Impact of fetal expression quantitative trait loci on transcriptome-wide association study of childhood leukemia.

Transcriptome-wide association studies increase the yield of loci associated with disease phenotypes by focusing on expression quantitative trait loci (eQTL). The major source of eQTL data for is the Gene and Tissue Expression (GTEx) project, which is comprised entirely of adults, mainly those >50 years of age at death. Since gene expression levels differ by developmental stage, it is not clear whether eQTLs derived from adult data sources are best suited for use in young-onset diseases such as pediatric cancers. To fill in this knowledge gap, we performed a large-scale eQTL mapping analysis in the GenCord study with newborn samples and compared it with GTEx. Under matched conditions, we found around 80% of the eQTLs in one study can be replicated in the other. However, among all eQTLs identified in GenCord (GTEx), 584 (1045) showed statistically significant differences in effect sizes in GTEx (GenCord). We further investigated how using fetal eQTL data can facilitate the genetic association study of acute lymphoblastic leukemia. GenCord and GTEx identified the same genetic loci with statistical significance; however, the overall association pattern was only weakly correlated. Our paper demonstrates age-differential eQTLs and shows their potential influence on childhood leukemia research.

Influence of alcohol consumption and alcohol metabolism variants on breast cancer risk among Black women: results from the AMBER consortium.

BACKGROUND: Moderate to heavy alcohol consumption is associated with an increased risk of breast cancer. The etiologic role of genetic variation in genes involved in ethanol metabolism has not been established, with little information available among women of African ancestry. METHODS: Our analysis from the African American Breast Cancer Epidemiology and Risk (AMBER) Consortium included 2889 U.S. Black women who were current drinkers at the time of breast cancer diagnosis (N cases = 715) and had available genetic data for four ethanol metabolism genomic regions (ADH, ALDH, CYP2E1, and ALDH2). We used generalized estimating equations to calculate genetic effects, gene* alcohol consumption (≥ 7drinks/week vs. < 7/week) interactions, and joint main plus interaction effects of up to 23,247 variants in ethanol metabolism genomic regions on odds of breast cancer. RESULTS: Among current drinkers, 21% of cases and 14% of controls reported consuming ≥ 7 drinks per week. We identified statistically significant genetic effects for rs79865122-C in CYP2E1 with odds of ER- breast cancer and odds of triple negative breast cancer, as well as a significant joint effect with odds of ER- breast cancer (≥ 7drinks per week OR = 3.92, < 7 drinks per week OR = 0.24, pjoint = 3.74 × 10-6). In addition, there was a statistically significant interaction of rs3858704-A in ALDH2 with consumption of ≥ 7 drinks/week on odds of triple negative breast cancer (≥ 7drinks per week OR = 4.41, < 7 drinks per week OR = 0.57, pint = 8.97 × 10-5). CONCLUSIONS: There is a paucity of information on the impact of genetic variation in alcohol metabolism genes on odds of breast cancer among Black women. Our analysis of variants in four genomic regions harboring ethanol metabolism genes in a large consortium of U.S. Black women identified significant associations between rs79865122-C in CYP2E1 and odds of ER- and triple negative breast cancer. Replication of these findings is warranted.

Minority children experience a higher risk of death from many central nervous system tumor types even after accounting for treatment received: A National Cancer Database analysis.

BACKGROUND: Brain tumors are the leading cause of death from disease in children. Racial/ethnic minority children have poorer outcomes than White children; however, it is not clear whether this association is mediated by treatment received. METHODS: Children (aged 0-19 years) diagnosed with brain tumors in the National Cancer Database (2004-2016) were identified. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) between race/ethnicity (Black, Hispanic, Asian/Pacific Islander, American Indian/Alaska Native, or White [reference]) and death. An inverse odds weighted mediation analysis was performed with treatment received as the mediator. RESULTS: Among 22,469 cases, White children (69% of the sample) had significantly better overall 12.5-year survival (P < .01). Black children (13% of the sample) and Hispanic children (14% of the sample) had an increased risk of death overall and for glioblastoma and oligodendroglioma. Compared with Whites, Asian/Pacific Islander children had a higher risk of death from choroid plexus tumors and a lower risk of death from medulloblastoma. There were no statistically significant meditating effects by treatment received, although the estimate was borderline in Hispanic children (indirect HR, 1.08; 95% CI, 0.99-1.18). A treatment-independent association between race/ethnicity and death remained for Hispanic children (direct HR, 1.18; 95% CI, 1.04-1.33) and Black children (direct HR, 1.28; 95% CI, 1.13-1.45). If deaths in minorities had equaled those in White children, 5% fewer total deaths and 15% fewer minority deaths would have occurred. CONCLUSIONS: Survival disparities exist in pediatric brain tumors and are largely independent of treatment received, but other mechanisms linked to race/ethnicity remain important.

Young adult males have worse survival than females that is largely independent of treatment received for many types of central nervous system tumors: A National Cancer Database analysis.

BACKGROUND: Central nervous system (CNS) tumors rank among the top 5 cancers diagnosed in young adults aged 20 to 39 years at diagnosis and show a clear male excess in incidence. It is unknown whether sex differences in survival persist across histologic types and depend on the treatment received. METHODS: From the National Cancer Database (2004-2016), young adults (aged 20-39 years) who had been diagnosed with CNS tumors were identified. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated as measures of association between sex and death via Cox regression. An inverse odds weighting mediation analysis was performed with treatment received as a mediator. RESULTS: There were 47,560 cases (47% male). Males had worse overall survival than females for 9 of 16 histologic types, including diffuse astrocytoma, glioblastoma, and meningioma (all P < .05). Males had an increased risk of death after a brain tumor diagnosis overall (HR, 1.47; 95% CI, 1.41-1.53) and for 8 histologies. There was a significant association between male sex and death overall that was mediated by treatment received (indirect-effect HR, 1.17; 95% CI, 1.15-1.18), but no single histology had a significant indirect effect. All histologies examined in mediation analyses had significant direct effects for sex. The excess mortality due to sex was 20% for all CNS tumors combined and 34% among males with CNS tumors. CONCLUSIONS: Overall, treatment received may mediate a portion of the association between sex and death after a CNS tumor, but sex itself appears to be a stronger risk factor for death in this study.

Genetic variants in anti-Müllerian hormone-related genes and breast cancer risk: results from the AMBER consortium.

PURPOSE: Circulating anti-Müllerian hormone (AMH) levels are positively associated with time to menopause and breast cancer risk. We examined breast cancer associations with single nucleotide polymorphisms (SNPs) in the AMH gene or its receptor genes, ACVR1 and AMHR2, among African American women. METHODS: In the AMBER consortium, we tested 65 candidate SNPs, and 1130 total variants, in or near AMH, ACVR1, and AMHR2 and breast cancer risk. Overall, 3649 cases and 4230 controls contributed to analyses. Odds ratios (OR) and 95% confidence intervals (CI) for breast cancer were calculated using multivariable logistic regression. RESULTS: After correction for multiple comparisons (false-discovery rate of 5%), there were no statistically significant associations with breast cancer risk. Without correction for multiple testing, four candidate SNPs in ACVR1 and one near AMH were associated with breast cancer risk. In ACVR1, rs13395576[C] was associated with lower breast cancer risk overall (OR 0.84; 95% CI 0.72, 0.97) and for ER+ disease (OR 0.75; CI 0.62, 0.89) (p < 0.05). Rs1220110[A] and rs1220134[T] each had ORs of 0.89-0.90 for postmenopausal and ER+ breast cancer (p ≤ 0.03). Conversely, rs1682130[T] was associated with higher risk of ER+ breast cancer (OR 1.17; 95% CI 1.04, 1.32). Near AMH, rs6510652[T] had ORs of 0.85-0.90 for breast cancer overall and after menopause (p ≤ 0.02). CONCLUSIONS: The present results, from a large study of African American women, provide limited support for an association between AMH-related polymorphisms and breast cancer risk and require replication in other studies.

Sex differences in associations between birth characteristics and childhood cancers: a five-state registry-linkage study.

BACKGROUND: There is a well-recognized male excess in childhood cancer incidence; however, it is unclear whether there is etiologic heterogeneity by sex when defined by epidemiologic risk factors. METHODS: Using a 5-state registry-linkage study (cases n = 16,411; controls n = 69,816), we estimated sex-stratified odds ratios (OR) and 95% confidence intervals (95% CI) between birth and demographic characteristics for 16 pediatric cancers. Evidence of statistical interaction (p-interaction < 0.01) by sex was evaluated for each characteristic in each cancer. RESULTS: Males comprised > 50% of cases for all cancers, except Wilms tumor (49.6%). Sex interacted with a number of risk factors (all p-interaction < 0.01) including gestational age for ALL (female, 40 vs. 37-39 weeks OR: 0.84, 95% CI 0.73-0.97) and ependymoma (female, 40 vs. 37-39 OR: 1.78, 95% CI 1.14-2.79; female, ≥ 41 OR: 2.01. 95% CI 1.29-3.14), birth order for AML (female, ≥ 3rd vs. 1st OR: 1.39, 95% CI 1.01-1.92), maternal education for Hodgkin lymphoma (male, any college vs. < high school[HS] OR: 1.47, 95% CI 1.03-2.09) and Wilms tumor (female, any college vs. HS OR: 0.74, 95% CI 0.59-0.93), maternal race/ethnicity for neuroblastoma (male, black vs. white OR: 2.21, 95% CI 1.21-4.03; male, Hispanic vs. white OR: 1.86, 95% CI 1.26-2.75; female, Asian/Pacific Islander vs. white OR: 0.28, 95% CI 0.12-0.69), and paternal age (years) for hepatoblastoma in males (< 24 vs. 25-29 OR: 2.17, 95% CI 1.13-4.19; ≥ 35 vs. 25-29 OR: 2.44, 95% CI 1.28-4.64). CONCLUSIONS: These findings suggest etiologic heterogeneity by sex for childhood cancers for gestational age, maternal education, and race/ethnicity and paternal age.

Childhood cancer incidence among specific Asian and Pacific Islander populations in the United States.

Despite the vast genetic and environmental diversity in Asia, individuals of Asian and Pacific Islander (API) descent are often combined into a single group for epidemiologic analyses within the U.S. We used the Surveillance, Epidemiology and End Results (SEER) Detailed Asian/Pacific Islander Database to calculate incidence rates for discrete groups among children aged 0 to 19 years. Due to sample size constraints we pooled incidence among regional groups based on countries of origin: East Asians (Chinese, Japanese, Korean), Southeast (SE) Asians (Vietnamese, Laotian, Cambodian), Asian Indian/Pakistani, Oceanians (Guamanian, Samoan, Tongan) and Filipinos. Incidence rate ratios (IRR) and 95% confidence intervals (CI) were calculated comparing each API regional group to Non-Hispanic Whites (NHW) and East Asians. Finally, we calculated the correlation between incidence of cancer in specific API ethnicities in SEER and in originating countries in the Cancer Incidence in Five Continents. Incidence rates among API regional groups varied. Acute lymphoblastic leukemia (ALL) was lower in children of SE Asian descent (IRR 0.65, 95% CI 0.44, 0.96) compared to NHW. Acute myeloid leukemia (AML) was more common among children from Oceania compared to NHW (IRR 3.88, 95% CI 1.83, 8.22). East Asians had higher incidence rates than SE Asians but lower rates compared to children from Oceania. Correlation of some incidence rates between US-based API ethnicities and originating countries were similar. The variation observed in childhood cancer incidence patterns among API groups may indicate differences in underlying genetics and/or patterns of exposure.

Survival differences by race/ethnicity among children and adolescents diagnosed with germ cell tumors.

Survival differences by racial and ethnic group have been reported in children and adolescents with germ cell tumors (GCTs), but whether these differences depend on stage of disease is unclear. Using the SEER 18 registries (2000-2015), we examined GCT survival differences by race/ethnicity (non-Hispanic white [NHW], Black, Asian/Pacific Islander [API], Hispanic) separately for males and females aged 0-19 years at diagnosis. We used Kaplan-Meier survival curves (Log-Rank p values) to characterize survival differences. Cox proportional hazards models were used to estimate hazard ratios (HR) and 95% confidence intervals (95% CI) for the association between race/ethnicity and death. Using an inverse odds weighting mediation analysis, we estimated the association between race/ethnicity and death treating stage of disease as the mediator. There were no significant racial/ethnic survival differences among females. Male survival differed by race/ethnicity (p < 0.0001) with NHW males having the best survival. Compared to NHW, API and Hispanic males had significantly higher risks of death (API HR: 2.18; 95% CI: 1.32-3.56; Hispanic HR: 1.98; 95% CI: 1.42-2.78) (model adjusted for age and year at diagnosis, tumor histology and location, stage). This association was mediated by stage of disease only among Hispanic males with gonadal tumors (indirect HR: 1.18; 95% CI: 1.03-1.35). The increased risk of death after a testicular GCT diagnosis observed among Hispanic males was mediated by stage of disease. For API males and Hispanic males with extragonadal tumors, other unidentified factors including differences in exposures, tumor biology or treatment received may impact the observed racial/ethnic survival disparities.

Incidence of second malignancies in individuals diagnosed with malignant peripheral nerve sheath tumors.

BACKGROUND: The incidence of malignant peripheral nerve sheath tumors (MPNSTs) is low in the general population, although individuals with Neurofibromatosis Type I (NF1) are particularly susceptible. These tumors generally have a high probability of metastasis. The rate and types of second malignancies (SMNs) after a primary diagnosis of MPNST are not well characterized. We aimed to quantify the rate of SMNs among individuals with a first primary MPNST using population-based data. METHODS: We estimated age-standardized incidence rates (SIRs) for SMNs among 1,579 primary MPNST cases between ages 0-85+ using SEER 18 (2000-2015). We estimated incidence rate ratios (IRRs) and 95% confidence intervals (95% CI) for SMNs in MPNST cases compared with general population rates. We conducted sex-stratified and age-restricted analyses (< 30 years at diagnosis). RESULTS: Seven percent (108/1579) of MPNST cases developed a SMN (SIR of 4635 cases/million). Compared to the general population, MPNST cases were more likely to develop SMNs (IRR: 29.3; 95% CI 23.8-34.8) and had a much higher rate of second MPNSTs (IRR: 15,992.9; 95% CI 9594.5-22,391.3). Aside from a second MPNST, second cancers were frequently diagnosed in the breast, lung, skin, and soft tissue in females and were myeloid and skin malignancies in males. When restricted to < 30 years of age, second MPNSTs were the most common cancers diagnosed. CONCLUSIONS: The rate of SMNs among MPNST cases is tremendously higher than that observed among individuals with other cancers, particularly for second MPNSTs. These findings suggest rates of SMNs may also be higher in NF1 individuals.

Differences in race, molecular and tumor characteristics among women diagnosed with invasive ductal and lobular breast carcinomas.

BACKGROUND: The dominant invasive breast cancer histologic subtype, ductal carcinoma, shows intrinsic subtype diversity. However, lobular breast cancers are predominantly Luminal A. Both histologic subtypes show distinct relationships with patient and tumor characteristics, but it is unclear if these associations remain after accounting for intrinsic subtype. METHODS: Generalized linear models were used to estimate relative frequency differences (RFDs) and 95% confidence intervals (95% CIs) for the associations between age, race, tumor characteristics, immunohistochemistry (IHC) and RNA-based intrinsic subtype, TP53 status, and histologic subtype in the Carolina Breast Cancer Study (CBCS, n = 3,182) and The Cancer Genome Atlas (TCGA, n = 808). RESULTS: Relative to ductal tumors, lobular tumors were significantly more likely to be Luminal A [CBCS RNA RFD: 44.9%, 95% CI (39.6, 50.1); TCGA: RFD: 50.5%, 95% CI (43.9, 57.1)], were less frequent among young (≤ 50 years) and black women, were larger in size, low grade, less frequently had TP53 pathway defects, and were diagnosed at later stages. These associations persisted among Luminal A tumors (n = 242). CONCLUSIONS: While histology is strongly associated with molecular characteristics, histologic associations with age, race, size, grade, and stage persisted after restricting to Luminal A subtype. Histology may continue to be clinically relevant among Luminal A breast cancers.

Generation of dual specific bivalent BiTEs (dbBIspecific T-cell engaging antibodies) for cellular immunotherapy.

BACKGROUND: Bispecific T-cell engaging antibodies (BiTES), comprising dual anti-CD3 and anti-tumor antigen scFv fragments, are important therapeutic agents for the treatment of cancer. The dual scFv construct for BiTES requires proper protein folding while their small molecular size leads to rapid kidney clearance. METHODS: An intact (150 kDa) anti-tumor antigen antibody to CEA was joined in high yield (ca. 30%) to intact (150 kDa) anti-murine and anti-human CD3 antibodies using hinge region specific Click chemistry to form dual-specific, bivalent BiTES (dbBiTES, 300 kDa). dbBiTEs were tested in vitro by EM, flow cytometry and cell cytoxicity and in vivo by PET tumor imaging and redirected T-cell therapy. RESULTS: The interlocked hinge regions are compatible with a structural model that fits the electron micrographs of 300 kDa particles. Compared to intact anti-CEA antibody, dbBiTES exhibit high in vitro cytotoxicity, high in vivo tumor targeting as demonstrated by PET imaging, and redirected dbBiTE coated T-cells (1 microgram/10 million cells) that kill CEA+ target cells in vivo in CEA transgenic mice. CONCLUSION: dbBiTE redirected T-cell therapy is a promising, efficient approach for targeting and killing cancer cells.

Sex ratio among childhood cancers by single year of age.

BACKGROUND: The male excess in childhood cancer incidence is well-established; however, the underlying biologic mechanisms remain unknown. Examining the association between male sex and childhood cancer by single year of age and tumor type may highlight important periods of risk such as variation in growth and hormonal changes, which will inform etiologic hypotheses. METHODS: Using data from the Surveillance, Epidemiology, and End Results (SEER) 18 registries (2000-2015), incidence rate ratios (IRR) and 95% confidence intervals (95% CI) were estimated as the measure of association between male sex and childhood cancer by single year of age (0-19). RESULTS: The IRR for male cancer overall was 1.19 (95% CI, 1.18-1.20) and was similar in magnitude at nearly every year of age. Burkitt lymphoma was strongly associated with male sex (IRRs ≥2 at each year of age). Increased incidence was observed among males for acute lymphoblastic leukemia, Hodgkin and non-Hodgkin lymphomas for nearly all years of age. Medulloblastoma was the only central nervous system tumor with a significant male predominance at nearly every age. Male sex displayed a consistent inverse association with nephroblastoma and thyroid carcinoma over the ages studied. CONCLUSIONS: Male sex was positively associated with most cancers. The higher incidence rates observed in males remained consistent over the childhood and adolescent periods, suggesting that childhood and adolescent hormonal fluctuations may not be the primary driving factor for the sex disparities in childhood cancer. The observed incidence disparities may be due to sex differences in exposures, genetics, or immune responses.

Klinefelter syndrome in males with germ cell tumors: A report from the Children's Oncology Group.

BACKGROUND: Males with Klinefelter syndrome (KS) (47,XXY) may be more likely to develop germ cell tumors (GCTs), particularly mediastinal GCTs. To date, there are no reports characterizing the prevalence of KS among male GCT cases. METHODS: The authors used array genotyping data from a Children's Oncology Group epidemiology study to estimate the prevalence of KS in males with GCTs (433 males aged birth-19 years). Using Fisher's exact tests, the authors examined differences in age at diagnosis, race/ethnicity, tumor location and histology, and several birth characteristics between cases of KS-GCT and GCT cases without chromosomal abnormalities. Using publicly available data, the authors estimated the 1-year risk, risk ratio, and corresponding 95% confidence interval of GCTs among KS cases. RESULTS: Based on analysis of array genotyping data, 3% of male GCT cases (13 cases) had KS. The additional X chromosome was of maternal origin in 7 of the 13 cases. Of these 13 KS cases, 5 of 9 KS-GCT cases with parental questionnaire data (56%) reported a diagnosis of KS. No significant differences were observed with regard to patient or birth characteristics between KS-GCT and non-KS-GCT cases. KS-GCT cases were significantly more likely to be diagnosed with mediastinal tumors than non-KS-GCT cases (P<.01). The authors estimated the risk of developing a GCT among males with KS to be 0.00025, or 1 per 4000 males (risk ratio, 18.8; 95% confidence interval, 11.7-30.0). CONCLUSIONS: Compared with males without chromosomal abnormalities, males with KS are more likely to be diagnosed with a mediastinal GCT. The presence of KS should be considered in males with a diagnosis of mediastinal GCT. In the current study, the authors report that approximately one-third of males with mediastinal germ cell tumors have Klinefelter syndrome, and therefore screening of these individuals for the syndrome may be warranted. Males with Klinefelter syndrome are 19 times as likely as males without Klinefelter syndrome to develop germ cell tumors.

Differences in DNA methylation profiles by histologic subtype of paediatric germ cell tumours: a report from the Children's Oncology Group.

BACKGROUND: Abnormal DNA methylation may be important in germ cell tumour (GCT) aetiology, as germ cells undergo complete epigenetic reprogramming during development. GCTs show differences in global and promoter methylation patterns by histologic subtype. We conducted an epigenome-wide study to identify methylation differences by GCT histology. METHODS: Using the Illumina HumanMethylation450K array we measured methylation in 154 paediatric GCTs (21 germinomas/seminomas/dysgerminoma, 70 yolk sac tumours [YST], 9 teratomas, and 54 mixed histology tumours). We identified differentially methylated regions (DMRs) between GCT histologies by comparing methylation beta values. RESULTS: We identified 8,481 DMRs (FWER < 0.05). Unsupervised hierarchical clustering of individual probes within DMRs resulted in four high level clusters closely corresponding to tumour histology. Clusters corresponding to age, location, sex and FFPE status were not observed within these DMRs. Germinomas displayed lower levels of methylation across the DMRs relative to the other histologic subtypes. Pathway analysis on the top 10% of genes with differential methylation in germinomas/seminomas/dysgerminoma compared to YST suggested angiogenesis and immune cell-related pathways displayed decreased methylation in germinomas/seminomas/dysgerminoma relative to YST. CONCLUSIONS: Paediatric GCT histologies have differential methylation patterns. The genes that are differentially methylated may provide insights into GCT aetiology including the timing of GCT initiation.

Reproductive risk factor associations with lobular and ductal carcinoma in the Carolina Breast Cancer Study.

BACKGROUND: Invasive lobular breast tumors display unique reproductive risk factor profiles. Lobular tumors are predominantly Luminal A subtype, and it is unclear whether reported risk factor associations are independent of molecular subtype. METHODS: Polytomous logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (95% CIs) for the associations between risk factors and histologic subtype [ductal (n = 2,856), lobular (n = 326), and mixed ductal-lobular (n = 473)] in the Carolina Breast Cancer Study (1993-2013). Three-marker immunohistochemical clinical subtypes were defined as Luminal A (ER+ or PR+/HER2-), Luminal B (ER+ or PR+/HER2+), Triple Negative (ER-/PR-/HER2-), and HER2+ (ER-/PR-/HER2+). RESULTS: In case-case analyses compared to ductal, lobular tumors were significantly associated with lactation duration > 12 months [OR 1.86, 95% CI (1.33-2.60)], age at first birth ≥ 26 years [OR: 1.35, 95% CI: (1.03-1.78)], and current oral contraceptive use [OR: 1.86, 95% CI: (1.08-3.20)]. Differences in risk factor associations between ductal and lobular tumors persisted after restricting to Luminal A subtype. CONCLUSIONS: Lobular tumors were associated with older age at first birth, increased lactation duration, and current oral contraceptive use. Etiologic heterogeneity by histology persisted after restricting to Luminal A subtype, suggesting both tumor histology and intrinsic subtype play integral parts in breast cancer risk.

Selective single cell isolation for genomics using microraft arrays.

Genomic methods are used increasingly to interrogate the individual cells that compose specific tissues. However, current methods for single cell isolation struggle to phenotypically differentiate specific cells in a heterogeneous population and rely primarily on the use of fluorescent markers. Many cellular phenotypes of interest are too complex to be measured by this approach, making it difficult to connect genotype and phenotype at the level of individual cells. Here we demonstrate that microraft arrays, which are arrays containing thousands of individual cell culture sites, can be used to select single cells based on a variety of phenotypes, such as cell surface markers, cell proliferation and drug response. We then show that a common genomic procedure, RNA-seq, can be readily adapted to the single cells isolated from these rafts. We show that data generated using microrafts and our modified RNA-seq protocol compared favorably with the Fluidigm C1. We then used microraft arrays to select pancreatic cancer cells that proliferate in spite of cytotoxic drug treatment. Our single cell RNA-seq data identified several expected and novel gene expression changes associated with early drug resistance.

Combined CD44, c-MET, and EGFR expression in p16-positive and p16-negative head and neck squamous cell carcinomas.

PURPOSE/OBJECTIVE(S): To examine the association between CD44 and c-MET expression in relation to p16 and EGFR in patients with head and neck squamous cell carcinoma (HNSCC). MATERIALS/METHODS: Immunohistochemical staining of CD44, p16, EGFR, and c-MET was performed on 105 locally advanced HNSCC patients treated with chemoradiation. CD44 expression was correlated with c-MET, EGFR, and p16, locoregional control (LRC), distant metastases (DM), disease-free survival (DFS) and overall survival (OS). RESULTS: High CD44 expression was present in 33% of patients and was associated with non-oropharynx primaries (P < 0.001), high c-MET expression (P < 0.001), p16-negative (P < 0.001) and EGFR-positive tumors (P < 0.001). Fifty-seven percent of CD44 high expressing tumors had high c-MET expression compared to 21% of CD44 low expressing tumors (P < 0.001). High CD44 expression predicted for worse LRC (HR: 2.44; 95% CI: 1.16-5.13; P = 0.018), DFS (HR: 2.61; 95% CI: 1.46-4.67; P = 0.001), and OS (HR: 2.52; 95% CI: 1.30-4.92; P = 0.007) but not DM (P = 0.57) on univariate analysis. Patients with both high CD44 and c-MET expression had a poor prognosis with a 2-year DFS of 30% compared to 70% in the rest of the cohort (P = 0.003). On multivariable analysis, after adjusting for site, T-stage, smoking history, and EGFR status, high c-MET (P = 0.039) and negative p16 status (P = 0.034) predicted for worse DFS, while high CD44 expression did not (P = 0.43). CONCLUSIONS: High CD44 expression is associated with high c-MET expression, p16-negative tumors, and EGFR-positive tumors. The combination of these markers predicts for poor prognosis in HNSCC patients treated with chemoradiation.

Alcohol intake and invasive breast cancer risk by molecular subtype and race in the Carolina Breast Cancer Study.

PURPOSE: Alcohol is an established breast cancer risk factor, but there is little evidence on whether the association differs between African Americans and whites. METHODS: Invasive breast cancers (n = 1,795; 1,014 white, 781 African American) and age- and race-matched controls (n = 1,558; 844 white, 714 African American) from the Carolina Breast Cancer Study (Phases I-II) were used to estimate odds ratios (ORs) and 95 % confidence interval (CI) for pre-diagnosis drinks per week and breast cancer risk. RESULTS: African American controls reported lower alcohol intake than white controls across all age groups. Light drinking (0 to ≤2 per week) was more prevalent among African American controls. Moderate-to-heavy drinking was more prevalent in white controls. African Americans who reported drinking >7 drinks per week had an elevated risk compared to light drinkers [adjusted OR, 95% CI 1.62 (1.03-2.54)]. A weaker association was observed among whites [adjusted OR, 95% CI 1.20 (0.87-1.67)]. The association of >7 drinks per week with estrogen receptor-negative [adjusted OR, 95% CI 2.17 (1.25-3.75)] and triple-negative [adjusted OR, 95% CI 2.12 (1.12-4.04)] breast cancers was significant for African American, but not white women. We observed significantly elevated ORs for heavy intake at ages <25 and >50 years of age for African American women only. We found no evidence of statistical interaction between alcohol intake and oral contraceptive use or smoking. CONCLUSIONS: Drinking more than seven alcoholic beverages per week increased invasive breast cancer risk among white and African American women, with significant increases only among African American women. Genetic or environmental factors that differ by race may mediate the alcohol-breast cancer risk association.

Military and mental health correlates of unemployment in a national sample of women veterans.

BACKGROUND: The unemployment rate is currently higher among women Veterans than among male Veterans and civilian women. Employment is a key social determinant of health, with unemployment being strongly associated with adverse health. OBJECTIVE: To identify military-related and health-related characteristics associated with unemployment in women Veterans. RESEARCH DESIGN AND SUBJECTS: Secondary analysis of workforce participants (n=1605) in the National Survey of Women Veterans telephone survey. MEASURES: Demographics, mental health conditions, health care utilization, and military experiences and effects. Unemployment was defined as being in the labor force but unemployed and looking for work. ANALYSIS: The χ analyses to identify characteristics of unemployed women Veterans; logistic regression to identify independent factors associated with unemployment. RESULTS: Ten percent of women Veterans were unemployed. Independent correlates of unemployment were screening positive for depression [odds ratio (OR)=4.7; 95% confidence interval [CI], 1.8-12.4], military service during wartime (OR=2.9; 95%, CI 1.1-7.3), and service in the regular military (vs. in the National Guards/Reserves only) (OR=6.8; 95% CI, 2.2-20.5). Two postactive duty perceptions related to not being respected and understood as a Veteran were each independently associated with unemployment. CONCLUSIONS: Whether depression underlies unemployment, is exacerbated by unemployment, or both, it is critical to identify and treat depression among women Veterans, and also to investigate women Veterans' experiences and identities in civilian life. Community-based employers may need education regarding women Veterans' unique histories and strengths. Women who served in the regular military and during wartime may benefit from job assistance before and after they leave the military. Gender-specific adaptation of employment services may be warranted.

Journal Club: Prevalence of flawed multiple-choice questions in continuing medical education activities of major radiology journals.

OBJECTIVE: The purpose of this study was to assess whether the continuing medical education (CME) multiple-choice questions (MCQs) in three major radiology journals adhere to standard question-writing principles. MATERIALS AND METHODS: All CME MCQs (total of 181) in the January 2013 editions of the AJR, RadioGraphics, and Radiology composed the test sample. Each question was evaluated by three reviewers for compliance with seven MCQ-writing guidelines that have been documented in the medical education literature as associated with frequent flaws in medical CME. RESULTS: Seventy-eight of the 181 (43%) questions contained one to four flaws. CONCLUSION: A large fraction of radiology CME questions violate standard question-writing principles.