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1.  Use of Positron Emission Tomography-Computerized Tomography (PET-CT) in the Management of Patients with Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL) 
Leukemia & lymphoma  2014;55(9):2079-2084.
Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL) cells typically have low 2-deoxy-2-[18F] fluoro-D-glucose (FDG) avidity and CLL patients have an increased risk of developing FDG-avid aggressive lymphomas, second malignancies, and infections. We hypothesized that FDG positron emission tomography-computed tomography of the trunk (PET-CT) is a sensitive method of detecting these complications in patients with CLL.
Of the of 2299 CLL patients seen in the Division of Hematology at Mayo Clinic Rochester between January 1, 2006 and December 31, 2011, 272 (11.8%) had 526 PET-CT scans and 472 (89.7%) of these were reported as abnormal. Among the 293 (55.7%) PET-CT scans used for routine evaluation of CLL, the PET component was of clinical value in only one instance. In contrast, in 83 (30.5%) patients, PET-CT scans used to evaluate new clinical complications localized high FDG avidity lesions for biopsies. This resulted in clinically relevant new diagnoses in 32 patients including more aggressive lymphoma (n=16), non-hematological malignancies (n=8), and opportunistic infections (n=3). Twenty-seven patients had high FDG avidity CLL, which was associated with prominent lymph node proliferation centers, an increased frequency of poor prognostic factors (17p13 deletion, unmutated IGHV, expression of ZAP-70 and CD38), and a shorter overall survival.
We conclude that FDG PET scans should not be used for routine surveillance of patients with CLL. However PET-CT scans are sensitive, but not specific, for detection of aggressive lymphomas, other cancers, and systemic infections in patients with CLL.
PMCID: PMC4419693  PMID: 24286263
Chronic lymphocytic leukemia; small lymphocytic lymphoma; PET; CT; imaging
2.  Impact of diabetes mellitus on clinical outcomes in patients undergoing surgical resection for pancreatic cancer: a retrospective, cohort study 
Diabetes mellitus (DM) has a bidirectional association with pancreatic cancer (PaC); however, its effect on clinical outcomes has not been thoroughly evaluated. We analyzed these data in a large sample of PaC subjects who had undergone surgical resection.
Subjects enrolled in the Mayo Clinic Pancreatic Cancer SPORE registry from 2000–2010 who had resection with curative intent were identified (n=488). Tumor size, cancer stage and postoperative median survival were evaluated. Median survivals were compared with Kaplan-Meier curves and Cox proportional hazards regression modelling.
A total of 275 (56%) subjects had DM prior to surgery. DM subjects had larger tumors compared to those without DM (3.6 cm vs. 3.3, p=0.002), even after controlling for covariates including age, BMI, and tumor grade. Cancer stage at the time of surgery was not affected by DM status(p=0.575). Pre-operative DM was not associated with increased risk of death using a multivariable survival analysis (HR 1.06, 95% CI 0.81–1.38, p=0.676)). The median survival following cancer resection was similar between subjects with and without DM (24 vs. 26 months, p=0.610). Additionally, postoperative survival was similar on the basis of duration of DM (new-onset vs. long-standing) and prior use of anti-diabetic treatments in diabetic subjects.
PaC subjects with DM have larger tumors than non-diabetic subjects. Despite this observation, preoperative DM does not negatively impact the cancer stage at the time of surgery or postoperative survival. Thus, the effect of DM on tumor size is either overshadowed by early metastatic spread of the cancer or is mitigated by the tumor resection.
PMCID: PMC4477801  PMID: 25070053
pancreatic cancer; diabetes mellitus; survival; insulin; metformin
3.  Incidence of Chronic Lymphocytic Leukemia and High Count Monoclonal B-cell Lymphocytosis using the 2008 Guidelines 
Cancer  2014;120(13):2000-2005.
The National Cancer Institute Working Group (NCI-WG 96) guidelines classified individuals having a B-cell clone with CLL immunophenotype as CLL if the absolute lymphocyte count (ALC) was ≥5 × 109/L. 2008 International Workshop on CLL guidelines (IWCLL 2008) classified as CLL if the absolute B-cell count is ≥5 × 109/L or as monoclonal B-cell lymphocytosis (MBL) if the absolute B-cell count is <5 × 109/L. This study of Olmsted County, Minnesota, assessed effects of these changes on incidence rates and presentation from 2000–2010.
Using diagnostic indices available through the Rochester Epidemiology Project and the Mayo CLL database, we identified all newly diagnosed CLL and high count MBL cases from 2000–2010. Age and sex specific incidence rates were determined.
With NCI-WG 96 criteria, there were 115 cases of CLL and 8 cases of MBL. Using IWCLL 2008 classification, there were 79 cases of CLL and 40 cases of MBL. Rai stage distribution (low, intermediate, high) using NCI-WG 96 was 60.9%, 33.9% and 5.2% compared to 43.0%, 49.4%, and 7.6% under IWCLL 2008 criteria. The age- and sex-adjusted incidence rate (per 100,000) for CLL and MBL were 10.0 and 0.66 using NCI-WG 96 versus 6.8 and 3.5 using IWCLL 2008. Median time to treatment (TTT) using NCI-WG 96 was 9.2 years versus 6.5 years with IWCLL 2008
Use of the IWCLL 2008 guidelines reduce the incidence of CLL, alter the distribution of initial Rai stage at diagnosis and shorten median TTT.
PMCID: PMC4124730  PMID: 24711224
Chronic lymphocytic leukemia; monoclonal B-cell lymphocytosis; incidence; epidemiology; natural history
4.  Variants Associated with Susceptibility to Pancreatic Cancer and Melanoma Do Not Reciprocally Affect Risk 
Melanoma cases may exist in pancreatic cancer kindreds, while there is increased risk of pancreatic cancer in familial melanoma. The two cancers may share genetic susceptibility variants in common.
Three dbGaP-deposited GWAS datasets (MD Anderson melanoma, PanScan 1, and PanScan 2 for pancreatic cancer) were used. Thirty-seven melanoma susceptibility variants in 22 genomic regions from published GWAS, plus melanoma-related genes and pathways were examined for pancreatic cancer risk in the PanScan datasets. Conversely, nine known pancreatic cancer susceptibility variants were examined for melanoma risk in the MD Anderson dataset.
In the PanScan data, initial associations were found with melanoma susceptibility variants in NCOA6 (rs4911442) (OR=1.32, 95% CI 1.03–1.70, p=0.03), YWHAZP5 (rs17119461) (OR=2.62, 95% CI 1.08–6.35, p=0.03), and YWHAZP5 (rs17119490) (OR=2.62, 95% CI 1.08–6.34, p=0.03), TYRP1 (p=0.04), and IFNA13 (p=0.04). In the melanoma dataset, two pancreatic cancer susceptibility variants were associated: NR5A2 (rs12029406) (OR=1.39, 95% CI 1.01–1.92, p=0.04) and CLPTM1L-TERT (rs401681) (OR=1.16, 95% CI 1.01–1.34, p=0.04). None of these associations remained significant after correcting for multiple comparisons.
Reported variants of melanoma genes and pathways do not play a role in pancreatic cancer predisposition. Reciprocally, pancreatic cancer susceptibility variants are not associated with melanoma risk.
Known melanoma-related genes and pathways, as well as GWAS-derived susceptibility variants of melanoma and pancreatic cancer, do not explain the shared genetic etiology of these two cancers.
PMCID: PMC4120837  PMID: 24642353
Shared etiology; pancreatic cancer; melanoma; association analysis
5.  Fatty Acids Found in Dairy, Protein, and Unsaturated Fatty Acids Are Associated with Risk of Pancreatic Cancer in a Case-Control Study 
Although many studies have investigated meat and total fat in relation to pancreatic cancer risk, few have investigated dairy, fish and specific fatty acids. We evaluated the association between intake of meat, fish, dairy, specific fatty acids and related nutrients and pancreatic cancer. In our American-based Mayo Clinic case-control study 384 cases and 983 controls frequency matched on recruitment age, race, sex, and residence area (Minnesota, Wisconsin, or Iowa, United States) between 2004 and 2009. All subjects provided demographic information and completed 144-item food frequency questionnaire. Logistic regression calculated odds ratios (OR) and 95% confidence intervals (95% CI) were adjusted for age, sex, cigarette smoking, body mass index, and diabetes mellitus. Significant inverse association (trend p-value < 0.05) between pancreatic cancer and the groupings (highest vs. lowest consumption quintile OR [95% CI]): meat replacement (0.67 [0.43–1.02]), total protein (0.58 [0.39–0.86]), vitamin B12 (0.67 [0.44, 1.01]), zinc (0.48 [0.32, 0.71]), phosphorus (0.62 [0.41, 0.93]), vitamin E (0.51 [0.33, 0.78]), polyunsaturated fatty acids (0.64 [0.42, 0.98]), and Linoleic Acid (fatty acid 18:2) (0.62 [0.40–0.95]). Increased risk associations were observed for saturated fatty acids (1.48 [0.97–2.23]), Butyric Acid (fatty acid 4:0) (1.77 [1.19–2.64]), Caproic Acid (fatty acid 6:0) (2.15 [1.42–3.27]), Caprylic Acid (fatty acid 8:0) (1.87 [1.27–2.76]), and Capric Acid (fatty acid 10:0) (1.83 [1.23–2.74]). Our study suggests that eating a diet high in total protein and certain unsaturated fatty acids is associated with decreased risk of developing pancreatic cancer in a dose dependent manner whereas fats found in dairy increase risk.
PMCID: PMC3942799  PMID: 24590454
Pancreatic Cancer; Meat Consumption; Fat Consumption; Dairy Consumption; Case-control Study
6.  New-onset diabetes in pancreatic cancer: A study in the primary care setting 
Onset of diabetes mellitus (DM) is often first noted by primary care physicians. New-onset DM (duration <36 months before PaC diagnosis) can be a harbinger of pancreatic cancer (PaC). However, its clinical significance remains unclear.
To determine the prevalence, onset, and delay in diagnosis of DM in PaC patients in the primary care setting, we retrospectively reviewed the records of consecutive patients followed in Mayo Clinic's primary care clinics (at least one visit in the preceding 2 years) from 1995 to 2009 who were eventually diagnosed with PaC. Onset of DM was the first date the fasting blood glucose was ≥126 mg/dl.
Of the 111 PaC patients (59 male, median age 74 years), 52 (47%) had DM of whom 30 (58%) had new-onset DM. Among the 30 with new-onset DM, 24 (80%) were asymptomatic (no cancer-specific symptoms), at DM onset. In these 24 patients, median duration of DM prior to PaC diagnosis was 6.5 (0.5e35) months, and median delay between onset and physician diagnosis of DM was 2.5 (0.25–14) months, which decreased from 8.8 (3.5–14) months in patients with DM onset between 1995 and 1999 to 0 (0–2) months, in patients with DM onset between 2004 and 2009. However, the proportion of patients with undiagnosed DM (~33%) remained unchanged.
Diabetes is very common (~50%) in PaC. In over a fifth of PaC, the onset of DM occurs when the cancer is asymptomatic, providing a potential window-of-opportunity to diagnose early PaC. However, nearly a third of new-onset DM in PaC remains undiagnosed.
PMCID: PMC4348043  PMID: 22487526
Pancreatic cancer; Diabetes mellitus; Primary care
7.  Do Variants Associated with Susceptibility to Pancreatic Cancer and Type 2 Diabetes Reciprocally Affect Risk? 
PLoS ONE  2015;10(2):e0117230.
Although type 2 diabetes mellitus is a known risk factor for pancreatic cancer, the existence of shared genetic susceptibility is largely unknown. We evaluated whether any reported genetic risk variants of either disease found by genome-wide association studies reciprocally confer susceptibility.
Data that were generated in previous genome-wide association studies (GENEVA Type 2 Diabetes; PanScan) were obtained through the National Institutes of Health database of Genotypes and Phenotypes (dbGaP). Using the PanScan datasets, we tested for association of 38 variants within 37 genomic regions known to be susceptibility factors for type 2 diabetes. We further examined whether type 2 diabetes variants predispose to pancreatic cancer risk stratified by diabetes status. Correspondingly, we examined the association of fourteen pancreatic cancer susceptibility variants within eight genomic regions in the GENEVA Type 2 Diabetes dataset.
Four plausible associations of diabetes variants and pancreatic cancer risk were detected at a significance threshold of p = 0.05, and one pancreatic cancer susceptibility variant was associated with diabetes risk at threshold of p = 0.05, but none remained significant after correction for multiple comparisons.
Currently identified GWAS susceptibility variants are unlikely to explain the potential shared genetic etiology between Type 2 diabetes and pancreatic cancer.
PMCID: PMC4319943  PMID: 25658847
8.  Skin Cancer Surveillance and Malignancies of the Skin in a Community-Dwelling Cohort of Patients With Newly Diagnosed Chronic Lymphocytic Leukemia 
Journal of Oncology Practice  2013;10(1):e1-e4.
The authors documented a low compliance with guidelines to screen for skin malignancy in a community-dwelling cohort of patients with newly diagnosed chronic lymphocytic leukemia.
Assess compliance with skin cancer screening guidelines in a community-dwelling cohort of patients with newly diagnosed chronic lymphocytic leukemia (CLL) and evaluate the clinical utility of such screening.
We identified patients diagnosed at Mayo Clinic with CLL between January 1, 2004, and June 1, 2012, who resided within 30 miles of Mayo Clinic. We evaluated adherence to skin cancer screening and identified the prevalence of skin malignancies during follow-up. Medical records were reviewed to document skin cancer screening and diagnosis of a skin malignancy.
Collectively, 113 individuals who met criteria were diagnosed with CLL during the study interval. Forty-one patients (36%) had a whole body skin examination by either a dermatologist or primary care provider documented within 6 months of diagnosis; of these; nine (8% of overall cohort; 22% of examined patients) had a skin malignancy identified. Fifteen additional skin malignancies were diagnosed during follow-up. There were a total of 24 skin malignancies (21% of cohort) diagnosed, including basal cell carcinoma (n = 10), squamous cell carcinoma (n = 11), sebaceous carcinomas (n = 2), and melanoma (n = 1).
We documented a low compliance with guidelines to screen for skin malignancy in a community-dwelling cohort of patients with newly diagnosed CLL. Standardized and systems-based approaches are likely to increase compliance with skin cancer screening guidelines in patients with CLL.
PMCID: PMC4500828  PMID: 23981385
9.  Patients with chronic lymphocytic leukaemia and clonal deletion of both 17p13.1 and 11q22.3 have a very poor prognosis 
British journal of haematology  2013;163(3):326-333.
Detection of a 17p13.1 deletion (loss of TP53) or 11q22.3 deletion (loss of ATM), by fluorescence in situ hybridization (FISH), in chronic lymphocytic leukaemia (CLL) patients is associated with a poorer prognosis. Because TP53 and ATM are integral to the TP53 pathway, we hypothesized that 17p13.1- (17p-) and 11q22.3- (11q-) occurring in the same cell (clonal 17p-/11q-) would confer a worse prognosis than either 17p- or 11q-. We studied 2184 CLL patients with FISH (1995–2012) for the first occurrence of 17p-, 11q-, or clonal 17p-/11q-. Twenty (1%) patients had clonal 17p-/11q-, 158 (7%) had 17p- (including 4 with 17p- and 11q- in separate clones), 247 (11%) had 11q-, and 1759 (81%) had neither 17p- nor 11q-. Eleven of 15 (73%) tested patients with clonal 17p-/11q- had dysfunctional TP53 mutations. Overall survival for clonal 17p-/11q- was significantly shorter (1.9 years) than 17p- (3.1 years, p = 0.04), 11q- (4.8 years, p = <0.0001), or neither 17p- nor 11q- (9.3 years, p = <0.0001). Clonal 17p-/11q- thus conferred significantly worse prognosis, suggesting that loss of at least one copy of both TP53 and ATM causes more aggressive disease. Use of an ATM/TP53 combination FISH probe set could identify these very-high risk patients.
PMCID: PMC3907074  PMID: 24032430
Chronic lymphocytic leukaemia; prognostic factors; fluorescencein situ hybridization (FISH); TP53; ATM
10.  Polymorphisms in Metabolism/Antioxidant Genes May Mediate the Effect of Dietary Intake on Pancreatic Cancer Risk 
Pancreas  2013;42(7):1043-1053.
A source of variation for inconsistent dietary-pancreatic cancer associations may be individuals carrying constitutional metabolism/antioxidant gene variants differentially benefit compared to homozygous individuals. Seventy-six tag SNPs were genotyped in thirteen candidate genes to test differential associations with pancreatic adenocarcinoma.
A clinic-based case-control design was used to rapidly ascertain 251 cases and 970 frequency matched controls who provided blood samples and completed a 144-item food frequency questionnaire. SNPs were evaluated using a dominant genetic model and dietary categories split on controls’ median intake. Logistic regression was used to calculate odds ratios and 95% confidence intervals, adjusted for potential confounders.
Significant increased associations (Bonferroni corrected P ≤ 0.0007) were observed for carriers of ≥ 1 minor allele for rs3816257 (glucosidase, alpha; acid [GAA]) and lower intake of deep-yellow vegetables (1.90[1.28,2.83]); and carriers of no minor allele for rs12807961 (catalyase [CAT]) and high total grains intake (2.48[1.50,4.09]) while those with ≥ 1 minor allele had a decreasing slope (across grains). The reference group was no minor alleles with low dietary intake.
Inter-individual variation in metabolism/antioxidant genes could interact with dietary intake to influence pancreatic cancer risk.
PMCID: PMC3779344  PMID: 24051964
Pancreatic cancer; dietary risk factors; interaction; case-control; genetic risk factors
11.  Diffuse Large B-Cell Lymphoma (Richter Syndrome) in Patients with Chronic Lymphocytic Leukaemia: A Cohort Study of Newly Diagnosed Patients 
British journal of haematology  2013;162(6):774-782.
Nearly all information about patients with chronic lymphocytic leukaemia (CLL) who develop diffuse large B-cell lymphoma (Richter syndrome [RS]) is derived from retrospective case series or patients treated on clinical trials. We used the Mayo Clinic CLL Database to identify patients with newly diagnosed CLL (1/2000–7/2011). Individuals who developed biopsy-proven RS during follow-up were identified. After median follow-up of 4 years, 37/1641 (2.3%) CLL patients developed RS. The rate of RS was approximately 0.5%/year. Risk of RS was associated with advanced Rai stage at diagnosis (p<0.001), high-risk FISH (p<0.0001), unmutated IGHV (p=0.003), and expression of ZAP-70 (p=0.02) and CD38 (p=0.001). The rate of RS doubled in patients treated for CLL (1%/year). Stereotyped B-cell receptors (odds-ratio=4.2; p=0.01) but not VH4–39 was associated with increased risk of RS. Treatment with combination of purine analogues and alkylating agents increased the risk of RS 3-fold (odds-ratio= 3.26, p=0.0003). Median survival after RS diagnosis was 2.1 years. The RS prognosis score stratified patients into three risk groups with median survivals of 0.5 years, 2.1 years and not reached. Both underlying characteristics of the CLL clone and subsequent CLL therapy influence the risk of RS. Survival after RS remains poor and new therapies are needed.
PMCID: PMC4098845  PMID: 23841899
transformation; aggressive lymphoma; stem cell transplantation; purine analogues; RS survival score
12.  Polymorphisms in genes related to one-carbon metabolism are not related to pancreatic cancer in PanScan and PanC4 
Cancer causes & control : CCC  2013;24(3):595-602.
The evidence of a relation between folate intake and one-carbon metabolism (OCM) with pancreatic cancer (PanCa) is inconsistent. In this study, the association between genes and single-nucleotide polymorphisms (SNPs) related to OCM and PanCa was assessed.
Using biochemical knowledge of the OCM pathway, we identified thirty-seven genes and 834 SNPs to examine in association with PanCa. Our study included 1,408 cases and 1,463 controls nested within twelve cohorts (PanScan). The ten SNPs and five genes with lowest p values (<0.02) were followed up in 2,323 cases and 2,340 controls from eight case-control studies (PanC4) that participated in PanScan2. The correlation of SNPs with metabolite levels was assessed for 649 controls from the European Prospective Investigation into Cancer and Nutrition.
When both stages were combined, we observed suggestive associations with PanCa for rs10887710 (MAT1A) (OR 1.13, 95%CI 1.04-1.23), rs1552462 (SYT9) (OR 1.27, 95%CI 1.02-1.59), and rs7074891 (CUBN) (OR 1.91, 95%CI 1.12-3.26). After correcting for multiple comparisons, no significant associations were observed in either the first or second stage. The three suggested SNPs showed no correlations with one-carbon biomarkers.
This is the largest genetic study to date to examine the relation between germline variations in OCM-related genes polymorphisms and the risk of PanCa. Suggestive evidence for an association between polymorphisms and PanCa was observed among the cohort-nested studies, but this did not replicate in the case-control studies. Our results do not strongly support the hypothesis that genes related to OCM play a role in pancreatic carcinogenesis.
PMCID: PMC4127987  PMID: 23334854
Pancreatic cancer; One-carbon metabolism; Polymorphisms; Biomarkers; Epidemiology
13.  Meat-Related Mutagens and Pancreatic Cancer: null results from a clinic-based case-control study 
Pancreatic cancer is a devastating disease for which the role of dietary factors remains inconclusive. The study objective was to evaluate risk of pancreatic cancer associated with meat preparation methods and meat-related mutagen consumption using a clinic-based case-control design.
There were 384 cases and 983 controls; subjects provided demographic information and completed a 144-item food frequency questionnaire, which was used to estimate meat mutagen intake using the National Cancer Institute's CHARRED database. Logistic regression was used to calculate odds ratios (OR) and 95% confidence intervals (95% CI), adjusted for factors including age, sex, cigarette smoking, body mass index, and diabetes mellitus.
Overall, the findings were null with respect to meat mutagen intake and pancreatic cancer.
The results do not support an association between well-done meat or meat-related mutagen intake and pancreatic cancer and contrast with generally increased risks reported in previous studies.
These data contribute to evidence regarding pancreatic cancer and potentially carcinogenic compounds in meat.
PMCID: PMC3702664  PMID: 23632817
14.  Nutrients from Fruit and Vegetable Consumption Reduce the Risk of Pancreatic Cancer 
Pancreatic cancer is a devastating disease for which the role of dietary factors remains inconclusive. Our objective was to evaluate the risk of pancreatic cancer associated with nutrients found in fruits and vegetables and nutrient supplementation using a clinic-based case-control design.
Our study included 384 rapidly ascertained cases and 983 controls frequency-matched on age at time of recruitment (in 5-year increments), race, sex, and region of residence. All subjects provided demographic information and completed a 144-item food frequency questionnaire in which they reported no change to their diet within 5 years prior to entering the study. Logistic regression was used to calculate odds ratios (OR) and 95% CIs, adjusted for age, sex, smoking, body mass index, energy intake, and alcohol consumption.
Results show a significant (trend p-value < 0.05) inverse association between pancreatic cancer and nutrient/supplement groupings in a dose-dependent manner including magnesium, potassium, selenium, alpha-carotene, beta-carotene, beta-cryptoxanthin, lutein and zeaxanthin, niacin, total alpha-tocopherol, total vitamin A activity, vitamin B6, and vitamin C. Adjusting for diabetes or total sugar intake did not result in significant changes.
We conclude that most nutrients obtained through consumption of fruits and vegetables may reduce the risk of developing pancreatic cancer.
PMCID: PMC3694591  PMID: 23620017
Pancreatic Cancer; Diet; Nutrients; Case-control; Fruits; Vegetables
15.  Mapping of the IRF8 gene identifies a 3’ UTR variant associated with risk of chronic lymphocytic leukemia but not other common non-Hodgkin lymphoma subtypes 
Our genome-wide association study (GWAS) of chronic lymphocytic leukemia (CLL) identified 4 highly-correlated intronic variants within the IRF8 gene that were associated with CLL. These results were further supported by a recent meta-analysis of our GWAS with two other GWAS of CLL, supporting the IRF8 gene as a strong candidate for CLL risk.
To refine the genetic association of CLL risk, we performed Sanger sequencing of IRF8 in 94 CLL cases and 96 controls. We then performed fine-mapping by genotyping 39 variants (of which 10 were identified from sequencing) in 745 CLL cases and 1521 controls. We also assessed these associations with risk of other non-Hodgkin lymphoma (NHL) subtypes.
The strongest association with CLL risk was observed with a common SNP located within the 3’ UTR of IRF8 (rs1044873, log additive odds ratio = 0.7, P=1.81×10−6). This SNP was not associated with the other NHL subtypes (all P>0.05).
We provide evidence that rs1044873 in the IRF8 gene accounts for the initial GWAS signal for CLL risk. This association appears to be unique to CLL with little support for association with other common NHL subtypes. Future work is needed to assess functional role of IRF8 in CLL etiology.
These data provide support that a functional variant within the 3’ UTR of IRF8 may be driving the GWAS signal seen on 16q24.1 for CLL risk.
PMCID: PMC3596428  PMID: 23307532
CLL; NHL; SNPs; IRF8; risk locus
16.  Statin and Non-steroidal Anti-inflammatory Drug (NSAID) Use In Relation to Clinical Outcome Among Patients with Rai Stage 0 Chronic Lymphocytic Leukemia (CLL) 
Leukemia & lymphoma  2010;51(7):1233-1240.
Statins and nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most commonly prescribed medications. In vitro studies suggest that statins and NSAIDs may have potential as anti-cancer therapies in low grade non-Hodgkin lymphomas including chronic lymphocytic leukemia (CLL) and a recent observational study found statin use was associated with improved event free survival in patients with follicular lymphoma. Other studies have suggested that statins reduce the efficacy of rituximab by inhibiting binding to CD20. We therefore conducted an observational cohort study of 686 patients with newly diagnosed Rai stage 0 CLL to evaluate whether statin or NSAID use was related to their clinical outcome or influenced the efficacy of rituximab therapy. At diagnosis, 136 (20%) patients took statins and 230 (34%) scheduled daily aspirin, ibuprofen, or naproxen. No difference in time to treatment was observed based on statin or NSAID use. Among patients receiving a rituximab containing first-line therapy, no difference in time to salvage treatment was observed based on statin use. Although previous studies suggested statins may improve event free survival among patients with follicular lymphoma, we find no impact of statins on time to initial therapy in this large study of patients with Rai stage 0 CLL. The in vitro observation that statins reduce rituximab efficacy does not appear to have clinical significance in CLL care.
PMCID: PMC3913168  PMID: 20496995
17.  Genome-wide Association Study Identifies Multiple Risk Loci for Chronic Lymphocytic Leukemia 
Berndt, Sonja I. | Skibola, Christine F. | Joseph, Vijai | Camp, Nicola J. | Nieters, Alexandra | Wang, Zhaoming | Cozen, Wendy | Monnereau, Alain | Wang, Sophia S. | Kelly, Rachel S. | Lan, Qing | Teras, Lauren R. | Chatterjee, Nilanjan | Chung, Charles C. | Yeager, Meredith | Brooks-Wilson, Angela R. | Hartge, Patricia | Purdue, Mark P. | Birmann, Brenda M. | Armstrong, Bruce K. | Cocco, Pierluigi | Zhang, Yawei | Severi, Gianluca | Zeleniuch-Jacquotte, Anne | Lawrence, Charles | Burdette, Laurie | Yuenger, Jeffrey | Hutchinson, Amy | Jacobs, Kevin B. | Call, Timothy G. | Shanafelt, Tait D. | Novak, Anne J. | Kay, Neil E. | Liebow, Mark | Wang, Alice H. | Smedby, Karin E | Adami, Hans-Olov | Melbye, Mads | Glimelius, Bengt | Chang, Ellen T. | Glenn, Martha | Curtin, Karen | Cannon-Albright, Lisa A. | Jones, Brandt | Diver, W. Ryan | Link, Brian K. | Weiner, George J. | Conde, Lucia | Bracci, Paige M. | Riby, Jacques | Holly, Elizabeth A. | Smith, Martyn T. | Jackson, Rebecca D. | Tinker, Lesley F. | Benavente, Yolanda | Becker, Nikolaus | Boffetta, Paolo | Brennan, Paul | Foretova, Lenka | Maynadie, Marc | McKay, James | Staines, Anthony | Rabe, Kari G. | Achenbach, Sara J. | Vachon, Celine M. | Goldin, Lynn R | Strom, Sara S. | Lanasa, Mark C. | Spector, Logan G. | Leis, Jose F. | Cunningham, Julie M. | Weinberg, J. Brice | Morrison, Vicki A. | Caporaso, Neil E. | Norman, Aaron D. | Linet, Martha S. | De Roos, Anneclaire J. | Morton, Lindsay M. | Severson, Richard K. | Riboli, Elio | Vineis, Paolo | Kaaks, Rudolph | Trichopoulos, Dimitrios | Masala, Giovanna | Weiderpass, Elisabete | Chirlaque, María-Dolores | Vermeulen, Roel C H | Travis, Ruth C. | Giles, Graham G. | Albanes, Demetrius | Virtamo, Jarmo | Weinstein, Stephanie | Clavel, Jacqueline | Zheng, Tongzhang | Holford, Theodore R | Offit, Kenneth | Zelenetz, Andrew | Klein, Robert J. | Spinelli, John J. | Bertrand, Kimberly A. | Laden, Francine | Giovannucci, Edward | Kraft, Peter | Kricker, Anne | Turner, Jenny | Vajdic, Claire M. | Ennas, Maria Grazia | Ferri, Giovanni M. | Miligi, Lucia | Liang, Liming | Sampson, Joshua | Crouch, Simon | Park, Ju-hyun | North, Kari E. | Cox, Angela | Snowden, John A. | Wright, Josh | Carracedo, Angel | Lopez-Otin, Carlos | Bea, Silvia | Salaverria, Itziar | Martin, David | Campo, Elias | Fraumeni, Joseph F. | de Sanjose, Silvia | Hjalgrim, Henrik | Cerhan, James R. | Chanock, Stephen J. | Rothman, Nathaniel | Slager, Susan L.
Nature genetics  2013;45(8):868-876.
PMCID: PMC3729927  PMID: 23770605
18.  Age at Diagnosis and the Utility of Prognostic Testing in Patients with Chronic Lymphocytic Leukemia (CLL) 
Cancer  2010;116(20):4777-4787.
To analyze the survival of CLL patients relative to age-matched individuals in the general population and determined the age-stratified utility of prognostic testing.
All 2487 patients diagnosed with CLL between January 1995 and June 2008 and cared for in the Mayo Division of Hematology were categorized by age at diagnosis and evaluated for differences in clinical characteristics, time to first treatment(TFT), and overall survival(OS).
Among Rai stage 0 patients, survival was shorter than the age-matched general population for patients age<55 years(p<0.001), 55-64 years(p<0.001), and 65-74 years(p<0.001) but not those age≥75 at diagnosis(p=NS). CD38, IGHV mutation, and ZAP-70 each predicted TFT independent of stage for all age groups(all p <0.04) but had less value for predicting OS, particularly as age increased. IGHV and FISH predicted OS independent of stage for patients
Survival of CLL patients age<75 is shorter than the age-matched general population regardless of disease stage. Among patients age<75, the simple combinations of stage and IGHV or stage and FISH identifies those with excess risk of death relative to the age-matched population. Although useful for predicting TFT independent of stage for patients of all ages, prognostic testing had little utility for predicting OS independent of stage among patients age≥75.
PMCID: PMC3902481  PMID: 20578179
Cancer  2011;118(7):1827-1837.
The impact of physicians’ disease-specific expertise on patient outcome is unknown. While previous studies suggest a survival advantage for cancer patients cared for at high volume centers, these observations may simply reflect referral bias or better access to advanced technologies, clinical trials, and multidisciplinary support at large centers.
We evaluated time to first treatment(TTFT) and overall survival(OS) of patients with newly diagnosed chronic lymphocytic leukemia/small lymphocytic lymphoma(CLL) at a single academic center based on whether they were cared for by a hematologist/oncologist who sub-specializes in CLL(CLL hematologist) or a hematologist/oncologist with expertise in other areas(non-CLL hematologist).
Among 1309 newly diagnosed patients with CLL cared for between 1999–2009, 773(59%) were cared for by CLL hematologists and 536 were cared for by non-CLL hematologists. Among early stage patients(Rai 0-I), median TTFT(9.2 vs. 6.1 years; p<0.001) and OS(10.5 years vs. 8.8 years; p<0.001) were superior for patients cared for by CLL hematologists. For all patients, OS was superior for patients cared for by CLL hematologists(10.5 years vs. 8.4 years; p=0.001). Physician’s disease-specific expertise remained an independent predictor of OS after adjusting for age, stage, sex, and lymphocyte count. Patients seen by a CLL hematologist were also more likely participate in clinical trials(48% vs. 16%; p<0.001).
Physician disease-specific expertise appears to influence outcome in patients with CLL. To the greatest extent possible, patients should be cared for by a hematologist/oncologist expert in the care of their specific malignancy. When not possible, practice guidelines developed by disease-specific experts should be followed.
PMCID: PMC3893049  PMID: 22009554
chronic lymphocytic lymphoma(CLL); small lymphocytic lymphoma (SLL); prognosis; physician expertise
British journal of haematology  2012;159(5):572-576.
A recent meta-analysis of three genome-wide association studies of chronic lymphocytic leukaemia (CLL) identified two common variants at the 6p21.31 locus that are associated with CLL risk. To verify and further explore the association of these variants with other non-Hodgkin lymphoma (NHL) subtypes, we genotyped 1196 CLL cases, 1699 NHL cases, and 2410 controls. We found significant associations between the 6p21.31 variants and CLL risk (rs210134: P=0.01; rs210142: P=6.8×10−3). These variants also showed a trend towards association with some of the other NHL subtypes. Our results validate the prior work and support specific genetic pathways for risk among NHL subtypes.
PMCID: PMC3614403  PMID: 23025533
CLL; NHL; SNPs; BAK1; risk locus
Human genetics  2012;131(9):10.1007/s00439-012-1183-1.
Adenocarcinoma of the pancreas is a significant cause of cancer mortality, and up to 10 % of cases appear to be familial. Heritable genomic copy number variants (CNVs) can modulate gene expression and predispose to disease. Here, we identify candidate predisposition genes for familial pancreatic cancer (FPC) by analyzing germline losses or gains present in one or more high-risk patients and absent in a large control group. A total of 120 FPC cases and 1,194 controls were genotyped on the Affymetrix 500K array, and 36 cases and 2,357 controls were genotyped on the Affymetrix 6.0 array. Detection of CNVs was performed by multiple computational algorithms and partially validated by quantitative PCR. We found no significant difference in the germline CNV profiles of cases and controls. A total of 93 non-redundant FPC-specific CNVs (53 losses and 40 gains) were identified in 50 cases, each CNV present in a single individual. FPC-specific CNVs overlapped the coding region of 88 RefSeq genes. Several of these genes have been reported to be differentially expressed and/or affected by copy number alterations in pancreatic adenocarcinoma. Further investigation in high-risk subjects may elucidate the role of one or more of these genes in genetic predisposition to pancreatic cancer.
PMCID: PMC3808836  PMID: 22665139
PLoS ONE  2013;8(9):e72311.
We developed an absolute risk model to identify individuals in the general population at elevated risk of pancreatic cancer.
Patients and Methods
Using data on 3,349 cases and 3,654 controls from the PanScan Consortium, we developed a relative risk model for men and women of European ancestry based on non-genetic and genetic risk factors for pancreatic cancer. We estimated absolute risks based on these relative risks and population incidence rates.
Our risk model included current smoking (multivariable adjusted odds ratio (OR) and 95% confidence interval: 2.20 [1.84–2.62]), heavy alcohol use (>3 drinks/day) (OR: 1.45 [1.19–1.76]), obesity (body mass index >30 kg/m2) (OR: 1.26 [1.09–1.45]), diabetes >3 years (nested case-control OR: 1.57 [1.13–2.18], case-control OR: 1.80 [1.40–2.32]), family history of pancreatic cancer (OR: 1.60 [1.20–2.12]), non-O ABO genotype (AO vs. OO genotype) (OR: 1.23 [1.10–1.37]) to (BB vs. OO genotype) (OR 1.58 [0.97–2.59]), rs3790844(chr1q32.1) (OR: 1.29 [1.19–1.40]), rs401681(5p15.33) (OR: 1.18 [1.10–1.26]) and rs9543325(13q22.1) (OR: 1.27 [1.18–1.36]). The areas under the ROC curve for risk models including only non-genetic factors, only genetic factors, and both non-genetic and genetic factors were 58%, 57% and 61%, respectively. We estimate that fewer than 3/1,000 U.S. non-Hispanic whites have more than a 5% predicted lifetime absolute risk.
Although absolute risk modeling using established risk factors may help to identify a group of individuals at higher than average risk of pancreatic cancer, the immediate clinical utility of our model is limited. However, a risk model can increase awareness of the various risk factors for pancreatic cancer, including modifiable behaviors.
PMCID: PMC3772857  PMID: 24058443
Carcinogenesis  2012;33(7):1384-1390.
Four loci have been associated with pancreatic cancer through genome-wide association studies (GWAS). Pathway-based analysis of GWAS data is a complementary approach to identify groups of genes or biological pathways enriched with disease-associated single-nucleotide polymorphisms (SNPs) whose individual effect sizes may be too small to be detected by standard single-locus methods. We used the adaptive rank truncated product method in a pathway-based analysis of GWAS data from 3851 pancreatic cancer cases and 3934 control participants pooled from 12 cohort studies and 8 case–control studies (PanScan). We compiled 23 biological pathways hypothesized to be relevant to pancreatic cancer and observed a nominal association between pancreatic cancer and five pathways (P < 0.05), i.e. pancreatic development, Helicobacter pylori lacto/neolacto, hedgehog, Th1/Th2 immune response and apoptosis (P = 2.0 × 10−6, 1.6 × 10−5, 0.0019, 0.019 and 0.023, respectively). After excluding previously identified genes from the original GWAS in three pathways (NR5A2, ABO and SHH), the pancreatic development pathway remained significant (P = 8.3 × 10−5), whereas the others did not. The most significant genes (P < 0.01) in the five pathways were NR5A2, HNF1A, HNF4G and PDX1 for pancreatic development; ABO for H. pylori lacto/neolacto; SHH for hedgehog; TGFBR2 and CCL18 for Th1/Th2 immune response and MAPK8 and BCL2L11 for apoptosis. Our results provide a link between inherited variation in genes important for pancreatic development and cancer and show that pathway-based approaches to analysis of GWAS data can yield important insights into the collective role of genetic risk variants in cancer.
PMCID: PMC3405651  PMID: 22523087
Cancer is a shared family experience that might provide an opportunity for lifestyle change among at-risk family members. The purpose of this study was to assess receptivity and preferences for cancer risk reduction programs among at-risk family members with two or more relatives affected with pancreas cancer.
We surveyed 401 at-risk family members in an existing pancreatic cancer family registry. Participants completed a mailed survey which examined demographic, medical, and psychosocial correlates of willingness to participate in lifestyle cancer risk reduction programs. Multivariable generalized estimating equation approaches were used to model preferences.
Overall, 85% (n = 342) of at-risk family members were receptive to lifestyle cancer risk reduction programs. Participant preferred programs focused on nutrition (36%, n = 116) and weight management (33%, n = 108), with Web/Internet (46%, n = 157) being the most preferred delivery channel. Most respondents preferred to participate in programs with their family or friends (74%, n = 182), rather than alone (25%, n = 85). In multivariable analysis, younger age (p = 0.008) and higher perceived likelihood of developing cancer (p = 0.03) were associated with willingness to participate in lifestyle programs.
Family members of those with pancreatic cancer are receptive to cancer risk reduction programs focusing on nutrition and weight management delivered via the internet. Further research is indicated to determine how to best incorporate a family-based approach when designing lifestyle intervention programs.
PMCID: PMC3691837  PMID: 23724897
Pancreatic cancer; Family; Health behavior change; Perceived risk; Risk reduction; Lifestyle
Cancer causes & control : CCC  2011;22(12):1613-1625.
Studies on fruit, vegetable, fiber, and grain consumption and pancreatic cancer risk are inconclusive. We used a clinic-based case–control study specifically designed to address limitations of both cohort and case–control studies to examine the relationship.
Participants were excluded who reported changing their diet within 5 years prior to study entry. And 384 rapidly ascertained cases and 983 controls (frequency matched on age (±5 years), race, sex, and residence) completed epidemiologic surveys and 144-item food frequency questionnaires. Odds ratios (OR) and 95% confidence intervals were calculated using logistic regression adjusted for age, sex, smoking, body mass index, energy intake, and alcohol consumption.
Comparing highest to lowest quintiles, we observed significant inverse associations (OR < 0.8) with significant trends (ptrend < 0.05) for citrus, melon, and berries, other fruits, dark green vegetables, deep yellow vegetables, tomato, other vegetables, dry bean and pea, insoluble fiber, soluble fiber, whole grains, and orange/grapefruit juice, and an increased association with non-whole grains. Results were similar after adjusting for diabetes or total sugar intake.
We provide evidence that lower consumption of fruits, vegetables, whole grains, and fiber is associated with having pancreatic cancer. This may have a role in developing prevention strategies.
PMCID: PMC3522747  PMID: 21915615
Diet; Risk; Questionnaire; Pancreatic cancer

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