|
1
|
Liu J, Kharazmi E, Liang Q, Chen Y, Sundquist J, Sundquist K, Fallah M. Maternal weight during pregnancy and risk of childhood acute lymphoblastic leukemia in offspring. Leukemia 2025; 39:590-598. [PMID: 39865137 PMCID: PMC11879861 DOI: 10.1038/s41375-025-02517-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2024] [Revised: 01/08/2025] [Accepted: 01/15/2025] [Indexed: 01/28/2025]
Abstract
In addition to biological factors, maternal exposures during pregnancy can contribute to leukemogenesis in offspring. We conducted a population-based cohort study in Sweden to investigate the association between risk of acute lymphoblastic leukemia (ALL) in offspring and maternal anthropometrics during pregnancy. A total of 2,961,435 live-born singletons during 1983-2018 were followed from birth to ALL diagnosis, end of age 18, or end of 2018. 1388 children were diagnosed with ALL (55.6% boys). We observed an increased risk of ALL among daughters of overweight/obese mothers in early pregnancy [Body mass index (BMI) ≥ 25 kg/m2; Standardized incidence ratio (SIR) = 1.4, 95% CI: 1.2-1.6] compared with the risk in daughters of mothers with normal BMI. This association was not found in their sons (SIR = 1.0, 95% CI: 0.9-1.1). Similar results were found for the association between ALL and maternal BMI before delivery. We did not find an association between low or high gestational weight gain (GWG) and risk of ALL (both SIRs = 1.0) in male/female offspring. These suggest that maternal overweight/obesity are important risk factors for childhood ALL in daughters, whereas GWG is not associated with risk of ALL. Further research on this mother-daughter association may shed light on a possible sex hormone/chromosome-related etiology of ALL.
Collapse
Affiliation(s)
- Jiaye Liu
- Risk Adapted Prevention Group, Division of Primary Cancer Prevention, German Cancer Research Center (DKFZ), Heidelberg, Germany
- Medical Faculty Heidelberg, Heidelberg University, Heidelberg, Germany
| | - Elham Kharazmi
- Risk Adapted Prevention Group, Division of Primary Cancer Prevention, German Cancer Research Center (DKFZ), Heidelberg, Germany
- Center for Primary Health Care Research, Department of Clinical Sciences, Lund University, Malmö, Sweden
| | - Qunfeng Liang
- Risk Adapted Prevention Group, Division of Primary Cancer Prevention, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Yafei Chen
- Risk Adapted Prevention Group, Division of Primary Cancer Prevention, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Jan Sundquist
- Center for Primary Health Care Research, Department of Clinical Sciences, Lund University, Malmö, Sweden
- University Clinic Primary Care Skåne, Region Skåne, Sweden
| | - Kristina Sundquist
- Center for Primary Health Care Research, Department of Clinical Sciences, Lund University, Malmö, Sweden
- University Clinic Primary Care Skåne, Region Skåne, Sweden
| | - Mahdi Fallah
- Risk Adapted Prevention Group, Division of Primary Cancer Prevention, German Cancer Research Center (DKFZ), Heidelberg, Germany.
- Center for Primary Health Care Research, Department of Clinical Sciences, Lund University, Malmö, Sweden.
- Institute of Primary Health Care (BIHAM), University of Bern, Bern, Switzerland.
| |
Collapse
|
|
2
|
Hindes MT, McElligott AM, Best OG, Ward MP, Selemidis S, Miles MA, Nturubika BD, Gregory PA, Anderson PH, Logan JM, Butler LM, Waugh DJ, O'Leary JJ, Hickey SM, Thurgood LA, Brooks DA. Metabolic reprogramming, malignant transformation and metastasis: Lessons from chronic lymphocytic leukaemia and prostate cancer. Cancer Lett 2025; 611:217441. [PMID: 39755364 DOI: 10.1016/j.canlet.2025.217441] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2024] [Revised: 12/22/2024] [Accepted: 01/01/2025] [Indexed: 01/06/2025]
Abstract
Metabolic reprogramming is a hallmark of cancer, crucial for malignant transformation and metastasis. Chronic lymphocytic leukaemia (CLL) and prostate cancer exhibit similar metabolic adaptations, particularly in glucose and lipid metabolism. Understanding this metabolic plasticity is crucial for identifying mechanisms contributing to metastasis. This review considers glucose and lipid metabolism in CLL and prostate cancer, exploring their roles in healthy and malignant states and during disease progression. In CLL, lipid metabolism supports cell survival and migration, with aggressive disease characterised by increased fatty acid oxidation and altered sphingolipids. Richter's transformation and aggressive lymphoma, however, exhibit a metabolic shift towards increased glycolysis. Similarly, prostate cell metabolism is unique, relying on citrate production in the healthy state and undergoing metabolic reprogramming during malignant transformation. Early-stage prostate cancer cells increase lipid synthesis and uptake, and decrease glycolysis, whereas metastatic cells re-adopt glucose metabolism, likely driven by interactions with the tumour microenvironment. Genetic drivers including TP53 and ATM mutations connect metabolic alterations to disease severity in these two malignancies. The bone microenvironment supports the metabolic demands of these malignancies, serving as an initiation niche for CLL and a homing site for prostate cancer metastases. By comparing these malignancies, this review underscores the importance of metabolic plasticity in cancer progression and highlights how CLL and prostate cancer may be models of circulating and solid tumours more broadly. The metabolic phenotypes throughout cancer cell transformation and metastasis, and the microenvironment in which these processes occur, present opportunities for interventions that could disrupt metastatic processes and improve patient outcomes.
Collapse
Affiliation(s)
- Madison T Hindes
- Clinical and Health Sciences, University of South Australia, Adelaide, Australia.
| | - Anthony M McElligott
- Discipline of Haematology, School of Medicine, Trinity Translational Medicine Institute, St. James's Hospital and Trinity College, Dublin, Ireland
| | - Oliver G Best
- Molecular Medicine and Genetics, College of Medicine and Public Health, Flinders University, Bedford Park, Adelaide, Australia
| | - Mark P Ward
- Department of Histopathology, Trinity College Dublin, St. James's Hospital, Dublin, Ireland
| | - Stavros Selemidis
- Centre for Respiratory Science and Health, School of Health and Biomedical Sciences, Royal Melbourne Institute of Technology University, Bundoora, Victoria, Australia
| | - Mark A Miles
- Centre for Respiratory Science and Health, School of Health and Biomedical Sciences, Royal Melbourne Institute of Technology University, Bundoora, Victoria, Australia
| | - Bukuru D Nturubika
- Clinical and Health Sciences, University of South Australia, Adelaide, Australia
| | - Philip A Gregory
- Centre for Cancer Biology, University of South Australia, Adelaide, Australia
| | - Paul H Anderson
- Clinical and Health Sciences, University of South Australia, Adelaide, Australia
| | - Jessica M Logan
- Clinical and Health Sciences, University of South Australia, Adelaide, Australia
| | - Lisa M Butler
- South Australian ImmunoGENomics Cancer Institute and Freemasons Centre for Male Health and Wellbeing, University of Adelaide, Adelaide, Australia; Solid Tumour Program, Precision Cancer Medicine theme, South Australian Health and Medical Research Institute, Adelaide, Australia
| | - David J Waugh
- Centre for Cancer Biology, University of South Australia, Adelaide, Australia
| | - John J O'Leary
- Department of Histopathology, Trinity College Dublin, St. James's Hospital, Dublin, Ireland
| | - Shane M Hickey
- Clinical and Health Sciences, University of South Australia, Adelaide, Australia
| | - Lauren A Thurgood
- Molecular Medicine and Genetics, College of Medicine and Public Health, Flinders University, Bedford Park, Adelaide, Australia
| | - Douglas A Brooks
- Clinical and Health Sciences, University of South Australia, Adelaide, Australia; Department of Histopathology, Trinity College Dublin, St. James's Hospital, Dublin, Ireland.
| |
Collapse
|
|
3
|
Varshney S, Kumar D, Choudhary R, Gupta A, Beg M, Shankar K, Rajan S, Srivastava A, Gupta S, Khandelwal N, Balaramnavar VM, Gaikwad AN. Flavopiridol inhibits adipogenesis and improves metabolic homeostasis by ameliorating adipose tissue inflammation in a diet-induced obesity model. Biomed Pharmacother 2024; 179:117330. [PMID: 39208666 DOI: 10.1016/j.biopha.2024.117330] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2024] [Revised: 08/14/2024] [Accepted: 08/21/2024] [Indexed: 09/04/2024] Open
Abstract
Repositioning of FDA approved/clinical phase drugs has recently opened a new opportunity for rapid approval of drugs, as it shortens the overall process of drug discovery and development. In previous studies, we predicted the possibility of better activity profiles of flavopiridol, the FDA approved orphan drug with better fit value 2.79 using a common feature pharmacophore model for anti-adipogenic compounds (CFMPA). The present study aimed to investigate the effect of flavopiridol on adipocyte differentiation and to determine the underlying mechanism. Flavopiridol inhibited adipocyte differentiation in different cell models like 3T3-L1, C3H10T1/2, and hMSCs at 150 nM. Flavopiridol was around 135 times more potent than its parent molecule rohitukine. The effect was mediated through down-regulation of key transcription factors of adipogenesis i.e. Peroxisome proliferator-activated receptor gamma (PPARγ), CCAAT/enhancer-binding protein alpha (C/EBPα), and their downstream targets, including adipocyte protein -2 (aP2) and fatty acid synthase (FAS). Further, results revealed that flavopiridol arrested the cell cycle in G1/S phase during mitotic clonal expansion by suppressing cell cycle regulatory proteins i.e. Cyclins and CDKs. Flavopiridol inhibited insulin-stimulated signalling in the early phase of adipocyte differentiation by downregulation of AKT/mTOR pathway. In addition, flavopiridol improved mitochondrial function in terms of increased oxygen consumption rate (OCR) in mature adipocytes. In the mouse model of diet-induced obesity, flavopiridol attenuated obesity-associated adipose tissue inflammation and improved serum lipid profile, glucose tolerance as well as insulin sensitivity. In conclusion, the FDA approved drug flavopiridol could be placed as a potential drug candidate for the treatment of cancer and obesity comorbid patients.
Collapse
Affiliation(s)
- Salil Varshney
- Division of Pharmacology, CSIR-Central Drug Research Institute, Lucknow 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Durgesh Kumar
- Division of Pharmacology, CSIR-Central Drug Research Institute, Lucknow 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Rakhi Choudhary
- Global Institute of Pharmaceutical Education and Research, Jaspur Road, Kashipur, Uttarakhand 244713, India
| | - Abhishek Gupta
- Division of Pharmacology, CSIR-Central Drug Research Institute, Lucknow 226031, India
| | - Muheeb Beg
- Division of Pharmacology, CSIR-Central Drug Research Institute, Lucknow 226031, India
| | - Kripa Shankar
- Division of Pharmacology, CSIR-Central Drug Research Institute, Lucknow 226031, India
| | - Sujith Rajan
- Division of Pharmacology, CSIR-Central Drug Research Institute, Lucknow 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Ankita Srivastava
- Division of Pharmacology, CSIR-Central Drug Research Institute, Lucknow 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Sanchita Gupta
- Division of Pharmacology, CSIR-Central Drug Research Institute, Lucknow 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Nilesh Khandelwal
- Division of Pharmacology, CSIR-Central Drug Research Institute, Lucknow 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Vishal M Balaramnavar
- Global Institute of Pharmaceutical Education and Research, Jaspur Road, Kashipur, Uttarakhand 244713, India; School of Pharmacy & Research Center, Sanskriti University, 281401 Mathura, UP, India
| | - Anil N Gaikwad
- Division of Pharmacology, CSIR-Central Drug Research Institute, Lucknow 226031, India.
| |
Collapse
|
|
4
|
Sun M, da Silva M, Bjørge T, Fritz J, Mboya IB, Jerkeman M, Stattin P, Wahlström J, Michaëlsson K, van Guelpen B, Magnusson PKE, Sandin S, Yin W, Lagerros YT, Ye W, Nwaru B, Kankaanranta H, Lönnberg L, Chabok A, Isaksson K, Pedersen NL, Elmståhl S, Lind L, Hedman L, Häggström C, Stocks T. Body mass index and risk of over 100 cancer forms and subtypes in 4.1 million individuals in Sweden: the Obesity and Disease Development Sweden (ODDS) pooled cohort study. THE LANCET REGIONAL HEALTH. EUROPE 2024; 45:101034. [PMID: 39253735 PMCID: PMC11381908 DOI: 10.1016/j.lanepe.2024.101034] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 04/15/2024] [Revised: 07/03/2024] [Accepted: 08/06/2024] [Indexed: 09/11/2024]
Abstract
Background Obesity, assessed by body mass index (BMI), is an established risk factor for 13 cancers. We aimed to identify further potential obesity-related cancers and to quantify their association with BMI relative to that of established obesity-related cancers. Methods Using Cox regression models on 4,142,349 individuals in Sweden (mean age 27.1 years at weight measurement), we calculated hazard ratios (HRs) for the association between BMI and the risk of 122 cancers and cancer subtypes, grouped by topography and morphology. Cancers with a positive association (i.e., HR >1) at an α-level of 0.05 for obesity (BMI ≥30 kg/m2) vs. normal weight (BMI 18.5-24.9 kg/m2) or per 5 kg/m2 higher BMI, for which obesity is not an established risk factor, were considered potentially obesity related. Findings After 100.2 million person-years of follow-up, 332,501 incident cancer cases were recorded. We identified 15 cancers in men and 16 in women as potentially obesity related. These were cancers of the head and neck, gastrointestinal tract, malignant melanoma, genital organs, endocrine organs, connective tissue, and haematological malignancies. Among these, there was evidence of differential associations with BMI between subtypes of gastric cancer, small intestine cancer, cervical cancer, and lymphoid neoplasms (P values for heterogeneity in HRs <0.05). The HR (95% confidence interval) per 5 kg/m2 higher BMI was 1.17 (1.15-1.20) in men and 1.13 (1.11-1.15) in women for potential obesity-related cancers (51,690 cases), and 1.24 (1.22-1.26) in men and 1.12 (1.11-1.13) in women for established obesity-related cancers (84,384 cases). Interpretation This study suggests a large number of potential obesity-related cancers could be added to already established ones. Importantly, the magnitudes of the associations were largely comparable to those of the already established obesity-related cancers. We also provide evidence of specific cancer subtypes driving some associations with BMI. Studies accounting for cancer-specific confounders are needed to confirm these findings. Funding Swedish Research Council, Swedish Cancer Society, Mrs. Berta Kamprad's Cancer Foundation, Crafoord Foundation, Cancer Research Foundation at the Department of Oncology, Malmö University Hospital, and China Scholarship Council.
Collapse
Affiliation(s)
- Ming Sun
- Department of Translational Medicine, Lund University, Malmö, Sweden
| | - Marisa da Silva
- Department of Translational Medicine, Lund University, Malmö, Sweden
| | - Tone Bjørge
- Department of Global Public Health and Primary Care, University of Bergen, Bergen, Norway
- Cancer Registry of Norway, Norwegian Institute of Public Health, Oslo, Norway
| | - Josef Fritz
- Department of Translational Medicine, Lund University, Malmö, Sweden
- Institute of Medical Statistics and Informatics, Medical University of Innsbruck, Innsbruck, Austria
| | - Innocent B Mboya
- Department of Translational Medicine, Lund University, Malmö, Sweden
| | | | - Pär Stattin
- Department of Surgical Sciences, Uppsala University, Uppsala, Sweden
| | - Jens Wahlström
- Section of Sustainable Health, Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden
| | - Karl Michaëlsson
- Medical Epidemiology, Department of Surgical Sciences, Uppsala University, Uppsala, Sweden
| | - Bethany van Guelpen
- Department of Diagnostics and Intervention, Oncology, Umeå University, Umeå, Sweden
- Wallenberg Centre for Molecular Medicine, Umeå University, Umeå, Sweden
| | - Patrik K E Magnusson
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
| | - Sven Sandin
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, USA
| | - Weiyao Yin
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
| | - Ylva Trolle Lagerros
- Division of Clinical Epidemiology, Department of Medicine, Solna, Karolinska Institutet, Stockholm, Sweden
- Center for Obesity, Academic Specialist Center, Stockholm Health Services, Stockholm, Sweden
| | - Weimin Ye
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
| | - Bright Nwaru
- Krefting Research Centre, Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- Wallenberg Centre for Molecular and Translational Medicine, University of Gothenburg, Gothenburg, Sweden
| | - Hannu Kankaanranta
- Krefting Research Centre, Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- Department of Respiratory Medicine, Seinäjoki Central Hospital, Seinäjoki, Finland
- Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
| | - Lena Lönnberg
- Center for Clinical Research, Region Västmanland, Uppsala University, Västerås, Sweden
| | - Abbas Chabok
- Center for Clinical Research, Region Västmanland, Uppsala University, Västerås, Sweden
| | - Karolin Isaksson
- Department of Clinical Sciences Lund, Lund University, Lund, Sweden
- Department of Surgery, Kristianstad Hospital, Kristianstad, Sweden
| | - Nancy L Pedersen
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
| | - Sölve Elmståhl
- Department of Clinical Sciences Malmö, Lund University, Malmö, Sweden
| | - Lars Lind
- Department of Medical Sciences, Uppsala University, Uppsala, Sweden
| | - Linnea Hedman
- Section of Sustainable Health, Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden
| | - Christel Häggström
- Northern Registry Centre, Department of Diagnostics and Intervention, Umeå University, Umeå, Sweden
| | - Tanja Stocks
- Department of Translational Medicine, Lund University, Malmö, Sweden
| |
Collapse
|
|
5
|
Vainer N, Rotbain Curovic V, Niemann CU, Slager SL, Rotbain EC. Understanding the interplay between chronic lymphocytic leukemia and type 2 diabetes. Expert Rev Hematol 2024; 17:617-629. [PMID: 39041465 DOI: 10.1080/17474086.2024.2383417] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2024] [Accepted: 07/18/2024] [Indexed: 07/24/2024]
Abstract
INTRODUCTION Comorbidities play an important role in the management of chronic lymphocytic leukemia (CLL) and may influence survival and treatment outcomes. Considering the aging general population and increasing incidence of type 2 diabetes (T2D), a comprehensive understanding of the interplay between CLL and T2D is essential for optimizing care and outcomes. AREAS COVERED We present current knowledge on co-existing CLL and T2D including prevalence, shared etiology and risk factors and how the conditions and treatment hereof may influence the outcome of one another. A literature search was performed using PubMed with the cutoff date on 1 February 2024. EXPERT OPINION The increased mortality observed in persons with CLL who have co-existing T2D is partially ascribed to infections, prompting physicians managing individuals with both conditions to consider closer monitoring during instances of infection and individualized prophylaxis. People with CLL and T2D should be managed for CLL in accordance with the international working group on CLL criteria, and we recommend that physicians exercise particular care not to delay treatment for these individuals. Multidisciplinary approaches with involvement of several specialties may be required for optimal supportive care of co-occurring T2D and CLL.
Collapse
Affiliation(s)
- Noomi Vainer
- Department of Hematology, Rigshospitalet, Copenhagen, Denmark
- Hematology Group, Danish Cancer Institute, Copenhagen, Denmark
- Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
| | | | - Carsten Utoft Niemann
- Department of Hematology, Rigshospitalet, Copenhagen, Denmark
- Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
| | - Susan L Slager
- Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN, USA
- Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, MN, USA
| | - Emelie Curovic Rotbain
- Department of Hematology, Rigshospitalet, Copenhagen, Denmark
- Hematology Group, Danish Cancer Institute, Copenhagen, Denmark
| |
Collapse
|
|
6
|
Abstract
PURPOSE OF REVIEW This review meticulously delves into existing literature and recent findings to elucidate the intricate link between obesity and clonal hematopoiesis of indeterminate potential (CHIP) associated clonal hematopoiesis. It aims to enhance our comprehension of this multifaceted association, offering insights into potential avenues for future research and therapeutic interventions. RECENT FINDINGS Recent insights reveal that mutations in CHIP-associated genes are not limited to symptomatic patients but are also present in asymptomatic individuals. This section focuses on the impact of obesity-induced inflammation and fatty bone marrow (FBM) on the development of CHIP-associated diseases. Common comorbidities such as obesity, diabetes, and infection, fostering pro-inflammatory environments, play a pivotal role in the acceleration of these pathologies. Our research underscores a notable association between CHIP and an increased waist-to-hip ratio (WHR), emphasizing the link between obesity and myeloid leukemia. Recent studies highlight a strong correlation between obesity and myeloid leukemias in both children and adults, with increased risks and poorer survival outcomes in overweight individuals. SUMMARY We discuss recent insights into how CHIP-associated pathologies respond to obesity-induced inflammation, offering implications for future studies in the intricate field of clonal hematopoiesis.
Collapse
Affiliation(s)
| | - Reuben Kapur
- Herman B Wells Center for Pediatric Research, Department of Pediatrics, Indianapolis, Indiana, USA
- Department of Microbiology & Immunology, Indiana University School of Medicine, Indianapolis, Indiana, USA
| |
Collapse
|
|
7
|
Vom Stein AF, Hallek M, Nguyen PH. Role of the tumor microenvironment in CLL pathogenesis. Semin Hematol 2024; 61:142-154. [PMID: 38220499 DOI: 10.1053/j.seminhematol.2023.12.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2023] [Revised: 12/02/2023] [Accepted: 12/23/2023] [Indexed: 01/16/2024]
Abstract
Chronic lymphocytic leukemia (CLL) cells extensively interact with and depend on their surrounding tumor microenvironment (TME). The TME encompasses a heterogeneous array of cell types, soluble signals, and extracellular vesicles, which contribute significantly to CLL pathogenesis. CLL cells and the TME cooperatively generate a chronic inflammatory milieu, which reciprocally reprograms the TME and activates a signaling network within CLL cells, promoting their survival and proliferation. Additionally, the inflammatory milieu exerts chemotactic effects, attracting CLL cells and other immune cells to the lymphoid tissues. The intricate CLL-TME interactions also facilitate immune evasion and compromise leukemic cell surveillance. We also review recent advances that have shed light on additional aspects that are substantially influenced by the CLL-TME interplay.
Collapse
Affiliation(s)
- Alexander F Vom Stein
- University of Cologne, Faculty of Medicine and University Hospital Cologne, Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf; Center for Molecular Medicine Cologne; CECAD Center of Excellence on Cellular Stress Responses in Aging-Associated Diseases, Cologne, Germany
| | - Michael Hallek
- University of Cologne, Faculty of Medicine and University Hospital Cologne, Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf; Center for Molecular Medicine Cologne; CECAD Center of Excellence on Cellular Stress Responses in Aging-Associated Diseases, Cologne, Germany
| | - Phuong-Hien Nguyen
- University of Cologne, Faculty of Medicine and University Hospital Cologne, Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf; Center for Molecular Medicine Cologne; CECAD Center of Excellence on Cellular Stress Responses in Aging-Associated Diseases, Cologne, Germany.
| |
Collapse
|
|
8
|
Alshaalan KS, Albawardi TK, Zhra M, Bin Sulaiman N, Jnied OY, Saleem RA, Aljada A. Differential Expression of LMNA/C and Insulin Receptor Transcript Variants in Peripheral Blood Mononuclear Cells of Leukemia Patients. J Clin Med 2024; 13:2568. [PMID: 38731097 PMCID: PMC11084221 DOI: 10.3390/jcm13092568] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2024] [Revised: 04/16/2024] [Accepted: 04/21/2024] [Indexed: 05/13/2024] Open
Abstract
Background: Recent research has identified alternative transcript variants of LMNA/C (LMNA, LMNC, LMNAΔ10, and LMNAΔ50) and insulin receptors (INSRs) as potential biomarkers for various types of cancer. The objective of this study was to assess the expression of LMNA/C and INSR transcript variants in peripheral blood mononuclear cells (PBMCs) of leukemia patients to investigate their potential as diagnostic biomarkers. Methods: Quantitative TaqMan reverse transcriptase polymerase chain reaction (RT-qPCR) was utilized to quantify the mRNA levels of LMNA/C (LMNA, LMNC, LMNAΔ10, and LMNAΔ50) as well as INSR (IR-A and IR-B) variants in PBMCs obtained from healthy individuals (n = 32) and patients diagnosed with primary leukemias (acute myeloid leukemia (AML): n = 17; acute lymphoblastic leukemia (ALL): n = 8; chronic myeloid leukemia (CML): n = 5; and chronic lymphocytic leukemia (CLL): n = 15). Results: Only LMNA and LMNC transcripts were notably present in PBMCs. Both exhibited significantly decreased expression levels in leukemia patients compared to the healthy control group. Particularly, the LMNC:LMNA ratio was notably higher in AML patients. Interestingly, IR-B expression was not detectable in any of the PBMC samples, precluding the calculation of the IR-A:IR-B ratio as a diagnostic marker. Despite reduced expression across all types of leukemia, IR-A levels remained detectable, indicating its potential involvement in disease progression. Conclusions: This study highlights the distinct expression patterns of LMNA/C and INSR transcript variants in PBMCs of leukemia patients. The LMNC:LMNA ratio shows promise as a potential diagnostic indicator for AML, while further research is necessary to understand the role of IR-A in leukemia pathogenesis and its potential as a therapeutic target.
Collapse
Affiliation(s)
- Khalid Saud Alshaalan
- College of Medicine, King Saud bin Abdulaziz University for Health Sciences, Riyadh 11481, Saudi Arabia
| | - Turki Khalid Albawardi
- College of Medicine, King Saud bin Abdulaziz University for Health Sciences, Riyadh 11481, Saudi Arabia
| | - Mahmoud Zhra
- Department of Biochemistry and Molecular Medicine, College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia; (M.Z.)
| | - Norah Bin Sulaiman
- Department of Biochemistry and Molecular Medicine, College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia; (M.Z.)
| | - Osama Yaheia Jnied
- Department of Biochemistry and Molecular Medicine, College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia; (M.Z.)
| | - Rimah Abdullah Saleem
- Department of Biochemistry and Molecular Medicine, College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia; (M.Z.)
| | - Ahmad Aljada
- Department of Biochemistry and Molecular Medicine, College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia; (M.Z.)
| |
Collapse
|
|
9
|
Marinelli Busilacchi E, Morsia E, Poloni A. Bone Marrow Adipose Tissue. Cells 2024; 13:724. [PMID: 38727260 PMCID: PMC11083575 DOI: 10.3390/cells13090724] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2024] [Revised: 04/19/2024] [Accepted: 04/19/2024] [Indexed: 05/13/2024] Open
Abstract
Bone marrow (BM) acts as a dynamic organ within the bone cavity, responsible for hematopoiesis, skeletal remodeling, and immune system control. Bone marrow adipose tissue (BMAT) was long simply considered a filler of space, but now it is known that it instead constitutes an essential element of the BM microenvironment that participates in homeostasis, influences bone health and bone remodeling, alters hematopoietic stem cell functions, contributes to the commitment of mesenchymal stem cells, provides effects to immune homeostasis and defense against infections, and participates in energy metabolism and inflammation. BMAT has emerged as a significant contributor to the development and progression of various diseases, shedding light on its complex relationship with health. Notably, BMAT has been implicated in metabolic disorders, hematological malignancies, and skeletal conditions. BMAT has been shown to support the proliferation of tumor cells in acute myeloid leukemia and niche adipocytes have been found to protect cancer cells against chemotherapy, contributing to treatment resistance. Moreover, BMAT's impact on bone density and remodeling can lead to conditions like osteoporosis, where high levels of BMAT are inversely correlated with bone mineral density, increasing the risk of fractures. BMAT has also been associated with diabetes, obesity, and anorexia nervosa, with varying effects on individuals depending on their weight and health status. Understanding the interaction between adipocytes and different diseases may lead to new therapeutic strategies.
Collapse
Affiliation(s)
- Elena Marinelli Busilacchi
- Hematology Laboratory, Department of Clinical and Molecular Sciences, DISCLIMO, Università Politecnica delle Marche, 60126 Ancona, Italy; (E.M.B.); (E.M.)
| | - Erika Morsia
- Hematology Laboratory, Department of Clinical and Molecular Sciences, DISCLIMO, Università Politecnica delle Marche, 60126 Ancona, Italy; (E.M.B.); (E.M.)
- Hematology, AOU delle Marche, 60126 Ancona, Italy
| | - Antonella Poloni
- Hematology Laboratory, Department of Clinical and Molecular Sciences, DISCLIMO, Università Politecnica delle Marche, 60126 Ancona, Italy; (E.M.B.); (E.M.)
- Hematology, AOU delle Marche, 60126 Ancona, Italy
| |
Collapse
|
|
10
|
Tsilingiris D, Vallianou NG, Spyrou N, Kounatidis D, Christodoulatos GS, Karampela I, Dalamaga M. Obesity and Leukemia: Biological Mechanisms, Perspectives, and Challenges. Curr Obes Rep 2024; 13:1-34. [PMID: 38159164 PMCID: PMC10933194 DOI: 10.1007/s13679-023-00542-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 11/06/2023] [Indexed: 01/03/2024]
Abstract
PURPOSE OF REVIEW To examine the epidemiological data on obesity and leukemia; evaluate the effect of obesity on leukemia outcomes in childhood acute lymphoblastic leukemia (ALL) survivors; assess the potential mechanisms through which obesity may increase the risk of leukemia; and provide the effects of obesity management on leukemia. Preventive (diet, physical exercise, obesity pharmacotherapy, bariatric surgery) measures, repurposing drugs, candidate therapeutic agents targeting oncogenic pathways of obesity and insulin resistance in leukemia as well as challenges of the COVID-19 pandemic are also discussed. RECENT FINDINGS Obesity has been implicated in the development of 13 cancers, such as breast, endometrial, colon, renal, esophageal cancers, and multiple myeloma. Leukemia is estimated to account for approximately 2.5% and 3.1% of all new cancer incidence and mortality, respectively, while it represents the most frequent cancer in children younger than 5 years. Current evidence indicates that obesity may have an impact on the risk of leukemia. Increased birthweight may be associated with the development of childhood leukemia. Obesity is also associated with worse outcomes and increased mortality in leukemic patients. However, there are several limitations and challenges in meta-analyses and epidemiological studies. In addition, weight gain may occur in a substantial number of childhood ALL survivors while the majority of studies have documented an increased risk of relapse and mortality among patients with childhood ALL and obesity. The main pathophysiological pathways linking obesity to leukemia include bone marrow adipose tissue; hormones such as insulin and the insulin-like growth factor system as well as sex hormones; pro-inflammatory cytokines, such as IL-6 and TNF-α; adipocytokines, such as adiponectin, leptin, resistin, and visfatin; dyslipidemia and lipid signaling; chronic low-grade inflammation and oxidative stress; and other emerging mechanisms. Obesity represents a risk factor for leukemia, being among the only known risk factors that could be prevented or modified through weight loss, healthy diet, and physical exercise. Pharmacological interventions, repurposing drugs used for cardiometabolic comorbidities, and bariatric surgery may be recommended for leukemia and obesity-related cancer prevention.
Collapse
Affiliation(s)
- Dimitrios Tsilingiris
- First Department of Internal Medicine, University Hospital of Alexandroupolis, Democritus University of Thrace, Dragana, 68100, Alexandroupolis, Greece
| | - Natalia G Vallianou
- Department of Internal Medicine, Evangelismos General Hospital, 45-47 Ipsilantou str, 10676, Athens, Greece
| | - Nikolaos Spyrou
- Tisch Cancer Institute Icahn School of Medicine at Mount Sinai, 1190 One Gustave L. Levy Place, New York, NY, 10029, USA
| | - Dimitris Kounatidis
- Department of Internal Medicine, Evangelismos General Hospital, 45-47 Ipsilantou str, 10676, Athens, Greece
| | | | - Irene Karampela
- 2nd Department of Critical Care, Medical School, University of Athens, Attikon General University Hospital, 1 Rimini Str, 12462, Athens, Greece
| | - Maria Dalamaga
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 75 Mikras Asias str, 11527, Athens, Greece.
| |
Collapse
|
|
11
|
Kumar V, Stewart JH. Obesity, bone marrow adiposity, and leukemia: Time to act. Obes Rev 2024; 25:e13674. [PMID: 38092420 DOI: 10.1111/obr.13674] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/21/2022] [Revised: 10/07/2023] [Accepted: 11/13/2023] [Indexed: 02/28/2024]
Abstract
Obesity has taken the face of a pandemic with less direct concern among the general population and scientific community. However, obesity is considered a low-grade systemic inflammation that impacts multiple organs. Chronic inflammation is also associated with different solid and blood cancers. In addition, emerging evidence demonstrates that individuals with obesity are at higher risk of developing blood cancers and have poorer clinical outcomes than individuals in a normal weight range. The bone marrow is critical for hematopoiesis, lymphopoiesis, and myelopoiesis. Therefore, it is vital to understand the mechanisms by which obesity-associated changes in BM adiposity impact leukemia development. BM adipocytes are critical to maintain homeostasis via different means, including immune regulation. However, obesity increases BM adiposity and creates a pro-inflammatory environment to upregulate clonal hematopoiesis and a leukemia-supportive environment. Obesity further alters lymphopoiesis and myelopoiesis via different mechanisms, which dysregulate myeloid and lymphoid immune cell functions mentioned in the text under different sequentially discussed sections. The altered immune cell function during obesity alters hematological malignancies and leukemia susceptibility. Therefore, obesity-induced altered BM adiposity, immune cell generation, and function impact an individual's predisposition and severity of leukemia, which should be considered a critical factor in leukemia patients.
Collapse
Affiliation(s)
- Vijay Kumar
- Department of Surgery, Laboratory of Tumor Immunology and Immunotherapy, Morehouse School of Medicine, Atlanta, Georgia, USA
| | - John H Stewart
- Department of Surgery, Laboratory of Tumor Immunology and Immunotherapy, Morehouse School of Medicine, Atlanta, Georgia, USA
| |
Collapse
|
|
12
|
Allegra A, Murdaca G, Mirabile G, Gangemi S. Protective Effects of High-Density Lipoprotein on Cancer Risk: Focus on Multiple Myeloma. Biomedicines 2024; 12:514. [PMID: 38540127 PMCID: PMC10967848 DOI: 10.3390/biomedicines12030514] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2024] [Revised: 02/21/2024] [Accepted: 02/23/2024] [Indexed: 04/03/2025] Open
Abstract
Lipid metabolism is intrinsically linked to tumorigenesis. And one of the most important characteristics of cancer is the modification of lipid metabolism and its correlation with oncogenic signaling pathways within the tumors. Because lipids function as signaling molecules, membrane structures, and energy sources, lipids are essential to the development of cancer. Above all, the proper immune response of tumor cells depends on the control of lipid metabolism. Changes in metabolism can modify systems that regulate carcinogenesis, such as inflammation, oxidative stress, and angiogenesis. The dependence of various malignancies on lipid metabolism varies. This review delves into the modifications to lipid metabolism that take place in cancer, specifically focusing on multiple myeloma. The review illustrates how changes in different lipid pathways impact the growth, survival, and drug-responsiveness of multiple myeloma cells, in addition to their interactions with other cells within the tumor microenvironment. The phenotype of malignant plasma cells can be affected by lipid vulnerabilities, and these findings offer a new avenue for understanding this process. Additionally, they identify novel druggable pathways that have a major bearing on multiple myeloma care.
Collapse
Affiliation(s)
- Alessandro Allegra
- Hematology Unit, Department of Human Pathology in Adulthood and Childhood “Gaetano Barresi”, University of Messina, Via Consolare Valeria, 98125 Messina, Italy; (A.A.); (G.M.)
| | - Giuseppe Murdaca
- Department of Internal Medicine, University of Genova, Viale Benedetto XV, 16132 Genova, Italy
- Allergology and Clinical Immunology Unit, San Bartolomeo Hospital, 19038 Sarzana, Italy
| | - Giuseppe Mirabile
- Hematology Unit, Department of Human Pathology in Adulthood and Childhood “Gaetano Barresi”, University of Messina, Via Consolare Valeria, 98125 Messina, Italy; (A.A.); (G.M.)
| | - Sebastiano Gangemi
- Allergy and Clinical Immunology Unit, Department of Clinical and Experimental Medicine, University of Messina, Via Consolare Valeria, 98125 Messina, Italy;
| |
Collapse
|
|
13
|
Egnell C, Hallböök H, Heyman M, Wartiovaara-Kautto U, Quist-Paulsen P, Schmiegelow K, Griskevicius L, Palk K, Toft N, Overgaard UM, Harila A, Ranta S. Impact of body mass index on outcome and treatment-related toxicity in young adults with acute lymphoblastic leukemia. Acta Oncol 2023; 62:1723-1731. [PMID: 37725524 DOI: 10.1080/0284186x.2023.2258450] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2023] [Accepted: 09/08/2023] [Indexed: 09/21/2023]
Abstract
BACKGROUND Data on outcome for patients in different body mass index (BMI) categories in young adults with acute lymphoblastic leukemia (ALL) are scarce. We explored survival and toxicities in different BMI categories in young adults with ALL. MATERIAL AND METHODS Patients aged 18-45 years, diagnosed with ALL between July 2008 and June 2022 in the Nordic countries, Estonia, or Lithuania, and treated according to the NOPHO ALL2008 protocol, were retrospectively enrolled and classified into different BMI categories. Endpoints were overall survival (OS), event-free survival (EFS) and cumulative incidence of relapse as well as incidence rate ratio (IRR) of severe predefined toxic events, and treatment delays. RESULTS The group comprised 416 patients, of whom 234 (56%) were stratified to non-high-risk (non-HR) treatment. In the non-HR group, patients with severe obesity, BMI ≥35 kg/m2 had worse EFS due to relapses but there was no effect on toxicity or treatment delays compared with the healthy-weight patients. There was no association between BMI category and OS, overall toxicity, or treatment delays in the patients with high-risk treatment. CONCLUSION Severe obesity is associated with worse EFS in young adults treated according to the non-HR arms of the NOPHO ALL2008 protocol. Poorer outcome is explained with a higher risk of relapse, possibly due to under treatment, and not caused by excess therapy-related mortality.
Collapse
Affiliation(s)
- Christina Egnell
- Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden
- Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm, Sweden
| | - Helene Hallböök
- Department of Medical Sciences, Haematology, Uppsala University, Uppsala, Sweden
| | - Mats Heyman
- Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden
- Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm, Sweden
| | | | - Petter Quist-Paulsen
- Department of Clinical and Molecular Medicine, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway
| | - Kjeld Schmiegelow
- Department of Pediatrics and Adolescent Medicine, University Hospital Rigshospitalet, Copenhagen, Denmark
| | | | - Katrin Palk
- Haematology Centre, North Estonia Medical Centre, Tallinn, Estonia
| | - Nina Toft
- Department of Haematology, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark
| | - Ulrik Malthe Overgaard
- Department of Haematology, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark
| | - Arja Harila
- Department of Women's and Children's Health, Uppsala University, Uppsala, Sweden
| | - Susanna Ranta
- Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden
- Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm, Sweden
| |
Collapse
|
|
14
|
Li Z, Rosen CJ. The Multifaceted Roles of Bone Marrow Adipocytes in Bone and Hematopoietic Homeostasis. J Clin Endocrinol Metab 2023; 108:e1465-e1472. [PMID: 37315208 PMCID: PMC12102716 DOI: 10.1210/clinem/dgad355] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/10/2023] [Revised: 06/07/2023] [Accepted: 06/09/2023] [Indexed: 06/16/2023]
Abstract
Bone marrow adipose tissue (BMAT) makes up a significant portion of the marrow space, ranging from 50% to 70%, in healthy adults. It expands with aging, obesity, anorexia nervosa, and irradiation, which are conditions associated with skeletal complications or hematopoietic disorders. Therefore, BMAT has been viewed as a negative component of the bone marrow niche for decades, although the mechanisms and causative relationships have not been well-addressed. Of note, recent studies have revealed that BMAT is a multifaceted tissue that can serve as an energy reservoir to fuel osteoblasts and hematopoietic cells under stressful situations, and also acts as an endocrine/paracrine organ to suppress bone formation and support hematopoiesis at steady-state conditions. In this review, we summarize the uniqueness of BMAT, the complex findings of previous studies, and update our understanding of the physiological roles of BMAT in bone and hematopoietic metabolism based on a newly established bone marrow adipocyte-specific mouse model.
Collapse
Affiliation(s)
- Ziru Li
- Center for Molecular Medicine, MaineHealth Institute for Research, Scarborough, ME 04074, USA
| | - Clifford J Rosen
- Center for Molecular Medicine, MaineHealth Institute for Research, Scarborough, ME 04074, USA
| |
Collapse
|
|
15
|
Foran JM, Sun Z, Lai C, Fernandez HF, Cripe LD, Ketterling RP, Racevskis J, Luger SM, Paietta E, Lazarus HM, Zhang Y, Bennett JM, Levine RL, Rowe JM, Litzow MR, Tallman MS. Obesity in adult acute myeloid leukemia is not associated with inferior response or survival even when dose capping anthracyclines: An ECOG-ACRIN analysis. Cancer 2023; 129:2479-2490. [PMID: 37185873 PMCID: PMC10932613 DOI: 10.1002/cncr.34807] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2022] [Revised: 02/04/2023] [Accepted: 03/02/2023] [Indexed: 05/17/2023]
Abstract
BACKGROUND Obesity (body mass index [BMI] ≥30 kg/m2 ) is an important epidemiological risk factor for developing acute myeloid leukemia (AML). Therefore, the authors studied the association of obesity with clinical and genetic phenotype and its impact on outcome in adults with AML. METHODS The authors analyzed BMI in 1088 adults who were receiving intensive remission induction and consolidation therapy in two prospective, randomized therapeutic clinical trials of the Eastern Cooperative Oncology Group-American College of Radiology Imaging Network: E1900 (ClinicalTrials.gov identifier NCT00049517; patients younger than 60 years) and E3999 (ClinicalTrials.gov identifier NCT00046930; patients aged 60 years or older). RESULTS Obesity was prevalent at diagnosis (33%) and, compared with nonobesity, was associated with intermediate-risk cytogenetics group (p = .008), poorer performance status (p = .01), and a trend toward older age (p = .06). Obesity was not associated with somatic mutations among a selected 18-gene panel that was tested in a subset of younger patients. Obesity was not associated with clinical outcome (including complete remission, early death, or overall survival), and the authors did not identify any patient subgroup that had inferior outcomes based on BMI. Obese patients were significantly more likely to receive <90% of the intended daunorubicin dose despite protocol specification, particularly in the E1900 high-dose (90 mg/m2 ) daunorubicin arm (p = .002); however, this did not correlate with inferior overall survival on multivariate analysis (hazard ratio, 1.39; 95% confidence interval, 0.90-2.13; p = .14). CONCLUSIONS Obesity is associated with unique clinical and disease-related phenotypic features in AML and may influence physician treatment decisions regarding daunorubicin dosing. However, the current study demonstrates that obesity is not a factor in survival, and strict adherence to body surface area-based dosing is not necessary because dose adjustments do not affect outcomes.
Collapse
Affiliation(s)
- James M. Foran
- Division of Hematology and Medical Oncology and Mayo Clinic Cancer Center, Mayo Clinic, Jacksonville, Florida
| | - Zhuoxin Sun
- ECOG-ACRIN Biostatistics Center, Dana Farber Cancer Institute, Boston, Massachusetts
| | - Catherine Lai
- Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Hugo F. Fernandez
- Blood & Marrow Transplantation, H. Lee Moffitt Cancer Center, Tampa, Florida
| | - Larry D. Cripe
- Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, Indiana
| | - Rhett P. Ketterling
- Department of Laboratory Medicine and Pathology and Division of Hematology, Mayo Clinic, Rochester, Minnesota
| | | | - Selina M. Luger
- Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania
| | | | | | - Yanming Zhang
- Cytogenetics Laboratory, Memorial Sloan Kettering Cancer Center, New York, New York
| | - John M. Bennett
- Hematopathology Division, Department of Pathology, James P. Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, New York
| | - Ross L. Levine
- Cytogenetics Laboratory, Memorial Sloan Kettering Cancer Center, New York, New York
| | | | - Mark R. Litzow
- Department of Laboratory Medicine and Pathology and Division of Hematology, Mayo Clinic, Rochester, Minnesota
| | - Martin S. Tallman
- Northwestern University Feinberg School of Medicine, Robert H.Lurie Comprehensive Cancer Center, Chicago, Illinois
| |
Collapse
|
|
16
|
Shang H, Hendryx M, Liang X, Shadyab AH, Luo J. A Longitudinal Study of Sleep Habits and Leukemia Incidence Among Postmenopausal Women. Am J Epidemiol 2023; 192:1315-1325. [PMID: 37191332 DOI: 10.1093/aje/kwad118] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2022] [Revised: 02/27/2023] [Accepted: 05/10/2023] [Indexed: 05/17/2023] Open
Abstract
We sought to assess the relationship between sleep duration, sleep disturbance, and leukemia incidence among postmenopausal women. This study included 130,343 postmenopausal women aged 50-79 years who were enrolled in the Women's Health Initiative (WHI) during 1993-1998. Information on self-reported typical sleep duration and sleep disturbance was obtained by questionnaire at baseline, and sleep disturbance level was defined according to the Women's Health Initiative Insomnia Rating Scale (WHIIRS). WHIIRS scores of 0-4, 5-8, and 9-20 comprised 37.0%, 32.6%, and 30.4% of all women, respectively. After an average of 16.4 years (2,135,109 cumulative person-years) of follow-up, 930 of the participants were identified as having incident leukemia. Compared with women with the lowest level of sleep disturbance (WHIIRS score 0-4), women with higher sleep disturbance levels (WHIIRS scores of 5-8 and 9-20) had 22% (95% confidence interval (CI): 1.04, 1.43) and 18% (95% CI: 1.00, 1.40) excess risks of leukemia, respectively, after multivariable adjustment. A significant dose-response trend was found for the association between sleep disturbance and leukemia risk (P for trend = 0.048). In addition, women with the highest level of sleep disturbance had a higher risk of myeloid leukemia (for WHIIRS score 9-20 vs. WHIIRS score 0-4, hazard ratio = 1.39, CI: 1.05, 1.83). Higher sleep disturbance level was associated with increased risk of leukemia, especially for myeloid leukemia among postmenopausal women.
Collapse
|
|
17
|
Recalde M, Pistillo A, Davila-Batista V, Leitzmann M, Romieu I, Viallon V, Freisling H, Duarte-Salles T. Longitudinal body mass index and cancer risk: a cohort study of 2.6 million Catalan adults. Nat Commun 2023; 14:3816. [PMID: 37391446 PMCID: PMC10313757 DOI: 10.1038/s41467-023-39282-y] [Citation(s) in RCA: 32] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2022] [Accepted: 05/31/2023] [Indexed: 07/02/2023] Open
Abstract
Single body mass index (BMI) measurements have been associated with increased risk of 13 cancers. Whether life course adiposity-related exposures are more relevant cancer risk factors than baseline BMI (ie, at start of follow-up for disease outcome) remains unclear. We conducted a cohort study from 2009 until 2018 with population-based electronic health records in Catalonia, Spain. We included 2,645,885 individuals aged ≥40 years and free of cancer in 2009. After 9 years of follow-up, 225,396 participants were diagnosed with cancer. This study shows that longer duration, greater degree, and younger age of onset of overweight and obesity during early adulthood are positively associated with risk of 18 cancers, including leukemia, non-Hodgkin lymphoma, and among never-smokers, head and neck, and bladder cancers which are not yet considered as obesity-related cancers in the literature. Our findings support public health strategies for cancer prevention focussing on preventing and reducing early overweight and obesity.
Collapse
Affiliation(s)
- Martina Recalde
- International Agency for Research on Cancer (IARC-WHO), 25 avenue Tony Garnier, CS 90627, 69366 Lyon Cedex 07, Lyon, France
- Fundació Institut Universitari per a la recerca a l'Atenció Primària de Salut Jordi Gol i Gurina (IDIAPJGol), Barcelona, Spain
- Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Andrea Pistillo
- Fundació Institut Universitari per a la recerca a l'Atenció Primària de Salut Jordi Gol i Gurina (IDIAPJGol), Barcelona, Spain
| | - Veronica Davila-Batista
- International Agency for Research on Cancer (IARC-WHO), 25 avenue Tony Garnier, CS 90627, 69366 Lyon Cedex 07, Lyon, France.
- Spanish Consortium for Research on Epidemiology and Public Health (CIBERESP), Instituto de Salud Carlos III, 28029, Madrid, Spain.
| | - Michael Leitzmann
- Department of Epidemiology and Preventive Medicine, University of Regensburg, Regensburg, Germany
| | - Isabelle Romieu
- Center for Research on Population Health, National Institute of Public Health, Mexico City, Mexico
| | - Vivian Viallon
- International Agency for Research on Cancer (IARC-WHO), 25 avenue Tony Garnier, CS 90627, 69366 Lyon Cedex 07, Lyon, France
| | - Heinz Freisling
- International Agency for Research on Cancer (IARC-WHO), 25 avenue Tony Garnier, CS 90627, 69366 Lyon Cedex 07, Lyon, France.
| | - Talita Duarte-Salles
- Fundació Institut Universitari per a la recerca a l'Atenció Primària de Salut Jordi Gol i Gurina (IDIAPJGol), Barcelona, Spain.
| |
Collapse
|
|
18
|
Pasupuleti SK, Ramdas B, Burns SS, Palam LR, Kanumuri R, Kumar R, Pandhiri TR, Dave UP, Yellapu NK, Zhou X, Zhang C, Sandusky GE, Yu Z, Honigberg MC, Bick AG, Griffin GK, Niroula A, Ebert BL, Paczesny S, Natarajan P, Kapur R. Obesity-induced inflammation exacerbates clonal hematopoiesis. J Clin Invest 2023; 133:e163968. [PMID: 37071471 PMCID: PMC10231999 DOI: 10.1172/jci163968] [Citation(s) in RCA: 58] [Impact Index Per Article: 29.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2022] [Accepted: 04/07/2023] [Indexed: 04/19/2023] Open
Abstract
Characterized by the accumulation of somatic mutations in blood cell lineages, clonal hematopoiesis of indeterminate potential (CHIP) is frequent in aging and involves the expansion of mutated hematopoietic stem and progenitor cells (HSC/Ps) that leads to an increased risk of hematologic malignancy. However, the risk factors that contribute to CHIP-associated clonal hematopoiesis (CH) are poorly understood. Obesity induces a proinflammatory state and fatty bone marrow (FBM), which may influence CHIP-associated pathologies. We analyzed exome sequencing and clinical data for 47,466 individuals with validated CHIP in the UK Biobank. CHIP was present in 5.8% of the study population and was associated with a significant increase in the waist-to-hip ratio (WHR). Mouse models of obesity and CHIP driven by heterozygosity of Tet2, Dnmt3a, Asxl1, and Jak2 resulted in exacerbated expansion of mutant HSC/Ps due in part to excessive inflammation. Our results show that obesity is highly associated with CHIP and that a proinflammatory state could potentiate the progression of CHIP to more significant hematologic neoplasia. The calcium channel blockers nifedipine and SKF-96365, either alone or in combination with metformin, MCC950, or anakinra (IL-1 receptor antagonist), suppressed the growth of mutant CHIP cells and partially restored normal hematopoiesis. Targeting CHIP-mutant cells with these drugs could be a potential therapeutic approach to treat CH and its associated abnormalities in individuals with obesity.
Collapse
Affiliation(s)
| | - Baskar Ramdas
- Herman B Wells Center for Pediatric Research, Department of Pediatrics and
| | - Sarah S. Burns
- Herman B Wells Center for Pediatric Research, Department of Pediatrics and
| | | | - Rahul Kanumuri
- Herman B Wells Center for Pediatric Research, Department of Pediatrics and
| | - Ramesh Kumar
- Herman B Wells Center for Pediatric Research, Department of Pediatrics and
| | | | - Utpal P. Dave
- Division of Hematology/Oncology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Nanda Kumar Yellapu
- Department of Biostatistics and Data Science, University of Kansas Medical Center, Kansas City, Kansas, USA
| | - Xinyu Zhou
- Department of Medical and Molecular Genetics and
| | - Chi Zhang
- Department of Medical and Molecular Genetics and
| | - George E. Sandusky
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Zhi Yu
- Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts, USA
- Program in Medical and Population Genetics and the Cardiovascular Disease Initiative, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA
| | - Michael C. Honigberg
- Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Alexander G. Bick
- Division of Genetic Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Gabriel K. Griffin
- Department of Pathology, Brigham and Women’s Hospital, Boston, Massachusetts, USA
- Epigenomics Program, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA
| | - Abhishek Niroula
- Program in Medical and Population Genetics and the Cardiovascular Disease Initiative, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA
| | - Benjamin L. Ebert
- Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Sophie Paczesny
- Department of Microbiology and Immunology, Medical University of South Carolina, Charlestown, South Carolina, USA
| | - Pradeep Natarajan
- Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts, USA
- Program in Medical and Population Genetics and the Cardiovascular Disease Initiative, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA
- Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA
| | - Reuben Kapur
- Herman B Wells Center for Pediatric Research, Department of Pediatrics and
- Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Indiana, USA
| |
Collapse
|
|
19
|
Geitgey DK, Lee M, Cottrill KA, Jaffe M, Pilcher W, Bhasin S, Randall J, Ross AJ, Salemi M, Castillo-Castrejon M, Kilgore MB, Brown AC, Boss JM, Johnston R, Fitzpatrick AM, Kemp ML, English R, Weaver E, Bagchi P, Walsh R, Scharer CD, Bhasin M, Chandler JD, Haynes KA, Wellberg EA, Henry CJ. The 'omics of obesity in B-cell acute lymphoblastic leukemia. J Natl Cancer Inst Monogr 2023; 2023:12-29. [PMID: 37139973 PMCID: PMC10157791 DOI: 10.1093/jncimonographs/lgad014] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2022] [Revised: 03/12/2023] [Accepted: 03/17/2023] [Indexed: 05/05/2023] Open
Abstract
The obesity pandemic currently affects more than 70 million Americans and more than 650 million individuals worldwide. In addition to increasing susceptibility to pathogenic infections (eg, SARS-CoV-2), obesity promotes the development of many cancer subtypes and increases mortality rates in most cases. We and others have demonstrated that, in the context of B-cell acute lymphoblastic leukemia (B-ALL), adipocytes promote multidrug chemoresistance. Furthermore, others have demonstrated that B-ALL cells exposed to the adipocyte secretome alter their metabolic states to circumvent chemotherapy-mediated cytotoxicity. To better understand how adipocytes impact the function of human B-ALL cells, we used a multi-omic RNA-sequencing (single-cell and bulk transcriptomic) and mass spectroscopy (metabolomic and proteomic) approaches to define adipocyte-induced changes in normal and malignant B cells. These analyses revealed that the adipocyte secretome directly modulates programs in human B-ALL cells associated with metabolism, protection from oxidative stress, increased survival, B-cell development, and drivers of chemoresistance. Single-cell RNA sequencing analysis of mice on low- and high-fat diets revealed that obesity suppresses an immunologically active B-cell subpopulation and that the loss of this transcriptomic signature in patients with B-ALL is associated with poor survival outcomes. Analyses of sera and plasma samples from healthy donors and those with B-ALL revealed that obesity is associated with higher circulating levels of immunoglobulin-associated proteins, which support observations in obese mice of altered immunological homeostasis. In all, our multi-omics approach increases our understanding of pathways that may promote chemoresistance in human B-ALL and highlight a novel B-cell-specific signature in patients associated with survival outcomes.
Collapse
Affiliation(s)
- Delaney K Geitgey
- Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA
- Aflac Cancer and Blood Disorders Center, Atlanta, GA, USA
| | - Miyoung Lee
- Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA
- Aflac Cancer and Blood Disorders Center, Atlanta, GA, USA
| | - Kirsten A Cottrill
- Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA
| | - Maya Jaffe
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA, USA
| | - William Pilcher
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA, USA
| | - Swati Bhasin
- Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA
- Aflac Cancer and Blood Disorders Center, Atlanta, GA, USA
- Children’s Healthcare of Atlanta, Atlanta, GA, USA
| | - Jessica Randall
- Emory Integrated Computational Core, Emory University, Atlanta, GA, USA
| | - Anthony J Ross
- Riley Children’s Health, Indiana University Health, Indianapolis, IN, USA
| | - Michelle Salemi
- Proteomics Core Facility, University of California Davis Genome Center, Davis, 95616, CA
| | - Marisol Castillo-Castrejon
- Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
- Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
- Harold Hamm Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
- University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Matthew B Kilgore
- Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA
| | - Ayjha C Brown
- Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA
- Aflac Cancer and Blood Disorders Center, Atlanta, GA, USA
| | - Jeremy M Boss
- Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA, USA
- Winship Cancer Institute, Atlanta, GA, USA
| | - Rich Johnston
- Emory Integrated Computational Core, Emory University, Atlanta, GA, USA
| | - Anne M Fitzpatrick
- Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA
- Children’s Healthcare of Atlanta, Atlanta, GA, USA
| | - Melissa L Kemp
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA, USA
- Emory Integrated Proteomics Core, Emory University School of Medicine, Atlanta, GA, USA
| | | | - Eric Weaver
- Shimadzu Scientific Instruments, Columbia, MD, USA
| | - Pritha Bagchi
- Emory Integrated Proteomics Core, Emory University School of Medicine, Atlanta, GA, USA
| | - Ryan Walsh
- Shimadzu Scientific Instruments, Columbia, MD, USA
| | - Christopher D Scharer
- Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA, USA
- Winship Cancer Institute, Atlanta, GA, USA
| | - Manoj Bhasin
- Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA
- Aflac Cancer and Blood Disorders Center, Atlanta, GA, USA
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA, USA
- Children’s Healthcare of Atlanta, Atlanta, GA, USA
- Winship Cancer Institute, Atlanta, GA, USA
| | - Joshua D Chandler
- Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA
- Children’s Healthcare of Atlanta, Atlanta, GA, USA
| | - Karmella A Haynes
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA, USA
- Winship Cancer Institute, Atlanta, GA, USA
| | - Elizabeth A Wellberg
- Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
- Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
- Harold Hamm Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
- University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Curtis J Henry
- Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA
- Aflac Cancer and Blood Disorders Center, Atlanta, GA, USA
- Children’s Healthcare of Atlanta, Atlanta, GA, USA
- Winship Cancer Institute, Atlanta, GA, USA
| |
Collapse
|
|
20
|
Kristensen DT, Nielsen LB, Jakobsen LHK, Kristensen TC, Jepsen LØ, Schöllkopf C, Theilgaard‐Mönch K, El‐Galaly TC, Roug AS, Severinsen MT. Effects of chemotherapy dose reductions in overweight patients with acute myeloid leukaemia: A Danish nationwide cohort study. Br J Haematol 2022; 199:539-548. [PMID: 36083781 PMCID: PMC9825846 DOI: 10.1111/bjh.18448] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2022] [Revised: 08/19/2022] [Accepted: 08/26/2022] [Indexed: 01/11/2023]
Abstract
Overweight patients with cancer are frequently reduced in chemotherapy dose due to toxicity concerns, although previous studies have indicated that dose reduction (DR) of overweight patients results in comparable toxicity but may compromise overall survival (OS). Current evidence regarding DR in patients with acute myeloid leukaemia (AML) is limited. To investigate the association between DR and outcome among overweight patients with AML we analysed a Danish nationwide cohort of overweight adult AML patients treated with remission induction chemotherapy. Among 536 patients identified, 10.1% were categorized as DR defined as 95% or less of full body surface area (BSA)-based dose. Risk factors for DR were high body mass index (BMI) and BSA, therapy-related AML and favourable cytogenetics. No significant differences were observed for rates of complete remission (CR), 30- and 90-day mortality between DR and non-DR patients. Furthermore, DR did not affect median relapse-free survival (RFS) [DR, 14.5 (95% confidence interval, 9.0-41.7) months; non-DR, 15.0 (12.3-19.3)] with an adjusted difference in five-year restricted mean survival time (Δ5y-RMST) of 0.2 (-8.4 to 8.8) months nor median OS (DR, 17.0 [11.9 to 45.5] months; non-DR, 17.5 [14.8 to 20.5]) with an adjusted Δ5y-RMST of 0.8 (-5.7 to 7.3) months. In conclusion, we found no statistically significant association between DR and outcomes among overweight patients with AML. However, we acknowledge the limited sample size and encourage further studies in this important subject.
Collapse
Affiliation(s)
- Daniel Tuyet Kristensen
- Department of Haematology, Clinical Cancer Research CenterAalborg University HospitalAalborgDenmark,Department of Clinical MedicineAalborg UniversityAalborgDenmark
| | - Lars Børty Nielsen
- Department of Haematology, Clinical Cancer Research CenterAalborg University HospitalAalborgDenmark,Department of Clinical MedicineAalborg UniversityAalborgDenmark
| | - Lasse Hjort Kyneb Jakobsen
- Department of Haematology, Clinical Cancer Research CenterAalborg University HospitalAalborgDenmark,Department of Mathematical SciencesAalborg UniversityAalborgDenmark
| | | | | | - Claudia Schöllkopf
- Department of HaematologyRigshospitalet, Copenhagen University HospitalCopenhagenDenmark
| | - Kim Theilgaard‐Mönch
- Department of HaematologyRigshospitalet, Copenhagen University HospitalCopenhagenDenmark
| | - Tarec Christoffer El‐Galaly
- Department of Haematology, Clinical Cancer Research CenterAalborg University HospitalAalborgDenmark,Department of Clinical MedicineAalborg UniversityAalborgDenmark
| | - Anne Stidsholt Roug
- Department of Haematology, Clinical Cancer Research CenterAalborg University HospitalAalborgDenmark,Department of Clinical MedicineAalborg UniversityAalborgDenmark,Department of HaematologyAarhus University HospitalAarhusDenmark
| | - Marianne Tang Severinsen
- Department of Haematology, Clinical Cancer Research CenterAalborg University HospitalAalborgDenmark,Department of Clinical MedicineAalborg UniversityAalborgDenmark
| |
Collapse
|
|
21
|
Tekalegn Y, Solomon D, Sahiledengle B, Assefa T, Negash W, Tahir A, Regassa T, Mamo A, Gezahegn H, Bekele K, Zenbaba D, Tasew A, Desta F, Atlaw D, Regassa Z, Nugusu F, Engida ZT, Tesfaye DG, Kene C, Nigussie WS, Chala D, Abdi AG, Beressa G, Woldeyohannes D, Rogers HL, Mwanri L. Prevalence of central obesity and its associated risk factors among adults in Southeast Ethiopia: A community-based cross-sectional study. PLoS One 2022; 17:e0265107. [PMID: 35930540 PMCID: PMC9355191 DOI: 10.1371/journal.pone.0265107] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Accepted: 07/21/2022] [Indexed: 11/18/2022] Open
Abstract
BACKGROUND Obesity and overweight are known public health problems that affect populations across the world. These conditions have been associated with a wide range of chronic diseases including type 2 diabetes mellitus, cardiovascular disease, and cancers. In Ethiopia, the literature regarding the burden of central (abdominal) obesity is scarce. This study aimed to fill this gap by assessing the prevalence and risk factors associated with central obesity among adults in Ethiopia. METHODS From May to July 2021, a community-based cross-sectional survey was conducted on a sample of 694 adults aged ≥18 years in administrative towns of Bale zone, Southeast Ethiopia. Multi-stage sampling followed by systematic random sampling was employed to identify study participants. Waist and hip circumferences were measured using standard protocols. The World Health Organization STEPS wise tool was used to assess risk factors associated with central obesity. Bi-variable and multi-variable binary logistic regression were used to identify factors associated with central obesity. Adjusted odds ratios (AOR) and their corresponding 95% confidence intervals (CI) have been reported to estimate the strength of associations. RESULTS The overall prevalence of central obesity using waist circumference was 39.01% [(95% CI: 35.36-42.76; 15.44% for men and 53.12% for women)]. Multi-variable binary logistic regression analysis revealed that female sex (AOR = 12.93, 95% CI: 6.74-24.79), Age groups: 30-39 years old (AOR = 2.8, 95% CI: 1.59-4.94), 40-49 years (AOR = 7.66, 95% CI: 3.87-15.15), 50-59 years (AOR = 4.65, 95% CI: 2.19-9.89), ≥60 years (AOR = 12.67, 95% CI: 5.46-29.39), occupational status like: housewives (AOR = 5.21, 95% CI: 1.85-14.62), self-employed workers (AOR = 4.63, 95% CI: 1.62-13.24), government/private/non-government employees (AOR = 4.68, 95% CI: 1.47-14.88), and skipping breakfast (AOR = 0.46, 95% CI: 0.23-0.9) were significantly associated with central obesity. CONCLUSIONS Abdominal obesity has become an epidemic in Bale Zone's towns in Southeastern Ethiopia. Female sex, age, being employed were positively associated with central obesity, while skipping breakfast was a protective factor.
Collapse
Affiliation(s)
- Yohannes Tekalegn
- Public Health Department, Goba Referral Hospital, Madda Walabu University, Bale Goba, Ethiopia
| | - Damtew Solomon
- Biomedical Department, Goba Referral Hospital, Madda Walabu University, Bale Goba, Ethiopia
| | - Biniyam Sahiledengle
- Public Health Department, Goba Referral Hospital, Madda Walabu University, Bale Goba, Ethiopia
| | - Tesfaye Assefa
- Nursing Department, Goba Referral Hospital, Madda Walabu University, Bale Goba, Ethiopia
| | - Wogene Negash
- Nursing Department, Goba Referral Hospital, Madda Walabu University, Bale Goba, Ethiopia
| | - Anwar Tahir
- Nursing Department, Goba Referral Hospital, Madda Walabu University, Bale Goba, Ethiopia
| | - Tadele Regassa
- Biomedical Department, Goba Referral Hospital, Madda Walabu University, Bale Goba, Ethiopia
| | - Ayele Mamo
- Pharmacy Department, Goba Referral Hospital, Madda Walabu University, Bale Goba, Ethiopia
| | - Habtamu Gezahegn
- Biomedical Department, Goba Referral Hospital, Madda Walabu University, Bale Goba, Ethiopia
| | - Kebebe Bekele
- Surgery Department, Goba Referral Hospital, Madda Walabu University, Bale Goba, Ethiopia
| | - Demisu Zenbaba
- Public Health Department, Goba Referral Hospital, Madda Walabu University, Bale Goba, Ethiopia
| | - Alelign Tasew
- Public Health Department, Goba Referral Hospital, Madda Walabu University, Bale Goba, Ethiopia
| | - Fikreab Desta
- Public Health Department, Goba Referral Hospital, Madda Walabu University, Bale Goba, Ethiopia
| | - Daniel Atlaw
- Biomedical Department, Goba Referral Hospital, Madda Walabu University, Bale Goba, Ethiopia
| | - Zegeye Regassa
- Nursing Department, Goba Referral Hospital, Madda Walabu University, Bale Goba, Ethiopia
| | - Fikadu Nugusu
- Public Health Department, Goba Referral Hospital, Madda Walabu University, Bale Goba, Ethiopia
| | - Zinash Teferu Engida
- Public Health Department, Goba Referral Hospital, Madda Walabu University, Bale Goba, Ethiopia
| | - Degefa Gomora Tesfaye
- Midwifery Department, Goba Referral Hospital, Madda Walabu University, Bale Goba, Ethiopia
| | - Chala Kene
- Midwifery Department, Goba Referral Hospital, Madda Walabu University, Bale Goba, Ethiopia
| | | | - Dereje Chala
- Nursing Department, Goba Referral Hospital, Madda Walabu University, Bale Goba, Ethiopia
| | - Adisu Gemechu Abdi
- Nursing Department, Goba Referral Hospital, Madda Walabu University, Bale Goba, Ethiopia
| | - Girma Beressa
- Public Health Department, Goba Referral Hospital, Madda Walabu University, Bale Goba, Ethiopia
| | - Demelash Woldeyohannes
- School of Medicine and Health Science, Department of Public health, Wachemo University, Hosana, Ethiopia
| | - Heather L. Rogers
- Biocruces Bizkaia Health Research Institute, Barakaldo, Bizkaia, Spain
- Ikerbasque Basque Foundation for Science Bilbao, Bilbao, Bizkaia, Spain
| | - Lillian Mwanri
- Torrens University Australia, Adelaide, South Australia, Australia
| |
Collapse
|
|
22
|
Huang J, Chan SC, Ngai CH, Lok V, Zhang L, Lucero-Prisno DE, Xu W, Zheng ZJ, Elcarte E, Withers M, Wong MCS. Disease Burden, Risk Factors, and Trends of Leukaemia: A Global Analysis. Front Oncol 2022; 12:904292. [PMID: 35936709 PMCID: PMC9355717 DOI: 10.3389/fonc.2022.904292] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2022] [Accepted: 06/07/2022] [Indexed: 11/13/2022] Open
Abstract
Leukaemia accounted for approximately 2.5% of all new cancer incidence and 3.1% of cancer-related mortality. The investigation of its risk factors and epidemiologic trends could help describe the geographical distribution and identify high-risk population groups. This study aimed to evaluate the global incidence, mortality, associated risk factors, and temporal trends of leukaemia by sex, age, and country. We extracted incidence and mortality of leukaemia from GLOBOCAN, CI5, WHO mortality database, NORDCAN, and SEER. We searched the WHO Global Health Observatory data repository for the age-standardised prevalence of lifestyle and metabolic risk factors. We tested the trends by calculating Average Annual Percentage Change (AAPC) from Joinpoint regression. The age-standardized rate of incidence and mortality were 5.4 and 3.3 per 100,000 globally. The incidence and mortality of leukaemia were associated with Human Development Index, Gross Domestics Products per capita, prevalence of smoking, physical activity, overweight, obesity, and hypercholesterolaemia at the country level. Overall, more countries were showing decreasing trends than increasing trends in incidence and mortality. However, an increasing trend of leukaemia incidence was found in Germany, Korea, Japan, Canada and the United Kingdom (AAPC, 2.32-0.98) while its mortality increased in the Philippines, Ecuador, Belarus, and Thailand (AAPC, 2.49-1.23). There was a decreasing trend of leukaemia for the past decade while an increase in incidence and mortality was observed in some populations. More intensive lifestyle modifications should be implemented to control the increasing trends of leukaemia in regions with these trends. Future studies may explore the reasons behind these epidemiological transitions.
Collapse
Affiliation(s)
- Junjie Huang
- The Jockey Club School of Public Health and Primary Care, Faculty of Medicine, Chinese University of Hong Kong, Hong Kong, Hong Kong SAR, China
| | - Sze Chai Chan
- The Jockey Club School of Public Health and Primary Care, Faculty of Medicine, Chinese University of Hong Kong, Hong Kong, Hong Kong SAR, China
| | - Chun Ho Ngai
- The Jockey Club School of Public Health and Primary Care, Faculty of Medicine, Chinese University of Hong Kong, Hong Kong, Hong Kong SAR, China
| | - Veeleah Lok
- Department of Global Public Health, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden
| | - Lin Zhang
- School of Population and Global Health, The University of Melbourne, Carlton, VIC, Australia
- School of Public Health, The Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Don Eliseo Lucero-Prisno
- Department of Global Health and Development, London School of Hygiene and Tropical Medicine, London, United Kingdom
| | - Wanghong Xu
- School of Public Health, Fudan University, Shanghai, China
| | - Zhi-Jie Zheng
- Department of Global Health, School of Public Health, Peking University, Beijing, China
| | - Edmar Elcarte
- College of Nursing, University of the Philippines, Manila, Philippines
| | - Mellissa Withers
- Department of Preventive Medicine, Institute for Global Health, University of Southern California, Los Angeles, CA, United States
- *Correspondence: Mellissa Withers, ; Martin C. S. Wong,
| | - Martin C. S. Wong
- The Jockey Club School of Public Health and Primary Care, Faculty of Medicine, Chinese University of Hong Kong, Hong Kong, Hong Kong SAR, China
- School of Public Health, The Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Department of Global Health, School of Public Health, Peking University, Beijing, China
- *Correspondence: Mellissa Withers, ; Martin C. S. Wong,
| |
Collapse
|
|
23
|
Hernandez M, Shin S, Muller C, Attané C. The role of bone marrow adipocytes in cancer progression: the impact of obesity. Cancer Metastasis Rev 2022; 41:589-605. [PMID: 35708800 DOI: 10.1007/s10555-022-10042-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/19/2022] [Accepted: 05/27/2022] [Indexed: 11/27/2022]
Abstract
Bone marrow adipose tissues (BMATs) and their main cellular component, bone marrow adipocytes (BMAds), are found within the bone marrow (BM), which is a niche for the development of hematological malignancies as well as bone metastasis from solid tumors such as breast and prostate cancers. In humans, BMAds are present within the hematopoietic or "red" BMAT and in the "yellow" BMAT where they are more densely packed. BMAds are emerging as new actors in tumor progression; however, there are many outstanding questions regarding their precise role. In this review, we summarized our current knowledge regarding the development, distribution, and regulation by external stimuli of the BMATs in mice and humans and addressed how obesity could affect these traits. We then discussed the specific metabolic phenotype of BMAds that appear to be different from "classical" white adipocytes, since they are devoid of lipolytic function. According to this characterization, we presented how tumor cells affect the in vitro and in vivo phenotype of BMAds and the signals emanating from BMAds that are susceptible to modulate tumor behavior with a specific emphasis on their metabolic crosstalk with cancer cells. Finally, we discussed how obesity could affect this crosstalk. Deciphering the role of BMAds in tumor progression would certainly lead to the identification of new targets in oncology in the near future.
Collapse
Affiliation(s)
- Marine Hernandez
- Institut de Pharmacologie Et Biologie Structurale, IPBS, Université de Toulouse, CNRS, UPS, Toulouse, France
- Equipe Labellisée Ligue Contre Le Cancer, Toulouse, France
| | - Sauyeun Shin
- Institut de Pharmacologie Et Biologie Structurale, IPBS, Université de Toulouse, CNRS, UPS, Toulouse, France
- Equipe Labellisée Ligue Contre Le Cancer, Toulouse, France
| | - Catherine Muller
- Institut de Pharmacologie Et Biologie Structurale, IPBS, Université de Toulouse, CNRS, UPS, Toulouse, France.
- Equipe Labellisée Ligue Contre Le Cancer, Toulouse, France.
| | - Camille Attané
- Institut de Pharmacologie Et Biologie Structurale, IPBS, Université de Toulouse, CNRS, UPS, Toulouse, France.
- Equipe Labellisée Ligue Contre Le Cancer, Toulouse, France.
| |
Collapse
|
|
24
|
Jafari-Delouei N, Naimi-Tabiei M, Farajollahi M, Sedaghat SM, Khandoozi S, Ghasemi-Kebria F, Dinparastisaleh R, Pourkhani A, Roshandel G. Incidence, Time Trends and Geographical Distribution of Leukemia and Multiple Myeloma in Golestan Province, Northern Iran, 2004-2017. ARCHIVES OF IRANIAN MEDICINE 2022; 25:360-365. [PMID: 35943015 PMCID: PMC11904270 DOI: 10.34172/aim.2022.59] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/07/2021] [Accepted: 09/22/2021] [Indexed: 06/15/2023]
Abstract
BACKGROUND Leukemia and multiple myeloma (MM) are the most common hematologic malignancies in Iran. This paper describes the geographic and temporal changes in their incidence in Golestan, northern Iran. METHODS Data on cases of leukemia and MM during 2004-2017 were obtained from the Golestan Population-based Cancer Registry (GPCR). The GPCR is a dynamic database of Golestan residents diagnosed with primary cancers. Age-standardized incidence rates (ASRs) (per 100000) of leukemia and MM were calculated using direct standardization method considering the world standard population. We used Joinpoint regression to assess incidence trends using the average annual percent change (AAPC). RESULTS In total, 2119 new cases of leukemia and MM were registered by the GPCR during 2004-2017. The ASRs of leukemia were 9.71 and 6.70 in males and females, respectively, while the rates were lower for MM: 2.66 and 1.97 in males and females, respectively. The incidence rates of leukemia suggested an increasing trend in urban population (AAPC=2.73; P value=0.154), while in rural area, the incidence rates were slightly decreasing (AAPC=- 0.73; P value=0.658). There were high incidence areas of leukemia in the central and western regions of Golestan. CONCLUSION Our results suggested high incidence rates of leukemia and MM in the Golestan province. We also found geographical diversities and increasing trends in the incidence of leukemia in the urban population. Exposure to occupational and environmental carcinogens including pesticides may partly explain high rates and the observed trends. Further investigations should be considered to clarify these points in our population.
Collapse
Affiliation(s)
- Nastaran Jafari-Delouei
- Golestan Research Center of Gastroenterology and Hepatology, Golestan University of Medical Sciences, Gorgan, Iran
| | | | - Mehran Farajollahi
- Golestan Research Center of Gastroenterology and Hepatology, Golestan University of Medical Sciences, Gorgan, Iran
| | | | | | - Fatemeh Ghasemi-Kebria
- Golestan Research Center of Gastroenterology and Hepatology, Golestan University of Medical Sciences, Gorgan, Iran
| | - Roshan Dinparastisaleh
- Outcomes After Critical Illness and Surgery Group, Johns Hopkins University, Division of Pulmonary and Critical Care Medicine, Johns Hopkins School of Medicine, Baltimore, MD, USA
| | | | - Gholamreza Roshandel
- Golestan Research Center of Gastroenterology and Hepatology, Golestan University of Medical Sciences, Gorgan, Iran
| |
Collapse
|
|
25
|
Tsilingiris D, Nasiri-Ansari N, Spyrou N, Magkos F, Dalamaga M. Management of Hematologic Malignancies in the Era of COVID-19 Pandemic: Pathogenetic Mechanisms, Impact of Obesity, Perspectives, and Challenges. Cancers (Basel) 2022; 14:2494. [PMID: 35626099 PMCID: PMC9139192 DOI: 10.3390/cancers14102494] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2022] [Revised: 05/14/2022] [Accepted: 05/16/2022] [Indexed: 02/04/2023] Open
Abstract
The COVID-19 pandemic brought about an unprecedented societal and healthcare system crisis, considerably affecting healthcare workers and patients, particularly those with chronic diseases. Patients with hematologic malignancies faced a variety of challenges, pertinent to the nature of an underlying hematologic disorder itself as well as its therapy as a risk factor for severe SARS-CoV-2 infection, suboptimal vaccine efficacy and the need for uninterrupted medical observation and continued therapy. Obesity constitutes another factor which was acknowledged since the early days of the pandemic that predisposed people to severe COVID-19, and shares a likely causal link with the pathogenesis of a broad spectrum of hematologic cancers. We review here the epidemiologic and pathogenetic features that obesity and hematologic malignancies share, as well as potential mutual pathophysiological links predisposing people to a more severe SARS-CoV-2 course. Additionally, we attempt to present the existing evidence on the multi-faceted crucial challenges that had to be overcome in this diverse patient group and discuss further unresolved questions and future challenges for the management of hematologic malignancies in the era of COVID-19.
Collapse
Affiliation(s)
- Dimitrios Tsilingiris
- First Department of Propaedeutic Internal Medicine, School of Medicine, National and Kapodistrian University of Athens, Laiko General Hospital, 17 St Thomas Street, 11527 Athens, Greece
| | - Narjes Nasiri-Ansari
- Department of Biological Chemistry, School of Medicine, National and Kapodistrian University of Athens, 75 Mikras Asias, 11527 Athens, Greece
| | - Nikolaos Spyrou
- Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Faidon Magkos
- Department of Nutrition, Exercise, and Sports, University of Copenhagen, DK-2200 Frederiksberg, Denmark
| | - Maria Dalamaga
- Department of Biological Chemistry, School of Medicine, National and Kapodistrian University of Athens, 75 Mikras Asias, 11527 Athens, Greece
| |
Collapse
|
|
26
|
The Global Burden of Leukemia and Its Attributable Factors in 204 Countries and Territories: Findings from the Global Burden of Disease 2019 Study and Projections to 2030. JOURNAL OF ONCOLOGY 2022; 2022:1612702. [PMID: 35509847 PMCID: PMC9061017 DOI: 10.1155/2022/1612702] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/03/2021] [Revised: 03/09/2022] [Accepted: 04/08/2022] [Indexed: 01/01/2023]
Abstract
Background. Leukemia is a common malignancy that has four main subtypes and is a threat to human health. Understanding the epidemiological status of leukemia and its four main subtypes globally is important for allocating appropriate resources, guiding clinical practice, and furthering scientific research. Methods. Average annual percentage changes (AAPCs) were calculated to estimate the change trends of age-standardized rates (ASRs) from 1990 to 2019 in 204 countries and territories. The risk factors for leukemia death and disability-adjusted life-year (DALY) were also analyzed. In addition, the future trends in ASRs were projected through 2030. Results. The total number of incident cases, deaths, and DALYs from leukemia in 2019 was 0.64, 0.33, and 11.66 million, respectively. Decreasing trends in age-standardized incidence rate (ASIR), the age-standardized death rate (ASDR), and age-standardized DALY rate were detected on a global level while increasing trends in ASIR were detected in the high-sociodemographic index (SDI) regions. The leukemia burden was heavier in males than in females. By cause, acute myeloid leukemia (AML), chronic myeloid leukemia (CML), and chronic lymphocytic leukemia (CLL) were more likely to impose a burden on the elderly, while acute lymphoblastic leukemia (ALL) showed a greater impact in the younger population. A significant positive correlation was observed between SDI and AAPC in ASIR, while SDI was negatively correlated with AAPCs in both ASDR and age-standardized DALY rate. Smoking remained the most significant risk factor associated with leukemia-related death and DALY, especially in males. Similar deaths and DALYs were caused by smoking and high body mass index (BMI) in females. Future projections through 2030 estimated that ASIR and ASDR will continue to increase, while the DALY rate is predicted to decline. Conclusions. Patterns and trends of leukemia burden are correlated with SDI. The estimated contributions to leukemia deaths indicate that timely measures are needed to reduce smoking and obesity.
Collapse
|
|
27
|
Association Between SHMT1 rs1979277 Polymorphism and Risk of Acute Lymphoblastic Leukemia: A Systematic Review and Meta-analysis. J Pediatr Hematol Oncol 2022; 44:e616-e622. [PMID: 33974584 DOI: 10.1097/mph.0000000000002173] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2021] [Accepted: 03/06/2021] [Indexed: 11/26/2022]
Abstract
OBJECTIVES The aim of this study was to explore the potential association the cytosolic serine hydroxy methyltransferase (SHMT1) rs1979277 polymorphism and the risk of acute lymphoblastic leukemia (ALL). MATERIALS AND METHODS Comprehensive search of Web of Science, PubMed, Ovid, Cochrane Library, Embase, China National Knowledge Infrastructure (CNKI), and China Biomedical Literature Database electronic database, was performed to identify relevant studies published throughout April 30, 2019. The heterogeneity in the study was judged by the I2 and P-values, and then the random ratio or fixed effect was used to calculate the pooled odds ratios (OR) based on the presence or absence of heterogeneity. Sensitivity analysis is used to estimate the impact of individual studies on aggregate estimates. The publication bias of the study was tested using a funnel plot and an Egger regression. RESULTS Nine studies with a total of 6492 participants (2971 patients; 3521 controls) were included in this meta-analysis. We found that SHMT1 rs1979277 polymorphism was not significantly associated with the risk of ALL in the dominant model: CC versus CT+TT (OR=0.84, 95% confidence interval [CI]: 0.46-1.54, P=0.57), recessive model: CC+CT versus TT (OR=0.81, 95% CI: 0.44-1.49, P=0.50) and allele model: C versus T (OR=0.84, 95% CI: 0.52-1.35, P=0.48). In subgroup analysis by ethnicity, no significant association were found in dominant, recessive and allele models in both Caucasian and Asian populations. CONCLUSION Our study indicated that the SHMT1 rs1979277 polymorphism was not associated with the risk of susceptibility to ALL.
Collapse
|
|
28
|
Kansal R. Fructose Metabolism and Acute Myeloid Leukemia. EXPLORATORY RESEARCH AND HYPOTHESIS IN MEDICINE 2022; 7:25-38. [DOI: 10.14218/erhm.2021.00042] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
|
|
29
|
Nitsche LJ, Mukherjee S, Cheruvu K, Krabak C, Rachala R, Ratnakaram K, Sharma P, Singh M, Yendamuri S. Exploring the Impact of the Obesity Paradox on Lung Cancer and Other Malignancies. Cancers (Basel) 2022; 14:cancers14061440. [PMID: 35326592 PMCID: PMC8946288 DOI: 10.3390/cancers14061440] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2021] [Revised: 03/01/2022] [Accepted: 03/09/2022] [Indexed: 02/06/2023] Open
Abstract
Simple Summary Studies have shown that obesity is associated with many adverse health effects, including worse cancer outcomes. Many studies paradoxically suggest a survival benefit for obesity in treatment outcomes of cancers such as non-small-cell lung cancer. This relationship is not seen in animal models. We hypothesize that this relationship is secondary to suboptimal quantification of adiposity, enhanced immunotherapy response, and variables such as sex, medications, and smoking status. There are many ways to measure and classify adiposity, but the ability to distinguish abdominal obesity is likely key in predicting accurate prognosis. There are many ways obesity impacts cancer treatment course from diagnosis to survivorship. In this paper, we aim to analyze the factors contributing to the obesity paradox and its effect on lung cancer. This can aid the treatment and prognosis of lung cancer and may support further research into obesity-specific impacts on this malignancy. Abstract There is a paradoxical relationship between obesity, as measured by BMI, and many types of cancer, including non-small-cell lung cancer. Obese non-small-cell lung cancer patients have been shown to fare better than their non-obese counterparts. To analyze the multifaceted effects of obesity on oncologic outcomes, we reviewed the literature on the obesity paradox, methods to measure adiposity, the obesity-related derangements in immunology and metabolism, and the oncologic impact of confounding variables such as gender, smoking, and concomitant medications such as statins and metformin. We analyzed how these aspects may contribute to the obesity paradox and cancer outcomes with a focus on lung cancer. We concluded that the use of BMI to measure adiposity is limited and should be replaced by a method that can differentiate abdominal obesity. We also concluded that the concomitant metabolic and immunologic derangements caused by obesity contribute to the obesity paradox. Medications, gender, and smoking are additional variables that impact oncologic outcomes, and further research needs to be performed to solidify the mechanisms.
Collapse
Affiliation(s)
- Lindsay Joyce Nitsche
- Department of Thoracic Surgery, Roswell Park Comprehensive Cancer Center, Elm and Carlton Streets, Buffalo, NY 14263, USA; (L.J.N.); (K.C.); (C.K.); (R.R.); (K.R.); (P.S.); (M.S.)
| | - Sarbajit Mukherjee
- Department of Medicine, Roswell Park Comprehensive Cancer Center, Elm and Carlton Streets, Buffalo, NY 14263, USA;
| | - Kareena Cheruvu
- Department of Thoracic Surgery, Roswell Park Comprehensive Cancer Center, Elm and Carlton Streets, Buffalo, NY 14263, USA; (L.J.N.); (K.C.); (C.K.); (R.R.); (K.R.); (P.S.); (M.S.)
| | - Cathleen Krabak
- Department of Thoracic Surgery, Roswell Park Comprehensive Cancer Center, Elm and Carlton Streets, Buffalo, NY 14263, USA; (L.J.N.); (K.C.); (C.K.); (R.R.); (K.R.); (P.S.); (M.S.)
| | - Rohit Rachala
- Department of Thoracic Surgery, Roswell Park Comprehensive Cancer Center, Elm and Carlton Streets, Buffalo, NY 14263, USA; (L.J.N.); (K.C.); (C.K.); (R.R.); (K.R.); (P.S.); (M.S.)
| | - Kalyan Ratnakaram
- Department of Thoracic Surgery, Roswell Park Comprehensive Cancer Center, Elm and Carlton Streets, Buffalo, NY 14263, USA; (L.J.N.); (K.C.); (C.K.); (R.R.); (K.R.); (P.S.); (M.S.)
| | - Priyanka Sharma
- Department of Thoracic Surgery, Roswell Park Comprehensive Cancer Center, Elm and Carlton Streets, Buffalo, NY 14263, USA; (L.J.N.); (K.C.); (C.K.); (R.R.); (K.R.); (P.S.); (M.S.)
| | - Maddy Singh
- Department of Thoracic Surgery, Roswell Park Comprehensive Cancer Center, Elm and Carlton Streets, Buffalo, NY 14263, USA; (L.J.N.); (K.C.); (C.K.); (R.R.); (K.R.); (P.S.); (M.S.)
| | - Sai Yendamuri
- Department of Thoracic Surgery, Roswell Park Comprehensive Cancer Center, Elm and Carlton Streets, Buffalo, NY 14263, USA; (L.J.N.); (K.C.); (C.K.); (R.R.); (K.R.); (P.S.); (M.S.)
- Correspondence: ; Tel.: +1-716-8458675
| |
Collapse
|
|
30
|
Marley AR, Domingues A, Ghosh T, Turcotte LM, Spector LG. Maternal BMI, Diabetes, and Gestational Weight Gain and Risk for Pediatric Cancer in Offspring: A Systematic Review and Meta-Analysis. JNCI Cancer Spectr 2022; 6:6537542. [PMID: 35603850 PMCID: PMC8982388 DOI: 10.1093/jncics/pkac020] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2021] [Revised: 01/18/2022] [Accepted: 01/20/2022] [Indexed: 11/17/2022] Open
Abstract
Background Pediatric cancer incidence has steadily increased concurrent with rising adult obesity, but associations between maternal obesity and associated comorbidities and pediatric cancer risk remain understudied. We aimed to quantitatively characterize associations of pediatric cancer risk with maternal prepregnancy body mass index (BMI), gestational weight gain, and maternal diabetes. Methods We performed a comprehensive and systematic literature search in Ovid and EMBASE from their inception to March 15, 2021. Eligible studies reported risk estimates and sample sizes and provided sufficient description of outcome and exposure ascertainment. Random effects models were used to estimate pooled effects. Results Thirty-four studies were included in the analysis. Prepregnancy BMI was positively associated with leukemia risk in offspring (odds ratio [OR] per 5-unit BMI increase =1.07, 95% confidence intervals [CI] = 1.04 to 1.11; I2 = 0.0%). Any maternal diabetes was positively associated with acute lymphoblastic leukemia risk (OR = 1.46, 95% CI = 1.28 to 1.67; I2 = 0.0%), even after restricting to birthweight-adjusted analyses (OR = 1.74, 95% CI = 1.29 to 2.34; I2 = 0.0%), and inversely associated with risk of central nervous system tumors (OR = 0.73, 95% CI = 0.55 to 0.97; I2 = 0.0%). Pregestational diabetes (OR = 1.57, 95% CI = 1.11 to 2.24; I2 = 26.8%) and gestational diabetes (OR = 1.40, 95% CI = 1.12 to 1.75; I2 = 0.0%) were also positively associated with acute lymphoblastic leukemia risk. No statistically significant associations were observed for gestational weight gain. Conclusions Maternal obesity and diabetes may be etiologically linked to pediatric cancer, particularly leukemia and central nervous system tumors. Our findings support weight management and glycemic control as important components of maternal and offspring health. Further validation is warranted.
Collapse
Affiliation(s)
- Andrew R Marley
- Division of Epidemiology & Clinical Research, Department of Pediatrics, University of Minnesota, Minneapolis, MN, USA
| | - Allison Domingues
- Division of Epidemiology & Clinical Research, Department of Pediatrics, University of Minnesota, Minneapolis, MN, USA
| | - Taumoha Ghosh
- Division of Hematology/Oncology, Department of Pediatrics, University of Miami, Miami, FL, USA
| | - Lucie M Turcotte
- Division of Hematology/Oncology, Department of Pediatrics, University of Minnesota, Minneapolis, MN, USA
- Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA
| | - Logan G Spector
- Division of Epidemiology & Clinical Research, Department of Pediatrics, University of Minnesota, Minneapolis, MN, USA
- Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA
| |
Collapse
|
|
31
|
Zivarpour P, Hallajzadeh J, Asemi Z, Sadoughi F, Sharifi M. Chitosan as possible inhibitory agents and delivery systems in leukemia. Cancer Cell Int 2021; 21:544. [PMID: 34663339 PMCID: PMC8524827 DOI: 10.1186/s12935-021-02243-w] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2021] [Accepted: 10/03/2021] [Indexed: 12/29/2022] Open
Abstract
Leukemia is a lethal cancer in which white blood cells undergo proliferation and immature white blood cells are seen in the bloodstream. Without diagnosis and management in early stages, this type of cancer can be fatal. Changes in protooncogenic genes and microRNA genes are the most important factors involved in development of leukemia. At present, leukemia risk factors are not accurately identified, but some studies have pointed out factors that predispose to leukemia. Studies show that in the absence of genetic risk factors, leukemia can be prevented by reducing the exposure to risk factors of leukemia, including smoking, exposure to benzene compounds and high-dose radioactive or ionizing radiation. One of the most important treatments for leukemia is chemotherapy which has devastating side effects. Chemotherapy and medications used during treatment do not have a specific effect and destroy healthy cells besides leukemia cells. Despite the suppressing effect of chemotherapy against leukemia, patients undergoing chemotherapy have poor quality of life. So today, researchers are focusing on finding more safe and effective natural compounds and treatments for cancer, especially leukemia. Chitosan is a valuable natural compound that is biocompatible and non-toxic to healthy cells. Anticancer, antibacterial, antifungal and antioxidant effects are examples of chitosan biopolymer properties. The US Food and Drug Administration has approved the use of this compound in medical treatments and the pharmaceutical industry. In this article, we take a look at the latest advances in the use of chitosan in the treatment and improvement of leukemia.
Collapse
Affiliation(s)
- Parinaz Zivarpour
- Department of Biological Sciences, Faculty of Basic Sciences, Higher Education Institute of Rab-Rashid, Tabriz, Iran
| | - Jamal Hallajzadeh
- Department of Biochemistry and Nutrition, Research Center for Evidence-Based Health Management, Maragheh University of Medical Sciences, Maragheh, Iran
| | - Zatollah Asemi
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran
| | - Fatemeh Sadoughi
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran
| | - Mehran Sharifi
- Department of Internal Medicine, School of Medicine, Cancer Prevention Research Center, Seyyed Al-Shohada Hospital, Isfahan University of Medical Sciences, Isfahan, Iran
| |
Collapse
|
|
32
|
Hu Y, Li Q, Hou M, Peng J, Yang X, Xu S. Magnitude and Temporal Trend of the Chronic Myeloid Leukemia: On the Basis of the Global Burden of Disease Study 2019. JCO Glob Oncol 2021; 7:1429-1441. [PMID: 34591599 PMCID: PMC8492379 DOI: 10.1200/go.21.00194] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2021] [Revised: 07/11/2021] [Accepted: 08/06/2021] [Indexed: 01/13/2023] Open
Abstract
PURPOSE To map the magnitudes and temporal trends of chronic myeloid leukemia (CML) along with its attributable risk factors, providing the essential foundation for targeted public policies at the national, regional, and global levels. MATERIALS AND METHODS We retrieved annual data on CML burden in 204 countries and regions from the Global Burden of Disease Study 2019 in 1990-2019. The estimated annual percentage change (EAPC) was calculated to quantify the temporal trends of CML burden by region, sex, and age group. RESULTS Globally, the age-standardized incidence rate of CML declined weakly over the past few years (EAPC: -1.04), but the number of incident cases increased by 54.1% to 65.8 × 103 in 2019. By contrast, a dramatic drop in death and disability-adjusted life years (DALYs) rate (EAPCs: -2.55; -2.69) led to a reduction in deaths and DALYs, especially in high-income regions. In 2019, the highest age-standardized death rate was observed in Ethiopia (1.89 per 100,000). The death rate of CML was pronounced among the population age above 70 years. DALYs of CML worldwide were primarily attributable to smoking (12.2%), high body mass index (5.0%), occupational exposure to benzene (0.9%), and occupational exposure to formaldehyde (0.3%) in 2019. CONCLUSION Although the mortality rate of CML has decreased significantly, the management of patients with CML cannot be neglected, especially in elders and developing regions.
Collapse
Affiliation(s)
- Yuefen Hu
- Department of Hematology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Qizhao Li
- Department of Hematology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Ming Hou
- Department of Hematology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Jun Peng
- Department of Hematology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Xiaorong Yang
- Clinical Epidemiology Unit, Qilu Hospital of Shandong University, Jinan, Shandong, China
| | - Shuqian Xu
- Department of Hematology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| |
Collapse
|
|
33
|
Common Genetic Aberrations Associated with Metabolic Interferences in Human Type-2 Diabetes and Acute Myeloid Leukemia: A Bioinformatics Approach. Int J Mol Sci 2021; 22:ijms22179322. [PMID: 34502231 PMCID: PMC8431701 DOI: 10.3390/ijms22179322] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Revised: 08/22/2021] [Accepted: 08/24/2021] [Indexed: 11/17/2022] Open
Abstract
Type-2 diabetes mellitus (T2D) is a chronic metabolic disorder, associated with an increased risk of developing solid tumors and hematological malignancies, including acute myeloid leukemia (AML). However, the genetic background underlying this predisposition remains elusive. We herein aimed at the exploration of the genetic variants, related transcriptomic changes and disturbances in metabolic pathways shared by T2D and AML, utilizing bioinformatics tools and repositories, as well as publicly available clinical datasets. Our approach revealed that rs11709077 and rs1801282, on PPARG, rs11108094 on USP44, rs6685701 on RPS6KA1 and rs7929543 on AC118942.1 comprise common SNPs susceptible to the two diseases and, together with 64 other co-inherited proxy SNPs, may affect the expression patterns of metabolic genes, such as USP44, METAP2, PPARG, TIMP4 and RPS6KA1, in adipose tissue, skeletal muscle, liver, pancreas and whole blood. Most importantly, a set of 86 AML/T2D common susceptibility genes was found to be significantly associated with metabolic cellular processes, including purine, pyrimidine, and choline metabolism, as well as insulin, AMPK, mTOR and PI3K signaling. Moreover, it was revealed that the whole blood of AML patients exhibits deregulated expression of certain T2D-related genes. Our findings support the existence of common metabolic perturbations in AML and T2D that may account for the increased risk for AML in T2D patients. Future studies may focus on the elucidation of these pathogenetic mechanisms in AML/T2D patients, as well as on the assessment of certain susceptibility variants and genes as potential biomarkers for AML development in the setting of T2D. Detection of shared therapeutic molecular targets may enforce the need for repurposing metabolic drugs in the therapeutic management of AML.
Collapse
|
|
34
|
Galati PC, Ribeiro CM, Pereira LTG, Amato AA. The association between excess body weight at diagnosis and pediatric leukemia prognosis: A systematic review and meta-analysis. Blood Rev 2021; 51:100870. [PMID: 34384603 DOI: 10.1016/j.blre.2021.100870] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2021] [Revised: 06/16/2021] [Accepted: 07/19/2021] [Indexed: 11/29/2022]
Abstract
Obesity affects the prognosis of several types of cancer. However, whether excess body weight is independently associated with adverse outcomes following initial pediatric acute leukemia (AL) treatment is still unclear. We conducted a systematic review and meta-analysis to investigate the impact of overweight/obesity at diagnosis on pediatric AL prognosis following initial treatment by performing an extensive database search up to January 22, 2021. Twenty-three studies were included, providing data for 15689 children with acute lymphoblastic leukemia (ALL) and 2506 children with acute myeloid leukemia (AML). Data from 12 studies were pooled in the meta-analysis. Children with overweight/obesity at diagnosis of ALL had poorer event free-survival (random-effects hazard ratio of 1.44, 95%CI 1.16-1.79, p = 0.0008), but no difference in overall survival (random-effects hazard ratio 1.33, 95%CI 0.77-2.29, p = 0.31) when compared with healthy-weight children. Children with overweight/obesity at diagnosis of AML had no difference in event-free survival (random-effects hazard ratio of 0.88, 95%CI 0.48-1.59, p = 0.66) or overall survival (random-effects hazard ratio 1.40, 95%CI 0.78-2.49, p = 0.26), when compared with healthy-weight children. This systematic review and meta-analysis indicates that overweight/obesity negatively affects the prognosis of children with ALL. Future studies should address the best approach to consider nutritional status in their management.
Collapse
Affiliation(s)
- Paula Cristina Galati
- Laboratory of Molecular Pharmacology, School of Health Sciences, University of Brasilia, Brazil; Children's Hospital of Brasilia José Alencar, Brasilia, Brazil
| | | | | | - Angélica Amorim Amato
- Laboratory of Molecular Pharmacology, School of Health Sciences, University of Brasilia, Brazil.
| |
Collapse
|
|
35
|
Li Z, MacDougald OA. Preclinical models for investigating how bone marrow adipocytes influence bone and hematopoietic cellularity. Best Pract Res Clin Endocrinol Metab 2021; 35:101547. [PMID: 34016532 PMCID: PMC8458229 DOI: 10.1016/j.beem.2021.101547] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Laboratory mice are a crucial preclinical model system for investigating bone marrow adipocyte (BMAd)-bone and BMAd-hematopoiesis interactions. In this review, we evaluate the suitability of mice to model common human diseases related to osteopenia or hematopoietic disorders, point out consistencies and discrepancies among different studies, and provide insights into model selection. Species, age, sex, skeletal site, and treatment protocol should all be considered when designing future studies.
Collapse
Affiliation(s)
- Ziru Li
- Department of Molecular & Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Ormond A MacDougald
- Department of Molecular & Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI, USA; Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA.
| |
Collapse
|
|
36
|
Orgel E, Framson C, Buxton R, Kim J, Li G, Tucci J, Freyer DR, Sun W, Oberley MJ, Dieli-Conwright C, Mittelman SD. Caloric and nutrient restriction to augment chemotherapy efficacy for acute lymphoblastic leukemia: the IDEAL trial. Blood Adv 2021; 5:1853-1861. [PMID: 33792627 PMCID: PMC8045487 DOI: 10.1182/bloodadvances.2020004018] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2020] [Accepted: 01/18/2021] [Indexed: 02/07/2023] Open
Abstract
Being overweight or obese (OW/OB) during B-cell acute lymphoblastic leukemia (B-ALL) induction is associated with chemoresistance as quantified by minimal residual disease (MRD). We hypothesized that caloric and nutrient restriction from diet/exercise could lessen gains in fat mass (FM) and reduce postinduction MRD. The Improving Diet and Exercise in ALL (IDEAL) trial enrolled patients 10 to 21 years old, newly diagnosed with B-ALL (n = 40), in comparison with a recent historical control (n = 80). Designed to achieve caloric deficits ≥20% during induction, reduce fat intake/glycemic load, and increase activity, IDEAL's end points were FM gain (primary), MRD ≥0.01%, and adherence/feasibility. Integrated biology explored biomarkers of OW/OB physiology. IDEAL intervention did not significantly reduce median FM change from baseline overall (+5.1% [interquartile range [IQR], 15.8] vs +10.7% [IQR, 16.0]; P = .13), but stratified analysis showed benefit in those OW/OB (+1.5% [IQR, 6.6] vs +9.7% [IQR, 11.1]; P = .02). After accounting for prognostic factors, IDEAL intervention significantly reduced MRD risk (odds ratio, 0.30; 95% confidence interval, 0.09-0.92; P = .02). The trial exceeded its adherence (≥75% of overall diet) and feasibility (≥80% completed visits) thresholds. Integrated biology found the IDEAL intervention increased circulating adiponectin and reduced insulin resistance. The IDEAL intervention was feasible, decreased fat gain in those OW/OB, and reduced MRD. This is the first study in any hematologic malignancy to demonstrate potential benefit from caloric restriction via diet/exercise to augment chemotherapy efficacy and improve disease response. A prospective, randomized trial is warranted for validation. These trials were registered at www.clinicaltrials.gov as #NCT02708108 (IDEAL trial) and #NCT01317940 (historical control).
Collapse
Affiliation(s)
| | | | - Rubi Buxton
- Division of Pediatric Rehabilitation Medicine, Children's Hospital Los Angeles, Los Angeles, CA
| | - Jiyoon Kim
- Department of Biostatistics and Computational Medicine, Jonathan and Karin Fielding School of Public Health, and
| | - Gang Li
- Department of Biostatistics and Computational Medicine, Jonathan and Karin Fielding School of Public Health, and
| | - Jonathan Tucci
- Division of Pediatric Endocrinology, UCLA Children's Discovery and Innovation Institute, David Geffen School of Medicine, University of California Los Angeles (UCLA), Los Angeles, CA
| | | | - Weili Sun
- Pediatric Hematology Oncology, Department of Pediatrics, City of Hope National Medical Center, Duarte, CA
| | - Matthew J Oberley
- Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles, Los Angeles, CA; and
| | - Christina Dieli-Conwright
- Division of Population Sciences, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA
| | - Steven D Mittelman
- Division of Pediatric Endocrinology, UCLA Children's Discovery and Innovation Institute, David Geffen School of Medicine, University of California Los Angeles (UCLA), Los Angeles, CA
| |
Collapse
|
|
37
|
Yassin MA, Kassem N, Ghassoub R. How I treat obesity and obesity related surgery in patients with chronic myeloid leukemia: An outcome of an ELN project. Clin Case Rep 2021; 9:1228-1234. [PMID: 33768817 PMCID: PMC7981640 DOI: 10.1002/ccr3.3738] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2020] [Revised: 11/17/2020] [Accepted: 12/17/2020] [Indexed: 01/31/2023] Open
Abstract
Obesity may affect treatment outcome in CML patients, therefore the treatment of this cohort of patients need careful monitoring, TKIs dose adjustment may be required for certain patients. Further studies are needed to determine the proper TKIs doses.
Collapse
Affiliation(s)
- Mohamed A. Yassin
- Hematology SectionMedical OncologyNational Center for Cancer care and ResearchHMCDohaQatar
| | - Nancy Kassem
- Department of PharmacyNational center for cancer care and Research HMCDohaQatar
| | - Rola Ghassoub
- Department of PharmacyNational center for cancer care and Research HMCDohaQatar
| |
Collapse
|
|
38
|
Podhorecka M. Metformin - its anti-cancer effects in hematologic malignancies. Oncol Rev 2021; 15:514. [PMID: 33747367 PMCID: PMC7967492 DOI: 10.4081/oncol.2021.514] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2020] [Accepted: 01/26/2021] [Indexed: 02/08/2023] Open
Abstract
The main anti-diabetic effect of metformin mediated through stimulation of adenosine monophosphate (AMP)-activated protein kinase (AMPK) is the inhibition of hepatic gluconeogenesis and triggering glucose uptake in skeletal muscles. Additionally, some new pathways, besides the AMPK activation, were discovered, that can explain wide-range properties of metformin. All these properties are now attracting the attention of researchers in the fields other than diabetes and the drug has been reported to have anti-cancer, immunoregulatory and anti-aging effects. Among others, the beneficial effects of metformin in hematological disorders like leukemias, lymphomas, and multiple myeloma were reported. Despite a great progress in therapy, these diseases are still incurable in most cases. Thus, there is an urgent need to discover novel, less toxic and more effective drugs especially for older or chemotherapy-resistant patients. In this review article, the current findings on the anti-cancer effect of metformin together with underlying possible mechanisms in blood cancers are discussed. However. to evaluate precisely these promising effects of metformin, more studies are required, because many of the published results are preclinical.
Collapse
Affiliation(s)
- Monika Podhorecka
- Department of Hematooncology and Bone Marrow Transplantation Medical University of Lublin, Poland
| |
Collapse
|
|
39
|
Kashanian SM, Li AY, Mustafa Ali M, Sutherland ME, Duong VH, Hambley BC, Zacholski K, El Chaer F, Holtzman NG, Imran M, Patzke CL, Cornu J, Duffy A, Dezern AE, Gojo I, Norsworthy KJ, Levis MJ, Smith BD, Baer MR, Ghiaur G, Emadi A. Increased body mass index is a risk factor for acute promyelocytic leukemia. EJHAEM 2021; 2:33-39. [PMID: 33693438 PMCID: PMC7943182 DOI: 10.1002/jha2.163] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/17/2020] [Accepted: 12/29/2020] [Indexed: 12/19/2022]
Abstract
Introduction Obesity has become increasingly prevalent worldwide and is a risk factor for many malignancies. We studied the correlation between body mass index (BMI) and the incidence of acute promyelocytic leukemia (APL), non-APL acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), and control hospitalized patients without leukemia in the same community. Methods Multi-center, retrospective analysis of 71,196 patients: APL (n=200), AML (n=437), ALL (n=103), non-leukemia hospitalized (n=70,456) admitted to University of Maryland and Johns Hopkins Cancer Centers, and University of Maryland Medical Center. Results Patients with APL had a significantly higher unadjusted mean and median BMI (32.5 kg/m2 and 30.3 kg/m2) than those with AML (28.3 kg/m2 and 27.1 kg/m2), ALL (29.3 kg/m2 and 27.7 kg/m2), and others (29.3 kg/m2 and 27.7 kg/m2) (p<0.001). Log-transformed BMI multivariable models demonstrated that APL patients had a significantly higher adjusted mean BMI by 3.7 kg/m2 (p<0.001) or approximately 10% (p<0.01) compared to the other groups, when controlled for sex, race, and age. Conclusions This study confirms that when controlled for sex, age, and race there is an independent association of higher BMI among patients with APL compared to patients with ALL, AML, and hospitalized individuals without leukemia in the same community.
Collapse
Affiliation(s)
- Sarah M. Kashanian
- Department of MedicineUniversity of Maryland School of MedicineBaltimoreMaryland
| | - Andrew Y. Li
- Department of MedicineUniversity of Maryland School of MedicineBaltimoreMaryland
| | - Moaath Mustafa Ali
- Department of MedicineUniversity of Maryland School of MedicineBaltimoreMaryland
- University of Maryland Greenebaum Comprehensive Cancer CenterBaltimoreMaryland
| | - Mark E. Sutherland
- Department of MedicineUniversity of Maryland School of MedicineBaltimoreMaryland
- Department of Pulmonary and Critical Care MedicineUniversity of Maryland School of MedicineBaltimoreMaryland
- Department of Emergency MedicineUniversity of Maryland School of MedicineBaltimoreMaryland
| | - Vu H. Duong
- Department of MedicineUniversity of Maryland School of MedicineBaltimoreMaryland
- University of Maryland Greenebaum Comprehensive Cancer CenterBaltimoreMaryland
| | - Bryan C. Hambley
- The Sidney Kimmel Comprehensive Cancer Center at Johns HopkinsBaltimoreMaryland
| | - Kyle Zacholski
- The Sidney Kimmel Comprehensive Cancer Center at Johns HopkinsBaltimoreMaryland
| | - Firas El Chaer
- Department of MedicineUniversity of Maryland School of MedicineBaltimoreMaryland
- University of Maryland Greenebaum Comprehensive Cancer CenterBaltimoreMaryland
| | - Noa G. Holtzman
- Department of MedicineUniversity of Maryland School of MedicineBaltimoreMaryland
- University of Maryland Greenebaum Comprehensive Cancer CenterBaltimoreMaryland
| | - Mohammad Imran
- Department of MedicineUniversity of Maryland School of MedicineBaltimoreMaryland
- University of Maryland Greenebaum Comprehensive Cancer CenterBaltimoreMaryland
| | - Ciera L. Patzke
- University of Maryland Greenebaum Comprehensive Cancer CenterBaltimoreMaryland
- Department of PharmacyUniversity of Maryland Medical CenterBaltimoreMaryland
| | - Jonathan Cornu
- Department of PharmacyUniversity of Maryland Medical CenterBaltimoreMaryland
| | - Alison Duffy
- University of Maryland Greenebaum Comprehensive Cancer CenterBaltimoreMaryland
- Department of PharmacyUniversity of Maryland Medical CenterBaltimoreMaryland
- University of Maryland School of PharmacyBaltimoreMaryland
| | - Amy E. Dezern
- The Sidney Kimmel Comprehensive Cancer Center at Johns HopkinsBaltimoreMaryland
| | - Ivana Gojo
- The Sidney Kimmel Comprehensive Cancer Center at Johns HopkinsBaltimoreMaryland
| | - Kelly J. Norsworthy
- The Sidney Kimmel Comprehensive Cancer Center at Johns HopkinsBaltimoreMaryland
| | - Mark J. Levis
- The Sidney Kimmel Comprehensive Cancer Center at Johns HopkinsBaltimoreMaryland
| | - B. Douglas Smith
- The Sidney Kimmel Comprehensive Cancer Center at Johns HopkinsBaltimoreMaryland
| | - Maria R. Baer
- Department of MedicineUniversity of Maryland School of MedicineBaltimoreMaryland
- University of Maryland Greenebaum Comprehensive Cancer CenterBaltimoreMaryland
| | - Gabriel Ghiaur
- The Sidney Kimmel Comprehensive Cancer Center at Johns HopkinsBaltimoreMaryland
| | - Ashkan Emadi
- Department of MedicineUniversity of Maryland School of MedicineBaltimoreMaryland
- University of Maryland Greenebaum Comprehensive Cancer CenterBaltimoreMaryland
- Department of PharmacologyUniversity of Maryland School of MedicineBaltimoreMaryland
| |
Collapse
|
|
40
|
Ochs MA, Perissinotti AJ, Marini BL, Burke PW, Bixby DL, Pettit KM, Benitez LL. Impact of high dose cytarabine dosing strategies in obese patients with acute myeloid leukemia. Leuk Res 2021; 102:106517. [PMID: 33561633 DOI: 10.1016/j.leukres.2021.106517] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2020] [Revised: 01/18/2021] [Accepted: 01/22/2021] [Indexed: 12/31/2022]
Abstract
High dose cytarabine (HIDAC) consolidation has demonstrated a survival benefit in patients with acute myeloid leukemia (AML). The increasing prevalence of obesity and the toxicity risk with this therapy renders important the quantification of potential risks with weight-based dosing in this patient population. The American Society of Clinical Oncology published recommendations on chemotherapy dosing in obese patients, but patients with leukemia were excluded from analysis. This was a retrospective comparison of safety and efficacy outcomes in obese and non-obese patients with AML who received HIDAC consolidation. Thirty-nine (41.9 %) patients received dose adjusted HIDAC in cycle 1. Nine of the 40 patients in the obese group received HIDAC dose-adjusted for obesity. The combined incidence of cycle delays, febrile neutropenia, or documented infection was 41.5 % in non-obese patients compared to 57.5 % in obese patients (p = 0.127). The median overall survival (OS) and event free survival (EFS) were not reached in both cohorts. The estimated 36-month overall survival was 76.4 % (95 % CI 0.623-0.905) in non-obese patients, compared to 66.1 % (95 % CI 0.472-0.85) in obese patients. There were no significant differences in safety or efficacy outcomes for obese versus non-obese patients who received HIDAC consolidation. For class III obesity, baseline dose-adjustments were more common.
Collapse
Affiliation(s)
- Madeleine A Ochs
- Department of Pharmacy Services and Clinical Pharmacy, Michigan Medicine, Ann Arbor, MI, USA
| | - Anthony J Perissinotti
- Department of Pharmacy Services and Clinical Pharmacy, Michigan Medicine, Ann Arbor, MI, USA
| | - Bernard L Marini
- Department of Pharmacy Services and Clinical Pharmacy, Michigan Medicine, Ann Arbor, MI, USA; University of Michigan College of Pharmacy, Ann Arbor, MI, USA
| | - Patrick W Burke
- Department of Internal Medicine and Division of Hematology and Oncology, Michigan Medicine and University of Michigan Medical School, Ann Arbor, MI, USA
| | - Dale L Bixby
- Department of Internal Medicine and Division of Hematology and Oncology, Michigan Medicine and University of Michigan Medical School, Ann Arbor, MI, USA
| | - Kristen M Pettit
- Department of Internal Medicine and Division of Hematology and Oncology, Michigan Medicine and University of Michigan Medical School, Ann Arbor, MI, USA
| | - Lydia L Benitez
- Department of Pharmacy Services and Clinical Pharmacy, Michigan Medicine, Ann Arbor, MI, USA; University of Michigan College of Pharmacy, Ann Arbor, MI, USA.
| |
Collapse
|
|
41
|
Zhang TJ, Xu ZJ, Gu Y, Ma JC, Wen XM, Zhang W, Deng ZQ, Qian J, Lin J, Zhou JD. Identification and validation of obesity-related gene LEP methylation as a prognostic indicator in patients with acute myeloid leukemia. Clin Epigenetics 2021; 13:16. [PMID: 33485366 PMCID: PMC7824952 DOI: 10.1186/s13148-021-01013-9] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2020] [Accepted: 01/13/2021] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Obesity confers enhanced risk for multiple diseases including cancer. The DNA methylation alterations in obesity-related genes have been implicated in several human solid tumors. However, the underlying role and clinical implication of DNA methylation of obesity-related genes in acute myeloid leukemia (AML) has yet to be elucidated. RESULTS In the discovery stage, we identified that DNA methylation-associated LEP expression was correlated with prognosis among obesity-related genes from the databases of The Cancer Genome Atlas. In the validation stage, we verified that LEP hypermethylation was a frequent event in AML by both targeted bisulfite sequencing and real-time quantitative methylation-specific PCR. Moreover, LEP hypermethylation, correlated with reduced LEP expression, was found to be associated with higher bone marrow blasts, lower platelets, and lower complete remission (CR) rate in AML. Importantly, survival analysis showed that LEP hypermethylation was significantly associated with shorter overall survival (OS) in AML. Moreover, multivariate analysis disclosed that LEP hypermethylation was an independent risk factor affecting CR and OS among non-M3 AML. By clinical and bioinformatics analysis, LEP may be also regulated by miR-517a/b expression in AML. CONCLUSIONS Our findings indicated that the obesity-related gene LEP methylation is associated with LEP inactivation, and acts as an independent prognostic predictor in AML.
Collapse
Affiliation(s)
- Ting-Juan Zhang
- Department of Hematology, Affiliated People's Hospital of Jiangsu University, 8 Dianli Rd., Zhenjiang, 212002, People's Republic of China.,Zhenjiang Clinical Research Center of Hematology, Zhenjiang, Jiangsu, People's Republic of China.,The Key Lab of Precision Diagnosis and Treatment in Hematologic Malignancies of Zhenjiang City, Zhenjiang, Jiangsu, People's Republic of China
| | - Zi-Jun Xu
- Zhenjiang Clinical Research Center of Hematology, Zhenjiang, Jiangsu, People's Republic of China.,The Key Lab of Precision Diagnosis and Treatment in Hematologic Malignancies of Zhenjiang City, Zhenjiang, Jiangsu, People's Republic of China.,Laboratory Center, Affiliated People's Hospital of Jiangsu University, 8 Dianli Rd., Zhenjiang, 212002, People's Republic of China
| | - Yu Gu
- Department of Hematology, Affiliated People's Hospital of Jiangsu University, 8 Dianli Rd., Zhenjiang, 212002, People's Republic of China.,Zhenjiang Clinical Research Center of Hematology, Zhenjiang, Jiangsu, People's Republic of China.,The Key Lab of Precision Diagnosis and Treatment in Hematologic Malignancies of Zhenjiang City, Zhenjiang, Jiangsu, People's Republic of China
| | - Ji-Chun Ma
- Zhenjiang Clinical Research Center of Hematology, Zhenjiang, Jiangsu, People's Republic of China.,The Key Lab of Precision Diagnosis and Treatment in Hematologic Malignancies of Zhenjiang City, Zhenjiang, Jiangsu, People's Republic of China.,Laboratory Center, Affiliated People's Hospital of Jiangsu University, 8 Dianli Rd., Zhenjiang, 212002, People's Republic of China
| | - Xiang-Mei Wen
- Zhenjiang Clinical Research Center of Hematology, Zhenjiang, Jiangsu, People's Republic of China.,The Key Lab of Precision Diagnosis and Treatment in Hematologic Malignancies of Zhenjiang City, Zhenjiang, Jiangsu, People's Republic of China.,Laboratory Center, Affiliated People's Hospital of Jiangsu University, 8 Dianli Rd., Zhenjiang, 212002, People's Republic of China
| | - Wei Zhang
- Department of Hematology, Affiliated People's Hospital of Jiangsu University, 8 Dianli Rd., Zhenjiang, 212002, People's Republic of China.,Zhenjiang Clinical Research Center of Hematology, Zhenjiang, Jiangsu, People's Republic of China.,The Key Lab of Precision Diagnosis and Treatment in Hematologic Malignancies of Zhenjiang City, Zhenjiang, Jiangsu, People's Republic of China
| | - Zhao-Qun Deng
- Zhenjiang Clinical Research Center of Hematology, Zhenjiang, Jiangsu, People's Republic of China.,The Key Lab of Precision Diagnosis and Treatment in Hematologic Malignancies of Zhenjiang City, Zhenjiang, Jiangsu, People's Republic of China.,Laboratory Center, Affiliated People's Hospital of Jiangsu University, 8 Dianli Rd., Zhenjiang, 212002, People's Republic of China
| | - Jun Qian
- Department of Hematology, Affiliated People's Hospital of Jiangsu University, 8 Dianli Rd., Zhenjiang, 212002, People's Republic of China. .,Zhenjiang Clinical Research Center of Hematology, Zhenjiang, Jiangsu, People's Republic of China. .,The Key Lab of Precision Diagnosis and Treatment in Hematologic Malignancies of Zhenjiang City, Zhenjiang, Jiangsu, People's Republic of China.
| | - Jiang Lin
- Department of Hematology, Affiliated People's Hospital of Jiangsu University, 8 Dianli Rd., Zhenjiang, 212002, People's Republic of China. .,Zhenjiang Clinical Research Center of Hematology, Zhenjiang, Jiangsu, People's Republic of China. .,The Key Lab of Precision Diagnosis and Treatment in Hematologic Malignancies of Zhenjiang City, Zhenjiang, Jiangsu, People's Republic of China. .,Laboratory Center, Affiliated People's Hospital of Jiangsu University, 8 Dianli Rd., Zhenjiang, 212002, People's Republic of China.
| | - Jing-Dong Zhou
- Department of Hematology, Affiliated People's Hospital of Jiangsu University, 8 Dianli Rd., Zhenjiang, 212002, People's Republic of China. .,Zhenjiang Clinical Research Center of Hematology, Zhenjiang, Jiangsu, People's Republic of China. .,The Key Lab of Precision Diagnosis and Treatment in Hematologic Malignancies of Zhenjiang City, Zhenjiang, Jiangsu, People's Republic of China.
| |
Collapse
|
|
42
|
da Cunha Júnior AD, Zanette DL, Pericole FV, Olalla Saad ST, Barreto Campello Carvalheira J. Obesity as a Possible Risk Factor for Progression from Monoclonal Gammopathy of Undetermined Significance Progression into Multiple Myeloma: Could Myeloma Be Prevented with Metformin Treatment? Adv Hematol 2021; 2021:6615684. [PMID: 33531904 PMCID: PMC7834834 DOI: 10.1155/2021/6615684] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2020] [Revised: 12/22/2020] [Accepted: 01/08/2021] [Indexed: 02/07/2023] Open
Abstract
Obesity is increasingly associated with the transformation of monoclonal gammopathy of undetermined significance (MGUS) into multiple myeloma (MM). Obesity, MGUS, and MM share common etiopathogenesis mechanisms including altered insulin axis and the action of inflammatory cytokines. Consistent with this interconnection, metformin could predominantly exert inhibition of these pathophysiological factors and thus be an attractive therapeutic option for MGUS. Despite the possible clinical significance, only a limited number of epidemiological studies have focused on obesity as a risk factor for MGUS and MM. This review describes multiple biological pathways modulated by metformin at the cellular level and their possible impacts on the biology of MGUS and its progression into MM.
Collapse
Affiliation(s)
- Ademar Dantas da Cunha Júnior
- Division of Oncology, Department of Internal Medicine, Faculty of Medical Sciences, State University of Campinas (UNICAMP), Campinas, SP, Brazil
- Hematology and Oncology Clinics, Cancer Hospital of Cascavel, União Oeste de Estudos e Combate ao Câncer (UOPECCAN), Cascavel, PR, Brazil
- Department of Internal Medicine, State University of Western Paraná (UNIOESTE), Cascavel, PR, Brazil
| | - Dalila Luciola Zanette
- Laboratory for Applied Science and Technology in Health, Carlos Chagas Institute (ICC), Oswaldo Cruz Foundation (Fiocruz), Rio de Janeiro, Brazil
| | | | | | - José Barreto Campello Carvalheira
- Division of Oncology, Department of Internal Medicine, Faculty of Medical Sciences, State University of Campinas (UNICAMP), Campinas, SP, Brazil
| |
Collapse
|
|
43
|
Recalde M, Davila-Batista V, Díaz Y, Leitzmann M, Romieu I, Freisling H, Duarte-Salles T. Body mass index and waist circumference in relation to the risk of 26 types of cancer: a prospective cohort study of 3.5 million adults in Spain. BMC Med 2021; 19:10. [PMID: 33441148 PMCID: PMC7807518 DOI: 10.1186/s12916-020-01877-3] [Citation(s) in RCA: 65] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/09/2020] [Accepted: 12/01/2020] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND A high body mass index (BMI) has been associated with increased risk of several cancers; however, whether BMI is related to a larger number of cancers than currently recognized is unclear. Moreover, whether waist circumference (WC) is more strongly associated with specific cancers than BMI is not well established. We aimed to investigate the associations between BMI and 26 cancers accounting for non-linearity and residual confounding by smoking status as well as to compare cancer risk estimates between BMI and WC. METHODS Prospective cohort study with population-based electronic health records from Catalonia, Spain. We included 3,658,417 adults aged ≥ 18 years and free of cancer at baseline between 2006 and 2017. Our main outcome measures were cause-specific hazard ratios (HRs) with 99% confidence intervals (CIs) for incident cancer at 26 anatomical sites. RESULTS After a median follow-up time of 8.3 years, 202,837 participants were diagnosed with cancer. A higher BMI was positively associated with risk of nine cancers (corpus uteri, kidney, gallbladder, thyroid, colorectal, breast post-menopausal, multiple myeloma, leukemia, non-Hodgkin lymphoma) and was positively associated with three additional cancers among never smokers (head and neck, brain and central nervous system, Hodgkin lymphoma). The respective HRs (per 5 kg/m2 increment) ranged from 1.04 (99%CI 1.01 to 1.08) for non-Hodgkin lymphoma to 1.49 (1.45 to 1.53) for corpus uteri cancer. While BMI was negatively associated to five cancer types in the linear analyses of the overall population, accounting for non-linearity revealed that BMI was associated to prostate cancer in a U-shaped manner and to head and neck, esophagus, larynx, and trachea, bronchus and lung cancers in an L-shaped fashion, suggesting that low BMIs are an approximation of heavy smoking. Of the 291,305 participants with a WC measurement, 27,837 were diagnosed with cancer. The 99%CIs of the BMI and WC point estimates (per 1 standard deviation increment) overlapped for all cancers. CONCLUSIONS In this large Southern European study, a higher BMI was associated with increased risk of twelve cancers, including four hematological and head and neck (only among never smokers) cancers. Furthermore, BMI and WC showed comparable estimates of cancer risk associated with adiposity.
Collapse
Affiliation(s)
- Martina Recalde
- Fundació Institut Universitari per a la recerca a l’Atenció Primària de Salut Jordi Gol i Gurina (IDIAPJGol), Gran Via Corts Catalanes, 587 àtic, 08007 Barcelona, Spain
- Universitat Autònoma de Barcelona, Campus de Bellaterra, 08193 Bellaterra, Spain
| | - Veronica Davila-Batista
- Fundació Institut Universitari per a la recerca a l’Atenció Primària de Salut Jordi Gol i Gurina (IDIAPJGol), Gran Via Corts Catalanes, 587 àtic, 08007 Barcelona, Spain
- International Agency for Research on Cancer (IARC-WHO), 150 Cours Albert Thomas, 69008 Lyon, France
- Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP), 28029 Madrid, Spain
| | - Yesika Díaz
- Fundació Institut Universitari per a la recerca a l’Atenció Primària de Salut Jordi Gol i Gurina (IDIAPJGol), Gran Via Corts Catalanes, 587 àtic, 08007 Barcelona, Spain
| | - Michael Leitzmann
- Department of Epidemiology and Preventive Medicine, University of Regensburg, Franz-Josef-Strauss-Allee 11, 93053 Regensburg, Germany
| | - Isabelle Romieu
- Center for Research on Population Health, National Institute of Public Health, Mexico City, Mexico
- Hubert Department of Global Health, Emory University, Atlanta, GA USA
| | - Heinz Freisling
- International Agency for Research on Cancer (IARC-WHO), 150 Cours Albert Thomas, 69008 Lyon, France
| | - Talita Duarte-Salles
- Fundació Institut Universitari per a la recerca a l’Atenció Primària de Salut Jordi Gol i Gurina (IDIAPJGol), Gran Via Corts Catalanes, 587 àtic, 08007 Barcelona, Spain
| |
Collapse
|
|
44
|
Association between high-density lipoprotein cholesterol level and risk of hematologic malignancy. Leukemia 2020; 35:1356-1364. [PMID: 33268820 DOI: 10.1038/s41375-020-01081-5] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2020] [Revised: 09/28/2020] [Accepted: 10/25/2020] [Indexed: 12/12/2022]
Abstract
This study investigated the relationships between HDL-C and major types of blood cancers. Competing risks regression was used to examine the hazard ratios of hematologic malignancies in 9,596,145 individuals (≥20 years) using data from the Korean National Health Insurance Service (2009-2017). The incidence of the following hematologic cancers was determined based on the International Classification of Diseases 10th revision: Multiple Myeloma (MM), Hodgkin Lymphoma (HL), Non-Hodgkin Lymphoma (NHL), Lymphoid Leukemia (LL), and Myeloid Leukemia (ML). During an average of 8.3 years of follow-up (79,179,225 person-years), 15,864 incident hematologic malignancies were identified. Compared to those in the highest HDL-C quartile, subjects in the lowest HDL-C quartile had the highest risk of all hematologic cancers combined (adjusted hazard ratio [HR], 95% confidence interval [95% CI] = 1.31, 1.25-1.37) and of each respective type of blood cancer, as follows: MM (HR 1.61, 95% CI, 1.46-1.76), HL (HR 1.35, 95% CI 1.07-1.70), NHL (HR 1.12, 95%CI 1.04-1.21), LL (HR 1.36, 95% CI 1.16-1.61), and ML (HR 1.33, 95% CI 1.22-1.45). Low HDL-C level was significantly associated with increased risk of hematologic malignancy, suggesting that a low HDL-C level is an independent risk factor and preclinical marker for hematologic malignancy.
Collapse
|
|
45
|
Van de Louw A, Zhu X, Frankenfield D. Obesity and malnutrition in critically ill patients with acute myeloid leukemia: Prevalence and impact on mortality. Nutrition 2020; 79-80:110956. [PMID: 32862120 DOI: 10.1016/j.nut.2020.110956] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2020] [Revised: 06/28/2020] [Accepted: 07/04/2020] [Indexed: 02/04/2023]
Abstract
OBJECTIVES Obese patients have an increased risk of developing acute myeloid leukemia (AML), which in turn predisposes to malnutrition. Obesity has been associated with improved survival in critically ill patients (obesity paradox), but this effect seems to disappear when adjusting for malnutrition. How obesity and malnutrition interplay to affect mortality in critically ill patients with AML has not been addressed and was the objective of this study. METHODS This was a retrospective chart review of adult patients with AML who were admitted to the medical intensive care unit and had a nutrition consultation between 2011 and 2018. Demographic characteristics, comorbidities, severity scores, and laboratory parameters, as well as data on vital organ support, hospital mortality, and long-term survival were collected. Obesity was defined by a body mass index of ≥30 kg/m2 and malnutrition per the American Society for Parenteral and Enteral Nutrition criteria. Patients were compared based on nutrition and weight status, and hospital and long-term mortality were analyzed with logistic regression and Kaplan-Meier curves. RESULTS We included 145 patients (57% obese, 30% malnourished) in the study. As time from AML diagnosis elapsed, obesity was less frequent and malnutrition more prevalent, with 25% of obese patients also presenting with malnutrition. Hospital mortality was 40% and associated with malnutrition in nonobese patients (odds ratio: 5.1; 95% confidence interval, 1.3-21.8; P = 0.02) and sequential organ failure assessment severity score (odds ratio: 1.5; 95% confidence interval, 1.3-1.7; P < 0.0001). Sensitivity analyses confirmed the association between malnutrition, but not obesity, and hospital mortality. Obese malnourished patients had lower long-term survival, but this was not significant (P = 0.25). CONCLUSIONS Critically ill patients with AML have a high prevalence of malnutrition and obesity, which are sometimes associated. Malnutrition, but not obesity, was associated with hospital mortality.
Collapse
Affiliation(s)
- Andry Van de Louw
- Division of Pulmonary and Critical Care Medicine, Penn State Health Hershey Medical Center, Hershey, Pennsylvania.
| | - Xijun Zhu
- Division of Pulmonary and Critical Care Medicine, Penn State Health Hershey Medical Center, Hershey, Pennsylvania
| | - David Frankenfield
- Department of Clinical Nutrition, Penn State Health Hershey Medical Center, Hershey, Pennsylvania
| |
Collapse
|
|
46
|
Orgel E, Sea JL, Mittelman SD. Mechanisms by Which Obesity Impacts Survival from Acute Lymphoblastic Leukemia. J Natl Cancer Inst Monogr 2020; 2019:152-156. [PMID: 31532535 DOI: 10.1093/jncimonographs/lgz020] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2019] [Revised: 04/22/2019] [Accepted: 07/01/2019] [Indexed: 01/29/2023] Open
Abstract
The prevalence of obesity has steadily risen over the past decades, even doubling in more than 70 countries. High levels of body fat (adiposity) and obesity are associated with endocrine and hormonal dysregulation, cardiovascular compromise, hepatic dysfunction, pancreatitis, changes in drug metabolism and clearance, inflammation, and metabolic stress. It is thus unsurprising that obesity can affect the development of and survival from a wide variety of malignancies. This review focuses on acute lymphoblastic leukemia, the most common malignancy in children, to explore the multiple mechanisms connecting acute lymphoblastic leukemia, obesity, and adipocytes, and the implications for leukemia therapy.
Collapse
Affiliation(s)
- Etan Orgel
- Children's Center for Cancer and Blood Diseases, Children's Hospital Los Angeles, Los Angeles, CA Department of Pediatrics, Keck School of Medicine, University of Southern California
| | - Jessica L Sea
- Division of Pediatric Endocrinology, UCLA Children's Discovery and Innovation Institute, David Geffen School of Medicine UCLA, Los Angeles, CA
| | - Steven D Mittelman
- Division of Pediatric Endocrinology, UCLA Children's Discovery and Innovation Institute, David Geffen School of Medicine UCLA, Los Angeles, CA
| |
Collapse
|
|
47
|
Van de Louw A, Zhu X, Frankenfield D. How obesity and malnutrition interplay to affect mortality in critically ill patients with hematological malignancies: a retrospective cohort study. Leuk Lymphoma 2020; 61:2027-2029. [PMID: 32366140 DOI: 10.1080/10428194.2020.1759053] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
Affiliation(s)
- Andry Van de Louw
- Division of Pulmonary and Critical Care Medicine, Penn State Health Hershey Medical Center, Hershey, PA, USA
| | - Xijun Zhu
- Division of Pulmonary and Critical Care Medicine, Penn State Health Hershey Medical Center, Hershey, PA, USA
| | - David Frankenfield
- Department of Clinical Nutrition, Penn State Health Hershey Medical Center, Hershey, PA, USA
| |
Collapse
|
|
48
|
Mogensen PR, Grell K, Schmiegelow K, Overgaard UM, Wolthers BO, Mogensen SS, Vaag A, Frandsen TL. Dyslipidemia at diagnosis of childhood acute lymphoblastic leukemia. PLoS One 2020; 15:e0231209. [PMID: 32251440 PMCID: PMC7135240 DOI: 10.1371/journal.pone.0231209] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2019] [Accepted: 03/18/2020] [Indexed: 01/19/2023] Open
Abstract
As survival of acute lymphoblastic leukemia (ALL) exceeds 90%, limiting therapy-related toxicity has become a key challenge. Cardio-metabolic dysfunction is a challenge during and after childhood ALL therapy. In a single center study, we measured triglycerides (TG), total cholesterol (TC), high (HDL) and low density lipoproteins (LDL) levels at diagnosis and assessed the association with BMI, early therapy response, on-therapy hyperlipidemia and the toxicities; thromboembolism, osteonecrosis and pancreatitis. We included 127 children (1.0-17.9 years) all treated according to the NOPHO ALL2008 protocol. Dyslipidemia was identified at ALL-diagnosis in 99% of the patients, dominated by reduced HDL levels (98%) and mild hypertriglyceridemia (61%). Hypertriglyceridemia was not associated with body mass index (P = 0.71). Five percent of patients had mild hypercholesterolemia, 14% had mild hypocholesterolemia, 13% had decreased and 1% elevated LDL-levels. Increased TG and TC levels at ALL-diagnosis were not associated with any on-therapy lipid levels. Lipid levels and BMI were not associated to MRD after induction therapy; However, BMI and hypercholesterolemia were associated with worse risk group stratification (P<0.045 for all). The cumulative incidence of thromboembolism was increased both for patients with hypo- (20.0%) and hypercholesterolemia (16.7%) compared to patients with normal TC levels (2.2%) at diagnosis (P = 0.0074). In conclusion, dyslipidemic changes were present prior to ALL-therapy in children with ALL but did not seem to affect dysmetabolic traits during therapy and were not predictive of on-therapy toxicities apart from an association between dyscholesterolemia at time of ALL-diagnosis and risk of thromboembolism. However, the latter should be interpreted with caution due to low number in the groups.
Collapse
Affiliation(s)
- Pernille Rudebeck Mogensen
- Department of Diabetes and Bone-metabolic Research Unit, University Hospital Rigshospitalet, Copenhagen, Denmark
- Department of Pediatrics and Adolescent Medicine, University Hospital Rigshospitalet, Copenhagen, Denmark
| | - Kathrine Grell
- Department of Pediatrics and Adolescent Medicine, University Hospital Rigshospitalet, Copenhagen, Denmark
- Section of Biostatistics, Department of Public Health, University of Copenhagen, Copenhagen, Denmark
| | - Kjeld Schmiegelow
- Department of Pediatrics and Adolescent Medicine, University Hospital Rigshospitalet, Copenhagen, Denmark
- Institute of Clinical Medicine, University of Copenhagen, Denmark
| | | | - Benjamin Ole Wolthers
- Department of Pediatrics and Adolescent Medicine, University Hospital Rigshospitalet, Copenhagen, Denmark
| | - Signe Sloth Mogensen
- Department of Pediatrics and Adolescent Medicine, University Hospital Rigshospitalet, Copenhagen, Denmark
| | - Allan Vaag
- Steno Diabetes Center Copenhagen, Copenhagen, Denmark
| | - Thomas Leth Frandsen
- Department of Pediatrics and Adolescent Medicine, University Hospital Rigshospitalet, Copenhagen, Denmark
| |
Collapse
|
|
49
|
Gomes CDC, da Silva CCG, do Nascimento PRP, Lemos TMDAM, Marcadenti A, Markoski MM, Fayh APT. Nutritional status and appetite-regulating hormones in early treatment of acute lymphoblastic leukemia among children and adolescents: a cohort study. SAO PAULO MED J 2020; 138:118-125. [PMID: 32491080 PMCID: PMC9662846 DOI: 10.1590/1516-3180.2019.0307.r1.19112019] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2019] [Accepted: 11/19/2019] [Indexed: 11/22/2022] Open
Abstract
BACKGROUND Children with acute lymphoblastic leukemia are at risk of malnutrition, but few studies have described the changes in nutritional status during the different phases of chemotherapy. OBJECTIVE To evaluate changes in nutritional status, food intake and appetite-regulating hormones among children and adolescents with acute lymphoblastic leukemia in the first phase of chemotherapy. DESIGN AND SETTING Cohort study developed in the pediatric oncology departments of two hospitals in the city of Natal, Rio Grande do Norte, Brazil. METHODS Fourteen children/adolescents (mean age of 7 years; 50% female) with acute lymphoblastic leukemia were monitored over the 28 days of an induction chemotherapy cycle. Anthropometric measurements, 24-hours food weight records and appetite-regulating hormone levels (ghrelin, leptin, insulin and cortisol) were obtained at three different times (before, in the middle and at the end of the induction phase). RESULTS Most of the patients (85.7%) had normal weight at the beginning of the treatment, and this did not change significantly during the 28 days. Energy and nutrient intakes improved from the start of the treatment to the midpoint, according to the ghrelin levels (from 511.1 ± 8.3 to 519.3 ± 6.6 pg/ml; P = 0.027). Other appetite-regulating hormones did not present changes. CONCLUSION Food consumption improves during the first phase of treatment, without alterations in anthropometric nutritional status.
Collapse
Affiliation(s)
- Camila de Carvalho Gomes
- MSc. Dietitian, Department of Nutrition, Universidade Federal do Rio Grande do Norte (UFRN), Natal (RN), Brazil.
| | - Cassia Camila Gomes da Silva
- BSc. Dietitian, Department of Nutrition, Universidade Federal do Rio Grande do Norte (UFRN), Natal (RN), Brazil.
| | | | | | - Aline Marcadenti
- PhD. Registered Nutritionist and Professor, Postgraduate Program on Health Sciences (Cardiology), Instituto de Cardiologia, Fundação Universitária de Cardiologia (IC/FUC), Porto Alegre (RS), Brazil; Professor, Postgraduate Program on Nutritional Sciences, Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), Porto Alegre (RS); and Researcher, Instituto de Pesquisa do Hospital do Coração (IP-HCor), São Paulo (SP), Brazil.
| | - Melissa Medeiros Markoski
- PhD. Biologist and Professor, Postgraduate Program on Biosciences, Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), Porto Alegre (RS), Brazil.
| | - Ana Paula Trussardi Fayh
- PhD. Dietitian and Associate Professor, Undergraduate Nutrition Program and Stricto Sensu Postgraduate Programs on Physical Education, Nutrition and Health Sciences, Universidade Federal do Rio Grande do Norte (UFRN), Natal (RN), Brazil.
| |
Collapse
|
|
50
|
Dhakal P, Lyden E, Lee A, Michalski J, Al-Kadhimi ZS, Maness LJ, Gundabolu K, Bhatt VR. Effects of Obesity on Overall Survival of Adults With Acute Myeloid Leukemia. CLINICAL LYMPHOMA, MYELOMA & LEUKEMIA 2020; 20:e131-e136. [PMID: 32029396 PMCID: PMC9302407 DOI: 10.1016/j.clml.2019.11.001] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/31/2019] [Revised: 10/14/2019] [Accepted: 11/01/2019] [Indexed: 12/23/2022]
Abstract
BACKGROUND The role of obesity in prognosis of acute myeloid leukemia (AML) is debatable. Our retrospective study aimed to determine the effect of obesity on overall survival (OS) in AML. PATIENTS AND METHODS AML patients diagnosed at University of Nebraska Medical Center were divided into 3 groups according to body mass index (BMI): normal (18.5-25 kg/m2) or underweight (< 18.5 kg/m2); overweight (25-30 kg/m2); and obese (≥ 30 kg/m2). Chi-square test, Kruskal-Wallis test, and ANOVA were used to examine the association of BMI with baseline characteristics. Mann-Whitney test was used for pairwise comparisons of hematopoietic cell transplantation (HCT) comorbidity index. Bonferroni correction was used to adjust P values. OS, defined as time from diagnosis to death from any cause, was determined by the Kaplan-Meier method; comparisons of survival curves were done using log-rank test. Cox regression analysis was performed to detect the effect of BMI on OS. RESULTS Of 314 patients, 38% were obese, 68% received intensive chemotherapy, and 30% underwent HCT. Patient characteristics for all BMI groups were similar except greater HCT comorbidity index in obese patients. Actual body weight was used to calculate the chemotherapy dose in 92% of obese patients. The rates of receipt of HCT in normal, overweight, and obese groups were 33%, 32%, and 25%, respectively (P = .6). One-year OS values for normal/underweight, overweight, and obese groups was 42%, 45%, and 39%, respectively (P = .31). On multivariate analysis, obesity was associated with worse OS compared to normal-weight (hazard ratio = 0.6; 95% confidence interval, 0.4-0.9; P = .03) but not overweight patients. CONCLUSION Obesity confers worse prognosis in AML. Differences in OS were not the result of differences in chemotherapy dose or receipt of HCT.
Collapse
Affiliation(s)
- Prajwal Dhakal
- Division of Oncology and Hematology, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE; Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE.
| | - Elizabeth Lyden
- Department of Biostatics, University of Nebraska Medical Center, Omaha, NE
| | - Andrea Lee
- Division of Oncology and Hematology, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE
| | - Joel Michalski
- Division of Oncology and Hematology, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE; Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE
| | - Zaid S Al-Kadhimi
- Division of Oncology and Hematology, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE; Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE
| | - Lori J Maness
- Division of Oncology and Hematology, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE; Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE
| | - Krishna Gundabolu
- Division of Oncology and Hematology, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE; Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE
| | - Vijaya Raj Bhatt
- Division of Oncology and Hematology, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE; Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE
| |
Collapse
|