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Bibliography on: Publications by FHCRC Researchers

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ESP: PubMed Auto Bibliography 25 Sep 2018 at 01:35 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: 2018-09-24

Williams LA, Richardson M, Kehm RD, et al (2018)

The association between sex and most childhood cancers is not mediated by birthweight.

Cancer epidemiology, 57:7-12 pii:S1877-7821(18)30315-1 [Epub ahead of print].

BACKGROUND: Male sex is associated with an increased risk of childhood cancer as is high birthweight. Given that sex determination precedes birthweight we conducted a mediation analysis to estimate the direct effect of sex in association with childhood cancer tumor type with birthweight as the mediator.

METHODS: Cases (n = 12,632) and controls (n = 64,439) (ages 0-14 years) were identified from population-based cancer and birth registries in Minnesota, New York, and Washington states (1970-2014). An inverse odds weighting (IOW) mediation analysis was used to estimate odds ratios (OR) and 95% confidence intervals (95% CI) as the measure of association between sex and cancer.

RESULTS: A significant indirect effect was observed for sex and lymphoid leukemia, mediated by birthweight (indirectOR: 1.03; 95% CI: 1.02-1.04). We observed significant direct effects for male sex and lymphoid leukemia (directOR: 1.16; 95% CI: 1.08-1.25), Hodgkin lymphoma (directOR: 1.48; 95% CI: 1.22-1.81), Burkitt lymphoma (directOR: 5.02; 95% CI: 3.40-7.42), other non-Hodgkin lymphoma (directOR: 1.42; 95% CI: 1.18-1.70), intracranial embryonal tumors (directOR: 1.49; 95% CI: 1.26-1.76), hepatoblastoma (directOR: 1.90; 95% CI: 1.40-2.59), and rhabdomyosarcoma (directOR: 1.47; 95% CI: 1.19-1.81). There were also inverse associations for extracranial GCTs (directOR: 0.41; 95% CI: 0.26-0.63) and thyroid carcinoma (directOR: 0.35; 95% CI: 0.25-0.50).

CONCLUSION: Significant direct effects for sex and numerous childhood cancer types suggests sex-specific factors such as differences in gene expression from the autosomes or the X chromosome, rather than birthweight, may underlie sex differences in tumor risk.

RevDate: 2018-09-24

Zick SM, Czuhajewski C, Fouladbakhsh JM, et al (2018)

Integrative Oncology Scholars Program: A Model for Integrative Oncology Education.

Journal of alternative and complementary medicine (New York, N.Y.), 24(9-10):1018-1022.

OBJECTIVES: Oncology providers are often confronted by patients who use complementary or alternative therapies, but have limited knowledge or confidence on how to advise patients on appropriate use. Despite this, there are few opportunities for oncology providers to learn about complementary or alternative therapies, while at the same time there is a high demand for integrative oncology (IO) training. To address a gap in IO educational opportunities, and particularly for nonphysicians, we created the Integrative Oncology Scholars (IOS) Program. The program's goal is to train 100 IO leaders and facilitate partnerships between them and complementary practitioners.

DESIGN: Four iterations of a year-long National Cancer Institute-funded educational program that combines in-person team-based learning and eLearning to teach the evidence, application, and philosophy supporting IO.

SETTINGS: In-person sessions take place at the University of Michigan, and eLearning is implemented using a Canvas website (Instructure, Inc., Salt Lake City, UT).

SUBJECTS: Nurses, social workers, physician assistants, psychologists, physicians, pharmacists, and physical/occupational therapists with active oncology practices. Educational intervention: Four cohorts of 25 oncology providers per year will learn the evidence base for complementary and alternative approaches to a wide number of oncology topics, including symptom control, dietary supplements commonly used by cancer patients, diet, and the utility of specific integrative approaches for common oncology side-effects such as fatigue.

OUTCOME MEASURES: A mixed methods approach will be used to evaluate overall IOS Program progress and individual scholar's impact on IO research, education, and clinical endeavors.

RESULTS: The first cohort of 25 IOS has been recruited and their education will begin in Summer 2018. Scholars come from 13 states and represent 23 different healthcare systems.

CONCLUSIONS: The IOS Program has the potential to increase the number of trained IO providers, educators, and researchers in the United States.

RevDate: 2018-09-24

Gilbert PB, AR Luedtke (2018)

Statistical Learning Methods to Determine Immune Correlates of Herpes Zoster in Vaccine Efficacy Trials.

The Journal of infectious diseases, 218(suppl_2):S99-S101.

Using Super Learner, a machine learning statistical method, we assessed varicella zoster virus-specific glycoprotein-based enzyme-linked immunosorbent assay (gpELISA) antibody titer as an individual-level signature of herpes zoster (HZ) risk in the Zostavax Efficacy and Safety Trial. Gender and pre- and postvaccination gpELISA titers had moderate ability to predict whether a 50-59 year old experienced HZ over 1-2 years of follow-up, with equal classification accuracy (cross-validated area under the receiver operator curve = 0.65) for vaccine and placebo recipients. Previous analyses suggested that fold-rise gpELISA titer is a statistical correlate of protection and supported the hypothesis that it is not a mechanistic correlate of protection. Our results also support this hypothesis.

RevDate: 2018-09-24

Laing KJ, Ouwendijk WJD, Koelle DM, et al (2018)

Immunobiology of Varicella-Zoster Virus Infection.

The Journal of infectious diseases, 218(suppl_2):S68-S74.

Varicella-zoster virus (VZV) causes clinically significant illness during acute and recurrent infection accompanied by robust innate and acquired immune responses. Innate immune cells in skin and ganglion secrete type I interferon (IFN-I) and proinflammatory cytokines to control VZV. Varicella-zoster virus subverts pattern recognition receptor sensing to modulate antigen presentation and IFN-I production. During primary infection, VZV hijacks T cells to disseminate to the skin and establishes latency in ganglia. Durable T- and B-cell memory formed within a few weeks of infection is boosted by reactivation or re-exposure. Antigen-specific T cells are recruited and potentially retained in VZV-infected skin to counteract reactivation. In latently VZV-infected ganglia, however, virus-specific T cells have not been recovered, suggesting that local innate immune responses control VZV latency. Antibodies prevent primary VZV infection, whereas T cells are fundamental to resolving disease, limiting severity, and preventing reactivation. In this study, we review current knowledge on the interactions between VZV and the human immune system.

RevDate: 2018-09-22

Russo JW, Gao C, Bhasin SS, et al (2018)

Downregulation of Dipeptidyl Peptidase 4 Accelerates Progression to Castration-Resistant Prostate Cancer.

Cancer research pii:0008-5472.CAN-18-0687 [Epub ahead of print].

The standard treatment for metastatic prostate cancer (PCa), androgen deprivation therapy (ADT), is designed to suppress androgen receptor (AR) activity. However, men invariably progress to castration-resistant prostate cancer (CRPC), and AR reactivation contributes to progression in most cases. To identify mechanisms that may drive CRPC, we examined a VCaP PCa xenograft model as tumors progressed from initial androgen sensitivity prior to castration to castration resistance and then on to relapse after combined therapy with further AR targeted drugs (abiraterone plus enzalutamide). AR activity persisted in castration-resistant and abiraterone/enzalutamide-resistant xenografts and was associated with increased expression of the AR gene and the AR-V7 splice variant. We then assessed expression of individual AR-regulated genes to identify those that persisted, thereby contributing to tumor growth, versus those that decreased and may therefore exhibit tumor suppressor activities. The most significantly decreased AR target gene was Dipeptidyl Peptidase 4 (DPP4), which encodes a membrane-anchored protein that cleaves dipeptides from multiple growth factors, resulting in their increased degradation. DPP4 mRNA and protein were also decreased in clinical CRPC cases, and inhibition of DPP4 with sitagliptin enhanced the growth of PCa xenografts following castration. Significantly, DPP4 inhibitors are frequently used to treat type 2 diabetes as they increase insulin secretion. Together these results implicate DPP4 as an AR-regulated tumor suppressor gene whose loss enhances growth factor activity and suggest that treatment with DPP4 inhibitors may accelerate emergence of resistance to ADT.

RevDate: 2018-09-22

Phipps W, Kansiime R, Stevenson P, et al (2018)

Peer Mentoring at the Uganda Cancer Institute: A Novel Model for Career Development of Clinician-Scientists in Resource-Limited Settings.

Journal of global oncology.

Cancer centers are beginning to emerge in low- and middle-income countries despite having relatively few oncologists and specialists in related fields. Uganda, like many countries in sub-Saharan Africa, has a cadre of highly motivated clinician-scientists-in-training who are committed to developing the capacity for cancer care and research. However, potential local mentors for these trainees are burdened with uniquely high demands on their time for clinical care, teaching, institutional development, advocacy, and research. Facilitated peer mentoring helps to fill skills and confidence gaps and teaches mentoring skills so that trainees can learn to support one another and regularly access a more senior facilitator/role model. With an added consultant component, programs can engage limited senior faculty time to address specific training needs and to introduce junior investigators to advisors and even potential dyadic mentors. Two years after its inception, our facilitated peer mentoring career development program at the Uganda Cancer Institute in Kampala is successfully developing a new generation of researchers who, in turn, are now providing role models and mentors from within their group. This program provides a practical model for building the next generation of clinical scientists in developing countries.

RevDate: 2018-09-22

Elzembely MM, Park JR, Riad KF, et al (2018)

Acute Complications After High-Dose Chemotherapy and Stem-Cell Rescue in Pediatric Patients With High-Risk Neuroblastoma Treated in Countries With Different Resources.

Journal of global oncology.

PURPOSE: High-dose chemotherapy with autologous stem-cell rescue (SCR) is a key component of high-risk neuroblastoma (HRNB) therapy. Carboplatin, etoposide, and melphalan (CEM) or busulfan and melphalan (Bu/Mel) are the most evaluated, effective high-dose chemotherapy for HRNB on the basis of results from major cooperative group studies. Toxicity profiles vary between these regimens, and practice variation exists regarding the preferred high-dose therapy (HDT). We sought to evaluate the safety of HDT and autologous SCR for HRNB in a resource-limited country (Egypt) compared with the resource-rich United States.

PATIENTS AND METHODS: We performed a retrospective comparative review of single CEM-based HDT/SCR outcomes through day 100 for HRNB at the Fred Hutchinson Cancer Research Center (FH) in the United States (2005 to 2015) versus Bu/Mel-based HDT at El-Sheikh Zayed Specialized Hospital (SZ) in Egypt (2009 to 2015).

RESULTS: Forty-four patients at FH and 77 patients at SZ were reviewed. Pretransplant hepatic comorbidities were significantly higher at SZ (29 of 77 v nine of 44; P = .05), with 19 of 77 patients at SZ having hepatitis infection. Engraftment was delayed after SZ-Bu/Mel therapy compared with FH-CEM therapy for neutrophils (median 12 days v 10 days, respectively; P < .001) and platelets (median 20 days v 18 days, respectively; P < .001). Sinusoidal obstruction syndrome occurred later, after SZ-Bu/Mel therapy (median 19 days v 7 days; P = .033), and four of eight cases were fatal (six of eight patients had underlying hepatitis infection), whereas three of three cases after FH-CEM therapy were moderately severe. Resource utilization associated with the number of days with fever, antibiotic use, and the number of transfusions administered was significantly higher after FH-CEM therapy than after SZ-Bu/Mel therapy.

CONCLUSION: Use of autologous stem-cell transplantation is feasible in the context of a resource-limited country.

RevDate: 2018-09-22

Hortobagyi GN, Pyle D, Cazap EL, et al (2018)

American Society of Clinical Oncology's Global Oncology Leadership Task Force: Findings and Actions.

Journal of global oncology.

In response to rising cancer incidence and mortality rates in low- and middle-income countries and the increasingly global profile of ASCO's membership, the ASCO Board of Directors appointed the Global Oncology Leadership Task Force (Task Force) to provide recommendations on ASCO's engagement in global oncology. To accomplish its work, the Task Force convened meetings of global oncology experts, conducted focus group discussions with member groups, did site visits to South America and India, and met regularly to analyze the findings and develop recommendations. Task Force findings included global concerns, such as access to care, and specific concerns of middle- and low-resource settings. The need to strengthen health systems and the importance of alliances with a range of international cancer stakeholders were emphasized. Task Force recommendations to the ASCO Board of Directors were based on a three-part global oncology strategy of professional development, improvement of access to quality care, and acceleration of global oncology research. Specific areas of focus within each of these strategic pillars are provided along with an update on areas of ASCO activity as these recommendations are implemented.

RevDate: 2018-09-22

Scheel JR, Molina Y, Anderson BO, et al (2018)

Breast Cancer Beliefs as Potential Targets for Breast Cancer Awareness Efforts to Decrease Late-Stage Presentation in Uganda.

Journal of global oncology.

PURPOSE: To assess breast cancer beliefs in Uganda and determine whether these beliefs are associated with factors potentially related to nonparticipation in early detection.

METHODS: A survey with open- and close-ended items was conducted in a community sample of Ugandan women to assess their beliefs about breast cancer. Linear regression was used to ascertain associations between breast cancer beliefs and demographic factors potentially associated with early detection, including socioeconomic factors, health care access, prior breast cancer knowledge, and personal detection practices.

RESULTS: Of the 401 Ugandan women surveyed, most had less than a primary school education and received medical care at community health centers. Most women either believed in or were unsure about cultural explanatory models for developing breast cancer (> 82%), and the majority listed these beliefs as the most important causes of breast cancer (69%). By comparison, ≤ 45% of women believed in scientific explanatory risks for developing breast cancer. Although most believed that regular screening and early detection would find breast cancer when it is easy to treat (88% and 80%, respectively), they simultaneously held fatalistic attitudes toward their own detection efforts, including belief or uncertainty that a cure is impossible once they could self-detect a lump (54%). Individual beliefs were largely independent of demographic factors.

CONCLUSION: Misconceptions about breast cancer risks and benefits of early detection are widespread in Uganda and must be addressed in future breast cancer awareness efforts. Until screening programs exist, most breast cancer will be self-detected. Unless addressed by future awareness efforts, the high frequency of fatalistic attitudes held by women toward their own detection efforts will continue to be deleterious to breast cancer early detection in sub-Saharan countries like Uganda.

RevDate: 2018-09-22

Menon MP, Coghill A, Mutyaba IO, et al (2018)

Association Between HIV Infection and Cancer Stage at Presentation at the Uganda Cancer Institute.

Journal of global oncology.

PURPOSE: The HIV epidemic has contributed to the increasing incidence of cancer in sub-Saharan Africa, where most patients with cancer present at an advanced stage. However, improved access to HIV care and treatment centers in sub-Saharan Africa may facilitate earlier diagnosis of cancer among patients who are HIV positive. To test this hypothesis, we characterized the stage of cancer and evaluated the factors associated with advanced stage at presentation among patients in Uganda.

METHODS: We conducted a retrospective analysis of adult patients with any of four specific cancers who presented for care in Kampala, Uganda, between 2003 and 2010. Demographic, clinical, and laboratory data were abstracted from the medical record, together with the outcome measure of advanced stage of disease (clinical stage III or IV). We identified measures for inclusion in a multivariate logistic regression model.

RESULTS: We analyzed 731 patients with both AIDS-defining cancers (cervical [43.1%], and non-Hodgkin lymphoma [18.3%]), and non-AIDS-defining cancers (breast [30.0%] and Hodgkin lymphoma [8.6%]). Nearly 80% of all patients presented at an advanced stage and 37% had HIV infection. More than 90% of patients were symptomatic and the median duration of symptoms before presentation was 5 months. In the multivariate model, HIV-positive patients were less likely to present at an advanced stage as were patients with higher hemoglobin and fewer symptoms.

CONCLUSION: Patients with limited access to primary care may present with advanced cancer because of a delay in diagnosis. However, patients with HIV now have better access to clinical care. Use of this growing infrastructure to increase cancer screening and referral is promising and deserves continued support, because the prognosis of HIV-positive patients with advanced cancer is characterized by poor survival globally.

RevDate: 2018-09-22

Zujewski JA, Dvaladze AL, Ilbawi A, et al (2018)

Knowledge Summaries for Comprehensive Breast Cancer Control.

Journal of global oncology.

Breast cancer is the most common cancer in women worldwide, affecting > 1.6 million women each year, projected to increase to 2.2 million cases annually by 2025. A disproportionate number of the > 500,000 women who die as a result of breast cancer each year reside in low-resource settings. Breast cancer control is an important component of cancer control planning and women's health programs, and tools are needed across the care continuum to reduce the cancer burden, especially in low-resource settings. Cancer control planning is complex and multifaceted. Evidence shows that outcomes are improved when prevention, early diagnosis, treatment, and palliation are integrated and synchronously developed within a country/region's health plan. The Knowledge Summaries for Comprehensive Breast Cancer Control are the product of a multiyear collaboration led by the Union for International Cancer Control, Breast Health Global Initiative, Pan American Health Organization, and Center for Global Health of the US National Cancer Institute. Fourteen knowledge summaries distilled from evidence-based, resource-stratified guidelines, and aligned with WHO guidance on breast cancer control, build a framework for resource prioritization pathways and delivery systems for breast cancer control at four levels of available resources: basic, limited, enhanced, and maximal. Each summary contains relevant content to inform breast cancer policy, clinical care, and advocacy, aiding in the development and implementation of policies and programs. These tools provide a common platform for stakeholders, including policymakers, administrators, clinicians, and advocates to engage in decision making appropriate to their local setting. The goal is to facilitate evidence-based policy actions and urgently advance implementation of an integrated approach to reduce breast cancer mortality and improve quality of life.

RevDate: 2018-09-22

Bender Ignacio R, Ghadrshenas M, Low D, et al (2018)

HIV Status and Associated Clinical Characteristics Among Adult Patients With Cancer at the Uganda Cancer Institute.

Journal of global oncology.

PURPOSE: HIV increases cancer incidence and mortality. In Uganda, the HIV epidemic has led to an elevated incidence of AIDS-defining cancers (ADCs) and non-AIDS-defining cancers (NADCs). Limited information exists about how frequently HIV infection complicates the presentation and manifestations of cancer in sub-Saharan Africa.

METHODS: We abstracted medical records from patients with cancer who were age 18 years or older who registered at the Uganda Cancer Institute from June through September 2015 to determine the burden of HIV. We used χ2 tests and generalized linear models to evaluate factors associated with HIV positivity. A sensitivity analysis estimated HIV prevalence in those untested.

RESULTS: Among 1,137 patients with cancer, 23% were HIV infected, 48% were HIV negative, and 29% had no recorded HIV status. Of those with recorded HIV status, 32% were HIV positive. Forty-two percent (149 of 361 patients) with ADCs were documented as HIV infected (51% of those with documented status) compared with 14% (108 of 776 patients) of those with NADCs (21% of those with documented status). In multivariable analysis, HIV infection was associated with ADC diagnosis (adjusted prevalence ratio [aPR] compared with NADC, 2.2; 95% CI, 1.5 to 3.0), younger age (aPR, 0.9 per decade increase; 95% CI, 0.8 to 1.0), and worse performance status scores (aPR, 1.2 per point ECOG increase; 95% CI, 1.0 to 1.5). When sensitivity analysis accounted for undocumented HIV status, the expected prevalence of HIV infection was 29% (range, 23% to 32%), and almost one fourth of expected HIV cases were undiagnosed or unrecorded.

CONCLUSION: The prevalence of HIV infection among Ugandan patients with cancer is substantially higher than in the general population. Patients with cancer and HIV tend to be younger and have poorer performance status. Greater awareness of the dual burden of cancer and HIV in Uganda and universal testing of patients with cancer may improve outcomes of HIV-associated malignancies.

RevDate: 2018-09-21

Romine PE, Eaton KD, Paulson KG, et al (2018)

Sarcoidosis presenting as isolated anasarca and hypercalcemia.

The American journal of medicine pii:S0002-9343(18)30876-3 [Epub ahead of print].

RevDate: 2018-09-21

Yun HY, Lampe JW, Tinker LF, et al (2018)

Serum Nitrogen and Carbon Stable Isotope Ratios Meet Biomarker Criteria for Fish and Animal Protein Intake in a Controlled Feeding Study of a Women's Health Initiative Cohort.

The Journal of nutrition pii:5099453 [Epub ahead of print].

Background: Natural abundance stable isotope ratios are candidate biomarkers of dietary intake that have not been evaluated in a controlled feeding study in a US population.

Objectives: Our goals were to evaluate dietary associations with serum carbon (CIR), nitrogen (NIR), and sulfur (SIR) isotope ratios in postmenopausal women, and to evaluate whether statistical models of dietary intake that include multiple isotopes and participant characteristics meet criteria for biomarker evaluation.

Methods: Postmenopausal women from the Women's Health Initiative (n = 153) were provided a 2-wk controlled diet that approximated each individual's habitual food intake. Dietary intakes of animal protein, fish/seafood, red meat, poultry, egg, dairy, total sugars, added sugars, sugar-sweetened beverages (SSBs), and corn products were characterized during the feeding period with the use of the Nutrition Data System for Research (NDS-R). The CIR, NIR, and SIR were measured in sera collected from fasting women at the beginning and the end of the feeding period. Linear models based on stable isotope ratios and participant characteristics predicted dietary intake. The criterion used for biomarker evaluation was R2 ≥ 0.36, based on the study's power to detect true associations with R2 ≥ 0.50.

Results: The NIR was associated with fish/seafood intake and met the criterion for biomarker evaluation (R2 = 0.40). The CIR was moderately associated with intakes of red meat and eggs, but not to the criterion for biomarker evaluation, and was not associated with intake of sugars (total, added, or SSB). A model of animal protein intake based on the NIR, CIR, and participant characteristics met the criterion for biomarker evaluation (R2 = 0.40). Otherwise, multiple isotopes did not improve models of intake, and improvements from including participant characteristics were modest.

Conclusion: Serum stable isotope ratios can, with participant characteristics, meet biomarker criteria as measures of fish/seafood and animal protein intake in a sample of postmenopausal women. This trial was registered at clinicaltrials.gov as NCT00000611.

RevDate: 2018-09-21

Kaluza J, Harris HR, Linden A, et al (2018)

Long-term consumption of fruits and vegetables and risk of chronic obstructive pulmonary disease: a prospective cohort study of women.

International journal of epidemiology pii:5101395 [Epub ahead of print].

Background: Fruits and vegetables, due to high antioxidant capacity, may protect the lung from oxidative damage caused by tobacco smoke and potentially prevent chronic obstructive pulmonary disease (COPD). Only one study based on baseline diet has examined fruit and vegetable consumption in relation to risk of COPD, and no previous studies have examined long-term diet.

Methods: We investigated whether long-term fruit and vegetable consumption was associated with COPD incidence among 34 739 women (age 48-83 years) in the population-based prospective Swedish Mammography Cohort. Fruit and vegetable consumption was assessed twice (1987, 1997) with a self-administered questionnaire. Cases of COPD were identified by linkage to the Swedish health register. Cox proportional hazard regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs).

Results: During follow-up from 2002 to 2014, 1512 women were diagnosed with COPD. Long-term fruit was associated with lower risk of COPD; women in the highest vs lowest quintile of consumption (≥2.5 vs <0.8 servings/day) had a 37% lower risk of COPD (95% CI: 25-48%; P-trend < 0.0001). No association was observed with long-term vegetable intake. Current and ex-smokers with low long-term consumption of fruits (<1 serving/day) in comparison to never smokers with high consumption (≥3 servings/day) had a 38-fold (HR: 38.1; 95% CI: 20.2-71.7) and 13-fold (HR: 12.5, 95% CI: 6.5-24.1) higher risk of COPD, respectively. However, no significant interaction between smoking status and fruit intake in relation to COPD incidence was observed (P-interaction = 0.95).

Conclusions: In this prospective cohort of middle-age and older women, long-term consumption of fruits but not vegetables was inversely associated with COPD incidence.

RevDate: 2018-09-21

Palanee-Phillips T, Roberts ST, Reddy K, et al (2018)

Impact of partner-related social harms on women's adherence to the dapivirine vaginal ring during a phase III trial.

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

BACKGROUND: Long-acting female-initiated methods like the dapivirine ring may give women greater agency in HIV-1 prevention. However, social harms, defined as non-medical adverse consequences of study participation or dapivirine ring use, may reduce product adherence and consequently HIV-1 protection.

BACKGROUND: Long-acting female-initiated methods like the dapivirine ring may give women greater agency in HIV-1 prevention. However, social harms, defined as non-medical adverse consequences of study participation or dapivirine ring use, may reduce product adherence and consequently HIV-1 protection.

RESULTS: Among 2629 women enrolled in ASPIRE, 85 (3.2%) reported 87 social harms during a median follow-up of 1.6 years. Women were significantly more likely to have low adherence, measured by plasma dapivirine levels, at visits with a social harm in the past month than at visits where no social harm was reported (adjusted risk ratio (aRR) 2.53, 95%CI 1.37-4.66, p=0.003). There was no association for social harms reported ≥1-month prior, suggesting an acute, short-term effect. Women were significantly more likely to not return a ring at visits with a social harm reported (aRR 24.70, 95%CI 18.57-32.85, p<0.001). In rings that were returned, social harms were not associated with residual dapivirine levels.

CONCLUSIONS: Although social harms were uncommon (<5% of women with >1 year of use), participants reporting social harms by male partners had lower adherence to the dapivirine ring. Strategies to mitigate non-adherence to product use related to social harms should be evaluated in future studies of female-controlled HIV-1 prevention options.This is an open access article distributed under the terms of the Creative Commons Attribution License 4.0 (CC BY), which permits unrestricted use, distribution, and reproduc in any medium, provided the original work is properly cited.

RevDate: 2018-09-21

Gandelman JS, Byrne MT, Mistry AM, et al (2018)

Machine learning reveals chronic graft-versus-host disease phenotypes and stratifies survival after stem cell transplant for hematologic malignancies.

Haematologica pii:haematol.2018.193441 [Epub ahead of print].

The application of machine learning in medicine has been productive in multiple fields, and has not previously been applied to analyze the complexity of chronic graft-versus-host disease organ involvement. Chronic graft-versus-host disease is classified by an overall composite score of mild, moderate or severe, which may overlook clinically relevant patterns in organ involvement. Here we applied a novel computational approach to chronic graft-versus-host disease with the goal of identifying phenotypic groups based on the subcomponents of the National Institutes of Health (NIH) Consensus Criteria. Computational analysis revealed 7 distinct patient groups with contrasting clinical risks. The high-risk group had an inferior overall survival compared to the low-risk group (HR 2.24 [95% CI 1.36-3.68]), and was independent of severity as measured by the NIH criteria. To test clinical applicability, knowledge was translated into a simplified clinical prognostic decision tree. Groups identified by the decision tree also stratified outcomes and closely matched those from the original analysis. Patients in the high and intermediate-risk decision tree groups had significantly shorter overall survival than those in the low-risk group (HR 2.79 [1.58-4.91] and HR 1.78 [1.06-3.01], respectively). Machine learning and other computational analyses may better reveal biomarkers and stratify risk than the current approach based on cumulative severity. This approach could now be explored in other disease models with complex clinical phenotypes. External validation must be completed prior to clinical application. Ultimately, this approach has the potential to reveal distinct pathophysiological mechanisms that may underlie clusters. Clinicaltrials.gov identifier: NCT00637689.

RevDate: 2018-09-20

Lohavanichbutr P, Zhang Y, Wang P, et al (2018)

Salivary metabolite profiling distinguishes patients with oral cavity squamous cell carcinoma from normal controls.

PloS one, 13(9):e0204249 pii:PONE-D-18-10277.

Oral cavity squamous cell carcinoma (OCC) and oropharyngeal squamous cell carcinoma (OPC) are among the most common cancers worldwide and are associated with high mortality and morbidity. The purpose of this study is to identify potential biomarkers to distinguish OCC/OPC from normal controls and to distinguish OCC patients with and without nodal metastasis. We tested saliva samples from 101 OCC, 58 OPC, and 35 normal controls using four analytical platforms (NMR, targeted aqueous by LC-MS/MS, global aqueous and global lipidomics by LC-Q-TOF). Samples from OCC and normal controls were divided into discovery and validation sets. Using linear regression adjusting for age, sex, race and experimental batches, we found the levels of two metabolites (glycine and proline) to be significantly different between OCC and controls (FDR < 0.1 for both discovery and validation sets) but did not find any appreciable differences in metabolite levels between OPC and controls or between OCC with and without nodal metastasis. Four metabolites, including glycine, proline, citrulline, and ornithine were associated with early stage OCC in both discovery and validation sets. Further study is warranted to confirm these results in the development of salivary metabolites as diagnostic markers.

RevDate: 2018-09-20

Elizaga ML, Li SS, Kochar NK, et al (2018)

Safety and tolerability of HIV-1 multiantigen pDNA vaccine given with IL-12 plasmid DNA via electroporation, boosted with a recombinant vesicular stomatitis virus HIV Gag vaccine in healthy volunteers in a randomized, controlled clinical trial.

PloS one, 13(9):e0202753 pii:PONE-D-18-05637.

BACKGROUND: The addition of plasmid cytokine adjuvants, electroporation, and live attenuated viral vectors may further optimize immune responses to DNA vaccines in heterologous prime-boost combinations. The objective of this study was to test the safety and tolerability of a novel prime-boost vaccine regimen incorporating these strategies with different doses of IL-12 plasmid DNA adjuvant.

METHODS: In a phase 1 study, 88 participants received an HIV-1 multiantigen (gag/pol, env, nef/tat/vif) DNA vaccine (HIV-MAG, 3000 μg) co-administered with IL-12 plasmid DNA adjuvant at 0, 250, 1000, or 1500 μg (N = 22/group) given intramuscularly with electroporation (Ichor TriGrid™ Delivery System device) at 0, 1 and 3 months; followed by attenuated recombinant vesicular stomatitis virus, serotype Indiana, expressing HIV-1 Gag (VSV-Gag), 3.4 ⊆ 107 plaque-forming units (PFU), at 6 months; 12 others received placebo. Injections were in both deltoids at each timepoint. Participants were monitored for safety and tolerability for 15 months.

RESULTS: The dose of IL-12 pDNA did not increase pain scores, reactogenicity, or adverse events with the co-administered DNA vaccine, or following the VSV-Gag boost. Injection site pain and reactogenicity were common with intramuscular injections with electroporation, but acceptable to most participants. VSV-Gag vaccine often caused systemic reactogenicity symptoms, including a viral syndrome (in 41%) of fever, chills, malaise/fatigue, myalgia, and headache; and decreased lymphocyte counts 1 day after vaccination.

CONCLUSIONS: HIV-MAG DNA vaccine given by intramuscular injection with electroporation was safe at all doses of IL-12 pDNA. The VSV-Gag vaccine at this dose was associated with fever and viral symptoms in some participants, but the vaccine regimens were safe and generally well-tolerated.

TRIAL REGISTRATION: Clinical Trials.gov NCT01578889.

RevDate: 2018-09-20

Steuten L, Mewes J, Lepage-Nefkens I, et al (2018)

Is Procalcitonin Biomarker-Guided Antibiotic Therapy a Cost-Effective Approach to Reduce Antibiotic Resistant and Clostridium difficile Infections in Hospitalized Patients?.

Omics : a journal of integrative biology, 22(9):616-625.

Antibiotics (AB) can reduce morbidity and mortality in the treatment of patients with sepsis and chronic obstructive pulmonary disease (COPD) exacerbations. Yet, AB overuse or misuse increases antibiotic resistance (ABR) and Clostridium difficile infections (CDI). This study projected the expected impact of a procalcitonin (PCT) biomarker testing strategy on incremental ABR cases and CDI, and costs of care in a population of patients hospitalized with suspected sepsis or a COPD exacerbation, in three European countries: the United Kingdom, Germany, and the Netherlands. Based on a systematic literature search and a decision model, we analyzed the number of ABR and CDI cases avoided and the incremental healthcare costs per patient from a societal perspective over the time horizon of a hospital stay. In the sepsis population, the PCT-guided antibiotic prescription strategy was projected to reduce the number of ABR cases with circa 6%, the number of CDI cases with 21%, and societal costs with circa €1300 per patient. In the COPD population, the number of ABR and CDI cases is reduced with circa 50%, and societal cost savings ranged €1701, €2473, and €2435 per patient in Germany, the Netherlands, and the United Kingdom, respectively. Model outcomes were most sensitive to the impact of the PCT-guided strategy on the number of intensive care unit days and general hospital ward days. Taken together, a PCT biomarker-guided antibiotic management strategy is likely to reduce the number of ABR and CDI cases and generate cost savings in a population of patients hospitalized with suspected sepsis or with a COPD exacerbation.

RevDate: 2018-09-20

Finak G, Mayer B, Fulp W, et al (2018)

DataPackageR: Reproducible data preprocessing, standardization and sharing using R/Bioconductor for collaborative data analysis.

Gates open research, 2:31.

A central tenet of reproducible research is that scientific results are published along with the underlying data and software code necessary to reproduce and verify the findings. A host of tools and software have been released that facilitate such work-flows and scientific journals have increasingly demanded that code and primary data be made available with publications. There has been little practical advice on implementing reproducible research work-flows for large 'omics' or systems biology data sets used by teams of analysts working in collaboration. In such instances it is important to ensure all analysts use the same version of a data set for their analyses. Yet, instantiating relational databases and standard operating procedures can be unwieldy, with high "startup" costs and poor adherence to procedures when they deviate substantially from an analyst's usual work-flow. Ideally a reproducible research work-flow should fit naturally into an individual's existing work-flow, with minimal disruption. Here, we provide an overview of how we have leveraged popular open source tools, including Bioconductor, Rmarkdown, git version control, R, and specifically R's package system combined with a new tool DataPackageR, to implement a lightweight reproducible research work-flow for preprocessing large data sets, suitable for sharing among small-to-medium sized teams of computational scientists. Our primary contribution is the DataPackageR tool, which decouples time-consuming data processing from data analysis while leaving a traceable record of how raw data is processed into analysis-ready data sets. The software ensures packaged data objects are properly documented and performs checksum verification of these along with basic package version management, and importantly, leaves a record of data processing code in the form of package vignettes. Our group has implemented this work-flow to manage, analyze and report on pre-clinical immunological trial data from multi-center, multi-assay studies for the past three years.

RevDate: 2018-09-20

Wang Z, Zolnik CP, Qiu Y, et al (2018)

Comparison of Fecal Collection Methods for Microbiome and Metabolomics Studies.

Frontiers in cellular and infection microbiology, 8:301.

Background: Integrated microbiome and metabolomics analyses hold the potential to reveal interactions between host and microbiota in relation to disease risks. However, there are few studies evaluating how field methods influence fecal microbiome characterization and metabolomics profiling. Methods: Five fecal collection methods [immediate freezing at -20°C without preservative, OMNIgene GUT, 95% ethanol, RNAlater, and Flinders Technology Associates (FTA) cards] were used to collect 40 fecal samples from eight healthy volunteers. We performed gut microbiota 16S rRNA sequencing, untargeted metabolomics profiling, and targeted metabolomics focusing on short chained fatty acids (SCFAs). Metrics included α-diversity and β-diversity as well as distributions of predominant phyla. To evaluate the concordance with the "gold standard" immediate freezing, the intraclass correlation coefficients (ICCs) for alternate fecal collection systems were calculated. Correlations between SCFAs and gut microbiota were also examined. Results: The FTA cards had the highest ICCs compared to the immediate freezing method for α-diversity indices (ICCs = 0.96, 0.96, 0.76 for Shannon index, Simpson's Index, Chao-1 Index, respectively), followed by OMNIgene GUT, RNAlater, and 95% ethanol. High ICCs (all >0.88) were observed for all methods for the β-diversity metric. For untargeted metabolomics, in comparison to immediate freezing which detected 621 metabolites at ≥75% detectability level, 95% ethanol showed the largest overlapping set of metabolites (n = 430; 69.2%), followed by FTA cards (n = 330; 53.1%) and OMNIgene GUT (n = 213; 34.3%). Both OMNIgene GUT (ICCs = 0.82, 0.93, 0.64) and FTA cards (ICCs = 0.87, 0.85, 0.54) had acceptable ICCs for the top three predominant SCFAs (butyric acid, propionic acid and acetic acid). Nominally significant correlations between bacterial genera and SCFAs (P < 0.05) were observed in fecal samples collected by different methods. Of note, a high correlation between the genus Blautia (known butyrate producer) and butyric acid was observed for both immediate freezing (r = 0.83) and FTA cards (r = 0.74). Conclusions: Four alternative fecal collection methods are generally comparable with immediate freezing, but there are differences in certain measures of the gut microbiome and fecal metabolome across methods. Choice of method depends on the research interests, simplicity of fecal collection procedures and ease of transportation to the lab, especially for large epidemiological studies.

RevDate: 2018-09-20

Wagner MJ, Cranmer LD, Loggers ET, et al (2018)

Propranolol for the treatment of vascular sarcomas.

Journal of experimental pharmacology, 10:51-58 pii:jep-10-051.

Vascular sarcomas are abnormal proliferations of endothelial cells. They range from benign hemangioma to aggressive angiosarcoma, and are characterized by dysregulated angiogenic signaling. Propranolol is a β-adrenergic receptor inhibitor that has demonstrated clinical efficacy in benign infantile hemangioma, and is now being used experimentally for more aggressive vascular sarcomas and other cancers. In this review, we discuss the use of propranolol in targeting these receptors in vascular tumors and other cancers.

RevDate: 2018-09-20

Woolfrey A, Wang T, Lee SJ, et al (2018)

Donor-specific anti-HLA antibodies in unrelated hematopoietic cell transplantation for non-malignant disorders.

RevDate: 2018-09-20

Wen FT, Bell SM, Bedford T, et al (2018)

Estimating Vaccine-Driven Selection in Seasonal Influenza.

Viruses, 10(9): pii:v10090509.

Vaccination could be an evolutionary pressure on seasonal influenza if vaccines reduce the transmission rates of some ("targeted") strains more than others. In theory, more vaccinated populations should have a lower prevalence of targeted strains compared to less vaccinated populations. We tested for vaccine-induced selection in influenza by comparing strain frequencies between more and less vaccinated human populations. We defined strains in three ways: first as influenza types and subtypes, next as lineages of type B, and finally as clades of influenza A/H3N2. We detected spatial differences partially consistent with vaccine use in the frequencies of subtypes and types and between the lineages of influenza B, suggesting that vaccines do not select strongly among all these phylogenetic groups at regional scales. We did detect a significantly greater frequency of an H3N2 clade with known vaccine escape mutations in more vaccinated countries during the 2014⁻2015 season, which is consistent with vaccine-driven selection within the H3N2 subtype. Overall, we find more support for vaccine-driven selection when large differences in vaccine effectiveness suggest a strong effect size. Variation in surveillance practices across countries could obscure signals of selection, especially when strain-specific differences in vaccine effectiveness are small. Further examination of the influenza vaccine's evolutionary effects would benefit from improvements in epidemiological surveillance and reporting.

RevDate: 2018-09-20

Hahn AW, Higano CS, Taplin ME, et al (2018)

Metastatic Castration-Sensitive Prostate Cancer: Optimizing Patient Selection and Treatment.

American Society of Clinical Oncology educational book. American Society of Clinical Oncology. Annual Meeting.

The treatment landscape for metastatic castration-sensitive prostate cancer (mCSPC) has rapidly evolved over the past 5 years. Although androgen-deprivation therapy (ADT) is still the backbone of treatment, the addition of docetaxel or abiraterone acetate has improved outcomes for patients with mCSPC and become standard of care. With multiple treatment options available for patients with mCSPC, treatment selection to optimize patient outcomes has become increasingly difficult. Here, we review the clinical trials involving ADT plus docetaxel or abiraterone and provide clinicians with guidelines for treatment. Although surgery and/or radiation are standard of care for localized, intermediate- and high-risk prostate cancer, these treatments are not routinely used as part of initial treatment plans for patients with de novo mCSPC. Recent clinical data are challenging that dogma, and we review the literature on the addition of surgery and radiation to systemic therapy for mCSPC. Finally, the standard of care for oligometastatic prostate cancer (a subset of mCSPC with limited metastases) has not been established compared with that for some other cancers. We discuss the recent studies on metastasis-directed therapy for treatment of oligometastatic prostate cancer.

RevDate: 2018-09-20

Dietrich B, Siefker-Radtke AO, Srinivas S, et al (2018)

Systemic Therapy for Advanced Urothelial Carcinoma: Current Standards and Treatment Considerations.

American Society of Clinical Oncology educational book. American Society of Clinical Oncology. Annual Meeting.

Urothelial carcinoma is the sixth most common malignancy in the United States. Although most are diagnosed with non-muscle-invasive malignancy, many patients will develop recurrent disease within 5 years, with 10% to 20% developing advanced muscle-invasive or more distant incurable disease. For such patients, clinical outcomes have remained suboptimal, although recent therapeutic advances have brought new hope to the field. Here, we discuss the main systemic treatment options available for the treatment of patients with advanced disease. This review begins with traditional chemotherapy, which remains a first-line treatment option for many patients. The second section focuses on the evolving landscape of immunotherapy, specifically on approved checkpoint inhibitors and future challenges. Last, we address advances in targeted treatments, including angiogenesis and fibroblast growth factor receptor (FGFR) inhibitors as well as antibody-drug conjugates. As the number of available treatment options continues to expand, ongoing trials to investigate the best sequence and combination strategies to incorporate these drugs into clinical practice will help delineate the future.

RevDate: 2018-09-20

Katz D, Palmerini E, SM Pollack (2018)

More Than 50 Subtypes of Soft Tissue Sarcoma: Paving the Path for Histology-Driven Treatments.

American Society of Clinical Oncology educational book. American Society of Clinical Oncology. Annual Meeting.

Sarcomas are a diverse group of cancers with mesenchymal origin. Although sarcomas comprise less than 1% of cancers, there are more than 50 different subtypes that are quite different from one another in terms of both their biology and clinical behavior. Historically, the need for adequate patient numbers in clinical trials has pushed sarcoma researchers to lump these very different malignancies together and treat the patients using a "one-size-fits-all" approach. However, with improvements in our scientific understanding, we are finally ready for a histology-tailored therapeutic approach to these complex diseases. In this review, we discuss key advances in our understanding of the biology underlying selected sarcoma subtypes and how targeting these subtypes is relevant therapeutically with respect to both molecularly targeted agents as well as immunotherapy.

RevDate: 2018-09-20

Dienstmann R, Salazar R, J Tabernero (2018)

Molecular Subtypes and the Evolution of Treatment Decisions in Metastatic Colorectal Cancer.

American Society of Clinical Oncology educational book. American Society of Clinical Oncology. Annual Meeting.

Colorectal cancer (CRC) has clinically relevant molecular heterogeneity at multiple levels: genomics, epigenomics, transcriptomics, and microenvironment features. Genomic events acquired during carcinogenesis remain drivers of cancer progression in the metastatic setting. For example, KRAS and NRAS mutations define a population refractory to epidermal growth factor receptor monoclonal antibodies, BRAFV600E mutations associate with poor outcomes under standard therapies and response to targeted inhibitors in combinations, and HER2 amplifications confer unique sensitivity to double HER2 blockade. Multiple rare gene alterations driving resistance to epidermal growth factor receptor monoclonal antibodies have been described, with substantial overlap in primary and acquired mechanisms, in line with a clonal selection process. In this context, sequential analysis of circulating tumor DNA has the potential to guide drug development in a treatment-refractory setting. Rare kinase fusion events and complex alterations in genes involved in DNA damage repair have been described, with emerging evidence for targetability. On the other hand, transcriptomic subtypes and pathway activation signatures have also shown prognostic and potential predictive value in metastatic CRC. These markers reflect stromal and immune microenvironment interactions with cancer cells. For example, the microsatellite instable or POLE ultramutant CRC population is particularly sensitive to immune checkpoint inhibitors, whereas tumors with a mesenchymal phenotype are characterized by activation of immunosuppressive molecules that mandate stratified development of novel immunotherapy combinations. Here, we review the expanding landscape of targetable oncogenic alterations and signatures in metastatic CRC and discuss the clinical implementation of novel molecular diagnostic tests.

RevDate: 2018-09-19

Rosenberg AR, Bradford MC, McCauley E, et al (2018)

Promoting Resilience in Adolescents and Young Adults With Cancer: Results From the PRISM Randomized Controlled Trial.

Cancer [Epub ahead of print].

BACKGROUND: Adolescents and young adults (AYAs) with cancer are at risk for poor psychosocial outcomes. This study aimed to determine whether a novel intervention targeting resilience resources would improve patient-reported resilience, quality of life, and psychological distress.

METHODS: In this parallel, phase 2 randomized controlled trial, English-speaking AYAs (12-25 years old) with cancer were randomized to the Promoting Resilience in Stress Management (PRISM) intervention or usual care (UC). PRISM is a brief, skills-based intervention targeting stress management, goal setting, cognitive reframing, and meaning making. Participants completed surveys at enrollment and 6 months. Mixed effects regression models evaluated associations between PRISM and the primary outcome (10-item Connor-Davidson Resilience Scale scores) and secondary outcomes (generic and cancer-related quality of life [Pediatric Quality of Life modules], psychological distress [Kessler-6], and anxiety/depression [Hospital Anxiety and Depression]) at 6 months.

RESULTS: Ninety-two AYAs were enrolled, were randomized, and completed baseline surveys (48 in the PRISM group and 44 in the UC group); 73% were 12 to 17 years old, and 62% had leukemia or lymphoma. Attrition was primarily due to medical complications and/or death; 36 PRISM participants and 38 UC participants completed 6-month surveys. PRISM was associated with improved resilience (+3.0 points; 95% confidence interval [CI], 0.5-5.4; P = .02) and cancer-specific quality of life (+9.6; 95% CI, 2.6-16.7; P = .01) and reduced psychological distress (-2.1; 95% CI, -4.1 to -0.2; P = .03) but not generic quality of life (+7.2; 95% CI, -0.8 to 15.2; P = .08). Although anxiety was similar between the groups, 2 PRISM participants (6%) and 8 UC participants (21%) met the criteria for depression at 6 months (odds ratio, 0.09; 95% CI, 0.01-1.09; P = .06).

CONCLUSIONS: PRISM was associated with improved psychosocial outcomes in comparison with UC, suggesting that brief, skills-based interventions for AYAs may provide a benefit.

RevDate: 2018-09-19

Tasdemir N, Bossart EA, Li Z, et al (2018)

Comprehensive phenotypic characterization of human invasive lobular carcinoma cell lines in 2D and 3D cultures.

Cancer research pii:0008-5472.CAN-18-1416 [Epub ahead of print].

Invasive lobular carcinoma (ILC) is the second most common subtype of breast cancer following invasive ductal carcinoma (IDC) and characterized by the loss of E-cadherin-mediated adherens junctions. Despite displaying unique histological and clinical features, ILC still remains a chronically understudied disease, with limited knowledge gleaned from available laboratory research models. Here we report a comprehensive 2D and 3D phenotypic characterization of four estrogen receptor-positive human ILC cell lines: MDA-MB-134, SUM44, MDA-MB-330 and BCK4. Compared to the IDC cell lines MCF7, T47D and MDA-MB-231, ultra-low attachment culture conditions revealed remarkable anchorage-independence unique to ILC cells, a feature not evident in soft agar gels. 3D Collagen I and Matrigel culture indicated a generally loose morphology for ILC cell lines, which exhibited differing preferences for adhesion to ECM proteins in 2D. Furthermore, ILC cells were limited in their ability to migrate and invade in wound-scratch and transwell assays, with the exception of haptotaxis to Collagen I. Transcriptional comparison of these cell lines confirmed the decreased cell proliferation and E-cadherin-mediated intercellular junctions in ILC while uncovering the induction of novel pathways related to cyclic nucleotide phosphodiesterase activity, ion channels, drug metabolism and alternative cell adhesion molecules such as N-cadherin, some of which were differentially regulated in ILC versus IDC tumors. Altogether, these studies provide an invaluable resource for the breast cancer research community and facilitate further functional discoveries towards understanding ILC, identifying novel drug targets, and ultimately improving the outcome of patients with ILC.

RevDate: 2018-09-18

Hennessey MJ, Ellis EM, Delorey MJ, et al (2018)

Seroprevalence and Symptomatic Attack Rate of Chikungunya Virus Infection, United States Virgin Islands, 2014-2015.

The American journal of tropical medicine and hygiene [Epub ahead of print].

When introduced into a naïve population, chikungunya virus generally spreads rapidly, causing large outbreaks of fever and severe polyarthralgia. We randomly selected households in the U.S. Virgin Islands (USVI) to estimate seroprevalence and symptomatic attack rate for chikungunya virus infection at approximately 1 year following the introduction of the virus. Eligible household members were administered a questionnaire and tested for chikungunya virus antibodies. Estimated proportions were calibrated to age and gender of the population. We enrolled 509 participants. The weighted infection rate was 31% (95% confidence interval [CI]: 26-36%). Among those with evidence of chikungunya virus infection, 72% (95% CI: 65-80%) reported symptomatic illness and 31% (95% CI: 23-38%) reported joint pain at least once per week approximately 1 year following the introduction of the virus to USVI. Comparing rates from infected and noninfected study participants, 70% (95% CI: 62-79%) of fever and polyarthralgia and 23% (95% CI: 9-37%) of continuing joint pain in patients infected with chikungunya virus were due to their infection. Overall, an estimated 43% (95% CI: 33-52%) of the febrile illness and polyarthralgia in the USVI population during the outbreak was attributable to chikungunya virus and only 12% (95% CI: 7-17%) of longer term joint pains were attributed to chikungunya virus. Although the rates of infection, symptomatic disease, and longer term joint symptoms identified in USVI are similar to other outbreaks of the disease, a lower proportion of acute fever and joint pain was found to be attributable to chikungunya virus.

RevDate: 2018-09-18

Randolph TW, Zhao S, Copeland W, et al (2018)

KERNEL-PENALIZED REGRESSION FOR ANALYSIS OF MICROBIOME DATA.

The annals of applied statistics, 12(1):540-566.

The analysis of human microbiome data is often based on dimension-reduced graphical displays and clusterings derived from vectors of microbial abundances in each sample. Common to these ordination methods is the use of biologically motivated definitions of similarity. Principal coordinate analysis, in particular, is often performed using ecologically defined distances, allowing analyses to incorporate context-dependent, non-Euclidean structure. In this paper, we go beyond dimension-reduced ordination methods and describe a framework of high-dimensional regression models that extends these distance-based methods. In particular, we use kernel-based methods to show how to incorporate a variety of extrinsic information, such as phylogeny, into penalized regression models that estimate taxonspecific associations with a phenotype or clinical outcome. Further, we show how this regression framework can be used to address the compositional nature of multivariate predictors comprised of relative abundances; that is, vectors whose entries sum to a constant. We illustrate this approach with several simulations using data from two recent studies on gut and vaginal microbiomes. We conclude with an application to our own data, where we also incorporate a significance test for the estimated coefficients that represent associations between microbial abundance and a percent fat.

RevDate: 2018-09-18

Bianchi-Frias D, Damodarasamy M, Hernandez SA, et al (2018)

The Aged Microenvironment Influences the Tumorigenic Potential of Malignant Prostate Epithelial Cells.

Molecular cancer research : MCR pii:1541-7786.MCR-18-0522 [Epub ahead of print].

The incidence of prostate cancer (PC) is directly linked to age, but age-associated changes that facilitate PC development and progression are poorly understood. This study investigated age-related changes in the prostate microenvironment for their influence on PC behavior. PC cells implanted orthotopically into the prostate demonstrated accelerated tumor growth in aged compared to young mice. Metastatic lesions following intravenous injection were also more numerous in aged mice. Tumors from young and aged mice showed no significant differences concerning their proliferation index, apoptosis or angiogenesis. However, analysis of tumor-infiltrating immune cells by immunohistochemistry (IHC) and RNA-sequencing (RNA-seq) revealed elevated numbers of macrophages in prostates from aged mice, which are quickly polarized towards a phenotype resembling pro-tumorigenic tumor-associated macrophages (TAMs) upon tumor cell engraftment. Older PC patients (>60 years old) in The Cancer Genome Atlas (TCGA) PRAD dataset displayed higher expression of macrophage markers (CD163 and VSIG4) which associated with higher rates of biochemical relapse. Remodeling of the collagenous extracellular matrix (ECM) was associated with PC growth and invasion in the aged microenvironment. Moreover, the collagen matrix extracted from aged mice enhanced the invasiveness and proliferation of PC cells in vitro. Together, these results demonstrate that the aged prostatic microenvironment can regulate the growth and metastasis of malignant prostate cells, highlighting the role of resident macrophages and their polarization towards a pro-tumorigenic phenotype, along with remodeling of the ECM.

IMPLICATIONS: These findings demonstrate the importance of age-associated tumor microenvironment (TME) alterations in regulating key aspects of prostate cancer progression.

RevDate: 2018-09-17

Hahn EA, Kallen MA, Jensen RE, et al (2016)

Measuring social function in diverse cancer populations: Evaluation of measurement equivalence of the Patient Reported Outcomes Measurement Information System® (PROMIS®) Ability to Participate in Social Roles and Activities short form.

Psychological test and assessment modeling, 58(2):403-421.

Conceptual and psychometric measurement equivalence of self-report questionnaires are basic requirements for valid cross-cultural and demographic subgroup comparisons. The purpose of this study was to evaluate the psychometric measurement equivalence of a 10-item PROMIS® Social Function short form in a diverse population-based sample of cancer patients obtained through the Measuring Your Health (MY-Health) study (n = 5,301). Participants were cancer survivors within six to 13 months of a diagnosis of one of seven cancer types, and spoke English, Spanish, or Mandarin Chinese. They completed a survey on sociodemographic and clinical characteristics, and health status. Psychometric measurement equivalence was evaluated with an item response theory approach to differential item functioning (DIF) detection and impact. Although an expert panel proposed that many of the 10 items might exhibit measurement bias, or DIF, based on gender, age, race/ethnicity, and/or education, no DIF was detected using the study's standard DIF criterion, and only one item in one sample comparison was flagged for DIF using a sensitivity DIF criterion. This item's flagged DIF had only a trivial impact on estimation of scores. Social function measures are especially important in cancer because the disease and its treatment can affect the quality of marital relationships, parental responsibilities, work abilities, and social activities. Having culturally relevant, linguistically equivalent and psychometrically sound patient-reported measures in multiple languages helps to overcome some common barriers to including underrepresented groups in research and to conducting cross-cultural research.

RevDate: 2018-09-17

Phillips AM, Ponomarenko AI, Chen K, et al (2018)

Destabilized adaptive influenza variants critical for innate immune system escape are potentiated by host chaperones.

PLoS biology, 16(9):e3000008 pii:PBIOLOGY-D-18-00045 [Epub ahead of print].

The threat of viral pandemics demands a comprehensive understanding of evolution at the host-pathogen interface. Here, we show that the accessibility of adaptive mutations in influenza nucleoprotein at fever-like temperatures is mediated by host chaperones. Particularly noteworthy, we observe that the Pro283 nucleoprotein variant, which (1) is conserved across human influenza strains, (2) confers resistance to the Myxovirus resistance protein A (MxA) restriction factor, and (3) critically contributed to adaptation to humans in the 1918 pandemic influenza strain, is rendered unfit by heat shock factor 1 inhibition-mediated host chaperone depletion at febrile temperatures. This fitness loss is due to biophysical defects that chaperones are unavailable to address when heat shock factor 1 is inhibited. Thus, influenza subverts host chaperones to uncouple the biophysically deleterious consequences of viral protein variants from the benefits of immune escape. In summary, host proteostasis plays a central role in shaping influenza adaptation, with implications for the evolution of other viruses, for viral host switching, and for antiviral drug development.

RevDate: 2018-09-17

Samples LS, SA Graf (2018)

On the front line: first choice pharmacotherapeutics for chronic lymphocytic leukemia.

Expert opinion on pharmacotherapy [Epub ahead of print].

Introduction Chronic lymphocytic leukemia (CLL) is a common hematologic malignancy with a highly variable clinical course. Frontline treatments include cytotoxic chemotherapies, immunotherapies, and small molecule inhibitors. Clinical and molecular factors guide treatment initiation and selection. Over the last decade, refinement of CLL risk stratification tools and growth of the arsenal of effective therapeutics have profoundly improved outcomes. These advances have concurrently increased the complexity of managing the early phases of treatment. Areas Covered This review describes the factors considered in the determination of first-line treatment of CLL. Areas of emphasis include assessment of patient fitness, disease classification and risk stratification, and the mechanisms, efficacy, and toxicities associated with available pharmacotherapeutics. Expert Opinion Multiple different treatments may be appropriate for a specific clinical scenario, and selection among them requires discussion of relative risks and benefits. Advances in frontline CLL treatment will continue to shift the treatment paradigm toward prioritizing quality of life alongside survival, limiting treatment and toxicity, and the development of biologically rational synergistic drug combinations and sequences.

RevDate: 2018-09-17

Radtke S, Humbert O, HP Kiem (2018)

Sorting Out the Best: Enriching Hematopoietic Stem Cells for Gene Therapy and Editing.

RevDate: 2018-09-16

Gandelman JS, Zic J, Dewan AK, et al (2018)

The Anatomic Distribution of Skin Involvement in Patients with Incident Chronic Graft-versus-Host Disease.

Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation pii:S1083-8791(18)30564-0 [Epub ahead of print].

Little is known about the anatomic distribution of cutaneous chronic graft-versus-host disease (cGVHD). Using data from the cGVHD Consortium Improving Outcomes Assessment Study, we describe the frequency and extent of erythema, superficial, and deep sclerosis in 8 anatomic sites in patients with incident disease (new cGVHD diagnosis within three months of study entry) and on systemic therapy. Of 339 patients with incident disease, 182 (54%) had skin involvement. When an extremity was involved, the same type of disease was present contralaterally in 92% of cases, revealing a high level of symmetry. As anticipated, erythema was the most common incident feature; however, sclerotic skin involvement at time of cGVHD diagnosis was more common than suggested by prior studies. Erythema occurred in 155 (85%) and sclerosis in 53 (29%) of the patients with skin involvement (respectively 46% and 16% of the the entire cohort of 339 incident cGVHD cases). Erythema was least common on the lower extremities (n=71, 39% of patients with skin involvement). Moveable sclerosis was rare on the head, neck, and scalp (n=4, 2%). Deep sclerosis did not occur in this region, and instead was most likely on the upper (n=14, 8%) and lower extremities (n=14, 8%). More than half of patients with erythema (n=107, 58.7%) had diffuse involvement (4 or more of 8 sites involved), compared to less than a third of those with sclerosis (n=16, 30.2%).

RevDate: 2018-09-16

Retèl VP, Steuten LMG, Geukes Foppen MH, et al (2018)

Early cost-effectiveness of tumor infiltrating lymphocytes (TIL) for second line treatment in advanced melanoma: a model-based economic evaluation.

BMC cancer, 18(1):895 pii:10.1186/s12885-018-4788-5.

BACKGROUND: An emerging immunotherapy is infusion of tumor infiltrating Lymphocytes (TIL), with objective response rates of around 50% versus 19% for ipilimumab. As an Advanced Therapeutic Medicinal Products (ATMP), TIL is highly personalized and complex therapy. It requests substantial upfront investments from the hospital in: expensive lab-equipment, staff expertise and training, as well as extremely tight hospital logistics. Therefore, an early health economic modelling study, as part of a Coverage with Evidence Development (CED) program, was performed.

METHODS: We used a Markov decision model to estimate the expected costs and outcomes (quality-adjusted life years; QALYs) for TIL versus ipilimumab for second line treatment in metastatic melanoma patients from a Dutch health care perspective over a life long time horizon. Three mutually exclusive health states (stable disease (responders)), progressive disease and death) were modelled. To inform further research prioritization, Value of Information (VOI) analysis was performed.

RESULTS: TIL is expected to generate more QALYs compared to ipilimumab (0.45 versus 0.38 respectively) at lower incremental cost (presently €81,140 versus €94,705 respectively) resulting in a dominant ICER (less costly and more effective). Based on current information TIL is dominating ipilimumab and has a probability of 86% for being cost effective at a cost/QALY threshold of €80,000. The Expected Value of Perfect Information (EVPI) amounted to €3 M.

CONCLUSIONS: TIL is expected to have the highest probability of being cost-effective in second line treatment for advanced melanoma compared to ipilimumab. To reduce decision uncertainty, a clinical trial investigating e.g. costs and survival seems most valuable. This is currently being undertaken as part of a CED program in the Netherlands Cancer Institute, Amsterdam, the Netherlands, in collaboration with Denmark.

RevDate: 2018-09-15

Zhan X, Xue L, Zheng H, et al (2018)

A small-sample kernel association test for correlated data with application to microbiome association studies.

Genetic epidemiology [Epub ahead of print].

Recent research has highlighted the importance of the human microbiome in many human disease and health conditions. Most current microbiome association analyses focus on unrelated samples; such methods are not appropriate for analysis of data collected from more advanced study designs such as longitudinal and pedigree studies, where outcomes can be correlated. Ignoring such correlations can sometimes lead to suboptimal results or even possibly biased conclusions. Thus, new methods to handle correlated outcome data in microbiome association studies are needed. In this paper, we propose the correlated sequence kernel association test (CSKAT) to address such correlations using the linear mixed model. Specifically, random effects are used to account for the outcome correlations and a variance component test is used to examine the microbiome effect. Compared to existing genetic association tests for longitudinal and family samples, we implement a correction procedure to better calibrate the null distribution of the score test statistic to accommodate the small sample size nature of data collected from a typical microbiome study. Comprehensive simulation studies are conducted to demonstrate the validity and efficiency of our method, and we show that CSKAT achieves a higher power than existing methods while correctly controlling the Type I error rate. We also apply our method to a microbiome data set collected from a UK twin study to illustrate its potential usefulness. A free implementation of our method in R software is available at https://github.com/jchen1981/SSKAT.

RevDate: 2018-09-15

Mensch BS, Richardson BA, Husnik M, et al (2018)

Vaginal Ring Use in a Phase 3 Microbicide Trial: A Comparison of Objective Measures and Self-reports of Non-adherence in ASPIRE.

AIDS and behavior pii:10.1007/s10461-018-2261-8 [Epub ahead of print].

This analysis compares self-reports of product use with objective measures of non-adherence-quarterly plasma dapivirine levels and monthly residual dapivirine (DPV) levels in used rings-in MTN-020/ASPIRE, a phase 3 trial of a monthly DPV vaginal ring among women aged 18-45 years in Malawi, South Africa, Uganda and Zimbabwe. For participants on active product (N = 1211) we assessed self-reported monthly non-adherence, as measured by (1) whether the ring was ever out, and out for ≥ 12 h in the previous month and, (2) by a self-rating scale assessing ability to keep the vaginal ring inserted, and compared the self-reports to two biomarkers of non-use separately and as a composite measure. For this analysis, a plasma DPV value ≤ 95 pg/ml and residual ring ≥ 23.5 mg were used to classify non-adherence (i.e. the ring never being in the vagina the previous month). Compared to self-reports, non-adherence was found to be substantially higher for the composite measure as well as its two components, an indication that ring removal was likely underreported in the trial. The discrepancy between the self-report measure of ring outage and the composite indicator was greater for those aged 18-21 than for those older, evidence that younger women are more likely to underreport non-adherence. Despite underreporting of non-adherence, self-reports of the ring never being out were significant in predicting the composite objective measure. Furthermore, the association between the self-rating scale and the objective measure was in the expected direction and significant, although 11% of those 18-21 and 7% of those 22+ who rated their ability to keep the ring inserted as good, very good or excellent in the 4 weeks prior to exit were considered non-adherent according to the objective measure. This analysis indicates that while self-reports are significantly associated with objective measures of adherence in the ASPIRE trial, they were inflated-more so by those younger-and therefore may have limited utility identifying those who have challenges using products as directed. ClinicalTrials.gov number NCT01617096.

RevDate: 2018-09-15

Fowler KR, Hyppa RW, Cromie GA, et al (2018)

Physical basis for long-distance communication along meiotic chromosomes.

Proceedings of the National Academy of Sciences of the United States of America pii:1801920115 [Epub ahead of print].

Viable gamete formation requires segregation of homologous chromosomes connected, in most species, by cross-overs. DNA double-strand break (DSB) formation and the resulting cross-overs are regulated at multiple levels to prevent overabundance along chromosomes. Meiotic cells coordinate these events between distant sites, but the physical basis of long-distance chromosomal communication has been unknown. We show that DSB hotspots up to ∼200 kb (∼35 cM) apart form clusters via hotspot-binding proteins Rec25 and Rec27 in fission yeast. Clustering coincides with hotspot competition and interference over similar distances. Without Tel1 (an ATM tumor-suppressor homolog), DSB and crossover interference become negative, reflecting coordinated action along a chromosome. These results indicate that DSB hotspots within a limited chromosomal region and bound by their protein determinants form a clustered structure that, via Tel1, allows only one DSB per region. Such a "roulette" process within clusters explains the observed pattern of crossover interference in fission yeast. Key structural and regulatory components of clusters are phylogenetically conserved, suggesting conservation of this vital regulation. Based on these observations, we propose a model and discuss variations in which clustering and competition between DSB sites leads to DSB interference and in turn produces crossover interference.

RevDate: 2018-09-15

Almassi N, Gao T, Lee B, et al (2018)

Impact of Neoadjuvant Chemotherapy on Pathologic Response in Patients With Upper Tract Urothelial Carcinoma Undergoing Extirpative Surgery.

Clinical genitourinary cancer pii:S1558-7673(18)30376-8 [Epub ahead of print].

BACKGROUND: Neoadjuvant chemotherapy (NAC) has been increasingly adopted in the management of high-grade upper tract urothelial carcinoma (UTUC), largely extrapolating from level I evidence in urothelial carcinoma of the bladder. Studies examining pathologic outcomes in patients with UTUC receiving NAC are mostly limited to retrospective, single-center studies with limited sample size, with results of a phase II trial recently presented. Hypothesizing that NAC is associated with improved pathologic response (PR), we compared pathologic outcomes in patients with high-grade UTUC who did and did not receive NAC before extirpative surgery.

PATIENTS AND METHODS: A total of 6174 patients with nonmetastatic, high-grade UTUC who underwent extirpative surgery from 2006 to 2014 were identified from the National Cancer Database. Patients were stratified by NAC status. PR was defined as pathologic stage less than clinical stage. Univariate and multivariable logistic regression analysis was employed to identify predictors of PR.

RESULTS: Two hundred sixty (4.2%) patients received NAC. A higher incidence of PR was observed in patients receiving NAC (25.2% vs. 1.8%; P < .001), with complete PR observed in 6.1% of patients receiving NAC and 0.4% of patients undergoing surgery alone. NAC (odds ratio [OR], 19.8; 95% confidence interval [CI], 11.8-33.5), nonwhite race (OR, 3.2; 95% CI, 1.7-6.3), and ureteral tumor location (OR, 1.6; 95% CI, 1.02-2.6) were independently associated with PR.

CONCLUSIONS: Examining a large national cancer registry, we observed a higher incidence of PR in patients with UTUC receiving NAC, validating findings of prior studies. Our findings support consideration of NAC in high grade UTUC. Prospective trials will better define the impact of NAC on pathologic and survival outcomes.

RevDate: 2018-09-14

Madenci AL, Weil BR, Liu Q, et al (2018)

Long-Term Risk of Venous Thromboembolism in Survivors of Childhood Cancer: A Report From the Childhood Cancer Survivor Study.

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

Purpose To estimate the incidence of late-occurring venous thromboembolism (VTE) among survivors of childhood cancer and to identify risk factors for VTE to facilitate diagnosis and prevention. Methods The Childhood Cancer Survivor Study is a multi-institutional cohort of 24,355 5-year childhood cancer survivors (diagnosed between 1970 and 1999; median age at last follow-up, 28.7 years [range, 5.6 to 58.9 years]; median follow-up since diagnosis, 21.3 years [range, 5.0 to 39.2 years]) and 5,051 sibling participants. The primary end point was self-reported late (≥ 5 years after cancer diagnosis) VTE. Rate ratios (RRs) were estimated with multivariable piecewise exponential models. Results Late VTE incidence among survivors and siblings was 1.1 and 0.5 events per 1,000 person-years, respectively (RR, 2.2; 95% CI, 1.7 to 2.8), with 2.5 excess events per 100 survivors over 35 years. Among survivors, risk factors for VTE were female sex (RR, 1.3; 95% CI, 1.1 to 1.6), cisplatin (reference none; 1 to 199 mg/m2: RR, 3.0 [95% CI, 1.4 to 6.5]; 200 to 399 mg/m2: RR, 1.9 [95% CI, 1.0 to 3.6]; ≥ 400 mg/m2: RR, 2.0 [95% CI, 1.2 to 3.3]), l-asparaginase (RR, 1.3; 95% CI, 1.0 to 1.7), obesity or underweight (reference body mass index [BMI] 18.5 to 24.9 kg/m2; BMI ≥ 30.0 kg/m2: RR, 1.6 [95% CI, 1.2 to 2.0]; BMI < 18.5 kg/m2: RR, 2.4 [95% CI, 1.7 to 3.4]), and late cancer recurrence or subsequent malignant neoplasm (RR, 4.6; 95% CI, 3.6 to 5.8). Among lower-extremity osteosarcoma survivors, limb salvage (reference amputation; RR, 3.1; 95% CI, 1.2 to 7.5) and cisplatin 200 to 399 or ≥ 400 mg/m2 (reference none; RR, 4.0 [95% CI, 1.1 to 14.6] and 2.9 [95% CI, 1.1 to 8.0], respectively) were independently associated with late VTE. VTE was associated with increased risk for nonexternal cause late mortality (RR, 1.9; 95% CI, 1.6 to 2.3). Conclusion Childhood cancer survivors are at increased risk for VTE across their lifespan and a diagnosis of VTE increases mortality risk. Interventions that target potentially modifiable comorbidities, such as obesity, warrant consideration, with prophylaxis for high-risk survivors, including those treated with cisplatin and limb-sparing approaches.

RevDate: 2018-09-14

Long GV, Tykodi SS, Schneider JG, et al (2018)

Assessment of nivolumab exposure and clinical safety of 480 mg every 4 weeks flat-dosing schedule in patients with cancer.

Annals of oncology : official journal of the European Society for Medical Oncology pii:5095691 [Epub ahead of print].

Background: A nivolumab monotherapy flat-dosing regimen of 480 mg every 4 weeks (Q4W) has been approved in the United States, Canada, and European Union as an alternative dosing regimen for several indications. Approvals of this Q4W regimen were based on population pharmacokinetic (PK) analyses, established flat exposure-response relationships, and clinical safety. The objective of this study was to compare the PK exposure of 480 mg Q4W with 3 mg/kg every 2 weeks (Q2W) and 240 mg Q2W using modeling and simulation, and to evaluate clinical safety of the Q4W regimen.

Patients and methods: Nivolumab PK exposure for the 480 mg Q4W schedule was simulated for 3817 patients across multiple tumor types and compared with those for the 3 mg/kg Q2W and 240 mg Q2W schedules. The safety profile of the Q4W schedule was assessed by analysis of clinical data from 61 patients who transitioned to nivolumab 480 mg Q4W from 3 mg/kg Q2W during four phase III clinical trials.

Results: Compared with 3 mg/kg Q2W, nivolumab 480 mg Q4W produced similar time-averaged concentration, approximately 16% lower trough concentration, and 45% higher peak concentration at steady state. The peak concentration for 480 mg Q4W was significantly lower than that of 10 mg/kg Q2W, a dose previously shown to have an acceptable tolerability and safety profile. Treatment-related adverse events (TRAEs) that started after transitioning from 3 mg/kg Q2W to 480 mg Q4W were reported in 14.8% of patients, with 1.6% of patients reporting grade 3-4 TRAEs. Pooled safety data for these patients are consistent with those for the 3 mg/kg Q2W schedules, and no new safety signals were identified.

Conclusions: The time-averaged steady-state exposure and safety profile of nivolumab 480 mg Q4W are consistent with that of 3 mg/kg Q2W across multiple tumor types. Nivolumab 480 mg Q4W represents a new dosing schedule option, and in addition to 240 mg Q2W, provides convenience and flexibility for patient care.

Clinical trial numbers: NCT01721772, NCT01668784, NCT01673867, NCT01642004.

RevDate: 2018-09-14

Gast CE, Silk AD, Zarour L, et al (2018)

Cell fusion potentiates tumor heterogeneity and reveals circulating hybrid cells that correlate with stage and survival.

Science advances, 4(9):eaat7828 pii:aat7828.

High lethality rates associated with metastatic cancer highlight an urgent medical need for improved understanding of biologic mechanisms driving metastatic spread and identification of biomarkers predicting late-stage progression. Numerous neoplastic cell intrinsic and extrinsic mechanisms fuel tumor progression; however, mechanisms driving heterogeneity of neoplastic cells in solid tumors remain obscure. Increased mutational rates of neoplastic cells in stressed environments are implicated but cannot explain all aspects of tumor heterogeneity. We present evidence that fusion of neoplastic cells with leukocytes (for example, macrophages) contributes to tumor heterogeneity, resulting in cells exhibiting increased metastatic behavior. Fusion hybrids (cells harboring hematopoietic and epithelial properties) are readily detectible in cell culture and tumor-bearing mice. Further, hybrids enumerated in peripheral blood of human cancer patients correlate with disease stage and predict overall survival. This unique population of neoplastic cells provides a novel biomarker for tumor staging, as well as a potential therapeutic target for intervention.

RevDate: 2018-09-13

Cook M, Baker K, Redman M, et al (2018)

Differential Outcomes Among Immunosuppressed Patients With Merkel Cell Carcinoma: Impact of Immunosuppression Type on Cancer-specific and Overall Survival.

American journal of clinical oncology [Epub ahead of print].

OBJECTIVES: Merkel cell carcinoma (MCC) is a rare, aggressive neuroendocrine skin cancer with higher incidence among whites, elderly, and immunosuppressed patients. Although immunosuppressed MCC patients are at higher risk of recurrence and MCC-related death, it is unknown whether immunosuppression type is associated with differential outcomes.

MATERIALS AND METHODS: We retrospectively evaluated 89 nonmetastatic MCC patients with a diagnosis of chronic immunosuppression. Immunosuppression was categorized as chronic lymphocytic leukemia (31% of cohort), other hematologic malignancies (18%), solid organ transplant (21%), autoimmune disease (21%), and human immunodeficiency virus acquired deficiency syndrome (8%). Progression-free survival (PFS) and MCC-specific survival (MSS) were estimated with the cumulative incidence function. Overall survival (OS) was estimated by the Kaplan-Meier method.

RESULTS: With a median follow-up of 52 months, 53 deaths occurred (42 from MCC, 7 unknown, and 4 non-MCC). Two-year PFS, MSS, and OS were 30%, 55%, and 52%, respectively. Human immunodeficiency virus/acquired deficiency syndrome and solid organ transplant patients were diagnosed with MCC at a younger age (median 55 and 59 y, respectively) and with more advanced stage disease compared with other immunosuppressed subgroups. PFS did not significantly differ among the 5 immunosuppression subgroups (P=0.30), but significant differences were observed in MSS and OS (both P=0.01). Controlling for potential confounders for OS, including age and stage, immunosuppression type was still significantly associated with risk of death (P=0.01).

CONCLUSIONS: Among immunosuppressed MCC patients, recurrent MCC is the major cause of mortality. The risk of death from MCC differs among immunosuppression types, suggesting important biological differences in host-tumor immune interactions.

RevDate: 2018-09-13

Cornetta K, Duffy L, Feldman SA, et al (2018)

Screening Clinical Cell Products for Replication Competent Retrovirus: The National Gene Vector Biorepository Experience.

Molecular therapy. Methods & clinical development, 10:371-378 pii:S2329-0501(18)30083-4.

Replication-competent retrovirus (RCR) is a safety concern for individuals treated with retroviral gene therapy. RCR detection assays are used to detect RCR in manufactured vector, transduced cell products infused into research subjects, and in the research subjects after treatment. In this study, we reviewed 286 control (n = 4) and transduced cell products (n = 282) screened for RCR in the National Gene Vector Biorepository. The transduced cell samples were submitted from 14 clinical trials. All vector products were previously shown to be negative for RCR prior to use in cell transduction. After transduction, all 282 transduced cell products were negative for RCR. In addition, 241 of the clinical trial participants were also screened for RCR by analyzing peripheral blood at least 1 month after infusion, all of which were also negative for evidence of RCR infection. The majority of vector products used in the clinical trials were generated in the PG13 packaging cell line. The findings suggest that screening of the retroviral vector product generated in PG13 cell line may be sufficient and that further screening of transduced cells does not provide added value.

RevDate: 2018-09-13

Kaluza J, Håkansson N, Harris HR, et al (2018)

Influence of anti-inflammatory diet and smoking on mortality and survival in men and women: two prospective cohort studies.

Journal of internal medicine [Epub ahead of print].

BACKGROUND: The associations between an anti-inflammatory diet and both all-cause and cause-specific mortality have been studied previously; however, the influence of an anti-inflammatory diet on survival time has not been investigated. Moreover, the potential modification of these associations by smoking status remains unclear.

OBJECTIVE: The aims of this study were to examine the associations between an anti-inflammatory diet index (AIDI) and all-cause and cause-specific mortality, to determine the association between the AIDI and differences in survival time and to assess effect modification by smoking status.

METHODS: The study population included 68 273 Swedish men and women (aged 45-83 years) at baseline. The anti-inflammatory potential of the diet was estimated using the validated AIDI, which includes 11 potential anti-inflammatory and five potential pro-inflammatory foods. Cox proportional hazards and Laplace regression were used to estimate hazard ratios and differences in survival time.

RESULTS: During 16 years of follow-up (1 057 959 person-years), 16 088 deaths [5980 due to cardiovascular disease (CVD) and 5252 due to cancer] were recorded. Participants in the highest versus lowest quartile of the AIDI had lower risks of all-cause (18% reduction, 95% CI: 14-22%), CVD (20%, 95% CI: 14-26%) and cancer (13%, 95% CI: 5-20%) mortality. The strongest inverse associations between the highest and lowest quartiles of AIDI and risk of mortality were observed in current smokers: 31%, 36% and 22% lower risks of all-cause, CVD and cancer mortality, respectively. The difference in survival time between current smokers in the lowest AIDI quartile and never smokers in the highest quartile was 4.6 years.

CONCLUSION: Adherence to a diet with high anti-inflammatory potential may reduce all-cause, CVD and cancer mortality and prolong survival time especially amongst smokers.

RevDate: 2018-09-13

Wang L, Y Huang (2018)

Evaluating classification performance of biomarkers in two-phase case-control studies.

Statistics in medicine [Epub ahead of print].

Biomarkers are playing an increasingly important role in disease screening, early detection, and risk prediction. The two-phase case-control sampling study design is widely used for the evaluation of candidate biomarkers. The sampling probabilities for cases and controls in the second phase can often depend on other covariates (sampling strata). This biased sampling can lead to invalid inference on a biomarker's classification accuracy if not properly accounted for. In this paper, we adopt the idea of inverse probability weighting and develop inverse probability weighting-based estimators for various measures of a biomarker's classification performance, including the points on the receiver operating characteristics (ROCs) curve, the area under the ROC curve (area under the curve), and the partial area under the curve. In particular, we consider classification accuracy estimators using sampling weights estimated conditionally on sampling strata and further improve their efficiency through the use of estimated weights that additionally take into account the auxiliary variables available from the phase-one cohort. We develop asymptotic properties of the proposed estimators and provide analytical variance for making inference. Extensive simulation studies demonstrate excellent performance of the proposed weighted estimators, while the traditional empirical estimator can be severely biased. We also investigate the advantages in efficiency gain for estimating various classification accuracy estimators through the use of auxiliary variables in addition to sampling strata and apply the proposed method to examples from a renal artery stenosis study and a prostate cancer study.

RevDate: 2018-09-13

Dou J, Vorobieva AA, Sheffler W, et al (2018)

De novo design of a fluorescence-activating β-barrel.

Nature pii:10.1038/s41586-018-0509-0 [Epub ahead of print].

The regular arrangements of β-strands around a central axis in β-barrels and of α-helices in coiled coils contrast with the irregular tertiary structures of most globular proteins, and have fascinated structural biologists since they were first discovered. Simple parametric models have been used to design a wide range of α-helical coiled-coil structures, but to date there has been no success with β-barrels. Here we show that accurate de novo design of β-barrels requires considerable symmetry-breaking to achieve continuous hydrogen-bond connectivity and eliminate backbone strain. We then build ensembles of β-barrel backbone models with cavity shapes that match the fluorogenic compound DFHBI, and use a hierarchical grid-based search method to simultaneously optimize the rigid-body placement of DFHBI in these cavities and the identities of the surrounding amino acids to achieve high shape and chemical complementarity. The designs have high structural accuracy and bind and fluorescently activate DFHBI in vitro and in Escherichia coli, yeast and mammalian cells. This de novo design of small-molecule binding activity, using backbones custom-built to bind the ligand, should enable the design of increasingly sophisticated ligand-binding proteins, sensors and catalysts that are not limited by the backbone geometries available in known protein structures.

RevDate: 2018-09-13

Alexander TB, Gu Z, Iacobucci I, et al (2018)

The genetic basis and cell of origin of mixed phenotype acute leukaemia.

Nature pii:10.1038/s41586-018-0436-0 [Epub ahead of print].

Mixed phenotype acute leukaemia (MPAL) is a high-risk subtype of leukaemia with myeloid and lymphoid features, limited genetic characterization, and a lack of consensus regarding appropriate therapy. Here we show that the two principal subtypes of MPAL, T/myeloid (T/M) and B/myeloid (B/M), are genetically distinct. Rearrangement of ZNF384 is common in B/M MPAL, and biallelic WT1 alterations are common in T/M MPAL, which shares genomic features with early T-cell precursor acute lymphoblastic leukaemia. We show that the intratumoral immunophenotypic heterogeneity characteristic of MPAL is independent of somatic genetic variation, that founding lesions arise in primitive haematopoietic progenitors, and that individual phenotypic subpopulations can reconstitute the immunophenotypic diversity in vivo. These findings indicate that the cell of origin and founding lesions, rather than an accumulation of distinct genomic alterations, prime tumour cells for lineage promiscuity. Moreover, these findings position MPAL in the spectrum of immature leukaemias and provide a genetically informed framework for future clinical trials of potential treatments for MPAL.

RevDate: 2018-09-12

Talarico S, Leverich CK, Wei B, et al (2018)

Increased H. pylori stool shedding and EPIYA-D cagA alleles are associated with gastric cancer in an East Asian hospital.

PloS one, 13(9):e0202925 pii:PONE-D-18-08653.

BACKGROUND: Helicobacter pylori infection increases risk for gastric cancer. Geographic variation in gastric cancer risk has been attributed to variation in carriage and type of the H. pylori oncogene cagA. Colonization density may also influence disease and cagA has been associated with higher shedding in stool. However, the relationship between H. pylori load in the stool and in the stomach is not clear.

METHODS: To investigate possible differences in H. pylori load in the stomach and shedding in stool, H. pylori load and cagA genotype were assessed using droplet digital PCR assays on gastric mucosa and stool samples from 49 urea breath test-positive individuals, including 25 gastric cancer and 24 non-cancer subjects at Henan Cancer Hospital, Henan, China.

RESULTS: Quantitation of H. pylori DNA indicated similar gastric loads among cancer and non-cancer cases, but the gastric cancer group had a median H. pylori load in the stool that was six times higher than that of the non-cancer subjects. While the cagA gene was uniformly present among study subjects, only 70% had the East Asian cagA allele, which was significantly associated with gastric cancer (Fisher's Exact Test, p = 0.03).

CONCLUSION: H. pylori persists in a subset of gastric cancer cases and thus may contribute to cancer progression. In this East Asian population with a high prevalence of the cagA gene, the East Asian allele could still provide a marker for gastric cancer risk.

IMPACT: This study contributes to our understanding of H. pylori dynamics in the context of pathological changes.

RevDate: 2018-09-12

Klupsch K, Baeriswyl V, Scholz R, et al (2018)

COVA4231, a potent CD3/CD33 bispecific FynomAb with IgG-like pharmacokinetics for the treatment of acute myeloid leukemia.

Leukemia pii:10.1038/s41375-018-0249-z [Epub ahead of print].

RevDate: 2018-09-12

Fu BC, Randolph TW, Lim U, et al (2018)

Temporal variability and stability of the fecal microbiome: the Multiethnic Cohort Study.

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-18-0348 [Epub ahead of print].

BACKGROUND: Measurement reliability and biological stability need to be considered when developing sampling protocols for population-based fecal microbiome studies.

METHODS: Stool samples were collected biannually over a two-year period and sequenced for the V1-V3 region of the 16S rRNA gene in 50 participants from the Multiethnic Cohort Study. We evaluated the temporal stability of the fecal microbiome on a community level with permutational multivariate analysis of variance (PERMANOVA), as well as on taxa and diversity measures with intraclass correlation coefficients.

RESULTS: Inter-individual differences were the predominant source of fecal microbiome variation, and variation within individual was driven more by changing abundances than the complete loss or introduction of taxa. Phyla and diversity measures were reliable over the two years. Most genera were stable over time, although those with low abundances tended to be more dynamic. Reliability was lower among participants who used antibiotics, with the greatest difference seen in samples taken within one month of reported use.

CONCLUSIONS: The fecal microbiome as a whole is stable over a two-year period, although certain taxa may exhibit more temporal variability.

IMPACT: When designing large epidemiologic studies, a single sample is sufficient to capture the majority of the variation in the fecal microbiome from 16S rRNA gene sequencing, while multiple samples may be needed for rare or less abundant taxa.

RevDate: 2018-09-11

DuBois SG, Laetsch TW, Federman N, et al (2018)

The Use of Neoadjuvant Larotrectinib in the Management of Children With Locally Advanced TRK Fusion Sarcomas.

Cancer [Epub ahead of print].

BACKGROUND: The highly selective oral tropomyosin receptor kinase (TRK) inhibitor larotrectinib has demonstrated significant activity in adult and pediatric TRK fusion cancers. In the current study, the authors describe the clinical course of children with locally advanced TRK fusion sarcoma who were treated preoperatively with larotrectinib and underwent subsequent surgical resection.

METHODS: A total of 24 children were treated on a pediatric phase 1 trial of larotrectinib (ClinicalTrials.gov identifier NCT02637687). Five children who had a documented TRK fusion sarcoma and underwent surgical resection were included in the current analysis. Tumor response (Response Evaluation Criteria In Solid Tumors [RECIST] version 1.1) and surgical outcomes were collected prospectively.

RESULTS: A total of 5 patients (median age, 2 years; range, 0.4-12 years) had locally advanced infantile fibrosarcoma (3 patients) or soft-tissue sarcoma (2 patients). Four patients had disease that was refractory to standard therapy. All 5 patients achieved a partial response to larotrectinib by version 1.1 of RECIST and underwent surgical resection after a median of 6 cycles (range, 4-9 cycles) of treatment. Surgical resections were R0 (negative resection margins with no tumor at the inked resection margin) in 3 patients, R1 (microscopic residual tumor at the resection margin) in 1 patient, and R2 (macroscopic residual tumor at the resection margin) in 1 patient. Three patients achieved complete (2 patients) or near-complete (>98% treatment effect; 1 patient) pathologic responses. These patients remained in follow-up and were no longer receiving larotrectinib for a minimum of 7 to 15 months postoperatively. Two patients had viable tumor at the time of surgical resection and positive resection margins and continued to receive adjuvant larotrectinib. No patients experienced postoperative complications or wound healing issues.

CONCLUSIONS: Children with locally advanced TRK fusion sarcomas may proceed to surgical resection after treatment with the selective TRK inhibitor larotrectinib, thereby sparing them the potentially significant morbidity noted with current approaches. These results support the evaluation of larotrectinib as presurgical therapy in children with newly diagnosed TRK fusion sarcomas.

RevDate: 2018-09-11

Waskito LA, Salama NR, Y Yamaoka (2018)

Pathogenesis of Helicobacter pylori infection.

Helicobacter, 23 Suppl 1:e12516.

In this review, we highlight progress in the last year in characterizing known virulence factors like flagella and the Cag type IV secretion system with sophisticated structural and biochemical approaches to yield new insight on the assembly and functions of these critical virulence determinants. Several aspects of Helicobacter pylori physiology were newly explored this year and evaluated for their functions during stomach colonization, including a fascinating role for the essential protease HtrA in allowing access of H. pylori to the basolateral side of the gastric epithelium through cleavage of the tight junction protein E-cadherin to facilitate CagA delivery. Molecular biology tools standard in model bacteria, including regulated gene expression during animal infection and fluorescent reporter gene fusions, were newly applied to H. pylori to explore functions for urease beyond initial colonization and establish high salt consumption as a mediator of gene expression changes. New sequencing technologies enabled validation of long postulated roles for DNA methylation in regulating H. pylori gene expression. On the cell biology side, elegant work using lineage tracing in the murine model and organoid primary cell culture systems has provided new insights into how H. pylori manipulates gastric tissue functions, locally and at a distance, to promote its survival in the stomach and induce pathologic changes. Finally, new work has bolstered the case for genomic variation as an important mechanism to generate phenotypic diversity during changing environmental conditions in the context of diet manipulation in animal infection models and during human experimental infection after vaccination.

RevDate: 2018-09-11

Armstrong AJ, Lin P, Higano CS, et al (2018)

Development and validation of a prognostic model for overall survival in chemotherapy-naïve men with metastatic castration-resistant prostate cancer.

Annals of oncology : official journal of the European Society for Medical Oncology pii:5094493 [Epub ahead of print].

Background: Prognostic models are needed that reflect contemporary practice for men with metastatic castration-resistant prostate cancer (mCRPC). We sought to identify predictive and prognostic variables for overall survival (OS) in chemotherapy-naïve men with mCRPC treated with enzalutamide.

Patients and methods: Patients from the PREVAIL trial database (enzalutamide versus placebo) were randomly split 2:1 into training (n=1159) and testing (n=550) sets. Using the training set, 23 predefined variables were analyzed and a multivariable model predicting OS was developed and validated in an independent testing set.

Results: Patient characteristics and outcomes were well balanced between training and testing sets; median OS was 32.7 months in each. The final validated multivariable model included 11 independent prognostic variables. Median OS for low-, intermediate-, and high-risk groups (testing set) defined by prognostic risk tertiles were not yet reached (NYR) (95% CI NYR-NYR), 34.2 months (31.5-NYR), and 21.1 months (17.5-25.0), respectively. Hazard ratios (95% CI) for OS in the low- and intermediate-risk groups versus high-risk group were 0.20 (0.14-0.29) and 0.40 (0.30-0.53), respectively. Secondary outcomes of response and progression differed widely in model-defined risk groups. Enzalutamide improved outcomes in all prognostic risk groups.

Conclusions: Our validated prognostic model incorporates variables routinely collected in chemotherapy-naïve men with mCRPC treated with enzalutamide, identifying subsets of patients with widely differing survival outcomes that provide useful information for external validation, patient care, and clinical trial design.

Trial registration: ClinicalTrials.gov: NCT01212991.

RevDate: 2018-09-11

Chambers LC, Srinivasan S, Lukehart SA, et al (2018)

Primary Syphilis in the Male Urethra - A Case Report.

Clinical infectious diseases : an official publication of the Infectious Diseases Society of America pii:5094508 [Epub ahead of print].

A man with nongonococcal urethritis had negative syphilis serology. We documented urethral Treponema pallidum infection using broad-range bacterial polymerase-chain-reaction and sequencing, targeted polymerase-chain-reaction, and immunofluorescence microscopy. The patient subsequently seroconverted for syphilis; symptoms resolved with penicillin. Early syphilis may present as urethritis. Urethral T. pallidum shedding can occur before seroconversion.

RevDate: 2018-09-11

Bloom JD (2018)

Estimating the frequency of multiplets in single-cell RNA sequencing from cell-mixing experiments.

PeerJ, 6:e5578 pii:5578.

In single-cell RNA-sequencing, it is important to know the frequency at which the sequenced transcriptomes actually derive from multiple cells. A common method to estimate this multiplet frequency is to mix two different types of cells (e.g., human and mouse), and then determine how often the transcriptomes contain transcripts from both cell types. When the two cell types are mixed in equal proportion, the calculation of the multiplet frequency from the frequency of mixed transcriptomes is straightforward. But surprisingly, there are no published descriptions of how to calculate the multiplet frequency in the general case when the cell types are mixed unequally. Here, I derive equations to analytically calculate the multiplet frequency from the numbers of observed pure and mixed transcriptomes when two cell types are mixed in arbitrary proportions, under the assumption that the loading of cells into droplets or wells is Poisson.

RevDate: 2018-09-11

Farrukee R, Zarebski AE, McCaw JM, et al (2018)

CHARACTERIZATION OF INFLUENZA B VIRUS VARIANTS WITH REDUCED NEURAMINIDASE INHIBITOR SUSCEPTIBILITY.

Antimicrobial agents and chemotherapy pii:AAC.01081-18 [Epub ahead of print].

Treatment options for influenza B virus infections are limited to neuraminidase inhibitors (NAIs) which block the neuraminidase (NA) glycoprotein on the virion surface. The development of NAI resistance would therefore result in a loss of antiviral treatment options for influenza B infections. This study characterized two contemporary influenza B viruses with known resistance-conferring NA amino acid substitutions, D197N and H273Y, detected during routine surveillance. The D197N and H273Y variants were characterized in vitro by assessing NA enzyme activity and affinity, as well as replication in cell culture compared to NAI-sensitive wild-type viruses. In vivo studies were also performed in ferrets to assess the replication and transmissibility of each variant. Mathematical models were used to analyse within-host and between-host fitness of variants relative to wild-type viruses. The data revealed that the H273Y variant had similar NA enzyme function relative to its wild-type but had slightly reduced replication and transmission efficiency in vivo The D197N variant had impaired NA enzyme function but there was no evidence of reduction in replication or transmission efficiency in ferrets. Our data suggest that the influenza B variant with H273Y NA substitution had a more notable reduction in fitness compared to wild-type viruses than the influenza B variant with the D197N NA substitution. Although a D197N variant is yet to become widespread, it is the most commonly detected NAI-resistant influenza B virus in surveillance studies. Our results highlight the need to carefully monitor circulating viruses for the spread of influenza B viruses with the D197N NA substitution.

RevDate: 2018-09-10

Checkoway H, Ilango S, Li W, et al (2018)

Occupational exposures and parkinsonism among Shanghai women textile workers.

American journal of industrial medicine [Epub ahead of print].

BACKGROUND: Endotoxin, a contaminant of cotton dust, is an experimental model for parkinsonism (PS).

METHODS: We investigated associations between exposures to endotoxin, solvents, magnetic fields, and night shift work, and neurologist-determined PS among Shanghai women textile workers, including 537 retired cotton factory workers ages ≥50 years and an age-matched reference group of 286 retired textile workers not exposed to cotton dust. Repeat exams were conducted 2.5 years after enrollment among 467 cotton workers and 229 reference workers.

RESULTS: We identified 39 prevalent PS cases and 784 non-cases. No consistent or statistically significant associations were observed for endotoxin, solvents, magnetic fields, or shift work with PS risk, severity, or progression.

CONCLUSIONS: Despite the null findings, additional studies of endotoxin exposure and risk of PS in other well-characterized occupational cohorts are warranted in view of toxicological evidence that endotoxin is a pathogenic agent and its widespread occurrence in multiple industries worldwide.

RevDate: 2018-09-10

Svatek RS, Tangen C, Delacroix S, et al (2018)

Background and Update for S1602 "A Phase III Randomized Trial to Evaluate the Influence of BCG Strain Differences and T Cell Priming with Intradermal BCG Before Intravesical Therapy for BCG-naïve High-grade Non-muscle-invasive Bladder Cancer.

European urology focus pii:S2405-4569(18)30234-7 [Epub ahead of print].

The S1602 Intergroup trial is a randomized phase III clinical trial that aims to test two important hypotheses: (1) priming with intradermal bacillus Calmette-Guérin (BCG) vaccine prior to standard intravesical BCG improves response to BCG in terms of recurrence-free survival and (2) Tokyo-172 BCG strain is non-inferior to TICE BCG in terms of time to high-grade recurrence. The study was approved by the Cancer Therapy Evaluation Program of the National Cancer Institute and activated in spring 2017. Here, we provide a synopsis of the study background, design, and update of the clinical trial.

RevDate: 2018-08-02

Khunger M, Rakshit S, Hernandez AV, et al (2018)

Premature Clinical Trial Discontinuation in the Era of Immune Checkpoint Inhibitors.

The oncologist pii:theoncologist.2018-0003 [Epub ahead of print].

BACKGROUND: Clinical trial completion is critical for new cancer therapies. Premature trial termination or withdrawal is common and impairs progress. We assessed factors of early terminated/withdrawn oncology trials focusing on trials with immune checkpoint inhibitors (ICI), hypothesizing that the latter may be associated with lower rates of premature discontinuation.

MATERIALS AND METHODS: We reviewed all adult, intervention, oncology trials registered in ClinicalTrials.gov (November 16, 2011, to April 16, 2015) to identify all terminated/withdrawn trials and reasons for termination. Logistics regression model was used to identify factors associated with early termination/withdrawal. Discontinuation rate was compared in trials with and without ICI.

RESULTS: We identified 12,875 trials (35% industry funded, 12% federal funded), of which 8.5% were prematurely terminated (5%) or withdrawn (3.5%); the main reasons were poor accrual (33%) and logistical (24%). ICI trials (n = 350) had a nonsignificant lower rate of termination or withdrawal compared with all other oncology trials (5.4% vs. 8.5%; p = .9) and were less likely to discontinue due to poor accrual (nonsignificant difference: 21% vs. 33%; p = .4). ICI trials were also less likely to discontinue compared with all other oncology drug trials (e.g., chemotherapy, targeted inhibitors, antiangiogenesis, biologics; 5.4% vs. 7.9%, respectively, nonsignificant difference). The 4-year cumulative incidence of failing to complete for reasons unrelated to toxicity or efficacy was 18% (95% confidence interval 16%-20%). There was no association between annual incidence across different tumor types or accrual goal and rate of trial termination.

CONCLUSION: Poor accrual represents the main cause of early cancer trial termination. Premature termination/withdrawal rate was not significantly lower in ICI compared with other trials. Clinical trial completion remains a high priority and can be influenced by provider and patient factors.

IMPLICATIONS FOR PRACTICE: Clinical trial completion is critical for new cancer therapies. Premature trial termination or withdrawal is common and impairs progress. This study assessed factors of early terminated/withdrawn oncology trials, focusing on trials with immune checkpoint inhibitors (ICI), and found that poor accrual represents the main cause of early cancer trial termination. Premature termination/withdrawal rate was not significantly lower in immune checkpoint inhibitor trials compared to other trials. The discussion herein is focused on measures taken by the National Cancer Institute and other institutions to improve clinical trial accrual and prevent premature clinical trial discontinuation.

RevDate: 2018-09-09

LaMonte MJ, Manson JE, Chomistek AK, et al (2018)

Physical Activity and Incidence of Heart Failure in Postmenopausal Women.

JACC. Heart failure pii:S2213-1779(18)30534-1 [Epub ahead of print].

OBJECTIVES: This study prospectively examined physical activity levels and the incidence of heart failure (HF) in 137,303 women, ages 50 to 79 years, and examined a subset of 35,272 women who, it was determined, had HF with preserved ejection fraction (HFpEF) and HF with reduced EF (HFrEF).

BACKGROUND: The role of physical activity in HF risk among older women is unclear, particularly for incidence of HFpEF or HFrEF.

METHODS: Women were free of HF and reported ability to walk at least 1 block without assistance at baseline. Recreational physical activity was self-reported. The study documented 2,523 cases of total HF, and 451 and 734 cases of HFrEF and HFpEF, respectively, during a mean 14-year follow-up.

RESULTS: After controlling for age, race, education, income, smoking, alcohol, hormone therapy, and hysterectomy status, compared with women who reported no physical activity (referent group), inverse associations were observed across incremental tertiles of total physical activity for overall HF (hazard ratio [HR]: Tertile 1 = 0.89, Tertile 2 = 0.74, Tertile 3 = 0.65; trend p < 0.001), HFpEF (HR: 0.93, 0.70, 0.68; p < 0.001), and HFrEF (HR: 0.81, 0.59, 0.68; p = 0.01). Additional controlling for potential mediating factors included attenuated time-varying coronary heart disease (CHD) (nonfatal myocardial infarction, coronary revascularization) diagnosis but did not eliminate the inverse associations. Walking, the most common form of physical activity in older women, was also inversely associated with HF risks (overall: 1.00, 0.98, 0.93, 0.72; p < 0.001; HFpEF: 1.00, 0.98, 0.87, 0.67; p < 0.001; HFrEF: 1.00, 0.75, 0.78, 0.67; p = 0.01). Associations between total physical activity and HF were consistent across subgroups, defined by age, body mass index, diabetes, hypertension, physical function, and CHD diagnosis. Analysis of physical activity as a time-varying exposure yielded findings comparable to those of baseline physical activity.

CONCLUSIONS: Higher levels of recreational physical activity, including walking, are associated with significantly reduced HF risk in community-dwelling older women.

RevDate: 2018-09-09

Kearns JT, Newcomb LF, DW Lin (2018)

Reply to Runqiang Yuan's Letter to the Editor re: James T. Kearns, Anna V. Faino, Lisa F. Newcomb, et al. Role of Surveillance Biopsy with No Cancer as a Prognostic Marker for Reclassification: Results from the Canary Prostate Active Surveillance Study. Eur Urol 2018;73:706-12.

RevDate: 2018-09-07

Sullivan LB (2018)

Metabolic Frugality Marks Cancer Cells for Immune Targeting.

Cell, 174(6):1344-1346.

Altered cell metabolism is ubiquitous in cancer cells; however, it remains challenging to exploit these alterations for cancer therapy. A new study reveals that metabolic alterations to the urea cycle promote tumor growth but unexpectedly also trigger mutations that mark cancer cells for recognition by immunotherapy.

RevDate: 2018-09-07

Chang ET, Lau EC, Van Landingham C, et al (2018)

Response to "Invited commentary: diesel exhaust and lung cancer -- aftermath of becoming an IARC Group 1 carcinogen" by Debra T. Silverman. Am J Epidemiol 2018 Mar 7. doi: 10.1093/aje/kwy036.

American journal of epidemiology pii:5091771 [Epub ahead of print].

RevDate: 2018-09-07

Tseng YD, Nguyen MH, Baker K, et al (2018)

Effect of Patient Immune Status on the Efficacy of Radiation Therapy and Recurrence-Free Survival Among 805 Patients With Merkel Cell Carcinoma.

International journal of radiation oncology, biology, physics, 102(2):330-339.

PURPOSE: Patients with Merkel cell carcinoma (MCC) with chronic immunosuppression (IS) have worse outcomes, but the mechanisms are not well understood. We hypothesized that these differences may be mediated in part by differential response to treatment, and we evaluated whether radiation therapy (RT) efficacy is altered among IS compared with immune-competent (IC) patients with MCC.

METHODS AND MATERIALS: Among 805 patients with MCC, recurrence-free survival (RFS) and patterns of first recurrence were compared between 89 IS and 716 IC patients with stage I to III MCC treated with curative intent. We used a Fine and Gray's competing risk multivariable analysis to estimate associations with RFS.

RESULTS: IS and IC patients with MCC had similar demographic and disease characteristics. Most (77% IC, 86% IS) were irradiated (median, 50.4 Gy IC, 50.3 Gy IS), although more IS patients were irradiated to the primary site (97% vs 81%). With a median follow-up of 54.4 months, IS patients had inferior RFS (2-year: 30% vs 57%; P < .0001) and higher rates of local recurrence as the first site of relapse (25% vs 12%; P = .0002). The association between RT and RFS differed by immune status (interaction P = .01). Although RT was associated with significantly improved RFS among IC patients (hazard ratio 0.56, 95% confidence interval 0.44-0.72), no difference in RFS was observed with RT among IS patients (hazard ratio 1.49, 95% confidence interval 0.70-3.17).

CONCLUSIONS: Radiation therapy efficacy at current standard RT doses for MCC is impaired among immunosuppressed patients with MCC. Although a strong link between durability of RT response and immune function does not appear to be evident in most cancers, our results may reflect an especially dynamic interaction between immune status and RT efficacy in MCC.

RevDate: 2018-09-07

Miller WC, Hoffman IF, Hanscom BS, et al (2018)

A scalable, integrated intervention to engage people who inject drugs in HIV care and medication-assisted treatment (HPTN 074): a randomised, controlled phase 3 feasibility and efficacy study.

Lancet (London, England), 392(10149):747-759.

BACKGROUND: People who inject drugs (PWID) have a high incidence of HIV, little access to antiretroviral therapy (ART) and medication-assisted treatment (MAT), and high mortality. We aimed to assess the feasibility of a future controlled trial based on the incidence of HIV, enrolment, retention, and uptake of the intervention, and the efficacy of an integrated and flexible intervention on ART use, viral suppression, and MAT use.

METHODS: This randomised, controlled vanguard study was run in Kyiv, Ukraine (one community site), Thai Nguyen, Vietnam (two district health centre sites), and Jakarta, Indonesia (one hospital site). PWID who were HIV infected (index participants) and non-infected injection partners were recruited as PWID network units and were eligible for screening if they were aged 18-45 years (updated to 18-60 years 8 months into study), and active injection drug users. Further eligibility criteria for index participants included a viral load of 1000 copies per mL or higher, willingness and ability to recruit at least one injection partner who would be willing to participate. Index participants were randomly assigned via a computer generated sequence accessed through a secure web portal (3:1) to standard of care or intervention, stratified by site. Masking of assignment was not possible due to the nature of intervention. The intervention comprised systems navigation, psychosocial counselling, and ART at any CD4 count. Local ART and MAT services were used. Participants were followed up for 12-24 months. The primary objective was to assess the feasibility of a future randomised controlled trial. To achieve this aim we looked at the following endpoints: HIV incidence among injection partners in the standard of care group, and enrolment and retention of HIV-infected PWID and their injection partners and the uptake of the integrated intervention. The study was also designed to assess the feasibility, barriers, and uptake of the integrated intervention. Endpoints were assessed in a modified intention-to-treat popualtion after exclusion of ineligible participants. This trial is registered on ClinicalTrials.gov, NCT02935296, and is active but not recruiting new participants.

FINDINGS: Between Feb 5, 2015, and June 3, 2016, 3343 potential index participants were screened, of whom 502 (15%) were eligible and enrolled. 1171 injection partners were referred, and 806 (69%) were eligible and enrolled. Index participants were randomly assigned to intervention (126 [25%]) and standard of care (376 [75%]) groups. At week 52, most living index participants (389 [86%] of 451) and partners (567 [80%] of 710) were retained, and self-reported ART use was higher among index participants in the intervention group than those in the standard of care group (probability ratio [PR] 1·7, 95% CI 1·4-1·9). Viral suppression was also higher in the intervention group than in the standard of care group (PR 1·7, 95% CI 1·3-2·2). Index participants in the intervention group reported more MAT use at 52 weeks than those in the standard of care group (PR 1·7, 95% CI 1·3-2·2). Seven incident HIV infections occurred, and all in injection partners in the standard of care group (intervention incidence 0·0 per 100 person-years, 95% CI 0·0-1·7; standard of care incidence 1·0 per 100 person-years, 95% CI 0·4-2·1; incidence rate difference -1·0 per 100 person-years, 95% CI -2·1 to 1·1). No severe adverse events due to the intervention were recorded.

INTERPRETATION: This vanguard study provides evidence that a flexible, scalable intervention increases ART and MAT use and reduces mortality among PWID. The low incidence of HIV in both groups impedes a future randomised, controlled trial, but given the strength of the effect of the intervention, its implementation among HIV-infected PWID should be considered.

FUNDING: US National Institutes of Health.

RevDate: 2018-09-07

Begcevic I, Tsolaki M, Brinc D, et al (2018)

Neuronal pentraxin receptor-1 is a new cerebrospinal fluid biomarker of Alzheimer's disease progression.

F1000Research, 7:1012.

Background: Alzheimer's disease (AD) is the most common type of dementia, with progressive onset of clinical symptoms. The main pathological hallmarks are brain deposits of extracellular amyloid beta plaques and intracellular neurofibrillary tangles (NFT). Cerebrospinal fluid reflects pathological changes in the brain; amyloid beta 1-42 is a marker of amyloid plaques, while total and phosphorylated tau are markers of NFT formation. Additional biomarkers associated with disease pathogenesis are needed, for better prognosis, more specific diagnosis, prediction of disease severity and progression and for improved patient classification in clinical trials. The aim of the present study was to evaluate brain-specific proteins as potential biomarkers of progression of AD. Methods: Overall, 30 candidate proteins were quantified in cerebrospinal fluid (CSF) samples from patients with mild cognitive impairment (MCI) and mild, moderate and severe AD dementia (n=101) using mass spectrometry-based selected reaction monitoring assays. ELISA was used for neuronal pentraxin receptor-1 (NPTXR) confirmation. Results: The best discrimination between MCI and more advanced AD stages (moderate and severe dementia) was observed for protein NPTXR (area under the curve, AUC=0.799). A statistically different abundance of this protein was observed between the two groups, with severe AD patients having progressively lower levels (p<0.05). ELISA confirmed lower levels in AD, in a separate cohort that included controls, MCI and AD patients. Conclusions: We conclude that NPTXR protein in CSF is a novel potential biomarker of AD progression and could have important utility in assessing treatment success in clinical trials.

RevDate: 2018-09-06

Weinstein AG, Henrich CC, Armstrong GT, et al (2018)

Roles of Positive Psychological Outcomes in Future Health Perception and Mental Health Problems: A Report from the Childhood Cancer Survivor Study.

Psycho-oncology [Epub ahead of print].

OBJECTIVE: Positive psychological outcomes among adolescent and young adult survivors of childhood cancer may influence long-term health status. We examined posttraumatic growth (PTG) and Life satisfaction (LS) in adolescence, and their impact on future emotional and physical health status in young adulthood.

METHODS: Survivors (n=2802) from the Childhood Cancer Survivor Study were longitudinally analyzed across social, emotional, and physical factors during adolescence (12-17 years old), and PTG (PTG-Inventory) and LS (Cantril-Ladder-of-Life) during young adulthood (19-24 years old). The impact of PTG and LS on survivors' future long-term mental health, physical health, and social skills was also examined (23-28 years old) using Structural Equation Modeling.

RESULTS: Survivors reported high levels of LS (M=7.43, range 1 to 10) and a positive impact from their cancer experience (M=48.78, range 0 to 105). Adolescent predictors of higher PTG included older age at diagnosis (p=0.001), experiencing more severe chronic health conditions (p=0.01), cancer recurrence/relapse (p=0.01), and being diagnosed with a non-CNS cancer (p=0.001). Higher perceived general health (p=0.01), higher social skills (p=0.001), and diagnosis with a non-CNS cancer (p=0.02) were associated with higher LS. Higher PTG during young adulthood predicted poorer perceived health (p=0.04) and worse emotional health (p=0.001) in later adulthood. Higher LS predicted better emotional health (p=0.001) and better perceived health (p=0.001).

CONCLUSIONS: While LS was found to help survivors have better perceived long-term emotional and physical health outcomes, survivors with higher PTG fond both positive and negative impacts from cancer. Future therapeutic trials to improve LS should be considered.

RevDate: 2018-09-06

Dai JY, Peters U, Wang X, et al (2018)

Diagnostics of Pleiotropy in Mendelian Randomization Studies: Global and Individual Tests for Direct Effects.

American journal of epidemiology pii:5090949 [Epub ahead of print].

Diagnosing pleiotropy is critical for assessing the validity of Mendelian randomization (MR) analyses. The popular MR-Egger method evaluates whether there is evidence of bias-generating pleiotropy among a set of candidate genetic instrumental variables. In this article, we propose GLIDE, GLobal and Individual tests for Direct Effects, a statistical method to systematically evaluate pleiotropy among the set of genetic variants, e.g., single nucleotide polymorphisms (SNPs), used for MR. As a global test, simulation experiments suggest that GLIDE is nearly uniformly more powerful than the MR-Egger method. As a sensitivity analysis, GLIDE is capable of detecting outliers in individual variant-level pleiotropy, in order to obtain a refined set of genetic instrumental variables. We used GLIDE to analyze both body-mass index and height for risk of colorectal cancer in the Genetics and Epidemiology of Colorectal Cancer Consortium. Among the body mass index associated SNPs and the height associated SNPs, several individual variants showed evidence of pleiotropy. Removal of these potentially pleiotropic SNPs resulted in attenuation of respective estimates of the causal effects. In summary, the proposed GLIDE method is useful for sensitivity analyses and improves the validity of MR.

RevDate: 2018-09-06

Phillips AM, Doud MB, Gonzalez LO, et al (2018)

Enhanced ER proteostasis and temperature differentially impact the mutational tolerance of influenza hemagglutinin.

eLife, 7: pii:38795 [Epub ahead of print].

Herein, we systematically and quantitatively evaluate whether endoplasmic reticulum (ER) proteostasis factors impact the mutational tolerance of secretory pathway proteins. We focus on influenza hemagluttinin (HA), a viral membrane protein that folds in the host's ER via a complex pathway. By integrating chemical methods to modulate ER proteostasis with deep mutational scanning to assess mutational tolerance, we discover that upregulation of ER proteostasis factors broadly enhances HA mutational tolerance across diverse structural elements. Remarkably, this proteostasis network-enhanced mutational tolerance occurs at the same sites where mutational tolerance is most reduced by propagation at fever-like temperature. These findings have important implications for influenza evolution, because influenza immune escape is contingent on HA possessing sufficient mutational tolerance to evade antibodies while maintaining the capacity to fold and function. More broadly, this work provides the first experimental evidence that ER proteostasis mechanisms define the mutational tolerance and, therefore, the evolution of secretory pathway proteins.

RevDate: 2018-09-06

Mueller BA, Doody DR, Weiss NS, et al (2018)

Hospitalization and mortality among pediatric cancer survivors: a population-based study.

Cancer causes & control : CCC pii:10.1007/s10552-018-1078-0 [Epub ahead of print].

PURPOSE: We examined serious long-term outcomes among childhood cancer survivors using population-based data.

METHODS: We used 1982-2014 Washington State data to compare hospitalization and/or death (including cause-specific) during up to 27 years follow-up among all 5+ year childhood cancer survivors < 20 years at diagnosis (n = 3,152) and a sample of comparison children within birth cohorts, with assessment by cancer type and child/family characteristics.

RESULTS: During follow-up (9 years median), 12% of survivors had hospitalizations; 4% died. Greatest absolute risks/1,000 person-years were for hospitalization/deaths due to cancers (8.1), infection (6.2), injuries (6.0), and endocrine/metabolic disorders (5.8). Hazard ratios (HR) and 95% confidence intervals (CI) for hospitalization (2.7, 95% CI 2.4-3.0) and any-cause death (14.7, 95% CI 11.3-19.1) were increased, and for all cause-specific outcomes examined, most notably cancer- (35.1, 95% CI 23.7-51.9), hematological- (6.7, 95% CI 5.3-8.5), nervous system- (6.4, 95% CI 5.2-7.8), and circulatory- (5.2, 95% CI 4.1-6.5) related outcomes. Hospitalizations occurred more often among females and those receiving radiation, with modest differences by urban/rural birth residence and race/ethnicity. Cause-specific outcomes varied by cancer type.

CONCLUSIONS: This study suggests increased risks for the rarely-studied outcomes of long-term fracture and injury, and confirms increased risks of selected other conditions among survivors. Multi-state pooling of population-based data would increase the ability to evaluate outcomes for uncommon cancer types and by racial/ethnic groups under-represented in many studies.

RevDate: 2018-09-05

Falk RT, Manson JE, Barnabei VM, et al (2018)

Estrogen metabolism in menopausal hormone users in the Women's Health Initiative Observational Study: Does it differ between estrogen plus progestin and estrogen alone?.

International journal of cancer [Epub ahead of print].

The WHI found an unexpected reduced breast cancer risk in women using CEE alone. We hypothesized CEE alone induces estrogen hydroxylation along the 2-pathway rather than the competing 16-pathway, a pattern linked to reduced postmenopausal breast cancer risk. 1864 women in a WHIOS case-control study of estrogen metabolism and ovarian and endometrial cancer were studied of whom 609 were current E+P users (351 used CEE+MPA), while 272 used E alone (162 used CEE). Fifteen EM were measured, and analyses conducted for each metabolite, hydroxylation pathway (2-, 4-, or 16-pathway), and ratios of pathway concentrations using inverse probability weighted linear regression. Compared to E+P users, all EM were higher in E alone users (significant for unconjugated estrone, total/conjugated estradiol, total/unconjugated 2-methoxyestrone, 4-methoxyestrone and unconjugated estriol). The relative concentrations of 2- and 4-pathway EM did not differ between the MHT users (2-pathway EM comprised 15% and 4-pathway EM <2% of the total), but 16-pathway EM were lower in E alone users (p=0.036). Ratios of 2- and 4-pathway EM compared to 16-pathway EM were significantly higher in E alone compared to E+P users. Similar but not significant patterns were observed in CEE-alone and CEE+MPA users. Our data suggest that compared to E+P users, women using E alone have more extensive metabolism via the 2- versus the competing 16-pathway. This is consistent with epidemiologic evidence of reduced postmenopausal breast cancer risk associated with this metabolic profile and may provide a clue to the breast cancer risk reduction in CEE alone users during the WHI. This article is protected by copyright. All rights reserved.

RevDate: 2018-09-05

Ishibashi M, Toyoshima M, Zhang X, et al (2018)

Tyrosine kinase receptor TIE-1 mediates platinum resistance by promoting nucleotide excision repair in ovarian cancer.

Scientific reports, 8(1):13207 pii:10.1038/s41598-018-31069-2.

Platinum resistance is one of the most challenging problems in ovarian cancer treatment. High-throughput functional siRNA screening identified tyrosine kinase with immunoglobulin-like and EGF-like domains 1 (TIE-1) as a gene that confers cells resistant to cisplatin. Conversely enforced over-expression of TIE-1 was validated to decrease cisplatin sensitivity in multiple ovarian cancer cell lines and up-regulation of TIE-1 was correlated with poor prognosis and cisplatin resistance in patients with ovarian cancer. Mechanistically, TIE-1 up-regulates the nucleotide excision repair (NER) system mediated by xeroderma pigmentosum complementation group C (XPC), thereby leading to decreased susceptibility to cisplatin-induced cell death without affecting cisplatin uptake and excretion. Importantly potentiation of therapeutic efficacy by TIE-1 inhibition was selective to DNA-adduct-type chemotherapeutic platinum reagents. Therefore, TIE-1 is suggested to promote XPC-dependent NER, rendering ovarian cancer cells resistant to platinum. Accompanied with novel findings, TIE-1 could represent as a novel therapeutic target for platinum-resistant ovarian cancer.

RevDate: 2018-09-05

Ogba N, Arwood NM, Bartlett NL, et al (2018)

Chimeric Antigen Receptor T-Cell Therapy.

Journal of the National Comprehensive Cancer Network : JNCCN, 16(9):1092-1106.

Patients with relapsed or refractory (R/R) cancers have a poor prognosis and limited treatment options. The recent approval of 2 chimeric antigen receptor (CAR) autologous T-cell products for R/R B-cell acute lymphoblastic leukemia and non-Hodgkin's lymphoma treatment is setting the stage for what is possible in other diseases. However, there are important factors that must be considered, including patient selection, toxicity management, and costs associated with CAR T-cell therapy. To begin to address these issues, NCCN organized a task force consisting of a multidisciplinary panel of experts in oncology, cancer center administration, and health policy, which met for the first time in March 2018. This report describes the current state of CAR T-cell therapy and future strategies that should be considered as the application of this novel immunotherapy expands and evolves.

RevDate: 2018-09-05

Mostaghel EA, Zhang A, Hernandez S, et al (2018)

Contribution of Adrenal Glands to Intra-tumor Androgens and Growth of Castration Resistant Prostate Cancer.

Clinical cancer research : an official journal of the American Association for Cancer Research pii:1078-0432.CCR-18-1431 [Epub ahead of print].

PURPOSE: Tumor androgens in castration resistant prostate cancer (CRPC) reflect de novo intra-tumoral synthesis or adrenal androgens. We used C.B.-17 SCID mice in which we observed adrenal CYP17A activity to isolate the impact of adrenal steroids on CRPC tumors in vivo Experimental Design: We evaluated tumor growth and androgens in LuCaP35CR and LuCaP96CR xenografts in response to adrenalectomy. We assessed protein expression of key steroidogenic enzymes in 185 CRPC metastases from 42 patients.

RESULTS: Adrenal glands of intact and castrated mice expressed CYP17A. Serum DHEA, AED and T in castrated mice became undetectable after adrenalectomy (all p<0.05). Adrenalectomy prolonged median survival (days) in both CRPC models (33 vs 179; 25 vs 301) and suppressed tumor steroids vs castration alone (T 0.64 vs 0.03pg/mg; DHT 2.3 vs 0.23pg/mg; and T 0.81 vs 0.03pg/mg, DHT 1.3 vs 0.04pg/mg; all p=<0.001). A subset of tumors recurred with increased steroid levels, and/or induction of AR, truncated AR variants, and GR. Metastases from 19 of 35 patients with AR positive tumors concurrently expressed enzymes for adrenal androgen utilization and 9 expressed enzymes for de novo steroidogenesis (HSD3B1, CYP17A, AKR1C3 and HSD17B3).

CONCLUSIONS: Mice are appropriate for evaluating adrenal impact of steroidogenesis inhibitors. A subset of adrenalectomy-resistant CRPC tumors demonstrate de novo androgen synthesis. Tumor growth and androgens were suppressed more strongly by surgical adrenalectomy than prior studies using abiraterone, suggesting reduction in adrenally-derived androgens beyond that achieved by abiraterone may have clinical benefit. Proof-of-concept studies with agents capable of achieving true 'non-surgical ADX' are warranted.

RevDate: 2018-09-05

Chambers LC, Morgan JL, Lowens MS, et al (2018)

Cross-sectional study of urethral exposures at last sexual episode associated with non-gonococcal urethritis among STD clinic patients.

Sexually transmitted infections pii:sextrans-2018-053634 [Epub ahead of print].

OBJECTIVE: Although Chlamydia trachomatis (CT) and Mycoplasma genitalium (MG) are major causes of non-gonococcal urethritis (NGU), up to 50% of cases are of unknown aetiology. We sought to identify urethral exposures at last sexual episode associated with NGU and non-CT/non-MG NGU to identify anatomical sites from which aetiologically relevant micro-organisms may be acquired.

METHODS: We enrolled STD clinic patients with and without NGU assigned male sex at birth and age ≥16 into a cross-sectional study. NGU was urethral symptoms or visible discharge plus ≥5 polymorphonuclear leucocytes without Neisseria gonorrhoeae. Urine was tested for CT and MG (Aptima). We used logistic regression to estimate the association between urethral exposures at last sex and NGU separately among cisgender men and transgender women who have sex with men (MSM/TGWSM) and cisgender men who have sex with women (MSW).

RESULTS: Between 8 August 2014 and 1 November 2017, we enrolled 432 patients, including 183 MSM/TGWSM (118 NGU+, 65 NGU-) and 249 MSW (126 NGU+, 123 NGU-). The mean age was 34; 59% were white. CT and MG were detected in 72 (30%) and 49 (20%) NGU+ participants, respectively. Compared with MSM/TGWSM reporting only non-urethral exposures at last sex, those reporting insertive anal intercourse (IAI) only (adjusted OR (AOR)=4.46, 95% CI 1.09 to 18.19) and IAI with insertive oral sex (IOS) (AOR=7.88, 95% CI 2.67 to 23.26) had higher odds of NGU. MSM/TGWSM reporting IOS only had no significant increased odds (AOR=1.67, 95% CI 0.58 to 4.85). Compared with MSW whose only urethral exposure at last sex was vaginal sex (VS), MSW reporting IOS and VS had similar odds of NGU (OR=0.84, 95% CI 0.50 to 1.41). The results were similar for non-CT/non-MG NGU.

CONCLUSIONS: Among MSM/TGWSM, IAI may lead to transmission of yet-unidentified rectal micro-organisms that cause non-CT/non-MG NGU, in addition to transmission of known pathogens. Sites of urethral exposure appear less important for understanding NGU risk among MSW due to minimal variation in behaviour.

RevDate: 2018-09-05

Jia D, Augert A, Kim DW, et al (2018)

Crebbp loss drives small cell lung cancer and increases sensitivity to HDAC inhibition.

Cancer discovery pii:2159-8290.CD-18-0385 [Epub ahead of print].

CREBBP, encoding an acetyltransferase, is among the most frequently mutated genes in small cell lung cancer (SCLC), a deadly neuroendocrine tumor type. We report acceleration of SCLC upon Crebbp inactivation in an autochthonous mouse model. Extending these observations beyond the lung, broad Crebbp deletion in mouse neuroendocrine cells cooperated with Rb1/Trp53 loss to promote neuroendocrine thyroid and pituitary carcinomas. Gene expression analyses showed that Crebbp loss results in reduced expression of tight junction and cell adhesion genes, including Cdh1, across neuroendocrine tumor types, while suppression of Cdh1 promoted transformation in SCLC. CDH1 and other adhesion genes exhibited reduced histone acetylation with Crebbp inactivation. Treatment with the histone deacetylase inhibitor Pracinostat increased histone acetylation and restored CDH1 expression. Additionally, a subset of Rb1/Trp53/Crebbp-deficient SCLC exhibited exceptional responses to Pracinostat in vivo. Thus, CREBBP acts as a potent tumor suppressor in SCLC and inactivation of CREBBP enhances responses to a targeted therapy.

RevDate: 2018-09-05

van Rhee F, Voorhees P, Dispenzieri A, et al (2018)

International, evidence-based consensus treatment guidelines for idiopathic multicentric Castleman disease.

Blood pii:blood-2018-07-862334 [Epub ahead of print].

Castleman Disease (CD) describes a group of heterogeneous hematologic disorders with characteristic histopathological features. CD can present with unicentric or multicentric (MCD) regions of lymph node enlargement. Some cases of MCD are caused by human herpesvirus-8 (HHV-8) whereas others are HHV-8-negative/idiopathic (iMCD). Treatment of iMCD is challenging and outcomes can be poor since no uniform treatment guidelines exist, few systematic studies have been conducted, and no agreed upon response criteria have been described. The purpose of this paper is to establish consensus, evidence-based treatment guidelines based on the severity of iMCD to improve outcomes. An international Working Group of 42 experts from ten countries was convened by the Castleman Disease Collaborative Network to establish consensus guidelines for the management of iMCD based on published literature, review of treatment effectiveness for 344 cases and expert opinion. The anti-interleukin-6 monoclonal antibody siltuximab (or tocilizumab, if siltuximab is not available) with or without corticosteroids is the preferred first-line therapy for iMCD. In the most severe cases, adjuvant combination chemotherapy is recommended. Additional agents are recommended, tailored by disease severity, as second- and third-line therapies for treatment failures. Response criteria were formulated to facilitate the evaluation of treatment failure or success. These guidelines should help treating physicians to stratify patients based on disease severity in order to select the best available therapeutic option. An international registry for patients with CD (ACCELERATE, NCT02817997) was established in October 2016 to collect patient outcomes to increase the evidence base for selection of therapies in the future.

RevDate: 2018-09-05

Mugwanya KK, Irungu E, Bukusi E, et al (2018)

Scale up of PrEP integrated in public health HIV care clinics: a protocol for a stepped-wedge cluster-randomized rollout in Kenya.

Implementation science : IS, 13(1):118 pii:10.1186/s13012-018-0809-7.

BACKGROUND: Antiretroviral therapy (ART) for HIV-infected persons and pre-exposure prophylaxis (PrEP) for uninfected persons are extraordinarily effective strategies for HIV prevention. In Africa, the region which shoulders the highest HIV burden, HIV care is principally delivered through public health HIV care clinics, offering an existing platform to incorporate PrEP delivery and maximize ART and PrEP synergies. However, successfully bringing this integrated approach to scale requires an implementation science evaluation in public health settings.

METHODS: The Partners Scale Up Project is a prospective, pragmatic implementation evaluation, designed as a stepped-wedge, cluster-randomized trial, operating at 24 clinics in Kenya. In collaboration with the Kenya Ministry of Health, we are catalyzing scaled implementation of PrEP delivery integrated in HIV care clinics. The intervention package includes staff training, clinic streamlined access to PrEP commodity from the Kenya Medical Supply Authority, and ongoing intensive technical assistance to rigorously assess how PrEP delivery is implemented. PrEP service delivery including retention efforts are conducted by the clinic staff with no additional resources from the project. Guided by the RE-AIM (Reach, Effectiveness, Adoption, Implementation, Maintenance) framework and Consolidated Framework for Implementation Science Research, project progress and learning are documented through ongoing monitoring and process evaluations, including chart abstraction and individual and key informant interviews, to evaluate pragmatic rollout and understand barriers and facilitators for successful PrEP delivery in this setting. In this staged rollout design, each step provides data for both pre-implementation (baseline) and implementation periods, and we will compare time points across steps in the baseline versus implementation periods.

DISCUSSION: Cost-effective delivery models are urgently needed to maximize the public health impact of PrEP and ART. The Partners Scale Up Project will set the stage for full-scale PrEP implementation fully run and owned by the Kenya Ministry of Health. The work combines nationally sponsored PrEP delivery with technical support and implementation science from academic partners, defining a new but sustainable paradigm for public health collaboration.

TRIAL REGISTRATION: Registered with ClinicalTrials.gov on February 14, 2017: NCT03052010 .

RevDate: 2018-09-04

Nava Rodrigues D, Rescigno P, Liu D, et al (2018)

Immunogenomic analyses associate immunological alterations with mismatch repair defects in prostate cancer.

The Journal of clinical investigation pii:121924 [Epub ahead of print].

BACKGROUND: Understanding the integrated immunogenomic landscape of advanced prostate cancer (APC) could impact stratified treatment selection.

METHODS: Defective mismatch repair (dMMR) status was determined by either loss of mismatch repair protein expression on IHC or microsatellite instability (MSI) by PCR in 127 APC biopsies from 124 patients (Royal Marsden [RMH] cohort); MSI by targeted panel next-generation sequencing (MSINGS) was then evaluated in the same cohort and in 254 APC samples from the Stand Up To Cancer/Prostate Cancer Foundation (SU2C/PCF). Whole exome sequencing (WES) data from this latter cohort were analyzed for pathogenic MMR gene variants, mutational load, and mutational signatures. Transcriptomic data, available for 168 samples, was also performed.

RESULTS: Overall, 8.1% of patients in the RMH cohort had some evidence of dMMR, which associated with decreased overall survival. Higher MSINGS scores associated with dMMR, and these APCs were enriched for higher T cell infiltration and PD-L1 protein expression. Exome MSINGS scores strongly correlated with targeted panel MSINGS scores (r = 0.73, P < 0.0001), and higher MSINGS scores associated with dMMR mutational signatures in APC exomes. dMMR mutational signatures also associated with MMR gene mutations and increased immune cell, immune checkpoint, and T cell-associated transcripts. APC with dMMR mutational signatures overexpressed a variety of immune transcripts, including CD200R1, BTLA, PD-L1, PD-L2, ADORA2A, PIK3CG, and TIGIT.

CONCLUSION: These data could impact immune target selection, combination therapeutic strategy selection, and selection of predictive biomarkers for immunotherapy in APC.

FUNDING: We acknowledge funding support from Movember, Prostate Cancer UK, The Prostate Cancer Foundation, SU2C, and Cancer Research UK.

RevDate: 2018-09-04

Shaw PA, McMurray R, Butte N, et al (2018)

Calibration of activity-related energy expenditure in the Hispanic Community Health Study/Study of Latinos (HCHS/SOL).

Journal of science and medicine in sport pii:S1440-2440(18)30444-4 [Epub ahead of print].

OBJECTIVES: Usual physical activity (PA) is a complex exposure and typical instruments to measure aspects of PA are subject to measurement error, from systematic biases and biological variability. This error can lead to biased estimates of associations between PA and health outcomes. We developed a calibrated physical activity measure that adjusts for measurement error in both self-reported and accelerometry measures of PA in adults from the US Hispanic Community Health Study/Study of Latinos (HCHS/SOL), a community-based cohort study.

DESIGN: Total energy expenditure (TEE) from doubly labeled water and resting energy expenditure (REE) from indirect calorimetry were measured in 445 men and women aged 18-74years in 2010-2012, as part of the HCHS/SOL Study of Latinos: Nutrition & Physical Activity Assessment Study (SOLNAS). Measurements were repeated in a subset (N=98) 6months later.

METHOD: Calibration equations for usual activity-related energy expenditure (AEE=0.90×TEE-REE) were developed by regressing this objective biomarker on self-reported PA and sedentary behavior, Actical accelerometer PA, and other subject characteristics.

RESULTS: Age, weight and height explained a significant amount of variation in AEE. Actical PA and wear-time were important predictors of AEE; whereas, self-reported PA was not independently associated with AEE. The final calibration equation explained fifty percent of variation in AEE.

CONCLUSIONS: The developed calibration equations can be used to obtain error-corrected associations between PA and health outcomes in HCHS/SOL. Our study represents a unique opportunity to understand the measurement characteristics of PA instruments in an under-studied Hispanic/Latino cohort.

RevDate: 2018-09-03

Belitskaya-Lévy I, Dysken M, Guarino P, et al (2018)

Impact of apolipoprotein E genotypes on vitamin E and memantine treatment outcomes in Alzheimer's disease.

Alzheimer's & dementia (New York, N. Y.), 4:344-349 pii:S2352-8737(18)30029-5.

Introduction: Because apolipoprotein E (APOE) genotypes are known risk factors for Alzheimer's disease (AD), they have been measured in clinical trial participants to determine their effect on treatment outcome.

Methods: We determined APOE genotypes in a subset of subjects (N = 415) who participated in a randomized controlled trial of vitamin E and memantine in 613 veterans with mild-to-moderate AD.

Results: Similar to the primary study, substudy participants receiving vitamin E also had slower functional decline than those receiving placebo. Overall, there was no difference in the rate of functional decline between APOE ε4 allele carriers and noncarriers. A significant interaction was observed between treatment and the APOE genotype on AD progression: ε4 carriers declined faster than noncarriers in the vitamin E plus memantine treatment arm.

Discussion: APOE genotypes may modulate AD treatment response and should be included in the design of future randomized controlled trials.

RevDate: 2018-09-03

Suzuki A, Gupta A, Long SK, et al (2018)

A Kinesin-5, Cin8, Recruits Protein Phosphatase 1 to Kinetochores and Regulates Chromosome Segregation.

Current biology : CB pii:S0960-9822(18)31122-9 [Epub ahead of print].

Kinesin-5 is a highly conserved homo-tetrameric protein complex responsible for crosslinking microtubules and pushing spindle poles apart. The budding yeast Kinesin-5, Cin8, is highly concentrated at kinetochores in mitosis before anaphase, but its functions there are largely unsolved. Here, we show that Cin8 localizes to kinetochores in a cell-cycle-dependent manner and concentrates near the microtubule binding domains of Ndc80 at metaphase. Cin8's kinetochore localization depends on the Ndc80 complex, kinetochore microtubules, and the Dam1 complex. Consistent with its kinetochore localization, a Cin8 deletion induces a loss of tension at the Ndc80 microtubule binding domains and a major delay in mitotic progression. Cin8 associates with Protein Phosphatase 1 (PP1), and mutants that inhibit its PP1 binding also induce a loss of tension at the Ndc80 microtubule binding domains and delay mitotic progression. Taken together, our results suggest that Cin8-PP1 plays a critical role at kinetochores to promote accurate chromosome segregation by controlling Ndc80 attachment to microtubules.

RevDate: 2018-09-02

Greene PA, Sayre G, Heffner JL, et al (2018)

Challenges to Educating Smokers About Lung Cancer Screening: a Qualitative Study of Decision Making Experiences in Primary Care.

Journal of cancer education : the official journal of the American Association for Cancer Education pii:10.1007/s13187-018-1420-y [Epub ahead of print].

We sought to qualitatively explore how those at highest risk for lung cancer, current smokers, experienced, understood, and made decisions about participation in lung cancer screening (LCS) after being offered in the target setting for implementation, routine primary care visits. Thirty-seven current smokers were identified within 4 weeks of being offered LCS at seven sites participating in the Veterans Health Administration Clinical Demonstration Project and interviewed via telephone using semi-structured qualitative interviews. Transcripts were coded by two raters and analyzed thematically using iterative inductive content analysis. Five challenges to smokers' decision-making lead to overestimated benefits and minimized risks of LCS: fear of lung cancer fixated focus on inflated screening benefits; shame, regret, and low self-esteem stemming from continued smoking situated screening as less averse and more beneficial; screening was mistakenly believed to provide general evaluation of lungs and reassurance was sought about potential damage caused by smoking; decision-making was deferred to providers; and indifference about numerical educational information that was poorly understood. Biased understanding of risks and benefits was complicated by emotion-driven, uninformed decision-making. Emotional and cognitive biases may interfere with educating and supporting smokers' decision-making and may require interventions tailored for their unique needs.

RevDate: 2018-09-01

Lau BW, Huh K, Madero-Marroquin R, et al (2018)

Hedgehog/GLI1 activation leads to leukemic transformation of myelodysplastic syndrome in vivo and GLI1 inhibition results in antitumor activity.

Oncogene pii:10.1038/s41388-018-0431-9 [Epub ahead of print].

Myelodysplastic syndromes (MDSs) are stem cell disorders with risk of transformation to acute myeloid leukemia (AML). Gene expression profiling reveals transcriptional expression of GLI1, of Hedgehog (Hh) signaling, in poor-risk MDS/AML. Using a murine model of MDS we demonstrated that constitutive Hh/Gli1 activation accelerated leukemic transformation and decreased overall survival. Hh/Gli1 activation resulted in clonal expansion of phenotypically defined granulocyte macrophage progenitors (GMPs) and acquisition of self-renewal potential in a non-self-renewing progenitor compartment. Transcriptome analysis of GMPs revealed enrichment in gene signatures of self-renewal pathways, operating via direct Gli1 activation. Using human cell lines we demonstrated that in addition to canonical Hh signaling, GLI1 is activated in a Smoothened-independent manner. GLI1 knockdown or inhibition with GANT61 resulted in decreased proliferation and clonogenic potential. Our data suggest that GLI1 activation is frequent in MDS during disease progression and inhibition of GLI1 is an attractive therapeutic target for a subset of patients.

RevDate: 2018-09-01

Rashidi A, Shanley R, Anasetti C, et al (2018)

Analysis of BMT CTN-0201 and -0901 samples did not reproduce the reported association between recipient REG3A rs7588571 and chronic GVHD.

RevDate: 2018-09-01

Appelbaum J, Wells D, Hiatt JB, et al (2018)

Fatal enteric plexus neuropathy after one dose of ipilimumab plus nivolumab: a case report.

Journal for immunotherapy of cancer, 6(1):82 pii:10.1186/s40425-018-0396-9.

BACKGROUND: Immune checkpoint inhibitors (ICIs) are the treatment of choice for several cancers and can be associated with remarkable clinical benefit, but can also cause serious immune-related adverse events (irAEs). Management of rare and severe irAEs is challenged by an incomplete knowledge of their natural history and pathogenetic mechanisms. We report a case of fatal acute-onset gastro-intestinal (GI) hypomotility from myenteric plexus neuropathy following a single dose of ipilimumab plus nivolumab given for treatment of Merkel cell carcinoma (MCC).

CASE PRESENTATION: A 66-year-old man with recurrent metastatic MCC involving several organs (liver, bones and disseminated retroperitoneal lymphadenopathy) developed profound pharyngeal dysphagia and ileus that started 7 days after receiving a single administration of combination immune checkpoint blockade consisting of nivolumab (3 mg/kg) and low-dose ipilimumab (1 mg/kg). A swallowing study showed oropharyngeal dysfunction and aspiration. Imaging studies were consistent with diffuse intestinal paresis. An extensive work-up did not reveal obvious causes of these symptoms, and enteric plexopathy was suspected. Empiric immune suppressive therapy was initiated urgently. Despite an escalating immunosuppressive regimen that included high dose steroids, tacrolimus and therapeutic plasma exchange, no improvement in GI motility was seen and the patient suffered repeated episodes of aspiration. Seven weeks after the onset of GI hypomotility, the patient succumbed to sepsis from intestinal perforations. At autopsy, histologic specimens obtained from the entire GI tract (pharynx to rectum) showed near complete loss of ganglion cells within the myenteric and submucosal plexuses. An associated inflammatory infiltrate was not seen, suggesting a 'burned out' phase of illness. C4d complement deposition was found at the ganglionic sites, suggesting antibody-mediated pathogenesis. Remarkably, at sites of previously suspected Merkel cell metastases, no residual viable Merkel cell carcinoma was identified.

CONCLUSIONS: GI-tract paresis due to myenteric neuritis is a rarely reported toxicity of ICIs. Because the window of reversibility is likely to be very brief, quick and decisive interventions are warranted. Subtle functional and anatomic perturbations of the myenteric nervous system from the use of ICIs may be more prevalent than realized and should be suspected and addressed in both clinical and investigational settings.

RevDate: 2018-09-01

Adrianse RL, Smith K, Gatbonton-Schwager T, et al (2018)

Perturbed maintenance of transcriptional repression on the inactive X-chromosome in the mouse brain after Xist deletion.

Epigenetics & chromatin, 11(1):50 pii:10.1186/s13072-018-0219-8.

BACKGROUND: The long noncoding RNA Xist is critical for initiation and establishment of X-chromosome inactivation during embryogenesis in mammals, but it is unclear whether its continued expression is required for maintaining X-inactivation in vivo.

RESULTS: By using an inactive X-chromosome-linked MeCP2-GFP reporter, which allowed us to enumerate reactivation events in the mouse brain even when they occur in very few cells, we found that deletion of Xist in the brain after establishment of X-chromosome inactivation leads to reactivation in 2-5% of neurons and in a smaller fraction of astrocytes. In contrast to global loss of both H3 lysine 27 trimethylation (H3K27m3) and histone H2A lysine 119 monoubiquitylation (H2AK119ub1) we observed upon Xist deletion, alterations in CpG methylation were subtle, and this was mirrored by only minor alterations in X-chromosome-wide gene expression levels, with highly expressed genes more prone to both derepression and demethylation compared to genes with low expression level.

CONCLUSION: Our results demonstrate that Xist plays a role in the maintenance of histone repressive marks, DNA methylation and transcriptional repression on the inactive X-chromosome, but that partial loss of X-dosage compensation in the absence of Xist in the brain is well tolerated.

RevDate: 2018-08-31

Romieu I, Biessy C, Carayol M, et al (2018)

Reproductive factors and molecular subtypes of breast cancer among premenopausal women in Latin America: the PRECAMA study.

Scientific reports, 8(1):13109 pii:10.1038/s41598-018-31393-7.

Etiological differences among breast cancer (BC) subtypes have not been clearly established, especially among young women in Latin America. This study examined the relationship between reproductive factors and BC subtypes among 288 BC cases (20-45 years) and population-based matched controls in four Latin American countries. Immunohistochemistry was determined centrally. Associations between BC and reproductive factors were determined. Older age at first full-term pregnancy (FFTP) (Odds Ratio (OR) = 1.11; 95% Confidence Interval (CI), 1.04-1.19 per year), longer time between menarche and FFTP (OR = 1.12; 95%CI: 1.04-1.20 per year), and older age at last pregnancy (OR = 1.10; 95%CI, 1.02-1.19 per year) were associated with an increased risk of estrogen receptor positive (ER+) tumors (n = 122). Ever pregnant (OR = 0.35; 95%CI, 0.13-0.96), number of childbirths (OR = 0.64; 95%CI, 0.47-0.87 per child), time since last birth (OR = 0.92; 95%CI, 0.85-0.99 per year), and history of breastfeeding (OR = 0.23; 95%CI, 0.09-0.58) were inversely associated with the risk of ER+ tumor. Older age at menarche (OR = 0.63; 95%CI, 0.45-0.89 per year) and longer duration of breastfeeding (OR = 0.97; 95%CI, 0.94-1.01 per month) were inversely associated with estrogen receptor negative (ER-) tumors (n = 48). Reproductive factors may be differentially associated with BC subtypes in young Latin American women.

RevDate: 2018-08-31

Lieberman NAP, DeGolier K, Kovar HM, et al (2018)

Characterization of the immune microenvironment of diffuse intrinsic pontine glioma: Implications for development of immunotherapy.

Neuro-oncology pii:5085631 [Epub ahead of print].

Background: Diffuse Intrinsic Pontine Glioma (DIPG) is a uniformly fatal CNS tumor diagnosed in 300 American children per year. Radiation is the only effective treatment and extends overall survival to a median of 11 months. Due to its location in the brainstem, DIPG tumors cannot be surgically resected. Immunotherapy has the ability to target tumor cells specifically, however, little is known about the tumor microenvironment in DIPGs. We sought to characterize infiltrating immune cells and immunosuppressive factor expression in pediatric low- and high-grade gliomas and DIPG.

Methods: Tumor microarrays were stained for infiltrating immune cells. RNA was isolated from snap-frozen tumor tissue and Nanostring analysis performed. DIPG and glioblastoma cells were co-cultured with healthy donor macrophages, T cells, or NK cells, and flow cytometry and cytotoxicity assays performed to characterize the phenotype and function, respectively, of the immune cells.

Results: DIPG tumors do not have increased macrophage or T cell infiltration relative to non-tumor control, nor do they overexpress immunosuppressive factors such as PD-L1 or TGF1. H3.3-K27M DIPG cells do not repolarize macrophages, but are not effectively targeted by activated allogeneic T cells. NK cells lysed all DIPG cultures.

Conclusions: DIPG tumors have neither a highly immunosuppressive nor inflammatory microenvironment. Therefore, major considerations for the development of immunotherapy will be the recruitment, activation, and retention of tumor-specific effector immune cells.

RevDate: 2018-08-31

Weiss A, D Hawkins (2017)

Desmoid tumours in children: when wait-and-see becomes wait-and-treat.

The Lancet. Child & adolescent health, 1(4):253-254.

RevDate: 2018-08-31

Kuzma JN, Cromer G, Hagman DK, et al (2018)

Consuming glucose-sweetened, not fructose-sweetened, beverages increases fasting insulin in healthy humans.

European journal of clinical nutrition pii:10.1038/s41430-018-0297-5 [Epub ahead of print].

Fructose-, compared to glucose-, sweetened beverages increase liver triglyceride content in the short-term, prior to weight gain. In secondary analyses of a randomized cross-over design study during which 24 healthy adults consumed 25% of their estimated energy requirement in the form of glucose-, fructose-, and high-fructose corn syrup-sweetened beverages in addition to an identical ad libitum diet for three periods of 8 days each, we investigated the hypothesis that fructose in sweetened beverages also triggers insulin resistance in the short term. Total energy intake, body weight, and fasting glucose did not differ among diet phases. However, there was a significant trend for higher fasting insulin (p = 0.042 for trend) and, among normal-weight participants, homeostasis model assessment index of insulin resistance (p = 0.034 for diet × adiposity interaction) according to the glucose content of the beverages. In conclusion, in contrast to our hypothesis, insulin resistance was increased with higher glucose vs. fructose content of the beverages in this short-term trial.

RevDate: 2018-08-30

Paulson KG, P Nghiem (2018)

One in a hundred million: Merkel cell carcinoma in pediatric and young adult patients is rare but more likely to present at advanced stages based on US registry data.

Journal of the American Academy of Dermatology pii:S0190-9622(18)32475-7 [Epub ahead of print].

RevDate: 2018-08-30

Ten Broeke SW, van der Klift HM, Tops CMJ, et al (2018)

Cancer Risks for PMS2-Associated Lynch Syndrome.

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

Purpose Lynch syndrome due to pathogenic variants in the DNA mismatch repair genes MLH1, MSH2, and MSH6 is predominantly associated with colorectal and endometrial cancer, although extracolonic cancers have been described within the Lynch tumor spectrum. However, the age-specific cumulative risk (penetrance) of these cancers is still poorly defined for PMS2-associated Lynch syndrome. Using a large data set from a worldwide collaboration, our aim was to determine accurate penetrance measures of cancers for carriers of heterozygous pathogenic PMS2 variants. Methods A modified segregation analysis was conducted that incorporated both genotyped and nongenotyped relatives, with conditioning for ascertainment to estimates corrected for bias. Hazard ratios (HRs) and corresponding 95% CIs were estimated for each cancer site for mutation carriers compared with the general population, followed by estimation of penetrance. Results In total, 284 families consisting of 4,878 first- and second-degree family members were included in the analysis. PMS2 mutation carriers were at increased risk for colorectal cancer (cumulative risk to age 80 years of 13% [95% CI, 7.9% to 22%] for males and 12% [95% CI, 6.7% to 21%] for females) and endometrial cancer (13% [95% CI, 7.0%-24%]), compared with the general population (6.6%, 4.7%, and 2.4%, respectively). There was no clear evidence of an increased risk of ovarian, gastric, hepatobiliary, bladder, renal, brain, breast, prostate, or small bowel cancer. Conclusion Heterozygous PMS2 mutation carriers were at small increased risk for colorectal and endometrial cancer but not for any other Lynch syndrome-associated cancer. This finding justifies that PMS2-specific screening protocols could be restricted to colonoscopies. The role of risk-reducing hysterectomy and bilateral salpingo-oophorectomy for PMS2 mutation carriers needs further discussion.

RevDate: 2018-08-30

Shen S, Unger JM, Crew KD, et al (2018)

Omega-3 fatty acid use for obese breast cancer patients with aromatase inhibitor-related arthralgia (SWOG S0927).

Breast cancer research and treatment pii:10.1007/s10549-018-4946-0 [Epub ahead of print].

PURPOSE: Although aromatase inhibitors (AIs) prolong survival in post-menopausal breast cancer (BC) patients, AI-associated arthralgia can lead to discontinuation. Obese patients have higher rates of AI arthralgia than non-obese patients, but treatment options are limited. Omega-3 fatty acid (O3-FA) treatment for AI arthralgia has produced mixed results.

METHODS: We performed an exploratory analysis of SWOG S0927, a multicenter randomized placebo-controlled trial of O3-FA use for AI arthralgia. Post-menopausal women with stage I-III BC taking an AI were randomized to 24 weeks of O3-FAs or placebo. Brief Pain Inventory (BPI) questionnaires and fasting serum were collected at baseline, 12, and 24 weeks. The BPI assessment included worst pain, average pain, and pain interference scores (range 0-10).

RESULTS: Among the 249 participants, 139 had BMI < 30 kg/m2 (56%) and 110 had BMI ≥ 30 kg/m2 (44%). Among obese patients, O3-FA use was associated with significantly lower BPI worst pain scores at 24 weeks compared with placebo (4.36 vs. 5.70, p = 0.02), whereas among non-obese patients, there was no significant difference in scores between treatment arms (5.27 vs. 4.58, p = 0.28; interaction p = 0.05). Similarly, O3-FA use was associated with lower BPI average pain and pain interference scores at 24 weeks compared with placebo among obese patients, but no significant difference between treatment arms in non-obese patients (interaction p = 0.005 and p = 0.01, respectively).

CONCLUSIONS: In obese BC patients, O3-FA use was associated with significantly reduced AI arthralgia compared to placebo.

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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.

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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.

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

ESP Usage

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

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

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

ESP Plans

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

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

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Papers in Classical Genetics

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

Digital Books

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

Timelines

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

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 )