Sex differences in outcomes in multiple myeloma Derman, Benjamin A.; Langerman, Spencer S.; Maric, Maya ...
British journal of haematology,
February 2021, Letnik:
192, Številka:
3
Journal Article
Based on limited evidence, the U.S. Food and Drug Administration (FDA) issued a black box warning for the use of tumor necrosis factor‐alpha inhibitors (TNFIs) and risk of non‐Hodgkin lymphoma (NHL). ...Our objective was to determine the risk of NHL associated with TNFI use by duration and type of anti‐TNF agent. We performed a nested case‐control study within a retrospective cohort of adults with rheumatologic conditions from a U.S. commercial health insurance database between 2009 and 2015. Use of TNFIs (infliximab, adalimumab, etanercept, golimumab and certolizumab pegol) and conventional‐synthetic disease‐modifying antirheumatic drugs (csDMARDs) was identified, and conditional logistic regression models were used to estimate adjusted odds ratios (OR) and 95% confidence intervals (CI) for risk of NHL. From a retrospective cohort of 55,446 adult patients, 101 NHL cases and 984 controls matched on age, gender and rheumatologic indication were included. Compared to controls, NHL cases had greater TNFI use (33% vs. 20%) but were similar in csDMARD use (70% vs. 71%). TNFI ever‐use was associated with nearly two‐fold increased risk of NHL (OR = 1.93; 95% CI: 1.16–3.20) with suggestion of increasing risk with duration (P‐trend = 0.05). TNF fusion protein (etanercept) was associated with increased NHL risk (OR = 2.73; 95% CI: 1.40–5.33), whereas risk with anti‐TNF monoclonal antibodies was not statistically significant (OR = 1.77; 95% CI: 0.87–3.58). In sensitivity analyses evaluating confounding by rheumatologic disease severity, channeling bias was not likely to account for our results. Our findings support the FDA black box warning for NHL. Continued surveillance and awareness of this rare but serious adverse outcome are warranted with new TNFIs and biosimilar products forthcoming.
What's new?
TNF inhibitors (TNFIs) are used to treat autoimmune and inflammatory disorders. However, the U.S. FDA has issued a black‐box warning for these drugs, as they may increase the risk of non‐Hodgkin lymphoma (NHL). In this large follow‐up study, the authors found that NHL risk increases with increased duration of TNFI use, and increased more with some TNFIs than with others. Continued awareness of this rare but serious adverse outcome is thus warranted, with new agents and biosimilar products entering the market or in the pipeline.
Thyroid cancer incidence is increasing worldwide at an alarming rate, yet little is known of the impact this increase will have on society. We sought to determine the clinical and economic burden of ...a sustained increase in thyroid cancer incidence in the United States and to understand how these burdens correlate with the National Cancer Institute's (NCI) prioritization of thyroid cancer research funding.
We used the NCI's SEER 13 database (1992-2009) and Joinpoint regression software to identify the current clinical burden of thyroid cancer and to project future incidence through 2019. We combined Medicare reimbursement rates with American Thyroid Association guidelines, and our clinical practice to create an economic model of thyroid cancer. We obtained research-funding data from the NCI's Office of Budget and Finance. RESULTS; By 2019, papillary thyroid cancer will double in incidence and become the third most common cancer in women of all ages at a cost of $18 to $21 billion dollars in the United States. Despite these substantial clinical and economic burdens, thyroid cancer research remains significantly underfunded by comparison, and in 2009 received only $14.7 million (ranked 30th) from the NCI.
The impact of thyroid cancer on society has been significantly underappreciated, as is evidenced by its low priority in national research funding levels.
Increased awareness in the medical community and the general public of the societal burden of thyroid cancer, and substantial increases in research on thyroid cancer etiology, prevention, and treatment are needed to offset these growing concerns.
Robust and clinically convenient biomarkers for cancer diagnosis, early detection, and prognosis have great potential to improve patient survival and are the key to precision medicine. The advent of ...next‐generation sequencing technologies enables a more sensitive and comprehensive profiling of genetic and epigenetic information in tumor‐derived materials. Researchers are now able to monitor the dynamics of tumorigenesis in new dimensions, such as using circulating cell‐free DNA (cfDNA) and tumor DNA (ctDNA). Mutation‐based assays in liquid biopsy cannot always provide consistent results across studies due partly to intra‐ and inter‐tumoral heterogeneity as well as technical limitations. In contrast, epigenetic analysis of patient‐derived cfDNA is a promising alternative, especially for early detection and disease surveillance, because epigenetic modifications are tissue‐specific and reflect the dynamic process of cancer progression. Therefore, cfDNA‐based epigenetic assays are emerging to be a highly sensitive, minimally invasive tool for cancer diagnosis and prognosis with great potential in future precise care of cancer patients. The major obstacle for applying epigenetic analysis of cfDNA, however, has been the lack of enabling techniques with high sensitivity and technical robustness. In this review, we summarized the advances in epigenome‐wide profiling of 5‐hydroxymethylcytosine (5hmC) in cfDNA, focusing on the detection approaches and potential role as biomarkers in different cancer types.
After publication of the updated World Health Organization (WHO) classification of tumors of hematopoietic and lymphoid tissues in 2008, the Pathology Working Group of the International Lymphoma ...Epidemiology Consortium (InterLymph) now presents an update of the hierarchical classification of lymphoid neoplasms for epidemiologic research based on the 2001 WHO classification, which we published in 2007. The updated hierarchical classification incorporates all of the major and provisional entities in the 2008 WHO classification, including newly defined entities based on age, site, certain infections, and molecular characteristics, as well as borderline categories, early and “in situ” lesions, disorders with limited capacity for clinical progression, lesions without current International Classification of Diseases for Oncology, 3rd Edition codes, and immunodeficiency-associated lymphoproliferative disorders. WHO subtypes are defined in hierarchical groupings, with newly defined groups for small B-cell lymphomas with plasmacytic differentiation and for primary cutaneous T-cell lymphomas. We suggest approaches for applying the hierarchical classification in various epidemiologic settings, including strategies for dealing with multiple coexisting lymphoma subtypes in one patient, and cases with incomplete pathologic information. The pathology materials useful for state-of-the-art epidemiology studies are also discussed. We encourage epidemiologists to adopt the updated InterLymph hierarchical classification, which incorporates the most recent WHO entities while demonstrating their relationship to older classifications.
Multiple myeloma (MM) and its precursors monoclonal gammopathy of undetermined significance (MGUS) and smoldering myeloma (SMM) are 2-3 times more common in African Americans (AA) than European ...Americans (EA). Although epigenetic changes are well recognized in the context of myeloma cell biology, the contribution of 5-hydroxymethylcytosines (5hmC) to racial disparities in MM is unknown. Using the 5hmC-Seal and next-generation sequencing, we profiled genome-wide 5hmC in circulating cell-free DNA (cfDNA) from 342 newly diagnosed patients with MM (n = 294), SMM (n = 18), and MGUS (n = 30). We compared differential 5hmC modifications between MM and its precursors among 227 EA and 115 AA patients. The captured 5hmC modifications in cfDNA were found to be enriched in B-cell and T-cell-derived histone modifications marking enhancers. Of the top 500 gene bodies with differential 5hmC levels between MM and SMM/MGUS, the majority (94.8%) were distinct between EA and AA and enriched with population-specific pathways, including amino acid metabolism in AA and mainly cancer-related signaling pathways in EA. These findings improved our understanding of the epigenetic contribution to racial disparities in MM and suggest epigenetic pathways that could be exploited as novel preventive strategies in high-risk populations. Keywords: Multiple myeloma, 5-hydroxymethylcytosine, Racial disparity, Epigenetic modification
Abstract Methylation-based liquid biopsies show promises in detecting cancer using circulating cell-free DNA; however, current limitations impede clinical application. Most assays necessitate ...substantial DNA inputs, posing challenges. Additionally, underrepresented tumor DNA fragments may go undetected during exponential amplification steps of traditional sequencing methods. Here, we report linear amplification-based bisulfite sequencing (LABS), enabling linear amplification of bisulfite-treated DNA fragments in a genome-wide, unbiased fashion, detecting cancer abnormalities with sub-nanogram inputs. Applying LABS to 100 patient samples revealed cancer-specific patterns, copy number alterations, and enhanced cancer detection accuracy by identifying tissue-of-origin and immune cell composition.
Several commonly used immune‐suppressing biologic drugs target proteins and cytokines involved in myeloma pathogenesis. Our objective was to determine whether targeted biologic disease‐modifying ...antirheumatic drugs (DMARDs) are associated with risk of multiple myeloma (MM). We conducted a nested case–control study within a retrospective cohort of 56,886 commercially insured adults undergoing treatment for rheumatoid arthritis, psoriatic arthritis or ankylosing spondylitis between 2009 and 2015 using the Truven Health MarketScan Databases. MM cases (n = 287) were matched to up to 10 controls (n = 2,760) on age, sex and rheumatologic indication using incidence density sampling without replacement. Our exposures of interest were biologic DMARDs targeting tumor necrosis factor‐alpha, interleukin 6, cytotoxic t‐lymphocyte‐associated protein‐4 and depletion of B cells. Relative risks were estimated as adjusted odds ratios (OR) and 95% confidence intervals (CI) using conditional logistic regression models. Cases and controls were similar with respect to use of prescription NSAIDs and concurrent conventional‐synthetic DMARDs. Cases had slightly fewer etanercept users (4% vs. 7%) and slightly more tocilizumab users (1.4% vs. 0.4%). Compared to patients treated with only conventional‐synthetic DMARDs, those receiving concomitant conventional‐synthetic plus biologic DMARDs had lower risk of developing MM (OR = 0.48; 95% CI 0.30–0.88; p = 0.02). Risks differed by drug target with an inverse association observed with use of etanercept inhibiting tumor necrosis factor‐alpha (OR = 0.55; 95% CI 0.30–1.02; p = 0.06) and a positive association with tocilizumab inhibiting interleukin‐6 (OR = 4.33; 95% CI 1.33–14.19; p = 0.02) compared to biologic DMARD‐naïve patients. Further investigation is warranted to understand the roles of drugs suppressing tumor necrosis factor‐alpha and interleukin‐6 in myeloma pathogenesis.
What's new?
Biologic disease‐modifying antirheumatic drugs (DMARDs) reduce inflammation and slow the progression of rheumatoid arthritis and other autoimmune conditions. In exerting these effects, DMARDs target proteins that are associated with the pathogenesis of multiple myeloma (MM). This retrospective cohort study shows that, compared to conventional synthetic DMARDs only, concomitant use of synthetic and biologic DMARDs is inversely associated with MM risk. However, observed associations differed by drug targets. Namely, the biologic DMARD etanercept, which inhibits tumor necrosis factor‐alpha, was inversely associated with MM, while tocilizumab, which blocks interleukin‐6, was positively associated with MM. Possible roles for these targets in MM therapy warrants further investigation.
Purpose
Frailty is assessed when making treatment decisions among older women with breast cancer (BC), which in turn impacts survival. We evaluated associations between pre-diagnosis frailty and ...risks of BC-specific and all-cause mortality in older women.
Methods
We conducted a retrospective cohort study of Medicare beneficiaries ages ≥ 65 years with stage I–III BC using the Surveillance, Epidemiology and End Results-Medicare Health Outcome Survey Data Resource. Frailty was measured using the deficit-accumulation frailty index, categorized as robust, pre-frail, or frail, at baseline and during follow-up. Fine and Gray competing risk and Cox proportional hazards models were used to estimate subdistribution hazard ratios (SHR) and hazard ratios (HR) with 95% confidence intervals (CI) for BC-specific and all-cause mortality, respectively.
Results
Among 2411 women with a median age of 75 years at BC diagnosis, 49.5% were categorized as robust, 29.4% were pre-frail and 21.1% were frail. Fewer frail women compared to robust women received breast-conserving surgery (52.8% vs. 61.5%, frail vs. robust, respectively) and radiation (43.5% vs. 51.8%). In multivariable analyses, degree of frailty was not associated with BC-specific mortality (frail vs robust SHR 1.47, 95% CI 0.97–2.24). However, frail women with BC had higher risks of all-cause mortality compared to robust women with BC (HR 2.32, 95% CI 1.84–2.92).
Conclusion
Among a cohort of older women with BC, higher degrees of frailty were associated with higher risk of all-cause mortality, but not BC-specific mortality. Future study should examine if preventing progression of frailty may improve all-cause mortality.
Extranodal natural killer/T-cell lymphoma (NKTCL) is an aggressive malignancy that has been etiologically linked to Epstein-Barr virus (EBV) infection, with EBV gene transcripts identified in almost ...all cases. However, the humoral immune response to EBV in NKTCL patients has not been well characterized. We examined the antibody response to EBV in plasma samples from 51 NKTCL cases and 154 controls from Hong Kong and Taiwan who were part of the multi-center, hospital-based AsiaLymph case-control study. The EBV-directed serological response was characterized using a protein microarray that measured IgG and IgA antibodies against 202 protein sequences representing the entire EBV proteome. We analyzed 157 IgG antibodies and 127 IgA antibodies that fulfilled quality control requirements. Associations between EBV serology and NKTCL status were disproportionately observed for IgG rather than IgA antibodies. Nine anti-EBV IgG responses were significantly elevated in NKTCL cases compared with controls and had ORs
> 6.0 (Bonferroni-corrected P-values < 0.05). Among these nine elevated IgG responses in NKTCL patients, three IgG antibodies (all targeting EBNA3A) are novel and have not been observed for other EBV-associated tumors of B-cell or epithelial origin. IgG antibodies against EBNA1, which have consistently been elevated in other EBV-associated tumors, were not elevated in NKTCL cases. We characterize the antibody response against EBV for patients with NKTCL and identify IgG antibody responses against six distinct EBV proteins. Our findings suggest distinct serologic patterns of this NK/T-cell lymphoma compared with other EBV-associated tumors of B-cell or epithelial origin.
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