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2.  Early prediction of treatment resistance in low-risk gestational trophoblastic neoplasia using population kinetic modelling of hCG measurements 
British Journal of Cancer  2013;108(9):1810-1816.
Background:
In low-risk gestational trophoblastic neoplasia (GTN) patients, a predictive marker for early identification of methotrexate (MTX) resistance would be useful. We previously demonstrated that kinetic modelling of human chorionic gonadotrophin (hCG) measurements could provide such a marker. Here we validate this approach in a large independent patient cohort.
Methods:
Serum hCG measurements of 800 low-risk GTN patients treated with MTX were analysed. The cohort was divided into Model and Test data sets. hCG kinetics were described from initial treatment day to day 50 using: ‘(hCG(time))=hCG0*exp(–k*time)+hCGres', where hCGres is the modelled residual production, hCG0 is the baseline hCG level, and k is the rate constant. HCGres-predictive value was investigated against previously reported predictors of MTX resistance.
Results:
Declining hCG measurements were well fitted by the model. The best discriminator of MTX resistance in the Model data set was hCGres, categorised by an optimal cut-off value of >20.44 IU l−1: receiver-operating characteristic (ROC) area under the curve (AUC)=0.87; Se=0.91; Sp=0.83. The predictive value of hCGres was reproducible using the Test data set: ROC AUC=0.87; Se=0.88; Sp=0.86. Multivariate analyses revealed hCGres as a better predictor of MTX resistance (HR=1.01, P<0.0001) and MTX failure-free survival (HR=13.25, P<0.0001) than other reported predictive factors.
Conclusion:
hCGres, a modelled kinetic parameter calculated after fully dosed three MTX cycles, has a reproducible value for identifying patients with MTX resistance.
doi:10.1038/bjc.2013.123
PMCID: PMC3664307  PMID: 23591194
gestational trophoblastic neoplasia; methotrexate; drug resistance; neoplasm; prognosis; decision support techniques; chorionic gonadotropin
3.  Effect of green tea supplementation on blood pressure among overweight and obese adults: a protocol for a systematic review 
BMJ Open  2014;4(4):e004971.
Introduction
Emerging randomised controlled trials (RCTs) exploring the effect of green tea (GT) supplementation or GT extract (GTE) on blood pressure (BP) among overweight and obese adults yielded inconclusive results. We aim to conduct a systematic review to summarise the evidence of RCTs until now, to clarify the efficacy of GT supplementation or GTE in BP in overweight and obese populations.
Methods and analysis
The Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE and ClinicalTrials.gov will be searched to retrieve potential RCTs. Unpublished studies will be identified by searching the abstract books or websites of the three major conference proceedings: the International Society of Hypertension, the Nutrition & Health Conference and the World Congress of Nutrition and Health. A random-effects meta-analysis will be performed to pool the mean difference for the change in BP from baseline (ie, postintervention BP minus baseline BP) between intervention groups and placebo groups of the included studies, presenting the pooled results with 95% CIs. Subgroups analyses will be conducted according to different doses of GT or GTE, trial duration, geographic regions, overweight versus obese participants, and participants with versus without change in body weight after intervention. Sensitivity analysis will be performed by excluding studies classified as having a high risk of bias, applying a fixed-effects model, using the postintervention BP for analyses and excluding trials with non-study cointerventions.
Ethics and dissemination
This systematic review will be published in a peer-reviewed journal. It will be disseminated electronically and in print. Summarising the RCT evidence to clarify the efficacy in BP among overweight and obese adults will aid in making the dietary recommendation of GT and improving the clinical management of hypertension.
Trial registration number
PROSPERO CRD42014007273.
doi:10.1136/bmjopen-2014-004971
PMCID: PMC3996813  PMID: 24742977
green tea; blood pressure; overweight; obese; systematic review protocol
4.  Feasibility of self-collection of fecal specimens by randomly sampled women for health-related studies of the gut microbiome 
BMC Research Notes  2014;7:204.
Background
The field of microbiome research is growing rapidly. We developed a method for self-collection of fecal specimens that can be used in population-based studies of the gut microbiome. We conducted a pilot study to test the feasibility of our methods among a random sample of healthy, postmenopausal women who are members of Kaiser Permanente Colorado (KPCO). We aimed to collect questionnaire data, fecal and urine specimens from 60 women, aged 55–69, who recently had a normal screening mammogram. We designed the study such that all questionnaire data and specimens could be collected at home.
Results
We mailed an invitation packet, consent form and opt-out postcard to 300 women, then recruited by telephone women who did not opt-out. Verbally consented women were mailed an enrollment package including a risk factor questionnaire, link to an online diet questionnaire, specimen collection kit, and instructions for collecting stool and urine. Specimens were shipped overnight to the biorepository. Of the 300 women mailed an invitation packet, 58 (19%) returned the opt-out postcard. Up to 3 attempts were made to telephone the remaining women, of whom 130 (43%) could not be contacted, 23 (8%) refused, and 12 (4%) were ineligible. Enrollment packages were mailed to 77 women, of whom 59 returned the risk factor questionnaire and specimens. We found no statistically significant differences between enrolled women and those who refused participation or could not be contacted.
Conclusions
We demonstrated that a representative sample of women can be successfully recruited for a gut microbiome study; however, significant personal contact and carefully timed follow-up from the study personnel are required. The methods employed by our study could successfully be applied to analytic studies of a wide range of clinical conditions that have been postulated to be influenced by the gut microbial population.
doi:10.1186/1756-0500-7-204
PMCID: PMC3974920  PMID: 24690120
Study design; Microbiome; Breast cancer
5.  Using multiple risk models with preventive interventions 
Statistics in medicine  2012;31(23):2687-2696.
An ideal preventive intervention would have negligible side effects and could be applied to the entire population, thus achieving maximal preventive impact. Unfortunately, many interventions have adverse effects as well as beneficial effects. For example, tamoxifen reduces the risk of breast cancer by about 50% and the risk of hip fracture by 45%, but increases the risk of stroke by about 60%; other serious adverse effects include endometrial cancer and pulmonary embolus. Hence, tamoxifen should only be given to the subset of the population with high enough risks of breast cancer and hip fracture such that the preventive benefits outweigh the risks. Recommendations for preventive use of tamoxifen have been based primarily on breast cancer risk. Age- and race-specific rates were considered for other health outcomes, but not risk models. In this paper, I investigate the extent to which modeling not only the risk of breast cancer, but also the risk of stroke, can improve the decision to take tamoxifen. These calculations also give insight into the relative benefits of improving the discriminatory accuracy of such risk models versus improving the preventive effectiveness or reducing the adverse risks of the intervention. Depending on the discriminatory accuracies of the risk models, there may be considerable advantage to modeling the risks of more than one health outcome.
doi:10.1002/sim.5443
PMCID: PMC3926659  PMID: 22733645
absolute risk models; breast cancer; disease prevention; modeling multiple risks; risk-based prevention strategy; risk versus benefit
6.  Role of Viruses in the Development of Atopic Disease in Pediatric Patients 
The prevalence of atopic diseases continues to rise in modernized countries, without a clear explanation for this increase. One potential cause identified from epidemiologic studies of children is respiratory RNA viral infections leading to development of recurrent wheezing, asthma, and allergic sensitization. We review human epidemiologic data that both support and refute the role of viruses in this process. Exploring recent murine models, we document possible immunologic mechanisms that could translate a viral infection into atopic disease. We further discuss evidence for a post-viral “atopic cycle” that could explain the development of multiple allergen sensitization, and we explore data available to suggest a connection between viral infections of the gastrointestinal tract with the development of food allergy. Taken together, this review documents evidence to support the “viral hypothesis”, and in particular, the role of RNA viruses in the development of atopic disease.
doi:10.1007/s11882-012-0295-y
PMCID: PMC3504451  PMID: 22911226
Virus; antiviral; immunology; atopy; asthma; food allergy; IgE
7.  Evaluating breast cancer risk projections for Hispanic women 
Breast cancer research and treatment  2011;132(1):10.1007/s10549-011-1900-9.
For Hispanic women, the Breast Cancer Risk Assessment Tool (BCRAT; “Gail Model”) combines 1990–1996 breast cancer incidence for Hispanic women with relative risks for breast cancer risk factors from non-Hispanic white (NHW) women. BCRAT risk projections have never been comprehensively evaluated for Hispanic women. We compared the relative risks and calibration of BCRAT risk projections for 6,353 Hispanic to 128,976 NHW postmenopausal participants aged 50 and older in the Women’s Health Initiative (WHI). Calibration was assessed by the ratio of the number of breast cancers observed with that expected by the BCRAT (O/E). We re-evaluated calibration for an updated BCRAT that combined BCRAT relative risks with 1993–2007 breast cancer incidence that is contemporaneous with the WHI. Cox regression was used to estimate relative risks. Discriminatory accuracy was assessed using the concordance statistic (AUC). In the WHI Main Study, the BCRAT underestimated the number of breast cancers by 18% in both Hispanics (O/E = 1.18, P = 0.06) and NHWs (O/E = 1.18, P < 0.001). Updating the BCRAT improved calibration for Hispanic women (O/E = 1.08, P = 0.4) and NHW women (O/E = 0.98, P = 0.2). For Hispanic women, relative risks for number of breast biopsies (1.71 vs. 1.27, P = 0.03) and age at first birth (0.97 vs. 1.24, P = 0.02) differed between the WHI and BCRAT. The AUC was higher for Hispanic women than NHW women (0.63 vs. 0.58, P = 0.03). Updating the BCRAT with contemporaneous breast cancer incidence rates improved calibration in the WHI. The modest discriminatory accuracy of the BCRAT for Hispanic women might improve by using risk factor relative risks specific to Hispanic women.
doi:10.1007/s10549-011-1900-9
PMCID: PMC3827770  PMID: 22147080
Hispanic; Breast cancer; Risk prediction; Risk assessment; BCRAT
8.  Genome-wide association studies of gastric adenocarcinoma and esophageal squamous cell carcinoma identify a shared susceptibility locus in PLCE1 at 10q23 
Nature genetics  2012;44(10):1090-1097.
We conducted a genome-wide association study of gastric cancer (GC) and esophageal squamous cell carcinoma (ESCC) in ethnic Chinese subjects in which we genotyped 551,152 single nucleotide polymorphisms (SNPs). We report a combined analysis of 2,240 GC cases, 2,115 ESCC cases, and 3,302 controls drawn from five studies. In logistic regression models adjusted for age, sex, and study, multiple variants at 10q23 had genome-wide significance for GC and ESCC independently. A notable signal was rs2274223, a nonsynonymous SNP located in PLCE1, for GC (P=8.40×1010; per allele odds ratio (OR) = 1.31) and ESCC (P=3.85×10−9; OR = 1.34). The association with GC differed by anatomic subsite. For tumors located in the cardia the association was stronger (P=4.19 × 10−15; OR= 1.57) and for those located in the noncardia stomach it was absent (P=0.44; OR=1.05). Our findings at 10q23 could provide insight into the high incidence rates of both cancers in China.
doi:10.1038/ng.2411
PMCID: PMC3513832  PMID: 22960999
9.  Isolated limb infusion chemotherapy for melanoma: an overview of early experience at the Adelaide Melanoma Unit 
Background
Isolated limb infusion (ILI) using cytotoxic agents has been demonstrated to be an effective and less invasive alternative modality than isolated limb perfusion for the treatment of melanoma localized to a limb. Percutaneous catheters were inserted into the axial artery and vein of the affected limb while using a pneumatic cuff to restrict limb vascular flow proximally to “isolate” the limb from the body and enable delivery of high-dose intra-arterial chemotherapy selectively to the limb. The ILI technique was developed at the Sydney Melanoma Unit (now renamed the Melanoma Institute Australia), and only a few other centers have reported separate results. We report our early results using the ILI technique for management of locally recurrent surgically nonresectable melanoma.
Methods and results
Twenty-eight ILI procedures were performed in 20 patients treated with one or more procedures between 1997 and 2007. Patient parameters and clinical responses were evaluated. The median follow-up duration was 15.9 months after the first ILI, with an overall response rate after one or more infusions of 70%, of which 35% were complete responders and 35% were partial responders, with a further 20% showing stable disease, giving a “clinically significant” response rate of 90%. After one ILI (n = 20), the overall response rate was 70%, with 20% complete responders and 50% partial responders, and 20% with stable disease. Low limb toxicities were generally observed, and no amputations were required.
Conclusion
ILI chemotherapy is a useful technique, which can be readily repeated for control of melanoma in the limb. It is generally well tolerated, and is capable of achieving a cure, delayed progression, or effective palliation in selected cases. The longest survivors in this series were 8 and 10 years from the last ILI.
doi:10.2147/CMAR.S45746
PMCID: PMC3753062  PMID: 23990731
metastatic melanoma; melphalan; actinomycin-D; regional therapy; intra-arterial infusion
10.  Acute kidney injury and residual renal function 
Critical Care  2012;16(4):144.
Acute kidney injury (AKI) occurring in patients admitted to the ICU may result in impaired renal function on long-term follow-up after ICU discharge. The damage induced by subclinical or manifest episodes of AKI may, in fact, produce an irreversible loss of a variable amount of renal mass with deleterious effects on overall renal function. This may be the case even though baseline glomerular filtration rate appears to return to normal but renal reserve is impaired. This may have an important effect on long-term outcomes, including progression to chronic kidney disease. Acute kidney insults should not be considered as isolated episodes but rather a sequence of progressive events that can lead to progressive deterioration of kidney tissue and eventual declines in renal function.
doi:10.1186/cc11426
PMCID: PMC3580707  PMID: 22866976
11.  Assessment of the human fecal microbiota: II. Reproducibility and associations of 16S rRNA pyrosequences 
Background
We conducted a pilot study of reproducibility and associations of microbial diversity and composition in fecal microbial DNA.
Methods and results
Participants (25 men, 26 women, ages 17–65 years) provided questionnaire data and multiple samples of one stool collected with two Polymedco and two Sarstedt devices pre-loaded with RNAlater. 16S rRNA genes in each fecal DNA aliquot were amplified, sequenced (Roche/454 Life Sciences), and assigned to taxa. Devices were compared for ease of use and reproducibility [intraclass correlation coefficient (ICC)] between duplicate aliquots on diversity and taxonomic assignment. Associations were tested by linear regression. Both collection devices were easy to use. Both alpha diversity (Shannon index) and beta diversity (UniFrac) were higher between than within duplicates (P≤10−8) and did not differ significantly by device (P≥0.62). Reproducibility was good (ICC ≥0.77) for alpha diversity and taxonomic assignment to the most abundant phyla, Firmicutes and Bacteroidetes (71.5% and 25.0% of sequences, respectively), but reproducibility was low (ICC≤0.48) for less abundant taxa. Alpha diversity was lower with non-antibiotic prescription medication (P=0.02), younger age (P=0.03) and marginally with higher body mass index (P=0.08).
Conclusions
With sampling from various parts of a stool, both devices provided good reproducibility on overall microbial diversity and classification for the major phyla, but not for minor phyla. Implementation of these methods should provide insights on how broad microbial parameters, but not necessarily rare microbes, affect risk for various conditions.
doi:10.1111/j.1365-2362.2012.02659.x
PMCID: PMC3369017  PMID: 22385292
Microbiome; alpha diversity; beta diversity; bacterial phylogenetics; medications; body mass index
12.  Assessment of the human fecal microbiota: I. Measurement and reproducibility of selected enzymatic activities 
Background
The intestinal microbial community has major effects on human health, but optimal research methods are unsettled. To facilitate epidemiologic and clinical research, we sought to optimize conditions and to assess reproducibility of selected core functions of the distal gut microbiota, β-glucuronidase and β-glucosidase bioactivities.
Methods and results
A colorimetric kinetic method was optimized and used to quantify activities of β-glucuronidase and β-glucosidase in human feces. Enzyme detection was optimal with neutral pH, snap freezing in liquid nitrogen, and rapid thawing to 37°C before protein extraction. Enzymatic stability was assessed by delayed freezing for 2–48 hours to mimic field settings. Activities decayed approximately 20% within 2 hours and 40% within 4 hours at room temperature. To formally assess reproducibility, 51 volunteers (25 male; mean age 39) used two devices to self-collect and rapidly chill four replicates of a stool. Devices were compared for mean enzymatic activities and intraclass correlation coefficients (ICC) in paired replicates of the self-collected specimens. Reproducibility was excellent with both devices for β-glucuronidase (ICC 0.92). The larger collection device had significantly higher reproducibility for β-glucosidase (ICC 0.92 vs. 0.76, P<0.0001) and higher mean activities for both enzymes (P<0.0001).
Conclusions
Optimal measurement of these core activities of the microbiota required a sufficient quantity of rapidly chilled or frozen specimens collected in PBS at pH7.0. Application of these methods to clinical and epidemiologic research could provide insights on how the intestinal microbiota affects human health.
doi:10.1111/j.1365-2362.2012.02660.x
PMCID: PMC3399928  PMID: 22409163
β-glucuronidase activity; β-glucosidase activity; feces; reproducibility
13.  Association Between BRCA1 and BRCA2 Mutations and Survival in Women with Invasive Epithelial Ovarian Cancer 
Bolton, Kelly L. | Chenevix-Trench, Georgia | Goh, Cindy | Sadetzki, Siegal | Ramus, Susan J. | Karlan, Beth Y. | Lambrechts, Diether | Despierre, Evelyn | Barrowdale, Daniel | McGuffog, Lesley | Healey, Sue | Easton, Douglas F. | Sinilnikova, Olga | Benitez, Javier | García, María J. | Neuhausen, Susan | Gail, Mitchell H. | Hartge, Patricia | Peock, Susan | Frost, Debra | Evans, D. Gareth | Eeles, Ros | Godwin, Andrew K. | Daly, Mary B. | Kwong, Ava | Ma, Edmond SK | Lázaro, Conxi | Blanco, Ignacio | Montagna, Marco | D’Andrea, Emma | Nicoletto, Ornella | Investigators, kConFab | Johnatty, Sharon E. | Kjær, Susanne Krüger | Jensen, Allan | Høgdall, Estrid | Goode, Ellen L. | Fridley, Brooke L. | Loud, Jennifer T. | Greene, Mark H. | Mai, Phuong L. | Chetrit, Angela | Lubin, Flora | Hirsh-Yechezkel, Galit | Glendon, Gord | Andrulis, Irene L. | Toland, Amanda E. | Senter, Leigha | Gore, Martin E. | Gourley, Charlie | Michie, Caroline O | Song, Honglin | Tyrer, Jonathan | Whittemore, Alice S. | McGuire, Valerie | Sieh, Weiva | Kristoffersson, Ulf | Olsson, Håkan | Borg, Åke | Levine, Douglas A. | Steele, Linda | Beattie, Mary S. | Chan, Salina | Nussbaum, Robert | Moysich, Kirsten B. | Gross, Jenny | Cass, Ilana | Walsh, Christine | Li, Andrew J. | Leuchter, Ronald | Gordon, Ora | Garcia-Closas, Montserrat | Gayther, Simon A. | Chanock, Stephen J. | Antoniou, Antonis C. | Pharoah, Paul D.P.
Context
Approximately 10 percent of women with invasive epithelial ovarian cancer (EOC) carry deleterious germline mutations in BRCA1 or BRCA2. A recent report suggested that BRCA2 related EOC was associated with an improved prognosis, but the effect of BRCA1 remains unclear.
Objective
To characterize the survival of BRCA carriers with EOC compared to non-carriers and to determine whether BRCA1 and BRCA2 carriers show similar survival patterns.
Design, Setting, and Participants
We pooled data from 26 studies on the survival of women with ovarian cancer. This included data on 1,213 EOC cases with pathogenic germline mutations in BRCA1 (909) or BRCA2 (304) and 2,666 non-carriers recruited and followed for variable times between 1987 and 2010; the median year of diagnosis was 1998.
Main Outcome Measures
Five year overall mortality.
Results
The five-year overall survival was 36 percent (95% CI: 34–38) for non-carriers, 44 percent (95% CI: 40–48) for BRCA1 carriers and 52 percent (95% CI: 46–58) for BRCA2 carriers. After adjusting for study and year of diagnosis, BRCA1 and BRCA2 carriers showed a more favorable survival than non-carriers (BRCA1, HR=0.78; 95% CI=0.68–0.89, P=2×10−4; BRCA2, HR = 0.61; 95% CI=0.50–0.76, P=6×10−6). These survival differences remained after additional adjustment for stage, grade, histology and age at diagnosis (BRCA1, HR=0.73, 95% CI=0.64–0.84, P=2×10−5; BRCA2, HR = 0.49, 95% CI=0.39–0.61, P=3×10−10).
Conclusions
Among patients with invasive epithelial ovarian cancer, having a germline mutation in BRCA1 or BRCA2 was associated with improved 5-year overall survival.
doi:10.1001/jama.2012.20
PMCID: PMC3727895  PMID: 22274685
14.  Risk Prediction for Breast, Endometrial, and Ovarian Cancer in White Women Aged 50 y or Older: Derivation and Validation from Population-Based Cohort Studies 
PLoS Medicine  2013;10(7):e1001492.
Ruth Pfeiffer and colleagues describe models to calculate absolute risks for breast, endometrial, and ovarian cancers for white, non-Hispanic women over 50 years old using easily obtainable risk factors.
Please see later in the article for the Editors' Summary
Background
Breast, endometrial, and ovarian cancers share some hormonal and epidemiologic risk factors. While several models predict absolute risk of breast cancer, there are few models for ovarian cancer in the general population, and none for endometrial cancer.
Methods and Findings
Using data on white, non-Hispanic women aged 50+ y from two large population-based cohorts (the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial [PLCO] and the National Institutes of Health–AARP Diet and Health Study [NIH-AARP]), we estimated relative and attributable risks and combined them with age-specific US-population incidence and competing mortality rates. All models included parity. The breast cancer model additionally included estrogen and progestin menopausal hormone therapy (MHT) use, other MHT use, age at first live birth, menopausal status, age at menopause, family history of breast or ovarian cancer, benign breast disease/biopsies, alcohol consumption, and body mass index (BMI); the endometrial model included menopausal status, age at menopause, BMI, smoking, oral contraceptive use, MHT use, and an interaction term between BMI and MHT use; the ovarian model included oral contraceptive use, MHT use, and family history or breast or ovarian cancer. In independent validation data (Nurses' Health Study cohort) the breast and ovarian cancer models were well calibrated; expected to observed cancer ratios were 1.00 (95% confidence interval [CI]: 0.96–1.04) for breast cancer and 1.08 (95% CI: 0.97–1.19) for ovarian cancer. The number of endometrial cancers was significantly overestimated, expected/observed = 1.20 (95% CI: 1.11–1.29). The areas under the receiver operating characteristic curves (AUCs; discriminatory power) were 0.58 (95% CI: 0.57–0.59), 0.59 (95% CI: 0.56–0.63), and 0.68 (95% CI: 0.66–0.70) for the breast, ovarian, and endometrial models, respectively.
Conclusions
These models predict absolute risks for breast, endometrial, and ovarian cancers from easily obtainable risk factors and may assist in clinical decision-making. Limitations are the modest discriminatory ability of the breast and ovarian models and that these models may not generalize to women of other races.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
In 2008, just three types of cancer accounted for 10% of global cancer-related deaths. That year, about 460,000 women died from breast cancer (the most frequently diagnosed cancer among women and the fifth most common cause of cancer-related death). Another 140,000 women died from ovarian cancer, and 74,000 died from endometrial (womb) cancer (the 14th and 20th most common causes of cancer-related death, respectively). Although these three cancers originate in different tissues, they nevertheless share many risk factors. For example, current age, age at menarche (first period), and parity (the number of children a woman has had) are all strongly associated with breast, ovarian, and endometrial cancer risk. Because these cancers share many hormonal and epidemiological risk factors, a woman with a high breast cancer risk is also likely to have an above-average risk of developing ovarian or endometrial cancer.
Why Was This Study Done?
Several statistical models (for example, the Breast Cancer Risk Assessment Tool) have been developed that estimate a woman's absolute risk (probability) of developing breast cancer over the next few years or over her lifetime. Absolute risk prediction models are useful in the design of cancer prevention trials and can also help women make informed decisions about cancer prevention and treatment options. For example, a woman at high risk of breast cancer might decide to take tamoxifen for breast cancer prevention, but ideally she needs to know her absolute endometrial cancer risk before doing so because tamoxifen increases the risk of this cancer. Similarly, knowledge of her ovarian cancer risk might influence a woman's decision regarding prophylactic removal of her ovaries to reduce her breast cancer risk. There are few absolute risk prediction models for ovarian cancer, and none for endometrial cancer, so here the researchers develop models to predict the risk of these cancers and of breast cancer.
What Did the Researchers Do and Find?
Absolute risk prediction models are constructed by combining estimates for risk factors from cohorts with population-based incidence rates from cancer registries. Models are validated in an independent cohort by testing their ability to identify people with the disease in an independent cohort and their ability to predict the observed numbers of incident cases. The researchers used data on white, non-Hispanic women aged 50 years or older that were collected during two large prospective US cohort studies of cancer screening and of diet and health, and US cancer incidence and mortality rates provided by the Surveillance, Epidemiology, and End Results Program to build their models. The models all included parity as a risk factor, as well as other factors. The model for endometrial cancer, for example, also included menopausal status, age at menopause, body mass index (an indicator of the amount of body fat), oral contraceptive use, menopausal hormone therapy use, and an interaction term between menopausal hormone therapy use and body mass index. Individual women's risk for endometrial cancer calculated using this model ranged from 1.22% to 17.8% over the next 20 years depending on their exposure to various risk factors. Validation of the models using data from the US Nurses' Health Study indicated that the endometrial cancer model overestimated the risk of endometrial cancer but that the breast and ovarian cancer models were well calibrated—the predicted and observed risks for these cancers in the validation cohort agreed closely. Finally, the discriminatory power of the models (a measure of how well a model separates people who have a disease from people who do not have the disease) was modest for the breast and ovarian cancer models but somewhat better for the endometrial cancer model.
What Do These Findings Mean?
These findings show that breast, ovarian, and endometrial cancer can all be predicted using information on known risk factors for these cancers that is easily obtainable. Because these models were constructed and validated using data from white, non-Hispanic women aged 50 years or older, they may not accurately predict absolute risk for these cancers for women of other races or ethnicities. Moreover, the modest discriminatory power of the breast and ovarian cancer models means they cannot be used to decide which women should be routinely screened for these cancers. Importantly, however, these well-calibrated models should provide realistic information about an individual's risk of developing breast, ovarian, or endometrial cancer that can be used in clinical decision-making and that may assist in the identification of potential participants for research studies.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001492.
This study is further discussed in a PLOS Medicine Perspective by Lars Holmberg and Andrew Vickers
The US National Cancer Institute provides comprehensive information about cancer (in English and Spanish), including detailed information about breast cancer, ovarian cancer, and endometrial cancer;
Information on the Breast Cancer Risk Assessment Tool, the Surveillance, Epidemiology, and End Results Program, and on the prospective cohort study of screening and the diet and health study that provided the data used to build the models is also available on the NCI site
Cancer Research UK, a not-for-profit organization, provides information about cancer, including detailed information on breast cancer, ovarian cancer, and endometrial cancer
The UK National Health Service Choices website has information and personal stories about breast cancer, ovarian cancer, and endometrial cancer; the not-for-profit organization Healthtalkonline also provides personal stories about dealing with breast cancer and ovarian cancer
doi:10.1371/journal.pmed.1001492
PMCID: PMC3728034  PMID: 23935463
15.  Lixivaptan – an evidence-based review of its clinical potential in the treatment of hyponatremia 
Core Evidence  2013;8:47-56.
Hyponatremia is the most common electrolyte abnormality seen in clinical practice. Most cases of euvolemic or hypervolemic hyponatremia involve arginine vasopressin (AVP). AVP leads to a concentrated urine and negative free water clearance. Given this primary role of AVP, antagonizing its effect through blockade of its receptor in the distal tubule is an attractive therapeutic target. Lixivaptan is a newer, non-peptide, vasopressin type 2 receptor antagonist. Recent studies have demonstrated efficacy. This review summarizes the clinical pharmacology and data for this new agent.
doi:10.2147/CE.S36744
PMCID: PMC3712664  PMID: 23874242
vasopressin; hyponatremia; heart failure; lixivaptan; therapy; outcomes
16.  Potential Usefulness of Single Nucleotide Polymorphisms to Identify Persons at High Cancer Risk: An Evaluation of Seven Common Cancers 
Journal of Clinical Oncology  2012;30(17):2157-2162.
Purpose
To estimate the likely number and predictive strength of cancer-associated single nucleotide polymorphisms (SNPs) that are yet to be discovered for seven common cancers.
Methods
From the statistical power of published genome-wide association studies, we estimated the number of undetected susceptibility loci and the distribution of effect sizes for all cancers. Assuming a log-normal model for risks and multiplicative relative risks for SNPs, family history (FH), and known risk factors, we estimated the area under the receiver operating characteristic curve (AUC) and the proportion of patients with risks above risk thresholds for screening. From additional prevalence data, we estimated the positive predictive value and the ratio of non–patient cases to patient cases (false-positive ratio) for various risk thresholds.
Results
Age-specific discriminatory accuracy (AUC) for models including FH and foreseeable SNPs ranged from 0.575 for ovarian cancer to 0.694 for prostate cancer. The proportions of patients in the highest decile of population risk ranged from 16.2% for ovarian cancer to 29.4% for prostate cancer. The corresponding false-positive ratios were 241 for colorectal cancer, 610 for ovarian cancer, and 138 or 280 for breast cancer in women age 50 to 54 or 40 to 44 years, respectively.
Conclusion
Foreseeable common SNP discoveries may not permit identification of small subsets of patients that contain most cancers. Usefulness of screening could be diminished by many false positives. Additional strong risk factors are needed to improve risk discrimination.
doi:10.1200/JCO.2011.40.1943
PMCID: PMC3397697  PMID: 22585702
17.  Clinical Outcome Prediction in Aneurysmal Subarachnoid Hemorrhage Using Bayesian Neural Networks with Fuzzy Logic Inferences 
Objective. The novel clinical prediction approach of Bayesian neural networks with fuzzy logic inferences is created and applied to derive prognostic decision rules in cerebral aneurysmal subarachnoid hemorrhage (aSAH). Methods. The approach of Bayesian neural networks with fuzzy logic inferences was applied to data from five trials of Tirilazad for aneurysmal subarachnoid hemorrhage (3551 patients). Results. Bayesian meta-analyses of observational studies on aSAH prognostic factors gave generalizable posterior distributions of population mean log odd ratios (ORs). Similar trends were noted in Bayesian and linear regression ORs. Significant outcome predictors include normal motor response, cerebral infarction, history of myocardial infarction, cerebral edema, history of diabetes mellitus, fever on day 8, prior subarachnoid hemorrhage, admission angiographic vasospasm, neurological grade, intraventricular hemorrhage, ruptured aneurysm size, history of hypertension, vasospasm day, age and mean arterial pressure. Heteroscedasticity was present in the nontransformed dataset. Artificial neural networks found nonlinear relationships with 11 hidden variables in 1 layer, using the multilayer perceptron model. Fuzzy logic decision rules (centroid defuzzification technique) denoted cut-off points for poor prognosis at greater than 2.5 clusters. Discussion. This aSAH prognostic system makes use of existing knowledge, recognizes unknown areas, incorporates one's clinical reasoning, and compensates for uncertainty in prognostication.
doi:10.1155/2013/904860
PMCID: PMC3639630  PMID: 23690884
18.  Fifteen-Year Effects of Helicobacter pylori, Garlic, and Vitamin Treatments on Gastric Cancer Incidence and Mortality 
In the Shandong Intervention Trial, 2 weeks of antibiotic treatment for Helicobacter pylori reduced the prevalence of precancerous gastric lesions, whereas 7.3 years of oral supplementation with garlic extract and oil (garlic treatment) or vitamin C, vitamin E, and selenium (vitamin treatment) did not. Here we report 14.7-year follow-up for gastric cancer incidence and cause-specific mortality among 3365 randomly assigned subjects in this masked factorial placebo-controlled trial. Conditional logistic regression was used to estimate the odds of gastric cancer incidence, and the Cox proportional hazards model was used to estimate the relative hazard of cause-specific mortality. All statistical tests were two-sided. Gastric cancer was diagnosed in 3.0% of subjects who received H pylori treatment and in 4.6% of those who received placebo (odds ratio = 0.61, 95% confidence interval = 0.38 to 0.96, P = .032). Gastric cancer deaths occurred among 1.5% of subjects assigned H pylori treatment and among 2.1% of those assigned placebo (hazard ratio [HR] of death = 0.67, 95% CI = 0.36 to 1.28). Garlic and vitamin treatments were associated with non-statistically significant reductions in gastric cancer incidence and mortality. Vitamin treatment was associated with statistically significantly fewer deaths from gastric or esophageal cancer, a secondary endpoint (HR = 0.51, 95% CI = 0.30 to 0.87; P = .014).
doi:10.1093/jnci/djs003
PMCID: PMC3309129  PMID: 22271764
19.  Estrogen Metabolism and Risk of Breast Cancer in Postmenopausal Women 
Background
Estrogens are recognized causal factors in breast cancer. Interindividual variation in estrogen metabolism may also influence the risk of breast cancer and could provide clues to mechanisms of breast carcinogenesis. Long-standing hypotheses about how estrogen metabolism might influence breast cancer have not been adequately evaluated in epidemiological studies because of the lack of accurate, reproducible, and high-throughput assays for estrogen metabolites.
Methods
We conducted a prospective case–control study nested within the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO). Participants included 277 women who developed invasive breast cancer (case subjects) and 423 matched control subjects; at PLCO baseline, all subjects were aged 55–74 years, postmenopausal and not using hormone therapy, and provided a blood sample. Liquid chromatography–tandem mass spectrometry was used to measure serum concentrations of 15 estrogens and estrogen metabolites, in unconjugated and conjugated forms, including the parent estrogens, estrone and estradiol, and estrogen metabolites in pathways defined by irreversible hydroxylation at the C-2, C-4, or C-16 positions of the steroid ring. We calculated hazard ratios (HRs) approximating risk in highest vs lowest deciles of individual estrogens and estrogen metabolites, estrogens and estrogen metabolites grouped by metabolic pathways, and metabolic pathway ratios using multivariable Cox proportional hazards models. All statistical tests were two-sided.
Results
Nearly all estrogens, estrogen metabolites, and metabolic pathway groups were associated with an increased risk of breast cancer; the serum concentration of unconjugated estradiol was strongly associated with the risk of breast cancer (HR = 2.07, 95% confidence interval [CI] = 1.19 to 3.62). No estrogen, estrogen metabolite, or metabolic pathway group remained statistically significantly associated with the risk of breast cancer after adjusting for unconjugated estradiol. The ratio of the 2-hydroxylation pathway to parent estrogens (HR = 0.66, 95% CI = 0.51 to 0.87) and the ratio of 4-hydroxylation pathway catechols to 4-hydroxylation pathway methylated catechols (HR = 1.34, 95% CI = 1.04 to 1.72) were statistically significantly associated with the risk of breast cancer and remained so after adjustment for unconjugated estradiol.
Conclusions
More extensive 2-hydroxylation of parent estrogens is associated with lower risk, and less extensive methylation of potentially genotoxic 4-hydroxylation pathway catechols is associated with higher risk of postmenopausal breast cancer.
doi:10.1093/jnci/djr531
PMCID: PMC3283536  PMID: 22232133
20.  Reduced fronto-cerebellar functional connectivity in chronic alcoholic patients 
BACKGROUND
Alcohol dependence is associated with neurocognitive deficits related to neuropathological changes in structure, metabolism, and function of the brain. Impairments of motor functioning in alcoholics have been attributed to well-characterized neuropathological brain abnormalities in cerebellum.
METHODS
Using functional magnetic resonance imaging (fMRI), we studied in vivo the functional connectivity between cerebellar and cortical brain regions. Participants were 10 uncomplicated chronic alcoholic patients studied after 5–7 days of abstinence when signs of withdrawal had abated, and 10 matched healthy controls. We focused on regions of prefrontal, frontal, temporal, and parietal cortex that exhibited an fMRI response associated with non-dominant hand finger tapping in the patients but not in the controls. We predicted that fronto-cerebellar functional connectivity would be diminished in alcoholics compared to controls.
RESULTS
Functional connectivity in a circuit involving premotor areas (Brodmann Area 6) and Lobule VI of the superior cerebellum was reduced in the patients compared to the controls. Functional connectivity was also reduced in a circuit involving prefrontal cortex (Brodmann Area 9) and Lobule VIII of the inferior cerebellum. Reductions in connectivity were specific to fronto-cerebellar circuits and were not found in other regions examined.
CONCLUSIONS
Our findings show a pattern in recently abstinent alcoholic patients of specific deficits in functional connectivity and recruitment of additional brain regions for performance of a simple finger tapping task. A small sample, differences in smoking, and a brief abstinence period preclude definitive conclusions, but this pattern of diminished fronto-cerebellar functional connectivity is highly compatible with the characteristic neuropathological lesions documented in alcoholics, and may reflect brain dysfunction associated with alcoholism.
doi:10.1111/j.1530-0277.2011.01614.x
PMCID: PMC3268944  PMID: 22085135
Alcohol; alcoholism; functional MRI; motor; connectivity
21.  Randomized, Double-blind, Placebo Controlled Trial of Polyphenon E in Prostate Cancer Patients before Prostatectomy: Evaluation of Potential Chemopreventive Activities 
Compelling pre-clinical and pilot clinical data support the role of green tea polyphenols in prostate cancer prevention. We conducted a randomized, double-blind, placebo controlled trial of Polyphenon E (enriched green tea polyphenol extract) in men with prostate cancer scheduled to undergo radical prostatectomy. The study aimed to determine the bioavailability of green tea polyphenols in prostate tissue and to measure its effects on systemic and tissue biomarkers of prostate cancer carcinogenesis. Participants received either Polyphenon E (containing 800 mg epigallocatechin gallate) or placebo daily for 3–6 weeks before surgery. Following the intervention, green tea polyphenol levels in the prostatectomy tissue were low to undetectable. Polyphenon E intervention resulted in favorable but not statistically significant changes in serum prostate specific antigen, serum insulin-like growth factor axis, and oxidative DNA damage in blood leukocytes. Tissue biomarkers of cell proliferation, apoptosis, and angiogenesis in the prostatectomy tissue did not differ between the treatment arms. The proportion of subjects who had a decrease in Gleason score between biopsy and surgical specimens was greater in those on Polyphenon E but was not statistically significant. The study's findings of low bioavailability and/or bioaccumulation of green tea polyphenols in prostate tissue and statistically insignificant changes in systemic and tissue biomarkers from 3–6 weeks of administration suggests that prostate cancer preventive activity of green tea polyphenols, if occurring, may be through indirect means and/or that the activity may need to be evaluated with longer intervention durations, repeated dosing, or in patients at earlier stages of the disease.
doi:10.1158/1940-6207.CAPR-11-0306
PMCID: PMC3273617  PMID: 22044694
Polyphenon E; green tea polyphenols; prostate cancer; chemoprevention
22.  Fecal microbial determinants of fecal and systemic estrogens and estrogen metabolites: a cross-sectional study 
Background
High systemic estrogen levels contribute to breast cancer risk for postmenopausal women, whereas low levels contribute to osteoporosis risk. Except for obesity, determinants of non-ovarian systemic estrogen levels are undefined. We sought to identify members and functions of the intestinal microbial community associated with estrogen levels via enterohepatic recirculation.
Methods
Fifty-one epidemiologists at the National Institutes of Health, including 25 men, 7 postmenopausal women, and 19 premenopausal women, provided urine and aliquots of feces, using methods proven to yield accurate and reproducible results. Estradiol, estrone, 13 estrogen metabolites (EM), and their sum (total estrogens) were quantified in urine and feces by liquid chromatography/tandem mass spectrometry. In feces, β-glucuronidase and β-glucosidase activities were determined by realtime kinetics, and microbiome diversity and taxonomy were estimated by pyrosequencing 16S rRNA amplicons. Pearson correlations were computed for each loge estrogen level, loge enzymatic activity level, and microbiome alpha diversity estimate. For the 55 taxa with mean relative abundance of at least 0.1%, ordinal levels were created [zero, low (below median of detected sequences), high] and compared to loge estrogens, β-glucuronidase and β-glucosidase enzymatic activity levels by linear regression. Significance was based on two-sided tests with α=0.05.
Results
In men and postmenopausal women, levels of total urinary estrogens (as well as most individual EM) were very strongly and directly associated with all measures of fecal microbiome richness and alpha diversity (R≥0.50, P≤0.003). These non-ovarian systemic estrogens also were strongly and significantly associated with fecal Clostridia taxa, including non-Clostridiales and three genera in the Ruminococcaceae family (R=0.57−0.70, P=0.03−0.002). Estrone, but not other EM, in urine correlated significantly with functional activity of fecal β-glucuronidase (R=0.36, P=0.04). In contrast, fecal β-glucuronidase correlated inversely with fecal total estrogens, both conjugated and deconjugated (R≤-0.47, P≤0.01). Premenopausal female estrogen levels, which were collected across menstrual cycles and thus highly variable, were completely unrelated to fecal microbiome and enzyme parameters (P≥0.6).
Conclusions
Intestinal microbial richness and functions, including but not limited to β-glucuronidase, influence levels of non-ovarian estrogens via enterohepatic circulation. Thus, the gut microbial community likely affects the risk for estrogen-related conditions in older adults. Understanding how Clostridia taxa relate to systemic estrogens may identify targets for interventions.
Trial registration
Not applicable.
doi:10.1186/1479-5876-10-253
PMCID: PMC3552825  PMID: 23259758
Microbiome; Feces; Enterohepatic circulation; β-glucuronidase; β-glucosidase; Postmenopausal estrogens; Fecal estrogens; Estrogen metabolites
23.  Granzyme B Regulates Antiviral CD8+ T cell Responses1 
Cytotoxic T lymphocytes and natural killer cells utilize the perforin/granzyme cytotoxic pathway to kill virally-infected cells and tumors. Human regulatory T cells also express functional granzymes and perforin and can induce autologous target cell death in vitro. Perforin-deficient mice die from excessive immune responses after viral challenges, implicating a potential role for this pathway in immune regulation. To further investigate the role of granzyme B in immune regulation in response to viral infections, we characterized the immune response in wild-type, granzyme B deficient, and perforin deficient mice infected with Sendai virus. Interestingly, granzyme B deficient mice, and to a lesser extent perforin deficient mice, exhibited a significant increase in the number of Ag-specific CD8+ T cells in the lungs and draining lymph nodes of virally infected animals. This increase was not the result of failure in viral clearance since viral titers in granzyme B-deficient mice were similar to wild-type mice and significantly less than perforin-deficient mice. Regulatory T cells from WT mice expressed high levels of granzyme B in response to infection, and depletion of regulatory T cells from these mice resulted in an increase in the number of Ag-specific CD8+ T cells, similar to that observed in granzyme B-deficient mice. Furthermore, granzyme B-deficient regulatory T cells displayed defective suppression of CD8+ T cell proliferation in vitro. Taken together these results suggest a role for granzyme B in the regulatory T cell compartment in immune regulation to viral infections.
doi:10.4049/jimmunol.1100891
PMCID: PMC3237805  PMID: 22084442
24.  Few Associations Found between Mold and Other Allergen Concentrations in the Home versus Skin Sensitivity from Children with Asthma after Hurricane Katrina in the Head-Off Environmental Asthma in Louisiana Study 
Mold and other allergen exposures exacerbate asthma symptoms in sensitized individuals. We evaluated allergen concentrations, skin test sensitivities, and asthma morbidity for 182 children, aged 4–12 years, with moderate to severe asthma, enrolled 18 months after Katrina, from the city of New Orleans and the surrounding parishes that were impacted by the storm, into the Head-off Environmental Asthma in Louisiana (HEAL) observational study. Dust (indoor) and air (indoor and outdoor) samples were collected at baseline of 6 and 12 months. Dust samples were evaluated for dust mite, cockroach, mouse, and Alternaria by immunoassay. Air samples were evaluated for airborne mold spore concentrations. Overall, 89% of the children tested positive to ≥1 indoor allergen, with allergen-specific sensitivities ranging from 18% to 67%. Allergen concentration was associated with skin sensitivity for 1 of 10 environmental triggers analyzed (cat). Asthma symptom days did not differ with skin test sensitivity, and surprisingly, increased symptoms were observed in children whose baseline indoor airborne mold concentrations were below median levels. This association was not observed in follow-up assessments. The lack of relationship among allergen levels (including mold), sensitivities, and asthma symptoms points to the complexity of attempting to assess these associations during rapidly changing social and environmental conditions.
doi:10.1155/2012/427358
PMCID: PMC3523147  PMID: 23304171
25.  Lower levels of plasmacytoid dendritic cells in peripheral blood are associated with a diagnosis of asthma 6 years after severe respiratory syncytial virus bronchiolitis 
Background
Plasmacytoid dendritic cells (DC) play a crucial role in antiviral immunity and promoting Th1 polarization, possibly protecting against development of allergic disease.
Objective
Examination of the relationship between peripheral blood plasmacytoid DC levels and manifestations of asthma and atopy early in life.
Methods
We have isolated peripheral blood mononuclear cells (PBMC) from 73 children (mean age ± SD: 6.6 ± 0.5 years old) participating in the RSV Bronchiolitis in Early Life (RBEL) study. Flow cytometry was performed on PBMC detecting DC surface-markers: Blood Dendritic Cell Antigens (BDCA) 1, 3, and 2 which identify myeloid type 1, type 2, and plasmacytoid cells respectively. Total serum IgE, peripheral eosinophil count, and allergy skin tests were documented.
Results
45% (n=33) of study participants had physician-diagnosed asthma by 6 years of age. These children had significantly lower quantities (mean ± SD) of plasmacytoid DC than their non-asthmatic counterparts (1020 ± 921 vs. 1952 ± 1170 cells per 106 PBMC, p=0.003). We found significantly lower numbers of myeloid dendritic cells in children with asthma (3836 ± 2472 cells per 106 PBMC) compared with those without (4768 ± 2224 cells per 106 PBMC, p=0.02); however, this divergence was not significant after adjusting for covariates of age, gender, race, skin test reactivity, smoke exposure, and day care attendance. We did not identify any direct association between DC levels and markers of atopy: skin test reactivity, peripheral eosinophilia, and IgE level.
Conclusion
Children who are diagnosed with asthma after severe RSV bronchiolitis appear to have a relative deficiency of plasmacytoid DC in peripheral blood.
doi:10.1111/j.1399-3038.2008.00818.x
PMCID: PMC3515331  PMID: 19140903
dendritic cell; asthma; respiratory syncytial virus

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