My primary area of expertise is in the diagnosis of lymphoid and myeloid neoplasms. I am interested in the use of modern molecular techniques as a diagnostic aid as well as in providing prognostic information. My current areas of research focus on these areas.
- Anatomic Pathology
Clinical Associate Professor, Pathology
Medical Director, Clinical Laboratory Informatics (2009 - Present)
Medical Director, Stanford Health Care Point of Care testing (2015 - Present)
Associate Medical Director, Laboratory Hematology (2007 - Present)
Boards, Advisory Committees, Professional Organizations
Member, College of American Pathologists Informatics Committee (2016 - Present)
Fellowship: Stanford University Hemapathology Fellowship (2005) CA
Residency: Stanford University Pathology Residency (2004) CA
Medical Education: UCLA David Geffen School Of Medicine Registrar (2001) CA
American Board of Pathology, Clinical Informatics (2014)
Board Certification: American Board of Pathology, Hematology (2005)
Board Certification: American Board of Pathology, Anatomic Pathology (2004)
Current Research and Scholarly Interests
My research interest is in the use of molecular methods to understand and characterize hematological neoplasms. My current investigations focus on the use of standard karyotyping, FISH studies, flow cytometry studies, and gene sequencing for diagnostic and prognostic evaluation of hematological neoplasms.
Graduate and Fellowship Programs
Hematopathology (Fellowship Program)
- Lupus erythematosus cells in a bone marrow aspirate JOURNAL OF HEMATOPATHOLOGY 2023
- 311.2: Risk factors for Epstein-Barr virus DNAemia in pediatric transplantation: A multicenter study in the United States. Transplantation 2023; 107 (10S1): 71-72
- Rapid Deployment of Whole Slide Imaging for Primary Diagnosis in Surgical Pathology at Stanford Medicine Responding to Challenges of the COVID-19 Pandemic ARCHIVES OF PATHOLOGY & LABORATORY MEDICINE 2023; 147 (3): 359-367
Epstein-Barr virus-associated post-transplant lymphoproliferative disorders in pediatric transplantation: A prospective multicenter study in the United States
View details for Web of Science ID 001002465500078
Mutations In Latent Membrane Protein 1 of Epstein-Barr Virus are Associated with Increased Risk for Post-Transplant Lymphoproliferative Disorder in Children.
American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons
Epstein-Barr virus (EBV)+ post-transplant lymphoproliferative disorder (PTLD) results in significant morbidity and mortality in pediatric transplant recipients. Identifying individuals at increased risk of EBV+ PTLD could influence clinical management of immunosuppression and other therapies, improving post-transplant outcomes. A seven-center prospective, observational clinical trial of 872 pediatric transplant recipients evaluated the presence of mutations at position 212 and 366 of EBV latent membrane protein 1 (LMP1) as an indicator of risk for EBV+ PTLD (Clinical Trials: NCT02182986). DNA was isolated from peripheral blood of EBV+ PTLD cases and matched controls (1:2 nested case-control), and the cytoplasmic tail of LMP1 sequenced. Thirty-four participants reached the primary endpoint of biopsy-proven EBV+ PTLD. DNA was sequenced from 32 PTLD cases and 62 matched controls. Both LMP1 mutations were present in 31/32 PTLD cases (96.9%) and in 45/62 matched controls (72.6%) (p=0.005, OR=11.7, 95% CI 1.5, 92.6). The presence of both G212S and S366T carries a nearly 12-fold increased risk for development of EBV+ PTLD. Conversely, transplant recipients without both LMP1 mutations carry a very low risk of PTLD. Analysis of mutations at positions 212 and 366 of LMP1 can be informative in stratifying patients for risk of EBV+ PTLD.
View details for DOI 10.1016/j.ajt.2023.02.014
View details for PubMedID 36796762
- Correlation of Mutational Profiles and Cytogenetics with Morphologic Dysplasia in Myelodysplastic Syndromes AMER SOC HEMATOLOGY. 2022: 4053-4055
- Characterization of Clinical, Molecular, and Prognostic Features of the WHO 2022 Classification System for Myelodysplastic Neoplasms (MDS) AMER SOC HEMATOLOGY. 2022: 6955-6957
Histiocytic Sarcoma With CCND1 Gene Rearrangement Clonally Related and Transdifferentiated From Mantle Cell Lymphoma.
American journal of clinical pathology
OBJECTIVES: Histiocytic neoplasms demonstrate shared gene translocations and clonal immunoglobulin gene rearrangements in cases of associated B-cell lymphomas. However, the evolution of these related disease processes remains largely uncertain, especially in the setting of a prior mantle cell lymphoma.METHODS: We describe a unique case of a histiocytic sarcoma that transdifferentiated from blastoid mantle cell lymphoma after extensive therapy. Cytogenic and molecular studies were performed and provided evidence for clonal progression.RESULTS: We present the first reported case of a patient with blastoid mantle cell lymphoma harboring a CCND1 rearrangement that progressed despite multiple therapeutic regimens and ultimately transdifferentiated into histiocytic sarcoma. The histiocytic sarcoma demonstrated a CCND1 rearrangement and targeted next-generation sequencing showed a pathogenic variant in NRAS, a gene involved in the RAS/MAPK pathway, known to play a role in the pathogenesis of histiocytic sarcomas. TP53, NOTCH2, CREBBP, and NFKBIE variants were also identified, which are often seen in B-cell lymphomas, while rarely described in histiocytic sarcoma.CONCLUSIONS: To our knowledge, this is the first report to provide evidence for clonal evolution of histiocytic sarcoma from blastoid mantle cell lymphoma based on cytogenic and molecular findings. The patient's protracted therapeutic course may have acted as an evolutionary driver promoting this transdifferentiation process.
View details for DOI 10.1093/ajcp/aqac087
View details for PubMedID 35964234
Rapid Deployment of Whole Slide Imaging for Primary Diagnosis in Surgical Pathology at Stanford Medicine.
Archives of pathology & laboratory medicine
Stanford Pathology began stepwise subspecialty implementation of whole slide imaging (WSI) in 2018 soon after the first US Food and Drug Administration approval. In 2020, during the COVID-19 pandemic, the Centers for Medicare & Medicaid Services waived the requirement for pathologists to perform diagnostic tests in Clinical Laboratory Improvement Amendments (CLIA)-licensed facilities. This encouraged rapid implementation of WSI across all surgical pathology subspecialties.To present our experience with validation and implementation of WSI at a large academic medical center encompassing a caseload of more than 50 000 cases per year.Validation was performed independently for 3 subspecialty services with a diagnostic concordance threshold above 95%. Analysis of user experience, staffing, infrastructure, and information technology was performed after department-wide expansion.Diagnostic concordance was achieved in 96% of neuropathology cases, 100% of gynecologic pathology cases, and 98% of immunohistochemistry cases. After full implementation, 8 high-capacity scanners were operational, with whole slide images generated on greater than 2000 slides per weekday, accounting for approximately 80% of histologic slides at Stanford Medicine. Multiple modifications in workflow and information technology were needed to improve performance. Within months of full implementation, most attending pathologists and trainees had adopted WSI for primary diagnosis.WSI across all surgical subspecialities is achievable at scale at an academic medical center; however, adoption required flexibility to adjust workflows and develop tailored solutions. WSI at scale supported the health and safety of medical staff while facilitating high-quality patient care and education during COVID-19 restrictions.
View details for DOI 10.5858/arpa.2021-0438-OA
View details for PubMedID 35802938
Mutations in latent membrane protein 1 of Epstein Barr virus are associated with increased risk of post-transplant lymphoproliferative disorder
View details for Web of Science ID 000783167500008
- Gelatinous transformation of the bone marrow in a previously healthy male presenting with pancytopenia. British journal of haematology 2022
Host microRNAs are decreased in pediatric solid-organ transplant recipients during EBV+ Post-transplant Lymphoproliferative Disorder.
Frontiers in immunology
2022; 13: 994552
Post-transplant lymphoproliferative disorder (PTLD) is a serious complication of solid organ transplantation. Predisposing factors include primary Epstein-Barr virus (EBV) infection, reactivation of EBV in recipient B cells, and decreased T cell immunity due to immunosuppression. In our previous studies EBV infection was demonstrated to markedly alter the expression of host B cell microRNA (miR). Specifically, miR-194 expression was uniquely suppressed in EBV+ B cell lines from PTLD patients and the 3'untranslated region of IL-10 was determined to be targeted by miR-194. Although EBV has been shown to regulate host miR expression in B cell lymphoma cell lines, the expression of miRs in the circulation of patients with EBV-associated PTLD has not been studied. The objective of this study was to determine if changes in miR expression are associated with EBV+ PTLD. In this study, we have shown that miR-194 is significantly decreased in EBV+PTLD tumors and that additional miRs, including miRs-17, 19 and 106a are also reduced in EBV+PTLD as compared to EBV-PTLD. We quantitated the levels of miRs-17, 19, 106a, 155, and 194 in the plasma and extracellular vesicles (EV; 50-70 nm as determined by nanoparticle tracking analysis) from pediatric recipients of solid organ transplants with EBV+ PTLD+ that were matched 1:2 with EBV+ PTLD- pediatric transplant recipients as part of the NIH-sponsored Clinical Trials in Organ Transplantation in Children, (CTOTC-06) study. Levels of miRs-17, 19, 106a, and 194 were reduced in the plasma and extracellular vesicles (EV) of EBV+ PTLD+ group compared to matched controls, with miRs-17 (p = 0.034; plasma), miRs-19 (p = 0.029; EV) and miR-106a (p = 0.007; plasma and EV) being significantly reduced. Similar levels of miR-155 were detected in the plasma and EV of all pediatric SOT recipients. Importantly, ~90% of the cell-free miR were contained within the EV supporting that EBV+ PTLD tumor miR are detected in the circulation and suggesting that EVs, containing miRs, may have the potential to target and regulate cells of the immune system. Further development of diagnostic, mechanistic and potential therapeutic uses of the miRs in PTLD is warranted.
View details for DOI 10.3389/fimmu.2022.994552
View details for PubMedID 36304469
Angioimmunoblastic T-cell lymphoma diagnosed from pleural fluid by integration of morphologic, immunophenotypic, and molecular findings.
An 88-year-old man with end-stage renal disease on hemodialysis presented with shortness of breath and was found to have lower extremity edema and bilateral pleural effusions on a chest X-ray. A therapeutic and diagnostic thoracentesis was performed, and cytologic examination revealed atypical mononuclear cells. Based on this, flow cytometry was performed on the pleural fluid, along with immunostains on the cellblock and a next-generation sequencing (NGS) panel. A definitive diagnosis of angioimmunoblastic T-cell lymphoma (AITL) was made based on demonstrating an atypical T follicular helper cell population expressing CD10, BCL6, CXCL13, CD200, CD57, and PD1, and detection of pathogenic variants in RHOA, IDH2, and TET2. This case represents the first reported case where a primary diagnosis of AITL was made on a body fluid specimen and highlights how immunophenotyping and NGS can provide a definitive diagnosis of AITL on a cytologic specimen.
View details for DOI 10.1002/dc.24861
View details for PubMedID 34449978
Human Germinal Center-associated Lymphoma (HGAL) Is a Reliable Marker of Normal and Neoplastic Follicular Helper T Cells Including Angioimmunoblastic T-Cell Lymphoma.
The American journal of surgical pathology
The diagnosis of angioimmunoblastic T-cell lymphoma (AITL) is complex and requires the demonstration of a T-follicular helper (TFH) phenotype. Immunophenotypic markers that detect the TFH phenotype are highly variable, thereby necessitating the use of 3 to 5 TFH markers to substantiate a TFH phenotype. We tested the utility of germinal center markers human germinal center-associated lymphoma (HGAL) and LIM-domain only 2 (LMO2) in detecting a TFH phenotype. We compared their staining to that of 6 TFH markers in current use, PD-1, ICOS, CXCL13, SAP, CD10, and BCL6, in a cohort of 23 AITL. Our results show that although both markers can detect a TFH phenotype, HGAL was superior to LMO2 in the percent of cells stained and the intensity of staining, 2 variables used to generate H-scores. Using H-scores as the metric, HGAL was most comparable to BCL6 among the currently used TFH markers and was more sensitive than CXCL13, SAP, CD10, and LMO2. PD-1 and ICOS emerged as the most robust of the 8 markers tested in this study in detecting a TFH phenotype. We conclude that HGAL is a reliable marker of TFH cells and can aid in the diagnosis of lymphomas of TFH derivation, particularly in the recognition of early patterns of AITL.
View details for DOI 10.1097/PAS.0000000000001852
View details for PubMedID 34907996
Reactive Eosinophil Proliferations in Tissue and the Lymphocytic Variant of Hypereosinophilic Syndrome.
American journal of clinical pathology
OBJECTIVES: The 2019 Society for Hematopathology and European Association for Haematopathology Workshop reviewed the spectrum of neoplastic, nonneoplastic, and borderline entities associated with reactive eosinophilia in tissue.METHODS: The workshop panel reviewed 46 cases covered in 2 workshop sessions.RESULTS: The 46 cases were presented with their consensus diagnoses during the workshop. Reactive eosinophilia in lymph nodes and other tissues may be accompanied by or be distinct from peripheral blood eosinophilia. Reactive etiologies included inflammatory disorders such as Kimura disease and IgG4-related disease, which may show overlapping pathologic features and reactions to infectious agents and hypersensitivity (covered in a separate review). Hodgkin, T-cell, and B-cell lymphomas and histiocytic neoplasms can result in reactive eosinophilia. The spectrum of these diseases is discussed and illustrated through representative cases.CONCLUSIONS: Reactive eosinophilia in lymph nodes and tissues may be related to both nonneoplastic and neoplastic lymphoid proliferations and histiocytic and nonhematolymphoid processes. Understanding the differential diagnosis of reactive eosinophilia and the potential for overlapping clinical and pathologic findings is critical in reaching the correct diagnosis so that patients can be treated appropriately.
View details for DOI 10.1093/ajcp/aqaa227
View details for PubMedID 33367482
- B-lymphoblastic leukemia arising in a patient with chronic neutrophilic leukemia. Blood advances 2020; 4 (21): 5389–92
- Acute myeloid leukemia with NPM1 and FLT3 ITD mimicking acute promyelocytic leukemia. Blood 2020; 136 (12): 1467
Myeloid Cell Nuclear Differentiation Antigen (MNDA) Positivity in Primary Follicles: Potential Pitfall in the Differential Diagnosis With Marginal Zone Lymphoma.
Applied immunohistochemistry & molecular morphology : AIMM
Myeloid cell nuclear differentiation antigen (MNDA) is an immunohistochemical marker that is used to distinguish marginal zone lymphomas (MZLs) from other small B-cell lymphomas. An index case that showed MNDA staining in primary follicles prompted the current study to evaluate whether MNDA expression is widespread in primary follicles and to address whether it poses a potential diagnostic pitfall. Of the 15 cases with primary follicles identified by a search of the laboratory information system, 7 had positive MNDA staining. In all cases, there was weak nuclear staining similar to what is typical of MNDA staining in MZLs. All cases showed intense nuclear signal in myeloid lineage cells such as neutrophils, which served as positive internal controls. The histologic and cytologic features of primary follicles and MZLs showed overlapping features, particularly in small biopsies. Our results indicate that weak nuclear MNDA staining can act as a potential pitfall in the evaluation of small B-cell lymphomas. Correlation with other immunohistochemical markers that are useful in the workup of small B-cell lymphomas, as well as those that outline immunoarchitectural features of lymphoid follicles, is suggested when both entities are part of the differential diagnosis. Our results underscore the need for caution in the interpretation of weak nuclear MNDA staining in the evaluation of small B-cell lymphomas.
View details for PubMedID 30640752
Prospective Analysis of EBV plus PTLD in a Multi-Center Study of Pediatric Transplant Recipients
LIPPINCOTT WILLIAMS & WILKINS. 2018: S319
View details for Web of Science ID 000444541200511
Implementation of Epic Beaker Clinical Pathology at Stanford University Medical Center
AMERICAN JOURNAL OF CLINICAL PATHOLOGY
2017; 147 (3): 261-272
To provide an account of implementation of the Epic Beaker 2014 clinical pathology module at Stanford University Medical Center and highlight strengths and weaknesses of the system.Based on a formal selection process, Stanford selected Epic Beaker to replace Sunquest as the clinical laboratory information system (LIS). The rationale included integration between the LIS and already installed Epic electronic medical record (EMR), reduction in the number of systems and interfaces, and positive patient identification (PPID). The build was significantly customized and included a first of its kind Epic-to-Epic interface. This was due to the clinical laboratory serving two hospitals (pediatric and adult) with independent instances of Epic.Test turnaround times showed improvement from historical baselines, mostly because of the implementation of PPID. PPID also resulted in significant reduction in mislabeled specimens.Epic 2014 Beaker clinical pathology is a viable LIS with adequate functionality for a large academic center. Strengths include PPID and integration with the EMR. Integration provides laboratory users with ready access to the patient's relevant clinical history to assist releasing of results and gives physician and nurse providers sophisticated add-on ordering and specimen collection workflows. Areas that could use further development include specimen aliquoting, quality control reporting, and maintenance tools.
View details for DOI 10.1093/AJCP/AQW221
View details for Web of Science ID 000397109200002
View details for PubMedID 28395051
Primary lymphoma of bone in the pediatric and young adult population.
2017; 60: 1-10
Primary lymphoma of bone (PLB) accounts for 3% to 7% of primary neoplasms of bone and must be distinguished from more common bone tumors in the pediatric population such as osteosarcoma, Ewing sarcoma, and other small round blue cell tumors. In this study, pathology databases from 4 institutions were queried for PLB in individuals 1 to 21 years old. A total of 54 cases of PLB were identified, including 41 diffuse large B-cell lymphomas (DLBCL, 76%), 8 B-lymphoblastic lymphomas (BLL, 15%), 3 anaplastic large cell lymphomas (ALCL, 6%), and 2 low-grade follicular lymphomas (4%). The male/female ratio was 1.8:1 and median age was 16 years (range, 2-21). Patients with DLBCL were significantly older (P<.001), and patients with ALCL and BLL were significantly younger (P=.050 and P=.008, respectively) when compared with the other patients. Due to necrosis, crush artifact, and/or insufficient material, 30% of cases required multiple biopsies for diagnosis. The femur, tibia, pelvic bones, humerus, and vertebrae were most commonly involved. DLBCL patients had significantly more solitary bone involvement (P=.001), whereas BLL had significantly more polyostotic involvement (P<.001). Of the 37 patients with outcome data, all had no evidence of disease on last follow-up. This largest pediatric series of PLB identifies DLBCL as the most frequent subtype and documents rarer occurrences of BLL, ALCL, and follicular lymphomas. The differential diagnosis of bone neoplasms in pediatric patients, including those with necrosis, should include PLB.
View details for DOI 10.1016/j.humpath.2016.07.028
View details for PubMedID 27554207
Hemophagocytic lymphohistiocytosis as a paraneoplastic syndrome associated with ovarian dysgerminoma.
Gynecologic oncology reports
2016; 17: 38-41
•Ovarian dysgerminoma associated with paraneoplastic fever, cytopenia and splenomegaly•Complete symptom resolution resulted from tumor resection and medical management•Non-hematolymphoid neoplasms are part of differential diagnosis in secondary HLH.
View details for DOI 10.1016/j.gore.2016.05.013
View details for PubMedID 27354999
View details for PubMedCentralID PMC4909829
Validation of Digital Whole Slide Imaging System for Breast Sentinel Lymph Node Touch Prep Analysis: A Single Institution Experience
NATURE PUBLISHING GROUP. 2016: 496A
View details for Web of Science ID 000369270703125
Initial Validation of Whole Slide Imaging (WSI) for Use in Frozen Section Consultation at Stanford University
NATURE PUBLISHING GROUP. 2016: 494A
View details for Web of Science ID 000369270703118
Initial Validation of Whole Slide Imaging (WSI) for Use in Frozen Section Consultation at Stanford University
NATURE PUBLISHING GROUP. 2016: 494A
View details for Web of Science ID 000370302503439
Validation of Digital Whole Slide Imaging System for Intraoperative Breast Sentinel Lymph Node Touch Prep Analysis: A Single Institution Experience
NATURE PUBLISHING GROUP. 2016: 496A
View details for Web of Science ID 000370302503446
- Cellular morphology of BRAF V600E-positive Langerhans cell histiocytosis BLOOD 2015; 126 (15): 1857-1857
Angioimmunoblastic T Cell Lymphoma: An Unusual Presentation of Posttransplant Lymphoproliferative Disorder in a Pediatric Patient
2014; 131 (2): 95-101
Posttransplant lymphoproliferative disorders (PTLD) are a potentially life-threatening complication of immunosuppression in transplant recipients. The majority of cases are Epstein-Barr virus-associated lesions of B cell origin. T cell PTLD is rare, particularly in pediatric patients. We present an unusual case of monomorphic T cell PTLD with features of angioimmunoblastic T cell lymphoma in an 8-year-old heart transplant patient, presenting with cranial nerve palsy. © 2013 S. Karger AG, Basel.
View details for DOI 10.1159/000353783
View details for Web of Science ID 000331488500006
View details for PubMedID 24157860
Evaluation of the Beckman Coulter UniCel DxH 800, Beckman Coulter LH 780, and Abbott Diagnostics Cell-Dyn Sapphire Hematology Analyzers on Adult Specimens in a Tertiary Care Hospital
AMERICAN JOURNAL OF CLINICAL PATHOLOGY
2011; 135 (6): 939-951
We evaluated the new Beckman Coulter DxH 800 hematology analyzer (Beckman Coulter, Miami, FL) vs the Abbott Diagnostics Cell-Dyn Sapphire (Abbott Diagnostics, Santa Clara, CA) and Beckman Coulter LH 780 hematology analyzers using 430 adult specimens. The DxH 800 provided a CBC and differential that correlated well with those of the Sapphire and LH 780, with most parameters showing correlation coefficients (r) of more than 0.97. In the instrument vs 400-cell manual differential comparison, all 3 instruments showed similar and acceptable accuracy to the reference method except for nucleated RBC (NRBC) enumeration, in which the DxH 800 and Sapphire outperformed the LH 780. We also compared clinical efficiency by determining whether flagged specimens showed abnormalities on a peripheral blood smear as defined by International Council for Standardization in Haematology criteria. The efficiency, sensitivity, and specificity of the DxH 800 were 77.0%, 87.1%, and 73.0%, respectively, compared with the Sapphire at 75.8%, 93.5%, and 68.8%, respectively, and LH 780 at 66.1%, 93.5%, and 55.3%, respectively.
View details for DOI 10.1309/AJCP1V3UXEIQTSLE
View details for PubMedID 21571967
Evaluation of the Beckman Coulter UniCel DxH 800 and Abbott Diagnostics Cell-Dyn Sapphire Hematology Analyzers on Pediatric and Neonatal Specimens in a Tertiary Care Hospital
AMERICAN JOURNAL OF CLINICAL PATHOLOGY
2011; 135 (6): 929-938
We evaluated the new UniCel DxH 800 hematology analyzer (Beckman Coulter, Miami, FL) vs the Cell-Dyn Sapphire (Abbott Diagnostics, Santa Clara, CA) using 156 pediatric specimens in Microtainer tubes (Becton Dickinson, Franklin Lakes, NJ). The CBC and differential showed good interinstrument correlation, including WBCs (r = 0.995), RBCs (r = 0.992), hemoglobin (r = 0.998), mean corpuscular volume (r = 0.988), platelets (r = 0.997), neutrophils (r = 0.988), lymphocytes (r = 0.984), monocytes (r = 0.815), eosinophils (r = 0.840), basophils (r = 0.049), and nucleated RBCs (NRBCs; r = 0.906). In the instrument vs 400-cell manual differential comparison, the DxH 800 and Sapphire showed comparable performance for nearly all parameters except for NRBCs, for which the DxH 800 correlated better (r = 0.989) than the Sapphire (r = 0.906). We also compared clinical efficiency by determining whether flagged specimens showed abnormalities on a peripheral blood smear as defined by International Council for Standardization in Haematology criteria. The efficiency of the DxH 800 was 78.0% vs the Sapphire at 68.1%. Both instruments showed identical sensitivity (91.1%), but the specificity for the DxH 800 (71.9%) was higher than that of the Sapphire (57.3%).
View details for DOI 10.1309/AJCP2EXNSLGGRVSQ
View details for PubMedID 21571966
Anti-CD47 Antibody Synergizes with Rituximab to Promote Phagocytosis and Eradicate Non-Hodgkin Lymphoma
2010; 142 (5): 699-713
Monoclonal antibodies are standard therapeutics for several cancers including the anti-CD20 antibody rituximab for B cell non-Hodgkin lymphoma (NHL). Rituximab and other antibodies are not curative and must be combined with cytotoxic chemotherapy for clinical benefit. Here we report the eradication of human NHL solely with a monoclonal antibody therapy combining rituximab with a blocking anti-CD47 antibody. We identified increased expression of CD47 on human NHL cells and determined that higher CD47 expression independently predicted adverse clinical outcomes in multiple NHL subtypes. Blocking anti-CD47 antibodies preferentially enabled phagocytosis of NHL cells and synergized with rituximab. Treatment of human NHL-engrafted mice with anti-CD47 antibody reduced lymphoma burden and improved survival, while combination treatment with rituximab led to elimination of lymphoma and cure. These antibodies synergized through a mechanism combining Fc receptor (FcR)-dependent and FcR-independent stimulation of phagocytosis that might be applicable to many other cancers.
View details for DOI 10.1016/j.cell.2010.07.044
View details for PubMedID 20813259
The Frequency of Immunoglobulin Heavy Chain Gene and T-Cell Receptor gamma-Chain Gene Rearrangements and Epstein-Barr Virus in ALK(+) and ALK(-) Anaplastic Large Cell Lymphoma and Other Peripheral T-Cell Lymphomas
JOURNAL OF MOLECULAR DIAGNOSTICS
2008; 10 (6): 502-512
We previously identified a relatively high frequency of B-cell proliferations along with simultaneous T-cell receptor gamma-chain gene (TRG) and immunoglobulin heavy chain gene (IGH) rearrangements in a series of angioimmunoblastic T-cell lymphoma and peripheral T-cell lymphoma, unspecified. Here, we report on a series of 74 peripheral T-cell lymphoma (PTCL) cases composed entirely of specific PTCL subtypes, including 28 cases of ALK+ anaplastic large-cell lymphoma (ALCL), 35 cases of ALK- ALCL, and 11 cases that represent other specific PTCL subtypes. We performed IGH and TRG gene rearrangement studies and in situ hybridization for Epstein-Barr virus (EBV) to determine the frequency of IGH clonality and to investigate the relationship between EBV, clonality, and associated B-cell proliferations. Using BIOMED-2 PCR assays, we detected TRG clones in 64 of 74 (86%) cases and IGH clones in 6 of 74 (8%) cases, with all IGH-positive cases exhibiting a concurrent TRG clone. Despite the detection of occasional IGH clones, there was no correlation between IGH clonality and EBV, and B-cell proliferations were not identified in any of the cases. These findings suggest that other factors contribute to IGH clonality and demonstrate that, in the absence of an associated B-cell proliferation, IGH clonality occurs infrequently (8%) in specific PTCL subtypes.
View details for DOI 10.2353/jmoldx.2008.080054
View details for Web of Science ID 000260533600007
View details for PubMedID 18832464
View details for PubMedCentralID PMC2570633
The Wilms' tumor gene WT1-GFP knock-in mouse reveals the dynamic regulation of WT1 expression in normal and leukemic hematopoiesis
2007; 21 (8): 1783-1791
The Wilms' tumor gene WT1 is overexpressed in most of human leukemias regardless of disease subtypes. To characterize the expression pattern of WT1 during normal and neoplastic hematopoiesis, we generated a knock-in reporter green fluorescent protein (GFP) mouse (WT1(GFP/+)) and assayed for WT1 expression in normal and leukemic hematopoietic cells. In normal hematopoietic cells, WT1 was expressed in none of the long-term (LT) hematopoietic stem cells (HSC) and very few (<1%) of the multipotent progenitor cells. In contrast, in murine leukemias induced by acute myeloid leukemia 1 (AML1)/ETO+TEL/PDGFbetaR or BCR/ABL, WT1 was expressed in 40.5 or 38.9% of immature c-kit(+)lin(-)Sca-1(+) (KLS) cells, which contained a subset, but not all, of transplantable leukemic stem cells (LSCs). WT1 expression was minimal in normal fetal liver HSCs and mobilized HSCs, both of which are stimulated for proliferation. In addition, overexpression of WT1 in HSCs did not result in proliferation or expansion of HSCs and their progeny in vivo. Thus, the mechanism by which expansion of WT1-expressing cells occurs in leukemia remains unclear. Nevertheless, our results demonstrate that the WT1(GFP/+) mouse is a powerful tool for analyzing WT1-expressing cells, and they highlight the potential of WT1, as a specific therapeutic target that is expressed in LSCs but not in normal HSCs.
View details for DOI 10.1038/sj.leu.2404752
View details for Web of Science ID 000248170100021
View details for PubMedID 17525726
The cancer stem cell hypothesis: a work in progress
2006; 86 (12): 1203-1207
There is a growing body of evidence that supports the idea that malignant tumors are initiated and maintained by a population of tumor cells that share similar biologic properties to normal adult stem cells. This model, the cancer stem cell (CSC) hypothesis, is based on the observation that tumors, like adult tissues, arise from cells that exhibit the ability to self-renew as well as give rise to differentiated tissue cells. Although the concept of the CSC is not entirely new, advances made over the past two decades in our understanding of normal stem cell biology in conjunction with the recent application of these concepts to experimentally define CSCs have resulted in the identification of CSCs in several human malignancies.
View details for DOI 10.1038/labinvest.3700488
View details for Web of Science ID 000242442400001
View details for PubMedID 17075578
The frequency of B- and T-cell gene Rearrangements and Epstein-Barr virus in T-cell lymphomas - A comparison between angioimmunoblastic T-cell lymphoma and peripheral T-cell lymphoma, unspecified with and without associated B-cell proliferations
JOURNAL OF MOLECULAR DIAGNOSTICS
2006; 8 (4): 466-475
We report on a series of 58 cases of angioimmunoblastic T-cell lymphoma (AILT) and 59 cases of peripheral T-cell lymphoma, unspecified (PTCL-NOS). Subsets of cases from both diagnostic groups were complicated by associated B-cell proliferations, and we performed B- and T-cell clonality studies and in situ hybridization for Epstein-Barr virus (EBV) to investigate the relationship between B-cell proliferation, B-cell clonality, and EBV. Using multiplex polymerase chain reaction assays based on the BIOMED-2 collaborative study, we detected TCRgamma T-cell clones in 78 and 81% of AILT and PTCL-NOS cases, respectively, and IGH B-cell clones in 34 and 35% of AILT and PTCL-NOS cases, respectively. The majority of cases contained EBV-positive cells, including 50% of AILT and 57% of PTCL-NOS cases, and cases with B-cell proliferations were more often EBV-positive. Although a relatively high rate of B-cell clonality has been shown for AILT, our findings for PTCL-NOS differ from previous reports in that B-cell clonality was relatively frequent. Overall, a positive B-cell clone correlated, in part, with the presence of a B-cell proliferation but not with EBV. Our findings demonstrate that B-cell clonality is a common finding in AILT and PTCL-NOS, and its presence should not negate the diagnosis established by morphologic, immunophenotypic, and clinical findings.
View details for DOI 10.2353/jmoldx.2006.060016
View details for Web of Science ID 000240256600010
View details for PubMedID 16931587
View details for PubMedCentralID PMC1867616