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2.
J Mol Diagn ; 23(12): 1774-1786, 2021 12.
Article in English | MEDLINE | ID: mdl-34562613

ABSTRACT

Although most small B-cell lymphomas (SBCLs) can be diagnosed using routine methods, challenges exist. For example, marginal zone lymphomas (MZLs) can be difficult to rule-in, in large part because no widely-used, sensitive, and specific biomarker is available for the marginal zone cell of origin. In this study, it was hypothesized that DNA methylation array profiling can assist with the classification of SBCLs, including MZLs. Extramedullary SBCLs, including challenging cases, were reviewed internally for pathology consensus and profiled. By combining the resulting array data set with data sets from other groups, a set of 26 informative probes was selected and used to train machine learning models to classify 4 common SBCLs: chronic lymphocytic leukemia/small lymphocytic lymphoma, follicular lymphoma, mantle cell lymphoma, and MZL. Prediction probability cutoff was used to separate classifiable from unclassifiable cases, and show that the trained model was able to classify 95% of independent test cases (n = 264/279). The concordance between model predictions and pathology diagnoses was 99.6% (n = 262/263) among classifiable test cases. One validation reference test case was reclassified based on model prediction. The model was also used to predict the diagnoses of two challenging SBCLs. Although the differential examined and data on difficult cases are limited, these results support accurate methylation-based classification of SBCLs. Furthermore, high specificities of predictions suggest that methylation signatures can be used to rule-in MZLs.


Subject(s)
DNA Methylation , Lymphoma, B-Cell/genetics , Lymphoma, B-Cell/pathology , Aged , Biomarkers, Tumor/genetics , Female , Humans , Lymph Nodes/pathology , Lymphoma, B-Cell/classification , Lymphoma, B-Cell/surgery , Lymphoma, B-Cell, Marginal Zone/genetics , Lymphoma, B-Cell, Marginal Zone/surgery , Middle Aged , Models, Biological , Proof of Concept Study , Reproducibility of Results
3.
Pathol Res Pract ; 226: 153589, 2021 Oct.
Article in English | MEDLINE | ID: mdl-34455365

ABSTRACT

Lymphomas associated with breast implants are mostly of the T-cell type. They are predominantly anaplastic lymphoma kinase-negative anaplastic large cell lymphoma (ALK-negative ALCL) characterized by CD30 positivity universally. Whilst the majority of primary breast lymphomas occurring in the absence of breast implants are of B-cell origin, there are few cases of implant-associated B-cell lymphomas reported to date in the literature, a subset of which are diffuse large B-cell lymphoma (DLBCL). Given the rarity of this entity, we describe two cases of breast implant-associated DLBCL. Both patients developed Epstein-Barr Virus (EBV)-positive large cell lymphoma of B-cell origin confined to the implant capsule with no evidence of systemic lymphoma. Considering the association with EBV, the activated B-cell phenotype and the presumed chronic inflammatory environment associated with the implant capsule, these might represent forms of DLBCL associated with chronic inflammation (DLBCL-CI) or fibrin-associated DLBCL (FA-DLBCL). Treatment included implant removal with total capsulectomy, and for one of the cases adjuvant systemic chemotherapy. Recognizing this rare type of breast implant-associated B-cell lymphoma could improve our understanding of this entity and hence develop appropriate management strategies.


Subject(s)
Breast Implants/adverse effects , Breast Neoplasms/etiology , Epstein-Barr Virus Infections/complications , Lymphoma, Large B-Cell, Diffuse/etiology , Adult , Carcinoma, Lobular/pathology , Female , Humans , Middle Aged , Neoplasms, Multiple Primary/pathology
6.
J Hematol Oncol ; 13(1): 96, 2020 07 16.
Article in English | MEDLINE | ID: mdl-32677994

ABSTRACT

CD47, or integrin-associated protein, is a cell surface ligand expressed in low levels by nearly all cells of the body. It plays an integral role in various immune responses as well as autoimmunity, by sending a potent "don't eat me" signal to prevent phagocytosis. A growing body of evidence demonstrates that CD47 is overexpressed in various hematological malignancies and its interaction with SIRPα on the phagocytic cells prevents phagocytosis of cancer cells. Additionally, it is expressed by different cell types in the tumor microenvironment and is required for establishing tumor metastasis. Overexpression of CD47 is thus often associated with poor clinical outcomes. CD47 has emerged as a potential therapeutic target and is being investigated in various preclinical studies as well as clinical trials to prove its safety and efficacy in treating hematological neoplasms. This review focuses on different therapeutic mechanisms to target CD47, either alone or in combination with other cell surface markers, and its pivotal role in impairing tumor growth and metastatic spread of various types of hematological malignancies.


Subject(s)
CD47 Antigen/physiology , Hematologic Neoplasms/physiopathology , Molecular Targeted Therapy , Neoplasm Proteins/physiology , Angiogenic Proteins/metabolism , Animals , Antibodies, Monoclonal, Humanized/therapeutic use , Antigens, Differentiation/metabolism , Antineoplastic Agents, Immunological/therapeutic use , CD47 Antigen/antagonists & inhibitors , Clinical Trials as Topic , Drug Delivery Systems , Drug Design , Drug Screening Assays, Antitumor , Hematologic Neoplasms/therapy , Humans , Integrins/metabolism , Leukemia/metabolism , Leukemia/physiopathology , Lymphoma, Non-Hodgkin/metabolism , Lymphoma, Non-Hodgkin/physiopathology , Molecular Mimicry , Myeloid Cells/metabolism , Neoplasm Metastasis , Neoplasm Proteins/antagonists & inhibitors , Oligopeptides/therapeutic use , Protein Binding , Protein Domains , Protein Interaction Mapping , Receptors, Immunologic/antagonists & inhibitors , Receptors, Immunologic/metabolism , Signal Transduction/physiology
7.
Br J Haematol ; 190(6): 864-868, 2020 09.
Article in English | MEDLINE | ID: mdl-32510594

ABSTRACT

Despite continuing improvements in the management of classical Hodgkin lymphoma (cHL), relapse remains associated with a risk of lymphoma-related mortality. The biological composition of relapse tumour biopsies shows interpatient variability, which can be leveraged to design prognostic biomarkers. Here, we validated the RHL30 assay, a previously reported gene expression model in an independent cohort of 41 patients with relapsed cHL. Patients classified as high-risk by the RHL30 assay had inferior failure-free survival (FFS) after autologous stem cell transplantation (2-year FFS 41% vs. 92%, P = 0·035). The RHL30 model is a robust biomarker that risk-stratifies patients considered for autologous stem cell transplantation.


Subject(s)
Biomarkers, Tumor/biosynthesis , Gene Expression Profiling , Gene Expression Regulation, Neoplastic , Hematopoietic Stem Cell Transplantation , Hodgkin Disease , Adult , Autografts , Female , Hodgkin Disease/metabolism , Hodgkin Disease/mortality , Hodgkin Disease/therapy , Humans , Male , Middle Aged , Risk Factors
8.
Biomark Res ; 6: 34, 2018.
Article in English | MEDLINE | ID: mdl-30555699

ABSTRACT

Enhancer of zeste homolog 2 (EZH2) is a histone methyltransferase that is of great interest in human cancer. It has been shown to have a dual nature, as it can act as a gene repressor or activator. Studies have highlighted the various roles of EZH2 in the pathophysiology of multiple myeloma (MM). It was also shown to have a role in the development of drug resistance in MM. There are several ongoing clinical trials of EZH2 inhibitors in haematological malignancies. Pre-clinical studies have provided a rationale for the therapeutic relevance of EZH2 inhibitors in MM. This paper reviews the evidence supporting the role of EZH2 in MM pathophysiology and drug resistance, with an emphasis on interactions between EZH2 and microRNAs, as well as the prognostic significance of EZH2 expression in MM. Furthermore, results from the pre-clinical studies of EZH2 inhibition in MM and currently available interim results from clinical trials of EZH2 inhibitors in haematological malignancies are presented. Preliminary data exploring anticipated mechanisms of resistance to EZH2 inhibitors are also reviewed. There is therefore strong evidence to support the relevance of targeting EZH2 for the treatment of MM.

10.
J Hematol Oncol ; 11(1): 46, 2018 03 27.
Article in English | MEDLINE | ID: mdl-29580288

ABSTRACT

Even with recent advances in therapy regimen, multiple myeloma patients commonly develop drug resistance and relapse. The relevance of targeting the PD-1/PD-L1 axis has been demonstrated in pre-clinical models. Monotherapy with PD-1 inhibitors produced disappointing results, but combinations with other drugs used in the treatment of multiple myeloma seemed promising, and clinical trials are ongoing. However, there have recently been concerns about the safety of PD-1 and PD-L1 inhibitors combined with immunomodulators in the treatment of multiple myeloma, and several trials have been suspended. There is therefore a need for alternative combinations of drugs or different approaches to target this pathway. Protein expression of PD-L1 on cancer cells, including in multiple myeloma, has been associated with intrinsic aggressive features independent of immune evasion mechanisms, thereby providing a rationale for the adoption of new strategies directly targeting PD-L1 protein expression. Drugs modulating the transcriptional and post-transcriptional regulation of PD-L1 could represent new therapeutic strategies for the treatment of multiple myeloma, help potentiate the action of other drugs or be combined to PD-1/PD-L1 inhibitors in order to avoid the potentially problematic combination with immunomodulators. This review will focus on the pathophysiology of PD-L1 expression in multiple myeloma and drugs that have been shown to modulate this expression.


Subject(s)
Multiple Myeloma/drug therapy , Programmed Cell Death 1 Receptor/metabolism , Humans
11.
Breast J ; 23(3): 315-322, 2017 May.
Article in English | MEDLINE | ID: mdl-27901301

ABSTRACT

The surgical management of phyllodes tumors (PTs) is still controversial. Some studies have suggested surgical margins ≥1 cm, but recent studies suggested that negative margins could be appropriate regardless of their width. To evaluate recurrence rates of PTs following surgery according to margins. Retrospective study of women who attended a tertiary breast cancer reference center between 1998 and 2010: 142 patients with a PT diagnosis, either at minimally invasive breast biopsy or at surgery, were identified. Clinical, pathologic and follow-up characteristics were assessed. Among 140 patients who underwent surgery, 64.3% of biopsies accurately predicted the final PT diagnosis at surgery. Forty-two (42/87, 48.3%) PTs had positive margins. Twenty-one (21/42, 50.0%) patients had a surgical revision of margins. Only one (1/42, 2.4%) had margins greater or equal to 1 cm. After a median follow-up of 1.29 years in benign PTs, 4.99 years in borderline PTs, and 5.42 years in malignant PTs, there were five local recurrences, three in originally benign PTs and two in borderline PTs. All were managed with surgery. Four had initial margins ≤1 mm. One patient with borderline PT had a local recurrence and later progressed to regional recurrence and metastasis. Free surgical margins are necessary to treat PT, and margins of at least 1 mm might be sufficient to prevent recurrence. Core needle biopsy might not be the best diagnostic tool for PTs.


Subject(s)
Breast Neoplasms/surgery , Margins of Excision , Phyllodes Tumor/surgery , Adult , Aged , Biopsy, Fine-Needle/statistics & numerical data , Breast Neoplasms/diagnostic imaging , Breast Neoplasms/epidemiology , Breast Neoplasms/pathology , Female , Follow-Up Studies , Humans , Mastectomy/statistics & numerical data , Middle Aged , Neoplasm Recurrence, Local/pathology , Phyllodes Tumor/diagnostic imaging , Phyllodes Tumor/epidemiology , Phyllodes Tumor/pathology , Quebec/epidemiology
12.
Anticancer Res ; 33(6): 2569-76, 2013 Jun.
Article in English | MEDLINE | ID: mdl-23749910

ABSTRACT

BACKGROUND: Trastuzumab has no major side-effects except the potential for cardiac toxicity. The main objective of this study was to evaluate the association between trastuzumab-associated cardiac toxicity and two potential risk factors: alcohol intake and HER2 polymorphisms. PATIENTS AND METHODS: In a retrospective cohort study of 237 women with non-metastatic HER2-positive breast cancer treated with trastuzumab, traditional risk factors were assessed by review of medical records, alcohol use by an administered questionnaire to women (n=132), and HER2 polymorphisms (Ile655Val and Ala1170Pro) using TaqMan assays (n=73). RESULTS: Association was observed between alcohol intake (10 drinks and more per week) during the trastuzumab treatment and cardiac toxicity (p=0.04). For polymorphisms, compared to Ile/Ile carriers, HER2 Ile/Val was associated with a higher risk of cardiac toxicity (p=0.02). CONCLUSION: Heavy alcohol use during the course of trastuzumab treatment and the HER2 Ile/Val genotype may constitute risk factors for cardiac toxicity.


Subject(s)
Alcohol Drinking , Antibodies, Monoclonal, Humanized/adverse effects , Antineoplastic Agents/adverse effects , Breast Neoplasms/drug therapy , Cardiotoxins , Genes, erbB-2 , Heart Diseases/chemically induced , Adult , Aged , Aged, 80 and over , Antibodies, Monoclonal, Humanized/therapeutic use , Antineoplastic Agents/therapeutic use , Breast Neoplasms/genetics , Cohort Studies , Female , Genotype , Heart/drug effects , Heart Failure/chemically induced , Humans , Middle Aged , Polymorphism, Single Nucleotide , Receptor, ErbB-2/genetics , Receptor, ErbB-2/metabolism , Retrospective Studies , Risk Factors , Surveys and Questionnaires , Trastuzumab , Ventricular Function, Left/drug effects
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