79 results on '"Daisy Alapat"'
Search Results
2. Longitudinal, natural history study reveals the disease burden of idiopathic multicentric Castleman disease
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Mateo Sarmiento Bustamante, Sheila K. Pierson, Yue Ren, Adam Bagg, Joshua D. Brandstadter, Gordan Srkalovic, Natalie Mango, Daisy Alapat, Mary Jo Lechowicz, Hongzhe Li, Frits van Rhee, Megan S. Lim, and David C. Fajgenbaum
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Idiopathic multicentric Castleman disease (iMCD) is a rare hematologic disorder with heterogeneous presentations ranging from moderate constitutional symptoms to life-threatening multiorgan system involvement. iMCD patients present with vastly different clinical subtypes, with some patients demonstrating thrombocytopenia, anasarca, fever/elevated C-reactive protein, reticulin fibrosis/renal failure, and organomegaly (TAFRO) and others demonstrating more mild/moderate symptoms with potential for severe disease (not otherwise specified, NOS). Due to its rarity and heterogeneity, the natural history and long-term burden of iMCD are poorly understood. We investigated real-world medical data from ACCELERATE, a large natural history registry of Castleman disease patients, to better characterize the long-term disease burden experienced by these patients. We found that iMCD-TAFRO patients face significant hospitalization burden, requiring more time in the hospital than iMCD-NOS patients during the year surrounding diagnosis (median [IQR] 36 [18, 61] days vs. 0 [0, 4] days; p
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- 2024
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3. Stem cell mutations can be detected in myeloma patients years before onset of secondary leukemias
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Ashwin Sridharan, Carolina D. Schinke, George Georgiev, Mariana Da Silva Ferreira, Victor Thiruthuvanathan, Ian MacArthur, Tushar D. Bhagat, Gaurav S. Choudhary, Srinivas Aluri, Jiahao Chen, Kith Pradhan, Yu Xia, Maya Panjikaran, Gregory Sims, Chirag K. Bhagat, Ryan Bender, Lauryn Keeler, Armin Graber, Christoph Heuck, Frederick A. Fletcher, Daisy Alapat, Niels Weinhold, Sarah K. Johnson, Amittha Wickrema, Bart Barlogie, Gareth J. Morgan, Aditi Shastri, Ulrich Steidl, Britta Will, and Amit Verma
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Specialties of internal medicine ,RC581-951 - Abstract
Abstract: Therapy-related acute myeloid leukemia and myelodysplastic syndromes (t-AML/t-MDS) are secondary hematologic malignancies associated with poor prognosis, warranting insights into their predisposing conditions and cells of origin. We identified patients with myeloma who developed t-AML/t-MDS and analyzed their stem and progenitor cells collected years before the onset of secondary disease. We demonstrate that aberrant stem cells with high CD123 expression can be detected long before the onset of overt leukemia. Rigorous sorting, followed by targeted sequencing, resulted in ultradeep functional depth of sequencing and revealed preexisting mutant hematopoietic stem cell (HSC) clones, mainly harboring TP53 mutations, that became the dominant population at the time of leukemic presentation. Taken together, these data show that HSCs can act as reservoirs for leukemia-initiating cells many years before the onset of myeloid leukemia.
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- 2019
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4. Predicting risk of progression in relapsed multiple myeloma using traditional risk models, focal lesion assessment with PET-CT and minimal residual disease status
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David Baker, Milan Bimali, Luis Carrillo, Archana Sachedina, Daisy Alapat, Md Shadiqul Hoque, Mathew Kottarathara, Richa Parikh, Amani Erra, Angel A. Mitma, Pankaj Mathur, Yetunde Ogunsesan, Lakshmi Yarlagadda, Sravani Gundarlapalli, Sharmilan Thanendrarajan, Maurizio Zangari, Frits van Rhee, Guido Tricot, and Carolina Schinke
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2021
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5. Virome capture sequencing does not identify active viral infection in unicentric and idiopathic multicentric Castleman disease.
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Christopher S Nabel, Stephen Sameroff, Dustin Shilling, Daisy Alapat, Jason R Ruth, Mitsuhiro Kawano, Yasuharu Sato, Katie Stone, Signe Spetalen, Federico Valdivieso, Michael D Feldman, Amy Chadburn, Alexander Fosså, Frits van Rhee, W Ian Lipkin, and David C Fajgenbaum
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Medicine ,Science - Abstract
Castleman disease (CD) describes a spectrum of heterogeneous disorders defined by characteristic lymph node histopathology. Enlarged lymph nodes demonstrating CD histopathology can occur in isolation (unicentric CD; UCD) sometimes accompanied by mild symptoms, or at multiple sites (multicentric CD, MCD) with systemic inflammation and cytokine-driven multi-organ dysfunction. The discovery that Kaposi sarcoma herpesvirus/human herpesvirus (HHV)-8 drives MCD in a subset of patients has led to the hypotheses that UCD and MCD patients with negative HHV-8 testing by conventional methods may represent false negatives, or that these cases are driven by another virus, known or unknown. To investigate these hypotheses, the virome capture sequencing for vertebrate viruses (VirCapSeq-VERT) platform was employed to detect RNA transcripts from known and novel viruses in fresh frozen lymph node tissue from CD patients (12 UCD, 11 HHV-8-negative MCD [idiopathic MCD; iMCD], and two HHV-8-positive MCD) and related diseases (three T cell lymphoma and three Hodgkin lymphoma). This assay detected HHV-8 in both HHV-8-positive cases; however, HHV-8 was not found in clinically HHV-8-negative iMCD or UCD cases. Additionally, no novel viruses were discovered, and no single known virus was detected with apparent association to HHV-8-negative CD cases. Herpesviridae family members, notably including Epstein-Barr virus (EBV), were detected in 7 out of 12 UCD and 5 of 11 iMCD cases with apparent correlations with markers of disease severity in iMCD. Analysis of a separate cohort of archival formalin-fixed, paraffin-embedded lymph node tissue by In situ hybridization revealed significantly fewer EBV-positive cells in UCD and iMCD compared to tissue from HHV-8-positive MCD and EBV-associated lymphoproliferative disorder. In an additional cohort, quantitative testing for EBV by PCR in peripheral blood during disease flare did not detect systemic EBV viremia, suggesting detection lymph node tissue is due to occult, local reactivation in UCD and iMCD. This study confirms that HHV-8 is not present in UCD and iMCD patients. Further, it fails to establish a clear association between any single virus, novel or known, and CD in HHV-8-negative cases. Given that distinct forms of CD exist with viral and non-viral etiological drivers, CD should be considered a group of distinct and separate diseases with heterogeneous causes worthy of further study.
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- 2019
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6. The level of deletion 17p and bi-allelic inactivation of TP53 has a significant impact on clinical outcome in multiple myeloma
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Sharmilan Thanendrarajan, Erming Tian, Pingping Qu, Pankaj Mathur, Carolina Schinke, Frits van Rhee, Maurizio Zangari, Leo Rasche, Niels Weinhold, Daisy Alapat, William Bellamy, Cody Ashby, Sandra Mattox, Joshua Epstein, Shmuel Yaccoby, Bart Barlogie, Antje Hoering, Michael Bauer, Brian A. Walker, Faith E. Davies, and Gareth J. Morgan
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2017
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7. The prognostic value of the depth of response in multiple myeloma depends on the time of assessment, risk status and molecular subtype
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Carolina Schinke, Antje Hoering, Hongwei Wang, Victoria Carlton, Sharmilan Thanandrarajan, Shayu Deshpande, Purvi Patel, Gabor Molnar, Sandra Susanibar, Meera Mohan, Pankaj Mathur, Muthukumar Radhakrishnan, Shadiqul Hoque, Jorge Jo Kamimoto, Monica Grazziutti, Frits van Rhee, Maurizio Zangari, Giovanni Insuasti-Beltran, Daisy Alapat, Ginell Post, Shmuel Yaccoby, Joshua Epstein, Leo Rasche, Sarah Johnson, Martin Moorhead, Tom Willis, Bart Barlogie, Brian Walker, Niels Weinhold, Faith E Davies, and Gareth J. Morgan
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2017
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8. Primary Bone Marrow Classical Hodgkin Lymphoma in HIV- Negative Population: Aggressive but Amenable
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Bhagirathbhai R Dholaria, Daisy Alapat, and Konstantinos Arnaoutakis
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Lymphoma ,HIV ,Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Classical Hodgkin Lymphoma has distinct clinopathological features and good response to treatment in most cases. Primary bone marrow limited Hodgkin Lymphoma is uncommon and primarily described in HIV positive patients. It behaves like a distinct entity with aggressive clinical course and poor response to available treatments. We discuss here a case of Hodgkin Lymphoma with isolated involvement of the bone marrow in an HIV negative patient, successfully treated with conventional chemotherapy.
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- 2014
9. Gastrointestinal, hepatic, and pancreatobiliary involvement by plasma cell neoplasms: clinicopathologic correlations in a retrospective cohort of 116 cases
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Justin T Kelley, Lanisha D Fuller, Keith K Lai, Rhonda K Yantiss, Siarhei Dzedzik, Daisy Alapat, Azin Mashayekhi, Lindsay Alpert, Raul S Gonzalez, Scott R Owens, Daniel A Arber, and Laura W Lamps
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Gastrointestinal Tract ,Histology ,Liver ,Humans ,General Medicine ,Multiple Myeloma ,Plasmacytoma ,Retrospective Studies ,Gastrointestinal Neoplasms ,Pathology and Forensic Medicine - Abstract
Plasma cell neoplasms (PCNs) may involve the gastrointestinal (GI) tract in two forms: plasmacytoma (PC), an isolated lesion that lacks marrow involvement, and extramedullary myeloma (EMM). However, previous literature on PCNs involving the GI tract, liver, and pancreas is limited. We evaluated the clinicopathologic features of the largest series of GI PCNs to date.Six institutional archives were searched for GI, liver, and pancreas cases involved with PCNs. Medical records were reviewed for clinical and imaging features. Histopathologic features evaluated included involved organ, tumor grade, and marrow involvement. Overall, 116 cases from 102 patients were identified. The tumors most presented as incidental findings (29%). The liver was most involved (47%), and masses/polyps (29%) or ulcers (21%) were the most common findings. Most cases had high-grade morphology (55%). The majority (74%) of GI PCNs were classified as EMM due to the presence of marrow involvement at some point during the disease course, occurring within a year of marrow diagnosis in 46% of patients. PC was classified in 26% of patients due to the lack of marrow involvement. Most (70%) patients died from disease within 10 years (median 14.1) of diagnosis and more than half (58%) died within 6 months.PC and EMM involving the GI tract, liver, and pancreas have a wide range of clinicopathologic presentations. Tumors may occur virtually anywhere in the GI tract or abdomen and may precede the diagnosis of marrow involvement. Both GI PC and EMM are associated with a poor prognosis.
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- 2022
10. The disease course of Castleman disease patients with fatal outcomes in the <scp>ACCELERATE</scp> registry
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David C, Fajgenbaum, Sheila K, Pierson, Karan, Kanhai, Adam, Bagg, Daisy, Alapat, Megan S, Lim, Mary Jo, Lechowicz, Gordan, Srkalovic, Thomas S, Uldrick, and Frits, van Rhee
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Fever ,Castleman Disease ,Disease Progression ,Humans ,Registries ,Hematology ,Thrombocytopenia - Abstract
Castleman disease (CD) describes a group of rare, potentially fatal lymphoproliferative disorders. To determine factors associated with mortality in CD, we analysed data from deceased patients in the ACCELERATE registry and compared them with matched controls. We analysed demographic, treatment and laboratory data from all deceased CD patients, matched controls and a subgroup of idiopathic multicentric Castleman disease (iMCD) patients. Of the 140 patients in ACCELERATE with a confirmed CD diagnosis, 10 had died. There were 72 patients with confirmed iMCD; six were deceased. The deceased CD cohort had more hospitalisations per year, higher overall hospitalisations and more days hospitalised per month, and received more treatment regimens per year than the matched-control group. Analysis of laboratory values showed a significantly decreased absolute lymphocyte count at months 3 and 6 in the deceased cohort compared with controls. Among iMCD patients, there was a higher proportion of iMCD-TAFRO (thrombocytopenia, anasarca, fever, reticulin myelofibrosis, renal dysfunction and organomegaly) cases in the deceased group. The deceased iMCD group had significantly lower immunoglobulin M, international normalised ratio and platelet count. These data demonstrate that there may be differences between patients who have fatal and non-fatal outcomes, and provide preliminary suggestions for parameters to evaluate further.
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- 2022
11. Synchronous plasma cell neoplasm and B lymphoblastic leukemia/lymphoma at initial presentation: first report of an unusual association with a good outcome
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Ivette Perez, Carolina Schinke, Sergio Pina-Oviedo, and Daisy Alapat
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Histology ,Hematology ,Pathology and Forensic Medicine - Published
- 2022
12. Predicting risk of progression in relapsed multiple myeloma using traditional risk models, focal lesion assessment with PET-CT and minimal residual disease status
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Amani Erra, Luis Carrillo, Pankaj Mathur, Daisy Alapat, Sravani Gundarlapalli, Sharmilan Thanendrarajan, Lakshmi Yarlagadda, Milan Bimali, Mathew Kottarathara, Maurizio Zangari, Angel A Mitma, Richa Parikh, David Baker, Guido Tricot, Frits van Rhee, Archana Sachedina, Yetunde Ogunsesan, Carolina Schinke, and Shadiqul Hoque
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medicine.medical_specialty ,PET-CT ,Neoplasm, Residual ,business.industry ,Hematology ,medicine.disease ,Minimal residual disease ,Focal lesion ,Fluorodeoxyglucose F18 ,Positron Emission Tomography Computed Tomography ,Positron-Emission Tomography ,medicine ,Humans ,Radiology ,Radiopharmaceuticals ,Letters to the Editor ,Multiple Myeloma ,business ,Multiple myeloma - Abstract
Not available.
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- 2021
13. Combinatorial treatment for unresectable unicentric Castleman disease
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Daisy Alapat, James Meek, Ralph Broadwater, Frits van Rhee, Mary E. Meek, and Meera Mohan
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Adult ,Male ,medicine.medical_specialty ,medicine.medical_treatment ,Disease ,Cryosurgery ,Pelvis ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,In patient ,Embolization ,Cyclophosphamide ,Therapeutic embolization ,Chemotherapy ,business.industry ,Castleman Disease ,Castleman disease ,Mediastinum ,Cryoablation ,Hematology ,General Medicine ,Middle Aged ,medicine.disease ,Combined Modality Therapy ,Embolization, Therapeutic ,Treatment Outcome ,Doxorubicin ,Vincristine ,Axilla ,Prednisone ,Female ,Rituximab ,Radiology ,business ,medicine.drug - Abstract
Unresectable, symptomatic unicentric Castleman disease (UCD) can represent a formidable therapeutic challenge. UCD masses are often highly vascularized offering the opportunity for therapeutic embolization. Herein, we report on 6 patients in which therapeutic embolization was combined with other medical interventions including surgery (n = 3), rituximab (n = 6), cryoablation (n = 2), and chemotherapy (n = 3). Five patients had significant tumor volume reductions (median: 83.2%; range: 76.7-100). All five responding patients had resolution of symptomatology. There were no serious complications in the patients who received embolization and proceeded to surgery. In conclusion, effective disease and symptom control can be obtained in patients with symptomatic, unresectable UCD by combining different therapeutic interventions.
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- 2021
14. Longitudinal, Real-World Data Reveal Treatment Effectiveness in Idiopathic Multicentric Castleman Disease and Support Current Treatment Guidelines
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Sheila K Pierson, Mateo Sarmiento Bustamante, Joshua D Brandstadter, Daisy Alapat, Adam Bagg, Mary Jo Lechowicz, Gordan Srkalovic, Megan S. Lim, Frits van Rhee, and David C Fajgenbaum
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
15. Idiopathic Multicentric Castleman Disease Interactive Disease Awareness and Educational Tool for Pathologists
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Elena Sabattini, Jadee Neff, Daisy Alapat, Thomas Tousseyn, Grzegorz Rymkiewicz, Henrique Moura de Paula, Kateřina Kamarádová, Santiago Montes Moreno, and Stephen Lade
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
16. Increased Comorbidities and Hospitalizations Associated with Idiopathic Multicentric Castleman Disease
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Mateo Sarmiento Bustamante, Sheila K Pierson, Yue Ren, Daisy Alapat, Adam Bagg, Joshua D Brandstadter, Mary Jo Lechowicz, Hongzhe Lee, Gordan Srkalovic, Megan S. Lim, Frits van Rhee, and David C Fajgenbaum
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
17. Tandem autologous stem cell transplantation in patients with persistent bone marrow minimal residual disease after first transplantation in multiple myeloma
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Meera Mohan, Sravani Gundarlapalli, Aniko Szabo, Naveen Yarlagadda, Sunilkumar Kakadia, Manojna Konda, Anusha Jillella, Amisha Fnu, Yetunde Ogunsesan, Lakshmi Yarlagadda, Nishant Thalambedu, Hussain Munawar, Monica Graziutti, Samer Al Hadidi, Daisy Alapat, Sharmilan Thanendrarajan, Maurizio Zangari, Frits van Rhee, and Carolina Schinke
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Neoplasm, Residual ,Receptors, Chimeric Antigen ,Bone Marrow ,Hematopoietic Stem Cell Transplantation ,Humans ,Hematology ,Multiple Myeloma ,Transplantation, Autologous ,Bone Marrow Transplantation ,Stem Cell Transplantation - Published
- 2022
18. Primary Plasma Cell Neoplasm of the Kidney Without Formation of a Mass and Its Renal Manifestations: An Interstitial Variant of Renal Plasmacytoma?
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Daisy Alapat, Autumn Wyeth, Sergio Pina-Oviedo, Neriman Gokden, and Maurizio Zangari
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Cancer Research ,Kidney ,Pathology ,medicine.medical_specialty ,business.industry ,Hematology ,Plasma cell neoplasm ,medicine.disease ,Light chain deposition disease ,medicine.anatomical_structure ,Oncology ,Proximal Tubulopathy ,Medicine ,Plasmacytoma ,Extramedullary plasmacytoma ,business - Published
- 2020
19. Stem cell mutations can be detected in myeloma patients years before onset of secondary leukemias
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Bart Barlogie, Tushar D. Bhagat, Armin Graber, Ryan Bender, Gaurav Choudhary, Frederick A. Fletcher, Maya Panjikaran, Victor Thiruthuvanathan, Daisy Alapat, Lauryn Keeler, Sarah K. Johnson, Ulrich Steidl, Chirag K Bhagat, Amittha Wickrema, Christoph Heuck, Jiahao Chen, George I. Georgiev, Ian C. MacArthur, Carolina Schinke, Aditi Shastri, Britta Will, Srinivas Aluri, Ashwin Sridharan, Gregory Sims, Niels Weinhold, Mariana da Silva Ferreira, Yu Xia, Amit Verma, Gareth J. Morgan, and Kith Pradhan
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0301 basic medicine ,Myeloid ,Hematopoiesis and Stem Cells ,03 medical and health sciences ,0302 clinical medicine ,hemic and lymphatic diseases ,Humans ,Medicine ,Progenitor cell ,Multiple myeloma ,business.industry ,Myelodysplastic syndromes ,Myeloid leukemia ,Hematopoietic stem cell ,Neoplasms, Second Primary ,Hematology ,Hematopoietic Stem Cells ,medicine.disease ,Leukemia, Myeloid, Acute ,Leukemia ,030104 developmental biology ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Mutation ,Cancer research ,Stem cell ,Multiple Myeloma ,business - Abstract
Therapy-related acute myeloid leukemia and myelodysplastic syndromes (t-AML/t-MDS) are secondary hematologic malignancies associated with poor prognosis, warranting insights into their predisposing conditions and cells of origin. We identified patients with myeloma who developed t-AML/t-MDS and analyzed their stem and progenitor cells collected years before the onset of secondary disease. We demonstrate that aberrant stem cells with high CD123 expression can be detected long before the onset of overt leukemia. Rigorous sorting, followed by targeted sequencing, resulted in ultradeep functional depth of sequencing and revealed preexisting mutant hematopoietic stem cell (HSC) clones, mainly harboring TP53 mutations, that became the dominant population at the time of leukemic presentation. Taken together, these data show that HSCs can act as reservoirs for leukemia-initiating cells many years before the onset of myeloid leukemia.
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- 2019
20. Correction: Bone marrow microenvironments that contribute to patient outcomes in newly diagnosed multiple myeloma: A cohort study of patients in the Total Therapy clinical trials
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Amrit P. Singh, Frank Schmitz, Adam Z. Rosenthal, Madhav V. Dhodapkar, Antje Hoering, Daisy Alapat, Yan Ren, Maurizio Zangari, Kelsie Smith, Samuel A. Danziger, Jake Gockley, Andrew Dervan, Alexander V. Ratushny, Mark McConnell, Robert M. Hershberg, Suzana Couto, Brian A Walker, Faith E. Davies, Alison Fitch, Wilbert B. Copeland, Gareth J. Morgan, Bart Barlogie, Phil Farmer, David J. Reiss, Brian Fox, Mary H. Young, Frits van Rhee, Cody Ashby, Katie Newhall, Nathan Petty, Michael A Bauer, Robert Z. Orlowski, and Matthew Trotter
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Oncology ,Male ,Cancer Treatment ,Myeloma ,030204 cardiovascular system & hematology ,Plasma Cell Disorders ,Hematologic Cancers and Related Disorders ,Cohort Studies ,White Blood Cells ,0302 clinical medicine ,Animal Cells ,Bone Marrow ,Medicine and Health Sciences ,Tumor Microenvironment ,030212 general & internal medicine ,Mast Cells ,Stage (cooking) ,Multiple myeloma ,Connective Tissue Cells ,General Medicine ,Hematology ,Middle Aged ,Prognosis ,Tumor Burden ,medicine.anatomical_structure ,Connective Tissue ,Medicine ,Female ,Cellular Types ,Anatomy ,Multiple Myeloma ,medicine.drug ,Cohort study ,Research Article ,Adult ,medicine.medical_specialty ,Immune Cells ,Immunology ,Plasma Cells ,03 medical and health sciences ,Malignant Tumors ,Internal medicine ,medicine ,Humans ,Myelomas and Lymphoproliferative Diseases ,Tumor microenvironment ,Blood Cells ,business.industry ,Cancer ,Biology and Life Sciences ,Cancers and Neoplasms ,Correction ,Cell Biology ,medicine.disease ,Thalidomide ,Clinical trial ,Eosinophils ,Biological Tissue ,Bone marrow ,business ,Granulocytes - Abstract
Background The tumor microenvironment (TME) is increasingly appreciated as an important determinant of cancer outcome, including in multiple myeloma (MM). However, most myeloma microenvironment studies have been based on bone marrow (BM) aspirates, which often do not fully reflect the cellular content of BM tissue itself. To address this limitation in myeloma research, we systematically characterized the whole bone marrow (WBM) microenvironment during premalignant, baseline, on treatment, and post-treatment phases. Methods and findings Between 2004 and 2019, 998 BM samples were taken from 436 patients with newly diagnosed MM (NDMM) at the University of Arkansas for Medical Sciences in Little Rock, Arkansas, United States of America. These patients were 61% male and 39% female, 89% White, 8% Black, and 3% other/refused, with a mean age of 58 years. Using WBM and matched cluster of differentiation (CD)138-selected tumor gene expression to control for tumor burden, we identified a subgroup of patients with an adverse TME associated with 17 fewer months of progression-free survival (PFS) (95% confidence interval [CI] 5–29, 49–69 versus 70–82 months, χ2 p = 0.001) and 15 fewer months of overall survival (OS; 95% CI –1 to 31, 92–120 versus 113–129 months, χ2 p = 0.036). Using immunohistochemistry-validated computational tools that identify distinct cell types from bulk gene expression, we showed that the adverse outcome was correlated with elevated CD8+ T cell and reduced granulocytic cell proportions. This microenvironment develops during the progression of premalignant to malignant disease and becomes less prevalent after therapy, in which it is associated with improved outcomes. In patients with quantified International Staging System (ISS) stage and 70-gene Prognostic Risk Score (GEP-70) scores, taking the microenvironment into consideration would have identified an additional 40 out of 290 patients (14%, premutation p = 0.001) with significantly worse outcomes (PFS, 95% CI 6–36, 49–73 versus 74–90 months) who were not identified by existing clinical (ISS stage III) and tumor (GEP-70) criteria as high risk. The main limitations of this study are that it relies on computationally identified cell types and that patients were treated with thalidomide rather than current therapies. Conclusions In this study, we observe that granulocyte signatures in the MM TME contribute to a more accurate prognosis. This implies that future researchers and clinicians treating patients should quantify TME components, in particular monocytes and granulocytes, which are often ignored in microenvironment studies., Author summary Why was this study done? The cells around a tumor, also known as the tumor microenvironment (TME), can help a tumor grow by suppressing the immune system or fight a tumor by mounting an immune response. Most studies of multiple myeloma (MM) have focused on the tumor itself, rather than the bone marrow (BM) TME in which the tumor is growing. We hypothesized that the MM TME held clues that could help us better treat patients. What did the researchers do and find? We used a gene-expression–based computational technique to determine which cell types were present in patient BM. Patients with BM lacking a family of innate immune cells called granulocytes presented with worse outcomes compared to other patients. As MM progresses from a predisease to a cancerous state, the percentage of granulocytes decreases; the patients with the fewest granulocytes had more serious diseases. What do these findings mean? If granulocytes help myeloma patients respond to therapy, then addressing the decline in granulocytes may improve MM treatment. Patients with MM and few granulocytes in their BM should be watched for worse outcomes.
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- 2021
21. Clinical implications of loss of bone marrow minimal residual disease negativity in multiple myeloma
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Naveen Yarlagadda, Jeffrey R. Sawyer, Dinesh Atwal, James Lopez, Yadav Pandey, Arya Mariam Roy, Sharmilan Thanendrarajan, Aniko Szabo, Samantha Kendrick, Meera Mohan, Frits van Rhee, Maurizio Zangari, Carolina Schinke, Richa Parikh, Erming Tian, Guido Tricot, and Daisy Alapat
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Oncology ,medicine.medical_specialty ,Neoplasm, Residual ,Combination therapy ,Salvage therapy ,Transplantation, Autologous ,Autologous stem-cell transplantation ,Median follow-up ,Bone Marrow ,hemic and lymphatic diseases ,Internal medicine ,medicine ,Humans ,Multiple myeloma ,business.industry ,Hematopoietic Stem Cell Transplantation ,Hematology ,Minimal Residual Disease Negativity ,medicine.disease ,Minimal residual disease ,body regions ,medicine.anatomical_structure ,Treatment Outcome ,Bone marrow ,Neoplasm Recurrence, Local ,business ,Multiple Myeloma - Abstract
Multiple myeloma (MM) patients frequently attain a bone marrow (BM) minimal residual disease (MRD) negativity status in response to treatment. We identified 568 patients who achieved BM MRD negativity following autologous stem cell transplantation (ASCT) and maintenance combination therapy with an immunomodulatory agent and a proteasome inhibitor. BM MRD was evaluated by next-generation flow cytometry (sensitivity of 10−5 cells) at 3- to 6-month intervals. With a median follow-up of 9.9 years from diagnosis (range, 0.4-30.9), 61% of patients maintained MRD negativity, whereas 39% experienced MRD conversion at a median of 6.3 years (range, 1.4-25). The highest risk of MRD conversion occurred within the first 5 years after treatment and was observed more often in patients with abnormal metaphase cytogenetic abnormalities (95% vs 84%; P = .001). MRD conversion was associated with a high risk of relapse and preceded it by a median of 1.0 years (range, 0-4.9). However, 27% of MRD conversion-positive patients had not yet experienced a clinical relapse, with a median follow-up of 9.3 years (range, 2.2-21.2). Landmark analyses using time from ASCT revealed patients with MRD conversion during the first 3 years had an inferior overall and progression-free survival compared with patients with sustained MRD negativity. MRD conversion correctly predicted relapse in 70%, demonstrating the utility of serial BM MRD assessment to complement standard laboratory and imaging to make informed salvage therapy decisions.
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- 2021
22. Persistent bone marrow minimal residual disease as a 'high‐risk' disease feature in multiple myeloma
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Jeffrey R. Sawyer, Daisy Alapat, Maurizio Zangari, Sravani Gundarlapalli, Samantha Kendrick, Guido Tricot, Meera Mohan, Sharmilan Thanendrarajan, Erming Tian, Frits van Rhee, Carolina Schinke, Naveen Yarlagadda, and Aniko Szabo
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Male ,Neoplasm, Residual ,business.industry ,Hematology ,Disease ,Middle Aged ,Prognosis ,medicine.disease ,Bioinformatics ,Survival Analysis ,Minimal residual disease ,Text mining ,medicine.anatomical_structure ,Bone Marrow ,Feature (computer vision) ,medicine ,Humans ,Female ,Bone marrow ,Multiple Myeloma ,business ,Multiple myeloma ,Aged - Published
- 2021
23. Combination of flow cytometry and functional imaging for monitoring of residual disease in myeloma
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Bart Barlogie, Ruslana Tytarenko, Manoj Kumar, Leo Rasche, Rohan Samant, Cody Ashby, Christopher P. Wardell, Brian A Walker, Sharmilan Thanendrarajan, Faith E. Davies, Michael A Bauer, R. van Hemert, Maurizio Zangari, Joshua Epstein, Carolina Schinke, Daisy Alapat, A F Williams, F. van Rhee, Niels Weinhold, Gareth J. Morgan, Grant Gershner, and James E. McDonald
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Oncology ,0301 basic medicine ,Cancer Research ,Neoplasm, Residual ,Salvage therapy ,Biochemistry ,0302 clinical medicine ,hemic and lymphatic diseases ,Medicine ,Multiple myeloma ,Hematology ,medicine.diagnostic_test ,Remission Induction ,Hematopoietic Stem Cell Transplantation ,Waldenstrom macroglobulinemia ,Flow Cytometry ,Prognosis ,3. Good health ,Survival Rate ,Positron emission tomography ,030220 oncology & carcinogenesis ,Radiology ,Multiple Myeloma ,medicine.medical_specialty ,Concordance ,Immunology ,Transplantation, Autologous ,Article ,03 medical and health sciences ,Internal medicine ,Exome Sequencing ,Biomarkers, Tumor ,Medical imaging ,Humans ,Survival rate ,business.industry ,Magnetic resonance imaging ,Cell Biology ,medicine.disease ,Minimal residual disease ,body regions ,Functional imaging ,Transplantation ,Diffusion Magnetic Resonance Imaging ,030104 developmental biology ,Positron-Emission Tomography ,business ,Follow-Up Studies - Abstract
Introduction The iliac crest is the usual sampling site for minimal residual disease (MRD) monitoring in Multiple Myeloma (MM). However, the disease distribution in the bone marrow (BM) is often heterogeneous. Functional imaging can be used to complement MRD detection at a single site, thereby accounting for asymmetrically distributed disease. Diffusion weighted MRI with background suppression (DWIBS) is a novel functional imaging method that can detect disease in a higher proportion of newly diagnosed MM (NDMM) patients than 18F-fluorodeoxyglucose positron emission tomography (PET), as it is independent of the tumor metabolism. Yet, its performance for monitoring of residual disease has not been described. The aims of this study were 1) to compare DWIBS to PET for the detection of residual disease in patients achieving complete remission (CR), and 2) to test whether DWIBS and PET could complement MRD flow cytometry with a sensitivity of 1x10-5. To address these aims, we investigated 168 NDMM and 33 relapsed patients for whom DWIBS, PET, and MRD were available at the onset of CR during first-line and salvage therapy, respectively. Methods All patients signed written consent in accordance with the Declaration of Helsinki. Residual focal lesions (FLs) were defined as well delineated focal intensities above the surrounding BM background. For DWIBS FLs were considered if restriction could be confirmed on ADC maps. 8-color MRD flow cytometry with a limit of detection of 1x10-5 was available for 83 NDMM and all 33 salvage therapy patients. The Kaplan-Meier method was used for survival analyses. PFS time was measured from onset of CR to relapse or death from any cause or censored at the date of last contact. Paired-end whole exome sequencing of CD138-enriched MM cells was performed on an Illumina HiSeq 2500. Mutations were called from BWA aligned sequencing reads using MuTect. Subclonal reconstruction was done using SciClone. Results Compared to PET, DWIBS detected more CR patients with residual FLs (21% vs. 6%), and the concordance between PET and DWIBS was low. Only 6 of the DWIBS-positive patients also presented with FLs in PET. Yet, 5 patients had PET+/DWIBS- FLs, suggesting that the two techniques are complementary. Both, DWIBS+ and PET+ FLs negatively impacted PFS (p For 83 patients MRD data were available. Combining MRD and imaging, residual disease was detectable in 53 patients (64%). The best outcome was seen for 30 double negative (MRD-/Imaging-) patients (3 events with a median follow-up of 3.6 years), the worst outcome was seen for 10 double positive (MRD+/Imaging+) patients (median PFS: 2.1 years). Only 4 of 86 patients were MRD-/Imaging+, indicating that residual FLs are rare in MRD-negative NDMM patients at a sensitivity of 1x10-5. A heterogeneous disease distribution is a common feature of late-stage patients. To test if this increased heterogeneity confounded MRD, we investigated a set of 33 heavily pretreated patients who achieved CR during salvage therapy. Combining MRD and imaging data, we detected residual disease in 25 patients (76%). Of note, the proportion of patients, who were MRD-negative but had residual FLs on functional imaging was significantly higher compared to NDMM (8/16 vs 4/34 patients, p=0.01). At the same time, 10 patients (30%) were MRD+ but Imaging-, supporting the idea that a combined MRD/Imaging approach can improve detection of residual disease and should be used in late-stage patients. To obtain insights in the underlying biology, we performed longitudinal multi-region sequencing of a subset of these CR patients. Our findings support the concept of persistence and progression of multiple spatially separated clones in the BM irrespective of being in an MRD-negative CR. Thereby, focal residual disease could be shown to contribute to relapse. Conclusion DWIBS is a promising tool for detection of residual disease and complements PET. The combination of MRD diagnostics and functional imaging improves prediction of outcome, with double-negativity and double positivity defining groups with excellent and dismal PFS, respectively. Prospective trials using this information to tailor therapy are warranted. From a biological perspective, this study highlights the confounding effects of spatial heterogeneity and limited dissemination of clones within the BM on MRD diagnostics. This may especially be true for patients achieving deep responses during salvage therapies. Disclosures Roy Choudhury: University of Arkansas for Medical Sciences: Employment, Research Funding. Epstein:University of Arkansas for Medical Sciences: Employment. Barlogie:International Workshop on Waldenström's Macroglobulinemia: Other: travel stipend; Millenium: Consultancy, Research Funding; Multiple Myeloma Research Foundation: Other: travel stipend; ComtecMed- World Congress on Controversies in Hematology: Other: travel stipend; Myeloma Health, LLC: Patents & Royalties: : Co-inventor of patents and patent applications related to use of GEP in cancer medicine licensed to Myeloma Health, LLC; European School of Haematology- International Conference on Multiple Myeloma: Other: travel stipend; Celgene: Consultancy, Research Funding; Dana Farber Cancer Institute: Other: travel stipend. Davies:Takeda: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Morgan:Celgene: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Janssen: Research Funding.
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- 2018
24. Outcomes of autologous stem cell transplant for cardiac AL-amyloidosis and cardiac light chain deposition disease
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Al-Ola Abdallah, Varinder Kaur, Shebli Atrash, and Daisy Alapat
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Adult ,Male ,Pathology ,medicine.medical_specialty ,Transplantation, Autologous ,Light chain deposition disease ,Bortezomib ,03 medical and health sciences ,0302 clinical medicine ,medicine ,AL amyloidosis ,Humans ,Pharmacology (medical) ,Immunoglobulin Light-chain Amyloidosis ,Multiple myeloma ,Aged ,Retrospective Studies ,Aged, 80 and over ,business.industry ,Amyloidosis ,Hematopoietic Stem Cell Transplantation ,Middle Aged ,medicine.disease ,Treatment Outcome ,Oncology ,030220 oncology & carcinogenesis ,Plasma cell disorder ,Female ,Stem cell ,business ,Multiple Myeloma ,030215 immunology - Abstract
Introduction Cardiac amyloidosis and light chain deposition disease (LCDD) are the most common cause of death in AL amyloidosis or LCDD. Methods Our multiple myeloma database identified 50 patients with cardiac amyloidosis or LCDD between January 2004 and January 2013. Descriptive analyses were performed on available data for patient characteristics, disease course, and outcomes. Results The median age at diagnosis was 61 years for those who received autologous hematopoietic stem cell transplant (ASCT) and 71 years for those who received only bortezomib-based chemotherapy; 62.5% (n = 30) of patients had elevated levels of NT-proBNP ≥323 ng/L, and 29.2% (n = 14) of patients had an elevated cTnT ≥0.1 µg/L. Echocardiogram findings showed a speckled appearance in 18% (n = 9) of patients, and 60% (n = 30) of patients had an increased diastolic intra-ventricular septum (IVSD) thickness measuring ≥1.3 cm; 64.3% (n = 18) of patients who underwent cardiac MRI showed subendocardial enhancement. Out of 48 patients who received treatment, 37 patients were diagnosed with cardiac amyloidosis and 11 patients were diagnosed with cardiac LCDD. Twenty-eight patients (75.7%) with cardiac amyloidosis received ASCT, compared to 34.3% (n = 9) patients who were ineligible for ASCT and received chemotherapy only. Patients who underwent ASCT had a median OS of 4.48 years compared to 1.82 years (p = 0.69) for those receiving chemotherapy alone. Conclusion Our single institution experience shows that ASCT is feasible for cardiac amyloidosis and/or cardiac LCDD. However, careful selection of proper patients and diligent supportive care are vital to decreasing transplant-related mortality.
- Published
- 2019
25. Eight-Color Flow Cytometry Phenotypic Markers and Disease Progression in Monoclonal Gammopathy of Unknown Significance
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Sharmilan Thanendrarajan, Frits van Rhee, Carolina Schinke, Jeffery R. Sawyer, Sravani Gundarlapalli, Naveen Yarlagadda, Erming Tian, Shebli Atrash, Shadiqul Hoque, Meera Mohan, Sunil Kakadia, Guido Tricot, Daisy Alapat, Fenghuang Zhan, and Maurizio Zangari
- Subjects
Pathology ,medicine.medical_specialty ,Immunology ,Disease progression ,Cell Biology ,Hematology ,Biology ,Biochemistry ,Phenotype ,Monoclonal gammopathy ,Unknown Significance ,medicine ,Color flow ,medicine.symptom ,Cytometry - Abstract
Introduction: Flow cytometric immunophenotyping is considered an indispensable tool for the diagnosis, classification, and monitoring of plasma cell disorders. Herein, we seek to study the clinical significance of expression of phenotype markers in monoclonal gammopathy of unknown significance (MGUS). Methods: We identified a cohort of patients with a diagnosis of MGUS from the institutional myeloma database. Bone marrow (BM) aspirate assessment was performed using 8-color immunophenotypic next-generation flow cytometric (NGF) analysis with a minimum sensitivity of 10 -5 cells at the time of diagnosis or first visit to our institution. BM aspirate samples were immunophenotyped on a FACSCanto II flow cytometer using antibodies (BD) to delineate normal and abnormal plasma cells [CD138 (V-500), CD38 (FITC), CD19 (PE-Cy7), CD45 (V-450), CD27 (PercpCy5.5), CD81 (APC-H-7), CD56 (APC) and CD20 (PE)]. The sensitivity or the Limit of Detection (LOD) for this assay was validated to 20 cells in 2 ×10 6 events (0.001%), and the reproducibility or Lower Limit of Quantitation (LLOQ) is 50 cells in 2 ×10 6 events. Clinical and laboratory variables were also collected. Based on previously published data, expression (CD19, CD45, CD81), and lack of expression (CD56, CD27, CD20) of the above-mentioned surface antigens were analyzed. Additional variables such as IgA isotype, size of M-protein (≥15 g/L), and abnormal free light chain ratio(abnFLR) (defined as 10) were included in regression fitting models. Results: A total of 157 patients with MGUS were included in this analysis. The median age at diagnosis was 60 years (range 24- 84), 84 (53 %) patients were female and 25 (16%) were African American. Overall, IgG Kappa (75/148, 50%) was the most common isotype. Fluorescent-in-situ hybridization (FISH) data were available in 35 patients with t (4:14) and t (14;16) seen in 3 patients each. At a median follow-up of 18.15 years (quantiles 11.35, 33.62), 28 patients experienced disease progression (25 to MM, 2 to Waldenstrom macroglobulinemia, and 1 Smoldering myeloma). The median progression-free survival of this cohort was 17.3 years. Among these, occurrences of the bone lesion (8/28; 28.6%) were the most common pattern of disease progression to MM. This analysis showed lower odds of progression with the expression of CD27 (OR-0.39, 95% CI 0.15-0.99) (figure 1A). Disease progression was more common in patients with an abnormal plasma cell clone size ≥ of 3.1% at diagnosis (60% vs. 12.5%, p=0.0005). An abnormal plasma cell clone of ≥3.1% at diagnosis, was associated with increased odds of progression (OR-10.79, 95% CI 4.02-28.98) and a shorter PFS (12.5 years versus NR, p=0.01) (figure 1B). Serum M-spike ≥1.5 g/dL (OR-3.54;95% 1.30-9.62) and abnFLR (OR-2.30, 95% CI 1.00-5.32) were also associated with a higher odds of progression. However, in this population, the presence of IgA isotype did not increase the odds of MGUS progression. In a stepwise regression model, serum M-spike≥1.5 g/dL, abnFLR, and the lack of expression of CD27 were associated with the risk of disease progression. Conclusion: In addition to previously published risk factors, our cohort shows that the expression of CD27 antigen by eight-color flow cytometry confers a lower risk of disease progression of MGUS. This is consistent with our previous report that CD27 is progressively down-regulated in the transition from normal plasma cells (NPC) to MGUS to MM (Zhan et al, Blood 2006). Furthermore, we show that size of the myeloma clone (≥ 3.1% ) is a possible surrogate marker for disease progression in MGUS. Figure 1: 1A shows forest plot of odds ratios for flow cytometry markers, IgA isotype, size of M protein, abnFLR and plasma cell clone size. 1B shows the Kaplan Meier estimates of PFS for patients stratifies by plasma cell clone size. Figure 1 Figure 1. Disclosures Mohan: Medical College of Wisconsin: Current Employment. Atrash: GSK: Research Funding; AMGEN: Research Funding; Jansen: Research Funding, Speakers Bureau.
- Published
- 2021
26. Characterization of Castleman Disease Reveals Patients with Oligocentric Adenopathy and Clinicopathologic Characteristics Similar to Unicentric Castleman Disease
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Daisy Alapat, David C. Fajgenbaum, Sheila K Pierson, Frits van Rhee, Thomas S. Uldrick, Adam Bagg, Gordan Srkalovic, Mary Jo Lechowicz, and Megan S. Lim
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Pathology ,medicine.medical_specialty ,business.industry ,Castleman disease ,Immunology ,medicine ,Cell Biology ,Hematology ,business ,medicine.disease ,Biochemistry - Abstract
Castleman disease (CD) describes a group of heterogeneous lymphoproliferative disorders with characteristic histopathology that are classified based on the number of enlarged lymph node (LN) stations, etiological drivers, and clinical phenotype. CD histopathology includes a broad spectrum from plasmacytic to hyaline/hyper vascular with a mixed pattern in between. Unicentric CD (UCD) involves a single enlarged LN station and mild symptoms, whereas multicentric CD (MCD) involves multiple stations of enlarged LNs and more severe symptoms. MCD is subclassifed into Human Herpesvirus-8 associated MCD, POEMS-associated MCD, and idiopathic MCD (iMCD). iMCD cases are further subdivided into thrombocytopenia, anasarca, fever/elevated C-reactive protein (CRP), renal dysfunction, organomegaly (TAFRO) or iMCD-not otherwise specified (NOS), who often have thrombocytosis and hypergammaglobulinemia. Recently, it has been reported that some iMCD patients can have more oligocentric lymphadenopathy (above or below the diaphragm) whereas others have generalized lymphadenopathy (above and below the diaphragm). Given the heterogeneity across CD, we leveraged data from a longitudinal natural history study of CD to characterize the spectrum of CD. Specifically, we set out to determine if patients with multicentric lymphadenopathy localized to above or below the diaphragm (oligocentric CD, OCD) appeared to be more similar to UCD or iMCD with more generalized lymphadenopathy. In total, 130 patients enrolled in an international CD registry were confirmed to have CD by a panel of experts. Patients were assigned UCD, OCD, or iMCD per the following: UCD, 1 station of enlarged LNs (N=32); OCD, ≥2 stations of enlarged LNs, either above or below the diaphragm (N=29); iMCD, ≥2 stations of enlarged LNs, both above and below the diaphragm (N=69). Clinical data is provided closest to date of diagnosis +/-90 days. Sustained response is defined as ≥50% symptom improvement sustained without the addition of subsequent drug treatments. When appropriate, statistical testing was performed by Chi-square, Fisher's exact, or two-tailed T test. Among the 69 iMCD patients, 42 (61%) were classified as TAFRO and 27 (39%) were NOS. In contrast, only 1 of 29 OCD patients (3%) was TAFRO and 28 (97%) were NOS. No UCD patients were TAFRO. Breakdown of histopathological subtype can be found in Table 1. There was a mean (SD) of 8.4 (3.7) enlarged LNs in iMCD at diagnosis, compared with 2.8 (1.4) in OCD and 1 (0) in UCD. While enlarged LNs in the abdomen/pelvis region occurred in 56% of UCD, only 19% of OCD patients demonstrated lymphadenopathy in this region. Clinically, OCD patients demonstrated symptoms and laboratory abnormalities more comparable to UCD than iMCD (Table 2). In fact, there was no difference in symptoms between UCD and OCD groups, while there were significantly more symptoms in iMCD than OCD. iMCD had significantly worse anemia, albumin, creatinine, CRP, and other markers of inflammation than OCD, whereas OCD patients had significantly increased CRP (p=0.03) and alkaline phosphatase (p=0.03) compared to UCD. IgM was greater in OCD than both UCD (p=0.02) and iMCD (p=0.01) (Table 2). The number of patients receiving drug treatments differed by subtype: 7 UCD (22%), 18 OCD (62%), and 67 iMCD (97%). Fifty-five patients (UCD: 1, OCD: 7, iMCD: 47) received anti-IL-6 therapy (+/- steroids), including the only FDA-approved drug, siltuximab. Sustained response to anti-IL-6 (+/- steroids) was observed in 23/47 (49%) iMCD, 3/7 (43%) OCD, and 0/1 UCD. Within iMCD clinical subgroups, response was observed in 12/27 (44%) iMCD-TAFRO and 11/20 (55%) iMCD-NOS as well as across the histopathogical subtypes, suggesting that anti-IL-6 therapy can be effective across the spectrum. Overall, this study highlights the heterogeneity of CD. Importantly, it uncovers a group of CD patients that meet diagnostic criteria for iMCD but their lymphadenopathy is confined to above or below the diaphragm and they appear to behave more similarly to UCD. Given that 1/3 of OCD patients were managed without drug treatment, further work is needed to determine the relative benefits of UCD-like surgical treatment versus iMCD-like drug-based therapy for OCD. The clinical subtype of TAFRO, which was present in more than half of the iMCD patients, was observed in only one OCD case and no UCD cases. Further work is needed to determine optimal treatments across these subgroups. Figure 1 Figure 1. Disclosures Bagg: Scopio Labs: Research Funding. Lim: EUSA Pharma: Honoraria. Srkalovic: Takeda: Speakers Bureau; Janssen Pharmaceuticals: Speakers Bureau; EUSA Pharma: Speakers Bureau; Foundation Medicine: Speakers Bureau. Uldrick: Merck: Other: Receives study drug; Roche: Research Funding; Regeneron: Current Employment; Celgene: Research Funding. Fajgenbaum: Pfizer: Other: Study drug for clinical trial of sirolimus; N/A: Other: Holds pending provisional patents for 'Methods of treating idiopathic multicentric Castleman disease with JAK1/2 inhibition' and 'Discovery and validation of a novel subgroup and therapeutic target in idiopathic multicentric Castleman disease'; EUSA Pharma: Research Funding.
- Published
- 2021
27. Concomitant Deletion of Short Arm (del 1p) and Amplification or Gain (1q21) of Chromosome 1 By Fluorescence in Situ Hybridization (FISH) Is Associated with Poor Clinical Outcome
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Daisy Alapat, Zimu Gong, Sharmilan Thanendrarajan, Jeffery R. Sawyer, Samantha Kendrick, Meera Mohan, Fenghuang Zhan, Maurizio Zangari, Guido Tricot, Frits van Rhee, Carolina Schinke, and Erming Tian
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medicine.diagnostic_test ,Concomitant ,Immunology ,medicine ,Chromosome ,%22">Fish ,Cell Biology ,Hematology ,Biology ,Biochemistry ,Molecular biology ,Fluorescence in situ hybridization - Abstract
Introduction- Chromosome 1 abnormalities in multiple myeloma (MM) are increasingly recognized as high risk defined features. While there is robust data on 1q21 gain and amplification (amp), the clinical characteristics and outcome of patients with del 1p is less defined. Novel agents are incorporated into a backbone of multi-agent chemotherapy and tandem autologous stem cell transplantation (ASCT) in successive Total Therapy (TT) protocols for MM patients. We hereby report the prognostic value of del 1p by FISH at enrollment in subjects treated on TT protocols. Methods: (FISH was performed on bone marrow obtained at the time of first visit to our institution or initial diagnosis. FISH probes were generated from specific BAC DNA clones for AHCYL1 gene locus (1p13.3) and CKS1B locus (1q21). MM cells were identified post-hybridization using isotype specific antibody conjugated with 7-amino-4-methylcoumarin-3-acetic acid (AMCA) to stain Ig-Kappa or Ig-Lambda light chain in cytoplasm (cIg) of myeloma tumor cells. The FISH signals in 100 myeloma cells were recorded. For this analysis, 3 copies of 1q21 are considered as 1q21 gain and ≥ 4 copies as 1q21 amp. A 20% cutoff point was used for detection of significant abnormalities, i.e. del 1p and 1q21 gain and amp. A multivariable logistic regression model was used to examine the combined effects of clinical variables on progression free (PFS) and overall survival (OS). Results- A total of 1133 patients were included in this analysis. The median age was 60 (range 30.2-75), 434 (38.3%) patients were female and 106 (9.4%) were African Americans. ISS stage III disease accounted for 287 (25.3%). GEP70 high-risk was noted in 160/1133 (14.1%) of all patients. Of all patients, 1084 (95.7%) had at least one ASCT and 812 (71.7%) had tandem upfront ASCT. Metaphase cytogenetic abnormalities were noted in 548 (48.4%). While del 1p was detected in 220 (19.4%) patients, 1q21 gain or amplification were observed in 300 (26.5%) and 150 (13.2%) patients, respectively. Isolated 1q21 gain and amplification without del 1p were seen in 235 (20.7%) and 121 (10.7%) patients. Overall, there was enrichment of high-risk features such as ISS stage III disease (5.7% vs 10.9% p=0.049), GEP70 high-risk (8.4% vs 36.8%), GEP 70 subtypes such as MF (4.6% vs 8.2%), MS (10.5% vs 13.6%) and PR (11.3% vs 22.7%) and abnormal cytogenetic abnormalities (45.7% vs 59.5% p= Conclusion: Deletion of short arm of chromosome 1p was observed in 19% of MM patients. Concomitant del 1p with 1q21 gain and /or amp was present in 8% of patients. The PFS and OS of patients with combined del1p/1q21gain abnormalities was significantly worse compared to del 1p alone and 1q21 gain alone and thus identifies a subset of patients with poor clinical outcome. Figure 1 Figure 1. Disclosures Mohan: Medical College of Wisconsin: Current Employment.
- Published
- 2021
28. Characterizing Mortality Associated with Idiopathic Multicentric Castleman Disease
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Frits van Rhee, Karan Kanhai, Daisy Alapat, Gordan Srkalovic, Thomas S. Uldrick, Sheila K Pierson, Mary Jo Lechowicz, Adam Bagg, David C. Fajgenbaum, and Megan S. Lim
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medicine.medical_specialty ,business.industry ,Immunology ,Medicine ,Cell Biology ,Hematology ,Multicentric Castleman Disease ,business ,Biochemistry ,Dermatology - Abstract
Idiopathic multicentric Castleman disease (iMCD) is a rare, life-threatening hematologic disorder involving multi-organ dysfunction driven by inflammatory cytokines, often including interleukin-6 (IL-6). The five-year overall survival rate varies considerably between cohorts, ranging from 50 to 77%. It is not well understood why administration of therapies such as the anti-IL-6 monoclonal antibody siltuximab induces complete and durable remission in some patients, whereas others succumb to their disease despite therapy. The aim of this study was to identify laboratory parameters associated with mortality in iMCD. To this end, iMCD patients enrolled in the ACCELERATE registry with fatal and non-fatal outcomes were compared. To determine differences in the laboratory profiles at time of diagnosis between the non-fatal (control) (n = 66) and fatal (mortality) (n = 6) iMCD groups, we performed two-tailed t-tests with Welch correction. P < 0.05 was considered significant. Due to the exploratory nature of this study and limited sample size, we did not perform correction for multiple comparisons among the 25 parameters assessed. In the fatal iMCD group, all patients were white, aged 15-66, and 33.3% were male. Four patients had a hypervascular histopathological subtype; one subtype was not stated, and one was mixed. The non-fatal iMCD group was mixed race and included 57.6% male patients; 38 patients had a hypervascular subtype, 19 had a mixed subtype, five patients had a plasmacytic subtype, three were not stated and one had a hyaline vascular subtype. The mean time from final diagnosis to death was 586.2 days (range: 16-2952 days). Around the time of diagnosis, immunoglobulin M (IgM) (Figure 1A), international normalized ratio (INR) (Figure 1B), and platelet count (PC) (Figure 1C) were significantly decreased in the fatal group compared with the non-fatal group (Figure 1D), with three mortality patients below the lower limit of normal (LLN) for IgM, and four mortality patients below the LLN for PC. Unlike the other two parameters, the INR levels were closer to normal in the fatal group than the non-fatal group. While C-reactive protein (CRP) levels were higher and hemoglobin (Hb) levels were lower in the mortality group, they did not surpass the significance threshold. These data provide new insights into differences between patients who have fatal and non-fatal outcomes. These preliminary findings from a small cohort of deceased patients demonstrate that patients with iMCD who have fatal outcomes may differ from those who do not. For instance, patients in the fatal group may be in a state of greater immune dysregulation (indicated by a lower IgM) and at increased risk of bleeding events (lower PC), compared with patients who go on to survive. The lower PC in the fatal group is likely reflective of patients with the recently-defined thrombocytopenia, anasarca, fever/elevated CRP, reticulin fibrosis/renal dysfunction, organomegaly (TAFRO) clinical subtype of iMCD having lower platelets and a more aggressive course. Thus, early evaluation of platelet count may be an early and actionable indicator of someone's likelihood of death. Additional research is needed into the role of PC and markers of inflammation and anemia in predicting mortality as well as the timing of decline of these markers. If validated in a larger cohort, certain laboratory values may be of use to identify patients at increased risk of death. Figure 1 Figure 1. Disclosures Kanhai: EUSA Pharma: Current Employment. Bagg: Scopio Labs: Research Funding. Lim: EUSA Pharma: Honoraria. Srkalovic: EUSA Pharma: Speakers Bureau; Takeda: Speakers Bureau; Foundation Medicine: Speakers Bureau; Janssen Pharmaceuticals: Speakers Bureau. Uldrick: Celgene: Research Funding; Merck: Other: Receives study drug; Roche: Research Funding; Regeneron: Current Employment. Fajgenbaum: EUSA Pharma: Research Funding; Pfizer: Other: Study drug for clinical trial of sirolimus; N/A: Other: Holds pending provisional patents for 'Methods of treating idiopathic multicentric Castleman disease with JAK1/2 inhibition' and 'Discovery and validation of a novel subgroup and therapeutic target in idiopathic multicentric Castleman disease'.
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- 2021
29. Metastatic prostate cancer with bone marrow infiltration mimicking multiple myeloma
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Sharmilan Thanendrarajan, Manoj Kumar, Daisy Alapat, and Pankaj Mathur
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Oncology ,medicine.medical_specialty ,Bone marrow infiltration ,smoldering myeloma ,Plasma cell dyscrasia ,Case Report ,Case Reports ,030218 nuclear medicine & medical imaging ,03 medical and health sciences ,Prostate cancer ,0302 clinical medicine ,Multiple myeloma ,Internal medicine ,medicine ,business.industry ,General Medicine ,medicine.disease ,prostate cancer ,plasma cell dyscrasia ,Male patient ,Bone lesion ,030220 oncology & carcinogenesis ,Concomitant ,Treatment strategy ,business - Abstract
Key Clinical Message Concomitant diagnosis of metastatic prostate cancer and a multiple myeloma in older male patients is challenging as both malignancies are usually associated with bone lesions. Exact knowledge, experience, and an interdisciplinary approach are required in order to differentiate between both malignancies and determine the exact treatment strategy.
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- 2017
30. Clinical characteristics, molecular profile and outcomes of myeloid sarcoma: a single institution experience over 13 years
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Pooja Motwani, Abdallah Ao, Laura F. Hutchins, Swami A, Kaur, Daisy Alapat, and Yogesh Jethava
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Adult ,Male ,medicine.medical_specialty ,Pathology ,Time Factors ,Myeloid ,CD33 ,CD34 ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,medicine ,Myeloid sarcoma ,Humans ,Sarcoma, Myeloid ,Aged ,Retrospective Studies ,Aged, 80 and over ,biology ,business.industry ,CD117 ,Myeloid leukemia ,Retrospective cohort study ,Hematology ,Middle Aged ,medicine.disease ,Treatment Outcome ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,biology.protein ,Female ,Sarcoma ,business ,030215 immunology - Abstract
Myeloid sarcoma (MS) is characterized by extramedullary infiltration by immature myeloid cells. Owing to rarity of this disease, the clinical features and overall outcomes are yet to be clarified.To define clinical characteristics, epidemiology, pathologic findings, treatment options and outcomes in MS.We conducted a retrospective review of 23 patients diagnosed with MS at our institute over a period of 13 years (2002-2015).MS presented mostly as a manifestation of relapsed acute myeloid leukemia, seen in 39% of patients. Skin and subcutaneous soft tissues were the most common sites of anatomic involvement (69.5%). Ninety five percent (n = 19) were positive for classical myeloid markers with either cytochemical staining (chloracetate-esterase, MPO), flow-cytometry (CD33, CD34, CD13 and CD117), or immunohistochemistry (CD34, CD43, CD68 and lysozyme). Of these, 52% were positive for CD33 (n = 12), 35% for CD68 (n = 8), 30% for CD34 (n = 7), and 26% for lysozyme (n = 6). Cytogenetic abnormalities were seen in 63% (n = 12/19) patients on bone-marrow aspirate, with five patients displaying a complex (n = 3) or monosomal (n = 2) karyotype. Twenty seven percent patients with a normal karyotype had presence of deleterious mutations (FLT3, ASXL, STAG and JAK2) on further testing with myeloid mutation panel. The Median overall survival (OS) of the entire cohort was 15.9 months (95% CI, 7.4-24.4 months). The OS was significantly better for patients65 years (24.6 vs. 3.4 months, p = 0.009) of age, and for those attaining a complete remission (CR) to induction therapy (25.7 vs. 0.8 months, p 0.001). All patients who underwent allogeneic hematopoietic stem cell transplant attained long-term remissions, with a median follow-up of 54 (range 32-120) months.Failure to achieve CR with induction therapy, and age65 years are associated with poor outcomes in MS. Allogeneic stem-cell transplant in first remission appears to be the most effective modality for achieving long-term remissions.
- Published
- 2017
31. The prognostic value of the depth of response in multiple myeloma depends on the time of assessment, risk status and molecular subtype
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Sharmilan Thanandrarajan, Giovanni Insuasti-Beltran, Antje Hoering, Shayu Deshpande, Faith E. Davies, Brian A Walker, Sandra Susanibar, Purvi Patel, Martin Moorhead, Monica Grazziutti, Shmuel Yaccoby, Ginell R. Post, Muthukumar Radhakrishnan, Frits van Rhee, Shadiqul Hoque, Sarah K. Johnson, Leo Rasche, Niels Weinhold, Gareth J. Morgan, Meera Mohan, Bart Barlogie, Pankaj Mathur, Carolina Schinke, Maurizio Zangari, Daisy Alapat, Thomas D. Willis, Jorge Jo Kamimoto, Gabor Molnar, Victoria Carlton, Joshua Epstein, and Hongwei Wang
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Oncology ,medicine.medical_specialty ,Neoplasm, Residual ,Time Factors ,Risk Assessment ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Humans ,Medicine ,Online Only Articles ,Multiple myeloma ,Risk status ,business.industry ,Complete remission ,High dose melphalan ,Hematology ,Prognosis ,medicine.disease ,Novel agents ,030220 oncology & carcinogenesis ,Immunology ,Stem cell ,Multiple Myeloma ,business ,030215 immunology - Abstract
Complete remission (CR) rates for multiple myeloma (MM) have increased to 60% with current treatment approaches, including high dose melphalan-based autologous stem cell transplant (ASCT) and novel agents, and are associated with improved survival.[1][1]–[3][2] Despite this improvement, highly
- Published
- 2017
32. Nasopharyngeal amyloidoma with osteolytic lesions leading to diagnosis of systemic light‐chain amyloidosis
- Author
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Manoj Kumar, Sharmilan Thanendrarajan, Christoph Heuck, Rodolfo Henrich Lobo, Pankaj Mathur, Daisy Alapat, and Sandra Susanibar-Adaniya
- Subjects
0301 basic medicine ,Amyloidoma ,Chemotherapy ,Pathology ,medicine.medical_specialty ,Unusual case ,business.industry ,Amyloidosis ,medicine.medical_treatment ,nasopharyngeal tumor ,Case Report ,General Medicine ,Case Reports ,Immunoglobulin light chain ,medicine.disease ,osteolytic lesions ,03 medical and health sciences ,030104 developmental biology ,systemic light‐chain amyloidosis ,Medicine ,business ,Head and neck - Abstract
Key Clinical Message Amyloidomas of the head and neck region are uncommon and generally considered a benign localized form of amyloidosis. Here, we describe “the unusual case of a young man” with a nasopharyngeal mass and osteolytic lesions caused by systemic light‐chain amyloidosis treated successfully with a combined surgical and chemotherapy approach.
- Published
- 2017
33. Virome capture sequencing does not identify active viral infection in unicentric and idiopathic multicentric Castleman disease
- Author
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David C. Fajgenbaum, Stephen Sameroff, Signe Spetalen, Mitsuhiro Kawano, Michael Feldman, Daisy Alapat, Amy Chadburn, Jason R. Ruth, Dustin Shilling, Katie L. Stone, Federico Valdivieso, Alexander Fosså, Frits van Rhee, Christopher S. Nabel, Yasuharu Sato, and W. Ian Lipkin
- Subjects
0301 basic medicine ,RNA viruses ,Male ,Pathology ,Epstein-Barr Virus Infections ,Herpesvirus 4, Human ,viruses ,030204 cardiovascular system & hematology ,medicine.disease_cause ,Pathology and Laboratory Medicine ,Hematologic Cancers and Related Disorders ,0302 clinical medicine ,Medicine and Health Sciences ,T-cell lymphoma ,Lymph node ,False Negative Reactions ,Multidisciplinary ,Castleman disease ,virus diseases ,Hematology ,Herpesviridae Infections ,Middle Aged ,medicine.anatomical_structure ,Oncology ,Medical Microbiology ,Virus Diseases ,Viral Pathogens ,Viruses ,Herpesvirus 8, Human ,Medicine ,Lymphomas ,Female ,Anatomy ,Pathogens ,Research Article ,Adult ,medicine.medical_specialty ,Herpesviruses ,Hepatitis B virus ,Science ,Histopathology ,Genome, Viral ,Microbiology ,Herpesviridae ,Virus ,Lymphatic System ,03 medical and health sciences ,dsRNA viruses ,medicine ,Epstein-Barr virus ,Humans ,Human virome ,Microbial Pathogens ,Aged ,business.industry ,Castleman Disease ,Organisms ,Biology and Life Sciences ,Cancers and Neoplasms ,medicine.disease ,Epstein–Barr virus ,Hepatitis viruses ,Lymphoma ,030104 developmental biology ,Anatomical Pathology ,Case-Control Studies ,DNA, Viral ,Lymph Nodes ,business ,DNA viruses - Abstract
Castleman disease (CD) describes a spectrum of heterogeneous disorders defined by characteristic lymph node histopathology. Enlarged lymph nodes demonstrating CD histopathology can occur in isolation (unicentric CD; UCD) sometimes accompanied by mild symptoms, or at multiple sites (multicentric CD, MCD) with systemic inflammation and cytokine-driven multi-organ dysfunction. The discovery that Kaposi sarcoma herpesvirus/human herpesvirus (HHV)-8 drives MCD in a subset of patients has led to the hypotheses that UCD and MCD patients with negative HHV-8 testing by conventional methods may represent false negatives, or that these cases are driven by another virus, known or unknown. To investigate these hypotheses, the virome capture sequencing for vertebrate viruses (VirCapSeq-VERT) platform was employed to detect RNA transcripts from known and novel viruses in fresh frozen lymph node tissue from CD patients (12 UCD, 11 HHV-8-negative MCD [idiopathic MCD; iMCD], and two HHV-8-positive MCD) and related diseases (three T cell lymphoma and three Hodgkin lymphoma). This assay detected HHV-8 in both HHV-8-positive cases; however, HHV-8 was not found in clinically HHV-8-negative iMCD or UCD cases. Additionally, no novel viruses were discovered, and no single known virus was detected with apparent association to HHV-8-negative CD cases. Herpesviridae family members, notably including Epstein-Barr virus (EBV), were detected in 7 out of 12 UCD and 5 of 11 iMCD cases with apparent correlations with markers of disease severity in iMCD. Analysis of a separate cohort of archival formalin-fixed, paraffin-embedded lymph node tissue by In situ hybridization revealed significantly fewer EBV-positive cells in UCD and iMCD compared to tissue from HHV-8-positive MCD and EBV-associated lymphoproliferative disorder. In an additional cohort, quantitative testing for EBV by PCR in peripheral blood during disease flare did not detect systemic EBV viremia, suggesting detection lymph node tissue is due to occult, local reactivation in UCD and iMCD. This study confirms that HHV-8 is not present in UCD and iMCD patients. Further, it fails to establish a clear association between any single virus, novel or known, and CD in HHV-8-negative cases. Given that distinct forms of CD exist with viral and non-viral etiological drivers, CD should be considered a group of distinct and separate diseases with heterogeneous causes worthy of further study.
- Published
- 2019
34. Predicting Risk of Progression in Relapsed Multiple Myeloma Using Minimal Residual Disease Status and Focal Lesion Assessment with PET-CT
- Author
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Frits van Rhee, Amani Erra, Daisy Alapat, Carolina Schinke, Sharmilan Thanendrarajan, Angel A Mitma, Maurizio Zangari, Luis Carrillo, Archana Sachedina, Pankaj Mathur, Mathew Kottarathara, Shadiqul Hoque, Milan Bimali, David Baker, Richa Parikh, and Guido Tricot
- Subjects
Oncology ,PET-CT ,medicine.medical_specialty ,Chemotherapy ,Combination therapy ,business.industry ,medicine.medical_treatment ,Immunology ,Daratumumab ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Minimal residual disease ,Transplantation ,Median follow-up ,Internal medicine ,medicine ,business ,Multiple myeloma - Abstract
Introduction - Despite improvement in Multiple Myeloma (MM) therapy, most patients will eventually experience disease relapse. The course of relapsed MM can be quite heterogeneous with some patients achieving long-term disease control while others experience rapid successive relapses with short survival. Other than genetic features, there is currently a lack of prognostic markers to guide intensity and duration of therapy in relapsed MM. In the present study, we elucidate the prognostic value of minimal residual disease (MRD) and focal lesion assessment by PET-CT in relapsed patients. Methods- We investigated 120 MM patients that were diagnosed between 2000-2016 and treated on our Total Therapy (TT) 2-6 protocols, which incorporated multi-agent chemotherapy and tandem transplantation. All 120 patients had achieved a complete remission (CR) after TT and relapsed subsequently after a median of 5 years (0.9-18). Focal lesions were assessed with PET-CT in 112 patients at diagnosis and relapse. Other features investigated included gene expression analysis (GEP) defined by the UAMS GEP70 at diagnosis and relapse (n=75) and FISH at diagnosis (n=84). Once treatment for relapsed disease was initiated, response to therapy, including sequential measurement of MRD by conventional 8 color flow cytometry with a sensitivity of 10-5 was assessed at least every 6-12 months. MM therapy after progression was directed by the treating physician and consisted mostly of combination therapy of a Proteasome Inhibitor with an IMiD and Dexamethasone (62%) or a Daratumumab combination (25%) or other (13%). Results- Median age at first progression was 65 years and median follow up time was post-relapse was 19 months (range 2.2-65 months). High risk FISH features, including deletion 17p, 1q amplification, t(4;14) and t(14;16) were present in 29% (25/84) of the patients, but were limited in predicting worse PFS post-relapse (p=0.3) and OS (p= 0.5); 75 patients had GEP performed at diagnosis and relapse showing a significant increase (p Conclusion- Current clinical practice for relapsed MM incorporates mainly cytogenetic features that on their own seem to have limited predictive value. Our study suggests that risk classification and prognostication of relapsed MM can be significantly improved by using GEP and focal lesion assessment. Furthermore, achievement of MRD negativity should be the goal in relapsed MM therapy to improve clinical outcome. Disclosures van Rhee: EUSA: Consultancy; CDCN: Consultancy; Karyopharm: Consultancy; Adaptive Biotech: Consultancy; Takeda: Consultancy.
- Published
- 2020
35. Epstein-Barr Virus-Induced Polymorphic Nodal Lymphoproliferative Disorder Presenting as Recurrent Fever and Scrotal Swelling: A Case Report and Review of Literature
- Author
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Krishna Joshi, Kevin Kuriakose, Rahul Ravilla, Yogita Rochlani, Anwar Rjoop, Daisy Alapat, and AppalaNaidu Sasapu
- Published
- 2016
36. Clinical implications of loss of minimal residual disease (MRD) negativity in multiple myeloma
- Author
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Dinesh Atwal, Samantha Kendrick, Naveen Yarlagadda, Meera Mohan, Frits van Rhee, Carolina Schinke, Daisy Alapat, Richa Parikh, Arya Mariam Roy, Yadav Pandey, Maurizio Zangari, Sharmilan Thanendrarajan, and James Lopez
- Subjects
Oncology ,Cancer Research ,medicine.medical_specialty ,MRD Negativity ,business.industry ,medicine.disease ,Minimal residual disease ,body regions ,03 medical and health sciences ,0302 clinical medicine ,hemic and lymphatic diseases ,030220 oncology & carcinogenesis ,Internal medicine ,medicine ,business ,Multiple myeloma ,030215 immunology - Abstract
8514 Background: Attainment of MRD negativity in multiple myeloma (MM) patients is increasingly considered an optimal therapeutic endpoint, but little is known about the MRD evolution in those who achieve this milestone. We investigated the clinical implication of loss of MRD negativity or MRD conversion in patients with ≥VGPR. Methods: We identified and followed 606 patients achieving a sustained ≥VGPR with bone marrow MRD negativity(≥ 2 consecutive reading) following treatment on a total therapy protocol and with a median follow-up of 10 y. All patient had negative PET and MRI DWIBS at enrollment. Serial BM aspirate MRD was determined by 8-color next generation flow (NGF, EuroFlow) with a minimal sensitivity of 10−5 cells. Results: Most MM patients were considered low risk with a UAMS GEP70 score of ≤ 0.66 (92%; 495/538) . While 60% (364/606) of patients had sustained MRD negativity, the remaining 40% (242/606) experienced MRD conversion with a 5.7 y median time from ASCT and 6.3 y from diagnosis. The risk of clinical relapse was significantly elevated in patients with MRD conversion compared to sustained MRD negativity (73%, 177/242 vs. 5%, 18/364; R.R. = 3.5; P< 0.0001). The median level of MRD positivity (> 0.2 ratio of MM cells to normal plasma cells) also highly correlated with relapse ( P< 0.0001). Loss of MRD negativity preceded clinical relapse by a median time of 1.1 years. Loss of MRD negativity without clinical relapse was seen in 27% (65/242). MRD conversion was associated with an inferior PFS and OS (PFS: 10.2 y vs. NR; P < 0.0001, H.R. 18.7; 95% CI 13.3 - 26.3 and OS: 26.1 y vs. NR; P= 0.01, H.R. 1.7; 95% CI 1.1 - 2.6). Furthermore, when MRD conversion was within 5 y of diagnosis compared > 5 y, patients had a worse OS ( P < 0.0001, H.R. 17.2; 95% CI 7.8 – 37.8). We also observed that MRD conversion later than 5 years from diagnosis did not affect the OS. In a subset of patients (n = 144) the timing of first MRD negativity following treatment was available. Attainment of MRD negativity within 6 months of diagnosis compared to any time after 6 months was predictive of future MRD conversion (65%, 17/26 vs.42%, 49/118; P = 0.03) and clinical relapse (54%, 14/26 vs.28%, 33/118; P = 0.02). Conclusions: MRD conversion occurs in a significant proportion of MM patients (40%) on long-term follow-up and predicts future clinical relapse. Significance of MRD conversion has a temporal relationship from diagnosis and portray inferior clinical outcome particularly within 5 years of diagnosis.
- Published
- 2020
37. Cytoplasmic Immunoglobulin Vs. DNA Analysis by Flow Cytometry
- Author
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Daisy, Alapat
- Subjects
Ploidies ,Cell Cycle ,Humans ,Immunoglobulins ,DNA, Neoplasm ,Flow Cytometry - Abstract
Cytoplasmic immunoglobulin (CIg) vs DNA by flow cytometric (FCM) method allows us to detect DNA content of the neoplastic plasma cells with monotypic cytoplasmic immunoglobulin and also provide us with clear distinction from normal polytypic plasma cells. Abnormalities in cellular DNA content (DNA aneuploidy) and cell cycle determination (proliferative activity) can be measured rapidly by flow cytometry. FCM can measure gross differences in DNA content and distinguish a cell population with normal DNA content, or diploid from a cell population with an abnormal or aneuploid DNA content. With the dual parameter procedure a monoclonal plasma cell population can be identified down to less than 0.1-0.05% of all cells.
- Published
- 2018
38. Fulminant onset of acute leukemia from normal hematopoiesis within 3 months of follow up for multiple myeloma treated with total therapy protocols
- Author
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Clyde Bailey, Daisy Alapat, Nathan Petty, Zeba N. Singh, Jeffrey R. Sawyer, Saad Z. Usmani, Bart Barlogie, Yogesh Jethava, Bijay Nair, Ginell R. Post, Sarah Waheed, and Frits van Rhee
- Subjects
Oncology ,medicine.medical_specialty ,Pathology ,Myeloid ,Fulminant ,Case Reports ,cytogenetic abnormalities ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Medicine ,In patient ,Metaphase ,Multiple myeloma ,030304 developmental biology ,0303 health sciences ,Acute leukemia ,business.industry ,Cytogenetics ,Normal hematopoiesis ,General Medicine ,medicine.disease ,3. Good health ,medicine.anatomical_structure ,myeloma ,030220 oncology & carcinogenesis ,business ,therapy-related myeloid neoplasm - Abstract
Key Clinical Message Assiduous surveillance for genetic aberrations is necessary in patients on cytotoxic therapies to detect therapy-related myeloid neoplasms (t-MN). Current modalities include metaphase cytogenetics and FISH. Since t-MN may develop abruptly in cytogenetically normal patients, a discussion exploring additional methods such as SNP-array and targeted-deep-sequencing to detect subchromosomal abnormalities is needed.
- Published
- 2015
39. Plasma Cell Neoplasms (PCNs) With Low-Risk, Favorable Gene Expression Subtypes Are More Often Associated With Therapy-Related Myelodysplastic Syndrome (t-MDS)
- Author
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Rodolfo Henrich Lobo, Daisy Alapat, Anwar Rjoop, and Soumya Pandey
- Subjects
business.industry ,Gene expression ,Cancer research ,Medicine ,General Medicine ,Plasma cell neoplasm ,business ,Therapy-related myelodysplastic syndrome - Published
- 2018
40. Treatment of Unresectable Unicentric Castleman Disease with Therapeutic Embolization
- Author
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Frits van Rhee, Katie L. Stone, Meera Mohan, James Meek, Ralph Broadwater, Amy D Greenway, Mary E. Meek, and Daisy Alapat
- Subjects
medicine.medical_specialty ,business.industry ,medicine.medical_treatment ,Castleman disease ,Immunology ,Mediastinum ,Cell Biology ,Hematology ,medicine.disease ,Debulking ,Biochemistry ,Cryosurgery ,medicine.anatomical_structure ,Embolism ,medicine ,Rituximab ,Radiology ,Embolization ,business ,medicine.drug ,Lenalidomide - Abstract
Introduction: Unicentric Castleman disease (UCD) is a rare non-clonal lymphoproliferative disorder affecting one lymph node station. UCD can be an incidental finding on radiologic studies, whilst other patients have symptomatology due to compression of vital structures. Surgical extirpation is the preferred therapy and is usually curative, but unresectable UCD can represent a therapeutic challenge. Castleman lymph nodes are often highly vascularized, which offers the opportunity for therapeutic embolization. We report a series of 6 patients with unresectable UCD who were treated with embolization either as sole therapy or supplemented by cryoablation and surgery. Methods: CT rotational angiography was performed to localize the arterial supply of UCD masses. Feeding vessels were selectively embolized using a 50:50 mixture of lipiodol and alcohol or 300-500 micron embospheres. A second arteriography was performed 2 to 3 months later to identify and embolize any new arterial channels. Results: Data is summarized in Table 1. Of a cohort of 47 patients with UCD, 6 (13%) were found to have symptomatic, unresectable disease. All patients were HIV and human herpesvirus-8 negative. The median patient age was 34 years (range: 28-34); five patients were male and one was female. Disease was localized to the pelvis (n=3), mediastinum (n=2), and axilla (n=1). In all but one case, the histology was of the hyaline vascular variety. Four patients had failed R-CHOP, rituximab/steroids, or both. In 2 patients, embolization was done as primary therapy, while 3 underwent additional surgery. In 5 patients, embolization was performed twice to ablate secondary arterial channels that had appeared after the first procedure. Adjunctive cryoablation at the time of embolization was applied in 2 patients. All treated patients had major reduction in their lymph node mass. The median reduction in tumor bulk was from 274cc (range:13-969) to 21cc (range: 3-394). One patient with an axillary mass involving the brachial plexus failed therapy and received radiation. A second patient had regrowth of the UCD and responded to combination lenalidomide and obinituzumab. Responses were sustained for at least 2 years in the remaining patients. Conclusion: A small number of case reports have been described UCD patients treated with arterial embolization as an immediate preoperative adjunct to surgery to limit intraoperative bleeding. In the present series, we utilized embolic devascularization to achieve cytoreduction rather than merely prevent surgical hemorrhage. Embolization was complemented by cryoablation and rendered surgery feasible. This case series highlights that effective disease control can be obtained of unresectable UCD using a multimodality approach in which vascular embolization plays a crucial role. Disclosures No relevant conflicts of interest to declare.
- Published
- 2018
41. Personalized Therapy in Multicentric Castleman Disease Produces Excellent Outcomes in a Tertiary Referral Center
- Author
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Frits van Rhee, Francisco Socola, Amy D Greenway, Samina Waheed, Katie L. Stone, Daisy Alapat, Kristen Carter, and Diane Glendinning
- Subjects
medicine.medical_specialty ,business.industry ,Immunology ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Chemotherapy regimen ,Gastroenterology ,Anasarca ,Siltuximab ,Organomegaly ,Transplantation ,chemistry.chemical_compound ,chemistry ,Internal medicine ,Medicine ,Rituximab ,medicine.symptom ,business ,Progressive disease ,medicine.drug ,POEMS syndrome - Abstract
Introduction. Multicentric Castleman Disease (MCD) is an inflammatory disorder characterized by lymphadenopathy. The clinical course of MCD is variable; some patients have mild symptoms while others develop hypercytokinemia progressing to organ failure. Severely ill patients often have the TAFRO-variety of MCD characterized by Thrombocytopenia, Anasarca, Fever, Reticulin marrow fibrosis, and Organomegaly. We report on 76 MCD patients: the largest series from a single institution. Methods. Data was collected from our institution and outside records via systematic chart review and standardized survey for self-reported symptoms. Laboratory data represent each patient's most severe episode. TAFRO- and non-TAFRO or "classical" iMCD subtypes were grouped (iMCD) for some analyses. Patients were classified as POEMS-associated MCD when they had MCD with full POEMS syndrome or clear features of POEMS. Results. Forty-nine patients had classical iMCD and 12 TAFRO-iMCD. Fifteen patients had POEMS-associated MCD, of which 8 had coexistent POEMS syndrome. iMCD and POEMS-associated MCD had similar age and sex, but the hyaline vascular variant was more common in iMCD (44.3 vs 6.7%, p=0.006) (Table 1). iMCD patients were more symptomatic in terms of night sweats (61.0 vs 33.3%, p=0.001) and fever (50.8 vs 20%, p=0.031) compared to POEMS-associated MCD, but had similar laboratory characteristics and disease activity (CHAP) scores. TAFRO-iMCD patients were mostly male and had more fever (91.6 vs 42.9%, p=0.002), anasarca (100 vs 24.5%, p Commonly-used treatment regimens for iMCD were the anti-IL6/IL6 receptor antibodies siltuximab and tocilizumab (n=41), rituximab ± steroids (n=23), steroids alone (n=13), and chemotherapy (n=7). There was a high rate of response to anti-IL6 therapy (97%) with a treatment failure (TF) rate of 5%. Two further relapses occurred in patients who discontinued therapy. Steroid monotherapy or rituximab + steroids yielded response rates of 46 and 82%, but were marred by high TF rates (85 and 43%). Chemotherapy responses were noted in 7 instances, but TF occurred twice. There were no significant differences in response to therapy comparing the classical and TAFRO-iMCD groups, but both patients failing anti-IL6 therapy had TAFRO-iMCD. Six TAFRO-iMCD patients received chemotherapy and 2 relapsed. Six patients with POEMS and CD underwent autologous stem cell transplant with major improvement in polyneuropathy and MCD; 2 experienced relapse of their MCD and one died of late myelodysplastic syndrome. One improved post irradiation of a plasmacytoma and 1 died of progressive disease. Most MCD patients with POEMS features received rituximab-based therapies; 6/7 were alive and 1 died of sepsis. There was no difference in overall survival (OS) among the three groups (p=0.35) with a median OS of 5.65 years (4 - 9.2, 95% CI) in the iMCD group, 7.9 years (4.5 - 11.8, 95% CI) in POEMS-associated MCD, and 5.85 years (3.2 - 8.7, 95% CI) in the TAFRO group. The 5-year OS was 91%, 94% and 100% for the iMCD, POEMS-associated MCD and TAFRO groups, respectively. Conclusions. In a tertiary referral setting, excellent outcomes were achieved in all subgroups, likely attributed to highly selective therapeutic choices. Anti-IL6 therapy for iMCD was reserved for patients with active disease and laboratory evidence of inflammatory syndrome. Some TAFRO-iMCD patients achieved complete responses with anti-IL6 therapy, while others fared well with chemotherapy. Rituximab-based therapy was given to those with more indolent iMCD and those with POEMS-associated MCD. The polyneuropathy of POEMS benefitted most from transplant. Significant differences were noted in VEGF levels both in POEMS-associated MCD and TAFRO-iMCD compared to classical iMCD cases, with each cohort presenting a distinct clinical picture suggesting differing underlying etiologies and cytokine profiles. IL6 levels were not different among groups, though this may be confounded by effects of prior therapy. A better understanding of the pathobiology of the MCD continuum is essential to developing more targeted therapies. Disclosures No relevant conflicts of interest to declare.
- Published
- 2018
42. Preemptive intravenous immunoglobulin allows safe and timely administration of antineoplastic therapies in patients with multiple myeloma and parvovirus B19 disease
- Author
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Jameel Muzaffar, Zainab Shahid, Alejandro Restrepo, Daisy Alapat, Lakshmikanth Katragadda, and Elias Anaissie
- Subjects
Male ,medicine.medical_specialty ,Pancytopenia ,Anemia ,viruses ,Antineoplastic Agents ,Parvoviridae Infections ,Autologous stem-cell transplantation ,hemic and lymphatic diseases ,Internal medicine ,Parvovirus B19, Human ,Humans ,Medicine ,Multiple myeloma ,Aged ,Transplantation ,Cytopenia ,biology ,business.industry ,Parvovirus ,Immunoglobulins, Intravenous ,virus diseases ,Middle Aged ,biology.organism_classification ,medicine.disease ,Hematologic Response ,Treatment Outcome ,Infectious Diseases ,Immunology ,Female ,Multiple Myeloma ,business ,Viral load ,Stem Cell Transplantation - Abstract
Background Parvovirus B19 (B19) disease is a rare cause of anemia in cancer patients and often goes unrecognized, causing delays in anticancer therapy. Methods A retrospective review was carried out of the records of patients with multiple myeloma who underwent melphalan-based autologous stem cell transplantation (MEL-ASCT) and developed B19 infection (January 2009–December 2011). Cases were defined by the presence of clinical and laboratory findings consistent with B19 disease in patients with repeatedly positive plasma quantitative polymerase chain reaction for parvovirus. Results Six patients qualified as cases; 5 presented with trilineage cytopenias (chronic in 1) and 1 with anemia later progressing to pancytopenia. Transfusion-dependent thrombocytopenia led to testing in 5 patients. Two of these patients also had manifestations of autoimmune disease. Therapy with intravenous immunoglobulin (IVIG) resulted in clinical and hematologic response in all; however, 1 patient, whose white blood cell counts and serum hemoglobin levels improved, required splenectomy for persistent thrombocytopenia. All patients required additional IVIG for recurrent B19 disease. Although viral load at diagnosis did not correlate with the severity of cytopenia, its decrease was associated with response during 17 of 20 evaluable episodes (P = 0.02). Preemptive IVIG allowed the safe administration of chemotherapy in 3 patients, including MEL-ASCT in 1. Conclusion Parvovirus B19 can cause severe disease in myeloma patients including ASCT recipients. Thrombocytopenia – not anemia – was the leading presentation and may be associated with autoimmune conditions. Patients with unexplained cytopenias, particularly when prolonged, should undergo testing for circulating parvovirus. A reduction in viral load was associated with response to IVIG, although additional therapy was needed for recurrent disease. Most importantly, preemptive IVIG allowed for safe and timely administration of antineoplastic therapy in patients with ongoing B19 disease.
- Published
- 2013
43. Prolonged prothrombin time correlates with serum monoclonal protein concentration in patients with plasma cell dyscrasia
- Author
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Ginell R. Post, Kristi J. Smock, Daisy Alapat, Steven R. Post, and Soumya Pandey
- Subjects
Male ,medicine.medical_specialty ,Pathology ,Myeloma protein ,Clinical Biochemistry ,Paraproteinemias ,Plasma cell dyscrasia ,Severity of Illness Index ,Gastroenterology ,Asymptomatic ,Reference Values ,Internal medicine ,medicine ,Coagulation testing ,Humans ,Blood Coagulation ,Multiple myeloma ,Aged ,Glycoproteins ,Prothrombin time ,medicine.diagnostic_test ,business.industry ,Biochemistry (medical) ,Fibrinogen ,Hematology ,General Medicine ,Middle Aged ,Plasma cell neoplasm ,medicine.disease ,Prothrombin Time ,Female ,Partial Thromboplastin Time ,medicine.symptom ,Multiple Myeloma ,business ,Partial thromboplastin time - Abstract
SummaryIntroduction Abnormal screening coagulation tests are frequently observed in asymptomatic patients with multiple myeloma and other plasma cell neoplasms. Methods Prothrombin time (PT), activated partial thromboplastin time (APTT) and fibrinogen activity were correlated with clinical history and disease parameters in patients referred to the Myeloma Institute for Research and Therapy. Results An isolated prolonged PT was the most common abnormal coagulation test (25%). Prolonged PT was more frequently observed in patients with multiple myeloma (n = 157) compared to MGUS patients (n = 34) or other diagnostic categories of plasma cell dyscrasia. There were no differences in age, gender, previous chemotherapy, or immunoglobulin isotype in patients with isolated prolonged PT (n = 62) compared to those with normal screening coagulation tests (n = 173). Fibrinogen activity was significantly lower in patients with prolonged PT; however, there was no correlation between fibrinogen activity and PT. Serum M protein concentrations were significantly greater in patients with prolonged PT and were positively correlated with PT. Conclusion An association between disease severity and prolonged PT is suggested by our finding that patients with multiple myeloma were more likely to have prolonged PT than patients with other plasma cell neoplasms. Of the factors examined, the monoclonal protein level was significantly higher in patients with isolated prolonged PT and correlated with PT.
- Published
- 2012
44. Cutaneous manifestations of multiple myeloma and other plasma cell proliferative disorders
- Author
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Alicia M. Schnebelen, Manisha Bhutani, Saad Z. Usmani, Zainab Shahid, and Daisy Alapat
- Subjects
Pathology ,medicine.medical_specialty ,Skin Neoplasms ,Plasma Cells ,Plasma cell ,030207 dermatology & venereal diseases ,03 medical and health sciences ,0302 clinical medicine ,Antibody activity ,Xanthomatosis ,Medicine ,Neoplasm ,Humans ,Skin Diseases, Infectious ,Schnitzler Syndrome ,Multiple myeloma ,Myeloproliferative Disorders ,business.industry ,Monoclonal immunoglobulin ,Hematology ,Amyloidosis ,medicine.disease ,Cryoglobulinemia ,medicine.anatomical_structure ,Oncology ,030220 oncology & carcinogenesis ,Scleromyxedema ,Monoclonal ,Immunology ,POEMS Syndrome ,Monoclonal protein ,business ,Multiple Myeloma ,Plasmacytoma - Abstract
Plasma cell proliferative disorders cause rare but extremely varied dermatologic manifestations that may occur as an accompaniment to established diagnoses, or may be a first clue of an underlying neoplasm in the setting of clinical suspicion. In some instances skin lesions result from aggregation of misfolded monoclonal immunoglobulins or their fragments, as in light chain-related systemic amyloidosis. On other occasions the cutaneous lesions result from deposits of malignant plasma cells or monoclonal proteins. In still others, the dermatologic manifestations are related to antibody activity of monoclonal protein, as in many cases of cryoglobulinemia. This report provides insights into the well-recognized cutaneous manifestations associated with plasma cell disorders.
- Published
- 2016
45. Low-cost computing and network communication for a point-of-care device to perform a 3-part leukocyte differential
- Author
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Timothy J. Muldoon, Daisy Alapat, Amy J. Powless, Lauren E. Feekin, and Joshua A. Hutcheson
- Subjects
medicine.medical_specialty ,Computer science ,Fingerstick ,02 engineering and technology ,Granulocyte ,01 natural sciences ,Hematology analyzer ,Internal medicine ,medicine ,Limit (mathematics) ,Point of care ,Whole blood ,Hematology ,medicine.diagnostic_test ,business.industry ,Monocyte ,010401 analytical chemistry ,Complete blood count ,Differential (mechanical device) ,Wbc count ,021001 nanoscience & nanotechnology ,0104 chemical sciences ,medicine.anatomical_structure ,Embedded system ,0210 nano-technology ,business ,Computer hardware - Abstract
Point-of-care approaches for 3-part leukocyte differentials (granulocyte, monocyte, and lymphocyte), traditionally performed using a hematology analyzer within a panel of tests called a complete blood count (CBC), are essential not only to reduce cost but to provide faster results in low resource areas. Recent developments in lab-on-a-chip devices have shown promise in reducing the size and reagents used, relating to a decrease in overall cost. Furthermore, smartphone diagnostic approaches have shown much promise in the area of point-of-care diagnostics, but the relatively high per-unit cost may limit their utility in some settings. We present here a method to reduce computing cost of a simple epi-fluorescence imaging system using a Raspberry Pi (single-board computer
- Published
- 2016
46. Strange Bedfellows: Mitotically Active Chronic Myeloid Leukemia in Molecular Complete Remission, Detected in Focal Lesion of Myeloma
- Author
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Jeffrey R. Sawyer, Bart Barlogie, Guru Subramanian Guru Murthy, Rohan Samant, and Daisy Alapat
- Subjects
Male ,Cancer Research ,Pathology ,medicine.medical_specialty ,Karyotype ,Fusion Proteins, bcr-abl ,Focal lesion ,Leukemia, Myelogenous, Chronic, BCR-ABL Positive ,medicine ,Humans ,In Situ Hybridization, Fluorescence ,Multiple myeloma ,Aged ,Active chronic ,medicine.diagnostic_test ,business.industry ,Remission Induction ,Myeloid leukemia ,Neoplasms, Second Primary ,Magnetic resonance imaging ,Hematology ,medicine.disease ,Magnetic Resonance Imaging ,Molecular Complete Remission ,Treatment Outcome ,Oncology ,Multiple Myeloma ,Tomography, X-Ray Computed ,business - Published
- 2014
47. Induction of Murine Syngeneic Graft-Versus-Host Disease by Cells of Recipient Origin
- Author
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C. Darrell Jennings, Jacqueline Perez, J. Scott Bryson, Daisy Alapat, Alan M. Kaplan, B E Caywood, and J. Anthony Brandon
- Subjects
Mice, Inbred C3H ,Transplantation ,Graft vs Host Disease ,Inflammation ,Mice, SCID ,T helper cell ,Biology ,Proinflammatory cytokine ,Mice, Inbred C57BL ,Mice ,Transplantation, Isogeneic ,medicine.anatomical_structure ,Immune system ,Syngeneic Graft ,Immunopathology ,Models, Animal ,Immunology ,Cyclosporine ,medicine ,Animals ,Bone marrow ,medicine.symptom ,Stem cell ,Immunosuppressive Agents ,Bone Marrow Transplantation - Abstract
Background. Syngeneic graft-versus-host disease (SGVHD) develops after lethal irradiation, reconstitution with syngeneic bone marrow (BM), and treatment with a 21-day course of the immunosuppressant cyclosporine A (CsA). Clinical symptoms of SGVHD appear 2-3 weeks after CsA treatment, with inflammation in the colon and liver. It has been demonstrated that CD4 + T cells and a T helper cell type 1 cytokine response (Th1) are involved in the development of SGVHD associated intestinal inflammation. The immune response associated with SGVHD is thought to be the result of the reconstitution of the recipient immune system with the syngeneic donor BM. However, definitive studies have not addressed this issue experimentally. Methods. To determine the origin of the effector cells that participate in SGVHD, C3H/HeN recipient mice were lethally irradiated and transplanted with BM from normal immunocompetent mice or from immunodeficient, severe combined immune deficient, or Rag-2 -/- animals. Results. CsA-treated animals, but not control animals, developed inflammation characteristic of SGVHD in the colon and liver regardless of the source of the donor marrow. Furthermore, immunologically, all CsA treated animals responded similarly with increased production of inflammatory cytokines and an increase in activated CD4 + T cells in the periphery and colon relative to controls. Conclusion. These results demonstrate that after lethal irradiation and in the absence of donor T cells, T cells of recipient origin can expand and mediate the induction of CsA-induced SGVHD.
- Published
- 2007
48. Acute Lymphoblastic Leukemia evolving from atypical Chronic Myelogenous Leukemia: Case Report and Review of the Literature
- Author
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Daisy Alapat, Yogesh Jethava, Pooja Motwani, Jonathon Gralewski, Sarah Jewell, Angela Pennisi, and Bellamy William
- Subjects
Oncology ,medicine.medical_specialty ,Blast Crisis ,business.industry ,Lymphoblastic Leukemia ,Diagnostic dilemma ,medicine.disease ,Philadelphia chromosome ,hemic and lymphatic diseases ,Internal medicine ,Immunology ,medicine ,Atypical chronic myeloid leukemia ,Leukocytosis ,medicine.symptom ,business ,Myeloid dysplasia ,Chronic myelogenous leukemia - Abstract
Atypical chronic myeloid leukemia (aCML) is a rare chronic myeloproliferative disorder characterized by leukocytosis, absence of Philadelphia chromosome or BCR-ABL rearrangement, and marked myeloid dysplasia. The diagnosis of aCML is difficult and challenging, more so if the initial presentation is with blast crisis. In the absence of characteristic mutational profile, blast crisis of aCML can lead to significant diagnostic dilemma. We describe a case of refractory acute lymphoblastic leukemia (ALL), needing critical evaluation of hemopathological and cytogenetic abnormalities. It was hypothesized that patient had undiagnosed aCML and presented with lymphoid blast crisis. To our knowledge, this is the first described case of aCML presenting with lymphoid blast crisis.
- Published
- 2015
49. The flow cytometry-defined light chain cytoplasmic immunoglobulin index and an associated 12-gene expression signature are independent prognostic factors in multiple myeloma
- Author
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Christoph Heuck, Faith E. Davies, Shmuel Yaccoby, Sarah K. Johnson, Xenofon Papanikolaou, Rashid Z Khan, Sarah Waheed, Bart Barlogie, Yogesh Jethava, Erming Tian, Clyde Bailey, Adam Z. Rosenthal, Joshua Epstein, Caleb K. Stein, Gareth J. Morgan, Rebecca Owens, Daisy Alapat, Maurizio Zangari, F. van Rhee, and Amy K. Joiner
- Subjects
Male ,Cancer Research ,Plasma cell ,Immunoglobulin light chain ,Real-Time Polymerase Chain Reaction ,Flow cytometry ,Fusion gene ,medicine ,Biomarkers, Tumor ,Humans ,RNA, Messenger ,Multiple myeloma ,Aged ,Neoplasm Staging ,Oligonucleotide Array Sequence Analysis ,biology ,medicine.diagnostic_test ,Reverse Transcriptase Polymerase Chain Reaction ,Gene Expression Profiling ,Hematology ,medicine.disease ,Flow Cytometry ,Prognosis ,Molecular biology ,3. Good health ,Gene expression profiling ,Survival Rate ,Real-time polymerase chain reaction ,medicine.anatomical_structure ,Oncology ,biology.protein ,Female ,Immunoglobulin Light Chains ,Original Article ,Antibody ,Multiple Myeloma - Abstract
As part of Total Therapy (TT) 3b, baseline marrow aspirates were subjected to two-color flow cytometry of nuclear DNA content and cytoplasmic immunoglobulin (DNA/CIG) as well as plasma cell gene expression profiling (GEP). DNA/CIG-derived parameters, GEP and standard clinical variables were examined for their effects on overall survival (OS) and progression-free survival (PFS). Among DNA/CIG parameters, the percentage of the light chain-restricted (LCR) cells and their cytoplasmic immunoglobulin index (CIg) were linked to poor outcome. In the absence of GEP data, low CIg 5.5 mg/l, a percentage of LCR cells exceeding 50%, C-reactive protein ⩾8 mg/l and GEP-derived high centrosome index. Further analysis revealed an association of low CIg with 12 gene probes implicated in cell cycle regulation, differentiation and drug transportation from which a risk score was developed in TT3b that held prognostic significance also in TT3a, TT2 and HOVON trials, thus validating its general applicability. Low CIg is a powerful new prognostic variable and has identified potentially drug-able targets.
- Published
- 2014
50. A role for semaphorin 3A signaling in the degeneration of hippocampal neurons during Alzheimer's disease
- Author
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Daniel P. Perl, Paul F. Good, Caryn Chu, Daisy Alapat, David Burstein, D. Stave Kohtz, Xiaping Wen, and A Hsu
- Subjects
Macromolecular Substances ,Nerve Tissue Proteins ,Receptors, Cell Surface ,tau Proteins ,Biology ,Hippocampal formation ,Hippocampus ,Biochemistry ,Epitopes ,Cellular and Molecular Neuroscience ,Semaphorin ,Alzheimer Disease ,medicine ,Humans ,Phosphorylation ,Axon ,Aged ,Aged, 80 and over ,Neurons ,Neurodegeneration ,Subiculum ,Semaphorin-3A ,SEMA3A ,medicine.disease ,Immunohistochemistry ,medicine.anatomical_structure ,nervous system ,Nerve Degeneration ,Intercellular Signaling Peptides and Proteins ,Axon guidance ,Neuron ,Microtubule-Associated Proteins ,Neuroscience ,Biomarkers ,Signal Transduction - Abstract
Among the earliest invariant neuropathological changes in Alzheimer's disease (AD) is the degeneration of vulnerable hippocampal CA1 and subicular pyramidal neurons. Semaphorin 3A (Sema3A) is a secreted protein that functions in signaling growth cone collapse, chemorepulsion and neuronal apoptosis during early development of the central nervous system. In this report we show that accumulation of an internalized form of Sema3A is associated with degeneration of neurons in vulnerable fields of the hippocampus during AD. Accumulation of Sema3A overlaps the appearance of phosphorylated MAP1B and tau in many neurons, suggesting that Sema3A signaling at some level may be coupled to these previously identified cytoskeletal markers of neurodegeneration. Consistent with this, we isolated and partially characterized a multiprotein complex from the hippocampus of patients with AD that contains phosphorylated MAP1B, collapsin-response mediator protein 2 (CRMP-2), Plexins A1 and A2, and a processed form of Sema3A. A model is presented in which aberrant release of Sema3A from expressing neurons in the subiculum during AD results in the internalization and transport of Sema3A from this field to CA1. Within the context of the myriad of potential insults that contribute to Alzheimer's and other neurodegenerative diseases, the bioactivity of Sema3A may contribute either directly to neurodegeneration by inducing neuronal collapse, or indirectly by abrogating the recovery capabilities of adult neurons faced with these insults.
- Published
- 2004
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