Fred Hutchison Cancer Research Center

Seattle, WA, United States

Fred Hutchison Cancer Research Center

Seattle, WA, United States
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Silva G.O.,University of North Carolina at Chapel Hill | Siegel M.B.,University of North Carolina at Chapel Hill | Mose L.E.,University of North Carolina at Chapel Hill | Parker J.S.,University of North Carolina at Chapel Hill | And 3 more authors.
Genome Biology | Year: 2017

Changes in the quantity of genetic material, known as somatic copy number alterations (CNAs), can drive tumorigenesis. Many methods exist for assessing CNAs using microarrays, but considerable technical issues limit current CNA calling based upon DNA sequencing. We present SynthEx, a novel tool for detecting CNAs from whole exome and genome sequencing. SynthEx utilizes a "synthetic-normal" strategy to overcome technical and financial issues. In terms of accuracy and precision, SynthEx is highly comparable to array-based methods and outperforms sequencing-based CNA detection tools. SynthEx robustly identifies CNAs using sequencing data without the additional costs associated with matched normal specimens. © 2017 The Author(s).

Chen X.,University of Queensland | Kask A.S.,University of Washington | Crichton M.L.,University of Queensland | McNeilly C.,University of Queensland | And 9 more authors.
Journal of Controlled Release | Year: 2010

HSV-2-gD2 DNA vaccine was precisely delivered to immunologically sensitive regions of the skin epithelia using dry-coated microprojection arrays. These arrays delivered a vaccine payload to the epidermis and the upper dermis of mouse skin. Immunomicroscopy results showed that, in 43 ± 5% of microprojection delivery sites, the DNA vaccine was delivered to contact with professional antigen presenting cells in the epidermal layer. Associated with this efficient delivery of the vaccine into the vicinity of the professional antigen presenting cells, we achieved superior antibody responses and statistically equal protection rate against an HSV-2 virus challenge, when compared with the mice immunized with intramuscular injection using needle and syringe, but with less than 1/10th of the delivered antigen. © 2010 Elsevier B.V. All rights reserved.

Lawless M.,University of Washington | Gulati R.,Fred Hutchison Cancer Research Center | Tretiakova M.,University of Washington
Histopathology | Year: 2017

Aims: Pathological stage pT1 bladder cancers constitute a clinically heterogeneous group. However, current staging guidelines for superficially invasive cancers do not acknowledge the variability in type and extent of lamina propria invasion in papillary urothelial carcinomas (PUCs), and historically proposed substaging systems showed either high interobserver variation or limited value in predicting patient outcomes. The aim of this study was to reappraise pT1 PUC substaging, with the objective of identifying a novel scheme that is reproducible and prognostically meaningful. Methods and results: pT1 PUCs diagnosed during 1999–2015 were retrospectively reviewed and characterized as focal invasion confined to the papillary stalk, focal invasion of the tumour base, or extensive invasion of the tumour base. Cases with concurrent flat carcinoma in situ, angiolymphatic invasion, absent muscularis propria or clinically advanced disease were excluded. We calculated cumulative incidence rates of recurrence, progression and death by tumour subtype, and evaluated differential risks by using log-rank tests and Kaplan–Meier curves stratified by type and extent of invasion. Among 62 patients satisfying the inclusion criteria, 22 of 29 patients with base-extensive invasion progressed, whereas four of 13 with base-focal and none of 20 with stalk-only invasion progressed. There was strong evidence that base-extensive patients had a higher risk of progression and death resulting from bladder cancer than base-focal or stalk-only patients (P < 0.0001). However, tumour subtype was not significantly associated with risk of recurrence (P = 0.21). Conclusions: We propose an innovative substaging approach for reporting the site and extent of lamina propria invasion in patients with pT1 PUC, allowing patient stratification for risk of progression. © 2017 John Wiley & Sons Ltd

Li L.,City of Hope National Medical Center | Li M.,City of Hope National Medical Center | Sun C.,City of Hope National Medical Center | Francisco L.,City of Hope National Medical Center | And 13 more authors.
Cancer Cell | Year: 2011

Therapy-related myelodysplasia or acute myeloid leukemia (t-MDS/AML) is a major complication of cancer treatment. We compared gene expression in CD34+ cells from patients who developed t-MDS/AML after autologous hematopoietic cell transplantation (aHCT) for lymphoma with controls who did not develop t-MDS/AML. We observed altered gene expression related to mitochondrial function, metabolism, and hematopoietic regulation in pre-aHCT samples from patients who subsequently developed t-MDS/AML. Progression to overt t-MDS/AML was associated with additional alterations in cell-cycle regulatory genes. An optimal 38-gene PBSC classifier accurately distinguished patients who did or did not develop t-MDS/AML in an independent group of patients. We conclude that genetic programs associated with t-MDS/AML are perturbed long before disease onset, and accurately identify patients at risk for this complication. © 2011 Elsevier Inc.

Stuber M.L.,University of California at Los Angeles | Meeske K.A.,Childrens Hospital of Los Angeles | Krull K.R.,St Judes Childrens Research Hospital | Leisenring W.,Fred Hutchison Cancer Research Center | And 8 more authors.
Pediatrics | Year: 2010

OBJECTIVE: This study compared the prevalence of symptoms of post-traumatic stress disorder (PTSD), with functional impairment and/or clinical distress, among very long-term survivors of childhood cancer and a group of healthy siblings. METHODS: A total of 6542 childhood cancer survivors >18 years of age who received diagnoses between 1970 and 1986 and 368 siblings of cancer survivors completed a comprehensive demographic and health survey. RESULTS: A total of 589 survivors (9%) and 8 siblings (2%) reported functional impairment and/or clinical distress in addition to the set of symptoms consistent with a full diagnosis of PTSD. Survivors had more than fourfold greater risk of PTSD, compared with siblings (odds ratio [OR]: 4.14 [95% confidence interval [CI]: 2.08-8.25]). With controlling for demographic and treatment variables, increased risk of PTSD was associated with educational level of high school or less (OR: 1.51 [95% CI: 1.16-1.98]), being unmarried (OR: 1.99 [95% CI: 1.58-2.50]), having annual income below $20 000 (OR: 1.63 [95% CI: 1.21-2.20]), and being unemployed (OR: 2.01 [95% CI: 1.62-2.51]). Intensive treatment also was associated with increased risk of full PTSD (OR: 1.36 [95% CI: 1.06-1.74]). CONCLUSIONS: PTSD was reported significantly more often by survivors of childhood cancer than by sibling control subjects. Although most survivors apparently are faring well, a subset reported significant impairment that may warrant targeted intervention. Copyright © 2010 by the American Academy of Pediatrics.

Thun M.J.,American Cancer Society | Carter B.D.,American Cancer Society | Feskanich D.,Harvard University | Freedman N.D.,U.S. National Cancer Institute | And 4 more authors.
New England Journal of Medicine | Year: 2013

BACKGROUND: The disease risks from cigarette smoking increased in the United States over most of the 20th century, first among male smokers and later among female smokers. Whether these risks have continued to increase during the past 20 years is unclear. METHODS: We measured temporal trends in mortality across three time periods (1959-1965, 1982-1988, and 2000-2010), comparing absolute and relative risks according to sex and self-reported smoking status in two historical cohort studies and in five pooled contemporary cohort studies, among participants who became 55 years of age or older during follow-up. RESULTS: For women who were current smokers, as compared with women who had never smoked, the relative risks of death from lung cancer were 2.73, 12.65, and 25.66 in the 1960s, 1980s, and contemporary cohorts, respectively; corresponding relative risks for male current smokers, as compared with men who had never smoked, were 12.22, 23.81, and 24.97. In the contemporary cohorts, male and female current smokers also had similar relative risks for death from chronic obstructive pulmonary disease (COPD) (25.61 for men and 22.35 for women), ischemic heart disease (2.50 for men and 2.86 for women), any type of stroke (1.92 for men and 2.10 for women), and all causes combined (2.80 for men and 2.76 for women). Mortality from COPD among male smokers continued to increase in the contemporary cohorts in nearly all the age groups represented in the study and within each stratum of duration and intensity of smoking. Among men 55 to 74 years of age and women 60 to 74 years of age, all-cause mortality was at least three times as high among current smokers as among those who had never smoked. Smoking cessation at any age dramatically reduced death rates. CONCLUSIONS: The risk of death from cigarette smoking continues to increase among women and the increased risks are now nearly identical for men and women, as compared with persons who have never smoked. Among men, the risks associated with smoking have plateaued at the high levels seen in the 1980s, except for a continuing, unexplained increase in mortality from COPD. Copyright © 2013 Massachusetts Medical Society.

Marty F.M.,Dana-Farber Cancer Institute | Ljungman P.,Karolinska Institutet | Papanicolaou G.A.,Sloan Kettering Cancer Center | Winston D.J.,University of California at Los Angeles | And 12 more authors.
The Lancet Infectious Diseases | Year: 2011

Background: Available drugs against cytomegalovirus have adverse effects that compromise their prophylactic use in recipients of allogeneic stem-cell transplants. We assessed the safety, tolerability, and antiviral activity of oral maribavir in such patients. Methods: In this placebo-controlled, randomised, double-blind, multicentre phase 3 study, we enrolled adult patients recipient-seropositive or donor-seropositive for cytomegalovirus who had undergone allogeneic stem-cell transplantation. Patients were recruited from 90 centres in Canada, Europe, and the USA. After engraftment, patients were stratified by recipient cytomegalovirus serostatus and conditioning regimen (myeloablative or reduced-intensity) and assigned (2:1) by masked computer-generated randomisation sequence to receive maribavir 100 mg twice daily or placebo for up to 12 weeks, with weekly blood cytomegalovirus surveillance. If the virus was detected, administration of study drug was stopped and pre-emptive anticytomegalovirus treatment started. The primary endpoint was cytomegalovirus disease within 6 months of transplantation. Analysis was by intention-to-treat. This study is registered with, NCT00411645. Findings: Between December, 2006, and May, 2008, 681 patients were enrolled and assigned to receive maribavir (454) or placebo (227). The incidence of cytomegalovirus disease within 6 months was 20 of 454 (4%) for the maribavir group and 11 of 227 (5%) for the placebo group (OR 0·90; 95% CI 0·42-1·92). During the 100 days following transplantation, cytomegalovirus infection rates as measured by pp65 antigenaemia were lower in the maribavir group (26·4%) than in the placebo group (34·8%; OR 0·67; 0·47-0·95), but not when measured by plasma cytomegalovirus DNA PCR (27·8% vs 30·4%; OR 0·88; 0·62-1·25), nor by initiation of treatment against cytomegalovirus (30·6% vs 37·4%; OR 0·73, 0·52-1·03). Maribavir was well tolerated: most adverse events, including incident acute graft-versus-host disease and neutropenia, affected both groups equally, except for taste disturbance (15% maribavir, 6% placebo). Interpretation: Compared with placebo, maribavir prophylaxis did not prevent cytomegalovirus disease when started after engraftment. Cytomegalovirus disease as a primary endpoint might not be sufficient to show improvements in cytomegalovirus prevention in recipients of allogeneic stem-cell transplants in the setting of pre-emptive antiviral treatment. Clinical and virological composite endpoints should be used in future trials. Funding: ViroPharma Incorporated. © 2011 Elsevier Ltd.

Minkina A.,University of Minnesota | Matson C.K.,University of Minnesota | Matson C.K.,Fred Hutchison Cancer Research Center | Lindeman R.E.,University of Minnesota | And 3 more authors.
Developmental Cell | Year: 2014

Mammalian sex determination initiates in the fetal gonad with specification of bipotential precursor cells into male Sertoli cells or female granulosa cells. This choice was long presumed to be irreversible, but genetic analysis in the mouse recently revealed that sexual fates must be maintained throughout life. Somatic cells in the testis or ovary, even in adults, can be induced to transdifferentiate to their opposite-sex equivalents by loss of a single transcription factor, DMRT1 in the testis or FOXL2 in the ovary. Here, we investigate what mechanism DMRT1 prevents from triggering transdifferentiation. We find that DMRT1 blocks testicular retinoic acid (RA) signaling from activating genes normally involved in female sex determination and ovarian development and show that inappropriate activation of these genes can drive sexual transdifferentiation. By preventing activation of potential feminizing genes, DMRT1 allows Sertoli cells to participate in RA signaling, which is essential for reproduction, without being sexually reprogrammed. © 2014 Elsevier Inc.

Carpenter K.M.,Alere Inc | Stoner S.A.,Talaria, Inc. | Schmitz K.,Oregon Health And Science University | McGregor B.A.,Fred Hutchison Cancer Research Center | Doorenbos A.Z.,University of Washington
Journal of Behavioral Medicine | Year: 2014

Cognitive behavioral stress management groups have been shown to be decrease psychological symptoms and increase adaptive coping in breast cancer patients, but dissemination of this effective intervention has been challenging. The goal of the present project was to develop an online cognitive behavioral stress management intervention for early stage breast cancer survivors and evaluate its effectiveness using a 2 group × 3 time randomized, waitlist-controlled design. Intervention and waitlist control group participants were assessed at three time points: at baseline; at 10 weeks, after which only intervention participants had used the workbook; and at 20 weeks, after which both groups had used the workbook. Results indicate that at 10 weeks intervention participants showed improved self-efficacy for coping with their cancer and for regulating negative mood and lower levels of cancer-related post-traumatic symptoms as compared to the control group, suggesting that an internet stress management intervention could be effective for helping breast cancer patients increase their confidence in their ability to cope with stress. © 2012 Springer Science+Business Media New York.

Brunstein C.G.,University of Minnesota | Gutman J.A.,Fred Hutchison Cancer Research Center | Weisdorf D.J.,University of Minnesota | Woolfrey A.E.,University of Minnesota | And 6 more authors.
Blood | Year: 2010

Effectiveness of double umbilical cord blood (dUCB) grafts relative to conventional marrow and mobilized peripheral blood from related and unrelated donors has yet to be established. We studied 536 patients at the Fred Hutchinson Cancer Research Center and University of Minnesota with malignant disease who underwent transplantation with an human leukocyte antigen (HLA)-matched related donor (MRD, n = 204), HLAallele-matched unrelated donor (MUD, n = 152) or 1-antigen-mismatched unrelated adult donor (MMUD, n = 52) or 4-6/6 HLA matched dUCB (n = 128) graft after myeloablative conditioning. Leukemia-free survival at 5 years was similar for each donor type (dUCB 51% [95% confidence interval (CI), 41%-59%]; MRD 33% [95% CI, 26%-41%]; MUD 48% [40%-56%]; MMUD 38% [95% CI, 25%-51%]). The risk of relapse was lower in recipients of dUCB (15%, 95% CI, 9%-22%) compared with MRD (43%, 95% CI, 35%-52%), MUD (37%, 95% CI, 29%-46%) and MMUD (35%, 95% CI, 21%-48%), yet nonrelapse mortality was higher for dUCB (34%, 95% CI, 25%-42%), MRD (24% (95% CI, 17%-39%), and MUD (14%, 95% CI, 9%-20%). We conclude that leukemia-free survival after dUCB transplantation is comparable with that observed after MRD and MUD transplantation. For patients without an available HLA matched donor, the use of 2 partially HLA-matched UCB units is a suitable alternative. © 2010 by The American Society of Hematology.

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