Publications by authors named "Ruth M Pfeiffer"

413 Publications

Inverse association of falciparum positivity with endemic Burkitt lymphoma is robust in analyses adjusting for pre-enrollment malaria in the EMBLEM case-control study.

Infect Agent Cancer 2021 Jun 7;16(1):40. Epub 2021 Jun 7.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Infections and Immunoepidemiology Branch, 9609 Medical Center Dr, Rm. 6E-118, MSC 3330, Bethesda, MD, 20892, USA.

Background: Falciparum and endemic Burkitt lymphoma (eBL) are co-endemic in Africa, but the malaria experience in eBL patients is unknown. A lower prevalence of falciparum has been reported in eBL patients, but those results are anecdotally attributed to pre-enrollment anti-malaria treatment.

Methods: We studied 677 eBL patients and 2920 community controls aged 0-15 years enrolled in six regions in Uganda, Tanzania, and Kenya during 2010-2016. Falciparum was diagnosed using thick blood film microscopy (TFM) and antigen-capture rapid diagnostic tests (RDTs). Guardians of the children answered a 40-item structured questionnaire about their child's pre-enrollment lifetime malaria history and treatment, demographics, socioeconomics, animal exposures, fevers, and hospitalizations. We utilized exploratory factor analysis to reduce the 40 questionnaire variables into six factors, including Inpatient malaria and Outpatient malaria factors that were surrogates of pre-enrollment anti-malaria treatment. The six factors accounted for 83-90% of the variance in the questionnaire data. We calculated odds ratios and 95% confidence intervals (OR 95% CI) of association of eBL with falciparum positivity, defined as positive both on TFM or RDTs, or only RDTs (indicative of recent infection) or TFM (indicative of current falciparum infection) versus no infection, using multivariable logistic regression, controlling for group of age (0-2, 3-5, 6-8, 9-11 and 12-15 years), sex, and study site and the afore-mentioned pre-enrollment factors.

Results: The prevalence of falciparum infection was 25.6% in the eBL cases and 45.7% in community controls (aOR = 0.43, 95% CI: 0.40, 0.47; P < 0.0001). The results were similar for recent falciparum infection (6.9% versus 13.5%, aOR = 0.44, 95% CI: 0.38, 0.50; P < 0.0001) and current falciparum infection (18.7% versus 32.1%, aOR = 0.47, 95% CI: 0.43, 0.51; P < 0.0001). These aORs for any, recent and current falciparum infection did not change when we adjusted for pre-enrollment factors (aORs = 0.46, =0.44, and = 0.51, respectively) were significantly lower in stratified analysis for any infection in children < 5 years (aOR = 0.46; 95% CI: 0.29, 0.75) or ≥ 10 years (aOR = 0.47; 95% CI: 0.32, 0.71).

Conclusion: Our study results reduce support for pre-enrollment antimalaria treatment as a sole explanation for the observed lower falciparum prevalence in eBL cases and open a space to consider alternative immunology-based hypotheses.
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http://dx.doi.org/10.1186/s13027-021-00377-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8186042PMC
June 2021

Prediagnostic circulating inflammation-related biomarkers and gastric cancer: A case-cohort study in Japan.

Cytokine 2021 Aug 10;144:155558. Epub 2021 May 10.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.

Gastric cancer is preceded by a chronic inflammatory process. Circulating levels of inflammation-related markers may reveal molecular pathways contributing to cancer development. Our study evaluated risk associations of gastric cancer with a wide range of systemic soluble inflammation and immune-response proteins. We performed a case-cohort analysis within the JPHC Study II, including a subcohort of 410 participants selected randomly within defined age and sex groups, and 414 individuals with incident gastric cancer. Ninety-two biomarkers were measured in baseline plasma using proximity extension assays. Gastric cancer multivariable hazard ratios were calculated for two to four quantiles used as ordinal variables of each biomarker by Cox proportional hazards regression models with age as the time metric. Of 73 evaluable biomarkers, three (CCL11, CCL20 and IL17C) were associated with increased gastric cancer risk and two (CCL23 and MMP1) with reduced cancer risk (P < 0.05). However, no association was statistically significant after a false discovery rate correction. This study largely expands the range of inflammation molecules evaluated for gastric cancer risk but failed to identify novel associations with this neoplasia.
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http://dx.doi.org/10.1016/j.cyto.2021.155558DOI Listing
August 2021

Relation of Quantitative Histologic and Radiologic Breast Tissue Composition Metrics With Invasive Breast Cancer Risk.

JNCI Cancer Spectr 2021 Jun 6;5(3):pkab015. Epub 2021 Feb 6.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institute of Health, USA.

Background: Benign breast disease (BBD) is a strong breast cancer risk factor, but identifying patients that might develop invasive breast cancer remains a challenge.

Methods: By applying machine-learning to digitized hematoxylin and eosin-stained biopsies and computer-assisted thresholding to mammograms obtained circa BBD diagnosis, we generated quantitative tissue composition metrics and determined their association with future invasive breast cancer diagnosis. Archival breast biopsies and mammograms were obtained for women (18-86 years of age) in a case-control study, nested within a cohort of 15 395 BBD patients from Kaiser Permanente Northwest (1970-2012), followed through mid-2015. Patients who developed incident invasive breast cancer (ie, cases; n = 514) and those who did not (ie, controls; n = 514) were matched on BBD diagnosis age and plan membership duration. All statistical tests were 2-sided.

Results: Increasing epithelial area on the BBD biopsy was associated with increasing breast cancer risk (odds ratio [OR] = 1.85, 95% confidence interval [CI] = 1.13 to 3.04; = .02). Conversely, increasing stroma was associated with decreased risk in nonproliferative, but not proliferative, BBD ( = .002). Increasing epithelium-to-stroma proportion (OR = 2.06, 95% CI =1.28 to 3.33; = .002) and percent mammographic density (MBD) (OR = 2.20, 95% CI = 1.20 to 4.03; = .01) were independently and strongly predictive of increased breast cancer risk. In combination, women with high epithelium-to-stroma proportion and high MBD had substantially higher risk than those with low epithelium-to-stroma proportion and low MBD (OR = 2.27, 95% CI = 1.27 to 4.06; = .005), particularly among women with nonproliferative ( = .01) vs proliferative ( = .33) BBD.

Conclusion: Among BBD patients, increasing epithelium-to-stroma proportion on BBD biopsies and percent MBD at BBD diagnosis were independently and jointly associated with increasing breast cancer risk. These findings were particularly striking for women with nonproliferative disease (comprising approximately 70% of all BBD patients), for whom relevant predictive biomarkers are lacking.
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http://dx.doi.org/10.1093/jncics/pkab015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8103888PMC
June 2021

Solid Organ Transplantation and Survival among Individuals with a History of Cancer.

Cancer Epidemiol Biomarkers Prev 2021 Apr 29. Epub 2021 Apr 29.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland.

Background: The success of immunotherapy highlights a possible role for immunity in controlling cancer during remission for patients with cancer in the general population. A prior cancer diagnosis is common among solid organ transplant candidates, and immunosuppressive medications administered to transplant recipients may increase recurrence risk.

Methods: Using linked data from the United States solid organ transplant registry and 13 cancer registries, we compared overall and cancer-specific survival among patients with cancer who did versus did not receive subsequent transplantation. We used Cox regression in cohort and matched analyses, controlling for demographic factors, cancer stage, and time since cancer diagnosis.

Results: The study included 10,524,326 patients with cancer, with 17 cancer types; 5,425 (0.05%) subsequently underwent solid organ transplantation. The median time from cancer diagnosis to transplantation was 5.7 years. Transplantation was associated with reduced overall survival for most cancers, especially cervical, testicular, and thyroid cancers [adjusted hazard ratios (aHR) for overall mortality, 3.43-4.88]. In contrast, transplantation was not associated with decreased cancer-specific survival for any cancer site, and we observed inverse associations for patients with breast cancer (aHRs for cancer-specific mortality, 0.65-0.67), non-Hodgkin lymphoma (0.50-0.51), and myeloma (0.39-0.42).

Conclusions: Among U.S. patients with cancer, subsequent organ transplantation was associated with reduced overall survival, likely due to end-stage organ disease and transplant-related complications. However, we did not observe adverse associations with cancer-specific survival, partly reflecting careful candidate selection.

Impact: These results do not demonstrate a detrimental effect of immunosuppression on cancer-specific survival and support current management strategies for transplant candidates with previous cancer diagnoses.
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http://dx.doi.org/10.1158/1055-9965.EPI-21-0044DOI Listing
April 2021

HLA zygosity increases risk of hepatitis B virus-associated hepatocellular carcinoma.

J Infect Dis 2021 Apr 14. Epub 2021 Apr 14.

Genomics Research Center, Academia Sinica, Taipei, Taiwan.

Background: Diversity in the human leukocyte antigen (HLA) genes might be associated with disease outcomes - the heterozygote advantage hypothesis. We tested this hypothesis in relation to hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC).

Methods: We utilized DNA from >10,000 Taiwanese individuals with current or past HBV infection to examine the association between HLA diversity and critical natural history steps in the progression from HBV infection to HCC. Individuals were classified as homozygotes at a given locus when imputed to carry the same 4-digit allele for the two HLA alleles at that locus.

Results: Increase in number of homozygous HLA class II loci was associated with an increased risk of chronic HBV infection (Ptrend=1.18×10 -7). Among chronic HBV carriers, increase in number of homozygous HLA class II loci was also associated with an increased risk of HBV-associated HCC (Ptrend=0.031). For individual HLA loci, HLA-DQB1 homozygosity was significantly associated with HCC risk (adjusted hazard ratio=1.40, 95% confidence interval=1.06-1.84). We also found that zygosity affects risk of HCC through its ability to affect viral control.

Conclusions: Homozygosity at HLA class II loci, particularly HLA-DQB1, is associated with a higher risk of HBV-associated HCC.
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http://dx.doi.org/10.1093/infdis/jiab207DOI Listing
April 2021

The Impact of Longitudinal Surveillance on Tumor Thickness for Melanoma-Prone Families with and without Pathogenic Germline Variants of and .

Cancer Epidemiol Biomarkers Prev 2021 Apr;30(4):676-681

Division of Cancer Epidemiology and Genetics, NCI, NIH, Rockville, Maryland.

Background: Skin cancer screening is routinely performed for members of melanoma-prone families, but longitudinal studies evaluating the efficacy of surveillance in this high-risk population are lacking.

Methods: We evaluated thickness for first primary melanomas diagnosed in melanoma-prone families (≥2 individuals with melanoma) enrolled in NCT00040352 (NCI familial melanoma study) from 1976 through 2014; enrolled patients received routine skin cancer screening and education about skin self-exams. We used linear and ordinal logistic regression models adjusted for gender and age with a generalized estimating equations approach to report changes in thickness and tumor (T) stage over time, comparing outcomes for NCI cases diagnosed before (pre-study) versus after study participation (prospective) and for NCI cases versus nonfamilial cases [Surveillance, Epidemiology, and End Results (SEER) 9 registries].

Results: Tumor thickness was evaluated for 293 NCI (pre-study = 246; prospective = 47) patients. Compared with NCI pre-study cases, NCI prospective melanomas were thinner (0.6 vs. 1.1 mm; < 0.001) and more likely to be T1 stage [39/47 (83%) vs. 98/246 (40%); < 0.001]. Similar findings ( < 0.05) were observed for familial cases with and without germline and mutations. Peters-Belson modeling suggested that calendar period effects of decreasing thickness in the general population (SEER 9) did not fully explain thickness trends in NCI families.

Conclusions: Participation in a longitudinal surveillance program providing skin cancer screening and education about skin self-exams was associated with thinner melanomas for members of melanoma-prone families.

Impact: The study findings support the clinical benefit of screening (physician and self) for this high-risk population.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-1521DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8049096PMC
April 2021

Translating the immediate effects of S-Ketamine using hippocampal subfield analysis in healthy subjects-results of a randomized controlled trial.

Transl Psychiatry 2021 Apr 1;11(1):200. Epub 2021 Apr 1.

Department of Psychiatry and Psychotherapy, Medical University of Vienna, Vienna, Austria.

Antidepressant doses of ketamine rapidly facilitate synaptic plasticity and modify neuronal function within prefrontal and hippocampal circuits. However, most studies have demonstrated these effects in animal models and translational studies in humans are scarce. A recent animal study showed that ketamine restored dendritic spines in the hippocampal CA1 region within 1 h of administration. To translate these results to humans, this randomized, double-blind, placebo-controlled, crossover magnetic resonance imaging (MRI) study assessed ketamine's rapid neuroplastic effects on hippocampal subfield measurements in healthy volunteers. S-Ketamine vs. placebo data were analyzed, and data were also grouped by brain-derived neurotrophic factor (BDNF) genotype. Linear mixed models showed that overall hippocampal subfield volumes were significantly larger (p = 0.009) post ketamine than post placebo (LS means difference=0.008, standard error=0.003). Post-hoc tests did not attribute effects to specific subfields (all p > 0.05). Trend-wise volumetric increases were observed within the left hippocampal CA1 region (p = 0.076), and trend-wise volumetric reductions were obtained in the right hippocampal-amygdaloid transition region (HATA) (p = 0.067). Neither genotype nor a genotype-drug interaction significantly affected the results (all p > 0.7). The study provides evidence that ketamine has short-term effects on hippocampal subfield volumes in humans. The results translate previous findings from animal models of depression showing that ketamine has pro-neuroplastic effects on hippocampal structures and underscore the importance of the hippocampus as a key region in ketamine's mechanism of action.
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http://dx.doi.org/10.1038/s41398-021-01318-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8016970PMC
April 2021

Risk factors for breast cancer development by tumor characteristics among women with benign breast disease.

Breast Cancer Res 2021 Mar 18;23(1):34. Epub 2021 Mar 18.

Albert Einstein College of Medicine, Jack and Pearl Resnick Campus, 1300 Morris Park Avenue, Belfer Building, Room 1301, Bronx, NY, 10461, USA.

Background: Among women diagnosed with invasive breast cancer, 30% have a prior diagnosis of benign breast disease (BBD). Thus, it is important to identify factors among BBD patients that elevate invasive cancer risk. In the general population, risk factors differ in their associations by clinical pathologic features; however, whether women with BBD show etiologic heterogeneity in the types of breast cancers they develop remains unknown.

Methods: Using a nested case-control study of BBD and breast cancer risk conducted in a community healthcare plan (Kaiser Permanente Northwest), we assessed relationships of histologic features in BBD biopsies and patient characteristics with subsequent breast cancer risk and tested for heterogeneity of associations by estrogen receptor (ER) status, tumor grade, and size. The study included 514 invasive breast cancer cases (median follow-up of 9 years post-BBD diagnosis) and 514 matched controls, diagnosed with proliferative or non-proliferative BBD between 1971 and 2006, with follow-up through mid-2015. Odds ratios (ORs) and 95% confidence intervals (CIs) were obtained using multivariable polytomous logistic regression models.

Results: Breast cancers were predominantly ER-positive (86%), well or moderately differentiated (73%), small (74% < 20 mm), and stage I/II (91%). Compared to patients with non-proliferative BBD, proliferative BBD with atypia conferred increased risk for ER-positive cancer (OR = 5.48, 95% CI = 2.14-14.01) with only one ER-negative case, P-heterogeneity = 0.45. The presence of columnar cell lesions (CCLs) at BBD diagnosis was associated with a 1.5-fold increase in the risk of both ER-positive and ER-negative tumors, with a 2-fold increase (95% CI = 1.21-3.58) observed among postmenopausal women (56%), independent of proliferative BBD status with and without atypia. We did not identify statistically significant differences in risk factor associations by tumor grade or size.

Conclusion: Most tumors that developed after a BBD diagnosis in this cohort were highly treatable low-stage ER-positive tumors. CCL in BBD biopsies may be associated with moderately increased risk, independent of BBD histology, and irrespective of ER status.
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http://dx.doi.org/10.1186/s13058-021-01410-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7977564PMC
March 2021

Assessing risk model calibration with missing covariates.

Biostatistics 2021 Feb 22. Epub 2021 Feb 22.

Biostatistics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, 9609 Medical Center Drive, Rockville, MD 20850, USA.

When validating a risk model in an independent cohort, some predictors may be missing for some subjects. Missingness can be unplanned or by design, as in case-cohort or nested case-control studies, in which some covariates are measured only in subsampled subjects. Weighting methods and imputation are used to handle missing data. We propose methods to increase the efficiency of weighting to assess calibration of a risk model (i.e. bias in model predictions), which is quantified by the ratio of the number of observed events, $\mathcal{O}$, to expected events, $\mathcal{E}$, computed from the model. We adjust known inverse probability weights by incorporating auxiliary information available for all cohort members. We use survey calibration that requires the weighted sum of the auxiliary statistics in the complete data subset to equal their sum in the full cohort. We show that a pseudo-risk estimate that approximates the actual risk value but uses only variables available for the entire cohort is an excellent auxiliary statistic to estimate $\mathcal{E}$. We derive analytic variance formulas for $\mathcal{O}/\mathcal{E}$ with adjusted weights. In simulations, weight adjustment with pseudo-risk was much more efficient than inverse probability weighting and yielded consistent estimates even when the pseudo-risk was a poor approximation. Multiple imputation was often efficient but yielded biased estimates when the imputation model was misspecified. Using these methods, we assessed calibration of an absolute risk model for second primary thyroid cancer in an independent cohort.
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http://dx.doi.org/10.1093/biostatistics/kxaa060DOI Listing
February 2021

Inflammatory profiles in Chilean Mapuche and non-Mapuche women with gallstones at risk of developing gallbladder cancer.

Sci Rep 2021 Feb 11;11(1):3686. Epub 2021 Feb 11.

Infections and Immunoepidemiology Branch, Division of Cancer Epidemiology and Genetics, National Institutes of Health, National Cancer Institute, Rockville, MD, USA.

Chile has high incidence rates of gallbladder cancer globally, particularly among Amerindian women, who also have a high prevalence of gallstones. We examined differences in inflammatory biomarkers between Mapuche and non-Mapuche women from the Chile Biliary Longitudinal Study, a cohort of women with ultrasound-detected gallstones. We randomly selected 200 Mapuche women frequency matched to non-Mapuche women on age and statin use Inflammatory biomarkers were analyzed using a multiplex assay and linear regression to assess associations of a priori markers (CCL20, CXCL10, IL-6, and IL-8) with ethnicity. Novel biomarkers were analyzed using exploratory factor analysis (EFA) and sufficient dimension reduction (SDR) to identify correlated marker groups, followed by linear regression to examine their association with ethnicity. The mean values of IL-8 were higher in Mapuche than non-Mapuche women (P = 0.04), while CCL20, CXCL10, and IL-6 did not differ significantly by ethnicity. EFA revealed two marker groups associated with ethnicity (P = 0.03 and P < 0.001). SDR analysis confirmed correlation between the biomarkers and ethnicity. We found higher IL-8 levels among Mapuche than non-Mapuche women. Novel inflammatory biomarkers were correlated with ethnicity and should be studied further for their role in gallbladder disease. These findings may elucidate underlying ethnic disparities in gallstones and carcinogenesis among Amerindians.
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http://dx.doi.org/10.1038/s41598-021-83300-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7878792PMC
February 2021

Least squares and maximum likelihood estimation of sufficient reductions in regressions with matrix-valued predictors.

Int J Data Sci Anal 2021 4;11(1):11-26. Epub 2020 Aug 4.

Faculty of Mathematics, Institute of Statistics and Mathematical Methods in Economics, TU Wien, Vienna, Austria.

We propose methods to estimate sufficient reductions in matrix-valued predictors for regression or classification. We assume that the first moment of the predictor matrix given the response can be decomposed into a and component via a Kronecker product structure. We obtain least squares and maximum likelihood estimates of the sufficient reductions in the matrix predictors, derive statistical properties of the resulting estimates and present fast computational algorithms with assured convergence. The performance of the proposed approaches in regression and classification is compared in simulations.We illustrate the methods on two examples, using longitudinally measured serum biomarker and neuroimaging data.
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http://dx.doi.org/10.1007/s41060-020-00228-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7840662PMC
August 2020

The Chile Biliary Longitudinal Study: A Gallstone Cohort.

Am J Epidemiol 2021 02;190(2):196-206

Gallbladder cancer (GBC) is a highly fatal cancer that can be cured through cholecystectomy if identified early. The presence of gallstones is the primary risk factor for GBC, but few people with gallstones develop GBC. A key question is what drives the development of GBC among persons with gallstones. We initiated the Chile Biliary Longitudinal Study (Chile BiLS) to address this question. From 2016 to 2019, Chile BiLS enrolled 4,726 women aged 50-74 years with ultrasound-detected gallstones from southern-central Chile, accounting for an estimated 36% of eligible women with gallstones in the study area. The median age was 59 years; 25% of the women were Amerindian (Mapuche), 60% were obese, 25% had diabetes, and 6% had cardiovascular disease. Participants will be followed for gallbladder dysplasia or cancer for 6 years. As of April 30, 2020, over 91% of those eligible completed the year 2 follow-up visit. Data being collected include epidemiologic and sociodemographic information, anthropometric measurements, blood pressure, and tooth counts. Biosamples being taken include baseline plasma, buffy coat, red blood cells, serum, blood clot from serum, and PAXgene whole blood (PreAnalytiX GmbH, Hombrechtikon, Switzerland). Complete gallbladder sampling is conducted for most participants undergoing cholecystectomy. The Chile BiLS cohort study will increase our understanding of GBC etiology and could identify potential risk stratification and early detection strategies in high-risk areas.
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http://dx.doi.org/10.1093/aje/kwaa199DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7850058PMC
February 2021

Circulating MicroRNAs in Relation to Esophageal Adenocarcinoma Diagnosis and Survival.

Dig Dis Sci 2021 Jan 6. Epub 2021 Jan 6.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, DHHS, Bethesda, MD, USA.

Background And Aims: Tissue miRNA can discriminate between esophageal adenocarcinoma (EA) and normal epithelium. However, no studies have examined a comprehensive panel of circulating miRNAs in relation to EA diagnosis and survival.

Methods: We used all 62 EA cases from the US Multi-Center case-control study with available serum matched 1:1 to controls. Cases were followed for vital status. MiRNAs (n = 2064) were assessed using the HTG EdgeSeq miRNA Whole Transcriptome Assay. Differential expression analysis of miRNAs in relation to case-control status was conducted. In cases, Cox regression models were fit to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for all-cause mortality. P values were adjusted using the Benjamini-Hochberg (BH) procedure for false discovery rate control. Predictive performance was assessed using cross-validation.

Results: Sixty-eight distinct miRNAs were significantly upregulated between cases and controls (e.g., miR-1255b-2-3p fold change = 1.74, BH-adjusted P = 0.01). Assessing the predictive performance of these significantly upregulated miRNAs yielded 60% sensitivity, 65% specificity, and 0.62 AUC. miR-4253 and miR-1238-5p were associated with risk of mortality after EA diagnosis (HR = 4.85, 95% CI: 2.30-10.23, BH-adjusted P = 0.04 and HR = 3.81, 95% CI: 2.02-7.19, BH-adjusted P = 0.04, respectively).

Conclusions: While they require replication, these findings suggest that circulating miRNAs may be associated with EA diagnosis and survival.
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http://dx.doi.org/10.1007/s10620-020-06740-2DOI Listing
January 2021

Mitochondrial DNA alterations underlie an irreversible shift to aerobic glycolysis in fumarate hydratase-deficient renal cancer.

Sci Signal 2021 01 5;14(664). Epub 2021 Jan 5.

Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.

Understanding the mechanisms of the Warburg shift to aerobic glycolysis is critical to defining the metabolic basis of cancer. Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is an aggressive cancer characterized by biallelic inactivation of the gene encoding the Krebs cycle enzyme fumarate hydratase, an early shift to aerobic glycolysis, and rapid metastasis. We observed impairment of the mitochondrial respiratory chain in tumors from patients with HLRCC. Biochemical and transcriptomic analyses revealed that respiratory chain dysfunction in the tumors was due to loss of expression of mitochondrial DNA (mtDNA)-encoded subunits of respiratory chain complexes, caused by a marked decrease in mtDNA content and increased mtDNA mutations. We demonstrated that accumulation of fumarate in HLRCC tumors inactivated the core factors responsible for replication and proofreading of mtDNA, leading to loss of respiratory chain components, thereby promoting the shift to aerobic glycolysis and disease progression in this prototypic model of glucose-dependent human cancer.
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http://dx.doi.org/10.1126/scisignal.abc4436DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8039187PMC
January 2021

Ambient Ultraviolet Radiation and Sebaceous Carcinoma Incidence in the United States, 2000-2016.

JNCI Cancer Spectr 2020 Apr 27;4(2):pkaa020. Epub 2020 Feb 27.

Radiation Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA.

Sebaceous carcinoma (SC) is an aggressive skin tumor. Although ultraviolet radiation (UVR) is an important risk factor for some skin cancer types, no population-level study has evaluated for an association between UVR and SC risk. Herein, we examined satellite-based ambient UVR in relation to SC incidence using Surveillance, Epidemiology, and End Results 18 cancer registry data (2000-2016). There were 3503 microscopically confirmed cases of SC diagnosed during the study period. For non-Hispanic whites, there was an association between increasing ambient UVR and SC risk (incidence rate ratio [per UVR quartile] = 1.15, 95% confidence interval = 1.11 to 1.19; two-sided <.001) including among individuals with and without putative Muir-Torre syndrome. In contrast, there was no association between ambient UVR and SC risk for other race and ethnicities. Our findings support a role for UVR in SC tumorigenesis, which suggests that photoprotection may reduce SC risk, particularly for high-risk populations (eg, Muir-Torre syndrome).
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http://dx.doi.org/10.1093/jncics/pkaa020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7190206PMC
April 2020

A Prospective Study of Circulating Chemokines and Angiogenesis Markers and Risk of Multiple Myeloma and Its Precursor.

JNCI Cancer Spectr 2020 Apr 16;4(2):pkz104. Epub 2019 Dec 16.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA.

Background: Experimental and clinical studies have implicated certain chemokines and angiogenic cytokines in multiple myeloma (MM) pathogenesis. To investigate whether systemic concentrations of these markers are associated with future MM risk and progression from its precursor, monoclonal gammopathy of undetermined significance (MGUS), we conducted a prospective study within the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial.

Methods: We measured concentrations of 45 immunologic and pro-angiogenic markers in sera from 241 MM case patients, 441 participants with nonprogressing MGUS, and 258 MGUS-free control participants using Luminex-based multiplex assays and enzyme-linked immunosorbent assays. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using multivariable logistic regression. We also evaluated absolute risk of progression using weighted Kaplan-Meier estimates. All statistical tests were two-sided.

Results: Prediagnostic levels of six markers were statistically significantly elevated among MM case patients compared with MGUS-free control participants using a false discovery rate of 10% (EGF, HGF, Ang-2, CXCL12, CCL8, and BMP-9). Of these, three angiogenesis markers were associated with future progression from MGUS to MM: EGF (fourth vs first quartile: OR = 3.01, 95% CI = 1.61 to 5.63, = .00028), HGF (OR = 2.59, 95% CI = 1.33 to 5.03, = .015), and Ang-2 (OR = 2.14, 95% CI = 1.15 to 3.98, = .07). A composite angiogenesis biomarker score substantially stratified risk of MGUS progression to MM beyond established risk factors for progression, particularly during the first 5 years of follow-up (areas under the curve of 0.71 and 0.64 with and without the angiogenesis marker score, respectively).

Conclusions: Our prospective findings provide new insights into mechanisms involved in MM development and suggest that systemic angiogenesis markers could potentially improve risk stratification models for MGUS patients.
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http://dx.doi.org/10.1093/jncics/pkz104DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7083234PMC
April 2020

Prospective assessment of a nasopharyngeal carcinoma risk score in a population undergoing screening.

Int J Cancer 2020 Dec 7. Epub 2020 Dec 7.

Department of Cancer Prevention, Sun Yat-sen University Cancer Center, Guangzhou, China.

Despite evidence suggesting the utility of Epstein-Barr virus (EBV) markers to stratify individuals with respect to nasopharyngeal carcinoma (NPC) risk in NPC high-risk regions, no validated NPC risk prediction model exists. We aimed to validate an EBV-based NPC risk score in an endemic population undergoing screening for NPC. This prospective study was embedded within an ongoing NPC screening trial in southern China initiated in 2008, with 51 235 adult participants. We assessed the score's discriminatory ability (area under the receiver-operator-characteristics curve, AUC). A new model incorporating the EBV score, sex and family history was developed using logistic regression and internally validated using cross-validation. AUCs were compared. We also calculated absolute NPC risk combining the risk score with population incidence and competing mortality data. A total of 151 NPC cases were detected in 2008 to 2016. The EBV-based score was highly discriminating, with AUC = 0.95 (95% CI = 0.93-0.97). For 90% specificity, the score had 87.4% sensitivity (95% CI = 81.0-92.3%). As specificity increased from 90% to 99%, the positive predictive value increased from 2.4% (95% CI = 1.9-3.0%) to 12.5% (9.9-15.5%). Correspondingly, the number of positive tests per detected NPC case decreased from 272 (95% CI = 255-290) to 50 (41-59). Combining the score with other risk factors (sex, first-degree family history of NPC) did not improve AUC. Men aged 55 to 59 years with the highest risk profile had the highest 5-year absolute NPC risk of 6.5%. We externally validated the discriminatory accuracy of a previously developed EBV score in a high-risk population. Adding nonviral risk factors did not improve NPC prediction.
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http://dx.doi.org/10.1002/ijc.33424DOI Listing
December 2020

Patterns of Human Leukocyte Antigen Class I and Class II Associations and Cancer.

Cancer Res 2021 02 3;81(4):1148-1152. Epub 2020 Dec 3.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland.

Human leukocyte antigen (HLA) gene variation is associated with risk of cancers, particularly those with infectious etiology or hematopoietic origin, given its role in immune presentation. Previous studies focused primarily on HLA allele/haplotype-specific associations. To answer whether associations are driven by HLA class I (essential for T-cell cytotoxicity) or class II (important for T-cell helper responses) genes, we analyzed GWAS from 24 case-control studies and consortia comprising 27 cancers (totaling >71,000 individuals). Associations for most cancers with infectious etiology or of hematopoietic origin were driven by multiple HLA regions, suggesting that both cytotoxic and helper T-cell responses are important. Notable exceptions were observed for nasopharyngeal carcinoma, an EBV-associated cancer, and CLL/SLL forms of non-Hodgkin lymphomas; these cancers were associated with HLA class I region only and HLA class II region only, implying the importance of cytotoxic T-cell responses for the former and CD4 T-cell helper responses for the latter. Our findings suggest that increased understanding of the pattern of HLA associations for individual cancers could lead to better insights into specific mechanisms involved in cancer pathogenesis. SIGNIFICANCE: GWAS of >71,000 individuals across 27 cancer types suggest that patterns of HLA Class I and Class II associations may provide etiologic insights for cancer.
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http://dx.doi.org/10.1158/0008-5472.CAN-20-2292DOI Listing
February 2021

Weight calibration to improve efficiency for estimating pure risks from the additive hazards model with the nested case-control design.

Biometrics 2020 Dec 3. Epub 2020 Dec 3.

Biostatistics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland.

We study the efficiency of covariate-specific estimates of pure risk (one minus the survival function) when some covariates are only available for case-control samples nested in a cohort. We focus on the semiparametric additive hazards model in which the hazard function equals a baseline hazard plus a linear combination of covariates with either time-varying or time-invariant coefficients. A published approach uses the design-based inclusion probabilities to reweight the nested case-control data. We obtain more efficient estimates of pure risks by calibrating the design weights to data available in the entire cohort, for both time-varying and time-invariant covariate coefficients. We develop explicit variance formulas for the weight-calibrated estimates based on influence functions. Simulations show the improvement in precision by using weight calibration and confirm the consistency of variance estimators and the validity of inference based on asymptotic normality. Examples are provided using data from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial Study (PLCO).
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http://dx.doi.org/10.1111/biom.13413DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8172655PMC
December 2020

Adenocarcinoma of the Uterine Cervix: Immunohistochemical Biomarker Expression and Diagnostic Performance.

Appl Immunohistochem Mol Morphol 2021 03;29(3):209-217

Department of Pathology, Lions Gate Hospital, Vancouver, BC, Canada.

Immunohistochemistry (IHC) improves the diagnosis of cervical adenocarcinoma but is not adequately studied. The performance of 16 antibodies previously reported as potentially discriminating between some histotypes was investigated in 184 tumors comprised of 12 histotype groups collapsed into 3 categories [47 adenocarcinomas in situ (AIS), 121 probable human papillomavirus-dependent adenocarcinomas (HPVD), and 16 of probable independence (HPVI)]. IHC sections from 5 tissue microarrays were scanned, and 3 pathologists independently reviewed images to assess staining percentages and intensities. Biomarker expression was based on published positive and negative cutoffs and agreement between any 2 pathologists. Differences between the 3 categories in the hierarchical ranking of biomarker positivity were analyzed by Random Forest classification, and between select groups by Unsupervised Hierarchical Clustering. Important category discriminants were combined in logistic regression models and the area under the curve (AUC) computed. Potential group discriminants were terminal cluster biomarkers with a 50% or more difference in positivity. Strong associations occurred between the lower expression of carcinoembryonic antigen and stromal actin in AIS compared with HPVD [AUC=0.70, 95% confidence interval (CI), 0.59-0.80] and in the higher expression of p16 and estrogen receptor in comparison to HPVI (AUC=0.86, 95% CI, 0.73-0.98), and between the higher expression of p16, carcinoembryonic antigen and estrogen receptor in HPVD compared with HPVI (AUC=0.88, 95% CI, 0.77-0.99). Between select groups, 9 biomarkers emerged as potential discriminants. Select IHC biomarkers can discriminate AIS from invasive adenocarcinomas, and invasive adenocarcinomas stratified by human papillomavirus dependency from each other. Independent replication in larger studies is needed, and to confirm discriminants of histotype groups.
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http://dx.doi.org/10.1097/PAI.0000000000000881DOI Listing
March 2021

Use of postmenopausal hormone therapies and risk of histology- and hormone receptor-defined breast cancer: results from a 15-year prospective analysis of NIH-AARP cohort.

Breast Cancer Res 2020 11 25;22(1):129. Epub 2020 Nov 25.

Metabolic Epidemiology Branch, Division of Cancer Epidemiology & Genetics, National Cancer Institute, National Institutes of Health, 9609 Medical Center Dr. rm 6E344, Bethesda, MD, 20892-9768, USA.

Background: Menopausal hormone therapy (MHT) increases breast cancer (BC) risk, but cohort studies largely consider use only at enrollment. Evidence is limited on how changes in MHT use alter the magnitude of risk, and whether risk varies between invasive and in situ cancer, by histology or by hormone receptor status.

Methods: We investigated the roles of estrogen-alone therapy (ET) and estrogen plus progestin therapy (EPT) on BC risk overall, by histology and estrogen receptor (ER) and progesterone receptor (PR) status, and on incidence of in situ disease, in the NIH-AARP cohort. Participants included 118,760 postmenopausal women (50-71 years), of whom 63.5% (n = 75,398) provided MHT use information at baseline in 1996 and in a follow-up survey in 2004, subsequent to the dissemination in 2002 of the Women's Health Initiative trial safety concerns regarding EPT. ET analyses included 50,476 women with hysterectomy (31,439 with follow-up data); EPT analyses included 68,284 women with intact uteri (43,959 with follow-up data). Adjusted hazard ratios (HRs) were estimated using Cox proportional hazards models using age as the time metric with follow-up through 2011.

Results: Eight thousand three hundred thirty-three incident BC cases were accrued, 2479 in women with follow-up data. BC risk was not elevated in current ET users at baseline (HR = 1.05, 95% confidence interval [CI] CI = 0.95-1.16) but was higher in women continuing use through 2004 (HR = 1.35, 95% CI = 1.04-1.75). Ever EPT use at baseline was associated with elevated BC risk overall (HR = 1.54 (1.44-1.64), with a doubling in risk for women with 10 or more years of use, for in situ disease, and across subtypes defined by histology and ER/PR status (all p < 0.004). Risk persisted in women who continued EPT through 2004 (HR = 1.80, 95% CI = 1.39-2.32). In contrast, no association was seen in women who discontinued EPT before 2004 (HR = 1.14, 95% CI = 0.99-1.30).

Conclusions: ET use was not associated with BC risk in this cohort, although excess risk was suggested in women who continued use through 2004. EPT use was linked to elevated in situ and invasive BC risk, and elevated risk across invasive BC histologic and hormone receptor-defined subtypes, with the highest risk for women who continued use through the 2004 follow-up survey.
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http://dx.doi.org/10.1186/s13058-020-01365-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7687781PMC
November 2020

Fatherhood status in relation to prostate cancer risks in two large U.S.-based prospective cohort studies.

Cancer Med 2021 01 21;10(1):405-415. Epub 2020 Nov 21.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, DHHS, Bethesda, MD, USA.

Background: Despite the high incidence and mortality of prostate cancer (PCa) in the Unites States, few risk factors have been consistently linked with these PCa outcomes. Assessing proxies of reproductive factors may offer insights into PCa pathogenesis. In this study, we examined fatherhood status as a proxy of fertility in relation to total, nonaggressive, aggressive, and fatal PCa.

Methods: We examined participants of two cohorts, the NIH-AARP Diet and Health (NIH-AARP) Study and Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. We used Cox proportional hazards regression to estimate hazard ratios (HRs) and 95% confidence intervals of associations between fatherhood status and number of children sired in relation to PCa incidence.

Results: Fatherhood status (one or more children vs. childless) was positively associated with total PCa risk in NIH-AARP or PLCO, but was not statistically significant (p = 0.06 and 0.55, respectively). Number of children sired indicated a slightly elevated risk of total PCa, but HRs were rarely significant and were of a fairly constant magnitude with no discernable trend relative to the childless referent group. Associations were similar for nonaggressive and aggressive PCa. The trend test for fatal PCa was statistically significant in NIH-AARP (p  < 0.01), despite none of the individual categorical point estimates reaching this threshold.

Conclusion: This study provides tentative evidence that fathering children is associated with a slightly increased PCa risk. Future research should strive to assess better proxies of reproductive function in relation to aggressive and fatal PCa to provide more specific evidence for this putative relationship.
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http://dx.doi.org/10.1002/cam4.3606DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7826462PMC
January 2021

Associations between daily aspirin use and cancer risk across strata of major cancer risk factors in two large U.S. cohorts.

Cancer Causes Control 2021 Jan 26;32(1):57-65. Epub 2020 Oct 26.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, 9609 Medical Center Drive, Rockville, MD, 20850, USA.

Purpose: Daily aspirin use has been shown to reduce risk of colorectal, and possibly other, cancers, but it is unknown if these benefits are consistent across subgroups of people with differing cancer risk factors. We investigated whether age, body mass index (BMI), smoking status, physical inactivity, and family history of cancer modify the effect of daily aspirin use on colorectal, ovarian, breast, endometrial and aggressive prostate cancer risk.

Methods: We pooled 423,495 individuals from two prospective, U.S.-based studies: the NIH-AARP Diet and Health Study (1995-2011) and the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (1993-2009). Using Cox proportional hazards regression, we examined associations between daily aspirin use (≥ 5 days/week) and risk of colorectal, ovarian, breast, endometrial, and aggressive prostate cancer, overall and across strata of risk factors.

Results: Daily aspirin use was associated with a 15% reduction in colorectal cancer risk (hazard ratio [HR]: 0.85, 95% confidence interval [CI] 0.80-0.89). Risk reductions were generally consistent across strata of risk factors but attenuated with increasing BMI (p-interaction = 0.16). For ovarian cancer, there was no significant association overall (HR: 0.93, 95% CI 0.80-1.08) but reduced risk among obese women (HR: 0.73, 95% CI 0.52-0.98, p-interaction = 0.12). Weak or null associations were observed for breast, endometrial, and aggressive prostate cancer, with no strong effect modification observed.

Conclusions: Daily aspirin use appears to reduce colorectal cancer risk regardless of other risk factors, though the potential modifying effect of BMI warrants further investigation and may need to be considered in risk-benefit calculations for aspirin use.
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http://dx.doi.org/10.1007/s10552-020-01357-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7855934PMC
January 2021

Cirrhotic controls in a pooled analysis of hepatitis D and hepatocellular carcinoma.

J Hepatol 2020 12 19;73(6):1583-1584. Epub 2020 Sep 19.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland, USA. Electronic address:

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http://dx.doi.org/10.1016/j.jhep.2020.07.012DOI Listing
December 2020

Projected Cancer Risks to Residents of New Mexico from Exposure to Trinity Radioactive Fallout.

Health Phys 2020 10;119(4):478-493

Division of Cancer Epidemiology & Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD.

The Trinity nuclear test, conducted in 1945, exposed residents of New Mexico to varying degrees of radioactive fallout. Companion papers in this issue have detailed the results of a dose reconstruction that has estimated tissue-specific radiation absorbed doses to residents of New Mexico from internal and external exposure to radioactive fallout in the first year following the Trinity test when more than 90% of the lifetime dose was received. Estimated radiation doses depended on geographic location, race/ethnicity, and age at the time of the test. Here, these doses were applied to sex- and organ-specific risk coefficients (without applying a dose and dose rate effectiveness factor to extrapolate from a population with high-dose/high-dose rates to those with low-dose/low-dose rates) and combined with baseline cancer rates and published life tables to estimate and project the range of radiation-related excess cancers among 581,489 potentially exposed residents of New Mexico. The total lifetime baseline number of all solid cancers [excluding thyroid and non-melanoma skin cancer (NMSC)] was estimated to be 183,000 from 1945 to 2034. Estimates of ranges of numbers of radiation-related excess cancers and corresponding attributable fractions from 1945 to 2034 incorporate various sources of uncertainty. We estimated 90% uncertainty intervals (UIs) of excess cancer cases to be 210 to 460 for all solid cancers (except thyroid cancer and NMSC), 80 to 530 for thyroid cancer, and up to 10 for leukemia (except chronic lymphocytic leukemia), with corresponding attributable fractions ranging from 0.12% to 0.25%, 3.6% to 20%, and 0.02% to 0.31%, respectively. In the counties of Guadalupe, Lincoln, San Miguel, Socorro, and Torrance, which received the greatest fallout deposition, the 90% UI for the projected fraction of thyroid cancers attributable to radioactive fallout from the Trinity test was estimated to be from 17% to 58%. Attributable fractions for cancer types varied by race/ethnicity, but 90% UIs overlapped for all race/ethnicity groups for each cancer grouping. Thus, most cancers that have occurred or will occur among persons exposed to Trinity fallout are likely to be cancers unrelated to exposures from the Trinity nuclear test. While these ranges are based on the most detailed dose reconstruction to date and rely largely on methods previously established through scientific committee agreement, challenges inherent in the dose estimation, and assumptions relied upon both in the risk projection and incorporation of uncertainty are important limitations in quantifying the range of radiation-related excess cancer risk.
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http://dx.doi.org/10.1097/HP.0000000000001333DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7497483PMC
October 2020

Risk factors for inflammatory and non-inflammatory breast cancer in North Africa.

Breast Cancer Res Treat 2020 Nov 2;184(2):543-558. Epub 2020 Sep 2.

Medical School of the City University of New York, New York, USA.

Purpose: Studies of the etiology of inflammatory breast cancer (IBC), a rare but aggressive breast cancer, have been hampered by limited risk factor information. We extend previous studies by evaluating a broader range of risk factors.

Methods: Between 2009 and 2015, we conducted a case-control study of IBC at six centers in Egypt, Tunisia, and Morocco; enrolled were 267 IBC cases and for comparison 274 non-IBC cases and 275 controls, both matched on age and geographic area to the IBC cases. We administered questionnaires and collected anthropometric measurements for all study subjects. We used multiple imputation methods to account for missing values and calculated odds ratios (ORs) and 95% confidence intervals (CIs) using polytomous logistic regression comparing each of the two case groups to the controls, with statistical tests for the difference between the coefficients for the two case groups.

Results: After multivariable adjustment, a livebirth within the previous 2 years (OR 4.6; 95% CI 1.8 to 11.7) and diabetes (OR 1.8; 95% CI 1.1 to 3.0) were associated with increased risk of IBC, but not non-IBC (OR 0.9; 95% CI 0.3 to 2.5 and OR 0.9; 95% CI 0.5 to 1.6 for livebirth and diabetes, respectively). A family history of breast cancer, inflammatory-like breast problems, breast trauma, and low socioeconomic status were associated with increased risk of both tumor types.

Conclusions: We identified novel risk factors for IBC and non-IBC, some of which preferentially increased risk of IBC compared to non-IBC. Upon confirmation, these findings could help illuminate the etiology and aid in prevention of this aggressive cancer.
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http://dx.doi.org/10.1007/s10549-020-05864-3DOI Listing
November 2020

Deaths Attributable to Cancer in the US Human Immunodeficiency Virus Population During 2001-2015.

Clin Infect Dis 2021 05;72(9):e224-e231

Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland, USA.

Background: Antiretroviral therapy (ART) has reduced mortality among people living with human immunodeficiency virus (HIV), but cancer remains an important cause of death. We characterized cancer-attributable mortality in the HIV population during 2001-2015.

Methods: We used data from population-based HIV and cancer registries in the United States (US). Cox proportional hazards regression models were used to estimate adjusted hazard ratios (HRs) associating cancer diagnoses with overall mortality, we could perhaps cut these words to accommodate the word limit. However readers will probably want to know what statistical adjustments were made to the model. Population-attributable fractions (PAFs) were calculated using these HRs and the proportion of deaths preceded by cancer. Cancer-specific PAFs and cancer-attributable mortality rates were calculated for demographic subgroups, AIDS-defining cancers (Kaposi sarcoma [KS], non-Hodgkin lymphoma [NHL], cervical cancer), and non-AIDS-defining cancers.

Results: Cancer-attributable mortality was 386.9 per 100 000 person-years, with 9.2% and 5.0% of deaths attributed to non-AIDS-defining and AIDS-defining cancers, respectively. Leading cancer-attributable deaths were from NHL (3.5%), lung cancer (2.4%), KS (1.3%), liver cancer (1.1%), and anal cancer (0.6%). Overall, cancer-attributable mortality declined from 484.0 per 100 000 person-years during 2001-2005 to 313.6 per 100 000 person-years during 2011-2015, while the PAF increased from 12.6% to 17.1%; the PAF for non-AIDS-defining cancers increased from 7.2% to 11.8% during 2011-2015. Cancer-attributable mortality was highest among those aged ≥60 years (952.2 per 100 000 person-years), with 19.0% of deaths attributed to non-AIDS-defining cancers.

Conclusions: Although cancer-attributable mortality has declined over time, it remains high and represents a growing fraction of deaths in the US HIV population. Mortality from non-AIDS-defining cancers may rise as the HIV population ages. ART access, early cancer detection, and improved cancer treatment are priorities for reducing cancer-attributable mortality.
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http://dx.doi.org/10.1093/cid/ciaa1016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8096269PMC
May 2021

Obesity and related conditions and risk of inflammatory breast cancer: a nested case-control study.

Breast Cancer Res Treat 2020 Sep 20;183(2):467-478. Epub 2020 Jul 20.

Division of Research, Kaiser Permanente Northern California, Oakland, CA, USA.

Purpose: Inflammatory breast cancer (IBC) is a rare, poorly understood and aggressive tumor. We extended prior findings linking high body mass index (BMI) to substantial increased IBC risk by examining BMI associations before and after adjustment for well-characterized comorbidities using medical record data for diabetes, insulin resistance, and disturbances of cholesterol metabolism in a general community healthcare setting.

Methods: We identified 247 incident IBC cases diagnosed at Kaiser Permanente Northern California between 2005 and 2017 and 2470 controls matched 10:1 on birth year and geographic area and with ≥ 13 months of continuous enrollment prior to diagnosis/index date. We assessed exposures from 6 years up to one year prior to the diagnosis/index date, using logistic regression to calculate odds ratios (ORs) with 95% confidence intervals (CIs).

Results: Before adjustment for comorbidities, ORs (95% CIs) for BMI of 25-< 30, 30-< 35, and ≥ 35 compared to < 25 kg/m were 1.5 (0.9-2.3), 2.0 (1.2-3.1), and 2.5 (1.4-4.4), respectively. After adjustment for pre-diabetes/diabetes, HDL-C and triglyceride levels, and dyslipidemia, corresponding ORs were 1.3 (0.8-2.1), 1.6 (0.9-2.9), and 1.9 (1.0-3.5). The OR for HDL-C levels < 50 mg/dL compared to ≥ 65 mg/dL was 2.0 (1.2-3.3) in the adjusted model. In a separate model the OR for a triglyceride/HDL-C ratio ≥ 2.50 compared to < 1.62 was 1.7 (1.1-2.8) after adjustment for BMI, pre-diabetes/diabetes, and dyslipidemia. Results did not differ significantly by estrogen receptor status.

Conclusions: Obesity and measures of insulin resistance independently increased IBC risk as did obesity and low HDL-C levels. These findings, if confirmed, have implications for IBC prevention.
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http://dx.doi.org/10.1007/s10549-020-05785-1DOI Listing
September 2020

Genetic Determinants of Cirrhosis and Hepatocellular Carcinoma Due to Fatty Liver Disease: What's the Score?

Hepatology 2020 09;72(3):794-796

Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD.

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http://dx.doi.org/10.1002/hep.31413DOI Listing
September 2020