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Bibliography on: Publications by FHCRC Researchers

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ESP: PubMed Auto Bibliography 19 Mar 2019 at 01:39 Created: 

Publications by FHCRC Researchers

The Fred Hutchinson Cancer Research Center began in 1975, with critical help from Washington State's U.S. Senator Warren Magnuson. Fred Hutch quickly became the permanent home to Dr. E. Donnall Thomas, who had spent decades developing an innovative treatment for leukemia and other blood cancers. Thomas and his colleagues were working to cure cancer by transplanting human bone marrow after otherwise lethal doses of chemotherapy and radiation. At the Hutch, Thomas improved this treatment and readied it for widespread use. Since then, the pioneering procedure has saved hundreds of thousands of lives worldwide. While improving bone marrow transplantation remains central to Fred Hutch's research, it is now only part of its efforts. The Hutch is home to five scientific divisions, three Nobel laureates and more than 2,700 faculty, who collectively have published more than 10,000 scientific papers, presented here as a full bibliography.

NOTE: From 1995 to 2009 I served as the Hutch's vice president for information technology — hence my interest in the organization. Although my role was in the admin division, if you dig through this bibliography, you will find a couple of papers with me as an author.

Created with PubMed® Query: "Fred Hutchinson Cancer Research"[AFFL] or FHCRC[AFFL] or "Fred Hutch"[AFFL] NOT pmcbook NOT ispreviousversion

Citations The Papers (from PubMed®)

RevDate: 2019-03-18

Singhvi A, S Shaham (2019)

Glia-Neuron Interactions in Caenorhabditis elegans.

Annual review of neuroscience [Epub ahead of print].

Glia are abundant components of animal nervous systems. Recognized 170 years ago, concerted attempts to understand these cells began only recently. From these investigations glia, once considered passive filler material in the brain, have emerged as active players in neuron development and activity. Glia are essential for nervous system function, and their disruption leads to disease. The nematode Caenorhabditis elegans possesses glial types similar to vertebrate glia, based on molecular, morphological, and functional criteria, and has become a powerful model in which to study glia and their neuronal interactions. Facile genetic and transgenic methods in this animal allow the discovery of genes required for glial functions, and effects of glia at single synapses can be monitored by tracking neuron shape, physiology, or animal behavior. Here, we review recent progress in understanding glia-neuron interactions in C. elegans. We highlight similarities with glia in other animals, and suggest conserved emerging principles of glial function. Expected final online publication date for the Annual Review of Neuroscience Volume 42 is July 8, 2019. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

RevDate: 2019-03-18

Yuan T, Fitzpatrick T, Ko NY, et al (2019)

Circumcision to prevent HIV and other sexually transmitted infections in men who have sex with men: a systematic review and meta-analysis of global data.

The Lancet. Global health, 7(4):e436-e447.

BACKGROUND: Men who have sex with men (MSM) are disproportionately affected by HIV and other sexually transmitted infections (STIs) worldwide. Previous reviews investigating the role of circumcision in preventing HIV and other STIs among MSM were inconclusive. Many new studies have emerged in the past decade. To inform global prevention strategies for HIV and other STIs among MSM, we reviewed all available evidence on the associations between circumcision and HIV and other STIs among MSM.

METHODS: In this systematic review and meta-analysis, we searched PubMed, Web of Science, BioMed Central, Scopus, ResearchGate, Cochrane Library, Embase, PsycINFO, Google Scholar, and websites of international HIV and STI conferences for studies published before March 8, 2018. Interventional or observational studies containing original quantitative data describing associations between circumcision and incident or prevalent infection of HIV and other STIs among MSM were included. Studies were excluded if MSM could not be distinguished from men who have sex with women only. We calculated pooled odds ratios (ORs) and their 95% CIs using random-effect models. We assessed risk of bias using the Newcastle-Ottawa scale.

FINDINGS: We identified 62 observational studies including 119 248 MSM. Circumcision was associated with 23% reduced odds of HIV infection among MSM overall (OR 0·77, 95% CI 0·67-0·89; number of estimates [k]=45; heterogeneity I2=77%). Circumcision was protective against HIV infection among MSM in countries of low and middle income (0·58, 0·41-0·83; k=23; I2=77%) but not among MSM in high-income countries (0·99, 0·90-1·09; k=20; I2=40%). Circumcision was associated with reduced odds of herpes simplex virus (HSV) infection among MSM overall (0·84, 0·75-0·95; k=5; I2=0%) and penile human papillomavirus (HPV) infection among HIV-infected MSM (0·71, 0·51-0·99; k=3; I2=0%).

INTERPRETATION: We found evidence that circumcision is likely to protect MSM from HIV infection, particularly in countries of low and middle income. Circumcision might also protect MSM from HSV and penile HPV infection. MSM should be included in campaigns promoting circumcision among men in countries of low and middle income. In view of the substantial proportion of MSM in countries of low and middle income who also have sex with women, well designed longitudinal studies differentiating MSM only and bisexual men are needed to clarify the effect of circumcision on male-to-male transmission of HIV and other STIs.

FUNDING: National Natural Science Foundation of China, National Science and Technology Major Project of China, Australian National Health and Medical Research Council Early Career Fellowship, Sanming Project of Medicine in Shenzhen, National Institutes of Health, Mega Projects of National Science Research for the 13th Five-Year Plan, Doris Duke Charitable Foundation.

RevDate: 2019-03-16

Kaluza J, Harris HR, Linden A, et al (2019)

Alcohol Consumption and Risk of Chronic Obstructive Pulmonary Disease: A Prospective Cohort Study of Men.

American journal of epidemiology pii:5381971 [Epub ahead of print].

Studies indicate an inverse association between moderate alcohol consumption and chronic inflammatory diseases; however, the association between alcohol consumption and chronic obstructive pulmonary disease (COPD) incidence has not been widely studied. We investigated the associations of total alcohol consumption and intake of specific alcoholic beverages with risk of COPD in a population-based prospective cohort study, the Cohort of Swedish Men (n = 44,254). Alcohol consumption was assessed with a self-administered questionnaire in 1997. During follow-up (1998-2014), 2,177 COPD cases were ascertained. Moderate alcohol consumption was associated with the lowest risk of COPD. A J-shaped association was observed for ethanol consumption (P for nonlinearity = 0.003) and beer consumption (P for nonlinearity < 0.001); for wine consumption, a U-shaped association was observed (P for nonlinearity < 0.001). Defining a "standard drink" as 12 g of ethanol, the multivariable-adjusted hazard ratios were 0.77 (95% confidence interval (CI): 0.66, 0.90) and 0.92 (95% CI: 0.81, 1.05) for beer consumption of 4.1-6.0 and >6.0 standard drinks/week (SDW) versus <1.0 SDW, respectively; 0.80 (95% CI: 0.69, 0.93) and 1.00 (95% CI: 0.83, 1.21) for wine consumption of 2.0-4.0 and >4.0 SDW versus <1.0 SDW, respectively; and 1.10 (95% CI: 0.98, 1.24) and 1.20 (95% CI: 0.99, 1.44) for liquor consumption of 2.0-4.0 and >4.0 SDW versus <1.0 SDW, respectively. In conclusion, our findings suggest that moderate beer and wine consumption, but not liquor consumption, may decrease risk of COPD. Additional studies are needed to confirm these associations.

RevDate: 2019-03-16

Bauermeister JA, Golinkoff JM, Carballo-Diéguez A, et al (2019)

A Mixed-Methods Study Examining Adherence to and Acceptability of Intravaginal Rings for HIV Prevention: Behavioral Results of MTN-027.

AIDS and behavior pii:10.1007/s10461-019-02457-0 [Epub ahead of print].

Intravaginal rings (IVR) containing antiretroviral drugs are a promising method for HIV prevention. We triangulated quantitative and qualitative assessments to evaluate the acceptability of four IVRs used continuously for 28 days as part of a Phase I trial (N = 48 HIV-negative women; ages 18-45). Adherence was high throughout the trial, yet 30% of participants reported involuntary IVR expulsions followed by re-insertion. Most participants (93.6%) felt comfortable with the IVR being inside their body. Participants reported liking the IVR more (36.2%) or the same amount (55.3%) since starting the study. When given the option of choosing between the IVR and/or a male condom for HIV-prevention, most reported preferring the IVR (n = 29, 63.0%), and over a quarter of the sample reported liking them equally (n = 12, 26.1%). We observed no differences in IVR acceptability across the study arms. High adherence and acceptability underscores the promise of an IVR as a female-controlled, sustained mechanism for HIV prevention.

RevDate: 2019-03-15

Roy R, Chatterjee A, Das D, et al (2019)

Genome-wide miRNA methylome analysis in oral cancer: possible biomarkers associated with patient survival.

Epigenomics [Epub ahead of print].

AIM: The methylome associated with miRNA loci was investigated in oral cancer to explore tobacco specific methylation and potential biomarkers for patient survival.

METHODS: Methylome data was generated from 16 pairs of cancer-normal tissues by reduced representation bisulfite sequencing method. Differentially methylated regions were identified using the DMAP pipeline. In silico validation and Kaplan-Meier survival analyses were performed on The Cancer Genome Atlas data based on our miRNA methylome data.

RESULTS: A total of 4310 unique differentially methylated regions, mapping to 144 miRNA loci, were identified. Three distinct groups of miRNAs were differentially methylated in cancer tissues from smokers, chewers and mixed habitués. Hypermethylation of miR-503, miR-200a/b, miR-320b and miR-489 was associated with worse 5-year survival.

CONCLUSION: Differential methylation patterns in miRNA loci are associated with poor survival underscoring their potential as predictive and prognostic biomarkers in oral cancer.

RevDate: 2019-03-15

LaCroix AZ, Bellettiere J, Rillamas-Sun E, et al (2019)

Association of Light Physical Activity Measured by Accelerometry and Incidence of Coronary Heart Disease and Cardiovascular Disease in Older Women.

JAMA network open, 2(3):e190419 pii:2727997.

Importance: To our knowledge, no studies have examined light physical activity (PA) measured by accelerometry and heart disease in older women.

Objective: To investigate whether higher levels of light PA were associated with reduced risks of coronary heart disease (CHD) or cardiovascular disease (CVD) in older women.

Prospective cohort study of older women from baseline (March 2012 to April 2014) through February 28, 2017, for up to 4.91 years. The setting was community-dwelling participants from the Women's Health Initiative. Participants were ambulatory women with no history of myocardial infarction or stroke.

Exposures: Data from accelerometers worn for a requested 7 days were used to measure light PA.

Main Outcomes and Measures: Cox proportional hazards regression models estimated hazard ratios (HRs) and 95% CIs for physician-adjudicated CHD and CVD events across light PA quartiles adjusting for possible confounders. Light PA was also analyzed as a continuous variable with and without adjustment for moderate to vigorous PA (MVPA).

Results: Among 5861 women (mean [SD] age, 78.5 [6.7] years), 143 CHD events and 570 CVD events were observed. The HRs for CHD in the highest vs lowest quartiles of light PA were 0.42 (95% CI, 0.25-0.70; P for trend <.001) adjusted for age and race/ethnicity and 0.58 (95% CI, 0.34-0.99; P for trend = .004) after additional adjustment for education, current smoking, alcohol consumption, physical functioning, comorbidity, and self-rated health. Corresponding HRs for CVD in the highest vs lowest quartiles of light PA were 0.63 (95% CI, 0.49-0.81; P for trend <.001) and 0.78 (95% CI, 0.60-1.00; P for trend = .004). The HRs for a 1-hour/day increment in light PA after additional adjustment for MVPA were 0.86 (95% CI, 0.73-1.00; P for trend = .05) for CHD and 0.92 (95% CI, 0.85-0.99; P for trend = .03) for CVD.

Conclusions and Relevance: The present findings support the conclusion that all movement counts for the prevention of CHD and CVD in older women. Large, pragmatic randomized trials are needed to test whether increasing light PA among older women reduces cardiovascular risk.

RevDate: 2019-03-15

Watts EL, Perez-Cornago A, Appleby PN, et al (2019)

The associations of anthropometric, behavioural and sociodemographic factors with circulating concentrations of IGF-I, IGF-II, IGFBP-1, IGFBP-2, and IGFBP-3 in a pooled analysis of 16,024 men from 22 studies.

International journal of cancer [Epub ahead of print].

Insulin-like growth factors (IGFs) and insulin-like growth factor binding proteins (IGFBPs) have been implicated in the aetiology of several cancers. To better understand whether anthropometric, behavioural, and sociodemographic factors may play a role in cancer risk via IGF signalling, we examined the cross-sectional associations of these exposures with circulating concentrations of IGFs (IGF-I, IGF-II) and IGFBPs (IGFBP-1, IGFBP-2, IGFBP-3). The Endogenous Hormones, Nutritional Biomarkers and Prostate Cancer Collaborative Group dataset includes individual participant data from 16,024 male controls (i.e. without prostate cancer) aged 22-89 years from 22 prospective studies. Geometric means of protein concentrations were estimated using analysis of variance, adjusted for relevant covariates. Older age was associated with higher concentrations of IGFBP-1 and IGFBP-2 and lower concentrations of IGF-I, IGF-II, and IGFBP-3. Higher body mass index was associated with lower concentrations of IGFBP-1 and IGFBP-2. Taller height was associated with higher concentrations of IGF-I and IGFBP-3 and lower concentrations of IGFBP-1. Smokers had higher concentrations of IGFBP-1 and IGFBP-2 and lower concentrations of IGFBP-3 than non-smokers. Higher alcohol consumption was associated with higher concentrations of IGF-II and lower concentrations of IGF-I and IGFBP-2. African Americans had lower concentrations of IGF-II, IGFBP-1, IGFBP-2 and IGFBP-3 and Hispanics had lower IGF-I, IGF-II and IGFBP-3 than non-Hispanic whites. These findings indicate that a range of anthropometric, behavioural, and sociodemographic factors are associated with circulating concentrations of IGFs and IGFBPs in men, which will lead to a greater understanding of the mechanisms through which these factors influence cancer risk. This article is protected by copyright. All rights reserved.

RevDate: 2019-03-15

Freitas-Andrade M, Wang N, Bechberger JF, et al (2019)

Targeting MAPK phosphorylation of Connexin43 provides neuroprotection in stroke.

The Journal of experimental medicine pii:jem.20171452 [Epub ahead of print].

Connexin43 (Cx43) function is influenced by kinases that phosphorylate specific serine sites located near its C-terminus. Stroke is a powerful inducer of kinase activity, but its effect on Cx43 is unknown. We investigated the impact of wild-type (WT) and knock-in Cx43 with serine to alanine mutations at the protein kinase C (PKC) site Cx43S368A, the casein kinase 1 (CK1) sites Cx43S325A/328Y/330A, and the mitogen-activated protein kinase (MAPK) sites Cx43S255/262/279/282A (MK4) on a permanent middle cerebral artery occlusion (pMCAO) stroke model. We demonstrate that MK4 transgenic animals exhibit a significant decrease in infarct volume that was associated with improvement in behavioral performance. An increase in astrocyte reactivity with a concomitant decrease in microglial reactivity was observed in MK4 mice. In contrast to WT, MK4 astrocytes displayed reduced Cx43 hemichannel activity. Pharmacological blockade of Cx43 hemichannels with TAT-Gap19 also significantly decreased infarct volume in WT animals. This study provides novel molecular insights and charts new avenues for therapeutic intervention associated with Cx43 function.

RevDate: 2019-03-15

McCune JS, Wang T, Bo-Subait K, et al (2019)

Association of antiepileptic medications with outcomes after allogeneic hematopoietic cell transplantation with busulfan/cyclophosphamide conditioning.

Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation pii:S1083-8791(19)30150-8 [Epub ahead of print].

High-dose busulfan (BU) followed by high-dose cyclophosphamide (CY) (BU/CY) before allogeneic hematopoietic cell transplantation (HCT) has long been used as treatment for hematologic malignancies. Administration of phenytoin or newer alternative anti-epileptic medications (AEMs) prevents seizures caused by BU. Phenytoin induces enzymes that increase exposure to active CY metabolites in vivo, whereas alternative AEMs do not have this effect. Lower exposure to active CY metabolites with the use of alternative AEMs could decrease the risk of toxicity but might increase the risk of recurrent malignancy after HCT. Previous studies have not determined whether outcomes with alternative AEMs differ from those with phenytoin in patients treated with BU/CY before allogeneic HCT. We studied a cohort of 2155 patients, 1460 treated with phenytoin and 695 treated with alternative AEMs, who received BU/CY before allogeneic HCT from 2004 through 2014. We found no differences suggesting decreased overall or relapse-free survival or increased risks of relapse, non-relapse mortality, acute or chronic GVHD, or regimen-related toxicity associated with the use of alternative AEMs as compared to phenytoin. The risk of dialysis was lower in the alternative AEM group than in the phenytoin group. Alternative AEMs are safe for prevention of seizures after BU administration and can avoid the undesirable toxicities and drug interactions caused by phenytoin.

RevDate: 2019-03-15

Minot SS (2019)

De novo Assembly Vastly Expands the Known Microbial Universe.

Trends in microbiology pii:S0966-842X(19)30058-7 [Epub ahead of print].

The study of the human microbiome relies heavily on the genomes of bacterial isolates that can be grown in culture. A recent study (Pasolli et al. Cell 2019;176:649-662) of stool microbiome samples generated over 150 000 microbial genomes without any culture, vastly expanding our knowledge of the biases in existing reference databases.

RevDate: 2019-03-13

Jariani A, Warth C, Deforche K, et al (2019)

SANTA-SIM: simulating viral sequence evolution dynamics under selection and recombination.

Virus evolution, 5(1):vez003 pii:vez003.

Simulations are widely used to provide expectations and predictive distributions under known conditions against which to compare empirical data. Such simulations are also invaluable for testing and comparing the behaviour and power of inference methods. We describe SANTA-SIM, a software package to simulate the evolution of a population of gene sequences forwards through time. It models the underlying biological processes as discrete components: replication, recombination, point mutations, insertion-deletions, and selection under various fitness models and population size dynamics. The software is designed to be intuitive to work with for a wide range of users and executable in a cross-platform manner.

RevDate: 2019-03-14

Rytlewski J, Deng S, Xie T, et al (2019)

Model to improve specificity for identification of clinically-relevant expanded T cells in peripheral blood.

PloS one, 14(3):e0213684 pii:PONE-D-19-01472.

Current methods to quantify T-cell clonal expansion only account for variance due to random sampling from a highly diverse repertoire space. We propose a beta-binomial model to incorporate time-dependent variance into the assessment of differentially abundant T-cell clones, identified by unique T Cell Receptor (TCR) β-chain rearrangements, and show that this model improves specificity for detecting clinically relevant clonal expansion. Using blood samples from ten healthy donors, we modeled the variance of T-cell clones within each subject over time and calibrated the dispersion parameters of the beta distribution to fit this variance. As a validation, we compared pre- versus post-treatment blood samples from urothelial cancer patients treated with atezolizumab, where clonal expansion (quantified by the earlier binomial model) was previously reported to correlate with benefit. The beta-binomial model significantly reduced the false-positive rate for detecting differentially abundant clones over time compared to the earlier binomial method. In the urothelial cancer cohort, the beta-binomial model enriched for tumor infiltrating lymphocytes among the clones detected as expanding in the peripheral blood in response to therapy compared to the binomial model and improved the overall correlation with clinical benefit. Incorporating time-dependent variance into the statistical framework for measuring differentially abundant T-cell clones improves the model's specificity for T-cells that correlate more strongly with the disease and treatment setting of-interest. Reducing background-level clonal expansion, therefore, improves the quality of clonal expansion as a biomarker for assessing the T cell immune response and correlations with clinical measures.

RevDate: 2019-03-14

Amico KR, Ramirez C, Caplan MR, et al (2019)

Perspectives of US women participating in a candidate PrEP study: adherence, acceptability and future use intentions.

Journal of the International AIDS Society, 22(3):e25247.

INTRODUCTION: Limited data exist on acceptability of candidate pre-exposure prophylaxis (PrEP) regimens among US women. We evaluated PrEP experiences, attitudes and future use intentions among sexually active women who completed the US-based HIV Prevention Trials Network 069/AIDS Clinical Trials Group 5305 study.

METHODS: Women participated in the study between March 2013 and November 2015. We analysed computer-assisted self-interview (CASI) surveys among 130 women and conducted in-depth interviews among a subset of 26 women from three sites. Interviews were conducted in mid/late-2015.

RESULTS: Most women (57%) reported very good/excellent PrEP adherence on CASI, although 21% acknowledged over-reporting adherence at least some of the time. Commitment to preventing HIV infection, a sense of ownership of the study, and keeping pills stored in a visible location facilitated adherence. Adherence barriers included "simply forgetting" and being away from home. Most women interviewed did not intend to use PrEP in the future because of lack of perceived need due to their own (as opposed to their partners') low-risk behaviour and concerns about affordability - but not because of side effects or other characteristics of the regimens.

DISCUSSION: Improving HIV prevention options for US women will require access to affordable PrEP as well as expanding women's understanding of relationship- and community-level factors that increase their risk of acquiring HIV.

RevDate: 2019-03-14

Mitchell KM, Hoots B, Dimitrov D, et al (2019)

Improvements in the HIV care continuum needed to meaningfully reduce HIV incidence among men who have sex with men in Baltimore, US: a modelling study for HPTN 078.

Journal of the International AIDS Society, 22(3):e25246.

INTRODUCTION: HIV prevalence is high among men who have sex with men (MSM) in Baltimore, Maryland, United States, and the levels of viral suppression among HIV-positive MSM are relatively low. The HIV Prevention Trials Network 078 trial seeks to increase the levels of viral suppression among US MSM by increasing the rates of diagnosis and linkage to care and treatment. We estimated the increases in viral suppression needed to reach different HIV incidence reduction targets, and the impact of meeting diagnosis and treatment targets.

METHODS: We used a mathematical model of HIV transmission among MSM from Baltimore, US, parameterised with behavioural data and fitted to HIV prevalence and care continuum data for Baltimore wherever possible, to project increases in viral suppression needed to reduce the HIV incidence rate among Baltimore MSM by 10, 20, 30 or 50% after 2, 5 and 10 years. We also projected HIV incidence reductions achieved if US national targets - 90% of people living with HIV (PLHIV) know their HIV serostatus, 90% of those diagnosed are retained in HIV medical care and 80% of those diagnosed are virally suppressed - or UNAIDS 90-90-90 targets (90% of PLHIV know their status, 90% of those diagnosed receive antiretroviral therapy (ART), 90% of those receiving ART are virally suppressed) are each met by 2020.

RESULTS: To reduce the HIV incidence rate by 20% and 50% after five years (compared with the base-case at the same time point), the proportion of all HIV-positive MSM who are virally suppressed must increase above 2015 levels by a median 13 percentage points (95% uncertainty interval 9 to 16 percentage points) from median 49% to 60%, and 27 percentage points (22 to 35) from 49% to 75% respectively. Meeting all three US or 90-90-90 UNAIDS targets results in a 48% (31% to 63%) and 51% (38% to 65%) HIV incidence rate reduction in 2020 respectively.

CONCLUSIONS: Substantial improvements in levels of viral suppression will be needed to achieve significant incidence reductions among MSM in Baltimore, and to meet 2020 US and UNAIDS targets. Future modelling studies should additionally consider the impact of pre-exposure prophylaxis for MSM.

RevDate: 2019-03-14

Galipeau PC, Oman KM, Paulson TG, et al (2019)

Correction to: NSAID use and somatic exomic mutations in Barrett's esophagus.

Genome medicine, 11(1):14 pii:10.1186/s13073-019-0625-y.

It was highlighted that in the original article [1] the Availability of data and materials section was incorrect.

RevDate: 2019-03-14

Díaz Santana MV, Hankinson SE, Bigelow C, et al (2019)

Urinary concentrations of phthalate biomarkers and weight change among postmenopausal women: a prospective cohort study.

Environmental health : a global access science source, 18(1):20 pii:10.1186/s12940-019-0458-6.

BACKGROUND: Some phthalates are endocrine disrupting chemicals used as plasticizers in consumer products, and have been associated with obesity in cross-sectional studies, yet prospective evaluations of weight change are lacking. Our objective was to evaluate associations between phthalate biomarker concentrations and weight and weight change among postmenopausal women.

METHODS: We performed cross-sectional (N = 997) and longitudinal analyses (N = 660) among postmenopausal Women's Health Initiative participants. We measured 13 phthalate metabolites and creatinine in spot urine samples provided at baseline. Participants' weight and height measured at in-person clinic visits at baseline, year 3, and year 6 were used to calculate body mass index (BMI). We fit multivariable multinomial logistic regression models to explore cross-sectional associations between each phthalate biomarker and baseline BMI category. We evaluated longitudinal associations between each biomarker and weight change using mixed effects linear regression models.

RESULTS: In cross-sectional analyses, urinary concentrations of some biomarkers were positively associated with obesity prevalence (e.g. sum of di (2-ethylhexyl) phthalate metabolites [ΣDEHP] 4th vs 1st quartile OR = 3.29, 95% CI 1.80-6.03 [p trend< 0.001] vs normal). In longitudinal analyses, positive trends with weight gain between baseline and year 3 were observed for mono-(2-ethyl-5-oxohexyl) phthalate, monoethyl phthalate (MEP), mono-hydroxybutyl phthalate, and mono-hydroxyisobutyl phthalate (e.g. + 2.32 kg [95% CI 0.93-3.72] for 4th vs 1st quartile of MEP; p trend < 0.001). No statistically significant associations were observed between biomarkers and weight gain over 6 years.

CONCLUSIONS: Certain phthalates may contribute to short-term weight gain among postmenopausal women.

RevDate: 2019-03-13

Schweizer MT, Gulati R, Beightol M, et al (2019)

Clinical determinants for successful circulating tumor DNA analysis in prostate cancer.

The Prostate [Epub ahead of print].

BACKGROUND: Plasma-based cell-free DNA is an attractive biospecimen for assessing somatic mutations due to minimally-invasive real-time sampling. However, next generation sequencing (NGS) of cell-free DNA (cfDNA) may not be appropriate for all patients with advanced prostate cancer (PC).

METHODS: Blood was obtained from advanced PC patients for plasma-based sequencing. UW-OncoPlex, a ∼2 Mb multi-gene NGS panel performed in the CLIA/CAP environment, was optimized for detecting cfDNA mutations. Tumor tissue and germline samples were sequenced for comparative analyses. Multivariate logistic regression was performed to determine the clinical characteristic associated with the successful detection of somatic cfDNA alterations (ie detection of at least one clearly somatic PC mutation).

RESULTS: Plasma for cfDNA sequencing was obtained from 93 PC patients along with tumor tissue (N = 67) and germline (N = 93) controls. We included data from 76 patients (72 prostate adenocarcinoma; 4 variant histology PC) in the analysis. Somatic DNA aberrations were detected in 34 cfDNA samples from patients with prostate adenocarcinoma. High PSA level, high tumor volume, and castration-resistance were significantly associated with successful detection of somatic cfDNA alterations. Among samples with somatic mutations detected, the cfDNA assay detected 93/102 (91%) alterations found in tumor tissue, yielding a clustering-corrected sensitivity of 92% (95% confidence interval 88-97%). All germline pathogenic variants present in lymphocyte DNA were also detected in cfDNA (N = 12). Somatic mutations from cfDNA were detected in 30/33 (93%) instances when PSA was >10 ng/mL.

CONCLUSIONS: Disease burden, including a PSA >10 ng/mL, is strongly associated with detecting somatic mutations from cfDNA specimens.

RevDate: 2019-03-13

Mannheimer S, Hirsch-Moverman Y, Franks J, et al (2019)

Factors Associated With Sex-Related Pre-exposure Prophylaxis Adherence Among Men Who Have Sex With Men in New York City in HPTN 067.

Journal of acquired immune deficiency syndromes (1999), 80(5):551-558.

BACKGROUND: HPTN 067 assessed the feasibility of daily and non-daily dosing of open-label emtricitabine/tenofovir disoproxil fumarate (FTC/TDF)-based pre-exposure prophylaxis (PrEP).

METHODS: Factors associated with sex-related PrEP adherence were assessed among men who have sex with men (MSM) randomized to one of 3 PrEP dosing arms in HPTN 067 in New York City. Sex-related PrEP adherence was defined per protocol as at least 1 PrEP tablet taken within 4 days pre-sex and at least 1 additional PrEP tablet taken within 24 hours post-sex, assessed via electronic drug monitoring and weekly interviews. Demographic data and behavioral measures were evaluated for association with sex-related PrEP adherence. Logistic regression for clustered data was used to estimate the unadjusted and adjusted odds ratios.

RESULTS: Of 176 randomized MSM participants, 59% were Black, 10% White, 25% Hispanic, and 6% other; median age was 31 years. In the multivariable analyses, higher sex-related PrEP adherence was significantly associated with daily dosing arm, older age, employment, and higher PrEP adherence behavioral skills. Lower sex-related PrEP adherence was significantly associated with identifying as Black or Hispanic (compared with White), opiate use, and reporting "I forgot" as an adherence barrier.

CONCLUSIONS: This analysis identified populations of MSM who might benefit from additional support to optimize PrEP adherence, including those who are younger, unemployed, or opiate users. MSM with lower PrEP behavioral skills may benefit from targeted interventions. Further study is needed to assess racial and ethnic disparities in PrEP adherence, which may reflect broader social and economic inequalities not captured in this study.

RevDate: 2019-03-13

Plantinga AM, Chen J, Jenq RR, et al (2019)

pldist: ecological dissimilarities for paired and longitudinal microbiome association analysis.

Bioinformatics (Oxford, England) pii:5341424 [Epub ahead of print].

MOTIVATION: The human microbiome is notoriously variable across individuals, with a wide range of 'healthy' microbiomes. Paired and longitudinal studies of the microbiome have become increasingly popular as a way to reduce unmeasured confounding and to increase statistical power by reducing large inter-subject variability. Statistical methods for analyzing such datasets are scarce.

RESULTS: We introduce a paired UniFrac dissimilarity that summarizes within-individual (or within-pair) shifts in microbiome composition and then compares these compositional shifts across individuals (or pairs). This dissimilarity depends on a novel transformation of relative abundances, which we then extend to more than two time points and incorporate into several phylogenetic and non-phylogenetic dissimilarities. The data transformation and resulting dissimilarities may be used in a wide variety of downstream analyses, including ordination analysis and distance-based hypothesis testing. Simulations demonstrate that tests based on these dissimilarities retain appropriate type 1 error and high power. We apply the method in two real datasets.

The R package pldist is available on GitHub at https://github.com/aplantin/pldist.

SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

RevDate: 2019-03-12

Henry NL, Unger JM, Till C, et al (2019)

Association between body mass index and response to duloxetine for aromatase inhibitor-associated musculoskeletal symptoms in SWOG S1202.

Cancer [Epub ahead of print].

BACKGROUND: Aromatase inhibitor (AI)-associated musculoskeletal symptoms (AIMSS) negatively impact adherence to and persistence with therapy. In SWOG S1202, patients with AIMSS who were treated with duloxetine, a serotonin norepinephrine reuptake inhibitor, reported improvement in pain by 12 weeks compared with placebo. Based on the authors' prior observation that responses to pain interventions differ between obese and nonobese patients, the current study examined whether response to duloxetine therapy differed by obesity status.

METHODS: In SWOG S1202, a total of 299 AI-treated postmenopausal women with stage I to III (AJCC 7th Edition) breast cancer who developed new or worsening average pain were enrolled, randomized to duloxetine or placebo, and treated for 12 weeks. Patient-reported outcomes were obtained at baseline and through 12 weeks. Patients were categorized into nonobese (body mass index [BMI] <30 kg/m2) or obese (BMI ≥30 kg/m2). The authors tested the interaction between intervention and obesity with respect to average pain at 12 weeks in the 289 eligible patients, using a P value of .05 to indicate statistical significance.

RESULTS: In approximately 54% of evaluable patients with a BMI ≥30 kg/m2 , the reduction in the mean average pain score between baseline and 12 weeks was statistically significantly greater for patients treated with duloxetine compared with those receiving placebo (-2.73 vs -1.64 points; P = .003). Conversely, in the nonobese patients, the reduction in the mean average pain score was similar in the 2 cohorts (-2.46 vs -2.34 points; P = .75). The P value for interaction was .02, thereby meeting the threshold criteria of the current study. Similar findings were evident for other pain-related patient-reported outcomes.

CONCLUSIONS: In this trial, obese patients with AIMSS obtained more analgesic benefit from duloxetine compared with nonobese patients. Additional studies are warranted to determine the biologic basis for these findings.

RevDate: 2019-03-12

Bates JE, Howell RM, Liu Q, et al (2019)

Therapy-Related Cardiac Risk in Childhood Cancer Survivors: An Analysis of the Childhood Cancer Survivor Study.

Journal of clinical oncology : official journal of the American Society of Clinical Oncology [Epub ahead of print].

PURPOSE: The impacts of radiotherapy dose and exposed cardiac volume, select chemotherapeutic agents, and age at exposure on risk for late-onset cardiac disease in survivors of childhood cancer remain unresolved.

PATIENTS AND METHODS: We determined the rates of severe to fatal cardiac disease in 24,214 5-year survivors in the Childhood Cancer Survivor Study diagnosed between 1970 and 1999 at a median age of 7.0 years (range, 0 to 20.9 years), with a median attained age of 27.5 years (range, 5.6 to 58.9 years). Using piecewise exponential models, we evaluated the association between cardiac disease rates and demographic and treatment characteristics.

RESULTS: The cumulative incidence of cardiac disease 30 years from diagnosis was 4.8% (95% CI, 4.3 to 5.2). Low to moderate radiotherapy doses (5.0 to 19.9 Gy) to large cardiac volumes (≥ 50% of heart) were associated with an increased rate of cardiac disease (relative rate, 1.6; 95% CI, 1.1 to 2.3) compared with survivors without cardiac radiotherapy exposure. Similarly, high doses (≥ 20 Gy) to small cardiac volumes (0.1% to 29.9%) were associated with an elevated rate (relative rate, 2.4; 95% CI, 1.4 to 4.2). A dose-response relationship was observed between anthracycline chemotherapy and heart failure with younger children (age ≤ 13 years) at the greatest risk for heart failure after comparable dosing.

CONCLUSION: These observations support advances in radiation field design and delivery technology to reduce cardiac dose/volume and should guide future treatment protocols. They also inform clinical practice guidelines for post-therapy surveillance and risk-reducing strategies.

RevDate: 2019-03-12

Shenoy MK, Fadrosh DW, Lin DL, et al (2019)

Gut microbiota in HIV-pneumonia patients is related to peripheral CD4 counts, lung microbiota, and in vitro macrophage dysfunction.

Microbiome, 7(1):37 pii:10.1186/s40168-019-0651-4.

Pneumonia is common and frequently fatal in HIV-infected patients, due to rampant, systemic inflammation and failure to control microbial infection. While airway microbiota composition is related to local inflammatory response, gut microbiota has been shown to correlate with the degree of peripheral immune activation (IL6 and IP10 expression) in HIV-infected patients. We thus hypothesized that both airway and gut microbiota are perturbed in HIV-infected pneumonia patients, that the gut microbiota is related to peripheral CD4+ cell counts, and that its associated products differentially program immune cell populations necessary for controlling microbial infection in CD4-high and CD4-low patients. To assess these relationships, paired bronchoalveolar lavage and stool microbiota (bacterial and fungal) from a large cohort of Ugandan, HIV-infected patients with pneumonia were examined, and in vitro tests of the effect of gut microbiome products on macrophage effector phenotypes performed. While lower airway microbiota stratified into three compositionally distinct microbiota as previously described, these were not related to peripheral CD4 cell count. In contrast, variation in gut microbiota composition significantly related to CD4 cell count, lung microbiota composition, and patient mortality. Compared with patients with high CD4+ cell counts, those with low counts possessed more compositionally similar airway and gut microbiota, evidence of microbial translocation, and their associated gut microbiome products reduced macrophage activation and IL-10 expression and increased IL-1β expression in vitro. These findings suggest that the gut microbiome is related to CD4 status and plays a key role in modulating macrophage function, critical to microbial control in HIV-infected patients with pneumonia.

RevDate: 2019-03-11

Donahu TF, Bagrodia A, Audenet F, et al (2018)

Genomic Characterization of Upper-Tract Urothelial Carcinoma in Patients With Lynch Syndrome.

JCO precision oncology, 2018:.

Purpose: Patients with Lynch syndrome (LS) have a significantly increased risk of developing upper-tract urothelial carcinoma (UTUC). Here, we sought to identify differences in the patterns of mutational changes in LS-associated versus sporadic UTUCs.

Patients and Methods: We performed targeted sequencing of 17 UTUCs from patients with documented LS-associated germline mutations (LS-UTUCs) using the Memorial Sloan Kettering Integrated Molecular Profiling of Actionable Cancer Targets targeted exon capture assay and compared the results with those from a recently characterized cohort of 82 patients with sporadic UTUC.

Results: Patients with LS-UTUC were significantly younger, had had less exposure to tobacco, and more often presented with a ureteral primary site compared with patients with sporadic UTUC. The median number of mutations per tumor was significantly greater in LS-UTUC tumors than in tumors from the sporadic cohort (58; interquartile range [IQR], 47-101 v 6; IQR, 4-10; P < .001), as was the MSIsensor score (median, 25.1; IQR, 17.9-31.2 v 0.03; IQR, 0-0.44; P < .001). Differences in the genetic landscape were observed between sporadic and LS-associated tumors. Alterations in KMT2D, CREBBP, or ARID1A or in DNA damage response and repair genes were present at a significantly higher frequency in LS-UTUC. CIC, NOTCH1, NOTCH3, RB1, and CDKN1B alterations were almost exclusive to LS-UTUC. Although FGFR3 mutations were identified in both cohorts, the R248C hotspot mutation was highly enriched in LS-UTUC.

Conclusion: LSand sporadic UTUCs have overlapping but distinct genetic signatures. LS-UTUC is associated with hypermutation and a significantly higher prevalence of FGFR3 R248C mutation. Prospective molecular characterization of patients to identify those with LS-UTUC may help guide treatment.

RevDate: 2019-03-11

Unger JM, Vaidya R, Hershman DL, et al (2019)

Systematic Review and Meta-Analysis of the Magnitude of Structural, Clinical, and Physician and Patient Barriers to Cancer Clinical Trial Participation.

Journal of the National Cancer Institute, 111(3):245-255.

BACKGROUND: Barriers to cancer clinical trial participation have been the subject of frequent study, but the rate of trial participation has not changed substantially over time. Studies often emphasize patient-related barriers, but other types of barriers may have greater impact on trial participation. Our goal was to examine the magnitude of different domains of trial barriers by synthesizing prior research.

METHODS: We conducted a systematic review and meta-analysis of studies that examined the trial decision-making pathway using a uniform framework to characterize and quantify structural (trial availability), clinical (eligibility), and patient/physician barrier domains. The systematic review utilized the PubMed, Google Scholar, Web of Science, and Ovid Medline search engines. We used random effects to estimate rates of different domains across studies, adjusting for academic vs community care settings.

RESULTS: We identified 13 studies (nine in academic and four in community settings) with 8883 patients. A trial was unavailable for patients at their institution 55.6% of the time (95% confidence interval [CI] = 43.7% to 67.3%). Further, 21.5% (95% CI = 10.9% to 34.6%) of patients were ineligible for an available trial, 14.8% (95% CI = 9.0% to 21.7%) did not enroll, and 8.1% (95% CI = 6.3% to 10.0%) enrolled. Rates of trial enrollment in academic (15.9% [95% CI = 13.8% to 18.2%]) vs community (7.0% [95% CI = 5.1% to 9.1%]) settings differed, but not rates of trial unavailability, ineligibility, or non-enrollment.

CONCLUSIONS: These findings emphasize the enormous need to address structural and clinical barriers to trial participation, which combined make trial participation unachievable for more than three of four cancer patients.

RevDate: 2019-03-11

Buckley SA, Mark NM, Othus M, et al (2019)

Diagnostic utility of bronchoscopy in adults with acute myeloid leukemia and other high-grade myeloid neoplasms.

Leukemia & lymphoma [Epub ahead of print].

RevDate: 2019-03-11

Fei Q, Wang D, Jasbi P, et al (2019)

Combining NMR and MS with Chemical Derivatization for Absolute Quantification with Reduced Matrix Effects.

Analytical chemistry [Epub ahead of print].

Absolute quantitation is a major challenge in metabolomics. Previously, we [ Nagana Gowda et al. Anal. Chem. 2018 , 90 , 2001 - 2009 ] showed that nuclear magnetic resonance (NMR) spectroscopy can guide absolute quantitation using mass spectrometry (MS); however, this method does not account for the matrix effect in MS measurements. To surmount this challenge, we have developed a novel method, qNMR-MS, for the absolute quantitation of metabolites using MS by combining it with NMR and chemical derivatization. Metabolite concentrations are first obtained using NMR for a reference sample. Subsequently, both reference and study samples are chemically derivatized with isotope-labeled and unlabeled reagents, respectively. The derivatized reference sample is then mixed with study samples and measured using MS. Comparison of paired isotope unlabeled and labeled MS peaks enables absolute quantitation with virtually no matrix effects. As a proof of concept, we applied the qNMR-MS method for absolute quantitation of amino acids using propyl-chloroformate (PCF) derivatization. For standards, the observed coefficients of determination (R2) of most amino acids were greater than 0.99 across concentrations of 0.2 to 20 uM. For human serum, the results of the qNMR-MS method are comparable to the conventional isotope-labeled internal standard (iSTD) method (R2 ≥ 0.99), with an average median coefficient of variation (CV) of 5.45%. The qNMR-MS method is relatively simple, highly quantitative, has high cost-efficiency (no iSTD required), and offers new avenues for the routine quantitation of amino acids in blood samples; it can, in principle, be extended to a wide variety of metabolites in different biological samples.

RevDate: 2019-03-08

Marcandalli J, Fiala B, Ols S, et al (2019)

Induction of Potent Neutralizing Antibody Responses by a Designed Protein Nanoparticle Vaccine for Respiratory Syncytial Virus.

Cell, 176(6):1420-1431.e17.

Respiratory syncytial virus (RSV) is a worldwide public health concern for which no vaccine is available. Elucidation of the prefusion structure of the RSV F glycoprotein and its identification as the main target of neutralizing antibodies have provided new opportunities for development of an effective vaccine. Here, we describe the structure-based design of a self-assembling protein nanoparticle presenting a prefusion-stabilized variant of the F glycoprotein trimer (DS-Cav1) in a repetitive array on the nanoparticle exterior. The two-component nature of the nanoparticle scaffold enabled the production of highly ordered, monodisperse immunogens that display DS-Cav1 at controllable density. In mice and nonhuman primates, the full-valency nanoparticle immunogen displaying 20 DS-Cav1 trimers induced neutralizing antibody responses ∼10-fold higher than trimeric DS-Cav1. These results motivate continued development of this promising nanoparticle RSV vaccine candidate and establish computationally designed two-component nanoparticles as a robust and customizable platform for structure-based vaccine design.

RevDate: 2019-03-07

van der Straten A, Browne EN, Shapley-Quinn MK, et al (2019)

First Impressions Matter: How Initial Worries Influence Adherence to the Dapivirine Vaginal Ring.

Journal of acquired immune deficiency syndromes (1999) [Epub ahead of print].

BACKGROUND: In MTN-020/ASPIRE, a dapivirine vaginal ring effectiveness trial in sub-Saharan Africa, we assessed whether worries about ring use changed over time and were associated with adherence.

METHODS: Participants (N=2585) were surveyed at baseline and follow-up about worries regarding daily ring use. First, they answered a question about general worries and then responded to 15 items covering specific worries. From a nested qualitative component (N=214), we extracted themes related to ring worries and adherence. Seven months into the trial, aggregate adherence data were shared with study sites as part of an intervention that included counseling and social support. Nonadherence was defined as dapivirine plasma levels of ≤95 pg/ml. Mixed-effect logistic regression models were used to assess changes in ring worries and nonadherence from baseline to month 3 and later.

RESULTS: Worry about wearing the ring decreased from 29% at baseline to 4% at month 3 (p<0.001), while having a specific worry decreased from 47% to 16% (p<0.001). Among those enrolled preintervention, 29% with baseline worries were nonadherent at month 3 (95% CI: 19%, 39%) compared to 14% without worries (95% CI: 9%, 19%; p=0.005); the difference persisted through month 6. There was no difference in nonadherence by baseline worry for those enrolled postintervention (p=0.40). In the qualitative subset, initial ring anxieties reportedly subsided with self-experimentation and practice and the beneficial influence of the intervention.

CONCLUSIONS: Although worries may be an initial deterrent to correct ring use, intervening early by leveraging social influences from peers and clinicians should facilitate successful adoption and correct ring use.

RevDate: 2019-03-07

Creary LE, Guerra SG, Chong W, et al (2019)

Next-generation HLA typing of 382 International Histocompatibility Working Group reference B-Lymphoblastoid cell lines: report from the 17th International HLA and Immunogenetics Workshop.

Human immunology pii:S0198-8859(19)30227-7 [Epub ahead of print].

Extended molecular characterization of HLA genes in the IHWG reference B-lymphoblastoid cell lines (B-LCLs) was one of the major goals for the 17th International HLA and Immunogenetics Workshop (IHIW). Although reference B-LCLs have been examined extensively in previous workshops complete high-resolution typing was not completed for all the classical class I and class II HLA genes. To address this, we conducted a single-blind study where select panels of B-LCL genomic DNA samples were distributed to multiple laboratories for HLA genotyping by next-generation sequencing methods. Identical cell panels comprised of 24 and 346 samples were distributed and typed by at least four laboratories in order to derive accurate consensus HLA genotypes. Overall concordance rates calculated at both 2- and 4-field allele-level resolutions ranged from 90.4% to 100%. Concordance for the class I genes ranged from 91.7 to 100%, whereas concordance for class II genes was variable; the lowest observed at HLA-DRB3 (84.2%). At the maximum allele-resolution 78 B-LCLs were defined as homozygous for all 11 loci. We identified 11 novel exon polymorphisms in the entire cell panel. A comparison of the B-LCLs NGS HLA genotypes with the HLA genotypes catalogued in the IPD-IMGT/HLA Database Cell Repository, revealed an overall allele match at 68.4%. Typing discrepancies between the two datasets were mostly due to the lower-resolution historical typing methods resulting in incomplete HLA genotypes for some samples listed in the IPD-IMGT/HLA Database Cell Repository. Our approach of multiple-laboratory NGS HLA typing of the B-LCLs has provided accurate genotyping data. The data generated by the tremendous collaborative efforts of the 17th IHIW participants is useful for updating the current cell and sequence databases and will be a valuable resource for future studies.

RevDate: 2019-03-06

Markey KA, KH Gartlan (2019)

Imaging Flow Cytometry to Assess Antigen-Presenting-Cell Function.

Current protocols in immunology [Epub ahead of print].

This unit describes methods for quantifying phagocytosis and imaging the immunological synapse between T cells and antigen-presenting cells (APCs), with both techniques delivering valuable information about APC function. These aspects of APC biology have traditionally been challenging to quantify, and imaging flow cytometry, which harnesses the high-throughput nature of flow cytometry combined with the capacity of microscopy to deliver spatial localization, facilitates analysis of these APC functions in a fashion that was previously not possible. Imaging flow cytometry allows large numbers of events to be captured and large amounts of fluorescence data to be quantified at the physical location of markers of interest, both on the cell surface and in intracellular compartments, combining key features of traditional flow cytometry and fluorescence microscopy. © 2019 by John Wiley & Sons, Inc.

RevDate: 2019-03-06

Baglia ML, Lin IH, Cartmel B, et al (2019)

Endocrine-related quality of life in a randomized trial of exercise on aromatase inhibitor-induced arthralgias in breast cancer survivors.

Cancer [Epub ahead of print].

BACKGROUND: The objective of this study was to evaluate the role of a 12-month exercise intervention on endocrine-related quality of life (QOL) and overall QOL among breast cancer survivors with aromatase inhibitor (AI)-induced arthralgia in the Hormones and Physical Exercise (HOPE) Study.

METHODS: This was a randomized controlled trial of 121 breast cancer survivors who were currently receiving AIs and experiencing at least mild arthralgia. QOL was assessed using the Functional Assessment of Cancer Therapy (FACT) questionnaires and the 36-Item Short Form Survey (SF-36) at baseline, 6 months, and 12 months. Participants were randomized to either a 1-year gym-based, supervised exercise intervention group (150 minutes of aerobic exercise and 2 strength-training sessions each week) or a usual care group. Effects of the intervention on QOL were assessed using mixed-model, repeated-measures analysis.

RESULTS: At 12 months, the exercise group had greater improvement in the overall QOL measures as well as the breast cancer-specific (scores, 2.2 vs 0.7; P = .02), endocrine-specific (scores, 5.6 vs 1.6; P < .001), and fatigue-specific (score, 5.8 vs 0.5; P < .001) subscales compared with the usual care group. The results indicated a stronger effect at 12 months versus 6 months after the intervention.

CONCLUSIONS: Combined aerobic and resistance exercise, such as treadmill walking and strength training, improved endocrine-related and overall QOL among breast cancer survivors who were experiencing adverse side effects from AIs. Because adverse side effects associated with AI use are quite common and this is the main reason for treatment discontinuation, this nonpharmacologic intervention could benefit many breast cancer survivors and increase successful adherence to AIs in breast cancer treatment.

RevDate: 2019-03-06

Chu AT, Holt SK, Wright JL, et al (2019)

Delays in radical cystectomy for muscle-invasive bladder cancer.

Cancer [Epub ahead of print].

BACKGROUND: Delays from the diagnosis of muscle-invasive bladder cancer (MIBC) to radical cystectomy (RC) longer than 12 weeks result in higher mortality and shorter progression-free survival. This study sought to identify factors associated with RC delays and to determine whether delays in care in the current treatment paradigm, which includes neoadjuvant chemotherapy (NAC), affect survival.

METHODS: Subjects with American Joint Committee on Cancer stage II urothelial carcinoma of the bladder who underwent RC from 2004 to 2012 were identified from the linked Surveillance, Epidemiology, and End Results national cancer registry and the Medicare claims database and were stratified into RC groups with or without NAC. Cox multivariable proportional hazard models and multivariable logistic regression models assessed the significance of delays in RC for survival and identified independent characteristics associated with RC delays, respectively.

RESULTS: This study identified 1509 patients with MIBC who underwent RC during the study period. In comparison with timely surgery, delays in RC increased overall mortality, regardless of the use of NAC (hazard ratio [HR] without NAC, 1.34; 95% confidence interval [CI], 1.03-1.76; HR after NAC, 1.63; 95% CI, 1.06-2.52). Patients proceeding to RC without NAC had higher odds of delayed care if they lived in a high-poverty neighborhood (odds ratio [OR], 1.37; 95% CI, 1.01-2.08) or nonmetropolitan area (OR, 1.61; 95% CI, 1.01-2.55), were men (OR, 2.22; 95% CI, 1.25-4.00), or required a provider transfer for bladder cancer care (OR, 1.82; 95% CI, 1.10-3.03).

CONCLUSIONS: Delays in care from the time of either the initial diagnosis or the completion of NAC to RC are associated with worse overall survival among patients with MIBC. Timely surgery is fundamental in the treatment of MIBC, and this necessitates attention to disparities in access to complex surgical care and care coordination.

RevDate: 2019-03-06

Denburg AE, Laher N, Mutyaba I, et al (2019)

The cost effectiveness of treating Burkitt lymphoma in Uganda.

Cancer [Epub ahead of print].

BACKGROUND: Perceptions of high cost and resource intensity remain political barriers to the prioritization of childhood cancer treatment programs in many low- and middle-income countries (LMICs). Little knowledge exists of the actual cost and cost-effectiveness of such programs. To improve outcomes for children with Burkitt lymphoma (BL), the most common childhood cancer in Africa, the Uganda Cancer Institute implemented a comprehensive BL treatment program in 2012. We undertook an economic evaluation of the program to ascertain the cost-effectiveness of BL therapy in a specific LIC setting.

METHODS: We compared the treatment of BL to usual care in a cohort of 122 patients treated between 2012 and 2014. Costs included variable, fixed, and family costs. Our primary measure of effectiveness was overall survival (OS). Patient outcomes were determined through prospective capture and retrospective chart abstraction. The cost per disability-adjusted life-year (DALY) averted was calculated using the World Health Organization's Choosing Interventions That Are Cost-Effective (WHO-CHOICE) methodology.

RESULTS: The 2-year OS with treatment was 55% (95% CI, 45% to 64%). The cost per DALY averted in the treatment group was US$97 (Int$301). Cumulative estimate of national DALYs averted through treatment was 8607 years, and the total national annual cost of treatment was US$834,879 (Int$2,590,845). The cost of BL treatment fell well within WHO-CHOICE cost-effectiveness thresholds. The ratio of cost per DALY averted to per capita gross domestic product was 0.14, reflecting a very cost-effective intervention.

CONCLUSION: This study demonstrates that treating BL with locally tailored protocols is very cost-effective by international standards. Studies of this kind will furnish crucial evidence to help policymakers prioritize the allocation of LMIC health system resources among noncommunicable diseases, including childhood cancer.

RevDate: 2019-03-09

de Montigny S, Boily MC, Mâsse BR, et al (2018)

Assessing the utility of the tipping point ratio to monitor HIV treatment programmes in the era of universal access to ART.

Infectious Disease Modelling, 3:85-96 pii:S2468-0427(17)30037-4.

Background: The epidemiological tipping point ratio (TPR) has been suggested as a useful indicator to monitor the scale-up of antiretroviral treatment (ART) programmes and determine when scale-up is sufficient to control the epidemic. TPR has been defined as the ratio of yearly number of new HIV infections to the yearly number of new ART initiations or to the yearly net increase in the number of people on ART. It has been used to rank the progress of treatment programmes across countries, with the objective of reaching a TPR value under 1. Our study aims to assess if TPR alone can be used as an indicator of ART success across settings by comparing the expected changes in HIV incidence and ART coverage when TPR is maintained constant over time. In particular, we focus on the effect of ART initiation timing (emphasis on ART being initiated early or late during HIV progression) on the interpretation of the TPR.

Methods: We used a dynamic model of HIV transmission in South Africa representing ART rollout leading to universal treatment in 2017. The model is calibrated to HIV incidence, HIV prevalence and ART coverage in 2012 in South Africa, and 1000 simulations are selected for the base-case scenario. To measure the effect of TPR, we simulate TPR-preserving interventions, maintaining TPR (yearly number of new ART initiations denominator) at the value observed in 2019 (between 0.65 and 1.25) for 15 years. We compare ART coverage and HIV incidence across TPR values and across strategies in which ART access is prioritized differently. In a secondary analysis, we illustrate the sensitivity of new ART initiations to ART retention, and we compare both definitions of the TPR.

Results: Our analysis shows that HIV incidence reduction is weakly correlated to TPR: the same reduction in HIV incidence (15%) can be achieved by implementing the same strategy with a wide range of TPR maintained (0.65-1.12). Assuming high retention in ART, TPR-preserving strategies prioritizing early ART initiation yield greater reduction in HIV incidence than strategies where most individuals initiate ART late. High ART coverage is associated with low HIV incidence and it can be reached with a TPR below or equal to one with strategies favoring early ART initiation. Low ART retention over time results in higher HIV incidence even if TPR is maintained low. If ART retention is low, strategies prioritizing late ART initiation are associated with lower HIV incidence than strategies where ART is initiated early. Maintaining a fixed TPR value based on the net increase in people on ART gives higher HIV incidence reduction and requires fast ART scale-up.

Conclusion: Our analysis suggests that the TPR is not an adequate indicator of ART programme impact, without information on ART coverage and retention. Achieving early initiation and adherence to treatment to improve ART coverage might be as important as attaining a specific TPR target. Comparisons of TPR in different settings should account for differences in epidemic conditions.

RevDate: 2019-03-05

Winters BR, Wen L, Holt SK, et al (2019)

Does the diagnosis of bladder cancer lead to higher rates of smoking cessation? Findings from the Medicare Health Outcomes Survey.

The Journal of urology [Epub ahead of print].

PURPOSE: Smoking is the most common risk factor for bladder cancer (BC) and is associated with adverse clinical outcomes. The diagnosis of BC represents a 'teachable moment' for smoking cessation. We investigate the likelihood of smoking cessation after BC diagnosis in a population database.

MATERIALS AND METHODS: We evaluated SEER-MHOS (1998-2013) for all patients diagnosed with incident BC who had pre- and post-diagnosis survey data available. We compared these patients to propensity matched non-cancer controls (NCCs) and to a cohort of incident renal cell carcinoma (RCC) patients. Differences in smoking cessation were compared between groups and multivariate logistic regression performed to assess the likelihood of smoking cessation.

RESULTS: 394 newly diagnosed bladder cancer patients were propensity matched to 1,970 NCCs and compared with 169 incident RCC patients. Baseline smoking prevalence was more common in patients diagnosed with BC (16%) compared with RCC (11%) (NS). The smoking cessation rates in BC patients was 27% compared with 21% in NCCs (p=0.30) and 26% in RCC patients (p=0.90). There were no significant differences in the adjusted odds ratios of quitting smoking in BC and RCC patients compared with NCCs (1.3, 95%CI: 0.7 - 2.5; 1.2, 95%CI: 0.5 - 3.6). Independent predictors of smoking cessation in BC patients included age (p=0.03), African American race (p=0.03), and college education (p=0.01).

CONCLUSIONS: Smoking cessation was not significantly different following the diagnosis of BC compared to propensity-matched NCCs. The proportion of individuals quitting was low overall, suggesting improved efforts are needed to utilize this teachable moment in BC patients.

RevDate: 2019-03-07

Neuhouser ML, Clowry C, Beatty SJ, et al (2019)

Rationale and design of the frequency of eating and Satiety Hormones (FRESH) study: A randomized cross-over clinical trial.

Contemporary clinical trials communications, 14:100334 pii:100334.

Background: The goal of the Frequency of Eating and Satiety Hormones (FRESH) Study is to understand the relationship between eating frequency (EF) and biomarkers of appetite and disease risk. This report gives the study rationale and design.

Methods: The FRESH study was conducted in n = 50 overweight and obese, but otherwise healthy, male and female adults aged 18-50 years. The protocol included four in-person clinic visits for protocol instruction, blood draws, anthropometry, and meal testing; all other activities were done at home. Participants completed two 21-day phases in random order with a two-week washout between phases. One phase was high EF (6 eating occasions/day) and the other was low EF (3 eating occasions/day). Each phase specified time of day for each eating occasion. Participants prepared their own meals throughout the study using study-provided individualized, structured meal plans ensuring that calories, macronutrients and micronutrients were identical during both study phases. Fasting blood was collected before and after each phase to test intervention effects on the biomarkers. At the end of each phase participants also completed extended appetite testing with meals prepared by the study clinic.

Results: Participants were recruited using print, radio, and digital ads. 60 participants consented to enroll; 10 dropped out due to work or school scheduling conflicts and 50 (target sample size) completed the study. Compliance was assessed by completion of daily on-line meal plan checklists.

Conclusions: The FRESH study will provide data on whether higher vs. lower daily EF in the context of constant energy and nutrient intake may be harmful or beneficial based on intervention effects on biomarkers of health and disease risk.

RevDate: 2019-03-04

Thompson B, Barrington WE, Briant KJ, et al (2019)

Educating Latinas about cervical cancer and HPV: a pilot randomized study.

Cancer causes & control : CCC pii:10.1007/s10552-019-01150-w [Epub ahead of print].

INTRODUCTION: The purpose of this study was to assess effects of three different educational intervention arms on knowledge of and intention to receive Pap testing and HPV co-testing.

METHODS: Three active educational intervention arms were developed: a fotonovela, a radionovela, and a digital story. A pilot randomized controlled trial of 160 Latinas was conducted to assess the effectiveness of the intervention arms in increasing knowledge of cervical cancer and HPV and intention to be screened for cervical cancer compared to an attention control group (flu vaccination).

RESULTS: Women in all three treatment arms significantly increased knowledge about cervical cancer compared to control arm (p = 0.02). Knowledge about cervical cancer screening also increased in the active arms compared to control (p = 0.0003). Knowledge of HPV risk also increased relative to the control (p = 0.0001). There were no significant differences between the intervention arms in increased knowledge of cervical cancer or cervical cancer screening (p = 0.57 and 0.16, respectively).

DISCUSSION: This study supported the use of small media interventions in narrative education form as effective in increasing knowledge and intention to be screened for cervical cancer. The three culturally relevant interventions, built on qualitative data, were all successful in increasing knowledge.

RevDate: 2019-03-04

Radtke S, Perez AM, Venkataraman R, et al (2019)

Preparation and Gene Modification of Nonhuman Primate Hematopoietic Stem and Progenitor Cells.

Journal of visualized experiments : JoVE.

Hematopoietic stem and progenitor cell (HSPC) transplantation has been a cornerstone therapy for leukemia and other cancers for nearly half a century, underlies the only known cure of human immunodeficiency virus (HIV-1) infection, and shows immense promise in the treatment of genetic diseases such as beta thalassemia. Our group has developed a protocol to model HSPC gene therapy in nonhuman primates (NHPs), allowing scientists to optimize many of the same reagents and techniques that are applied in the clinic. Here, we describe methods for purifying CD34+ HSPCs and long-term persisting hematopoietic stem cell (HSC) subsets from primed bone marrow (BM). Identical techniques can be employed for the purification of other HSPC sources (e.g., mobilized peripheral blood stem cells [PBSCs]). Outlined is a 2 day protocol in which cells are purified, cultured, modified with lentivirus (LV), and prepared for infusion back into the autologous host. Key readouts of success include the purity of the CD34+ HSPC population, the ability of purified HSPCs to form morphologically distinct colonies in semisolid media, and, most importantly, gene modification efficiency. The key advantage to HSPC gene therapy is the ability to provide a source of long-lived cells that give rise to all hematopoietic cell types. As such, these methods have been used to model therapies for cancer, genetic diseases, and infectious diseases. In each case, therapeutic efficacy is established by enhancing the function of distinct HSPC progeny, including red blood cells, T cells, B cells, and/or myeloid subsets. The methods to isolate, modify, and prepare HSPC products are directly applicable and translatable to multiple diseases in human patients.

RevDate: 2019-03-07

Zheng Y (2018)

Study Design Considerations for Cancer Biomarker Discoveries.

The journal of applied laboratory medicine, 3(2):282-289.

Background: Biomarker discovery studies have generated an array of omic data, however few novel biomarkers have reached clinical use. Guidelines for rigorous study designs are needed.

Content: Biases frequently occur in sample selection, outcome ascertainment, or unblinded sample handling and assaying process. The principles of a prospective-specimen collection and retrospective-blinded-evaluation (PRoBE) design can be adapted to mitigate various sources of biases in discovery. We recommend establishing quality biospecimen repositories using matched two-phase designs to minimize biases and maximize efficiency. We also highlight the importance of taking the clinical context into consideration in both sample selection and power calculation for discovery studies.

Summary: Biomarker discovery research should follow rigorous design principles in sample se- lection to avoid biases. Consideration of clinical application and the corresponding biomarker performance characteristics in study designs will lead to a more fruitful discovery study.

Impact: Appropriate study designs will improve the quality and clinical rigor of biomarker discovery studies.

RevDate: 2019-03-06

Gopaulakrishnan S, Pollack S, Stubbs BJ, et al (2019)

restfulSE: A semantically rich interface for cloud-scale genomics with Bioconductor.

F1000Research, 8:21.

Bioconductor's SummarizedExperiment class unites numerical assay quantifications with sample- and experiment-level metadata. SummarizedExperiment is the standard Bioconductor class for assays that produce matrix-like data, used by over 200 packages. We describe the restfulSE package, a deployment of this data model that supports remote storage. We illustrate use of SummarizedExperiment with remote HDF5 and Google BigQuery back ends, with two applications in cancer genomics. Our intent is to allow the use of familiar and semantically meaningful programmatic idioms to query genomic data, while abstracting the remote interface from end users and developers.

RevDate: 2019-03-02

Bolaños-Meade J, Reshef R, Fraser R, et al (2019)

Three prophylaxis regimens (tacrolimus, mycophenolate mofetil, and cyclophosphamide; tacrolimus, methotrexate, and bortezomib; or tacrolimus, methotrexate, and maraviroc) versus tacrolimus and methotrexate for prevention of graft-versus-host disease with haemopoietic cell transplantation with reduced-intensity conditioning: a randomised phase 2 trial with a non-randomised contemporaneous control group (BMT CTN 1203).

The Lancet. Haematology, 6(3):e132-e143.

BACKGROUND: Prevention of graft-versus-host disease (GvHD) without malignant relapse is the overall goal of allogeneic haemopoietic cell transplantation (HCT). We aimed to evaluate regimens using either maraviroc, bortezomib, or post-transplantation cyclophosphamide for GvHD prophylaxis compared with controls receiving the combination of tacrolimus and methotrexate using a novel composite primary endpoint to identify the most promising intervention to be further tested in a phase 3 trial.

METHODS: In this prospective multicentre phase 2 trial, adult patients aged 18-75 years who received reduced-intensity conditioning HCT were randomly assigned (1:1:1) by random block sizes to tacrolimus, mycophenolate mofetil, and post-transplantation cyclophosphamide (cyclophosphamide 50 mg/kg on days 3 and 4, followed by tacrolimus starting on day 5 and mycophenolate mofetil starting on day 5 at 15 mg/kg three times daily not to exceed 1 g from day 5 to day 35); tacrolimus, methotrexate, and bortezomib (bortezomib 1·3 mg/m2 intravenously on days 1, 4, and 7 after HCT); or tacrolimus, methotrexate, and maraviroc (maraviroc 300 mg orally twice daily from day -3 to day 30 after HCT). Methotrexate was administered as a 15 mg/m2 intravenous bolus on day 1 and 10 mg/m2 intravenous bolus on days 3, 6, and 11 after HCT; tacrolimus was given intravenously at a dose of 0·05 mg/kg twice daily (or oral equivalent) starting on day -3 (except the post-transplantation cyclophosphamide, as indicated), with a target level of 5-15 ng/mL. Tacrolimus was continued at least until day 90 and was tapered off by day 180. Each study group was compared separately to a contemporary non-randomised prospective cohort of patients (control group) who fulfilled the same eligibility criteria as the trial, but who were treated with tacrolimus and methotrexate at centres not participating in the trial. The primary endpoint (GvHD-free, relapse-free survival [GRFS]) was defined as the time from HCT to onset of grade 3-4 acute GvHD, chronic GvHD requiring systemic immunosuppression, disease relapse, or death. The study was analysed by modified intention to treat. The study is closed to accrual and this is the planned analysis. This trial is registered with ClinicalTrials.gov, number NCT02208037.

FINDINGS: Between Nov 17, 2014, and May 18, 2016, 273 patients from 31 US centres were randomly assigned to the three study arms: 89 to tacrolimus, methotrexate, and bortezomib; 92 to tacrolimus, methotrexate, and maraviroc; 92 to tacrolimus, mycophenolate mofetil, and post-transplantation cyclophosphamide; and six were excluded. Between Aug 1, 2014, and Sept 14, 2016, 224 controls received tacrolimus and methotrexate. Controls were generally well matched except for more frequent comorbidities than the intervention groups and a different distribution of types of conditioning regimens used. Compared with controls, the hazard ratio for GRFS was 0·72 (90% CI 0·54-0·94; p=0·044) for tacrolimus, mycophenolate mofetil, and post-transplantation cyclophosphamide, 0·98 (0·76-1·27; p=0·92) for tacrolimus, methotrexate, and bortezomib, and 1·10 (0·86-1·41; p=0·49) for tacrolimus, methotrexate, and maraviroc. 238 patients experienced grade 3 or 4 toxicities: 12 (13%) had grade 3 and 67 (73%) grade 4 events with tacrolimus, mycophenolate mofetil, and post-transplantation cyclophosphamide; ten (11%) had grade 3 and 68 (76%) had grade 4 events with tacrolimus, methotrexate, and bortezomib; and 18 (20%) had grade 3 and 63 (68%) had grade 4 events with tacrolimus, methotrexate, and maraviroc. The most common toxicities were haematological (77 [84%] for tacrolimus, mycophenolate mofetil, and post-transplantation cyclophosphamide; 73 [82%] for tacrolimus, methotrexate, and bortezomib; and 78 [85%] for tacrolimus, methotrexate, and maraviroc) and cardiac (43 [47%], 44 [49%], and 43 [47%], respectively).

INTERPRETATION: Tacrolimus, mycophenolate mofetil, and post-transplantation cyclophosphamide was the most promising intervention, yielding the best GRFS; this regimen is thus being prospectively compared with tacrolimus and methotrexate in a phase 3 randomised trial.

FUNDING: US National Health, Lung, and Blood Institute; National Cancer Institute; National Institute of Allergy and Infectious Disease; and Millennium Pharmaceuticals.

RevDate: 2019-03-01

Bien SA, Su YR, Conti DV, et al (2019)

Genetic variant predictors of gene expression provide new insight into risk of colorectal cancer.

Human genetics pii:10.1007/s00439-019-01989-8 [Epub ahead of print].

Genome-wide association studies have reported 56 independently associated colorectal cancer (CRC) risk variants, most of which are non-coding and believed to exert their effects by modulating gene expression. The computational method PrediXcan uses cis-regulatory variant predictors to impute expression and perform gene-level association tests in GWAS without directly measured transcriptomes. In this study, we used reference datasets from colon (n = 169) and whole blood (n = 922) transcriptomes to test CRC association with genetically determined expression levels in a genome-wide analysis of 12,186 cases and 14,718 controls. Three novel associations were discovered from colon transverse models at FDR ≤ 0.2 and further evaluated in an independent replication including 32,825 cases and 39,933 controls. After adjusting for multiple comparisons, we found statistically significant associations using colon transcriptome models with TRIM4 (discovery P = 2.2 × 10- 4, replication P = 0.01), and PYGL (discovery P = 2.3 × 10- 4, replication P = 6.7 × 10- 4). Interestingly, both genes encode proteins that influence redox homeostasis and are related to cellular metabolic reprogramming in tumors, implicating a novel CRC pathway linked to cell growth and proliferation. Defining CRC risk regions as one megabase up- and downstream of one of the 56 independent risk variants, we defined 44 non-overlapping CRC-risk regions. Among these risk regions, we identified genes associated with CRC (P < 0.05) in 34/44 CRC-risk regions. Importantly, CRC association was found for two genes in the previously reported 2q25 locus, CXCR1 and CXCR2, which are potential cancer therapeutic targets. These findings provide strong candidate genes to prioritize for subsequent laboratory follow-up of GWAS loci. This study is the first to implement PrediXcan in a large colorectal cancer study and findings highlight the utility of integrating transcriptome data in GWAS for discovery of, and biological insight into, risk loci.

RevDate: 2019-03-01

Kunkle BW, Grenier-Boley B, Sims R, et al (2019)

Genetic meta-analysis of diagnosed Alzheimer's disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing.

Nature genetics, 51(3):414-430.

Risk for late-onset Alzheimer's disease (LOAD), the most prevalent dementia, is partially driven by genetics. To identify LOAD risk loci, we performed a large genome-wide association meta-analysis of clinically diagnosed LOAD (94,437 individuals). We confirm 20 previous LOAD risk loci and identify five new genome-wide loci (IQCK, ACE, ADAM10, ADAMTS1, and WWOX), two of which (ADAM10, ACE) were identified in a recent genome-wide association (GWAS)-by-familial-proxy of Alzheimer's or dementia. Fine-mapping of the human leukocyte antigen (HLA) region confirms the neurological and immune-mediated disease haplotype HLA-DR15 as a risk factor for LOAD. Pathway analysis implicates immunity, lipid metabolism, tau binding proteins, and amyloid precursor protein (APP) metabolism, showing that genetic variants affecting APP and Aβ processing are associated not only with early-onset autosomal dominant Alzheimer's disease but also with LOAD. Analyses of risk genes and pathways show enrichment for rare variants (P = 1.32 × 10-7), indicating that additional rare variants remain to be identified. We also identify important genetic correlations between LOAD and traits such as family history of dementia and education.

RevDate: 2019-03-01

Carlos RC, Sicks JD, Chiles C, et al (2019)

Lung Cancer Screening in the National Cancer Institute Community Oncology Research Program: Availability and Service Organization.

Journal of the American College of Radiology : JACR pii:S1546-1440(18)31581-3 [Epub ahead of print].

PURPOSE: Annual low-dose CT (LDCT) for lung screening in high-risk individuals decreases both lung cancer-specific mortality and all-cause mortality. Community oncology practice networks constituting the National Cancer Institute Community Oncology Research Program (NCORP) conduct clinical trials across the cancer spectrum. The authors report access to and characteristics of LDCT screening for lung cancer in these community oncology practices.

METHODS: A landscape capacity assessment was conducted in 2017 across the NCORP network. The primary outcome was the proportion of adult oncology practice groups offering LDCT lung screening on site. The secondary outcomes were the proportion of those screening services (1) with radiologist participation in service management and (2) offered at ACR Designated Lung Cancer Screening Centers.

RESULTS: Fifty-two percent of components and subcomponents responded to at least some portion of the assessment, representing 217 practice groups. Analyzing the 211 adult oncology practice groups responding to the primary question, 73% offered lung screening services on site. Radiologists participated in managing 69% of these services. Forty-seven percent were offered in ACR Designated Lung Cancer Screening Centers. Minority and underserved practice groups were less likely to offer lung screening; however, this association dissipated when analyses focused on practices within the United States. Safety net and Critical Access Hospital designation increased the likelihood of screening availability.

CONCLUSIONS: The majority of community oncology practice groups within the NCORP offered lung screening on site, although radiologist participation in service management and ACR Lung Cancer Screening Center designation, markers of service quality, were more variable.

RevDate: 2019-03-01

Bansal A, Sullivan SD, Lin VW, et al (2019)

Estimating Long-Term Survival for Patients with Relapsed or Refractory Large B-cell Lymphoma Treated with Chimeric Antigen Receptor Therapy: A Comparison of Standard and Mixture Cure Models.

Medical decision making : an international journal of the Society for Medical Decision Making [Epub ahead of print].

Patients treated with anti-CD19 chimeric antigen receptor (CAR) T-cell therapies have shown either sustained remission or rapid progression. Traditional survival modeling may underestimate outcomes in these situations, by assuming the same mortality rate for all patients. To illustrate this issue, we compare standard parametric models to mixture cure models for estimating long-term overall survival in patients with relapsed or refractory large B-cell lymphoma treated with axicabtagene ciloleucel (axi-cel). Compared to standard models without cure proportions, mixture cure models have similar fit, but substantially different extrapolated survival. Standard models (Weibull and generalized gamma) estimate mean survival of 2.0 years (95% CI (1.5, 3.0)) and 3.0 years (95% CI (1.7, 5.6)), respectively, compared to 15.7 years (95% CI (9.3, 21.1)) and 17.5 yrs (12.0, 22.8) from mixture cure models (using Weibull and generalized gamme distributions). For cancer therapies where substantial fractions achieve long term remission, our results suggest that assumptions of the modeling approach should be considered. Given sufficient follow-up, mixture cure models may provide a more accurate estimate of long-term overall survival compared with standard models.

RevDate: 2019-03-01

Stoner MCD, Rucinski KB, Edwards JK, et al (2019)

The Relationship Between School Dropout and Pregnancy Among Adolescent Girls and Young Women in South Africa: A HPTN 068 Analysis.

Health education & behavior : the official publication of the Society for Public Health Education [Epub ahead of print].

BACKGROUND: Prevention of both school dropout and teen pregnancy represent clear public health priorities for South Africa, yet their complex and potentially cyclical relationship has not been fully explored.

OBJECTIVE: To further understand how this relationship operates, we analyzed data from a randomized trial of young women aged 13 to 20 years enrolled in school in rural South Africa to estimate the association between pregnancy and subsequent dropout and between dropout and subsequent pregnancy.

METHOD: We examined inverse probability (IP) of exposure-weighted survival curves for school dropout by pregnancy and for pregnancy by school dropout. We used weighted curves to calculate 1-, 2-, and 3-year risk differences and risk ratios. Additionally, we used an IP-weighted marginal structural cox model to estimate a hazard ratio (HR) for each relationship.

RESULTS: Dropout from school was associated with subsequent pregnancy (HR 3.58; 95% confidence interval [CI] [2.04, 6.28]) and pregnancy was associated with subsequent school dropout (HR 2.36; 95% CI [1.29, 4.31]). Young women who attended school but attended fewer days had a higher hazard of pregnancy than those who attended more school (HR 3.64; 95% CI [2.27, 5.84]).

CONCLUSION: Pregnancy is both a cause and a consequence of school dropout. Consideration of school attendance and academic performance could ultimately enhance pregnancy prevention efforts in this population. Programs should be tailored differently for (1) girls who have dropped out of school, (2) those who are in school and at risk for pregnancy, and (3) those who are in school and become pregnant.

RevDate: 2019-02-28

Khanal S, DA Galloway (2019)

High-risk human papillomavirus oncogenes disrupt the Fanconi anemia DNA repair pathway by impairing localization and de-ubiquitination of FancD2.

PLoS pathogens, 15(2):e1007442 pii:PPATHOGENS-D-18-02065 [Epub ahead of print].

Persistent expression of high-risk HPV oncogenes is necessary for the development of anogenital and oropharyngeal cancers. Here, we show that E6/E7 expressing cells are hypersensitive to DNA crosslinking agent cisplatin and have defects in repairing DNA interstrand crosslinks (ICL). Importantly, we elucidate how E6/E7 attenuate the Fanconi anemia (FA) DNA crosslink repair pathway. Though E6/E7 activated the pathway by increasing FancD2 monoubiquitination and foci formation, they inhibited the completion of the repair by multiple mechanisms. E6/E7 impaired FancD2 colocalization with double-strand breaks (DSB), which subsequently hindered the recruitment of the downstream protein Rad51 to DSB in E6 cells. Further, E6 expression caused delayed FancD2 de-ubiquitination, an important process for effective ICL repair. Delayed FancD2 de-ubiquitination was associated with the increased chromatin retention of FancD2 hindering USP1 de-ubiquitinating activity, and persistently activated ATR/CHK-1/pS565 FancI signaling. E6 mediated p53 degradation did not hamper the cell cycle specific process of FancD2 modifications but abrogated repair by disrupting FancD2 de-ubiquitination. Further, E6 reduced the expression and foci formation of Palb2, which is a repair protein downstream of FancD2. These findings uncover unique mechanisms by which HPV oncogenes contribute to genomic instability and the response to cisplatin therapies.

RevDate: 2019-03-08

Ramanathan RK, McDonough SL, Philip PA, et al (2019)

Phase IB/II Randomized Study of FOLFIRINOX Plus Pegylated Recombinant Human Hyaluronidase Versus FOLFIRINOX Alone in Patients With Metastatic Pancreatic Adenocarcinoma: SWOG S1313.

Journal of clinical oncology : official journal of the American Society of Clinical Oncology [Epub ahead of print].

PURPOSE: Pegylated recombinant human hyaluronidase (PEGPH20) degrades hyaluronan (HA) and, in combination with chemotherapy, prolongs survival in preclinical models. The activity of PEGPH20 with modified fluorouracil, leucovorin, irinotecan, and oxaliplatin (mFOLFIRINOX) was evaluated in patients with metastatic pancreatic cancer (mPC).

MATERIALS AND METHODS: Patients had untreated mPC, a performance status of 0 to 1, and adequate organ function. Tumor HA status was not required for eligibility. After a phase Ib dose-finding study of mFOLFIRINOX plus PEGPH20, the phase II open-label study randomly assigned patients (1:1) to the combination arm or to mFOLFIRINOX alone (n = 138). The primary end point was overall survival (OS).

RESULTS: PEGPH20 dosages of 3 µg/kg every 2 weeks were more tolerable than twice-weekly dosages used in the phase I study, so 3 µg/kg every 2 weeks was the phase II dosage. An amendment instituted enoxaparin prophylaxis in the PEGPH20 combination arm as a result of increased thromboembolic (TE) events. The planned interim futility analysis when 35 deaths (of 103 analyzable patients) occurred resulted in an OS hazard ratio (HR) of 2.07 that favored the control arm, and the study was closed to accrual. The treatment-related grade 3 to 4 toxicity was significantly increased in the PEGPH20 combination arm relative to control (odds ratio, 2.7; 95% CI, 1.1 to 7.1). The median OS in the mFOLFIRINOX arm was 14.4 months (95% CI, 10.1 to 15.7 months) versus 7.7 months (95% CI, 4.6 to 9.3 months) in the PEGPH20 combination arm.

CONCLUSION: Addition of PEGPH20 to mFOLFIRINOX seems to be detrimental in patients unselected for tumor HA status. This combination caused increased toxicity (mostly GI and TE events) and resulted in decreased treatment duration compared with mFOLFIRINOX alone. The median OS in the mFOLFIRINOX control arm (14.4 months) is, to our knowledge, the longest yet reported and can be considered for patients with good PS.

RevDate: 2019-02-28

Daniel LC, Wang M, Mulrooney DA, et al (2019)

Sleep, emotional distress, and physical health in survivors of childhood cancer: A report from the Childhood Cancer Survivor Study.

Psycho-oncology [Epub ahead of print].

OBJECTIVE: Sleep disorders are associated with psychological and physical health, though reports in long-term survivors of childhood cancer are limited. We characterized the prevalence and risk factors for behaviors consistent with sleep disorders in survivors and examined longitudinal associations with emotional distress and physical health outcomes.

METHODS: Survivors (n=1933; median [IQR] age=35 [30, 41]) and siblings (n=380; age=33 [27, 40]) from the Childhood Cancer Survivor Study completed measures of sleep quality, fatigue, and sleepiness. Emotional distress and physical health outcomes were assessed approximately five years before and after the sleep survey. Multivariable logistic or modified Poisson regression models examined associations with cancer diagnosis, treatment exposures, and emotional and physical health outcomes.

RESULTS: Survivors were more likely to report poor sleep efficiency (30.8% vs. 24.7%; prevalence ratio [PR]=1.26, 95% confidence interval [1.04-1.53]), daytime sleepiness (18.7% vs. 14.2%; PR=1.31[1.01-1.71]), and sleep supplement use (13.5% vs. 8.3%; PR=1.56[1.09-2.22]) than siblings. Survivors who developed emotional distress were more likely to report poor sleep efficiency (PR=1.70[1.40-2.07]), restricted sleep time (PR=1.35[1.12-1.62]), fatigue (PR=2.11[1.92-2.32]), daytime sleepiness (PR=2.19[1.71-2.82]), snoring (PR=1.85[1.08-3.16]), and more sleep medication (PR=2.86[2.00-4.09]) and supplement use (PR=1.89[1.33-2.69]). Survivors reporting symptoms of insomnia (PR=1.46[1.02-2.08]), fatigue (PR=1.31[1.01-1.72]), and using sleep medications (PR=2.16[1.13-4.12]) were more likely to develop migraines/headaches.

CONCLUSIONS: Survivors report more sleep difficulties and efforts to manage sleep than siblings. These sleep behaviors are related to worsening or persistently elevated emotional distress and may result in increased risk for migraines. Behavioral interventions targeting sleep may be important for improving health outcomes.

RevDate: 2019-02-28

Kanate AS, Kumar A, Dreger P, et al (2019)

Maintenance Therapies for Hodgkin and Non-Hodgkin Lymphomas After Autologous Transplantation: A Consensus Project of ASBMT, CIBMTR, and the Lymphoma Working Party of EBMT.

JAMA oncology pii:2726032 [Epub ahead of print].

Importance: Maintenance therapies are often considered as a therapeutic strategy in patients with lymphoma following autologous hematopoietic cell transplantation (auto-HCT) to mitigate the risk of disease relapse. With an evolving therapeutic landscape, where novel drugs are moving earlier in therapy lines, evidence relevant to contemporary practice is increasingly limited. The American Society for Blood and Marrow Transplantation (ASBMT), Center for International Blood and Marrow Transplant Research (CIBMTR), and European Society for Blood and Marrow Transplantation (EBMT) jointly convened an expert panel with diverse expertise and geographical representation to formulate consensus recommendations regarding the use of maintenance and/or consolidation therapies after auto-HCT in patients with lymphoma.

Observations: The RAND-modified Delphi method was used to generate consensus statements where at least 75% vote in favor of a recommendation was considered as consensus. The process included 3 online surveys moderated by an independent methodological expert to ensure anonymity and an in-person meeting. The panel recommended restricting the histologic categories covered in this project to Hodgkin lymphoma (HL), mantle cell lymphoma (MCL), diffuse large B-cell lymphoma (DLBCL), and follicular lymphoma. On completion of the voting process, the panel generated 22 consensus statements regarding post auto-HCT maintenance and/or consolidation therapies. The grade A recommendations included endorsement of: (1) brentuximab vedotin (BV) maintenance and/or consolidation in BV-naïve high-risk HL, (2) rituximab maintenance in MCL undergoing auto-HCT after first-line therapy, (3) rituximab maintenance in rituximab-naïve FL, and (4) No post auto-HCT maintenance was recommended in DLBCL. The panel also developed consensus statements for important real-world clinical scenarios, where randomized data are lacking to guide clinical practice.

Conclusions and Relevance: In the absence of contemporary evidence-based data, the panel found RAND-modified Delphi methodology effective in providing a rigorous framework for developing consensus recommendations for post auto-HCT maintenance and/or consolidation therapies in lymphoma.

RevDate: 2019-02-28

Conant EF, Barlow WE, Herschorn SD, et al (2019)

Association of Digital Breast Tomosynthesis vs Digital Mammography With Cancer Detection and Recall Rates by Age and Breast Density.

JAMA oncology pii:2726028 [Epub ahead of print].

Importance: Breast cancer screening examinations using digital breast tomosynthesis (DBT) has been shown to be associated with decreased false-positive test results and increased breast cancer detection compared with digital mammography (DM). Little is known regarding the size and stage of breast cancer types detected and their association with age and breast density.

Objective: To determine whether screening examinations using DBT detect breast cancers that are associated with an improved prognosis and to compare the detection rates by patient age and breast density.

This retrospective analysis of prospective cohort data from 3 research centers in the Population-based Research Optimizing Screening Through Personalized Regimens (PROSPR) consortium included data of women aged 40 to 74 years who underwent screening examinations using DM and DBT from January 1, 2011, through September 30, 2014. Statistical analysis was performed from November 8, 2017, to August 14, 2018.

Exposures: Use of DBT as a supplement to DM at breast cancer screening examination.

Main Outcomes and Measures: Recall rate, cancer detection rate, positive predictive value, biopsy rate, and distribution of invasive cancer subtypes.

Results: Among 96 269 women (mean [SD] patient age for all examinations, 55.9 [9.0] years), patient age was 56.4 (9.0) years for DM and 54.6 (8.9) years for DBT. Of 180 340 breast cancer screening examinations, 129 369 examinations (71.7%) used DM and 50 971 examinations (28.3%) used DBT. Screening examination with DBT (73 of 99 women [73.7%]) was associated with the detection of smaller, more often node-negative, HER2-negative, invasive cancers compared with DM (276 of 422 women [65.4%]). Screening examination with DBT was also associated with lower recall (odds ratio, 0.64; 95% CI, 0.57-0.72; P < .001) and higher cancer detection (odds ratio, 1.41; 95% CI, 1.05-1.89; P = .02) compared with DM for all age groups even when stratified by breast density. The largest increase in cancer detection rate and the greatest shift toward smaller, node-negative invasive cancers detected with DBT was for women aged 40 to 49 years. For women aged 40 to 49 years with nondense breasts, the cancer detection rate for examinations using DBT was 1.70 per 1000 women higher compared with the rate using DM; for women with dense breasts, the cancer detection rate was 2.27 per 1000 women higher for DBT. For these younger women, screening with DBT was associated with only 7 of 28 breast cancers (25.0%) categorized as poor prognosis compared with 19 of 47 breast cancers (40.4%) when screening with DM.

Conclusions and Relevance: The findings suggest that screening with DBT is associated with increased specificity and an increased proportion of breast cancers detected with better prognosis compared with DM. In the subgroup of women aged 40 to 49 years, routine DBT screening may have a favorable risk-benefit ratio.

RevDate: 2019-02-28

Kiweewa FM, Brown E, Mishra A, et al (2019)

Acquisition of Sexually Transmitted Infections among Women Using a Variety of Contraceptive Options: A prospective Study among High-risk African Women.

Journal of the International AIDS Society, 22(2):e25257.

INTRODUCTION: In many African settings, women concurrently face substantial risk of human immunodeficiency virus type 1 (HIV-1) infection, sexually transmitted infections (STIs) and unintended pregnancies. Few studies have evaluated STI risk among users of hormonal implants and copper intrauterine devices (IUDs) although these long-acting reversible contraceptive methods are being promoted widely because of their benefits. Within a prospective study of women at risk for HIV-1, we compared the risk of acquisition of Chlamydia trachomatis, Neisseria gonorrhoeae and Trichomonas vaginalis among women using different contraceptive methods.

METHODS: MTN-020/ASPIRE was a randomized trial of the dapivirine vaginal ring for HIV-1 prevention among 2629 women aged 18 to 45 years from Malawi, South Africa, Uganda and Zimbabwe, of whom 2264 used copper IUDs or progestin-based injectables or implants during follow-up. Screening for the above STIs occurred semi-annually.

RESULTS: Over 3440 person-years of follow-up, 408 cases of C. trachomatis (incidence 11.86/100 person-years), 196 of N. gonorrhoeae (5.70/100 person-years) and 213 cases of T. vaginalis (6.19/100 person-years) were detected. C. trachomatis and N. gonorrhoeae incidence were not significantly different across contraceptive methods. T. vaginalis incidence was significantly higher for copper IUD users compared to depot medroxyprogesterone acetate (DMPA), implant and norethisterone enanthate users.

CONCLUSION: Among African women at high HIV-1 risk, STIs were common. Risk of cervical infections did not differ across contraceptive methods. Significantly higher rates of T. vaginalis were observed among progestin-based methods compared to copper IUD users. Overall, these findings call for more intensive routine screening for STIs, and they support current World Health Organization guidance that women should have a wide range of contraceptive options.

RevDate: 2019-02-28

Maloney DG (2019)

Anti-CD19 CAR T cell therapy for lymphoma - off to the races!.

Nature reviews. Clinical oncology pii:10.1038/s41571-019-0183-7 [Epub ahead of print].

RevDate: 2019-03-03

Li AZ, Corey L, J Zhu (2019)

Random-Reaction-Seed Method for Automated Identification of Neurite Elongation and Branching.

Scientific reports, 9(1):2908 pii:10.1038/s41598-019-39962-0.

Conventional deterministic algorithms (i.e., skeletonization and edge-detection) lack robustness and sensitivity to reliably detect the neurite elongation and branching of low signal-to-noise-ratio microscopy images. Neurite outgrowth experiments produce an enormous number of images that require automated measurement; however, the tracking of neurites is easily lost in the automated process due to the intrinsic variability of neurites (either axon or dendrite) under stimuli. We have developed a stochastic random-reaction-seed (RRS) method to identify neurite elongation and branching accurately and automatically. The random-seeding algorithm of RRS is based on the hidden-Markov-model (HMM) to offer a robust enough way for tracing arbitrary neurite structures, while the reaction-seeding algorithm of RRS secures the efficiency of random seeding. It is noteworthy that RRS is capable of tracing a whole neurite branch by only one initial seed, so that RRS is proficient at quantifying extensive amounts of neurite outgrowth images with noisy background in microfluidic devices of biomedical engineering fields. The method also showed notable performance for reconstructing of net-like structures, and thus is expected to be proficient for biomedical feature extractions in a wide range of applications, such as retinal vessel segmentation and cell membrane profiling in spurious-edge-tissues.

RevDate: 2019-02-28

Varelias A, Gartlan KH, Wilkinson AN, et al (2019)

Expansion of IL-17A-secreting CD8+ mucosa-associated invariant T cells in peripheral blood following stem cell mobilization.

Blood advances, 3(5):718-723.

RevDate: 2019-02-27

Richardson LA, Schmid SL, Bhandoola A, et al (2019)

The PLOS Biology XV Collection: 15 Years of Exceptional Science Highlighted across 12 Months.

PLoS biology, 17(2):e3000180 pii:PBIOLOGY-D-19-00349 [Epub ahead of print].

RevDate: 2019-02-27

Inamoto Y, Petriček I, Burns L, et al (2019)

Correction: Non-GVHD ocular complications after hematopoietic cell transplantation: expert review from the Late Effects and Quality of Life Working Committee of the CIBMTR and Transplant Complications Working Party of the EBMT.

In the original version of this article, author 'Aisha Al-Khinji' was incorrectly listed as 'Aisha Ahmed'. This has now been corrected in both the PDF and HTML versions of the article to 'Aisha Al-Khinji'.

RevDate: 2019-03-03

Yeshurun M, Weisdorf D, Rowe JM, et al (2019)

The impact of the graft-versus-leukemia effect on survival in acute lymphoblastic leukemia.

Blood advances, 3(4):670-680.

Allogeneic hematopoietic cell transplant is a potential curative therapy for acute lymphoblastic leukemia (ALL). Delineating the graft-versus-leukemia (GVL) effect as a function of graft-versus-host disease (GVHD) offers the potential to improve survival. We examined 5215 transplant recipients with ALL reported to the Center for International Blood and Marrow Transplant Research registry. Overall survival (OS) was compared according to the presence and severity of GVHD and evaluated in 3 cohorts: 2593 adults in first or second complete remission (CR1/CR2), 1619 pediatric patients in CR1/CR2, and 1003 patients with advanced (CR ≥3 or active disease) ALL. For patients in CR1/CR2, development of acute GVHD (aGVHD) or chronic GVHD (cGVHD) was associated with lower risk of relapse than no GVHD (hazard ratio [HR], 0.49-0.69). Patients with advanced ALL developing grades III and IV aGVHD or cGVHD were also at lower risk of relapse (HRs varied from 0.52 to 0.67). Importantly, adult and children in CR1/CR2 with grades I and II aGVHD without cGVHD experienced the best OS compared with no GVHD (reduction of mortality with HR, 0.83-0.76). Increased nonrelapse mortality accompanied grades III and IV aGVHD (HRs varied from 2.69 to 3.91) in all 3 cohorts and abrogated any protection from relapse, resulting in inferior OS. Patients with advanced ALL had better OS (reduction in mortality; HR, 0.69-0.73) when they developed cGVHD with or without grades I and II aGVHD. In conclusion, GVHD was associated with an increased GVL effect in ALL. GVL exerted a net beneficial effect on OS only if associated with low-grade aGVHD in CR1/CR2 or with cGVHD in advanced ALL.

RevDate: 2019-02-27

Marcum ZA, Hohl SD, Gray SL, et al (2019)

Brain Health and Dementia Prevention: A Mixed-method Analysis.

American journal of health behavior, 43(2):300-310.

Objective: In this study, we assessed patient knowledge, beliefs, and attitudes about brain health and strategies for Alzheimer's disease and related dementias (ADRD) prevention. Methods: We administered a Web-based survey consisting of 17 questions about brain health and strategies for ADRD prevention in a convenience sample of 1661 patients in an integrated healthcare delivery system in Washington state between February and March 2018. We calculated frequency distributions of the quantitative data and conducted inductive content analysis of qualitative data. Results: Most respondents were female (77%), 51-70 years of age (64%), and white (89%). Although most agreed it is possible to improve brain health and reduce personal ADRD risk, one- third lacked confidence that they could take action to reduce personal ADRD risk. Participants' responses to open-ended questions revealed 10 themes grouped into 3 organizing categories regarding their perceptions about how to prevent ADRD onset: (1) understand ADRD; (2) stay engaged; and (3) manage one's own health and healthcare. Conclusions: Survey respondents were engaged and aware of dementia prevention, but they lacked access to personally action- able evidence..

RevDate: 2019-02-28

Xue KS, JD Bloom (2019)

Reconciling disparate estimates of viral genetic diversity during human influenza infections.

RevDate: 2019-02-28

Godwin CD, Fromm JR, Othus M, et al (2019)

Pre-transplant bone marrow monocytic myeloid-derived suppressor cell frequency is not associated with outcome after allogeneic hematopoietic cell transplantation for acute myeloid leukemia in remission.

RevDate: 2019-02-25

Mossavar-Rahmani Y, Kamensky V, Manson JE, et al (2019)

Artificially Sweetened Beverages and Stroke, Coronary Heart Disease, and All-Cause Mortality in the Women's Health Initiative.

Stroke, 50(3):555-562.

Background and Purpose- We examine the association between self-reported consumption of artificially sweetened beverages (ASB) and stroke and its subtypes, coronary heart disease, and all-cause mortality in a cohort of postmenopausal US women. Methods- The analytic cohort included 81 714 women from the Women's Health Initiative Observational Study, a multicenter longitudinal study of the health of 93 676 postmenopausal women of ages 50 to 79 years at baseline who enrolled in 1993 to 1998. This prospective study had a mean follow-up time of 11.9 years (SD of 5.3 years.) Participants who completed a follow-up visit 3 years after baseline were included in the study. Results- Most participants (64.1%) were infrequent consumers (never or <1/week) of ASB, with only 5.1% consuming ≥2 ASBs/day. In multivariate analyses, those consuming the highest level of ASB compared to never or rarely (<1/wk) had significantly greater likelihood of all end points (except hemorrhagic stroke), after controlling for multiple covariates. Adjusted models indicated that hazard ratios and 95% confidence intervals were 1.23 (1.02-1.47) for all stroke; 1.31 (1.06-1.63) for ischemic stroke; 1.29 (1.11-1.51) for coronary heart disease; and 1.16 (1.07-1.26) for all-cause mortality. In women with no prior history of cardiovascular disease or diabetes mellitus, high consumption of ASB was associated with more than a 2-fold increased risk of small artery occlusion ischemic stroke hazard ratio =2.44 (95% confidence interval, 1.47-4.04.) High consumption of ASBs was associated with significantly increased risk of ischemic stroke in women with body mass index ≥30; hazard ratio =2.03 (95% confidence interval, 1.38-2.98). Conclusions- Higher intake of ASB was associated with increased risk of stroke, particularly small artery occlusion subtype, coronary heart disease, and all-cause mortality. Although requiring replication, these new findings add to the potentially harmful association of consuming high quantities of ASB with these health outcomes.

RevDate: 2019-02-25

Zhao W, Zheng J, Chen YQ, et al (2019)

Adjusted time-varying population attributable hazard in case-control studies.

Statistical methods in medical research [Epub ahead of print].

Population attributable fraction is a widely used measure for quantifying the disease burden associated with a modifiable exposure of interest at the population level. It has been extended to a time-varying measure, population attributable hazard function, to provide additional information on when and how the exposure's impact varies over time. However, like the classic population attributable fraction, the population attributable hazard is generally biased if confounders are present. In this article, we provide a natural definition of adjusted population attributable hazard to take into account the effects of confounders, and its alternative that is identifiable from case-control studies under the rare disease assumption. We propose a novel estimator, which combines the odds ratio estimator from logistic regression model, and the conditional density function estimator of the exposure and confounding variables distribution given the failure times of cases or the current times of controls from a kernel smoother. We show that the proposed estimators are consistent and asymptotically normal with variance that can be estimated empirically from the data. Simulation studies demonstrate that the proposed estimators perform well in finite sample sizes. Finally, we illustrate the method by an analysis of a case-control study of colorectal cancer. Supplementary materials for this article are available online.

RevDate: 2019-02-25

McKean M, Oba J, Ma J, et al (2019)

Tyrosine Kinase Inhibitor and Immune Checkpoint Inhibitor Responses in KIT-Mutant Metastatic Melanoma.

The Journal of investigative dermatology, 139(3):728-731.

RevDate: 2019-02-24

Marshall CH, Sokolova AO, McNatty AL, et al (2019)

Differential Response to Olaparib Treatment Among Men with Metastatic Castration-resistant Prostate Cancer Harboring BRCA1 or BRCA2 Versus ATM Mutations.

European urology pii:S0302-2838(19)30110-1 [Epub ahead of print].

BACKGROUND: Poly ADP-ribose polymerase (PARP) inhibitors, such as olaparib, are being explored as a treatment option for metastatic castration-resistant prostate cancer (mCRPC) in men harboring mutations in homologous recombination DNA-repair genes. Whether responses to PARP inhibitors differ according to the affected gene is currently unknown.

OBJECTIVE: To determine whether responses to PARP inhibitors differ between men with BRCA1/2 and those with ATM mutations.

This was a multicenter retrospective review of 23 consecutive men with mCRPC and pathogenic germline and/or somatic BRCA1/2 or ATM mutations treated with olaparib at three academic sites in the USA.

The proportion of patients achieving a ≥50% decline in prostate-specific antigen (PSA50 response) was compared using Fisher's exact test. Clinical and radiographic progression-free survival (PFS) and overall survival were estimated using Kaplan-Meier analyses and compared using the log-rank test.

RESULTS AND LIMITATIONS: The study included two men with BRCA1 mutations, 15 with BRCA2 mutations, and six with ATM mutations. PSA50 responses to olaparib were achieved in 76% (13/17) of men with BRCA1/2 versus 0% (0/6) of men with ATM mutations (Fisher's exact test; p=0.002). Patients with BRCA1/2 mutations had median PFS of 12.3mo versus 2.4mo for those with ATM mutations (hazard ratio 0.17, 95% confidence interval 0.05-0.57; p=0.004). Limitations include the retrospective design and relatively small sample size.

CONCLUSIONS: Men with mCRPC harboring ATM mutations experienced inferior outcomes to PARP inhibitor therapy compared to those harboring BRCA1/2 mutations. Alternative therapies should be explored for patients with ATM mutations.

PATIENT SUMMARY: Mutations in BRCA1/2 and ATM genes are common in metastatic prostate cancer. In this study we compared outcomes for men with BRCA1/2 mutations to those for men with ATM mutations being treated with olaparib. We found that men with ATM mutations do not respond as well as men with BRCA1/2 mutations.

RevDate: 2019-02-22

Kilari D, D'Souza A, Fraser R, et al (2019)

Autologous Transplantation for Male Germ Cell Tumors: Improved Outcomes over 3 decades.

Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation pii:S1083-8791(19)30140-5 [Epub ahead of print].

PURPOSE: The curative potential of autologous hematopoietic cell transplantation (autoHCT) for male germ cell tumors (GCT) is well established. Optimal timing and number (single, ST vs. tandem, TT vs. three) of autoHCT are controversial with wide practice variation.

PATIENTS AND METHODS: We examined survival trends among 2,395 recipients of autoHCT for male GCT between 1990-2015 reported to the Center for International Blood and Marrow Transplant Research. Trends and outcomes were analyzed by year of transplant for intervals 1990-94 (N = 288), 1995-99 (N = 351), 2000-04 (N = 376), 2005-09 (N = 509) and 2010-15 (N = 871). Multivariate analysis was restricted to the subset from 2000-2015 (n = 267) with research level data.

RESULTS: Median follow up was 51 months. Median age at autoHCT was 31 years; 633(26%) had primary extragonadal GCT and 1,167 (49%) underwent TT. The 3-year progression-free (PFS) and overall survival (OS) improved from 24 (18-31)% and 35 (29-40)% in 1990-94 to 47 (43-50)% and 54 (50-57)% in 2010-15 (p < 0.0001), respectively. TT recipients were more likely to undergo autoHCT as first salvage treatment than ST recipients. The proportion of TT increased from 38% of all autoHCT in 2000-04 to 77% in 2010-15. Non-seminoma histology, residual disease at autoHCT, > 1 line of pre-transplant chemotherapy and ST versus TT were associated with inferior PFS and OS.

CONCLUSIONS: Post-transplant survival has improved significantly over time for relapsed/refractory male GCT and was associated with the increased use of TT (compared with ST) and earlier autoHCT in the disease course.

RevDate: 2019-02-22

Cohen JA, Baldassari LE, Atkins HL, et al (2019)

AUTOLOGOUS HEMATOPOIETIC CELL TRANSPLANTATION FOR TREATMENT-REFRACTORY RELAPSING MULTIPLE SCLEROSIS: POSITION STATEMENT FROM THE AMERICAN SOCIETY FOR BLOOD AND MARROW TRANSPLANTATION.

Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation pii:S1083-8791(19)30139-9 [Epub ahead of print].

Multiple sclerosis (MS) is a chronic, disabling, immune-mediated, central nervous system demyelinating and degenerative disease. Approved disease modifying therapies may be incompletely effective in some patients with highly active relapsing disease and high risk of disability. Immunoablative or myeloablative therapy followed by autologous hematopoietic cell transplantation (AHCT) has been investigated in retrospective studies, clinical trials, and meta-analyses/systematic reviews as an approach to address this unmet clinical need. On behalf of the American Society for Blood and Bone Marrow Transplantation (ASBMT), a panel of experts in AHCT and MS convened to review available evidence and make recommendations on MS as an indication for AHCT. Review of recent literature identified eight retrospective studies, eight clinical trials, and three meta-analyses/systematic reviews. In aggregate, these studies indicate that AHCT is an efficacious and safe treatment for active relapsing forms of MS to prevent clinical relapses, MRI lesion activity, and disability worsening, and to reverse disability, without unexpected adverse events. Based on the available evidence, the ASBMT recommends that treatment-refractory relapsing MS with high risk of future disability be considered a "standard of care, clinical evidence available" indication for AHCT. Collaboration of neurologists with expertise in treating MS and transplant physicians with experience performing AHCT for autoimmune disease is crucial for appropriate patient selection and optimizing transplant procedures to improve patient outcomes. Transplant centers in the United States and Canada are strongly encouraged to report baseline and outcomes data on patients receiving AHCT for multiple sclerosis to the Center for International Blood and Marrow Transplant Research.

RevDate: 2019-02-22

Moon AM, Weiss NS, Beste LA, et al (2019)

Reply.

RevDate: 2019-02-22

Leeman J, Askelson N, Ko LK, et al (2019)

Understanding the processes that Federally Qualified Health Centers use to select and implement colorectal cancer screening interventions: a qualitative study.

Translational behavioral medicine pii:5363222 [Epub ahead of print].

Colorectal cancer (CRC) screening is highly effective at reducing cancer-related morbidity and mortality, yet screening rates remain suboptimal. Evidence-based interventions can increase screening rates, particularly when they target multiple levels (e.g., patients, providers, health care systems). However, effective interventions remain underutilized. Thus, there is a pressing need to build capacity to select and implement multilevel CRC screening interventions. We report on formative research aimed at understanding how Federally Qualified Health Center (FQHC) staff select and implement CRC screening interventions, which will inform development of capacity-building strategies. We report the qualitative findings from a study that used a mixed methods design, starting with a quantitative survey followed by a qualitative study. In-depth interviews were conducted with 28 staff from 14 FQHCs in 8 states. The Consolidated Framework for Implementation Research (CFIR) guided interview questions and data analysis. Related to the CFIR process domain, few respondents described conducting formal assessments of factors contributing to low screening rates prior to planning their interventions. Many described engaging champions, implementation leaders, and external change agents. Few described a systematic approach to executing implementation plans beyond conducting plan-do-study-act cycles. Reflection and evaluation consisted primarily of reviewing Uniform Data System performance measures. Findings also include themes related to factors influencing these implementation processes. Although FQHCs are implementing CRC screening interventions, they are not actively targeting the multilevel factors influencing their CRC screening rates. Our findings on gaps in FQHCs' implementation processes will inform development of strategies to build capacity to select and implement multilevel CRC screening interventions.

RevDate: 2019-03-06

Hart SFM, Mi H, Green R, et al (2019)

Uncovering and resolving challenges of quantitative modeling in a simplified community of interacting cells.

PLoS biology, 17(2):e3000135 pii:PBIOLOGY-D-18-00513.

Quantitative modeling is useful for predicting behaviors of a system and for rationally constructing or modifying the system. The predictive power of a model relies on accurate quantification of model parameters. Here, we illustrate challenges in parameter quantification and offer means to overcome these challenges, using a case example in which we quantitatively predict the growth rate of a cooperative community. Specifically, the community consists of two Saccharomyces cerevisiae strains, each engineered to release a metabolite required and consumed by its partner. The initial model, employing parameters measured in batch monocultures with zero or excess metabolite, failed to quantitatively predict experimental results. To resolve the model-experiment discrepancy, we chemically identified the correct exchanged metabolites, but this did not improve model performance. We then remeasured strain phenotypes in chemostats mimicking the metabolite-limited community environments, while mitigating or incorporating effects of rapid evolution. Almost all phenotypes we measured, including death rate, metabolite release rate, and the amount of metabolite consumed per cell birth, varied significantly with the metabolite environment. Once we used parameters measured in a range of community-like chemostat environments, prediction quantitatively agreed with experimental results. In summary, using a simplified community, we uncovered and devised means to resolve modeling challenges that are likely general to living systems.

RevDate: 2019-02-22

Thill M, Thatcher N, Hanes V, et al (2019)

Biosimilars: what the oncologist should know.

Future oncology (London, England) [Epub ahead of print].

As originator biologic medicines lose patent protection, some biopharmaceutical companies are focusing on developing similar versions of these costly and complex therapies with a goal of providing more affordable treatment options. Many of these molecules, known as biosimilars, are now approved worldwide and several more are expected to be introduced in the near future. As more biosimilars become available, it is important for clinicians to become familiar with this new category of products and understand how biosimilars are developed, how their development differs from that of originator biologics and how they differ from generics. This review aims to provide the practicing clinician with the knowledge needed to understand biosimilars, along with some guidance on their use in treating oncologic diseases.

RevDate: 2019-02-27

Acharya UH, Dhawale T, Yun S, et al (2019)

Management of cytokine release syndrome and neurotoxicity in chimeric antigen receptor T-cell therapy.

Expert review of hematology [Epub ahead of print].

INTRODUCTION: Chimeric antigen receptor (CAR) T cell immunotherapy has demonstrated remarkable anti-tumor activity in B-cell malignancies and is under investigation in other hematologic malignancies and solid tumors. While highly efficacious, post-infusion T cell activity often results in massive cytokine release precipitating cytokine release syndrome (CRS), the signature toxicity of CAR T cells. This toxicity is characterized by systemic immune activation resulting in fever, hypotension, respiratory insufficiency and capillary leak. Either in conjunction with or in the absence of CRS, a subset of patients may also develop mild to severe neurotoxicity. Although the precise pathogenesis of CRS and neurotoxicity aren't fully elucidated, risk factors and mitigation strategies have been reported. Areas covered: This manuscript provides an in-depth overview of the pathogenesis, clinical characteristics, current toxicity management strategies, and future perspectives pertaining to CRS and neurotoxicity. Expert Opinion: As CAR T cell based therapies gain popularity in the management of various malignancies, the complimentary toxicities of CRS and neurotoxicity pose a clinical challenge in practice. Risk adaptive modeling incorporating disease profile, patient demographics, lymphodepletion, cell dosing, CAR T construct, and potentially cytokine gene polymorphisms may be instructive to asses individualized risk and optimal CRS/neurotoxicity management.

RevDate: 2019-03-06

Hemming ML, Klega KS, Rhoades J, et al (2019)

Detection of Circulating Tumor DNA in Patients With Leiomyosarcoma With Progressive Disease.

JCO precision oncology, 2019:.

Purpose: Leiomyosarcoma (LMS) is a soft tissue sarcoma characterized by multiple copy number alterations (CNAs) and without common recurrent single nucleotide variants. We evaluated the feasibility of detecting circulating tumor DNA (ctDNA) with next-generation sequencing in a cohort of patients with LMS whose tumor burden ranged from no evidence of disease to metastatic progressive disease.

Patients and Methods: Cell-free DNA in plasma samples and paired genomic DNA from resected tumors were evaluated from patients with LMS by ultra-low passage whole genome sequencing (ULP-WGS). Sequencing reads were aligned to the human genome and CNAs identified in cell-free DNA and tumor DNA by ichorCNA software to determine the presence of ctDNA. Clinical data were reviewed to assess disease burden and clinicopathologic features.

Results: We identified LMS ctDNA in eleven of sixteen patients (69%) with disease progression and total tumor burden over 5 cm. Sixteen patients with stable disease or low disease burden at the time of blood draw were found to have no detectable ctDNA. Higher ctDNA fraction of total cell-free DNA was associated with increasing tumor size and disease progression. Conserved CNAs were found between primary tumors and ctDNA in each case, and recurrent CNAs were found across LMS samples. ctDNA levels declined following resection of progressive disease in one case and became detectable upon disease relapse in another individual patient.

Conclusion: These results suggest that ctDNA, assayed by a widely available sequencing approach, may be useful as a biomarker for a subset of uterine and extrauterine LMS. Higher levels of ctDNA correlate with tumor size and disease progression. Liquid biopsies may assist in guiding treatment decisions, monitoring response to systemic therapy, surveying for disease recurrence and differentiating benign and malignant smooth muscle tumors.

RevDate: 2019-03-01

Lin J, Xue X, Anastos K, et al (2019)

Elevated Microparticle Tissue Factor Activity is Associated with Carotid Artery Plaque in HIV Infected Women.

Journal of acquired immune deficiency syndromes (1999) [Epub ahead of print].

BACKGROUND: Expression of tissue factor (TF) on the surface of activated monocytes may trigger thrombosis, leading to clotting risk, inflammation, and atherosclerosis. TF-positive microparticles (MP-TF) represent a functionally active form of TF that may be promulgated by long-term HIV infection. We hypothesized that greater MP-TF activity is associated with carotid artery plaque in HIV+ women.

SETTING: In a case-control study nested within the Women's Interagency HIV Study (WIHS), eligible HIV+ participants underwent B-mode carotid artery ultrasound at 2 study visits occurring 7 years apart. Cases were defined by presence of at least 1 carotid artery plaque assessed at either visit. Cases were matched 1:2 to controls who were found not to have carotid artery plaques.

METHODS: Conditional logistic regression estimated the association of MP-TF activity with presence of carotid artery plaque, adjusting for demographic and behavioral characteristics, HIV-related factors, cardiometabolic risk factors, and serum inflammation biomarkers (hsCRP, IL-6, sCD14, sCD163, Gal-3, Gal-3BP).

RESULTS: Elevated MP-TF activity (>0.537 pg/mL) was found to be significantly associated with greater odds of plaque (adjusted odds ratio 3.86, 95% CI 1.06-14.07, p=0.04). The association was attenuated after further adjustment for IL-6, but was unaffected by adjustment for other biomarkers including those denoting monocyte activation.

CONCLUSIONS: Our findings suggest a link among HIV infection, innate immune system perturbation, coagulation, and atherosclerosis.

RevDate: 2019-03-02

Sangaramoorthy M, Hines LM, Torres-Mejía G, et al (2019)

A pooled analysis of breast-feeding and breast cancer risk by hormone receptor status in parous Hispanic women.

Epidemiology (Cambridge, Mass.) [Epub ahead of print].

BACKGROUND: Data on breast-feeding and breast cancer risk are sparse and inconsistent for Hispanic women.

METHODS: Pooling data for nearly 6,000 parous Hispanic women from four population-based studies conducted between 1995 and 2007 in the U.S. and Mexico, we examined the association of breast-feeding with risk of breast cancer overall and subtypes defined by estrogen receptor (ER) and progesterone receptor (PR) status, as well as the joint effects of breast-feeding, parity, and age at first birth. We calculated odds ratios (ORs) and 95% confidence intervals (CIs) using logistic regression.

RESULTS: Among parous Hispanic women, older age at first birth was associated with increased breast cancer risk, whereas parity was associated with reduced risk. These associations were found for hormone receptor positive (HR+) breast cancer only and limited to premenopausal women. Age at first birth and parity were not associated with risk of ER-PR- breast cancer. Increasing duration of breast-feeding was associated with decreasing breast cancer risk (≥25 vs. 0 months: OR=0.73, 95% CI=0.60-0.89, Ptrend =0.03), with no heterogeneity by menopausal status or subtype. At each parity level, breast-feeding further reduced HR+ breast cancer risk. Additionally, breast-feeding attenuated the increase in risk of HR+ breast cancer associated with older age at first birth.

CONCLUSIONS: Our findings suggest that breast-feeding is associated with reduced risk of both HR+ and ER-PR- breast cancer among Hispanic women, as reported for other populations, and may attenuate the increased risk in women with a first pregnancy at older ages.

RevDate: 2019-03-01

VanderWeele TJ, Luedtke AR, van der Laan MJ, et al (2019)

Selecting optimal subgroups for treatment using many covariates.

Epidemiology (Cambridge, Mass.) [Epub ahead of print].

We consider the problem of selecting the optimal subgroup to treat when data on covariates is available from a randomized trial or observational study. We distinguish between four different settings including (i) treatment selection when resources are constrained, (ii) treatment selection when resources are not constrained, (iii) treatment selection in the presence of side effects and costs, and (iv) treatment selection to maximize effect heterogeneity. We show that, in each of these cases, the optimal treatment selection rule involves treating those for whom the predicted mean difference in outcomes comparing those with versus without treatment, conditional on covariates, exceeds a certain threshold. The threshold varies across these four scenarios but the form of the optimal treatment selection rule does not. The results suggest a move away from traditional subgroup analysis for personalized medicine. New randomized trial designs are proposed so as to implement and make use of optimal treatment selection rules in health care practice.

RevDate: 2019-03-06

Escala-Garcia M, Guo Q, Dörk T, et al (2019)

Genome-wide association study of germline variants and breast cancer-specific mortality.

British journal of cancer pii:10.1038/s41416-019-0393-x [Epub ahead of print].

BACKGROUND: We examined the associations between germline variants and breast cancer mortality using a large meta-analysis of women of European ancestry.

METHODS: Meta-analyses included summary estimates based on Cox models of twelve datasets using ~10.4 million variants for 96,661 women with breast cancer and 7697 events (breast cancer-specific deaths). Oestrogen receptor (ER)-specific analyses were based on 64,171 ER-positive (4116) and 16,172 ER-negative (2125) patients. We evaluated the probability of a signal to be a true positive using the Bayesian false discovery probability (BFDP).

RESULTS: We did not find any variant associated with breast cancer-specific mortality at P < 5 × 10-8. For ER-positive disease, the most significantly associated variant was chr7:rs4717568 (BFDP = 7%, P = 1.28 × 10-7, hazard ratio [HR] = 0.88, 95% confidence interval [CI] = 0.84-0.92); the closest gene is AUTS2. For ER-negative disease, the most significant variant was chr7:rs67918676 (BFDP = 11%, P = 1.38 × 10-7, HR = 1.27, 95% CI = 1.16-1.39); located within a long intergenic non-coding RNA gene (AC004009.3), close to the HOXA gene cluster.

CONCLUSIONS: We uncovered germline variants on chromosome 7 at BFDP < 15% close to genes for which there is biological evidence related to breast cancer outcome. However, the paucity of variants associated with mortality at genome-wide significance underpins the challenge in providing genetic-based individualised prognostic information for breast cancer patients.

RevDate: 2019-02-24

Fourati S, Ribeiro SP, Blasco Tavares Pereira Lopes F, et al (2019)

Integrated systems approach defines the antiviral pathways conferring protection by the RV144 HIV vaccine.

Nature communications, 10(1):863 pii:10.1038/s41467-019-08854-2.

The RV144 vaccine trial showed reduced risk of HIV-1 acquisition by 31.2%, although mechanisms that led to protection remain poorly understood. Here we identify transcriptional correlates for reduced HIV-1 acquisition after vaccination. We assess the transcriptomic profile of blood collected from 223 participants and 40 placebo recipients. Pathway-level analysis of HIV-1 negative vaccinees reveals that type I interferons that activate the IRF7 antiviral program and type II interferon-stimulated genes implicated in antigen-presentation are both associated with a reduced risk of HIV-1 acquisition. In contrast, genes upstream and downstream of NF-κB, mTORC1 and host genes required for viral infection are associated with an increased risk of HIV-1 acquisition among vaccinees and placebo recipients, defining a vaccine independent association with HIV-1 acquisition. Our transcriptomic analysis of RV144 trial samples identifies IRF7 as a mediator of protection and the activation of mTORC1 as a correlate of the risk of HIV-1 acquisition.

RevDate: 2019-02-27
CmpDate: 2019-02-27

Khorana AA, Soff GA, Kakkar AK, et al (2019)

Rivaroxaban for Thromboprophylaxis in High-Risk Ambulatory Patients with Cancer.

The New England journal of medicine, 380(8):720-728.

BACKGROUND: Ambulatory patients receiving systemic cancer therapy are at varying risk for venous thromboembolism. However, the benefit of thromboprophylaxis in these patients is uncertain.

METHODS: In this double-blind, randomized trial involving high-risk ambulatory patients with cancer (Khorana score of ≥2, on a scale from 0 to 6, with higher scores indicating a higher risk of venous thromboembolism), we randomly assigned patients without deep-vein thrombosis at screening to receive rivaroxaban (at a dose of 10 mg) or placebo daily for up to 180 days, with screening every 8 weeks. The primary efficacy end point was a composite of objectively confirmed proximal deep-vein thrombosis in a lower limb, pulmonary embolism, symptomatic deep-vein thrombosis in an upper limb or distal deep-vein thrombosis in a lower limb, and death from venous thromboembolism and was assessed up to day 180. In a prespecified supportive analysis involving the same population, the same end point was assessed during the intervention period (first receipt of trial agent to last dose plus 2 days). The primary safety end point was major bleeding.

RESULTS: Of 1080 enrolled patients, 49 (4.5%) had thrombosis at screening and did not undergo randomization. Of the 841 patients who underwent randomization, the primary end point occurred in 25 of 420 patients (6.0%) in the rivaroxaban group and in 37 of 421 (8.8%) in the placebo group (hazard ratio, 0.66; 95% confidence interval [CI], 0.40 to 1.09; P = 0.10) in the period up to day 180. In the prespecified intervention-period analysis, the primary end point occurred in 11 patients (2.6%) in the rivaroxaban group and in 27 (6.4%) in the placebo group (hazard ratio, 0.40; 95% CI, 0.20 to 0.80). Major bleeding occurred in 8 of 405 patients (2.0%) in the rivaroxaban group and in 4 of 404 (1.0%) in the placebo group (hazard ratio, 1.96; 95% CI, 0.59 to 6.49).

CONCLUSIONS: In high-risk ambulatory patients with cancer, treatment with rivaroxaban did not result in a significantly lower incidence of venous thromboembolism or death due to venous thromboembolism in the 180-day trial period. During the intervention period, rivaroxaban led to a substantially lower incidence of such events, with a low incidence of major bleeding. (Funded by Janssen and others; CASSINI ClinicalTrials.gov number, NCT02555878.).

RevDate: 2019-02-20

Todd JL, Hill JA, GS Cheng (2019)

Herpesviruses: Silent Instigators of Lung Injury after Hematopoietic Cell Transplant.

American journal of respiratory and critical care medicine [Epub ahead of print].

RevDate: 2019-02-20

Beieler A, Magaret A, Zhou Y, et al (2019)

Outpatient Parenteral Antimicrobial Therapy in Vulnerable Populations-- People Who Inject Drugs and the Homeless.

Journal of hospital medicine, 14(2):105-109.

Outpatient parenteral antimicrobial therapy (OPAT) programs can provide high-value care but may be challenging in people who inject drugs (PWID) and homeless individuals. We conducted a single-center, retrospective, cohort study of adults who received OPAT at an urban, public health hospital from January 1, 2015 to April 30, 2016, grouped by PWID and housing status. Outcomes included clinical cure, length of stay, secondary bacteremia, line-tampering, and readmission. A total of 596 patients (homeless PWID (9%), housed PWID (8%), homeless non-PWID (8%), and housed non-PWID (75%), received OPAT. Assuming that patients lost to follow-up failed therapy, homeless PWID were least likely to achieve cure compared with housed non-PWID, (odds ratio [OR] = 0.33, 95% CI 0.18-0.59; P < .001). Housed PWID were also less likely to achieve cure (OR = 0.37, 95% CI 0.20-0.67; P = .001). Cure rates did not differ in patients not lost to follow-up. OPAT can be effective in PWID and the homeless, but loss to follow-up is a significant barrier.

RevDate: 2019-03-05

Deng N, Li M, Shen D, et al (2019)

LRP1 receptor-mediated immunosuppression of α-MMC on monocytes.

International immunopharmacology, 70:80-87 pii:S1567-5769(19)30176-6 [Epub ahead of print].

Alpha-MMC is a type I ribosome-inactivating protein purified from bitter gourd that has strong anti-tumour and antiviral activity. Alpha-MMC also has immunosuppressive effects, but the mechanism of these immunosuppressive effects remains unclear. It is reported that the binding of α-MMC to its specific cell membrane LRP1 receptor is key to its biological effects. In this study, we investigated the effect of α-MMC on cytotoxicity and cytokine release regulation in three immune cells, human monocyte THP-1 cells, B-lymphocyte WIL2 cells and T-lymphocyte H9 cells, and explored the correlation between this effect and LRP1 receptor distribution on these three cell types. We demonstrate that α-MMC has a significant effect of apoptosis induction and cytokine release in THP-1 cells but has no effect on WIL2-S and H9 cells. Specifically, at a non-cytotoxic dose (80 μg/ml), α-MMC regulates THP-1 cells by inhibiting IL-1β, IL-2, IL-8, IL-9, IL-12, MIP-1α/β, MCP-1 and TNF-α expression and enhancing IL-1ra and RANTES expression, resulting in the inhibition of cellular immune function. Subsequent experiments showed that the cytokine expression regulated by α-MMC can be blocked by silencing the LRP1 receptor of α-MMC. Further research indicated that phosphorylation of 9 signalling proteins of the MAPK pathway was significantly regulated by α-MMC and was blocked by LRP1 silencing. We conclude that the regulation of cytokine expression induced by α-MMC in monocyte THP-1 cells is mediated by the LRP1 receptor, likely via the MAPK signalling pathway. Our results suggest that the inhibition effect on monocytes/macrophages mediates the immunosuppressive function of α-MMC. Due to the selective cytotoxicity and cytokine release regulation of α-MMC in monocytes/macrophages, α-MMC may be used for killing Tumour-Associated Macrophages (M2 subtypes) or inhibiting their cytokine release in the tumour microenvironment.

RevDate: 2019-03-07

Hirayama AV, CJ Turtle (2019)

Toxicities of CD19 CAR-T cell immunotherapy.

American journal of hematology [Epub ahead of print].

CD19-targeted chimeric antigen receptor (CAR)-modified T (CAR-T) cell immunotherapy has demonstrated impressive results in B-cell malignancies, and CAR-T cell therapies targeting other antigens are in development for other cancers. Cytokine release syndrome (CRS) and neurotoxicity can be life-threatening in a subset of patients. The severity of CRS and neurotoxicity can be impacted by the disease burden, lymphodepletion regimen, and CAR-T cell dose. Tocilizumab and corticosteroids have been used to manage these toxicities, enabling CD19 CAR-T cells to be administered without obvious compromise in efficacy. Consensus criteria for grading and managing toxicities will facilitate the widespread application of this treatment modality.

RevDate: 2019-03-08

Hirayama AV, Gauthier J, Hay KA, et al (2019)

The response to lymphodepletion impacts PFS in aggressive non-Hodgkin lymphoma patients treated with CD19 CAR-T cells.

Blood pii:blood-2018-11-887067 [Epub ahead of print].

Factors associated with durable remission after CD19 chimeric antigen receptor (CAR)-modified T cell immunotherapy for aggressive B-cell non-Hodgkin lymphoma (NHL) have not been identified. We report multivariable analyses of factors impacting response and progression-free survival (PFS) in aggressive NHL patients treated with cyclophosphamide and fludarabine (Cy/Flu) lymphodepletion followed by 2x106 CD19 CAR-T cells/kg. The best overall response rate (ORR) was 51%, with 40% of patients achieving complete remission (CR). The median PFS of aggressive NHL patients who achieved CR was 20.0 months (median follow-up 26.9 months). Multivariable analysis of clinical and treatment characteristics, serum biomarkers, and CAR-T cell manufacturing and pharmacokinetic data showed that a lower pre-lymphodepletion serum LDH and a favorable cytokine profile, defined as serum day 0 MCP-1 and peak IL-7 concentrations above the median, were associated with better PFS. MCP-1 and IL-7 concentrations increased after lymphodepletion and higher intensity of Cy/Flu lymphodepletion was associated with higher probability of a favorable cytokine profile. PFS was superior in patients who received high-intensity lymphodepletion and achieved a favorable cytokine profile compared to those who received the same intensity of lymphodepletion without achieving a favorable cytokine profile. Even in high-risk patients with pre-lymphodepletion serum LDH above normal, a favorable cytokine profile after lymphodepletion was associated with a low risk of a PFS event. Strategies to augment the cytokine response to lymphodepletion could be tested in future studies of CD19 CAR-T cell immunotherapy for aggressive B-cell NHL.

RevDate: 2019-03-09

Williams KL, Stumpf M, Naiman NE, et al (2019)

Identification of HIV gp41-specific antibodies that mediate killing of infected cells.

PLoS pathogens, 15(2):e1007572 pii:PPATHOGENS-D-18-01942.

Antibodies that mediate killing of HIV-infected cells through antibody-dependent cellular cytotoxicity (ADCC) have been implicated in protection from HIV infection and disease progression. Despite these observations, these types of HIV antibodies are understudied compared to neutralizing antibodies. Here we describe four monoclonal antibodies (mAbs) obtained from one individual that target the HIV transmembrane protein, gp41, and mediate ADCC activity. These four mAbs arose from independent B cell lineages suggesting that in this individual, multiple B cell responses were induced by the gp41 antigen. Competition and phage peptide display mapping experiments suggested that two of the mAbs target epitopes in the cysteine loop that are highly conserved and a common target of HIV gp41-specific antibodies. The amino acid sequences that bind these mAbs are overlapping but distinct. The two other mAbs were competed by mAbs that target the C-terminal heptad repeat (CHR) and the fusion peptide proximal region (FPPR) and appear to both target a similar unique conformational epitope. These gp41-specific mAbs mediated killing of infected cells that express high levels of Env due to either pre-treatment with interferon or deletion of vpu to increase levels of BST-2/Tetherin. They also mediate killing of target cells coated with various forms of the gp41 protein, including full-length gp41, gp41 ectodomain or a mimetic of the gp41 stump. Unlike many ADCC mAbs that target HIV gp120, these gp41-mAbs are not dependent on Env structural changes associated with membrane-bound CD4 interaction. Overall, the characterization of these four new mAbs that target gp41 and mediate ADCC provides evidence for diverse gp41 B cell lineages with overlapping but distinct epitopes within an individual. Such antibodies that can target various forms of envelope protein could represent a common response to a relatively conserved HIV epitope for a vaccine.

RevDate: 2019-03-09

Marceau West R, Lu W, Rotroff DM, et al (2019)

Identifying individual risk rare variants using protein structure guided local tests (POINT).

PLoS computational biology, 15(2):e1006722 pii:PCOMPBIOL-D-18-01123.

Rare variants are of increasing interest to genetic association studies because of their etiological contributions to human complex diseases. Due to the rarity of the mutant events, rare variants are routinely analyzed on an aggregate level. While aggregation analyses improve the detection of global-level signal, they are not able to pinpoint causal variants within a variant set. To perform inference on a localized level, additional information, e.g., biological annotation, is often needed to boost the information content of a rare variant. Following the observation that important variants are likely to cluster together on functional domains, we propose a protein structure guided local test (POINT) to provide variant-specific association information using structure-guided aggregation of signal. Constructed under a kernel machine framework, POINT performs local association testing by borrowing information from neighboring variants in the 3-dimensional protein space in a data-adaptive fashion. Besides merely providing a list of promising variants, POINT assigns each variant a p-value to permit variant ranking and prioritization. We assess the selection performance of POINT using simulations and illustrate how it can be used to prioritize individual rare variants in PCSK9, ANGPTL4 and CETP in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) clinical trial data.

RevDate: 2019-02-22

Prentice RL, Y Huang (2018)

Nutritional Epidemiology Methods and Related Statistical Challenges and Opportunities.

Statistical theory and related fields, 2(1):2-10.

The public health importance of nutritional epidemiology research is discussed, along with methodologic challenges to obtaining reliable information on dietary approaches to chronic disease prevention. Measurement issues in assessing dietary intake need to be addressed to obtain reliable disease association information. Selfreported dietary data typically incorporate major random and systematic biases. In-take biomarkers offer potential for more reliable analyses, but biomarkers have been established only for a few dietary variables, and these may be too expensive to apply to all participants in large epidemiologic cohorts. A possible way forward involves additional nutritional biomarker development using high-dimensional metabolomic profiling, using blood and urine specimens, in conjunction with further development of statistical approaches for accommodating measurement error with failure time response data. Statisticians have the opportunity to contribute greatly to worldwide public health through the development of statistical methods to address these nutritional epidemiology research challenges, as is elaborated in this contribution.

RevDate: 2019-03-01

Justice AE, Karaderi T, Highland HM, et al (2019)

Protein-coding variants implicate novel genes related to lipid homeostasis contributing to body-fat distribution.

Nature genetics, 51(3):452-469.

Body-fat distribution is a risk factor for adverse cardiovascular health consequences. We analyzed the association of body-fat distribution, assessed by waist-to-hip ratio adjusted for body mass index, with 228,985 predicted coding and splice site variants available on exome arrays in up to 344,369 individuals from five major ancestries (discovery) and 132,177 European-ancestry individuals (validation). We identified 15 common (minor allele frequency, MAF ≥5%) and nine low-frequency or rare (MAF <5%) coding novel variants. Pathway/gene set enrichment analyses identified lipid particle, adiponectin, abnormal white adipose tissue physiology and bone development and morphology as important contributors to fat distribution, while cross-trait associations highlight cardiometabolic traits. In functional follow-up analyses, specifically in Drosophila RNAi-knockdowns, we observed a significant increase in the total body triglyceride levels for two genes (DNAH10 and PLXND1). We implicate novel genes in fat distribution, stressing the importance of interrogating low-frequency and protein-coding variants.

RevDate: 2019-02-19

Triplette M, Thayer JH, Pipavath SN, et al (2019)

Poor Uptake of Lung Cancer Screening: Opportunities for Improvement.

Journal of the American College of Radiology : JACR pii:S1546-1440(18)31583-7 [Epub ahead of print].

Lung cancer screening with low-dose chest CT has been demonstrated to reduce lung cancer mortality among a subset of high-risk current and former smokers. Despite randomized trial evidence and widespread guideline recommendations, uptake of lung cancer screening among currently eligible individuals remains poor. Recent studies estimate that less than 5% of all eligible individuals have undergone screening. Moreover, inappropriate screening of ineligible individuals seems to be common, and among those who have been screened, follow-up may also be poor. In this review, the authors examine recent studies demonstrating the current state of suboptimal implementation of lung cancer screening. The authors also introduce both patient- and provider-facing evidence-based interventions that may improve implementation of screening. These include tailored navigation interventions to overcome patient barriers throughout the screening care continuum and interventions to improve the identification of eligible individuals for providers. Further evidence on best practices around the implementation of lung cancer screening is essential to ensure that recent evidence can be translated into practice to improve the early detection of lung cancer for high-risk individuals.

RevDate: 2019-03-01

Buchbinder EI, Dutcher JP, Daniels GA, et al (2019)

Therapy with high-dose Interleukin-2 (HD IL-2) in metastatic melanoma and renal cell carcinoma following PD1 or PDL1 inhibition.

Journal for immunotherapy of cancer, 7(1):49 pii:10.1186/s40425-019-0522-3.

BACKGROUND: Metastatic melanoma (mM) and renal cell carcinoma (mRCC) are often treated with anti-PD-1 based therapy, however not all patients respond and further therapies are needed. High dose interleukin-2 (HD IL-2) can lead to durable responses in a subset of mM and mRCC patients. The efficacy and toxicity of HD IL-2 therapy following anti-PD-1 or anti-PD-L1 therapy have not yet been explored.

METHODS: Reports on mM and mRCC patients who had received HD IL-2 after PD-1 or PD-L1 inhibition were queried from the PROCLAIMSM database. Patient characteristics, toxicity and efficacy were analyzed.

RESULTS: A total of 57 patients (40 mM, 17 mRCC) were treated with high dose IL-2 after PD-1 or PD-L1 inhibition and had data recorded in the PROCLAIM database. The best overall response rate to HD IL-2 was 22.5% for mM (4 complete response (CR), 5 partial responses (PRs)) and 24% for mRCC (2 CRs, 2 PRs). The toxicity related to HD IL-2 observed in these patients was similar to that observed in patients treated with HD IL-2 without prior checkpoint blockade. One patient who had received prior PD-L1 blockade developed drug induced pneumonitis with HD IL-2 requiring steroid therapy.

CONCLUSION: In this retrospective analysis, HD IL-2 therapy displayed durable antitumor activity in mM and mRCC patients who progressed following treatment with PD-1 and PD-L1 inhibition. The toxicities were generally manageable and consistent with expectations from HD IL-2 but physicians should watch for immune related toxicities such as pneumonitis. This analysis supports the development of randomized prospective trials to assess the proper sequencing and combination of immune checkpoint blockade and cytokine therapy.

RevDate: 2019-03-08

Panagopoulou P, Skalkidou A, Marcotte E, et al (2019)

Parental age and the risk of childhood acute myeloid leukemia: results from the Childhood Leukemia International Consortium.

Cancer epidemiology, 59:158-165 pii:S1877-7821(18)30647-7 [Epub ahead of print].

BACKGROUND: Parental age has been associated with several childhood cancers, albeit the evidence is still inconsistent.

AIM: To examine the associations of parental age at birth with acute myeloid leukemia (AML) among children aged 0-14 years using individual-level data from the Childhood Leukemia International Consortium (CLIC) and non-CLIC studies.

MATERIAL/METHODS: We analyzed data of 3182 incident AML cases and 8377 controls from 17 studies [seven registry-based case-control (RCC) studies and ten questionnaire-based case-control (QCC) studies]. AML risk in association with parental age was calculated using multiple logistic regression, meta-analyses, and pooled-effect estimates. Models were stratified by age at diagnosis (infants <1 year-old vs. children 1-14 years-old) and by study design, using five-year parental age increments and controlling for sex, ethnicity, birthweight, prematurity, multiple gestation, birth order, maternal smoking and education, age at diagnosis (cases aged 1-14 years), and recruitment time period.

RESULTS: Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) derived from RCC, but not from the QCC, studies showed a higher AML risk for infants of mothers ≥40-year-old (OR = 6.87; 95% CI: 2.12-22.25). There were no associations observed between any other maternal or paternal age group and AML risk for children older than one year.

CONCLUSIONS: An increased risk of infant AML with advanced maternal age was found using data from RCC, but not from QCC studies; no parental age-AML associations were observed for older children.

RevDate: 2019-02-22

Nishida-Aoki N, TS Gujral (2019)

Emerging approaches to study cell-cell interactions in tumor microenvironment.

Oncotarget, 10(7):785-797 pii:26585.

Cell-cell interactions are of crucial importance for tissue formation, homeostasis, regeneration processes, and immune response. Recent studies underlined contribution of cell-cell interaction in tumor microenvironment (TME) for tumor progression and metastasis. Cancer cells modify the host cells to tumor-supportive traits, and the modified host cells contribute to tumor progression by interacting with cancer cells and further modifying other normal cells. However, the complex interaction networks of cancer cells and host cells remained largely unknown. Recent advances in high throughput microscopy and single cells-based molecular analyses have unlocked a new era for studying cell-cell interactions in the complex tissue microenvironment at the resolution of a single cell. Here, we review various model systems and emerging experimental approaches that are used to study cell-cell interactions focusing on the studies of TME. We discuss strengths and weaknesses of each model system and each experimental approach, and how upcoming approaches can solve current fundamental questions of cell-cell interactions in TME.

RevDate: 2019-02-18

Cato L, de Tribolet-Hardy J, Lee I, et al (2019)

ARv7 Represses Tumor-Suppressor Genes in Castration-Resistant Prostate Cancer.

Cancer cell pii:S1535-6108(19)30042-X [Epub ahead of print].

Androgen deprivation therapy for prostate cancer (PCa) benefits patients with early disease, but becomes ineffective as PCa progresses to a castration-resistant state (CRPC). Initially CRPC remains dependent on androgen receptor (AR) signaling, often through increased expression of full-length AR (ARfl) or expression of dominantly active splice variants such as ARv7. We show in ARv7-dependent CRPC models that ARv7 binds together with ARfl to repress transcription of a set of growth-suppressive genes. Expression of the ARv7-repressed targets and ARv7 protein expression are negatively correlated and predicts for outcome in PCa patients. Our results provide insights into the role of ARv7 in CRPC and define a set of potential biomarkers for tumors dependent on ARv7.

RevDate: 2019-03-08

Grinde KE, Brown LA, Reiner AP, et al (2019)

Genome-wide Significance Thresholds for Admixture Mapping Studies.

American journal of human genetics, 104(3):454-465.

Admixture mapping studies have become more common in recent years, due in part to technological advances and growing international efforts to increase the diversity of genetic studies. However, many open questions remain about appropriate implementation of admixture mapping studies, including how best to control for multiple testing, particularly in the presence of population structure. In this study, we develop a theoretical framework to characterize the correlation of local ancestry and admixture mapping test statistics in admixed populations with contributions from any number of ancestral populations and arbitrary population structure. Based on this framework, we develop an analytical approach for obtaining genome-wide significance thresholds for admixture mapping studies. We validate our approach via analysis of simulated traits with real genotype data for 8,064 unrelated African American and 3,425 Hispanic/Latina women from the Women's Health Initiative SNP Health Association Resource (WHI SHARe). In an application to these WHI SHARe data, our approach yields genome-wide significant p value thresholds of 2.1 × 10-5 and 4.5 × 10-6 for admixture mapping studies in the African American and Hispanic/Latina cohorts, respectively. Compared to other commonly used multiple testing correction procedures, our method is fast, easy to implement (using our publicly available R package), and controls the family-wise error rate even in structured populations. Importantly, we note that the appropriate admixture mapping significance threshold depends on the number of ancestral populations, generations since admixture, and population structure of the sample; as a result, significance thresholds are not, in general, transferable across studies.

RevDate: 2019-02-16

Dahlberg A, F Milano (2019)

Improved survival after cord blood transplantation: single center experience in pediatric patients over a two-decade period.

Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation pii:S1083-8791(19)30135-1 [Epub ahead of print].

RevDate: 2019-02-15

Inskip PD, Veiga LHS, Brenner AV, et al (2019)

Hyperthyroidism Following Radiation Therapy for Childhood Cancer: A Report from the Childhood Cancer Survivor Study.

International journal of radiation oncology, biology, physics pii:S0360-3016(19)30204-4 [Epub ahead of print].

BACKGROUND: The association of hyperthyroidism with exposure to ionizing radiation is poorly understood. This study addresses the risk of hyperthyroidism in relation to incidental therapeutic radiation dose to the thyroid and pituitary glands in a large cohort of survivors of childhood cancer.

METHODS: Utilizing the Childhood Cancer Survivor Study, a cohort of five-year survivors of childhood cancer diagnosed at hospitals in the United States and Canada between 1970 and 1986, the occurrence of hyperthyroidism through 2009 was ascertained among 12,183 survivors based on serial questionnaires. Radiation doses to the thyroid and pituitary glands were estimated from radiotherapy records, and chemotherapy exposures were abstracted from medical records. Binary outcome regression was used to estimate prevalence odds ratios (ORs) for hyperthyroidism at five years from diagnosis of childhood cancer and Poisson regression to estimate incidence rate ratios (RRs) after the first five years.

RESULTS: Survivors reported 179 cases of hyperthyroidism, of which 148 were diagnosed five or more years after their cancer diagnosis. The cumulative proportion of survivors diagnosed with hyperthyroidism by 30 years after the cancer diagnosis was 2.5% (95% CI: 2.0-2.9) among those who received radiotherapy. A linear relation adequately described the thyroid radiation dose-response for prevalence of self-reported hyperthyroidism five years after cancer diagnosis (excess OR/Gy=0.24; 95% CI: 0.06-0.95) and incidence rate thereafter (excess RR/Gy = 0.06; 95% CI: 0.03-0.14) over the dose range of 0-63 Gy. Neither radiation dose to the pituitary gland nor chemotherapy was associated significantly with hyperthyroidism. Radiation-associated risk remained elevated > 25 years after exposure.

CONCLUSIONS: Risk of hyperthyroidism following radiotherapy during childhood is positively associated with external radiation dose to the thyroid gland, with radiation-related excess risks persisting for > 25 years. Neither radiation dose to the pituitary gland nor chemotherapy exposures were associated with hyperthyroidism among childhood cancer survivors through early adulthood.

RevDate: 2019-03-01

Wheeler DP, Fields SD, Beauchamp G, et al (2019)

Pre-exposure prophylaxis initiation and adherence among Black men who have sex with men (MSM) in three US cities: results from the HPTN 073 study.

Journal of the International AIDS Society, 22(2):e25223.

INTRODUCTION: Randomized clinical trials have demonstrated the efficacy of antiretroviral pre-exposure prophylaxis (PrEP) in preventing HIV acquisition among men who have sex with men (MSM). However, limited research has examined initiation and adherence to PrEP among Black MSM (BMSM) in the United States (US) who are disproportionately represented among newly HIV infected and late to care individuals. This research reports on the HIV Prevention Trials Network 073 (HPTN 073) study aimed to examine PrEP initiation, utilization and adherence among Black MSM utilizing the theoretically principled, culturally informed and client-centered care coordination (C4) model.

METHODS: The HPTN 073 study enrolled and followed 226 HIV-uninfected Black MSM in three US cities (Los Angeles, CA; Washington DC; and Chapel Hill, NC) from February 2013 through September 2015. Study participants were offered once daily oral emtricitabine/tenofovir (FTC/TDF) PrEP combined with C4 and followed up for 52 weeks. Participants received HIV testing, risk reduction education and clinical monitoring.

RESULTS: Of the 226 men enrolled, 178 participants initiated PrEP (79%), and of these 64% demonstrated PrEP utilization at week 26 (mid-point of the study) based on pharmacokinetic testing. Condomless anal sex with an HIV-infected or unknown status casual male partner was statistically significantly associated with a greater likelihood of PrEP initiation (adjusted odds ratio (OR) 4.4, 95% confidence interval (CI) 1.7, 11.7). Greater age (≥25 vs. <25, OR 2.95, 95% CI 1.37 -6.37), perception of having enough money (OR 3.6, 95% CI 1.7 to 7.7) and knowledge of male partner taking PrEP before sex (OR 2.22, 95% CI 1.03 to 4.79) were statistically significantly associated with increased likelihood of PrEP adherence at week 26. Annualized HIV incidence was 2.9 (95% CI 1.2 to 7.9) among those who initiated PrEP, compared to 7.7 (95% CI 2.5 to 24.1) among those who did not initiate PrEP (p = 0.18).

CONCLUSIONS: Results suggest a high level of PrEP initiation among at-risk Black MSM, a group historically characterized as hard to reach. The data support the importance of addressing contextual factors that affect PrEP initiation and adherence, and of additional research on the ultimate benefit of PrEP in HIV prevention among Black MSM.

RevDate: 2019-02-15

Chow EJ, Leger KJ, Bhatt NS, et al (2019)

Pediatric Cardio-Oncology: Epidemiology, Screening, Prevention, and Treatment.

Cardiovascular research pii:5320534 [Epub ahead of print].

With five-year survival of children with cancer exceeding 80% in developed countries, premature cardiovascular disease is now a major cause of early morbidity and mortality. In addition to the acute and chronic cardiotoxic effects of anthracyclines, related chemotherapeutics, and radiation, a growing number of new molecular targeted agents may also have detrimental effects on the cardiovascular system. Survivors of childhood cancer also may have earlier development of conventional cardiovascular risk factors such as hypertension, dyslipidemia, and diabetes, which further increase their risk of serious cardiovascular disease. This review will examine the epidemiology of acute and chronic cardiotoxicity relevant to pediatric cancer patients, including genetic risk factors. We will also provide an overview of current screening recommendations, including the evidence regarding both imaging (e.g., echocardiography and magnetic resonance imaging) and blood-based biomarkers. Various primary and secondary prevention strategies will also be discussed, primarily in relation to anthracycline-related cardiomyopathy. Finally, we review the available evidence related to the management of systolic and diastolic dysfunction in pediatric cancer patients and childhood cancer survivors.

RevDate: 2019-02-15

Zhang X, Tu W, Manson JE, et al (2019)

Racial/Ethnic Differences in 25-Hydroxy Vitamin D and Parathyroid Hormone Levels and Cardiovascular Disease Risk Among Postmenopausal Women.

Journal of the American Heart Association, 8(4):e011021.

Background Recent evidence suggests that racial/ethnic differences in circulating levels of free or bioavailable 25-hydroxy vitamin D (25[ OH ]D) rather than total 25(OH)D may explain apparent racial disparities in cardiovascular disease (CVD). We prospectively examined black-white differences in the associations of total, free, and bioavailable 25(OH)D, vitamin D-binding protein, and parathyroid hormone levels at baseline with incident CVD (including nonfatal myocardial infarction, nonfatal stroke, and CVD death) in postmenopausal women. Methods and Results We conducted a case-cohort study among 79 705 postmenopausal women, aged 50 to 79 years, who were free of CVD at baseline in the WHI-OS (Women's Health Initiative Observational Study). A subcohort of 1300 black and 1500 white participants were randomly chosen as controls; a total of 550 black and 1500 white women who developed incident CVD during a mean follow-up of 11 years were chosen as cases. We directly measured total 25(OH)D, vitamin D-binding protein, albumin, parathyroid hormone, and calculated free and bioavailable 25(OH)D. Weighted Cox proportional hazards models were used to examine their associations with CVD risk. Although vitamin D-binding protein and total, free, and bioavailable 25(OH)D were not significantly associated with CVD risk in black or white women, a significant positive association between parathyroid hormone and CVD risk persisted in white women (hazard ratio comparing the highest quartile with the lowest, 1.37; 95% CI , 1.06-1.77) but not in black women (hazard ratio comparing the highest quartile with the lowest, 1.12; 95% CI, 0.79-1.58), independent of total, free, and bioavailable 25(OH)D or vitamin D-binding protein. Conclusions Circulating levels of vitamin D biomarkers are not related to CVD risk in either white or black women. Higher parathyroid hormone levels may be an independent risk factor for CVD in white women.

RevDate: 2019-03-03

Karlsson A, Jauhiainen A, Gulati R, et al (2019)

A natural history model for planning prostate cancer testing: Calibration and validation using Swedish registry data.

PloS one, 14(2):e0211918 pii:PONE-D-18-28167.

Recent prostate cancer screening trials have given conflicting results and it is unclear how to reduce prostate cancer mortality while minimising overdiagnosis and overtreatment. Prostate cancer testing is a partially observable process, and planning for testing requires either extrapolation from randomised controlled trials or, more flexibly, modelling of the cancer natural history. An existing US prostate cancer natural history model (Gulati et al, Biostatistics 2010;11:707-719) did not model for differences in survival between Gleason 6 and 7 cancers and predicted too few Gleason 7 cancers for contemporary Sweden. We re-implemented and re-calibrated the US model to Sweden. We extended the model to more finely describe the disease states, their time to biopsy-detectable cancer and prostate cancer survival. We first calibrated the model to the incidence rate ratio observed in the European Randomised Study of Screening for Prostate Cancer (ERSPC) together with age-specific cancer staging observed in the Stockholm PSA (prostate-specific antigen) and Biopsy Register; we then calibrated age-specific survival by disease states under contemporary testing and treatment using the Swedish National Prostate Cancer Register. After calibration, we were able to closely match observed prostate cancer incidence trends in Sweden. Assuming that patients detected at an earlier stage by screening receive a commensurate survival improvement, we find that the calibrated model replicates the observed mortality reduction in a simulation of ERSPC. Using the resulting model, we predicted incidence and mortality following the introduction of regular testing. Compared with a model of the current testing pattern, organised 8 yearly testing for men aged 55-69 years was predicted to reduce prostate cancer incidence by 14% and increase prostate cancer mortality by 2%. The model is open source and suitable for planning for effective prostate cancer screening into the future.

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ESP Quick Facts

ESP Origins

In the early 1990's, Robert Robbins was a faculty member at Johns Hopkins, where he directed the informatics core of GDB — the human gene-mapping database of the international human genome project. To share papers with colleagues around the world, he set up a small paper-sharing section on his personal web page. This small project evolved into The Electronic Scholarly Publishing Project.

ESP Support

In 1995, Robbins became the VP/IT of the Fred Hutchinson Cancer Research Center in Seattle, WA. Soon after arriving in Seattle, Robbins secured funding, through the ELSI component of the US Human Genome Project, to create the original ESP.ORG web site, with the formal goal of providing free, world-wide access to the literature of classical genetics.

ESP Rationale

Although the methods of molecular biology can seem almost magical to the uninitiated, the original techniques of classical genetics are readily appreciated by one and all: cross individuals that differ in some inherited trait, collect all of the progeny, score their attributes, and propose mechanisms to explain the patterns of inheritance observed.

ESP Goal

In reading the early works of classical genetics, one is drawn, almost inexorably, into ever more complex models, until molecular explanations begin to seem both necessary and natural. At that point, the tools for understanding genome research are at hand. Assisting readers reach this point was the original goal of The Electronic Scholarly Publishing Project.

ESP Usage

Usage of the site grew rapidly and has remained high. Faculty began to use the site for their assigned readings. Other on-line publishers, ranging from The New York Times to Nature referenced ESP materials in their own publications. Nobel laureates (e.g., Joshua Lederberg) regularly used the site and even wrote to suggest changes and improvements.

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When the site began, no journals were making their early content available in digital format. As a result, ESP was obliged to digitize classic literature before it could be made available. For many important papers — such as Mendel's original paper or the first genetic map — ESP had to produce entirely new typeset versions of the works, if they were to be available in a high-quality format.

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Early support from the DOE component of the Human Genome Project was critically important for getting the ESP project on a firm foundation. Since that funding ended (nearly 20 years ago), the project has been operated as a purely volunteer effort. Anyone wishing to assist in these efforts should send an email to Robbins.

ESP Plans

With the development of methods for adding typeset side notes to PDF files, the ESP project now plans to add annotated versions of some classical papers to its holdings. We also plan to add new reference and pedagogical material. We have already started providing regularly updated, comprehensive bibliographies to the ESP.ORG site.

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Cancer is the generic name for more than 100 diseases in which cells begin to grow and divide in an uncontrolled manner. Usually, when cells get too old or damaged, they die and new cells take their place. Cancer begins when genetic changes impair this orderly process so that some cells start to grow uncontrollably. The Emperor of All Maladies is a "biography" of cancer — from its first documented appearances thousands of years ago through the epic battles in the twentieth century to cure, control, and conquer it to a radical new understanding of its essence. This is a must read book for anyone with an interest in cancer. R. Robbins

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Papers in Classical Genetics

The ESP began as an effort to share a handful of key papers from the early days of classical genetics. Now the collection has grown to include hundreds of papers, in full-text format.

Digital Books

Along with papers on classical genetics, ESP offers a collection of full-text digital books, including many works by Darwin (and even a collection of poetry — Chicago Poems by Carl Sandburg).

Timelines

ESP now offers a much improved and expanded collection of timelines, designed to give the user choice over subject matter and dates.

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Biographical information about many key scientists.

Selected Bibliographies

Bibliographies on several topics of potential interest to the ESP community are now being automatically maintained and generated on the ESP site.

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