Cyclin-Dependent Kinase 4/6 Inhibitors and Dermatologic Adverse Events: Results from the EADV Task Force "Dermatology for Cancer Patients"

Treatment with cyclin-dependent kinase 4/6 inhibitor (CDK4/6i), has demonstrated significantly improved progression-free survival in patients with hormone receptor-positive, HER2-negative, advanced breast cancer, when used in combination with endocrine therapies. However, limited data exists on its cutaneous adverse events (AE). The aim of our retrospective study was to investigate the prevalence, types and management of cutaneous AE during CDK4/6i. 79 adult advanced breast cancer patients affected by 125 skin adverse events during treatment with CDK4/6i were recruited at eleven centers. The most frequent cutaneous reactions were pruritus (49/79 patients), alopecia (25/79), and ec-zematous lesions (24/79). We showed that skin reactions are usually mild in severity, and prompt management may limit the negative impact on patients, facilitating beneficial continuation of oncologic treatment

Idiopathic Pulmonary Fibrosis (IPF) incidence and prevalence in Italy

Background: Studies of Idiopathic Pulmonary Fibrosis (IPF) epidemiology show regional variations of incidence and prevalence; no epidemiological studies have been carried out in Italy. Objective: To determine incidence and prevalence rates of IPF in the population of a large Italian region.Methods: in this cross-sectional study study data were collected on all patients of 18 years of age and older admitted as primary or secondary idiopathic fibrosing alveolitis (ICD9-CM 516.3) to Lazio hospitals, from 1/1/2005 to 31/12/2009, using regional hospital discharge, population and cause of death databases. Reporting accuracy was assessed on a random sample of hospital charts carrying the ICD9-CM 516.3, 516.8, 516.9 and 515 codes, by reviewing radiology and pathology findings to define cases as IPF “confident”, “possible” or “inconsistent”. Results: Annual prevalence and incidence of IPF were estimated at 25.6 per 100,000 and 7.5 per 100,000 using the ICD9-CM code 516.3 without chart audit while they were estimated at 31.6 per 100,000 and at 9,3 per 100,000 for the IPF “confident” definition after hospital chart audit. Conclusion: The data provide a first estimate of IPF incidence in Italy and indicate that incidence and prevalence in southern European regions may be similar to those observed in northern Europe and North America. (Sarcoidosis Vasc Diffuse Lung Dis 2014; 31: 191-197

Multiple endocrine neoplasia type 2 syndromes (MEN 2): results from the ItaMEN network analysis on the prevalence of different genotypes and phenotypes.

OBJECTIVE: Multiple endocrine neoplasia type 2 (MEN 2) is a genetic disease characterized by medullary thyroid carcinoma (MTC) associated (MEN 2A and 2B) or not familial MTC (FMTC) with other endocrine neoplasia due to germline RET gene mutations. The prevalence of these rare genetic diseases and their corresponding RET mutations are unknown due to the small size of the study population. METHODS: We collected data on germline RET mutations of 250 families with hereditary MTC followed in 20 different Italian centres. RESULTS AND CONCLUSIONS: The most frequent RET amino acid substitution was Val804Met (19.6%) followed by Cys634Arg (13.6%). A total of 40 different germline RET mutations were present. Six families (2.4%) were negative for germline RET mutations. The comparison of the prevalence of RET germline mutations in the present study with those published by other European studies showed a higher prevalence of Val804Met and Ser891Ala mutations and a lower prevalence of Leu790Phe and Tyr791Phe (P<0.0001). A statistically significant higher prevalence of mutations affecting non-cysteine codons was also found (P<0.0001). Furthermore, the phenotype data collection showed an unexpected higher prevalence of FMTC (57.6%) with respect to other MEN 2 syndromes (34% MEN 2A and 6.8% of MEN 2B). In conclusion, we observed a statistically significant different pattern of RET mutations in Italian MEN 2 families with respect to other European studies and a higher prevalence of FMTC phenotype. The different ethnic origins of the patients and the particular attention given to analysing apparently sporadic MTC for RET germline mutations may explain these findings

Duffy antigen receptor for chemokines mediates chemokine endocytosis through a macropinocytosis-like process in endothelial cells

Background: The Duffy antigen receptor for chemokines (DARC) shows high affinity binding to multiple inflammatory CC and CXC chemokines and is expressed by erythrocytes and endothelial cells. Recent evidence suggests that endothelial DARC facilitates chemokine transcytosis to promote neutrophil recruitment. However, the mechanism of chemokine endocytosis by DARC remains unclear. Methodology/Principal Findings: We investigated the role of several endocytic pathways in DARC-mediated ligand internalization. Here we report that, although DARC co-localizes with caveolin-1 in endothelial cells, caveolin-1 is dispensable for DARC-mediated 125I-CXCL1 endocytosis as knockdown of caveolin-1 failed to inhibit ligand internalization. 125I-CXCL1 endocytosis by DARC was also independent of clathrin and flotillin-1 but required cholesterol and was, in part, inhibited by silencing Dynamin II expression. 125I-CXCL1 endocytosis was inhibited by amiloride, cytochalasin D, and the PKC inhibitor Gö6976 whereas Platelet Derived Growth Factor (PDGF) enhanced ligand internalization through DARC. The majority of DARC-ligand interactions occurred on the endothelial surface, with DARC identified along plasma membrane extensions with the appearance of ruffles, supporting the concept that DARC provides a high affinity scaffolding function for surface retention of chemokines on endothelial cells. Conclusions/Significance: These results show DARC-mediated chemokine endocytosis occurs through a macropinocytosis-like process in endothelial cells and caveolin-1 is dispensable for CXCL1 internalization. © 2011 Zhao et al

Galectin-3 immunodetection in follicular thyroid neoplasms: a prospective study on fine-needle aspiration samples

Fine-needle aspiration cytology, which is well established to be accurate for the diagnosis of thyroid cancer, may be inconclusive for the follicular thyroid neoplasms. As galectin-3 was suggested to be a marker of malignant thyrocytes, we investigated whether this protein might be helpful in the diagnosis of aspirates classified as undeterminate by cytology. After establishing an easy processing of aspirates for galectin-3 immunodetection, a series of aspirates categorised as benign (n=63), malignant (n=17) or undeterminate (n=34) was prospectively analysed for galectin-3. Only the patients with malignant or undeterminate lesions underwent surgery. Most lesions (86%) diagnosed as malignant by cytology or after surgery were positive for galectin-3. The majority of lesions (94%) classified as benign by cytology or after surgery was negative for galectin-3. The positive and negative predictive values were 83 and 95%, respectively. When focusing on the undeterminate lesions, the sensitivity and specificity were 75 and 90%, respectively, while the positive and negative predictive values were 82 and 87%, respectively. The specificity and the positive predictive value were higher (100%) when considering the percentage of stained cells. Altogether these results show that galectin-3 constitutes a useful marker in the diagnosis of thyroid lesions classified as undeterminate by conventional cytology

Secretome of apoptotic peripheral blood cells (APOSEC) confers cytoprotection to cardiomyocytes and inhibits tissue remodelling after acute myocardial infarction: a preclinical study

Heart failure following acute myocardial infarction (AMI) is a major cause of morbidity and mortality. Our previous observation that injection of apoptotic peripheral blood mononuclear cell (PBMC) suspensions was able to restore long-term cardiac function in a rat AMI model prompted us to study the effect of soluble factors derived from apoptotic PBMC on ventricular remodelling after AMI. Cell culture supernatants derived from irradiated apoptotic peripheral blood mononuclear cells (APOSEC) were collected and injected as a single dose intravenously after myocardial infarction in an experimental AMI rat model and in a porcine closed chest reperfused AMI model. Magnetic resonance imaging (MRI) and echocardiography were used to quantitate cardiac function. Analysis of soluble factors present in APOSEC was performed by enzyme-linked immunosorbent assay (ELISA) and activation of signalling cascades in human cardiomyocytes by APOSEC in vitro was studied by immunoblot analysis. Intravenous administration of a single dose of APOSEC resulted in a reduction of scar tissue formation in both AMI models. In the porcine reperfused AMI model, APOSEC led to higher values of ejection fraction (57.0 vs. 40.5%, p < 0.01), a better cardiac output (4.0 vs. 2.4 l/min, p < 0.001) and a reduced extent of infarction size (12.6 vs. 6.9%, p < 0.02) as determined by MRI. Exposure of primary human cardiac myocytes with APOSEC in vitro triggered the activation of pro-survival signalling-cascades (AKT, Erk1/2, CREB, c-Jun), increased anti-apoptotic gene products (Bcl-2, BAG1) and protected them from starvation-induced cell death. Intravenous infusion of culture supernatant of apoptotic PBMC attenuates myocardial remodelling in experimental AMI models. This effect is probably due to the activation of pro-survival signalling cascades in the affected cardiomyocytes

Secretion of Novel SEL1L Endogenous Variants Is Promoted by ER Stress/UPR via Endosomes and Shed Vesicles in Human Cancer Cells

We describe here two novel endogenous variants of the human endoplasmic reticulum (ER) cargo receptor SEL1LA, designated p38 and p28. Biochemical and RNA interference studies in tumorigenic and non-tumorigenic cells indicate that p38 and p28 are N-terminal, ER-anchorless and more stable relative to the canonical transmembrane SEL1LA. P38 is expressed and constitutively secreted, with increase after ER stress, in the KMS11 myeloma line and in the breast cancer lines MCF7 and SKBr3, but not in the non-tumorigenic breast epithelial MCF10A line. P28 is detected only in the poorly differentiated SKBr3 cell line, where it is secreted after ER stress. Consistently with the presence of p38 and p28 in culture media, morphological studies of SKBr3 and KMS11 cells detect N-terminal SEL1L immunolabeling in secretory/degradative compartments and extracellularly-released membrane vesicles. Our findings suggest that the two new SEL1L variants are engaged in endosomal trafficking and secretion via vesicles, which could contribute to relieve ER stress in tumorigenic cells. P38 and p28 could therefore be relevant as diagnostic markers and/or therapeutic targets in cancer

International Consensus Statement on Allergy and Rhinology: Allergic Rhinitis.

BACKGROUND: Critical examination of the quality and validity of available allergic rhinitis (AR) literature is necessary to improve understanding and to appropriately translate this knowledge to clinical care of the AR patient. To evaluate the existing AR literature, international multidisciplinary experts with an interest in AR have produced the International Consensus statement on Allergy and Rhinology: Allergic Rhinitis (ICAR:AR). METHODS: Using previously described methodology, specific topics were developed relating to AR. Each topic was assigned a literature review, evidence-based review (EBR), or evidence-based review with recommendations (EBRR) format as dictated by available evidence and purpose within the ICAR:AR document. Following iterative reviews of each topic, the ICAR:AR document was synthesized and reviewed by all authors for consensus. RESULTS: The ICAR:AR document addresses over 100 individual topics related to AR, including diagnosis, pathophysiology, epidemiology, disease burden, risk factors for the development of AR, allergy testing modalities, treatment, and other conditions/comorbidities associated with AR. CONCLUSION: This critical review of the AR literature has identified several strengths; providers can be confident that treatment decisions are supported by rigorous studies. However, there are also substantial gaps in the AR literature. These knowledge gaps should be viewed as opportunities for improvement, as often the things that we teach and the medicine that we practice are not based on the best quality evidence. This document aims to highlight the strengths and weaknesses of the AR literature to identify areas for future AR research and improved understanding