Association of tumor-infiltrating lymphocytes with distant disease-free survival in the ShortHER randomized adjuvant trial for patients with early HER2+ breast cancer.

BACKGROUND: There is the need to identify new prognostic markers to refine risk stratification for HER2-positive early breast cancer patients. The aim of this study was to evaluate the association of tumor-infiltrating lymphocytes (TILs) with distant disease-free survival (DDFS) in patients with HER2-positive early breast cancer enrolled in the ShortHER adjuvant trial which compared 9 weeks versus 1-year trastuzumab in addition to chemotherapy, and to test the interaction between TILs and treatment arm. PATIENTS AND METHODS: Stromal TILs were assessed for 866 cases on centralized hematoxylin and eosin-stained tumor slides. The association of TILs as 10% increments with DDFS was assessed with Cox models. Kaplan-Meier curves were estimated for patients with TILs ≥20% and TILs <20%. Median follow-up was 6.1 years. RESULTS: Median TILs was 5% (Q1-Q3 1%-15%). Increased TILs were independently associated with better DDFS in multivariable model [hazard ratio (HR) 0.73, 95% confidence interval (CI) 0.59-0.89, P = 0.006, for each 10% TILs increment]. Five years DDFS rates were 91.1% for patients with TILs <20% and 95.7% for patients with TILs ≥20% (P = 0.025). The association between 10% TILs increments and DDFS was significant for patients randomized to 9 weeks of trastuzumab (HR 0.60, 95% CI 0.41-0.88) but not for patients treated with 1 year of trastuzumab (HR 0.89, 95% CI 0.71-1.12; test for interaction P = 0.088). For patients with TILs <20%, the HR for the comparison between the short versus the long arm was 1.75 (95% CI 1.09-2.80, P=0.021); whereas, for patients with TILs ≥20% the HR for the comparison of short versus long arm was 0.23 (95% CI 0.05-1.09, P = 0.064), resulting in a significant interaction (P = 0.015). CONCLUSIONS: TILs are an independent prognostic factor for HER2-positive early breast cancer patients treated with adjuvant chemotherapy and trastuzumab and may refine the ability to identify patients at low risk of relapse eligible for de-escalated adjuvant therapy.

Chemical, biochemical, and microbiological properties of soils from abandoned and extensively cultivated olive orchards.

The abandonment of olive orchards is a phenomenon of great importance triggered mainly by economic and social causes. The aim of this study was to investigate some chemical, biochemical, and microbiological properties in a soil of a southern olive grove abandoned for 25 years. In order to define the effect of the long-term land abandonment on soil properties, an adjacent olive grove managed according to extensive practices was taken as reference (essentially minimum tillage and no fertilization). Soil organic matter, total nitrogen, and pH were significantly higher in the abandoned olive grove due to the absence of tillage and the natural inputs of organic matter at high C/N ratio which, inter alia, increased the number of cellulolytic bacteria and stimulated the activity of ß -glucosidase, an indicator of a more advanced stage of soil evolution. The soil of the abandoned olive orchard showed a lower number of total bacteria and fungi and a lower microbial diversity, measured by means of the Biolog method, as a result of a sort of specialization trend towards low quality organic substrates. From this point of view, the extensive cultivation management seemed to not induce a disturbance to microbiological communities.

Optimizing choices and sequences in the diagnostic-therapeutic landscape of advanced triple-negative breast cancer: An Italian consensus paper and critical review.

Triple-negative (TN) metastatic breast cancer (mBC) represents the most challenging scenario withing mBC framework, and it has been only slightly affected by the tremendous advancements in terms of drug availability and survival prolongation we have witnessed in the last years for advanced disease. However, although chemotherapy still represents the mainstay of TN mBC management, in the past years, several novel effective agents have been developed and made available in the clinical practice setting. Within this framework, a panel composed of a scientific board of 17 internationally recognized breast oncologists and 42 oncologists working within local spoke centers, addressed 26 high-priority statements, including grey areas, regarding the management of TN mBC. A structured methodology based on a modified Delphi approach to administer the survey and the Nominal Group Technique to capture perceptions and preferences on the management of TN mBC within the Italian Oncology community were adopted. The Panel produced a set of prioritized considerations/consensus statements reflecting the Panel position on diagnostic and staging approach, first-line and second-line treatments of PD-L1-positive/germline BRCA (gBRCA) wild-type, PD-L1-positive/gBRCA mutated, PD-L1-negative/gBRCA wild-type and PD-L1-negative/gBRCA mutated TN mBC. The Panel critically and comprehensively discussed the most relevant and/or unexpected results and put forward possible interpretations for statements not reaching the consensus threshold.

Major advancements in metastatic breast cancer treatment: when expanding options means prolonging survival.

In the last years we have witnessed tremendous advancements in the treatment landscape of metastatic breast cancer (MBC), leading to a progressive prolongation of progression-free survival and, in some cases, also of overall survival. This led to a substantial increase of advanced disease treatability. In the present review we comprehensively and critically describe the most significant progresses in the therapeutic scenario of MBC according to BC subtype. In particular, we reviewed studies reporting practice-changing data in hormone receptor-positive/human epidermal growth factor receptor 2 (HER2)-negative, HER2-positive and triple-negative BC, with also a hint to BRCA-related tumors and the emerging HER2-low-positive category.

Survival after neoadjuvant therapy with trastuzumab-lapatinib and chemotherapy in patients with HER2-positive early breast cancer: a meta-analysis of randomized trials.

BACKGROUND: Studies testing the addition of lapatinib to neoadjuvant trastuzumab + chemotherapy reported an increase in pathologic complete response (pCR), with, nevertheless, discordant results in terms of survival, mainly due to suboptimal power. We here leverage the meta-analytic approach to resolve these inconsistencies. METHODS: We conducted a meta-analysis of randomized phase II/III studies testing lapatinib + trastuzumab in combination with neoadjuvant chemotherapy for human epidermal growth factor receptor (HER2)-positive early breast cancer (BC). Recurrence-free survival (RFS) and overall survival (OS) were adopted as survival endpoints. Pooled hazard ratios (HR) were obtained for the effect of lapatinib + trastuzumab versus trastuzumab, pCR versus no-pCR in the whole study populations and pCR versus no-pCR according to hormone receptor status. RESULTS: Four phase II/III randomized trials were included in the meta-analysis (CALGB 40601, Cher-LOB, NSABP-B41, NeoALTTO) for an overall population of 1410 patients receiving neoadjuvant chemotherapy in association with either trastuzumab, lapatinib or their combination. RFS was significantly improved with dual HER2 blockade as compared to trastuzumab [HR 0.62, 95% confidence interval (CI) 0.46-0.85]. Dual blockade also led to significantly improved OS (HR 0.65, 95% CI 0.43-0.98). For all treatments combined, patients achieving pCR had better RFS and OS than those with residual disease (HR 0.45, 95% CI 0.34-0.60, and HR 0.32, 95% CI 0.22-0.48, for RFS and OS, respectively). In patients with hormone receptor-negative tumors, pCR was associated with 65% and 73% relative reduction of risk of relapse and death, respectively. Patients with hormone receptor-positive tumors also experienced improved RFS if they achieved pCR; however, the benefit was smaller than that in hormone receptor-negative disease. CONCLUSION: Findings from this meta-analysis further validate the role of pCR as a strong predictor of outcome in patients with HER2-positive BC, especially in hormone receptor-negative disease. Moreover, we provide robust evidence that dual blockade with lapatinib + trastuzumab in combination with neoadjuvant chemotherapy prolongs OS, suggesting that the role of lapatinib could be reconsidered in the early setting.

Europe-wide reduction in primary productivity caused by the heat and drought in 2003.

Future climate warming is expected to enhance plant growth in temperate ecosystems and to increase carbon sequestration. But although severe regional heatwaves may become more frequent in a changing climate, their impact on terrestrial carbon cycling is unclear. Here we report measurements of ecosystem carbon dioxide fluxes, remotely sensed radiation absorbed by plants, and country-level crop yields taken during the European heatwave in 2003. We use a terrestrial biosphere simulation model to assess continental-scale changes in primary productivity during 2003, and their consequences for the net carbon balance. We estimate a 30 per cent reduction in gross primary productivity over Europe, which resulted in a strong anomalous net source of carbon dioxide (0.5 Pg C yr(-1)) to the atmosphere and reversed the effect of four years of net ecosystem carbon sequestration. Our results suggest that productivity reduction in eastern and western Europe can be explained by rainfall deficit and extreme summer heat, respectively. We also find that ecosystem respiration decreased together with gross primary productivity, rather than accelerating with the temperature rise. Model results, corroborated by historical records of crop yields, suggest that such a reduction in Europe's primary productivity is unprecedented during the last century. An increase in future drought events could turn temperate ecosystems into carbon sources, contributing to positive carbon-climate feedbacks already anticipated in the tropics and at high latitudes.

The transcriptome of Populus in elevated CO reveals increased anthocyanin biosynthesis during delayed autumnal senescence.

*The delay in autumnal senescence that has occurred in recent decades has been linked to rising temperatures. Here, we suggest that increasing atmospheric CO2 may partly account for delayed autumnal senescence and for the first time, through transcriptome analysis, identify gene expression changes associated with this delay. *Using a plantation of Populus x euramericana grown in elevated [CO2] (e[CO2]) with free-air CO2 enrichment (FACE) technology, we investigated the molecular and biochemical basis of this response. A Populus cDNA microarray was used to identify genes representing multiple biochemical pathways influenced by e[CO2] during senescence. Gene expression changes were confirmed through real-time quantitative PCR, and leaf biochemical assays. *Pathways for secondary metabolism and glycolysis were significantly up-regulated by e[CO2] during senescence, in particular, those related to anthocyanin biosynthesis. Expressed sequence tags (ESTs) representing the two most significantly up-regulated transcripts in e[CO2], LDOX (leucoanthocyanidin dioxgenase) and DFR (dihydroflavonol reductase), gave (e[CO2]/ambient CO(2) (a[CO2])) expression ratios of 39.6 and 19.3, respectively. *We showed that in e[CO2] there was increased autumnal leaf sugar accumulation and up-regulation of genes determining anthocyanin biosynthesis which, we propose, prolongs leaf longevity during natural autumnal senescence.

Seasonal and diurnal variations of greenhouse gases in Florence (Italy): Inferring sources and sinks from carbon isotopic ratios.

In this study, the results of a continuous monitoring of (i) CO2 fluxes, and (ii) CO2 and CH4 concentrations and carbon isotopic ratios (δ13C-CO2 and δ13C-CH4) in air, carried out from 7 to 21 July 2017 and from October 10 to December 15, 2017 in the city centre of Florence, are presented. The measurements were performed from the roof of the historical building of the Ximenes Observatory. CO2 flux data revealed that the metropolitan area acted as a net source of CO2 during the whole observation period. According to the Keeling plot analysis, anthropogenic contributions to atmospheric CO2 were mainly represented by vehicular traffic (about 30%) and natural gas combustion (about 70%), the latter contributing 7 times more in December than in July. Moreover, the measured CO2 fluxes were about 80% higher in fall than in summer, confirming that domestic heating based on natural gas is the dominant CO2 emitting source in the municipality of Florence. Even though the continuous monitoring revealed a shift in the δ13C-CO2 values related to photosynthetic uptake of atmospheric CO2, the isotopic effect induced by plant activity was restricted to few hours in October and, to a lesser extent, in November. This suggests that urban planning policies should be devoted to massively increase green infrastructures in the metropolitan area in order to counterbalance anthropogenic emissions. During fall, the atmospheric CH4 concentrations were sensibly higher with respect to those recorded in summer, whilst the δ13C-CH4 values shifted towards heavier values. The Keeling plot analysis suggested that urban CH4 emissions were largely related to fugitive emissions from the natural gas distribution pipeline network. On the other hand, δ13C-CH4 monitoring allowed to recognize vehicular traffic as a minor CH4 emitting source.

A new method to evaluate patient characteristic response to ultrafiltration during hemodialysis.

BACKGROUND: Several factors are involved in the pathogenesis of dialysis discomfort interfering with optimal fluid removal and reducing the efficacy of the treatment; the most important one is a decrease in blood volume caused by an imbalance between ultrafiltration (UF) and plasmarefilling (PR) rates. OBJECTIVES: This study is aimed at devising a method to tailor the dialysis therapy to each individual patient, by analyzing the relationship between PR and UF during the sessions in stable patients and widening the knowledge of fluid exchanges during the treatment. METHODS: Thirty stable patients undergoing maintenance hemodialysis were enrolled. Three dialysis sessions were monitored for each patient; systemic pressure, blood composition, blood volume % variation, weight loss and conductivity were recorded repeatedly. A Plasma Refilling Index (PRI), defined and calculated by means of parameters measured throughout the dialysis, was introduced as a novel instrument to study plasma refilling phenomena. Results. The PRI provides understanding of patient response (in terms of plasma refilling) to the set UF. In the monitored sessions, the PRI trend is found to be characteristic of each patient; a PRI course that is at variance with the characteristic trend is a signal of inadequate or unusual dialysis scheduling. Moreover, statistical analysis highlights two different PRI trends during the first hour and during the rest of the treatment, suggesting the presence of different treatment phases. CONCLUSION: The main advantage of the PRI index is that it is non-invasive peculiar to each patient and easy to compute in a dialysis routine based on online data recorded by the monitor. A deviation from the characteristic trend may be a warning for the clinician. The analysis of the PRI trend also suggests how to modulate UF as a function of interstitial to intravascular fluid removal balance during dialysis.

Chemotherapy for advanced HER2-negative breast cancer: Can one algorithm fit all?

HER2negative (HER2-) metastatic breast cancer (MBC) represents a challenging scenario for clinicians due to its great biological and clinical heterogeneity. Although management of HER2-MBC currently relies on several options, CT still remains a worthwhile strategy to be exploited. However, to date, there is not an univoque algorithm capable of guiding the choice of the proper CT agent/regimen, sequence and duration. Evidence from randomized clinical trials (RCT) and meta-analyses can actually help guiding the decision making process, however the definition of a standard of care for all HER2-MBC patients may be impractical, also in the light of the identification of new promising molecular and immunotherapeutic agents. The purpose of this work is to review available evidence on the role of CT for HER2-MBC with particular emphasis on the need to outline personalized therapeutic strategies for each patient.

Net carbon storage in a poplar plantation (POPFACE) after three years of free-air CO2 enrichment.

A high-density plantation of three genotypes of Populus was exposed to an elevated concentration of carbon dioxide ([CO(2)]; 550 micromol mol(-1)) from planting through canopy closure using a free-air CO(2) enrichment (FACE) technique. The FACE treatment stimulated gross primary productivity by 22 and 11% in the second and third years, respectively. Partitioning of extra carbon (C) among C pools of different turnover rates is of critical interest; thus, we calculated net ecosystem productivity (NEP) to determine whether elevated atmospheric [CO(2)] will enhance net plantation C storage capacity. Free-air CO(2) enrichment increased net primary productivity (NPP) of all genotypes by 21% in the second year and by 26% in the third year, mainly because of an increase in the size of C pools with relatively slow turnover rates (i.e., wood). In all genotypes in the FACE treatment, more new soil C was added to the total soil C pool compared with the control treatment. However, more old soil C loss was observed in the FACE treatment compared with the control treatment, possibly due to a priming effect from newly incorporated root litter. FACE did not significantly increase NEP, probably as a result of this priming effect.

Biochar-macrofauna interplay: Searching for new bioindicators.

Biochar incorporation in agricultural soils has been proposed as a climate change mitigation strategy and has proved to substantially increase crop productivity via physical, chemical and biological mechanisms. The changes induced in soil properties are known to have a direct impact on soil ecosystem with consequences for soil biota community that, in turn, can influence biochar aging in soil. Despite several studies investigated in the interplay between biochar and soil microbiology, there is a clear lack of information on groups that live in the most superficial ground layers: soil meso and macro fauna. These groups are of great importance if we consider that biochar application should ideally be located in the soil's surface layer (0-30 cm). Our study is the first attempt to investigate the interactions between biochar soil amendments and aboveground soil macro-meso fauna in a field crop. This was made setting-up a randomized-block experiment on a processing tomato crop in northern Italy, using three different biochar types and periodically monitoring soil parameters and fauna abundances along the crop growing cycle in summer 2013. Results show that the impact of biochar application on soil fauna as a whole is small when compared to that of agricultural management, suggesting that this amendment does not have short-term ecological interferences. Nevertheless, ants exhibited variations in abundances and distribution connected to properties of amended soils such as temperature, pH and humidity, proving that they can be effectively used as a target group in the study of interactions between biochar and soil biota.

The impact of elevated CO2 on growth and photosynthesis in Agrostis canina L. ssp. monteluccii adapted to contrasting atmospheric CO2 concentrations.

The aim of this study was to characterise growth and photosynthetic capacity in plants adapted to long-term contrasting atmospheric CO2 concentrations (C a). Seeds of Agrostis canina L. ssp. monteluccii were collected from a natural CO2 transect in central-western Italy and plants grown in controlled environment chambers at both ambient and elevated CO2 (350 and 700 µmol mol-1) in nutrient-rich soil. Seasonal mean C a at the source of the plant material ranged from 610 to 451 µmol CO2 mol-1, derived from C4 leaf stable carbon isotope discrimination (δ13C). Under chamber conditions, CO2 enrichment stimulated the growth of all populations. However, plants originating from elevated C a exhibited higher initial relative growth rates (RGRs) irrespective of chamber CO2 concentrations and a positive relationship was found between RGR and C a at the seed source. Seed weight was positively correlated with C a, but differences in seed weight were found to explain no more than 34% of the variation in RGRs at elevated CO2. Longer-term experiments (over 98 days) on two populations originating from the extremes of the transect (451 and 610 µmol CO2 mol-1) indicated that differences in growth between populations were maintained when plants were grown at both 350 and 700 µmol CO2 mol-1. Analysis of leaf material revealed an increase in the cell wall fraction (CWF) in plants grown at elevated CO2, with plants originating from high C a exhibiting constitutively lower levels but a variable response in terms of the degree of lignification. In vivo gas exchange measurements revealed no significant differences in light and CO2 saturated rates of photosynthesis and carboxylation efficiency between populations or with CO2 treatment. Moreover, SDS-PAGE/ LISA quantification of leaf ribulose bisphosphate carboxylase/oxygenase (Rubisco) showed no difference in Rubisco content between populations or CO2 treatments. These findings suggest that long-term adaptation to growth at elevated CO2 may be associated with a potential for increased growth, but this does not appear to be linked with differences in the intrinsic capacity for photosynthesis.

An approach to computer automation of the extracorporeal circulation.

In order to move towards extracorporeal circulation (ECC) automation, a virtual simulation of the process was designed. The ECC model is composed of a virtual patient linked to a virtual ECC circuit. A user interface panel allows to set control parameters for the simulation and to visualize results. It is possible to switch between manual and automatic control. Meaningful hemodynamic and hematochemical variables are continuously shown along with a score (from 0 to 10). The virtual model can play a crucial role in educating and training the personnel devoted to the managing of the heart-lung machine.

Methane and carbon dioxide fluxes and source partitioning in urban areas: the case study of Florence, Italy.

Long-term fluxes of CO(2), and combined short-term fluxes of CH(4) and CO(2) were measured with the eddy covariance technique in the city centre of Florence. CO(2) long-term weekly fluxes exhibit a high seasonality, ranging from 39 to 172% of the mean annual value in summer and winter respectively, while CH(4) fluxes are relevant and don't exhibit temporal variability. Contribution of road traffic and domestic heating has been estimated through multi-regression models combined with inventorial traffic and CH(4) consumption data, revealing that heating accounts for more than 80% of observed CO(2) fluxes. Those two components are instead responsible for only 14% of observed CH(4) fluxes, while the major residual part is likely dominated by gas network leakages. CH(4) fluxes expressed as CO(2) equivalent represent about 8% of CO(2) emissions, ranging from 16% in summer to 4% in winter, and cannot therefore be neglected when assessing greenhouse impact of cities.

Locating industrial VOC sources with aircraft observations.

Observation and characterization of environmental pollution, focussing on Volatile Organic Compounds (VOCs), in a high-risk industrial area, are particularly important in order to provide indications on a safe level of exposure, indicate eventual priorities and advise on policy interventions. The aim of this study is to use the Solid Phase Micro Extraction (SPME) method to measure VOCs, directly coupled with atmospheric measurements taken on a small aircraft environmental platform, to evaluate and locate the presence of VOC emission sources in the Marghera industrial area. Lab analysis of collected SPME fibres and subsequent analysis of mass spectrum and chromatograms in Scan Mode allowed the detection of a wide range of VOCs. The combination of this information during the monitoring campaign allowed a model (Gaussian Plume) to be implemented that estimates the localization of emission sources on the ground.

Impact of biochar application to a Mediterranean wheat crop on soil microbial activity and greenhouse gas fluxes.

Biochar has been recently proposed as a management strategy to improve crop productivity and global warming mitigation. However, the effect of such approach on soil greenhouse gas fluxes is highly uncertain and few data from field experiments are available. In a field trial, cultivated with wheat, biochar was added to the soil (3 or 6 kg m(-2)) in two growing seasons (2008/2009 and 2009/2010) so to monitor the effect of treatments on microbial parameters 3 months and 14 months after char addition. N(2)O, CH(4) and CO(2) fluxes were measured in the field during the first year after char addition. Biochar incorporation into the soil increased soil pH (from 5.2 to 6.7) and the rates of net N mineralization, soil microbial respiration and denitrification activity in the first 3 months, but after 14 months treated and control plots did not differ significantly. No changes in total microbial biomass and net nitrification rate were observed. In char treated plots, soil N(2)O fluxes were from 26% to 79% lower than N(2)O fluxes in control plots, excluding four sampling dates after the last fertilization with urea, when N(2)O emissions were higher in char treated plots. However, due to the high spatial variability, the observed differences were rarely significant. No significant differences of CH(4) fluxes and field soil respiration were observed among different treatments, with just few exceptions. Overall the char treatments showed a minimal impact on microbial parameters and GHG fluxes over the first 14 months after biochar incorporation.