Role of GSTM1 and GSTT1 genotypes in differentiated thyroid cancer and interaction with lifestyle factors: Results from case-control studies in France and New Caledonia.

BACKGROUND: GSTM1 and GSTT1 are involved in detoxification of xenobiotics, products of oxidative stress and in steroid hormones metabolism. We investigated whether GSTM1 and GSTT1 gene deletion was associated with DTC risk and explored interaction with non-genetic risk factors of DTC. METHODS: The study included 661 DTC cases and 736 controls from two case-control studies conducted in France and New Caledonia. Odds ratios (OR) and their confidence interval (CI) for DTC associated with GST genotypes, alcohol drinking, tobacco smoking, body mass index and hormonal factors were calculated using logistic regression models. RESULTS: Results are presented for Europeans and Melanesians combined, as no heterogeneity between groups was detected. We found that DTC risk increased with obesity and decrease with alcohol drinking. After stratification by gene deletion status, the OR for obesity was 5.75, (95%CI 2.25-14.7) among individuals with GSTT1 and GSTM1-deleted genotype, and 1.26, (95%CI 0.89-1.77) in carriers of both genes (p-interaction = 0.02). The OR for drinking ≥1 glass/week was 0.33 (95%CI 0.15-0.74) in GSTT1-null individuals while it was 1.01 (95%CI 0.67-1.52) in non-null carriers of the gene (p-interaction = 0.01). No interaction between GST genotypes and other non-genetic risk factors was detected. CONCLUSION: GSTM1 and GSTT1 genotypes may modulate the DTC risk associated with BMI and alcohol consumption.

Dietary Inflammatory Index and Differentiated Thyroid Carcinoma Risk: A Population-Based Case-Control Study in New Caledonia.

Despite research efforts, current knowledge of the etiology of thyroid carcinoma remains limited. To explore the potential role of diet-induced inflammation, we examined the association between differentiated thyroid cancer risk and the energy-adjusted Dietary Inflammatory Index (E-DII) in a population-based case-control study conducted in New Caledonia, a Pacific archipelago with one of the highest recorded thyroid cancer incidence rates in the world. The E-DII was computed from food frequency questionnaire information on usual dietary intake. Logistic regression analyses were performed on data from 324 histologically confirmed cases of papillary or follicular carcinoma, diagnosed from 1993 to 1999, and 402 controls. Positive associations between E-DII and thyroid cancer risk were observed (comparing extreme tertiles, odds ratio = 1.67, 95% confidence interval: 1.08, 2.58; P for trend = 0.002), with stronger associations found for larger carcinomas (P for trend = 0.0005). Stratified analyses showed an increased risk of thyroid cancer associated with the E-DII among Southern province residents (P for trend = 0.003), Melanesian women (P for trend = 0.02), obese participants (P for trend = 0.006), and ever-smokers (P for trend = 0.0005). Our results suggest that a proinflammatory diet-especially when concomitant with other inflammation-inducing conditions or habits (e.g., obesity, smoking)-is associated with increased risk of thyroid carcinoma.

Efficacy of THN102 (a combination of modafinil and flecainide) on vigilance and cognition during 40-hour total sleep deprivation in healthy subjects: Glial connexins as a therapeutic target.

AIMS: THN102 is a novel combination of modafinil and low-dose flecainide, targeting glial connexin activity to modulate modafinil effects. We investigated THN102 efficacy compared to modafinil and to placebo on vigilance and cognitive function during 40-hour total sleep deprivation (TSD). METHODS: Twenty healthy men participated in a double-blind, randomized, incomplete-block 3-period cross-over trial with 5 treatments (n = 12 per group): placebo (PBO), modafinil 100 mg (MOD100), THN102 100/1, 100/3, 100/9 (modafinil 100 mg and flecainide 1, 3 or 9 mg). Each period included a baseline day and a TSD day with treatments administered 3 times (01:00, 09:00 and 19:00). Reaction time in psychomotor vigilance test, subjective somnolence and vital signs were assessed before and during treatment. Working memory (2-Back) and executive processes (Go/noGo for vigilance and inhibition, Wisconsin card sorting task for mental flexibility, and Tower of London test for planning) were evaluated at 16:30. RESULTS: At 5 hours postdose−1 (after 23 hours TSD, primary endpoint), THN102 100/1 resulted in statistically higher psychomotor vigilance test speed vs MOD100 (3.97 ± 0.09 vs 3.74 ± 0.14, P < .05). No increase in effect was observed with higher flecainide doses in combinations. Most THN102 doses vs MOD100 also improved the number of correct responses in 2-Back and Go errors in Go/noGo (P < .05 for all doses), and perseverative responses in Wisconsin card sorting task (for 100/1 and 100/9). No impact on cardiac conduction was noted with THN102, and safety was similar to MOD100. CONCLUSIONS: THN102 seems more efficient than modafinil on vigilance, working memory and executive functions, opening new perspectives in management of hypersomnolence disorders.

Prevalence of benign epileptiform variants during initial EEG examination in French military aircrew.

INTRODUCTION: In France, a systematic EEG is performed during initial examination in military aircrew applicants, which may provide an estimation of the prevalence of benign epileptiform variants in healthy adults. METHODS: We analyzed standard EEG (21 scalp electrodes, 20minutes, 400Hz sampling rate) of military aircrew applicants examined in the French Main Aeromedical Center in 2016. EEGs were analyzed using both bipolar and referential montages. The collected data were EEG abnormalities and benign epileptiform variants. The kappa inter-observer index for the detection of benign epileptiform variants was calculated. RESULTS: Our population was composed of 495 subjects (86.7% males, mean age 22.5±4.8 years), wishing to become a pilot in 69.7% of cases. None of the applicants reported any neurological disease and none was taking regular medication. EEG was considered as normal for 96.4% of them. Encountered EEG abnormalities were mainly asymmetric and sharp slow wave bursts. Drowsiness was recorded during 13.9% of these EEG. Benign epileptiform variants were present in 7.7% of our population: anterior theta activities (4%), posterior slow waves (2.8%), alpha variants (0.6%) and wicket spikes (0.2%). Hyperventilation induced EEG slowing in 14.1% of cases. During intermittent photic stimulation, physiological photic driving was observed in 15.2% of subjects. DISCUSSION: Many previous studies have been dedicated to the prevalence of benign epileptiform variants but results are often heterogeneous and based on patients in whom there was an indication for EEG. Our results thus bring data on benign epileptiform variants prevalence in a young adult population characterized by the absence of neurologic disorders. Our study demonstrates that anterior theta activities, posterior slow waves, alpha variants and wicket spikes are the most frequent benign EEG variants in such a young adult population.

Fine-mapping of two differentiated thyroid carcinoma susceptibility loci at 9q22.33 and 14q13.3 detects novel candidate functional SNPs in Europeans from metropolitan France and Melanesians from New Caledonia.

Incidence of differentiated thyroid carcinoma varies considerably between countries and ethnic groups, with particularly high incidence rates in Melanesians of New Caledonia. Differentiated thyroid cancer (DTC) has a familial relative risk higher than other cancers, highlighting the contribution of inherited factors to the disease. Recently, genome-wide association studies (GWAS) identified several DTC susceptibility loci. The most robust associations were reported at loci 9q22 (rs965513 and rs1867277) and 14q13 (rs944289 and rs116909734). In this study, we performed a fine-mapping study of the two gene regions among Europeans and Melanesians from Metropolitan France and New Caledonia. We examined 81 single nucleotide polymorphisms (SNPs) at 9q22 and 561 SNPs at 14q13 in Europeans (625 cases/776 controls) and in Melanesians (244 cases/189 controls). The association with the four SNPs previously identified in GWAS was replicated in Europeans while only rs944289 was replicated in Melanesians. Among Europeans, we found that the two SNPs previously reported at 9q22 were not independently associated to DTC and that rs965513 was the predominant signal; at 14q13, we showed that the haplotype rs944289[C]-rs116909374[C]-rs999460[T] was significantly associated with DTC risk and that the association with rs116909374 differed by smoking status (p-interaction = 0.03). Among Melanesians, a new independent signal was observed at 14q13 for rs1755774 which is strongly correlated to rs2787423; this latter is potentially a functional variant. Significant interactions with parity (p < 0.05) and body mass index were observed for rs1755774 and rs2787423. This study contributed to a better characterization of the DTC loci 9q22 and 14q13 in Europeans and in Melanesians and has identified novel variants to be prioritized for further functional studies.

Family history of malignant and benign thyroid diseases and risk of thyroid cancer: a population-based case-control study in New Caledonia.

PURPOSE: Exceptionally high incidence rates of thyroid cancer have been observed in New Caledonia, particularly in Melanesian women, but familial aggregation of thyroid diseases in this population is unknown. We study the association between family history of malignant or benign thyroid diseases and non-medullary thyroid cancer in this country. METHODS: We conducted a population-based case-control study including 332 cases with papillary or follicular carcinoma diagnosed in 1993-1999 and 412 controls, matched by sex and 5-year age-group. RESULTS: Thyroid cancer was associated with a history of thyroid cancer in first-degree relatives (odds ratio (OR), 3.2; 95 % CI, 1.6-6.2) and with a family history of multinodular goiter (OR, 3.6; 95 % CI, 1.9-7.0). The ORs did not change by age at diagnosis and with the number of affected relatives. The study provides evidence that the familial component of thyroid cancer is particularly strong in men. Thyroid cancer was not associated with a family history of thyroid diseases in Melanesians from the Loyalty Islands, the area with the highest incidence rates for thyroid cancer, possibly indicating a high frequency of genetic susceptibility variants and lack of genetic variation in this population subgroup. CONCLUSION: Overall our findings confirm an elevated risk of thyroid cancer in individuals with a family history of malignant or benign thyroid diseases, particularly in Melanesians where familial aggregation of thyroid cancer had never been investigated before. The study of genetic variants in candidate susceptibility genes for thyroid cancer may help clarifying the absence of an association in the subgroup of Melanesians from the Loyalty Islands.

Role of dietary iodine and cruciferous vegetables in thyroid cancer: a countrywide case-control study in New Caledonia.

Exceptionally high incidence rates of thyroid cancer have been reported in New Caledonia, particularly in Melanesian women. To clarify the reasons of this elevated incidence, we conducted a countrywide population-based case-control study in the multiethnic population of Caledonian women. The study included 293 cases of thyroid cancer and 354 population controls. Based on a food frequency questionnaire, we investigated the role in thyroid cancer of food items rich in iodine-such as seafood-and of vegetables containing goitrogens-such as cruciferous vegetables. A measure of total daily iodine intake based on a food composition table was also used. Our findings provided little support for an association between thyroid cancer and consumption of fish and seafood. We found that high consumption of cruciferous vegetables was associated with thyroid cancer among women with low iodine intake (OR = 1.86; 95% CI: 1.01-3.43 for iodine intake <96 microg/day). The high consumption of cruciferous vegetables among Melanesian women, a group with mild iodine deficiency, may contribute to explain the exceptionally high incidence of thyroid cancer in this group.

Alcohol drinking, tobacco smoking, and anthropometric characteristics as risk factors for thyroid cancer: a countrywide case-control study in New Caledonia.

Exceptionally high incidence rates of thyroid cancer are observed in New Caledonia, particularly in Melanesian women. To investigate further the etiology of thyroid cancer and to clarify the reasons of this elevated incidence, the authors conducted a countrywide population-based case-control study in this multiethnic population. The study included 332 cases with histologically verified papillary or follicular carcinoma (293 women and 39 men) diagnosed in 1993-1999 and 412 population controls (354 women and 58 men) frequency matched by gender and 5-year age group. Thyroid cancer was negatively associated with tobacco smoking and alcohol drinking, but no inverse dose-response relation was observed. Height was positively associated with thyroid cancer, particularly in men. Strong positive associations with weight and body mass index were observed in Melanesian women aged 50 years or more, with an odds ratio of 5.5 (95% confidence interval: 1.5, 20.3) for a body mass index of 35 kg/m2 or greater compared with normal-weight women, and there was a clear dose-response trend. This study clarifies the role of overweight for thyroid cancer in postmenopausal women. Because of the high prevalence of obesity among Melanesian women of New Caledonia, this finding may explain in part the exceptionally elevated incidence of thyroid cancer in this group.

Time trends and geographic variations for thyroid cancer in New Caledonia, a very high incidence area (1985-1999).

Thyroid cancer incidence in New Caledonia is the highest reported in the world and is approximately 10-fold higher than in most developed countries. We describe the incidence patterns in this country according to histological and sociodemographic characteristics to give clues about potential etiologic factors. Another objective is to see whether the incidence figures are related to enhanced detection of small size carcinomas. The study included all 498 cases of thyroid cancer diagnosed in 1985-1999. Pathology reports were systematically reviewed to determine the histological type of the tumor and the size of the cancerous nodules. The incidence of carcinomas < or =10 mm was taken as an indicator of enhanced detection due to improved screening procedures. The age-standardized incidence rates in 1985-1999 were exceptionally high in Melanesian women (71.4/100,000) and men (10.4/100,000). The incidence increased three-fold in women from 1995 onwards. The increase in incidence was more striking for papillary carcinomas < or =10 mm than for large size carcinomas, but an increased incidence of carcinomas >10 mm was also observed among women. The analysis by municipality of residence in Melanesian women showed that the incidence was twice as high in 1995-1999 in the Loyalty Islands as in the rest of the country. The sharp increase of thyroid cancer incidence in 1985-1999 in New Caledonia was partly related to enhanced detection of small size carcinomas. The elevated incidence of thyroid cancers, as well as the ethnic and geographic disparities, may result from common environmental or lifestyle risk factors that need to be identified.

Role of goiter and of menstrual and reproductive factors in thyroid cancer: a population-based case-control study in New Caledonia (South Pacific), a very high incidence area.

Exceptionally high incidence rates of thyroid cancer have been reported for Melanesian women in New Caledonia (South Pacific). To investigate the occurrence of thyroid cancer in that country and to clarify the role of goiter and hormonal factors in that disease in women, a countrywide population-based case-control study was conducted in 1993-1999. The study included 293 cases, identified through pathology registers and whose thyroid cancer was verified histologically, and 354 population controls. Thyroid cancer was associated with goiter, age at menarche, irregular menstruation, and hysterectomy. There was a dose-response trend with number of full-term pregnancies (p = 0.01), with an odds ratio of 2.2 (95% confidence interval: 1.1, 4.3) for women with eight or more pregnancies. Miscarriage, particularly as an outcome of the first pregnancy, was also indicated as a risk factor. The association between voluntary abortion and thyroid microcarcinoma could be explained by enhanced medical surveillance and improved cancer detection in women undergoing abortion. Oral contraceptives and hormone replacement therapy were unrelated to thyroid cancer. The very high birth rate among Melanesian women in New Caledonia, as well as late age at menarche, may explain, in part, their elevated incidence of thyroid cancer.