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Undifferentiated Nasopharyngeal Carcinoma (UNPC) is associated with Epstein-Barr Virus (EBV) and characterized by an abundant immune infiltrate potentially influencing the prognosis. Thus, we retrospectively assessed the significance of immunosuppression in the UNPC microenvironment as prognostic biomarker of treatment failure in a non-endemic area, and monitored the variation of systemic EBV-specific immunity before and after chemoradiotherapy (CRT). DNA and RNA were extracted from diagnostic biopsies obtained by tumor and adjacent mucosa from 63 consecutive EBV+ UNPC patients who underwent radical CRT. Among these patients 11 relapsed within 2 years. The expression of the EBV-derived UNPC-specific BARF1 gene and several immune-related genes was monitored through quantitative RT-PCR and methylation-specific PCR analyses. Peripheral T cell responses against EBV and BARF1 were measured in 14 patients (7 relapses) through IFN-γ ELISPOT assay. We found significantly higher expression levels of BARF1, CD8, IFN-γ, IDO, PD-L1, and PD-1 in UNPC samples compared to healthy tissues. CD8 expression was significantly reduced in both tumor and healthy tissues in UNPC patients who relapsed within two years. We observed a hypomethylated FOXP3 intron 1 exclusively in relapsed UNPC patients. Finally, we noticed a significant decrease in EBV- and BARF1-specific T-cells after CRT only in relapsing patients. Our data suggest that a high level of immunosuppression (low CD8, hypomethylated FoxP3) in UNPC microenvironment may predict treatment failure and may allow an early identification of patients who could benefit from the addition of immune modulating strategies to improve first line CRT.

Aims Coronary artery calcification (CAC) measured on cardiac computed tomography (CT) is an important risk marker for cardiovascular disease (CVD) and has been included in the prevention guidelines. The aim of this study was to describe CAC score reference values in the middle-aged and elderly population and to develop a freely available CAC calculator. Methods and results All participants from two population-based cardiac CT screening cohorts (DanRisk and DANCAVAS) were included. The CAC score was measured as a part of a screening session. Positive CAC scores were log-transformed and non-parametrically regressed on age for each gender, and percentile curves were transposed according to proportions of zero CAC scores. Men had higher CAC scores than women, and the prevalence and extend of CAC increased steadily with age. An online CAC calculator was developed, http://flscripts.dk/cacscore. After entering sex, age, and CAC score, the CAC score percentile and the coronary age are depicted including a figure with the specific CAC score and 25%, 50%, 75%, and 90% percentiles. The specific CAC score can be compared to the entire background population or only those without prior CVD. Conclusion This study provides modern population-based reference values of CAC scores in men and woman and a freely accessible online CAC calculator. Physicians and patients are very familiar with blood pressure and lipids, but unfamiliar with CAC scores. Using the calculator makes it easy to see if a CAC value is low, moderate, or high, when a physician in the future communicate and discusses a CAC score with a patient.

Computational knee models that replicate the joint motion are important tools to discern difficult-to-measure functional joint biomechanics. Numerous knee kinematic models of different complexity, with either generic or subject-specific anatomy, have been presented and used to predict three-dimensional tibiofemoral (TFJ) and patellofemoral (PFJ) joint kinematics of cadavers or healthy adults, but not pediatric populations. The aims of this study were: (i) to develop subject-specific TFJ and PFJ kinematic models, with TFJ models having either rigid or extensible ligament constraints, for eight healthy pediatric participants and (ii) to validate the estimated joint and ligament kinematics against in vivo kinematics measured from magnetic resonance imaging (MRI) at four TFJ flexion angles. Three different TFJ models were created from MRIs and used to solve the TFJ kinematics: (i) 5-rigid-link parallel mechanism with rigid surface contact and isometric anterior cruciate (ACL), posterior cruciate (PCL) and medial collateral (MCL) ligaments (Δ L null ) , (ii) 6-link parallel mechanism with minimized ACL, PCL, MCL and lateral collateral ligament (LCL) length changes (Δ L min ) and (iii) 6-link parallel mechanism with prescribed ACL, PCL, MCL and LCL length variations (Δ L match ). Each model’s geometrical parameters were optimized using a Multiple Objective Particle Swarm algorithm. When compared to MRI-measured data, Δ L null and Δ L match performed the best, with average root mean square errors below 6.93° and 4.23 mm for TFJ and PFJ angles and displacements, respectively, and below 2.01 mm for ligament lengths ( L null and Δ L match can be used to estimate three-dimensional pediatric TFJ, PFJ and ligament kinematics and can be incorporated into lower-limb models to estimate joint kinematics and kinetics during dynamic tasks.

Accurate representation of bone shape is important for subject-specific musculoskeletal models as it may influence modelling of joint kinematics, kinetics, and muscle dynamics. Statistical shape modelling is a method to estimate bone shape from minimal information, such as anatomical landmarks, and to avoid the time and cost associated with reconstructing bone shapes from comprehensive medical imaging. Statistical shape models (SSM) of lower limb bones have been developed and validated for adult populations but are not applicable to paediatric populations. This study aimed to develop SSM for paediatric lower limb bones and evaluate their reconstruction accuracy using sparse anatomical landmarks.We created three-dimensional models of 56 femurs, 29 pelves, 56 tibias, 56 fibulas, and 56 patellae through segmentation of magnetic resonance images taken from 29 typically developing children (15 females; 13 ± 3.5 years). The SSM for femur, pelvis, tibia, fibula, patella, haunch (i.e., combined femur and pelvis), and shank (i.e., combined tibia and fibula) were generated from manual segmentation of comprehensive magnetic resonance images to describe the shape variance of the cohort. We implemented a leave-one-out cross-validation method wherein SSM were used to reconstruct novel bones (i.e., those not included in SSM generation) using full- (i.e., full segmentation) and sparse- (i.e., anatomical landmarks) input, and then compared these reconstructions against bones segmented from magnetic resonance imaging. Reconstruction performance was evaluated using root mean squared errors (RMSE, mm), Jaccard index (0-1), Dice similarity coefficient (DSC) (0-1), and Hausdorff distance (mm). All results reported in this abstract are mean ± standard deviation.Femurs, pelves, tibias, fibulas, and patellae reconstructed via SSM using full-input had RMSE between 0.89 ± 0.10 mm (patella) and 1.98 ± 0.38 mm (pelvis), Jaccard indices between 0.77 ± 0.03 (pelvis) and 0.90 ± 0.02 (tibia), DSC between 0.87 ± 0.02 (pelvis) and 0.95 ± 0.01 (tibia), and Hausdorff distances between 2.45 ± 0.57 mm (patella) and 9.01 ± 2.36 mm (pelvis). Reconstruction using sparse-input had RMSE ranging from 1.33 ± 0.61 mm (patella) to 3.60 ± 1.05 mm (pelvis), Jaccard indices ranging from 0.59 ± 0.10 (pelvis) to 0.83 ± 0.03 (tibia), DSC ranging from 0.74 ± 0.08 (pelvis) to 0.90 ± 0.02 (tibia), and Hausdorff distances ranging from 3.21 ± 1.19 mm (patella) to 12.85 ± 3.24 mm (pelvis).The SSM of paediatric lower limb bones showed reconstruction accuracy consistent with previously developed SSM and outperformed adult-based SSM when used to reconstruct paediatric bones.

The CDKN1B gene, encoding for the CDK inhibitor p27kip1, is mutated in defined human cancer subtypes, including breast, prostate carcinomas and small intestine neuroendocrine tumors. Lessons learned from small intestine neuroendocrine tumors suggest that CDKN1B mutations could be subclonal, raising the question of whether a deeper sequencing approach could lead to the identification of higher numbers of patients with mutations. Here, we addressed this question and analyzed human cancer biopsies from breast (n = 396), ovarian (n = 110) and head and neck squamous carcinoma (n = 202) patients, using an ultra‐deep sequencing approach. Notwithstanding this effort, the mutation rate of CDKN1B remained substantially aligned with values from the literature, showing that essentially only hormone receptor‐positive breast cancer displayed CDKN1B mutations in a relevant number of cases (3%). However, the analysis of copy number variation showed that another fraction of luminal breast cancer displayed loss (8%) or gain (6%) of the CDKN1B gene, further reinforcing the idea that the function of p27kip1 is important in this type of tumor. Intriguingly, an enrichment for CDKN1B alterations was found in samples from premenopausal luminal breast cancer patients (n = 227, 4%) and in circulating cell‐free DNA from metastatic luminal breast cancer patients (n = 59, 8.5%), suggesting that CDKN1B alterations could correlate with tumor aggressiveness and/or occur later during disease progression. Notably, many of the identified somatic mutations resulted in p27kip1 protein truncation, leading to loss of most of the protein or of its C‐terminal domain. Using a gene‐editing approach in a luminal breast cancer cell line, MCF‐7, we observed that the expression of p27kip1 truncating mutants that lose the C‐terminal domains failed to rescue most of the phenotypes induced by CDKN1B gene knockout, indicating that the functions retained by the C‐terminal portion are critical for its role as an oncosuppressor, at least in luminal breast cancer. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.

With the aim to dissect the effect of adult height on head and neck cancer (HNC), we use the Mendelian randomization (MR) approach to test the association between genetic instruments for height and the risk of HNC. 599 single nucleotide polymorphisms (SNPs) were identified as genetic instruments for height, accounting for 16% of the phenotypic variation. Genetic data concerning HNC cases and controls were obtained from a genome-wide association study. Summary statistics for genetic association were used in complementary MR approaches: the weighted genetic risk score (GRS) and the inverse-variance weighted (IVW). MR-Egger regression was used for sensitivity analysis and pleiotropy evaluation. From the GRS analysis, one standard deviation (SD) higher height (6.9 cm; due to genetic predisposition across 599 SNPs) raised the risk for HNC (Odds ratio (OR), 1.14; 95% Confidence Interval (95%CI), 0.99–1.32). The association analyses with potential confounders revealed that the GRS was associated with tobacco smoking (OR = 0.80, 95% CI (0.69–0.93)). MR-Egger regression did not provide evidence of overall directional pleiotropy. Our study indicates that height is potentially associated with HNC risk. However, the reported risk could be underestimated since, at the genetic level, height emerged to be inversely associated with smoking.

A 25-year-old female with high-grade spindle cell sarcoma of the thyroid persistent after thyroidectomy performed at another hospital was referred to our institute. Chemotherapy followed by surgery with intraoperative radiotherapy and postoperative intensity-modulated radiotherapy were planned within the sarcoma board. Chemotherapy was discontinued after two cycles because of local disease progression and surgery with intraoperative radiotherapy, was anticipated. The treatment was completed with postoperative radiotherapy. After 36 months off-therapy, the patient was free of disease without significant late effects. Thyroid sarcomas are very rare and there is no consensus on their clinical management. Hence, case reports are useful to share treatment options. In this patient case, the histotype and the high-grade disease required a combined therapy program, managed in a multidisciplinary setting.

Schwann cells (SCs) are myelinating cells of the peripheral nervous system. Although SCs are known to express different channels and receptors on their surface, little is known about the activation and function of these proteins. Ionotropic glutamate receptors are thought to play an essential role during development of SC lineage and during peripheral nerve injury and therefore we sought to study their functional properties. We established a novel preparation of living peripheral nerve slices with preserved cellular architecture, and used a patch-clamp technique to study α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic-acid (AMPA)-receptor-mediated currents in SCs for the first time. We found that the majority of SCs in the nerves dissected from embryonic and neonatal mice of both sexes respond to the application of glutamate with inward current mediated by Ca 2+ -permeable AMPA receptors (AMPARs). Using stationary fluctuation analysis we demonstrate that single-channel conductance of AMPARs in SCs is 8-11 pS which is comparable to neurons. We further show that when SCs become myelinating, they downregulate functional AMPARs. This study is the first to demonstrate AMPAR-mediated conductance in SCs of vertebrates, to investigate elementary properties of AMPARs in these cells, and to provide detailed electrophysiological and morphological characterisation of SCs at different stages of development. SIGNIFICANCE STATEMENT We provide several important conceptual and technical advances in the research of the peripheral nervous system (PNS). We pioneer the first description of AMPA receptor mediated currents in the PNS glia of vertebrates and provide new insights into the properties of AMPA receptor channels in peripheral glia, e.g. their Ca 2+ permeability and single-channel conductance. We describe for the first time, the electrophysiological and morphological properties of Schwann cells (SCs) at different stages of development and show that functional AMPA receptors are expressed only in developing but not in mature SCs. Finally, we introduce a preparation of peripheral nerve slices for patch-clamp recordings. This preparation opens new possibilities for studying the physiology of SCs in animal models and in surgical human samples.

To evaluate the impact of time to treatment initiation (TTI) on overall survival in patients with head-and-neck squamous cell carcinoma (HNSCC).In the period 2003-2009, 1616 HNSCC patients were diagnosed in Friuli Venezia Giulia Region, Northeastern Italy, including 462 oral, 346 oropharyngeal, 212 hypopharyngeal, and 596 laryngeal cancers. Clinical information, including date and type of first treatment, and follow-up were retrieved from the regional Cancer Registry and a population-based health database collecting comprehensive health information on people living in the Region. Multivariate hazard ratio (HR) and confidence intervals (CI) were calculated through Cox model.Overall, the median TTI was 28days, (Q1-Q3: 13-45days), but significant variations emerged according to anatomical site, cancer stage, treatment approach, and care transition to specialized centers. Five-year overall survival decreased with increasing treatment delay from 62% for TTI30days to 39% for TTI≥90days (p0.01). HR of death was 1.13 (95% CI: 0.92-1.39) for TTI between 45-89days, and 1.47 (1.05-2.05) for TTI≥90days. The association between TTI and poor prognosis was stronger for laryngeal cancers and early-stage HNSCCs. Further, care transition from community hospitals to specialized centers was associated to a better prognosis (HR=0.73; 95% CI: 0.60-0.88).Our study findings suggest that HNSCC patients treated within 45days from diagnosis have increased survival probabilities and that early-stage patients suffered the most from treatment delay. Furthermore, care transition to specialized centers -though competitive to timely treatment- improves survival by providing the most innovative technologies and treatment approaches.

BACKGROUND: Dietary habits have been related to the risk of nasopharyngeal carcinoma (NPC), but information on a wide range of macro- and micronutrients is still lacking, particularly for low-incidence countries. METHODS: We conducted a hospital-based case-control study in Italy on 198, histologically confirmed, NPC cases of Caucasian ethnicity of 18-76 years of age. Controls were 594 Caucasian cancer-free patients admitted to general hospitals for acute conditions. Nutrients intake was assessed through a validated food-frequency questionnaire. Adjusted odds ratios (ORs) and the corresponding confidence intervals (CIs) were estimated through logistic regression. RESULTS: Dietary intake of carotenoids were inversely related to NPC risk, notably carotene (OR for highest vs lowest quartile=0.46; 95% CI: 0.26-0.79), α-carotene (OR=0.57; 95% CI: 0.33-0.97), and β-carotene (OR=0.42; 95% CI: 0.24-0.75). Increased NPC risk was observed for elevate cholesterol intake (OR=1.85; 95% CI: 1.12-3.05). CONCLUSION: Study findings suggest a protective effect of carotenoids against NPC in a low-risk population, adding further support to a possible beneficial role of a diet rich in fruits and vegetables in cancers of the head and neck.

The long-term results of the EORTC 24954 trial comparing sequential versus alternating chemotherapy and radiotherapy (RT) for patients with locally advanced laryngeal and hypopharyngeal cancer are reported. From 1996 to 2004, 450 patients were randomly assigned (1-1) to a sequential arm (SA = induction cisplatin-5fluorouracil followed by a 70Gy-RT for the responders or a total laryngectomy and post-operative RT for the non-responders) and an alternating arm (AA = cisplatin-5fluorouracil alternated with three 2-week courses of 20 Gy-RT for a total dose of 60 Gy). Median follow-up was 10.2 years. Ten-year survival with functional larynx (primary end-point) and overall survival were similar in both arms (18.7% and 33.6% in SA versus 18.3% and 31.6% in AA). Late toxicity was also similar; however, a trend for higher larynx preservation and better laryngeal function was observed in AA. (C) 2016 Elsevier Ltd. All rights reserved.

Scanty data are available on familial risk in oral and pharyngeal cancer. The relationship between oral and pharyngeal cancer and family history of cancer in first-degree relatives was investigated using data from a multicentric case-control study conducted in Italy and Switzerland between 1992 and 2005 on 956 cases aged less than 79 years, with histologically confirmed incident oral and pharyngeal cancer, and 2362 controls admitted to hospital for acute, nonneoplastic conditions. Logistic regression models conditioned on sex, age, study centre, and including terms for education, tobacco smoking, alcohol drinking, and number of siblings were used to estimate the odds ratios (OR) of oral and pharyngeal cancer. The multivariate ORs were similar for a family history of oral and pharyngeal cancer (2.6, 95% confidence interval, CI, 1.5-4.5) and laryngeal cancer (3.8, 95% CI, 2.0-7.2). The OR was 3.1 (95% CI, 2.0-4.8) for oral and pharyngeal cancer and laryngeal cancer combined. The OR was 7.1 (95% CI, 1.3-37.2) for subjects with 2 or more first-degree relatives with oral and pharyngeal/laryngeal cancers. Significant increases in risk were also observed for a family history of melanoma (OR = 5.8; 95% CI, 1.3-26.4) and lung cancer (OR = 1.4; 95% CI, 1.0-2.0). Compared to subjects without family history, nonsmokers, and non or moderate drinkers, the OR was 42.6 for current smokers, heavy drinkers with family history. History of oral and pharyngeal cancer and laryngeal cancer is a strong determinant of oral and pharyngeal cancer risk, independent from tobacco and alcohol.

Background Inclusion of new biomarkers to improve a personalized treatment approach for oropharyngeal squamous cell carcinoma (OPSCC) is urgently needed. Hypomethylation of the Long interspersed nucleotide element-1 (LINE-1) repetitive elements, a widely accepted surrogate of overall genomic DNA methylation content, was found to be associated with a poor prognosis in several cancers. At present, no studies have investigated the influence of LINE-1 methylation levels on OPSCC relapse. The main goal of this study was the evaluation of the prognostic value of LINE-1 methylation status in predicting early tumor relapse in locally advanced OPSCC. Methods We retrospectively reviewed a cohort of 77 patients with stage III–IVB OPSCC. Methylation of LINE-1 repetitive sequences was evaluated by real-time quantitative methylation-specific PCR in formalin-fixed paraffin-embedded tissues. The prognostic relevance of LINE-1 methylation was assessed by comparing patients who relapsed within 2 years from the end of treatment (cases) with those who did not (controls). Results were validated in an independent cohort of 33 patients with OPSCC. Results With respect to early OPSCC relapse, the mean LINE-1 methylation level was significantly lower in relapsed cases than in control group (p

PURPOSE: The role of dietary habits in the etiology of nasopharyngeal carcinoma (NPC) has been extensively investigated in high-incidence areas, but evidence is scanty in low-incidence populations. This study aimed to investigate the relationship between NPC risk and a wide range of food groups in the Italian population. METHODS: We conducted a hospital-based case-control study in Italy on 198, histologically confirmed, NPC cases of Caucasian ethnicity, aged 18-76 years. Controls were 594 Caucasian cancer-free patients admitted to general hospitals for acute conditions. Odds ratios (ORs) and the corresponding confidence intervals (CIs) were estimated through logistic regression, adjusting for socio-demographic characteristics, tobacco smoking, alcohol drinking, and energy intake. RESULTS: Elevated vegetable consumption was inversely related to NPC risk (OR for highest vs. lower quartile = 0.51; 95 % CI 0.29-0.90). The association was particularly strong for yellow- or red-pigmented vegetables (OR = 0.31; 95 % CI 0.18-0.54), and this effect was stronger among never smokers (OR = 0.18; 95 % CI 0.06-0.55) than among ever smokers (OR = 0.37; 95 % CI 0.19-0.71). Increased NPC risk emerged for elevated eggs consumption (OR = 2.50; 95 % CI 1.44-4.32; p-trend

Nasopharyngeal carcinoma (NPC) is rare in western Countries. Tobacco smoking is a well-recognised risk factor, whereas the role of alcohol drinking is still in debate. We conducted a hospital-based case-control study in Italy on 150, histologically-confirmed, NPC cases of Caucasian ethnicity, aged 18-76 years, including 118 undifferentiated NPCs and 22 differentiated squamous-cell NPC. Controls were 450 Caucasian cancer-free patients admitted to general hospitals for acute conditions. Cases and controls were matched according to sex, age, and place of residence. Logistic regression was used to estimate odds ratios (OR) and the corresponding 95% confidence intervals (CI) while adjusting for known confounders. No significant association emerged between tobacco smoking and all NPCs (OR for current vs. never smokers = 1.52; 95% CI: 0.89-2.60). Conversely, for differentiated NPC only, statistically significant elevated OR were associated with increasing smoking intensity (OR for >= 15 cigarettes/day = 5.40; 95% CI: 1.34-21.76) and duration of the habit (OR for >= 32 years = 4.48; 95% CI: 1.11-18.04). Although alcohol drinking was not, per se, significantly associated to NPC risk, the combination of tobacco smoking and alcohol drinking accounted for 57% of differentiated NPCs, whereas it accounted for only 14% of undifferentiated carcinomas. Our findings suggest that, in western populations, NPC includes two separate entities: the differentiated NPC, associated with tobacco smoking like other cancers of head and neck, and the undifferentiated NPC, upon which tobacco smoking has little or no influence. (C) 2011 Elsevier Ltd. All rights reserved.

Genome-wide association studies (GWAS) have been successful in identifying common genetic variation involved in susceptibility to etiologically complex disease. We conducted a GWAS to identify common genetic variation involved in susceptibility to upper aero-digestive tract (UADT) cancers. Genome-wide genotyping was carried out using the Illumina HumanHap300 beadchips in 2,091 UADT cancer cases and 3,513 controls from two large European multi-centre UADT cancer studies, as well as 4,821 generic controls. The 19 top-ranked variants were investigated further in an additional 6,514 UADT cancer cases and 7,892 controls of European descent from an additional 13 UADT cancer studies participating in the INHANCE consortium. Five common variants presented evidence for significant association in the combined analysis (p≤5×10−7). Two novel variants were identified, a 4q21 variant (rs1494961, p = 1×10−8) located near DNA repair related genes HEL308 and FAM175A (or Abraxas) and a 12q24 variant (rs4767364, p = 2×10−8) located in an extended linkage disequilibrium region that contains multiple genes including the aldehyde dehydrogenase 2 (ALDH2) gene. Three remaining variants are located in the ADH gene cluster and were identified previously in a candidate gene study involving some of these samples. The association between these three variants and UADT cancers was independently replicated in 5,092 UADT cancer cases and 6,794 controls non-overlapping samples presented here (rs1573496-ADH7, p = 5×10−8; rs1229984-ADH1B, p = 7×10−9; and rs698-ADH1C, p = 0.02). These results implicate two variants at 4q21 and 12q24 and further highlight three ADH variants in UADT cancer susceptibility., Author Summary We have used a two-phased study approach to identify common genetic variation involved in susceptibility to upper aero-digestive tract cancer. Using Illumina HumanHap300 beadchips, 2,091 UADT cancer cases and 3,513 controls from two large European multi-centre UADT cancer studies, as well as 4,821 generic controls, were genotyped for a panel 317,000 genetic variants that represent the majority of common genetic in the human genome. The 19 top-ranked variants were then studied in an additional series of 6,514 UADT cancer cases and 7,892 controls of European descent from an additional 13 UADT cancer studies. Five variants were significantly associated with UADT cancer risk after the completion of both stages, including three residing within the alcohol dehydrogenase genes (ADH1B, ADH1C, ADH7) that have been previously described. Two additional variants were found, one near the ALDH2 gene and a second variant located in HEL308, a DNA repair gene. These results implicate two variants 4q21 and 12q24 and further highlight three ADH variants UADT cancer susceptibility.

Delahaye-Sourdeix, Manon Anantharaman, Devasena Timofeeva, Maria N Gaborieau, Valerie Chabrier, Amelie Vallee, Maxime P Lagiou, Pagona Holcatova, Ivana Richiardi, Lorenzo Kjaerheim, Kristina Agudo, Antonio Castellsague, Xavier Macfarlane, Tatiana V Barzan, Luigi Canova, Cristina Thakker, Nalin S Conway, David I Znaor, Ariana Healy, Claire M Ahrens, Wolfgang Zaridze, David Szeszenia-Dabrowska, Neonilia Lissowska, Jolanta Fabianova, Eleonora Mates, Ioan Nicolae Bencko, Vladimir Foretova, Lenka Janout, Vladimir Curado, Maria Paula Koifman, Sergio Menezes, Ana Wunsch-Filho, Victor Eluf-Neto, Jose Boffetta, Paolo Fernandez Garrote, Leticia Polesel, Jerry Lener, Marcin Jaworowska, Ewa Lubinski, Jan Boccia, Stefania Rajkumar, Thangarajan Samant, Tanuja A Mahimkar, Manoj B Matsuo, Keitaro Franceschi, Silvia Byrnes, Graham Brennan, Paul McKay, James D eng 1R03DE020116/DE/NIDCR NIH HHS/ R01CA092039 05/05S1/CA/NCI NIH HHS/ Research Support, N.I.H., Extramural 2015/04/04 06:00 J Natl Cancer Inst. 2015 Apr 2;107(5). pii: djv037. doi: 10.1093/jnci/djv037. Print 2015 May.; International audience; Deleterious BRCA2 genetic variants markedly increase risk of developing breast cancer. A rare truncating BRCA2 genetic variant, rs11571833 (K3326X), has been associated with a 2.5-fold risk of lung squamous cell carcinoma but only a modest 26% increase in breast cancer risk. We analyzed the association between BRCA2 SNP rs11571833 and upper aerodigestive tract (UADT) cancer risk with multivariable unconditional logistic regression adjusted by sex and combinations of study and country for 5942 UADT squamous cell carcinoma case patients and 8086 control patients from nine different studies. All statistical tests were two-sided. rs11571833 was associated with UADT cancers (odds ratio = 2.53, 95% confidence interval = 1.89 to 3.38, P = 3x10(-10)) and was present in European, Latin American, and Indian populations but extremely rare in Japanese populations. The association appeared more apparent in smokers (current or former) compared with never smokers (P het = .026). A robust association between a truncating BRCA2 variant and UADT cancer risk suggests that treatment strategies orientated towards BRCA2 mutations may warrant further investigation in UADT tumors.

PURPOSE: Head and Neck Squamous Cell Carcinomas (HNSCC) cause more than 300,000 deaths worldwide each year. Locoregional and distant recurrences represent worse prognostic events and accepted surrogate markers of patients’ overall survival. No valid biomarker and salvage therapy exist to identify and treat patients at high-risk of recurrence. We aimed to verify if selected microRNAs (miRs) could be used as biomarkers of recurrence in HNSCC. EXPERIMENTAL DESIGN: A Nanostring array was used to identify miRs associated with locoregional recurrence in 44 HNSCC patients. Bioinformatic approaches validated the signature and identified potential miR targets. Validation experiments were performed using an independent cohort of primary HNSCC samples and a panel of HNSCC cell lines. In vivo experiments validated the in vitro results. RESULTS: Our data identified a four-miR signature that classified HNSCC patients at high- or low-risk of recurrence. These miRs collectively impinge on the epithelial-mesenchymal transition process. In silico and wet lab approaches showed that miR-9, expressed at high levels in recurrent HNSCC, targets SASH1 and KRT13, while miR-1, miR-133 and miR-150, expressed at low levels in recurrent HNSCC, collectively target SP1 and TGFβ pathways. A six-genes signature comprising these targets identified patients at high risk of recurrences, as well. Combined pharmacological inhibition of SP1 and TGFβ pathways induced HNSCC cell death and, when timely administered, prevented recurrence formation in a preclinical model of HNSCC recurrence. CONCLUSIONS: By integrating different experimental approaches and competences, we identified critical mediators of recurrence formation in HNSCC that may merit to be considered for future clinical development. TRANSLATIONAL RELEVANCE. Most of HNSCC patients are diagnosed with a locally advanced disease and are treated with the combination of surgery, radiotherapy, and chemotherapy. This highly toxic approach is curative in about half of the cases but recurrent patients do not have effective salvage therapies. Therefore there is the urgency to identify and validate solid biomarkers able to classify patients at high risk that may benefit for specific targeted approaches. Our work tackled these two unmet clinical needs and identified a microRNA signature of locoregional recurrence in HNSCC patients. Starting from this signature, we identified two druggable pathways (i.e. SP1 and TGFβ) that when timely and concomitantly targeted efficiently prevented recurrence formation in a preclinical model. Both SP1 and TGFβ inhibitors have been already used to treat human patients, thus our work is of potential immediate translational relevance.

SUMMARY Sentinel node (SN) biopsy of head and neck cancer is still considered investigational, and agreement on the width of the surgical sampling has not yet been reached. From May 1999 to Dec 2009, 209 consecutive patients entered a prospective study: 61.7% had primary tumour of the oral cavity and 23.9% of the oropharynx. SN was not found in 26 patients. Based on these data and definitive histopathological analysis, we proposed six hypothetic scenarios to understand the percentage of neck recurrences following different treatments Among patients with identified SN, 54 cases were pN+: 47 in SN and 7 in a different node. Considering the six hypothetic scenarios: "only SN removal", "SN level dissection", "neck dissection from the tumour site to SN level", "selective neck dissection of three levels (SND)", "dissection from level I to IV" and "comprehensive I-V dissection", neck recurrences could be expected in 6.5%, 3.8%, 2.18%, 2.73%, 1.09% and 1.09% of cases, respectively. SN biopsy can be considered a useful tool to personalize the surgical approach to a N0 carcinoma. The minimum treatment of the neck is probably dissection of the levels between the primary tumour and the level containing the SN(s). Outside the framework of a clinical study, the best treatment can still be considered SND.

The intake of flavonoids has been inversely related to the risk of various common neoplasms, but scanty data exist on oral and pharyngeal cancer. We used data from a case-control study conducted in Italy between 1992 and 2005 to examine the relationship between flavonoid intake and oral and pharyngeal cancer risk. The study included 805 cases with incident, histologically confirmed oral and pharyngeal cancer, and 2,081 hospital controls admitted for acute, nonneoplastic conditions. We have applied data on food and beverage content of six major classes of flavonoids, on dietary information collected through a validated food-frequency questionnaire. The odds ratios (OR) were calculated using multiple logistic regression models, conditioned on study center, sex, and age. After adjustment for education, tobacco, alcohol, body mass index, and non–alcohol energy intake, ORs for the highest versus the lowest quintile of intake were 0.51 [95% confidence intervals (95% CI), 0.37-0.71] for flavanones, 0.62 (CI, 0.43-0.89) for flavonols, and 0.56 (95% CI, 0.40-0.78) for total flavonoids. No significant association emerged for isoflavones (OR, 0.90), anthocyanidins (OR, 0.86), flavan-3-ols (OR, 0.84), and flavones (OR, 0.75). The ORs were consistent across strata of age, sex, education, body mass index, tobacco, and alcohol. After allowance for vegetable and fruit consumption, the inverse relations with total flavonoids and flavanones remained significant, whereas that with flavonols became nonsignificant. None of the associations were significant after further allowance for vitamin C, probably on account of the high collinearity between these compounds. (Cancer Epidemiol Biomarkers Prev 2007;16(8):1621–5)

The incidence of cancers of the upper aerodigestive tract (UADT) is increasing throughout the world. To date the increases have been proportionally greatest among young people. Several reports have suggested that they often do not have a history of tobacco smoking or heavy alcohol consumption. Objectives were to determine the contribution of lifestyle factors to the etiology of UADT cancers occurring in those aged less than 50 years. A case-control study was conducted in 10 European countries. Cases were cancers of the oral cavity and pharynx, larynx and esophagus, and hospital or population controls were age and sex matched. RESULTS: There were 356 cases younger than 50 years and 419 controls. Risk was strongly related to current smoking [odds ratio (OR) 5.5 95% ; confidence interval (CI) (3.3, 9.2)], and risk increased with number of pack-years smoked. Risk was also related to alcohol consumption for both current (OR 1.8 ; 0.97, 3.3) and past (OR 3.4 ; 1.6, 7.4) drinkers, and risk increased with number of drink-years. Persons frequently consuming fruits and vegetables were at significantly reduced risk. Risk factors already identified as being important for UADT cancers in adults are also important influences on risk in younger adults. The implication of these results is that the public health message in preventing UADT cancers remains the same to young and old alike.

Aims and background Each year in Italy there are approximately 14,000 new cases and 7,000 deaths from cancer of the upper aerodigestive tract, which includes malignant tumors originating from the oral cavity, pharynx, larynx and esophagus. Established etiological factors include tobacco consumption and heavy alcohol drinking. The study of single nucleotide polymorphisms in upper aerodigestive tract cancer etiology may help to identify high-risk subgroups and to better understand the pathways leading to the development of these cancers. Methods Italian results on about 500 cases and 500 controls from a large case-control study (ARCAGE) conducted in 10 European countries are presented with the major objectives of updating results on the effects of alcohol and tobacco consumptions in northern Italy, investigating the role of genetic variation with regard to the metabolism of alcohol and carcinogens from tobacco smoke, and evaluating possible interactions of these single nucleotide polymorphisms with these carcinogens. Results The present study confirmed the importance of tobacco smoking and alcohol drinking as the main risk factors for upper aerodigestive tract cancers, indicating that about 68% of cancers among populations in northern Italy can be attributed to the combination of these risk factors. Significant associations between metabolizing phase I genes (CYP1A1 and CYP2A6), phase II genes (GSTA2) and upper aerodigestive tract cancers were found. A polymorphism of ADH1C has been associated with an increased risk of upper aerodigestive tract cancers, suggesting that the less rapid alcohol metabolizers are more susceptible to upper aerodigestive tract cancer risk. Conclusions Our results suggest that the ADH1C allele modifies the carcinogenic dose response for alcohol in the upper aerodigestive tract, giving rise to a gene-environment interaction. The role of genes as possible modifiers of life-style risks seems the most reliable.

BACKGROUND: The role of low doses of cisplatin and concomitant postoperative radiotherapy in high risk head and neck squamous cell carcinoma has not yet been defined. METHODS: Patients treated with definitive surgery, who had histological evidence of involvement of more than 2 lymph nodes, extracapsular extension of disease, perineural and/or intravascular invasion, involved or close surgical margins, received postoperative radiotherapy plus 75 mg/m2 of cisplatin every 3 weeks during the radiotherapy cycle. The primary endpoints were to evaluate treatment compliance and overall, cause-specific, and disease-free survival. RESULTS: A total of 142 patients were enrolled. With a median follow-up of 40 months, 5-year overall survival was 68%, cause-specific survival 78% and disease-free survival 82%. At multivariate analysis surgical margins status and extracapsular lymph node invasion were the only statistically significant prognostic factors. Fifty-three percent of the patients developed severe mucositis and 14% hematologic toxicity of grade 3. The 3 planned concomitant chemotherapy cycles were delivered to 48% of the patients. CONCLUSIONS: Postoperative radiotherapy and concomitant low-dose cisplatin was an effective treatment in high risk head and neck patients. The total toxicity observed was lower compared with that reported with higher doses of cisplatin, although the delivery of all the 3 planned chemotherapy cycles was challenging. The distant failure rate was high, which was an unsatisfactory result. Cancer 2009. © 2009 American Cancer Society.

Cancers of the upper aerodigestive tract (UADT) include those of the oral cavity, pharynx (other than nasopharynx), larynx, and esophagus. Tobacco smoking and consumption of alcoholic beverages are established causes of UADT cancers, whereas reduced intake of vegetables and fruits are likely causes. The role of genetic predisposition and possible interactions of genetic with exogenous factors, however, have not been adequately studied. Moreover, the role of pattern of smoking and drinking, as well as the exact nature of the implicated dietary variables, has not been clarified. To address these issues, the International Agency for Research on Cancer initiated in 2002 the alcohol-related cancers and genetic susceptibility (ARCAGE) in Europe project, with the participation of 15 centers in 11 European countries. Information and biological data from a total of 2304 cases and 2227 controls have been collected and will be used in a series of analyses. A total of 166 single nucleotide polymorphisms of 76 genes are being studied for genetic associations with UADT cancers. We report here the methodology of the ARCAGE project, main demographic and lifestyle characteristics of the cases and controls, as well as the distribution of cases by histology and subsite. About 80% of cases were males and fewer than 20% of all cases occurred before the age of 50 years. Overall, the most common subsite was larynx, followed by oral cavity, oropharynx, esophagus and hypopharynx. Close to 90% of UADT cancers were squamous cell carcinomas. A clear preponderance of smokers and alcohol drinkers among UADT cases compared with controls was observed.

Purpose The aim of the study was to compare the efficacy of parecoxib for postoperative analgesia after endoscopic turbinate and sinus surgery with the prodrug of acetaminophen, proparacetamol. Materials and Methods Fifty American Society of Anesthesiology (ASA) physical status I-II patients, receiving functional endoscopic sinus surgery (FESS) and endoscopic turbinectomy, were investigated in a prospective, randomized, double-blind manner. After local infiltration with 1% mepivacaine, patients were randomly allocated to receive intravenous (IV) administration of either 40 mg of parecoxib (n = 25) or 2 g of proparacetamol (n = 25) 15 min before discontinuation of total IV anaesthesia with propofol and remifentanil. A blinded observer recorded the incidence and severity of pain at admission to the post anaesthesia care unit (PACU) at 10, 20, and 30 min after PACU admission, and every 1 h thereafter for the first 6 postoperative h. Results The area under the curve of VAS (AUCVAS) calculated during the study period was 669 (28 - 1901) cm·min in the proparacetamol group and 635 (26 - 1413) cm·min in the parecoxib group (p = 0.34). Rescue morphine analgesia was required by 14 patients (56%) in the proparacetamol group and 12 patients (48%) in the parecoxib (p ≥ 0.05), while mean morphine consumption was 5 - 3.5 mg and 5 - 2.0 mg in the proparacetamol groups and parecoxib, respectively (p ≥ 0.05). No differences in the incidence of side effects were recorded between the 2 groups. Patient satisfaction was similarly high in both groups, and all patients were uneventfully discharged 24 h after surgery. Conclusion In patients undergoing endoscopic nasal surgery, prior infiltration with local anaesthetics, parecoxib administered before discontinuing general anaesthetic, is not superior to proparacetamol in treating early postoperative pain.

Although previous studies on tobacco and alcohol and the risk of upper-aerodigestive-tract (UADT) cancers have clearly shown dose-response relations with the frequency and duration of tobacco and alcohol, studies on addiction to tobacco smoking itself as a risk factor for UADT cancer have not been published, to our knowledge. The aim of this report is to assess whether smoking addiction is an independent risk factor or a refinement to smoking variables (intensity and duration) for UADT squamous cell carcinoma (SCC) risk in the multicenter case-control study (ARCAGE) in Western Europe. The analyses included 1,586 ever smoking UADT SCC cases and 1,260 ever smoking controls. Addiction was measured by a modified Fagerström score (first cigarette after waking up, difficulty refraining from smoking in places where it is forbidden and cigarettes per day). Adjusted odds ratios (ORs) and 95% confidence intervals (95% CIs) for UADT cancers with addiction variables were estimated with unconditional logistic regression. Among current smokers, the participants who smoked their first cigarette within 5 min of waking up were two times more likely to develop UADT SCC than those who smoked 60 min after waking up. Greater tobacco smoking addiction was associated with an increased risk of UADT SCC among current smokers (OR = 3.83, 95% CI: 2.56-5.73 for score of 3-7 vs. 0) but not among former smokers. These results may be consistent with a residual effect of smoking that was not captured by the questionnaire responses (smoking intensity and smoking duration) alone, suggesting addiction a refinement to smoking variables. What's new? Previous studies have clearly shown dose-response relationships between tobacco/alcohol use and the risk of upper-aerodigestive- tract (UADT) cancers, but these studies have focused only on the variables of frequency and duration of use. In this study, the authors asked whether addiction to smoking might be an independent risk factor. They found that addiction was indeed associated with UADT cancer risk among current smokers. This addiction-cancer association suggests that it is important to include questions that elicit information regarding smoking addiction when accounting for smoking effect through questionnaire information. Copyright © 2013 UICC.

The general relationship between cancers of the upper aerodigestive tract (UADT) and alcohol drinking is established. Nevertheless, it is uncertain whether different types of alcoholic beverages (wine, beer and liquor) carry different UADT cancer risks. Our study included 2,001 UADT cancer cases and 2,125 controls from 14 centres in 10 European countries. All cases were histologically or cytologically confirmed squamous cell carcinomas. Controls were frequency matched by sex, age and centre. Logistic regression models were used to estimate odds ratios (OR) and 95 % confidence intervals (95 %CI) adjusted for age, sex, centre, education level, vegetable and fruit intake, tobacco smoking and alcohol drinking, where appropriate. Risk of beverage-specific alcohol consumption were calculated among 'pure drinker' who consumed one beverage type exclusively, among 'predominant drinkers' who consumed one beverage type to more than 66 % and among 'mixed drinkers' who consumed more than one beverage type to similar proportions. Compared to never drinkers and adjusted for cumulative alcohol consumption, the OR and 95 %CI for wine, beer and liquor drinking, respectively, were 1.24 (0.86, 1.78), 1.54 (1.05, 2.27) and 0.94 (0.53, 1.64) among 'pure drinkers' (p value for heterogeneity across beverage types = 0.306), 1.05 (0.76,1.47), 1.25 (0.87,1.79) and 1.43 (0.95, 2.16) among 'predominant drinkers' (p value = 0.456), and 1.09 (0.79, 1.50), 1.20 (0.88, 1.63) and 1.12 (0.82, 1.53) among 'mixed drinkers' (p value = 0.889). Risk of UADT cancer increased with increasing consumption of all three alcohol beverage types. Our findings underscore the strong and comparable carcinogenic effect of ethanol in wine, beer and liquor on organs of the UADT. © Springer Science+Business Media B.V. 2012.

Background: Sequence variants located at 15q25 have been associated with lung cancer and propensity to smoke. We recently reported an association between rs16969968 and risk of upper aerodigestive tract (UADT) cancers (oral cavity, oropharynx, hypopharynx, larynx, and esophagus) in women (OR = 1.24, P = 0.003) with little effect in men (OR = 1.04, P = 0.35). Methods: In a coordinated genotyping study within the International Head and Neck Cancer Epidemiology (INHANCE) consortium, we have sought to replicate these findings in an additional 4,604 cases and 6,239 controls from 10 independent UADT cancer case–control studies. Results: rs16969968 was again associated with UADT cancers in women (OR = 1.21, 95% CI = 1.08–1.36, P = 0.001) and a similar lack of observed effect in men [OR = 1.02, 95% CI = 0.95–1.09, P = 0.66; P-heterogeneity (Phet) = 0.01]. In a pooled analysis of the original and current studies, totaling 8,572 UADT cancer cases and 11,558 controls, the association was observed among females (OR = 1.22, 95% CI = 1.12–1.34, P = 7 × 10−6) but not males (OR = 1.02, 95% CI = 0.97–1.08, P = 0.35; Phet = 6 × 10−4). There was little evidence for a sex difference in the association between this variant and cigarettes smoked per day, with male and female rs16969968 variant carriers smoking approximately the same amount more in the 11,991 ever smokers in the pooled analysis of the 14 studies (Phet = 0.86). Conclusions: This study has confirmed a sex difference in the association between the 15q25 variant rs16969968 and UADT cancers. Impact: Further research is warranted to elucidate the mechanisms underlying these observations. Cancer Epidemiol Biomarkers Prev; 20(4); 658–64. ©2011 AACR.

An efficent antitumor and antiviral cellular immune response requires optimal interferon-gamma (IFN-gamma) secretion and perforin expression in CD8(+) T cells. The aim of this study was to define whether CD4(+) and CD8(+) T cells from patients with undifferentiated carcinoma of nasopharyngeal type (UCNT), a tumor regularly associated with the Epstein-Barr virus (EBV), have abnormal phenotype profiles, cytokine production, perforin and CD3-zeta expressions. Our data showed that CD4 and CD8 subset distribution was not grossly altered in the peripheral blood of UCNT patients, while tumor biopsies contained an increased proportion of CD8(+) T cells. The analysis of the CD4(+) subset showed a defect in interleukin-2 (IL-2) production and a moderate increase of IL-10 production, a situation consistent with a Th1/Th2 imbalance. We have also demonstrated that CD8(+) lymphocytes from UCNT patients had a marked impairment of IFN-gamma secretion and perforin expression. This impairment was not related to the presence of detectable EBV DNA in the plasma. In UCNT patients, the blockade of the perforin pathway and of IFN-gamma production may constitute important mechanisms for immune escape by the tumor and for impaired control of EBV replication.

Background: Genetic variants in 15q25 have been identified as potential risk markers for lung cancer (LC), but controversy exists as to whether this is a direct association, or whether the 15q variant is simply a proxy for increased exposure to tobacco carcinogens. Methods: We performed a detailed analysis of one 15q single nucleotide polymorphism (SNP) (rs16969968) with smoking behaviour and cancer risk in a total of 17 300 subjects from five LC studies and four upper aerodigestive tract (UADT) cancer studies. Results: Subjects with one minor allele smoked on average 0.3 cigarettes per day (CPD) more, whereas subjects with the homozygous minor AA genotype smoked on average 1.2 CPD more than subjects with a GG genotype (P20 CPD) [odds ratio (OR)=1.13, 95% confidence interval (CI) 0.96-1.34, P=0.13 for heterozygotes and 1.81, 95% CI 1.39-2.35 for homozygotes, P

BACKGROUND During the last 20 years, survival rates of head and neck carcinoma patients in the United States and Europe have plateaued. To determine the factors that can reduce mortality rates, we examined changes in clinical presentation and survival rates across 24 years of treatment of head and neck carcinoma patients. METHODS A retrospective study of patients with head and neck carcinoma was conducted from January 1, 1975, to December 31, 1998. We identified 2143 eligible patients with squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx, and larynx. Changes in gender, clinical stage, and therapy were evaluated separately for each site of cancer across five consecutive periods. Probability of dying and overall survival rates were estimated. Odds ratios (ORs) and hazard ratios were calculated. RESULTS An increase in T1 versus T2 or higher stage carcinoma was more probable for the oral cavity and larynx (OR = 4.1 and 3.0, respectively) in the last versus the earliest period. An increase in radical treatments was more probable for carcinomas of the oral cavity, oropharynx, hypopharynx, and larynx (10.2, 34.8, 12.5, and 2.1-fold, respectively) in the last versus the earliest period. A decreasing trend of probability of dying from the first head and neck carcinoma during the 1970s versus the 1990s was found. The overall survival rates at 5 years was 32% in 1975–1978 versus 51% in 1989–1993. CONCLUSIONS In contrast with survival rates in the United States and Europe, our findings show a significant increase in overall survival rates during the last 20 years. This increase is attributable to changes in diagnostic-therapeutic approaches and to early consultation with a physician for symptoms arising in the head and neck region. Cancer 2002;95:540–52. © 2002 American Cancer Society. DOI 10.1002/cncr.10682

The aim of this study is to assess the impact of prognostic factors in patients with locoregionally advanced nasopharyngeal cancer (NPC), WHO type II-III, treated with two different radiation therapy (RT) schedules: standard radiation therapy (SRT), and accelerated hyperfractionated radiation therapy (HART), with or without sequential chemotherapy. Between January 1986 and December 1999, 78 consecutive NPC patients were treated either with SRT (until August 1993) or with HART (from September 1993). Of the 78 patients, 60 were males and 18 females, the median age was 56 years (range 14-83). Nine patients had a non-keratinizing carcinoma (WHO type II) and 69 an undifferentiated carcinoma (WHO type III). Five-year overall survival rate (OS) was 62%. Two months after RT, 73 patients were in complete remission. Disease-free survival (DFS) rates at 5 years were: 85% for the HART and 59% for the SRT group, respectively. A multivariate analysis, age (hazard ratio, HR=4.17 for > or = 60 vs.

The aim of this study was to evaluate the oncologic outcomes after a selective neck dissection (SND), both in elective and therapeutic settings, with particular regard to regional recurrence rate.Retrospective analysis of 827 patients with head and neck primary tumors submitted to SND from 1999 to 2011 in two large hospital centers of northern Italy.A total of 40 neck recurrences were found in the whole series, with the same incidence after primary or salvage surgery (4.4% and 5.2%, respectively), but only 22 neck recurrences occurred in the same side of the dissected neck (3.0%). Factors predicting an increase of ipsilateral neck relapse were pathologically positive nodes, number of positive nodes, and nodal ratio (ratio between positive nodes and total nodal removed), but the risk of regional relapse did not exceed 5.0% in any subgroups. A total of 320 patients (39%) had postoperative radiotherapy (52.0% and 22.0% after primary and salvage surgery, respectively). Considering the primary surgery group alone, postoperative radiotherapy produced only a light reduction of homolateral neck recurrence rate in patients with pathological positive nodes (2.4% vs. 5.0%), but it impacted significantly disease-specific survival, both in pathological classification of nodes (pN)1 and pN2-3 patients.The SND can be considered a safe and sound procedure both in primary surgery and in salvage setting. Postoperative radiotherapy adds minor advantage to regional control only in node-positive patients but may impact survival.4.

The protective effect of inhaled anticholinergic drugs in the methacholine-induced bronchospasm is well-known. The objective of this study was to assess if any possible differences may be found among Ipratropium (IB), Oxitropium (OXI) and Tiotropium (TIO) pre-treatments to obtain the protective effect. Forty-four patients with intermittent bronchial asthma and PD(20)FEV(1)200 microg were selected (24 M, 20 F; mean age 32 +/- 8.8). On the baseline, they had mean FEV(1)%: 98.8 +/- 8.54 of theoretical and mean PD(15)FEV(1) 111.8 +/- 61.04 microg. After 72 hours, all patients underwent a second methacholine challenge and were given Ipratropium (40 microg by MDI in 14 pts) or Oxitropium (200 microg by MDI in 14 pts) or Tiotropium (18 microg by Handihaler in 16 pts) sixty minutes before the test. Sixty minutes after the bronchodilator inhalation, the FEV(1)% increase was higher (p0.05) in OXI (6.7 +/- 4.83%) and TIO groups (6.11 +/- 2.54%) than in the IB group (3.8 +/- 1.96%). In the IB group PD(15)FEV(1) and PD(20)FEV(1) were obtained in all patients, while in the OXI group they were obtained in 12 and 5 pts respectively and in the TIO group in 14 and 5 pts respectively. Normal hyperreactivity was obtained in 2 patients, in both OXI and TIO groups. In OXI and TIO, the PD(15) obtained after drug pre-medication, was similar (respectively 1628 +/- 955.7 and 1595.5 +/- 990 microg), but higher (p0.0001) in comparison to the PD(15) measured in the IB group (532.2 +/- 434.8 microg). Also, the dose-response slope (decline percentage of FEV(1)/cumulative methacholine dose) after PD(15) was similar in both OXI and TIO groups but different in the IB group. A significant relationship (p0.01) was found between PD(15)FEV(1) (obtained in 40 pts) and the increase in FEV(1)% obtained 60 minutes after bronchodilator inhalations (r = 0.53). In conclusion, with a standard dose, both Oxitropium and Tiotropium seem to have the same protective effect in bronchial asthma but higher than Ipratropium. It's probable that the best dose of Ipratropium should be a higher one than the usual dose taken.

Alcohol is an important risk factor for upper aerodigestive cancers and is principally metabolized by alcohol dehydrogenase (ADH) enzymes. We have investigated six ADH genetic variants in over 3,800 aerodigestive cancer cases and 5,200 controls from three individual studies. Gene variants rs1229984 (ADH1B) and rs1573496 (ADH7) were significantly protective against aerodigestive cancer in each individual study and overall (P = 10-10 and 10 -9, respectively). These effects became more apparent with increasing alcohol consumption (P for trend = 0.0002 and 0.065, respectively). Both gene effects were independent of each other, implying that multiple ADH genes may be involved in upper aerodigestive cancer etiology. © 2008 Nature Publishing Group.

Purpose: Cytokines such as IL-10 and IL-18 seem to be involved in the inflammatory response of undifferentiated carcinoma of nasopharyngeal type (UCNT). The aim of this study was to evaluate the correlation between functional single nucleotide polymorphisms (SNPs) in the promoter region of IL-10 and IL-18 genes and the virological and clinical characteristics in a large case series of Caucasian patients suffering from UCNT, a tumor regularly associated with the Epstein Barr Virus (EBV). Methods: Eighty-nine patients with histologically confirmed UCNT and 130 healthy donors were included in our study. DNA was examined for the polymorphisms of IL-10 gene at positions –1082, −819, −592 by direct sequencing and IL-18 gene at position −607 and −137 by allele –specific PCR. EBV DNA serum viremia was evaluated by QC-PCR. Results: The distributions of the IL-10 and IL-18 genetic variants were not different between UCNT patients and healthy controls. The frequency of IL-10 –1082G allele, which is associated with high IL-10 expression, showed a nearly statistically significant increase in UCNT patients EBV DNA-negative as compared to healthy controls (OR=3.3 95% CI: 1.2–9.8). Subjects with C/C or C/G combined IL-18 genotypes showed an increased risk of being with Stages III-IV (OR=2.1 95% CI: 1.2–6.6). Conclusion: This study was performed to improve the definition of the pathogenetic factors implicated in UCNT by addressing the correlation between cytokine polymorphisms and clinical parameters. This is the first study investigating the possible role of the IL-18 and IL-10 polymorphisms in the development and outcome of UCNT. In our genetic analysis there is no evidence for involvement of IL-10 promoter polymorphisms alone in the genetic predisposition to this tumor. On the other hand, IL18 genetic variants may represent a genetic risk factor for tumor aggressiveness.

Patients affected by squamous cell carcinoma of the head and neck (HNSCC) show frequent occurrence of multiple cancers and widespread precancerous lesions in the mucosa of the upper respiratory tract, a phenomenon known as field cancerization. In this study, we investigated the role of genetic instability in the development of HNSCC and in particular in tumour multiplicity phenomena of the upper respiratory tract. For this purpose, we analysed microsatellite instability (MI) and loss of heterozygosity (LOH) at 20 loci mapping on five chromosomal arms in 67 HNSCC patients, 45 of whom had a single cancer and 22 had multiple primary tumours. The possible involvement of the hMLH1 gene in genetic instability and as a potential target of 3p21 deletion phenomena in head and neck cancers was also investigated. Our data indicate that mismatch repair-related genetic instability plays a minor role in the carcinogenesis of HNSCC and in tumour multiplicity of the head and neck region. Moreover, our results exclude a role for the hMLH1 gene as a determinant of MI and as a specific gene target of deletion at 3p21 in HNSCC. We conclude that presumably other genetic mechanisms, such as those hypothesized for MI-negative hereditary non-polyposis colorectal cancer patients, may play a major role in the carcinogenesis of the mucosa of the upper respiratory tract. Images Figure 1 Figure 2

For the first time, we present data on species composition and distributions of nemacheilid loaches in the Choman River basin of Kurdistan province, Iran. Two genera and four species are recorded from the area, of which three species are new for science: Oxynoemacheilus kurdistanicus, O. zagrosensis, O. chomanicus spp. nov., and Turcinoemacheilus kosswigi Băn. et Nalb. Detailed and illustrated morphological descriptions and univariate and multivariate analysis of morphometric and meristic features are for each of these species. Forty morphometric and eleven meristic characters were used in multivariate analysis to select characters that could discriminate between the four loach species. Discriminant Function Analysis revealed that sixteen morphometric measures and five meristic characters have the most variability between the loach species. The dendrograms based on cluster analysis of Mahalanobis distances of morphometrics and a combination of both characters confirmed two distinct groups: Oxynoemacheilus spp. and T. kosswigi. Within Oxynoemacheilus, O. zagrosensis and O. chomanicus are more similar to one other rather to either is to O. kurdistanicus.

The importance of early therapy intensification in B-cell CLL (B-CLL) patients remains to be defined. Even though several studies have been published, no randomized trials comparing directly autologous stem cell transplant (ASCT) and the accepted conventional therapy (that is, rituximab, fludarabine and CY; R-FC) have been reported so far. To assess the benefit of a first-line aggressive therapy, we designed a multicenter, randomized, phase 3 trial comparing R-FC and high-dose chemotherapy supported by ASCT in patients under 65 years of age, with stage B(II) or C B-CLL. Primary end point was CR: 96 patients were enrolled (48 in each arm). On an intent-to-treat basis, the CR rates in the ASCT and R-FC arms were 62.5% and 58%, respectively. After 5 years of follow-up, PFS was 60.4% in the ASCT arm and 65.1% in the R-FC arm, time to progression 65.8 and 70.5%, and overall survival 88% vs 88.1%, respectively. Our trial demonstrates, for the first time in a randomized manner, that frontline ASCT does not translate into a survival advantage when compared with benchmark chemoimmunotherapy in B-CLL patients; the possibility of its clinical benefit in certain subgroups remains uncertain.

Objective: To provide information on the effects of alcohol and tobacco on laryngeal cancer and its subsites. Methods: This was a case-control study conducted between 1992 and 2000 in northern Italy and Switzerland. A total of 527 cases of incident squamous-cell carcinoma of the larynx and 1297 hospital controls frequency-matched with cases on age, sex, and area of residence were included. Odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were estimated using multiple logistic regression. Results: In comparison with never smokers, ORs were 19.8 for current smokers and 7.0 for ex-smokers. The risk increased in relation to the number of cigarettes (OR = 42.9 for greater than or equal to25 cigarettes/day) and for duration of smoking (OR = 37.2 for greater than or equal to40 years). For alcohol, the risk increased in relation to number of drinks (OR = 5.9 for greater than or equal to56 drinks per week). Combined alcohol and tobacco consumption showed a multiplicative (OR = 177) rather than an additive risk. For current smokers and current drinkers the risk was higher for supraglottis (ORs 54.9 and 2.6, respectively) than for glottis (ORs 7.4 and 1.8) and others subsites (ORs 10.9 and 1.9). Conclusions: Our study shows that both cigarette smoking and alcohol drinking are independent risk factors for laryngeal cancer. Heavy consumption of alcohol and cigarettes determined a multiplicative risk increase, possibly suggesting biological synergy.

To elucidate the relationship, if any, of p53 gene expression according to smoking and drinking habits, 135 subjects with cancer of the upper aero-digestive tract were sampled from a case-control investigation conducted in Pordenone province, Northeast Italy, between 1986 and 1991. Adequate pathological material for immunohistochemical analysis was available for 83 subjects. Level of p53 expression was classified according to intensity on immunoreaction and percentage of p53-positive cells. Mutations were analyzed by means of single-strand conformation polymorphism and sequencing in 8 p53-positive life-long non-smokers exposed to various levels of alcohol intake. The association between p53 expression and smoking status and alcohol intake was evaluated by means of odds ratios, and 95% confidence intervals. Significantly, more men (39/65) than women (6/18) had elevated p53 expression. No significant trend of increasing percentage of p53-positive cancers with increasing smoking and drinking level was detected, especially after allowance for gender. With respect to specific mutation pattern, in 8 life-long non smokers who drank alcohol, 6 mutations involved G:C base pairs. G-to-A transitions were identified in 4 cases. The present study does not support an association between elevated p53 expression and tobacco smoking or alcohol intake. It provides an example of a molecular biology study in the framework of a large epidemiological investigation.

Genome-wide association studies (GWAS) identified several genetic risk factors for breast cancer, however, most of them were validated among women of European ancestry. This study examined single-nucleotide polymorphisms (SNPs) contributing to breast cancer in Chinese (984 cases and 2206 controls) and German (311 cases and 960 controls) populations. Eighteen SNPs significantly associated with breast cancer, previously identified in GWAS were genotyped. Twelve SNPs passed quality control and were subjected to statistical analysis. Seven SNPs were confirmed to be significantly associated with breast cancer in the Chinese population, reflecting three independent loci (ESR1, FGFR2, TOX3) and five of these were also confirmed in the German population. The strongest association was identified for rs2046210 in the Chinese (odds ratio (OR)=1.42, 95% confidence interval (CI)=1.28-1.59, P=1.9 × 10(-10)) and rs3803662 in the German population (OR=1.43, 95% CI=1.17-1.74, P=4.01 × 10(-4)), located upstream of the ESR1 and TOX3 gene, respectively. For the first time, rs3757318 at 6q25.1, located next to the gene encoding estrogen receptor α (ESR1) was found to be strongly associated with breast cancer (OR=1.33, 95% CI=1.18-1.49, P=1.94 × 10(-6)) in the Chinese population. The frequency of this variant was markedly lower in the German population and the association was not significant. Despite the genetic differences, essentially the same risk loci were identified in the Chinese and the German populations. Our study suggested the existence of common genetic factors as well as disease susceptibility differences for breast cancer in both populations and highlighted the importance of performing comparison analyses for disease susceptibility within ethnic populations.

BackgroundThe role of sentinel node biopsy in head and neck cancer is currently being explored. Patients with positive sentinel nodes were investigated to establish if additional metastases were present in the neck, their distribution, and their impact on outcome.MethodsIn all, 109 patients (n = 109) from 15 European centers, with cT1/2,N0 tumors, and a positive sentinel lymph node were identified. Kaplan-Meier and univariate and multivariate logistic regression analysis were used to identify variables that predicted for additional positive nodes and their position within the neck.ResultsA total of 122 neck dissections were performed in 109 patients. Additional positive nodes were found in 34.4% of cases (42/122: 18 same, 21 adjacent, and 3 nonadjacent neck level). Additional nodes, especially if outside the sentinel node basin, had an impact on outcome.ConclusionsThe results are preliminary but suggest that both the number and the position of positive sentinel nodes may identify different prognostic groups that may allow further tailoring of management plans.

We investigated the association between occupational history and upper aerodigestive tract (UADT) cancer risk in the ARCAGE European case-control study. The study included 1,851 patients with incident cancer of the oral cavity, oropharynx, hypopharynx, larynx or esophagus and 1,949 controls. We estimated odds ratios (OR) and 95% confidence intervals (CI) for ever employment in 283 occupations and 172 industries, adjusting for smoking and alcohol. Men (1,457 cases) and women (394 cases) were analyzed separately and we incorporated a semi-Bayes adjustment approach for multiple comparisons. Among men, we found increased risks for occupational categories previously reported to be associated with at least one type of UADT cancer, including painters (OR = 1.74, 95% CI: 1.01-3.00), bricklayers (1.58, 1.05-2.37), workers employed in the erection of roofs and frames (2.62, 1.08-6.36), reinforced concreters (3.46, 1.11-10.8), dockers (2.91, 1.05-8.05) and workers employed in the construction of roads (3.03, 1.23-7.46), general construction of buildings (1.44, 1.12-1.85) and cargo handling (2.60, 1.17-5.75). With the exception of the first three categories, risks both increased when restricting to long duration of employment and remained elevated after semi-Bayes adjustment. Increased risks were also found for loggers (3.56, 1.20-10.5) and cattle and dairy farming (3.60, 1.15-11.2). Among women, there was no clear evidence of increased risks of UADT cancer in association with occupations or industrial activities. This study provides evidence of an association between some occupational categories and UADT cancer risk among men. The most consistent findings, also supported by previous studies, were obtained for specific workers employed in the construction industry.

Summary Background Small cell carcinoma (SCC) is a distinct pathologic entity that may also occur in extrapulmonary sites. In this report the retrospective results of multimodal therapy of primitive extrapulmonary (E) SCC, in a single institution series, are presented. Methods Twenty-four patients (pts) with ESCC were referred to the Centro di Riferimento Oncologico, Aviano, Italy, from 1986 to 1992. Clinico-therapeutic findings were evaluated in 20 pts. Their ages ranged from 20 to 87, with a median of 60.5 years. Primary tumor sites were urinary bladder (5 pts), prostate (4 pts), larynx (3 pts), kidney (2 pts), ovary, skin, oropharynx, trachea, uterine cervix, ethmoid, and stomach (1 pt each); lymph node metastases of unknown origin were observed in 3 pts. More than 50% of pts presented extensive disease. Results Histologically, 16 cases were pure ESCCs and 8 cases were combined, 4 of them with adenocarcinoma, 2 with transitional cell carcinoma, and 2 with squamous cell carcinoma. Immunohistochemical studies, performed in 7 cases, demonstrated the epithelial nature of these tumors. The cis-platin-VP16 (PE) regimen was used in 13 pts, and 9 of them (69%) obtained objective responses after chemotherapy (CT) alone, with 3 complete remissions (CR) and 6 partial remissions (PR). Median CR and PR duration was 13+ and 24 months, respectively. Radiotherapy was performed in 7/13 pts after induction CT and before consolidation CT. The objective response rate was 100%, with 6 CR and 1 PR. No severe toxic side effects and no toxic deaths were reported. A patient treated with surgery alone for a urinary bladder tumor showed continuous long-term survival, while 1 of 2 pts treated with radiotherapy alone obtained PR. Conclusions The PE regimen has an activity similar to the one observed in pulmonary SCC.

Malignancies arising in the head and neck area are heterogeneous diseases, each with its own natural history and prognosis. Cancer of the larynx, for example, has a better prognosis than cancer of the hypopharynx [1]. However, due to the relatively low number of cases in each anatomic site, and because the predominant lesion is squamous cell carcinoma, they are usually considered together in clinical trials.

To analyze the results of isolated on-pump coronary artery bypass graft surgery (CABG) in patients70 years-old in comparison to patients70 years-old.Patients undergoing isolated CABG were selected for the study. The patients were grouped in G1 (age70 years-old) and G2 (age70 years-old). The endpoints were in-hospital mortality, acute myocardial infarction (AMI), stroke, reexploration for bleeding, intra-aortic balloon for circulatory shock, respiratory complications, acute renal failure, mediastinitis, sepsis, atrial fibrillation, and complete atrioventricular block (CAVB).1,033 patients were included, 257 (24.8%) in G1 and 776 (75.2%) in G2. Patients in G1 were more likely to have in-hospital mortality than G2 (8.9% vs. 3.6%, respectively; P=0.001), while the incidence of AMI was similar (5.8% vs. 5.5%; P=0.87) than G2. More patients in G1 had re-exploration for bleeding (12.1% vs. 6.1%; P=0.003). G1 had more incidence of respiratory complications (21.4% vs. 9.1%; P0.001), mediastinitis (5.1% vs. 1.9%; P=0.013), stroke (3.9% vs. 1.3%; P=0.016), acute renal failure (7.8% vs. 1.3%; P0.001), sepsis (3.9% vs. 1.9%;P=0.003), atrial fibrillation (15.6% vs. 9.8%; P=0.016), and CAVB (3.5% vs. 1.2%; P=0.023) than G2. There was no significant difference in the use of intra-aortic balloon. In the forward stepwise multivariate logistic regression analysis age70-year-old was an independent predictive factor for higher in-hospital mortality (P=0.004), reexploration for bleeding (P=0.002), sepsis (P=0.002), respiratory complications (P0.001), mediastinitis (P=0.016), stroke (P=0.029), acute renal failure (P0.001), atrial fibrillation (P=0.021) and CAVB (P=0.031).This study suggests that patients70 years-old were at increased risk of death and other complications in the CABG's postoperative period in comparison to younger patients.

Summary To evaluate the outcome of Undifferentiated Nasopharyngeal Carcinomas (UCNT) treated with intensity-modulated radiation therapy with Simultaneous Integrated Boost (SIB), following induction chemotherapy. Between January 2006 and June 2009, 52 patients with stage II B-IVA/B UCNT were treated either with linac-IMRT or Tomotherapy. All patients were scheduled to receive three cycles of cisplatin based neoadjuvant chemotherapy. With a median follow-up of 38.5 months (range 12.3–64.1), 3 year overall survival (OS), disease-free survival (DFS), and DFS by T2a–2b and T3–T4-stage were 95.0%, 84.6%, 89.0%, and 78.0%, respectively. At multivariate analysis, none of the examined prognostic factors reported statistical significance. N-classification was not a significant predictive factor for either OS or development of distant metastases. T-stage alone had a borderline effect on DFS and development of metastases. No difference between Tomotherapy and linac-IMRT emerged in terms of loco-regional control and development of severe, acute, and late toxicities. The most significant severe, acute toxicities were grade 3 (32.7%) and grade 4 (7.7%) mucositis. No grades 3 and 4 late toxicities were observed. The most commonly observed late effect was xerostomia, 11.5% patients complained grade 2 xerostomia. The severity of grade 2 xerostomia diminished over time with only four patients not improving salivation. IMRT-SIB following neoadjuvant chemotherapy was very satisfactory in terms of local control, regional control, DFS and OS rates in patients with stage IIB to IVB UCNT. In our experience, adding concurrent chemotherapy to IMRT after neoadjuvant chemotherapy in loco-regional widespread disease resulted to be the indicated approach.

Previous studies reported an inverse relationship between body mass index (BMI) and upper aerodigestive tract (UADT) cancers. Examining change in BMI over time may clarify these previous observations. We used data from 2, 048 cases and 2, 173 hospital- and population-based controls from ten European countries (alcohol-related cancers and genetic susceptibility in Europe study) to investigate the relationship with BMI and adult change in BMI on UADT cancer risk. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated for associations between BMI at three time intervals and BMI change on UADT cancer development, adjusting for center, age, sex, education, fruit and vegetable intake, smoking and alcohol consumption. We found an inverse relationship between UADT cancers and BMI at time of interview and 2 years before interview. No association was found with BMI at 30 years of age. Regarding BMI change between age 30 and 2 years before interview, BMI decrease (BMI change