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.
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.
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).
Pembrolizumab monotherapy had a manageable safety profile and showed durable antitumor activity as first-line therapy for patients with PD-L1-positive mTNBC.
ClinicalTrials.gov, NCT02447003.
Eribulin mesylate is a non-taxane microtubule dynamics inhibitor that recently gained Food and Drug Administration approval for late-line metastatic breast cancer (MBC).
In this single-arm, ...multicentre open-label phase II trial Japanese patients pretreated with an anthracycline and a taxane received 1.4 mg/m2 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.
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).
Eribulin exhibited efficacy and tolerability in Japanese patients with heavily pretreated MBC.
PKN is a serine/threonine protein kinase that has a catalytic domain homologous to protein kinase C (PKC) family members and a unique regulatory region containing antiparallel coiled-coil (ACC) ...domains. PKN is the first identified serine/threonine protein kinase that can bind to and be activated by a small GTPase Rho, and it can also be activated by fatty acids such as arachidonic acid in vitro. PKN is widely distributed in various organisms such as mammal, frog, fly, and starfish. There are at least three different isoforms of PKN (PKNα/PAK-1/PRK-1, PKNβ, and PRK2/PAK-2/PKNγ) in mammals, each of which shows different enzymological properties, tissue distribution, and varied functions.
This study uses a neural network technique to produce maps of the partial pressure of oceanic carbon dioxide (pCO2sea ) in the North Pacific on a 0.25° latitude × 0.25° longitude grid from 2002 to ...2008. The pCO2sea distribution was computed using a self-organizing map (SOM) originally utilized to map the pCO2sea in the North Atlantic. Four proxy parameters - sea surface temperature (SST), mixed layer depth, chlorophyll a concentration, and sea surface salinity (SSS) - are used during the training phase to enable the network to resolve the nonlinear relationships between the pCO2sea distribution and biogeochemistry of the basin. The observed pCO2sea data were obtained from an extensive dataset generated by the volunteer observation ship program operated by the National Institute for Environmental Studies (NIES). The reconstructed pCO2sea values agreed well with the pCO2sea measurements, with the root-mean-square error ranging from 17.6 μatm (for the NIES dataset used in the SOM) to 20.2 μatm (for independent dataset). We confirmed that the pCO2sea estimates could be improved by including SSS as one of the training parameters and by taking into account secular increases of pCO2sea that have tracked increases in atmospheric CO2 . Estimated pCO2sea values accurately reproduced pCO2sea data at several time series locations in the North Pacific. The distributions of pCO2sea revealed by 7 yr averaged monthly pCO2sea maps were similar to Lamont-Doherty Earth Observatory pCO2sea climatology, allowing, however, for a more detailed analysis of biogeochemical conditions. The distributions of pCO2sea anomalies over the North Pacific during the winter clearly showed regional contrasts between El Niño and La Niña years related to changes of SST and vertical mixing.
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.
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.
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
mm
/s) were significantly higher than normal and metastatic lymph nodes (0.86 ± 0.10 × 10
mm
/s,
< .001, and 0.73 ± 0.10 × 10
mm
/s,
< .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 (
< .001 to
= .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 (
< .001 to
= .001). The retropharyngeal lymph node, superior cervical ganglion, and inferior ganglion of the vagus nerve formed a line from anteromedial to posterolateral.
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.
Airborne radionuclides from the accident of Fukushima Dai-ichi Nuclear Power Plant (FDNPP) in 2011 were measured at the RIKEN Wako Institute, Japan, about 220 km to the southwest of FDNPP, from March ...15, 2011 to March 16, 2012. Radioactivity concentrations of 140Ba, 137Cs, 136gCs, 134gCs, 133gI, 132Te, 131I, 129mTe, 110mAg, 99Mo, and 95gNb (m: metastable state; g: ground state) were determined by γ-ray spectrometry with a germanium detector. The time variations of the radioactivity concentrations and their ratios in Wako are discussed by referring to those of the ambient effective dose rate as well as the amount of rainfall. The pronounced peaks of the radioactivity concentrations were observed on March 15, 20-21, and 29-31, 2011. The highest concentrations for typical radionuclides in unit Bq m-3 were 8.8 ± 0.2 for 137Cs, 1.2 ± 0.2 for 136gCs, 8.5 ± 0.2 for 134gCs, 4.7 ± 0.3 for 133gI, 58 ± 2 for 132Te, 8.0 ± 1.2 for 129mTe, and 35 ± 1 for 131I in the sample collected in the period of March 15, 2011, 11:15-11:45 JST (Japan Standard Time). The 134gCs/137Cs radioactivity ratio was determined to be 1.0 ± 0.1 for March 11, 2011, and this value was consistent with other observations related to the FDNPP accident. The environmental radioactive contamination in Wako occurred mainly on March 21, 2011, due to the first rainfall after the accident.
We examined potential interferences from water vapor and atmospheric background gases (N2 , O2 , and Ar), and biases by isotopologues of target species, on accurate measurement of atmospheric CO2 and ...CH4 by means of wavelength-scanned cavity ring-down spectroscopy (WS-CRDS). Changes of the background gas mole fractions in the sample air substantially impacted the CO2 and CH4 measurements: variation of CO2 and CH4 due to relative increase of each background gas increased as Ar < O2 < N2 , suggesting similar relation for the pressure-broadening effects (PBEs) among the background gas. The pressure-broadening coefficients due to variations in O2 and Ar for CO2 and CH4 are empirically determined from these experimental results. Calculated PBEs using the pressure-broadening coefficients are linearly correlated with the differences between the mole fractions of O2 and Ar and their ambient abundances. Although the PBEs calculation showed that impact of natural variation of O2 is negligible on the CO2 and CH4 measurements, significant bias was inferred for the measurement of synthetic standard gases. For gas standards balanced with purified air, the PBEs were estimated to be marginal (up to 0.05 ppm for CO2 and 0.01 ppb for CH4 ) although the PBEs were substantial (up to 0.87 ppm for CO2 and 1.4 ppb for CH4 ) for standards balanced with synthetic air. For isotopic biases on CO2 measurements, we compared experimental results and theoretical calculations, which showed excellent agreement within their uncertainty. We derived instrument-specific water correction functions empirically for three WS-CRDS instruments (Picarro EnviroSense 3000i, G-1301, and G-2301), and evaluated the transferability of the water correction function from G-1301 among these instruments. Although the transferability was not proven, no significant difference was found in the water vapor correction function for the investigated WS-CRDS instruments as well as the instruments reported in the past studies within the typical analytical precision at sufficiently low water concentrations (<0.7% for CO2 and <0.6% for CH4 ). For accurate measurements of CO2 and CH4 in ambient air, we concluded that WS-CRDS measurements should be performed under complete dehumidification of air samples, or moderate dehumidification followed by application of a water vapor correction function, along with calibration by natural air-based standard gases or purified air-balanced synthetic standard gases with the isotopic correction.
Highlights • Network activity (NA) was induced by kainate in mouse ACC using submerged slice. • NA was more robust in the superficial layer than in the deep layer. • TTX, blockers of glutamate or ...GABAA receptors and gap junction greatly diminished NA.
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