Is gestational hypertension beneficial in twin pregnancies?

OBJECTIVES: Hypertensive disorders of pregnancy are commonly associated with impaired foetal growth. However, some studies observed that gestational hypertension in twin pregnancy could be beneficial for foetal growth. The aim of this study is to investigate the influence of gestational hypertension on neonatal birth weight among twin pregnancies. STUDY DESIGN: This is a retrospective study about the comparison of 196 hypertensive twin pregnancies to 912 normotensive ones, who gave birth in the teaching hospital "A. Gemelli" in Rome from 1980 to 2006. MAIN OUTCOME MEASURES: Birth weight, inter-twin weight discordance and rate of small for gestational age neonates in the first and second twin. RESULTS: Birth weight, inter-twin weight discordance and rate of small for gestational age neonates were similar between the two groups. In the normotensive group, the discordance >25% was associated with lower gestational age at the delivery (p<0.00001), data not observed in the hypertensive group. The rate of pregnancies with second twin small for gestational age rose while paralleling the degree of the discordance in both groups. CONCLUSION: Gestational hypertension in twin pregnancies, if compared to normotensive ones, is not detrimental for foetal growth.

A large cross-sectional survey investigating the knowledge of cervical cancer risk aetiology and the predictors of the adherence to cervical cancer screening related to mass media campaign.

OBJECTIVES: The aims of this study were to compare the characteristics of women who got a Pap-test during the mass media campaign, carried out in an Italian region by broadcasts advertising, and two years later and to identify the determinants of knowledge of cervical cancer etiology and of the adherence to the mass media campaign. METHODS: A cross-sectional survey was carried out through a self-administered questionnaire. RESULTS: A total of 8570 randomly selected women were surveyed, 823 of these had a Pap-test during the mass media campaign period and 7747 two years later. Higher educational level, being not married, and living in urban areas were the main independent characteristics associated with a higher level of knowledge of cervical cancer etiology, although a previous treatment following a Pap smear abnormality was the strongest predictor (OR=2.88; 95% CI: 2.43-3.41). During the campaign period women had the Pap-test more frequently as a consequence of the mass media campaign (OR=8.28; 95% CI; 5.51-12.45). CONCLUSIONS: Mass media campaign is a useful tool to foster cervical screening compliance; however, its short-term effect suggests repeating it regularly.

Risk of venous thromboembolism associated with single and combined effects of Factor V Leiden, Prothrombin 20210A and Methylenetethraydrofolate reductase C677T: a meta-analysis involving over 11,000 cases and 21,000 controls.

Genetic and environmental factors interact in determining the risk of venous thromboembolism (VTE). The risk associated with the polymorphic variants G1691A of factor V (Factor V Leiden, FVL), G20210A of prothrombin (PT20210A) and C677T of methylentetrahydrofolate reductase (C677T MTHFR) genes has been investigated in many studies. We performed a pooled analysis of case-control and cohort studies investigating in adults the association between each variant and VTE, published on Pubmed, Embase or Google through January 2010. Authors of eligible papers, were invited to provide all available individual data for the pooling. The Odds Ratio (OR) for first VTE associated with each variant, individually and combined with the others, were calculated with a random effect model, in heterozygotes and homozygotes (dominant model for FVL and PT20210A; recessive for C677T MTHFR). We analysed 31 databases, including 11,239 cases and 21,521 controls. No significant association with VTE was found for homozygous C677T MTHFR (OR: 1.38; 95 % confidence intervals [CI]: 0.98-1.93), whereas the risk was increased in carriers of either heterozygous FVL or PT20210 (OR = 4.22; 95 % CI: 3.35-5.32; and OR = 2.79;95 % CI: 2.25-3.46, respectively), in double heterozygotes (OR = 3.42; 95 %CI 1.64-7.13), and in homozygous FVL or PT20210A (OR = 11.45; 95 %CI: 6.79-19.29; and OR: 6.74 (CI 95 % 2.19-20.72), respectively). The stratified analyses showed a stronger effect of FVL on individuals ≤ 45 years (p value for interaction = 0.036) and of PT20210A in women using oral contraceptives (p-value for interaction = 0.045). In this large pooled analysis, inclusive of large studies like MEGA, no effect was found for C677T MTHFR on VTE; FVL and PT20210A were confirmed to be moderate risk factors. Notably, double carriers of the two genetic variants produced an impact on VTE risk significantly increased but weaker than previously thought.

A systematic review and meta-analysis of the diagnostic accuracy of anti-heat shock protein 70 antibodies for the detection of autoimmune hearing loss.

OBJECTIVE: We reviewed case-control studies concerning the diagnostic accuracy of Heat Shock Protein 70 (Hsp-70) auto antibodies in the detection of immunomediated inner ear disease. MATERIALS AND METHODS: We searched for relevant articles published in English language on PubMed and Scopus up to December 2011. A quality assessment of the retrieved articles was performed using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS) 2 tool. Pooled data on the accuracy of the test were calculated, where possible. RESULTS: Three articles were deemed eligible. Among them, 2 evaluated the relationship between Hsp-70 and immunomediated inner ear disease by using the Western blot, whereas one report used the enzyme-linked immunosorbent assay method. Pooled sensitivity of Western blot test for Hsp-70 was 0.70 (95% confidence interval [CI], 0.59-0.80), with a large heterogeneity (I = 72.7%), and pooled specificity was 0.98 (95% CI, 0.87-1.00), with an I of 61.0%. Pooled positive likelihood ratios (LR) was 14.7 (95% CI, 2.1-104.1; I = 31.4%), and pooled negative LR was 0.32 (95% CI, 0.10-0.70; I = 78.8%). Sensitivity and specificity of enzyme-linked immunosorbent assay test for Hsp-70 auto antibodies was 0.85 (95% CI, 0.55-0.98) and 0.98 (95% CI, 0.86-1.00). Risk of bias was performed by using QUADAS 2 tool, with high scores obtained for patient selection and index test domains and low for the applicability criterion. DISCUSSION: This review shows that studies on autoimmune hearing loss diagnosis based on the detection of Hsp-70 autoantibodies used different inclusion and methodologic criteria and are affected from potential bias. Additional studies are actually required to identify an accurate laboratory diagnostic method for the autoimmune hearing loss.

Methodological quality of English-language genetic guidelines on hereditary breast-cancer screening and management: an evaluation using the AGREE instrument.

BACKGROUND: We examined the methodological quality of guidelines on syndromes conferring genetic susceptibility to breast cancer. METHODS: PubMed, EMBASE, and Google were searched for guidelines published up to October 2010. All guidelines in English were included. The Appraisal of Guidelines, Research and Evaluation (AGREE) instrument was used to assess the quality of the guidelines, and their reported evidence base was evaluated. RESULTS: Thirteen guidelines were deemed eligible: seven had been developed by independent associations, and the other six had national/state endorsements. Four guidelines performed satisfactorily, achieving a score of greater than 50% in all six AGREE domains. Mean ± SD standardized scores for the six AGREE domains were: 90 ± 9% for 'scope and purpose', 51 ± 18% for 'stakeholder involvement', 55 ± 27% for 'rigour of development', 80 ± 11% for 'clarity and presentation', 37 ± 32% for 'applicability', and 47 ± 38% for 'editorial independence'. Ten of the thirteen guidelines were found to be based on research evidence. CONCLUSIONS: Given the ethical implications and the high costs of genetic testing for hereditary breast cancer, guidelines on this topic should provide clear and evidence-based recommendations. Our analysis shows that there is scope for improving many aspects of the methodological quality of current guidelines. The AGREE instrument is a useful tool, and could be used profitably by guidelines developers to improve the quality of recommendations.

Patient-centeredness and e-health among Italian hospitals: results of a cross-sectional web-based survey.

OBJECTIVES: Given the growing recognition of patient-centeredness as a healthcare quality indicator and its limited implementation in practice, our study evaluated how the Italian hospitals (ItHs), including research hospitals (IRCCSs), research teaching hospitals (THs), and independent public hospital trusts (AOs), address the dimension of online data access through their institutional Web sites to promote a patient-centered care. MATERIALS AND METHODS: To address patient-centeredness and e-health, eight specific indicators adapted from the Euro Health Consumer Index were evaluated from 169 ItHs: online booking of healthcare services; access to medical records; register of legitimate doctors; waiting times for most commonly delivered healthcare services; transport information; centralized booking; public relations office; and pain management hospital committee. Univariate and bivariate statistics and a logistic regression analysis have been performed. RESULTS: The majority of the ItHs were under public ownership, and half of them are located in Northern Italy. From the logistic regression analysis, AOs appeared to be more likely to develop a patient-centered healthcare approach (odds ratio [OR]=3.69; 95% confidence interval [CI] 1.14-11.89) compared with IRCCSs or THs. In addition, when grouped together, all public hospitals show more than threefold higher implementation of patient-centeredness strategies (OR=3.60; 95% CI 1.49-8.72) with respect to private ones. Northern hospitals are more likely to ensure wider implementation of a patient-centered approach to healthcare (OR=3.37; 95% CI 1.49-7.62). CONCLUSIONS: According to our results, most of the ItHs are under public ownership, and half of them are located in the northern regions of Italy. The higher implementation of patient-centeredness strategies observed for Northern hospitals highlights interregional disparity in healthcare that needs a coordinated effort at both the hospital and policymaker levels to ensure a widespread implementation of patient-centered care among all Italian regions.

A case-control study on the effect of Apolipoprotein E genotypes on gastric cancer risk and progression.

BACKGROUND: Apolipoprotein E (ApoE) is a multifunctional protein playing both a key role in the metabolism of cholesterol and triglycerides, and in tissue repair and inflammation. The ApoE gene (19q13.2) has three major isoforms encoded by ε2, ε3 and ε4 alleles with the ε4 allele associated with hypercholesterolemia and the ε2 allele with the opposite effect. An inverse relationship between cholesterol levels and gastric cancer (GC) has been previously reported, although the relationship between apoE genotypes and GC has not been explored so far. METHODS: One hundred and fifty-six gastric cancer cases and 444 hospital controls were genotyped for apoE polymorphism (ε2, ε3, ε4 alleles). The relationship between GC and putative risk factors was measured using the adjusted odds ratios (ORs) and their 95% confidence intervals (CIs) from logistic regression analysis. A gene-environment interaction analysis was performed. The effect of the apoE genotypes on survival from GC was explored by a Kaplan-Meier analysis and Cox proportional hazard regression model. RESULTS: Subjects carrying at least one apoE ε2 allele have a significant 60% decrease of GC risk (OR=0.40, 95% CI: 0.19 - 0.84) compared with ε3 homozygotes. No significant interaction emerged between the ε4 or ε2 allele and environmental exposures, nor ε2 or ε4 alleles affected the median survival times, even after correcting for age, gender and stadium. CONCLUSIONS: Our study reports for the first time a protective effect of the ε2 allele against GC, that might be partly attributed to the higher antioxidant properties of ε2 compared with the ε3 or ε4 alleles. Given the study's sample size, further studies are required to confirm our findings.

A case-control study on the effects of the apolipoprotein E genotypes in nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) has reached epidemic proportions being the most common cause of chronic liver disease in Western countries. The Apolipoprotein E (ApoE) gene has three major isoforms encoded by the ε2, ε3, and ε4 alleles, with the ε4 allele associated with hypercholesterolemia and the ε2 allele with the opposite effect. The role of apoE genotypes on NAFLD has been previously investigated with conflicting results. Our hospital-based case-control study conducted in Italy aims to explore the effect of the apoE genotypes on NAFLD risk and their effect on the clinical features of NAFLD patients. 310 NAFLD cases and 422 controls were genotyped for apoE. Adjusted odds ratios (ORs) and 95% confidence intervals (CI) from logistic regression were used to explore the relationship between NAFLD and apoE genotypes, as well as their interaction with selected demographic and lifestyle factors. ApoE ε4 allele carriers showed a statistically significant two-fold reduction of NAFLD risk (OR = 0.51, 95% CI: 0.28-0.93) compared with ε3 homozygotes. A statistically significant lower HDL cholesterol level was observed for ApoE ε4 carriers if compared with ε3/ε3 genotype or ApoE ε2 carriers with a nearly linear decreasing trend from ApoE ε2 to ApoE ε4 carriers. Our study reports for the first time a protective effect of the ε4 allele towards NAFLD that might be attributable to its role in the regulation of hepatic triglycerides rich very low-density lipoproteins secretion.

p73 G4C14-to-A4T14 gene polymorphism and interaction with p53 exon 4 Arg72Pro on cancer susceptibility: a meta-analysis of the literature.

The p73 gene (1p36-33) is involved in cancer development through cell growth inhibition by inducing apoptosis in a p53-like manner. The p73 G4C14-to-A4T14 dinucleotide polymorphism, consisting of two single-nucleotide polymorphisms in the non-coding region of exon 2 that are in complete linkage disequilibrium, has been extensively studied in association with cancer risk. We performed a meta-analysis of published studies that examined the association between this p73 G4C14-to-A4T14 polymorphism and cancer by searching for relevant studies on Medline and Embase up to February 28, 2010. Pooling data from 19 case-control studies that included 6510 cancer cases and 5711 controls, we found that carriers of the p73 G4C14-to-A4T14 homozygous variant genotype (AT/AT) had an increased global risk of cancer [odds ratio (OR) = 1.30, 95% confidence interval (CI), 1.03-1.65]. There was no evidence of an effect modification of p73 AT/AT by age, gender, ethnicity or smoking status in subgroup analyses; however, a 1.35-fold statistically significant increased risk was found among individuals <55 years old. In case-only analysis, the homozygous p73 G4C14-to-A4T14 variant of p73 genotype was associated with the presence of the p53 exon 4 Arg72Pro allele (OR = 1.30, 95% CI, 1.02-1.64), which is suggestive of a biological interaction between the two genes in carcinogenesis. In conclusion, the p73 G4C14-to-A4T14 homozygous variant genotype might be a risk factor for cancer, especially in combination with the p53 exon 4 Arg72Pro polymorphism. Further studies looking at p73 G4C14-to-A4T14 and p53 exon 4 Arg72Pro interaction are required to support our findings.

Quality evaluation of guidelines on genetic screening, surveillance and management of hereditary colorectal cancer.

BACKGROUND: We examined the methodological quality of guidelines on colorectal cancer genetic susceptibility syndromes. METHODS: PubMed, EMBASE, and Google were searched up to July 2010. Adjourned guidelines in English were included. The Appraisal of Guidelines, Research and Evaluation (AGREE) instrument was used to assess their quality, and the reported evidence base of the guidelines was evaluated. RESULTS: The search yielded 17 eligible guidelines: 11 were developed by independent associations, while 6 had national\state endorsement. Only three guidelines performed satisfactorily, achieving a score >50% in all 6 AGREE domains. Mean standardized scores for the 6 AGREE domains were: 'scope and purpose', 83.9 ± 22.5%; 'stakeholder involvement', 35.6 ± 24.9%; 'rigour of development', 48.6 ± 25.3%; 'clarity and presentation', 71.6 ± 19.3%; 'applicability', 33.8 ± 30.1%; 'editorial independence', 42.2 ± 39.7%. Guidelines with national endorsement performed better in all the domains, with a statistically significant difference in three domains. Fifteen guidelines out of 17 were found to be based on research evidence. CONCLUSIONS: There is scope, in many areas, for improving the guidelines analysed, among which are the involvement of various professional figures and patients' representatives, and policies for their application. The AGREE instrument is a useful tool and could also be used profitably by guideline developers to improve the quality of recommendations.

A case-control study on the effect of apoliprotein E genotype on head and neck cancer risk.

BACKGROUND: The apolipoprotein E gene (apoE) has three major isoforms encoded by the ε2, ε3, and ε4 alleles, with the ε4 allele associated with hypercholesterolemia and the ε2 allele with the opposite effect. An inverse relationship between cholesterolemia and head and neck cancer (HNC) has been previously reported, although the relationship between apoE genotypes and HNC has not been explored to date. METHODS: Four hundred and seventeen HNC cases and 436 hospital controls were genotyped for apoE polymorphisms. Adjusted odds ratios (ORs) and 95% confidence intervals (CI) from logistic regression were used to explore the relationship between HNC and putative risk factors. A gene-environment interaction analysis was done. RESULTS: A borderline significant 40% decreased HNC risk (OR, 0.58; 95% CI, 0.31-1.05) was observed for individuals carrying at least one ε2 allele. Females carrying at least one ε2 allele showed a 60% risk reduction (OR, 0.43; 95% CI, 0.21-0.90) for HNC compared with ε3 homozygotes. A statistically significant interaction was found between alcohol use and the ε4 allele (P for interaction = 0.04), with a 2-fold increased risk (OR, 2.06; 95% CI, 0.95-4.48) among ever drinkers with an ε4 allele, with respect to ε3 homozygote nondrinkers. CONCLUSIONS: Our study provides novel evidence of a possible protective effect of the ε2 allele against HNC, probably due to its increased antioxidant properties. IMPACT: According to our results, apolipoprotein E may play a different role in carcinogenesis other than its well-known role in regulating blood serum cholesterol levels.

Use of trastuzumab in HER2-positive metastatic breast cancer beyond disease progression: a systematic review of published studies.

AIMS AND BACKGROUND: Trastuzumab, a humanized monoclonal antibody directed against the extracellular domain of ErbB, has determined clinical benefit for women affected by metastatic or early stage HER2-positive breast cancer and never previously treated with trastuzumab. Trastuzumab is generally used as first-line treatment of HER2+ metastatic breast cancer and is currently administered beyond progression even without clear evidence supporting such clinical practice. In fact, HER2-positive metastatic breast cancer has a high risk of progressing after first-line therapy, and second-line treatments vary. The aim of the study was to investigate by a systematic review the efficacy of trastuzumab-based treatments beyond progression in HER2-positive metastatic breast cancer. MATERIALS AND METHODS: We performed a systematic review using Medline, Embase and Cochrane Library data bases and publications in principal meetings or congresses of oncology in Europe and America until September 2008. The main selection criterium was the reporting of time to progression, calculated from the start of each trastuzumab-based therapy to the date of progressive disease or death. RESULTS: Twelve studies were selected that included a total of 516 patients. The weighted mean time to progression was 23.66 weeks (standard deviation, 4.37) and the median was 26 weeks (range, 13-39). Interestingly, combined trastuzumab plus vinorelbine treatment showed a lower mean and median time to progression (20.59 and 19.57 weeks, respectively), whereas trastuzumab plus capecitabine yielded a mean time to progression of 30.33 weeks. CONCLUSIONS: The added value of the present study has been to provide a quantitative summary measure of time to progression which can be used for comparisons between current and future available regimens.

A systematic review evaluating the methodological aspects of meta-analyses of genetic association studies in cancer research.

Meta-analyses and Individual Patient Data (IPD) meta-analyses of genetic association studies are a powerful tool to summarize the scientific evidences, however their application present considerable potential and several pitfalls. We reviewed systematically all published meta-analyses and IPD meta-analyses of genetic association studies in the field of cancer research, searching for relevant studies on the Medline, Embase, and HuGE Reviews Archive databases until January 2009. The association between selected predictors of methodological quality and the year of publication was also evaluated. 144 meta-analyses involving 299 gene-disease associations, and 25 IPD meta-analyses on 83 gene-disease were included. Overall quality of the reports showed a substantial improvement over time, as authors have become more inclusive of primary papers published in all languages since 2005 (P-value = 0.087), as well as statistical heterogeneity and publication bias were evaluated more systematically. Only 35.4% of the meta-analyses, however, adopted a comprehensive bibliographic search strategy to identify the primary reports, 63.9% did not specify the language of the included studies, 39.8% did not test for Hardy-Weinberg Equilibrium (HWE), while 62.2 and 75.9% of the meta-analyses and IPD meta-analyses, respectively, did not declare the scientific rationale for the genetic model chosen. Additionally, the HWE assessment showed a substantial decreasing trend over time (P-value = 0.031) while publication bias was more often evaluated when statistical heterogeneity was actually present (P-value = 0.007). Although we showed a general methodological improvement over time, guidelines on conducting and reporting meta-analyses of genetic association studies are needed to enhance their methodological quality.

Early mannan detection in bronchoalveolar lavage fluid with preemptive treatment reduces the incidence of invasive Candida infections in preterm infants.

BACKGROUND: Candida colonization is an important predictor for development of invasive fungal infection (IFI). We investigated whether early detection of Candida mannan (Mn) in bronchoalveolar lavage fluid (BALF) reduces IFI among preterm infants. METHODS: We conducted an observational study of infants with gestational age of < or =28 weeks, where a group undergoing Candida surveillance cultures (pre-Mn detection group) was compared with a group defined after the initiation of routine use of Candida Mn detection in BALF (Mn detection group). Antifungal treatment was started based on positive microbiologic (surveillance culture or Mn-antigen assay) results. RESULTS: No significant differences were detected when the groups were compared for several predictors of IFI. IFI was observed for 12 (23%) of 51 infants in the pre-Mn detection group, and for 0 (0%) of 29 infants in the Mn detection group (P = 0.003). Surveillance cultures in the pre-Mn detection group became positive at 15.0 +/- 7.2 days after birth, whereas the mean age at time of positive Mn antigen results in the Mn detection group was 4.3 +/- 3.1 days (P < 0.0001). Among 16 infants positive for surveillance cultures, 12 (75%) developed IFI (P < 0.0001). CONCLUSIONS: This study suggests that Candida Mn detection in BALF may be useful for earlier identification and preemptive therapy targeting preterm infants at high risk of IFI.

A case-control study on the combined effects of p53 and p73 polymorphisms on head and neck cancer risk in an Italian population.

BACKGROUND: The purpose of this study is to analyze the combined effects of selected p53 and p73 polymorphisms and their interaction with lifestyle habits on squamous cell carcinoma of the head and neck (SCCHN) risk and progression in an Italian population. METHODS: Two hundred and eighty-three cases and 295 hospital controls were genotyped for p53 polymorphisms on exon 4 (Arg72Pro), intron 3 and 6, and p73 G4C14-to-A4T14. Their association with SCCHN was estimated using a logistic regression analysis, while a multinomial logistic regression approach was applied to calculate the effect of the selected polymorphisms on SCCHN different sites (oral cavity, oropharynx, hypopharynx and larynx). We performed an haplotype analysis of the p53 polymorphisms, and a gene-gene interaction analysis for the combined effects of p73 G4C14-to-A4T14 and p53 polymorphisms. RESULTS: We found a significant increased risk of SCCHN among individuals with combined p73 exon 2 G4A and p53 intron 3 variant alleles (OR = 2.22, 95% CI: 1.08-4.56), and a protective effect for those carrying the p53 exon 4-p53 intron 6 diplotype combination (OR = 0.67; 95% CI: 0.47-0.92). From the gene-environment interaction analysis we found that individuals aged < 45 years carrying p73 exon 2 G4A variant allele have a 12.85-increased risk of SCCHN (95% CI: 2.10-78.74) compared with persons of the same age with the homozygous wild type genotype. Improved survival rate was observed among p53 intron 6 variant allele carriers (Hazard Ratio = 0.51 (95% CI: 0.23-1.16). CONCLUSION: Our study provides for the first time evidence that individuals carrying p53 exon 4 and p53 intron 6 variant alleles are significantly protected against SCCHN, and also shows that an additional risk is conferred by the combination of p73 exon 2 G4C14-to-A4T14 and p53 intron 3 variant allele. Larger studies are required to confirm these findings.

A case-control study on the effect of p53 and p73 gene polymorphisms on gastric cancer risk and progression.

The p53 protein and its functional homologue p73 share several functions in modulating cell-cycle control and apoptosis. Based on the functional interaction between p53 and p73 in carcinogenesis, we investigated the combined effect of p73 G4C14-to-A4T14 and p53 gene polymorphisms and their interaction with selected environmental factors, on the risk for gastric cancer in a hospital-based case-control study conducted in Italy. The effect of these polymorphisms on cancer progression was also investigated. One hundred and fifteen gastric cancer cases and 295 hospital controls were genotyped for p73 G4C14-to-A4T14, and p53 exon 4 (Arg72Pro), intron 3 and intron 6 polymorphisms. An increased risk for gastric cancer was found to be associated with the inheritance of the p73 homozygous variant genotype among the gastric cancer intestinal histotype (odds ratio (OR)=6.75; 95% confidence interval (95% CI)=1.88-24.24). An effect modification of the p73 variant allele by gender was observed [(OR=2.82; 95%CI=1.24-6.40) among females, versus an OR of 0.70 (95%CI=0.32-1.54) among males; p-value for homogeneity among strata estimates =0.03]. Gene-gene interaction analyses demonstrated that individuals with combined p53 exon 4 and intron 6 variant alleles are borderline significantly protected from gastric cancer (OR=0.52; 95% CI=0.26-1.07; p-value for interaction =0.005), which was confirmed by the haplotype analysis. Finally, a poorer survival was observed among carriers of the variant allele of p53 intron 6 if compared with those carrying both wild-type alleles (p-value for log-rank test =0.02). This study shows that the p73 G4C14-to-A4T14 polymorphism may be a risk factor for gastric cancer, as reported from other studies in different tumour sites among Caucasians. Along with the protective effect of p53 exon 4-intron 6 allelic variants, already noted for breast and lung cancer, our results require confirmation from larger studies.

Aldehyde dehydrogenase 2 and head and neck cancer: a meta-analysis implementing a Mendelian randomization approach.

Alcohol drinking at high doses is a risk factor for head and neck cancer, and exposure to acetaldehyde, the principle metabolite of alcohol, is supposed to account for the increased risk. Individuals homozygous for the 2 variant allele of aldehyde dehydrogenase 2 (ALDH2) are unable to metabolize acetaldehyde, which prevents them from alcohol drinking, whereas 1 2 have 6-fold higher blood acetaldehyde concentration postalcohol consumption with respect to 1 1. According to the concept of Mendelian randomization, because this polymorphism is distributed randomly during gamete formation, its association with head and neck cancer should be not confounded by smoking. We carried out a meta-analysis of ALDH2 and head and neck cancer searching for relevant studies on Medline and Embase up to January 31, 2008, and investigated the consistency between the expected odds ratio (OR) among drinkers from the largest pooled analysis among never smokers and the observed OR from this meta-analysis by an interaction test. Six studies were selected (945 cases, 2,917 controls). The OR of head and neck cancer among 2 2 was 0.53 [95% confidence interval (95% CI), 0.28-1.00] relative to 1 1 and 1.83 (95% CI, 1.21-2.77) among 1 2. The expected OR for head and neck cancer due to alcohol intake among 1 1 was 1.38 (95% CI, 0.88-2.17) and the observed OR among 1 1 compared with 2*2 from this meta-analysis was 1.88 (95% CI, 1.00-3.57; P for interaction = 0.43). Besides showing the effectiveness of the Mendelian randomization approach, these findings support the theory that alcohol increases head and neck cancer risk through the carcinogenic action of acetaldehyde.

A systematic review of meta-analyses on gene polymorphisms and gastric cancer risk.

BACKGROUND: Individual variations in gastric cancer risk have been associated in the last decade with specific variant alleles of different genes that are present in a significant proportion of the population. Polymorphisms may modify the effects of environmental exposures, and these gene-environment interactions could partly explain the high variation of gastric cancer incidence around the world. The aim of this report is to carry out a systematic review of the published meta-analyses of studies investigating the association between gene polymorphisms and gastric cancer risk, and describe their impact at population level. Priorities on the design of further primary studies are then provided. METHODS: A structured bibliographic search on Medline and EMBASE databases has been performed to identify meta-analyses on genetic susceptibility to gastric cancer, without restriction criteria. We report the main results of the meta-analyses and we describe the subgroup analyses performed, focusing on the detection of statistical heterogeneity. We investigated publication bias by pooling the primary studies included in the meta-analyses, and we computed the population attributable risk (PAR) for each polymorphism. RESULTS: Twelve meta-analyses and one pooled-analysis of community based genetic association studies were included, focusing on nine genes involved in inflammation (IL-1beta, IL-1RN, IL-8), detoxification of carcinogens (GSTs, CYP2E1), folate metabolism (MTHFR), intercellular adhesion (E-cadherin) and cell cycle regulation (p53). According to their random-Odds Ratios, individuals carrying one of the IL-1RN *2, IL-1beta -511T variant alleles or homozygotes for MTHFR 677T are significantly at higher risk of gastric cancer than those with the wild type homozygote genotypes, showing high PARs. The main sources of heterogeneity in the meta-analyses were ethnicity, quality of the primary study, and selected environmental co-exposures. Effect modification by Helicobacter pylori infection for subjects carrying the unfavourable variant of IL-1 polymorphisms and by low folate intake for individuals homozygotes for MTHFR 677T allele has been reported, while genes involved in the detoxification of carcinogens show synergistic interactions. Publication bias was observed (Egger test, p = 0.03). DISCUSSION: The published meta-analyses included in our systematic review focused on polymorphisms having a small effect in increasing gastric cancer risk per se. Nevertheless, the risk increase by interacting with environmental exposures and in combination with additional unfavourable polymorphisms. Unfortunately meta-analyses are underpowered for many subgroup analyses, so additional primary studies performed on larger population and collecting data on environmental and genetic co-exposures are demanded.

Diversity, parental germline origin, and phenotypic spectrum of de novo HRAS missense changes in Costello syndrome.

Activating mutations in v-Ha-ras Harvey rat sarcoma viral oncogene homolog (HRAS) have recently been identified as the molecular cause underlying Costello syndrome (CS). To further investigate the phenotypic spectrum associated with germline HRAS mutations and characterize their molecular diversity, subjects with a diagnosis of CS (N = 9), Noonan syndrome (NS; N = 36), cardiofaciocutaneous syndrome (CFCS; N = 4), or with a phenotype suggestive of these conditions but without a definitive diagnosis (N = 12) were screened for the entire coding sequence of the gene. A de novo heterozygous HRAS change was detected in all the subjects diagnosed with CS, while no lesion was observed with any of the other phenotypes. While eight cases shared the recurrent c.34G>A change, a novel c.436G>A transition was observed in one individual. The latter affected residue, p.Ala146, which contributes to guanosine triphosphate (GTP)/guanosine diphosphate (GDP) binding, defining a novel class of activating HRAS lesions that perturb development. Clinical characterization indicated that p.Gly12Ser was associated with a homogeneous phenotype. By analyzing the genomic region flanking the HRAS mutations, we traced the parental origin of lesions in nine informative families and demonstrated that de novo mutations were inherited from the father in all cases. We noted an advanced age at conception in unaffected fathers transmitting the mutation.

Obstructive sleep apnea in Costello syndrome.

Costello syndrome (CS) was initially described by Costello in 1971; it is caused by a germline mutation in HRAS proto-oncogene. The aim of the present study was to evaluate the respiratory activity during sleep in a group of subjects with CS. We studied 10 consecutive patients, 4 males and 6 females, aged 3-29 years, affected by CS. All patients underwent clinical, neurological, otholaryngologic and radiologic evaluation, and a full-night polysomnography in the sleep laboratory. Polysomnography showed that seven patients presented a relevant number of respiratory events of obstructive type during sleep. The apnea-hypopnea index (AHI) ranged from 0 to 19.2 events per hour (mean index = 7.5 +/- 6.9 events/hr). In one patient AHI was not evaluable because of tracheostomy. Apnea induced mild or moderate hemoglobin desaturations (mean of lowest SpO2 values = 85.4 +/- 5.5%). Only sporadic respiratory pauses of central type were observed (mean number of central apnea per study: 7.2 +/- 6.8 events/hr). Sleep structure was fragmented, with a high number of awakenings (mean number of awakenings was 13.2 +/- 8.1; of these, 4.8 +/- 2.5 lasted longer than 2 min). In all patients, otolaryngologic and radiologic observations revealed one or more sites of narrowing in the upper airways. Our results suggest that Costello patients have a high prevalence of obstructive sleep-related respiratory disorders, which need to be assessed by means of polysomnography.