 0.003). CONCLUSIONS: Our findings suggest that the EQ-5D index value was higher in patients treated with S-1 during first-line chemotherapy. Considering non-inferiority of S-1 in terms of OS, obtained quality-adjusted life years may be greater in the S-1 arm.

Galectin-7 in the stratum corneum: a biomarker of the skin barrier function.

OBJECTIVE: Skin barrier disruption often occurs in diseased and damaged skin conditions such as atopic dermatitis (AD). We focused the galectin-7 protein (Gal-7) as a biomarker of skin condition and assessed whether the content of Gal-7 in stratum corneum (scGal-7) could be used as an indicator of skin barrier disruption and as an index of local skin symptoms in AD patients. METHODS: Alteration of Gal-7 expression levels in keratinocyte and scGal-7 contents after barrier disruption by sodium dodecyl sulphate were evaluated in vitro and in vivo, respectively. Correlation between scGal-7 content and transepidermal water loss (TEWL) was examined in 126 healthy subjects. We performed single measurements of scGal-7 contents in 34 AD patients and serial measurements of 15 inpatients among them. SC samples were collected by the tape-stripping method, and scGal-7 content was determined using enzyme-linked immunosorbent assay. RESULTS: Gal-7 expression in keratinocytes increased after barrier disruption. The scGal-7 content reflected the disruption of the skin barrier. The scGal-7 contents and TEWL values correlated in healthy subjects. The scGal-7 level was higher in AD patients than in healthy subjects. The scGal-7 contents in the cheek and neck of AD patients significantly correlated with the total and local skin lesion severity scores. Serial measurements in the inpatients showed that the scGal-7 contents in the cheek and neck decreased in tandem with local severity scores in response to treatment. CONCLUSION: Measurement of scGal-7 content in tape-stripped samples was useful for the evaluation of the skin barrier function in dry skin conditions such as AD.

Kainate-induced network activity in the anterior cingulate cortex.

Anterior cingulate cortex (ACC) plays a pivotal role in higher order processing of cognition, attention and emotion. The network oscillation is considered an essential means for integration of these CNS functions. The oscillation power and coherence among related areas are often dis-regulated in several psychiatric and pathological conditions with a hemispheric asymmetric manner. Here we describe the network-based activity of field potentials recorded from the superficial layer of the mouse ACC in vitro using submerged type recordings. A short activation by kainic acid administration to the preparation induced populational activities ranging over several frequency bands including theta (3-8Hz), alpha (8-12Hz), beta (13-30Hz), low gamma (30-50Hz) and high gamma (50-80Hz). These responses were repeatable and totally abolished by tetrodotoxin, and greatly diminished by inhibitors of ionotropic and metabotropic glutamate receptors, GABAA receptor or gap-junctions. These observations suggest that the kainate-induced network activity can be a useful model of the network oscillation in the ACC circuit.

Inverse estimation of radon flux distribution for East Asia using measured atmospheric radon concentration.

In this study, the (222)Rn flux density distribution at surface was estimated in East Asia with the Bayesian synthesis inversion using measurement data and a long-range atmospheric (222)Rn transport model. Surface atmospheric (222)Rn concentrations measured at Hateruma Island in January 2008 were used. The estimated (222)Rn flux densities were generally higher than the prior ones. The area-weighted mean (222)Rn flux density for East Asia in January 2008 was estimated to be 44.0 mBq m(-2) s(-1). The use of the estimated (222)Rn flux density improved the discrepancy of the model-calculated concentrations with the measurements at Hateruma Island.

Annihilation dynamics of stringlike topological defects in a nematic lyotropic liquid crystal.

Topological defects can appear whenever there is some type of ordering. Its ubiquity in nature has been the subject of several studies, from early Universe to condensed matter. In this work, we investigated the annihilation dynamics of defects and antidefects in a lyotropic nematic liquid crystal (ternary mixture of potassium laurate, decanol and deionized-destillated water) using the polarized optical light microscopy technique. We analyzed Schlieren textures with topological defects produced due to a symmetry breaking in the transition of the isotropic to nematic calamitic phase after a temperature quench. As result, we obtained for the distance D between two annihilating defects (defect-antidefect pair), as a function of time t remaining for the annihilation, the scaling law D âˆ t(α), with α = 0.390 and standard deviation σ = 0.085. Our findings go in the direction to extend experimental results related to dynamics of defects in liquid crystals since only thermotropic and polymerics ones had been investigated. In addition, our results are in good quantitative agreement with previous investigations on the subject.

Antipersistent behavior of defects in a lyotropic liquid crystal during annihilation.

We report on the dynamical behavior of defects of strength s=±1/2 in a lyotropic liquid crystal during the annihilation process. By following their positions using time-resolved polarizing microscopy technique, we present statistically significant evidence that the relative velocity between defect pairs is Gaussian distributed, antipersistent, and long-range correlated. We further show that simulations of the Lebwohl-Lasher model reproduce quite well our experimental findings.

A phase II study of eribulin in Japanese patients with heavily pretreated metastatic breast cancer.

BACKGROUND: Eribulin mesylate is a non-taxane microtubule dynamics inhibitor that recently gained Food and Drug Administration approval for late-line metastatic breast cancer (MBC). PATIENTS AND METHODS: In this single-arm, multicentre open-label phase II trial Japanese patients pretreated with an anthracycline and a taxane received 1.4 mg/m(2) eribulin mesylate (2- to 5-min i.v. infusion on days 1 and 8 of a 21-day cycle). The primary efficacy end point was overall response rate (ORR) by independent review. RESULTS: Patients (N = 80) had received a median of three prior chemotherapy regimens (range 1-5). ORR was 21.3% [95% confidence interval (CI) 12.9-31.8; all partial responses (PRs)], stable disease (SD) occurred in 30 patients (37.5%) and the clinical benefit rate (complete response + PR + SD ≥6 months) was 27.5% (95% CI 18.1-38.6). Median duration of response was 3.9 months (95% CI 2.8-4.9), progression-free survival was 3.7 months (95% CI 2.0-4.4) and overall survival was 11.1 months (95% CI 7.9-15.8). The most frequent treatment-related grade 3/4 adverse events were neutropenia (95.1%), leukopenia (74.1%) and febrile neutropenia (13.6%). Grade 3 peripheral neuropathy occurred in 3.7% of patients (no grade 4). CONCLUSIONS: Eribulin exhibited efficacy and tolerability in Japanese patients with heavily pretreated MBC.

Anomalous-diffusion approach applied to the electrical response of water.

We investigate the electrical response of Milli-Q deionized water by using a fractional diffusion equation of distributed order with the interfaces (i.e., the boundary conditions at the electrodes limiting the sample) governed by integrodifferential equations. We also consider that the positive and negative ions have the same mobility and that the electric potential profile across the sample satisfies Poisson's equation. In addition, the good agreement between the experimental data and this approach evidences the presence of anomalous diffusion due to the surface effects in this system.

The pro-apoptotic BH3-only protein Bim regulates cell cycle progression of hematopoietic progenitors during megakaryopoiesis.

SUMMARY BACKGROUND: The pro-apoptotic BH3-only protein Bim is recognized as a pivotal regulator of apoptosis induced by the depletion of cytokines. In the present study, we examined the role of Bim in megakaryopoiesis. METHODS: Megakaryocyte (MK) progenitors obtained from bim knockout (KO) mice were analyzed in vitro for liability to apoptosis after the depletion of cytokines, ability to differentiate into MKs and proliferation/cell cycle progression in response to thrombopoietin (TPO). The production of platelets in vitro was evaluated by assaying the formation of proplatelets in MKs. Megakaryopoiesis in vivo was observed in a mouse model of thrombocytopenia induced by injecting fluorouracil (5-FU). RESULTS: Bim-deficient CD34-/c-kit+/Sca-1+/Lineage- stem cells and MKs were highly resistant to apoptosis induced by cytokine depletion, suggesting that Bim is involved in the apoptotic process in both stem cells and MKs. As bim KO mice exhibited splenomegaly and thrombocytopenia, splenectomized mice were used for experiments in vivo. Platelet recovery after 5-FU-induced thrombocytopenia was significantly delayed in bim KO mice. Corresponding with this, numbers of MKs in the recovery phase bone marrow were significantly reduced in bim KO mice. Culture of c-kit+/Lineage- progenitors with TPO revealed that Bim-deficient cells poorly proliferate and differentiate into CD41+ cells in comparison with wild-type (WT) cells. However, once differentiated into MKs, these cells matured normally. Furthermore, cell cycle analyses demonstrated that transition from the G1 to the S phase was delayed in Bim-deficient stem cells. CONCLUSIONS: In the present study, we demonstrated that Bim plays a pivotal role in the regulation of cell cycle progression in hepatopoietic progenitors during megakaryopiesis.

Elucidation of structural requirements of mastoparan for mast cell activation-toward the comprehensive prediction of cryptides acting on mast cells.

Mastoparan, a toxic peptide from wasp venom, induces various biological functions including histamine release from rat peritoneal mast cells. Here we report that, for the activation of mast cells by mastoparan, at least two positively charged side chains are required on the hydrophilic side of the amphiphilic structure of the peptide. The present results are expected to be utilized for the bioinformatic and comprehensive identification of endogenous mast cell-stimulating cryptides.

Calcineurin-mediated dephosphorylation of c-Jun Ser-243 is required for c-Jun protein stability and cell transformation.

The proto-oncogene c-Jun plays an important role in regulating tumor progression. We previously reported that the serine/threonine phosphatase calcineurin (CaN, also called PP2B) dephosphorylates the C-terminus (Ser-243) of c-Jun, resulting in the increase in c-Jun and Sp1 interaction, and subsequent c-Jun-induced gene expression. Here, we demonstrate the interaction of c-Jun and CaN in the nucleus of living cells by fluorescence resonance energy transfer assay and that this interaction is mediated through the calmodulin-binding domain of CaN. Furthermore, c-Jun protein stability was altered by CaN-mediated dephosphorylation at the Ser-243 site of c-Jun. The half-life of the c-Jun mutant, c-Jun-S243A was longer than that of the wild-type c-Jun. Moreover, silencing of endogenous CaN expression led to increased c-Jun ubiquitination and decreased stability. In 46% of clinical cervical tissue samples obtained from patients with cervical cancer, enhanced c-Jun and CaN expression, as well as decreased phospho-Ser-243 expression levels were detected. Our results suggest that CaN stabilizes c-Jun by dephosphorylating c-Jun at Ser-243 to enhance its tumorigenic ability.

Direct assessment of international consistency of standards for ground-level ozone: strategy and implementation toward metrological traceability network in Asia.

An international exercise to directly assess consistency of standards for ground-level ozone in East Asia was conducted as part of the East Asian Regional Experiment 2005 (EAREX 2005) in the framework of the Atmospheric Brown Clouds (ABC) project. Ten organizations collaboratively participated in the intercomparison. Four groups representing Japan, Korea, Hong Kong, and Taiwan made comparisons at the Gosan super observatory, Jeju Island, Korea, in March 2005, with ozone instruments calibrated to their national standards, and four Japanese groups made off-site comparisons with laboratory-level standards. All comparisons generally indicated good agreement with the standard reference photometer (SRP) 35, built by the National Institute of Standards and Technology (USA) and maintained by the National Institute for Environmental Studies (Japan). The assessment was expanded to measurement networks contributing to the World Meteorological Organization's Global Atmospheric Watch (WMO/GAW) program as part of off-site comparisons, and excellent agreement was achieved. These efforts contribute to propagating traceability of the national metrology standards among the atmospheric science community, to ensuring comparability of the existing ozone measurements, and to establishing an integrated network of air quality monitoring in Asia.

Defect-antidefect correlations in a lyotropic liquid crystal from a cosmological point of view.

In this work, we analyze the defect and antidefect distribution in the nematic calamitic phase of a lyotropic liquid crystal [the ternary mixture formed by potassium laurate (KL), decanol (DeOH), and water]. We obtain defects with wedge disclinations of strength +/-1/2, and the scaling exponent determined by the defect-antidefect correlation was 0.29+/-0.07. This value is in good agreement with the theoretical value of 14 obtained by the Kibble mechanism. The constant of the scaling relation of the defect and antidefect distribution is also discussed. We compare our results with the values obtained by Digal [Phys. Rev. Lett. 83, 5030 (1999)] who used a thermotropic liquid crystal.

Hematopoietic stem cell transplantation for natural killer-cell lineage neoplasms.

Neoplasms of natural killer (NK)-lineage are rare. Their prognosis is generally poor except for cases of solitary nasal NK-cell lymphoma. The NK-cell Tumor Study Group performed a survey in Japan on patients diagnosed between 1994 and 1998. Of 228 patients selected for analysis, 40 underwent HSCT (15 allografts and 25 autografts). The underlying diseases were myeloid/NK cell precursor acute leukemia (n = 4), blastic NK-cell lymphoma (n = 11), aggressive NK-cell leukemia (n = 3), and nasal-type extranodal NK-cell lymphoma (n = 22). At the time of HSCT, 22 patients were in complete remission (CR), 11 were in relapse, and seven were primary refractory. All patients received myeloablative conditioning regimens including total-body irradiation. Sixteen died of disease progression, and six of treatment-related causes. Overall, 4-year survival was 39% with a median follow-up of 50 months; this was significantly better than that of patients who did not undergo HSCT (21%, P = 0.0003). For patients transplanted in CR, the 4-year overall survival was 68%, which was significantly better than that of patients who went into CR but did not undergo HSCT (P = 0.03). These findings suggest that the HSCT is a promising treatment strategy for NK-cell lineage.