Racial and ethnic differences in epithelial ovarian cancer risk: an analysis from the Ovarian Cancer Association Consortium.

BACKGROUND: Limited estimates exist on risk factors for epithelial ovarian cancer (EOC) in Asian, Hispanic, and Native Hawaiian/Pacific Islander (NHPI) women. METHODS: Participants included 1734 Asian (785 cases, 949 controls), 266 NHPI (99 cases, 167 controls), 1149 Hispanic (505 cases, 644 controls), and 24,189 White (9,981 cases, 14,208 controls) women from 11 studies in the Ovarian Cancer Association Consortium. Logistic regression models estimated odds ratios (ORs) and 95% confidence intervals (CIs) for risk associations by race and ethnicity. RESULTS: Heterogeneity in EOC risk associations by race and ethnicity (p ≤ 0.02) was observed for oral contraceptive (OC) use, parity, tubal ligation and smoking. We observed inverse associations with EOC risk for OC use and parity across all groups; associations were strongest in NHPI and Asian women. The inverse association for tubal ligation with risk was most pronounced for NHPI participants (OR=0.25, 95% CI 0.13-0.48), versus Asian and White participants, respectively (OR=0.68, 95% CI 0.51-0.90; OR=0.78, 95% CI 0.73-0.85). CONCLUSIONS: Differences in EOC risk factor associations were observed across racial and ethnic groups, which could in part be due to varying prevalence of EOC histotypes. Inclusion of greater diversity in future studies is essential to inform prevention strategies.

Disorganization of language and working memory systems in frontal versus temporal lobe epilepsy.

Cognitive impairment is a common comorbidity of epilepsy and adversely impacts people with both frontal lobe (FLE) and temporal lobe (TLE) epilepsy. While its neural substrates have been investigated extensively in TLE, functional imaging studies in FLE are scarce. In this study, we profiled the neural processes underlying cognitive impairment in FLE and directly compared FLE and TLE to establish commonalities and differences. We investigated 172 adult participants (56 with FLE, 64 with TLE and 52 controls) using neuropsychological tests and four functional MRI tasks probing expressive language (verbal fluency, verb generation) and working memory (verbal and visuo-spatial). Patient groups were comparable in disease duration and anti-seizure medication load. We devised a multiscale approach to map brain activation and deactivation during cognition and track reorganization in FLE and TLE. Voxel-based analyses were complemented with profiling of task effects across established motifs of functional brain organization: (i) canonical resting-state functional systems; and (ii) the principal functional connectivity gradient, which encodes a continuous transition of regional connectivity profiles, anchoring lower-level sensory and transmodal brain areas at the opposite ends of a spectrum. We show that cognitive impairment in FLE is associated with reduced activation across attentional and executive systems, as well as reduced deactivation of the default mode system, indicative of a large-scale disorganization of task-related recruitment. The imaging signatures of dysfunction in FLE are broadly similar to those in TLE, but some patterns are syndrome-specific: altered default-mode deactivation is more prominent in FLE, while impaired recruitment of posterior language areas during a task with semantic demands is more marked in TLE. Functional abnormalities in FLE and TLE appear overall modulated by disease load. On balance, our study elucidates neural processes underlying language and working memory impairment in FLE, identifies shared and syndrome-specific alterations in the two most common focal epilepsies and sheds light on system behaviour that may be amenable to future remediation strategies.

Optimal Surgical Extent for Memory and Seizure Outcome in Temporal Lobe Epilepsy.

OBJECTIVE: Postoperative memory decline is an important consequence of anterior temporal lobe resection (ATLR) for temporal lobe epilepsy (TLE), and the extent of resection may be a modifiable factor. This study aimed to define optimal resection margins for cognitive outcome while maintaining a high rate of postoperative seizure freedom. METHODS: This cohort study evaluated the resection extent on postoperative structural MRI using automated voxel-based methods and manual measurements in 142 consecutive patients with unilateral drug refractory TLE (74 left, 68 right TLE) who underwent standard ATLR. RESULTS: Voxel-wise analyses revealed that postsurgical verbal memory decline correlated with resections of the posterior hippocampus and inferior temporal gyrus, whereas larger resections of the fusiform gyrus were associated with worsening of visual memory in left TLE. Limiting the posterior extent of left hippocampal resection to 55% reduced the odds of significant postoperative verbal memory decline by a factor of 8.1 (95% CI 1.5-44.4, p = 0.02). Seizure freedom was not related to posterior resection extent, but to the piriform cortex removal after left ATLR. In right TLE, variability of the posterior extent of resection was not associated with verbal and visual memory decline or seizures after surgery. INTERPRETATION: The extent of surgical resection is an independent and modifiable risk factor for cognitive decline and seizures after left ATLR. Adapting the posterior extent of left ATLR might optimize postoperative outcome, with reduced risk of memory impairment while maintaining comparable seizure-freedom rates. The current, more lenient, approach might be appropriate for right ATLR. ANN NEUROL 2022;91:131-144.

Cognitive phenotype of juvenile absence epilepsy: An investigation of patients and unaffected siblings.

OBJECTIVE: The cognitive profile of juvenile absence epilepsy (JAE) remains largely uncharacterized. This study aimed to: (1) elucidate the neuropsychological profile of JAE; (2) identify familial cognitive traits by investigating unaffected JAE siblings; (3) establish the clinical meaningfulness of JAE-associated cognitive traits; (4) determine whether cognitive traits across the idiopathic generalized epilepsy (IGE) spectrum are shared or syndrome-specific, by comparing JAE to juvenile myoclonic epilepsy (JME); and (5) identify relationships between cognitive abilities and clinical characteristics. METHODS: We investigated 123 participants-23 patients with JAE, 16 unaffected siblings of JAE patients, 45 healthy controls, and 39 patients with JME-who underwent a comprehensive neuropsychological test battery including measures within four cognitive domains: attention/psychomotor speed, language, memory, and executive function. We correlated clinical measures with cognitive performance data to decode effects of age at onset and duration of epilepsy. RESULTS: Cognitive performance in individuals with JAE was reduced compared to controls across attention/psychomotor speed, language, and executive function domains; those with ongoing seizures additionally showed lower memory scores. Patients with JAE and their unaffected siblings had similar language impairment compared to controls. Individuals with JME had worse response inhibition than those with JAE. Across all patients, those with older age at onset had better attention/psychomotor speed performance. SIGNIFICANCE: JAE is associated with wide-ranging cognitive difficulties that encompass domains reliant on frontal lobe processing, including language, attention, and executive function. JAE siblings share impairment with patients on linguistic measures, indicative of a familial trait. Executive function subdomains may be differentially affected across the IGE spectrum. Cognitive abilities are detrimentally modulated by an early age at seizure onset.

Episodic memory network connectivity in temporal lobe epilepsy.

OBJECTIVE: Temporal lobe epilepsy (TLE) affects brain networks and is associated with impairment of episodic memory. Temporal and extratemporal reorganization of memory functions is described in functional magnetic resonance imaging (fMRI) studies. Functional reorganizations have been shown at the local activation level, but network-level alterations have been underinvestigated. We aim to investigate the functional anatomy of memory networks using memory fMRI and determine how this relates to memory function in TLE. METHODS: Ninety patients with unilateral TLE (43 left) and 29 controls performed a memory-encoding fMRI paradigm of faces and words with subsequent out-of-scanner recognition test. Subsequent memory event-related contrasts of words and faces remembered were generated. Psychophysiological interaction analysis investigated task-associated changes in functional connectivity seeding from the mesial temporal lobes (MTLs). Correlations between changes in functional connectivity and clinical memory scores, epilepsy duration, age at epilepsy onset, and seizure frequency were investigated, and between connectivity supportive of better memory and disease burden. Connectivity differences between controls and TLE, and between TLE with and without hippocampal sclerosis, were explored using these confounds as regressors of no interest. RESULTS: Compared to controls, TLE patients showed widespread decreased connectivity between bilateral MTLs and frontal lobes, and increased local connectivity between the anterior MTLs bilaterally. Increased intrinsic connectivity within the bilateral MTLs correlated with better out-of-scanner memory performance in both left and right TLE. Longer epilepsy duration and higher seizure frequency were associated with decreased connectivity between bilateral MTLs and left/right orbitofrontal cortex (OFC) and insula, connections supportive of memory functions. TLE due to hippocampal sclerosis was associated with greater connectivity disruption within the MTL and extratemporally. SIGNIFICANCE: Connectivity analyses showed that TLE is associated with temporal and extratemporal memory network reorganization. Increased bilateral functional connectivity within the MTL and connectivity to OFC and insula are efficient, and are disrupted by greater disease burden.

Hippocampal Shape Is Associated with Memory Deficits in Temporal Lobe Epilepsy.

OBJECTIVE: Cognitive problems, especially disturbances in episodic memory, and hippocampal sclerosis are common in temporal lobe epilepsy (TLE), but little is known about the relationship of hippocampal morphology with memory. We aimed to relate hippocampal surface-shape patterns to verbal and visual learning. METHODS: We analyzed hippocampal surface shapes on high-resolution magnetic resonance images and the Adult Memory and Information Processing Battery in 145 unilateral refractory TLE patients undergoing epilepsy surgery, a validation set of 55 unilateral refractory TLE patients, and 39 age- and sex-matched healthy volunteers. RESULTS: Both left TLE (LTLE) and right TLE (RTLE) patients had lower verbal (LTLE 44 ± 11; RTLE 45 ± 10) and visual learning (LTLE 34 ± 8, RTLE 30 ± 8) scores than healthy controls (verbal 58 ± 8, visual 39 ± 6; p < 0.001). Verbal learning was more impaired the greater the atrophy of the left superolateral hippocampal head. In contrast, visual memory was worse with greater bilateral inferomedial hippocampal atrophy. Postsurgical verbal memory decline was more common in LTLE than in RTLE (reliable change index in LTLE 27% vs RTLE 7%, p = 0.006), whereas there were no differences in postsurgical visual memory decline between those groups. Preoperative atrophy of the left hippocampal tail predicted postsurgical verbal memory decline. INTERPRETATION: Memory deficits in TLE are associated with specific morphological alterations of the hippocampus, which could help stratify TLE patients into those at high versus low risk of presurgical or postsurgical memory deficits. This knowledge could improve planning and prognosis of selective epilepsy surgery and neuropsychological counseling in TLE. ANN NEUROL 2020 ANN NEUROL 2020;88:170-182.

The clinical utility of a memory specialization index in epilepsy surgery patients with unilateral hippocampal sclerosis.

OBJECTIVE: Although group studies provide some support for the material-specific model of memory function, there are considerable individual variations in memory function in people with temporal lobe epilepsy, even in those with the same underlying pathology. In this proof-of-concept study, we examined the sensitivity and specificity of a single measure of an individual's relative strength for the encoding of verbal or visual learning. METHODS: Six hundred ninety-two patients with left hemisphere language dominance and unilateral hippocampal sclerosis completed verbal and visual encoding tasks with similar test structures as part of their presurgical evaluation. Three hundred one patients had right hippocampal sclerosis (RHS), and 391 patients had left hippocampal sclerosis (LHS). A memory specialization index (MSI) was calculated by subtracting the Visual Learning z-score from the Verbal Learning z-score. A positive value on the MSI indicates a relative strength in verbal learning. A negative score indicates a relative strength in visual learning. RESULTS: Employing cut-offs of ±1, the MSI had a positive predictive value of 71% (confidence interval [CI] 95% 0.64-0.77) for LHS and 64% (CI 95% 0.55-0.74) for RHS and was superior to the standalone z-scores from the verbal and visual tests in each respect. In the LHS group, the MSI was significantly correlated with age and duration of epilepsy. Older patients who had a longer duration of epilepsy were more likely to demonstrate a similar level of impairment in both verbal and visual learning, with a decreasing discrepancy between the scores on the two tasks over time. SIGNIFICANCE: Our MSI provides a measure with high specificity for RHS. The pattern of strengths and weaknesses in visual and verbal encoding may evolve with age and duration of epilepsy, and clinicians should be aware of these factors when interpreting the lateralizing significance of test scores, particularly in a presurgical setting.

Decoupling of functional and structural language networks in temporal lobe epilepsy.

OBJECTIVE: To identify functional and structural alterations in language networks of people with temporal lobe epilepsy (TLE), who frequently present with naming and word-finding difficulties. METHODS: Fifty-five patients with unilateral TLE (29 left) and 16 controls were studied with auditory and picture naming functional magnetic resonance imaging (fMRI) tasks. Activation maxima in the left posterobasal temporal lobe were used as seed regions for whole-brain functional connectivity analyses (psychophysiological interaction). White matter language pathways were investigated using diffusion tensor imaging and neurite orientation dispersion and density imaging metrics extracted along fiber bundles starting from fMRI-guided seeds. Regression analyses were performed to investigate the correlation of functional connectivity with diffusion MRI metrics. RESULTS: In the whole group of patients and controls, weaker functional connectivity from the left posterobasal temporal lobe (1) to the bilateral anterior temporal lobe, precentral gyrus, and lingual gyrus during auditory naming and (2) to the bilateral occipital cortex and right fusiform gyrus during picture naming was associated with decreased neurite orientation dispersion and higher free water fraction of white matter tracts. Compared to controls, TLE patients exhibited fewer structural connections and an impaired coupling of functional and structural metrics. SIGNIFICANCE: TLE is associated with an impairment and decoupling of functional and structural language networks. White matter damage, as evidenced by diffusion abnormalities, may contribute to impaired functional connectivity and language dysfunction in TLE.

Estrogen Plus Progestin Hormone Therapy and Ovarian Cancer: A Complicated Relationship Explored.

BACKGROUND: Menopausal estrogen-alone therapy is a risk factor for endometrial and ovarian cancers. When a progestin is included with the estrogen daily (continuous estrogen-progestin combined therapy), there is no increased risk of endometrial cancer. However, the effect of continuous estrogen-progestin combined therapy on risk of ovarian cancer is less clear. METHODS: We pooled primary data from five population-based case-control studies in the Ovarian Cancer Association Consortium, including 1509 postmenopausal ovarian cancer cases and 2295 postmenopausal controls. Information on previous menopausal hormonal therapy use, as well as ovarian cancer risk factors, was collected using in-person interviews. Logistic regression was used to assess the association between use of continuous estrogen-progestin combined therapy and risk of ovarian cancer by duration and recency of use and disease histotype. RESULTS: Ever postmenopausal use of continuous estrogen-progestin combined therapy was not associated with increased risk of ovarian cancer overall (OR = 0.85, 95% CI = 0.72, 1.0). A decreased risk was observed for mucinous ovarian cancer (OR = 0.40, 95% CI = 0.18, 0.91). The other main ovarian cancer histotypes did not show an association (endometrioid: OR = 0.86, 95% CI = 0.57, 1.3, clear cell: OR = 0.68, 95% CI = 0.40, 1.2; serous: OR = 0.98, 95% CI = 0.80, 1.2). CONCLUSIONS: Given that estrogen-alone therapy has been shown to be associated with increased risk of ovarian cancer, these findings are consistent with the hypothesis that adding a progestin each day ameliorates the carcinogenic effects of estrogen on the cells of origin for all histotypes of ovarian cancer.

Motor hyperactivation during cognitive tasks: An endophenotype of juvenile myoclonic epilepsy.

OBJECTIVE: Juvenile myoclonic epilepsy (JME) is the most common genetic generalized epilepsy syndrome. Myoclonus may relate to motor system hyperexcitability and can be provoked by cognitive activities. To aid genetic mapping in complex neuropsychiatric disorders, recent research has utilized imaging intermediate phenotypes (endophenotypes). Here, we aimed to (a) characterize activation profiles of the motor system during different cognitive tasks in patients with JME and their unaffected siblings, and (b) validate those as endophenotypes of JME. METHODS: This prospective cross-sectional investigation included 32 patients with JME, 12 unaffected siblings, and 26 controls, comparable for age, sex, handedness, language laterality, neuropsychological performance, and anxiety and depression scores. We investigated patterns of motor system activation during episodic memory encoding and verb generation functional magnetic resonance imaging (fMRI) tasks. RESULTS: During both tasks, patients and unaffected siblings showed increased activation of motor system areas compared to controls. Effects were more prominent during memory encoding, which entailed hand motion via joystick responses. Subgroup analyses identified stronger activation of the motor cortex in JME patients with ongoing seizures compared to seizure-free patients. Receiver-operating characteristic curves, based on measures of motor activation, accurately discriminated both patients with JME and their siblings from healthy controls (area under the curve: 0.75 and 0.77, for JME and a combined patient-sibling group against controls, respectively; P < .005). SIGNIFICANCE: Motor system hyperactivation represents a cognitive, domain-independent endophenotype of JME. We propose measures of motor system activation as quantitative traits for future genetic imaging studies in this syndrome.

Abnormal hippocampal structure and function in juvenile myoclonic epilepsy and unaffected siblings.

Juvenile myoclonic epilepsy is the most common genetic generalized epilepsy syndrome, characterized by a complex polygenetic aetiology. Structural and functional MRI studies demonstrated mesial or lateral frontal cortical derangements and impaired fronto-cortico-subcortical connectivity in patients and their unaffected siblings. The presence of hippocampal abnormalities and associated memory deficits is controversial, and functional MRI studies in juvenile myoclonic epilepsy have not tested hippocampal activation. In this observational study, we implemented multi-modal MRI and neuropsychological data to investigate hippocampal structure and function in 37 patients with juvenile myoclonic epilepsy, 16 unaffected siblings and 20 healthy controls, comparable for age, gender, handedness and hemispheric dominance as assessed with language laterality indices. Automated hippocampal volumetry was complemented by validated qualitative and quantitative morphological criteria to detect hippocampal malrotation, assumed to represent a neurodevelopmental marker. Neuropsychological measures of verbal and visuo-spatial learning and an event-related verbal and visual memory functional MRI paradigm addressed mesiotemporal function. We detected a reduction of mean left hippocampal volume in patients and their siblings compared with controls (P < 0.01). Unilateral or bilateral hippocampal malrotation was identified in 51% of patients and 50% of siblings, against 15% of controls (P < 0.05). For bilateral hippocampi, quantitative markers of verticalization had significantly larger values in patients and siblings compared with controls (P < 0.05). In the patient subgroup, there was no relationship between structural measures and age at disease onset or degree of seizure control. No overt impairment of verbal and visual memory was identified with neuropsychological tests. Functional mapping highlighted atypical patterns of hippocampal activation, pointing to abnormal recruitment during verbal encoding in patients and their siblings [P < 0.05, familywise error (FWE)-corrected]. Subgroup analyses indicated distinct profiles of hypoactivation along the hippocampal long axis in juvenile myoclonic epilepsy patients with and without malrotation; patients with malrotation also exhibited reduced frontal recruitment for verbal memory, and more pronounced left posterior hippocampal involvement for visual memory. Linear models across the entire study cohort indicated significant associations between morphological markers of hippocampal positioning and hippocampal activation for verbal items (all P < 0.05, FWE-corrected). We demonstrate abnormalities of hippocampal volume, shape and positioning in patients with juvenile myoclonic epilepsy and their siblings, which are associated with reorganization of function and imply an underlying neurodevelopmental mechanism with expression during the prenatal stage. Co-segregation of abnormal hippocampal morphology in patients and their siblings is suggestive of a genetic imaging phenotype, independent of disease activity, and can be construed as a novel endophenotype of juvenile myoclonic epilepsy.

A comprehensive gene-environment interaction analysis in Ovarian Cancer using genome-wide significant common variants.

As a follow-up to genome-wide association analysis of common variants associated with ovarian carcinoma (cancer), our study considers seven well-known ovarian cancer risk factors and their interactions with 28 genome-wide significant common genetic variants. The interaction analyses were based on data from 9971 ovarian cancer cases and 15,566 controls from 17 case-control studies. Likelihood ratio and Wald tests for multiplicative interaction and for relative excess risk due to additive interaction were used. The top multiplicative interaction was noted between oral contraceptive pill (OCP) use (ever vs. never) and rs13255292 (p value = 3.48 × 10-4 ). Among women with the TT genotype for this variant, the odds ratio for OCP use was 0.53 (95% CI = 0.46-0.60) compared to 0.71 (95%CI = 0.66-0.77) for women with the CC genotype. When stratified by duration of OCP use, women with 1-5 years of OCP use exhibited differential protective benefit across genotypes. However, no interaction on either the multiplicative or additive scale was found to be statistically significant after multiple testing correction. The results suggest that OCP use may offer increased benefit for women who are carriers of the T allele in rs13255292. On the other hand, for women carrying the C allele in this variant, longer (5+ years) use of OCP may reduce the impact of carrying the risk allele of this SNP. Replication of this finding is needed. The study presents a comprehensive analytic framework for conducting gene-environment analysis in ovarian cancer.

Genome-wide association studies identify susceptibility loci for epithelial ovarian cancer in east Asian women.

OBJECTIVE: Genome-wide association studies (GWASs) for epithelial ovarian cancer (EOC) have focused largely on populations of European ancestry. We aimed to identify common germline variants associated with EOC risk in Asian women. METHODS: Genotyping was performed as part of the OncoArray project. Samples with >60% Asian ancestry were included in the analysis. Genotyping was performed on 533,631 SNPs in 3238 Asian subjects diagnosed with invasive or borderline EOC and 4083 unaffected controls. After imputation, genotypes were available for 11,595,112 SNPs to identify associations. RESULTS: At chromosome 6p25.2, SNP rs7748275 was associated with risk of serous EOC (odds ratio [OR] = 1.34, P = 8.7 × 10-9) and high-grade serous EOC (HGSOC) (OR = 1.34, P = 4.3 × 10-9). SNP rs6902488 at 6p25.2 (r2 = 0.97 with rs7748275) lies in an active enhancer and is predicted to impact binding of STAT3, P300 and ELF1. We identified additional risk loci with low Bayesian false discovery probability (BFDP) scores, indicating they are likely to be true risk associations (BFDP <10%). At chromosome 20q11.22, rs74272064 was associated with HGSOC risk (OR = 1.27, P = 9.0 × 10-8). Overall EOC risk was associated with rs10260419 at chromosome 7p21.3 (OR = 1.33, P = 1.2 × 10-7) and rs74917072 at chromosome 2q37.3 (OR = 1.25, P = 4.7 × 10-7). At 2q37.3, expression quantitative trait locus analysis in 404 HGSOC tissues identified ESPNL as a putative candidate susceptibility gene (P = 1.2 × 10-7). CONCLUSION: While some risk loci were shared between East Asian and European populations, others were population-specific, indicating that the landscape of EOC risk in Asian women has both shared and unique features compared to women of European ancestry.

Left temporal lobe language network connectivity in temporal lobe epilepsy.

Impairment of naming function is a critical problem for temporal lobe epilepsy patients, yet the neural correlates of the disruption of temporal lobe language networks are poorly understood. Using functional MRI, we investigated the activation and task-related functional connectivity of left temporal lobe language networks and their relation to clinical naming performance and disease characteristics. We studied 59 adult patients with temporal lobe epilepsy (35 left temporal lobe epilepsy) and 32 healthy controls with auditory and visual naming functional MRI tasks. Time series of activation maxima in the left posterior inferior temporal lobe were extracted to create a psychophysiological interaction regressor for subsequent seed-based whole-brain task-related functional connectivity analyses. Correlational analyses were performed to assess the association of functional MRI activation and functional connectivity with clinical naming scores, age of onset of epilepsy, and duration of epilepsy. Auditory naming elicited activation in the left posterior inferior temporal gyrus and visual naming in the left fusiform gyrus across all groups. Activations in the left inferior temporal gyrus, left thalamus and left supplementary motor region during auditory naming as well as left fusiform activations during picture naming correlated with better clinical naming performance. Functional connectivity analyses indicated coupling of left posterior inferior temporal regions to bilateral anterior and posterior temporal lobe regions and the bilateral inferior precentral gyrus as well as contralateral occipital cortex. Stronger functional connectivity was associated with better clinical naming performance in all groups. In patients with left temporal lobe epilepsy only, functional connectivity increased with later age of onset of epilepsy and shorter disease duration. This suggests that onset of seizures early in life and prolonged disease duration lead to disrupted recruitment of temporal lobe networks ipsilateral to the seizure focus, which might account for naming deficits in temporal lobe epilepsy.

Ovarian cancer risk, ALDH2 polymorphism and alcohol drinking: Asian data from the Ovarian Cancer Association Consortium.

The aldehyde dehydrogenase 2 (ALDH2) polymorphism rs671 (Glu504Lys) causes ALDH2 inactivation and adverse acetaldehyde exposure among Asians, but little is known of the association between alcohol consumption and rs671 and ovarian cancer (OvCa) in Asians. We conducted a pooled analysis of Asian ancestry participants in the Ovarian Cancer Association Consortium. We included seven case-control studies and one cohort study comprising 460 invasive OvCa cases, 37 borderline mucinous OvCa and 1274 controls of Asian descent with information on recent alcohol consumption. Pooled odds ratios (OR) with 95% confidence intervals (CI) for OvCa risk associated with alcohol consumption, rs671 and their interaction were estimated using logistic regression models adjusted for potential confounders. No significant association was observed for daily alcohol intake with invasive OvCa (OR comparing any consumption to none = 0.83; 95% CI = 0.58-1.18) or with individual histotypes. A significant decreased risk was seen for carriers of one or both Lys alleles of rs671 for invasive mucinous OvCa (OR = 0.44; 95% CI = 0.20-0.97) and for invasive and borderline mucinous tumors combined (OR = 0.48; 95% CI = 0.26-0.89). No significant interaction was observed between alcohol consumption and rs671 genotypes. In conclusion, self-reported alcohol consumption at the quantities estimated was not associated with OvCa risk among Asians. Because the rs671 Lys allele causes ALDH2 inactivation leading to increased acetaldehyde exposure, the observed inverse genetic association with mucinous ovarian cancer is inferred to mean that alcohol intake may be a risk factor for this histotype. This association will require replication in a larger sample.

Adult height is associated with increased risk of ovarian cancer: a Mendelian randomisation study.

BACKGROUND: Observational studies suggest greater height is associated with increased ovarian cancer risk, but cannot exclude bias and/or confounding as explanations for this. Mendelian randomisation (MR) can provide evidence which may be less prone to bias. METHODS: We pooled data from 39 Ovarian Cancer Association Consortium studies (16,395 cases; 23,003 controls). We applied two-stage predictor-substitution MR, using a weighted genetic risk score combining 609 single-nucleotide polymorphisms. Study-specific odds ratios (OR) and 95% confidence intervals (CI) for the association between genetically predicted height and risk were pooled using random-effects meta-analysis. RESULTS: Greater genetically predicted height was associated with increased ovarian cancer risk overall (pooled-OR (pOR) = 1.06; 95% CI: 1.01-1.11 per 5 cm increase in height), and separately for invasive (pOR = 1.06; 95% CI: 1.01-1.11) and borderline (pOR = 1.15; 95% CI: 1.02-1.29) tumours. CONCLUSIONS: Women with a genetic propensity to being taller have increased risk of ovarian cancer. This suggests genes influencing height are involved in pathways promoting ovarian carcinogenesis.

Effects of carbamazepine and lamotrigine on functional magnetic resonance imaging cognitive networks.

OBJECTIVE: To investigate the effects of sodium channel-blocking antiepileptic drugs (AEDs) on functional magnetic resonance imaging (fMRI) language network activations in patients with focal epilepsy. METHODS: In a retrospective study, we identified patients who were treated at the time of language fMRI scanning with either carbamazepine (CBZ; n = 42) or lamotrigine (LTG; n = 42), but not another sodium channel-blocking AED. We propensity-matched 42 patients taking levetiracetam (LEV) as "patient-controls" and included further 42 age- and gender-matched healthy controls. After controlling for age, age at onset of epilepsy, gender, and antiepileptic comedications, we compared verbal fluency fMRI activations between groups and out-of-scanner psychometric measures of verbal fluency. RESULTS: Patients on CBZ performed less well on a verbal fluency tests than those taking LTG or LEV. Compared to either LEV-treated patients or controls, patients taking CBZ showed decreased activations in left inferior frontal gyrus and patients on LTG showed abnormal deactivations in frontal and parietal default mode areas. All patient groups showed fewer activations in the putamen bilaterally compared to controls. In a post hoc analysis, out-of-scanner fluency scores correlated positively with left putamen activation. SIGNIFICANCE: Our study provides evidence of AED effects on the functional neuroanatomy of language, which might explain subtle language deficits in patients taking otherwise well-tolerated sodium channel-blocking agents. Patients on CBZ showed dysfunctional frontal activation and more pronounced impairment of performance than patients taking LTG, which was associated only with failure to deactivate task-negative networks. As previously shown for working memory, LEV treatment did not affect functional language networks.

rs495139 in the TYMS-ENOSF1 Region and Risk of Ovarian Carcinoma of Mucinous Histology.

Thymidylate synthase (TYMS) is a crucial enzyme for DNA synthesis. TYMS expression is regulated by its antisense mRNA, ENOSF1. Disrupted regulation may promote uncontrolled DNA synthesis and tumor growth. We sought to replicate our previously reported association between rs495139 in the TYMS-ENOSF1 3' gene region and increased risk of mucinous ovarian carcinoma (MOC) in an independent sample. Genotypes from 24,351 controls to 15,000 women with invasive OC, including 665 MOC, were available. We estimated per-allele odds ratios (OR) and 95% confidence intervals (CI) using unconditional logistic regression, and meta-analysis when combining these data with our previous report. The association between rs495139 and MOC was not significant in the independent sample (OR = 1.09; 95% CI = 0.97⁻1.22; p = 0.15; N = 665 cases). Meta-analysis suggested a weak association (OR = 1.13; 95% CI = 1.03⁻1.24; p = 0.01; N = 1019 cases). No significant association with risk of other OC histologic types was observed (p = 0.05 for tumor heterogeneity). In expression quantitative trait locus (eQTL) analysis, the rs495139 allele was positively associated with ENOSF1 mRNA expression in normal tissues of the gastrointestinal system, particularly esophageal mucosa (r = 0.51, p = 1.7 × 10-28), and nonsignificantly in five MOC tumors. The association results, along with inconclusive tumor eQTL findings, suggest that a true effect of rs495139 might be small.

Memory network plasticity after temporal lobe resection: a longitudinal functional imaging study.

Anterior temporal lobe resection can control seizures in up to 80% of patients with temporal lobe epilepsy. Memory decrements are the main neurocognitive complication. Preoperative functional reorganization has been described in memory networks, but less is known of postoperative reorganization. We investigated reorganization of memory-encoding networks preoperatively and 3 and 12 months after surgery. We studied 36 patients with unilateral medial temporal lobe epilepsy (19 right) before and 3 and 12 months after anterior temporal lobe resection. Fifteen healthy control subjects were studied at three equivalent time points. All subjects had neuropsychological testing at each of the three time points. A functional magnetic resonance imaging memory-encoding paradigm of words and faces was performed with subsequent out-of-scanner recognition assessments. Changes in activations across the time points in each patient group were compared to changes in the control group in a single flexible factorial analysis. Postoperative change in memory across the time points was correlated with postoperative activations to investigate the efficiency of reorganized networks. Left temporal lobe epilepsy patients showed increased right anterior hippocampal and frontal activation at both 3 and 12 months after surgery relative to preoperatively, for word and face encoding, with a concomitant reduction in left frontal activation 12 months postoperatively. Right anterior hippocampal activation 12 months postoperatively correlated significantly with improved verbal learning in patients with left temporal lobe epilepsy from preoperatively to 12 months postoperatively. Preoperatively, there was significant left posterior hippocampal activation that was sustained 3 months postoperatively at word encoding, and increased at face encoding. For both word and face encoding this was significantly reduced from 3 to 12 months postoperatively. Patients with right temporal lobe epilepsy showed increased left anterior hippocampal activation on word encoding from 3 to 12 months postoperatively compared to preoperatively. On face encoding, left anterior hippocampal activations were present preoperatively and 12 months postoperatively. Left anterior hippocampal and orbitofrontal cortex activations correlated with improvements in both design and verbal learning 12 months postoperatively. On face encoding, there were significantly increased left posterior hippocampal activations that reduced significantly from 3 to 12 months postoperatively. Postoperative changes occur in the memory-encoding network in both left and right temporal lobe epilepsy patients across both verbal and visual domains. Three months after surgery, compensatory posterior hippocampal reorganization that occurs is transient and inefficient. Engagement of the contralateral hippocampus 12 months after surgery represented efficient reorganization in both patient groups, suggesting that the contralateral hippocampus contributes to memory outcome 12 months after surgery.

Risk Prediction for Epithelial Ovarian Cancer in 11 United States-Based Case-Control Studies: Incorporation of Epidemiologic Risk Factors and 17 Confirmed Genetic Loci.

Previously developed models for predicting absolute risk of invasive epithelial ovarian cancer have included a limited number of risk factors and have had low discriminatory power (area under the receiver operating characteristic curve (AUC) < 0.60). Because of this, we developed and internally validated a relative risk prediction model that incorporates 17 established epidemiologic risk factors and 17 genome-wide significant single nucleotide polymorphisms (SNPs) using data from 11 case-control studies in the United States (5,793 cases; 9,512 controls) from the Ovarian Cancer Association Consortium (data accrued from 1992 to 2010). We developed a hierarchical logistic regression model for predicting case-control status that included imputation of missing data. We randomly divided the data into an 80% training sample and used the remaining 20% for model evaluation. The AUC for the full model was 0.664. A reduced model without SNPs performed similarly (AUC = 0.649). Both models performed better than a baseline model that included age and study site only (AUC = 0.563). The best predictive power was obtained in the full model among women younger than 50 years of age (AUC = 0.714); however, the addition of SNPs increased the AUC the most for women older than 50 years of age (AUC = 0.638 vs. 0.616). Adapting this improved model to estimate absolute risk and evaluating it in prospective data sets is warranted.