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Aim and background Axillary dissection in patients positive for sentinel lymph nodes is currently under discussion in the literature, since approximately only 50% of such patients has metastases in the remaining lymph nodes. To identify patients at risk for non-sentinel lymph nodes metastases, a nomogram was developed by the Breast Service of the Memorial Sloan-Kettering Cancer Center. The aim of this study was to assess the nomogram's predictive accuracy in a population of Italian breast cancer patients in our hospital. Materials and methods The system of calculation used as variables prognostic factors of breast cancer: pathologic size, tumor type and nuclear grade, lymphovascular invasion, multifocality, estrogen receptor status, method of detection of the sentinel lymph nodes metastases (frozen section, serial hematoxylin-eosin, routine hematoxylin-eosin, and immunohistochemistry), number of positive and number of negative sentinel lymph nodes. Results and conclusions To measure the discrimination of the nomogram, a receiver-operating characteristic curve was construed, and the area under the curve was calculated. However, the area under the curve was 0.72, a very high value considering that the limit of acceptability is 0.70–0.80. The calculation system developed by the Memorial Sloan-Kettering Cancer Center provides a predictive value on the histopathologic state of sentinel lymph nodes.

Flat epithelial atypia (FEA) may represent the earliest precursor of low-grade breast cancer and often coexists with more advanced atypical proliferative breast lesions such as atypical ductal hyperplasia (ADH) and lobular intraepithelial neoplasia (LIN). The present study aims to investigate the association between morphological parameters of FEA and presence of malignancy at surgical excision (SE) and the clinical significance of the association of FEA with ADH and/or LIN. This study included 589 cases of stereotactic 11-gauge vacuum-assisted needle core biopsy (VANCB), reporting a diagnosis of FEA, ADH or LIN with subsequent SE from 14 pathology departments in Italy. Available slides were reviewed, with 114 (19.4 %) showing a malignant outcome at SE. Among the 190 cases of pure FEA, no statistically significant association emerged between clinical–pathological parameters of FEA and risk of malignancy. Logistic regression analyses showed an increased risk of malignancy according to the extension of ADH among the 275 cases of FEA associated with ADH (p = 0.004) and among the 34 cases of FEA associated with ADH and LIN (p = 0.02). In the whole series, a statistically significant increased malignancy risk emerged according to mammographic R1–R3/R4–R5 categories (OR = 1.56; p = 0.04), extension (OR = 1.24; p = 0.04) and grade (OR = 1.94; p = 0.004) of cytological atypia of FEA. The presence of ADH was associated with an increased malignancy risk (OR = 2.85; p < 0.0001). Our data confirm the frequent association of FEA with ADH and/or LIN. A diagnosis of pure FEA on VANCB carries a 9.5 % risk of concurrent malignancy and thus warrants follow-up excision because none of the clinical–pathological parameters predicts which cases will present carcinoma on SE.

Percutaneous core biopsy (CB) has been introduced to increase the ability of accurately diagnosing breast malignancies without the need of resorting to surgery. Compared to conventional automated 14 gauge needle core biopsy (NCB), vacuum-assisted needle core biopsy (VANCB) allows obtaining larger specimens and has recognized advantages particularly when the radiological pattern is represented by microcalcifications. Regardless of technical improvements, a small percentage of percutaneous CBs performed to detect breast lesions are still classified, according to European and UK guidelines, in the borderline B3 category, including a group of heterogeneous lesions with uncertain malignant potential. We aimed to assess the prevalence and positive predictive values (PPV) on surgical excision (SE) of B3 category (overall and by sub-categories) in a large series of non-palpable breast lesions assessed through VANCB, also comparison with published data on CB. Overall, 26,165 consecutive stereotactic VANCB were identified in 22 Italian centres: 3107 (11.9%) were classified as B3, of which 1644 (54.2%) proceeded to SE to establish a definitive histological diagnosis of breast pathology. Due to a high proportion of microcalcifications as main radiological pattern, the overall PPV was 21.2% (range 10.6%-27.3% for different B3 subtypes), somewhat lower than the average value (24.5%) from published studies (range 9.9%-35.1%). Our study, to date the largest series of B3 with definitive histological assessment on SE, suggests that B3 lesions should be referred for SE even if VANCB is more accurate than NCB in the diagnostic process of non-palpable, sonographically invisible breast lesions.

The p16 gene, which encodes a physiological inhibitor of the cyclin D-CDK4 complex, is now considered as an important tumour-suppressor gene in a variety of tumours. A marked reduction of its expression has been reported to occur without significant genetic alterations in human pituitary adenomas, although rare point mutations of uncertain functional significance have been described. On the other hand, p16 gene silencing due to hypermethylation has been reported in several human primary tumours. The aim of this study was to further investigate the pathogenetic events leading to p16 gene inactivation in pituitary tumours.To screen a european series of human pituitary tumours for p16 gene alterations and possible gene hypermethylation.A representative series of 31 human pituitary tumours-30 macroadenomas, including a MEN-1 non-secreting pituitary adenoma and a non-MEN-1 familial giant GH-secreting adenoma, and one FSH-secreting pituitary carcinoma-was studied.Polymerase chain reaction/single strand conformation polymorphism (PCR-SSCP) analysis was used to screen for p16 gene alterations in all cases. Direct sequencing of PCR-products was obtained by the di-deoxynucleotide method where suspected abnormalities of the PCR-SSCP analysis were observed. In 24 samples, a methylation-specific PCR assay (MSP-PCR) was used to determine p16 gene methylation status.Two sporadic cases of pituitary adenomas had a similar single A to G base substitution leading to an heterozygous Ala140Thr p16 polymorphism, which has not previously been described in such tumours, but is known to be functionally silent. No other p16 abnormality could be suspected from PCR-SSCP analysis in this series. In contrast, the presence of methylated-specific PCR products was observed in 20/24 cases (83.3%).This study confirms that p16 gene mutations are not involved in the pathogenesis of human pituitary tumours, although polymorphisms can be demonstrated, depending on the population considered. In contrast, the high incidence of hypermethylation of the p16 gene suggests that such an alteration occurs early in pituitary tumours, and may play a role in pituitary tumorigenesis.

Bruno Balbi,1 Claudia Sangiorgi,1 Isabella Gnemmi,1 Ilaria Ferrarotti,2 Davide Vallese,1 Elena Paracchini,1 Lorena Delle Donne,1 Luciano Corda,3 Paolo Baderna,4 Angelo Corsico,2 Mauro Carone,1 Paola Brun,5 Francesco Cappello,6,7 Fabio LM Ricciardolo,8 Paolo Ruggeri,9 Sharon Mumby,10 Ian M Adcock,10 Gaetano Caramori,9 Antonino Di Stefano11Istituti Clinici Scientifici Maugeri, IRCCS, Division of Pneumology and Laboratory of Cytoimmunopathology of the Heart and Lung, Veruno, Italy; 2Department of Internal Medicine and Medical Therapy, University of Pavia, Pavia, Italy; 3Medicina Respiratoria, Seconda Medicina Interna, Spedali Civili, Brescia, Italy; 4Division of Pneumology, Aosta Hospital, Aosta, Italy; 5Department of Molecular Medicine, University of Padova, Padova, Italy; 6Dipartimento di Biomedicina Sperimentale e Neuroscienze Cliniche, Sezione di Anatomia Umana, Università di Palermo, Palermo, Italy; 7Euro-mediterranean Institute of Science and Technology (IEMEST), Palermo, Italy; 8Department of Clinical and Biological Sciences, A.O.U., San Luigi Gonzaga, Orbassano, University of Turin, Turin, Italy; 9UOC Di Pneumologia, Dipartimento di Scienze Biomediche, Odontoiatriche e Delle Immagini Morfologiche e Funzionali (BIOMORF), Università di Messina, Messina, Italy; 10Airways Disease Section, National Heart and Lung Institute, Imperial College London, UKCorrespondence: Antonino Di StefanoIstituti Clinici Scientifici Maugeri Irccs, Via Maugeri, 4, Pavia 27100, ItalyTel +39 032 288 4711Fax +39 032 288 4776Email antonino.distefano@icsmaugeri.itBackground: Airway inflammation may drive the progression of chronic obstructive pulmonary disease (COPD) associated with alpha-1 antitrypsin deficiency (AATD), but the relationship between airway microbiota and inflammation has not been investigated.Methods: We studied 21 non-treated AATD (AATD-noT) patients, 20 AATD-COPD patients under augmentation therapy (AATD-AT), 20 cigarette smoke-associated COPD patients, 20 control healthy smokers (CS) and 21 non-smokers (CON) with normal lung function. We quantified sputum inflammatory cells and inflammatory markers (IL-27, CCL3, CCL5, CXCL8, LTB4, MPO) by ELISA, total bacterial load (16S) and pathogenic bacteria by qRT-PCR.Results: AATD-AT patients were younger but had similar spirometric and DLCO values compared to cigarette smoke-associated COPD, despite a lower burden of smoking history. Compared to cigarette smoke-associated COPD, AATD-noT and AATD-AT patients had lower sputum neutrophil levels (p=0.0446, p=0.0135), total bacterial load (16S) (p=0.0081, p=0.0223), M. catarrhalis (p=0.0115, p=0.0127) and S. pneumoniae (p=0.0013, p=0.0001). Sputum IL-27 was significantly elevated in CS and cigarette smoke-associated COPD. AATD-AT, but not AATD-noT patients, had IL-27 sputum levels (pg/ml) significantly lower than COPD (p=0.0297) and these positively correlated with FEV1% predicted values (r=0.578, p=0.0307).Conclusions: Compared to cigarette smoke-associated COPD, AATD-AT (COPD) patients have a distinct airway inflammatory and microbiological profile. The decreased sputum bacterial load and IL-27 levels in AATD-AT patients suggests that augmentation therapy play a role in these changes.Keywords: alpha-1antitrypsin deficiency, COPD, chronic airway inflammation, respiratory disability, sputum

Introduction Implant osseointegration is strongly influenced by the bone quality at the implant insertion site. The present work aims to create distribution diagrams showing the average bone density at each position within the jaws. Materials and methods Data were retrospectively collected from 4 oral surgeons who sought bone-density measurements during implant placement using a torque-measuring implant micromotor. Statistical analyses were performed to investigate whether bone density correlated with the patients' sex and age and whether the bone-density values at different positions within each arch correlated to each other. Results Records of 2408 patients and 6060 bone-density readings were retrieved, and density distribution diagrams were created. Density values showed a significant variation within subjects. Within the same jaw, density between adjacent positions showed significant differences. Density at a given position correlated significantly with that at the other positions in most cases. Bone density was significantly lower in women than in men; no significant correlation was found between bone density and the patient age. Conclusions Bone density of patients displays significant interindividual variation, thus meaningful assessment must be conducted on a patient-by-patient basis.

Background: The aim of this study was to assess the feasibility and the safety of early discharge (within 72 h) after transfemoral transcatheter aortic valve implantation (TAVI) and to identify baseline features and/or periprocedural variables, which may affect post-TAVI lengthofstay (LoS) duration. Methods and results: Patients discharged within 72 h of TAVI (early discharge group) were compared with consecutive patients discharged after 3 days (late discharge group). Propensity-matched cohorts of patients with a 2:1 ratio were created to better control confounding bias. Among 465 patients, 107 (23.0%) were discharged within 3 days of the procedure. Multivariable regression analysis of unmatched patients demonstrated that baseline New York Heart Association (NYHA) class IV (OR:0.22, 95% CI 0.05 to 0.96; p=0.045) and any bleeding (OR:0.31, 95% CI 0.74 to 0.92; p=0.031) were less likely to be associated with early discharge after TAVI. Conversely, the year of procedure (OR:1.66, 95% CI 1.25 to 2.20; p

Aims The aim of this study was to compare outcomes with the use of two haemostasis strategies after transfemoral transcatheter aortic valve implantation (TAVI) - one Prostar® vs. two ProGlide® devices (Abbott Vascular Inc., Santa Clara, CA, USA). Methods and results This was a retrospective study enrolling consecutive patients undergoing fully percutaneous transfemoral TAVI in our centre (Ferrarotto Hospital, Catania, Italy) from January 2012 to October 2014. All patients were dichotomised according to the vascular closure device (VCD) used for common femoral artery haemostasis (Prostar vs. ProGlide). All outcomes were defined according to VARC-2 criteria. The study population encompassed a total of 278 patients. Of these, 153 (55.1%) underwent TAVI using the Prostar, and 125 (44.9%) using two ProGlide devices. Vascular complications occurred in 48 patients (17.3%), being more frequent in the ProGlide group (11.8% vs. 24.0%, p=0.007). Patients who had TAVI using the ProGlide were also more likely to have a higher rate of percutaneous closure device failure (4.6% vs. 12.8%, p=0.013). Percutaneous peripheral intervention was performed in 13.7% and 28.0% of Prostar and ProGlide cases, respectively (p=0.003). Conclusions Patients undergoing transfemoral TAVI had significantly lower rates of vascular complications and percutaneous closure device failures when the Prostar was used compared with two ProGlide devices.

The tumor suppressor gene CDKN1B encodes for a 27-kDa cyclin-dependent kinase inhibitory protein, p27Kip1, which together with its well-established role in the inhibition of cell proliferation, displays additional activities in the control of gene transcription and cell motility. p27Kip1 thus represents a good candidate for a gene therapy approach, especially in those cancers refractory to the conventional therapies, like human glioblastoma. Here, we show that overexpression of p27Kip1 in glioblastoma cell lines induced cell cycle arrest and inhibition of cell motility through extracellular matrix substrates. The use of adenoviral vectors in the treatment of glioblastoma in vivo showed that p27Kip1 was able to block not only cancer cell growth but also local invasion and tumor-induced neoangiogenesis. The latter effect was due to the ability of p27 to impair both endothelial cell growth and motility, thus preventing proper vessel formation in the tumor. The block of neoangiogenesis depended on cytoplasmic p27Kip1 antimigratory activity and was linked to its ability to bind to and inhibit the microtubule-destabilizing protein stathmin. Our work provides the first evidence that a successful p27Kip1-based gene therapy is linked to tumor microenvironment modification, thus opening new perspectives to the use of gene therapy approaches for the treatment of refractory cancers. [Mol Cancer Ther 2008;7(5):1164–75]