Real-World Clinical, Psychosocial and Financial Burden of Atopic Dermatitis: Results from the Spanish Cohort of the MEASURE-AD Trial. / Carga clínica, psicosocial y económica de la dermatitis atópica en vida real: resultados de la cohorte española del estudio MEASURE-AD.

BACKGROUND: Atopic dermatitis (AD) is one of the most prevalent skin diseases, but there are numerous knowledge gaps surrounding the impact this disease has on quality of life (QoL), mental health, and out-of-pocket expenses involved in the management of AD. The available scientific evidence on the multidimensional burden of AD is usually based on studies with measures reported by patients themselves. METHODS: In this context, the MEASURE-AD trial was developed as a cross-sectional, multicenter, multinational trial using patient- and physician-reported measures to characterize the multidimensional burden of AD in adults with moderate-to-severe AD. RESULTS: This paper presents the results of the Spanish cohort. We found that Spanish adults with moderate-to-severe AD and high EASI score (21.1-72) had a significantly increased disease burden, high severity of symptoms such as itch and sleep disturbances, impaired mental health and QoL, higher use of health care resources, and more out-of-pocket expenses than patients with low EASI scores (0-7 or 7.1-21). CONCLUSIONS: This study provides information to better understand disease burden, and identify aspects to be improved in the management of AD.

Impact of the healthcare reorganization of the Local Health Authority services in Rieti (Italy) during the SARS-CoV-2 pandemic.

Background: The need to contain the spread of the SARS-CoV-2 pandemic has forced national and local organizations to define and implement targeted emergency response and management measures. As the knowledge about the infection grew, a wider range of organizational measures were deployed. Methods: This study involves the SARS-CoV-2 infected people managed by the Local Health Authority of Rieti (Italy). Diagnostic test waiting times and hospital admission rates in the Province of Rieti are investigated as the pandemic evolved. Trends were analyzed in relation to the tempora spreading of SARS-CoV-2, to the organizational actions taken by the Local Health Authority of Rieti, and to the deployment of actions across the territory. A municipalities classification of the province of Rieti was conducted after a cluster analysis based on the diagnostic test waiting times and the hospital admission rates. Results: Our findings show a declining trend, thus indicating a possible positive effect of the measures taken to contain the pandemic. The cluster analysis of the municipalities of the Province of Rieti makes evident an inhomogeneous geographical distribution of examined parameters (diagnostic test waiting times and the hospital admission rates), demonstrating the capability of Local Health Authority of Rieti to reach even the most disadvantaged areas and implying that the differences are due to the demographical variabilities. Conclusion: Despite some limitations, this study outlines the importance of management measures in response of the pandemic. These measures should adapt to social, cultural and geographical nature of the territory involved. The findings of the present study will contribute to the update of further pandemic preparedness plans of the Local Health Authorities.

Polystyrene nanoplastics affect the human ubiquitin structure and ubiquitination in cells: a high-resolution study.

Humans are estimated to consume several grams per week of nanoplastics (NPs) through exposure to a variety of contamination sources. Nonetheless, the effects of these polymeric particles on living systems are still mostly unknown. Here, by means of CD, NMR and TEM analyses, we describe at an atomic resolution the interaction of ubiquitin with polystyrene NPs (PS-NPs), showing how a hard protein corona is formed. Moreover, we report that in human HeLa cells exposure to PS-NPs leads to a sensible reduction of ubiquitination. Our study overall indicates that PS-NPs cause significant structural effects on ubiquitin, thereby influencing one of the key metabolic processes at the base of cell viability.

Combining PARP inhibition and immune checkpoint blockade in ovarian cancer patients: a new perspective on the horizon?

Immune checkpoint inhibitors (ICIs) have completely reshaped the treatment of many malignancies, with remarkable improvements in survival outcomes. In ovarian cancer (OC), however, this emerging class of drugs has not yet found a favorable use due to results from phase I and II studies, which have not suggested a substantial antitumoral activity of these agents when administered as monotherapy. Robust preclinical data seem to suggest that the combination ICIs with poly(ADP-ribose) polymerase (PARP) inhibitors (PARPis) may result in a synergistic activity; furthermore, data from phase II clinical studies, evaluating this combination, have shown encouraging outcomes especially for those OC patients not suitable for platinum retreatment. While waiting for ongoing phase III clinical trial results, which will clarify the role of ICIs in combination with PARPis in the newly diagnosed OC, this review aims to summarize the preclinical data and clinical evidence available to date.

Outcomes after reperfusion therapies in patients with ACA stroke: A multicenter cohort study from the EVATRISP collaboration.

BACKGROUND: Patients with stroke secondary to occlusions of the anterior cerebral artery (ACA) often have poor outcomes. The optimal acute therapeutic intervention for these patients remains unknown. METHODS: Patients with isolated ACA-stroke were identified from 10 centers participating in the EndoVascular treatment And ThRombolysis in Ischemic Stroke Patients (EVATRISP) prospective registry. Patients treated with endovascular thrombectomy (EVT) were compared to those treated with intravenous thrombolysis (IVT). Odds ratios with 95% confidence intervals (OR; 95%CI) were calculated using multivariate regression analysis. RESULTS: Included were 92 patients with ACA-stroke. Of the 92 ACA patients, 55 (60%) were treated with IVT only and 37 (40%) with EVT (±bridging IVT). ACA patients treated with EVT had more often wake-up stroke (24% vs. 6%, p = 0.044) and proximal ACA occlusions (43% vs. 24%, p = 0.047) and tended to have higher stroke severity on admission [NIHSS: 10.0 vs 7.0, p = 0.054). However, odds for favorable outcome, mortality or symptomatic intracranial hemorrhage did not differ significantly between both groups. Exploration of the effect of clot location inside the ACA showed that in patients with A1 or A2/A3 ACA occlusions the chances of favorable outcome were not influenced by treatment allocation to IVT or EVT. DISCUSSION: Treatment with either IVT or EVT could be safe with similar effect in patients with ACA-strokes and these effects may be independent of clot location within the occluded ACA.

Association between atherogenic index of plasma and carotid intima-media thickness in a cohort of Mediterranean women.

The association between early atherosclerosis (IMT) and Atherogenic index of plasma (AIP), a marker of atherogenicity (log triglycerides/HDL Cholesterol) was evaluated in a population-based cohort study in women, aged 30-69, living in the metropolitan area of Naples, Southern Italy (Progetto ATENA). Serum cholesterol, HDL-cholesterol, LDL-cholesterol, Triglyceride, Insulin, HOMA, Apo B, hs-CPR were measured in 390 menopausal women, as a part of 5.062 participants of the cohort. Women in the second and third tertile of AIP showed an increased common carotid intima-media thickness compared with those in the first tertile: II vs I tertile (O.R. = 2.24, p = 0.007), III vs I tertile (O.R. = 2.29, p = 0.005), adjusted for age and Systolic pressure or II vs I tertile (O.R. = 2.19, p = 0.014), III vs I tertile (O.R. = 2.13, p = 0.026), adjusted for age, Systolic pressure, Body mass index and Apo B. Women in the second and third tertile of AIP compared to those in the first tertile, showed an OR of 2.14 (p = 0.016) and 1.99 (p = 0.033) respectively, of having elevates level of IMT, adjusted for traditional cardiovascular risk factor (age, Systolic Pressure, BMI, LDL Cholesterol, Diabetes diagnosis). This finding shows that in this group of menopausal women increased IMT is associated with elevated AIP independently of age and different cardiovascular risk factors. These results are in line with the hypothesis that AIP may be an useful clinical tools to give additional information in the risk assessment for atherosclerotic disease, in particular in postmenopausal women.

KRD (carfilzomib and lenalidomide plus dexamethasone) for the treatment of relapsed or refractory multiple myeloma in the real-life: a retrospective survey in 123 patients.

From April 2016, carfilzomib, in combination with lenalidomide and dexamethasone (KRD), became available for use in the daily practice in Italy for patients with relapsed or refractory multiple myeloma (RRMM). We performed a retrospective survey at 14 different institutions from Southern Italy in order to evaluate patient characteristics and treatment results from an unselected series of patients treated accordingly so far. One hundred and twenty-three consecutive patients were included, with a median of 2 previous lines of therapy (range 1-9) and a median age of 63 years (range 39-82). At the time of analysis, median number of courses administered is 11 (range 1-34), and all patients are evaluable for response. Overall response rate including complete remission, very good partial remission, and partial remission is 85%. After a median follow-up of 27 months, median overall and progression-free survival are 33 and 23 months, respectively. Sixty-three patients are alive and between them, 45 (37%) are in continuous remission. Sixty patients have died (49%), mainly from progressive disease. There were 6 treatment-related deaths (5% of the whole patient population). Overall, hematological and non-hematological toxicity were manageable, mostly on outpatient basis. Arterial hypertension has been observed in 43 cases (35%) but did not lead to treatment interruption. Our data demonstrate that in real life, KRD is highly effective and well tolerated in the majority of patients with RRMM.

Oncology and Cardiac Rehabilitation: An Underrated Relationship.

Cancer and cardiovascular diseases are globally the leading causes of mortality and morbidity. These conditions are closely related, beyond that of sharing many risk factors. The term bidirectional relationship indicates that cardiovascular diseases increase the likelihood of getting cancer and vice versa. The biological and biochemical pathways underlying this close relationship will be analyzed. In this new overlapping scenario, physical activity and exercise are proven protective behaviors against both cardiovascular diseases and cancer. Many observational studies link an increase in physical activity to a reduction in either the development or progression of cancer, as well as to a reduction in risk in cardiovascular diseases, a non-negligible cause of death for long-term cancer survivors. Exercise is an effective tool for improving cardio-respiratory fitness, quality of life, psychological wellbeing, reducing fatigue, anxiety and depression. Finally, it can counteract the toxic effects of cancer therapy. The protection obtained from physical activity and exercise will be discussed in the various stages of the cancer continuum, from diagnosis, to adjuvant therapy, and from the metastatic phase to long-term effects. Particular attention will be paid to the shelter against chemotherapy, radiotherapy, cardiovascular risk factors or new onset cardiovascular diseases. Cardio-Oncology Rehabilitation is an exercise-based multi-component intervention, starting from the model of Cardiac Rehabilitation, with few modifications, to improve care and the prognosis of a patient's cancer. The network of professionals dedicated to Cardiac Rehabilitation is a ready-to-use resource, for implementing Cardio-Oncology Rehabilitation.

Uterine PEComa with aggressive behavior: A review with an additional case of spontaneous vaginal expulsion.

Perivascular epithelioid cell tumor (PEComa) is a rare mesenchymal tumor originating from perivascular epitheloid cells showing melanocytic and smooth muscle differentiation. The uterus represents the second most common site of origin. A 49 years woman presented to our Hospital for a vaginal spontaneous expulsion of a mass suggestive for malignant mesenchymal tumor. The patient underwent total hysterectomy and bilateral salpingo-oophorectomy and the histopathological report was compliant with a PEComa with aggressive behavior. Medical Literature databases about PEComa were searched. The current literature identified near 90 cases of uterine PEComas and they are categorized as uncertain malignant potential or with aggressive behavior. Primary surgical excision represents the gold-standard treatment. Recently targeted therapy with mTOR inhibitors has been introduced with an important beneficial. In this paper we review the Literature about the uPEComa with aggressive behavior reporting the first case of spontaneous vaginal expulsion.

[COP21 - Organization and activity of a medical cover under "pressure"]. / COP21 ­ Organisation et bilan d'une médicalisation sous haute tension.

INTRODUCTION: The United Nations Climate Conference (COP21) gathered in France for delegations from all around the world, with 20,000 delegates from 195 countries every day, including 150 heads of states during the first 48hours. A specific medical cover was organized in a particular "post-attacks" context and with harsh constraints due to delimitation of an inner zone under the sole UN authority ("blue zone"). OBJECTIVE: To evaluate medical means involved and medical activity. METHODS: Medical cover was managed by SAMU 93 in collaboration with zonal SAMU and regional health agency for the entire site including the "blue zone". End-points: engaged workforce, number of visits, including transfers and medicalized transfers. RESULTS: In "France zone" (operational headquarters): an emergency physician dispatcher and an assistant for 20 days. In "blue zone": 20 rescuers, mobile intensive care unit H24 and two emergency physicians (consultations) 12/24hours for 16 days. A total of 47 doctors, 25 nurses, 25 paramedics and 20 assistants participated in the medical service. This corresponded to three emergency physician full medical time equivalents (FMTE) for 16 days. Consultations performed: 1238 or 97/day resulting in 34 (3%) transfers including seven medicalized. Patients were 706 (57%) men and 495 (43%) women, with mean age of 43±1 years. Trauma patients were most numerous (20%). CONCLUSION: Medical means involved were consistent for 16 days. The medical activity was sustained, but medicalized transfer rarely required.

Genetic landscape of ultra-stable chronic lymphocytic leukemia patients.

Background: Chronic lymphocytic leukemia (CLL) has a heterogeneous clinical course. Beside patients requiring immediate treatment, others show an initial indolent phase followed by progression and others do not progress for decades. The latter two subgroups usually display mutated IGHV genes and a favorable FISH profile. Patients and methods: Patients with absence of disease progression for over 10 years (10-34) from diagnosis were defined as ultra-stable CLL (US-CLL). Forty US-CLL underwent extensive characterization including whole exome sequencing (WES), ultra-deep sequencing and copy number aberration (CNA) analysis to define their unexplored genetic landscape. Microarray analysis, comparing US-CLL with non-US-CLL with similar immunogenetic features (mutated IGHV/favorable FISH), was also carried out to recognize US-CLL at diagnosis. Results: WES was carried out in 20 US-CLL and 84 non-silent somatic mutations in 78 genes were found. When re-tested in a validation cohort of 20 further US-CLL, no recurrent lesion was identified. No clonal mutations of NOTCH1, BIRC3, SF3B1 and TP53 were found, including ATM and other potential progression driving mutations. CNA analysis identified 31 lesions, none with known poor prognostic impact. No novel recurrent lesion was identified: most cases showed no lesions (38%) or an isolated del(13q) (31%). The expression of 6 genes, selected from a gene expression profile analysis by microarray and quantified by droplet digital PCR on a cohort of 79 CLL (58 US-CLL and 21 non-US-CLL), allowed to build a decision-tree capable of recognizing at diagnosis US-CLL patients. Conclusions: The genetic landscape of US-CLL is characterized by the absence of known unfavorable driver mutations/CNA and of novel recurrent genetic lesions. Among CLL patients with favorable immunogenetics, a decision-tree based on the expression of 6 genes may identify at diagnosis patients who are likely to maintain an indolent disease for decades.

Effects of miRNA-15 and miRNA-16 expression replacement in chronic lymphocytic leukemia: implication for therapy.

Chronic lymphocytic leukemia (CLL) clones are characterized by loss of a critical region in 13q14.3, (del(13)(q14)) involving the microRNA (miRNA) cluster miR-15a and miR-16-1. We have investigated the effects of replacement of miR-15a and miR-16-1. CLL cells transfected with these miRNA mimics exhibited a decrease in cell viability in vitro and impaired capacity for engraftment and growth in NOD/Shi-scid,γcnull (NSG) mice. No synergistic effects were observed when the two miRNA mimics were combined. The phenomena were not restricted to CLL with the del(13)(q14) lesion. Similar effects induced by miRNA mimics were seen in cells with additional chromosomal abnormalities with the exception of certain CLL clones harboring TP53 alterations. Administration of miRNA mimics to NSG mice previously engrafted with CLL clones resulted in substantial tumor regression. CLL cell transfection with miR-15a and miR-16-1-specific inhibitors resulted in increased cell viability in vitro and in an enhanced capacity of the engrafted cells to grow in NSG mice generating larger splenic nodules. These data demonstrate that the strong control by miR-15a and miR-16-1 on CLL clonal expansion is exerted also at the level of full-blown leukemia and provide indications for a miRNA-based therapeutic strategy.

lncRNA profiling in early-stage chronic lymphocytic leukemia identifies transcriptional fingerprints with relevance in clinical outcome.

Long non-coding RNAs (lncRNAs) represent a novel class of functional RNA molecules with an important emerging role in cancer. To elucidate their potential pathogenetic role in chronic lymphocytic leukemia (CLL), a biologically and clinically heterogeneous neoplasia, we investigated lncRNAs expression in a prospective series of 217 early-stage Binet A CLL patients and 26 different subpopulations of normal B-cells, through a custom annotation pipeline of microarray data. Our study identified a 24-lncRNA-signature specifically deregulated in CLL compared with the normal B-cell counterpart. Importantly, this classifier was validated on an independent data set of CLL samples. Belonging to the lncRNA signature characterizing distinct molecular CLL subgroups, we identified lncRNAs recurrently associated with adverse prognostic markers, such as unmutated IGHV status, CD38 expression, 11q and 17p deletions, and NOTCH1 mutations. In addition, correlation analyses predicted a putative lncRNAs interplay with genes and miRNAs expression. Finally, we generated a 2-lncRNA independent risk model, based on lnc-IRF2-3 and lnc-KIAA1755-4 expression, able to distinguish three different prognostic groups in our series of early-stage patients. Overall, our study provides an important resource for future studies on the functions of lncRNAs in CLL, and contributes to the discovery of novel molecular markers with clinical relevance associated with the disease.

A phase II, single-arm, prospective study of bendamustine plus melphalan conditioning for second autologous stem cell transplantation in de novo multiple myeloma patients through a tandem transplant strategy.

This phase II trial evaluates, for the first time, the safety and efficacy of bendamustine plus high-dose melphalan (HDM) as a conditioning regimen before the second autologous stem cell transplantation (ASCT) in previously untreated multiple myeloma (MM) patients. In total, 32 ASCT patients received HDM (200 mg/m(2)) as conditioning for the first ASCT. After 3-6 months from the first ASCT, responding patients underwent a second ASCT following bendamustine (200 mg/m(2)) and HDM (140 mg/m(2)). High-dose chemotherapy and ASCT were performed with complete neutrophil and platelet recovery in all patients. The median number of days to neutrophil and platelet engraftment was 11 (range 9-15) and 12 (range 10-19), respectively. Only one subject experienced grade 3 diarrhea; the rate of mucositis and vomiting was significantly lower with the bendamustine plus HDM regimen compared with the HDM-only regimen (81.2 vs 96.9%, P=0.025 and 78.1 vs 100%, P=0.008). Overall response rate (ORR) was 81.2% after the first transplant, and 90.6% after the second, while complete response rates were 46.8 and 62.5%, respectively (P=0.016). Actuarial 2-year PFS and OS were 79% (95% confidence interval (CI), 60-98) and 97% (95% CI, 91-100), respectively. Bendamustine+HDM is feasible as the conditioning regimen for second ASCT in MM patients. The present study may pave the way for phase III studies specifically aimed at further investigating this combination strategy. The role of this combination in MM for conditioning regimen in a first or single ASCT setting should be also investigated.

Very Early Carotid Endarterectomy After Intravenous Thrombolysis.

OBJECTIVE/BACKGROUND: The timing of carotid endarterectomy (CEA) after thrombolysis is still a matter of debate. The aim of this study was to analyse a cohort of patients undergoing urgent endarterectomy after intravenous thrombolysis for acute ischaemic stroke. METHODS: This was an observational study. Prospective databases were reviewed and matched to identify patients who underwent CEA early after intravenous thrombolysis (2009-14). The focus was carotid surgery performed within 12 hours of stroke onset in patients with a high grade (≥70%) symptomatic carotid stenosis, associated with vulnerable plaques or stroke in evolution, and evidence of a significant salvageable ischaemic penumbra on perfusion computed tomography scan. Demographic and clinical information, as well as data on relevant outcomes were extracted. RESULTS: Thirty four consecutive stroke patients who underwent CEA within 2 weeks of thrombolysis for acute ischaemic stroke and ipsilateral high grade carotid stenosis were identified. In 11 patients the surgical procedure was performed within 12 hours of the onset of symptoms. All patients showed a clinical improvement after combined treatment. The 3 month outcome was favourable (modified Rankin Scale ≤ 2) in 10 patients. No haemorrhagic complications were registered. There was neither peri-operative stroke nor stroke within 3 months of surgery. One patient died from acute myocardial infarction 3 days after intervention. CONCLUSION: This experience suggests that very early CEA after thrombolysis, aimed at removing the source of potential embolisation and restoring blood flow, may be safe and can lead to a favourable outcome.

Frequent detection of high human papillomavirus DNA loads in oral potentially malignant disorders.

Human papillomavirus (HPV) is estimated to be the cause of 40--80% of the squamous cell carcinoma of the oropharynx but only of a small fraction of the oral cavity cancers. The prevalence of oral HPV infection has significantly increased in the last decade, raising concerns about the role of HPV in progression of oral potentially malignant disorders (OPMD) toward squamous cell carcinomas. We sought to study HPV infection in patients with oral lesions, and in control individuals, using non-invasive and site-specific oral brushing and sensitive molecular methods. HPV DNA positivity and viral loads were evaluated in relation to patient data and clinical diagnosis. We enrolled 116 individuals attending Dental Clinics: 62 patients with benign oral lesions (e.g. fibromas, papillomatosis, ulcers) or OPMD (e.g. lichen, leukoplakia) and 54 controls. Oral cells were collected with Cytobrush and HPV-DNA was detected with quantitative real-time PCR for the more common high-risk (HR) and low-risk (LR) genotypes. HPV detection rate, percentage of HR HPVs and HPV-DNA loads (namely HPV16 and in particular, HPV18) were significantly higher in patients than in controls. Lichen planus cases had the highest HPV-positive rate (75.0%), hairy leukoplakia the lowest (33.3%). This study detected unexpectedly high rates of HPV infection in cells of the oral mucosa. The elevated HR HPV loads found in OPMD suggest the effectiveness of quantitative PCR in testing oral lesions. Prospective studies are needed to establish whether elevated viral loads represent a clinically useful marker of the risk of malignant progression.

Appearance of fetal posterior fossa at 11-14 weeks in fetuses with Dandy-Walker malformation or chromosomal anomalies.

OBJECTIVE: To describe the sonographic appearance of fetal posterior fossa anatomy at 11-14 weeks of pregnancy and to assess the outcome of fetuses with increased intracranial translucency (IT) and/or brainstem-to-occipital bone (BSOB) diameter. METHODS: Reference ranges for brainstem (BS), IT and cisterna magna (CM) measurements, BSOB diameter and the BS : BSOB ratio were obtained from the first-trimester ultrasound examination of 233 fetuses with normal postnatal outcome (control group). The intraobserver and interobserver variability of measurements were investigated using 73 stored ultrasound images. In addition, a study group of 17 fetuses with increased IT and/or BSOB diameter was selected to assess outcome. RESULTS: No significant intraobserver or interobserver variability was found for any measurement in the control group. In the study group, IT was increased in all cases and BSOB diameter was above the 95(th) centile of the calculated normal range in all but two (88%) cases. In 13/17 study cases, only two of the three posterior brain spaces were recognized on ultrasound. These 13 fetuses had a larger BSOB diameter than did the four cases that showed all three posterior brain spaces, and had severe associated anomalies including Dandy-Walker malformation (DWM) and/or chromosomal anomalies. CONCLUSIONS: Visualization of the fetal posterior fossa anatomy at 11-14 weeks' gestation is feasible. Increased fluid in the posterior brain at 11-14 weeks, particularly in the case of non-visibility of the septation that divides the future fourth ventricle from the CM, is an important risk factor for cystic posterior fossa malformations, in particular DWM, and/or chromosomal aberrations. Copyright © 2015 ISUOG. Published by John Wiley & Sons Ltd.