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26.  Parents’ Ages at Birth and Risk of Adult-onset Hematologic Malignancies Among Female Teachers in California 
American Journal of Epidemiology  2010;171(12):1262-1269.
Although advanced parental age at one's birth has been associated with increased risk of breast and prostate cancers, few studies have examined its effect on adult-onset sporadic hematologic malignancies. The authors examined the association of parents’ ages at women's births with risk of hematologic malignancies among 110,999 eligible women aged 22–84 years recruited into the prospective California Teachers Study. Between 1995 and 2007, 819 women without a family history of hematologic malignancies were diagnosed with incident lymphoma, leukemia (primarily acute myeloid leukemia), or multiple myeloma. Multivariable-adjusted Cox proportional hazards models provided estimates of relative risks and 95% confidence intervals. Paternal age was positively associated with non-Hodgkin lymphoma after adjustment for race and birth order (relative risk for age ≥40 vs. <25 years = 1.51, 95% confidence interval: 1.08, 2.13; P-trend = 0.01). Further adjustment for maternal age did not materially alter the association. By contrast, the elevated non-Hodgkin lymphoma risk associated with advanced maternal age (≥40 years) became null when paternal age was included in the statistical model. No association was observed for acute myeloid leukemia or multiple myeloma. Advanced paternal age may play a role in non-Hodgkin lymphoma etiology. Potential etiologic mechanisms include de novo gene mutations, aberrant paternal gene imprinting, or telomere/telomerase biology.
doi:10.1093/aje/kwq090
PMCID: PMC2915497  PMID: 20507900
cohort studies; hematologic neoplasms; leukemia, myeloid, acute; lymphoma, non-Hodgkin; maternal age; paternal age
27.  “Racial and social class gradients in life expectancy in contemporary California” 
Social science & medicine (1982)  2010;70(9):1373-1380.
Life expectancy, or the estimated average age of death, is among the most basic measures of a population's health. However, monitoring differences in life expectancy among sociodemographically defined populations has been challenging, at least in the United States (US), because death certification does not include collection of markers of socioeconomic status (SES). In order to understand how SES and race/ethnicity independently and jointly affected overall health in a contemporary US population, we assigned a small area-based measure of SES to all 689,036 deaths occurring in California during a three-year period (1999-2001) overlapping the most recent US census. Residence at death was geocoded to the smallest census area available (block group) and assigned to a quintile of a multifactorial SES index. We constructed life tables using mortality rates calculated by age, sex, race/ethnicity and neighborhood SES quintile, and produced corresponding life expectancy estimates. We found a 19.6 (±0.6) year gap in life expectancy between the sociodemographic groups with the longest life expectancy (highest SES quintile of Asian females; 84.9 years) and the shortest (lowest SES quintile of African-American males; 65.3 years). A positive SES gradient in life expectancy was observed among whites and African-Americans but not Hispanics or Asians. Age-specific mortality disparities varied among groups. Race/ethnicity and neighborhood SES had substantial and independent influences on life expectancy, underscoring the importance of monitoring health outcomes simultaneously by these factors. African-American males living in the poorest 20% of California neighborhoods had life expectancy comparable to that reported for males living in developing countries. Neighborhood SES represents a readily available metric for ongoing surveillance of health disparities in the US.
doi:10.1016/j.socscimed.2010.01.003
PMCID: PMC2849870  PMID: 20171001
racial disparities; social class disparities; life expectancy; California; population-based; USA; socioeconomic status (SES)
28.  Disparities in Breast Cancer Survival Among Asian Women by Ethnicity and Immigrant Status: A Population-Based Study 
American journal of public health  2010;100(5):861-869.
Objectives
We investigated heterogeneity in ethnic composition and immigrant status among US Asians as an explanation for disparities in breast cancer survival.
Methods
We enhanced data from the California Cancer Registry and the Surveillance, Epidemiology, and End Results program through linkage and imputation to examine the effect of immigrant status, neighborhood socioeconomic status, and ethnic enclave on mortality among Chinese, Japanese, Filipino, Korean, South Asian, and Vietnamese women diagnosed with breast cancer from 1988 to 2005 and followed through 2007.
Results
US-born women had similar mortality rates in all Asian ethnic groups except the Vietnamese, who had lower mortality risk (hazard ratio [HR]=0.3; 95% confidence interval [CI]=0.1, 0.9). Except for Japanese women, all foreign-born women had higher mortality than did US-born Japanese, the reference group. HRs ranged from 1.4 (95% CI=1.2, 1.7) among Koreans to 1.8 (95% CI=1.5, 2.2) among South Asians and Vietnamese. Little of this variation was explained by differences in disease characteristics.
Conclusions
Survival after breast cancer is poorer among foreign- than US-born Asians. Research on underlying factors is needed, along with increased awareness and targeted cancer control.
doi:10.2105/AJPH.2009.176651
PMCID: PMC2853623  PMID: 20299648
29.  Crossveinless-2 is required for the relocalization of Chordin protein within the vertebral field in mouse embryos 
Developmental biology  2010;347(1):204-215.
Bone morphogenetic proteins (BMPs), as well as the BMP-binding molecules Chordin (Chd), Crossveinless-2 (CV2) and Twisted Gastrulation (Tsg), are essential for axial skeletal development in the mouse embryo. We previously reported a strong genetic interaction between CV2 and Tsg and proposed a role for this interaction in the shaping of the BMP morphogenetic field during vertebral development. In the present study we investigated the roles of CV2 and Chd in the formation of the vertebral morphogenetic field. We performed immunostainings for CV2 and Chd protein on wild-type, CV2−/− or Chd−/− mouse embryo sections at the stage of onset of the vertebral phenotypes. By comparing mRNA and protein localizations we found that CV2 does not diffuse away from its place of synthesis, the vertebral body. The most interesting finding of this study was that Chd synthesized in the intervertebral disc accumulates in the vertebral body. This relocalization does not take place in CV2−/− mutants. Instead, Chd was found to accumulate at its site of synthesis in CV2−/− embryos. These results indicate a CV2-dependent flow of Chd protein from the intervertebral disc to the vertebral body. Smad1/5/8 phosphorylation was decreased in CV2−/−vertebral bodies. This impaired BMP signaling may result from the decreased levels of Chd/BMP complexes diffusing from the intervertebral region. The data indicate a role for CV2 and Chd in the establishment of the vertebral morphogenetic field through the long-range relocalization of Chd/BMP complexes. The results may have general implications for the formation of embryonic organ-forming morphogenetic fields.
doi:10.1016/j.ydbio.2010.08.025
PMCID: PMC2975673  PMID: 20807528
BMP signaling; CV2; Chd; Chdl-1; Chdl-2; long-range signaling; morphogenetic field; vertebral development; Tolloid; Twisted gastrulation
30.  GWAS of Follicular Lymphoma Reveals Allelic Heterogeneity at 6p21.32 and Suggests Shared Genetic Susceptibility with Diffuse Large B-cell Lymphoma 
PLoS Genetics  2011;7(4):e1001378.
Non-Hodgkin lymphoma (NHL) represents a diverse group of hematological malignancies, of which follicular lymphoma (FL) is a prevalent subtype. A previous genome-wide association study has established a marker, rs10484561 in the human leukocyte antigen (HLA) class II region on 6p21.32 associated with increased FL risk. Here, in a three-stage genome-wide association study, starting with a genome-wide scan of 379 FL cases and 791 controls followed by validation in 1,049 cases and 5,790 controls, we identified a second independent FL–associated locus on 6p21.32, rs2647012 (ORcombined = 0.64, Pcombined = 2×10−21) located 962 bp away from rs10484561 (r2<0.1 in controls). After mutual adjustment, the associations at the two SNPs remained genome-wide significant (rs2647012:ORadjusted = 0.70, Padjusted = 4×10−12; rs10484561:ORadjusted = 1.64, Padjusted = 5×10−15). Haplotype and coalescence analyses indicated that rs2647012 arose on an evolutionarily distinct haplotype from that of rs10484561 and tags a novel allele with an opposite (protective) effect on FL risk. Moreover, in a follow-up analysis of the top 6 FL–associated SNPs in 4,449 cases of other NHL subtypes, rs10484561 was associated with risk of diffuse large B-cell lymphoma (ORcombined = 1.36, Pcombined = 1.4×10−7). Our results reveal the presence of allelic heterogeneity within the HLA class II region influencing FL susceptibility and indicate a possible shared genetic etiology with diffuse large B-cell lymphoma. These findings suggest that the HLA class II region plays a complex yet important role in NHL.
Author Summary
Earlier studies have established a marker rs10484561, in the HLA class II region on 6p21.32, associated with increased follicular lymphoma (FL) risk. Here, in a three-stage genome-wide association study of 1,428 FL cases and 6,581 controls, we identified a second independent FL–associated marker on 6p21.32, rs2647012, located 962 bp away from rs10484561. The associations at two SNPs remained genome-wide significant after mutual adjustment. Haplotype and coalescence analyses indicated that rs2647012 arose on an evolutionarily distinct lineage from that of rs10484561 and tags a novel allele with an opposite, protective effect on FL risk. Moreover, in an analysis of the top 6 FL–associated SNPs in 4,449 cases of other NHL subtypes, rs10484561 was associated with risk of diffuse large B-cell lymphoma. Our results reveal the presence of allelic heterogeneity at 6p21.32 in FL risk and suggest a shared genetic etiology with the common diffuse large B-cell lymphoma subtype.
doi:10.1371/journal.pgen.1001378
PMCID: PMC3080853  PMID: 21533074
31.  Geographical and Ethnic Distribution of the HBV C/D Recombinant on the Qinghai-Tibet Plateau 
PLoS ONE  2011;6(4):e18708.
Two forms of hepatitis B virus (HBV) C/D recombinant have been identified in western China, but little is known about their geographical and ethnic distributions, and particularly the clinical significance and specific mutations in the pre-core region. To address these questions, a total of 624 chronic HBV carriers from four ethnic populations representing five provinces in western China were enrolled in this study. Genotypes were firstly determined by restriction fragment length polymorphism, and then confirmed by full or partial genome nucleotide sequencing. The distribution of HBV genotypes was as follows: HBV/B: 40 (6.4%); HBV/C: 221 (35.4%); HBV/D: 39 (6.3%); HBV/CD: 324 (51.9%). In the 324 HBV C/D recombinant infections, 244 (75.3%) were infected with the “CD1” and 80 (24.7%) were infected with the “CD2.” The distribution of HBV genotypes exhibited distinct patterns in different regions and ethnic populations. Geographically, the C/D recombinant was the most prevalent HBV strain on the Qinghai-Tibet Plateau. Ethnically, the C/D recombinant had a higher prevalence in Tibetan patients than in other populations. Clinically, patients with HBV/CD1 showed significantly lower levels of serum total bilirubin than patients with HBV/C2. The prevalence of HBeAg was comparable between patients with HBV/CD1 and HBV/C2 (63.3% vs 50.0%, P = 0.118) whether patients were taken together or stratified by age into three groups (65.6% vs 58.8% in <30 years, P = 0.758; 61.9% vs 48.0% in 30–50 years, P = 0.244; 64.3% vs 33.3%, P = 0.336). Virologically HBV/CD1 had a significantly lower frequency of G1896A than HBV/C2. In conclusion, the HBV C/D recombinant is restricted to the Qinghai-Tibet Plateau in western China and is found predominantly in Tibetans. The predominance of the premature pre-core stop mutation G1896A in patients with the HBV C/D recombinant may account for the higher prevalence of HBeAg in these patients.
doi:10.1371/journal.pone.0018708
PMCID: PMC3073994  PMID: 21494570
32.  Hidden Breast Cancer Disparities in Asian Women: Disaggregating Incidence Rates by Ethnicity and Migrant Status 
American journal of public health  2010;100(Suppl 1):S125-S131.
Objectives
We estimated trends in breast cancer incidence rates for specific Asian populations in California to determine if disparities exist by immigrant status and age.
Methods
To calculate rates by ethnicity and immigrant status, we obtained data for 1998 through 2004 cancer diagnoses from the California Cancer Registry and imputed immigrant status from Social Security Numbers for the 26% of cases with missing birthplace information. Population estimates were obtained from the 1990 and 2000 US Censuses.
Results
Breast cancer rates were higher among US- than among foreign-born Chinese (incidence rate ratio [IRR] = 1.84; 95% confidence interval [CI] = 1.72, 1.96) and Filipina women (IRR = 1.32; 95% CI=1.20, 1.44), but similar between US- and foreign-born Japanese women. US-born Chinese and Filipina women who were younger than 55 years had higher rates than did White women of the same age. Rates increased over time in most groups, as high as 4% per year among foreign-born Korean and US-born Filipina women. From 2000–2004, the rate among US-born Filipina women exceeded that of White women.
Conclusions
These findings challenge the notion that breast cancer rates are uniformly low across Asians and therefore suggest a need for increased awareness, targeted cancer control, and research to better understand underlying factors.
doi:10.2105/AJPH.2009.163931
PMCID: PMC2837454  PMID: 20147696
33.  Genome-wide association study of follicular lymphoma identifies a risk locus at 6p21.32 
Nature genetics  2010;42(8):661-664.
To identify susceptibility loci for non-Hodgkin lymphoma (NHL) subtypes, we conducted a three-stage genome-wide association study. We identified two variants associated with follicular lymphoma (FL) in 1,465 FL cases/6,958 controls at 6p21.32 (rs10484561, rs7755224, r2=1.0; combined p-values=1.12×10-29, 2.00×10-19), providing further support that MHC genetic variation influences FL susceptibility. Confirmatory evidence of a previously reported association was also found between chronic lymphocytic leukemia/small lymphocytic lymphoma and rs735665 (combined p-value=4.24×10-9).
doi:10.1038/ng.626
PMCID: PMC2913472  PMID: 20639881
34.  Aspirin and other non-steroidal anti-inflammatory drugs in relation to Hodgkin lymphoma risk in Northern Denmark 
There are few known modifiable risk factors for Hodgkin lymphoma (HL), but the recent finding of an inverse association between routine regular-strength aspirin use and HL risk suggests that aspirin may protect against HL development. To further investigate this association using prospectively collected data, we conducted a population-based case-control study in Northern Denmark. A total of 478 incident HL cases were identified in nationwide health care databases from 1991 through 2008. Ten population controls were matched to each case on age, sex, and county using risk-set sampling. Use of aspirin, selective cyclooxygenase-2 (sCOX-2) inhibitors, and other NSAIDs from 1989 through 2007 was ascertained by linkage to a population-based prescription database. Conditional logistic regression was used to estimate odds ratios (ORs) for associations between medication use and risk of HL. The OR for ever use (>2 prescriptions) compared with never/rare use (≤2 prescriptions) of low-dose aspirin was 0.7 (95% confidence interval [CI]: 0.5–1.2). The association with low-dose aspirin use did not vary appreciably by recentness, duration, or intensity of use. Recent use (>2 prescriptions in the 1–2 years before the index date), short-term use (<7 years), and medium/high-intensity use (≥25% of duration of use covered by prescription) of sCOX-2 inhibitors or other NSAIDs was associated with increased HL risk, possibly due to prodromal symptoms among cases. In conclusion, our results provide some evidence of a protective effect of low-dose aspirin, but not other NSAIDs, against HL development.
doi:10.1158/1055-9965.EPI-09-0909
PMCID: PMC2837543  PMID: 20056623
non-steroidal anti-inflammatory drugs; Hodgkin lymphoma; epidemiology; risk; prevention
35.  San Francisco Hep B Free: A Grassroots Community Coalition to Prevent Hepatitis B and Liver Cancer 
Journal of Community Health  2010;36(4):538-551.
Chronic hepatitis B is the leading cause of liver cancer and the largest health disparity between Asian/Pacific Islanders (APIs) and the general US population. The Hep B Free model was launched to eliminate hepatitis B infection by increasing hepatitis B awareness, testing, vaccination, and treatment among APIs by building a broad, community-wide coalition. The San Francisco Hep B Free campaign is a diverse public/private collaboration unifying the API community, health care system, policy makers, businesses, and the general public in San Francisco, California. Mass-media and grassroots messaging raised citywide awareness of hepatitis B and promoted use of the existing health care system for hepatitis B screening and follow-up. Coalition partners reported semi-annually on activities, resources utilized, and system changes instituted. From 2007 to 2009, over 150 organizations contributed approximately $1,000,000 in resources to the San Francisco Hep B Free campaign. 40 educational events reached 1,100 healthcare providers, and 50% of primary care physicians pledged to screen APIs routinely for hepatitis B. Community events and fairs reached over 200,000 members of the general public. Of 3,315 API clients tested at stand-alone screening sites created by the campaign, 6.5% were found to be chronically infected and referred to follow-up care. A grassroots coalition that develops strong partnerships with diverse organizations can use existing resources to successfully increase public and healthcare provider awareness about hepatitis B among APIs, promote routine hepatitis B testing and vaccination as part of standard primary care, and ensure access to treatment for chronically infected individuals.
doi:10.1007/s10900-010-9339-1
PMCID: PMC3130910  PMID: 21125320
Hepatitis B; Liver cancer; Asian Americans; Pacific Islander Americans; Community networks; Healthcare coalitions
36.  Disparities in survival after Hodgkin lymphoma: a population-based study 
Cancer causes & control : CCC  2009;20(10):1881-1892.
Survival after Hodgkin lymphoma (HL) is generally favorable, but may vary by patient demographic characteristics. The authors examined HL survival according to race/ethnicity and neighborhood socioeconomic status (SES), determined from residential census block group at diagnosis. For 12,492 classical HL patients ≥15 years diagnosed in California during 1988-2006 and followed through 2007, we determined risk of overall and HL-specific death using Cox proportional hazards regression; analyses were stratified by age and Ann Arbor stage. Irrespective of disease stage, patients with lower neighborhood SES had worse overall and HL-specific survival than patients with higher SES. Patients with the lowest quintile of neighborhood SES had a 64% (patients aged 15-44 years) and 36% (≥45 years) increased risk of HL-death compared to patients with the highest quintile of SES; SES results were similar for overall survival. Even after adjustment for neighborhood SES, blacks and Hispanics had increased risks of HL-death 74% and 43% (15-44 years) and 40% and 17% (≥45 years), respectively, higher than white patients. The racial/ethnic differences in survival were evident for all stages of disease. These data provide evidence for substantial, and probably remediable, racial/ethnic and neighborhood SES disparities in HL outcomes.
doi:10.1007/s10552-009-9382-3
PMCID: PMC2888633  PMID: 19557531
Hodgkin disease; survival; mortality; social class; census
37.  Body Size, Recreational Physical Activity, and B-Cell Non-Hodgkin Lymphoma Risk Among Women in the California Teachers Study 
American Journal of Epidemiology  2009;170(10):1231-1240.
Nutritional status and physical activity are known to alter immune function, which may be relevant to lymphomagenesis. The authors examined body size measurements and recreational physical activity in relation to risk of B-cell non-Hodgkin lymphoma (NHL) in the prospective California Teachers Study. Between 1995 and 2007, 574 women were diagnosed with incident B-cell NHL among 121,216 eligible women aged 22–84 years at cohort entry. Multivariable-adjusted relative risks and 95% confidence intervals were estimated by fitting Cox proportional hazards models for all B-cell NHL combined and for the 3 most common subtypes: diffuse large B-cell lymphoma, follicular lymphoma, and B-cell chronic lymphocytic leukemia/small lymphocytic lymphoma. Height was positively associated with risk of all B-cell NHLs (for >1.70 vs. 1.61–1.65 m, relative risk = 1.50, 95% confidence interval: 1.16, 1.96) and chronic lymphocytic leukemia/small lymphocytic lymphoma (relative risk = 1.93, 95% confidence interval: 1.09, 3.41). Weight and body mass index at age 18 years were positive predictors of B-cell NHL risk overall. These findings indicate that greater height, which may reflect genetics, early life immune function, infectious exposures, nutrition, or growth hormone levels, may play a role in NHL etiology. Adiposity at age 18 years may be more relevant to NHL etiology than that in later life.
doi:10.1093/aje/kwp268
PMCID: PMC2781760  PMID: 19822569
body mass index; body size; cohort studies; exercise; hip; lymphoma, non-Hodgkin; waist-hip ratio
38.  Long-term and recent recreational physical activity and survival after breast cancer: the California Teachers Study 
Introduction
Long-term physical activity is associated with lower breast cancer risk. Little information exists on its association with subsequent survival.
Methods
California Teachers Study cohort members provided information in 1995–1996 on long-term (high school through age 54 years) and recent (past 3 years) participation in moderate and strenuous recreational physical activities. The 3,539 women diagnosed with invasive breast cancer after cohort entry and through December 31, 2004, were followed through December 31, 2005. Of these, 460 women died, 221 from breast cancer. Moderate and strenuous physical activities were combined into low (≤0.50 hr/wk/yr of any activity), intermediate (0.51–3.0 hr/wk/yr of moderate or strenuous activity but no activity >3.0 hr/wk/yr) or high activity (>3.0 hr/wk/yr of either activity type). Multivariable relative risks (RR) and 95% confidence intervals (CI) for mortality were estimated using Cox proportional hazards methods, adjusting for race/ethnicity, estrogen receptor status, disease stage, and baseline information on comorbidities, body mass index, and caloric intake.
Results
Women with high or intermediate levels of long-term physical activity had lower risk of breast cancer death (RR=0.53, 95% CI=0.35–0.80; and RR=0.65, 95% CI=0.45–0.93, respectively) than women with low activity levels. These associations were consistent across estrogen receptor status and disease stage, but confined to overweight women. Deaths due to causes other than breast cancer were related only to recent activity.
Conclusions
Consistent long-term participation in physical activity before breast cancer diagnosis may lower risk of breast cancer death, providing further justification for public health strategies to increase physical activity throughout the lifespan.
doi:10.1158/1055-9965.EPI-09-0538
PMCID: PMC2783945  PMID: 19843680
39.  Family history of breast cancer and all-cause mortality after breast cancer diagnosis in the Breast Cancer Family Registry 
Background
Although having a family history of breast cancer is a well established breast cancer risk factor, it is not known whether it influences mortality after breast cancer diagnosis.
Methods
Subjects were 4,153 women with first primary incident invasive breast cancer diagnosed between 1991 and 2000, and enrolled in the Breast Cancer Family Registry through population-based sampling in Northern California, USA; Ontario, Canada; and Melbourne and Sydney, Australia. Cases were oversampled for younger age at diagnosis and/or family history of breast cancer. Carriers of germline mutations in BRCA1 or BRCA2 were excluded. Cases and their relatives completed structured questionnaires assessing breast cancer risk factors and family history of cancer. Cases were followed for a median of 6.5 years, during which 725 deaths occurred. Cox proportional hazards regression was used to evaluate associations between family history of breast cancer at the time of diagnosis and risk of all-cause mortality after breast cancer diagnosis, adjusting for established prognostic factors.
Results
The hazard ratios for all-cause mortality were 0.98 (95% confidence interval [CI]=0.84-1.15) for having at least one first- or second-degree relative with breast cancer, and 0.85 (95% CI=0.70-1.02) for having at least one first-degree relative with breast cancer, compared with having no such family history. Estimates did not vary appreciably when stratified by case or tumor characteristics.
Conclusions
Family history of breast cancer is not associated with all-cause mortality after breast cancer diagnosis for women without a known germline mutation in BRCA1 or BRCA2. Therefore, clinical management should not depend on family history of breast cancer.
doi:10.1007/s10549-008-0255-3
PMCID: PMC2728159  PMID: 19034644
breast cancer; survival; mortality; family history
40.  Uncovering disparities in survival after non-small-cell lung cancer among Asian/Pacific Islander ethnic populations in California 
Asians may have better survival after non-small-cell lung cancer (NSCLC) than non-Asians. However, it is unknown whether survival varies among the heterogeneous U.S. Asian/Pacific Islander (API) populations. Therefore, this study aimed to quantify survival differences among APIs with NSCLC. Differences in overall and disease-specific survival were analyzed in the California Cancer Registry among 16,577 API patients diagnosed with incident NSCLC between 1988 and 2007. Adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) were estimated using Cox proportional hazards regression models with separate baseline hazards by disease stage. Despite better overall and disease-specific survival among APIs compared with non-Hispanic Whites, differences were evident across API populations. Among women, Japanese (overall survival HR=1.16, 95% CI=1.06–1.27) and APIs other than those in the six largest ethnic groups (“other APIs”; HR=1.19, 95% CI=1.07–1.33) had significantly poorer overall and disease-specific survival than Chinese. By contrast, South Asian women had significantly better survival than Chinese (HR=0.79, 95% CI=0.63–0.97). Among men, Japanese (HR=1.15, 95% CI=1.07–1.24), Vietnamese (HR=1.07, 95% CI=1.00–1.16), and other APIs (HR=1.18, 95% CI=1.08–1.28) had significantly poorer overall and disease-specific survival than Chinese. Other factors independently associated with poorer survival were lower neighborhood SES, involvement with a non-university-teaching hospital, unmarried status, older age, and earlier year of diagnosis. APIs have significant ethnic differences in NSCLC survival that may be related to disparate lifestyles, biology, and especially health care access or use. To reduce the nationwide burden of lung cancer mortality, it is critical to identify and ameliorate hidden survival disparities such as those among APIs.
doi:10.1158/1055-9965.EPI-09-0332
PMCID: PMC2764550  PMID: 19622719
non-small-cell lung cancer; survival; Asian Americans; Pacific Islanders; ethnic groups
41.  Pre-diagnosis reproductive factors and all-cause mortality for women with breast cancer in the Breast Cancer Family Registry 
Studies have examined the prognostic relevance of reproductive factors prior to breast cancer (BC) diagnosis, but most have been small and overall their findings inconclusive. Associations between reproductive risk factors and all-cause mortality after BC diagnosis were assessed using a population-based cohort of 3,107 women of white European ancestry with invasive BC (1,130 from Melbourne and Sydney, Australia; 1,441 from Ontario, Canada; and 536 from Northern California, USA). During follow-up with a median of 8.5 years, 567 deaths occurred. At recruitment, questionnaire data were collected on oral contraceptive use, number of full-term pregnancies, age at first full-term pregnancy, time from last full-term pregnancy to BC diagnosis, breastfeeding, age at menarche and menopause and menopausal status at BC diagnosis. Hazard ratios (HR) for all-cause mortality were estimated using Cox proportional hazards models with and without adjustment for age at diagnosis, study center, education and body mass index. Compared with nulliparous women, those who had a child up to 2 years, or between 2 to 5 years, prior to their BC diagnosis were more likely to die. The unadjusted HR estimates were 2.75 (95%CI=1.98–3.83, p<0.001) and 2.20 (95%CI=1.65–2.94, p<0.001), respectively, and the adjusted estimates were 2.25 (95%CI=1.59–3.18, p<0.001) and 1.82 (95%CI=1.35–2.46, p<0.001), respectively). When evaluating the prognosis of women recently diagnosed with BC, the time since last full-term pregnancy should be routinely considered along with other established host and tumor prognostic factors, but consideration of other reproductive factors may not be warranted.
doi:10.1158/1055-9965.EPI-08-1014
PMCID: PMC2746957  PMID: 19505912
Breast cancer; survival; reproductive; outcome; pregnancy
42.  Polymorphic variation in NFKB1 and other aspirin-related genes and risk of Hodgkin lymphoma 
We found that regular use of aspirin may reduce the risk of Hodgkin lymphoma (HL), a common cancer of adolescents and young adults in the US. To explore possible biological mechanisms underlying this association, we investigated whether polymorphic variation in genes involved in nuclear factor (NF)-κB activation and inhibition, other inflammatory pathways, and aspirin metabolism influences HL risk. Twenty single nucleotide polymorphisms (SNPs) in seven genes were genotyped in DNA from 473 classical HL cases and 373 controls enrolled between 1997 and 2000 in a population-based case-control study in the Boston, Massachusetts, metropolitan area and the state of Connecticut. We selected target genes and SNPs primarily using a candidate-SNP approach and estimated haplotypes using the expectation-maximization algorithm. We used multivariable logistic regression to estimate odds ratios (ORs) for associations with HL risk. HL risk was significantly associated with rs1585215 in NFKB1 (AG vs. AA: OR=2.1, 95% confidence interval [CI]=1.5–2.9; GG vs. AA: OR=3.5, 95% CI=2.2–5.7, Ptrend=1.7×10−8) and with NFKB1 haplotypes (Pglobal=6.0×10−21). Similar associations were apparent across categories of age, sex, tumor Epstein-Barr virus status, tumor histology, and regular aspirin use, although statistical power was limited for stratified analyses. Nominally significant associations with HL risk were detected for SNPs in NFKBIA and CYP2C9. HL risk was not associated with SNPs in IKKA/CHUK, PTGS2/COX2, UDP1A6, or LTC4S. In conclusion, genetic variation in the NF-κB pathway appears to influence risk of HL. Pooled studies are needed to detect any heterogeneity in the association with NF-κB across HL subgroups, including aspirin users and non-users.
doi:10.1158/1055-9965.EPI-08-1130
PMCID: PMC2720066  PMID: 19223558
Hodgkin lymphoma; genetic polymorphism; nuclear factor kappa B; NFKB1 protein; aspirin; case-control
43.  Hepatitis B and liver cancer knowledge and practices among healthcare and public health professionals in China: a cross-sectional study 
BMC Public Health  2010;10:98.
Background
Chronic hepatitis B virus (HBV) infection is the leading cause of liver disease and liver cancer and a major source of health-related discrimination in China. To better target HBV detection and prevention programs, it is necessary to assess existing HBV knowledge, educational resources, reporting, and preventive practices, particularly among those health professionals who would be responsible for implementing such programs.
Methods
At the China National Conference on the Prevention and Control of Viral Hepatitis on April 26-29, 2004, the Asian Liver Center at Stanford University partnered with the China Foundation for Hepatitis Prevention and Control to distribute a voluntary written questionnaire to Chinese healthcare and public health professionals from regional and provincial Chinese Centers for Disease Control and Prevention, health departments, and medical centers. Correct responses to survey questions were summed into a total knowledge score, and multivariate linear regression was used to compare differences in the score by participant characteristics.
Results
Although the median score was 81% correct, knowledge about HBV was inadequate, even among such highly trained health professionals. Of the 250 participants who completed the survey, 34% did not know that chronic HBV infection is often asymptomatic and 29% did not know that chronic HBV infection confers a high risk of cirrhosis, liver cancer, and premature death. Furthermore, 34% failed to recognize all the modes of HBV transmission and 30% did not know the importance of the hepatitis B vaccine in preventing liver disease. Respondents who reported poorer preventive practices, such as not having personally been tested for HBV and not routinely disposing of used medical needles, scored significantly lower in HBV knowledge than those who reported sound preventive practices. Of note, 38% of respondents reported positive HBsAg results to patients' employers and 25% reported positive results to patients' schools, thereby subjecting those with positive results to potential discriminatory practices.
Conclusions
These results indicate that there is a need for development of effective educational programs to improve HBV knowledge among health professionals and the general public to avoid missed vaccination opportunities, reduce misconceptions, and eliminate discrimination based on chronic hepatitis B in China.
doi:10.1186/1471-2458-10-98
PMCID: PMC2847983  PMID: 20184740
44.  Reproductive Factors and Non-Hodgkin Lymphoma Risk in the California Teachers Study 
PLoS ONE  2009;4(12):e8135.
Background
Non-Hodgkin lymphoma (NHL) is a malignancy etiologically linked to immunomodulatory exposures and disorders. Endogenous female sex hormones may modify immune function and influence NHL risk. Few studies have examined associations between reproductive factors, which can serve as surrogates for such hormonal exposures, and NHL risk by subtype.
Methodology/Principal Findings
Women in the California Teachers Study cohort provided detailed data in 1995–1996 on reproductive history. Follow-up through 2007 identified 574 women with incident B-cell NHL. Hazard rate ratios (RR) and 95% confidence intervals (CI) were estimated using Cox proportional hazards models to assess associations between reproductive factors and all B-cell NHL combined, diffuse large B-cell lymphomas, follicular lymphomas, and B-cell chronic lymphocytic leukemias/small lymphocytic lymphomas. Pregnancy was marginally associated with lower risk of B-cell NHL (RR = 0.84, 95% CI = 0.68–1.04). Much of the reduction in risk was observed after one full-term pregnancy relative to nulligravid women (RR = 0.75, 95% CI = 0.54–1.06; P for trend <0.01), particularly for diffuse large B-cell lymphomas (P for trend = 0.13), but not among women who had only incomplete pregnancies. Age at first full-term pregnancy was marginally inversely associated with B-cell NHL risk overall (P for trend = 0.08) and for diffuse large B-cell lymphomas (P for trend = 0.056). Breast feeding was not associated with B-cell NHL risk overall or by subtype.
Conclusions
Full-term pregnancy and early age at first full-term pregnancy account for most of the observed reduction in B-cell NHL risk associated with gravidity. Pregnancy-related hormonal exposures, including prolonged and high-level exposure to progesterone during a full-term pregnancy may inhibit development of B-cell NHL.
doi:10.1371/journal.pone.0008135
PMCID: PMC2780313  PMID: 19956586
45.  The burden of liver cancer in Asians and Pacific Islanders in the Greater San Francisco Bay Area, 1990 through 2004 
Cancer  2007;109(10):2100-2108.
Background
No previous U.S. study has examined time trends in the incidence rate of liver cancer in the high-risk Asian/Pacific Islander population. We evaluated liver cancer incidence trends in Chinese, Filipino, Japanese, Korean, and Vietnamese males and females in the Greater San Francisco Bay Area of California between 1990 and 2004.
Methods
Populations at risk were estimated using the cohort component demographic method. Annual percentage changes (APCs) in age-adjusted incidence rates of primary liver cancer among Asians/Pacific Islanders in the Greater Bay Area Cancer Registry were calculated using joinpoint regression analysis.
Results
The incidence rate of liver cancer between 1990 and 2004 did not change significantly in Asian/Pacific Islander males or females overall. However, the incidence rate declined, albeit statistically non-significantly, in Chinese males (APC =−1.6% [95% confidence interval (CI) =−3.4%, 0.3%], Japanese males (APC = −4.9%, 95% CI =−10.7%, 1.2%), and Japanese females (APC =−3.6%, 95% CI =−8.9%, 2.0%). Incidence rates remained consistently high for Vietnamese, Korean, and Filipino males and females. Trends in the incidence rate of hepatocellular carcinoma were comparable to those for liver cancer. While disparities in liver cancer incidence between Asians/Pacific Islanders and other racial/ethnic groups diminished between 1990–1994 and 2000–2004, those among Asian subgroups increased.
Conclusions
Liver cancer continues to affect Asian/Pacific Islander Americans disproportionately, with consistently high incidence rates in most subgroups. Culturally targeted prevention methods are needed to reduce the high rates of liver cancer in this growing population in the U.S.
doi:10.1002/cncr.22642
PMCID: PMC2777532  PMID: 17385214
Asian Americans; epidemiology; hepatocellular carcinoma; liver cancer; surveillance
46.  Racial/ethnic variation in EBV-positive classical Hodgkin lymphoma in California populations 
Epstein-Barr virus (EBV) is detected in the tumor cells of some but not all Hodgkin lymphoma (HL) patients, and evidence indicates that EBV-positive and –negative HL are distinct entities. Racial/ethnic variation in EBV-positive HL in international comparisons suggests etiologic roles for environmental and genetic factors, but these studies used clinical series and evaluated EBV presence by differing protocols. Therefore, we evaluated EBV presence in the tumors of a large (n=1,032), racially and sociodemographically diverse series of California incident classical HL cases with uniform pathology re-review and EBV detection methods. Tumor EBV-positivity was associated with Hispanic and Asian/Pacific Islander (API) but not black race/ethnicity, irrespective of demographic and clinical factors. Complex race-specific associations were observed between EBV-positive HL and age, sex, histology, stage, neighborhood socioeconomic status (SES), and birth place. In Hispanics, EBV-positive HL was associated not only with young and older age, male sex, and mixed cellularity histology, but also with foreign birth and lower SES in females, suggesting immune function responses to correlates of early childhood experience and later environmental exposures, respectively, as well as of pregnancy. For APIs, a lack of association with birth place may reflect the higher SES of API than Hispanic immigrants. In blacks, EBV-positive HL was associated with later-stage disease, consistent with racial/ethnic variation in certain cytokine polymorphisms. The racial/ethnic variation in our findings suggests that EBV-positive HL results from an intricate interplay of early- and later-life environmental, hormonal, and genetic factors leading to depressed immune function and poorly controlled EBV infection.
doi:10.1002/ijc.23741
PMCID: PMC2775059  PMID: 18646185
Hodgkin lymphoma; Epstein-Barr virus; racial/ethnic variation; epidemiology
47.  Development of the vertebral morphogenetic field in the mouse: interactions between Crossveinless-2 and Twisted gastrulation 
Developmental biology  2008;323(1):6-18.
Crossveinless-2 (Cv2), Twisted Gastrulation (Tsg) and Chordin (Chd) are components of an extracellular biochemical pathway that regulates Bone Morphogenetic Protein (BMP) activity during dorso-ventral patterning of Drosophila and Xenopus embryos, the formation of the fly wing, and mouse skeletogenesis. Because the nature of their genetic interactions remained untested in the mouse, we generated a null allele for Cv2 which was crossed to Tsg and Chd mutants to obtain Cv2;Tsg and Cv2;Chd compound mutants. We found that Cv2 is essential for skeletogenesis as its mutation caused the loss of multiple bone structures and posterior homeotic transformation of the last thoracic vertebra. During early vertebral development, Smad1 phosphorylation in the intervertebral region was decreased in the Cv2 mutant, even though CV2 protein is normally located in the future vertebral bodies. Because Cv2 mutation affects BMP signaling at a distance, this suggested that CV2 is involved in the localization of the BMP morphogenetic signal. Cv2 and Chd mutations did not interact significantly. However, mutation of Tsg was epistatic to all CV2 phenotypes. We propose a model in which CV2 and Tsg participate in the generation of a BMP signaling morphogenetic field during vertebral formation in which CV2 serves to concentrate diffusible Tsg/BMP4 complexes in the vertebral body cartilage.
doi:10.1016/j.ydbio.2008.08.019
PMCID: PMC2647368  PMID: 18789316
BMP; Crossveinless-2; Chordin; Twisted Gastrulation; Tolloid; vertebra; morphogenetic field; cartilage; pattern formation
48.  Serum YKL-40 and IL-6 Levels in Hodgkin Lymphoma 
Purpose
Serum levels of the inflammatory markers YKL-40 and IL-6 are increased in many conditions, including cancers. We examined serum YKL-40 and IL-6 levels in patients with Hodgkin lymphoma (HL), a tumor with strong immunologic reaction to relatively few tumor cells, especially in nodular sclerosis HL.
Experimental Design
We analyzed Danish and Swedish patients with incident HL (N=470) and population controls from Denmark (N= 245 for YKL-40; N= 348 for IL-6). Serum YKL-40 and IL-6 levels were determined by ELISA, and log-transformed data were analysed by linear regression, adjusting for age and sex.
Results
Serum levels of YKL-40 and IL-6 were increased in HL patients compared to controls (YKL-40: 3.6-fold, IL-6: 8.3-fold; both p<0.0001). In samples from pre-treatment HL patients (N=176), levels were correlated with more advanced stages (ptrend 0.0001 for YKL-40 and 0.013 for IL-6) and in those with B symptoms, but levels were similar in nodular sclerosis and mixed cellularity subtypes, by EBV status, and in younger (<45 years old) and older patients. Patients tested soon after treatment onset had significantly lower levels than pre-treatment patients, but even >6 months after treatment onset, serum YKL-40 and IL-6 levels remained significantly increased, compared to controls. In patients who died (N=12), pre-treatment levels for both YKL-40 and IL-6 were higher than in survivors, although not statistically significantly.
Conclusions
Serum YKL-40 and IL-6 levels were increased in untreated HL patients and those with more advanced stages but did not differ significantly by HL histology. Following treatment, serum levels were significantly lower.
doi:10.1158/1078-0432.CCR-08-1026
PMCID: PMC2613488  PMID: 18980992
49.  Lung cancer incidence in never-smokers 
Purpose
Lung cancer is a leading cause of cancer death worldwide. While smoking remains the predominant cause of lung cancer, lung cancer in never-smokers is an increasingly prominent public health issue. Data on this topic, particularly lung cancer incidence rates in never-smokers, however, are limited.
Methods
We review the existing literature on lung cancer incidence and mortality rates among never-smokers and present new data regarding rates in never-smokers from large, population-based cohorts: 1) Nurses’ Health Study, 2) Health Professionals Follow-up Study, 3) California Teachers Study, 4) Multiethnic Cohort Study, 5) Swedish Lung Cancer Register in the Uppsala/Örebro region, and the 6) First National Health and Nutrition Examination Survey Epidemiologic Follow-up Study.
Results
Truncated age-adjusted incidence rates of lung cancer among never-smokers aged 40 to 79 years in these six cohorts ranged from 14.4 to 20.8 per 100,000 person-years in women and 4.8 to 13.7 per 100,000 person-years in men, supporting earlier observations that women are more likely than men to have non-smoking-associated lung cancer. The distinct biology of lung cancer in never-smokers is apparent in differential responses to epidermal growth factor receptor inhibitors and an increased prevalence of adenocarcinoma histology in never-smokers.
Conclusion
Lung cancer in never-smokers is an important public health issue needing further exploration of its incidence patterns, etiology, and biology.
doi:10.1200/JCO.2006.07.2983
PMCID: PMC2764546  PMID: 17290054
50.  Recent trends in breast cancer incidence in US white women by county-level urban/rural and poverty status 
BMC Medicine  2009;7:31.
Background
Unprecedented declines in invasive breast cancer rates occurred in the United States between 2001 and 2004, particularly for estrogen receptor-positive tumors among non-Hispanic white women over 50 years. To understand the broader public health import of these reductions among previously unstudied populations, we utilized the largest available US cancer registry resource to describe age-adjusted invasive and in situ breast cancer incidence trends for non-Hispanic white women aged 50 to 74 years overall and by county-level rural/urban and poverty status.
Methods
We obtained invasive and in situ breast cancer incidence data for the years 1997 to 2004 from 29 population-based cancer registries participating in the North American Association of Central Cancer Registries resource. Annual age-adjusted rates were examined overall and by rural/urban and poverty of patients' counties of residence at diagnosis. Joinpoint regression was used to assess trends by annual quarter of diagnosis.
Results
Between 2001 and 2004, overall invasive breast cancer incidence fell 13.2%, with greater reductions among women living in urban (-13.8%) versus rural (-7.5%) and low- (-13.0%) or middle- (-13.8%) versus high- (-9.6%) poverty counties. Most incidence rates peaked around 1999 then declined after second quarter 2002, although in rural counties, rates decreased monotonically after 1999. Similar but more attenuated patterns were seen for in situ cancers.
Conclusion
Breast cancer rates fell more substantially in urban and low-poverty, affluent counties than in rural or high-poverty counties. These patterns likely reflect a major influence of reductions in hormone therapy use after July 2002 but cannot exclude possible effects due to screening patterns, particularly among rural populations where hormone therapy use was probably less prevalent.
doi:10.1186/1741-7015-7-31
PMCID: PMC2714853  PMID: 19558637

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