James R Cerhan

Mayo Clinic - Rochester, Рочестер, Minnesota, United States

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Publications (452)3124.22 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Data from the National LymphoCare Study (a prospective, multicentre registry that enrolled follicular lymphoma (FL) patients from 2004 to 2007) were used to determine disease characteristics, treatment patterns, outcomes and prognosis for elderly FL (eFL) patients. Of 2650 FL patients, 209 (8%) were aged >80 years; these eFL patients more commonly had grade 3 disease, less frequently received chemoimmunotherapy and anthracyclines, and had lower response rates when compared to younger patients. With a median follow-up of 6.9 years, 5-year overall survival (OS) for eFL patients was 59%; 38% of deaths were lymphoma-related. No treatment produced superior OS among eFL patients. In multivariate Cox models, anaemia, B-symptoms and male sex predicted worse OS (P < 0·01); a prognostic index of these factors (0, 1 or ≥2 present) predicted OS [hazard ratio (95% CI): ≥2 vs. 0, 4·72 (2·38-9·33); 1 vs. 0, 2·63 (1·39-4·98)], with a higher concordance index (0·63) versus the Follicular Lymphoma International Prognostic Index (0·55). The index was validated in an independent cohort. In the largest prospective US-based eFL cohort, no optimal therapy was identified and nearly 40% of deaths were lymphoma-related, representing baseline outcomes in the modern era. © 2015 John Wiley & Sons Ltd.
    British Journal of Haematology 04/2015; DOI:10.1111/bjh.13399 · 4.96 Impact Factor
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    ABSTRACT: Peripheral T-cell lymphomas (PTCLs) are generally aggressive non-Hodgkin lymphomas with poor overall survival rates following standard therapy. One-third of PTCLs express interferon regulatory factor-4 (IRF4), a tightly-regulated transcription factor involved in lymphocyte growth and differentiation. IRF4 drives tumor growth in several lymphoid malignancies and has been proposed as a candidate therapeutic target. Since direct IRF4 inhibitors are not clinically available, we sought to characterize the mechanism by which IRF4 expression is regulated in PTCLs. We demonstrated that IRF4 is constitutively expressed in PTCL cells and drives Myc expression and proliferation. Using an inhibitor screen, we identified NF-κB as a candidate regulator of IRF4 expression and cell proliferation. We then demonstrated that the NF-κB subunits, p52 and RelB, were transcriptional activators of IRF4. Further analysis showed that activation of CD30 promotes p52 and RelB activity and subsequent IRF4 expression. Finally, we showed that IRF4 transcriptionally regulates CD30 expression. Taken together, these data demonstrate a novel positive feedback loop involving CD30, NF-κB, and IRF4; further evidence for this mechanism was demonstrated in human PTCL tissue samples. Accordingly, NF-κB inhibitors may represent a clinical means to disrupt this feedback loop in IRF4-positive PTCLs. Copyright © 2015 American Society of Hematology.
    Blood 04/2015; DOI:10.1182/blood-2014-05-578575 · 9.78 Impact Factor
  • Journal of Clinical Oncology 03/2015; DOI:10.1200/JCO.2014.60.5535 · 17.88 Impact Factor
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    ABSTRACT: There are several suspected environmental risk factors for non-Hodgkin lymphoma (NHL). The associations between NHL and environmental chemical exposures have typically been evaluated for individual chemicals (i.e., one-by-one). We determined the association between a mixture of 27 correlated chemicals measured in house dust and NHL risk. We conducted a population-based case-control study of NHL in four National Cancer Institute - Surveillance, Epidemiology, and End Results centers: Detroit, Iowa, Los Angeles, and Seattle from 1998-2000. We used weighted quantile sum (WQS) regression to model the association of a mixture of chemicals and risk of NHL. The WQS index was a sum of weighted quartiles for 5 polychlorinated biphenyls (PCBs), 7 polycyclic aromatic hydrocarbons (PAHs), and 15 pesticides. We estimated chemical mixture weights and effects for study sites combined and for each site individually, and also for histologic subtypes of NHL. The WQS index was statistically significantly associated with NHL overall (odds ratio [OR]=1.30; 95% CI: 1.08, 1.56; p=0.006; for one quartile increase) and in the study sites of Detroit (OR=1.71; 95% CI: 1.02, 2.92; p=0.045), Los Angeles (OR=1.44; 95% CI: 1.00, 2.08; p=0.049), and Iowa (OR=1.76; 95% CI: 1.23, 2.53; p=0.002). The index was marginally statistically significant in Seattle (OR=1.39; 95% CI: 0.97, 1.99; p=0.071). The most highly-weighted chemicals for predicting risk overall were PCB congener 180 and propoxur. Highly-weighted chemicals varied by study site; PCBs were more highly-weighted in Detroit and pesticides were more highly-weighted in Iowa. An index of chemical mixtures was significantly associated with NHL. Our results show the importance of evaluating chemical mixtures when studying cancer risk.
    Environmental Health Perspectives 03/2015; DOI:10.1289/ehp.1408630 · 7.03 Impact Factor
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    ABSTRACT: Background Patients with chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), or non-Hodgkin lymphoma (NHL) are at increased risk for the development of skin malignancies.Objectives This study was conducted to estimate the incidences of rare skin malignancies in patients with CLL/SLL or NHL.Methods Patients with a diagnosis of CLL/SLL or NHL recorded in the Surveillance, Epidemiology and End Results (SEER) database during 1992–2007 were identified. Diagnoses of specific skin malignancies were identified from SEER files.ResultsDuring 1992–2007, a total of 128,674 patients with first diagnoses of CLL/SLL or NHL were recorded in SEER; 4743 were excluded because follow-up data were unavailable. Among the remaining 123,931 patients, 28,964 had CLL/SLL and 94,967 had NHL. Standardized incidence ratios (SIRs) for invasive malignant melanoma, Merkel cell carcinoma, malignant fibrous histiocytoma, dermatofibrosarcoma protuberans, Kaposi's sarcoma, and sebaceous carcinoma were 2.3, 8.2, 3.6, 2.5, 2.9, and 1.4, respectively, in CLL/SLL patients and 1.6, 3.2, 1.5, 1.3, 17.6, and 0.8, respectively, in NHL patients. When invasive melanoma was stratified by patient age and sex, the highest SIR (17.8) was found in men aged 0–49 years with CLL (P < 0.001).Conclusions Patients with CLL/SLL or NHL have a higher risk for the subsequent development of rare skin cancers. Given the more aggressive nature of these malignancies in this setting, regular monitoring for the development and prompt treatment of cutaneous malignancy is prudent in patients with NHL and particularly in patients with CLL. Regular use of sun protection may decrease the morbidity associated with skin cancer in this immunosuppressed population.
    International journal of dermatology 03/2015; DOI:10.1111/ijd.12564 · 1.23 Impact Factor
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    ABSTRACT: Autoimmune conditions and immune system-related genetic variations are associated with risk of non-Hodgkin lymphoma (NHL). In a pooled analysis of 8,692 NHL cases and 9,260 controls from 14 studies (1988-2007) within the International Lymphoma Epidemiology Consortium, we evaluated the interaction between immune system genetic variants and autoimmune conditions in NHL risk. We evaluated the immunity-related single nucleotide polymorphisms rs1800629 (tumor necrosis factor gene (TNF) G308A), rs1800890 (interleukin-10 gene (IL10) T3575A), rs6457327 (human leukocyte antigen gene (HLA) class I), rs10484561 (HLA class II), and rs2647012 (HLA class II)) and categorized autoimmune conditions as primarily mediated by B-cell or T-cell responses. We constructed unconditional logistic regression models to measure associations between autoimmune conditions and NHL with stratification by genotype. Autoimmune conditions mediated by B-cell responses were associated with increased NHL risk, specifically diffuse large B-cell lymphoma (odds ratio (OR) = 3.11, 95% confidence interval (CI): 2.25, 4.30) and marginal zone lymphoma (OR = 5.80, 95% CI: 3.82, 8.80); those mediated by T-cell responses were associated with peripheral T-cell lymphoma (OR = 2.14, 95% CI: 1.35, 3.38). In the presence of the rs1800629 AG/AA genotype, B-cell-mediated autoimmune conditions increased NHL risk (OR = 3.27, 95% CI: 2.07, 5.16; P-interaction = 0.03) in comparison with the GG genotype (OR = 1.82, 95% CI: 1.31, 2.53). This interaction was consistent across major B-cell NHL subtypes, including marginal zone lymphoma (P-interaction = 0.02) and follicular lymphoma (P-interaction = 0.04). © The Author 2015. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
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    ABSTRACT: Background:Nulliparity is an endometrial cancer risk factor, but whether or not this association is due to infertility is unclear. Although there are many underlying infertility causes, few studies have assessed risk relations by specific causes.Methods:We conducted a pooled analysis of 8153 cases and 11 713 controls from 2 cohort and 12 case-control studies. All studies provided self-reported infertility and its causes, except for one study that relied on data from national registries. Logistic regression was used to estimate adjusted odds ratios (OR) and 95% confidence intervals (CI).Results:Nulliparous women had an elevated endometrial cancer risk compared with parous women, even after adjusting for infertility (OR=1.76; 95% CI: 1.59-1.94). Women who reported infertility had an increased risk compared with those without infertility concerns, even after adjusting for nulliparity (OR=1.22; 95% CI: 1.13-1.33). Among women who reported infertility, none of the individual infertility causes were substantially related to endometrial cancer.Conclusions:Based on mainly self-reported infertility data that used study-specific definitions of infertility, nulliparity and infertility appeared to independently contribute to endometrial cancer risk. Understanding residual endometrial cancer risk related to infertility, its causes and its treatments may benefit from large studies involving detailed data on various infertility parameters.British Journal of Cancer advance online publication, 17 February 2015; doi:10.1038/bjc.2015.24 www.bjcancer.com.
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    ABSTRACT: Background: Cigarette smoking (smoking), hormone therapy (MHT), and folate intake (folate) are each thought to influence colorectal cancer (CRC) risk, but the underlying molecular mechanisms remain incompletely defined. Expression of estrogen receptor beta (ESR2) has been associated with CRC stage and survival. Methods: In this prospective cohort study, we examined smoking, MHT, and folate -associated CRC risks by ESR2protein expression level among participants in the Iowa Women's Health Study (IWHS). Self-reported exposure variables were assessed at baseline. Archived, paraffin-embedded CRC tissue specimens were collected and evaluated for ESR2protein expression by immunohistochemistry. Multivariate Cox regression models were fit to estimate relative risks (RRs) and 95% confidence intervals (CIs) for associations between smoking, MHT, or folate and ESR2-defined CRC subtypes. Results: Informative environmental exposure and protein expression data were available for 491 incident CRC cases. Positive associations between ESR2-low and -high tumors and several smoking-related variables were noted, most prominently with average number of cigarettes per day (RR = 4.24; 95% CI = 1.81-9.91 for ESR2-low and RR=2.15; 95%CI=1.05-4.41 for ESR2-high for >40 cigarettes compared to non-smokers). For MHT, a statistically significant association with ESR2-low tumors was observed with longer duration of exposure (RR = 0.54; 95% CI = 0.26-1.13 for > 5 years compared to never use). No associations were found for folate. Conclusions: In this study, smoking and MHT were associated with ESR2expression patterns. Impact: These data support possible heterogeneous effects from smoking and MHT on ERβ-related pathways of colorectal carcinogenesis in older women. Copyright © 2015, American Association for Cancer Research.
    Cancer Epidemiology Biomarkers & Prevention 02/2015; DOI:10.1158/1055-9965.EPI-14-0756 · 4.32 Impact Factor
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    ABSTRACT: Diffuse large B-cell lymphoma (DLBCL) is an aggressive subtype of non-Hodgkin lymphoma (NHL) and is the most common NHL subtype diagnosed worldwide. The first large-scale genome-wide association study (GWAS) of DLBCL with over 4000 cases conducted among individuals of European ancestry recently identified five independent SNPs that achieved genome-wide significance, and two SNPs that showed a suggestive association with DLBCL risk. In order to evaluate whether Eastern Asians and individuals of European ancestry share similar genetic risk factors for this disease, we attempted to replicate these GWAS findings in a pooled series of 1124 DLBCL cases and 3596 controls from Hong Kong, South Korea, and Thailand. Three of the five genome-wide significant SNPs from the DLBCL GWAS were significantly associated with DLBCL in our study population, including the top finding from the GWAS, EXOC2 rs116446171, which achieved genome-wide significance in our data (per allele OR = 2.04, 95% CI = 1.63-2.56; ptrend = 3.9 x 10(-10) ). Additionally, we observed a significant association with PVT1 rs13255292 (per allele OR = 1.34, 95% CI = 1.19-1.52; ptrend = 2.1 x 10(-6) ), which was the second strongest finding in the GWAS, and with HLA-B rs2523607 (per allele OR = 3.05, 95% CI = 1.32-7.05; ptrend = 0.009). Our study, which provides the first evaluation in Eastern Asians of SNPs definitively associated with DLBCL risk in individuals of European ancestry, indicates that at least some of the genetic factors associated with risk of DLBCL are similar between these populations. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    European Journal Of Haematology 01/2015; DOI:10.1111/ejh.12513 · 2.41 Impact Factor
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    ABSTRACT: Key points •We report a cell based pharmacological screening strategy to identify new therapeutic targets in mutant NRAS transformed leukemia cells. •The screen and mechanistic analysis identified a previously unknown synergy between GCK and ACK1/AKT in mutant NRAS transformed cells. Abstract Oncogenic forms of NRAS are frequently associated with hematologic malignancies and other cancers, making them important therapeutic targets. Inhibition of individual downstream effector molecules such as RAF kinase have been complicated by the rapid development of resistance or activation of bypass pathways. For the purpose of identifying novel targets in NRAS-transformed cells, we performed a chemical screen using mutant NRAS transformed Ba/F3 cells to identify compounds with selective cytotoxicity. One of the compounds identified, GNF-7, potently and selectively inhibited NRAS-dependent cells in pre-clinical models of AML and ALL. Mechanistic analysis revealed that its effects were mediated in part through combined inhibition of ACK1/AKT and of MAP4K2 (GCK). Similar to genetic "synthetic lethal" approaches, these results suggest that small molecule screens can be used to identity novel therapeutic targets in cells addicted to RAS oncogenes.
    Blood 01/2015; · 9.78 Impact Factor
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    ABSTRACT: Marginal zone lymphoma (MZL) is the third most common subtype of B-cell non-Hodgkin lymphoma. Here we perform a two-stage GWAS of 1,281 MZL cases and 7,127 controls of European ancestry and identify two independent loci near BTNL2 (rs9461741, P=3.95 × 10(-15)) and HLA-B (rs2922994, P=2.43 × 10(-9)) in the HLA region significantly associated with MZL risk. This is the first evidence that genetic variation in the major histocompatibility complex influences MZL susceptibility.
    Nature Communications 01/2015; 6:5751. DOI:10.1038/ncomms6751 · 10.74 Impact Factor
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    ABSTRACT: Abstract The optimal treatment of follicular lymphoma (FL) is not established. Rituximab is an important component of FL treatment making the impact of chemotherapy on FL less clear. We reviewed 649 FL at the University of Iowa/Mayo Clinic from 2002 to 2009 looking for the association of total dose delivery (TDD), delivered dose intensity (DDI) of cyclophosphamide and doxorubicin on survival. 337 of 649 FL received R-monotherapy/R-chemotherapy as frontline systemic therapy. After a median follow-up duration of 52.7 months, EFS and OS were similar between the two groups with a trend toward better EFS in R-chemotherapy cohort (HR=1.24, p=0.28). In the R-chemotherapy group, increased TDD and DDI of doxorubicin were associated with improved EFS only in patients who did not receive R-maintenance (HR=0.81;P=0.02 and HR=0.94;P=0.04) but not in patients who underwent R-maintenance. Cyclophosphamide was not associated with EFS. Thus, in the immunochemotherapy era, chemotherapy dose delivery tradition requires further evaluation in FL.
    Leukemia and Lymphoma 12/2014; DOI:10.3109/10428194.2014.994206 · 2.61 Impact Factor
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    ABSTRACT: Cutaneous malignancy is associated with worse outcomes in patients with chronic lymphocytic leukemia (CLL). We sought to identify the incidence and recurrence rate of nonmelanoma skin cancer (NMSC) in patients with non-Hodgkin lymphoma (NHL). NMSC incidence was calculated and Cox proportional hazards models were used to evaluate associations with risk of recurrence for patients with NHL between 1976 and 2005 who were in the Rochester Epidemiology Project research infrastructure. We identified 282 patients with CLL or small lymphocytic lymphoma and 435 with non-CLL NHL. The incidence of basal cell carcinoma and squamous cell carcinoma was 1829.3 (95% confidence interval [CI] 1306.7-2491.1) and 2224.9 (95% CI 1645.9-2941.6), respectively, in patients with CLL. The cumulative recurrence rate at 8 years after treatment with Mohs micrographic surgery was 8.3% (95% CI 0.0%-22.7%) for basal cell carcinoma and 13.4% (95% CI 0.0%-25.5%) for squamous cell carcinoma in patients with CLL. This was a retrospective cohort study. After Mohs micrographic surgery and standard excision of NMSC, patients with NHL had a skin cancer recurrence rate that was higher than expected. Careful treatment and monitoring of patients with NHL and NMSC are warranted. Copyright © 2014 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.
    Journal of the American Academy of Dermatology 12/2014; 72(2). DOI:10.1016/j.jaad.2014.10.028 · 5.00 Impact Factor
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    ABSTRACT: Background: Mantle cell lymphoma (MCL) is a unique type of lymphoma with a prognosis intermediate between indolent and aggressive types. The purpose of this study was to study blood cytokine levels in newly diagnosed and relapsed MCL patients with respect to patterns of abnormalities and relationship to the MCL International Prognostic Index (MIPI) score.Patients and Methods: We analyzed blood levels of 30 cytokines using a multiplex ELISA in 88 patients with newly diagnosed MCL (pre-treatment levels) and 20 with relapsed MCL and compared them with controls without known lymphoma. Elevated cytokine levels were compared with clinical outcome and the MIPI score.Results: In the 88 newly diagnosed MCL patients we found significantly elevated levels compared to controls of IL-12, IP-10, sIL-2Rα, MIG, IL-1RA, IL-8, MIP-1α and MIP-1β (all p<0.05). Of these elevated cytokines, sIL-2Rα, IL-8, MIG, MIP-1α and MIP-1β were predictive of inferior event-free survival, and sIL-2Rα (HR=1.94; p=0.038), IL-8 (HR=2.17; p=0.015), and MIP-1β (HR=2.10; p=0.016) were independent of MIPI score; only sIL-2Rα (HR=2.35; p=0.041) was associated with overall survival after adjustment for MIPI. In the relapsed MCL patient group, the only significantly elevated plasma cytokines that predicted EFS were sILȐ2Rα (HR=2.90; p=0.04) and IL-8 (HR=3.75; p=0.02).Conclusion: Elevated blood levels of sIL-2Rα and the pro-inflammatory cytokines IL-8 and MIP-1β are poor prognostic factors in MCL patients and independent of MIPI score. These factors, if validated, will provide important additions to the MIPI and guide the development of new therapies for patients with elevated levels of these cytokines.
    American Journal of Hematology 12/2014; 89(12). DOI:10.1002/ajh.23838 · 3.48 Impact Factor
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    ABSTRACT: Follicular lymphoma (FL), an indolent neoplasm caused by a t(14;18) chromosomal translocation that juxtaposes the BCL2 gene and immunoglobulin locus, has a variable clinical course and frequently undergoes transformation to an aggressive lymphoma. Although BCL2 mutations have been previously described, their relationship to FL progression remains unclear. Here we evaluated the frequency and nature of BCL2 mutations in two independent cohorts of grade 1 and 2 FL patients along with the correlation between BCL2 mutations, transformation risk and survival. The prevalence of BCL2 coding sequence mutations was 12% in FL at diagnosis and 53% at transformation (p <0.0001). The presence of these BCL2 mutations at diagnosis correlated with increased risk of transformation (hazard ratio 3.6, 95% CI 2.0-6.2, p <0.0001) and increased risk of death due to lymphoma (median survival 9.5 years with BCL2 mutations vs. 20.4 years without, p = 0.012). In multivariate analysis, BCL2 mutations and high FL international prognostic index were independent risk factors for transformation and death due to lymphoma. Some mutant Bcl-2 proteins exhibited enhanced antiapoptotic capacity in vitro. Accordingly, BCL2 mutations can affect antiapoptotic Bcl-2 function, are associated with increased AID expression and correlate with increased risk of transformation and death due to lymphoma. Copyright © 2014 American Society of Hematology.
    Blood 12/2014; DOI:10.1182/blood-2014-04-571786 · 9.78 Impact Factor
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    ABSTRACT: The serum immunoglobulin free light chain (FLC) assay quantitates free kappa (κ) and lambda (λ) light chains. FLC elevations in patients with diffuse large B-cell lymphoma (DLBCL), Hodgkin lymphoma (HL), and chronic lymphocytic leukemia (CLL) are associated with an inferior survival. These increases in FLC can be monoclonal (as in myeloma) or polyclonal. The goal was to estimate the frequency of these elevations within distinct types of B-cell and T-cell non-Hodgkin lymphoma (NHL) and whether the FLC measurements are associated with event-free survival (EFS). We studied serum for FLC abnormalities using normal laboratory reference ranges to define an elevated κ or λ FLC. Elevations were further classified as polyclonal or monoclonal. 492 patients were studied: 453 B-cell and 34 T-cell NHL patients. 29% (142/453) had an elevated FLC of which 10% were monoclonal elevations. Within B-cell NHL, FLC abnormalities were most common in lymphoplasmacytic lymphoma (79%), MCL (68%) and MALT (31%); they were least common in FL (15%). The hazard ratio (HR) for EFS in all patients was 1.41 (95% CI; 1.11-1.81); in all B-cell NHL the HR was 1.44 (95% CI 1.11-1.96); in all T-cell NHL the HR was 1.17 (95% CI 0.55-2.49). FLC abnormalities predicted an inferior OS (HR = 2.75, 95% CI: 1.93-3.90, p<0.0001). The serum FLC assay is useful for prognosis in both B-cell and T-cell types of NHL. In B-cell NHL further discrimination between a monoclonal and polyclonal elevation may be helpful and should be analyzed in prospective clinical trials.
    American Journal of Hematology 12/2014; 89(12). DOI:10.1002/ajh.23839 · 3.48 Impact Factor
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    ABSTRACT: Serum cytokines and chemokines may reflect tumor biology and host response in follicular lymphoma (FL). To determine whether addition of these biological factors may further refine prognostication, 30 cytokines and chemokines were measured by multiplex ELISA in pre-treatment serum specimens from newly diagnosed FL patients (n=209) prospectively enrolled on the University of Iowa/Mayo Clinic SPORE Molecular Epidemiology Resource (MER) between 2002-2008 and from 400 matched controls. Cytokine levels were correlated with clinical outcome in patients who were observed or received single agent rituximab, or those who received chemotherapy. Correlations with outcome in chemotherapy treated patients were further examined in a separate cohort of 183 SWOG patients and all patients were then included in a meta-analysis. Six cytokines were associated with outcome in the MER after adjusting for the FLIPI. In patients who were observed or treated with rituximab alone, increased serum IL-12 and IL-1RA (p=0.005 and 0.02) were associated with a shorter EFS. In patients receiving chemotherapy, HGF, IL-8, IL-1RA and CXCL9 (p=0.015, 0.048, 0.004 and 0.0005) predicted a shorter EFS. When the MER chemotherapy treated patients and SWOG patients were combined in a meta-analysis, IL-2R, IL-1RA and CXCL9 (p= 0.013, 0.042 and 0.0012) were associated with a poor EFS. Copyright © 2014 American Society of Hematology.
    Blood 11/2014; 125(6). DOI:10.1182/blood-2014-06-583369 · 9.78 Impact Factor
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    ABSTRACT: Nitrate and nitrite are precursors in the endogenous formation of N-nitroso compounds (NOC), potential human carcinogens. We evaluated the association of nitrate and nitrite ingestion with postmenopausal ovarian cancer risk in the Iowa Women's Health Study. Among 28,555 postmenopausal women, we identified 315 incident epithelial ovarian cancers from 1986 to 2010. Dietary nitrate and nitrite intakes were assessed at baseline using food frequency questionnaire data. Drinking water source at home was obtained in a 1989 follow-up survey. Nitrate-nitrogen (NO3 -N) and total trihalomethane (TTHM) levels for Iowa public water utilities were linked to residences and average levels were computed based on each woman's duration at the residence. We computed multivariable-adjusted hazard ratios (HR) and 95% confidence intervals (CI) using Cox proportional hazards regression. We tested interactions of nitrate with TTHMs and dietary factors known to influence NOC formation. Ovarian cancer risk was 2.03 times higher (CI=1.22-3.38, ptrend =0.003) in the highest quartile (≥2.98 mg/L) compared with the lowest quartile (≤0.47 mg/L; reference) of NO3 -N in public water, regardless of TTHM levels. Risk among private well users was also elevated (HR=1.53, CI=0.93-2.54) compared with the same reference group. Associations were stronger when vitamin C intake was <median (pinteraction =0.01 and 0.33 for private well and public supplies, respectively). Dietary nitrate was inversely associated with ovarian cancer risk (ptrend =0.02); whereas, dietary nitrite from processed meats was positively associated with the risk (ptrend =0.04). Our findings indicate that high nitrate levels in public drinking water and private well use may increase ovarian cancer risk among postmenopausal women. This article is protected by copyright. All rights reserved. Copyright © 2014 UICC.
    International Journal of Cancer 11/2014; DOI:10.1002/ijc.29365 · 5.01 Impact Factor
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    Blood Cancer Journal 10/2014; 4:e256. DOI:10.1038/bcj.2014.80 · 2.88 Impact Factor
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    ABSTRACT: Genome-wide association studies (GWASs) of follicular lymphoma (FL) have previously identified human leukocyte antigen (HLA) gene variants. To identify additional FL susceptibility loci, we conducted a large-scale two-stage GWAS in 4,523 case subjects and 13,344 control subjects of European ancestry. Five non-HLA loci were associated with FL risk: 11q23.3 (rs4938573, p = 5.79 × 10(-20)) near CXCR5; 11q24.3 (rs4937362, p = 6.76 × 10(-11)) near ETS1; 3q28 (rs6444305, p = 1.10 × 10(-10)) in LPP; 18q21.33 (rs17749561, p = 8.28 × 10(-10)) near BCL2; and 8q24.21 (rs13254990, p = 1.06 × 10(-8)) near PVT1. In an analysis of the HLA region, we identified four linked HLA-DRβ1 multiallelic amino acids at positions 11, 13, 28, and 30 that were associated with FL risk (pomnibus = 4.20 × 10(-67) to 2.67 × 10(-70)). Additional independent signals included rs17203612 in HLA class II (odds ratio [ORper-allele] = 1.44; p = 4.59 × 10(-16)) and rs3130437 in HLA class I (ORper-allele = 1.23; p = 8.23 × 10(-9)). Our findings further expand the number of loci associated with FL and provide evidence that multiple common variants outside the HLA region make a significant contribution to FL risk.
    The American Journal of Human Genetics 10/2014; 95(4):462-71. DOI:10.1016/j.ajhg.2014.09.004 · 10.99 Impact Factor

Publication Stats

14k Citations
3,124.22 Total Impact Points


  • 2001–2015
    • Mayo Clinic - Rochester
      • • Department of Health Science Research
      • • Department of Internal Medicine
      • • Department of Laboratory Medicine & Pathology
      Рочестер, Minnesota, United States
    • Columbia University
      • Department of Health and Behavior Studies
      New York, New York, United States
    • Vanderbilt University
      • Center for Health Services Research
      Nashville, MI, United States
    • National Institute of Environmental Health Sciences
      • Epidemiology Branch
      Durham, NC, United States
  • 2014
    • University of Minnesota Rochester
      Рочестер, Minnesota, United States
  • 2007–2014
    • National Institutes of Health
      • • Branch of Radiation Epidemiology
      • • Division of Cancer Epidemiology and Genetics
      베서스다, Maryland, United States
  • 2004–2014
    • National Cancer Institute (USA)
      • • Radiation Epidemiology
      • • Division of Cancer Epidemiology and Genetics
      베서스다, Maryland, United States
    • Mayo Foundation for Medical Education and Research
      • • Division of Epidemiology
      • • Department of Health Sciences Research
      Рочестер, Michigan, United States
    • University of Minnesota Twin Cities
      • Department of Pediatrics
      Minneapolis, Minnesota, United States
    • Moffitt Cancer Center
      Tampa, Florida, United States
  • 2013
    • University of Toronto
      Toronto, Ontario, Canada
  • 2012
    • Universitätsklinikum Freiburg
      • Center for Chronic Immunodeficiency (CCI)
      Freiburg, Lower Saxony, Germany
  • 2011
    • Rochester College
      Rochester, New York, United States
  • 2010
    • University of California, Berkeley
      • School of Public Health
      Berkeley, California, United States
  • 2002–2010
    • University of Minnesota Duluth
      • Department of Mechanical and Industrial Engineering
      Duluth, Minnesota, United States
    • University of Alabama at Birmingham
      • Division of Clinical Immunology and Rheumatology
      Birmingham, AL, United States
  • 2009
    • University of Rochester
      • James P. Wilmot Cancer Center
      Rochester, NY, United States
  • 1993–2009
    • University of Iowa
      Iowa City, Iowa, United States
    • University of Miami
      • Department of Epidemiology and Public Health
      كورال غيبلز، فلوريدا, Florida, United States
  • 2008
    • University of Cambridge
      • Department of Oncology
      Cambridge, England, United Kingdom
  • 2005–2007
    • University of Washington Seattle
      Seattle, Washington, United States
    • University of South Florida
      Tampa, Florida, United States
    • University of California, San Diego
      San Diego, California, United States
  • 2006
    • Samuel Lunenfeld Research Institute
      Toronto, Ontario, Canada
    • University of New Mexico
      • Department of Pathology
      Albuquerque, New Mexico, United States
    • Johns Hopkins University
      Baltimore, Maryland, United States
  • 2003
    • University of Nebraska Medical Center
      Omaha, Nebraska, United States
  • 1998
    • University of Southern California
      • Department of Preventive Medicine
      Los Ángeles, California, United States
  • 1996
    • University of Florence
      Florens, Tuscany, Italy