Treatment options for previously treated metastatic triple-negative breast cancer (mTNBC) are limited. In cohort A of the phase II KEYNOTE-086 study, we evaluated pembrolizumab as second or later ...line of treatment for patients with mTNBC.
Eligible patients had centrally confirmed mTNBC, ≥1 systemic therapy for metastatic disease, prior treatment with anthracycline and taxane in any disease setting, and progression on or after the most recent therapy. Patients received pembrolizumab 200 mg intravenously every 3 weeks for up to 2 years. Primary end points were objective response rate in the total and PD-L1–positive populations, and safety. Secondary end points included duration of response, disease control rate (percentage of patients with complete or partial response or stable disease for ≥24 weeks), progression-free survival, and overall survival.
All enrolled patients (N = 170) were women, 61.8% had PD-L1–positive tumors, and 43.5% had received ≥3 previous lines of therapy for metastatic disease. ORR (95% CI) was 5.3% (2.7–9.9) in the total and 5.7% (2.4–12.2) in the PD-L1–positive populations. Disease control rate (95% CI) was 7.6% (4.4–12.7) and 9.5% (5.1–16.8), respectively. Median duration of response was not reached in the total (range, 1.2+–21.5+) and in the PD-L1–positive (range, 6.3–21.5+) populations. Median PFS was 2.0 months (95% CI, 1.9–2.0), and the 6-month rate was 14.9%. Median OS was 9.0 months (95% CI, 7.6–11.2), and the 6-month rate was 69.1%. Treatment-related adverse events occurred in 103 (60.6%) patients, including 22 (12.9%) with grade 3 or 4 AEs. There were no deaths due to AEs.
Pembrolizumab monotherapy demonstrated durable antitumor activity in a subset of patients with previously treated mTNBC and had a manageable safety profile.
ClinicalTrials.gov, NCT02447003
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The phase Ib KEYNOTE-173 study was conducted to assess the safety and preliminary antitumor activity of neoadjuvant chemotherapy plus pembrolizumab in high-risk, early-stage, non-metastatic ...triple-negative breast cancer (TNBC).
Six pembrolizumab plus chemotherapy regimens were evaluated (cohorts A–F). All cohorts received a pembrolizumab 200-mg run-in dose (cycle 1), then eight cycles of pembrolizumab in combination with a taxane with or without carboplatin for 12 weeks, and then doxorubicin and cyclophosphamide for an additional 12 weeks before surgery. Primary end points were safety and recommended phase II dose (RP2D); secondary end points were pathological complete response (pCR) rate, objective response rate, and event-free and overall survival. Exploratory end points were the relationship between outcome and potential biomarkers, such as tumor programmed death ligand 1 (PD-L1) expression (combined positive score) and stromal tumor-infiltrating lymphocyte levels (sTILs).
Sixty patients were enrolled between 18 February 2016, and 28 February 2017. Dose-limiting toxicities occurred in 22 patients, most commonly febrile neutropenia (n = 10 across cohorts). Four cohorts (B, C, D, F) did not meet the RP2D threshold; two cohorts did (A, E). The most common grade ≥3 treatment-related adverse event was neutropenia (73%). Immune-mediated adverse events and infusion reactions occurred in 18 patients (30%) and were grade ≥3 in six patients (10%). The pCR rate (ypT0/Tis ypN0) across all cohorts was 60% (range 49%–71%). Twelve-month event-free and overall survival rates ranged from 80% to 100% across cohorts (100% for four cohorts). Higher pre-treatment PD-L1 combined positive score, and pre- and on-treatment sTILs were significantly associated with higher pCR rates (P = 0.0127, 0.0059, and 0.0085, respectively).
Combination neoadjuvant chemotherapy and pembrolizumab for high-risk, early-stage TNBC showed manageable toxicity and promising antitumor activity. In an exploratory analysis, the pCR rate showed a positive correlation with tumor PD-L1 expression and sTIL levels.
ClinicalTrials.gov identifier: NCT02622074.
•Neoadjuvant pembrolizumab + chemotherapy showed no unexpected safety findings in patients with high-risk, early-stage TNBC.•Two chemotherapy regimens met the RP2D threshold: nab-paclitaxel 125 mg/m2 qw; paclitaxel 80 mg/m2 qw + carboplatin AUC5 q3w.•pCR rate (ypT0/Tis ypN0) across all cohorts was 60% and 12-month EFS and OS rates ranged from 80% to 100% across cohorts.•pCR rate showed positive correlation with tumor PD-L1 expression and stromal tumor-infiltrating lymphocyte levels.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Alpine dwarf shrub communities are phenologically linked with snowmelt timing, so early spring exposure may increase risk of freezing damage during early development, and consequently reduce seasonal ...growth. We examined whether environmental factors (duration of snow cover, elevation) influenced size and the vulnerability of shrubs to spring freezing along elevational gradients and snow microhabitats by modelling the past frequency of spring freezing events. We sampled biomass and measured the size of Salix herbacea, Vaccinium myrtillus, Vaccinium uliginosum and Loiseleuria procumbens in late spring. Leaves were exposed to freezing temperatures to determine the temperature at which 50 % of specimens are killed for each species and sampling site. By linking site snowmelt and temperatures to long-term climate measurements, we extrapolated the frequency of spring freezing events at each elevation, snow microhabitat and per species over 37 years. Snowmelt timing was significantly driven by microhabitat effects, but was independent of elevation. Shrub growth was neither enhanced nor reduced by earlier snowmelt, but decreased with elevation. Freezing resistance was strongly species dependent, and did not differ along the elevation or snowmelt gradient. Microclimate extrapolation suggested that potentially lethal freezing events (in May and June) occurred for three of the four species examined. Freezing events never occurred on late snow beds, and increased in frequency with earlier snowmelt and higher elevation. Extrapolated freezing events showed a slight, non-significant increase over the 37-year record. We suggest that earlier snowmelt does not enhance growth in four dominant alpine shrubs, but increases the risk of lethal spring freezing exposure for less freezing-resistant species.
•This ESMO Clinical Practice Guideline provides key recommendations and algorithms for managing metastatic breast cancer.•It covers diagnosis, staging, risk assessment, treatment, disease monitoring, ...palliative care and the patient perspective.•ESMO-MCBS and ESCAT scores are given to describe the levels of evidence for treatment choices.•The authors comprise an international expert group, with recommendations based on available evidence and expert opinion.•In clinical practice, all recommendations provided need to be discussed with patients in a shared decision-making approach.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Verticillium wilt (VW) caused by the soil-borne fungus Verticillium dahliae Kleb, is the most limiting disease in all traditional olive-growing regions worldwide. This pathogen colonizes the vascular ...system of plants, blocking water flow and eventually inducing water stress. The present study explored the use of high-resolution thermal imagery, chlorophyll fluorescence, structural and physiological indices (xanthophyll, chlorophyll a+b, carotenoids and blue/green/red B/G/R indices) calculated from multispectral and hyperspectral imagery as early indicators of water stress caused by VW infection and severity. The study was conducted in two olive orchards naturally infected with V. dahliae. Time series of airborne thermal, multispectral and hyperspectral imagery was acquired in three consecutive years and related to VW severity at the time of the flights. Concurrently to the airborne campaigns, field measurements conducted at leaf and tree-crown levels showed a significant increase in crown temperature (Tc) minus air temperature (Ta) and a decrease in leaf stomatal conductance (G) across VW severity levels, identifying VW-infected trees at early stages of the disease. Higher Tc−Ta and G values measured in the field were associated with higher VW severity levels. At leaf level, the reduction in G caused by VW infection was associated with a significant increase in the Photochemical Reflectance Index (PRI570) and a decrease in chlorophyll fluorescence (F). The airborne flights enabled the early detection of VW by using canopy-level image-derived airborne Tc−Ta, Crop Water Stress Index (CWSI) calculated from the thermal imagery, blue/blue–green/blue–red ratios (B/BG/BR indices) and chlorophyll fluorescence, confirming the results obtained in the field. Airborne Tc−Ta showed rising values with a significant increase of ~2K at low VW severity levels, and was significantly correlated with G (R2=0.76, P=0.002) and PRI570 (R2=0.51, P=0.032). Early stages of disease development could be differentiated based on a CWSI increase as VW developed, obtaining a strong correlation with G (R2=0.83, P<0.001). Likewise, the canopy-level chlorophyll fluorescence dropped at high VW severity levels, showing a significant increase as disease progressed. These results indicate the potentials of an early detection of V. dahliae infection and discrimination of VW severity levels using remote sensing. Indicators based on crown temperature such as CWSI, and visible ratios B/BG/BR as well as fluorescence were effective in detecting VW at early stages of disease development. In affected trees, the structural indices PRI, chlorophyll and carotenoid indices, and the R/G ratio were good indicators to assess the damage caused by the disease.
•Early detection of Verticillium wilt (VW) was investigated with remote sensing•Leaf data and airborne imagery correlated with physiology status due to the disease•Crown temperature (Tc-Ta, CWSI) were effective in detecting VW at early stages•Hyperspectral indices B, BG1, BR1 and fluorescence detected VW at early stages•Structural indices (NDVI) and pigment indices were good only to assess damage
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Anoxic biodesulfurization has been achieved in several bioreactor systems that have shown robustness and high elimination capacities (ECs). However, the high operating costs of this technology, which ...are mainly caused by the high requirements of nitrite or nitrate, make its full-scale application difficult. In the present study, the use of biologically produced nitrate/nitrite by nitrification of two different ammonium substrates, namely synthetic medium and landfill leachate, is proposed as a novel alternative. The results demonstrate the feasibility of using both ammonium substrates as nutrient solutions. A maximum elemental sulfur production of 95 ± 1% and a maximum H2S EC of 141.18 g S-H2S m−3 h−1 (RE = 95.0%) was obtained using landfill leachate as the ammonium source. Next Generation Sequencing (NGS) analysis of the microbial community revealed that the most common genera present in the desulfurizing bioreactor were Sulfurimonas (91.8–50.9%) followed by Thauera (1.1–24.2%) and Lentimicrobium (2.0–9.7%).
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•Landfill leachate and raw biogas are effluents emitted mainly by landfills.•The studied system converts NH4+ and H2S into recoverable S0 and non-toxic N2.•Landfill leachate was used as the sole nutrient source by the biological system.•A maximum elimination capacity of 141.18 g S-H2S m−3 h−1 (RE = 95.0%) was obtained.•The results support the full-scale application of the system in real landfills.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Pertuzumab (P) combined with trastuzumab (H)-based chemotherapy improves efficacy in early and advanced HER2-positive breast cancer. We assessed the tolerability, with particular focus on cardiac ...safety, of H and P with chemotherapy in the neoadjuvant treatment of HER2-positive early breast cancer.
In this multicenter, open-label phase II study, patients with operable, locally advanced, or inflammatory breast cancer were randomized 1 : 1 : 1 to receive six neoadjuvant cycles q3w (Arm A: 5-fluorouracil, epirubicin, cyclophosphamide FEC + H + P ×3 → docetaxel T + H + P ×3; Arm B: FEC ×3 → T + H + P ×3; Arm C: T + carboplatin + H TCH+P ×6). pCR was assessed at surgery and adjuvant therapy given to complete 1 year of H.
Two hundred twenty-five patients were randomized. During neoadjuvant treatment, two patients (2.7%; Arm B) experienced symptomatic left ventricular systolic dysfunction (LVSD) and 11 patients (Arm A: 4 5.6%; Arm B: 4 5.3%; Arm C: 3 3.9%) had declines in left ventricular ejection fraction of ≥10% points from baseline to <50%. Diarrhea was the most common adverse event. pCR (ypT0/is) was reported for 61.6% (Arm A), 57.3% (Arm B), and 66.2% (Arm C) of patients.
The combination of P with H and standard chemotherapy resulted in low rates of symptomatic LVSD.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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