Alcohol and cigarette consumption predict mortality in patients with head and neck cancer: A pooled analysis within the International Head and Neck Cancer Epidemiology (INHANCE) Consortium

Background: This study evaluated whether demographics, pre-diagnosis lifestyle habits and clinical data are associated with the overall survival (OS) and head and neck cancer (HNC)-specific survival in patients with HNC. Patients and methods: We conducted a pooled analysis, including 4759 HNC patients from five studies within the International Head and Neck Cancer Epidemiology (INHANCE) Consortium. Cox proportional hazard ratios (HRs) and the corresponding 95% confidence intervals (CIs) were estimated including terms reported significantly associated with the survival in the univariate analysis. Results: Five-year OS was 51.4% for all HNC sites combined: 50.3% for oral cavity, 41.1% for oropharynx, 35.0% for hypopharynx and 63.9% for larynx. When we considered HNC-specific survival, 5-year survival rates were 57.4% for all HNC combined: 54.6% for oral cavity, 45.4% for oropharynx, 37.1% for hypopharynx and 72.3% for larynx. Older ages at diagnosis and advanced tumour staging were unfavourable predictors of OS and HNC-specific survival. In laryngeal cancer, low educational level was an unfavourable prognostic factor for OS (HR=2.54, 95% CI 1.01-6.38, for high school or lower versus college graduate), and status and intensity of alcohol drinking were prognostic factors both of the OS (current drinkers HR=1.73, 95% CI 1.16-2.58) and HNC-specific survival (current drinkers HR=2.11, 95% CI 1.22-3.66). In oropharyngeal cancer, smoking status was an independent prognostic factors for OS. Smoking intensity ( > 20 cigarettes/day HR=1.41, 95% CI 1.03-1.92) was also an independent prognostic factor for OS in patients with cancer of the oral cavity. Conclusions: OS and HNC-specific survival differ among HNC sites. Pre-diagnosis cigarette smoking is a prognostic factor of the OS for patients with cancer of the oral cavity and oropharynx, whereas pre-diagnosis alcohol drinking is a prognostic factor of OS and HNC-specific survival for patients with cancer of the larynx. Low educational level is an unfavourable prognostic factor for OS in laryngeal cancer patients

Analysis of the molecular interactions of the potent analgesic S1RA with the \u3c31 receptor

The highly selective \u3c31 receptor antagonist S1RA is endowed with a surprisingly high affinity for its target protein given a missing fundamental hydrophobic pharmacophoric requirement. Here we show that, with respect to other potent \u3c31 ligands, S1RA is able to compensate this loss by fulfilling all other pharmacophoric requirements and by gaining in solvation energy

Fluorinated PET Tracers for Molecular Imaging of \u3c31 Receptors in the Central Nervous System.

At first the role of \u3c31 receptors in various neurological, psychiatric and neurodegenerative disorders is discussed. In the second part, the principle of positron emission tomography (PET ) is described and the known fluorinated PET tracers for labeling of \u3c31 receptors are presented. The third part focuses on fluoroalkyl substituted spirocyclic PET tracers, which represent the most promising class of fluorinated PET tracers reported so far. The homologous fluoroalkyl derivatives 12-15 show high \u3c31 affinity (K i = 0.59-1.4 nM) and high selectivity over the \u3c32 subtype (408-1331-fold). The enantiomers of the fluoroethyl derivative fluspidine 13 were prepared and pharmacologically characterized. Whereas the (S)-configured enantiomer (S)-13 (K i = 2.3 nM) is 4-fold less active than the (R)-enantiomer (R)-13 (K i = 0.57 nM), (S)-13 is metabolically more stable. The interactions of (S)-13 and (R)-13 with the \u3c31 receptor were analyzed at the molecular level using the 3D homology model. In an automated radiosynthesis [18F](S)-13 and [18F](R)-13 were prepared by nucleophilic substitution of the tosylates (S)-17 and (R)-17 with K[18F]F in high radiochemical yield, high radiochemical purity and short reaction time. Application of both enantiomers [18F](S)-13 and [18F](R)-13 to mice and piglets led to fast uptake into the brain, but [18F](R)-13 did not show washout from the brain indicating a quasi-irreversible binding. Both radiotracers [18F](S)-13 and [18F](R)-13 were able to label regions in the mouse and piglet brain with high \u3c31 receptor density. The specific binding of the enantiomeric tracers [18F](S)-13 and [18F](R)-13 could be replaced by the selective \u3c31 ligand SA4503

Pd-Catalyzed Direct C-H Bond Functionalization of Spirocyclic \u3c3(1) Ligands: Generation of a Pharmacophore Model and Analysis of the Reverse Binding Mode by Docking into a 3D Homology Model of the \u3c3(1) Receptor.

To explore the hydrophobic binding region of the \u3c3(1) receptor protein, regioisomeric spirocyclic thiophenes 9-11 were developed as versatile building blocks. Regioselective \u3b1- and \u3b2-arylation using the catalyst systems PdCl(2)/bipy/Ag(2)CO(3) and PdCl(2)/P[OCH(CF(3))(2)](3)/Ag(2)CO(3) allowed the introduction of various aryl moieties at different positions in the last step of the synthesis. The increasing \u3c3(1) affinity in the order 4 < 5/6 < 7/8 indicates that the positions of the additional aryl moiety and the S atom in the spirocyclic thiophene systems control the \u3c3(1) affinity. The main features of the pharmacophore model developed for this class of \u3c3(1) ligands are a positive ionizable group, a H-bond acceptor group, two hydrophobic moieties, and one hydrophobic aromatic group. Docking of the ligands into a \u3c3(1) 3D homology model via molecular mechanics/Poisson-Boltzmann surface area calculations led to a very good correlation between the experimentally determined and estimated free energy of receptor binding. These calculations support the hypothesis of a reverse binding mode of ligands bearing the aryl moiety at the "top" (compounds 2, 3, 7, and 8) and "left" (compounds 4, 5, and 6) positions, respectively

Drinking of mat\ue9 and the risk of cancers of the upper aerodigestive tract in Latin America: A case-control study

Cancers of the upper aerodigestive tract (UADT: oral cavity, oropharynx, hypopharynx, larynx, esophagus) have high incidence rates all over the world and they are especially frequent in some parts of Latin America. In this study, we have evaluated the role of the consumption of mat\ue9, a hot herb-based beverage, based on 1168 UADT squamous-cell carcinoma cases and 1,026 frequency-matched controls enrolled from four centers in Brazil and Argentina. The effect of mat\ue9 drinking on the risk of head-and-neck cancers was borderline significant. A significant effect was observed only for cancer of the esophagus (OR 3.81 (95% CI 1.75-8.30)). While duration of mat\ue9 drinking was associated with the risk of all UADT cancers, the association with cumulative mat\ue9 consumption was restricted to esophageal cancer (p-value of linear trend 0.006). The analyses of temperature at which mat\ue9 was drunk were not conclusive. The increased risk associated with mat\ue9 drinking was more evident in never-smokers and never-alcohol drinkers than in other individuals. Our study strengthens the evidence of an association between mat\ue9 drinking and esophageal cancer; the hypothesis of an association with other UADT cancers remains to be clarified. \ua9 2010 Springer Science+Business Media B.V

The Sigma Enigma:In Vitro/in SilicoSite-Directed Mutagenesis Studies Unveil \u3c31Receptor Ligand Binding

The \u3c31 receptor is an integral membrane protein that shares no homology with other receptor systems, has no unequivocally identified natural ligands, but appears to play critical roles in a wide variety of cell functions. While the number of reports of the possible functions of the \u3c31 receptor is increasing, almost no information about the three-dimensional structure of the receptor and/or possible modes of interaction of the \u3c31 protein with its ligands have been described. Here we performed an in vitro/in silico investigation to analyze the molecular interactions of the \u3c31 receptor with its prototypical agonist (+)-pentazocine. Accordingly, 23 mutant \u3c31 isoforms were generated, and their interactions with (+)-pentazocine were determined experimentally. All direct and/or indirect effects exerted by the mutant residues on the receptor-agonist interactions were reproduced and rationalized in silico, thus shining new light on the three-dimensional structure of the \u3c31 receptor and its ligand binding site

Oral health and risk of squamous cell carcinoma of the head and neck and esophagus: Results of two multicentric case-control studies

Poor oral health has been reported as a risk factor in the etiology of head and neck cancer. Data on oral health were ascertained as part of two multicenter case-control studies comprising 924 cases and 928 controls in central Europe and 2,286 cases and 1,824 controls in Latin America. Incident cases of squamous cell carcinoma of the head and neck (oral cavity, pharynx, larynx) and esophagus, as well as age (in quinquennia)- and sex frequency-matched controls, were enrolled from 1998 to 2003. Poor condition of the mouth (central Europe: odds ratio (OR) = 2.89, 95% confidence interval (CI): 1.74, 4.81; Latin America: OR = 1.89, 95% CI: 1.47, 2.42), lack of toothbrush use (Latin America: OR = 2.36, 95% CI: 1.28, 4.36), and daily mouthwash use (Latin America: OR = 3.40, 95% CI: 1.96, 5.89) emerged as risk factors for head and neck cancer, independent of tobacco use and alcohol consumption. Missing between six and 15 teeth was an independent risk factor for esophageal cancer (central Europe: OR = 2.84, 95% CI: 1.26, 6.41; Latin America: OR = 2.18, 95% CI: 1.04, 4.59). These results indicate that periodontal disease (as indicated by poor condition of the mouth and missing teeth) and daily mouthwash use may be independent causes of cancers of the head, neck, and esophagus. \ua9 The Author 2007. Published by the Johns Hopkins Bloomberg School of Public Health. All rights reserved