Highly reversible extrinsic electrocaloric effects over a wide temperature range in epitaxially strained SrTiO3 films.

Electrocaloric effects have been experimentally studied in ferroelectrics and incipient ferroelectrics, but not incipient ferroelectrics driven ferroelectric using strain. Here we use optimally oriented interdigitated surface electrodes to investigate extrinsic electrocaloric effects in low-loss epitaxial SrTiO3 films near the broad second-order 243 K ferroelectric phase transition created by biaxial in-plane coherent tensile strain from DyScO3 substrates. Our extrinsic electrocaloric effects are an order of magnitude larger than the corresponding effects in bulk SrTiO3 over a wide range of temperatures including room temperature, and unlike electrocaloric effects associated with first-order transitions they are highly reversible in unipolar applied fields. Additionally, the canonical Landau description for strained SrTiO3 films works well if we set the low-temperature zero-field polarization along one of the in-plane pseudocubic <100> directions. In future, similar strain engineering could be exploited for other films, multilayers and bulk samples to increase the range of electrocaloric materials for energy efficient cooling.

Guideline Application in Real world: multi-Institutional Based survey of Adjuvant and first-Line pancreatic Ductal adenocarcinoma treatment in Italy. Primary analysis of the GARIBALDI survey.

BACKGROUND: Information about the adherence to scientific societies guidelines in the 'real-world' therapeutic management of oncological patients are lacking. This multicenter, prospective survey was aimed to improve the knowledge relative to 2017-2018 recommendations of the Italian Association of Medical Oncology (AIOM). PATIENTS AND METHODS: Treatment-naive adult patients with pancreatic adenocarcinoma were enrolled. Group A received adjuvant therapy, group B received primary chemotherapy, and group C had metastatic disease. The results on patients accrued until 31 October 2019 with a mature follow-up were presented. RESULTS: Since July 2017, 833 eligible patients of 923 (90%) were enrolled in 44 Italian centers. The median age was 69 years (range 36-89 years; 24% >75 years); 48% were female; 93% had Eastern Cooperative Oncology Group (ECOG) performance status (PS) score of 0 or 1; group A: 16%, group B: 30%; group C: 54%; 72% Nord, 13% Center, 15% South. In group A, guidelines adherence was 68% [95% confidence interval (CI) 59% to 76%]; 53% of patients received gemcitabine and 15% gemcitabine + capecitabine; median CA19.9 was 29 (range 0-7300; not reported 15%); median survival was 36.4 months (95% CI 27.5-47.3 months). In group B, guidelines adherence was 96% (95% CI 92% to 98%); 55% of patients received nab-paclitaxel + gemcitabine, 27% FOLFIRINOX, 12% gemcitabine, and 3% clinical trial; median CA19.9 was 337 (range 0-20220; not reported 9%); median survival was 18.1 months (95% CI 15.6-19.9 months). In group C, guidelines adherence was 96% (95% CI 94% to 98%); 71% of patients received nab-paclitaxel + gemcitabine, 16% gemcitabine, 8% FOLFIRINOX, and 4% clinical trial; liver and lung metastases were reported in 76% and 23% of patients, respectively; median CA19.9 value was 760 (range 0-1374500; not reported 9%); median survival was 10.0 months (95% CI 9.1-11.1 months). CONCLUSIONS: The GARIBALDI survey shows a very high rate of adherence to guidelines and survival outcome in line with the literature. CA19.9 testing should be enhanced; nutritional and psychological counseling represent an unmet need. Enrollment to assess adherence to updated AIOM guidelines is ongoing.

Characterization of the HER2 status in BRCA-mutated breast cancer: a single institutional series and systematic review with pooled analysis.

BACKGROUND: Pathogenic variants (PVs) in BRCA1/2 genes account for ∼6% of breast and 20% of ovarian cancers. Most breast tumors developed by BRCA1 carriers are triple negative. BRCA2 tumors have similar rates of estrogen receptor positivity as sporadic controls but are less likely to be human epidermal growth factor receptor 2 (HER2)-positive. Prevalence of HER2 positivity among breast cancers (BCs) in BRCA1/2 mutation carriers is poorly and variably described, ranging from 0% to 10% and 0% to 13% in BRCA1 and BRCA2 carriers, respectively. PATIENTS AND METHODS: We assessed the prevalence of HER2 positivity among a single institutional cohort of 398 BCs developed in carriers of BRCA1/2 PVs (240 BRCA1, 158 BRCA2). Subsequently, a systematic review of the literature and pooled analysis was carried out. RESULTS: In our series we found a 7% HER2 positivity rate among all first BRCA1/2 BCs overall. In BRCA1 carriers, 5.4% of BCs were HER2-positive compared with 9.5% in BRCA2-mutated patients. Among bilateral BCs, HER2-positive cases were 15.2% in the BRCA1 group and 23.1% in the BRCA2 group. Notably, six BRCA1 and eight BRCA2 carriers showed discordant HER2 status between BC and bilateral BC (23.7%, 14/59). The systematic review included 21 083 BRCA1/2 patients from 73 eligible studies. The pooled rate of BRCAmut/HER2-positive BCs is 9.1% (95% confidence interval 7.3% to 11.2%). BRCA1 and BRCA2 when reported as separate data ranged from 0% to 33.3% (mean 8.3%) and from 0% to 86% (mean 10.3%), respectively. CONCLUSIONS: As compared with sporadic cases, BCs occurring in BRCA1 and/or BRCA2 PVs carriers are less frequently HER2-positive. Prevalence of HER2 positivity in our series was consistent with pooled analysis and did not exceed 10%. Although not common, co-existence of BRCA mutations and HER2 overexpression and/or gene amplification should be acknowledged. More research is needed to better characterize this subgroup of patients who should not be excluded a priori from clinical trials of targeted therapy for BRCA1/2-driven cancers.

Large magnetoelectric coupling in multiferroic oxide heterostructures assembled via epitaxial lift-off.

Epitaxial films may be released from growth substrates and transferred to structurally and chemically incompatible substrates, but epitaxial films of transition metal perovskite oxides have not been transferred to electroactive substrates for voltage control of their myriad functional properties. Here we demonstrate good strain transmission at the incoherent interface between a strain-released film of epitaxially grown ferromagnetic La0.7Sr0.3MnO3 and an electroactive substrate of ferroelectric 0.68Pb(Mg1/3Nb2/3)O3-0.32PbTiO3 in a different crystallographic orientation. Our strain-mediated magnetoelectric coupling compares well with respect to epitaxial heterostructures, where the epitaxy responsible for strong coupling can degrade film magnetization via strain and dislocations. Moreover, the electrical switching of magnetic anisotropy is repeatable and non-volatile. High-resolution magnetic vector maps reveal that micromagnetic behaviour is governed by electrically controlled strain and cracks in the film. Our demonstration should inspire others to control the physical/chemical properties in strain-released epitaxial oxide films by using electroactive substrates to impart strain via non-epitaxial interfaces.

Voltage-driven annihilation and creation of magnetic vortices in Ni discs.

Using photoemission electron microscopy (PEEM) to image ferromagnetism in polycrystalline Ni disks, and ferroelectricity in their single-crystal BaTiO3 substrates, we find that voltage-driven 90° ferroelectric domain switching serves to reversibly annihilate each magnetic vortex via uniaxial compressive strain, and that the orientation of the resulting bi-domain reveals the chirality of the annihilated vortex. Micromagnetic simulations reveal that only 60% of this strain is required for annihilation. Voltage control of magnetic vortices is novel, and should be energetically favourable with respect to the use of a magnetic field or an electrical current. In future, stray field from bi-domains could be exploited to read vortex chirality. Given that core polarity can already be read via stray field, our work represents a step towards four-state low-power memory applications.

Exchange-bias via nanosegregation in novel Fe2-x Mn1+x Al (x = -0.25, 0, 0.25) Heusler films.

Exchange-bias has been reported in bulk nanocrystalline Fe2MnAl, but individual thin films of this Heusler alloy have never been studied so far. Here we study the structural and magnetic properties of nanocrystalline thin films of Fe2-x Mn1+x Al (x = -0.25, 0 and 0.25) obtained by sputtering and ex situ post-deposition annealing. We find that Fe2MnAl films display exchange-bias, and that varying Mn concentration determines the magnitude of the effect, which can be either enhanced (in Fe1.75Mn1.25Al) or suppressed (in Fe2.25Mn0.75Al). X-ray diffraction shows that our films present a mixed L21-B2 Heusler structure where increasing Mn concentration favors the partial transformation of the L21 phase into the B2 phase. Scanning transmission electron microscopy (STEM) and energy dispersive X-ray spectroscopy (EDX) reveal that this composition-driven L21 → B2 transformation is accompanied by phase segregation at the nanoscale. As a result, the Fe2-x Mn1+x Al films that show exchange-bias (x = 0, 0.25) are heterogeneous, with nanograins of an Fe-rich phase embedded in a Mn-rich matrix (a non-negative matrix factorisation algorithm was used to give an indication of the phase composition from EDX data). Our comparative analysis of XRD, magnetometry and X-ray magnetic circular dichroism (XMCD), shows that the Fe-rich nanograins and Mn-rich matrix are composed of a ferromagnetic L21 phase and an antiferromagnetic B2 phase, respectively, thus revealing that exchange-coupling between these two phases is the cause of the exchange-bias effect. Our work should inspire the development of single-layer, environmentally friendly spin valve devices based on nanocomposite Heusler films.

Prognostic factors associated with survival in a large cohort of gastric cancer patients resected over a decade at a single Italian center: the Cremona experience.

BACKGROUND: Incidence of gastric cancer (GC) shows different distribution in Italy, with higher incidence in the north and center. We retrospectively analyzed the clinical data of patients resected at the Hospital of Cremona between January 2007 and December 2016. Available clinical variables were linked with survival to identify possible prognostic factors. MATERIALS AND METHODS: Variables analyzed were age, sex, type of surgery, site, histology, invasion, nodal status, resection margins, grade, HER2 status, Helicobacter pylori infection (neo)adjuvant chemotherapy, adjuvant chemoradiotherapy, neutrophil-to-lymphocyte ratio, number of nodes removed and type of lymphadenectomy. Overall survival (OS) was estimated by the Kaplan-Meier method and differences between groups by the log-rank test. Data on OS were analyzed by Cox regression and the final model was obtained using the step-wise method. RESULTS: 379 patients were considered, out of which 195 were operated from 2007 to 2011 and 184 from 2012 to 2016. Median follow-up was 25.5 months, median OS 31.3 months and time to recurrence 23.2 months. D2 resection rate increased from 36% (period 2007-2011) to 74% in 2012-2016 (p = 0.01) with a higher mean number of nodes collected (20.98 for 2007-2011 and 23.53 for 2012-2016, p = 0.040). Only 37% of patients received a postoperative treatment. At multivariate analysis, variables associated with OS were age (p = 0.002), stage (p < 0.001), resection margins status (p < 0.001), adjuvant chemotherapy (p < 0.010) and tumor location (cardia vs non-cardia) (p = 0.029). CONCLUSIONS: Our analysis shows that completeness of resection and lower stage are strong predictors of long-term survival in GC, providing the rationale for adjuvant and neoadjuvant approaches (chemotherapy, radiotherapy or combined). Cardial GC has worse prognosis compared to distal cancers. TRIAL REGISTRATION NUMBER: Service evaluation number 256, protocol 16821/17, date 05 June 2017.

Shear-strain-mediated magnetoelectric effects revealed by imaging.

Large changes in the magnetization of ferromagnetic films can be electrically driven by non-180° ferroelectric domain switching in underlying substrates, but the shear components of the strains that mediate these magnetoelectric effects have not been considered so far. Here we reveal the presence of these shear strains in a polycrystalline film of Ni on a 0.68Pb(Mg1/3Nb2/3)O3-0.32PbTiO3 substrate in the pseudo-cubic (011)pc orientation. Although vibrating sample magnetometry records giant magnetoelectric effects that are consistent with the hitherto expected 90° rotations of a global magnetic easy axis, high-resolution vector maps of magnetization (constructed from photoemission electron microscopy data, with contrast from X-ray magnetic circular dichroism) reveal that the local magnetization typically rotates through smaller angles of 62-84°. This shortfall with respect to 90° is a consequence of the shear strain associated with ferroelectric domain switching. The non-orthogonality represents both a challenge and an opportunity for the development and miniaturization of magnetoelectric devices.

Epidemiological, clinical and pathological characteristics of gastric neoplasms in the province of Cremona: the experience of the first population-based specialized gastric cancer registry in Italy.

BACKGROUND: The gastric cancer incidence rate differs widely across geographical areas. In Italy, in the province of Cremona the incidence is high, compared to the national situation. For this reason a specialized population-based registry was set up. METHODS: The collection encompasses all gastric cancers diagnosed in the three districts of the province since January 1, 2010. The main data sources were the pathological and Hospital Discharge Records and patient clinical charts. Only diagnoses of primary gastric cancer were considered. For each case the following variables were registered: personal data, medical history and symptoms at diagnosis; imaging assessments performed, details on surgery and other treatments received; genetic background and biomolecular characteristics; social and environmental factors. RESULTS: As of November 2017, 1087 cases were collected; of which 876, diagnosed up to December 2015, were analyzed. Male/female ratio was 1.4. The European Age-standardized Incidence Rate was 41.4 for males and 28.3 for females as compared to a national average of 33.3 and 17.0 respectively. Median age at diagnosis was 73 for male and 78 for female. Helicobacter Pylori infection was present in fewer than 20% of cases. HER-2 gene was amplified in about 25% of cases. Primary tumour location was the gastro-esophageal junction or cardia in 17.5% in males and 8.3% in females. The majority of cases (58.3%) were diagnosed at an advanced stage and overall only 41.2% underwent surgery. Median overall survival was 14.8 months for men and 18.5 for women. Age standardized 5-year relative survival was 31.4% for men and 40.5% for females. Neoadjuvant treatment was performed in fewer than 10% of patients who underwent surgery, and the rate of postoperative therapy adherence was low. DISCUSSION: This study shows a high gastric cancer incidence in the province of Cremona, with a geographical spread across different districts. Moreover, a high percentage of gastric cancers were detected at an advanced stage of disease and a low rate of 5-year relative survival was registered. Based on these findings, effective preventive interventional health strategies and screening procedures need to be implemented to reduce the impact of this pathology in this geographical area.

Tumor regression grade and survival after neoadjuvant treatment in gastro-esophageal cancer: A meta-analysis of 17 published studies.

INTRODUCTION: Major pathologic regression after neoadjuvant therapy is a strong and favorable prognostic factor in several types of cancer (breast, rectal and bladder). This information is less clear and has yet to be systematically evaluated in upper gastrointestinal tumors. We performed a meta-analysis to evaluate the prognostic impact of tumor regression after preoperative therapy on disease-free survival (DFS) and overall survival (OS) in gastro-esophageal cancer patients. METHODS: we searched for relevant articles in PubMed, SCOPUS, Web of Science, CINAHL, LILACS, Ovid, Cochrane Library, Google Scholar and Embase up to June 2, 2016. Data of tumor regression (complete or near-complete pathologic response) that independently correlated with OS and DFS in multivariate analysis were extracted, and the proper hazard ratios (HRs) with corresponding 95% confidence intervals (95% CIs) were pooled according to the random effect model. RESULTS: a total of 17 studies-which included 3145 patients-were considered in the final analysis. Major pathologic response was significantly related with better OS (HR 0.46, 95% CI 0.32-0.66, P < 0.001) and DFS (HR = 0.40, 95% CI 0.26-0.62, P < 0.001). Pathologic complete response (pCR) or major tumor regression were associated with the same degree of benefit in outcome compared to no or minimal pathologic regression, regardless of histology. CONCLUSION: major pathologic response is associated with a significant improvement in OS compared to no response or minor pathologic changes after neoadjuvant therapy in gastro-esophageal cancers. This should be considered a robust prognostic factor to guide postoperative treatment and follow-up.

Estimating 12-week death probability in patients with refractory metastatic colorectal cancer: the Colon Life nomogram.

Background: Regorafenib and TAS-102 have recently demonstrated statistically significant survival gains in patients with refractory metastatic colorectal cancer (mCRC). Life expectancy ≥12 weeks was an inclusion criterion in registrative trials, and the identification of proper clinical selection tools for the daily use of these drugs in heavily pre-treated patients is needed to improve the cost-benefit ratio. We aimed at building a nomogram able to predict death probability within 12 weeks from the date of assessment of refractory mCRC. Patients and methods: Four hundred eleven refractory mCRC patients with ECOG performance status (PS) ≤2 receiving regorafenib, TAS-102 or other treatments were used as developing set. Putative prognostic variables were selected using a random forest model and included in a binary logistic model from which the nomogram was developed. The nomogram was externally validated and its performance was evaluated by examining calibration (how close predictions were to the actual outcome) and discriminative ability (Harrell C index) both on developing (internal validation) and validating (external validation) sets. Results: Four variables were selected and included in the nomogram: PS (P < 0.0001), primary tumor resection (P = 0.027), LDH value (P = 0.0001) and peritoneal involvement (P = 0.081). In the developing set, the nomogram discriminative ability was high (C = 0.778), and was confirmed in the validating set (C = 0.778), where the overall outcome was better as a consequence of the enrichment in patients receiving regorafenib or TAS-102 (46% versus 34%; P < 0.0001). Conclusions: Our nomogram may be a useful tool to predict the probability of death within 12 weeks in patients with refractory mCRC. Based on four easy-to-collect variables, the 'Colon Life' nomogram and free app for smartphones may improve mCRC patients' selection for later-line therapies and assist researchers for the enrollment in clinical trials in this setting.

Long Spin Diffusion Length in Few-Layer Graphene Flakes.

We report a spin valve with a few-layer graphene flake bridging highly spin-polarized La_{0.67}Sr_{0.33}MnO_{3} electrodes, whose surfaces are kept clean during lithographic definition. Sharp magnetic switching is verified using photoemission electron microscopy with x-ray magnetic circular dichroism contrast. A naturally occurring high interfacial resistance ∼12 MΩ facilitates spin injection, and a large resistive switching (0.8 MΩ at 10 K) implies a 70-130 µm spin diffusion length that exceeds previous values obtained with sharp-switching electrodes.

Magnetoelectric CoFe2O4/polyvinylidene fluoride electrospun nanofibres.

Magnetoelectric 0-1 composites comprising CoFe2O4 (CFO) nanoparticles in a polyvinylidene fluoride (PVDF) polymer-fibre matrix have been prepared by electrospinning. The average diameter of the electrospun composite fibres is ∼325 nm, independent of the nanoparticle content, and the amount of the crystalline polar ß phase is strongly enhanced when compared to pure PVDF polymer fibres. The piezoelectric response of these electroactive nanofibres is modified by an applied magnetic field, thus evidencing the magnetoelectric character of the CFO/PVDF 0-1 composites.

Non-volatile electrically-driven repeatable magnetization reversal with no applied magnetic field.

Repeatable magnetization reversal under purely electrical control remains the outstanding goal in magnetoelectrics. Here we use magnetic force microscopy to study a commercially manufactured multilayer capacitor that displays strain-mediated coupling between magnetostrictive Ni electrodes and piezoelectric BaTiO(3)-based dielectric layers. In an electrode exposed by polishing approximately normal to the layers, we find a perpendicularly magnetized feature that exhibits non-volatile electrically driven repeatable magnetization reversal with no applied magnetic field. Using micromagnetic modelling, we interpret this nominally full magnetization reversal in terms of a dynamic precession that is triggered by strain from voltage-driven ferroelectric switching that is fast and reversible. The anisotropy field responsible for the perpendicular magnetization is reversed by the electrically driven magnetic switching, which is, therefore, repeatable. Our demonstration of non-volatile magnetic switching via volatile ferroelectric switching may inspire the design of fatigue-free devices for electric-write magnetic-read data storage.

Giant and reversible extrinsic magnetocaloric effects in La0.7Ca0.3MnO3 films due to strain.

Large thermal changes driven by a magnetic field have been proposed for environmentally friendly energy-efficient refrigeration, but only a few materials that suffer hysteresis show these giant magnetocaloric effects. Here we create giant and reversible extrinsic magnetocaloric effects in epitaxial films of the ferromagnetic manganite La(0.7)Ca(0.3)MnO(3) using strain-mediated feedback from BaTiO(3) substrates near a first-order structural phase transition. Our findings should inspire the discovery of giant magnetocaloric effects in a wide range of magnetic materials, and the parallel development of nanostructured bulk samples for practical applications.

Early diagnosis of deep vein thrombosis following total hip replacement using impedance plethysmography: advantages and limitations of this approach.

Early diagnosis of deep vein thrombosis (DVT) following total hip replacement is of fundamental importance given the particularly high incidence of thromboembolic complications and the limited effectiveness of available preventive measures. The authors report the results of postoperative monitoring of the lower limbs using impedance plethysmography (IPG). The validity of the computerized plethysmograph used in this study has been confirmed by previous clinical studies, in which this instrument demonstrated high sensitivity and specificity of diagnosis of deep vein thrombosis in the symptomatic patient. In the present study, however, the instrument is applied to a group of mostly asymptomatic patients, many of whom have non-occlusive DVT. One hundred thirty-two patients underwent IPG both one the day before surgery and on the seventh day after surgery. The postoperative IPG was positive in seven asymptomatic patients (5.3%). Proximal DVT was confirmed by phlebography in five patients (3.7%) and found to be absent in two patients (false positives: 1.5%), for a positive predictive value of 71%. IPG also found proximal DVT to be absent in three patients with postoperative signs and/or symptoms compatible with a thrombotic complication in the lower limbs. The character of the study did not permit collection of data as to IPG sensitivity in the asymptomatic patient, which is presumably quite lower than in the symptomatic patient. Therefore, phlebography remains the most reliable test for diagnosis of asymptomatic DVT. However, systematic monitoring by phlebography is not feasible for logistic, economic, and ethical reasons. Postoperative use of IPG may at least partially reduce the risks connected with thromboembolic complications.