Tissue Microarray Is a Useful Tool in the Evaluation of Genes Implicated in Transformation of Follicular Lymphoma.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2267-2267 ◽  
Author(s):  
Abigail Lee ◽  
Andrew Davies ◽  
Andrew Clear ◽  
Maria Calaminici ◽  
Janet Matthews ◽  
...  
Keyword(s):  
Gene Expression ◽  
Follicular Lymphoma ◽  
Tissue Microarray ◽  
Molecular Mechanisms ◽  
De Novo ◽  
B Cell Lymphoma ◽  
Follicular Dendritic Cell ◽  
Response To Therapy ◽  
Aurora Kinase B ◽  
General Response

Abstract A subset of patients (pts.) with follicular lymphoma (FL) will transform to a more aggressive histological sub-type, most typically diffuse large B-cell lymphoma (DLBCL). In general response to therapy is poor and survival short. Paired analysis of samples pre- and post transformation suggest that the molecular mechanisms underlying transformation (Tx) are heterogeneous. In order to independently validate recurring changes in gene/protein expression at transformation (GC phenotype of TxDLBCL, Davies et al., 2002; loss of follicular dendritic Cell (FDC) markers, Shiozawa et al., 2003) a Tx-tissue microarray (Tx-TMA) was created comprising serial samples from 35 pts. (median age 54yrs (22–81) at the time of transformation). In these pts. transformation occurred a median of 3.1years from diagnosis (range 0–15.4) and for each pt. ‘set’ at least 1 pre-Tx FL sample (1–3; n=56), and 1 (1–4; n=44) post transformation sample were represented on the array. To ensure that the Tx-TMA cores accurately represented the corresponding full tissue sections a panel of routine immunohistochemical (IHC) diagnostic markers (n=9) were scored. The concordance between Tx-TMA and full sections (n=10) was >90%. The Tx-TMA was then used to investigate the phenotype of transformed DLBCL, according to the germinal centre (GC)/non-GC like model of de novo DLBCL. Using CD10, BCL6 and MUM1 expression to discriminate between the two subclasses of DLBCL the methodology was first validated on a de novo DLBCL TMA (n=31; 20/31 (65%) non-GC, 11/31 (35%) GC phenotype; 5-yr survival for non-GC pts. 51% and for GC pts., 73%). IHC confirmed the results of gene expression profiling indicating that in 31/35 (89%) pts. transformed DLBCL was of GC phenotype (28/35 (80%) CD10+ and 3/35 (9%) CD10-, BCL6+, MUM1-). Of the remainder, 4/35 were CD10-, BCL6+, of which 3/4 were MUM1+ (3/35 (9%) non-GC phenotype; 1/4 MUM1 was not assessable). Similarly the Tx-TMA confirmed loss of FDC markers (CD21 and CD23) on transformation. Samples from 28 pts were evaluable for CD21 and CD23 IHC expression. In 71% (20/28) of pts. the FDC meshwork was lost or became more sparse on transformation (CD21 loss 15/28 (54%); CD23 loss 17/28 (61%)). The most discriminating changes in gene expression on transformation are now being assessed by IHC. Aurora kinase B (ARKB) is an attractive therapeutic target given that disruption of ARK function results in the induction of apoptosis in RL, a t(14:18) positive DLBCL cell line (Harrington et al. 2004). The observed elevation in ARKB transcription on transformation was confirmed by IHC in this series. The Tx-TMA showed ARKB expression increased on Tx in 13/33 (40%) pts., potentially defining a subset of pts. who might be considered for ARKB directed therapies. Expression of ARKB was low throughout in 18/33 (55%) pts and decreased in 2/33 (6%) pts.; difference in ARKB expression was not significantly associated with survival. These preliminary studies suggest that the availability of TMA of serial biopsies from pts. with transformed FL will provide a powerful means of assessing the relevance of gene expression, both within the tumour and the microenvironment while facilitating the selection of patients most likely to benefit from directed therapeutic approaches.

scholarly journals S100 TREATMENT-DEPENDENCE OF HIGH-RISK GENE EXPRESSION SIGNATURES IN DE NOVO FOLLICULAR LYMPHOMA

HemaSphere ◽  
2019 ◽  
Vol 3 (S1) ◽  
pp. 1
Author(s):  
C. Bolen ◽  
W. Hiddemann ◽  
R. Marcus ◽  
M. Herold ◽  
S. Huet ◽  
...  
Keyword(s):  
Gene Expression ◽  
High Risk ◽  
Follicular Lymphoma ◽  
De Novo ◽  
Risk Gene ◽  
Gene Expression Signatures

scholarly journals PD-L1 and tumor-associated macrophages in de novo DLBCL

2019 ◽  
Vol 3 (4) ◽  
pp. 531-540 ◽  
Author(s):  
Ronald McCord ◽  
Christopher R. Bolen ◽  
Hartmut Koeppen ◽  
Edward E. Kadel ◽  
Mikkel Z. Oestergaard ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Activation ◽  
Immune Cell ◽  
De Novo ◽  
Single Agent ◽  
B Cell Lymphoma ◽  
Staining Procedure ◽  
Immune Cell Activation ◽  
Improved Outcomes ◽  
Risk Patients

Abstract Programmed death-ligand 1 (PD-L1) and its receptor, programmed cell death-1 (PD-1), are important negative regulators of immune cell activation. Therapeutically targeting PD-1/PD-L1 in diffuse large B-cell lymphoma (DLBCL) patients with a single agent has limited activity, meriting a deeper understanding of this complex biology and of available PD-L1 clinical assays. In this study, we leveraged 2 large de novo DLBCL phase 3 trials (GOYA and MAIN) to better understand the biologic and clinical relevance of PD-L1 in de novo DLBCL. PD-L1 was expressed on myeloid cells in 85% to 95% of DLBCL patients (depending on staining procedure), compared with 10% on tumor cells, and correlated with macrophage gene expression. PD-L1 did not identify high-risk patients in de novo DLBCL; it correlated with STAT3, macrophage gene expression, and improved outcomes among a subset of patients. These results may help identify immunologically distinct DLBCL subsets relevant for checkpoint blockade. GOYA and MAIN trials were registered at www.clinicaltrials.gov as #NCT01287741 and #NCT00486759, respectively.

Impact of MYC and BCL2 structural variants in tumors of DLBCL morphology and mechanisms of false-negative MYC IHC

Blood ◽  
2020 ◽  
Author(s):  
Brett J Collinge ◽  
Susana Ben-Neriah ◽  
Lauren C. Chong ◽  
Merrill Boyle ◽  
Aixiang Jiang ◽  
...  
Keyword(s):  
Gene Expression ◽  
B Cell ◽  
De Novo ◽  
Cell Lymphoma ◽  
False Negative ◽  
Gene Expression Signature ◽  
B Cell Lymphoma ◽  
Copy Number Variations ◽  
Similar Gene Expression Profile ◽  
Double Hit

When the WHO defined high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements (HGBL-DH/TH) as a clinical category, rearrangements were the only structural variant (SV) incorporated. An "atypical double-hit" entity has been proposed, encompassing tumors with concurrent MYC and BCL2 SVs other than co-occurring translocations - i.e. copy number variations (CNVs). While the identification of a gene expression signature (DHITsig) shared among tumors harboring MYC and BCL2 rearrangements (HGBL-DH/TH-BCL2) has confirmed a shared underlying biology, the biological implication of MYC and BCL2 CNVs requires further elucidation. We performed a comprehensive analysis of MYC and BCL2 SVs, as determined by fluorescent in situ hybridization (FISH), in a cohort of 802 de novo tumors with diffuse large B-cell lymphoma (DLBCL) morphology. While BCL2 CNVs were associated with increased expression, MYC CNVs were not. Furthermore, MYC and BCL2 CNVs, in the context of atypical double-hit, did not confer a similar gene expression profile as HGBL-DH/TH-BCL2. Finally, while MYC IHC has been proposed as a screening tool for FISH testing, two mechanisms were observed that uncoupled MYC rearrangement from IHC positivity. 1) low MYC mRNA expression and 2) false-negative immunohistochemistry (IHC) staining mediated by a single nucleotide polymorphism resulting in an asparagine to serine substitution at the 11th amino acid residue of MYC (MYC-N11S). Taken together, these results support the current exclusion of MYC and BCL2 CNVs from HGBL-DH/TH and highlight the ability of a molecular based classification system to identify tumors with shared biology that FISH and IHC fail to fully capture.

T-cell-rich B-cell lymphomas: diagnosis and response to therapy of 44 patients.

1995 ◽  
Vol 13 (7) ◽  
pp. 1742-1750 ◽  
Author(s):  
J P Greer ◽  
W R Macon ◽  
R E Lamar ◽  
S N Wolff ◽  
R S Stein ◽  
...  
Keyword(s):  
T Cell ◽  
B Cell ◽  
Combination Chemotherapy ◽  
De Novo ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Response To Therapy ◽  
B Cell Lymphomas ◽  
Intermediate Grade ◽  
Large B Cell

PURPOSE Clinicopathologic features of 44 patients with well-documented T-cell-rich B-cell lymphomas (TCRBCLs) were reviewed to determine if there were distinguishing clinical characteristics and to evaluate the responsiveness to therapy. PATIENTS AND METHODS Forty-one patients had de novo TCRBCL, while three patients had a prior diagnosis of diffuse large B-cell lymphoma. Seventeen TCRBCLs were identified from a retrospective analysis of 176 lymphomas diagnosed before 1988 as peripheral T-cell lymphoma (PTCLs). The initial pathologic diagnosis was incorrect in 36 of 44 cases (82%), usually due to the absence of adequate immunophenotypic and/or genotypic studies at the initial study. RESULTS The median age of patients was 53 years (range, 17 to 92), and the male-to-female ratio was 1.4:1. B symptoms were present in 22 of 41 patients (54%); splenomegaly was detected in 11 patients (25%). Clinical stage at diagnosis was as follows: I (n = 8), II (n = 6), III (n = 15), IV (n = 14), and unstaged (n = 1). Although therapy was heterogeneous, the disease-free survival (DFS) and overall survival (OS) rates at 3 years for patients with de novo TCRBCL were 29% and 46%, respectively. A complete response (CR) to combination chemotherapy for intermediate-grade lymphomas was observed in 16 of 26 patients (62%); 11 of these patients (42%) had a continuous CR, compared with one of 14 patients (7%) who received radiation therapy or therapy for low-grade lymphoma or Hodgkin's disease (HD) (P < .05). However, there was no difference in OS between patients who received chemotherapy for intermediate-grade lymphoma versus other therapies (49% v 48%) due to a high response rate to salvage therapies, including seven patients without disease after marrow transplantation. CONCLUSION TCRBCLs are difficult to recognize without immunoperoxidase studies. Patients with TCRBCL have clinical features similar to patients with other large B-cell lymphomas, except they may have more splenomegaly and advanced-stage disease; they should receive combination chemotherapy directed at large-cell lymphomas.

Array-CGH Identifies Regions, Including the FOXP1 Locus, Associated with Different Clinical Outcome in Diffuse Large B-Cell Lymphomas (DLBCL) Treated with R-CHOP

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 478-478
Author(s):  
Marta Scandurra ◽  
Paola M.V. Rancoita ◽  
Timothy C. Greiner ◽  
Wing C. Chan ◽  
Julie M. Vose ◽  
...  
Keyword(s):  
Complete Remission ◽  
B Cell ◽  
De Novo ◽  
B Cell Lymphoma ◽  
Response To Therapy ◽  
Poor Responders ◽  
Score Distribution ◽  
Genomic Aberrations ◽  
Large B Cell

Abstract Background. Diffuse large B-cell lymphoma (DLBCL) consists of a heterogeneous group of tumors. More than 30% of cases are not cured with R-CHOP chemotherapy. Aim. To identify genomic aberrations that could affect the response to therapy, we performed an arrayCGH study on uniformly treated DLBCL patients. Materials and Methods. Tumor samples were analyzed with Affymetrix Human Mapping 250K SNP arrays. Eligibility criteria were diagnosis of de novo DLBCL, first line treatment with R-CHOP or R-CHOP-like regimens, availability of frozen biopsy and of clinical baseline and follow-up data. Exclusion criteria were: primary mediastinal DLBCL, primary central nervous system DLBCL, HIV-positivity. Material has been collected according to the local IRB guidelines. Results. Genomic tumor profiles have been obtained in 163 samples from 10 Institutions; 23/163 cases were excluded from this analysis because the information on response was not available; 140/163 cases fulfilled the study requirements. The clinical parameters of the patients reflected the normal DLBLC population, as shown by the IPI score distribution (0–1 in 30%, 2 in 37%, 3 in 23% and 4–5 in 10%). The median follow-up was 23 months (range 1–1251). Complete remission was observed in 108/140 (77%) patients, partial response in 21 (15%), stable disease in 6 (4%) and progression in 5 (2%). Genomic differences were observed between complete responders (108 cases) and the remaining patients, grouped together as poor responders (32 cases). The latter group had more gains of 3p14.1 (FOXP1 locus), 3q29, 11q24.3, and losses of 2p11.2-p13.3, 8p23.1- pter, 10p12.31-p13, 15q11.2-q14, 15q21.1 and copy neutral LOH of chromosome 9p. On the converse, 1q gains were more common among patients achieving complete remission. No differences were observed for other common region of gains (7, 12, 18q/BCL2) or losses (1p, 6q, 17p/TP53). Conclusions. Specific genomic aberrations are associated with the response to R-CHOP in patients with DLBCL. In particular, the gain of the 3p14.1 (FOXP1 locus), which is associated with a lack of response to R-CHOP, suggests that the role of FOXP1 should be further investigated in DLBCL.

Gene Expression Signature of Host Immune Response Is Predictive of Follicular Lymphoma Patient Survival in Independent Cohorts, and Correlates with Transformation to Diffuse Large B-Cell Lymphoma.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2951-2951
Author(s):  
Ash A Alizadeh ◽  
Andrew J Gentles ◽  
Sylvia K Plevritis ◽  
Ronald Levy
Keyword(s):  
Gene Expression ◽  
Immune Response ◽  
Follicular Lymphoma ◽  
B Cell ◽  
Immune Cells ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Large B Cell Lymphoma ◽  
Large B Cell ◽  
Independent Cohort

Abstract Abstract 2951 Poster Board II-927 Background: Expression signatures of infiltrating immune cells [1] have been shown to predict survival in follicular lymphoma (FL), but have not been cross-validated in independent patient cohorts [2,3]. These signatures may relate biologically to the frequency of infiltrating including T-cells and macrophages, or to specific transcription programs within tumor cells and/or the tumor microenvironment. We sought to evaluate the validity of this model in an independent cohort of patients with FL, assessing its relationship to outcomes including histological transformation and death. Methods: The immune response (IR) predictor score proposed by Dave et al. [1] was applied to gene expression data from an independent cohort of 88 FL patients [4] with known survival outcomes and history of transformation to diffuse large B-cell lymphoma (DLBCL). Genes (n=66) corresponding to IR1 and IR2 signatures were mapped from Affymetrix microarrays [1] to a custom cDNA array [4] via Entrez Gene ID, and the composite IR score was calculated per the scheme proposed by Dave et al. Results: The IR score was predictive of patient outcome in the 88 patient test set as a continuous variable (p=0.001, HR=2.01, 95% CI 0.50-1.30). Partitioning of patients into high and low risk groups based on the median IR score across the cohort robustly separated survival curves (Figure A). The IR score was significantly higher in FL patients known to undergo transformation to DLBCL (Figure B: mean IR score of -0.6 in non-transforming FL vs. -0.2 in transforming FL; p∼10-11, t-test). Conclusions: The IR score of Dave et al. was highly significant as a predictor of survival in the independent patient cohort [4]. Moreover, the score was significantly associated with propensity of FL to transform to DLBCL. To our knowledge, immune cell infiltration has not previously been implicated in transformation. 1. Dave SS et al. (2004) Prediction of survival in follicular lymphoma based on molecular features of tumor-infiltrating immune cells. N Engl J Med 351(21): 2159-2169. 2. Tibshirani R (2005) Immune signatures in follicular lymphoma. N Engl J Med 352: 1496-1497. 3. Chu G Hong WJ, Warnke R, Chu G (2005). Immune Signatures in Follicular Lymphoma (Corres). N Engl J Med. 352: 1496-1497. 4. Glas AM et al. (2005) Gene expression profiling in follicular lymphoma to assess clinical aggressiveness and to guide the choice of treatment. Blood 105(1): 301-307. Disclosures: No relevant conflicts of interest to declare.

Gene expression profile in flow-associated pulmonary arterial hypertension with neointimal lesions

2010 ◽  
Vol 298 (4) ◽  
pp. L483-L491 ◽  
Author(s):  
Mirjam E. van Albada ◽  
Beatrijs Bartelds ◽  
Hans Wijnberg ◽  
Saffloer Mohaupt ◽  
Michael G. Dickinson ◽  
...  
Keyword(s):  
Gene Expression ◽  
Blood Flow ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Pulmonary Blood Flow ◽  
Molecular Mechanisms ◽  
Expression Profiles ◽  
Response To Therapy ◽  
High Morbidity ◽  
Pulmonary Arterial

Pulmonary arterial hypertension (PAH) is a pulmonary angioproliferative disease with high morbidity and mortality, characterized by a typical pattern of pulmonary vascular remodeling including neointimal lesions. In congenital heart disease, increased pulmonary blood flow has appeared to be a key mediator in the development of these characteristic lesions, but the molecular mechanisms underlying the pulmonary vascular lesions are largely unknown. We employed a rat model of flow-associated PAH, which induced specific pulmonary neointimal lesions. We identified gene expression profiles in rats specifically related to the addition of increased pulmonary blood flow to monocrotaline and the associated occurrence of neointimal lesions. Increased pulmonary blood flow induced the expression of the transcription factors activating transcription factor-3 (ATF3) and early growth response factor-1 (EGR-1), for which presence was confirmed in neointimal lesions. Monocrotaline alone induced increased numbers of activated mast cells and their products. We further identified molecular pathways that may be involved in treatment with the prostacyclin analog iloprost, a vasoactive compound with clinically beneficial effects in patients with PAH, which were similar to pathways described in samples from patient studies. These pathways, associated with the development of angioproliferative lesions as well as with the response to therapy in PAH, may provide new therapeutic targets.

scholarly journals Transformation of Follicular Lymphoma to Double Hit B-Cell Lymphoma Causing Hypercalcemia in a 69-Year-Old Female: A Case Report and Review of the Literature

2014 ◽  
Vol 2014 ◽  
pp. 1-8 ◽  
Author(s):  
Sakshi Kapur ◽  
Miles B. Levin
Keyword(s):  
Follicular Lymphoma ◽  
B Cell ◽  
De Novo ◽  
Cell Lymphoma ◽  
Care Center ◽  
Tertiary Care ◽  
B Cell Lymphoma ◽  
Low Grade ◽  
Severe Hypercalcemia ◽  
Double Hit

Double hit B-cell lymphomas are rare tumors that are defined by a chromosomal breakpoint affecting the MYC/8q24 locus in combination with another recurrent breakpoint, mainly a t(14;18)(q32;q21) involving BCL2. These tumors mostly occur in adults and carry a very poor prognosis. Double hit lymphomas can occur de novo, or arise from transformation of follicular lymphoma. We report a case of a 69-year-old female with abdominal distention and progressively worsening weakness over six months. Patient presented with severe hypercalcemia and multiple intra-abdominal/pelvic masses. Histopathology results of the abdominal mass were compatible with a double hit B-cell lymphoma. However, bone marrow biopsy results showed a low grade follicular lymphoma, thus suggesting peripheral transformation of follicular lymphoma to double hit B-cell lymphoma. Patient was transferred to a tertiary care center and was started on combination chemotherapy (EPOCH: doxorubicin, etoposide, vincristine, cyclophosphamide, and prednisone). Our paper highlights not only transformation of follicular lymphoma to double hit B-cell lymphoma and the challenges encountered in diagnosing and treating these aggressive tumors, but also the association of new onset/worsening hypercalcemia in such patients.

scholarly journals Immune polychemotherapy regimen choice in B-cell non-Hodgkin lymphoma of high and low malignancy based on the identification of the mutational c-myc and BCL 2 genes

2021 ◽  
Author(s):  
Dilyara R. Kaidarova ◽  
Raiymkul K. Karakulov ◽  
Saule T. Gabbasova ◽  
Meruert K. Karazhanova ◽  
Svetlana A. Lyubko
Keyword(s):  
Gene Expression ◽  
B Cell ◽  
Gene Expression Profile ◽  
Expression Profile ◽  
B Cell Lymphoma ◽  
Response To Therapy ◽  
High Dose ◽  
Molecular Subgroups ◽  
Proliferative Index ◽  
Ki 67

Introduction: The relevance of research is conditioned by the study of the gene expression profile for the identification of molecular subgroups of non-Hodgkin B-cell lymphomas (NHBCLs) in haematology. Aim: The aim of this research was to study the gene expression profile with the identification of molecular subgroups in patients with NHBCLs for personalised treatment. Material and methods: This paper is aimed at analysing the frequency and role of expression of c-myc, B-cell lymphoma 2 (BCL 2) proteins and the Ki 67 proliferative index in patients with NHBCLs and conducting personalised therapy to improve the immediate effectiveness and immediate treatment results. Results and discussion: The paper presents the results of the use of high-dose polychemotherapy (PCT) in 9 patients out of 80 with NHBCL during co-expression of the c-myc, BCL 2 mutational gene and with high values of the Ki 67 proliferative index. High-dose chemotherapy (HDCT) was performed according to the R+HyperCVAD scheme (6 courses) and hematopoietic stem cell (HSC) autotransplantation improved the immediate effectiveness of therapy, with a complete remission rate of 80% and an event-free survival of 28 months. Conclusions: The study of molecular genetic characteristics in 80 patients with NHBCLs revealed co-expression of the c-myc and BCL 2 mutational gene in 9 out of 80 patients, and they differed in the aggressive course, ‘poor’ response to therapy, which predetermined the use of high-dose PCT with transplantation of autologous stem cells.

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