Publications by authors named "April Chiu"

65 Publications

Core Stability Exercises in Addition to Usual Care Physiotherapy Improve Stability and Balance After Stroke: A Systematic Review and Meta-analysis.

Arch Phys Med Rehabil 2021 04 22;102(4):762-775. Epub 2020 Oct 22.

Department of Physiotherapy, La Trobe University, College of Science, Health and Engineering, School of Allied Health.

Objective: To systematically review the effect of core stability exercises in addition to usual care physiotherapy on patient outcomes after stroke.

Data Sources: Cumulative Index to Nursing and Allied Health, MEDLINE, Physiotherapy Evidence Database (PEDro), PubMed, and EMBASE were searched to November 2018.

Study Selection: Eleven randomized controlled trials that compared usual care physiotherapy with usual care physiotherapy with additional core stability exercises in people with stroke were included. The initial search yielded 1876 studies.

Data Extraction: Two independent reviewers applied inclusion and exclusion criteria and extracted data on methodological quality using the PEDro scale, participant characteristics, intervention details, outcome measures, and results.

Data Synthesis: Postintervention means and SDs were pooled to calculate either the standardized mean difference (SMD) or the mean difference (MD) and 95% CIs using a random-effects model and inverse variance methods. There was moderate quality evidence to suggest the addition of core stability exercises to usual care physiotherapy improved trunk control (SMD, 0.94; 95% CI, 0.44-1.44; I=69%), functional dynamic balance (SMD, 1.23; 95% CI, 0.5-1.97; I=71%), and walking speed (MD, 0.27m/s; 95% CI, 0.01-0.52; I=40%) in people with acute and chronic stroke. No significant effect was found when assessing functional ambulation categories or the timed Up and Go test, and mixed results were found for global functioning.

Conclusions: The addition of core stability exercises to usual care physiotherapy after stroke may lead to improved trunk control and dynamic balance. Therefore, core stability exercises should be included in rehabilitation if improvements in these domains will help clients achieve their goals. Future trials should consider incorporating outcomes of body kinematics during functional tasks to assess movement quality and assess participation outcomes.
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http://dx.doi.org/10.1016/j.apmr.2020.09.388DOI Listing
April 2021

Aggressive B-cell Lymphoma with MYC/TP53 Dual Alterations Displays Distinct Clinicopathobiological Features and Response to Novel Targeted Agents.

Mol Cancer Res 2021 02 5;19(2):249-260. Epub 2020 Nov 5.

Duke University Medical Center, Division of Hematopathology and Department of Pathology, Durham, North Carolina.

Diffuse large B-cell lymphoma (DLBCL) is the major type of aggressive B-cell lymphoma. High-grade B-cell lymphoma (HGBCL) with / double-hit (DH) represents a distinct entity with dismal prognosis after standard immunochemotherapy in the current WHO lymphoma classification. However, whether mutation synergizes with MYC abnormalities ( rearrangement and/or Myc protein overexpression) contributing to HGBCL-like biology and prognosis is not well investigated. In this study, patients with DLBCL with MYC/TP53 abnormalities demonstrated poor clinical outcome, high-grade morphology, and distinct gene expression signatures. To identify more effective therapies for this distinctive DLBCL subset, novel MYC/TP53/BCL-2-targeted agents were investigated in DLBCL cells with MYC/TP53 dual alterations or HGBCL-/-DH. A BET inhibitor INCB057643 effectively inhibited cell viability and induced apoptosis in DLBCL/HGBCL cells regardless of // status. Combining INCB057643 with a MDM2-p53 inhibitor DS3032b significantly enhanced the cytotoxic effects in HGBCL-DH without mutation, while combining with the BCL-2 inhibitor venetoclax displayed potent therapeutic synergy in DLBCL/HGBCL cells with and without concurrent mutation. Reverse-phase protein arrays revealed the synergistic molecular actions by INCB057643, DS3032b and venetoclax to induce cell-cycle arrest and apoptosis and to inhibit AKT/MEK/ERK/mTOR pathways, as well as potential drug resistance mechanisms mediated by upregulation of Mcl-1 and RAS/RAF/MEK/ERK pathways. In summary, these findings support subclassification of DLBCL/HGBCL with dual MYC/TP53 alterations, which demonstrates distinct pathobiologic features and dismal survival with standard therapy, therefore requiring additional targeted therapies. IMPLICATIONS: The clinical and pharmacologic studies suggest recognizing DLBCL with concomitant mutation and MYC abnormalities as a distinctive entity necessary for precision oncology practice. VISUAL OVERVIEW: http://mcr.aacrjournals.org/content/molcanres/19/2/249/F1.large.jpg.
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http://dx.doi.org/10.1158/1541-7786.MCR-20-0466DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8092941PMC
February 2021

XPO1 expression worsens the prognosis of unfavorable DLBCL that can be effectively targeted by selinexor in the absence of mutant p53.

J Hematol Oncol 2020 11 4;13(1):148. Epub 2020 Nov 4.

Division of Hematopathology, Department of Pathology, Duke University Medical Center, Durham, NC, 27710, USA.

The XPO1 inhibitor selinexor was recently approved in relapsed/refractory DLBCL patients but only demonstrated modest anti-DLBCL efficacy, prompting us to investigate the prognostic effect of XPO1 in DLBCL patients and the rational combination therapies in high-risk DLBCL. High XPO1 expression (XPO1) showed significant adverse prognostic impact in 544 studied DLBCL patients, especially in those with BCL2 overexpression. Therapeutic study in 30 DLBCL cell lines with various molecular and genetic background found robust cytotoxicity of selinexor, especially in cells with BCL2-rearranged (BCL2-R) DLBCL or high-grade B-cell lymphoma with MYC/BCL2 double-hit (HGBCL-DH). However, expression of mutant (Mut) p53 significantly reduced the cytotoxicity of selinexor in overall cell lines and the BCL2-R and HGBCL-DH subsets, consistent with the favorable impact of XPO1 observed in Mut-p53-expressing patients. The therapeutic effect of selinexor in HGBCL-DH cells was significantly enhanced when combined with a BET inhibitor INCB057643, overcoming the drug resistance in Mut-p53-expressing cells. Collectively, these data suggest that XPO1 worsens the survival of DLBCL patients with unfavorable prognostic factors such as BCL2 overexpression and double-hit, in line with the higher efficacy of selinexor demonstrated in BCL2-R DLBCL and HGBCL-DH cell lines. Expression of Mut-p53 confers resistance to selinexor treatment, which can be overcome by combined INCB057643 treatment in HGBCL-DH cells. This study provides insight into the XPO1 significance and selinexor efficacy in DLBCL, important for developing combination therapy for relapsed/refractory DLBCL and HGBCL-DH.
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http://dx.doi.org/10.1186/s13045-020-00982-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7641823PMC
November 2020

Primary lymphoma of the breast: A report of two cases.

Clin Imaging 2020 Dec 26;68:295-299. Epub 2020 Aug 26.

Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA.

Primary breast lymphoma (PBL) should be distinguished from secondary breast lymphoma arising in the setting of lymphoma elsewhere in the body. Multimodality imaging is key to diagnosing PBL, and imaging manifestations thereof may indicate PBL and alter the treatment course. Treatment options including chemotherapy, radiation therapy, and/or surgery depend on histology. We report two cases of PBL, illustrating the transformative impact that multimodality imaging may have on clinical management.
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http://dx.doi.org/10.1016/j.clinimag.2020.08.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7683364PMC
December 2020

A refined cell-of-origin classifier with targeted NGS and artificial intelligence shows robust predictive value in DLBCL.

Blood Adv 2020 07;4(14):3391-3404

Division of Hematopathology and Department of Pathology, Duke University Medical Center, Durham, NC.

Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous entity of B-cell lymphoma. Cell-of-origin (COO) classification of DLBCL is required in routine practice by the World Health Organization classification for biological and therapeutic insights. Genetic subtypes uncovered recently are based on distinct genetic alterations in DLBCL, which are different from the COO subtypes defined by gene expression signatures of normal B cells retained in DLBCL. We hypothesize that classifiers incorporating both genome-wide gene-expression and pathogenetic variables can improve the therapeutic significance of DLBCL classification. To develop such refined classifiers, we performed targeted RNA sequencing (RNA-Seq) with a commercially available next-generation sequencing (NGS) platform in a large cohort of 418 DLBCLs. Genetic and transcriptional data obtained by RNA-Seq in a single run were explored by state-of-the-art artificial intelligence (AI) to develop a NGS-COO classifier for COO assignment and NGS survival models for clinical outcome prediction. The NGS-COO model built through applying AI in the training set was robust, showing high concordance with COO classification by either Affymetrix GeneChip microarray or the NanoString Lymph2Cx assay in 2 validation sets. Although the NGS-COO model was not trained for clinical outcome, the activated B-cell-like compared with the germinal-center B-cell-like subtype had significantly poorer survival. The NGS survival models stratified 30% high-risk patients in the validation set with poor survival as in the training set. These results demonstrate that targeted RNA-Seq coupled with AI deep learning techniques provides reproducible, efficient, and affordable assays for clinical application. The clinical grade assays and NGS models integrating both genetic and transcriptional factors developed in this study may eventually support precision medicine in DLBCL.
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http://dx.doi.org/10.1182/bloodadvances.2020001949DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7391158PMC
July 2020

Genetic Factors in Acute Myeloid Leukemia With Myelodysplasia-Related Changes.

Am J Clin Pathol 2020 04;153(5):656-663

Division of Hematopathology, Rochester, MN.

Objectives: Acute myeloid leukemia with myelodysplasia-related changes (AML-MRC) is a heterogeneous category with a broad range of underlying genetic abnormalities. We investigated the significance of genetic factors in a large series of AML-MRC cases.

Methods: The morphologic findings, genetic data, and patient outcomes were assessed in 186 AML-MRC cases.

Results: The median overall survival (OS) was dismal in AML-MRC patients (median, 7.6 months; 95% confidence interval, 5-10.6 months). Karyotypically normal cases and cytogenetically abnormal cases without myelodysplastic syndrome (MDS)-related cytogenetic abnormalities showed similar OS, significantly better than cases carrying MDS-related cytogenetic abnormalities. MDS-related cytogenetic abnormalities, monosomal or complex karyotype, and history of MDS or myelodysplastic/myeloproliferative neoplasm were all associated with dismal outcome.

Conclusions: AML-MRC predicts a poor prognosis. Our study supports the finding that the genetic profile plays a key role in determining prognosis in AML-MRC as defined according to the World Health Organization revised fourth edition (2017) diagnostic criteria.
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http://dx.doi.org/10.1093/ajcp/aqz206DOI Listing
April 2020

Mixed-phenotype large granular lymphocytic leukemia: a rare subtype in the large granular lymphocytic leukemia spectrum.

Hum Pathol 2018 11 24;81:96-104. Epub 2018 Jun 24.

Division of Hematopathology, Mayo Clinic, Rochester, 200 First Street SW, Rochester, MN 55905, USA. Electronic address:

Large granular lymphocytic leukemia (LGLL) is a chronic proliferation of cytotoxic lymphocytes in which more than 70% of patients develop cytopenia(s) requiring therapy. LGLL includes T-cell LGLL and chronic lymphoproliferative disorder of natural killer (NK) cells. The neoplastic cells in LGLL usually exhibit a single immunophenotype in a patient, with CD8-positive/αβ T-cell type being the most common, followed by NK-cell, γδ T-cell, and CD4-positive/αβ T-cell types. We investigated a total of 220 LGLL cases and identified 12 mixed-phenotype LGLLs (5%): 7 cases with coexistent αβ T-cell and NK-cell clones and 5 with coexistent αβ and γδ T-cell clones. With a median follow-up of 48 months, the clinicopathological characteristics of these patients seemed similar to those of typical LGLL patients. Treatment was instituted in 9 patients, and 5 patients (55%) attained complete hematologic response or partial response. The therapeutic response rate of this cohort is comparable to the reported overall response rate of 40% to 60% in typical LGLL patients. Three patients who did not receive any treatment had progressive or persistent cytopenias. Interestingly, inverted proportions of 2 clones at disease recurrence were identified in 4 patients (36%) and stable clonal proportions in 7 patients (64%). Mixed-phenotype LGLL is rare, and this study underscores the importance of recognizing this rare type of LGLL in patients who may benefit from LGLL treatment.
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http://dx.doi.org/10.1016/j.humpath.2018.06.023DOI Listing
November 2018

Clinical Significance of PTEN Deletion, Mutation, and Loss of PTEN Expression in De Novo Diffuse Large B-Cell Lymphoma.

Neoplasia 2018 06 4;20(6):574-593. Epub 2018 May 4.

Hospital Universitario Marqués de Valdecilla, Santander, Spain.

PTEN loss has been associated with poorer prognosis in many solid tumors. However, such investigation in lymphomas is limited. In this study, PTEN cytoplasmic and nuclear expression, PTEN gene deletion, and PTEN mutations were evaluated in two independent cohorts of diffuse large B-cell lymphoma (DLBCL). Cytoplasmic PTEN expression was found in approximately 67% of total 747 DLBCL cases, more frequently in the activated B-cell-like subtype. Nuclear PTEN expression was less frequent and at lower levels, which significantly correlated with higher PTEN mRNA expression. Remarkably, loss of PTEN protein expression was associated with poorer survival only in DLBCL with AKT hyperactivation. In contrast, high PTEN expression was associated with Myc expression and poorer survival in cases without abnormal AKT activation. Genetic and epigenetic mechanisms for loss of PTEN expression were investigated. PTEN deletions (mostly heterozygous) were detected in 11.3% of DLBCL, and showed opposite prognostic effects in patients with AKT hyperactivation and in MYC rearranged DLBCL patients. PTEN mutations, detected in 10.6% of patients, were associated with upregulation of genes involved in central nervous system function, metabolism, and AKT/mTOR signaling regulation. Loss of PTEN cytoplasmic expression was also associated with TP53 mutations, higher PTEN-targeting microRNA expression, and lower PD-L1 expression. Remarkably, low PTEN mRNA expression was associated with down-regulation of a group of genes involved in immune responses and B-cell development/differentiation, and poorer survival in DLBCL independent of AKT activation. Collectively, multi-levels of PTEN abnormalities and dysregulation may play important roles in PTEN expression and loss, and that loss of PTEN tumor-suppressor function contributes to the poor survival of DLBCL patients with AKT hyperactivation.
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http://dx.doi.org/10.1016/j.neo.2018.03.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5994742PMC
June 2018

Crystal-Storing Histiocytosis in Bone Marrow: A Clinicopathologic Study of Eight Cases and Review of the Literature.

Am J Clin Pathol 2018 Jan;149(2):148-163

Department of Laboratory Medicine and Pathology, Division of Hematopathology, Mayo Clinic, Rochester, MN.

Objectives: We report the clinicopathologic characteristics of eight cases of crystal-storing histiocytosis (CSH) with bone marrow (BM) involvement (BM-CSH) and review CSH cases published in the English literature.

Methods: We queried our pathology database for BM cases with CSH mentioned in the final diagnosis/comments from June 2011 to August 2016.

Results: Eight cases of BM-CSH were identified. The underlying diagnoses consisted predominantly of plasma cell disorders (88%) associated with monotypic κ light chain. In BM aspirates, crystals within histiocytes exhibited a morphologic spectrum including brightly eosinophilic, needle-like, or globule-like. In BM core biopsies, the histiocytes were often in aggregates with intracellular needle-like and/or globular, refractile inclusions.

Conclusions: BM-CSH is a rare phenomenon and exhibits a heterogeneous crystalline and histiocytic appearance warranting accurate recognition to avoid misinterpretation of a granulomatous condition or storage disorder. In addition, prompt assessment for an underlying B-cell lymphoma or clonal plasmacytic neoplasm is indicated.
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http://dx.doi.org/10.1093/ajcp/aqx150DOI Listing
January 2018

JAK2/IDH-mutant-driven myeloproliferative neoplasm is sensitive to combined targeted inhibition.

J Clin Invest 2018 02 22;128(2):789-804. Epub 2018 Jan 22.

Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

Patients with myeloproliferative neoplasms (MPNs) frequently progress to bone marrow failure or acute myeloid leukemia (AML), and mutations in epigenetic regulators such as the metabolic enzyme isocitrate dehydrogenase (IDH) are associated with poor outcomes. Here, we showed that combined expression of Jak2V617F and mutant IDH1R132H or Idh2R140Q induces MPN progression, alters stem/progenitor cell function, and impairs differentiation in mice. Jak2V617F Idh2R140Q-mutant MPNs were sensitive to small-molecule inhibition of IDH. Combined inhibition of JAK2 and IDH2 normalized the stem and progenitor cell compartments in the murine model and reduced disease burden to a greater extent than was seen with JAK inhibition alone. In addition, combined JAK2 and IDH2 inhibitor treatment also reversed aberrant gene expression in MPN stem cells and reversed the metabolite perturbations induced by concurrent JAK2 and IDH2 mutations. Combined JAK2 and IDH2 inhibitor therapy also showed cooperative efficacy in cells from MPN patients with both JAK2mut and IDH2mut mutations. Taken together, these data suggest that combined JAK and IDH inhibition may offer a therapeutic advantage in this high-risk MPN subtype.
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http://dx.doi.org/10.1172/JCI94516DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5785272PMC
February 2018

De novo pure erythroid leukemia: refining the clinicopathologic and cytogenetic characteristics of a rare entity.

Mod Pathol 2018 05 12;31(5):705-717. Epub 2018 Jan 12.

Division of Hematopathology, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.

Per the revised fourth edition World Health Organization classification of acute myeloid leukemia, pure erythroid leukemia is now the sole type of acute erythroid leukemia. The diagnosis of this rare entity is often challenging and the cytologic overlap with non-neoplastic (eg, megaloblastic anemia) and neoplastic entities (eg, other types of acute leukemia and non-hematopoietic malignancies) warrants a significant degree of clinical, laboratory, immunophenotypic, and genetic investigation. Given the limited number of reports of this rare and diagnostically challenging entity, we report detailed clinicopathologic characteristics from 15 patients, the largest series thus far, of primary de novo pure erythroid leukemia to provide further diagnostic insights into this entity and reveal strategies for making the diagnosis. We found that de novo pure erythroid leukemia is a disease of adults (median age 68 years), exhibits a striking male predominance, is universally associated with an abnormal karyotype and has an exceedingly poor overall median survival of 1.4 months. Given the general inability of immunophenotypic markers to discriminate neoplastic from non-neoplastic erythroid proliferations, key features identified in this study to help establish the diagnosis of pure erythroid leukemia and exclude mimickers include circulating pronormoblasts, clear-cut dysplasia in erythroid, granulocytic, and/or megakaryocytic lineage, utilization of a broad immunophenotypic panel, TP53 immunohistochemical positivity, and identification of a complex, often highly complex, karyotype. Given the gravity of a diagnosis of de novo pure erythroid leukemia, it should be rendered with utmost confidence.
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http://dx.doi.org/10.1038/modpathol.2017.175DOI Listing
May 2018

Bone marrow fibrosis in chronic myelomonocytic leukemia is associated with increased megakaryopoiesis, splenomegaly and with a shorter median time to disease progression.

Oncotarget 2017 Nov 17;8(61):103274-103282. Epub 2017 Oct 17.

Department of Pathology and Laboratory Medicine, New York Presbyterian Hospital-Weill Cornell Medicine, New York, NY, USA.

Bone marrow (BM) fibrosis is an adverse prognostic marker in several myeloid neoplasms, particularly in myelodysplastic syndrome (MDS) with fibrosis; however, its significance in chronic myelomonoctyic leukemia (CMML) has not been evaluated. We performed a retrospective analysis to investigate the prognostic and clinicopathological features of CMML with and without BM fibrosis. The study included specimens from a total of 83 untreated CMML patients from 2 large institutions. Patients with any amount of BM fibrosis (MF-1 or higher; MF1+) had significantly shorter progression-free survival (MF1+, 28.3 months vs MF0, not reached; = 0.001, log rank test), splenomegaly ( = 0.016), and increased BM megakaryocytes ( = 0.04) compared to patients without BM fibrosis (MF-0). No association was observed between fibrosis and peripheral blood parameters, presence of JAK2 V617F mutation, BM blasts, or overall survival. Our study demonstrates the importance of assessing BM fibrosis in CMML. Similar to MDS, the presence of BM fibrosis may identify a distinct subgroup of CMML patients (CMML-F) with a more aggressive clinical course.
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http://dx.doi.org/10.18632/oncotarget.21870DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5732726PMC
November 2017

A case of acute myeloid leukemia with e6a2 BCR-ABL fusion transcript acquired after progressing from chronic myelomonocytic leukemia.

Leuk Res Rep 2017 31;7:17-19. Epub 2017 Jan 31.

Department of Laboratory Medicine and Pathology Mayo Clinic, 200 First St. SW, Rochester, MN 55905, USA.

Philadelphia (Ph) chromosome is a cytogenetic hallmark of chronic myeloid leukemia (CML). Most patients with CML harbor either the e13a2 or e14a2 BCR-ABL fusion product, while a small subset of the cases expresses e1a2 or e19a2 transcripts. We report a patient with chronic myelomonocytic leukemia (CMML), initially Ph chromosome negative at presentation, with rapid disease progression to acute myeloid leukemia (AML) and appearance of Ph chromosome and BCR-ABL e6a2, a very uncommon fusion transcript. The AML was refractory to treatment with subsequent emergence and dominance of a Ph negative leukemic clone. The patient expired shortly after disease progression.
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http://dx.doi.org/10.1016/j.lrr.2017.01.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5328719PMC
January 2017

RelA NF-κB subunit activation as a therapeutic target in diffuse large B-cell lymphoma.

Aging (Albany NY) 2016 12;8(12):3321-3340

Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

It has been well established that nuclear factor kappa-B (NF-κB) activation is important for tumor cell growth and survival. RelA/p65 and p50 are the most common NF-kB subunits and involved in the classical NF-kB pathway. However, the prognostic and biological significance of RelA/p65 is equivocal in the field. In this study, we assessed RelA/p65 nuclear expression by immunohistochemistry in 487 patients with diffuse large B-cell lymphoma (DLBCL), and studied the effects of molecular and pharmacological inhibition of NF-kB on cell viability. We found RelA/p65 nuclear expression, without associations with other apparent genetic or phenotypic abnormalities, had unfavorable prognostic impact in patients with stage I/II DLBCL. Gene expression profiling analysis suggested immune dysregulation and antiapoptosis may be relevant for the poorer prognosis associated with p65 hyperactivation in germinal center B-cell-like (GCB) DLBCL and in activated B-cell-like (ABC) DLBCL, respectively. We knocked down individual NF-κB subunits in representative DLBCL cells in vitro, and found targeting p65 was more effective than targeting other NF-κB subunits in inhibiting cell growth and survival. In summary, RelA/p65 nuclear overexpression correlates with significant poor survival in early-stage DLBCL patients, and therapeutic targeting RelA/p65 is effective in inhibiting proliferation and survival of DLBCL with NF-κB hyperactivation.
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http://dx.doi.org/10.18632/aging.101121DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5270671PMC
December 2016

CD30 Expression Is Rare in Myeloid Leukemia Cutis: A Study of 55 Cases and Implications for Routine Diagnostic Algorithms.

Am J Dermatopathol 2017 May;39(5):351-357

*Department of Dermatology, Weill Cornell Medical College, New York, NY; and †Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY.

Expression of CD30 in blastoid cutaneous infiltrates typically signifies a CD30 lymphoproliferative disorder, often requiring minimal immunohistochemical workup, if clinically consonant. However, myeloid and other hematologic malignancies often express CD30. We retrospectively examined the prevalence of CD30 expression in 41 patients (median age 59) and 55 biopsies with the diagnosis of leukemia cutis (LC) to determine whether an extensive immunohistochemical workup is warranted in all large, round cell CD30 cutaneous infiltrates. Each patient had refractory or recurrent disease, the histologic presence of a large mononuclear cell infiltrate, and varied cytogenetics. CD30 mononuclear cells within the infiltrate ranged from rare to many in 22 biopsies (22/55). In 18 biopsies, CD30 cells were interpreted as lymphocytic based on morphology, strong cytoplasmic and Golgi staining for CD30, and negative CD34 and CD117 staining. One case showing 3+ staining of lymphocytes was identified as a posttransplant lymphoproliferative disorder. The second 3+ case was favored to represent a subset of CD30-positive acute myeloid leukemia. Three other cases with 1+ membranous and cytoplasmic staining were interpreted as myeloid leukemia. In conclusion, CD30 positivity in myeloid leukemia in the skin is rare and does not often exhibit the strong membranous (2+ or 3+) and/or Golgi staining seen in reactive lymphocytes. Acute myeloid leukemia or myeloid LC may occasionally show 1+ (and rarely 2-3+) cytoplasmic/membranous or nonspecific blush nuclear CD30 labeling. Strong diffuse staining for CD30 should prompt consideration of a reactive lymphoid/lymphoproliferative process, and, when the clinical likelihood of CD30 LC is low, may obviate the need for further immunohistochemistry.
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http://dx.doi.org/10.1097/DAD.0000000000000755DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5398922PMC
May 2017

Assessment of CD37 B-cell antigen and cell of origin significantly improves risk prediction in diffuse large B-cell lymphoma.

Blood 2016 12 19;128(26):3083-3100. Epub 2016 Oct 19.

Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH; and.

CD37 (tetraspanin TSPAN26) is a B-cell surface antigen widely expressed on mature B cells. CD37 is involved in immune regulation and tumor suppression but its function has not been fully elucidated. We assessed CD37 expression in de novo diffuse large B-cell lymphoma (DLBCL), and investigated its clinical and biologic significance in 773 patients treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) and 231 patients treated with CHOP. We found that CD37 loss (CD37) in ∼60% of DLBCL patients showed significantly decreased survival after R-CHOP treatment, independent of the International Prognostic Index (IPI), germinal center B-cell-like (GCB)/activated B-cell-like (ABC) cell of origin, nodal/extranodal primary origin, and the prognostic factors associated with CD37, including TP53 mutation, NF-κB, Myc, phosphorylated STAT3, survivin, p63, and BCL6 translocation. CD37 positivity predicted superior survival, abolishing the prognostic impact of high IPI and above biomarkers in GCB-DLBCL but not in ABC-DLBCL. Combining risk scores for CD37 status and ABC cell of origin with the IPI, defined as molecularly adjusted IPI for R-CHOP (M-IPI-R), or IPI plus immunohistochemistry (IHC; IPI+IHC) for CD37, Myc, and Bcl-2, significantly improved risk prediction over IPI alone. Gene expression profiling suggested that decreased CD20 and increased PD-1 levels in CD37 DLBCL, ICOSLG upregulation in CD37 GCB-DLBCL, and CD37 functions during R-CHOP treatment underlie the pivotal role of CD37 status in clinical outcomes. In conclusion, CD37 is a critical determinant of R-CHOP outcome in DLBCL especially in GCB-DLBCL, representing its importance for optimal rituximab action and sustained immune responses. The combined molecular and clinical prognostic indices, M-IPI-R and IPI+IHC, have remarkable predictive values in R-CHOP-treated DLBCL.
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http://dx.doi.org/10.1182/blood-2016-05-715094DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5201094PMC
December 2016

Cerebellar EBV-associated diffuse large B cell lymphoma following angioimmunoblastic T cell lymphoma.

J Hematop 2015 Dec 18;8(4):235-241. Epub 2015 Mar 18.

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

Epstein-Barr virus (EBV)-associated B cell lymphoproliferative disorders may be seen in patients with angioimmunoblastic T cell lymphoma (AITL). Although both nodal and extranodal sites of involvement have been described, central nervous system involvement by B cell lymphoma following AITL has not previously been documented. We report a first example of such unusual presentation, in which an 80-year-old man developed diffuse large B cell lymphoma (DLBCL) in the cerebellum 4 months after the initial diagnosis of AITL. EBV-encoded RNAs were detected in the DLBCL, suggesting that EBV played a pivotal role in the pathogenesis of high-grade histologic progression of AITL. The patient survived less than 9 months after his initial diagnosis of AITL. We believe that this case expands the spectrum of extranodal manifestation of EBV-positive B cell lymphoma associated with AITL and illustrates the importance of recognition of this association when encountering unusual central nervous system lesions in patients with known AITL.
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http://dx.doi.org/10.1007/s12308-015-0241-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4993208PMC
December 2015

Brentuximab vedotin and AVD followed by involved-site radiotherapy in early stage, unfavorable risk Hodgkin lymphoma.

Blood 2016 09 25;128(11):1458-64. Epub 2016 Jul 25.

Memorial Sloan Kettering Cancer Center, New York, NY; and.

This multicenter pilot study assessed the safety and efficacy of brentuximab vedotin (BV) and AVD (adriamycin, vinblastine, and dacarbazine) followed by 30 Gy involved site radiation therapy (ISRT). Patients with newly diagnosed, early stage classical Hodgkin lymphoma (HL) with unfavorable-risk features were treated with 4 cycles of BV and AVD. Patients who achieved a negative positron emission tomography (PET) scan (Deauville score of 1-3) received 30 Gy ISRT. Thirty patients received treatment and were assessable for toxicity. Twenty-nine patients completed 4 cycles of BV + AVD, and 25 patients BV + AVD + 30 Gy ISRT. No clinically significant noninfectious pneumonitis was observed. Serious adverse events (≥grade 3) were reported in 4 patients, including febrile neutropenia, peripheral neuropathy, and hypertension. After 2 and 4 cycles of BV + AVD, 90% (26 of 29) and 93% (27 or 29) of patients achieved a negative PET scan, respectively. Two patients with biopsy-proven primary refractory HL were treated off-study. All 25 patients who completed BV + AVD + ISRT achieved a complete response. With a median follow-up of 18.8 months, by intent to treat, the 1-year progression-free survival is 93.3% (95% confidence interval, 84-102). Overall, the treatment was well-tolerated with no evidence of significant pulmonary toxicity. The majority of patients (≥90%) achieved negative interim PET scans after 2 and 4 cycles of BV + AVD. Excluding the 2 primary refractory patients, all patients are disease free, suggesting that this is a highly active treatment program even in patients with substantial disease bulk. This trial was registered at www.clinicaltrials.gov as #NCT01868451.
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http://dx.doi.org/10.1182/blood-2016-03-703470DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5025897PMC
September 2016

Clinical and Biologic Significance of MYC Genetic Mutations in De Novo Diffuse Large B-cell Lymphoma.

Clin Cancer Res 2016 07 29;22(14):3593-605. Epub 2016 Feb 29.

Hospital Universitario Marqués de Valdecilla, Santander, Spain.

Purpose: MYC is a critical driver oncogene in many cancers, and its deregulation in the forms of translocation and overexpression has been implicated in lymphomagenesis and progression of diffuse large B-cell lymphoma (DLBCL). The MYC mutational profile and its roles in DLBCL are unknown. This study aims to determine the spectrum of MYC mutations in a large group of patients with DLBCL, and to evaluate the clinical significance of MYC mutations in patients with DLBCL treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) immunochemotherapy.

Experimental Design: We identified MYC mutations in 750 patients with DLBCL using Sanger sequencing and evaluated the prognostic significance in 602 R-CHOP-treated patients.

Results: The frequency of MYC mutations was 33.3% at the DNA level (mutations in either the coding sequence or the untranslated regions) and 16.1% at the protein level (nonsynonymous mutations). Most of the nonsynonymous mutations correlated with better survival outcomes; in contrast, T58 and F138 mutations (which were associated with MYC rearrangements), as well as several mutations occurred at the 3' untranslated region, correlated with significantly worse survival outcomes. However, these mutations occurred infrequently (only in approximately 2% of DLBCL). A germline SNP encoding the Myc-N11S variant (observed in 6.5% of the study cohort) was associated with significantly better patient survival, and resulted in reduced tumorigenecity in mouse xenografts.

Conclusions: Various types of MYC gene mutations are present in DLBCL and show different impact on Myc function and clinical outcomes. Unlike MYC gene translocations and overexpression, most MYC gene mutations may not have a role in driving lymphomagenesis. Clin Cancer Res; 22(14); 3593-605. ©2016 AACR.
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http://dx.doi.org/10.1158/1078-0432.CCR-15-2296DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4947447PMC
July 2016

p63 expression confers significantly better survival outcomes in high-risk diffuse large B-cell lymphoma and demonstrates p53-like and p53-independent tumor suppressor function.

Aging (Albany NY) 2016 Feb;8(2):345-65

Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

The role of p53 family member p63 in oncogenesis is the subject of controversy. Limited research has been done on the clinical implications of p63 expression in diffuse large B-cell lymphoma (DLBCL). In this study, we assessed p63 expression in de novo DLBCL samples (n=795) by immunohistochemistry with a pan-p63-monoclonal antibody and correlated it with other clinicopathologic factors and clinical outcomes. p63 expression was observed in 42.5% of DLBCL, did not correlate with p53 levels, but correlated with p21, MDM2, p16INK4A, Ki-67, Bcl-6, IRF4/MUM-1 and CD30 expression, REL gains, and BCL6 translocation. p63 was an independent favorable prognostic factor in DLBCL, which was most significant in patients with International Prognostic Index (IPI) >2, and in activated-B-cell-like DLBCL patients with wide- type TP53. The prognostic impact in germinal-center-B-cell-like DLBCL was not apparent, which was likely due to the association of p63 expression with high-risk IPI, and potential presence of ∆Np63 isoform in TP63 rearranged patients (a mere speculation). Gene expression profiling suggested that p63 has both overlapping and distinct functions compared with p53, and that p63 and mutated p53 antagonize each other. In summary, p63 has p53-like and p53-independent functions and favorable prognostic impact, however this protective effect can be abolished by TP53 mutations.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4789587PMC
http://dx.doi.org/10.18632/aging.100898DOI Listing
February 2016

Prognostic impact of concurrent MYC and BCL6 rearrangements and expression in de novo diffuse large B-cell lymphoma.

Oncotarget 2016 Jan;7(3):2401-16

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

Double-hit B-cell lymphoma is a common designation for a group of tumors characterized by concurrent translocations of MYC and BCL2, BCL6, or other genes. The prognosis of concurrent MYC and BCL6 translocations is not well known. In this study, we assessed rearrangements and expression of MYC, BCL2 and BCL6 in 898 patients with de novo diffuse large B-cell lymphoma treated with standard chemotherapy (cyclophosphamide, doxorubicin, vincristine, and prednisone plus rituximab). Neither BCL6 translocation alone (more frequent in activated B-cell like diffuse large B-cell lymphoma) nor in combination with MYC translocation (observed in 2.0% of diffuse large B-cell lymphoma) predicted poorer survival in diffuse large B-cell lymphoma patients. Diffuse large B-cell lymphoma patients with MYC/BCL6 co-expression did have significantly poorer survival, however, MYC/BCL6 co-expression had no effect on prognosis in the absence of MYC/BCL2 co-expression, and had no additive impact in MYC+/BCL2+ cases. The isolated MYC+/BCL6+/BCL2- subset, more frequent in germinal center B-cell like diffuse large B-cell lymphoma, had significantly better survival compared with the isolated MYC+/BCL2+/BCL6- subset (more frequent in activated B-cell like diffuse large B-cell lymphoma). In summary, diffuse large B-cell lymphoma patients with either MYC/BCL6 rearrangements or MYC/BCL6 co-expression did not always have poorer prognosis; MYC expression levels should be evaluated simultaneously; and double-hit B-cell lymphoma needs to be refined based on the specific genetic abnormalities present in these tumors.
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http://dx.doi.org/10.18632/oncotarget.6262DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4823044PMC
January 2016

Clinical features, tumor biology, and prognosis associated with MYC rearrangement and Myc overexpression in diffuse large B-cell lymphoma patients treated with rituximab-CHOP.

Mod Pathol 2015 Dec 6;28(12):1555-73. Epub 2015 Nov 6.

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

MYC dysregulation, including MYC gene rearrangement and Myc protein overexpression, is of increasing clinical importance in diffuse large B-cell lymphoma (DLBCL). However, the roles of MYC and the relative importance of rearrangement vs overexpression remain to be refined. Gaining knowledge about the tumor biology associated with MYC dysregulation is important to understand the roles of MYC and MYC-associated biology in lymphomagenesis. In this study, we determined MYC rearrangement status (n=344) and Myc expression (n=535) in a well-characterized DLBCL cohort, individually assessed the clinical and pathobiological features of patients with MYC rearrangement and Myc protein overexpression, and analyzed the prognosis and gene expression profiling signatures associated with these MYC abnormalities in germinal center B-cell-like and activated B-cell-like DLBCL. Our results showed that the prognostic importance of MYC rearrangement vs Myc overexpression is significantly different in germinal center B-cell-like vs activated B-cell-like DLBCL. In germinal center B-cell-like DLBCL, MYC-rearranged germinal center B-cell-like DLBCL patients with Myc overexpression significantly contributed to the clinical, biological, and prognostic characteristics of the overall Myc-overexpressing germinal center B-cell-like DLBCL group. In contrast, in activated B-cell-like DLBCL, the occurrence, clinical and biological features, and prognosis of Myc overexpression were independent of MYC rearrangement. High Myc levels and Myc-independent mechanisms, either tumor cell intrinsic or related to tumor microenvironment, conferred significantly worse survival to MYC-rearranged germinal center B-cell-like DLBCL patients, even among Myc(high)Bcl-2(high) DLBCL patients. This study provides new insight into the tumor biology and prognostic effects associated with MYC dysregulation and suggest that detection of both MYC translocations and evaluation of Myc and Bcl-2 expression is necessary to predict the prognosis of DLBCL patients.
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http://dx.doi.org/10.1038/modpathol.2015.118DOI Listing
December 2015

Dose-dependent role of the cohesin complex in normal and malignant hematopoiesis.

J Exp Med 2015 Oct 5;212(11):1819-32. Epub 2015 Oct 5.

Human Oncology and Pathogenesis Program, Leukemia Service, Department of Medicine, Department of Pathology, Molecular Cytology Core Facility, and Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, NY 10065 Human Oncology and Pathogenesis Program, Leukemia Service, Department of Medicine, Department of Pathology, Molecular Cytology Core Facility, and Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, NY 10065 Human Oncology and Pathogenesis Program, Leukemia Service, Department of Medicine, Department of Pathology, Molecular Cytology Core Facility, and Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, NY 10065

Cohesin complex members have recently been identified as putative tumor suppressors in hematologic and epithelial malignancies. The cohesin complex guides chromosome segregation; however, cohesin mutant leukemias do not show genomic instability. We hypothesized that reduced cohesin function alters chromatin structure and disrupts cis-regulatory architecture of hematopoietic progenitors. We investigated the consequences of Smc3 deletion in normal and malignant hematopoiesis. Biallelic Smc3 loss induced bone marrow aplasia with premature sister chromatid separation and revealed an absolute requirement for cohesin in hematopoietic stem cell (HSC) function. In contrast, Smc3 haploinsufficiency increased self-renewal in vitro and in vivo, including competitive transplantation. Smc3 haploinsufficiency reduced coordinated transcriptional output, including reduced expression of transcription factors and other genes associated with lineage commitment. Smc3 haploinsufficiency cooperated with Flt3-ITD to induce acute leukemia in vivo, with potentiated Stat5 signaling and altered nucleolar topology. These data establish a dose dependency for cohesin in regulating chromatin structure and HSC function.
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http://dx.doi.org/10.1084/jem.20151317DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4612085PMC
October 2015

Prognostic impact of c-Rel nuclear expression and REL amplification and crosstalk between c-Rel and the p53 pathway in diffuse large B-cell lymphoma.

Oncotarget 2015 Sep;6(27):23157-80

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

Dysregulated NF-κB signaling is critical for lymphomagenesis. The regulation, function, and clinical relevance of c-Rel/NF-κB activation in diffuse large B-cell lymphoma (DLBCL) have not been well studied. In this study we analyzed the prognostic significance and gene-expression signature of c-Rel nuclear expression as surrogate of c-Rel activation in 460 patients with de novo DLBCL. Nuclear c-Rel expression, observed in 137 (26.3%) DLBCL patients frequently associated with extranoal origin, did not show significantly prognostic impact in the overall- or germinal center B-like-DLBCL cohort, likely due to decreased pAKT and Myc levels, up-regulation of FOXP3, FOXO3, MEG3 and other tumor suppressors coincided with c-Rel nuclear expression, as well as the complicated relationships between NF-κB members and their overlapping function. However, c-Rel nuclear expression correlated with significantly poorer survival in p63+ and BCL-2- activated B-cell-like-DLBCL, and in DLBCL patients with TP53 mutations. Multivariate analysis indicated that after adjusting clinical parameters, c-Rel positivity was a significantly adverse prognostic factor in DLBCL patients with wild type TP53. Gene expression profiling suggested dysregulations of cell cycle, metabolism, adhesion, and migration associated with c-Rel activation. In contrast, REL amplification did not correlate with c-Rel nuclear expression and patient survival, likely due to co-amplification of genes that negatively regulate NF-κB activation. These insights into the expression, prognostic impact, regulation and function of c-Rel as well as its crosstalk with the p53 pathway underscore the importance of c-Rel and have significant therapeutic implications.
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http://dx.doi.org/10.18632/oncotarget.4319DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4695110PMC
September 2015

Prognostic and biological significance of survivin expression in patients with diffuse large B-cell lymphoma treated with rituximab-CHOP therapy.

Mod Pathol 2015 Oct 7;28(10):1297-314. Epub 2015 Aug 7.

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

Survivin, a member of the inhibitor of apoptosis protein family, is overexpressed in a variety of human neoplasms. The prognostic significance of survivin expression in diffuse large B-cell lymphoma patients treated with rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) is unclear. We used standard immunohistochemistry methods to quantify survivin expression in 463 patients with de novo diffuse large B-cell lymphoma who received the R-CHOP. Of the 463 patients, 269 (58%) had survivin overexpression with a cutoff of >25%, associated with an International Prognostic Index score of >2 (P=0.015), disease in ≥2 extranodal sites (P=0.011), and a high Ki-67 index (P<0.0001). Among patients with activated B cell-like disease, the overall survival rate of survivin-positive patients was significantly lower than that of survivin-negative patients (P=0.033); multivariate analysis confirmed that in these patients, survivin overexpression was an independent prognostic factor for survival. Among patients with wild-type p53 overexpression, the overall survival and progression-free survival rates of the survivin-positive group were significantly lower than those of the survivin-negative group (P=0.035 and P=0.04 respectively). In STAT3-positive patients, survivin overexpression was associated with significantly better survival. Among patients with activated B cell-like disease, survivin-positive compared with survivin-negative groups had significantly different gene expression signatures, including genes involved in mitosis or tumor cell proliferation. Our results indicate that survivin is an independent prognostic factor for poor outcome in patients with activated B cell-like disease treated with the R-CHOP regimen, and patients with survivin-positive activated B cell-like diffuse large B-cell lymphoma seem to benefit less from this treatment and may require additional novel agents.
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http://dx.doi.org/10.1038/modpathol.2015.94DOI Listing
October 2015