Fred Hutchinson Cancer Research Center

About: Fred Hutchinson Cancer Research Center is a nonprofit organization based out in Cape Town, South Africa. It is known for research contribution in the topics: Population & Transplantation. The organization has 12322 authors who have published 30954 publications receiving 2288772 citations. The organization is also known as: Fred Hutch & The Hutch.

FBW7 mutations in leukemic cells mediate NOTCH pathway activation and resistance to γ-secretase inhibitors

Abstract: gamma-secretase inhibitors (GSIs) can block NOTCH receptor signaling in vitro and therefore offer an attractive targeted therapy for tumors dependent on deregulated NOTCH activity To clarify the basis for GSI resistance in T cell acute lymphoblastic leukemia (T-ALL), we studied T-ALL cell lines with constitutive expression of the NOTCH intracellular domain (NICD), but that lacked C-terminal truncating mutations in NOTCH1 Each of the seven cell lines examined and 7 of 81 (86%) primary T-ALL samples harbored either a mutation or homozygous deletion of the gene FBW7, a ubiquitin ligase implicated in NICD turnover Indeed, we show that FBW7 mutants cannot bind to the NICD and define the phosphodegron region of the NICD required for FBW7 binding Although the mutant forms of FBW7 were still able to bind to MYC, they do not target it for degradation, suggesting that stabilization of both NICD and its principle downstream target, MYC, may contribute to transformation in leukemias with FBW7 mutations In addition, we show that all seven leukemic cell lines with FBW7 mutations were resistant to the MRK-003 GSI Most of these resistant lines also failed to down-regulate the mRNA levels of the NOTCH targets MYC and DELTEX1 after treatment with MRK-003, implying that residual NOTCH signaling in T-ALLs with FBW7 mutations contributes to GSI resistance

Differences in breast cancer stage, treatment, and survival by race and ethnicity.

Abstract: Background In the United States, black and Hispanic white women with breast cancer present with more advanced stages and have poorer survival rates than non-Hispanic whites, whereas Asians and Pacific Islanders do not. However, Asians and Pacific Islanders and Hispanic whites are heterogeneous populations, and few studies have evaluated breast cancer stage, treatments, and mortality rates for subgroups of these populations. Methods Using data from 11 population-based tumor registries that participate in the Surveillance, Epidemiology, and End Results Program, we conducted a retrospective cohort study to evaluate the relationship between race and ethnicity and breast cancer stage, treatments, and mortality rates. The cohort of 124 934 women diagnosed as having a first primary invasive breast carcinoma between January 1, 1992, and December 31, 1998, included 97 999 non-Hispanic whites, 10 560 blacks, 322 American Indians, 8834 Asians and Pacific Islanders, and 7219 Hispanic whites. Results Relative to non-Hispanic whites, blacks, American Indians, Hawaiians, Indians and Pakistanis, Mexicans, South and Central Americans, and Puerto Ricans had 1.4- to 3.6-fold greater risks of presenting with stage IV breast cancer. Blacks, Mexicans, and Puerto Ricans were 20% to 50% more likely to receive or elect a first course of surgical and radiation treatment not meeting the 2000 National Comprehensive Cancer Network standards. In addition, blacks, American Indians, Hawaiians, Vietnamese, Mexicans, South and Central Americans, and Puerto Ricans had 20% to 200% greater risks of mortality after a breast cancer diagnosis. Conclusions Differences in breast cancer stage, treatments, and mortality rates are present by race and ethnicity. Breast cancer survival may be improved by targeting factors, particularly socioeconomic factors, that underlie these differences.

Estrogen therapy and coronary-artery calcification.

Abstract: A B S T R AC T BACKGROUND Calcified plaque in the coronary arteries is a marker for atheromatous-plaque burden and is predictive of future risk of cardiovascular events. We examined the relationship between estrogen therapy and coronary-artery calcium in the context of a randomized clinical trial. METHODS In our ancillary substudy of the Women’s Health Initiative trial of conjugated equine estrogens (0.625 mg per day) as compared with placebo in women who had undergone hysterectomy, we performed computed tomography of the heart in 1064 women aged 50 to 59 years at randomization. Imaging was conducted at 28 of 40 centers after a mean of 7.4 years of treatment and 1.3 years after the trial was completed (8.7 years after randomization). Coronary-artery calcium (or Agatston) scores were measured at a central reading center without knowledge of randomization status. RESULTS The mean coronary-artery calcium score after trial completion was lower among women receiving estrogen (83.1) than among those receiving placebo (123.1) (P = 0.02 by rank test). After adjustment for coronary risk factors, the multivariate odds ratios for coronary-artery calcium scores of more than 0, 10 or more, and 100 or more in the group receiving estrogen as compared with placebo were 0.78 (95% confidence interval, 0.58 to 1.04), 0.74 (0.55 to 0.99), and 0.69 (0.48 to 0.98), respectively. The corresponding odds ratios among women with at least 80% adherence to the study estrogen or placebo were 0.64 (P = 0.01), 0.55 (P<0.001), and 0.46 (P = 0.001). For coronaryartery calcium scores of more than 300 (vs. <10), the multivariate odds ratio was 0.58 (P = 0.03) in an intention-to-treat analysis and 0.39 (P = 0.004) among women with at least 80% adherence. CONCLUSIONS Among women 50 to 59 years old at enrollment, the calcified-plaque burden in the coronary arteries after trial completion was lower in women assigned to estrogen than in those assigned to placebo. However, estrogen has complex biologic effects and may influence the risk of cardiovascular events and other outcomes through multiple pathways. (ClinicalTrials.gov number, NCT00000611.)

Effect of HLA compatibility on engraftment of bone marrow transplants in patients with leukemia or lymphoma.

Abstract: We analyzed the relevance of HLA compatibility to sustained marrow engraftment in 269 patients with hematologic neoplasms who underwent bone marrow transplantations. Each patient received marrow from a family member who shared one HLA haplotype with the patient but differed to a variable degree for the HLA-A, B, and D antigens of the haplotype not shared. These 269 patients were compared with 930 patients who received marrow from siblings with identical HLA genotypes. All patients were treated with cyclophosphamide and total-body irradiation followed by the infusion of unmodified donor marrow cells. The rate of graft failure was 12.3 percent among the recipients of marrow from a donor with only one identical haplotype, as compared with 2.0 percent among recipients of marrow from a sibling with the same HLA genotype (both haplotypes inherited from the same parents) (P less than 0.0001). The incidence of graft failure correlated with the degree of donor HLA incompatibility. Graft failure occurred in 3 of 43 transplants (7 percent) from donors who were phenotypically HLA-matched with their recipient (haplotypes similar, but not inherited from the same parents), in 11 of 121 donors (9 percent) incompatible for one HLA locus, in 18 of 86 (21 percent) incompatible for two loci, and in 1 of 19 (5 percent) incompatible for three loci (P = 0.028). In a multivariate binary logistic regression analysis, independent risk factors associated with graft failure were donor incompatibility for HLA-B and D (relative risk = 2.1; 95 percent confidence interval, 1.7 to 2.5; P = 0.0004) and a positive crossmatch for anti-donor lymphocytotoxic antibody (relative risk = 2.3; 95 percent confidence interval, 1.8 to 2.8; P = 0.0038). Residual host lymphocytes were detected in 11 of 14 patients with graft failure, suggesting that the mechanism for graft failure could be host-mediated immune rejection. We conclude that donor HLA incompatibility and prior alloimmunization are significant risk factors for graft failure, and that a more effective immunosuppressive regimen than those currently used is needed for consistent achievement of sustained engraftment of marrow transplanted from donors who are not HLA-identical siblings.