The collective discussion during the NCI course highlighted the pervasiveness of health disparities across all areas represented by course participants and suggested these issues are the largest impediment to achieving cancer prevention goals.
The National Cancer Institute Principles and Practice of Cancer Prevention and Control course is a 4-week course encompassing a variety of cancer prevention and control topics that is open to attendees from medical, academic, government, and related institutions around the world. Themes related to the challenges health disparities present to cancer prevention efforts and potential solutions to these issues emerged from facilitated group discussions among the 2012 course participants.
Materials and Methods:
Small-group discussion sessions with participants (n = 85 from 33 different countries) and facilitators (n = 9) were held once per week throughout the 4-week course. Facilitators prepared open-ended questions related to course topics. Participants provided responses reflecting their opinions of topics on the basis of experiences in their countries. A thematic analysis was conducted to explore themes emerging from the discussion groups.
The varied influences of health disparities on cancer prevention efforts among > 30 countries represented prominent themes across discussion groups. Participants discussed the interplay of individual characteristics, including knowledge and culture, interpersonal relationships such as family structure and gender roles, community and organizational factors such as unequal access to health care and access to treatment, and national-level factors including policy and government structure.
The ideas and solutions presented here are from a geographically and professionally diverse group of individuals. The collective discussion highlighted the pervasiveness of health disparities across all areas represented by course participants and suggested that disparities are the largest impediment to achieving cancer prevention goals.
This article features qualitative data from in-depth interviews of alumni from a long-standing, structured, postdoctoral research training program. Alumni from diverse scientific disciplines and representing 25 years of the program’s history reflected on the training curriculum and career preparation as it relates to their current career path.
Published evaluations of career preparation of alumni from long-standing postdoctoral fellowship programs in the biomedical sciences are limited and often focus on quantitative analysis of data from extant publicly available sources. Qualitative methods provide the opportunity to gather robust information about specific program elements from structured postdoctoral training programs and the influence of this training on subsequent career paths of alumni. In-depth interviews with a subset of the National Cancer Institute’s Cancer Prevention Fellowship Program (CPFP) alumni (n = 27), representing more than 25 years of the program’s history and multiple career sectors, were conducted to assess alumni reflections on the training environment and career preparation during their time in the CPFP. NVivo software was used to analyze data and identify major themes. Four main themes emerged from these interviews, including: the value of structured training curriculum, mentorship, transdisciplinary environment, and professional identity. Even when reflecting on training that occurred one to two decades earlier, alumni were able to highlight specific components of a structured postdoctoral training program as influencing their research and career trajectories. These results may have relevance for those interested in assessing how postdoctoral training can influence fellows throughout their careers and understanding salient features of structured programs.
The purpose of this study was to compare longitudinally sampled maternal angiogenic proteins between singleton and twin pregnancies.
Placental growth factor (PlGF), soluble fms-like tyrosine kinase-1 (sFlt-1), and soluble endoglin (sEng) from healthy pregnant women were quantified at 10, 18, 26 and 35 weeks’ gestation (n=91), and during the third trimester (31–39 weeks) and at delivery (33–41 weeks; n=41). Geometric means and 95% confidence intervals were calculated for gestational age adjusted angiogenic protein concentrations and compared between matched twin and singleton pregnancies.
Maternal sFlt-1 concentrations and the sFlt-1/PlGF ratio were higher in twins than singletons across pregnancy and at delivery, with the greatest differences at week 35 [sFlt-1: 36916 vs. 10151 pg/mL; p<0.0001; sFlt-1/PlGF: 168.4 vs. 29.0; p<0.0001]. Maternal concentrations of s-endoglin also were higher in the third trimester and delivery. Maternal PlGF concentrations were lower in twin than singleton pregnancies at week 35 only [219.2 vs. 350.2 pg/mL; p<0.0001]. Placental weight appeared to be inversely correlated with maternal sFlt-1/PlGF ratio at the end of the pregnancy in both twins and singletons.
Higher maternal anti-angiogenic proteins in twin than singleton pregnancies does not appear to be due to greater placental mass in the former, and may be one explanation for the increased risk of preeclampsia in women carrying multiple gestations. Determining whether women with a history of multiple gestations have an altered cardiovascular disease and breast cancer risk, like those with a history of preeclampsia, is warranted.
twins; singletons; angiogenic balance; pregnancy; sFlt-1; endoglin
The Ninth Annual AACR Frontiers in Cancer Prevention Research conference was held in Philadelphia in November 7–10, 2010. Its thematic focus was “Prevention: From Basic Science to Public Health Benefit.” Telomere plasticity, the microenvironment, inflammation, transformation to the metastatic phenotype, and pathways to obesity were highlighted as important elements of carcinogenesis amenable to intervention. The integration of information from novel technologies related to physical biology, molecular and genetic profiles, and imaging along with behavioral and clinical parameters have advanced risk stratification and early detection. Cancer prevention represents a powerful testing ground for the development of individually tailored intervention and for increasing the efficiency of drug discovery. Advances in clinical trials relate to more efficient design strategies, have shown first-in-human targeting capabilities, and have developed powerful strategies to overcome accrual barriers. Tailored intervention strategies now show high efficacy on large cohorts across several cancer types. These successes are expected to increase.
The purpose of this study was to examine the career paths of alumni from the National Cancer Institute (NCI) Cancer Prevention Fellowship Program (CPFP), a structured in-house postdoctoral training program of 3–4 years duration, and specifically what proportion of the alumni were currently performing cancer prevention-related activities. The analyses here included 119 CPFP alumni and 85 unsuccessful CPFP applicants, all of whom completed postdoctoral training between 1987–2011 and are currently employed. Postdoctoral training experiences and current career outcomes data were collected via online surveys. Differences between groups were assessed using chi-square and Fisher’s exact test p-values and subsequent regression analyses adjusted for differences between the groups. Compared to 15.3% of unsuccessful CPFP applicants, 52.1% of CPFP alumni (odds ratio [OR] = 4.99, 95% confidence interval [95% CI): 1.91–13.0) were currently spending the majority of their time working in cancer prevention. Among those doing any cancer prevention-focused work, 54.3% of CPFP alumni spent the majority of their time performing cancer prevention research activities when compared to 25.5% of unsuccessful applicants (OR = 4.26, 95% CI: 1.38–13.2). In addition to the independent effect of the NCI CPFP, scientific discipline, and employment sector were also associated with currently working in cancer prevention and involvement in cancer prevention research-related activities. These results from a structured postdoctoral training program are relevant not only to the cancer prevention community but also to those interested in evaluating alignment of postdoctoral training programs with available and desired career paths more broadly.
Inflammation within the preterm placenta is common and leads to adverse outcomes for premature infants. The risks of complications are different between iatrogenic (e.g. preeclampsia) and spontaneous (e.g. preterm labor and membrane rapture) causes of preterm delivery, suggesting different underlying biology contributes to these placental conditions.
Method of Study
Thirty preterm singleton placentas from the following groups were analyzed: 1) severe preeclampsia (PE), 2) preterm premature membrane rupture (pPROM) and 3) preterm labor (PL). Proinflammatory and anti-inflammatory cytokines, adhesion and angiogenic molecules were measured in placental lysates using a multiplex assay. K-means cluster analysis was used to generate patterns of protein level intensity.
Three cluster patterns were apparent. Placentas from PE had high levels of VEGF combined with low levels of acute inflammatory proteins (IL-1β, IL-18, IL-6, TNF-α), low IL-1 RA and high TGF-β. PL and pPROM had higher anti-inflammatory IL-1 RA and thrombomodulin combined with lower VEGF, regardless of proinflammatory cytokines and adhesion molecules. Half of the PL and pPROM cases had clusters of heightened inflammatory responses (lower TGF-β clustered with higher intensity of inflammatory mediators).
Discriminating protein patterns were elucidated and may serve as a foundation from which to understand the biological mechanisms underlying these pregnancy complications.
inflammation; placenta; preterm labor; preterm premature membrane rupture; preterm delivery
The Summer Curriculum in Cancer Prevention has been sponsored by the National Cancer Institute’s Cancer Prevention Fellowship Program for over two decades. This curriculum includes a four-week course entitled “Principles and Practice of Cancer Prevention and Control.” The ultimate goal of this course is to present the most current cancer prevention research to a diverse workforce of researchers and practitioners eager to address the current challenges in this field. The course covers the current status of cancer prevention research and practice, ranging from epidemiology and clinical practice, and from basic to behavioral science research. It is comprised of lectures grouped into nine modules representing broad and specific topics relevant to cancer prevention. Course participants come from a broad cross-section of career stages, professions, and research interests, and are from across the United States and other countries. Over time and in response to feedback from participants, the course has developed to meet the needs and expectations of this diverse audience, and may serve as a model for those interested in cancer prevention education and training in other countries.
international; training; epidemiology; public health
The objective of this study was to comprehensively profile biological factors in pregnancy that have been postulated to be important components of the in utero environment and may also have relevance to later susceptibility to cancer and other chronic diseases.
Steroid sex hormones, IGFs, and angiogenic factors were measured in maternal and cord serum from term, normotensive pregnancies. Spearman correlations and linear regression estimated relationships among the biological factors and clinical characteristics.
The analytes were generally not correlated between maternal and fetal circulations. However, significant correlations were demonstrated among several analytes within maternal or cord samples. A few analytes were associated with clinical characteristics (e.g., maternal IGF-1and IGFBP-3 were inversely correlated with offspring birth weight, while maternal leptin and cord testosterone were positively correlated with this characteristic). Maternal androgens were higher in African-Americans than whites and maternal PlGF and soluble fms-like tyrosine kinase-1 (sFlt-1) were higher in male than female offspring.
There were significant correlations among analytes but the patterns differed depending on whether they were measured in the maternal or fetal circulation. The number and magnitude of correlations among analytes, however, should affect the design and interpretation of future studies.
African-American; angiogenic factors; IGF; leptin; prolactin
We sought to determine if maternal characteristics are associated with angiogenic profile in the first and second trimester of normotensive pregnancies.
Circulating levels of maternal placental like growth factor (PlGF), soluble fms-like tyrosine kinase receptor (sFlt1), and soluble endoglin (sEng) were measured in serum samples collected during the first (median 11.3 weeks) and second trimester (median 17.1 weeks) of 182 normotensive pregnancies. Diastolic blood pressure (DBP), systolic blood pressure (SBP), and mean arterial pressure (MAP) were measured at the same visits when samples were collected to measure angiogenic factors. Linear regression analysis was used to examine associations of the angiogenic measures with maternal characteristics. The association between blood pressure measures and concentrations of angiogenic factors was evaluated using Spearman correlation and linear regression analysis.
In adjusted analyses, nulliparous women had higher sFlt1 concentrations in both first (P=0.06) and second (P=0.001) trimester. Higher BMI was associated with greater sFlt1 concentrations in both the first (P=0.004) and second trimester (P=0.008), but significantly lower sEng concentrations in both trimesters (P=0.002 for first trimester and P=0.0009 for second). Nulliparity and higher BMI also were associated with higher sFlt1/PLGF anti-angiogenic ratios in both first (p=0.05 and p=0.007, respectively) and second trimesters (p=0.003 and p=0.02, respectively). First trimester sFlt1 levels were weakly correlated with first trimester SBP (rs=0.18, p=0.03) and MAP (rs=0.16, p=0.04). Second trimester sEng levels were inversely associated with second trimester MAP (rs= −0.17, p=0.05). Including blood pressure measures in the linear regression models did not change the reported associations of angiogenic factors with maternal characteristics.
These results demonstrate that even early in normotensive pregnancies maternal characteristics are associated with variations in angiogenic profile across this population.
Pregnancy; angiogenic factors; sFlt1; PlGF; soluble endoglin; maternal
Insulin-like growth factor 1 (IGF-1) levels are positively related to some cancers and negatively related to cardiovascular disease. These conditions are also related to insulin resistance and high body weight leading to the hypothesis that IGF-1 levels may, in part, mediate the association of high body weight with these health outcomes. Using the National Health and Nutrition Examination Survey (NHANES) III population, we examined the associations between IGF-1, IGFBP-3, and the IGF-1/IGFBP-3 molar ratio with anthropometric measures in a large, United States population-based study where these associations could also be stratified by race/ethnicity and gender.
The study population consisted of 3168 women and 2635 men (44% non-Hispanic white, 28.2% non-Hispanic black and 27.7% Mexican-American). Anthropometric measures were obtained by trained personnel in the NHANES mobile examination centers. IGF-1 and IGFBP-3 were measured using immunoassays by staff at Diagnostic System Laboratories (DSL) Inc. (Webster, TX). Associations of IGF-1, IGFBP-3 and IGF-1/IGFBP-3 molar ratio with anthropometric variables across race/ethnicity and gender were evaluated using linear regression modeling.
Body mass index (BMI) was inversely associated with IGF-1 levels across all of the race/ethnicity and gender subgroups. In contrast, BMI, waist:hip ratio (WHR), and waist circumference were positively associated with IGFBP-3 levels only in non-Hispanic black men and non-Hispanic white women. The IGF-1/IGFBP-3 molar ratio was inversely associated with all anthropometric measures, except height, in all subgroups of the population.
The significant inverse associations of BMI with IGF-1 levels and of all anthropometric variables, except height, with the IGF-1:IGFBP-3 molar ratio in all subgroups do not support existing hypotheses that associations of excess weight with negative health outcomes, such as specific cancer diagnoses, are mediated through high IGF-1 levels.
BMI; obesity; cancer; IGF
The association of maternal weight gain with serum hormone concentrations was explored in 75 women who had healthy, singleton pregnancies. Estradiol, estriol, estrone, androstenedione, testosterone, dehydroepiandrosterone (DHEA) and DHEA sulfate concentrations were measured both in maternal and mixed umbilical cord serum to assess hormone levels in both the maternal and fetal circulation at delivery. Our data show no association of maternal or cord steroid hormone concentrations with pregnancy weight gain. Increased exposure to steroid hormones, especially estrogens, during pregnancy has been hypothesized to play a role in subsequent breast cancer risk for both mother and female offspring. Our results are not consistent with an effect of pregnancy weight gain being mediated by this pathway as reflected by hormone concentrations at the end of pregnancy.
Pregnancy; breast cancer; estrogens; androgens
The pregnancy–lactation cycle (PLC) is a period in which the breast is transformed from a less-developed, nonfunctional organ into a mature, milk-producing gland that has evolved to meet the nutritional, developmental, and immune protection needs of the newborn. Cessation of lactation initiates a process whereby the breast reverts to a resting state until the next pregnancy. Changes during this period permanently alter the morphology and molecular characteristics of the breast (molecular histology) and produce important, yet poorly understood, effects on breast cancer risk. To provide a state-of-the-science summary of this topic, the National Cancer Institute invited a multidisciplinary group of experts to participate in a workshop in Rockville, Maryland, on March 2, 2012. Topics discussed included: 1) the epidemiology of the PLC in relation to breast cancer risk, 2) breast milk as a biospecimen for molecular epidemiological and translational research, and 3) use of animal models to gain mechanistic insights into the effects of the PLC on breast carcinogenesis. This report summarizes conclusions of the workshop, proposes avenues for future research on the PLC and its relationship with breast cancer risk, and identifies opportunities to translate this knowledge to improve breast cancer outcomes.
As part of a 2 day conference on October 15 and 16, 2009, a nine-member task force composed of scientists, clinicians, educators, administrators, and students from across the United States was formed to discuss research, discovery, and technology obstacles to progress in cancer prevention and control, specifically those related to the cancer prevention workforce. This article summarizes the task force’s findings on the current state of the cancer prevention workforce in this area and its needs for the future. The task force identified two types of barriers impeding the current cancer prevention workforce in research, discovery, and technology from reaching its fullest potential: 1) limited cross-disciplinary research opportunities with underutilization of some disciplines is hampering discovery and research in cancer prevention, and 2) new research avenues are not being investigated because technology development and implementation are lagging. Examples of impediments and desired outcomes are provided in each of these areas. Recommended solutions to these problems are based on the goals of enhancing the current cancer prevention workforce and accelerating the pace of discovery and clinical translation.
Cancer prevention; training; workforce; technology; research
The National Cancer Institute (NCI) career development (K) awards program supports investigators to develop their cancer research programs and achieve independence. The NCI Center for Cancer Training conducted a K program evaluation by analyzing outcomes of awardees and individuals who applied to the program but were not funded. The evaluation covered seven NCI mechanisms (K01, K07, K08, K11, K22, K23, and K25) between 1980 and 2008. Descriptive statistics and regression modeling were performed on the full cohort (n = 2,893 individuals, 4,081 K applications) and a comparison cohort described herein. K awardees proportionately received more subsequent NIH grants and authored more publications, and time to first R01 grant was unaffected. Of those not pursuing research, K awardees were more likely to participate in activities signaling continued scientific engagement. The NCI K program had a positive impact, not only on participants’ biomedical research careers but also on achieving outcomes significant to the scientific enterprise.
Electronic supplementary material
The online version of this article (doi:10.1007/s13187-012-0444-y) contains supplementary material, which is available to authorized users.
Evaluation; Career development; Training; Outcomes
Hemodilution refers to reduced concentrations of analytes in the blood secondary to increased fluid volume. Given that obesity is associated with expanded vascular volume, hemodilution may result in a lower ratio of blood concentrations of analytes among heavier subjects. Assessing the relationship of hormone concentration to total mass varies by body mass index (BMI) is etiologically important because obesity is related to hormone metabolism and cancer risk.
We evaluated data for 194 postmenopausal controls in an endometrial cancer case-control study. Height, weight, and serum hormone concentrations were measured previously. We estimated serum hormone mass from concentration based on estimates of calculated plasma volume. We assessed the effect of BMI on relationships of sex steroid hormone concentration and mass using multivariate linear regression.
Higher BMI was associated with increased estrone, estrone sulfate, estradiol, and albumin-bound estradiol concentrations and masses (p-trend <0.001). With increasing BMI, androstenedione concentration did not change significantly (p-trend=0.548), but its mass increased (p-trend=0.024).
Relationships of sex steroid hormone concentration and mass were generally similar, except for androstenedione in which the relationship was only significant for mass. Future studies to assess both sex steroid hormone concentration and mass may have value in etiological research.
sex steroid hormones; obesity; hemodilution
Studies suggest that high circulating levels of prolactin increase breast cancer risk. It is unclear if genetic variations in prolactin (PRL) or prolactin receptor (PRLR) genes also play a role. Thus, we examined the relationship between single nucleotide polymorphisms (SNPs) in PRL and PRLR, serum prolactin levels and breast cancer risk in a population-based case-control study.
We genotyped 8 PRL and 20 PRLR tag SNPs in 1965 breast cancer cases and 2229 matched controls, aged 20-74, and living in Warsaw or Łódź, Poland. Serum prolactin levels were measured by immunoassay in a subset of 773 controls. Odds ratios (ORs) and 95% confidence intervals (CIs) for genotype associations with breast cancer risk were estimated using unconditional logistic regression, adjusted for age and study site. Geometric mean prolactin levels were estimated using linear regression models adjusted for age, study site, blood collection time, and menstrual cycle day (premenopausal women).
Three SNPs were associated with breast cancer risk: in premenopausal women, PRLR rs249537 (T vs. C per-allele OR 1.39, 95% CI 1.07 - 1.80, P = 0.01); and in postmenopausal women, PRLR rs7718468 (C vs. T per-allele OR 1.16, 95% CI 1.03 - 1.30, P = 0.01) and PRLR rs13436213 (A vs. G per-allele OR 1.13 95% CI 1.01 - 1.26, P = 0.04). However, mean serum prolactin levels for these SNPs did not vary by genotype (P-trend > 0.05). Other SNPs were associated with serum prolactin levels: PRLR rs62355518 (P-trend = 0.01), PRLR rs10941235 (P-trend = 0.01), PRLR rs1610218 (P-trend = 0.01), PRLR rs34024951 (P-trend = 0.02), and PRLR rs9292575 (P-trend = 0.03) in premenopausal controls and PRL rs849872 (P-trend = 0.01) in postmenopausal controls.
Our data provide limited support for an association between common variations in PRLR and breast cancer risk. Altered serum prolactin levels were not associated with breast cancer risk-associated variants, suggesting that common genetic variation is not a strong predictor of prolactin-associated breast cancer risk in this population.
Absolute and relative concentrations of estrogens and estrogen metabolites (EM) are important for clinical decisions, as well as for epidemiologic, experimental, and clinical research on hormonal carcinogenesis. Radioimmunoassays (RIA) and enzyme-linked immunosorbent assays (ELISA) are routinely used for measuring EM in blood and urine due to efficiency and low cost. Here we compare absolute and ranked concentrations of estrone, estradiol, and estriol measured by indirect RIA and of 2-hydroxyestrone and 16α-hydroxyestrone measured by ELISA to the concentrations obtained using a novel liquid-chromatography-tandem mass spectrometry (LC-MS/MS) method which measures 15 EM concurrently. We used overnight urine samples collected from control women (362 premenopausal, 168 postmenopausal) participating in a population-based case-control study of breast cancer among Asian-American women ages 20–55 years. When comparing RIA or ELISA levels to LC-MS/MS, absolute concentrations for the five EM ranged from 1.6–2.9 and 1.4–11.8 times higher in premenopausal and postmenopausal women, respectively, (all p<0.0001). However, LC-MS/MS measurements were highly correlated [Spearman r (rs) =0.8–0.9] with RIA and ELISA measurements in premenopausal women, and moderately correlated (rs=0.4–0.8) in postmenopausal women. Measurements of the 2-hydroxyestrone:16α-hydroxyestrone ratio, a putative biomarker of breast cancer risk, were moderately correlated in premenopausal women (rs=0.6–0.7) but only weakly correlated in postmenopausal women (rs=0.2). LC-MS/MS had higher intraclass correlation coefficients (≥99.6%) and lower coefficients of variation (≤9.4%) than ELISA (≥97.2% and ≤14.2%) and RIA (≥95.2% and ≤17.8%). Comparison with the LC-MS/MS method suggests that the widely used RIA and ELISA EM measures may be problematic, especially at low EM levels characteristic of postmenopausal women.
estrone; estradiol; LC-MS; RIA; ELISA