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Zhang JJ, Cheng L, Qiao Q, Xiao XL, Lin SJ, He YF, Sha RL, Sha J, Ma Y, Zhang HL, Ye XR. Adenosine triphosphate-induced cell death in heart failure: Is there a link? World J Cardiol 2025; 17:105021. [PMID: 40308621 PMCID: PMC12038699 DOI: 10.4330/wjc.v17.i4.105021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2025] [Revised: 02/22/2025] [Accepted: 04/02/2025] [Indexed: 04/21/2025] Open
Abstract
Heart failure (HF) has emerged as one of the foremost global health threats due to its intricate pathophysiological mechanisms and multifactorial etiology. Adenosine triphosphate (ATP)-induced cell death represents a novel form of regulated cell deaths, marked by cellular energy depletion and metabolic dysregulation stemming from excessive ATP accumulation, identifying its uniqueness compared to other cell death processes modalities such as programmed cell death and necrosis. Growing evidence suggests that ATP-induced cell death (AICD) is predominantly governed by various biological pathways, including energy metabolism, redox homeostasis and intracellular calcium equilibrium. Recent research has shown that AICD is crucial in HF induced by pathological conditions like myocardial infarction, ischemia-reperfusion injury, and chemotherapy. Thus, it is essential to investigate the function of AICD in the pathogenesis of HF, as this may provide a foundation for the development of targeted therapies and novel treatment strategies. This review synthesizes current advancements in understanding the link between AICD and HF, while further elucidating its involvement in cardiac remodeling and HF progression.
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Affiliation(s)
- Jing-Jing Zhang
- Department of Cardiovascular Medicine, Fuwai Yunnan Hospital, Chinese Academy Medical Sciences, Kunming 650000, Yunnan Province, China
| | - Lu Cheng
- Department of Cardiovascular Medicine, Fuwai Yunnan Hospital, Chinese Academy Medical Sciences, Kunming 650000, Yunnan Province, China
| | - Qian Qiao
- Department of Cardiovascular Medicine, Fuwai Yunnan Hospital, Chinese Academy Medical Sciences, Kunming 650000, Yunnan Province, China
| | - Xue-Liang Xiao
- Department of Critical Care Medicine, Ninglang Yi Autonomous County People's Hospital, Lijiang 674300, Yunnan Province, China
| | - Shao-Jun Lin
- Department of Critical Care Medicine, Ninglang Yi Autonomous County People's Hospital, Lijiang 674300, Yunnan Province, China
| | - Yue-Fang He
- Department of Critical Care Medicine, Ninglang Yi Autonomous County People's Hospital, Lijiang 674300, Yunnan Province, China
| | - Ren-Luo Sha
- Department of Critical Care Medicine, Ninglang Yi Autonomous County People's Hospital, Lijiang 674300, Yunnan Province, China
| | - Jun Sha
- Department of Critical Care Medicine, Ninglang Yi Autonomous County People's Hospital, Lijiang 674300, Yunnan Province, China
| | - Yin Ma
- Department of Critical Care Medicine, Ninglang Yi Autonomous County People's Hospital, Lijiang 674300, Yunnan Province, China
| | - Hao-Ling Zhang
- Department of Biomedical Science, Advanced Medical and Dental Institute, University Sains Malaysia, Penang 13200, Malaysia.
| | - Xue-Rui Ye
- Department of Cardiovascular Medicine, Fuwai Yunnan Hospital, Chinese Academy Medical Sciences, Kunming 650000, Yunnan Province, China
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Yu J, Sun X, Gao G, Yu L, Wang J, Qiu L, Qian Z, Li W, Zhang H. CMOEP regimen in the treatment of untreated peripheral T-cell lymphoma: a multicenter, single-arm, phase I study. Front Immunol 2025; 16:1551723. [PMID: 40292284 PMCID: PMC12021869 DOI: 10.3389/fimmu.2025.1551723] [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: 12/26/2024] [Accepted: 03/24/2025] [Indexed: 04/30/2025] Open
Abstract
The current first-line treatment for peripheral T-cell lymphoma (PTCL) has a typically poor prognosis. Developing a new regimen is urgently needed. This phase I study evaluated the maximum tolerated dose (MTD), safety, and efficacy of mitoxantrone hydrochloride liposome (Lipo-MIT) plus cyclophosphamide, vincristine, etoposide, and prednisone (COEP) in untreated PTCL. Patients with untreated PTCL were enrolled and received Lipo-MIT (15, 18, and 20 mg/m2) following a 3 + 3 dose-escalation design plus standard doses of COEP (750 mg/m2 cyclophosphamide, 1.4 mg/m2 vincristine, 60 mg/m2 etoposide, and 100 mg prednisone) every 3 weeks for 6 cycles. Primary endpoint was MTD; secondary endpoints were safety, overall response rate (ORR), complete response (CR) rate, progression-free survival (PFS), and overall survival (OS). As of the cut-off date (October 29, 2024), 13 patients received the Lipo-MIT plus COEP (CMOEP) regimen. No patients experienced dose-limiting toxicities (DLT); MTD was 20 mg/m2 and the recommended phase 2 dose was 18 mg/m2. Common ≥grade 3 hematologic toxicities included neutrophil count decreased (76.9%), white blood cell decreased (76.9%), and lymphocyte count decreased (46.2%). Most common ≥grade 3 non-hematologic toxicity was lung infection (15.4%). No deaths due to toxicities were reported. Among 12 patients evaluated for best response, ORR (95% CI, 73.5-100.0), and the CR rate was 66.7% (95% CI, 34.9-90.1). At a median follow-up of 8.5 months, the median PFS and OS were both not reached. The CMOEP regimen had a manageable safety profile and an encouraging clinical efficacy for PTCL patients, which warrants further investigation. Clinical trial registration ClinicalTrials.gov, identifier NCT05458180.
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Affiliation(s)
- Jingwei Yu
- Department of Lymphoma, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, the Sino-US Center for Lymphoma and Leukemia Research, Tianjin, China
| | - Xiuhua Sun
- Department of Lymphoma of the Head and Neck, The Second Hospital of Dalian Medical University, Dalian, China
| | - Guangxun Gao
- Department of Hematology, The First Affiliated Hospital, the Air Force Medical University, Xi’an, China
| | - Li Yu
- Department of Hematology, The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Jiesong Wang
- Department of Medical Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, China
| | - Lihua Qiu
- Department of Lymphoma, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, the Sino-US Center for Lymphoma and Leukemia Research, Tianjin, China
| | - Zhengzi Qian
- Department of Lymphoma, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, the Sino-US Center for Lymphoma and Leukemia Research, Tianjin, China
| | - Wei Li
- Department of Lymphoma, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, the Sino-US Center for Lymphoma and Leukemia Research, Tianjin, China
| | - Huilai Zhang
- Department of Lymphoma, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, the Sino-US Center for Lymphoma and Leukemia Research, Tianjin, China
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Xing Y, Huang J, Zhang Y, Wang Y, Qi S. Advancing the understanding and management of angioimmunoblastic T-cell lymphoma: insights into its pathogenesis, clinical features, and emerging therapeutic strategies. Front Oncol 2025; 15:1479179. [PMID: 40098700 PMCID: PMC11911338 DOI: 10.3389/fonc.2025.1479179] [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: 08/11/2024] [Accepted: 02/10/2025] [Indexed: 03/19/2025] Open
Abstract
Angioimmunoblastic T-cell lymphoma (AITL) is a clinically aggressive non-Hodgkin lymphoma associated with many immune disorders. The incidence of AITL has gradually increased in Asia in recent years. Malignant AITL cells originate from T follicular helper cells, which have a unique morphology and complex biological characteristics. High-throughput sequencing studies have identified many gene mutations associated with its pathogenesis, including mutations in tet methylcytosine dioxygenase 2 (TET2), isocitrate dehydrogenase (NADP+) 2 (IDH2), DNA methyltransferase 3 alpha (DNMT3A), ras homolog family member A (RHOA), and T cell receptor-related genes. Currently, there is no standardized treatment for AITL, the first-line chemotherapy is ineffective, the recurrence rate is high, the overall prognosis of patients is poor, and the median survival time does not exceed three years. New drugs are urgently needed. However, with continuous in-depth study of the molecular genetic mechanism of AITL, some new drugs and therapies have been tested for patients with relapsed and refractory AITL, achieving some therapeutic effects. Increasing clinical studies are evaluating new potential targets for AITL based on specific molecular markers, gradually improving individualized treatment and ultimately improving the clinical prognosis of patients with AITL. This review first summarizes the progress of research on the etiology, clinical pathological characteristics, and molecular genetic mechanisms of AITL to enhance understanding of the disease. It then summarizes the progress of research on its treatment strategies to provide some references for clinically diagnosing and treating AITL.
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Affiliation(s)
- Yurou Xing
- Thoracic Oncology Ward, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Junmeng Huang
- Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Yi Zhang
- Thoracic Oncology Ward, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Yongsheng Wang
- Thoracic Oncology Ward, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Shaochong Qi
- The Quzhou Affiliated Hospital of Wenzhou Medical University, Quzhou People’s Hospital, Quzhou, China
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4
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O'Connor OA, Ma H, Chan JYS, Kim SJ, Yoon SE, Kim WS. Peripheral T-cell lymphoma: From biology to practice to the future. Cancer Treat Rev 2024; 129:102793. [PMID: 39002211 DOI: 10.1016/j.ctrv.2024.102793] [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: 03/18/2024] [Revised: 06/23/2024] [Accepted: 06/24/2024] [Indexed: 07/15/2024]
Abstract
Recent advancements in comprehending peripheral T-cell lymphomas (PTCLs) validate and broaden our perspective, highlighting their diverse nature and the varying molecular mechanisms underlying the entities. Based on a comprehensive accumulated understanding, the PTCLs currently overcome the most challenging features of any disease: rarity, incredible heterogeneity, and a lack of any established standard of care. The treatments deployed in the front-line are extrapolated from regimens developed for other diseases. The recent approval of the three drugs brentuximab vedotin (BV), pralatrexate, and belinostat for patients with relapsed or refractory disease has provided clues about pathophysiology and future directions, though challenges satisfying post-marketing requirements (PMR) for those accelerated approvals have led to one of those drugs being withdrawn and put the other two in jeopardy. Edits of the front-line regimens, often called CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone)-plus approaches, look more like CHOP-minus strategies, as the toxicity of five-drug regimens often reduces the dose intensity of the added 'novel' drug, nullifying any hope of an advance. The turmoil in the field produced by the aforementioned, coupled with an ever-changing classification, has left the field uncertain about the path forward. Despite these challenges, empiric findings from studies of novel drug approaches, coupled with a logic emerging from studies of PTCL lymphomagenesis, have begun to illuminate, albeit faintly for some, a potential direction. The empiric finding that drugs targeting the discrete components of the PTCL epigenome, coupled with the description of multiple mutations in genes that govern epigenetic biology, offers, at the very least, an opportunity to finally be hypothesis-driven. The most recent recognition that the only combination of drugs shown to markedly improve progression-free survival (PFS) in patients with relapsed disease is one based on dual targeting of different and discrete components of that epigenetic biology has established a possibility that circumnavigating chemotherapy addition studies is both plausible, feasible, and likely the best prospect for a quantum advance in this disease. Herein, we analyze PTCL through a 2025 lens, highlighting and underscoring walls that have impeded progress. We will critically explore all the clues and the panoramic view of PTCL research.
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Affiliation(s)
- Owen A O'Connor
- University of Virginia Comprehensive Cancer Center, Charlottesville, VA, United States
| | - Helen Ma
- VA Long Beach Healthcare System, Long Beach, CA, United States; University of California-Irvine, Orange, CA, United States
| | | | - Seok Jin Kim
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Sang Eun Yoon
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Won Seog Kim
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
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Liang L, Jiang M. Case report: Good response to CMOP regimen containing mitoxantrone hydrochloride liposome (PLM60) as induction chemotherapy in patients with angioimmunoblastic T-cell lymphoma. Front Oncol 2024; 14:1331154. [PMID: 38357199 PMCID: PMC10864495 DOI: 10.3389/fonc.2024.1331154] [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: 10/31/2023] [Accepted: 01/15/2024] [Indexed: 02/16/2024] Open
Abstract
Angioimmunoblastic T-cell lymphoma (AITL) is a highly aggressive subtype of peripheral T-cell lymphoma. The current prognosis with the first-line standard of care remains unsatisfactory, necessitating the exploration of more effective treatment options. We reported 5 cases of AITL receiving CMOP (mitoxantrone hydrochloride liposome, cyclophosphamide, vincristine, and prednisone). Cases 1 and 2 initially received CHOP as first-line induction therapy but switched to CMOP due to inadequate efficacy and cardiac adverse events. Cases 3, 4, and 5 were newly diagnosed and received CMOP. All patients achieved complete remission with acceptable cardiotoxicities and hematologic toxicities. After study treatment discontinuation, Cases 1 and 3 underwent autologous stem cell transplantation, and Cases 4 and 5 received oral maintenance agents. At the last follow-up, 4 patients remained in remission and 1 (Case 2) exhibited tumor recurrence. CMOP showed promise as a potential treatment option for AITL patients. Further research is essential to identify its efficacy and safety.
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Affiliation(s)
| | - Ming Jiang
- Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, China
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Ihlamur M, Akgul B, Zengin Y, Korkut ŞV, Kelleci K, Abamor EŞ. The mTOR Signaling Pathway and mTOR Inhibitors in Cancer: Next-generation Inhibitors and Approaches. Curr Mol Med 2024; 24:478-494. [PMID: 37165594 DOI: 10.2174/1566524023666230509161645] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2022] [Revised: 02/03/2023] [Accepted: 02/07/2023] [Indexed: 05/12/2023]
Abstract
mTOR is a serine/threonine kinase that plays various roles in cell growth, proliferation, and metabolism. mTOR signaling in cancer becomes irregular. Therefore, drugs targeting mTOR have been developed. Although mTOR inhibitors rapamycin and rapamycin rapalogs (everolimus, rapamycin, temsirolimus, deforolimus, etc.) and new generation mTOR inhibitors (Rapalink, Dual PI3K/mTOR inhibitors, etc.) are used in cancer treatments, mTOR resistance mechanisms may inhibit the efficacy of these drugs. Therefore, new inhibition approaches are developed. Although these new inhibition approaches have not been widely investigated in cancer treatment, the use of nanoparticles has been evaluated as a new treatment option in a few types of cancer. This review outlines the functions of mTOR in the cancer process, its resistance mechanisms, and the efficiency of mTOR inhibitors in cancer treatment. Furthermore, it discusses the next-generation mTOR inhibitors and inhibition strategies created using nanoparticles. Since mTOR resistance mechanisms prevent the effects of mTOR inhibitors used in cancer treatments, new inhibition strategies should be developed. Inhibition approaches are created using nanoparticles, and one of them offers a promising treatment option with evidence supporting its effectiveness.
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Affiliation(s)
- Murat Ihlamur
- Department of Bioengineering, Faculty of Chemical and Metallurgical Engineering, Yildiz Technical University, Istanbul, Turkey
- Department of Electronics and Automation, Biruni University, Istanbul, Turkey
| | - Busra Akgul
- Department of Bioengineering, Faculty of Chemical and Metallurgical Engineering, Yildiz Technical University, Istanbul, Turkey
| | - Yağmur Zengin
- Biomedical Engineering Institute, Department of Biomedical Engineering, Bogazici University, Istanbul, Turkey
| | - Şenay Vural Korkut
- Department of Molecular Biology and Genetics, Faculty of Arts and Sciences, Yildiz Technical University, Istanbul, Turkey
| | - Kübra Kelleci
- Department of Bioengineering, Faculty of Chemical and Metallurgical Engineering, Yildiz Technical University, Istanbul, Turkey
- Department of Medical Services and Techniques, Beykoz University, Istanbul, Turkey
| | - Emrah Şefik Abamor
- Department of Bioengineering, Faculty of Chemical and Metallurgical Engineering, Yildiz Technical University, Istanbul, Turkey
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Wartewig T, Daniels J, Schulz M, Hameister E, Joshi A, Park J, Morrish E, Venkatasubramani AV, Cernilogar FM, van Heijster FHA, Hundshammer C, Schneider H, Konstantinidis F, Gabler JV, Klement C, Kurniawan H, Law C, Lee Y, Choi S, Guitart J, Forne I, Giustinani J, Müschen M, Jain S, Weinstock DM, Rad R, Ortonne N, Schilling F, Schotta G, Imhof A, Brenner D, Choi J, Ruland J. PD-1 instructs a tumor-suppressive metabolic program that restricts glycolysis and restrains AP-1 activity in T cell lymphoma. NATURE CANCER 2023; 4:1508-1525. [PMID: 37723306 PMCID: PMC10597841 DOI: 10.1038/s43018-023-00635-7] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/22/2022] [Accepted: 08/15/2023] [Indexed: 09/20/2023]
Abstract
The PDCD1-encoded immune checkpoint receptor PD-1 is a key tumor suppressor in T cells that is recurrently inactivated in T cell non-Hodgkin lymphomas (T-NHLs). The highest frequencies of PDCD1 deletions are detected in advanced disease, predicting inferior prognosis. However, the tumor-suppressive mechanisms of PD-1 signaling remain unknown. Here, using tractable mouse models for T-NHL and primary patient samples, we demonstrate that PD-1 signaling suppresses T cell malignancy by restricting glycolytic energy and acetyl coenzyme A (CoA) production. In addition, PD-1 inactivation enforces ATP citrate lyase (ACLY) activity, which generates extramitochondrial acetyl-CoA for histone acetylation to enable hyperactivity of activating protein 1 (AP-1) transcription factors. Conversely, pharmacological ACLY inhibition impedes aberrant AP-1 signaling in PD-1-deficient T-NHLs and is toxic to these cancers. Our data uncover genotype-specific vulnerabilities in PDCD1-mutated T-NHL and identify PD-1 as regulator of AP-1 activity.
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Affiliation(s)
- Tim Wartewig
- TranslaTUM, Center for Translational Cancer Research, Technical University of Munich, Munich, Germany
- Institute of Clinical Chemistry and Pathobiochemistry, School of Medicine, Technical University of Munich, Munich, Germany
- Center of Molecular and Cellular Oncology, Yale School of Medicine, Yale University, New Haven, CT, USA
| | - Jay Daniels
- Department of Biochemistry and Molecular Genetics, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA
- Department of Dermatology, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA
| | - Miriam Schulz
- TranslaTUM, Center for Translational Cancer Research, Technical University of Munich, Munich, Germany
- Institute of Clinical Chemistry and Pathobiochemistry, School of Medicine, Technical University of Munich, Munich, Germany
| | - Erik Hameister
- TranslaTUM, Center for Translational Cancer Research, Technical University of Munich, Munich, Germany
- Institute of Clinical Chemistry and Pathobiochemistry, School of Medicine, Technical University of Munich, Munich, Germany
| | - Abhinav Joshi
- TranslaTUM, Center for Translational Cancer Research, Technical University of Munich, Munich, Germany
- Institute of Clinical Chemistry and Pathobiochemistry, School of Medicine, Technical University of Munich, Munich, Germany
| | - Joonhee Park
- Department of Biochemistry and Molecular Genetics, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA
- Department of Dermatology, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA
| | - Emma Morrish
- TranslaTUM, Center for Translational Cancer Research, Technical University of Munich, Munich, Germany
- Institute of Clinical Chemistry and Pathobiochemistry, School of Medicine, Technical University of Munich, Munich, Germany
- German Cancer Consortium (DKTK), Heidelberg, Germany
| | - Anuroop V Venkatasubramani
- Protein Analysis Unit, Biomedical Center, Faculty of Medicine, Ludwig-Maximilians-Universität Munich, Martinsried, Germany
| | - Filippo M Cernilogar
- Department of Molecular Biology, Biomedical Center, Faculty of Medicine, Ludwig-Maximilians-Universität Munich, Martinsried, Germany
| | - Frits H A van Heijster
- Department of Nuclear Medicine, School of Medicine, Technical University of Munich, Munich, Germany
| | - Christian Hundshammer
- Department of Nuclear Medicine, School of Medicine, Technical University of Munich, Munich, Germany
| | - Heike Schneider
- Institute of Clinical Chemistry and Pathobiochemistry, School of Medicine, Technical University of Munich, Munich, Germany
| | - Filippos Konstantinidis
- TranslaTUM, Center for Translational Cancer Research, Technical University of Munich, Munich, Germany
- Institute of Clinical Chemistry and Pathobiochemistry, School of Medicine, Technical University of Munich, Munich, Germany
| | - Judith V Gabler
- TranslaTUM, Center for Translational Cancer Research, Technical University of Munich, Munich, Germany
- Institute of Clinical Chemistry and Pathobiochemistry, School of Medicine, Technical University of Munich, Munich, Germany
| | - Christine Klement
- Institute of Molecular Oncology and Functional Genomics, School of Medicine, Technical University of Munich, Munich, Germany
| | - Henry Kurniawan
- Experimental and Molecular Immunology, Department of Infection and Immunity, Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg
- Immunology and Genetics, Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Belvaux, Luxembourg
| | - Calvin Law
- Department of Biochemistry and Molecular Genetics, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA
- Department of Dermatology, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA
| | - Yujin Lee
- Department of Biochemistry and Molecular Genetics, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA
- Department of Dermatology, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA
| | - Sara Choi
- Department of Biochemistry and Molecular Genetics, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA
- Department of Dermatology, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA
| | - Joan Guitart
- Department of Dermatology, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA
| | - Ignasi Forne
- Protein Analysis Unit, Biomedical Center, Faculty of Medicine, Ludwig-Maximilians-Universität Munich, Martinsried, Germany
| | - Jérôme Giustinani
- Institut Mondor de Recherche Biomédicale, Inserm U955, Paris-Est Créteil University, Créteil, France
| | - Markus Müschen
- Center of Molecular and Cellular Oncology, Yale School of Medicine, Yale University, New Haven, CT, USA
- Department of Immunobiology, Yale University, New Haven, CT, USA
| | - Salvia Jain
- Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - David M Weinstock
- Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
- Merck Research Laboratories, Boston, MA, USA
| | - Roland Rad
- Institute of Molecular Oncology and Functional Genomics, School of Medicine, Technical University of Munich, Munich, Germany
- Department of Medicine II, School of Medicine, Technical University of Munich, Munich, Germany
| | - Nicolas Ortonne
- Institut Mondor de Recherche Biomédicale, Inserm U955, Paris-Est Créteil University, Créteil, France
- Pathology Department, AP-HP Inserm U955, Henri Mondor Hospital, Créteil, France
| | - Franz Schilling
- Department of Nuclear Medicine, School of Medicine, Technical University of Munich, Munich, Germany
| | - Gunnar Schotta
- Department of Molecular Biology, Biomedical Center, Faculty of Medicine, Ludwig-Maximilians-Universität Munich, Martinsried, Germany
| | - Axel Imhof
- Protein Analysis Unit, Biomedical Center, Faculty of Medicine, Ludwig-Maximilians-Universität Munich, Martinsried, Germany
| | - Dirk Brenner
- Experimental and Molecular Immunology, Department of Infection and Immunity, Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg
- Immunology and Genetics, Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Belvaux, Luxembourg
- Odense Research Center for Anaphylaxis, Department of Dermatology and Allergy Center, Odense University Hospital, University of Southern Denmark, Odense, Denmark
| | - Jaehyuk Choi
- Department of Biochemistry and Molecular Genetics, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA.
- Department of Dermatology, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA.
- Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL, USA.
- Center for Genetic Medicine, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA.
- Center for Human Immunobiology, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA.
- Center for Synthetic Biology, Northwestern University, Evanston, IL, USA.
| | - Jürgen Ruland
- TranslaTUM, Center for Translational Cancer Research, Technical University of Munich, Munich, Germany.
- Institute of Clinical Chemistry and Pathobiochemistry, School of Medicine, Technical University of Munich, Munich, Germany.
- German Cancer Consortium (DKTK), Heidelberg, Germany.
- German Center for Infection Research (DZIF), partner site Munich, Munich, Germany.
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Yang H, Xun Y, Ke C, Tateishi K, You H. Extranodal lymphoma: pathogenesis, diagnosis and treatment. MOLECULAR BIOMEDICINE 2023; 4:29. [PMID: 37718386 PMCID: PMC10505605 DOI: 10.1186/s43556-023-00141-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2023] [Accepted: 08/18/2023] [Indexed: 09/19/2023] Open
Abstract
Approximately 30% of lymphomas occur outside the lymph nodes, spleen, or bone marrow, and the incidence of extranodal lymphoma has been rising in the past decade. While traditional chemotherapy and radiation therapy can improve survival outcomes for certain patients, the prognosis for extranodal lymphoma patients remains unsatisfactory. Extranodal lymphomas in different anatomical sites often have distinct cellular origins, pathogenic mechanisms, and clinical manifestations, significantly influencing their diagnosis and treatment. Therefore, it is necessary to provide a comprehensive summary of the pathogenesis, diagnosis, and treatment progress of extranodal lymphoma overall and specifically for different anatomical sites. This review summarizes the current progress in the common key signaling pathways in the development of extranodal lymphomas and intervention therapy. Furthermore, it provides insights into the pathogenesis, diagnosis, and treatment strategies of common extranodal lymphomas, including gastric mucosa-associated lymphoid tissue (MALT) lymphoma, mycosis fungoides (MF), natural killer/T-cell lymphoma (nasal type, NKTCL-NT), and primary central nervous system lymphoma (PCNSL). Additionally, as PCNSL is one of the extranodal lymphomas with the worst prognosis, this review specifically summarizes prognostic indicators and discusses the challenges and opportunities related to its clinical applications. The aim of this review is to assist clinical physicians and researchers in understanding the current status of extranodal lymphomas, enabling them to make informed clinical decisions that contribute to improving patient prognosis.
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Affiliation(s)
- Hua Yang
- Department of Basic Medicine and Biomedical Engineering, School of Medicine, Foshan University, Foshan, 528000, China
| | - Yang Xun
- Department of Basic Medicine and Biomedical Engineering, School of Medicine, Foshan University, Foshan, 528000, China
| | - Chao Ke
- Department of Neurosurgery and Neuro-Oncology, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, China
| | - Kensuke Tateishi
- Department of Neurosurgery, Graduate School of Medicine, Yokohama City University, Yokohama, 2360004, Japan
| | - Hua You
- Laboratory for Excellence in Systems Biomedicine of Pediatric Oncology, Department of Pediatric Hematology and Oncology, Chongqing Key Laboratory of Pediatrics, Ministry of Education Key Laboratory of Child Development and Disorders, China International Science and Technology Cooperation base of Child development and Critical Disorders, National Clinical Research Center for Child Health and Disorders, Children's Hospital of Chongqing Medical University, Chongqing, 401122, China.
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9
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Kim SJ, Jo JC, Yoon DH, Yang DH, Yoon SE, Lee GW, Kong JH, Park Y, Kang KW, Lee HS, Oh SY, Shin HJ, Lee WS, Choi YS, Jeong SH, Kim MK, Kang HJ, Yi JH, Lim SN, Yhim HY, Do YR, Yun HJ, Eom HS, Lee MH, Suh C, Kim WS. Comparison of first-line treatment with CHOP versus ICED in patients with peripheral T-cell lymphoma eligible for upfront autologous stem cell transplantation. Front Oncol 2023; 13:1230629. [PMID: 37675232 PMCID: PMC10477982 DOI: 10.3389/fonc.2023.1230629] [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: 05/29/2023] [Accepted: 07/31/2023] [Indexed: 09/08/2023] Open
Abstract
Introduction Upfront autologous stem cell transplantation (ASCT) has been recommended for patients who are newly diagnosed with peripheral T-cell lymphoma (PTCL), and CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), an anthracycline-based chemotherapy has been the frontline chemotherapy for PTCL. However, it is not clear whether anthracycline-based chemotherapies such as CHOP could be standard induction therapy for PTCL. Methods We conducted a randomized phase II study to compare CHOP with fractionated ifosfamide, carboplatin, etoposide, and dexamethasone (ICED) for patients eligible for ASCT. The primary endpoint was progression-free survival (PFS) and secondary endpoints included objective response rate, overall survival (OS), and safety profiles. Results Patients were randomized into either CHOP (n = 69) or ICED (n = 66), and the characteristics of both arms were not different. PTCL-not otherwise specified (NOS, n = 60) and angioimmunoblastic T-cell lymphoma (AITL, n = 53) were dominant. The objective response rate was not different between CHOP (59.4%) and ICED (56.1%), and the 3-year PFS was not different between CHOP (36.7%) and ICED (33.1%). In AITL patients, CHOP was favored over ICED whereas ICED was associated with more cytopenia and reduced dose intensity. Patients who received upfront ASCT after achieving complete response to CHOP or ICED showed 80% of 3-year OS. Discussion In summary, our study showed no therapeutic difference between CHOP and ICED in terms of response and PFS. Thus, CHOP might remain the reference regimen especially for AITL based on its better outcome in AITL, and upfront ASCT could be recommended as a consolidation of complete response in patients with PTCL.
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Affiliation(s)
- Seok Jin Kim
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
- Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Jae-Cheol Jo
- Department of Hematology and Oncology, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Republic of Korea
| | - Dok Hyun Yoon
- Department of Oncology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea
| | - Deok-Hwan Yang
- Department of Internal Medicine, Chonnam National University Hwasun Hospital, Chonnam National University Medical School, Gwangju, Republic of Korea
| | - Sang Eun Yoon
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Gyeong-Won Lee
- Division of Hematology and Oncology, Department of Internal Medicine, Gyeongsang National University Hospital, Gyeongsang National University College of Medicine, Changwon, Republic of Korea
| | - Jee Hyun Kong
- Department of Hematology-oncology, Division of Internal Medicine, Wonju Severance Christian Hospital, Yonsei University Wonju College of Medicine, Wonju, Republic of Korea
- Cancer of Evidence Based Medicine, Institute of Convergence Science, Yonsei University, Seoul, Republic of Korea
| | - Yong Park
- Department of Internal Medicine, Korea University College of Medicine, Korea University Anam Hospital, Seoul, Republic of Korea
| | - Ka-Won Kang
- Department of Internal Medicine, Korea University College of Medicine, Korea University Anam Hospital, Seoul, Republic of Korea
| | - Ho-Sup Lee
- Department of Internal Medicine, Kosin University Gospel Hospital, Busan, Republic of Korea
| | - Sung Yong Oh
- Department of Internal Medicine, Dong-A University Medical Center, Busan, Republic of Korea
| | - Ho-Jin Shin
- Department of Internal Medicine, Pusan National University Hospital, Busan, Republic of Korea
| | - Won Sik Lee
- Department of Internal Medicine, Inje University Busan Paik Hospital, Busan, Republic of Korea
| | - Yoon Seok Choi
- Division of Hematology-Oncology, Department of Internal Medicine, Ajou University School of Medicine, Suwon, Republic of Korea
| | - Seong Hyun Jeong
- Division of Hematology-Oncology, Department of Internal Medicine, Ajou University School of Medicine, Suwon, Republic of Korea
| | - Min Kyoung Kim
- Department of Internal Medicine, Yeungnam University College of Medicine, Daegu, Republic of Korea
| | - Hye Jin Kang
- Department of Internal Medicine, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences, Seoul, Republic of Korea
| | - Jun Ho Yi
- Department Internal Medicine, Chung-Ang University Hospital, Seoul, Republic of Korea
| | - Sung-Nam Lim
- Department of Internal Medicine, Haeundae Baek Hospital, Busan, Republic of Korea
| | - Ho-Young Yhim
- Department of Internal Medicine, Jeonbuk National University Medical School, Research Institute of Clinical Medicine of Jeonbuk National University-Biomedical Research Institute of Jeonbuk National University Hospital, Jeonju, Republic of Korea
| | - Young Rok Do
- Department of Internal Medicine, Dongsan Medical Center, Daegu, Republic of Korea
| | - Hwan Jung Yun
- Department of Internal Medicine, Chungnam National University Hospital, Daejeon, Republic of Korea
| | - Hyeon-Seok Eom
- Hematology-Oncology Clinic, National Cancer Center, Go-Yang, Republic of Korea
| | - Mark Hong Lee
- Division of Hematology-Oncology, Department of Internal Medicine, Konkuk University Medical Center, Seoul, Republic of Korea
| | - Cheolwon Suh
- Department of Oncology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea
| | - Won Seog Kim
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
- Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
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10
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Milunović V, Smoljanović IM, Patekar MB, Zatezalo V, Kursar M, Radić-Krišto D, Kolonić SO, Gašparov S. First-Line Therapy for Nodal T-cell Non-Hodgkin Lymphomas: an Unmet Need in Hematology. Curr Oncol Rep 2023; 25:813-824. [PMID: 37043116 DOI: 10.1007/s11912-023-01400-w] [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] [Accepted: 03/06/2023] [Indexed: 04/13/2023]
Abstract
PURPOSEOF REVIEW The main aim of this review is to summarize first-line therapy of nodal T-cell non-Hodgkin lymphoma. RECENT FINDINGS Current treatment with CHOP chemotherapy results in poor outcomes in the majority of patients. However, there are advances within the field. First breakthrough is the ECHELON-2 trial which showed that the addition of brentuximab vedotin improves outcomes in anaplastic large cell lymphoma. However, other types of peripheral T-cell non-Hodgkin lymphoma were underrepresented with optimal treatment not known. Second breakthrough is an increase of autologous stem cell transplantation usage in the first complete metabolic remission, except in ALK + anaplastic large cell lymphoma, offering better disease control. Despite advances in the field, CHOP remains the standard treatment for the majority of these lymphomas, but multiple trials are underway with the aim to improve this unmet need in hematology and, hopefully, leading us to a new era in the treatment of peripheral T-cell lymphomas.
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Affiliation(s)
- Vibor Milunović
- Division of Hematology, Clinical Hospital Merkur, Zajčeva 19, 10000, Zagreb, Croatia.
| | - Inga Mandac Smoljanović
- Division of Hematology, Clinical Hospital Merkur, Zajčeva 19, 10000, Zagreb, Croatia
- School of Medicine, University of Zagreb, Zagreb, Croatia
| | | | - Viktor Zatezalo
- Division of Hematology, Clinical Hospital Merkur, Zajčeva 19, 10000, Zagreb, Croatia
| | - Marin Kursar
- Division of Hematology, Clinical Hospital Merkur, Zajčeva 19, 10000, Zagreb, Croatia
| | - Delfa Radić-Krišto
- Division of Hematology, Clinical Hospital Merkur, Zajčeva 19, 10000, Zagreb, Croatia
- School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Slobodanka Ostojić Kolonić
- Division of Hematology, Clinical Hospital Merkur, Zajčeva 19, 10000, Zagreb, Croatia
- School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Slavko Gašparov
- School of Medicine, University of Zagreb, Zagreb, Croatia
- Clinical Department of Pathology and Cytology, Clinical Hospital Merkur, Zagreb, Croatia
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11
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Du J, Jin S, Zhang M, Fu X, Yang J, Zhang L, Chen Z, Huang Z, Li W, Hou J, Wang T. Precise diagnosis and targeted therapy of nodal T-follicular helper cell lymphoma (T-FHCL). Front Oncol 2023; 13:1163190. [PMID: 37188182 PMCID: PMC10175683 DOI: 10.3389/fonc.2023.1163190] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2023] [Accepted: 04/17/2023] [Indexed: 05/17/2023] Open
Abstract
Nodal T-follicular helper cell lymphoma (T-FHCL) derived from T-follicular helper (Tfh) cell falls into a heterogeneous category of peripheral T-cell lymphoma (PTCL). Due to the limited number of therapeutic regimens and limited first-line efficacy, T-FHCL has a poor prognosis, and there is an urgent need for effective targeted therapies. With advancements in sequencing technologies, especially single-cell sequencing and next-generation sequencing, more specific genetic aberrations characteristic of T-FHCL can be discovered, allowing for precise molecular diagnosis and specific research on novel agents. Many biomarker-targeting agents, used either alone or in combination, have been tested, and they have generally enhanced the therapeutic outcomes of T-FHCL. Histone deacetylase inhibitors achieve significant clinical benefits in the treatment of T-FHCL, especially in combination therapy. Chimeric antigen receptor T-cell (CAR-T-cell) immunotherapies, hematopoietic stem cell transplantation, and other potential agents merit further study.
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Affiliation(s)
- Jun Du
- Department of Hematology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Shikai Jin
- Department of Clinical Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Minghui Zhang
- Department of Clinical Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xuehang Fu
- Department of Hematology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Jingwen Yang
- Department of Clinical Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Liwen Zhang
- Department of Clinical Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zhenwei Chen
- Department of Clinical Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zoufang Huang
- Department of Hematology, The First Affiliated Hospital of Gannan Medical University, Ganzhou, China
| | - Weisong Li
- Department of Pathology, The First Affiliated Hospital of Gannan Medical University, Ganzhou, China
| | - Jian Hou
- Department of Hematology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Ting Wang
- Department of Hematology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
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12
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Sibon D. Peripheral T-Cell Lymphomas: Therapeutic Approaches. Cancers (Basel) 2022; 14:cancers14092332. [PMID: 35565460 PMCID: PMC9104854 DOI: 10.3390/cancers14092332] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2022] [Accepted: 05/04/2022] [Indexed: 11/21/2022] Open
Abstract
Simple Summary Peripheral T-cell lymphomas are a group of rare cancers of T cells or natural killer cells, most often with a poor prognosis. In recent years, significant progress has been made through the development of more specific therapies. This review aims to provide an up-to-date overview of current treatments in nodal PTCL. Abstract Peripheral T-cell lymphomas (PTCLs) are a heterogeneous group of rare neoplasms of mature T cells or natural killer (NK) cell. PTCLs usually have an aggressive course and a poor outcome. In recent years, significant progress has been made in the knowledge of the molecular lymphomagenesis of PTCLs, and through the development of new, more specific therapeutic molecules, one can hope in the coming years for more personalized medicine and improved patient prognosis. This review aims to provide an up-to-date overview of the current therapeutic approaches in nodal PTCLs.
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Affiliation(s)
- David Sibon
- Lymphoid Malignancies Department, Henri Mondor University Hospital, AP-HP, 94000 Créteil, France;
- Faculty of Medicine and Health, Campus Henri Mondor, Paris-Est Créteil University, 94000 Créteil, France
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13
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Song L, Liu S, Zhao S. Everolimus (RAD001) combined with programmed death-1 (PD-1) blockade enhances radiosensitivity of cervical cancer and programmed death-ligand 1 (PD-L1) expression by blocking the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR)/S6 kinase 1 (S6K1) pathway. Bioengineered 2022; 13:11240-11257. [PMID: 35485300 PMCID: PMC9208494 DOI: 10.1080/21655979.2022.2064205] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Cervical cancer (CC) is the 4th most prevalent malignancy in females. This study explored the mechanism of everolimus (RAD001) combined with programmed death-1 (PD-1) blockade on radiosensitivity by phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway and autophagy in CC cells. Low-radiosensitive CaSki cells were selected as study objects. After RAD001 treatment, PI3K/AKT/mTOR pathway activation, autophagy, migration and invasion abilities, autophagy-related proteins (LC3-I, LC3-II, and p62), and PD-L1 expression in CC cells were detected. After triple treatment of radiotherapy (RT), RAD001, and PD-1 blockade to the CC mouse models, tumor weight and volume were recorded. Ki67 expression, the number of CD8 + T cells, and the ability to produce IFN-γ and TNF-α in tumor tissues were determined. RAD001 promoted autophagy by repressing PI3K/AKT/mTOR pathway, augmented RT-induced apoptosis, and weakened migration and invasion, thereby increasing CC cell radiosensitivity. RAD001 elevated RT-induced PD-L1 level. RT combined with RAD001 and PD-1 blockade intensified the inhibitory effect of RT on tumor growth, reduced the amount of Ki67-positive cells, enhanced radiosensitivity of CC mice, and increased the quantity and killing ability of CD8 + T cells. Briefly, RAD001 combined with PD-1 blockade increases radiosensitivity of CC by impeding the PI3K/AKT/mTOR pathway and potentiating cell autophagy.
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Affiliation(s)
- Lili Song
- Department of Obstetrics and Gynecology, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Shikai Liu
- Department of Obstetrics and Gynecology, Cangzhou Central Hospital, Cangzhou, Hebei, China
| | - Sufen Zhao
- Department of Obstetrics and Gynecology, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
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14
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Ashaye AO, Burnett H, Abogunrin S, Panchmatia H, Ovcinnikova O, Dalal M. The clinical and economic burden of peripheral T-cell lymphoma: a systematic literature review. Future Oncol 2021; 18:519-535. [PMID: 34851173 DOI: 10.2217/fon-2021-1032] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Aim: To understand the burden of treatment-naive peripheral T-cell lymphoma (PTCL). Methods: A systematic literature review was conducted in November 2020 following best practice methodology. Results: Fifty-five clinical studies were included, mostly investigating cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) or 'CHOP-like' regimens, with combination regimens showing similar effectiveness to CHOP alone. Aside from the combination of brentuximab vedotin + cyclophosphamide, doxorubicin and prednisone (A+CHP), other available treatments showed no statistically significant benefit over CHOP in terms of overall or progression-free survival in overall PTCL patients. The mean monthly cost per patient in the USA ranged from $6328 to $9356 based on six studies. One economic evaluation demonstrated A+CHP to be a more cost-effective treatment option than CHOP. Conclusion: Further research is needed to understand the humanistic and cost impact of frontline treatment for PTCL and its specific subtypes.
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Affiliation(s)
- Ajibade O Ashaye
- Takeda Development Center Americas, Inc., Lexington, MA 02421, USA
| | | | | | | | | | - Mehul Dalal
- Takeda Development Center Americas, Inc., Lexington, MA 02421, USA
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15
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Venkataraman V, Massoth LR, Sullivan RJ, Friedmann AM. Secondary histiocytic sarcoma with BRAF V600E mutation responsive to MAPK-targeted therapy presenting with recurrence with mTOR mutation responsive to mTOR-targeted therapy. Pediatr Blood Cancer 2021; 68:e29166. [PMID: 34061432 DOI: 10.1002/pbc.29166] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2021] [Revised: 05/13/2021] [Accepted: 05/19/2021] [Indexed: 12/16/2022]
Affiliation(s)
- Vinayak Venkataraman
- Departments of Medicine and Pediatrics, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Lucas R Massoth
- Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Ryan J Sullivan
- Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Alison M Friedmann
- Department of Pediatrics, Massachusetts General Hospital, Boston, Massachusetts, USA
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16
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Kim J, Cho J, Byeon S, Kim WS, Kim SJ. Comparison of first-line treatments of peripheral T-cell lymphoma according to regimen: A systematic review and meta-analysis. Hematol Oncol 2021; 39:664-673. [PMID: 34487565 DOI: 10.1002/hon.2924] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Revised: 08/23/2021] [Accepted: 08/27/2021] [Indexed: 12/17/2022]
Abstract
Peripheral T-cell lymphomas (PTCLs) are known to have an aggressive clinical course and grave prognosis. Several recommended first-line treatment regimens are available, but identification of the superior treatment remain elusive. We conducted a systematic review and meta-analysis to determine which study-level factors and group of regimens affect survival outcomes. The MEDLINE, Embase, and Cochrane databases were searched from inception to January 2021, and phase II or III clinical studies evaluating the efficacy of chemotherapy regimens were included. Random effects models were used to estimate 3-year overall survival rate, complete remission rate, and subgroup differences. Meta-regressions were carried out with adjustments for relevant covariates. Overall, 34 cohorts from 28 studies comprising 1424 PTCL patients were included in the pooled analysis. Chemotherapy regimens were divided into four groups: cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP), CHOP plus etoposide, gemcitabine-based, and others. The pooled 3-year overall survival rate was 0.49 (95% confidence interval [CI] 0.43-0.54) for CHOP, 0.61 (95% CI 0.52-0.70) for CHOP plus etoposide, 0.39 (95% CI 0.30-0.47) for gemcitabine-based, and 0.61 (95% CI 0.44-0.78) for others. CHOP plus etoposide was significantly better than CHOP, with the latter used as a reference (coefficient of 0.11; p = 0.035), with adjustment for the proportion of International Prognostic Index score 4-5 in meta-regression analysis. Although grossly divided groups were pooled and analyzed, among four regimen groups for frontline PTCL treatment CHOP plus etoposide showed better survival than CHOP.
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Affiliation(s)
- Jinchul Kim
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.,Department of Hematology-Oncology, Inha University College of Medicine and Hospital, Incheon, Korea
| | - Jinhyun Cho
- Department of Hematology-Oncology, Inha University College of Medicine and Hospital, Incheon, Korea
| | - Seonggyu Byeon
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.,Department of Internal Medicine, Chungbuk National University Hospital, Chungbuk National University College of Medicine, Cheongju, Korea
| | - Won Seog Kim
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.,Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Seok Jin Kim
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.,Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University School of Medicine, Seoul, Korea
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17
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Cortés JR, Palomero T. Biology and Molecular Pathogenesis of Mature T-Cell Lymphomas. Cold Spring Harb Perspect Med 2021; 11:cshperspect.a035402. [PMID: 32513675 DOI: 10.1101/cshperspect.a035402] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Peripheral T-cell lymphomas (PTCLs) constitute a highly heterogeneous group of hematological diseases with complex clinical and molecular features consistent with the diversity of the T-cell type from which they originate. In the past several years, the systematic implementation of high-throughput genomic technologies for the analysis of T-cell malignancies has supported an exponential progress in our understanding of the genetic drivers of oncogenesis and unraveled the molecular complexity of these diseases. Recent findings have helped redefine the classification of T-cell malignancies and provided novel biomarkers to improve diagnosis accuracy and analyze the response to therapy. In addition, multiple novel targeted therapies including small-molecule inhibitors, antibody-based approaches, and immunotherapy have shown promising results in early clinical analysis and have the potential to completely change the way T-cell malignancies have been treated traditionally.
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Affiliation(s)
| | - Teresa Palomero
- Institute for Cancer Genetics.,Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, New York 10032, USA
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18
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Manji F, Puckrin R, Stewart DA. Novel synthetic drugs for the treatment of non-Hodgkin lymphoma. Expert Opin Pharmacother 2021; 22:1417-1427. [PMID: 33711241 DOI: 10.1080/14656566.2021.1902988] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Introduction: Over the past two decades, deeper understanding of B-cell signaling pathways and other mechanisms of lymphomagenesis have yielded promising targets for novel drugs in the treatment of non-Hodgkin lymphoma.Areas covered: This article provides a comprehensive review of approved synthetic drugs targeting the BTK, PI3K, immunomodulation, proteasome, HDAC, EZH2, and nuclear export pathways in non-Hodgkin lymphoma. The review includes coverage of the pharmacology, efficacy, toxicity, and active areas of research for each drug. The authors also provide their expert perspectives on the field and their opinions for the future.Expert opinion: Although novel synthetic drugs have generally not impacted clinical practice to the same extent as immune and cellular therapies, there remains an important role for targeted drugs in the treatment of non-Hodgkin lymphoma, particularly in the relapsed setting and for patients ineligible for more intensive therapies. Clinical outcomes and tolerability may improve further with the development of newer generations of synthetic drugs and emerging combination regimens with other targeted and immune therapies.
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Affiliation(s)
- Farheen Manji
- Princess Margaret Cancer Centre, University of Toronto, Toronto, Ontaria, Canada
| | - Robert Puckrin
- Postgraduate Medical Education, University of Calgary, Calgary, Alberta, Canada
| | - Douglas A Stewart
- Department of Oncology, University of Calgary, Calgary, Alberta, Canada
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19
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Sakata-Yanagimoto M, Fukumoto K, Karube K, Chiba S. Molecular understanding of peripheral T-cell lymphomas, not otherwise specified (PTCL, NOS): A complex disease category. J Clin Exp Hematop 2021; 61:61-70. [PMID: 33716242 PMCID: PMC8265491 DOI: 10.3960/jslrt.20059] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Peripheral T-cell lymphoma, not otherwise specified (PTCL, NOS) includes various
diseases. Attempts have been made to identify distinct properties of disease within the
PTCL, NOS classification and evaluate their significance to prognosis. Comprehensive gene
expression analysis and evaluation of genomic abnormalities have successfully identified
specific diseases from heterogeneous PTCL, NOS cases. For example, cases with properties
of T follicular helper cells have been identified and classified as an entity resembling
angioimmunoblastic T-cell lymphoma (AITL), based on both immunohistochemistry and genomic
features. Here, we focus on the molecular pathology of PTCL, NOS and discuss recent
changes relevant to its classification.
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Affiliation(s)
- Mamiko Sakata-Yanagimoto
- Department of Hematology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.,Department of Hematology, University of Tsukuba Hospital, Tsukuba, Japan.,Department of Hematology, Comprehensive Human Biosciences, University of Tsukuba, Tsukuba, Japan
| | - Kota Fukumoto
- Department of Hematology, University of Tsukuba Hospital, Tsukuba, Japan.,Department of Hematology, Comprehensive Human Biosciences, University of Tsukuba, Tsukuba, Japan
| | - Kennosuke Karube
- Department of Pathology and Cell Biology, Graduate School of Medicine and Faculty of Medicine, University of the Ryukyus, Nishihara, Japan
| | - Shigeru Chiba
- Department of Hematology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.,Department of Hematology, University of Tsukuba Hospital, Tsukuba, Japan.,Department of Hematology, Comprehensive Human Biosciences, University of Tsukuba, Tsukuba, Japan
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20
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Abeyakoon C, van der Weyden C, Harrop S, Khot A, Dickinson M, Yannakou CK, Prince HM. Advances in Frontline Management of Peripheral T-cell Lymphoma. CLINICAL LYMPHOMA MYELOMA & LEUKEMIA 2021; 21:368-378. [PMID: 33610499 DOI: 10.1016/j.clml.2021.01.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/01/2020] [Revised: 01/12/2021] [Accepted: 01/16/2021] [Indexed: 10/22/2022]
Abstract
Peripheral T-cell lymphomas (PTCLs) are a heterogeneous group of lymphomas that are frequently associated with a poor prognosis. For many decades, the standard-of-care has been CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone)-based therapy, but it is well-recognized that survival outcomes are unsatisfactory, especially when compared with B-cell lymphomas. Major recent advances in cancer diagnosis and management have the potential to significantly improve PTCL outcomes. These include: (1) improved diagnostic techniques that incorporate molecular genetic data to further refine diagnosis and subtyping; (2) the development of novel agents; and (3) improved monitoring modalities, such as 18F-fluorodeoxyglucose positron emission tomography-computed tomography scans and circulating tumor DNA. In this review, we aim to explore these 3 advances in the context of frontline management of PTCL.
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Affiliation(s)
- Chathuri Abeyakoon
- Department of Haematology, Epworth HealthCare, Melbourne, Victoria, Australia.
| | - Carrie van der Weyden
- Department of Haematology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
| | - Sean Harrop
- Department of Haematology, Epworth HealthCare, Melbourne, Victoria, Australia; Department of Haematology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
| | - Amit Khot
- Department of Haematology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Victoria, Australia; Department of Haematology, Royal Melbourne Hospital, Melbourne, Victoria, Australia
| | - Michael Dickinson
- Department of Haematology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
| | - Costas K Yannakou
- Department of Haematology, Epworth HealthCare, Melbourne, Victoria, Australia
| | - H Miles Prince
- Department of Haematology, Epworth HealthCare, Melbourne, Victoria, Australia; Department of Haematology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Victoria, Australia
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21
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Wolska-Washer A, Smolewski P, Robak T. Advances in the pharmacotherapeutic options for primary nodal peripheral T-cell lymphoma. Expert Opin Pharmacother 2021; 22:1203-1215. [PMID: 33524268 DOI: 10.1080/14656566.2021.1882997] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
INTRODUCTION Peripheral T cell lymphomas (PTCL) are a group of heterogenous hematologic malignancies derived from post-thymic T lymphocytes and mature NK cells. Conventional chemotherapy does not guarantee a good outcome. AREAS COVERED The article summarizes recent investigational therapies and their mechanism of action, as well as the pharmacological properties, clinical activity, and toxicity of new agents in the treatment of primary nodal PTCLs. The review scrutinized papers included in the MEDLINE (PubMed) database between 2010 and October 2020. These were supplemented with a manual search of conference proceedings from the previous five years of the American Society of Hematology, European Hematology Association, and American Society of Clinical Oncology. Further relevant publications were obtained by reviewing the references from the chosen articles. EXPERT OPINION PTCLs have proved difficult to treat and investigate because of their rarity. Studies of aggressive lymphoma, including a small proportion of T-cell lymphomas, found that any benefit from intensified traditional chemotherapy in patients with PTCL is accompanied by increased toxicity. However, the management of PTCL is beginning to change dramatically, thanks to the use of more sophisticated agents targeting the mechanisms of disease development.
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Affiliation(s)
- Anna Wolska-Washer
- Department of Experimental Hematology, Medical University of Lodz, Lodz. Poland.,Copernicus Memorial Hospital, Lodz. Poland
| | - Piotr Smolewski
- Department of Experimental Hematology, Medical University of Lodz, Lodz. Poland.,Copernicus Memorial Hospital, Lodz. Poland
| | - Tadeusz Robak
- Copernicus Memorial Hospital, Lodz. Poland.,Department of Hematology, Medical University of Lodz, Lodz. Poland
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Abstract
PURPOSE OF REVIEW Peripheral T cell lymphomas (PTCLs) are a heterogeneous group of non-Hodgkin lymphomas with inferior prognosis compared with their B cell counterparts characterized by frequent relapses, resulting in a median 5-year survival of approximately 30%. Their diverse clinicopathologic features challenge existing treatment paradigms that treat all patients uniformly. Here we review recent advances in the treatment of these diseases. RECENT FINDINGS While current treatment still relies largely on combination chemotherapy, the introduction of more effective novel and targeted therapies has improved outcomes in certain subtypes. Increasing understanding of the underlying biology of PTCL has prompted further subclassification by genetic and molecular subgroups. Overall, the most significant advances in PTCL management have resulted from improved understanding and classification of the biology of PTCL. Ongoing development of subtype-specific targeted therapies will be essential to improve long-term outcomes of patients with these diseases.
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Affiliation(s)
- Pamela B Allen
- Winship Institute of Emory University, 1365 Clifton Rd NE, Suite 4400, Atlanta, GA, USA
| | - Barbara Pro
- Department of Medicine, Division of Hematology/Oncology, Northwestern University Feinberg School of Medicine, Robert H. Lurie Comprehensive Cancer Center, Northwestern University, 676 N. St. Clair Street, Suite 850, Chicago, IL, 60611, USA.
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Magaway C, Kim E, Jacinto E. Targeting mTOR and Metabolism in Cancer: Lessons and Innovations. Cells 2019; 8:cells8121584. [PMID: 31817676 PMCID: PMC6952948 DOI: 10.3390/cells8121584] [Citation(s) in RCA: 149] [Impact Index Per Article: 24.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2019] [Revised: 12/02/2019] [Accepted: 12/03/2019] [Indexed: 12/14/2022] Open
Abstract
Cancer cells support their growth and proliferation by reprogramming their metabolism in order to gain access to nutrients. Despite the heterogeneity in genetic mutations that lead to tumorigenesis, a common alteration in tumors occurs in pathways that upregulate nutrient acquisition. A central signaling pathway that controls metabolic processes is the mTOR pathway. The elucidation of the regulation and functions of mTOR can be traced to the discovery of the natural compound, rapamycin. Studies using rapamycin have unraveled the role of mTOR in the control of cell growth and metabolism. By sensing the intracellular nutrient status, mTOR orchestrates metabolic reprogramming by controlling nutrient uptake and flux through various metabolic pathways. The central role of mTOR in metabolic rewiring makes it a promising target for cancer therapy. Numerous clinical trials are ongoing to evaluate the efficacy of mTOR inhibition for cancer treatment. Rapamycin analogs have been approved to treat specific types of cancer. Since rapamycin does not fully inhibit mTOR activity, new compounds have been engineered to inhibit the catalytic activity of mTOR to more potently block its functions. Despite highly promising pre-clinical studies, early clinical trial results of these second generation mTOR inhibitors revealed increased toxicity and modest antitumor activity. The plasticity of metabolic processes and seemingly enormous capacity of malignant cells to salvage nutrients through various mechanisms make cancer therapy extremely challenging. Therefore, identifying metabolic vulnerabilities in different types of tumors would present opportunities for rational therapeutic strategies. Understanding how the different sources of nutrients are metabolized not just by the growing tumor but also by other cells from the microenvironment, in particular, immune cells, will also facilitate the design of more sophisticated and effective therapeutic regimen. In this review, we discuss the functions of mTOR in cancer metabolism that have been illuminated from pre-clinical studies. We then review key findings from clinical trials that target mTOR and the lessons we have learned from both pre-clinical and clinical studies that could provide insights on innovative therapeutic strategies, including immunotherapy to target mTOR signaling and the metabolic network in cancer.
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Wang X, Wu J, Zhang M. Advances in the treatment and prognosis of anaplastic lymphoma kinase negative anaplastic large cell lymphoma. ACTA ACUST UNITED AC 2019; 24:440-445. [PMID: 31072226 DOI: 10.1080/16078454.2019.1613290] [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] [Indexed: 12/18/2022]
Abstract
Anaplastic lymphoma kinase negative anaplastic large cell lymphoma (ALK- ALCL) is a definite entity in the WHO 2016 Classification that represents 2-3% of non-Hodgkin lymphoma (NHL) and 12% of T-cell NHL cases. ALK- ALCL lacks ALK protein expression, but expresses CD30 and has morphologic features similar to ALK positive anaplastic large cell lymphoma (ALK+ ALCL). Some studies indicate that ALK- ALCL and ALK+ ALCL possess different molecular and genetic characteristics. Besides, ALK- ALCL is worse than ALK+ ALCL in terms of treatment outcome, prognosis, and long-term survival. This review is aimed at summarizing information about ALK- ALCL, especially with respect to the treatment and prognosis.
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Affiliation(s)
- Xiaoli Wang
- a Department of Oncology , Lymphoma Diagnosis and Treatment Centre of Henan Province, The First Affiliated Hospital of Zhengzhou University , Zhengzhou , People's Republic of China
| | - Jingjing Wu
- a Department of Oncology , Lymphoma Diagnosis and Treatment Centre of Henan Province, The First Affiliated Hospital of Zhengzhou University , Zhengzhou , People's Republic of China
| | - Mingzhi Zhang
- a Department of Oncology , Lymphoma Diagnosis and Treatment Centre of Henan Province, The First Affiliated Hospital of Zhengzhou University , Zhengzhou , People's Republic of China
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Abstract
PURPOSE OF REVIEW Peripheral T-cell lymphoma (PTCL) is a heterogeneous group of mature T-cell and natural killer (NK)-cell neoplasms in the WHO 2016 classification. Patient prognosis is poor when treated with CHOP, and there is an unmet need for new drugs. Several agents have been developed for PTCL, and their use is the subject of this review. RECENT FINDINGS Phase 2 studies demonstrated the activity of new drugs in Relapsed/refractory PTCL. Only four compounds were approved by the food and drug administration: romidepsin and belinostat, which are epigenetic modifiers, the antifolate agent pralatrexate, the immuno-conjugate brentuximab vedotin. New combinations have been tested, but the results were disappointing. Given the latest progress in biology, targeted agents are evaluated in different subtypes of PTCL. Relapsed anaplastic large-cell lymphoma exhibits improved prognosis with the approved anti-CD30 drug conjugate brentuximab vedotin. Localized nasal NK/T is treated with radiotherapy and nonanthracycline chemotherapy with L-asparaginase. Recently, immune checkpoint inhibitors demonstrated activity in NK/T lymphoma and can be used in elderly patients. SUMMARY Treatment remains a challenge for PTCL, and several targeted drugs provide new approaches. Progress will be made incrementally in the different subtypes. One of the critical situations facing new drugs is the ability to run robust clinical trials in rare diseases.
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Abstract
INTRODUCTION Peripheral T-cell lymphoma (PTCL) is a relatively rare, heterogeneous group of mature T-cell neoplasms generally associated with poor prognosis, partly because of refractoriness against conventional cytotoxic chemotherapies. To improve the outcome of patients with PTCL, the clinical development of several novel agents is currently under investigation. AREAS COVERED Since the first approval of pralatrexate (dihydrofolate reductase inhibitor) by the US Food and Drug Administration, belinostat, romidepsin (histone deacetylase inhibitors), and brentuximab vedotin (anti-CD30 antibody-drug conjugate) have been approved in the US, and many other countries. In addition, mogamulizumab (anti-CC chemokine receptor 4 antibody), chidamide (histone deacetylase inhibitor), and forodesine (purine nucleoside phosphorylase inhibitor) have been approved in Asian countries, including China, and Japan. In this review, we have summarized the available data regarding these approved agents and new agents currently under development for PTCL. EXPERT OPINION Novel agents will be a promising therapeutic option in selected patients with relapsed/refractory PTCL and will change the daily clinical practice in the treatment of PTCL. However, these are not a curative option when used as a single agent. Further clinical developments are expected, comprising 1) combination therapies of new agents with cytotoxic chemotherapies; 2) 'novel-novel' combinations; 3) immune therapies, including chimeric antigen receptor T-cell therapy; and 4) predictive marker analysis.
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Affiliation(s)
- Yuta Ito
- a Department of Hematology , National Cancer Center Hospital , Tokyo , Japan
| | - Shinichi Makita
- a Department of Hematology , National Cancer Center Hospital , Tokyo , Japan
| | - Kensei Tobinai
- a Department of Hematology , National Cancer Center Hospital , Tokyo , Japan
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Ma H, Davarifar A, Amengual JE. The Future of Combination Therapies for Peripheral T Cell Lymphoma (PTCL). Curr Hematol Malig Rep 2018; 13:13-24. [PMID: 29397528 DOI: 10.1007/s11899-018-0432-3] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
PURPOSE OF REVIEW Peripheral T cell lymphoma is a rare heterogeneous group of diseases which are characterized by poor outcomes to treatment and short overall survival. In the past decade, several new therapies targeting T cell biology have been approved in the relapsed setting. These new therapies, such as pralatrexate, romidepsin, belinostat, and brentuximab vedotin, have begun to make their way into practice. Despite these advances, outcomes have not changed dramatically. In recent years, efforts have been made to incorporate these new therapies into combination strategies to treat this challenging disease entity. Herein we will review some of the latest developments. RECENT FINDINGS With the new WHO classification, discrete entities of PTCL are now being identified by molecular and phenotypic markers. This new classification is critical to our ability to define disease entities which may respond to certain classes of targeted therapy. Some such mutations include genes controlling epigenetics (TET2, IDH2, DNMT3A, RHOA, CD28). As such, epigenetic therapies such as histone deacetylase (HDAC) inhibitors have become the platform to which other novel therapies or chemotherapy has been added. Early phase clinical studies have demonstrated that combination therapy with romidepsin plus other agents known to have activity in T cell lymphoma have enhanced clinical benefit for this group of diseases. In addition, the antibody drug conjugate, brentuximab vedotin has been shown to have potent activity in T cell lymphomas expressing CD30. This drug is being studied as well with other targeted therapies and chemotherapy in an effort to improve response rates and progression-free survival. Although T cell lymphomas remain a highly challenging group of diseases to treat, new efforts to leverage drugs that discretely target the biology that drives T cell lymphomagenesis in combination provide hope that improved outcomes may be realized in the near future.
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Affiliation(s)
- Helen Ma
- Center for Lymphoid Malignancies, Division of Hematology and Oncology, Department of Medicine, Columbia University Medical Center, 51 West 51st Street, Suite 200, New York, NY, 10019, USA
| | - Ardy Davarifar
- Center for Lymphoid Malignancies, Division of Hematology and Oncology, Department of Medicine, Columbia University Medical Center, 51 West 51st Street, Suite 200, New York, NY, 10019, USA
| | - Jennifer E Amengual
- Center for Lymphoid Malignancies, Division of Hematology and Oncology, Department of Medicine, Columbia University Medical Center, 51 West 51st Street, Suite 200, New York, NY, 10019, USA.
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28
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Cross Talk Networks of Mammalian Target of Rapamycin Signaling With the Ubiquitin Proteasome System and Their Clinical Implications in Multiple Myeloma. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2018; 343:219-297. [PMID: 30712673 DOI: 10.1016/bs.ircmb.2018.06.001] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Multiple myeloma (MM) is the second most common hematological malignancy and results from the clonal amplification of plasma cells. Despite recent advances in treatment, MM remains incurable with a median survival time of only 5-6years, thus necessitating further insights into MM biology and exploitation of novel therapeutic approaches. Both the ubiquitin proteasome system (UPS) and the PI3K/Akt/mTOR signaling pathways have been implicated in the pathogenesis, and treatment of MM and different lines of evidence suggest a close cross talk between these central cell-regulatory signaling networks. In this review, we outline the interplay between the UPS and mTOR pathways and discuss their implications for the pathophysiology and therapy of MM.
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A Novel Combination of the mTORC1 Inhibitor Everolimus and the Immunomodulatory Drug Lenalidomide Produces Durable Responses in Patients With Heavily Pretreated Relapsed Lymphoma. CLINICAL LYMPHOMA MYELOMA & LEUKEMIA 2018; 18:664-672.e2. [PMID: 30104176 DOI: 10.1016/j.clml.2018.06.013] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/04/2018] [Revised: 06/03/2018] [Accepted: 06/11/2018] [Indexed: 02/07/2023]
Abstract
BACKGROUND Treatment outcomes have improved in lymphoid malignancies but relapse remains inevitable for most patients. Everolimus and lenalidomide have shown clinical activity as single agents in patients with relapsed and refractory Hodgkin and non-Hodgkin lymphomas. PATIENTS AND METHODS The present phase I/II trial for patients with relapsed and refractory lymphoid malignancy opened at Mayo Clinic from January 2011 to May 2013. The trial used a standard cohort 3 + 3 design to determine the maximum tolerated dose for the combination. Stem cell transplantation had failed in 27 of the patients (49%), 63% had stage IV disease, and ≥ 3 previous therapies had failed in 78%. RESULTS Of the 58 patients, enrolled, 55 were evaluable for analysis. The maximum tolerated dose was 5 mg/d for everolimus plus 10 mg/d for 21 days for lenalidomide. The most common grade ≥ 3 toxicities were hematologic and included neutropenia (56%), leukopenia (38%), and thrombocytopenia (33%). Seven patients discontinued the study because of adverse events. One patient died of disease progression. The overall response rate was 27% (15 of 55), with 38% (21 of 55) having stable disease. CONCLUSION The present phase I/II trial of everolimus and lenalidomide for R/R lymphoma has shown the combination to be tolerable, with neutropenia as the main dose-limiting toxicity. Encouraging responses were seen in this heavily pretreated group, and the patients with a response had meaningful duration of response.
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Margolskee E, Jobanputra V, Jain P, Chen J, Ganapathi K, Nahum O, Levy B, Morscio J, Murty V, Tousseyn T, Alobeid B, Mansukhani M, Bhagat G. Genetic landscape of T- and NK-cell post-transplant lymphoproliferative disorders. Oncotarget 2018; 7:37636-37648. [PMID: 27203213 PMCID: PMC5122338 DOI: 10.18632/oncotarget.9400] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2016] [Accepted: 05/06/2016] [Indexed: 12/21/2022] Open
Abstract
Post-transplant lymphoproliferative disorders of T- or NK-cell origin (T/NK-PTLD) are rare entities and their genetic basis is unclear. We performed targeted sequencing of 465 cancer-related genes and high-resolution copy number analysis in 17 T-PTLD and 2 NK-PTLD cases. Overall, 377 variants were detected, with an average of 20 variants per case. Mutations of epigenetic modifier genes (TET2, KMT2C, KMT2D, DNMT3A, ARID1B, ARID2, KDM6B, n=11). and inactivation of TP53 by mutation and/or deletion(n=6) were the most frequent alterations, seen across disease subtypes, followed by mutations of JAK/STAT pathway genes (n=5). Novel variants, including mutations in TBX3 (n=3), MED12 (n=3) and MTOR (n=1), were observed as well. High-level microsatellite instability was seen in 1 of 14 (7%) cases, which had a heterozygous PMS2 mutation. Complex copy number changes were detected in 8 of 16 (50%) cases and disease subtype-specific aberrations were also identified. In contrast to B-cell PTLDs, the molecular and genomic alterations observed in T/NK-PTLD appear similar to those reported for peripheral T-cell lymphomas occurring in immunocompetent hosts, which may suggest common genetic mechanisms of lymphoma development.
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Affiliation(s)
- Elizabeth Margolskee
- Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY, USA
| | - Vaidehi Jobanputra
- Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY, USA
| | - Preti Jain
- Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY, USA
| | - Jinli Chen
- Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY, USA
| | - Karthik Ganapathi
- Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY, USA
| | - Odelia Nahum
- Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY, USA
| | - Brynn Levy
- Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY, USA
| | - Julie Morscio
- Department of Pathology, Translational Cell and Tissue Research Laboratory, UZ Leuven/KU Leuven, Leuven, Belgium
| | - Vundavalli Murty
- Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY, USA
| | - Thomas Tousseyn
- Department of Pathology, Translational Cell and Tissue Research Laboratory, UZ Leuven/KU Leuven, Leuven, Belgium
| | - Bachir Alobeid
- Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY, USA
| | - Mahesh Mansukhani
- Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY, USA
| | - Govind Bhagat
- Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY, USA
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31
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Li P, Liu H, Zhang Z, Lv X, Wang H, Ma J, Ma Z, Qu X, Teng YE. Expression and Comparison of Cbl-b in Lung Squamous Cell Carcinoma and Adenocarcinoma. Med Sci Monit 2018; 24:623-635. [PMID: 29384143 PMCID: PMC5802325 DOI: 10.12659/msm.908076] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Background Non-small cell lung carcinoma (NSCLC) mainly includes lung squamous cell carcinoma and adenocarcinoma. This study aimed to investigate the difference between the expression of Cbl-b in lung squamous cell carcinoma and adenocarcinoma. Material/Methods The clinical features and survival data of NSCLC patients and Cbl-b mRNA (FPKM) were obtained from the TCGA database. Then, lung squamous cell carcinoma and adenocarcinoma cell lines were transfected with lentivirus-mediated RNA interference vector to knockdown the expression of Cbl-b. Next, a Transwell assay was performed to study the effect of Cbl-b shRNA on migration and invasion of lung squamous cell carcinoma and adenocarcinoma cells. Finally, Western blot analysis was performed to measure the expressions of PI3K, p-PI3K, AKT, p-AKT, ERK1/2, p-ERK1/2, GSK3β, p-GSK3β, mTOR, and p-mTOR protein in lung adenocarcinoma and squamous cell carcinoma cells. Results The correlation of Cbl-b expression and OS was different between NSCLC adenocarcinoma and squamous carcinoma. After transfection, the expression of Cbl-b was inhibited in A549, H1975, and SW900 cells. Cbl-b shRNA promoted the migration and invasion of lung adenocarcinoma A549 and H1975 cells, but it inhibited the invasion of lung squamous cell carcinoma SW900 cells. In addition, Cbl-b regulated the expression of PI3K and ERK1/2-GSK3β pathway proteins in A549 and SW900 cells. Conclusions The OS of Cbl-b mRNA low expression in lung adenocarcinoma and squamous cell carcinoma was different. The difference in signal pathways may be one of the reasons for the difference in the correlation between Cbl-b expression and the survival rate of these 2 pathological types of lung cancer.
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Affiliation(s)
- Peng Li
- Department of Medical Oncology, The First Hospital of China Medical University, Shenyang, Liaoning, China (mainland).,Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Shenyang, Liaoning, China (mainland)
| | - Hongliang Liu
- Department of Medicine, Duke University School of Medicine, Durham, NC, USA.,Duke Cancer Institute, Duke University Medical Center, Durham, NC, USA
| | - Zhiqiang Zhang
- Department of Medical Oncology, The First Hospital of China Medical University, Shenyang, Liaoning, China (mainland).,Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Shenyang, Liaoning, China (mainland)
| | - Xiaodong Lv
- Central Laboratory, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, Henan, China (mainland)
| | - Huijuan Wang
- Department of Internal Medicine, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, Henan, China (mainland)
| | - Jie Ma
- Department of Molecular Pathology, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, Henan, China (mainland)
| | - Zhiyong Ma
- Department of Internal Medicine, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, , China (mainland)
| | - Xiujuan Qu
- Department of Medical Oncology, The First Hospital of China Medical University, Shenyang, Liaoning, China (mainland).,Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Shenyang, Liaoning, China (mainland)
| | - Yue-E Teng
- Department of Medical Oncology, The First Hospital of China Medical University, Shenyang, Liaoning, China (mainland).,Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Shenyang, Liaoning, China (mainland)
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32
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Lymphoma epidemiology in Korea and the real clinical field including the Consortium for Improving Survival of Lymphoma (CISL) trial. Int J Hematol 2018; 107:395-404. [DOI: 10.1007/s12185-018-2403-9] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2017] [Accepted: 01/12/2018] [Indexed: 12/18/2022]
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33
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Schoch LK, Asiama A, Zahurak M, Shanbhag S, Hurtt J, Sawyer K, Swinnen LJ, Wagner-Johnston N, Jones RJ, Ambinder RF, Gladstone DE. Pharmacokinetically-targeted dosed everolimus maintenance therapy in lymphoma patients. Cancer Chemother Pharmacol 2017; 81:347-354. [PMID: 29234922 DOI: 10.1007/s00280-017-3499-y] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2017] [Accepted: 12/08/2017] [Indexed: 11/24/2022]
Abstract
BACKGROUND Everolimus, an mTOR inhibitor, is active in refractory lymphomas. However, toxicity with flat dosing limits its usage. Speculatively, pharmacokinetically-targeted dosing could improve tolerability. Therefore, we studied serum-trough dosing with rituximab as maintenance after high-dose cyclophosphamide (HDC) consolidation in lymphoma patients. PATIENTS/METHODS After HDC, everolimus was dosed to serum trough levels (goal 3-15 ng/mL), with quarterly rituximab infusions for 1 year while maintaining < grade II non-hematologic and < grade III hematologic toxicities. Adult patients in first PR/CR with: mantle cell, transformed, double-hit, or high risk chronic lymphocytic leukemia or in second PR for any relapsed B cell lymphoma were eligible. Prophylaxis was given for encapsulated organisms, HSV and PCP. Serum IgG levels were maintained > 500 mg/dL. RESULTS 49 patients, median age: 59.0 years enrolled; MCL (26), CLL (10), transformed lymphoma (7), and other histologies (6). During the life of the study, the most frequent everolimus dosing has been 2.5 mg daily or 2.5 mg every other day; at these doses, serum levels are within the therapeutic range and non-hematologic toxicity is rare. At a median follow-up of 27.1 months, three patients remain on active therapy. Two patients withdrew secondary to potentially-attributable adverse events including a bacterial pneumonia and a viral pneumonia; this low rate of discontinuation compares well to other long-term everolimus trials. While a 58 and 76% EFS at 30 months for the entire cohort and MCL cohort, respectively, compares similarly to previously published HDC/rituximab data, longer follow-up is required. CONCLUSIONS Pharmacokinetically-targeted dosing appears to increase everolimus tolerability. This finding may be applicable to other patient populations.
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Affiliation(s)
- L K Schoch
- The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, 401 N. Broadway room 1363, Baltimore, MD, 21287, USA
| | - A Asiama
- The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, 401 N. Broadway room 1363, Baltimore, MD, 21287, USA
| | - M Zahurak
- The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, 401 N. Broadway room 1363, Baltimore, MD, 21287, USA
| | - S Shanbhag
- The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, 401 N. Broadway room 1363, Baltimore, MD, 21287, USA
| | - J Hurtt
- The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, 401 N. Broadway room 1363, Baltimore, MD, 21287, USA
| | - K Sawyer
- The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, 401 N. Broadway room 1363, Baltimore, MD, 21287, USA
| | - L J Swinnen
- The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, 401 N. Broadway room 1363, Baltimore, MD, 21287, USA
| | - N Wagner-Johnston
- The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, 401 N. Broadway room 1363, Baltimore, MD, 21287, USA
| | - R J Jones
- The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, 401 N. Broadway room 1363, Baltimore, MD, 21287, USA
| | - R F Ambinder
- The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, 401 N. Broadway room 1363, Baltimore, MD, 21287, USA
| | - Douglas E Gladstone
- The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, 401 N. Broadway room 1363, Baltimore, MD, 21287, USA.
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Abstract
Owing to the rarity of peripheral T-cell lymphoma (PTCL) and the heterogeneity of subtypes, there are no compelling data to guide the therapeutic approaches for such patients. Over the years, there have been remarkable advances in molecular subtyping and treatment of PTCL, although there are still many areas to be explored. In this review, we summarize recent updates on the evolution of understanding and treatment for PTCL.
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Affiliation(s)
- Jun Ho Yi
- Division of Hematology-Oncology, Department of Medicine, Chung-Ang University , Seoul, Korea, South
| | - Seok Jin Kim
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine , Seoul, Korea, South
| | - Won Seog Kim
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine , Seoul, Korea, South
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35
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Roswarski J, Roschewski M, Lucas A, Melani C, Pittaluga S, Jaffe ES, Steinberg SM, Waldmann TA, Wilson WH. Phase I dose escalation study of the anti-CD2 monoclonal antibody, siplizumab, with DA-EPOCH-R in aggressive peripheral T-cell lymphomas. Leuk Lymphoma 2017; 59:1466-1469. [PMID: 29032710 DOI: 10.1080/10428194.2017.1387908] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Affiliation(s)
- Joseph Roswarski
- a Center for Cancer Research, National Cancer Institute , Bethesda , MD , USA.,b Walter Reed National Military Medical Center , Bethesda , MD , USA
| | - Mark Roschewski
- a Center for Cancer Research, National Cancer Institute , Bethesda , MD , USA
| | - Andrea Lucas
- a Center for Cancer Research, National Cancer Institute , Bethesda , MD , USA
| | - Christopher Melani
- a Center for Cancer Research, National Cancer Institute , Bethesda , MD , USA
| | - Stefania Pittaluga
- c Laboratory of Pathology, National Cancer Institute , Bethesda , MD , USA
| | - Elaine S Jaffe
- c Laboratory of Pathology, National Cancer Institute , Bethesda , MD , USA
| | - Seth M Steinberg
- a Center for Cancer Research, National Cancer Institute , Bethesda , MD , USA
| | - Thomas A Waldmann
- a Center for Cancer Research, National Cancer Institute , Bethesda , MD , USA
| | - Wyndham H Wilson
- a Center for Cancer Research, National Cancer Institute , Bethesda , MD , USA
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36
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Ham JS, Park HY, Ryu KJ, Ko YH, Kim WS, Kim SJ. Elevated serum interleukin-10 level and M2 macrophage infiltration are associated with poor survival in angioimmunoblastic T-cell lymphoma. Oncotarget 2017; 8:76231-76240. [PMID: 29100307 PMCID: PMC5652701 DOI: 10.18632/oncotarget.19301] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2017] [Accepted: 06/05/2017] [Indexed: 11/30/2022] Open
Abstract
Interleukin-10 (IL-10) induces an immunosuppressive microenvironment including M2 macrophages, inhibiting anti-tumor immunity. The aim of this study was to evaluate whether serum IL-10 level at diagnosis and tissue infiltration of M2 macrophages could predict survival outcome of patients with angioimmunoblastic T-cell lymphoma (AITL). We measured serum levels of IL-5, IL-10, IL-12, and interferon-gamma (IFN-γ) at diagnosis in AITL and other common subtypes of nodal T-cell lymphoma including peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS), ALK-negative anaplastic large cell lymphoma (ALCL) or ALK-positive ALCL between September 2008 and December 2014. We also analyzed the infiltration of CD68- and CD163-positive macrophages in tumor tissue of AITL. In total, 97 patients with AITL (n=37), PTCL-NOS (n=40), ALK-negative ALCL (n=11), or ALK-positive ALCL (n=9) were treated with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone). Among cytokines, only the serum level of IL-10 was significantly higher in AITL patients than in other subtypes (P < 0.05). Compared to other subtypes, the association of serum IL-10 with overall survival (OS) was only significant in AITL. Accordingly, the response to CHOP chemotherapy was significantly worse in the high IL-10 group, and infiltration of CD163-positive M2 macrophages was significantly associated with OS in AITL. In conclusion, this study demonstrated the prognostic relevance of serum IL-10 and tissue infiltration of M2 macrophages in AITL patients. Our results suggest the possible use of these variables as potential therapeutic targets and novel prognostic indicators in patients with AITL.
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Affiliation(s)
- Jun Soo Ham
- Division of Hematology and Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Ha Young Park
- Department of Pathology, Inje University Busan Paik Hospital, Busan, Korea
| | - Kyung Ju Ryu
- Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Seoul, Korea
| | - Young Hyeh Ko
- Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Won Seog Kim
- Division of Hematology and Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Seok Jin Kim
- Division of Hematology and Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.,Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Seoul, Korea
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Al-Zahrani M, Savage KJ. Peripheral T-Cell Lymphoma, Not Otherwise Specified. Hematol Oncol Clin North Am 2017; 31:189-207. [DOI: 10.1016/j.hoc.2016.11.009] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
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Willemsen M, Schouten HC. Inappropriate costimulation and aberrant DNA methylation as therapeutic targets in angioimmunoblastic T-cell lymphoma. Biomark Res 2017; 5:6. [PMID: 28194275 PMCID: PMC5299773 DOI: 10.1186/s40364-017-0085-8] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2016] [Accepted: 02/03/2017] [Indexed: 12/22/2022] Open
Abstract
Angioimmunoblastic T-cell lymphoma (AITL) is one of the most common subtypes of peripheral T-cell lymphoma. Advances in understanding the mutational landscape of AITL have not resulted in improved prognosis nor consensus regarding optimal first-line and second-line treatment. The recently proposed multistep tumorigenesis model for AITL provides a theoretical framework of AITL oncogenesis. In this model, early mutations in epigenetic modifiers interact with late cooperative mutations to enable malignant transformation. Frequent mutations in epigenetic modifiers suggest that aberrant DNA methylation contributes to AITL oncogenesis. Several research groups have reported findings suggesting that inappropriate costimulation acts as a late cooperative mutation. Drugs targeting inappropriate costimulation have already been approved for the treatment of several malignancies or autoimmune diseases. Additionally, aberrant DNA methylation was recently shown to potentiate inappropriate costimulation in a subset of AITL cases. Therefore, drugs targeting inappropriate costimulation and hypomethylating agents might have synergistic effects. Both offer promising new therapeutic options in AITL treatment. This commentary summarizes the main findings on aberrant DNA methylation and inappropriate costimulation in AITL and proposes several already approved drugs for AITL treatment. Hopefully, these will contribute to improving the still dismal prognosis of AITL patients.
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Affiliation(s)
- Mathijs Willemsen
- Department of Internal Medicine, Division of Hematology, Maastricht University Medical Centre, PO Box 5800, 6202 AZ Maastricht, The Netherlands
| | - Harry C Schouten
- Department of Internal Medicine, Division of Hematology, Maastricht University Medical Centre, PO Box 5800, 6202 AZ Maastricht, The Netherlands
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Calimeri T, Ferreri AJM. m-TOR inhibitors and their potential role in haematological malignancies. Br J Haematol 2017; 177:684-702. [PMID: 28146265 DOI: 10.1111/bjh.14529] [Citation(s) in RCA: 42] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2016] [Accepted: 09/28/2016] [Indexed: 12/22/2022]
Abstract
It is widely demonstrated that the PI3K-AKT-mTOR signalling is critical in normal myeloid and lymphoid development and function. Thus, it is not strange that this pathway is often deregulated in haematological tumours, providing a strong preclinical rationale for the use of drugs targeting the PI3K-AKT-mTOR axis in haematological malignancies. The main focus of this review is to examine the mammalian target of rapamycin (mTOR, also termed mechanistic target of rapamycin [MTOR]) signalling pathways and to provide a brief overview of rapalogs and second-generation mTOR inhibitors used to target its aberrant activation in cancer treatment. We will also discuss the results obtained with the use of these agents in patients with acute leukaemia, Hodgkin lymphoma, non-Hodgkin lymphomas, multiple myeloma and Waldenström macroglobulinaemia. Ongoing clinical trials in haematological malignancies that are investigating first- and second-generation mTOR inhibitors as single agents and as components of combination regimens are also presented.
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Affiliation(s)
- Teresa Calimeri
- Unit of Lymphoid Malignancies, Department of Onco-Haematology, IRCCS San Raffaele Scientific Institute, Milano, Italy
| | - Andrés J M Ferreri
- Unit of Lymphoid Malignancies, Department of Onco-Haematology, IRCCS San Raffaele Scientific Institute, Milano, Italy
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