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Yu ZP, Sun KX, Zhang D, Yu ZQ, Chen DY, Zhu H, Si H, Dai PF. Development and Preclinical Evaluation of a Gallium-68 Labeled Novel Diagnostic Tracer for Visualizing ALK Expression in Tumor. Eur J Pharm Sci 2025:107087. [PMID: 40169071 DOI: 10.1016/j.ejps.2025.107087] [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: 01/27/2025] [Revised: 03/18/2025] [Accepted: 03/29/2025] [Indexed: 04/03/2025]
Abstract
Anaplastic lymphoma kinase (ALK) is prominently expressed in numerous malignant tumors, which lead to aberrant tumor proliferation, invasion and metastasis. Ceritinib (LDK378), as second-generation targeted drugs, has been used to treat advanced ALK-positive non-small cell lung cancer (NSCLC). Herein, we sought to develop a novel ALK-positron emission tomography/magnetic resonance (PET/MR) tracer 68Ga-DOTA-CTB (68Ga labeled ceritinib) based on ceritinib scaffold to monitor the ALK expression levels during targeted therapy with ceritinib. The 68Ga-DOTA-CTB radiotracer, obtained via a simple labeling procedure, exhibits favorable radiochemical purity, stability, and pharmacokinetic properties. Subsequently, cellular uptake experiments have demonstrated that 68Ga-DOTA-CTB could be accumulated in H2228 cells. Imaging and biodistribution experiments have revealed significant uptake of the radiotracer in the tumors of the experimental group, while tumors in the blocking group, which were saturated with an excess of precursor, exhibited a markedly reduced level of radioactivity. These empirical findings suggest that 68Ga-DOTA-CTB holds substantial potential as a novel PET/MR imaging tracer for ALK-positive tumors.
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Affiliation(s)
- Zhen-Peng Yu
- Department of Nuclear Medicine, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, 230022, China
| | - Ke-Xin Sun
- Department of Nuclear Medicine, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, 230022, China
| | - Dan Zhang
- Department of Nuclear Medicine, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, 230022, China
| | - Zhi-Qiang Yu
- Department of Nuclear Medicine, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, 230022, China
| | - Deng-Yun Chen
- Department of Nuclear Medicine, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, 230022, China
| | - Hong Zhu
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, 230022, China..
| | - Hongwei Si
- Department of Nuclear Medicine, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, 230022, China..
| | - Peng-Fei Dai
- Department of Nuclear Medicine, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, 230022, China.; Anhui province key laboratory of tumor immune microenvironment and immunotherapy, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, 230022, China..
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Atiq MA, Balan J, Blackburn PR, Gross JM, Voss JS, Jin L, Fadra N, Davila JI, Pitel BA, Siqueira Parrilha Terra SB, Minn KT, Jackson RA, Hofich CD, Willkomm KS, Peterson BJ, Clausen SN, Rumilla KM, Gupta S, Lo YC, Ida CM, Molligan JF, Thangaiah JJ, Petersen MJ, Sukov WR, Guo R, Giannini C, Schoolmeester JK, Fritchie K, Inwards CY, Folpe AL, Oliveira AM, Torres-Mora J, Kipp BR, Halling KC. SARCP, a Clinical Next-Generation Sequencing Assay for the Detection of Gene Fusions in Sarcomas: A Description of the First 652 Cases. J Mol Diagn 2025; 27:74-95. [PMID: 39521244 DOI: 10.1016/j.jmoldx.2024.10.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2023] [Revised: 10/11/2024] [Accepted: 10/23/2024] [Indexed: 11/16/2024] Open
Abstract
An amplicon-based targeted next-generation sequencing (NGS) assay for the detection of gene fusions in sarcomas was developed, validated, and implemented. This assay can detect fusions in targeted regions of 138 genes and BCOR internal tandem duplications. This study reviews our experience with testing on the first 652 patients analyzed. Gene fusions were detected in 238 (36.5%) of 652 cases, including 83 distinct fusions in the 238 fusion-positive cases, 10 of which had not been previously described. Among the 238 fusion-positive cases, the results assisted in establishing a diagnosis for 137 (58%) cases, confirmed a suspected diagnosis in 66 (28%) cases, changed a suspected diagnosis in 25 (10%) cases, and were novel fusions with unknown clinical significance in 10 (4%) cases. Twenty-six cases had gene fusions (ALK, ROS1, NTRK1, NTRK3, and COL1A1::PDGFB) for which there are targetable therapies. BCOR internal tandem duplications were identified in 6 (1.2%) of 485 patients. Among the 138 genes in the panel, 66 were involved in one or more fusions, and 72 were not involved in any fusions. There was little overlap between the genes involved as 5'-partners (31 different genes) and 3'-partners (37 different genes). This study shows the clinical utility of a next-generation sequencing gene fusion detection assay for the diagnosis and treatment of sarcomas.
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Affiliation(s)
- Mazen A Atiq
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
| | - Jagadheshwar Balan
- Department of Quantitative Health Sciences Research, Mayo Clinic, Rochester, Minnesota
| | - Patrick R Blackburn
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
| | - John M Gross
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
| | - Jesse S Voss
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
| | - Long Jin
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
| | - Numrah Fadra
- Department of Quantitative Health Sciences Research, Mayo Clinic, Rochester, Minnesota
| | - Jaime I Davila
- Department of Quantitative Health Sciences Research, Mayo Clinic, Rochester, Minnesota
| | - Beth A Pitel
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
| | | | - Kay T Minn
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
| | - Rory A Jackson
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
| | - Christopher D Hofich
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
| | - Kurt S Willkomm
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
| | - Brenda J Peterson
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
| | - Sydney N Clausen
- University of Minnesota Medical School, Duluth, Duluth, Minnesota
| | - Kandelaria M Rumilla
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
| | - Sounak Gupta
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
| | - Ying-Chun Lo
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
| | - Cris M Ida
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
| | - Jeremy F Molligan
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
| | | | - Matthew J Petersen
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
| | - William R Sukov
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
| | - Ruifeng Guo
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
| | - Caterina Giannini
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
| | | | - Karen Fritchie
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
| | - Carrie Y Inwards
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
| | - Andrew L Folpe
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
| | - Andre M Oliveira
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
| | - Jorge Torres-Mora
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
| | - Benjamin R Kipp
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota.
| | - Kevin C Halling
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota.
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3
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Khoubila N, Sraidi S, Madani A, Tazi I. Anaplastic Large-cell Lymphoma in Children: State of the Art in 2023. J Pediatr Hematol Oncol 2024; 46:217-224. [PMID: 38912833 DOI: 10.1097/mph.0000000000002875] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2023] [Accepted: 04/04/2024] [Indexed: 06/25/2024]
Abstract
Anaplastic large-cell lymphoma is a rare disease and account for approximately 10% to 15% of pediatric non-Hodgkin lymphomas. They are characterized by extended stages, a high frequency of B signs and extra nodal involvement. Multiagent chemotherapy cures ∽60% to 75% of patients and relapse occurs in 35% of cases. For relapsed patients, various treatments ranging from vinblastine monotherapy to therapeutic intensification with hematopoietic stem cell transplantation have been evaluated, but there is currently no consensus on the optimal therapeutic strategy. New therapeutic perspectives are being evaluated for relapses and refractory forms as well as high-risk forms including monoclonal antibodies (Anti CD30), ALK inhibitors, and CART cells.
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Affiliation(s)
- Nisrine Khoubila
- Department of Hematology and Pediatric Oncology, Hospital 20 August 1953, CHU Ibn Rochd, Faculty of Medicine and Pharmacy, Hassan II University, Casablanca
| | - Sofia Sraidi
- Department of Hematology and Pediatric Oncology, Hospital 20 August 1953, CHU Ibn Rochd, Faculty of Medicine and Pharmacy, Hassan II University, Casablanca
| | - Abdellah Madani
- Department of Hematology and Pediatric Oncology, Hospital 20 August 1953, CHU Ibn Rochd, Faculty of Medicine and Pharmacy, Hassan II University, Casablanca
| | - Illias Tazi
- Department of Clinical Hematology, CHU Mohamed VI, Cadi Ayyad University, Marrakech, Morocco
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4
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Morito D. Molecular structure and function of mysterin/RNF213. J Biochem 2024; 175:495-505. [PMID: 38378744 DOI: 10.1093/jb/mvae020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2023] [Revised: 01/19/2024] [Accepted: 01/24/2024] [Indexed: 02/22/2024] Open
Abstract
Mysterin is a large intracellular protein harboring a RING finger ubiquitin ligase domain and is also referred to as RING finger protein 213 (RNF213). The author performed the first molecular cloning of the mysterin gene as the final step in genetic exploration of cerebrovascular moyamoya disease (MMD) and initiated the next round of exploration to understand its molecular and cellular functions. Although much remains unknown, accumulating findings suggest that mysterin functions in cells by targeting massive intracellular structures, such as lipid droplets (LDs) and various invasive pathogens. In the latter case, mysterin appears to directly surround and ubiquitylate the surface of pathogens and stimulate cell-autonomous antimicrobial reactions, such as xenophagy and inflammatory response. To date, multiple mutations causing MMD have been identified within and near the RING finger domain of mysterin; however, their functional relevance remains largely unknown. Besides the RING finger, mysterin harbors a dynein-like ATPase core and an RZ finger, another ubiquitin ligase domain unique to mysterin, while functional exploration of these domains has also just commenced. In this review, the author attempts to summarize the core findings regarding the molecular structure and function of the mysterin protein, with an emphasis on the perspective of MMD research.
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Affiliation(s)
- Daisuke Morito
- Department of Biochemistry, Showa University School of Medicine, Hatanodai 1-5-8, Shinagawa, Tokyo 142-0064, Japan
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Abramov DS, Fedorova AS, Tuzova EA, Myakova NV, Konovalov DM. [ALK-positive anaplastic large cell lymphoma of paranasal sinuses: two cases report and literature review]. Arkh Patol 2024; 86:42-47. [PMID: 39073541 DOI: 10.17116/patol20248604142] [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] [Indexed: 07/30/2024]
Abstract
ALK-positive anaplastic large cell lymphoma is a rare T-cell lymphoma with ALK gene rearrangement that develops in children and young adults. The disease almost always affects the lymph nodes, and extranodal areas are also frequently involved. This article describes two cases of atypical localization of ALK-positive anaplastic large cell lymphoma with involvement of the paranasal sinuses.
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Affiliation(s)
- D S Abramov
- Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russia
| | - A S Fedorova
- Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russia
| | - E A Tuzova
- Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russia
| | - N V Myakova
- Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russia
| | - D M Konovalov
- Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russia
- Russian Medical Academy of Continuous Professional Education, Moscow, Russia
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Linos K, Chang JC, Busam KJ. A cutaneous epithelioid vascular tumor harboring a TPM3::ALK fusion. Genes Chromosomes Cancer 2024; 63:e23207. [PMID: 37787425 PMCID: PMC10842594 DOI: 10.1002/gcc.23207] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2023] [Revised: 09/13/2023] [Accepted: 09/23/2023] [Indexed: 10/04/2023] Open
Abstract
Substantial progress has been made in understanding the molecular pathways associated with vascular tumors over the last two decades. In addition to mutations and copy number aberrations, fusions have emerged as significant contributors to the pathogenesis of a notable subset of vascular tumors. In this report, we present a case of an unusual intradermal vascular tumor with epithelioid cytomorphology. Immunohistochemistry revealed diffuse positivity for CD31, ERG and Factor VIII, supporting its endothelial lineage. RNA sequencing (ArcherFusion Plex) revealed the presence of an in-frame fusion between the genes TPM3 Exon 8 and ALK Exon 20. Immunohistochemistry confirmed ALK expression by the endothelial cells. To our knowledge, this is the first documented case of a vascular tumor harboring an ALK fusion. It may fall within the spectrum of epithelioid hemangiomas; nevertheless, we cannot definitively exclude the possibility of it being a distinct and potentially unique benign entity on its own.
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Affiliation(s)
- Konstantinos Linos
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA
| | - Jason C Chang
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA
| | - Klaus J Busam
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA
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Diao L, Li W, Jiang Q, Huang H, Zhou E, Peng B, Chen X, Zeng Z, He C. Inflammatory myofibroblastic tumor of the submandibular gland Harboring MSN-ALK gene fusion: A case report and literature review. Heliyon 2023; 9:e22928. [PMID: 38144359 PMCID: PMC10746421 DOI: 10.1016/j.heliyon.2023.e22928] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2023] [Revised: 11/20/2023] [Accepted: 11/22/2023] [Indexed: 12/26/2023] Open
Abstract
Inflammatory myofibroblastic tumors (IMTs) are rare lesions with distinct clinical, pathological, and molecular characteristics. IMTs typically arise in the abdominal soft tissues, including the mesentery, omentum, and retroperitoneum, followed by the lungs and mediastinum, and usually affect both children and young adults. Herein, we present a rare case of an IMT in the submandibular gland of a 47-year-old male patient. Microscopically, the tumor displayed an infiltrative growth pattern with diffuse glandular tissue destruction. Their backgrounds revealed characteristic spindles and inflammatory cells. Immunohistochemistry revealed positivity for anaplastic lymphoma kinase (ALK), smooth muscle actin, and calponin in neoplastic cells. The inflammatory cells and some neoplastic cells were positive for CD68. In contrast, negative staining for cytokeratin, desmin, and CD30 was observed. Furthermore, fluorescence in situ hybridization revealed ALK gene rearrangements, and next-generation sequencing detected a moesin (MSN)-ALK gene fusion. This case highlights a rare and unique occurrence of IMT originating from the submandibular gland, which exhibited an MSN-ALK gene fusion.
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Affiliation(s)
- Limei Diao
- Department of Pathology, Chongqing University Cancer Hospital, Chongqing, 400030, China
- Chongqing Cancer Multi-omics Big Data Application Engineering Research Center, Chongqing University Cancer Hospital, Chongqing, 400030, China
| | - Wen Li
- Department of Pathology, Chongqing University Cancer Hospital, Chongqing, 400030, China
- Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing University Cancer Hospital, Chongqing, 400030, China
| | - Qingming Jiang
- Department of Pathology, Chongqing University Cancer Hospital, Chongqing, 400030, China
- Chongqing Cancer Multi-omics Big Data Application Engineering Research Center, Chongqing University Cancer Hospital, Chongqing, 400030, China
| | - Haiping Huang
- Department of Pathology, Chongqing University Cancer Hospital, Chongqing, 400030, China
- Chongqing Cancer Multi-omics Big Data Application Engineering Research Center, Chongqing University Cancer Hospital, Chongqing, 400030, China
| | - Enle Zhou
- Department of Pathology, Chongqing University Cancer Hospital, Chongqing, 400030, China
- Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing University Cancer Hospital, Chongqing, 400030, China
| | - Bingjie Peng
- Department of Pathology, Chongqing University Cancer Hospital, Chongqing, 400030, China
- Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing University Cancer Hospital, Chongqing, 400030, China
| | - Xiaoling Chen
- Department of pharmacy, Chongqing University Jiangjin Hospital, Chongqing, 402260, China
| | - Zhen Zeng
- Department of Pathology, Chongqing University Cancer Hospital, Chongqing, 400030, China
- Chongqing Cancer Multi-omics Big Data Application Engineering Research Center, Chongqing University Cancer Hospital, Chongqing, 400030, China
| | - Changqing He
- Department of Pathology, Chongqing University Cancer Hospital, Chongqing, 400030, China
- Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing University Cancer Hospital, Chongqing, 400030, China
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Wangsiricharoen S, Gjeorgjievski SG, Bahrami A, Torres-Mora J, Zou YS, Michal M, Charville GW, Gross JM. Non-cutaneous syncytial myoepitheliomas are identical to cutaneous counterparts: a clinicopathologic study of 24 tumors occurring at diverse locations. Virchows Arch 2023; 483:665-675. [PMID: 37548750 DOI: 10.1007/s00428-023-03609-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2023] [Revised: 07/13/2023] [Accepted: 07/21/2023] [Indexed: 08/08/2023]
Abstract
AIMS Cutaneous syncytial myoepithelioma (CSM) is a rare myoepithelioma variant of skin, characterized by intradermal syncytial growth of spindle cells with a distinct immunophenotype of EMA and S100 positivity and infrequent keratin expression. While CSM was first described as a cutaneous tumor, singular non-cutaneous cases have since been reported in bone. We aimed to investigate the clinicopathological features of this variant across all anatomic sites through a large multi-institutional study. METHODS AND RESULTS We complied a total of 24 myoepitheliomas with syncytial growth from our files. The tumors occurred in 12 male and 12 female patients (M:F = 1:1), with a median age of 31 years (range, 9-69 years). While the majority of tumors (75%, n = 18) occurred in skin, a significant subset (25%, n = 6) arose in non-cutaneous sites, including bone (n = 3), bronchus/trachea (n = 2), and interosseous membrane of tibia/fibula (n = 1). Tumor size ranged from 0.4 to 5.9 cm. Clinical follow-up (7 patients; range 14-202 months; median 56.5 months) showed a single local recurrence 8 years after incomplete skin excision but no metastases; all patients were alive at the time of last follow-up without evidence of disease. Histologically, all tumors were pink at low-power and characterized by a syncytial growth of bland ovoid, spindled, or histiocytoid cells with eosinophilic cytoplasm and prominent perivascular lymphoplasmacytic inflammation. One-third displayed adipocytic metaplasia (8/24). Rare cytologic atypia was seen but was not associated with increased mitotic activity. All tumors expressed S100, SMA, and/or EMA. Keratin expression was absent in most cases. Molecular analysis was performed in 16 cases, all showing EWSR1-rearrangments. In total, 15/15 (100%) harbored an EWSR1::PBX3 fusion, whereas 1 case EWSR1 FISH was the only molecular study performed. CONCLUSION Syncytial myoepithelioma is a rare but recognizable morphologic variant of myoepithelioma which may have a predilection for skin but also occurs in diverse non-cutaneous sites. Our series provides evidence supporting a reappraisal of the term "cutaneous syncytial myoepithelioma," as 25% of patients in our series presented with non-cutaneous tumors; thus, we propose the term "syncytial myoepithelioma" to aid pathologist recognition and avoidance of potentially confusing terminology when referring to non-cutaneous examples. The behavior of syncytial myoepithelioma, whether it arises in cutaneous or non-cutaneous sites, is indolent and perhaps benign with a small capacity for local recurrence.
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Affiliation(s)
| | | | - Armita Bahrami
- Department of Pathology, Emory University School of Medicine, Atlanta, GA, USA
| | | | - Ying S Zou
- Department of Pathology, Johns Hopkins University School of Medicine, 401 N Broadway, Weinberg Building 2245, Baltimore, MD, 21231, USA
| | - Michael Michal
- Department of Pathology, Faculty of Medicine in Plzen, Charles University, Pilsen, Czech Republic
- Bioptical Laboratory, Ltd., Pilsen, Czech Republic
| | - Gregory W Charville
- Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA
| | - John M Gross
- Department of Pathology, Johns Hopkins University School of Medicine, 401 N Broadway, Weinberg Building 2245, Baltimore, MD, 21231, USA.
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Wu R, Lim MS. Updates in pathobiological aspects of anaplastic large cell lymphoma. Front Oncol 2023; 13:1241532. [PMID: 37810974 PMCID: PMC10556522 DOI: 10.3389/fonc.2023.1241532] [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: 06/16/2023] [Accepted: 09/04/2023] [Indexed: 10/10/2023] Open
Abstract
Anaplastic large cell lymphomas (ALCL) encompass several distinct subtypes of mature T-cell neoplasms that are unified by the expression of CD30 and anaplastic cytomorphology. Identification of the cytogenetic abnormality t(2;5)(p23;q35) led to the subclassification of ALCLs into ALK+ ALCL and ALK- ALCL. According to the most recent World Health Organization (WHO) Classification of Haematolymphoid Tumours as well as the International Consensus Classification (ICC) of Mature Lymphoid Neoplasms, ALCLs encompass ALK+ ALCL, ALK- ALCL, and breast implant-associated ALCL (BI-ALCL). Approximately 80% of systemic ALCLs harbor rearrangement of ALK, with NPM1 being the most common partner gene, although many other fusion partner genes have been identified to date. ALK- ALCLs represent a heterogeneous group of lymphomas with distinct clinical, immunophenotypic, and genetic features. A subset harbor recurrent rearrangement of genes, including TYK2, DUSP22, and TP63, with a proportion for which genetic aberrations have yet to be characterized. Although primary cutaneous ALCL (pc-ALCL) is currently classified as a subtype of primary cutaneous T-cell lymphoma, due to the large anaplastic and pleomorphic morphology together with CD30 expression in the malignant cells, this review also discusses the pathobiological features of this disease entity. Genomic and proteomic studies have contributed significant knowledge elucidating novel signaling pathways that are implicated in ALCL pathogenesis and represent candidate targets of therapeutic interventions. This review aims to offer perspectives on recent insights regarding the pathobiological and genetic features of ALCL.
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Affiliation(s)
| | - Megan S. Lim
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, United States
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Chang B, Wang Z, Ren M, Yao Q, Zhao L, Zhou X. A Novel CASC15-ALK and TFG-ROS1 Fusion Observed in Uterine Inflammatory Myofibroblastic Tumor. Int J Gynecol Pathol 2023; 42:451-459. [PMID: 36730016 DOI: 10.1097/pgp.0000000000000926] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
The majority of inflammatory myofibroblastic tumors (IMTs) in the gynecologic tract occur in the uterine corpus and harbor anaplastic lymphoma kinase ( ALK ) rearrangement. Herein, we report 1 uterine IMT case with a novel fusion involving ALK and 1 uterine IMT case with ROS1 rearrangement. The ages of the patients were 56 and 57 yr, respectively. The tumor size was 10.0 and 8.0 cm, respectively. Both patients had stage IB disease. Histologically, the 2 IMT cases had classic morphologic features and predominantly comprised bland spindle cells with hypercellular (fascicular/storiform) and hypocellular (myxoid rich) areas admixed with variably prominent lymphoplasmacytic infiltration. Immunohistochemically, the ALK -rearranged case was positive for ALK , and the ROS1 -rearranged case was positive for ROS1 . Both cases were diffusely positive for desmin. The tumor cells were variably positive for estrogen receptor (1/2 cases, 50.0%) and progesterone receptor (1/2 cases, 50.0%). Targeted RNA sequencing revealed one case each with either a novel CASC15-ALK or TFG-ROS 1 fusion. We identified a novel ALK fusion partner CASC15 in IMT and described the first uterine IMT with a TFG-ROS1 fusion. This study improves our understanding of molecular events in IMT.
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11
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Chen Y, Yuan Y, Chen Y, Jiang X, Hua X, Chen Z, Wang J, Liu H, Zhou Q, Yu Y, Yang Z, Yu Y, Wang Y, Wang Q, Li Y, Chen J, Wang Y. Novel signaling axis of FHOD1-RNF213-Col1α/Col3α in the pathogenesis of hypertension-induced tunica media thickening. J Mol Cell Cardiol 2023; 182:57-72. [PMID: 37482037 DOI: 10.1016/j.yjmcc.2023.07.008] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2023] [Revised: 07/05/2023] [Accepted: 07/15/2023] [Indexed: 07/25/2023]
Abstract
Hypertension-induced tunica media thickening (TMT) is the most important fundamental for the subsequent complications like stroke and cardiovascular diseases. Pathogenically, TMT originates from both vascular smooth muscle cells (VSMCs) hypertrophy due to synthesizing more amount of intracellular contractile proteins and excess secretion of extracellular matrix. However, what key molecules are involved in the pathogenesis of TMT is unknown. We hypothesize that formin homology 2 domain-containing protein 1 (FHOD1), an amply expressed mediator for assembly of thin actin filament in VSMCs, is a key regulator for the pathogenesis of TMT. In this study, we found that FHOD1 expression and its phosphorylation/activation were both upregulated in the arteries of three kinds of hypertensive rats. Ang-II induced actin filament formation and hypertrophy through activation and upregulation of FHOD1 in VSMCs. Active FHOD1-mediated actin filament assembly and secretions of collagen-1α/collagen-3α played crucial roles in Ang-II-induced VSMCs hypertrophy in vitro and hypertensive TMT in vivo. Proteomics demonstrated that activated FL-FHOD1 or its C-terminal diaphanous-autoregulatory domain significantly upregulated RNF213 (ring finger protein 213), a 591-kDa cytosolic E3 ubiquitin ligase with its loss-of-functional mutations being a susceptibility gene for Moyamoya disease which has prominent tunica media thinning in both intracranial and systemic arteries. Mechanistically, activated FHOD1 upregulated its downstream effector RNF213 independently of its classical pathway of decreasing G-actin/F-actin ratio, transcription, and translation, but dependently on its C-terminus-mediated stabilization of RNF213 protein. FHOD1-RNF213 signaling dramatically promoted collagen-1α/collagen-3α syntheses in VSMCs. Our results discovered a novel signaling axis of FHOD1-RNF213-collagen-1α/collagen-3α and its key role in the pathogenesis of hypertensive TMT.
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Affiliation(s)
- Yuanyuan Chen
- Molecular Cardiology Research Laboratory, Department of Cardiology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200092, China
| | - Yuchan Yuan
- Molecular Cardiology Research Laboratory, Department of Cardiology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200092, China
| | - Yuhan Chen
- Molecular Cardiology Research Laboratory, Department of Cardiology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200092, China
| | - Xueze Jiang
- Molecular Cardiology Research Laboratory, Department of Cardiology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200092, China
| | - Xuesheng Hua
- Molecular Cardiology Research Laboratory, Department of Cardiology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200092, China
| | - Zhiyong Chen
- Molecular Cardiology Research Laboratory, Department of Cardiology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200092, China
| | - Julie Wang
- Department of Computer Science, Brown University, Providence, RI 02912, USA
| | - Hua Liu
- Department of Intensive Care Med, Zhongshan Hospital of Fudan University, Shanghai 200032, China
| | - Qing Zhou
- Molecular Cardiology Research Laboratory, Department of Cardiology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200092, China
| | - Ying Yu
- Molecular Cardiology Research Laboratory, Department of Cardiology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200092, China
| | - Zhenwei Yang
- Molecular Cardiology Research Laboratory, Department of Cardiology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200092, China
| | - Yi Yu
- Molecular Cardiology Research Laboratory, Department of Cardiology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200092, China
| | - Yongqin Wang
- Division of Rheumatology and Immunology, University of Toledo Medical center, 3120 Glendale Avenue, Toledo, OH 43614, USA
| | - Qunshan Wang
- Molecular Cardiology Research Laboratory, Department of Cardiology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200092, China
| | - Yigang Li
- Molecular Cardiology Research Laboratory, Department of Cardiology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200092, China
| | - Jie Chen
- Molecular Cardiology Research Laboratory, Department of Cardiology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200092, China.
| | - Yuepeng Wang
- Molecular Cardiology Research Laboratory, Department of Cardiology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200092, China.
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12
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Cordier F, Hoorens A, Ferdinande L, Van Dorpe J, Creytens D. Inflammatory myofibroblastic tumor of the distal common bile duct: Literature review with focus on pathological examination. World J Clin Cases 2023; 11:4734-4739. [PMID: 37584005 PMCID: PMC10424039 DOI: 10.12998/wjcc.v11.i20.4734] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/17/2023] [Revised: 05/31/2023] [Accepted: 06/26/2023] [Indexed: 07/06/2023] Open
Abstract
Inflammatory myofibroblastic tumor (IMT) of the biliary tract is rare, and often difficult to diagnose or to distinguish from other tumors due to its atypical clinical presentation and nonspecific radiological features. Histologically, IMTs are (myo)fibroblastic neoplasms with a prominent inflammatory infiltrate. They are characterized by receptor tyrosine kinase gene rearrangements, most often involving an anaplastic lymphoma kinase (ALK) translocation. The final diagnosis of IMT depends on histopathology and immunohistochemical examination. In this manuscript, we provide a clinical and morphomolecular overview of IMT and the difficulties that may arise in using immunohistochemical and molecular techniques in diagnosing IMT.
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Affiliation(s)
- Fleur Cordier
- Department of Pathology, Ghent University Hospital, Ghent 9000, Belgium
| | - Anne Hoorens
- Department of Pathology, Ghent University Hospital, Ghent 9000, Belgium
| | | | - Jo Van Dorpe
- Department of Pathology, Ghent University Hospital, Ghent 9000, Belgium
| | - David Creytens
- Department of Pathology, Ghent University Hospital, Ghent 9000, Belgium
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13
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Drieux F, Lemonnier F, Gaulard P. How molecular advances may improve the diagnosis and management of PTCL patients. Front Oncol 2023; 13:1202964. [PMID: 37427095 PMCID: PMC10328093 DOI: 10.3389/fonc.2023.1202964] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2023] [Accepted: 05/22/2023] [Indexed: 07/11/2023] Open
Abstract
Peripheral T-cell lymphomas (PTCL) comprised more than 30 rare heterogeneous entities, representing 10 to 15% of adult non-Hodgkin lymphomas. Although their diagnosis is still mainly based on clinical, pathological, and phenotypic features, molecular studies have allowed for a better understanding of the oncogenic mechanisms involved and the refinement of many PTCL entities in the recently updated classifications. The prognosis remains poor for most entities (5-year overall survival < 30%), with current conventional therapies based on anthracyclin-based polychemotherapy regimen, despite many years of clinical trials. The recent use of new targeted therapies appears to be promising for relapsed/refractory patients, such as demethylating agents in T-follicular helper (TFH) PTCL. However further studies are needed to evaluate the proper combination of these drugs in the setting of front-line therapy. In this review, we will summarize the oncogenic events for the main PTCL entities and report the molecular targets that have led to the development of new therapies. We will also discuss the development of innovative high throughput technologies that aid the routine workflow for the histopathological diagnosis and management of PTCL patients.
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Affiliation(s)
- Fanny Drieux
- Service d’Anatomie et de Cytologie Pathologiques, INSERM U1245, Centre Henri Becquerel, Rouen, France
| | - François Lemonnier
- Unité hémopathies Lymphoïdes, Hôpitaux Universitaires Henri Mondor, Assistance Publique des Hôpitaux de Paris, Créteil, France
- Institut Mondor de Recherche Biomédicale, INSERM U955, Université Paris Est Créteil, Créteil, France
| | - Philippe Gaulard
- Institut Mondor de Recherche Biomédicale, INSERM U955, Université Paris Est Créteil, Créteil, France
- Département de Pathologie, Hôpitaux Universitaires Henri Mondor, Assistance Publique des Hôpitaux de Paris, Créteil, France
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14
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Yu Y, Wang Z, Wang L, Wang Q, Tang R, Xiang S, Deng Q, Hou T, Sun H. Deciphering the Shared and Specific Drug Resistance Mechanisms of Anaplastic Lymphoma Kinase via Binding Free Energy Computation. RESEARCH (WASHINGTON, D.C.) 2023; 6:0170. [PMID: 37342628 PMCID: PMC10278961 DOI: 10.34133/research.0170] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 04/27/2023] [Accepted: 05/25/2023] [Indexed: 06/23/2023]
Abstract
Anaplastic lymphoma kinase (ALK), a tyrosine receptor kinase, has been proven to be associated with the occurrence of numerous malignancies. Although there have been already at least 3 generations of ALK inhibitors approved by FDA or in clinical trials, the occurrence of various mutations seriously attenuates the effectiveness of the drugs. Unfortunately, most of the drug resistance mechanisms still remain obscure. Therefore, it is necessary to reveal the bottom reasons of the drug resistance mechanisms caused by the mutations. In this work, on the basis of verifying the accuracy of 2 main kinds of binding free energy calculation methodologies [end-point method of Molecular Mechanics with Poisson-Boltzmann/Generalized Born and Surface Area (MM/PB(GB)SA) and alchemical method of Thermodynamic Integration (TI)], we performed a systematic analysis on the ALK systems to explore the underlying shared and specific drug resistance mechanisms, covering the one-drug-multiple-mutation and multiple-drug-one-mutation cases. Through conventional molecular dynamics (cMD) simulation in conjunction with MM/PB(GB)SA and umbrella sampling (US) in conjunction with contact network analysis (CNA), the resistance mechanisms of the in-pocket, out-pocket, and multiple-site mutations were revealed. Especially for the out-pocket mutation, a possible transfer chain of the mutation effect was revealed, and the reason why different drugs exhibited various sensitivities to the same mutation was also uncovered. The proposed mechanisms may be prevalent in various drug resistance cases.
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Affiliation(s)
- Yang Yu
- Department of Medicinal Chemistry,
China Pharmaceutical University, Nanjing 210009, Jiangsu, P. R. China
| | - Zhe Wang
- Innovation Institute for Artificial Intelligence in Medicine ofZhejiang University, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, Zhejiang, P. R. China
| | - Lingling Wang
- Department of Medicinal Chemistry,
China Pharmaceutical University, Nanjing 210009, Jiangsu, P. R. China
| | - Qinghua Wang
- Department of Medicinal Chemistry,
China Pharmaceutical University, Nanjing 210009, Jiangsu, P. R. China
| | - Rongfan Tang
- Department of Medicinal Chemistry,
China Pharmaceutical University, Nanjing 210009, Jiangsu, P. R. China
| | - Sutong Xiang
- Department of Medicinal Chemistry,
China Pharmaceutical University, Nanjing 210009, Jiangsu, P. R. China
| | - Qirui Deng
- Department of Medicinal Chemistry,
China Pharmaceutical University, Nanjing 210009, Jiangsu, P. R. China
| | - Tingjun Hou
- Innovation Institute for Artificial Intelligence in Medicine ofZhejiang University, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, Zhejiang, P. R. China
| | - Huiyong Sun
- Department of Medicinal Chemistry,
China Pharmaceutical University, Nanjing 210009, Jiangsu, P. R. China
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15
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Epithelioid Fibrous Histiocytoma with CARS-ALK Fusion: First Case Report. Dermatopathology (Basel) 2023; 10:25-29. [PMID: 36648781 PMCID: PMC9844486 DOI: 10.3390/dermatopathology10010003] [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: 08/02/2022] [Revised: 12/19/2022] [Accepted: 12/27/2022] [Indexed: 01/06/2023] Open
Abstract
Epithelioid fibrous histiocytoma (EFH) is a type of uncommon skin tumor mostly harboring Anaplastic Lymphoma Kinase (ALK) gene rearrangement, with different fusion partners reported. Whether this tumor is a separate entity or has a relationship with conventional fibrous histiocytomas is still a matter of debate. Benign course is the rule after complete surgical excision. A rare subtype of EFH with fusiform cells has been described, with specific fusion partners. Inflammatory myofibroblastic tumor (IMT) is a type of soft tissue tumor rarer than EFH, and it can display distant metastases. Some cases of primary cutaneous IMT included two with Cysteinyl-tRNA Synthetase 1 (CARS)-ALK rearrangement. IMT can have the same fusion partners as EFH, such as DCTN1, TMP3 or EML4 genes. We report the case of a 42-year-old woman presenting EFH with fusiform morphology harboring CARS-ALK fusion and discuss similarities and differences with IMT.
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16
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Qiu YF, Song LH, Jiang GL, Zhang Z, Liu XY, Wang G. Hallmarks of Anaplastic Lymphoma Kinase Inhibitors with Its Quick Emergence of Drug Resistance. PHARMACEUTICAL FRONTS 2022. [DOI: 10.1055/s-0042-1758542] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Anaplastic lymphoma kinase (ALK) is one of the most popular targets for anticancer therapies. In the past decade, the use of anaplastic lymphoma tyrosine kinase inhibitors (ALK-TKIs), including crizotinib and ceritinib, has been a reliable and standard options for patients with lung cancer, particularly for patients with nonsmall cell lung carcinoma. ALK-targeted therapies initially benefit the patients, yet, resistance eventually occurs. Therefore, resistance mechanisms of ALK-TKIs and the solutions have become a formidable challenge in the development of ALK inhibitors. In this review, based on the knowledge of reported ALK inhibitors, we illustrated the crystal structures of ALK, summarized the resistance mechanisms of ALK-targeted drugs, and proposed potential therapeutic strategies to prevent or overcome the resistance.
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Affiliation(s)
- Yong-Fu Qiu
- Novel Technology Center of Pharmaceutical Chemistry, Shanghai Institute of Pharmaceutical Industry, Co., Ltd., China State Institute of Pharmaceutical Industry, Shanghai, People's Republic of China
| | - Lian-Hua Song
- Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, Zhejiang University of Technology, Hangzhou, People's Republic of China
| | - Gang-Long Jiang
- Novel Technology Center of Pharmaceutical Chemistry, Shanghai Institute of Pharmaceutical Industry, Co., Ltd., China State Institute of Pharmaceutical Industry, Shanghai, People's Republic of China
| | - Zhen Zhang
- Novel Technology Center of Pharmaceutical Chemistry, Shanghai Institute of Pharmaceutical Industry, Co., Ltd., China State Institute of Pharmaceutical Industry, Shanghai, People's Republic of China
- School of Chemistry and Chemical Engineering, Shanghai University of Engineering Science, Shanghai, People's Republic of China
| | - Xu-Yan Liu
- Novel Technology Center of Pharmaceutical Chemistry, Shanghai Institute of Pharmaceutical Industry, Co., Ltd., China State Institute of Pharmaceutical Industry, Shanghai, People's Republic of China
| | - Guan Wang
- Novel Technology Center of Pharmaceutical Chemistry, Shanghai Institute of Pharmaceutical Industry, Co., Ltd., China State Institute of Pharmaceutical Industry, Shanghai, People's Republic of China
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17
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Functional and pathologic association of aminoacyl-tRNA synthetases with cancer. Exp Mol Med 2022; 54:553-566. [PMID: 35501376 PMCID: PMC9166799 DOI: 10.1038/s12276-022-00765-5] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2021] [Revised: 12/21/2021] [Accepted: 12/30/2021] [Indexed: 11/26/2022] Open
Abstract
Although key tumorigenic and tumor-suppressive factors have been unveiled over the last several decades, cancer remains the most life-threatening disease. Multiomic analyses of patient samples and an in-depth understanding of tumorigenic processes have rapidly revealed unexpected pathologic associations of new cellular factors previously overlooked in cancer biology. In this regard, the newly discovered activities of human aminoacyl-tRNA synthases (ARSs) deserve attention not only for their pathological significance in tumorigenesis but also regarding diagnostic and therapeutic implications. ARSs are not only essential enzymes covalently linking substrate amino acids to cognate tRNAs for protein synthesis but also function as regulators of cellular processes by sensing different cellular conditions. With their catalytic role in protein synthesis and their regulatory role in homeostasis, functional alterations or dysregulation of ARSs might be pathologically associated with tumorigenesis. This review focuses on the potential implications of ARS genes and proteins in different aspects of cancer based on various bioinformatic analyses and experimental data. We also review their diverse activities involving extracellular secretion, protein–protein interactions, and amino acid sensing, which are related to cancers. The newly discovered cancer-related activities of ARSs are expected to provide new opportunities for detecting, preventing and curing cancers. Enzymes called aminoacyl-tRNA synthetases (ARSs), which play a central role in all life, are becoming implicated in several aspects of cancer in ways that may lead to new approaches for prevention, detection and treatment. ARS enzymes catalyse the ligation of amino acids to transfer RNA molecules to allow amino acids to combine in the correct sequences to form proteins. Jung Min Han, Sunghoon Kim and colleagues at Yonsei University, Incheon, South Korea, review researches implicating ARS enzymes and the genes that code for them in a variety of cancers. The behavior of ARS enzymes and their genes are found to be altered in several types of cancer cells in ways that may either initiate or support the onset and development of the disease, through which they could be suggested as targets for novel anti-cancer drugs.
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18
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Lanic MD, Le Loarer F, Rainville V, Sater V, Viennot M, Beaussire L, Viailly PJ, Angot E, Hostein I, Jardin F, Ruminy P, Laé M. Detection of sarcoma fusions by a next-generation sequencing based-ligation-dependent multiplex RT-PCR assay. Mod Pathol 2022; 35:649-663. [PMID: 35075283 DOI: 10.1038/s41379-021-00980-x] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2021] [Revised: 11/18/2021] [Accepted: 11/19/2021] [Indexed: 11/09/2022]
Abstract
Morphological, immunohistochemical, and molecular methods often need to be combined for accurate diagnosis and optimal clinical management of sarcomas. Here, we have developed, a new molecular diagnostic assay, for the detection of gene fusions in sarcomas. This targeted multiplexed next-generation sequencing (NGS)-based method utilizes ligation dependent reverse-transcriptase polymerase chain reaction (LD-RT-PCR-NGS) to detect oncogenic fusion transcripts involving 137 genes, leading to 139 gene fusions known to be recurrently rearranged in soft-tissue and bone tumors. 158 bone and soft-tissue tumors with previously identified fusion genes by fluorescent in situ hybridization (FISH) or RT-PCR were selected to test the specificity and the sensitivity of this assay. RNA were extracted from formalin-fixed paraffin-embedded (n = 143) or frozen (n = 15) material (specimen; n = 42 or core needle biopsies; n = 116). Tested tumors encompassed 23 major translocation-related sarcomas types, including Ewing and Ewing-like sarcomas, rhabdomyosarcomas, desmoplastic small round-cell tumors, clear-cell sarcomas, infantile fibrosarcomas, endometrial stromal sarcomas, epithelioid hemangioendotheliomas, alveolar soft-part sarcomas, biphenotypic sinonasal sarcomas, extraskeletal myxoid chondrosarcomas, myxoid/round-cell liposarcomas, dermatofibrosarcomas protuberans and solitary fibrous tumors. In-frame fusion transcripts were detected in 98.1% of cases (155/158). Gene fusion assay results correlated with conventional techniques (FISH and RT-PCR) in 155/158 tumors (98.1%). These data demonstrate that this assay is a rapid, robust, highly sensitive, and multiplexed targeted RNA sequencing assay for the detection of recurrent gene fusions on RNA extracted from routine clinical specimens of sarcomas (formalin-fixed paraffin-embedded or frozen). It facilitates the precise diagnosis and identification of tumors with potential targetable fusions. In addition, this assay can be easily customized to cover new fusions.
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Affiliation(s)
- Marie-Delphine Lanic
- INSERM U1245, Cancer Center Henri Becquerel, Institute of Research and Innovation in Biomedicine (IRIB), University of Normandy, UNIROUEN, Rouen, France
| | - François Le Loarer
- Department of Pathology, Institut Bergonié, cours de l'Argonne, 33000, Bordeaux, France
| | - Vinciane Rainville
- INSERM U1245, Cancer Center Henri Becquerel, Institute of Research and Innovation in Biomedicine (IRIB), University of Normandy, UNIROUEN, Rouen, France
| | - Vincent Sater
- INSERM U1245, Cancer Center Henri Becquerel, Institute of Research and Innovation in Biomedicine (IRIB), University of Normandy, UNIROUEN, Rouen, France
| | - Mathieu Viennot
- INSERM U1245, Cancer Center Henri Becquerel, Institute of Research and Innovation in Biomedicine (IRIB), University of Normandy, UNIROUEN, Rouen, France
| | - Ludivine Beaussire
- INSERM U1245, Cancer Center Henri Becquerel, Institute of Research and Innovation in Biomedicine (IRIB), University of Normandy, UNIROUEN, Rouen, France.,Department of Pathology, Centre Henri Becquerel, rue d'Amiens, 76038, Rouen, France
| | - Pierre-Julien Viailly
- INSERM U1245, Cancer Center Henri Becquerel, Institute of Research and Innovation in Biomedicine (IRIB), University of Normandy, UNIROUEN, Rouen, France
| | - Emilie Angot
- Department of Pathology, Rouen University Hospital, 76031, Rouen, France
| | - Isabelle Hostein
- Department of Pathology, Institut Bergonié, cours de l'Argonne, 33000, Bordeaux, France
| | - Fabrice Jardin
- INSERM U1245, Cancer Center Henri Becquerel, Institute of Research and Innovation in Biomedicine (IRIB), University of Normandy, UNIROUEN, Rouen, France
| | - Philippe Ruminy
- INSERM U1245, Cancer Center Henri Becquerel, Institute of Research and Innovation in Biomedicine (IRIB), University of Normandy, UNIROUEN, Rouen, France.
| | - Marick Laé
- INSERM U1245, Cancer Center Henri Becquerel, Institute of Research and Innovation in Biomedicine (IRIB), University of Normandy, UNIROUEN, Rouen, France. .,Department of Pathology, Centre Henri Becquerel, rue d'Amiens, 76038, Rouen, France.
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19
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Anaplastic Large Cell Lymphoma: Molecular Pathogenesis and Treatment. Cancers (Basel) 2022; 14:cancers14071650. [PMID: 35406421 PMCID: PMC8997054 DOI: 10.3390/cancers14071650] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2022] [Revised: 03/18/2022] [Accepted: 03/21/2022] [Indexed: 11/25/2022] Open
Abstract
Simple Summary Anaplastic large cell lymphoma is a rare type of disease that occurs throughout the world and has four subtypes. A summary and comparison of these subtypes can assist with advancing our knowledge of the mechanism and treatment of ALCL, which is helpful in making progress in this field. Abstract Anaplastic large cell lymphoma (ALCL) is an uncommon type of non-Hodgkin’s lymphoma (NHL), as well as one of the subtypes of T cell lymphoma, accounting for 1 to 3% of non-Hodgkin’s lymphomas and around 15% of T cell lymphomas. In 2016, the World Health Organization (WHO) classified anaplastic large cell lymphoma into four categories: ALK-positive ALCL (ALK+ALCL), ALK-negative ALCL (ALK−ALCL), primary cutaneous ALCL (pcALCL), and breast-implant-associated ALCL (BIA-ALCL), respectively. Clinical symptoms, gene changes, prognoses, and therapy differ among the four types. Large lymphoid cells with copious cytoplasm and pleomorphic characteristics with horseshoe-shaped or reniform nuclei, for example, are found in both ALK+ and ALK−ALCL. However, their epidemiology and pathogenetic origins are distinct. BIA-ALCL is currently recognized as a new provisional entity, which is a noninvasive disease with favorable results. In this review, we focus on molecular pathogenesis and management of anaplastic large cell lymphoma.
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20
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Georgantzoglou N, Green D, Winnick KN, Sumegi J, Charville GW, Bridge JA, Linos K. Molecular investigation of
ALK
‐rearranged epithelioid fibrous histiocytomas identifies
CLTC
as a novel fusion partner and evidence of fusion‐independent transcription activation. Genes Chromosomes Cancer 2022; 61:471-480. [DOI: 10.1002/gcc.23038] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2022] [Revised: 03/09/2022] [Accepted: 03/10/2022] [Indexed: 11/07/2022] Open
Affiliation(s)
- Natalia Georgantzoglou
- Department of Pathology and Laboratory Medicine Dartmouth Hitchcock Medical Center Lebanon New Hampshire USA
| | - Donald Green
- Department of Pathology and Laboratory Medicine Dartmouth Hitchcock Medical Center Lebanon New Hampshire USA
| | - Kimberly N. Winnick
- Department of Pathology and Laboratory Medicine Dartmouth Hitchcock Medical Center Lebanon New Hampshire USA
| | - Janos Sumegi
- Division of Molecular Diagnostics ProPath Dallas Texas USA
| | - Gregory W. Charville
- Stanford University School of Medicine Department of Pathology Stanford California USA
| | - Julia A. Bridge
- Division of Molecular Diagnostics ProPath Dallas Texas USA
- Departments of Pathology/Microbiology and Orthopaedic Surgery University of Nebraska Medical Center Omaha Nebraska USA
| | - Konstantinos Linos
- Department of Pathology and Laboratory Medicine Dartmouth Hitchcock Medical Center Lebanon New Hampshire USA
- Geisel School of Medicine at Dartmouth New Hampshire USA
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21
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A G H, Kumar S, Singla S, Kurian N. Aggressive Inflammatory Myofibroblastic Tumor of Distal Pancreas: A Diagnostic and Surgical Challenge. Cureus 2022; 14:e22820. [PMID: 35399449 PMCID: PMC8980218 DOI: 10.7759/cureus.22820] [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] [Accepted: 03/03/2022] [Indexed: 11/05/2022] Open
Abstract
An inflammatory myofibroblastic tumor (IMT) is a rare soft tissue neoplasm of unknown etiology. It is a slow-growing tumor of borderline malignant potential. Distant metastases and recurrence after complete excision are rare. Establishing a preoperative diagnosis is difficult because of its nonspecific clinic-radiological features. Although the majority of cases have been reported in the lungs, it can affect any part of the body. The pancreatic inflammatory myofibroblastic tumor is very rare and only 26 cases have been reported in the medical literature. These tumors mostly arise from the head of the pancreas, whereas occurrence in the body or tail region is rather unusual. Here, we report a case of a 55-year-old male patient with a locally advanced inflammatory myofibroblastic tumor arising from the pancreatic tail. Complete excision of tumor required multi-visceral resection (distal pancreaticosplenectomy with jejunal and colonic segmental resection). The diagnosis of inflammatory myofibroblast tumor was made on the basis of histopathology and immunohistochemistry.
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22
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Han Q, He X, Cui L, Qiu Y, Li Y, Chen H, Zhang H. Case Report: Early Distant Metastatic Inflammatory Myofibroblastic Tumor Harboring EML4-ALK Fusion Gene: Study of Two Typical Cases and Review of Literature. Front Med (Lausanne) 2022; 9:826705. [PMID: 35280868 PMCID: PMC8907662 DOI: 10.3389/fmed.2022.826705] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2021] [Accepted: 01/24/2022] [Indexed: 11/13/2022] Open
Abstract
Inflammatory myofibroblastic tumor (IMT) is a distinctive neoplasm that frequently arises in the lung and accounts for ~1% of lung tumors. Distant metastatic IMT is extremely rare and has been poorly investigated. This analysis was specifically performed to explore the clinicopathological and genetic features of early distant metastatic IMT. Two typical patients with distant metastatic IMTs were selected, which accounted for 1.13% of all diagnosed IMTs in the last 5 years. One patient was a 55 year-old male, and the other patient was a 56 year-old female. Both primary tumors arose from the lung, and the initial clinical symptoms of the two patients involved coughing. Both of the imaging examinations showed low-density nodular shadows in the lungs with enhancement around the mass. Microscopically, dense arranged tumor cells, prominent cellular atypia, and high mitotic activity with atypical form were more prominent in the metastatic lesions than in the primary lesions. All of the primary and metastatic tumors in both cases showed positive anaplastic lymphoma kinase (ALK) immunostaining and ALK rearrangement via fluorescence in situ hybridization. The EML4 (exon 6)-ALK (exon 20) fusion variant (v3a/b) was identified by using next-generation sequencing (NGS) and was verified by using reverse transcription polymerase chain reaction (RT-PCR). Furthermore, intronic variants of NOTCH1 and synonymous variants of ARAF were also detected via NGS in one IMT for the first time and were verified in all of the primary and metastatic lesions via PCR. Distant metastasis occurred during a short period of time (1 and 2 months) after the first surgery. One patient presented with multiple metastases to the subcutaneous tissue and bone that responded to ALK inhibitor alectinib therapy, and the tumor was observed to regress 10 months after the initial ALK inhibitor therapy. In contrast, the other patient presented with subcutaneous neck metastasis without ALK inhibitor treatment and succumbed to the disease within 3 months after the surgery. This study demonstrated the possible role of EML4-ALKv3a/b in the malignant progression of IMT and proposed certain therapeutic effects of ALK inhibitors on multiple metastatic IMTs.
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Affiliation(s)
- Qianqian Han
- Department of Pathology, West China Hospital, Sichuan University, Chengdu, China
| | - Xin He
- Department of Pathology, West China Hospital, Sichuan University, Chengdu, China
| | - Lijuan Cui
- Department of Pathology, Suining Central Hospital, Suining, China
| | - Yan Qiu
- Department of Pathology, West China Hospital, Sichuan University, Chengdu, China
| | - Yuli Li
- Department of Pathology, West China Hospital, Sichuan University, Chengdu, China
| | - Huijiao Chen
- Department of Pathology, West China Hospital, Sichuan University, Chengdu, China
| | - Hongying Zhang
- Department of Pathology, West China Hospital, Sichuan University, Chengdu, China
- *Correspondence: Hongying Zhang
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23
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Rakheja D, Park JY, Fernandes NJ, Watt TC, Laetsch TW, Collins RRJ. Pediatric Non-Myofibroblastic Primitive Spindle Cell Tumors with ALK Gene Rearrangements and Response to Crizotinib. Int J Surg Pathol 2022; 30:706-715. [PMID: 35164578 DOI: 10.1177/10668969221080072] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
We describe two poorly differentiated, non-myofibroblastic (SMA-, S100+, CD34±), spindle cell neoplasms with immunohistochemical positivity for ALK and with ALK gene rearrangements leading to PLEKHH2::ALK and CLTC::ALK fusions, respectively. ALK protein overexpression and/or gene fusions should be evaluated in poorly differentiated spindle cell neoplasms, even when there is an absence of a myofibroblastic phenotype. A positive ALK evaluation has therapeutic implications as both tumors responded to single-agent treatment with the tyrosine kinase inhibitor crizotinib.
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Affiliation(s)
- Dinesh Rakheja
- Department of Pathology, 12334University of Texas Southwestern Medical Center, Dallas, TX, USA.,Children's Health, Dallas, TX, USA
| | - Jason Y Park
- Department of Pathology, 12334University of Texas Southwestern Medical Center, Dallas, TX, USA.,Children's Health, Dallas, TX, USA
| | - Neil J Fernandes
- Children's Health, Dallas, TX, USA.,Department of Radiology, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Tanya C Watt
- Children's Health, Dallas, TX, USA.,Division of Pediatric Hematology/Oncology, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Theodore W Laetsch
- Division of Oncology, 6567Children's Hospital of Philadelphia and Perelman School of Medicine and Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA
| | - Rebecca R J Collins
- Department of Pathology, 12334University of Texas Southwestern Medical Center, Dallas, TX, USA.,Children's Health, Dallas, TX, USA
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24
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Kerr DA, Thompson LDR, Tafe LJ, Jo VY, Neyaz A, Divakar P, Paydarfar JA, Pastel DA, Shirai K, John I, Seethala RR, Salgado CM, Deshpande V, Bridge JA, Kashofer K, Brčić I, Linos K. Clinicopathologic and Genomic Characterization of Inflammatory Myofibroblastic Tumors of the Head and Neck: Highlighting a Novel Fusion and Potential Diagnostic Pitfall. Am J Surg Pathol 2021; 45:1707-1719. [PMID: 34001695 DOI: 10.1097/pas.0000000000001735] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Inflammatory myofibroblastic tumor (IMT) is a distinctive fibroblastic and myofibroblastic spindle cell neoplasm with an accompanying inflammatory cell infiltrate and frequent receptor tyrosine kinase activation at the molecular level. The tumor may recur and rarely metastasizes. IMT is rare in the head and neck region, and limited information is available about its clinicopathologic and molecular characteristics in these subsites. Therefore, we analyzed a cohort of head and neck IMTs through a multi-institutional approach. Fourteen cases were included in the provisional cohort, but 1 was excluded after molecular analysis prompted reclassification. Patients in the final cohort included 7 males and 6 females, with a mean age of 26.5 years. Tumors were located in the larynx (n=7), oral cavity (n=3), pharynx (n=2), and mastoid (n=1). Histologically, all tumors showed neoplastic spindle cells in storiform to fascicular patterns with associated chronic inflammation, but the morphologic spectrum was wide, as is characteristic of IMT in other sites. An underlying fusion gene event was identified in 92% (n=11/12) of cases and an additional case was ALK-positive by IHC but could not be evaluated molecularly. ALK represented the driver in all but 1 case. Rearrangement of ALK, fused with the TIMP3 gene (n=6) was most commonly detected, followed by 1 case each of the following fusion gene partnerships: TPM3-ALK, KIF5B-ALK, CARS-ALK, THBS1-ALK, and a novel alteration, SLC12A2-ROS1. The excluded case was reclassified as spindle cell rhabdomyosarcoma after detection of a FUS-TFCP2 rearrangement and retrospective immunohistochemical confirmation of rhabdomyoblastic differentiation, illustrating an important diagnostic pitfall. Two IMT patients received targeted therapy with crizotinib, with a demonstrated radiographic response. One tumor recurred but none metastasized. These results add to the growing body of evidence that kinase fusions can be identified in the majority of IMTs and that molecular analysis can lead to increased diagnostic accuracy and broadened therapeutic options for patients.
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Affiliation(s)
- Darcy A Kerr
- Departments of Pathology and Laboratory Medicine
- Geisel School of Medicine at Dartmouth, Hanover, NH
| | - Lester D R Thompson
- Department of Pathology, Southern California Permanente Medical Group, Woodland Hills, CA
| | - Laura J Tafe
- Departments of Pathology and Laboratory Medicine
- Geisel School of Medicine at Dartmouth, Hanover, NH
| | - Vickie Y Jo
- Department of Pathology, Brigham and Women's Hospital and Harvard Medical School
| | - Azfar Neyaz
- Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA
| | | | - Joseph A Paydarfar
- Section of Otolaryngology, Dartmouth-Hitchcock Medical Center, Lebanon
- Geisel School of Medicine at Dartmouth, Hanover, NH
| | - David A Pastel
- Radiology
- Geisel School of Medicine at Dartmouth, Hanover, NH
| | - Keisuke Shirai
- Medical Oncology
- Geisel School of Medicine at Dartmouth, Hanover, NH
| | - Ivy John
- Department of Pathology, University of Pittsburgh
| | | | - Claudia M Salgado
- Department of Pathology, Children's Hospital of Pittsburgh, Pittsburgh, PA
| | - Vikram Deshpande
- Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA
| | - Julia A Bridge
- Molecular Division, ProPath LLC, Dallas, TX
- Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE
| | - Karl Kashofer
- Diagnostic and Research Institute of Pathology, Medical University of Graz, Graz, Austria
| | - Iva Brčić
- Diagnostic and Research Institute of Pathology, Medical University of Graz, Graz, Austria
| | - Konstantinos Linos
- Departments of Pathology and Laboratory Medicine
- Geisel School of Medicine at Dartmouth, Hanover, NH
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25
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Tan SY, Al-Ibraheemi A, Ahrens WA, Oesterheld JE, Fanburg-Smith JC, Liu YJ, Spunt SL, Rudzinski ER, Coffin C, Davis JL. ALK rearrangements in infantile fibrosarcoma-like spindle cell tumours of soft tissue and kidney. Histopathology 2021; 80:698-707. [PMID: 34843129 DOI: 10.1111/his.14603] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2021] [Revised: 11/23/2021] [Accepted: 11/24/2021] [Indexed: 12/11/2022]
Abstract
AIMS Recurrent alterations in receptor tyrosine kinase (RTK) and downstream effectors are described in infantile fibrosarcoma (IFS)/cellular congenital mesoblastic nephroma (cCMN) and a subset of spindle cell sarcomas, provisionally designated 'NTRK-rearranged' spindle cell neoplasms. These two groups of tumours demonstrate overlapping morphologies and harbour alterations in NTRK1/2/3, RET, MET, ABL1, ROS1, RAF1 and BRAF, although their relationship is not fully elucidated. We describe herein a cohort of paediatric tumours with clinicopathological features not typical for inflammatory myofibroblastic tumour, but rather with similarities to cCMN/IFS harbouring ALK fusions. METHODS AND RESULTS Clinicopathological features were assessed and partner agnostic targeted RNA sequencing on clinically validated platforms were performed. Tumours occurred in patients aged from 2 to 10 years (median age 2 years) with a 2:2 male to female ratio and an average size of 8.4 cm. Two tumours arose in soft tissues and two in the kidney. Morphological features included spindle to ovoid cells arranged in long fascicles or haphazardly within a myxoid to collagenised stroma; a subset of cases had either dilated, ectatic vessels or focal perivascular hyalinosis. By immunohistochemistry, all cases tested showed cytoplasmic expression of anaplastic lymphoma kinase (ALK) and one case demonstrated co-expression of CD34 and S100. CONCLUSIONS This series of ALK-rearranged IFS-like tumours expands the spectrum of targetable kinases altered in these tumours and reinforces the potential overlap between IFS/cCMN-like tumours and the provisional entity of 'NTRK-rearranged' spindle cell neoplasms.
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Affiliation(s)
- Serena Y Tan
- Department of Pathology, Stanford University School of Medicine, Palo Alto, CA, USA
| | - Alyaa Al-Ibraheemi
- Department of Pathology, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA
| | | | - Javier E Oesterheld
- Department of Pediatrics, Levine Children's Hospital, Atrium Health, Charlotte, NC, USA
| | - Julie C Fanburg-Smith
- Department of Pathology, Pediatrics and Orthopedics, PennState Health, Penn State Children's Hospital, Penn State College of Medicine, Hershey, PA, USA
| | - Yajuan J Liu
- Department of Laboratory Medicine and Pathology, University of Washington School of Medicine, Seattle, WA, USA
| | - Sheri L Spunt
- Department of Pediatrics, Stanford University School of Medicine, Palo Alto, CA, USA
| | - Erin R Rudzinski
- Department of Laboratories, Seattle Children's Hospital, Seattle, WA, USA
| | - Cheryl Coffin
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, TN, USA
| | - Jessica L Davis
- Department of Pathology, Oregon Health & Sciences University, Portland, OR, USA
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26
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Qiu L, Cho JH, Jelloul FZ, Vega F. SOHO State of the Art Updates and Next Questions: Pathology and Pathogenesis of Nodal Peripheral T-Cell Lymphomas. CLINICAL LYMPHOMA MYELOMA & LEUKEMIA 2021; 22:287-296. [PMID: 34776400 DOI: 10.1016/j.clml.2021.10.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/07/2021] [Revised: 09/30/2021] [Accepted: 10/09/2021] [Indexed: 10/20/2022]
Abstract
Peripheral T-cell lymphomas (PTCLs) are a heterogeneous and often clinically aggressive group of neoplasms derived from mature post-thymic T-lymphocytes. These neoplasms are rare and usually diagnostically challenging. Our understanding of the pathogenesis of PTCL is increasing and this improved knowledge is leading us to better molecular characterization, more objective and accurate diagnostic criteria, more effective risk assessment, and potentially better treatments. The focus of this paper is to present a brief overview of the current pathology criteria and molecular and genetic features of nodal peripheral T-cell lymphomas focusing on distinct genetically and molecularly defined subgroups that are being recognized within each major nodal PTCL category. It is expected that the molecular stratification will improve the diagnosis and will provide novel therapeutic opportunities (biomarker-driven and targeted therapies) that might benefit and change the outcomes of patients with these neoplasms.
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Affiliation(s)
- Lianqun Qiu
- Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Jeong Hee Cho
- Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Fatima Zahra Jelloul
- Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Francisco Vega
- Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, Texas; UT Health Graduate School of Biomedical Sciences, Houston, Texas.
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27
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Schöffski P, Kubickova M, Wozniak A, Blay JY, Strauss SJ, Stacchiotti S, Switaj T, Bücklein V, Leahy MG, Italiano A, Isambert N, Debiec-Rychter M, Sciot R, Lee CJ, Speetjens FM, Nzokirantevye A, Neven A, Kasper B. Long-term efficacy update of crizotinib in patients with advanced, inoperable inflammatory myofibroblastic tumour from EORTC trial 90101 CREATE. Eur J Cancer 2021; 156:12-23. [PMID: 34392187 DOI: 10.1016/j.ejca.2021.07.016] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2021] [Accepted: 07/10/2021] [Indexed: 01/26/2023]
Abstract
PURPOSE European Organisation for Research and Treatment of Cancer (EORTC) 90101 (CREATE) was a prospective, multicentric, non-randomised, open-label phase II basket trial to assess the efficacy and safety of crizotinib in patients with different types of cancers, including advanced inflammatory myofibroblastic tumour (IMT) with or without anaplastic lymphoma kinase (ALK) rearrangements. Here, we report updated results with long-term follow-up. PATIENTS/METHODS After central reference pathology, eligible ALK-positive and ALK-negative patients with advanced/metastatic IMT deemed incurable with surgery, radiotherapy or systemic therapy received oral crizotinib 250 mg twice daily. The ALK status was assessed centrally using immunohistochemistry and fluorescence in situ hybridisation. The primary end-point was the proportion of patients who achieved an objective response (i.e. complete or partial response). If ≥6 ALK-positive patients achieved a confirmed response, the trial would be deemed successful. RESULTS At data cut-off on 28th January 2021, we performed the final analysis of this trial. Of the 20 eligible and treated patients (19 of whom were evaluable for efficacy), with a median follow-up of 50 months, five were still on crizotinib treatment (4/12 ALK-positive and 1/8 ALK-negative patients). The updated objective response rate (ORR) was 66.7% (95% confidence interval [CI] 34.9-90.1%) in ALK-positive patients and 14.3% (95% CI 0.0-57.9%) in ALK-negative patients. In the ALK-positive and ALK-negative patients, the median progression-free survival was 18.0 months (95% CI 4.0-NE) and 14.3 months (95% CI 1.2-31.1), respectively; 3-year overall survival rates were 83.3% (95% CI 48.2-95.6) and 34.3% (95% CI 4.8-68.5). Safety results were consistent with previously reported data. CONCLUSION These updated results confirm previous findings that crizotinib is effective, with durable responses, in patients with locally advanced or metastatic ALK-positive IMT. With further follow-up after the original primary analysis, the ORR increased, as patients derived long-term benefit and some responses converted from stable disease to partial responses. CLINICAL TRIAL NUMBER EORTC 90101, NCT01524926.
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Affiliation(s)
- Patrick Schöffski
- Department of General Medical Oncology, University Hospitals Leuven, Leuven Cancer Institute, Department of Oncology, KU Leuven, Laboratory of Experimental Oncology, Leuven, Belgium; Laboratory of Experimental Oncology, Department of Oncology, KU Leuven, Leuven, Belgium.
| | | | - Agnieszka Wozniak
- Laboratory of Experimental Oncology, Department of Oncology, KU Leuven, Leuven, Belgium
| | - Jean-Yves Blay
- Department of Medical Oncology, Centre Léon Bérard/Université Claude Bernard Lyon Institute, Lyon, France
| | - Sandra J Strauss
- Department of Oncology, University College London Hospitals NHS Trust, London, UK
| | - Silvia Stacchiotti
- Department of Medical Oncology, IRCCS Fondazione Istituto Nazionale Tumori, Milano, Italy
| | - Tomasz Switaj
- Department of Soft Tissue/Bone Sarcoma and Melanoma, Maria Sklodowska-Curie Institute-Oncology Center, Warsaw, Poland
| | - Veit Bücklein
- Klinikum der Universität München, Medizinische Klinik III, Campus Grosshadern, Munich, Germany
| | | | | | - Nicolas Isambert
- Department of Medical Oncology, Centre Georges François Leclerc, Dijon, France
| | | | - Raf Sciot
- Department of Pathology, University Hospitals Leuven, KU Leuven, Leuven, Belgium
| | - Che-Jui Lee
- Department of General Medical Oncology, University Hospitals Leuven, Leuven Cancer Institute, Department of Oncology, KU Leuven, Laboratory of Experimental Oncology, Leuven, Belgium
| | - Frank M Speetjens
- Department of Medical Oncology, Leiden University Medical Center, Leiden, Netherlands
| | | | - Anouk Neven
- European Organisation for Research and Treatment of Cancer, Brussels, Belgium
| | - Bernd Kasper
- Sarcoma Unit, Mannheim University Medical Center, University of Heidelberg, Mannheim, Germany
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28
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Mahajan P, Casanova M, Ferrari A, Fordham A, Trahair T, Venkatramani R. Inflammatory myofibroblastic tumor: molecular landscape, targeted therapeutics, and remaining challenges. Curr Probl Cancer 2021; 45:100768. [PMID: 34244015 DOI: 10.1016/j.currproblcancer.2021.100768] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2021] [Accepted: 06/21/2021] [Indexed: 12/29/2022]
Abstract
Inflammatory myofibroblastic tumor (IMT) is a rare mesenchymal tumor of intermediate malignant potential that predominantly affects children, adolescents and young adults. IMT has a predilection for the lung, abdomen, pelvis, and retroperitoneum, however, can affect any part of the body. IMT is typically localized, and multifocal or metastatic disease is uncommon. Complete surgical resection is the treatment of choice when feasible. There is no established standard of care for unresectable and advanced IMT. Approximately half of IMTs harbor anaplastic lymphoma kinase (ALK) gene rearrangements, and fusions involving ROS1, PDGFRβ, RET and NTRK have also been described. Given the molecular landscape of IMT, management of these tumors has evolved to include tyrosine kinase inhibitors and novel targeted therapeutics. This review highlights the molecular characteristics, evolution of targeted therapies and the remaining challenges in the management of IMT.
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Affiliation(s)
- Priya Mahajan
- Department of Pediatrics, Texas Children's Cancer and Hematology Centers, Baylor College of Medicine, Houston, Texas
| | - Michela Casanova
- Pediatric Oncology Unit, Fondazione IRCCS Istituto Nazionale Tumori, Milano, Italy
| | - Andrea Ferrari
- Pediatric Oncology Unit, Fondazione IRCCS Istituto Nazionale Tumori, Milano, Italy
| | - Ashleigh Fordham
- Children's Cancer Institute, C25 Lowy Cancer Research Centre, UNSW Sydney New South Wales, Australia
| | - Toby Trahair
- Children's Cancer Institute, C25 Lowy Cancer Research Centre, UNSW Sydney New South Wales, Australia; Kids Cancer Centre, Sydney Children's Hospital, Randwick, New South Wales, Australia; School of Women's and Children's Health, UNSW Medicine, New South Wales, Australia
| | - Rajkumar Venkatramani
- Department of Pediatrics, Texas Children's Cancer and Hematology Centers, Baylor College of Medicine, Houston, Texas.
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29
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Drieux F, Ruminy P, Sater V, Marchand V, Fataccioli V, Lanic MD, Viennot M, Viailly PJ, Sako N, Robe C, Dupuy A, Vallois D, Veresezan L, Poullot E, Picquenot JM, Bossard C, Parrens M, Lemonnier F, Jardin F, de Leval L, Gaulard P. Detection of Gene Fusion Transcripts in Peripheral T-Cell Lymphoma Using a Multiplexed Targeted Sequencing Assay. J Mol Diagn 2021; 23:929-940. [PMID: 34147695 DOI: 10.1016/j.jmoldx.2021.04.013] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2020] [Revised: 04/19/2021] [Accepted: 04/28/2021] [Indexed: 10/21/2022] Open
Abstract
The genetic basis of peripheral T-cell lymphoma (PTCL) is complex and encompasses several recurrent fusion transcripts discovered over the past years by means of massive parallel sequencing. However, there is currently no affordable and rapid technology for their simultaneous detection in clinical samples. Herein, we developed a multiplex ligation-dependent RT-PCR-based assay, followed by high-throughput sequencing, to detect 33 known PTCL-associated fusion transcripts. Anaplastic lymphoma kinase (ALK) fusion transcripts were detected in 15 of 16 ALK-positive anaplastic large-cell lymphomas. The latter case was further characterized by a novel SATB1_ALK fusion transcript. Among 239 other PTCLs, representative of nine entities, non-ALK fusion transcripts were detected in 24 samples, mostly of follicular helper T-cell (TFH) derivation. The most frequent non-ALK fusion transcript was ICOS_CD28 in nine TFH-PTCLs, one PTCL not otherwise specified, and one adult T-cell leukemia/lymphoma, followed by VAV1 rearrangements with multiple partners (STAP2, THAP4, MYO1F, and CD28) in five samples (three PTCL not otherwise specified and two TFH-PTCLs). The other rearrangements were CTLA4_CD28 (one TFH-PTCL), ITK_SYK (two TFH-PTCLs), ITK_FER (one TFH-PTCL), IKZF2_ERBB4 (one TFH-PTCL and one adult T-cell leukemia/lymphoma), and TP63_TBL1XR1 (one ALK-negative anaplastic large-cell lymphoma). All fusions detected by our assay were validated by conventional RT-PCR and Sanger sequencing in 30 samples with adequate material. The simplicity and robustness of this targeted multiplex assay make it an attractive tool for the characterization of these heterogeneous diseases.
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Affiliation(s)
- Fanny Drieux
- INSERM U1245, Centre Henri Becquerel, Rouen, France; Pathology Department, Centre Henri Becquerel, Rouen, France; INSERM U955, Université Paris-Est, Créteil, France
| | | | | | | | - Virginie Fataccioli
- INSERM U955, Université Paris-Est, Créteil, France; Pathology Department, Groupe Hospitalier Henri Mondor, AP-HP, Créteil, France
| | | | | | | | - Nouhoum Sako
- INSERM U955, Université Paris-Est, Créteil, France
| | | | | | - David Vallois
- Institute of Pathology, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland
| | | | - Elsa Poullot
- INSERM U955, Université Paris-Est, Créteil, France; Pathology Department, Groupe Hospitalier Henri Mondor, AP-HP, Créteil, France
| | | | | | - Marie Parrens
- Pathology Department, Hôpital Haut-Lévêque, Bordeaux, France
| | - François Lemonnier
- INSERM U955, Université Paris-Est, Créteil, France; Hematology Department, Lymphoma Unit, Henri Mondor Hospital, Public Assistance Hospital of Paris, Créteil, France
| | | | - Laurence de Leval
- Institute of Pathology, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland
| | - Philippe Gaulard
- INSERM U955, Université Paris-Est, Créteil, France; Pathology Department, Groupe Hospitalier Henri Mondor, AP-HP, Créteil, France.
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30
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Shijie L, Zhen P, Kang Q, Hua G, Qingcheng Y, Dongdong C. Deregulation of CLTC interacts with TFG, facilitating osteosarcoma via the TGF-beta and AKT/mTOR signaling pathways. Clin Transl Med 2021; 11:e377. [PMID: 34185412 PMCID: PMC8214859 DOI: 10.1002/ctm2.377] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2020] [Revised: 03/11/2021] [Accepted: 03/15/2021] [Indexed: 01/05/2023] Open
Abstract
Although the treatment of osteosarcoma has improved, the overall survival rate of this common type of osseous malignancies has not changed for four decades. Thus, new targets for better therapeutic regimens are urgently needed. In this study, we found that high expression of clathrin heavy chain (CLTC) was an independent prognostic factor for tumor-free survival (HzR, 3.049; 95% CI, 1.476-6.301) and overall survival (HzR, 2.469; 95% CI, 1.005-6.067) of patients with osteosarcoma. Down-regulation of CLTC resulted in tumor-suppressive effects in vitro and in vivo. Moreover, we found that CLTC was transcriptionally regulated by a transcription factor-specificity protein 1 (SP1), which binds to the CLTC promoter at the -320 to -314-nt and +167 to +173-nt loci. Mechanistic investigations further revealed that CLTC elicited its pro-tumor effects by directly binding to and stabilizing trafficking from the endoplasmic reticulum to the Golgi regulator (TFG). Importantly, overexpression of TFG rescued both the tumor-suppressive effect and inhibition of the TGF-β and AKT/mTOR pathways caused by CLTC down-regulation, which indicated that the activity of CLTC was TFG-dependent. Immunohistochemistry analysis confirmed that CLTC expression was positively correlated with TFG expression. These findings collectively highlight CLTC as a new prognostic biomarker for patients with osteosarcoma, and the interruption of the SP1/CLTC/TFG axis may serve as a novel therapeutic strategy for osteosarcoma.
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Affiliation(s)
- Li Shijie
- Department of OrthopedicsShanghai Jiao Tong University Affiliated Sixth People's HospitalShanghaiChina
| | - Pan Zhen
- Department of OrthopedicsShanghai Jiao Tong University Affiliated Sixth People's HospitalShanghaiChina
| | - Qin Kang
- Department of Trauma and Reconstructive SurgeryRWTH Aachen University HospitalAachenGermany
| | - Guo Hua
- Department of OrthopedicsShanghai Jiao Tong University Affiliated Sixth People's HospitalShanghaiChina
| | - Yang Qingcheng
- Department of OrthopedicsShanghai Jiao Tong University Affiliated Sixth People's HospitalShanghaiChina
| | - Cheng Dongdong
- Department of OrthopedicsShanghai Jiao Tong University Affiliated Sixth People's HospitalShanghaiChina
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Debonis SA, Bongiovanni A, Pieri F, Fausti V, De Vita A, Riva N, Gurrieri L, Vanni S, Diano D, Mercatali L, Ibrahim T. ALK-negative lung inflammatory myofibroblastic tumor in a young adult: A case report and literature review of molecular alterations. Medicine (Baltimore) 2021; 100:e25972. [PMID: 34011083 PMCID: PMC8137108 DOI: 10.1097/md.0000000000025972] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2021] [Accepted: 04/28/2021] [Indexed: 01/05/2023] Open
Abstract
RATIONALE Inflammatory myofibroblastic tumor (IMT) is a rare mesenchymal tumor that is prevalent among children and adolescents. Surgery is the most important therapeutic approach for IMT and complete resection is recommended. Although 50% of IMTs show anaplastic lymphoma kinase (ALK) rearrangements, crizotinib has proven an effective therapeutic approach. However, the genetic landscape of this tumor is still not fully understood and treatment options are limited, especially in the majority of ALK-negative tumors. PATIENT CONCERNS We describe the clinical case of a healthy 18-year-old female in whom a pulmonary nodule was incidentally detected. DIAGNOSES Following a small increase in the size of the nodule, the patient underwent both 18FDG-PET/CT and 68Ga-PET/CT, resulting in a suspicion of bronchial hamartoma. INTERVENTIONS The patient underwent surgery and a salivary gland-like lung tumor was diagnosed. OUTCOMES After surgery, the patient was referred to our cancer center, where a review of the histology slides gave a final diagnosis of ALK-negative lung IMT. Given the histology, it was decided not to administer adjuvant therapy and the patient was placed in a 3-monthly follow-up program. The patient is still disease-free 2 years post-surgery. LESSONS Although there is no standard of care for the treatment of IMT, identifying genomic alterations could help to redefine the management of patients with negative-ALK disease. Our review of the literature on IMT and other kinase fusions revealed, in addition to ALK rearrangements, the potential association of ROS1, NTRK, RET, or PDGFR beta alterations with the tumor.
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Affiliation(s)
- Silvia Angela Debonis
- Osteoncology and Rare Tumors Center, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori,” Meldola
| | - Alberto Bongiovanni
- Osteoncology and Rare Tumors Center, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori,” Meldola
| | | | - Valentina Fausti
- Osteoncology and Rare Tumors Center, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori,” Meldola
| | - Alessandro De Vita
- Osteoncology and Rare Tumors Center, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori,” Meldola
| | - Nada Riva
- Osteoncology and Rare Tumors Center, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori,” Meldola
| | - Lorena Gurrieri
- Osteoncology and Rare Tumors Center, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori,” Meldola
| | - Silvia Vanni
- Osteoncology and Rare Tumors Center, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori,” Meldola
| | - Danila Diano
- Radiology Unit, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori,” Meldola, Italy
| | - Laura Mercatali
- Osteoncology and Rare Tumors Center, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori,” Meldola
| | - Toni Ibrahim
- Osteoncology and Rare Tumors Center, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori,” Meldola
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Abstract
OBJECTIVES This review describes our approach to the diagnosis of all 4 anaplastic large cell lymphoma (ALCL) entities. METHODS ALCLs are a group of CD30-positive mature T-cell lymphomas with similar morphologic and phenotypic characteristics but variable clinical and genetic features. They include systemic ALK-positive ALCL, systemic ALK-negative ALCL, primary cutaneous ALCL, and the recently described provisional entity breast implant-associated ALCL. RESULTS In cases with classic features, the diagnosis of ALCL is often straightforward. However, variant histology, the importance of clinical history, and multiple antigenic aberrancies all present challenges to accurate diagnosis and subclassification. CONCLUSIONS A systematic approach to the diagnosis of ALCL and awareness of potential mimics are critical to avoid misdiagnosis. It is also crucial to correctly identify localized forms of ALCL to avoid classification as systemic ALCL and subsequent overtreatment.
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Affiliation(s)
- Catalina Amador
- Department of Pathology and Microbiology, University of Nebraska, Omaha, NE, USA
| | - Andrew L Feldman
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
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Pineda-Díaz J, Solar I, Hershkovitz D, Drukman I, Sher O. Intraarticular Inflammatory Myofibroblastic Tumor of the Left Knee With ALK-CARS Fusion Detected With Archer Fusionplex Sarcoma NGS Panel: Case Report and Literature Review. Int J Surg Pathol 2020; 29:216-222. [PMID: 32631118 DOI: 10.1177/1066896920937770] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
Inflammatory myofibroblastic tumor (IMT) is a lesion of intermediate biological potential with local recurrences and rare metastases found in multiple anatomical locations. We present a case of a pure intraarticular IMT of the knee, a location that has not been previously documented, with genetic confirmation of ALK-CARS fusion detected with next-generation sequencing. A 20-year-old healthy male was admitted to the orthopedic oncology department due to several months of pain and restriction in movement of his left knee. On magnetic resonance imaging, multiple intraarticular nodular lesions were seen. The patient underwent 2 synovectomies within the course of 1 year. The initial biopsy was interpreted as nodular fasciitis. The second biopsy revealed exuberant tissue displaying compact fascicles of spindle cells intermixed with myxoid areas in a background of inflammatory cells, highly suggestive for IMT. Due to the unusual intraarticular location, equivocal ALK immunostaining and the differential diagnosis with nodular fasciitis, we performed targeted next-generation sequencing using Archer FusionPlex Sarcoma panel, which can identify multiple fusions in a single assay. An ALK-CARS fusion was found, supporting the diagnosis of IMT. This report emphasizes the added value of broad molecular analysis in cases with unusual clinical presentation, equivocal immunohistochemistry, and a wide differential diagnosis.
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Affiliation(s)
| | - Irit Solar
- 26738Tel-Aviv Sourasky Medical Center, Tel-Aviv, Israel
| | - Dov Hershkovitz
- 26738Tel-Aviv Sourasky Medical Center, Tel-Aviv, Israel.,Tel-Aviv University, Tel-Aviv, Israel
| | - Ido Drukman
- 26738Tel-Aviv Sourasky Medical Center, Tel-Aviv, Israel
| | - Osnat Sher
- 26738Tel-Aviv Sourasky Medical Center, Tel-Aviv, Israel
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34
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Yang J, Li J, Gu WY, Jin L, Duan YL, Huang S, Zhang M, Wang XS, Liu Y, Zhou CJ, Gao C, Zheng HY, Zhang YH. Central nervous system relapse in a pediatric anaplastic large cell lymphoma patient with CLTC/ALK translocation treated with alectinib: A case report. World J Clin Cases 2020; 8:1685-1692. [PMID: 32420302 PMCID: PMC7211542 DOI: 10.12998/wjcc.v8.i9.1685] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2020] [Revised: 04/08/2020] [Accepted: 04/20/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND The aberrant expression of the anaplastic lymphoma kinase (ALK) gene in ALK-positive (ALK+) anaplastic large cell lymphoma (ALCL) is usually due to t(2;5)/NPM-ALK. However, rarely, aberrant ALK expression can also result from a rearrangement of the ALK gene with various partner genes. Central nervous system (CNS) metastasis is very rare in ALK+ALCL. Patients with CNS involvement show an inferior prognosis.
CASE SUMMARY Here, we present the case of an 8-year-old girl diagnosed with ALK+ALCL. She presented with fever, skin nodules, leg swelling, and abdominal pain over the preceding 6 mo. She had extensive involvement and showed an extraordinary rare translocation, t(2;17)/CLTC-ALK, as demonstrated by RNA-seq. She underwent chemotherapy as per ALCL99, followed by vinblastine (VBL) maintenance treatment, and achieved complete remission. However, she developed CNS relapse during VBL monotherapy. The patient achieved a durable second remission with high-dose chemotherapy (including methotrexate 8 g/m2) and continuous treatment with alectinib and VBL.
CONCLUSION Alectinib showed significant and durable CNS effects in this patient. However, more cases are needed to prove the efficacy and safety of alectinib for pediatric ALK+ALCL patients.
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Affiliation(s)
- Jing Yang
- Beijing Key Laboratory of Pediatric Hematology Oncology, National Discipline of Pediatrics, Ministry of Education, MOE Key Laboratory of Major Diseases in Children; Hematology Oncology Center, Beijing Children's Hospital, Capital Medical University, National Center for Children’s Health, Beijing 100045, China
| | - Jun Li
- Beijing Key Laboratory of Pediatric Hematology Oncology, National Discipline of Pediatrics, Ministry of Education, MOE Key Laboratory of Major Diseases in Children; Hematology Oncology Center, Beijing Children's Hospital, Capital Medical University, National Center for Children’s Health, Beijing 100045, China
| | - Wei-Yue Gu
- Chigene (Beijing) Translational Medical Research Center Co., Ltd., Beijing 101111, China
| | - Ling Jin
- Beijing Key Laboratory of Pediatric Hematology Oncology, National Discipline of Pediatrics, Ministry of Education, MOE Key Laboratory of Major Diseases in Children; Hematology Oncology Center, Beijing Children's Hospital, Capital Medical University, National Center for Children’s Health, Beijing 100045, China
| | - Yan-Long Duan
- Beijing Key Laboratory of Pediatric Hematology Oncology, National Discipline of Pediatrics, Ministry of Education, MOE Key Laboratory of Major Diseases in Children; Hematology Oncology Center, Beijing Children's Hospital, Capital Medical University, National Center for Children’s Health, Beijing 100045, China
| | - Shuang Huang
- Beijing Key Laboratory of Pediatric Hematology Oncology, National Discipline of Pediatrics, Ministry of Education, MOE Key Laboratory of Major Diseases in Children; Hematology Oncology Center, Beijing Children's Hospital, Capital Medical University, National Center for Children’s Health, Beijing 100045, China
| | - Meng Zhang
- Beijing Key Laboratory of Pediatric Hematology Oncology, National Discipline of Pediatrics, Ministry of Education, MOE Key Laboratory of Major Diseases in Children; Hematology Oncology Center, Beijing Children's Hospital, Capital Medical University, National Center for Children’s Health, Beijing 100045, China
| | - Xi-Si Wang
- Beijing Key Laboratory of Pediatric Hematology Oncology, National Discipline of Pediatrics, Ministry of Education, MOE Key Laboratory of Major Diseases in Children; Hematology Oncology Center, Beijing Children's Hospital, Capital Medical University, National Center for Children’s Health, Beijing 100045, China
| | - Yi Liu
- Beijing Key Laboratory of Pediatric Hematology Oncology, National Discipline of Pediatrics, Ministry of Education, MOE Key Laboratory of Major Diseases in Children; Hematology Oncology Center, Beijing Children's Hospital, Capital Medical University, National Center for Children’s Health, Beijing 100045, China
| | - Chun-Ju Zhou
- Beijing Key Laboratory of Pediatric Hematology Oncology, National Discipline of Pediatrics, Ministry of Education, MOE Key Laboratory of Major Diseases in Children; Hematology Oncology Center, Beijing Children's Hospital, Capital Medical University, National Center for Children’s Health, Beijing 100045, China
| | - Chao Gao
- Beijing Key Laboratory of Pediatric Hematology Oncology, National Discipline of Pediatrics, Ministry of Education, MOE Key Laboratory of Major Diseases in Children; Hematology Oncology Center, Beijing Children's Hospital, Capital Medical University, National Center for Children’s Health, Beijing 100045, China
| | - Hu-Yong Zheng
- Beijing Key Laboratory of Pediatric Hematology Oncology, National Discipline of Pediatrics, Ministry of Education, MOE Key Laboratory of Major Diseases in Children; Hematology Oncology Center, Beijing Children's Hospital, Capital Medical University, National Center for Children’s Health, Beijing 100045, China
| | - Yong-Hong Zhang
- Beijing Key Laboratory of Pediatric Hematology Oncology, National Discipline of Pediatrics, Ministry of Education, MOE Key Laboratory of Major Diseases in Children; Hematology Oncology Center, Beijing Children's Hospital, Capital Medical University, National Center for Children’s Health, Beijing 100045, China
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35
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Maurus K, Appenzeller S, Roth S, Brändlein S, Kneitz H, Goebeler M, Rosenwald A, Geissinger E, Wobser M. Recurrent Oncogenic JAK and STAT Alterations in Cutaneous CD30-Positive Lymphoproliferative Disorders. J Invest Dermatol 2020; 140:2023-2031.e1. [PMID: 32147503 DOI: 10.1016/j.jid.2020.02.019] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2019] [Revised: 01/23/2020] [Accepted: 02/06/2020] [Indexed: 12/16/2022]
Abstract
The group of cutaneous CD30-positive lymphoproliferative disorders (LPD) comprises two different entities, namely lymphomatoid papulosis (LyP) and cutaneous anaplastic large T-cell lymphoma (cALCL). LyP constitutes a benign lymphoproliferation with spontaneously regressing papules, whereas cALCL presents with solitary or multiple skin tumors with a low propensity to disseminate. To elucidate the hitherto largely unknown molecular pathogenesis of these entities, we performed comprehensive next-generation sequencing in a well-characterized cohort of 12 patients. Considering the low tumor cell content of LyP, we applied targeted sequencing technologies with a hybrid capture-based DNA library preparation approach and for the identification of fusion transcripts an anchored multiplex PCR enrichment kit. As the major finding, we detected, in 50% of LPD, genetic events that implied a constitutively activated Janus kinase-signal transducer and activator of transcription signaling (JAK-STAT) pathway in these entities. The identified molecular aberrations comprised either pathogenic STAT mutations or oncogenic fusion transcripts comprising effector domains of JAK. With respect to LyP, we report to our knowledge such previously unreported genetic aberrations in this specific entity. The detection of these convergent aberrations within the JAK-STAT signaling pathway deciphers common potential driving mechanisms of lymphomagenesis within LPD being shared between LyP and cALCL. Moreover, the presence of these oncogenic alterations paves the way to develop novel personalized treatment strategies.
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Affiliation(s)
- Katja Maurus
- Institute of Pathology, University of Wuerzburg, Wuerzburg, Germany; Comprehensive Cancer Center Mainfranken, University of Wuerzburg, Wuerzburg, Germany.
| | - Silke Appenzeller
- Comprehensive Cancer Center Mainfranken, University of Wuerzburg, Wuerzburg, Germany
| | - Sabine Roth
- Institute of Pathology, University of Wuerzburg, Wuerzburg, Germany; Comprehensive Cancer Center Mainfranken, University of Wuerzburg, Wuerzburg, Germany
| | - Stephanie Brändlein
- Institute of Pathology, University of Wuerzburg, Wuerzburg, Germany; Comprehensive Cancer Center Mainfranken, University of Wuerzburg, Wuerzburg, Germany
| | - Hermann Kneitz
- Comprehensive Cancer Center Mainfranken, University of Wuerzburg, Wuerzburg, Germany; Department of Dermatology, Venereology and Allergology and Skin Cancer Center, University Hospital Wuerzburg, Wuerzburg, Germany
| | - Matthias Goebeler
- Comprehensive Cancer Center Mainfranken, University of Wuerzburg, Wuerzburg, Germany; Department of Dermatology, Venereology and Allergology and Skin Cancer Center, University Hospital Wuerzburg, Wuerzburg, Germany
| | - Andreas Rosenwald
- Institute of Pathology, University of Wuerzburg, Wuerzburg, Germany; Comprehensive Cancer Center Mainfranken, University of Wuerzburg, Wuerzburg, Germany
| | - Eva Geissinger
- Institute of Pathology, University of Wuerzburg, Wuerzburg, Germany; Comprehensive Cancer Center Mainfranken, University of Wuerzburg, Wuerzburg, Germany
| | - Marion Wobser
- Comprehensive Cancer Center Mainfranken, University of Wuerzburg, Wuerzburg, Germany; Department of Dermatology, Venereology and Allergology and Skin Cancer Center, University Hospital Wuerzburg, Wuerzburg, Germany
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36
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Abstract
Anaplastic large cell lymphomas are a rare subtype of peripheral/mature T-cell lymphomas which are clinically, pathologically and genetically heterogeneous. Both ALK-positive (ALK+) and ALK-negative (ALK-) ALCL are composed of large lymphoid cells with abundant cytoplasm and pleomorphic features with horseshoe-shaped and reniform nuclei. ALK+ ALCL were considered as a definite entity in the 2008 World Health Organization classification of hematopoietic and lymphoid tissues. ALK-ALCL was included as a provisional entity in the WHO 2008 edition and in the most recent 2017 edition, it is now considered a distinct entity that includes cytogenetic subsets that appear to have prognostic implications (e.g. 6p25 rearrangements at IRF4/DUSP22 locus). ALK+ ALCLs are distinct in epidemiology and pathogenetic origin and should be distinguished from ALK-ALCL, cutaneous ALCL and breast implant associated ALCL which have distinct clinical course and pathogenetic features. Breast implant-associated ALCL is now recognized as a new provisional entity distinct from other ALK-ALCL; notably that it is a noninvasive disease associated with excellent outcome. In this article, we will provide an overview of the salient themes relevant to the pathology and genetic mechanisms in ALCL.
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Affiliation(s)
- Vasiliki Leventaki
- Department of Pathology, Medical College of Wisconsin, Milwaukee, WI, United States
| | - Siddharth Bhattacharyya
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA United States
| | - Megan S Lim
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA United States.
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37
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Irshaid L, Xu ML. ALCL by any other name: the many facets of anaplastic large cell lymphoma. Pathology 2019; 52:100-110. [PMID: 31706671 DOI: 10.1016/j.pathol.2019.09.007] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2019] [Revised: 09/08/2019] [Accepted: 09/12/2019] [Indexed: 12/29/2022]
Abstract
Anaplastic large cell lymphomas (ALCLs) encompass a group of CD30(+) non-Hodgkin T-cell lymphomas. While the different subtypes of ALCLs may share overlapping clinical patient demographics as well as histological and immunohistochemical phenotypes, these tumours can drastically differ in clinical behaviour and genetic profiles. Currently, four distinct ALCL entities are recognised in the 2016 WHO classification: anaplastic lymphoma kinase (ALK)(+), ALK(-), primary cutaneous and breast implant-associated. ALK(+) ALCL demonstrates a spectrum of cell cytology ranging from small to large lymphoma cells and characteristic 'hallmark' cells. ALK(+) ALCL consistently demonstrates ALK gene rearrangements and carries a favourable prognosis. ALK(-) ALCL morphologically and immunohistochemically mimics ALK(+) ALCL but lacks the ALK gene rearrangement. ALK(-) ALCLs are associated with variable prognoses depending on specific gene rearrangements; while DUSP22-rearranged cases have favourable outcomes similar to ALK(+) ALCLs, cases with p63 rearrangements carry a dismal prognosis and 'triple-negative' cases (those lacking ALK, DUSP22 and TP63 rearrangements) have an intermediate prognosis. Primary cutaneous ALCL presents as a skin lesion, lacks the ALK gene translocation and carries a favourable prognosis, similar or superior to ALK(+) ALCL. Breast implant-associated ALCL presents as a seroma with a median of 8-10 years after implant placement, lacks the ALK gene translocation and has an overall favourable but variable prognosis, depending on extent of disease at diagnosis and treatment. In this review, we present the clinical, pathological and genetic features of the ALCLs with emphasis on practical points and differential diagnoses for practising pathologists.
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Affiliation(s)
- Lina Irshaid
- Department of Pathology, Yale New Haven Hospital, Yale University School of Medicine, New Haven, CT, United States
| | - Mina L Xu
- Department of Pathology, Yale New Haven Hospital, Yale University School of Medicine, New Haven, CT, United States.
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38
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Kong X, Pan P, Sun H, Xia H, Wang X, Li Y, Hou T. Drug Discovery Targeting Anaplastic Lymphoma Kinase (ALK). J Med Chem 2019; 62:10927-10954. [PMID: 31419130 DOI: 10.1021/acs.jmedchem.9b00446] [Citation(s) in RCA: 77] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
As a receptor tyrosine kinase of insulin receptor (IR) subfamily, anaplastic lymphoma kinase (ALK) has been validated to play important roles in various cancers, especially anaplastic large cell lymphoma (ALCL), nonsmall cell lung cancer (NSCLC), and neuroblastomas. Currently, five small-molecule inhibitors of ALK, including Crizotinib, Ceritinib, Alectinib, Brigatinib, and Lorlatinib, have been approved by the U.S. Food and Drug Administration (FDA) against ALK-positive NSCLCs. Novel type-I1/2 and type-II ALK inhibitors with improved kinase selectivity and enhanced capability to combat drug resistance have also been reported. Moreover, the "proteolysis targeting chimera" (PROTAC) technique has been successfully applied in developing ALK degraders, which opened a new avenue for targeted ALK therapies. This review provides an overview of the physiological and biological functions of ALK, the discovery and development of drugs targeting ALK by focusing on their chemotypes, activity, selectivity, and resistance as well as potential therapeutic strategies to overcome drug resistance.
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Affiliation(s)
- Xiaotian Kong
- Hangzhou Institute of Innovative Medicine, College of Pharmaceutical Sciences , Zhejiang University , Hangzhou , Zhejiang 310058 , China.,Institute of Functional Nano and Soft Materials (FUNSOM) , Soochow University , Suzhou , Jiangsu 215123 , China
| | - Peichen Pan
- Hangzhou Institute of Innovative Medicine, College of Pharmaceutical Sciences , Zhejiang University , Hangzhou , Zhejiang 310058 , China
| | - Huiyong Sun
- Hangzhou Institute of Innovative Medicine, College of Pharmaceutical Sciences , Zhejiang University , Hangzhou , Zhejiang 310058 , China
| | - Hongguang Xia
- Department of Biochemistry & Research Center of Clinical Pharmacy of the First Affiliated Hospital , Zhejiang University , Hangzhou 310058 , China
| | - Xuwen Wang
- Hangzhou Institute of Innovative Medicine, College of Pharmaceutical Sciences , Zhejiang University , Hangzhou , Zhejiang 310058 , China
| | - Youyong Li
- Institute of Functional Nano and Soft Materials (FUNSOM) , Soochow University , Suzhou , Jiangsu 215123 , China
| | - Tingjun Hou
- Hangzhou Institute of Innovative Medicine, College of Pharmaceutical Sciences , Zhejiang University , Hangzhou , Zhejiang 310058 , China
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39
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Ducray SP, Natarajan K, Garland GD, Turner SD, Egger G. The Transcriptional Roles of ALK Fusion Proteins in Tumorigenesis. Cancers (Basel) 2019; 11:cancers11081074. [PMID: 31366041 PMCID: PMC6721376 DOI: 10.3390/cancers11081074] [Citation(s) in RCA: 57] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2019] [Revised: 07/17/2019] [Accepted: 07/23/2019] [Indexed: 12/14/2022] Open
Abstract
Anaplastic lymphoma kinase (ALK) is a tyrosine kinase involved in neuronal and gut development. Initially discovered in T cell lymphoma, ALK is frequently affected in diverse cancers by oncogenic translocations. These translocations involve different fusion partners that facilitate multimerisation and autophosphorylation of ALK, resulting in a constitutively active tyrosine kinase with oncogenic potential. ALK fusion proteins are involved in diverse cellular signalling pathways, such as Ras/extracellular signal-regulated kinase (ERK), phosphatidylinositol 3-kinase (PI3K)/Akt and Janus protein tyrosine kinase (JAK)/STAT. Furthermore, ALK is implicated in epigenetic regulation, including DNA methylation and miRNA expression, and an interaction with nuclear proteins has been described. Through these mechanisms, ALK fusion proteins enable a transcriptional programme that drives the pathogenesis of a range of ALK-related malignancies.
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Affiliation(s)
- Stephen P Ducray
- Division of Cellular and Molecular Pathology, Department of Pathology, University of Cambridge, Cambridge CB20QQ, UK
| | | | - Gavin D Garland
- Division of Cellular and Molecular Pathology, Department of Pathology, University of Cambridge, Cambridge CB20QQ, UK
| | - Suzanne D Turner
- Division of Cellular and Molecular Pathology, Department of Pathology, University of Cambridge, Cambridge CB20QQ, UK.
| | - Gerda Egger
- Department of Pathology, Medical University Vienna, 1090 Vienna, Austria.
- Ludwig Boltzmann Institute Applied Diagnostics, 1090 Vienna, Austria.
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40
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Wang K, Guo R, Siegal GP, Wei S. Inflammatory myofibroblastic tumor of bone harboring an ALK gene amplification. Pathol Res Pract 2019; 215:152535. [PMID: 31326196 DOI: 10.1016/j.prp.2019.152535] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2019] [Revised: 06/14/2019] [Accepted: 07/12/2019] [Indexed: 11/25/2022]
Abstract
Inflammatory myofibroblastic tumor (IMT) is a neoplastic proliferation of myofibroblastic/fibroblastic cells with a variable admixture of inflammatory cells. It primarily affects soft tissue and viscera of children and young adults. IMT occurring in bone is extremely rare. Approximately 50% of IMTs carry a clonal rearrangement of the anaplastic lymphoma kinase (ALK) gene, while other receptor tyrosine kinase gene rearrangements have been seen in a small subset of IMT. Herein, we report the first case of IMT which harbors an ALK gene amplification rather than a rearrangement thus resulting in overexpression of the protein, arising from the femur of a 24-year-old man. Our case provides a novel pathogenesis for IMT. An overview of cytogenetic abnormalities of IMT is also integrated into this report.
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Affiliation(s)
- Kai Wang
- Department of Pathology, the University of Alabama at Birmingham, Birmingham, AL 35249, United States
| | - Rongjun Guo
- Department of Pathology, the University of Alabama at Birmingham, Birmingham, AL 35249, United States
| | - Gene P Siegal
- Department of Pathology, the University of Alabama at Birmingham, Birmingham, AL 35249, United States; Department of Genetics, the University of Alabama at Birmingham, Birmingham, AL 35249, United States
| | - Shi Wei
- Department of Pathology, the University of Alabama at Birmingham, Birmingham, AL 35249, United States.
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41
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Trahair T, Gifford AJ, Fordham A, Mayoh C, Fadia M, Lukeis R, Wood AC, Valvi S, Walker RD, Blackburn J, Heyer EE, Mercer TR, Barbaric D, Marshall GM, MacKenzie KL. Crizotinib and Surgery for Long-Term Disease Control in Children and Adolescents With ALK-Positive Inflammatory Myofibroblastic Tumors. JCO Precis Oncol 2019; 3:1800297. [PMID: 32914017 PMCID: PMC7446396 DOI: 10.1200/po.18.00297] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/25/2019] [Indexed: 12/15/2022] Open
Abstract
PURPOSE Before anaplastic lymphoma kinase (ALK) inhibitors, treatment options for ALK-positive inflammatory myofibroblastic tumors (AP-IMTs) were unsatisfactory. We retrospectively analyzed the outcome of patients with AP-IMT treated with crizotinib to document response, toxicity, survival, and features associated with relapse. METHODS The cohort comprised eight patients with AP-IMT treated with crizotinib and surgery. Outcome measures were progression-free and overall survival after commencing crizotinib, treatment-related toxicities, features associated with relapse, outcome after relapse, and outcome after ceasing crizotinib. RESULTS The median follow-up after commencing crizotinib was 3 years (range, 0.9 to 5.5 years). The major toxicity was neutropenia. All patients responded to crizotinib. Five were able to discontinue therapy without recurrence (median treatment duration, 1 year; range, 0.2 to 3.0 years); one continues on crizotinib. Two critically ill patients with initial complete response experienced relapse while on therapy. Both harbored RANBP2-ALK fusions and responded to alternative ALK inhibitors; one ultimately died as a result of progressive disease, whereas the other remains alive on treatment. Progression-free and overall survival since commencement of crizotinib is 0.75 ± 0.15% and 0.83 ± 0.15%, respectively. CONCLUSION We confirm acceptable toxicity and excellent disease control in patients with AP-IMT treated with crizotinib, which may be ceased without recurrence in most. Relapses occurred in two of three patients with RANBP2-ALK translocated IMT, which suggests that such patients require additional therapy.
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Affiliation(s)
- Toby Trahair
- Sydney Children's Hospital, Randwick, New South Wales, Australia.,Children's Cancer Institute, Sydney, New South Wales, Australia.,University of New South Wales, Sydney, New South Wales, Australia
| | - Andrew J Gifford
- Children's Cancer Institute, Sydney, New South Wales, Australia.,Prince of Wales Hospital, Randwick, New South Wales, Australia
| | | | - Chelsea Mayoh
- Children's Cancer Institute, Sydney, New South Wales, Australia
| | - Mitali Fadia
- Canberra Hospital, Garran, Australian Capital Territory, Australia.,Australian National University Medical School, Acton, Australian Capital Territory, Australia
| | - Robyn Lukeis
- St Vincent's Hospital, Darlinghurst, New South Wales, Australia
| | | | - Santosh Valvi
- Perth Children's Hospital, Perth, Western Australia, Australia
| | - Roderick D Walker
- Queensland Children's Hospital, South Brisbane, Queensland, Australia
| | - James Blackburn
- University of New South Wales, Sydney, New South Wales, Australia.,Garvan Institute of Medical Research, Sydney, New South Wales, Australia
| | - Erin E Heyer
- Garvan Institute of Medical Research, Sydney, New South Wales, Australia
| | - Tim R Mercer
- University of New South Wales, Sydney, New South Wales, Australia.,Garvan Institute of Medical Research, Sydney, New South Wales, Australia.,Altius Institute for Biomedical Sciences, Seattle, WA
| | - Draga Barbaric
- Sydney Children's Hospital, Randwick, New South Wales, Australia
| | - Glenn M Marshall
- Sydney Children's Hospital, Randwick, New South Wales, Australia.,Children's Cancer Institute, Sydney, New South Wales, Australia.,University of New South Wales, Sydney, New South Wales, Australia
| | - Karen L MacKenzie
- Children's Medical Research Institute, Westmead New South Wales, Australia
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42
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Inflammatory Myofibroblastic Tumor Arising in the Cul-De-Sac, Mimicking Ectopic Decidua. Int J Gynecol Pathol 2019; 38:253-257. [DOI: 10.1097/pgp.0000000000000505] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
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43
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Takeuchi K. Discovery Stories of RET Fusions in Lung Cancer: A Mini-Review. Front Physiol 2019; 10:216. [PMID: 30941048 PMCID: PMC6433883 DOI: 10.3389/fphys.2019.00216] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2018] [Accepted: 02/20/2019] [Indexed: 12/29/2022] Open
Abstract
In 2004, a chemical inhibitor of the kinase activity of EGFR was reported to be effective in a subset of lung cancer patients with activating somatic mutations of EGFR. It remained unclear, however, whether kinase fusion genes also play a major role in the pathogenesis of lung cancers. The discovery of the EML4-ALK fusion kinase in 2007 was a breakthrough for this situation, and kinase fusion genes now form a group of relevant targetable oncogenes in lung cancer. In this mini-review article, the discovery of REarrangement during Transfection fusions, the third kinase fusion gene in lung cancer, is briefly described.
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Affiliation(s)
- Kengo Takeuchi
- Division of Pathology, The Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan.,Pathology Project for Molecular Targets, The Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan
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44
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ALK Gene Fusions in Epithelioid Fibrous Histiocytoma: A Study of 14 Cases, With New Histopathological Findings. Am J Dermatopathol 2019; 40:805-814. [PMID: 29329131 DOI: 10.1097/dad.0000000000001085] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Previous studies showed that ALK is often positive in epithelioid fibrous histiocytoma (EFH). Two cases of EFH with ALK gene fusions have been recorded. Our objective was to study a series of EFH to present histopathological variations of EFH, identify novel ALK gene fusions, and determine whether there is a correlation between histopathological features and particular gene. We investigated 14 cases of EFH, all ALK immunopositive. The cases were assessed histopathologically as well as for ALK and TFE-3 rearrangements using FISH and ALK gene fusions using next-generation sequencing. The analysis of the sequencing results was performed using the Archer Analysis software (v5; ArcherDX Inc). The study group consisted of 8 female and 6 male patients, ranging in age from 18 to 79 years (mean 42 years; median 37.5 years). All presented with a solitary lesion. Microscopically, most lesions were polypoid and composed of epithelioid cells with ample cytoplasm. In addition, a variable number of bi-, tri-, or multinucleated, spindled, multilobated, cells with eccentric nuclei, cells with nuclear pseudoinclusions, mucinous, and grooved cells were admixed. In 5 cases, the predominant epithelioid cell component consisted of rather small cells, whereas spindled cells dominated in 3 cases. Of these, 2 lesions were composed rather of pale eosinophilic to clear cells, occasioning a resemblance to PEComa or leiomyoma. Immunohistochemically, all cases expressed ALK and 11 were positive for TFE-3. The break apart test for ALK was positive in 11 cases, whereas specimens from the remaining 3 cases were not analyzable. ALK genes fusions were found in all but 3 cases and included SQSTM1-ALK (3), VCL-ALK (3), TMP3-ALK (2), PRKAR2A-ALK (1), MLPH-ALK (1), and EML4-ALK (1). No correlation between histological features and type of ALK fusion was found. TFE-3 break apart test was negative. It is concluded that ALK-immunopositive EFH shows ALK gene fusions that involve various protein-coding genes, implicated in a variety of biological processes. Rare variants of EFH rather consist of spindled "non-epithelioid" cells.
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45
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Cao Z, Gao Q, Fu M, Ni N, Pei Y, Ou WB. Anaplastic lymphoma kinase fusions: Roles in cancer and therapeutic perspectives. Oncol Lett 2019; 17:2020-2030. [PMID: 30675269 PMCID: PMC6341817 DOI: 10.3892/ol.2018.9856] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2018] [Accepted: 11/27/2018] [Indexed: 12/12/2022] Open
Abstract
Receptor tyrosine kinase (RTK) anaplastic lymphoma kinase (ALK) serves a crucial role in brain development. ALK is located on the short arm of chromosome 2 (2p23) and exchange of chromosomal segments with other genes, including nucleophosmin (NPM), echinoderm microtubule-associated protein-like 4 (EML4) and Trk-fused gene (TFG), readily occurs. Such chromosomal translocation results in the formation of chimeric X-ALK fusion oncoproteins, which possess potential oncogenic functions due to constitutive activation of ALK kinase. These proteins contribute to the pathogenesis of various hematological malignancies and solid tumors, including lymphoma, lung cancer, inflammatory myofibroblastic tumors (IMTs), Spitz tumors, renal carcinoma, thyroid cancer, digestive tract cancer, breast cancer, leukemia and ovarian carcinoma. Targeting of ALK fusion oncoproteins exclusively, or in combination with ALK kinase inhibitors including crizotinib, is the most common therapeutic strategy. As is often the case for small-molecule tyrosine kinase inhibitors (TKIs), drug resistance eventually develops via an adaptive secondary mutation in the ALK fusion oncogene, or through engagement of alternative signaling mechanisms. The updated mechanisms of a variety of ALK fusions in tumorigenesis, proliferation and metastasis, in addition to targeted therapies are discussed below.
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Affiliation(s)
- Zhifa Cao
- Zhejiang Provincial Key Laboratory of Silkworm Bioreactors and Biomedicine, College of Life Sciences, Zhejiang Sci-Tech University, Hangzhou, Zhejiang 310018, P.R. China
| | - Qian Gao
- Emergency Department, Tianjin Fourth Central Hospital, Fourth Central Hospital Affiliated with Nankai University, Tianjin 300140, P.R. China
| | - Meixian Fu
- Zhejiang Provincial Key Laboratory of Silkworm Bioreactors and Biomedicine, College of Life Sciences, Zhejiang Sci-Tech University, Hangzhou, Zhejiang 310018, P.R. China
| | - Nan Ni
- Zhejiang Provincial Key Laboratory of Silkworm Bioreactors and Biomedicine, College of Life Sciences, Zhejiang Sci-Tech University, Hangzhou, Zhejiang 310018, P.R. China
| | - Yuting Pei
- Zhejiang Provincial Key Laboratory of Silkworm Bioreactors and Biomedicine, College of Life Sciences, Zhejiang Sci-Tech University, Hangzhou, Zhejiang 310018, P.R. China
| | - Wen-Bin Ou
- Zhejiang Provincial Key Laboratory of Silkworm Bioreactors and Biomedicine, College of Life Sciences, Zhejiang Sci-Tech University, Hangzhou, Zhejiang 310018, P.R. China
- Zhejiang Provincial Key Laboratory of Applied Enzymology, Yangtze Delta Region Institute of Tsinghua University, Jiaxing, Zhejiang 314006, P.R. China
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46
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Larose H, Burke GAA, Lowe EJ, Turner SD. From bench to bedside: the past, present and future of therapy for systemic paediatric ALCL, ALK. Br J Haematol 2019; 185:1043-1054. [PMID: 30681723 DOI: 10.1111/bjh.15763] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Anaplastic large cell lymphoma (ALCL) is a T cell Non-Hodgkin Lymphoma that mainly presents in paediatric and young adult patients. The majority of cases express a chimeric fusion protein resulting in hyperactivation of anaplastic lymphoma kinase (ALK) as the consequence of a chromosomal translocation. Rarer cases lack expression of ALK fusion proteins and are categorised as ALCL, ALK-. An adapted regimen of an historic chemotherapy backbone is still used to this day, yielding overall survival (OS) of over 90% but with event-free survival (EFS) at an unacceptable 70%, improving little over the past 30 years. It is clear that continued adaption of current therapies will probably not improve these statistics and, for progress to be made, integration of biology with the design and implementation of future clinical trials is required. Indeed, advances in our understanding of the biology of ALCL are outstripping our ability to clinically translate them; laboratory-based research has highlighted a plethora of potential therapeutic targets but, with high survival rates combined with a scarcity of funding and patients to implement paediatric trials of novel agents, progress is slow. However, advances must be made to reduce the side-effects of intensive chemotherapy regimens whilst maintaining, if not improving, OS and EFS.
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Affiliation(s)
- Hugo Larose
- Department of Pathology, Division of Cellular and Molecular Pathology, University of Cambridge, Cambridge, UK.,European Research Initiative for ALK-related malignancies (www.erialcl.net), Cambridge, UK
| | - G A Amos Burke
- Department of paediatric oncology, Addenbrooke's Hospital, Cambridge, UK
| | - Eric J Lowe
- Division of Pediatric Hematology-Oncology, Children's Hospital of the Kings Daughter, Norfolk, Virginia, USA
| | - Suzanne D Turner
- Department of Pathology, Division of Cellular and Molecular Pathology, University of Cambridge, Cambridge, UK.,European Research Initiative for ALK-related malignancies (www.erialcl.net), Cambridge, UK
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47
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Vargas-Madueno F, Gould E, Valor R, Ngo N, Zhang L, Villalona-Calero MA. EML4-ALK Rearrangement and Its Therapeutic Implications in Inflammatory Myofibroblastic Tumors. Oncologist 2018; 23:1127-1132. [PMID: 29739898 PMCID: PMC6263129 DOI: 10.1634/theoncologist.2018-0014] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2018] [Accepted: 03/06/2018] [Indexed: 12/25/2022] Open
Abstract
With the advent of precision medicine, medical oncology is undergoing a transcendental change. These molecular studies have allowed us to learn about potential targeted therapies for patients with advanced cancers. Perhaps the best-known example of success in precision medicine is chronic myeloid leukemia and its response to tyrosine kinase inhibitors targeting the BCR-ABL kinase. Since that original discovery, the role of molecular therapeutics has expanded, and it now presents us with treatment options for common malignancies and rare atypical tumors. In this article, we present a case of a 61-year-old female with a recurrent pulmonary inflammatory myofibroblastic tumor. Subsequent molecular studies revealed an ALK rearrangement. The significance of this alteration in this tumor type and its therapeutic implications are discussed herein. KEY POINTS This case exemplifies the heterogeneous behavior of inflammatory myofibroblastic tumors (IMTs) and the current role of targeted therapy in the therapeutic armamentarium of neoplastic processes.As evidenced by the different mutations found in IMTs, it is of great importance to perform next-generation sequencing in uncommon neoplasms.These studies can find different potential targets and therapeutic options for patients devoid of standard effective therapies.
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Affiliation(s)
- Fernando Vargas-Madueno
- Miami Cancer Institute at Baptist Health South Florida, Miami, Florida, USA
- Department of Humanities, Health & Society, Herbert Wertheim College of Medicine at the Florida International University, Miami, Florida, USA
| | - Edwin Gould
- Department of Pathology, Baptist Health South Florida, Miami, Florida, USA
| | - Raul Valor
- Department of Interventional Pulmonology, Subsection Chief, Pulmonary, Interventional Pulmonology Baptist Hospital of Miami, Miami, Florida, USA
| | - Nhu Ngo
- Department of Pathology & Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia, USA
| | - Linsheng Zhang
- Department of Pathology & Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia, USA
| | - Miguel A Villalona-Calero
- Miami Cancer Institute at Baptist Health South Florida, Miami, Florida, USA
- Department of Humanities, Health & Society, Herbert Wertheim College of Medicine at the Florida International University, Miami, Florida, USA
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48
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Schöffski P, Sufliarsky J, Gelderblom H, Blay JY, Strauss SJ, Stacchiotti S, Rutkowski P, Lindner LH, Leahy MG, Italiano A, Isambert N, Debiec-Rychter M, Sciot R, Van Cann T, Marréaud S, Nzokirantevye A, Collette S, Wozniak A. Crizotinib in patients with advanced, inoperable inflammatory myofibroblastic tumours with and without anaplastic lymphoma kinase gene alterations (European Organisation for Research and Treatment of Cancer 90101 CREATE): a multicentre, single-drug, prospective, non-randomised phase 2 trial. THE LANCET RESPIRATORY MEDICINE 2018; 6:431-441. [PMID: 29669701 DOI: 10.1016/s2213-2600(18)30116-4] [Citation(s) in RCA: 125] [Impact Index Per Article: 17.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/17/2018] [Revised: 03/07/2018] [Accepted: 03/07/2018] [Indexed: 01/26/2023]
Abstract
BACKGROUND An inflammatory myofibroblastic tumour (IMFT) is a rare mesenchymal neoplasm characterised by anaplastic lymphoma kinase (ALK) gene rearrangements. We assessed the activity and safety of crizotinib, a tyrosine kinase inhibitor, targeting ALK in patients with advanced IMFT either with or without ALK alterations. METHODS We did a multicentre, biomarker-driven, single-drug, non-randomised, open-label, two-stage phase 2 trial (European Organisation for Research and Treatment of Cancer 90101 CREATE) at 13 study sites (five university hospitals and eight specialty clinics) in eight European countries (Belgium, France, Germany, Italy, Netherlands, Poland, Slovakia, and the UK). Eligible participants were patients aged at least 15 years with a local diagnosis of advanced or metastatic IMFT deemed incurable with surgery, radiotherapy, or systemic therapy; measurable disease; an Eastern Cooperative Oncology Group performance status of 0-2; and adequate haematological, renal, and liver function. Central reference pathology was done for confirmation of the diagnosis, and ALK positivity or negativity was assessed centrally using immunohistochemistry and fluorescence in-situ hybridisation based on archival tumour tissue and defined as ALK immunopositivity or rearrangements in at least 15% of tumour cells. Eligible ALK-positive and ALK-negative patients received oral crizotinib 250 mg twice per day administered on a continuous daily dosing schedule (the duration of each treatment cycle was 21 days) until documented disease progression, unacceptable toxicity, or patient refusal. If at least two of the first 12 eligible and assessable ALK-positive patients achieved a confirmed complete or partial response according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, a maximum of 35 patients were to be enrolled. If at least six ALK-positive patients achieved a confirmed response, the trial would be deemed successful. The primary endpoint was the proportion of patients who achieved an objective response (ie, a complete or partial response) as per RECIST 1.1, with response confirmation assessed by the local investigator every other cycle. Activity and safety endpoints were analysed in the per-protocol population. This trial is registered with ClinicalTrials.gov, number NCT01524926. FINDINGS Between Oct 3, 2012, and April 12, 2017, we recruited and treated 20 eligible participants, 19 of whom were assessable for the primary endpoint. Median follow-up was 863 days (IQR 358-1304). Six of 12 ALK-positive patients (50%, 95% CI 21·1-78·9) and one of seven ALK-negative patients (14%, 0·0-57·9) achieved an objective response. The most common treatment-related adverse events in the 20 participants were nausea (11 [55%]), fatigue (9 [45%]), blurred vision (nine [45%]), vomiting (seven [35%]), and diarrhoea (seven [35%]). Eight serious adverse events occurred in five patients: pneumonia, fever of unknown cause, a heart attack with increased creatinine and possible sepsis, an abdominal abscess with acute renal insufficiency, and a QT prolongation. INTERPRETATION With 50% of participants with ALK-positive tumours achieving an objective response, crizotinib met the prespecified criteria for success in this trial. The results presented here support the rationale for inhibiting ALK in patients with IMFT. Crizotinib could be considered as the standard of care for patients with locally advanced or metastatic ALK-positive IMFT who do not qualify for curative surgery. FUNDING The European Organisation for Research and Treatment of Cancer and Pfizer.
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Affiliation(s)
- Patrick Schöffski
- Department of General Medical Oncology, Leuven Cancer Institute, University Hospitals Leuven, Leuven, Belgium; Laboratory of Experimental Oncology, Department of Oncology, KU Leuven, Leuven, Belgium.
| | | | - Hans Gelderblom
- Department of Medical Oncology, Leiden University Medical Center, Leiden, Netherlands
| | - Jean-Yves Blay
- Department of Medical Oncology, Centre Léon Bérard/Université Claude Bernard Lyon Institute, Lyon, France
| | - Sandra J Strauss
- Department of Oncology, University College London Hospitals NHS Trust, London, UK
| | - Silvia Stacchiotti
- Department of Medical Oncology, IRCCS Fondazione Istituto Nazionale Tumori, Milano, Italy
| | - Piotr Rutkowski
- Department of Soft Tissue/Bone Sarcoma and Melanoma, Maria Sklodowska-Curie Institute-Oncology Center, Warsaw, Poland
| | - Lars H Lindner
- Klinikum der Universität München, Medizinische Klinik III, Campus Grosshadern, Munich, Germany
| | | | | | - Nicolas Isambert
- Department of Medical Oncology, Centre Georges François Leclerc, Dijon, France
| | | | - Raf Sciot
- Department of Pathology, University Hospitals Leuven, KU Leuven, Leuven, Belgium
| | - Thomas Van Cann
- Department of General Medical Oncology, Leuven Cancer Institute, University Hospitals Leuven, Leuven, Belgium; Laboratory of Experimental Oncology, Department of Oncology, KU Leuven, Leuven, Belgium
| | - Sandrine Marréaud
- European Organisation for Research and Treatment of Cancer, Brussels, Belgium
| | | | - Sandra Collette
- European Organisation for Research and Treatment of Cancer, Brussels, Belgium
| | - Agnieszka Wozniak
- Laboratory of Experimental Oncology, Department of Oncology, KU Leuven, Leuven, Belgium
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49
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Montes-Mojarro IA, Steinhilber J, Bonzheim I, Quintanilla-Martinez L, Fend F. The Pathological Spectrum of Systemic Anaplastic Large Cell Lymphoma (ALCL). Cancers (Basel) 2018; 10:cancers10040107. [PMID: 29617304 PMCID: PMC5923362 DOI: 10.3390/cancers10040107] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2018] [Revised: 03/30/2018] [Accepted: 04/02/2018] [Indexed: 12/11/2022] Open
Abstract
Anaplastic large cell lymphoma (ALCL) represents a group of malignant T-cell lymphoproliferations that share morphological and immunophenotypical features, namely strong CD30 expression and variable loss of T-cell markers, but differ in clinical presentation and prognosis. The recognition of anaplastic lymphoma kinase (ALK) fusion proteins as a result of chromosomal translocations or inversions was the starting point for the distinction of different subgroups of ALCL. According to their distinct clinical settings and molecular findings, the 2016 revised World Health Organization (WHO) classification recognizes four different entities: systemic ALK-positive ALCL (ALK+ ALCL), systemic ALK-negative ALCL (ALK− ALCL), primary cutaneous ALCL (pC-ALCL), and breast implant-associated ALCL (BI-ALCL), the latter included as a provisional entity. ALK is rearranged in approximately 80% of systemic ALCL cases with one of its partner genes, most commonly NPM1, and is associated with favorable prognosis, whereas systemic ALK− ALCL shows heterogeneous clinical, phenotypical, and genetic features, underlining the different oncogenesis between these two entities. Recognition of the pathological spectrum of ALCL is crucial to understand its pathogenesis and its boundaries with other entities. In this review, we will focus on the morphological, immunophenotypical, and molecular features of systemic ALK+ and ALK− ALCL. In addition, BI-ALCL will be discussed.
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Affiliation(s)
- Ivonne A Montes-Mojarro
- Institute of Pathology and Neuropathology and Comprehensive Cancer Center Tübingen, Eberhard-Karls-University, Liebermeisterstraße 8, 72076 Tübingen, Germany.
| | - Julia Steinhilber
- Institute of Pathology and Neuropathology and Comprehensive Cancer Center Tübingen, Eberhard-Karls-University, Liebermeisterstraße 8, 72076 Tübingen, Germany.
| | - Irina Bonzheim
- Institute of Pathology and Neuropathology and Comprehensive Cancer Center Tübingen, Eberhard-Karls-University, Liebermeisterstraße 8, 72076 Tübingen, Germany.
| | - Leticia Quintanilla-Martinez
- Institute of Pathology and Neuropathology and Comprehensive Cancer Center Tübingen, Eberhard-Karls-University, Liebermeisterstraße 8, 72076 Tübingen, Germany.
| | - Falko Fend
- Institute of Pathology and Neuropathology and Comprehensive Cancer Center Tübingen, Eberhard-Karls-University, Liebermeisterstraße 8, 72076 Tübingen, Germany.
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50
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Sharma GG, Mota I, Mologni L, Patrucco E, Gambacorti-Passerini C, Chiarle R. Tumor Resistance against ALK Targeted Therapy-Where It Comes From and Where It Goes. Cancers (Basel) 2018; 10:E62. [PMID: 29495603 PMCID: PMC5876637 DOI: 10.3390/cancers10030062] [Citation(s) in RCA: 66] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2018] [Revised: 02/25/2018] [Accepted: 02/26/2018] [Indexed: 12/12/2022] Open
Abstract
Anaplastic lymphoma kinase (ALK) is a validated molecular target in several ALK-rearranged malignancies, particularly in non-small-cell lung cancer (NSCLC), which has generated considerable interest and effort in developing ALK tyrosine kinase inhibitors (TKI). Crizotinib was the first ALK inhibitor to receive FDA approval for ALK-positive NSCLC patients treatment. However, the clinical benefit observed in targeting ALK in NSCLC is almost universally limited by the emergence of drug resistance with a median of occurrence of approximately 10 months after the initiation of therapy. Thus, to overcome crizotinib resistance, second/third-generation ALK inhibitors have been developed and received, or are close to receiving, FDA approval. However, even when treated with these new inhibitors tumors became resistant, both in vitro and in clinical settings. The elucidation of the diverse mechanisms through which resistance to ALK TKI emerges, has informed the design of novel therapeutic strategies to improve patients disease outcome. This review summarizes the currently available knowledge regarding ALK physiologic function/structure and neoplastic transforming role, as well as an update on ALK inhibitors and resistance mechanisms along with possible therapeutic strategies that may overcome the development of resistance.
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Affiliation(s)
- Geeta Geeta Sharma
- Department of Medicine and Surgery, University of Milano-Bicocca, Monza 20900, Italy.
| | - Ines Mota
- Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin 10124, Italy.
| | - Luca Mologni
- Department of Medicine and Surgery, University of Milano-Bicocca, Monza 20900, Italy.
- Galkem Srl, Monza 20900, Italy.
| | - Enrico Patrucco
- Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin 10124, Italy.
| | - Carlo Gambacorti-Passerini
- Department of Medicine and Surgery, University of Milano-Bicocca, Monza 20900, Italy.
- Galkem Srl, Monza 20900, Italy.
- Hematology and Clinical Research Unit, San Gerardo Hospital, Monza 20900, Italy.
| | - Roberto Chiarle
- Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin 10124, Italy.
- Department of Pathology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
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