Androgen receptor mutations in prostate cancer

We analyzed the frequency and relevance of mutations in the coding region of the androgen receptor (AR) in genomic DNA extracted from 137 specimens of prostate cancer. The specimens were obtained from the primary tumors of patients affected by stage B disease [15 nonmicrodissected (group 1A) and 84 microdissected (group 1B)] and from the metastatic deposits of individuals with stage D1 disease [8 nonmicrodissected (group 2A) and 30 microdissected (group 2B)] who had not undergone androgen ablation therapy. The study was conducted by PCR-single strand conformational polymorphism (SSCP) analysis of exons 2-8 in the four groups and direct sequence analysis of exon 1 in group 1B. As positive and negative controls, we used genomic DNA extracted from genital skin fibroblasts of patients affected by various forms of androgen resistance with known mutations in the AR. To control for genetic instability, PCR-SSCP analysis of exon 2 of the human progesterone receptor was carried out on each specimen. The overall number of mutations detected was 11 (8%). No mutations were detected in any of the 99 patients with stage B disease. Eleven mutations were detected in exons 2-8 in 8 of the 38 patients with stage D1 disease (all in group 2B). Simultaneous analysis of exon 2 of the progesterone receptor was carried out, and no SSCP changes were identified. These data suggest that AR mutations are rare and presumably do not play a role in the initial phase of prostatic carcinogenesis. The presence of a significant number of AR mutations in metastatic disease indicates that mutations of this molecule may play a role in the most advanced phases of the natural history of this disease, either by facilitating growth or acquisition of the metastatic phenotype

Circulating levels of IL-1 family cytokines and receptors in Alzheimer's disease: new markers of disease progression?

BACKGROUND: Although the mechanisms underlying AD neurodegeneration are not fully understood, it is now recognised that inflammation could play a crucial role in the initiation and progression of AD neurodegeneration. A neuro-inflammatory network, based on the anomalous activation of microglial cells, includes the production of a number of inflammatory cytokines both locally and systemically. These may serve as diagnostic markers or therapeutic targets for AD neurodegeneration. METHODS: We have measured the levels of the inflammation-related cytokines and receptors of the IL-1 family in serum of subjects with AD, compared to mild cognitive impairment (MCI), subjective memory complaints (SMC), and normal healthy subjects (NHS). Using a custom-made multiplex ELISA array, we examined ten factors of the IL-1 family, the inflammation-related cytokines IL-1α, IL-1β, IL-18, and IL-33, the natural inhibitors IL-1Ra and IL-18BP, and the soluble receptors sIL-1R1, sIL-1R2, sIL-1R3, and sIL-1R4. RESULTS: The inflammatory cytokines IL-1α and IL-1β, their antagonist IL-1Ra, and their soluble receptor sIL-1R1 were increased in AD. The decoy IL-1 receptor sIL-1R2 was only increased in MCI. IL-33 and its soluble receptor sIL-1R4 were also significantly higher in AD. The soluble form of the accessory receptor for both IL-1 and IL-33 receptor complexes, sIL-1R3, was increased in SMC and even more in AD. Total IL-18 levels were unchanged, whereas the inhibitor IL-18BP was significantly reduced in MCI and SMC, and highly increased in AD. The levels of free IL-18 were significantly higher in MCI. CONCLUSIONS: AD is characterised by a significant alteration in the circulating levels of the cytokines and receptors of the IL-1 family. The elevation of sIL-1R4 in AD is in agreement with findings in other diseases and can be considered a marker of ongoing inflammation. Increased levels of IL-1Ra, sIL-1R1, sIL-1R4, and IL-18BP distinguished AD from MCI and SMC, and from other inflammatory diseases. Importantly, sIL-1R1, sIL-1R3, sIL-1R4, and IL-18BP negatively correlated with cognitive impairment. A significant elevation of circulating sIL-1R2 and free IL-18, not present in SMC, is characteristic of MCI and disappears in AD, making them additional interesting markers for evaluating progression from MCI to AD

Association between anti-citrullinated alpha enolase antibodies and clinical features in a cohort of patients with rheumatoid arthritis: a pilot study.

In recent years several antibodies against citrullinated peptides (ACPAs) have been identified in patients with rheumatoid arthritis (RA) and their pathogenic, diagnostic and prognostic significance is under intense investigation. Among ACPAs, those targeting citrullinated alpha enolase (anti-CEP1) have been identified in RA but data about their ability to predict the development of erosive disease are conflicting. Furthermore, no data are currently available concerning their possible association with extra-articular manifestations (EAMs) in RA. The aim of this study was to investigate the prevalence and significance of anti-CEP1 from a prognostic point of view. In this pilot study we confirmed that anti-CEP1 Abs are associated with higher prevalence of bone erosions, but we also provided the first evidence of an association between anti-CEP1 Abs and RA interstitial lung disease (ILD). These results provide the basis to investigate the association between anti-CEP1 Abs and EAMs in larger cohorts of RA patients to possibly confirm its role as biomarker for RA-ILD

Distinct profile of inflammatory and remodelling biomarkers in sputum of severe asthmatic patients with or without persistent airway obstruction

Background: Both inflammatory and remodelling processes are associated with irreversible airway obstruction observed in severe asthma. Our aim was to characterize a group of severe asthmatic patients with or without persistent airway obstruction in relation to specific sputum inflammatory and remodelling biomarkers. Methods: Forty-five patients under regular high-dose inhaled corticosteroid/ß-2agonist treatment were studied, after a follow-up period of at least 2 years, with a minimum of 4 visits. Periostin, TGF-ß, RANTES, IL-8, GM-CSF, FGF-2, and cell counts were measured in induced sputum. Serum periostin was also measured. Results: Sputum induction was successfully performed in all but 5 patients. There were no significant differences in demographic and clinical data between patients with non-persistent obstruction (NO: FEV1/VC>88%pred.) and those with persistent obstruction (O: a not completely reversible obstruction with FEV1/VC<88%pred. at each visit before the study visit). Patients with persistent obstruction had significantly higher sputum periostin and TGF-ß concentrations than NO patients and a trend of higher serum periostin levels. GM-CSF and FGF-2 were significantly increased in NO compared to O patients. No differences between groups were found for RANTES, IL-8 and differential cell counts. Sputum periostin inversely correlated with functional parameters (prebronch. FEV1: rho = −0.36, p < 0.05; postbronch. FEV1: rho = −0.33, p = 0.05). Patients with high sputum periostin concentration (>103.3 pg/ml: median value) showed an absolute number of sputum eosinophils significantly higher than patients with low sputum periostin; this behavior was unobserved when serum periostin was considered. Conclusions: Only periostin and TGF-ß identified a subgroup of severe asthmatic patients with persistent airway obstruction. Sputum periostin was also inversely associated with FEV1 and proved to be a more sensitive biomarker than serum periostin to identify severe asthmatics with higher sputum eosinophilia

Microsomal prostaglandin E2 synthase-1 is induced by conditional expression of RET/PTC in thyroid PCCL3 cells through the activation of the MEK-ERK pathway

RET/PTC rearrangements are believed to be tumor-initiating events in papillary thyroid carcinomas. We identified microsomal prostaglandin E2 synthase-1 (mPGES-1) as a RET/PTC-inducible gene through subtraction hybridization cloning and expression profiling with custom microarrays. The inducible prostaglandin E2 (PGE2) biosynthetic enzymes cyclooxygenase-2 (COX-2) and mPGES-1 are up-regulated in many cancers. COX-2 is overexpressed in thyroid malignancies compared with benign nodules and normal thyroid tissues. Eicosanoids may promote tumorigenesis through effects on tumor cell growth, immune surveillance, and angiogenesis. Conditional RET/PTC1 or RET/PTC3 expression in PCCL3 thyroid cells markedly induced mPGES-1 and COX-2. PGE2 was the principal prostanoid and up-regulated (by approximately 60-fold), whereas hydroxyeicosatetraenoic acid metabolites were decreased, consistent with shunting of prostanoid biosynthesis toward PGE2 by coactivation of the two enzymes. RET/PTC activated mPGES-1 gene transcription. Based on experiments with kinase inhibitors, with PCCL3 cell lines with doxycycline-inducible expression of RET/PTC mutants with substitutions of critical tyrosine residues in the kinase domain, and lines with inducible expression of activated mutants of H-RAS and MEK1, RET/PTC was found to regulate mPGES-1 through Shc-RAS-MEK-ERK. These data show a direct relationship between activation of a tyrosine kinase receptor oncogene and regulation of PGE2 biosynthesis. As enzymes involved in prostanoid biosynthesis can be targeted with pharmacological inhibitors, these findings may have therapeutic implications

Sialoendoscopy: state of the art, challenges and further perspectives. Round Table, 101st SIO National Congress, Catania 2014

This draft of the Official Round Table held during the 101st SIO National Congress is an updated review on sialoendoscopy, a technique used for diagnosis and treatment of obstructive pathologies of salivary glands in a minimally invasive fashion. This review treats many aspects of salivary gland endoscopy, starting from anatomy to deal with the more advanced surgical techniques and analyses the main decisional algorithms proposed in the literature. In addition, particular attention was directed to the current limitations of this technique and to the potential developments that sialoendoscopy could have in the near future

Upper and lower airway inflammation in severe asthmatics: a guide for a precision biologic treatment

Background and aims: Severe asthma may require the prescription of one of the biologic drugs currently available, using surrogate markers of airway inflammation (serum IgE levels and allergic sensitization for anti-IgE, or blood eosinophils for anti-IL5/IL5R). Our objective: to assess upper and lower airway inflammation in severe asthmatics divided according to the eligibility criteria for one of the target biologic treatments. Methods: We selected 91 severe asthmatics, uncontrolled despite high-dose ICS-LABA, and followed for >6 months with optimization of asthma treatment. Patients underwent clinical, functional and biological assessment, including induced sputum and nasal cytology. They were then clustered according to the eligibility criteria for omalizumab or mepolizumab/benralizumab. Results: Four clusters were selected: A (eligible for omalizumab, n = 23), AB (both omalizumab and mepolizumab, n = 26), B (mepolizumab, n = 22) and C (non-eligible for both omalizumab and mepolizumab, n = 20). There was no difference among clusters for asthma control (Asthma Control Test and Asthma Control Questionnaire 7), pre-bronchodilator forced expiratory volume in 1 s, serum IgE and fractional exhaled nitric oxide levels. Sputum eosinophils were numerically higher in clusters AB and B, in agreement with the higher levels of blood eosinophils. Allergic rhinitis was more frequent in clusters A and AB, while chronic rhinosinusitis with nasal polyps prevalence increased progressively from A to C. Eosinophils in nasal cytology were higher in clusters AB, B and C. Conclusion: Eosinophilic upper and lower airway inflammation is present in the large majority of severe asthmatics, independently from the prescription criteria for the currently available biologics, and might suggest the use of anti-IL5/IL5R or anti IL4/13 also in patients without blood eosinophilia. The reviews of this paper are available via the supplemental material section

Salvage carbon dioxide transoral laser microsurgery for laryngeal cancer after (chemo)radiotherapy: a European Laryngological Society consensus statement

Purpose: To provide expert opinion and consensus on salvage carbon dioxide transoral laser microsurgery (CO2 TOLMS) for recurrent laryngeal squamous cell carcinoma (LSCC) after (chemo)radiotherapy [(C)RT]. Methods: Expert members of the European Laryngological Society (ELS) Cancer and Dysplasia Committee were selected to create a dedicated panel on salvage CO2 TOLMS for LSCC. A series of statements regarding the critical aspects of decision-making were drafted, circulated, and modified or excluded in accordance with the Delphi process. Results: The expert panel reached full consensus on 19 statements through a total of three sequential evaluation rounds. These statements were focused on different aspects of salvage CO2 TOLMS, with particular attention on preoperative diagnostic work-up, treatment indications, postoperative management, complications, functional outcomes, and follow-up. Conclusion: Management of recurrent LSCC after (C)RT is challenging and is based on the need to find a balance between oncologic and functional outcomes. Salvage CO2 TOLMS is a minimally invasive approach that can be applied to selected patients with strict and careful indications. Herein, a series of statements based on an ELS expert consensus aimed at guiding the main aspects of CO2 TOLMS for LSCC in the salvage setting is presented

Sialendoscopy for salivary stones: principles, technical skills and therapeutic experience

La scialoadenite cronica ostruttiva rappresenta una delle più frequenti patologie non-neoplastiche delle ghiandole salivari e la scialoendoscopia è sempre più utilizzata nella sua diagnosi e nel suo trattamento, associata o meno con la litotripsia laser. La scialoendoscopia può essere inoltre associata ad approcci esterni mini-invasivi nelle litiasi troppo voluminose per essere rimosse con un approccio unicamente endoscopico. Il presente articolo riporta lesperienza delle Cliniche Otorinolaringoiatriche dellOspedale SantOrsola-Malpighi di Bologna e dellAzienda Ospedaliero Universitaria di Cagliari, Italia. È stata eseguita unanalisi retrospettiva su 48 pazienti (26 femmine, 22 maschi; età media di 45,3 anni; range 8-83 anni) trattati per patologia cronica ostruttiva delle ghiandole salivari maggiori mediante procedure chirurgiche endoscopiche o combinate da novembre 2010 ad aprile 2016 presso lAzienda-Ospedaliero-Universitaria di Cagliari. I risultati dellOspedale SantOrsola-Malpighi di Bologna erano stati precedentemente pubblicati. Gli aspetti tecnici della scialoendoscopia sono stati accuratamente descritti. I pazienti trattati presso lAzienda Ospedaliero Universitaria di Cagliari presentavano una patologia unilaterale in 40 casi e bilaterale in 8 casi; sono state trattate 56 ghiandole salivari maggiori (22 sottomandibolari e 34 parotidi). 5 pazienti sono stati sottoposti a scialoendoscopia bilaterale per parotite ricorrente giovanile, 10 per patologia ostruttiva non litiasica e 33 (68,75%) presentavano calcoli salivari (1 paziente presentava una litiasi parotidea bilaterale). Solo 8 pazienti sono stati sottoposti a scialectomia radicale per via esterna (5 scialectomie sottomandibolare e 3 parotidectomie). La chirurgia conservativa nei pazienti con scialoadenite cronica ostruttiva appare efficace e può essere realizzata mediante un approccio puramente endoscopico o combinato, con unalta percentuale di successo. La procedura richiede una strumentazione adeguata e deve essere eseguita da un chirurgo esperto, che abbia svolto un training specifico scialoendoscopico, in modo da evitare le possibili complicanze maggiori e minori. La scialectomia tradizionale rappresenta la extrema ratio, limitata nei casi in cui un approccio conservativo sia risultato inefficace o controindicato

Skin rash and response to cetuximab treatment: a retrospective single-center analysis

Background: The standard of care for patients with recurrent/metastatic head and neck squamous cell cancer (R/M HNSCC) not susceptible for surgery or reirradiation is chemotherapy with 5-FU and cisplatin plus cetuximab. Skin rash (SR) is a common adverse event of cetuximab. In patients treated with cetuximab for colorectal cancer there is strong evidence of a better outcome in those who undergo moderate or high grade of SR, and some retrospective data seem to confirm this finding in HNSCC. We report our experience. Materials and methods: We retrospectively reviewed 107 patients treated with cetuximab for R/M HNSCC from January 2014 to December 2016. Patients were divided in two groups by the grade of SR (G0-1 and G2-4), conforming to Common Terminology Criteria for Adverse Events (CTCAE) v 4.0. Progression-free survival (PFS) was computed as time of progression or death since the date of assessment of recurrent/metastatic disease. Overall response rate (ORR) was computed as the sum of partial and complete responses and evaluated according to RECIST 1.1. PFS and ORR were correlated to the grade of rash. Results: 67 patients were evaluable for PFS: among them PFS was significantly longer (p 0.0014) in those who underwent a G2-4 rash (9,3 months) vs G0-1 (4,9 months). Hazard Ratio was 2,445 (CI 1.412-4.232). 95 patients were evaluable for ORR: among them G0-1 group had 4,2%, while G2-4 group had 36,8% of ORR. Conclusions: Our results support data of literature on improved outcome according to the development of skin rash in HNSCC. SR might be considered a predictive marker of response in these patients; nonetheless further ad hoc studies would be interesting