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Kalfoutzou A, Spanou K, Mylonakis A, Lagopoulou V, Dimitrakoudi M, Korovila A, Piperis C, Tsiouri E, Mostratou E. Breaking point: Systemic mastocytosis manifesting as severe osteoporosis. Oncoscience 2025; 12:13-20. [PMID: 39911853 PMCID: PMC11796133 DOI: 10.18632/oncoscience.614] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2024] [Accepted: 01/27/2025] [Indexed: 02/07/2025] Open
Abstract
Systemic mastocytosis (SM) encompasses a wide spectrum of myeloproliferative disorders defined by the aggregation of abnormal mast cells in various tissues, including the bone marrow, gastrointestinal tract, liver and lymph nodes. The release of tryptase, interleukins and cytokines by the accumulated mast cells causes a multi-system response that can range from mild flushing and pruritus to severe anaphylactic reactions, gastrointestinal disturbances, and cardiovascular symptoms, including hypotension and syncope. Furthermore, severe osteoporosis manifesting as bone-lytic lesions or pathologic fractures due to mast cell mediator-triggered bone resorption, is a rather common manifestation of SM, occurring in more than two-thirds of patients. The vast majority of SM cases harbor the D816V KIT mutation, which is an independent prognostic factor, and serves as a therapeutic target. This is a rare case of a young male who presented with new-onset back pain due to osteoporotic fractures and was diagnosed with SM without the D816V KIT mutation. Our case aims to emphasize one of the most underrecognised causes of osteoporosis in adults, and to shed light on a frequently misdiagnosed yet potentially severe hematologic disorder.
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Affiliation(s)
- Areti Kalfoutzou
- Department of Medical Oncology, 251 Air Force General Hospital, Athens 115 25, Greece
| | - Kalliroi Spanou
- Department of Pathology, 251 Air Force General Hospital, Athens 115 25, Greece
| | - Adam Mylonakis
- First Department of Surgery, “Laiko” General Hospital, National and Kapodistrian University of Athens 115 27, Greece
| | | | - Maria Dimitrakoudi
- Department of Hematology, “Laiko” General Hospital, National and Kapodistrian University of Athens 115 27, Greece
| | - Alexandra Korovila
- Department of Radiation Oncology, Alexandra Regional General Hospital, Athens 115 28, Greece
| | - Christos Piperis
- Department of Cardiology, “Georgios Gennimatas” General Hospital, Athens 115 27, Greece
| | - Eleni Tsiouri
- Second Department of Internal Medicine, 251 Air Force General Hospital, Athens 115 25, Greece
| | - Eleni Mostratou
- Second Department of Internal Medicine, 251 Air Force General Hospital, Athens 115 25, Greece
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2
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Theoharides TC, Twahir A, Kempuraj D. Mast cells in the autonomic nervous system and potential role in disorders with dysautonomia and neuroinflammation. Ann Allergy Asthma Immunol 2024; 132:440-454. [PMID: 37951572 DOI: 10.1016/j.anai.2023.10.032] [Citation(s) in RCA: 11] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2023] [Revised: 09/16/2023] [Accepted: 10/06/2023] [Indexed: 11/14/2023]
Abstract
Mast cells (MC) are ubiquitous in the body, and they are critical for not only in allergic diseases but also in immunity and inflammation, including having potential involvement in the pathophysiology of dysautonomias and neuroinflammatory disorders. MC are located perivascularly close to nerve endings and sites such as the carotid bodies, heart, hypothalamus, the pineal gland, and the adrenal gland that would allow them not only to regulate but also to be affected by the autonomic nervous system (ANS). MC are stimulated not only by allergens but also many other triggers including some from the ANS that can affect MC release of neurosensitizing, proinflammatory, and vasoactive mediators. Hence, MC may be able to regulate homeostatic functions that seem to be dysfunctional in many conditions, such as postural orthostatic tachycardia syndrome, autism spectrum disorder, myalgic encephalomyelitis/chronic fatigue syndrome, and Long-COVID syndrome. The evidence indicates that there is a possible association between these conditions and diseases associated with MC activation. There is no effective treatment for any form of these conditions other than minimizing symptoms. Given the many ways MC could be activated and the numerous mediators released, it would be important to develop ways to inhibit stimulation of MC and the release of ANS-relevant mediators.
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Affiliation(s)
- Theoharis C Theoharides
- Institute for Neuro-Immune Medicine, Dr. Kiran C. Patel College of Osteopathic Medicine, Nova Southeastern University, Ft. Lauderdale, Florida; Laboratory of Molecular Immunopharmacology and Drug Discovery, Department of Immunology, Tufts University School of Medicine, Boston, Massachusetts.
| | - Assma Twahir
- Institute for Neuro-Immune Medicine, Dr. Kiran C. Patel College of Osteopathic Medicine, Nova Southeastern University, Ft. Lauderdale, Florida
| | - Duraisamy Kempuraj
- Institute for Neuro-Immune Medicine, Dr. Kiran C. Patel College of Osteopathic Medicine, Nova Southeastern University, Ft. Lauderdale, Florida
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Zmorzynski S, Kimicka-Szajwaj A, Szajwaj A, Czerwik-Marcinkowska J, Wojcierowski J. Genetic Changes in Mastocytes and Their Significance in Mast Cell Tumor Prognosis and Treatment. Genes (Basel) 2024; 15:137. [PMID: 38275618 PMCID: PMC10815783 DOI: 10.3390/genes15010137] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2023] [Revised: 01/12/2024] [Accepted: 01/20/2024] [Indexed: 01/27/2024] Open
Abstract
Mast cell tumors are a large group of diseases occurring in dogs, cats, mice, as well as in humans. Systemic mastocytosis (SM) is a disease involving the accumulation of mast cells in organs. KIT gene mutations are very often seen in abnormal mast cells. In SM, high KIT/CD117 expression is observed; however, there are usually no KIT gene mutations present. Mastocytoma (MCT)-a form of cutaneous neoplasm-is common in animals but quite rare in humans. KIT/CD117 receptor mutations were studied as the typical changes for human mastocytosis. In 80% of human cases, the KIT gene substitution p.D816H was present. In about 25% of MCTs, metastasis was observed. Changes in the gene expression of certain genes, such as overexpression of the DNAJ3A3 gene, promote metastasis. In contrast, the SNORD93 gene blocks the expression of metastasis genes. The panel of miR-21-5p, miR-379, and miR-885 has a good efficiency in discriminating healthy and MCT-affected dogs, as well as MCT-affected dogs with and without nodal metastasis. Further studies on the pathobiology of mast cells can lead to clinical improvements, such as better MCT diagnosis and treatment. Our paper reviews studies on the topic of mast cells, which have been carried out over the past few years.
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Larouche V, Paré MF, Grenier PO, Wieckowska A, Gagné E, Laframboise R, Jabado N, De Bie I. A Review of the Clinical Features and Management of Systemic Congenital Mastocytosis through the Presentation of An Unusual Prenatal-Onset Case. Curr Oncol 2023; 30:8992-9003. [PMID: 37887549 PMCID: PMC10605361 DOI: 10.3390/curroncol30100649] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2023] [Revised: 09/23/2023] [Accepted: 10/01/2023] [Indexed: 10/28/2023] Open
Abstract
Mastocytosis is a heterogeneous group of rare hematological disorders that can occur in infancy. We report a 16-year-old girl who presented with an aggressive form of systemic congenital mastocytosis, associated with a significant global developmental delay, deafness, and multiple anomalies. At 4 years of age, she developed a germinoma presenting as an invasive spinal mass. Extensive cytogenetic, metabolic, and molecular genetic studies that included whole-exome sequencing studies revealed a KIT alteration (NM_000222.3(KIT):c2447A > 7 pAsp816Val) and likely pathogenic variant in the DNA from peripheral blood and skin lesions. C-kit was also found to be overexpressed in the spinal tumor cells. We compared the features of this child to those of six previously reported pediatric patients with cutaneous mastocytosis, microcephaly, microtia, and/or hearing loss reported in OMIM as mastocytosis, conductive hearing loss, and microtia (MIM 248910), for which the etiology has not yet been determined. This report extends the currently recognized spectrum of KIT-related disorders and provides clues as to the potential etiology of a syndromic form of congenital mastocytosis. International efforts to understand the benefits of long-term targeted therapy with tyrosine kinase inhibitors for this KIT-altered rare disease should continue to be evaluated in clinical trials.
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Affiliation(s)
- Valérie Larouche
- Department of Pediatric Hemato-oncology, Centre Hospitalier Universitaire de Quebec-Université Laval, Quebec, QC G1V4G2, Canada
| | | | - Pierre-Olivier Grenier
- Department of Dermatology, Centre Hospitalier Universitaire de Quebec-Université Laval, Quebec, QC G1V4G2, Canada
| | - Anna Wieckowska
- Departement of Pediatric, Centre Hospitalier Universitaire de Quebec-Université Laval, Quebec, QC G1V4G2, Canada
| | - Eric Gagné
- Department of Pathology, Centre Hospitalier Universitaire de Quebec-Université Laval, Quebec, QC G1V4G2, Canada
| | - Rachel Laframboise
- Department of Medical Genetics, Centre Hospitalier Universitaire de Quebec-Université Laval, Quebec, QC G1V4G2, Canada
| | - Nada Jabado
- Department of Pediatric Hemato-Oncology, Montreal Children’s Hospital, McGill University Health Centre, Montreal, QC G1V4G2, Canada
| | - Isabelle De Bie
- Division of Medical Genetics, Department of Specialized Medicine, McGill University Health Centre, Montreal, QC G1V4G2, Canada
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Elvevi A, Elli EM, Lucà M, Scaravaglio M, Pagni F, Ceola S, Ratti L, Invernizzi P, Massironi S. Clinical challenge for gastroenterologists-Gastrointestinal manifestations of systemic mastocytosis: A comprehensive review. World J Gastroenterol 2022; 28:3767-3779. [PMID: 36157547 PMCID: PMC9367223 DOI: 10.3748/wjg.v28.i29.3767] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/03/2021] [Revised: 06/06/2022] [Accepted: 07/11/2022] [Indexed: 02/06/2023] Open
Abstract
Mastocytosis is a rare and heterogeneous disease characterized by various clinical and biological features that affect different prognoses and treatments. The disease is usually divided into 2 principal categories: cutaneous and systemic disease (SM). Clinical features can be related to mast cell (MC) mediator release or pathological MC infiltration. SM is a disease often hard to identify, and the diagnosis is based on clinical, biological, histological, and molecular criteria with different specialists involved in the patient's clinical work-up. Among all manifestations of the disease, gastrointestinal (GI) symptoms are common, being present in 14%-85% of patients, and can significantly impair the quality of life. Here we review the data regarding GI involvement in SM, in terms of clinical presentations, histological and endoscopic features, the pathogenesis of GI symptoms, and their treatment.
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Affiliation(s)
- Alessandra Elvevi
- Gastroenterology Division, San Gerardo Hospital, University of Milano – Bicocca School of Medicine, Monza 20900, Italy
| | - Elena Maria Elli
- Hematology Division and Bone Marrow Transplant Unit, San Gerardo Hospital, Monza 20900, Italy
| | - Martina Lucà
- Gastroenterology Division, San Gerardo Hospital, University of Milano – Bicocca School of Medicine, Monza 20900, Italy
| | - Miki Scaravaglio
- Gastroenterology Division, San Gerardo Hospital, University of Milano – Bicocca School of Medicine, Monza 20900, Italy
| | - Fabio Pagni
- Department of Medicine and Surgery, Section of Pathology, San Gerardo Hospital, University of Milano – Bicocca School of Medicine, Monza 20900, Italy
| | - Stefano Ceola
- Department of Medicine and Surgery, Section of Pathology, San Gerardo Hospital, University of Milano – Bicocca School of Medicine, Monza 20900, Italy
| | - Laura Ratti
- Gastroenterology Division, San Gerardo Hospital, University of Milano – Bicocca School of Medicine, Monza 20900, Italy
| | - Pietro Invernizzi
- Gastroenterology Division, San Gerardo Hospital, University of Milano – Bicocca School of Medicine, Monza 20900, Italy
| | - Sara Massironi
- Gastroenterology Division, San Gerardo Hospital, University of Milano – Bicocca School of Medicine, Monza 20900, Italy
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Martin M. Mast Cells: When the Best Defense Is an Attack? Int J Mol Sci 2022; 23:ijms23073570. [PMID: 35408929 PMCID: PMC8998320 DOI: 10.3390/ijms23073570] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Revised: 03/21/2022] [Accepted: 03/23/2022] [Indexed: 11/16/2022] Open
Abstract
The main goal of this Special Issue was to highlight the recent advances made on the role of mast cells (MCs) in host defense and pathology [...].
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Affiliation(s)
- Margarita Martin
- Biochemistry Unit, Biomedicine Department, Faculty of Medicine, University of Barcelona, 08036 Barcelona, Spain;
- Clinical and Experimental Respiratory Immunoallergy (IRCE), Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain
- ARADyAL (Asthma, Drug Adverse Reactions and Allergy) Research Network, 28029 Madrid, Spain
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Tefferi A, Kittur J, Farrukh F, Begna KH, Patnaik MM, Al-Kali A, Elliott MA, Reichard KK, Gangat N, Pardanani A. Cladribine therapy for advanced and indolent systemic mastocytosis: Mayo Clinic experience in 42 consecutive cases. Br J Haematol 2021; 196:975-983. [PMID: 34729775 DOI: 10.1111/bjh.17932] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2021] [Revised: 10/16/2021] [Accepted: 10/18/2021] [Indexed: 01/08/2023]
Abstract
We describe our single institution experience with cladribine therapy in 42 patients with systemic mastocytosis (SM): 22 advanced (adv-SM; median age 65 years, 68% males) and 20 indolent/smouldering SM (ISM/SSM; median age 56 years, 45% males); subcategories included eight aggressive, 13 associated with another haematological neoplasm, one mast cell leukaemia, 17 ISM and three SSM. Overall/major response rates were 77%/45% for adv-SM and 70%/60% for ISM/SSM, and median (range) duration of response 10 (4-75) and 46 (4-140) months respectively. A >50% reduction in bone marrow mast cell burden and serum tryptase level was documented in 63% and 67% of patients with adv-SM and 50% and 46% with ISM/SSM respectively. The presence of KIT proto-oncogene, receptor tyrosine kinase (KIT)D816V predicted response in adv-SM: 17 (90%) of 19 with and none of three without the mutation responded (P < 0·01). Treatment-emergent adverse events were mostly limited to transient cytopenias: Grade 3/4 neutropenia, thrombocytopenia, or lymphopenia occurred in 27%, 27% and 27% of patients with adv-SM, and 5%, 5% and 30% with ISM/SSM respectively. The present study provides practical information that might be considered when making treatment choices between cladribine and newer KIT-targeted therapies and identifies the absence of KITD816V as a potential marker of cladribine resistance in advanced SM; the latter observation needs confirmation in a larger study.
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Affiliation(s)
- Ayalew Tefferi
- Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA
| | - Jaya Kittur
- Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA
| | - Faiqa Farrukh
- Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA
| | - Kebede H Begna
- Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA
| | - Mrinal M Patnaik
- Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA
| | - Aref Al-Kali
- Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA
| | - Michelle A Elliott
- Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA
| | - Kaaren K Reichard
- Division of Hematopathology, Department of Laboratory Medicine, Mayo Clinic, Rochester, MN, USA
| | - Naseema Gangat
- Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA
| | - Animesh Pardanani
- Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA
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Jackson CW, Pratt CM, Rupprecht CP, Pattanaik D, Krishnaswamy G. Mastocytosis and Mast Cell Activation Disorders: Clearing the Air. Int J Mol Sci 2021; 22:ijms222011270. [PMID: 34681933 PMCID: PMC8540348 DOI: 10.3390/ijms222011270] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2021] [Revised: 10/14/2021] [Accepted: 10/15/2021] [Indexed: 12/11/2022] Open
Abstract
Mast cells are derived from hematopoietic stem cell precursors and are essential to the genesis and manifestations of the allergic response. Activation of these cells by allergens leads to degranulation and elaboration of inflammatory mediators, responsible for regulating the acute dramatic inflammatory response seen. Mast cells have also been incriminated in such diverse disorders as malignancy, arthritis, coronary artery disease, and osteoporosis. There has been a recent explosion in our understanding of the mast cell and the associated clinical conditions that affect this cell type. Some mast cell disorders are associated with specific genetic mutations (such as the D816V gain-of-function mutation) with resultant clonal disease. Such disorders include cutaneous mastocytosis, systemic mastocytosis (SM), its variants (indolent/ISM, smoldering/SSM, aggressive systemic mastocytosis/ASM) and clonal (or monoclonal) mast cell activation disorders or syndromes (CMCAS/MMAS). Besides clonal mast cell activations disorders/CMCAS (also referred to as monoclonal mast cell activation syndromes/MMAS), mast cell activation can also occur secondary to allergic, inflammatory, or paraneoplastic disease. Some disorders are idiopathic as their molecular pathogenesis and evolution are unclear. A genetic disorder, referred to as hereditary alpha-tryptasemia (HαT) has also been described recently. This condition has been shown to be associated with increased severity of allergic and anaphylactic reactions and may interact variably with primary and secondary mast cell disease, resulting in complex combined disorders. The role of this review is to clarify the classification of mast cell disorders, point to molecular aspects of mast cell signaling, elucidate underlying genetic defects, and provide approaches to targeted therapies that may benefit such patients.
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Affiliation(s)
- Clayton Webster Jackson
- Department of Medicine, Wake Forest School of Medicine, Winston-Salem, NC 27101, USA; (C.W.J.); (C.M.P.)
| | - Cristina Marie Pratt
- Department of Medicine, Wake Forest School of Medicine, Winston-Salem, NC 27101, USA; (C.W.J.); (C.M.P.)
| | | | - Debendra Pattanaik
- The Division of Allergy and Immunology, UT Memphis College of Medicine, Memphis, TN 38103, USA;
| | - Guha Krishnaswamy
- Department of Medicine, Wake Forest School of Medicine, Winston-Salem, NC 27101, USA; (C.W.J.); (C.M.P.)
- The Bill Hefner VA Medical Center, The Division of Allergy and Immunology, Salisbury, NC 28144, USA
- Correspondence: or
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Sumbly V, Landry I, Iqbal S, Bhatti Z, Alshamam MS, Ashfaq S, Rizzo V. The Role of Avapritinib for the Treatment of Systemic Mastocytosis. Cureus 2021; 13:e18385. [PMID: 34729266 PMCID: PMC8556140 DOI: 10.7759/cureus.18385] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/29/2021] [Indexed: 01/08/2023] Open
Abstract
Systemic mastocytosis is a rare hematologic disorder characterized by the clonal proliferation of mast cells in extra-cutaneous organs. This disease can be further subdivided into five different phenotypes: indolent systemic mastocytosis (ISM), smoldering systemic mastocytosis (SSM), aggressive systemic mastocytosis (ASM), systemic mastocytosis with an associated hematological neoplasm (SM-AHN) and mast cell leukemia (MCL). The tyrosine kinase inhibitor (and also potent KIT D816V inhibitor) avapritinib, initially approved for the treatment of gastrointestinal stromal tumors (GISTs) bearing a PDGFRA exon 18 mutation, also showed great promise in patients with systemic mastocytosis, a disease known to be driven by a mutation in KIT (D816V). We present an overview of this rare disorder, including a review of the current understanding of the genetic mechanisms which lead to the disease state, the action of the tyrosine kinase inhibitors, as well as the latest clinical trial data which led to the current recommendations for the use of avapritinib.
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Affiliation(s)
- Vikram Sumbly
- Internal Medicine, Icahn School of Medicine at Mount Sinai, New York City Health and Hospitals, Queens, USA
| | - Ian Landry
- Medicine, Icahn School of Medicine at Mount Sinai, New York City Health and Hospitals, Queens, USA
| | - Saba Iqbal
- Internal Medicine, Icahn School of Medicine at Mount Sinai, New York City Health and Hospitals, Queens, USA
| | - Zamaraq Bhatti
- Internal Medicine, Icahn School of Medicine at Mount Sinai, New York City Health and Hospitals, Queens, USA
| | - Mohsen S Alshamam
- Internal Medicine, Icahn School of Medicine at Mount Sinai, New York City Health and Hospitals, Queens, USA
| | | | - Vincent Rizzo
- Internal Medicine, Icahn School of Medicine at Mount Sinai, New York City Health and Hospitals, Queens, USA
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