Mutational Analysis of Circulating Tumor DNA in Patients With Estrogen Receptor-Positive/Human Epidermal Growth Factor Receptor 2-Negative Advanced Breast Cancer Receiving Palbociclib: Results From the TREnd Trial.

PURPOSE: To identify prognostic circulating biomarkers to cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i), we performed a mutational analysis on circulating tumor DNA (ctDNA) samples from patients included in the TREnd trial, which randomly assigned patients to receive the CDK4/6i palbociclib alone or with the endocrine treatment (ET) to which they had progressed. METHODS: Forty-six patients were enrolled in this substudy. Plasma was collected before treatment (T0), after the first cycle of therapy (T1), and at the time of progression (T2). ctDNA hybridization and capture were performed using the Illumina TruSight Tumor 170 Kit. Acquired mutations were confirmed by digital polymerase chain reaction. Progression-free survival analysis was estimated using the Kaplan-Meier method and compared with the log-rank test. RESULTS: The most frequently mutated genes at T0 were ESR1 (23%), PIK3CA (17%), AR, FGFR2, and TP53 (10%). Mutations in ESR1 at T0 conferred higher risk of progression in the entire population (P = .02) and in patients treated with palbociclib + ET (P = .04). ESR1 mutation effect remained significant after correction for clinical variables (P = .03). PIK3CA mutations at T0 were not prognostic, but higher risk of progression was observed when a broader analysis of PI3K pathway was performed (P = .04). At T2, we observed the emergence of nine new mutations in seven genes. CONCLUSION: Mutations in ESR1 and in PI3K pathway genes at T0 were associated with worse prognosis in palbociclib-treated patients. We describe the emergence of newly acquired mutations in palbociclib-treated patients, which might potentially affect subsequent treatment.

Meta-Analysis of Herbicide Non-Target Effects on Pest Natural Enemies.

A critical component of integrated pest management is minimizing disruption of biological control by reducing the use of pesticides with significant non-target effects on natural enemies. Insecticide non-target effects testing for natural enemies has become increasingly common, but research examining the non-target effects of herbicides on natural enemies is scarce, and recommendations regarding herbicide selectivity are non-existent. We used meta-analysis to summarize laboratory bioassays testing non-target effects of herbicides on arthropod natural enemies and identify patterns in taxon susceptibility and active ingredient toxicity. Data were extracted from 78 papers representing 801 total observations. Herbicides increased natural enemy mortality and decreased longevity, reproduction, and predation. Mesostigmatan mites and hemipterans were the most sensitive to herbicides, and spiders, neuropterans, and hymenopterans were the least sensitive. Mortality was higher in juvenile predators versus parasitoids but did not differ between adults; parasitoid juveniles are likely better protected within the host. In terms of acute mortality, metribuzin, glufosinate, and oxyfluorfen were the most harmful herbicides. Only nicosulfuron, rimsulfuron, pendimethalin, phenmedipham, atrazine, and urea did not increase natural enemy mortality. The large effect size of glufosinate is particularly concerning, as it is the most likely replacement herbicide for glyphosate in many crops. Many active ingredients remain under-studied. Our analysis indicates that herbicides have a strong potential to disrupt biological control in cropping systems.

MIMESIS: minimal DNA-methylation signatures to quantify and classify tumor signals in tissue and cell-free DNA samples.

DNA-methylation alterations are common in cancer and display unique characteristics that make them ideal markers for tumor quantification and classification. Here we present MIMESIS, a computational framework exploiting minimal DNA-methylation signatures composed by a few dozen informative DNA-methylation sites to quantify and classify tumor signals in tissue and cell-free DNA samples. Extensive analyses of multiple independent and heterogenous datasets including >7200 samples demonstrate the capability of MIMESIS to provide precise estimations of tumor content and to enable accurate classification of tumor type and molecular subtype. To assess our framework for clinical applications, we designed a MIMESIS-informed assay incorporating the minimal signatures for breast cancer. Using both artificial samples and clinical serial cell-free DNA samples from patients with metastatic breast cancer, we show that our approach provides accurate estimations of tumor content, sensitive detection of tumor signal and the ability to capture clinically relevant molecular subtype in patients' circulation. This study provides evidence that our extremely parsimonious approach can be used to develop cost-effective and highly scalable DNA-methylation assays that could support and facilitate the implementation of precision oncology in clinical practice.

Alternative food sources for Amblydromella caudiglans (Phytoseiidae) and effects on predation.

The addition of supplemental food sources for natural enemies is a growing component of conservation and augmentative biological control. Supplemental foods can be used to retain natural enemies when prey are scarce and to promote survival, fecundity, longevity, and development of natural enemy populations, especially generalist natural enemies. Amblydromella caudiglans (Schuster) (Acari: Phytoseiidae) is one of the most abundant predatory mites found in commercial apple orchards in Washington, USA, and contributes to spider mite control. However, because its widespread presence in commercial apple orchards was only recently discovered, how supplementary food sources affect its performance is unknown. In laboratory studies, we evaluated the performance (fecundity, retention, prey consumption) of the generalist phytoseiid A. caudiglans on commercially available supplemental food sources, including factitious prey (Ephestia eggs and Artemia brine shrimp cysts), and pollens of apple, pear, and cattail. We determined that A. caudiglans will not consume Ephestia eggs and performs best on cattail and pear pollens. Combinations of food sources did not enhance the performance of this predator compared to the best performing single-sources. The presence of alternative food sources did not decrease A. caudiglans predation of twospotted spider mite nymphs, except for Artemia brine shrimp cysts, which had a substantial handling time. These results lay the groundwork for identifying a way to promote and retain this natural enemy in tree fruit cropping systems through the use of food resource applications or floral plantings.

Risk assessment of disease recurrence in early breast cancer: A serum metabolomic study focused on elderly patients.

BACKGROUND: We previously showed that metabolomics predicts relapse in early breast cancer (eBC) patients, unselected by age. This study aims to identify a "metabolic signature" that differentiates eBC from advanced breast cancer (aBC) patients, and to investigate its potential prognostic role in an elderly population. METHODS: Serum samples from elderly breast cancer (BC) patients enrolled in 3 onco-geriatric trials, were retrospectively analyzed via proton nuclear magnetic resonance (1H NMR) spectroscopy. Three nuclear magnetic resonance (NMR) spectra were acquired for each serum sample: NOESY1D, CPMG, Diffusion-edited. Random Forest (RF) models to predict BC relapse were built on NMR spectra, and resulting RF risk scores were evaluated by Kaplan-Meier curves. RESULTS: Serum samples from 140 eBC patients and 27 aBC were retrieved. In the eBC cohort, median age was 76 years; 77% of patients had luminal, 10% HER2-positive and 13% triple negative (TN) BC. Forty-two percent of patients had tumors >2 cm, 43% had positive axillary nodes. Using NOESY1D spectra, the RF classifier discriminated free-from-recurrence eBC from aBC with sensitivity, specificity and accuracy of 81%, 67% and 70% respectively. We tested the NOESY1D spectra of each eBC patient on the RF models already calculated. We found that patients classified as "high risk" had higher risk of disease recurrence (hazard ratio (HR) 3.42, 95% confidence interval (CI) 1.58-7.37) than patients at low-risk. CONCLUSIONS: This analysis suggests that a "metabolic signature", identified employing NMR fingerprinting, is able to predict the risk of disease recurrence in elderly patients with eBC independently from standard clinicopathological features.

Nontarget Impacts of Herbicides on Spiders in Orchards.

Spiders are key predators in many agroecosystems, including orchards. Despite the importance of spiders in biological control, pesticide nontarget effects on this group are poorly described. This is especially true for herbicides, which spiders frequently encounter as they move between the ground cover and tree canopy. We sought to determine the nontarget effects of seven herbicides used in orchards on three species of spiders that are commonly found in Washington state (USA) orchards: Pelegrina aeneola (Curtis) (Araneae: Salticidae), Philodromus cespitum (Walckenaer) (Araneae: Philodromidae), and Phanias watonus (Chamberlin & Ivie) (Araneae: Salticidae). Immature spiders were collected from orchards and used in laboratory assays. Single spiders were placed in vials with dried herbicide residues and mortality was evaluated after 1, 2, and 5 d. We also evaluated herbicide impacts on prey consumption rates and on spider movement using motion-tracking software. Only oxyfluorfen caused significant spider mortality. P. cespitum seemed to be less acutely sensitive to oxyfluorfen than the two salticid species. Several herbicide treatments significantly increased locomotion in P. cespitum, whereas rimsulfuron numerically decreased movement of P. aeneola. Sulfonylurea herbicides (rimsulfuron, halosulfuron) decreased prey consumption of P. aeneola. Our work indicates that although spiders may be less acutely sensitive to some pesticides than beneficial insects, they can be affected by sublethal effects of herbicides. Future work should determine if herbicide applications impact spider abundance in the field and reduce biological control services. In general, more work is needed on the impacts of herbicides on natural enemies.

Comparison of Bioassays Used to Determine Onion Thrips (Thysanoptera: Thripidae) Susceptibility to Spinetoram.

Onion thrips (Thrips tabaci Lindeman) is one of onion's most damaging insect pests and has a history of developing resistance across insecticide classes. The susceptibility of T. tabaci populations to insecticides can be determined using laboratory bioassays. Three types of bioassays have been documented in the literature specifically for use with T. tabaci: vial assay (contact only), feeding assay (ingestion only), and leaf-dip assay (contact + ingestion). The objectives of this study were to 1) compare insecticide susceptibility levels of a T. tabaci population using these three assays and 2) determine which bioassay's results were most similar to those generated from exposing thrips to whole plants treated with insecticide. All experiments were conducted using a colony of T. tabaci known to be susceptible to insecticides and all were evaluated for their susceptibility to spinetoram (Radiant SC). Results indicated that 1) each bioassay generated a unique concentration-mortality relationship and LC50 value (0.01, 0.03 and 1.6 ppm for leaf-dip, vial, and feeding assays, respectively), and 2) all bioassays overestimated the susceptibility of the population relative to the whole-plant assay (LC50 = 5.3 ppm). Attributes of these bioassays are discussed relative to their future use in insecticide resistance monitoring programs for T. tabaci.

Precision Oncology via NMR-Based Metabolomics: A Review on Breast Cancer.

Precision oncology is an emerging approach in cancer care. It aims at selecting the optimal therapy for the right patient by considering each patient's unique disease and individual health status. In the last years, it has become evident that breast cancer is an extremely heterogeneous disease, and therefore, patients need to be appropriately stratified to maximize survival and quality of life. Gene-expression tools have already positively assisted clinical decision making by estimating the risk of recurrence and the potential benefit from adjuvant chemotherapy. However, these approaches need refinement to further reduce the proportion of patients potentially exposed to unnecessary chemotherapy. Nuclear magnetic resonance (NMR) metabolomics has demonstrated to be an optimal approach for cancer research and has provided significant results in BC, in particular for prognostic and stratification purposes. In this review, we give an update on the status of NMR-based metabolomic studies for the biochemical characterization and stratification of breast cancer patients using different biospecimens (breast tissue, blood serum/plasma, and urine).

Circulating tumor cells and palbociclib treatment in patients with ER-positive, HER2-negative advanced breast cancer: results from a translational sub-study of the TREnd trial.

BACKGROUND: Circulating tumor cells (CTCs) are prognostic in patients with advanced breast cancer (ABC). However, no data exist about their use in patients treated with palbociclib. We analyzed the prognostic role of CTC counts in patients enrolled in the cTREnd study, a pre-planned translational sub-study of TREnd (NCT02549430), that randomized patients with ABC to palbociclib alone or palbociclib plus the endocrine therapy received in the prior line of treatment. Moreover, we evaluated RB1 gene expression on CTCs and explored its prognostic role within the cTREnd subpopulation. METHODS: Forty-six patients with ER-positive, HER2-negative ABC were analyzed. Blood samples were collected before starting palbociclib treatment (timepoint T0), after the first cycle of treatment (timepoint T1), and at disease progression (timepoint T2). CTCs were isolated and counted by CellSearch® System using the CellSearch™Epithelial Cell kit. Progression-free survival (PFS), clinical benefit (CB) during study treatment, and time to treatment failure (TTF) after study treatment were correlated with CTC counts. Samples with ≥ 5 CTCs were sorted by DEPArray system® (DA). RB1 and GAPDH gene expression levels were measured by ddPCR. RESULTS: All 46 patients were suitable for CTCs analysis. CTC count at T0 did not show significant prognostic value in terms of PFS and CB. Patients with at least one detectable CTC at T1 (n = 26) had a worse PFS than those with 0 CTCs (n = 16) (p = 0.02). At T1, patients with an increase of at least three CTCs showed reduced PFS compared to those with no increase (mPFS = 3 versus 9 months, (p = 0.004). Finally, patients with ≥ 5 CTCs at T2 (n = 6/23) who received chemotherapy as post-study treatment had a shorter TTF (p = 0.02). Gene expression data for RB1 were obtained from 19 patients. CTCs showed heterogeneous RB1 expression. Patients with detectable expression of RB1 at any timepoint showed better, but not statistically significant, outcomes than those with undetectable levels. CONCLUSIONS: CTC count seems to be a promising modality in monitoring palbociclib response. Moreover, CTC count at the time of progression could predict clinical outcome post-palbociclib. RB1 expression analysis on CTCs is feasible and may provide additional prognostic information. Results should be interpreted with caution given the small studied sample size.

Insights into How Spinosad Seed Treatment Protects Onion From Onion Maggot (Diptera: Anthomyiidae).

Onion maggot, Delia antiqua (Meigen), is a serious pest of onion Allium cepa L. in northern temperate regions. Over the last decade, D. antiqua has been managed principally using a pesticide seed treatment package containing the reduced-risk insecticide spinosad. While spinosad protects onion seedlings from D. antiqua, very little is known regarding how protection occurs. The main objectives of this study were to assess susceptibility of 1- and 2-wk-old larvae to spinosad through two different modes of exposure: ingestion and contact, and to evaluate larval feeding behavior in choice and no-choice tests with onion seedlings grown from treated and untreated seeds. Results showed that spinosad was more than twice as lethal to 1-wk than 2-wk-old larvae when it was ingested, but was equally toxic to both larval ages via contact exposure. In choice assays, larvae preferred feeding on untreated plants; however, without a choice, larvae fed and survived equally well on untreated and treated plants, suggesting that spinosad may have a deterrent effect. In a field study, levels of spinosad within young onion plants and in the soil around roots were monitored in addition to the cumulative number of onion seedlings killed by D. antiqua. Spinosad was detected in the soil and in both aboveground and belowground plant tissue, indicating that spinosad translocates into foliage, but declines in plant tissue and soil as plant mortality from D. antiqua feeding increases. Together, these results provide valuable insight into how spinosad protects onion seedlings and reveal key areas in need of further investigation.

Conventional Soil Management May Promote Nutrients That Lure an Insect Pest to a Toxic Crop.

Slow and consistent nutrient release by organic fertilizers can improve plant nutrient balance and defenses, leading to herbivore avoidance of organically managed crops in favor of conventional crops with weaker defenses. We propose that this relative attraction to conventional plants, coupled with the use of genetically modified, insecticidal crops (Bt), has created an unintentional attract-and-kill system. We sought to determine whether Bt and non-Bt corn Zea mays L. plants grown in soil collected from five paired organic and conventional fields differed in attractiveness to European corn borer [Ostrinia nubilalis (Hübner)] moths, by conducting ovipositional choice and flight tunnel assays. We then examined the mechanisms driving the observed differences in attraction by comparing soil nutrient profiles, soil microbial activity, plant nutrition, and plant volatile profiles. Finally, we assessed whether European corn borer abundance near corn fields differed based on soil management. European corn borer preferred plants grown in conventional soil but did not discriminate between Bt and non-Bt corn. Organic management and more alkaline soil were associated with an increased soil magnesium:potassium ratio, which increased plant magnesium, and were linked to reduced European corn borer oviposition. There was an inconsistent trend for higher European corn borer moth activity near conventional fields. Our results extend the mineral balance hypothesis describing conventional plant preference by showing that it can also improve attraction to plants with genetically inserted toxins. Unintentional attract (to conventional) and (Bt) kill is a plausible scenario for pest declines in response to Bt corn adoption, but this effect may be obscured by variation in other management practices and landscape characteristics.

A Dose-finding Study of Metronomic Oral Vinorelbine in Combination With Oral Cyclophosphamide and Bevacizumab in Patients With Advanced Breast Cancer.

BACKGROUND: Metronomic chemotherapy can induce disease control in patients with metastatic breast cancer (MBC) and has better safety profiles than conventional chemotherapy. Evidence suggests that cytotoxics can be anti-angiogenic in pre-clinical models and may have synergistic effects when combined with anti-vascular endothelial growth factor therapies. PATIENTS AND METHODS: Patients pretreated with ≥ 1 prior line of therapy for MBC received oral cyclophosphamide 50 mg daily in combination with oral vinorelbine at escalating doses of 20 mg (V20), 30 mg (V30), and 40 mg (V40) 3 times per week, and intravenous bevacizumab 15 mg/kg every 3 weeks. Patients with human epidermal growth factor receptor 2-positive disease were given the same regimen plus standard trastuzumab. Doses were escalated when 3 patients completed 3 treatment cycles of V20 and V30, without experiencing dose-limiting toxicities. The recommended dose was then tested in a further 6 patients. Circulating tumour cells and circulating endothelial cells (CEC) were measured in 30 mL of whole blood samples at baseline, after cycle 1, and at the disease progression. RESULTS: Fifteen patients were recruited from June 2013 to October 2015. The median age was 61 years (range, 29-72 years); 80% had estrogen receptor-positive and 33% had human epidermal growth factor receptor 2-positive disease. At least 67% had visceral metastases, and 80% had received ≥ 2 lines of prior treatment. No dose-limiting toxicities were observed at the 3 dose-levels, making V40 the recommended dose. Overall 8 (53%) patients developed grade 2 adverse events (arthralgia, n = 3 [20%]; asthenia, n = 2 [13%]; diarrhea, n = 2 [13%]; leukopenia, n = 2 [13%]). Bevacizumab was associated with grade 3 hypertension (n = 3 [20%]). Stable disease as best response was observed in 11 (73.3%) patients. The clinical benefit rate was 66.6% (10/15 patients). The median time to progression was 6.9 months. At baseline, CECs were more commonly detectable than circulating tumor cells; however, no statistical correlation was found between CEC kinetics and response. CONCLUSION: A metronomic vinorelbine dose of 40 mg combined with cyclophosphamide and bevacizumab is a promising treatment regimen in pretreated patients with MBC.

Cell-Free DNA-Methylation-Based Methods and Applications in Oncology.

Liquid biopsy based on cell-free DNA (cfDNA) enables non-invasive dynamic assessment of disease status in patients with cancer, both in the early and advanced settings. The analysis of DNA-methylation (DNAm) from cfDNA samples holds great promise due to the intrinsic characteristics of DNAm being more prevalent, pervasive, and cell- and tumor-type specific than genomics, for which established cfDNA assays already exist. Herein, we report on recent advances on experimental strategies for the analysis of DNAm in cfDNA samples. We describe the main steps of DNAm-based analysis workflows, including pre-analytics of cfDNA samples, DNA treatment, assays for DNAm evaluation, and methods for data analysis. We report on protocols, biomolecular techniques, and computational strategies enabling DNAm evaluation in the context of cfDNA analysis, along with practical considerations on input sample requirements and costs. We provide an overview on existing studies exploiting cell-free DNAm biomarkers for the detection and monitoring of cancer in early and advanced settings, for the evaluation of drug resistance, and for the identification of the cell-of-origin of tumors. Finally, we report on DNAm-based tests approved for clinical use and summarize their performance in the context of liquid biopsy.

Plasma Thymidine Kinase Activity as a Biomarker in Patients with Luminal Metastatic Breast Cancer Treated with Palbociclib within the TREnd Trial.

PURPOSE: Thymidine kinase 1 (TK1) is downstream to the CDK4/6 pathway, and TK activity (TKa) measured in blood is a dynamic marker of outcome in patients with advanced breast cancer (ABC). This study explores TK1 as a biomarker of palbociclib response, both in vitro and in patients with ABC. EXPERIMENTAL DESIGN: Modulation of TK1 levels and activity by palbociclib were studied in seven estrogen receptor-positive breast cancer cell lines: sensitive (PDS) and with palbociclib acquired resistance (PDR). TKa was assayed in plasma obtained at baseline (T0), after one cycle (T1), and at disease progression on palbociclib (T2) in patients enrolled in the "To Reverse ENDocrine Resistance" (TREnd) trial (n = 46). RESULTS: Among E2F-dependent genes, TK1 was significantly downregulated after short-term palbociclib. Early TKa reduction by palbociclib occurred in PDS but not in PDR cells. In patients, median TKa (mTKa) at T0 was 75 DiviTum units per liter (Du/L), with baseline TKa not proving prognostic. At T1, mTKa decreased to 35 Du/L, with a minority of patients (n = 8) showing an increase-correlating with a worse outcome than those with decreased/stable TKa (n = 33; mPFS 3.0 vs 9.0 months; P = 0.002). At T2, mTKa was 251 Du/L; patients with TKa above the median had worse outcomes on post-study treatment compared with those with lower TKa (2.9 vs 8.7 months; P = 0.05). CONCLUSIONS: TK is a dynamic marker of resistance to palbociclib which may lead to early identification of patients in whom treatment escalation may be feasible. In addition, TKa may stratify prognosis in patients with acquired resistance to palbociclib.

Clinical outcomes after palbociclib with or without endocrine therapy in postmenopausal women with hormone receptor positive and HER2-negative metastatic breast cancer enrolled in the TREnd trial.

Currently, there is limited data regarding the effectiveness of standard subsequent line therapies such as endocrine therapy, chemotherapy, or targeted agents after progression on CDK4/6 inhibitor-based regimens. This paper describes time-to-treatment failure beyond progression on palbociclib or palbociclib+endocrine therapy in patients enrolled in the phase II, multicenter TREnd trial. Our results indicate that there is limited benefit from post-palbociclib treatment, regardless of the type of therapy received. A small population of long responders were identified who demonstrated ongoing benefit from a subsequent line of endocrine therapy after progression to palbociclib-based regimens. A translational research program is ongoing on this population of outliers.

The optimal duration of adjuvant endocrine therapy in early luminal breast cancer: A concise review.

Patients with luminal early breast cancer are at risk of relapse, even after five years of adjuvant endocrine therapy. To date, no biomarkers have been clinically validated to identify those patients at risk of late recurrence, who might benefit from extended adjuvant endocrine therapy. In recent decades, multiple clinical trials have tested the role of extending adjuvant endocrine therapies in patients with luminal disease. However, the data currently at our disposal are conflicting. This article reviews all the major trials concerning extended adjuvant endocrine regimens, and formulates some general conclusions and hypotheses of future study.

Monitoring Onion Thrips (Thysanoptera: Thripidae) Susceptibility to Spinetoram in New York Onion Fields.

Onion thrips (Thrips tabaci Lindeman) is a severe pest of onion (Allium cepa L.). Their management relies on frequent applications of foliar insecticides, including spinetoram (Radiant® SC), which has a novel mode of action and is effective at controlling large populations. However, despite being widely used for the past 10 yr, susceptibility to spinetoram has not been evaluated formally in New York state, where nearly 3,000 hectares of onion are planted annually. Over 2 yr (2017-2018), the susceptibility of onion thrips to spinetoram was assessed from populations collected in commercial onion fields in New York. LC50s for adults were generated from feeding assays and ranged from 2.07 to 5.08 ppm, but grower reports indicate that onion thrips populations continue to be susceptible to spinetoram. Moreover, both regional and temporal variations in susceptibility were similar among these populations based on survival at individual concentrations tested, despite significant differences in LC50s. These results suggest some genetic heterogeneity among onion thrips populations and serve as a valuable reference for the continued monitoring of onion thrips susceptibility to spinetoram, contributing to ongoing efforts to manage insecticide resistance in this system.

Platinum-based Agent and Fluorouracil in Metastatic Breast Cancer: A Retrospective Monocentric Study with a Review of the Literature.

BACKGROUND: The combination of platinum with 5-fluorouracil has scarcely been studied in metastatic breast cancer. As this combination does not lead to significant hepatic metabolism, in some clinical situations it may prove useful, especially in cases with liver dysfunction and an urgent clinical need for rapid tumor shrinkage. A retrospective study was conducted to evaluate the efficacy and safety of the combination of cisplatin and 5-fluorouracil in patients with metastatic breast cancer with significant alterations of biochemistry. PATIENTS AND METHODS: A total of 109 patients with metastatic breast cancer and liver dysfunction were treated; time-to-progression, overall survival and trends in liver function were evaluated. RESULTS: The median time-to-progression was 3.4 months, and median overall survival was 7.8 months. About 50% of patients obtained a complete, partial or stable biochemical response and 24 patients were subsequently able to receive additional therapies. CONCLUSION: Our results show that this therapeutic doublet represents a clinically effective, safe and well-tolerated treatment option for patients with metastatic breast cancer and liver dysfunction.

The role of abemaciclib in treatment of advanced breast cancer.

Until recently, the mainstay of treatment in the majority of hormone receptor (HR)-positive, human epidermal growth factor 2 receptor (HER2)-negative advanced breast cancer (ABC) has consisted of single-agent endocrine therapy (ET). However, as understanding of endocrine resistance has grown, newer targeted agents have come to the fore. Inhibition of cyclin-dependent kinase complexes 4 and 6 (CDK4/6) combined with ET has shown significant activity in HR+ HER2- ABC, with impressive results in terms of progression-free survival (PFS) when compared with ET alone. This review summarizes the seminal findings pertaining to CDK4/6 inhibition in this population, specifically focusing on abemaciclib, contrasted with palbociclib and ribociclib. Potential directions for future studies are discussed, as a way of addressing outstanding issues such as establishing optimal treatment sequencing and agent combinations, appropriate patient selection to derive maximal benefits, predictive biomarkers and the employment of CDK4/6 inhibition beyond the ABC setting.

A randomized comparison trial of two and four-step approaches to teaching Cardio-Pulmonary Reanimation.

BACKGROUND AND AIM OF THE WORK: The treatment of cardiac arrest in an extra-hospital environment improves with the increase in the number of people able to establish an early Cardio-Pulmonary Reanimation (CPR). The main aim of the study was to assess the validity of the two-step method in case of prolonged CPR. METHODS: A randomized comparison study was conducted in the University Nursing School of a Northern Italian town, during the 2015/16 academic year, among 60 students, to teach them CPR techniques, through two different teaching methods (4-step and the 2-step of CPR training). The effectiveness of the maneuvers performed on mannequins equipped with skill-meter was verified. RESULTS: Our study did not highlight any significant difference between the two methods of CPR training. The comparison between the two methods regarding their efficacy in practical teaching of CPR, highlighted by this study, proved the validity of both the 4-minute continuous method (1st method) and the 30:2 method (2nd method). CONCLUSIONS: The results of the study showed no differences between the 2-step and the 4-step methods, in the effectiveness of cardiac massage. The correct execution of chest compressions during a CPR is the key to increase the patient's chances of rescue. Research has shown that any interruption in the execution of chest compressions, leads to a progressive reduction of the effectiveness of cardiac massage, with negative consequences on the prognosis of the patient undergoing at CPR.