Publications by authors named "James R Cerhan"

425 Publications

Pathway to Ascertain the Role of Pharmacogenomics in Healthcare Utilization Outcomes [Response to Letter].

Pharmgenomics Pers Med 2021 6;14:545-546. Epub 2021 May 6.

Division of Epidemiology, Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.

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http://dx.doi.org/10.2147/PGPM.S316851DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8111333PMC
May 2021

Anthracycline treatment, cardiovascular risk factors and the cumulative incidence of cardiovascular disease in a cohort of newly diagnosed lymphoma patients from the modern treatment era.

Am J Hematol 2021 May 10. Epub 2021 May 10.

Division of Hematology, Mayo Clinic, Rochester, Minnesota, USA.

The development of cardiovascular disease (CVD) in long-term survivors of lymphoma is of increasing importance. Here, we characterize the cumulative incidence and risk factors for CVD in lymphoma patients diagnosed in the current treatment era. From 2002-2015, newly diagnosed lymphoma patients (>18 years) were enrollment into a prospective cohort study that captured incident CVD, consisting of congestive heart failure (CHF), acute coronary syndrome (ACS), valvular heart disease (VHD), and arrhythmia. The cumulative incidence of CVD was calculated with death modeled as a competing risk. We estimated the association of treatment with anthracyclines or radiotherapy and traditional CVD risk factors with incidence of CVD using hazard ratios (HR) and 95% confidence intervals (CI) estimated from Cox regression. After excluding prevalent CVD at lymphoma diagnosis, the study consisted of 3063 patients with a median age of 59 years (range 18-95). The cumulative incidence of CVD at 10-years was 10.7% (95% CI, 9.5%-12.1%). In multivariable analysis, increasing age (HR = 1.05 per year, p < 0.001), male sex (HR = 1.36, p = 0.02), current smoker (HR = 2.10, p < 0.001), BMI > 30 kg/m (HR = 1.45, p = 0.01), and any anthracycline treatment (HR = 1.57, p < 0.001) were all significantly associated with risk of CVD. Anthracyclines were associated with increased risk of CHF (HR = 2.71, p < 0.001) and arrhythmia (HR = 1.61, p < 0.01), but not VHD (HR = 0.84, p = 0.58) or ACS (HR = 1.32, p = 0.24) after adjustment for CVD risk factors. Even in the modern treatment era, CVD remains common in lymphoma survivors and preventive efforts are required that address both treatment and CVD risk factors.
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http://dx.doi.org/10.1002/ajh.26230DOI Listing
May 2021

Epidemiology of Marginal Zone Lymphoma.

Ann Lymphoma 2021 Mar 30;5. Epub 2021 Mar 30.

Department of Internal Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN 55905.

In 2016 there were an estimated 7,460 newly diagnosed patients with marginal zone lymphoma (MZL) in the US, which comprised 7% of all mature non-Hodgkin lymphomas (NHL). Based on data from the US SEER-18 program from 2001-2017, the age-standardized incidence rate for MZL was 19.6 per 1,000,000 person-years; 9% of MZL cases were splenic MZL (SMZL), 30% nodal MZL (NMZL), and 61% extranodal MZL (EMZL) of mucusa-associated lymphoid tissue (MALT). Incidence rates were slightly higher in men for SMZL and NMZL, but similar for EMZL, and increased steeply with age for all MZL subtypes. The incidence (age-standardized per 1,000,000) of MZL was highest among non-Hispanic whites (20.7), followed by Hispanics of all races (17.6), non-Hispanic blacks (15.4), and Asian/Pacific islanders (15.0). The incidence of MZL increased +1.0% per year in the US from 2001-2017, with increases reported in other countries during this timeframe. The 5-year relative survival rate for MZL in the US was 89.8% and was similar across racial/ethnic groups and by sex; survival rates have been increasing in the US and other countries. Established risk factors for MZL (or MZL subtypes) include family history of NHL, genetic loci in the HLA region, infection (gastric MALT lymphoma), and several autoimmune diseases (Sjögren syndrome, systemic lupus erythematosus and Hashimoto thyroiditis), with strong (but not definitive) evidence for (ocular adnexal MALT lymphoma), (cutaneous MZL), hepatitis C virus, human immunodeficiency virus, and solid organ transplantation. Promising risk factors that require additional study include other infections, other autoimmune conditions, trichloroethylene exposure, certain occupations, hair dye, cigarette smoking, sun exposure (protective), and alcohol use (protective). MZL is a model of an antigen-driven malignancy, where epidemiologic risk factors, tissue-specific factors, and host immune response (including the impact of chronic inflammation and immunosuppression) drive lymphomagenesis with implications for prevention.
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http://dx.doi.org/10.21037/aol-20-28DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8020862PMC
March 2021

Common genetic polymorphisms contribute to the association between chronic lymphocytic leukaemia and non-melanoma skin cancer.

Int J Epidemiol 2021 Mar 22. Epub 2021 Mar 22.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA.

Background: Epidemiological studies have demonstrated a positive association between chronic lymphocytic leukaemia (CLL) and non-melanoma skin cancer (NMSC). We hypothesized that shared genetic risk factors between CLL and NMSC could contribute to the association observed between these diseases.

Methods: We examined the association between (i) established NMSC susceptibility loci and CLL risk in a meta-analysis including 3100 CLL cases and 7667 controls and (ii) established CLL loci and NMSC risk in a study of 4242 basal cell carcinoma (BCC) cases, 825 squamous cell carcinoma (SCC) cases and 12802 controls. Polygenic risk scores (PRS) for CLL, BCC and SCC were constructed using established loci. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs).

Results: Higher CLL-PRS was associated with increased BCC risk (OR4th-quartile-vs-1st-quartile = 1.13, 95% CI: 1.02-1.24, Ptrend = 0.009), even after removing the shared 6p25.3 locus. No association was observed with BCC-PRS and CLL risk (Ptrend = 0.68). These findings support a contributory role for CLL in BCC risk, but not for BCC in CLL risk. Increased CLL risk was observed with higher SCC-PRS (OR4th-quartile-vs-1st-quartile = 1.22, 95% CI: 1.08-1.38, Ptrend = 1.36 × 10-5), which was driven by shared genetic susceptibility at the 6p25.3 locus.

Conclusion: These findings highlight the role of pleiotropy regarding the pathogenesis of CLL and NMSC and shows that a single pleiotropic locus, 6p25.3, drives the observed association between genetic susceptibility to SCC and increased CLL risk. The study also provides evidence that genetic susceptibility for CLL increases BCC risk.
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http://dx.doi.org/10.1093/ije/dyab042DOI Listing
March 2021

Association Between Chronic Statin Use and 30-Day Mortality in Hospitalized Patients With COVID-19.

Mayo Clin Proc Innov Qual Outcomes 2021 Apr 14;5(2):442-446. Epub 2021 Mar 14.

Division of Infectious Diseases, Mayo Clinic, Rochester, MN.

Objective: To determine the association between chronic statin use and mortality in patients hospitalized with coronavirus disease 2019 (COVID-19).

Patients And Methods: We identified a retrospective cohort of patients requiring admission at the Mayo Clinic using our enterprise-wide COVID-19 registry from March 1, 2020, through September 30, 2020. Available information included age, sex, use of statins, medical comorbidities, and 30-day mortality. We estimated the association of statins with 30-day mortality using odds ratios and 95% CIs from logistic regression modeling.

Results: Patients (N=1295) between the ages of 30 and 80 years tested positive for COVID-19 and required admission during the study period, of whom 500 (38.6%) were taking statins at admission. Patients taking statins were older and more likely to have diabetes mellitus or congestive heart failure. Within 30 days of diagnosis, 59 (4.6%) died. In multivariable analysis, statin users did not have statistically different odds of death within 30 days with an odds ratio of 1.14 (95% CI, 0.64 to 2.03; =.67) compared to nonusers.

Conclusion: Patients with COVID-19 taking statins had similar 30-day mortality to those not taking statins after adjusting for relevant covariates. Although this is partly influenced by a higher prevalence of risk factors for more severe COVID-19 presentation not entirely adjusted for by the Charlson comorbidity index, these data would not support statins as a likely therapeutic intervention for COVID-19 in the hospital setting.
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http://dx.doi.org/10.1016/j.mayocpiqo.2021.02.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7955930PMC
April 2021

Outcomes of COVID-19 With the Mayo Clinic Model of Care and Research.

Mayo Clin Proc 2021 03 26;96(3):601-618. Epub 2020 Dec 26.

Division of Infectious Diseases, Mayo Clinic, Rochester, MN.

Objective: To report the Mayo Clinic experience with coronavirus disease 2019 (COVID-19) related to patient outcomes.

Methods: We conducted a retrospective chart review of patients with COVID-19 diagnosed between March 1, 2020, and July 31, 2020, at any of the Mayo Clinic sites. We abstracted pertinent comorbid conditions such as age, sex, body mass index, Charlson Comorbidity Index variables, and treatments received. Factors associated with hospitalization and mortality were assessed in univariate and multivariate models.

Results: A total of 7891 patients with confirmed COVID-19 infection with research authorization on file received care across the Mayo Clinic sites during the study period. Of these, 7217 patients were adults 18 years or older who were analyzed further. A total of 897 (11.4%) patients required hospitalization, and 354 (4.9%) received care in the intensive care unit (ICU). All hospitalized patients were reviewed by a COVID-19 Treatment Review Panel, and 77.5% (695 of 897) of inpatients received a COVID-19-directed therapy. Overall mortality was 1.2% (94 of 7891), with 7.1% (64 of 897) mortality in hospitalized patients and 11.3% (40 of 354) in patients requiring ICU care.

Conclusion: Mayo Clinic outcomes of patients with COVID-19 infection in the ICU, hospital, and community compare favorably with those reported nationally. This likely reflects the impact of interprofessional multidisciplinary team evaluation, effective leveraging of clinical trials and available treatments, deployment of remote monitoring tools, and maintenance of adequate operating capacity to not require surge adjustments. These best practices can help guide other health care systems with the continuing response to the COVID-19 pandemic.
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http://dx.doi.org/10.1016/j.mayocp.2020.12.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7831394PMC
March 2021

Aspirin and other nonsteroidal anti-inflammatory drugs, statins and risk of non-Hodgkin lymphoma.

Int J Cancer 2021 Aug 8;149(3):535-545. Epub 2021 Mar 8.

Division of Epidemiology, Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, USA.

Non-steroidal anti-inflammatory drugs (NSAIDs) and statin drugs may protect against the development of non-Hodgkin lymphoma (NHL), but data are limited, particularly for NHL subtypes. Furthermore, some in vitro, animal and epidemiologic data suggest there may be a synergistic effect of these two agents, but there has been no test of this hypothesis in NHL. We evaluated the self-reported use of NSAIDs and statins in a clinic-based study of 1703 NHL patients and 2199 frequency-matched controls. Unconditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs), adjusted for potential confounding variables. We observed an inverse association of regular use of low-dose aspirin with risk of NHL (OR = 0.82; 95% CI 0.70-0.96) that was stronger with longer duration of use (P < .01). There were no associations for use of regular or extra-strength aspirin, ibuprofen, other NSAIDs, statins or other cholesterol-lowering drugs with NHL risk, while an inverse association with COX-2 inhibitors was equivocal. There was also no interaction of low-dose aspirin and statins on NHL risk. Inverse associations of similar magnitude to all NHL were observed for regular use of low-dose aspirin with diffuse large B-cell, follicular, marginal zone and all other lymphomas, although not all associations were statistically significant. In conclusion, low-dose aspirin but not regular/extra strength aspirin, other NSAIDs or statin use was associated with lower risk of NHL. Beyond the potential for the primary prevention of NHL, these data also point to a role of anti-platelet or other effects of low-dose aspirin in lymphomagenesis that warrant follow-up.
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http://dx.doi.org/10.1002/ijc.33541DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8192479PMC
August 2021

No Association Between Pharmacogenomics Variants and Hospital and Emergency Department Utilization: A Mayo Clinic Biobank Retrospective Study.

Pharmgenomics Pers Med 2021 11;14:229-237. Epub 2021 Feb 11.

Division of Epidemiology, Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.

Background: The use of pharmacogenomics data is increasing in clinical practice. However, it is unknown if pharmacogenomics data can be used more broadly to predict outcomes like hospitalization or emergency department (ED) visit. We aim to determine the association between selected pharmacogenomics phenotypes and hospital utilization outcomes (hospitalization and ED visits).

Methods: This cohort study utilized 10,078 patients from the Mayo Clinic Biobank in the RIGHT protocol with sequence and interpreted phenotypes for 10 selected pharmacogenes including , and . The primary outcome was hospitalization with ED visits as a secondary outcome. We used Cox proportional hazards model to test the association between each pharmacogenomics phenotype and the risk of the outcomes.

Results: During the follow-up period (median [in years] = 7.3), 13% (n=1354) and 8% (n=813) of the subjects experienced hospitalization and ED visits, respectively. Compared to subjects who did not experience hospitalization, hospitalized patients were older (median age [in years]: 67 vs 65), poorer self-rated health (15% vs 4.7% for fair/poor), and higher disease burden (median number of chronic conditions: 7 vs 4) at baseline. There was no association of hospitalization with any of the pharmacogenomics phenotypes. The pharmacogenomics phenotypes were not associated with disease burden, a well-established risk factor for hospital utilization outcomes. Similar findings were observed for patients with ED visits during the follow-up period.

Conclusion: We found no association of 10 well-established pharmacogenomics phenotypes with either hospitalization or ED visits in this relatively large biobank population and outside the context of specific drug use related to these genes. Traditional risk factors for hospitalization like age and self-rated health were much more likely to predict hospitalization and/or ED visits than this pharmacogenomics information.
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http://dx.doi.org/10.2147/PGPM.S281645DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7886254PMC
February 2021

Impact of Organ Function-Based Clinical Trial Eligibility Criteria in Patients With Diffuse Large B-Cell Lymphoma: Who Gets Left Behind?

J Clin Oncol 2021 May 2;39(15):1641-1649. Epub 2021 Feb 2.

Division of Hematology, Mayo Clinic, Rochester, MN.

Purpose: Exclusion of patients needing urgent treatment or requiring novel biomarkers before enrollment has impacted the ability to enroll real-world patients in frontline trials of diffuse large B-cell lymphoma (DLBCL). The impact of baseline organ function-based eligibility criteria on this effect and clinical trial exclusion is less well-understood.

Methods: Consecutive patients with newly diagnosed lymphoma were enrolled from 2002 to 2015 into the Molecular Epidemiology Resource (MER) of the University of Iowa and Mayo Clinic Lymphoma Specialized Program of Research Excellence. The current analysis includes 1,265 patients with DLBCL receiving standard immunochemotherapy. Organ function parameters were identified from criteria for hemoglobin, absolute neutrophil count, platelet count, creatinine clearance, and bilirubin, as reported in frontline DLBCL trials. Abstracted laboratory values from MER were used to determine the percent (%) of patients excluded. Outcomes and cause-of-death analyses comparing ineligible and eligible groups in MER were conducted. An interactive online tool was developed to estimate exclusions based on organ function for future trial design.

Results: Between 9% and 24% of MER patients with DLBCL receiving standard immunochemotherapy were excluded on the basis of baseline organ function alone. Ineligible patients based on organ function had significantly inferior event-free survival (hazard ratios, 1.67-2.16), overall survival (hazard ratios, 1.87-2.56), and event-free survival at 24 months (odds ratio, 1.71-2.16). Ineligible patients were more likely to die from lymphoma progression than increased therapy-related complications.

Conclusion: Current national and international trials exclude up to 24% of patients from participation on the basis of organ function alone. A significant difference in the outcomes, notably lymphoma-related death, suggests issues with generalization and potential exclusion of high-risk patients. These data will help future clinical trial development and meet US Food and Drug Administration and ASCO recommendations to increase trial accrual.
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http://dx.doi.org/10.1200/JCO.20.01935DOI Listing
May 2021

Natural history of monoclonal B-cell lymphocytosis among relatives in CLL families.

Blood 2021 Apr;137(15):2046-2056

Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD.

Chronic lymphocytic lymphoma (CLL) has one of the highest familial risks among cancers. Monoclonal B-cell lymphocytosis (MBL), the precursor to CLL, has a higher prevalence (13%-18%) in families with 2 or more members with CLL compared with the general population (5%-12%). Although, the rate of progression to CLL for high-count MBLs (clonal B-cell count ≥500/µL) is ∼1% to 5%/y, no low-count MBLs have been reported to progress to date. We report the incidence and natural history of MBL in relatives from CLL families. In 310 CLL families, we screened 1045 relatives for MBL using highly sensitive flow cytometry and prospectively followed 449 of them. MBL incidence was directly age- and sex-adjusted to the 2010 US population. CLL cumulative incidence was estimated using Kaplan-Meier survival curves. At baseline, the prevalence of MBL was 22% (235/1045 relatives). After a median follow-up of 8.1 years among 449 relatives, 12 individuals progressed to CLL with a 5-year cumulative incidence of 1.8%. When considering just the 139 relatives with low-count MBL, the 5-year cumulative incidence increased to 5.7%. Finally, 264 had no MBL at baseline, of whom 60 individuals subsequently developed MBL (2 high-count and 58 low-count MBLs) with an age- and sex-adjusted incidence of 3.5% after a median of 6 years of follow-up. In a screening cohort of relatives from CLL families, we reported progression from normal-count to low-count MBL to high-count MBL to CLL, demonstrating that low-count MBL precedes progression to CLL. We estimated a 1.1% annual rate of progression from low-count MBL, which is in excess of that in the general population.
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http://dx.doi.org/10.1182/blood.2020006322DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8057266PMC
April 2021

Clinical characteristics and outcomes of primary versus secondary gastrointestinal mantle cell lymphoma.

Blood Cancer J 2021 Jan 7;11(1). Epub 2021 Jan 7.

Division of Hematology, Mayo Clinic, Rochester, MN, USA.

Primary gastrointestinal (GI) mantle cell lymphoma (MCL) is rare and the optimal management is unknown. We reviewed 800 newly diagnosed MCL cases and found 22 primary (2.8%) and 79 (9.9%) secondary GI MCL cases. Age, sex, and performance status were similar between primary and secondary cases. Secondary cases had more elevations in lactate dehydrogenase (28% vs 0%, P = 0.03) and a trend for a higher MCL international prognostic index (P = 0.07). Observation or local therapy was more common for primary GI MCL (29% vs 8%, P < 0.01), and autologous stem-cell transplant was more common for secondary GI MCL (35% vs 14%, P < 0.05). The median follow-up was 85 months. Primary and secondary GI MCL had similar 5-year progression-free survival (PFS) (30% vs 28%, P = 0.59) and overall survival (OS) (65% vs 66%, P = 0.83). The extent of GI involvement in primary GI MCL affected treatment selection but not outcome, with a 5-year PFS of 43% vs 14% vs 31% (P = 0.48) and OS of 57% vs 71% vs 69% (P = 0.54) in cases with single lesion vs multiple lesions in 1 organ vs multiple lesions in ≥2 organs. Less aggressive frontline treatment for primary GI MCL is reasonable. It is unknown whether more aggressive treatment can result in improved outcomes.
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http://dx.doi.org/10.1038/s41408-020-00394-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7791108PMC
January 2021

Associations between tissue-based CD3+ T-lymphocyte count and colorectal cancer survival in a prospective cohort of older women.

Mol Carcinog 2021 01 17;60(1):15-24. Epub 2020 Nov 17.

Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, Minnesota, USA.

Tumor-infiltrating lymphocytes in colorectal cancer (CRC) predict better survival. However, associations between T-lymphocyte count in histologically normal tissues from patients with CRC and survival remain uncertain. We examined associations of CD3+ T-cells in colorectal tumor and histologically normal tissues with CRC-specific and all-cause mortality in the prospective Iowa Women's Health Study. Tissue microarrays were constructed using paraffin-embedded colorectal tissue samples from 464 women with tumor tissues and 314 women with histologically normal tissues (55-69 years at baseline) diagnosed with incident CRC from 1986 to 2002 and followed through 2014 (median follow-up 20.5 years). Three tumor and two histologically normal tissue cores for each patient were immunostained using CD3+ antibody and quantified, and the counts were averaged across the cores in each tissue. Cox proportional hazards regression estimated hazard ratios (HR) and 95% confidence interval (CI) for CRC-specific and all-cause mortality. After adjustment for age at diagnosis, body mass index, smoking status, tumor grade, and stage, HRs (95% CI) for the highest versus lowest tertile of tumor CD3+ score were 0.59 (0.38-0.89) for CRC-specific mortality and 0.82 (0.63-1.05) for all-cause mortality; for histologically normal CD3+ score, the corresponding HRs (95% CI) were 0.47 (0.19-1.17) and 0.50 (0.27-0.90), respectively. The CD3+ score combining the tumor and histologically normal scores was inversely associated with CRC-specific and all-cause mortality. Although the association between tumor CD3+ score and all-cause mortality was not significant, both higher CD3+ T-lymphocyte counts in tumor and histologically normal scores tended to be associated with lower CRC-specific and all-cause mortality.
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http://dx.doi.org/10.1002/mc.23267DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7745624PMC
January 2021

Somatic copy number gains in MYC, BCL2, and BCL6 identifies a subset of aggressive alternative-DH/TH DLBCL patients.

Blood Cancer J 2020 11 9;10(11):117. Epub 2020 Nov 9.

Division of Hematology, Mayo Clinic, Rochester, MN, USA.

Double/triple hit lymphoma (DH/TH), known as high-grade B-cell lymphoma (HGBL), is an aggressive diffuse large B cell lymphoma (DLBCL), defined as having concurrent MYC, BCL2, and/or BCL6 gene rearrangements. While gene rearrangements represent significant genetic events in cancer, copy number alterations (CNAs) also play an important role, and their contributions to rearrangements have yet to be fully elucidated. Using FISH and high-resolution CNA data, we defined the landscape of concurrent gene rearrangements and copy gains in MYC, BCL2, and BCL6, in a cohort of 479 newly diagnosed DLBCL. We also show that concurrent translocations and copy number alterations, in combinations similar to DH/TH, identify a unique subset of DLBCL, alternative DH/TH, that have survival outcomes similar to DH/TH DLBCL patients.
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http://dx.doi.org/10.1038/s41408-020-00382-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7652824PMC
November 2020

The association of health behaviors with quality of life in lymphoma survivors.

Leuk Lymphoma 2021 02 13;62(2):271-280. Epub 2020 Oct 13.

Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA.

The impact of change in health behaviors (physical activity [PA], alcohol and smoking) on quality of life (QOL) in lymphoma survivors is not well understood. We evaluated the associations of health behaviors with QOL domains at diagnosis and at 3-year follow-up (FU3) in 2805 lymphoma survivors. We report clinically significant QOL score differences, defined as scores that exceeded a minimally important difference threshold and were statistically significant. Current smoking was associated with lower QOL at baseline ( < 0.01) and at FU3 ( < 0.01). Meeting the American Cancer Society PA guidelines was associated with better functional wellbeing and overall QOL at FU3 ( < 0.01). An increase in PA from baseline to FU3 was associated with improvement in physical, functional wellbeing and overall QOL at FU3 compared to baseline ( < 0.01). Thus, QOL in lymphoma survivors is associated with their health behaviors and active interventions to promote positive lifestyle changes in lymphoma survivors are needed.
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http://dx.doi.org/10.1080/10428194.2020.1830389DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8063513PMC
February 2021

Chronic lymphocytic leukemia (CLL) risk is mediated by multiple enhancer variants within CLL risk loci.

Hum Mol Genet 2020 09;29(16):2761-2774

Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55905, USA.

Chronic lymphocytic leukemia (CLL) is the most common adult leukemia in Western countries. It has a strong genetic basis, showing a ~ 8-fold increased risk of CLL in first-degree relatives. Genome-wide association studies (GWAS) have identified 41 risk variants across 41 loci. However, for a majority of the loci, the functional variants and the mechanisms underlying their causal roles remain undefined. Here, we examined the genetic and epigenetic features associated with 12 index variants, along with any correlated (r2 ≥ 0.5) variants, at the CLL risk loci located outside of gene promoters. Based on publicly available ChIP-seq and chromatin accessibility data as well as our own ChIP-seq data from CLL patients, we identified six candidate functional variants at six loci and at least two candidate functional variants at each of the remaining six loci. The functional variants are predominantly located within enhancers or super-enhancers, including bi-directionally transcribed enhancers, which are often restricted to immune cell types. Furthermore, we found that, at 78% of the functional variants, the alternative alleles altered the transcription factor binding motifs or histone modifications, indicating the involvement of these variants in the change of local chromatin state. Finally, the enhancers carrying functional variants physically interacted with genes enriched in the type I interferon signaling pathway, apoptosis, or TP53 network that are known to play key roles in CLL. These results support the regulatory roles for inherited noncoding variants in the pathogenesis of CLL.
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http://dx.doi.org/10.1093/hmg/ddaa165DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7530532PMC
September 2020

Delineation of clinical and biological factors associated with cutaneous squamous cell carcinoma among patients with chronic lymphocytic leukemia.

J Am Acad Dermatol 2020 Dec 16;83(6):1581-1589. Epub 2020 Jul 16.

Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota. Electronic address:

Background: The incidence of cutaneous squamous cell carcinoma (SCC) in patients with chronic lymphocytic leukemia (CLL) is significantly higher compared with age- and sex-matched controls.

Objective: To evaluate the association of factors associated with SCC risk.

Methods: Clinical CLL and SCC data were obtained from Mayo Clinic CLL Resource and self-reported questionnaires among patients with newly diagnosed CLL. We computed the CLL International Prognostic Index (CLL-IPI) from CLL prognostic factors, and a polygenic risk score from SCC susceptibility variants. We used Cox regression to estimate hazard ratios (HRs) and 95% confidence intervals (CIs).

Results: Among 1269 patients with CLL, the median follow-up was 7 years, and SCC subsequently developed in 124 patients. Significant associations with SCC risk were history of skin cancer (HR=4.80; 95% CI: 3.37-6.83), CLL-IPI (HR=1.42; 95% CI: 1.13-1.80), and polygenic risk score (HR=2.58; 95% CI: 1.50-4.43). In a multivariable model, these factors were independent predictors (C statistic = 0.69; 95% CI: 0.62-0.76). T-cell immunosuppressive treatments were also associated with SCC risk (HR=2.29; 95% CI: 1.47-3.55; adjusted for age, sex, and prior SCC).

Limitations: The sample size decreases when combining all risk factors in a single model.

Conclusion: SCC risk includes history of skin cancer, an aggressive disease at time of CLL diagnosis, receiving T-cell immunosuppressive treatments, and high polygenic risk score. Future studies should develop prediction models that include these factors to improved screening guidelines.
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http://dx.doi.org/10.1016/j.jaad.2020.06.1024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7669637PMC
December 2020

Epidemiology of Follicular Lymphoma.

Authors:
James R Cerhan

Hematol Oncol Clin North Am 2020 08 5;34(4):631-646. Epub 2020 May 5.

Department of Health Sciences Research, Mayo Clinic, 200 1st Street Southwest, Rochester, MN 55905, USA. Electronic address:

Follicular lymphoma (FL) is a common indolent lymphoma subtype in Western countries. FL incidence increases with age, and shows considerable variation by race/ethnicity and geography. In the United States and France, FL incidence has been stable since 2000, whereas in other Western and Asian countries it has been increasing. Five-year relative survival rates have been increasing in Western and Asian countries. Progress on identifying FL-specific risk factors has accelerated with the implementation of the InterLymph nested classification and the availability of larger epidemiologic studies and pooled analyses. Identification of risk factors for FL requires further research.
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http://dx.doi.org/10.1016/j.hoc.2020.02.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7323888PMC
August 2020

Impact of Diverse Data Sources on Computational Phenotyping.

Front Genet 2020 3;11:556. Epub 2020 Jun 3.

Division of Digital Health Sciences, Department of Health Sciences Research, Mayo Clinic, Rochester, MN, United States.

Electronic health records (EHRs) are widely adopted with a great potential to serve as a rich, integrated source of phenotype information. Computational phenotyping, which extracts phenotypes from EHR data automatically, can accelerate the adoption and utilization of phenotype-driven efforts to advance scientific discovery and improve healthcare delivery. A list of computational phenotyping algorithms has been published but data fragmentation, i.e., incomplete data within one single data source, has been raised as an inherent limitation of computational phenotyping. In this study, we investigated the impact of diverse data sources on two published computational phenotyping algorithms, rheumatoid arthritis (RA) and type 2 diabetes mellitus (T2DM), using Mayo EHRs and Rochester Epidemiology Project (REP) which links medical records from multiple health care systems. Results showed that both RA (less prevalent) and T2DM (more prevalent) case selections were markedly impacted by data fragmentation, with positive predictive value (PPV) of 91.4 and 92.4%, false-negative rate (FNR) of 26.6 and 14% in Mayo data, respectively, PPV of 97.2 and 98.3%, FNR of 5.2 and 3.3% in REP. T2DM controls also contain biases, with PPV of 91.2% and FNR of 1.2% for Mayo. We further elaborated underlying reasons impacting the performance.
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http://dx.doi.org/10.3389/fgene.2020.00556DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7283539PMC
June 2020

Tumor mutational load predicts time to first treatment in chronic lymphocytic leukemia (CLL) and monoclonal B-cell lymphocytosis beyond the CLL international prognostic index.

Am J Hematol 2020 08 7;95(8):906-917. Epub 2020 May 7.

Division of Hematology /Oncology, Mayo Clinic, Scottsdale, Arizona, USA.

Next-generation sequencing identified about 60 genes recurrently mutated in chronic lymphocytic leukemia (CLL). We examined the additive prognostic value of the total number of recurrently mutated CLL genes (i.e., tumor mutational load [TML]) or the individually mutated genes beyond the CLL international prognostic index (CLL-IPI) in newly diagnosed CLL and high-count monoclonal B-cell lymphocytosis (HC MBL). We sequenced 59 genes among 557 individuals (112 HC MBL/445 CLL) in a multi-stage design, to estimate hazard ratios (HR) and 95% confidence intervals (CI) for time-to-first treatment (TTT), adjusted for CLL-IPI and sex. TML was associated with shorter TTT in the discovery and validation cohorts, with a combined estimate of continuous HR = 1.27 (CI:1.17-1.39, P = 2.6 × 10 ; c-statistic = 0.76). When stratified by CLL-IPI, the association of TML with TTT was stronger and validated within low/intermediate risk (combined HR = 1.54, CI:1.37-1.72, P = 7.0 × 10 ). Overall, 80% of low/intermediate CLL-IPI cases with two or more mutated genes progressed to require therapy within 5 years, compared to 24% among those without mutations. TML was also associated with shorter TTT in the HC MBL cohort (HR = 1.53, CI:1.12-2.07, P = .007; c-statistic = 0.71). TML is a strong prognostic factor for TTT independent of CLL-IPI, especially among low/intermediate CLL-IPI risk, and a better predictor than any single gene. Mutational screening at early stages may improve risk stratification and better predict TTT.
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http://dx.doi.org/10.1002/ajh.25831DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7409825PMC
August 2020

Targeting of inflammatory pathways with R2CHOP in high-risk DLBCL.

Leukemia 2021 02 5;35(2):522-533. Epub 2020 Mar 5.

Division of Hematology, Mayo Clinic, Rochester, MN, USA.

Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoma, and front line therapies have not improved overall outcomes since the advent of immunochemotherapy. By pairing DNA and gene expression data with clinical response data, we identified a high-risk subset of non-GCB DLBCL patients characterized by genomic alterations and expression signatures capable of sustaining an inflammatory environment. These mutational alterations (PIM1, SPEN, and MYD88 [L265P]) and expression signatures (NF-κB, IRF4, and JAK-STAT engagement) were associated with proliferative signaling, and were found to be enriched in patients treated with RCHOP that experienced unfavorable outcomes. However, patients with these high-risk mutations had more favorable outcomes when the immunomodulatory agent lenalidomide was added to RCHOP (R2CHOP). We are the first to report the genomic validation of a high-risk phenotype with a preferential response towards R2CHOP therapy in non-GCB DLBCL patients. These conclusions could be translated to a clinical setting to identify the ~38% of non-GCB patients that could be considered high-risk, and would benefit from alternative therapies to standard RCHOP based on personalized genomic data.
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http://dx.doi.org/10.1038/s41375-020-0766-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7483252PMC
February 2021

Characteristics Associated With Recruitment and Re-contact in Mayo Clinic Biobank.

Front Public Health 2020 4;8. Epub 2020 Feb 4.

Division of Epidemiology, Department of Health Sciences Research, Mayo Clinic, Rochester, MN, United States.

To better understand the characteristics associated with a participant's willingness to consent to the Mayo Clinic Biobank (MCB) and examine factors associated with willingness to participate in follow-up studies embedded within MCB that require re-contact and participant approval. Consent rates were compared across patient demographics to the MCB. Rates of participation to follow-up studies were also compared across demographics and request types. Among 272,102 Mayo Clinic patients invited to the MCB, 48,314 (19%) consented across the three recruitment sites within 90 days of initial invitation. A significant age by gender interaction was identified, showing young males consent at a lower rate than young females and older males consent at a higher rate than older females. Over the recruitment time frame of 2009-2015, there was a significant decrease in consent rates (decline of 2.5%/year). Of the 57,041 consented MCB participants, 33,487 participants (59%) have been invited to participate in follow-up studies via re-contact. Follow-up studies of the MCB may require participants to provide additional samples, complete questionnaires, and/or release their identity to a research team. MCB participants have been invited to enroll in a median of two studies (IQR: 1-3). Seventy-one percent of participants consented to at least one follow-up study, with individual follow-up study consent rates ranging from 14 to 87% depending on study type, with a median consent rate of 61% (IQR: 47-70%). Studies requesting return of a questionnaire had the highest participation rates. White participants, older participants, and participants with some college or a degree were significantly more likely to participate to follow-up studies, while there was no association with gender. Consent rates among younger and non-white patients were lower than in older, white patients. However, we also found that participation rates among those already enrolled in the biobank were much higher than those seen in new recruitment efforts, external to an existing biobank. We thus demonstrate an important way that biobanks can advance precision medicine goals: through provision of populations from which studies can draw participants for future studies.
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http://dx.doi.org/10.3389/fpubh.2020.00009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7010638PMC
May 2021

Lipid Trait Variants and the Risk of Non-Hodgkin Lymphoma Subtypes: A Mendelian Randomization Study.

Cancer Epidemiol Biomarkers Prev 2020 05 27;29(5):1074-1078. Epub 2020 Feb 27.

Emory University, Atlanta, Georgia.

Background: Lipid traits have been inconsistently linked to risk of non-Hodgkin lymphoma (NHL). We examined the association of genetically predicted lipid traits with risk of diffuse large B-cell lymphoma (DLBCL), chronic lymphocytic leukemia (CLL), follicular lymphoma (FL), and marginal zone lymphoma (MZL) using Mendelian randomization (MR) analysis.

Methods: Genome-wide association study data from the InterLymph Consortium were available for 2,661 DLBCLs, 2,179 CLLs, 2,142 FLs, 824 MZLs, and 6,221 controls. SNPs associated ( < 5 × 10) with high-density lipoprotein (HDL, = 164), low-density lipoprotein (LDL, = 137), total cholesterol (TC, = 161), and triglycerides (TG, = 123) were used as instrumental variables (IV), explaining 14.6%, 27.7%, 16.8%, and 12.8% of phenotypic variation, respectively. Associations between each lipid trait and NHL subtype were calculated using the MR inverse variance-weighted method, estimating odds ratios (OR) per standard deviation and 95% confidence intervals (CI).

Results: HDL was positively associated with DLBCL (OR = 1.14; 95% CI, 1.00-1.30) and MZL (OR = 1.09; 95% CI, 1.01-1.18), while TG was inversely associated with MZL risk (OR = 0.90; 95% CI, 0.83-0.99), all at nominal significance ( < 0.05). A positive trend was observed for HDL with FL risk (OR = 1.08; 95% CI, 0.99-1.19; = 0.087). No associations were noteworthy after adjusting for multiple testing.

Conclusions: We did not find evidence of a clear or strong association of these lipid traits with the most common NHL subtypes. While these IVs have been previously linked to other cancers, our findings do not support any causal associations with these NHL subtypes.

Impact: Our results suggest that prior reported inverse associations of lipid traits are not likely to be causal and could represent reverse causality or confounding.
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http://dx.doi.org/10.1158/1055-9965.EPI-19-0803DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7196490PMC
May 2020

Genetically Determined Height and Risk of Non-hodgkin Lymphoma.

Front Oncol 2019 28;9:1539. Epub 2020 Jan 28.

Interdisciplinary Department of Medicine, University of Bari, Bari, Italy.

Although the evidence is not consistent, epidemiologic studies have suggested that taller adult height may be associated with an increased risk of some non-Hodgkin lymphoma (NHL) subtypes. Height is largely determined by genetic factors, but how these genetic factors may contribute to NHL risk is unknown. We investigated the relationship between genetic determinants of height and NHL risk using data from eight genome-wide association studies (GWAS) comprising 10,629 NHL cases, including 3,857 diffuse large B-cell lymphoma (DLBCL), 2,847 follicular lymphoma (FL), 3,100 chronic lymphocytic leukemia (CLL), and 825 marginal zone lymphoma (MZL) cases, and 9,505 controls of European ancestry. We evaluated genetically predicted height by constructing polygenic risk scores using 833 height-associated SNPs. We used logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CI) for association between genetically determined height and the risk of four NHL subtypes in each GWAS and then used fixed-effect meta-analysis to combine subtype results across studies. We found suggestive evidence between taller genetically determined height and increased CLL risk (OR = 1.08, 95% CI = 1.00-1.17, = 0.049), which was slightly stronger among women (OR = 1.15, 95% CI: 1.01-1.31, = 0.036). No significant associations were observed with DLBCL, FL, or MZL. Our findings suggest that there may be some shared genetic factors between CLL and height, but other endogenous or environmental factors may underlie reported epidemiologic height associations with other subtypes.
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http://dx.doi.org/10.3389/fonc.2019.01539DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6999122PMC
January 2020

Genome-wide Association Study Identifies HLA-DPB1 as a Significant Risk Factor for Severe Aplastic Anemia.

Am J Hum Genet 2020 02 30;106(2):264-271. Epub 2020 Jan 30.

Center for International Blood and Marrow Transplant Research, Medical College of Wisconsin, Milwaukee, WI 53226, USA; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.

Severe aplastic anemia (SAA) is a rare disorder characterized by hypoplastic bone marrow and progressive pancytopenia. The etiology of acquired SAA is not understood but is likely related to abnormal immune responses and environmental exposures. We conducted a genome-wide association study of individuals with SAA genetically matched to healthy controls in discovery (359 cases, 1,396 controls) and validation sets (175 cases, 1,059 controls). Combined analyses identified linked SNPs in distinct blocks within the major histocompatibility complex on 6p21. The top SNP encodes p.Met76Val in the P4 binding pocket of the HLA class II gene HLA-DPB1 (rs1042151A>G, odds ratio [OR] 1.75, 95% confidence interval [CI] 1.50-2.03, p = 1.94 × 10) and was associated with HLA-DP cell surface expression in healthy individuals (p = 2.04 × 10). Phylogenetic analyses indicate that Val76 is not monophyletic and likely occurs in conjunction with different HLA-DP binding groove conformations. Imputation of HLA-DPB1 alleles revealed increased risk of SAA associated with Val76-encoding alleles DPB103:01, (OR 1.66, p = 1.52 × 10), DPB110:01 (OR 2.12, p = 0.0003), and DPB101:01 (OR 1.60, p = 0.0008). A second SNP near HLA-B, rs28367832G>A, reached genome-wide significance (OR 1.49, 95% CI 1.22-1.78, p = 7.27 × 10) in combined analyses; the association remained significant after excluding cases with clonal copy-neutral loss-of-heterozygosity affecting class I HLA genes (8.6% of cases and 0% of controls). SNPs in the HLA class II gene HLA-DPB1 and possibly class I (HLA-B) are associated with SAA. The replacement of Met76 to Val76 in certain HLA-DPB1 alleles might influence risk of SAA through mechanisms involving DP peptide binding specificity, expression, and/or other factors affecting DP function.
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http://dx.doi.org/10.1016/j.ajhg.2020.01.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7010969PMC
February 2020

Leveraging gene expression subgroups to classify DLBCL patients and select for clinical benefit from a novel agent.

Blood 2020 03;135(13):1008-1018

Celgene Institute for Translational Research Europe, a Bristol-Myers Squibb Company, Seville, Spain.

Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease, commonly described by cell-of-origin (COO) molecular subtypes. We sought to identify novel patient subgroups through an unsupervised analysis of a large public dataset of gene expression profiles from newly diagnosed de novo DLBCL patients, yielding 2 biologically distinct subgroups characterized by differences in the tumor microenvironment. Pathway analysis and immune deconvolution algorithms identified higher B-cell content and a strong proliferative signal in subgroup A and enriched T-cell, macrophage, and immune/inflammatory signals in subgroup B, reflecting similar biology to published DLBCL stratification research. A gene expression classifier, featuring 26 gene expression scores, was derived from the public dataset to discriminate subgroup A (classifier-negative, immune-low) and subgroup B (classifier-positive, immune-high) patients. Subsequent application to an independent series of diagnostic biopsies replicated the subgroups, with immune cell composition confirmed via immunohistochemistry. Avadomide, a CRL4CRBN E3 ubiquitin ligase modulator, demonstrated clinical activity in relapsed/refractory DLBCL patients, independent of COO subtypes. Given the immunomodulatory activity of avadomide and the need for a patient-selection strategy, we applied the gene expression classifier to pretreatment biopsies from relapsed/refractory DLBCL patients receiving avadomide (NCT01421524). Classifier-positive patients exhibited an enrichment in response rate and progression-free survival of 44% and 6.2 months vs 19% and 1.6 months for classifier-negative patients (hazard ratio, 0.49; 95% confidence interval, 0.280-0.86; P = .0096). The classifier was not prognostic for rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone or salvage immunochemotherapy. The classifier described here discriminates DLBCL tumors based on tumor and nontumor composition and has potential utility to enrich for clinical response to immunomodulatory agents, including avadomide.
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http://dx.doi.org/10.1182/blood.2019002414DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7099333PMC
March 2020

Compliance with cancer screening and influenza vaccination guidelines in non-Hodgkin lymphoma survivors.

J Cancer Surviv 2020 06 2;14(3):316-321. Epub 2020 Jan 2.

Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA.

Purpose: Compliance with US Preventive Services Task Force (USPSTF) age-appropriate cancer screening and immunization guidelines in lymphoma survivors is not known. We sought to measure compliance in non-Hodgkin lymphoma (NHL) survivors and identify any differences based on patient, disease, and treatment characteristics.

Methods: Eligible NHL survivors were identified from the Molecular Epidemiology Resource (MER) prospective cohort study. Survivors self-reported colorectal, breast, and prostate cancer screening and influenza immunization in a questionnaire 3 years post-diagnosis (FU3). The USPSTF guidelines were used to define compliance. Chi-square tests were used to compare characteristics of compliant versus non-compliant survivors.

Results: A total of 1833 MER participants from 2005 to 2012 completed a FU3. Rates of breast and prostate cancer screening were 96% and 72%, respectively. No differences in compliance based on patient or disease characteristics or treatment were observed. Ninety-two percent of survivors were compliant with colorectal cancer screening. Older age, indolent lymphoma histology, and 2008-2012 year of diagnosis were associated with higher compliance. Eighty-two percent of survivors were compliant with influenza vaccination and older age was associated with higher compliance.

Conclusion: NHL survivors have high compliance with USPSTF recommendations for cancer screening and immunization. Survivors who are younger or have aggressive lymphomas are less likely to meet the colorectal cancer screening guidelines. Older survivors are more likely to receive influenza vaccination.

Implications For Cancer Survivors: Measures to further improve preventive care for NHL survivors, especially those younger in age, are necessary.
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http://dx.doi.org/10.1007/s11764-019-00846-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7261247PMC
June 2020