Publications by authors named "David M Dorfman"

109 Publications

Impact of sickle cell trait on morbidity and mortality from SARS-CoV-2 infection.

Blood Adv 2021 09;5(18):3690-3693

Division of Hematology, Department of Internal Medicine, and.

The COVID-19 pandemic has highlighted racial health disparities within the United States. Although social determinants of health are the most likely drivers of this disparity, it is possible that genetic traits enriched in the black population like sickle cell trait (SCT) could worsen the morbidity and mortality of infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Patients admitted for SARS-CoV-2 infection who identified as black or African American were included in the study (n = 166). Blood remnants were tested for SCT, and clinical data were abstracted from the chart. There was no difference in mortality between those with SCT and those without. There was no difference in respiratory complications between groups, but those without SCT had a much higher burden of chronic lung disease (P = .004). Those with SCT had higher creatinine on admission (P = .004), but no difference in in-hospital renal complications (P = .532). Notably, 12% of the cohort had SCT, which is higher than the expected 7.31% (P = .025). Our study did not show any evidence of increased end organ damage, morbidity, or mortality from SARS-CoV-2 infection among patients with SCT but did show differences in admission creatinine and preexisting lung disease.
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http://dx.doi.org/10.1182/bloodadvances.2021004977DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8479384PMC
September 2021

Laboratory Workup of Lymphoma in Adults.

Am J Clin Pathol 2021 01;155(1):12-37

Department of Medicine, Odette Cancer Centre/Sunnybrook Health Sciences Centre, Toronto, Canada.

Objectives: The diagnostic workup of lymphoma continues to evolve rapidly as experience and discovery lead to the addition of new clinicopathologic entities and techniques to differentiate them. The optimal clinically effective, efficient, and cost-effective approach to diagnosis that is safe for patients can be elusive, in both community-based and academic practice. Studies suggest that there is variation in practice in both settings.

The Aim Of This Review Is To: develop an evidence-based guideline for the preanalytic phase of testing, focusing on specimen requirements for the diagnostic evaluation of lymphoma.

Methods: The American Society for Clinical Pathology, the College of American Pathologists, and the American Society of Hematology convened a panel of experts in the laboratory workup of lymphoma to develop evidence-based recommendations. The panel conducted a systematic review of the literature to address key questions. Using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach, recommendations were derived based on the available evidence, the strength of that evidence, and key judgments as defined in the GRADE Evidence to Decision framework.

Results: Thirteen guideline statements were established to optimize specimen selection, ancillary diagnostic testing, and appropriate follow-up for safe and accurate diagnosis of indolent and aggressive lymphoma.

Conclusions: Primary diagnosis and classification of lymphoma can be achieved with a variety of specimens. Application of the recommendations can guide decisions about specimen suitability, diagnostic capabilities, and correct utilization of ancillary testing. Disease prevalence in patient populations, availability of ancillary testing, and diagnostic goals should be incorporated into algorithms tailored to each practice environment.
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http://dx.doi.org/10.1093/ajcp/aqaa191DOI Listing
January 2021

Laboratory Workup of Lymphoma in Adults: Guideline From the American Society for Clinical Pathology and the College of American Pathologists.

Arch Pathol Lab Med 2021 03;145(3):269-290

The Department of Medicine, Odette Cancer Centre/Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada (Cheung).

Context.—: The diagnostic workup of lymphoma continues to evolve rapidly as experience and discovery led to the addition of new clinicopathologic entities and techniques to differentiate them. The optimal clinically effective, efficient, and cost-effective approach to diagnosis that is safe for patients can be elusive, in both community-based and academic practice. Studies suggest that there is variation in practice in both settings.

Objective.—: To develop an evidence-based guideline for the preanalytic phase of testing, focusing on specimen requirements for the diagnostic evaluation of lymphoma.

Design.—: The American Society for Clinical Pathology, the College of American Pathologists, and the American Society of Hematology convened a panel of experts in the laboratory workup of lymphoma to develop evidence-based recommendations. The panel conducted a systematic review of literature to address key questions. Using the Grading of Recommendations Assessment, Development, and Evaluation approach, recommendations were derived based on the available evidence, strength of that evidence, and key judgements as defined in the Grading of Recommendations Assessment, Development, and Evaluation Evidence to Decision framework.

Results.—: Thirteen guideline statements were established to optimize specimen selection, ancillary diagnostic testing, and appropriate follow-up for safe and accurate diagnosis of indolent and aggressive lymphoma.

Conclusions.—: Primary diagnosis and classification of lymphoma can be achieved with a variety of specimens. Application of the recommendations can guide decisions on specimen suitability, diagnostic capabilities, and correct use of ancillary testing. Disease prevalence in patient populations, availability of ancillary testing, and diagnostic goals should be incorporated into algorithms tailored to each practice environment.
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http://dx.doi.org/10.5858/arpa.2020-0261-SADOI Listing
March 2021

Participation in the College of American Pathologists Laboratory Accreditation Program Decreases Variability in B-Lymphoblastic Leukemia and Plasma Cell Myeloma Flow Cytometric Minimal Residual Disease Testing: A Follow-up Survey.

Arch Pathol Lab Med 2021 03;145(3):336-342

From the Division of Hematopathology, Department of Laboratory Medicine and Pathology, University of Minnesota Medical Center, Minneapolis (Hupp, Linden).

Context.—: Minimal residual disease (MRD) testing by flow cytometry is ubiquitous in hematolymphoid neoplasm monitoring, especially B-lymphoblastic leukemia (B-ALL), for which it provides predictive information and guides management. Major heterogeneity was identified in 2014. Subsequently, new Flow Cytometry Checklist items required documentation of the sensitivity determination method and required lower level of detection (LLOD) inclusion in final reports. This study assesses Laboratory Accreditation Program (LAP) participation and new checklist items' impact on flow cytometry MRD testing.

Objectives.—: To survey flow cytometry laboratories about MRD testing for B-ALL and plasma cell myeloma. In particular, enumerate the laboratories performing MRD testing, the proportion performing assays with very low LLODs, and implementation of new checklist items.

Design.—: Supplemental questions were distributed in the 2017-A mailing to 548 flow cytometry laboratories subscribed to the College of American Pathologists FL3 Proficiency Testing Survey (Flow Cytometry-Immunophenotypic Characterization of Leukemia/Lymphoma).

Results.—: The percentage of laboratories performing MRD studies has significantly decreased since 2014. Wide ranges of LLOD and collection event numbers were reported for B-ALL and plasma cell myeloma. Most laboratories determine LLOD by using dilutional studies and include it in final reports; a higher proportion of LAP participants used these practices than nonparticipants.

Conclusions.—: Several MRD testing aspects vary among laboratories receiving FL3 Proficiency Testing materials. After the survey in 2014, new checklist items were implemented. As compared to 2014, fewer laboratories are performing MRD studies. While LLOD remains heterogeneous, a high proportion of LAP subscribers follow the new checklist requirements and, overall, target LLOD recommendations from disease-specific working groups are met.
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http://dx.doi.org/10.5858/arpa.2019-0493-CPDOI Listing
March 2021

miR-15a/16-1 deletion in activated B cells promotes plasma cell and mature B-cell neoplasms.

Blood 2021 04;137(14):1905-1919

Department of Oncologic Pathology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.

Chromosome 13q deletion [del(13q)], harboring the miR-15a/16-1 cluster, is one of the most common genetic alterations in mature B-cell malignancies, which originate from germinal center (GC) and post-GC B cells. Moreover, miR-15a/16 expression is frequently reduced in lymphoma and multiple myeloma (MM) cells without del(13q), suggesting important tumor-suppressor activity. However, the role of miR-15a/16-1 in B-cell activation and initiation of mature B-cell neoplasms remains to be determined. We show that conditional deletion of the miR-15a/16-1 cluster in murine GC B cells induces moderate but widespread molecular and functional changes including an increased number of GC B cells, percentage of dark zone B cells, and maturation into plasma cells. With time, this leads to development of mature B-cell neoplasms resembling human extramedullary plasmacytoma (EP) as well as follicular and diffuse large B-cell lymphomas. The indolent nature and lack of bone marrow involvement of EP in our murine model resembles human primary EP rather than MM that has progressed to extramedullary disease. We corroborate human primary EP having low levels of miR-15a/16 expression, with del(13q) being the most common genetic loss. Additionally, we show that, although the mutational profile of human EP is similar to MM, there are some exceptions such as the low frequency of hyperdiploidy in EP, which could account for different disease presentation. Taken together, our studies highlight the significant role of the miR-15a/16-1 cluster in the regulation of the GC reaction and its fundamental context-dependent tumor-suppression function in plasma cell and B-cell malignancies.
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http://dx.doi.org/10.1182/blood.2020009088DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8033455PMC
April 2021

Evaluation of Antifactor-Xa Heparin Assay and Activated Partial Thromboplastin Time Values in Patients on Therapeutic Continuous Infusion Unfractionated Heparin Therapy.

Clin Appl Thromb Hemost 2019 Jan-Dec;25:1076029619876030

Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.

Clinical uncertainty exists regarding which assay should be designated as the standard monitoring coagulation test for intravenous unfractionated heparin (UFH). Several studies have compared the use of activated partial thromboplastin time (aPTT) and antifactor-Xa (anti-Xa) and have come out with varying results. The correlation between these 2 tests varied, markedly from strong to weak. Some have demonstrated that monitoring with anti-Xa heparin assay leads to fewer dose adjustments, resulting in fewer laboratory tests, while others have not. In the current study, we evaluated the correlation between aPTT and anti-Xa values to guide clinical management of UFH, with the intention to develop a new correlation nomogram.
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http://dx.doi.org/10.1177/1076029619876030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6829967PMC
March 2020

Highly differentiated cytotoxic T cells in inclusion body myositis.

Brain 2019 09;142(9):2590-2604

Brigham and Women's Hospital Department of Neurology, Division of Neuromuscular Disease, and Harvard Medical School, Boston, MA, USA.

Inclusion body myositis is a late onset treatment-refractory autoimmune disease of skeletal muscle associated with a blood autoantibody (anti-cN1A), an HLA autoimmune haplotype, and muscle pathology characterized by cytotoxic CD8+ T cell destruction of myofibres. Here, we report on translational studies of inclusion body myositis patient muscle compared with a diverse set of other muscle disease samples. Using available microarray data on 411 muscle samples from patients with inclusion body myositis (n = 40), other muscle diseases (n = 265), and without neuromuscular disease (normal, n = 106), we identified a signature of T-cell cytotoxicity in inclusion body myositis muscle coupled with a signature of highly differentiated CD8 T-cell effector memory and terminally differentiated effector cells. Further, we examined killer cell lectin-like receptor G1 (KLRG1) as a marker of this population of cells, demonstrated the correlation of KLRG1 gene expression with lymphocyte cytotoxicity across 28 870 human tissue samples, and identified the presence of KLRG1 on pathogenic inclusion body myositis muscle invading T cells and an increase in KLRG1 expressing T cells in inclusion body myositis blood. We examined inclusion body myositis muscle T-cell proliferation by Ki67 immunohistochemistry demonstrating that diseased muscle-invading T cells are minimally or non-proliferative, in accordance with known properties of highly differentiated or terminally differentiated T cells. We found low expression of KLRG1 on infection-protective human lymphoid tissue central memory T cells and autoimmune-protective human blood regulatory T cells. Targeting highly differentiated cytotoxic T cells could be a favourable approach to treatment of inclusion body myositis.
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http://dx.doi.org/10.1093/brain/awz207DOI Listing
September 2019

Pleomorphic mantle cell lymphoma mimicking diffuse large B-cell lymphoma in peripheral blood and bone marrow.

Am J Hematol 2019 10 29;94(10):1170-1171. Epub 2019 Apr 29.

Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.

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http://dx.doi.org/10.1002/ajh.25491DOI Listing
October 2019

Highly efficient therapeutic gene editing of human hematopoietic stem cells.

Nat Med 2019 05 25;25(5):776-783. Epub 2019 Mar 25.

Division of Hematology/Oncology, Boston Children's Hospital , Boston, MA, USA.

Re-expression of the paralogous γ-globin genes (HBG1/2) could be a universal strategy to ameliorate the severe β-globin disorders sickle cell disease (SCD) and β-thalassemia by induction of fetal hemoglobin (HbF, αγ). Previously, we and others have shown that core sequences at the BCL11A erythroid enhancer are required for repression of HbF in adult-stage erythroid cells but are dispensable in non-erythroid cells. CRISPR-Cas9-mediated gene modification has demonstrated variable efficiency, specificity, and persistence in hematopoietic stem cells (HSCs). Here, we demonstrate that Cas9:sgRNA ribonucleoprotein (RNP)-mediated cleavage within a GATA1 binding site at the +58 BCL11A erythroid enhancer results in highly penetrant disruption of this motif, reduction of BCL11A expression, and induction of fetal γ-globin. We optimize conditions for selection-free on-target editing in patient-derived HSCs as a nearly complete reaction lacking detectable genotoxicity or deleterious impact on stem cell function. HSCs preferentially undergo non-homologous compared with microhomology-mediated end joining repair. Erythroid progeny of edited engrafting SCD HSCs express therapeutic levels of HbF and resist sickling, while those from patients with β-thalassemia show restored globin chain balance. Non-homologous end joining repair-based BCL11A enhancer editing approaching complete allelic disruption in HSCs is a practicable therapeutic strategy to produce durable HbF induction.
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http://dx.doi.org/10.1038/s41591-019-0401-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6512986PMC
May 2019

Use of a Blast Dominance-Hematogone Index for the Flow Cytometric Evaluation of Myelodysplastic Syndrome (MDS).

Am J Clin Pathol 2019 05;151(6):584-592

Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA.

Objectives: We tested whether combined flow cytometric assessment of loss of blast heterogeneity and decreased hematogones is a diagnostically useful approach for evaluation of myelodysplastic syndrome (MDS).

Methods: Bone marrow samples from patients with known MDS were analyzed by 10-color flow cytometric immunophenotyping and compared with normal bone marrow samples.

Results: There was loss of blast heterogeneity in patients with MDS compared with normal bone marrow samples, based on the relative size of the dominant blast population (83.0% vs 64.8%) and fewer hematogones (0.08% vs 1.39%). The size of the largest blast population divided by the fraction of hematogones (blast dominance-hematogone [BDH] index) was significantly larger in MDS compared with normal cases (27,084 vs 190, P < .0001; receiver operating characteristic area under the curve = 0.96).

Conclusions: The BDH index is more sensitive and specific than loss of blast heterogeneity or decrease in hematogones for detecting MDS in bone marrow samples and may be useful in clinical practice.
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http://dx.doi.org/10.1093/ajcp/aqz004DOI Listing
May 2019

Utility of a Simple and Robust Flow Cytometry Assay for Rapid Clonality Testing in Mature Peripheral T-Cell Lymphomas.

Am J Clin Pathol 2019 04;151(5):494-503

Department of Pathology, Brigham and Women's Hospital, Boston, MA.

Objectives: Flow cytometry immunophenotyping is limited by poor resolution of T-cell clones. A newly described antibody was recently used to distinguish normal peripheral blood T cells from malignant T-cell clones. Here, we evaluate this antibody as a new diagnostic tool for detecting T-cell clonality in mature peripheral T-cell lymphomas.

Methods: Immunostaining for the T-cell receptor β chain constant region 1 (TRBC1) along with routine T-cell markers was performed on 51 peripheral blood and two bone marrow samples submitted to the flow cytometry laboratory for suspected T-cell malignancy.

Results: TRBC immunophenotyping identified malignant T-cell clones with 97% sensitivity and 91% specificity. Findings correlated with molecular T-cell clonality testing. In cases with equivocal molecular results, TRBC1 immunophenotyping provided additional diagnostic information.

Conclusions: TRBC1 flow cytometric immunophenotyping is a robust and inexpensive method for identifying T-cell clonality that could easily be incorporated into routine flow cytometric practice.
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http://dx.doi.org/10.1093/ajcp/aqy173DOI Listing
April 2019

Acute myeloid leukemia with minimal differentiation (AML M0) mimicking acute lymphoblastic leukemia.

Am J Hematol 2019 08 5;94(8):955-956. Epub 2018 Dec 5.

Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.

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http://dx.doi.org/10.1002/ajh.25354DOI Listing
August 2019

Utility of Combined EZH2, p-ERK1/2, p-STAT, and MYC Expression in the Differential Diagnosis of EZH2-positive Hodgkin Lymphomas and Related Large B-Cell Lymphomas.

Am J Surg Pathol 2019 01;43(1):102-109

Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.

EZH2 is a methyltransferase that plays an important tumorigenic role in various neoplasms. We previously found that EZH2 is expressed in a range of aggressive B-cell lymphomas (ABCLs), T-cell lymphomas, and histiocytic neoplasms, with differential expression of intracellular signaling molecules p-ERK, MYC, and p-STAT3, potential regulators of EZH2 expression. We studied EZH2 expression in nodular lymphocyte predominant Hodgkin lymphoma (NLPHL), classic Hodgkin lymphoma (cHL), T-cell/histiocyte-rich large B-cell lymphoma (THRLBCL), and B-cell Lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphomas and classic Hodgkin lymphoma (BCLu-DLBCL/cHL), as well as the coexpression of p-ERK, MYC, and p-STAT3 in these neoplasms. The neoplastic LP cells of NLPHL and Hodgkin/Reed-Sternberg cells of cHL were strongly positive for EZH2, as were the neoplastic cells in THRLBCL and BCLu-DLBCL/cHL. EZH2 expression correlated with proliferation rate, as assessed by Ki-67 staining. LP cells in NLPHL and Hodgkin/Reed-Sternberg cells in cHL were strongly positive for p-ERK, p-STAT3, and MYC, as were the neoplastic cells in THRLBCL and BCLu-DLBCL/cHL, in contrast to the differential expression of these molecules seen in ABCLs. These findings suggest that combined expression of p-ERK, MYC, and p-STAT3 is a useful immunohistochemical pattern for the diagnosis of EZH2-positive Hodgkin lymphomas and related lymphomas, in contrast to ABCLs. Furthermore, the overexpression of EZH2, in association with coexpression of tumorigenic signaling molecules, suggests an oncogenic role for this molecule in the development of Hodgkin lymphomas and related lymphomas. THRLBCL and BCLu-DLBCL/cHL appear to have a mechanism for the regulation of EZH2 expression that is similar to NLPHL and cHL and different from that of ABCLs. In addition, EZH2 and associated signaling cascades may serve as therapeutic targets for the treatment of Hodgkin lymphomas and related lymphomas.
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http://dx.doi.org/10.1097/PAS.0000000000001180DOI Listing
January 2019

Highly atypical myeloblasts in acute myeloid leukaemia with myelodysplasia-related changes in a patient with short telomere syndrome.

Br J Haematol 2018 11 24;183(4):536. Epub 2018 Jul 24.

Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.

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http://dx.doi.org/10.1111/bjh.15505DOI Listing
November 2018

Leukemic-phase progression of aleukemic mast cell leukemia.

Blood 2018 05;131(21):2406

Brigham and Women's Hospital.

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http://dx.doi.org/10.1182/blood-2018-02-831388DOI Listing
May 2018

Targetable vulnerabilities in T- and NK-cell lymphomas identified through preclinical models.

Nat Commun 2018 05 22;9(1):2024. Epub 2018 May 22.

Department of Pathology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA.

T- and NK-cell lymphomas (TCL) are a heterogenous group of lymphoid malignancies with poor prognosis. In contrast to B-cell and myeloid malignancies, there are few preclinical models of TCLs, which has hampered the development of effective therapeutics. Here we establish and characterize preclinical models of TCL. We identify multiple vulnerabilities that are targetable with currently available agents (e.g., inhibitors of JAK2 or IKZF1) and demonstrate proof-of-principle for biomarker-driven therapies using patient-derived xenografts (PDXs). We show that MDM2 and MDMX are targetable vulnerabilities within TP53-wild-type TCLs. ALRN-6924, a stapled peptide that blocks interactions between p53 and both MDM2 and MDMX has potent in vitro activity and superior in vivo activity across 8 different PDX models compared to the standard-of-care agent romidepsin. ALRN-6924 induced a complete remission in a patient with TP53-wild-type angioimmunoblastic T-cell lymphoma, demonstrating the potential for rapid translation of discoveries from subtype-specific preclinical models.
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http://dx.doi.org/10.1038/s41467-018-04356-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5964252PMC
May 2018

Expression of enhancer of zeste homolog 2 (EZH2) protein in histiocytic and dendritic cell neoplasms with evidence for p-ERK1/2-related, but not MYC- or p-STAT3-related cell signaling.

Mod Pathol 2018 04 12;31(4):553-561. Epub 2018 Jan 12.

Brigham and Women's Hospital and Harvard Medical School, Department of Pathology, Boston, MA, USA.

EZH2 is an important enzymatic subunit of the epigenetic regulator polycomb repressive complex 2 (PRC2), which controls gene silencing through post-translational modification, and is overexpressed in various carcinomas and hematopoietic neoplasms. We found that the majority of cases of histiocytic and dendritic cell neoplasms, including histiocytic sarcoma, follicular dendritic cell sarcoma, Langerhans cell histiocytosis, and interdigitating dendritic cell sarcoma, show strong EZH2 expression by immunohistochemical staining, in contrast to benign histiocytic lesions and normal cellular counterparts, which did not show EZH2 expression, suggesting that this molecule may function as an oncogenic protein in these neoplasms. We correlated EZH2 expression with that of p-ERK1/2, MYC, and p-STAT3, potential regulators of EZH2, and found that 60-80% of these cases showed strong p-ERK1/2 expression, and only a minority of cases showed positivity for MYC or p-STAT3 in neoplastic cells. In cases of follicular dendritic cell sarcoma, Langerhans cell histiocytosis, histiocytic sarcoma, and interdigitating dendritic cell sarcoma with strong EZH2 expression, 90%, 89%, 70%, and 100% of cases showed co-expression of p-ERK1/2 with EZH2, respectively, while only a small percentage of these cases showed MYC or p-STAT3 co-expression with EZH2 (≤30%). These findings suggest that the p-ERK1/2 signaling cascade, but not the p-STAT3 and MYC signaling cascades, may regulate EZH2 expression in histiocytic and dendritic cell neoplasms, and that EZH2 and the p-ERK1/2 signaling cascade could serve as therapeutic targets for the treatment of these neoplasms. Interestingly, only a minority of cases of blastic plasmacytoid dendritic cell neoplasm exhibited high EZH2 expression, and only a minority of these cases showed p-ERK1/2 co-expression, suggesting that alternative mechanisms may contribute to tumorigenesis in this aggressive neoplasm.
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http://dx.doi.org/10.1038/modpathol.2017.174DOI Listing
April 2018

Clinical Flow Cytometry: State-of-the-Art and New Approaches.

Authors:
David M Dorfman

Clin Lab Med 2017 12 20;37(4):xiii-xiv. Epub 2017 Sep 20.

Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA. Electronic address:

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http://dx.doi.org/10.1016/j.cll.2017.09.001DOI Listing
December 2017

Mast Cell Disease Assessment by Flow Cytometric Analysis.

Clin Lab Med 2017 12 10;37(4):869-878. Epub 2017 Oct 10.

Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA. Electronic address:

Mast cells are present at a low frequency in bone marrow, rendering high-sensitivity multiparametric flow cytometric analysis an ideal method to assess antigen expression on mast cells. This article discusses the normal antigen expression profile of mast cells, established criteria to identify neoplastic mast cells, and new immunophenotypic markers and approaches to identify the presence of neoplastic mast cells in cases of mastocytosis.
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http://dx.doi.org/10.1016/j.cll.2017.07.008DOI Listing
December 2017

Flow Cytometry of T cells and T-cell Neoplasms.

Clin Lab Med 2017 12 3;37(4):725-751. Epub 2017 Oct 3.

Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA. Electronic address:

Flow cytometry is ideally suited for the immunophenotypic analysis of T-cell neoplasia. This article covers the spectrum of flow cytometric findings associated with frequently encountered benign and neoplastic T-cell populations and details the most common immunophenotypic features associated with specific neoplasms of both immature and mature T cells.
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http://dx.doi.org/10.1016/j.cll.2017.07.002DOI Listing
December 2017

Realgar nanoparticles versus ATO arsenic compounds induce in vitro and in vivo activity against multiple myeloma.

Br J Haematol 2017 12 19;179(5):756-771. Epub 2017 Oct 19.

Cancer Research Institute, Biomedical Research Center SAS, Bratislava, Slovakia.

Multiple myeloma (MM), a B cell malignancy characterized by clonal proliferation of plasma cells in the bone marrow, remains incurable despite the use of novel and conventional therapies. In this study, we demonstrated MM cell cytotoxicity triggered by realgar (REA; As S ) nanoparticles (NREA) versus Arsenic trioxide (ATO) against MM cell lines and patient cells. Both NREA and ATO showed in vivo anti-MM activity, resulting in significantly decreased tumour burden. The anti-MM activity of NREA and ATO is associated with apoptosis, evidenced by DNA fragmentation, depletion of mitochondrial membrane potential, cleavage of caspases and anti-apoptotic proteins. NREA induced G /M cell cycle arrest and modulation of cyclin B1, p53 (TP53), p21 (CDKN1A), Puma (BBC3) and Wee-1 (WEE1). Moreover, NREA induced modulation of key regulatory molecules in MM pathogenesis including JNK activation, c-Myc (MYC), BRD4, and histones. Importantly, NREA, but not ATO, significantly depleted the proportion and clonogenicity of the MM stem-like side population, even in the context of the bone marrow stromal cells. Finally, our study showed that both NREA and ATO triggered synergistic anti-MM activity when combined with lenalidomide or melphalan. Taken together, the anti-MM activity of NREA was more potent compared to ATO, providing the preclinical framework for clinical trials to improve patient outcome in MM.
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http://dx.doi.org/10.1111/bjh.14974DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5705577PMC
December 2017

Ectopic Intrathyroidal Thymic Tissue Mimicking Thyroid Nodules in Children.

J Ultrasound Med 2018 Mar 29;37(3):783-791. Epub 2017 Aug 29.

Thyroid Section, Division of Endocrinology, Diabetes, and Hypertension, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.

Ectopic intrathyroidal thymic tissue is a benign lesion of nonthyroid origin occasionally found in the pediatric thyroid gland. Accurate diagnosis of such lesions is critical to avoid unnecessary biopsy or surgery. Twelve children referred to our center for the concern of thyroid nodules were found to have intrathyroidal thymic tissue. Most of the lesions had a classic sonographic appearance of a hypoechoic mass with sharp margins and multiple focal internal nonshadowing echogenicities identical to thymic tissue. Sonography and, in select cases, fine-needle aspiration can be used to diagnose benign thymic tissue within the thyroid and avoid unnecessary surgery.
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http://dx.doi.org/10.1002/jum.14360DOI Listing
March 2018

Flow Cytometric Patterns of CD200 and CD1d Expression Distinguish CD10-Negative, CD5-Negative Mature B-Cell Lymphoproliferative Disorders.

Am J Clin Pathol 2017 Jul;148(1):33-41

Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA.

Objectives: The importance of distinguishing mature B-cell lymphoproliferative disorders (B-LPDs) is highlighted by the distinct treatments used for and varying prognoses seen in association with these different diseases. Immunophenotyping allows for accurate and efficient differentiation of many B-LPDs. Recently, we showed that CD200 is highly expressed in hairy cell leukemia (HCL) but not in marginal zone lymphoma (MZL), lymphoplasmacytic lymphoma (LPL), or hairy cell leukemia-variant (HCL-v). Here, we assessed the usefulness of a flow cytometric panel combining CD200 and CD1d with CD25, CD103, and CD11c to distinguish CD10-, CD5- B-LPDs.

Methods: We analyzed the expression of CD200 and CD1d by flow cytometric analysis in 79 cases of CD10-, CD5- mature B-LPDs.

Results: Distinct patterns of CD200 and CD1d expression were seen in the examined B-LPDs. HCL showed bright positivity for CD200 along with positive staining for CD1d, whereas HCL-v showed low levels of expression for both markers. LPL demonstrated positive staining for CD200 in combination with dim to negative staining for CD1d. In contrast, MZL was commonly positive for CD1d and negative for CD200.

Conclusions: Flow cytometric analysis of CD200 and CD1d, along with CD25, CD103, and CD11c, can aid in the diagnosis of CD10-, CD5- mature B-LPDs.
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http://dx.doi.org/10.1093/ajcp/aqx041DOI Listing
July 2017

T-cell transcription factor GATA-3 is an immunophenotypic marker of acute leukemias with T-cell differentiation.

Hum Pathol 2017 07 24;65:166-174. Epub 2017 May 24.

Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.

T-cell transcription factor GATA-3, known to play a role in early T-cell development and in the development of T-cell neoplasms, is expressed at high levels in fetal and adult thymus, as well as in acute leukemias with T-cell differentiation, including T-lymphoblastic leukemia/lymphoma (22/22 cases), early T-cell precursor lymphoblastic leukemia (11/11 cases), and mixed-phenotype acute leukemia, T/myeloid (4/5 cases), but only rarely in acute myeloid leukemia/myeloid sarcoma (1/36 cases), and not in B-lymphoblastic leukemia (0/16 cases). In contrast, T-bet, the other T-cell transcription factor that controls Th1/Th2 T-cell fate, is not expressed to any significant extent in immature thymocytes or in cases of T-lymphoblastic leukemia or acute myeloid leukemia/myeloid sarcoma, but is expressed in most cases (15/16) of B-lymphoblastic leukemia and in mixed-phenotype acute leukemia, B/myeloid. GATA-3-positive acute leukemias with T-cell differentiation were also found to express proto-oncogene C-MYC, in an average of 52% of neoplastic cells, which, along with GATA-3, may contribute to leukemogenesis, as suggested by transgenic mouse models. We conclude that GATA-3 is a sensitive and specific marker for the diagnosis of acute leukemias with T-cell differentiation and may be a useful addition to the panel of immunophenotypic markers for the diagnostic evaluation of acute leukemias.
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http://dx.doi.org/10.1016/j.humpath.2017.05.009DOI Listing
July 2017

Myocardial Induction of Type 3 Deiodinase in Dilated Cardiomyopathy.

Thyroid 2017 05 5;27(5):732-737. Epub 2017 Apr 5.

1 Thyroid Program, Division of Endocrinology, Boston Children's Hospital , Boston, Massachusetts.

Background: The thyroid hormone-inactivating enzyme type 3 deiodinase (D3) is induced during hypertrophic and ischemic cardiomyopathy, leading to a state of local cardiac hypothyroidism. Whether D3 induction occurs in dilated cardiomyopathy is unknown.

Methods: This study characterized changes in cardiac D3 and thyroid hormone signaling in a transgenic model of progressive dilated cardiomyopathy (TG9 mice).

Results: Cardiac D3 was dramatically induced 15-fold during the progression of dilated cardiomyopathy in TG9 mice. This D3 induction localized to cardiomyocytes and was associated with a decrease in myocardial thyroid hormone signaling.

Conclusions: Cardiac D3 is induced in a mouse model of dilated cardiomyopathy, indicating that D3 induction may be a general response to diverse forms of cardiomyopathy.
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http://dx.doi.org/10.1089/thy.2016.0570DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5421592PMC
May 2017

An unusual case of chronic lymphocytic leukemia/small lymphocytic lymphoma with nodular morphology.

Leuk Lymphoma 2017 08 6;58(8):2014-2016. Epub 2016 Dec 6.

a Department of Pathology , Brigham and Women's Hospital, Harvard Medical School , Boston , MA , USA.

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http://dx.doi.org/10.1080/10428194.2016.1265119DOI Listing
August 2017

A novel 3D mesenchymal stem cell model of the multiple myeloma bone marrow niche: biologic and clinical applications.

Oncotarget 2016 Nov;7(47):77326-77341

Department of Medical Oncology, Jerome Lipper Multiple Myeloma Center, Dana Farber Cancer Institute, Department of Medical Oncology, Boston, MA, USA.

Specific niches within the tumor bone marrow (BM) microenvironment afford a sanctuary for multiple myeloma (MM) clones due to stromal cell-tumor cell interactions, which confer survival advantage and drug resistance. Defining the sequelae of tumor cell interactions within the MM niches on an individualized basis may provide the rationale for personalized therapies. To mimic the MM niche, we here describe a new 3D co-culture ex-vivo model in which primary MM patient BM cells are co-cultured with mesenchymal stem cells (MSC) in a hydrogel 3D system. In the 3D model, MSC with conserved phenotype (CD73+CD90+CD105+) formed compact clusters with active fibrous connections, and retained lineage differentiation capacity. Extracellular matrix molecules, integrins, and niche related molecules including N-cadherin and CXCL12 are expressed in 3D MSC model. Furthermore, activation of osteogenesis (MMP13, SPP1, ADAMTS4, and MGP genes) and osteoblastogenic differentiation was confirmed in 3D MSC model. Co-culture of patient-derived BM mononuclear cells with either autologous or allogeneic MSC in 3D model increased proliferation of MM cells, CXCR4 expression, and SP cells. We carried out immune profiling to show that distribution of immune cell subsets was similar in 3D and 2D MSC model systems. Importantly, resistance to novel agents (IMiDs, bortezomib, carfilzomib) and conventional agents (doxorubicin, dexamethasone, melphalan) was observed in 3D MSC system, reflective of clinical resistance. This 3D MSC model may therefore allow for studies of MM pathogenesis and drug resistance within the BM niche. Importantly, ongoing prospective trials are evaluating its utility to inform personalized targeted and immune therapy in MM.
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http://dx.doi.org/10.18632/oncotarget.12643DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5357212PMC
November 2016

Flow Cytometry of Nonhematopoietic Neoplasms.

Acta Cytol 2016 27;60(4):336-343. Epub 2016 Aug 27.

Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pa., USA.

Many epithelial neoplasms can be analyzed by flow cytometry (FC), particularly from serous cavity effusion samples, using EpCAM, a cell adhesion molecule expressed on most normal epithelial cells and expressed at a higher level in most epithelial neoplasms. A simple 3-color flow cytometric panel can provide a high sensitivity and specificity compared to cytomorphology. FC provides more rapid immunophenotyping than conventional immunohistochemical staining, can identify rare malignant cells that could be missed by a cytological exam alone, and can be utilized to evaluate limited samples such as cerebrospinal fluid or fine-needle aspiration samples. Flow cytometric analysis for epithelial antigens can be combined with DNA ploidy analysis or assessment of the nucleus-to-cytoplasm ratio. Panels of flow cytometric markers are useful for the assessment of pediatric nonhematopoietic neoplasms, including neuroblastomas, primitive neuroectodermal tumors, Wilms' tumor, rhabdomyosarcomas, germ cell tumors, and hemangiopericytomas, as well as small-round-blue-cell tumors in adults, including small-cell carcinomas.
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http://dx.doi.org/10.1159/000448371DOI Listing
January 2017

FLOCK cluster analysis of plasma cell flow cytometry data predicts bone marrow involvement by plasma cell neoplasia.

Leuk Res 2016 09 19;48:40-5. Epub 2016 Jul 19.

Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, United States.

We analyzed plasma cell populations in bone marrow samples from 353 patients with possible bone marrow involvement by a plasma cell neoplasm, using FLOCK (FLOw Clustering without K), an unbiased, automated, computational approach to identify cell subsets in multidimensional flow cytometry data. FLOCK identified discrete plasma cell populations in the majority of bone marrow specimens found by standard histologic and immunophenotypic criteria to be involved by a plasma cell neoplasm (202/208 cases; 97%), including 34 cases that were negative by standard flow cytometric analysis that included clonality assessment. FLOCK identified discrete plasma cell populations in only a minority of cases negative for involvement by a plasma cell neoplasm by standard histologic and immunophenotypic criteria (38/145 cases; 26%). Interestingly, 55% of the cases negative by standard analysis, but containing a FLOCK-identified discrete plasma cell population, were positive for monoclonal gammopathy by serum protein electrophoresis and immunofixation. FLOCK-identified and quantitated plasma cell populations accounted for 3.05% of total cells on average in cases positive for involvement by a plasma cell neoplasm by standard histologic and immunophenotypic criteria, and 0.27% of total cells on average in cases negative for involvement by a plasma cell neoplasm by standard histologic and immunophenotypic criteria (p<0.0001; area under the curve by ROC analysis=0.96). The presence of a FLOCK-identified discrete plasma cell population was predictive of the presence of plasma cell neoplasia with a sensitivity of 97%, compared with only 81% for standard flow cytometric analysis, and had specificity of 74%, PPV of 84% and NPV of 95%. FLOCK analysis, which has been shown to provide useful diagnostic information for evaluating patients with suspected systemic mastocytosis, is able to identify neoplastic plasma cell populations analyzed by flow cytometry, and may be helpful in the diagnostic evaluation of bone marrow samples for involvement by plasma cell neoplasia.
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http://dx.doi.org/10.1016/j.leukres.2016.07.003DOI Listing
September 2016
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