Abstract
The Atlantic Meridional Overturning Circulation (AMOC) is a key component of the global climate but is not simulated consistently across models or model resolutions. Here, we use a hierarchy ...of the global coupled model HadGEM3‐GC3.1, with ocean resolutions of 1°, ¼°, and 1/12°, to evaluate the subpolar AMOC and its sensitivity to horizontal resolution. In line with observations, the models show that the mean overturning and surface forced water mass transformation (SFWMT) are concentrated in the eastern subpolar gyre rather than in the Labrador Sea. However, the magnitude of the overturning along the OSNAP line at medium and high resolutions is 25% and 40% larger than in the observations, respectively. This disagreement in overturning strength is noted for both OSNAP East and OSNAP West, and is mainly due to anomalously large SFWMT rather than anomalously large interior mixing or overflow transport from the Nordic Seas. Over the Labrador Sea, the intensification of SFWMT with resolution is explained by a combination of two main biases. Anomalously warm surface water enhances heat loss and reduces the extension of marginal sea ice, which increases the surface density flux over the boundary of the basin. A bias in salinity leads to anomalously dense surface water that shifts the outcropping area of the AMOC isopycnal and results in intense dense water formation along the boundary of the basin at medium and high resolutions. Thus, our analysis sheds light on a range of model biases responsible for large overturning over the Labrador Sea in climate models.
Plain Language Summary
The circulation and formation of dense water over the North Atlantic plays a key role for the Northern Hemisphere climate as it influences sea surface temperature, the formation of hurricane and the intensity of rainfall over Europe. It is thus important to evaluate how this circulation will change in a context of global climate change. However, the simulated overturning is not necessarily consistent with observations and differs across models or model resolutions. In this work, we evaluate the impact of horizontal resolution for the overturning over the subpolar gyre in the climate model HadGEM3‐GC3.1. We find that its magnitude at medium and high resolutions is 25% and 40% larger than in the observations, respectively. The water mass transformation induced by the air‐sea exchanges (SFWMT) over the subpolar gyre mainly explains this disagreement. Over the Labrador Sea, the relatively strong SFWMT in these models is related to anomalously small sea ice coverage as well as anomalously warm and salty surface water.
Key Points
The subpolar overturing is 25% and 40% too strong in HadGEM3‐GC3.1 at medium and high resolutions compared to OSNAP observations
The anomalously large overturning at OSNAP is consistent with anomalously large surface forced transformations over the subpolar gyre
Large surface forced transformation over the Labrador Sea is explained by anomalously warm and salty water over the boundary of the basin
Purpose
A 4-weekly schedule of pegylated liposomal doxorubicin (PLD) has been approved for the treatment of metastatic breast cancer (MBC). Phase II trials have suggested interest in a 2-weekly ...regimen. This study aimed to compare the efficacy and safety of these two schedules.
Methods
Data from MBC patients treated with PLD between 2011 and 2021 were retrospectively collected. The objective was to demonstrate the noninferiority of the 2-weekly versus the 4-weekly schedule in terms of 6-month progression-free survival (PFS). The prespecified noninferiority margin was calculated as 1.20. A propensity score to receive either schedule was estimated using a gradient boosting algorithm. Survival analyses using Cox regression models weighted by the propensity score were performed to compare the schedules.
Results
Among the 192 patients included, 96 (50%) underwent each schedule. The median number of previous systemic therapies was 4 (IQR, 3 to 6). Anthracyclines were previously given in early breast cancer in 63.9% of patients. The median follow-up was 10.0 months (IQR, 5.0 to 20.1). A comparable distribution of adverse events was observed. The median PFS was 3.2 months (95% CI, 2.9 to 3.9), and the median overall survival was 12.1 months (95% CI, 10.8 to 14.9). The weighted hazard ratio for PFS was 1.12 (90% CI, 0.82 to 1.54), including the noninferiority boundaries.
Conclusion
PLD appeared to be a well-tolerated drug in this heavily pretreated MBC population. The efficacy and safety of the 2-weekly schedule did not provide any advantage, suggesting no interest in changing the registered regimen.
Bevacizumab combined with paclitaxel as first-line chemotherapy for patients with HER2-negative metastatic breast cancer (MBC) has led to mixed results in randomized trials, with an improvement in ...progression-free survival (PFS) but no statistically significant overall survival (OS) benefit. Real-life data could help in assessing the value of this combination.
This study aimed to describe the outcome following first-line paclitaxel with or without bevacizumab in the French Epidemiological Strategy and Medical Economics (ESME) database of MBC patients, established in 2014 by Unicancer. The primary and secondary end points were OS and PFS, respectively.
From 2008 to 2013, 14 014 MBC patient files were identified, including 10 605 patients with a HER2-negative status. Of these, 3426 received paclitaxel and bevacizumab (2127) or paclitaxel (1299) as first-line chemotherapy. OS adjusted for major prognostic factors was significantly longer in the paclitaxel and bevacizumab group compared with paclitaxel hazard ratio (HR) 0.672, 95% confidence interval (CI) 0.601–0.752; median survival time 27.7 versus 19.8 months. Results were consistent in all supportive analyses (using a propensity score for adjustment and as a matching factor for nested case–control analyses) and sensitivity analyses. Similar results were observed for the adjusted PFS, favoring the combination (HR 0.739, 95% CI 0.672–0.813; 8.1 versus 6.4 months).
In this large-scale, real-life setting, patients with HER2-negative MBC who received paclitaxel plus bevacizumab as first-line chemotherapy had a significantly better OS and PFS than those receiving paclitaxel. Despite robust methodology, real-life data are exposed to important potential biases, and therefore, results need to be treated with caution. Our data cannot therefore support extension of current use of bevacizumab in MBC.
A series of new perovskite oxides Sr₁.₆K₀.₄Fe₁₊ₓ Mo₁₋ₓ O₆₋δ (x = 0.2, 0.4, 0.6) were synthesised by solid state reaction method. Synthesis of Sr₁.₆K₀.₄Fe₁₊ₓ Mo₁₋ₓ O₆₋δ (x = 0.2, 0.4, 0.6) was ...achieved above 700 °C in 5 % H₂/Ar, albeit with the formation of impurity phases. Phase stability upon redox cycling was only observed for sample Sr₁.₆K₀.₄Fe₁.₄Mo₀.₆O₆₋δ. Redox cycling of Sr₁.₆K₀.₄Fe₁₊ₓ Mo₁₋ₓ O₆₋δ (x = 0.2, 0.4, 0.6) demonstrates a strong dependence on high temperature reduction to achieve high conductivities. After the initial reduction at 1200 °C in 5 %H₂/Ar, then re-oxidation in air at 700 °C and further reduction at 700 °C in 5 %H₂/Ar, the attained conductivities were between 0.1 and 58.4 % of the initial conductivity after reduction 1200 °C in 5 %H₂/Ar depending on the composition. In the investigated new oxides, sample Sr₁.₆K₀.₄Fe₁.₄Mo₀.₆O₆₋δ is most redox stable also retains reasonably high electrical conductivity, ~70 S/cm after reduction at 1200 °C and 2–3 S/cm after redox cycling at 700 °C, indicating it is a potential anode for SOFCs.
We present a pooled analysis of predictive and prognostic values of circulating tumour cells (CTC) and circulating endothelial cells (CEC) in two prospective trials of patients with inflammatory ...breast cancer (IBC) treated with neoadjuvant chemotherapy combined with neoadjuvant and adjuvant bevacizumab.
Nonmetastatic T4d patients were enrolled in two phase II multicentre trials, evaluating bevacizumab in combination with sequential neoadjuvant chemotherapy of four cycles of FEC followed by four cycles of docetaxel in HER2-negative tumour (BEVERLY-1) or docetaxel and trastuzumab in HER2-positive tumour (BEVERLY-2). CTC and CEC were detected in 7.5 and 4ml of blood, respectively, with the CellSearch System.
From October 2008 to September 2010, 152 patients were included and 137 were evaluable for CTC and CEC. At baseline, 55 patients had detectable CTC (39%). After four cycles of chemotherapy, a dramatic drop in CTC to a rate of 9% was observed (P<0.01). Pathological complete response (pCR) rate was 40%. No correlation was found between CTC or CEC levels and pCR rate. Median follow-up was 43 months. CTC detection (≥1 CTC/7.5ml) at baseline was associated with shorter 3-year disease-free survival (39% versus 70% for patients without CTC, P<0.01, HR 2.80) and shorter 3-year overall survival (OS) (P<0.01). In multivariate analysis, independent prognostic parameters for shorter survival were absence of hormonal receptors, no pCR and CTC detection at baseline. CEC level at baseline or variations during treatment had no prognostic value.
In this pooled analysis of two prospective trials in nonmetastatic IBC, detection rate of CTC was 39% with a strong and independent prognostic value for survival. Combination of pCR after neoadjuvant treatment with no CTC detection at baseline isolated a subgroup of IBC with excellent OS (94% 3-year OS), suggesting that CTC count could be part of IBC stratification in prospective trials.
Five trials assessed lapatinib and trastuzumab (L+T) combined with paclitaxel-containing chemotherapy regimens. They showed high pathological complete response rates, but at the cost of toxicity. ...This trial assesses L+T combined with docetaxel. The use of docetaxel rather than paclitaxel does not avoid much of the toxicity. Regarding efficacy our results are very consistent with NSABP-B41 trial.
Neoadjuvant trials conducted using a double HER2 blockade with lapatinib and trastuzumab, combined with different paclitaxel-containing chemotherapy regimens, have shown high pathological complete response (pCR) rates, but at the cost of important toxicity. We hypothesised that this toxicity might be due to a specific interaction between paclitaxel and lapatinib. This trial assesses the toxicity and activity of the combination of docetaxel with lapatinib and trastuzumab.
Patients with stage IIA to IIIC HER2-positive breast cancer received six cycles of chemotherapy (three cycles of docetaxel followed by three cycles of fluorouracil, epirubicin, cyclophosphamide). They were randomised 1 : 1 : 1 to receive during the first three cycles either lapatinib (1000 mg orally daily), trastuzumab (4 mg/kg loading dose followed by 2 mg/kg weekly), or trastuzumab + lapatinib at the same dose. The primary end point was pCR rate defined as ypT0/is. Secondary end points included safety and toxicity. pCR rate defined as ypT0/is ypN0 was assessed as an exploratory analysis. In June 2012, arm A was closed for futility based on the results from other studies.
From October 2010 to January 2013, 128 patients were included in 14 centres. The percentage of the 122 assessable patients with pCR in the breast, and pCR in the breast and nodes, was numerically highest in the lapatinib + trastuzumab group (60% and 56%, respectively), intermediate in the trastuzumab group (52% and 52%), and lowest in the lapatinib group (46% and 36%).
Frequency (%) of the most common grade 3–4 toxicities in the lapatinib /trastuzumab/lapatinib + trastuzumab arms were: febrile neutropenia 23/15/10, diarrhoea 9/2/18, infection (other) 9/4/8, and hepatic toxicity 0/2/8.
This study demonstrates a numerically modest pCR rate increase with double anti-HER2 blockade plus chemotherapy, but suggests that the use of docetaxel rather than paclitaxel may not reduce toxicity.
NCT00450892.
Efficacy of endocrine therapy in HR+/HER2- metastatic breast cancer could differ depending on the presence of BRCA1/2 germline mutation.
The ESME metastatic breast cancer platform (NCT03275311) is a ...French real world database. Multivariable models including a time-varying approach and landmark analyses assessed the association between time-dependent gBRCA status (categorised as gBRCAm, gBRCAwt (wild type), and untested), overall survival (OS), and first-line progression-free survival (PFS1).
A total of 170 patients were gBRCAm carriers, 676 gBRCAwt, and 12,930 were untested at baseline. In the multivariable analysis, gBRCAm carriers overall had a lower OS compared to gBRCAwt (adjusted HR 95% CI 1.26 1.03-1.55). gBRCAm patients treated with front-line endocrine therapy had lower adjusted OS (adjusted HR 95% CI = 1.54 1.03-2.32) and PFS1 (adjusted HR 95% CI 1.58 1.17-2.12) compared to gBRCAwt patients. However, for patients who received frontline chemotherapy, neither OS nor PFS1 differed between gBRCAm carriers and the other groups (HR versus gBRCAwt for OS: 1.12 0.88-1.41, p = 0.350; PFS1: 1.09 0.90-1.31, p = 0.379).
In this large cohort of HR+/HER2- MBC patients treated in a pre-CDK4/6 inhibitors era, gBRCAm status was associated with a lower OS and lower PFS following first-line endocrine therapy, but not following first-line chemotherapy.
Triple-negative breast cancer (TNBC) is a heterogeneous group of tumors for some of which the epithelial growth factor receptor (EGFR) pathway may play an important role. We investigated the efficacy ...and toxicity of an anti-EGFR antibody (panitumumab) combined with a standard neoadjuvant anthracycline–taxane-based chemotherapy in patients with operable, stage II–III, TNBC.
Treatment in this multicentric neoadjuvant pilot study consisted of panitumumab (9mg/kg) for eight cycles q.3 weeks combined with four cycles of 5-fluorouracil, epidoxorubicin and cyclophosphamide (FEC100: 500/100/500mg/m2) q.3 weeks, followed by four cycles of docetaxel (T: 100mg/m2) q.3 weeks. Following therapy, all patients underwent surgical resection. Pathologic complete response (pCR) in assessable patients was the main end point while clinical response, toxicity and ancillary studies were secondary end points. Paraffin-embedded and frozen tumor samples were systematically collected with the aim to identify predictive biomarkers of efficacy and resistance in order to select biologically defined subpopulations for potential further clinical development of the anti-EGFR antibody.
Sixty patients were included with 47 assessable for pathologic response. The pCR rates were 46.8% 95% confidence interval (CI): 32.5% to 61.1% and 55.3% 95% CI: 41.1% to 69.5% according, respectively, to Chevallier and Sataloff classifications. The complete clinical response (cCR) rate was 37.5%. Conservative surgery was carried out in 87% of cases. Toxicity was manageable. The association of high EGFR and low cytokeratin 8/18 expression in tumor cells on one hand and high density of CD8+ tumor-infiltrating lymphocytes on the other hand were significantly predictive of pCR.
Panitumumab in combination with FEC100 followed by docetaxel appears efficacious, with acceptable toxicity, as neoadjuvant therapy of operable TNBC. Several biomarkers could help define large subsets of patients with a high probability of pCR, suggesting a potential interest to further develop this combination in biologically defined subgroups of patients with TNBC.
NCT00933517.
The Reykjanes Ridge strongly influences the circulation of the North Atlantic Subpolar Gyre as it flows to the Irminger Sea from the Iceland Basin. The circulation is composed of two main along‐ridge ...currents: the southwestward East Reykjanes Ridge Current (ERRC) in the Iceland Basin and the northeastward Irminger Current (IC) in the Irminger Sea. To study their interconnection through the ridge, as well as their connections with the interior of each basin, velocity and hydrological measurements were carried out along and perpendicular to the crest of the Reykjanes Ridge in June–July 2015 as part of the Reykjanes Ridge Experiment project. This new data set changes our view of the ERRC and IC as it reveals undocumented along‐stream evolutions of their hydrological properties, structures, and transports. These evolutions are due to flows connecting the ERRC and IC branches at specific locations set by the bathymetry of the ridge and to significant connections with the interiors of the basins. Overall, the ERRC transport increases by 3.2 Sv between 63°N and 59.5°N and remains almost constantly southward. In the Irminger Sea, the increase in IC transport of 13.7 Sv between 56°N and 59.5°N, and the evolution of its properties are explained by both cross‐ridge flows and inflows from the Irminger Sea. Further north, bathymetry steers the IC northwestward into the Irminger Sea. At 63°N, the IC water masses are mostly issued from the cross‐ridge flow.
Plain Language Summary
Along pathways in the North Atlantic Subpolar Gyre, the warm and salty water of the North Atlantic Current is densified by intense winter air‐sea buoyancy loss. This transformation preconditions this water mass for convection in the Irminger and Labrador Seas. Good knowledge of circulation in the Iceland Basin and Irminger Sea, strongly influenced by the Reykjanes Ridge, is needed to understand the along‐stream evolution of its properties. Two main conduits flow anticyclonically around the Reykjanes Ridge: the East Reykjanes Ridge Current (ERRC) in the Iceland Basin and the Irminger Current in the Irminger Sea. From in‐situ measurements carried out in the vicinity of the Reykjanes Ridge, we first investigated the along‐stream evolution of the ERRC and IC properties and structures and show their interconnections through the complex bathymetry of the Reykjanes Ridge as well as their connections with the interiors of the basins. Contrary to what has been generally thought, we found that the ERRC and IC do not flow continuously into one top‐to‐bottom current along the ridge but are composed of complex inflows and outflows that locally modify the strength and properties of the ERRC and IC.
Key Points
Flows from the Iceland Basin and across the Reykjanes Ridge drive along‐stream evolution of the East Reykjanes Ridge Current
The Irminger Current is shaped not only by the westward cross‐ridge flow but by inflow from the western subpolar gyre south of about 59.5°N
North of 59°N, the Irminger Current branches tilt northwestward and are joined by two additional branches from the cross‐ridge flow
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