In the phase III IMpassion130 trial, combining atezolizumab with first-line nanoparticle albumin-bound-paclitaxel for advanced triple-negative breast cancer (aTNBC) showed a statistically significant ...progression-free survival (PFS) benefit in the intention-to-treat (ITT) and programmed death-ligand 1 (PD-L1)-positive populations, and a clinically meaningful overall survival (OS) effect in PD-L1-positive aTNBC. The phase III KEYNOTE-355 trial adding pembrolizumab to chemotherapy for aTNBC showed similar PFS effects. IMpassion131 evaluated first-line atezolizumab–paclitaxel in aTNBC.
Eligible patients no prior systemic therapy or ≥12 months since (neo)adjuvant chemotherapy were randomised 2:1 to atezolizumab 840 mg or placebo (days 1, 15), both with paclitaxel 90 mg/m2 (days 1, 8, 15), every 28 days until disease progression or unacceptable toxicity. Stratification factors were tumour PD-L1 status, prior taxane, liver metastases and geographical region. The primary endpoint was investigator-assessed PFS, tested hierarchically first in the PD-L1-positive immune cell expression ≥1%, VENTANA PD-L1 (SP142) assay population, and then in the ITT population. OS was a secondary endpoint.
Of 651 randomised patients, 45% had PD-L1-positive aTNBC. At the primary PFS analysis, adding atezolizumab to paclitaxel did not improve investigator-assessed PFS in the PD-L1-positive population hazard ratio (HR) 0.82, 95% confidence interval (CI) 0.60-1.12; P = 0.20; median PFS 6.0 months with atezolizumab–paclitaxel versus 5.7 months with placebo–paclitaxel. In the PD-L1-positive population, atezolizumab–paclitaxel was associated with more favourable unconfirmed best overall response rate (63% versus 55% with placebo–paclitaxel) and median duration of response (7.2 versus 5.5 months, respectively). Final OS results showed no difference between arms (HR 1.11, 95% CI 0.76-1.64; median 22.1 months with atezolizumab–paclitaxel versus 28.3 months with placebo–paclitaxel in the PD-L1-positive population). Results in the ITT population were consistent with the PD-L1-positive population. The safety profile was consistent with known effects of each study drug.
Combining atezolizumab with paclitaxel did not improve PFS or OS versus paclitaxel alone.
NCT03125902.
•The phase III IMpassion131 trial evaluated atezolizumab combined with paclitaxel as first-line therapy for aTNBC.•The primary endpoint was investigator-assessed PFS, tested hierarchically in the PD-L1+ and then ITT populations.•Neither PFS nor OS was improved with the combination of atezolizumab plus paclitaxel in either population.•These findings may result from imbalances in prognostic features or chance findings in a relatively small trial.•IMpassion131 results highlight the need for further research into immunotherapy for TNBC.
Nucleoside analogues can induce toxic effects on mitochondria by inhibiting the human DNA polymerase gamma. The toxic effects can range from increased serum lactate levels to potentially fatal lactic ...acidosis. We studied changes in mitochondrial DNA relative to nuclear DNA in the peripheral-blood cells of patients with symptomatic, nucleoside-induced hyperlactatemia.
Total DNA was extracted from blood cells. A nuclear gene and a mitochondrial gene were quantified by real-time polymerase chain reaction. Three groups were studied: 24 controls not infected with the human immunodeficiency virus (HIV), 47 HIV-infected asymptomatic patients who had never been treated with antiretroviral drugs, and 8 HIV-infected patients who were receiving antiretroviral drugs and had symptomatic hyperlactatemia. The patients in the last group were studied longitudinally before, during, and after antiretroviral therapy.
Symptomatic hyperlactatemia was associated with marked reductions in the ratios of mitochondrial to nuclear DNA, which, during therapy, averaged 68 percent lower than those of non-HIV-infected controls and 43 percent lower than those of HIV-infected asymptomatic patients never treated with antiretroviral drugs. After the discontinuation of antiretroviral therapy, there was a statistically significant increase in the ratio of mitochondrial to nuclear DNA (P=0.02). In the patients followed longitudinally, the decline in mitochondrial DNA preceded the increase in venous lactate levels.
Mitochondrial DNA levels are significantly decreased in patients with symptomatic, nucleoside-related hyperlactatemia, an effect that resolves on the discontinuation of therapy.
We present new limits on exotic keV-scale physics based on 478 kg d of Majorana Demonstrator commissioning data. Constraints at the 90% confidence level are derived on bosonic dark matter (DM) and ...solar axion couplings, Pauli exclusion principle violating (PEPV) decay, and electron decay using monoenergetic peak signal limits above our background. Our most stringent DM constraints are set for 11.8 keV mass particles, limiting g_{Ae}<4.5×10^{-13} for pseudoscalars and (α^{'}/α)<9.7×10^{-28} for vectors. We also report a 14.4 keV solar axion coupling limit of g_{AN}^{eff}×g_{Ae}<3.8×10^{-17}, a 1/2β^{2}<8.5×10^{-48} limit on the strength of PEPV electron transitions, and a lower limit on the electron lifetime of τ_{e}>1.2×10^{24} yr for e^{-}→ invisible.
The purpose of this study was to determine whether a heart failure (HF) management strategy using continuous intracardiac pressure monitoring could decrease HF morbidity.
Patients with HF may ...experience frequent decompensations that require hospitalization despite intensive treatment and follow-up.
The COMPASS-HF (Chronicle Offers Management to Patients with Advanced Signs and Symptoms of Heart Failure) study was a prospective, multicenter, randomized, single-blind, parallel-controlled trial of 274 New York Heart Association functional class III or IV HF patients who received an implantable continuous hemodynamic monitor. Patients were randomized to a Chronicle (Medtronic Inc., Minneapolis, Minnesota) (n = 134) or control (n = 140) group. All patients received optimal medical therapy, but the hemodynamic information from the monitor was used to guide patient management only in the Chronicle group. Primary end points included freedom from system-related complications, freedom from pressure-sensor failure, and reduction in the rate of HF-related events (hospitalizations and emergency or urgent care visits requiring intravenous therapy).
The 2 safety end points were met with no pressure-sensor failures and system-related complications in only 8% of the 277 patients who underwent implantation (all but 4 complications were successfully resolved). The primary efficacy end point was not met because the Chronicle group had a nonsignificant 21% lower rate of all HF-related events compared with the control group (p = 0.33). A retrospective analysis of the time to first HF hospitalization showed a 36% reduction (p = 0.03) in the relative risk of a HF-related hospitalization in the Chronicle group.
The implantable continuous hemodynamic monitor-guided care did not significantly reduce total HF-related events compared with optimal medical management. Additional trials will be necessary to establish the clinical benefit of implantable continuous hemodynamic monitor-guided care in patients with advanced HF.
The aim of this project was evaluate the effectiveness of an oil sprinkling system as a dust-reduction method for swine production facilities. This article presents the results of the second-year ...experiment of a multi-year study. The first-year experiment demonstrated that a 5% oil-water emulsion automatically applied at the rate of 3 and 5 g/pig/day achieved a 23% to 34% reduction in total dust. The modifications for the second year experiment included: (1) increasing oil application rate to 7 and 8 g/pig/day, (2) replacing sprinkler heads to achieve a smaller droplet size and a more direct spray pattern on pen-floor surfaces, and (3) more closely matching the treatment and control rooms by stage in the pig production cycle. Four swine finishing rooms were used for this study; two were treatment rooms (soybean oil at 7 g/pig/day, and canola oil 8 g/pig/day) and two were control rooms. The treatment rooms had a low-pressure oil-sprinkling system, which sprinkled 5% oil-to-water mixture 12 times per day, 12 s each time. Concentrations of several environmental contaminants were measured. The average total dust concentration in the control rooms was 1.39 mg/m3. The average total dust concentration in the treatment rooms was 0.65 mg/m3. The treatment reduced dust by an average of 52%, (p = 0.0001). There was no difference in the degree of dust control between soybean oil and canola oil. The respirable dust concentrations were very low in all rooms, and there were no significant differences between rooms in ammonia, carbon dioxide, temperature, or humidity.
To determine the false-negative rate in screening mammography, the capability of computer-aided detection (CAD) to identify these missed lesions, and whether or not CAD increases the radiologists' ...recall rate.
All available screening mammograms that led to the detection of biopsy-proved cancer (n = 1,083) and the most recent corresponding prior mammograms (n = 427) were collected from 13 facilities. Panels of radiologists evaluated the retrospectively visible prior mammograms by means of blinded review. All mammograms were analyzed by a CAD system that marks features associated with cancer. The recall rates of 14 radiologists were prospectively measured before and after installation of the CAD system.
At retrospective review, 67% (286 of 427) of screening mammography-detected breast cancers were visible on the prior mammograms. At independent, blinded review by panels of radiologists, 27% (115 of 427) were interpreted as warranting recall on the basis of a statistical evaluation index; and the CAD system correctly marked 77% (89 of 115) of these cases. The original attending radiologists' sensitivity was 79% (427 of 427 + 115). There was no statistically significant increase in the radiologists' recall rate when comparing the values before (8.3%) with those after (7.6%) installation of the CAD system.
The original attending radiologists had a false-negative rate of 21% (115 of 427 + 115). CAD prompting could have potentially helped reduce this false-negative rate by 77% (89 of 115) without an increase in the recall rate.
We assessed the associations between population-based polygenic risk scores (PRS) for breast (BC) or epithelial ovarian cancer (EOC) with cancer risks for BRCA1 and BRCA2 pathogenic variant carriers.
...Retrospective cohort data on 18,935 BRCA1 and 12,339 BRCA2 female pathogenic variant carriers of European ancestry were available. Three versions of a 313 single-nucleotide polymorphism (SNP) BC PRS were evaluated based on whether they predict overall, estrogen receptor (ER)–negative, or ER-positive BC, and two PRS for overall or high-grade serous EOC. Associations were validated in a prospective cohort.
The ER-negative PRS showed the strongest association with BC risk for BRCA1 carriers (hazard ratio HR per standard deviation=1.29 95% CI 1.25–1.33, P=3×10−72). For BRCA2, the strongest association was with overall BC PRS (HR=1.31 95% CI 1.27–1.36, P=7×10−50). HR estimates decreased significantly with age and there was evidence for differences in associations by predicted variant effects on protein expression. The HR estimates were smaller than general population estimates. The high-grade serous PRS yielded the strongest associations with EOC risk for BRCA1 (HR=1.32 95% CI 1.25–1.40, P=3×10−22) and BRCA2 (HR=1.44 95% CI 1.30–1.60, P=4×10−12) carriers. The associations in the prospective cohort were similar.
Population-based PRS are strongly associated with BC and EOC risks for BRCA1/2 carriers and predict substantial absolute risk differences for women at PRS distribution extremes.
The Majorana Demonstrator is an ultralow-background experiment searching for neutrinoless double-beta decay in ^{76}Ge. The heavily shielded array of germanium detectors, placed nearly a mile ...underground at the Sanford Underground Research Facility in Lead, South Dakota, also allows searches for new exotic physics. Free, relativistic, lightly ionizing particles with an electrical charge less than e are forbidden by the standard model but predicted by some of its extensions. If such particles exist, they might be detected in the Majorana Demonstrator by searching for multiple-detector events with individual-detector energy depositions down to 1 keV. This search is background-free, and no candidate events have been found in 285 days of data taking. New direct-detection limits are set for the flux of lightly ionizing particles for charges as low as e/1000.
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