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Yang M, Wang Z, Xue J, Dai J, Zhu C, Qin X. Subsequent primary cancer risk and mortality among premenopausal breast cancer survivors. Sci Rep 2025; 15:10829. [PMID: 40155641 PMCID: PMC11953267 DOI: 10.1038/s41598-024-84606-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2024] [Accepted: 12/24/2024] [Indexed: 04/01/2025] Open
Abstract
Patients with premenopausal breast cancer (preBC) usually have long-term survivorship. However, less is known about the risk pattern of subsequent primary cancer (SPC) and noncancer diseases among them. Here, this study aimed to evaluate the risk of developing SPCs and mortality among preBC survivors. In this population-based, retrospective cohort study, 5-year preBC survivors diagnosed at age 20-59 years during 1992-2014, in the 11 Surveillance, Epidemiology and End Result registries were included. Standardized incidence ratio (SIR) and standardized mortality ratio (SMR) were estimated for SPCs and mortality by cause, respectively. Among 181,947 survivors (mean age at diagnosis, 49.1 years; 65.9% White), there were 12,503 SPC cases, 4,280 SPC-related deaths, and 10,591 noncancer-related deaths. SPC risk was increased compared with the general population (SIR 1.06, [95% CI, 1.04-1.08]). The elevated risk was primarily associated with soft tissue cancer, bones/joints cancer, and acute non-lymphocytic leukemia (SIRs 2.01 [95% CI, 1.73-2.33], 1.78 [95% CI, 1.21-2.53], and 1.68 [95% CI, 1.46-1.93], respectively). Young-onset, Asian survivors, those with hormone receptor-negative BC, and initially treated with chemo-radiotherapy were at high-risk. The risk of dying from SPCs was also increased (SMR 1.07, [95% CI, 1.04-1.10]) and featured with similarly vulnerable subpopulations. Survivors of non-White ethnicity had a higher risk of dying from noncancer diseases. This study highlighted the excess risk of developing and dying from SPCs among preBC survivors, suggesting that targeted healthcare is warranted. Strategies for SPCs and noncancer comorbidity management are in great demand to achieve better long-term survivorship among preBC patients.
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Affiliation(s)
- Mei Yang
- The Affiliated Changzhou No. 2 People's Hospital of Nanjing Medical University, No. 219 Xinglong Lane, Changzhou City, Jiangsu, China
| | - Zhihuai Wang
- The Affiliated Changzhou No. 2 People's Hospital of Nanjing Medical University, No. 219 Xinglong Lane, Changzhou City, Jiangsu, China
| | - Jiao Xue
- The Affiliated Changzhou No. 2 People's Hospital of Nanjing Medical University, No. 219 Xinglong Lane, Changzhou City, Jiangsu, China
| | - Jianbo Dai
- The Affiliated Changzhou No. 2 People's Hospital of Nanjing Medical University, No. 219 Xinglong Lane, Changzhou City, Jiangsu, China
| | - Chunfu Zhu
- The Affiliated Changzhou No. 2 People's Hospital of Nanjing Medical University, No. 219 Xinglong Lane, Changzhou City, Jiangsu, China
| | - Xihu Qin
- The Affiliated Changzhou No. 2 People's Hospital of Nanjing Medical University, No. 219 Xinglong Lane, Changzhou City, Jiangsu, China.
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McCarty R, Trabert B, Kriebel D, Millar M, Birmann B, Grieshober L, Barnard M, Collin L, Lawson‐Michod K, Gibson B, Sawatzki J, Carter M, Yoder V, Gilreath J, Shami P, Doherty J. Tattoos and Risk of Hematologic Cancer: A Population-Based Case-Control Study in Utah. Cancer Med 2024; 13:e70260. [PMID: 39444249 PMCID: PMC11499570 DOI: 10.1002/cam4.70260] [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: 04/09/2024] [Revised: 08/26/2024] [Accepted: 09/12/2024] [Indexed: 10/25/2024] Open
Abstract
BACKGROUND Approximately one-third of US adults have a tattoo, and the prevalence is increasing. Tattooing can result in long-term exposure to carcinogens and inflammatory and immune responses. METHODS We examined tattooing and risk of hematologic cancers in a population-based case-control study with 820 cases diagnosed 2019-2021 and 8200 frequency-matched controls, ages 18-79 years. We calculated odds ratios (OR) and 95% confidence intervals (CI) using multivariable-adjusted logistic regression models. RESULTS The prevalence of tattooing was 22% among Hodgkin lymphoma (HL) cases, 11% among non-Hodgkin lymphoma (NHL) cases, 16% among myeloid neoplasm cases, and 15% among controls. Though there were no clear patterns of associations between ever receiving a tattoo and risk of HL, NHL, or myeloid neoplasms overall, in analyses restricted to ages 20-60 years, ever receiving a tattoo (OR 2.06 [95% CI 1.01, 4.20]) and receiving a tattoo 10+ years prior (OR 2.64 [95% CI 1.23, 5.68]) were associated with an aggregated group of rarer mature B-cell NHLs. We also observed elevated risks for a 10+ year latency for myelodysplastic syndromes and chronic myeloid leukemia (OR 1.48 [95% CI 0.40, 5.41], and OR 1.24 [95% CI 0.45, 3.43], respectively). CONCLUSIONS Though estimates were imprecise, we found some suggestive evidence that tattooing may be associated with an increased risk of certain hematologic cancer subtypes. With an estimated 46% prevalence of tattooing in US individuals ages 30-49, additional studies are needed to understand the degree to which these exposures may be associated with hematologic cancer risk.
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Affiliation(s)
- Rachel D. McCarty
- Huntsman Cancer Institute, University of UtahSalt Lake CityUtahUSA
- Department of Population Health Sciences Spencer Fox Eccles School of MedicineUniversity of Utah Intermountain Healthcare, University of UtahSalt Lake CityUtahUSA
| | - Britton Trabert
- Huntsman Cancer Institute, University of UtahSalt Lake CityUtahUSA
- Department of Obstetrics and Gynecology, Spencer Fox Eccles School of MedicineUniversity of UtahSalt Lake CityUtahUSA
| | - David Kriebel
- Lowell Center for Sustainable ProductionUniversity of Massachusetts LowellLowellMassachusettsUSA
| | - Morgan M. Millar
- Huntsman Cancer Institute, University of UtahSalt Lake CityUtahUSA
- Department of Internal MedicineUniversity of UtahSalt Lake CityUtahUSA
- Utah Cancer RegistryUniversity of UtahSalt Lake CityUtahUSA
| | - Brenda M. Birmann
- Channing Division of Network Medicine, Department of MedicineBrigham and Women's Hospital and Harvard Medical SchoolBostonMassachusettsUSA
| | - Laurie Grieshober
- Huntsman Cancer Institute, University of UtahSalt Lake CityUtahUSA
- Department of Population Health Sciences Spencer Fox Eccles School of MedicineUniversity of Utah Intermountain Healthcare, University of UtahSalt Lake CityUtahUSA
| | - Mollie E. Barnard
- Huntsman Cancer Institute, University of UtahSalt Lake CityUtahUSA
- Department of Population Health Sciences Spencer Fox Eccles School of MedicineUniversity of Utah Intermountain Healthcare, University of UtahSalt Lake CityUtahUSA
- Slone Epidemiology Center, Boston University Chobanian and Avedisian School of MedicineBostonMassachusettsUSA
| | - Lindsay J. Collin
- Huntsman Cancer Institute, University of UtahSalt Lake CityUtahUSA
- Department of Population Health Sciences Spencer Fox Eccles School of MedicineUniversity of Utah Intermountain Healthcare, University of UtahSalt Lake CityUtahUSA
| | - Katherine A. Lawson‐Michod
- Huntsman Cancer Institute, University of UtahSalt Lake CityUtahUSA
- Department of Population Health Sciences Spencer Fox Eccles School of MedicineUniversity of Utah Intermountain Healthcare, University of UtahSalt Lake CityUtahUSA
| | - Brody Gibson
- Huntsman Cancer Institute, University of UtahSalt Lake CityUtahUSA
- Department of Population Health Sciences Spencer Fox Eccles School of MedicineUniversity of Utah Intermountain Healthcare, University of UtahSalt Lake CityUtahUSA
| | - Jenna Sawatzki
- Huntsman Cancer Institute, University of UtahSalt Lake CityUtahUSA
| | | | - Valerie Yoder
- Utah Cancer RegistryUniversity of UtahSalt Lake CityUtahUSA
| | | | - Paul J. Shami
- Huntsman Cancer Institute, University of UtahSalt Lake CityUtahUSA
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Brandt C, Vo JB, Gierach GL, Cheng I, Torres VN, Lawrence WR, McCullough LE, Veiga LH, de González AB, Ramin C. Second primary cancer risks according to race and ethnicity among U.S. breast cancer survivors. Int J Cancer 2024; 155:996-1006. [PMID: 38685564 PMCID: PMC11250897 DOI: 10.1002/ijc.34971] [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: 12/20/2023] [Revised: 03/16/2024] [Accepted: 03/26/2024] [Indexed: 05/02/2024]
Abstract
Breast cancer survivors have an increased risk of developing second primary cancers, yet risks by race and ethnicity have not been comprehensively described. We evaluated second primary cancer risks among 717,335 women diagnosed with first primary breast cancer (aged 20-84 years and survived ≥1-year) in the SEER registries using standardized incidence ratios (SIRs; observed/expected). SIRs were estimated by race and ethnicity compared with the racial- and ethnic-matched general population, and further stratified by clinical characteristics of the index breast cancer. Poisson regression was used to test for heterogeneity by race and ethnicity. SIRs for second primary cancer differed by race and ethnicity with the highest risks observed among non-Hispanic/Latina Asian American, Native Hawaiian, or other Pacific Islander (AANHPI), non-Hispanic/Latina Black (Black), and Hispanic/Latina (Latina) survivors and attenuated risk among non-Hispanic/Latina White (White) survivors (SIRAANHPI = 1.49, 95% CI = 1.44-1.54; SIRBlack = 1.41, 95% CI = 1.37-1.45; SIRLatina = 1.45, 95% CI = 1.41-1.49; SIRWhite = 1.09, 95% CI = 1.08-1.10; p-heterogeneity<.001). SIRs were particularly elevated among AANHPI, Black, and Latina survivors diagnosed with an index breast cancer before age 50 (SIRs range = 1.88-2.19) or with estrogen receptor-negative tumors (SIRs range = 1.60-1.94). Heterogeneity by race and ethnicity was observed for 16/27 site-specific second cancers (all p-heterogeneity's < .05) with markedly elevated risks among AANHPI, Black, and Latina survivors for acute myeloid and acute non-lymphocytic leukemia (SIRs range = 2.68-3.15) and cancers of the contralateral breast (SIRs range = 2.60-3.01) and salivary gland (SIRs range = 2.03-3.96). We observed striking racial and ethnic differences in second cancer risk among breast cancer survivors. Additional research is needed to inform targeted approaches for early detection strategies and treatment to reduce these racial and ethnic disparities.
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Affiliation(s)
- Carolyn Brandt
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD USA
| | - Jacqueline B. Vo
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD USA
| | - Gretchen L. Gierach
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD USA
| | - Iona Cheng
- Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, CA, USA
- Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA
- Greater Bay Area Cancer Registry, University of California San Francisco, CA, USA
| | - Vanessa N. Torres
- Cancer Research Center for Health Equity, Cedars-Sinai Medical Center, Los Angeles, CA USA
| | - Wayne R. Lawrence
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD USA
| | | | - Lene H.S. Veiga
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD USA
| | - Amy Berrington de González
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD USA
- Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK
| | - Cody Ramin
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD USA
- Cancer Research Center for Health Equity, Cedars-Sinai Medical Center, Los Angeles, CA USA
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Diao Y, Wang R, Cui J, Jin C, Chen Y, Li X. Risk factors for secondary thyroid cancer in patients with breast cancer: a propensity‑matched SEER analysis. Sci Rep 2024; 14:12679. [PMID: 38830880 PMCID: PMC11148100 DOI: 10.1038/s41598-024-59209-x] [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: 10/07/2023] [Accepted: 04/08/2024] [Indexed: 06/05/2024] Open
Abstract
With the rapid development of imaging technology and comprehensive treatment in modern medicine, the early diagnosis rate of breast cancer is constantly improving, and the prognosis is also improving; As breast cancer patients survive longer, the risk of developing second primary cancers increases. Since both breast and thyroid are Hormone receptor sensitive organs, which are regulated by hypothalamus pituitary target gland endocrine axis, changes in body endocrine status may lead to the occurrence of these two diseases in succession or simultaneously. This study extracted clinical data and survival outcomes of breast cancer patients registered in the Surveillance, Epidemiology and End Results (SEER) database between 2010 and 2019. After matching the case and controls with propensity scores, the selected patients were randomly split into training and test datasets at a ratio of 7:3. Univariate and multivariate COX proportional regression analysis is used to determine independent risk factors for secondary thyroid cancer and construct a column chart prediction model. Age, ethnicity, whether radiotherapy, tumor primary location, N stage, M stage were identified by Cox regression as independent factors affecting secondary thyroid cancer in patients with breast cancer patients, and a risk factor nomogram was established to predict patients' 3 and 5 year survival probabilities. The AUC values for 3 and 5 years in the training set were 0.713, 0.707, and the c-index was 0.693 (95% CI 0.67144, 0.71456), and the AUC values for 3 and 5 years in the validation set were 0.681, 0.681, and the c-index was 0.673 (95% CI 0.64164, 0.70436), respectively.
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Affiliation(s)
- Yizhuo Diao
- Department of Epidemiology and Health Statistics, Dalian Medical University, 9 Lvshun South Road, Dalian, 116044, Liaoning, China
| | - Ruiqi Wang
- Department of Epidemiology and Health Statistics, Dalian Medical University, 9 Lvshun South Road, Dalian, 116044, Liaoning, China
| | - Jiaxue Cui
- Department of Epidemiology and Health Statistics, Dalian Medical University, 9 Lvshun South Road, Dalian, 116044, Liaoning, China
| | - Chenxin Jin
- Department of Epidemiology and Health Statistics, Dalian Medical University, 9 Lvshun South Road, Dalian, 116044, Liaoning, China
| | - Yongxing Chen
- Department of Epidemiology and Health Statistics, Dalian Medical University, 9 Lvshun South Road, Dalian, 116044, Liaoning, China
| | - Xiaofeng Li
- Department of Epidemiology and Health Statistics, Dalian Medical University, 9 Lvshun South Road, Dalian, 116044, Liaoning, China.
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Jing L, Zhang B, Sun J, Feng J, Fu D. Prognostic insights and immune microenvironment delineation in acute myeloid leukemia by ferroptosis-derived signature. Heliyon 2024; 10:e28237. [PMID: 38532996 PMCID: PMC10963645 DOI: 10.1016/j.heliyon.2024.e28237] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2023] [Revised: 03/13/2024] [Accepted: 03/14/2024] [Indexed: 03/28/2024] Open
Abstract
Acute myeloid leukemia (AML) represents as a prevalent and formidable hematological malignancy, characterized by notably low 5-year survival rates. Ferroptosis has been found to be correlated with cancer initiation, therapeutic response, and clinical outcome. Nevertheless, the involvement of Ferroptosis-related genes (FRGs) in AML remains ambiguous. Five independent AML cohorts totaling 1,470 (GSE37642, GSE12417, GSE10358, Beat-AML, and TCGA-AML) patients with clinical information were used to systematically investigated the influence of these FRGs expression on outcome and tumor microenvironment. The integration of these datasets led to the subdivision into training and validation sets. Nineteen FRGs were identified as correlated with the overall survival (OS) of AML patients, primarily enriched in ferroptosis, fatty acid metabolism, and leukemia-related signaling pathways. The prognostic signature, consisting of 11 FRGs, was formulated using LASSO-Cox stepwise regression analysis. Patients with high-risk scores exhibited reduced survival compared to those in the low-risk group. The receiver operating characteristic (ROC) analysis underscored the signature's robust predictive accuracy. The high predictive efficacy was confirmed by both internal and external validation datasets. Leukemia and signaling related to immune regulation were mainly enriched pathways of the differentially expressed genes by comparing high- and low-risk groups. The immune composition deconvolution might indicate an immunosuppressive niche in the high-risk patients. The pRRophetic algorithm exploration unveiled chemical drugs with potentially sensitivity among patients in both groups. Collectively, our study developed a ferroptosis-derived prognostic signature that provides the OS prediction and identifies the immune microenvironment for AML patients on large-scale AML cohorts.
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Affiliation(s)
- Lijun Jing
- Department of Neurology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Biyu Zhang
- School of Chemical Engineering & Pharmacy, Wuhan Institute of Technology, Wuhan, 430205, China
| | - Jinghui Sun
- College of Medicine, Medical University of South Carolina, Charleston, SC, 29425, United States
| | - Jueping Feng
- Department of Oncology, Wuhan Fourth Hospital, Wuhan, 430033, China
| | - Denggang Fu
- College of Medicine, Medical University of South Carolina, Charleston, SC, 29425, United States
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6
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Liu L, Lewis N, Sun W, Whiting J, Hoover S, Costa RLB. Retrospective Study of Treatment Patterns and Natural History of Patients with T1a/b N0 Triple-Negative Breast Cancers: A Single-Institution Experience. Oncology 2023; 101:765-772. [PMID: 37527637 DOI: 10.1159/000533149] [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: 03/07/2023] [Accepted: 07/11/2023] [Indexed: 08/03/2023]
Abstract
INTRODUCTION T1a/b, node-negative (node-), triple-negative breast cancers (TNBCs) are underrepresented in randomized drug-approving clinical trials. Given their low incidence, the clinicopathological features, natural history, and treatment patterns of these tumors remain insufficiently understood. METHODS We conducted a single-institution retrospective cohort study of patients with T1a/b, N0, M0 TNBCs. Deidentified patient- and tumor-related data were collected and summarized. Kruskal-Wallis, χ2, or Fisher exact tests were used to evaluate associations of interest. Kaplan-Meier methods, log-rank tests, and Cox's proportional hazards models were applied for survival analyses. RESULTS Of 108 cases of node- TNBCs measuring ≤2 cm, 34 node- T1a/b tumors were included in our analysis. All cases had an intermediate to high histological grade, and most had a Ki-67 score of ≥20%. All patients received adjuvant chemotherapy, and many underwent mastectomy (47%). Docetaxel combined with cyclophosphamide was the most common adjuvant chemotherapy regimen (75%). We did not observe significant associations between improved outcomes and treatment with anthracycline-containing regimens. Among patients with node- pT1a/b tumors, the estimated 3-year recurrence-free survival (RFS) and distant RFS rates were both 96.3% (95% CI: 76.5-99.5), and the overall survival rate was estimated to be 100% (95% CI: 100-100). There were no cases of local recurrences observed. CONCLUSIONS In our cohort, all patients with T1a/b node- TNBCs were treated with adjuvant chemotherapy and had favorable outcomes even when treated with anthracycline-sparing regimens.
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Affiliation(s)
- Langfeier Liu
- Morsani College of Medicine, University of South Florida, Tampa, Florida, USA
| | - Nicholas Lewis
- Morsani College of Medicine, University of South Florida, Tampa, Florida, USA
| | - Weihong Sun
- Department of Breast Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA
| | - Junmin Whiting
- Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA
| | - Susan Hoover
- Department of Breast Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA
| | - Ricardo L B Costa
- Department of Breast Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA
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Lustberg MB, Kuderer NM, Desai A, Bergerot C, Lyman GH. Mitigating long-term and delayed adverse events associated with cancer treatment: implications for survivorship. Nat Rev Clin Oncol 2023; 20:527-542. [PMID: 37231127 PMCID: PMC10211308 DOI: 10.1038/s41571-023-00776-9] [Citation(s) in RCA: 64] [Impact Index Per Article: 32.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/26/2023] [Indexed: 05/27/2023]
Abstract
Despite the importance of chemotherapy-associated adverse events in oncology practice and the broad range of interventions available to mitigate them, limited systematic efforts have been made to identify, critically appraise and summarize the totality of evidence on the effectiveness of these interventions. Herein, we review the most common long-term (continued beyond treatment) and late or delayed (following treatment) adverse events associated with chemotherapy and other anticancer treatments that pose major threats in terms of survival, quality of life and continuation of optimal therapy. These adverse effects often emerge during and continue beyond the course of therapy or arise among survivors in the months and years following treatment. For each of these adverse effects, we discuss and critically evaluate their underlying biological mechanisms, the most commonly used pharmacological and non-pharmacological treatment strategies, and evidence-based clinical practice guidelines for their appropriate management. Furthermore, we discuss risk factors and validated risk-assessment tools for identifying patients most likely to be harmed by chemotherapy and potentially benefit from effective interventions. Finally, we highlight promising emerging supportive-care opportunities for the ever-increasing number of cancer survivors at continuing risk of adverse treatment effects.
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Affiliation(s)
- Maryam B Lustberg
- Department of Medicine, Yale University School of Medicine, New Haven, CT, USA
| | | | - Aakash Desai
- Department of Medicine, Mayo Clinic School of Medicine, Rochester, MN, USA
| | - Cristiane Bergerot
- Centro de Câncer de Brasília, Instituto Unity de Ensino e Pesquisa, Brasilia, Brazil
| | - Gary H Lyman
- Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, WA, USA.
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Tong J, Aksenov S, Siegel BM, Wei L, Rodgers WH. A Rare Case of Blastic Plasmacytoid Dendritic Cell Neoplasm Occurred in Postchemotherapy of Breast Cancer. Case Rep Hematol 2023; 2023:7573037. [PMID: 37457315 PMCID: PMC10344635 DOI: 10.1155/2023/7573037] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2022] [Revised: 03/29/2023] [Accepted: 06/22/2023] [Indexed: 07/18/2023] Open
Abstract
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and highly aggressive hematologic malignancy that arises from plasmacytoid dendritic cells. BPDCN typically presents with skin lesions and may involve peripheral blood, bone marrow, lymph nodes, or extranodal sites. It usually arises de novo, and some BPDCN cases are associated with or develop into myeloid neoplasms. Here, we report a case of a 57-year-old female presenting with cervical lymphadenopathy and skin rashes during the COVID-19 pandemic in 2021 following multiple types of postmastectomy therapy for breast cancer. The patient was ultimately diagnosed with BPCDN by lymph node biopsy. To the best of our knowledge, this is the first case report of BPDCN occurring postchemotherapy of breast cancer.
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Affiliation(s)
- Jiankun Tong
- Department of Pathology, New York Presbyterian Queens, 56-45 Main Street, Flushing, NY 11355, USA
| | - Sergei Aksenov
- Department of Pathology, New York Presbyterian Queens, 56-45 Main Street, Flushing, NY 11355, USA
| | - Beth M. Siegel
- Department of Surgery, Section of Breast Surgery, New York Presbyterian Queens, 58-04 Main Street, Flushing, NY 11355, USA
| | - Lihong Wei
- Consultant Hematology & Medical Oncology, Queens Medical Associates, 176-60 Union Tpke # 360, Fresh Meadows, NY 11366, USA
| | - William H. Rodgers
- Department of Pathology, New York Presbyterian Queens, 56-45 Main Street, Flushing, NY 11355, USA
- Weill Cornell Medical College, 525 East 68th Street, Box 130, New York, NY 10065, USA
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9
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Li S, Li F, Wan D, Chen Z, Pan J, Liang XJ. A micelle-based stage-by-stage impelled system for efficient doxorubicin delivery. Bioact Mater 2023; 25:783-795. [PMID: 37056277 PMCID: PMC10086681 DOI: 10.1016/j.bioactmat.2022.07.001] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2022] [Revised: 06/23/2022] [Accepted: 07/04/2022] [Indexed: 11/15/2022] Open
Abstract
Chemotherapy remains the mainstay of cancer treatment, benefiting millions of patients each year, but the side effects of chemotherapy drugs severely limit their clinical use. Doxorubicin (DOX) can cause various side effects such as heart damage and treatment-related tumors. The effective use of active and passive targeting will improve the clinical application of DOX. Here, TPGS3350 and bioactive peptides were utilized to construct a micelle-based stage-by-stage impelled efficient system (missiles) for DOX delivery (DOX missiles). By taking advantage of the EPR effect, DOX missiles are efficiently enriched at the tumor site. After being cleaved by matrix metalloproteinase2 (MMP2), the peptide (VRGD) targets tumor cells to facilitate uptake of the missiles by the tumor cells via receptor-mediated endocytosis. The intracellular activated caspase-3-catalyzed explosion of DOX missiles further enables efficient tumor killing. This study provides an efficient approach for DOX delivery and toxicity reduction.
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Affiliation(s)
- Sunfan Li
- School of Chemical Engineering and Technology, Tiangong University, Tianjin, 300387, PR China
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology of China, No. 11, First North Road, Zhongguancun, Beijing, 100190, PR China
| | - Fangzhou Li
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology of China, No. 11, First North Road, Zhongguancun, Beijing, 100190, PR China
| | - Dong Wan
- School of Chemical Engineering and Technology, Tiangong University, Tianjin, 300387, PR China
| | - Zuqin Chen
- Medical School of Chinese PLA, No.28 Fuxing Road, Beijing, 100853, PR China
- Department of Radiology, The First Medical Centre, Chinese PLA General Hospital, Beijing, PR China
- Department of Radiology, Chinese PAP Guangxi Corps Hospital, Nanning, Guangxi, PR China
| | - Jie Pan
- School of Chemical Engineering and Technology, Tiangong University, Tianjin, 300387, PR China
| | - Xing-Jie Liang
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology of China, No. 11, First North Road, Zhongguancun, Beijing, 100190, PR China
- University of Chinese Academy of Sciences, Beijing, 100049, PR China
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10
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Ramin C, Veiga LHS, Vo JB, Curtis RE, Bodelon C, Aiello Bowles EJ, Buist DSM, Weinmann S, Feigelson HS, Gierach GL, Berrington de Gonzalez A. Risk of second primary cancer among women in the Kaiser Permanente Breast Cancer Survivors Cohort. Breast Cancer Res 2023; 25:50. [PMID: 37138341 PMCID: PMC10155401 DOI: 10.1186/s13058-023-01647-y] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2022] [Accepted: 04/03/2023] [Indexed: 05/05/2023] Open
Abstract
BACKGROUND Breast cancer survivors are living longer due to early detection and advances in treatment and are at increased risk for second primary cancers. Comprehensive evaluation of second cancer risk among patients treated in recent decades is lacking. METHODS We identified 16,004 females diagnosed with a first primary stage I-III breast cancer between 1990 and 2016 (followed through 2017) and survived ≥ 1 year at Kaiser Permanente (KP) Colorado, Northwest, and Washington. Second cancer was defined as an invasive primary cancer diagnosed ≥ 12 months after the first primary breast cancer. Second cancer risk was evaluated for all cancers (excluding ipsilateral breast cancer) using standardized incidence ratios (SIRs), and a competing risk approach for cumulative incidence and hazard ratios (HRs) adjusted for KP center, treatment, age, and year of first cancer diagnosis. RESULTS Over a median follow-up of 6.2 years, 1,562 women developed second cancer. Breast cancer survivors had a 70% higher risk of any cancer (95%CI = 1.62-1.79) and 45% higher risk of non-breast cancer (95%CI = 1.37-1.54) compared with the general population. SIRs were highest for malignancies of the peritoneum (SIR = 3.44, 95%CI = 1.65-6.33), soft tissue (SIR = 3.32, 95%CI = 2.51-4.30), contralateral breast (SIR = 3.10, 95%CI = 2.82-3.40), and acute myeloid leukemia (SIR = 2.11, 95%CI = 1.18-3.48)/myelodysplastic syndrome (SIR = 3.25, 95%CI = 1.89-5.20). Women also had elevated risks for oral, colon, pancreas, lung, and uterine corpus cancer, melanoma, and non-Hodgkin lymphoma (SIR range = 1.31-1.97). Radiotherapy was associated with increased risk for all second cancers (HR = 1.13, 95%CI = 1.01-1.25) and soft tissue sarcoma (HR = 2.36, 95%CI = 1.17-4.78), chemotherapy with decreased risk for all second cancers (HR = 0.87, 95%CI = 0.78-0.98) and increased myelodysplastic syndrome risk (HR = 3.01, 95%CI = 1.01-8.94), and endocrine therapy with lower contralateral breast cancer risk (HR = 0.48, 95%CI = 0.38-0.60). Approximately 1 in 9 women who survived ≥ 1 year developed second cancer, 1 in 13 developed second non-breast cancer, and 1 in 30 developed contralateral breast cancer by 10 years. Trends in cumulative incidence declined for contralateral breast cancer but not for second non-breast cancers. CONCLUSIONS Elevated risks of second cancer among breast cancer survivors treated in recent decades suggests that heightened surveillance is warranted and continued efforts to reduce second cancers are needed.
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Affiliation(s)
- Cody Ramin
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, 9609 Medical Center Drive, Bethesda, MD, USA.
- Cancer Research Center for Health Equity, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
| | - Lene H S Veiga
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, 9609 Medical Center Drive, Bethesda, MD, USA
| | - Jacqueline B Vo
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, 9609 Medical Center Drive, Bethesda, MD, USA
| | - Rochelle E Curtis
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, 9609 Medical Center Drive, Bethesda, MD, USA
| | - Clara Bodelon
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, 9609 Medical Center Drive, Bethesda, MD, USA
| | - Erin J Aiello Bowles
- Kaiser Permanente Washington Health Research Institute, Kaiser Permanente Washington, Seattle, WA, USA
| | - Diana S M Buist
- Kaiser Permanente Washington Health Research Institute, Kaiser Permanente Washington, Seattle, WA, USA
- Bernard J. Tyson Kaiser Permanente School of Medicine, Pasadena, CA, USA
| | - Sheila Weinmann
- Kaiser Permanente Center for Health Research, Kaiser Permanente Northwest, Portland, OR, USA
| | - Heather Spencer Feigelson
- Bernard J. Tyson Kaiser Permanente School of Medicine, Pasadena, CA, USA
- Institute for Health Research, Kaiser Permanente, Denver, CO, USA
| | - Gretchen L Gierach
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, 9609 Medical Center Drive, Bethesda, MD, USA
| | - Amy Berrington de Gonzalez
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, 9609 Medical Center Drive, Bethesda, MD, USA
- Division of Genetics and Epidemiology, ICR, London, UK
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Kim D, Oh J, Seok JH, Lee HS, Jeon S, Yoon CI. Risk of Secondary Cancer after Adjuvant Tamoxifen Treatment for Ductal Carcinoma In Situ: A Nationwide Cohort Study in South Korea. Diagnostics (Basel) 2023; 13:diagnostics13040792. [PMID: 36832280 PMCID: PMC9954831 DOI: 10.3390/diagnostics13040792] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2022] [Revised: 02/05/2023] [Accepted: 02/16/2023] [Indexed: 02/22/2023] Open
Abstract
Endocrine therapy is the mainstay treatment for hormone receptor-positive ductal carcinoma in situ. The aim of this study was to examine the long-term secondary malignancy risk of tamoxifen therapy. The data of patients diagnosed with breast cancer between January 2007 and December 2015 were retrieved from the database of the Health Insurance Review and Assessment Service of South Korea. The International Classification of Diseases, 10th revision, was used to track all-site cancers. Age at the time of surgery, chronic disease status, and type of surgery were considered covariates in the propensity score matching analysis. The median follow-up duration was 89 months. Forty-one patients in the tamoxifen group and nine in the control group developed endometrial cancer. The Cox regression hazard ratio model showed that tamoxifen therapy was the only significant predictor of the development of endometrial cancer (hazard ratio, 2.791; 95% confidence interval, 1.355-5.747; p = 0.0054). No other type of cancer was associated with long-term tamoxifen use. In consonance with the established knowledge, the real-world data in this study demonstrated that tamoxifen therapy is related to an increased incidence of endometrial cancer.
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Affiliation(s)
- Dooreh Kim
- Division of Breast Surgery, Department of Surgery, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea
| | - Jooyoung Oh
- Department of Psychiatry, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
| | - Jeong-Ho Seok
- Department of Psychiatry, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
| | - Hye Sun Lee
- Biostatistics Collaboration Unit, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
| | - Soyoung Jeon
- Biostatistics Collaboration Unit, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
| | - Chang Ik Yoon
- Division of Breast Surgery, Department of Surgery, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea
- Correspondence: ; Tel.: +82-2-2258-6109
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12
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Di Nardo P, Lisanti C, Garutti M, Buriolla S, Alberti M, Mazzeo R, Puglisi F. Chemotherapy in patients with early breast cancer: clinical overview and management of long-term side effects. Expert Opin Drug Saf 2022; 21:1341-1355. [DOI: 10.1080/14740338.2022.2151584] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Affiliation(s)
- Paola Di Nardo
- Department of Medical Oncology, CRO Aviano, National Cancer Institute, IRCCS, Aviano, Italy
| | - Camilla Lisanti
- Department of Medical Oncology, CRO Aviano, National Cancer Institute, IRCCS, Aviano, Italy
| | - Mattia Garutti
- Department of Medical Oncology, CRO Aviano, National Cancer Institute, IRCCS, Aviano, Italy
| | - Silvia Buriolla
- Department of Medicine (DAME), University of Udine, Udine, Italy
| | - Martina Alberti
- Department of Medicine (DAME), University of Udine, Udine, Italy
| | - Roberta Mazzeo
- Department of Medicine (DAME), University of Udine, Udine, Italy
| | - Fabio Puglisi
- Department of Medical Oncology, CRO Aviano, National Cancer Institute, IRCCS, Aviano, Italy
- Department of Medicine (DAME), University of Udine, Udine, Italy
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13
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Rugo HS, Singer L. First, do no harm: risk of secondary cancer after breast cancer treatment. Lancet Oncol 2022; 23:1350-1352. [DOI: 10.1016/s1470-2045(22)00627-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2022] [Accepted: 10/03/2022] [Indexed: 11/30/2022]
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Doney K, Leisenring W, Linden H. Allogeneic hematopoietic cell transplantation in patients with a hematologic malignancy and a prior history of breast cancer. Breast Cancer Res Treat 2022; 194:507-516. [PMID: 35779160 DOI: 10.1007/s10549-022-06658-5] [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: 03/29/2022] [Accepted: 06/08/2022] [Indexed: 11/02/2022]
Abstract
PURPOSE To compare the outcome of allogeneic stem cell transplantation for myeloid malignancies in breast cancer survivors to a contemporaneous control group. METHODS Medical records of all patients with a history of breast cancer who received allogeneic stem cell transplants at a single, tertiary referral Comprehensive Cancer Center between 2002 and 2019 were reviewed. Transplant outcomes were compared to 289 control patients without a history of breast cancer from the same time period. Main outcomes included survival, disease-free survival, non-relapse mortality, relapse or progression of hematologic malignancy, and incidence of recurrent breast cancer after hematopoietic cell transplantation. Comparisons between women with a history of breast cancer and controls utilized propensity score weighting to balance patient characteristics. RESULTS Forty women, ages 30-74 years, with a history of breast cancer received an allogeneic hematopoietic cell transplant for a hematologic malignancy between December 2002 and February 2019. Twelve of the 40 patients are alive with a median survival of 7.4 years (range, 1.9-16.8 years). None of the patients had evidence of recurrent breast cancer prior to death or date of last contact. In multivariable Cox models, all transplant outcomes were similar between the patients and the control group with hematopoietic cell transplant comorbidity score as the most important confounding factor for adjustment in these models. CONCLUSION A history of treated breast cancer should not exclude patients from consideration for allogeneic hematopoietic cell transplantation.
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Affiliation(s)
- Kristine Doney
- Clinical Research Division, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave. N, D5-280, PO Box 19024, Seattle, WA, 98109-1024, USA. .,University of Washington Medical Center, Seattle, WA, USA.
| | - Wendy Leisenring
- Clinical Research Division, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave. N, D5-280, PO Box 19024, Seattle, WA, 98109-1024, USA.,University of Washington Medical Center, Seattle, WA, USA
| | - Hannah Linden
- University of Washington Medical Center, Seattle, WA, USA.,Seattle Cancer Care Alliance, Seattle, WA, USA
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15
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Association Between Granulocyte Colony-Stimulating Factor (G-CSF) Use and Myelodysplastic Syndrome (MDS) or Acute Myeloid Leukemia (AML) Among Elderly Patients with Breast, Lung, or Prostate Cancer. Adv Ther 2022; 39:2778-2795. [PMID: 35430673 DOI: 10.1007/s12325-022-02141-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2022] [Accepted: 03/17/2022] [Indexed: 11/01/2022]
Abstract
INTRODUCTION Patients diagnosed with cancer have an increased risk both for myelodysplastic syndromes (MDS) and for acute myeloid leukemia (AML) following treatment. METHODS Using SEER-Medicare data, we selected patients aged 66 years and older who completed systemic therapy between 2002 and 2014 for breast (stage I-III), lung (stage I-III), or prostate (stage I-IV) cancer. For each cancer, we estimated the risk of a composite endpoint of MDS or AML in patients receiving granulocyte colony-stimulating factor (G-CSF) vs. not. RESULTS The 10-year cumulative risk difference (granulocyte colony-stimulating factor [G-CSF] - no G-CSF) for MDS-AML was 0.45% (95% CI 0.13-0.77%) in breast cancer and 0.39% (95% CI 0.15-0.62%) in lung cancer. G-CSF use was associated with a hazard ratio of 1.60 (95% CI 1.07-2.40) in breast cancer and 1.50 (95% CI 0.99-2.29) in lung cancer. Filgrastim use was associated with a hazard ratio of 1.01 (95% CI 1.00-1.03) per administration in breast cancer and 1.02 (95% CI 0.99-1.05) per administration in lung cancer. Pegfilgrastim was associated with a hazard ratio of 1.08 (95% CI 1.01-1.15) per administration in breast cancer and 1.12 (95% CI 1.00-1.25) per administration in lung cancer. Analyses in prostate cancer were limited because of the low number of events. CONCLUSIONS The use of G-CSF in patients diagnosed with breast and lung cancer is associated with an increased risk of MDS-AML. However, the MDS-AML absolute risk difference is very low.
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16
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Comparison of Anticancer Drug Toxicities: Paradigm Shift in Adverse Effect Profile. Life (Basel) 2021; 12:life12010048. [PMID: 35054441 PMCID: PMC8777973 DOI: 10.3390/life12010048] [Citation(s) in RCA: 69] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2021] [Revised: 12/17/2021] [Accepted: 12/24/2021] [Indexed: 02/06/2023] Open
Abstract
The inception of cancer treatment with chemotherapeutics began in the 1940s with nitrogen mustards that were initially employed as weapons in World War II. Since then, treatment options for different malignancies have evolved over the period of last seventy years. Until the late 1990s, all the chemotherapeutic agents were small molecule chemicals with a highly nonspecific and severe toxicity spectrum. With the landmark approval of rituximab in 1997, a new horizon has opened up for numerous therapeutic antibodies in solid and hematological cancers. Although this transition to large molecules improved the survival and quality of life of cancer patients, this has also coincided with the change in adverse effect patterns. Typically, the anticancer agents are fraught with multifarious adverse effects that negatively impact different organs of cancer patients, which ultimately aggravate their sufferings. In contrast to the small molecules, anticancer antibodies are more targeted toward cancer signaling pathways and exhibit fewer side effects than traditional small molecule chemotherapy treatments. Nevertheless, the interference with the immune system triggers serious inflammation- and infection-related adverse effects. The differences in drug disposition and interaction with human basal pathways contribute to this paradigm shift in adverse effect profile. It is critical that healthcare team members gain a thorough insight of the adverse effect differences between the agents discovered during the last twenty-five years and before. In this review, we summarized the general mechanisms and adverse effects of small and large molecule anticancer drugs that would further our understanding on the toxicity patterns of chemotherapeutic regimens.
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Targeting transcription of MCL-1 sensitizes HER2-amplified breast cancers to HER2 inhibitors. Cell Death Dis 2021; 12:179. [PMID: 33589591 PMCID: PMC7884408 DOI: 10.1038/s41419-021-03457-6] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2020] [Revised: 12/23/2020] [Accepted: 01/03/2021] [Indexed: 12/22/2022]
Abstract
Human epidermal growth factor receptor 2 gene (HER2) is focally amplified in approximately 20% of breast cancers. HER2 inhibitors alone are not effective, and sensitizing agents will be necessary to move away from a reliance on heavily toxic chemotherapeutics. We recently demonstrated that the efficacy of HER2 inhibitors is mitigated by uniformly low levels of the myeloid cell leukemia 1 (MCL-1) endogenous inhibitor, NOXA. Emerging clinical data have demonstrated that clinically advanced cyclin-dependent kinase (CDK) inhibitors are effective MCL-1 inhibitors in patients, and, importantly, well tolerated. We, therefore, tested whether the CDK inhibitor, dinaciclib, could block MCL-1 in preclinical HER2-amplified breast cancer models and therefore sensitize these cancers to dual HER2/EGFR inhibitors neratinib and lapatinib, as well as to the novel selective HER2 inhibitor tucatinib. Indeed, we found dinaciclib suppresses MCL-1 RNA and is highly effective at sensitizing HER2 inhibitors both in vitro and in vivo. This combination was tolerable in vivo. Mechanistically, liberating the effector BCL-2 protein, BAK, from MCL-1 results in robust apoptosis. Thus, clinically advanced CDK inhibitors may effectively combine with HER2 inhibitors and present a chemotherapy-free therapeutic strategy in HER2-amplified breast cancer, which can be tested immediately in the clinic.
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Jeon YW, Lim ST, Gwak H, Park SY, Shin J, Han HS, Suh YJ. Clinical utilization of long-acting granulocyte colony-stimulating factor (pegfilgrastim) prophylaxis in breast cancer patients with adjuvant docetaxel-cyclophosphamide chemotherapy. Ann Surg Treat Res 2021; 100:59-66. [PMID: 33585350 PMCID: PMC7870427 DOI: 10.4174/astr.2021.100.2.59] [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: 09/01/2020] [Revised: 10/28/2020] [Accepted: 11/24/2020] [Indexed: 02/04/2023] Open
Abstract
Purpose Treatment with 4 cycles of docetaxel and cyclophosphamide (TC) in the adjuvant setting is associated with better outcomes than treatment with doxorubicin and cyclophosphamide (AC). However, Western guidelines have indicated that TC confers a high risk (>20%) of febrile neutropenia (FN), while AC confers an intermediate risk (10%-20%) of FN. Threrefore, we evaluated the incidence of FN and the clinical utilization of pegfilgrastim prophylaxis after adjuvant TC chemotherapy. Methods We categorized 201 patients who received adjuvant TC chemotherapy into 3 groups according to the method of prophylaxis and compared neutropenic events, other adverse events, and hospital care costs in the 3 groups. Results The incidence of grade 4 neutropenia decreased from 93.0% in patients without prophylaxis to 82.4% in those who received secondary prophylaxis and 16.7% in those who received primary prophylaxis. Although the incidence of FN was not different between patients without prophylaxis and patients who received secondary prophylaxis (15.7% and 14.9%), none of the patients who received primary prophylaxis developed FN. Moreover, a decrease in neutropenic events resulted in a significant decrease in the mean duration of neutropenia (2.50 days to 0.08 days, P < 0.001), the risk of hospitalization (29.8% to 2.2%, P < 0.001), and the mean total hospital care cost for all chemotherapy cycles (790.80 to 486.00 US dollars, P < 0.001). Conclusion The use of pegfilgrastim prophylaxis during adjuvant TC chemotherapy is associated with significant decreases in the incidence of neutropenic events, hospitalization, and hospital care cost compared to those seen in patients without prophylaxis.
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Affiliation(s)
- Ye Won Jeon
- Department of Surgery, The Catholic University of Korea, St. Vincent's Hospital, Suwon, Korea
| | - Seung Taek Lim
- Department of Surgery, The Catholic University of Korea, St. Vincent's Hospital, Suwon, Korea
| | - Hongki Gwak
- Department of Surgery, The Catholic University of Korea, St. Vincent's Hospital, Suwon, Korea
| | - Seon Young Park
- Department of Surgery, The Catholic University of Korea, St. Vincent's Hospital, Suwon, Korea
| | - Juhee Shin
- Department of Nursing, The Catholic University of Korea, St. Vincent's Hospital, Suwon, Korea
| | - Hye Sug Han
- Department of Nursing, The Catholic University of Korea, St. Vincent's Hospital, Suwon, Korea
| | - Young Jin Suh
- Department of Surgery, The Catholic University of Korea, St. Vincent's Hospital, Suwon, Korea
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Qi X, Liu J, Li X, Fan M, Huang N, Sun R. Saikosaponin a contributed to CCIN treatment by promoting neutrophil bactericidal activity via activation CBL-dependent ERK pathway. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2021; 82:153444. [PMID: 33421903 DOI: 10.1016/j.phymed.2020.153444] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/13/2020] [Revised: 08/26/2020] [Accepted: 12/22/2020] [Indexed: 06/12/2023]
Abstract
BACKGROUND Despite granulocyte colony-stimulating factor (GCSF) is widely used in clinical, cancer chemotherapy induced neutropenia (CCIN) infection and infection-related mortality is high for lack of functionally mature neutrophils. Generating functional neutrophils is new therapeutic approaches to reduce CCIN-associated infection and mortality. Saikosaponin a (SSA) is one of the major bioactive components of Radix Bupleuri (RB) and exerts immunoregulatory effects. PURPOSE The present study aims to investigate the efficacy and mechanism of SSA in CCIN therapy. METHODS SSA was applied both in vitro and in vivo to assess the efficacy of CCIN therapy. The differentiation of neutrophils was measured by Nitroblue tetrazolium (NBT) reduction assay and Giemsa staining assay. The neutrophil differentiation related real-time transcription factors were detected by quantitative PCR (RT-qPCR) and Western Blot. Bacteria killing assay was used to assess the ability of fighting infection. Network pharmacology was employed to explore the mechanism network, and the predicted pathways were validated by Western Blot. RESULTS We found that SSA contributed to generate functional mature neutrophils which capable of fighting infection both in vitro and in vivo. Network pharmacology prediction showed 55 pathways were predicted involved in SSA against CCIN. Further validation showed that CBL-ERK1/2 pathway was activated by SSA, which could upregulate PU.1 and CEBPβ expression leading to neutrophil differentiation. CONCLUSIONS Our findings suggest a natural regimen SSA regenerates microbicidal neutrophils to effectively reduce CCIN-associated infection via activating CBL-ERK1/2 pathway, providing a rationale for future therapeutic approaches.
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Affiliation(s)
- Xiaotian Qi
- The Second Hospital, Cheeloo College of Medicine, Shandong University, No. 247 Beiyuan Street, Jinan, Shandong, 250033, China; Institute of Advanced Medical Research, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China
| | - Jing Liu
- The Second Hospital, Cheeloo College of Medicine, Shandong University, No. 247 Beiyuan Street, Jinan, Shandong, 250033, China; Institute of Advanced Medical Research, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China
| | - Xiaoyu Li
- Department of Medical Pathomorphology, Shandong Academy of Traditional Chinese Medicine, Jinan, 250014, Shandong, China
| | - Mengyue Fan
- The Second Hospital, Cheeloo College of Medicine, Shandong University, No. 247 Beiyuan Street, Jinan, Shandong, 250033, China; Institute of Advanced Medical Research, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China
| | - Nana Huang
- The Second Hospital, Cheeloo College of Medicine, Shandong University, No. 247 Beiyuan Street, Jinan, Shandong, 250033, China
| | - Rong Sun
- The Second Hospital, Cheeloo College of Medicine, Shandong University, No. 247 Beiyuan Street, Jinan, Shandong, 250033, China; Institute of Advanced Medical Research, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China.
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Lapidari P, Vaz-Luis I, Di Meglio A. Side effects of using granulocyte-colony stimulating factors as prophylaxis of febrile neutropenia in cancer patients: A systematic review. Crit Rev Oncol Hematol 2021; 157:103193. [DOI: 10.1016/j.critrevonc.2020.103193] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2020] [Revised: 11/16/2020] [Accepted: 11/19/2020] [Indexed: 12/29/2022] Open
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Ji Y, Li S, Zhang X, Liu Y, Lu Q, Li Q, Chen W, Sheng J, Jiang K, Liang H, Sha S, Li M, Chen Z, Zheng P, Wang M, Feng Y, Wang L, Wu H, Liu H, Huang Y, Yin Z, Xue X. The prophylactic and therapeutic effects of moxibustion combined with traditional Chinese medicine decoction for treating chemotherapy-induced myelosuppression in early-stage breast cancer: study protocol for a randomized controlled trial. Trials 2020; 21:844. [PMID: 33046128 PMCID: PMC7549227 DOI: 10.1186/s13063-020-04749-6] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2020] [Accepted: 09/17/2020] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND Traditional Chinese medicine (TCM) has a long history of use in breast cancer, but lacking systematic evidence to support its clinical benefits. In this study, we evaluated the prophylactic and therapeutic effects of moxibustion combined with decoctions for treating chemotherapy-induced myelosuppression (CIM) in early-stage breast cancer patients. METHODS This is a randomized controlled clinical trial single-blinded for TCM decoction but not moxibustion. Patients are equally divided into the control group without decoction and moxibustion treatment (control), the decoction+moxibustion group (MD), and the placebo+moxibustion group (MP), according to the following stratification factors: age (below 40s, 40s, 50s, and 60s or above), chemotherapy regimen (anthracyclines, taxanes, anthracyclines+taxane, and others), and chemotherapy strategy (adjuvant and neoadjuvant). The TCM decoction is Wenshen Shengbai Decoction. The anticipated sample size is 462 cases (154 cases in each group). All participants are expected to treat with chemotherapy and recombinant human granulocyte colony-stimulating factor (rhG-CSF). The primary outcomes include the proportion of patients with relief of leukopenia and/or neutropenia, the myelosuppression-associated serious adverse event including grade 3-4 leukopenia and/or neutropenia, and febrile neutropenia, and the dose of rhG-CSF. The secondary outcomes include chemotherapy adherence, stratified analysis, adverse reactions, quality of life by EORTC Breast-Cancer-Specific Quality of Life Questionnaire including EORTC QLQ-C30 (V3.0) and QLQ-BR23, TCM Constitution, and 3-year disease-free survival and overall survival. Baseline information including age, surgical approach, chemotherapy regimen and strategy, pathological stage, and molecular subtype will be recorded. DISCUSSION This will be the first randomized controlled trial to evaluate the efficacy of moxibustion combined with TCM decoction in treating CIM in early-stage breast cancer patients, aiming to standardize the TCM decoction and moxibustion method, thus providing evidence for its clinical benefit. TRIAL REGISTRATION chictr.org.cn ChiCTR-INR-16009557 . Registered on 23 October 2016.
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Affiliation(s)
- Yajie Ji
- Department of Breast Surgery, Yueyang Hospital of Integrated Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200437 China
| | - Siyu Li
- Department of Breast Surgery, Yueyang Hospital of Integrated Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200437 China
| | - Xinyue Zhang
- Department of Breast Surgery, Yueyang Hospital of Integrated Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200437 China
| | - Yu Liu
- Department of Breast Surgery, Yueyang Hospital of Integrated Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200437 China
| | - Qing Lu
- Department of Breast Surgery, Yueyang Hospital of Integrated Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200437 China
| | - Qiong Li
- Department of Breast Surgery, Yueyang Hospital of Integrated Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200437 China
| | - Weili Chen
- Department of Breast Surgery, Yueyang Hospital of Integrated Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200437 China
| | - Jiayu Sheng
- Department of Breast Surgery, Yueyang Hospital of Integrated Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200437 China
| | - Ke Jiang
- Department of Breast Surgery, Yueyang Hospital of Integrated Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200437 China
| | - Hongli Liang
- Department of Breast Surgery, Yueyang Hospital of Integrated Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200437 China
| | - Shanyan Sha
- Department of Breast Surgery, Yueyang Hospital of Integrated Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200437 China
| | - Mengting Li
- Department of Breast Surgery, Yueyang Hospital of Integrated Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200437 China
| | - Zongxin Chen
- Department of Breast Surgery, Yueyang Hospital of Integrated Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200437 China
| | - Peiyi Zheng
- Department of Breast Surgery, Yueyang Hospital of Integrated Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200437 China
| | - Minhong Wang
- Department of Breast Surgery, Yueyang Hospital of Integrated Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200437 China
| | - Yuanyuan Feng
- Department of Breast Surgery, Yueyang Hospital of Integrated Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200437 China
| | - Lei Wang
- Department of Breast Surgery, Yueyang Hospital of Integrated Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200437 China
| | - Huangan Wu
- Shanghai Research Institute of Acupuncture and Meridian, Shanghai University of Traditional Chinese Medicine, Shanghai, 200030 China
| | - Huirong Liu
- Shanghai Research Institute of Acupuncture and Meridian, Shanghai University of Traditional Chinese Medicine, Shanghai, 200030 China
| | - Yan Huang
- Shanghai Research Institute of Acupuncture and Meridian, Shanghai University of Traditional Chinese Medicine, Shanghai, 200030 China
| | - Zhiguang Yin
- Shanghai Research Institute of Acupuncture and Meridian, Shanghai University of Traditional Chinese Medicine, Shanghai, 200030 China
| | - Xiaohong Xue
- Department of Breast Surgery, Yueyang Hospital of Integrated Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200437 China
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22
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Shallis RM, Weiss JJ, Deziel NC, Gore SD. Challenging the concept of de novo acute myeloid leukemia: Environmental and occupational leukemogens hiding in our midst. Blood Rev 2020; 47:100760. [PMID: 32988660 DOI: 10.1016/j.blre.2020.100760] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2020] [Revised: 07/28/2020] [Accepted: 08/27/2020] [Indexed: 12/20/2022]
Abstract
Myeloid neoplasms like acute myeloid leukemia (AML) originate from genomic disruption, usually in a multi-step fashion. Hematopoietic stem/progenitor cell acquisition of abnormalities in vital cellular processes, when coupled with intrinsic factors such as germline predisposition or extrinsic factors such as the marrow microenvironment or environmental agents, can lead to requisite pre-leukemic clonal selection, expansion and evolution. Several of these entities have been invoked as "leukemogens." The known leukemogens are numerous and are found in the therapeutic, occupational and ambient environments, however they are often difficult to implicate for individual patients. Patients treated with particular chemotherapeutic agents or radiotherapy accept a calculated risk of therapy-related AML. Occupational exposures to benzene, dioxins, formaldehyde, electromagnetic and particle radiation have been associated with an increased risk of AML. Although regulatory agencies have established acceptable exposure limits in the workplace, accidental exposures and even ambient exposures to leukemogens are possible. It is plausible that inescapable exposure to non-anthropogenic ambient leukemogens may be responsible for many cases of non-inherited de novo AML. In this review, we discuss the current understanding of leukemogens as they relate to AML, assess to what extent the term "de novo" leukemia is meaningful, and describe the potential to identify and characterize new leukemogens.
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Affiliation(s)
- Rory M Shallis
- Section of Hematology, Department of Medicine, Yale University School of Medicine, New Haven, USA.
| | - Julian J Weiss
- Section of Hematology, Department of Medicine, Yale University School of Medicine, New Haven, USA
| | - Nicole C Deziel
- Department of Environmental Health Sciences, Yale School of Public Health, New Haven, CT, USA
| | - Steven D Gore
- Section of Hematology, Department of Medicine, Yale University School of Medicine, New Haven, USA
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23
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Jabagi MJ, Vey N, Goncalves A, Le Tri T, Zureik M, Dray-Spira R. Risk of secondary hematologic malignancies associated with breast cancer chemotherapy and G-CSF support: A nationwide population-based cohort. Int J Cancer 2020; 148:375-384. [PMID: 32683691 DOI: 10.1002/ijc.33216] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2020] [Revised: 07/03/2020] [Accepted: 07/07/2020] [Indexed: 12/19/2022]
Abstract
Our study aimed to analyze the risk of hematologic malignancies (HM) associated with the use of G-CSF with chemotherapy for BC. Using the French National Health Data System, we examined the HM risks in patients diagnosed with an incident breast cancer between 2007 and 2015, who received chemotherapy for BC. Main outcomes were acute myeloid leukemia (AML), Myelodysplastic syndrome (MDS), myeloproliferative neoplasms (MPNs), multiple myeloma (MM), Hodgkin lymphoma or non-Hodgkin lymphoma (HL/NHL) and acute lymphoblastic leukemia or lymphocytic lymphoma (ALL/LL). Among a total of 122 373 BC survivors, 38.9% received chemotherapy only and 61.1% received chemotherapy + G-CSF. Overall, 781 cases of hematologic malignancies occurred. We observed a nonsignificant increase in the risk of AML (aHR, 1.3; 95% CI, 1.0-1.7), of MDS (aHR, 1.3; 95% CI, 0.9-1.8) and of ALL/LL (aHR, 2.0; 95% CI, 1.0-4.4) among patients treated by chemotherapy + G-CSF compared to chemotherapy only. In analyses by dose, we observed a slight increase in the risk of AML (1-3 doses: aHR, 1.2; 95% CI, 0.8-1.7/4+ doses: aHR, 1.3; 95% CI, 1.0-1.8) and of MDS (1-3 doses: aHR, 1.1; 95% CI, 0.7-1.7/4+ doses: aHR, 1.4; 95% CI, 1.0-1.9), a significant increase in risk of ALL (1-3 doses: aHR, 1.5; 95% CI, 0.5-3.9 / 4+ doses: aHR, 2.3; 95% CI, 1.0-5.1) with increasing cycles of G-CSF. Our population-based study showed that the ALL/LL was the only HM at increased risk with the use of growth factors with a possible dose-effect relationship. Our data regarding the risk of all the other HM are reassuring.
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Affiliation(s)
- Marie Joelle Jabagi
- EPI-PHARE (French National Agency for Medicines and Health Products Safety (ANSM) and French National Health Insurance (CNAM)), Saint-Denis, France
| | - Norbert Vey
- Inserm, CNRS, Institut Paoli-Calmettes, CRCM, Aix-Marseille University, Marseille, France
| | - Anthony Goncalves
- Inserm, CNRS, Institut Paoli-Calmettes, CRCM, Aix-Marseille University, Marseille, France
| | - Thien Le Tri
- EPI-PHARE (French National Agency for Medicines and Health Products Safety (ANSM) and French National Health Insurance (CNAM)), Saint-Denis, France
| | - Mahmoud Zureik
- EPI-PHARE (French National Agency for Medicines and Health Products Safety (ANSM) and French National Health Insurance (CNAM)), Saint-Denis, France
| | - Rosemary Dray-Spira
- EPI-PHARE (French National Agency for Medicines and Health Products Safety (ANSM) and French National Health Insurance (CNAM)), Saint-Denis, France
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24
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Abstract
The anthracycline doxorubicin (Doxo) and its analogs daunorubicin (Daun), epirubicin (Epi), and idarubicin (Ida) have been cornerstones of anticancer therapy for nearly five decades. However, their clinical application is limited by severe side effects, especially dose-dependent irreversible cardiotoxicity. Other detrimental side effects of anthracyclines include therapy-related malignancies and infertility. It is unclear whether these side effects are coupled to the chemotherapeutic efficacy. Doxo, Daun, Epi, and Ida execute two cellular activities: DNA damage, causing double-strand breaks (DSBs) following poisoning of topoisomerase II (Topo II), and chromatin damage, mediated through histone eviction at selected sites in the genome. Here we report that anthracycline-induced cardiotoxicity requires the combination of both cellular activities. Topo II poisons with either one of the activities fail to induce cardiotoxicity in mice and human cardiac microtissues, as observed for aclarubicin (Acla) and etoposide (Etop). Further, we show that Doxo can be detoxified by chemically separating these two activities. Anthracycline variants that induce chromatin damage without causing DSBs maintain similar anticancer potency in cell lines, mice, and human acute myeloid leukemia patients, implying that chromatin damage constitutes a major cytotoxic mechanism of anthracyclines. With these anthracyclines abstained from cardiotoxicity and therapy-related tumors, we thus uncoupled the side effects from anticancer efficacy. These results suggest that anthracycline variants acting primarily via chromatin damage may allow prolonged treatment of cancer patients and will improve the quality of life of cancer survivors.
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25
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Tralongo AC, Antonuzzo A, Pronzato P, Sbrana A, Turrini M, Zoratto F, Danova M. Management of chemotherapy-induced neutropenia in patients with cancer: 2019 guidelines of the Italian Medical Oncology Association (AIOM). TUMORI JOURNAL 2020; 106:273-280. [PMID: 32538316 DOI: 10.1177/0300891620927093] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Neutropenia is the most frequent side effect of commercially available myelosuppressive drugs and its most significant complication is febrile neutropenia. It is associated with increased hospital admissions and higher probability of death. Prophylaxis with the administration of granulocyte colony-stimulating factor can prevent neutropenia caused by anticancer drugs. The correct administration of these drugs and the management of febrile neutropenia are extremely important in the treatment of patients with cancer.
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Affiliation(s)
| | | | - Paolo Pronzato
- Medical Oncology, AOU San Martino IRCCS IST Genova, Genova, Italy
| | | | | | | | - Marco Danova
- Internal Medicine and Medical Oncology, ASST Pavia, Pavia, Italy
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26
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Sheng JY, Visvanathan K, Thorner E, Wolff AC. Breast cancer survivorship care beyond local and systemic therapy. Breast 2020; 48 Suppl 1:S103-S109. [PMID: 31839149 DOI: 10.1016/s0960-9776(19)31135-x] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Despite persistent inequities in access to care and treatments, advances in combined modality care have led to a steady improvement in outcomes for breast cancer patients across the globe. When estimating the magnitude of clinical benefit of therapies, providers and patients must contend with a multitude of factors that impact treatment decisions and can have long-term effects on quality of life and survival. These include commonly described early toxicities, like aromatase inhibitor-associated musculoskeletal syndrome and neuropathy. But longer-term comorbidities often observed among cancer survivors including weight gain, obesity, infertility, psychological distress, sexual dysfunction, second cancers, bone loss, and body image issues can have lasting effects on quality of life. Equally important, system-level factors such as access to care and resource allocation can have a systemic impact on survival and on the quality of survivorship. Financial toxicity including underemployment can have a lasting impact on patients and caregivers. The resulting disparities in access to treatment can help explain much of the observed variability in outcomes, even within high-income countries like the US. This article revisits some of secondary effects from therapies discussed in a prior 2015 review article, along with other impediments to the optimal delivery of breast cancer care that can affect patients anywhere.
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Affiliation(s)
- Jennifer Y Sheng
- The Johns Hopkins University School of Medicine, The Johns Hopkins Bloomberg School of Public Health, and The Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA
| | - Kala Visvanathan
- The Johns Hopkins University School of Medicine, The Johns Hopkins Bloomberg School of Public Health, and The Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA
| | - Elissa Thorner
- The Johns Hopkins University School of Medicine, The Johns Hopkins Bloomberg School of Public Health, and The Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA
| | - Antonio C Wolff
- The Johns Hopkins University School of Medicine, The Johns Hopkins Bloomberg School of Public Health, and The Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA.
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27
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Kaplan HG, Calip GS, Malmgren JA. Maximizing Breast Cancer Therapy with Awareness of Potential Treatment-Related Blood Disorders. Oncologist 2020; 25:391-397. [PMID: 32073195 PMCID: PMC7216464 DOI: 10.1634/theoncologist.2019-0099] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2019] [Accepted: 01/29/2020] [Indexed: 01/18/2023] Open
Abstract
In this review we summarize the impact of the various modalities of breast cancer therapy coupled with intrinsic patient factors on incidence of subsequent treatment-induced myelodysplasia and acute myelogenous leukemia (t-MDS/AML). It is clear that risk is increased for patients treated with radiation and chemotherapy at younger ages. Radiation is associated with modest risk, whereas chemotherapy, particularly the combination of an alkylating agent and an anthracycline, carries higher risk and radiation and chemotherapy combined increase the risk markedly. Recently, treatment with granulocyte colony-stimulating factor (G-CSF), but not pegylated G-CSF, has been identified as a factor associated with increased t-MDS/AML risk. Two newly identified associations may link homologous DNA repair gene deficiency and poly (ADP-ribose) polymerase inhibitor treatment to increased t-MDS/AML risk. When predisposing factors, such as young age, are combined with an increasing number of potentially leukemogenic treatments that may not confer large risk singly, the risk of t-MDS/AML appears to increase. Patient and treatment factors combine to form a biological cascade that can trigger a myelodysplastic event. Patients with breast cancer are often exposed to many of these risk factors in the course of their treatment, and triple-negative patients, who are often younger and/or BRCA positive, are often exposed to all of them. It is important going forward to identify effective therapies without these adverse associated effects and choose existing therapies that minimize the risk of t-MDS/AML without sacrificing therapeutic gain. IMPLICATIONS FOR PRACTICE: Breast cancer is far more curable than in the past but requires multimodality treatment. Great care must be taken to use the least leukemogenic treatment programs that do not sacrifice efficacy. Elimination of radiation and anthracycline/alkylating agent regimens will be helpful where possible, particularly in younger patients and possibly those with homologous repair deficiency (HRD). Use of colony-stimulating factors should be limited to those who truly require them for safe chemotherapy administration. Further study of a possible leukemogenic association with HRD and the various forms of colony-stimulating factors is badly needed.
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Affiliation(s)
| | - Gregory S. Calip
- Center for Pharmacoepidemiology and Pharmacoeconomic Research, University of Illinois at ChicagoChicagoIllinoisUSA
| | - Judith A. Malmgren
- Healthstat Consulting Inc.SeattleWashingtonUSA
- Department of Epidemiology, University of WashingtonSeattleWashingtonUSA
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28
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Cheon H, Dziewulska KH, Moosic KB, Olson KC, Gru AA, Feith DJ, Loughran TP. Advances in the Diagnosis and Treatment of Large Granular Lymphocytic Leukemia. Curr Hematol Malig Rep 2020; 15:103-112. [PMID: 32062772 PMCID: PMC7234906 DOI: 10.1007/s11899-020-00565-6] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
PURPOSE OF REVIEW The past decade in LGL leukemia research has seen increased pairing of clinical data with molecular markers, shedding new insights on LGL leukemia pathogenesis and heterogeneity. This review summarizes the current standard of care of LGL leukemia, updates from clinical trials, and our congruent improved understanding of LGL pathogenesis. RECENT FINDINGS Various clinical reports have identified associations between stem, bone marrow, and solid organ transplants and incidence of LGL leukemia. There is also a potential for underdiagnosis of LGL leukemia within the rheumatoid arthritis patient population, emphasizing our need for continued study. Preliminary results from the BNZ-1 clinical trial, which targets IL-15 along with IL-2 and IL-9 signaling pathways, show some evidence of clinical response. With advances in our understanding of LGL pathogenesis from both the bench and the clinic, exciting avenues for investigations lie ahead for LGL leukemia.
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Affiliation(s)
- HeeJin Cheon
- Department of Medicine, Division of Hematology & Oncology, University of Virginia Cancer Center, PO Box 800334, Charlottesville, VA, 22908-0334, USA
- Department of Biochemistry and Molecular Genetics, Charlottesville, VA, 22908, USA
- Medical Scientist Training Program, Charlottesville, VA, 22908, USA
| | - Karolina H Dziewulska
- Department of Medicine, Division of Hematology & Oncology, University of Virginia Cancer Center, PO Box 800334, Charlottesville, VA, 22908-0334, USA
- Department of Pathology, University of Virginia School of Medicine, Charlottesville, VA, 22908, USA
| | - Katharine B Moosic
- Department of Medicine, Division of Hematology & Oncology, University of Virginia Cancer Center, PO Box 800334, Charlottesville, VA, 22908-0334, USA
- Department of Pathology, University of Virginia School of Medicine, Charlottesville, VA, 22908, USA
| | - Kristine C Olson
- Department of Medicine, Division of Hematology & Oncology, University of Virginia Cancer Center, PO Box 800334, Charlottesville, VA, 22908-0334, USA
| | - Alejandro A Gru
- Department of Pathology, University of Virginia School of Medicine, Charlottesville, VA, 22908, USA
| | - David J Feith
- Department of Medicine, Division of Hematology & Oncology, University of Virginia Cancer Center, PO Box 800334, Charlottesville, VA, 22908-0334, USA
| | - Thomas P Loughran
- Department of Medicine, Division of Hematology & Oncology, University of Virginia Cancer Center, PO Box 800334, Charlottesville, VA, 22908-0334, USA.
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29
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Shallis RM, Podoltsev NA, Gowda L, Zeidan AM, Gore SD. Cui bono? Finding the value of allogeneic stem cell transplantation for lower-risk myelodysplastic syndromes. Expert Rev Hematol 2020; 13:447-460. [PMID: 32182435 DOI: 10.1080/17474086.2020.1744433] [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] [Indexed: 01/19/2023]
Abstract
Introduction: The myelodysplastic syndromes (MDS) vary in their risk of disease progression; progression includes increasingly severe bone marrow failure, reclassification as acute myeloid leukemia (AML), and death. Prognostic tools guide recommendations for allogeneic stem cell transplantation (alloSCT), the only curative option. AlloSCT is typically reserved for patients with higher-risk MDS as defined by existing prognostic tools, although additional clinical and biological factors in lower-risk patients may influence this dogma.Areas covered: This review discusses the current understanding of MDS risk stratification as it pertains to the use of alloSCT in subpopulations of MDS patients with a particular focus on the use of alloSCT in patients with lower-risk disease.Expert commentary: Though high-quality data are lacking, some lower-risk MDS patients may benefit from alloSCT, which offers the only prospect of cure. Understanding the etiologic role and prognostic impact of recurring genetic events may improve existing risk stratification and become integral facets of prognostic schemata. The identification of additional factors influencing the prognoses of patients currently lumped together as 'lower-risk' will likewise improve the selection of MDS patients for early intervention or aggressive therapies such as alloSCT.
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Affiliation(s)
- Rory M Shallis
- Section of Hematology, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA.,Yale Cancer Center, New Haven, CT, USA
| | - Nikolai A Podoltsev
- Section of Hematology, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA.,Yale Cancer Center, New Haven, CT, USA
| | - Lohith Gowda
- Section of Hematology, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA.,Yale Cancer Center, New Haven, CT, USA
| | - Amer M Zeidan
- Section of Hematology, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA.,Yale Cancer Center, New Haven, CT, USA
| | - Steven D Gore
- Section of Hematology, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA.,Yale Cancer Center, New Haven, CT, USA
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30
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Adams MR, Moody CT, Sollinger JL, Brudno Y. Extracellular-Matrix-Anchored Click Motifs for Specific Tissue Targeting. Mol Pharm 2020; 17:392-403. [PMID: 31829613 DOI: 10.1021/acs.molpharmaceut.9b00589] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Local presentation of cancer drugs by injectable drug-eluting depots reduces systemic side effects and improves efficacy. However, local depots deplete their drug stores and are difficult to introduce into stiff tissues, or organs, such as the brain, that cannot accommodate increased pressure. We present a method for introducing targetable depots through injection of activated ester molecules into target tissues that react with and anchor themselves to the local extracellular matrix (ECM) and subsequently capture systemically administered small molecules through bioorthogonal click chemistry. A computational model of tissue-anchoring depot formation and distribution was verified by histological analysis and confocal imaging of cleared tissues. ECM-anchored click groups do not elicit any noticeable local or systemic toxicity or immune response and specifically capture systemically circulating molecules at intradermal, intratumoral, and intracranial sites for multiple months. Taken together, ECM anchoring of click chemistry motifs is a promising approach to specific targeting of both small and large therapeutics, enabling repeated local presentation for cancer therapy and other diseases.
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Affiliation(s)
- Mary R Adams
- Joint Department of Biomedical Engineering , University of North Carolina, Chapel Hill and North Carolina State University , Raleigh. 911 Oval Drive , Raleigh , North Carolina 27695 , United States
| | - Christopher T Moody
- Joint Department of Biomedical Engineering , University of North Carolina, Chapel Hill and North Carolina State University , Raleigh. 911 Oval Drive , Raleigh , North Carolina 27695 , United States
| | - Jennifer L Sollinger
- Joint Department of Biomedical Engineering , University of North Carolina, Chapel Hill and North Carolina State University , Raleigh. 911 Oval Drive , Raleigh , North Carolina 27695 , United States
| | - Yevgeny Brudno
- Joint Department of Biomedical Engineering , University of North Carolina, Chapel Hill and North Carolina State University , Raleigh. 911 Oval Drive , Raleigh , North Carolina 27695 , United States.,Lineberger Comprehensive Cancer Center , University of North Carolina, Chapel Hill , 450 West Dr. , Chapel Hill , North Carolina 27599 , United States
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31
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Khaled SAA, Nabih O, Abdel Aziz NM, Mahran DG. Myeloid Leukemias: A Glance at Middle Eastern Centers. J Blood Med 2019; 10:425-433. [PMID: 31908557 PMCID: PMC6926095 DOI: 10.2147/jbm.s221317] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2019] [Accepted: 08/23/2019] [Indexed: 11/23/2022] Open
Abstract
BACKGROUND AND OBJECTIVES Myeloid leukemias (MLs) are clonal stem cell disorders affecting myeloid lineage cells. Advances in cytogenetic and molecular studies partially disclosed the mystery about risk factors and pathophysiology of MLs. Regarding incidence, risk factors, response to treatment, and overall survival of patients, research showed differences among different countries. However, the Western registry data are the basis for the documented description of MLs in medical textbooks. This research aimed to study MLs in Middle Eastern health centers. Egypt has the highest population in the Middle East; furthermore, 96.6% of the population is native Egyptians; accordingly the study focused on Egypt. PATIENTS AND METHODS Data of 468 patients with MLs were collected from hospital records at two big tertiary health centers. They were grouped into group 1 (chronic myeloid leukemia, CML) and group 2 (acute myeloid leukemia, AML); the latter was subgrouped into 2a (primary AML) and 2b (secondary AML). RESULTS AND CONCLUSIONS The median age of patients was 43 years; males predominate in group 2a and females in groups 1 and 2b. 37.2% of group 1 patients were treated with Gleevec. Hematopoietic stem cell transplantation was planned for only 5% of group 2 and 18% relapsed. Of groups 1 and 2 patients, 25% and 12%, respectively, stopped follow up, and 15% and 35% died. ORR and overall survival were 53%, 27% and 7%, 0.4% for groups 1 and 2, respectively. Conclusively, this study showed a young age of ML patients, with female predominance in CML, and poor outcome. This reflected racial, ethnic and risk factor differences in incidence of MLs.
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Affiliation(s)
- Safaa AA Khaled
- Department of Internal Medicine, Clinical Hematology Unit, Assiut University Hospital, Faculty of Medicine, Assiut University, Assiut, Egypt
- Unit of Bone Marrow Transplantation, South Egypt Cancer Institute, Assiut, Egypt
| | - Ola Nabih
- Department of Clinical Oncology, Assiut University Hospital, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Nashwa M Abdel Aziz
- Department of Medical Oncology, South Egypt Cancer Institute, Assiut University, Assiut, Egypt
| | - Dalia G Mahran
- Department of Public Health and Community Medicine, Faculty of Medicine, Assiut University, Assiut, Egypt
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32
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Lalya I, Essadi I, Belbaraka R, El Omrani A, Khouchani M. Acute Myeloid Leukemia After Treatment of Early Breast Cancer: Case Report and Literature Review. INDIAN JOURNAL OF GYNECOLOGIC ONCOLOGY 2019. [DOI: 10.1007/s40944-019-0308-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
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33
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Shoket N, Muzamil J, Zargar TB, Wani B, Toka V, Bhat JR, Bhat GM, Shiekh AA. Clinical Profile of Acute Myeloid Leukemia in North India and Utility of Nontransplant Measures in its Management. Indian J Med Paediatr Oncol 2019. [DOI: 10.4103/ijmpo.ijmpo_175_17] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Abstract
Abstract
Introduction: Acute myeloid leukemia (AML) is a clonal accumulation of myeloid precursors in body tissues, which ultimately leads to bone marrow failure. This is an 8-year prospective, observational study in which 254 patients were enrolled. Aim of the Study: To document the clinical profile of AML and differential outcome in M3 versus non-M3 phenotype and to see impact of different variables on its survival. Methods: Patients enrolled in the study were examined, evaluated, and given standard 3:7 induction protocol, and acute promyelocytic leukemia (APML) patients were given the ICAPL 2006 protocol. Results: In our study, males outnumbered females and most of our patients were in 20–60 years of age group. The better prognosis was in patients who were in the second decade of life. Total leukocyte count and platelet count had a significant impact on the survival of the a patient. Bone marrow morphology of M3 type has extremely good prognosis and was the most common FAB type seen in our study. Flow cytometric markers such as CD15, CD33, CD117, and myeloperoxidase had positivity among 90% of patients. Overall survival is around 40% in whole-study group, 87% in APML group, and 16.5% in non-M3 group. There are still unmet needs in managing the non-M3 patients in resource-constraint countries where allogenic transplant and newer drugs have the least access. For improving the outcome in M3 AML, further newer molecules such as Flt3 and PIK3 inhibitors are being used in trials. Conclusion: There are still unmet needs in managing the non-M3 patients in resource-constraint countries where allogenic transplant and newer drugs have the least access. For improving the outcome in M3 AML, further newer molecules such as Flt3 and PIK3 inhibitors are being used in trials.
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Affiliation(s)
- Nadeem Shoket
- Departments of Medical Oncology, Sheri Kashmir Institute of Medical Sciences, Srinagar, Jammu and Kashmir, India
| | - Javvid Muzamil
- Departments of Medical Oncology, Sheri Kashmir Institute of Medical Sciences, Srinagar, Jammu and Kashmir, India
| | - Tasneef Banoo Zargar
- Departments of Medical Oncology, Sheri Kashmir Institute of Medical Sciences, Srinagar, Jammu and Kashmir, India
| | - Burhan Wani
- Departments of Medical Oncology, Sheri Kashmir Institute of Medical Sciences, Srinagar, Jammu and Kashmir, India
| | - Vishal Toka
- Departments of Medical Oncology, Sheri Kashmir Institute of Medical Sciences, Srinagar, Jammu and Kashmir, India
| | - Javid Rasool Bhat
- Departments of Clinical Hematology, Sheri Kashmir Institute of Medical Sciences, Srinagar, Jammu and Kashmir, India
| | - Gull Mohammad Bhat
- Departments of Medical Oncology, Sheri Kashmir Institute of Medical Sciences, Srinagar, Jammu and Kashmir, India
| | - Aejaz Aziz Shiekh
- Departments of Medical Oncology, Sheri Kashmir Institute of Medical Sciences, Srinagar, Jammu and Kashmir, India
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34
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Shallis RM, Wang R, Davidoff A, Ma X, Zeidan AM. Epidemiology of acute myeloid leukemia: Recent progress and enduring challenges. Blood Rev 2019; 36:70-87. [PMID: 31101526 DOI: 10.1016/j.blre.2019.04.005] [Citation(s) in RCA: 530] [Impact Index Per Article: 88.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2018] [Revised: 04/06/2019] [Accepted: 04/26/2019] [Indexed: 01/08/2023]
Abstract
Acute myeloid leukemia (AML) is a malignant disorder of the bone marrow which is characterized by the clonal expansion and differentiation arrest of myeloid progenitor cells. The age-adjusted incidence of AML is 4.3 per 100,000 annually in the United States (US). Incidence increases with age with a median age at diagnosis of 68 years in the US. The etiology of AML is heterogeneous. In some patients, prior exposure to therapeutic, occupational or environmental DNA-damaging agents is implicated, but most cases of AML remain without a clear etiology. AML is the most common form of acute leukemia in adults and has the shortest survival (5-year survival = 24%). Curative therapies, including intensive chemotherapy and allogeneic stem cell transplantation, are generally applicable to a minority of patients who are younger and fit, while most older individuals exhibit poor prognosis and survival. Differences in patient outcomes are influenced by disease characteristics, access to care including active therapies and supportive care, and other factors. After many years without therapeutic advances, several new therapies have been approved and are expected to impact patient outcomes, especially for older patients and those with refractory disease.
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Affiliation(s)
- Rory M Shallis
- Section of Hematology, Department of Internal Medicine, Yale University School of Medicine, New Haven, USA
| | - Rong Wang
- Cancer Outcomes, Public Policy, and Effectiveness Research (COPPER) Center, Yale University, New Haven, USA; Department of Chronic Disease Epidemiology, School of Public Health, Yale University, New Haven, USA
| | - Amy Davidoff
- Cancer Outcomes, Public Policy, and Effectiveness Research (COPPER) Center, Yale University, New Haven, USA; Department of Health Policy and Management, School of Public Health, Yale University, New Haven, USA
| | - Xiaomei Ma
- Cancer Outcomes, Public Policy, and Effectiveness Research (COPPER) Center, Yale University, New Haven, USA; Department of Chronic Disease Epidemiology, School of Public Health, Yale University, New Haven, USA
| | - Amer M Zeidan
- Section of Hematology, Department of Internal Medicine, Yale University School of Medicine, New Haven, USA; Cancer Outcomes, Public Policy, and Effectiveness Research (COPPER) Center, Yale University, New Haven, USA.
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Hochheiser L, Hornberger J, Turner M, Lyman GH. Multi-gene assays: effect on chemotherapy use, toxicity and cost in estrogen receptor-positive early stage breast cancer. J Comp Eff Res 2019; 8:289-304. [DOI: 10.2217/cer-2018-0137] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023] Open
Abstract
Aim: To assess multi-gene assay (MGA) effects on chemotherapy use, toxicities, recurrences, and costs in estrogen receptor-positive early breast cancer. Methods: Meta-analysis performed using data from public databases. Results: Studies included 12,202 women. Relative to no testing, chemotherapy use was higher with 12-gene and 70-gene and lower with PAM50 (commercial) and 21-gene MGAs. Overall, 1643 distant recurrences occurred with no testing, declining by 231 (21-gene), 121 (70-gene), 54 (12-gene) and 94 (PAM50); only the 21-gene assay resulted in no risk of increasing the number of distant recurrences. Relative to ‘no testing’, total cost of care declined only with 21-gene MGA. Conclusion: MGAs differ in chemotherapy use and related outcomes for women with estrogen receptor-positive early breast cancer.
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Affiliation(s)
- Lou Hochheiser
- Professor Emeritus, Department of Family Practice, University of Vermont, Burlington, VT 83001, USA
| | | | | | - Gary H Lyman
- Fred Hutchinson Cancer Center & The University of Washington, Seattle, WA 98109, USA
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Zeidan AM, Shallis RM, Wang R, Davidoff A, Ma X. Epidemiology of myelodysplastic syndromes: Why characterizing the beast is a prerequisite to taming it. Blood Rev 2019; 34:1-15. [DOI: 10.1016/j.blre.2018.09.001] [Citation(s) in RCA: 75] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2018] [Revised: 09/01/2018] [Accepted: 09/17/2018] [Indexed: 02/08/2023]
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Guru Murthy GS, Abedin S. Myeloid malignancies after treatment for solid tumours. Best Pract Res Clin Haematol 2019; 32:40-46. [PMID: 30927974 DOI: 10.1016/j.beha.2019.02.012] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2018] [Revised: 02/18/2019] [Accepted: 02/22/2019] [Indexed: 12/21/2022]
Abstract
The cure rate for several solid tumour malignancies including breast cancers, head and neck cancers, bone cancers, and sarcoma has improved remarkably with the advent of neoadjuvant and adjuvant therapies. Unfortunately, exposure to chemotherapy or radiation as a part of these treatments exposes patients to the risk of subsequent myeloid malignancies. Therapy related myeloid malignancies have certain characteristic findings. They typically arise within 10 years of treatment exposure, they are seen in younger patients, and the greatest risk is in patients who receive therapy with alkylating agents or topoisomerase II inhibitors. Solid tumours whose therapies utilize these agents at higher doses, namely bone/soft tissue cancers, testicular cancer, anal cancer, and brain tumours, appear to be the groups at highest risk for T-MN. Beyond these patients, emerging populations diagnosed with T-MN include prior platinum exposure, and patients requiring G-CSF support with chemotherapy.
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Affiliation(s)
- Guru Subramanian Guru Murthy
- Division of Haematology and Oncology, Medical College of Wisconsin, Milwaukee, WI, USA; Instructor of Medicine, 9200 W Wisconsin Ave, Milwaukee, WI 53226, USA.
| | - Sameem Abedin
- Division of Haematology and Oncology, Medical College of Wisconsin, Milwaukee, WI, USA.
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The leukemia strikes back: a review of pathogenesis and treatment of secondary AML. Ann Hematol 2019; 98:541-559. [PMID: 30666431 DOI: 10.1007/s00277-019-03606-0] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2018] [Accepted: 01/04/2019] [Indexed: 12/17/2022]
Abstract
Secondary AML is associated with a disproportionately poor prognosis, consistently shown to exhibit inferior response rates, event-free survival, and overall survival in comparison with de novo AML. Secondary AML may arise from the evolution of an antecedent hematologic disorder, or it may arise as a complication of prior cytotoxic chemotherapy or radiation therapy in the case of therapy-related AML. Because of the high frequency of poor-risk cytogenetics and high-risk molecular features, such as alterations in TP53, leukemic clones are often inherently chemoresistant. Standard of care induction had long remained conventional 7 + 3 until its reformulation as CPX-351, recently FDA approved specifically for secondary AML. However, recent data also suggests relatively favorable outcomes with regimens based on high-dose cytarabine or hypomethylating agents. With several investigational agents being studied, the therapeutic landscape becomes even more complex, and the treatment approach involves patient-specific, disease-specific, and therapy-specific considerations.
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Jabagi MJ, Vey N, Goncalves A, Le Tri T, Zureik M, Dray-Spira R. Evaluation of the Incidence of Hematologic Malignant Neoplasms Among Breast Cancer Survivors in France. JAMA Netw Open 2019; 2:e187147. [PMID: 30657534 PMCID: PMC6484549 DOI: 10.1001/jamanetworkopen.2018.7147] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
IMPORTANCE Breast cancer survivors are at an increased risk of developing certain types of hematologic malignant neoplasm after diagnosis. OBJECTIVE To estimate the incidence of various types of hematologic malignant neoplasm in breast cancer survivors, both in absolute terms and in association with the general population. DESIGN, SETTING, AND PARTICIPANTS This nationwide cohort study conducted in France used data from the French National Health Data System, a database that contains all of French residents' health-related expenses. All French women aged 20 to 85 years with an incident breast cancer diagnosis between July 1, 2006, and December 31, 2015, were included (n = 439 704) and followed up until hematologic malignant neoplasm occurrence, death, loss of follow-up, or December 31, 2016, whichever came first. Comparisons were made with all French women in the general population who were registered in the French general health insurance program each year from January 1, 2007, and December 31, 2016. Data analysis was performed from January 23, 2018, to May 25, 2018. MAIN OUTCOMES AND MEASURES Main outcomes were incident hematologic malignant neoplasm cases occurring at least 6 months after breast cancer diagnosis. The various types of hematologic malignant neoplasm considered were acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), myeloproliferative neoplasms (MPNs), multiple myeloma (MM), Hodgkin lymphoma or non-Hodgkin lymphoma (HL/NHL), and acute lymphoblastic leukemia or lymphocytic lymphoma (ALL/LL). Incidence of these various types was estimated among breast cancer survivors and compared with the incidence in women in the general population. RESULTS The 439 704 women in the study had a median (interquartile range [IQR]) age of 59 (50-69) years and were followed up for a median (IQR) duration of 5 (2.8-7.5) years. Overall, 3046 cases of hematologic malignant neoplasm occurred: 509 cases (16.7%) of AML (crude incidence rate [CIR] per 100 000 person-years, 24.5; 95% CI, 22.4-26.8), 832 cases (27.3%) of MDS (CIR, 40.1; 95% CI, 37.4-42.9), and 267 cases (8.8%) of MPN (CIR, 12.8; 95% CI, 11.4-14.5). Lymphoid neoplasm cases included 420 cases (13.8%) of MM (CIR, 20.3; 95% CI, 18.4-22.3), 912 cases (29.9%) of HL/NHL (CIR, 44.4; 95% CI, 41.1-50.0), and 106 cases (3.5%) of ALL/LL (CIR, 5.1; 95% CI, 4.2-6.2). Compared with the general population, breast cancer survivors had statistically significantly higher incidence of AML (standardized incidence rate ratio [SIRR], 2.8; 95% CI, 2.5-3.2) and MDS (SIRR, 5.0; 95% CI, 4.4-5.7) and, to a lesser extent, MM (SIRR, 1.5; 95% CI, 1.3-1.7]) and ALL/LL (SIRR, 2.0; 95% CI, 1.3-3.0). CONCLUSIONS AND RELEVANCE The finding that AML and MDS still occur among breast cancer survivors today, and that ALL/LL and MM may also be of concern, merits the continuous monitoring of hematologic malignant neoplasms and the thorough investigations into their underlying mechanisms.
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Affiliation(s)
- Marie Joelle Jabagi
- University of Paris Sud, Paris-Saclay University, Paris, France
- Health Product Epidemiology Department, French National Agency for Medicines and Health Products Safety, Saint-Denis, France
| | - Norbert Vey
- Aix-Marseille University, CNRS, Inserm, Institut Paoli-Calmettes, Hematology Department, CRCM, Marseille, France
| | - Anthony Goncalves
- Aix-Marseille University, CNRS, Inserm, Institut Paoli-Calmettes, Medical Oncology Department, CRCM, Marseille, France
| | - Thien Le Tri
- Health Product Epidemiology Department, French National Agency for Medicines and Health Products Safety, Saint-Denis, France
| | - Mahmoud Zureik
- Health Product Epidemiology Department, French National Agency for Medicines and Health Products Safety, Saint-Denis, France
- Versailles Saint-Quentin-en-Yvelines University, Montigny-Le-Bretonneux, AP-HP Hôpital Sainte Perine Hospital, Paris, France
| | - Rosemary Dray-Spira
- Health Product Epidemiology Department, French National Agency for Medicines and Health Products Safety, Saint-Denis, France
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Adjuvant Chemotherapy for HER2-Negative Early-Stage Breast Cancer. Breast Cancer 2019. [DOI: 10.1007/978-3-319-96947-3_15] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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Sanford NN, Miao R, Wang H, Goldberg S, Jacobson A, Brunner AM, Cote GM, Yock TI, Ebb DH, Chen YB, Jee KW, Hornicek F, DeLaney TF, Choy E, Chen YL. Characteristics and Predictors for Secondary Leukemia and Myelodysplastic Syndrome in Ewing and Osteosarcoma Survivors. Int J Radiat Oncol Biol Phys 2019; 103:52-61. [PMID: 30165126 DOI: 10.1016/j.ijrobp.2018.08.037] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2018] [Revised: 08/07/2018] [Accepted: 08/21/2018] [Indexed: 12/19/2022]
Abstract
PURPOSE Long-term survivors of Ewing sarcoma (ES) and osteosarcoma may be at risk for therapy-related acute leukemia or myelodysplastic syndrome (t-AL/MDS). METHODS AND MATERIALS We retrospectively reviewed the clinicopathologic characteristics of 1071 patients with osteosarcoma (n = 757) and ES (n = 314) who were treated between 1985 and 2014. Multivariable competing risk analysis was used to analyze predictors of t-AL/MDS, including a radiation dose (≥55.8 Gy vs <55.8 Gy) × disease site (pelvis/spine vs other) interaction term. A supplemental nested case-control study was conducted to assess the association between cumulative chemotherapy dose and t-AL/MDS. RESULTS The median follow-up for surviving patients was 97 months (range, 0.03-380). Twenty patients developed t-AL/MDS, all of whom received chemotherapy and 15 of whom were treated with radiation therapy. Radiation therapy to ≥55.8 Gy was associated with development of t-AL/MDS (adjusted hazard ratio, 2.89; 95% confidence interval [CI], 1.23-6.80; P = .015), and there was a significant radiation dose × disease site interaction term (adjusted hazard ratio, 6.70; 95% CI, 2.71-16.53; Pinteraction < .001). The 5-year cumulative incidence of t-AL/MDS in patients receiving ≥55.8 Gy radiation therapy to the pelvis or spine was 5.0% (95% CI, 0.9-14.9) for osteosarcoma and 10.7% for ES (95% CI, 3.3-23.2). In our nested case-control study, cumulative doses of ifosfamide and etoposide were associated with development of t-AL/MDS. CONCLUSIONS Patients with osteosarcoma and ES receiving ≥55.8 Gy of radiation therapy to the pelvis or spine appear to be at increased risk for t-AL/MDS. Treatment with high cumulative doses of chemotherapy may further augment this risk.
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Affiliation(s)
- Nina N Sanford
- Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
| | - Ruoyu Miao
- Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
| | - Haotong Wang
- Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
| | - Saveli Goldberg
- Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
| | - Alex Jacobson
- Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
| | - Andrew M Brunner
- Department of Medical Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
| | - Gregory M Cote
- Department of Medical Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
| | - Torunn I Yock
- Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
| | - David H Ebb
- Department of Pediatric Oncology Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
| | - Yi-Bin Chen
- Department of Medical Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
| | - Kyung-Wook Jee
- Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
| | - Francis Hornicek
- Department of Orthopedic Surgery, University of California Los Angeles, Los Angeles, California
| | - Thomas F DeLaney
- Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
| | - Edwin Choy
- Department of Medical Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
| | - Yen-Lin Chen
- Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
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Englinger B, Pirker C, Heffeter P, Terenzi A, Kowol CR, Keppler BK, Berger W. Metal Drugs and the Anticancer Immune Response. Chem Rev 2018; 119:1519-1624. [DOI: 10.1021/acs.chemrev.8b00396] [Citation(s) in RCA: 174] [Impact Index Per Article: 24.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Affiliation(s)
- Bernhard Englinger
- Institute of Cancer Research and Comprehensive Cancer Center, Department of Medicine I, Medical University of Vienna, Borschkegasse 8a, A-1090 Vienna, Austria
| | - Christine Pirker
- Institute of Cancer Research and Comprehensive Cancer Center, Department of Medicine I, Medical University of Vienna, Borschkegasse 8a, A-1090 Vienna, Austria
| | - Petra Heffeter
- Institute of Cancer Research and Comprehensive Cancer Center, Department of Medicine I, Medical University of Vienna, Borschkegasse 8a, A-1090 Vienna, Austria
- Research Cluster “Translational Cancer Therapy Research”, University of Vienna and Medical University of Vienna, Vienna, Austria
| | - Alessio Terenzi
- Research Cluster “Translational Cancer Therapy Research”, University of Vienna and Medical University of Vienna, Vienna, Austria
- Institute of Inorganic Chemistry, Faculty of Chemistry, University of Vienna, Waehringer Strasse 42, A-1090 Vienna, Austria
| | - Christian R. Kowol
- Research Cluster “Translational Cancer Therapy Research”, University of Vienna and Medical University of Vienna, Vienna, Austria
- Institute of Inorganic Chemistry, Faculty of Chemistry, University of Vienna, Waehringer Strasse 42, A-1090 Vienna, Austria
| | - Bernhard K. Keppler
- Research Cluster “Translational Cancer Therapy Research”, University of Vienna and Medical University of Vienna, Vienna, Austria
- Institute of Inorganic Chemistry, Faculty of Chemistry, University of Vienna, Waehringer Strasse 42, A-1090 Vienna, Austria
| | - Walter Berger
- Institute of Cancer Research and Comprehensive Cancer Center, Department of Medicine I, Medical University of Vienna, Borschkegasse 8a, A-1090 Vienna, Austria
- Research Cluster “Translational Cancer Therapy Research”, University of Vienna and Medical University of Vienna, Vienna, Austria
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Incidence of secondary myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) in patients with ovarian or breast cancer in a real-world setting in the United States. Gynecol Oncol 2018; 151:190-195. [DOI: 10.1016/j.ygyno.2018.09.003] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2018] [Revised: 08/09/2018] [Accepted: 09/03/2018] [Indexed: 11/20/2022]
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Risk and survival of chronic myeloid leukemia after breast cancer: A population-based study. Curr Probl Cancer 2018; 43:213-221. [PMID: 30195804 DOI: 10.1016/j.currproblcancer.2018.08.005] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2018] [Revised: 07/09/2018] [Accepted: 08/17/2018] [Indexed: 11/23/2022]
Abstract
BACKGROUND We aimed to investigate the risk and survival of chronic myeloid leukemia (CML) after breast cancer (BC) diagnosis. METHODS We used the Surveillance, Epidemiology, and End Results 'SEER' database. Females, diagnosed with BC between 1992 and 2014, were selected and followed for the development of CML after a 6-month latency period from BC diagnosis. We used the Multiple Primary Standardized Incidence Ratios session of the SEER*Stat software (version 8.3.4) to calculate the Observed/Expected (O/E) ratios with 95% confidence intervals (CI). To calculate the overall survival, we performed an unadjusted Kaplan-Meier analysis using the SPSS software. RESULTS We included 474,866 females with BC, of which 178 were later diagnosed with CML. We found the risk of CML to increase significantly after BC diagnosis (O/E = 1.26, 95% CI: 1.08-1.45) and the risk was specifically higher within the first 5 years of diagnosis (O/E = 1.45, 95% CI: 1.16-1.8). When the risk was stratified by cancer stage, localized BC was associated with a significant increase in CML risk within 5 years of diagnosis (O/E = 1.4, 95% CI: 1.06-1.82), while regional BC was associated with a significant increase in CML risk after more than 5 years of diagnosis (O/E = 1.59, 95% CI: 1.09-2.25). Moreover, radiotherapy, chemotherapy, and presence of hormonal receptors were associated with a significant increase in CML risk in BC patients. The median overall survival of CML after BC was 28 months. CONCLUSION Breast cancer patients have an increased risk of developing CML and further investigation is required to establish the causes of this finding.
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Tang HM, Tang HL. Anastasis: recovery from the brink of cell death. ROYAL SOCIETY OPEN SCIENCE 2018; 5:180442. [PMID: 30839720 PMCID: PMC6170572 DOI: 10.1098/rsos.180442] [Citation(s) in RCA: 53] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/20/2018] [Accepted: 08/23/2018] [Indexed: 05/11/2023]
Abstract
Anastasis is a natural cell recovery phenomenon that rescues cells from the brink of death. Programmed cell death such as apoptosis has been traditionally assumed to be an intrinsically irreversible cascade that commits cells to a rapid and massive demolition. Interestingly, recent studies have demonstrated recovery of dying cells even at the late stages generally considered immutable. Here, we examine the evidence for anastasis in cultured cells and in animals, review findings illuminating the potential mechanisms of action, discuss the challenges of studying anastasis and explore new strategies to uncover the function and regulation of anastasis, the identification of which has wide-ranging physiological, pathological and therapeutic implications.
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Affiliation(s)
- Ho Man Tang
- Institute for Basic Biomedical Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
- School of Life Sciences, Chinese University of Hong Kong, Shatin, Hong Kong
| | - Ho Lam Tang
- Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
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Lung cancer induced from chemotherapy a 20 years old case. Respir Med Case Rep 2018; 24:32-34. [PMID: 29977753 PMCID: PMC6010615 DOI: 10.1016/j.rmcr.2018.03.013] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2018] [Revised: 03/21/2018] [Accepted: 03/25/2018] [Indexed: 12/03/2022] Open
Abstract
Lung cancer is diagnosed at a late stage although we have novel diagnostic tools. The association of smoking and other environmental factors are well known. However; there are cases where a malignancy is associated with previous radiation treatment. There is an association between radiotherapy treatment and cancer incidence. We present a case where lung cancer and laryngeal cancer was induced 20 years after radiation therapy of a hogkin lymphoma.
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Sanford NN, Martin AM, Brunner AM, Cote GM, Choy E, DeLaney TF, Aizer AA, Chen YL. Secondary Acute Leukemia in Sarcoma Patients: A Population-Based Study. Int J Radiat Oncol Biol Phys 2018; 100:687-694. [PMID: 29413281 DOI: 10.1016/j.ijrobp.2017.11.011] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2017] [Revised: 10/20/2017] [Accepted: 11/07/2017] [Indexed: 12/19/2022]
Abstract
PURPOSE To compare rates of secondary acute leukemia between sarcoma patients and the general population, using data from the National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) registry, and to examine whether various patient, tumor, and treatment factors were associated with development of a secondary acute leukemia. METHODS AND MATERIALS Patients with a primary diagnosis of connective tissue malignancy between 1973 and 2008 in the SEER database were included. Multivariable competing risk analysis was used to determine risk factors associated with subsequent development of acute leukemia. Using observed-to-expected ratios, we compared incidence rates of secondary acute leukemia between sarcoma patients and the general population. RESULTS A total of 72,945 patients were identified, with median follow-up of 131 months. On multivariable competing risk analysis, factors associated with increased risk of secondary acute leukemia included receipt of radiation therapy (hazard ratio [HR] 1.67, P=.02), distant disease (HR 2.67, P=.004), male gender (HR 1.53, P=.03), year of diagnosis (HR 0.98, P=.049), and Ewing sarcoma histology (HR 9.95, P < .0001) and osteosarcoma histology (HR 5.06, P=.0001). The observed-to-expected ratio for development of a secondary acute leukemia was 3.67 (95% confidence interval [CI] 1.95-6.28), 3.41 (95% CI 2.73-4.20), and 1.6 (95% CI 1.38-8.19) for acute lymphocytic leukemia, acute myeloid leukemia, and acute monocytic leukemia, respectively. The 10-year cumulative incidence of secondary acute leukemia for patients who did and did receive radiation therapy was 0.3% versus 0.1% (P=.02). CONCLUSIONS Patients treated for sarcoma, in particular those with Ewing sarcoma and osteosarcoma histology, seem to have a higher incidence of secondary acute leukemia as compared with the general population. Treatment factors including radiation therapy and chemotherapy seem to play a role in this increased risk, although the absolute incidence nevertheless remains very small.
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Affiliation(s)
- Nina N Sanford
- Department of Radiation Oncology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts; Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
| | - Allison M Martin
- Department of Radiation Oncology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
| | - Andrew M Brunner
- Department of Medical Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
| | - Gregory M Cote
- Department of Medical Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
| | - Edwin Choy
- Department of Medical Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
| | - Thomas F DeLaney
- Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
| | - Ayal A Aizer
- Department of Radiation Oncology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
| | - Yen-Lin Chen
- Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
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Tang HM, Fung MC, Tang HL. Detecting Anastasis In Vivo by CaspaseTracker Biosensor. J Vis Exp 2018. [PMID: 29443051 DOI: 10.3791/54107] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023] Open
Abstract
Anastasis (Greek for "rising to life") is a recently discovered cell recovery phenomenon whereby dying cells can reverse late-stage cell death processes that are generally assumed to be intrinsically irreversible. Promoting anastasis could in principle rescue or preserve injured cells that are difficult to replace such as cardiomyocytes or neurons, thereby facilitating tissue recovery. Conversely, suppressing anastasis in cancer cells, undergoing apoptosis after anti-cancer therapies, may ensure cancer cell death and reduce the chances of recurrence. However, these studies have been hampered by the lack of tools for tracking the fate of cells that undergo anastasis in live animals. The challenge is to identify the cells that have reversed the cell death process despite their morphologically normal appearance after recovery. To overcome this difficulty, we have developed Drosophila and mammalian CaspaseTracker biosensor systems that can identify and permanently track the anastatic cells in vitro or in vivo. Here, we present in vivo protocols for the generation and use of the CaspaseTracker dual biosensor system to detect and track anastasis in Drosophila melanogaster after transient exposure to cell death stimuli. While conventional biosensors and protocols can label cells actively undergoing apoptotic cell death, the CaspaseTracker biosensor can permanently label cells that have recovered after caspase activation - a hallmark of late-stage apoptosis, and simultaneously identify active apoptotic processes. This biosensor can also track the recovery of the cells that attempted other forms of cell death that directly or indirectly involved caspase activity. Therefore, this protocol enables us to continuously track the fate of these cells and their progeny, facilitating future studies of the biological functions, molecular mechanisms, physiological and pathological consequences, and therapeutic implications of anastasis. We also discuss the appropriate controls to distinguish cells that undergo anastasis from those that display non-apoptotic caspase activity in vivo.
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Affiliation(s)
- Ho Man Tang
- Institute for Basic Biomedical Sciences, Johns Hopkins University School of Medicine; School of Life Sciences, Chinese University of Hong Kong;
| | - Ming Chiu Fung
- School of Life Sciences, Chinese University of Hong Kong;
| | - Ho Lam Tang
- Department of Neurosurgery, Johns Hopkins University School of Medicine;
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Kurkjian CJ, Guo H, Montgomery ND, Cheng N, Yuan H, Merrill JR, Sempowski GD, Brickey WJ, Ting JPY. The Toll-Like Receptor 2/6 Agonist, FSL-1 Lipopeptide, Therapeutically Mitigates Acute Radiation Syndrome. Sci Rep 2017; 7:17355. [PMID: 29230065 PMCID: PMC5725477 DOI: 10.1038/s41598-017-17729-9] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2016] [Accepted: 11/16/2017] [Indexed: 02/03/2023] Open
Abstract
Risks of radiation exposure from nuclear incidents and cancer radiotherapy are undeniable realities. These dangers urgently compel the development of agents for ameliorating radiation–induced injuries. Biologic pathways mediated by myeloid differentiation primary response gene 88 (MyD88), the common adaptor for toll–like receptor (TLR) and Interleukin–1 receptor signaling, are critical for radioprotection. Treating with agonists prior to radiation enhances survival by activating TLR signaling, whereas radiomitigating TLR–activating therapeutics given after exposure are less defined. We examine the radiomitigation capability of TLR agonists and identify one that is superior for its efficacy and reduced toxic consequences compared to other tested agonists. We demonstrate that the synthetic TLR2/6 ligand Fibroblast–stimulating lipopeptide (FSL–1) substantially prolongs survival in both male and female mice when administered 24 hours after radiation and shows MyD88–dependent function. FSL–1 treatment results in accelerated hematopoiesis in bone marrow, spleen and periphery, and augments systemic levels of hematopoiesis–stimulating factors. The ability of FSL–1 to stimulate hematopoiesis is critical, as hematopoietic dysfunction results from a range of ionizing radiation doses. The efficacy of a single FSL–1 dose for alleviating radiation injury while protecting against adverse effects reveals a viable radiation countermeasures agent.
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Affiliation(s)
- Cathryn J Kurkjian
- Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA
| | - Hao Guo
- Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA
| | - Nathan D Montgomery
- Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC, USA
| | - Ning Cheng
- Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA.,Oral Biology Curriculum, School of Dentistry, University of North Carolina, Chapel Hill, NC, USA
| | - Hong Yuan
- Department of Radiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.,Biomedical Imaging Research Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Joseph R Merrill
- Biomedical Imaging Research Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | | | - W June Brickey
- Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA
| | - Jenny P-Y Ting
- Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA. .,Department of Genetics, University of North Carolina, Chapel Hill, NC, USA.
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