Publications by authors named "Mina L Xu"

43 Publications

Role of MBD3-SOX2 axis in residual myeloma following pomalidomide.

Leukemia 2021 Feb 18. Epub 2021 Feb 18.

Winship Cancer Institute, Emory University, Atlanta, GA, USA.

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http://dx.doi.org/10.1038/s41375-021-01145-0DOI Listing
February 2021

Myeloid sarcoma, chloroma, or extramedullary acute myeloid leukemia tumor: A tale of misnomers, controversy and the unresolved.

Blood Rev 2020 Oct 30:100773. Epub 2020 Oct 30.

Section of Hematology, Department of Medicine, Yale University School of Medicine and Yale Cancer Center, New Haven, USA. Electronic address:

The World Health Organization classification and definition of "myeloid sarcoma" is imprecise and misleading. A more accurate term is "extramedullary acute myeloid leukemia tumor (eAML)." The pathogenesis of eAML has been associated with aberrancy of cellular adhesion molecules, chemokine receptors/ligands and RAS-MAPK/ERK signaling. eAML can present with or without synchronous or metachronous intramedullary acute myeloid leukemia (AML) so a bone marrow evaluation is always recommended. Accurate diagnosis of eAML requires tissue biopsy. eAML confined to one or a few sites is frequently treated with local therapy such as radiotherapy. About 75-90% of patients with isolated eAML will develop metachronous intramedullary AML with a median latency period ranging from 4 to 12 months; thus, patients with isolated eAML may also be treated with systemic anti-leukemia therapy. eAML does not appear to have an independent prognostic impact; selection of post-remission therapy including allogeneic hematopoietic cell transplant (alloHCT) is typically guided by intramedullary disease risk. Management of isolated eAML should be individualized based on patient characteristics as well as eAML location and cytogenetic/molecular features. The role of PET/CT in eAML is also currently being elucidated. Improving outcomes of patients with eAML requires further knowledge of its etiology and mechanism(s) as well as therapeutic approaches beyond conventional chemotherapy, ideally in the context of controlled trials.
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http://dx.doi.org/10.1016/j.blre.2020.100773DOI Listing
October 2020

Cutaneous Involvement in Plasma Cell Myeloma.

Am J Clin Pathol 2021 01;155(1):106-116

Department of Pathology, Yale School of Medicine, New Haven, CT.

Objectives: Plasma cell myeloma (PCM) involving skin is rare and occurs in 1% to 4% of patients with PCM. We evaluated the clinicopathologic features, cytogenetic findings and clinical follow-up in a series of PCM cases with cutaneous involvement.

Methods: Cases of PCM with cutaneous involvement were retrospectively reviewed with clinical data.

Results: Skin involvement in PCM occurred in older individuals (mean, 75 years) and was more frequent in men (7/10 patients). All cases showed bone marrow involvement preceding the cutaneous lesions. Histopathologically, the infiltrate was plasmacytic (n = 5) or primitive or plasmablastic (n = 4), and 1 case showed predominantly lymphoplasmacytic features with cyclin D1 immunoreactivity and CCND1 gene rearrangement. Concurrent amyloid deposition was seen in one biopsy, and another case demonstrated coexisting squamous cell carcinoma. The most common immunophenotype was CD138+, CD20-, and CD56+ with light chain restriction. Cytogenetic analysis (available for 7 cases) showed multiple hyperdiploid abnormalities. Follow-up was available for 8 cases (mean, 42 months; range, 11-156 months) and showed short-term disease-related death in 7 of 8 patients.

Conclusions: Cutaneous involvement in PCM demonstrates a diverse cytomorphologic spectrum with plasmacytic, plasmablastic, or lymphoplasmacytic features and may show concurrent amyloid deposition or neoplasms such as squamous cell carcinoma. Cutaneous involvement typically occurs late in the course of the disease and likely portends poor outcome.
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http://dx.doi.org/10.1093/ajcp/aqaa122DOI Listing
January 2021

Tumor response and endogenous immune reactivity after administration of HER2 CAR T cells in a child with metastatic rhabdomyosarcoma.

Nat Commun 2020 07 15;11(1):3549. Epub 2020 Jul 15.

Texas Children's Cancer and Hematology Centers, Texas Children's Hospital, Baylor College of Medicine, Houston, TX, USA.

Refractory metastatic rhabdomyosarcoma is largely incurable. Here we analyze the response of a child with refractory bone marrow metastatic rhabdomyosarcoma to autologous HER2 CAR T cells. Three cycles of HER2 CAR T cells given after lymphodepleting chemotherapy induces remission which is consolidated with four more CAR T-cell infusions without lymphodepletion. Longitudinal immune-monitoring reveals remodeling of the T-cell receptor repertoire with immunodominant clones and serum autoantibodies reactive to oncogenic signaling pathway proteins. The disease relapses in the bone marrow at six months off-therapy. A second remission is achieved after one cycle of lymphodepletion and HER2 CAR T cells. Response consolidation with additional CAR T-cell infusions includes pembrolizumab to improve their efficacy. The patient described here is a participant in an ongoing phase I trial (NCT00902044; active, not recruiting), and is 20 months off T-cell infusions with no detectable disease at the time of this report.
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http://dx.doi.org/10.1038/s41467-020-17175-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7363864PMC
July 2020

T-cell and NK-cell lymphomas in the lung.

Semin Diagn Pathol 2020 Nov 16;37(6):273-282. Epub 2020 May 16.

Director of Hematopathology, Department of Pathology & Laboratory Medicine, Yale University School of Medicine, 310 Cedar Street, New Haven, CT, 06510, United States. Electronic address:

While the lung is frequently involved by systemic lymphoma, primary pulmonary lymphoma accounts for less than 1% of all extranodal ymphomas. In particular, T-cell lymphoma is very rare in the lung, as a primary or secondary lesion. Patients with pulmonary T-cell lymphoma usually present with cough, dyspnea, pain, fever, recurrent infections, and hemoptysis. Typical radiologic features include pulmonary nodules, consolidation, solid pulmonary opacities, cystic changes, hilar adenopathy, and pleural effusions. Patients with these clinical and radiologic findings are frequently presumed to have pneumonia and initially treated with empirical antibiotics. Therefore, CT-guided needle biopsy, bronchoscopic examination, or even wedge biopsy should be considered when clinical symptoms show deterioration despite adequate antibiotic therapy. Precise pathologic diagnosis and molecular characterization are recommended in all cases, following the World Health Organization (WHO) classification. Principles of treatment typically vary with the different histologic types of T-cell lymphoma.
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http://dx.doi.org/10.1053/j.semdp.2020.04.003DOI Listing
November 2020

Differential effects of PD-L1 versus PD-1 blockade on myeloid inflammation in human cancer.

JCI Insight 2020 06 18;5(12). Epub 2020 Jun 18.

Department of Hematology/Oncology, Emory University, Atlanta, Georgia, USA.

BACKGROUNDPD-1 and PD-L1 have been studied interchangeably in the clinic as checkpoints to reinvigorate T cells in diverse tumor types. Data for biologic effects of checkpoint blockade in human premalignancy are limited.METHODSWe analyzed the immunologic effects of PD-L1 blockade in a clinical trial of atezolizumab in patients with asymptomatic multiple myeloma (AMM), a precursor to clinical malignancy. Genomic signatures of PD-L1 blockade in purified monocytes and T cells in vivo were also compared with those following PD-1 blockade in lung cancer patients. Effects of PD-L1 blockade on monocyte-derived DCs were analyzed to better understand its effects on myeloid antigen-presenting cells.RESULTSIn contrast to anti-PD-1 therapy, anti-PD-L1 therapy led to a distinct inflammatory signature in CD14+ monocytes and increase in myeloid-derived cytokines (e.g., IL-18) in vivo. Treatment of AMM patients with atezolizumab led to rapid activation and expansion of circulating myeloid cells, which persisted in the BM. Blockade of PD-L1 on purified monocyte-derived DCs led to rapid inflammasome activation and synergized with CD40L-driven DC maturation, leading to greater antigen-specific T cell expansion.CONCLUSIONThese data show that PD-L1 blockade leads to distinct systemic immunologic effects compared with PD-1 blockade in vivo in humans, particularly manifest as rapid myeloid activation. These findings also suggest an additional role for PD-L1 as a checkpoint for regulating inflammatory phenotype of myeloid cells and antigen presentation in DCs, which may be harnessed to improve PD-L1-based combination therapies.TRIAL REGISTRATIONNCT02784483.FUNDINGThis work is supported, in part, by funds from NIH/NCI (NCI CA197603, CA238471, and CA208328).
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http://dx.doi.org/10.1172/jci.insight.129353DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7406262PMC
June 2020

Glucosylsphingosine but not Saposin C, is the target antigen in Gaucher disease-associated gammopathy.

Mol Genet Metab 2020 04 5;129(4):286-291. Epub 2020 Feb 5.

Department of Medicine, Yale University, New Haven, CT, USA. Electronic address:

In Gaucher disease type 1 (GD1), genetic deficiency of lysosomal glucocerebrosidase results in the accumulation of glucosylceramide and glucosylsphingosine (GlcSph), that underlie chronic lipid-mediated metabolic inflammation. An important age-related phenotype is high risk of monoclonal gammopathy (MG), including multiple myeloma. We identified GlcSph, a pathological lyso-sphingolipid exclusively elevated in GD, as a mediator of B cell activation and as an antigenic target for GD1-associated MG. Saposin C (SapC), is a lipid-binding protein and activator of lysosomal glucocerebrosidase, which when mutated, cause a rare variant of GD. Sera of GD1 patients with MG of diverse immunoglobulin types were compared to GD patients without gammopathy for reactivity against GlcSph and SapC. We show reactivity of clonal immunoglobulin in GD1 to GlcSph but not to SapC. In two patients with GD1 and gammopathy, GlcSph-reduction therapy with eliglustat resulted in reduction in clonal Ig. Together, our data show that GlcSph but not SapC is the antigenic target in GD1-associated MG and that therapy aimed at reducing the levels of immunogenic lipid resulted in reduction of clonal immunoglobulin in vivo.
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http://dx.doi.org/10.1016/j.ymgme.2020.01.009DOI Listing
April 2020

Disseminated, yet dissembled: Rare infections behind the veil of classical hairy cell leukemia.

Leuk Res 2020 03 31;90:106315. Epub 2020 Jan 31.

Section of Hematology, Department of Medicine, Yale University School of Medicine, New Haven, USA. Electronic address:

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http://dx.doi.org/10.1016/j.leukres.2020.106315DOI Listing
March 2020

EBV-Positive Primary Large B-Cell Lymphoma: The Role of Immunohistochemistry and XPO1 in the Diagnosis of Mediastinal Lymphomas.

Appl Immunohistochem Mol Morphol 2020 Nov/Dec;28(10):725-730

Departments of Pathology and Laboratory Medicine.

Primary mediastinal (thymic) large B-cell lymphoma (PMBL) is described as almost always negative for Epstein-Barr virus (EBV). In the context of a mediastinal lymphoma, the distinction between PMBL, classical Hodgkin lymphoma, diffuse large B-cell lymphoma, and mediastinal gray-zone lymphoma can be very difficult; hence, EBV positivity often argues against PMBL. We present a 19-year-old man with mediastinal mass morphologically consistent with PMBL. The tumor expressed classic immunophenotype, including positivity for CD20, CD19, MAL, OCT2, BOB1, BCL6, CD79a, and subset positivity for CD30. However, the tumor was EBV-positive by in situ hybridization. Next-generation sequencing detected somatic mutations in XPO1 (E571K), SMARCB1 (L356fs), and MYCC (T73A). Although the immunophenotype and XPO1 mutation are characteristic of PMBL, EBV expression is uncommon. Since EBV positivity can occur in rare PMBLs, it should not be the deciding factor in the diagnosis. This is the first EBV-positive PMBL in which mutational profiling has been reported. Aside from providing diagnostic support, the finding of the XPO1 E571K mutation may suggest a targeted therapeutic option.
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http://dx.doi.org/10.1097/PAI.0000000000000820DOI Listing
December 2019

ALCL by any other name: the many facets of anaplastic large cell lymphoma.

Pathology 2020 Jan 6;52(1):100-110. Epub 2019 Nov 6.

Department of Pathology, Yale New Haven Hospital, Yale University School of Medicine, New Haven, CT, United States. Electronic address:

Anaplastic large cell lymphomas (ALCLs) encompass a group of CD30(+) non-Hodgkin T-cell lymphomas. While the different subtypes of ALCLs may share overlapping clinical patient demographics as well as histological and immunohistochemical phenotypes, these tumours can drastically differ in clinical behaviour and genetic profiles. Currently, four distinct ALCL entities are recognised in the 2016 WHO classification: anaplastic lymphoma kinase (ALK)(+), ALK(-), primary cutaneous and breast implant-associated. ALK(+) ALCL demonstrates a spectrum of cell cytology ranging from small to large lymphoma cells and characteristic 'hallmark' cells. ALK(+) ALCL consistently demonstrates ALK gene rearrangements and carries a favourable prognosis. ALK(-) ALCL morphologically and immunohistochemically mimics ALK(+) ALCL but lacks the ALK gene rearrangement. ALK(-) ALCLs are associated with variable prognoses depending on specific gene rearrangements; while DUSP22-rearranged cases have favourable outcomes similar to ALK(+) ALCLs, cases with p63 rearrangements carry a dismal prognosis and 'triple-negative' cases (those lacking ALK, DUSP22 and TP63 rearrangements) have an intermediate prognosis. Primary cutaneous ALCL presents as a skin lesion, lacks the ALK gene translocation and carries a favourable prognosis, similar or superior to ALK(+) ALCL. Breast implant-associated ALCL presents as a seroma with a median of 8-10 years after implant placement, lacks the ALK gene translocation and has an overall favourable but variable prognosis, depending on extent of disease at diagnosis and treatment. In this review, we present the clinical, pathological and genetic features of the ALCLs with emphasis on practical points and differential diagnoses for practising pathologists.
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http://dx.doi.org/10.1016/j.pathol.2019.09.007DOI Listing
January 2020

Practical Approaches on CD30 Detection and Reporting in Lymphoma Diagnosis.

Am J Surg Pathol 2020 02;44(2):e1-e14

Departments of Pathology and Dermatology, University of Virginia, Charlottesville, VA.

While our understanding of the biology of CD30 in lymphoma continues to evolve, our need to detect and measure its expression at the protein level remains critically important for diagnosis and patient care. In addition to its diagnostic and prognostic utility, CD30 has emerged as a vehicle for drug targeting through the antibody-drug conjugate brentuximab-vedotin (BV). Given the numerous ways that CD30 is utilized and its emergence as a predictive/prognostic biomarker, pathologists must come to a general consensus on the best reporting structure and methodology to ensure appropriate patient care. In this manuscript, we review the indications for testing, various modalities for testing, technical challenges, pitfalls, and potential standards of reporting. The following questions will try to be addressed in the current review article: What defines a "POSITIVE" level of CD30 expression?; How do we evaluate and report CD30 expression?; What are the caveats in the evaluation of CD30 expression?
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http://dx.doi.org/10.1097/PAS.0000000000001368DOI Listing
February 2020

Proapoptotic protein BIM as a novel prognostic marker in mantle cell lymphoma.

Hum Pathol 2019 11 16;93:54-64. Epub 2019 Aug 16.

Department of Pathology, Yale New Haven Hospital, Yale School of Medicine, New Haven, CT 06510. Electronic address:

Mantle cell lymphoma (MCL) is an aggressive B-cell lymphoma. Numerous studies have demonstrated many genetic aberrations in MCL in addition to the characteristic t(11:14), including frequent biallelic deletions of Bim, a proapoptotic member of the BCL-2 family. In mice, Bim deletion coupled with cyclin D1 overexpression generates pathologic and molecular features of human MCL. Since the regulation of apoptosis is crucial in MCL pathogenesis, we hypothesize that BIM expression may be associated with tumor cell survival. Clinical data and tissue from 100 nodal MCL cases between 1988 and 2009 were collected from three large academic medical centers. The average patient age of our MCL cohort was 65.5 years old (range, 42-97) with a 2:1 male to female ratio. Immunohistochemistry was performed with a validated anti-BIM antibody. Patients were separated into low and high BIM-expressing categories with a cutoff of 80%. As expected for a proapoptotic tumor suppressor, patients with high BIM expression were less likely to have progressive disease and more likely to have a complete response (P = .022). In addition, high BIM-expressing MCL tumors revealed a trend toward increased overall survival with this trend persisting in sub-analysis of Ann Arbor stages III and IV. No correlation between BIM expression, Ki-67 index, and MIPI score was observed, suggesting a role for BIM as a novel independent prognostic factor. While BIM is only one member of a complex family of apoptosis-regulating proteins, these findings may yield clinically relevant information for the prognosis and therapeutic susceptibility of MCL.
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http://dx.doi.org/10.1016/j.humpath.2019.08.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7038910PMC
November 2019

Histiocytic and Dendritic Cell Neoplasms.

Surg Pathol Clin 2019 Sep 8;12(3):805-829. Epub 2019 Jun 8.

Department of Pathology, Yale University School of Medicine, 310 Cedar Street, New Haven, CT 06510-3218, USA; Department of Laboratory Medicine, Yale University School of Medicine, 310 Cedar Street, New Haven, CT 06510-3218, USA. Electronic address:

Histiocytic and dendritic cell neoplasms are very rare, belonging to a group that share morphologic, immunophenotypic, and ultrastructural characteristics of mature histiocytic/dendritic neoplasms. Histiocytic and dendritic cell neoplasms may arise de novo or in association with B-cell, T-cell, or myeloid neoplasms. Recent molecular findings, particularly the discoveries of the mutations in the RAS-RAF-MEK-ERK pathway, have greatly advanced the diagnosis and treatment options. Histiocytic and dendritic cell neoplasms may closely resemble each other, non-hematopoietic neoplasms, and even reactive processes. Therefore, it is essential to understand the clinicopathologic characteristics, differential diagnoses, and pitfalls of each entity.
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http://dx.doi.org/10.1016/j.path.2019.03.013DOI Listing
September 2019

Philadelphia chromosome-negative acute leukemia in patients with chronic myeloid leukemia.

Am J Hematol 2019 10 28;94(10):E256-E259. Epub 2019 Jul 28.

Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

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http://dx.doi.org/10.1002/ajh.25571DOI Listing
October 2019

Clinicopathologic characteristics and novel biomarkers of aggressive B-cell lymphomas in the nasopharynx.

Ann Diagn Pathol 2019 Aug 17;41:129-135. Epub 2019 Jun 17.

Department of Pathology, Yale School of Medicine, 310 Cedar Street, New Haven, CT 06510, United States of America. Electronic address:

Background: The most common nasopharyngeal lymphoma in the United States are B-cell non-Hodgkin lymphomas (B-NHL). Relatively little is known about the clinicopathologic features of these cases. In this study, we characterize a bi-institutional cohort of aggressive B-NHL primary to the nasopharyngeal area. We compare and contrast EBV-positive versus EBV-negative cases and evaluate expression of SSTR2, CD30, and PD-L1, potential markers for targeted therapeutics.

Methods And Results: We retrieved 53 cases of aggressive B-NHL from the two institutions. Staining was performed for in situ EBV (EBER), CD30, SSTR2 and PD-L1. The response to initial therapy, disease-free interval, and survival at two- and five-year following initial diagnosis were used as primary clinical outcome. Overall, 13 out of 53 cases (23%) were EBV positive. CD30 expression was more frequent in EBV-positive than in EBV-negative cases (4/6 vs 1/17). Seven of 14 (50%) cases tested demonstrated expression of PD-L1 within tumor cells; the two EBV-positive DLBCL tested showed substantial PD-L1 reactivity. Six of 15 (40%) cases tested were positive for SSTR2. The three EBV-positive patients with available outcome data died within one year of diagnosis; in contrast, the EBV-negative cases showed survival rate of 100% (8/8) and 83% (5/6) at two- and five-year follow-up, respectively.

Discussion: The aggressive B-NHLs of the nasopharynx show differences between EBV-positive versus EBV-negative cases. The association of EBV-positive cases with expression of CD30 and PD-L1 may be particularly informative for targeted therapies. A significant number of cases expresses SSTR2, which could render them susceptible to somatostatin analogue and peptide receptor radionuclide therapies. Finally, our limited case series suggest that EBV negativity may be associated with a better prognosis.
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http://dx.doi.org/10.1016/j.anndiagpath.2019.06.007DOI Listing
August 2019

Mantle Cell Lymphoma With Mantle Zone Growth Pattern.

Am J Clin Pathol 2019 07;152(2):132-145

Department of Pathology, Yale University School of Medicine, New Haven, CT.

Objectives: To characterize the clinical and pathologic features of mantle cell lymphoma with mantle zone growth pattern (MCL-MZGP).

Methods: The clinicopathologic data from 35 cases of MCL-MZGP obtained in 12 centers were analyzed.

Results: The patients with MCL-MZGP typically sought treatment at high clinical stages (81%). Intriguingly, 40% (14/35) of cases were incidentally noted. The lymph nodes with MCL-MZGP showed preserved architecture and expanded mantles containing lymphoma cells with classic or small cell cytology. MCL-MZGP was positive for BCL2 (96%, bright), CD5 (82%, moderate), cyclin D1 (100%), and SOX11 (89%). Clinically, our study revealed no significant difference in the overall survival between patients managed with observation alone and those who received chemotherapy.

Conclusions: MCL-MZGP was often incidentally identified and resembled reactive mantles. Therefore, recognition of this unusual morphology emphasizes the utility of cyclin D1 immunostain in the cases with suspicious morphology. However, the clinical significance of these findings is still unclear.
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http://dx.doi.org/10.1093/ajcp/aqz043DOI Listing
July 2019

Clinicopathologic and genetic characterization of nonacute -mutated myeloid neoplasms.

Blood Adv 2019 05;3(9):1540-1545

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

-mutated myeloid neoplasms ( MNs) with <20% blood or bone marrow blasts are rare and have been previously shown in limited case series to exhibit an aggressive clinical course. We assembled the largest cohort of MN cases to date (n = 45) and compared it with MN (n = 95) and de novo acute myeloid leukemia (AML; n = 119) patients. Compared with MN, MN were associated with younger age ( = .007), a normal karyotype ( < .0001), more frequent mutations involving ( = .01) and ( = .03), and fewer involving ( = .003), ( = .0004), and ( = .02). Mutations involving or () ( = .007) and (internal tandem duplication, < .0001; noninternal tandem duplication, = .01) were less frequent in MN than in AML. In multivariable analyses performed in patients with myelodysplastic syndrome only, total mutation count (hazard ratio [HR], 1.3; = .05), mutation (HR, 3.6; = .02), mutation (HR, 5.2; = .01), and higher International Prognostic Scoring System-R score (HR, 1.7; = .0003) were independently associated with shorter overall survival, whereas stem cell transplant conferred a favorable effect (HR, 0.1; < .0001). These data suggest that MN are biologically distinct from MN. Similar to AML, patients with -mutated myelodysplastic syndrome may benefit from more intensive therapeutic regimens.
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http://dx.doi.org/10.1182/bloodadvances.2019000090DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6517660PMC
May 2019

Allogeneic stem cell transplantation and combination antiretroviral therapy: cautions, complications, and considerations.

Leuk Lymphoma 2019 10 3;60(10):2584-2587. Epub 2019 Apr 3.

Division of Hematology, Department of Medicine, Yale University School of Medicine , New Haven , CT , USA.

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http://dx.doi.org/10.1080/10428194.2019.1594221DOI Listing
October 2019

Corrigendum: Microenvironment Cell Contribution to Lymphoma Immunity.

Front Oncol 2018 8;8:522. Epub 2018 Nov 8.

Departments of Pathology & Laboratory Medicine, Yale University School of Medicine, New Haven, CT, United States.

[This corrects the article DOI: 10.3389/fonc.2018.00288.].
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http://dx.doi.org/10.3389/fonc.2018.00522DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6237016PMC
November 2018

Be careful of the masquerades: differentiating secondary myelodysplasia from myelodysplastic syndromes in clinical practice.

Ann Hematol 2018 Dec 14;97(12):2333-2343. Epub 2018 Aug 14.

Division of Hematology/Medical Oncology, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA.

In patients suspected to have myelodysplastic syndrome (MDS), especially in those patients without cytogenetic abnormalities or blast excess, accurate morphologic review by an expert hematopathologist and meticulous exclusion of other secondary causes of myelodysplasia are vital to establish the diagnosis. Errors in diagnosis can lead to dangerous consequences such as the administration of hypomethylating agents, lenalidomide, or even the use of intensive chemotherapy or allogeneic hematopoietic cell transplantation in patients who do not have an underlying MDS or even a malignant hematopoietic process. Additionally, beyond the possible harm and lack of efficacy of such therapies if the diagnosis of MDS is erroneous, the secondary myelodysplasia and resultant cytopenias are not likely to resolve unless the underlying etiology is identified and addressed. Discriminating a malignant process such as MDS from non-malignant secondary myelodysplasia can be quite challenging, and community hematologists/oncologists should consider referral to specialized physicians (both clinical experts and experienced hematopathologists) if there is any doubt regarding the diagnosis. In this article, we present a representative case series of patients from our own practice who posed diagnostic dilemmas and propose a systematic approach for assessment for secondary causes of myelodysplasia.
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http://dx.doi.org/10.1007/s00277-018-3474-7DOI Listing
December 2018

Microenvironment Cell Contribution to Lymphoma Immunity.

Front Oncol 2018 27;8:288. Epub 2018 Jul 27.

Departments of Pathology & Laboratory Medicine, Yale University School of Medicine, New Haven, CT, United States.

Lymphoma microenvironment is a complex system composed of stromal cells, blood vessels, immune cells as well as extracellular matrix, cytokines, exosomes, and chemokines. In this review, we describe the function, localization, and interactions between various cellular components. We also summarize their contribution to lymphoma immunity in the era of immunotherapy. Publications were identified from searching Pubmed. Primary literature was carefully evaluated for replicability before incorporating into the review. We describe the roles of mesenchymal stem/stromal cells (MSCs), lymphoma-associated macrophages (LAMs), dendritic cells, cytotoxic T cells, PD-1 expressing CD4+ tumor infiltrating lymphocytes (TILs), T-cells expressing markers of exhaustion such as TIM-3 and LAG-3, regulatory T cells, and natural killer cells. While it is not in itself a cell, we also include a brief overview of the lymphoma exosome and how it contributes to anti-tumor effect as well as immune dysfunction. Understanding the cellular players that comprise the lymphoma microenvironment is critical to developing novel therapeutics that can help block the signals for immune escape and promote tumor surveillance. It may also be the key to understanding mechanisms of resistance to immune checkpoint blockade and immune-related adverse events due to certain types of immunotherapy.
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http://dx.doi.org/10.3389/fonc.2018.00288DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6073855PMC
July 2018

Conviction in the face of affliction: a case series of Jehovah's Witnesses with myeloid malignancies.

Ann Hematol 2018 11 7;97(11):2245-2248. Epub 2018 Aug 7.

Division of Hematology/Medical Oncology, Department of Medicine, Yale University School of Medicine, New Haven, CT, USA.

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http://dx.doi.org/10.1007/s00277-018-3459-6DOI Listing
November 2018

Patients with common variable immunodeficiency with autoimmune cytopenias exhibit hyperplastic yet inefficient germinal center responses.

J Allergy Clin Immunol 2019 01 20;143(1):258-265. Epub 2018 Jun 20.

Department of Immunobiology, Yale University School of Medicine, New Haven, Conn; Department of Medicine, Yale University School of Medicine, New Haven, Conn. Electronic address:

Background: The lack of pathogen-protective, isotype-switched antibodies in patients with common variable immunodeficiency (CVID) suggests germinal center (GC) hypoplasia, yet a subset of patients with CVID is paradoxically affected by autoantibody-mediated autoimmune cytopenias (AICs) and lymphadenopathy.

Objective: We sought to compare the physical characteristics and immunologic output of GC responses in patients with CVID with AIC (CVID+AIC) and without AIC (CVID-AIC).

Methods: We analyzed GC size and shape in excisional lymph node biopsy specimens from 14 patients with CVID+AIC and 4 patients with CVID-AIC. Using paired peripheral blood samples, we determined how AICs specifically affected B-and T-cell compartments and antibody responses in patients with CVID.

Results: We found that patients with CVID+AIC displayed irregularly shaped hyperplastic GCs, whereas GCs were scarce and small in patients with CVID-AIC. GC hyperplasia was also evidenced by an increase in numbers of circulating follicular helper T cells, which correlated with decreased regulatory T-cell frequencies and function. In addition, patients with CVID+AIC had serum endotoxemia associated with a dearth of isotype-switched memory B cells that displayed significantly lower somatic hypermutation frequencies than their counterparts with CVID-AIC. Moreover, IgG B cells from patients with CVID+AIC expressed VH4-34-encoded antibodies with unmutated Ala-Val-Tyr and Asn-His-Ser motifs, which recognize both erythrocyte I/i self-antigens and commensal bacteria.

Conclusions: Patients with CVID+AIC do not contain mucosal microbiota and exhibit hyperplastic yet inefficient GC responses that favor the production of untolerized IgG B-cell clones that recognize both commensal bacteria and hematopoietic I/i self-antigens.
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http://dx.doi.org/10.1016/j.jaci.2018.06.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6400323PMC
January 2019

Small Cell Variant of Intravascular Large B-Cell Lymphoma: Highlighting a Potentially Fatal and Easily Missed Diagnosis.

Biomed Res Int 2018 3;2018:9413015. Epub 2018 Apr 3.

Department of Pathology and Laboratory Medicine, Yale University School of Medicine, New Haven, CT, USA.

Context: Intravascular large B-cell lymphoma (IVLBCL) is a rare non-Hodgkin B-cell lymphoma with a poor prognosis. While typically described as comprising large atypical cells restricted to the lumina of small blood vessels, it can show variability in cell size.

Objective: To report the clinicopathologic features of the IVLBCL with small cell morphology and discuss the practical implications of our findings.

Design: We searched our archives for all IVLBCL diagnosed in our institution for the last 25 years (1992-2017). Slides were reviewed independently by two hematopathologists.

Results: We found a total of 11 cases of IVLBCL. Bone marrow, brain, lymph node, pericardium, small bowel, and fallopian tube and ovary were the organs in which the lymphoma was initially diagnosed. One of the cases initially diagnosed in the marrow showed intrasinusoidal involvement by a small cell lymphoma; the diagnosis was confirmed by random skin biopsies showing intravascular large cells with the same phenotype. Retrospective review of the liver on this case also showed the intrasinusoidal involvement by the disease consisting of small cells. In another case, IVLBCL that was initially diagnosed in a small bowel biopsy was retrospectively found in a breast biopsy, but with small cell morphology.

Conclusions: Our findings suggest that, in the presence of high clinical suspicion, IVLBCL should be high in the differential diagnosis when lymphoma is predominantly intravascular, even when the tumor cells are small. A timely diagnosis of this entity can be critical. Hence, awareness of a small cell variant of IVLBCL should be increased.
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http://dx.doi.org/10.1155/2018/9413015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5903319PMC
October 2018

Changes in bone marrow innate lymphoid cell subsets in monoclonal gammopathy: target for IMiD therapy.

Blood Adv 2017 Nov 20;1(25):2343-2347. Epub 2017 Nov 20.

Department of Medicine.

Altered number, subset composition, and function of bone marrow innate lymphoid cells are early events in monoclonal gammopathies.Pomalidomide therapy leads to reduction in Ikzf1 and Ikzf3 and enhanced human innate lymphoid cell function in vivo.
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http://dx.doi.org/10.1182/bloodadvances.2017012732DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5729633PMC
November 2017

Dendritic Cell Markers and PD-L1 are Expressed in Mediastinal Gray Zone Lymphoma.

Appl Immunohistochem Mol Morphol 2018 Nov/Dec;26(10):e101-e106

Department of Pathology, Yale University, New Haven, CT.

Aims: Mediastinal gray zone lymphoma (MGZL) is a rare entity with morphologic, immunophenotypic, and genetic features intermediate between classic Hodgkin lymphoma (CHL) and primary mediastinal large B-cell lymphoma (PMBL). It is challenging to differentiate from CHL and PMBL. A specific dendritic cell gene expression profile can distinguish CHL and MGZL from PMBL. We hypothesized that the dendritic markers fascin and CD123 may be helpful in distinguishing MGZL from CHL and PMBL. We also investigated programmed death-ligand 1 (PD-L1) expression in MGZL, which may have therapeutic significance in this difficulty to treat tumor.

Methods: Representative sections from 89 CHL, 20 PMBL, and 7 MGZL cases were stained for fascin, CD123, and PD-L1, and scored on a scale from 0 to 3+. Most (71%) MGZLs stained for CD123, as well as some (23%) CHLs, and few (11%) PMBLs. All MGZLs stained for fascin, as well as most (90%) CHLs, and approximately half (53%) of the PMBLs. PD-L1 was positive in all MGZLs, most (77%) CHLs and most (66%) PMBLs.

Conclusions: Our study is the first to show CD123 is positive in a subset of formalin-fixed, paraffin-embedded MGZLs and CHLs, in contrast to PMBL which is largely negative. Staining for fascin was not significantly different between the lymphomas, but was less likely to be positive in PMBL. These findings suggest a role for CD123 and fascin in supporting diagnoses of MGZL and CHL, and in ruling out PMBL. By immunohistochemistry, PD-L1 is positive in MGZL, pointing to its therapeutic potential.
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http://dx.doi.org/10.1097/PAI.0000000000000615DOI Listing
September 2019

Lymph node stromal and vascular proliferations.

Semin Diagn Pathol 2018 Jan 15;35(1):67-75. Epub 2017 Nov 15.

Neogenomics, Aliso Viejo, CA, United States.

The recognition and reporting of stromal and vascular lesions of the lymph node is rife with difficulties including relative rarity, a lack of familiarity with lesions and the challenges of using ancillary studies appropriately. In this manuscript, we highlight a range of benign stromal and vascular abnormalities that can be identified in nodal specimens.
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http://dx.doi.org/10.1053/j.semdp.2017.11.004DOI Listing
January 2018

Limitations of poor bone marrow aspirations (for an accurate diagnosis) despite the multimodal analytical era: A longitudinal retrospective study.

Am J Hematol 2017 Oct 24;92(10):E600-E602. Epub 2017 Aug 24.

Diagnostic Radiology and Bioimaging Sciences, Yale University School of Medicine, New Haven, Connecticut.

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http://dx.doi.org/10.1002/ajh.24839DOI Listing
October 2017

Anterior Chamber Non-Hodgkin Lymphoma of the Iris Masquerading as Uveitis-Glaucoma-Hyphema Syndrome.

Ocul Oncol Pathol 2016 Oct 12;2(4):230-233. Epub 2016 May 12.

Department of Ophthalmology and Visual Science, New Haven, Conn., USA; Department of Ophthalmic Oncology, Smilow Cancer Hospital, New Haven, Conn., USA.

Purpose: To report a case of iris non-Hodgkin lymphoma initially thought to be uveitis-glaucoma-hyphema (UGH) syndrome.

Methods: We reviewed the clinical, radiographic, and histopathologic findings in a patient with recurrent hyphemas and increased ocular pressure who eventually was found to have a rapidly growing iris mass.

Results: An 89-year-old man with a history of cataract extraction and mantle cell lymphoma developed recurrent hyphema, which was subsequently revealed to be due to an iris mass. A biopsy revealed non-Hodgkin lymphoma that could not be formally subclassified but was suspicious for mantle cell lymphoma. The tumor showed a partial response to ibrutinib.

Conclusion: Iris lymphoma can masquerade as a cause of recurrent hyphema after cataract extraction. Ophthalmologists should be aware of this presentation, especially in patients with a history of lymphoma.
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http://dx.doi.org/10.1159/000445119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5091236PMC
October 2016

Single agent blinatumumab as frontline therapy for an 85-year-old patient with B cell precursor acute lymphoblastic leukemia.

Ann Hematol 2016 Oct 29;95(11):1895-8. Epub 2016 Jul 29.

Section of Hematology/Department of Internal Medicine and Yale Cancer Center, Yale University School of Medicine, Smilow Cancer Hospital at Yale-New Haven, New Haven, USA.

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http://dx.doi.org/10.1007/s00277-016-2761-4DOI Listing
October 2016