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This study evaluated single intra-articular injections of Hymovis MO.RE., a hyaluronic acid hexadecyl derivative (HYADD4-G), to manage post-traumatic or degenerative knee or ankle chondropathy in professional soccer players.Twenty-five players affected by knee (n = 12) or ankle (n = 13) chondropathy were prospectively enrolled and treated by two single Hymovis MO.RE. (32 mg/4 ml) injections at the beginning of the football season (V0, baseline) and at mid-season (V1, 19-20 weeks thereafter), and were followed-up until the end of the season (V2, after further 19-20 weeks). Knee cases were evaluated using the 2000 IKDC knee subjective examination form and the modified Lysholm scoring system. Ankle cases were evaluated using the American Orthopaedic Foot Ankle Society (AOFAS) ankle-hindfoot score. Patients were also evaluated using a VAS Likert scale and a four-category scale recording both the patient's and the doctor's assessment on joint mobility in degrees and overall treatment efficacy. Adverse events, patient withdrawals and local reaction to injections were also assessed.In knee patients, the 2000 IKDC subjective score improved from 46.8 ± 11.4 at V0 to 83.1 ± 12.5 at V2. Their modified Lysholm score improved from 58.8 ± 8.9 at V0 to 90.6 ± 8.3 at V2. In the ankle patients, the AOFAS score improved from 52.2 ± 5.6 at V0 to 96.4 ± 4.5 at V2. VAS Likert values and subjective evaluations improved at V1 and were maintained at V2. No side effects were recorded.A single Hymovis MO.RE. (32 mg/4 ml) intra-articular injection, repeated after 19-20 weeks, may be a viable option to improve symptoms and function in professional soccer players suffering from knee and ankle chondropathy.

Objective Germline BRCA1-2 pathogenic variants (gBRCApv) increase the risk of pancreatic cancer and predict for response to platinating agents and poly(ADP-ribose) polymerase inhibitors. Data on worldwide gBRCApv incidence among pancreatic ductal adenocarcinoma (PDAC) patients are sparse and describe a remarkable geographic heterogeneity. The aim of this study is to analyze the epidemiology of gBRCApv in Italian patients. Materials and methods Patients of any age with pancreatic adenocarcinoma, screened within 3 months from diagnosis for gBRCApv in Italian oncologic centers systematically performing tests without any selection. For the purposes of our analysis, breast, ovarian, pancreas, and prostate cancer in a patient's family history was considered as potentially BRCA-associated. Patients or disease characteristics were examined using the χ2 test or Fisher's exact test for qualitative variables and the Student's t-test or Mann–Whitney test for continuous variables, as appropriate. Results Between June 2015 and May 2020, 939 patients were tested by 14 Italian centers; 492 (52%) males, median age 62 years (range 28-87), 569 (61%) metastatic, 273 (29%) with a family history of potentially BRCA-associated cancers. gBRCA1-2pv were found in 76 patients (8.1%; 9.1% in metastatic; 6.4% in non-metastatic). The gBRCA2/gBRCA1 ratio was 5.4 : 1. Patients with gBRCApv were younger compared with wild-type (59 versus 62 years, P = 0.01). The gBRCApv rate was 17.1% among patients 70 years old (none out of 94 patients >73 years old). gBRCApv frequency in 845 patients, Highlights • This is the largest case series of incident PDAC patients screened for germline BRCA1-2 pathologic variants (gBRCApv). • The incidence of gBRCA1-2pv was 8.1% in the whole population; 9.1% in metastatic patients; 6.4% in non-metastatic patients. • No gBRCA1-2pv was observed over the age of 73. • These data suggest screening all PDAC patients

Epidermal growth factor receptor (EGFR) inhibitors are valuable therapeutics in metastatic colorectal cancer (mCRC). Anti-EGFR monoclonal antibodies (MoAbs), such as cetuximab or panitumumab, in combination with chemotherapy are effective treatment options for patients with RAS and BRAF wild-type mCRC. Nevertheless, several issues are still open concerning the optimal use of anti-EGFR drugs in the continuum of care of mCRC. Novel approaches for increasing the efficacy of anti-EGFR therapies include better molecular selection of EGFR-dependent mCRC, intensification of chemotherapy, combination of anti-EGFR MoAbs and immune checkpoint inhibitors, and reintroduction of EGFR blockade or 'rechallenge' in selected patients who have previously responded to anti-EGFR MoAb therapy. An extensive translational research program was conducted in the Cetuximab After Progression in KRAS wIld-type colorectal cancer patients-Gruppo Oncologico dell' Italia Meridionale (CAPRI-GOIM) study with the aims of determining which subgroups of patients could benefit from the continuous inhibition of EGFR, from evaluating the role of liquid biopsy-based and its concordance with tissue-based molecular testing, and from investigating novel potential mechanisms of resistance to anti-EGFR therapies. In this review, we summarize the translational and clinical findings of the CAPRI-GOIM program in the context of the current knowledge of therapeutic strategies and of ongoing research on more appropriate uses of anti-EGFR therapies in RAS and BRAF wild-type mCRC patients.

Goal: To present a framework for data sharing, curation, harmonization and federated data analytics to solve open issues in healthcare, such as, the development of robust disease prediction models. Methods: Data curation is applied to remove data inconsistencies. Lexical and semantic matching methods are used to align the structure of the heterogeneous, curated cohort data along with incremental learning algorithms including class imbalance handling and hyperparameter optimization to enable the development of disease prediction models. Results: The applicability of the framework is demonstrated in a case study of primary Sjögren's Syndrome, yielding harmonized data with increased quality and more than 85% agreement, along with lymphoma prediction models with more than 80% sensitivity and specificity. Conclusions: The framework provides data quality, harmonization and analytics workflows that can enhance the statistical power of heterogeneous clinical data and enables the development of robust models for disease prediction. © 2020 Lippincott Williams and Wilkins. All rights reserved.

Objectives: Salivary gland ultrasonography (SGUS) is increasingly applied for the management of primary Sjögren's syndrome (pSS). This study aims to: (i) compare the reliability between two SGUS scores; (ii) test the reliability among sonographers with different levels of experience. Methods: In the reliability exercise, two four-grade semi-quantitative SGUS scoring systems, namely De Vita et al. and OMERACT, were tested. The sonographers involved in work-package 7 of the HarmonicSS project from nine countries in Europe were invited to participate. Different levels of sonographers were identified on the basis of their SGUS experience and of the knowledge of the tested scores. A dedicated atlas was used as support for SGUS scoring. Results: Twenty sonographers participated in the two rounds of the reliability exercise. The intra-rater reliability for both scores was almost perfect, with a Light's kappa of 0.86 for the De Vita et al. score and 0.87 for the OMERACT score. The inter-rater reliability for the De Vita et al. and the OMERACT score was substantial with Light's Kappa of 0.75 and 0.77, respectively. Furthermore, no significant difference was noticed among sonographers with different levels of experience. Conclusion: The two tested SGUS scores are reliable for the evaluation of major salivary glands in pSS, and even less-expert sonographers could be reliable if adequately instructed. © Copyright © 2020 Zabotti, Zandonella Callegher, Tullio, Vukicevic, Hocevar, Milic, Cafaro, Carotti, Delli, De Lucia, Ernst, Ferro, Gattamelata, Germanò, Giovannini, Hammenfors, Jonsson, Jousse-Joulin, Macchioni, Parisi, Perricone, Stradner, Filipovic, Tzioufas, Valent and De Vita.

We investigate the elastoviscoplastic flow through porous media by numerical simulations. We solve the Navier–Stokes equations combined with the elastoviscoplastic model proposed by Saramito for the stress tensor evolution [1]. In this model, the material behaves as a viscoelastic solid when unyielded, and as a viscoelastic Oldroyd-B fluid for stresses higher than the yield stress. The porous media is made of a symmetric array of cylinders, and we solve the flow in one periodic cell. We find that the solution is time-dependent even at low Reynolds numbers as we observe oscillations in time of the unyielded region especially at high Bingham numbers. The volume of the unyielded region slightly decreases with the Reynolds number and strongly increases with the Bingham number; up to 70% of the total volume is unyielded for the highest Bingham numbers considered here. The flow is mainly shear dominated in the yielded region, while shear and elongational flow are equally distributed in the unyielded region. We compute the relation between the pressure drop and the flow rate in the porous medium and present an empirical closure as function of the Bingham and Reynolds numbers. The apparent permeability, normalized with the case of Newtonian fluids, is shown to be greater than 1 at low Bingham numbers, corresponding to lower pressure drops due to the flow elasticity, and smaller than 1 for high Bingham numbers, indicating larger dissipation in the flow owing to the presence of the yielded regions. Finally we investigate the effect of the Weissenberg number on the distribution of the unyielded regions and on the pressure gradient.

Background: By the end of 2020, coronavirus disease 2019 (COVID-19) would have indelibly marked the cancer care setting. With Italy at the forefront of pandemic, unprecedented measures were adopted to tackle the quality care issue. As a result of pausing screening programs, diagnostic delays might affect the years to come. Aim of our multicenter Italian study is to evaluate whether the COVID-19 outbreak has impacted on likelihood of receiving timely diagnosis, staging and treatment for colorectal cancer (CRC) patients (pts) after March 2020 compared to pre-pandemic time. Methods: Medical records of all consecutive newly diagnosed CRC pts referred to 4 Italian Oncology Departments between March and December 2020 were examined. Access rate (number of pts/days) and temporal intervals between date of symptoms onset, radiological and cytohistological diagnosis, treatment start and first radiological evaluation were analyzed and compared with the same months of 2019. Differences between the two years were evaluated using Fisher’s exact test or chi-square test for categorical variables and unpaired Student t test, or the Mann-Whitney U test for continuous variables. Results: A reduction (20%) in newly diagnosed CRC cases was seen when compared with 2019 (214 vs 268). The decline was greater in the lockdown period compared to the other months (percentage drop 40 % vs 12%). Newly CRC pts in 2020 were less likely to be diagnosed with early stage (stage I-II-III) CRC (67% vs 72%). Other clinical and tumor characteristics were similar regardless of the year. Looking at pts management, no differences emerged in terms of interval between symptom onset and radiological diagnosis (median 19 days in 2020 vs 28 days in 2019, p = 0.88), symptom onset and cytohistological diagnosis (25 vs 36 days, p = 0.27), symptom onset and treatment start (median 86 vs 100 days, p = 0.79). However, less CRC were discussed in multidisciplinary tumor meetings during the 2020 (45% vs 54%, p = 0.07). Conclusions: While COVID-19 repercussions will be likely felt for decades to come, our data suggest an alarming drop in early-stage CRC diagnoses during the first pandemic year. Conversely, our study draws the attention on the efforts made to ensure diagnostic-therapeutic pathways proper operation. Legal entity responsible for the study: The authors. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.

The effect of wind on the wave breaking induced by the modulational instability is investigated numerically using the open source software Gerris. The two-phase flow is modelled by the two-dimensional Navier–Stokes equations for a single incompressible fluid and a Volume of Fluid technique is employed to capture the air–water interface. The flow is initialized as a fundamental wave component with two side-band perturbations so that the breaking is induced via the Benjamin–Feir instability mechanism. In order to investigate its effect on the wave evolution and on the breaking process, a uniform wind, twice the phase speed, is assigned in the air phase. The simulation covers the initial development of the wind profile, the growth of the modulational instability, the breaking and post breaking phases. Results show the occurrence of air flow separation from the wave crests shortly after the initial start. Pressure and tangential stress acting on the free surface are computed. It is shown that due to the flow separation there is a favourable pressure gradient about the wave crests whereas the tangential stresses are generally in favour of the wave propagation on the back of the wave but are opposed to the propagation along the forward face and in the wave trough. An initial growth of the energy content in water is observed, followed by a dissipation stage which is not related to the breaking process. In agreement with the experiments, the growth rate of the side-bands is reduced when compared to the corresponding no-wind solution. Because of the slower growth, the limiting condition for the onset of the breaking is reached with some delay. At the end of the breaking process, when the downshift is completed, the amplitude of the left side-band in the wind case is somewhat lower than that for the no-wind case. No substantial differences have been found in terms of the total energy dissipated by the whole breaking process although the dissipation rate for the wind case is noticeably higher. The higher dissipation rate observed in the wind case is found to be related to the larger amount of air entrained by the breaking process.

Data quality assessment has gained attention in the recent years since more and more companies and medical centers are highlighting the importance of an automated framework to effectively manage the quality of their big data. Data cleaning, also known as data curation, lies in the heart of the data quality assessment and is a key aspect prior to the development of any data analytics services. In this work, we present the objectives, functionalities and methodological advances of an automated framework for data curation from a medical perspective. The steps towards the development of a system for data quality assessment are first described along with multidisciplinary data quality measures. A three-layer architecture which realizes these steps is then presented. Emphasis is given on the detection and tracking of inconsistencies, missing values, outliers, and similarities, as well as, on data standardization to finally enable data harmonization. A case study is conducted in order to demonstrate the applicability and reliability of the proposed framework on two well-established cohorts with clinical data related to the primary Sjögren's Syndrome (pSS). Our results confirm the validity of the proposed framework towards the automated and fast identification of outliers, inconsistencies, and highly-correlated and duplicated terms, as well as, the successful matching of more than 85% of the pSS-related medical terms in both cohorts, yielding more accurate, relevant, and consistent clinical data. © 2019

Mechanisms of acquired resistance to trastuzumab-based treatment in gastric cancer are largely unknown. In this study, we analyzed 22 pairs of tumor samples taken at baseline and post-progression in patients receiving chemotherapy and trastuzumab for advanced HER2-positive [immunohistochemistry (IHC) 3+ or 2+ with in-situ hybridization (ISH) amplification] gastric or gastroesophageal cancers. Strict clinical criteria for defining acquired trastuzumab resistance were adopted. Loss of HER2 positivity and loss of HER2 over-expression were defined as post-trastuzumab IHC score

Background The prognostic role of Progesterone receptor (PR) expression in early invasive breast cancer (BC) remains controversial. The aim of this retrospective analysis was to investigate the impact of PR expression levels on outcome of patients with luminal-like Her2 negative early BC. Methods A population cohort of 441 primary invasive ER+/Her2- early BC patients from a single cancer center underwent surgery and received adjuvant endocrine therapy from 2000 to 2017 was retrieved. To assess the impact of the different PR levels on the prognosis, we calculated the Distant Free Survival (DFS) and the Breast Cancer Specific Survival (BCSS) according to 4 subtypes established on the basis of Ki67 value and PR expression rate (Subtype 1: PR ≥ 20%/Ki67 Results The rates of progression disease were 8%, 19%, 30% and 12% in subtype 1, 2, 3 and 4, respectively. Low PR expression ( Conclusions Our study revealed different outcomes among patients with early BC according to different PR expression levels. Noteworthy, in patients with Ki67 ≥20%, low PR expression levels ( Legal entity responsible for the study The authors. Funding Has not received any funding. Disclosure A. Diana: Travel / Accommodation / Expenses: Ipsen, Novartis, Pharmamar, Italfarmaco. F. Carlino: Travel / Accommodation / Expenses: Italfarmaco, Gentili. E. Franzese: Travel / Accommodation / Expenses: Roche. S. Centonze: Travel / Accommodation / Expenses: Thesaro, Roche, Gentili. F. De Vita: Advisory / Consultancy: Roche, Amgen, Celgene, Lilly. F. Ciardiello: Advisory / Consultancy: Merck, Roche, Lilly, Bayer, Amgen, Pfizer, Servier. M. Orditura: Honoraria (self): Epionpharma, Italfarmaco; Travel / Accommodation / Expenses: Roche; Research grant / Funding (institution): EISAI. All other authors have declared no conflicts of interest.

Background. High neutrophil to lymphocyte ratio (NLR) has shown to be a predictor of poor outcomes in various malignancies, including pancreatic cancer. Methods. We assessed 70 consecutive pts with histologically confirmed mPC who received chemotherapy with nab-paclitaxel/gemcitabine at two different European oncologic centers between January 2012 and November 2015. Variables assessed for prognostic correlations included age ≥ 66, sex, Karnofsky PS score, primary tumor site, baseline CA19.9 level ≥ 59xULN, 12-week decrease of the CA19.9 level ≥ 50% from baseline, basal bilirubin level, baseline NLR, biliary stent implantation, and liver metastasis. Survival analyses were generated according to the Kaplan-Meier method. Univariate and multivariate analyses were performed by a Cox proportional hazard model. Results. According to NLR values, the patients were divided into two groups: high and low. Low group patients showed a better median PFS (7 months versus 5 months) and median OS (13 months versus 7 months) in respect to high group patients. At multivariate analysis, Karnofsky PS Conclusions. Baseline NLR is an independent predictor of survival of patients with mPC receiving palliative chemotherapy and could be useful to develop a simple clinical score to identify a subgroup of patients with a low chance to benefit from chemotherapy.

Two inhibitors of phosphatidylinositol 3-kinase (PI3K) pathway taselisib, targeting the mutant PI3K-subunit-alpha (PI3KA) and ipatasertib, AKT-inhibitor, are currently under clinical investigation in breast cancer (BC) patients. We have previously demonstrated the anti-tumor efficacy of these anti-PI3K/AKT-inibitors in combination with anti-microtubule drugs in human BC cell lines, through a complete cytoskeleton disorganization. In this work, we generated ex-vivo three-dimensional (3D) cultures from human BC as a model to test drug efficacy and to identify new molecular biomarkers for selection of BC patients suitable for anti-PI3K/AKT-inibitors treatment. We have established 3D cultures from 25/27 human BC samples, in which the ability of growth in vitro replicates the clinical and biological aggressiveness of the original tumors. According to the results of next generation sequencing analysis, a direct correlation was found between PI3KA mutations and the sensitivity in 3D models in vitro to taselisib and ipatasertib alone and combined with anti-microtubule agents. Moreover, mutations in HER and MAPK families related genes, including EGFR, KRAS and BRAF, were found in resistant samples, suggesting their potential role as negative predictive factors of response to these agents. Thus, we demonstrated that ex vivo 3D cultures from human BC patients allow a rapid and efficient drug screening for chemotherapies and targeted agents in genetically selected patients and represent an innovative model to identify new biomarkers of drug resistance.

In the cetuximab after progression in KRAS wild-type colorectal cancer patients (CAPRI) trial patients with metastatic colorectal cancer (mCRC) received 5-fluorouracil, folinic acid and irinotecan (FOLFIRI) and cetuximab in first line followed by 5-Fluorouracil, folinic acid, oxaliplatin (FOLFOX) with or without cetuximab until progression. Limited data are available on the efficacy and safety of anti-epidermal growth factor receptor (anti-EGFR) agents on elderly patients with mCRC. In the current study we evaluated the efficacy and safety of FOLFIRI plus cetuximab in age-defined subgroups. Background: In the cetuximab after progression in KRAS wild-type colorectal cancer patients ( CAPRI) trial patients with metastatic colorectal cancer (mCRC) received 5-fluorouracil, folinic acid and irinotecan (FOLFIRI) and cetuximab in first line followed by 5-Fluorouracil, folinic acid, oxaliplatin (FOLFOX) with or without cetuximab until progression. Limited data are available on the efficacy and safety of anti-epidermal growth factor receptor (anti-EGFR) agents on elderly patients with mCRC. In the current study we evaluated the efficacy and safety of FOLFIRI plus cetuximab in age-defined subgroups.Methods: A post-hoc analysis was performed in CAPRI trial patients; outcomes (progression-free survival (PFS), overall response rate (ORR), safety) were analysed by agegroups and stratified according to molecular characterisation. 3 age cut-offs were used to define the elderly population (>= 65; >= 70 and >= 75 years).Results: 340 patients with mCRC were treated in first line with FOLFIRI plus cetuximab. Among those, 154 patients were > 65 years, 86 > 70 years and 35 > 75 years. Next-generation sequencing (NGS) was performed in 182 patients. Among them, 87 patients were > 65 years, 46 > 70 and 17 > 75. 104 of 182 patients were wild type (WT) for KRAS, NRAS, BRAF, PIK3CA genes. In the quadruple WT group, 51 patients were >= 65 years; 29 were >= 70; 9 were >= 75. Median PFS was similar within the age-subgroups in the intention-to-treat population, NGS cohort and quadruple WT patients, respectively. Likewise, ORR was not significantly different among age-subgroups in the 3 populations. Safety profile was acceptable and similarly reported among all age-groups, with the exception of grade >= 3 diarrhoea (55% vs 25%, p=0.04) and neutropaenia (75% vs 37%, p=0.03) in patients >= 75 years and grade >= 3 fatigue (31% vs 20%, p=0.01) in patients < 75 years.Conclusions: Tolerability of cetuximab plus FOLFIRI was acceptable in elderly patients. Similar ORR and PFS were observed according to age-groups. No differences in adverse events were reported among the defined subgroups with the exception of higher incidence of grade >= 3 diarrhoea and neutropaenia in patients >= 75 years and grade >= 3 fatigue in patients < 75 years.

Autoimmune diseases are a complex set of diseases characterized by immune system activation and, although many progresses have been done in the last 15 years, several unmet needs in the management of these patients may be still identified. Recently, a panel of international Experts, divided in different working groups according to their clinical and scientific expertise, were asked to identify, debate and formulate a list of key unmet needs within the field of rheumatology, serving as a roadmap for research as well as support for clinicians. After a systematic review of the literature, the results and the discussions from each working group were summarised in different statements. Due to the differences among the diseases and their heterogeneity, a large number of statements was produced and voted by the Experts to reach a consensus in a plenary session. At all the steps of this process, including the initial discussions by the steering committee, the identification of the unmet needs, the expansion of the working group and finally the development of statements, a large agreement was attained. This work confirmed that several unmet needs may be identified and despite the development of new therapeutic strategies as well as a better understanding of the effects of existing therapies, many open questions still remain in this field, suggesting a research agenda for the future and specific clinical suggestions which may allow physicians to better manage those clinical conditions still lacking of scientific clarity. © 2017

// Floriana Morgillo 1 , Carminia Maria Della Corte 1 , Anna Diana 1 , Concetta di Mauro 2 , Vincenza Ciaramella 1 , Giusi Barra 3 , Valentina Belli 1 , Elisena Franzese 1 , Roberto Bianco 2 , Evaristo Maiello 4 , Ferdinando De Vita 1 , Fortunato Ciardiello 1 and Michele Orditura 1 1 Oncologia Medica, Dipartimento di Internistica Clinica e Sperimentale “F. Magrassi”, Universita degli Studi della Campania “Luigi Vanvitelli”, Napoli, Italy 2 Oncologia Medica, Dipartimento di Medicina Clinica e Chirurgia, Universita degli Studi di Napoli “Federico II”, Napoli, Italy 3 Immunologia Clinica, Dipartimento di Internistica Clinica e Sperimentale “F. Magrassi”, Universita degli Studi della Campania “Luigi Vanvitelli”, Napoli, Italy 4 IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Foggia, Italy Correspondence to: Floriana Morgillo, email: florianamorgillo@yahoo.com , floriana.morgillo@unicampana.it Keywords: AKT, breast cancer, taselisib, ipatasertib, novel drugs Received: March 22, 2017 Accepted: July 26, 2017 Published: August 22, 2017 ABSTRACT Purpose: The Phosphatidylinositol 3-kinase (PI3Ks) pathway is commonly altereted in breast cancer patients, but its role is still unclear. Taselisib, a mutant PI3Kα selective inhibitor, and ipatasertib, an AKT inhibitor, are currently under investigation in clinical trials in combination with paclitaxel or hormonal therapies in breast cancer. The aim of this study was to evaluate if PI3K or AKT inhibition can prevent resistance to chemotherapy and potentiate its efficacy. Experimental design: The efficacy of combined treatment of ipatasertib and taselisib plus vinorelbine or paclitaxel or eribulin was evaluated in vitro on human breast cancer cells (with different expression profile of hormonal receptors, HER2, and of PI3Ka mutation) on cell survival by using MTT (3,(4,5-dimethylthiazol-2)2,5 difeniltetrazolium bromide) and colony forming assays on cell apoptosis by flow-cytometry analysis. We also investigated the effect of combined treatment on downstream intracellular signaling, by western blot analysis, and on metastatic properties, by migration assays. Finally, we analyzed changes in cell cytoskeleton by immunofluorescence. Results: A significant synergism of ipatasertib or taselisib plus anti-microtubule chemotherapy in terms of anti-proliferative, pro-apoptotic and anti-metastatic effect was observed. The combined treatment completely inhibited the activation of proteins downstream of PI3K and MAPK pathways and affected the expression of survivin. Combined treatments completely disorganized the cytoskeleton in human breast cancer cells, with contemporary delocalization of survivin from cytoplasm to nucleus, thus suggesting a potential mechanism for this combination. Conclusions: Targeting PI3K may enhance the efficacy of anti-microtubule drugs in human breast cancer cells.

OBJECTIVES: The effects of vitamin D on the heart have been studied in patients with cardiac disease, but not in healthy persons. We investigated the relation between vitamin D status and left ventricular (LV) structure and function in community-dwelling subjects without heart disease. DESIGN: The relationship between concentrations of 25-hydroxyvitamin D [25(OH)D], a marker of vitamin D reserve, and LV transthoracic echocardiography measures was analysed in 711 participants in the Baltimore Longitudinal Study of Aging who were without cardiac disease. RESULTS: Mean 25(OH)D in the study population was 32.3 ± 11.4 ng mL(-1) ; only 15.5% of subjects had moderate or severe vitamin D deficiency [25(OH)D < 20 ng mL(-1) ]. Adjusting for age, body mass index, cardiovascular disease risk factors, physical activity, calcium and parathyroid hormone, 25(OH)D was positively correlated with LV thickness (β 0.095, SE 0.039, P < 0.05) and LV mass index (β 7.5, SE 2.6, P < 0.01). A significant nonlinear relation between 25(OH)D and LV concentric remodelling was observed. LV remodelling was more likely in participants with 25(OH)D levels

Objective: There are no well-defined criteria for assessing the efficacy and quality of wound dressings, and evaluation is often simplistic and based on the subjective opinion of the health-care professional. The aim of this study was to identify specific parameters suitable for measuring dressings' performance, and to recommend laboratory tests able to evaluate these specific criteria in an objective manner. Method: After reviewing all tests currently used in Italy and examining the criteria for evaluating the quality of dressings, the authors selected 12 clinically significant parameters. These parameters were measured using standard and non-standard tests, and in some cases, these tests were modified and improved to simulate real-life conditions more accurately. Results: Most of the tests used were able to discriminate well between dressings belonging to different brands, with some tests being more suitable than others for the assessment of specific dressings. Conclusion: These results highlighted some issues in the standard testing procedures, such as the need of a suitable fluid that mimics the real exudate, and the importance of standard temperature and humidity conditions during testing. Our study paves the way for a larger project aimed at a systematic evaluation of dressing quality able to assess every wound dressing on the market.

This work focuses on the comparison between Newtonian and non-Newtonian blood flows through a bileaflet mechanical heart valve in the aortic root. The blood, in fact, is a concentrated suspension of cells, mainly red blood cells, in a Newtonian matrix, the plasma, and consequently its overall behavior is that of a non-Newtonian fluid owing to the action of the cells’ membrane on the fluid part. The common practice, however, assumes the blood in large vessels as a Newtonian fluid since the shear rate is generally high and the effective viscosity becomes independent of the former. In this paper, we show that this is not always the case even in the aorta, the largest artery of the systemic circulation, owing to the pulsatile and transitional nature of the flow. Unexpectedly, for most of the pulsating cycle and in a large part of the fluid volume, the shear rate is smaller than the threshold level for the blood to display a constant effective viscosity and its shear thinning character might affect the system dynamics. A direct inspection of the various flow features has shown that the valve dynamics, the transvalvular pressure drop and the large-scale features of the flow are very similar for the Newtonian and non-Newtonian fluid models. On the other hand, the mechanical damage of the red blood cells (hemolysis), induced by the altered stress values in the flow, is larger for the non-Newtonian fluid model than for the Newtonian one.

Background Cetuximab plus chemotherapy is a first-line treatment option in metastatic KRAS and NRAS wild-type colorectal cancer (CRC) patients. No data are currently available on continuing anti-epidermal growth factor receptor (EGFR) therapy beyond progression. Patients and methods We did this open-label, 1:1 randomized phase II trial at 25 hospitals in Italy to evaluate the efficacy of cetuximab plus 5-fluorouracil, folinic acid and oxaliplatin (FOLFOX) as second-line treatment of KRAS exon 2 wild-type metastatic CRC patients treated in first line with 5-fluorouracil, folinic acid and irinotecan (FOLFIRI) plus cetuximab. Patients received FOLFOX plus cetuximab (arm A) or FOLFOX (arm B). Primary end point was progression-free survival (PFS). Tumour tissues were assessed by next-generation sequencing (NGS). This report is the final analysis. Results Between 1 February 2010 and 28 September 2014, 153 patients were randomized (74 in arm A and 79 in arm B). Median PFS was 6.4 [95% confidence interval (CI) 4.7–8.0] versus 4.5 months (95% CI 3.3–5.7); [hazard ratio (HR), 0.81; 95% CI 0.58–1.12; P = 0.19], respectively. NGS was performed in 117/153 (76.5%) cases; 66/117 patients (34 in arm A and 32 in arm B) had KRAS, NRAS, BRAF and PIK3CA wild-type tumours. For these patients, PFS was longer in the FOLFOX plus cetuximab arm [median 6.9 (95% CI 5.5–8.2) versus 5.3 months (95% CI 3.7–6.9); HR, 0.56 (95% CI 0.33–0.94); P = 0.025]. There was a trend in better overall survival: median 23.7 [(95% CI 19.4–28.0) versus 19.8 months (95% CI 14.9–24.7); HR, 0.57 (95% CI 0.32–1.02); P = 0.056]. Conclusions Continuing cetuximab treatment in combination with chemotherapy is of potential therapeutic efficacy in molecularly selected patients and should be validated in randomized phase III trials.

Background Multiple sclerosis, a demyelinating disease of the central nervous system, is the most common cause of neurological disability in young adults. Four types of disease have been defined: benign or stable, relapsing remitting, secondary progressive, and primary progressive multiple sclerosis.

This pooled analysis was performed using individual patient data from three phase II trials that included on the whole 113 esophageal cancer treated preoperatively with chemoradiotherapy (CRT), in order to analyze the efficacy and survival outcomes according to the achievement of the pathologic complete response (pCR). Thirty-nine patients were treated with 5-fluorouracil/cisplatin and RT (40 Gy), 33 patients received paclitaxel/cisplatin weekly during weeks 1-6 with and RT (46 Gy), 41 patients were treated with induction bio-chemotherapy with cetuximab and FOLFOX-4 followed by concomitant cetuximab and RT of 50.4 Gy. One hundred and two out of 113 resected patients were included in the survival analysis. The median overall survival (OS) time for the whole population was 21.5 months. The 12, 24, and 36 months OS rates were 85.4, 45.2, and 33%, respectively. The difference in survival probability between patients with pCR and patients with partial response or stable disease after treatment was significant (P= 0.0002, hazard ratios = 0.21, 95% CI 0.18-0.60). On multivariate analysis, the pathologic response and histology were the only covariates independently associated with OS (P= 0.0157 and P= 0.0212, respectively). In our series, complete responder patients had a significant longer survival probability after treatment when compared to patients with partial response or stable disease.

"Background: Preoperative chemoradiotherapy (CRT) improves the survival of patients with oesophageal cancer when compared with surgery alone.. . Methods: We conducted a phase II, multicenter trial of FOLFOX-4 and cetuximab in patients with locally advanced oesophageal cancer (LAEC) followed by daily radiotherapy (180 cGy fractions to 5040 cGy) with concurrent weekly cetuximab. Cytokines levels potentially related to cetuximab efficacy were assessed using multiplex-bead assays and enzyme-linked immunosorbent assay at baseline, at week 8 and at week 17. Primary end point was complete pathological response rate (pCR).. . Results: In all, 41 patients were enroled. Among 30 patients who underwent surgery, a pCR was observed in 8 patients corresponding to a rate of 27%. The most frequent grade 3\/4 toxicity was skin (30%) and neutropenia (30%). The 36-month survival rates were 85 and 52% in patients with pathological CR or PR vs 38 and 33% in patients with SD or PD.. . Conclusions: Incorporating cetuximab into a preoperative regimen for LAEC is feasible; no correlation between cytokines changes and patient outcome was observed. Positron emission tomography\/computed tomography study even if influenced by the small number of patients appears to be able to predict patients outcome both as early and late metabolic response.. . " Background: Preoperative chemoradiotherapy (CRT) improves the survival of patients with oesophageal cancer when compared with surgery alone. Methods: We conducted a phase II, multicenter trial of FOLFOX-4 and cetuximab in patients with locally advanced oesophageal cancer (LAEC) followed by daily radiotherapy (180 cGy fractions to 5040 cGy) with concurrent weekly cetuximab. Cytokines levels potentially related to cetuximab efficacy were assessed using multiplex-bead assays and enzyme-linked immunosorbent assay at baseline, at week 8 and at week 17. Primary end point was complete pathological response rate (pCR). Results: In all, 41 patients were enroled. Among 30 patients who underwent surgery, a pCR was observed in 8 patients corresponding to a rate of 27%. The most frequent grade 3/4 toxicity was skin (30%) and neutropenia (30%). The 36-month survival rates were 85 and 52% in patients with pathological CR or PR vs 38 and 33% in patients with SD or PD. Conclusions: Incorporating cetuximab into a preoperative regimen for LAEC is feasible; no correlation between cytokines changes and patient outcome was observed. Positron emission tomography/computed tomography study even if influenced by the small number of patients appears to be able to predict patients outcome both as early and late metabolic response. © 2011 Cancer Research UK All rights reserved.

In the last decade dramatic improvements have been obtained in the treatment of metastatic colorectal cancer. Thanks to the introduction in the clinical practice of new drugs such as Irinotecan and Oxaliplatin, and modern biological drugs such as Bevacizumab and Cetuximab, the response rate, progression-free and overall survival are about 50-60%, 9-11 and 20-24 months respectively. Despite this progress, many questions remain unsolved especially those related to the optimal duration of treatment and the role of maintenance therapy. To treat until progression (or unacceptable toxicity) is the classical way but in the common clinical practice is frequent to perform an induction therapy (until the maximum response is obtained) followed by a complete stop and restart on progression, or by a maintenance without the drug/s responsible of the major cumulative toxicities. The following report focus on the role of different strategies respect to the classic "treatment until progression".

Capecitabine is an orally administered fluoropyrimidine carbamate which has been developed as a prodrug of 5-FU with the goal to improve its tolerability and intratumoral drug concentration. The review aims to provide an evidence-based update of clinical trials investigating the clinical efficacy, adverse-event profile, dosage and administration of this drug, alone or in combination with conventional chemotherapeutics and/or new target-oriented drugs, in the management of colorectal cancer patients. © 2010 Elsevier Ltd.

In this article, we describe the integration of a multiresolution (MR) approach into a few fast factorization methods for the method-of-moments (MoM), with specific attention to the analysis of large nonperiodic arrays. The MR approach allows a physics-based preconditioning scheme (as opposed to algebraic preconditioners) that requires a low-memory occupation and a low-computational cost for its generation and application to fast factorizations. In particular, we present a theoretical and experimental analysis that shows that the complexity of the resulting fast-MR algorithm is still of the order of the original fast factorization method. © 2010 Wiley Periodicals, Inc. Microwave Opt Technol Lett 52: 1719–1724, 2010; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/mop.25320

Description of a technique and prospective follow-up study. The aim of this study was to present our experience in the surgical treatment of ischial pressure sores, especially recurrence. The Department of Plastic and Reconstructive Surgery and Spinal Injuries Unit, CTO Hospital, Rome, Italy. From 1995 to 1997, the authors used in 12 consecutive paraplegic patients, who had a grade III or IV decubitus ulcer in the ischial area only, two different and independent flaps coupled together in a ‘criss-cross’ musculocutaneous flap: a split-muscle gluteus maximus flap and a rhomboid fasciocutaneous local flap. The average follow-up period was 3 years and 9 months. Details of the operative procedure are presented to prove that this criss-cross closure of the ischial pressure sore beneficial for patients with spinal cord injury. All flaps survived; recurrence of the decubitus ulcer occurred in one patient (8%). Pressure-sore-free survival after surgery was 20 months in the patient with recurrence and an average of 26 months in patients without recurrence. The results obtained confirm this procedure to be safe and useful. We believe this technique to be a valuable alternative for the reconstruction of primary or recurrent ischial pressure ulcers.

Summary The epidermal growth factor receptor (EGFR) is a transmembrane tyrosine kinase receptor involved in the proliferation and survival of cancer cells. EGFR is the first molecular target against which monoclonal antibodies (mAb) have been developed for cancer therapy. Here we review the mechanisms underlying the effects of EGFR-specific mAb in cancer therapy. The efficacy of EGFR-specific mAb in cancer occurs thanks to inhibition of EGFR-generated signalling; furthermore, the effects of antibodies on the immune system seem to play an important role in determining the overall anti-tumour response. In this review, attention is focused on cetuximab and panitumumab, two mAb introduced recently into clinical practice for treatment of metastatic colorectal and head and neck cancer which target the external part of EGFR.

In this letter, we present an efficient technique based on the extension of the adaptive integral method (AIM) that allows the full-wave analysis of electrically large multilayered printed arrays that have one or more planar metallizations and vertical conductors. The array patches can be of arbitrary shape and orientation and are modeled with subdomain triangular basis functions. This method makes use of a 2D-FTT/CG scheme, reducing the CPU time per iteration to O(N log2N) and the memory requirement to O(N).

Summary Background In Italy, infections with carbapenem-resistant Klebsiella pneumoniae (CRKP) have increased markedly since 2009, creating unprecedented problems in healthcare settings and limiting treatment options for infected patients. Aim To assess the attributable mortality due to CRKP in ten Italian hospitals and to describe the clinical characteristics of patients with an invasive CRKP and carbapenem-susceptible K. pneumoniae (CSKP) infection. Methods We conducted a matched cohort study, and calculated crude and attributable mortality for CRKP. The attributable mortality was calculated by subtracting the crude mortality rate of the patients with CSKP from the crude mortality rate of the patients with CRKP. We also described the clinical characteristics of CRKP and CSKP patients and analysed the determinants of mortality by using conditional Poisson regression. Findings The study included 98 patients, 49 with CRKP and 49 with CSKP. CRKP patients had undergone more invasive procedures and also tended to have more serious conditions, measured by higher Simplified Acute Physiology Score II. The attributable mortality of CRKP at 30 days was 41%. CRKP patients were three times more likely to die within 30 days [matched incidence rate ratio (mIRR): 3.0; 95% confidence interval (CI): 1.5–6.1]. Adjusting for potential confounders, the risk remained the same (adjusted mIRR: 3.0; 95% CI: 1.3–7.1). Conclusion CRKP infection had a marked effect on patient mortality, even after adjusting for other patient characteristics. To control the spread of CRKP we recommend prioritization of control measures in hospitals where CRKP is found.

BACKGROUND: Pancreatic neuroendocrine tumors (pNETs) are uncommon entities. pNETs are often small, slow growing, clinically silent neoplasms. However, they have an almost unpredictable biological behaviour with a not negligible malignant potential. Surgery still represents the treatment of choice, but the high morbidity associated to the enucleation or the formal pancreatectomy should be considered in the decision of the proper treatment. Management of these neoplasms is still debated, and indications for a conservative observational approach and for parenchyma sparing resections are not yet standardized. METHOD: We review the state of art on indications for the conservative management of pNETs. Searches on MEDLINE database were performed to identify articles reporting prognostic systems, biochemical screening, observational management, medical treatment and surgical strategies for pNETs. DISCUSSION: Currently, an accurate 'wait-and-see' policy is recommended by the European Neuroendocrine Tumor Society (ENETS) only for non-functioning pNETs (NF-pNETs) 2 cm and symptomatic F-pNETs of any size. CONCLUSION: More studies are needed to further clarify and predict the biologic behaviour of pNETs and increase the indications for conservative observational management and parenchyma sparing pancreas resections.

Frailty is a condition of increased vulnerability to cope with stressors, predisposing to the development of disability in basic and instrumental activities of daily living, falling, institutionalization and finally death. It is characterized by the loss of functional reserve in multiple domains resulting in a reduced tolerance to common external stresses. The pathogenetic steps conducting to frailty are not completely clear, but there is increasing evidence of a crucial role of insulin resistance and systemic inflammation in the development of frailty, disability, and related medical conditions. These two conditions may act directly, through a negative impact on homeostatic regulation and cross-systems compensation, or indirectly, by the effect of several diseases strongly related to frailty. Therefore, counteracting insulin resistance and systemic inflammation could be a powerful way to prevent the development of frailty and/or of its adverse outcomes. In this framework, diet and physical exercise may represent two important weapons in the prevention of frailty; indeed, current literature supports the effectiveness of a correct lifestyle based on a healthy diet (Mediterranean type diet) and regular physical exercise on frailty primary prevention. Studies on secondary prevention of frailty suggest that multi-component and resistance training, together with adequate energy and protein intake, might be helpful although data are still lacking. The efficacy of dietary supplementation in secondary prevention of frailty, albeit promising, remains to be confirmed in large clinical trials.

The aims of this multicentre, randomised phase III trial were to evaluate: (1) the role of levamisol (LEV); and (2) the role of folinic acid (FA), added to 5-fluorouracil (5FU) in the adjuvant treatment of colorectal cancer. Patients with histologically proven, radically resected stage II or III colon or rectal cancer were eligible. The study had a 2x2 factorial design with four treatment arms: (a) 5FU alone, (b) 5FU+LEV, (c) 5FU+FA, (d) 5FU+LEV+FA, and two planned comparisons, testing the role of LEV and of FA, respectively. From March 1991, to September 1998, 1327 patients were randomised. None of the two comparisons resulted in a significant disease-free (DFS) or overall (OAS) survival advantage. The hazard ratio (HR) of relapse was 0.89 (95\% confidence intervals (CI): 0.73-1.09) for patients receiving FA and 0.99 (95\% CI 0.80-1.21) for those receiving LEV; corresponding HRs of death were 1.02 (95\% CI: 0.80-1.30) and 0.94 (95\% CI 0.73-1.20). Nonhaematological toxicity (all grade vomiting, diarrhoea, mucositis, congiuntivitis, skin, fever and fatigue) was significantly worse with FA, while all other toxicities were similar. In the present trial, there was no evidence that the addition of FA or LEV significantly prolongs DFS and OAS of radically resected colorectal cancer patients..

Gastric cancer is still a major health problem and a leading cause of cancer mortality despite a worldwide decline in incidence. Surgical resection with curative potential is the only treatment modality of scientific proven effectiveness. Many phase III trials of adjuvant therapy have been conducted, however, postoperative treatment modalities have not proven to be superior to pos-surgical observation alone. Therefore, at present the routine use of adjuvant therapy should be regarded as an investigational approach. Improved clinical trial designs with standardized surgical techniques and the incorporation of newer active drugs are needed.

In this paper, we present a time-domain (TD) raw signal simulator for an interferometric synthetic aperture radar (SAR). We consider the case of a spaceborne SAR operating in stripmap, spotlight, and hybrid modes, but the case of an airborne SAR can be considered as well. The spaceborne platform is considered as traveling on its nominal (Keplerian) orbit, and the targets are located on an ellipsoidal earth. We describe an accurate TD simulator, highlighting its usefulness in studying the effects on the SAR impulse response and on images from targets with limited extension due to operational conditions different from the nominal one.