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Bibliography on: Publications by FHCRC Researchers

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ESP: PubMed Auto Bibliography 18 Jan 2020 at 05:17 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: 2020-01-17

Moncla LH, Bedford T, Dussart P, et al (2020)

Quantifying within-host diversity of H5N1 influenza viruses in humans and poultry in Cambodia.

PLoS pathogens, 16(1):e1008191 pii:PPATHOGENS-D-19-01252 [Epub ahead of print].

Avian influenza viruses (AIVs) periodically cross species barriers and infect humans. The likelihood that an AIV will evolve mammalian transmissibility depends on acquiring and selecting mutations during spillover, but data from natural infection is limited. We analyze deep sequencing data from infected humans and domestic ducks in Cambodia to examine how H5N1 viruses evolve during spillover. Overall, viral populations in both species are predominated by low-frequency (<10%) variation shaped by purifying selection and genetic drift, and half of the variants detected within-host are never detected on the H5N1 virus phylogeny. However, we do detect a subset of mutations linked to human receptor binding and replication (PB2 E627K, HA A150V, and HA Q238L) that arose in multiple, independent humans. PB2 E627K and HA A150V were also enriched along phylogenetic branches leading to human infections, suggesting that they are likely human-adaptive. Our data show that H5N1 viruses generate putative human-adapting mutations during natural spillover infection, many of which are detected at >5% frequency within-host. However, short infection times, genetic drift, and purifying selection likely restrict their ability to evolve extensively during a single infection. Applying evolutionary methods to sequence data, we reveal a detailed view of H5N1 virus adaptive potential, and develop a foundation for studying host-adaptation in other zoonotic viruses.

RevDate: 2020-01-17

Gruffaz M, Zhang T, Marshall V, et al (2020)

Signatures of oral microbiome in HIV-infected individuals with oral Kaposi's sarcoma and cell-associated KSHV DNA.

PLoS pathogens, 16(1):e1008114 pii:PPATHOGENS-D-19-01331 [Epub ahead of print].

Infection by Kaposi's sarcoma-associated herpesvirus (KSHV) is necessary for the development of Kaposi's sarcoma (KS), which most often develops in HIV-infected individuals. KS frequently has oral manifestations and KSHV DNA can be detected in oral cells. Numerous types of cancer are associated with the alteration of microbiome including bacteria and virus. We hypothesize that oral bacterial microbiota affects or is affected by oral KS and the presence of oral cell-associated KSHV DNA. In this study, oral and blood specimens were collected from a cohort of HIV/KSHV-coinfected individuals all previously diagnosed with KS, and were classified as having oral KS with any oral cell-associated KSHV DNA status (O-KS, n = 9), no oral KS but with oral cell-associated KSHV DNA (O-KSHV, n = 10), or with neither oral KS nor oral cell-associated KSHV DNA (No KSHV, n = 10). We sequenced the hypervariable V1-V2 region of the 16S rRNA gene present in oral cell-associated DNA by next generation sequencing. The diversity, richness, relative abundance of operational taxonomic units (OTUs) and taxonomic composition of oral microbiota were analyzed and compared across the 3 studied groups. We found impoverishment of oral microbial diversity and enrichment of specific microbiota in O-KS individuals compared to O-KSHV or No KSHV individuals. These results suggest that HIV/KSHV coinfection and oral microbiota might impact one another and influence the development of oral KS.

RevDate: 2020-01-17

Devall M, Jennelle LT, Bryant J, et al (2020)

Modeling the effect of prolonged ethanol exposure on global gene expression and chromatin accessibility in normal 3D colon organoids.

PloS one, 15(1):e0227116 pii:PONE-D-19-19903.

In this study we aimed to explore the potential biological effect of ethanol exposure on healthy colon epithelial cells using normal human colon 3D organoid "mini-gut" cultures. In numerous published studies ethanol use has been shown to be an environmental risk factor for colorectal cancer (CRC) development; however, the influence of ethanol exposure on normal colon epithelial cell biology remains poorly understood. We investigated the potential molecular effects of ethanol exposure in normal colon 3D organoids in a small pilot study (n = 3) using RNA-seq and ATAC-seq. We identify 1965 differentially expressed genes and 2217 differentially accessible regions of chromatin in response to ethanol treatment. Further, by cross-referencing our results with previously published analysis in colorectal cancer cell lines, we have not only validated a number of reported differentially expressed genes, but also identified several novel candidates for future investigation. In summary, our data highlights the potential importance for the use of normal colon 3D organoid models as a novel tool for the investigation of the relationship between the effects of environmental risk factors associated with colorectal cancer and the molecular mechanisms through which they confer this risk.

RevDate: 2020-01-17

Schenk JM, Newcomb LF, Zheng Y, et al (2020)

Reply by Authors.

The Journal of urology [Epub ahead of print].

RevDate: 2020-01-17

McTiernan A (2020)

Dose Finding in Physical Activity and Cancer Risk Reduction.

RevDate: 2020-01-17

Sim JA, Hyun G, Gibson TM, et al (2020)

Negligible Effects of the Survey Modes for Patient-Reported Outcomes: A Report From the Childhood Cancer Survivor Study.

JCO clinical cancer informatics, 4:10-24.

PURPOSE: This study compared the measurement properties for multiple modes of survey administration, including postal mail, telephone interview, and Web-based completion of patient-reported outcomes (PROs) among survivors of childhood cancer.

METHODS: The population included 6,974 adult survivors of childhood cancer in the Childhood Cancer Survivor Study who completed the Brief Symptom Inventory-18 (BSI-18), which measured anxiety, depression, and somatization symptoms. Scale reliability, construct validity, and known-groups validity related to health status were tested for each mode of completion. The multiple indicators and multiple causes technique was used to identify differential item functioning (DIF) for the BSI-18 items that responded through a specific survey mode. The impact of the administration mode was tested by comparing differences in BSI-18 scores between the modes accounting for DIF effects.

RESULTS: Of the respondents, 58%, 27%, and 15% completed postal mail, Web-based, and telephone surveys, respectively. Survivors who were male; had lower education, lower household income, or poorer health status; or were treated with cranial radiotherapy were more likely to complete a telephone-based survey compared with either a postal mail or Web-based survey (all P < .05). Scale reliability and validity were equivalent across the 3 survey options. One, 2, and 5 items from the anxiety, depression, and somatization domains, respectively, were identified as having significant DIF among survivors who responded by telephone (P < .05). However, estimated BSI-18 domain scores, especially depression and anxiety, between modes did not differ after accounting for DIF effects.

CONCLUSION: Certain survivor characteristics were associated with choosing a specific mode for PRO survey completion. However, measurement properties among these modes were equivalent, and the impact of using a specific mode on scores was minimal.

RevDate: 2020-01-17

Bricker JB, Watson NL, Heffner JL, et al (2020)

A Smartphone App Designed to Help Cancer Patients Stop Smoking: Results From a Pilot Randomized Trial on Feasibility, Acceptability, and Effectiveness.

JMIR formative research, 4(1):e16652 pii:v4i1e16652.

BACKGROUND: Persistent smoking after a cancer diagnosis predicts worse treatment outcomes and mortality, but access to effective smoking cessation interventions is limited. Smartphone apps can address this problem by providing a highly accessible, low-cost smoking cessation intervention designed for patients with a recent cancer diagnosis.

OBJECTIVE: This study aimed to summarize our development process and report the trial design, feasibility, participant acceptability, preliminary effectiveness, and impact on processes of change (eg, cancer stigma) of the first-known smoking cessation smartphone app targeted for cancer patients.

METHODS: We used an agile, user-centered design framework to develop a fully automated smartphone app called Quit2Heal that provided skills training and stories from cancer survivors focusing on coping with internalized shame, cancer stigma, depression, and anxiety as core triggers of smoking. Quit2Heal was compared with the National Cancer Institute's QuitGuide, a widely used stop smoking app for the general population, in a pilot double-blinded randomized trial with a 2-month follow-up period. Participants were 59 adult smokers diagnosed with cancer within the past 12 months and recruited through 2 cancer center care networks and social media over a 12-month period. The most common types of cancer diagnosed were lung (21/59, 36%) and breast (10/59, 17%) cancers. The 2-month follow-up survey retention rate was 92% (54/59) and did not differ by study arm (P=.15).

RESULTS: Compared with QuitGuide participants, Quit2Heal participants were more satisfied with their assigned app (90% [19/21] for Quit2Heal vs 65% [17/26] for QuitGuide; P=.047) and were more likely to report that the app assigned to them was made for someone like them (86% [18/21] for Quit2Heal vs 62% [16/26] for QuitGuide; P=.04). Quit2Heal participants opened their app a greater number of times during the 2-month trial period, although this difference was not statistically significant (mean 10.0, SD 14.40 for Quit2Heal vs mean 6.1, SD 5.3 for QuitGuide; P=.33). Self-reported 30-day point prevalence quit rates at the 2-month follow-up were 20% (5/25) for Quit2Heal versus 7% (2/29) for QuitGuide (odds ratio 5.16, 95% CI 0.71-37.29; P=.10). Quit2Heal participants also showed greater improvement in internalized shame, cancer stigma, depression, and anxiety, although these were not statistically significant (all P>.05).

CONCLUSIONS: In a pilot randomized trial with a high short-term retention rate, Quit2Heal showed promising acceptability and effectiveness for helping cancer patients stop smoking. Testing in a full-scale randomized controlled trial with a longer follow-up period and a larger sample size is required to test the effectiveness, mediators, and moderators of this promising digital cessation intervention.

TRIAL REGISTRATION: ClinicalTrials.gov NCT03600038; https://clinicaltrials.gov/ct2/show/NCT03600038.

RevDate: 2020-01-17

Zhao Ruoqing YQ, Zhu R, Chen G, et al (2020)

Constructing dynamic treatment regimes with shared parameters for censored data.

Statistics in medicine [Epub ahead of print].

Dynamic treatment regimes are sequential decision rules that adapt throughout disease progression according to a patient's evolving characteristics. In many clinical applications, it is desirable that the format of the decision rules remains consistent over time. Unlike the estimation of dynamic treatment regimes in regular settings, where decision rules are formed without shared parameters, the derivation of the shared decision rules requires estimating shared parameters indexing the decision rules across different decision points. Estimation of such rules becomes more complicated when the clinical outcome of interest is a survival time subject to censoring. To address these challenges, we propose two novel methods: censored shared-Q-learning and censored shared-O-learning. Both methods incorporate clinical preferences into a qualitative rule, where the parameters indexing the decision rules are shared across different decision points and estimated simultaneously. We use simulation studies to demonstrate the superior performance of the proposed methods. The methods are further applied to the Framingham Heart Study to derive treatment rules for cardiovascular disease.

RevDate: 2020-01-17

Harris LJ, Rout ED, Labadie JD, et al (2020)

Clinical Features of Canine Nodal T-Cell Lymphomas Classified as CD8+ or CD4-CD8- by Flow Cytometry.

Veterinary and comparative oncology [Epub ahead of print].

Canine T-cell lymphoma (TCL) encompasses a heterogeneous group of diseases with variable clinical presentation, cytomorphology, immunophenotype, and biologic behavior. The most common types of TCL in dogs involving peripheral lymph nodes include indolent T-zone lymphoma (TZL) and biologically aggressive peripheral T-cell lymphoma (PTCL). TCL phenotypes can be categorized by expression of the surface antigen molecules CD4 and CD8. The majority of TCL cases are CD4+ , with far fewer cases being CD8+ or CD4- CD8- . The clinical features of CD4+ TCLs have been previously described. The less common TCL phenotypes, however, are poorly characterized with little to no information about prognosis. In this retrospective study, we describe and correlate the presenting clinical signs, flow cytometry, and outcomes of 119 dogs diagnosed with nodal, non-TZL, CD8+ or CD4- CD8- TCL by flow cytometry. Skin lesions present at the time of diagnosis were more commonly observed in the CD8+ TCL group. Mediastinal enlargement and/or hypercalcemia were more commonly seen in the CD4- CD8- TCL group. Dogs with either CD8+ or CD4- CD8- TCLs had aggressive clinical disease with median overall survival (OS) times of 198 days and 145 days, respectively. In both groups, neoplastic cell size determined by flow cytometry ranged from small to large, and large cell size was associated with shorter OS times (median OS=61 days). Cases classified as small cell had a median OS of 257 days. Expression levels of MHC class II and CD5 were highly variable among cases but were not prognostically significant in this group of patients. This article is protected by copyright. All rights reserved.

RevDate: 2020-01-17

Bae J, Parayath N, Ma W, et al (2020)

Correction: BCMA peptide-engineered nanoparticles enhance induction and function of antigen-specific CD8+ cytotoxic T lymphocytes against multiple myeloma: clinical applications.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

RevDate: 2020-01-17

Escala-Garcia M, Abraham J, Andrulis IL, et al (2020)

A network analysis to identify mediators of germline-driven differences in breast cancer prognosis.

Nature communications, 11(1):312 pii:10.1038/s41467-019-14100-6.

Identifying the underlying genetic drivers of the heritability of breast cancer prognosis remains elusive. We adapt a network-based approach to handle underpowered complex datasets to provide new insights into the potential function of germline variants in breast cancer prognosis. This network-based analysis studies ~7.3 million variants in 84,457 breast cancer patients in relation to breast cancer survival and confirms the results on 12,381 independent patients. Aggregating the prognostic effects of genetic variants across multiple genes, we identify four gene modules associated with survival in estrogen receptor (ER)-negative and one in ER-positive disease. The modules show biological enrichment for cancer-related processes such as G-alpha signaling, circadian clock, angiogenesis, and Rho-GTPases in apoptosis.

RevDate: 2020-01-16

Martens KL, Khalighi PR, Li S, et al (2020)

Comparative effectiveness of rasburicase versus allopurinol for cancer patients with renal dysfunction and hyperuricemia.

Leukemia research, 89:106298 pii:S0145-2126(20)30003-5 [Epub ahead of print].

While rasburicase has shown efficacy to rapidly correct hyperuricemia compared with allopurinol, its overall impact in improving clinically significant outcomes, such as acute kidney injury (AKI), in tumor lysis syndrome (TLS) is unknown. In this retrospective cohort study, we included all hospitalized cancer patients with hyperuricemia and AKI who received rasburicase +/- allopurinol or allopurinol alone from 2009 to 2015. Inverse probability of treatment weighting using propensity score was used to account for potential confounders and to estimate the causal effect associated with differential drug treatment. 150 patients met inclusion criteria; 89 received rasburicase +/- allopurinol and 61 received allopurinol alone. Weighted outcome regression analysis demonstrated that rasburicase was associated with significantly lower mean uric acid nadir at 7 days compared to allopurinol (2.70 versus 5.82 mg/dL, p < 0.01). However, likelihood of renal function recovery (OR = 0.90, p = 0.79), creatinine nadir by 7 days (1.80 versus 1.66 mg/dL, p = 0.51), and final creatinine by 30 days (2.08 versus 2.07 mg/dL, p = 0.98) did not significantly differ. In conclusion, the clinical benefit of rasburicase in promoting renal function recovery in cancer patietns with concurrent hyperuricemia and renal failure remains inconclusive. Our results suggest that correction of hyperuricemia as a surrogate endpoint may not be associated with significant renal function improvement, particularly if renal dysfunction is unrelated to TLS.

RevDate: 2020-01-16

Phelan EA, Rillamas-Sun E, Johnson L, et al (2020)

Determinants, circumstances and consequences of injurious falls among older women living in the community.

Injury prevention : journal of the International Society for Child and Adolescent Injury Prevention pii:injuryprev-2019-043499 [Epub ahead of print].

OBJECTIVE: To identify the risk factors of women who fell with injury relative to women who did not fall or fell without injury and to describe the circumstances and consequences of injurious and non-injurious falls.

METHODS: We analysed 5074 older women from the Objective Physical Activity and Cardiovascular Health Study who prospectively tracked their falls using a 13-month calendar. Women with a reported fall were phone interviewed about fall-related details, including injuries. Risk factors were identified from surveys and clinical home visits. Logistic regression models were used to calculate adjusted ORs and 95% CIs for injurious falls relative to not falling or falling without injury. Circumstances of injurious and non-injurious falls were compared.

RESULTS: At least one fall was experienced by 1481 (29%) participants. Of these, 1043 were phone interviewed, of whom 430 (41%) reported at least one injurious fall. Relative to not falling, the risk factor most strongly associated with experiencing an injurious fall was having fallen ≥2 times (OR 4.0, CI 2.7 to 5.8) in the past year. Being black was protective for fall-related injury (OR 0.6, CI 0.4 to 0.9). No strong associations in risk factors were observed for injurious relative to non-injurious falls. Injurious falls were more likely to occur away from and outside of the home (p<0.05). Over half of those who injured self-managed their injury.

CONCLUSION: Falling repeatedly is a powerful risk factor for injurious falls. Those who have fallen more than once should be prioritised for interventions to mitigate the risk of an injurious fall.

RevDate: 2020-01-16

Mulrooney DA, Hyun G, Ness KK, et al (2020)

Major cardiac events for adult survivors of childhood cancer diagnosed between 1970 and 1999: report from the Childhood Cancer Survivor Study cohort.

BMJ (Clinical research ed.), 368:l6794.

OBJECTIVE: To investigate the impact of modifications to contemporary cancer protocols, which minimize exposures to cardiotoxic treatments and preserve long term health, on serious cardiac outcomes among adult survivors of childhood cancer.

DESIGN: Retrospective cohort study.

SETTING: 27 institutions participating in the Childhood Cancer Survivor Study.

PARTICIPANTS: 23 462 five year survivors (6193 (26.4%) treated in the 1970s, 9363 (39.9%) treated in the 1980s, and 7906 (33.6%) treated in the 1990s) of leukemia, brain cancer, Hodgkin lymphoma, non-Hodgkin lymphoma, renal tumors, neuroblastoma, soft tissue sarcomas, and bone sarcomas diagnosed prior to age 21 years between 1 January 1970 and 31 December 1999. Median age at diagnosis was 6.1 years (range 0-20.9) and 27.7 years (8.2-58.3) at last follow-up. A comparison group of 5057 siblings of cancer survivors were also included.

MAIN OUTCOME MEASURES: Cumulative incidence and 95% confidence intervals of reported heart failure, coronary artery disease, valvular heart disease, pericardial disease, and arrhythmias by treatment decade. Events were graded according to the National Cancer Institute's Common Terminology Criteria for Adverse Events. Multivariable subdistribution hazard models were used to estimate hazard ratios by decade, and mediation analysis examined risks with and without exposure to cardiotoxic treatments.

RESULTS: The 20 year cumulative incidence of heart failure (0.69% for those treated in the 1970s, 0.74% for those treated in the 1980s, 0.54% for those treated in the 1990s) and coronary artery disease (0.38%, 0.24%, 0.19%, respectively), decreased in more recent eras (P<0.01), though not for valvular disease (0.06%, 0.06%, 0.05%), pericardial disease (0.04%, 0.02%, 0.03%), or arrhythmias (0.08%, 0.09%, 0.13%). Compared with survivors with a diagnosis in the 1970s, the risk of heart failure, coronary artery disease, and valvular heart disease decreased in the 1980s and 1990s but only significantly for coronary artery disease (hazard ratio 0.65, 95% confidence interval 0.45 to 0.92 and 0.53, 0.36 to 0.77, respectively). The overall risk of coronary artery disease was attenuated by adjustment for cardiac radiation (0.90, 0.78 to 1.05), particularly among survivors of Hodgkin lymphoma (unadjusted for radiation: 0.77, 0.66 to 0.89; adjusted for radiation: 0.87, 0.69 to 1.10).

CONCLUSIONS: Historical reductions in exposure to cardiac radiation have been associated with a reduced risk of coronary artery disease among adult survivors of childhood cancer. Additional follow-up is needed to investigate risk reductions for other cardiac outcomes.

TRIAL REGISTRATION: ClinicalTrials.gov NCT01120353.

RevDate: 2020-01-17

Chlebowski RT, Rapp S, Aragaki AK, et al (2020)

Low-fat dietary pattern and global cognitive function: Exploratory analyses of the Women's Health Initiative (WHI) randomized Dietary Modification trial.

EClinicalMedicine, 18:100240.

Background: Meta-analyses of observational studies associate adherence to several dietary patterns with cognitive health. However, limited evidence from full scale, randomized controlled trials precludes causal inference regarding dietary effects on cognitive function.

Methods: The Women's Health Initiative (WHI) Dietary Modification (DM) randomized trial, in 48,835 postmenopausal women, included a subset of 1,606 WHI Memory Study (WHIMS) participants >= 65 years old, to assess low-fat dietary pattern influence on global cognitive function, evaluated with annual screening (Modified Mini-Mental State Examinations [3MSE]). Participants were randomized by a computerized, permuted block algorithm, stratified by age group and center, to a dietary intervention (40%) to reduce fat intake to 20% of energy and increase fruit, vegetable and grain intake or usual diet comparison groups (60%). The study outcome was possible cognition impairment (failed cognitive function screening) through the 8.5 year (median) dietary intervention. Those failing screening received a comprehensive, multi-phase cognitive function assessment to classify as: no cognitive impairment, mild cognitive impairment, or probable dementia. Exploratory analyses examined the composite endpoint of death after possible cognitive impairment through 18.7 years (median) follow-up. The WHI trials are registered at ClinicalTrials.gov:NCT00000611.

Findings: Among the 1,606 WHIMS participants, the dietary intervention statistically significantly reduced the incidence of possible cognitive impairment (n = 126; hazard ratio [HR] 0.59 95% confidence interval [CI] 0.38-0. 91, P = 0.01) with HR for dietary influence on subsequent mild cognitive impairment of 0.65 (95% CI 0.35-1.19) and HR of 0.63 (95% CI 0.19-2.10) for probable dementia (PD). Through 18.7 years, deaths from all-causes after possible cognitive impairment were non-significantly lower in the dietary intervention group (0.56% vs 0.77%, HR 0.83 95% CI 0.35 to 2.00, P = 0.16).

Interpretation: Adoption of a low-fat eating pattern, representing dietary moderation, significantly reduced risk of possible cognitive impairment in postmenopausal women.

Funding: Several Institutes of the US National Institutes of Health.

RevDate: 2020-01-14

Trabert B, Tworoger SS, O'Brien KM, et al (2020)

The risk of ovarian cancer increases with an increase in the lifetime number of ovulatory cycles: an analysis from the Ovarian Cancer Cohort Consortium (OC3).

Cancer research pii:0008-5472.CAN-19-2850 [Epub ahead of print].

Repeated exposure to the acute pro-inflammatory environment that follows ovulation at the ovarian surface and distal fallopian tube over a woman's reproductive years may increase ovarian cancer risk. To address this, analyses included individual-level data from 558,709 naturally menopausal women across 20 prospective cohorts, among whom 3,246 developed invasive epithelial ovarian cancer (2045 serous, 319 endometrioid, 184 mucinous, 121 clear cell, 577 other/unknown). Cox models were used to estimate multivariable-adjusted hazard ratios (HR) between lifetime ovulatory cycles (LOC) and its components and ovarian cancer risk overall and by histotype. Women in the 90th percentile of LOC (>514 cycles) were almost twice as likely to be diagnosed with ovarian cancer than women in the 10th percentile (<294) [HR (95% confidence interval): 1.92 (1.60-2.30)]. Risk increased 14% per five-year increase in LOC (60 cycles) [(1.10-1.17)]; this association remained after adjustment for LOC components: number of pregnancies and oral contraceptive use [1.08 (1.04-1.12)]. The association varied by histotype, with increased risk of serous [1.13 (1.09-1.17)], endometrioid [1.20 (1.10-1.32)], and clear cell [1.37 (1.18-1.58)], but not mucinous [0.99 (0.88-1.10), P-heterogeneity=0.01] tumors. Heterogeneity across histotypes was reduced [P-heterogeneity=0.15] with adjustment for LOC components [1.08 serous, 1.11 endometrioid, 1.26 clear cell, 0.94 mucinous]. Although the 10-year absolute risk of ovarian cancer is small, it roughly doubles as the number of LOC rises from ~300 to 500. The consistency and linearity of effects strongly support the hypothesis that each ovulation leads to small increases in the risk of most ovarian cancers, a risk which cumulates through life, suggesting this as an important area for identifying intervention strategies.

RevDate: 2020-01-17

Zheng Y, Hua X, Win AK, et al (2020)

A new comprehensive colorectal cancer risk prediction model incorporating family history, personal characteristics, and environmental factors.

Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology pii:1055-9965.EPI-19-0929 [Epub ahead of print].

BACKGROUND: Reducing colorectal cancer (CRC) incidence and mortality through early detection would improve efficacy if targeted. We developed a CRC risk-prediction model incorporating personal, family, genetic and environmental risk factors to enhance prevention.

METHODS: A familial risk profile (FRP) was calculated to summarize individuals' risk based on detailed cancer family history, family structure, probabilities of mutation in major CRC susceptibility genes, and a polygenic component. We developed risk models including individuals' FRP or binary CRC family-history (FH), and CRC risk factors collected at enrollment using population-based CRC cases (N=4,445) and controls (N=3,967) recruited by the Colon Cancer Family Registry Cohort (CCFRC). Model validation used CCFRC follow-up data for population-based (N=12,052) and clinic-based (N=5,584) relatives with no cancer history at recruitment to assess model calibration (expected/observed rate ratio E/O) and discrimination (area under the receiver-operating-characteristic curve, AUC).

RESULTS: The E/O (95% confidence interval [CI]) for FRP models for population-based relatives were 1.04(0.74-1.45) and 0.86(0.64-1.20) for men and women, and for clinic-based relatives were 1.15(0.87-1.58) and 1.04(0.76-1.45). The age-adjusted AUC (95% CI) for FRP models were 0.69(0.60-0.78) and 0.70(0.62-0.77) for population-based relatives, and 0.77(0.69-0.84) and 0.68(0.60-0.76) for clinic-based relatives. The incremental values of AUC for FRP over FH models for population-based relatives were 0.08(0.01-0.15) and 0.10(0.04-0.16) for men and women, and for clinic-based relatives were 0.11(0.05-0.17) and 0.11(0.06-0.17).

CONCLUSIONS: Both models calibrated well. The FRP-based model provided better risk-stratification and risk-discrimination than the FH-based model.

IMPACT: Our findings suggested detailed family history may be useful for targeted risk-based screening and clinical management.

RevDate: 2020-01-13

Chang CP, La Vecchia C, Serraino D, et al (2020)

Dietary glycaemic index, glycaemic load and head and neck cancer risk: a pooled analysis in an international consortium.

British journal of cancer pii:10.1038/s41416-019-0702-4 [Epub ahead of print].

High dietary glycaemic index (GI) and glycaemic load (GL) may increase cancer risk. However, limited information was available on GI and/or GL and head and neck cancer (HNC) risk. We conducted a pooled analysis on 8 case-control studies (4081 HNC cases; 7407 controls) from the International Head and Neck Cancer Epidemiology (INHANCE) consortium. We estimated the odds ratios (ORs) and 95% confidence intervals (CIs) of HNC, and its subsites, from fixed- or mixed-effects logistic models including centre-specific quartiles of GI or GL. GI, but not GL, had a weak positive association with HNC (ORQ4 vs. Q1 = 1.16; 95% CI = 1.02-1.31). In subsites, we found a positive association between GI and laryngeal cancer (ORQ4 vs. Q1 = 1.60; 95% CI = 1.30-1.96) and an inverse association between GL and oropharyngeal cancer (ORQ4 vs. Q1 = 0.78; 95% CI = 0.63-0.97). This pooled analysis indicates a modest positive association between GI and HNC, mainly driven by laryngeal cancer.

RevDate: 2020-01-17

Arya M, Marren RE, Marek HG, et al (2020)

Success of Supplementing National HIV Testing Recommendations With a Local Initiative in a Large Health Care System in the U.S. South.

Journal of acquired immune deficiency syndromes (1999), 83(2):e6-e9.

RevDate: 2020-01-13

Bunge KE, Levy L, Szydlo DW, et al (2020)

Brief Report: Phase IIa Safety Study of a Vaginal Ring Containing Dapivirine in Adolescent Young Women.

Journal of acquired immune deficiency syndromes (1999), 83(2):135-139.

BACKGROUND: Young women aged 15-24 years are disproportionately affected by the HIV epidemic. Two phase III trials of a vaginal ring containing 25-mg dapivirine demonstrated HIV-1 risk reduction in adult women older than 21 years but not in those aged 18-21 years. Lack of protection was correlated with low adherence.

METHODS: In this phase-IIa, randomized, double-blind, placebo-controlled, US, multicenter trial of the dapivirine ring in sexually active females, aged 15-17 years, participants were randomized 3:1 to a dapivirine or placebo ring to be inserted monthly for 6 months (NCT02028338). Primary safety end points included grade 2 product related adverse events and any grade 3 and higher adverse events. Adherence to ring use was assessed by plasma dapivirine concentrations, residual levels in used rings, and self-report. A plasma dapivirine concentration of >95 pg/mL was used to define short-term adherence; a residual ring level of <23.5 mg was used to define long-term adherence. Acceptability was assessed through computer-assisted self-interviews.

RESULTS: Ninety-six participants were enrolled across 6 US sites. The median age was 16.0 years. There were no differences in safety outcomes between treatment arms. Adherence to the dapivirine ring was demonstrated by both plasma measurements (87%) and residual drug levels in rings (95%). Forty-two percent (95% confidence interval: 32 to 52) of participants reported that they never removed the ring. Participants noted no discomfort due to the ring at 87% of visits and "liking" the ring at 93% of visits.

CONCLUSION: The dapivirine vaginal ring, a promising topical microbicide, was well tolerated and acceptable in young US adolescents.

RevDate: 2020-01-13

Miropolsky EM, Baker KS, Abbey-Lambertz M, et al (2020)

Participant Perceptions on a Fitbit and Facebook Intervention for Young Adult Cancer Survivors: A Qualitative Study.

Journal of adolescent and young adult oncology [Epub ahead of print].

Purpose: Among cancer survivors, physical activity (PA) is associated with reductions in cancer recurrence, morbidity, and mortality. Most young adult (YA) survivors do not attain adequate PA. Digital modalities, specifically wearable activity monitors with a paired mobile application and private social media group for support offer a promising approach for promoting PA among YAs. We conducted a pilot randomized controlled trial of this intervention. To evaluate its acceptability and perceptions of the intervention components, we conducted qualitative interviews with those in the intervention. The results of our interviews serve to refine future interventions to better serve this population. Methods: Semistructured qualitative interviews with 13 YA cancer survivors ages 20-39 who participated in the intervention assessed perceptions of the digital components of the study and buddy system of nominating a friend to participate in PA with the survivor. Analyses included a qualitative thematic analysis of the interview transcripts and coded interview segments into three predetermined categories: facilitators, limitations, and suggestions. Results: Participants described wide-ranging benefits of the intervention, citing the Fitbit device and buddy system as major motivators to engage in PA and reach goals. Most participants noted feelings of increased physical and emotional wellness. The most-cited limitation of the intervention was the automated text messages, which participants found impersonal. Suggestions for improvement included integrating more elements of competition and group challenges. Conclusion: This digital PA intervention was perceived as feasible and acceptable to YA cancer survivors and appears promising for promoting PA and improving long-term health and quality of life. Clinicaltrial.gov identifier number: NCT03233581; Date of registration: July 28, 2017.

RevDate: 2020-01-13

Bowerman KL, Varelias A, Lachner N, et al (2020)

Continuous pre- and post-transplant exposure to a disease-associated gut microbiome promotes hyper-acute graft-versus-host disease in wild-type mice.

Gut microbes [Epub ahead of print].

Objective: The gut microbiome plays a key role in the development of acute graft-versus-host disease (GVHD) following allogeneic hematopoietic stem cell transplantation. Here we investigate the individual contribution of the pre- and post-transplant gut microbiome to acute GVHD using a well-studied mouse model.Design: Wild-type mice were cohoused with IL-17RA-/ - mice, susceptible to hyperacute GVHD, either pre- or post-transplant alone or continuously (i.e., pre- and post-transplant). Fecal samples were collected from both WT and IL-17RA-/ - mice pre- and post-cohousing and post-transplant and the microbiome analyzed using metagenomic sequencing.Results: Priming wild-type mice via cohousing pre-transplant only is insufficient to accelerate GVHD, however, accelerated disease is observed in WT mice cohoused post-transplant only. When mice are cohoused continuously, the effect of priming and exacerbation is additive, resulting in a greater acceleration of disease in WT mice beyond that seen with cohousing post-transplant only. Metagenomic analysis of the microbiome revealed pre-transplant cohousing is associated with the transfer of specific species within two as-yet-uncultured genera of the bacterial family Muribaculaceae; CAG-485 and CAG-873. Post-transplant, we observed GVHD-associated blooms of Enterobacteriaceae members Escherichia coli and Enterobacter hormaechei subsp. steigerwaltii, and hyperacute GVHD gut microbiome distinct from that associated with delayed-onset disease (>10 days post-transplant).Conclusion: These results clarify the importance of the peri-transplant microbiome in the susceptibility to acute GVHD post-transplant and demonstrate the species-specific nature of this association.

RevDate: 2020-01-13

Yu EYW, Dai Y, Wesselius A, et al (2020)

Coffee consumption and risk of bladder cancer: a pooled analysis of 501,604 participants from 12 cohort studies in the BLadder Cancer Epidemiology and Nutritional Determinants (BLEND) international study.

European journal of epidemiology pii:10.1007/s10654-019-00597-0 [Epub ahead of print].

Recent epidemiological studies have shown varying associations between coffee consumption and bladder cancer (BC). This research aims to elucidate the association between coffee consumption and BC risk by bringing together worldwide cohort studies on this topic. Coffee consumption in relation to BC risk was examined by pooling individual data from 12 cohort studies, comprising of 2601 cases out of 501,604 participants. Pooled multivariate hazard ratios (HRs), with corresponding 95% confidence intervals (CIs), were obtained using multilevel Weibull regression models. Furthermore, dose-response relationships were examined using generalized least squares regression models. The association between coffee consumption and BC risk showed interaction with sex (P-interaction < 0.001) and smoking (P-interaction = 0.001). Therefore, analyses were stratified by sex and smoking. After adjustment for potential confounders, an increased BC risk was shown for high (> 500 ml/day, equivalent to > 4 cups/day) coffee consumption compared to never consumers among male smokers (current smokers: HR = 1.75, 95% CI 1.27-2.42, P-trend = 0.002; former smokers: HR = 1.44, 95% CI 1.12-1.85, P-trend = 0.001). In addition, dose-response analyses, in male smokers also showed an increased BC risk for coffee consumption of more than 500 ml/day (4 cups/day), with the risk of one cup (125 ml) increment as 1.07 (95% CI 1.06-1.08). This research suggests that positive associations between coffee consumption and BC among male smokers but not never smokers and females. The inconsistent results between sexes and the absence of an association in never smokers indicate that the associations found among male smokers is unlikely to be causal and is possibly caused by residual confounding of smoking.

RevDate: 2020-01-13

Inadomi J, B Jung (2020)

Colorectal Cancer-Recent Advances and Future Challenges.

Gastroenterology, 158(2):289-290.

RevDate: 2020-01-11

Martin PJ, EW Petersdorf (2020)

In Memoriam: John A. Hansen.

Bone marrow transplantation pii:10.1038/s41409-019-0724-9 [Epub ahead of print].

RevDate: 2020-01-14

Sheih A, Voillet V, Hanafi LA, et al (2020)

Clonal kinetics and single-cell transcriptional profiling of CAR-T cells in patients undergoing CD19 CAR-T immunotherapy.

Nature communications, 11(1):219.

Chimeric antigen receptor (CAR) T-cell therapy has produced remarkable anti-tumor responses in patients with B-cell malignancies. However, clonal kinetics and transcriptional programs that regulate the fate of CAR-T cells after infusion remain poorly understood. Here we perform TCRB sequencing, integration site analysis, and single-cell RNA sequencing (scRNA-seq) to profile CD8+ CAR-T cells from infusion products (IPs) and blood of patients undergoing CD19 CAR-T immunotherapy. TCRB sequencing shows that clonal diversity of CAR-T cells is highest in the IPs and declines following infusion. We observe clones that display distinct patterns of clonal kinetics, making variable contributions to the CAR-T cell pool after infusion. Although integration site does not appear to be a key driver of clonal kinetics, scRNA-seq demonstrates that clones that expand after infusion mainly originate from infused clusters with higher expression of cytotoxicity and proliferation genes. Thus, we uncover transcriptional programs associated with CAR-T cell behavior after infusion.

RevDate: 2020-01-10

Zhang Y, Wymant C, Laeyendecker O, et al (2020)

Evaluation of phylogenetic methods for inferring the direction of HIV transmission: HPTN 052.

Clinical infectious diseases : an official publication of the Infectious Diseases Society of America pii:5699877 [Epub ahead of print].

BACKGROUND: Phylogenetic analysis can be used to assess HIV transmission in populations. We inferred the direction of HIV transmission using whole-genome HIV sequences from couples with known linked infection and known transmission direction.

METHODS: Complete next generation sequencing (NGS) data were obtained for 105 unique index-partner sample pairs from 32 couples enrolled in the HIV Prevention Trials Network (HPTN) 052 trial (up to two samples/person). Index samples were obtained up to 5.5 years before partner infection; partner samples were obtained near the time of seroconversion. The bioinformatics method, phyloscanner, was used to infer transmission direction. Analyses were performed using samples from individual sample pairs, samples from all couples (one sample/person; group analysis) and all available samples (multi-sample group analysis). Analysis was also performed using NGS data from defined regions of the HIV genome (gag, pol, env).

RESULTS: Using whole-genome NGS data, transmission direction was inferred correctly (index to partner) for 98/105 (93.3%) of the individual sample pairs, 99/105 (94.3%) sample pairs using group analysis, and 31 (96.9%) of the 32 couples using multi-sample group analysis. There were no cases where the incorrect transmission direction (partner to index) was inferred. The accuracy of the method was higher with greater time between index and partner sample collection. Pol region sequences performed better than env or gag sequences for inferring transmission direction.

CONCLUSIONS: We demonstrate the potential of a phylogenetic method to infer the direction of HIV transmission between two individuals using whole-genome and pol NGS data.

RevDate: 2020-01-10

Chen J, Liao A, Powers EN, et al (2020)

Aurora B-dependent Ndc80 degradation regulates kinetochore composition in meiosis.

Genes & development pii:gad.333997.119 [Epub ahead of print].

The kinetochore complex is a conserved machinery that connects chromosomes to spindle microtubules. During meiosis, the kinetochore is restructured to accommodate a specialized chromosome segregation pattern. In budding yeast, meiotic kinetochore remodeling is mediated by the temporal changes in the abundance of a single subunit called Ndc80. We previously described the regulatory events that control the timely synthesis of Ndc80. Here, we report that Ndc80 turnover is also tightly regulated in meiosis: Ndc80 degradation is active in meiotic prophase, but not in metaphase I. Ndc80 degradation depends on the ubiquitin ligase APCAma1 and is mediated by the proteasome. Importantly, Aurora B-dependent Ndc80 phosphorylation, a mark that has been previously implicated in correcting erroneous microtubule-kinetochore attachments, is essential for Ndc80 degradation in a microtubule-independent manner. The N terminus of Ndc80, including a 27-residue sequence and Aurora B phosphorylation sites, is both necessary and sufficient for kinetochore protein degradation. Finally, defects in Ndc80 turnover predispose meiotic cells to chromosome mis-segregation. Our study elucidates the mechanism by which meiotic cells modulate their kinetochore composition through regulated Ndc80 degradation, and demonstrates that Aurora B-dependent regulation of kinetochores extends beyond altering microtubule attachments.

RevDate: 2020-01-10

Lafita-Navarro MC, Liaño-Pons J, Quintanilla A, et al (2020)

The MNT transcription factor autoregulates its expression and supports proliferation in MYC-associated factor X (MAX)-deficient cells.

The Journal of biological chemistry pii:RA119.010389 [Epub ahead of print].

MAX network transcriptional repressor (MNT) is an MXD family transcription factor of the bHLH family. MNT dimerizes with another transcriptional regulator, MYC-associated factor X (MAX), and down-regulates genes by binding to E boxes. MAX also dimerizes with MYC, an oncogenic bHLH transcription factor. Upon E-box binding, the MYC-MAX dimer activates gene expression. MNT also binds to MAX dimerization protein MLX (MLX), and MNT-MLX and MNT-MAX dimers coexist. However, all MNT functions have been attributed to MNT-MAX dimers, and no functions of the MNT-MLX dimer have been described. MNT's biological role has been linked to its function as a MYC oncogene modulator, but little is known about its regulation. We show here that MNT localizes to the nucleus of MAX-expressing cells and that MNT-MAX dimers bind and repress the MNT promoter, an effect that depends on one of the two E boxes on this promoter. In MAX-deficient cells, MNT was overexpressed and redistributed to the cytoplasm. Interestingly, MNT was required for cell proliferation even in the absence of MAX. We show that in MAX-deficient cells, MNT binds to MLX, but also forms homodimers. RNA-Seq experiments revealed that MNT regulates the expression of several genes even in the absence of MAX, with many of these genes being involved in cell cycle regulation and DNA repair. Of note, MNT-MNT homodimers regulated the transcription of some genes involved in cell proliferation. The tight regulation of MNT and its functionality even without MAX suggest a major role for MNT in cell proliferation.

RevDate: 2020-01-10

Kang SK, Lee CI, JM Liao (2020)

Radiology's Financial Portfolio: An Introduction to the Special Money Issue.

Journal of the American College of Radiology : JACR, 17(1 Pt B):99-100.

RevDate: 2020-01-10

Manohar P, Ramsey S, V Shankaran (2020)

Economic Impact of Imaging Overutilization in Cancer Care.

Journal of the American College of Radiology : JACR, 17(1 Pt B):137-140.

RevDate: 2020-01-09

Attia EF, Bhatraju PK, Triplette M, et al (2020)

Endothelial activation, innate immune activation, and inflammation are associated with post-bronchodilator airflow limitation and obstruction among adolescents living with HIV.

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

BACKGROUND: Chronic inflammation, innate immune activation, T-cell imbalance and endothelial activation have been linked with lung diseases. We sought to determine whether markers of these pathophysiologic pathways were associated with spirometry and chest CT abnormalities among adolescents living with HIV (ALWH).

SETTING: Coptic Hope Center for Infectious Diseases in Nairobi, Kenya METHODS:: We performed a cross-sectional study of ALWH (10-19 years old). Participants underwent chest CT, spirometry and venipuncture for serum biomarkers. We also collected demographic, anthropometric, T-cell subset, antiretroviral therapy, and exposure data. We compared characteristics and biomarkers by airflow obstruction (post-bronchodilator FEV1/FVC z-score [zFEV1/FVC] < -1.64). We used multivariable linear regression to determine associations of log10-transformed biomarkers and chest CT abnormalities with lower post-bronchodilator zFEV1/FVC (airflow limitation). We performed exploratory principal components analysis on biomarkers, and determined associations of factors with post-bronchodilator zFEV1/FVC and chest CT abnormalities.

RESULTS: Of 47 participants with acceptable quality spirometry, 21 (45%) were female, median age was 13 years and 96% had perinatally-acquired HIV. Median CD4 was 672 cells/µL. Overall, 28% had airflow obstruction and 78% had a chest CT abnormality; airflow obstruction was associated with mosaic attenuation (p=0.001). Higher endothelial activation (sVCAM-1, sICAM-1), inflammation and innate immune activation (SAA, sTREM-1, sCD163), and T-cell imbalance (lower CD4/CD8) markers were associated with airflow limitation. Factors comprising endothelial and innate immune activation were associated with airflow limitation.

CONCLUSIONS: Endothelial activation, innate immune activation, T-cell imbalance, and chronic inflammation are associated with airflow limitation and obstruction, providing insights into chronic lung disease pathophysiology among ALWH.

RevDate: 2020-01-09

Zhong J, Jermusyk A, Wu L, et al (2020)

A Transcriptome-Wide Association Study (TWAS) Identifies Novel Candidate Susceptibility Genes for Pancreatic Cancer.

Journal of the National Cancer Institute pii:5698709 [Epub ahead of print].

BACKGROUND: Although 20 pancreatic cancer susceptibility loci have been identified through genome-wide association studies (GWAS) in individuals of European ancestry, much of its heritability remains unexplained and the genes responsible largely unknown.

METHODS: To discover novel pancreatic cancer risk loci and possible causal genes, we performed a pancreatic cancer transcriptome-wide association study (TWAS) in Europeans using three approaches, FUSION, MetaXcan and SMulTiXcan. We integrated GWAS summary statistics from 9,040 pancreatic cancer cases and 12,496 controls, with gene expression prediction models built using transcriptome data from histologically normal pancreatic tissue samples (NCI Laboratory of Translational Genomics, LTG (n = 95) and Genotype-Tissue Expression, GTEx v7 (n = 174) datasets), and data from 48 different tissues (GTEx v7, n = 74-421 samples).

RESULTS: We identified 25 genes whose genetically predicted expression was statistically significantly associated with pancreatic cancer risk (FDR < 0.05), including 14 candidate genes at 11 novel loci (1p36.12: CELA3B; 9q31.1: SMC2, SMC2-AS1; 10q23.31: RP11-80H5.9; 12q13.13: SMUG1; 14q32.33: BTBD6; 15q23: HEXA; 15q26.1: RCCD1; 17q12:, PNMT, CDK12, PGAP3; 17q22: SUPT4H1; 18q11.22: RP11-888D10.3; and 19p13.11: PGPEP1) and 11 at 6 known risk loci (5p15.33: TERT, CLPTM1L, ZDHHC11B; 7p14.1: INHBA; 9q34.2: ABO; 13q12.2: PDX1; 13q22.1: KLF5; and 16q23.1: WDR59, CFDP1, BCAR1, TMEM170A). The association for 12 of these genes (CELA3B, SMC2, and PNMT at novel risk loci, and TERT, CLPTM1L, INHBA, ABO, PDX1, KLF5, WDR59, CFDP1 and BCAR1 at known loci) remained statistically significant after Bonferroni correction.

CONCLUSIONS: By integrating gene expression and genotype data, we identified novel pancreatic cancer risk loci and candidate functional genes that warrant further investigation.

RevDate: 2020-01-09

Woodward WA, Barlow WE, Jagsi R, et al (2020)

Association Between 21-Gene Assay Recurrence Score and Locoregional Recurrence Rates in Patients With Node-Positive Breast Cancer.

JAMA oncology pii:2758265 [Epub ahead of print].

Importance: The 21-gene assay recurrence score is increasingly used to personalize treatment recommendations for systemic therapy in postmenopausal women with estrogen receptor (ER)- or progesterone receptor (PR)-positive, node-positive breast cancer; however, the relevance of the 21-gene assay to radiotherapy decisions remains uncertain.

Objective: To examine the association between recurrence score and locoregional recurrence (LRR) in a postmenopausal patient population treated with adjuvant chemotherapy followed by tamoxifen or tamoxifen alone.

This cohort study was a retrospective analysis of the Southwest Oncology Group S8814, a phase 3 randomized clinical trial of postmenopausal women with ER/PR-positive, node-positive breast cancer treated with tamoxifen alone, chemotherapy followed by tamoxifen, or concurrent tamoxifen and chemotherapy. Patients at North American clinical centers were enrolled from June 1989 to July 1995. Medical records from patients with recurrence score information were reviewed for LRR and radiotherapy use. Primary analysis included 316 patients and excluded 37 who received both mastectomy and radiotherapy, 9 who received breast-conserving surgery without documented radiotherapy, and 5 with unknown surgical type. All analyses were performed from January 22, 2016, to August 9, 2019.

Main Outcomes and Measures: The LRR was defined as a recurrence in the breast; chest wall; or axillary, infraclavicular, supraclavicular, or internal mammary lymph nodes. Time to LRR was tested with log-rank tests and Cox proportional hazards regression for multivariate models.

Results: The final cohort of this study comprised 316 women with a mean (range) age of 60.4 (44-81) years. Median (interquartile range) follow-up for those without LRR was 8.7 (7.0-10.2) years. Seven LRR events (5.8%) among 121 patients with low recurrence score and 27 LRR events (13.8%) among 195 patients with intermediate or high recurrence score occurred. The estimated 10-year cumulative incidence rates were 9.7% for those with a low recurrence score and 16.5% for the group with intermediate or high recurrence score (P = .02). Among patients who had a mastectomy without radiotherapy (n = 252), the differences in the 10-year actuarial LRR rates remained significant: 7.7 % for the low recurrence score group vs 16.8% for the intermediate or high recurrence score group (P = .03). A multivariable model controlling for randomized treatment, number of positive nodes, and surgical type showed that a higher recurrence score was prognostic for LRR (hazard ratio [HR], 2.36; 95% CI, 1.02-5.45; P = .04). In a subset analysis of patients with a mastectomy and 1 to 3 involved nodes who did not receive radiation therapy, the group with a low recurrence score had a 1.5% rate of LRR, whereas the group with an intermediate or high recurrence score had a 11.1% LRR (P = .051).

Conclusions and Relevance: This study found that higher recurrence scores were associated with increased LRR after adjustment for treatment, type of surgical procedure, and number of positive nodes. This finding suggests that the recurrence score may be used, along with accepted clinical variables, to assess the risk of LRR during radiotherapy decision-making.

RevDate: 2020-01-09

Ko NY, Hong S, Winn RA, et al (2020)

Association of Insurance Status and Racial Disparities With the Detection of Early-Stage Breast Cancer.

JAMA oncology pii:2758266 [Epub ahead of print].

Importance: Compared with non-Hispanic white women, racial/ethnic minority women receive a diagnosis of breast cancer at a more advanced stage and have higher morbidity and mortality with breast cancer diagnosis. Access to care with adequate insurance may be associated with earlier diagnosis, expedited treatment, and improved prognosis.

Objective: To examine the extent to which insurance is associated with access to timely breast cancer diagnosis and breast cancer stage differences among a large, diverse population of US patients with breast cancer.

This retrospective, cross-sectional population-based study used data from the Surveillance, Epidemiology, and End Results Program on 177 075 women aged 40 to 64 years who received a diagnosis of stage I to III breast cancer between January 1, 2010, and December 31, 2016. Statistical analysis was performed from August 1, 2017, to October 1, 2019.

Main Outcomes and Measures: The primary outcome was the risk of having a more advanced stage of breast cancer at diagnosis (ie, stage III vs stages I and II). Mediation analyses were conducted to determine associations of race/ethnicity and proportion of observed differences mediated by health insurance status with earlier stage of diagnosis.

Results: A total of 177 075 women (mean [SD] age, 53.5 [6.8] years; 148 124 insured and 28 951 uninsured or receiving Medicaid) were included in the study. A higher proportion of women either receiving Medicaid or who were uninsured received a diagnosis of locally advanced breast cancer (stage III) compared with women with health insurance (20% vs 11%). In multivariable models, non-Hispanic black (odds ratio [OR], 1.46 [95% CI, 1.40-1.53]), American Indian or Alaskan Native (OR, 1.31 [95% CI, 1.07-1.61]) and Hispanic (OR, 1.35 [95% CI, 1.30-1.42]) women had higher odds of receiving a diagnosis of locally advanced disease (stage III) compared with non-Hispanic white women. When adjusting for health insurance and other socioeconomic factors, associations between race/ethnicity and risk of locally advanced breast cancer were attenuated (non-Hispanic black: OR, 1.29 [95% CI, 1.23-1.35]; American Indian or Alaskan Native: OR, 1.11 [95% CI, 0.91-1.35]; Hispanic: OR, 1.17 [95% CI, 1.12-1.22]). Nearly half (45%-47%) of racial differences in the risk of locally advanced disease were mediated by health insurance.

Conclusions and Relevance: This study's findings suggest that nearly half of the observed racial/ethnic disparities in higher stage at breast cancer diagnosis are mediated by health insurance coverage.

RevDate: 2020-01-09

Taylor JA, Bratton BP, Sichel SR, et al (2020)

Distinct cytoskeletal proteins define zones of enhanced cell wall synthesis in Helicobacter pylori.

eLife, 9: pii:52482 [Epub ahead of print].

Helical cell shape is necessary for efficient stomach colonization by Helicobacter pylori, but the molecular mechanisms for generating helical shape remain unclear. The helical centerline pitch and radius of wild-type H. pylori cells dictate surface curvatures of considerably higher positive and negative Gaussian curvatures than those present in straight- or curved-rod H. pylori. Quantitative 3D microscopy analysis of short pulses with either N-acetylmuramic acid or D-alanine metabolic probes showed that cell wall growth is enhanced at both sidewall curvature extremes. Immunofluorescence revealed MreB is most abundant at negative Gaussian curvature, while the bactofilin CcmA is most abundant at positive Gaussian curvature. Strains expressing CcmA variants with altered polymerization properties lose helical shape and associated positive Gaussian curvatures. We thus propose a model where CcmA and MreB promote PG synthesis at positive and negative Gaussian curvatures, respectively, and that this patterning is one mechanism necessary for maintaining helical shape.

RevDate: 2020-01-09

Jones SMW, Yi JC, Jim HSL, et al (2020)

Age and gender differences in financial distress among hematopoietic cell transplant survivors.

Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer pii:10.1007/s00520-019-05291-1 [Epub ahead of print].

PURPOSE: Cancer has long-term financial consequences. Adolescent and young adult (AYA) and middle-aged cancer survivors may experience more financial toxicity than older adults. This study examined age differences in financial distress in hematopoietic cell transplant survivors and whether these differences result from measurement bias, more financial barriers to care, or an overall higher level of distress.

METHODS: Hematologic malignancy survivors (n = 1135, 2-10 years post-transplant) completed the Cancer and Treatment Distress Scale (CTXD) and demographics as part of the baseline assessment for a randomized clinical trial. The CTXD has seven subscales, but for this study, we examined the financial distress subscale and the overall score. Item response theory analyses tested for bias by age and gender. Multivariate linear regression tested the association of age and gender with the CTXD scores while controlling for financial barriers to care.

RESULTS: No bias was found on the CTXD. AYA (p < 0.01) and middle-aged adults (p < 0.001) reported more financial and overall distress than older (age 65+) adults. The same association of age and financial distress was observed in women (p < 0.01). However, only middle-aged men (p < 0.01) reported more financial and overall distress than older men; AYA men did not (p > 0.18). Financial barriers to care were not associated with financial or overall distress.

CONCLUSIONS: Part of the increase in financial distress with younger age may be due to a higher risk of general distress. Policy initiatives to control cancer costs should consider life stage and the unique financial challenges at different ages for men and women.

RevDate: 2020-01-09

Marty FM, Chemaly RF, Mullane KM, et al (2019)

A Phase 2b, Randomized, Double-blind, Placebo-Controlled Multicenter Study Evaluating Antiviral Effects, Pharmacokinetics, Safety, and Tolerability of Presatovir in Hematopoietic Cell Transplant Recipients with Respiratory Syncytial Virus (RSV) Infection of the Lower Respiratory Tract.

Clinical infectious diseases : an official publication of the Infectious Diseases Society of America pii:5648099 [Epub ahead of print].

BACKGROUND: Presatovir significantly reduced nasal viral load, signs, and symptoms of respiratory syncytial virus (RSV) infection in a human challenge study. We evaluated presatovir in hematopoietic-cell transplant (HCT) recipients with RSV lower respiratory tract infection (LRTI).

METHODS: Patients with confirmed RSV in upper and lower respiratory tract and new chest X-ray abnormalities were randomized (1:1), stratified by supplemental oxygen and ribavirin use, to receive oral presatovir 200 mg or placebo every 4 days for 5 doses. The primary endpoint was time-weighted average change in nasal RSV viral load through day 9. Secondary endpoints included supplemental oxygen-free days, incident respiratory failure requiring mechanical ventilation, and all-cause mortality.

RESULTS: From January 31, 2015, to March 20, 2017, 60 patients from 17 centers were randomized (31 presatovir, 29 placebo); 59 received study treatment (50 allogeneic, 9 autologous HCT). In the efficacy population (29 presatovir, 28 placebo), presatovir treatment did not significantly reduce time-weighted average change in viral load (-1.12 vs -1.09 log10 copies/mL; treatment difference -0.02 log10 copies/mL, 95% confidence interval: -.62, .57; P = .94), median supplemental oxygen-free days (26 vs 28 days, P = .84), incident respiratory failure (10.3 vs 10.7%, P = .98), or all-cause mortality (0 vs 7.1%, P = .19) versus placebo. Adverse events were similar between arms (presatovir 80%, placebo 79%). Resistance-associated substitutions in RSV fusion protein emerged in 6/29 presatovir-treated patients.

CONCLUSIONS: Presatovir treatment was well tolerated in HCT patients with RSV LRTI but did not improve virologic or clinical outcomes versus placebo.

CLINICAL TRIALS REGISTRATION: www.clinicaltrials.gov, NCT02254421; EudraCT, #2014-002475-29.

RevDate: 2020-01-09

Estey E, Karp JE, Emadi A, et al (2020)

Recent drug approvals for newly diagnosed acute myeloid leukemia: gifts or a Trojan horse?.

Leukemia pii:10.1038/s41375-019-0704-5 [Epub ahead of print].

Since 2017 the US Food and Drug Administration (FDA) has approved glasdegib, venetoclax, ivosidenib, midostaurin, CPX- 351, and gemtuzumab ozogamicin (GO) to treat persons with newly diagnosed acute myeloid leukemia. The European Medicines Agency (EMA) has done likewise for midostaurin, CPX-351, and GO. While increasing options for persons, particularly older ones, for whom current therapy is unsatisfactory, or simply not given, these approvals raise several concerns. Although the venetoclax and glasdegib approvals were for persons considered "unfit" for intensive induction, the criteria for fitness were not well defined (age ≥75 per se being insufficient) and are frequently subjective, making it likely that many subjects in the venetoclax and glasdegib registration trials were fit for intensive induction; for example, none had performance status 3-4. Fitness must be assessed together with the potential efficacy of a proposed therapy. We note the modest complete remission rates and durations in the venetoclax + hypomethylating agent trial. Although these formed the basis for FDA approval, it is unclear that better results might not have obtained with more intense induction, as several studies, with considerably longer-follow up, have suggested. Hence, we question the venetoclax (and glasdegib) approvals absent randomized comparisons with intense induction. Given the uncertain relation in older individuals between survival and complete remission (CR), much less responses less than CR, we are skeptical of the sole use of these responses in the ivosidenib and venetoclax approvals; we also question the use of survival, without event-free survival, in the glasdegib approval. Noting the midostaurin and CPX-351 approvals included populations not participating in the registration studies we suggest means to address this issue as well as those involving fitness, randomization, and endpoints.

RevDate: 2020-01-17

James JB, Gunn AL, DM Akob (2020)

Binning Singletons: Mentoring through Networking at ASM Microbe 2019.

mSphere, 5(1): pii:5/1/e00643-19.

The American Society for Microbiology (ASM) national conference, Microbe, is the flagship meeting for microbiologists across the globe. The presence of roughly 10,000 attendees provides enormous opportunities for networking and learning. However, such a large meeting can be intimidating to many, especially early career scientists, students, those attending alone, and those from historically underrepresented groups. While mentorship is widely valued by ASM and its members, finding concrete ways to develop new and diverse mentoring opportunities can be a challenge. We recognized the need for an initiative aimed at expanding peer-to-peer mentoring, facilitating networking, and providing support for Microbe attendees; therefore, we created the program Binning Singletons for ASM Microbe 2019. The program consisted of five steps named after tools or phenomena in the profession of microbiology: (i) Identify the Singletons (e.g., individuals attending alone), (ii) Bin the Singletons, (iii) Horizontal Transfer, (iv) Quorum Sensing, and (v) Exponential Growth. These steps resulted in the matching of participants unsure of how to get the most out of their conference experience (e.g., singletons) with mentors who assisted with meeting planning, networking, and/or impostor syndrome. Started on social media only a month before ASM Microbe 2019, the program successfully launched despite limited time and resources. Binning Singletons improved inclusivity and networking opportunities for participants at the conference. Here, we discuss what worked, and what can be improved, with an eye toward development of the Binning Singletons model for future conferences to provide opportunities to increase inclusivity, networking, and accessibility for singletons and build a stronger scientific community.

RevDate: 2020-01-08

Hershman DL, Accordino MK, Shen S, et al (2020)

Association between nonadherence to cardiovascular risk factor medications after breast cancer diagnosis and incidence of cardiac events.

Cancer [Epub ahead of print].

BACKGROUND: Cardiovascular disease (CVD) is the leading cause of death among patients with early-stage breast cancer (BC), but adherence to cardiovascular disease risk factor (CVD-RF) medications is reported to be poor in BC survivors. The objective of the current study was to determine the association between nonadherence to CVD-RF medications and cardiovascular events in BC survivors.

METHODS: The authors included patients with stages I to III BC from the Surveillance, Epidemiology, and End Results (SEER)-Medicare database who had Medicare part D coverage and who were taking at least 1 CVD-RF medication prior to their BC diagnosis (2008-2013). Logistic regression was performed to define factors associated with nonadherence. Cox regression was used to calculate the association between nonadherence and new cardiac events after treatment.

RESULTS: Among 15,576 patients included in the current analysis, 4797 (30.8%) were nonadherent to at least 1 category after the initial BC treatment period. Black race, greater comorbidity burden, more advanced cancer stage, hormone receptor-negative status, and receipt of chemotherapy were found to be associated with nonadherence. Nonadherence after treatment demonstrated a trend toward an increased risk of a subsequent cardiac event (hazard ratio [HR], 1.15; 95% CI 1.00-1.33 [P = .06]). This effect size increased with nonadherence to a greater number of medications (P < .01). There was an increased risk of experiencing a cardiac event noted with becoming nonadherent to hypertension medications (HR, 1.33; 95% CI, 1.18-1.51 [P < .0001]), hyperlipidemia medications (HR, 1.21; 95% CI, 1.05-1.40 [P = .009]), and diabetes medications (HR, 1.31; 95% CI, 1.10-1.56 [P = .003]).

CONCLUSIONS: Nonadherence to CVD-RF medications after treatment of BC is associated with an increased risk of a cardiac event. Improving outcomes and reducing morbidity after a diagnosis of BC requires attention to non-BC conditions.

RevDate: 2020-01-08

Donczew R, Warfield L, Pacheco D, et al (2020)

Two roles for the yeast transcription coactivator SAGA and a set of genes redundantly regulated by TFIID and SAGA.

eLife, 9: pii:50109 [Epub ahead of print].

Deletions within genes coding for subunits of the transcription coactivator SAGA caused strong genome-wide defects in transcription and SAGA-mediated chromatin modifications. In contrast, rapid SAGA depletion produced only modest transcription defects at 13% of protein-coding genes - genes that are generally more sensitive to rapid TFIID depletion. However, transcription of these 'coactivator-redundant' genes is strongly affected by rapid depletion of both factors, showing the overlapping functions of TFIID and SAGA at this gene set. We suggest that this overlapping function is linked to TBP-DNA recruitment. The remaining 87% of expressed genes that we term 'TFIID-dependent' are highly sensitive to rapid TFIID depletion and insensitive to rapid SAGA depletion. Genome-wide mapping of SAGA and TFIID found binding of both factors at many genes independent of gene class. DNA analysis suggests that the distinction between the gene classes is due to multiple components rather than any single regulatory factor or promoter sequence motif.

RevDate: 2020-01-08

Genkinger JM, Wu K, Wang M, et al (2020)

Measures of body fatness and height in early and mid-to-late adulthood and prostate cancer: risk and mortality in The Pooling Project of Prospective Studies of Diet and Cancer.

Annals of oncology : official journal of the European Society for Medical Oncology, 31(1):103-114.

BACKGROUND: Advanced prostate cancer etiology is poorly understood. Few studies have examined associations of anthropometric factors (e.g. early adulthood obesity) with advanced prostate cancer risk.

PATIENTS AND METHODS: We carried out pooled analyses to examine associations between body fatness, height, and prostate cancer risk. Among 830 772 men, 51 734 incident prostate cancer cases were identified, including 4762 advanced (T4/N1/M1 or prostate cancer deaths) cases, 2915 advanced restricted (same as advanced, but excluding localized cancers that resulted in death) cases, 9489 high-grade cases, and 3027 prostate cancer deaths. Cox proportional hazards models were used to calculate study-specific hazard ratios (HR) and 95% confidence intervals (CI); results were pooled using random effects models.

RESULTS: No statistically significant associations were observed for body mass index (BMI) in early adulthood for advanced, advanced restricted, and high-grade prostate cancer, and prostate cancer mortality. Positive associations were shown for BMI at baseline with advanced prostate cancer (HR = 1.30, 95% CI = 0.95-1.78) and prostate cancer mortality (HR = 1.52, 95% CI = 1.12-2.07) comparing BMI ≥35.0 kg/m2 with 21-22.9 kg/m2. When considering early adulthood and baseline BMI together, a 27% higher prostate cancer mortality risk (95% CI = 9% to 49%) was observed for men with BMI <25.0 kg/m2 in early adulthood and BMI ≥30.0 kg/m2 at baseline compared with BMI <25.0 kg/m2 in early adulthood and BMI <30.0 kg/m2 at baseline. Baseline waist circumference, comparing ≥110 cm with <90 cm, and waist-to-hip ratio, comparing ≥1.00 with <0.90, were associated with significant 14%-16% increases in high-grade prostate cancer risk and suggestive or significant 20%-39% increases in prostate cancer mortality risk. Height was associated with suggestive or significant 33%-56% risks of advanced or advanced restricted prostate cancer and prostate cancer mortality, comparing ≥1.90 m with <1.65 m.

CONCLUSION: Our findings suggest that height and total and central adiposity in mid-to-later adulthood, but not early adulthood adiposity, are associated with risk of advanced forms of prostate cancer. Thus, maintenance of healthy weight may help prevent advanced prostate cancer.

RevDate: 2020-01-15

Fachal L, Aschard H, Beesley J, et al (2020)

Fine-mapping of 150 breast cancer risk regions identifies 191 likely target genes.

Nature genetics, 52(1):56-73.

Genome-wide association studies have identified breast cancer risk variants in over 150 genomic regions, but the mechanisms underlying risk remain largely unknown. These regions were explored by combining association analysis with in silico genomic feature annotations. We defined 205 independent risk-associated signals with the set of credible causal variants in each one. In parallel, we used a Bayesian approach (PAINTOR) that combines genetic association, linkage disequilibrium and enriched genomic features to determine variants with high posterior probabilities of being causal. Potentially causal variants were significantly over-represented in active gene regulatory regions and transcription factor binding sites. We applied our INQUSIT pipeline for prioritizing genes as targets of those potentially causal variants, using gene expression (expression quantitative trait loci), chromatin interaction and functional annotations. Known cancer drivers, transcription factors and genes in the developmental, apoptosis, immune system and DNA integrity checkpoint gene ontology pathways were over-represented among the highest-confidence target genes.

RevDate: 2020-01-17

Thomas JD, Polaski JT, Feng Q, et al (2020)

RNA isoform screens uncover the essentiality and tumor-suppressor activity of ultraconserved poison exons.

Nature genetics, 52(1):84-94.

While RNA-seq has enabled comprehensive quantification of alternative splicing, no correspondingly high-throughput assay exists for functionally interrogating individual isoforms. We describe pgFARM (paired guide RNAs for alternative exon removal), a CRISPR-Cas9-based method to manipulate isoforms independent of gene inactivation. This approach enabled rapid suppression of exon recognition in polyclonal settings to identify functional roles for individual exons, such as an SMNDC1 cassette exon that regulates pan-cancer intron retention. We generalized this method to a pooled screen to measure the functional relevance of 'poison' cassette exons, which disrupt their host genes' reading frames yet are frequently ultraconserved. Many poison exons were essential for the growth of both cultured cells and lung adenocarcinoma xenografts, while a subset had clinically relevant tumor-suppressor activity. The essentiality and cancer relevance of poison exons are likely to contribute to their unusually high conservation and contrast with the dispensability of other ultraconserved elements for viability.

RevDate: 2020-01-11

Kachuri L, Johansson M, Rashkin SR, et al (2020)

Immune-mediated genetic pathways resulting in pulmonary function impairment increase lung cancer susceptibility.

Nature communications, 11(1):27.

Impaired lung function is often caused by cigarette smoking, making it challenging to disentangle its role in lung cancer susceptibility. Investigation of the shared genetic basis of these phenotypes in the UK Biobank and International Lung Cancer Consortium (29,266 cases, 56,450 controls) shows that lung cancer is genetically correlated with reduced forced expiratory volume in one second (FEV1: rg = 0.098, p = 2.3 × 10-8) and the ratio of FEV1 to forced vital capacity (FEV1/FVC: rg = 0.137, p = 2.0 × 10-12). Mendelian randomization analyses demonstrate that reduced FEV1 increases squamous cell carcinoma risk (odds ratio (OR) = 1.51, 95% confidence intervals: 1.21-1.88), while reduced FEV1/FVC increases the risk of adenocarcinoma (OR = 1.17, 1.01-1.35) and lung cancer in never smokers (OR = 1.56, 1.05-2.30). These findings support a causal role of pulmonary impairment in lung cancer etiology. Integrative analyses reveal that pulmonary function instruments, including 73 novel variants, influence lung tissue gene expression and implicate immune-related pathways in mediating the observed effects on lung carcinogenesis.

RevDate: 2020-01-10

Brown P, Inaba H, Annesley C, et al (2020)

Pediatric Acute Lymphoblastic Leukemia, Version 2.2020, NCCN Clinical Practice Guidelines in Oncology.

Journal of the National Comprehensive Cancer Network : JNCCN, 18(1):81-112.

Acute lymphoblastic leukemia (ALL) is the most common pediatric malignancy. Advancements in technology that enhance our understanding of the biology of the disease, risk-adapted therapy, and enhanced supportive care have contributed to improved survival rates. However, additional clinical management is needed to improve outcomes for patients classified as high risk at presentation (eg, T-ALL, infant ALL) and who experience relapse. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for pediatric ALL provide recommendations on the workup, diagnostic evaluation, and treatment of the disease, including guidance on supportive care, hematopoietic stem cell transplantation, and pharmacogenomics. This portion of the NCCN Guidelines focuses on the frontline and relapsed/refractory management of pediatric ALL.

RevDate: 2020-01-10

Becker PS, Griffiths EA, Alwan LM, et al (2020)

NCCN Guidelines Insights: Hematopoietic Growth Factors, Version 1.2020.

Journal of the National Comprehensive Cancer Network : JNCCN, 18(1):12-22.

Management of febrile neutropenia (FN) is an integral part of supportive care for patients undergoing cancer treatment. The NCCN Guidelines for Hematopoietic Growth Factors provide suggestions for appropriate evaluation, risk determination, prophylaxis, and management of FN. These NCCN Guidelines are intended to guide clinicians in the appropriate use of growth factors for select patients undergoing treatment of nonmyeloid malignancies. These NCCN Guidelines Insights highlight important updates to the NCCN Guidelines regarding the incorporation of newly FDA-approved granulocyte-colony stimulating factor biosimilars for the prevention and treatment of FN.

RevDate: 2020-01-09

O'Brien KM, Tworoger SS, Harris HR, et al (2020)

Association of Powder Use in the Genital Area With Risk of Ovarian Cancer.

JAMA, 323(1):49-59.

Importance: The relationship between use of powder in the genital area and ovarian cancer is not established. Positive associations reported in case-control studies have not been confirmed in cohort studies.

Objective: To estimate the association between use of powder in the genital area and ovarian cancer using prospective observational data.

Data were pooled from 4 large, US-based cohorts: Nurses' Health Study (enrollment 1976; follow-up 1982-2016; n = 81 869), Nurses' Health Study II (enrollment 1989; follow-up 2013-2017; n = 61 261), Sister Study (enrollment 2003-2009; follow-up 2003-2017; n = 40 647), and Women's Health Initiative Observational Study (enrollment 1993-1998; follow-up 1993-2017; n = 73 267).

Exposures: Ever, long-term (≥20 years), and frequent (≥1/week) use of powder in the genital area.

Main Outcomes and Measures: The primary analysis examined the association between ever use of powder in the genital area and self-reported incident ovarian cancer. Covariate-adjusted hazard ratios (HRs) and 95% CIs were estimated using Cox proportional hazards models.

Results: The pooled sample included 252 745 women (median age at baseline, 57 years) with 38% self-reporting use of powder in the genital area. Ten percent reported long-term use, and 22% reported frequent use. During a median of 11.2 years of follow-up (3.8 million person-years at risk), 2168 women developed ovarian cancer (58 cases/100 000 person-years). Ovarian cancer incidence was 61 cases/100 000 person-years among ever users and 55 cases/100 000 person-years among never users (estimated risk difference at age 70 years, 0.09% [95% CI, -0.02% to 0.19%]; estimated HR, 1.08 [95% CI, 0.99 to 1.17]). The estimated HR for frequent vs never use was 1.09 (95% CI, 0.97 to 1.23) and for long-term vs never use, the HR was 1.01 (95% CI, 0.82 to 1.25). Subgroup analyses were conducted for 10 variables; the tests for heterogeneity were not statistically significant for any of these comparisons. While the estimated HR for the association between ever use of powder in the genital area and ovarian cancer risk among women with a patent reproductive tract was 1.13 (95% CI, 1.01 to 1.26), the P value for interaction comparing women with vs without patent reproductive tracts was .15.

Conclusions and Relevance: In this analysis of pooled data from women in 4 US cohorts, there was not a statistically significant association between use of powder in the genital area and incident ovarian cancer. However, the study may have been underpowered to identify a small increase in risk.

RevDate: 2020-01-14

Lamp K, McGovern S, Fong Y, et al (2020)

Proportions of CD4 test results indicating advanced HIV disease remain consistently high at primary health care facilities across four high HIV burden countries.

PloS one, 15(1):e0226987 pii:PONE-D-19-27242.

BACKGROUND: Globally, nearly 22 million HIV-infected patients are currently accessing antiretroviral treatment; however, almost one million people living with HIV died of AIDS-related illnesses in 2018. Advanced HIV disease remains a significant issue to curb HIV-related mortality.

METHODS: We analyzed 864,389 CD4 testing records collected by 1,016 Alere Pima Analyzers implemented at a variety of facilities, including peripheral facilities, between January 2012 and December 2016 across four countries in sub-Saharan Africa. Routinely collected data and programmatic records were used to analyze the median CD4 counts and proportions of patients with advanced HIV disease by country, facility type, and year.

RESULTS: Median CD4 counts were between 409-444 cells/ul each year since 2012 with a median in 2016 of 444 cells/ul (n = 319,829). The proportion of test results returning CD4 counts above 500 cells/ul has increased slowly each year with 41.8% (95% CI: 41.6-41.9%) of tests having a CD4 count above 500 cells/ul in 2016. Median CD4 counts were similar across facility types. The proportion of test results indicating advanced HIV disease has remained fairly consistent: 19.4% (95% CI: 18.8-20.1%) in 2012 compared to 16.1% (95% CI: 16.0-16.3%) in 2016. The proportion of test results indicating advanced HIV disease annually ranged from 14.5% in Uganda to 29.8% in Cameroon. 6.9% (95% CI: 6.8-7.0%) of test results showed very advanced HIV disease (CD4<100 cells/ul) in 2016.

CONCLUSIONS: The proportion of CD4 test results indicating advanced disease was relatively high and consistent across four high HIV burden countries.

RevDate: 2020-01-07

Buckley SA, Halpern AB, Othus M, et al (2020)

Development and validation of the AML-QOL: a quality of life instrument for patients with acute myeloid leukemia.

Leukemia & lymphoma [Epub ahead of print].

There is currently no validated quality of life (QOL) instrument specific to patients with acute myeloid leukemia (AML). A previous cross-sectional interview-based study elicited concepts for inclusion in a novel QOL instrument. Here, we further develop and validate this new instrument, the AML-QOL. Iterative revisions of the draft AML-QOL were refined based on feedback from 16 patients, 8 medical providers, and 3 psychometricians. The instrument underwent factor analysis based on responses from 202 patients with AML and analogous aggressive myeloid neoplasms receiving AML-like therapy. A prospective validation study was then undertaken in 50 patients who completed the AML-QOL at multiple time points while undergoing a cycle of intensive chemotherapy to establish test-retest reliability and sensitivity to change. The final AML-QOL contains 27 items and is categorized into 5 domains (Physical, Social, Cognitive, Anxiety, Depression), one Symptom Index, a single item assessing overall quality of life, and a Summary Score. The AML-QOL domains show high internal consistency (median alpha: 0.85), good test-retest reliability (median interclass correlation: 0.82), and had convergent and divergent validity when compared to a non-disease-specific instrument (the EORTC QLQ-C30). The Summary Score demonstrated good sensitivity to change when anchored to patient perception of QOL change. The AML-QOL is a reliable and valid measure of QOL in patients with AML and analogous aggressive myeloid neoplasms. A clinically meaningful difference is 8-10 points out of 100 on the Summary Score.

RevDate: 2020-01-06

Topazian HM, Stoner MCD, Edwards JK, et al (2020)

Variations in HIV risk by young women's age and partner age-disparity in rural South Africa (HPTN 068).

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

BACKGROUND: Nearly all population-level research showing positive associations between age-disparate partnerships and HIV acquisition among adolescent girls and young women (AGYW) has classified age disparity as ≥5 or ≥10 years. We describe variations in one-year risk of HIV infection after exposure to sexual partner(s) of continuous age disparities.

METHODS: Longitudinal data from the HPTN 068 randomized trial in South Africa was used to estimate one-year risk of HIV infection at various age pairings. The parametric g-formula was employed to estimate risk at up to five annual time points, stratified by maximum partner age difference, maximum partner age, and AGYW age.

RESULTS: AGYW reported an older partner in 86% of 5,351 age pairings. The one-year risk of HIV infection rapidly increased with maximum partner age difference among girls ages 13 to 14, from 0·01 with a same-age partner, to 0·21 with a partner ten years older, and 0·24 with a partner 15 years older. A gradual increase occurred among AGYW ages 15 to 16, up to 0·13 with a partner 15 years older, and 0·09 among AGYW 17 to 18 with partners 8 to 11 years older. Risk of HIV infection among AGYW ages 19 to 21 remained relatively constant across maximum partner age differences.

CONCLUSION: Age differences between AGYW and their sexual partners have a greater effect on HIV risk infection in younger compared to older AGYW. Considering both the age of an AGYW and her sexual partners provides granular insight into identifying key groups for HIV transmission prevention efforts.

RevDate: 2020-01-08

Storbeck KH, EA Mostaghel (2019)

Canonical and Noncanonical Androgen Metabolism and Activity.

Advances in experimental medicine and biology, 1210:239-277.

Androgens are critical drivers of prostate cancer. In this chapter we first discuss the canonical pathways of androgen metabolism and their alterations in prostate cancer progression, including the classical, backdoor and 5α-dione pathways, the role of pre-receptor DHT metabolism, and recent findings on oncogenic splicing of steroidogenic enzymes. Next, we discuss the activity and metabolism of non-canonical 11-oxygenated androgens that can activate wild-type AR and are less susceptible to glucuronidation and inactivation than the canonical androgens, thereby serving as an under-recognized reservoir of active ligands. We then discuss an emerging literature on the potential non-canonical role of androgen metabolizing enzymes in driving prostate cancer. We conclude by discussing the potential implications of these findings for prostate cancer progression, particularly in context of new agents such as abiraterone and enzalutamide, which target the AR-axis for prostate cancer therapy, including mechanisms of response and resistance and implications of these findings for future therapy.

RevDate: 2020-01-04

Hosseinipour MC, Innes C, Naidoo S, et al (2020)

Phase 1 HIV vaccine trial to evaluate the safety and immunogenicity of HIV subtype C DNA and MF59-adjuvanted subtype C Env protein.

Clinical infectious diseases : an official publication of the Infectious Diseases Society of America pii:5695901 [Epub ahead of print].

BACKGROUND: The Pox-Protein Public-Private Partnership (P5) is performing a suite of trials to evaluate the bivalent subtype C envelope (Env) protein (TV1.C and 1086.C gp120) vaccine in the context of different adjuvants and priming agents for HIV-1 prevention.

METHODS: In the HIV Vaccine Trials Network (HVTN) 111 trial, we compared safety and immunogenicity of DNA prime followed by DNA/protein boost with DNA/protein co-administration injected intramuscularly via either needle/syringe or a needle-free injection device (Biojector). One hundred thirty-two healthy, HIV-1-uninfected adults were enrolled from Zambia, South Africa and Tanzania and were randomized to one of six arms: DNA prime, protein boost by needle/syringe; DNA and protein co-administration by needle/syringe; placebo by needle/syringe; DNA prime, protein boost with DNA given by Biojector; DNA and protein co-administration with DNA given by Biojector; and placebo by Biojector.

RESULTS: All vaccinations were safe and well tolerated. DNA and protein co-administration was associated with increased HIV-1 V1/V2 antibody response rate, a known correlate of decreased HIV-1 infection risk. DNA administration by Biojector elicited significantly higher CD4+ T-cell response rates to HIV Env than by needle/syringe in the prime/boost regimen (85.7% vs. 55.6%, p=0.02), but not in the co-administration regimen (43.3% vs. 48.3%, p=0.61).

CONCLUSIONS: Both the prime/boost and co-administration regimens are safe and may be promising for advancement into efficacy trials depending on whether cellular versus humoral responses are desired.Trial Registration: South African National Clinical Trials Registry (Application ID 3947; DoH number DOH-27-0715-4917) and ClinicalTrials.gov (NCT02997969).

RevDate: 2020-01-04

Falzarano SM, Nyame YA, McKenney JK, et al (2020)

Clinicopathologic features and outcomes of anterior-dominant prostate cancer: implications for diagnosis and treatment.

Prostate cancer and prostatic diseases pii:10.1038/s41391-019-0199-1 [Epub ahead of print].

OBJECTIVE: This study aims to describe the pathological features and clinical outcomes in anterior-dominant prostate cancer (APCA) compared to posterior/posterolateral-dominant prostate cancer (PPCA) among men treated with radical prostatectomy for localized prostate cancer.

METHODS: This is a single-institution, matched case-control analysis of short-term clinical outcomes stratified by pathologic tumor location at radical prostatectomy. Pathologic data extracted by expert genitourinary pathologists on tumor location was linked to clinical and oncologic outcomes data from a prospective institutional database for analysis.

RESULTS: From 2005 to 2013, 1580 patients were identified for analysis with 150 (9.5%) having APCA. One-hundred and thirty two of these APCA men had complete clinical data and were matched to 353 men with PPCA (~1:3 ratio) by GrdGrp at surgery, margin status, and pathologic T stage. There were no racial/ethnic differences between APCA and PPCA (p = 0.13). Men with APCA demonstrated a higher median PSA at diagnosis (6.4 [4.6-9.1] ng/mL vs 5.6 [4.4-8.1] ng/mL; p = 0.04), a higher rate of GrdGrp 1 disease at diagnosis (57.7% vs. 40.0%, p = 0.003), and lower rates of abnormal digital rectal examination (DRE) (10.1% vs. 23.2%, p = 0.003) when compared to PPCA. The rate of surgical upgrading was higher among men with APCA vs. PPCA (55.3% vs 42.0%, p = 0.015). Freedom from biochemical failure (BF) at 5-years was 85.1% (95% CI 73.1-98.9) for APCA and 82.9% (95% CI 69.2-99.5) for men with PPCA (p = 0.70, log-rank test).

CONCLUSIONS: The majority of anterior tumors were undetectable by DRE and were associated with higher PSA at diagnosis. Despite presenting mostly as low/intermediate grade cancers, more than half of the men with APCA had upgrading at surgery and slightly more than 40% had positive margins and/or extraprostatic disease. When matched to a cohort of posterior predominant tumors, no differences were seen in the rate of biochemical-failure after prostatectomy.

RevDate: 2020-01-04

Schweizer MT, EY Yu (2020)

"Matching" the "mismatch" repair deficient prostate cancer with immunotherapy.

Clinical cancer research : an official journal of the American Association for Cancer Research pii:1078-0432.CCR-19-3780 [Epub ahead of print].

Mismatch repair gene mutations are uncommon in advanced prostate cancer; however, in those harboring these alterations, immune checkpoint blockade can be effective. As such, assays that can accurately identify these men are critically important. Cell-free circulating tumor DNA-based sequencing approaches appear to be one viable approach for identifying these patients.

RevDate: 2020-01-08

Wang T, Maden SK, Luebeck GE, et al (2020)

Dysfunctional epigenetic aging of the normal colon and colorectal cancer risk.

Clinical epigenetics, 12(1):5.

BACKGROUND: Chronological age is a prominent risk factor for many types of cancers including colorectal cancer (CRC). Yet, the risk of CRC varies substantially between individuals, even within the same age group, which may reflect heterogeneity in biological tissue aging between people. Epigenetic clocks based on DNA methylation are a useful measure of the biological aging process with the potential to serve as a biomarker of an individual's susceptibility to age-related diseases such as CRC.

METHODS: We conducted a genome-wide DNA methylation study on samples of normal colon mucosa (N = 334). Subjects were assigned to three cancer risk groups (low, medium, and high) based on their personal adenoma or cancer history. Using previously established epigenetic clocks (Hannum, Horvath, PhenoAge, and EpiTOC), we estimated the biological age of each sample and assessed for epigenetic age acceleration in the samples by regressing the estimated biological age on the individual's chronological age. We compared the epigenetic age acceleration between different risk groups using a multivariate linear regression model with the adjustment for gender and cell-type fractions for each epigenetic clock. An epigenome-wide association study (EWAS) was performed to identify differential methylation changes associated with CRC risk.

RESULTS: Each epigenetic clock was significantly correlated with the chronological age of the subjects, and the Horvath clock exhibited the strongest correlation in all risk groups (r > 0.8, p < 1 × 10-30). The PhenoAge clock (p = 0.0012) revealed epigenetic age deceleration in the high-risk group compared to the low-risk group.

CONCLUSIONS: Among the four DNA methylation-based measures of biological age, the Horvath clock is the most accurate for estimating the chronological age of individuals. Individuals with a high risk for CRC have epigenetic age deceleration in their normal colons measured by the PhenoAge clock, which may reflect a dysfunctional epigenetic aging process.

RevDate: 2020-01-17

Inamoto Y, Lee SJ, Onstad LE, et al (2020)

Refined National Institutes of Health response algorithm for chronic graft-versus-host disease in joints and fascia.

Blood advances, 4(1):40-46.

Implementation of the 2014 National Institutes of Health (NIH) response algorithm for joint/fascia graft-versus-host disease (GVHD) has identified real-world limits to its application. To refine the 2014 NIH response algorithm, we analyzed multicenter prospective observational data from the Chronic GVHD Consortium. The training cohort included 209 patients and the replication cohort included 191 patients with joint/fascia involvement during their course of chronic GVHD. Linear mixed models with random patient effect were used to evaluate correlations between response categories and clinician- or patient-perceived changes in joint status as an anchor of response. Analysis of the training cohort showed that a 2-point change in total photographic range of motion (P-ROM) score was clinically meaningful. The results also suggested that a change from 0 to 1 on the NIH joint/fascia score should not be considered as worsening and suggested that both the NIH joint/fascia score and total P-ROM score, but not individual P-ROM scores, should be used for response assessment. On the basis of these results, we developed an evidence-based refined algorithm, the utility of which was examined in an independent replication cohort. Using the refined algorithm, ∼40% of responses were reclassified, largely mitigating most divergent responses among individual joints and changes from 0 to 1 on the NIH joint/fascia score. The refined algorithm showed robust point estimates and tighter 95% confidence intervals associated with clinician- or patient-perceived changes, compared with the 2014 NIH algorithm. The refined algorithm provides a superior, evidence-based method for measuring therapeutic response in joint/fascia chronic GVHD.

RevDate: 2020-01-03

Zhou J, Nutescu EA, Han J, et al (2020)

Clinical trajectories, healthcare resource use, and costs of long-term hematopoietic stem cell transplantation survivors: a latent class analysis.

Journal of cancer survivorship : research and practice pii:10.1007/s11764-019-00842-1 [Epub ahead of print].

PURPOSE: To identify patterns of healthcare utilization in allogeneic and autologous hematopoietic stem cell transplantation (HSCT) recipients and evaluate factors associated with high-need and high-cost post-transplantation care.

METHODS: Latent class analysis of a retrospective cohort of long-term allogeneic (n = 436) and autologous (n = 888) HSCT survivors within the Truven MarketScan database (2009-2014). We assessed factors associated with the latent classes by comparing post-transplantation healthcare utilization including inpatient admissions and length of stay, emergency room visits, specialist visits, and primary care provider visits.

RESULTS: Four utilization classes were identified in allogeneic and autologous HSCT recipients: (i) outpatient specialist care dominant (51.8% and 57.3%), (ii) outpatient primary care dominant (10.3% and 25.7%), (iii) outpatient/inpatient balanced (20.6% and 13.5%), and (iv) inpatient dominant (17.2% and 3.5%). Mean monthly healthcare expenditures in the inpatient dominant utilization class were $41,097 and $25,556 for allogeneic and autologous survivors, respectively, which were two to five times higher compared with other classes during the 2-year post-transplantation period. Factors associated with the high utilization class were transfusion (OR = 1.87, 95% CI 1.06-3.30) and 100-day post-transplant graft-versus-host-disease (OR = 1.76, 95% CI 1.05-2.94) in allogeneic HSCT; higher baseline Charlson comorbidity index (OR = 1.45, 95% CI 1.19-1.76) in autologous HSCT.

CONCLUSION: Based on distinct patterns of healthcare utilization following HSCT, we identified factors associated with higher resource utilization and greater healthcare related expenditures.

Earlier identification of high-cost and high-need HSCT long-term survivors could pave the way for clinicians to offer more continuous engagement in survivorship care delivery.

RevDate: 2020-01-06

Crawford KHD, JD Bloom (2019)

alignparse: A Python package for parsing complex features from high-throughput long-read sequencing.

Journal of open source software, 4(44):.

Advances in sequencing technology have made it possible to generate large numbers of long, high-accuracy sequencing reads. For instance, the new PacBio Sequel platform can generate hundreds of thousands of high-quality circular consensus sequences in a single run (Hebert et al., 2018; Rhoads & Au, 2015). Good programs exist for aligning these reads for genome assembly (Chaisson & Tesler, 2012; Li, 2018). However, these long reads can also be used for other purposes, such as sequencing PCR amplicons that contain various features of interest. For instance, PacBio circular consensus sequences have been used to identify the mutations in influenza viruses in single cells (Russell et al, 2019), or to link barcodes to gene mutants in deep mutational scanning (Matreyek et al., 2018). For such applications, the alignment of the sequences to the targets may be fairly trivial, but it is not trivial to then parse specific features of interest (such as mutations, unique molecular identifiers, cell barcodes, and flanking sequences) from these alignments. Here we describe alignparse, a Python package for parsing complex sets of features from long sequences that map to known targets. Specifically, it allows the user to provide complex target sequences in Genbank Flat File format that contain an arbitrary number of user-defined sub-sequence features (Sayers et al., 2019). It then aligns the sequencing reads to these targets and filters alignments based on whether the user-specified features are present with the desired identities (which can be set to different thresholds for different features). Finally, it parses out the sequences, mutations, and/or accuracy (sequence quality) of these features as specified by the user. The flexibility of this package therefore fulfills the need for a tool to extract and analyze complex sets of features in large numbers of long sequencing reads.

RevDate: 2020-01-02

Keech CA, Morrison R, Anderson P, et al (2019)

A Phase 1 Randomized, Placebo-controlled, Observer-blinded Trial to Evaluate the Safety and Immunogenicity of Inactivated Streptococcus pneumoniae Whole-cell Vaccine in Adults.

The Pediatric infectious disease journal [Epub ahead of print].

BACKGROUND: Broadly protective pneumococcal vaccines that are affordable for low-resource countries are needed. Streptococcus pneumoniae whole cell vaccine (wSp) is an investigational vaccine that contains killed cells from a nonencapsulated strain of S. pneumoniae (SPn) with aluminum hydroxide adjuvant. Studies in mice demonstrated protection against nasopharyngeal carriage (T-cell-mediated) and invasive pneumococcal disease (antibody-mediated). The aim of this randomized, double-blind, placebo-controlled Phase 1 study was to assess safety, tolerability and immunogenicity of wSp in healthy adults.

METHODS: Forty-two participants were randomized into 3 dose cohorts to receive 0.1, 0.3, or 0.6 mg of wSp or saline intramuscularly. Participants received a 3-dose vaccination schedule spaced by 4-week intervals. Postvaccination assessments included solicited reactogenicity events through day 7, blood chemistry and hematology assessments at day 7, and adverse events (AEs) through day 84. Participants were monitored for serum antibody and peripheral blood mononuclear cell cytokine responses to pneumococcal antigens. A 6-month telephone follow-up was completed to assess for any additional AEs.

RESULTS: wSp was safe and well tolerated. Reactogenicity was acceptable and no untoward safety signals were observed. wSp elicited potentially clinically significant rises (defined arbitrarily as at least a 2-fold rise) in immunoglobulin G responses to multiple pneumococcal antigens, including pneumococcal surface protein A and pneumolysin. Functional antibody responses were observed with the highest dose of wSp (0.6 mg). Increases in T-cell cytokine responses, including interleukin 17A, were also seen among wSp vaccines.

CONCLUSIONS: wSp was safe and well tolerated in healthy US adults, eliciting pneumococcal antigen-specific antibody and T-cell cytokine responses.

RevDate: 2020-01-02

Yeh JM, Ward ZJ, Chaudhry A, et al (2020)

Life Expectancy of Adult Survivors of Childhood Cancer Over 3 Decades.

JAMA oncology pii:2757844 [Epub ahead of print].

Importance: Advances in childhood and adolescent cancer treatment have been associated with increased rates of cure during the past 3 decades; however, improvement in adult life expectancy for these individuals has not yet been reported.

Objectives: To project long-term survival and assess whether life expectancy will improve among adult survivors of childhood cancer who were treated in more recent decades.

A microsimulation model of competing mortality risks was developed using data from the Childhood Cancer Survivor Study on 5-year survivors of childhood cancer diagnosed between 1970 and 1999. The model included (1) late recurrence, (2) treatment-related late effects (health-related [subsequent cancers, cardiac events, pulmonary conditions, and other] and external causes), and (3) US background mortality rates.

Exposures: Treatment subgroups (no treatment or surgery only, chemotherapy alone, radiotherapy alone, and radiotherapy with chemotherapy) and individuals with acute lymphoblastic leukemia during childhood by era (1970-1979, 1980-1989, and 1990-1999).

Main Outcomes and Measures: Conditional life expectancy (defined as the number of years a 5-year survivor can expect to live), cumulative cause-specific mortality risk, and 10-year mortality risks conditional on attaining ages of 30, 40, 50, and 60 years.

Results: Among the hypothetical cohort of 5-year survivors of childhood cancer representative of the Childhood Cancer Survivor Study participants (44% female and 56% male; mean [SD] age at diagnosis, 7.3 [5.6] years), conditional life expectancy was 48.5 years (95% uncertainty interval [UI], 47.6-49.6 years) for 5-year survivors diagnosed in 1970-1979, 53.7 years (95% UI, 52.6-54.7 years) for those diagnosed in 1980-1989, and 57.1 years (95% UI, 55.9-58.1 years) for those diagnosed in 1990-1999. Compared with individuals without a history of cancer, these results represented a gap in life expectancy of 25% (95% UI, 24%-27%) (16.5 years [95% UI, 15.5-17.5 years]) for those diagnosed in 1970-1979, 19% (95% UI, 17%-20%) (12.3 years [95% UI, 11.3-13.4 years]) for those diagnosed in 1980-1989, and 14% (95% UI, 13%-16%) (9.2 years [95% UI, 8.3-10.4 years]) for those diagnosed in 1990-1999. During the 3 decades, the proportion of survivors treated with chemotherapy alone increased (from 18% in 1970-1979 to 54% in 1990-1999), and the life expectancy gap in this chemotherapy-alone group decreased from 11.0 years (95% UI, 9.0-13.1 years) to 6.0 years (95% UI, 4.5-7.6 years). In contrast, during the same time frame, only modest improvements in the gap in life expectancy were projected for survivors treated with radiotherapy (21.0 years [95% UI, 18.5-23.2 years] to 17.6 years [95% UI, 14.2-21.2 years]) or with radiotherapy and chemotherapy (17.9 years [95% UI, 16.7-19.2 years] to 14.8 years [95% UI, 13.1-16.7 years]). For the largest group of survivors by diagnosis-those with acute lymphoblastic leukemia-the gap in life expectancy decreased from 14.7 years (95% UI, 12.8-16.5 years) in 1970-1979 to 8.0 years (95% UI, 6.2-9.7 years).

Conclusions and Relevance: Evolving treatment approaches are projected to be associated with improved life expectancy after treatment for pediatric cancer, in particular among those who received chemotherapy alone for their childhood cancer diagnosis. Despite improvements, survivors remain at risk for shorter lifespans, especially when radiotherapy was included as part of their childhood cancer treatment.

RevDate: 2020-01-02

Park S, Song CS, Lin CL, et al (2020)

Inhibitory Interplay of SULT2B1b Sulfotransferase with AKR1C3 Aldo-keto Reductase in Prostate Cancer.

Endocrinology pii:5693375 [Epub ahead of print].

SULT2B1b (SULT2B) is a prostate-expressed hydroxysteroid sulfotransferase, which may regulate intracrine androgen homeostasis by mediating 3β-sulfation of DHEA, the precursor for DHT biosynthesis. The aldo-keto reductase AKR1C3 regulates androgen receptor (AR) activity in castration-resistant prostate cancer (CRPC) by promoting tumor-tissue androgen biosynthesis from adrenal DHEA and also by functioning as an AR-selective coactivator. Herein we report that SULT2B-depleted CRPC cells, arising from stable RNA interference or gene knockout, are markedly upregulated for AKR1C3, activated for ERK1/2 survival signal, and induced for epithelial-to-mesenchymal(EMT)-like changes. EMT was evident from increased mesenchymal proteins and elevated EMT-inducing transcription factors SNAI1 and TWIST1 in immunoblot and single-cell mass cytometry analyses. SULT2B-knockout cells showed greater motility and invasion in vitro; growth escalation in xenograft study; and enhanced metastatic potential predicted on the basis of decreased cell stiffness and adhesion revealed from atomic force microscopy analysis. While AR and androgen levels were unchanged, AR activity was elevated, since PSA and FKBP5 mRNA induction by DHT-activated AR was several-fold higher in SULT2B-silenced cells. AKR1C3 silencing prevented ERK1/2 activation and SNAI1 induction in SULT2B-depleted cells. SULT2B was undetectable in nearly all CRPC metastases from fifty autopsy cases. Primary tumors showed variable and Gleason score independent SULT2B levels. CRPC metastases lacking SULT2B expressed AKR1C3. Since AKR1C3 is frequently elevated in advanced prostate cancer, the inhibitory influence of SULT2B on AKR1C3 upregulation, ERK1/2 activation, EMT-like induction and on cell motility and invasiveness may be clinically significant. Pathways regulating the inhibitory SULT2B-AKR1C3 axis may inform new avenue(s) for targeting SULT2B-deficient prostate cancer.

RevDate: 2020-01-08

Chow LQM (2020)

Head and Neck Cancer.

The New England journal of medicine, 382(1):60-72.

RevDate: 2020-01-08

Pendergrass SA, Buyske S, Jeff JM, et al (2019)

A phenome-wide association study (PheWAS) in the Population Architecture using Genomics and Epidemiology (PAGE) study reveals potential pleiotropy in African Americans.

PloS one, 14(12):e0226771.

We performed a hypothesis-generating phenome-wide association study (PheWAS) to identify and characterize cross-phenotype associations, where one SNP is associated with two or more phenotypes, between thousands of genetic variants assayed on the Metabochip and hundreds of phenotypes in 5,897 African Americans as part of the Population Architecture using Genomics and Epidemiology (PAGE) I study. The PAGE I study was a National Human Genome Research Institute-funded collaboration of four study sites accessing diverse epidemiologic studies genotyped on the Metabochip, a custom genotyping chip that has dense coverage of regions in the genome previously associated with cardio-metabolic traits and outcomes in mostly European-descent populations. Here we focus on identifying novel phenome-genome relationships, where SNPs are associated with more than one phenotype. To do this, we performed a PheWAS, testing each SNP on the Metabochip for an association with up to 273 phenotypes in the participating PAGE I study sites. We identified 133 putative pleiotropic variants, defined as SNPs associated at an empirically derived p-value threshold of p<0.01 in two or more PAGE study sites for two or more phenotype classes. We further annotated these PheWAS-identified variants using publicly available functional data and local genetic ancestry. Amongst our novel findings is SPARC rs4958487, associated with increased glucose levels and hypertension. SPARC has been implicated in the pathogenesis of diabetes and is also known to have a potential role in fibrosis, a common consequence of multiple conditions including hypertension. The SPARC example and others highlight the potential that PheWAS approaches have in improving our understanding of complex disease architecture by identifying novel relationships between genetic variants and an array of common human phenotypes.

RevDate: 2020-01-17

Inadomi JM, Issaka RB, BB Green (2019)

What Multi-Level Interventions Do We Need to Increase the Colorectal Cancer Screening Rate to 80%?.

Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association pii:S1542-3565(19)31495-8 [Epub ahead of print].

Screening reduces colorectal cancer mortality; however, this remains the second leading cause of cancer deaths in the United States and adherence to colorectal cancer screening falls far short of the National Colorectal Cancer Roundtable goal of 80%. Numerous studies have examined the effectiveness of interventions to increase colorectal cancer screening uptake. Outreach is the active dissemination of screening outside of the primary care setting, such as mailing fecal blood tests to individuals' homes. Navigation uses trained personnel to assist individuals through the screening process. Patient education may take the form of brochures, videos, or websites. Provider education can include feedback about screening rates of patient panels. Reminders to healthcare providers can be provided by dashboards of patients due for screening. Financial incentives provide monetary compensation to individuals when they complete screening tests, either as fixed payments or via a lottery. Individual preference for specific screening strategies has also been examined in several trials, with a choice of screening strategies yielding higher adherence than recommendation of a single strategy.

RevDate: 2019-12-30

McDermott CL, Engelberg RA, JR Curtis (2019)

Authors' Response to: Novel Data Linkage for Quality Improvement in Palliative and End-of-Life Care.

RevDate: 2020-01-02

Wu ES, Urban RR, Krantz EM, et al (2020)

The association between HIV infection and cervical cancer presentation and survival in Uganda.

Gynecologic oncology reports, 31:100516.

Our objective was to determine how HIV infection impacts cervical cancer stage at presentation and overall survival (OS) among Ugandan women. This was a prospective study of 149 women diagnosed with cervical cancer from 2013 to 2015 at the Uganda Cancer Institute. Poisson regression models were fit to calculate prevalence ratios (PR) for the association between HIV infection and late stage at cancer diagnosis. The association between HIV infection and OS after cervical cancer diagnosis was evaluated using Cox proportional hazards models. The cohort included 53 HIV-positive and 96 HIV-negative participants. Median age at diagnosis was 44 years for HIV-positive and 54 years for HIV-negative participants. Seventy-seven percent of HIV-positive participants received antiretroviral therapy. Median baseline CD4 count was 373 cells/mm3 for HIV-positive participants versus 926 cells/mm3 for HIV-negative participants. Thirty-two percent of HIV-positive participants were diagnosed with late stage cervical cancer (III-IV) versus 39% of HIV-negative participants. No association was found between late stage at cancer diagnosis and HIV infection (PR adjusted for age, parity and transport cost 1.0, 95%CI 0.6-1.8). Most women presenting for care received cancer treatment, though almost half who received radiotherapy did not complete treatment. The median OS was 13.7 months for HIV-positive participants and 24.3 months for HIV-negative participants. After adjusting for age and stage, HIV infection was weakly associated with OS (HR 1.3, 95%CI 0.8-2.2). In Uganda, cervical cancer is often incompletely treated and survival remains poor. HIV infection was not associated with cervical cancer stage at diagnosis, but may be weakly associated with shorter survival.

RevDate: 2019-12-29

Murphy N, Carreras-Torres R, Song M, et al (2019)

Circulating Levels of Insulin-like Growth Factor 1 and Insulin-like Growth Factor Binding Protein 3 Associate With Risk of Colorectal Cancer Based on Serologic and Mendelian Randomization Analyses.

Gastroenterology pii:S0016-5085(19)41951-3 [Epub ahead of print].

BACKGROUND AIMS: Human studies examining associations between circulating levels of insulin-like growth factor 1 (IGF1) and insulin-like growth factor binding protein 3 (IGFBP3) and colorectal cancer risk have reported inconsistent results. We conducted complementary serologic and Mendelian randomization (MR) analyses to determine whether alterations in circulating levels of IGF1 or IGFBP3 are associated with colorectal cancer development.

METHODS: Serum levels of IGF1 and other proteins were measured in blood samples collected from 397,380 participants from the UK Biobank, from 2006 through 2010. Incident cancer cases and cancer cases recorded first in death certificates were identified through linkage to national cancer and death registries. Complete follow up was available through March 31, 2016. For the MR analyses, we identified genetic variants associated with circulating levels of IGF1 and IGFBP3. The association of these genetic variants with colorectal cancer was examined with 2-sample MR methods using genome-wide association study consortia data (52,865 cases with colorectal cancer and 46,287 individuals without [controls]) RESULTS: After a median follow-up period of 7.1 years, 2665 cases of colorectal cancer were recorded. In a multivariable-adjusted model, circulating level of IGF1 level associated with colorectal cancer risk (hazard ratio per 1 standard deviation increment of IGF1, 1.11; 95% CI, 1.05-1.17). Similar associations were found by sex, follow-up time, and tumor subsite. In the MR analyses, a 1 standard deviation increment in IGF1 level, predicted based on genetic factors, was associated with a higher risk of colorectal cancer risk (odds ratio, 1.08; 95% CI, 1.03-1.12; P=3.3 x 10-4). Level of IGFBP3, predicted based on genetic factors, was associated with colorectal cancer risk (odds ratio per 1 standard deviation increment, 1.12; 95% CI, 1.06-1.18; P =4.2 x 10-5). Colorectal cancer risk was associated with only 1 variant in IGFBP3 (rs11977526), which also associated with anthropometric traits and circulating level of IGF2.

CONCLUSIONS: In an analysis of blood samples from almost 400,000 participants in the UK Biobank, we found an association between circulating level of IGF1 and colorectal cancer. Using genetic data from 52,865 cases with colorectal cancer and 46,287 controls, a higher level of IGF1, determined by genetic factors, was associated with colorectal cancer. Further studies are needed to determine how this signaling pathway might contribute to colorectal carcinogenesis.

RevDate: 2019-12-29

Bewersdorf JP, Shallis RM, Boddu PC, et al (2019)

The minimal that kills: Why defining and targeting measurable residual disease is the "Sine Qua Non" for further progress in management of acute myeloid leukemia.

Blood reviews pii:S0268-960X(19)30164-X [Epub ahead of print].

Patients with acute myeloid leukemia (AML) who achieve morphologic remission in the bone marrow after initial treatment often continue to harbor residual leukemic cells that can give rise to disease relapse. Achievement of a deeper remission has been associated with a reduced risk of relapse and improved event-free and overall survival in several studies. However, standardization of diagnostic techniques, sample acquisition and test timing are needed before minimal, also known as measurable, residual disease (MRD) quantification can be used to guide treatment decision making. Furthermore, clinical trial evidence that preemptive intervention at MRD level can alter the natural history of AML is required. Herein, we outline the current landscape of MRD assessment in AML, summarize the available evidence and challenges, and highlight the potential for MRD status to serve as a surrogate endpoint for hard clinical outcomes and as an approvable endpoint in clinical trials for regulatory purposes.

RevDate: 2020-01-04

Kawai K, VoPham T, Drucker A, et al (2019)

Ultraviolet Radiation Exposure and the Risk of Herpes Zoster in Three Prospective Cohort Studies.

Mayo Clinic proceedings pii:S0025-6196(19)30758-X [Epub ahead of print].

OBJECTIVE: To examine the association between ultraviolet radiation (UVR) exposure and the risk of herpes zoster (HZ) in 3 prospective cohorts.

PATIENTS AND METHODS: We included 205,756 participants from the Health Professionals Follow-up Study (HPFS; 1986-2008), Nurses' Health Study (NHS; 1996-2012), and Nurses' Health Study II (NHS II; 1991-2013). Ambient UVR exposure was based on updated geocoded address histories linked with a high-resolution spatiotemporal ultraviolet model. Incident HZ cases were identified by self-reported clinician diagnosis. Sunburn history and medical, lifestyle, and dietary factors were assessed using biennial questionnaires. Multivariable Cox proportional hazards models were used.

RESULTS: A total of 24,201 cases of HZ occurred during 3,626,131 person-years. Ambient UVR exposure was associated with a higher risk of HZ in men (HPFS: multivariable-adjusted hazard ratio [MVHR] comparing highest vs lowest quintiles, 1.14; 95% CI, 1.02-1.29; P=.03 for trend) but not in women (NHS: MVHR, 0.99; 95% CI, 0.93-1.05; NHS II: MVHR, 0.96; 95% CI, 0.90-1.03). A higher lifetime number of severe sunburns was associated with a higher risk of HZ in all cohorts (HPFS: MVHR for ≥10 sunburns vs none, 1.08; 95% CI, 0.96-1.20; P=.02 for trend; NHS: MVHR, 1.14; 95% CI, 1.05-1.22; P=.01 for trend; NHS II: MVHR, 1.13; 95% CI, 1.00-1.28; P<.001 for trend).

CONCLUSION: Ambient UVR exposure was associated with a higher risk of HZ in men but not in women. A history of severe sunburn was associated with a modest increased risk of HZ in men and women, possibly because of immunosuppression from overexposure to the sun.

RevDate: 2020-01-09

Raffield LM, Iyengar AK, Wang B, et al (2020)

Allelic Heterogeneity at the CRP Locus Identified by Whole-Genome Sequencing in Multi-ancestry Cohorts.

American journal of human genetics, 106(1):112-120.

Whole-genome sequencing (WGS) can improve assessment of low-frequency and rare variants, particularly in non-European populations that have been underrepresented in existing genomic studies. The genetic determinants of C-reactive protein (CRP), a biomarker of chronic inflammation, have been extensively studied, with existing genome-wide association studies (GWASs) conducted in >200,000 individuals of European ancestry. In order to discover novel loci associated with CRP levels, we examined a multi-ancestry population (n = 23,279) with WGS (∼38× coverage) from the Trans-Omics for Precision Medicine (TOPMed) program. We found evidence for eight distinct associations at the CRP locus, including two variants that have not been identified previously (rs11265259 and rs181704186), both of which are non-coding and more common in individuals of African ancestry (∼10% and ∼1% minor allele frequency, respectively, and rare or monomorphic in 1000 Genomes populations of East Asian, South Asian, and European ancestry). We show that the minor (G) allele of rs181704186 is associated with lower CRP levels and decreased transcriptional activity and protein binding in vitro, providing a plausible molecular mechanism for this African ancestry-specific signal. The individuals homozygous for rs181704186-G have a mean CRP level of 0.23 mg/L, in contrast to individuals heterozygous for rs181704186 with mean CRP of 2.97 mg/L and major allele homozygotes with mean CRP of 4.11 mg/L. This study demonstrates the utility of WGS in multi-ethnic populations to drive discovery of complex trait associations of large effect and to identify functional alleles in noncoding regulatory regions.

RevDate: 2019-12-28

Heffner JL, Kelly MM, Waxmonsky J, et al (2019)

Pilot Randomized Controlled Trial of Web-Delivered Acceptance and Commitment Therapy Versus Smokefree.gov for Smokers With Bipolar Disorder.

Nicotine & tobacco research : official journal of the Society for Research on Nicotine and Tobacco pii:5687033 [Epub ahead of print].

INTRODUCTION: Smokers with bipolar disorder (BD) are less successful at quitting than the general population. In this study, we evaluated in a pilot randomized controlled trial a novel, targeted, web-based intervention for smokers with BD based on acceptance and commitment therapy (ACT) and designed for reach and disseminability.

METHODS: Daily smokers (n=51) with bipolar I or II disorder were recruited from four US sites and randomly assigned to one of two web-based smoking cessation interventions-ACT-based WebQuit Plus (n=25) or Smokefree.gov (n=26) over a 10-week treatment period. All participants received nicotine patch for 8 weeks. Key outcomes were trial design feasibility, intervention acceptability, and cessation at end-of-treatment and 1-month follow-up.

RESULTS: We screened 119 to enroll 51 participants (target sample size=60) over 24 months. The most common reason for ineligibility was inability to attend study appointments. Retention was 73% at end-of-treatment and 80% at follow-up, with no differences by arm. Mean number of logins was twice as high for WebQuit Plus (10.3 vs. 5.3). Usefulness of program skills was rated higher for WebQuit Plus (75% vs. 29%). Biochemically-confirmed, 7-day abstinence at end-of-treatment was 12% in WebQuit Plus vs. 8% in Smokefree.gov (OR=1.46, 95% CI=0.21-9.97). At follow-up, abstinence rates were 8% in both arms.

CONCLUSIONS: Trial design produced favorable retention rates, although alternative recruitment methods will be needed for a larger trial. At end-of-treatment, acceptability and estimated effect size of WebQuit Plus relative to Smokefree.gov were promising and support continued program refinement and evaluation.

IMPLICATIONS: In this first randomized, controlled trial of a targeted intervention for smokers with bipolar disorder, we found that the ACT-based WebQuit Plus intervention, delivered in combination with nicotine patch, had promising acceptability and cessation outcomes relative to Smokefree.gov. The observed signals for acceptability and cessation suggest that the WebQuit Plus program should be refined based on participant feedback and evaluated in a larger trial. Feasibility findings from this study also provide direction for refining trial procedures to enhance recruitment of smokers with bipolar disorder.

RevDate: 2020-01-08

Giel-Moloney M, Esteban M, Oakes BH, et al (2019)

Recombinant HIV-1 vaccine candidates based on replication-defective flavivirus vector.

Scientific reports, 9(1):20005.

Multiple approaches utilizing viral and DNA vectors have shown promise in the development of an effective vaccine against HIV. In this study, an alternative replication-defective flavivirus vector, RepliVax (RV), was evaluated for the delivery of HIV-1 immunogens. Recombinant RV-HIV viruses were engineered to stably express clade C virus Gag and Env (gp120TM) proteins and propagated in Vero helper cells. RV-based vectors enabled efficient expression and correct maturation of Gag and gp120TM proteins, were apathogenic in a sensitive suckling mouse neurovirulence test, and were similar in immunogenicity to recombinant poxvirus NYVAC-HIV vectors in homologous or heterologous prime-boost combinations in mice. In a pilot NHP study, immunogenicity of RV-HIV viruses used as a prime or boost for DNA or NYVAC candidates was compared to a DNA prime/NYVAC boost benchmark scheme when administered together with adjuvanted gp120 protein. Similar neutralizing antibody titers, binding IgG titers measured against a broad panel of Env and Gag antigens, and ADCC responses were observed in the groups throughout the course of the study, and T cell responses were elicited. The entire data demonstrate that RV vectors have the potential as novel HIV-1 vaccine components for use in combination with other promising candidates to develop new effective vaccination strategies.

RevDate: 2019-12-28

Steach HR, DeBuysscher BL, Schwartz A, et al (2019)

Cross-Reactivity with Self-Antigen Tunes the Functional Potential of Naive B Cells Specific for Foreign Antigens.

Journal of immunology (Baltimore, Md. : 1950) pii:jimmunol.1900799 [Epub ahead of print].

Upon Ag exposure, naive B cells expressing BCR able to bind Ag can undergo robust proliferation and differentiation that can result in the production of Ab-secreting and memory B cells. The factors determining whether an individual naive B cell will proliferate following Ag encounter remains unclear. In this study, we found that polyclonal naive murine B cell populations specific for a variety of foreign Ags express high levels of the orphan nuclear receptor Nur77, which is known to be upregulated downstream of BCR signaling as a result of cross-reactivity with self-antigens in vivo. Similarly, a fraction of naive human B cells specific for clinically-relevant Ags derived from respiratory syncytial virus and HIV-1 also exhibited an IgMLOW IgD+ phenotype, which is associated with self-antigen cross-reactivity. Functionally, naive B cells expressing moderate levels of Nur77 are most likely to proliferate in vivo following Ag injection. Together, our data indicate that BCR cross-reactivity with self-antigen is a common feature of populations of naive B cells specific for foreign Ags and a moderate level of cross-reactivity primes individual cells for optimal proliferative responses following Ag exposure.

RevDate: 2019-12-27

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

The Authors Respond.

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

RevDate: 2020-01-17

Kim NJ, Hyun TS, Pergam SA, et al (2019)

Disseminated adenovirus infection after autologous stem cell transplant.

Adenovirus is an infrequent but challenging viral complication of transplantation that is rarely reported after autologous stem cell transplant. We present a case of disseminated adenovirus infection in a woman who received an autologous stem cell transplant for treatment of multiple sclerosis. After presenting with post-transplant episodic diarrhea and viremia, endoscopic biopsies and immunohistochemical staining confirmed the diagnosis of disseminated adenovirus infection. Her symptoms and viremia resolved after treatment with cidofovir. This case demonstrates that a high index of suspicion, a systematic clinical approach, and immunohistochemical tissue staining are necessary to diagnose disseminated adenovirus infection in an unexpected host.

RevDate: 2020-01-08

Myers KC, Furutani E, Weller E, et al (2019)

Clinical features and outcomes of patients with Shwachman-Diamond syndrome and myelodysplastic syndrome or acute myeloid leukaemia: a multicentre, retrospective, cohort study.

The Lancet. Haematology pii:S2352-3026(19)30206-6 [Epub ahead of print].

BACKGROUND: Data to inform surveillance and treatment for leukaemia predisposition syndromes are scarce and recommendations are largely based on expert opinion. This study aimed to investigate the clinical features and outcomes of patients with myelodysplastic syndrome or acute myeloid leukaemia and Shwachman-Diamond syndrome, an inherited bone marrow failure disorder with high risk of developing myeloid malignancies.

METHODS: We did a multicentre, retrospective, cohort study in collaboration with the North American Shwachman-Diamond Syndrome Registry. We reviewed patient medical records from 17 centres in the USA and Canada. Patients with a genetic (biallelic mutations in the SBDS gene) or clinical diagnosis (cytopenias and pancreatic dysfunction) of Shwachman-Diamond syndrome who developed myelodysplastic syndrome or acute myeloid leukaemia were eligible without additional restriction. Medical records were reviewed between March 1, 2001, and Oct 5, 2017. Masked central review of bone marrow pathology was done if available to confirm leukaemia or myelodysplastic syndrome diagnosis. We describe the clinical features and overall survival of these patients.

FINDINGS: We initially identified 37 patients with Shwachman-Diamond syndrome and myelodysplastic syndrome or acute myeloid leukaemia. 27 patients had samples available for central pathology review and were reclassified accordingly (central diagnosis concurred with local in 15 [56%] cases), 10 had no samples available and were classified based on the local review data, and 1 patient was excluded at this stage as not eligible. 36 patients were included in the analysis, of whom 10 (28%) initially presented with acute myeloid leukaemia and 26 (72%) initially presented with myelodysplastic syndrome. With a median follow-up of 4·9 years (IQR 3·9-8·4), median overall survival for patients with myelodysplastic syndrome was 7·7 years (95% CI 0·8-not reached) and 0·99 years (95% CI 0·2-2·4) for patients with acute myeloid leukaemia. Overall survival at 3 years was 11% (95% CI 1-39) for patients with leukaemia and 51% (29-68) for patients with myelodysplastic syndrome. Management and surveillance were variable. 18 (69%) of 26 patients with myelodysplastic syndrome received upfront therapy (14 haematopoietic stem cell transplantation and 4 chemotherapy), 4 (15%) patients received no treatment, 2 (8%) had unavailable data, and 2 (8%) progressed to acute myeloid leukaemia before receiving treatment. 12 patients received treatment for acute myeloid leukaemia-including the two patients initially diagnosed with myelodysplastic who progressed- two (16%) received HSCT as initial therapy and ten (83%) received chemotherapy with intent to proceed with HSCT. 33 (92%) of 36 patients (eight of ten with leukaemia and 25 of 26 with myelodysplastic syndrome) were known to have Shwachman-Diamond syndrome before development of a myeloid malignancy and could have been monitored with bone marrow surveillance. Bone marrow surveillance before myeloid malignancy diagnosis was done in three (33%) of nine patients with leukaemia for whom surveillance status was confirmed and 11 (46%) of 24 patients with myelodysplastic syndrome. Patients monitored had a 3-year overall survival of 62% (95% CI 32-82; n=14) compared with 28% (95% CI 10-50; n=19; p=0·13) without surveillance. Six (40%) of 15 patients with available longitudinal data developed myelodysplastic syndrome in the setting of stable blood counts.

INTERPRETATION: Our results suggest that prognosis is poor for patients with Shwachman-Diamond syndrome and myelodysplastic syndrome or acute myeloid leukaemia owing to both therapy-resistant disease and treatment-related toxicities. Improved surveillance algorithms and risk stratification tools, studies of clonal evolution, and prospective trials are needed to inform effective prevention and treatment strategies for leukaemia predisposition in patients with Shwachman-Diamond syndrome.

FUNDING: National Institute of Health.

RevDate: 2020-01-08

Dudas G, T Bedford (2019)

The ability of single genes vs full genomes to resolve time and space in outbreak analysis.

BMC evolutionary biology, 19(1):232.

BACKGROUND: Inexpensive pathogen genome sequencing has had a transformative effect on the field of phylodynamics, where ever increasing volumes of data have promised real-time insight into outbreaks of infectious disease. As well as the sheer volume of pathogen isolates being sequenced, the sequencing of whole pathogen genomes, rather than select loci, has allowed phylogenetic analyses to be carried out at finer time scales, often approaching serial intervals for infections caused by rapidly evolving RNA viruses. Despite its utility, whole genome sequencing of pathogens has not been adopted universally and targeted sequencing of loci is common in some pathogen-specific fields.

RESULTS: In this study we highlighted the utility of sequencing whole genomes of pathogens by re-analysing a well-characterised collection of Ebola virus sequences in the form of complete viral genomes (≈19 kb long) or the rapidly evolving glycoprotein (GP, ≈2 kb long) gene. We have quantified changes in phylogenetic, temporal, and spatial inference resolution as a result of this reduction in data and compared these to theoretical expectations.

CONCLUSIONS: We propose a simple intuitive metric for quantifying temporal resolution, i.e. the time scale over which sequence data might be informative of various processes as a quick back-of-the-envelope calculation of statistical power available to molecular clock analyses.

RevDate: 2019-12-26

Konstantinopoulos PA, S Vinayak (2019)

BRCA Mutations and Homologous Recombination Repair Deficiency in Treatment With Niraparib Combined With Pembrolizumab-Reply.

JAMA oncology pii:2757519 [Epub ahead of print].

RevDate: 2020-01-15

Zost SJ, Lee J, Gumina ME, et al (2019)

Identification of Antibodies Targeting the H3N2 Hemagglutinin Receptor Binding Site following Vaccination of Humans.

Cell reports, 29(13):4460-4470.e8.

Antibodies targeting the receptor binding site (RBS) of the influenza virus hemagglutinin (HA) protein are usually not broadly reactive because their footprints are typically large and extend to nearby variable HA residues. Here, we identify several human H3N2 HA RBS-targeting monoclonal antibodies (mAbs) that are sensitive to substitutions in conventional antigenic sites and are therefore not broadly reactive. However, we also identify an H3N2 HA RBS-targeting mAb that is exceptionally broadly reactive despite being sensitive to substitutions in residues outside of the RBS. We show that similar antibodies are present at measurable levels in the sera of some individuals but that they are inefficiently elicited by conventional vaccines. Our data indicate that HA RBS-targeting antibodies can be effective against variable viral strains even when they are somewhat sensitive to substitutions in HA residues adjacent to the RBS.

RevDate: 2019-12-25

Arthur RS, Xue X, Kamensky V, et al (2019)

The association between DXA-derived body fat measures and breast cancer risk among postmenopausal women in the Women's Health Initiative.

Cancer medicine [Epub ahead of print].

BACKGROUND: Most studies demonstrating an association between excess adiposity and postmenopausal breast cancer have used anthropometric measures, particularly body mass index (BMI). However, more direct body fat measures may more accurately determine the relationship between body fat distribution and breast cancer risk.

METHODS: Cox proportional hazards regression models were created to examine the associations of dual-energy x-ray absorptiometry (DXA) body fat measures (at baseline and during follow-up) with breast cancer risk among 10 931 postmenopausal women from the Women's Health Initiative cohort. A total of 639 incident invasive breast cancer cases (including 484 estrogen receptor positive (ER+) cases) were ascertained after a median follow-up of 15.0 years.

RESULTS: Excess whole body fat mass and trunk fat mass were positively associated with risk invasive breast cancer risk. These associations persisted even after additional adjustment for standard anthropometric measures. In time-dependent analyses, we observed that both whole body fat mass and trunk fat mass, in the highest versus lowest category, were associated with a doubling of risk of invasive breast cancer overall (HR: 2.17; 95% CI: 1.54-3.05 and 2.20; 1.55-3.14, respectively) and of ER+ breast cancer (2.05; 1.37-3.05 and 2.03; 1.34-3.07, respectively). The remaining DXA measures were also positively associated with breast cancer risk in baseline and time-dependent analyses.

CONCLUSION: These findings suggest that DXA-derived body fat measures are positively associated with breast cancer risk after adjustment for BMI and other conventional breast cancer risk factors.

RevDate: 2019-12-27

Wang X, O'Connell K, Jeon J, et al (2019)

Combined effect of modifiable and non-modifiable risk factors for colorectal cancer risk in a pooled analysis of 11 population-based studies.

BMJ open gastroenterology, 6(1):e000339.

Objective: 'Environmental' factors associated with colorectal cancer (CRC) risk include modifiable and non-modifiable variables. Whether those with different non-modifiable baseline risks will benefit similarly from reducing their modifiable CRC risks remains unclear.

Design: Using 7945 cases and 8893 controls from 11 population-based studies, we combined 17 risk factors to characterise the overall environmental predisposition to CRC (environmental risk score (E-score)). We estimated the absolute risks (ARs) of CRC of 10 and 30 years across E-score using incidence-rate data from the Surveillance, Epidemiology, and End Results programme. We then combined the modifiable risk factors and estimated ARs across the modifiable risk score, stratified by non-modifiable risk profile based on genetic predisposition, family history and height.

Results: Higher E-score was associated with increased CRC risk (ORquartile, 1.33; 95% CI 1.30 to 1.37). Across E-scores, 30-year ARs of CRC increased from 2.5% in the lowest quartile (Q1) to 5.9% in the highest (Q4) quartile for men, and from 2.1% to 4.5% for women. The modifiable risk score had a stronger association in those with high non-modifiable risk (relative excess risk due to interaction=1.2, 95% CI 0.5 to 1.9). For those in Q4 of non-modifiable risk, a decrease in modifiable risk reduced 30-year ARs from 8.9% to 3.4% for men and from 6.0% to 3.2% for women, a level lower or comparable to the average population risk.

Conclusions: Changes in modifiable risk factors may result in a substantial decline in CRC risk in both sexes. Those with high inherited risk may reap greater benefit from lifestyle modifications. Our results suggested comprehensive evaluation of environmental factors may facilitate CRC risk stratification.

RevDate: 2019-12-24

Smakaj E, Babrak L, Ohlin M, et al (2019)

Benchmarking immunoinformatic tools for the analysis of antibody repertoire sequences.

Bioinformatics (Oxford, England) pii:5686386 [Epub ahead of print].

Antibody repertoires reveal insights into the biology of the adaptive immune system and empower diagnostics and therapeutics. There are currently multiple tools available for the annotation of antibody sequences. All downstream analyses such as choosing lead drug candidates depend on the correct annotation of these sequences; however, a thorough comparison of the performance of these tools has not been investigated. Here, we benchmark the performance of commonly used immunoinformatic tools, i.e., IMGT/HighV-QUEST, IgBLAST, and MiXCR, in terms of reproducibility of annotation output, accuracy and speed using simulated and experimental high-throughput sequencing datasets.We analyzed changes in IMGT reference germline database in the last 10 years in order to assess the reproducibility of the annotation output. We found that only 73/183 (40%) V, D, and J human genes were shared between the reference germline sets used by the tools. We found that the annotation results differed between tools. In terms of alignment accuracy, MiXCR had the highest average frequency of gene mishits, 0.02 mishit frequency, and IgBLAST the lowest, 0.004 mishit frequency. Reproducibility in the output of complementarity determining 3 regions (CDR3 a.a.) ranged from 4.3 to 77.6% with preprocessed data. In addition, run time of the tools was assessed: MiXCR was the fastest tool for number of sequences processed per unit of time. These results indicate that immunoinformatic analyses greatly depend on the choice of bioinformatics tool. Our results support informed decision-making to immuno-informaticians based on repertoire composition and sequencing platforms.

AVAILABILITY: All tools utilized in the paper are free for academic use.

SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

RevDate: 2020-01-09

Alobaidi A, Nabulsi NA, Talon B, et al (2019)

Depressive symptoms, mental health-related quality of life, and survival among older patients with multiple myeloma.

Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer pii:10.1007/s00520-019-05246-6 [Epub ahead of print].

PURPOSE: To examine the impact of pre-diagnosis depressive symptoms and mental health-related quality of life (HRQOL) on survival among older patients with multiple myeloma (MM).

METHODS: We performed a retrospective cohort study using the Surveillance, Epidemiology, and End Results-Medicare Health Outcomes Survey data resource. Patients aged 65 years and older diagnosed with first primary MM between 1998 and 2014 were identified, and presence of depressive symptoms was determined based on responses to 3 depression screening questions prior to MM diagnosis. Veterans RAND 12 mental component summary (MCS) scores were analyzed to evaluate mental HRQOL. We used multivariable Cox proportional hazards models to estimate hazard ratios (HR) and 95% confidence intervals (CI) for risks of all-cause and cancer-specific mortality.

RESULTS: Of 522 patients, mean (SD) age at diagnosis was 76.9 (6.1) years and 158 (30%) reported depressive symptoms. Patients with depressive symptoms had a higher number of comorbid conditions and nearly all (84%) scored below the median MCS. Pre-diagnosis depressive symptoms were not associated with all-cause (HR = 1.01, 95% CI 0.79-1.29) or cancer-specific mortality (HR = 0.94, 95% CI 0.69-1.28). MM patients scoring in the second MCS tertile (vs the highest tertile) had a modestly increased risk of all-cause (HR = 1.19, 95% CI 0.91-1.55) and cancer-specific mortality (HR = 1.17, 95% CI 0.86-1.60), but these estimates were not statistically significant.

CONCLUSION: Pre-diagnosis depressive symptoms and lower mental HRQoL did not impact survival among older MM patients. Highly prevalent depressive symptoms among older MM patients deserve clinical attention. Such efforts can inform clinicians in tailoring care for this vulnerable population.

RevDate: 2019-12-26

Boehmer U, Potter J, Clark MA, et al (2019)

Neighborhood Characteristics and Colorectal Cancer Survivors' Quality of Care.

Health equity, 3(1):619-627.

Purpose: Quality cancer care entails receipt of a Survivorship Care Plan (SCP). The purpose of this study was to determine differences in SCP delivery by patient-level and neighborhood characteristics. Methods: We obtained California cancer registry data on individuals who were diagnosed with stage I, II, or III colorectal cancer (CRC) between 2012 and 2015 and resided in predetermined geographic areas. We then mailed them a questionnaire, which queried about receipt of a SCP and its content. SCP was defined by content, as summary of cancer treatment, cancer surveillance recommendations, and/or an individualized preventive care. Using logistic regression modeling, each measure of SCP, as well as the summary measure (none vs. any), was evaluated by person-level characteristics. Subsequently, neighborhood-level characteristics were added to the model to explore their additional value. Results: Overall 80% of CRC survivors received a SCP. Receipt of SCPs was associated with person-level characteristics, while neighborhood characteristics did not make an additional contribution. Young, male employed survivors and those with more recent diagnoses or later cancer stages had greater odds of receiving a SCP. Conclusion: When providing SCPs, health care providers prioritize patient groups who they may perceive as vulnerable or likely to benefit from SCPs.

RevDate: 2019-12-24

Rendle KA, Burnett-Hartman AN, Neslund-Dudas C, et al (2019)

Evaluating Lung Cancer Screening Across Diverse Healthcare Systems: A Process Model from the Lung PROSPR Consortium.

Cancer prevention research (Philadelphia, Pa.) pii:1940-6207.CAPR-19-0378 [Epub ahead of print].

Numerous organizations, including the United States Preventive Services Task Force, recommend annual lung cancer screening (LCS) with low-dose computed tomography (LDCT) for high-risk adults who meet specific criteria. Despite recommendations and national coverage for screening-eligible adults through the Centers for Medicare and Medicaid Services, LCS uptake in the United States remains low (<4%). In recognition of the need to improve and understand LCS across the population, as part of the larger Population-based Research to Optimize the Screening PRocess (PROSPR) consortium, the National Cancer Institute funded the Lung PROSPR Research Consortium consisting of five diverse healthcare systems in Colorado, Hawaii, Michigan, Pennsylvania, and Wisconsin. Using various methods and data sources, the center aims to examine utilization and outcomes of LCS across diverse populations, and assess how variations in the implementation of LCS programs shape outcomes across the screening process. This commentary presents the PROSPR LCS process model, which outlines the interrelated steps needed to complete the screening process from risk assessment to treatment. In addition to guiding planned projects within the Lung PROSPR Research Consortium, this model provides insights on the complex steps needed to implement, evaluate, and improve LCS outcomes in community practice.

RevDate: 2019-12-24

Davies SM, Iannone R, Alonzo TA, et al (2019)

A Phase 2 Trial of KIR Mismatched Unrelated Donor Transplantation Using In Vivo T-cell Depletion with ATG in AML: Children's Oncology Group AAML05P1 Study.

Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation pii:S1083-8791(19)31652-0 [Epub ahead of print].

AML patients receiving killer immunoglobulin-like receptor (KIR) mismatched haploidentical HSCT have improved survival. COG AAML05P1 is a prospective phase 2 trial of unrelated donor (URD) HSCT in which KIR typing of donors was available to the treating physician at donor selection, aiming to determine feasibility (defined as the ability to obtain donor samples from unrelated donors and perform and return KIR data before transplant) of prospective selection of KIR mismatched donors and effect on outcomes. The study accrued 90 evaluable patients. Patients ≤ 30 years old with high risk AML at presentation or relapsed AML were eligible. After enrollment as many as 5 potential URD samples were KIR typed (including gene expression) in a central laboratory and results reported to the treating physician, who made the final donor selection. Cases were categorized as KIR matched or mismatched using different published strategies. Overall survival, disease-free survival (DFS), and relapse did not differ significantly by KIR mismatch. Acute GVHD was significantly lower in recipients of KIR mismatched stem cells (35% vs 60%, p= 0.027). We examined DFS according to time to NK-receptor recovery after HSCT. NKp44 recovery was significantly associated with KIR mismatch and with decreased DFS and increased relapse risk in multivariate Cox analysis (p= 0.006 and 0.009, respectively). We show that prospective selection of URD according to KIR type was feasible, acute GVHD was reduced, but survival did not differ using any model of KIR mismatch. The study enrolled mostly matched transplants, however, so ligand-ligand mismatch was rare and therefore sample size was insufficient to determine potential benefit according to this model. Cord blood recipients demonstrated a trend towards improved DFS with KIR mismatch, but the study was not powered to detect a difference in this small subset of patients. Our data suggest that recovery of NK receptor expression might influence DFS after HSCT.

RevDate: 2020-01-10

Kowalski MH, Qian H, Hou Z, et al (2019)

Use of >100,000 NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium whole genome sequences improves imputation quality and detection of rare variant associations in admixed African and Hispanic/Latino populations.

PLoS genetics, 15(12):e1008500 pii:PGENETICS-D-19-00914.

Most genome-wide association and fine-mapping studies to date have been conducted in individuals of European descent, and genetic studies of populations of Hispanic/Latino and African ancestry are limited. In addition, these populations have more complex linkage disequilibrium structure. In order to better define the genetic architecture of these understudied populations, we leveraged >100,000 phased sequences available from deep-coverage whole genome sequencing through the multi-ethnic NHLBI Trans-Omics for Precision Medicine (TOPMed) program to impute genotypes into admixed African and Hispanic/Latino samples with genome-wide genotyping array data. We demonstrated that using TOPMed sequencing data as the imputation reference panel improves genotype imputation quality in these populations, which subsequently enhanced gene-mapping power for complex traits. For rare variants with minor allele frequency (MAF) < 0.5%, we observed a 2.3- to 6.1-fold increase in the number of well-imputed variants, with 11-34% improvement in average imputation quality, compared to the state-of-the-art 1000 Genomes Project Phase 3 and Haplotype Reference Consortium reference panels. Impressively, even for extremely rare variants with minor allele count <10 (including singletons) in the imputation target samples, average information content rescued was >86%. Subsequent association analyses of TOPMed reference panel-imputed genotype data with hematological traits (hemoglobin (HGB), hematocrit (HCT), and white blood cell count (WBC)) in ~21,600 African-ancestry and ~21,700 Hispanic/Latino individuals identified associations with two rare variants in the HBB gene (rs33930165 with higher WBC [p = 8.8x10-15] in African populations, rs11549407 with lower HGB [p = 1.5x10-12] and HCT [p = 8.8x10-10] in Hispanics/Latinos). By comparison, neither variant would have been genome-wide significant if either 1000 Genomes Project Phase 3 or Haplotype Reference Consortium reference panels had been used for imputation. Our findings highlight the utility of the TOPMed imputation reference panel for identification of novel rare variant associations not previously detected in similarly sized genome-wide studies of under-represented African and Hispanic/Latino populations.

RevDate: 2020-01-08

Cram JA, Fiore-Gartland AJ, Srinivasan S, et al (2019)

Human gut microbiota is associated with HIV-reactive immunoglobulin at baseline and following HIV vaccination.

PloS one, 14(12):e0225622.

Antibodies that recognize commensal microbial antigens may be cross reactive with a part of the human immunodeficiency virus (HIV) envelope glycoprotein gp41. To improve understanding of the role of the microbiota in modulating the immune response to HIV vaccines, we studied the associations of the gut microbiota composition of participants in the HIV Vaccine Trials Network 096 clinical trial with their HIV-specific immune responses in response to vaccination with a DNA-prime, pox virus boost strategy designed to recapitulate the only efficacious HIV-vaccine trial (RV144). We observed that both levels of IgG antibodies to gp41 at baseline and post-vaccination levels of IgG antibodies to the Con.6.gp120.B, ZM96.gp140 and gp70 B.CaseA V1-V2 antigens were associated with three co-occurring clusters of family level microbial taxa. One cluster contained several families positively associated with gp41-specific IgG and negatively associated with vaccine-matched gp120, gp140 and V1-V2-specific IgG responses. A second cluster contained families that negatively associated with gp41 and positively associated with gp120, gp140 and V1-V2-specific IgG responses. A third cluster contained microbial groups that did not correlate with any immune responses. Baseline and post-vaccination levels of gp41 IgG were not significantly correlated, suggesting that factors beyond the microbiome that contribute to immune response heterogeneity. Sequence variant richness was positively associated with gp41, p24, pg140 and V1-V2 specific IgG responses, gp41 and p24 IgA responses, and CD4+ T cell responses to HIV-1 proteins. Our findings provide preliminary evidence that the gut microbiota may be an important predictor of vaccine response.

RevDate: 2020-01-13

Li W, Li R, Feng Z, et al (2019)

Semiparametric isotonic regression analysis for risk assessment under nested case-control and case-cohort designs.

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

RevDate: 2020-01-08

Archambault AN, Su YR, Jeon J, et al (2019)

Cumulative Burden of Colorectal Cancer-Associated Genetic Variants is More Strongly Associated With Early-onset vs Late-onset Cancer.

Gastroenterology pii:S0016-5085(19)41937-9 [Epub ahead of print].

BACKGROUND & AIMS: Early-onset colorectal cancer (CRC, in persons younger than 50 years old) is increasing in incidence; yet, in the absence of a family history of CRC, this population lacks harmonized recommendations for prevention. We aimed to determine whether a polygenic risk score (PRS) developed from 95 CRC-associated common genetic risk variants was associated with risk for early-onset CRC.

METHODS: We studied risk for CRC associated with a weighted PRS in 12,197 participants younger than 50 years old vs 95,865 participants 50 years or older. PRS was calculated based on single-nucleotide polymorphisms associated with CRC in a large-scale genome-wide association study as of January 2019. Participants were pooled from 3 large consortia that provided clinical and genotyping data: the Colon Cancer Family Registry, the Colorectal Transdisciplinary study, and the Genetics and Epidemiology of Colorectal Cancer Consortium and were all of genetically defined European descent. Findings were replicated in an independent cohort of 72,573 participants.

RESULTS: Overall associations with CRC per standard deviation of PRS were significant for early-onset cancer, and were stronger compared with late-onset cancer (P for interaction=.01); when we compared the highest PRS quartile with the lowest, risk increased 3.7-fold for early-onset CRC (95% CI, 3.28-4.24) vs 2.9-fold for late-onset CRC (95% CI, 2.80-3.04). This association was strongest for participants without a first-degree family history of CRC (P for interaction=5.61x10-5). When we compared the highest with the lowest quartiles in this group, risk increased 4.3-fold for early-onset CRC (95% CI, 3.61-5.01) vs 2.9-fold for late-onset CRC (95% CI, 2.70-3.00). Sensitivity analyses were consistent with these findings.

CONCLUSIONS: In an analysis of associations with CRC per standard deviation of PRS, we found the cumulative burden of CRC-associated common genetic variants to associate with early-onset cancer, and to be more strongly associated with early-onset than late-onset cancer-particularly in the absence of CRC family history. Analyses of PRS, along with environmental and lifestyle risk factors, might identify younger individuals who would benefit from preventative measures.

RevDate: 2019-12-21

Verdial FC, Madtes DK, Cheng GS, et al (2019)

Multidisciplinary Team Based Management of Incidentally Detected Lung Nodules.

Chest pii:S0012-3692(19)34401-0 [Epub ahead of print].

BACKGROUND: Each year, over 1.5 million Americans are diagnosed with an incidentally-detected lung nodule. Practice guidelines attempt to balance the benefit of early detection of lung cancer with the risks of diagnostic testing, but adherence to guidelines is low. We sought to determine guideline-adherence rates in the setting of a multidisciplinary nodule clinic and describe reasons for non-adherence as well as associated outcomes.

METHODS: We performed a cohort study with 3 years of follow-up on patients ≥35 years of age with an incidentally-detected lung nodule evaluated in a multidisciplinary clinic that used the 2005 Fleischner Society Guidelines.

RESULTS: Among 113 patients, 67% (95% confidence interval [CI] 58-76%) were recommended a guideline-concordant nodule evaluation whereas 7.1% (95% CI 3.1-13%) and 26% (95% CI 18-25) were recommended less or more intense evaluation, respectively. In contrast, 58% (95% CI 48-67%), 22% (95% CI 18-25%), and 23% (95% CI 16-32%) received a guideline-concordant, less intense, or more intense evaluation, respectively. The most common reason for recommending guideline-discordant care was concern for two different diagnoses that would each benefit from early detection and treatment. A majority of lung cancer diagnoses (88%) occurred in patients who received guideline-concordant care. There were no lung cancer cases in those who received less intense nodule care.

CONCLUSIONS: A multidisciplinary nodule clinic may serve as a system-level intervention to promote guideline-concordant care, while also providing a multidisciplinary basis by which to deviate from guidelines in order to address the needs of a heterogeneous patient population.

RevDate: 2020-01-14

Chow EJ, Baldwin LM, Hagen AM, et al (2019)

Communicating health information and improving coordination with primary care (CHIIP): Rationale and design of a randomized cardiovascular health promotion trial for adult survivors of childhood cancer.

Contemporary clinical trials, 89:105915 pii:S1551-7144(19)30631-7 [Epub ahead of print].

BACKGROUND: Long-term survival for children diagnosed with cancer exceeds 80%. Notably, premature cardiovascular disease has become the leading non-cancer cause of late mortality among these survivors.

METHODS/DESIGN: This randomized controlled trial (RCT; NCT03104543) focuses on adult participants in the Childhood Cancer Survivor Study identified as high risk for ischemic heart disease or heart failure due to their cancer treatment. Participants undergo a home-based evaluation of blood pressure and laboratory tests to determine the prevalence of undiagnosed and/or undertreated hypertension, dyslipidemia, and diabetes. Those with abnormal values are then enrolled in an RCT to test the efficacy of a 12-month personalized, remotely delivered survivorship care plan (SCP) intervention designed to reduce undertreatment of these three target conditions. The intervention approximates a clinical encounter and is based on chronic disease self-management strategies.

RESULTS: With a goal of 750, currently 342 out of 742 eligible participants approached have enrolled (46.1%). Initially, we randomized participants to different recruitment strategies, including shorter approach packets and a tiered consent, but did not find significant differences in participation rates (40.7% to 42.9%; p = .95). Subsequently, slightly greater participation was seen with larger upfront unconditional incentive checks ($50 vs. $25: 50.7% vs. 44.1%; p = .10). Overall, the financial impact of the $50 upfront incentive was cost neutral, and possibly cost-saving, vs. a $25 upfront incentive.

CONCLUSION: The overall study will determine if a National Academy of Medicine-recommended SCP intervention can improve cardiovascular outcomes among long-term survivors of childhood cancer. Modifications to the recruitment strategy may improve participation rates over time.

RevDate: 2020-01-11

Gelman H, Dines JN, Berg J, et al (2019)

Recommendations for the collection and use of multiplexed functional data for clinical variant interpretation.

Genome medicine, 11(1):85.

Variants of uncertain significance represent a massive challenge to medical genetics. Multiplexed functional assays, in which the functional effects of thousands of genomic variants are assessed simultaneously, are increasingly generating data that can be used as additional evidence for or against variant pathogenicity. Such assays have the potential to resolve variants of uncertain significance, thereby increasing the clinical utility of genomic testing. Existing standards from the American College of Medical Genetics and Genomics (ACMG)/Association for Molecular Pathology (AMP) and new guidelines from the Clinical Genome Resource (ClinGen) establish the role of functional data in variant interpretation, but do not address the specific challenges or advantages of using functional data derived from multiplexed assays. Here, we build on these existing guidelines to provide recommendations to experimentalists for the production and reporting of multiplexed functional data and to clinicians for the evaluation and use of such data. By following these recommendations, experimentalists can produce transparent, complete, and well-validated datasets that are primed for clinical uptake. Our recommendations to clinicians and diagnostic labs on how to evaluate the quality of multiplexed functional datasets, and how different datasets could be incorporated into the ACMG/AMP variant-interpretation framework, will hopefully clarify whether and how such data should be used. The recommendations that we provide are designed to enhance the quality and utility of multiplexed functional data, and to promote their judicious use.

RevDate: 2019-12-20

Hourigan CS, Dillon LW, Gui G, et al (2019)

Impact of Conditioning Intensity of Allogeneic Transplantation for Acute Myeloid Leukemia With Genomic Evidence of Residual Disease.

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

PURPOSE: Patients with acute myeloid leukemia (AML) in remission remain at risk for relapse even after allogeneic hematopoietic cell transplantation (alloHCT). AML measurable residual disease (MRD) status before alloHCT has been shown to be prognostic. Whether modulation of the intensity of the alloHCT conditioning regimen in patients with AML who test positive for MRD can prevent relapse and improve survival is unknown.

METHODS: Ultra-deep, error-corrected sequencing for 13 commonly mutated genes in AML was performed on preconditioning blood from patients treated in a phase III clinical trial that randomly assigned adult patients with myeloid malignancy in morphologic complete remission to myeloablative conditioning (MAC) or reduced-intensity conditioning (RIC).

RESULTS: No mutations were detected in 32% of MAC and 37% of RIC recipients; these groups had similar survival (3-year overall survival [OS], 56% v 63%; P = .96). In patients with a detectable mutation (next-generation sequencing [NGS] positive), relapse (3-year cumulative incidence, 19% v 67%; P < .001) and survival (3-year OS, 61% v 43%; P = .02) was significantly different between the MAC and RIC arms, respectively. In multivariable analysis for NGS-positive patients, adjusting for disease risk and donor group, RIC was significantly associated with increased relapse (hazard ratio [HR], 6.38; 95% CI, 3.37 to 12.10; P < .001), decreased relapse-free survival (HR, 2.94; 95% CI, 1.84 to 4.69; P < .001), and decreased OS (HR, 1.97; 95% CI, 1.17 to 3.30; P = .01) compared with MAC. Models of AML MRD also showed benefit for MAC over RIC for those who tested positive.

CONCLUSION: This study provides evidence that MAC rather than RIC in patients with AML with genomic evidence of MRD before alloHCT can result in improved survival.

RevDate: 2020-01-08

Mhlanga FG, Balkus JE, Singh D, et al (2019)

Feasibility and Safety of IUD Insertion by Mid-Level Providers in Sub-Saharan Africa.

International perspectives on sexual and reproductive health, 45:61-69.

CONTEXT: The copper IUD is safe and effective, but underutilized in Sub-Saharan Africa, in part because of a lack of trained providers. The World Health Organization recommends training mid-level providers-including nurses and midwives-to insert IUDs; however, the safety of such task shifting has not been evaluated in Sub-Saharan Africa.

METHODS: Data were drawn from baseline surveys and study charts of 535 sexually active women aged 18-45 who used a copper IUD while participating in an HIV-prevention clinical trial conducted from August 2012 through June 2015 in Malawi, South Africa, Uganda and Zimbabwe. IUDs were inserted by study physicians, nurses and midwives trained as part of the trial, and by local nonstudy providers. Chi-square and Fisher's exact tests were used to compare women's experiences of adverse events-such as irregular bleeding, pelvic pain or device expulsion-by provider type.

RESULTS: Half (54%) of women reported experiencing an adverse event; the most common were irregular bleeding and pelvic pain (45% and 25%, respectively). Compared with women who had received an IUD from a study physician or study nurse, greater proportions of women who had received one from a nonstudy provider reported any adverse event (76% vs. 49% and 51%, respectively), irregular bleeding (57% vs. 41% and 45%) and pelvic pain (35% vs. 15% and 32%); the difference between study physicians and nurses was significant only for pelvic pain. Expulsion rates were comparable for study nurses and nonstudy providers (12.3 and 11.9 per 100 woman-years, respectively), but lower for study physicians (7.3 per 100 woman-years).

CONCLUSIONS: The findings support task shifting of IUD insertion to mid-level providers to improve IUD access in Sub-Saharan Africa.

RevDate: 2020-01-08

Huang Y, Zhang Y, Bailer R, et al (2019)

Prediction of Serum HIV-1 Neutralization Titers After Passive Administration of VRC01.

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

BACKGROUND: VRC01 is a human IgG1 broadly neutralizing antibody (bnAb) that binds to the HIV-1 envelope glycoprotein. It is being evaluated in two ongoing efficacy trials, the first assessment of a passively-administered bnAb for HIV-1 prevention. HVTN 104 was a Phase 1 trial of VRC01.

SETTING: We measured serum concentrations and serum neutralization of VRC01 in 1079 longitudinal samples collected after passive administration of VRC01 in 84 HVTN 104 participants. As assays for measuring VRC01 serum neutralization titers are resource-intensive, we investigated approaches to predicting such titers.

METHODS: Serum concentration was measured using an anti-idiotypic ELISA assay. Serum neutralization ID50 titers and in vitro neutralization potency IC50 of the VRC01 clinical lot were measured against Env-pseudoviruses. Three approaches were used to predict serum neutralization ID50 titers based on 1) observed serum concentration divided by IC50, 2) pharmacokinetics model-predicted serum concentration divided by IC50, and, 3) joint modeling of the longitudinal serum concentrations and ID50 titers.

RESULTS: All three approaches yielded satisfactory prediction of neutralization titers against viruses of varied sensitivities; the median fold-differences (FDs) of observed-over-predicted ID50 titers were between 0.95 and 1.37. Approach 3 generally performed the best with FDs between 0.95 and 0.99, and <70% mean squared prediction error relative to Approach 1. Similar results were obtained for ID80 titers.

CONCLUSION: VRC01 serum neutralization could be accurately predicted, especially when using pharmacokinetics models. The proposed prediction approaches could potentially save significant resources for the characterization of serum neutralization of VRC01, including for other bnAbs and bnAb combinations.

RevDate: 2019-12-19

Ambrosone CB, Zirpoli GR, Hutson AD, et al (2019)

Dietary Supplement Use During Chemotherapy and Survival Outcomes of Patients With Breast Cancer Enrolled in a Cooperative Group Clinical Trial (SWOG S0221).

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

PURPOSE: Despite reported widespread use of dietary supplements during cancer treatment, few empirical data with regard to their safety or efficacy exist. Because of concerns that some supplements, particularly antioxidants, could reduce the cytotoxicity of chemotherapy, we conducted a prospective study ancillary to a therapeutic trial to evaluate associations between supplement use and breast cancer outcomes.

METHODS: Patients with breast cancer randomly assigned to an intergroup metronomic trial of cyclophosphamide, doxorubicin, and paclitaxel were queried on their use of supplements at registration and during treatment (n =1,134). Cox proportional hazards regression adjusting for clinical and lifestyle variables was used. Recurrence and survival were indexed at 6 months after enrollment using a landmark approach.

RESULTS: There were indications that use of any antioxidant supplement (vitamins A, C, and E; carotenoids; coenzyme Q10) both before and during treatment was associated with an increased hazard of recurrence (adjusted hazard ratio [adjHR], 1.41; 95% CI, 0.98 to 2.04; P = .06) and, to a lesser extent, death (adjHR, 1.40; 95% CI, 0.90 to 2.18; P = .14). Relationships with individual antioxidants were weaker perhaps because of small numbers. For nonantioxidants, vitamin B12 use both before and during chemotherapy was significantly associated with poorer disease-free survival (adjHR, 1.83; 95% CI, 1.15 to 2.92; P < .01) and overall survival (adjHR, 2.04; 95% CI, 1.22 to 3.40; P < .01). Use of iron during chemotherapy was significantly associated with recurrence (adjHR, 1.79; 95% CI, 1.20 to 2.67; P < .01) as was use both before and during treatment (adjHR, 1.91; 95% CI, 0.98 to 3.70; P = .06). Results were similar for overall survival. Multivitamin use was not associated with survival outcomes.

CONCLUSION: Associations between survival outcomes and use of antioxidant and other dietary supplements both before and during chemotherapy are consistent with recommendations for caution among patients when considering the use of supplements, other than a multivitamin, during chemotherapy.

RevDate: 2019-12-19

Woodfield MC, Carpenter PA, SA Pergam (2019)

Shots, Not Moonshots-The Importance of Broad Population Immunization to Patients Who Undergo Cancer Treatment.

JAMA oncology pii:2757399 [Epub ahead of print].

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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.

ESP Content

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.

ESP Help

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.

Biographies

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.

ESP Picks from Around the Web (updated 07 JUL 2018 )